Process for the preparation of [(5-{2-cyclopropyl-6-[4-fluoro-3-(propan- 2-yl)phenyl]imidazo[1,2-a]pyrazin-3-yl}-4-fluoro-1h-indazol-1- yl)methoxy]phosphonic acid

Abstract

The present invention relates to a process for the preparation of [(5-{2- cyclopropyl-6-[4-fluoro-3-(propan-2-yl)phenyl]imidazo[1,2-a]pyrazin-3-yl}-4- fluoro-1H-indazol-1-yl)methoxy]phosphonic acid (compound I), and pharmaceutically acceptable salts thereof, which have anthelmintic activity and can therefore be used in the treatment or prevention of a helminth infection such as in particular schistosomiasis, also known as bilharzia, and / or fascioliasis. The present invention also relates to precursors of compound (I), and to processes for the preparation of these precursors. And the present invention further relates to processes for the preparation of a solid state form of compound (I).

Description

[0001] Foreignfiling_text P24-237-SEC-WO01 20250922

[0002] 1

[0003] Process for the preparation of [(5-{2-cyclopropyl-6-[4-fluoro-3-(propan- 2-yl)phenyl]imidazo[1,2-a]pyrazin-3-yl}-4-fluoro-1H-indazol-1- yl)methoxy]phosphonic acid

[0004] 5 The present invention relates to a process for the preparation of [(5-{2- cyclopropyl-6-[4-fluoro-3-(propan-2-yl)phenyl]imidazo[1,2-a]pyrazin-3-yl}-4- fluoro-1 H-indazol-1-yl)methoxy]phosphonic acid (compound I), and pharmaceutically acceptable salts thereof, which have anthelmintic activity and can therefore be used in the treatment or prevention of a helminth infection such as in particular schistosomiasis, also known as bilharzia, and / or fascioliasis. The present invention also relates to precursors of compound I, and to processes for the preparation of these precursors as well as their use. And the present invention further relates to processes for the preparation of a solid state form of compound I.

[0005] WO2018 / 130853 A1 discloses 2-Cyclopropyl-3-(4-fluoro-1 H-indazol-5-yl)-6- (4-fluoro-3-isopropyl-phenyl)-imidazo[1,2-a]pyrazine (compound 6) together with a preparation process.

[0006]

[0007] [(5-{2-cyclopropyl-6-[4-fluoro-3-(propan-2-yl)phenyl]imidazo[1,2-a]pyrazin-3- yl}-4-fluoro-1 H-indazol-1-yl)methoxy]phosphonic acid (compound I)

[0008]

[0009] Foreignfiling_text P24-237-SEC-WO01 20250922

[0010] 2

[0011] is described in PCT / EP2024 / 066890, which also includes a process for its preparation, with 2-Cyclopropyl-3-(4-fluoro-1 H-indazol-5-yl)-6-(4-fluoro-3- isopropyl-phenyl)-imidazo[1,2-a]pyrazine (compound 6) serving as an intermediate. However, this process is not suitable for large-scale production 5 in particular because of following issues:

[0012] - High catalyst loadings

[0013] - Poor catalyst activity

[0014] - Unsuitable solvents (especially in view of waste water treatment) - Formation of regioisomers (which requires labour intensive regioisomers separation via preparative chromatography)

[0015] - Several chromatographic purification steps necessary

[0016] - Low yields due to side-reactions

[0017] - High cost of goods.

[0018] Based on this, one object of the present invention is to provide a safe and efficient preparation process, which can address some or all of the issues described above and be applied on a multikilogram scale. This object has been achieved by the provision of the processes described herein.

[0019] Advantages of the process of the present invention are in particular:

[0020] - Lower catalyst loadings

[0021] - Higher catalyst activity

[0022] - Lower cost of goods compared to initial process

[0023] - No chromatographic purification steps required

[0024] - Simplified handling of exhaust gases and wash waters

[0025] Brief Description of the Drawings

[0026] Fig. 1a X-ray diffractogram of NF6

[0027] 30 Fig. 1b DSC scan of NF6

[0028] Fig. 1 c TG scan of NF6

[0029] Fig. 1d Water vapour sorption isotherm (25°C) of NF6 Foreignfiling_text P24-237-SEC-WO01 20250922

[0030] 3

[0031] Fig. 2a X-ray diffractogram of crystalline form A2

[0032] Fig. 2b Electron diffraction structure of crystalline form A2 along a-axis Fig. 2c DSC scan of crystalline form A2

[0033] Fig. 2dTG scan of crystalline form A2

[0034] 5 Fig. 2e Water vapour sorption isotherm (25°C)

[0035] Description of the Process

[0036] The processes according to the present invention are summarized in Scheme 1. The individual steps are described in more detail below. Foreignfiling_text P24-237-SEC-WO01 20250922

[0037] step 1 step 2 B2pin2base base

[0038]

[0039] Pd-catalyst Pd-catalyst organic solvent organic solvent / water then MeSO3H

[0040]

[0041] brominating agent solvent then step 4 base / water

[0042] 20

[0043] CH2O or paraformaldehyde solvent Step 7

[0044] alcohol, water, buffer Step 9

[0045]

[0046] Foreignfiling_text P24-237-SEC-WO01 20250922

[0047] 5

[0048] Scheme 1: Overview of the processes according to the invention

[0049] One aspect of the present invention relates to a process for the preparation of compound I

[0050] 5

[0051]

[0052] or a pharmaceutically acceptable salt thereof, comprising following steps:

[0053] • formation of compound 7

[0054]

[0055] via regio-selective reaction of compound 6

[0056]

[0057] with formaldehyde or para-formaldehyde (this step is in the following also referred as step 7);

[0058] • formation of compound 8

[0059]

[0060] 30

[0061] via phosphorylation of compound 7 Foreignfiling_text P24-237-SEC-WO01 20250922

[0062]

[0063] (this step is in the following also 5

[0064] referred as step 8); and

[0065] formation of compound I

[0066]

[0067] via hydrolysis of the alcoholate substituents of compound 8

[0068] (this step is in the following also referred as step 9).

[0069]

[0070] In another important aspect of the invention this process further comprises one or more of the following steps:

[0071] • Synthesis of compound 1

[0072] Bpin

[0073] F Me

[0074]

[0075] 1

[0076] via Miyaura borylation of 2-fluoro-5-bromocumene A

[0077] 30 Foreignfiling_text P24-237-SEC-WO01 20250922

[0078] 7

[0079] A

[0080] (this step is in the following also referred as step 1); 5

[0081] • formation of compound 2

[0082]

[0083] via a Suzuki coupling reaction between compound 1

[0084] Bpin

[0085] F Me

[0086]

[0087] 1

[0088] and 2-amino-5-bromopyrazine B (this step is in the following also referred as step 2);

[0089] • formation of compound 3

[0090]

[0091] via addition of 2-bromo-1-cyclopropylethan-1-one C and subsequent ring formation after release of free base of compound 2 (this step is in the following also referred as step 3);

[0092] • formation of compound 4

[0093] 30

[0094]

[0095] via bromination of compound 3 Foreignfiling_text P24-237-SEC-WO01 20250922

[0096]

[0097] (this step is in the following also referred 5 as step 4);

[0098] • formation of compound D1

[0099] F

[0100] via THP protection of compound D

[0101] D(this step is in the following also referred as step D1 );

[0102]

[0103] • formation of compound D1(B)

[0104] THP D1(B)

[0105] / O

[0106] Y: B(OH)2, Bv

[0107]

[0108] via borylation reaction of compound D1

[0109] (this step is in the following also referred as step

[0110]

[0111] D1(B));

[0112] • formation of compound 5

[0113] Me N N

[0114] 30

[0115] 5

[0116]

[0117] VN

[0118] via Suzuki coupling reaction between compound 4 Foreignfiling_text P24-237-SEC-WO01 20250922

[0119] N

[0120] Me

[0121] and compound D1(B)

[0122] 5 F

[0123] _ / L, B(OH)2

[0124] N II I

[0125]

[0126] THPD1<B>

[0127] (this step is in the following also referred as step 5);

[0128] formation of compound 6

[0129]

[0130] via deprotection of the THP group of compound 5 (this step is in the following also referred as step 6).

