Novel indazole acetylene derivatives

Abstract

The present invention relates to novel compounds having the general formula (I) JPEG2023550902000076.jpg46170 or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 2’ , R 3 , R 4 , and R 5 is as described herein. The compounds of formula (I) can be used as medicines.

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 manufacture, pharmaceutical compositions containing them, and their use as therapeutic active substances.

[0002] The present invention relates, in particular, to novel compounds of formula (I). JPEG0007840327000001.jpg46170[In the formula, R 1 is hydrogen or halogen; R 2 and R 2’ These are independently selected from hydrogen and alkyl; or R 2 and R 2’ They, together with the carbon atoms to which they bond, form a cycloalkyl group; R 3 is hydrogen or halogen; R 4 is alkyl; R 5 [It is a hydroxyalkyl (heterocycloalkyl)alkyl] or relating to the pharmaceutically acceptable salt thereof. [Background technology]

[0003] The HER family of 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 receptor forms homodimers and heterodimers, and subsequent activation of endogenous 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 BiolBiol. Feb;2(2): 127-37). Disdysregulation of EGFR due to overexpression or mutation is associated with many types of human cancer, including colorectal cancer, pancreatic cancer, glioma, head and neck cancer, and lung cancer, particularly non-small cell lung cancer (NSCLC), and several EGFR-targeting agents have been developed over many 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, is approved in many countries as a treatment for relapsed NSCLC.

[0004] In some NSCLC patients whose tumors have somatic kinase domain mutations, significant monotherapy activity of EGFR tyrosine kinase inhibitors is observed, but the clinical benefit is significantly reduced in patients with wild-type EGFR (Paez, J. et al. (2004). EGFR mutations in lung cancer: correspondence 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. Some of the developed mutant-selective irreversible inhibitors are highly active against the T790M mutant, but their efficacy may be compromised by acquired mutations such as C797S, a cysteine residue that forms the key covalent bond (Thress, K. S. 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)). The C797S mutation was further reported by Wang to be a major 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 that cause 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 (Targeting EGFR L858R / T790M and EGFR L858R / T790M / C797S resistance mutations in NSCLC: Current developments in medicinal chemistry, Med Res Rev 2018; 1 - 32) have reported on EGFR L858R / T790M and EGFR L858R / T790M / C797SThis report presents a review article on targeting resistance mutations.

[0006] Since the most readily available EGFR tyrosine kinase inhibitors target the ATP site of the kinase, there is a need for new therapeutic agents that work in different ways, such as targeting drug-resistant EGFR variants.

[0007] Recent studies suggest that intentionally targeting allosteric sites may 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). [Overview of the Initiative]

[0008] Therefore, there is an unmet need for the creation of selective molecules that specifically inhibit EGFR variants, including T790M / L858R, T790M / L858R / C797S, L858R, and / or L858R / C797S, particularly those containing T790M and C797S, which are useful for the treatment and / or prophylactic measures of cancer.

[0009] The compounds of formula (I) described herein have improved EGFR potency and selectivity, as well as improved physicochemical properties, for EGFR variants including T790M / L858R, T790M / L858R / C779S, L858R and / or L858R / C797S, particularly for EGFR variants including T790M and C797S.

[0010] In this specification, the term “alkyl” means, alone or in combination, a linear or branched alkyl group having 1 to 8 carbon atoms, particularly a linear or branched alkyl group having 1 to 6 carbon atoms, and more specifically a linear or branched alkyl group having 1 to 4 carbon atoms. Examples of linear and branched C1-C8 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec.-butyl, isomer pentyl, isomer hexyl, isomer heptyl, and isomer octyl, particularly methyl, ethyl, propyl, butyl, and pentyl. Specific examples of “alkyl” are methyl, ethyl, propyl, isopropyl, and tert.-butyl. Methyl is a specific example of “alkyl” in the compound of formula (I).

[0011] The terms "alkoxy" or "alkyloxy," either alone or in combination, mean that the term "alkyl" refers to a group of the formula alkyl-O-, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy, having the meanings set forth above. Examples of exceptions to "alkoxy" are methoxy, ethoxy, and tert-butoxy.

[0012] The term "oxy," either alone or in combination, refers to an -O- group.

[0013] The term "halogen" or "halo" means, alone or in combination, fluorine, chlorine, bromine, or iodine, and in particular fluorine or chlorine. A specific "halogen" or "halo" is fluorine. The term "halo" means, in combination with another group, at least one halogen, in particular substituted with one to five halogens, in particular substituted with one to four halogens, i.e., substituted with one, two, three, or four halogens, of the group.

[0014] The term "haloalkyl" refers to an alkyl group that, alone or in combination, is substituted with at least one halogen, particularly substituted with 1 to 5 halogens, and especially substituted with 1 to 3 halogens. Specific examples of "haloalkyl" are difluoromethyl and trifluoromethyl.

[0015] The terms "hydroxyl" and "hydroxy," either alone or in combination, refer to the -OH group.

[0016] The term "carbonyl," either alone or in combination, refers to a -C(O)- group.

[0017] The term "amino," either alone or in combination, refers to a primary amino group (-NH2), a secondary amino group (-NH-), or a tertiary amino group (-N-).

[0018] The term "alkylamino" refers to an alkyl group bonded to an -NH- group, either alone or in combination. The term "dialkylamino" refers to two alkyl groups bonded to an -N- atom.

[0019] The term "sulfonyl," either alone or in combination, refers to the -SO2- group.

[0020] The term "heterocycloalkyl" refers to a monocyclic or bicyclic ring system consisting of 4 to 9 ring atoms, either alone or in combination, that contains 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. A bicyclic ring system consists of two rings that share one or two ring atoms in common. Examples of "heterocycloalkyl" rings include morpholinyl, piperidinyl, azetidinyl, and piperazinyl. A specific example of a "heterocycloalkyl" ring is piperidinyl.

[0021] The term "cycloalkyl" alone or in combination refers to a monovalent saturated cyclic hydrocarbon group having 3 to 8 ring carbon atoms. Examples of "cycloalkyl" groups include cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl, or cycloheptyl. A specific example of a "cycloalkyl" group is cyclopropyl.

[0022] The terms "piperidinyl" and "piperidyl" are interchangeable and, either alone or in combination, refer to a saturated monocycle containing five carbocyclic atoms and one nitrogen-cyclic atom.

[0023] The term "pharmaceutically acceptable salt" refers to a salt of a compound of formula (I) that retains the biological efficacy and properties of a free base or free acid, and is not biologically or otherwise undesirable. Salts are formed from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and 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 base or an organic base to a free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts that can be derived from organic bases include, but are not limited to, 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, and polyimine resins. Specific pharmaceutically acceptable salts of the compound of formula (I) are hydrochloride, formate, and trifluoroacetate.

[0024] 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, an appropriate protecting group (e.g., “Protectivegroups in Organic Chemistry” by TW Greene and PgM Wuts, 3) rd Protecting groups (as described in Ed., 1999, Wiley, New York) can be introduced before key steps in which methods well known in the art are applied. Such protecting groups can be removed in later steps of synthesis using standard methods described in the literature. Examples of protecting groups include tert-butoxycarbonyl (Boc), 9-fluorenylmethylcarbamate (Fmoc), 2-trimethylsilylethylcarbamate (Teoc), carbobenzyloxy (Cbz), and p-methoxybenzyloxycarbonyl (Moz).

[0025] The compound of formula (I) may contain several chiral centers and may exist as an optically pure enantiomer, a mixture of enantiomers such as a racemate, an optically pure diastereoisomer, a mixture of diastereoisomers, a diastereoisomer racemate, or a mixture of diastereoisomer racemates.

[0026] The term "chiral carbon atom" refers to a carbon atom having four different substituents. According to the Cahn-Ingold-Prelog rule, a chiral carbon atom can have either an "R" or "S" stereoconfiguration.

[0027] Therefore, the present invention relates particularly to the following: R 1 A compound according to the present invention, wherein the compound is hydrogen or fluorocarbon; R 1 A compound according to the present invention, wherein the compound is hydrogen; R 1 A compound according to the present invention, wherein the halogen is... R 1 A compound according to the present invention, wherein the compound is fluoro; R 2 and R2’ However, independently selected from hydrogen or methyl; or R 2 and R 2’ However, these compounds, together with the carbon atoms to which they are bonded, form a cycloalkyl group; R 2 and R 2’ However, independently selected from hydrogen or alkyl; or R 2 and R 2’ However, these compounds, together with the carbon atoms to which they are bonded, form a cyclopropyl compound according to the present invention; R 2 and R 2’ However, independently selected from hydrogen or methyl; or R 2 and R 2’ However, these compounds, together with the carbon atoms to which they are bonded, form a cyclopropyl compound according to the present invention; R 2 and R 2’ Both are alkyl at the same time; or R 2 and R 2’ However, these compounds, together with the carbon atoms to which they are bonded, form a cycloalkyl group; R 2 and R 2’ Both are methyl at the same time; or R 2 and R 2’ However, these compounds, together with the carbon atoms to which they are bonded, form a cyclopropyl compound according to the present invention; R 2 and R 2’ However, independently, a compound according to the present invention, selected from hydrogen or methyl; R 2 and R 2’ A compound according to the present invention, wherein both atoms are alkyl at the same time; R 2 and R 2’ A compound according to the present invention in which both are methyl at the same time; R 2 and R 2’ However, these compounds, together with the carbon atoms to which they are bonded, form a cycloalkyl group; R 2 and R 2’ However, these compounds, together with the carbon atoms to which they are bonded, form a cyclopropyl compound according to the present invention; R 3 A compound according to the present invention, wherein the compound is hydrogen or fluorocarbon; R 3 A compound according to the present invention, wherein the compound is hydrogen; R 3 A compound according to the present invention, wherein the halogen is... R 3 A compound according to the present invention, wherein the compound is fluoro; R 4 A compound according to the present invention, wherein the compound is methyl; R 5 The compound according to the present invention, wherein is a hydroxyalkyl(piperidinyl)alkyl compound; R 5 Compounds according to the present invention, wherein is hydroxymethyl(piperidinyl)methyl; and R 5 The compound according to the present invention, wherein is hydroxymethyl(heterocycloalkyl)methyl.

