Novel indazole derivatives

Abstract

The present invention relates to novel compounds having the general formula (I) TIFF2023551769000035.tif44170 or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 and R 4 is as described herein. The compounds of formula (I) can be used as medicines.

Description

Technical Field

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

[0002] The present invention particularly relates to novel compounds of formula (I) TIFF0007840324000001.tif44170[wherein, R , , , , 3 , 4 , , , ,

[0003] and R 2 are independently selected from halogen and hydrogen; R 3 is alkyl or haloalkyl; R 4 is heterocycloalkyl, dialkylaminoalkyl, (alkyl)(halo)heterocycloalkyl, hydroxyalkylheterocycloalkylalkoxy, alkylheterocycloalkyl, hydroxyalkylheterocycloalkylalkylcycloalkyl or alkoxyalkylheterocycloalkyl] or a pharmaceutically acceptable salt thereof.

Background Art

[0003] The HER family of receptor tyrosine kinases are mediators of cell proliferation, differentiation, and survival. This receptor family includes four distinct members, namely, epidermal growth factor receptor (EGFR, ErbB1, or HER1), HER2 (ErbB2), HER3 (ErbB3), and HER4 (ErbB4). Upon ligand binding, the receptors form homo- and heterodimers, and subsequent activation of the intrinsic tyrosine kinase activity results in 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). Dysregulation of EGFR by overexpression or mutation is associated with many human cancer types, 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 the years (Ciardiello, F., and Tortora, G. (2008).EGFR antagonists in cancer treatment.The New England journal of medicine 358, 1160-1174). Erlotinib (Tarceva®), a reversible inhibitor of EGFR tyrosine kinase, is approved in many countries as a treatment for recurrent 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 in the receptor's ATP site. While several developed mutant-selective irreversible inhibitors are highly active against T790M mutants, their efficacy may be impaired by acquired mutations in the C797S cysteine ​​residue, which forms the key covalent bond (Thress, K. Set 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 further reported that the C797S mutation is 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). An additional mutation causing resistance to osimertinib has 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) discusses EGFR in the treatment of NSCLC. 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 and ethyl are specific examples of “alkyl” in the compounds of formula (I).

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

[0012] The 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. Specific examples of "alkoxy" are methoxy and ethoxy.

[0013] The term "oxy," either alone or in combination, refers to an -O- group.

[0014] 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, a substitution of the group with at least one halogen, in particular 1 to 5 halogens, in particular 1 to 4 halogens, i.e., 1, 2, 3, or 4 halogens.

[0015] The term "haloalkyl" refers to an alkyl group that, alone or in combination, is substituted with at least one halogen, particularly with 1 to 5 halogens, and especially with 1 to 3 halogens. A specific example of a "haloalkyl" is difluoromethyl.

[0016] The terms "hydroxyl" and "hydroxy," either alone or in combination, refer to the -OH group.

[0017] The term "carbonyl," either alone or in combination, refers to a -C(O)- group.

[0018] 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-).

[0019] The term "alkylamino" refers to an alkyl group bonded to an -NH- group. The term "dialkylamino" refers to two alkyl groups bonded to an -N- atom. A specific example of "dialkylamino" is dimethylamino.

[0020] The term "heterocycloalkyl" refers to a monovalent, saturated, or partially unsaturated monocyclic or bicyclic ring system consisting of 4 to 9 ring atoms, containing 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 sharing one or two ring atoms. Examples of heterocycloalkyls include oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, piperidyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl, azetidinyl, and piperazinyl. Specific examples of heterocycloalkyls are morpholinyl and piperidinyl.

[0021] 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.

[0022] The term "pharmaceutically acceptable salt" refers to salts of the compounds of formula (I) that retain the biological effectiveness and properties of the free base or free acid and are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., 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, etc. These salts may also be prepared by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts, etc. Salts derived from organic bases include 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., but are not limited to these. Particularly pharmaceutically acceptable salts of the compounds of formula (I) are hydrochloride, methanesulfonate, and citrate.

[0023] If one of the starting materials or compounds of formula (I) contains one or more functional groups that are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (e.g., “Protective groups in Organic Chemistry” by T. W. Greene and P.g. M. Wuts, 3 rdProtecting 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).

[0024] 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.

[0025] 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.

[0026] Therefore, the present invention relates particularly to the following: R 1 and R 2 However, the compound according to the present invention is independently selected from fluorine and hydrogen; R 1 and R 2 A compound according to the present invention, wherein one of the elements is a halogen and the other is hydrogen; R 1 and R 2 The compound according to the present invention, wherein one of the atoms is fluorine and the other is hydrogen.

[0027] R 1 and R 2 However, both are hydrogen at the same time, the compound according to the present invention; R 3 A compound according to the present invention, wherein is methyl or fluoromethyl; R3 A compound according to the present invention, wherein is methyl or difluoromethyl; R 3 A compound according to the present invention, wherein the alkyl group is; R 3 A compound according to the present invention, wherein the compound is methyl; R 3 A compound according to the present invention, wherein the compound is fluoromethyl; R 3 A compound according to the present invention, wherein the compound is difluoromethyl; R 4 The compound according to the present invention is morpholinyl, dialkylaminoalkyl, (alkyl)(halo)piperidinyl, hydroxyalkylpiperidinylalkoxy, alkylpiperidinyl, hydroxyalkylpiperidinylalkyl(bicyclo[1.1.1]pentanyl), or alkoxyalkylpiperidinyl; R 4 The compound according to the present invention is morpholinyl, dimethylaminoethyl, dimethylaminomethyl, (ethyl)(fluoro)piperidinyl), hydroxymethylpiperidinylethoxy, ethylpiperidinyl, hydroxymethylpiperidinylmethyl(bicyclo[1.1.1]pentanyl), or methoxyethylpiperidinyl; R 4 The compounds according to the present invention are dialkylaminoalkyl, dialkylaminoalkyl, hydroxyalkylpiperidinylalkoxy, or hydroxyalkylpiperidinylalkyl (bicyclo[1.1.1]pentanyl); and R 4 The compound according to the present invention is dimethylaminoethyl, dimethylaminomethyl, hydroxymethylpiperidinylethoxy, or hydroxymethylpiperidinylmethyl (bicyclo[1.1.1]pentanyl).

