Patent Description:
The Src Homolgy-<NUM> phosphatase (SHP2) is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene that contributes to multiple cellular functions including proliferation, differentiation, cell cycle maintenance and migration. SHP2 is involved in signaling through the Ras-mitogen-activated protein kinase, the JAK-STAT or the phosphoinositol <NUM>-kinase-AKT pathways.

The compound with the name (<NUM>,<NUM>)-<NUM>-(<NUM>-amino-<NUM>-((<NUM>-amino-<NUM>-chloropyridin-<NUM>-yl)thio)pyrazin-<NUM>-yl)-<NUM>-methyl-<NUM>-oxa-<NUM>-azaspiro[<NUM>]decan-<NUM>-amine, which has the formula I:
<CHM>
as well as pharmaceutically acceptable salts therof are described in <CIT> as an inhibitor of SHP2. Various therapeutic and treatment methods are also described.

SHP2 has two N-terminal Src homology <NUM> domains (N-SH2 and C-SH2), a catalytic domain (PTP), and a C-terminal tail. The two SH2 domains control the subcellular localization and functional regulation of SHP2. The molecule exists in an inactive, self-inhibited conformation stabilized by a binding network involving residues from both the N-SH2 and PTP domains. Stimulation by, for example, cytokines or growth factors leads to exposure of the catalytic site resulting in enzymatic activation of SHP2.

Mutations in the PTPN11 gene and subsequently in SHP2 have been identified in several human diseases, such as Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon. SHP2, therefore, represents a highly attractive target for the development of novel therapies for the treatment of various diseases. The compound that can be manufactured according to the present invention fulfills the need of small molecules that inhibit the activity of SHP2.

<CIT> describes three methods for the manufacture of the compound of the formula I which can be characterized by the following reaction schemes (for further details see <CIT>). These synthesis methods, while essentially feasible, can be improved upon (for example, using less material and producing less waste, while improving reaction safety). The methods can be summarized substantially as follows:
Scheme <NUM>: This shows the three Routes B to D disclosed in <CIT>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>.

The HCl salt compound A17 (equivalent to B7, C10 and D10) is then converted into the compound of the formula I as follows:
<CHM>.

The manufacture of Y10a (equivalent to Z17a and Y7a), and detailed in <CIT>, is achieved as follows:.

Each of the above routes are suitable for the commercial synthesis of a compound of formula I. However, the synthesis route B (above) requires the use of equivalent (equimolar) amounts of lactone B2 (equivalent to C2 and D2) to get B3. This represents a relatively large quantity of B2 for commerical manufacture particularly because it is used in the first step of the overall synthesis.

In addition, in order to achieve a good conversion of the compound from B3 to B4, at least a five fold molar excess (<NUM> equivalents) of hydroxylamine hydrochloride is required. This is less than ideal for a large scale synthesis due to the thermo safety risk.

Surprisingly, the present invention overcomes both the large quantities of material requirement and the thermo safety risk by manufacturing B4 using a new intermediate B3' with a chemical structure uniquely distinct from B3 and C3.

Less material is required in this improved synthesis to synthesize B4. Firstly, much less of the hydroxylamine hydrochloride is required (much less than <NUM> equivalents) to accomplish the reaction from B3' to B4. Additionally, less of the L-lactide B2, approximately half of the relative (equivalent) amount of B2 is required for the reaction with B1 (equivalent to A5).

This new way of manufacture of intermediate B4, in a specific form not meaning to be limiting to the scope of the invention, can be described by the following reaction scheme, SCHEME A:
<CHM>.

The reaction via the novel intermediate B3' (<NUM>-(tert-butyl) <NUM>-ethyl (S)-<NUM>-(<NUM>-hydroxypropanoyl)piperidine-<NUM>,<NUM>-dicarboxylate) thus allows for a drastic improvement of the reaction for the manufacture ultimately culminating in the synthesis of the compound of formula I.

A further improvement of the synthesis of the compound of formula I disclosed in <CIT> relates to the variant (i) for the manufacture of the compound Y7c (above). The anhydrous Na<NUM>S used in this reaction is pyrophoric and not commercially available in large scale. In addition, the use of the tetrabutylammonium salt required for work-up is poorly biodegradable.

While the compound Z17c could also be manufactured via variants (ii) or (iii) above, these also have the disadvantage of requiring a thiol compound and quite strong reaction conditions and strong reagents, e.g. using sodium ethoxylate.

This issue, however, can be resolved in a surprising and convenient way which, in a specific form not meaning to be limiting to the scope of the invention, can be described by the following reaction scheme, SCHEME B:
<CHM>.

(Note Y7c' corresponds to Z17c in variants (ii) and (iii) above). Instead sodium sulfide is replaced with sodium thiosulfate. Sodium thiosulphate is not pyrophoric and is available in large scale. In addition, the materials used are cheaper and uses a more environmentally friendly solvent. The workup is simplified and the reaction mixture is free of tetrabutylammonium salt and odorless.

In one aspect , the present invention provides a method for the manufacture of a compound of Formula I as mentioned above, or a pharmaceutically acceptable salt, acid co-crystal, hydrate or other solvate thereof.

In a further aspect, the present invention provides a method for the manufacture of a compound of Formula I as mentioned above, or a pharmaceutically acceptable salt, acid co-crystal, hydrate or other solvate thereof (these varaints are also included where subsequently only a compound of the formula I is referred to), said method comprising reacting a compound of the formula II with a compound of the formula III according to the following reaction scheme:
<CHM>.

In both cases (i) and (ii) just mentioned, in a preferred independent second aspect of the invention (meaning that the reaction from the compound of the formula V up to and including to the compound of formula VI) is an own invention embodiment), or as part of the manufacture of the compound of the formula I, the manufacturing of a compound of the formula II, in a first step preferably followed by the further steps defined by further invention embodiments defined below, comprises reacting a compound of the formula V:
<CHM>.

This reaction of the second embodiment of the invention as such is also an embodiment of the invention.

As a further independent embodiment of the invention or preferably in a further step, a compound of the formula VI as just described is cyclized with hydroxylamine, or a salt thereof, to yield a hydroxylamine compound of the formula VII, respectively:
<CHM>
wherein R<NUM> is as defined for a compound of the formula IV.

The two reaction steps of the compound of the formula V with L-Lactide to yield the compound of formula VI and the subsequent cyclization with hydroxylamine to yield the compound of the formula VII form also an independent and important invention embodiment.

As a further independent embodiment, in a further step, a compound of the formula VII is either (a-i) hydrogenated to yield an amino compound of the formula VIII:
<CHM>.

In another preferred embodiment , in a further step after reaction (a-i) just described, a compound of the formula VIII is either (b-i) reduced to yield a compound of the formula IX:
<CHM>.

In another preferred embodiment, in a further step after reaction (a-ii) described above, a compound of the formula VIII* is in a further reaction (b-ii) hydrogenated in the presence of a chiral hydrogenation catalyst to yield a compound of the formula X*:
<CHM>.

The following novel key intermediate also represent an own invention embodiment:.

A further embodiment of the present invention, as part of the overall synthesis of a compound of the formula (III) and/or the synthesis of a compound of the formula (I), relates to a new method of manufacture (synthesis) of the intermediate of the formula (III)
<CHM>
wherein LG is a leaving group, comprising reacting a compound of the formula (XV),
<CHM>
wherein LG is a leaving group and Mt is (then especially with regard to charge relatively half an atom of metal per sulfur) is an earth alkaline metal or (preferably) (then especially in the ratio of one Mt to one S) an alkaline metal atom, with a compound of the formula (XVI),
<CHM>
to yield the compound of the formula (III), where the reaction takes place under transition metal free reaction conditions.

The following definitions define more general features in a preferred more specific way, and it is possible to replace one, more than one or all of the more general features in the invention variants = embodiments by a more specific definition, which defines more specific invention embodiments.

The conditions for the reactions described above are especially chosen as follows:
The reaction of a compound II with a compound of the formula III, wherein LG is a leaving group, preferably halo, especially bromo or more especially chloro, preferably takes place in the presence of a weak base, such as an alkali metal carbonate or metal-hydrogencarbonate, in a mixed solvent composed of aprotic solvent, such as an N,N-Dialkylamide of an alkanoic acid, for example dimethal acetamide or dimethyl formamide, and water, or in a mixed solvent composed of aprotic solvent such as sulfolane, and alcoholic solvent such as isopropanol, and water, at preferably elevated temperatures, for example in the range from <NUM> to the boiling point of the reaction mixtures, for example from <NUM> to <NUM>.

