Combination of allosteric and normal EGFR inhibitors for treatment of cancer

Abstract

The present invention relates to a combination therapy of cancer using an allosteric EGFR inhibitor and a normal EGFR inhibitor, as well as uses and pharmaceutical compositions thereof.

Description

[0001] The present invention relates to a novel combination product of an orthosteric EGFR inhibitor and a selective allosteric EGFR inhibitor containing EGFR mutants of T790M / L858R, T790M / L858R / C797S, L858R, and L858R / C797S, as well as uses and pharmaceutical compositions thereof.

[0002] The present invention particularly provides a combination product of an allosteric EGFR inhibitor and an orthosteric EGFR inhibitor, wherein the allosteric EGFR inhibitor is a compound of formula (I)

[0003]

[0004] in

[0005] L is a bond or an alkynylene group;

[0006] R 1 is hydrogen or halogen;

[0007] R 2 and R 2 ' is independently selected from hydrogen and alkyl;

[0008] or R 2 and R 2 'Together with the carbon atom to which they are attached they form a cycloalkyl group;

[0009] R 3 is hydrogen, halogen or haloalkyl;

[0010] R 4 is alkyl or halogen;

[0011] R 5 is (heterocycloalkyl)alkyl or heterocycloalkyl, wherein (heterocycloalkyl)alkyl is optionally substituted by one or two independently selected from R 6 wherein the heterocycloalkyl group is optionally substituted by one or two independently selected from R 7 Substituents are substituted;

[0012] R 6 is independently selected at each occurrence from alkyl, cycloalkyl, hydroxy and hydroxyalkyl; and

[0013] R 7 is independently selected at each occurrence from alkyl, cycloalkyl, hydroxy and hydroxyalkyl;

[0014] or a pharmaceutically acceptable salt thereof.

[0015] HER family receptor tyrosine kinases are mediators of cell growth, differentiation and survival. The receptor family includes four different members, namely, epidermal growth factor receptor (EGFR, ErbB1 or HER1), HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4). After ligand binding, the receptor forms homodimers and heterodimers, and then the activation of endogenous tyrosine kinase activity leads to receptor autophosphorylation and activation of downstream signal transduction molecules (Yarden, Y., Sliwkowski, MX. Untangling the ErbB signalling network. Nature Review Mol Cell Biol. February 2001; 2 (2): 127-37). EGFR deregulation through overexpression or mutation has been implicated in many types of human cancers, including colorectal cancer, pancreatic cancer, glioma, head and neck cancer, and lung cancer, especially non-small cell lung cancer (NSCLC), and several EGFR targeting agents have been developed over the years (Ciardiello, F. and Tortora, G. (2008). EGFR antagonists in cancer treatment. The New England journal of medicine 358, 1160-1174). Erlotinib A reversible EGFR tyrosine kinase inhibitor approved in many countries for the treatment of recurrent NSCLC.

[0016] Impressive single-agent activity of EGFR tyrosine kinase inhibitors was observed in a subset of NSCLC patients whose tumors had somatic kinase domain mutations, but the clinical benefit was greatly reduced in patients with wild-type EGFR (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 EGFR somatic mutations are exon 19 deletions (of which δ746-750 is the most common mutation) and exon 21 amino acid substitutions (of which L858R is the most common mutation) (Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 2007 March; 7(3): 169-81).

[0017] Often due to the secondary T790M mutation in the receptor ATP site, treatment resistance frequently occurs. Some mutant selective irreversible inhibitors developed (such as, for example, osimertinib, ametinib, lazertinib and vometinib) have high activity against T790M mutants, but their efficacy may be impaired by the acquired mutation of C797S, i.e., the acquired mutation of the cysteine ​​residue with which it forms a key covalent bond (Thress, KS et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat. Med. 21, 560–562 (2015)). Wang also reported C797S mutation as the main mechanism of resistance to T790M-targeted EGFR inhibitors (Wang et al. EGFR C797S mutation mediates resistance to third-generation inhibitors in T790M-positive non-small cell lung cancer, J Hematol Oncol. 2016; 9: 59). Yang described other mutations that lead to resistance to osimertinib, such as L718Q. (Yang et al., Investigating Novel Resistance Mechanisms to Third-Generation EGFR Tyrosine Kinase Inhibitor Osimertinib in Non–Small Cell Lung Cancer Patients, Clinical Cancer Research, DOI: 10.1158 / 1078-0432.CCR-17-2310) Lu et al. (Targeting EGFRL858R / T790M and EGFR L858R / T790M / C797S resistance mutations in NSCLC: Current developments in medicinal chemistry, Med Res Rev 2018; 1-32) report in a review article on targeting EGFRL858R / T790M and EGFRL858R / T790M / C797S resistance mutations in NSCLC treatment.

[0018] Since most available EGFR tyrosine kinase inhibitors target the ATP site of the kinase, new therapeutic agents that act differently, for example by targeting drug-resistant EGFR mutants, are needed.

[0019] Recent studies have shown that purposeful targeting of allosteric sites can lead to mutant-selective inhibitors (Jia et al. Overcoming EGFR (T790M) and EGFR (C797S) resistance with mutant-selective allosteric inhibitors, June 2016, Nature 534, 129-132)

[0020] Therefore, it is necessary to generate selective molecules that specifically inhibit EGFR mutants containing T790M / L858R, T790M / L858R / C797S, L858R, L858R / C797S. Such selective inhibitors can be used for therapeutic and / or prophylactic treatment of cancer, especially EGFR mutants containing T790M and C797S.

[0021] Importantly, such selective allosteric inhibitors are designed to treat cancers characterized by EGFR mutants that are resistant to orthosteric EGFR inhibitors. The rationale is that once resistance develops, treatment can be switched from orthosteric EGFR inhibitors to allosteric EGFR inhibitors designed specifically to target mutants carrying T790M and / or C797S mutations.

[0022] The present invention relates to a combination product of an orthosteric EGFR inhibitor and a selective allosteric EGFR inhibitor corresponding to a compound of formula (I). The compound of formula (I) effectively targets T790M / L858R, T790M / L858R / C797S, L858R, L858R / C797S mutations and has low in vitro liver clearance (Tables 1 and 2). Importantly, the compound of formula (I) also effectively targets the in vivo L858R / C797S mutation in Ba / F3-based allografts ( Figure 1 ), which causes resistance to orthosteric EGFR inhibitors. Surprisingly, combination treatment with clinically relevant doses of the approved orthosteric EGFR inhibitor osimertinib and the allosteric EGFR inhibitor of formula (I) significantly improved tumor regression in mice bearing NCI-H1975 xenografts, which are EGFR-bearing mice. L858R / T790M Established models of double-mutated EGFR-driven NSCLC ( Figure 2Importantly, binding of the EGFR inhibitor of formula (I) increases the residence time of the orthosteric EGFR inhibitor osimertinib by about 120-fold and thereby accelerates the rate of covalent binding of osimertinib to EGFR ( Figure 3 This surprising positive synergy between the allosteric EGFR inhibitor of formula (I) and the orthosteric EGFR inhibitor has not been reported before and provides a promising new treatment strategy for patients with EGFR-related cancers, especially non-small cell lung cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 : (A) Compound Example 6 (squares) and Compound Example 3 (triangles) in Ba / F3 EGFR L858R / C797S Antitumor activity in allografts at 10 mpk and 30 mpk, respectively, orally twice daily. Black arrows indicate dosing. Tumor control ratios (TCRs) below 1.0 indicate tumor growth inhibition, with confidence intervals (CIs) reflecting data distribution. Upper limits of the CI below 1.0 confirm statistical significance. No significant changes in body weight occurred in the different groups.

[0024] Figure 2 (A) Compound Example 6 alone and in combination with osimertinib in NCI-H1975 NSCLC-derived tumors (EGFR L858R / T790M xenografts). Black arrows indicate dosing. TCRs below 1.0 indicate tumor growth inhibition, where the CI reflects the data distribution. CI upper limits below 1.0 confirm statistical significance. There were no significant changes in body weight across groups. (B) Antitumor activity of Example 1 alone and in combination with osimertinib in NCI-H1975 NSCLC-derived tumors (EGFR L858R / T790M Figure 2 shows the anti-tumor activity in 100% leukemia (xenografts). Black arrows indicate dosing. TCRs below 1.0 indicate tumor growth inhibition, where the CI reflects the data distribution. The upper limit of the CI below 1.0 confirms statistical significance.

[0025] Figure 3 (A) Binding kinetics measured by stopped-flow fluorescence. When bound, osimertinib quenches the TRp fluorescence of EGFR. (B) Binding kinetics directly show that in the presence of allosteric inhibitor compound example 1, osimertinib reacts faster with the EGFR kinase domain (L858R), indicating positive synergy. (C) Global fitting of the kinetic data reveals the mechanism of positive synergy: compound example 1 increases the residence time of osimertinib by about 120 times, and thus accelerates the rate of formation of important covalent bonds.

[0026] The term "inhibitor" refers to a compound that competes with a specific ligand to bind to a specific receptor, or reduces or prevents the specific ligand from binding to a specific receptor, or reduces or prevents the function of a specific protein. Specifically, the inhibitor used herein refers to a compound that targets, reduces or inhibits EGFR activity, and the specific inhibitor has an IC50 value of less than 1 μM, less than 500nM, less than 200nM, less than 100nM, less than 50nM, less than 25nM, less than 10nM, less than 5nM, 2nM or less than 1nM. 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" relates to an EGFR inhibitor that binds tightly to the active site, such as, for example, erlotinib, gefitinib, osimertinib, ametinib, lazertinib and vometinib or a pharmaceutically acceptable salt thereof, in particular the mesylate. Non-limiting examples of orthosteric EGFR inhibitors include cetuximab Panitumumab Osimertinib (merelectinib, ), erlotinib Gefitinib Necitumumab (Portrazza TM ), neratinib Lapatinib Vandetanib and brigatinib

[0027] The term "IC50" refers to the concentration of a particular compound required to inhibit 50% of a particular measured activity.

