Novel indazole derivatives

Abstract

The present invention provides novel compounds # imgabs0 # having the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3 and R4 are as defined herein. The compounds of formula (I) are useful as medicaments.

Description

[0001] The present invention relates to compounds as selective allosteric inhibitors of EGFR mutants containing T790M / L858R, T790M / L858R / C797S, L858R and / or L858R / C797S, the production of the compounds, pharmaceutical compositions containing the compounds and the use of the compounds as therapeutically active substances.

[0002] The present invention particularly relates to a novel compound of formula (I),

[0003]

[0004] in

[0005] R 1 and R 2 are independently selected from alkyl, or R 1 and R 2 Together with the carbon to which they are attached they form a cycloalkyl group;

[0007] R 3 is alkyl or haloalkyl; and

[0008] R 4 is hydrogen or halogen;

[0009] or a pharmaceutically acceptable salt thereof.

[0010] HER family receptor tyrosine kinases are mediators of cell growth, differentiation and survival. The receptor family includes four different members, namely, epidermal growth factor receptor (EGFR, ErbB1 or HER1), HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4). After ligand binding, the receptor forms homodimers and heterodimers, and then the activation of endogenous tyrosine kinase activity leads to receptor autophosphorylation and activation of downstream signal transduction molecules (Yarden, Y., Sliwkowski, MX. Untangling the ErbB signalling network. Nature Review Mol Cell Biol. February 2001; 2 (2): 127-37). EGFR deregulation through overexpression or mutation has been implicated in many types of human cancers, 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 A reversible EGFR tyrosine kinase inhibitor approved in many countries for the treatment of recurrent NSCLC.

[0011] Impressive single-agent activity of EGFR tyrosine kinase inhibitors has been observed in a subset of NSCLC patients whose tumors harbor somatic kinase domain mutations, but the clinical benefit is greatly reduced in patients with wild-type EGFR (Paez 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, of which delta 746-750 is the most prevalent mutation, and exon 21 amino acid substitutions, of which L858R is the most common 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).

[0012] Often due to the secondary T790M mutation in the receptor ATP site, treatment resistance frequently occurs. Some mutant selective irreversible inhibitors developed have high activity for T790M mutants, but their efficacy can be impaired by the acquired mutation of C797S, which is a cysteine ​​residue that forms a key covalent bond with them (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)). Wang also reports C797S mutation as the main 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). Yang et al. described other mutations that cause resistance to osimertinib, for example, 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. (Targeting EGFR L858R / T790M and EGFR L858R / T790M / C797S Resistance mutations in NSCLC: Current developments in medicinal chemistry, Med Res Rev 2018; 1-32) on targeting EGFR in the treatment of NSCLC L858R / T790M and EGFR L858R / T790M / C797S Reports in review articles on resistance mutations.

[0013] Since most available EGFR tyrosine kinase inhibitors target the ATP site of the kinase, new therapeutic agents that act differently, for example by targeting drug-resistant EGFR mutants, are needed.

[0014] Recent studies have shown that purposefully targeting allosteric sites can lead to mutant-selective inhibitors (Jia et al. Overcoming EGFR (T790M) and EGFR (C797S) resistance with mutant-selective allosteric inhibitors, June 2016, Nature 534, 129-132)

[0015] Therefore, there is indeed an unmet need to generate selective molecules that specifically inhibit EGFR mutants containing T790M / L858R, T790M / L858R / C797S, L858R and / or L858R / C797S, which can be used for therapeutic and / or preventive treatment of cancer, especially EGFR mutants containing T790M and C797S.

[0016] The compounds of formula (I) as described herein do have improved EGFR potency and selectivity as well as improved physicochemical properties against EGFR mutants containing T790M / L858R, T790M / L858R / C797S, L858R and / or L858R / C797S, especially EGFR mutants containing T790M and C797S.

[0017] In this specification, the term "alkyl" refers, alone or in combination, 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 and more particularly a straight or branched chain alkyl group having 1 to 4 carbon atoms. Examples of straight and branched C1-C8 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, isomeric amyl, isomeric hexyl, isomeric heptyl and isomeric octyl, particularly methyl, ethyl, propyl, butyl and amyl. Specific examples of alkyl are methyl, ethyl, propyl, isopropyl and tert-butyl. Methyl and ethyl are specific examples of "alkyl" in compounds of formula (I).

[0018] The term "cycloalkyl", alone or in combination, refers to a cyclic ring system of one or more rings containing 3 to 8 carbon atoms and particularly containing 3 to 6 carbon atoms. Examples of "cycloalkyl" are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[1.1.1]pentanyl, bicyclo[1.1.1]hexyl and bicyclo[1.1.1]heptyl. A specific example of "cycloalkyl" is bicyclo[1.1.1]pentanyl.

[0019] The term "halogen" or "halo" alone or in combination means fluorine, chlorine, bromine or iodine and in particular fluorine or chlorine. A specific "halogen" or "halo" is fluorine. The term "halo" in combination with another group means that the group is substituted with at least one halogen, in particular with one to five halogens, in particular one to four halogens, i.e. one, two, three or four halogens.

[0020] The term "haloalkyl", alone or in combination, refers to an alkyl group substituted with at least one halogen, especially with one to five halogens, particularly one to three halogens. Particular examples of "haloalkyl" are fluoromethyl, difluoromethyl and trifluoromethyl.

[0021] The term "pharmaceutical salt" refers to the salt of those compounds of formula (I) that retain the biological effect and characteristics of free alkali or free acid, and these salts are not undesirable in biology or other aspects. These salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. (particularly 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, methylsulfonic acid, ethylsulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, etc. In addition, these salts can be prepared by adding inorganic bases or organic bases to free acids. Salts derived from inorganic bases include but are not limited to sodium, potassium, lithium, ammonium, calcium, magnesium salts, etc. 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 pharmaceutically acceptable salts of the compounds of formula (I) are hydrochlorides, methanesulfonates and citrates.

