Imidazo [1, 2-a] pyrazine derivatives and their use in treatment of helminth infections

Abstract

The present invention relates to compounds of formulae (I), (II) and (III) and pharmaceutically acceptable salts or solvates thereof that impair the viability of schistosome and liver fluke parasites. The invention also relates to pharmaceutical compositions comprising such compounds, salts or solvates thereof, and to the use of such compounds as medicaments, in particular in the treatment or prevention of helminth infections, for example, in particular schistosomiasis, also known as schistosomiasis, and / or fascioliasis.

Description

TECHNICAL FIELD

[0001] The present invention relates to compounds of formula (I), (II) and (III) and pharmaceutically acceptable salts or solvates thereof, which impair the viability of Schistosoma and Fasciola parasites. The present invention further relates to pharmaceutical compositions comprising such compounds, salts or solvates thereof, and the use of such compounds as medicaments, in particular for the treatment or prevention of helminth infections, such as in particular schistosomiasis (also known as bilharzia) and / or fascioliasis. BACKGROUND

[0002] Schistosomiasis is one of the major neglected diseases, affecting over 200 million people in sub-Saharan Africa, the Middle East and South America. It is a parasitic disease caused by flatworms of the genus Schistosoma, such as but not limited to S. mansoni, S. haematobium and S. japonicum. Infection is due to the larval stage of the worm, which subsequently develops via the cercariae stage into the adult worm (Colley, D. G., Bustinduy, A. L., Secor, W. E. and King, C. H. (2014) Human schistosomiasis. Lancet 383, 2253.).

[0003] Two drugs, praziquantel and oxamniquine, are approved for the treatment of schistosomiasis. Oxamniquine has a narrow activity spectrum, i.e. only against S. mansoni (Spangenberg T., ACS Infect. Dis. 2021, 7, 5, 939-942).

[0004] Based on a recently described high-throughput screening method using the larval stage of Schistosoma worms, and subsequent use of the method to identify a set of hit molecules. Paveley, R. A. et al. (2012) "Whole organism high-content screening by label-free, image-based Bayesian classification for parasitic diseases." PLoS Negl Trop Dis 6(7): e1762 and Mansour, N. R., et al. (2016) "High Throughput Screening Identifies Novel Lead Compounds with Activity against Larval, Juvenile and Adult Schistosoma mansoni" PLoS Negl Trop Dis 10(4): e0004659 discloses a series based on imidazopyrazine derivatives with sub-micromolar EC50values against larval, juvenile and adult stages of S. mansoni 50 .

[0005] WO2018130853 A1 describes the preparation of bicyclic compounds and their use in the treatment of schistosomiasis.

[0006] WO2020016235 A1 describes the preparation of bicyclic compounds and their use in the treatment of schistosomiasis.

[0007] There is still a need in the art for additional compounds active as anti-schistosomal agents which combine good pharmacokinetic properties, sufficient activity (preferably against all three major infective worm species and against both the juvenile and adult worms) and sufficient solubility.

[0008] We have surprisingly found that compounds of formula (I), (I), (III) have sufficient potency while combining other advantageous properties such as, in particular, solubility. SUMMARY

[0010] In a first embodiment, the present application provides a compound of formula (I), (II) or (III),

[0011]

[0012] wherein:

[0013] R1 It is a cyclopropyl, cyclobutyl, F, or a C1-C3 alkyl group optionally substituted with up to 5 F atoms;

[0014] R 2 It is a cyclopropyl, cyclobutyl, F, or a C1-C3 alkyl group optionally substituted with up to 5 F atoms;

[0015] R 3 With R 4 Each of the following groups represents residues independently:

[0016]

[0017] R 5 For residues selected from the following groups:

[0018]

[0019] X is CH or N; and

[0020] R 6 With R 7 Each can be represented independently as H or CH3.

[0021] In a second embodiment, the present invention provides compounds of formula (I), (II) or (III) as defined above, or pharmaceutically acceptable salts or solvates thereof, for use in a therapy.

[0022] In a third embodiment, the present invention provides compounds of formula (I), (II), or (III) as defined above, or pharmaceutically acceptable salts or solvates thereof, for the treatment of helminth infections caused by schistosomes and / or liver flukes. Specifically, the present invention provides compounds of formula (I), (II), or (III) as defined above, or pharmaceutically acceptable salts or solvates thereof, for the treatment of helminth infections, wherein the helminth infection is schistosomiasis and / or fascioliasis.

[0023] In a fourth embodiment, the present invention provides the use of compounds of formula (I), (II) or (III) as defined above, or pharmaceutically acceptable salts or solvates thereof, in the preparation of medicaments for treating worm infections (e.g., particularly schistosomiasis and / or fascioliasis).

[0024] In a fifth embodiment, the present invention provides a method for treating worm infections (e.g., particularly schistosomiasis and / or fascioliasis), comprising administering to a patient in need a therapeutically effective amount of a compound of formula (I), (II) or (III) as defined above, or a pharmaceutically acceptable salt or solvate thereof.

[0025] In a sixth embodiment, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), (II) or (III) as defined above, or a pharmaceutically acceptable salt or solvate thereof. In a further embodiment, such a pharmaceutical composition further comprises an anthelmintic agent. And in a further important embodiment, such a pharmaceutical composition further comprises a pharmaceutically acceptable carrier, adjuvant or vehicle thereof.

[0026] DETAILED DESCRIPTION

[0027] Definitions of terms

[0028] The following definitions apply to the terms as used throughout this specification, unless otherwise limited in specific instances.

[0029] As used herein, the term "C1-C3alkyl" means straight and branched chain saturated hydrocarbon radicals having 1, 2, or 3 carbon atoms, for example: methyl, ethyl, n-propyl, and isopropyl.

[0030] "Pharmaceutically acceptable salt" means a salt as described in standard text books on salt formation processes, 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 in accordance with the present application include those formed with organic or inorganic acids or bases. In particular, suitable salts with acids in accordance with the present application include salts with mineral acids, strong organic carboxylic acids, for example alkanecarboxylic acids of 1 to 4 carbon atoms, which are unsubstituted or substituted, for example by halogen, for example saturated or unsaturated dicarboxylic acids, for example hydroxycarboxylic acids, for example amino acids, or with organic sulphonic acids, for example C1-C4alkyl- or aryl-sulphonic 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, methanesulphonic, ethanesulphonic, p-toluenesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic, benzenesulphonic, isethionic, ascorbic, malic, phthalic, aspartic and glutamic, lysine and arginine acids. Other acids, which can not in themselves be pharmaceutically acceptable, can be useful in the preparation of compounds of the application and their pharmaceutically acceptable acid addition salts.

[0031] Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as potassium and sodium, alkaline earth metal salts such as calcium and magnesium, and salts with organic bases such as dicyclohexylamine, N-methyl-D-glucamine, morpholine, thiomorpholine, piperidine, pyrrolidine, mono-, di- or tri-lower alkylamines such as ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethyl- propylamine, or mono-, di- or trihydroxy lower alkylamines such as mono-, di- or triethanolamine. Corresponding internal salts can furthermore be formed.

[0032] “Pharmaceutically acceptable solvate” means a molecular complex comprising a compound of the present application and one or more pharmaceutically acceptable solvent molecules (e.g., water or ethanol). Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents having stoichiometric or non-stoichiometric proportions of solute to solvent. These complexes are known as “solvates”. For example, complexes with water are known as “hydrates”. Solvates (e.g., hydrates) exist when a pharmaceutical substance incorporates solvent (e.g., water) in the crystal lattice. Any organic compound can form complexes with solvents in which they react or precipitate or crystallize from the solvent. These complexes are known as “solvates”. For example, complexes with water are known as “hydrates”. Solvates (e.g., hydrates) exist when a pharmaceutical substance incorporates solvent (e.g., water) in the crystal lattice in stoichiometric or non-stoichiometric proportions. Hydrates are routinely screened for in pharmaceutical substances because they can be encountered at any stage of the pharmaceutical manufacturing process or upon storage of the pharmaceutical substance or dosage form. Solvates are described in S. Byrn et al., Pharmaceutical Research, 1995. 12(7): p. 954-954, and Water-Insoluble Drug Formulation, 2nd Edition, R. Liu, CRC Press, p. 553, which are incorporated herein by reference.

[0033] “Therapy”, “treatment” and “treating” include prophylactic and curative treatment of a condition, disease or disorder in a human or animal. It also includes slowing down, blocking, controlling or stopping the progression of a condition, disease or disorder in a human or animal. It also includes preventing, curing, slowing down, blocking, controlling or stopping a symptom of a condition, disease or disorder in a human or animal.

[0034] Throughout the present invention, “prophylactic” and “prevention” specifically include, but are not limited to, chemoprevention and chemoprophylaxis.

[0035] According to the present invention, a “patient” can be a human or an animal.

[0036] Throughout the present invention, all residues appearing more than once can be identical or different, i.e. independently of each other. For example, in formula (I) or formula (II), each instance of R 1 and R 2 may have a different meaning (within the scope of the respective definition).

[0037] The compounds of formula (I) according to the present invention - depending on the nature of the substituents which they can bear - can have one or more chiral centers. Thus, they can appear in various enantiomeric and diastereomeric forms, and in racemic or optically active form, as appropriate. The present invention thus also relates to the optically active forms, the enantiomers, the racemates, the diastereomers, and mixtures thereof in all proportions, collectively referred to as: "stereoisomers". It can be desirable to use a particular stereoisomer, for example one particular enantiomer or diastereomer of a certain compound. In these cases, the compounds according to the present invention, or even intermediates thereof, obtained as racemates - can be separated by chemical or physical measures known to those skilled in the art to isolate the stereoisomeric (enantiomeric, diastereomeric) compounds. Compounds of the present invention having one or more chiral centers and appearing as racemates or as mixtures of enantiomers or diastereomers, can be resolved into their optically pure or enriched isomers, i.e. enantiomers or diastereomers, for example by methods known per se. The separation of the compounds of the present invention can be carried out by chromatographic methods, for example column separation on chiral or achiral phases, or by recrystallization from optionally optically active solvents, or by using optically active acids or bases, or by derivatization with optically active reagents (for example, as optically active alcohols) and subsequent elimination of the group. Another method which can be applied to obtain one or more particular stereoisomers of the compounds of the present invention in enriched or pure form makes use of stereoselective synthesis procedures, for example, by applying starting materials in stereoisomerically enriched or pure form (for example using pure or enriched (R)- or (S)-enantiomers of a certain starting material bearing a chiral center) or by utilizing chiral reagents or catalysts, in particular enzymes.

[0038] The dotted line dividing the bond line (see for example in the definition of R 3 and R 4 ) shows the bond of a certain residue to its adjacent atom.

[0039] The term "pharmaceutically acceptable carrier, adjuvant or vehicle" means a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of this application include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0040] Anthelmintics are agents that act against the diseases of humans and animals caused by infection with parasites (helminths), for example, pyrantel or triclabendazole.

[0041] The present application also relates to a compound of formula (I), (II) or (III) as defined above, or a pharmaceutically acceptable salt or solvate thereof, for use in therapy, in particular for use in the treatment of schistosomiasis and / or fascioliasis.

[0042] The present application also relates to a medicament (or pharmaceutical composition or formulation) comprising a compound of formula (I), (II) or (III) as defined above, or a pharmaceutically acceptable salt or solvate thereof, for use in therapy, in particular for use in the treatment of schistosomiasis and / or fascioliasis.

[0043] The present application also relates to the use of a compound of formula (I), (II) or (III) as defined above, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of schistosomiasis and / or fascioliasis.

[0044] The present application also relates to a method of treating schistosomiasis and / or fascioliasis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II) or (III) as defined above, or a pharmaceutically acceptable salt or solvate thereof.

[0045] The amount of active ingredient required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the subject under treatment, including the type, species, age, weight, sex, and medical condition of the subject as well as the severity of the condition or disease undergoing therapy, and can readily be determined and open by a physician, veterinarian or clinician having ordinary skill in the art. The effective amount of the drug required to prevent, counter or arrest the progress of the condition is readily determined and open by one having ordinary skill in the art.