[0131] Another important aspect of the present invention relates to compound 7, which is an important precursor of compounds 8 and I, a use of compound 7 for the preparation of compound 8 and / or compound I, and a process for the preparation of compound 7

[0132]

[0133] characterized in that compound 6

[0134] 30

[0135]

[0136] is treated with CH2O or para-formaldehyde (this process is described in more detail under step 6). Foreignfiling_text P24-237-SEC-WO01 20250922

[0137] 10

[0138] Another important aspect of the present invention relates to compound 8, which is an important precursor of compound I, a use of compound 8 for the preparation of compound I, and a process for the preparation of compound 8 5

[0139]

[0140] characterized in that compound 6

[0141]

[0142] is treated with CH2O or para-formaldehyde to form (this step is in the following also referred as step 2) (this reaction is described in more detail in step 7);

[0143]

[0144] which is subsequently phosphorylated (this phosphorylation is described in more detail in step 8).

[0145] Another important aspect of the present invention relates to a process for the preparation of solid-state form A2 of compound I, which represents a stable solid-state form that possesses a property profile suitable for pharmaceutical applications. Particular advantages of form A2 are good crystallinity and 30 favourable thermodynamic solubility levels and dissolution kinetics in intestinal media. Foreignfiling_text P24-237-SEC-WO01 20250922

[0146] 11

[0147] This process for the preparation of solid-state form A2 of compound I includes following steps:

[0148] (a) suspending compound I in a suitable solvent and stirring the resulting mixture at a temperature between 40-60°C;

[0149] 5 (b) cooling of the mixture resulting from step a) to a temperature in the range of 10-30°C;

[0150] (c) isolating the solid resulting from step b) and drying the solid at a temperature in the range of 30-50°C.

[0151] “Pharmaceutically acceptable salt" means a salt such as those described in standard texts on salt formation, see for example: P. Stahl, et al., Handbook of Pharmaceutical Salts: Properties, Selection and Use (VCHA / Wiley-VCH, 2002), or S. M. Berge, et al., " Pharmaceutical Salts" (1977) Journal of Pharmaceutical Sciences, 66, 1-19. Suitable salts according to the invention include those formed with organic or inorganic acids or bases. In particular, suitable salts formed with acids according to the invention include those formed with mineral acids, strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, such as saturated or unsaturated dicarboxylic acids, such as hydroxycarboxylic acids, such as amino acids, or with organic sulfonic acids, such as C1-C4 alkyl- or aryl-sulfonic acids which are unsubstituted or substituted, for example by halogen. Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulphuric, nitric, citric, tartaric, acetic, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, succinic, perchloric, fumaric, maleic, glycolic, lactic, salicylic, oxaloacetic, methanesulfonic, ethanesulfonic,

[0152] p-toluenesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic, isethionic, ascorbic, malic, phthalic, aspartic, and glutamic acids, lysine and arginine. Other acids, which may or may not in themselves 30 be pharmaceutically acceptable, may be useful as intermediates in obtaining the compounds of the invention and their pharmaceutical acceptable acid addition salts. Foreignfiling_text P24-237-SEC-WO01 20250922

[0153] 12

[0154] Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts, for example those of potassium and sodium, alkaline earth metal salts, for example those of calcium and magnesium, and salts with organic bases, 5 for example dicyclohexylamine, N-methyl-D-glucomine, morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, for example ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine, or a mono-, di- or trihydroxy lower alkylamine, for example mono-, di- or triethanolamine. Corresponding internal salts may furthermore be formed.

[0155] Embodiments of the Invention

[0156] Step 1

[0157] According to one embodiment of the invention compound 1 is synthesized via Miyaura borylation of 2-fluoro-5-bromocumene A in a suitable organic solvent and at a suitable temperature, wherein the reaction mixture is extracted with an aqueous solution of an inorganic base after the reaction.

[0158] This synthesis, which is performed under standard or similar Miyaura borylation conditions, involves reacting the brominated compound A with bis(pinacolato)boron or a similar reagent (with a substituent other than pinacolate at the boron) in the presence of a suitable base and a suitable palladium catalyst.

[0159] In this context a suitable base is an organic or inorganic base such as KOAc, K2CO3 or K3PO4 with stoichiometry of 1 to 3 equivalents.

[0160] A suitable palladium catalyst may be either formed in-situ with

[0161] 30 Pd(OAc)2, Pd2(dba)3 or alternative palladium sources with an organic ligand or be a pre-formed complex like for example Pd(PPhs)4, Pd(dppf)Cl2, Pd(dppf)Cl2. DCM or Pd(Amphos)2Cl2, (Bis(di-tert-butyl(4- Foreignfiling_text P24-237-SEC-WO01 20250922

[0162] 13

[0163] dimethylaminophenyl)phosphin)dichlorpalladium(ll)). The palladium catalyst is used with a stoichiometry of 0.1 to 5mol%, preferably with a stoichiometry of 0.1-1mol%, more preferably with a stoichiometry of 0.1-0.5mol% and even more preferably with a stoichiometry of 0.1 mol%. Preferably the palladium 5 catalyst is Pd(Amphos)2Cl2 with a stoichiometry of 0.1-0.5mol%, most preferably with a stoichiometry of 0.1 mol%.

[0164] A suitable organic solvent is THF, MeTHF, MeCN, an ether, an ester or toluene.

[0165] A suitable reaction temperature is in the range of 40-110°C. Preferably the temperature is in the range of 85-110°C and more preferably in the range of 100-110°C.

[0166] The inorganic base, which is used in aqueous solution for the extraction, is preferably selected from KOAc, NaOAc, NaOH, KOH, Na2CO3, NaHCO3and K2CO3. The aqueous solution contains preferably 1-10% (w / w) inorganic base. In a particular preferred embodiment, the aqueous solution contains 3- 7% (w / w) (preferably 5% (w / w)) inorganic base. In a very special embodiment, the aqueous solution contains 5% Na2CO3.

[0167] Preferably the reaction mixture is filtered (preferably over silica gel) prior to the extraction with the basic aqueous solution.

[0168] Step 2

[0169] According to one embodiment of the invention compound 2 is obtained via a Suzuki coupling reaction between compound 1 and 2-amino-5- bromopyrazine B in a suitable organic solvent and at a suitable temperature.

[0170] 30 Foreignfiling_text P24-237-SEC-WO01 20250922

[0171] 14

[0172] This synthesis, which is performed under standard or similar Suzuki coupling conditions, involves reacting compounds 1 and B in the presence of a suitable base and a suitable palladium catalyst.

[0173] 5 A suitable base for this reaction is an inorganic base such as for example KOAc, K2CO3 or K3PO4 with stoichiometry of 1 to 3 equivalents.

[0174] A suitable palladium catalyst may be either formed in-situ with Pd(OAc)2, Pd2(dba)3 or alternative palladium sources with an organic ligand or be a pre-formed complex like for example Pd(PPhs)4, Pd(dppf)Cl2, Pd(dppf)Cl2. DCM or Pd(Amphos)2Cl2, (Bis(di-tert-butyl(4- dimethylaminophenyl)phosphin)dichlorpalladium(ll)). The palladium catalyst is used with a stoichiometry of 0.1 to 5mol%. Preferably the palladium catalyst is Pd(Amphos)2Cl2 with a stoichiometry of 0.1-1mol%, more preferably with a stoichiometry of 0.1-0.5mol% and even more preferably with a stoichiometry of 0.1 mol%.

[0175] A suitable solvent is a mixture of water with an organic solvent selected from THF, MeTHF, MeCN, ether, acetone, ethyl acetate and toluene.

[0176] A suitable temperature is in the range of 40-110°C. Preferably the temperature is in the range of 85-110°C and more preferably in the range of 100-110°C.

[0177] After work-up the reaction product is preferably isolated via precipitation of a salt formed with an organic or inorganic Bronsted acid. Preferably salt 2 is formed via precipitation with methanesulfonic acid as this gives a particular high yield.

[0178] 30 Foreignfiling_text P24-237-SEC-WO01 20250922

[0179] 15

[0180] Step 3

[0181] According to one embodiment of the invention compound 3 is synthesized via addition of 2-bromo-1-cyclopropylethan-1-one C and following ring formation in a suitable organic solvent and at a suitable temperature. This ring

[0182] 5 formation is preformed after release of free base of compound 2.

[0183] The release of free base involves reacting compound 2 in the presence of an excess of a suitable inorganic base in a biphasic mixture of water with a suitable organic solvent followed by phase separation.

[0184] The released free base is then reacting with an excess of 2-bromo-1- cyclopropylethan-1-one C (preferably with a stoichiometry of 1 to 1.5 equivalents). A suitable organic solvent for the ring formation is e.g. MeCN or toluene. A suitable temperature for the ring formation, wherein the suitable temperature in the range 20-80°C, preferably in the range of 30-60°C and more preferably at 40°C.

[0185] A suitable inorganic base for the biphasic mixture is for example NaOH or KOH. A suitable organic solvent for the biphasic mixture is for example DCM or EtOAc.