The deprotecting (i) of a compound of the formula IV wherein R<NUM> is a secondary amino protecting group and R<NUM> is a protected amino group and R<NUM> is hydrogen to yield a compound of the formula II preferably takes place in the presence of a strong acid HnA, such as trifluoroacetic acid, trifluoromethane sulfonic acid or preferably an inorganic acid, for example sulfuric acid, phosphoric acid or especially a hydrogen halide, most especially hydrogen chloride, in a solvent, for example an alcohol, such as ethanol or especially methanol, or a mixture of alcohols (especially if R<NUM> is a benzyloxycarbonyl or especially alkoxycarbonyl, such as tert-butoxycarbonyl), or in an ester solvent such as isopropyl acetate (IPAc,) or in the presence of water (especially if R<NUM> is an acyl, especially lower alkanoyl, for example acetyl) at preferred temperatures in the range from <NUM> to the boiling temperature of the solvent, for example from <NUM> to (especially where R<NUM> is acyl) <NUM>.

The alternative reducing (ii) of a compound of the formula IV wherein R<NUM> is a secondary amino protecting group, R<NUM> is amino and R<NUM> is hydroxyl preferably takes place with a trialkylsilane, especially triethylsilane, in the presence of a strong inorganic or preferably (strong) organic acid, especially trifluoromethane sulfonic acid, in an appropriate aprotic solvent, such as an ether or especially acetonitrile, and subsequent addition of the acid HnAto yield the (salt or cocrystal) compound of formula II.

The reaction of the compound of the formula V with L-Lactide to yield a compound of the formula VI preferably takes place in the presence of a strong base, especially an alkyl-alkaline metals, such as n-butyllithium, and a nitrogen base, especially di-isopropylamine or diethylamine, in a solvent, such as an acyclic or especially cyclic ether, especially tetrahydrofuran or preferably <NUM>-methyltetrahydrofuran, at preferably low temperatures, for example in the range from -<NUM> to -<NUM>. If the reaction is conducted nearer to -<NUM> to -<NUM>, especially in the range from -<NUM> to -<NUM>, and preferably if the amount of the compound of L-lactide (the L form of the lactide) corresponds to <NUM> to <NUM> mol percent, preferably <NUM> to <NUM> mol %, more preferably <NUM> to <NUM> mol %, in relation to the mol amount of the compound of formula V, that is, roughly about half of the molar amount of the compound of formula V, the result is a compound of the formula VI. Mol % refers to mole percent.

The cyclization of a compound of the formula VI with hydroxylamine, or a salt thereof, to the compound of the formula VII preferably takes place with an acid addition salt of hydroxylamine, for example a hydrogen halide salt thereof, such as the hydrochloride salt thereof, in the presence of a weak base, for example an alkali metal alkanoate, such as sodium acetate, in solvent, for example an acyclic or especially cyclic ether, especially tetrahydrofuran or preferably <NUM>-methyltetrahydrofuran, at preferred temperatures in the range from <NUM> to <NUM>, for example from <NUM> to <NUM>.

The hydrogenation (a-i) of the hydroxylamine compound of the formula VII to the corresponding amine of the formula VIII preferably takes place as heterogeneous hydrogenation in the presence of a hydrogenation catalyst, for example platinum, palladium, rhodium, or ruthenium or other highly active catalysts, which operate at lower temperatures (for example from <NUM> to <NUM>) and lower pressures (for example, <NUM> bar) of H<NUM>, or non-precious metal catalysts, especially those based on nickel (such as Raney nickel and Urushibara nickel) at elevated temperatures and higher H<NUM> pressure, for example in the range from <NUM> to <NUM> bar, such as from <NUM> to <NUM> bar. The reaction is conducted in a polar solvent, especially an alcohol, for example an alkanol, such as ethanol or especially methanol.

The acylation (a-ii) of the hydroxyl compound of the formula VII under reducing conditions to the compound of the formula VIII* preferably takes place in the presence of an acylating agent, especially an anhydride of a carboxylic acid, such as an alkanoic acid anhydride, especially acetanhydride, in the presence of an ignoble metal, such as zinc (for example as zinc amalgam) or especially iron, and an acid, either an inorganic acid, such as a hydrogen halogenide, for example hydrogen chloride, sulfuric acid or an organic acid, such as the carboxylic acid corresponding to the anhydride, especially an alkanoic acid, especially acetic acid, as reductant, in an inert organic solvent, such as a hydrocarbon or an aromatic compound, for example toluene or xylylene, at preferably elevated temperatures in the range from <NUM> to the boiling point of the reaction mixture, for example in the range from <NUM> to <NUM>.

Acyl, in the context of the present invention, refers to a moiety of an organic acid where in the acyl rest itself the carboxyl (-COOH) group is bound to a carbon (for example as in acetyl = H<NUM>CCOO-), not (as for example in tert-butoxycarbonyl) to an oxygen.

The reduction (b-i) of a compound of the formula VIII to a compound of the formula IX preferably takes place with a complex hydride reducing the oxo in formula VIII to the hydroxy in formula IX, such as diisobutylaluminium hydride, in an aprotic solvent, such as an ether or especially a cyclic ether, such as tetrahydrofurane, at preferably low temperatures in the range from -<NUM> to -<NUM>, for example from -<NUM> to -<NUM>.

In the case where then the compound of the formula IX, as compound corresponding to the respective compound of the formula IV, is reduced to the compound of the formula II, the reduction preferably takes place with a trialkylsilane, especially triethylsilane, in an acid, especially a strong organic sulfonic acid, such as trifluoromethane sulfonic acid, in an aprotic solvent, such as a hydrocarbon, an ester or especially a nitrile, such as acetonitrile, at preferably elevated temperatures in the range from <NUM> to the boiling point of the reaction mixture, for example from <NUM> to <NUM>. The subsequent reaction with the acid HnA preferably takes place in a protic, potentially aqueous solvent, such as isopropyl alcohol.

The reaction (c-i) of a compound of the formula VIII with an amino group inserting agent, especially a dialkanoyldicarbonate, especially di-tert-butyldicarbonate (= Boc anhydride) is preferably conducted in the presence of an tertiary amine, such as a tri-alkyl-amine, especially diisopropylethylamine, or in the presence of a weak inorganic base, such as an alkali metal carbonate or metal-hydrogencarbonate, in an aprotic solvent, especially a halogenated hydrocarbon, such as dichloromethane, or in an ether or especially a cyclic ether, such as tetrahydrofurane at preferred temperatures in the range from <NUM> to <NUM>, for example from <NUM> to <NUM>, resulting in a compound of the formula X.

The reducing of a compound of the formula X to a compound of the formula XI preferably takes place in the presence of a complex hydride capable of reducing the lactone group in formula X to the open ring in formula XI with two hydroxy groups, such as lithium borohydride and/or sodium borohydride, in an aprotic solvent, such as a linear or preferably a cyclic ether, for example tetrahydrofurane or <NUM>-methyl tetrahydrofurane, preferably at a temperature in the range from <NUM> to <NUM>, for example at <NUM> to <NUM>.

The reaction of a compound of the formula XI, leading to introduction of a leaving group of the formula LG2, with a leaving group forming agent LG*-X in which X is halogen, especially chloro, LG* is an electrophilic radical capable, with the hydroxy to which it is bound, of forming a leaving group LG2, especially a sulfonylhalogenide, preferably toluolsolfonylchloride or more preferably <NUM>,<NUM>,<NUM>-triisopropylbenzenesulfonyl chloride, to yield a compound of the formula XII preferably takes place in the presence of a base, such as an alkali metal hydroxide, for example sodium hydroxide, in an aqueous organic solvent, such as an aqueous halogenated hydrocarbon, for example dichloromethane, or in an ether or especially a cyclic ether, such as tetrahydrofurane, at preferred temperatures in the range fom -<NUM> to <NUM>, for example from -<NUM> to <NUM>.

The cyclization of a compound of the formula XII to a compound of the formula XIII under basic conditions in the presence or absence of a phase transfer catalyst, for example a tetraalkylammonium halogenide, such as tetra-n-butylammoniumbromide, in the presence of a base, especially an alkali metal hydroxide, such as sodium hydroxide, in an aqueous organic solvent, such as an aqueous halogenated hydrocarbon, for example dichloromethane, or in an ether or especially a cyclic ether, such as tetrahydrofurane at preferred temperatures in the range fom <NUM> to <NUM>, for example from <NUM> to <NUM>.

The deprotection of a compound of the formula XIII preferably takes place with the acid HnA which is part of the salt of the resulting formula II in a polar solvent, such as an alcohol, for example an alkanol, such as ethanol or especially methanol, or in a ester solvent such as isopropyl acetate (IPAc), at preferred temperatures in the range from <NUM> to <NUM>, for example at <NUM> to <NUM>.

