Macrocyclic compounds for the treatment of cancer

Abstract

The present invention relates to a compound represented by formula (I), TIFF2025525565000091.tif73170 (in the formula, R 1 ~R 7 , A 1 and A 2 is as described herein) and pharmaceutically acceptable salts thereof, as well as compositions comprising and methods of using said compounds.

Description

[Technical Field]

[0001] The present invention relates to organic compounds useful for therapy and / or prophylaxis in mammals, particularly inhibitors of KRAS mutants, which are 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 generally associated with poor prognosis, particularly in colorectal, pancreatic, and lung cancers. As the most frequently mutated RAS isoform, KRAS has been intensively studied over 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 represent 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 hydrolyzes GTP to GDP. KRAS is structurally 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 RAF in the mitogen-activated protein kinase (MAPK) pathway or PI3K in the 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 are involved in catalyzing the exchange of GDP for GTP, enhancing intrinsic GTPase activity, or promoting RAS-mediated GTP hydrolysis. In response to extracellular stimuli, the inactive RAS-GDP binds to the RAF RAS-binding domain (RAF RBD ), which directly binds to activated RAS-GTP, recruiting the RAF kinase family from the cytoplasm to the membrane, where they dimerize and become active. Activated RAF then propagates growth signals through a series of phosphorylation reactions on its downstream mitogen-activated protein kinases (MEKs) and extracellular signal-regulated kinases (ERKs). 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 possess a conserved RBD for forward transduction of MAPK signaling, which is frequently used to characterize KRAS inhibition (e.g., the KRAS-BRAF complex described herein). RBD In the case of KRAS, mutations at positions 12, 13, 61, and 146 result in a shift to an active KRAS form by impairing nucleotide hydrolysis or activating nucleotide exchange, resulting in overactivation of the MAPK pathway, leading 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, when the first-line drug AMG510 was rapidly approved as a second-line treatment for KRAS G12C-driven non-small cell lung cancer (NSCLC). Nevertheless, clinically acquired resistance to KRAS G12C inhibitors emerges rigorously with disease progression after approximately 6 months of treatment. Secondary RAS mutations at oncogene hotspots (e.g., G12 / G13 / Q61) and within the switch II pocket (e.g., H95, R68, and Y96) have been observed, all of which converge to reactivate RAS-MAPK signaling. Furthermore, over 85% of all KRAS mutant or wild-type amplification-driven cancers still lack novel therapeutics. Collectively, both the myriad escape mechanisms and the variety of oncogene alleles highlight the urgent medical need for additional KRAS treatments. Thus, the inventors have invented oral compounds that target and inhibit KRAS alleles for the treatment of KRAS mutant-driven cancers.

[0006] First-generation KRAS G12C inhibitors, such as sotrosib and adagrasib, which target the "GDP-bound" form (RASOFF) of the KRAS G12C mutation, have demonstrated promising efficacy. Although this treatment has benefited many patients with activating KRAS mutations, nearly all patients who initially benefit eventually develop resistance through various mechanisms. Increasing cases of KRAS G12C second mutations have been identified in patient samples, such as Y96D, R68S, H95D, H95Q, H95R, and V8L (Tanaka et al., Cancer Discovery (2021), Awad et al., NEJM (2021), Ho et al., EJC (2021), Zhao et al., Nature (2021), Tsai et al., JCI (2022)), or discovered through saturation mutagenesis (Siyu et al., PNAS (2022)) and ENU mutagenesis (Takamasa et al., J Thorac Oncol (2021)) that showed resistance to KRAS(OFF) G12C inhibitors. Thus, there is an unmet need to prevent the acquisition of one or more mutations in RAS that confer resistance to RAS(OFF) inhibitors. Summary of the Invention

[0007] The present invention relates to a compound represented by formula (I), TIFF2025525565000002.tif73170 (in the formula, R 1 teeth, TIFF2025525565000003.tif26170, 3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[5,1-c][1,4]oxazinyl or (C 1~6 alkyl)oxoimidazolidinyl, R 8 is C 1~6 is alkyl, R 9 is ((C 1~6 Alkyl)2amino)azetidinyl, C 1~6 Alkylpiperazinyl, Haloazetidinyl, Halo C 1~6 Alkylamino, HaloC1~6 Alkylaminoazetidinyl, HaloC 1~6 Alkylpiperazinyl, hydroxy(C 1~6 alkyl)piperidinyl or morpholinyl; R 2 is C 1~6 is alkyl, R 3 is H or a halogen, R 4 is H or a halogen, R 5 is C 1~6 Alkyl or haloC 1~6 is alkyl, R 6 is C 1~6 Alkoxy C 1~6 is alkyl, R 7 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 3 and R 4 is not H at the same time) or a pharmaceutically acceptable salt thereof.

[0008] The present invention also relates to their manufacture, to medicinal products based on the compounds according to the invention and their production, and to the use of those compounds of formula (I) or (Ia) as inhibitors of KRAS.

[0009] The compound of formula (I) or (Ia) exhibits good KRAS inhibition against G12C, G12D and G12V. In another embodiment, the compound of the present invention exhibits good cancer cell inhibition and human hepatocyte stability. Furthermore, the compound of formula (I) or (Ia) also exhibits good or improved cytotoxicity and solubility profile. Furthermore, the compound of the present invention has excellent pharmacokinetic properties compared with reference compounds. [Brief explanation of the drawings]

[0010] [Figure 1] X-ray crystallographic analysis of compound G5. DETAILED DESCRIPTION OF THE INVENTION

[0011] 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, tert-butyl, etc. 1~6 "Alkyl" groups are methyl, ethyl, and n-propyl.

[0012] "C 1~6 The term "alkoxy" refers to C 1~6 It represents alkyl-O-.

[0013] "C 1~6 The term "alkylene" refers to a linear or branched saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a bi-branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms. 1~6 Examples of alkylene groups include methylene, ethylene, propylene, 2-methylpropylene, butylene, 2-ethylbutylene, pentylene, and hexylene.

[0014] The terms "halogen" and "halo" are used interchangeably herein to refer to fluoro, chloro, bromo, or iodo.

