Process for preparing a pyrazolo[1,5-a]pyrimidinyl carboxamide compound

Abstract

There is provided a process for preparing 5,7-dimethyl-N-((1R,4R)-4- (pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, said process comprising at least a step of amide coupling a 5,7-Dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid with trans-4-(pentyloxy)cyclohexanamine using carbonyldiimidazole (CDI).

Description

Process for preparing a pyrazolo[l,5-a]pyrimidinyl carboxamide compoundField of the Invention

[0001] The present invention relates to a process for preparing 5,7-dimethyl- / V- ((! / ?, 4 / ?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide.Background to the Invention

[0002] Gaucher disease is a genetic disorder associated with a deficiency of the lysosomal enzyme, glucocerebrosidase. Gaucher disease has been reported to have an incidence of approximately 1 in 20,000 live births in the general population, and it is a common lysosomal storage disorder. Current treatments for patients suffering from this disease include enzyme replacement therapy, which tends to be expensive, analgesics for bone pain relief, and medical procedures such as blood and platelet transfusions, splenectomy, and joint replacement for patients who experience bone erosion. However, new treatment options are needed with improved efficacy across a broader range of patients and / or reduced adverse side effects.

[0003] Mutations in the gene encoding glucocerebrosidase are also a risk factor for Parkinson's disease and diffuse Lewy Body Disease. Parkinson's disease is a degenerative disorder of the central nervous system associated with death of dopamine-containing cells in a region of the midbrain. Parkinson's disease afflicts millions of people, and the incidence of the disease increases with age. Treatment of Parkinson's disease frequently involves use of levodopa and dopamine agonists. However, these drugs can produce significant side effects such as hallucinations, insomnia, nausea, and constipation. In addition, patients often develop tolerance to these drugs such that the drugs become ineffective at treating the symptoms of the disease, while sometimes also producing a movement disorder side effect called dyskinesia. Diffuse Lewy Body disease is a dementia that is sometimes confused with Alzheimer's disease.

[0004] Despite the advances made to date, there still remains a need for new therapeutic agents for treating Gaucher disease, Parkinson's disease, and related medical disorders.

[0005] 5,7-dimethyl- / V-((l / ?,4 / ?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5- a]pyrimidine-3-carboxamide (hereinafter referred to as compound of Formula (A)) has been described in WO 2016 / 073895 Al, WO 2017 / 192841 Al and WO 2019 / 126776 Al (incorporated herein by reference and referred to subsequently as "WO ’895", "WO ’841"and "WO '776" respectively). This compound has been shown to have potential as a treatment for inter alia Gaucher disease, Parkinson's disease and related medical disorders. However, there are a number of aspects of the preparation method described in WO '895, WO '841 and WO '776 that could be improved upon.

[0006] In that respect, the present invention provides a process for preparing the compound of Formula A having a number of improvements over the processes of WO '895, WO '841 and WO '776. In particular, such improvements relate to improved control over the formation of the useful polymorphic form B of the compound of Formula A, reduced production of impurities, improved yields and simplification of various aspects of the process.Summary of the Invention

[0007] In a first aspect of the invention, there is provided a process for preparing a compound of Formula (A):Formula (A) said process comprising a step of: amide coupling a compound of Formula (VII) with a compound of Formula (IV) using carbonyldiimidazole (CDI) to produce the compound of Formula (A)Formula (IV).

[0008] The use of CDI as the amide coupling reagent has been found to be particularly advantageous. In the WO '895 and WO '841 processes, HATU is used as the amide coupling reagent. The use of HATU, which has a high molecular weight, is less efficient in terms of atom economy; HATU's mediation also produces more by-products and so the purification step of the compound of Formula (A) is more demanding. Furthermore, HATU may have safety issues, being potentially explosive and difficult to transport, thus its use is not preferred for large scale manufacturing of the compound of Formula A.Furthermore, in WO '895 and WO '841 the use of HATU requires the addition of an excess of DIPEA. In the WO '776 process, HOPO is used as the amide coupling reagent. It has been found that HOPO is a class 2 (ICH M7) impurity which needs to be strictly controlled in the final API. The use of CDI has been found to avoid the need to use HOPO and CDI does not produce any such serious impurities in the final API product. Furthermore, the use of CDI avoids the need to add additional base to the reaction mixture since the CDI is able to also function as a base. Finally, in WO '776 the use of HOPO requires the addition of EDC and DIPEA. In the present invention, only CDI (in a DMF solvent) is required. This provides a simplified process step, available at lower cost.

[0009] In a first embodiment of the aspect, the process further comprises one or more of the following steps:(a) protection of the amine group of a compound of Formula (I) with at least one protecting group (PG) to form a compound of Formula (II);Formula (I) Formula (II) wherein Ri=PG and R2=H or PG(b) alkylation of the compound of Formula (II) to produce a compound of Formula (III), optionally in a salt form;Formula (III) wherein Ri=PG and R2=H or PG(c) deprotection of the compound of Formula (III) to produce the compound of Formula (IV), optionally wherein both compounds are in a salt form;Formula (IV)(d) cyclisation of a compound of Formula (V) with acetylacetone to produce a compound of Formula (VI);ormu a ( ) Formula (VI)(e) hydrolysing the compound of Formula (VI) to produce the compound of Formula (VII)Formula (VII); optionally wherein the process comprises all of steps (a) to (e).[OO1O] In a second embodiment of the aspect, the process comprises one or more of the following: step (a) comprises benzylation with a benzylating agent in the presence of K2CO3 and dimethylformamide (DMF) at a temperature of about 20 to about 50 °C, optionally wherein the reaction is quenched at a temperature of less than or equal to about 50 °C, preferably between about 35 to about 45 °C; in step (b) the alkylation is performed with an alkylating agent in the presence of a base and dimethylformamide (DMF) at a temperature of about -6 °C to about 0 °C, and optionally further comprising a step of converting the compound of Formula (III) to the HCI salt form; step (c) comprises hydrogenolysis which is performed in the presence of a solvent comprising ethanol at a temperature of about 20 °C to about 60 °C and in the presence of hydrogen and Pd / C catalyst; in step (d) the cyclisation is performed in the presence of a solvent comprising acetic acid and at a temperature of from about 20 °C to about 70 °C;step (e) comprises ester hydrolysis that is performed in the presence of a base, preferably NaOH, at a temperature of about 40 °C to about 80 °C for a time of between about 3 hours to about 8 hours; and in step (f) the amide coupling is performed at a temperature of about 15 °C to about 35 °C in the presence of a solvent, preferably wherein the solvent is dimethylformamide (DMF).

[0011] In a third embodiment of the aspect, wherein step (a) comprises benzylation of the compound of Formula (I) with a benzylating agent to produce a compound of Formula (IIA), preferably wherein the benzylating agent comprises (bromomethyl)benzene (BnBr) or (chloromethyl)benzene (BnCI); andFormula (IIA) wherein the benzylating agent is added in an amount of between about 1.9 to about 2.1 molar equivalents, preferably about 2.0 molar equivalents.

[0012] In a fourth embodiment of the aspect, wherein in step (a) the reaction mixture after benzylation is quenched at a temperature less than about 50 °C, preferably between about 35 to about 45 °C, further preferably at about 40 °C.

[0013] In a fifth embodiment of the aspect, the benzylating agent is added dropwise to the reaction mixture, preferably over a period of time of at least about 5 hours, most preferably at least about 6 hours.

[0014] In a sixth embodiment of the aspect, in step (b) the alkylation is performed in the presence of a base and DMF solvent, preferably wherein DMSO is not used in step (b).

[0015] In a seventh embodiment of the aspect, in step (b) the alkylation is carried out at a temperature of about -10 to about 10 °C, preferably about -6 to about 0 °C.

[0016] In an eighth embodiment of the aspect, in step (b) about 3 to about 6 molar equivalents of 1-bromo-pentane are used, preferably about 4.5 molar equivalents.

[0017] In a ninth embodiment of the aspect, the process comprises one or more of the following: in step (a) reacting with BoczO in the presence of K2CO3, NaHCOs, NEts or NaOH and preferably a DCM and water or 1,4-dioxane and water solvent; in step (b) alkylating with an alkylating agent, preferably bromopentane (Br(CH2)4CH3), preferably in the presence of t-BuOK and a DMF solvent; in step (c) deprotecting with an acid, preferably HCI, and optionally a further step of removing acid by reacting with a base;in step (d) the cyclisation is performed in the presence of a solvent comprising acetic acid and at a temperature of from about 20 °C to about 70 °C; step (e) comprises ester hydrolysis that is performed in the presence of a base, preferably NaOH, at a temperature of about 40 °C to about 80 °C for a time of between about 3 hours to about 8 hours; and in step (f) the amide coupling is performed at a temperature of about 15 °C to about 35 °C in the presence of a solvent, preferably wherein the solvent is dimethylformamide (DMF).

[0018] In a tenth embodiment of the aspect, the process comprises one or more of the following steps:(a) protection of the amine group of a compound of Formula (I) with a cyclic protecting group (cPG) to form a compound of Formula (II);Formula (I) Formula (II) wherein Ri and R2 form together a cPG(b) alkylation of the compound of Formula (II) to produce a compound of Formula (III), optionally in a salt form;Formula (III) wherein Ri and R2 form together a cPG(c) deprotection of the compound of Formula (III) to produce the compound of Formula (IV), optionally wherein both compounds are in a salt form;Formula (IV)(d) cyclisation of a compound of Formula (V) with acetylacetone to produce a compound of Formula (VI);or u a Formula (VI)(e) hydrolysing the compound of Formula (VI) to produce the compound of Formula (VII)Formula (VII); optionally wherein the process comprises all of steps (a) to (e).

[0019] In an eleventh embodiment of the aspect, the process comprises one or more of the following : in step (a) reacting with hexane-2, 5-dione in the presence of acetic acid (AcOH) in MeOH or EtOH, preferably in MeOH; in step (b) alkylating with an alkylating agent, preferably bromopentane (Br(CH2)4CH3), preferably in the presence of t-BuOK and a DMF solvent; in step (c) deprotecting with hydroxylamine hydrochloride in the presence of base, such as triethylamine (TEA), NaOH or NazCOs, preferably NaOH in EtOH / water; in step (d) the cyclisation is performed in the presence of a solvent comprising acetic acid and at a temperature of from about 20 °C to about 70 °C; step (e) comprises ester hydrolysis that is performed in the presence of a base, preferably NaOH, at a temperature of about 40 °C to about 80 °C for a time of between about 3 hours to about 8 hours; and in step (f) the amide coupling is performed at a temperature of about 15 °C to about 35 °C in the presence of a solvent, preferably wherein the solvent is DMF.

[0020] In a twelfth embodiment of the aspect, comprising in step (e) subsequently adding an acid, wherein the acid is citric acid, preferably added at about 40 to about 65 °C and in an amount of about 1.5 equivalents.

[0021] In a thirteenth embodiment of the aspect, after the addition of acid, the compound of Formula (VII) prepared in step (e) is isolated by precipitation in EtOH and subjecting the reaction mixture to repeated heating to about 50 to about 55 °C and cooling to about 25 to about 35 °C.

[0022] In a fourteenth embodiment of the aspect, in step (f) about 1 to about 1.5 molar equivalents of CDI are added, preferably about 1.2 molar equivalents.

[0023] In a fifteenth embodiment of the aspect, the process further comprises recrystallising the compound of Formula (A), preferably wherein said re-crystallisation comprises the steps: i) dissolving the compound of Formula (A) in methyl ethyl ketone (MEK) at a temperature of about 15 °C to about 35 °C to produce a solution; ii) filtering the solution; iii) recrystallising the compound of Formula (A) with heptane between about 14 to about 25 °C, preferably about 17 ± 3 °C; iv) removing the MEK by distillation whilst maintaining the temperature at about 17±3° C; and v) drying the resultant cake at a temperature not more than about 35 °C.

[0024] In a sixteenth embodiment of the aspect, the process produces the compound of Formula (A) comprising one or more, or all, of Impurities A to F individually in an amount of less than or equal to 0.05 %w / w, and / or wherein the process produces the compound of Formula (A) comprising Impurity G, wherein Impurity G is present in an amount of less than or equal to about 0.05 %w / w.Detailed DescriptionDefinitions

[0025] To facilitate an understanding of the present invention, a number of terms and phrases are defined below.

[0026] The terms "a" and "an" as used herein mean "one or more" and include the plural unless the context is inappropriate.

[0027] The term "alkyl" as used herein (or indirectly in relation to an "alkylating agent" or the like) refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as Ci- Cizalkyl, Ci-Cioalkyl, and Ci-Cealkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l-propyl, 2-methyl-2-propyl, 2- methyl-l-butyl, 3-methyl-l-butyl, 2-methyl-3-butyl, 2,2-dimethyl-l-propyl, 2-methyl- 1- pentyl, 3-methyl-l-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4- methyl-2-pentyl, 2,2-dimethyl-l-butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc. Alkylating agent takes its normal definition and refers to any compound capable of reacting to donate an alkyl group or radical.

[0028] The abbreviation "Bn" as used herein refers to benzyl, which has the formula:

[0029] The symbol " " indicates a point of attachment.

[0030] Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic acid, and the like. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.

[0031] Examples of bases include, but are not limited to, alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides, ammonia, and the like.

[0032] Examples of salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include anions of the compounds of the present invention compounded with a suitable cation such as Na+, and the like.

[0033] Abbreviations as used herein include 2-hydroxypyridine-N-oxide (HOPO); 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC); diisopropylethylamine (DIPEA); dimethylformamide (DMF); dimethylacetamide (DMAc); methylene chloride (DCM); tert-butoxycarbonyl (Boc); fluorenylmethoxycarbonyl (Fmoc); Boc anhydride ((BOC)2O); dimethylsulfoxide (DMSO); methyl ethyl ketone (MEK); ethyl acetate (EtOAc); methyl tert-butyl ether (MTBE); active pharmaceutical ingredient (API); X-ray powder diffractogram (XRPD); High-performance liquid chromatography (HPLC).

[0034] The term "work-up", and similar such terms like "worked-up", used herein take their usual meaning in the art, and generally refer to one or more manipulations or steps carried out in order to isolate and / or purify the product(s) of the reaction.

[0035] Reference to "V" herein, refers to volume equivalents. Volume equivalents takes its usual meaning in the art, namely that it refers to the number of volumes in relation to the mass of a reactant. It can be expressed as volume in L divided by mass of a reactant in kg (or, for example, in mL / g). When calculating volume equivalents, the weight of the reactant is converted into volume using a theoretical density of 1 g / ml. For example, if there is 10 kg of the reactant and 20 L of solvent this would equate to 2 vol.(or V) of solvent in relation to the reactant. Herein, the reactant used as a basis for calculating volume equivalents in each reaction step is the starting material which undergoes a chemical change to form the desired product of that reaction step. For the avoidance of doubt, unless specified otherwise, the reactant used as a basis for calculating volume equivalents in the reaction steps described herein is defined as the compound of: Formula I in step (a), Formula II in step (b), Formula III in step (c), Formula V in step (d), Formula VI in step (e), Formula VII in step (f) and Formula (A) for the recrystallisation of said compound. For the embodiments described herein using a Boc protecting group, step (c) can take place in the work up of the crude reaction product of step (b), in which case steps (b) and (c) are somewhat combined and the compound of Formula (II) will be considered to be the reactant for the purpose of calculating volume equivalents.

[0036] Reference herein to "equivalents" or "eq" or"equiv" is to "molar equivalents" in the absence of any other indication. Molar equivalents takes its usual meaning in the art, namely that the number of moles of a given reagent divided by the number of moles of a reactant (the reactant being defined herein in the same manner as in relation to "volume equivalents"). For example, if there is 100 mol of the reactant (1 eq.) and 200 mol of reagent A, there are 2 eq. of reagent A.

[0037] As a general matter, compositions specifying a percentage are weight-to- weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.

[0038] Unless otherwise stated, or for other reasons obviously not correct, the reactions described herein take place in the, or substantially in the, liquid phase. Other phases may be possible for one or more aspects of the process described herein, as will be readily understood.

[0039] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps. The order of steps in any processes or methods that are described herein is not to be limited, unless there is an explicit indication as to the order in which the steps should be carried out.Preparation of 5,7-dimethyl- / V-((l / ?,4 / ?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5- a]pyrimidine-3-carboxamide

[0040] The present invention relates to an improved process for the preparation of 5,7-dimethyl- / V-((lR,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (compound of Formula (A)). In this respect, the inventors of the present invention have identified a number of improvements that can be made to the process for preparing the compound of Formula (A) compared to the preparation method described in WO '776.Formula (A)

[0041] The preparation of the compound of Formula (A) described herein generally follows the following synthetic route.

[0042] In a first step, generally referred to herein as step (a), there is protection of the amine group of a compound of Formula (I) with at least one protecting group (PG) to form a compound of Formula (II)Formula (I) Formula (II) wherein Ri=PG and R2=H or PG.

[0043] Alternatively, in a first step (a), there is protection of the amine group of a compound of Formula (I) with a cyclic protecting group to form a compound of Formula(II)Formula (I) Formula (II) wherein Ri and R2 form together a cPG.

[0044] In a second step, generally referred to herein as step (b), alkylating the compound of Formula (II) to produce a compound of Formula (III), optionally in a salt formFormula (III) wherein Ri=PG and R2=H or PG.

[0045] When alternatively Ri and R2 form together a cPG, in a second step (b), alkylating the compound of Formula (II) to produce a compound of Formula (III), optionally in a salt formFormula (III) wherein Ri and R2 form together a cPG.

[0046] In a third step, generally referred to herein as step (c), deprotecting the compound of formula (III) to produce a compound of formula (IV), optionally wherein both compounds are in a salt formFormula (IV).

[0047] In a fourth step, generally referred to herein as step (d), there is cyclisation of a compound of formula (V) with acetylacetone to produce a compound of Formula (VI)ormu a ( ) Formula (VI).

[0048] In a fifth step, generally referred to herein as step (e), hydrolysing the compound of Formula (VI) to produce the compound of Formula (VII)Formula (VII).