[0186] Step 4

[0187] According to one embodiment of the invention compound 4 is synthesized via bromination of compound 3 in a suitable organic solvent and at a suitable temperature.

[0188] This synthesis involves reacting compound 3 in the presence of a bromination agent. A suitable bromination agent is for example Br2 or NBS, 30 preferably with a stoichiometry of 1 to 1.3 equivalents.

[0189] A suitable organic solvent is for example DCM, CHCl3or 1,2-dichloroethane. Foreignfiling_text P24-237-SEC-WO01 20250922

[0190] 16

[0191] And a suitable reaction temperature is in the range of -15 to 20°C, preferably in the range of -10 to 10°C, more preferably between -5 to 5°C, and most preferably at 0°C.

[0192] 5

[0193] After the reaction the reaction mixture is tempered to 60-75°C (preferably 60- 70°C, most preferably 67°C) and a cooling ramp down to -15°C is started. When a temperature of about 35°C is reached, methanol is slowly added during cooling, which leads to precipitation of compound 4.

[0194] Step D1

[0195] According to one embodiment of the invention compound D1 is obtained via THP protection of compound D. This protection is performed under standard or similar conditions, in the presence of an excess of DHP (3,4-dihydro-2H-pyrane) and a suitable acidic catalyst in a suitable solvent (e.g. DCM, toluene) and at a suitable temperature between 10 and 50°C.

[0196] DHP is preferably used with a stoichiometry of 1 to 1.5 equivalents.

[0197] A suitable acidic catalyst is p-TsOH (p-Toluenesulfonic acid) or PPTS (Pyridinium-p-toluenesulfonat), with a stoichiometry of 0.05 to 0.5 equivalents. Preferably the acidic catalyst is resin-bound like e.g. p-TSOH on resin.

[0198] A suitable organic solvent is for example DCM or toluene.

[0199] A suitable reaction temperature is in the range of 10-50°C. Preferably the temperature is in the range of 15-35°C and more preferably in the range of 30 20-30°C, most preferably the reaction is 25°C. Foreignfiling_text P24-237-SEC-WO01 20250922

[0200] 17

[0201] Step D1(B)

[0202] According to one embodiment of the invention compound D1(B) is synthesized via borylation reaction of compound D1. This borylation reaction is done either via boronic acid formation (Y=B(OH)2) or via Miyaura

[0203] 5 borylation (Y=Bpin) under typical conditions (see Miyaura borylation conditions described for step 1).

[0204] In the case of boronic acid formation, the process involves the halogenmetal exchange of compound D1 with a suitable organometallic base in a suitable solvent mixture at a suitable temperature followed by reaction with trimethylborate or other boric acid esters with different alcoholate substituents preferably with a stoichiometry of 1 to 1.3 equivalents and also preferably at the same temperature.

[0205] Suitable organometallic base is n-BuLi, s-BuLi, f-BuLi or LDA, preferably with a stoichiometry of 1 to 1.2 equivalents.

[0206] A suitable solvent mixture contains THF, MeTHF, toluene or other ether and n-hexane or n-heptane.

[0207] A suitable temperature is in the range of -80 to -25°C, preferably in the range of -70 to -60°C.

[0208] Step 5

[0209] According to one embodiment of the invention compound 5 is obtained via Suzuki coupling reaction between compound 4 and compound D1(B) in a suitable organic solvent and at a suitable temperature.

[0210] 30 This Suzuki coupling, which is performed under standard or similar conditions, involves reacting compounds 4 and D1(B) in the presence of a suitable base and a suitable palladium catalyst. Foreignfiling_text P24-237-SEC-WO01 20250922

[0211] 18

[0212] A suitable base for this reaction is an inorganic base such as for example KOAc, K2CO3 or K3PO4 with stoichiometry of 1 to 3 equivalents.

[0213] 5 A suitable palladium catalyst may be either formed in-situ with Pd(OAc)2, Pd2(dba)3 or alternative palladium sources with an organic ligand or be a pre-formed complex like for example Pd(PPhs)4, Pd(dppf)Cl2, Pd(dppf)Cl2. DCM or Pd(Amphos)2Cl2, (Bis(di-tert-butyl(4- dimethylaminophenyl)phosphin)dichlorpalladium(ll)). The palladium catalyst is used with a stoichiometry of 0.1 to 5mol%. Preferably the palladium catalyst is Pd(Amphos)2Cl2 with a stoichiometry of 0.1-1mol%, more preferably with a stoichiometry of 0.1-0.5mol% and even more preferably with a stoichiometry of 0.1 mol%.

[0214] A suitable solvent is a mixture of water with an organic solvent selected from THF, MeTHF, MeCN, ether, acetone, ethyl acetate and toluene.

[0215] A suitable temperature is in the range of 40-110°C. Preferably the temperature is in the range of 85-110°C and more preferably in the range of 100-110°C.

[0216] Step 6

[0217] According to one embodiment of the invention compound 6 is obtained via deprotection of the THP group of compound 5.

[0218] The deprotection is performed under standard or similar conditions and involves treating the compound 5 under suitable acidic conditions in a suitable organic solvent at a suitable temperature.

[0219] 30

[0220] Suitable acidic conditions are achieved by using TFA, HCl or MeSO3H with an excess from 1 to 30 equivalents. Foreignfiling_text P24-237-SEC-WO01 20250922

[0221] 19

[0222] A suitable organic solvent is DCM or CHCl3. And a suitable temperature is in the range of 10 to 40°C, preferably in the range of 20 to 30°C, most preferably the temperature is 25°C.

[0223] 5

[0224] Step 7

[0225] According to one embodiment of the invention compound 7 is obtained via regio-selective reaction of compound 6 with formaldehyde.

[0226] The process involves reacting compound 6 with an aqueous solution of formaldehyde or with paraformaldehyde (with a stoichiometry from 1 to 5 equivalents) in a suitable organic solvent (e.g. MeCN, acetone, THF, MeTHF, EtOAc, ether or ester) at a suitable temperature between 10 and 80°C.

[0227] Formaldehyde or paraformaldehyde are preferably used with a stoichiometry from 1 to 5 equivalents.

[0228] A suitable organic solvent is MeCN, acetone, THF, MeTHF, EtOAc, iPrOAc, tBuOAc, MTBE (methyl tert-butyl ether) or Et2O.

[0229] A suitable temperature is in the range of 10 and 80°C, preferably in the range of 20-35°C.

[0230] Step 8

[0231] According to one embodiment of the invention compound 8 is obtained via phosphorylation of compound 7 in a suitable organic solvent and at a suitable temperature.

[0232] 30 The process involves reacting compound 7 with a suitable phosphorylation reagent type phosphoramidite in the presence of a suitable coupling reagent. Foreignfiling_text P24-237-SEC-WO01 20250922

[0233] 20

[0234] A suitable phosphorylation reagent type phosphoramidite is e.g. di-tert-butyl- diisopropylphosphoramidite, if R1= fBu, or an alternative phosphoram idite with corresponding alcoholate substituent, if R1= Me, Et, / Pr or benzyl. The phosphorylation reagent is preferably used with a stoichiometry of 1 to 3 5 equivalents.

[0235] A suitable coupling reagent is tetrazole or a similar reagent like 5-phenyl-2H- tetrazole or other substituted tetrazole, triazole or imidazole. The coupling reagent is preferably used with a stoichiometry of 1 to 3 equivalents.

[0236] A suitable organic solvent is THF, MeTHF, AcN, DCM, MTBE, Et2O, EtOAc, / PrOAc or fBuOAc.

[0237] A suitable temperature is in the range of -10 to 40°C.

[0238] In a preferred embodiment R1represents fBu. This group facilitates subsequent cleavage of corresponding alcoholate substituents, thereby improving the overall yield.

[0239] After the phosphorylation a suitable oxidation reagent is added to the reaction mixture at temperature (-15 to 50°C) to afford compound 8.

[0240] A suitable oxidation reagent is an aqueous solution of hydrogen peroxide or fe / t-Butoxyperoxide, preferably with a stoichiometry of 1 to 10 equivalents.

[0241] Step 9

[0242] According to one embodiment of the invention compound I is obtained via hydrolysis of the alcoholate substituents (“OR1”) of compound 8.

[0243] 30 Foreignfiling_text P24-237-SEC-WO01 20250922

[0244] 21

[0245] This hydrolysis involves treating compound 8 in a mixture of a suitable alcohol and water in the presence of a suitable acid and / or buffer solution at a suitable temperature.

