New indazole derivatives

Abstract

The present invention relates to novel compounds having the general formula (I) TIFF2025515833000039.tif39170, or a pharma- ceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 and R 4 is as described herein.The compounds of formula (I) may be used as pharmaceuticals.

Description

[Technical field]

[0001] The present invention relates to compounds that are selective allosteric inhibitors of EGFR mutants, including T790M / L858R, T790M / L858R / C797S, L858R, and / or L858R / C797S, their preparation, pharmaceutical compositions containing them, and their use as therapeutically active substances.

[0002] The present invention relates in particular to a compound of formula (I) TIFF2025515833000002.tif39170 (in the formula, R 1 and R 2 is independently selected from alkyl, or R 1 and R 2 together with the carbons to which they are attached form a cycloalkyl; R 3 is alkyl or haloalkyl; R 4 is hydrogen or a halogen, or a pharma- ceutically acceptable salt thereof. [Background technology]

[0003] The HER family receptor tyrosine kinases are mediators of cell proliferation, differentiation, and survival. This receptor family includes four distinct members: epidermal growth factor receptor (EGFR, ErbB1, or HER1), HER2 (ErbB2), HER3 (ErbB3), and HER4 (ErbB4). Upon ligand binding, the receptors form homodimers and heterodimers, and the subsequent activation of intrinsic tyrosine kinase activity leads to receptor autophosphorylation and activation of downstream signaling molecules (Yarden, Y., Sliwkowski, MX. Untangling the ErbB signalling network. Nature Review Mol Cell Biol. 2001, Feb; 2(2): 127-37). Deregulation of EGFR by overexpression or mutation has been implicated in many types of human cancer, including colorectal cancer, pancreatic cancer, glioma, head and neck cancer, and lung cancer, especially non-small cell lung cancer (NSCLC), and several EGFR-targeting agents have been developed over the years (Ciardiello, F., and Tortora, G. (2008). EGFR antagonists in cancer treatment. The New England journal of medicine 358, 1160-1174). Erlotinib (Tarceva®), a reversible inhibitor of EGFR tyrosine kinase, has been approved in numerous countries for the treatment of recurrent NSCLC.

[0004] In a subset of NSCLC patients whose tumors harbor somatic kinase domain mutations, remarkable single-agent activity of EGFR tyrosine kinase inhibitors is observed, whereas clinical benefit in patients with wild-type EGFR is substantially reduced (Paez, J. et al. (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science (New York, NY 304, 1497-1500). The most common somatic mutations in EGFR are exon 19 deletions with delta 746-750 being the most common mutation, and exon 21 amino acid substitutions with L858R being the most frequent mutation (Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 2007 Mar;7(3):169-81).

[0005] Treatment resistance occurs frequently and is often due to secondary T790M mutations within the ATP site of the receptor. Although several developed mutant-selective irreversible inhibitors are highly active against T790M mutants, their efficacy can be compromised by acquired mutations in C797S, the cysteine ​​residue where they form the key covalent bond (Thress, KS et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat. Med. 21, 560-562 (2015)). It was further reported by Wang that the C797S mutation is the primary mechanism of resistance to T790M-targeted EGFR inhibitors (Wang et al. EGFR C797S mutation mediates resistance to third-generation inhibitors in T790M-positive non-small cell lung cancer, J Hematol Oncol. 2016;9:59). Additional mutations causing resistance to osimertinib have been described by Yang (e.g., L718Q) (Yang et al., Investigating Novel Resistance Mechanisms to Third-Generation EGFR Tyrosine Kinase Inhibitor Osimertinib in Non-Small Cell Lung Cancer Patients, Clinical Cancer Research, DOI:10.1158 / 1078-0432.CCR-17-2310). Lu et al. (EGFR in NSCLC L858R / T790M and EGFR L858R / T790M / C797S Targeting resistance mutations: Current developments in medicinal chemistry, Med Res Rev 2018;1-32) is a review of EGFR resistance mutations in the treatment of NSCLC. L858R / T790M and EGFR L858R / T790M / C797S reported in a review article on targeting resistance mutations.

[0006] Because most available EGFR tyrosine kinase inhibitors target the ATP site of the kinase, new therapeutic agents that work differently, for example by targeting drug-resistant EGFR mutations, are needed.

[0007] Recent studies suggest that deliberate targeting of allosteric sites may lead to mutation-selective inhibitors (Jia et al., Overcoming EGFR(T790M)and EGFR(C797S)resistance with mutant-selective allosteric inhibitors, June 2016, Nature 534, 129-132)

[0008] Thus, there is an unmet need for the generation of selective molecules that specifically inhibit EGFR mutants containing T790M / L858R, T790M / L858R / C797S, L858R and / or L858R / C797S, particularly EGFR mutants containing T790M and C797S, that are useful in the therapeutic and / or prophylactic treatment of cancer. Summary of the Invention

[0009] The compounds of formula (I) described herein have improved EGFR potency and selectivity against EGFR mutants containing T790M / L858R, T790M / L858R / C797S, L858R and / or L858R / C797S, in particular against EGFR mutants containing T790M and C797S, as well as improved physicochemical properties.

[0010] As used herein, the term "alkyl", alone or in combination, refers to a straight or branched chain alkyl group having 1 to 8 carbon atoms, particularly a straight or branched chain alkyl group having 1 to 6 carbon atoms, more particularly a straight or branched chain alkyl group having 1 to 4 carbon atoms. Examples of straight and branched chain C1-C8 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec.-butyl, isomeric pentyls, isomeric hexyls, isomeric heptyls, and isomeric octyls, particularly methyl, ethyl, propyl, butyl, and pentyl. Specific examples of alkyl are methyl, ethyl, propyl, isopropyl, and tert-butyl. Methyl and ethyl are specific examples of "alkyl" in the compounds of formula (I).

[0011] The term "cycloalkyl", alone or in combination, means a cyclic ring system of one or more rings containing 3 to 8 carbon atoms, in particular containing 3 to 6 carbon atoms. Examples of "cycloalkyl" are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, cycloheptyl, cyclooctanyl, bicyclo[1.1.1]pentanyl, bicyclo[1.1.1]hexanyl and bicyclo[1.1.1]heptanyl. A specific example of "cycloalkyl" is bicyclo[1.1.1]pentanyl.

[0012] The term "halogen" or "halo", alone or in combination, means fluorine, chlorine, bromine, or iodine, in particular fluorine or chlorine. A particular "halogen" or "halo" is fluorine. The term "halo", in combination with another group, means substitution of the group with at least one halogen, in particular 1 to 5 halogens, in particular 1 to 4 halogens, i.e. 1, 2, 3, or 4 halogen substitution.

[0013] The term "haloalkyl", alone or in combination, refers to an alkyl group substituted with at least one halogen, particularly substituted with 1 to 5 halogens, and especially substituted with 1 to 3 halogens. Particular examples of "haloalkyl" are fluoromethyl, difluoromethyl and trifluoromethyl.

[0014] The term "pharmaceutical acceptable salt" refers to a salt of a compound of formula (I) that retains the biological effectiveness and properties of the free base or free acid, which is not biologically or otherwise undesirable. Salts are formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, especially hydrochloric acid, and organic acids, such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, and the like. These salts may also be prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins, etc. Particular pharma- ceutically acceptable salts of the compounds of formula (I) are the hydrochloride, methanesulfonate, citrate salts.