[0028] In this specification, the term "alkyl" refers, alone or in combination, to a straight or branched chain alkyl group having 1 to 8 carbon atoms, particularly a straight or branched chain alkyl group having 1 to 6 carbon atoms and more particularly a straight or branched chain alkyl group having 1 to 4 carbon atoms. Examples of straight and branched C1-C8 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, isomeric amyl, isomeric hexyl, isomeric heptyl and isomeric octyl, particularly methyl, ethyl, propyl, butyl and amyl. Specific examples of "alkyl" are methyl, ethyl, propyl, isopropyl and tert-butyl. Methyl is a specific example of "alkyl" in compounds of formula (I).

[0029] The term "alkoxy" refers, alone or in combination, to a group of the formula "alkyl-O-", wherein the term "alkyl" has the meaning given previously, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. Specific examples of "alkoxy" are methoxy, ethoxy and tert-butoxy.

[0030] The term "alkylene" alone or in combination means a straight chain saturated divalent hydrocarbon radical of 1 to 7 carbon atoms or a divalent branched saturated divalent hydrocarbon radical 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.

[0031] The term "alkynylene" alone or in combination means a straight 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 alkynylene groups include ethynylene, 2,2-dimethylethynylene, propynylene, 2-methylpropynylene, butynylene, and pentynylene. A specific example of "alkynylene" is ethynylene.

[0032] The term "oxy" alone or in combination refers to an -O- group.

[0033] The term "halogen" or "halo" alone or in combination means fluorine, chlorine, bromine or iodine and in particular fluorine or chlorine. A specific "halogen" or "halo" is fluorine. The term "halo" in combination with another group means that the group is substituted with at least one halogen, in particular with one to five halogens, in particular one to four halogens, i.e. one, two, three or four halogens.

[0034] The term "haloalkyl", alone or in combination, refers to an alkyl group substituted with at least one halogen, particularly with one to five halogens, in particular one to three halogens. Specific examples of "haloalkyl" are difluoromethyl and trifluoromethyl.

[0035] The term "hydroxyl" or "hydroxy", alone or in combination, refers to a -OH group.

[0036] The term "carbonyl" alone or in combination refers to a -C(O)- group.

[0037] The term "heterocycloalkyl" refers, alone or in combination, to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system having 4 to 9 ring atoms, containing 1, 2 or 3 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Bicyclic means consisting of two rings having one or two common ring atoms. Examples of "heterocycloalkyl" are morpholinyl, piperidinyl, azetidinyl and piperazinyl. Specific examples of "heterocycloalkyl" are piperidinyl and morpholinyl.

[0038] The term "cycloalkyl", alone or in combination, means a monovalent saturated cyclic hydrocarbon group having 3 to 8 ring-forming carbon atoms. Examples of "cycloalkyl" are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. A specific example of a "cycloalkyl" group is cyclopropyl.

[0039] The terms "piperidinyl" and "piperidinyl" are interchangeable and, alone or in combination, refer to a saturated monocyclic ring containing 5 carbon ring atoms and one nitrogen ring atom.

[0040] The term "pharmaceutical salt" refers to salts that retain the biological effects and properties of free alkali or free acid, which are not undesirable biologically or otherwise. These salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. (particularly hydrochloric acid) and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methylsulfonic acid, ethylsulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, etc. In addition, these salts can be prepared by adding inorganic bases or organic bases to free acids. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium salts, etc. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines and basic ion exchange resins (such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins, etc.). Particularly pharmaceutically acceptable salts of the compound of formula (I) are hydrochlorides, mesylate salts and citrate salts. Particularly pharmaceutically acceptable salts of osimertinib are methanesulfonic acid salts, also known as mesylate salts.

[0041] In one embodiment, the present invention provides a kit comprising an orthosteric EGFR inhibitor as described herein and an allosteric EGFR inhibitor of formula (I), prescription information (also referred to as "instructions"), a blister pack or bottle (HDPE or glass), and a container. The prescription information preferably includes advice to the patient regarding the administration of a combination of an orthosteric EGFR inhibitor and an allosteric EGFR inhibitor as described herein for treatment;

[0042] According to the Cahn-Ingold-Prelog convention, an asymmetric carbon atom may be in the "R" or "S" configuration. The compounds of formula (I) may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers (e.g., racemates), optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates, or mixtures of diastereomeric racemates.

[0043] Furthermore, the present invention includes all substituents of the compounds of formula (I) in their corresponding deuterated forms, where applicable.

[0044] In some embodiments providing optically pure enantiomers, optically pure enantiomers mean that the compound contains >90% by weight of the desired isomer, specifically >95% by weight of the desired isomer, or more specifically >99% by weight of the desired isomer, the weight percentages being based on the total weight of the isomers of the compound. Chirally pure compounds or chirally enriched compounds can be prepared by chiral selective synthesis or by enantiomer separation. Separation of enantiomers can be performed on the final product, or alternatively on a suitable intermediate.

[0045] The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments (e.g., in the form of pharmaceutical preparations). Pharmaceutical preparations can be administered internally, such as orally (e.g., in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g., in the form of nasal sprays), rectally (e.g., in the form of suppositories) or topically to the eye (e.g., in the form of solutions, ointments, gels or water-soluble polymer inserts). However, they can also be administered parenterally, such as intramuscularly, intravenously or intraocularly (e.g., in the form of sterile injections).

[0046] The compound of formula (I) and its pharmaceutically acceptable salt can be processed with pharmaceutically inert inorganic or organic adjuvants to produce tablets, coated tablets, dragees, hard gelatin capsules, injections or topical preparations. For example, lactose, corn starch or its derivatives, talcum powder, stearic acid or its salts etc. can be used as such adjuvants for tablets, dragees and hard gelatin capsules.

[0047] Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid substances and liquid polyols and the like.

[0048] Suitable adjuvants for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like.

[0049] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

[0050] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols and the like.

[0051] Suitable adjuvants for topical ophthalmic preparations are, for example, cyclodextrins, mannitol or numerous other carriers and excipients known in the art.

[0052] In addition, the pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffer masking agents or antioxidants. They may also contain other therapeutically valuable substances.

[0053] The following examples illustrate but do not limit the invention, but are merely representative of the invention. The pharmaceutical composition conveniently contains about 1 mg to 500 mg, particularly 1 mg to 100 mg, of a compound of formula (I). The pharmaceutical composition conveniently contains about 1 mg to 500 mg, particularly 1 mg to 100 mg, of a compound of formula (II). In certain embodiments, the pharmaceutical composition containing the compound of formula (I) additionally contains about 1 mg to 500 mg, particularly 80 mg, of an orthosteric EGFR inhibitor in a fixed dose combination.

[0054] Non-limiting examples of compositions according to the invention are:

[0055] Preparation of pharmaceutical compositions containing the compounds of the present invention:

[0056] Tablets of the following composition are produced in a conventional manner:

[0057]

[0058] Preparation Procedure

[0059] 1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water.

[0060] 2. Dry the granules at 50°C.

[0061] 3. Pass the particles through suitable grinding equipment.

[0062] 4. Add ingredient 5 and mix for three minutes; press on a suitable press.

[0063] Capsules of the following composition are produced in a conventional manner:

[0064]

[0065] Preparation Procedure

[0066] 1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes.

[0067] 2. Add ingredients 4 and 5 and mix for 3 minutes.

[0068] 3. Fill into suitable capsules.

[0069] The compound of formula (I), lactose and corn starch are first mixed in a mixer and then in a pulverizer. The mixture is returned to the mixer; talc is added thereto and mixed uniformly.

[0070] The mixture is filled by machine into suitable capsules, such as hard gelatin capsules.

[0071] The following injections are prepared in a conventional manner:

[0072] Element mg / injection. Compound of formula (I) 3 Polyethylene glycol 400 150 Acetic acid Adjust pH to 5.0 Water for injection Add to 1.0ml

[0073] Examples

[0074] abbreviation

[0075] AcOH = acetic acid; ATP = adenosine triphosphate; BID = twice daily; CAS = Chemical Abstracts Service; CDI = 1,1'-carbonyldiimidazole; Cl int = intrinsic clearance; c max = maximum plasma concentration; D = study day; DCM = dichloromethane; DME = dimethoxyethane; DMF = dimethylformamide; DMSO = dimethyl sulfoxide; ESI = electrospray ionization; EtOAc = ethyl acetate; EtOH = ethanol; HATU = hexafluorophosphate azabenzotriazole tetramethyl uronium; LDA = lithium diisopropylamide; MeOH = methanol; MS = mass spectrometry; NMR = nuclear magnetic resonance; PO = oral; QD = once daily; RT = room temperature; SC = subcutaneous; THF = tetrahydrofuran.

[0076] The following examples are provided to illustrate the present invention. They should not be considered as limiting the scope of the invention, but are merely representative.

[0077] If preparations are obtained as mixtures of enantiomers, the pure enantiomers may be obtained by methods described herein or by methods known to those skilled in the art such as, for example, chiral chromatography or crystallization.

[0078] Example 1

[0079] 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

[0080]

[0081] Step 1: 4-Bromo-3,6-dichloro-2-fluorobenzaldehyde

[0082]

[0083] 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. A THF solution of LDA (2 mol / l) (21.2 ml, 42.5 mmol, 1.1 equivalents) was added and the mixture was stirred at -75 ° C for 20 minutes. N, N-dimethylformamide (2.82 g, 3.0 ml, 38.6 mmol, 1 equivalent) was added dropwise and stirred for 1 hour. A solution of acetic acid in ether (1:1, 10 ml) was added. The mixture was warmed to room temperature. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried (MgSO4), filtered and concentrated in vacuo to give the crude title compound as a light yellow solid (quantitative yield). The compound can be used in the next step without further purification.