[0028] The present invention further, 2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(7-methyl-6-(4-morpholinophenyl)-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; rac-2-(6-(4-(2-(dimethylamino)ethyl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; 2-(6-(4-((3S,4S)-1-ethyl-3-fluoropiperidine-4-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; 2-(6-(4-((3R,4R)-1-ethyl-3-fluoropiperidine-4-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; 2-[6-[4-[(dimethylamino)methyl]phenyl]-7-methyl-4-(trifluoromethyl)indazol-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-(1,3-thiazol-2-yl)acetamide; 2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(2-(4-(hydroxymethyl)piperidine-1-yl)ethoxy)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(1-ethylpiperidine-4-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-((dimethylamino)methyl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(3-((4-(hydroxymethyl)piperidine-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(1-(2-methoxyethyl)piperidine-4-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(2-(4-(hydroxymethyl)piperidine-1-yl)ethoxy)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; and 2-(7-(difluoromethyl)-6-(4-morpholinophenyl)-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; compounds selected from or its pharmaceutically acceptable salt; 2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(7-methyl-6-(4-morpholinophenyl)-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; rac-2-(6-(4-(2-(dimethylamino)ethyl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; 2-[6-[4-[(dimethylamino)methyl]phenyl]-7-methyl-4-(trifluoromethyl)indazol-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-(1,3-thiazol-2-yl)acetamide; 2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(2-(4-(hydroxymethyl)piperidine-1-yl)ethoxy)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-((dimethylamino)methyl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(3-((4-(hydroxymethyl)piperidine-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(2-(4-(hydroxymethyl)piperidine-1-yl)ethoxy)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; and 2-(7-(difluoromethyl)-6-(4-morpholinophenyl)-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; Compounds selected from the present invention or relating to the pharmaceutically acceptable salt thereof.

[0029] Methods for producing the compound of formula (I) described herein are also an object of the present invention.

[0030] The compounds of formula (I)A 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.

[0031] In TIFF0007840324000002.tif116170 scheme 1, R 1 , R 2 , R 3 and R 4 This is defined herein.

[0032] Compounds of formula (I) can be prepared according to Scheme 1 or as described in the examples. Starting materials can be commercially available or prepared according to known methods.

[0033] 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 Suzuki reaction and other well-known synthetic methods for functional group transformation, phenyl-R 4 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.

[0034] The corresponding pharmaceutically acceptable salts with 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 the compound of formula I to a pharmaceutically acceptable salt with a base can be carried out by treating such a compound with such a base. One possible method for forming such a salt 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 pharmaceutically acceptable salts are hydrochloride, formate, and trifluoroacetate salts.

[0035] Unless their preparations are described in the examples, the compounds of formula (I) and all intermediate products can be prepared by similar methods or by methods described herein.

[0036] 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.

[0037] Therefore, the present invention also relates to a method for preparing compounds according to the present invention, (a) Compound of formula (B1) TIFF0007840324000003.tif35170 is reacted in a suitable solvent in the presence of a base to obtain compound (B2). TIFF0007840324000004.tif35170[In formula, M + is Na + Li + The process of bringing the base to a state that is either a protonated base or a protonated base; (b) React the compound of formula (B2) in a suitable solvent in the presence of an acid to obtain the compound of formula (B3). The process of obtaining TIFF0007840324000005.tif35170; (c) Compound of formula (B3) and compound of formula (B4) The process involves reacting TIFF0007840324000006.tif20170 in the presence of a coupling agent and a base; Includes R 1 , R 2 , R 3 , and R 4 However, as defined above, this relates to a method in which R is H or alkyl.

[0038] Conveniently, R is either H or methyl.

[0039] In the reaction of step (a), the base can be, for example, LiOH or NaOH. Conveniently, the base is LiOH.

[0040] In the reaction of step (a), the concentration of the base may be between approximately 0.1 M and 5 M, particularly between approximately 0.2 M and 4 M, and more specifically between approximately 0.5 M and 2 M. Conveniently, the concentration of the base is approximately 1 M.

[0041] In the reaction of step (a), the solvent may be, for example, EtOH, THF, MeOH, water, or a mixture thereof. Conveniently, the solvent is THF, water, or a mixture thereof.

[0042] The favorable conditions for the reaction in step (a) may be between approximately 0°C and 90°C, particularly between approximately 5°C and 80°C, and more specifically between approximately 10°C and 50°C.

[0043] The reaction in step (b) can be conveniently carried out in a solvent. The solvent may be, for example, EtOH, MeOH, THF, water, or a mixture thereof.

[0044] In step (b), the acid may be, for example, hydrochloric acid.

[0045] Favorable conditions for process (b) may be between approximately 0°C and approximately 90°C, particularly between approximately 5°C and approximately 80°C, and more specifically between approximately 10°C and approximately 50°C.

[0046] The reaction in step (c) can be conveniently carried out in a solvent. The solvent may be, for example, DMSO or DMF. Conveniently, the solvent is DMF.

[0047] The reaction in step (c) can be conveniently carried out in the presence of a coupling agent. The coupling agent may be, for example, HATU.

[0048] The reaction in step (c) can be conveniently carried out in the presence of a base. The base may be, for example, diethylamine, trimethylamine, or a Hünig base. Conveniently, the base is a Hünig base.

[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 schedule of administration, 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-focal administration. Parenteral administration includes 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 its pharmaceutical composition) or to assist in the manufacture of a pharmaceutical product (i.e., a medicine).

[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; Compounds of formula (I) or pharmaceutically acceptable salts thereof for use in 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 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 appropriate modifications of the methods disclosed herein. Their absolute stereochemistry can be determined, if necessary, 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 a suitable intermediate.

[0063] Furthermore, one embodiment of the present invention is a compound of formula (I) described herein, when manufactured according to any one of the processes described herein.

[0064] Compounds of formula (I) or pharmaceutically acceptable salts thereof can be used pharmaceutically (for example, in the form of pharmaceutical preparations). Pharmaceutical preparations of the present invention can be administered orally (for example, in the form of tablets, coated tablets, sugar-coated tablets, hard and soft gelatin capsules, solutions, emulsions, or suspensions), intranasally (for example, in the form of nasal sprays), rectally (for example, in the form of suppositories), or topically (for example, 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 (for example, in the form of sterile injection solutions).

[0065] Compounds of formula (I) or pharmaceutically acceptable salts thereof can be processed 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 salts thereof, etc., can be used as such 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, semi-solid substances, and liquid polyols.

[0067] Suitable adjuvants for the production of solutions and syrups include, for example, water, polyols, sucrose, reverse sugars, 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-solid polyols, 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. Pharmaceutical preparations may also contain other substances of therapeutic value.

[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 (e.g., 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, which may be between 0.1 mg and 25 mg, may be a single dose per day, a single dose per week, multiple doses per day (2 to 4 times), or multiple doses per week. However, where indicated, it is clear that the upper or lower limits stated herein may be exceeded.

[0073] 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.