[0049] In a sixth step, generally referred to herein as step (f), amide coupling a compound of Formula (VII) with a compound of Formula (IV) using carbonyldiimidazole (CDI) to produce the compound of Formula (A).Preparation of trans-4-(pentyloxy)cyclohexanamine (compound of Formula (IV))Formula (IV)

[0050] The first stage of the synthetic route is the formation of the compound of Formula (IV). The first step typically involves the addition of one or more protecting groups to the amine group of trans-4-aminocyclohexanol (compound of Formula (I)). Without limiting the present invention, it has been found that particularly preferred protecting groups are selected from benzyl, Boc (tert-butoxycarbonyl) and Fmoc (fluorenylmethoxycarbonyl). Alternatively, the protecting group is a cyclic protecting group which forms a heterocyclic ring with the primary amine of the compound of Formula (I). In this case, without limiting the present invention, it has been found that particularly / V-2,5- dimethylpyrrole is a preferred protecting group.Process using benzyl protecting group

[0051] As in WO '776, one preferred embodiment of the invention relates to the use of benzyl group(s) as the protecting group of trans-4-aminocyclohexanol (compound of Formula (I)) in order to prepare trans-4-(pentyloxy)cyclohexanamine (compound of Formula (IV)).««SFormula ( Formula HA) Formula (H1A) . Hd Formula (IV) . HC1Step (a)

[0052] The benzylation of trans-4-aminocyclohexanol (compound of Formula (I)) to prepare trans-N, / V-dibenzyl-4-aminocyclohexanol (compound of Formula (IIA)) can be achieved using any compound that is able to react to provide a benzyl group i.e., any benzylating agent. However, preferred are benzyl halides e.g., BnF, BnBr, BnCI, Bnl but particularly preferred is BnBr. In a preferred embodiment, the compound of Formula (I) is reacted with BnBr in the presence of K2CO3 and a solvent. Preferably the K2CO3 is anhydrous. Any suitable solvent may be used, although particularly preferred is dimethylformamide (DMF). Suitable amounts of K2CO3 and solvent are used. For example, K2CO3 may be used in an amount of about 0.5 to about 10 molar equivalents, preferably about 1 to about 4 equivalents, most preferably about 1.5 equivalents. For example, the solvent such as DMF may be used in an amount of about 1 to about 10 V, preferably about 3 to about 7 V, most preferably about 6 V. Initially the K2CO3 and solvent are charged to a reactor at a temperature of between about 20 to about 30 °C, preferably about 25 °C. The temperature is then typically increased to about 30 to about 40 °C, preferably about 35 °C. In certain embodiments, the benzylating agent is then added to the reactor. Preferably the benzylating agent, such as BnBr, is added dropwise to the reactor, most preferably over a period of time of at least 5 hours, most preferably at least 6 hours. In certain embodiments, the benzylating agent, such as BnBr, is added in an amount of between about 1.8 to about 2.2 molar equivalents, preferably about 1.9 to about 2.1, most preferably about 2 (or 2.0) molar equivalents. Typically, the reactor temperature is then increased further, preferably to between about 35 °C to about 45 °C, most preferably about 40 °C and then allowed to stir for at least about 6 hours, most preferably at least about 8 hours. In certain embodiments, the reaction mixture is then quenched with water. The reaction mixture is quenched at a temperature of less than or equal to about 50 °C, preferably less than or equal to about 45 °C, most preferably less than or equal to about 40 °C or at about 40 °C. In certain embodiments, the reaction mixture is subsequently stirred at a lower temperature of between about 30 to about 40 °C, most preferably at about 35 °C. Preferably mixture is then cooled further before the work-up is carried out and the reaction product obtained.

[0053] Preferably the reaction steps take place under an inert atmosphere, preferably a nitrogen atmosphere. Preferably the yield of step (a) is greater than 80%, preferably greater than 85%. Preferably the purity of the product is at least about 95%, more preferably at least about 98% as measured by HPLC.

[0054] It has been identified that the benzylation step carried out in the process of WO '776 results in the formation of various benzylated impurities, such as, N-dibenzyl-4- (benzyloxy)cyclohexan-l-amine:

[0055] This benzylated impurity is particularly problematic since it was very difficult to purge and consequently it leads to an impurity (N-(trans-4-(benzyloxy)cyclohexyl)-5,7- dimethylpyrazolo[l,5-a]pyrimidine-3-carboxamide) seen in the final API. It has been identified that adding BnBr slowly, in specific amounts and carrying out quenching at below certain temperatures, advantageously minimizes the formation of this benzylated impurity. In this respect, it has been identified that adding BnBr in an amount of about 2 molar equivalents particularly minimizes the formation of this benzylated impurity. Furthermore, adding BnBr in a dropwise manner over an extended period of time (preferably at least 6 hours) further reduces the formation of this benzylated impurity. Controlling the quenching temperature to be not more than about 50 °C (preferably about 45 to about 50 °C), further reduces the formation of this benzylated impurity. Carrying out one or more of the above measures has been found to advantageously reduce formation of this benzylated impurity to less than 0.1 %.Step (b)

[0056] The alkylation of the compound of Formula (IIA) to produce a compound of Formula (IIIA), optionally in a salt form, can be achieved by using any suitable alkylating agent. However, particularly preferred as alkylating agent is a source of a pentyl group, in particular 1-bromopentane.

[0057] In certain embodiments, the alkylation takes place in presence of a solvent. Any suitable solvent may be used, however DMF has been found to be particularly preferable. Alternatively, the solvent may be DMAc. In certain embodiments, the solvent does not include any DMSO. In certain embodiments, the alkylation takes place in a DMF solvent, in the presence of a t-butoxide base such as t-BuOK and with 1-bromopentane as the alkylating agent. Preferably the alkylating agent is 1-bromopentane and preferably added in an amount of between about 3 to about 6 equivalents, or about 4 to about 5equivalents, or about 4.5 equivalents. In certain embodiments, about 3 to about 6 equivalents of t-BuOK are used, preferably about 4 to about 5 equivalents, most preferably about 4.5 equivalents. Preferably the reaction takes place at a temperature of about -10 °C to about 0 °C, preferably about -6 ° to about 0 °C, most preferably about -3 °C. This reaction temperature has been found to be advantageous in that it provides a good conversion and low value of impurities, while still allowing the reaction mixture to be stirred. Lower temperatures were found to make the mixture too difficult to stir. In certain embodiments, the reaction mixture comprising solvent, alkylating agent and compound of Formula IIA is added to a reactor at a temperature of between about 10 °C to about 30 °C, preferably about 15 °C to about 25 °C, most preferably about 20 °C, before cooling the reaction mixture down to the aforementioned temperature ranges and subsequently introducing the t-BuOK, optionally in the presence of additional solvent, to the reaction mixture. In certain embodiments, once the reaction is completed, water, followed by n- heptane, is added to the reaction mixture in a suitable amount in order to extract the compound of Formula IIIA.

[0058] Preferably, the reaction product of the alkylation is converted into a salt form, preferably a HCI salt form. This is performed by reacting the reaction product of the alkylation step with HCI in EtOAc solution. Further preferably, n-heptane is also added to the reaction mixture, most preferably in a dropwise manner for a duration of between 1 to 3 hours. In certain embodiments, the reaction product is, in a final step, worked-up and crystallised.

[0059] Preferably the alkylation and HCI salt formation steps take place under an inert atmosphere, preferably a nitrogen atmosphere. Preferably the yield of step (b) is greater than 85%, most preferably greater than 90%.

[0060] Advantageously, it has been found that DMF is a particularly suitable solvent for this step. This is because it has been found to reduce the poisoning of the catalyst used in the subsequent hydrogenolysis step. Although the use of DMF has been found to introduce the formation of a genotoxic impurity, the work-up destroys the impurity with acid. It has also been found that avoiding the use of DMSO is particularly useful since it prevents poisoning of the catalyst used in the subsequent hydrogenolysis step (step (c)) caused by the presence of residual DMSO. In this respect, controlling the content of bromoalkanes has been found to be particularly advantageous in order to minimize the Pd catalyst poisoning in the subsequent step. DMAc has also been found to be a particularly useful solvent in the reaction and provides the advantage of avoiding completely any formation of genotoxic impurities (2-((trans-4-(dibenzylamino)cyclohexyl)oxy)-N,N- dimethyl-2-(pentyloxy)acetamide) and optionally other impurities.

[0061] Conversion to the acid salt form has been found to be useful since it allowed for an improvement in purity of the final product and also since it was not possible to isolate the compound of Formula IIIA as a free base. Furthermore, it has been found thatconverting the product into a HCI salt form using at least about 1.5 equivalents of HCI at about 35 to about 45 °C, preferably about 40 °C, reduces the presence of impurity 2- ((trans-4-(dibenzylamino)cyclohexyl)oxy)-N,N-dimethyl-2-(pentyloxy)acetamide). The order of addition of the components of the reaction mixture has also found to be important in preparing the HCI salt form. In this respect, adding EtOAc first, followed by HCI in EtOAc, at a temperature of about 15 to about 25 °C, preferably about 20 °C, and then adding the reaction product of the alkylation step in preferably about 3 to about 6 hours at substantially the same temperature, before heating to about 35 to about 45 °C, preferably 40 °C, has been found to be advantageous in reducing the formation of impurity 2-((trans- 4-(dibenzylamino)cyclohexyl)oxy)-N,N-dimethyl-2-(pentyloxy)acetamide). Finally, stirring the reaction mixture for about 14 to about 22, preferably about 16 to about 20, hours at a temperature of about 40 to about 60 °C following the addition of all the reaction mixture components specified in the preceding sentence, and subsequently cooling to approximately room temperature, has been found to be advantageous in that it improves the filtration ability of the composition. The addition of heptane in the HCI formation phase is beneficial to improve the control of precipitation / crystallization.Step (c)

[0062] The compound of Formula (IIIA) from step (b) is deprotected to produce a compound of Formula (IVA), optionally wherein both compounds are in a salt form.

[0063] Preferably the deprotection is a hydrogenolysis reaction. While any suitable reagents may be used that are typically used in hydrogenolysis processes, particularly preferred is the use of hydrogen together with a Pd / C catalyst. In certain embodiments, about 2 to about 5 wt% Pd / C catalyst is used, preferably about 2.5 to about 3.5 wt%, most preferably about 3% wt%. In certain embodiments, the hydrogenolysis takes place at a temperature of about 20 °C to about 60 °C, preferably about 45 °C to about 55 °C. Preferably the reaction takes place in the presence of an ethanol solvent, although any suitable solvent may be used. Preferably ethanol is used as a solvent in an amount of at least 4V, preferably about 5 V. An approximately 90%v / v to 100%v / v ratio (i.e., a 9: 1 ratio) of ethanokwater solvent mix could be used, which has been found to prevent precipitation during sampling or filtration if more catalyst was required (improves the solubility of the monobenzylated intermediate). EtOH:H2O about 9: 1 has been found to particularly improve the solubility of the intermediate in the temperature range of about 20-50 °C. This is useful when sampling the reaction, as it is required to cool down the reaction from about 50 °C to about 30 °C for safety reasons, or in the case of needing to filter the catalyst.

[0064] Any suitable conditions for hydrogenolysis may be used, including catalytic transfer hydrogenation with a suitable hydrogen source such as ammonium formate, aswill be readily understood. Particularly preferred is the addition of hydrogen under a pressure of between about 0.5 to about 1.1 MPa, preferably about 0.6 to about 1.0 MPa. The addition of hydrogen should be added under this pressure, while the temperature of the reaction is gradually increased to no more than about 50 °C, preferably wherein the temperature is gradually increased to about 50 °C.

[0065] The reaction to produce the compound of Formula (IVA) is preferably carried out under a hydrogen atmosphere, and during sampling or load of reagents a nitrogen atmosphere is present. Finally, the reaction products are worked-up and purified in a suitable manner. During the work-up it has been found that addition of ethyl acetate to the filtrate, in a dropwise manner leads to more controlled crystallization of the compound of Formula (IVA). Preferably the ethyl acetate is added slowly, over a period of at least 1 hour, preferably between about 1 to about 3 hours. Preferably the yield of step (c) is greater than 85%, most preferably greater than 90%. Preferably the compound of Formula (IVA) is obtained in a salt form, preferably a HCI salt form.Use of alternative protecting groupsIt has been found that alternative protecting groups to benzyl can be used in the process of preparing trans-4-(pentyloxy)cyclohexanamine (compound of Formula (IV)). In one alternative embodiment, the protecting group used is a Boc protecting group. In a further alternative embodiment, the protecting group is an Fmoc protecting group. In a further alternative embodiment, the protecting group is / V-2,5-dimethylpyrrole protecting group. It will be readily understood that some of the conditions and features of the process steps (a) to (c), relating to benzylation, are also applicable to the use of Boc and Fmoc as protecting groups. Furthermore, some of the conditions and features of the process steps (a) to (c), relating to benzylation, are also applicable to the use of / V-2,5-dimethylpyrrole as the protecting group. However, certain alternative reaction conditions and features are preferred, when using Boc or Fmoc as protecting groups in the process of preparing the compound of Formula (IV), as described below.Boc protecting group

[0066] In embodiments relating to the use of a Boc protecting group, the compound of Formula (I) is converted to a compound of Formula (IV) according to the following:

[0067] In certain embodiments, Formula (IIB) is produced, although it is also envisaged that the amine group could also be protected with two Boc groups. Preferably di-tert-butyl dicarbonate (BoczO) is used to prepare the compound of Formula (IIB) from Formula (I). In certain embodiments, about 0.1 to about 2 equivalents of BOC2O are used, preferably about 0.2 to about 1.5 equivalents and most preferably about 0.33 to about 1.25 equivalents. Any suitable solvent may be used, but particularly preferred is DCM. Preferably the reaction takes place for between about 10 to about 30 hours, preferably about 15 to about 23 hours, most preferably about 17 to about 19 hours or about 18 hours. Preferably the temperature of the reaction is between about 15 to about 25 °C, preferably about 17 to about 23 °C or about 20 °C. In certain embodiments the reaction takes place in the presence of (1) EtsN and DCM; (2) NaHCOs, DCM and water; (3) K2CO3, DCM and water; (4) NaOH, dioxane and water; or (5) K2CO3, DCM and water.

[0068] Typically, the crude reaction product is then worked up and filtered to obtain the final product. Preferably the yield of the reaction product is at least 70 percent, or at least 75 percent, or at least 80%, or at least 85%, or at least 90%. In certain embodiments, the purity of the final product is at least about 85%, preferably at least 90 or 95%.

[0069] In a step (b), the compound of Formula (IIB) from step (a) is alkylated with an alkylating agent to prepare a compound of Formula (III), wherein PG = Boc. In certain embodiments, this step is carried out in any suitable solvent, preferably DMF under an inert atmosphere, preferably a nitrogen atmosphere. In certain embodiments, the alkylating agent is any suitable alkylating agent as described in relation to benzylation. Preferred is 1-bromopentane. Preferably, the compound of Formula (IIB) is reacted with about 1 to about 2 equivalents of 1-bromopentane, preferably about 1.3 to about 1.8 equivalents, most preferably about 1.5 (or 1.50) equivalents. In certain embodiments, the reaction temperature is between about -5 °C to about 5 °C, preferably about 0 °C. Preferably, the reaction is carried out under conditions sufficient to prepare a compound of Formula (IIIB). Although in the reaction scheme above, step (c) appears to be a separate step to step (b), in a preferred embodiment step (c) takes place in the work up of the crude reaction product of step (b). Preferably, an acid in a solvent is introduced in this step inorder to deprotect the compound of Formula (IIIB) (which is an intermediate) and also generate the HCI salt form of the compound of Formula (IV). In certain embodiments, HCI and preferably ethyl acetate are the acid and solvent respectively. In a final step the reaction product is isolated. In certain embodiments, the yield of product obtained is at least 30%, preferably at least 35% or at least 40%. In certain embodiments, the purity of the product obtained is at least 85%, preferably at least 90% or at least 95% measured by HPLC.

[0070] It has been found that the use of a Boc-protecting group can result in over alkylation to form a di-alkylated impurity (i.e., the compound of Formula (IV) having the N-group also alkylated), which can result in a lower product yield being obtained. It has surprisingly been found that the use of a phase transfer catalyst in step (b), preferably tetrabutylammonium bromide (optionally also tetrabutylammonium iodide) helps to avoid the formation of the di-alkylated impurity. In certain embodiments, the biphasic reaction with phase transfer catalyst and a base is carried in any suitable combination of an organic solvent and water. In certain embodiments, the organic solvent is toluene, DMF, 1,4- dioxane, THF or DCM. Preferably, the solvent is a combination of toluene and water, wherein the amount of water is below 50% (v / v); more preferably the amount of water is below 25% (v / v). In certain embodiments, the compound of Formula (IIB) is reacted in the presence of about 0.01 to about 0.5 equivalents of the phase transfer catalyst, preferably about 0.01 to about 0.05 equivalents. In certain embodiments any suitable base can be used. Preferably, the base may be selected from Na or K salts (M); MOH, M2CO2, MHCO3, M3PO4, M2HPO4. Preferably, the compound of Formula (IIB) is reacted in the presence of about 3 to about 5 equivalents of KOH. In certain embodiments, the reaction temperature is between about 50 °C to about 120 °C, preferably about 80 °C.N-2,5-Dimethylpyrrole protecting group

[0071] One preferred embodiment of the invention relates to the use of / V-2,5- dimethylpyrrole as the protecting group of trans-4-aminocyclohexanol (compound of Formula (I)) in order to prepare trans-4-(pentyloxy)cyclohexanamine (compound of Formula (IV)). Advantages of this protecting group relates to the atom efficiency since the intermediate (IIC) has lower molecular weight than (IIA) or (IIB); also, the chromophore present in this protecting group, makes it UV visible thus enabling the reaction progress to be followed by HPLC; and, finally, this protecting group fully blocks the amino group from dialkylation in the subsequent step.

[0072] In embodiments relating to the use of a / V-2,5-dimethylpyrrole protecting group, the compound of Formula (I) is converted to a compound of Formula (IV) according to the following:Formula (I) Formula (IIC) Formula (IIIC) Formula (IV).HCI

[0073] In step (a), hexane-2, 5-dione is used to prepare the compound of Formula (IIC) from Formula (I) by cyclisation. In certain embodiments, the reaction takes place in the presence of about 1 to about 3 equivalents of acetic acid, preferably about 1 to about 2.4 equivalents and most preferably about 2 to about 2.4 equivalents. Any suitable solvent may be used, but particularly preferred is MeOH. Preferably the reaction takes place for between about 4 to about 16 hours, preferably about 6 to about 14 hours, most preferably about 8 to about 12 hours or about 10 hours. Preferably the temperature of the reaction is between about 25 to about 85 °C, preferably about 40 to about 70 °C or about 65 °C.

[0074] Typically, once conversion into Formula IIC is complete according to HPLC, TLC or LCMS, about 5 vol. of water is added before cooling down to 20 °C and perform seeding. The solid is left under stirring overnight at 5°C. Preferably the solid is filtered and washed with water (two times 4 vol.) to obtain the final product. Preferably the yield of the reaction product is at least 40 %, or at least 47 %, or at least 56 %. In certain embodiments, the purity of the final product is at least about 85%, preferably at least 90 or 95%.

[0075] In a step (b), the compound of Formula (IIC) from step (a) is alkylated with an alkylating agent to prepare a compound of Formula (IIIC), wherein PG = / V-2,5- dimethylpyrrole. In certain embodiments, this step is carried out in other suitable polar aprotic solvents, like amide based (DMF, DMAc, NMP,) or DMSO under an inert atmosphere; preferably, the reaction is carried out in DMF, preferably under a nitrogen atmosphere. In certain embodiments, the alkylating agent is any suitable alkylating agent as described in relation to benzylation. Preferred is 1-bromopentane. Preferably, the compound of Formula (IIC) is reacted with about 1.5 to about 3.5 equivalents of 1-bromopentane, preferably about 2 to about 3 equivalents, most preferably about 2.5 (or 2.50) equivalents. In certain embodiments, the reaction is carried out in the presence of a base, preferably wherein the base is tBuOK. In certain embodiments, the reaction temperature is between about -5 °C to about 5 °C, preferably about -3 °C. Preferably, the reaction is carried out under conditions sufficient to prepare a compound of Formula (IIIC).

[0076] The compound of Formula (IIIC) from step (b) is deprotected to produce a compound of Formula (IV), optionally (IV) compound is in a salt form.

