Macrocycles useful as KRAS inhibitors

Abstract

The present invention relates to a compound of formula (I) TIFF2025525315000057.tif64170[where, R 1 From R 6 , A 1 and A 2 is as described herein], and pharmaceutically acceptable salts thereof, compositions comprising same, and methods of using same as KRAS inhibitors.

Description

[Technical Field]

[0001] The present invention relates to organic compounds useful for the treatment and / or prophylaxis in mammals, particularly for the inhibition of mutant KRAS, which is useful for treating cancer. [Background technology]

[0002] RAS is one of the most well-known proto-oncogenes. Approximately 30% of human cancers contain mutations in its three most notable members, KRAS, HRAS, and NRAS, making them the most common oncogene drivers. KRAS mutations are commonly associated with poor prognosis, particularly in colorectal, pancreatic, and lung cancers. As the most frequently mutated RAS isoform, KRAS has been intensively studied in the past few years. Among the most commonly occurring KRAS alleles (including G12D, G12V, G12C, G13D, G12R, G12A, G12S, and Q61H), G12C, G12D, and G12V account for more than half of all K-RAS-driven cancers across colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), and lung adenocarcinoma (LUAD). Notably, KRAS wild-type amplification is also found in approximately 7% of all KRAS-altered cancers (ovarian, esophagogastric, and uterine), making it among the top alterations.

[0003] All RAS proteins belong to the small GTPase family, which hybridizes GTP to GDP. Structurally, KRAS is divided into an effector-binding lobe followed by an allosteric lobe and a carboxy-terminal region responsible for membrane anchoring. The effector lobe contains the P-loop, switch I, and switch II regions. The switch I / II loop plays an important role in KRAS downstream signaling by mediating protein-protein interactions with effector proteins, including RAFs in the mitogen-activated protein kinase (MAPK) pathway or phosphatidylinositol 3-kinase (PI3K) / protein kinase B (AKT) pathway.

[0004] The KRAS protein switches from an inactive to an active form via binding to GTP and GDP, respectively. Under physiological conditions, the transition between these two states is regulated by guanine nucleotide exchange factors (GEFs), such as Son Of Sevenless homolog 1 (SOS1), or GTPase-activating proteins (GAPs), which catalyze the exchange of GDP for GTP, enhance intrinsic GTPase activity, or promote RAS-mediated GTP hydrolysis. In response to extracellular stimuli, the inactive RAS-GDP binds to the RAF RAS-binding domain (RAF RBD ), which converts RAFs into activated RAS-GTP, which directly binds to KRAS and recruits the RAF kinase family from the cytoplasm to the membrane, where they dimerize and become active. Activated RAFs then carry out a series of phosphorylation reactions on their downstream mitogen-activated protein kinases (MEKs) and extracellular signal-regulated kinases (ERKs), propagating growth signals. Of the RAF family of protein kinases (three known isoforms, ARAF, BRAF, and CRAF / RAF1), BRAF is the most frequently mutated and remains the most potent activator of MEK. Although individual RAS and RAF family members have revealed distinct binding preferences, all RAFs retain a conserved RBD for forward propagation of MAPK signaling, which is frequently used to characterize KRAS inhibition (e.g., the KRAS-BRAF complex described herein). RBD With respect to KRAS, mutations at positions 12, 13, 61, and 146 result in a shift to the active KRAS form through impaired nucleotide hydrolysis or activation of nucleotide exchange, resulting in overactivation of the MAPK pathway, which leads to tumorigenesis.

[0005] Despite its well-recognized importance in cancer malignancy, ongoing efforts in the past failed to develop approved therapies for KRAS mutant cancers until recently, and the first-line drug AMG510 was rapidly approved as a second-line treatment in KRAS G12C-driven non-small cell lung cancer (NSCLC). Nevertheless, clinically acquired resistance to KRAS G12C inhibitors rapidly emerges with disease progression after approximately 6 months of treatment. Secondary RAS mutations within the switch II pocket (e.g., H95, R68, and Y96) have been observed, all of which converge to reactivate RAS-MAPK signaling at oncogene hotspots (e.g., G12 / G13 / Q61). Furthermore, over 85% of all KRAS mutant or wild-type amplification-driven cancers still lack novel drugs. Taken together, both the myriad escape mechanisms and various oncogene alleles highlight the urgent medical need for additional KRAS therapeutics. Thus, the inventors have invented oral compounds that target and inhibit KRAS alleles for the treatment of KRAS mutant-driven cancers. Summary of the Invention

[0006] The present invention relates to a compound of formula (I) TIFF2025525315000002.tif64170[In the formula, R 1 is 3-oxabicyclo[3.1.0]hexanyl, C 1-6 Alkyl C 3-7 Cycloalkyl, cyano C 3-7 Cycloalkyl or haloC 1-6 Alkyl C 3-7 is cycloalkyl; R 2 is H or halogen; R 3 is H or halogen; R 4 is C 1-6 Alkyl or haloC 1-6 is alkyl; R 5 is C 1-6 Alkoxy C 1-6 is alkyl; R 6 is morpholinyl, (haloC 1-6 alkyl)piperazinyl or C 1-6 alkylpiperazinyl; A 1 is thiazolylene; A 2 is C 1-6 is alkylene; However, R 2 and R 3 and H cannot be simultaneously] or a pharmaceutically acceptable salt thereof.

[0007] The present invention also relates to their preparation, to medicaments based on the compounds according to the invention, and to their production, as well as to the use of compounds of formula (I) or (Ia) thereof as inhibitors of KRAS.

[0008] The compounds of formula (I) or (Ia) show good KRAS inhibition for G12C and G12V. In another embodiment, the compounds of the present invention show good cancer cell inhibition and stability in human hepatocytes. In addition, the compounds of formula (I) or (Ia) also show good or improved cytotoxicity and solubility profiles. Furthermore, the compounds of the present invention have good pharmacokinetic properties compared with reference compounds. DETAILED DESCRIPTION OF THE INVENTION

[0009] definition "C 1-6 The term "alkyl" refers to saturated straight or branched chain alkyl groups containing 1 to 6, especially 1 to 4, carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. 1-6 "Alkyl" groups are methyl, ethyl, and n-propyl.

[0010] "C 1-6 The term "alkoxy" refers to C 1~6 It means alkyl-O-.

[0011] "C1-6 The term "alkylene" means a linear or branched saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a divalent branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms. 1-6 Examples of the alkylene group include methylene, ethylene, propylene, 2-methylpropylene, butylene, 2-ethylbutylene, pentylene, and hexylene.

[0012] The terms "halogen" and "halo" are used interchangeably herein and refer to fluoro, chloro, bromo, or iodo.

[0013] "Haro C 1-6 The term "alkyl" refers to a C-6 alkyl group in which at least one of the hydrogen atoms is replaced by the same or different halogen atom, in particular a fluoro atom. 1-6 means an alkyl group. Examples of haloalkyl include monofluoro-, difluoro-, or trifluoro-methyl, -ethyl, or -propyl, such as 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl, or trifluoromethyl.

[0014] "C 3-7 The term "cycloalkyl" means a monovalent saturated monocyclic or bicyclic hydrocarbon radical of 3 to 7 ring carbon atoms. Bicyclic means consisting of two saturated carbocyclic rings having one or more carbon atoms in common. Examples of monocyclic cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Examples of bicyclic cycloalkyl are bicyclo[1.1.0]butyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, or bicyclo[2.2.2]octanyl.

[0015] The term "thiazolylene" means a divalent thiazolyl group.

[0016] The term "oxo" refers to a divalent oxygen atom =O.

[0017] The term "dimethylmethylene" means TIFF2025525315000003.tif13170.

[0018] The term "protecting group" means a group that selectively blocks a reactive site in a multifunctional compound so that a chemical reaction can be carried out selectively at an otherwise unprotected reactive site, in the sense conventionally associated with synthetic chemistry. The protecting group can be removed at an appropriate point. Exemplary protecting groups are amino-protecting groups, carboxy-protecting groups, or hydroxy-protecting groups.

[0019] Those skilled in the art will recognize that the following structures of compounds of formula (I) and (I') are equivalent, particularly with respect to the chiral centers: TIFF2025525315000004.tif61170

[0020] The term "pharmaceutically acceptable salt" means a salt that is not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts.

[0021] The term "pharmaceutically acceptable acid addition salt" means a pharmaceutically acceptable salt formed with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like, and an organic acid selected from aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

[0022] The term "pharmaceutically acceptable base addition salt" refers to a pharmaceutically acceptable salt formed with an organic or inorganic base. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperidine, N-ethylpiperidine, and polyamine resins.

[0023] The term "pharmaceutically active metabolite" refers to a pharmacologically active product produced through metabolism in the body of a particular compound or its salt. After entering the body, most drugs are substrates for chemical reactions that can alter their physical properties and biological effects. These metabolic transformations usually affect the polarity of the compounds of the invention and change how the drug is distributed in and excreted from the body. However, in some cases, drug metabolism is necessary for therapeutic effect.

[0024] The term "therapeutically effective amount" means an amount of a compound or molecule of the invention that, when administered to a subject, (i) treats or prevents a particular disease, condition, or disorder, (ii) reduces, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. A therapeutically effective amount will vary depending on the compound, the condition being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0025] The term "pharmaceutical composition" means a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable excipients, to be administered to a mammal, e.g., a human, in need thereof.

[0026] The terms "pharmaceutically acceptable excipient," "pharmaceutically acceptable carrier," and "therapeutically inactive excipient" can be used interchangeably and refer to any pharmaceutically acceptable ingredient in a pharmaceutical composition used in formulating a pharmaceutical product, such as a disintegrant, binder, filler, solvent, buffer, tonicity agent, stabilizer, antioxidant, surfactant, carrier, diluent, or lubricant, that has no therapeutic activity and is non-toxic to a subject to which it is administered.

[0027] KRAS inhibitors The present invention relates to a compound represented by the formula (I): TIFF2025525315000005.tif64170[In the formula, R 1 is 3-oxabicyclo[3.1.0]hexanyl, C 1-6 Alkyl C 3-7 Cycloalkyl, cyano C 3-7 Cycloalkyl or haloC 1-6 Alkyl C 3-7 is cycloalkyl; R 2 is H or a halogen; R 3 is H or a halogen; R 4 is C 1-6 Alkyl or haloC 1-6 is alkyl; R 5 is C 1-6 Alkoxy C 1-6 is alkyl; R 6 is morpholinyl, (haloC 1-6 alkyl)piperazinyl or C 1-6 alkylpiperazinyl; A 1 is thiazolylene; A2 is C 1-6 is alkylene; However, R 2 and R 3 and H cannot be simultaneously] or a pharmaceutically acceptable salt thereof.

[0028] Another embodiment of the present invention is (ii) a compound of formula (Ia) TIFF2025525315000006.tif72170[In the formula, R 1 is 3-oxabicyclo[3.1.0]hexanyl, C 1-6 Alkyl C 3-7 Cycloalkyl, cyano C 3-7 Cycloalkyl or haloC 1-6 Alkyl C 3-7 is cycloalkyl; R 2 is H or a halogen; R 3 is H or a halogen; R 4 is C 1-6 Alkyl or haloC 1-6 is alkyl; R 5 is C 1-6 Alkoxy C 1-6 is alkyl; R 6 is morpholinyl, (haloC 1-6 alkyl)piperazinyl or C 1-6 alkylpiperazinyl; A 1 is thiazolylene; A 2 is C 1-6 is alkylene; However, R 2 and R 3 and H cannot be simultaneously] or a pharmaceutically acceptable salt thereof.