[0046] Compounds

[0047] The present application provides a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt or solvate thereof,

[0048]

[0049] wherein:

[0050] R 1 is cyclopropyl, cyclobutyl, F or C1-C3 alkyl optionally substituted with up to 5 F atoms;

[0051] R 2 is cyclopropyl, cyclobutyl, F or C1-C3 alkyl optionally substituted with up to 5 F atoms;

[0052] R 3 and R 4 each, independently of one another, denotes a residue selected from the following group:

[0053]

[0054] R 5 is a residue selected from the following group:

[0055]

[0056] X is CH or N; and

[0057] R 6 and R 7 each, independently of one another, denotes H or CH3.

[0058] In some embodiments, the compound of the present application is of formula (I) as defined above.

[0059] In some embodiments, the compound of the present application is of formula (II) as defined above.

[0060] In some embodiments, the compound of the present application is of formula (II) as defined above.

[0061] R 1 is selected from the group consisting of cyclopropyl, cyclobutyl, F or C1-C3 alkyl optionally substituted with up to 5 F atoms. Preferably R 1 is selected from the group consisting of cyclopropyl, F or C1-C3 alkyl optionally substituted with up to 5 F atoms. Even more preferably R 1 is selected from the group consisting of F, cyclopropyl, methyl, ethyl, n-propyl, i-propyl, CHF2, CF3 and CH2CF3. R 1 Most preferably is i-propyl.

[0062] R 2cyclopropyl, F or Ci-C3-alkyl optionally substituted with up to 5 F atoms. Preferably R 2 cyclopropyl, F or Ci-C3-alkyl optionally substituted with up to 5 F atoms. Even more preferably R 2 F, cyclopropyl, methyl, ethyl, n-propyl, i-propyl, CHF2, CF3and CH2CF3. Most preferably R 2 Most preferably cyclopropyl.

[0063] R 3 is selected from the group consisting of:

[0064] ,

[0065] wherein

[0066] R 6 and R 7 each, independently of one another, denote H or CH3(preferably R 6 and R 7 each denote H), and

[0067] X is CH or N.

[0068] Preferably R 3 is selected from the group consisting of:

[0069] .

[0070] R 4 is selected from the group consisting of:

[0071] ,

[0072] wherein

[0073] R 6 and R 7 each, independently of one another, denote H or CH3(preferably R 6 and R 7 each denote H), and

[0074] X is CH or N.

[0075] Preferably R 4 is selected from the group consisting of:

[0076] .

[0077] R 5 is selected from the group consisting of:

[0078]

[0079] wherein

[0080] R 6 and R 7 each, independently of one another, denotes H or CH3(preferably R 6 and R 7 each denotes H), and

[0081] X is CH or N.

[0082] R 5 is preferably selected from the group consisting of:

[0083]

[0084] wherein

[0085] R 6 and R 7 each, independently of one another, denotes H or CH3(preferably R 6 and R 7 each denotes H).

[0086] Preferred embodiments of the present application comprise compounds of formula (I) or (II).

[0087] Further preferred embodiments of the present application comprise compounds of formula (I), (II) or (III), wherein

[0088] R 1 is isopropyl; and

[0089] R 2 is cyclopropyl.

[0090] In these preferred embodiments, particularly important embodiments include compounds of formula (I) or (II), wherein

[0091] R 1 is isopropyl; and

[0092] R 2 is cyclopropyl.

[0093] According to the above defined compounds, wherein the compounds are selected from the following group:

[0094] General synthesis methods

[0095] The processes for synthesizing the compounds of the application are illustrated by the following schemes. The starting materials and reagents used to prepare these compounds are either available from commercial suppliers or can be prepared by methods apparent to those skilled in the art. The general synthesis of starting materials SM1, SM2, SM3 and SM4 is for example described in detail in WO2018130853 A1. Furthermore, the synthesis procedures of SM1, SM2, SM3 and SM4 are described in the experimental section below.

[0096] General procedure 1:

[0097] The present application provides processes for preparing compounds of formula (I) and (II), wherein the residues R 1 and R 2 are according to the definition of the application, and R 3 and R 4 represent CH2OPO(OH)2. The process involves SM1 or SM2, which is N-alkylated to provide an intermediate, which can then be subjected to hydrolysis in the next step to form the corresponding phosphate ester derivative.

[0098]

[0099] General procedure 2:

[0100] The present application provides processes for preparing compounds of formula (I) and (II), wherein the residues R 1 and R 2 are according to the definition of the application, and R 3 is:

[0101] .

[0102] The process involves SM1 or SM2, which is condensed with formaldehyde, and then treated with a reagent to form a carbamate. The ester function can then be subjected to hydrolysis to form the corresponding carboxylic acid.

[0103]

[0104] General procedure 3:

[0105] The present application provides processes for preparing compounds of formula (I) and (II), wherein the residues R 1 and R 2 are according to the definition of the application, and R 3 is:

[0106] .

[0107] The process involves SM1 or SM2, which is treated with an alkylating reagent to form the corresponding N-alkylated adduct. The ester function can then be subjected to hydrolysis to form the corresponding carboxylic acid.

[0108]

[0109] General procedure 4:

[0110] The present application provides a process for the preparation of compounds of formula (I) and (II) wherein the residue R 1 and R 2 are according to the definition of the present application, and R 3 is:

[0111] .

[0112] The process involves SM1, SM2, SM3 or SM4 which is treated with an alkylating agent to form the corresponding N-alkylated adduct. The ester function can then be hydrolyzed to form the corresponding carboxylic acid.

[0113]

[0114] General procedure 5:

[0115] The present application provides a process for the preparation of compounds of formula (I) and (II) wherein the residue R 1 and R 2 are according to the definition of the present application, and R 3 is:

[0116] ,

[0117] wherein R 6 = CH3. The process involves SM1 or SM2 which is treated with an alkylating agent to form the corresponding N-alkylated adduct.

[0118]

[0119] General procedure 6:

[0120] The present application provides a process for the preparation of compounds of formula (I) and (II) wherein the residue R 1 and R 2 are according to the definition of the present application, and R 3 is:

[0121] .

[0122] The process involves SM1 or SM2 which is esterified to form the corresponding adduct. In a second step, the amine is deprotected.

[0123]

[0124] General procedure 7:

[0125] The present application provides a process for preparing a compound of formula (III), wherein the residue R 1 and R 2 are according to the definition of the present application, and R 5 is CH2OPO(OH)2. The process involves SM3 or SM4 which is O-alkylated to provide an intermediate which can then be subjected to hydrolysis in the next step to form the corresponding phosphate derivative.

[0126]

[0127] General procedure 8:

[0128] The present application provides a process for preparing a compound of formula (III), wherein the residue R 1 and R 2 are according to the definition of the present application, and R 5 is one of the following residues:

[0129] .

[0130] The process involves SM3 or SM4 which is esterified as exemplarily shown below:

[0131] Examples

[0132] Abbreviations

[0133] ACN: acetonitrile

[0134] AcOH: acetic acid

[0135] Bispin: bis-(pinacolato)-diboron

[0136] DMAP: 4-dimethylaminopyridine

[0137] DCM: dichloromethane

[0138] DMF: dimethylformamide

[0139] DMSO: dimethylsulfoxide

[0140] EA: ethyl acetate

[0141] EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0142] HPLC: high pressure liquid chromatography

[0143] prep-HPLC: preparative high pressure liquid chromatography

[0144] LCMS (or LS-MS): liquid chromatography-mass spectrometry

[0145] NMR: nuclear magnetic resonance

[0146] pet ether: petroleum ether

[0147] PyBop: benzotriazol-1-yl-oxytripyrrolodinophosphonium hexafluorophosphate

[0148] RT: room temperature

[0149] TEA: triethylamine

[0150] TFA: trifluoroacetic acid

[0151] THF: tetrahydrofuran

[0152] TLC: thin layer chromatography

[0153] TMS-Br: trimethylsilyl bromide

[0154] HPLC method:

[0155] “TFA method”

[0156] Column: X Bridge C8 (50 X 4.6) mm, 3.5 pm, mobile phase A: 0.1% TFA in water. Mobile phase B: ACN, flow rate: 2.0 mL / min

[0157] “HCOOH method”

[0158] Column: X Bridge C8 (50 X 4.6) mm, 3.5 pm, mobile phase A: 0.1% FA in water. Mobile phase B: ACN, flow rate: 2.0 mL / min

[0159] “Ammonium bicarbonate method”

[0160] Column: X-Bridge C8 (50 X 4.6) mm, 3.5 pm, mobile phase A: 10 mM ammonium bicarbonate in water. Mobile phase B: ACN, flow rate: 1.0 mL / min

[0161] “Ammonium acetate method”

[0162] Column: X-Bridge C8 (50 X 4.6) mm, 3.5 pm, mobile phase A: 10 mM ammonium acetate in water. Mobile phase B: ACN, flow rate: 1.0 mL / min

[0163] Synthesis of SM1

[0164] Synthesis of boronate ester compound 8:

[0165]

[0166] Step-1 : To a stirred solution of 5-bromo-4-fluoro-lH-indazole (150 g, 698 mmol) in DCM (2.0 L), p-toluenesulfonic acid (60.1 g, 349 mmol) was added followed by 3,4-dihydro-2H-pyran (70.4 g, 837 mmol) at 25 °C and the reaction mixture was stirred at 25 °C for 16 h. After completion of the reaction, the reaction mixture was diluted with water (2.0 L) and extracted with DCM (2.0 mL). The organic layer was washed with water (500.0 mL) and brine (500.0 mL). The collected organic layer was dried over sodium sulfate, filtered and the filtrate was evaporated under reduced pressure to obtain crude product. The crude product was purified by flash column chromatography using 230-400 mesh silica gel and using 15-32% ethyl acetate in petroleum ether as an eluent to afford compound 3 (160 g, 76.7 % yield) as off white solid.

[0167] LCMS: For the following calculation: C12H12BrFN2O, Exact mass: 298.01, Observed 301.0 (M+2), RT. 2.88 min, 84.17 % (maximum).

[0168] 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.09 (d, J = 0.80 Hz, 1H), 7.50-7.48 (m, 1H), 7.32-7.28 (m, 1H), 5.73-5.70 (m, 1H), 4.03-3.99 (m, 1H), 3.79-3.73- (m, 1H), 2.54 (t, J = 9.20 Hz, 1H), 2.18-2.08 (m, 2H), 1.81-1.68 (m, 3H).

[0169] Step-2: To a stirred solution of compound 3 (160 g, 531.11 mmol) and bis-(pinacolato)-diboron (163.06 g, 642.14 mmol) in dioxane (1100 mL), potassium acetate (130.12 g, 1327.7 mmol) was added. The reaction mixture was degassed by continuous bubbling of nitrogen gas for 30 min. After that PdCl2(dppf)-CH2Cl2 adduct (43.3 g, 53.11 mmol) was added at 25 °C and the reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction, the reaction mixture was diluted with water (2.0 L) and extracted with ethyl acetate (2.0 L). The organic layer was washed with water (1.0 L) and brine (1.0 L). The collected organic layer was dried over sodium sulfate, filtered and the filtrate was evaporated under reduced pressure to get the crude product. The crude product was purified by flash column chromatography using 230-400 mesh silica gel and using 5-10% ethyl acetate in petroleum ether as an eluent to get compound 8 (174 g, 93.9 % yield) as a gummy solid.

[0170] LCMS: For the following calculated: C18H24BFN2O3, Exact mass: 347.1, Observed 301.0 (M+2), RT. 2.97 min, 94.07 % (max),

[0171] HPLC: 3.95 min, 99.91 % (max).

[0172] 1 H NMR (400 MHz, CDCl3): δ 8.12 (t, J = 2.00 Hz, 1H), 7.72-7.69 (m, 1H), 7.40-7.26 (m, 1H), 5.74-5.71 (m, 1H), 4.05-4.01 (m, 1H), 3.78-3.72 (m, 1H), 2.54 (s, 1H), 2.55-2.06 (m, 2H), 1.80-1.75 (3H), 1.37 (s, 12H).