[0246] 5 Preferably the hydrolysis is performed at a pH in the range of 0-8 or 2-8, more preferably in the range of 3-5.

[0247] A suitable alcohol is MeOH, EtOH, / PrOH or 1-BuOH.

[0248] A suitable acid is hydrochloric acid, formic acid, sulfuric acid, acetic acid, nitric acid, methane sulfonic acid.

[0249] A suitable buffer solution is acetate buffer, phosphate buffer, ammonium buffer.

[0250] A suitable temperature is in the range of 20 to 80°C.

[0251] In a preferred embodiment R1represents fBu.

[0252] Slurry solid form conversion step

[0253] One embodiment of the invention relates to a process for the preparation of solid-state form A2 of compound I, includes following steps:

[0254] (a) suspending compound I in a suitable solvent (such as in particular 2-propanol) and stirring the resulting mixture (preferably for several hours, particular preferably for 10-30h, even more preferably for 15-25h) at a temperature between 40-60°C (preferably 45-55°C, and more preferably at 50°C);

[0255] (b) cooling of the mixture resulting from step a) to a temperature in the 30 range of 10-30°C (preferably 15-25°C, most preferably 20°C);

[0256] (c) isolating the solid resulting from step b) and drying the solid at a temperature in the range of 30-50°C (preferably in the range of 35-45°C, Foreignfiling_text P24-237-SEC-WO01 20250922

[0257] 22

[0258] most preferably at 40°C). A particular embodiment of the invention includes drying the solid at a temperature in the range of 30-50°C (preferably in the range of 35-45°C, most preferably at 40°C) for several hours (preferably for at least 25-60h, more preferably for at least 30-60h, even more preferably for 5 at least 40-50h).

[0259] In a preferred embodiment the solid material used in step a) of this solid form conversion represents material obtained according to Step 9.

[0260] Abbreviations

[0261] AcOH: acetic acid

[0262] AcN: acetonitrile

[0263] B(OMe)3: trimethylborate

[0264] B2pin2: bis(pinacolato)diboron

[0265] DCM: Dichloromethane

[0266] DHP: 3,4-dihydro-2H-pyrane

[0267] Et: Ethyl group

[0268] EtOAc: Ethyl Acetate

[0269] El: electron impact

[0270] HPLC: High Pressure Liquid Chromatography

[0271] / Pr: / so-Propyl group

[0272] KOAc: potassium acetate

[0273] prep-HPLC: preparative High Pressure Liquid Chromatography

[0274] LCMS (or LS-MS): Liquid Chromatography-Mass spectrometry

[0275] Me: Methyl group

[0276] MeCN: Acetonitrile

[0277] Me2SO3H: Methanesulfonic acid

[0278] MeTHF: 2-methyl-tetrahydrofurane

[0279] 30 m.p.: Melting point

[0280] MS: Mass spectrometry

[0281] n-BuLi: n-Butyllithium Foreignfiling_text P24-237-SEC-WO01 20250922

[0282] 23

[0283] NBS: -bromosuccinimide

[0284] NMR: Nuclear Magnetic Resonance

[0285] p-TSOH: para-toluenesulfonic acid

[0286] Pd(Amphos)2Cl2

[0287] 5 RT: Room Temperature

[0288] (fBuO)2PN( / Pr)2: Di-terf-butyl-diisopropylphosphoramidite

[0289] fBu: tert-butyl group

[0290] TFA: Trifluoroacetic acid

[0291] THF: Tetrathydrofuran

[0292] TLC: Thin Layer Chromatography

[0293] Examples and Experimental Data

[0294] NMR spectra were recorded on a 500 MHz NMR spectrometer for1H-NMR, on a 470 MHz for19F-NMR and on a 202 MHz for31P-NMR. Chemical Shifts are reported in ppm relative to tetramethylsilane; coupling constants (J) are reported in hertz. Commercially available starting materials are used as received without further purification.

[0295] Example 1 (Step 1)

[0296] Br Bpin

[0297] F Me 1.5 eq. KOAc2 F Me

[0298] A 0.01 eq. Pd(Amphos)2CI21

[0299]

[0300] toluene, 110°C

[0301] 2-fluoro-5-bromocumene A (24kg, 110.56mol) and toluene (200kg) are pumped into a reactor previously filled with bis(pinacolato)diboron (29.5kg, 116.17mol, 1.05eq) and potassium acetate (16.3kg, 166.09mol, 1.5eq). The mixture is stirred and heated to reflux before addition of the catalyst

[0302] 30

[0303] Pd(Amphos)2Cl2 (783g, 1.106mol, 0.01 eq). After 10h stirring time, the reaction mixture is cooled down to 30°C and filtered over silica gel (25kg Foreignfiling_text P24-237-SEC-WO01 20250922

[0304] 24

[0305] preconditioned with toluene). After washing the filter with toluene (150kg), the filtrate is washed with a 5% aqueous solution of sodium carbonate (105kg) and with water (100kg). The resulting organic phase (380kg) containing 2-(4- fluoro-3-isopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (compound 5 1, 30kg, 87.5% purity, 99.39mol, 90% yield) is used directly for the following step.

[0306] Example 2 (Step 2)

[0307] F Me °eQ Pd(Amphos)2CI21 1 04 eq 1 5 eq K2CO3

[0308] toluene / water4:1, 110°C

[0309]

[0310] then MeSO3H

[0311] The toluene solution (352kg) of 1 (27.8kg, 87.5% purity, 92.1 mol, 1.04eq) and water (100kg) are pumped into a reactor previously filled with 2-amino-5- bromopyrazine B (15.4kg, 88.45mol) and potassium carbonate (18.4kg, 132.7mol, 1.5eq). The mixture is stirred and heated to reflux before addition of the catalyst Pd(Amphos)2Cl2 (1.88kg, 2.65mol, 0.03eq). After 16h stirring time, the reaction mixture is cooled down to 25°C, the phases are separated. The organic phase is washed twice with water (2*100kg) and finally filtered over silica gel (25kg preconditioned with toluene). After washing the filter with ethyl acetate (150kg), the filtrate is evaporated and concentrated.

[0312] Methanesulfonic acid (10.9kg, 113.4mol, 1,3eq) is slowly added at 50°C whereas the formed salt precipitates. After cooling down to 0°C, the suspension is filtered, the wet cake is washed with cold ethyl acetate (50kg) and finally dried under vacuum at 50°C affording

[0313] 5-[4-fluoro-3-(propan-2-yl)phenyl]pyrazin-2-aminium methanesulfonate 30

[0314] (compound 2, 29.8kg, 92.1% purity, 83.8mol, 95% yield).

[0315] C14H18O3SFN3(327.38g.mol-1), m.p. 238-240°C

[0316] 1H NMR (DMSO-d6): 8.50 (s, 1 H), 8.32 (s, 1 H), 7.88-7.90 (m, 1 H), Foreignfiling_text P24-237-SEC-WO01 20250922

[0317] 25

[0318] 7.77-7.80 (m, 1 H), 7.20-7.23 (m, 1 H), 3.18-3.24 (m, 1 H), 2.44 (s, 3H), 1.26 (d, J=5Hz, 6H).

[0319] 19F NMR (DMSO-d6): -120.3 (s, 1F),

[0320] MS (El) m / z (%): 232.1 (100) [M+], 217.1 (5), 188.1 (10), 163.1 (2), 146.0 (2).

[0321] 5

[0322] Example 3 (Step 3)

[0323] 5-[4-fluoro-3-(propan-2-yl)phenyl]pyrazin-2-aminium methanesulfonate 2

[0324]

[0325] (27.8kg, 92.1% purity, 78.2mol) is suspended in dichloromethane (225kg) in a reactor. Water (92kg) and aqueous sodium hydroxide 32% (21.8kg, 174.4mol) are pumped and the mixture is stirred until complete dissolution. After having settled, the phases are separated, the aqueous phase is extracted with dichloromethane (102kg) and the combined organic phases 20 are evaporated. Acetonitrile (400kg) is added and distillation is further applied until a residual volume of around 100L. After addition of further acetonitrile (100kg), 2-bromo-1-cyclopropylethan-1-one C (16.6kg, 101.8mol, 1.3eq) is added, the temperature is increased to 40°C and the reaction mixture is stirred for 60h. After cooling down to 0°C, the suspension is filtered, the wet cake washed with cold acetonitrile (60kg) and finally dried under vacuum at 40°C affording

[0326] 2-cyclopropyl-6-[4-fluoro-3-(propan-2-yl)phenyl]imidazo[1,2-a]pyrazin-7-ium bromide (compound 3, 24.9kg, 87.5% purity, 57.9mol, 74% yield).