[0077] Preferably the deprotection is an aminolysis reaction, particularly preferred is the use of hydroxylamine hydrochloride. In certain embodiments, about 10 equivalents of hydroxylamine hydrochloride is used. In certain embodiments, the hydrolysis takes place at a temperature of about 60 °C to about 100 °C, preferably about 65 °C to about 85 °C, preferably at about 80 °C. Preferably the reaction takes place in the presence of an ethanol solvent, although any suitable solvent may be used. Preferably ethanol is used as a solvent in an amount of at least 50 V, preferably about 66 V. An approximately 66%v / v to 100%v / v ratio (i.e., a 9: 1 ratio) of ethanokwater solvent mix can be used.

[0078] Any suitable conditions for hydrolysis may be used, including basic hydrolysis in the presence of a base such as NaOH, TEA or NazCCh; preferably, the base is NaOH. In certain embodiments, about 2.5 to about 5 equivalents of NaOH is used.

[0079] Finally, the reaction products are worked-up and purified in a suitable manner. During the work-up it has been found that extraction performed by acidifying to pH 2-3 removes impurities related to starting material, such as 2,5-hexanedione. Then, the pH is adjusted to 13-14 and the product (IV) is extracted with MTBE, to remove the impurity dioxime of 2,5-hexanedione. Preferably the yield of the reaction product is at least 37%, or at least 60%, or at least 79%. In certain embodiments, the purity of the final product is at least about 85%, preferably at least 90 %.Other protecting groups

[0080] Other groups known in the art to function as protecting groups may be suitable for use in the process. In particular, Fmoc may be used as the protecting group in a further alternative embodiment. When using Fmoc, the solvents could be selected from a mixture of acetonitrile and water or DCM. In certain embodiments, the reaction could be carried out at or room temperature and in the presence of a base, for example, NazCOs or NEts or any other suitable base. One particular example would be the use of NEts in a mixture of 1,4-dioxane and water. Deprotection of the Fmoc protecting group can be carried out by any suitable deprotecting agent, such as a base, for example, piperidine or piperazine.Preparation of 5,7-Dimethylpyrazolo[l,5-a]pyrimidine-3-carboxylic acid (Compound of Formula (VII))Formula (VII)

[0081] In certain embodiments, the compound of Formula (VII) is prepared according to the following reaction pathway:

[0082] While a number of different protecting groups have been identified for use in steps (a) to (c) of the synthetic route, it can be readily understood that the conditions of steps (d) to (e) do not generally change depending on the particular protecting group, and associated method steps, used in steps (a) to (c).Step (d)

[0083] In certain embodiments, a step (d) of preparing ethyl 5, 7- dimethylpyrazolo[l,5-a]pyrimidine-3-carboxylate (a compound of Formula (VI)) from ethyl 3-aminopyrazole-4-carboxylate (a compound of Formula (V)) is carried out. The compound of Formula (V) may be obtained commercially or prepared by methods known in the art. Preferably the step involves a cyclisation reaction, preferably carried out with acetylacetone. In certain embodiments, the cyclisation is performed in the presence of a solvent comprising toluene and acetic acid. In alternative embodiments, the reaction with acetylacetone can be carried out in an acetic acid and ethanol solvent mix.

[0084] In certain embodiments, between about 0.2 to about 2 equivalents of acetic acid is added, preferably between about 0.4 to about 1.5 equivalents or between about 0.5 to about 1 equivalents, optionally about 0.68 equivalents. In certain embodiments, between about 0.5 to about 2 equivalents, or about 0.8 to about 1.5, or about 1 to about 1.5, or about 1.05 to about 1.3, or about 1.2 equivalents of acetyl acetone is used.

[0085] In certain embodiments, the cyclisation reaction takes place at a temperature of from about 20 °C to about 70 °C, preferably about 35 to about 65 °C, preferably about 45 to about 55 °C, most preferably about 50 °C. In certain embodiments, the reaction is carried out for between about 4 to about 20 hours, preferably about 5 to about 12 hours or about 5 to about 8 hours. In certain embodiments, the reaction mixture is subsequently heated to a higher temperature of between about 50 to about 80 °C, preferably about 60 to about 70 °C, most preferably about 65 °C. Preferably, in this subsequent step n-heptane is added to the reaction mixture. Preferably at least some of the n-heptane is added dropwise.

[0086] In certain embodiments, the crude reaction product is worked-up and purified. Preferably, seeds of the compound of Formula (V) are added to the mixture during crystallisation. Preferably, said seeds are added in an amount of between about 0.05 to about 0.15 wt%. In certain embodiments, the crystallisation is carried out in a toluene: n-heptane mixture, preferably in about a 1:6 volume ratio. In preferred embodiments, the crystallisation is carried out in a toluene: n-heptane mixture when the reaction solvent is a toluene and acetic acid mix.

[0087] In alternative embodiments, the crystallisation is carried out in an ethanol :n- heptane mix when the reaction solvent is an ethanol and acetic acid mix. Preferably, the ratio of ethanolm-heptane is about 5:95. Surprisingly, it has been found that crystallisation using an ethanol -heptane solvent mix can be tailored in order to favour either the formation of polymorph I or polymorph II of the compound of Formula VI. Preferably in this alternative embodiment, the compound of Formula VI is crystallised initially using ethanol. In a subsequent step, various amounts of n-heptane are sequentially added. It has been surprisingly found that adding about 11 to about 13 V (V being relative to the mass of the compound of Formula V, key starting material), preferably about 12 V, of n- heptane polymorph II of the compound of Formula VI was obtained. The 12 V achieved complete dissolution of the material at approximately 65 °C and the product was obtained upon cooling. However, surprisingly it was found that adding about 7 to about 9 V, preferably about 8 V, of n-heptane, in a sequential manner, polymorph I of the compound of Formula VI was obtained. The addition of 8 V of n-heptane resulted in the formation of a slurry at approximately 65 °C and the product was isolated upon cooling. Preferably, the cooling when favouring polymorph I comprises decreasing the temperature of the reaction mixture to about 15 to about 25 °C, preferably about 20 °C, further preferably stirring for approximately 6 to 10 hours, most preferably about 8 hours. Preferably, there is a further step of reducing the temperature further to between about 3 to about 10 °C, preferably about 5 °C, preferably for approximately 15-60 mins, most preferably for about 20 to about 40 minutes or about 30 minutes. Preferably, the cooling when favouring polymorph II comprises: the temperature is decreased directly to a lower temperature, for example about 0 to about 10 °C, preferably about 3 to about 7 °C, or about 5 °C, further preferably stirring for approximately 6 to 10 hours, most preferably about 8 hours. Precipitating from ethanol and n-heptane has been found to offer better control of the solid properties, for example, particle size is significantly bigger and more crystalline when compared with using toluene / acetic acid.

[0088] In certain embodiments, the reaction is carried out under an inert atmosphere, preferably a nitrogen atmosphere. In certain embodiments, the yield of the final product obtained is greater than 80%, or greater than 85%, preferably greater than 90%. Preferably the purity of the compound of Formula (VI) obtained is greater than about 95%, preferably greater than 99% or greater than 99.5% measured by HPLC.Step (e)

[0089] In certain embodiments, a step (e) of preparing ethyl 5,7- dimethylpyrazolo[l,5-a]pyrimidine-3-carboxylate (a compound of Formula (VII)) is carried out. Preferably, this step is a hydrolysis reaction carried out under suitable conditions for hydrolysis to take place. In certain embodiments, the ester hydrolysis takes place in the presence of a base. Any suitable base may be used, but preferably NaOH is used. Preferably about 1 to about 2 equivalents of NaOH are used, most preferably about 1.1 to about 1.4 equivalents or about 1.2 to about 1.4 equivalents or about 1.3 equivalents. In certain embodiments, the reaction takes place for about 2 to about 10 hours, preferably about 3 to about 8 hours. Preferably water is also added to the reaction mixture. In certain embodiments, the reaction takes place at about 40 to about 80 °C, preferably about 50 to about 70 °C, preferably about 55 to about 65 °C or at about 60 °C. It has been found that the yield of the decarboxylation of the ester group is dramatically improved (i.e., the amount of decarboxylation side product produced is reduced) when performed in the presence of these amounts of aqueous NaOH and the specified temperatures. On acidification of the reaction mixture, it has been found that if it is too hot the product is decarboxylated. The by-product can be removed, but there is significant product loss. The temperature of the acidification therefore needs to be controlled and preferably the drying needs to be done in three stages to ensure that the residual HCI is removed before heating the product to full drying temperature.

[0090] Step (e) typically comprises a second step of acidification. In said step, preferably the temperature is reduced to about 40 to about 50 °C, preferably about 44 °C and an acid is added. Preferably the acid is HCI in an amount of about 1 to about 2 equivalents, preferably about 1.4 equivalents. The acid is added dropwise in some embodiments.

[0091] Alternatively, the acid used in the acidification step may be citric acid. Preferably citric acid is added dropwise to the reactor. In certain embodiments, the citric acid is added in an amount of between about 0.5 to about 3 equivalents, preferably about 1 to about 2 equivalents, most preferably about 1.5 equivalents. The reaction takes place at between about 40 to about 50 °C, preferably about 44 °C. Alternatively, higher temperatures may be used, for example between about 50 to about 70 °C, preferably about 60 °C. The use of citric acid in this way has been found to improve crystallinity and solid properties of the product of this step. In particular, the crystallization suspension with citric acid has been found to be more stable than with HCI. Furthermore, the use of citric acid has been found to help reduce the amount of decarboxylation. When citric acid is used in the acidification step, the compound of Formula (VII) prepared in step (e) is isolated by precipitation in EtOH and subjecting the reaction mixture to repeated heatingto about 50-55 °C and cooling to about 25-35 °C. This has been found to be advantageous in that the solids are isolated with improved properties, such as fewer lumps and less agglomeration.

[0092] The crude reaction product is worked-up and purified to obtain the final product. In certain embodiments, seeds of the compound of Formula (VII) are used to promote crystallisation, preferably wherein between about 0.3 to about 1 wt% seeds are added, preferably about 0.5 wt%.

[0093] In certain embodiments, the reaction is carried out under an inert atmosphere, preferably a nitrogen atmosphere. In certain embodiments, the yield of the final product obtained is greater than 80%, or greater than 85%, preferably greater than 90% or 95%. Preferably the purity of the compound of Formula (VII) obtained is greater than about 95%, preferably greater than 99% or greater than 99.5% measured by HPLC.Preparation of 5,7-dimethyl- / V-((l / ?,4 / ?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5- a]pyrimidine-3-carboxamide (compound of Formula (A))Formula (A)

[0094] The final step of the synthetic route may generally be described by the following:Formula (VIIJ Formula (A}

[0095] Herein this step is typically denoted step (f). Although steps (a) to (e) are described herein, it will be readily understood that the compounds of Formula (IV)(optionally in salt form) and Formula (VII) could be obtained through alternative processes and still used in this step (e).

[0096] In certain embodiments the compound of Formula (IV) is in a HCI salt form and is converted into the free base form by reaction with a suitable base. Preferably the base is NaOH and the reaction takes place in the presence of H2O and MTBE. In alternative embodiments, the compound of Formula (IV) can be used in the amide coupling step (f) without reaction with a base i.e., in the acid salt form and not in the free base form.

[0097] In certain embodiments the compound of Formula (IV) is converted to the free base form using a base, preferably NaOH. In certain embodiments, between about 1 to about 2 equivalents of NaOH are added, preferably about 1.2 to about 1.6 equivalents, most preferably about 1.4 equivalents. Preferably this reaction is carried out in the presence of MTBE, most preferably wherein MTBE is present in an amount of about 5 to about 10 V, most preferably about 8 V.

[0098] In an initial step the compound of Formula (VII) is reacted with carbonyldiimidazole (CDI), preferably in the presence of a DMF solvent. Surprisingly it has been found that the use of CDI as the amide coupling reagent provides significant benefits over the amide coupling reagents used in the WO '776 process. In the WO '895 and WO '841 processes, HATU is used as the amide coupling reagent. The use of HATU, having a high molecular weight, is less efficient in terms of atom economy; HATU's mediation also produces more by-products difficult to remove, e.g. tetra methyl urea and hydroxyazabenzotriazole derivative salts, thus the purification step of compound of Formula (A) is more laborious. It is known that amide coupling with HATU also requires concomitant use of a base such as DIPEA. In the WO '776 process HOPO is used. It has been found that HOPO is a class 2 impurity which needs to be strictly controlled in the final API. The use of CDI has been found to avoid the need to use HOPO and CDI does not produce any such serious impurities in the final API product. Furthermore, the use of CDI avoids the need to add additional base to the reaction mixture since the CDI is able to also function as base. In WO '776 the use of EDC and DIPEA in combination with HOPO is required. In the present invention, only CDI (in a DMF solvent) is required. This provides a simplified process step, available at lower cost. CDI is also considerably less expensive than HATU, EDC or HOPO and thus provides a more cost-effective process.

[0099] In certain embodiments, CDI is added in an amount of between about 0.5 to about 2 equivalents, preferably about 0.7 to about 1.5 equivalents, most preferably about 1.2 (or 1.20) equivalents to react with the compound of Formula (VII). Advantageously, the use of CDI in the coupling step produces a gas, CO2, which escapes the reactor and drives the reaction to completion. This enables low amounts of CDI and other reactants to be used.[OO1OO] The coupling with CDI preferably takes place at a temperature of about 15 to about 35 °C, preferably about 20 to about 30 °C or about 25 to about 30 °C. Followingthe reaction with CDI, water may be added for the hydrolysis of CDI. Following this step, the intermediate coupled with CDI may be reacted with the free based compound of Formula (IV) in MTBE to prepare the compound of Formula (A).[OO1O1] It has also advantageously been found that the resulting imidazole is DMF soluble and enough to keep the reaction medium basic for catalysing the coupling. It also leads to a simplification of the work-up steps and crystallization procedures, epimerization free, as well as reducing the overall number of by-products, compared to HOPO / EDCI / DIPEA coupling.

[0102] In certain embodiments, the compound of Formula (A) is crystallised according to the following procedure:• Temperature increase to between 30 to 50 °C, preferably about 40 °C;• Water added dropwise for a period of between 30 mins to 4 hours, preferably 1 to 2 hours and preferably in an amount of 1 to 4 V, preferably about 2 V;• Mixture stirred for between 1 to 6 hours, preferably about 2 to about 5 hours before cooling to less than 25 °C, preferably cooling to about 20 °C;• Mixture stirred for 10-15 hours before addition of, preferably about 4 V of, water dropwise for 1 to 3 hours;• Mixture stirred for 3-6 hours;• Solid centrifuged and washed with DMF:H2O (about 1: 1), before washing with water and drying under vacuum.

[0103] In certain embodiments, the reaction is carried out under an inert atmosphere, preferably a nitrogen atmosphere. In certain embodiments, the yield of the final product obtained is greater than 70%, or greater than 75%, preferably greater than 80%. Preferably the purity of the compound of Formula (A) obtained is greater than about 95%, preferably greater than 99% or greater than 99.5%, measured by HPLC.

[0104] In certain embodiments, the process of the present invention produces the crude compound of Formula (A) having low levels of impurities present. In particular, the process produces the crude compound of Formula (A) having low levels of Impurities A to F.

[0105] In certain embodiments, the crude compound of Formula (A) produced by the process of the present invention comprises one or more, or all, of the Impurities A to F, preferably individually in an amount of less than or equal to about 0.15 %w / w, preferably less than or equal to about 0.10 %w / w, preferably less than or equal to about 0.05 %w / w, preferably less than or equal to about 0.01 %w / w.

[0106] Advantageously, it has been found that the use of a Boc or / V-2,5- dimethylpyrrole protecting group in steps (a) and (b) of the process avoids the formation of certain impurities such as Impurity E. In particular, it has been found that the use of an / V-2,5-dimethylpyrrole protecting group avoids the formation of any specific impurity derived from the / V-2,5-dimethylpyrrole group in the final API. Especially advantageous is that the use of an / V-2,5-dimethylpyrrole protecting group avoids the formation / presence of any dialkylated (dibenzylated) impurity (i.e., the compound of Formula IV with the N- group also benzylated).

[0107] Acceptable levels of Impurities A, B, D and F has been identified as less than or equal to about 0.10 %w / w. Acceptable levels of Impurities C and E have been identified as being less than or equal to about 0.15 %w / w. In certain embodiments, the crude compound of Formula (A) comprises Impurity A in an amount of less than or equal to about 0.10 %w / w, preferably less than or equal to about 0.05 %w / w, preferably less than or equal to about 0.01 %w / w. In certain embodiments, the crude compound of Formula (A) comprises Impurity B in an amount of less than or equal to about 0.10 %w / w, preferably less than or equal to about 0.05 %w / w, preferably less than or equal to about 0.01 %w / w. In certain embodiments, the crude compound of Formula (A) comprises Impurity C in an amount of less than or equal to about 0.15 %w / w, preferably less than or equal to about 0.10 %w / w, preferably less than or equal to about 0.05 %w / w, preferably less than or equal to about 0.01 %w / w. In certain embodiments, the crude compound of Formula (A) comprises Impurity D in an amount of less than or equal to about 0.10 %w / w, preferably less than or equal to about 0.05 %w / w, preferably less than or equal to about 0.01 %w / w. In certain embodiments, the crude compound of Formula (A) comprises Impurity E in an amount of less than or equal to about 0.15 %w / w, preferably less than or equal to about 0.10 %w / w, preferably less than or equal to about 0.05 %w / w, preferably less than or equal to about 0.01 %w / w. In certain embodiments, the crude compound of Formula (A) comprises Impurity F in an amount of less than or equal to about 0.10 %w / w, preferably less than or equal to about 0.05 %w / w, preferably less than or equal to about 0.01 %w / w.

[0108] In certain embodiments, the crude compound of Formula (A) comprises Impurity A in an amount of less than or equal to about 0.10 %w / w, Impurity B in an amount of less than or equal to about 0.10 %w / w, Impurity C in an amount of less than or equal to about 0.15 %w / w, Impurity D in an amount of less than or equal to about 0.10 %w / w, Impurity E in an amount of less than or equal to about 0.15 %w / w and Impurity F in an amount of less than or equal to about 0.15 %w / w. In certain embodiments, thecrude compound of Formula (A) comprises one or more, or all, of Impurities A to F in an amount lower than the limit of quantification (LOQ), considered to be less than about 0.05 %w / w. Therefore, Impurities A to F are present in the crude compound of Formula (A) prepared according to the process of the invention in particularly acceptable low amounts.

[0109] In certain embodiments, impurities other than those containing a pyrazolopyrimidine group may be present. In certain embodiments, the crude compound of Formula (A) comprises Impurity G. Optionally this impurity is present in addition to one or more of Impurities A to F. Preferably, Impurity G is present in the crude compound of Formula (A) in an amount of less than about 0.5 %w / w, preferably less than about 0.4 %w / w, preferably less than about 0.3 %w / w, preferably less than about 0.2 %w / w, preferably less than about 0.1 %w / w, or preferably less than about 0.05 %w / w.Impurity GThe compound of Formula (A)Formula (A)

[0110] WO' 776 has identified the compound of Formula (A) and provided characterization of this compound. Compound of Formula A is present in four polymorphic forms: Form A (used in previous phase I clinical trials), Form B (thermodynamically most stable form at room temperature), Form C (metastable form) and Form D (hydrated form). Particularly preferred are Forms A and B, which are defined below.