[0028] The present invention further includes the following: 2-[4-(difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide; 2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-[6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-4-(trifluoromethyl)indazol-2-yl]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-4-(trifluoromethyl)indazol-2-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-indazol-2-yl]-2-(5,5-dimethyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-indazol-2-yl]-2-(5-ethyl-5-methyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide; 2-(5-ethyl-5-methyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-2-[6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-4-(trifluoromethyl)indazol-2-yl]-N-thiazol-2-yl-acetamide; and 2-(5,5-dimethyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-2-[6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-4-(trifluoromethyl)indazol-2-yl]-N-thiazol-2-yl-acetamide; A compound selected from, or relating to the pharmaceutically acceptable salt thereof.

[0029] The present invention further includes the following: 2-[4-(difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-indazol-2-yl]-2-(5,5-dimethyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-indazol-2-yl]-2-(5-ethyl-5-methyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide; 2-(5-ethyl-5-methyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-2-[6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-4-(trifluoromethyl)indazol-2-yl]-N-thiazol-2-yl-acetamide; and 2-(5,5-dimethyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-2-[6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-4-(trifluoromethyl)indazol-2-yl]-N-thiazol-2-yl-acetamide; A compound selected from, or relating to the pharmaceutically acceptable salt thereof.

[0030] A particular embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound of formula (I) being 2-[4-(difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-indazol-2-yl]-2-(5,5-dimethyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide.

[0031] A particular embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound of formula (I) being 2-[4-(difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-indazol-2-yl]-2-(5-ethyl-5-methyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide.

[0032] A particular embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound of formula (I) being 2-(5-ethyl-5-methyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-2-[6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-4-(trifluoromethyl)indazol-2-yl]-N-thiazol-2-yl-acetamide.

[0033] A particular embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound of formula (I) being 2-(5,5-dimethyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-2-[6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-4-(trifluoromethyl)indazol-2-yl]-N-thiazol-2-yl-acetamide.

[0034] Methods for producing the compound of formula (I) described herein are also an object of the present invention.

[0035] The compounds of formula (I) of the present invention can be prepared by sequential or convergent synthetic routes. The synthesis of the compounds of the present invention is shown in the following Scheme 1 and description of specific examples. The skills required to carry out the reactions and the purification of the resulting products are known to those skilled in the art. The substituents and indicators used in the following description of the process have the significance set forth herein unless otherwise noted. The order of the reactions is not limited to that shown in Scheme 1, but the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivity. The starting materials are commercially available or can be prepared by methods similar to those shown below, by methods described in the references or examples cited herein, or by methods known in the art.

[0036] Scheme 1 In JPEG0007840327000002.jpg131170 scheme 1, R 1 , R 2 , R 3 , R 4 and R 5 This is defined herein.

[0037] The indazole of formula II can be alkylated with an alkylating agent such as ethyl bromoacetate or methyl bromoacetate in a solvent such as dimethylacetamide or acetonitrile at ambient temperature or a high temperature, in the presence or absence of a base such as triethylamine or cesium carbonate, to obtain the indazole of formula III. This compound can be deprotonated with a base such as LDA or LHMDS and treated with a proline derivative pre-activated by treatment with CDI or the like to obtain the compound of formula IV. This reaction can be carried out in a solvent such as THF at a temperature from -78°C to room temperature. The protecting group of compound IV can be cleaved by treatment with an acid such as HCl or TFA in dioxane, for example. Subsequently, treatment with potassium thiocyanate in a solvent such as EtOH at room temperature or a slightly elevated temperature yields the compound of formula V. Conversion to imidazole VI can be achieved by treatment with hydrogen peroxide in a solvent such as acetic acid, treatment with ranney nickel, or by other methods known in the art. By using well-known methods such as the Sonogashira reaction and other well-known synthetic methods for functional group transformation, acetylene-R 5 Compound VII can be obtained by introducing [the compound]. The conversion to the compound of formula (I) can be achieved by saponification with a base such as LiOH or NaOH in a solvent such as EtOH, THF, or water, followed by amide coupling with aminothiazole or its derivative using a coupling agent such as HATU. Alternatively, ester-amide conversion can be directly performed using aminothiazole and a reagent such as trimethylaluminum or isopropylmagnesium chloride.

[0038] The corresponding pharmaceutically acceptable salts of compounds of formula (I) with an acid can be obtained by standard methods known to those skilled in the art, for example, by dissolving the compound of formula I in a suitable solvent such as dioxane or tetrahydrofuran and adding an appropriate amount of the corresponding acid. The product can usually be isolated by filtration or chromatography. The conversion of compounds of formula I to their pharmaceutically acceptable salts by a base can be carried out by treating such compounds with such a base. One possible method for forming such salts is, for example, by adding 1 / n equivalents of a basic salt such as M(OH)n (where M = metal or ammonium cation and n = number of hydroxyl anions) to a solution containing the compound in a suitable solvent (e.g., ethanol, ethanol-water mixture, tetrahydrofuran-water mixture) and removing the solvent by evaporation or freeze-drying. Specific salts of compounds of formula (I) are hydrochloride, formate, and trifluoroacetate.

[0039] Unless otherwise described in the examples, the compounds of formula (I) and all intermediate products can be prepared by similar methods or by methods described herein.

[0040] It will be understood that the compound of general formula (I) in the present invention can be derivatized with a functional group to provide a derivative that can be converted back to the parent compound in vivo.

[0041] Therefore, the present invention also relates to a process for preparing a compound of formula (I), and a compound of formula (B1). JPEG0007840327000003.jpg43170 is a compound of formula (B2). The reaction involves reacting JPEG0007840327000004.jpg19170 with a base, a Pd(II) catalyst, and a Cu(I) source, where R 1 , R 2 , R 3 , R 4 , and R 5 The definition above is for a process where X is a halogen.

[0042] In the process described above, X is conveniently bromine.

[0043] In the process of the present invention, the base is, for example, piperidine, morpholine, diisopropylamine diethylamine, trimethylamine, cesium carbonate, or a mixture thereof. Conveniently, the base is trimethylamine.

[0044] In the process of the present invention, the catalyst may be, for example, bis-(triphenylphosphine)-palladium(II) dichloride.

[0045] The source of Cu(I) can be copper(I) iodide in particular.

[0046] The process of the present invention may, conveniently, be carried out in a solvent such as DMF, THF, diethylamine, trimethylamine, or a mixture thereof. Conveniently, the solvent is DMF.

[0047] Conditions favorable to the process of the present invention may be between about 20°C and 120°C, particularly between about 40°C and 110°C, and more specifically between about 60°C and 100°C. Conditions favorable to the process may be around 80°C.

[0048] Conditions favorable to the process of the present invention may be between about 0.25 hours and 20 hours, particularly between about 0.5 hours and 10 hours, and more specifically between about 1 hour and 5 hours. Conditions favorable to the process may be between about 1.5 hours and 2.5 hours.

[0049] The present invention also relates to compounds according to the present invention when produced according to the method of the present invention.

[0050] Another embodiment of the present invention provides a pharmaceutical composition or pharmaceutical containing the compound of the present invention and a therapeutically inert carrier, diluent, or excipient, as well as a method of using the compound of the present invention to prepare such compositions and pharmaceuticals. In one example, the compound of formula (I) may be formulated by mixing it with a physiologically acceptable carrier, i.e., a carrier that is not toxic to the recipient at doses and concentrations used in the dosage form of herbal medicine, at an appropriate pH and desired purity, at ambient temperature. The pH of the formulation depends mainly on the specific use and the 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 may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0051] The composition is formulated, taken, and administered in a manner consistent with appropriate medical practice. Factors to be considered in this regard include the specific disorder being treated, the specific mammal being treated, the individual patient's clinical condition, the cause of the disorder, the site of drug delivery, the method of administration, the administration schedule, and other factors known to the healthcare professional.

[0052] The compounds of the present invention may be administered by any suitable means, including orally, topically (including buccal and sublingual), rectally, vaginally, percutaneously, parenterally, subcutaneously, intraperitoneally, intrapulmonaryly, intradermally, intrathecally, and epidurally, as well as intranasally, and, if desired for local treatment, intra-lesional administration. Parenteral administration may include intramuscular, intravenous, intra-arterial, intraperitoneal, or subcutaneous administration.