[0084] Step 2: 6-Bromo-4,7-dichloro-1H-indazole

[0085]

[0086] To a solution of 4-bromo-3,6-dichloro-2-fluorobenzaldehyde (Example 1, Step 1) (10.5g, 38.6mmol) in dioxane (50ml) was added hydrazine hydrate (3.86g, 3.78ml, 77.2mmol, 2.0 equiv). The mixture was stirred at room temperature for 3 days. Hydrazine hydrate (386mg, 0.38ml, 7.72mmol, 0.2 equiv) was added and the mixture was warmed to 70°C for 7 hours. 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 hours. The solid was collected by filtration, washed with a small amount of acetonitrile, and then dried to give the title compound (7.8g, 76% yield) as an off-white solid. m / z 267.0 / 269.0, [M+H] + ,ESI pos,Br isotope. Step 3: Ethyl 2-(6-bromo-4,7-dichloro-indazol-2-yl)acetate

[0087]

[0088] To a solution of 6-bromo-4,7-dichloro-1H-indazole (Example 1, Step 2) (7.84 g, 29.5 mmol, equiv: 1) in N,N-dimethylacetamide (11.5 mL) was added ethyl 2-bromoacetate (9.85 g, 6.53 ml, 59 mmol, 2.0 equiv). The reaction mixture was stirred at 100 °C for 16 hours. Ice was added and the precipitated solid was collected by filtration and then washed with water. The compound was crystallized from boiling ethanol. The solid was collected by filtration, washed with a small amount of ethanol, and then 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.

[0089] Step 4: (2S,4R)-2-[2-(6-bromo-4,7-dichloro-indazol-2-yl)-3-ethoxy-3-oxo-propionyl]- 4-Fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester

[0090]

[0091] A solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (2.34 g, 10 mmol, 1.55 equiv) in tetrahydrofuran (11 ml) was cooled in an ice bath. Carbonyldiimidazole (1.63 g, 10 mmol, 1.55 equiv) was added. The cooling bath was removed and the mixture was stirred for 3 hours to give 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. A solution of LDA in tetrahydrofuran (2 mol / l) (5.0 ml, 10 mmol, 1.55 equiv) was added dropwise over 5 minutes. The mixture was stirred at -70 °C for 30 minutes. Solution A was added dropwise over 5 minutes. The mixture was warmed to room temperature overnight in the cooling bath. After adding saturated aqueous NH4Cl solution, the mixture was extracted twice with ethyl acetate. The organic layers were washed with water, combined, dried over sodium sulfate and concentrated to dryness to give the crude title compound (quantitative yield), which was used in the next step without further purification. m / z 566.1 / 568.1, [M+H] + ,ESI pos,Br isotope.

[0092] Step 5: 2-(6-Bromo-4,7-dichloro-indazol-2-yl)-2-[(6R)-6-fluoro-3-thioxo-2,5,6,7-tetrahydropyridine] Ethyl pyrolu[1,2-c]imidazol-1-yl]acetate

[0093]

[0094] A solution of (2S,4R)-2-[2-(6-bromo-4,7-dichloro-indazol-2-yl)-3-ethoxy-3-oxo-propionyl]-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (Example 1, Step 4) (4.23 g, 6.41 mmol) in HCl, 4M 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 HCl, 1M in ethanol (12.8 ml) were added and stirred at room temperature for 40 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over MgSO4, filtered, concentrated and dried 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.

[0095] Step 6: 2-(6-Bromo-4,7-dichloro-indazol-2-yl)-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1, 2-c]imidazol-1-yl]ethyl acetate

[0096]

[0097] A solution of ethyl 2-(6-bromo-4,7-dichloro-indazol-2-yl)-2-[(6R)-6-fluoro-3-thioxo-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazo-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 eq.) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. Excess hydrogen peroxide was destroyed by the addition of saturated sodium sulfite solution. After adding some water (just enough to dissolve all the salts) and ethyl acetate, the mixture was brought to pH 9 by careful addition of solid sodium carbonate. The mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and then concentrated. The product was purified by chromatography (SiO2, 0-100% ethyl acetate in heptane) to afford the title compound as a light brown solid (0.81 g, 58% yield). m / z 475.0 / 477.0, [M+H] + ,ESI pos,Br isotope.

[0098] Step 7: 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]acetic acid

[0099]

[0100] 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 eq.) and cesium carbonate (205 mg, 0.63 mmol, 3 eq.) were mixed with toluene (3.0 ml) and degassed by bubbling argon through the mixture under ultrasonic treatment. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15 mg, 0.02 mmol, 0.1 eq.) 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 (SiO2, 0% to 40% methanol in ethyl acetate) to afford the title compound (82 mg, 69% yield) as a light brown amorphous solid. m / z 558.4, [M+H] + ,ESI pos.

[0101] 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

[0102]

[0103] To 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 LiOH 1M (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 thiazole-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. Water was added and 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 (SiO2, 0% to 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.

[0104] Example 2

[0105] 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

[0106]

[0107] Step 1: 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]acetic acid ethyl ester

[0108]

[0109] A suspension of intermediate 1 (0.5 g, 1.06 mmol, eq.: 1.0), (4-morpholinophenyl)boronic acid (CAS 186498-02-2, 329 mg, 1.59 mmol, eq.: 1.5) and K2CO3 (183 mg, 1.33 mmol, eq.: 1.25) in 2-MeTHF (6 mL), water (1 mL) was degassed with argon for 10 minutes. Dichloro[bis(diphenylphosphinophenyl)ether]palladium(II) (CAS 205319-06-8, 91 mg, 127 μmol, eq.: 0.12) was added. The reaction mixture was stirred at 85 °C for 5 hours. AcOH (191 mg, 182 μL, 3.18 mmol, eq.: 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 Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 50% (EtOAc / EtOH / aq.NH3 75:25:2) in heptane) to afford the title compound as an off-white solid (433 mg, 743 μmol, 70% yield). m / z 554.4 [M+H] + ,ESI pos.

[0110] 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

[0111]

[0112] To 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, eq: 1.0) in THF (9 mL) and MeOH (9 mL) was added LiOH (1 M aq., 2.6 mL, 2.6 mmol, eq: 2.0). The reaction mixture was stirred at room temperature for 2 hours. HCl (5 Naq., 520 μL, 2.6 mmol, eq: 2.0) was added (pH 6). Toluene was added and the reaction mixture was concentrated in vacuo. Formic acid is dissolved in DMSO (6mL), thiazole-2-amine (195mg, 1.95mmol, eq.: 1.5), DIPEA (840mg, 1.14mL, 6.5mmol, eq.: 5.0) and HATU (742mg, 1.95mmol, eq.: 1.5) are added. The reaction mixture is stirred at room temperature for 1.5 hours. The reaction mixture is poured into EtOAc / THF 2:1 and washed with water and brine. The organic layer is dried over Na2SO4 and concentrated in vacuo. The crude material is purified by flash chromatography (silica gel, 40g, 0% to 5% MeOH in DCM). The product is freeze-dried to obtain the title compound as an off-white solid (501mg, 63% yield). m / z 608.3[M+H] + ,ESI pos.

[0113] Example 3

[0114] 2-[4-(Difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazol-5,1'-cyclopropane]-1-yl-N-thiazol-2-yl-acetamide

[0115]

[0116] Step 1: 1-Bromo-5-(difluoromethyl)-3-fluoro-2-methyl-benzene

[0117]

[0118] Morpholino sulfur trifluoride (CAS#51010-74-3, 24.8g, 17.3mL, 135mmol, 1.5 equivalents) is added to the cooling solution of 3-bromo-5-fluoro-4-methylbenzaldehyde (CAS#1370411-47-4, 20.5g, 89.7mmol, 1.0 equivalents) in dichloromethane (98mL) in batches. The reaction mixture is stirred at 0°C to 5°C for 20 minutes, and then stirred at room temperature for 16 hours. Saturated NaHCO3 aqueous solution (300mL) is carefully added under ice cooling. The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is poured into dichloromethane and washed with water. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The crude material is purified by flash chromatography (silica gel, 120g, 100% pentane) to obtain the title compound, which is a colorless oil (18.6g, yield 87%). 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)

[0119] Step 2: 6-Bromo-4-(difluoromethyl)-7-methyl-1H-indazole

[0120]

[0121] A solution of 1-bromo-5-(difluoromethyl)-3-fluoro-2-methyl-benzene (Example 1, Step 1) (26.4 g, 110 mmol, 1.0 equiv) in tetrahydrofuran (240 mL) was cooled to -75 °C. A solution of lithium diisopropylamide (2M in tetrahydrofuran / heptane / ethylbenzene, 66.3 mL, 133 mmol, 1.2 equiv) was added dropwise, maintaining the temperature below -70 °C. The reaction mixture was stirred at -75 °C for 30 minutes. Ethyl formate (16.4 g, 17.7 mL, 220 mmol, 2.0 equiv) was added below -70 °C. The reaction mixture was stirred at -75 °C for 30 minutes. Acetic acid (16.6 g, 15.8 mL, 277 mmol, 2.5 equiv) was added below -55 °C. The reaction mixture was allowed to warm to room temperature, poured into ethyl acetate and washed with diluted aqueous HCl, water and brine. The organic layer is dried over sodium sulfate and concentrated in vacuo to obtain the assumed 4-bromo-6-(difluoromethyl)-2-fluoro-3-methyl-benzaldehyde, which is a yellow oil (29.5g) that can be used without further purification. The assumed crude 4-bromo-6-(difluoromethyl)-2-fluoro-3-methyl-benzaldehyde (29.5g) is dissolved in dimethoxyethane (150mL). O-methylhydroxylamine hydrochloride (10.2g, 122mmol, 1.1 equivalents) and potassium carbonate (30.6g, 221mmol, 2.0 equivalents) are added. The reaction mixture is stirred at 45°C for 2.5 hours, then filtered through sintered glass and washed with dimethoxyethane (2x). The filtrate is concentrated in vacuo. The oxime ether intermediate is dissolved in dimethyl sulfoxide (150mL). Hydrazine hydrate (83g, 80.5mL, 1.66mol, 15 equivalents) was added. The reaction mixture was stirred at 110°C for 3 hours. The reaction mixture was poured into a mixture of ethyl acetate / tetrahydrofuran 5:1. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 2x 120g, gradient 0% to 30% ethyl acetate in heptane) to obtain the title compound (13.5g, 45% yield) as a white solid (13.5g, 45% yield). LCMS: m / z 260.9 / 262.8[M+H] + ,ESIpos,Br isotope.