[0015] If one of the starting materials or compounds of formula (I) of the present invention contains one or more functional groups that are not stable or are reactive under the reaction conditions of one or more reaction steps, a suitable protecting group (e.g., as described in "Protective Groups in Organic Chemistry" by TW Greene and PG M Huts, 3 rdProtective groups (such as those described in J. Chem. Soc., 1999, Wiley, New York) may be introduced before the critical step applying methods well known in the art. Such protecting groups may be removed at a later stage of the synthesis using standard methods described in the literature. Examples of protecting groups are tert-butoxycarbonyl (Boc), 9-fluorenylmethylcarbamate (Fmoc), 2-trimethylsilylethylcarbamate (Teoc), carbobenzyloxy (Cbz), and p-methoxybenzyloxycarbonyl (Moz).

[0016] The compounds of formula (I) may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers, such as racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0017] The term "asymmetric carbon atom" means a carbon atom that has four different substituents. According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom can be of the "R" or "S" configuration.

[0018] Thus, the present invention relates in particular to: R 1 and R 2 is methyl or R 1 and R 2 together with the carbon to which they are attached form a cyclopropyl; R 1 and R 2 together with the carbon to which they are attached form a cyclopropyl; R 1 and R 2 is methyl; R 3 is alkyl; R 3 is methyl or fluoromethyl; R3 is methyl; R 4 is hydrogen or fluoro; R 4 is hydrogen; and R 4 The compound according to the invention, wherein is fluoro.

[0019] The present invention further comprises: 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazol-5,1'-cyclopropane]-1-yl-N-thiazol-2-yl-acetamide; 2-[7-methyl-6-(4-morpholinophenyl)-4-(trifluoromethyl)indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazol-5,1'-cyclopropane]-1-yl-N-thiazol-2-yl-acetamide; and A compound selected from 2-(5,5-dimethyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-2-[7-methyl-6-(4-morpholinophenyl)-4-(trifluoromethyl)indazol-2-yl]-N-thiazol-2-yl-acetamide, or a pharma- ceutically acceptable salt thereof.

[0020] The present invention further comprises: 2-[7-methyl-6-(4-morpholinophenyl)-4-(trifluoromethyl)indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazol-5,1'-cyclopropane]-1-yl-N-thiazol-2-yl-acetamide; and A compound selected from 2-(5,5-dimethyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-2-[7-methyl-6-(4-morpholinophenyl)-4-(trifluoromethyl)indazol-2-yl]-N-thiazol-2-yl-acetamide, or a pharma- ceutically acceptable salt thereof.

[0021] The present invention further comprises: 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazol-5,1'-cyclopropane]-1-yl-N-thiazol-2-yl-acetamide; or a pharma- ceutically acceptable salt thereof.

[0022] Processes for preparing the compounds of formula (I) described herein are also an object of the present invention.

[0023] The preparation of the compounds of formula (I) of the present invention may be carried out in sequential or convergent synthetic routes. Exemplary syntheses of the compounds of the present invention are shown in the description of specific examples. The skills required to carry out the reactions and purification of the resulting products are known to those skilled in the art. The substituents and indices used in the description of the following methods have the meanings previously indicated herein unless otherwise indicated. The order of the reactions is not limited to that shown in the specific examples, but depending on the starting materials and their respective reactivities, the order of the reaction steps may be freely changed. The starting materials are commercially available or may be prepared by methods similar to those shown below, methods described in the references or examples cited herein, or methods known in the art.

[0024] The present invention also relates to a compound according to the invention when prepared according to the process of the invention.

[0025] Other embodiments of the present invention provide pharmaceutical compositions or medicaments containing the compounds of the present invention and therapeutically inert carriers, diluents or excipients, as well as methods of using the compounds of the present invention to prepare such compositions and medicaments. In one example, the compounds of formula (I) may be formulated by mixing at ambient temperature with a physiologically acceptable carrier, i.e., a carrier that is not toxic to the recipient at the doses and concentrations used in herbal dosage forms, at an appropriate pH and desired purity. The pH of the formulation will depend primarily on the particular application and the concentration of the compound, but is preferably in the range of about 3 to about 8. In one example, the compounds of formula (I) are formulated in acetate buffer at pH 5. In other embodiments, the compounds of formula (I) are sterile. The compounds may be stored, for example, as solid or amorphous compositions, as lyophilized formulations, or as aqueous solutions.

[0026] The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to consider in this regard include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the administration schedule, and other factors known to medical practitioners.

[0027] The compounds of the present invention can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, and epidural and intranasal, and, if desired for localized treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0028] The compounds of the present invention may be administered in any convenient administrative form, such as tablets, powders, capsules, liquids, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain conventional components of pharmaceutical formulations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and additional active agents.

[0029] Typical preparation is prepared by mixing the compound of the present invention with carrier or excipient.Suitable carrier and excipient are well known to those skilled in the art, and are described in, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems.Philadelphia: Lippincott, Williams&Wilkins,2004;Gennaro, Alfonso R., et al.Remington: The Science and Practice of Pharmacy.Philadelphia: Lippincott, Williams&Wilkins,2000;and Rowe, Raymond C.Handbook of Pharmaceutical Excipients.Chicago, Pharmaceutical Press,2005. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricating agents, emulsifying agents, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, flavors, flavorings, diluents, and other known additives to present the drug (i.e., a compound of the invention or a pharmaceutical composition thereof) aesthetically or to aid in the manufacture of a pharmaceutical product (i.e., a drug product).

[0030] The present invention therefore in particular provides: A compound of formula (I) or a pharma- ceutically acceptable salt thereof for use as a therapeutically active substance; a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof and a therapeutically inert carrier; A compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in the treatment or prevention of cancer; A compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in the treatment or prevention of non-small cell lung cancer; a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in the treatment or prophylaxis of cancer, in particular non-small cell lung cancer; Use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof for treating or preventing cancer, in particular non-small cell lung cancer; Use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof for preparing a medicament for treating or preventing cancer, in particular non-small cell lung cancer; and The present invention also relates to a method for treating or preventing cancer, in particular non-small cell lung cancer, which comprises administering to a patient in need thereof an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0031] A particular embodiment of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) as described herein or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable auxiliary substance.

[0032] Certain embodiments of the present invention relate to a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for use in the treatment or prophylaxis of cancer characterized by at least one EGFR mutation selected from T790M / L858R, T790M / L858R / C797S, L858R, and L858R / C797S, in particular non-small cell lung cancer.

[0033] Certain embodiments of the present invention relate to a method for treating or preventing cancer, particularly non-small cell lung cancer, wherein at least one EGFR mutation selected from T790M / L858R, T790M / L858R / C797S, L858R, and L858R / C797S is present in the cancer. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I) as described herein or a pharma- ceutically acceptable salt thereof.

[0034] Furthermore, the present invention includes, where applicable, all substituents of the compounds of formula (I) and the corresponding deuterated forms.

[0035] Furthermore, the present invention includes, where applicable, all optical isomers of the compounds of formula (I), i.e., diastereomers, diastereomeric mixtures, racemic mixtures, all corresponding enantiomers and / or tautomers thereof, and solvates thereof.

[0036] The compounds of formula (I) may contain one or more asymmetric centers and therefore may occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Depending on the nature of the various substituents on the molecule, additional asymmetric centers may be present. Each such asymmetric center independently produces two optical isomers, and all possible optical isomers and diastereomers, both as mixtures and as pure or partially purified compounds, are intended to be included in the present invention. The present invention is meant to encompass all such isomeric forms of these compounds. The independent synthesis of these diastereomers or their chromatographic separation may be achieved as known in the art by appropriate modification of the methods disclosed herein. Their absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates, which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated to isolate the individual enantiomers. Resolution may be carried out by methods known in the art, such as coupling a racemic mixture of a compound to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods such as fractional recrystallization or chromatography.