[0053] The compounds of the present invention can be administered in any convenient dosage form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, and patches. Such compositions may contain elements common in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and further activators.

[0054] Typical formulations are prepared by mixing the compound of the present invention with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, 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, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, flow enhancers, processing aids, colorants, sweeteners, fragrances, flavorings, diluents, and other known additives to provide accurate presentation of a drug (i.e., the compound or pharmaceutical composition thereof of the present invention) or to assist in the manufacture of a pharmaceutical (i.e., a pharmaceutical).

[0055] Therefore, the present invention also relates in particular to the following: Compounds of formula (I) or pharmaceutically acceptable salts thereof for use as therapeutic active substances; A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a therapeutically inactive carrier; Compounds of formula (I) or pharmaceutically acceptable salts thereof for use in the treatment or prevention of cancer; Compounds of formula (I) or pharmaceutically acceptable salts thereof for use in the treatment or prevention of non-small cell lung cancer; The use of compounds of formula (I) or pharmaceutically acceptable salts thereof for the treatment or prevention of cancer, particularly non-small cell lung cancer; The use of compounds of formula (I) or pharmaceutically acceptable salts thereof for the preparation of medicines for the treatment or prevention of cancer, particularly non-small cell lung cancer; and A method for the treatment or prevention of cancer, particularly 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.

[0056] Specific embodiments of the present invention relate to a pharmaceutical composition comprising a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable auxiliary substance.

[0057] One embodiment of the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of cancer characterized by at least one EGFR mutation selected from T790M / L858R, T790M / L858R / C797S, L858R, and L858R / C797S, particularly non-small cell lung cancer.

[0058] One embodiment of the present invention relates to a method for the treatment or prevention of cancer, particularly non-small cell lung cancer, in which at least one EGFR mutation selected from T790M / L858R, T790M / L858R / C797S, L858R, and L858R / C797S is present in the cancer, comprising administering an effective amount of a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof to a patient in need.

[0059] Furthermore, the present invention includes, where applicable, all substituents of the corresponding deuterated form of the compound of formula (I).

[0060] Furthermore, the present invention includes, where applicable, all optical isomers of the compound of formula (I), namely diastereoisomers, diastereoisomer mixtures, racemic mixtures, all their corresponding enantiomers, and / or tautomers, as well as solvated compounds thereof.

[0061] Compounds of formula (I) may contain one or more chiral centers and thus may result in racemates, racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers. Depending on the nature of various substituents on the molecule, additional chiral centers may be present. Each of these chiral centers independently produces two optical isomers, and all possible optical isomers and diastereomers as mixtures and pure or partially purified compounds are intended to be included in the present invention. The present invention means that it encompasses all such isomeric forms of these compounds. The independent synthesis of these diastereomers or their chromatographic separation can be achieved as known in the art by appropriately modifying the methodologies disclosed herein. Their absolute stereochemistry can, if necessary, be determined by X-ray crystallography of crystalline products or crystalline intermediates derivatized with reagents containing chiral centers of known absolute configuration. If desired, racemic mixtures of the compounds can be separated to isolate the individual enantiomers. Separation can be carried out by methods known in the art, such as coupling a racemic mixture of compounds enantiomerically with pure compounds to form a diastereoisomer mixture, and then separating the individual diastereomers by standard methods such as fractional recrystallization or chromatography.

[0062] In embodiments where an optically pure enantiomer is provided, an optically pure enantiomer means that the compound contains more than 90% by weight of the desired isomer, more specifically more than 95% by weight of the desired isomer, or more specifically more than 99% by weight of the desired isomer, where the weight percentage is based on the total weight of the isomers of the compound. Chiralally pure or chiralally concentrated compounds can be prepared by chiral selective synthesis or by separation of enantiomers. Separation of enantiomers can be performed on the final product or on alternatively suitable intermediates.

[0063] Furthermore, one embodiment of the present invention is a compound of formula (I) described herein, when produced by any one of the steps described.

[0064] Compounds of formula (I) or pharmaceutically acceptable salts thereof can be used as pharmaceuticals (e.g., in the form of pharmaceutical preparations). Pharmaceutical formulations of the present invention can be administered orally (e.g., in the form of tablets, coated tablets, sugar-coated tablets, hard and soft gelatin capsules, solutions, emulsions, or suspensions), intranasally (e.g., in the form of nasal sprays), rectally (e.g., in the form of suppositories), or topically (e.g., in the form of solutions, ointments, gels, or water-soluble polymer inserts). However, administration can also be carried out parenterally, such as intramuscularly, intravenously, or intraocularly (e.g., in the form of sterile injection solutions).

[0065] Compounds of formula (I) or pharmaceutically acceptable salts thereof may be treated with pharmaceutically inert inorganic or organic adjuvants for the manufacture of tablets, coated tablets, sugar-coated tablets, hard gelatin capsules, injections, or topical formulations. Lactose, corn starch or derivatives thereof, talc, stearic acid or their corresponding salts, etc., can be used as adjuvants for tablets, sugar-coated tablets, and hard gelatin capsules, for example.

[0066] Suitable adjuvants for soft gelatin capsules include, for example, vegetable oils, waxes, fats and oils, semi-solid substances, and liquid polyols.

[0067] Suitable adjuvants for the manufacture of liquid and syrup formulations include, for example, water, polyols, sucrose, invert sugar, and glucose.

[0068] Suitable adjuvants for injection solutions include, for example, water, alcohol, polyol, glycerol, and vegetable oil.

[0069] Suitable adjuvants for suppositories include, for example, natural oils or hydrogenated oils, waxes, fats, semi-solids, or liquid polyols.

[0070] Suitable adjuvants for topical ophthalmic formulations include, for example, cyclodextrin, mannitol, or many other carriers and excipients known in the art.

[0071] Furthermore, pharmaceutical preparations may contain preservatives, solubilizers, viscosity enhancers, stabilizers, humectants, emulsifiers, sweeteners, colorants, flavorings, salts to alter osmotic pressure, buffers, masking agents, or antioxidants. They may also contain other therapeutically useful substances.

[0072] Dosages can be varied widely to suit the individual requirements of each specific case. Generally, for oral administration, the daily dose is approximately 0.1 mg to 20 mg per kg of body weight, preferably approximately 0.5 mg to 4 mg per kg of body weight (for example, approximately 300 mg per person), preferably administered individually in 1 to 3 divided doses, which, if appropriate, can be composed of equal amounts, for example. For topical administration, the formulation may contain 0.001% to 15% by weight of the drug and the required amount between 0.1 mg and 25 mg.

[0073] Preparations containing the compound of formula (I) may be administered as a single dose per day, a single dose per week, multiple doses per day (2 to 4 times), or multiple doses per week. However, if this is indicated, it is clear that the upper or lower limits stated herein may be exceeded.

[0074] Pharmaceutical composition Compounds of formula (I) or pharmaceutically acceptable salts thereof can be used as therapeutic 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, sugar-coated tablets, hard gelatin capsules and soft gelatin capsules, solutions, emulsions, or suspensions. However, administration may also be carried out rectally, for example, in the form of suppositories, or parenterally, for example, in the form of injections.

[0075] Compounds of formula (I) or pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert inorganic or organic carriers for the manufacture of pharmaceutical formulations. Lactose, corn starch or its derivatives, talc, stearic acid, or their salts, for example, can be used as carriers for tablets, coated tablets, sugar-coated tablets, and hard gelatin capsules. Suitable carriers for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solids, and liquid polyols. However, depending on the properties of the active substance, a carrier is usually not required for soft gelatin capsules. Suitable carrier materials for the manufacture of solutions and syrups include, for example, water, polyols, glycerol, and vegetable oils. Suitable carriers for suppositories include, for example, natural oils or hydrogenated oils, waxes, fats and oils, semi-liquids, or liquid polyols.

[0076] Furthermore, pharmaceutical preparations may contain pharmaceutically acceptable auxiliary substances such as preservatives, solubilizers, stabilizers, humectants, emulsifiers, sweeteners, colorants, flavorings, salts, buffers, masking agents, or antioxidants to alter osmotic pressure. Pharmaceutical preparations may also contain other substances of further therapeutic value.

[0077] A pharmaceutical product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutic inert carrier is also provided by the present invention, the method of which comprises preparing the compound of formula (I) and / or a pharmaceutically acceptable salt thereof and, optionally, one or more other therapeutically valuable substances together with one or more therapeutic inert carriers in a herbal administration form.

[0078] Dosage can vary widely and must be adjusted to the individual requirements of each specific case. For oral administration, adult doses can range from approximately 0.01 mg to approximately 1000 mg per day of the corresponding amount of the compound of general formula (I) or a pharmaceutically acceptable salt thereof. The daily dose may be administered as a single dose or in divided doses, and may exceed the upper limit if an upper limit is recognized.

[0079] The following examples illustrate the present invention without limiting it, but are merely representative examples. The pharmaceutical preparations conveniently contain about 1 to 500 mg, particularly 1 to 100 mg, of the compound of formula (I). Examples of compositions according to the present invention are as follows.