[0029] A further embodiment of the present invention is (iii) R 1 But C 1-6 Alkyl C3-7 Cycloalkyl or haloC 1-6 Alkyl C 3-7 cycloalkyl; or a pharmaceutically acceptable salt thereof.

[0030] A further embodiment of the present invention is (iv) R 1 is methylcyclopropyl or (difluoromethyl)cyclopropyl; or a pharmaceutically acceptable salt thereof.

[0031] A further embodiment of the present invention is (v) R 2 is H or fluoro.

[0032] A further embodiment of the present invention is (vi) R 3 is H or fluoro; or a pharmaceutically acceptable salt thereof.

[0033] A further embodiment of the present invention is (vii) R 4 is ethyl or 2,2,2-trifluoroethyl; or a pharmaceutically acceptable salt thereof.

[0034] A further embodiment of the present invention is a compound represented by the formula (viii) R 5 is 1-methoxyethyl; or a pharmaceutically acceptable salt thereof.

[0035] A further embodiment of the present invention is (ix) R 6 is morpholinyl or C 1-6 A compound of formula (I) or (Ia) according to any one of (i) to (viii), or a pharmaceutically acceptable salt thereof, which is alkylpiperazinyl.

[0036] A further embodiment of the present invention is (x)R 6 is morpholinyl or 4-methylpiperazin-1-yl; or a pharmaceutically acceptable salt thereof. A further embodiment of the present invention is (xi) A 1 but, TIFF2025525315000007.tif19170, and bond "a" is attached to the indole ring; or a compound of formula (I) or (Ia) according to any one of (i) to (x), or a pharmaceutically acceptable salt thereof.

[0037] A further embodiment of the present invention is (xii) A 2 is dimethylmethylene; or a pharmaceutically acceptable salt thereof.

[0038] Another embodiment of the present invention is a method for producing a compound comprising: (xiii) R 1 But C 1-6 Alkyl C 3-7 Cycloalkyl or haloC 1-6 Alkyl C 3-7 is cycloalkyl; R 2 is H or a halogen; R 3 is H or a halogen; R 4 But C 1-6 Alkyl or haloC 1-6 is alkyl; R 5 But C 1-6 Alkoxy C 1-6 is alkyl; R 6 is morpholinyl or C 1-6 alkylpiperazinyl; A 1 but, TIFF2025525315000008.tif19170, and bond "a" connects to the indole ring; A 2 But C 1-6 is alkylene; However, R 2 and R 3 and H cannot be simultaneously. A compound of formula (I) or (Ia) according to (i) or (ii), or a pharmaceutically acceptable salt thereof.

[0039] Another embodiment of the present invention is a compound represented by the formula (xiv): R 1 is 2-methylcyclopropyl or 2-(difluoromethyl)cyclopropyl; R 2 is H or fluoro; R 3 is H or fluoro; R 4 is ethyl or 2,2,2-trifluoroethyl; R 5 is (1S)-1-methoxyethyl; R 6 is morpholinyl or 4-methylpiperazin-1-yl; A 1 but, TIFF2025525315000009.tif19170, and bond "a" connects to the indole ring; A 2 is dimethylmethylene; However, R 2 and R 3 and H cannot be simultaneously. (xiii) is a compound of formula (I) or (Ia) according to (xiii), or a pharmaceutically acceptable salt thereof.

[0040] Another embodiment of the present invention is (xv) the following: (1S,2S)-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-2-methyl-cyclopropanecarboxamide; (1R,5S)-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-oxabicyclo[3.1.0]hexane-6-carboxamide; (1S,2S)-2-(Difluoromethyl)-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]cyclopropanecarboxamide; (1S,2S)-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-2-methyl-cyclopropanecarboxamide; (1S,2S)-2-cyano-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]cyclopropanecarboxamide; (1R,2R)-2-cyano-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]cyclopropanecarboxamide; (1S,2S)-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-2-methyl-cyclopropanecarboxamide; (1S,2S)-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-2-methyl-cyclopropanecarboxamide; (1S,2S)-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-2-methyl-cyclopropanecarboxamide; (1S,2S)-N-[(7S,13S)-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-2-methyl-cyclopropanecarboxamide; (1S,2S)-2-(Difluoromethyl)-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]cyclopropanecarboxamide; and (1S,2S)-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-2-methyl-cyclopropanecarboxamide; or a pharmaceutically acceptable salt thereof.

[0041] Another embodiment of the present invention relates to a method for the preparation of a compound according to any one of (xvi)(i) to (xv), the method comprising the steps of: a) reacting a compound of formula (II) with a compound of formula (II) in the presence of a coupling reagent and a base to form a compound of formula (I) TIFF2025525315000010.tif63170(II) and acid(III) TIFF2025525315000011.tif15170(III) [wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , A 1 and A 2 is as defined in any one of (i) to (xiv); the coupling reagent is T3P, HATU, PyBOP, or EDCI / HOBt; and the base is TEA, DIEPA, or DMAP. Includes.

[0042] Another embodiment of the present invention is (xvii) a compound or pharmaceutically acceptable salt according to any one of (i) to (xv) for use as a therapeutically active substance.

[0043] Another embodiment of the present invention is (xviii) a pharmaceutical composition comprising a compound according to any one of (i) to (xv) and a pharmaceutically acceptable excipient.

[0044] Another embodiment of the present invention is (xix) the use of a compound according to any one of (i) to (xv) for treating a KRAS G12C protein-associated disease.

[0045] Another embodiment of the present invention is (xx) the use of a compound according to any one of (i) to (xv) for treating KRAS G12C, G12D and G12V protein-associated diseases.

[0046] Another embodiment of the invention is (xxi) the use of a compound according to any one of (i) to (xv) for inhibiting the interaction of RAS with downstream effectors, wherein the downstream effectors are RAF and PI3K.

[0047] Another embodiment of the present invention is (xxii) the use of a compound according to any one of (i) to (xv) for inhibiting the signaling of the proliferating oncogenes MAPK and PI3K.

[0048] Another embodiment of the present invention is (xxiii) the use of a compound according to any one of (i) to (xv) for the treatment or prevention of KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic cancer, colorectal cancer, lung cancer, esophageal cancer, gallbladder cancer, melanoma, ovarian cancer and endometrial cancer.

[0049] Another embodiment of the present invention is (xxiv) the use of a compound according to any one of (i) to (xv) for the treatment or prevention of KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer.

[0050] Another embodiment of the present invention is (xxv) a compound or pharmaceutically acceptable salt according to any one of (i) to (xv) for the treatment or prevention of KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer.

[0051] Another embodiment of the present invention is (xxvi) the use of a compound according to any one of (i) to (xv) for the preparation of a medicament for the treatment or prevention of KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer.

[0052] Another embodiment of the present invention is (xxvii) a method for treating or preventing a KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer, the method comprising administering a therapeutically effective amount of a compound defined in any one of (i) to (xv).

[0053] Another embodiment of the present invention is a compound or pharmaceutically acceptable salt according to any one of (i) to (xv) when prepared by the process of (xxviii)(xvi).

[0054] Pharmaceutical Compositions and Administration Another embodiment provides pharmaceutical compositions or medicaments containing a compound of the present invention and a therapeutically inert carrier, diluent, or excipient, as well as methods of using the compounds of the present invention to prepare such compositions and medicaments. In one example, a compound of Formula (I) can be formulated into a galenic dosage form by mixing it at ambient temperature, at an appropriate pH, and to the desired purity level with a physiologically acceptable carrier, i.e., a carrier that is non-toxic to recipients at the dosage amounts and concentrations employed. The pH of the formulation will depend primarily on the particular application and compound concentration, but preferably ranges anywhere from about 3 to about 8. In one example, a compound of Formula (I) is formulated in acetate buffer at pH 5. In another embodiment, the compound of Formula (I) is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0055] The composition is formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this regard include the specific disorder to be treated, the specific mammal to be treated, the clinical condition of the individual patient, the cause of the disorder, the drug delivery site, the administration method, the administration schedule, and other factors known to medical professionals. The "effective amount" of the compound to be administered is determined by such considerations and is the minimum amount necessary to inhibit the interaction between mutant RAS (e.g., KRAS G12C) and RAF and block the signal transduction of oncogenic MAPK. For example, such an amount may be below the amount that is toxic to normal cells or the mammal as a whole.

[0056] In one embodiment, a pharmaceutically effective amount of a compound of the invention administered parenterally per dose is about 0.1 to 1000 mg / kg of patient body weight per day, alternatively about 0.1 to 1000 mg / kg, with a typical initial range of the compound used being 0.3 to 15 mg / kg / day. In another embodiment, oral unit dosage forms such as tablets and capsules preferably contain about 1 to about 1000 mg of a compound of the invention.

[0057] The compounds of the present invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, and epidural and intranasal administration, and, where localized treatment is desired, intralesional administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0058] The compounds of the present invention may be administered in any convenient dosage form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components common in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and additional active agents.

[0059] Typical formulations are prepared by mixing the compound of the present invention with carriers or additives.Suitable carriers and additives are well known to those skilled in the art and are described in detail in, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, flavors, flavoring agents, diluents, and other known additives to present the drug (i.e., the compound of the present invention or a pharmaceutical composition thereof) aesthetically or to aid in the manufacture of a pharmaceutical product (i.e., a medicament).

[0060] An example of a suitable oral dosage form is a tablet containing about 1 to 1,000 mg of a compound of the present invention, comprising about 1 to 1,000 mg of anhydrous lactose, about 1 to 1,000 mg of croscarmellose sodium, about 1 to 1,000 mg of polyvinylpyrrolidone (PVP) K30, and about 1 to 1,000 mg of magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of PVP. The resulting composition can be dried, granulated, mixed with magnesium stearate, and compressed into tablet form using conventional equipment. An example of an aerosol formulation can be prepared by dissolving, for example, 5 to 400 mg of a compound of the present invention in an appropriate buffer solution, such as phosphate buffer, and adding an isotonicity agent, such as sodium chloride, as needed. The solution may be filtered, for example, using a 0.2 micron filter, to remove impurities and contaminants.

[0061] Thus, one embodiment includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof. A further embodiment includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.

[0062] Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in treating mutant KRAS-driven cancers.Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in treating mutant KRAS-driven cancers.

[0063] The following compositions A and B illustrate typical compositions of the present invention and serve merely as representative examples thereof.

[0064] Composition A The compounds of the invention can be used in a manner known per se as active ingredient for the production of tablets of the following composition: TIFF2025525315000012.tif55170

[0065] Composition B The compounds of the invention can be used in a manner known per se as active ingredient for the production of tablets of the following composition: TIFF2025525315000013.tif55170

[0066] Indications and Treatments The compounds of the present invention induce a novel binding pocket in KRAS by driving the formation of a high-affinity ternary complex between the KRAS protein and the widely expressed cyclophilin A (CYPA), which inhibits the interaction of KRAS with downstream effectors such as RAF and PI3K. Therefore, the compounds of the present invention are useful for inhibiting proliferating oncogenic MAPK and PI3K signaling and reducing cell proliferation, particularly in cancer cells. The compounds of the present invention are useful for blocking RAS signaling in cells expressing RAS mutants, such as KRAS mutation-driven pancreatic cancer, colorectal cancer, lung cancer, esophageal cancer, gallbladder cancer, melanoma, ovarian cancer, and endometrial cancer. Alternatively, the compounds of the present invention are useful for blocking RAS signaling in malignant solid tumors where the oncogenic role of KRAS mutations is enhanced by dysregulation or mutation of effector pathways such as MAPK, PI3K-AKT, and mTOR (mammalian target of rapamycin)-driven signaling, for targeted therapy in pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer.