[0327] C18H19BrFN3(376.27g.mol-1)

[0328] 30

[0329] 1H NMR (DMSO-d6): 9.30 (s, 1 H), 9.19(s, 1 H), 8.10 (s, 1 H),

[0330] 8.01-8.03 (m, 1 H), 7.89-7.92 (m, 1 H), 7.29-7.33 (m, 1 H), 3.21-3.29 (m, 1 H), 2.22-2.28 (m, 1 H), 1.30 (d, J=5Hz, 6H), 1.11-1.15 (m, 2H), 0.97-0.99 (m, 2H). Foreignfiling text P24-237-SEC-WO01 20250922

[0331] 19F NMR (DMSO-d6): -119.2 (s, 1F),

[0332] MS (El) m / z (%): 295.1 (100) [M], 280.1 (15), 216.1 (6), 172.0 (4), 146.0 (6), 80.0 (5).

[0333] 5 Example 4 (Step 4)

[0334] Me hT Me

[0335] 3

[0336]

[0337] 2-cyclopropyl-6-[4-fluoro-3-(propan-2-yl)phenyl]imidazo[1,2-a]pyrazin-7-ium bromide 3 (18kg, 87.5% purity, 41.8mol) is dissolved in dichloromethane (220kg) in a reactor. After cooling down to 0°C, N-bromosuccinimide (9kg, 50.5mol, 1.2eq) is added portionwise and the reaction mixture is stirred at 5°C for 2h. After tempering at 20°C, water (150kg) and finally aqueous sodium hydroxide 32% (37.6kg, 300.8mol) are pumped into the reactor. After having settled, the phases are separated and the aqueous phase is extracted with dichloromethane (150kg). The combined organic phases are evaporated until a residual volume of around 50L, tetrahydrofurane (301kg) is added and distillation is pursued until a residual volume of around 50L. The reactor is tempered to 67°C and refluxed 30min before starting a cooling ramp down to -15°C. When a temperature of 35°C is reached, methanol (120kg) is slowly added during cooling. The suspension is finally filtered, the wet cake washed with cold methanol (50kg) and dried under vacuum at 40°C affording

[0338] 3-bromo-2-cyclopropyl-6-[4-fluoro-3-(propan-2-yl)phenyl]imidazo[1,2-a]pyrazi ne (compound 4, 12.4kg, 99% purity, 32.7mol, 78% yield).

[0339] C18H17BrFN3(374.25g.mol-1), m.p. 140°C

[0340] 1H NMR (CDCI3): 8.96 (s, 1 H), 8.23 (s, 1 H), 7.86-7.88 (m, 1 H),

[0341] 7.69-7.72 (m, 1 H), 7.10-7.13 (m, 1 H), 3.28-3.34 (m, 1 H), 2.12-2.17 (m, 1 H), 30 1.34 (d, J=5Hz, 6H), 1.09-1.19 (m, 4H).

[0342] 19F NMR (CDCI3): -118.7 (s, 1F), Foreignfiling_text P24-237-SEC-WO01 20250922

[0343] 27

[0344] MS (El) m / z (%): 375.1 (100) [M]+, 358.0 (24), 347.0 (12), 294.1 (68), 278.1 (28), 251.1 (6), 188.1 (7), 172.0 (6), 146.0 (15), 81.9 (11).

[0345] Example 5 (Step D1)

[0346] 5

[0347]

[0348] 0.17 eq. p-TsOH on resin

[0349] DCM, 20°C

[0350] 5-bromo-4-fluoro-1 H-indazole D (16.5kg, 76.7mol) and para-toluenesulfonic acid polymer bound (3.8kg, 12.9mol, 3.4mmol / g, 0.17eq) are suspended in dichloromethane (125kg) in a reactor. 3,4-dihydro-2H-pyrane (7.2kg, 85mol, 1,1eq) is slowly added at 25°C and the reaction mixture is stirred for 14h before being filtered. The resin is washed with dichloromethane (31kg) and the filtrate is evaporated until a residual volume of around 40L. After addition of 2-propanol (90kg), the distillation is pursued until a residual volume of around 50L. Further 2-propanol (90kg) is added, the mixture is distilled until a residual volume of around 90L, then tempered to 85°C for complete dissolution and finally cooled down to -5°C. The suspension is filtered, the wet cake washed with cold 2-propanol (40kg) and dried under vacuum at 30°C affording 5-bromo-4-fluoro-1-(oxan-2-yl)-1 H-indazole (compound D1, 16.3kg, 99.7% purity, 54.2mol, 71% yield).

[0351] C12H12BrFN2O (299.14g.mol-1), m.p. 77°C

[0352] 1H NMR (DMSO-d6): 8.28 (s, 1H), 7.66-7.58 (m, 2H), 5.92-5.88 (m, 1H), 3.89-3.85 (m, 1H), 3.79-3.70 (m, 1H), 2.38-2.29 (m, 1H), 2.05-1.96 (m, 2H), 1.77-1.71 (m, 1H), 1.60-1.55 (m, 2H).

[0353] 19F NMR (DMSO-d6): -112.6 (d, 1F),

[0354] MS (El) m / z (%): 301 (10) [M]++, 214 (100), 135 (8), 84 (48), 55 (28).

[0355] 30 Foreignfiling_text P24-237-SEC-WO01 20250922

[0356] 28

[0357] Example 6 (Step D1(B))

[0358] F F

[0359] , _ / L / Br. _ / L. B(OH)2

[0360] m step D1(B)

[0361] T

[0362]

[0363] HP D1 1. 1.05 eq. n-BuLi, Hexane THPD1(B)

[0364] MeTHF, -65°C

[0365] 5 2. 1.05 eq. B(OMe)3

[0366] 3. AcOH, 20°C

[0367] 4. NaOH, H2O, MeTHF

[0368] 5. HCI

[0369] 5-bromo-4-fluoro-1-(oxan-2-yl)-1H-indazole D1 (14kg, 99.7% purity, 46.8mol) is dissolved in 2-methyl-tetrahydrofurane (45kg) at 25°C before cooling down to -65°C. A solution of n-BuLi 15% in hexane is slowly added (21kg, 49.1 mol, 1,05eq) while keeping the temperature below -60°C, followed by slow addition of a solution of trimethylborate (5.2kg, 49.1 mol, 1.05eq) in 2-methyl- tetrahydrofurane (7kg) at the same temperature. The mixture is then tempered to 0°C before addition of acetic acid (6.2kg, 103mol, 2.2eq) and subsequently of aqueous sodium hydroxide 32% (15.8kg, 126.4mol) and water (26kg). After having settled, the phases are separated and the organic phase is extracted with aqueous sodium hydroxide 32% (10.2kg, 81.6mol) and water (10.6kg). The combined aqueous phase are pumped back into the reactor, neutralized with HCI 25% (26kg, 175mol) at 0°C and extracted at 20°C three times with 2-methyl-tetrahydrofurane (52kg, 30kg & 20kg). The resulting combined organic phases (122kg) containing

[0370] [4-fluoro-1-(oxan-2-yl)-1H-indazol-5-yl]boronic acid (compound D1(B), 9.7kg, 92.1% purity, 34.1 mol, 73% yield) is tempered at 0°C before use for the following step.

[0371] Example 7 (Step 5)

[0372] THPD1<B>

[0373] 30 step 5

[0374] 0 01 eq Pd(AmphoS)2CI22 eq K2CO3

[0375]

[0376] MeTHF, H2O, 78°C Foreignfiling_text P24-237-SEC-WO01 20250922

[0377] 29

[0378] 2-methyl-tetrahydrofurane (99kg) and water (32kg) are pumped into a reactor previously filled with

[0379] 3-bromo-2-cyclopropyl-6-[4-fluoro-3-(propan-2-yl)phenyl]imidazo[1,2-a]pyrazi ne 4 (8.2kg, 98.5% purity, 21.5mol) and potassium carbonate (6kg, 43.4mol, 5 2eq). The mixture is stirred and heated to reflux before addition of the catalyst Pd(Amphos)2Cl2 (155g, 0.22mol, 0.01 eq) and subsequent slow addition of a 2-methyl-tetrahydrofurane solution (136kg) of D1(B) (8kg, 92.2% purity, 27.9mol, 1.3eq). After 1h stirring time, the reaction mixture is cooled down to 25°C and stirring stopped. The settled phases are separated, the organic phase is washed twice with water (2*42kg) and the combined aqueous phases are extracted with 2-methyl-tetrahydrofurane (22kg). The combined organic phases are finally filtered over silica gel (12kg preconditioned with 2-methyl-tetrahydrofurane). After washing the filter with 2-methyl-tetrahydrofurane (20kg), the filtrate is evaporated and concentrated until a residual volume of around 20L. After addition of ethyl acetate (40kg), the distillation is pursued until a residual volume of around 20L. Further ethyl acetate (40kg) is added, the mixture is distilled until a residual volume of around 40L and finally cooled down to -5°C, stirred for 18h at that temperature and further cooled down to -15°C. After long stirring time (24h), the suspension is filtered, the wet cake washed with cold ethyl acetate (15kg) and dried under vacuum at 40°C affording

[0380] 5-{2-cyclopropyl-6-[4-fluoro-3-(propan-2-yl)phenyl]imidazo[1,2-a]pyrazin-3-yl} -4-fluoro-1-(oxan-2-yl)-1H-indazole (compound 5, 8.8kg, 96.1% purity, 16.5mol, 77% yield).