[0080] Example A Tablets with the following composition are manufactured by the usual method: JPEG0007840327000005.jpg55170 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 an appropriate grinding device. 4. Add ingredient 5, mix for 3 minutes, and compress using a suitable press.

[0081] Example B-1 To manufacture capsules with the following composition: JPEG0007840327000006.jpg55170 Manufacturing Procedure 1. Mix ingredients 1, 2, and 3 in a suitable blender for 30 minutes. 2. Add ingredients 4 and 5 and mix for 3 minutes. 3. Fill into appropriate capsules.

[0082] The compound of formula (I), lactose, and corn starch are first mixed in a mixer, and then in a grinder. The mixture is returned to the mixer, and talc is added and mixed thoroughly. The mixture is then filled into suitable capsules, such as hard gelatin capsules, by machine.

[0083] Example B-2 To manufacture soft gelatin capsules with the following composition: JPEG0007840327000007.jpg49170JPEG0007840327000008.jpg49170

[0084] Manufacturing procedure The compound of formula (I) is dissolved in the warm melt of the other components, and the mixture is filled into soft gelatin capsules of the appropriate size. The filled soft gelatin capsules are processed according to the usual procedure.

[0085] Example C Prepare suppositories with the following composition: JPEG0007840327000009.jpg29170

[0086] Manufacturing procedure Dissolve the suppository paste in a glass or steel container, mix thoroughly, and cool to 45°C. Add the finely powdered compound of formula (I) and stir until completely dispersed. Pour the mixture into suppository molds of appropriate size, let cool, then remove the suppositories from the molds and individually wrap them in wax paper or metal foil.

[0087] Example D Prepare an injectable solution with the following composition: JPEG0007840327000010.jpg33170

[0088] Manufacturing procedure The compound of formula (I) is dissolved in a mixture of polyethylene glycol 400 and some water for injection. The pH is adjusted to 5.0 with acetic acid. The remaining water is added to adjust the volume to 1.0 ml. The solution is filtered, filled into vials using an appropriate excess volume, and sterilized.

[0089] Example E Prepare a sachet with the following composition: JPEG0007840327000011.jpg59170

[0090] Manufacturing procedure The compound of formula (I) is mixed with lactose, microcrystalline cellulose, and sodium carboxymethylcellulose, and granulated with a mixture of polyvinylpyrrolidone in water. Magnesium stearate and flavoring additives are mixed into the granules and filled into sachets. [Examples]

[0091] Abbreviation AcOH = acetic acid; ATP = adenosine triphosphate; CAS = chemical information retrieval service; CDI = 1,1'-carbonyldiimidazole; DCM = dichloromethane; DME = dimethoxyethane; DMF = ditylformamide; DMSO = dimethyl sulfoxide; Depositphotos = ethyl acetate; EtOH = ethanol; HATU = hexafluorophosphate azabenzotriazole tetramethyluronium; LDA = lithium diisopropylamide; MeOH = methanol; MS = mass spectrometry; NMR = nuclear magnetic resonance; rt = room temperature; THF = tetrahydrofuran.

[0092] The following embodiments are provided for illustrative purposes of the present invention. They should not be considered limiting to the scope of the invention, but rather should be understood as representative examples.

[0093] Example 1 2-[4-(difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide JPEG0007840327000012.jpg37170

[0094] Step 1: 1-Bromo-5-(difluoromethyl)-3-fluoro-2-methylbenzene A solution of 3-bromo-5-fluoro-4-methylbenzaldehyde (CAS 1370411-47-4, 20.5 g, 89.7 mmol, Eq: 1.0) in a DCM (98 mL) was cooled in an ice bath. Morphorinosulfur trifluoride (CAS 51010-74-3, 24.8 g, 17.3 mL, 135 mmol, Eq: 1.5) was added in several portions. The reaction mixture was stirred at 0-5°C for 20 minutes, then stirred at rt for 16 hours. While cooling on ice, an aqueous solution of NaHCO3 (300 mL) was carefully added. The reaction mixture was stirred at rt for 1 hour. The reaction mixture was poured into a DCM and washed with water. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude substance was purified by flash chromatography (silica gel, 120 g, 100% pentane) to obtain the title compound as a colorless oil (18.6 g, 87% yield). 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)

[0095] Step 2: 6-bromo-4-(difluoromethyl)-7-methyl-1H-indazole JPEG0007840327000014.jpg291701-Bromo-5-(difluoromethyl)-3-fluoro-2-methylbenzene (Example 1, Step 1) (26.4g, 110 mmol, Eq:1.0) was added to a solution in THF (240 mL) and cooled to -75°C. LDA (2M in THF / heptane / ethylbenzene, 66.3 mL, 133 mmol, Eq:1.2) was added dropwise at below -70°C. The reaction mixture was stirred at -75°C for 30 minutes. Ethyl formate (16.4g, 17.7 mL, 220 mmol, Eq:2.0) was added at -70°C. The reaction mixture was stirred at -75°C for 30 minutes. AcOH (16.6g, 15.8 mL, 277 mmol, Eq:2.5) was added at below -55°C. The reaction mixture was heated in rt, poured into siRNA, and washed with diluted aqueous HCl, water, and brine. The organic layer was dried over Na2SO4 and concentrated under vacuum to obtain the presumed 4-bromo-6-(difluoromethyl)-2-fluoro-3-methylbenzaldehyde as a yellow oil (29.5 g), which was used without further purification.

[0096] Crude 4-bromo-6-(difluoromethyl)-2-fluoro-3-methylbenzaldehyde (29.5 g) was dissolved in DME (150 mL). O-methylhydroxylamine hydrochloride (10.2 g, 122 mmol, Eq: 1.84) and K2CO3 (30.6 g, 221 mmol, Eq: 3.34) were added. The reaction mixture was stirred at 45°C for 2.5 hours, then filtered through sintered glass and washed with DME (2 ×). The filtrate was concentrated under vacuum. The oxime ether intermediate was dissolved in DMSO (150 mL). Hydrazine hydrate (83 g, 80.5 mL, 1.66 mol, Eq: 25) was added. The reaction mixture was stirred at 110°C for 3 hours. The reaction mixture was poured into HCl / THF 5:1 and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude substance was purified by flash chromatography (silica gel, 2 × 120 g, heptane with 0% to 30% RINKAN) to obtain the title compound as a white solid (13.5 g, 74% yield). m / z 258.9, 260.8 [M+H] +, ESI pos, Br isotopes.

[0097] Step 3: Ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]acetate JPEG0007840327000015.jpg291706-bromo-4-(difluoromethyl)-7-methyl-1H-indazole (Example 1, Step 2) (19 g, 72.8 mmol, Eq: 1.0) was added to a solution in DMF (75 mL) with ethyl 2-bromoacetate (18.2 g, 12.2 mL, 109 mmol, Eq: 1.5). The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was poured over siRNA and washed with water and brine. The organic layer was dried over Na₂SO₄ and concentrated under vacuum. The crude product was purified by flash chromatography (silica gel, 2 × 120 g, 0%~20% siRNA in heptane) to obtain the title compound as a yellow solid (21.2 g, 80% yield). m / z 346.9, 348.8, [M+H] + , ESI pos, Br isotopes.

[0098] Step 4: tert-butyl (2S,4R)-2-[2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-3-ethoxy-3-oxo-propanoyl]-4-fluoropyrrolidine-1-carboxylate Preparation of tert-butyl (2S,4R)-4-fluoro-2-(imidazole-1-carbonyl)pyrrolidine-1-carboxylate: JPEG0007840327000017.jpg34170 A solution of (2S,4R)-1-tert-butoxycarbonyl-4-fluoropyrrolidine-2-carboxylic acid (CAS 203866-14-2, 30 g, 129 mmol, Eq: 1.0) in a 300 mL DCM container was to which 1,1'-carbonyldiimidazole (25 g, 154 mmol, Eq: 1.2) was added in several portions at 0°C. The reaction mixture was stirred in rt for 3 hours. The reaction mixture was washed with water (3 ×) and 1 M NaHCO3 aqueous solution (1 ×). The organic layer was dried over Na2SO4 and concentrated under vacuum at 30°C to obtain tert-butyl (2S,4R)-4-fluoro-2-(imidazole-1-carbonyl)pyrrolidine-1-carboxylate (36.6 g, 129 mmol, 100% yield) as a white solid, which was stored at -20°C before use. 1 H NMR (chloroform-d, 300 MHz) δ 8.27 (s, 1H), 7.56 (br d, 1H, J=1.4 Hz), 7.15 (br d, 1H, J=12.1 Hz), 4.9-5.2 (m, 1H), 3.6-4.1 (m, 2H), 2.0-2.9 (m, 2H), 1.2-1.5 (m, 9H).