[0015] "Haro C1~6 The term "alkyl" refers to 1~6 C in which at least one hydrogen atom of the alkyl group is replaced by the same or different halogen atom, in particular a fluoro atom 1~6 represents 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, fluoroethyl, or trifluoromethyl.

[0016] "C 3~7 The term "cycloalkyl" means a monovalent saturated monocyclic or bicyclic hydrocarbon radical containing 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 cycloalkyls are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Examples of bicyclic cycloalkyls are bicyclo[1.1.0]butyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, or bicyclo[2.2.2]octanyl.

[0017] "Thiazolylene" refers to a divalent thiazolyl group.

[0018] The term "oxo" refers to a divalent oxygen atom =O.

[0019] The term "oxoimidazolidinyl" means means TIFF2025525565000004.tif22170.

[0020] The term "haloazetidinyl" refers to an azetidinyl group in which at least one of the hydrogen atoms of the azetidinyl group has been replaced by the same or different halogen atom, in particular a fluoro atom. Haloazetidinyl includes fluoroazetidinyl and difluoroazetidinyl.

[0021] The term "dimethylmethylene" Represents TIFF2025525565000005.tif16170.

[0022] The term "protecting group" refers to 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.

[0023] Those skilled in the art will recognize that the following structures of compounds of formula (Ia) and (Ia') are equivalent, particularly with respect to the chiral centers. TIFF2025525565000006.tif124170

[0024] 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.

[0025] The term "pharmaceutically acceptable acid addition salt" means a pharmaceutically acceptable salt such as 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.

[0026] 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 salts, potassium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines, including natural 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.

[0027] The term "pharmaceutically active metabolite" refers to a pharmacologically active product produced by metabolism in the body of a particular compound or its salt. After entering the body, most drugs become substrates for chemical reactions that can change their physical properties and biological effects. These metabolic transformations usually affect the polarity of the compounds of the present invention and alter how the drug is distributed in and excreted from the body. However, in some cases, drug metabolism is required for therapeutic effect.

[0028] 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.

[0029] The term "pharmaceutical composition" refers to a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable excipients, for administration to a mammal, e.g., a human in need thereof.

[0030] The terms "pharmaceutically acceptable excipient," "pharmaceutically acceptable carrier," and "therapeutically inactive excipient" are used interchangeably and refer to any pharmaceutically acceptable ingredient in a pharmaceutical composition used in the formulation of a medicament, 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.

[0031] KRAS inhibitors The present invention relates to a compound represented by the formula (I): TIFF2025525565000007.tif73170 (in the formula, R 1 teeth, TIFF2025525565000008.tif26170, 3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[5,1-c][1,4]oxazinyl or (C 1~6 alkyl)oxoimidazolidinyl, R 8 is C 1~6 is alkyl, R 9 is ((C 1~6 Alkyl)2amino)azetidinyl, C 1~6 Alkylpiperazinyl, Haloazetidinyl, Halo C 1~6 Alkylamino, HaloC 1~6 Alkylaminoazetidinyl, HaloC 1~6 Alkylpiperazinyl, hydroxy(C 1~6 alkyl)piperidinyl or morpholinyl; R 2 is C 1~6 is alkyl, R 3is H or a halogen, R 4 is H or a halogen, R 5 is C 1~6 Alkyl or haloC 1~6 is alkyl, R 6 is C 1~6 Alkoxy C 1~6 is alkyl, R 7 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 3 and R 4 is not H at the same time) or a pharmaceutically acceptable salt thereof.

[0032] Another embodiment of the present invention is (ii) a compound of formula (Ia) TIFF2025525565000009.tif73170 (in the formula, R 1 teeth, TIFF2025525565000010.tif26170, 3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[5,1-c][1,4]oxazinyl or (C 1~6 alkyl)oxoimidazolidinyl, R 8 is C 1~6 is alkyl, R 9 is ((C 1~6 Alkyl)2amino)azetidinyl, C 1~6 Alkylpiperazinyl, Haloazetidinyl, Halo C 1~6 Alkylamino, HaloC 1~6 Alkylaminoazetidinyl, HaloC 1~6 Alkylpiperazinyl, hydroxy(C 1~6alkyl)piperidinyl or morpholinyl; R 2 is C 1~6 is alkyl, R 3 is H or a halogen, R 4 is H or a halogen, R 5 is C 1~6 Alkyl or haloC 1~6 is alkyl, R 6 is C 1~6 Alkoxy C 1~6 is alkyl, R 7 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 3 and R 4 is not H at the same time) or a pharmaceutically acceptable salt thereof.

[0033] A further embodiment of the present invention is (iii) a compound of formula (I) or (Ia) according to (i) or (ii), or a pharmaceutically acceptable salt thereof, wherein R 1 teeth, TIFF2025525565000011.tif26170, R 8 is C 1~6 alkyl, and R 9 is C 1~6 Alkylpiperazinyl, HaloC 1~6 It is alkylpiperazinyl or morpholinyl.

[0034] A further embodiment of the present invention is (iv) a compound of formula (I) or (Ia) according to any one of (i) to (iii), or a pharmaceutically acceptable salt thereof, wherein R 1 teeth TIFF2025525565000012.tif26170, R 8 is methyl and R 9 is 4-methylpiperazin-1-yl, 4-(2,2,2-trifluoroethyl)piperazin-1-yl or morpholinyl.

[0035] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to any one of (v)(i) to (iv), wherein R 1 is methyl-(4-methylpiperazine-1-carbonyl)amino, methyl-[4-(2,2,2-trifluoroethyl)piperazine-1-carbonyl]amino or methyl(morpholine-4-carbonyl)amino.

[0036] A further embodiment of the present invention is (vi) a compound of formula (I) or (Ia) according to any one of (i) to (v), or a pharmaceutically acceptable salt thereof, wherein R 2 is isopropyl.

[0037] A further embodiment of the present invention is (vii) a compound of formula (I) or (Ia) according to any one of (i) to (vi) or a pharmaceutically acceptable salt thereof, wherein R 3 is H or fluoro.

[0038] A further embodiment of the present invention is (viii) a compound of formula (I) or (Ia) according to any one of (i) to (vii) or a pharmaceutically acceptable salt thereof, wherein R 3 is fluoro.

