Combinations of allosteric and orthosteric EGFR inhibitors for the treatment of cancer

Abstract

The present invention relates to a combination therapy for cancer with an allosteric EGFR inhibitor and an orthosteric EGFR inhibitor, as well as its use and pharmaceutical composition.

Description

Technical Field

[0001] The present invention relates to a novel combination of an orthosteric EGFR inhibitor and a selective allosteric EGFR inhibitor of T790M / L858R, T790M / L858R / C797S, L858R, L858R / C797S containing an EGFR variant, and its use and pharmaceutical composition.

[0002] In particular, the present invention is a combination of an allosteric EGFR inhibitor and an orthosteric EGFR inhibitor, wherein the allosteric EGFR inhibitor has the formula (I) TIFF2025516543000001.tif52170 (wherein, L is a bond or alkynylene, R 1 is hydrogen or halogen, R 2 and R 2’ are independently selected from hydrogen and alkyl, or or R 2 and R 2’ together with the carbon atom to which they are attached form cycloalkyl, R 3 is hydrogen, halogen or haloalkyl, R 4 is alkyl or halogen, R 5 is (heterocycloalkyl) alkylene or heterocycloalkyl, and (heterocycloalkyl) alkylene may be substituted with one or two substituents independently selected from R 6 and heterocycloalkyl may be substituted with one or two substituents independently selected from R 7 and R 6 in each case is independently selected from alkyl, cycloalkyl, hydroxy and hydroxyalkyl, R 7which, in each case, is independently selected from alkyl, cycloalkyl, hydroxy and hydroxyalkyl) provides a combination which is a compound of 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 different members, namely, epidermal growth factor receptor (EGFR, ErbB1, or HER1), HER2 (ErbB2), HER3 (ErbB3), and HER4 (ErbB4). When a ligand binds, 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, M. X. Untangling the ErbB signalling network. Nature Review Mol Cell Biol. 2001 Feb;2(2):127-37). Dysregulation of EGFR by overexpression or mutation is associated with many types of human cancer, including colorectal cancer, pancreatic cancer, glioma, head and neck cancer, and lung cancer, particularly non-small cell lung cancer (NSCLC), and several EGFR targeting agents have been developed over 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 for the treatment of recurrent NSCLC.

[0004] In a subset of NSCLC patients with tumors having somatic kinase domain mutations, significant single-agent activity of EGFR tyrosine kinase inhibitors is observed, but the clinical benefit in wild-type EGFR patients is substantially reduced (Paez, J. et al. (2004). EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science (New York, NY 304, 1497-1500)). The most common somatic mutations of EGFR are exon 19 deletions with delta746-750 being the most common mutation and exon 21 amino acid substitutions with L858R being the most frequent mutation (Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 2007 Mar;7(3):169-81).

[0005] Treatment resistance occurs frequently and is often due to secondary T790M mutations within the ATP-binding site of the receptor. Some of the developed mutant-selective irreversible inhibitors, such as osimertinib, almonertinib, lazertinib, and flumonertinib, etc., are highly active against the T790M variant, but their effectiveness may be impaired by acquired mutations in C797S, the cysteine residue that forms the key covalent bond (Thress, K. S. et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat. Med. 21, 560 - 562 (2015)). The C797S mutation was further reported by Wang to be a major mechanism of resistance to T790M-targeted EGFR inhibitors (Wang et al. EGFR C797S mutation mediates resistance to third-generation inhibitors in T790M-positive non-small cell lung cancer, J Hematol Oncol. 2016;9:59). Additional mutations causing resistance to osimertinib, such as L718Q, have been described by Yang (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 EGFRL858R / T790M and EGFRL858R / T790M / C797S resistance mutations in NSCLC: Current developments in medicinal chemistry, Med Res Rev 2018;1-32) reported a review article on targeting EGFRL858R / T790M and EGFRL858R / T790M / C797S resistance mutations in NSCLC treatment.

[0006] Since the most available EGFR tyrosine kinase inhibitors target the ATP site of the kinase, new therapeutic agents with different functions are needed, such as targeting drug-resistant EGFR variants.

[0007] Recent studies have suggested that targeting allosteric sites intentionally 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).

[0008] Therefore, there is a need to generate selective molecules that specifically inhibit T790M / L858R, T790M / L858R / C797S, L858R, and L858R / C797S, including EGFR variants. Such selective inhibitors may be useful for the therapeutic and / or prophylactic treatment of cancer, especially T790M and C797S containing EGFR variants.

[0009] Importantly, such selective allosteric inhibitors are designed to treat cancers characterized by EGFR variants that are resistant to orthosteric EGFR inhibitors. Reasonably, once drug resistance occurs, the treatment can be switched from an orthosteric EGFR inhibitor to an allosteric EGFR inhibitor specially designed to target variants with the T790M and / or C797S mutations.

Summary of the Invention

[0010] The present invention relates to a combination of an orthosteric EGFR inhibitor and a selective allosteric EGFR inhibitor corresponding to the compound of formula (I). The compound of formula (I) efficiently targets the T790M / L858R, T790M / L858R / C797S, L858R, L858R / C797S mutations and has low hepatic clearance in vitro (Tables 1 and 2). Importantly, the compound of formula (I) also efficiently targets the L858R / C797S mutation in vivo in Ba / F3-based xenografts (Figure 1), which are mutations that cause resistance to orthosteric EGFR inhibitors. Surprisingly, combination treatment at clinically relevant doses of the approved orthosteric EGFR inhibitor osimertinib and the allosteric EGFR inhibitor of formula (I) dramatically improved tumor regression in mice bearing the NCI-H1975 xenograft (which is an established model of EGFR-driven NSCLC with double mutations) (Figure 2). Importantly, the binding of the EGFR inhibitor of formula (I) increased the residence time of the orthosteric EGFR inhibitor osimertinib by about 120-fold, thus accelerating the rate at which osimertinib covalently binds to EGFR (Figure 3). This surprising positive synergy between the allosteric EGFR inhibitor of formula (I) and the orthosteric EGFR inhibitor provides a promising new treatment strategy for patients with EGFR-related cancers, particularly non-small cell lung cancer, which has not been reported previously. L858R / T790M Importantly, the binding of the EGFR inhibitor of formula (I) increased the residence time of the orthosteric EGFR inhibitor osimertinib by about 120-fold, thus accelerating the rate at which osimertinib covalently binds to EGFR (Figure 3). This surprising positive synergy between the allosteric EGFR inhibitor of formula (I) and the orthosteric EGFR inhibitor provides a promising new treatment strategy for patients with EGFR-related cancers, particularly non-small cell lung cancer, which has not been reported previously.

Brief Description of the Drawings

[0011]

Figure 1

Figure 2

Figure 3

[0012] The term "inhibitor" refers to a compound that competes with the binding of a specific ligand to a specific receptor, reduces binding, or prevents binding, or a compound that reduces or prevents the function of a specific protein. In particular, the inhibitors used therein refer to compounds that target, reduce, or inhibit EGFR activity, and certain inhibitors have an IC50 value of less than 1 μM, less than 500 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 25 nM, less than 10 nM, less than 5 nM, less than 2 nM, or less than 1 nM. In some embodiments of the present invention, the term "EGFR inhibitor" refers to a compound that reduces EGFR kinase activity by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99%. The term "orthosteric EGFR inhibitor" refers to an EGFR inhibitor that binds near the active site, such as erlotinib, gefitinib, osimertinib, almonertinib, lazertinib, and flumonertinib, or a pharmaceutically acceptable salt thereof, particularly the mesylate salt. Non-limiting examples of orthosteric EGFR inhibitors include cetuximab (Erbitux®), panitumumab (Vectibix®), osimertinib (merelectinib, Tagrisso®), erlotinib (Tarceva®), gefitinib (Iressa®), necitumumab (Portrazza™), neratinib (Nerlynx®), lapatinib (Tykerb®), vandetanib (Caprelsa®), and brigatinib (Alunbrig®).

[0013] The term "IC50" refers to the concentration of a specific compound required to inhibit 50% of a specific measured activity.

[0014] As used herein, the term "alkyl" alone or in combination means a straight or branched chain alkyl group having from 1 to 8 carbon atoms, particularly a straight or branched chain alkyl group having from 1 to 6 carbon atoms, more particularly a straight or branched chain alkyl group having from 1 to 4 carbon atoms. Examples of straight and branched chain C1-C8 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, isomeric pentyl, isomeric hexyl, isomeric heptyl, and isomeric octyl, particularly methyl, ethyl, propyl, butyl, and pentyl. Specific examples of "alkyl" are methyl, ethyl, propyl, isopropyl, and tert-butyl. Methyl is a specific example of "alkyl" in the compounds of formula (I).

[0015] The term "alkoxy" or "alkyloxy" alone or in combination means a group of the formula alkyl-O- where the term "alkyl" has the meaning given above, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. Specific examples of "alkoxy" are methoxy, ethoxy, and tert-butoxy.

[0016] The term "alkylene" alone or in combination denotes a straight chain saturated divalent hydrocarbon group of 1 to 7 carbon atoms or a divalent branched saturated divalent hydrocarbon group of 3 to 7 carbon atoms. Examples of alkylene groups include methylene, ethylene, propylene, 2-methylpropylene, butylene, 2-ethylbutylene, pentylene, hexylene. A specific example of "alkylene" is methylene.

[0017] The term "alkynylene", alone or in combination, refers to a straight-chain divalent hydrocarbon chain of 2 to 6 carbon atoms or a branched divalent hydrocarbon chain of 3 to 6 carbon atoms having at least one triple bond. Exemplary alkynylenes include ethynylene, 2,2-dimethylethynylene, propynylene, 2-methylpropynylene, butynylene, and pentynylene. A specific example of "alkynylene" is ethynylene.

[0018] The term "oxy", alone or in combination, means an -O- group.

[0019] The term "halogen" or "halo", alone or in combination, means fluorine, chlorine, bromine, or iodine, and in particular, fluorine or chlorine. A specific "halogen" or "halo" is fluorine. The term "halo", in combination with another group, means substitution of the group with at least one halogen, in particular 1 to 5 halogens, especially 1 to 4 halogens, i.e., 1, 2, 3, or 4 halogen substitutions.

[0020] The term "haloalkyl", alone or in combination, represents an alkyl group substituted with at least one halogen, in particular 1 to 5 halogens, especially 1 to 3 halogens. Specific examples of "haloalkyl" are difluoromethyl and trifluoromethyl.

[0021] The terms "hydroxyl" and "hydroxy", alone or in combination, mean an -OH group.

[0022] The term "carbonyl", alone or in combination, means a -C(O)- group.

[0023] The term "heterocycloalkyl", alone or in combination, means a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system consisting of 4 to 9 ring atoms, including 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Bicyclic means consisting of two rings having 1 or 2 ring atoms in common. Examples of "heterocycloalkyl" are morpholinyl, piperidinyl, azetidinyl, and piperazinyl, and specific examples of "heterocycloalkyl" are piperidinyl and morpholinyl.