[0173] Synthesis of SM1

[0174]

[0175] Step-1: To a stirred solution of 4-bromo-1-fluoro-2-isopropylbenzene (300 g, 1.382 mol) in dioxane (3.0 L), bis(pinacolato)diboron (421.13 g, 1.658 mol) and potassium acetate (203.44 g, 2.073 mol) was added. The reaction mixture was degassed by continuous bubbling of nitrogen gas for 30 min. After 25 °C, PdCl2(dppf)-CH2Cl2adduct (56.42 g, 69.1 mmol) was added and the reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction, the reaction mixture was filtered through celite and the filtrate was evaporated under reduced pressure to get crude compound 2 as black liquid (366.0 g). The crude product was used directly for the next step.

[0176] GCMS: For the following calculation: C15H22BFO2, Exact mass: 264.17, observed 264.1, RT. 3.909 min, 73.84 % (max),

[0177] Step-2: To a stirred solution of 5-bromo-pyrazin-2-amine (200 g, 1.149 mol) in dioxane (2.5 L) and water (630.0 mL), compound 2 (364.13 g, 1.379 mol) and potassium carbonate (237.8 g, 1.723 mol) was added. The reaction mixture was degassed by continuous bubbling of nitrogen gas for 30 min. After 25 °C, tetrakis(triphenylphosphine)palladium(0) (66.35 g, 57.45 mmol) was added and the reaction mixture was stirred at 110 °C for 16 h. After completion of the reaction, the reaction mixture was diluted with water (3000.0 mL) and extracted with ethyl acetate (2000.0 mL). The organic layer was washed with water (500.0 mL) and brine (500.0 mL). The collected organic layer was dried over sodium sulfate, filtered and the filtrate was evaporated under reduced pressure to get crude product. The crude product was purified by column chromatography using 60-120 mesh silica gel and 35-40% ethyl acetate in petroleum ether as eluent to get compound 4 as off white solid (230.0 g, 87.7).

[0178] LCMS: For the following calculation: C13H14FN3, Exact mass: 231.12, observed 232.2 (M+H), RT. 2.032 min, 98.20 % (max),

[0179] 1 H NMR (400 MHz, DMSO-d 6H NMR (400 MHz, DMSO-d6): δ 8.51 (d, J = 1.20 Hz, 1H), 7.95 (d, J = 1.60 Hz, 1H), 7.87 (dd, J = 2.40, 7.60 Hz, 1H), 7.77-7.73 (m, 1H), 7.19-7.14 (m, 1H), 6.54 (s, 2H), 3.21 (t, J = 6.80 Hz, 1H), 1.27 (d, J = 6.80 Hz, 1H).

[0180] Step-3: To a stirred solution of compound 4 (230 g, 994 mmol) in acetonitrile (2.5 L), 2-bromo-l-cyclopropylethan-l-one (195 g, 1193 mmol) was added at 25 °C and the reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction, the reaction mixture was filtered and washed with acetonitrile (500.0 mL) and dried to get compound 6 (220 g, 74.9 % yield) as off white solid.

[0181] LCMS: For the following calculation: C18H18FN3, Exact Mass: 295.15, Obs. 296.2 (M+H), RT. 2.096 min, 91.08 % (max).

[0182] 1 H NMR (400 MHz, DMSO-d6): δ 8.51 (d, J = 1.20 Hz, 1H), 7.95 (d, J = 1.60 Hz, 1H), 7.87 (dd, J = 2.40, 7.60 Hz, 1H), 7.77-7.73 (m, 1H), 7.19-7.14 (m, 1H), 6.54 (s, 2H), 3.21 (t, J = 6.80 Hz, 1H), 1.27 (d, J = 6.80 Hz, 1H). 6 ) δ 9.26 (s, 1H), 9.16 (s, 1H), 8.077 (s, 1H), 8.02 (dd, J = 2.80, 9.60 Hz, 1H), 7.92-7.87 (m, 1H), 7.30 (t, J = 11.60 Hz, 1H), 3.25 (t, J = 9.20 Hz, 1H), 2.26-2.22 (m, 1H), 1.30 (d, J = 9.20 Hz, 6H), 1.12-1.08 (m, 2H), 0.98-0.96 (m, 2H).

[0183] Step-4: To a stirred solution of compound 6 (220 g 745.6 mmol) in DCM (10.0 mL), NBS (146.02 g, 820.33 mmol) was added at 25 °C and the reaction mixture was stirred at 25 °C for 30 min. After completion of the reaction, the reaction mixture was diluted with water (2.0 L) and extracted with DCM (2.0 L). The organic layer was washed with water (1.0 L). The collected organic layer was dried over sodium sulfate, filtered and the filtrate was evaporated under reduced pressure to get the crude product. The crude product was washed with acetonitrile (1.0 L) to get compound 7 (91 g, 32.6 % yield) as off white solid.

[0184] LCMS: For the following calculation: C18H17BrFN3, Exact mass: 374.06, observed 376.0 (M+2), RT. 3.306 min, 99.79 % (max).

[0185] 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.02 (d, J = 2.00 Hz, 1H), 8.70 (d, J = 1.60 Hz, 1H), 8.09 (dd, J = 2.80, 9.80 Hz, 1H), 5.01 - 7.96 (m, 1H), 3.25 (t, J = 9.20 Hz, 1H), 3.27 (t, J = 9.60 Hz, 1H), 2.19 - 2.09 (m, 1H), 1.30 (d, J = 9.20 Hz, 6H), 1.10 - 1.06 (m, 2H), 1.03 - 1.00 (m, 2H).

[0186] Step-5: In a 50.0 mL sealed tube, compound 7 (90 g, 240.64 mmol) was dissolved in dioxane (1.0 L) and water (400.0 mL) followed by addition of compound 8 (91.58 g, 264.70 mmol) and potassium phosphate tribasic (76.52 g, 360.96 mmol). The reaction mixture was continuously purged with nitrogen gas for 30 minutes for degassing. After that, tetrakis(triphenylphosphine) palladium (0) (13.89 g, 12.032 mmol) was added at 25 °C and the reaction mixture was stirred at 110 °C for 16 hours. After completion of the reaction, the reaction mixture was diluted with water (2.0 L) and extracted with ethyl acetate (2.0 L). The organic layer was washed with water (1.0 L) and brine (1.0 L). The collected organic layer was dried over sodium sulfate, filtered and the filtrate was evaporated under reduced pressure to get the crude product. The crude product was purified by flash column chromatography using 230-400 mesh silica gel and using 25-30% ethyl acetate in petroleum ether as an eluent to get compound 9 (107 g, 86.6 % yield) as a gummy solid.

[0187] LCMS: For the following calculation: C30H29F2N5O, Exact mass: 513.23, observed 514.3 (M+H), RT. 2.57 min, 94.8 % (max),

[0188] 1 H NMR (400 MHz, DMSO-d 6) : δ 9.10 (d, J = 1.60 Hz, 1H), 8.55 (s, 1H), 8.40 (s, 1H), 8.02 (d, J = 7.60 Hz, 1H), 7.85 (d, J = 11.60 Hz, 2H), 7.70 (t, J = 11.60 Hz, 1H), 7.16-7.13 (m, 1H), 6.00 (d, J = 10.40 Hz, 1H), 3.95 (d, J = 10.40 Hz, 1H), 3.82 (t, J = 8.00 Hz, 1H), 2.11-1.95 (m, 4H), 1.80 (d, J = 6.80 Hz, 2H), 1.62 (s, 2H), 1.26 (d, J = 9.20 Hz, 6H), 1.07-0.97 (m, 4H).

[0189] Step-6: To a stirred solution of compound 9 (107 g, 208.57 mmol) in DCM (1.0 L) was added TFA (398.94 mL, 5214.25 mmol) at 0°C and the reaction mixture was stirred at 25°C for 16 h. After completion of the reaction, the reaction mass was evaporated under reduced pressure to get the crude product. The crude product was neutralized with sodium bicarbonate solution (2.0 L) and extracted with 20% methanol in DCM (8.0 L). The collected organic layer was dried over sodium sulphate, filtered and the filtrate was evaporated under reduced pressure to get the crude product. The crude product was washed with methanol (2.0 L) to get SM1 (57 g, 63.70 % yield) as off-white solid.

[0190] Pd content removal: To a stirred solution of SM1 (57 g) in THF (3.0 L) was added SiliaMetS® Thiol (1.0 g), SiliaMetS® Diamine (1.0 g), SiliaMetS® Cystine (1.0 g), SiliaMetS® DMT (1.0 g), SiliaMetS® Thio urea (1.0 g) at 25°C and the reaction mixture was stirred at 25°C for 16 h. Then filtered through celite, washed with THF, concentrated and the same process was repeated twice. After three treatments, the filtrate was evaporated under reduced pressure to get a solid. The solid was washed with methanol and filtered to get SM1 as off-white solid. Though LC-MS and HPLC >95%, NMR showed trace amount of THF and DCM.

[0191] Removal of THF (or) DCM: To remove the trapped solvents THF and DCM, SM1 was slowly dissolved in hot DMSO (2.0 L) and stirred at 25 °C for 30 min. After that water (2.0 L) was added at 25 °C and stirred for 3 h. The resulting solid was filtered and washed with water (1.0 L). The solid was dried under reduced pressure to get SM1 as off-white solid.

[0192] Removal of DMSO: To remove the trapped DMSO, the compound was stirred with methanol (1.5 mL) and water (1.5 mL) at 90 °C for 16 h. The mixture was then cooled to 35 °C and filtered. The solid was washed with methanol (500.0 mL) and water (500.0 mL) to get SM1 (50 g) as off-white solid.

[0193] LCMS: For the following calculation: C25H21F2N5, Exact mass: 429.18, observed 430.2 (M+H), RT. 2.28 min, 99.37 % (max),

[0194] HPLC: 5.16 min, 97.72 % (max).

[0195] 1 H NMR (400 MHz, DMSO-d 6 ): δ 13.65 (s, 1H), 9.10 (d, J = 1.20 Hz, 1H), 8.53 (t, J = 1.60 Hz, 1H), 8.36 (d, J = 0.80 Hz, 1H), 8.01 (dd, J = 2.40, 7.40 Hz, 1H), 7.86-7.82 (m, 1H), 7.65-7.59 (m, 2H), 7.18 (t, J = 1.60 Hz, 1H), 3.23-3.16 (m, 1H), 1.98-1.92 (m, 1H), 1.26 (d, J = 6.80 Hz, 6H), 1.04-0.98 (m, 4H).

[0196] Synthesis of SM2

[0197]

[0198] Step-1 : A mixture of 5-bromo-pyrazine-2-carboxylic acid amide (140 g, 805 mmol) and 3-bromo-l, l, l-trifluoropropan-2-one (292 g, 1529 mmol) in 2-propanol (4200 mL) was stirred at 80 °C for 4 h and then at 90 °C for 80 h. After completion of the reaction, the reaction mixture was evaporated under vacuum to get the crude product. The crude product was purified by flash column, the product was eluted with 8-10% ethyl acetate in petroleum ether. The fractions were combined and evaporated under vacuum to get compound 3 (120 g, 54.7 %).

[0199] LCMS: Calculated for C7H3BrF3N3, 266.021, Observed 268.0 (M+H), RT. 1.813 min, 97.63 % (max),

[0200] GCMS: 3.933 min, 96.32 % (max).

[0201] 1 H NMR (400 MHz, DMSO): δ 9.14 (s, 1H), 9.00 (s, 1H), 8.64 (s, 1H).

[0202] Step-2: To a stirred solution of 6-bromo-2-(trifluoromethyl)imidazo[l,2- a]pyrazine (75 g, 282 mmol) in DMF (2000 ml) was added N-chlorosuccinimide (56.5 g, 423 mmol) and stirred at 90 °C for 16 h. The reaction was monitored by TLC. The reaction was diluted with cold water (500 mL) and extracted with ethyl acetate (2 x 250 mL). The organic phase was washed with cold water (2 x 200 mL), brine solution (250 mL) and dried under vacuum to get the crude product. The crude product was purified by flash column, the product was eluted with 2-5% ethyl acetate in petroleum ether. The fractions were evaporated under vacuum to get compound 4 as light yellow solid (82 g, 92 %).