The hydrogenation of a compound of the formula VIII* to a compound of the formula X* in the presence of a chiral hydrogenation catalyst (usually formed from a precatalyst, for example on Ruthenium(I) basis, such as Bis(norbornadiene)rhodium(I)tetrafluoroborate and a chiral ligand), for example as defined below, preferably takes place with hydrogen under elevated pressure, for example in the range of from <NUM> to <NUM> bar, such as <NUM> to <NUM> bar, in a polar solvent, especially and <NUM>,<NUM>,<NUM>-trifluoroethanol, at temperatures preferably ranging from <NUM> to <NUM>, for example from <NUM> to <NUM>. This hydrogenation more generally takes place with hydrogen in the presence of a transition metal catalyst, preferably in the presence of a transition metal catalyst comprising an organometallic complex and a chiral ligand. The reduction may occur under hetero- or homogeneous hydrogenation conditions, preferably under homogeneous hydrogenation conditions. The transition metal is selected from group <NUM> or <NUM> of the periodic table. Therefore, the transition metal catalyst comprises, for example, Cobalt (Co), Rhodium (Rh), Iridium (Ir), Nickel (Ni), Palladium (Pd) and/or Platinum (Pt).

Among the chiral catalysts, all those allowing the hydrogenation of the double bond in the compound of formula VIII* to yield the configuration at the former double bond shown in formula X* are appropriate. It is further preferred that the chiral ligand comprises a chiral ferrocene.

Mixtures of two or more such ligands, especially those defined by the formulae above, are also possible.

Usually, the active catalyst is formed by mixing <NUM> to <NUM>, preferably <NUM> to <NUM>, more preferably <NUM> to <NUM> mole of chiral ligand with <NUM> mole of transition metal atoms comprised in the transition metal catalyst. For example, if a dimer transition metal catalyst is employed, preferably two moles of chiral ligand are reacted with one mole of transition metal catalyst in order to form the "active catalyst".

The chiral ligand is typically added to the reaction mixture in a solution prepared with the same solvent used for the reaction.

The reduction of a compound of the formula X* to a compound of the formula XI* under ring opening preferably takes place in the presence of a complex hydride capable of reducing the lactone group in formula X to the open ring in formula XI with two hydroxy groups, such as lithium borohydride, in an aprotic solvent, such as a linear or preferably a cyclic ether, for example tetrahydrofurane, preferably at a temperature in the range from <NUM> to <NUM>, for example at <NUM> to <NUM>.

Amino protecting groups are preferably groups that can be cleaved by not too harsh acidic conditions, for example in the presence of a hydrogen halogenide, such as HCl, or in the case where a compound of formula II is the direct reaction product, an acid of the formula HnA as defined for a compound of the formula II, especially wherein n is <NUM> and A is a halogenide anion, especially a chloride anion. For example, each of <NUM>-fluorenylmethoxycarbonyl, allyloxycarbonyl or especially tert-butoxycarbonyl is to be mentioned; however, also acyl groups, especially alkanoyl groups, e.g. with <NUM> to <NUM> carbon atoms, such as acetyl, are also appropriate amino protecting groups.

The reaction of a compound of formula XI*, leading to introduction of a leaving group of the formula LG2, with a leaving group forming agent LG*-X in which X is halogen, especially chloro, LG* is an electrophilic radical capable, with the hydroxy to which it is (to be) bound, of forming a leaving group LG2, especially a sulfonylhalogenide, preferably toluolsolfonylchloride, to yield a compound of the formula XII* preferably takes place in the presence of a base, such as an alkali metal hydroxide, for example sodium hydroxide, in an aqueous organic solvent, such as an aqueous halogenated hydrocarbon, for example dichloromethane, at preferred temperatures in the range fom <NUM> to <NUM>, for example from <NUM> to <NUM>.

The cyclization of a compound of formula XII* to a compound of the formula XIII* preferably takes place under basic conditions in the presence of a phase transfer catalyst, for example a tetraalkylammonium halogenide, such as tetra-n-butylammoniumbromide, in the presence of a base, especially an alkali metal hydroxide, such as sodium hydroxide, in an aqueous organic solvent, such as an aqueous halogenated hydrocarbon, for example dichloromethane, at preferred temperatures in the range fom <NUM> to <NUM>, for example from <NUM> to <NUM>.

The deprotection of a compound of the formula XIII* preferably takes place with the acid HnA which is part of the salt of the resulting formula II in a polar solvent, such as an alcohol, for example an alkanol, such as ethanol or especially methanol, at preferably elevated temperatures in the range from <NUM> to <NUM>, for example at <NUM> to <NUM>.

The compound of the formula III can be obtained as described in <CIT>. Preferably, however, it can be prepared as follows:
The compound of the formula III, in a further single invention embodiment or as part of the total synthesis of a compound of the formula I according to invention with steps mentioned above and below, is according to one embodiment preferably obtained by reacting a compound of the formula XIV:
<CHM>
(which can be obtained from the corresponding trichloro compound, <NUM>,<NUM>-<NUM>-thrichloropyrazine (instead of the NH<NUM> and the LG, chloro is present in the precursor of compound XIV, respectively), with ammonia as described in <CIT>), wherein LG is a leaving group as defined for a compound of the formula III, especially halo, more preferably iodo, bromo or in particular chloro, with a metal thiosulfate salt (which may be a hydrate or not), especially an alkaline metal or earth alkaline metal thiosulfate salt, more preferably an alkaline metal thiosulfate, most preferably with sodium thiosulfate, in the presence of an acid in an appropriate solvent, followed by treatment with an aqueous base, to yield a compound of the formula XV:
<CHM>
wherein Mt is (then with regard to charge relatively half an atom of metal per sulfur) an earth alkaline metal or preferably (then in the ratio of one Mt to the one S) an alkaline metal atom, especially a sodium atom, and LG is a leaving group as just defined.

This reaction preferably takes place in an appropriate solvent, such as an aqueous alcohol, for example methanol or ethanol in mixture with water, in the presence of an acid, such as an inorganic acid, for example phosphoric acid and/or sodium dihydrogen phosphate, or preferably an organic acid, such as a sulfonic acid or more preferably of a strong carboxylic acid, e.g. a trihaloacetic acid, such as trifluoroacetic acid, or especially a carboxylic acid carrying more than one carboxyl (-COOH) group, e.g. two to three such groups, most especially citric acid (which generates less waste than phosphate buffer <NUM>% H<NUM>PO<NUM>/NaH<NUM>PO<NUM>), at temperatures in the range from <NUM> to the boiling temperature of the reaction mixture, preferably at a temperature in the range from <NUM> to <NUM>, most preferably in the range form <NUM> to <NUM>, e.g. at about <NUM>.

The compound of the formula XV is then, in a further preferred invention embodiment after manufacture of the compound of the formula XV as just described, in a yet further preferred embodiment of the invention as part of the total synthesis of the compound of the formula I, reacted with a compound of the formula XVI:
<CHM>.

The reaction preferably takes place in the presence of a noble metal complex, especially formed from Pd<NUM>(dbba)<NUM>, in the presence of a ligand, such as Xantphos, and of a tertiary nitrogen base, such as diisopropylamine, in an aprotic solvent, such as an ether, for example a cyclic ether, especially dioxane, at preferably elevated temperatures, for example in the range from <NUM> to the boiling point of the reaction mixture. Alternatively, the reaction can be conducted under Ullmann type reaction conditions e.g. with copper salt such as copper(I)iodide and diamine ligand such as phenanthroline ligand as complex former in an appropriate solvent or solvent mixture, e.g. in an aqueous alcohol, such as aqueous methanol, ethanol, propanol or especially isopropanol, at preferred temperatures in the range from <NUM> to <NUM>, e.g. at <NUM> to <NUM>.

In the case of the new invention embodiment of the manufacture of a compound of the formula (III) from a compound of the formula XV under transition metal free reaction conditions, that is, especially in the absence of a catalyst comprising or being an organometal catalyst, particularly in the absence of a catalytic copper salt or a catalytic noble metal complex or the reaction preferably takes place in an appropriate solvent or solvent mixture, e.g. in an aqueous alcohol, such as aqueous methanol, ethanol, propanol or especially isopropanol, in the presence of an acid, such as an inorganic acid, for example phosphoric acid and/or sodium dihydrogen phosphate, or preferably an organic acid, such as an acetic acid or more preferably of a strong carboxylic acid, e.g. a trihaloacetic acid, such as trifluoroacetic acid, or especially a carboxylic acid carrying more than one carboxyl (-COOH) group, e.g. two to three such groups, most especially citric acid (which has the additional advantage of generating less waste than phosphate buffer <NUM>% H<NUM>PO<NUM>/NaH<NUM>PO<NUM>), at temperatures in the range from <NUM> to the boiling temperature of the reaction mixture, preferably at a temperature in the range from <NUM> to <NUM>, most preferably in the range form <NUM> to <NUM>.