[0039] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to any one of (ix)(i) to (viii) or a pharmaceutically acceptable salt thereof, wherein R 4 is H or fluoro.

[0040] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to any one of (x)(i) to (ix), or a pharmaceutically acceptable salt thereof, wherein R 4 is H.

[0041] A further embodiment of the present invention is (xi) a compound of formula (I) or (Ia) according to any one of (i) to (x), or a pharmaceutically acceptable salt thereof, wherein R 5 Halo C 1~6 It is alkyl.

[0042] A further embodiment of the present invention is (xii) a compound of formula (I) or (Ia) according to any one of (i) to (xi), or a pharmaceutically acceptable salt thereof, wherein R 5 is 2,2,2-trifluoroethyl.

[0043] A further embodiment of the present invention is (xiii) a compound of formula (I) or (Ia) according to any one of (i) to (xii), or a pharmaceutically acceptable salt thereof, wherein R 6 is 1-methoxyethyl.

[0044] A further embodiment of the present invention is (xiv) a compound of formula (I) or (Ia) according to any one of (i) to (xiii), or a pharmaceutically acceptable salt thereof, wherein R 7 Ha (Haro C 1~6 alkyl)piperazinyl.

[0045] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to any one of (xv)(i) to (xiv), or a pharmaceutically acceptable salt thereof, wherein R 7 is 4-(2,2,2-trifluoroethyl)piperazin-1-yl

[0046] A further embodiment of the present invention is a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (xvi)(i) to (xv), wherein A 1 teeth TIFF2025525565000013.tif20170, and bond "a" connects to the indole ring.

[0047] A further embodiment of the present invention is a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (xvii)(i) to (xvi), wherein A 2 is dimethylmethylene.

[0048] Another embodiment of the present invention is a compound of formula (I) or (Ia) according to (xviii)(i) or (ii), During the ceremony, R 1 but, TIFF2025525565000014.tif26170, R 8 But C 1~6 alkyl, and R 9 But C 1~6 Alkylpiperazinyl, HaloC 1~6 alkylpiperazinyl or morpholinyl, R 2 But C 1~6 is alkyl, R 3 is a halogen, R 4 is H, R 5 But, Haro C 1~6 is alkyl, R 6 But C 1~6 Alkoxy C 1~6 is alkyl, R 7 However, (Haro C 1~6 alkyl)piperazinyl, A 1 but TIFF2025525565000015.tif20170, wherein bond "a" connects to the indole ring; A 2 But C 1~6 is alkylene, The compound is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0049] Another embodiment of the present invention is a compound of formula (I) or (Ia) according to (xix)(xviii), During the ceremony, R 1 is methyl-(4-methylpiperazine-1-carbonyl)amino, methyl-[4-(2,2,2-trifluoroethyl)piperazine-1-carbonyl]amino or methyl(morpholine-4-carbonyl)amino; R 2 is isopropyl, R 3 But it is fluoro, R 4 is H, R 5 is 2,2,2-trifluoroethyl, R 6 is (1S)-1-methoxyethyl, R 7 is 4-(2,2,2-trifluoroethyl)piperazin-1-yl, A 1 but TIFF2025525565000016.tif20170, wherein bond "a" connects to the indole ring; A 2 is dimethylmethylene, The compound is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0050] The present invention relates to a compound of formula (i') (I): TIFF2025525565000017.tif73170 (in the formula, R 1 teeth, TIFF2025525565000018.tif26170 or (C 1~6 alkyl)oxoimidazolidinyl, R 8 is C 1~6 is alkyl, R 9 is ((C 1~6alkyl)2amino)azetidinyl, haloazetidinyl or morpholinyl; R 2 is C 1~6 is alkyl, R 3 is H or a halogen, R 4 is H or a halogen, R 5 is C 1~6 Alkyl or haloC 1~6 is alkyl, R 6 is C 1~6 Alkoxy C 1~6 is alkyl, R 7 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 3 and R 4 is not H at the same time) or a pharmaceutically acceptable salt thereof.

[0051] Another embodiment of the present invention is (ii') a compound represented by formula (Ia): TIFF2025525565000019.tif73170 (in the formula, R 1 teeth, TIFF2025525565000020.tif26170 or (C 1~6 alkyl)oxoimidazolidinyl, R 8 is C 1~6 is alkyl, R 9 is ((C 1~6 alkyl)2amino)azetidinyl, haloazetidinyl or morpholinyl; R 2 is C 1~6 is alkyl, R 3 is H or a halogen, R 4 is H or a halogen, R 5 is C 1~6 Alkyl or haloC 1~6 is alkyl, R 6 is C 1~6 Alkoxy C 1~6 is alkyl, R 7 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 3 and R 4 is not H at the same time) or a pharmaceutically acceptable salt thereof.

[0052] A further embodiment of the present invention is (iii') a compound of formula (I) or (Ia) according to (i') or (ii'), or a pharmaceutically acceptable salt thereof, wherein R 1 teeth TIFF2025525565000021.tif26170, R 8 is C 1~6 alkyl, and R 9 is haloazetidinyl or morpholinyl.

[0053] A further embodiment of the present invention is (iv') a compound of formula (I) or (Ia) according to any one of (i') to (iii'), or a pharmaceutically acceptable salt thereof, wherein R 1 teeth TIFF2025525565000022.tif26170, R 8 is methyl and R 9 is 3,3-difluoroazetidin-1-yl or morpholinyl.

[0054] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to any one of (v')(i') to (iv'), wherein R 1 is (3,3-difluoroazetidine-1-carbonyl)-methyl-amino or methyl(morpholine-4-carbonyl)amino.

[0055] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to any one of (i) to (v), or a pharmaceutically acceptable salt thereof, wherein R 2 is isopropyl.

[0056] A further embodiment of the present invention is (vii') a compound of formula (I) or (Ia) according to any one of (i') to (vi') or a pharmaceutically acceptable salt thereof, wherein R 3 is H or fluoro.

[0057] A further embodiment of the present invention is (viii') a compound of formula (I) or (Ia) according to any one of (i') to (vii') or a pharmaceutically acceptable salt thereof, wherein R 3 is fluoro.