[0381] C30H29F2N5O (513.58g.mol-1), m.p. 161-164°C

[0382] 1H NMR (DMSO-d6): 9.10 (s, 1 H), 8.55 (s, 1 H), 8.40 (s, 1 H),

[0383] 8.01-8.03 (m, 1 H), 7.83-7.85 (m, 2H), 7.68-7.71 (m, 1 H), 7.14-7.18 (m, 1 H), 5.98-6.01 (m, 1 H), 3.92-3.96 (m, 1 H), 3.78-3.83 (m, 1 H), 3.17-3.22 (m, 1 H), 2.41-2.46 (m, 1 H), 2.02-2.10 (m, 1 H), 1.93-1.98 (m, 1 H), 1.76-1.82 (m, 1 H), 30 1.61-1.66 (m, 1 H), 1.25 (d, J=5Hz, 6H), 0.98-1.04 (m, 4H).

[0384] 19F NMR (DMSO-d6): -115.3 (s, 1F), -120.0, (s, 1F).

[0385] MS (El) m / z (%): 513.2 (40) [M], 429.2 (100), 409.2 (22), 384.1 (4), Foreignfiling_text P24-237-SEC-WO01 20250922

[0386] 30

[0387] 364.1 (3), 199.0 (3), 146.0 (2), 85.1 (14), 67.0 (6), 57.1 (6), 41.0 (2).

[0388] Example 8 (Step 6)

[0389] 5

[0390] step 6 25 eq. TFA, DCM, 0°C then 25°C

[0391]

[0392] 5-{2-cyclopropyl-6-[4-fluoro-3-(propan-2-yl)phenyl]imidazo[1,2-a]pyrazin-3-yl} -4-fluoro-1-(oxan-2-yl)-1H-indazole 5 (8.2kg, 96.1% purity, 15.3mol) is suspended in dichloromethane (113kg) in a reactor and cooled down to 0°C. Trifluoroacetic acid (45kg, 394mol, 25eq) is slowly added and the reaction mixture is then warmed up to 25°C and stirred for 14h. After cooling down to 10°C, the reaction mixture is washed three times with water (3*43kg), diluted with dichloromethane (80kg) and methanol (20kg) and neutralized with aqueous sodium hydroxide 4.3% (33.5kg). After addition of dichloromethane (241kg) and methanol (61kg) and vigorous stirring at 35°C, the phases are allowed to settle for 3h. The phases are separated and the aqueous phase is extracted twice with dichloromethane (2*33kg). The combined organic phases are evaporated and concentrated until a residual volume of around 30L. After addition of methanol (50kg), the distillation is pursued until a residual volume of around 30L. Further methanol (25kg) is added, the mixture is distilled until a residual volume of around 30L and then heated up to 50°C, stirred at that temperature for 1 h and finally cooled down to 0°C. The suspension is filtered, the wet cake washed with cold methanol (18kg) and dried under vacuum at 40°C affording 5-{2-cyclopropyl-6-[4-fluoro-3- (propan-2-yl)phenyl]imidazo[1,2-a]pyrazin-3-yl}-4-fluoro-1 H-indazole (compound 6, 5.2kg, 99.4% purity, 12.0mol, 79% yield).

[0393] 30 C25H21F2N5(429.46g.mol-1), m.p. 296-300°C

[0394] 1H NMR (DMSO-d6): 9.10 (s, 1 H), 8.55 (s, 1 H), 8.40 (s, 1 H),

[0395] 8.01-8.03 (m, 1 H), 7.83-7.85 (m, 2H), 7.68-7.71 (m, 1 H), 7.14-7.18 (m, 1 H), Foreignfiling_text P24-237-SEC-WO01 20250922

[0396] 31

[0397] 5.98-6.01 (m, 1H), 3.92-3.96 (m, 1H), 3.78-3.83 (m, 1H), 3.17-3.22 (m, 1H), 2.41-2.46 (m, 1H), 2.02-2.10 (m, 1H), 1.93-1.98 (m, 1H), 1.76-1.82 (m, 1H), 1.61-1.66 (m, 1H), 1.25 (d, J=5Hz, 6H), 0.98-1.04 (m, 4H).

[0398] 19F NMR (DMSO-d6): -115.3 (s, 1F), -120.0, (s, 1F).

[0399] 5 MS (El) m / z (%): 429.2 (100) [M], 409.2 (21), 384.1 (4), 367.1 (4), 206.6 (4), 199.1 (6), 187.1 (4), 173.0 (6), 158.0 (3), 146.0 (7).

[0400]

[0401] 5-{2-cyclopropyl-6-[4-fluoro-3-(propan-2-yl)phenyl]imidazo[1,2-a]pyrazin-3-yl} 4-fluoro-1 H-indazole 6 (4kg, 99.4% purity, 9.26mol) is suspended in ethyl acetate (23kg) in a reactor. The mixture is tempered at 25°C before addition of an aqueous formaldehyde 37% solution (1.25kg, 15.4mol, 1.66eq) and stirred for 9h. n-heptane (15kg) is subsequently added and the reactor content is cooled down to 0°C. After stirring at that temperature for 1 h, the suspension is filtered, the wet cake washed with a mixture of n-heptane / ethyl acetate (10kg / 10kg) and dried under vacuum at 28°C affording

[0402] (5-{2-cyclopropyl-6-[4-fluoro-3-(propan-2-yl)phenyl]imidazo[1,2-a]pyrazin-3- yl}-4-fluoro-1H-indazol-1-yl)methanol (compound 7, 4.1kg, 94.8% purity, 8.6mol, 93% yield).

[0403] C26H23F2N5O (459.49g.mol-1), m.p. 224-228°C

[0404] 1H NMR (DMSO-d6): 9.10 (s, 1 H), 8.55 (m, 1 H), 8.38 (s, 1 H),

[0405] 8.00-8.02 (m, 1 H), 7.82-7.85 (m, 2H), 7.69-7.72 (m, 1 H), 7.15-7.18 (m, 1 H), 6.93-6.96 (m, 1 H), 5.83-5.84 (m, 2H), 3.17-3.22 (m, 1 H), 1.93-1.99 (m, 1 H), 1.25 (d, J=5Hz, 6H), 0.97-1.06 (m, 4H).

[0406] 3019F NMR (DMSO-d6): -115.5 (m, 1F), -120.1 (m, 1F).

[0407] MS (El) m / z (%): 429.2 (100) [M], 409.2 (21), 384.1 (4), 367.1 (2), 206.6 (3), 199.1 (6), 187.1 (3), 173.0 (4), 158.0 (3), 146.0 (7). Foreignfiling_text P24-237-SEC-WO01 20250922

[0408] 32

[0409] Example 10 (Step 8)

[0410] 5

[0411]

[0412] (5-{2-cyclopropyl-6-[4-fluoro-3-(propan-2-yl)phenyl]imidazo[1,2-a]pyrazin-3-yl } 4-fluoro-1 H-indazol-1-yl)methanol 7 (300g, 94.8% purity, 0.62mol) is suspended in methyl-tetrahydrofurane (2.7kg) and tempered at 35°C. Di-tert- butyl-diisopropylphosphoramidite (370.4g, 1.31 mol, 2.3eq) and a tetrazole solution in acetonitrile (~0.45M) (3.89L, 1.31 mol, 2.3eq) are added. After stirring for 110min, the suspension is cooled down to 0°C before slow addition of an aqueous solution of hydrogen peroxide (35%) (186mL, 2.16mol, 3.8eq) within 30min. After further 20min stirring, the mixture is warmed up to 35°C. After stirring for 5h and cooling down to 0°C, an aqueous solution of sodium thiosulfate (20%) (1.75L, 2.16mol, 3.8eq) is added, the mixture is finally allowed to settle and the phases are separated. The organic phase is washed with brine (1,2L), both aqueous phases are combined and extracted with methyl-tetrahydrofurane (0.9kg), the combined organic phases are evaporated. The residue is taken in acetone (0.69kg), heated up to 56°C and then cooled down to -20°C before filtration of the resulting suspension. The wet cake is washed with cold acetone / water 4 / 1 mixture (0.5kg) and dried under vacuum at 40°C affording di-tert-butyl (5-{2-cyclopropyl-6-[4-fluoro-3-(propan-2-yl)phenyl]imidazo[1,2-a]pyrazin-3-yl }-4-fluoro-1 H-indazol-1-yl)methyl phosphate (compound 8 with R1= fBu;

[0413] 307g, 90.4% purity, 0.43mol, 75% yield).