Among the advantages of this synthesis variant (which corresponds to a further variant for the manufacture of a compound (III) by variants (i), (ii) or (iii) as described above and thus is also called variant (iv) herein for the manufacture of the compound (III) herein, especially in the form of intermediate Y7a=Y10a=Z17a, there is, in contrast to variant (i) mentioned above, no requirement of copper catalyst removal (e.g. with charcoal), especially by oxidation of the copper by bubbling through oxygen, which may bring a safety issue, and it does not require the use of the potentially mutagenic phenanthroline ligand; while in comparison to variants (ii) and (iii) above there is no need of an expensive Pd catalyst, therefore, the present variant is highly advantageous especially in larger scale synthesis, e.g. in the more than <NUM> scale.

Preferably, this variant (iv) is characterized by the following reaction scheme:
<CHM>
wherein Y7c' = Z17c corresponds to a compound of the formula (XV) and Y7b = Z17b corresponds to a compound of the formula (XVI). A specific variation of this embodiment is mentioned in the Examples.

In a preferred embodiment of the invention, the new reaction is part of the overall manufacture of a compound of the formula (III) with the preceding reaction steps as described herein, especially part of the overall manufacture of the compound of the formula (I) including this particular variant of the manufacture of a compound of the formula (III) as described herein.

The compound of formula XVI can preferably be obtained by reacting a compound of the formula XVII:
<CHM>
with iodine in the presence of a strong base.

This reaction preferably takes place in the presence of a strong base, especially an alkyl-alkaline metal, such as n-butylllithium, and a nitrogen base, especially di-isopropylamine or diethylamine, in a solvent, such as an acyclic or especially cyclic ether, preferably tetrahyro-furane, at preferably low temperatures, for example in the range from -<NUM> to -<NUM>.

This results in a compound of the formula XVIII:
<CHM>
which is then treated with ammonia to yield the compound of the formula XVI.

This reaction then preferably takes place in the presence of free ammonia and an inert polar solvent, such as DMSO, especially at elevated temperatures, preferably in the range from <NUM> to the boiling point of the reaction mixture, for example at <NUM> to <NUM>.

Another embodiment of the invention comprises the manufacture of a compound of the formula II and a compound of the formula III as described above, namely a method for the manufacture of a compound of Formula I, or a pharmaceutically acceptable salt, acid co-crystal, hydrate or other solvate thereof, said method comprising reacting a compound of formula II with a compound of formula III according to the following reaction scheme:
<CHM>
wherein LG is a leaving group, A is the anion of a protic acid, and n, m and p are independently <NUM>, <NUM> or <NUM>, so that the salt of the formula II is electrically neutral.

Where compounds are being referred to above during process descriptions or as such, the mentioning of the compound also includes salts, hydrates or solvates thereof, where such forms are not excluded e.g. due to lack of groups that might form salts.

Unsubstituted (preferred) or substituted alkyl where mentioned is especially C<NUM>-C<NUM>-alkyl, preferably C<NUM>-C<NUM>-alkyl, and may be linear or branched; preferred are methyl, ethyl, propyl, isopropyl, n-butyl, sec. -butyl or tert-butyl.

Unsubstituted (preferred) or substituted cycloalkyl especially refers to a saturated ring having <NUM> to <NUM> ring carbon atoms, especially to C<NUM>-C<NUM>-cycloalkyl, such as cyclopentyl, cyclohexyl of cycloheptyl.

Unsubstituted or substituted aryl especially refers to C<NUM>-C<NUM>-aryl, especially phenyl, naphthyl or fluorenyl.

Where substituted is mentioned, this preferably refers to substitution with one or more substituents the skilled person knows not to interfere with any of the described reaction, especially moieties selected from C<NUM>-C<NUM>-alkoxy, C<NUM>-C<NUM>-alkanoyloxy, hydroxyl, carboxy, C<NUM>-C<NUM>-alkoxycarbonyl, or (especially in the case of substituted alkyl) phenyl, naphthyl or fluorenyloxymethyl.

The following examples serve to illustrate the invention without limiting the scope otherwise defined herein; they are, however, preferred invention embodiments as well. Abbreviations used: Ac (acetate); AcOH (acetic acid); Ac<NUM>O (aceticanhydride); aq (aqueous); Boc (tert-butoxycarbonyl); Boc<NUM>O (Di-tert-butyl dicarbonate); Brine (sodium chloride solution saturated at RT); n-Bu<NUM>NBr (Tetra-(n-butyl)ammonium bromide); n-BuLi (n-Butyllithium); calcd (calculated); DCM (dichloromethane); DIBAL-H (Diisobutylaluminiumhydride); DIPEA (Di(isopropyl)ethylamine); DMAc (dimethyl acetamide); DMSO (dimethyl sulfoxide); DMSO-d<NUM> (perdeuterated dimethyl sulfoxide); eq or equiv. (equivalents); Et (Ethyl); EtOAc (ethyl acetate); EtOH (ethanol); HRMS (High Resolution Mass Spectroscopy); hrs. (Hour(s)); IPA (Isopropyl alcohol); IPAc (isopropyl acetate); IT (Internal Temperatur (of a reaction mixture)); L (liter(s)); LDA (lithium diisopropyl amide); LOQ (Limit of Quantification); MCC (Microcrystalline Cellulose); Me (Methyl); MeOH (Methanol); <NUM>-MeTHF (<NUM>-methyl tetrahydrofurane; MTBE (methyl tertiary-butyl ether); NMR (Nuclear Magnetic Resonance); PA (Polyamide); iPrOH (Isopropanpol); iPr<NUM>NH (diisopropyl amine); qNMR (quantitative NMR); rt, Rt or RT (Room Temperature (about <NUM> to <NUM>)); TBAB (Tetra-(n-butyl)ammoniumbromide); Tf-OH (triflic acid); THF (Tetrahydrofurane); TsCl (Tosylchloride); TPSCl (<NUM>,<NUM>,<NUM>-triisopropylbenzenesulfonyl chloride); Triflic acid (Trifluoromethane sulfonic acid); wt% (weight percent) and Xantphos (<NUM>,<NUM>-Bis(diphenylphosphino)-<NUM>,<NUM>-dimethylxanthene).

In detail, the synthesis steps are as follows:.

A <NUM> reactor with an impeller stirrer was charged with diisopropylamine (<NUM>, <NUM> mol, <NUM> equiv. ) and <NUM>-methyltetrahydrofuran (<NUM>) under a nitrogen atmosphere. The mixture was stirred (mid to high speed) and cooled to IT = <NUM>±<NUM>. A solution of n-BuLi (<NUM> in hexanes solution, <NUM>, <NUM> mol, <NUM> equiv. ) was added at IT = <NUM>±<NUM>. The freshly prepared LDA in <NUM>-methyltetrahydrofuran was then cooled to IT = -<NUM>±<NUM>. A solution of B1(<NUM>, <NUM> mol, <NUM> equiv) in <NUM>-methyltetrahydrofuran (<NUM>) was added at IT = -<NUM>±<NUM>. The resulting yellow solution was stirred at IT = -<NUM>±<NUM> for <NUM> hours. Then a solution of B2 (<NUM>, <NUM> mol, <NUM> equiv. ) in <NUM>-methyltetrahydrofuran (<NUM>) was added dropwise at IT = - <NUM>±<NUM>. The mixture was stirred at IT = -<NUM>±<NUM> for an additional <NUM> hour. A solution of acetic acid (<NUM>, <NUM> mol, <NUM> equiv. ) in <NUM>-methyltetrahydrofuran (<NUM>) was added at IT = - <NUM>±<NUM> (note: highly exothermic). The resulting suspension was allowed to warm to IT = <NUM>±<NUM>, then a solution of <NUM>% hydrochloric acid (<NUM>) was added to the reactor. The biphasic mixture was warmed to IT = <NUM>±<NUM>. The reaction mixture was transferred to an extraction vessel, the bottom aqueous layer was disposed. <NUM> wt% aq. NaCl (<NUM>) was added, and the biphasic mixture was stirred for <NUM> hours. The bottom aqueous layer was disposed. The top organic phase was collected and stored under nitrogen at <NUM>±<NUM> as a solution of B3' in <NUM>-methyltetrahydrofuran (<NUM>). HRMS m/z calcd for C<NUM>H<NUM>NO<NUM> [M+H]+ <NUM>, found <NUM>.