[0067] Another embodiment includes a method of treating or preventing cancer in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I), a stereoisomer, tautomer, prodrug, or a pharmaceutically acceptable salt thereof.

[0068] synthesis The compounds of the present invention can be prepared by any conventional means. Suitable methods for synthesizing these compounds and their starting materials are provided in the following schemes and examples. Unless otherwise indicated, all substituents, particularly R 1 From R 6 , A1 and A 2 is as defined above. Furthermore, unless expressly specified otherwise, all reactions, reaction conditions, abbreviations and symbols have meanings well known to one skilled in the art of organic chemistry. A general synthetic route for preparing compounds of formula (I) is shown below.

[0069] Scheme 1 TIFF2025525315000014.tif57170 The compound of formula II was synthesized according to the procedure described in Intermediate A to I. The compound of formula (I) could be obtained by the coupling reaction between the acid (III) and the compound of formula (II) using one or more coupling reagents, such as T3P, HATU, PyBOP and EDCI / HOBt, in the presence of a base, such as TEA, DIEPA and DMAP.

[0070] The compounds of the present invention can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art, for example (chiral) HPLC or SFC. In another embodiment, the compounds of formula (I) can be obtained according to the above scheme by using the corresponding chiral starting materials.

[0071] The present invention also relates to a method for producing a method for manufacturing a semiconductor device comprising the steps of: a) reacting a compound of formula (II) with a compound of formula (II) in the presence of a coupling reagent and a base to form a compound of formula (I) TIFF2025525315000015.tif63170(II) and acid(III) Coupling reaction between TIFF2025525315000016.tif15170(III) The present invention relates to a process for the preparation of a compound of formula (I), comprising In step a), the coupling reagent can be, for example, T3P, HATU, PyBOP or EDCI / HOBt; the base can be, for example, TEA, DIEPA or DMAP.

[0072] Compounds of formula (I) or (Ia) when prepared according to the above process are also an object of the present invention. [Example]

[0073] The present invention will be more fully understood by reference to the following examples, which should not, however, be construed as limiting the scope of the invention.

[0074] Abbreviation The present invention will be more fully understood by reference to the following examples, which should not, however, be construed as limiting the scope of the invention. The abbreviations used herein are as follows:

[0075] TIFF2025525315000017.tif252170TIFF2025525315000018.tif236170

[0076] General experimental conditions Intermediates and final compounds were purified by flash chromatography using one of the following instruments: i) a Biotage SP1 system and Quad 12 / 25 cartridge module; ii) an ISCO Combi-Flash Chromatography instrument. Silica gel brand and pore size: i) KP-SIL 60Å, particle size: 40-60 μm; ii) CAS Registry Number: Silica Gel: 63231-67-4, particle size: 47-60 micron; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd., pore size: 200-300 or 300-400.

[0077] Intermediates and final compounds are XBridge TM Prep-C18 (5 μm, OBD™ 30 × 100 mm) column, SunFire TM Prep-C18 (5 μm, OBD TMPurification was performed by preparative HPLC on a reversed-phase column using a Phenomenex Synergi-C18 (10 μm, 25 × 150 mm) or Phenomenex Gemini-C18 (10 μm, 25 × 150 mm) column (30 × 100 mm), a Waters AutoP purification system (Sample Manager 2767, Pump 2525, detectors: Micromass ZQ and UV2487, solvent systems: acetonitrile and 0.1% ammonium hydroxide in water; acetonitrile and 0.1% FA in water, or acetonitrile and 0.1% TFA in water), or a Gilson-281 purification system (Pump 322, detector: UV156, solvent systems: acetonitrile and 0.05% ammonium hydroxide in water; acetonitrile and 0.225% FA in water; acetonitrile and 0.05% HCl in water; acetonitrile and 0.075% TFA in water; or acetonitrile and water).

[0078] For SFC chiral separations, intermediates were separated on chiral columns (Daicel chiralpak IC, 5 μm, 30 × 250 mm), AS (10 μm, 30 × 250 mm), or AD (10 μm, 30 × 250 mm) using a Mettler Toledo Multigram III system SFC, a Waters 80Q preparative SFC, or a Thar80 preparative SFC, solvent systems: CO₂ and IPA (0.5% TEA in IPA) or CO₂ and MeOH (0.1% NH₃·H₂O in MeOH), back pressure 100 bar, and UV detection at 254 or 220 nm.

[0079] LC / MS spectra of the compounds were analyzed by LC / MS (Waters TM Acquisition was performed using an Alliance 2795-Micromass ZQ, Shimadzu Alliance 2020-Micromass ZQ, or Agilent Alliance 6110-Micromass ZQ. LC / MS conditions were as follows (run time 3 or 1.5 min): Acidic conditions I: A: 0.1% TFA in H2O; B: 0.1% TFA in acetonitrile; Acidic conditions II: A: 0.0375% TFA in H2O, B: 0.01875% TFA in acetonitrile; Basic condition I: A: 0.1% NH3·H2O in H2O; B: acetonitrile; Basic conditions II: A: 0.025% NH3·H2O in H2O; B: acetonitrile; Neutral conditions: A: H2O; B: acetonitrile. Mass spectra (MS): Usually only ions representing the parent mass are reported, and unless otherwise specified, the mass ions quoted are positive mass ions (M−H) + .

[0080] NMR spectra were obtained using a Bruker Avance 400 MHz or 500 MHz.

[0081] Microwave-assisted reactions were performed in a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were carried out under an argon or nitrogen atmosphere. Reagents were used as received from suppliers without further purification unless otherwise specified.

[0082] Preparation example Preparation of intermediates Intermediate A 1-[6-[(1S)-1-Methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-3-pyridyl]-4-methyl-piperazine TIFF2025525315000019.tif42170

[0083] The title intermediate A was prepared according to the following scheme: TIFF2025525315000020.tif109170

[0084] Step 1: Preparation of 3-bromo-2-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)pyridine (Compound A2) To a solution of 3-bromo-2-[(1S)-1-methoxyethyl]pyridine (compound A1, 2.0 g, 9.26 mmol) and bis(pinacolato)diboron (3.5 g, 13.9 mmol) in THF (30 mL) was added 4,4'-di-tert-butyl-2,2'-bipyridine (372.7 mg, 1.39 mmol) and [Ir(OMe)(COD)] (306.3 mg, 0.460 mmol). The mixture was stirred at 75 °C under N protection for 16 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (EA / PE: 0-20%) to obtain 3-bromo-2-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)pyridine (compound A2, 2.4 g) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ ppm 8.91(d,J=1.4Hz,1H), 8.21(d,J=1.4Hz,1H), 4.95(q,J=6.5Hz,1H), 3.30(s,3H), 1.49(d,J=6.5Hz,3H), 1.35(s,12H).

[0085] Step 2: Preparation of 3-bromo-5-iodo-2-[(1S)-1-methoxyethyl]pyridine (Compound A3) To a solution of 3-bromo-2-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)pyridine (compound A2, 2.5 g, 7.3 mmol) in ACN (40 mL) was added N-iodosuccinimide (4.1 g, 18.27 mmol). The mixture was stirred at 90 °C for 40 h under N protection. The reaction was quenched with a saturated solution of NaSO (40 mL), and the reaction mixture was extracted with EtOAc (30 mL, twice). The combined organic layers were washed with brine (50 mL), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (EA / PE: 0-20%) to give 3-bromo-5-iodo-2-[(1S)-1-methoxyethyl]pyridine (compound A3, 660 mg) as a yellow oil. MS calculated value 342 (MH + ), measured value 341.8 (MH +).

[0086] Step 3: Preparation of benzyl 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound A5) To a solution of 3-bromo-5-iodo-2-[(1S)-1-methoxyethyl]pyridine (compound A3, 660 mg, 1.9 mmol) and 1-Cbz-piperazine (compound A4, 425.1 mg, 1.9 mmol) in toluene (10 mL) was added cesium carbonate (1.6 g, 4.83 mmol), (R)-BINAP (60.1 mg, 0.1 mmol), and palladium(II) acetate (43.3 mg, 0.19 mmol). The mixture was stirred at 100° C. under N protection for 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (EA / PE: 0-50%) to give benzyl 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound A5, 740 mg) as a yellow solid. MS calculated: 434.1 (MH + ), measured value 434.1 (MH + ).

[0087] Step 4: Preparation of 1-[6-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-3-pyridyl]-4-methyl-piperazine (Intermediate A) To a solution of benzyl 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound A5, 740 mg, 1.7 mmol) and bis(pinacolato)diboron (519.2 mg, 2.04 mmol) in toluene (12 mL) was added KOAc (418.0 mg, 4.26 mmol) and Pd(dppf)Cl (124.7 mg, 0.170 mmol). The reaction mixture was stirred at 90 °C for 12 hours under N protection. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was filtered through a silica gel column to give 1-[6-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-3-pyridyl]-4-methyl-piperazine (Intermediate A, 470 mg) as a brown solid. MS calculated 482.3 (MH + ), measured value 482.2 (MH + ).

[0088] Intermediate B Methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)-propanoyl]hexahydropyridazine-3-carboxylate TIFF2025525315000021.tif52170

[0089] Intermediate B was prepared according to the following scheme: TIFF2025525315000022.tif154170

[0090] Step 1: Preparation of (4-bromothiazol-2-yl)methanol (Compound B2) To a solution of 4-bromothiazole-2-carboxaldehyde (compound B1, 6.0 g, 31.25 mmol) in methanol (70 mL) was added sodium borohydride (1.7 g, 46.87 mmol) at 0° C. The mixture was stirred at 25° C. for 1 hour. The reaction was quenched with water (300 mL) at 0° C., and the reaction mixture was extracted with ethyl acetate (200 mL, 3 times). The combined organic phases were washed with brine (150 mL, 2 times), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (4-bromothiazol-2-yl)methanol (compound B2, 6 g) as a colorless oil.

[0091] Step 2: Preparation of 4-bromo-2-(bromomethyl)thiazole (Compound B3) To a solution of (4-bromothiazol-2-yl)methanol (compound B2, 6.0 g, 30.92 mmol) in DCM (80 mL) was added CBr4 (15.4 g, 46.38 mmol) and triphenylphosphine (12.1 g, 46.38 mmol) at 0 °C. After stirring at 25 °C for 1 h, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column eluted with ethyl acetate (0-10%) in petroleum ether to give (4-bromothiazol-2-yl)methanol (compound B3, 6.0 g) as a yellow oil. MS calculated 255.9 (MH + ), measured value 255.9 (MH + ).