[0122] Step 3: Ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]acetate

[0123]

[0124] To a solution of 6-bromo-4-(difluoromethyl)-7-methyl-1H-indazole (Example 1, Step 2) (19 g, 72.8 mmol, 1.0 equiv) in N,N-dimethylformamide (75 mL) was added ethyl 2-bromoacetate (CAS#105-36-2, 18.2 g, 12.2 mL, 109 mmol, 1.5 equiv). The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was poured into ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 2 x 120 g, gradient 0% to 20% ethyl acetate in heptane) to give the title compound (21.2 g, 80% yield) as a yellow solid. LCMS: m / z 346.9 / 348.8, [M+H] + ,ESI pos,Br isotope.

[0125] Step 4: (5R)-5-[2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-3-ethoxy-3-oxo- [propionyl]-4-azaspiro[2.4]heptane-4-carboxylic acid tert-butyl ester

[0126]

[0127] Preparation of tert-butyl (5R)-5-(imidazole-1-carbonyl)-4-azaspiro[2.4]heptane-4-carboxylate

[0128]

[0129] To a solution of (5R)-4-tert-butoxycarbonyl-4-azaspiro[2.4]heptane-5-carboxylic acid (CAS#2007916-06-3, 1.02 g, 4.21 mmol, 1.0 equiv) in dichloromethane (17 mL) was added 1,1'-carbonyldiimidazole (818 mg, 5.04 mmol, 1.2 equiv) in three portions, and the reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was poured into a saturated NaHCO3 aqueous solution and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to obtain (5R)-5-(imidazole-1-carbonyl)-4-azaspiro[2.4]heptane-4-carboxylic acid tert-butyl ester (1.30 g, 95% yield, 90% purity) as an off-white solid which was used directly in the next step.

[0130] A solution of 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazole-2-yl]ethyl acetate (Example 1, Step 3) (1.2g, 3.46mmol, 1.0 equivalent) in tetrahydrofuran (16mL) was cooled to -50°C. NaHMDS (1M in tetrahydrofuran) (4mL, 4mmol, 1.16 equivalent) was added and the reaction mixture was stirred at -50°C for 45 minutes. A solution of the aforementioned (5R)-5-(imidazole-1-carbonyl)-4-azaspiro[2.4]heptane-4-carboxylic acid tert-butyl ester (1.29g, 3.98mmol, 1.15 equivalent) in tetrahydrofuran (16mL) was added dropwise at -50°C. The reaction mixture was stirred at -50°C for 30 minutes. Then, the cooling bath was removed, and the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled and quenched with saturated NH4Cl aqueous solution, diluted with water and extracted with ethyl acetate. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3 aqueous solution and then washed with brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (2.37 g, 96% yield, 80% purity) as a light brown foam which was used without further purification. LCMS: m / z 570.3 / 572.3 [M+H] + ,ESI pos,Br isotope.

[0131] Step 5: 2-[6-Bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2- c] Ethyl imidazole-5,1'-cyclopropane-1-yl acetate

[0132]

[0133] A mixture of (5R)-5-[2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-3-ethoxy-3-oxo-propionyl]-4-azaspiro[2.4]heptane-4-carboxylic acid tert-butyl ester (Example 1, Step 4) (2.36 g, 3.31 mmol, 1.0 eq., 80% purity) and HCl (4M in 1,4-dioxane, 4.2 mL, 16.8 mmol, 5.07 eq.). The reaction mixture was stirred at room temperature for 1 hour. HCl (4M in 1,4-dioxane, 1 mL, 4.0 mmol, 1.21 eq.) was added, and the reaction mixture was stirred at room temperature for 30 minutes. HCl (4M in 1,4-dioxane, 1 mL, 4.0 mmol, 1.21 eq.) was added, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethanol (7.6 mL) and water (2.0 mL). Potassium thiocyanate (419mg, 4.31mmol, 1.3 equivalents) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled and pyridine (3.91g, 4mL, 49.46mmol, 14.9 equivalents) was slowly added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 1N KHSO4+ water and extracted three times with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in a vacuum. The crude material was dissolved in acetic acid (7.6mL) and cooled to 0°C. Hydrogen peroxide (35% by weight solution in water, 0.580mL, 6.62mmol, 2.0 equivalents) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 1 hour. Excess hydrogen peroxide was destroyed with a 1M aqueous solution of Na2S2O3. The mixture was carefully alkalized with solid Na2CO3 and extracted twice with ethyl acetate. The organic layer was washed with brine, merged, dried over sodium sulfate, filtered and concentrated in a vacuum. The crude material was adsorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, 24 g, gradient 0% to 100% ethyl acetate in heptane). All fractions containing product were combined and concentrated in vacuo to give the title compound (882 mg, 53% yield) as a light yellow solid. LCMS: m / z 479.3 / 481.3 [M+H] + ,ESI pos,Br isotope.

[0134] Step 6: 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-spiro[6,7-dihydro Pyridine Ethyl pyrolu[1,2-c]imidazol-5,1'-cyclopropane]-1-yl acetate

[0135]

[0136] A mixture of 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazol-5,1'-cyclopropane]-1-yl-acetic acid ethyl ester (Example 1, Step 5) (350 mg, 0.69 mmol, 1.00 equiv), (4-morpholinophenyl)boronic acid (CAS#186498-02-2, 187 mg, 0.90 mmol, 1.30 equiv), cesium carbonate (679 mg, 2.08 mmol, 3.00 equiv) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride and dichloromethane complex (82 mg, 0.10 mmol, 0.14 equiv) in 1,4-dioxane (6.0 mL) was flushed with argon and stirred at 100°C for 2 hours. The reaction mixture is cooled to room temperature, then extracted with ethyl acetate and water. The aqueous layer is back-extracted with ethyl acetate. The organic layer is washed with water and brine. The combined organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The crude material is adsorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, 24g, gradient 0% to 90% ethyl acetate in heptane). All fractions containing the product are combined and concentrated to obtain the title compound (352mg, yield 81%, 90% purity), which is off-white foam. LCMS: m / z 562.5[M+H] + ,ESI pos. Step 7: 2-[4-(difluoromethyl)-7-methyl- 6-(4-morpholinophenyl)indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazol-5,1'-cyclopropane]-1-yl- N-Thiazol-2-yl-acetamide

[0137]

[0138] To a solution of 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazol-5,1'-cyclopropane]-1-yl-acetic acid ethyl ester (Example 1, Step 6) (346 mg, 0.55 mmol, 1.0 equiv) in ethanol (1.8 mL) and tetrahydrofuran (1.8 mL) was added lithium hydroxide (1 M aqueous solution, 0.64 mL, 0.64 mmol, 1.15 equiv). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was evaporated and co-evaporated twice with toluene. The residue is suspended in N, N-dimethylformamide (1.8mL), and N, N-diisopropylethylamine (0.30mL, 1.72mmol, 3.1 equivalents), thiazole-2-amine (72mg, 0.72mmol, 1.3 equivalents) and HATU (274mg, 0.72mmol, 1.3 equivalents) are added. The reaction mixture is stirred at room temperature for 45 minutes. The reaction mixture is extracted with ethyl acetate and water. The water layer is extracted with ethyl acetate. The organic layer is washed with water three times and washed once with brine. The combined organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The crude product is adsorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, 25g, gradient 0% to 5% methanol in dichloromethane). All fractions containing the product are combined and concentrated in vacuo. The residue was adsorbed on ISOLUTE HM-N and repurified by flash chromatography (Si-amine, 12 g, gradient 0% to 10% methanol in ethyl acetate). All fractions containing product were combined and concentrated to give the title compound (183 mg, 53% yield) as an off-white foam. LCMS: m / z 616.4 [M+H] + ,ESI pos.

[0139] Example 4

[0140] 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

[0141]

[0142] Step 1: Ethyl 2-(6-bromo-4-fluoro-indazol-2-yl)acetate

[0143]

[0144] A mixture of 6-bromo-4-fluoro-1H-indazole (CAS 885520-23-0) (1 equivalent), ethyl 2-bromoacetate (2 equivalents) and N,N-dimethylacetamide (a small amount to produce a solution) 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, yield 53%) was purified using flash chromatography (silica gel, 0% to 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] + .

[0145] Step 2: 2[-2-(6-Bromo-4-fluoro-indazol-2-yl)-3-ethoxy-3-oxo-propionyl]pyrrolidine-1-carboxylic acid ester

[0146]

[0147] Ethyl 2-(6-bromo-4-fluoro-indazol-2-yl)acetate (1 eq) was reacted with CDI preactivated (tert-butoxycarbonyl)-L-proline (CAS 15761-39-4) (1.55 eq) in the presence of LDA (1.55 eq) in THF at -70°C to room temperature. The reaction gave the title compound 2[-2-(6-bromo-4-fluoro-indazol-2-yl)-3-ethoxy-3-oxo-propionyl]pyrrolidine-1-carboxylate.