[0414] 30 C34H40F2N5O4P (651.68g.mol-1), m.p. 152-157°C

[0415] 1H NMR (DMSO-d6): 9.11 (s, 1H), 8.54 (s, 1H), 8.49 (m, 1H),

[0416] 7.97-7.99 (m, 1H), 7.79-7.87 (m, 3H), 7.16-7.20 (m, 1H), 6.29-6.31 (m, 2H), Foreignfiling_text P24-237-SEC-WO01 20250922

[0417] 33

[0418] 3.15-3.22 (m, 1 H), 1.89-1.95 (m, 1 H), 1.37 (s, 18H), 1.25 (d, J=5Hz, 6H), 0.97-1.05 (m, 4H).

[0419] 19F NMR (DMSO-d6): -115.5 (m, 1F), -120.0 (m, 1F).

[0420] 31P NMR (DMSO-d6): -11.5 (s, 1 P),

[0421] 5 MS (El) m / z (%): 652.3 (100) [M]+, 596.2 (12), 540.2 (18), 430.2 (95).

[0422] Example 11 (Step 9)

[0423] Step 9 iPrOH, water acetate buffer

[0424]

[0425] Di-tert-butyl (5-{2-cyclopropyl-6-[4-fluoro-3-(propan-2-yl)phenyl]imidazo[1,2-a]pyrazin-3- yl}-4-fluoro-1H-indazol-1-yl)methyl phosphate 8 (132.3g, 87.4% purity, 0.177mol) is suspended in 2-propanol (1.09kg) and acetate buffer 0.1mol / L (1.34kg) and stirred for 9h before cooling down to -3°C. The suspension is filtered, the wet cake washed with cold 2-propanol (690g) and dried at 35°C under vacuum affording [(5-{2-cyclopropyl-6-[4-fluoro-3-(propan-2- yl)phenyl]imidazo[1,2-a]pyrazin-3yl}-4-fluoro-1 H-indazol-1 -yl)methoxy]phosph onic acid (compound I, 55.7g, 98.1% purity, 0.101 mol, 57% yield).

[0426] C26H24F2N5O4P (539.47g. mol-1), m.p. 208-215°C

[0427] 1H NMR (DMSO-d6): 9.10 (s, 1H), 8.54 (s, 1H), 8.49 (m, 1H),

[0428] 8.00-8.02 (m, 1H), 7.76-7.87 (m, 3H), 7.15-7.19 (m, 1H), 6.24 (d, J=5Hz, 2H), 3.17-3.22 (m, 1H), 1.92-1.97 (m, 1H), 1.25 (d, J=5Hz, 6H), 0.97-1.05 (m, 4H).

[0429] 19F NMR (DMSO-d6): -115.4 (m, 1F), -120.0 (m, 1F).

[0430] 31P NMR (DMSO-d6): -2.7 (s, 1P).

[0431] 30 MS (El) m / z (%): 540.2 (100) [M]+, 510.1 (6), 430.2 (96). Foreignfiling_text P24-237-SEC-WO01 20250922

[0432] 34

[0433] Example 12 (Slurry for solid form conversion)

[0434] [(5-{2-cyclopropyl-6-[4-fluoro-3-(propan-2- yl)phenyl]imidazo[1,2-a]pyrazin-3yl}-4-fluoro-1 H-indazol-1 -yl)methoxy]phosph 5 onic acid (compound I, 278.6 g, 98.1 % purity, 0.51 mol, crystalline material NF6) was suspended in 2-propanol (2.52 Kg). The mixture is stirred for 23 h at 50°C, before it is cooled to 20°C. The solid is isolated by filtration and the resulting cake washed with 2-propanol (585 g). The isolated cake is then dried at 40°C for 48 h to obtain solid state from A2 of

[0435] [(5-{2-cyclopropyl-6-[4-fluoro-3-(propan-2

[0436] yl)phenyl]imidazo[1,2-a]pyrazin-3yl}-4-fluoro-1 H-indazol-1 -yl)methoxy]phosph onic acid (compound I).

[0437] All crystalline material and solid state forms can be characterized according to standard methods which can be found in e.g. in Rolf Hilfiker, ‘Polymorphism in the Pharmaceutical Industry’, Wiley-VCH. Weinheim 2006 (Chapter 6: X-Ray Diffraction, Chapter 6: Vibrational Spectroscopy, Chapter 3: Thermal Analysis, Chapter 9: Water Vapour Sorption, and references therein) and H. G. Brittain, ‘Polymorphism in Pharmaceutical Solids, Vol. 95, Marcel Dekker Inc., New York 1999 (Chapter 6 and references therein).

[0438] As used herein, unless stated otherwise, the X-ray powder diffractogram measurements are taken using monochromatic Cu-Kai radiation wavelength 1.5406 A. Furthermore, unless stated otherwise, the X-ray powder diffractogram measurements are taken at room temperature.

[0439] Material designated as NF6 of compound I

[0440] The crystalline material provided in example 11 represents phase impure, very weakly crystalline material, which is designated as form NF6.

[0441] 30 NF6 shows following physical properties:

[0442] Weakly crystalline Foreignfiling_text P24-237-SEC-WO01 20250922

[0443] 35

[0444] Phase mixture of different solid state forms including A2 and other forms

[0445] Thermal stability up to 198°C

[0446] Slightly hygroscopic acc. to Ph. Eur.

[0447] 5

[0448] A Powder X-Ray Diffraction pattern of NF6 has been obtained by standard techniques as described in the European Pharmacopeia 6th Edition chapter 2.9.33, and is characterised by the X-ray powder diffractogram (monochromatic Cu-Kα1 radiation, λ = 1.5406 Å, Stoe StadiP 611 KL transmission diffractometer) shown in Fig. 1a. A peak list corresponding to the XRPD depicted in Fig. 1a is shown in the following table:

[0449] Table: Powder X-ray peak list of NF6

[0450] No. °2θ (Cu-Kα1 radiation) ± 0.2°

[0451] 1 4.0

[0452] 2 6.7

[0453] 3 7.2

[0454] 4 12.3

[0455] 5 13.3

[0456] 6 14.6

[0457] 7 16.7

[0458] 8 19.2

[0459] 9 19.9

[0460] 10 20.4

[0461] 11 23.6

[0462] 30

[0463]

[0464] Foreignfiling_text P24-237-SEC-WO01 20250922

[0465] 36

[0466] DSC and TGA profiles are displayed in Fig. 1b and Fig. 1c. DSC scan of NF6 was acquired on a Mettler-Toledo DSC 821 with a heating rate of 5 K / min, using nitrogen purge gas at 50 mL / min. TGA scan of NF6 was acquired on a Mettler-Toledo TGA 851 with a heating rate of 5 K / min, using nitrogen purge 5 gas at 50 mL / min.

[0467] Water Vapor Sorption isotherm (25 °C) of material NF6 is displayed in Fig.

[0468] 1d. Water Vapour Sorption isotherm was acquired on a DVS-Intrinsic system from SMS.

[0469] Solid state form A2 of compound I

[0470] A Powder X-Ray Diffraction pattern of form A2 has been obtained by standard techniques as described in the European Pharmacopeia 6th Edition chapter 2.9.33, and is characterised by the X-ray powder diffractogram (monochromatic Cu-Kα1 radiation, λ = 1.5406 Å, Stoe StadiP 611 KL transmission diffractometer) shown in Fig. 2a. A peak list corresponding to the XRPD depicted in Fig. 2a is shown in the following table:

[0471] Table: Powder X-ray peak list of form A2

[0472] No. °2θ (Cu-Kα1 radiation) ± 0.2°

[0473] 1 4.2

[0474] 2 6.9

[0475] 3 7.8

[0476] 4 12.7

[0477] 5 14.4

[0478] 30 6 14.7

[0479] 7 19.9

[0480]

[0481] Foreignfiling_text P24-237-SEC-WO01 20250922

[0482] 37

[0483] 8 20.6

[0484] 9 21.0

[0485] 10 21.7

[0486] 5 11 22.5

[0487] 12 23.7

[0488] 13 25.9

[0489] 14 27.3

[0490] 15 28.0

[0491]

[0492] Electron diffraction structure data were obtained on form A2 (Rigaku Oxford Diffraction XtaLAB Synergy-ED, HyPix-ED Detector at 293 K). Fig. 2b shows the electron diffraction structure of form A2 along the a-axis.