[0024] The term "cycloalkyl", alone or in combination, represents a monovalent saturated cyclic hydrocarbon group having 3 to 8 ring carbon atoms. Examples of "cycloalkyl" are cyclopropyl, cyclobutanil, cyclopentyl, cyclohexyl, or cycloheptyl. A specific example of a "cycloalkyl" group is cyclopropyl.

[0025] The terms "piperidinyl" and "piperidyl" are interchangeable and, alone or in combination, mean a saturated monocyclic ring containing 5 carbon ring atoms and 1 nitrogen ring atom.

[0026] The term "pharmaceutically acceptable" refers to salts which retain the biological effectiveness and properties of the free bases or free acids and which 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 or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. 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. Particularly pharmaceutically acceptable salts of the compounds of formula (I) are hydrochloride, methanesulfonate, and citrate. A specific pharmaceutically acceptable salt of osimertinib is methanesulfonate, also referred to as mesylate salt.

[0027] In one embodiment, the present invention provides a kit comprising an orthosteric EGFR inhibitor and an allosteric EGFR inhibitor of formula (I) as described herein, prescription information also known as a "leaflet", a blister package or a bottle (HDPE or glass), and a container. The prescription information preferably includes advice to the patient regarding the administration of the combination of the orthosteric EGFR inhibitor and the allosteric EGFR inhibitor treatment as described herein.

[0028] According to the Cahn-Ingold-Prelog rules, an asymmetric carbon atom can have an "R" or "S" configuration. The compounds of formula (I) may contain several asymmetric centers and can exist as optically pure enantiomers, mixtures of enantiomers such as racemates, optically pure diastereoisomers, mixtures of diastereoisomers, racemates of diastereoisomers or mixtures of racemates of diastereoisomers.

[0029] Furthermore, the present invention includes all substituents of the corresponding deuterated forms of the compounds of formula (I) where applicable.

[0030] 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, specifically more than 95% by weight of the desired isomer, or more specifically more than 99% by weight of the desired isomer, and said weight percentages are based on the total weight of the isomers of the compound. Chiral pure or chiral enriched compounds can be prepared by chiral selective synthesis or by separation of enantiomers. Separation of enantiomers can be carried out on the final product or on a suitable intermediate.

[0031] The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments (for example in the form of pharmaceutical preparations). The pharmaceutical preparations of the present invention can be administered orally (for example in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (for example in the form of a nasal spray), rectally (for example in the form of a suppository), or topically to the eye (for example in the form of a solution, ointment, gel or water-soluble polymer insert). However, administration can also be carried out parenterally (for example in the form of a sterile injectable solution), such as intramuscularly, intravenously or intravitreally.

[0032] The compounds of formula (I) and their pharmaceutically acceptable salts can be treated with pharmaceutically inert inorganic or organic adjuvants for the manufacture of tablets, coated tablets, dragees, hard gelatin capsules, injection solutions or topical preparations. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used, for example, as such adjuvants for tablets, dragees and hard gelatin capsules.

[0033] Adjuvants suitable for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances, and liquid polyols, etc.

[0034] Adjuvants suitable for the manufacture of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc.

[0035] Adjuvants suitable for injection solutions are, for example, water, alcohol, polyols, glycerol, vegetable oils, etc.

[0036] Adjuvants suitable for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.

[0037] Suitable adjuvants for ophthalmic topical preparations are, for example, cyclodextrin, mannitol, or many other carriers and additives known in the art.

[0038] Furthermore, pharmaceutical preparations can contain preservatives, solubilizers, viscosity increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for changing the osmotic pressure, buffers, masking agents, or antioxidants. They can also contain still other therapeutically valuable substances.

[0039] The following examples are illustrative but not limiting of the invention. The pharmaceutical composition preferably contains from about 1 to 500 mg, particularly 1 to 100 mg, of the compound of formula (I). The pharmaceutical composition preferably contains from about 1 to 500 mg, particularly 1 to 100 mg, of the compound of formula (II). In certain embodiments, the pharmaceutical composition containing the compound of formula (I) further contains from about 1 to 500 mg, particularly 80 mg, of an orthosteric EGFR inhibitor in a fixed-dose combination.

[0040] Non-limiting examples of the compositions according to the invention are as follows: Preparation of pharmaceutical compositions containing the compounds of the invention: Tablets of the following composition are manufactured by conventional methods: [Table] TIFF2025516543000002.tif68170

[0041] Manufacturing procedure 1. Mix components 1, 2, 3 and 4 and granulate with purified water. 2. Dry the granules at 50 °C. 3. Pass the granules through suitable comminuting equipment. 4. Add component 5, mix for 3 minutes and compress with a suitable press.

[0042] Capsules of the following composition are manufactured by conventional methods. [Table] TIFF2025516543000003.tif69170

[0043] Manufacturing procedure 1. Mix components 1, 2 and 3 in a suitable mixer for 30 minutes. 2. Add components 4 and 5 and mix for 3 minutes. 3. Fill into suitable capsules.

[0044] The compounds 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 approximatively. The mixture is filled into suitable capsules by machine, such as hard gelatin capsules.

[0045] Injection solutions of the following composition are prepared in a conventional manner. [Table] TIFF2025516543000004.tif44170

Examples

[0046] Abbreviations AcOH = acetic acid; ATP = adenosine triphosphate; BID = twice a day; CAS = Chemical Abstracts Service; CDI = 1,1'-carbonyldiimidazole; Cl int = intrinsic clearance; c max = maximum plasma concentration; D = test day; DCM = dichloromethane; DME = dimethoxyethane; DMF = dimethylformamide; DMSO = dimethyl sulfoxide; ESI = electrospray ionization; EtOAc = ethyl acetate; EtOH = ethanol; HATU = O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; LDA = lithium diisopropylamide; MeOH = methanol; MS = mass spectrometry; NMR = nuclear magnetic resonance; PO = per os; QD = once a day; RT = room temperature; SC = subcutaneous; THF = tetrahydrofuran.

[0047] The following examples are provided to illustrate the invention. These should not be construed as limiting the scope of the invention, but rather as representative thereof.

[0048] When a preparation example is obtained as a mixture of enantiomers, the pure enantiomers can be obtained by the methods described herein or methods known to those skilled in the art, such as chiral chromatography or crystallization.

[0049] Example 1 2-[4,7-Dichloro-6-(4-morpholinophenyl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF2025516543000005.tif41170 Step 1: 4-Bromo-3,6-dichloro-2-fluorobenzaldehyde TIFF2025516543000006.tif30170 A solution of 1-bromo-2,5-dichloro-3-fluorobenzene (9.41 g, 38.6 mmol) in tetrahydrofuran (70 ml) was cooled in a dry ice / acetone bath. 2 mol / l LDA (21.2 ml, 42.5 mmol, 1.1 eq) in THF was added and the mixture was stirred at -75 °C for 20 min. N,N-Dimethylformamide (2.82 g, 3.0 ml, 38.6 mmol, 1 eq) was added dropwise and the mixture was stirred for 1 h. An acetic acid solution in ether (1:1, 10 ml) was added. The mixture was warmed to room temperature. After adding water, the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried (MgSO 4 ), filtered, concentrated under reduced pressure, and the crude title compound was obtained as a pale yellow solid in quantitative yield. The compound was used in the next step without further purification.

[0050] Step 2: 6-Bromo-4,7-dichloro-1H-indazole TIFF2025516543000007.tifTo a solution of 4-bromo-3,6-dichloro-2-fluorobenzaldehyde (Example 1, Step 1) (10.5 g, 38.6 mmol) in dioxane (50 ml), hydrazine hydrate (3.86 g, 3.78 ml, 77.2 mmol, 2.0 eq) was added. The mixture was stirred at room temperature for 3 days. Hydrazine hydrate (386 mg, 0.38 ml, 7.72 mmol, 0.2 eq) was added and the mixture was warmed at 70 °C for 7 h. After cooling to room temperature, water was added and the precipitated solid was collected by filtration. A small amount of acetonitrile was added to the solid and stirred for 2 h. The solid was collected by filtration, washed with a small amount of acetonitrile and dried to give the title compound (7.8 g, 76% yield) as a greyish white solid. m / z 267.0 / 269.0, [M+H] + ,ESI pos, Br isotope.

[0051] Step 3: Ethyl 2-(6-bromo-4,7-dichloro-indazol-2-yl)acetate TIFF2025516543000008.tifTo a solution of 6-bromo-4,7-dichloro-1H-indazole (Example 1, Step 2) (7.84 g, 29.5 mmol, eq: 1) in N,N-dimethylacetamide (11.5 mL), ethyl 2-bromoacetate (9.85 g, 6.53 ml, 59 mmol, 2.0 eq) was added. The reaction mixture was stirred at 100 °C for 16 h. Ice was added and the precipitated solid was collected by filtration and washed with water. The compound was crystallized from boiling ethanol. The solid was collected by filtration, washed with a small amount of ethanol and dried to give the title compound as a white solid (7.5 g, 70% yield). m / z 353.0, 355.0, [M+H] + ,ESI pos, Br isotope.

[0052] Step 4: tert-Butyl (2S,4R)-2-[2-(6-bromo-4,7-dichloro-indazol-2-yl)-3-ethoxy-3-oxo-propanoyl]-4-fluoro-pyrrolidine-1-carboxylate A solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (2.34 g, 10 mmol, 1.55 eq) in tetrahydrofuran (11 ml) was cooled in an ice bath. Carbonyldiimidazole (1.63 g, 10 mmol, 1.55 eq) was added. The cooling bath was removed and the mixture was stirred for 3 h to obtain solution A. A solution of ethyl 2-(6-bromo-4,7-dichloro-indazol-2-yl)acetate (Example 1, Step 3) (2.28 g, 6.5 mmol) in tetrahydrofuran (11 ml) was cooled to -70 °C. 2 M LDA in tetrahydrofuran (5.0 ml, 10 mmol, 1.55 eq) was added dropwise within 5 min. The mixture was stirred at -70 °C for 30 min. Solution A was added dropwise within 5 min. The mixture was warmed in the cooling bath overnight to room temperature. After adding saturated NH 4 Cl aqueous solution, the mixture was extracted twice with ethyl acetate. The organic layer was washed with water, combined, dried over sodium sulfate, concentrated to dryness, and the crude title compound (quantitative yield) was obtained and used in the next step without further purification. m / z 566.1 / 568.1, [M+H] + , ESI pos, Br isotope.

[0053] Step 5: Ethyl 2-(6-bromo-4,7-dichloro-indazol-2-yl)-2-[(6R)-6-fluoro-3-thioxo-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl]acetate TIFF2025516543000010.tif A solution of tert-butyl (2S,4R)-2-[2-(6-bromo-4,7-dichloro-indazol-2-yl)-3-ethoxy-3-oxo-propionyl]-4-fluoro-pyrrolidine-1-carboxylate (Example 1, Step 4) (4.23 g, 6.41 mmol) in 4M HCl in dioxane (11 ml) was stirred at room temperature for 1 hour. The mixture was concentrated to dryness. The residue was dissolved in ethanol (37 ml), potassium thiocyanate (829 mg, 8.53 mmol, 1.33 equiv) and 1M HCl in ethanol (12.8 ml) were added, and the mixture was stirred at room temperature for 40 hours. After adding water, the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over MgSO 4 and filtered, concentrated to dryness to give the crude title compound (2.5 g, 76% yield), which was used in the next step without further purification. m / z 509.0 / 511.0, [M+H] + , ESI pos, Br isotope.