[0092] Step 3: Preparation of 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl]methyl]thiazole (Compound B5) To a mixture of (R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (compound B4, 4.3 g, 23.45 mmol) in THF (60 mL) was slowly added n-butyllithium (10 mL, 25.22 mmol, 2.5 M) at −78° C. After the addition, the mixture was stirred at −78° C. for 0.5 h. 4-Bromo-2-(bromomethyl)thiazole (compound B3, 5.4 g, 21.02 mmol) was added to the above mixture at −78° C., which was stirred for an additional 1 h. The reaction was quenched with a saturated solution of NH4Cl (100 mL), and the reaction mixture was extracted with EtOAc (100 mL, twice). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography to give 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl]methyl]thiazole (compound B5, 3.6 g) as a yellow oil. MS calculated 360 (MH + ), measured value 359.9 (MH + ).

[0093] Step 4: Preparation of methyl (2S)-2-amino-3-(4-bromothiazol-2-yl)propanoate (Compound B6) To a solution of 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl]methyl]thiazole (compound B5, 3.6 g, 10 mmol) in ACN (20 mL) was added hydrochloric acid (66.6 mL, 0.3 M). The mixture was stirred at 25 °C for 2 hours. The mixture was basified with a saturated solution of NaHCO to pH = 8. The mixture was extracted with EtOAc (80 mL, 6 times). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give methyl (2S)-2-amino-3-(4-bromothiazol-2-yl)propanoate (compound B6, 3.1 g) as a yellow oil. MS calculated 264.9 (MH + ), measured value 264.9 (MH + ).

[0094] Step 5: Preparation of methyl (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoate (Compound B7) To a solution of methyl (2S)-2-amino-3-(4-bromothiazol-2-yl)propanoate (compound B6, 3.1 g, 11.69 mmol) in DCM (40 mL) was added triethylamine (2.9 g, 29.23 mmol) and (Boc)2O (3.8 g, 17.54 mmol). After stirring at 30 °C for 12 h, the mixture was concentrated under reduced pressure. The residue was purified on a silica gel column eluted with ethyl acetate in petroleum ether (0-30%) to give methyl (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoate (compound B7, 3.2 g) as a yellow oil. MS calculated 387 (Mn + ), measured value 386.9 (MNa + ).

[0095] Step 6: Preparation of (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)-propanoic acid (compound B8) To a solution of methyl (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoate (compound B7, 3.2 g, 8.76 mmol) in THF (30 mL), methanol (2 mL), and water (10 mL) was added lithium hydroxide (0.4 mL, 43.81 mmol). After stirring at 25 °C for 1 h, the reaction mixture was acidified to pH = 5 with a 1 M solution of HCl. The mixture was extracted with EtOAc (40 mL, twice). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoic acid (compound B8, 3.1 g) as a yellow oil. MS calculated 373 (MNa + ), measured value 372.9 (MNa + ).

[0096] Step 7: Preparation of methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (Intermediate B) To a solution of (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoic acid (compound B8, 3.1 g, 8.83 mmol) in DCM (50 mL) was added methyl (3S)-hexahydropyridazine-3-carboxylate hydrochloride (compound B9, 2.4 g, 13.24 mmol), EDCI (3.4 g, 17.65 mmol), 1-hydroxybenzotriazole (238.5 mg, 1.77 mmol), and NMM (9.92 mL, 88.26 mmol) at 0 °C. After stirring at 25 °C for 1 h, the reaction mixture was diluted with water (60 mL) and extracted with EtOAc (60 mL, 3 times). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column, eluting with ethyl acetate in petroleum ether (10-30%), to give methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (Intermediate B, 2.4 g). MS calculated 477 (MH + ), measured value 476.9 (MH + ).

[0097] Intermediate C (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]Octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione TIFF2025525315000023.tif55170

[0098] The title intermediate C was prepared according to the following scheme: TIFF2025525315000024.tif187170TIFF2025525315000025.tif206170

[0099] Step 1: Preparation of 1-(5-bromo-6-fluoro-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropan-1-one (Compound C3) To a mixture of 3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropanoyl chloride (compound C1, 35.0 g, 116.8 mmol) in DCM (400 mL) at 0 °C was slowly added a solution of SnCl (97.2 mL, 121.5 mmol). After stirring at −40 °C for 0.5 h, 5-bromo-6-fluoro-1H-indole (compound C2, 25.0 g, 116.8 mmol) in DCM (200 mL) was added dropwise to the mixture, which was stirred at −40 °C for 15 min. After completion of the reaction, it was quenched with saturated aqueous NaHCO (800 mL), and the reaction mixture was extracted with EtOAc (900 mL, twice). The combined organic layers were washed with brine (700 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was triturated with a solution (100 mL, petroleum ether:ethyl acetate=8:1) and filtered. The filter cake was dried in vacuo to give 1-(5-bromo-6-fluoro-1H-indol-3-yl)-3-((tertbutyldiphenylsilyl)oxy)-2,2-dimethylpropan-1-one (compound C3, 50.0 g) as a yellow solid. MS calculated 552.1 (MH + ), measured value 552.1 (MH + ).

[0100] Step 2: Preparation of [3-(5-bromo-6-fluoro-1H-indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound C4) To a mixture of 1-(5-bromo-6-fluoro-1H-indol-3-yl)-3-((tertbutyldiphenylsilyl)oxy)-2,2-dimethylpropan-1-one (compound C3, 50.0 g, 90.49 mmol) in THF (600 mL) was added LiBH (48.4 mL, 193.49 mmol, 4 M in THF) dropwise at 0 °C. The mixture was stirred at 70 °C for 24 h under a nitrogen atmosphere. After completion of the reaction, it was quenched by slowly adding water (600 mL) at 0 °C, and the reaction mixture was extracted with EtOAc (600 mL, twice). The combined organic layers were washed with brine (600 mL), dried over Na SO , filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (20% to 33% EtOAc in PE) to give [3-(5-bromo-6-fluoro-1H-indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound C4, 46.0 g) as a white solid. MS calculated 538.1 (MH + ), measured value 538.2 (MH + ).

[0101] Step 3: Preparation of [3-(5-bromo-6-fluoro-2-iodo-1H-indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound C5) To a mixture of [3-(5-bromo-6-fluoro-1H-indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound C4, 35.4 g, 65.73 mmol) and iodine (18.4 g, 72.3 mmol) in THF (400 mL) was added silver trifluoromethanesulfonate (20.3 g, 78.88 mmol) at 0 °C. The mixture was stirred at 0 °C for 10 minutes. After the reaction was completed, it was quenched with saturated NaSO (400 mL) and EtOAc (400 mL), and the reaction mixture was filtered. The organic layer was washed with brine (100 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (0% to 2.5% EtOAc in PE) to give [3-(5-bromo-6-fluoro-2-iodo-1H-indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound C5, 43.0 g) as a yellow solid. MS calculated 664.0 (MH + ), measured value 664.1 (MH + ).

[0102] Step 4: Preparation of benzyl 4-[5-[5-bromo-3-[3-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-propyl]-6-fluoro-1H-indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound C6) To a mixture of [3-(5-bromo-6-fluoro-2-iodo-1H-indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (Compound C5, 16.7 g, 25.13 mmol) and benzyl 4-[6-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-3-pyridyl]piperazine-1-carboxylate (Intermediate A, 16.7 g, 34.69 mmol) in a mixture of 1,4-dioxane (270 mL) / toluene (90 mL) / water (90 mL) was added potassium phosphate (15.7 g, 73.92 mmol) and Pd(dppf)Cl (920 mg, 1.26 mmol). The mixture was stirred at 70° C. under a nitrogen atmosphere for 12 hours. After the reaction was completed, the mixture was filtered and concentrated in vacuo. The residue was purified by silica column chromatography (20% to 50% EtOAc in PE) to give 4-[5-[5-bromo-3-[3-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-propyl]-6-fluoro-1H-indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound C6, 19.5 g) as a white solid. MS calculated 891.3 (MH + ), measured value 891.3 (MH + ).

[0103] Step 5: Preparation of benzyl 4-[(5M)-5-[5-bromo-3-[3-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-propyl]-6-fluoro-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound C7) To a solution of 4-[5-[5-bromo-3-[3-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-propyl]-6-fluoro-1H-indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound C6, 14.5 g, 16.26 mmol) and CsCO (15.9 g, 48.77 mmol) in DMF (200 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (37.7 g, 162.56 mmol) dropwise at 0 °C, and the mixture was stirred at 20 °C for 12 h. After the reaction was complete, EtOAc (70 mL) and water (100 mL) were added, and the layers were separated. The aqueous phase was extracted with EtOAc (70 mL, twice). The combined organic layers were washed with brine (100 mL, 4 times), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica column chromatography to give benzyl 4-[(5M)-5-[5-bromo-3-[3-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-propyl]-6-fluoro-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound C7, 8.0 g, PEAK1, faster eluting) as a yellow oil. MS calculated 973.3 (MH + ), measured value 973.2 (MH + ).

[0104] Step 6: Preparation of benzyl 4-[(5M)-5-[5-bromo-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound C8) To a solution of benzyl 4-[(5M)-5-[5-bromo-3-[3-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-propyl]-6-fluoro-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound C7, 10.5 g, 10.78 mmol) in DMF (130 mL) was added cesium fluoride (8.2 g, 53.9 mmol), and the mixture was stirred at 60 °C for 24 h. After the reaction was complete, EtOAc (100 mL) and water (100 mL) were added, and the layers were separated. The aqueous phase was extracted with EtOAc (100 mL, 2 times). The combined organic layers were washed with brine (80 mL, 3 times), dried over Na SO , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica column chromatography (25% to 66% EtOAc in PE) to give benzyl 4-[(5M)-5-[5-bromo-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound C8, 6.5 g) as a yellow solid. MS calculated 735.2 (MH + ), measured value 735.1 (MH + ).

[0105] Step 7: Preparation of benzyl 4-[(5M)-5-[6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound C9) To a solution of benzyl 4-[(5M)-5-[5-bromo-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound C8, 5.4 g), bis(pinacolato)diboron (2.8 g, 11.01 mmol), and potassium acetate (1.2 mL, 18.35 mmol) in toluene (70 mL) was added Pd(dppf)Cl (537.1 mg, 0.73 mmol). The mixture was degassed and purged with nitrogen three times, and the mixture was stirred at 90 °C for 12 hours. After the reaction was complete, the mixture was cooled to room temperature. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by silica column chromatography (25% to 66% EtOAc in PE) to give benzyl 4-[(5M)-5-[6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound C9, 5.2 g) as a yellow oil. MS calculated 783.3 (MH + ), measured value 783.3 (MH + ).

[0106] Step 8: Preparation of methyl (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]-2-(tert-butoxycarbonylamino)-propanoyl]hexahydropyridazine-3-carboxylate (Compound C10) Methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (Intermediate B, 2.7 g, 5.69 mmol), benzyl methyl ... methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl To a mixture of 4-[(5M)-5-[6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound C9, 4.9 g, 6.32 mmol), KPO (3.4 g, 15.81 mmol) and Pd(dtbpf)Cl (412.2 mg, 0.63 mmol) were added under a nitrogen atmosphere. The mixture was stirred at 70 °C for 12 hours. After the reaction was completed, the mixture was concentrated in vacuo to give a residue. The residue was purified by silica column (10% to 75% EtOAc in PE) to give methyl (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]-2-(tert-butoxycarbonylamino)-propanoyl]hexahydropyridazine-3-carboxylate (compound C10, 3.6 g) as a brown solid. MS calculated 1053.4 (MH + ), measured value 1053.3 (MH + ).