[0037] In embodiments where optically pure enantiomers are provided, optically pure enantiomers means that the compound contains more than 90% by weight of the desired isomer, specifically more than 95% by weight of the desired isomer, or more specifically more than 99% by weight of the desired isomer, said weight percentage being based on the total weight of the isomers of the compound. Chirally pure or chirally enriched compounds can be prepared by chiral selective synthesis or by separation of enantiomers. Separation of enantiomers can be carried out on the final product or on a suitable intermediate.

[0038] Also, one embodiment of the present invention is a compound of formula (I) as described herein when prepared according to any one of the processes described.

[0039] The compound of formula (I) or its pharmaceutically acceptable salts can be used as medicines (e.g., in the form of pharmaceutical preparations).The pharmaceutical preparations of the present invention can be administered internally, such as orally (e.g., in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g., in the form of nasal sprays), rectally (e.g., in the form of suppositories), or topically to the eye (e.g., in the form of solutions, ointments, gels or water-soluble polymeric inserts).However, administration can also be carried out parenterally, such as intramuscularly, intravenously, or intraocularly (e.g., in the form of sterile injectable solutions).

[0040] The compound of formula (I) or its pharma- ceutically acceptable salts can be processed with pharma- ceutically inert, inorganic or organic adjuvants for the preparation of tablets, coated tablets, sugar-coated tablets, hard gelatin capsules, injections or external preparations.Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc., can be used as such adjuvants for tablets, doracea and hard gelatin capsules.

[0041] Suitable adjuvants for soft gelatin capsules include, by way of example, vegetable oils, waxes, fats, semisolids, liquid polyols, etc.

[0042] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose etc.

[0043] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

[0044] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semisolid or liquid polyols etc.

[0045] Suitable adjuvants for topical ophthalmic preparations are, by way of example, cyclodextrin, mannitol, or many other carriers and excipients known in the art.

[0046] In addition, the pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying osmotic pressure, buffers, masking agents, or antioxidants. The pharmaceutical preparations may also contain other therapeutically valuable substances.

[0047] The dosage may vary widely and is adapted to the individual requirements in each particular case. In general, for oral administration, a daily dosage of about 0.1 mg to 20 mg per kg of body weight, preferably about 0.5 mg to 4 mg per kg of body weight (e.g. about 300 mg per person), preferably divided into 1 to 3 individual doses, which may, if appropriate, consist of, for example, equal amounts. For topical administration, the formulation may contain 0.001% to 15% by weight of the medicament, and the required dose, which may be between 0.1 and 25 mg, may be administered either by a single dose per day or per week, by multiple doses (2 to 4 times) per day, or by multiple doses per week. However, it will be clear that the upper or lower limits given herein may be exceeded, where this is indicated. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0048] Pharmaceutical Compositions The compound of formula (I) or its pharmaceutically acceptable salt can be used as therapeutically active substance, for example, in the form of pharmaceutical preparation.The pharmaceutical preparation can be administered orally, for example, in the form of tablet, coated tablet, sugar-coated tablet, hard gelatin capsule and soft gelatin capsule, solution, emulsion or suspension.However, administration can also be carried out rectally, for example, in the form of suppository, or parenterally, for example, in the form of injection solution.

[0049] The compound of formula (I) or its pharmaceutically acceptable salt can be processed with pharmaceutically inert inorganic or organic carriers for the manufacture of pharmaceutical preparations. Lactose, corn starch or its derivatives, talc, and stearic acid or its salts can be used as carriers for tablets, coated tablets, sugar-coated tablets, and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. However, depending on the nature of the active substance, carriers are usually not required for soft gelatin capsules. Suitable carrier materials for the manufacture of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils, etc. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, etc.

[0050] In addition, pharmaceutical preparations may contain pharma- ceutically acceptable auxiliary substances such as preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying osmotic pressure, buffers, masking agents, or antioxidants, etc. Pharmaceutical preparations may also contain other therapeutically valuable substances.

[0051] A medicament containing a compound of formula (I) or a pharma- ceutically acceptable salt thereof and a therapeutically inert carrier is also provided by the present invention, the process for the preparation of which comprises bringing a compound of formula (I) and / or a pharma- ceutically acceptable salt thereof, and optionally one or more other therapeutically valuable substances, together with one or more therapeutically inert carriers, into a galenical dosage form.

[0052] The dosage may vary within a wide range and must be adjusted to the individual requirements in each specific case. In the case of oral administration, the dosage for adults may vary from about 0.01 mg to about 1000 mg per day of the compound of general formula (I) or the corresponding amount of its pharma-ceutically acceptable salt. The daily dosage may be administered in a single dose or in divided doses, and may even exceed the upper limit if it proves to be indicated.

[0053] The following examples are illustrative of the invention without limiting it, but merely representative of the invention. Pharmaceutical preparations advantageously contain about 1-500 mg, in particular 1-100 mg, of a compound of formula (I). Examples of compositions according to the invention are as follows:

[0054] Example A Tablets of the following composition are prepared in the usual manner: [Table 1]

[0055] Manufacturing procedure 1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water. 2. Dry the granules at 50°C. 3. Pass the granules through a suitable grinding device. 4. Add ingredient 5, mix for 3 minutes and compress in a suitable press.

[0056] Example B-1 A capsule formulation is prepared having the following composition: [Table 2]

[0057] Manufacturing procedure 1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes. 2. Add ingredients 4 and 5 and mix for 3 minutes. 3. Fill into suitable capsules.

[0058] The compound of formula (I), lactose and cornstarch are mixed first in a mixer and then in a grinder. The mixture is returned to the mixer; talc is added and mixed thoroughly. The mixture is filled into a suitable capsule, such as a hard gelatin capsule, by machine.

[0059] Example B-2 Soft gelatin capsules are prepared having the following composition: [Table 3] [Table 4]

[0060] Manufacturing procedure The compound of formula (I) is dissolved in a warm melt of the other ingredients and the mixture is filled into a suitable sized soft gelatin capsule The filled soft gelatin capsule is treated according to the usual procedures.

[0061] Example C Prepare a suppository of the following composition: [Table 5]

[0062] Manufacturing procedure The suppository paste is melted in a glass or steel container, thoroughly mixed, and cooled to 45° C. The finely powdered compound of formula (I) is then added thereto and stirred until completely dispersed. The mixture is poured into appropriately sized suppository molds and allowed to cool, after which the suppositories are removed from the molds and individually wrapped in wax paper or metal foil.

[0063] Example D An injection solution having the following composition is prepared: [Table 6]

[0064] Manufacturing procedure A compound of formula (I) is dissolved in a mixture of polyethylene glycol 400 and water for injection (partially). The pH is adjusted to 5.0 with acetic acid. The remaining amount of water is added and the volume is adjusted to 1.0 ml. The solution is filtered, filled into vials with appropriate overages, and sterilized.

[0065] Example E A sachet of the following composition is prepared: [Table 7]

[0066] Manufacturing procedure A compound of formula (I) is mixed with lactose, microcrystalline cellulose and sodium carboxymethylcellulose and granulated with a mixture of polyvinylpyrrolidone in water. The granules are mixed with magnesium stearate and flavour additives and filled into sachets. EXAMPLES

[0067] Working Example Abbreviation AcOH = acetic acid; ATP = adenosine triphosphate; BOC = tert-butyloxycarbonyl; BPR = backpressure regulator; CAS = chemical abstract service; CDI = 1,1'-carbonyldiimidazole; DCM = dichloromethane; DIPEA = diisopropylethylamine; DME = dimethoxyethane; DMF = dimethylformamide; DMSO = dimethylsulfoxide; dppf = 1,1'-bis(diphenylphosphino)ferrocene; EtOAc = ethyl acetate; EtOH = ethanol; HATU = azabenzotriazole tetramethyluronium hexafluorophosphate; LDA = lithium diisopropylamide; MeOH = methanol; MS = mass spectrometry; NMR = nuclear magnetic resonance; rt = room temperature; THF = tetrahydrofuran.