[0058] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to any one of (ix')(i') to (viii') or a pharmaceutically acceptable salt thereof, wherein R 4 is H or fluoro.

[0059] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to any one of (x')(i') to (ix'), or a pharmaceutically acceptable salt thereof, wherein R 4 is H.

[0060] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to any one of (xi') (i') to (x'), or a pharmaceutically acceptable salt thereof, wherein R 5 is ethyl or 2,2,2-trifluoroethyl.

[0061] A further embodiment of the present invention is (xii') a compound of formula (I) or (Ia) according to any one of (i') to (xi'), or a pharmaceutically acceptable salt thereof, wherein R 6 is 1-methoxyethyl.

[0062] A further embodiment of the present invention is (xiii') a compound of formula (I) or (Ia) according to any one of (i') to (xii'), or a pharmaceutically acceptable salt thereof, wherein R 7 is 4-(2,2,2-trifluoroethyl)piperazin-1-yl or morpholinyl.

[0063] A further embodiment of the present invention is a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (xiv')(i') to (xiii'), wherein A 1 teeth TIFF2025525565000023.tif20170, and bond "a" connects to the indole ring.

[0064] A further embodiment of the present invention is a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (xv')(i') to (xiv'), wherein A 2 is dimethylmethylene.

[0065] Another embodiment of the present invention is a compound of formula (I) or (Ia) according to (xvi') (i') or (ii'), During the ceremony, R 1 but, TIFF2025525565000024.tif26170, R 8 But C1~6 alkyl, and R 9 is haloazetidinyl or morpholinyl; R 2 But C 1~6 is alkyl, R 3 is a halogen, R 4 is H, R 5 But C 1~6 Alkyl or haloC 1~6 is alkyl, R 6 But C 1~6 Alkoxy C 1~6 is alkyl, R 7 morpholinyl or (haloC 1~6 alkyl)piperazinyl, A 1 but TIFF2025525565000025.tif20170, wherein bond "a" connects to the indole ring; A 2 But C 1~6 is alkylene, The compound is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0066] Another embodiment of the present invention is a compound of formula (I) or (Ia) according to (xvii')(xvi'), During the ceremony, R 1 is (3,3-difluoroazetidine-1-carbonyl)-methyl-amino or methyl(morpholine-4-carbonyl)amino, R 2 is isopropyl, R 3 But it is fluoro, R 4 is H, R 5 is ethyl or 2,2,2-trifluoroethyl, R 6 is (1S)-1-methoxyethyl, R7 is 4-(2,2,2-trifluoroethyl)piperazin-1-yl or morpholinyl; A 1 but TIFF2025525565000026.tif20170, wherein bond "a" connects to the indole ring; A 2 is dimethylmethylene, The compound is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0067] Another embodiment of the present invention is (xx) a compound of formula (I) or (Ia) selected from: 3-(Dimethylamino)-N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N-methyl-azetidine-1-carboxamide; 3-(Dimethylamino)-N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N-methyl-azetidine-1-carboxamide; N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N-methyl-morpholine-4-carboxamide; 3-(Dimethylamino)-N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N-methyl-azetidine-1-carboxamide; N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N-methyl-morpholine-4-carboxamide; N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N-methyl-morpholine-4-carboxamide; N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-3,3-difluoro-N-methyl-azetidine-1-carboxamide; (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]-3-methyl-2-(3-methyl-2-oxo-imidazolidin-1-yl)butanamide; N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N-methyl-morpholine-4-carboxamide; N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N-methyl-morpholine-4-carboxamide; N-[(1S)-1-[[(7S,13S)-24-fluoro-20-(20M)-[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]carbamoyl]-2-methyl-propyl]-N-methyl-morpholine-4-carboxamide; 3-(Dimethylamino)-N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N-methyl-azetidine-1-carboxamide; (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]-3-methyl-2-[methyl(2,2,2-trifluoroethylcarbamoyl)amino]butanamide; N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N-methyl-3-(trifluoromethyl)azetidine-1-carboxamide; (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]-3-methyl-2-(3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[5,1-c][1,4]oxazin-2-yl)butanamide; (3R)-N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-3-hydroxy-N,3-dimethyl-piperidine-1-carboxamide; N-[(1S)-1-[[(7S,13S)-25-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]carbamoyl]-2-methyl-propyl]-N-methyl-morpholine-4-carboxamide; N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N,4-dimethyl-piperazine-1-carboxamide; and N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N-methyl-4-(2,2,2-trifluoroethyl)piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

[0068] Another embodiment of the present invention is (xxi) a process for the preparation of a compound according to any one of (i) to (xix) or (i') to (xvii'), 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), TIFF2025525565000027.tif57170 and acid (III), TIFF2025525565000028.tif27170, In the formula, R1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , A 1 and A 2 is defined as described in any one of (i) to (xix), wherein the coupling reagent is T3P, HATU, PyBOP, or EDCI / HOBt, and the base is TEA, DIEPA, or DMAP.

[0069] Another embodiment of the present invention is (xxii) a compound or a pharmaceutically acceptable salt according to any one of (i) to (xx) or (i') to (xvii') for use as a therapeutically active substance.

[0070] Another embodiment of the present invention is a pharmaceutical composition comprising a compound according to any one of (xxiii)(i)-(xx) or (i')-(xvii') and a pharmaceutically acceptable excipient.

[0071] Another embodiment of the present invention is (xxiv) the use of a compound according to any one of (i) to (xx) or (i') to (xvii') for treating a KRAS G12C protein-associated disease.

[0072] Another embodiment of the present invention is (xxv) the use of a compound according to any one of (i) to (xx) or (i') to (xvii') for treating a KRAS G12C, G12D and G12V protein-associated disease.

[0073] Another embodiment of the present invention is (xxvi) the use of a compound according to any one of (i) to (xx) or (i') to (xvii') for inhibiting RAS interaction with downstream effectors, wherein the downstream effectors are RAF and PI3K.

[0074] Another embodiment of the present invention is (xxvii) the use of a compound according to any one of (i) to (xx) or (i') to (xvii') for inhibiting propagated oncogenic MAPK and PI3K signaling.