[0203] LCMS: Calculated for C21H15FN2O4S, 300.46, Observed 300.0 (M-H), RT. 2.227 min, 95.22 % (max),

[0204] 1 H NMR (400 MHz, DMSO): δ 9.18 (s, 1H), 8.96 (s, 1H).

[0205] Step-3: To a stirred solution of 6-bromo-3-chloro-2-(trifluoromethyl)imidazo[l,2- a]pyrazine (6.5 g, 21.63 mmol) in dioxane (60 ml) and water (20 ml), was added 2-(4- fluoro-3-isopropylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (6.00 g, 22.71 mmol) and K2CO3(4.48 g, 32.4 mmol). The reaction mixture was degassed by continuous bubbling of nitrogen gas for 10 min. After that tetrakis(triphenylphosphine) palladium(0) (2.500 g, 2.163 mmol) was added at 25 °C and the reaction mixture was stirred at 100 °C for 16 h. TLC monitoring confirmed the completion of the reaction. The reaction mixture was filtered through celite, extracted with EA and washed with water and brine solution. The organic layer was dried over sodium sulfate, concentrated and purified by column chromatography to get compound 6 (4.25 g, 54.9%).

[0206] LCMS: Calculated for C16H12ClF4N3 357.7, observed 358.1 (M+H), RT. 3.37 min, 99.3 % (maximum),

[0207] 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.38 (d, J = 1.20 Hz, 1H), 9.01 (d, J = 1.20 Hz, 1H), 8.15-8.13 (m, 1H), 8.08-8.04 (m, 1H), 7.32-7.28 (m, 1H), 3.34-3.22 (m, 1H), 1.31 (d, J = 7.20 Hz, 6H).

[0208] Step-4: To a stirred solution of 3-bromo-6-(4-fluoro-3-isopropylphenyl)-2- (trifluoromethyl)imidazo[l,2-a]pyrazine (4.25 g, 10.57 mmol) in dioxane (50 ml) and water (15 ml), potassium phosphate tribasic (3.36 g, 15.85 mmol) and 4-fluoro-l- (tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazole (4.39 g, 12.68 mmol) were added. The reaction mixture was degassed by continuous bubbling of nitrogen gas for 10 min. After that, tetrakis(triphenylphosphine)palladium(0) (1.221 g, 1.057 mmol) was added at 25 °C and the reaction mixture was stirred at 110 °C for 16 h. TLC monitoring confirmed the completion of the reaction. The reaction mixture was extracted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, concentrated and purified by column to get compound 8 (5.2 g, 89%).

[0209] LCMS: Calculated for C28H14F5N5O 541.53, observed 542.1 (M+H), RT. 3.16 min, 98.4% (max),

[0210] 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.45 (d, J = 1.20 Hz, 1H), 8.66 (d, J = 23.60 Hz, 1H), 8.44 (d, J = 3.20 Hz, 1H), 8.07-8.03 (m, 1H), 7.91-7.84 (m, 2H), 7.68-7.64 (m, 1H), 7.22-7.17 (m, 1H), 6.01 (d, J = 9.20 Hz, 1H), 3.97-3.94 (m, 1H), 3.85-3.78 (m, 1H), 3.24-3.17 (m, 1H), 2.47-2.34 (m, 1H), 2.08-2.00 (m, 2H), 1.82-1.80 (m, 1H), 1.64-1.62 (m, 2H), 1.17 (d, J = 7.20 Hz, 6H).

[0211] Step-5: To a stirred solution of 3-(4-fluoro-l-(tetrahydro-2H-pyran-2-yl)-lH- indazol-5-yl)-6-(4-fluoro-3-isopropylphenyl)-2-(trifluoromethyl)imidazo[l,2- a]pyrazine (5.2 g, 9.60 mmol) in DCM (35 mL) was added TFA (35 mL, 9.60 mmol) at 0 °C and the reaction mixture was stirred at 25 °C for 16 h. TLC monitoring confirmed the completion of the reaction. The reaction mixture was concentrated, neutralized with 10% NaHC03solution and extracted with DCM. The organic layer was dried over sodium sulfate, concentrated and washed with ACN to get SM2 (2.2 g, 49.6%) as off-white solid.

[0212] LCMS: For the following calculated: C23H16F5N5 457.41, Obs 458.0 (M+H), RT. 2.27 min, 99.0 % (max),

[0213] 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.44 (d, J = 1.60 Hz, 1H), 8.62 (s, 1H), 8.38 (s, 1H), 8.03 (dd, J = 2.40, 7.60 Hz, 1H), 7.89-7.85 (m, 1H), 7.65-7.58 (m, 1H), 7.58-7.55 (m, 1H), 7.21-7.17 (m, 1H), 3.23-3.16 (m, 1H), 1.25 (d, J = 6.80 Hz, 6H).

[0214] Synthesis of SM3

[0215]

[0216] Step-1: To a stirred solution of compound 1 (400 mg, 0.995 mmol) and compound 2 (2-fluoro-4-hydroxyphenyl)boronic acid (217 mg, 1.392 mmol) in 1,4-dioxane (14 mL), pentanol (14.00 mL) and water (3 mL) was added potassium carbonate (137 mg, 0.995 mmol). It was then degassed for 5 min and dichloro(bis(di-tert-butyl)-4-dimethylaminophenylphosphine)palladium (35.2 mg, 0.050 mmol) was added. The reaction mixture was stirred in microwave at 130 °C for about 1 h. The solvent was then removed and purified by preparative HPLC to get SM3 (45 mg, 10%),

[0217] LCMS: For C22H16F5N3O 433.38, observed 434.2 (M+H), RT. 3.0 min, 99.1 % (max),

[0218] HPLC: 6.2 min, 99.8% (max).

[0219] 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.00 (s, 1H), 8.71 (s, 1H), 7.74 (d, J = 2.00 Hz, 1H), 7.65-7.61 (m, 2H), 7.58 (d, J = 6.80 Hz, 1H), 7.47-7.44 (m, 1H), 7.44-7.27 (m, 2H), 3.20-3.13 (m, 1H), 1.17 (d, J = 6.80 Hz, 6H).

[0220] Synthesis of SM4

[0221]

[0222] Step-1: To a stirred solution of compound 1 (1.2 g, 6.90 mmol), 2-(4-fluoro-3- isopropylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (2.004 g, 7.59 mmol), K2CO3 (1.906 g, 13.79 mmol) in 1,4-dioxane (12 ml) and water (4 ml). Then degassed for 5 min and added tetrakis(triphenylphosphine)palladium(0) (0.797 g, 0.690 mmol). The reaction mixture was refluxed at 110 °C for 16 h. The reaction mixture was extracted with ethyl acetate to get compound 3 (900 mg, 60.9%).

[0223] LCMS: For C13H14FN3 231.12, observed 232.2 (M+H), RT. 2.12 min, 98.1% (max).

[0224] Step-2: To a stirred solution of compound 3 (500 mg, 2.162 mmol) in acetonitrile (6 ml) was added 2-bromo-l-cyclopropylethan-l-one (352 mg, 2.162 mmol). The reaction mixture was refluxed at 100 °C for 16 h, the solid was filtered to get compound 5 (425 mg, 80%).

[0225] LCMS: For C18H18FN3 295.15, observed 296.1 (M+H), RT. 2.5 min, 96.9% (max), 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.28 (s, 2H), 8.02-7.90 (m, 3H), 7.33-7.27 (m, 1H), 3.25 (t, J = 9.20 Hz, 1H), 2.28-2.21 (m, 1H), 1.29 (d, J = 8.80 Hz, 6H), 1.12-1.08 (m, 2H), 1.09-0.99 (m, 2H),

[0226] Step-3: To the stirred solution of compound 5 (422 mg, 1.429 mmol) in DCE (6 ml), NBS (280 mg, 1.572 mmol) was added. The reaction mixture was refluxed at 80 °C for 3 h. The reaction mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over Na2S04and concentrated to get compound 6 (305 mg, 72.2 %).

[0227] LCMS: For C18H17BrFN3 373.06, observed 373.9 (M+H), RT. 3.1 min, 95.7 % (max).

[0228] 1 H NMR (400 MHz, MeOD): δ 8.89 (s, 1H), 8.56 (s, 1H), 8.02-8.00 (m, 1H), 7.87-7.83 (m, 1H), 7.18 (t, J = 8.80 Hz, 1H), 2.23-2.20 (m, 1H), 2.04 (s, 7H), 1.37 (d, J = 6.80 Hz, 6H), 1.15-1.12 (m, 4H),

[0229] Step-4: To a stirred solution of compound 6 (300 mg, 0.802 mmol), 3-fluoro-4- (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) phenol (191 mg, 0.802 mmol), potassium carbonate (222 mg, 1.603 mmol) in 1, 4-dioxane (8 ml) and water (2 ml). Then degassed for 5 min and added tetrakis(triphenylphosphine)palladium(0) (93 mg, 0.080 mmol). The reaction mixture was refluxed in microwave at 130 °C for 1 h. The reaction mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2S04and concentrated. The resulting residue was purified by preparative HPLC to afford SM4 (110 mg, 50%)

[0230] LCMS: Calcd. for C24H21F2N3O 405.45, Obs. 406.3 (M+H), RT. 2.3 min, 99.9 % (max).

[0231] HPLC: 4.8 min, 98.2 % (max).

[0232] 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.41 (s, 1H), 9.06 (s, 1H), 8.40 (t, J = 1.60 Hz, 1H), 8.01-7.98 (m, 1H), 7.86-7.82 (m, 1H), 7.22-7.17 (m, 1H), 6.89-6.84 (m, 2H), 3.24-3.20 (m, 1H), 1.95-1.92 (m, 1H), 1.27 (d, J = 6.80 Hz, 6H), 1.00 (t, J = 8.40 Hz, 4H).

[0233] Synthesis of compounds A1 and A8 (Method 1):

[0234]

[0235] Step-1 : To a stirred solution of SM1 (2.5 g, 5.82 mmol) in DMF (10 ml), cesium carbonate (5.68 mg, 17.46 mmol) and di-tert-butylphosphinic acid chloride (2.26 g, 8.74 mmol) were added at 25 °C. The reaction mixture was stirred at 60 °C for 16 h. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine. The organic layer was dried over sodium sulfate and concentrated to get the crude product. The crude product was purified by column chromatography using 230-400 mesh silica gel using 27-30% ethyl acetate in petroleum ether as eluent to get compound (a) and compound (b) (2.6 g, 68.6%) as gummy solid. LCMS showed two peaks corresponding to the mass of the product.

[0236] LCMS: Calculated for C34H40F2N5O4P, Exact mass 651.28, observed 652.2 (M+H), RT. 3.100 and 3.188 min, 28.9 and 66.9% (max) respectively.

[0237] Step-2: The mixture containing compound (a) and compound (b) (2.6 g, 0.460 mmol) was taken in acetic acid (20.0 mL) and water (20.0 mL) and stirred at 60 °C for 3 h. After completion of the reaction, the reaction mixture was evaporated under reduced pressure to get the crude mixture and purified by preparative HPLC. The collected fractions were lyophilized to get compound A1 (270 mg, 28.2 % yield) and compound A8 (290 mg, 30.2%) as off white solid. Peak 1 corresponds to compound A1 and peak 2 corresponds to compound A8.

[0238] Compound A1 :

[0239] LCMS: Calculated for C26H24F2N5O4P, Exact mass 539.15, observed 540.03 (M+H), RT. 1.54 min, 97.69% (max).

[0240] HPLC: 3.711 min, 97.40% (max).

[0241] 1 H NMR (400 MHz, DMSO-d 6): δ 9.10 (s, 1H), 8.88 (s, 1H), 8.54 (s, 1H), 8.02 (d, J=7.20 Hz, 1H), 7.83-7.86 (m, 1H), 7.75 (d, J=8.80 Hz, 1H), 7.55 (t, J=8.40 Hz, 1H), 7.18 (t, J=9.60 Hz, 1H), 6.17 (d, J=10.80 Hz, 2H), 3.20 (t, J=7.20 Hz, 1H), 1.93-2.05 (m, 1H), 1.26 (d, J=7.20 Hz, 6H), 0.96-1.05 (m, 4H).