[0074] Compounds of formula (I) or pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert inorganic or organic carriers for the manufacture of pharmaceutical preparations. 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-liquid polyols, or liquid polyols.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] Example A Tablets with the following composition are manufactured in the usual manner: TIFF0007840324000007.tif54170 Manufacturing Procedure 1. Mix ingredients 1, 2, 3, and 4 together and granulate with purified water. 2. Dry the granules at 50°C. 3. Pass the granules through an appropriate grinding machine. 4. Add ingredient 5 and mix for 3 minutes; compress with an appropriate press.

[0080] Example B-1 To manufacture capsules with the following composition: TIFF0007840324000008.tif53170 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.

[0081] 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; talc is added and mixed thoroughly. The mixture is then filled into suitable capsules, such as hard gelatin capsules, using a machine.

[0082] Example B-2 To manufacture soft gelatin capsules with the following composition: TIFF0007840324000009.tif49170TIFF0007840324000010.tif50170

[0083] 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.

[0084] Example C To manufacture suppositories with the following composition: TIFF0007840324000011.tif28170

[0085] 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.

[0086] Example D Prepare an injectable solution with the following composition: TIFF0007840324000012.tif33170

[0087] Manufacturing procedure Dissolve the compound of formula (I) in a mixture of polyethylene glycol 400 and some water for injection. Adjust the pH to 5.0 with acetic acid. Add the remaining water to adjust the volume to 1.0 ml. Filter the solution, fill the vial with an appropriate excess volume, and sterilize.

[0088] Example E Prepare a sachet with the following composition: TIFF0007840324000013.tif59170

[0089] 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. The granules are mixed with magnesium stearate and flavoring additives and filled into sachets. [Examples]

[0090] Abbreviation AcOH = acetic acid; ATP = adenosine triphosphate; BOC = tert-butyloxycarbonyl; BPR = back pressure regulator; CAS = chemical information retrieval service; CDI = 1,1'-carbonyldiimidazole; DCM = dichloromethane; DIPEA = diisopropylethylamine; DME = dimethoxyethane; DMF = ditylformamide; DMSO = dimethyl sulfoxide; dppf = 1,1'-bis(diphenylphosphino)ferrocene; 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.

[0091] 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.

[0092] Synthesis of intermediates Substituted indazole(II) compounds are known or can be prepared in the same manner as known methods or by the methods described below.

[0093] 6-bromo-7-methyl-4-(trifluoromethyl)-1H-indazole Step 1: 1-Bromo-3-fluoro-2-methyl-5-(trifluoromethyl)benzene 1-Bromo-3-fluoro-5-(trifluoromethyl)benzene (12.7 g) was dissolved in tetrahydrofuran (60 ml) and cooled to -75°C. LDA(THF (2.1 mol / l in 27.4 ml)) was added dropwise. After stirring at -75°C for 30 minutes, iodomethane (8.16 g) 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 (15.42 g) was subjected to valve-to-valve distillation at approximately 10 mbar and an oven temperature of 60-80°C to obtain the title compound as a colorless liquid (11.91 g) containing 8 mol% ethylbenzene. 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. Investigating the reaction in the same manner as in the synthesis of 4-bromo-3,6-dichloro-2-fluorobenzaldehyde yielded the crude title compound as a brown liquid. 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)

[0094] 6-Bromo-7-(difluoromethyl)-4-(trifluoromethyl)-2H-indazole Step 1: 2-Bromo-6-fluoro-4-(trifluoromethyl)benzaldehyde A chilled solution of 1-bromo-3-fluoro-5-(trifluoromethyl)benzene (20 g) in THF (247 ml) was added dropwise to a solution of LDA (2 mol / l) in THF (45.3 ml) at -78°C. After stirring at -78°C for 40 minutes, ethyl formate (6.1 g) was added, and the reaction mixture was warmed to 0°C and stirred for 2.5 hours. Water was added, and the reaction mixture was extracted twice with ethyl. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (silica gel, 330 g, 0%~20% ethyl in heptane) to obtain 2-bromo-6-fluoro-4-(trifluoromethyl)benzaldehyde (18.2 g) as a yellow oil. 1 H NMR (CHLOROFORM-d, 300 MHz) δ 10.36 (s, 1H), 7.76 (s, 1H), 7.42 (td, 1H, J=0.7, 9.9 Hz), 1.2-1.4 (m, 1H) Step 2: 1-Bromo-2-(difluoromethyl)-3-fluoro-5-(trifluoromethyl)benzene 18.2 g of 2-bromo-6-fluoro-4-(trifluoromethyl)benzaldehyde was slowly added to a cooled solution in 260 ml of dichloromethane with N,N-diethyl-1,1,1-trifluoro-14-sulfanamine (CAS 38078-09-0, 11.4 g) under ice bath cooling. The reaction mixture was slowly brought to room temperature and stirred for 2 hours. The reaction product was carefully quenched by adding saturated aqueous NaHCO3 solution. The mixture was washed with brine and extracted with dichloromethane. The organic layer was concentrated under vacuum, and the crude product was purified by silica gel chromatography (silica gel, 330 g, 0%~20% ethyl phosphate in heptane) to obtain 1-bromo-2-(difluoromethyl)-3-fluoro-5-(trifluoromethyl)benzene (9.69 g) as a colorless oil. MS: 292.1[M+H]+,Br isotope Step 3: 4-Bromo-3-(difluoromethyl)-2-fluoro-6-(trifluoromethyl)benzaldehyde Similar to the synthesis of 2-bromo-6-fluoro-4-(trifluoromethyl)benzaldehyde, 1-bromo-2-(difluoromethyl)-3-fluoro-5-(trifluoromethyl)benzene was first treated with LDA in tetrahydrofuran at -75°C, followed by treatment with ethyl formate. The compound was investigated in the same manner as the synthesis of 2-bromo-6-fluoro-4-(trifluoromethyl)benzaldehyde, and purified by column chromatography (SiO2, 120 g, 0%-20% ethyl in heptane) to obtain the title compound as a bright yellow solid. Step 4: 6-bromo-7-(difluoromethyl)-4-(trifluoromethyl)-2H-indazole 5.0 g of 4-bromo-3-(difluoromethyl)-2-fluoro-6-(trifluoromethyl)benzaldehyde was added to a solution in 31.8 ml of ethanol, to which 1.32 g of hydrazine hydrate was added. The mixture was stirred at 70°C for 30 minutes. 17 g of N,N-diisopropylethylamine was added, and the reaction mixture was stirred overnight. The reaction mixture was evaporated, the residue was diluted with water, and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to obtain crude 6-bromo-7-(difluoromethyl)-4-(trifluoromethyl)-2H-indazole (4.66 g) as a bright yellow solid. MS: m / e = 315.0 ([M+H] + )

[0095] General method A: Alkylation of indazole A mixture of indazole (II, 1 equivalent), ethyl 2-bromoacetate (2 equivalents), and N,N-dimethylacetamide (a small amount to form a solution) is heated to 100°C until the reaction is complete (usually 5 to 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 positional isomer can be achieved by chromatography, or in specific cases by recrystallization from a solvent such as EtOH, acetonitrile, or dichloromethane.