[0111] Crystalline Form A may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 5.7 ± 0.2, 11.5 ± 0.2, 11.8 ± 0.2, and 12.8 ± 0.2. In certain embodiments, such a compound in crystalline form may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 5.7 ± 0.2, 11.5 ± 0.2, 11.8 ± 0.2, 12.8 ± 0.2, 17.2 ± 0.2, 18.7 ± 0.2, 19.6 ± 0.2, 22.3 ± 0.2, and 27.3 ± 0.2.

[0112] In certain embodiments, the compound in crystalline polymorphic Form A is characterized by the X-ray powder diffraction pattern expressed in terms of diffractionangle 20, and optionally inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak) as set forth in Table 1.TABLE 1 - X-RAY POWDER DIFFRACTOGRAM DATA OF CRYSTALLINE POLYMORPHIC FORM A.

[0113] The relative intensity of the peak at said diffraction angles (20) is at least 20% with respect to the most intense peak in the X-ray powder diffraction pattern.

[0114] In certain embodiments, such compound in crystalline form may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (29): 5.7 ± 0.2, 12.8 ± 0.2, 14.4 ± 0.2, and 17.1 ± 0.2. In certain embodiments, such compound in crystalline form may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 5.7 ± 0.2, 12.8 ± 0.2, 14.4 ± 0.2, 17.1 ± 0.2, 22.3 ± 0.2, 23.0 ± 0.2 and 27.2 ± 0.2.

[0115] In certain embodiments, the compound in crystalline polymorphic Form A is characterized by the X-ray powder diffraction pattern expressed in terms of diffractionangle 20 and optionally relative intensity (expressed as a percentage with respect to the most intense peak) as set forth in Table 2.TABLE 2 - X-RAY POWDER DIFFRACTOGRAM DATA OF CRYSTALLINE POLYMORPHIC FORM A.

[0116] In certain embodiments, the pharmaceutical composition is further characterized by the feature that the relative intensity of the peak at said diffraction angles (20) is at least 20% with respect to the most intense peak in the X-ray powder diffraction pattern.

[0117] The compound in crystalline polymorphic Form A may exist in a monoclinic crystal system and have a P2i / c space group. The compound in crystalline polymorphic Form A may be characterized by the crystallographic unit cell parameters as set forth in Table 3.TABLE 3 - UNIT CELL PARAMETERS OF CRYSTALLINE POLYMORPHIC FORM A.

[0118] Crystalline form B may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 4.0 ± 0.2, 10.9 ± 0.2, 12.3 ± 0.2, and 16.2 ± 0.2. In certain embodiments, the compound in crystalline form may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 4.0 ± 0.2, 10.9 ± 0.2, 12.3 ± 0.2, 16.2 ± 0.2, 20.2 ± 0.2, 21.1 ± 0.2, 21.5 ± 0.2, 24.7 ± 0.2, 27.6 ± 0.2.

[0119] In certain embodiments, the compound in crystalline polymorphic Form B is characterized by the X-ray powder diffraction pattern expressed in terms of diffraction angle 20, and optionally inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak) as set forth in Table 4.TABLE 4 - X-RAY POWDER DIFFRACTOGRAM DATA OF CRYSTALLINE POLYMORPHIC FORM B.

[0120] The relative intensity of the peak at said diffraction angles (20) is at least 20% with respect to the most intense peak in the X-ray powder diffraction pattern.

[0121] The compound in crystalline form may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (29): 4.2 ± 0.2, 10.9 ± 0.2, 11.5 ± 0.2, and 12.4 ± 0.2. In certain embodiments, the compound in crystalline form may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 4.2 ± 0.2, 10.9 ± 0.2, 11.5 ± 0.2, 12.4 ± 0.2, 16.3 ± 0.2, 21.5 ± 0.2, 22.3 ± 0.2, 22.4 ± 0.2, 22.9 ± 0.2 and 23.0 ± 0.2.

[0122] The compound in crystalline polymorphic Form B may be characterized by the X-ray powder diffraction pattern expressed in terms of diffraction angle 20 and optionally relative intensity (expressed as a percentage with respect to the most intense peak) as set forth in Table 5.TABLE 5 - X-RAY POWDER DIFFRACTOGRAM DATA OF CRYSTALLINE POLYMORPHIC FORM B.

[0123] In certain embodiments, the pharmaceutical composition is further characterized by the feature that the relative intensity of the peak at said diffraction angles (20) is at least 20% with respect to the most intense peak in the X-ray powder diffraction pattern.

[0124] The compound in crystalline polymorphic Form B may exist in a monoclinic crystal system and have a P2i / c space group. The compound in crystalline polymorphic Form B may be characterized by the crystallographic unit cell parameters as set forth in Table 6.TABLE 6 - UNIT CELL PARAMETERS OF CRYSTALLINE POLYMORPHIC FORM B.

[0125] Particularly preferred herein is the formation of polymorph form B. Typically the final steps of the process relate to carrying out process steps to isolate polymorph form B. Therefore, various methods are described that preference the formation of this polymorphic form.Recrvstallisation

[0126] In certain embodiments, the compound of Formula (A) is recrystallised in order to prepare the compound of Formula (A) in a desired crystalline form. In certain embodiments, the crystalline form is form B.

[0127] In certain embodiments the crystalline product of the amide coupling step comprises a mixture of polymorphic forms A and B. Preferably, recrystallization of the compound of Formula (A) takes place with a mixture of MEK and n-heptane. In certain embodiments the recrystallization protocol comprises one or more or all of the following steps, typically under an inert atmosphere (such as a nitrogen atmosphere): i) dissolving the compound of Formula (A) in methyl ethyl ketone (MEK) at a temperature of about 15 °C to about 35 °C to produce a solution; ii) filtering the solution; iii) recrystallising the compound of Formula (A) with n-heptane between about 14 to about 25 °C, preferably about 17 ± 3 °C; iv) removing the MEK by distillation whilst maintaining the temperature at 17±3° C; and v) drying the resultant cake at a temperature not more than 35 °C.

[0128] In certain embodiments MEK is added in an amount of about 7 to about 15 V, preferably in a first amount of about 6V and a subsequent amount of about 5 V. Preferably this takes place at a reactor temperature of preferably about 25 °C. The solution is stirred until the solid is dissolved, preferably for about 1 to about 3 hours.

[0129] N-heptane is preferably added to the solution in an amount of about 2 to about 5 V, preferably about 3.6 V. In certain case the temperature is set for about 2 to about 4 hours. Concentration under vacuum preferably takes place to prepare the crystal form B.

[0130] In certain embodiments, the yield of this step is at least 85%, preferably at least 90%, most preferably at least 95%. As measured by HPLC, preferably the purity is at least 99%, or at least 99.5% or wherein the purity is 100%.

[0131] It has been found that the recrystallization protocol identified herein advantageously allows the isolation of polymorph form B with 100% purity.

[0132] In certain embodiments, the purified crystalline form of the compound of Formula (A) (i.e., in "drug substance" form) produced by the process of the presentinvention comprises total impurities in an amount of less than or equal to about 0.5 %w / w, preferably less than or equal to about 0.1 %w / w, preferably less than or equal to about 0.05 %w / w. It has been identified that acceptable levels of impurities in the crystalline form of the compound of Formula (A) are less than or equal to 0.5 %w / w. Therefore, impurities are present, in the crystalline compound of Formula (A) produced by the process of the present invention, in an acceptable amount. It has been found that in certain embodiments, the crystalline compound of Formula (A) comprises total impurities in an amount lower than the limit of quantification (LOQ), considered to be less than about 0.05 %w / w. Therefore, all impurities in the crude compound of Formula (A), prepared according to the process of the invention, are present particularly acceptable low amounts.

[0133] In certain embodiments, the crystalline form of the compound of Formula (A) comprises Impurity C in an amount of less than or equal to about 0.15 %w / w, preferably less than or equal to about 0.10 %w / w, or less than about 0.05 %w / w and / or Impurity E in an amount of less than or equal to about 0.15 %w / w, preferably less than or equal to about 0.10 %w / w, or less than about 0.05 %w / w. It has been identified that acceptable individual levels of Impurities C and E in the crystalline form of the compound of Formula (A) are less than or equal to 0.15 %w / w. Therefore, Impurities C and E are present, in the crystalline compound of Formula (A) produced by the process of the present invention, in acceptable amounts. In certain embodiments, the crystalline compound of Formula (A) comprises Impurities C and E individually in an amount lower than the limit of quantification (LOQ), considered to be less than about 0.05 %w / w. Therefore, Impurities C and E are present, in the crude compound of Formula (A) prepared according to the process of the invention, in particularly acceptable low amounts. It is to be understood that less than a certain amount also includes the case in which none of the impurity is present. In certain embodiments, impurities other than those containing a pyrazolopyrimidine group may be present. In certain embodiments, the crystalline compound of Formula (A) comprises Impurity G. Optionally this impurity is present in addition to one or more of Impurities A to F. Preferably, Impurity G is present in the crystalline compound of Formula (A) in an amount of less than about 0.1 %w / w, preferably less than about 0.05 %w / w, preferably less than about 0.04 %w / w, preferably less than about 0.03 %w / w, preferably less than about 0.02 %w / w, or preferably less than about 0.01 %w / w. References throughout the description to the amounts of Impurities A to G are determined by HPLC. The HPLC methods used herein for Impurities A to G are described in the table below. References herein to the overall chemical purity, or total presence of impurities, of the final product of the compound of Formula (A) are also measured in accordance with HPLC test method 1.

[0134] In certain embodiments, the crystalline form of the compound of Formula (A) can be used in a pharmaceutical composition, the composition further comprising any suitable pharmaceutically acceptable carrier(s). It is particularly preferred to have a low amount of Impurities A to F present in the compound of Formula (A) when the compound is to be used in a pharmaceutical composition, and when being administered to a patent, such as to treat a disorder selected from the group consisting of Gaucher disease, Parkinson's disease, Lewy body disease, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, an anxiety disorder, major depression, polycystic kidney disease, type 2 diabetes, open angle glaucoma, multiple sclerosis, endometriosis, and multiple myeloma. In said use, a therapeutically effective amount of the compound is administered to a patient in need thereof.Jet Milling

[0135] In certain embodiments, the recrystallised compound of Formula (A) is subjected to jet milling. The recrystallised compound of Formula (A) is in polymorphicform B. Preferably the recrystallised compound of Formula (A) is first sieved in a 20-mesh sieve. The sieved material has a Dio of preferably between about 20 to about 40 pm, most preferably about 30 pm; a Dso of preferably between about 300 to about 400 pm, most preferably about 340 pm and a D90 of between about 900 to about 1000 pm, most preferably about 930 pm. In certain embodiments, following the sieving step, the sieved compound is jet milled, preferably at a feeding and milling pressure of between about 0.1 to about 0.7 MPa, preferably about 0.2 to about 0.6 MPa, preferably about 0.3 to about 0.5 MPa and most preferably about 0.4 MPa. In certain embodiments, the jet milled material has a Dio of greater than 1 pm, a D50 of between about 5 pm and about 30 pm and D90 of less than or equal to 60 pm. Advantageously, the jet milling step allows for better oral formulation preparation.Micronization

[0136] In certain embodiments, if the particle size distribution (PSD) properties of the compound are not satisfactory, then a micronization step may be performed. This means that the crystalline compound of Formula A that may be used in the preparation of a solid dosage form for end use, is micronized to reduce its particle size.

[0137] The particle size (distribution) of the micronized 5,7-dimethyl-N-((lR,4R)- 4-(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide can be measured using any method known to the skilled person. For example, a laser light scattering method can be used, for example, using dry measurement with an air pressure of 1.0 bar and a feed rate of 35%. The particle size can be defined using the parameters D10, D50, and / or D90 or using any combination. The parameter D90 signifies the point in the size distribution, up to and including which, 90% of the total volume of material in the sample is 'contained'. For example, if the D90 is 60 pm, this means that 90% of the sample has a particle size of 60 pm or smaller. The definition for D50 is then the size point below which 50% of the material is contained. Similarly, the D10 is that size below which 10% of the material is contained. Possible values for D10, D50 and D90 are defined below. These may be used in isolation or in combination.

[0138] In the following description, the use of the expression 'micronized 5,7- Dimethyl-N-((lR,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide having a particle size of D90' refers to the size which 90% of the total volume of material in the sample is below or equal to. For example, the expression 'micronized 5,7-Dimethyl- N-((lR,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide having a particle size of D90: < 100 pm' means that at least 90% of the total volume of material in the sample has a particle size which is less than or equal to 100 pm. Similarly, the expression 'micronized 5,7-Dimethyl-N-((lR,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5- a]pyrimidine-3-carboxamide having a particle size of D50: 1pm - 60pm' means that 50%of the total volume of material in the sample has a particle size which is more than or equal to 1pm and less than or equal to 60pm. Further, the expression 'micronized 5,7-Dimethyl- N-((lR,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide having a particle size of DIO: > 0.3 pm' means that less than 10% of the total volume of material in the sample has a particle size which is less than 0.3 pm.

[0139] Preferably, the particle size of the micronized 5,7-Dimethyl-N-((lR,4R)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide is the particle size of the material that is to be used in the preparation of the solid dosage form. Preferably, this is the particle size of the material prior to the preparation of the solid dosage form.

[0140] In a further embodiment, the micronized 5,7-Dimethyl-N-((lR,4R)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide has a particle size of D50: 1pm - 60pm, preferably 3pm - 50 pm, or more preferably 5pm - 30pm.

[0141] In another embodiment, the micronized 5,7-Dimethyl-N-((lR,4R)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide has a particle size of DIO: > 0.3 pm, preferably > 0.5 pm, or more preferably > 1 pm.

[0142] In a further embodiment, the micronized 5,7-Dimethyl-N-((lR,4R)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide has a particle size of D90: < 100 pm, preferably < 80 pm, or more preferably < 60 pm.

[0143] In a further embodiment, the 5,7-Dimethyl-N-((lR,4R)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide has a particle size of DIO: > 0.3 pm; D50: 1pm - 60pm; and D90: < 100 pm. Preferably the 5,7-Dimethyl-N- ((lR,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide has a particle size of DIO: > 0.5 pm; D50: 2pm - 50pm; and D90: < 80 pm; or even more preferably DIO: > 1 pm; D50: 5pm - 30pm; and D90: < 60 pm.

[0144] If the particle size of the active compound is too large, the pharmacological characteristics of the active may be impaired. For example, the compound may have poor oral bioavailability as the large particles can take too long to dissolve in the intestinal fluids in the gastrointestinal tract of a patient. Additionally, the homogeneity of dosage (e.g. homogeneity of Formula A in a tablet or within tablets) may be compromised. If the particle size of the Formula A is too small, it can be difficult to prepare tablets. For example, small particles can exhibit poor flow characteristics or poor compression properties which may make it difficult to generate tablets or capsules with the required properties. In some cases, tablets or capsules prepared using particles that are too small may have poor hardness, exhibit poor homogeneity of content and / or exhibit poor uniformity of mass. This is particularly important if the manufacturing process is a direct compression or capsule filling.

[0145] Processing of the crystalline compound to the defined particle size may be done by any suitable method known to the skilled person. For example, the crystallinecompound may be micronized. This may be by jet milling, mechanical milling, fluid milling, crushing or grinding. In a particular embodiment, jet milling is used.

[0146] In an embodiment, there is provided a crystalline form of 5,7-dimethyl- / V- ((! / ?, 4 / ?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide having a particle size as defined below: a) D50 is 1pm - 60 pm, preferably 2pm - 50pm, or more preferably 5pm - 30pm; b) DIO is > 0.3 pm, preferably > 0.5pm, or more preferably > 1 pm; and / or c) D90 is < 100pm, preferably < 80pm, or more preferably < 60pm.

[0147] In certain embodiments, the crystalline form of 5,7-dimethyl-N-((lR,4R)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide has a particle size of DIO: > 1 pm; D50: 5pm - 30pm; and D90: < 60 pm, preferably DIO: > 0.5 pm; D50: 2pm - 50pm; and D90: < 80 pm, even more preferably DIO: > 0.3 pm; D50: 1pm - 60pm; and D90: < 100 pm.

[0148] DIO, D50 and D90 are as defined above for the expression 'micronized 5,7- Dimethyl- / V-((lR,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide having a particle size of...'. The particle size of the micronized 5,7-Dimethyl- / V-((lR,4R)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide can be measured using any method known to the skilled person. For example, a laser light scattering method using dry measurement with an air pressure of 1.0 bar and a feed rate of 35%.

[0149] As discussed above, the particle size of the crystalline form of 5,7-dimethyl- / V-((lR,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide can impact the properties of any resultant pharmaceutical composition. If the particle size of the active compound is too large, the pharmacological characteristics of the active may be impaired. For example, the compound may have poor oral bioavailability as the large particles can take too long to dissolve in the intestinal fluids in the gastrointestinal tract of a patient. Additionally, the homogeneity of dosage (e.g. homogeneity of Formula A in a tablet or within tablets) may be compromised. If the particle size of the Formula A is too small, it can be difficult to prepare tablets. For example, small particles can exhibit poor characteristics or poor compression properties which may make it difficult to generate tablets or capsules with the required properties. In some cases, tablets or capsules prepared using particles that are too small may have poor hardness, exhibit poor homogeneity of content and / or exhibit poor uniformity of mass. This is particularly important if the manufacturing process is a direct compression or capsule filling.

[0150] Preferably, the crystalline form of 5,7-dimethyl-N-((lR,4R)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide is Form A or Form B. More preferably, the crystalline form is Form B. Form B is identified as the presence of peak (20) 12.2 ± 0.2 in an X-ray diffraction pattern and Form A is identified as the presence of peaks (20) at 5.6± 0.2 and 17.1 ± 0.2 in an X-ray diffraction pattern.

[0151] The crystalline polymorphic forms of the compound of Formula A are preferably in a predefined particle size distribution. If the Formula A particles resulting from its synthesis are not of an appropriate particle size, the crystalline polymorphic forms of Formula A may further be processed to a predefined particle size. Processing of the crystalline compound to the defined particle size may be done by any suitable method known to the skilled person. For example, the crystalline compound may be micronized. This may be by jet milling, mechanical milling, fluid milling, crushing or grinding.

[0152] One method of micronizing the crystalline particles of Formula A is to use a jet mill. A jet mill grinds materials by using a high-speed jet of compressed air or inert gas to impact particles into each other. Optionally, Formula A may be sieved prior to micronizing using, for example, a 20-mesh sieve.

[0153] The following Micronization example is provided.

[0154] Bulk and tapped density, Carr index, compressibility index, Hausner ratio, real density, porosity, relative solid content, and flow rate were obtained for the micronized compound of Formula A. The results are summarized in the table below.