[0242] Compound A8:

[0243] LCMS: For the following calculation: C26H24F2N5O4P, exact mass 539.15, observed mass 540.1 (M+H), RT. 1.61 min, 96.27% (maximum).

[0244] HPLC: 3.87 min, 94.37% (maximum).

[0245] 1 H NMR (400 MHz, DMSO-d) 6 ): δ 9.11 (s, 1H), 8.54-8.49 (m, 2H), 8.02 (d, J=6.00 Hz, 1H), 7.76-7.87 (m, 3H), 7.18 (t, J=9.60 Hz, 1H), 6.24 (d, J=8.40 Hz, 2H), 3.42-3.49 (m, 2H), 3.20 (t, J=6.40 Hz, 1H), 1.91-1.99 (m, 1H), 1.26 (d, J=6.80 Hz, 1H), 0.96-1.05 (m, 4H).

[0246] Synthesis of compound A2:

[0247]

[0248] Step 1: TEA (0.790 mL, 5.67 mmol) was added to a solution of piperidine-4-carboxylic acid tert-butyl ester (350 mg, 1.889 mmol) and 4-nitrobenzene chloroformate (457 mg, 2.267 mmol) in DCM (10 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. After the reaction was complete, the reaction mixture was quenched with water and extracted with DCM. The organic phase was dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (35% ethyl acetate) to give compound (c) (660 mg, 100%).

[0249] 1 H-NMR (400 MHz, DMSO-d 6 ): δ 8.28 (d, J = 4.80 Hz, 2H), 8.19 (d, J = 9.20 Hz, 2H), 4.05 (s, 1H), 3.62 (s, 1H), 2.49-2.50 (m, 1H), 1.54-1.54 (m, 2H), 1.42-1.52 (m, 2H), 1.18 (s, 9H),

[0250] Step-2: To a stirred solution of compound (c) (153 mg, 0.435 mmol) and compound (d) (200 mg, 0.435 mmol) in DMF (10 mL), potassium tert-butoxide (73.3 mg, 0.653 mmol) was added. The reaction mixture was stirred for 16 h at 25 °C. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with water and brine solution. The organic phase was dried over sodium sulphate and concentrated. The resulting residue was purified by preparative HPLC to afford compound (e) (106 mg, 36.2 %).

[0251] LCMS: Calculated for C37H40F2N6O4 670.76, observed 671.5 (M+H), RT. 2.6 min, 99.4% (maximum),

[0252] 1 H-NMR (400 MHz, DMSO-d 6 ): δ 9.11 (s, 2H), 8.51-8.54 (m, 1H), 8.03 (d, J = 2.40 Hz, 1H), 8.01 (d, J = 2.00 Hz, 1H), 7.91-7.93 (m, 1H), 7.19 (t, J = 1.60 Hz, 1H), 6.48 (d, J = 18.40 Hz, 2H), 4.01-4.06 (m, 2H), 3.17-3.20 (m, 1H), 2.00 (s, 1H), 1.94-1.97 (m, 2H), 1.38 (s, 10H), 1.21 (s, 6H), 1.01-1.18 (m, 4H).

[0253] Step-3: To a stirred solution of compound (e) (106 mg, 0.158 mmol) in DCM (4 mL), TFA (0.037 mL, 0.474 mmol) was added at 0°C. The reaction mixture was stirred at 25 °C for 2 h. After completion of reaction, the reaction mixture was concentrated, the crude obtained was purified by preparative HPLC to afford compound A2 (25 mg, 25.6 %),

[0254] LCMS: Calcd. for C33H32F2N6O4 614.65, Obs. 615.3 (M+H), RT. 2.1 min, 99.5% (max),

[0255] HPLC: 4.9 min, 99.9% (max),

[0256] 1 H-NMR (400 MHz, DMSO-d 6 ): δ 9.11 (s, 1H), 8.54 (s, 1H), 8.26 (s, 1H), 8.00-8.01 (m, 1H), 7.92 (m, 1H), 7.78-7.85 (m, 1H), 7.17-7.22 (m, 1H), 6.48 (d, J = 17.20 Hz, 2H), 3.20-3.88 (m, 4H), 2.93-3.18 (m, 1H), 2.67-2.68 (m, 2H), 2.45-2.50 (m, 3H), 2.40-2.41 (m, 2H), 1.80 (s, 6H), 1.01-1.38 (m, 4H).

[0257] Synthesis of compound A3:

[0258]

[0259] Step 1 : To a stirred solution of compound (a) (300 mg, 1.350 mmol) and sodium bicarbonate (454 mg, 5.40 mmol) in DCM (6 mL) and water (6.00 mL) was added tetrabutylammonium hydrogen sulfate (45.8 mg, 0.135 mmol) at 0 °C and the reaction was kept stirring for 10 min. Then compound (b) (312 mg, 1.890 mmol) was added and the reaction mixture was stirred at 25 °C for 16 h. The progress of reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was quenched with water and extracted with DCM. The combined organic layers were then dried over anhydrous sodium sulfate and concentrated under reduced pressure to get the crude product. The crude product was purified by flash column chromatography using 230-400 mesh silica gel using 5-6% ethylacetate in petroleum ether as an eluent to afford compound (c) (242 mg, 66.2%).

[0260] 1 H NMR (400 MHz, DMSO-d 6 ): d 8.06-8.12 (m, 4H), 6.14 (s, 2H), 1.57 (s, 9H).

[0261] Step 2: To a stirred solution of SM1 (300 mg, 0.698 mmol) in THF (10 mL) was added potassium tert-butoxide (117 mg, 0.419 mmol) and compound (c) (232 mg, 1.047 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 4 h. The progress of reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was diluted with water and extracted with ethylacetate. The combined organic layers were then dried over anhydrous sodium sulfate and concentrated under reduced pressure to get the crude product. The crude product was purified by flash column chromatography using 230-400 mesh silica gel using 15% ethylacetate in petroleum ether as an eluent to afford compound (d) (304 mg, 65.6%).

[0262] LCMS: Calculated for C38H35F2N5O4, Exact mass 663.726, Observed 664.4 (M+H), RT. 2.744 min, 98.876 (max).

[0263] 1 H NMR (400 MHz, DMSO-d 6) : δ 9.11 (d, J = 1.60 Hz, 1H), 8.58 (d, J = 5.60 Hz, 2H), 8.01-8.09 (m, 7H), 7.83 (d, J = 8.40 Hz, 2H), 7.17 (t, J = 13.60 Hz, 1H), 6.82 (s, 2H), 1.56 (s, 9H), 1.16-1.26 (m, 6H), 1.02-1.26 (m, 5H).

[0264] Step 3: To a stirred solution of compound (d) (304 mg, 0.458 mmol) in DCM (2 mL) was added TFA (0.118 mL, 0.458 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. The reaction progress was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was concentrated and the crude obtained was purified by preparative HPLC to afford compound A3 (81.89 mg, 29. %) as off-white solid.

[0265] LCMS: For the following C34H27F2N5O4, Exact mass 607.618, Obs. 608.3 (M+H), RT. 2.285 min, 99.93% (max).

[0266] HPLC: 5.409 min, 99.94% (max).

[0267] 1 H NMR (400 MHz, DMSO-d 6 ) : δ 13.43 (s, 1H), 9.11 (d, J = 1.20 Hz, 1H), 8.57-8.60 (m, 2H), 8.07 (s, 6H), 7.80-7.85 (m, 2H), 7.15-7.19 (m, 1H), 6.83 (s, 2H), 3.18-3.23 (m, 1H), 1.93-1.98 (m, 1H), 1.25 (d, J = 6.80 Hz, 6H), 0.99-1.05 (m, 4H).

[0268] Synthesis of compound A5:

[0269]

[0270] Step 1 : To a stirred solution of compound (a) (250 mg, 1.452 mmol) and sodium bicarbonate (488 mg, 5.81 mmol) in DCM (6 ml) and water (6.00 mL) was added tetrabutylammonium hydrogen sulfate (49.3 mg, 0.145 mmol) at 0 °C. The reaction mixture was kept stirring for 10 min. Then compound (b) (0.206 mL, 2.033 mmol) was added at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. The progress of reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were then dried over anhydrous sodium sulfate and concentrated under reduced pressure to get the crude product. The crude product was purified by flash column chromatography using 230-400 mesh silica gel and 7% ethyl acetate in petroleum ether as an eluent to afford compound (c) (234 mg, 73%).

[0271] 1 H NMR (400 MHz, DMSO-d 6 ): d 6.72-6.82 (m, 2H), 5.97 (s, 2H), 1.48 (s, 9H).

[0272] Step 2: To a stirred solution of SM1 (150 mg, 0.349 mmol) in THF (6 mL) was added potassium tert-butoxide (47.0 mg, 0.419 mmol). After stirring for 15 min at 25 °C, a solution of compound (c) (117 mg, 0.524 mmol) in THF (3 mL) was added drop wise. The reaction mixture was stirred at 25 °C for 16 h. The progress of reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were then dried over anhydrous sodium sulfate and concentrated under reduced pressure to get the crude product. The crude product was purified by flash column chromatography using 230-400 mesh silica gel and 19% ethyl acetate in petroleum ether as an eluent to afford compound (d) (94 mg, 51.3%).

[0273] LCMS: Calculated for C34H33F2N5O4, Exact mass 615.682, Observed 614.5 (M+H), RT. 2.635 min, 93.63% max).

[0274] 1 H NMR (400 MHz, DMSO-d 6): δ 9.11 (d, J=1.60 Hz, 1H), 8.55-8.57 (m, 2H), 8.01-8.03 (m, 1H), 7.95-7.93 (m, 1H), 7.79-7.86 (m, 2H), 7.15-7.20 (m, 1H), 6.71 (d, J=1.20 Hz, 2H), 6.67 (s, 2H), 3.17-3.24 (m, 1H), 1.92-2.00 (m, 1H), 1.45 (d, J=5.20 Hz, 9H), 1.25-1.27 (m, 6H), 0.99-1.05 (m, 4H).

[0275] Step 3: TFA (0.048 mL, 0.186 mmol) was added to a solution of compound (d) (114 mg, 0.186 mmol) in DCM (4 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. The reaction progress was monitored by TLC and LCMS. After the reaction was complete, the reaction mixture was concentrated and purified by preparative HPLC. The resulting fraction was then lyophilized to give compound A5 (45.82 mg, 44.2%).

[0276] LCMS: For the following calculation: C30H25F2N5O4, exact mass 557.558, observed mass 558.3 ​​(M+H), RT. 2.219 min, 99.4% (maximum).

[0277] HPLC: 5.080 min, 99.9% (maximum).

[0278] 1 H NMR (400 MHz, DMSO-d) 6 ): δ13.35 (s, 1H), 9.11 (d, J=1.20 Hz, 1H), 8.55-8.58 (m, 2H), 8.02 (dd, J=2.40, 7.40 Hz, 1H), 7.94-7.96 (m, 1H), 7.78-7.87 (m, 2H), 7.18 (t, J=1.6Hz, 1H), 6.72-6.80 (m, 2H), 6.67-6.68 (m, 2H), 3.18-3.22 (m, 2H), 1.26 (d, J=7.20 Hz, 6H), 0.99-1.05 (m, 4H).

[0279] Synthesis of compound A6:

[0280]

[0281] Step-1: To a stirred solution of compound (a) and sodium bicarbonate (451 mg, 5.37 mmol) in DCM (6 mL) and water (6 mL) was added tetrabutylammonium hydrogen sulfate (45.6 mg, 0.134 mmol) at 0°C. The reaction mixture was stirred for 10 min and chloromethyl chlorosulfate (310 mg, 1.880 mmol) was added. The reaction mixture was stirred at 25°C for 16 h. TLC monitoring confirmed the completion of the reaction. The reaction mixture was quenched with water and extracted with DCM. The organic layer was dried over sodium sulfate, concentrated to get the crude mixture. The resulting residue was purified by silica gel (230-400 mesh) column chromatography using 10% ethyl acetate in petroleum ether as eluent to afford compound (b) (260 mg, 83%).