[0096] Using general method A, the following intermediate (III) was prepared: TIFF0007840324000014.tif51170

[0097] Boronic acid derivatives are known or can be prepared in the same manner as known methods or by the methods described below.

[0098] [4-[(3S,4S)-1-ethyl-3-fluoro-4-piperidyl]phenyl]boronic acid or [4-[(3R,4R)-1-ethyl-3-fluoro-4-piperidyl]phenyl]boronic acid Step 1: tert-butyl(3S,4S)-4-(4-bromophenyl)-3-hydroxy-piperidine-1-carboxylate and tert-butyl(3R,4R)-4-(4-bromophenyl)-3-hydroxy-piperidine-1-carboxylate A solution of tert-butyl 4-(4-bromophenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (CAS 273727-44-9, 30 g, 79.8 mmol, Eq: 1.0, 90% purity) in THF (275 mL) was cooled to 0°C. Boranetetrahydrofuran complex (1.0 M solution in THF, CAS 14044-65-6, 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 rt for 16 hours. 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 minutes. 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 hours. The reaction mixture was cooled to rt, and the excess peroxide was quenched by adding 2 M 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 under vacuum. The crude product was suspended in diisopropyl ether and filtered. The solid was washed with diisopropyl ether and dried under vacuum to obtain the title compound as a white solid (26.74 g, 92% yield). m / z 258.1 [M-BOC+H ]+ ESI pos. Step 2: tert-butyl(3S,4S)-4-(4-bromophenyl)-3-fluoropiperidine-1-carboxylate and tert-butyl(3R,4R)-4-(4-bromophenyl)-3-fluoropiperidine-1-carboxylate A solution of tert-butyl(3S,4S)-4-(4-bromophenyl)-3-hydroxy-piperidine-1-carboxylate and tert-butyl(3R,4R)-4-(4-bromophenyl)-3-hydroxy-piperidine-1-carboxylate (37.2 g, 99.2 mmol, Eq: 1) in dichloromethane (500 mL) was cooled to -78°C. Deoxofluor® (50% solution in THF, CAS 202289-38-1, 79 g, 65.8 mL, 179 mmol, Eq: 1.8) was added dropwise at -78°C. The reaction mixture was slowly warmed to rt and stirred at rt for 16 hours. The reaction mixture was quenched with aqueous NaHCO3 solution. The mixture was stirred for 30 minutes (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 under vacuum. The crude material was adsorbed onto isolute HM-N and purified by flash chromatography (silica gel, 330 g, 0%-40% RINKAN in heptane) to obtain the title compound as a bright yellow oil (31.7 g, 85% yield). m / z 304.1 [M-tBu+H] + ESI pos. Step 3: tert-butyl(3S,4S)-4-(4-bromophenyl)-3-fluoropiperidine-1-carboxylate or tert-butyl(3R,4R)-4-(4-bromophenyl)-3-fluoropiperidine-1-carboxylate The title compound was obtained as a colorless oil by chiral separation of tert-butyl(3S,4S)-4-(4-bromophenyl)-3-fluoropiperidine-1-carboxylate and tert-butyl(3R,4R)-4-(4-bromophenyl)-3-fluoropiperidine-1-carboxylate (31.8 g, 88.8 mmol, Eq: 1.0) using SFC (column: IG, 12 nm, 5 μm, 250 × 30 mm, eluent: Isocratic 5% isopropanol-BPR, 80 g / min from 120 ba) to obtain m / z 304.0 [M-tBu+H ]+ The absolute stereochemistry of the ESI pos. was not determined. Step 4: (3S,4S)-4-(4-bromophenyl)-3-fluoropiperidine hydrochloride or (3R,4R)-4-(4-bromophenyl)-3-fluoropiperidine hydrochloride To a solution of tert-butyl(3S,4S)-4-(4-bromophenyl)-3-fluoropiperidine-1-carboxylate or tert-butyl(3R,4R)-4-(4-bromophenyl)-3-fluoropiperidine-1-carboxylate (10.5 g, 29.3 mmol, Eq: 1.0) in DCM (100 mL), HCl (4 M in 1,4-dioxane, 73.3 mL, 293 mmol, Eq: 10) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under vacuum. The residue was taken into 40 mL of Et2O, and the mixture was stirred for 10 minutes. The reaction mixture was filtered through sintered glass and washed with Et2O. The white solid was dried under vacuum to obtain the title compound (9.5 g, purity 90%, yield 99%). m / z 260.0 [M+H ]+, ESI pos. Step 5: (3S,4S)-4-(4-bromophenyl)-1-ethyl-3-fluoropiperidine or (3R,4R)-4-(4-bromophenyl)-1-ethyl-3-fluoropiperidine (3S,4S)-4-(4-bromophenyl)-3-fluoropiperidine hydrochloride or (3R,4R)-4-(4-bromophenyl)-3-fluoropiperidine hydrochloride (9.50 g, 32.2 mmol, Eq: 1.0) was added to a solution in THF (148 mL) with NEt3 (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 rt. The reaction mixture was stirred at 35°C for 30 minutes and at 55°C for 3 hours. The reaction mixture was poured into RINKAN and washed with Na2CO3 / water and brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude substance was purified by flash chromatography (silica gel, 40 g, 1% MeOH in DCM) to obtain the title compound as a yellow oil (7.20 g, 74% yield). m / z 287.9[M+H] + ,ESI pos. Step 6: [4-[(3S,4S)-1-ethyl-3-fluoro-4-piperidyl]phenyl]boronic acid or [4-[(3R,4R)-1-ethyl-3-fluoro-4-piperidyl]phenyl]boronic acid A solution of (3S,4S)-4-(4-bromophenyl)-1-ethyl-3-fluoropiperidine or (3R,4R)-4-(4-bromophenyl)-1-ethyl-3-fluoropiperidine (1.000 g, 3.49 mmol, Eq: 1.0) in THF (8.0 mL) was cooled to -76°C. n-butyllithium (1.6 M in hexane, 2.4 mL, 3.84 mmol, Eq: 1.1) was added dropwise, and the reaction mixture was stirred at -76°C for 2 hours. Triethyl borate (618 mg, 0.72 mL, 4.23 mmol, Eq: 1.21) was added at -76°C, and the reaction mixture was stirred at -76°C for 15 minutes. Then, the dry ice bath was removed, and the reaction mixture was stirred at rt (1.5 h). The reaction mixture was quenched with saturated NH4Cl aqueous solution (10 mL) and stirred at rt for 15 minutes. The mixture was extracted with ethyl acetate. The aqueous layer was back-extracted with ethyl acetate. The organic layers were washed with water and brine. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude material was purified by flash chromatography (silica gel, 24 g, 0%-10% MeOH in DCM) to obtain the title compound as an off-white solid (744 mg, 90% purity, 76% yield). m / z 252.2 [M+H] + ESI pos.