[0148] Step 3: 2-(6-bromo-4-fluoro-indazol-2-yl)-2-(3-thioxo-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazole Azole-1- Ethyl acetate

[0149]

[0150] 2[-2-(6-Bromo-4-fluoro-indazol-2-yl)-3-ethoxy-3-oxo-propionyl]pyrrolidine-1-carboxylate (1 eq) was reacted with HCl (in dioxane) at room temperature. Nest, KSCN (1.33 eq) was added in the presence of HCl in ethanol at room temperature. The reaction gave ethyl 2-(6-bromo-4-fluoro-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate.

[0151] Step 4: 2-(6-Bromo-4-fluoro-indazol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl) Ethyl acetate

[0152]

[0153] Hydrogen peroxide, 35% (1.12 g, 1.01 mL, 11.5 mmol, 4 eq.) was added dropwise to a solution of 2-(6-bromo-4-fluoro-indazole-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)ethyl acetate (2.88 mmol, 1 eq.) in acetic acid (10 mL) at 10 °C. The reaction mixture was stirred at room temperature for 1 hour. Excess hydrogen peroxide was destroyed by adding a saturated sodium sulfate solution. After adding some water (just enough to dissolve all salts) and ethyl acetate, the mixture was brought to pH 9 by carefully adding solid sodium carbonate. The mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated. The product was purified by chromatography (silica gel, 0-100% ethyl acetate in n-heptane) to obtain the title compound as a brown gum (51% yield from step 2 to step 4). 1H NMR (300MHz, chloroform-d) δ = 8.22 (s, 1H), 7.66 (t, J = 1.0Hz, 1H), 7.50 (s, 1H), 6.80 (dd, J = 1.2, 9.5Hz, 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]+.

[0154] Step 5: 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

[0155]

[0156] To a solution of ethyl 2-(6-bromo-4-fluoro-indazole-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (1 eq) in ethanol (3 mL) was added lithium hydroxide 1 M (1.1 eq). The reaction was stirred for 1 hour, the solvent was evaporated, and the residue was concentrated and co-evaporated twice with toluene to remove water. The reaction mixture was diluted in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (345 mg, 0.466 mL, 2.67 mmol, 3 eq), thiazol-2-ylamine (116 mg, 1.16 mmol, 1.3 eq) and HATU (440 mg, 1.16 mmol, 1.3 eq) were added. Stirred at room temperature for 1 hour, the reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, methanol in dichloromethane 0% to 10%) to give 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. step 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

[0157]

[0158] To a 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 eq) in N,N-dimethylformamide (5 mL) was added 4-ethynylbenzaldehyde (49 mg, 0.375 mmol, 1 eq), triethylamine (113.83 mg, 0.157 mL, 1.12 mmol, 3 eq), triphenylphosphine (10 mg, 0.037 mmol, 0.100 eq), bis(triphenylphosphine)palladium(II) chloride (13 mg, 0.019 mmol, 0.050 eq) and copper(I) iodide (3.57 mg, 0.019 mmol, 0.050 eq). The vial is capped and heated in a microwave at 110 ° C for 20 minutes, then 4-ethynylbenzaldehyde (49mg, 0.375mmol, 1 equivalent) is added, and the vial is heated again at 110 ° C for 20 minutes. The program is repeated three times. In total, the reaction mixture is stirred at 110 ° C for 5x20 minutes. The reaction mixture is poured into water and extracted with ethyl acetate (4x). The combined organic layer is washed with salt water, dried over sodium sulfate, filtered and concentrated in a vacuum. The crude product is purified by flash chromatography (silica gel, methanol in ethyl acetate 0% to 10%), and further merged with piperidine-4-alcohol (1.3 equivalents) and sodium triacetoxyborohydride (70mg, 0.332mmol, 1.6 equivalents). The reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is poured into saturated NaHCO3 solution, and extracted three times with a mixture of dichloromethane / methanol 9:1. The combined organic layer is dried over sodium sulfate, filtered and concentrated in a vacuum. The crude product was purified by flash chromatography (silica gel, methanol in ethyl acetate 0% to 10%) to give the title compound (16% yield, off-white solid).

[0159] 1 H NMR (300MHz, chloroform-d) δ = 8.26 (s, 1H), 7.71 (s, 1H), 7.58 (s, 1H), 7.54-7.46 (m, 3 H),7.34-7.29(m,2H),7.00(d,J=3.6Hz,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 [MH] - .

[0160] Example 5

[0161] 2-[4-(Difluoromethyl)-6-[2-[4-[[4-(Hydroxymethyl)-1-piperidinyl]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

[0162]

[0163] Step 1: (2R)-2-[2-[6-bromo-4-(difluoromethyl)-7-methylindazol-2-yl]-3-ethoxy-3-oxopropane [acyl]pyrrolidine-1-carboxylic acid tert-butyl ester

[0164]

[0165] Ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]acetate (0.65 g, 1.87 mmol, eq: 1.0) was dissolved in THF (7.58 mL) and cooled to -75°C. LDA (2M in THF, 1.12 mL, 2.25 mmol, eq: 1.20) was added dropwise over 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-fluoro-pyrrolidine-2-carboxylic acid) (0.77 g, 2.9 mmol, eq: 1.55) in THF (7.58 mL) was added slowly at -75°C, stirred at -75°C for 30 minutes, then allowed to warm to room temperature and stirred at room temperature for 18 hours. After adding a saturated aqueous solution of NH4Cl, the reaction mixture was extracted twice with EtOAc. The organic layer was washed with water. The combined organic layers were dried over Na2SO4 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.

[0166] Step 2: 2-[6-Bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-(3-thioxo-2,5,6,7-tetrahydropyridine Slightly ethyl 2-(1,2-c]imidazol-1-yl)acetate

[0167]

[0168] Analogously to Example 7, step 5, (2R)-tert-butyl 2-[2-[6-bromo-4-(difluoromethyl)-7-methylindazol-2-yl]-3-ethoxy-3-oxopropanoyl]pyrrolidine-1-carboxylate (1.4 g, 72% purity, 1.85 mmol) was treated with HCl 4M 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.

[0169] Step 3: 2-[6-Bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1, 2- c]imidazol-1-yl)acetic acid ethyl ester

[0170]

[0171] Analogously to Example 7, step 6, ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-(3-thioxo-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl)acetate (1.06 g, 85% purity, 1.86 mmol) was treated with hydrogen peroxide and p-toluenesulfonic acid monohydrate to give the title compound as a yellow foam (360 mg, 43% yield). m / z 453.0, 454.9 [M+H] + ,ESI pos,Br isotope.

[0172] Step 4: 2-[6-Bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1, 2- c] imidazol-1-yl)-N-thiazol-2-yl-acetamide

[0173]

[0174] The title compound was obtained as a light yellow foam, MS: m / e=509.1 / 511.1 (M+H + ), using a chemistry analogous to that described in Example 7, Step 7, starting from ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (Example 5, Step 3) and thiazol-2-amine.

[0175] Step 5: 2-[4-(Difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidinyl]methyl]phenyl]acetylene yl]-7-methyl-indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl- Acetamide

[0176]

[0177] The title compound was obtained as a brown solid, MS: m / e=656.5 (M+H +), using a chemistry analogous to that described in Example 7, Step 10, starting from 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide (Example 5, Step 4) and [1-[(4-ethynylphenyl)methyl]-4-piperidinyl]methanol hydrochloride (Example 7, Step 9).

[0178] Example 6

[0179] 2-[4-(Difluoromethyl)-6-[2-[4-[[4-(Hydroxymethyl)-1-piperidinyl]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

[0180]

[0181] Step 1: (5S)-5-[2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-3-ethoxy-3-one- [Propionyl]-4-azaspiro[2,4]heptane-4-carboxylic acid tert-butyl ester

[0182]

[0183] Analogously to Example 1, Step 4, (5S)-4-tert-butoxycarbonyl-4-azaspiro[2.4]heptane-5-carboxylic acid was treated with carbonyldiimidazole to give Solution A. Ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]acetate was deprotonated with LDA and treated with Solution A at -78°C. After stirring overnight at room temperature and working up analogously to Example 7, Step 4, the crude title compound was obtained as a light yellow foam which was used in the next step without further purification. MS: m / e=572.3 ([M+H] + )

[0184] Step 2: 2-[6-Bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2- c]imidazole-5,1'-cyclopropane-1-yl-acetic acid ethyl ester

[0185]

[0186] Analogously to Example 1, step 5, (5S)-5-[2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-3-ethoxy-3-keto-propionyl]-4-azaspiro[2.4]heptane-4-carboxylic acid tert-butyl ester was deprotected using HCl in dioxane and then reacted with potassium thiocyanate to give the crude intermediate, which was used in the next step without further purification.

[0187] Analogously to Example 7, step 6, the intermediate was treated with hydrogen peroxide in AcOH to give the title compound as a light yellow foam. MS: m / e = 481.2 ([M+H] + )

[0188] Step 3: 2-[6-Bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2- c]imidazole-5,1'-cyclopropane]-1-yl-N-thiazol-2-yl-acetamide

[0189]

[0190] The title compound was obtained as a light yellow foam, MS: m / e=535.0 (M+H + ), using a chemistry analogous to that described in Example 7, Step 7, starting from ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazol-5,1'-cyclopropane]-1-yl-acetic acid (Example 6, Step 2) and thiazol-2-amine.

[0191] Step 4: 2-[4-(difluoromethyl)-6-[2-(4-formylphenyl)ethynyl]-7-methyl-indazol-2-yl]-2-spiro [6,7-Dihydropyrrolo[1,2-c]imidazol-5,1'-cyclopropane]-1-yl-N-thiazol-2-yl-acetamide

[0192]

[0193] The title compound was obtained as a dark brown amorphous solid, MS: m / e=583.3 (M+H + ), using chemistry analogous to that described in Example 7, Step 10, starting from 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazol-5,1'-cyclopropane]-1-yl-N-thiazol-2-yl-acetamide (Example 6, Step 3) and 4-ethynylbenzaldehyde.