[0054] Step 6: Ethyl 2-(6-bromo-4,7-dichloro-indazol-2-yl)-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate TIFF2025516543000011.tif Ethyl 2-(6-bromo-4,7-dichloro-indazol-2-yl)-2-[(6R)-6-fluoro-3-thioxo-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl]acetate (Example 1, Step 5) (1.46 g, 2.88 mmol) in acetic acid (10 ml) was cooled to 10 °C. Hydrogen peroxide, 35% (1.12 g, 1.01 ml, 11.5 mmol, 4 equiv) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. The excess hydrogen peroxide was destroyed by the addition of saturated sodium bisulfite solution. After adding a small amount of water (an amount sufficient to dissolve all salts) and ethyl acetate, the pH was adjusted to 9 by carefully adding solid sodium carbonate to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated. The product was chromatographed (SiO 2, purified by ethyl acetate (0 - 100% in heptane), and the title compound (0.81 g, 58% yield) was obtained as a light brown solid. m / z 475.0 / 477.0, [M+H] + , ESI pos, Br isotope.

[0055] Step 7: Ethyl 2-[4,7-dichloro-6-(4-morpholinophenyl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate TIFF2025516543000012.tif32170 Ethyl 2-(6-bromo-4,7-dichloro-indazol-2-yl)-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (Example 1, Step 6) (100 mg, 0.21 mmol), (4-morpholinophenyl)boronic acid (130 mg, 0.63 mmol, 3 equiv) and cesium carbonate (205 mg, 0.63 mmol, 3 equiv) were mixed in toluene (3.0 ml) and the mixture was degassed by bubbling argon through the mixture under sonication. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15 mg, 0.02 mmol, 0.1 equiv) was added and the mixture was stirred in a sealed tube at 110 °C for 30 minutes. The mixture was cooled to room temperature, diluted with ethyl acetate, washed with semi-concentrated sodium carbonate solution, dried over sodium sulfate and concentrated. The crude material was purified by flash chromatography (SiO 2 , (0% - 40% methanol in ethyl acetate), and the title compound (82 mg, 69% yield) was obtained as a light brown amorphous solid. m / z 558.4, [M+H] + , ESI pos.

[0056] Step 8: 2-[4,7-Dichloro-6-(4-morpholinophenyl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF2025516543000013.tif37170 A solution of ethyl 2-[4,7-dichloro-6-(4-morpholinophenyl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (Example 1, Step 7) (40 mg, 0.071 mmol) in tetrahydrofuran (1.1 ml) was added with 1 M LiOH (101 μl, 0.10 mmol, 1.5 eq) and water (400 μl). The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated and dried. The residue was dissolved in N,N-dimethylformamide (1.1 ml). After adding thiazol-2-amine (9 mg, 0.086 mmol, 1.2 eq), HATU (33 mg, 0.086 mmol, 1.2 eq) and Hunig's base (28 mg, 0.037 ml, 0.21 mmol, 3 eq), the mixture was stirred at room temperature for 1 hour. After adding water, the mixture was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The crude material was purified by flash chromatography (SiO 2 , 0% - 40% methanol in ethyl acetate) to give the title compound (22 mg, 50% yield) as a light brown solid. m / z 612.4, [M+H] + , ESI pos.

[0057] Example 2 2-[4-(Difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF2025516543000014.tif36170 Step 1: Ethyl 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate TIFF2025516543000015.tif351702 - Intermediate 1 (0.5 g, 1.06 mmol, equivalent: 1.0) in MeTHF (6 mL) and water (1 mL), (4 - morpholinophenyl)boronic acid (CAS 186498 - 02 - 2, 329 mg, 1.59 mmol, equivalent: 1.5), and K 2 CO 3 (183 mg, 1.33 mmol, equivalent: 1.25,) suspension was degassed with argon for 10 minutes. Dichloro[bis(diphenylphosphinophenyl)ether]palladium(II) (CAS 205319 - 06 - 8, 91 mg, 127 μmol, equivalent: 0.12) was added. The reaction mixture was stirred at 85 °C for 5 hours. AcOH (191 mg, 182 μL, 3.18 mmol, equivalent: 3.0) was added. The reaction mixture was poured into EtOAc / THF 2:1 and washed with water and brine. The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, 12 g, 0% - 50% in heptane (EtOAc / EtOH / aqueous NH 3 75:25:2)) to give the title compound as an off - white solid (433 mg, 743 μmol, 70% yield). m / z 554.4 [M + H] + , ESI pos.

[0058] Step 2: 2 - [4 - (difluoromethyl) - 7 - methyl - 6 - (4 - morpholinophenyl)indazol - 2 - yl] - 2 - [(6R) - 6 - fluoro - 6,7 - dihydro - 5H - pyrrolo[1,2 - c]imidazol - 1 - yl] - N - thiazol - 2 - yl - acetamide TIFF2025516543000016.tif A solution of ethyl 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (720 mg, 1.3 mmol, equivalent: 1.0) in THF (9 mL) and MeOH (9 mL) was added with LiOH (1 M aqueous solution, 2.6 mL, 2.6 mmol, equivalent: 2.0). The reaction mixture was stirred at room temperature for 2 h. HCl (5 N aqueous solution, 520 μL, 2.6 mmol, equivalent: 2.0) was added (pH 6). Toluene was added and the reaction mixture was concentrated in vacuo. The carboxylic acid was dissolved in DMSO (6 mL), and thiazol-2-amine (195 mg, 1.95 mmol, equivalent: 1.5), DIPEA (840 mg, 1.14 mL, 6.5 mmol, equivalent: 5.0) and HATU (742 mg, 1.95 mmol, equivalent: 1.5) were added. The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was poured into EtOAc / THF 2:1 and washed with water and brine. The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, 40 g, 0% - 5% MeOH in DCM). The product was lyophilized to give the title compound as an off-white solid (501 mg, 63% yield). m / z 608.3 [M+H] + , ESI pos.

[0059] Example 3 2-[4-(Difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazole-5,1'-cyclopropane]-1-yl-N-thiazol-2-yl-acetamide; TIFF2025516543000017.tif Step 1: 1-Bromo-5-(bromomethyl)-3-fluoro-2-methyl-benzene TIFF2025516543000018.tif 26170 A cooled solution of 3-bromo-5-fluoro-4-methylbenzaldehyde (CAS No. 1370411-47-4, 20.5 g, 89.7 mmol, 1.0 equiv) in dichloromethane (98 mL) was added portionwise with morpholinium sulfatotrifluoride (CAS No. 51010-74-3, 24.8 g, 17.3 mL, 135 mmol, 1.5 equiv). The reaction mixture was stirred at 0 - 5 °C for 20 min and then at room temperature for 16 h. Saturated NaHCO 3 aqueous solution (300 mL) was carefully added under ice-cooling. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into dichloromethane and washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the crude material by flash chromatography (silica gel, 120 g, 100% pentane) gave the title compound (18.6 g, 87% yield) as a colorless oil. 1 H NMR (300 MHz, chloroform-d) δ = 7.50 (s, 1H), 7.16 (d, J = 9.1 Hz, 1H), 6.57 (t, J = 56.0 Hz, 1H), 2.50 - 2.22 (m, 3H)

[0060] Step 2: 6-Bromo-4-(difluoromethyl)-7-methyl-1H-indazole A solution of 1-bromo-5-(difluoromethyl)-3-fluoro-2-methyl-benzene (Example 1, Step 1) (26.4 g, 110 mmol, 1.0 eq) in tetrahydrofuran (240 mL) was cooled to -75 °C. While maintaining the temperature below -70 °C, a solution of lithium diisopropylamide (2 M in tetrahydrofuran / heptane / ethylbenzene, 66.3 mL, 133 mmol, 1.2 eq) was added dropwise. The reaction mixture was stirred at -75 °C for 30 minutes. Ethyl formate (16.4 g, 17.7 mL, 220 mmol, 2.0 eq) was added below -70 °C. The reaction mixture was stirred at -75 °C for 30 minutes. Acetic acid (16.6 g, 15.8 mL, 277 mmol, 2.5 eq) was added below -55 °C. The reaction mixture was warmed to room temperature, poured into ethyl acetate, and washed with dilute aqueous HCl, water, and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to give the putative 4-bromo-6-(difluoromethyl)-2-fluoro-3-methyl-benzaldehyde as a yellow oil (29.5 g), which was used without further purification. The putative crude 4-bromo-6-(difluoromethyl)-2-fluoro-3-methyl-benzaldehyde (29.5 g) was dissolved in dimethoxyethane (150 mL). O-Methylhydroxylamine hydrochloride (10.2 g, 122 mmol, 1.1 eq) and potassium carbonate (30.6 g, 221 mmol, 2.0 eq) were added. The reaction mixture was stirred at 45 °C for 2.5 hours, then filtered through a sintered glass filter and washed with dimethoxyethane (twice). The filtrate was concentrated in vacuo. The oxime ether intermediate was dissolved in dimethyl sulfoxide (150 mL). Hydrazine hydrate (83 g, 80.5 mL, 1.66 mol, 15 eq) was added. The reaction mixture was stirred at 110 °C for 3 hours. The reaction mixture was poured into a 5:1 mixture of ethyl acetate / tetrahydrofuran. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 2 × 120 g, gradient 0% - 30% ethyl acetate in heptane) to give the title compound (13.5 g, 45% yield) as a white solid (13.5 g, 45% yield).LCMS: m / z 260.9 / 262.8 [M+H]. + , ESI pos, Br isotope.

[0061] Step 3: Ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-1H-indazol-2-yl]acetate TIFF2025516543000020.tif26170A solution of 6-bromo-4-(difluoromethyl)-7-methyl-1H-indazole (Example 1, Step 2) (19 g, 72.8 mmol, 1.0 eq) in N,N-dimethylformamide (75 mL) was added with ethyl 2-bromoacetate (CAS No. 105-36-2, 18.2 g, 12.2 mL, 109 mmol, 1.5 eq). The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was poured into ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 2 × 120 g, gradient 0% - 20% ethyl acetate in heptane) to give the title compound (21.2 g, 80% yield) as a yellow solid. LCMS: m / z 346.9 / 348.8 [M+H] + , ESI pos, Br isotope.