[0022] If one of the starting materials or compounds of formula (I) contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups may be introduced before the key steps using methods known in the art (such as described in "Protective Groups in Organic Chemistry" by TW Greene and PGM Wuts, 3rd edition, 1999, Wiley, New York). 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-butyloxycarbonyl (Boc), 9-fluorenylmethylcarbamate (Fmoc), 2-trimethylsilylethylcarbamate (Teoc), benzyloxycarbonyl (Cbz) and p-methoxybenzyloxycarbonyl (Moz).

[0023] The compounds of formula (I) may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers (eg racemates), optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0024] The term "asymmetric carbon atom" means a carbon atom having four different substituents. According to the Cahn-Ingold-Prelog convention, an asymmetric carbon atom can be in the "R" or "S" configuration.

[0025] Therefore, the present invention relates to:

[0026] According to the compound of the present invention, wherein R 1 and R 2 is methyl, or R 1 and R 2 Together with the carbon to which they are attached they form a cyclopropyl group;

[0027] According to the compound of the present invention, wherein R 1 and R 2 Together with the carbon to which they are attached they form a cyclopropyl group;

[0028] According to the compound of the present invention, wherein R 1 and R 2 is methyl;

[0029] According to the compound of the present invention, wherein R 3 is an alkyl group;

[0030] According to the compound of the present invention, wherein R 3 is methyl or fluoromethyl;

[0031] According to the compound of the present invention, wherein R 3 is methyl;

[0032] According to the compound of the present invention, wherein R 4 is hydrogen or fluorine;

[0033] According to the compound of the present invention, wherein R 4 is hydrogen; and

[0034] According to the compound of the present invention, wherein R 4 For fluorine.

[0035] The present invention further relates to a compound selected from

[0036] 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;

[0037] 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 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;

[0038] or a pharmaceutically acceptable salt thereof.

[0039] The present invention further relates to a compound selected from

[0040] 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 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;

[0041] or a pharmaceutically acceptable salt thereof.

[0042] The present invention further relates to

[0043] 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;

[0044] or a pharmaceutically acceptable salt thereof.

[0045] Processes for the manufacture of compounds of formula (I) as described herein are also an object of the present invention.

[0046] The preparation of the compound of formula (I) of the present invention can be carried out in order or by converging synthetic routes. An exemplary synthesis of the compound of the present invention is shown in the description of the specific examples. The skills required for the reaction and purification of the resulting product are known to those skilled in the art. Unless otherwise indicated, the substituents and labels used in the following description of the process have the meanings given herein before. The reaction sequence is not limited to the sequence shown in the specific examples, but, depending on the starting material and its corresponding reactivity, the order of the reaction steps can be freely changed. The starting material is commercially available, or can be prepared by a method similar to the method given below, by a method described in the specification or in the reference cited in the embodiment, or by methods known in the art.

[0047] The present invention also relates to a compound according to the invention produced by a process according to the invention.

[0048] Another embodiment of the present invention provides a pharmaceutical composition or medicine containing the compounds of this invention and a therapeutic inert carrier, diluent or excipient, and a method for preparing such compositions and medicines using the compounds of this invention. In one example, the compound of formula (I) can be formulated as a galenical administration form by mixing with a physiologically acceptable carrier (i.e., a carrier that is nontoxic to the recipient at the dosage and concentration used) at ambient temperature under appropriate pH and desired purity. The pH of the formulation depends primarily on the specific use and concentration of the compound, but is preferably in the range of about 3 to about 8. In one example, the compound of formula (I) is formulated in an acetate buffer at pH 5. In another embodiment, the compound of formula (I) is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0049] The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this context 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 timing of administration, and other factors known to practitioners.

[0050] 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 necessary for local treatment) intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

[0051] The compounds of the present invention can be administered in any convenient administration form, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain conventional components of pharmaceutical preparations, for example, diluents, carriers, pH adjusters, sweeteners, fillers and other active agents.

[0052] The usual formulations are prepared by mixing the compounds of the invention and carriers or excipients. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, for example, Ansel, Howard C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams and Wilkins, 2004; Gennaro, Alfonso R. et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams and Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulation may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavoring agents, flavoring agents, diluents and other known additives to provide an aesthetically pleasing display of the drug (e.g., a compound of the invention or a pharmaceutical composition thereof) or to aid in the preparation of a pharmaceutical product (e.g., a drug).

[0053] Therefore, the present invention also particularly relates to:

[0054] A compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a therapeutically active substance;

[0055] A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier;

[0056] A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating or preventing cancer;

[0057] A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating or preventing non-small cell lung cancer;

[0058] A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating or preventing cancer, especially non-small cell lung cancer;

[0059] A use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating or preventing cancer, especially non-small cell lung cancer;

[0060] A use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for preparing a medicament for treating or preventing cancer, in particular non-small cell lung cancer; and

[0061] A method for treating or preventing cancer, in particular non-small cell lung cancer, comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0062] A certain embodiment of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein and a pharmaceutically acceptable adjuvant substance.

[0063] A certain embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein for use in the treatment or prevention of cancer, in particular non-small cell lung cancer, characterized in that at least one EGFR mutation is selected from T790M / L858R, T790M / L858R / C797S, L858R and L858R / C797S.

[0064] A certain embodiment of the present invention relates to a method for treating or preventing cancer, in particular 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 comprising administering an effective amount of a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0065] Furthermore, the present invention includes all substituents of the compounds of formula (I) in their corresponding deuterated forms, where applicable.

[0066] Furthermore, the present invention includes all optical isomers of the compounds of formula (I) where applicable, ie diastereomers, diastereomeric mixtures, racemic mixtures, all corresponding enantiomers and / or tautomers thereof and solvates thereof.

[0067] Compounds of formula (I) may contain one or more asymmetric centers and may therefore 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 will independently produce two optical isomers, and it is intended that all possible optical isomers and diastereomers in the form of mixtures and as pure compounds or partially purified compounds are included in the present invention. The present invention is intended to cover all such isomeric forms of these compounds. The independent synthesis of these diastereomers or their chromatographic separation can be achieved by making appropriate changes to the methods disclosed herein as known in the art. The absolute stereochemistry of the crystalline product or crystalline intermediate can be determined by x-ray crystallography, and if necessary, these products or intermediates can be derivatized using reagents containing asymmetric centers of known absolute configuration. If necessary, the racemic mixture of the compound can be separated so that the individual enantiomers are separated. Separation can be carried out by methods well known in the art, such as coupling a racemic mixture of the compounds to an enantiomerically pure compound to form a diastereomeric mixture followed by separation of the individual diastereomers by standard methods such as fractional crystallization or chromatography.