A <NUM> reactor with an impeller stirrer was charged with B3' in <NUM>-methyltetrahydrofuran (<NUM>). <NUM>-Methyltetrahydrofuran (<NUM>) was added, and the resulting mixture was distilled under vacuum at IT ≤ <NUM> until <NUM> of distillate was collected. Additional <NUM>-methyltetrahydrofuran (<NUM>) was added, and the resulting mixture was distilled under vacuum at IT ≤ <NUM> until <NUM> of distillate was collected. Water content in the residue was tested to be < <NUM> ppm. Hydroxylamine hydrochloride (<NUM>, <NUM> mol, <NUM> equiv. ) and sodium acetate (<NUM>, <NUM> mol, <NUM> equiv. ) was then added. The resulting suspension was stirred (high speed) at IT = <NUM>±<NUM> for <NUM> hours. The suspension was cooled to IT = <NUM>±<NUM>. Water (<NUM>) was then added, and the mixture was stirred for <NUM> hour. The bottom aqueous phase was disposed. <NUM> wt% aq. NaCl (<NUM>) was added, and the biphasic mixture was stirred for <NUM> hour. The bottom aqueous phase was disposed. The top organic phase was collected and distilled under vacuum at IT ≤ <NUM> until <NUM> of distillate was collected. Toluene (<NUM>) was added, and the suspension was distilled under vacuum at IT ≤ <NUM> until <NUM> of distillate was collected. The resulting suspension was heated to IT = <NUM>±<NUM> with stirring (stirring speed = <NUM> rpm). n-Heptane (<NUM>) was added slowly (stirring speed = <NUM> rpm) over <NUM> hours. The resulting suspension was cooled to <NUM>±<NUM> over <NUM> hours. and filtered with a Nutsche filter (<NUM>, PA). The filter cake was rinsed with n-heptane (<NUM>), collected and dried under vacuum. B4 was obtained as a white solid, <NUM> (ee = <NUM>%, assay by qNMR = <NUM>%, yield = <NUM>% over two steps). <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ = <NUM> (s, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (s, <NUM>).

Step a and step b together in their sequential arrangement also represent a preferred invention embodiment.

To a <NUM> reactor with an impeller stirrer under an nitrogen atmosphere was added Raney-Ni (<NUM>) and MeOH (<NUM>), followed by tert-butyl (S)-<NUM>-(hydroxyimino)-<NUM>-methyl-<NUM>-oxo-<NUM>-oxa-<NUM>-azaspiro[<NUM>]decane-<NUM>-carboxylate B4 (<NUM>, <NUM> mmol). The reactor was purged with nitrogen three times and then with hydrogen three times. The mixture was stirred for <NUM> hrs under a hydrogen pressure of <NUM> bar at IT=<NUM>. The reaction mixture was filtered through microcrystalline cellulose and the filter cake was washed with MeOH (<NUM>). The filtrate was concentrated to dryness to give a white solid (<NUM>). EtOAc (<NUM>) was added to the solid, the resulting suspension was heated to reflux (JT = <NUM>) and n-heptane (<NUM>) was added portionwise. The resulting clear solution was cooled to rt during <NUM> hrs and left standing overnight to give B5 as a colorless crystalline product (<NUM>, cis/trans><NUM>/<NUM>, <NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>) δ = <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

A <NUM> three-necked round bottomed flask under an nitrogen atmosphere was charged with tert-butyl (<NUM>,<NUM>)-<NUM>-amino-<NUM>-methyl-<NUM>-oxo-<NUM>-oxa-<NUM>-azaspiro[<NUM>]decane-<NUM>-carboxylate B5 (<NUM>, <NUM> mmol) and THF (<NUM>). The solution was cooled to an IT = -<NUM>, <NUM> DIBAL (<NUM>, <NUM> mmol, <NUM> eq) was added dropwise during <NUM>. The reaction was stirred at -<NUM> for <NUM>. A saturated aqueous Na,K-tartrate solution (<NUM>) was added carefully to quench the reaction while maintaining the IT = -<NUM> to -<NUM>. The mixture was stirred vigorously at <NUM>-<NUM> until two clear phases were obtained (ca. <NUM> hrs) and extracted with EtOAc (<NUM>×<NUM>). The combined organic extracts were washed with <NUM> wt% brine (<NUM>), dried over Na<NUM>SO<NUM>, filtered and concentrated to give B6 as a viscous oil (<NUM>, <NUM> wt%, <NUM> % assay yield), which was used in the next step without further purification. <NUM>H NMR (<NUM>, CDCl<NUM>) δ = <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

To a <NUM> round bottomed flask was added <NUM> of the above viscous oil and acetonitrile (<NUM>). The flask was cooled in an ice-water bath and triethylsilane (<NUM>, <NUM> mmol), triflic acid (<NUM>, <NUM> mmol) was added subsequently. The reaction was then stirred for <NUM> hr in a <NUM> oil bath. The reaction was then cooled to <NUM>-<NUM> and poured into a separation funnel and washed with n-heptane (<NUM>×<NUM>). The acetonitrile layer was separated and concentrated to dryness to give a colorless oil, which was diluted in EtOAc (<NUM>). 6N HCl in isopropanol (<NUM>) was added dropwise with stirring, white solid precipitated out. MTBE (<NUM>) was added and the white suspension was stirred for <NUM> hrs and filtered. The filter cake was washed with EtOAc (<NUM>×<NUM>) to give a white solid, which was dissolved in MeOH (<NUM>), EtOAc (<NUM>) was added dropwise with stirring. The resulting white suspension was filtered and washed with EtOAc (<NUM>×<NUM>) to give B7 as a white solid (<NUM>, <NUM> wt%, <NUM>% over two steps). <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ = <NUM> (br s, <NUM>), <NUM> (br s, <NUM>), <NUM> (br s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (ABq, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

To a <NUM> Schlenk tube was added <NUM>-((<NUM>-amino-<NUM>-chloropyridin-<NUM>-yl)thio)-<NUM>-chloropyrazin-<NUM>-amine Y7a (<NUM>, <NUM> mmol), (<NUM>S,<NUM>S)-<NUM>-methyl-<NUM>-oxa-<NUM>-azaspiro[<NUM>]decan-<NUM>-amine dihydrochloride B7 (<NUM>, <NUM> mmol, <NUM> eq), DMAc (<NUM>) and <NUM> wt% aq. K<NUM>CO<NUM> (<NUM>, <NUM> mmol, <NUM> eq). The mixture was stirred for <NUM> hrs in a <NUM> oil bath and cooled to <NUM>-<NUM>. <NUM> wt% Brine (<NUM>) was added and the mixture was extracted with EtOAc (<NUM>×<NUM>). The combined extracts were washed with <NUM> wt% Brine (<NUM>×<NUM>), dried over anhydrous Na<NUM>SO<NUM> and filtered. The filtrate was concentrated to dryness to give B8 as a yellow solid (<NUM>, <NUM>%). <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ = <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

These two steps correspond to steps a and b in Route ALFA (cf. Example <NUM>) and yield Compound C4 = B4.

To a <NUM> round bottomed flask under a nitrogen atmosphere was added subsequently tert-butyl-<NUM>-(hydroxyimino)-<NUM>-methyl-<NUM>-oxo-<NUM>-oxa-<NUM>-azaspiro[<NUM>]decane-<NUM>-carboxylate C4 (<NUM>, <NUM> mol), toluene (<NUM>), acetic anhydride (<NUM>, <NUM> mmol), acetic acid (<NUM>, <NUM> mmol) and iron (<NUM>, <NUM> mmol). The mixture was stirred vigorously for <NUM> hrs in a <NUM> oil bath and cooled to rt. The suspension was filtered through microcrystalline cellulose to remove solid residue, which was then washed with EtOAc (<NUM>×<NUM>). The combined filtrates were cooled in an ice-water bath and washed with <NUM> wt% NaHCO<NUM> (<NUM>) and <NUM> wt% brine (<NUM>). The organic layer was separated, dried over Na<NUM>SO<NUM> and filtered. The filtrate was evaporated to dryness. The residue was purified by column chromatography (silica gel, EtOAc/n-heptane = <NUM>/<NUM> to <NUM>/<NUM>, v/v) and further purified by recrystallization from EtOAc/n-heptane to give C5 as white needle crystals (<NUM>, <NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>) δ = <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>).