[0155] The compound of Formula A was micronized using a jet-mill PM6 with the following process parameters: feed rate - 20%, control feeding pressure - 0.4 MPa (target 4 bar, range: 3.5 - 5.5 bar) and milling pressure - 0.4 MPa (target 4 bar, range :3.5 - 5.5 bar). Particle size was measured using a Malvern, mastersizer 3000 using a laser light scattering method.Table - Pharmacotechnical characterization of compound of Formula A

[0156] The order of the steps of the processes described herein is exemplary (unless a certain order is necessitated through the explicit wording of the steps), but the steps may be carried out in any suitable order, or simultaneously where appropriate. Additionally, steps may be added or substituted in, or individual steps may be deleted from any of the processes without departing from the scope of the subject matter described herein.

[0157] It will be understood that the description of preferred embodiments herein is given by way of example only and that various modifications may be made by those skilled in the art. What has been described above includes examples of one or more embodiments. It is, of course, not possible to describe every conceivable modification and alteration of the above process and apparatus for purposes of describing the aforementioned aspects, but one of ordinary skill in the art can recognize that many further modifications and permutations of various aspects are possible. Accordingly, the described aspects are intended to embrace all such alterations, modifications, and variations that fall within the scope of the appended claims.Examples

[0158] The invention is now described with reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention.Example 1 - Preparation of trans-4-(pentyloxy)cyclohexanaminium chloride (compound of Formula (IV) in a salt form)Step 1 - Preparation of tra / 7s- / V, / V-Dibenzyl-4-aminocvclohexanol (compound of Formula (HA))

[0159] Under nitrogen atmosphere, DMF (126 L, 6.0 V), trans-4-aminocyclohexanol (compound of Formula (I)) (21 kg, 1.0 eq.) and anhydrous K2CO3 (37.8 kg, 1.5 eq.) were charged to the reactor at 25 °C; after this, DMF (21 L, 1.0 V) was charged to wash the reactor walls at 25°C. The temperature was adjusted to 35 °C and BnBr (62.37 kg, 2.0eq.) was added dropwise to the reactor. The temperature was increased to 40 °C and the mixture was left stirring for at least 8 hours. After this, and at the same temperature, purified water (63 L, 3.0 V) was added dropwise to the reactor (solid precipitation); then, a second charge of purified water (210 L, 10.0 V) was added dropwise to the reactor at 40 °C. The temperature was adjusted to 35 °C and the slurry was left stirring for at least 2 hours; after this, the slurry was cooled down to 25 °C and left stirring for at least 2 hours. The solid was centrifuged and the wet cake was washed with a solution of DMF:H2O (1 :2, 63 L, 3.0 V). Purified water (315 L; 15.0 V) and the wet cake were charged into the reactor at 25 °C; then, purified water (10.5 L, 0.5 V) was added to wash the reactor walls. The mixture was left stirring for 1 hour at 25 °C. The solid was centrifuged and the wet cake was washed with purified water (63 L, 3.0 V) one time and then washed with n-heptane (105 L, 5.0V) one time. The cake was dried under vacuum at 45 °C for at least 12 h and 47.69 kg were obtained (88% yield and purity of 98.98% area by HPLC). A minor amount of the tribenzylated side product was also observed (benzylation at the hydroxy group in addition to the benzylation on the amine group).Formula (Q Formula { IA)Step 2 - Preparation of tra / 7s- / V, / V-Dibenzyl-4-(pentyloxy)cvclohexanaminium chloride (compound of Formula (IIIA))

[0160] To prepare t-BuOK in DMF solution, under nitrogen atmosphere, DMF (236.9 L, 5.0 V) was charged to a reactor at 20 °C; then, t-BuOK (90.02 kg, 5.0 eq.) was charged at the same temperature and left stirring until complete dissolution.

[0161] Under nitrogen atmosphere, DMF (189.52 kg, 4.0 V), trans-N, N-Dibenzyl-4- aminocyclohexanol (compound of Formula (IIA) from step 1) (47.38 kg, 1.0 eq.) and 1- Bromopentane (108.97 kg, 4.5 eq.) were charged to a reactor at 20 °C; after this, the reaction mixture was cooled down to -3 °C and t-BuOK (81.02 kg, 4.5 eq.) in DMF solution was added dropwise to the reactor (heat release, control the temperature during the charge; the charging time should take place with not less than 5 hours). The solution was left stirring for 1-3 hours at the same temperature; if necessary, additional 1- Bromopentane (12.32 kg, 0.5 eq.) could be charged to the reactor followed by t-BuOK (9.0kg, 0.5 eq.) in DMF (23.69 L, 0.5 V). After this, at 0 °C, water (260.6 L, 5.5 V) was added in 2-6 h to the reactor. The temperature was adjusted to 5 °C before n-heptane (260.6 L, 5.5 V) was charged and it was stirred for 0.5 to 1 h. The temperature was adjusted to 20 °C and it was stirred for 0.5 to 1 h before the stirring was stopped to allow phase separation. The organic phase was kept in the reactor. Purified water (260.6 L, 5.5 V) was charged and it was stirred for 0.5 to 1 h; the stirring was stopped to allow phase separation and the organic phase was kept in the reactor. This procedure was repeated. If the area% of DMF is more than 0.2%, perform one more water washing (260.6 L, 5.5 V) and keep the organic phase in a reactor.

[0162] To prepare the HCI salt, under nitrogen atmosphere, EtOAc (142.14 L, 3.0 V) was charged to the reactor at 20 °C; after this, HCI (4 M) in EtOAc solution (73.44 kg, 2.0 eq.) was added at the same temperature; the trans- / V, / V-Dibenzyl-4- (pentyloxy)cyclohexanaminium chloride (compound of Formula (IIIA)) freebase product in n-heptane solution was added during 3-6 hours to the reactor; the solution was left stirring for 0.5-1 hour and then the temperature was adjusted to 40 °C and left stirring for 16-20 hours. After this, n-heptane (47.38 kg, 1.0 V) was added dropwise in 1-3 hours to reactor; the reaction mixture was cooled down to 20 °C. The reaction mixture was concentrated under vacuum until the total volume was 426.42 L- 473.8 L (9.0-10.0 V) and it was left stirring for 2-5 hours at 20 °C. The solid was centrifuged and washed with a solution of n- heptane:EtOAc (2: 1, 99.5 L, 2.1 V) one time and then washed with n-heptane (94.76 L, 2.0 V) one time. The cake was dried under vacuum oven at 45 °C for 16-24 hours and 61.46 kg were obtained (94% yield and purity of 98.38% area by HPLC).Formula HI A) Formula (III A) Formula (IIIAJ . HCHStep 3- Preparation of tra / s-4-(Dentyloxy)cvclohexanaminium chloride (compound ofFormula (IV) in HCI salt form)

[0163] EtOH (240 L, 4.0 V) and trans-N, N-Dibenzyl-4- (pentyloxy)cyclohexanaminium chloride (compound of Formula (IIIA)) (60 kg, 1.0 eq.) from step 2 were charged to the reactor under nitrogen atmosphere and the feeding port was rinsed with EtOH (60 L, 1.0 V). The temperature was set at 25 °C and the mixture was left stirring for at least 30 mins. Pd / C (1.80 kg, 3% w / w) was charged to the reactor and the addition funnel and charging port were rinsed with EtOH (30 L, 0.50 V). The reactor was heated slowly, and hydrogen was charged (hydrogen pressure between 0.6-1.0 MPa) until the temperature was 50 °C. The mixture was left stirring for 20-30 hours.* After this, the reactor was cooled down to 30 °C and the solid was filtered. The filtrate was charged to the reactor and concentrated under vacuum until the total volume was 90 L-150 L (1.5-2.5 V). Ethyl acetate (240 L, 4.0 V) was added dropwise in 1-3 hours to the reactor. The solution was concentrated under vacuum until the total volume was 150 L - 210 L (2.5-3.5 V). After this, the temperature of the reaction mixture was increased to 45 °C and it was left stirring 0.1-1 hour before starting to cool down to 20 °C; the slurry was left stirring for 3-6 hours. The solid was centrifuged and washed with ethyl acetate:ethanol (30: 1, 60 L, 1.0 V x 2 ) twice. If the purity of trans-4-(Pentyloxy)cyclohexanaminium chloride (Compound of Formula (IV) in HCI salt form) is not above 98.0%, repeat the slurry and centrifugation procedure. The cake was dried under vacuum oven at 43 °C for 16-24 hours and 31.24 kg were obtained (93% yield and purity of 99.63% area by HPLC).Formula (IHA) , HCl Formula (IV . HCI* In one campaign, during this stirring period two portions of additional Pd / C catalyst were charged (first portion 1% w / w; second portion 3% w / w) to push the reaction to completion.Example 2 - Preparation of 5,7-Dimethylpyrazolo[l,5-a]pyrimidine-3-carboxylic acid (compound of Formula (VII))Step 1 - Preparation of Ethyl 5, 7-dimethylDyrazolori,5-alDyrimidine-3-carboxylate (compound of Formula (VI))

[0164] Under nitrogen atmosphere, toluene (97.5 L, 5.0 V) and ethyl 3- aminopyrazole-4-carboxylate (compound of Formula (V)) (19.50 kg, 1.0 eq.) were charged to a reactor at 25 °C; after this, toluene (19.50 L, 1.0 V) was charged to wash the walls. Glacial acetic acid (5.07 kg, 0.68 eq.) and acetyl acetone (15.02 kg, 1.2 eq.) were added to the reactor at 25 °C and the reaction mixture was heated to 50 °C. The temperature was kept at 50 °C and it was left stirring for 5-8 hours before cooling down to 25 °C. The solution was concentrated under vacuum until the total volume was 78 L- 97.5 L (4.0-5.0 V). Toluene (39 L, 2.0 V) was charged to the reactor and the solution was concentrated until the total volume was 68.25 L-87.75 L (3.5-4.5 V). After this, the temperature of the reaction mixture was increased to 65 °C and it was left stirring for 0.5-1 hour, n-heptane (156 L, 8.0 V) was added dropwise in 2-6 hours to the reactor at 65 °C; a second charge of n-heptane (68.25 L, 3.5 V) was added dropwise in 2-6 hours to the reactor and it was left stirring for 0.5-1 hour. The reaction mixture was cooled down to 60 °C and it was left stirring for 1-2 hours before seeds of compound of Formula (VI) were charged to the reactor; the reaction mixture was cooled down to 55 °C and left stirring for 2-4 hours before cooling down to 8°C (solid precipitation). The solid was centrifuged and washed with toluenem-heptane (1:6, 39 L, 2.0 V) one time and n-heptane (39 L, 2.0 V) one time. If the %area of the compound of Formula (VI) is not higher than 98.0% reslurry and centrifuge the solid. The cake was dried under vacuum at 45 °C for 6-10 hours and 25.65 kg were obtained (91.4% yield and purity of 99.86%area by HPLC).Formula V) Formula (VI)Step 2 - Preparation of 5,7-Dimethylpyrazolori,5-alpyrimidine-3-carboxylic acid(Compound of Formula (VID)

[0165] Under nitrogen atmosphere, purified water (50.8 L, 2.0 V) was charged to a reactor at 20 °C; then, NaOH (6.10 kg, 1.3 eq.) was charged to the reactor and the solution was left stirring for 1-5 hours until the solid was dissolved; the NaOH aqueous was transferred from the reactor to a clean drum.

[0166] Under nitrogen atmosphere, purified water (177.8 L, 7.0 V) and the compound of Formula (VI) (25.40 kg, 1.0 eq.) from step 1 were charged to the reactor at 25 °C; purified water (25.4 L, 1.0 V) was added to wash the walls of the reactor. After this, the prepared NaOH aqueous was added to the reactor and the temperature was increased to 60 °C. The solution was left stirring at this temperature for 3-8 hours.

[0167] The temperature of the reaction mixture was set to 44 °C and after this, 37% HCI (16 kg, 1.4 eq.) was added dropwise to the reactor (if necessary, dropwise additional 37% HCI (0.229 kg, 0.02 eq.); the reaction mixture was left stirring for 0.5-1 hour before cooling down to 2.5 °C; the solution was left stirring at this temperature for 2-6 hours. The solid was centrifuged and the cake was washed with purified water (50.8 L, 2.0 V) four times. The cake was dried under vacuum at 40 °C and 21.38 kg were obtained (96% yield and purity of 100% area by HPLC).Example 3 - Preparation of 5,7-dimethyl- / V-((l / ?,4 / ?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (Compound of Formula (A))

[0168] Part 1 : Under nitrogen atmosphere, purified water (41.32 L, 2.0 V) and NaOH (5.99 kg, 1.4 eq.) were charged to a reactor at 20 °C; after this, purified water (10.33 L, 0.5 V) was added to wash the walls and the solution was left stirring for 0.5-3 hours until the solid was dissolved; the solution was transferred from the reactor to a clean drum.

[0169] Part 2: Under nitrogen atmosphere, purified water (30.99 L, 1.5 V) and NaCI(2.27 kg, 0.11 wt.%) were charged to the reactor at 20 °C; after this, purified water (10.33 L, 0.5 V) was charged to wash the walls and the solution was left stirring for 0.5-3 hours until the solid was dissolved; the solution was transferred from the reactor to a clean drum.

[0170] Part 3: Under nitrogen atmosphere, purified water (62 L, 3.0 V) and the compound of Formula (IV) in HCI salt form (27.84 kg, 1.15 eq.), from step 3 of Example 1, were charged to the reactor at 25 °C; after this, purified water (16.5 L, 0.8 V) was charged to wash the walls and then MTBE (165.28 L, 8.0 V) was charged to the reactor and the solution was left stirring for 0.5-1 hour; after this, the solution was cooled down to 5 °C and the NaOH (5.99 kg, 1.4 eq.) aqueous solution (prepared in advance in part 1) was charged in 0.5-2 hours; then, the temperature of the reaction mixture was increased to 25 °C and it was left stirring for 1-3 hours. The agitation was stopped, and the phases were separated. The organic phase was washed two times: the first with 5% NaCI aqueous (41.32 L, 2.0 V) prepared in advance in part 2 and the second with purified water (41.32 L, 2.0 V). Then, the organic phase was concentrated under vacuum until the total volume was 51.65 L - 72.31 L (2.5-3.5 V). MTBE (62 L, 3.0 V) was charged to the reactor and the solution was concentrated under vacuum until the total volume was 51.65 L - 72.31 L (2.5-3.5 V).

[0171] Part 4: Under nitrogen atmosphere, DMF (92.97 L, 4.5 V), the compound of Formula (VII) (20.66 kg, 1.0 eq.), from step 2 of Example 2, and l,l'-carbonyldiimidazole (21.07 kg, 1.2 eq.) were charged to the reactor at 25 °C; DMF (10.33 L, 0.5 V) was added to wash the walls. The temperature of the reaction mixture was increased to 28 °C, and it was left stirring for 2-5 hours. If necessary, charge additional l,l'-carbonyldiimidazole (1.76 kg, 0.1 eq.) to the reactor at 28 °C and leave it stirring for 2-5 hours. After this, purified water (1.178 kg, 0.6 eq.) was charged to the reactor and it was left stirring for 1- 4 hours. Under nitrogen atmosphere, the compound of Formula (IV) Free Base in MTBE solution (27.84 kg ,1.15 eq.), from Part 3, was charged to the reactor in 1-2 hours; MTBE (4.132 L, 0.2 V) was charged to rinse the drum and then it was transferred to the reactor. The solution was left stirring for 16-24 hours and then DMF (20.66 L, 1.0 V) was charged to the reactor. The solution was concentrated under vacuum until the total volume was 123.96 L - 165.28 L (6.0-8.0 V).

[0172] Part 5: The reaction mixture temperature was increased to 40 °C and purified water (41.32 L, 2.0 V) was added dropwise to the reactor in 1-2 hours; the reaction mixture was left stirring for 2-5 hours before cooling down to 20 °C; the slurry was left stirring for 10-15 hours and then purified water (82.64 L, 4.0 V) was added dropwise in 1- 3 hours to the reactor; the slurry was left stirring for 3-6 hours. After this, the solid was centrifuged and the cake was washed with DMF:H2O (1: 1, 20.66 L, 1.0 V x 2) two times and then washed with purified water (41.32 L, 2.0 V) one time*. The cake was dried under vacuum at 55 °C for 15-24 hours and 32.35 kg were obtained (83.3% yield and 100% purity by HPLC).* In one campaign, at this stage the wet cake was dissolved in acetonitrile (25.5 V), the temperature adjusted to 27°C and stirred for 2-6 hours. The solution was filtered via a polish filter (0.22 pirn). The solution was concentrated under vacuum to 5.0 - 7.0 V at a temperature below 35°C. The temperature was adjusted to 20°C and purified water was added (14.0 V) in 2-4 hours. The slurry was stirred for 4-8 hours at 20°C, and afterwards filtered and washed with purified water (4.0 V).Formula (Vtl; Formula {A}Example 4 - Recrystallisation of 5,7-dimethyl- / V-((l / ?,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (Compound of Formula (A))

[0173] Under nitrogen atmosphere, MEK (192 L, 6.0 V) and the compound of Formula (A) from Example 3 in crude (32 kg, 1.0 eq.) were charged to a reactor at 25 °C; MEK (160 L, 5.0 V) was added to wash the walls. The solution was left stirring for 1-3 hours until the solid was dissolved. After this, the solution from the reactor was transferred to a clean drum.

[0174] Under nitrogen atmosphere, the crude compound of Formula (A) in MEK solution was transferred to another reactor via a polish filter. The temperature was set at 17 °C and n-heptane (115.2 kg, 3.6 V) was charged in 2-4 hours. The solution was concentrated under vacuum until the total volume was 320 L - 352 L (10-11 V). In the event that there is no solid precipitation, proceed to the 2ndconcentration directly; if there is solid precipitation, take a solid sample for XRPD test, and ensure that the crystal form is polymorph form B; if it is not form B, proceed to the 2ndconcentration (and repeat if required). The reactor temperature was kept at 17 °C before cooling down to 0 °C and it was left stirring for 6-12 hours. A solid sample was taken for XRPD test to make sure that the crystal form is form B; if not form B, keep at 0 °C and stir for 6-12 hours; sample solid every 6-10 hours for XRPD until the crystal form is form B. The solid was centrifuged and washed with MEK:n-heptane (1 : 10, 57.6 L, 1.8 V ) and then with n-heptane (57.6 L, 1.8V). The cake was dried under vacuum at 30 °C for 16-24 hours and 30.67 kg were obtained (95% yield and purity of 100% by HPLC).Form A or B Form BExample 5 - Jet milling of 5,7-dimethyl- / V-((l / ?,4 / ?)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (Compound of Formula (A)

[0175] 27 kg of the compound of Formula (A) from Example 4 were sieved with a20-mesh sieve. After this, this the compound of Formula (A) in Form B sieved was charged into the feeder of the jet mill; the feeding pressure and the milling pressure were controlled at 0.4 MPa. 26.36 kg of product were collected (98% yield and purity of 100% by HPLC).

[0176] Examples 1 to 5 therefore provide an efficient and effective way of preparing the compound of Formula (A).