[0107] Step 9: Preparation of (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]-2-(tert-butoxycarbonylamino)propanoyl]hexahydro-dropidazine-3-carboxylic acid (Compound C11) To a solution of methyl (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]-2-(tert-butoxycarbonylamino)-propanoyl]-hexahydropyridazine-3-carboxylate (Compound C10, 3.6 g, 3.42 mmol) in DCE (50 mL) was added trimethylstannanol (2.4 g, 13.67 mmol), and the mixture was stirred at 60 °C for 12 h. After the reaction was complete, EtOAc (80 mL) and water (60 mL) were added, and the layers were separated. The aqueous phase was extracted with EtOAc (80 mL, twice). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]-2-(tert-butoxycarbonylamino)propanoyl]hexahydro-dropidazine-3-carboxylic acid (Compound C11, 4.3 g) as a brown solid. MS calculated value 1039.4 (MH + ), measured value 1039.2 (MH + ).

[0108] Step 10: Benzyl 4-[5-[(7S,13S)-7-(tert-butoxycarbonylamino)-24-fluoro-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Preparation of ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-(20M)-20-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound C12) To a mixture of (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]-2-(tert-butoxycarbonylamino)propanoyl]hexahydro-dropidazine-3-carboxylic acid (Compound C11, 4.3 g, 4.14 mmol) in DCM (430 mL) was added DIEA (14.4 mL, 82.76 mmol), EDCI (11.9 g, 62.07 mmol), and 1-hydroxybenzotriazole (1.4 g, 10.35 mmol) at 0 °C. The mixture was stirred at 15° C. for 12 hours. After the reaction was complete, the mixture was concentrated in vacuo, then diluted with water (80 mL) and extracted with EtOAc (80 mL, twice). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (EtOAc in PE = 25% to 66%) to give benzyl 4-[5-[(7S,13S)-7-(tert-butoxycarbonylamino)-24-fluoro-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26]octacosa-1(25),2,5(28),19,22(26),23-hexaen-(20M)-20-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound C12, 3.1 g) was obtained as a yellow gum. MS calculated 1021.4 (MH + ), measured value 1021.2 (MH + ).

[0109] Step 11: tert-butyl N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Preparation of ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamate (compound C13) Benzyl 4-[5-[(7S,13S)-7-(tert-butoxycarbonylamino)-24-fluoro-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26To a mixture of ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-(20M)-20-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound C12, 3.1 g, 3.04 mmol) and aqueous formaldehyde (775.0 mg, 9.55 mmol) was added Pd(OH) on activated carbon (2.79 g, 3.97 mmol). The mixture was degassed and purged with H three times. The mixture was hydrogenated at 30 °C for 18 h. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated in vacuo to give tert-butyl N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamate (compound C13, 2.6 g) was obtained as a brown solid. MS calculated 901.3 (MH + ), measured value 901.3 (MH + ).

[0110] Step 12: (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]Preparation of octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (intermediate C) tert-Butyl N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 To a mixture of 2.6 g (2.89 mmol) of octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamate (Compound C13), TFA (14.0 mL, 181.72 mmol) was added. The mixture was stirred at 15 °C for 0.5 h. After the reaction was complete, the mixture was concentrated in vacuo, diluted with saturated NaHCO (30 mL), and extracted with EtOAc (30 mL, 3 times). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, concentrated in vacuo, and purified to afford (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]Octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate C, 2.0 g) was obtained as a yellow solid, which was used directly in the next step. MS calculated 801.3 (MH + ), measured value 801.2 (MH + ).

[0111] Intermediate D (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.12,5 .1 9,13 .0 22,26 ]Octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione TIFF2025525315000026.tif62170

[0112] The title compound was prepared in a manner similar to the preparation of Intermediate C by using iodoethane instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate.

[0113] Intermediate E (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]Octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione TIFF2025525315000027.tif56170

[0114] The compounds were prepared according to the following scheme: TIFF2025525315000028.tif189170TIFF2025525315000029.tif132170

[0115] Step 1: Preparation of 1-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]-4-(2,2,2-trifluoroethyl)piperazine (Compound E2) To a mixture of 3-bromo-5-iodo-2-[(1S)-1-methoxyethyl]pyridine (compound A3, 2.03 g, 5.95 mmol) and 1-(2,2,2-trifluoroethyl)piperazine (compound E1, 1.0 g, 5.95 mmol) in toluene (15 mL) was added CsCO (4.85 g, 14.88 mmol), (R)-binap (92.6 mg, 0.15 mmol), and Pd(OAc) (66.8 mg, 0.3 mmol). The reaction mixture was degassed and purged with nitrogen three times, and the mixture was stirred at 100 °C under a nitrogen atmosphere for 12 h. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography to give 1-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]-4-(2,2,2-trifluoroethyl)piperazine (compound E2, 2.0 g) as a yellow oil. MS calculated 382.2 (MH + ), measured value 382.1 (MH + ).

[0116] Step 2: 1-[6-[(1S)-1-Methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-3-pyridyl]-4-(2,2,2-trifluoroethyl)piperazine (Compound E3) To a solution of 1-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]-4-(2,2,2-trifluoroethyl)piperazine (Compound E2, 3.2 g, 8.37 mmol), bis(pinacolato)diboron (3.19 g, 12.56 mmol), and KOAc (2.1 g, 20.93 mmol) in toluene (50 mL) was added Pd(dppf)Cl (306.3 mg, 0.42 mmol). The mixture was degassed and purged with nitrogen three times, and the mixture was stirred at 90 °C under a nitrogen atmosphere for 12 h. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue that was purified by reverse-phase column chromatography to give 1-[6-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-3-pyridyl]-4-(2,2,2-trifluoroethyl)piperazine (compound E3, 1.9 g) as a yellow gum. MS calculated 430.2 (MH + ), measured value 348.4 (M-C6H 10 +H + ).

[0117] Step 3: Preparation of [3-[5-bromo-6-fluoro-2-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1H-indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound E4) To a solution of 1-[6-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-3-pyridyl]-4-(2,2,2-trifluoroethyl)piperazine (compound E3, 1.9 g, 4.41 mmol), [3-(5-bromo-6-fluoro-2-iodo-1H-indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound C5, 2.1 g, 3.15 mmol) in 1,4-dioxane (24 mL), water (8 mL), and toluene (8 mL) was added KPO (2.1 g, 9.5 mmol) and Pd(dppf)Cl (231 mg, 0.37 mmol). The mixture was degassed by bubbling nitrogen through it for 2 minutes, and the reaction mixture was stirred at 70°C for 12 hours. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (30% to 60% EtOAc in PE) to give [3-[5-bromo-6-fluoro-2-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1H-indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound E4, 960.0 mg) as a yellow gum. MS calculated 839.3 (MH + ), measured value 839.3 (MH + ).

[0118] Step 4: Preparation of [3-[5-bromo-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound E5) To a solution of [3-[5-bromo-6-fluoro-2-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1H-indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound E4, 1 g, 1.14 mmol) in DMF (35 mL) was added CsCO (1.1 g, 3.44 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.7 g, 11.63 mmol) at 0° C. After stirring at 20° C. for 15 h, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (50 mL, 3 times). The combined organics were washed with brine (50 mL, 3 times), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by column chromatography (30%-40% EtOAc in PE) to give [3-[5-bromo-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound E5, 640.0 mg, faster eluting) as a white solid. MS calculated 921.3 (MH + ), measured value 921.4 (MH + ).

[0119] Step 5: Preparation of 3-[5-bromo-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propan-1-ol (Compound E6) To a solution of [3-[5-bromo-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (Compound E5, 640.0 mg, 0.69 mmol) in DMF (7 mL) was added cesium fluoride (421.8 mg, 2.78 mmol). The mixture was stirred at 60° C. for 16 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (30% to 60% EtOAc in PE) to give 3-[5-bromo-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propan-1-ol (compound E6, 360.0 mg) as a yellow oil. MS calculated 683.2 (MH + ), measured value 683.1 (MH + ).

[0120] Step 6: Preparation of 3-[5-bromo-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propan-1-ol (Compound E7) To a solution of 3-[5-bromo-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propan-1-ol (compound E6, 360.0 mg, 0.53 mmol), bis(pinacolato)diboron (200.6 mg, 0.79 mmol) in toluene (6 mL) was added potassium acetate (0.08 mL, 1.32 mmol) and Pd(dppf)Cl (40 mg, 0.1 mmol). The reaction mixture was degassed by bubbling nitrogen through it for 5 minutes and then stirred at 80 °C for 15 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (30% to 50% EtOAc in PE) to give 3-[5-bromo-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propan-1-ol (compound E7, 300.0 mg) as a yellow gum. MS calculated 731.4 (MH + ), measured value 731.4 (MH + ).

[0121] Step 7: Preparation of methyl (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylate (Compound E8) 3-[5-bromo-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propan-1-ol (compound E7, 0.3 g, 0.4 mL) in toluene (3 mL), 1,4-dioxane (1 mL), and water (1 mL) To a mixture of (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (Intermediate B, 196.7 mg, 0.41 mmol) and methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (Intermediate B, 196.7 mg, 0.41 mmol) was added KPO (221.3 mg, 1.04 mmol) and Pd(dtbpf)Cl (27.05 mg, 0.04 mmol). The mixture was stirred at 70 °C for 12 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (60% to 80% EtOAc in PE) to give methyl (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylate (compound E8, 200.0 mg) as a yellow gum. MS calculated 1001.4 (MH + ), measured value 1001.4 (MH + ).

[0122] Step 8: Preparation of (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylic acid (Compound E9) To a mixture of methyl (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylate (Compound E8, 200.0 mg, 0.2 mmol) in DCE (5 mL) was added MeSnOH (200.0 mg, 1.11 mmol). The mixture was stirred at 60° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. EtOAc (10 mL) and water (10 mL) were added to the residue, and the layers were separated. The aqueous phase was extracted with EtOAc (15 mL, twice). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylic acid (Compound E9, 188.0 mg) as a brown solid. MS calculated value 987.4 (MH + ), measured value 987.4 (MH + ).

[0123] Step 9: tert-butyl N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Preparation of ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamate (compound E10) To a mixture of (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylic acid (Compound E9, 188.0 mg, 0.19 mmol) in DCM (20 mL) was added DIEA (0.7 mL, 3.81 mmol), EDCI (550.0 mg, 2.87 mmol) and HOBt (65.0 mg, 0.48 mmol) at 0 °C. After stirring at 20°C for 12 hours, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by column chromatography (50% to 70% EtOAc in PE) to give tert-butyl N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .022,26 ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamate (compound E10, 110.0 mg) was obtained as a yellow solid. MS calculated 969.4 (MH + ), measured value 969.5 (MH + ).

[0124] Step 10: (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Preparation of ]-octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (intermediate E) tert-Butyl N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26To a solution of ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamate (Compound E10, 110.0 mg, 0.11 mmol) was added TFA (1.0 mL, 12.98 mmol). The mixture was stirred at 20 °C for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give a residue. Sat. NaHCO3 aq. (20 mL) was added, and the mixture was extracted with EtOAc (15 mL, 3 times). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified to afford (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]-Octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate E, 98.0 mg) was obtained as a yellow solid. MS calculated 869.4 (MH + ), measured value 869.2 (MH + ).