[0068] In embodiments where an optically pure enantiomer is provided, an optically pure enantiomer means that the compound contains >90% by weight of the desired isomer, particularly >95% by weight of the desired isomer, or more particularly >99% by weight of the desired isomer, the weight percentages being based on the total weight of the isomers of the compound. Chirally pure compounds or chirally enriched compounds can be prepared by chiral selective synthesis or by enantiomer separation. Separation of enantiomers can be performed on the final product, or alternatively on a suitable intermediate.

[0069] Furthermore, embodiments of the present invention are compounds of formula (I) described herein, made according to any of the methods described herein.

[0070] The compound of formula (I) or a pharmaceutically acceptable salt thereof can be used as a medicament (e.g., in the form of a pharmaceutical preparation). The pharmaceutical preparation 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 polymer inserts). However, it can also be administered parenterally, such as intramuscularly, intravenously or intraocularly (e.g., in the form of sterile injections).

[0071] The compound of formula (I) or its pharmaceutically acceptable salt can be processed with a pharmaceutically inert inorganic or organic adjuvant to produce tablets, coated tablets, dragees, hard gelatin capsules, injections or topical preparations. For example, lactose, corn starch or its derivatives, talcum powder, stearic acid or its salts, etc. can be used as such adjuvants for tablets, dragees and hard gelatin capsules.

[0072] Suitable adjuvants for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semisolid substances and liquid polyols and the like.

[0073] Suitable adjuvants for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like.

[0074] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

[0075] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols and the like.

[0076] Suitable adjuvants for topical ophthalmic preparations are, for example, cyclodextrins, mannitol or numerous other carriers and excipients known in the art.

[0077] In addition, the pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. The pharmaceutical preparations may also contain other therapeutically valuable substances.

[0078] Dosage can vary over a wide range and will be suitable for various requirements in each particular case. Generally speaking, in the case of oral administration, a daily dose of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g., about 300 mg per person) should be suitable, and it is preferably divided into 1 to 3 separate doses (which may be composed of, for example, the same amount). In the case of topical administration, the formulation may include 0.001% to 15% of the drug by weight, and the desired dose may be 0.1 mg to 25 mg, a single administration every day or every week, or multiple administrations every day (2 to 4 times), or multiple administrations every week. However, it is apparent that when shown as applicable, the upper or lower limits given herein may be exceeded.

[0079] Pharmaceutical composition

[0080] The compounds of formula (I) or their pharmaceutically acceptable salts can be used as therapeutically active substances, for example, in the form of pharmaceutical preparations. Pharmaceutical preparations can be administered orally, for example, in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. However, administration can also be carried out rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions.

[0081] Formula (I) compound or its pharmaceutically acceptable salt can be processed with pharmaceutically inert inorganic or organic carriers for the production of pharmaceutical preparations. For example, lactose, corn starch or its derivatives, talcum powder, stearic acid or its salts, etc. can be used as such carriers for tablets, coated tablets, dragees and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols, etc. However, depending on the characteristics of the active substance, carriers are often not required in the case of soft gelatin capsules. Suitable carriers for the production 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.

[0082] In addition, the pharmaceutical preparations may contain pharmaceutically acceptable adjuvant substances, such as preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. The pharmaceutical preparations may also contain other therapeutically valuable substances.

[0083] The present invention also provides a medicament comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier and a process for the production thereof, the process comprising bringing the compound of formula (I) and / or a pharmaceutically acceptable salt thereof and, if necessary, one or more other therapeutically valuable substances together with one or more therapeutically inert carriers into a galenical administration form.

[0084] The dosage is variable within a wide range, but will have to be adjusted according to the individual needs of each particular case. In the case of oral administration, the dosage for adults can be changed from about 0.01 mg to about 1000 mg per day of a compound of the general formula (I) or a corresponding amount of a pharmaceutically acceptable salt thereof. The daily dose can be administered as a single dose or in multiple divided doses, and in addition, the upper limit may be exceeded when it is found that there is an indication that the upper limit may be exceeded.

[0085] The following examples illustrate but do not limit the present invention, but are merely representative of the present invention. Pharmaceutical preparations conveniently contain about 1 mg to 500 mg, in particular 1 mg to 100 mg, of a compound of formula (I). Examples of compositions according to the present invention are:

[0086] Example A

[0087] Tablets of the following composition are produced in a conventional manner:

[0088]

[0089]

[0090] Table 1: Possible tablet compositions

[0091] Preparation Procedure

[0092] 1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water.

[0093] 2. Dry the granules at 50°C.

[0094] 3. Pass the particles through suitable grinding equipment.

[0095] 4. Add ingredient 5 and mix for three minutes; press on a suitable press.

[0096] Example B-1

[0097] Capsules of the following composition were produced:

[0098]

[0099] Table 2: Possible capsule composition

[0100] Preparation Procedure

[0101] 1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes.

[0102] 2. Add ingredients 4 and 5 and mix for 3 minutes.

[0103] 3. Fill into suitable capsules.

[0104] The compound of formula (I), lactose and corn starch are first mixed in a mixer and then in a pulverizer. The mixture is returned to the mixer; talc is added thereto and mixed thoroughly. The mixture is filled into suitable capsules, such as hard gelatin capsules, by machine.

[0105] Example B-2

[0106] Soft gelatin capsules with the following composition are manufactured:

[0107]

[0108] Table 3: Possible soft gelatin capsule composition

[0109]

[0110] Table 4: Possible soft gelatin capsule compositions

[0111] Preparation Procedure

[0112] The compound of formula (I) is dissolved in the warm melt of the other ingredients and the mixture is filled into soft gelatin capsules of suitable size. The filled soft gelatin capsules are processed according to the general procedures.