[0177] Carrying out the procedure outlined in Examples 1 to 4 (and optionally also Example 5), produced the compound of Formula (A) containing Impurities A to G in amounts below the limit of quantification, when measured by the HPLC methods described herein.Example 6 - Alternative preparation of trans-4-(pentyloxy)cyclohexanaminium chloride (compound of Formula (IV) in HCI salt form)

[0178] EtOH:water mixture (9: 1, 10 mL, 5.0 V) and compound of Formula (IIIA) in HCI salt form (2.0 g, 1.0 eq.) were charged to the reactor under nitrogen atmosphere. The temperature was set at 25 °C and the mixture was left stirring for at least 30 mins. Pd / C (0.128 g, 3% w / w) was charged to the reactor and the addition funnel, and the charging port were rinsed with EtOH:water mixture (9: 1, 1 mL, 0.50 V). The reactor was heated slowly, and hydrogen was charged (at atmospheric pressure using a balloon) until the temperature was 50 °C. The mixture was left stirring for 55 hours and the conversion to product was 96.7 wt.% by LC-MS. After this, the reactor was cooled down to 20 °C and the solid was filtered through celite and washed twice with Ethanol (2 mL, 1.0 V). The filtrate was dried under vacuum at 30 °C using a rotary evaporator (compound of Formula (IV) in HCI salt form: 0.921 g; yield: 83.48%).Formula (H5A) . HCI Formula (IV) . HCI

[0179] A 9: 1 ratio of ethanol: water solvent mix has been found to prevent precipitation during sampling or filtration if more catalyst was required (improves the solubility of the monobenzylated intermediate), compared to Example 1, step 3 above which instead uses only an ethanol solvent.Example 7 - Alternative preparation of trans-4-(pentyloxy)cyclohexanaminium chloride (compound of Formula (IV) in HCI salt form) using Boc protecting groupStep 1 - Preparation of tert-butyl N-(4-hvdroxycvclohexyl)carbamate (compound of Formula (IIB))

[0180] Five different sets of conditions were tested to prepare the compound of Formula (IIB).

[0181] Conditions: Et3N, DCM

[0182] Trans-4-aminocyclohexanol (compound of Formula (I)) (1.00 eq., 1.00 g, 8.68 mmol) was dissolved in DCM (5 mL). Triethylamine (1.50 eq., 1.8 mL, 13.0 mmol) was added and after this di-tert-butyl dicarbonate (0.330 eq., 0.64 g, 2.87 mmol) dissolved in DCM (5 mL) was added to the reaction. The reaction was left stirring for 18 h at 20 °C. Conversion to product was observed by Mass Spectroscopy. After this, the organic phase was extracted 2 times with water (10 mL). The organic phase was dried completely in a rotavapor. EtOH (4mL, ~2 V) was added to dissolve triethylamine and maintain the product as a solid. The slurry was filtered and the solid was dried in the vacuum oven (m obtained = 100 mg, yield = 5.35%, purity = 95% by NMR, DMSO-d6, 600 MHz: 6 ppm 6.67 (d, 1H), 4.50 (d, 1H), 3.30 (s, 1H), 3.13 (s, 1H), 1.76 (m, 4H), 1.36 (s, 9H), 1.14 (m, 4H)).

[0183] Conditions: NaHCO3, DCM: water

[0184] Trans-4-aminocyclohexanol (compound of Formula (I)) (1.00 eq., 1.00 g, 8.68 mmol) was dissolved in DCM (5mL). Sodium bicarbonate (1.50 eq., 1.09 g, 13.0 mmol) was dissolved in water (lOmL) and added to the reaction. After this, di-tert-butyl dicarbonate (0.330 eq., 0.64 g, 2.87 mmol), dissolved in DCM (5 mL), was added to thereaction. The reaction was left stirring for 18 h at 20 °C. Conversion to product was observed by MS. After this, HCI 4M in water was added to neutralize some of the base (final pH 9-10). The phases were separated, and the organic phase was dried completely in the rotavapor to obtain an off-white solid (m obtained = 0.5 g, yield = 26.75%, purity = 95% by NMR).

[0185] Conditions: K2CO3, DCM: water

[0186] Trans-4-aminocyclohexanol (compound of Formula (I)) (1.00 eq., 20.00 g, 174 mmol) was dissolved in DCM (lOOmL). Potassium carbonate (2.00 eq., 47.99 g, 347 mmol) was dissolved in water (200mL) and added to the reaction. After this, di-tert-butyl dicarbonate (0.330 eq., 12.76 g, 57.3 mmol), dissolved in DCM (lOOmL), was added to the reaction. The reaction was left stirring for 18 h at 20 °C. Conversion to product was observed by MS. The phases were separated, 100 mL of EtOAc were added and the organic phase was dried completely in the rotavapor to obtain an off-white solid (compound of Formula (IIB) : m= 15.4g, purity = 90 % by NMR). The aqueous phase was washed again with ~100 mL of EtOAc. The aqueous phase still had some starting material to react and, since only 0.33 eq. of di-tert-butyl dicarbonate had been used, the aqueous phase was resubmitted to reaction by adding 26 g of di-tert-butyl dicarbonate (0.66 eq.) dissolved in 200 mL of DCM. The reaction was left stirring overnight. Conversion to product was observed. The phases were separated, and the organic phase was dried completely in the rotavapor to obtain an off-white solid (compound of Formula (IIB): m= 10.725 g, purity = 70 % by NMR). Overall yield of 70%.

[0187] Conditions: NaOH, dioxane:water

[0188] Trans-4-aminocyclohexanol (compound of Formula (I)) (1.00 eq, 5.00 g,43.4 mmol) was dissolved in 1,4-Dioxane (20mL). Sodium hydroxide (1.00 eq, 1.74 g,43.4 mmol) was dissolved in Water (30mL) and added to the reaction. After this, di-tert- butyl dicarbonate (1.25 eq, 12.08 g, 54.3 mmol), dissolved in 1,4-Dioxane (20mL), was added to the reaction. A solid precipitate was formed after 0.5 h. The reaction was left stirring for 18 h at 20 °C. Conversion to product was observed by MS after 3 h. The slurry was filtered and then it was added 40 mL of water to precipitate more product. The solid was filtered in the same filter used for the first filtration. The solid was dried in the vacuum oven to obtain a white solid (m=8.721 g, 93.3% yield and 95% purity by NMR).

[0189] Conditions: K2CO3, DCM: water

[0190] Trans-4-aminocyclohexanol (compound of Formula (I)) (1.00 eq, 5.00 g,43.4 mmol) was dissolved in DCM (25mL). Potassium carbonate (1.00 eq, 6.00 g, 43.4 mmol) was dissolved in water (50mL) and added to the reaction. After this, di-tert-butyl dicarbonate (1.02 eq, 9.86 g, 44.3 mmol), dissolved in DCM (25mL), was added to the reaction. The reaction was left stirring for 18 h at 20 °C and a solid precipitate was formed. Conversion to product was observed by MS after 3 h. The solid was filtered and dried in the vacuum oven to obtain a white solid (m=7.505 g, 80.3% yield and 95% purity byNMR).Formula (I) Formula II B)Step 2 - Preparation of trans-4-(Pentyloxy)cvclohexanaminium chloride (Compound of Formula (IV) in HCI salt form)

[0191] Two different sets of conditions were tested to prepare the intermediate compound of Formula (IIIB), towards compound of Formula (IV) in HCI salt form.

[0192] Conditions: t-BuOK, DMF

[0193] Tert-butyl N-(4-hydroxycyclohexyl)carbamate (compound of Formula (IIB) from step 1) (1.00 eq., 5.00 g, 23.2 mmol) was dissolved in DMF (20 mL) under N2. 1- bromopentane (1.50 eq., 4.3 mL, 34.8 mmol) was added to the reaction mixture and the temperature was decreased to 0 °C. A solution of t-BuOK (1.50 eq., 3.91 g, 34.8 mmol) in DMF (20mL) (previously prepared) was added into the reaction mixture in 1 h (~24 mL / h). After this, the reaction was left stirring for 0.5 h at room temperature. Water (25 mL) and Heptane (25 mL) were added, and the mixture was left stirring overnight. The phases were separated. The organic phase was mixed with EtOAc (10 mL) and HCI in EtOAc (16 mL) at 20 °C and the resulting solid was filtered and dried in the vacuum oven. Product was isolated as a white solid (m obtained = 2.3 g, yield = 44.7%, purity = 95% by NMR).FCI

[0194] To minimize alkylation, a biphasic reaction with phase transfer catalyst (PTC) was performed as described in the following.

[0195] Conditions: KOH, TBAB, toluene:water

[0196] Tert-butyl N-(4-hydroxycyclohexyl)carbamate (compound of Formula (IIB)(1.00 eq., 1.00 g, 4.64 mmol), tetrabutylammonium bromide (0.0500 eq., 0.075 g, 0.232 mmol) and Potassium hydroxide (3.00 eq., 0.78 g, 13.9 mmol) were dissolved in Toluene (lOmL). Then, 1-bromopentane (3.00 eq., 1.7 mL, 13.9 mmol) was added. The reaction was left stirring at 80-85 °C overnight. After this, the reaction was cooled down to room temperature and the organic phase was washed 4 times with saturated ammonium chloride solution (4x10 mL). The organic phase was completely dried under vacuum and the crude was dissolved in ethyl acetate (lOmL). After this, hydrogen chloride (2.10 eq., 3.3 mL, 9.75 mmol) in EtOAc 3-4M was added and the reaction was left stirring overnight. The solid was filtered and dried to afford a white solid (m=0.58g, yield = 39%, purity = 70% by NMR and LC-MS).Formula (IIB) Formula (IIIB) Formula (IV).HCIExample 8 - Alternative preparation of trans-4-(pentyloxy)cyclohexanaminium chloride (compound of Formula (IV) in HCI salt form) using N-2,5- dimethylpyrrole protecting groupStep 1 - Preparation of 4-(2,5-dimethylpyrrol-lyl)cvclohexanol (compound ofFormula (IIP)

[0197] Conditions for 10 g scale reaction: acetic acid, MeOH

[0198] Trans-4-aminocyclohexanol (compound of Formula (I)) (1.00 eq., 10.00 g, 86.8 mmol) was dissolved in methanol (50 mL, 5 vol.) and acetonylacetone (1.00 eq., 10 mL, 86.8 mmol) was added. After this, acetic acid (1.00 eq., 5.0 mL, 86.8 mmol) was added and the temperature was increased to 65 °C. The reaction was left stirring for 8 h (reaction complete) at this temperature. An additional 1 eq. of AcOH was added after 4.5 h and then the reaction was left stirring for 2 h before addition of 50 mL (5 vol.) of water at 65 °C before cooling down to 20 °C and perform seeding. The solid was left stirring overnight at 5 °C. Then, the solid was filtered and washed two times with 40 mL (4 vol.)of water. The solid was dried in the vacuum oven to afford trans-4-(2,5-dimethylpyrrol- lyl)cyclohexanol (mass obtained = 9.4 g, yield = 56%, purity = 95% by NMR).Formula (I) Formula (IIC)Step 2 - Preparation of trans-2, 5-dimethyl-l-((lr,4r)-4-(pentyloxy)cvclohexyl)-lH-pyrrole (Compound of Formula (IIIO)

[0199] 7ra / 7s-4-(2,5-dimethylpyrrol-l-yl)cyclohexanol (compound of Formula (IIC) from step 1) (1.00 eq., 2.50 g, 12.9 mmol) was dissolved in DMF (8.75mL). Then, 1- bromopentane (2.50 eq., 4.0 mL, 32.3 mmol) was added and the reaction temperature was decreased to -3 °C. Potassium tert-butoxide (2.50 eq., 3.63 g, 32.3 mmol) dissolved in DMF (11.25mL) was added over 1 h using a syringe pump (15 mL / h). The reaction was monitored by HPLC; when conversion was about 93.9%, 1.0 eq. of 1-bromopentane and 1.0 eq. of t-BuOK were added. Once conversion was 97.1%, water (12.5 mL) was added in 1 h at 0 °C and then, the temperature was increased to 20 °C before adding ethyl acetate (12.5 mL); the phases were separated. The organic phase was washed 2 times with 25 mL of water and dried completely under vacuum to afford an oil (mass obtained =~3.207 g, purity = 96.5% by LC-MS, purity 5% by NMR).Formula (IIC) Formula (IIIC)Step 3 - Preparation of tra / 7s-4-(Pentyloxy)cvclohexanaminium chloride (Compound of Formula (IV) in HCI salt form)

[0200] Two different sets of conditions were tested to prepare the compound of Formula (IV).

[0201] Conditions: NaOH, EtOH / water, 80 °C

[0202] 2,5-dimethyl-l-(4-pentoxycyclohexyl)pyrrole (1.00 eq., 150 mg, 0.569 mmol) was dissolved in Ethanol (2.25mL) and Water (1.125mL). Then, Sodium hydroxide (2.50 eq., 57 mg, 1.42 mmol) was added and it was left stirring for 5 minutes. After this,Hydroxylamine hydrochloride (5.00 eq., 198 mg, 2.85 mmol) was added and the temperature was increased to 80 °C. The mixture was left stirring for 24 h. Another 5 eq. of hydroxylamine hydrochloride and 2.5 eq. of NaOH were added and 1 mL of EtOH. The reaction mixture was cooled down to room temperature and 5 mL of water were added followed by 5 mL of MTBE and the phases were separated. The aqueous phase was acidified until pH~2-3 and it was recombined with the organic phase. The phases were separated and it was possible to extract most of the starting material to the organic phase whereas the Product and 2,5-hexanedione related impurities remained in the aqueous phase. Another extraction with ~10 mL of MTBE was performed to extract more impurities to the organic phase (including 2,5-hexanedione related impurities). After this, the aqueous phase was basified to pH~13-14 and an extraction with ~10mL of MTBE was performed. At this point, most of the product was in the organic phase whereas the 2,5-hexanedione related impurities stayed in the aqueous phase. The organic phase was dried to afford an oil (mass obtained = 83 mg. yield = 79%; purity 85% by NMR).

[0203] Conditions: NaOH, MeOH / water, 65 °C

[0204] 2,5-dimethyl-l-(4-pentoxycyclohexyl)pyrrole (1.00 eq., 1.89 g, 7.17 mmol) was dissolved in Methanol (28.32 mL). Sodium hydroxide (5.00 eq., 1.43 g, 35.8 mmol) and Hydroxylamine hydrochloride (10.0 eq., 4.98 g, 71.7 mmol) were dissolved in water (9.44mL) and after full dissolution it was added to the methanol solution. Then, the temperature was increased to 65 °C and the mixture was stirred for 20 h. The reaction mixture was cooled down to room temperature and the pH was measured (7-8). 10 mL of water were added and then NaOH was added until pH was 12. After this, 25 mL of MTBE were added, and the phases were separated. The organic phase was dried completely and then 10 mL of EtOAc were added and the mixture was stirred. After this, hydrogen chloride (2.00 eq., 4.8 mL, 14.3 mmol) in EtOAc 3 M was added and it was left stirring for 1 h before cooling down to 5 °C where seeding with Formula (IV).HCI compound was performed; it was left stirring for 2 h. The slurry was filtered and the solid was dried (mass obtained = 0.6 g. yield = 37%; purity 90% by NMR).Formula (IIIC) Formula (IV).HCI Formula (IV)

[0205] Examples 7 and 8 show that protecting groups other than a benzyl protecting group can be used to effectively prepare the compound of Formula (IV).

[0206] Example 8 also shows that protecting groups such as cyclic amines can be used to effectively prepare the compound of Formula (IV).Example 9 - Alternative preparation of Ethyl 5, 7-dimethylpyrazolo[l,5- a]pyrimidine-3-carboxylate (compound of Formula (VI)) to control formation of polymorph II of Formula (VI)

[0207] In a 1 L jacketed reactor, under nitrogen atmosphere, ethanol (240 mL, 4.0 V) and ethyl 3-aminopyrazole-4-carboxylate (compound of Formula (IV)) (60 g, 1.0 eq.) were charged to the reactor at 25 °C; after this, ethanol (120 mL, 1.0 V) was charged to wash the walls. Glacial acetic acid (15 mL, 0.68 eq.) and acetyl acetone (47 mL, 1.2 eq.) were added to the reactor at 25 °C and the reaction mixture was heated to 50 °C. The temperature was kept at 50 °C and it was left stirring for 5-8 hours. The solution was concentrated under vacuum until the total volume was 240 mL (4.0 V). n-heptane (480 mL, 8.0 V) was charged to the reactor and the solution was concentrated until the total volume was 480 mL (8.0 V). n-heptane (240 mL, 4.0 V) was charged to the reactor and the solution was concentrated until the total volume was 480 mL (8.0 V) (product precipitated), n-heptane (240 mL, 4.0 V) was charged and after this, the temperature of the reaction mixture was increased to 65 °C and it was left stirring for 0.5-1 hour. The reaction mixture temperature was decreased to 20 °C and left stirring for 8 hours before cooling down to 5°C for 0.5 h. The solid was filtered and washed with ethanolm-heptane (5:95, 180 mL, 3.0 V). The cake was dried under vacuum at 45 °C for 6-10 hours (compound of Formula (VI) : 74.9 g; 88% yield; light yellow crystalline solid; 99.80% purity; 0.08% Ethyl 3-hydroxy-lH-pyrazole-4-carboxylate; 0.12% dimer m / z 397; polymorph II of the intermediate compound of Formula (VI) where the crystalline solid exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 5.1 ± 0.2, 10.2 ± 0.2).Ennuis

[0208] Example 9 provides conditions that have been found to be particularly effective for preparing polymorph II of the compound of Formula (VI). Overall, the use of an ethanol mix compared to toluene was found to lead to more controlled crystallization and the slurry formed upon product crystallization during cooling was easy to stir. Furthermore, the isolated solid had a higher bulk density, making it easier to handle andstore.Example 10 - Alternative preparation of Ethyl 5, 7-dimethylpyrazolo[l,5- a]pyrimidine-3-carboxylate (compound of Formula (VI)) to control formation of polymorph I of Formula (VI)

[0209] Under nitrogen atmosphere, ethanol (240 mL, 4.0 V) and ethyl 3- aminopyrazole-4-carboxylate (compound of Formula (IV)) (60 g, 1.0 eq.) were charged to the reactor at 25 °C; after this, ethanol (120 mL, 1.0 V) was charged to wash the walls. Glacial acetic acid (15 mL, 0.68 eq.) and acetyl acetone (47 mL, 1.2 eq.) were added to the reactor at 25 °C and the reaction mixture was heated to 50 °C. The temperature was kept at 50 °C and it was left stirring for 5-8 hours. The solution was concentrated under vacuum until the total volume was 240 mL (4.0 V). n-heptane (240 mL, 4.0 V) was charged to the reactor and the solution was concentrated until the total volume was 300 mL (5.0 V). n-heptane (180 mL, 3.0 V) was charged to the reactor and the solution was concentrated until the total volume was 300 mL (5.0 V) (product precipitated), n-heptane (180 mL, 3.0 V) was charged to the reactor and the solution was concentrated until the total volume was 300 mL (5.0 V). The temperature of the reaction mixture was increased to 65 °C and it was left stirring for 0.5-1 hour. The reaction mixture temperature was decreased to 5 °C and left stirring for 8 hours. The solid was filtered and washed with ethanolm-heptane (5:95, 180 mL, 3.0 V). The cake was dried under vacuum at 45 °C for 6-10 hours (compound of Formula (VI) : 77.0 g; 91% yield; light yellow crystalline needles; 99.80% purity; 0.07% Ethyl 3-hydroxy-lH-pyrazole-4-carboxylate; 0.13% dimer m / z 397; polymorph I of the intermediate compound of Formula (VI) where the crystalline solid exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 9.2 ± 0.2, 11.2 ± 0.2).