[0125] Intermediate F (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]Octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione TIFF2025525315000030.tif57170

[0126] The title compound was prepared in a manner similar to the preparation of Intermediate E by using iodoethane instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate.

[0127] intermediate G (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo-[17.5.2.1 2,5 .1 9,13 .0 22,26 ]Octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione TIFF2025525315000031.tif49170

[0128] The title compound was prepared in a manner similar to that for the preparation of intermediate E by using iodoethane and morpholine in place of 2,2,2-trifluoroethyl trifluoromethanesulfonate and 1-(2,2,2-trifluoroethyl)piperazine (compound E1).

[0129] Intermediate H (7S,13S)-7-amino-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]Octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione TIFF2025525315000032.tif56170

[0130] The title compound was prepared in a manner similar to the preparation of intermediate C by using 5-bromo-4-fluoro-1H-indole instead of 5-bromo-6-fluoro-1H-indole (compound C2).

[0131] Intermediate I (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]Octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione TIFF2025525315000033.tif56170

[0132] The title compound was prepared in a manner similar to the preparation of intermediate E by using morpholine instead of 1-(2,2,2-trifluoroethyl)piperazine (compound E1).

[0133] Example 1 (1S,2S)-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-2-methyl-cyclopropanecarboxamide TIFF2025525315000034.tif69170

[0134] A solution of (1S,2S)-2-methylcyclopropanecarboxylic acid (compound 1a, 64.3 mg, 0.64 mmol) in DMF (2 mL) was treated with DIEA (0.3 mL, 1.61 mmol), HATU (366.5 mg, 0.96 mmol), and (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]Octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate D, 240.0 mg, 0.32 mmol) was added at 0 °C. After stirring at 20 °C for 16 h, the reaction mixture was poured into ice water (10 mL) and extracted with EA (20 mL, 3 times). The combined organic layers were washed with brine (20 mL), dried over Na SO , and concentrated under reduced pressure to give a residue. The resulting residue was purified by silica gel chromatography to give (1S,2S)-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-2-methyl-cyclopropanecarboxamide (Example 1, 156.41 mg) was obtained as a white solid. MS calculated 829.5 (MH + ), measured value 829.5 (MH + ). 1H NMR (400MHz, methanol-d4) δ=8.64(d,J=7.6Hz,1H), 8.58(d,J=8.4Hz,1H), 8.42(d,J=2.9Hz,1H), 7 .63(d,J=2.4Hz,1H), 7.34(d,J=2.8Hz,1H), 7.31(d,J=12.7Hz,1H), 5.79-5.73(m,1H), 4.44(br d,J=11.4Hz,1H), 4.28-4.13(m,4H), 3.77-3.68(m,2H), 3.41-3.37(m,4H), 3.28-3.13(m,2H), 3.02(br d,J=13.6Hz,1H), 2.77-2.74(m,4H), 2.63(br d,J=14.3Hz,1H), 2.44(s,3H), 2.21-2.13(m,1H), 1.97(s,2H), 1.68-1.58(m,1H), 1.51- 1.47(m,1H), 1.42(d,J=6.2Hz,2H), 1.37(d,J=6.6Hz,4H), 1.13(d,J=6.0Hz,3H), 1.08(br dd,J=4.2, 8.6Hz,1H), 0.98(t,J=7.0Hz,3H), 0.95-0.89(m,4H), 0.67-0.62(m,1H), 0.50(s,3H)ppm.

[0135] Example 2 (1R,5S)-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-oxabicyclo[3.1.0]hexane-6-carboxamide TIFF2025525315000035.tif67170

[0136] The title compound was prepared in a manner similar to that of Example 1, by substituting (1S,5R)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid for (1S,2S)-2-methylcyclopropanecarboxylic acid (Compound 1a). Example 2 (10.2 mg) was obtained as a white solid. MS calculated 857.4 (MH + ), measured value 857.1 (MH + ). 1 H NMR (400MHz, acetonitrile-d3) δ=8.61(d,J=7.6Hz,1H), 8.41(d,J=2.8Hz,1H), 7.62(d,J=2.5Hz,1H), 7.33-7.28(m,1H), 7.18(d,J=2.8Hz,1H), 7.04(br d,J=9.5Hz,1H), 5.68(br t,J=8.8Hz,1H), 4.41-4.30(m,2H), 4.20-4.05(m,4H), 3.88-3.83(m,2H), 3.71-3.64(m,4H), 3.37(br d,J=14.9Hz,1H), 3.28-3.24(m,4H), 3.22-3.17(m,3H), 3.13(br dd,J=9.1, 15.0Hz,1H), 2.91(br d,J=14.9Hz,1H), 2.70(dt,J=2.7, 12.9Hz,1H), 2.58(br d,J=14.1Hz,1H), 2.50(br t,J=4.8Hz,4H), 2.30-2.22(m,4H), 1.78-1.72(m,1H), 1.57-1.50(m,2H), 1.36(d,J=6.1Hz,3H), 1.27(br s,1H), 0.96(br t,J=7.1Hz,3H), 0.88(s,3H), 0.47(s,3H)ppm.

[0137] Example 3 (1S,2S)-2-(Difluoromethyl)-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]cyclopropanecarboxamide TIFF2025525315000036.tif71170

[0138] The title compound was prepared in a manner similar to that of Example 1, by substituting (1S,2S)-2-(difluoromethyl)cyclopropanecarboxylic acid for (1S,2S)-2-methylcyclopropanecarboxylic acid (compound 1a). Example 3 (31.4 mg) was obtained as a yellow solid. MS calculated 865.4 (MH + ), measured value 865.1 (MH + ). 1 H NMR(400MHz,CHLOROFORM-d)δ=8.76(br d,J=2.6Hz,1H), 8.66(d,J=7.6Hz,1H), 7.63(d,J=2.1Hz,1H), 7.30(br d,J=2.4Hz,1H), 7.12(d,J=12.3Hz,1H), 6.78(br d,J=9.9Hz,1H), 6.00-5.92(m,1H), 4.66-4.53(m,1H), 4.36(q,J=6.2Hz,1H), 4.31-4.23(m,1H), 4.19 -4.04(m,2H), 3.89-3.86(m,1H), 3.78-3.66(m,4H), 3.47-3.44(m,1H), 3.41(s,3H), 3.24-3.05(m,6H) ), 2.93(s,3H), 2.89-2.80(m,1H), 2.78-2.70(m,1H), 2.53-2.39(m,1H), 2.29-2.18(m,1H), 2.08-1.6 6(m,5H), 1.53-1.45(m,3H), 1.19-1.14(m,2H), 1.37-1.08(m,2H), 1.02-0.87(m,6H), 0.50(s,3H)ppm.

[0139] Example 4 (1S,2S)-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-2-methyl-cyclopropanecarboxamide TIFF2025525315000037.tif65170

[0140] The title compound was prepared in a manner similar to that prepared in Example 1 from (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (intermediate D), instead of (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ] was prepared by using octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate C). Example 4 (15.7 mg) was obtained as a white solid. MS calculated 883.5 (MH + ), measured value 883.1 (MH + ). 1H NMR (400MHz, methanol-d4) δ=8.67(d,J=7.6Hz,1H), 8.50(d,J=2.8Hz,1H), 7.70(d,J=2.0Hz,1H), 7.54-7.49(m,1H), 7.49-7.45(m,1H), 5.71(d,J=9.2Hz) ,1H), 5.20-5.14(m,1H), 4.47-4.41(m,1H), 4.24-4.18(m,2H), 4.09-3.94 (m,2H), 3.80-3.61(,5H), 3.49-3.43(m,2H), 3.35(s,3H), 3.17-3.12(m,2H ), 3.00(s,3H), 2.83-2.76(m,1H), 2.57(d,J=14.4Hz,1H), 2.23-2.16(m,1 H), 1.99-1.93(m,1H), 1.84-1.77(m,1H), 1.68-1.61(m,1H), 1.52-1.48(m, 1H), 1.47-1.41(m,4H), 1.27-1.22(m,1H), 1.13(d,J=6.0Hz,3H), 1.11-1. 05(m,2H), 0.96(s,3H), 0.90-0.77(m,1H), 0.68-0.62(m,1H), 0.44(s,3H).

[0141] Examples 5 and 6 (1S,2S)-2-cyano-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]cyclopropanecarboxamide and (1R,2R)-2-cyano-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5.1 9,13 .0 22,26 ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]cyclopropanecarboxamide TIFF2025525315000038.tif66170

[0142] The compounds were prepared according to the following scheme: TIFF2025525315000039.tif153170

[0143] Step 1: (1S,2S)-2-cyano-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]cyclopropanecarboxamide and (1R,2R)-2-cyano-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Preparation of ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]cyclopropanecarboxamide A solution of trans-2-cyanocyclopropanecarboxylic acid (compound 5a, 11.2 mg, 0.1 mmol) in DMF (0.5 mL) was treated with DIEA (0.1 mL, 0.33 mmol), HATU (76.4 mg, 0.2 mmol), and (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]Octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate D, 50.0 mg, 0.07 mmol) was added at 0° C. After stirring at 20° C. for 16 h, the reaction mixture was purified by prep-HPLC and SFC to give Example 5 (13.4 mg, faster eluting) as a white solid and Example 6 (9.9 mg, slower eluting) as a white solid.

[0144] Example 5: MS calculated 840.4 (MH + ), measured value 840.1 (MH + ). 1H NMR(400MHz,CHLOROFORM-d)δ=8.63(d,J=7.3Hz,1H), 8.49(d,J=2.8Hz,1H), 7.59(d,J=2.0Hz,1H), 7.12-7.07(m,2H), 6.88(br d,J=8.4Hz,1H), 5.92(t,J=8.9Hz,1H), 4.60(br dd,J=2.4,12.5Hz,1H), 4.30-4.19(m,3H), 4.08-3.99(m,2H), 3.85(br d,J=11.1Hz,1H), 3.74-3.70(m,1H), 3.49(br d,J=3.4Hz,4H), 3.36(s,3H), 3.20-3.13(m,2H), 2.76-2.68(m,4H), 2.63(s,1H), 2.46(br d,J=14.2Hz,1H),2.25-2.20(m,2H),2.01(s,1H),1.95-1.90(m,2H),1.58(td,J=5.0,9.8Hz,2 H), 1.47-1.42(m,5H), 1.30-1.22(m,4H), 0.97(t,J=7.1Hz,3H), 0.91(s,2H), 0.47(s,3H)ppm.

[0145] Example 6: MS calculated value 840.4 (MH + ), measured value 840.1 (MH + ). 1H NMR(400MHz,CHLOROFORM-d)δ=8.64(d,J=7.6Hz,1H), 8.51(d,J=2.9Hz,1H), 7.63(d,J=2.2Hz,1H), 7.13-7.07(m,2H), 6.88(d,J=9.5Hz,1H) ), 5.95(t,J=8.9Hz,1H), 4.65-4.57(m,1H), 4.32-4.21(m,3H), 4.12-3.96(m,2H), 3.86(d,J=10.8Hz,1H), 3.75(d,J=11.1Hz,1H), 3.48(br d,J=14.7Hz,1H), 3.37(s,3H), 3.34-3.29(m,4H), 3.19(dd,J=8.8, 15.0Hz,1H), 3.05(br d,J=14.2Hz,1H), 2.76-2.62(m,5H), 2.52(br d,J=14.3Hz,1H), 2.41(s,3H), 2.27-2.19(m,2H), 2.04-2.00(m,2H), 1.48-1.43 (m,4H), 1.32-1.23(m,2H), 1.00(t,J=7.1Hz,3H), 0.92(s,4H), 0.49(s,3H)ppm.