[0493] Form A2 crystallizes in the monoclinic space group P2₁ with the lattice parameters (at 293 K) a = 4.6±0.1 Å, b = 13.3±0.1 Å, c = 41.6±0.2 Å, and β = 93.1±0.5° (with α = γ = 90°). From the electron diffraction structure it is obvious that form A2 represents an anhydrous form.

[0494] Form A2 is a crystalline anhydrous form, which is further characterised by the following physical properties:

[0495] - Thermal behaviour of form A2 shows a melting peak onset at approx.

[0496] 206 ± 2°C (based on multiple measurements on different samples of form A2). Thermogravimetric analysis reveals very low weight loss <1 wt% up to this temperature. DSC and TGA profiles are displayed in Fig. 2c and Fig 2d. DSC scan of form A2 was acquired on a Mettler- Toledo DSC 821 with a heating rate of 5 K / min, using nitrogen purge gas at 50 mL / min. TGA scan of form A2 was acquired on a Mettler- 30 Toledo TGA 851 with a heating rate of 5 K / min, using nitrogen purge gas at 50 mL / min. Foreignfiling_text P24-237-SEC-WO01 20250922

[0497] 38

[0498] - Water Vapour Sorption behaviour of form A2 reveals slightly water uptake levels ~0.9 wt% in the relative humidity (rh) range 0-80% rh, and slightly elevated water uptake levels 1.6 wt% in the relative humidity (rh) range 90-98% rh. Form A2 can be classified as slightly 5 hygroscopic acc. to Ph. Eur. Criteria (section 5.11.). Water Vapor Sorption isotherm (25 °C) of form A2 is displayed in Fig. 2e. Water Vapour Sorption isotherm was acquired on a DVS-Intrinsic system from SMS.

[0499] - Dissolution level of form A2 in Fasted-State Simulated Intestinal Fluid [FaSSIF, pH 6.5] at 37°C was determined to be approx. ≥759µg / mL (after 2 h) (see example 13).

[0500] - Thermodynamic solubility (24 h) of form A1 at 37°C was determined to be ≥ 5100 µg / mL in Fasted-State Simulated Intestinal Fluid [FaSSIF, pH 6.5], and ≥ 5198 µg / mL in USP Phosphate buffer [pH 7.4], respectively (see example 14).

[0501] Overall, form A2 reveals good solid-state properties (good crystallinity, slightly hygroscopic, high thermal stability).

[0502] Example 13: Mini-Dissolution data of NF6 and crystalline form A2 Approximately 5 mg of [(5-{2-cyclopropyl-6-[4-fluoro-3-(propan-2- yl)phenyl]imidazo[1,2-a]pyrazin-3-yl}-4-fluoro-1 H-indazol-1 - yl)methoxy]phosphonic acid of form NF6 and form A2, were weighed into 7 mL glass vials, and dispersed in 7 mL FaSSIF medium (pH 6.5).

[0503] All dispersions were agitated at 37°C for up to 2 hours. At defined time intervals (30 min, 60 min, 120 min), sample aliquots of homogeneous dispersions were withdrawn by a syringe, and filtrated via syringe filter adapters (PTFE, 0.45 µm). Clear filtrates were analysed by HPLC for dissolved quantities of [(5-{2-cyclopropyl-6-[4-fluoro-3-(propan-2- 30 yl)phenyl]imidazo[1,2-a]pyrazin-3-yl}-4-fluoro-1 H-indazol-1 - yl)methoxy]phosphonic acid. Foreignfiling_text P24-237-SEC-WO01 20250922

[0504] 39

[0505] Results from mini dissolution studies are summarised below.

[0506] Time Dissolution levels in FaSSIF

[0507] pH 6.5 (pg / mL)

[0508] 5 NF6 Form A2

[0509] 30 min ≥809 ≥771

[0510] 60 min ≥816 ≥759

[0511]

[0512] 120 min ≥813 ≥759

[0513] Example 14: Solubility data of NF6 and form A2

[0514] a) Thermodynamic solubility data (37°C) of free base forms Approximately 5-20 mg of [(5-{2-cyclopropyl-6-[4-fluoro-3-(propan-2- yl)phenyl]imidazo[1,2-a]pyrazin-3-yl}-4-fluoro-1 H-indazol-1 - yl)methoxy]phosphonic acid solid material NF6 and crystalline form A2 were dispersed in 1-2 mL of FaSSIF medium (pH 6.5) or 1-2 mL of USP Phosphate buffer pH 7.4 in a 4 mL glass vial and shaken at 37°C for 24h. If necessary, pH was adjusted after 1h and 6h.

[0515] Dispersions were then filtrated through 0.45 µm PTFE syringe filters and clear filtrates were analysed by HPLC for dissolved quantities of ([(5-{2- cyclopropyl-6-[4-fluoro-3-(propan-2-yl)phenyl]imidazo[1,2-a]pyrazin-3-yl}-4- fluoro-1 H-indazol-1 -yl)methoxy]phosphonic acid.

[0516] 30 Foreignfiling text P24-237-SEC-WO01 20250922

[0517] 40

[0518] Results from thermodynamic solubility determinations are summarised below.

[0519] Form Thermodynamic Thermodynamic 5 solubility solubility PBS FaSSIF pH 6.5 buffer 7.4 NF6 ≥3801 µg / mL ≥4121 µg / mL Form ≥ 5100 µg / mL ≥ 5198 µg / mL A2

[0520]

[0521] 30

Claims

Foreignfiling_text P24-237-SEC-WO01 20250922Claims1.A process for the preparation of compound I,5or a pharmaceutically acceptable salt thereof, comprising following steps:• formation of compound 7via regio-selective reaction of compound 6with formaldehyde or para-formaldehyde;• formation of compound 8via phosphorylation of compound 7Foreignfiling text P24-237-SEC-WO01 2025092242and5• formation of compound Ivia hydrolysis of the alcoholate substituents of compound 8.

2. The process according to claim 1, characterized in that the process further comprises one or more of following steps:• Synthesis of compound 1Bpinvia Miyaura borylation of 2-fluoro-5-bromocumene ABrF MeA(step 1 );• formation of compound 230Foreignfiling text P24-237-SEC-WO01 20250922435via a Suzuki coupling reaction between compound 1Bpinand 2-amino-5-bromopyrazine B (step 2);• formation of compound 33via addition of 2-bromo-1-cyclopropylethan-1-one C and subsequent ring formation after release of free base of compound 2 (step 3); • formation of compound 4via bromination of compound 3©30(step 4);• formation of compound D1Foreignfiling text P24-237-SEC-WO01 2025092244via THP protection of compound D5F• formation of compound D1(B)via borylation reaction of compound D1F(step D1);• formation of compound 5via Suzuki coupling reaction between compound 4and compound D1(B)30B(OH)2Foreignfiling text P24-237-SEC-WO01 2025092245(step 5);• formation of compound 65via deprotection of the THP group of compound 5 (this step is in the following also referred as step 6).

3. The process according to claim 1 or 2, wherein R1represents fBu.

4. Compound 7, characterized by following formula:

5. Use of compound 7 in a process for the preparation of compound 8 and / or compound I.

6. A process for preparation of compound 7, characterized in that compound 7 is formed via regio-selective reaction of compound 6with formaldehyde or para-formaldehyde.

307. Compound 8, characterized by following formula, wherein R1represents Me, Et, iPr, tBu or benzyl:Foreignfiling_text P24-237-SEC-WO01 2025092258. A compound according claim 7, wherein R1represents fBu.

9. Use of compound 8 according to claim 7 or claim 8 in a process for the preparation of compound I.

10. A process for the preparation of compound 8 according to claim 7, characterized in that compound 8 is formed via phosphorylation of compound 711. A process for preparing solid state form A2 of compound I, comprising following steps:(a) suspending compound I in a suitable solvent and stirring the resulting mixture at a temperature between 40-60°C;(b) cooling of the mixture resulting from step a) to a temperature in the range of 10-30°C;(c) isolating the solid resulting from step b) and drying the solid at a temperature in the range of 30-50°C.30

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