[0068] The following examples are provided to illustrate the present invention and should not be considered as limiting the scope of the invention, but should be understood as merely representative thereof.

[0069] Synthesis of intermediates The substituted indazoles (II) are known or may be prepared analogously to known methods or using the methods described below.

[0070] 6-Bromo-7-methyl-4-(trifluoromethyl)-1H-indazole Step 1: 1-Bromo-3-fluoro-2-methyl-5-(trifluoromethyl)benzene 1-Bromo-3-fluoro-5-(trifluoromethyl)benzene (12.7 g) was dissolved in tetrahydrofuran (60 ml) and cooled to -75°C. 2.1 mol / l LDA in THF (27.4 ml) was added dropwise. After stirring at -75°C for 30 min, iodomethane (8.16 g) was added dropwise. The mixture was allowed to warm to room temperature overnight. After addition of half-saturated ammonium chloride solution and ethyl acetate, the layers were separated and extracted once more with ethyl acetate. The organic layers were washed with water, combined, dried over sodium sulfate and concentrated. The remaining brown liquid (15.42 g) was bulb-to-bulb distilled at approximately 10 mbar and an oven temperature of 60-80°C to give the title compound as a colourless liquid (11.91 g) containing 8 mol% ethylbenzene.

[0071] Step 2: 4-Bromo-2-fluoro-3-methyl-6-(trifluoromethyl)benzaldehyde Similar to the synthesis of 4-bromo-3,6-dichloro-2-fluorobenzaldehyde, 1-bromo-3-fluoro-2-methyl-5-(trifluoromethyl)benzene was first treated with LDA in tetrahydrofuran at −75° C., followed by N,N-dimethylformamide. Workup similar to that for 4-bromo-3,6-dichloro-2-fluorobenzaldehyde gave the crude title compound as a brown liquid.

[0072] Step 3: 6-Bromo-7-methyl-4-(trifluoromethyl)-1H-indazole Analogous to the synthesis of 6-bromo-4-chloro-7-methoxy-2H-indazole, a solution of 4-bromo-2-fluoro-3-methyl-6-(trifluoromethyl)benzaldehyde was heated with excess hydrazine hydrate to give the title compound as a light yellow solid. MS: m / e=278.9 ([M+H] + ,Br)

[0073] General Method A: Alkylation of Indazoles A mixture of indazole (II, 1 eq.), ethyl 2-bromoacetate (2 eq.) and N,N-dimethylacetamide (small amount to produce a solution) is heated to 100 °C until completion of the reaction (usually 5-48 h). After cooling to room temperature, ice is added and the precipitated solid is collected by filtration and washed with water. Purification of the desired regioisomer can be achieved by chromatography or in certain cases by recrystallization from solvents such as EtOH, acetonitrile or dichloromethane.

[0074] Using general method A, the following intermediates (III) were prepared: [table] TIFF2025515833000010.tif61170

[0075] The boronic acid derivatives are known or may be prepared analogously to known methods or using the methods described below.

[0076] [4-[(3S,4S)-1-Ethyl-3-fluoro-4-piperidyl]phenyl]boronic acid or [4-[(3R,4R)-1-Ethyl-3-fluoro-4-piperidyl]phenyl]boronic acid Step 1: tert-Butyl (3S,4S)-4-(4-bromophenyl)-3-hydroxy-piperidine-1-carboxylate and tert-butyl (3R,4R)-4-(4-bromophenyl)-3-hydroxy-piperidine-1-carboxylate A solution of tert-butyl 4-(4-bromophenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (CAS273727-44-9, 30 g, 79.8 mmol, 1.0 equiv, 90% purity) in THF (275 mL) was cooled to 0° C. Borane tetrahydrofuran complex (1.0 M solution in THF, CAS14044-65-6, 87.8 mL, 87.8 mmol, 1.1 equiv) was added dropwise at 0° C. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was cooled to 0° C. NaOH (5 M in water, 40 mL, 200 mmol, 2.51 equiv) was added dropwise and the reaction mixture was stirred at 0° C. for 30 min. Hydrogen peroxide (35 wt % in water, 19.4 g, 17.5 mL, 200 mmol, 2.5 equiv) was added and the reaction mixture was stirred at 50° C. for 2.5 h. The reaction mixture was cooled to room temperature and the excess peroxide was dissolved in 2 M Na 2 S 2 O 3 The mixture was quenched by the addition of aqueous solution of sodium hydroxide. The mixture was diluted with ethyl acetate and water. The aqueous layer was back-extracted twice with ethyl acetate. The combined organic layers were extracted with Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The crude product was suspended in diisopropyl ether and filtered. The solid was washed with diisopropyl ether and dried under reduced pressure to give the title compound as a white solid (26.74 g, 92% yield). m / z 258.1 [M-BOC+H] + ,ESI pos.

[0077] Step 2: tert-Butyl (3S,4S)-4-(4-bromophenyl)-3-fluoro-piperidine-1-carboxylate and tert-butyl (3R,4R)-4-(4-bromophenyl)-3-fluoro-piperidine-1-carboxylate A solution of tert-butyl (3S,4S)-4-(4-bromophenyl)-3-hydroxy-piperidine-1-carboxylate and tert-butyl (3R,4R)-4-(4-bromophenyl)-3-hydroxy-piperidine-1-carboxylate (37.2 g, 99.2 mmol, 1 equiv.) in dichloromethane (500 mL) was cooled to −78° C. Deoxofluor® (50% solution in THF, CAS202289-38-1, 79 g, 65.8 mL, 179 mmol, 1.8 equiv.) was added dropwise at −78° C. The reaction mixture was allowed to warm slowly to room temperature and stirred at room temperature for 16 hours. The reaction mixture was diluted with saturated NaHCO 3 The mixture was stirred for 30 min (pH 7). The organic layer was separated. The aqueous layer was back-extracted with DCM. The combined organic layers were washed with Na 2 SO 4 The crude material was adsorbed onto Isolute HM-N and purified by flash chromatography (silica gel, 330 g, 0% to 40% EtOAc in heptane) to give the title compound as a pale yellow oil (31.7 g, 85% yield). m / z 304.1 [M-tBu+H] + ,ESI pos.

[0078] Step 3: tert-butyl (3S,4S)-4-(4-bromophenyl)-3-fluoro-piperidine-1-carboxylate or tert-butyl (3R,4R)-4-(4-bromophenyl)-3-fluoro-piperidine-1-carboxylate Chiral separation of tert-butyl (3S,4S)-4-(4-bromophenyl)-3-fluoro-piperidine-1-carboxylate and tert-butyl (3R,4R)-4-(4-bromophenyl)-3-fluoro-piperidine-1-carboxylate (31.8 g, 88.8 mmol, 1.0 equiv.) by SFC (column: IG, 12 nm, 5 μm, 250 × 30 mm, eluent: isocratic 5% isopropanol-BPR at 120 bar - 80 g / min) gave the title compound as a colorless oil (13.27 g, 40% yield). m / z 304.0 [M-tBu + H] +, ESI pos. The absolute stereochemistry was not determined.