[0099] (1-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)piperidine-4-yl)methanol [1-[2-(4-bromophenoxy)ethyl]-4-piperidyl]methanol (CAS 1226008-23-6, 1.3 g, 4.14 mmol, Eq: 1), bis(pinacolate)diborone (1.16 g, 4.55 mmol, Eq: 1.1), and potassium acetate (1.22 g, 12.4 mmol, Eq: 3.0) were added to a mixture in 1,4-dioxane (15 mL) to which Pd(dppf)Cl2·CH2Cl2 (303 mg, 414 μmol, Eq: 0.1). The reaction mixture was flashed with argon and stirred at 90°C for 3 hours. The reaction mixture was concentrated in vacuum and purified by flash chromatography (silica gel, 50 g, 0%~20% MeOH in DCM) to obtain the title compound as a dark brown oil (1.45 g, 80% purity, 77% yield). m / z 362.2 [M+H] + ESI pos.

[0100] (1-((3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)bicyclo[1.1.1]pentan-1-yl)methyl)piperidine-4-yl)methanol In a heat-dried flask, (1-((3-(4-bromophenyl)bicyclo[1.1.1]pentan-1-yl)methyl)piperidine-4-yl)methanol (295 mg) as described in step 3 of Example 50 was dissolved in 1,4-dioxane (6.58 ml) under an inert atmosphere. Bis(pinacolate)diborone (235 mg) and potassium acetate (248 mg) were added. The mixture was degassed under sonication, and then 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (75.6 mg) was added. The flask was placed on a heat block preheated to 90°C with a reflux condenser. The reaction mixture was stirred for 40 minutes. The reaction mixture was transferred to a 150 mL round-bottom flask and the isolate was added. The solvent was removed, and the residue was loaded onto an amine-modified gel (0-10% DCM:MeOH, 40 g) for flash column chromatography. All fractions containing the product were combined and concentrated to obtain the title compound (286 mg) as a brown solid. MS: m / e = 398.3 ([M+H]+)

[0101] 1-(2-methoxyethyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine Step 1: 4-(4-bromophenyl)-1-(2-methoxyethyl)piperidine To a solution of 4-(4-bromophenyl)piperidine (7 g, 29.1 mmol, Eq: 1.0, CAS 80980-89-8), 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. The reaction mixture was stirred at rt for 3 hours and at 50°C for 16 hours. The reaction mixture was poured into H2O and extracted with AcOEt (2×). The organic layers were combined, dried over Na2SO4, and concentrated under vacuum. The crude product was purified by flash chromatography (silica gel, 80 g, 0%~10% MeOH in DCM) to obtain the title compound as a yellow semi-solid (5.08 g, yield 58%). m / z 300.1[M+H]+,ESI pos. Step 2: 1-(2-methoxyethyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl]piperidine 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), bis(pinacolate)diborone (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) were added. The reaction mixture was flushed with argon and stirred at 90°C for 3 hours. The crude product was purified by flash chromatography (Si-amine, 40 g, 0%~10% MeOH in siRNA) to obtain the title compound as a brown liquid (1.98 g, 24% yield, 70% purity). m / z 346.2 [M+H]+, ESI pos.

[0102] Example 1 2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(7-methyl-6-(4-morpholinophenyl)-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide TIFF0007840324000015.tif63170 Step 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 A solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (3.76 g) in tetrahydrofuran (28.8 ml) was cooled in an ice bath. Carbonyl diimidazole (2.62 g) was added. The condenser was removed and the mixture was stirred for 3 hours to obtain solution A. A solution of ethyl 2-(6-bromo-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)acetate (3.8 g) in tetrahydrofuran (28.8 ml) was cooled to -75°C. THF (8.07 ml) containing LDA, 2 mol / l was added dropwise within 5 minutes. The mixture was stirred at -75°C for 40 minutes. Solution A was added dropwise within 5 minutes. The mixture was warmed to room temperature overnight in a condenser. After adding saturated NH4Cl aqueous solution, the mixture was extracted twice with RINKAN. The organic layers were washed with water, combined, dried over sodium sulfate, and concentrated to dryness to obtain the crude title compound (7.69 g), which was used in the next step without further purification. MS: m / e = 578.4 ([MH] - ) Step 2: 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 A solution of tert-butyl (2S,4R)-2-(2-(6-bromo-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-3-ethoxy-3-oxopropanoyl)-4-fluoropyrrolidine-1-carboxylate (7.69 g) in 4 M HCl with dioxane (23.2 ml) was stirred at room temperature for 1 hour. The mixture was concentrated to dryness. The residue was dissolved in ethanol (67.3 ml), and potassium thiocyanate (1.71 g) and 1 M HCl (EtOH) (26.5 ml) were added and stirred overnight. Water was added, and the mixture was extracted with ELISA. The organic layer was washed with water, dried over MgSO4, filtered, concentrated, and dried to obtain the crude title compound (5.32 g), which was used in the next step without further purification. MS: m / e = 519.3 ([MH] - ) Step 3: 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 A solution of 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 (5.32 g) in AcOH (20 ml) and water (2 ml) was cooled to 10°C. 35% hydrogen peroxide (6.64 g) was added dropwise. The reaction mixture was stirred at room temperature for 2.5 hours. Excess hydrogen peroxide was destroyed by the addition of saturated sodium sulfite solution. After adding some water (enough to dissolve all the salts) and ethyl acetate, the mixture was brought to pH 9 by carefully adding solid sodium carbonate. The mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated. The product was purified by chromatography (SiO2, ethyl acetate) to obtain the title compound (1.14 g) as a brown solid. MS:m / e=489.3([M+H] + ) Step 4: Ethyl 2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(7-methyl-6-(4-morpholinophenyl)-4-(trifluoromethyl)-2H-indazol-2-yl)acetate 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 (130 mg), (4-morpholinophenyl)boronic acid (68.8 mg), and cesium carbonate (260 mg) were mixed with toluene (3.71 ml) and N,N-dimethylacetamide (2.23 ml), and the mixture was degassed by bubbling argon through it under sonication. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (19.4 mg) was added, and the mixture was stirred in a shielded tube at 115°C for 40 minutes. The mixture was cooled to room temperature, diluted with ethyl acetate, washed with water, dried over sodium sulfate, and concentrated. The crude substance was purified by flash chromatography (SiO2, SiO2) to obtain the title compound (111.7 mg) as a light brown solid. MS: m / e = 570.4 ([MH] - ) Step 5: 2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(7-methyl-6-(4-morpholinophenyl)-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide Ethyl 2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(7-methyl-6-(4-morpholinophenyl)-4-(trifluoromethyl)-2H-indazol-2-yl) acetate (111 mg) was added to THF (1.93 ml), to which 1 M LiOH (233 μl) and water (643 μl) were added. The mixture was stirred at room temperature for 1 hour. HCl, 1 M water (233 μl), and water (10 ml) were added. The THF was evaporated without heating. The precipitated solid was collected by filtration, washed with water, and dried to obtain crude 2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(7-methyl-6-(4-morpholinophenyl)-4-(trifluoromethyl)-2H-indazol-2-yl)acetic acid (84.6 mg) as an off-white solid. The acid was dissolved in DMF (2.75 ml). Thiazol-2-amine (20.3 mg), HATU (76.9 mg), and Hünig base (60.4 mg) were added, and the mixture was stirred at room temperature for 1 hour and left overnight. Water was added, and the mixture was extracted with ethyl acetate. The tissue layers were combined, dried, filtered, and concentrated. The crude substance was purified by flash chromatography (0% to 40% MeOH in SiO2, AcOEt) to obtain the title compound (86 mg) as a light brown solid. MS: m / e = 626.3 ([M + H] + )