[0099] KO tBu (4.53 g, 40.3 mmol, Eq: 2.0) was dissolved in THF (18 mL). The reaction mixture was cooled to -55°C. 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]ethyl acetate (Example 1, Step 3) (7 g, 20.2 mmol, Eq: 1.0) was added dropwise to THF (24 mL) at a temperature below -50°C. The reaction mixture was stirred between -50°C and -55°C for 1 hour. The previously prepared tert-butyl(2S,4R)-4-fluoro-2-(imidazole-1-carbonyl)pyrrolidine-1-carboxylate (6.85 g, 24.2 mmol, Eq: 1.2) was added dropwise to THF (50 mL) at a temperature below -50°C. The reaction mixture was stirred at -50°C for 15 minutes, and then warmed to -30°C. 10% aqueous citric acid (60 mL) was added at below -20°C, and the mixture was stirred at 0°C for 1 hour. The reaction mixture was poured onto toluene and washed with water and brine. The organic layer was dried over Na₂SO₄ and concentrated under vacuum at 30°C to obtain the title compound as a yellow amorphous semi-solid (12.9 g, 20.2 mmol, 88% purity, 100% yield). m / z 562.1, 563.9 [M+H] + , ESI pos, Br isotopes.

[0100] Step 5: Ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-3-thioxo-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl]acetate JPEG0007840327000018.jpg34170 A solution of tert-butyl(2S,4R)-2-[2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-3-ethoxy-3-oxo-propanoyl]-4-fluoropyrrolidine-1-carboxylate (Example 1, Step 4) (12.9 g, 20.2 mmol, Eq: 1.0) in ethanol (24 mL) was mixed with HCl (1.25 M in ethanol, 80.6 mL, 101 mmol, Eq: 5.0). The reaction mixture was stirred at 55°C for 1 hour. The reaction mixture was cooled to rt, and then water (6 mL) and potassium thiocyanate (2.55 g, 26.2 mmol, Eq: 1.3) were added. The reaction mixture was stirred to rt for 30 minutes. Ethanol was removed under vacuum at 30°C, and pyridine (23.9 g, 24.5 mL, 302 mmol, Eq: 15) was added. The reaction mixture was stirred in rt for 75 minutes. The reaction mixture was poured into RINKAN and washed with 2N aqueous HCl (until the aqueous phase reached pH 1), water, and brine. The organic layer was dried over Na2SO4 and concentrated under vacuum to obtain the title compound as a yellow semi-solid (9.65 g, 60% purity, 57% yield). m / z 502.9, 505.9 [M+H] + , ESI pos, Br isotopes.

[0101] Step 6: Ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate To a suspension of p-toluenesulfonic acid monohydrate (10.9 g, 57.5 mmol, Eq: 5.0) in acetonitrile (70 mL), hydrogen peroxide (35% aq., 8.38 g, 7.42 mL, 86.3 mmol, Eq: 7.5) was added dropwise at 0-3°C to obtain a colorless solution. After 10 minutes, ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-3-thioxo-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl]acetate (Example 1, Step 5) (9.65 g, 11.5 mmol, Eq: 1.0) was added dropwise to acetonitrile (28 mL) at a temperature below 8°C. The reaction mixture was stirred at 0°C for 1.5 hours. The reaction mixture was poured into ethyl acetate and washed with Na2CO3 solution and brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude substance was purified by flash chromatography (silica gel, 120 g, 0%~60% (HCl / EtOH / aq. NH375:25:2 in heptane)) to obtain the title compound as a yellow foam (3.96 g, 73% yield). m / z 469.1, 471.1 [M+H] + ESI pos.

[0102] Step 7: 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide Ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (Example 1, Step 6) (200 mg, 0.424 mmol) was dissolved in 2 ml of methanol and 2 ml of THF. LiOH (1 M in water) (0.4 ml, 0.424 mmol, Eq: 1.0) was added at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness under vacuum, and the residue was dissolved in 2 ml of DMF. Thiazol-2-amine (42 g, 0.424 mmol, Eg: 1.0), Hünig base (0.37 ml, 2.12 mmol, Eq: 5.0), and HATU (194 mg, 0.509 mmol, Eq: 1.2) were added at room temperature. The mixture was stirred at room temperature for 90 minutes. The reaction mixture was extracted with water and then extracted twice with ethyl acetate. The organic layer was extracted with water, dried over sodium sulfate, and concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with a dichloromethane:methanol gradient of 100:0 to 90:10 to obtain the desired product (115 mg, yield 49%) as a bright yellow solid (MS: m / e = 527.1 (M+H) + ))

[0103] Step 8: [1-[(4-ethynylphenyl)methyl]-4-piperidyl]methanol JPEG0007840327000021.jpg211704-Ethynylbenzaldehyde (20.5 g, 157.5 mmol) was dissolved in 525 ml of dichloromethane. Piperidine-4-ylmethanol (20 g, 173.2 mmol, Eq: 1.1) and sodium triacetoxyborohydride (53.4 g, 252.0 mmol, Eq: 1.6) were added at room temperature. The mixture was stirred at room temperature for 4 hours. The reaction mixture was extracted with 1 M sodium carbonate solution and extracted twice with water using dichloromethane. The organic layer was dried over sodium sulfate and concentrated to dryness to obtain the desired product (34.8 g, 91% yield) as a bright yellow solid. MS: m / e = 527.1 (M+H + ).

[0104] Step 9: [1-[(4-ethynylphenyl)methyl]-4-piperidyl]methanol hydrochloride [1-[(4-ethynylphenyl)methyl]-4-piperidyl]methanol (Example 1, Step 8) (34.8g) was dissolved in 200 ml of tetrahydrofuran. 4M hydrogen chloride solution in 1,4-dioxane (39.4 ml, 158 mmol, Eq: 1.0) was added dropwise at 10-20°C. A white precipitate formed, and the mixture was stirred for 2 hours. The precipitate was collected by filtration, washed three times with 50 ml of tetrahydrofuran, and dried under vacuum to obtain the title compound (38.6 g, 92%) as a white solid. MS: m / e = 527.1(M+H + ).

[0105] Step 10: 2-[4-(difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide JPEG0007840327000023.jpg391702-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide (Example 1, Step 7) (100 mg, 0.19 mmol) and [1-[(4-ethynylphenyl)methyl]-4-piperidyl]methanol hydrochloride (Example 1, Step 9) (76 mg, 0.286 mmol, Eq: 1.5) were dissolved in 5 ml of DMF. Triethylamine (0.1 ml, 0.76 mmol, Eq: 4.0), bis-(triphenylphosphine)-palladium(II) dichloride (7 mg, 0.01 mmol, Eq: 0.05), triphenylphosphine (5 mg, 0.019 mmol, Eq: 0.1), and copper(I) iodide (2 mg, 0.01 mmol, Eq: 0.05) were added, and the mixture was stirred at 80°C for 2 hours. The reaction mixture was extracted with water and then extracted three times with dichloromethane. The organic layer was dried over sodium sulfate and concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column with a dichloromethane:methanol:ethanol gradient of 100:0 to 75:25 to obtain the desired product (7 mg, yield 5%) as a bright yellow oil (MS: m / e = 674.5 (M+H)). + ))

[0106] Example 2 2-[4-(difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide JPEG0007840327000024.jpg34170

[0107] Step 1: tert-butyl (2R)-2-[2-[6-bromo-4-(difluoromethyl)-7-methylindazol-2-yl]-3-ethoxy-3-oxopropanoyl]pyrrolidine-1-carboxylate Ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]acetate, prepared as described in step 3 (0.65 g, 1.87 mmol, Eq: 1.0) of intermediate 1, was dissolved in THF (7.58 mL) and cooled to -75°C. LDA (2 M in THF, 1.12 mL, 2.25 mmol, Eq: 1.20) was added dropwise within 5 minutes. The reaction mixture was stirred at -75°C for 40 minutes. A solution of tert-butyl (2S)-2-(imidazole-1-carbonyl)pyrrolidine-1-carboxylate (prepared from (2S)-1-tert-butoxycarbonyl-4-fluoropyrrolidine-2-carboxylic acid, as in step 4 of intermediate 1) (0.77 g, 2.9 mmol, Eq: 1.55) in THF (7.58 mL) was slowly added at -75°C, stirred at -75°C for 30 minutes, then warmed to rt and stirred at rt for 18 hours. After the addition of saturated NH4Cl solution, the reaction mixture was extracted twice with ELISA. The organic layer was washed with water. The combined organic layers were dried over Na2SO4 and concentrated under vacuum to obtain the title compound (1.41 g, 72% purity, 99% yield), which was used in the next step without further purification. m / z 544.1, 546.0 [M+H ]+ , ESI pos.Br isotopes.

[0108] Step 2: Ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-(3-thioxo-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl)acetate JPEG0007840327000026.jpg35170 Similar to step 5 of Example 1, tert-butyl (2R)-2-[2-[6-bromo-4-(difluoromethyl)-7-methylindazol-2-yl]-3-ethoxy-3-oxopropanoyl]pyrrolidine-1-carboxylate (1.4 g, 72% purity, 1.85 mmol) was treated with 4 M HCl in dioxane and potassium thiocyanate to obtain the title compound as a brown oil (1.07 g, 85% purity, 100% yield), which was used in the next step without further purification. m / z 485.0, 486.9 [M+H] + , ESI pos, Br isotopes.

[0109] Step 3: Ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate JPEG0007840327000027.jpg28170 Similar to step 6 of Example 1, ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-(3-thioxo-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl) acetate (1.06 g, 85% purity, 1.86 mmol) was treated with hydrogen peroxide and p-toluenesulfonic acid monohydrate to obtain the title compound as a yellow foam (360 mg, 43% yield). m / z 453.0, 454.9 [M+H] + , ESI pos, Br isotopes.