[0075] Another embodiment of the present invention is (xxviii) the use of a compound according to any one of (i)-(xx) or (i')-(xvii') for treating or preventing a 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.

[0076] Another embodiment of the present invention is (xxix) the use of a compound according to any one of (i)-(xx) or (i')-(xvii') 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.

[0077] Another embodiment of the present invention is (xxx) a compound or pharmaceutically acceptable salt according to any one of (i) to (xx) or (i') to (xvii') 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.

[0078] Another embodiment of the present invention is (xxxi) a compound or pharmaceutically acceptable salt according to any one of (i) to (xx) or (i') to (xvii') for the treatment or prevention of a KRAS mutation-driven cancer, wherein the cancer comprises a first mutation that is G12C and a second mutation at a position selected from V8A, V9Y, S17E, T58I, A59T, S65W, R68S, D69P, M72I, D92R, H95N, Y96D, Q99F, Q99W, Y96H and F156L.

[0079] Another embodiment of the present invention is (xxxii) the use of a compound according to any one of (i) to (xx) or (i') to (xvii') for the preparation of a medicament 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.

[0080] Another embodiment of the present invention is (xxxiii) the use of a compound according to any one of (i) to (xx) or (i') to (xvii') for the preparation of a medicament for the treatment or prevention of a KRAS mutation-driven cancer, wherein the cancer comprises a first mutation that is G12C and a second mutation at a position selected from V8A, V9Y, S17E, T58I, A59T, S65W, R68S, D69P, M72I, D92R, H95N, Y96D, Q99F, Q99W, Y96H and F156L.

[0081] Another embodiment of the present invention is (xxxiv) a method of 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 (xx) or (i') to (xvii').

[0082] Another embodiment of the invention is (xxxv) a method of treating or preventing a KRAS mutation-driven cancer, wherein the cancer comprises a first mutation that is G12C and a second mutation at a position selected from V8A, V9Y, S17E, T58I, A59T, S65W, R68S, D69P, M72I, D92R, H95N, Y96D, Q99F, Q99W, Y96H and F156L.

[0083] Another embodiment of the present invention is a compound or pharmaceutically acceptable salt according to any one of (i)-(xx) or (i')-(xvii') when prepared according to the process of (xxxvi)(xxi).

[0084] 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 degree of purity with a physiologically acceptable carrier, i.e., a carrier that is nontoxic to recipients at the dosages and concentrations used. The pH of the formulation will depend primarily on the particular application and the concentration of the compound, but is preferably in the range of 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.

[0085] The composition is formulated, dosed and administered in a manner consistent with good medical practice.The factors to be considered in this regard include the specific disorder to be treated, the specific mammal to be treated, the clinical symptoms of individual patients, the cause of the disorder, the delivery site of the drug, the method of administration, the administration schedule and other factors known to medical professionals.The "effective amount" of the compound to be administered is governed by such considerations, and is the minimum amount required to inhibit the interaction between mutant RAS (for example, KRAS G12C) and RAF and block oncogenic MAPK signal transduction.For example, this amount may be below the amount that is toxic to normal cells or mammals as a whole.

[0086] In one example, a pharmaceutically effective amount of a compound of the invention administered parenterally per dose ranges from about 0.1 to 1000 mg / kg of patient body weight per day, alternatively about 0.1 to 1000 mg / kg of patient body weight per day, 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 from about 1 to about 1000 mg of a compound of the invention.

[0087] The compounds of the present invention can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural, and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0088] The compounds of the present invention may be administered in any convenient dosage form, such as tablets, powders, capsules, liquids, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain conventional ingredients in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and additional active agents.

[0089] Typical preparation is prepared by mixing the compound of the present invention with carrier or excipient.Suitable carrier and excipient 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, lubricating agents, emulsifying agents, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, flavors, flavorings, diluents, and other known additives to present the drug (i.e., a compound of the present invention or a pharmaceutical composition thereof) aesthetically or to aid in the manufacture of a pharmaceutical product (i.e., a drug product).

[0090] An example of a suitable oral dosage form is a tablet containing approximately 1-1000 mg of a compound of the present invention formulated with approximately 1-1000 mg of anhydrous lactose, approximately 1-1000 mg of croscarmellose sodium, approximately 1-1000 mg of polyvinylpyrrolidone (PVP) K30, and approximately 1-1000 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 tablets using conventional equipment. An example aerosol formulation can be prepared by dissolving, for example, 5-400 mg of a compound of the present invention in a suitable buffer solution, such as phosphate buffer, and adding, if desired, an isotonicity agent, such as a salt such as sodium chloride. The solution can be filtered, for example, using a 0.2 micron filter, to remove impurities and contaminants.

[0091] 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.

[0092] 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.

[0093] The following compositions A and B illustrate typical compositions of the present invention and serve merely as representative thereof.

[0094] Composition A The compounds of the present invention can be used as active ingredients in a manner known per se to produce tablets of the following composition: Per tablet Active ingredient 200mg Microcrystalline cellulose 155mg Cornstarch 25mg Talc 25mg Hydroxypropyl methylcellulose 20mg 425mg

[0095] Composition B

[0096] The compounds of the present invention can be used as an active ingredient in a manner known per se to produce capsules of the following composition: Per capsule Active ingredient 100.0mg Cornstarch 20.0mg Lactose 95.0mg Talc 4.5mg Magnesium stearate 0.5mg 220.0mg

[0097] Indications and Treatment Methods The compounds of the present invention induce a new 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 KRAS interaction with downstream effectors such as RAF and PI3K. Therefore, the compounds of the present invention are useful for inhibiting propagating oncogenic MAPK and PI3K signaling and reducing cell proliferation, particularly in cancer cells. The compounds of the present invention are useful for terminating RAS signaling in cells expressing RAS mutants, such as pancreatic cancer, colorectal cancer, lung cancer, esophageal cancer, gallbladder cancer, melanoma, ovarian cancer, and endometrial cancer, which are driven by KRAS mutations. Alternatively, the compounds of the present invention are useful for terminating 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, and are useful for targeted therapy in pancreatic adenocarcinoma, colorectal cancer, non-small cell lung cancer, and other cancers.