[0282] 1 H NMR (400 MHz, DMSO-d 6 ): δ 5.73 (s, 2H), 3.70 (m, 1H), 2.11-2.14 (m, 2H), 2.07-2.10 (m, 4H), 1.56-1.58 (m, 4H).

[0283] Step-2: To a stirred solution of SM1 (200 mg, 0.466 mmol) in THF (10 mL) was added cyclohexane-1,4-dicarboxylic acid 1-chloromethyl 4-methyl ester (193 mg, 0.699 mmol) and potassium tert-butoxide (78 mg, 0.699 mmol). The reaction mixture was stirred at room temperature for 16 h. TLC monitoring confirmed the completion of the reaction. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine solution, dried over sodium sulfate and concentrated to get the crude residue. Compound A6 was isolated after column purification and purified by preparative compound A6 (50 mg, 17.25%).

[0284] LCMS: Calculated for C 34 H 33 F2N5O3 597.67, observed 598.4 (M+H), RT. 2.62 min, 95.47 % (max).

[0285] HPLC: 6.30 min, 96.09 % (max).

[0286] 1 H NMR (400 MHz, DMSO-d 6) δ 9.13 (s, 1H), 8.84 (s, 1H), 8.61 (s, 1H), 8.38 (d, J = 8.40 Hz, 1H), 8.02 (d, J = 7.60 Hz, 1H), 7.96 (t, J = 7.20 Hz, 1H), 7.85-7.87 (m, 1H), 7.18 (t, J = 9.20 Hz, 1H), 3.63 (s, 3H), 3.17-3.22 (m, 1H), 2.06-2.13 (m, 4H), 1.95-2.00 (m, 1H), 1.48-1.69 (m, 4H), 1.26 (d, J = 6.80 Hz, 6H), 1.00-1.05 (m, 4H).

[0287] Synthesis of Compound A7 (hydrochloride salt):

[0288]

[0289] Step 1 : To a stirred solution of SM1 (190 mg, 0.442 mmol) and DIPEA (86 mg, 0.664 mmol) in DMF (6 mL) was added PyBOP (460 mg, 0.885 mmol) and compound (a) (126 mg, 0.664 mmol). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was extracted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, concentrated and purified using 30% ethyl acetate in petroleum ether as an eluent over a column of silica gel (230-400 mesh) to afford compound (b) (160 mg, 58.9 %).

[0290] LCMS: Calculated for C33H34F2N6O3 600.671, Observed 601.3 (M+H), RT. 3.28 min, 97.95% (maximum).

[0291] Step 2: To a stirred solution of compound (b) (100 mg, 0.166 mmol) in DCM (5 ml) was added trifluoroacetic acid (0.552 mL, 7.16 mmol) and the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated at 25 °C and purified by preparative HPLC with HCI method. The sample was then lyophilized to afford hydrochloride salt of compound A7 (72 mg, 78 %).

[0292] LCMS: Calculated for C28H27ClF2N6O 500.55, Observed 501.1 (M+H), RT. 2.03 min, 97.12% (maximum).

[0293] HPLC: 4.141 min, 97.87% (max).

[0294] 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.14 (s, 1H), 8.86 (s, 1H), 8.58 (s, 1H), 8.36 (s, 1H), 8.02-7.99 (m, 2H), 8.04 (d, J = 15.20 Hz, 2H), 7.86 (d, J = 2.40 Hz, 1H), 7.19 (d, J = 1.60 Hz, 1H), 3.66 (t, J = 6.80 Hz, 2H), 3.30 (t, J = 6.40 Hz, 2H), 3.22-3.19 (m, 1H), 1.98-1.94 (m, 1H), 1.26 (d, J = 6.80 Hz, 6H), 1.06-0.99 (m, 4H).

[0295] Synthesis of compound A8 (Method 2):

[0296]

[0297] Step-1: To a stirred solution of SM1 (27 g, 62.9 mmol) in DMF (75 mL) was added Cs2CO3(30.7 g, 94 mmol) and di-tert-butyl (chloromethyl) phosphate (compound 1) (17.8 g, 69.2 mmol) at 25 °C. The reaction mixture was stirred at 60 °C for 4 h. The progress of reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic fraction was washed with brine (150 mL), dried over sodium sulphate and evaporated under vacuum to get a crude mixture of compound 2 and compound 3. The crude product was purified by SFC and fractions were concentrated and worked up using DCM (400 mL) and water (2 x 250 mL).

[0298] LCMS (crude): For the following calculated: C34H40F2N5O4P, Exact mass 651.28, observed 652.2 (M+H), RT. 2.469 and 2.533 min, 43.32% and 49.46% (max) respectively.

[0299] The crude residue obtained from step-1 was purified by SFC to get compound 2 (18.8 g, 41.4%) and compound 3 (6.6 g, 15.0%).

[0300] Compound 2:

[0301] LCMS: For the following calculation: C34H40F2N5O4P, Exact mass 651.28, observed 652.2 (M+H), RT. 2.566 min, 93.05% (max).

[0302]

[0303] Step-2: Compound 2 (18.8 g, 6.75 mmol) was taken in IPA (188 mL) and water (188 mL). It was stirred at 50 °C for 20 h. The reaction was monitored by LCMS and HPLC. After completion of the reaction, the reaction mixture was cooled to RT, filtered the precipitated solid, washed with IPA (100 mL) and dried in vacuum to get compound A8 (11.2 g, 71.97%).

[0304] LCMS: For the following calculation: C26H24F2N5O4P, Exact mass 539.15, observed 540.0 (M+H), RT. 1.798 min, 98.82% (max).

[0305] HPLC: 3.896 min, 99.80% (max).

[0306] 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.11 (s, 1H), 8.55 (s, 1H), 8.49 (s, 1H), 8.02-8.00 (m, 1H), 7.88-7.76 (m, 3H), 7.19-7.15 (m, 1H), 6.24 (d, J = 8.40 Hz, 2H), 3.23-3.18 (m, 1H), 1.97-1.93 (m, 1H), 1.26 (d, J = 6.80 Hz, 6H), 1.04-0.99 (m, 4H).

[0307] Synthesis of compound A9:

[0308]

[0309] Step-1: To a stirred solution of (E)-4-(tert-butoxy)-4-oxobut-2-enoic acid (500 mg, 2.90 mmol) and sodium bicarbonate (976 mg, 11.62 mmol) in DCM (12 mL) and water (12 mL) was added tetrabutylammonium hydrogen sulfate (99 mg, 0.290 mmol) at 0 °C and the reaction was kept stirring for 10 min. Then chloromethyl chlorosulfate (671 mg, 4.07 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The progress of reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with water and extracted with DCM. The organic layer was dried over sodium sulfate, concentrated and purified by column. The product was eluted in 6% ethyl acetate in petroleum ether. The fractions were evaporated under vacuum to get compound 3 (0.50 g, 78%).

[0310] 1 H NMR (400 MHz, DMSO-d 6 ): d 6.81-6.71 (m, 2H), 5.97 (s, 2H), 1.47 (s, 9H).

[0311] Step-2: To a stirred solution of SM2 (300 mg, 0.656 mmol) in THF (3 mL) was added potassium tert-butoxide (110 mg, 0.984 mmol). After cooling to 0 °C, a solution of tert-butyl (chloromethyl)fumarate (174 mg, 0.787 mmol) in THF (1 mL) was added drop wise. The reaction mixture was stirred at RT for 2 h. TLC monitoring confirmed the completion of reaction. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and purified by column. The product was eluted in 14% ethyl acetate in petroleum ether. The fractions were evaporated under vacuum to get compound 4 (250 mg, 29.38%).

[0312] LCMS: Calculated for C32H28F5N5O4 641.60, observed 642.1 (M+H), RT. 2.87 min, 98.7% (maximum).

[0313] Step-3: To a stirred solution of compound 4 (250 mg, 0.390 mmol) in DCM (2 mL) was added TFA (1481 mg, 3.90 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h. After completion of reaction, the reaction mixture was concentrated to get crude mixture and purified by preparative HPLC. The fractions were lyophilized to get compound A9 (0.1 g, 43.6%) as off white solid.

[0314] LCMS: For the following calculation: C28H20F5N5O4 585.49, observed 586.2 (M+H), RT. 2.5 min, 98.87 % (max).

[0315] HPLC: 5.65 min, 99.54 % (max).

[0316] 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.45 (d, J = 1.20 Hz, 1H), 8.70 (s, 1H), 8.56 (d, J = 0.40 Hz, 1H), 8.06-8.03 (m, 1H), 7.96-7.90 (m, 1H), 7.90-7.88 (m, 1H), 7.76-7.72 (m, 1H), 7.23-7.18 (m, 1H), 6.81-6.77 (m, 1H), 6.70-6.67 (m, 1H), 6.59-6.56 (m, 1H), 6.46-6.42 (m, 1H), 3.24-3.15 (m, 1H), 1.26 (d, J = 7.20 Hz, 1H).

[0317] 13 C NMR (400 MHz, DMSO-d 6 ): δ 166.62, 165.10, 162.28, 159.84, 154.89, 152.35, 144.42, 144.07, 139.68, 139.20, 135.44, 133.34, 132.35, 130.99, 128.26, 126.43, 120.66, 120.15, 116.24, 114.89, 108.25, 104.39, 71.17, 27.70, 22.85.

[0318] 19 F NMR (400 MHz, DMSO-d 6 ): δ -119.0, -115.8, -73.46.

[0319] Synthesis of Compound A10:

[0320]

[0321] Step-1 : To a stirred solution of SM2 (1 g, 2.186 mmol) in DMF (10 mL) was added cesium carbonate (2.137 g, 6.56 mmol) and di-tert-butyl (chloromethyl) phosphate (0.848 g, 3.28 mmol) at 25 °C and the reaction mixture was stirred at 60 °C for 4 h. Reaction monitoring by LC-MS showed 26% and 2% of two regioisomers and 32% and 27% of mono-tert-butyl cleaved product mass. The reaction mixture was then extracted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, concentrated and the crude mixture of compound 2 and compound 3 (1.5 g) was taken as such for the next step.

[0322] Step-2: The mixture of compound 2 and compound 3 (1.5 g, 2.006 mmol) was taken in acetic acid (3 mL) and water (3 mL) and stirred at 60 °C for 2 h. TLC monitoring confirmed completion of the reaction. The reaction mixture was concentrated to get the crude mixture which was analyzed by LC-MS having 31% and 29% of two regioisomers. After purification by preparative HPLC, two fractions were isolated and lyophilized. Peak 1 matched with compound A10 (0.28 g, 22.4%)

[0323] LCMS: For the following calculated: C24H19F5N5O4P 567.41, Observed 568.2 (M+H), RT. 2.2 min, 96.2 % (max),

[0324] HPLC: 4.41 min, 97.31% (max).

[0325] 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.45 (d, J = 1.60 Hz, 1H), 8.93 (d, J = 0.80 Hz, 1H), 8.65 (s, 1H), 8.05-8.03 (m, 1H), 7.91-7.87 (m, 1H), 7.75 (d, J = 8.80 Hz, 1H), 7.50-7.46 (m, 1H), 7.23-7.18 (m, 1H), 6.18 (d, J = 10.80 Hz, 2H), 3.26-3.17 (m, 1H), 1.26 (d, J = 7.20 Hz, 6H).

[0326] 13 C NMR (400 MHz, DMSO-d 6) δ 162.28, 159.83, 155.68, 153.1, 151.72, 144.46, 139.42, 135.40, 134.44, 132.37, 128.82, 126.41, 124.80, 123.37, 120.60, 116.15, 115.49, 114.77, 102.74, 76.47, 27.69, 22.86.

[0327] 19 F NMR (400 MHz, DMSO-d 6 ) δ -119.0, -115.8, -73.46.