[0110] Step 4: 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide Starting with ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl) acetate (Example 2, Step 3) and thiazol-2-amine, the title compound was obtained as a bright yellow foam using the same chemistry as described in Step 7 of Example 1. MS: m / e = 509.1 / 511.1 (M+H + )

[0111] Step 5: 2-[4-(difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide Starting from JPEG0007840327000029.jpg361702-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl acetamide (Example 2, step 4) and [1-[(4-ethynylphenyl)methyl]-4-piperidyl]methanol hydrochloride (Example 1, step 9), the title compound was obtained as a brown solid using the same chemistry as described in step 10 of Example 1. MS: m / e = 656.5 (M+H + ).

[0112] Example 3 2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-[6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-4-(trifluoromethyl)indazol-2-yl]-N-thiazol-2-yl-acetamide JPEG0007840327000030.jpg39170

[0113] Step 1: 1-Bromo-3-fluoro-2-methyl-5-(trifluoromethyl)benzene JPEG0007840327000031.jpg331701-Bromo-3-fluoro-5-(trifluoromethyl)benzene (12.7g) was dissolved in tetrahydrofuran (60ml) and cooled to -75°C. LDA (2.1 mol / l in THF (27.4ml)) was added dropwise. After stirring at -75°C for 30 minutes, iodomethane (8.16g) was added dropwise. The mixture was warmed to room temperature overnight. After the addition of semi-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 remaining brown liquid (15.42g) was subjected to valve-to-valve distillation at approximately 10 mbar and an oven temperature of 60-80°C to obtain the title compound containing 8 mol% ethylbenzene as a colorless liquid (11.91g).

[0114] 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 treatment with N,N-dimethylformamide. Following the same procedure as in the synthesis of 4-bromo-3,6-dichloro-2-fluorobenzaldehyde, the crude title compound was obtained as a brown liquid.

[0115] Step 3: 6-bromo-7-methyl-4-(trifluoromethyl)-1H-indazole Similar 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 an excess of hydrazine hydrate to obtain the title compound as a bright yellow solid. MS: m / e = 278.9 ([M + H] + ,Br)

[0116] Step 4: Ethyl 2-(6-bromo-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)acetate Starting with 6-bromo-7-methyl-4-(trifluoromethyl)-1H-indazole (Example 3, Step 3), the title compound was obtained as a bright yellow solid using the same chemistry as described in Step 3 of Example 1. MS: m / e = 365.1 / 367.1 (M+H + ).

[0117] Step 5: tert-butyl (2S,4R)-2-(2-(6-bromo-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-3-ethoxy-3-oxopropanoyl)-4-fluoropyrrolidine-1-carboxylate JPEG0007840327000035.jpg39170 Similar to step 4 of Example 1, (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid was treated with carbonyldiimidazole to obtain solution A. Ethyl 2-(6-bromo-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)acetate was deprotonated with LDA and treated with solution A at -78°C. After stirring overnight at room temperature and investigating similarly to step 4 of Example 1, the crude title compound was obtained and used in the next step without further purification. MS: m / e = 578.4 ([MH] - )

[0118] Step 6: Ethyl 2-(6-bromo-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl) acetate JPEG0007840327000036.jpg32170 Similar to step 5 of Example 1, tert-butyl (2S,4R)-2-(2-(6-bromo-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-3-ethoxy-3-oxopropanoyl)-4-fluoropyrrolidine-1-carboxylate was deprotected using HCl in dioxane, followed by reaction with potassium thiocyanate to obtain the crude title compound, which was used in the next step without further purification. MS: m / e = 519.3 ([MH] - )

[0119] Step 6: Ethyl 2-(6-bromo-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate JPEG0007840327000037.jpg31170 Similar to step 6 of Example 1, ethyl 2-(6-bromo-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl) acetate was treated with hydrogen peroxide in AcOH to obtain the title compound as a brown solid. MS: m / e = 489.3 ([M+H] + )

[0120] Step 7: 2-[6-bromo-7-methyl-4-(trifluoromethyl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide JPEG0007840327000038.jpg 36170 Ethyl 2-(6-bromo-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (Example 3, Step 6) and thiazol-2-amine were used as starting materials, and the title compound was obtained as a white solid using the same chemistry as described in Step 7 of Example 1. MS: m / e = 543.1 / 545.1 (M+H + ).

[0121] Step 8: 2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-[6-[2-(4-formylphenyl)ethynyl]-7-methyl-4-(trifluoromethyl)indazol-2-yl]-N-thiazol-2-yl-acetamide JPEG0007840327000039.jpg 38170 2-[6-bromo-7-methyl-4-(trifluoromethyl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide (Example 3, Step ⑦) and 4-ethynylbenzaldehyde were used as starting materials, and the title compound was obtained as a white solid using the same chemistry as described in Step 10 of Example 1. MS: m / e = 593.4 (M+H + ).

[0122] Step 9: 2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-[6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-4-(trifluoromethyl)indazol-2-yl]-N-thiazol-2-yl-acetamide JPEG0007840327000040.jpg 37170 2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-[6-[2-(4-formylphenyl)ethynyl]-7-methyl-4-(trifluoromethyl)indazol-2-yl]-N-thiazol-2-yl-acetamide (Example 3, Step 8) and piperidin-4-ylmethanol were used as starting materials, and the title compound was obtained as a white solid using the same chemistry as described in Step 8 of Example 1. MS: m / e = 690.6 (M+H + ).

[0123] Example 4 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-4-(trifluoromethyl)indazol-2-yl]-N-thiazol-2-yl-acetamide JPEG0007840327000041.jpg39170

[0124] Step 1: tert-butyl (2R)-2-(2-(6-bromo-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate JPEG0007840327000042.jpg38170 (tert-butoxycarbonyl)-L-proline (2.38 g) was dissolved in THF (15 ml) under argon and cooled to 0°C. CDI (1.79 g) was added. The temperature was raised to room temperature and the mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate and washed with water, sodium bicarbonate solution, and brine. The organic layers were combined, dried over sodium sulfate, concentrated, and dried. Ethyl 2-(6-bromo-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)acetate (Example 3, Step 4) (2.6 g) was dissolved in THF (15 ml) and cooled to -76°C. LDA (2 M, 4.45 ml) was added dropwise at -76°C. The reaction mixture was stirred at -76°C for 40 minutes. Subsequently, the activated amide solution prepared above was added dropwise to THF (15 ml) at -75°C. The mixture was stirred at -75°C for 30 minutes, then slowly warmed to rt and stirred at rt for 5 hours. The reaction mixture was quenched with saturated NH4Cl solution and then extracted with ethyl acetate. The aqueous layer was back-extracted with ethyl acetate. The organic layers were washed with brine. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under vacuum to obtain the crude title compound (6 g, purity approximately 68%), which was used in the next step without further purification. MS: m / e = 564.1 ([M + H] + )

[0125] Step 2: Ethyl 2-(6-bromo-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate JPEG0007840327000043.jpg32170 Similar to steps 5 and 6 of Example 1, tert-butyl (2R)-2-(2-(6-bromo-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate was deprotected using HCl in dioxane, followed by reaction with potassium thiocyanate, and then with hydrogen peroxide in AcOH to obtain the title compound as a bright yellow solid. MS: m / e = 471.2 ([M+H]+)

[0126] Step 3: 2-[6-bromo-7-methyl-4-(trifluoromethyl)indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide Starting with ethyl 2-(6-bromo-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl) acetate (Example 4, Step 2) and thiazol-2-amine, the title compound was obtained as a bright yellow foam using the same chemistry as described in Step 7 of Example 1. MS: m / e = 525.1 / 527.1 (M+H + ).

[0127] Step 4: 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-4-(trifluoromethyl)indazol-2-yl]-N-thiazol-2-yl-acetamide Starting from JPEG0007840327000045.jpg391702-[6-bromo-7-methyl-4-(trifluoromethyl)indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl acetamide (Example 4, step 3) and [1-[(4-ethynylphenyl)methyl]-4-piperidyl]methanol hydrochloride (Example 1, step 9), the title compound was obtained as a bright yellow solid using the same chemistry as described in step 10 of Example 1. MS: m / e = 674.4 (M+H + ).

[0128] Example 5 2-[4-(difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-indazol-2-yl]-2-(5,5-dimethyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide JPEG0007840327000046.jpg40170

[0129] Step 1: (5S)-5-[2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-3-ethoxy-3-keto-propanoyl]-2,2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester JPEG0007840327000047.jpg37170 Similar to step 4 of Example 1, (2S)-1-tert-butoxycarbonyl-5,5-dimethyl-proline was treated with carbonyldiimidazole to obtain solution A. 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]ethyl acetate was deprotonated with LDA and treated with solution A at -78°C. After stirring overnight at room temperature and scrutinizing as in step 4 of Example 1, the crude title compound was obtained as a white foam and used in the next step without further purification. MS: m / e = 572.3 ([M+H] + )

[0130] Step 2: 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-(5,5-dimethyl-6,7-dihydropyrrole[1,2-c]imidazol-1-yl) acetate ethyl ester JPEG0007840327000048.jpg31170 Similar to step 5 of Example 1, (5S)-5-[2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-3-ethoxy-3-keto-propanoyl]-2,2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester was deprotected with HCl in dioxane, and subsequently reacted with potassium thiocyanate to obtain a crude intermediate, which was used in the next step without further purification.