[0062] Step 4: tert-Butyl (5R)-5-[2-[6-bromo-4-(difluoromethyl)-7-methyl-1H-indazol-2-yl]-3-ethoxy-3-oxopropanoyl]-4-azaspiro[2.4]heptane-4-carboxylate TIFF2025516543000021.tif41170Preparation of tert-butyl (5R)-5-(imidazole-1-carbonyl)-4-azaspiro[2.4]heptane-4-carboxylate TIFF2025516543000022.tif38170

[0063] A solution of (5R)-4-tert-butoxycarbonyl-4-azaspiro[2.4]heptane-5-carboxylic acid (CAS No. 2007916-06-3, 1.02 g, 4.21 mmol, 1.0 eq) in dichloromethane (17 mL) was added with 1,1'-carbonyldiimidazole (818 mg, 5.04 mmol, 1.2 eq) in three portions, and the reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was poured into a saturated NaHCO 3 aqueous solution and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give tert-butyl (5R)-5-(imidazole-1-carbonyl)-4-azaspiro[2.4]heptane-4-carboxylate (1.30 g, yield 95%, purity 90%) as an off-white solid, which was used directly in the next step.

[0064] A solution of ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-1H-indazol-2-yl]acetate (Example 1, Step 3) (1.2 g, 3.46 mmol, 1.0 eq) in tetrahydrofuran (16 mL) was cooled to -50 °C. NaHMDS (1 M in tetrahydrofuran) (4 mL, 4 mmol, 1.16 eq) was added, and the reaction mixture was stirred at -50 °C for 45 min. A solution of the above tert-butyl (5R)-5-(imidazole-1-carbonyl)-4-azaspiro[2.4]heptane-4-carboxylate (1.29 g, 3.98 mmol, 1.15 eq) in tetrahydrofuran (16 mL) was added dropwise at -50 °C. The reaction mixture was stirred at -50 °C for 30 min. Then, the cooling bath was removed and the reaction mixture was warmed to room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled, quenched with saturated NH 4 Cl aqueous solution, diluted with water, and extracted with ethyl acetate. The aqueous layer was back-extracted with ethyl acetate. The organic layers were washed with saturated NaHCO 3 aqueous solution and then brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (2.37 g, yield 96%, purity 80%) as a light brown foam, which was used without further purification. LCMS: m / z 570.3 / 572.3 [M+H]+ , ESI pos, Br isotope.

[0065] Step 5: Ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-1H-indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazole-5,1'-cyclopropane]-1-yl-acetate A mixture of TIFF2025516543000023.tif28170 tert-butyl (5R)-5-[2-[6-bromo-4-(difluoromethyl)-7-methyl-1H-indazol-2-yl]-3-ethoxy-3-oxopropanoyl]-4-azaspiro[2.4]heptane-4-carboxylate (Example 1, Step 4) (2.36 g, 3.31 mmol, 1.0 eq., purity 80%) and HCl (4 M in 1,4-dioxane, 4.2 mL, 16.8 mmol, 5.07 eq.). The reaction mixture was stirred at room temperature for 1 h. HCl (4 M in 1,4-dioxane, 1 mL, 4.0 mmol, 1.21 eq.) was added and the reaction mixture was stirred at room temperature for 30 min. HCl (4 M in 1,4-dioxane, 1 mL, 4.0 mmol, 1.21 eq.) was added and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethanol (7.6 mL) and water (2.0 mL). Potassium thiocyanate (419 mg, 4.31 mmol, 1.3 eq.) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was cooled and pyridine (3.91 g, 4 mL, 49.46 mmol, 14.9 eq.) was slowly added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into 1N KHSO 4 + water and extracted 3 times with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was dissolved in acetic acid (7.6 mL) and cooled to 0 °C. Hydrogen peroxide (35 wt% solution in water, 0.580 mL, 6.62 mmol, 2.0 eq.) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 1 h. Excess hydrogen peroxide was destroyed with a 1M aqueous solution of Na 2 S 2 O 3 The mixture was destroyed with a 1M aqueous solution of Na 2 CO 3It was carefully basified and extracted twice with ethyl acetate. The organic layer was washed with brine, combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 24 g, gradient 0% - 100% ethyl acetate in heptane). All fractions containing the product were combined and concentrated in vacuo to give the title compound (882 mg, 53% yield) as a pale yellow solid. LCMS: m / z 479.3 / 481.3 [M+H] + , ESI pos, Br isotope.

[0066] Step 6: Ethyl 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazole-5,1'-cyclopropane]-1-yl-acetate TIFF2025516543000024.tif371701, Ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-1H-indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazole-5,1'-cyclopropane]-1-yl-acetate (Example 1, Step 5) (350 mg, 0.69 mmol, 1.00 eq), (4-morpholinophenyl)boronic acid (CAS No. 186498-02-2, 187 mg, 0.90 mmol, 1.30 eq), cesium carbonate (679 mg, 2.08 mmol, 3.00 eq) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex (82 mg, 0.10 mmol, 0.14 eq) in dichloromethane were flushed with argon and stirred at 100 °C for 2 h. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 24 g, gradient 0% - 90% ethyl acetate in heptane). All fractions containing the product were combined and concentrated to give the title compound (352 mg, yield 81%, purity 90%) as an off-white foam. LCMS: m / z 562.5 [M+H] + , ESI pos.

[0067] Step 7: 2-[4-(Difluoromethyl)-7-methyl-6-(4-morpholinophenyl)-1H-indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazole-5,1'-cyclopropane]-1-yl-N-thiazol-2-yl-acetamide; TIFF2025516543000025.tif37170Ethyl 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazole-5,1'-cyclopropane]-1-yl-acetate (Example 1, Step 6) (346 mg, 0.55 mmol, 1.0 equiv) in ethanol (1.8 mL) and tetrahydrofuran (1.8 mL) was added lithium hydroxide (1 M aqueous solution, 0.64 mL, 0.64 mmol, 1.15 equiv). The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was evaporated and co-evaporated twice with toluene. The residue was suspended in N,N-dimethylformamide (1.8 mL), and N,N-diisopropylethylamine (0.30 mL, 1.72 mmol, 3.1 equiv), thiazol-2-amine (72 mg, 0.72 mmol, 1.3 equiv) and HATU (274 mg, 0.72 mmol, 1.3 equiv) were added. The reaction mixture was stirred at room temperature for 45 min. The reaction mixture was extracted with ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed three times with water and once with brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 25 g, gradient 0% - 5% methanol in dichloromethane). All fractions containing the product were combined and concentrated in vacuo. The residue was adsorbed onto ISOLUTE HM-N and re-purified by flash chromatography (Si-amine, 12 g, gradient 0% - 10% methanol in ethyl acetate). All fractions containing the product were combined and concentrated to give the title compound (183 mg, 53% yield) as an off-white foam. LCMS: m / z 616.4 [M+H] + , ESI pos.

[0068] Example 4 2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-((4-((4-hydroxypiperidin-1-yl)methyl)phenyl)ethynyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide TIFF2025516543000026.tif61170 Project 1: Ethyl 2-(6-bromo-4-fluoro-indazol-2-yl)acetate TIFF2025516543000027.tif20170 A mixture of 6-bromo-4-fluoro-1H-indazole (CAS 885520-23-0) (1 equivalent), ethyl 2-bromoacetate (2 equivalents) and a small amount (to form a solution) of N,N-dimethylacetamide was heated to 100 °C until the reaction was complete. After cooling to room temperature, ice was added and the precipitated solid was collected by filtration and washed with water. The title compound (off-white solid, 53% yield) was purified using flash chromatography (silica gel, 0% - 40% ethyl acetate in n-heptane). 1 H NMR (chloroform-d, 300 MHz) δ = 8.08 (d, 1H, J = 0.8 Hz), 7.68 (t, 1H, J = 1.1 Hz), 6.87 (dd, 1H, J = 1.3, 9.6 Hz), 5.18 (s, 2H), 4.28 (q, 2H, J = 7.3 Hz), 1.30 (t, 3H, J = 7.2 Hz). MS (ESI) m / z 302.9 [M+H] + .

[0069] Step 2: 2[-2-(6-bromo-4-fluoro-indazol-2-yl)-3-ethoxy-3-oxo-propanoyl]pyrrolidine-1-carboxylate TIFF2025516543000028.tif26170 Ethyl 2-(6-bromo-4-fluoro-indazol-2-yl)acetate (1 equivalent) was reacted with CDI pre-activated tert-butoxycarbonyl)-L-proline (CAS 15761-39-4) (1.55 equivalents) in the presence of LDA (1.55 equivalents) in THF at -70 °C to room temperature. This reaction gave the title compound 2[-2-(6-bromo-4-fluoro-indazol-2-yl)-3-ethoxy-3-oxo-propanoyl]pyrrolidine-1-carboxylate.

[0070] Step 3: Ethyl 2-(6-bromo-4-fluoro-indazol-2-yl)-2-(3-thioxo-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl)acetate TIFF2025516543000029.tif 241702 [-2-(6-bromo-4-fluoro-indazol-2-yl)-3-ethoxy-3-oxo-propanoyl]pyrrolidine-1-carboxylate (1 equivalent) was reacted with HCl (in dioxane) at room temperature. Next, KSCN (1.33 equivalents) was added at room temperature in the presence of HCl in ethanol. This reaction gave ethyl 2-(6-bromo-4-fluoro-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate.

[0071] Step 4: Ethyl 2-(6-bromo-4-fluoro-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate A solution of ethyl 2-(6-bromo-4-fluoro-1H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (2.88 mmol, 1 equiv) in acetic acid (10 mL) was added dropwise with 35% hydrogen peroxide (1.12 g, 1.01 mL, 11.5 mmol, 4 equiv) at 10 °C. The reaction mixture was stirred at room temperature for 1 h. The excess hydrogen peroxide was destroyed by the addition of saturated sodium bisulfite solution. After adding a small amount of water (an amount sufficient to dissolve all salts) and ethyl acetate, the pH was adjusted to 9 by carefully adding solid sodium carbonate to the mixture. 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 (silica gel, 0 - 100% ethyl acetate in n-heptane) to give the title compound as a brown rubbery solid (51% yield from step 2 to step 4). 1H NMR (300 MHz, chloroform-d) δ = 8.22 (s, 1H), 7.66 (t, J = 1.0 Hz, 1H), 7.50 (s, 1H), 6.80 (dd, J = 1.2, 9.5 Hz, 1H), 6.39 (s, 1H), 4.39 - 4.19 (m, 2H), 4.10 - 3.97 (m, 2H), 2.95 - 2.60 (m, 4H), 1.42 - 1.10 (m, 3H). MS (ESI) m / z 409.0 [M+H]+.

[0072] Step 5: 2-(6-Bromo-4-fluoro-1H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide A solution of ethyl 2-(6-bromo-4-fluoro-1H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (1 equiv) in ethanol (3 mL) was treated with lithium hydroxide 1 M (1.1 equiv). The reaction mixture was stirred for 1 h, the solvent was evaporated, the residue was concentrated and co-evaporated twice with toluene to remove water. The reaction mixture was diluted with N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (345 mg, 0.466 mL, 2.67 mmol, 3 equiv), thiazol-2-amine (116 mg, 1.16 mmol, 1.3 equiv) and HATU (440 mg, 1.16 mmol, 1.3 equiv) were added. After stirring for 1 h at room temperature, the reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification of the residue by flash chromatography (silica gel, 0% - 10% methanol in dichloromethane) afforded 2-(6-bromo-4-fluoro-1H-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide.