[0079] Step 4: (3S,4S)-4-(4-bromophenyl)-3-fluoro-piperidine hydrochloride or (3R,4R)-4-(4-bromophenyl)-3-fluoro-piperidine hydrochloride To a solution of tert-butyl (3S,4S)-4-(4-bromophenyl)-3-fluoro-piperidine-1-carboxylate or tert-butyl (3R,4R)-4-(4-bromophenyl)-3-fluoro-piperidine-1-carboxylate (10.5 g, 29.3 mmol, 1.0 equiv.) in DCM (100 mL) was added HCl (4 M in 1,4-dioxane, 73.3 mL, 293 mmol, 10 equiv.). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in 40 mL of Et 2 The mixture was stirred for 10 min. The reaction mixture was filtered through a sintered glass filter and diluted with Et 2 The white solid was dried under reduced pressure to give the title compound (9.5 g, purity 90%, yield 99%). m / z 260.0 [M+H] +, ESI pos.

[0080] Step 5: (3S,4S)-4-(4-bromophenyl)-1-ethyl-3-fluoro-piperidine or (3R,4R)-4-(4-bromophenyl)-1-ethyl-3-fluoro-piperidine To a suspension of (3S,4S)-4-(4-bromophenyl)-3-fluoro-piperidine hydrochloride or (3R,4R)-4-(4-bromophenyl)-3-fluoro-piperidine hydrochloride (9.50 g, 32.2 mmol, 1.0 equiv.) in THF (148 mL) was added NEt 3 (6.53 g, 8.99 mL, 64.5 mmol, 2.0 equiv.) was added. Diethyl sulfate (CAS 64-67-5, 5.97 g, 5.07 mL, 38.7 mmol, equiv.: 1.2) was added dropwise at room temperature. The reaction mixture was stirred at 35° C. for 30 min and at 55° C. for 3 h. The reaction mixture was poured into EtOAc and Na 2 CO 3 The organic layer was washed with Na2 SO 4 The crude material was purified by flash chromatography (silica gel, 40 g, 1% MeOH in DCM) to give the title compound as a yellow oil (7.20 g, 74% yield). m / z 287.9 ​​[M+H] + ,ESI pos.

[0081] Step 6: [4-[(3S,4S)-1-ethyl-3-fluoro-4-piperidyl]phenyl]boronic acid or [4-[(3R,4R)-1-ethyl-3-fluoro-4-piperidyl]phenyl]boronic acid A solution of (3S,4S)-4-(4-bromophenyl)-1-ethyl-3-fluoro-piperidine or (3R,4R)-4-(4-bromophenyl)-1-ethyl-3-fluoro-piperidine (1.000 g, 3.49 mmol, 1.0 equiv) in THF (8.0 mL) was cooled to -76°C. n-Butyl lithium (1.6 M in hexanes, 2.4 mL, 3.84 mmol, 1.1 equiv) was added dropwise and the reaction mixture was stirred at -76°C for 2 h. Triethyl borate (618 mg, 0.72 mL, 4.23 mmol, 1.21 equiv) was added at -76°C and the reaction mixture was stirred at -76°C for 15 min. The dry ice bath was then removed and the reaction mixture was stirred at room temperature (1.5 h). The reaction mixture was diluted with saturated NH 4 The mixture was quenched with aqueous Cl (10 mL) and stirred at room temperature for 15 min. The mixture was extracted with EtOAc. The aqueous layer was back-extracted with EtOAc. The organic layer was washed with water and brine. The combined organic layers were washed with Na 2 SO 4 The crude material was purified by flash chromatography (silica gel, 24 g, 0% to 10% MeOH in DCM) to give the title compound as an off-white solid (744 mg, 90% purity, 76% yield). m / z 252.2 [M+H] + ,ESI pos.

[0082] (1-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)piperidin-4-yl)methanol A mixture of [1-[2-(4-bromophenoxy)ethyl]-4-piperidyl]methanol (CAS 1226008-23-6, 1.3 g, 4.14 mmol, 1.0 equiv.), bis(pinacolato)diboron (1.16 g, 4.55 mmol, 1.1 equiv.), potassium acetate (1.22 g, 12.4 mmol, 3.0 equiv.) in 1,4-dioxane (15 mL) was diluted with Pd(dppf)Cl 2 ·CH 2 Cl 2 (303 mg, 414 μmol, 0.1 equiv.) was added. The reaction mixture was flushed with argon and stirred at 90° C. for 3 h. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography (silica gel, 50 g, 0% to 20% MeOH in DCM) to give the title compound as a dark brown oil (1.45 g, 80% purity, 77% yield). m / z 362.2 [M+H] + ,ESI pos.

[0083] (1-((3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)bicyclo[1.1.1]pentan-1-yl)methyl)piperidin-4-yl)methanol In a flame-dried flask, (1-((3-(4-bromophenyl)bicyclo[1.1.1]pentan-1-yl)methyl)piperidin-4-yl)methanol (295 mg) described in step 3 of Example 50 was dissolved in 1,4-dioxane (6.58 ml) under inert atmosphere. Bis(pinacolato)diboron (235 mg) and potassium acetate (248 mg) were added. The mixture was degassed under sonication, after which 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (75.6 mg) was added. The flask was placed on a heat block preheated to 90° C. equipped with a reflux condenser. The reaction was stirred for 40 min. The reaction mixture was transferred to a 150 mL round-bottom flask and the isolated material was added. The solvent was removed and the residue was loaded onto flash column chromatography on amine-modified gel (0-10% DCM:MeOH, 40 g). All fractions containing the product were combined and concentrated to give the title compound (286 mg) as a brown solid. MS: m / e=398.3 ([M+H]+).

[0084] 1-(2-Methoxyethyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]piperidine Step 1: 4-(4-bromophenyl)-1-(2-methoxyethyl)piperidine To a solution of 4-(4-bromophenyl)piperidine (7 g, 29.1 mmol, 1.0 equiv, CAS80980-89-8) was added DIPEA (7.53 g, 10.2 ml, 58.3 mmol, 2.0 equiv) and 1-bromo-2-methoxyethane (4.86 g, 3.29 ml, 35 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 3 h and at 50° C. for 16 h. The reaction mixture was stirred at H 2 O and extracted with AcOEt (2 times). The organic layers were combined and 2 SO 4 The mixture was dried at 40° C. and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80 g, 0% to 10% MeOH in DCM) to give the title compound as a yellow semi-solid (5.08 g, 58% yield). m / z 300.1 [M+H]+, ESI pos.

[0085] Step 2: 1-(2-Methoxyethyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl]piperidine A solution of 4-(4-bromophenyl)-1-(2-methoxyethyl)piperidine (5 g, 16.8 mmol, 1.0 equiv.) in 1,4-dioxane (100 ml) was treated with bis(pinacolato)diboron (5.53 g, 21.8 mmol, 1.3 equiv.), KOAc (4.94 g, 50.3 mmol, 3.0 equiv.) and Pd(dppf)Cl 2 ·CH 2 Cl 2 (859 mg, 1.17 mmol, 0.07 equiv) was added. The reaction mixture was flushed with argon and stirred at 90 °C for 3 h. The crude material was purified by flash chromatography (Si-amine, 40 g, 0% to 10% MeOH in EtOAc) to give the title compound as a brown liquid (1.98 g, 24% yield, 70% purity). m / z 346.2 [M+H]+, ESI pos.