[0146] Example 7 (1S,2S)-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-2-methyl-cyclopropanecarboxamide TIFF2025525315000040.tif71170

[0147] The title compound was prepared in a manner similar to that prepared in Example 1 from (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (intermediate D), instead of (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ] was prepared by using octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate F). Example 7 (12.5 mg) was obtained as a yellow solid. MS calculated 897.4 (MH + ), measured value 897.6 (MH + ). 1H NMR (400MHz, methanol-d4) δ=8.68(d,J=7.6Hz,1H), 8.38(d,J=2.8Hz,1H), 7.78(d ,J=2.4Hz,1H), 7.65(d,J=2.4Hz,1H), 7.35(d,J=12.8Hz,1H), 5.81(d,J=8.8Hz ,1H), 4.48-4.40(m,1H), 4.38-4.31(m,1H), 4.30-4.19(m,1H), 4.16-4.01(m,2 H), 3.81-3.68(m,2H), 3.49-3.44(m,4H), 3.43-3.40(m,1H), 3.37(s,3H), 3.21 -3.12(m,3H), 3.04-3.95(m,1H), 2.92-2.86(m,4H), 2.81-2.70(m,2H), 2.21-2 .11(m,1H), 1.99-1.89(m,1H), 1.84-1.70(m,1H), 1.67-1.57(m,1H), 1.51-1.4 6(m,1H), 1.44(d,J=6.4Hz,3H), 1.25-1.19(m,1H), 1.15-1.10(m,3H), 1.09-1. 05(m,1H), 1.04-1.00(m,3H), 0.94(s,3H), 0.66-0.61(m,1H), 0.59(s,3H)ppm.

[0148] Example 8 (1S,2S)-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-2-methyl-cyclopropanecarboxamide TIFF2025525315000041.tif62170

[0149] The title compound was prepared in a manner similar to that prepared in Example 1 from (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (intermediate D), instead of (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo-[17.5.2.1 2,5 .1 9,13 .0 22,26 ] was prepared by using octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate G). Example 8 (135.4 mg) was obtained as a pale yellow solid. MS calculated 816.4 (MH + ), measured value 816.1 (MH + ). 1H NMR (400MHz, methanol-d4) δ=8.70(d,J=7.5Hz,1H), 8.37(d,J=2.7Hz,1H), 7.95(br s,1H), 7.65(d,J=2.3Hz,1H), 7.37(d,J=12.6Hz,1H), 5.82(br d,J=8.9Hz,1H), 4.47-4.38(m,2H), 4.31-4.23(m,1H), 4.15-4.10(m,1H), 4.05-3.98(m,1H), 3.88(br t,J=4.7Hz,4H), 3.79(br d,J=11.0Hz,1H), 3.71(d,J=10.6Hz,1H), 3.47-3.38(m,10H), 3.00(br d,J=15.0Hz,1H), 2.84-2.72(m,2H), 2.19-2.12(m,1H), 1.97-1.90(m,1H), 1.64(br d,J=2.7Hz,1H), 1.50-1.45(m,4H), 1.23(br dd,J=4.2, 9.5Hz,2H), 1.12(d,J=5.9Hz,3H), 1.05(q,J=6.8Hz,4H), 0.96(s,3H), 0.62(s,3H)ppm.

[0150] Example 9 (1S,2S)-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-2-methyl-cyclopropanecarboxamide TIFF2025525315000042.tif74170

[0151] The title compound was prepared in a manner similar to that prepared in Example 1 from (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (intermediate D), instead of (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ] was prepared by using octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate E). Example 9 (27.7 mg) was obtained as an off-white solid. MS calculated 951.4 (MH + ), measured value 951.2 (MH + ). 1H NMR (400MHz, methanol-d4) δ=8.69(d,J=7.6Hz,1H), 8.42(d,J=2.8Hz,1H), 7.69(d,J=2.4Hz,1H), 7.56-7.43(m,2H), 5.73(d,J=8.8Hz,1H), 5.24-5.08 (m,1H), 4.83-4.78(m,1H), 4.49-4.39(m,1H), 4.26-4.15(m,2H), 3.82-3 .65(m,2H), 3.48-3.38(m,5H), 3.36(s,3H), 3.30-3.25(m,1H), 3.20-3.09 (m,3H), 2.88(t,J=4.8Hz,4H), 2.84-2.75(m,1H), 2.67-2.59(m,1H), 2.2 6-2.15(m,1H), 1.99-1.91(m,1H), 1.87-1.74(m,1H), 1.70-1.56(m,1H), 1 .52-1.47(m,1H), 1.45(d,J=6.0Hz,3H), 1.28-1.19(m,1H), 1.15-1.10(m ,3H), 1.10-1.05(m,1H), 0.97(s,3H), 0.71-0.59(m,1H), 0.49(s,3H)ppm.

[0152] Example 10 (1S,2S)-N-[(7S,13S)-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-2-methyl-cyclopropanecarboxamide TIFF2025525315000043.tif69170

[0153] The title compound was prepared in a manner similar to that prepared in Example 1 from (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (intermediate D), instead of (7S,13S)-7-amino-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ] was prepared by using octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate H). Example 10 (11.2 mg) was obtained as a white solid. MS calculated 883.4 (MH + ), measured value 883.5 (MH + ). 1 H NMR (400MHz, methanol-d4) δ=8.50(d,J=2.8Hz,1H), 7.52-7.37(m,4H), 6.03 - 5.88(m,1H), 5.19-5.07(m,1H), 4.80-4.76(m,2H), 4.44-4.34(m,2H), 4.12-3.96(m,3H) ), 3.72-3.47(m,6H), 3.41-3.33(m,2H), 3.28-3.25(m,2H), 3.19-3.05(m,5H), 2.99(s,4 H), 2.59-2.52(m,1H), 1.66-1.53(m,1H), 1.44(d,J=6.0Hz,3H), 1.39-1.29(m,2H), 1.26 -1.17(m,2H), 1.10-1.05(m,3H), 1.05-1.01(m,1H), 0.80(s,3H), 0.65-0.52(m,3H)ppm.

[0154] Example 11 (1S,2S)-2-(Difluoromethyl)-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]cyclopropanecarboxamide TIFF2025525315000044.tif69170

[0155] The title compound was prepared in a manner similar to that prepared in Example 1 from (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (intermediate D) and (1S,2S)-2-methylcyclopropanecarboxylic acid (compound 1a), (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo-[17.5.2.1 2,5 .1 9,13 .0 22,26 ] was prepared by using octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate G) and (1S,2S)-2-(difluoromethyl)cyclopropanecarboxylic acid. Example 11 (33.2 mg) was obtained as a yellow solid. MS calculated 852.4 (MH+ ), measured value 852.2 (MH + ). 1 H NMR(400MHz,CHLOROFORM-d)δ=8.91(br s,1H), 8.66(d,J=7.6Hz,1H), 7.62(d,J=2.2Hz,1H), 7.41(s,1H), 7.13(s,1H), 7.10(s,1H), 6.75(br d,J=8.9Hz,1H), 5.99-5.93(m,1H), 5.83(d,J=3.1Hz,1H), 4.60(br d,J=11.9Hz,1H), 4.38(br d,J=6.4Hz,1H), 4.21(br d,J=9.2Hz,1H), 4.13-4.06(m,2H), 3.87(br d,J=11.4Hz,2H), 3.79-3.65(m,2H), 3.45(br d,J=15.2Hz,1H), 3.41(s,2H), 3.39-3.35(m,4H), 3.17(br dd,J=8.6, 15.0Hz,2H), 3.10(br d,J=11.6Hz,1H), 2.80-2.63(m,2H), 2.50(br d,J=13.9Hz,1H), 2.20(br d,J=10.9Hz,1H), 1.99(br d,J=17.9Hz,1H), 1.87-1.78(m,2H), 1.67-1.59(m,1H), 1.53(d,J=6.4Hz,3H), 1.33-1.21(m,3H), 1.18-1.12(m,1H), 1.01(br t,J=7.0Hz,3H), 0.94(s,3H), 0.53(s,3H)ppm.

[0156] Example 12 (1S,2S)-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-2-methyl-cyclopropanecarboxamide TIFF2025525315000045.tif66170

[0157] The title compound was prepared in a manner similar to that prepared in Example 1 from (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (intermediate D), instead of (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ] was prepared by using octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate I). Example 12 (150 mg) was obtained as a white solid. MS calculated 870.4 (MH + ), measured value 870.5 (MH + ). 1H NMR (400 MHz, methanol-d4) δ = 8.65-8.63 (d, J = 7.6 Hz, 1H), 8.41-8.40 (d, J = 2.8 Hz, 1H), 7.70-7.65 (d, J = 2.4 Hz, 1H), 7.50-7.40 (d, J = 12.4 Hz, 1H), 7.31-7.28 (d, J = 2.4 Hz, 1H), 5.76-5. 66(d,J=8.0Hz,1H), 5.18-5.05(m,1H), 4.96-4.88(m,1H), 4.47-4.39(m,1H), 4.23-4.10( m,2H), 3.90-3.83(t,J=4.8Hz,J=9.6Hz,4H), 3.80-3.75(d,J=10.8Hz,1H), 3.71-3.63(m, 1H), 3.49-3.42(m,1H), 3.30-3.29(m,3H), 3.28-3.21(m,4H), 3.14-3.07(d,J=14.4Hz,1H ), 2.86-2.77(m,1H), 2.63-2.55(d,J=14.4Hz,1H), 2.23-2.14(m,1H), 1.98-1.89(m,1H), 1.84-1.72(m,1H), 1.65-1.56(m,1H), 1.52-1.46(m,1H),1.45-1.40(d,J=6.4Hz,3H), 1.3 0-1.19(m,2H), 1.13-1.06(m,4H), 0.95(s,3H), 0.69-0.58(m,1H), 0.48-0.39(s,3H)ppm.

[0158] Biological Examples Compound A122 of WO2022060836 (Table 1a, page 70) is cited as a reference compound of the present invention. TIFF2025525315000046.tif91170

[0159] Example 13 Cell viability assay The purpose of this cell assay was to determine the effect of test compounds on the proliferation of human cancer cell lines NCI-H358 (ATCC-CRL5807), AGS (ATCC-CRL-1739), and SW620 (ATCC-CCL-227) over a 3-day treatment period by quantifying the amount of NADPH present at the endpoint using the Cell Counting Kit-8.

[0160] Cells were seeded into 96-well assay plates (Corning-3699) at 5,000 cells / well (NCI-H358), 2,000 cells / well (AGS), or 2,000 cells / well (SW620) and incubated overnight. Then, on the day of the assay, diluted compounds were added to a final concentration of 0.5% DMSO. After 72 hours of incubation, one-tenth the volume of Cell Counting Kit-8 (Dnjindo-CK04) was added to each well. After 2 hours of incubation, the signal (OD450 minus OD650) was read using EnVision. IC 50 was determined by fitting a four-parameter sigmoidal concentration-response model.