[0073] Step 6: 2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-((4-((4-hydroxypiperidin-1-yl)methyl)phenyl)ethynyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide TIFF2025516543000032.tif57170A solution of 2-(6-bromo-4-fluoro-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide (1 equiv) in N,N-dimethylformamide (5 mL) was added with 4-ethynylbenzaldehyde (49 mg, 0.375 mmol, 1 equiv), triethylamine (113.83 mg, 0.157 mL, 1.12 mmol, 3 equiv), triphenylphosphine (10 mg, 0.037 mmol, 0.100 equiv), bis(triphenylphosphine)palladium(II) chloride (13 mg, 0.019 mmol, 0.050 equiv) and copper(I) iodide (3.57 mg, 0.019 mmol, 0.050 equiv). The vial was capped and heated in a microwave at 110 °C for 20 min, then 4-ethynylbenzaldehyde (49 mg, 0.375 mmol, 1 equiv) was added and the vial was heated again at 110 °C for 20 min. This procedure was repeated 3 times. In total, the reaction mixture was stirred at 110 °C for 5 × 20 min. The reaction mixture was poured into water and extracted with ethyl acetate (4 times). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% - 10% methanol in ethyl acetate) and further combined with piperidin-4-ol (1.3 equiv) and sodium triacetoxyborohydride (70 mg, 0.332 mmol, 1.6 equiv). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was poured into saturated NaHCO3 solution and extracted 3 times with a 9:1 mixture of dichloromethane / methanol. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the crude material by flash chromatography (silica gel, 0% - 10% methanol in ethyl acetate) gave the title compound (yield 16%, off-white solid). 11H NMR (300 MHz, chloroform-d) δ = 8.26 (s, 1H), 7.71 (s, 1H), 7.58 (s, 1H), 7.54 - 7.46 (m, 3H), 7.34 - 7.29 (m, 2H), 7.00 (d, J = 3.6 Hz, 1H), 6.87 - 6.79 (m, 1H), 6.52 (s, 1H), 4.06 - 3.96 (m, 2H), 3.77 - 3.66 (m, 1H), 3.55 - 3.47 (m, 2H), 2.79 - 2.70 (m, 2H), 2.65 - 2.51 (m, 4H), 2.23 - 2.10 (m, 2H), 1.94 - 1.85 (m, 2H), 1.72 - 1.47 (m, 4H). MS (ESI) m / z 594.6 [M-H] - .

[0074] Example 5 2-[4-(Difluoromethyl)-6-[2-[4-[[4-(Hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide TIFF2025516543000033.tif31170 Step 1: tert-Butyl (2R)-2-[2-[6-bromo-4-(difluoromethyl)-7-methylindazol-2-yl]-3-ethoxy-3-oxopropanoyl]pyrrolidine-1-carboxylate TIFF2025516543000034.tif 32170 Ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-1H-indazol-2-yl]acetate (0.65 g, 1.87 mmol, equivalent: 1.0) was dissolved in THF (7.58 mL) and cooled to -75 °C. LDA (2 M in THF, 1.12 mL, 2.25 mmol, equivalent: 1.20) was added dropwise within 5 minutes. The reaction mixture was stirred at -75 °C for 40 minutes. A solution of tert-butyl (2S)-2-(imidazole-1-carbonyl)pyrrolidine-1-carboxylate (prepared from (2S)-1-tert-butoxycarbonyl-4-fluoropyrrolidine-2-carboxylic acid) (0.77 g, 2.9 mmol, equivalent: 1.55) in THF (7.58 mL) was added slowly at -75 °C, stirred at -75 °C for 30 minutes, then warmed to room temperature and stirred at room temperature for 18 hours. After adding saturated NH 4 Cl aqueous solution, the reaction mixture was extracted twice with EtOAc. The organic layer was washed with water. The combined organic layers were dried over Na 2 SO 4 and concentrated in vacuo to give the title compound (1.41 g, 72% purity, 99% yield), which was used in the next step without further purification. m / z 544.1, 546.0 [M+H] + , ESI pos. Br isotope.

[0075] Step 2: Ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-1H-indazol-2-yl]-2-(3-thioxo-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl)acetate TIFF2025516543000035.tif31170 Similar to Step 5 of Example 7, tert-butyl (2R)-2-[2-[6-bromo-4-(difluoromethyl)-7-methyl-1H-indazol-2-yl]-3-ethoxy-3-oxopropanoyl]pyrrolidine-1-carboxylate (1.4 g, 72% purity, 1.85 mmol) was treated with 4M HCl in dioxane and potassium thiocyanate to give the title compound as a brown oil (1.07 g, 85% purity, 100% yield), which was used in the next step without further purification. m / z 485.0, 486.9 [M+H] + ,ESI pos, Br isotope.

[0076] Step 3: Ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-1H-indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate TIFF2025516543000036.tif26170 Similar to Step 6 of Example 7, ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-1H-indazol-2-yl]-2-(3-thioxo-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl)acetate (1.06 g, 85% purity, 1.86 mmol) was treated with hydrogen peroxide and p-toluenesulfonic acid monohydrate to give the title compound as a yellow foam (360 mg, 43% yield). m / z 453.0, 454.9 [M+H] + ,ESI pos, Br isotope.

[0077] Step 4: 2-[6-bromo-4-(difluoromethyl)-7-methyl-1H-indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide TIFF2025516543000037.tif Starting from 2-ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-1H-indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (Example 5, Step 3) and thiazol-2-amine, and using the same chemistry as described in Step 7 of Example 7, the title compound was obtained as a pale yellow foam, MS: m / e = 509.1 / 511.1 (M+H + )

[0078] Step 5: 2-[4-(Difluoromethyl)-6-[2-[4-[[4-(Hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-1H-indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide TIFF2025516543000038.tif Starting from 2-[6-bromo-4-(difluoromethyl)-7-methyl-1H-indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide (Example 5, Step 4) and [1-[(4-ethynylphenyl)methyl]-4-piperidyl]methanol hydrochloride (Example 7, Step 9), and using the same chemistry as described in Step 10 of Example 7, the title compound was obtained as a brown solid, MS: m / e = 656.5 (M+H + )

[0079] Example 6 2-[4-(Difluoromethyl)-6-[2-[4-[[4-(Hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-1H-indazol-2-yl]-2-(5-ethyl-5-methyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide TIFF2025516543000039.tif36170 Step 1: (5S)-5-[2-[6-Bromo-4-(difluoromethyl)-7-methyl-1H-indazol-2-yl]-3-ethoxy-3-oxopropanoyl]-4-azaspiro[2.4]heptane-4-carboxylic acid tert-butyl ester TIFF2025516543000040.tif36170 In the same manner as in Step 4 of Example 1, (5S)-4-tert-butoxycarbonyl-4-azaspiro[2.4]heptane-5-carboxylic acid was treated with carbonyldiimidazole to obtain Solution A. Ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-1H-indazol-2-yl]acetate was deprotonated with LDA and treated with Solution A at -78°C. After stirring overnight at room temperature and performing post-treatment in the same manner as in Step 4 of Example 7, the crude title compound was obtained as a pale yellow foam and used in the next step without further purification. MS: m / e = 572.3 ([M+H] + )

[0080] Step 2: Ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-1H-indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazole-5,1'-cyclopropane]-1-yl-acetate TIFF2025516543000041.tif26170 In the same manner as in Step 5 of Example 1, (5S)-5-[2-[6-bromo-4-(difluoromethyl)-7-methyl-1H-indazol-2-yl]-3-ethoxy-3-oxopropanoyl]-4-azaspiro[2.4]heptane-4-carboxylic acid tert-butyl ester was deprotected using HCl in dioxane, followed by reaction with potassium thiocyanate to obtain a crude intermediate, which was used in the next step without further purification.

[0081] In the same manner as in Step 6 of Example 7, the intermediate was treated with hydrogen peroxide in AcOH to obtain the title compound as a pale yellow foam. MS: m / e = 481.2 ([M+H] + )

[0082] Step 3: 2-[6-Bromo-4-(difluoromethyl)-7-methyl-1H-indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazole-5,1'-cyclopropan]-1-yl-N-thiazol-2-yl-acetamide TIFF2025516543000042.tif311702-[6-Bromo-4-(difluoromethyl)-7-methyl-1H-indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazole-5,1'-cyclopropan]-1-yl-ethyl acetate (Example 6, Step 2) and thiazol-2-amine were used as starting materials, and the same chemistry as described in Step 7 of Example 7 was employed to obtain the title compound as a pale yellow foam: MS: m / e = 535.0 (M+H + )

[0083] Step 4: 2-[4-(Difluoromethyl)-6-[2-(4-formylphenyl)ethynyl]-7-methyl-1H-indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazole-5,1'-cyclopropan]-1-yl-N-thiazol-2-yl-acetamide TIFF2025516543000043.tif321702-[6-Bromo-4-(difluoromethyl)-7-methyl-1H-indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazole-5,1'-cyclopropan]-1-yl-N-thiazol-2-yl-acetamide (Example 6, Step 3) and 4-ethynylbenzaldehyde were used as starting materials, and the same chemistry as described in Step 10 of Example 7 was employed to obtain the title compound as a dark brown amorphous solid, MS: m / e = 583.3 (M+H + )

[0084] Step 5: 2-[4-(Difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-1H-indazol-2-yl]-2-(5-ethyl-5-methyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide TIFF2025516543000044.tif321702 - [4-(Difluoromethyl)-6-[2-(4-formylphenyl)ethynyl]-7-methyl-1H-indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazole-5,1'-cyclopropane]-1-yl-N-thiazol-2-yl-acetamide (Example 6, Step 4) and starting from piperidin-4-ylmethanol, using the same chemistry as described in Step 8 of Example 7, the title compound was obtained as a pale yellow solid, MS: m / e = 682.5 (M+H + )

[0085] Example 7 2-[4-(Difluoromethyl)-6-[2-[4-[[4-(Hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-1H-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF2025516543000045.tif35170 Step 1: 1-Bromo-5-(bromomethyl)-3-fluoro-2-methylbenzene TIFF2025516543000046.tif26170 A solution of 3-bromo-5-fluoro-4-methylbenzaldehyde (CAS 1370411-47-4, 20.5 g, 89.7 mmol, equivalent: 1.0) in DCM (98 mL) was cooled in an ice bath. Morpholino sulfur trifluoride (CAS 51010-74-3, 24.8 g, 17.3 mL, 135 mmol, equivalent: 1.5) was added portionwise. The reaction mixture was stirred at 0 - 5 °C for 20 minutes and then at room temperature for 16 hours. While ice-cooling, saturated NaHCO 3 aqueous solution (300 mL) was carefully added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into DCM and washed with water. The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, 120 g, 100% pentane) to give the title compound as a colorless oil (18.6 g, yield 87%). 11H NMR (300 MHz, chloroform-d) δ = 7.50 (s, 1H), 7.16 (d, J = 9.1 Hz, 1H), 6.57 (t, J = 56.0 Hz, 1H), 2.50 - 2.22 (m, 3H)

[0086] Step 2: 6-Bromo-4-(difluoromethyl)-7-methyl-1H-indazole A solution of 1-bromo-5-(difluoromethyl)-3-fluoro-2-methylbenzene (Example 1, Step 1) (26.4 g, 110 mmol, equivalent: 1.0) in THF (240 mL) was cooled to -75 °C. LDA (2 M in THF / heptane / ethylbenzene, 66.3 mL, 133 mmol, equivalent: 1.2) was added dropwise at below -70 °C. The reaction mixture was stirred at -75 °C for 30 minutes. Ethyl formate (16.4 g, 17.7 mL, 220 mmol, equivalent: 2.0) was added at below -70 °C. The reaction mixture was stirred at -75 °C for 30 minutes. AcOH (16.6 g, 15.8 mL, 277 mmol, equivalent: 2.5) was added at below -55 °C. The reaction mixture was warmed to room temperature, poured into EtOAc, and washed with dilute aqueous HCl, water, and brine. The organic layer was dried over Na 2 SO 4 and concentrated in vacuo to give the putative 4-bromo-6-(difluoromethyl)-2-fluoro-3-methylbenzaldehyde as a yellow oil (29.5 g) and used without further purification.