[0113] Example C

[0114] Suppositories with the following composition are manufactured:

[0115]

[0116] Table 5: Possible suppository compositions

[0117] Preparation Procedure

[0118] In a glass or steel container, the suppository base is melted, mixed thoroughly and cooled to 45°C. At this point, a fine powder of the compound of formula (I) is added and stirred until the compound is completely dispersed. The mixture is poured into a suppository mold of suitable size and left to cool; the suppositories are then removed from the mold and individually wrapped in wax paper or metal foil.

[0119] Example D

[0120] Produce an injection of the following composition:

[0121]

[0122] Table 6: Possible compositions of injection solutions

[0123] Preparation Procedure

[0124] The compound of formula (I) is dissolved in a mixture of polyethylene glycol 400 and water for injection (part). The pH is adjusted to 5.0 by acetic acid. The volume is adjusted to 1.0 ml by adding the remainder of water. The solution is filtered, filled into a vial with an appropriate excess and sterilized.

[0125] Example E

[0126] A sachet with the following composition is manufactured:

[0127]

[0128]

[0129] Table 7: Possible composition of sachets

[0130] Preparation Procedure

[0131] The compound of formula (I) is mixed with lactose, microcrystalline cellulose and sodium carboxymethylcellulose and granulated with a mixture of polyvinyl pyrrolidone in water. The granules are mixed with magnesium stearate and flavoring additives and filled into bags.

[0132] Examples

[0133] abbreviation

[0134] AcOH = acetic acid; ATP = adenosine triphosphate; BOC = tert-butyloxycarbonyl; BPR = back pressure regulator; CAS = Chemical Abstracts Service; CDI = 1,1'-carbonyldiimidazole; DCM = dichloromethane; DIPEA = diisopropylethylamine; DME = dimethoxyethane; DMF = dimethylformamide; DMSO = dimethyl sulfoxide; dppf = 1,1'-bis(diphenylphosphino)ferrocene; EtOAc = ethyl acetate; EtOH = ethanol; HATU = hexafluorophosphate azabenzotriazole tetramethyl uronium; LDA = lithium diisopropylamide; MeOH = methanol; MS = mass spectrometry; NMR = nuclear magnetic resonance; rt = room temperature; THF = tetrahydrofuran.

[0135] The following examples are provided to illustrate the present invention. They should not be considered as limiting the scope of the invention, but are merely representative.

[0136] Synthesis of intermediates

[0137] Substituted indazoles (II) are known or can be prepared analogously to known methods or using the methods described below.

[0138] 6-Bromo-7-methyl-4-(trifluoromethyl)-1H-indazole

[0139] Step 1: 1-Bromo-3-fluoro-2-methyl-5-(trifluoromethyl)benzene

[0140] 1-Bromo-3-fluoro-5-(trifluoromethyl)benzene (12.7 g) was dissolved in tetrahydrofuran (60 ml) and cooled to -75 °C. LDA, 2.1 mol / l, 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 adding a half-saturated ammonium chloride solution and ethyl acetate, the layers were separated and extracted again with ethyl acetate. The organic layers were washed with water, combined, dried over sodium sulfate, and concentrated. The residual brown liquid (15.42 g) was distilled bulb by bulb at ~10 mbar and 60-80 °C oven temperature to obtain the title compound as a colorless liquid (11.91 g) containing 8 mol% of ethylbenzene.

[0141] Step 2: 4-Bromo-2-fluoro-3-methyl-6-(trifluoromethyl)benzaldehyde

[0142] Analogously 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 analogously to the synthesis of 4-bromo-3,6-dichloro-2-fluorobenzaldehyde afforded the crude title compound as a brown liquid.

[0143] Step 3: 6-Bromo-7-methyl-4-(trifluoromethyl)-1H-indazole

[0144] Analogously 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 afford the title compound as a pale yellow solid. MS: m / e = 278.9 ([M+H] + ,Br)

[0145] General Method A: Alkylation of Indazole

[0146] A mixture of indazole (II, 1 equivalent), ethyl 2-bromoacetate (2 equivalents) and N,N-dimethylacetamide (a small amount to produce a solution) is heated to 100 ° C until the reaction is complete (usually 5-48 hours). 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 accomplished by chromatography, or in some cases by recrystallization from solvents such as EtOH, acetonitrile or dichloromethane.

[0147] Using general procedure A, the following intermediate (III) was prepared:

[0148]

[0149] The boronic acid derivatives are known or can be prepared analogously to known methods or using the methods described below.

[0150] [4-[(3S,4S)-1-ethyl-3-fluoro-4-piperidinyl]phenyl]boronic acid or [4-[(3R,4R)-1-ethyl-3-fluoro-4-piperidinyl]phenyl]boronic acid Step 1: (3S,4S)-4-(4-bromophenyl)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester and (3R, 4R)-4-(4-bromophenyl)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester

[0151] A solution of tert-butyl 4-(4-bromophenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (CAS273727-44-9, 30 g, 79.8 mmol, Eq: 1.0, purity 90%) 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, Eq: 1.1) 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, Eq: 2.51) was added dropwise and the reaction mixture was stirred at 0°C for 30 min. Hydrogen peroxide (35 wt.% aqueous solution, 19.4 g, 17.5 mL, 200 mmol, Eq: 2.5) 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 quenched by adding a 2M Na2S2O3 aqueous solution. The mixture was diluted with ethyl acetate and water. The aqueous layer was back-extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was suspended in diisopropyl ether and filtered. The solid was washed with diisopropyl ether and dried in vacuo to obtain the title compound as a white solid (26.74 g, 92% yield). m / z 258.1 [M-BOC+H] + , ESI pos.

[0152] Step 2: (3S,4S)-4-(4-bromophenyl)-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester and (3R,4R)-4-(4-bromophenyl)-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester tert-Butyl)-3-fluoro-piperidine-1-carboxylate

[0153] A solution of (3S,4S)-4-(4-bromophenyl)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester and (3R,4R)-4-(4-bromophenyl)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (37.2 g, 99.2 mmol, Eq: 1) was cooled to -78°C in dichloromethane (500 mL). Add dropwise at -78°C (50% THF solution, CAS202289-38-1, 79g, 65.8mL, 179mmol, Eq: 1.8). The reaction mixture was allowed to slowly warm to room temperature and stirred at room temperature for 16h. The reaction mixture was quenched with saturated NaHCO3 aqueous solution. The mixture was stirred for 30min (pH 7). The organic layer was separated. The aqueous layer was back-extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was adsorbed on Isolute HM-N and purified by flash chromatography (silica gel, 330g, 0% to 40% EtOAc in heptane) to give the title compound as a light yellow oil (31.7g, 85% yield). m / z 304.1[M-tBu+H] +, ESI pos.