[0103] Example 2 rac-2-(6-(4-(2-(dimethylamino)ethyl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide TIFF0007840324000016.tif63170 Step 1: rac-ethyl 2-(6-(4-(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate Similar to step 4 of Example 1, rac-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 1, step 3) was reacted with (4-(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)phenyl)boronic acid in toluene in the presence of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and cesium carbonate to obtain the title compound as a light brown solid. MS: m / e = 644.4 ([M+H] + ) Step 2: rac-tert-butyl (4-(2-(1-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-6-yl)phenethyl)(methyl)carbamate Similar to step 5 of Example 1, rac-ethyl 2-(6-(4-(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl) acetate was first treated with LiOH, and the resulting acid was reacted with thiazole-2-amine in the presence of HATU and a Hünig base to obtain the title compound as a light brown oil. MS: m / e = 698.7 ([M+H] + ) Step 3: rac-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(7-methyl-6-(4-(2-(methylamino)ethyl)phenyl)-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide hydrochloride rac-tert-butyl (4-(2-(1-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-6-yl)phenethyl)(methyl)carbamate (60.7 mg) was added to a solution containing dichloromethane (2 ml) and methanol (1 ml), to which HCl, 4 M in dioxane (1.09 ml) was added. The mixture was stirred at room temperature for 3 hours. The mixture was concentrated, suspended once in dichloromethane, concentrated again, and dried to obtain the crude title compound (87.2 mg) as a light brown oil. MS: m / e = 596.3 ([MH]-) Step 4: rac-2-(6-(4-(2-(dimethylamino)ethyl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide rac-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(7-methyl-6-(4-(2-(methylamino)ethyl)phenyl)-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide hydrochloride (87.2 mg) and water containing 37% formaldehyde (24.8 mg) were combined with ethanol (2 ml) under argon. After stirring for 10 minutes, sodium triacetoxyborohydride (175 mg) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into a saturated aqueous solution of NaHCO3 and extracted with ethyl acetate. The organic layers were combined and washed with brine. The organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude substance was purified by flash chromatography (NH2-SiO2, 0%-5% MeOH in dichloromethane) to obtain the title compound (28.8 mg) as an off-white solid. MS: m / e = 610.5 ([MH] - )

[0104] Example 3 2-(6-(4-((3S,4S)-1-ethyl-3-fluoropiperidine-4-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide or 2-(6-(4-((3R,4R)-1-ethyl-3-fluoropiperidine-4-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide TIFF0007840324000017.tif75170 Step 1: Ethyl 2-(6-(4-((3S,4S)-1-ethyl-3-fluoropiperidine-4-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl) acetate or Ethyl 2-(6-(4-((3R,4R)-1-ethyl-3-fluoropiperidine-4-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl) acetate Similar to step 4 of Example 1, rac-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 (Step 3 of Example 1) was reacted with [4-[(3S,4S)-1-ethyl-3-fluoro-4-piperidyl]phenyl]boronic acid or [4-[(3R,4R)-1-ethyl-3-fluoro-4-piperidyl]phenyl]boronic acid or [4-[(3R,4R)-1-ethyl-3-fluoro-4-piperidyl]phenyl]boronic acid in toluene in the presence of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and cesium carbonate to obtain the title compound as a light brown solid. MS:m / e=614.5([MH] - ) Step 2: 2-(6-(4-((3S,4S)-1-ethyl-3-fluoropiperidine-4-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide or 2-(6-(4-((3R,4R)-1-ethyl-3-fluoropiperidine-4-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide Similar to step 5 of Example 1, ethyl 2-(6-(4-((3S,4S)-1-ethyl-3-fluoropiperidine-4-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl) acetate or ethyl 2-(6-(4-((3R,4R)-1-ethyl-3-fluoropiperidine-4-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl) acetate was first treated with LiOH, and the resulting acid was reacted with thiazole-2-amine in the presence of HATU and a Hünig base to obtain the title compound as an off-white solid. MS: m / e = 668.5 ([MH] - )

[0105] Example 4 2-[6-[4-[(dimethylamino)methyl]phenyl]-7-methyl-4-(trifluoromethyl)indazol-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-(1,3-thiazol-2-yl)acetamide TIFF0007840324000018.tif64170 Step 1: Ethyl 2-(6-(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate Similar to step 4 of Example 1, rac-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 1, step 3) was reacted with (4-(((tert-butoxycarbonyl)aminomethyl)phenyl)boronic acid in toluene in the presence of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and cesium carbonate to obtain the title compound as an off-white solid. MS: m / e = 616.7 ([M+H] + ) Step 2: tert-butyl (4-(2-(1-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-6-yl)benzyl)carbamate Similar to step 5 of Example 1, ethyl 2-(6-(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl) acetate was first treated with LiOH, and the resulting acid was reacted with thiasol-2-amine in the presence of HATU and a Hünig base to obtain the title compound as a light brown solid. MS: m / e = 670.4 ([M+H] + ) Step 3: 2-(6-(4-(aminomethyl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide Similar to step 3 of Example 2, a solution of tert-butyl (4-(2-(1-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-6-yl)benzyl)carbamate in a mixture of dichloromethane and methanol was treated with HCl in dioxane to obtain the title compound as a bright yellow solid. MS: m / e = 568.3 ([MH] - ) Step 4: rac-2-(6-(4-(2-(dimethylamino)ethyl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide Similar to step 4 of Example 2, 2-(6-(4-(aminomethyl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide was reacted with formaldehyde in the presence of sodium triacetoxyborohydride to obtain the title compound as an off-white solid. MS: m / e = 596.5 ([MH] - )