[0087] The putative crude 4-bromo-6-(difluoromethyl)-2-fluoro-3-methylbenzaldehyde (29.5 g) was dissolved in DME (150 mL). O-Methylhydroxylamine hydrochloride (10.2 g, 122 mmol, equivalent: 1.84) and K 2 CO 3(30.6 g, 221 mmol, equivalent: 3.34) was added. The reaction mixture was stirred at 45 °C for 2.5 h, filtered through sintered glass, and washed with DME (twice). The filtrate was concentrated in vacuo. The oxime ether intermediate was dissolved in DMSO (150 mL). Hydrazine hydrate (83 g, 80.5 mL, 1.66 mol, equivalent: 25) was added. The reaction mixture was stirred at 110 °C for 3 h. The reaction mixture was poured into EtOAc / THF 5:1 and washed with water and brine. The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, 2 × 120 g, 0% - 30% EtOAc in heptane) to give the title compound as a white solid (13.5 g, 74% yield). m / z 258.9, 260.8 [M+H] + , ESI pos, Br isotope.

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

[0089] Step 4: tert-Butyl (2S,4R)-2-[2-[6-Bromo-4-(difluoromethyl)-7-methyl-1H-indazol-2-yl]-3-ethoxy-3-oxopropanoyl]-4-fluoropyrrolidine-1-carboxylate TIFF2025516543000049.tif36170Preparation of tert-Butyl (2S,4R)-4-fluoro-2-(imidazole-1-carbonyl)pyrrolidine-1-carboxylate: TIFF2025516543000050.tif31170

[0090] To a solution of (2S,4R)-1-tert-butoxycarbonyl-4-fluoropyrrolidine-2-carboxylic acid (CAS 203866-14-2, 30 g, 129 mmol, equivalent: 1.0) in DCM (300 mL) was added 1,1'-carbonyldiimidazole (25 g, 154 mmol, formula: 1.2) portionwise at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was washed with water (3x) and 1 M NaHCO 3 aqueous solution (1x). The organic layer was dried over Na 2 SO 4 and concentrated in vacuo at 30 °C to give tert-butyl (2S,4R)-4-fluoro-2-(imidazole-1-carbonyl)pyrrolidine-1-carboxylate (36.6 g, 129 mmol, 100% yield) as a white solid and stored at -20 °C before use. 1 1H NMR (Chloroform-d, 300 MHz) δ 8.27 (s, 1H), 7.56 (br d, 1H, J = 1.4 Hz), 7.15 (br d, 1H, J = 12.1 Hz), 4.9 - 5.2 (m, 1H), 3.6 - 4.1 (m, 2H), 2.0 - 2.9 (m, 2H), 1.2 - 1.5 (m, 9H).

[0091] KO tBu (4.53 g, 40.3 mmol, equivalent: 2.0) was dissolved in THF (18 mL). The reaction mixture was cooled to -55 °C. A solution of ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]acetate (Example 1, Step 3) (7 g, 20.2 mmol, equivalent: 1.0) in THF (24 mL) was added dropwise at below -50 °C. The reaction mixture was stirred at -50 °C to -55 °C for 1 hour. A solution of tert-butyl (2S,4R)-4-fluoro-2-(imidazole-1-carbonyl)pyrrolidine-1-carboxylate (6.85 g, 24.2 mmol, equivalent: 1.2), prepared previously, in THF (50 mL) was added dropwise at below -50 °C. The reaction mixture was stirred at -50 °C for 15 minutes and then warmed to -30 °C. 10% aqueous citric acid solution (60 mL) was added at below -20 °C and the mixture was stirred at 0 °C for 1 hour. The reaction mixture was poured into EtOAc and washed with water and brine. The organic layer was dried over Na 2 SO 4 and concentrated in vacuo at 30 °C to give the title compound as a yellow amorphous semi-solid (12.9 g, 20.2 mmol, purity 88%, yield 100%). m / z 562.1, 563.9 [M+H] + , ESI pos, Br isotope.

[0092] Step 5: Ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-3-thioxo-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl]acetate TIFF2025516543000051.tif A solution of tert-butyl (2S,4R)-2-[2-[6-bromo-4-(difluoromethyl)-7-methyl-1H-indazol-2-yl]-3-ethoxy-3-oxopropanoyl]-4-fluoro-pyrrolidine-1-carboxylate (Example 1, Step 4) (12.9 g, 20.2 mmol, equivalent: 1.0) in ethanol (24 mL) was added with HCl (1.25 M in ethanol, 80.6 mL, 101 mmol, equivalent: 5.0). The reaction mixture was stirred at 55 °C for 1 hour. The reaction mixture was cooled to room temperature, and water (6 mL) and potassium thiocyanate (2.55 g, 26.2 mmol, equivalent: 1.3) were added. The reaction mixture was stirred at room temperature for 30 minutes. Ethanol was removed in vacuo at 30 °C, and pyridine (23.9 g, 24.5 mL, 302 mmol, equivalent: 15) was added. The reaction mixture was stirred at room temperature for 75 minutes. The reaction mixture was poured into EtOAc and washed with 2N aqueous HCl solution (until the aqueous phase reached pH 1), water, and brine. The organic layer was dried over Na 2 SO 4 and concentrated in vacuo to afford the title compound as a yellow semi-solid (9.65 g, purity 60%, yield 57%). m / z 502.9, 505.9 [M+H] + , ESI pos, Br isotope.

[0093] Step 6: Ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-1H-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate TIFF2025516543000052.tifA suspension of p-toluenesulfonic acid monohydrate (10.9 g, 57.5 mmol, equivalent: 5.0) in acetonitrile (70 mL) was added dropwise with hydrogen peroxide (35% aqueous solution, 8.38 g, 7.42 mL, 86.3 mmol, equivalent: 7.5) at 0 - 3 °C to obtain a colorless solution. After 10 minutes, a solution of 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-3-thioxo-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl]acetate (Example 1, Step 5) (9.65 g, 11.5 mmol, equivalent: 1.0) in acetonitrile (28 mL) was added dropwise at below 8 °C. The reaction mixture was stirred at 0 °C for 1.5 hours. The reaction mixture was poured into EtOAc and washed with Na 2 CO 3 solution and brine. The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, 120 g, 0% - 60% in heptane (EtOAc / EtOH / aqueous solution NH 3 75:25:2)) to obtain the title compound as a yellow foam (3.96 g, yield 73%). m / z 469.1, 471.1 [M+H] + , ESI pos.

[0094] Step 7: 2-[6-Bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF2025516543000053.tifEthyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-1H-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (Example 1, Step 6) (200 mg, 0.424 mmol) was dissolved in 2 ml of methanol and 2 ml of THF. LiOH (1 M in water) (0.4 ml, 0.424 mmol, equivalent: 1.0) was added at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness in vacuo and the residue was dissolved in 2 ml of DMF. Thiazol-2-amine (42 mg, 0.424 mmol, equivalent: 1.0), Hunig's base (0.37 ml, 2.12 mmol, equivalent: 5.0) and HATU (194 mg, 0.509 mmol, equivalent: 1.2) were added at room temperature. The mixture was stirred at room temperature for 90 minutes. The reaction mixture was extracted with water and twice with ethyl acetate. The organic layer was extracted with water, dried over sodium sulfate and concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with a gradient of dichloromethane:methanol from 100:0 to 90:10 to give the desired product (115 mg, 49% yield) as a pale yellow solid. MS: m / e = 527.1 (M+H + ).

[0095] Step 8: [1-[(4-Ethynylphenyl)methyl]-4-piperidyl]methanol TIFF2025516543000054.tif4-Ethynylbenzaldehyde (20.5 g, 157.5 mmol) was dissolved in 525 ml of dichloromethane. Piperidin-4-ylmethanol (20 g, 173.2 mmol, equivalent: 1.1) and sodium triacetoxyborohydride (53.4 g, 252.0 mmol, equivalent: 1.6) were added at room temperature. The mixture was stirred at room temperature for 4 hours. The reaction mixture was extracted with 1 M sodium carbonate solution and twice with water with dichloromethane. The organic layer was dried over sodium sulfate and concentrated to dryness to give the desired product (34.8 g, 91% yield) as a pale yellow solid. MS: m / e = 527.1 (M+H + ).

[0096] Step 9: [1-[(4-Ethynylphenyl)methyl]-4-piperidyl]methanol hydrochloride TIFF2025516543000055.tif21170[1-[(4-Ethynylphenyl)methyl]-4-piperidyl]methanol (Example 1, Step 8) (34.8 g) was dissolved in 200 ml of tetrahydrofuran. A 4 M hydrogen chloride solution in 1,4-dioxane (39.4 ml, 158 mmol, equivalent: 1.0) was added dropwise at 10 - 20 °C. A white precipitate formed and was stirred for 2 hours. The precipitate was collected by filtration, washed three times with 50 ml of tetrahydrofuran, and dried in vacuo to give the title compound (38.6 g, 92%) as a white solid. MS: m / e = 527.1 (M+H + )

[0097] Step 10: 2-[4-(Difluoromethyl)-6-[2-[4-[[4-(Hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF2025516543000056.tif361702 - [6 - Bromo - 4 - (difluoromethyl) - 7 - methyl - indazol - 2 - yl] - 2 - [(6R) - 6 - fluoro - 6,7 - dihydro - 5H - pyrrolo[1,2 - c]imidazol - 1 - yl] - N - thiazol - 2 - yl - acetamide (Example 1, Step 7) (100 mg, 0.19 mmol) and [1 - [(4 - ethynylphenyl)methyl] - 4 - piperidyl]methanol hydrochloride (Example 1, Step 9) (76 mg, 0.286 mmol, equivalent: 1.5) were dissolved in 5 ml of DMF. Triethylamine (0.1 ml, 0.76 mmol, equivalent: 4.0), bis - (triphenylphosphine) - palladium(II) dichloride (7 mg, 0.01 mmol, equivalent: 0.05), triphenylphosphine (5 mg, 0.019 mmol, equivalent: 0.1) and copper(I) iodide (2 mg, 0.01 mmol, equivalent: 0.05) were added and the mixture was stirred at 80 °C for 2 hours. The reaction mixture was extracted with water and then extracted three times with dichloromethane. The organic layer was dried over sodium sulfate and concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with a gradient of dichloromethane:methanol from 100:0 to 75:25 to give the desired product (7 mg, 5% yield) as a pale yellow oil. MS: m / e = 674.5 (M + H + ).