[0210] Example 10 provides conditions that have been found to be particularly effective for preparing polymorph I of the compound of Formula (VI). Overall, the use of an ethanol mix compared to toluene was found to lead to more controlled crystallization and the slurry formed upon product crystallization during cooling was easy to stir. Furthermore, the isolated solid had a higher bulk density, making it easier to handle and store.Example 11 - Alternative preparation of 5,7-Dimethylpyrazolo[l,5-a]pyrimidine- 3-carboxylic acid (compound of Formula (VII))

[0211] The reaction is performed in a 10 L vacuum jacketed reactor. Under nitrogen atmosphere, a solution of aqueous NaOH is prepared. Purified water (1 L, 2.0 V) was charged to the reactor at 20 °C; then, NaOH (118.6 g, 1.3 eq.) was charged to the reactor and the solution left stirring for 1-5 hours until the solid was dissolved; transfer the NaOH aqueous from the reactor to a clean drum.

[0212] Under nitrogen atmosphere, purified water (3.5 L, 7.0 V) and the compound of Formula (VI) (500 g, 1.0 eq.) were charged to the reactor at 25 °C; purified water (0.5 L, 1.0 V) was added to wash the walls of the reactor. After this, the previously prepared NaOH aqueous was added to the reactor and the temperature was increased to 60 °C. The solution was left stirring at this temperature for 3-8 hours.

[0213] The temperature of the reaction mixture was set to 44 °C and after this, citric acid 3M (1.14 L, 1.5 eq.) was added dropwise to the reactor; the reaction mixture was left stirring for 0.5-1 hour before cooling down to 2.5 °C; the solution was left stirring at this temperature for 2-6 hours. The solid was filtered and the cake was washed with purified water (1 L, 2.0 V) for four times. The cake was dried under vacuum at 40 °C (compound of Formula (VII) : 424.52g, 97 % yield, 95 % purity by NMR).Formula (Vlj Formula (V;i jExample 12 - Alternative preparation of 5,7-Dimethylpyrazolo[l,5-a]pyrimidine- 3-carboxylic acid (compound of Formula (VII))

[0214] The reaction is performed in a 10 L vacuum jacketed reactor. Under nitrogen atmosphere, a solution of aqueous NaOH is prepared. Purified water (120 mL, 2.0 V) was charged to the reactor at 20 °C; then, NaOH (14.23 g, 1.3 eq.) was charged to the reactor and the solution left stirring for 1-5 hours until the solid was dissolved; transfer the NaOH aqueous from the reactor to a clean drum.

[0215] Under nitrogen atmosphere, purified water (300 mL, 5.0 V), ethanol (180 mL, 3.0 V) and the compound of Formula (VI) (60 g, 1.0 eq.) were charged to the reactor at 25 °C. After this, the prepared NaOH aqueous was added to the reactor and the temperature was increased to 60 °C. The solution was left stirring at this temperature for 2 hours.

[0216] The temperature of the reaction mixture was maintained at 60 °C and after this, citric acid 3M (137 mL, 1.5 eq.) was added dropwise to the reactor; the reaction mixture was left stirring for 0.5-1 hour before cooling down to 45 °C; then, the reaction mixture was cooled down to 40 °C and after this to 38 °C where seeds (0.5 wt.%) of the compound of Formula (VII) were charged (precipitation started). The reaction mixture temperature was increased to 50 °C for 2 h before cooling down to 2.5 °C and it was left stirring for 2 hours. The solid was filtered and the cake was washed with EtOH:water 1:3 (120 mL, 2.0 V x 1) one time and then with purified water (120 mL, 2.0 V x 3) three times. The cake was dried under vacuum at 40 °C (compound of Formula (VII) : 49.43 g, 94 % yield, 95% purity by NMR).Formula VI ) Formula (V;i)

[0217] Examples 11 and 12 show that citric acid can be used in this step instead ofHCI (as per Example 2, step 2) and that ethanol can be used as a cosolvent.Example 13 - Reducing the formation of impurities in step (a)

[0218] Example 13 demonstrates that in step (a) the impurity, N-dibenzyl-4- (benzyloxy)cyclohexan-l-amine, is reduced to very low amounts when using 2.0 equivalents of BnBr .Amounts represent purity (%area) by HPLC method:Mobile Phase A: 0.05% TFA in Water, Mobile Phase B: 0.05% TFA in ACN, Column: Xbridge C18, 4.6x150mm, 3.5pm Flow rate: 1 mL / min, Injection volume: 5 pL, Column Temperature: 30 °C, Detection: 220 nm, Run Time: 20.1 minutes, Post run: 5 minutes.Embodiments of the invention

[0219] The invention herein can also be described with reference to the following numbered embodiments.1. A process for preparing a compound of Formula (A):Formula (A) said process comprising the following steps:(a) protection of the amine group of a compound of Formula (I) with at least one protecting group (PG) to form a compound of Formula (II);Formula (I) Formula (II) wherein Ri=PG and R2=H or PG(b) alkylation of the compound of Formula (II) to produce a compound of Formula (III), optionally in a salt form;Formula (III) wherein Ri=PG and R2=H or PG(c) deprotection of the compound of Formula (III) to produce a compound of Formula (IV), optionally wherein both compounds are in a salt form;Formula (IV)(d) cyclisation of a compound of Formula (V) with acetylacetone to produce a compound of Formula (VI);ormu a ( ) Formula (VI)(e) hydrolysing the compound of Formula (VI) to produce the compound of Formula (VII)Formula (VII); and(f) amide coupling the compound of Formula (VII) with the compound of Formula (IV) using carbonyldiimidazole (CDI) to produce the compound of Formula (A). A process for preparing a compound of Formula (A):Formula (A) said process comprising the following steps:(a) protection of the amine group of a compound of Formula (I) with a cyclic protecting group (cPG) to form a compound of Formula (II);Formula (I) Formula (II) wherein Ri and R2 form together a cPG(b) alkylation of the compound of Formula (II) to produce a compound of Formula (III), optionally in a salt form;Formula (III) wherein Ri and R2 form together a cPG(c) deprotection of the compound of Formula (III) to produce a compound of Formula (IV), optionally wherein both compounds are in a salt form;Formula (IV)(d) cyclisation of a compound of Formula (V) with acetylacetone to produce a compound of Formula (VI);ormu a ( ) Formula (VI)(e) hydrolysing the compound of Formula (VI) to produce the compound of Formula (VII)Formula (VII); and(f) amide coupling the compound of Formula (VII) with the compound of Formula (IV) using carbonyldiimidazole (CDI) to produce the compound of Formula (A). The process of embodiment 1, wherein the process comprises one or more of the following: step (a) comprises benzylation with a benzylating agent in the presence of K2CO3 and dimethylformamide (DMF) at a temperature of about 20 to about 50 °C, optionally wherein the reaction is quenched at a temperature of less than or equal to about 50 °C, preferably between about 35 to about 45 °C; in step (b) the alkylation is performed with an alkylating agent in the presence of a base and dimethylformamide (DMF) at a temperature of -6 °C to 0 °C, and optionally further comprising a step of converting the compound of Formula (III) to the HCI salt form; step (c) comprises hydrogenolysis which is performed in the presence of a solvent comprising ethanol at a temperature of about 20 °C to about 60 °C and in the presence of hydrogen and Pd / C catalyst; in step (d) the cyclisation is performed in the presence of a solvent comprising acetic acid and at a temperature of from about 20 °C to about 70 °C; step (e) comprises ester hydrolysis that is performed in the presence of a base, preferably NaOH, at a temperature of about 40 °C to about 80 °C for a time of between about 3 hours to about 8 hours; in step (f) the amide coupling is performed at a temperature of about 15 °C to about 35 °C in the presence of a solvent, preferably wherein the solvent is dimethylformamide (DMF). The process of embodiment 1, wherein the process comprises one or more of the following: in step (a) reacting with BOC2O in the presence of K2CO3, NaHCOs, Nets or NaOH and preferably a DCM and water or 1,4-dioxane and water solvent;in step (b) alkylating with an alkylating agent, preferably bromopentane (Br(CH2)4CH3), preferably in the presence of t-BuOK and a DMF solvent; in step (c) deprotecting with an acid, preferably HCI, and optionally a further step of removing acid by reacting with a base; in step (d) the cyclisation is performed in the presence of a solvent comprising acetic acid and at a temperature of from about 20 °C to about 70 °C; step (e) comprises ester hydrolysis that is performed in the presence of a base, preferably NaOH, at a temperature of about 40 °C to about 80 °C for a time of between about 3 hours to about 8 hours; and in step (f) the amide coupling is performed at a temperature of about 15 °C to about 35 °C in the presence of a solvent, preferably wherein the solvent is dimethylformamide (DMF). The process of embodiment 2, wherein the process comprises one or more of the following: in step (a) reacting with hexane-2, 5-dione in the presence of acetic acid in MeOH or EtOH, preferably MeOH; in step (b) alkylating with an alkylating agent, preferably bromopentane (Br(CH2)4CH3), preferably in the presence of t-BuOK and a DMF solvent; in step (c) deprotecting with hydroxylamine hydrochloride in the presence of base such as TEA, NaOH or Na2CO3, preferably NaOH in EtOH / water solvent; in step (d) the cyclisation is performed in the presence of a solvent comprising acetic acid and at a temperature of from about 20 °C to about 70 °C; step (e) comprises ester hydrolysis that is performed in the presence of a base, preferably NaOH, at a temperature of about 40 °C to about 80 °C for a time of between about 3 hours to about 8 hours; and in step (f) the amide coupling is performed at a temperature of about 15 °C to about 35 °C in the presence of a solvent, preferably wherein the solvent is dimethylformamide (DMF). The process of any preceding embodiment, further comprising re-crystallising the compound of Formula (A), preferably wherein said re-crystallisation comprises the steps: i) dissolving the compound of Formula (A) in methyl ethyl ketone (MEK) at a temperature of about 15 °C to about 35 °C to produce a solution; ii) filtering the solution; iii) recrystallising the compound of Formula (A) with heptane between about 14 to about 25 °C, preferably about 17 ± 3 °C;iv) removing the MEK by distillation whilst maintaining the temperature at about 17±3° C; and v) drying the resultant cake at a temperature not more than about 35 °C. The process of embodiment 6, wherein the purity of the recrystalised compounds of Formula (A) is greater than about 90%, preferably greater than or equal to about 95%. The process of embodiments 6 and 7, wherein the process further comprises micronizing the recrystallised compound of Formula (A), preferably jet milling the recrystallised compound of Formula (A). The process of embodiment 8, wherein the recrystallised compound of Formula (A) is sieved through a 20-mesh sieve prior to micronization. The process of embodiment 9, wherein the sieved material has a Dio of between about 10 to 50 pm, a Dso of between about 300 to about 400 pm and a D90 of between about 900 to about 1000 pm. The process of embodiments 8 and 9, wherein the jet milling feeding and milling pressure is controlled at from about 0.3 Mpa to about 0.55Mpa, preferably about 0.4 Mpa. The process of any preceding embodiment, comprising isolating the compound of Formula (A) in the form of a crystalline solid, preferably wherein the crystalline solid exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 4.2 ± 0.2, 10.9 ± 0.2, 11.5 ± 0.2, 12.4 ± 0.2, 16.3 ± 0.2, 21.5 ± 0.2, 22.3 ± 0.2, 22.4 ± 0.2, 22.9 ± 0.2 and 23.0 ± 0.2. The process of any preceding embodiment, wherein in step (a) the at least one protecting group is selected from Benzyl, Boc and Fmoc. The process of any preceding embodiment, wherein the yield of the compound of Formula (II) after step (a) is greater than about 80%, preferably greater than about 85%. The process of embodiments 1, 3 or 6 to 14, wherein step (a) comprises benzylation of the compound of Formula (I) with a benzylating agent to produce a compoundof Formula (IIA), preferably wherein the benzylating agent comprises (bromomethyl)benzene (BnBr) or (chloromethyl)benzene (BnCI).Formula (IIA) The process of embodiment 15, wherein the benzylation is in the presence of K2CO3 and dimethylformamide (DMF) at a temperature of about 20-50 °C, preferably about 30-40 °C, and then quenched with water at about 30-50 °C, preferably about 35-45 °C. The process of embodiments 15 and 16, wherein the benzylating agent is added in an amount of between about 1.9 to about 2.1 molar equivalents, preferably about 2.0 molar equivalents. The process of embodiments 15 to 17, wherein the reaction mixture after benzylation is quenched at a temperature less than about 50 °C, preferably between about 35 to about 45 °C, further preferably at about 40 °C. The process of embodiments 15 to 18, wherein the reaction mixture is subsequently stirred at a lower temperature after quenching. The process of embodiments 15 to 19, wherein the benzylating agent is added dropwise to the reaction mixture, preferably over a period of time of at least about 5 hours, most preferably at least about 6 hours. The process of embodiments 1, 3 or 6 to 20, wherein in step (b) the alkylation is performed in the presence of a base and DMF solvent, preferably wherein DMSO is not used in step (b). The process of embodiments 1, 3 or 6 to 21, wherein the alkylation is carried out at a temperature of about -10 to about 10 °C, preferably about -6 to about 0 °C. The process of embodiments 1, 3 or 6 to 22, wherein the alkylating agent is 1- bromo-pentane. The process of embodiment 23, wherein 3 to 6 molar equivalents of 1-bromo- pentane are used, preferably about 4.5 molar equivalents.The process of embodiments 21 to 24, wherein the base is t-BuOK, preferably in an amount of about 4 to about 5 molar equivalents. The process of embodiments 1, 3 or 6 to 25, wherein the process further comprises isolating the compound of Formula (III) as a HCI salt after step (b) with heptane and HCI in EtOAc. The process of embodiments 1, 3 or 6 to 26, wherein isolating the compound of Formula (III) after step (b) further comprises initially adding EtOAc, subsequently adding HCI in the EtOAc and warming up to about 30 to about 50 °C, to obtain the compound of Formula (III) in HCI salt form. The process of embodiments 1, 3 or 6 to 27, wherein in step (c), the deprotection comprises hydrogenolysis and is optionally performed in the presence of a solvent at a temperature of about 20 °C to about 60 °C, preferably about 45 °C to about 55 °C and in the presence of a suitable hydrogenation catalyst. The process of embodiment 28, wherein the hydrogenolysis is performed at a H2 pressure of less than about 1 MPa, preferably about 0.6 to about 1 MPa. The process of embodiments 28 and 29, wherein the deprotection is performed with hydrogen in the presence of a Pd / C catalyst, preferably in an amount of about 2.5- 3.5 wt%, preferably about 3 wt%. The process of embodiments 28 to 30, wherein the solvent comprises ethanol in an amount of at least about 4V, preferably about 5.0 V. The process of embodiments 26 to 31, wherein the solvent is an ethanol and water mixture, preferably wherein ethanol is in an amount of about 90%v / v to about 100%v / v. The process of embodiments 1, 3 and 6 to 32, wherein the deprotection in step (c) produces the compound of Formula (IV) in salt form, preferably a HCI salt form. The process of embodiments 1, 4 and 6 to 14, wherein step (a) comprises reacting the compound of Formula (I) with BOC2O to produce a compound of Formula (IIB).Formula (IIB) The process of embodiment 34, wherein step (a) is performed in the presence of K2CO3 and preferably a DCM and water solvent. The process of embodiments 34 and 35, wherein step (b) comprises alkylating with Br(CH2)4CH3, preferably in the presence of t-BuOK and a DMF solvent. The process of embodiments 34 and 35, wherein step (b) comprises alkylating with Br(CH2)4CH3 in the presence of KOH and preferably a toluene and water solvent. The process of embodiments 34, 35 and 37, wherein step (b) comprises alkylating with Br(CH2)4CH3 in the presence of a phase transfer catalyst, preferably tetrabutylammonium bromide. The process of embodiments 34 to 38, subsequently deprotecting with an acid, preferably HCI. The process of embodiments 2, 5 to 12, wherein step (a) comprises reacting the compound of Formula (I) with acetonylacetone to produce a compound of Formula (IIC).Formula (IIC) The process of embodiment 40, wherein step (a) is performed in the presence of acetic acid and preferably methanol solvent. The process of embodiments 40 and 41, wherein step (b) comprises alkylating with Br(CH2)4CH3, preferably in the presence of t-BuOK and a DMF solvent.The process of embodiments 40 to 42, wherein step (c) comprises deprotecting with hydroxylamine chloride and preferably a methanol or ethanol and water solvent. The process of embodiments 40 to 43, wherein step (c) is performed in the presence of a base, preferably NaOH. The process of any preceding embodiment, wherein in step (d) between about 1.05 to about 1.30 molar equivalents of acetyl acetone is used, preferably about 1.10 to about 1.30. The process of any preceding embodiment, wherein in step (d) the cyclisation is performed at a temperature of from about 20 °C to about 70 °C, preferably about 45 to about 55 °C. The process of any preceding embodiment, wherein a solvent comprising one or more of acetic acid, toluene and ethanol is used in the cyclisation of step (d), preferably a mix of ethanol and acetic acid. The process of embodiment 47, further comprising crystalising the compound of Formula (VI) in a mixture of EtOH and heptane. The process of any preceding embodiment, further comprising in step (d) crystalising by adding seeds of the compound of Formula (V), preferably in an amount of between about 0.05 to about 0.15 wt%. The process of any preceding embodiment, wherein the yield of the compound of Formula (VI) in step (d) is greater than about 85%, preferably greater than about 90%. The process of any preceding embodiment, wherein in step (e) the ester hydrolysis is performed in the presence of a base, preferably NaOH. The process of embodiment 51, wherein the ester hydrolysis is performed at a temperature of about 40 °C to about 80 °C, preferably about 55 °C to about 65 °C, for about 3 hours to about 8 hours. The process of any preceding embodiment, wherein in step (e) aqueous NaOH is the base and is added in an amount of between about 1.1 to about 2.0 molar equivalents, preferably about 1.2 to about 1.4 molar equivalents.The process of any preceding embodiment, wherein in step (e) aqueous NaOH is added and controlled at about 1.3 molar equivalents, preferably in a solvent comprising water and ethanol. The process of embodiments 51 to 54, comprising subsequently adding an acid, preferably one of HCI and citric acid. The process of embodiment 55, wherein the acid is citric acid preferably added at about 40 to about 65 °C and in an amount of about 1.5 equivalents. The process of embodiments 55 and 56, wherein after the addition of acid, the compound of Formula (VII) prepared in step (e) is isolated by precipitation in EtOH and subjecting the reaction mixture to repeated heating to about 50-55 °C and cooling to about 25-35 °C. The process of any preceding embodiment, wherein the yield of compounds of Formula (VII) after step (e) is greater than about 90%, preferably greater than about 95%. The process of any preceding embodiment, wherein in step (f) about 1 to about 1.5 molar equivalents of CDI are added, preferably about 1.2 molar equivalents. The process of any preceding embodiment, wherein in step (f) the amide coupling is carried out at a temperature of about 15 °C to about 35 °C, optionally about 20 °C to about 30 °C. The process of any preceding embodiment, wherein in step (f) the amide coupling is carried out in the presence of a solvent, preferably wherein the solvent is dimethylformamide (DMF). The process of any preceding embodiment, wherein in step (f) the compound of Formula (IV) is reacted in a salt form, preferably a HCI salt form, or wherein the compound of Formula (IV) is reacted in a freebase form, preferably further comprising a step of reacting the salt form compound of Formula (IV) with a base to remove acid. The process of embodiment 62, wherein the base comprises aqueous NaOH, preferably in the presence of an MTBE solvent. The process of any preceding embodiment, wherein the process produces thecompound of Formula (A) wherein (1) impurities are present in an amount of less or equal to about 0.5 %w / w, preferably less than or equal to about 0.05 %w / w; and / or (2) comprising one or more, or all, of Impurities A to F individually in an amount of less than or equal to about 0.05 %w / w;and / or wherein the process produces the compound of Formula (A) comprising Impurity G, wherein Impurity G is present in an amount of less than or equal to about 0.1 %w / w, preferably less than or equal to about 0.05 %w / w.Impurity <365. A process for preparing a compound of Formula (A):Formula (A) said process comprising a step of: amide coupling a compound of Formula (VII) with a compound of Formula (IV) using carbonyldiimidazole (CDI) to produce the compound of Formula (A)Formula (IV). The process of embodiment 65, further comprising one or more of the following steps:(a) protection of the amine group of a compound of Formula (I) with at least one protecting group (PG) to form a compound of Formula (II);Formula (I) Formula (II) wherein Ri=PG and R2=H or PG(b) alkylation of the compound of Formula (II) to produce a compound of Formula (III), optionally in a salt form;Formula (III) wherein Ri=PG and R2=H or PG(c) deprotection of the compound of Formula (III) to produce a compound of Formula (IV), optionally wherein both compounds are in a salt form;Formula (IV)(d) cyclisation of a compound of Formula (V) with acetylacetone to produce a compound of Formula (VI);ormu a ( ) Formula (VI)(e) hydrolysing the compound of Formula (VI) to produce the compound of Formula (VII)Formula (VII). The process of embodiment 66, comprising all of steps (a) to (e). A process for preparing a compound of Formula (II), said process comprising protection of the amine group of a compound of Formula (I) with at least one protecting group (PG) to form the compound of Formula (II).Formula (I) Formula (II) wherein Ri=PG and R2=H or PGA process for preparing a compound of Formula (III), said process comprising alkylation of a compound of Formula (II) to produce the compound of Formula (III), optionally in a salt form.Formula (II) Formula (III) wherein Ri=PG and R2=H or PG A process for preparing a compound of Formula (IV), said process comprising deprotection of a compound of Formula (III) to produce the compound of Formula (IV), optionally in a salt form.Formula (III) Formula (IV) wherein Ri=PG and R2=H or PG The process for preparing a compound of Formula (IV) of embodiment 70, further comprising the following steps: protection of an amine group of a compound of Formula (I) with at least one protecting group (PG) to form a compound of Formula (II)Formula (I) Formula (II) wherein Ri=PG and R2=H or PG; alkylation of the compound of Formula (II) to produce the compound of Formula (III), optionally in a salt form.The process of embodiment 65, further comprising one or more of the following steps:(a) protection of the amine group of a compound of Formula (I) with a cyclic protecting group (cPG) to form a compound of Formula (II);Formula (I) Formula (II) wherein Ri and R2 form together a cPG(b) alkylation of the compound of Formula (II) to produce a compound of Formula (III), optionally in a salt form;Formula (III) wherein Ri and R2 form together a cPG(c) deprotection of the compound of Formula (III) to produce a compound of Formula (IV), optionally wherein both compounds are in a salt form;Formula (IV)(d) cyclisation of a compound of Formula (V) with acetylacetone to produce a compound of Formula (VI);or u a Formula (VI)(e) hydrolysing the compound of Formula (VI) to produce the compound of Formula (VII)Formula (VII). The process of embodiment 72, comprising all of steps (a) to (e). A process for preparing a compound of Formula (II), said process comprising protection of the amine group of a compound of Formula (I) with a cyclic protecting group (cPG) to form the compound of Formula (II).Formula (I) Formula (II) wherein Ri and R2 form together a cPG A process for preparing a compound of Formula (III), said process comprising alkylation of a compound of Formula (II) to produce the compound of Formula (III), optionally in a salt form.Formula (II) Formula (III) wherein Ri and R2 form together a cPGA process for preparing a compound of Formula (IV), said process comprising deprotection of a compound of Formula (III) to produce the compound of Formula (IV), optionally in a salt form.Formula (III) ' Formula (IV) wherein Ri and R2 form together a cPG The process of embodiment 76, further comprising the following steps: protection of an amine group of a compound of Formula (I) with a cyclic protecting group (cPG) to form a compound of Formula (II)Formula (I) Formula (II) wherein Ri and R2 form together a cPG; alkylation of the compound of Formula (II) to produce the compound of Formula (III), optionally in a salt form. A process for preparing a compound of Formula (VI), said process comprising cyclisation of a compound of Formula (V) with acetylacetone to produce a compound of Formula (VI).ormu a ( ) Formula (VI) A process for preparing a compound of Formula (VII), hydrolysing a compound of Formula (VI) to produce the compound of Formula (VII).Formula (VII) The process of embodiment 79, further comprising cyclisation of a compound of Formula (V) with acetylacetone to produce the compound of Formula (VI).Formula (V) The process of embodiments 68 to 80, wherein the compound is prepared as an intermediate in the synthesis of a compound of Formula (A).Formula (A) A process for preparing a compound of Formula (A), the process comprising recrystallizing the compound of Formula (A) in methyl ethyl ketone (MEK) and / or jet milling a recrystallized compound of Formula (A).Formula (A) The process of embodiments 65 to 82, wherein the process comprises any of the compatible features of embodiments 1 to 64. A solid dosage form comprising 5,7-Dimethyl-N-((lR,4R)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide.The solid dosage form according to embodiment 84, comprising micronized 5,7- Dimethyl-N-((lR,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3- carboxamide. The solid dosage form according to embodiments 84 to 85, wherein the solid dosage form comprises 5,7-Dimethyl-N-((lR,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5- a]pyrimidine-3-carboxamide having a particle size of D50: 1pm - 60pm. The solid dosage form according to embodiment 86, wherein D50 is 3pm - 50 pm. The solid dosage form according to embodiment 86, wherein D50 is 5pm - 30pm. The solid dosage form of embodiments 84 to 88, wherein the solid dosage form comprises 5,7-Dimethyl-N-((lR,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5- a]pyrimidine-3-carboxamide having a particle size of DIO: > 0.3 pm. The solid dosage form of embodiment 89, wherein D10 is > 0.5 pm. The solid dosage form embodiment 89, wherein D10 is > 1 pm. The solid dosage form of embodiments 84 to 91, wherein the solid dosage form comprises 5,7-Dimethyl-N-((lR,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5- a]pyrimidine-3-carboxamide having a particle size of D90: < 100 pm. The solid dosage form of embodiment 92, wherein D90 is < 80 pm. The solid dosage form of embodiment 92, wherein D90 is < 60 pm. The solid dosage form of embodiments 84 to 94, wherein the solid dosage form comprises 5,7-Dimethyl-N-((lR,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5- a]pyrimidine-3-carboxamide having a particle size of D10: > 0.3 pm; D50: 1pm - 60pm; and D90: < 100 pm. The solid dosage form of embodiment 95, wherein the 5,7-Dimethyl-N-((lR,4R)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide has a particle size of D10: > 0.5 pm; D50: 2pm - 50pm; and D90: < 80 pm.The solid dosage form of embodiment 95, wherein the 5,7-Dimethyl-N-((lR,4R)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide has a particle size of DIO: > 1 pm; D50: 5pm - 30pm; and D90: < 60 pm. A crystalline form of 5,7-dimethyl-N-((lR,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide having a particle size as defined below:D50 is 1pm - 60 pm, preferably 2pm - 50pm, or more preferably 5pm - 30pm; D10 is > 0.3 pm, preferably > 0.5pm, or more preferably > 1 pm; and / or D90 is < 100pm, preferably < 80pm, or more preferably < 60pm. The crystalline form of embodiment 98 having a particle size of D10: > 0.3 pm; D50: 1pm - 60pm; and D90: < 100 pm, preferably a particle size of D10: > 0.5 pm; D50: 2pm - 50pm; and D90: < 80 pm, even more preferably D10: > 1 pm; D50: 5pm - 30pm; and D90: < 60 pm. . The crystalline form of embodiments 98 and 99, wherein the crystalline form is prepared by micronizing a crystalline particle of 5,7-dimethyl-N-((lR,4R)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide. . The crystalline form of embodiments 98 to 100, wherein micronization is performed by jet milling, mechanical milling, fluid milling, crushing or grinding. . The crystalline form of embodiments 98 to 101, wherein the crystalline form is Form A or Form B. . A compound, preferably in crystalline form, of 5,7-dimethyl-N-((lR,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide wherein impurities are present in an amount of less than or equal to about 0.5 %w / w, preferably less than about 0.05 %w / w. . A compound, preferably in crystalline form, of 5,7-dimethyl-N-((lR,4R)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide having a chemical purity of about 99.5 % by more, preferably of about 99.95% or more, further preferably as measured by a HPLC method described herein. . A compound, preferably in crystalline form, of 5,7-dimethyl-N-((lR,4R)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide wherein one ormore, or all, of Impurities A to F are individually present in an amount of less than or equal to about 0.15 %w / w, preferably less than about 0.05 %w / w.Impurity B. The compound of embodiment 105, wherein one or more, or all, of Impurities A to F are individually present in an amount below the limit of quantification. . A compound, preferably in crystalline form, of 5,7-dimethyl-N-((lR,4R)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide which comprises Impurity G, preferably wherein Impurity G is present in an amount of less than or equal to about 0.1 %w / w, preferably less than or equal to about 0.05 %w / w.Impurity G . The compound of embodiment 107, wherein the amount of Impurity G is below the limit of quantification. . The compound of embodiments 107 and 108, wherein one or more, or all, of Impurities A to F are individually present in an amount of less than or equal to about 0.15 %w / w, preferably less than about 0.05 %w / w, further preferably wherein one or more, or all, of Impurities A to F are individually present in an amount below the limit of quantification. . A compound, preferably in crystalline form, of 5,7-dimethyl-N-((lR,4R)-4- (pentyloxy)cyclohexyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide, obtainable by, orobtained by, the process of any of embodiments 1 to 83. . The compound of embodiment 110, wherein the compound is as defined in any of embodiments 103 to 109. . A pharmaceutical composition comprising a compound of any one of embodiments 103-111 and a pharmaceutically acceptable carrier. . A method of treating a disorder selected from the group consisting of Gaucher disease, Parkinson's disease, Lewy body disease, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, an anxiety disorder, major depression, polycystic kidney disease, type 2 diabetes, open angle glaucoma, multiple sclerosis, endometriosis, and multiple myeloma, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of embodiments 103-111 to treat the disorder. . The compound of any of embodiments 103-111 for use in the treatment of a disorder selected from the group consisting of Gaucher disease, Parkinson's disease, Lewy body disease, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, an anxiety disorder, major depression, polycystic kidney disease, type 2 diabetes, open angle glaucoma, multiple sclerosis, endometriosis, and multiple myeloma, said use comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of embodiments 103-111 to treat the disorder.