To a vial under a nitrogen atmosphere was added [Rh(NBD)<NUM>]BF<NUM> (<NUM>, <NUM> mmol), ligand L* (from Johnson Matthey & Brandenberger AG, Zürich, Schweiz) (<NUM>, <NUM> mmol) and DCM (<NUM>). The resulting solution was stirred for <NUM> minutes before solvent was removed to give a yellow solid. To the vial under a nitrogen atmosphere was added tert-butyl <NUM>-acetamido-<NUM>-methyl-<NUM>-oxo-<NUM>-oxa-<NUM>-azaspiro[<NUM>]dec-<NUM>-ene-<NUM>-carboxylate C5 (<NUM>, <NUM> mmol) and <NUM>,<NUM>,<NUM>-trifluoroethanol (TFE) (<NUM>). The vial was placed into a hydrogenation reactor. The reactor was purged with nitrogen three times and then with hydrogen three times. The mixture was stirred for <NUM> hrs under a hydrogen pressure of <NUM> bar at IT=<NUM>. The reaction was cooled to <NUM>-<NUM>, filtered through a short silica pad and concentrated to dryness to give C6 as a white solid (<NUM>, <NUM>%). <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ = <NUM> (br d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

To a <NUM> Schlenk flask under a nitrogen atmosphere was added tert-butyl (<NUM>S,<NUM>S)-<NUM>-acetamido-<NUM>-methyl-<NUM>-oxo-<NUM>-oxa-<NUM>-azaspiro[<NUM>]decane-<NUM>-carboxylate C6 (<NUM>, <NUM> mmol) and THF (<NUM>). The flask was cooled in an ice-water bath. <NUM> LiBH<NUM> in THF (<NUM>) was added dropwise and the reaction was stirred for <NUM> hrs at <NUM>-<NUM>. The reaction was cooled in an ice-water bath and quenched by adding <NUM> wt% NaHCO<NUM> (<NUM>) dropwise. The mixture was separated and the water layer was extracted by EtOAc (<NUM>×<NUM>). The combined extracts were washed with <NUM> wt% brine (<NUM>). The organic layer was separated, dried over Na<NUM>SO<NUM> and filtered. The filtrate was evaporated to dryness. The residue was purified by column chromatography (silica gel, EtOAc/n-heptane = <NUM>/<NUM> to <NUM>/<NUM>, v/v) to give C7 as a colorless viscous oil (<NUM>, <NUM>%). <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ = <NUM> (br d, J = <NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (br s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

To a <NUM> Schlenk tube under a nitrogen atmosphere was added NaOH (<NUM>, <NUM> mmol) and water (<NUM>). The tube was cooled in an ice-water bath and a solution of tert-butyl <NUM>-((<NUM>,<NUM>)-<NUM>-acetamido-<NUM>-hydroxypropyl)-<NUM>-(hydroxymethyl)piperidine-<NUM>-carboxylate C7 (<NUM>, <NUM> mmol) and TsCl (<NUM>, <NUM> mmol) in DCM (<NUM>) was added dropwise. The mixture was then stirred for <NUM> hrs at <NUM>-<NUM>. n-Bu<NUM>NBr (<NUM>, <NUM> mmol) was added followed by NaOH (<NUM>, <NUM> mmol) in water (<NUM>). The mixture was then stirred for <NUM> hrs at <NUM>-<NUM>. The organic layer was separated, washed with <NUM> wt% brine (<NUM>), dried over Na<NUM>SO<NUM> and filtered. The filtrate was evaporated to dryness to give C9 as a white solid (<NUM>, <NUM>%). <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ = <NUM> (br d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (ABq, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

To a <NUM> sealed tube was added tert-butyl (<NUM>S,<NUM>S)-<NUM>-acetamido-<NUM>-methyl-<NUM>-oxa-<NUM>-azaspiro[<NUM>]decane-<NUM>-carboxylate C9 (<NUM>, <NUM> mmol) and 6N aq. HCl (<NUM>). The reaction was stirred for <NUM> hrs in a <NUM> oil bath. The reaction was then cooled to <NUM>-<NUM> and concentrated to dryness to give C10 as a white solid (<NUM>, <NUM>%). <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ = <NUM> (br s, <NUM>), <NUM> (br s, <NUM>), <NUM> (br s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (ABq, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

To a <NUM> Schlenk tube was added <NUM>-((<NUM>-amino-<NUM>-chloropyridin-<NUM>-yl)thio)-<NUM>-chloropyrazin-<NUM>-amine Y10a (<NUM>, <NUM> mmol), (<NUM>S,<NUM>S)-<NUM>-methyl-<NUM>-oxa-<NUM>-azaspiro[<NUM>]decan-<NUM>-amine dihydrochloride C10 (<NUM>, <NUM> mmol, <NUM> eq), DMAc (<NUM>) and <NUM> wt% aq. K<NUM>CO<NUM> (<NUM>, <NUM> mmol, <NUM> eq). The mixture was stirred for <NUM> hrs in a <NUM> oil bath and cooled to <NUM>-<NUM>. <NUM> wt% Brine (<NUM>) was added and the mixture was extracted with EtOAc (<NUM>×<NUM>). The combined extracts were washed with <NUM> wt% Brine (<NUM>×<NUM>), dried over anhydrous Na<NUM>SO<NUM> and filtered. The filtrate was concentrated to dryness to give C11 as a yellow solid (<NUM>, <NUM>%). <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ = <NUM> (d, J= <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

These two steps correspond to steps a and b in Route ALFA (cf. Example <NUM>) and yield Compound D4 = B4.

To a <NUM> reactor with an impeller stirrer under an nitrogen atmosphere was added Raney-Ni (<NUM>) and MeOH (<NUM>), followed by tert-butyl (S)-<NUM>-(hydroxyimino)-<NUM>-methyl-<NUM>-oxo-<NUM>-oxa-<NUM>-azaspiro[<NUM>]decane-<NUM>-carboxylate D4 (<NUM>, <NUM> mmol). The reactor was purged with nitrogen three times and then with hydrogen three times. The mixture was stirred for <NUM> hrs under a hydrogen pressure of <NUM> bar at IT=<NUM>. The reaction mixture was filtered through microcrystalline cellulose and the filter cake was washed with MeOH (<NUM>). The filtrate was concentrated to dryness to give a white solid (<NUM>). EtOAc (<NUM>) was added to the solid, the resulting suspension was heated to reflux (IT = <NUM>) and n-heptane (<NUM>) was added portionwise. The resulting clear solution was cooled to rt during <NUM> hrs and left standing overnight to give D5 as colorless crystals (<NUM>, cis/trans><NUM>/<NUM>, <NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>) δ = <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

To a <NUM> Schlenk tube was added tert-butyl (<NUM>S,<NUM>S)-<NUM>-amino-<NUM>-methyl-<NUM>-oxo-<NUM>-oxa-<NUM>-azaspiro[<NUM>]decane-<NUM>-carboxylate D5 (<NUM>, <NUM> mmol) and DCM (<NUM>). The tube was cooled in an ice-water bath. Diisopropylamine (<NUM>, <NUM> mmol) was added dropwise followed by Boc<NUM>O (<NUM>, <NUM> mmol). The reaction was then stirred for <NUM> hrs at <NUM>-<NUM>. The organic layer was separated, washed with <NUM> wt% brine (<NUM>), dried over Na<NUM>SO<NUM> and filtered. The filtrate was evaporated to dryness to give D6 as a colorless oil (<NUM>, <NUM>%), which gradually solidified upon standing. HRMS m/z calcd for C<NUM>H<NUM>N<NUM>O<NUM> [M+H]+ <NUM>, found <NUM>.

To a <NUM> Schlenk flask under a nitrogen atmosphere was added tert-butyl (<NUM>S,<NUM>S)-<NUM>-((tert-butoxycarbonyl)amino)-<NUM>-methyl-<NUM>-oxo-<NUM>-oxa-<NUM>-azaspiro[<NUM>]decane-<NUM>-carboxylate D6 (<NUM>, <NUM> mmol) and THF (<NUM>). The flask was cooled in an ice-water bath. <NUM> LiBH<NUM> in THF (<NUM>) was added dropwise and the reaction was stirred for <NUM> hrs at <NUM>-<NUM>. The reaction was cooled in an ice-water bath and quenched by adding <NUM> wt% NaHCO<NUM> (<NUM>) dropwise. The mixture was separated and the water layer was extracted by EtOAc (<NUM>×<NUM>). The combined extracts were washed with <NUM> wt% brine (<NUM>). The organic layer was separated, dried over Na<NUM>SO<NUM> and filtered. The filtrate was evaporated to dryness to give D7 as a colorless viscous oil (<NUM>, <NUM>%). HRMS m/z calcd for C<NUM>H<NUM>N<NUM>O<NUM> [M+H]+ <NUM>, found <NUM>.