[0098] Another embodiment includes a method of treating or preventing cancer in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0099] 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 illustrated in the following schemes and examples. All substituents, particularly R 1 ~R 7 , A 1 and A 2 are as defined above unless otherwise specified. Further, unless otherwise specified, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to one skilled in the art of organic chemistry.

[0100] A general synthetic route for preparing compounds of formula (I) is shown below. Scheme 1 TIFF2025525565000029.tif53170 The compound of formula II was synthesized according to the procedure described in Intermediates A to J. The compound of formula (I) can be obtained by coupling reaction of the acid (III) with the compound of formula (II) with a coupling reagent such as T3P, HATU, PyBOP and EDCI / HOBt in the presence of a base such as TEA, DIEPA and DMAP.

[0101] The compounds of the present invention may be obtained as mixtures of diastereomers or enantiomers that 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.

[0102] The present invention also provides the following: a) reacting a compound of formula (II) with a compound of formula (I) in the presence of a coupling reagent and a base to form a compound of formula (I), TIFF2025525565000030.tif49170 compound and acid (III), TIFF2025525565000031.tif27170, a process for the preparation of a compound of formula (I) comprising the step of coupling reaction with In step a), the coupling reagent may be, for example, T3P, HATU, PyBOP or EDCI / HOBt, and the base may be, for example, TEA, DIEPA or DMAP.

[0103] Compounds of formula (I) or (Ia) when prepared according to the above process are also an object of the present invention. [Example]

[0104] 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.

[0105] 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.

[0106] The abbreviations used herein are as follows: ACN: acetonitrile aq.:Aqueous solution BOC-L-valine: (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid Boc-N-Me-Val-OH: N-(tert-butoxycarbonyl)-N-methyl-L-valine (Boc)2O: di-tert-butyl dicarbonate (R)-binap: (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl CDCl3: deuterated chloroform CDI: 1,1'-carbonyldiimidazole CD3OD: deuterated methanol COMU: (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate DIEPA: N,N-diethylpropylamine DIBAL-H: Diisobutylaluminum hydride DMAP: 4-dimethylaminopyridine DMF: dimethylformamide DMP: 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one DMSO: dimethyl sulfoxide EDCI: N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride EtOAc or EA: Ethyl acetate FRET: Fluorescence Resonance Energy Transfer HATU: (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) hr(s): hour(s) HPLC: High-performance liquid chromatography HOBt: N-hydroxybenzotriazole H-VAL-OTBU:HCl(S)-tert-butyl 2-amino-3-methylbutanoate hydrochloride [Ir(OMe)(COD)]2: (1,5-cyclooctadiene)(methoxy)iridium(I) dimer LDA: lithium diisopropylamide MS: (ESI): Mass spectrometry (electrospray ionization) min(s): Minute(s) MTBE: Methyl tert-butyl ether NMM: N-methylmorpholine NaBH(OAc)3: sodium triacetoxyborohydride NMR: nuclear magnetic resonance NMO: 4-methylmorpholine N-oxide obsd. measured value Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(dtbpf)Cl2: [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) prep-HPLC: preparative high-performance liquid chromatography PyBOP: Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate RT or rt: room temperature sat.: saturation SFC: Supercritical Fluid Chromatography TEA: Triethylamine TFA: Trifluoroacetic acid THF: tetrahydrofuran TEA: Trimethylamine TMEDA: Tetramethylethylenediamine TMSCF3: Trifluoromethyltrimethylsilane T3P: Propylphosphonic anhydride

[0107] 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. The silica gel brands and pore sizes were: 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, pore size: 200-300 or 300-400, manufactured by Qingdao Haiyang Chemical Co., Ltd.

[0108] Intermediates and final compounds were purified by preparative HPLC on reversed-phase columns using an XBridge™ Prep-C18 (5 μm, OBD™ 30 × 100 mm) column, a SunFire™ Prep-C18 (5 μm, OBD™ 30 × 100 mm) column, a Phenomenex Synergi-C18 (10 μm, 25 × 150 mm) column, or a Phenomenex Gemini-C18 (10 μm, 25 × 150 mm) column on a Waters AutoP Purification System (Sample Manager 2767, Pump 2525, Detectors: Micromass ZQ and UV2487, Solvent system: acetonitrile and 0.1% ammonium hydroxide in water; acetonitrile and 0.1% FA in water or acetonitrile and 0.1% TFA in water). or Gilson-281 purification system (pump 322, detector: UV156, solvent system: 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).

[0109] For SFC chiral separations, intermediates were separated by chiral columns (Daicel chiralpak IC, 5 μm, 30 × 250 mm), AS (10 μm, 30 × 250 mm), or AD (10 μm, 30 × 250 mm) on a Mettler Toledo Multigram III SFC system, a Waters 80Q preparative SFC, or a Thar 80 preparative SFC, using CO₂ and IPA (0.5% TEA in IPA) or CO₂ and MeOH (0.1% NH₃·H₂O in MeOH) as solvent systems, at 100 bar backpressure and detection at 254 or 220 nm.

[0110] LC / MS spectra of the compounds were obtained using an LC / MS (Waters™ Alliance 2795-Micromass ZQ, Shimadzu Alliance 2020-Micromass ZQ, or Agilent Alliance 6110-Micromass ZQ). The LC / MS conditions were as follows (run time 3 or 1.5 minutes): 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 condition II: A: 0.025% NH3·H2O in H2O, B: acetonitrile, Neutral conditions: A: H2O, B: Acetonitrile

[0111] Mass spectra (MS): Generally, only ions representing the parent mass are reported; unless otherwise stated, the mass ions quoted are positive mass ions (M−H). + is.

[0112] NMR spectra were obtained using a Bruker Avance 400 MHz or 500 MHz.

[0113] Microwave-assisted reactions were performed on a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were carried out under an argon or nitrogen atmosphere. Reagents were obtained commercially and used without further purification unless otherwise noted.

[0114] Preparation example The following examples are intended to illustrate the meaning of the present invention but do not in any way represent a limitation within the meaning of the present invention.