[0161] TIFF2025525315000047.tif146170

[0162] Example 14 Interaction assay between KRAS-BRAF and CYPA (500 nM) In this example, TR-FRET was also used to measure compound- or compound-CYPA-dependent disruption of the KRAS G12C-BRAF complex. This protocol was also used to measure disruption of KRAS G12D or KRAS G12V binding to BRAF by compounds of the present invention. Tagless CYPA, GMPPNP-loaded 6His-KRAS protein, and GST-BRAF were assayed in assay buffer containing 25 mM HEPES pH=7.4 (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, Thermo, 15630080), 0.002% Tween 20, 0.1% BSA, 100 mM NaCl, 5 mM MgCl2, and 10 μM GMPPNP (guanosine 5'-[β,γ-imido]triphosphate trisodium salt hydrate, Sigma, G0635). RBD The compounds were mixed in wells of a 384-well assay plate at final concentrations of 50 nM, 6.25 nM, and 1 nM, respectively. The compounds were present in the plate wells as a 16-point, 3-fold dilution series starting at a final concentration of 10 μM, and the mixture was incubated for 3 hours. A mixture of MAb anti-6His-XL665 (Cisbio, 61HISXLB) and MAb anti-GST-TB cryptate (Cisbio, 61GSTTLB) was then added at final concentrations of 6.67 nM and 0.21 nM, respectively, and the plate was incubated for an additional 1.5 hours. TR-FRET signals were read using a PHERstar FSX microplate reader (Ex 320 nm, Em 665 / 615 nm). Compounds that facilitate disruption of the KRAS-BRAF complex were identified as those that induce a decrease in the TR-FRET ratio compared to DMSO control wells.

[0163] TIFF2025525315000048.tif136170

[0164] Example 15 pERK inhibition assay This assay measures the ability of test compounds to inhibit ERK phosphorylation, downstream signaling of KRAS G12C in NCI-H358 cells, KRAS G12D in AGS cells, and KRAS G12V in SW620 cells. NCI-H358 (ATCC-CRL5807), AGS (ATCC-CRL-1739), and SW620 (ATCC-CCL-227) cells were all grown and maintained in RPMI-1640 medium (Thermo Fisher Scientific) containing 10% fetal bovine serum and 1% penicillin / streptomycin. The day before compound addition, cells were seeded into tissue-culture-treated 96-well plates (Corning-3699) at densities of 30,000, 20,000, and 30,000 cells / well for NCI-H358, AGS, and SW620, respectively, and allowed to attach overnight. The diluted compounds were then added to a final concentration of 0.5% DMSO. After 4 hours of incubation, the medium was removed, 100 μL of 4% formaldehyde was added, and the assay plate was incubated at room temperature for 20 minutes. The plate was then washed once with phosphate-buffered saline (PBS) and permeabilized with 100 μL of chilled methanol for 10 minutes. Nonspecific antibody binding to the plate was blocked with 50 μL of 1× BSA blocking buffer (Thermo-37520, diluted 10-fold with phosphate-buffered saline Tween (PBST)) for at least 1 hour at room temperature.

[0165] The amount of phosphorylated ERK was determined using an antibody specific for the phosphorylated form of ERK. The primary antibody (pERK, CST-4370, Cell Signaling Technology) was diluted 1:300 in blocking buffer, and 50 μL was aliquoted into each well and incubated overnight at 4°C. Cells were washed five times with PBST for 5 minutes. The secondary antibody (HRP-conjugated anti-rabbit IgG, CST-7074, Cell Signaling Technology) was diluted 1:1000 in blocking buffer, and 50 μL was added to each well and incubated for 1–2 hours at room temperature. Cells were washed five times with PBST for 5 minutes each, and 100 μL of TMB ELISA substrate (abcam-ab171523) was added and gently shaken for 20 minutes. 50 μL of stop solution (abcam-ab171529) was added, and the signal (OD450) was then read using EnVision. I C 50 was determined by fitting a four-parameter sigmoidal concentration-response model.

[0166] TIFF2025525315000049.tif146170

Claims

1. Formula (I) [In the formula, R １ is 3-oxabicyclo[3.1.0]hexanyl, C １－６ Alkyl C ３－７ Cycloalkyl, cyano C ３－７ Cycloalkyl or haloC １－６ Alkyl C ３－７ is cycloalkyl, R ２ is H or a halogen, R ３ is H or a halogen, R ４ is C １－６ Alkyl or haloC １－６ is alkyl, R ５ is C １－６ Alkoxy C １－６ is alkyl, R ６ is morpholinyl, (haloC １－６ alkyl)piperazinyl or C １－６ alkylpiperazinyl, A １ is thiazolylene, A ２ is C １－６ is alkylene, However, R ２ and R ３ and H cannot be H at the same time. or a pharmaceutically acceptable salt thereof.

2. Formula (Ia) [In the formula, R １ is 3-oxabicyclo[3.1.0]hexanyl, C １－６ Alkyl C ３－７ Cycloalkyl, cyano C ３－７ Cycloalkyl or haloC １－６ Alkyl C ３－７ is cycloalkyl, R ２ is H or a halogen, R ３ is H or a halogen, R ４ is C １－６ Alkyl or haloC １－６ is alkyl, R ５ is C １－６ Alkoxy C １－６ is alkyl, R ６ is morpholinyl, (haloC １－６ alkyl)piperazinyl or C １－６ alkylpiperazinyl, A １ is thiazolylene, A ２ is C １－６ is alkylene, However, R ２ and R ３ and H cannot be H at the same time. or a pharmaceutically acceptable salt thereof.

3. R １ But C １－６ Alkyl C ３－７ Cycloalkyl or haloC １－６ Alkyl C ３－７ 3. The compound of claim 1 or 2, which is cycloalkyl.

4. R １ The compound of any one of claims 1 to 3, wherein is methylcyclopropyl or (difluoromethyl)cyclopropyl.

5. R ２ 5. The compound of claim 1, wherein is H or fluoro.

6. R ３ 6. The compound of claim 1, wherein is H or fluoro.

7. R ４ The compound according to any one of claims 1 to 6, wherein is ethyl or 2,2,2-trifluoroethyl.

8. R ５ The compound of any one of claims 1 to 7, wherein is 1-methoxyethyl.

9. R ６ is morpholinyl or C １－６ 9. The compound of any one of claims 1 to 8, which is alkylpiperazinyl.

10. R ６ The compound of any one of claims 1 to 9, wherein is morpholinyl or 4-methylpiperazin-1-yl.

11. A １ but and bond "a" is attached to the indole ring.

12. A ２ 12. The compound of claim 1, wherein is dimethylmethylene.

13. R １ But C １－６ Alkyl C ３－７ Cycloalkyl or haloC １－６ Alkyl C ３－７ is cycloalkyl, R ２ is H or a halogen; R ３ is H or a halogen; R ４ But C １－６ Alkyl or haloC １－６ is alkyl, R ５ But C １－６ Alkoxy C １－６ is alkyl, R ６ is morpholinyl or C １－６ alkylpiperazinyl, A １ but, and bond "a" is attached to the indole ring; A ２ But C １－６ is alkylene, However, R ２ and R ３ and H cannot be at the same time, 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

14. R １ is 2-methylcyclopropyl or 2-(difluoromethyl)cyclopropyl, R ２ is H or fluoro; R ３ is H or fluoro; R ４ is ethyl or 2,2,2-trifluoroethyl, R ５ is (1S)-1-methoxyethyl, R ６ is morpholinyl or 4-methylpiperazin-1-yl, A １ but, and bond "a" is attached to the indole ring; A ２ is dimethylmethylene, However, R ２ and R ３ and H cannot be at the same time, 14. The compound of claim 13 or a pharmaceutically acceptable salt thereof.

15. (1S,2S)-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ .1 ９，１３ .0 ２２，２６ ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-2-methyl-cyclopropanecarboxamide; (1R,5S)-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ .1 ９，１３ .0 ２２，２６ ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-oxabicyclo[3.1.0]hexane-6-carboxamide; (1S,2S)-2-(Difluoromethyl)-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ .1 ９，１３ .0 ２２，２６ ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]cyclopropanecarboxamide; (1S,2S)-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ .1 ９，１３ .0 ２２，２６ ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-2-methyl-cyclopropanecarboxamide; (1S,2S)-2-cyano-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ .1 ９，１３ .0 ２２，２６ ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]cyclopropanecarboxamide; (1R,2R)-2-cyano-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ .1 ９，１３ .0 ２２，２６ ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]cyclopropanecarboxamide; (1S,2S)-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ .1 ９，１３ .0 ２２，２６ ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-2-methyl-cyclopropanecarboxamide; (1S,2S)-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ .1 ９，１３ .0 ２２，２６ ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-2-methyl-cyclopropanecarboxamide; (1S,2S)-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ .1 ９，１３ .0 ２２，２６ ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-2-methyl-cyclopropanecarboxamide; (1S,2S)-N-[(7S,13S)-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ .1 ９，１３ .0 ２２，２６ ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-2-methyl-cyclopropanecarboxamide; (1S,2S)-2-(Difluoromethyl)-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ .1 ９，１３ .0 ２２，２６ ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]cyclopropanecarboxamide; and (1S,2S)-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ .1 ９，１３ .0 ２２，２６ ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-2-methyl-cyclopropanecarboxamide; or a pharmaceutically acceptable salt thereof.

16. The following steps: a) reacting a compound of formula (II) with a compound of formula (II) in the presence of a coupling reagent and a base to form a compound of formula (I) (II) and acid (III) (III) Including, In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , A １ and A ２ is as claimed in any one of claims 1 to 14, The coupling reagent is T ３ P, HATU, PyBOP or EDCI / HOBt, and the base is TEA, DIEPA or DMAP; 16. A process for preparing a compound according to any one of claims 1 to 15.

17. 16. A compound or a pharmaceutically acceptable salt according to any one of claims 1 to 15 for use as a therapeutically active substance.

18. 16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 and a pharmaceutically acceptable excipient.

19. 20. Use of a compound according to any one of claims 1 to 15 for treating a KRAS G12C protein-associated disease.

20. 20. Use of a compound according to any one of claims 1 to 15 for treating KRAS G12C, G12D and G12V protein-associated diseases.

21. 20. Use of a compound according to any one of claims 1 to 15 to inhibit the interaction of RAS with downstream effectors, wherein the downstream effectors are RAF and PI3K.

22. 20. Use of a compound according to any one of claims 1 to 15 for inhibiting proliferating oncogene MAPK and PI3K signalling.

23. 20. Use of a compound according to any one of claims 1 to 15 for the treatment or prevention of KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic cancer, colorectal cancer, lung cancer, esophageal cancer, gallbladder cancer, melanoma, ovarian cancer and endometrial cancer.

24. 20. Use of a compound according to any one of claims 1 to 15 for the treatment or prevention of KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer and non-small cell lung cancer.

25. 16. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 15 for the treatment or prevention of KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer and non-small cell lung cancer.

26. Use of a compound described in any one of claims 1 to 15 for the preparation of a medicament for the treatment or prevention of KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer and non-small cell lung cancer.

27. A method for the treatment or prevention of KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer, comprising administering a therapeutically effective amount of a compound described in any one of claims 1 to 15.

28. 17. A compound or pharmaceutically acceptable salt of any one of claims 1 to 15 when prepared according to the method of claim 16.

29. The invention described above.

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