[0154] Step 3: (3S,4S)-4-(4-bromophenyl)-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester or (3R,4R)-4-(4-bromophenyl)-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester 1-Methyl-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester

[0155] Chiral separation of (3S,4S)-4-(4-bromophenyl)-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester and (3R,4R)-4-(4-bromophenyl)-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester (31.8 g, 88.8 mmol, Eq: 1.0) was performed by SFC (column: IG, 12 nm, 5 μm, 250 x 30 mm, eluent: isocratic 5% isopropanol-BPR, 120 bar to 80 g / min) to afford the title compound as a colorless oil (13.27 g, 40% yield). m / z 304.0 [M-tBu+H] + , ESI pos. Absolute stereochemistry not determined.

[0156] Step 4: (3S,4S)-4-(4-bromophenyl)-3-fluoro-piperidine hydrochloride or (3R,4R)-4-(4-bromophenyl)-3-fluoro-piperidine Fluoro-piperidine hydrochloride

[0157] To a solution of (3S,4S)-4-(4-bromophenyl)-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester or (3R,4R)-4-(4-bromophenyl)-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester (10.5 g, 29.3 mmol, Eq: 1.0) in DCM (100 mL) was added HCl (4M in 1,4-dioxane, 73.3 mL, 293 mmol, Eq: 10). The reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated in vacuo. The residue was taken up in 40 mL of Et2O and the mixture was stirred for 10 min. The reaction mixture was filtered through a sintered glass and washed with Et2O. The white solid was dried in vacuo to give the title compound (9.5 g, purity 90%, yield 99%). m / z 260.0 [M+H] + , ESI pos.

[0158] Step 5: (3S,4S)-4-(4-bromophenyl)-1-ethyl-3-fluoro-piperidine or (3R,4R)-4-(4-bromophenyl)-1-ethyl-3-fluoro-piperidine Ethyl-3-fluoro-piperidine

[0159] 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, Eq: 1.0) in THF (148 mL) was added NEt (6.53 g, 8.99 mL, 64.5 mmol, Eq: 2.0). Diethyl sulfate (CAS 64-67-5, 5.97 g, 5.07 mL, 38.7 mmol, Eq: 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 then poured into EtOAc and washed with Na2CO3 / water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 1% MeOH in DCM) to afford the title compound as a yellow oil (7.20 g, 74% yield). m / z 287.9 ​​[M+H] + , ESI pos.

[0160] Step 6: [4-[(3S,4S)-1-ethyl-3-fluoro-4-piperidinyl]phenyl]boronic acid or [4-[(3R,4R)-1-ethyl- 3-Fluoro-4-piperidinyl]phenyl]boronic acid

[0161] A solution of (3S, 4S)-4-(4-bromophenyl)-1-ethyl-3-fluoro-piperidine or (3R, 4R)-4-(4-bromophenyl)-1-ethyl-3-fluoro-piperidine (1.000g, 3.49mmol, Eq: 1.0) in THF (8.0mL) was cooled to -76 °C. n-Butyl lithium (1.6M in hexane, 2.4mL, 3.84mmol, Eq: 1.1) was added dropwise and the reaction mixture was stirred at -76 °C for 2h. Triethyl borate (618mg, 0.72mL, 4.23mmol, Eq: 1.21) was added at -76 °C and the reaction mixture was stirred at -76 °C for 15min. Then, the dry ice bath was removed and the reaction mixture was stirred at room temperature (1.5h). The reaction mixture was quenched with saturated NH4Cl aqueous solution (10mL) and stirred at room temperature for 15min. 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 dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 24g, 0% to 10% MeOH in DCM) to obtain the title compound as an off-white solid (744mg, 90% purity, 76% yield). m / z 252.2[M+H] + , ESI pos.

[0162] (1-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)piperidin-4-yl)methanol

[0163] To a mixture of [1-[2-(4-bromophenoxy)ethyl]-4-piperidinyl]methanol (CAS 1226008-23-6, 1.3 g, 4.14 mmol, Eq: 1.0), bis(pinacolato)diboron (1.16 g, 4.55 mmol, Eq: 1.1), potassium acetate (1.22 g, 12.4 mmol, Eq: 3.0) in 1,4-dioxane (15 mL) was added Pd(dppf)Cl2.CH2Cl2 (303 mg, 414 μmol, Eq: 0.1). The reaction mixture was purged with argon and stirred at 90 °C for 3 h. The reaction mixture was concentrated in vacuo 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.

[0164] (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

[0165] In a flame dried flask, (1-((3-(4-bromophenyl)bicyclo[1.1.1]pentan-1-yl)methyl)piperidin-4-yl)methanol (295 mg), as described in Example 50, Step 3, was dissolved in 1,4-dioxane (6.58 ml) under an inert atmosphere and bis(pinacolato)diboron (235 mg) and potassium acetate (248 mg) were added. The mixture was degassed under sonication and then 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(ii) dichloromethane complex (75.6 mg) was added. The flask was placed on a 90°C preheated heating block with a reflux condenser. The reaction was stirred for 40 min. The reaction mixture was transferred to a 150 mL round bottom flask and a spacer was added. The solvent was removed and the residue was loaded for flash column chromatography on an amine modified gel (0-10% DCM:MeOH, 40 g). All fractions containing product were combined and concentrated to give the title compound (286 mg) as a brown solid. MS: m / e = 398.3 ([M+H]+)

[0166] 1-(2-Methoxyethyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine

[0167] Step 1: 4-(4-bromophenyl)-1-(2-methoxyethyl)piperidine

[0168] DIPEA (7.53 g, 10.2 ml, 58.3 mmol, Eq: 2.0) and 1-bromo-2-methoxyethane (4.86 g, 3.29 ml, 35 mmol, Eq: 1.2) were added to 4-(4-bromophenyl)piperidine (7 g, 29.1 mmol, Eq: 1.0, CAS 80980-89-8). The reaction mixture was stirred at room temperature for 3 h and stirred at 50 ° C for 16 h. The reaction mixture was poured into H2O and extracted with AcOEt (2x). The organic layers were combined, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80 g, 0% to 10% MeOH in DCM) to obtain the title compound as a yellow semi-solid (5.08 g, 58% yield). m / z 300.1 [M+H]+, ESI pos.