[0328] 19 P NMR (400 MHz, DMSO-d 6 ) δ -2.63.

[0329] Synthesis of Compound A11:

[0330]

[0331] Step-1: To a solution of SM3 (250 mg, 0.577 mmol) in DMF (5 mL) was added cesium carbonate (564 mg, 1.731 mmol) and di-tert-butyl (chloromethyl) phosphate (179 mg, 0.692 mmol). The reaction mixture was stirred at 60 °C for 16 h. Reaction monitoring by LC-MS confirmed the completion of the reaction. The reaction mixture was then quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated to get the crude mixture of compound 2 and used as such for the next step.

[0332] LCMS: Calculated for C31H35F5N3O5P 655.6, observed 656.3 (M+H), RT. 2.9 min, 73.5 % (max),

[0333] Step-2: Compound 2 (370 mg, 0.564 mmol) was taken in water (3 mL) and acetic acid (3 mL) and stirred at 60 °C for 6 h. The crude mixture showed 52% product mass by LC-MS. After purification by preparative HPLC, fractions were lyophilized to get compound A11 (0.1 g, 32.6%) as off-white solid.

[0334] LCMS: Calculated for C23H19F5N3O5P 543.39, observed 544.0 (M+H), RT. 2.12 min, 99.79 % (max),

[0335] HPLC: 4.6 min, 99.8 % (max).

[0336] 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.43 (d, J = 1.60 Hz, 1H), 7.91-7.87 (m, 1H), 7.70 (t, J = 8.40 Hz, 1H), 7.29 (d, J = 2.40 Hz, 1H), 7.27-7.16 (m, 2H), 5.70 (d, J = 11.60 Hz, 2H), 3.26-3.19 (m, 1H), 1.28 (d, J = 6.80 Hz, 6H).

[0337] 13 C NMR (400 MHz, DMSO-d 6 ): δ 162.77, 160.13, 159.50, 144.45, 139.65, 139.12, 135.41, 134.39, 133.77, 135.37, 126.49, 123.76, 120.187, 116.19, 114.61, 113.31, 106.67, 104. 66, 87.85, 27.71, 22.88.

[0338] 19 F NMR (400 MHz, DMSO-d 6 ): δ -119.0, -110.1, -74.7.

[0339] 19 P NMR (400 MHz, DMSO-d 6 ): δ -2.97.

[0340] Synthesis of compound A12:

[0341]

[0342] Step-1: To a stirred solution of SM3 (300 mg, 0.692 mmol) in chloroform (15 mL), TEA (210 mg, 2.077 mmol) and diethyl chlorophosphate (358 mg, 2.077 mmol) were added. It was stirred at 62 °C for 16 h. TLC monitoring confirmed the completion of the reaction. The reaction mixture was quenched with water and extracted with DCM. The organic layer was dried over sodium sulphate, concentrated and purified by column to afford compound 2 (0.260 g, 51.2 %).

[0343] LCMS: For C26H25F5N3O4P 569.47, observed 570.0 (M+H), RT. 2.68 min, 77.7 % (max),

[0344] Step-2: To a stirred solution of compound 2 (260 mg, 0.457 mmol) in DCM (8 mL), TMS-Br (1398 mg, 9.13 mmol) was added. The reaction mixture was stirred at reflux for 16 h. TLC monitoring confirmed the completion of the reaction. The reaction mixture was concentrated to get the crude mixture with 71% product mass and purified by preparative HPLC. After purification, the fractions were lyophilized to get compound A12 (80 mg, 33.4%).

[0345] LCMS: For C22H17F5N3O4P 513.36, observed 514.1 (M+H), RT. 1.85 min, 97.9 % (max),

[0346] HPLC: 4.34 min, 99.9 % (max).

[0347] 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.40 (d, J = 1.20 Hz, 1H), 8.51 (s, 1H), 8.03-8.00 (m, 1H), 7.88-7.84 (m, 1H), 7.55 (t, J = 8.80 Hz, 1H), 7.36 (d, J = 2.00 Hz, 1H), 7.33 (d, J = 2.40 Hz, 1H), 7.19-7.09 (m, 1H), 3.24-3.18 (m, 1H), 1.26 (d, J = 6.80 Hz, 6H).

[0348] 13 C NMR (400 MHz, DMSO-d 6 ): δ 162.26, 161.92, 159.81, 159.47, 144.42, 139.56, 139.04, 135.36, 134.47, 132.67, 126.33, 123.30, 120.54, 116.64, 116.05, 114.48, 108.18, 107.69, 27.68, 22.85.

[0349] 19 F NMR (400 MHz, DMSO-d 6 ): δ -119.1, -111.1, -73.5.

[0350] 19 P NMR (400 MHz, DMSO-d 6 ): δ -5.68.

[0351] Synthesis of Compound A13:

[0352]

[0353] To a stirred solution of SM3 (300 mg, 0.692 mmol) in DMF (8 mL) was added N- methylmorpholine (0.228 mL, 2.077 mmol), EDC (199 mg, 1.038 mmol) and compound 1 (88 mg, 0.761 mmol). It was stirred at RT for 16 h. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The resulting residue was purified by preparative HPLC with TFA method and the fractions were lyophilized to get compound A13 (59 mg, 16%).

[0354] LCMS: Calculated for C26H18F5N3O4 531.439, observed 531.9 (M+H), RT. 2.825 min, 99.338 % (max).

[0355] HPLC: 5.674 min, 99.149 % (max)

[0356] 1 H NMR (400 MHz, DMSO-d 6 ): δ 13.46 (s, 1H), 9.45 (d, J = 1.20 Hz, 1H), 8.63 (s, 1H), 8.05-8.02 (m, 1H), 7.92-7.88 (m, 2H), 7.84 (t, J = 8.40 Hz, 1H), 7.62-7.59 (m, 1H), 7.43-7.41 (m, 1H), 7.25 (t, J = 1.60 Hz, 2H), 3.24-3.19 (m, 1H), 1.27 (d, J = 7.20 Hz, 6H).

[0357] 13 C NMR (400 MHz, DMSO-d 6): δ 165.99, 163.15, 162.32, 161.78, 159.87, 159.30, 153.32, 144.47, 139.50, 137.10, 135.43, 134.37, 1 33.68, 132.36, 131.93, 126.42, 120.57, 119.42, 116.20, 114.79, 111.23, 72.75, 60.72, 27.69, 22.88.

[0358] 19 F NMR (400 MHz, DMSO-d) 6 ): δ -118.98, -109.77, -74.24.

[0359] Synthesis of compound A14:

[0360]

[0361] Step 1: Cesium carbonate (0.422 g, 1.295 mmol) and di-tert-butyl (chloromethyl) phosphate (0.134 g, 0.518 mmol) were added to a stirred solution of SM4 in DMF (5 mL). The reaction mixture was stirred at 60 °C for 4 h. The reaction progress was monitored by LCMS. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with aqueous brine, dried over sodium sulfate, and evaporated under vacuum to obtain compound 2 (190 g, 0.291 mmol, 67.3%). The crude product was used as is in the next step.

[0362] LCMS: For the following calculation: C33H40F2N3O5P, 627.670, observed value 628.3 (M+H), RT. 3.318 min, 96.01% (maximum),

[0363] Step 2: Compound 2 (0.19 g, 0.303 mmol) was placed in acetic acid (3 mL) and water (3.00 mL) and stirred at 60 °C for 16 h. The reaction progress was monitored by LCMS. After the reaction was complete, the reaction mixture was evaporated under vacuum to obtain a crude mixture. The crude product was purified by preparative HPLC and the fractions were lyophilized to obtain a white solid, A14 (32 mg, 20.39%).

[0364] LCMS: For the following calculation: C25H24F2N3O5P, 515.454, observed value 516.1 (MH), RT. 2.458 min, 99.41% (maximum),

[0365] HPLC: 4.621 min, 98.91% (maximum).

[0366] 1 H NMR (400 MHz, DMSO-d) 6 ): δ 9.08 (s, 1H), 8.46 (s, 1H), 8.02-7.99 (m, 1H), 7.86-7.82 (m, 1H), 7.73-7.69 (m, 1H), 7.28-7.25 (m, 1H), 7.20-7.16 (m, 2H), 5.69 (d, J=11.60 Hz, 2H), 3.24-3.17(m, 1H), 1.95-1.90(m, 1H), 1.27(d, J=6.80 Hz, 6H), 1.01(d, J=9.60 Hz, 4H),

[0367] 13 C NMR (400 MHz, DMSO-d) 6 ): δ 162.20, 161.95, 159.64, 159.13, 150.43, 141.42, 139.30, 138.13, 135.27, 133.27, 125.97, 117.56, 116.16, 115.93, 113.59, 113.49, 109.02, 105.06, 87.92, 27.65, 22.92, 9.48, 9.03.

[0368] 19 F NMR (400 MHz, DMSO-d) 6 ): δ -120.02, -109.15, -73.74. 31P NMR (400 MHz, DMSO-d 6 ): δ -3.05.

[0369] Synthesis of compound A15:

[0370]

[0371] Step 1: TEA (0.208 mL, 1.480 mmol) and diethyl chlorophosphate (255 mg, 1.480 mmol) were added to a stirred solution of SM4 (200 mg, 0.493 mmol) in chloroform (3 mL). The reaction mixture was stirred at 60 °C for 16 h. The reaction progress was monitored by LCMS. After the reaction was complete, the reaction mixture was concentrated, and the crude mixture was purified by rapid column chromatography using a solution of 45% ethyl acetate in petroleum ether as the eluent. The collected fraction was concentrated and dried under reduced pressure to obtain a colorless liquid compound 2 (190 mg, 70.4%).

[0372] LCMS: For C28H30F2N3O4P, 541.536, observed 542.00 (M+H), RT. 3.06 min, 99.94% (max).

[0373] 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.10 (s, 1H), 8.52 (s, 1H), 8.01 (dd, J = 2.00, 7.40 Hz, 1H), 7.85-7.87 (m, 2H), 7.44 (dd, J = 1.60, 11.00 Hz, 1H), 7.36 (d, J = 8.40 Hz, 1H), 7.21 (t, J = 10.00 Hz, 1H), 4.28-4.21 (m, 4H), 3.21 (s, 1H), 1.95-1.92 (m, 1H), 1.37-1.31 (m, 6H), 1.28-1.23 (m, 6H), 1.07-1.00 (m, 4H).

[0374] Step-2: To the stirred solution of compound 2 (140 mg, 0.259 mmol) in DCM (3 mL), TMS-Br (0.671 mL, 5.17 mmol) was added. The reaction mixture was stirred at 40 °C for 13 h. The progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was evaporated under vacuum to get the crude mixture and purified by preparative HPLC. The fractions were lyophilized to get compound A15 (30 mg, 0.028 mmol, 10.82%) as a white solid.

[0375] LCMS: For C24H22F2N3O4P, 485.428, observed 486.0. (M+H), RT. 1.698 min, 97.77% (max).

[0376] HPLC: 3.551 min, 97.76 % (max).

[0377] 1 H NMR (400 MHz, DMSO-d 6) δ 9.08 (s, 1H), 8.48 (s, 1H), 8.01 (dd, J = 2.40, 7.40 Hz, 1H), 7.86-7.82 (m, 1H), 7.74 (t, J = 8.40 Hz, 1H), 7.35-7.29 (m, 2H), 7.21-7.16 (m, 1H), 3.24-3.17 (m, 1H), 1.96-1.90 (m, 1H), 1.26 (d, J = 7.20 Hz, 6H), 1.02-0.99 (m, 4H).

[0378] 13 C NMR (400 MHz, DMSO-d6) δ 161.96, 161.71, 159.53, 159.25, 154.30, 150.51, 139.35, 138.17, 135.26, 133.19, 125.99, 117.37, 116.16, 115.93, 113.68, 110.79, 109.15, 108.90, 27.65, 22.91, 9.52, 9.02. 6 ) δ 161.96, 161.71, 159.53, 159.25, 154.30, 150.51, 139.35, 138.17, 135.26, 133.19, 125.99, 117.37, 116.16, 115.93, 113.68, 110.79, 109.15, 108.90, 27.65, 22.91, 9.52, 9.02.