[0098] Example 8 - In Vitro Property Evaluation Cell Line Ba / F3 cell lines stably expressing EGFR mutants L858R (#2039), L858R / C797S (#C2052) and L858R / T790M / C797S (#2056) were purchased from CrownBio. NCI - H1975 cells (#CRL - 5908), NCI - H2073 cells (#CRL - 5918) and A431 cells (#CRL - 1555) were purchased from ATCC. NCI - H3255 cells were obtained from NCI (#CVCL_6831). The cells were maintained at 37 °C and 5% CO 2Maintained in a humidified incubator. Ba / F3 EGFR-LR cells, Ba / F3 EGFR-LRTM cells, Ba / F3 EGFR-LRCS cells, and Ba / F3 EGFR-LRTMCS cells were grown in RPMI 1640 GlutaMAX medium (Thermo Fisher Scientific #61870010) supplemented with 10% fetal bovine serum (FBS; VWR #07068-085). NCI-H1975 cells, NCI-H3255 cells, NCI-H2073 cells, A431 cells, and PC-9 cells were cultured in RPMI 1640 medium with ATCC modification (Thermo Fisher Scientific #A10491) supplemented with 10% FBS. Verification of the identity and absence of cross-contamination of cell lines by other cell lines was performed by short tandem repeat PCR analysis (for human cell lines only) and MALDI-TOF analysis. The absence of mycoplasma contamination was verified by testing antibiotic-free cultured cells for 10 - 14 days using the kit MycoAlert™ Mycoplasma Detection Kit (Lonza #LT07-318). All cell lines were used for no more than 20 passages after thawing for all experiments described.

[0099] Homogeneous time-resolved fluorescence (HTRF) cell assay For the homogeneous time-resolved fluorescence (HTRF) assay, cells were transferred into RPMI 1640 phenol red-free medium containing 10% FBS (Thermo Fisher Scientific #11835063) and seeded into 384-well plates (Greiner #781080) at a density of 15,000 cells / well (Ba / F3), 16,000 cells / well (H1975) and 10,000 cells / well (H3255) at a volume of 12 μl / well. 5,000 cells / well (H2073) and 10,000 cells / well (A-431) were seeded at a volume of 11 μl / well. Control wells containing only medium were also prepared. The plates were centrifuged at 300 g for 30 seconds and incubated overnight at 37°C. The next day, compounds were added at concentrations ranging from 0.316 nM to 10 mM in 1 / 4 log dilutions, and DMSO (Sigma #D2650) was compensated according to a final content of 0.1%. The plates were incubated at 37°C for 4 hours. For H2073 cells and A-431 cells in particular, 1 μl of 300 ng / ml EGF (final concentration 25 ng / ml) was added to each well after 4 hours of incubation, and the cells were incubated at 37°C for an additional 5 minutes. Finally, the cells were lysed in the HTRF lysis buffer provided by the kit (see below) and stored at -80°C until further use. Subsequently, the HTRF assay for pEGFR (CisBio #64EG1PEH) or pERK (CisBio #64AERPEH) was performed according to the manufacturer's instructions.

[0100] Cell viability assay For the cell viability assay, Ba / F3 cells in growth medium containing 10% FBS were seeded at 2,000 cells / well in 50 μl in a 384-well black clear-bottom plate (Falcon #353962). Compounds were added at concentrations ranging from 0.316 nM to 10 mM in 1 / 4 log dilutions, and DMSO (Sigma #D2650) was compensated according to a final content of 0.1%. The plates were incubated at 37 °C for 72 hours. After treatment with the compounds, 25 μl / well of CellTiter-Glo 2.0 reagent (Promega #G9243) was added, the plates were incubated at room temperature for 10 minutes, and luminescence was quantified according to the manufacturer's protocol.

[0101] In vitro metabolic stability In vitro metabolic stability was evaluated in short-term hepatocyte suspensions of human and rat. Primary pooled cryopreserved hepatocytes obtained from BioIVT (Westbury, NY, USA) were thawed and suspended in William's E medium supplemented with 10% fetal bovine serum. The suspended hepatocytes were pre-incubated at 37 °C (5% CO2), and the reaction was initiated by adding the compounds. The final assay conditions were 1 μM compound (final assay solvent concentration 0.01% DMSO), 1 × 106 hepatocytes / mL incubation. The mixture was then incubated at 37 °C (5% CO2) for up to 2 hours. Before storage at -80 °C until analysis by LC-MS / MS, the samples were placed on dry ice to stop the reaction. The natural logarithm of the percentage of the initial drug concentration in the incubation samples was plotted against time, and linear regression analysis was applied using GraphPad Prism version 7.04 for Windows (GraphPad Software, La Jolla, CA) to define the slope. The in vitro hepatocyte intrinsic hepatocyte clearance rate (CL int ) was calculated from the slope of the linear regression - slope, where V represents the volume of the incubation in μL and N is the number of hepatocytes per incubation as detailed in Equation X: TIFF2025516543000057.tif15170

[0102] The results of various in vitro assays are shown in Tables 1 and 2. [Table 1]

[0103] Reference compound EAI045 (left) and JBJ-04-125-02 (right): TIFF2025516543000059.tif27170 [Table 2]

[0104] Orthosteric EGFR inhibitor osimertinib (left) and erlotinib (right): TIFF2025516543000061.tif28170

[0105] Example 9 - In Vivo Efficacy Study The study was conducted at Charles River Discovery Research Service GmbH (Germany).

[0106] Mice were maintained under pathogen-free conditions on a 12-hour light / 12-hour dark daily cycle. The experiments were conducted in accordance with the animal welfare guidelines (Federation of European Laboratory Animal Science Associations), and the test protocol was reviewed and approved by the local authority.

[0107] A subcutaneous cell line-derived model with Ba / F3 cell clones was established by injecting cells (1×10 7 ) into the right flank of female Balb / c nude mice. After randomization, compound treatment was initiated when the tumor size reached 100 - 200 mm 3 . For the subcutaneous xenograft model derived from the human NSCLC NCI-H1975 cell line, 5×10 6 cells were injected into the right flank of female Balb / c mice, and the mice were randomized. When the tumor reached approximately 150 mm 3After reaching, it was assigned to the treatment group. The inoculation procedure was carried out under surgical anesthesia using the support of the positioning device and an inhalation mask with isoflurane / O 2 It was carried out with the surgical anesthesia using.

[0108] Example 6 of the allosteric EGFR inhibitor was formulated with osimertinib containing 10% PEG400 and 5% sorbitol in water and 1% DMSO and 30% PEG300 in water. Daily oral treatment was started after randomization of the mice. Individual tumor volumes were monitored by regular caliper measurements and calculated according to the formula (TV = (length × width2). The tumor volumes of each test group are shown as the mean (mm 3 ) of SEM during the test observation period. All raw data were exported from the local database to a tab-limited csv file, processed using the statistical software R, and visualized with Shiny (script written by Dr. S. Wilson, PS BIOMICS, RICB).

[0109] Since the data showed an asymmetric behavior, the data on primary tumor growth were statistically analyzed at test D38 (final day of control) using non-parametric methods. Briefly, in a randomized 2-sample design, the treatment-to-control ratio (TCR) and its two-sided parametric (Fieller, 1954) or non-parametric (Hothorn and Munzel, 2000) confidence intervals (CI) (1 - a) were calculated. A TCR less than 1.0 indicated tumor growth inhibition, and the CI reflected the data distribution. A higher CI less than 1.0 supported statistical significance. Tumor growth inhibition was calculated according to the following formula: Based on the median, 100 - [mean(TV 処置 - TV ベースライン ) / mean(TV ビヒクル - TV ベースライン )] Tumor regression was calculated according to the formula: mean[(TV ベースライン - TV 処置 ) / TV ベースライン ) × 100 (based on the median). A positive value indicates tumor regression.

[0110] Embodiments with specific numbers assigned 1. A combination of an allosteric EGFR inhibitor and an orthosteric EGFR inhibitor, wherein the allosteric EGFR inhibitor is of formula (I) TIFF2025516543000062.tif52170(wherein L is a bond or alkynylene, R 1 is hydrogen or halogen, R 2 and R 2’ are independently selected from hydrogen and alkyl, or or R 2 and R 2’ together with the carbon atom to which they are attached form cycloalkyl, R 3 is hydrogen, halogen or haloalkyl, R 4 is alkyl or halogen, R 5 is (heterocycloalkyl)alkylene or heterocycloalkyl, (heterocycloalkyl)alkylene may be substituted with one or two substituents independently selected from R6, and heterocycloalkyl may be substituted with one or two substituents independently selected from R7, R 6 is in each case independently selected from alkyl, cycloalkyl, hydroxy and hydroxyalkyl, R 7 is in each case independently selected from alkyl, cycloalkyl, hydroxy and hydroxyalkyl) a compound of, or a pharmaceutically acceptable salt thereof, the combination.

[0111] 2. The allosteric EGFR inhibitor is of formula (I) TIFF2025516543000063.tif52170(wherein L is a bond or alkynylene, R 1 is hydrogen or halogen, R 2and R 2’ is independently selected from hydrogen and alkyl, or R 2 and R 2’ together with the carbon atom to which they are attached form cycloalkyl, R 3 is hydrogen, halogen or haloalkyl, R 4 is alkyl or halogen, R 5 is (heterocycloalkyl)alkylene or heterocycloalkyl, and (heterocycloalkyl)alkylene may be substituted with one or two substituents independently selected from R 6 and heterocycloalkyl may be substituted with one or two substituents independently selected from R 7 ), R 6 in each case is independently selected from alkyl, cycloalkyl, hydroxy and hydroxyalkyl, R 7 in each case is independently selected from alkyl, cycloalkyl, hydroxy and hydroxyalkyl) The combination according to embodiment 1, which is a compound of

[0112] 3. The combination according to embodiment 1 or 2, wherein L is a bond or ethynylene.

[0113] 4. The combination according to any one of embodiments 1 to 3, wherein R 1 is hydrogen or fluoro.

[0114] 5. The combination according to any one of embodiments 1 to 4, wherein R 2 and R 2’ are hydrogen or together with the carbon atom to which they are attached form cyclopropyl.

[0115] 6. The combination according to any one of embodiments 1 to 5, wherein R 3 is halogen or haloalkyl.