[0194] Step 5: 2-[4-(Difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidinyl]methyl]phenyl]acetylene [7-methyl-indazol-2-yl]-2-(5-ethyl-5-methyl-6,7-dihydropyrrolo[1,2-c]imidazol-1-yl)-N-thiazole Oxazol-2-yl-acetamide

[0195]

[0196] The title compound was obtained as a light yellow solid, MS: m / e=682.5 (M+H + ), using chemistry analogous to that described in Example 7, Step 8, starting from 2-[4-(difluoromethyl)-6-[2-(4-formylphenyl)ethynyl]-7-methyl-indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazol-5,1'-cyclopropane]-1-yl-N-thiazol-2-yl-acetamide (Example 6, Step 4) and piperidin-4-ylmethanol.

[0197] Example 7

[0198] 2-[4-(Difluoromethyl)-6-[2-[4-[[4-(Hydroxymethyl)-1-piperidinyl]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

[0199]

[0200] Step 1: 1-Bromo-5-(difluoromethyl)-3-fluoro-2-methylbenzene

[0201]

[0202] 3-bromo-5-fluoro-4-methylbenzaldehyde (CAS1370411-47-4, 20.5g, 89.7mmol, equivalent: 1.0) solution in DCM (98mL) is cooled with an ice bath. Morpholino sulfur trifluoride (CAS 51010-74-3, 24.8g, 17.3mL, 135mmol, equivalent: 1.5) is added in batches. The reaction mixture is stirred at 0°C to 5°C for 20 minutes, and then stirred at room temperature for 16 hours. With ice cooling, saturated NaHCO3 aqueous solution (300mL) is carefully added. The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is poured into DCM and washed with water. The organic layer is dried over Na2SO4 and concentrated in vacuo. The crude material is purified by flash chromatography (silica gel, 120g, 100% pentane) to obtain the title compound, which is a colorless oil (18.6g, yield 87%). 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)

[0203] Step 2: 6-Bromo-4-(difluoromethyl)-7-methyl-1H-indazole

[0204]

[0205] A solution of 1-bromo-5-(difluoromethyl)-3-fluoro-2-methylbenzene (Example 1, Step 1) (26.4 g, 110 mmol, eq: 1.0) in THF (240 mL) was cooled to -75°C. LDA (2M in THF / heptane / ethylbenzene, 66.3 mL, 133 mmol, eq: 1.2) was added dropwise below -70°C. The reaction mixture was stirred at -75°C for 30 minutes. Ethyl formate (16.4 g, 17.7 mL, 220 mmol, eq: 2.0) was added below -70°C. The reaction mixture was stirred at -75°C for 30 minutes. AcOH (16.6 g, 15.8 mL, 277 mmol, eq: 2.5) was added below -55°C. The reaction mixture was allowed to warm to room temperature and poured into EtOAc and washed with dilute aqueous HCl, water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to give the assumed 4-bromo-6-(difluoromethyl)-2-fluoro-3-methylbenzaldehyde as a yellow oil (29.5 g) which was used without further purification.

[0206] The assumed crude 4-bromo-6-(difluoromethyl)-2-fluoro-3-methylbenzaldehyde (29.5 g) was dissolved in DME (150 mL). O-methylhydroxylamine hydrochloride (10.2 g, 122 mmol, eq.: 1.84) and K2CO3 (30.6 g, 221 mmol, eq.: 3.34) were added. The reaction mixture was stirred at 45 °C for 2.5 hours, then filtered through sintered glass and washed with DME (2x). 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, eq.: 25) was added. The reaction mixture was stirred at 110 °C for 3 hours. The reaction mixture was poured into EtOAc / THF 5:1 and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 2 x 120 g, 0% to 30% EtOAc in heptane) to afford the title compound as a white solid (13.5 g, 74% yield). m / z 258.9, 260.8 [M+H] + ,ESI pos,Br isotope.

[0207] Step 3: Ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]acetate

[0208]

[0209] To a solution of 6-bromo-4-(difluoromethyl)-7-methyl-1H-indazole (Example 1, Step 2) (19 g, 72.8 mmol, eq.: 1.0) in DMF (75 mL) was added ethyl 2-bromoacetate (18.2 g, 12.2 mL, 109 mmol, eq.: 1.5). The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was poured into EtOAc and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 2 x 120 g, 0% to 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.

[0210] Step 4: (2S,4R)-2-[2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-3-ethoxy-3-oxo [[(4-(2-(2-((4-(((- ...

[0211]

[0212] Preparation of tert-butyl (2S,4R)-4-fluoro-2-(imidazole-1-carbonyl)pyrrolidine-1-carboxylate:

[0213]

[0214] To a solution of (2S, 4R)-1-tert-butoxycarbonyl-4-fluoro-pyrrolidine-2-carboxylic acid (CAS203866-14-2, 30 g, 129 mmol, eq.: 1.0) in DCM (300 mL), 1,1'-carbonyldiimidazole (25 g, 154 mmol, eq.: 1.2) was added in portions at 0 °C. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with water (3x) and 1M NaHCO (1x) aqueous solution. The organic layer was dried over Na2SO4 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, which was stored at -20 °C before use. 1 H NMR (chloroform-d, 300 MHz) δ 8.27 (s, 1H), 7.56 (br d, 1H, J = 1.4 Hz), 7.15 (br d, 1H, J = 12.1 Hz), 4.9-5.2 (m, 1H), 3.6-4.1 (m, 2H), 2.0-2.9 (m, 2H), 1.2-1.5 (m, 9H).

[0215] Will KO tBu (4.53 g, 40.3 mmol, eq.: 2.0) was dissolved in THF (18 mL). The reaction mixture was cooled to -55 °C. A solution of ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]acetate (Example 1, Step 3) (7 g, 20.2 mmol, eq.: 1.0) in THF (24 mL) was added dropwise below -50 °C. The reaction mixture was stirred between -50 °C and -55 °C for 1 hour. A solution of previously prepared tert-butyl (2S, 4R)-4-fluoro-2-(imidazole-1-carbonyl)pyrrolidine-1-carboxylate (6.85 g, 24.2 mmol, eq.: 1.2) in THF (50 mL) was added dropwise below -50 °C. The reaction mixture was stirred at -50 °C for 15 minutes and then allowed to warm to -30 °C. 10% aqueous citric acid solution (60 mL) was added 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 Na2SO4 and concentrated in vacuo at 30°C to give the title compound as a yellow amorphous semisolid (12.9 g, 20.2 mmol, 88% purity, 100% yield). m / z 562.1, 563.9 [M+H] + ,ESI pos,Br isotope.

[0216] Step 5: 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]acetic acid ethyl ester

[0217]

[0218] To a solution of (2S,4R)-2-[2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-3-ethoxy-3-oxo-propionyl]-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (Example 1, Step 4) (12.9 g, 20.2 mmol, eq: 1.0) in ethanol (24 mL) was added HCl (1.25 M in ethanol, 80.6 mL, 101 mmol, eq: 5.0). The reaction mixture was stirred at 55 °C for 1 hour. The reaction mixture was cooled to room temperature, and then water (6 mL) and potassium thiocyanate (2.55 g, 26.2 mmol, eq: 1.3) were added. The reaction mixture was stirred at room temperature for 30 minutes. The ethanol was removed in vacuo at 30 °C, and pyridine (23.9 g, 24.5 mL, 302 mmol, eq: 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 HCl aqueous solution (until the pH of the aqueous phase was 1), water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to give the title compound as a yellow semisolid (9.65 g, 60% purity, 57% yield). m / z 502.9, 505.9 [M+H] + ,ESI pos,Br isotope.

[0219] Step 6: 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]acetic acid

[0220]

[0221] To a suspension of p-toluenesulfonic acid monohydrate (10.9 g, 57.5 mmol, eq.: 5.0) in acetonitrile (70 mL), hydrogen peroxide (35% aq., 8.38 g, 7.42 mL, 86.3 mmol, eq.: 7.5) was added dropwise at 0°C to 3°C to obtain a colorless solution. After 10 minutes, ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-3-thioxo-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl]acetate (Example 1, Step 5) (9.65 g, 11.5 mmol, eq.: 1.0) was added dropwise in acetonitrile (28 mL) 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 Na2CO3 solution and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 120 g, 0% to 60% (EtOAc / EtOH / aq.NH3 75:25:2) in heptane) to give the title compound as a yellow foam (3.96 g, 73% yield). m / z 469.1 471.1 [M+H]+ ,ESI pos.

[0222] 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

[0223]

[0224] 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]acetic acid ethyl ester (Example 1, Step 6) (200 mg, 0.424 mmol) was dissolved in 2 ml of methanol and 2 ml of THF. LiOH (1M in water) (0.4 ml, 0.424 mmol, eq: 1.0) was added at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness under vacuum and the residue was dissolved in 2 ml of DMF. Thiazole-2-amine (42 mg, 0.424 mmol, eq: 1.0) and Hunig's base (0.37 ml, 2.12 mmol, eq: 5.0) and HATU (194 mg, 0.509 mmol, eq: 1.2) were added at room temperature. The mixture was stirred for 90 minutes at room temperature. The reaction mixture was extracted with water and extracted twice with ethyl acetate. The organic layer was extracted with water, dried over sodium sulfate, and concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column, eluting with a gradient of dichloromethane: methanol 100:0 to 90:10 to obtain the desired product (115 mg, yield 49%), which was a light yellow solid, MS: m / e=527.1 (M+H + ). Step 8: [1-[(4-ethynylphenyl)methyl]-4-piperidinyl]methanol

[0225]

[0226] 4-Ethynylbenzaldehyde (20.5 g, 157.5 mmol) was dissolved in 525 ml of dichloromethane. Piperidin-4-ylmethanol (20 g, 173.2 mmol, eq.: 1.1) and sodium triacetoxyborohydride (53.4 g, 252.0 mmol, eq.: 1.6) were added at room temperature. The mixture was stirred at room temperature for 4 hours. The reaction mixture was extracted with 1 M sodium carbonate solution and extracted twice with dichloromethane. The organic layer was dried over sodium sulfate and concentrated to dryness to obtain the desired product (34.8 g, yield 91%), which was a light yellow solid, MS: m / e=527.1 (M+H + ).