[0106] Example 5 2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(2-(4-(hydroxymethyl)piperidine-1-yl)ethoxy)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide TIFF0007840324000019.tif64170 Step 1: Ethyl 2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(2-(4-(hydroxymethyl)piperidine-1-yl)ethoxy)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)acetate Similar to step 4 of Example 1, rac-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 1, step 3) was reacted with (1-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)piperidine-4-yl)methanol in a mixture of THF and water in the presence of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and cesium carbonate to obtain the title compound as a brown solid. MS: m / e = 644.4 ([M+H] + ) Step 2: 2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(2-(4-(hydroxymethyl)piperidine-1-yl)ethoxy)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide Similar to step 5 of Example 1, ethyl 2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(2-(4-(hydroxymethyl)piperidine-1-yl)ethoxy)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl) acetate was first treated with LiOH, and the resulting acid was reacted with thiasol-2-amine in the presence of HATU and a Hünig base to obtain the title compound as a brown solid. MS: m / e = 698.3 ([M+H] + )

[0107] Example 6 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(1-ethylpiperidine-4-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide TIFF0007840324000020.tif67170 process 1: tert-butyl (2R)-2-(2-(6-bromo-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate (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 (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. Then, the solution of the activated amide prepared above in THF (15 ml) was added dropwise 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 (6.0 g, purity approximately 68%), which was used in the next step without further purification. MS: m / e = 564.1 ([M + H] + ) 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 Similar to steps 2 and 3 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 with 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]+) Step 3: Ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(1-ethylpiperidine-4-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)acetate Similar to step 4 of Example 1, 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 was reacted with 1-ethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine in a mixture of THF and water in the presence of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and cesium carbonate to obtain the title compound as a light brown solid. MS: m / e = 580.5 ([M+H] + ) Step 4: 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(1-ethylpiperidine-4-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide Similar to step 5 of Example 1, ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(1-ethylpiperidine-4-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl) acetate was first treated with LiOH, and the resulting acid was reacted with thiasol-2-amine in the presence of HATU and a Hünig base to obtain the title compound as a bright red solid. MS: m / e = 634.5 ([M + H] + )

[0108] Example 7 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-((dimethylamino)methyl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide TIFF0007840324000021.tif62170 Step 1: Ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-((dimethylamino)methyl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)acetate Similar to step 4 of Example 1, 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 6, step 2) was reacted with N,N-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methaneamine (CAS: 878197-87-6) in a mixture of THF and water in the presence of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and cesium carbonate to obtain the title compound as a light brown solid. MS: m / e = 526.4 ([M+H] + ) Step 2: 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-((dimethylamino)methyl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide Similar to step 5 of Example 1, ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-((dimethylamino)methyl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl) acetate was first treated with LiOH, and the resulting acid was reacted with thiazole-2-amine in the presence of HATU and a Hünig base to obtain the title compound as a colorless rubber. MS: m / e = 578.4 ([MH] - )

[0109] Example 8 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(3-((4-(hydroxymethyl)piperidine-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide TIFF0007840324000022.tif68170 Step 1: Ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(3-((4-(hydroxymethyl)piperidine-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)acetate Similar to step 4 of Example 1, 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 6, step 2) was reacted with (1-((3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)bicyclo[1.1.1]pentan-1-yl)methyl)piperidine-4-yl)methanol in a mixture of THF and water in the presence of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and cesium carbonate to obtain the title compound as a brown solid. MS: m / e = 662.5 ([M+H] + ) Step 2: 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(3-((4-(hydroxymethyl)piperidine-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide Similar to step 5 of Example 1, ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(3-((4-(hydroxymethyl)piperidine-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl) acetate was first treated with LiOH, and the resulting acid was reacted with thiasol-2-amine in the presence of HATU and a Hünig base to obtain the title compound as a light brown solid. MS: m / e = 716.5 ([M+H] + )

[0110] Example 9 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(1-(2-methoxyethyl)piperidine-4-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide TIFF0007840324000023.tif70170 Step 1: Ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(1-(2-methoxyethyl)piperidine-4-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)acetate Similar to step 4 of Example 1, 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 6, step 2) was reacted with 1-(2-methoxyethyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine in a mixture of THF and water in the presence of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and cesium carbonate to obtain the title compound as a brown solid. MS: m / e = 610.3 ([M+H] + ) Step 2: 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(1-(2-methoxyethyl)piperidine-4-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide Similar to step 5 of Example 1, ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(1-(2-methoxyethyl)piperidine-4-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl) acetate was first treated with LiOH, and the resulting acid was reacted with thiasol-2-amine in the presence of HATU and a Hünig base to obtain the title compound as a brown solid. MS: m / e = 664.4 ([M+H] + )

[0111] Example 10 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(2-(4-(hydroxymethyl)piperidine-1-yl)ethoxy)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide TIFF0007840324000024.tif62170 Step 1: Ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(2-(4-(hydroxymethyl)piperidine-1-yl)ethoxy)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)acetate Similar to step 4 of Example 1, 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 6, step 2) was reacted with (1-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)piperidine-4-yl)methanol in a mixture of THF and water in the presence of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and cesium carbonate to obtain the title compound as a brown solid. MS: m / e = 626.3 ([M+H] + ) Step 2: 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(2-(4-(hydroxymethyl)piperidine-1-yl)ethoxy)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide Similar to step 5 of Example 1, ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(2-(4-(hydroxymethyl)piperidine-1-yl)ethoxy)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl) acetate was first treated with LiOH, and the resulting acid was reacted with thiasol-2-amine in the presence of HATU and a Hünig base to obtain the title compound as a brown solid. MS: m / e = 680.3 ([M+H] + )