[0379] 19 F NMR (400 MHz, DMSO-d6) δ -120.0, -109.09, -74.13. 6 ) δ -120.0, -109.09, -74.13.

[0380] 31 P NMR (400 MHz, DMSO-d6) δ -6.43. 6 ) δ -6.43.

[0381] Synthesis of compound A16:

[0382]

[0383] Step-1: To a stirred solution of SM4 (200 mg, 0.493 mmol) and (E)-4-(tert- butoxy)-4-oxobut-2-enoic acid (102 mg, 0.592 mmol) in DCM (0.5 mL), DMAP (60.3 mg, 0.493 mmol and EDCHCl (115 mg, 0.740 mmol) were added. The reaction mixture was stirred at 25 °C for 16 h. The progress of reaction was monitored by LCMS. After completion of reaction, the reaction mixture was evaporated under vacuum. The crude mixture was purified by flash column using 20% ethyl acetate in petroleum ether as an eluent. The collected fractions were concentrated and dried under reduced pressure to afford compound 2 (100 mg, 33.0 %) as a yellow gummy solid.

[0384] LCMS: For C32H31F2N3O4, 559.614, observed 560.00 (M+H), RT. 3.474 min, 91.36% (max).

[0385] 1 H-NMR (400 MHz, DMSO-d 6 ): δ 9.10 (s, 1H), 8.53 (s, 1H), 8.02 (d, J = 7.20 Hz, 1H), 8.00-7.83 (m, 2H), 7.58-7.54 (m, 1H), 7.41-7.38 (m, 1H), 7.20 (t, J = 11.60 Hz, 1H), 6.94 (s, 2H), 3.26-3.19 (m, 1H), 1.99-1.94 (m, 1H), 1.46 (s, 9H), 1.28-1.15 (m, 6H), 1.04-1.00 (m, 4H).

[0386] Step-2: To the stirred solution of compound 2 (100 mg, 0.179 mmol) in DCM (2 mL), TFA (0.6 mL, 7.79 mmol) was added. The reaction mixture was stirred at 25 °C for 2 h. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was concentrated under vacuum to get the crude product. The crude product was purified by preparative HPLC and the fractions were lyophilized to get compound A16 (50 mg, 0.071 mmol) as a white solid.

[0387] LCMS: For C28H23F2N3O4, 503.506, observed 504.1. (M+H), RT. 2.227 min, 99.29% (max).

[0388] HPLC: 5.101 min, 99.06 % (max).

[0389] 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.11 (s, 1H), 8.54 (s, 1H), 8.54 (dd, J =, Hz, 1H), 7.89-7.84 (m, 2H), 7.58 (dd, J = 2.00, 10.80 Hz, 1H), 7.40 (dd, J = 2.00, 8.40 Hz, 1H), 7.23-7.18 (m, 1H), 6.96 (s, 2H), 3.25-3.18 (m, 1H), 1.99-1.93 (m, 1H), 1.27 (d, J = 6.80 Hz, 6H), 1.05-1.01 (m, 4H).

[0390] 13 C NMR (400 MHz, DMSO-d 6 ): δ 163.34, 161.99, 161.52, 159.55, 159.05, 152.22, 150.63, 141.43, 139.39, 138.27, 137.03, 135.29, 133.17, 132.87, 126.10, 125.96, 119.40, 117.14, 116.17, 115.94, 113.66, 111.52, 27.63, 22.91, 9.58, 9.02.

[0391] 19 F NMR (400 MHz, DMSO-d 6 ): δ -119.93, -108.66, -74.87.

[0392] Activity and solubility

[0393] Kinetic solubility

[0394] Solubility tests were performed using the micro shake flask method. Calibration standards (10220 μΜ) were prepared in DMSO using a 10 mM stock solution of each compound. The same 10 mM stock solution was accurately dispensed in duplicate into a 96-well plate and the DMSO was evaporated (MiVac Genevac, 90 minutes, 37 °C). Thereafter, the samples were reconstituted in aqueous solution (200 μΜ) and shaken (20 hours, 25 °C). The solutions were analyzed by HPLC DAD (Agilent 1200 rapid separation HPLC with diode array detector). A best fit calibration curve was constructed using the calibration standards, which was used to determine the solubility of the aqueous samples.

[0395] Activity

[0396] Female NMRI mice (3 weeks of age, body weight approximately 14-20 g) were purchased from Charles River (Sulzfeld). Prior to experimental treatment, the animals were allowed to acclimatize for 1 week under controlled conditions (22°C, 50% humidity, 12 hours light, and free access to water and rodent chow). For obtaining adult schistosomes, NMR! mice were subcutaneously infected with 80 to 100 cercariae. After 49 days, mice were euthanized with CO2and worms were collected from the portal vein and mesenteric vein. Three pairs of adult worm schistosomes were placed in each well of a 24-well plate with 2-2.5 ml medium and various concentrations (e.g. 1 mM, 0.1 mM, 0.01 mM, 0.001 mM) of the above compounds. The medium consisted of RPMI 1640 (Invitrogen, Carlsbad, CA) supplemented with 5% fetal calf serum (iFCS, 100 U / ml) and 1% penicillin / streptomycin mixture (Invitrogen, 100 U / mL). Each compound was initially tested once in 2 wells. Schistosomes incubated in not more than 1% DMSO served as a control. Worms were kept in an incubator at 37°C and 5% CO2for up to 72 hours. After 24 hours, the condition of the worms was assessed by microscopy.

[0397] FaSSIF solubility

[0398] Accurately weigh 2.0 mg of compound into a Uniprep®syringe filter (5 ml 0.45 pm) and add 2 mL of solvent and shake at 37°C for 24 hours. Check the pH after 6 to 8 hours and adjust with 0.1 N HC1 or 0.1 N NaOH solution if the pH deviates more than 0.05 units. After 24 hours, filter the suspension and determine the concentration of dissolved material by HPLC after appropriate dilution with the respective buffer if necessary. The results are expressed in mg / ml.

[0399] Table 1:

[0400] “A”: kinetic solubility > 150 mM; “B”: kinetic solubility 80-149 mM; “C”: kinetic solubility 20-80 mM.

[0401] “A”: FaSSIF solubility > 1 mg / mL; “B”: kinetic solubility > 0.1-1 mg / mL; “C”: kinetic solubility 0.01-0.1 mg / mL.

Claims

1. A compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 is cyclopropyl, cyclobutyl, F or C1-C3 alkyl optionally substituted with up to 5 F atoms; R 2 is cyclopropyl, cyclobutyl, F or C1-C3 alkyl optionally substituted with up to 5 F atoms, R 3 with R 4 each, independently of one another, denotes a residue selected from the group of: R 5 is a residue selected from the group consisting of: X is CH or N; and R 6 with R 7 each, independently of one another, denotes H or CH3.

2. The compound according to claim 1, wherein R 6 and R 7 each represent H.

3. The compound according to claim 1 or 2, wherein R 1 is methyl, ethyl, n-propyl, i-propyl, CF3or F; and R 2 is methyl, ethyl, n-propyl, i-propyl, cyclopropyl, CF3or F.

4. The compound according to claim 1, 2 or 3, wherein R 3 with R 4 each, independently of one another, denotes a residue selected from the group of: and R 5 is a group selected from the group consisting of 。 5. The compound according to claim 1 of formula (I), (II).

6. The compound according to claim 1, 2, 3, 4 or 5, wherein R 1 is isopropyl; and R 2 is cyclopropyl.

7. A compound selected from the group consisting of: [(5-{2-cyclopropyl-6-[4-fluoro-3-(propan-2-yl)phenyl]imidazo[l,2-a]pyrazin-3-yl}-4- fluoro-2H-indazol-2-yl)methoxy]phosphonic acid; 1-{[(5-{2-cyclopropyl-6-[4-fluoro-3-(propan-2-yl)phenyl]imidazo[l,2-a]pyrazin-3-yl}-4- fluoro-lH-indazol-l-yl)methoxy]carbonyl}piperidine-4-carboxylic acid; 4-{[(5-{2-cyclopropyl-6-[4-fluoro-3-(propan-2-yl)phenyl]imidazo[l,2-a]pyrazin-3-yl}-4- fluoro-lH-indazol-l-yl)methoxy]carbonyl}benzoic acid; (2E)-4-[(5-{2-cyclopropyl-6-[4-fluoro-3-(propan-2-yl)phenyl]imidazo[l,2-a]pyrazin-3-yl}- 4-fluoro-lH-indazol-l-yl)methoxy]-4-oxobut-2-enoic acid; 4-(5-{2-cyclopropyl-6-[4-fluoro-3-(propan-2-yl)phenyl]imidazo[l,2-a]pyrazin-3-yl}-4- fluoro-lH-indazol-l-yl) cyclohexane- 1 -carboxylic acid methyl ester; 3-amino-l-(5-{2-cyclopropyl-6-[4-fluoro-3-(propan-2-yl)phenyl]imidazo[l,2-a]pyrazin-3- yl}-4-fluoro-lH-indazol-l-yl)propan-l-one; [(5-{2-cyclopropyl-6-[4-fluoro-3-(propan-2-yl)phenyl]imidazo[l,2-a]pyrazin-3-yl}-4- fluoro-lH-indazol-l-yl)methoxy]phosphonic acid; (2E)-4-[(4-fluoro-5-{6-[4-fluoro-3-(propan-2-yl)phenyl]-2-(trifluoromethyl)imidazo[l,2- a]pyrazin-3-yl}-lH-indazol-l-yl)methoxy]-4-oxobut-2-enoic acid; [(4-fluoro-5-{6-[4-fluoro-3-(propan-2-yl)phenyl]-2-(trifluoromethyl)imidazo[l,2-a]pyrazin- 3-yl}-lH-indazol-l-yl)methoxy]phosphonic acid; [(3-fluoro-4-{6-[4-fluoro-3-(propan-2-yl)phenyl]-2-(trifluoromethyl)imidazo[l,2-a]pyrazin- 3-yl}phenoxy)methoxy]phosphonic acid; (3-fluoro-4-{6-[4-fluoro-3-(propan-2-yl)phenyl]-2-(trifluoromethyl)imidazo[l,2-a]pyrazin- 3-yl}phenoxy)phosphonic acid; (2E)-4-(3-fluoro-4-{6-[4-fluoro-3-(propan-2-yl)phenyl]-2- (trifluoromethyl)imidazo[l,2-a]pyrazin-3-yl}phenoxy)-4-oxobut-2-enoic acid; [(4-{2-cyclopropyl-6-[4-fluoro-3-(propan-2-yl)phenyl]imidazo[l,2- a]pyrazin-3-yl}-3-fluorophenoxy)methoxy]phosphonic acid; (4-{2-cyclopropyl-6-[4-fluoro-3-(propan-2-yl)phenyl]imidazo[l,2- a]pyrazin-3-yl}-3-fluorophenoxy)phosphonic acid; (2E)-4-(4-{2-cyclopropyl-6-[4-fluoro-3-(propan-2-yl)phenyl]imidazo[l,2- a]pyrazin-3-yl}-3-fluorophenoxy)-4-oxobut-2-enoic acid.

8. A compound as defined in any one of claims 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, for use in therapy.

9. A compound as defined in any one of claims 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of helminth infections caused by blood flukes and / or liver flukes.

10. The compound for use as defined in claim 9, wherein the helminth infection is schistosomiasis and / or fascioliasis.

11. Use of a compound as defined in any one of claims 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of helminth infections, for example, in particular, schistosomiasis and / or fascioliasis.

12. A method of treating helminth infections, for example, in particular, schistosomiasis and / or fascioliasis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound as defined in any one of claims 1 to 7, or a pharmaceutically acceptable salt or solvate thereof.

13. A pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in any one of claims 1 to 7, or a pharmaceutically acceptable salt or solvate thereof.

14. The pharmaceutical composition of claim 13, further comprising an anthelmintic agent.

15. The pharmaceutical composition of claim 13 or 14, further comprising a pharmaceutically acceptable carrier, adjuvant or excipient thereof.

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