[0169] Step 2: 1-(2-methoxyethyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- base)

[0170] phenyl]piperidine

[0171] To a solution of 4-(4-bromophenyl)-1-(2-methoxyethyl)piperidine (5 g, 16.8 mmol, Eq: 1.0) in 1,4-dioxane (100 ml) was added bis(pinacolato)diboron (5.53 g, 21.8 mmol, Eq: 1.3), KOAc (4.94 g, 50.3 mmol, Eq: 3.0) and Pd(dppf)Cl2.CH2Cl2 (859 mg, 1.17 mmol, Eq: 0.07). The reaction mixture was purged with argon and stirred at 90 °C for 3 h. The crude material was purified by flash chromatography (silica gel, 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]+, ESIpos.

[0172] Example 1

[0173] 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

[0174]

[0175] Step 1: 1-Bromo-5-(difluoromethyl)-3-fluoro-2-methyl-benzene

[0176]

[0177] To a cooling solution of 3-bromo-5-fluoro-4-methylbenzaldehyde (CAS#1370411-47-4, 20.5 g, 89.7 mmol, 1.0 equiv) in dichloromethane (98 mL) was added trifluorinated morpholine sulfur (CAS#51010-74-3, 24.8 g, 17.3 mL, 135 mmol, 1.5 equiv) in portions. The reaction mixture was stirred at 0-5 ° C for 20 minutes and then at room temperature for 16 hours. Saturated NaHCO3 aqueous solution (300 mL) was carefully added under ice cooling. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into dichloromethane and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 120 g, 100% pentane) to obtain the title compound (18.6 g, 87% yield), which was a colorless oil. 1 H NMR (300 MHz, chloroform-d) δ = 7.50 (s, 1H), 7.16 (d, J = 9.1 Hz, 1H), 6.57 (t, J = 56.0 Hz, 1H), 2.50-2.22 (m, 3H)

[0178] Step 2: 6-Bromo-4-(difluoromethyl)-7-methyl-1H-indazole

[0179]

[0180] 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, keeping 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 allowed to warm to room temperature, poured into ethyl acetate and washed with diluted aqueous HCl, water and brine. The organic layer is dried over sodium sulfate and concentrated in vacuo to give the assumed 4-bromo-6-(difluoromethyl)-2-fluoro-3-methyl-benzaldehyde as a yellow oil (29.5 g) which can be used without further purification. The assumed crude 4-bromo-6-(difluoromethyl)-2-fluoro-3-methyl-benzaldehyde (29.5 g) is dissolved in dimethoxyethane (150 mL). O-methylhydroxylamine hydrochloride (10.2 g, 122 mmol, 1.1 equivalents) and potassium carbonate (30.6 g, 221 mmol, 2.0 equivalents) are added. The reaction mixture is stirred at 45 ° C for 2.5 hours, then filtered through sintered glass and washed with dimethoxyethane (2x). The filtrate is concentrated in vacuo. The oxime ether intermediate is dissolved in dimethyl sulfoxide (150 mL). Hydrazine hydrate (83 g, 80.5 mL, 1.66 mol, 15 equivalents) is added. The reaction mixture was stirred at 110 ° C for 3 hours. The reaction mixture was poured into a mixture of ethyl acetate / tetrahydrofuran 5: 1. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 2 x 120 g, gradient 0% to 30% ethyl acetate in heptane) to give the title compound (13.5 g, yield 45%) as a white solid. LCMS: m / z 260.9 / 262.8 [M+H] + ,ESI pos,Br isotope.

[0181] Step 3: Ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]acetate

[0182]

[0183] To 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#105-36-2, 18.2 g, 12.2 mL, 109 mmol, 1.5 equiv). The reaction mixture was stirred at 100 °C for 16 hours. 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 in vacuo. The crude material was purified by flash chromatography (silica gel, 2 x 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.

[0184] Step 4: (5R)-5-[2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-3-ethoxy-3-oxo- C [acyl]-4-azaspiro[2.4]heptane-4-carboxylic acid tert-butyl ester

[0185]

[0186] Preparation of tert-butyl (5R)-5-(imidazole-1-carbonyl)-4-azaspiro[2.4]heptane-4-carboxylate

[0187]

[0188] To a solution of (5R)-4-tert-butoxycarbonyl-4-azaspiro[2.4]heptane-5-carboxylic acid (CAS#2007916-06-3, 1.02 g, 4.21 mmol, 1.0 equiv) in dichloromethane (17 mL) was added 1,1'-carbonyldiimidazole (818 mg, 5.04 mmol, 1.2 equiv) in three portions, and the reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was poured into a saturated NaHCO3 solution and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give (5R)-5-(imidazole-1-carbonyl)-4-azaspiro[2.4]heptane-4-carboxylic acid tert-butyl ester (1.30 g, 95% yield, 90% purity) as an off-white solid which was used directly in the next step.

[0189] A solution of 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazole-2-yl]ethyl acetate (Example 1, Step 3) (1.2 g, 3.46 mmol, 1.0 equiv) in tetrahydrofuran (16 mL) was cooled to -50 ° C. NaHMDS (1 M in tetrahydrofuran) (4 mL, 4 mmol, 1.16 equiv) was added and the reaction mixture was stirred at -50 ° C for 45 minutes. At -50 ° C, a solution of the above-mentioned (5R)-5-(imidazole-1-carbonyl)-4-azaspiro[2.4]heptane-4-carboxylic acid tert-butyl ester (1.29 g, 3.98 mmol, 1.15 equiv) in tetrahydrofuran (16 mL) was added dropwise. The reaction mixture was stirred at -50 ° C for 30 minutes. Then, the cooling bath was removed, and the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled and quenched with a saturated NH4Cl aqueous solution, diluted with water and extracted with ethyl acetate. The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaHCO3 solution and then with brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (2.37 g, 96% yield, 80% purity) as a light brown foam which was used directly without further purification. LCMS: m / z 570.3 / 572.3 [M+H] + ,ESI pos,Br isotope.