[0131] Similar to step 6 of Example 1, the intermediate was treated with hydrogen peroxide in AcOH to obtain the title compound as a colorless oil. MS: m / e = 489.3 ([M + H] + )

[0132] Step 3: 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-(5,5-dimethyl-6,7-dihydropyrrole[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide JPEG0007840327000049.jpg361702 - Ethyl [6-bromo-4-(difluoromethyl)-7-methyl-1H-indazol-2-yl]-2-(5,5-dimethyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)acetate (Example 5, Step 2) and thiazol-2-amine were used as starting materials, and the same chemistry as described in Step 7 of Example 1 was employed to obtain the title compound as a light yellow foam. MS: m / e = 537.2 (M+H + ).

[0133] Step 4: 2-[4-(difluoromethyl)-6-[2-(4-formylphenyl)ethynyl]-7-methyl-indazol-2-yl]-2-(5,5-dimethyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide JPEG0007840327000050.jpg361702 - [6-Bromo-4-(difluoromethyl)-7-methyl-1H-indazol-2-yl]-2-(5,5-dimethyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide (Example 5, Step 3) and 4-ethynylbenzaldehyde were used as starting materials, and the same chemistry as described in Step 10 of Example 1 was employed to obtain the title compound as a dark brown foam. MS: m / e = 585.4 (M+H + ).

[0134] Step 5: 2-[4-(difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-indazol-2-yl]-2-(5,5-dimethyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide JPEG0007840327000051.jpg381702 - [4-(Difluoromethyl)-6-[2-(4-formylphenyl)ethynyl]-7-methyl-1H-indazol-2-yl]-2-(5,5-dimethyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide (Example 5, Step 4) and piperidin-4-ylmethanol were used as starting materials, and the same chemistry as described in Step 8 of Example 1 was employed to obtain the title compound as a light yellow solid. MS: m / e = 684.7 (M+H + ).

[0135] Example 6 2-[4-(difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-indazol-2-yl]-2-(5-ethyl-5-methyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide JPEG0007840327000052.jpg40170

[0136] Step 1: (5S)-5-[2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-3-ethoxy-3-keto-propanoyl]-4-azaspiro[2,4]heptane-4-carboxylic acid tert-butyl ester JPEG0007840327000053.jpg41170 Similar to step 4 of Example 1, (5S)-4-tert-butoxycarbonyl-4-azaspiro[2.4]heptane-5-carboxylic acid was treated with carbonyldiimidazole to obtain solution A. 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]ethyl acetate was deprotonated with LDA and treated with solution A at -78°C. After stirring overnight at room temperature and scrutinizing as in step 4 of Example 1, the crude title compound was obtained as a bright yellow foam and used in the next step without further purification. MS: m / e = 572.3 ([M+H] + )

[0137] Step 2: 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-spiro[6,7-dihydropyrrole[1,2-c]imidazole-5,1'-cyclopropane]-1-yl-ethyl acetate JPEG0007840327000054.jpg30170 Similar to step 5 of Example 1, (5S)-5-[2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-3-ethoxy-3-keto-propanoyl]-4-azaspiro[2.4]heptan-4-carboxylic acid tert-butyl ester was deprotected with HCl in dioxane, followed by reaction with potassium thiocyanate to obtain a crude intermediate, which was used in the next step without further purification.

[0138] Similar to step 6 of Example 1, the intermediate was treated with hydrogen peroxide in AcOH to obtain the title compound as a bright yellow foam. MS: m / e = 481.2 ([M + H] + )

[0139] Step 3: 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-spiro[6,7-dihydropyrrole[1,2-c]imidazole-5,1'-cyclopropane]-1-yl-N-thiazol-2-yl-acetamide Starting from JPEG0007840327000055.jpg341702-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-spiro[6,7-dihydropyrrole[1,2-c]imidazole-5,1'-cyclopropane]-1-yl-ethyl acetate (Example 6, Step 2) and thiazol-2-amine, the title compound was obtained as a bright yellow foam using the same chemistry as described in Step 7 of Example 1. MS: m / e = 535.0 (M+H + ).

[0140] Step 4: 2-[4-(difluoromethyl)-6-[2-(4-formylphenyl)ethynyl]-7-methyl-indazol-2-yl]-2-spiro[6,7-dihydropyrrole[1,2-c]imidazole-5,1'-cyclopropane]-1-yl-N-thiazol-2-yl-acetamide Starting from JPEG0007840327000056.jpg341702-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-spiro[6,7-dihydropyrrole[1,2-c]imidazole-5,1'-cyclopropane]-1-yl-N-thiazol-2-ylacetamide (Example 6, Step 3) and 4-ethynylbenzaldehyde, the title compound was obtained as a dark brown amorphous material using the same chemistry as described in Step 10 of Example 1. MS: m / e = 583.3 (M+H + ).

[0141] Step 5: 2-[4-(difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-indazol-2-yl]-2-(5-ethyl-5-methyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide Starting from JPEG0007840327000057.jpg361702-[4-(difluoromethyl)-6-[2-(4-formylphenyl)ethynyl]-7-methyl-indazol-2-yl]-2-spiro[6,7-dihydropyrrole[1,2-c]imidazole-5,1'-cyclopropane]-1-yl-N-thiazol-2-ylacetamide (Example 6, Step 4) and piperidine-4-ylmethanol, the title compound was obtained as a bright yellow solid using the same chemistry as described in Step 8 of Example 1. MS: m / e = 682.5 (M+H + ).

[0142] Example 7 2-(5-ethyl-5-methyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-2-[6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-4-(trifluoromethyl)indazol-2-yl]-N-thiazol-2-yl-acetamide JPEG0007840327000058.jpg38170

[0143] Step 1: 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 JPEG0007840327000059.jpg35170 Similar to step 4 of Example 1, (5S)-4-tert-butoxycarbonyl-4-azaspiro[2.4]heptane-5-carboxylic acid was treated with carbonyldiimidazole to obtain solution A. Ethyl 2-(6-bromo-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)acetate was deprotonated with LDA and treated with solution A at -78°C. After stirring overnight at room temperature and scrutinizing as in step 4 of Example 1, the crude title compound was obtained as a light brown foam and used in the next step without further purification. MS: m / e = 590.3 ([M+H] + )

[0144] Step 2: Ethyl 2-[6-bromo-7-methyl-4-(trifluoromethyl)indazol-2-yl]-2-(5-ethyl-5-methyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)acetate Similar to step 5 of Example 1, tert-butyl (5S)-5-[2-[6-bromo-7-methyl-4-(trifluoromethyl)indazol-2-yl]-3-ethoxy-3-oxo-propanoyl]-4-azaspiro[2.4]heptan-4-carboxylate was deprotected with HCl in dioxane, followed by reaction with potassium thiocyanate to obtain a crude intermediate, which was used in the next step without further purification.

[0145] Similar to step 6 of Example 1, the intermediate was treated with hydrogen peroxide in AcOH to obtain the title compound as a white foam. MS: m / e = 499.2 ([M + H] + )

[0146] Step 3: 2-[6-bromo-7-methyl-4-(trifluoromethyl)indazol-2-yl]-2-(5-ethyl-5-methyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide Starting from ethyl 2-[6-bromo-7-methyl-4-(trifluoromethyl)indazol-2-yl]-2-(5-ethyl-5-methyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl) acetate (Example 7, Step 2) and thiazol-2-amine, the title compound was obtained as a bright yellow foam using the same chemistry as described in Step 7 of Example 1. MS: m / e = 552.9 (M+H + ).

[0147] Step 4: 2-[6-[2-(4-formylphenyl)ethynyl]-7-methyl-4-(trifluoromethyl)indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazole-5,1'-cyclopropane]-1-yl-N-thiazol-2-ylacetamide Starting with JPEG0007840327000062.jpg351702-[6-bromo-7-methyl-4-(trifluoromethyl)indazol-2-yl]-2-(5-ethyl-5-methyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl acetamide (Example 7, Step 3) and 4-ethynylbenzaldehyde, the title compound was obtained as a dark brown foam using the same chemistry as described in Step 10 of Example 1. MS: m / e = 601.4 (M+H + ).

[0148] Step 5: 2-(5-ethyl-5-methyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-2-[6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-4-(trifluoromethyl)indazol-2-yl]-N-thiazol-2-yl-acetamide Starting from JPEG0007840327000063.jpg361702-[6-[2-(4-formylphenyl)ethynyl]-7-methyl-4-(trifluoromethyl)indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazole-5,1'-cyclopropane]-1-yl-N-thiazol-2-ylacetamide (Example 7, Step 4) and piperidine-4-ylmethanol, the title compound was obtained as a bright yellow solid using the same chemistry as described in Step 8 of Example 1. MS: m / e = 700.6 (M+H + ).