[0227] Step 9: [1-[(4-ethynylphenyl)methyl]-4-piperidinyl]methanol hydrochloride

[0228]

[0229] [1-[(4-ethynylphenyl)methyl]-4-piperidinyl]methanol (Example 1, Step 8) (34.8 g) was dissolved in 200 ml of tetrahydrofuran. A 4M solution of hydrogen chloride in 1,4-dioxane (39.4 ml, 158 mmol, equivalent: 1.0) was added dropwise at 10°C to 20°C. A white precipitate was formed and stirred for 2 hours. The precipitate was collected by filtration, washed with three 50 ml portions 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 + ).

[0230] Step 10: 2-[4-(Difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidinyl]methyl]phenyl]acetylene yl]-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

[0231]

[0232] 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 (Example 1, Step 7) (100 mg, 0.19 mmol) and [1-[(4-ethynylphenyl)methyl]-4-piperidinyl]methanol hydrochloride (Example 1, Step 9) (76 mg, 0.286 mmol, Eq: 1.5) were dissolved in 5 ml of DMF. Triethylamine (0.1 ml, 0.76 mmol, eq: 4.0), dichlorobis(triphenylphosphine)palladium(II) (7 mg, 0.01 mmol, eq: 0.05), triphenylphosphine (5 mg, 0.019 mmol, eq: 0.1) and copper(I) iodide (2 mg, 0.01 mmol, eq: 0.05) were added and the mixture was stirred at 80 °C for 2 hours. The reaction mixture was extracted with water and 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 100:0 to 75:25 to obtain the desired product (7 mg, 5% yield) as a light yellow oil, MS: m / e=674.5 (M+H + ).

[0233] Example 8 In vitro characterization

[0234] Cell lines

[0235] 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). Cells were maintained in a humidified incubator at 37°C and 5% CO2. Ba / F3 EGFR-LR, Ba / F3 EGFR-LRTM, Ba / F3 EGFR-LRCS and Ba / F3 EGFR-LRTMCS cells were grown in RPMI1640GlutaMAX medium (Thermo Fisher Scientific #61870010) supplemented with 10% fetal bovine serum (FBS; VWR#07068-085). NCI-H1975, NCI-H3255, NCI-H2073, A431 and PC-9 cells were cultured in RPMI 1640 medium with ATCC modifications (Thermo Fisher Scientific #A10491) supplemented with 10% FBS. Cell line identity and the absence of cross-contamination from other cell lines were verified by short tandem repeat-PCR analysis (human cell lines only) and MALDI-TOF analysis. The MycoAlert TM The Mycoplasma Detection Kit (Lonza #LT07-318) tested cells grown without antibiotics for 10 to 14 days to verify the absence of mycoplasma contamination. For all described experiments, all cell lines were used with no more than 20 passages after thawing.

[0236] Homogeneous Time-Resolved Fluorescence (HTRF) Cell Assay

[0237] For homogeneous time-resolved fluorescence (HTRF) assays, cells were transferred to RPMI 1640 phenol red-free medium (Thermo Fisher Scientific #11835063) containing 10% FBS and plated in 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) in a volume of 12 μl / well. 5'000 cells / well (H2073) and 10'000 cells / well (A-431) were plated in a volume of 11 μl / well. Control wells with medium only were also prepared. The plates were centrifuged at 300 g for 30 seconds and incubated overnight at 37°C. The next day, the compound was added to a concentration ranging from 0.316nM to 10mM with a 1 / 4log dilution, and DMSO (Sigma#D2650) was compensated to a final content of 0.1%. The plate was incubated for 4 hours at 37°C. Particularly for H2073 and A-431 cells, 1 μl of 300ng / ml EGF (final concentration 25ng / ml) was added to each well after 4 hours of incubation, and the cells were incubated for another 5 minutes at 37°C. The cells were finally lysed in the HTRF lysis buffer provided by the test kit (see below), and stored at -80°C until further use. The HTRF assay of pEGFR (CisBio#64EG1PEH) or pERK (CisBio#64AERPEH) was then performed according to the manufacturer's instructions.

[0238] Cell viability assay

[0239] For cell viability assay, Ba / F3 cells in growth medium containing 10% FBS were plated at 2'000 cells / well in 50 μl in 384-well black clear bottom plates (Falcon #353962), and compounds were added to concentrations ranging from 0.316 nM to 10 mM at 1 / 4 log dilutions, and DMSO (Sigma #D2650) was compensated accordingly to a final content of 0.1%. Plates were incubated at 37°C for 72 hours. After treatment with compounds, 25 μl / well CellTiter-Glo 2.0 reagent (Promega #G9243) was added, and the plates were incubated at room temperature for 10 minutes, and luminescence was quantified according to the manufacturer's protocol.

[0240] In vitro metabolic stability

[0241] In vitro metabolic stability was assessed in human and rat short-term hepatocyte suspensions. Primary pooled frozen 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 compound. The final assay conditions were 1 μM compound (final assay solvent concentration 0.01% DMSO), 1x 106 hepatocytes / mL incubation. The mixture was then incubated at 37°C (5% CO2) for up to 2 hours. The reaction was stopped by placing the sample on dry ice and then stored at -80°C until analysis by LC-MS / MS. The natural logarithm of the initial drug concentration percentage in the incubated 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. In vitro hepatocyte intrinsic clearance (CL int ) was calculated from the slope of the linear regression (-slope), where V represents the incubation volume (in μL) and N represents the number of hepatocytes per incubation, as detailed in Equation X:

[0242]

[0243] The results of various in vitro assays are shown in Tables 1 and 2

[0244] Table 1. In vitro data of Examples 1 to 6 and reference compounds JBJ-04-125-02 and EAI045

[0245]

[0246] a In the stably expressed EGFR L858R / C797S and EGFR L858R / T790M / C797S IC of pEGFR inhibition determined by HTRF assay in Ba / F3 cell line 50 . b In the presence of stably expressed EGFR L858R / C797S and EGFR L858R / T790M / C797S IC determined by cell titer glo assay in Ba / F3 cell line 90 and IC 50 . c Intrinsic clearance in liver hepatocytes.

[0247] Reference compounds EAI045 (left) and JBJ-04-125-02 (right):

[0248]

[0249] Table 2. Expression of WT EGFR, EGFR L858R EGFR L858R / T790M In human cancer cells, the IC of EGFR inhibitors 50 (nM) value.

[0250]

[0251] Orthosteric EGFR inhibitors osimertinib (left) and erlotinib (right):

[0252]

[0253] Example 9 - In vivo efficacy study

[0254] The research was conducted at Charles River Discovery Research Service GmbH, Germany.

[0255] Mice were housed under pathogen-free conditions with a daily 12-hour light / 12-hour dark cycle. Experiments were performed according to animal welfare guidelines (European Federation for Laboratory Animal Science), and the study protocol was reviewed and approved by local authorities.

[0256] The cells were injected (1x10 7 ) into the right flank of female Balb / c nude mice to establish a subcutaneous cell line-derived model with Ba / F3 cell clones. When the tumor size reached 100-200 mm 3 Compound treatment was initiated after randomization. For the subcutaneous cell line-derived xenograft model of human NSCLC NCI-H1975, 5x10 6 Cells were injected into the right flank of female Balb / c mice when tumors reached approximately 150 mm 3 After that, the mice were randomly assigned to treatment groups. The inoculation procedure was performed with the support of a stereotaxic apparatus, and anesthesia for surgery was performed using isoflurane / O2 using an inhalation mask.

[0257] Allosteric EGFR inhibitor Example 6 was formulated with 10% PEG400 and 5% solutol in water, and osimertinib was formulated with 1% DMSO and 30% PEG300 in water. After random assignment of mice, daily oral treatment was started. Individual tumor volumes were monitored by conventional caliper measurements and calculated according to the formula (TV = (length x width 2)). The tumor volumes of each study group are shown as mean values ​​with SEM during the study observation period, in mm 3All raw data were exported from the local database into tab-limited csv files and processed using the statistical software R and visualized using Shiny (scripts written by Dr. S. Wilson, PS BIOMICS, RICB).

[0258] Since the data show asymmetric behavior, nonparametric methods are used in the study D38 (the last day of the control) to perform statistical analysis on the data of primary tumor growth. In short, in a randomized double sample design, treatment and control ratio (TCR) and its bilateral parameters (Fieller, 1954) or nonparametric (Hothorn and Munzel, 2000) confidence interval (CI) (1-a) are calculated. TCR lower than 1.0 indicates tumor growth inhibition, wherein CI reflects data distribution. The upper limit of CI lower than 1.0 is confirmed to be statistically significant. Tumor growth inhibition is calculated according to the following formula: 100-[mean (TV 治疗 -TV 基线 ) / average(TV 媒介物 -TV 基线 )], which is based on the median. Tumor regression was calculated according to the following formula: Mean [(TV 基线 -TV 治疗 ) / TV 基线 ) x 100, which is based on the median. Positive values ​​indicate tumor regression.