Claims

Claims1. A process for preparing a compound of Formula (A):Formula (A) said process comprising a step of: amide coupling a compound of Formula (VII) with a compound of Formula (IV) using carbonyldiimidazole (CDI) to produce the compound of Formula (A)ormu a ( ) Formula (IV).

2. The process of claim 1, further comprising one or more of the following steps:(a) protection of the amine group of a compound of Formula (I) with at least one protecting group (PG) to form a compound of Formula (II);Formula (I) Formula (II) wherein Ri=PG and R2=H or PG(b) alkylation of the compound of Formula (II) to produce a compound of Formula (III), optionally in a salt form;Formula (III) wherein Ri=PG and R2=H or PG(c) deprotection of the compound of Formula (III) to produce the compound of Formula (IV), optionally wherein both compounds are in a salt form;Formula (IV)(d) cyclisation of a compound of Formula (V) with acetylacetone to produce a compound of Formula (VI);ormu a ( ) Formula (VI)(e) hydrolysing the compound of Formula (VI) to produce the compound of Formula (VII)Formula (VII); optionally wherein the process comprises all of steps (a) to (e).

3. The process of claim 2, wherein the process comprises one or more of the following : step (a) comprises benzylation with a benzylating agent in the presence of K2CO3 and dimethylformamide (DMF) at a temperature of about 20 to about 50 °C,optionally wherein the reaction is quenched at a temperature of less than or equal to about 50 °C, preferably between about 35 to about 45 °C; in step (b) the alkylation is performed with an alkylating agent in the presence of a base and dimethylformamide (DMF) at a temperature of about -6 °C to about 0 °C, and optionally further comprising a step of converting the compound of Formula (III) to the HCI salt form; step (c) comprises hydrogenolysis which is performed in the presence of a solvent comprising ethanol, at a temperature of about 20 °C to about 60 °C, and in the presence of hydrogen and Pd / C catalyst; in step (d) the cyclisation is performed in the presence of a solvent comprising acetic acid and at a temperature of from about 20 °C to about 70 °C; step (e) comprises ester hydrolysis that is performed in the presence of a base, preferably NaOH, at a temperature of about 40 °C to about 80 °C for a time of between about 3 hours to about 8 hours; and in step (f) the amide coupling is performed at a temperature of about 15 °C to about 35 °C in the presence of a solvent, preferably wherein the solvent is dimethylformamide (DMF).

4. The process of claims 2 or 3, wherein step (a) comprises benzylation of the compound of Formula (I) with a benzylating agent to produce a compound of Formula (IIA), preferably wherein the benzylating agent comprises (bromomethyl)benzene (BnBr) or (chloromethyl)benzene (BnCI); andwherein the benzylating agent is added in an amount of between about 1.9 to about 2.1 molar equivalents, preferably about 2.0 molar equivalents.

5. The process of any of claims 2 to 4, wherein in step (a) the reaction mixture after benzylation is quenched at a temperature less than about 50 °C, preferably between about 35 to about 45 °C, further preferably at about 40 °C.

6. The process of any of claims 2 to 5, wherein the benzylating agent is added dropwise to the reaction mixture, preferably over a period of time of at least about 5 hours, most preferably at least about 6 hours.

7. The process of any of claims 2 to 6, wherein in step (b) the alkylation is performed in the presence of a base and DMF solvent, preferably wherein DMSO is not used in step (b).

8. The process of any of claims 2 to 7, wherein in step (b) the alkylation is carried out at a temperature of about -10 to about 10 °C, preferably about -6 to about 0 °C.

9. The process of claims 2 to 8, wherein in step (b) about 3 to about 6 molar equivalents of 1-bromo-pentane are used, preferably about 4.5 molar equivalents.

10. The process of claims 1 or 2, wherein the process comprises one or more of the following: in step (a) reacting with BoczO in the presence of K2CO3, NaHCOs, NEts or NaOH and preferably a DCM and water or 1,4-dioxane and water solvent; in step (b) alkylating with an alkylating agent, preferably bromopentane (Br(CH2)4CH3), preferably in the presence of t-BuOK and a DMF solvent; in step (c) deprotecting with an acid, preferably HCI, and optionally a further step of removing acid by reacting with a base; in step (d) the cyclisation is performed in the presence of a solvent comprising acetic acid and at a temperature of from about 20 °C to about 70 °C; step (e) comprises ester hydrolysis that is performed in the presence of a base, preferably NaOH, at a temperature of about 40 °C to about 80 °C for a time of between about 3 hours to about 8 hours; and in step (f) the amide coupling is performed at a temperature of about 15 °C to about 35 °C in the presence of a solvent, preferably wherein the solvent is dimethylformamide (DMF).

11. The process of claim 1, further comprising one or more of the following steps:(a) protection of the amine group of a compound of Formula (I) with a cyclic protecting group (cPG) to form a compound of Formula (II);Formula (I) Formula (II) wherein Ri and R2 form together a cPG(b) alkylation of the compound of Formula (II) to produce a compound of Formula (III), optionally in a salt form;Formula (III) wherein Ri and R2 form together a cPG(c) deprotection of the compound of Formula (III) to produce the compound of Formula (IV), optionally wherein both compounds are in a salt form;Formula (IV)(d) cyclisation of a compound of Formula (V) with acetylacetone to produce a compound of Formula (VI);ormu a ( ) Formula (VI)(e) hydrolysing the compound of Formula (VI) to produce the compound of Formula (VII)Formula (VII); optionally wherein the process comprises all of steps (a) to (e).

12. The process of claims 1 or 11, wherein the process comprises one or more of the following: in step (a) reacting with hexane-2, 5-dione in the presence of acetic acid in MeOH or EtOH, preferably MeOH;in step (b) alkylating with an alkylating agent, preferably bromopentane (Br(CH2)4CH3), preferably in the presence of t-BuOK and a DMF solvent; in step (c) deprotecting with hydroxylamine hydrochloride, preferably in the presence of NaOH in EtOH / water solvent; in step (d) the cyclisation is performed in the presence of a solvent comprising acetic acid and at a temperature of from about 20 °C to about 70 °C; step (e) comprises ester hydrolysis that is performed in the presence of a base, preferably NaOH, at a temperature of about 40 °C to about 80 °C for a time of between about 3 hours to about 8 hours; and in step (f) the amide coupling is performed at a temperature of about 15 °C to about 35 °C in the presence of a solvent, preferably wherein the solvent is dimethylformamide (DMF).

13. The process of any of claims 2 to 12, comprising in step (e) subsequently adding an acid, wherein the acid is citric acid, preferably added at 40 to 65 °C and in an amount of about 1.5 equivalents.

14. The process of claim 13, wherein after the addition of acid, the compound of Formula (VII) prepared in step (e) is isolated by precipitation in EtOH and subjecting the reaction mixture to repeated heating to about 50 to about 55 °C and cooling to about 25 to about 35 °C.

15. The process of any preceding claim, wherein in step (f) about 1 to about 1.5 molar equivalents of CDI are added, preferably about 1.2 molar equivalents.

16. The process of any preceding claim, further comprising re-crystallising the compound of Formula (A), preferably wherein said re-crystallisation comprises the steps: i) dissolving the compound of Formula (A) in methyl ethyl ketone (MEK) at a temperature of about 15 °C to about 35 °C to produce a solution; ii) filtering the solution; iii) recrystallising the compound of Formula (A) with heptane between about 14 to about 25 °C, preferably about 17 ± 3 °C; iv) removing the MEK by distillation whilst maintaining the temperature at about 17±3° C; and v) drying the resultant cake at a temperature not more than about 35 °C.

17. The process of any preceding claim, wherein the process produces the compound of Formula (A) comprising one or more, or all, of Impurities A to F individually in an amount of less than or equal to about 0.05 %w / w;Impurity A Impurity 8 Impurity Cand / or wherein the process produces the compound of Formula (A) comprising Impurity G, wherein Impurity G is present in an amount of less than or equal to about 0.05 %w / w.Impurity G

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