[0190] Step 5: 2-[6-Bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2- c]imidazole-5,1'-cyclopropane-1-yl-acetic acid ethyl ester

[0191]

[0192] A mixture of (5R)-5-[2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-3-ethoxy-3-oxo-propionyl]-4-azaspiro[2.4]heptane-4-carboxylic acid tert-butyl ester (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 hour. 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 minutes. 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 minutes. The reaction mixture was diluted with ethanol (7.6mL) and water (2.0mL). Potassium thiocyanate (419mg, 4.31mmol, 1.3 equivalents) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled, and pyridine (3.91g, 4mL, 49.46mmol, 14.9 equivalents) was slowly added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 1N KHSO4+ water and extracted three times with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was dissolved in acetic acid (7.6mL) and cooled to 0°C. At 0°C, hydrogen peroxide (35wt.% aqueous solution, 0.580mL, 6.62mmol, 2.0 equivalents) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. Excess hydrogen peroxide was destroyed with a 1M Na2S2O3 aqueous solution. The mixture was carefully alkalized with solid Na2CO3 and extracted twice with ethyl acetate. The organic layer was washed with brine, merged, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was adsorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, 24 g, gradient 0% to 100% ethyl acetate in heptane). All fractions containing the product were combined and concentrated in vacuo to give the title compound (882 mg, 53% yield) as a light yellow solid. LCMS: m / z 479.3 / 481.3 [M+H] + ,ESI pos,Br isotope.

[0193] Step 6: 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-spiro[6,7-dihydro Ethyl pyrrolo[1,2-c]imidazol-5,1'-cyclopropane]-1-yl acetate

[0194]

[0195] A mixture of 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazol-5,1'-cyclopropane]-1-yl-acetic acid ethyl ester (Example 1, Step 5) (350 mg, 0.69 mmol, 1.00 equiv), (4-morpholinophenyl)boronic acid (CAS#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) complexed 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 hours. 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 layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was adsorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, 24g, gradient 0% to 90% ethyl acetate in heptane solution). All fractions containing the product were combined and concentrated to obtain the title compound (352mg, yield 81%, purity 90%), which was an off-white foam. LCMS: m / z 562.5[M+H] + ,ESI pos.

[0196] Step 7: 2-[4-(Difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-spiro[6,7-dihydro Pyrrolo[1,2-c]imidazol-5,1'-cyclopropane]-1-yl-N-thiazol-2-yl-acetamide

[0197]

[0198] To a solution of 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-acetic acid ethyl ester (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 hours. The reaction mixture was evaporated and co-evaporated 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), thiazole-2-amine (72 mg, 0.72 mmol, 1.3 equiv) and HATU (274 mg, 0.72 mmol, 1.3 equiv). The reaction mixture was stirred at room temperature for 45 minutes. 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 on 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 on ISOLUTE HM-N and re-purified 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.

[0199] Example 2

[0200] 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

[0201]

[0202] Step 1: 1-Bromo-3-fluoro-2-methyl-5-(trifluoromethyl)benzene

[0203]

[0204] 1-Bromo-3-fluoro-5-(trifluoromethyl)benzene (12.7 g, 52.2 mmol, 1.0 eq) 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 eq) was added dropwise. After stirring at -75 °C for 30 minutes, iodomethane (8.16 g, 3.6 ml, 57.4 mmol, 1.1 eq) was added dropwise. The mixture was allowed to warm to room temperature overnight. After adding a half-saturated ammonium chloride solution and ethyl acetate, the layers were separated and extracted again with ethyl acetate. The organic layers were washed with water, combined, dried over sodium sulfate and concentrated in vacuo. The residual brown liquid (15.42 g) was distilled bulb by bulb at about 10 mbar and 60-80 °C oven temperature to obtain the title compound as a colorless liquid (11.9 g, 89% yield).

[0205] Step 2: 6-Bromo-7-methyl-4-(trifluoromethyl)-1H-indazole

[0206]

[0207] The title compound was obtained as a light yellow solid, LCMS: m / z 278.9 [M+H] + , ESI pos, using chemistry similar to that described in Example 1, Step 2, starting from 1-bromo-3-fluoro-2-methyl-5-(trifluoromethyl)benzene (Example 2, Step 1).

[0208] Step 3: Ethyl 2-(6-bromo-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)acetate

[0209]

[0210] The title compound was obtained as a light yellow solid, LCMS: m / z 365.1 / 367.1 [M+H] + , ESI pos, Br isotope, using chemistry similar to that described in Example 1, Step 3, starting from 6-bromo-7-methyl-4-(trifluoromethyl)-1H-indazole (Example 2, Step 2).

[0211] Step 4: (5S)-5-[2-[6-bromo-7-methyl-4-(trifluoromethyl)indazol-2-yl]-3-ethoxy-3-oxo- [propionyl]-4-azaspiro[2.4]heptane-4-carboxylic acid tert-butyl ester

[0212]

[0213] Analogously to Example 1, Step 4, (5S)-4-tert-butoxycarbonyl-4-azaspiro[2.4]heptane-5-carboxylic acid was treated with carbonyldiimidazole 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 reprocessing analogously to 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.

[0214] Step 5: 2-[6-Bromo-7-methyl-4-(trifluoromethyl)indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2- c]imidazole-5,1'-cyclopropane-1-yl-acetic acid ethyl ester

[0215]

[0216] Analogously to Example 1, Step 5, (5S)-5-[2-[6-bromo-7-methyl-4-(trifluoromethyl)indazol-2-yl]-3-ethoxy-3-oxo-propionyl]-4-azaspiro[2.4]heptane-4-carboxylic acid tert-butyl ester (Example 2, Step 4) was deprotected using HCl in dioxane and then 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.