To a <NUM> Schlenk tube under a nitrogen atmosphere was added NaOH (<NUM>, <NUM> mmol) and water (<NUM>). The tube was cooled in an ice-water bath and a solution of tert-butyl <NUM>-((<NUM>,<NUM>)-<NUM>-((tert-butoxycarbonyl)amino)-<NUM>-hydroxypropyl)-<NUM>-(hydroxymethyl)piperidine-<NUM>-carboxylate D7 (<NUM>, <NUM> mmol) and TsCl (<NUM>, <NUM> mmol) in DCM (<NUM>) was added dropwise. The mixture was then stirred for <NUM> hrs at <NUM>-<NUM>. n-Bu<NUM>NBr (<NUM>, <NUM> mmol) was added followed by NaOH (<NUM>, <NUM> mmol) in water (<NUM>). The mixture was then stirred for <NUM> hrs at <NUM>-<NUM>. The organic layer was separated, washed with <NUM> wt% brine (<NUM>), dried over Na<NUM>SO<NUM> and filtered. The filtrate was evaporated to dryness to give D9 as a colorless oil (<NUM>, <NUM>%). HRMS m/z calcd for C<NUM>H<NUM>N<NUM>O<NUM> [M+H]+ <NUM>, found <NUM>.

To a <NUM> Schlenk tube was added tert-butyl (<NUM>S,<NUM>S)-<NUM>-((tert-butoxycarbonyl)amino)-<NUM>-methyl-<NUM>-oxa-<NUM>-azaspiro[<NUM>]decane-<NUM>-carboxylate D9 (<NUM>, <NUM> mmol), 6N HCl in isopropanol (<NUM>) and methanol (<NUM>). The reaction was stirred for <NUM> hrs at <NUM>-<NUM> and concentrated to dryness to give D10 as a white solid (<NUM>, <NUM>%). <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ = <NUM> (br s, <NUM>), <NUM> (br s, <NUM>), <NUM> (br s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (ABq, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

To a <NUM> Schlenk tube was added <NUM>-((<NUM>-amino-<NUM>-chloropyridin-<NUM>-yl)thio)-<NUM>-chloropyrazin-<NUM>-amine Y10a (<NUM>, <NUM> mmol), (<NUM>S,<NUM>S)-<NUM>-methyl-<NUM>-oxa-<NUM>-azaspiro[<NUM>]decan-<NUM>-amine dihydrochloride D10 (<NUM>, <NUM> mmol, <NUM> eq), DMAc (<NUM>) and <NUM> wt% aq. K<NUM>CO<NUM> (<NUM>, <NUM> mmol, <NUM> eq). The mixture was stirred for <NUM> hrs in a <NUM> oil bath and cooled to <NUM>-<NUM>. <NUM> wt% Brine (<NUM>) was added and the mixture was extracted with EtOAc (<NUM>×<NUM>). The combined extracts were washed with <NUM> wt% Brine (<NUM>×<NUM>), dried over anhydrous Na<NUM>SO<NUM> and filtered. The filtrate was concentrated to dryness to give D11 as a yellow solid (<NUM>, <NUM>%). <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ = <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

Step a and Step b are conducted as described in Example <NUM>, Route ALFA.

To the hydrogenation reactor was added MeOH (<NUM>, <NUM> V) and D4 (<NUM>, <NUM> eq. The reactor was replaced with nitrogen for <NUM> times. Raney Ni (<NUM>) was then added to the reactor, and the reactor was replaced with hydrogen for <NUM> times. The reactor was heated to <NUM>~<NUM> and stirred for <NUM>. Then the hydrogen pressure was adjusted to <NUM>~<NUM> bar, and the temperature was adjusted to <NUM>~<NUM> slowly. The reaction was stirred at <NUM>~<NUM> under <NUM>~<NUM> bar for <NUM>. The mixture was filtered over celite, and the filter cake was washed with MeOH. The filtrate was concentrated until <NUM> w residue was left and IPA (3V) was then added. The mixture was heated to <NUM>~<NUM> and a clear solution was obtained. The solution was cooled to <NUM>~<NUM>, and stirred for <NUM>. n-Heptane (<NUM> V) was added dropwise to the solution. The mixture was stirred for <NUM>, cooled to <NUM>~<NUM> and stirred for additional <NUM>. Then n-heptane (<NUM> V) was added dropwise to the mixture. The mixture was cooled to <NUM>~<NUM>, stirred for <NUM>, and filtered. The filter cake was washed with a mixture of IPA (<NUM> w) and n-heptane (<NUM> w), then washed with n-heptane (<NUM> V), and dried at <NUM> to get D5 (<NUM>, <NUM>% yield, ee=<NUM>%, de=<NUM>%, purity = <NUM>%).

To a <NUM> Radley reactor was added D5 (<NUM>, <NUM> mmol), (Boc)<NUM>O (<NUM>, <NUM> mmol), IPAc (<NUM>) and KHCO<NUM> (<NUM>, <NUM> mmol) in water (<NUM>). The mixture was stirred at <NUM> for <NUM>. The organic layer was separated, washed with water (<NUM>) and concentrated to give a residue (<NUM>). The residue was heated to <NUM> and n-heptane (<NUM>) was added over <NUM>. The mixture was cooled to <NUM>, stirred for <NUM> and filtered. The filter cake was washed with n-heptane (<NUM>) and dried under vacuum to give D6 as a white solid (<NUM>, <NUM>% yield).

To <NUM> flexy cube reactor under N<NUM> atomsphere was added D6 (<NUM>, <NUM> mmol), NaBH<NUM> (<NUM>, <NUM> mmol, <NUM> eq) and <NUM>-MeTHF (<NUM>). The mixture was stirred at <NUM> for <NUM> and then cooled to <NUM>. MeOH (<NUM>, <NUM> V) was added and stirred for <NUM>. <NUM> wt% aq. Citric acid (<NUM>) was added and the mixture was separated. The organic layer was washed with <NUM> wt% aq. NaOH (<NUM> × <NUM>) and then with <NUM> wt% aq. NaCl (<NUM>). The organic layer was filtered through MCC, concentrated and swapped with THF to give D7 in THF (<NUM>, <NUM> wt%, <NUM>% yield), which was used directly in the next step.

To a <NUM> Radley reactor was added <NUM> wt% aq. NaOH (<NUM>). The solution was cooled to -<NUM>±<NUM>. D7 in THF (<NUM>, <NUM> wt%) was added. A solution of TPSCl (<NUM>) in THF (<NUM>) was then added in <NUM>. The reaction was stirred for <NUM> at -<NUM>±<NUM> to give full conversion into D8. Then <NUM> wt% aq. NaOH (<NUM>) was added slowly and the reaction mixture was heated to <NUM>±<NUM> and stirred for <NUM>. The organic phase was separated and concentrated to give a residue (<NUM>). The residue was stirred at <NUM> for <NUM>. Then water (<NUM>) was added over <NUM> at <NUM>. The mixture was cooled to <NUM> over <NUM>, stirred for <NUM> at <NUM> and filtered. The filter cake was washed with water (<NUM>× <NUM>) and transferred to a <NUM> Radley reactor. MTBE (<NUM>) and <NUM> wt% NaCl (<NUM>) was added. The mixture was stirred for <NUM> and separated. The oragnic phase was distilled to give a residue (<NUM>). The residue was stirred at <NUM> for <NUM>. n-Heptane (<NUM>) was added dropwise over <NUM>. The mixture was cooled to <NUM> over <NUM>, stirred for <NUM> at <NUM> and filtered. The filter cake was washed with n-heptane (<NUM>) and dried to give D9 as a white solid (<NUM>, <NUM>% yield).

To a <NUM> flexy cube reactor was added D9 (<NUM>, <NUM> mmol) and IPAc (<NUM>). HCl in IPA (<NUM> wt%, <NUM>) was added over <NUM>. The reaction mixture was then stirred for <NUM> and filtered. The filter cake was washed with IPAc and dried to give D10 as a white solid (<NUM>, <NUM>% yield).

To a <NUM> flexy cube reactor was added Y10a (<NUM>, <NUM> mmol), IPA (<NUM>), water (<NUM>), sulfolane (<NUM>), D10 (<NUM>, <NUM> mmol) and then K<NUM>CO<NUM> ( <NUM>, <NUM> mmol). The mixture was heated to <NUM> and stirred for <NUM>. Water (<NUM>) was charged and the mixture was stirred for <NUM> at <NUM>, then cooled to <NUM>. THF (<NUM>) was added and the mixture was stirred for <NUM> at <NUM>. The organic phase was separated at <NUM> and then concentrated under vacuum at <NUM> to give a residue (<NUM>). Water (<NUM>) was charged at <NUM> and the solution was stirred for <NUM>. Seeds (<NUM>) was added and stirred for <NUM> at <NUM>. Water (<NUM>) was charged over <NUM> at <NUM>. The mixture was cooled to <NUM> over <NUM> and stirred at <NUM> for <NUM>, then filtered. The filter cake was washed with water (<NUM> × <NUM>) and dried to give D11 as a beige solid (<NUM>, <NUM>% yield, <NUM>% purity).