[0115] Preparation of intermediates Intermediate A 1-[6-[(1S)-1-Methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]-4-methyl-piperazine TIFF2025525565000032.tif51170 Title Intermediate A was prepared according to the following scheme. TIFF2025525565000033.tif109170

[0116] Step 1: Preparation of 3-bromo-2-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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 give 3-bromo-2-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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).

[0117] 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-dioxaborolan-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 under N protection for 40 h. 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 in vacuo. 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 + ).

[0118] 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 in vacuo. 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 + ).

[0119] Step 4: Preparation of 1-[6-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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 under N protection for 12 hours. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column to give 1-[6-[(1S)-1-methoxymethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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 + ).

[0120] Intermediate B Methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)-propanoyl]hexahydropyridazine-3-carboxylate TIFF2025525565000034.tif52170 Intermediate B was prepared according to the following scheme: TIFF2025525565000035.tif155170

[0121] 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 in vacuo to give (4-bromothiazol-2-yl)methanol (compound B2, 6 g) as a colorless oil.

[0122] 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 in vacuo. The residue was purified by silica gel column eluting with ethyl acetate in petroleum ether (0-10%) 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 + ).

[0123] 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 in vacuo. 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 + ).

[0124] 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 (6 x 80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo 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 + ).

[0125] 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 in vacuo. The residue was purified by 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 + ).

[0126] 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 hour, the reaction mixture was acidified with 1 M HCl solution to pH = 5. 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 in vacuo 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 + ).

[0127] 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 layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by 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 + ).

[0128] 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-tetraazapentacyclo[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 TIFF2025525565000036.tif56170 The title intermediate C was prepared according to the following scheme. TIFF2025525565000037.tif203170TIFF2025525565000038.tif207170

[0129] Step 1: 1-(5-bromo-6-fluoro-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl) Preparation of (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, a solution of SnCl (97.2 mL, 121.5 mmol) was slowly added. After the mixture was stirred 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, and the mixture was stirred at −40 °C for another 15 min. After the reaction was complete, 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 + ).

[0130] 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 under a nitrogen atmosphere for 24 hours. After the reaction was complete, 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 + ).

[0131] 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), silver trifluoromethanesulfonate (20.3 g, 78.88 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 10 minutes. After the reaction was completed, it was quenched with saturated aqueous 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 (EtOAc in PE = 0% to 2.5%) 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 + ).

[0132] 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-dioxaborolan-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), potassium phosphate (15.7 g, 73.92 mmol) and Pd(dppf)Cl (920 mg, 1.26 mmol) were added. The mixture was stirred under a nitrogen atmosphere at 70°C for 12 hours. After the reaction was complete, the mixture was filtered, and the filtrate was 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 + ).

[0133] 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), 2,2,2-trifluoroethyl trifluoromethanesulfonate (37.7 g, 162.56 mmol) was added 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 in vacuo 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, faster eluting) as a yellow oil. MS calculated 973.3 (MH + ), measured value 973.2 (MH + ).

[0134] 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 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-[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 + ).

[0135] 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-dioxaborolan-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 completion of the reaction, the reaction 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-dioxaborolan-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 + ).

[0136] 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 4-[(5M)-5-[6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-5-(4,4, To a mixture of [5,5-tetramethyl-1,3,2-dioxaborolan-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 complete, 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 + ).

[0137] 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]hexahydropyridazine-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), trimethylstannanol (2.4 g, 13.67 mmol) was added, and the mixture was stirred at 60 ° C. for 12 hours. 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, 2 times). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo 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]hexahydropyridazine-3-carboxylic acid (compound C11, 4.3 g) as a brown solid. MS calculated 1039.4 (MH + ), measured value 1039.2 (MH + ).

[0138] 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-tetraazapentacyclo[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]hexahydropyridazine-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-tetraazapentacyclo[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 + ).

[0139] 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-tetraazapentacyclo[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-tetraazapentacyclo[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)2 on activated carbon (2.79 g, 3.97 mmol). The mixture was degassed and purged with H2 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-tetraazapentacyclo[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 + ).

[0140] 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-tetraazapentacyclo[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-tetraazapentacyclo[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 and extracted with saturated NaHCO (30 mL) and EtOAc (30 mL, 3 times). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give (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-tetraazapentacyclo[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 + ).

[0141] 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-tetraazapentacyclo[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 The title compound was prepared in a manner similar to the preparation of TIFF2025525565000039.tif62170 Intermediate C by using iodoethane instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate.

[0142] 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-tetraazapentacyclo[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 The compound TIFF2025525565000040.tif57170 was prepared according to the following scheme: TIFF2025525565000041.tif191170TIFF2025525565000042.tif134170

[0143] 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 under a nitrogen atmosphere at 100 °C 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 + ).

[0144] Step 2: 1-[6-[(1S)-1-Methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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 under a nitrogen atmosphere at 90 °C 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-dioxaborolan-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 + ).

[0145] 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-dioxaborolan-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 + ).

[0146] 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 SO, filtered, and concentrated in vacuo 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, 0.69 mmol, faster eluting) as a white solid. MS calculated 921.3 (MH + ), measured value 921.4 (MH + ).

[0147] 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 + ).

[0148] 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 (129 mg, 1.32 mmol) and Pd(dppf)Cl (40 mg, 0.1 mmol). The reaction mixture was degassed by bubbling nitrogen 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 + ).

[0149] 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), KPO (221.3 mg, 1.04 mmol) and Pd(dtbpf)Cl (27.05 mg, 0.04 mmol) were added. The mixture was stirred at 70 °C under a nitrogen atmosphere for 12 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 (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 + ).

[0150] 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 in vacuo 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 in vacuo 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 + ).

[0151] 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-tetraazapentacyclo[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), DIEA (0.7 mL, 3.81 mmol), EDCI (550.0 mg, 2.87 mmol) and HOBt (65.0 mg, 0.48 mmol) were added at 0 °C. After stirring at 20° C. for 12 h, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL, 3×). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated in vacuo 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-tetraazapentacyclo[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 + ).