[0259] Specific numbered embodiments

[0260] 1. A combination product of an allosteric EGFR inhibitor and an orthosteric EGFR inhibitor, wherein the allosteric EGFR inhibitor is a compound of formula (I)

[0261]

[0262] in

[0263] L is a bond or an alkynylene group;

[0264] R 1 is hydrogen or halogen;

[0265] R 2 and R 2 ' is independently selected from hydrogen and alkyl;

[0266] or R 2 and R 2 'Together with the carbon atom to which they are attached they form a cycloalkyl group;

[0267] R 3 is hydrogen, halogen or haloalkyl;

[0268] R 4is alkyl or halogen;

[0269] R 5 is (heterocycloalkyl)alkyl or heterocycloalkyl, wherein (heterocycloalkyl)alkyl is optionally substituted with one or two substituents independently selected from R6, and wherein heterocycloalkyl is optionally substituted with one or two substituents independently selected from R7;

[0270] R 6 is independently selected at each occurrence from alkyl, cycloalkyl, hydroxy and hydroxyalkyl; and

[0271] R 7 is independently selected at each occurrence from alkyl, cycloalkyl, hydroxy and hydroxyalkyl;

[0272] or a pharmaceutically acceptable salt thereof.

[0273] 2. The combination product according to embodiment 1, wherein the allosteric EGFR inhibitor is a compound of formula (I)

[0274]

[0275] in

[0276] L is a bond or an alkynylene group;

[0277] R 1 is hydrogen or halogen;

[0278] R 2 and R 2 ' is independently selected from hydrogen and alkyl;

[0279] or R 2 and R 2 'Together with the carbon atom to which they are attached they form a cycloalkyl group;

[0280] R 3 is hydrogen, halogen or haloalkyl;

[0281] R 4 is alkyl or halogen;

[0282] R 5 is (heterocycloalkyl)alkyl or heterocycloalkyl, wherein (heterocycloalkyl)alkyl is optionally substituted by one or two independently selected from R 6 wherein the heterocycloalkyl group is optionally substituted by one or two independently selected from R 7 Substituents are substituted;

[0283] R 6 is independently selected at each occurrence from alkyl, cycloalkyl, hydroxy and hydroxyalkyl; and

[0284] R 7is independently selected at each occurrence from alkyl, cycloalkyl, hydroxy and hydroxyalkyl.

[0285] 3. The combination product according to embodiment 1 or 2, wherein L is a bond or ethynylene.

[0286] 4. The combination product according to any one of embodiments 1 to 3, wherein R 1 is hydrogen or fluorine.

[0287] 5. The combination product according to any one of embodiments 1 to 4, wherein R 2 and R 2 ' is hydrogen, or together with the carbon atom to which they are attached, forms a cyclopropyl group.

[0288] 6. The combination product according to any one of embodiments 1 to 5, wherein R 3 is halogen or halogenated alkyl.

[0289] 7. The combination product according to any one of embodiments 1 to 6, wherein R 3 is chloro or difluoromethyl.

[0290] 8. The combination product according to any one of embodiments 1 to 7, wherein R 4 Methyl or chlorine.

[0291] 9. The combination product according to any one of embodiments 1 to 8, wherein R 5 is morpholinyl or piperidinylmethylene, which is optionally substituted with hydroxymethyl.

[0292] 10. A combination product according to any one of embodiments 1 to 9, wherein the compound of formula (I) is selected from

[0293] 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;

[0294] 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;

[0295] 2-[4-(Difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazol-5,1′-cyclopropane]-1-yl-N-thiazol-2-yl-acetamide;

[0296] 2-[4-(Difluoromethyl)-6-[2-[4-[[4-(Hydroxymethyl)-1-piperidinyl]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

[0297] 2-[4-(Difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidinyl]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.

[0298] 11. A combination product according to any one of embodiments 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.

[0299] 12. A combination product according to any one of embodiments 1 to 9, wherein the compound of formula (I) is 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.

[0300] 13. A combination product according to any one of embodiments 1 to 9, wherein the compound of formula (I) is 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazol-5,1'-cyclopropane]-1-yl-N-thiazol-2-yl-acetamide.

[0301] 14. A combination product 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-piperidinyl]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.

[0302] 15. A combination product 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-piperidinyl]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.

[0303] 16. The combination product according to any one of embodiments 1 to 15, wherein the orthosteric EGFR inhibitor is selected from cetuximab, panitumumab, osimertinib, erlotinib, gefitinib, naximol, neratinib, lapatinib, vandetanib, brigatinib, ametinib, lazertinib and vometinib, or a pharmaceutically acceptable salt thereof, in particular selected from osimertinib, ametinib, lazertinib and vometinib, or a pharmaceutically acceptable salt thereof.

[0304] 17. The combination product according to any one of embodiments 1 to 16, wherein the orthosteric EGFR inhibitor is osimertinib or a pharmaceutically acceptable salt thereof.

[0305] 18. The combination product according to any one of embodiments 1 to 16, wherein the orthosteric EGFR inhibitor is ametinib or a pharmaceutically acceptable salt thereof.

[0306] 19. The combination product according to any one of embodiments 1 to 16, wherein the orthosteric EGFR inhibitor is lazertinib or a pharmaceutically acceptable salt thereof.

[0307] 20. The combination product according to any one of embodiments 1 to 16, wherein the orthosteric EGFR inhibitor is vometinib or a pharmaceutically acceptable salt thereof.

[0308] 21. The combination product according to any one of embodiments 1 to 16 for use as therapeutically active substance.

[0309] 22. A pharmaceutical composition comprising a combination product according to any one of embodiments 1 to 20 and a therapeutically inert carrier.

[0310] 23. A 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.

[0311] 24. Use of a combination product according to any one of embodiments 1 to 20 for the treatment or prevention of cancer, particularly non-small cell lung cancer.

[0312] 25. Use of a combination product according to any one of embodiments 1 to 20 for the preparation of a medicament for the treatment or prevention of cancer, particularly non-small cell lung cancer.

[0313] 26. Use of a combination product according to any one of embodiments 1 to 20 for the preparation of a medicament for the treatment or prevention of non-small cell lung cancer.

[0314] 27. A method for treating or preventing cancer, in particular non-small cell lung cancer, comprising administering to a patient in need thereof an effective amount of a combination product according to any one of embodiments 1 to 20.

[0315] 28. The combination product, 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.

[0316] 29. The combination product, 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.

[0317] 30. The combination product, 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.

[0318] 31. The combination product, 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.

[0319] 32. The combination product, 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.

[0320] 33. The combination product, 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 product of an allosteric EGFR inhibitor and an orthosteric EGFR inhibitor, wherein the allosteric EGFR inhibitor is a compound of formula (I), in L is a bond or an alkynylene group; R 1 is hydrogen or halogen; R 2 and 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 they form a cycloalkyl group; R 3 is hydrogen, halogen or haloalkyl; R 4 is alkyl or halogen; R 5 is (heterocycloalkyl)alkyl or heterocycloalkyl, wherein (heterocycloalkyl)alkyl is optionally substituted by one or two independently selected from R 6 wherein the heterocycloalkyl group is optionally substituted by one or two independently selected from R 7 Substituents are substituted; R 6 is independently selected at each occurrence from alkyl, cycloalkyl, hydroxy and hydroxyalkyl; and R 7 is independently selected at each occurrence from alkyl, cycloalkyl, hydroxy and hydroxyalkyl; or a pharmaceutically acceptable salt thereof.

2. The combination product according to claim 1, wherein the allosteric EGFR inhibitor is a compound of formula (I), in L is a bond or an alkynylene group; R 1 is hydrogen or halogen; R 2 and 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 they form a cycloalkyl group; R 3 is hydrogen, halogen or haloalkyl; R 4 is alkyl or halogen; R 5 is (heterocycloalkyl)alkyl or heterocycloalkyl, wherein (heterocycloalkyl)alkyl is optionally substituted by one or two independently selected from R6 wherein the heterocycloalkyl group is optionally substituted by one or two independently selected from R 7 Substituents are substituted; R 6 is independently selected at each occurrence from alkyl, cycloalkyl, hydroxy and hydroxyalkyl; and R 7 is independently selected at each occurrence from alkyl, cycloalkyl, hydroxy and hydroxyalkyl.

3. A combination product according to claim 1 or 2, wherein L is a bond or an ethynylene group.

4. A combination product according to any one of claims 1 to 3, wherein R 1 is hydrogen or fluorine.

5. A combination product according to any one of claims 1 to 4, wherein R 2 and R 2 ' is hydrogen, or together with the carbon atom to which they are attached, forms a cyclopropyl group.

6. A combination product according to any one of claims 1 to 5, wherein R 3 is halogen or halogenated alkyl.

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

8. A combination product according to any one of claims 1 to 7, wherein R 4 Methyl or chlorine.

9. A combination product according to any one of claims 1 to 8, wherein R 5 is morpholinyl or piperidinylmethylene, which is optionally substituted with hydroxymethyl.

10. A combination product according to any one of claims 1 to 9, wherein the compound of formula (I) is selected from 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]imidazol-5,1′-cyclopropane]-1-yl-N-thiazol-2-yl-acetamide; 2-[4-(Difluoromethyl)-6-[2-[4-[[4-(Hydroxymethyl)-1-piperidinyl]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-piperidinyl]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.

11. A combination product 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. A combination product 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-piperidinyl]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 product according to any one of claims 1 to 12, wherein the orthosteric EGFR inhibitor is selected from cetuximab, panitumumab, osimertinib, erlotinib, gefitinib, nacitinib, neratinib, lapatinib, vandetanib, brigatinib, ametinib, lazertinib and vometinib, or a pharmaceutically acceptable salt thereof, in particular selected from osimertinib, ametinib, lazertinib and vometinib, or a pharmaceutically acceptable salt thereof.

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

15. A combination product according to any one of claims 1 to 14 for use as therapeutically active substance.

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

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

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

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

20. Use of a combination product 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 treating or preventing cancer, in particular non-small cell lung cancer, comprising administering to a patient in need thereof an effective amount of a combination product according to any one of claims 1 to 14.

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

23. The combination product, 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 product, 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 product, 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 product, 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 product, 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 herein described.

Images