[0086] Example 1 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazol-5,1'-cyclopropane]-1-yl-N-thiazol-2-yl-acetamide TIFF2025515833000011.tif37170Step 1: 1-Bromo-5-(difluoromethyl)-3-fluoro-2-methyl-benzene TIFF2025515833000012.tif26170To a cooled solution of 3-bromo-5-fluoro-4-methylbenzaldehyde (CAS no. 1370411-47-4, 20.5 g, 89.7 mmol, 1.0 equiv.) in dichloromethane (98 mL), morpholinosulfur trifluoride (CAS no. 51010-74-3, 24.8 g, 17.3 mL, 135 mmol, 1.5 equiv.) was added in portions. The reaction mixture was stirred at 0-5 °C for 20 min and then at room temperature for 16 h. Saturated NaHCO 3Aqueous solution (300 mL) was carefully added under ice cooling. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into dichloromethane and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, 120 g, 100% pentane) to give the title compound (18.6 g, 87% yield) as a colorless oil. 1 HNMR (300MHz, chloroform d) δ = 7.50 (s, 1H), 7.16 (d, J = 9.1Hz, 1H), 6.57 (t, J = 56.0Hz, 1H), 2.50-2.22 (m, 3H)

[0087] Step 2: 6-Bromo-4-(difluoromethyl)-7-methyl-1H-indazole TIFF2025515833000013.tif26170 A solution of 1-bromo-5-(difluoromethyl)-3-fluoro-2-methyl-benzene (Example 1, step 1) (26.4 g, 110 mmol, 1.0 equiv) in tetrahydrofuran (240 mL) was cooled to -75°C. A solution of lithium diisopropylamide (2M in tetrahydrofuran / heptane / ethylbenzene, 66.3 mL, 133 mmol, 1.2 equiv) was added dropwise while maintaining the temperature below -70°C. The reaction mixture was stirred at -75°C for 30 minutes. Ethyl formate (16.4 g, 17.7 mL, 220 mmol, 2.0 equiv) was added below -70°C. The reaction mixture was stirred at -75°C for 30 minutes. Acetic acid (16.6 g, 15.8 mL, 277 mmol, 2.5 equiv) was added below -55 °C. The reaction mixture was warmed to room temperature, poured into ethyl acetate, washed with dilute aqueous HCl, water, and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the presumed 4-bromo-6-(difluoromethyl)-2-fluoro-3-methyl-benzaldehyde as a yellow oil (29.5 g) which was used without further purification. The crude presumed 4-bromo-6-(difluoromethyl)-2-fluoro-3-methyl-benzaldehyde (29.5 g) was dissolved in dimethoxyethane (150 mL). O-Methylhydroxylamine hydrochloride (10.2 g, 122 mmol, 1.1 equiv) and potassium carbonate (30.6 g, 221 mmol, 2.0 equiv) were added. The reaction mixture was stirred at 45° C. for 2.5 hours, then filtered through sintered glass and washed with dimethoxyethane (2×). The filtrate was concentrated under reduced pressure. The oxime ether intermediate was dissolved in dimethyl sulfoxide (150 mL). Hydrazine hydrate (83 g, 80.5 mL, 1.66 mol, 15 equiv.) was added. The reaction mixture was stirred at 110° C. for 3 hours. The reaction mixture was poured into a 5:1 mixture of ethyl acetate / tetrahydrofuran. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, 2×120 g, gradient 0% to 30% ethyl acetate in heptane) to give the title compound (13.5 g, 45% yield) as a white solid. LCMS: m / z 260.9 / 262.8 [M+H] +,ESI pos,Br isotope.

[0088] Step 3: Ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]acetate TIFF2025515833000014.tif26170To a solution of 6-bromo-4-(difluoromethyl)-7-methyl-1H-indazole (Example 1, step 2) (19 g, 72.8 mmol, 1.0 equiv) in N,N-dimethylformamide (75 mL) was added ethyl 2-bromoacetate (CAS number 105-36-2, 18.2 g, 12.2 mL, 109 mmol, 1.5 equiv). The reaction mixture was stirred at 100° C. for 16 h. The reaction mixture was poured into ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, 2×120 g, gradient 0% to 20% ethyl acetate in heptane) to give the title compound (21.2 g, 80% yield) as a yellow solid. LCMS: m / z 346.9 / 348.8 [M+H] + ,ESI pos,Br isotope.

[0089] Step 4: tert-Butyl (5R)-5-[2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-3-ethoxy-3-oxo-propanoyl]-4-azaspiro[2.4]heptane-4-carboxylate TIFF2025515833000015.tif41170 Preparation of tert-butyl (5R)-5-(imidazole-1-carbonyl)-4-azaspiro[2.4]heptane-4-carboxylate TIFF2025515833000016.tif38170To a solution of (5R)-4-tert-butoxycarbonyl-4-azaspiro[2.4]heptane-5-carboxylic acid (CAS no. 2007916-06-3, 1.02 g, 4.21 mmol, 1.0 equiv.) in dichloromethane (17 mL), 1,1'-carbonyldiimidazole (818 mg, 5.04 mmol, 1.2 equiv.) was added in three portions and the reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was cooled to room temperature with saturated NaHCO 3 Poured into aqueous solution and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (5R)-5-(imidazole-1-carbonyl)-4-azaspiro[2.4]heptane-4-carboxylate (1.30 g, 95% yield, 90% purity) as an off-white solid, which was used directly in the next step.

[0090] A solution of ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]acetate (Example 1, step 3) (1.2 g, 3.46 mmol, 1.0 equiv.) in tetrahydrofuran (16 mL) was cooled to -50°C. NaHMDS (1M in tetrahydrofuran) (4 mL, 4 mmol, 1.16 equiv.) was added and the reaction mixture was stirred at -50°C for 45 min. A solution of the above tert-butyl (5R)-5-(imidazole-1-carbonyl)-4-azaspiro[2.4]heptane-4-carboxylate (1.29 g, 3.98 mmol, 1.15 equiv.) in tetrahydrofuran (16 mL) was added dropwise at -50°C. The reaction mixture was stirred at -50°C for 30 min. The cooling bath was then removed and the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled and saturated NH 4 The mixture was quenched with aqueous Cl, diluted with water and extracted with ethyl acetate. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with saturated NaHCO 3The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (2.37 g, 96% yield, 80% purity) as a light brown foam which was used without further purification. LCMS: m / z 570.3 / 572.3 [M+H] + ,ESI pos,Br isotope.

[0091] Step 5: Ethyl-2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazol-5,1'-cyclopropan]-1-yl-acetate TIFF2025515833000017.tif27170 Mixture of tert-butyl (5R)-5-[2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-3-ethoxy-3-oxo-propanoyl]-4-azaspiro[2.4]heptane-4-carboxylate (Example 1, step 4) (2.36 g, 3.31 mmol, 1.0 eq, 80% purity) and HCl (4M in 1,4-dioxane, 4.2 mL, 16.8 mmol, 5.07 eq). The reaction mixture was stirred at room temperature for 1 h. HCl (4M in 1,4-dioxane, 1 mL, 4.0 mmol, 1.21 eq) was added and the reaction mixture was stirred at room temperature for 30 min. HCl (4M in 1,4-dioxane, 1 mL, 4.0 mmol, 1.21 equiv) was added and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethanol (7.6 mL) and water (2.0 mL). Potassium thiocyanate (419 mg, 4.31 mmol, 1.3 equiv) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was cooled and pyridine (3.91 g, 4 mL, 49.46 mmol, 14.9 equiv) was added slowly. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with 1N KHSO 4The mixture was poured into water and extracted three times with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was dissolved in acetic acid (7.6 mL) and cooled to 0° C. Hydrogen peroxide (35% by weight in water, 0.580 mL, 6.62 mmol, 2.0 equiv.) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 h. Excess hydrogen peroxide was quenched with Na 2 S 2 O 3 The mixture was decomposed with a 1M aqueous solution of solid Na 2 CO 3 The mixture was carefully basified with 500 ml of ethyl acetate and extracted twice with ethyl acetate. The organic layers were washed with brine, combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 24 g, gradient 0% to 100% ethyl acetate in heptane). All fractions containing product were combined and concentrated in vacuo to give the title compound (882 mg, 53% yield) as a pale yellow solid. LCMS: m / z 479.3 / 481.3 [M+H] + ,ESI pos,Br isotope.