[0217] Step 6: 2-[7-methyl-6-(4-morpholinophenyl)-4-(trifluoromethyl)indazol-2-yl]-2-spiro[6,7-dihydro Ethyl pyrrolo[1,2-c]imidazol-5,1'-cyclopropane]-1-yl acetate

[0218]

[0219] The title compound was obtained as a light brown foam, LCMS: m / z 580.4 [M+H] + , ESI pos, using chemistry analogous to that described in Example 1, Step 6, starting from ethyl 2-[6-bromo-7-methyl-4-(trifluoromethyl)indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazol-5,1'-cyclopropane]-1-yl-acetic acid (Example 2, Step 5) and (4-morpholinophenyl)boronic acid.

[0220] Step 7: 2-[7-methyl-6-(4-morpholinophenyl)-4-(trifluoromethyl)indazol-2-yl]-2-spiro[6,7-dihydro Pyrrolo[1,2-c]imidazol-5,1'-cyclopropane]-1-yl-N-thiazol-2-yl-acetamide

[0221]

[0222] The title compound was obtained as a light red solid, LCMS: m / z 634.4 [M+H] + , ESI pos, using a chemistry analogous to that described in Example 1, Step 7, starting from ethyl 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-acetic acid ethyl ester (Example 2, Step 6) and thiazol-2-amine.

[0223] Example 3

[0224] 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

[0225]

[0226] Step 1: 5-[2-[6-bromo-7-methyl-4-(trifluoromethyl)indazol-2-yl]-3-ethoxy-3-oxo-propionyl 2,2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

[0227]

[0228] Analogously to Example 1, Step 4, 1-tert-butoxycarbonyl-5,5-dimethyl-proline was treated with carbonyldiimidazole 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 reprocessing analogously to 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.

[0229] Step 2: 2-[6-bromo-7-methyl-4-(trifluoromethyl)indazol-2-yl]-2-(5,5-dimethyl-6,7-dihydropyridine Ethyl pyrolu[1,2-c]imidazol-1-yl)acetate

[0230]

[0231] Analogously to Example 1, Step 5, 5-[2-[6-bromo-7-methyl-4-(trifluoromethyl)indazol-2-yl]-3-ethoxy-3-oxo-propionyl]-2,2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (Example 3, Step 1) was deprotected using HCl in dioxane, followed by reaction with potassium thiocyanate and hydrogen peroxide in acetic acid to afford the title compound as a light yellow foam. LCMS: m / z 501.2 [M+H] + ,ESI pos.

[0232] Step 3: 2-(5,5-dimethyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-2-[7-methyl-6-(4-morpholino)- Ethyl [(4-(trifluoromethyl)indazol-2-yl)-1-[( ...

[0233]

[0234] The title compound was obtained as a light brown foam, LCMS: m / z 582.5 [M+H] + , ESI pos, using chemistry analogous to that described in Example 1, Step 6, 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.

[0235] Step 4: 2-(5,5-dimethyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-2-[7-methyl-6-(4-morpholino)- [(4-(trifluoromethyl)indazol-2-yl)-N-thiazol-2-yl)acetamide (phenyl)

[0236]

[0237] The title compound was obtained as a white solid, LCMS: m / z 636.4 [M+H] + , ESI pos, using chemistry analogous to that described in Example 1, Step 7, 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.

[0238] Example 4

[0239] HTRF Phospho-EGFR LRCs Assay (Cells)

[0240] Cell lines and culture media

[0241] 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.

[0242] Regulations

[0243] As described above, Greiner Bio-One, Nr.784-08 microtiter plates were pre-filled with 12.5 nl of a DMSO solution of the compound to be tested (dose response) or DMSO alone, and then cells were transferred to the microtiter plate at 20,000 cells / well and 12.5 μl of growth medium / well. After the plate was rotated at 300 x g for 30 seconds, the cells were incubated for 4 hours at 37C, 5% CO2, and 95% humidity. 4 μl / well of supplementary lysis buffer (Cis-bio, Phospho-EGFRHTRF kit, 64EG1PEH) was added to the compound mixture for cell lysis, followed by incubation at room temperature for 30 minutes under shaking (400 rpm). The plate was then frozen and stored overnight at -80°C. The next day, after the plate was thawed, 4 μl of a mixture of anti-Phospho-EGFR cryptates and anti-Phospho-EGFR-d2 antibodies prepared in detection buffer was added. The covered plates were then allowed to stand for 4 hours at room temperature before reading the fluorescence emission at 616 and 665 nm using an Envision plate reader (Perkin Elmer). The data were analyzed in a similar manner as described above using a normalized ratio of 665 to 616 signals multiplied by 10,000.

[0244] The results are shown in Table 8.

[0245] Table 8: BaF3 cell HTRF Phospho EGFR LRCS assay data

[0246]

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof in R 1 and R 2 are independently selected from alkyl, or R 1 and R 2 Together with the carbon to which they are attached they form a cycloalkyl group; R 3 is alkyl or haloalkyl; and R 4 is hydrogen or halogen.

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

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

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

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

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

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

8. A compound according to any one of claims 1 to 6, wherein R 4 For fluorine.

9. A compound selected from the following according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof: 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 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.

10. A method for preparing a compound according to any one of claims 1 to 9, comprising at least one of the following steps: (a) making a compound of formula (B1) In a suitable solvent and in the presence of a base, a compound of formula (B2) is obtained. Among them, M + for Na + , Li + or a protonated base; (b) reacting the compound of formula (B2) in a suitable solvent in the presence of an acid to produce a compound of formula (B3) as well as (c) reacting a compound of formula (B3) with a compound of formula (B4) reacting in the presence of a suitable coupling agent and a base; Where R 1 , R 2 , R 3 and R 4 As defined in any one of claims 1 to 9; and Wherein R is H or alkyl.

11. A compound according to any one of claims 1 to 9, which is prepared according to the process of claim 10.

12. Compounds according to any one of claims 1 to 9 for use as therapeutically active substances.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and a therapeutically useful 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. Use of a compound according to any one of claims 1 to 9 for 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 treating or preventing cancer, in particular non-small cell lung cancer, comprising administering to a patient in need thereof an effective amount of a compound as defined in any one of claims 1 to 9.

18. The invention as herein described.

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