[0112] Example 11 2-(7-(difluoromethyl)-6-(4-morpholinophenyl)-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide TIFF0007840324000025.tif63170 Step 1: tert-butyl (2S,4R)-2-(2-(6-bromo-7-(difluoromethyl)-4-(trifluoromethyl)-2H-indazol-2-yl)-3-ethoxy-3-oxopropanoyl)-4-fluoropyrrolidine-1-carboxylate Similar to Step 1 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-(difluoromethyl)-4-(trifluoromethyl)-2H-indazol-2-yl)acetate was deprotonated using LDA and treated with solution A at -78°C. After stirring overnight at room temperature and investigating in the same manner as in Step 1 of Example 1, the crude title compound was obtained and used in the next step without further purification. MS: m / e = 618.3 ([M+H] + ), Br isotope Step 2: Ethyl 2-(6-bromo-7-(difluoromethyl)-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 Similar to step 2 of Example 1, tert-butyl (2S,4R)-2-(2-(6-bromo-7-(difluoromethyl)-4-(trifluoromethyl)-2H-indazol-2-yl)-3-ethoxy-3-oxopropanoyl)-4-fluoropyrrolidine-1-carboxylate was deprotected with HCl in dioxane, and subsequently reacted with potassium thiocyanate to obtain the crude title compound, which was used in the next step without further purification. MS: m / e = 557.2 ([M+H] + ), Br. Step 3: Ethyl 2-(6-bromo-7-(difluoromethyl)-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate Similar to step 3 of Example 1, ethyl 2-(6-bromo-7-(difluoromethyl)-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 bright yellow solid. MS: m / e = 457.1 ([M+H] + , Br. Step 4: Ethyl 2-(4-chloro-7-fluoro-6-(4-morpholinophenyl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate Similar to step 4 of Example 1, ethyl 2-(6-bromo-7-(difluoromethyl)-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl) acetate was treated with (4-morpholinophenyl)boronic acid in dioxane in the presence of cesium carbonate and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) to obtain the title compound as an off-white solid. MS: m / e = 608.4 ([M+H]+) Step 5: 2-(7-(difluoromethyl)-6-(4-morpholinophenyl)-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide Similar to step 5 of Example 1, ethyl 2-(4-chloro-7-fluoro-6-(4-morpholinophenyl)-2H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl) acetate was first treated with LiOH, and the resulting acid was reacted with thiazole-2-amine in the presence of HATU and a Hünig base to obtain the title compound as a yellow solid. MS: m / e = 662.4 ([M + H]+)

[0113] Example 12 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.

[0114] 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.

[0115] The results are shown in Table 1. TIFF0007840324000026.tif221170TIFF0007840324000027.tif220170TIFF0007840324000028.tif219170

Claims

1. Equation (I) [In the formula, R １ and R ２ These are independently selected from halogens and hydrogen; R ３ is alkyl or haloalkyl; R ４ [These are heterocycloalkyl, dialkylaminoalkyl, (alkyl)(halo)heterocycloalkyl, hydroxyalkylheterocycloalkylalkoxy, alkylheterocycloalkyl, hydroxyalkylheterocycloalkylalkylcycloalkyl, or alkoxyalkylheterocycloalkyl] Compounds thereof, or pharmaceutically acceptable salts thereof.

2. R １ and R ２ The compound according to claim 1, wherein fluorine and hydrogen are selected independently.

3. R １ and R ２ The compound according to claim 1, wherein one of the elements is fluorine and the other is hydrogen.

4. R ３ The compound according to any one of claims 1 to 3, wherein R is alkyl or difluoroalkyl.

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

6. R ４ The compound according to any one of claims 1 to 5, wherein the compound is morpholinyl, dialkylaminoalkyl, (alkyl)(halo)piperidinyl, hydroxyalkylpiperidinylalkoxy, alkylpiperidinyl, hydroxyalkylpiperidinylalkyl(bicyclo[1.1.1]pentanyl), or alkoxyalkylpiperidinyl.

7. R ４ The compound according to any one of claims 1 to 6, wherein the compound is morpholinyl, dimethylaminoethyl, dimethylaminomethyl, (ethyl)(fluoro)piperidinyl, hydroxymethylpiperidinylethoxy, ethylpiperidinyl, hydroxymethylpiperidinylmethyl(bicyclo[1.1.1]pentanyl), or methoxyethylpiperidinyl.

8. 2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(7-methyl-6-(4-morpholinophenyl)-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; rac-2-(6-(4-(2-(dimethylamino)ethyl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; 2-(6-(4-((3S,4S)-1-ethyl-3-fluoropiperidine-4-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; 2-(6-(4-((3R,4R)-1-ethyl-3-fluoropiperidine-4-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; 2-[6-[4-[(dimethylamino)methyl]phenyl]-7-methyl-4-(trifluoromethyl)indazol-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-(1,3-thiazol-2-yl)acetamide; 2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(2-(4-(hydroxymethyl)piperidine-1-yl)ethoxy)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(1-ethylpiperidine-4-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-((dimethylamino)methyl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(3-((4-(hydroxymethyl)piperidine-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(1-(2-methoxyethyl)piperidine-4-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(2-(4-(hydroxymethyl)piperidine-1-yl)ethoxy)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; and 2-(7-(difluoromethyl)-6-(4-morpholinophenyl)-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; A compound according to any one of claims 1 to 7, selected from, or a pharmaceutically acceptable salt thereof.

9. 2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(7-methyl-6-(4-morpholinophenyl)-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; rac-2-(6-(4-(2-(dimethylamino)ethyl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; 2-[6-[4-[(dimethylamino)methyl]phenyl]-7-methyl-4-(trifluoromethyl)indazol-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-(1,3-thiazol-2-yl)acetamide; 2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(2-(4-(hydroxymethyl)piperidine-1-yl)ethoxy)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-((dimethylamino)methyl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(3-((4-(hydroxymethyl)piperidine-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(2-(4-(hydroxymethyl)piperidine-1-yl)ethoxy)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; and 2-(7-(difluoromethyl)-6-(4-morpholinophenyl)-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; A compound according to any one of claims 1 to 8, selected from, or a pharmaceutically acceptable salt thereof.

10. A method for preparing a compound according to any one of claims 1 to 9, (a) Compound of formula (B1) The compounds of formula (B2) are reacted in a suitable solvent in the presence of a base to obtain the compound of formula (B2). [In the formula, M ＋ is Na ＋ Li ＋ The process of bringing the base to a state that is either a protonated base or a protonated base; (b) React the compound of formula (B2) in a suitable solvent in the presence of an acid to obtain the compound of formula (B3). The process of obtaining; (c) Compound of formula (B3) and compound of formula (B4) The process involves reacting the two in the presence of a coupling agent and a base; Includes R １ , R ２ , R ３ , and R ４ A method as described in any one of claims 1 to 9, wherein R is H or alkyl.

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

12. A pharmaceutical agent for treating or preventing cancer, comprising the compound described in any one of claims 1 to 9.

13. The pharmaceutical product according to claim 12, wherein the cancer is non-small cell lung cancer.

14. Use of the compound according to any one of claims 1 to 9 for preparing a medicament for treating or preventing cancer.

15. The use according to claim 14, wherein the cancer is non-small cell lung cancer.

Images