[0092] Step 6: Ethyl 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazol-5,1'-cyclopropan]-1-yl-acetate TIFF2025515833000018.tif37170 Ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazol-5,1'-cyclopropan]-1-yl-acetate (Example 1, Step 5) (350 mg, 0.69 mmol, 1.00 equiv.), (4-morpholinophenyl)boronic acid (CAS A mixture of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex (No. 186498-02-2, 187 mg, 0.90 mmol, 1.30 equiv.), cesium carbonate (679 mg, 2.08 mmol, 3.00 equiv.) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (82 mg, 0.10 mmol, 0.14 equiv.) in 1,4-dioxane (6.0 mL) was flushed with argon and stirred at 100 °C for 2 h. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 24 g, gradient 0% to 90% ethyl acetate in heptane). All fractions containing product were combined and concentrated to give the title compound (352 mg, 81% yield, 90% purity) as an off-white foam. LCMS: m / z 562.5 [M+H] + ,ESI pos.

[0093] Step 7: 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazol-5,1'-cyclopropane]-1-yl-N-thiazol-2-yl-acetamide TIFF2025515833000019.tif37170 To a solution of ethyl 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazol-5,1'-cyclopropan]-1-yl-acetate (Example 1, step 6) (346 mg, 0.55 mmol, 1.0 equiv.) in ethanol (1.8 mL) and tetrahydrofuran (1.8 mL) was added lithium hydroxide (1 M aqueous solution, 0.64 mL, 0.64 mmol, 1.15 equiv.). The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was evaporated and coevaporated twice with toluene. The residue was suspended in N,N-dimethylformamide (1.8 mL) and N,N-diisopropylethylamine (0.30 mL, 1.72 mmol, 3.1 equiv), thiazol-2-amine (72 mg, 0.72 mmol, 1.3 equiv) and HATU (274 mg, 0.72 mmol, 1.3 equiv) were added. The reaction mixture was stirred at room temperature for 45 min. The reaction mixture was extracted with ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed three times with water and once with brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 25 g, gradient 0% to 5% methanol in dichloromethane). All fractions containing the product were combined and concentrated in vacuo. The residue was adsorbed onto ISOLUTE HM-N and repurified by flash chromatography (Si-Amine, 12 g, gradient 0% to 10% methanol in ethyl acetate). All fractions containing product were combined and concentrated to give the title compound (183 mg, 53% yield) as an off-white foam. LCMS: m / z 616.4 [M+H] + ,ESI pos.

[0094] Example 2 2-[7-Methyl-6-(4-morpholinophenyl)-4-(trifluoromethyl)indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazol-5,1'-cyclopropane]-1-yl-N-thiazol-2-yl-acetamide TIFF2025515833000020.tif38170Step 1: 1-Bromo-3-fluoro-2-methyl-5-(trifluoromethyl)benzene TIFF2025515833000021.tif301701-Bromo-3-fluoro-5-(trifluoromethyl)benzene (12.7 g, 52.2 mmol, 1.0 equiv) was dissolved in tetrahydrofuran (60 ml) and cooled to -75°C. LDA (2.1 M in tetrahydrofuran, 27.4 ml, 57.5 mmol, 1.1 equiv) was added dropwise. After stirring at -75°C for 30 min, iodomethane (8.16 g, 3.6 ml, 57.4 mmol, 1.1 equiv) was added dropwise. The mixture was allowed to warm to room temperature overnight. After addition of half-saturated ammonium chloride solution and ethyl acetate, the layers were separated and extracted once more with ethyl acetate. The organic layers were washed with water, combined, dried over sodium sulfate, and concentrated under reduced pressure. The residual brown liquid (15.42 g) was bulb-to-bulb distilled at approximately 10 mbar and an oven temperature of 60-80° C. to give the title compound as a colourless liquid (11.9 g, 89% yield).

[0095] Step 2: 6-Bromo-7-methyl-4-(trifluoromethyl)-1H-indazole TIFF2025515833000022.tif311701-Starting from bromo-3-fluoro-2-methyl-5-(trifluoromethyl)benzene (Example 2, Step 1), and using chemistry similar to that described in Example 1, Step 2, the title compound was obtained as a pale yellow solid, LCMS: m / z 278.9 [M+H] + ,ESI pos.

[0096] Step 3: Ethyl 2-(6-bromo-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)acetate TIFF2025515833000023.tif301706-Starting from bromo-7-methyl-4-(trifluoromethyl)-1H-indazole (Example 2, Step 2), using chemistry similar to that described in Example 1, Step 3, the title compound was obtained as a pale yellow solid, LCMS: m / z 365.1 / 367.1 [M+H]+ , ESI pos, Br isotope.

[0097] Step 4: tert-Butyl (5S)-5-[2-[6-bromo-7-methyl-4-(trifluoromethyl)indazol-2-yl]-3-ethoxy-3-oxo-propanoyl]-4-azaspiro[2.4]heptane-4-carboxylate TIFF2025515833000024.tif36170 (5S)-4-tert-butoxycarbonyl-4-azaspiro[2.4]heptane-5-carboxylic acid was treated with carbonyldiimidazole as in Example 1, step 4 to give solution A. Ethyl 2-(6-bromo-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)acetate (Example 2, step 3) was deprotonated with LDA and treated with solution A at -78°C. After stirring at room temperature for 16 hours and workup as in Example 1, step 4, the crude title compound was obtained as a light brown foam, which was used in the next step without further purification. LCMS: m / z 590.3 [M+H] + ,ESI pos.

[0098] Step 5: Ethyl 2-[6-bromo-7-methyl-4-(trifluoromethyl)indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazol-5,1'-cyclopropan]-1-yl-acetate TIFF2025515833000025.tif26170 Analogously to Example 1, step 5, tert-butyl (5S)-5-[2-[6-bromo-7-methyl-4-(trifluoromethyl)indazol-2-yl]-3-ethoxy-3-oxo-propanoyl]-4-azaspiro[2.4]heptane-4-carboxylate (Example 2, step 4) was deprotected using HCl in dioxane and subsequently reacted with potassium thiocyanate and hydrogen peroxide in acetic acid to give the title compound as a white foam. LCMS: m / z 499.2 [M+H] + ,ESI pos.

[0099] Step 6: Ethyl 2-[7-methyl-6-(4-morpholinophenyl)-4-(trifluoromethyl)indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazol-5,1'-cyclopropan]-1-yl-acetate TIFF2025515833000026.tif37170 Starting from ethyl 2-[6-bromo-7-methyl-4-(trifluoromethyl)indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazol-5,1'-cyclopropan]-1-yl-acetate (Example 2, step 5) and (4-morpholinophenyl)boronic acid, using chemistry similar to that described in Example 1, step 6, the title compound was obtained as a light brown foam, LCMS: m / z 580.4 [M+H] + ,ESI pos.

[0100] Step 7: 2-[7-methyl-6-(4-morpholinophenyl)-4-(trifluoromethyl)indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazol-5,1'-cyclopropane]-1-yl-N-thiazol-2-yl-acetamide Starting from TIFF2025515833000027.tif35170 ethyl 2-[7-methyl-6-(4-morpholinophenyl)-4-(trifluoromethyl)indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazol-5,1'-cyclopropan]-1-yl-acetate (Example 2, step 6) and thiazol-2-amine, using chemistry similar to that described in Example 1, step 7, the title compound was obtained as a pale red solid. LCMS: m / z 634.4 [M+H] + ,ESI pos.