[0149] Example 8 2-(5,5-dimethyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-2-[6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-4-(trifluoromethyl)indazol-2-yl]-N-thiazol-2-yl-acetamide JPEG0007840327000064.jpg35170

[0150] Step 1: 5-[2-[6-bromo-7-methyl-4-(trifluoromethyl)indazol-2-yl]-3-ethoxy-3-ketopropanoyl]-2,2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester JPEG0007840327000065.jpg35170 Similar to step 4 of Example 1, (2S)-1-tert-butoxycarbonyl-5,5-dimethyl-proline was treated with carbonyldiimidazole to obtain solution A. Ethyl 2-(6-bromo-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)acetate was deprotonated with LDA and treated with solution A at -78°C. After stirring overnight at room temperature and scrutinizing as in step 4 of Example 1, the crude title compound was obtained as a light brown foam and used in the next step without further purification. MS: m / e = 590.3 ([M+H] + )

[0151] Step 2: 2-[6-bromo-7-methyl-4-(trifluoromethyl)indazol-2-yl]-2-(5,5-dimethyl-6,7-dihydropyrrole[1,2-c]imidazol-1-yl) acetate ethyl ester JPEG0007840327000066.jpg28170 Similar to step 5 of Example 1, 5-[2-[6-bromo-7-methyl-4-(trifluoromethyl)indazol-2-yl]-3-ethoxy-3-keto-propanoyl]-2,2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester was deprotected with HCl in dioxane, and subsequently reacted with potassium thiocyanate to obtain a crude intermediate, which was used in the next step without further purification.

[0152] Similar to step 6 of Example 1, the intermediate was treated with hydrogen peroxide in AcOH to obtain the title compound as a bright yellow foam. MS: m / e = 501.2 ([M+H] + )

[0153] Step 3: 2-[6-bromo-7-methyl-4-(trifluoromethyl)indazol-2-yl]-2-(5,5-dimethyl-6,7-dihydropyrrole[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide Starting from JPEG0007840327000067.jpg331702-[6-bromo-7-methyl-4-(trifluoromethyl)indazol-2-yl]-2-(5,5-dimethyl-6,7-dihydropyrrole[1,2-c]imidazol-1-yl)acetic acid ethyl ester (Example 8, Step 2) and thiazol-2-amine, the title compound was obtained as a bright yellow foam using the same chemistry as described in Step 7 of Example 1. MS: m / e = 555.1 (M+H + ).

[0154] Step 4: 2-(5,5-dimethyl-6,7-dihydropyrrole[1,2-c]imidazol-1-yl)-2-[6-[2-(4-formylphenyl)ethynyl]-7-methyl-4-(trifluoromethyl)indazol-2-yl]-N-thiazol-2-yl-acetamide Starting with JPEG0007840327000068.jpg351702-[6-bromo-7-methyl-4-(trifluoromethyl)indazol-2-yl]-2-(5,5-dimethyl-6,7-dihydropyrrole[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide (Example 8, Step 3) and 4-ethynylbenzaldehyde, the title compound was obtained as a dark brown foam using the same chemistry as described in Step 10 of Example 1. MS: m / e = 603.4 (M+H + ).

[0155] Step 5: 2-[4-(difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-indazol-2-yl]-2-(5,5-dimethyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide Starting from JPEG0007840327000069.jpg341702-(5,5-dimethyl-6,7-dihydropyrrole[1,2-c]imidazol-1-yl)-2-[6-[2-(4-formylphenyl)ethynyl]-7-methyl-4-(trifluoromethyl)indazol-2-yl]-N-thiazol-2-ylacetamide (Example 8, Step 4) and piperidine-4-ylmethanol, the title compound was obtained as a bright yellow solid using the same chemistry as described in Step 8 of Example 1. MS: m / e = 702.5 (M+H + ).

[0156] Example 9 HTRF phosphorylated EGFR LRCS assay (cells) Cell lines and culture media The BaF3-LRCS cell line was obtained from Crownbio (San Diego, California, USA). The cells were maintained at 37°C and 5% CO2 in RPMI ATCC (Gibco 31870) supplemented with 10% fetal bovine serum (FBS) (Gibco) + 2 mM glutamine + 0.5 μg / ml puromycin.

[0157] protocol After pre-filling the plate with 12.5 nl of DMSO solution of the compound to be tested (dose-response) or DMSO alone, cells were transferred to a Greiner Bio-One microtiter plate No. 784-08 at a rate of 20,000 cells / well in 12.5 μl of growth medium / well as described above. After rotating the plate at 300 × g for 30 seconds, the cells were incubated for 4 hours at 37°C, 5% CO2, and 95% humidity. The cells were lysed by adding them to a compound mixture of 4 μl / well of 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 following day, after thawing the plate, 4 μl of a mixture of anti-phosphorylated EGFR cryptotate and anti-phosphorylated EGFR-d2 antibody solution prepared in supplemented detection buffer was added to each well. Next, the covered plates were incubated at room temperature for 4 hours, after which fluorescence emission at 616 and 665 nm was read using an Envision reader (PerkinElmer). The data were analyzed in the same manner as described above, by multiplying the normalized ratio of the 665 vs. 616 signals by 10,000.

[0158] The results are shown in Table 1. JPEG0007840327000070.jpg232170JPEG0007840327000071.jpg227170

Claims

1. Compound of formula (I) [In the formula, R １ is hydrogen or halogen; R ２ and R ２’ These are independently selected from hydrogen and alkyl; or R ２ and R ２’ Together with the carbon atoms to which they are bonded, they form a cycloalkyl group; R ３ is hydrogen or halogen; R ４ is alkyl; R ５ [It is a hydroxyalkyl (heterocycloalkyl) alkyl] or a pharmaceutically acceptable salt thereof.

2. R １ The compound according to claim 1, wherein R is hydrogen or fluoro.

3. R １ The compound according to claim 1 or 2, wherein the compound is hydrogen.

4. R ２ and R ２’ Either is independently selected from hydrogen or methyl, or R ２ and R ２’ The compound according to any one of claims 1 to 3, wherein they form a cyclopropyl group together with the carbon atoms to which they are bonded.

5. R ２ and R ２’ Both are alkyl at the same time, or R ２ and R ２’ The compound according to any one of claims 1 to 4, wherein they form a cycloalkyl group together with the carbon atoms to which they are bonded.

6. R ２ and R ２’ Both are methyl at the same time, or R ２ and R ２’ The compound according to any one of claims 1 to 5, wherein they form a cyclopropyl group together with the carbon atoms to which they are bonded.

7. R ３ The compound according to any one of claims 1 to 6, wherein is hydrogen or fluoro.

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

9. R ５ The compound according to any one of claims 1 to 8, wherein is a hydroxyalkyl (piperidinyl)alkyl compound.

10. R ５ The compound according to any one of claims 1 to 9, wherein is hydroxymethyl(piperidinyl)methyl.

11. 2-[4-(difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide; 2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-[6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-4-(trifluoromethyl)indazol-2-yl]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-4-(trifluoromethyl)indazol-2-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-indazol-2-yl]-2-(5,5-dimethyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-indazol-2-yl]-2-(5-ethyl-5-methyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide; 2-(5-ethyl-5-methyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-2-[6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-4-(trifluoromethyl)indazol-2-yl]-N-thiazol-2-yl-acetamide; and 2-(5,5-dimethyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-2-[6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-4-(trifluoromethyl)indazol-2-yl]-N-thiazol-2-yl-acetamide; A compound according to any one of claims 1 to 10, selected from, or a pharmaceutically acceptable salt thereof.

12. 2-[4-(difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-indazol-2-yl]-2-(5,5-dimethyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-indazol-2-yl]-2-(5-ethyl-5-methyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide; 2-(5-ethyl-5-methyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-2-[6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-4-(trifluoromethyl)indazol-2-yl]-N-thiazol-2-yl-acetamide; and 2-(5,5-dimethyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-2-[6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-4-(trifluoromethyl)indazol-2-yl]-N-thiazol-2-yl-acetamide; A compound according to any one of claims 1 to 11, selected from, or a pharmaceutically acceptable salt thereof.

13. The compound, The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.

14. The compound, The compound according to any one of claims 1 to 13.

15. A method for preparing the compound according to any one of claims 1 to 14, the compound of formula (B1) The compound of formula (B2) The process involves reacting with a base, a Pd(II) catalyst, and a Cu(I) source, where R １ , R ２ , R ３ , R ４ , and R ５ A method as described in any one of claims 1 to 14, wherein X is a halogen.

16. The compound according to any one of claims 1 to 14, when produced according to the manufacturing method described in claim 15.

17. A compound according to any one of claims 1 to 14 for use as a therapeutically active substance.

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

19. A compound according to any one of claims 1 to 14, for use in the treatment or prevention of cancer.

20. The compound according to claim 19, wherein the cancer is non-small cell lung cancer.

21. A pharmaceutical agent for the treatment or prevention of cancer, comprising the compound described in any one of claims 1 to 14.

22. The pharmaceutical product according to claim 21, wherein the cancer is non-small cell lung cancer.

23. Use of the compound according to any one of claims 1 to 14 for preparing a medicament for the treatment or prevention of cancer.

24. The use according to claim 23, wherein the cancer is non-small cell lung cancer.

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