The reaction steps are conducted as follows:
Step a (for variants A and B): <NUM>,<NUM>,<NUM>-trichloropyrazine (<NUM>, <NUM> mmol, <NUM> equiv) and ammonia solution (<NUM>% wt, <NUM>, <NUM>, <NUM> mol, <NUM> equiv) were added to a <NUM>-L sealed reactor. The mixture was heated to <NUM> and stirred for <NUM>, and the reaction was completed. The reaction mixture was cooled to <NUM> and filtered to give a brown filter cake. The brown filter cake was dissolved in acetone (<NUM>), and filtered. To the filtrate was added petroleum ether (<NUM>). The suspension was stirred for <NUM>, and filtered to give the crude product. The crude product was slurried in combined solvents of petroleum ether and acetone (<NUM>/<NUM>, <NUM>) and filtered to give the product Y7d (<NUM>, <NUM> mmol, <NUM>% yield) as a light yellow solid. <NUM> NMR (<NUM>, DMSO-d6) δ = <NUM> (s, <NUM>). The advantage of this (also generalized) method is that no column chromatrography is required to obtain Y7d.

The transformation was demonstrated in the kilo-lab, the detailed experimental procedure is described by the following:
To a <NUM> reactor with an impellor stirrer under a nitrogen atmosphere was added Y7d (<NUM>, <NUM> mol), EtOH (<NUM>), water (<NUM>) and citric acid monohydrate (<NUM>, <NUM> mol). The brown suspension was heated to IT = <NUM>±<NUM> to give a clear dark solution. <NUM> wt% aq. Na<NUM>S<NUM>O<NUM>·<NUM><NUM>O (<NUM>, <NUM> mol) was added in <NUM> at IT = <NUM>±<NUM> and the resulting yellow suspension was stirred for <NUM> at this temperature. A solution of citric acid monohydrate (<NUM>, <NUM> mol) in water (<NUM>) was added slowly and then <NUM> wt% aq. Na<NUM>S<NUM>O<NUM>·<NUM><NUM>O (<NUM>, <NUM> mol) was added in <NUM> at IT = <NUM>±<NUM>. The yellow suspension was stirred at IT = <NUM>±<NUM> for <NUM>, cooled to IT = <NUM>±<NUM> and filtered. The filter cake was washed with water (<NUM>) and transferred to another reactor under a nitrogen atmosphere. <NUM> wt% aq. NaOH (<NUM>, <NUM> mol) was then added slowly, the resulting yellow suspension was stirred at IT = <NUM>±<NUM> for <NUM> and filtered. The filter cake was washed with water (<NUM>). The filtrate was obtained as a brown aqueous solution of Y7c' (<NUM>, <NUM> wt%, <NUM>% HPLC purity, <NUM>% yield) which was used directly in the next step. <NUM>H NMR (<NUM>, D<NUM>O) δ = <NUM> (s, <NUM>).

Under nitrogen atmosphere, n-BuLi (<NUM>, <NUM>) was added dropwise to a solution of <NUM>-chloro-<NUM>-fluoropyridine (<NUM>) in THF (<NUM>) at -<NUM>. Then the resultant mixture was stirred for <NUM>. Then a solution of I<NUM> (<NUM>) in THF (<NUM>) was added dropwise. After addition, the reaction mixture was stirred for <NUM>, and then quenched with sat. Na<NUM>SO<NUM> (<NUM>), and warmed to <NUM>-<NUM>. Phase was separated. The aqueous phase was extracted with EA (<NUM> x <NUM>). The combined organic phase was washed with sat. Na<NUM>SO<NUM> (<NUM> x <NUM>), brine (<NUM>), and dried over Na<NUM>SO<NUM>. The organic phase was concentrated under vacuum. The residue was slurried in MeOH (<NUM>), filtered, and dried to offer <NUM>-chloro-<NUM>-fluoro-<NUM>-iodopyridine 1c (<NUM>, yield <NUM>%).

Into a solution of Compound 1c (<NUM>) in DMSO (<NUM>) was passed through NH<NUM> (gas) at <NUM> overnight. TLC showed the reaction was finished. The reaction mixture was cooled to RT. The reaction mixture was added to water (<NUM>). The solid was collected and washed with water (<NUM>), dried to afford Z17b (= Y7b) (<NUM>, yield <NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>) δ = <NUM> (d, J= <NUM>, <NUM>), <NUM> (s, J = <NUM>, <NUM>), <NUM> (bs, <NUM>).

To a <NUM> radley reactor under a nitrogen atmosphere was added Y7c' water solution (<NUM>, <NUM> wt%, <NUM> mmol), water (<NUM>) and IPA (<NUM>). The brown solution was degassed with nitrogen for <NUM>. Citric acid monohydrate (<NUM>, <NUM> mmol) was added with stirring to get a yellow suspension. Y7b (<NUM>, <NUM> mmol), CuI (<NUM>, <NUM> mmol) and <NUM>,<NUM>-phenanthroline (<NUM>, <NUM> mmol) was added subsequently. The mixture was heated to <NUM> and stirred for <NUM>, then the temperature was raised to <NUM> over <NUM>. The mixture was stirred at <NUM> for <NUM>. The reaction was then cooled to rt and filtered. The filter cake was washed with a mixed solvent of THF/water (<NUM>/<NUM>) and transferred to another reactor. THF (<NUM>) and water (<NUM>) was added, active carbon (<NUM>) was then added and the mixture was stirred at <NUM> for <NUM>. The mixture was then cooled to <NUM> and filtered through MCC. MCC was rinsed with a mixed solvent of THF/water (<NUM>/<NUM>) and the filtrate was concentrated to give a residue of <NUM>. The residue was stirred at <NUM> for <NUM>, water (<NUM>) was added dropwise over <NUM>, the resulting suspension was cooled to <NUM> over <NUM> and stirred at this temperature for <NUM>. The mixture was filtered and the filter cake was washed with a mixed solvent of THF/water (<NUM>/<NUM>) to give a yellow solid (<NUM>, <NUM>% yield).

To a mixture of Z17c (<NUM>, assay <NUM>%, <NUM> mol) in <NUM>,<NUM>-dioxane (<NUM>) was added Xantphos (<NUM>, <NUM> mmol, <NUM> eq), Pd<NUM>(dba)<NUM> (<NUM>, <NUM> mmol, <NUM>. 0075eq), Z17b (<NUM>, <NUM> mol) and DIPEA (<NUM>, <NUM>. The system was vacuated and purged with nitrogen gas three times. The mixture was stirred at <NUM> for <NUM> under N<NUM>. The mixture was cooled to rt and water (<NUM>) was added, filtered. The cake was washed with EA (<NUM>). The filtrate was extracted with EA (<NUM> x <NUM>). The organic phase was concentrated in vacuum to offer the crude product which was combined with the cake. Then DCM (<NUM>) was added to the crude product and stirred at <NUM>-<NUM> for <NUM> and then filtered. The filter cake was slurried with CH<NUM>Cl<NUM> (<NUM>) for <NUM> hrs and filtered. The filter cake was slurred in CH<NUM>Cl<NUM> (<NUM>) for <NUM> hrs and filtered. Then the filter cake was dried in vacuum to give Z17a (<NUM>, <NUM> %) as light yellow solid. <NUM>H NMR (<NUM>, DMSO-d6)δ = <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (bs, <NUM>), <NUM> (bs, <NUM>), <NUM> (d, J= <NUM>, <NUM>)
Alternative route for the manufacture of compound Z17a = Y7a = Y10a:
This ( as such also inventive) route is conducted as follows:
<CHM>.

Claim 1:
A method for the manufacture of a compound of Formula I, or a pharmaceutically acceptable salt, acid co-crystal, hydrate or other solvate thereof, said method comprising reacting a compound of formula II with a compound of formula III according to the following reaction scheme:
<CHM>
wherein LG is a leaving group, A is the anion of a protic acid, and n, m and p are independently <NUM>, <NUM> or <NUM>, so that the salt of the formula II is electrically neutral, wherein the compound of formula II is manufactured in a method comprising reacting a compound of the formula V:
<CHM>
wherein R<NUM> is a secondary amino protecting group and R<NUM> is a carboxyl protecting group, in the presence of a strong base with L lactide of the formula:
<CHM>
to yield a compound of the formula VI:
<CHM>
wherein R<NUM> is a secondary amino protecting group and R<NUM> is unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl or unsubstituted or substituted aryl, and
cyclizing the compound of formula VI with hydroxylamine, or a salt thereof, respectively, to yield a hydroxylamine compound of the formula VII:
<CHM>
wherein R<NUM> is a secondary amino protecting group.