[0116] 7.R 3 is chloro or difluoromethyl, the combination according to any one of Embodiments 1 to 6.

[0117] 8.R 4 is methyl or chloro, the combination according to any one of Embodiments 1 to 7.

[0118] 9.R 5 is morpholinyl or piperidinylmethylene optionally substituted with hydroxymethyl, the combination according to any one of Embodiments 1 to 8.

[0119] 10. The compound of formula (I) is 2-[4,7-dichloro-6-(4-morpholinophenyl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazole-5,1'-cyclopropane]-1-yl-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide; and 2-[4-(Difluoromethyl)-6-[2-[4-[[4-(Hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-1H-indazol-2-yl]-2-(5-ethyl-5-methyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide The combination according to any one of embodiments 1 to 9, selected from

[0120] 11. The combination according to any one of embodiments 1 to 9, wherein the compound of formula (I) is 2-[4,7-dichloro-6-(4-morpholinophenyl)-1H-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide.

[0121] 12. The combination according to any one of embodiments 1 to 9, wherein the compound of formula (I) is 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)-1H-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide.

[0122] 13. The combination according to any one of embodiments 1 to 9, wherein the compound of formula (I) is 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)-1H-indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazole-5,1'-cyclopropane]-1-yl-N-thiazol-2-yl-acetamide.

[0123] 14. The combination according to any one of embodiments 1 to 9, wherein the compound of formula (I) is 2-[4-(difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-1H-indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide.

[0124] 15. The combination according to any one of embodiments 1 to 9, wherein the compound of formula (I) is 2-[4-(difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-indazol-2-yl]-2-(5-ethyl-5-methyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide.

[0125] 16. The combination according to any one of embodiments 1 to 15, wherein the orthosteric EGFR inhibitor is selected from cetuximab, panitumumab, osimertinib, erlotinib, gefitinib, necitumumab, neratinib, lapatinib, vandetanib, brigatinib, almonertinib, lazertinib and flumonertinib, or a pharmaceutically acceptable salt thereof, particularly, selected from osimertinib, almonertinib, lazertinib and flumonertinib, or a pharmaceutically acceptable salt thereof.

[0126] 17. The combination according to any one of embodiments 1 to 16, wherein the orthosteric EGFR inhibitor is osimertinib or a pharmaceutically acceptable salt thereof.

[0127] 18. The combination according to any one of embodiments 1 to 16, wherein the orthosteric EGFR inhibitor is almonertinib or a pharmaceutically acceptable salt thereof.

[0128] 19. The combination according to any one of embodiments 1 to 16, wherein the orthosteric EGFR inhibitor is lazertinib or a pharmaceutically acceptable salt thereof.

[0129] 20. The combination according to any one of embodiments 1 to 16, wherein the orthosteric EGFR inhibitor is flumonertinib or a pharmaceutically acceptable salt thereof.

[0130] 21. The combination according to any one of embodiments 1 to 16 for use as a therapeutic active substance.

[0131] 22. A pharmaceutical composition comprising the combination according to any one of embodiments 1 to 20 and a therapeutically inert carrier.

[0132] 23. The combination according to any one of embodiments 1 to 20 for use in the treatment or prevention of cancer, particularly non-small cell lung cancer.

[0133] 24. Use of the combination according to any one of embodiments 1 to 20 for the treatment or prevention of cancer, particularly non-small cell lung cancer.

[0134] 25. Use of the combination according to any one of embodiments 1 to 20 for preparing a medicament for the treatment or prevention of cancer, particularly non-small cell lung cancer.

[0135] 26. Use of the combination according to any one of embodiments 1 to 20 for preparing a medicament for the treatment or prevention of non-small cell lung cancer.

[0136] 27. A method for the treatment or prevention of cancer, particularly non-small cell lung cancer, comprising administering an effective amount of the combination according to any one of embodiments 1 to 20 to a patient in need thereof.

[0137] 28. The combination, use, method or pharmaceutical composition according to any one of embodiments 21 to 27, wherein both the allosteric EGFR inhibitor and the orthosteric EGFR inhibitor are administered orally.

[0138] 29. The combination, use, method or pharmaceutical composition according to any one of embodiments 21 to 28, wherein the allosteric EGFR inhibitor is administered simultaneously with the orthosteric EGFR inhibitor.

[0139] 30. The combination, use, method or pharmaceutical composition according to any one of embodiments 21 to 29, wherein the allosteric EGFR inhibitor and the orthosteric EGFR inhibitor are co-formulated.

[0140] 31. The combination, use, method or pharmaceutical composition according to any one of embodiments 21 to 28, wherein the allosteric EGFR inhibitor and the orthosteric EGFR inhibitor are administered sequentially.

[0141] 32. The combination, use, method or pharmaceutical composition according to any one of embodiments 23 to 27, wherein the cancer is associated with at least one EGFR mutation selected from del19, L858R, T790M and C797S.

[0142] 33. The combination, use, method or pharmaceutical composition according to any one of embodiments 23 to 27, wherein the cancer is associated with at least two EGFR mutations selected from del19, L858R, T790M and C797S.

Claims

1. A combination of an allosteric EGFR inhibitor and an orthosteric EGFR inhibitor, wherein the allosteric EGFR inhibitor is of formula (I) (wherein L is a bond or alkynylene, R １ is hydrogen or a halogen, and R ２ and R ２’ is independently selected from hydrogen and alkyl, or or R ２ and R ２’ together with the carbon atoms to which they are attached form a cycloalkyl, R ３ is hydrogen, halogen or haloalkyl, R ４ is alkyl or halogen, R ５ is (heterocycloalkyl)alkylene or heterocycloalkyl, and (heterocycloalkyl)alkylene may be substituted with one or two substituents independently selected from R ６ and heterocycloalkyl may be substituted with one or two substituents independently selected from R ７ and may be substituted with one or two substituents independently selected from R ６ is independently selected from alkyl, cycloalkyl, hydroxy and hydroxyalkyl in each case, R ７ which, in each case, is independently selected from alkyl, cycloalkyl, hydroxy and hydroxyalkyl) or a pharmaceutically acceptable salt thereof, the combination.

2. The allosteric EGFR inhibitor is of formula (I) (wherein L is a bond or alkynylene, R １ is hydrogen or halogen, and R ２ and R ２’ is independently selected from hydrogen and alkyl, or or R ２ and R ２’ together with the carbon atoms to which they are attached form a cycloalkyl, R ３ is hydrogen, halogen or haloalkyl, R ４ is alkyl or halogen, R ５ is (heterocycloalkyl)alkylene or heterocycloalkyl, and (heterocycloalkyl)alkylene may be substituted with one or two substituents independently selected from R ６ and heterocycloalkyl may be substituted with one or two substituents independently selected from R ７ and may be substituted with one or two substituents independently selected from R ６ is independently selected from alkyl, cycloalkyl, hydroxy and hydroxyalkyl in each case, R ７ is, in each case, independently selected from alkyl, cycloalkyl, hydroxy and hydroxyalkyl) The combination according to claim 1, which is a compound of

3. The combination according to claim 1 or 2, wherein L is a bond or ethynylene.

4. R １ The combination according to any one of claims 1 to 3, wherein R is hydrogen or fluoro.

5. R ２ and R ２’ is hydrogen or forms a cyclopropyl together with the carbon atoms to which they are attached, the combination according to any one of claims 1 to 4.

6. R ３ The combination according to any one of claims 1 to 5, wherein R is halogen or haloalkyl.

7. R ３ The combination according to any one of claims 1 to 6, wherein R is chloro or difluoromethyl.

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

9. R ５ The combination according to any one of claims 1 to 8, wherein R is morpholinyl or piperidinylmethylene which may be substituted with hydroxymethyl.

10. The compound of formula (I) is 2-[4,7-dichloro-6-(4-morpholinophenyl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazole-5,1'-cyclopropane]-1-yl-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide; and 2-[4-(difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-indazol-2-yl]-2-(5-ethyl-5-methyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide The combination according to any one of claims 1 to 9, selected from

11. The combination according to any one of claims 1 to 9, wherein the compound of formula (I) is 2-[4,7-dichloro-6-(4-morpholinophenyl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide.

12. The combination according to any one of claims 1 to 9, wherein the compound of formula (I) is 2-[4-(difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-indazol-2-yl]-2-(5-ethyl-5-methyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide.

13. The combination according to any one of claims 1 to 12, wherein the orthosteric EGFR inhibitor is selected from cetuximab, panitumumab, osimertinib, erlotinib, gefitinib, necitumumab, neratinib, lapatinib, vandetanib, brigatinib, almonertinib, lazertinib and flumonertinib, or a pharmaceutically acceptable salt thereof, in particular, selected from osimertinib, almonertinib, lazertinib and flumonertinib, or a pharmaceutically acceptable salt thereof.

14. The combination according to any one of claims 1 to 12, wherein the orthosteric EGFR inhibitor is osimertinib or a pharmaceutically acceptable salt thereof.

15. The combination according to any one of claims 1 to 14 for use as a therapeutic active substance.

16. A pharmaceutical composition comprising the combination according to any one of claims 1 to 14 and a therapeutically inert carrier.

17. The combination according to any one of claims 1 to 14 for use in the treatment or prevention of cancer, particularly non-small cell lung cancer.

18. Use of the combination according to any one of claims 1 to 14 for the treatment or prevention of cancer, particularly non-small cell lung cancer.

19. Use of the combination according to any one of claims 1 to 11 for the preparation of a medicament for the treatment or prevention of cancer, particularly non-small cell lung cancer.

20. Use of the combination according to any one of claims 1 to 14 for the preparation of a medicament for the treatment or prevention of non-small cell lung cancer.

21. A method for the treatment or prevention of cancer, particularly non-small cell lung cancer, comprising administering to a patient in need thereof an effective amount of the combination according to any one of claims 1 to 14.

22. The combination, use, method or pharmaceutical composition according to any one of claims 15 to 21, wherein both the allosteric EGFR inhibitor and the orthosteric EGFR inhibitor are administered orally.

23. The combination, use, method or pharmaceutical composition according to any one of claims 15 to 22, wherein the allosteric EGFR inhibitor is administered simultaneously with the orthosteric EGFR inhibitor.

24. The combination, use, method or pharmaceutical composition according to any one of claims 15 to 23, wherein the allosteric EGFR inhibitor and the orthosteric EGFR inhibitor are co-formulated.

25. The combination, use, method or pharmaceutical composition according to any one of claims 15 to 22, wherein the allosteric EGFR inhibitor and the orthosteric EGFR inhibitor are administered sequentially.

26. The combination, use, method or pharmaceutical composition according to any one of claims 17 to 21, wherein the cancer is associated with at least one EGFR mutation selected from del19, L858R, T790M and C797S.

27. The combination, use, method or pharmaceutical composition according to any one of claims 17 to 21, wherein the cancer is associated with at least two EGFR mutations selected from del19, L858R, T790M and C797S.

28. The invention as described previously herein.

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