[0101] Example 3 2-(5,5-Dimethyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-2-[7-methyl-6-(4-morpholinophenyl)-4-(trifluoromethyl)indazol-2-yl]-N-thiazol-2-yl-acetamide TIFF2025515833000028.tif38170 Step 1: tert-Butyl 5-[2-[6-bromo-7-methyl-4-(trifluoromethyl)indazol-2-yl]-3-ethoxy-3-oxo-propanoyl]-2,2-dimethyl-pyrrolidine-1-carboxylate TIFF2025515833000029.tif36170 1-tert-butoxycarbonyl-5,5-dimethyl-proline was treated with carbonyldiimidazole as in Example 1, step 4 to give solution A. Ethyl 2-(6-bromo-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)acetate (Example 2, step 3) was deprotonated with LDA and treated with solution A at -78°C. After stirring at room temperature for 16 hours and workup as in Example 1, step 4, the crude title compound was obtained as a light brown foam, which was used in the next step without further purification. LCMS: m / z 590.3 [M+H] + ,ESI pos.

[0102] Step 2: Ethyl 2-[6-bromo-7-methyl-4-(trifluoromethyl)indazol-2-yl]-2-(5,5-dimethyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)acetate TIFF2025515833000030.tif26170 Analogous to Example 1, step 5, tert-butyl 5-[2-[6-bromo-7-methyl-4-(trifluoromethyl)indazol-2-yl]-3-ethoxy-3-oxo-propanoyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (Example 3, step 1) was deprotected using HCl in dioxane and subsequently reacted with potassium thiocyanate and hydrogen peroxide in acetic acid to give the title compound as a pale yellow foam. LCMS: m / z 501.2 [M+H] + ,ESI pos.

[0103] Step 3: Ethyl 2-(5,5-dimethyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-2-[7-methyl-6-(4-morpholinophenyl)-4-(trifluoromethyl)indazol-2-yl]acetate TIFF2025515833000031.tif37170 Starting from ethyl 2-[6-bromo-7-methyl-4-(trifluoromethyl)indazol-2-yl]-2-(5,5-dimethyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)acetate (Example 3, step 2) and (4-morpholinophenyl)boronic acid, using chemistry similar to that described in Example 1, step 6, the title compound was obtained as a light brown foam, LCMS: m / z 582.5 [M+H] + ,ESI pos.

[0104] Step 4: 2-(5,5-dimethyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-2-[7-methyl-6-(4-morpholinophenyl)-4-(trifluoromethyl)indazol-2-yl]-N-thiazol-2-yl-acetamide TIFF2025515833000032.tif35170 Starting from ethyl 2-(5,5-dimethyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-2-[7-methyl-6-(4-morpholinophenyl)-4-(trifluoromethyl)indazol-2-yl]acetate (Example 3, step 3) and thiazol-2-amine, using chemistry similar to that described in Example 1, step 7, the title compound was obtained as a white solid, LCMS: m / z 636.4 [M+H] + ,ESI pos.

[0105] Example 4 HTRF phosphorylated EGFR LRCS assay (cells) Cell lines and media The BaF3-LRCS cell line was obtained from Crownbio (San Diego, CA, USA). Cells were maintained in RPMI ATCC (Gibco 31870) + 2 mM glutamine + 0.5 μg / ml puromycin supplemented with 10% fetal bovine serum (FBS) (Gibco) at 37 °C, 5% CO2.

[0106] protocol After the plate was pre-filled with 12.5 μl of the DMSO solution of the compounds to be tested (dose response) or DMSO alone, the cells were transferred as described above to Greiner Bio-One No. 784-08 microtiter plates at 20000 cells / well in 12.5 μl of growth medium / well. After spinning the plate at 300×g for 30 seconds, the cells were incubated for 4 hours at 37° C., 5% CO2, 95% humidity. The cells were lysed by adding 4 μl / well of the compound mixture in supplemented lysis buffer (Cis-bio, phosphorylated EGFR HTRF kit, 64EG1PEH), followed by incubation at room temperature for 30 minutes with shaking (400 rpm). The plate was then frozen and stored overnight at −80° C. The next day, after thawing the plate, 4 μl of a mixture of anti-phosphorylated EGFR cryptate and anti-phosphorylated EGFR-d2 antibody solutions prepared in supplemented detection buffer was added to each well. The covered plates were then incubated for 4 hours at room temperature, after which the fluorescence emissions were read at 616 and 665 nm using an Envision reader (Perkin Elmer). Data were analyzed in the same manner as above, with the normalized ratio of 665 to 616 signals multiplied by 10,000.

[0107] The results are shown in Table 8. [Table 8]

Claims

1. Formula (I) (In the formula, R １ and R ２ is independently selected from alkyl, or R １ and R ２ together with the carbons to which they are attached form a cycloalkyl; R ３ is alkyl or haloalkyl; R ４ is hydrogen or a halogen, or a pharma- ceutically acceptable salt thereof.

2. R １ and R ２ is methyl, or R １ and R ２ 13. The compound of claim 1 , wherein together with the carbon to which they are attached form a cyclopropyl.

3. R １ and R ２ 3. The compound of claim 1 or 2, wherein together with the carbon to which they are attached form a cyclopropyl.

4. R １ and R ２ The compound according to claim 1 or 2, wherein is methyl.

5. R ３ The compound according to any one of claims 1 to 4, wherein is methyl.

6. R ４ The compound according to any one of claims 1 to 5, wherein is hydrogen or fluoro.

7. R ４ The compound according to any one of claims 1 to 6, wherein is hydrogen.

8. R ４ The compound according to any one of claims 1 to 6, wherein is fluoro.

9. 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazol-5,1'-cyclopropane]-1-yl-N-thiazol-2-yl-acetamide; 2-[7-methyl-6-(4-morpholinophenyl)-4-(trifluoromethyl)indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazol-5,1′-cyclopropane]-1-yl-N-thiazol-2-yl-acetamide; and Compounds according to any one of claims 1 to 8 selected from 2-(5,5-dimethyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-2-[7-methyl-6-(4-morpholinophenyl)-4-(trifluoromethyl)indazol-2-yl]-N-thiazol-2-yl-acetamide, or a pharma- ceutically acceptable salt thereof.

10. A process for preparing a compound according to any one of claims 1 to 9, comprising the steps of: (a) Formula (B1) in a suitable solvent in the presence of a base to obtain a compound of formula (B2) (In the formula, M ＋ But Na ＋ , Li ＋ or a protonated base; (b) reacting the compound of formula (B2) in the presence of an acid in a suitable solvent to obtain a compound of formula (B3): obtaining a compound of formula (I); and (c) reacting a compound of formula (B3) with a compound of formula (B4) Compound (In the formula, R １ , R ２ , R ３ and R ４ is as defined in any one of claims 1 to 9, wherein R is H or alkyl. in the presence of a suitable coupling agent and base; method.

11. A compound according to any one of claims 1 to 9 when produced according to the method of claim 10.

12. A compound according to any one of claims 1 to 9 for use as a therapeutically active substance.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and a therapeutically inert carrier.

14. A compound according to any one of claims 1 to 9 for use in the treatment or prevention of cancer, in particular non-small cell lung cancer.

15. 10. Use of a compound according to any one of claims 1 to 9 for use in the treatment or prevention of cancer, in particular non-small cell lung cancer.

16. Use of a compound according to any one of claims 1 to 9 for the preparation of a medicament for the treatment or prevention of cancer, in particular non-small cell lung cancer.

17. A method for the treatment or prevention of cancer, in particular non-small cell lung cancer, comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 9.

18. 13. The invention as hereinbefore described.

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