[0152] 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-tetraazapentacyclo[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-tetraazapentacyclo[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 in vacuo to give a residue. Saturated aqueous NaHCO3 (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, and concentrated in vacuo to give (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-tetraazapentacyclo[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 + ).

[0153] 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-tetraazapentacyclo[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 TIFF2025525565000043.tif57170 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.

[0154] 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-tetraazapentacyclo-[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 TIFF2025525565000044.tif216170TIFF2025525565000045.tif207170

[0155] Step 1: Preparation of 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (Compound G1) To a mixture of 3-bromo-5-iodo-2-[(1S)-1-methoxyethyl]pyridine (compound A3, 30 g, 87.73 mmol) and morpholine (7.6 g, 87.73 mmol) in toluene (450 mL) was added CsCO (57.2 g, 175.45 mmol), (R)-binap (2.7 g, 4.39 mmol), and Pd(OAc) (0.98 g, 4.39 mmol). The reaction 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. The residue was purified by column chromatography to give 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (compound G1, 21 g) as a yellow oil. MS calculated value 301.1 (MH + ), measured value 301.1 (MH + ).

[0156] Step 2: Preparation of 4-[6-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]morpholine (Compound G2) A solution of 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (Compound G1, 21 g, 63.3 mmol), bis(pinacolato)diboron (24.0 g, 94.63 mmol), and KOAc (13.6 g, 138.79 mmol) in toluene (500 mL) was added to Pd(dppf)Cl (4.4 g, 6.31 mmol). The mixture was degassed and purged with nitrogen three times, and the mixture was stirred under a nitrogen atmosphere at 90 °C for 12 h. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the crude product 4-[6-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]morpholine (compound G2, 45 g) as a yellow gum, which was used in the next step. MS calculated 349.2 (MH + ), measured value 349.2 (MH + ).

[0157] Step 3: Preparation of [3-[5-bromo-6-fluoro-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1H-indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound G3) To a solution of 4-[6-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]morpholine (compound G2, 40.6 g, 46.65 mmol), [3-(5-bromo-6-fluoro-2-iodo-1H-indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound C5, 31 g, 46.65 mmol) in 1,4-dioxane (420 mL) and water (80 mL) was added K3PO4 (29.7 g, 2.33 mmol) and Pd(dppf)Cl2 (1.7 g, 0.29 mmol). The mixture was degassed by bubbling nitrogen through it for 2 minutes, and the reaction mixture was stirred at 90 °C for 18 hours. After cooling to room temperature, the reaction mixture was extracted with EA (200 mL, 3 times). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography to give [3-[5-bromo-6-fluoro-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1H-indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound G3, 17.2 g) as a yellow oil. MS calculated 758.3 (MH + ), measured value 758.3 (MH + ).

[0158] Step 4: Preparation of [3-[5-bromo-1-ethyl-6-fluoro-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound G4) To a solution of [3-[5-bromo-6-fluoro-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1H-indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound G3, 15 g, 19.77 mmol) in DMF (300 mL) was added CsCO (19.3 g, 59.3 mmol) and iodoethane (6.16 g, 39.53 mmol) at 0 °C. After stirring at 20 °C for 16 h, the reaction mixture was poured into water (200 mL) and extracted with EtOAc (200 mL, 3 times). The combined organic layers were washed with brine (10 mL, 3 times), dried over NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give [3-[5-bromo-1-ethyl-6-fluoro-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound G4, 14.7 g) as a yellow oil. MS calculated 786.3 (MH + ), measured value 786.4 (MH + ).

[0159] Step 5: Preparation of 3-[5-bromo-1-ethyl-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-3-yl]-2,2-dimethyl-propan-1-ol (Compound G5) and 3-[5-bromo-1-ethyl-6-fluoro-(2P)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-3-yl]-2,2-dimethyl-propan-1-ol (Compound G6) To a solution of [3-[5-bromo-1-ethyl-6-fluoro-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound G4, 14.7 g, 18.68 mmol) in DMF (160 mL) was added cesium fluoride (14.2 g, 93.41 mmol). The mixture was stirred at 60 °C for 48 h. After cooling to room temperature, EtOAc (300 mL) and water (300 mL) were added to the reaction mixture, and the layers were separated. The aqueous phase was extracted with EtOAc (200 mL, 3 times). The combined organic layers were washed with brine (200 mL, 4 times), dried over Na SO , filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give 3-[5-bromo-1-ethyl-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-3-yl]-2,2-dimethyl-propan-1-ol (compound G5, 6 g, faster elution) as a colorless foam and 3-[5-bromo-1-ethyl-6-fluoro-(2P)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-3-yl]-2,2-dimethyl-propan-1-ol (compound G6, 4.5 g, slower elution) as a colorless foam. Compound G5: MS calculated 548.2 (MH + ), measured value 548.2 (MH + ). 1 H NMR (400MHz, methanol-d4) δ=8.41(d,J=2.4Hz,1H),7.92(d,J=6.8Hz,1H),7.3 7-7.33(m,2H),4.58(s,1H),4.05-3.98(m,2H),3.87-3.82(m,5H),3.27-3.2 3(m,4H),3.15-3.13(m,1H),3.00(s,3H),2.75-2.71(m,1H),2.24-2.22(m, 1H),1.42(d,J=6.4Hz,3H),1.22(t,J=7.2Hz,3H),0.76(s,3H),0.76(s,3H).

[0160] X-ray crystallography of compound G5 The absolute configuration of compound G5 was confirmed by single-crystal X-ray crystallography (Figure 1).

[0161] Step 6: Preparation of 3-[1-ethyl-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indol-3-yl]-2,2-dimethyl-propan-1-ol (Compound G7) To a solution of 3-[5-bromo-1-ethyl-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-3-yl]-2,2-dimethyl-propan-1-ol (Compound G5, 6 g, 10.94 mmol), bis(pinacolato)diboron (4.2 g, 16.41 mmol) in toluene (60 mL) was added potassium acetate (2.7 g, 27.35 mmol) and Pd(dppf)Cl (0.8 g, 1.09 mmol). The reaction mixture was degassed by bubbling nitrogen through it for 5 minutes and then stirred at 90 °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 to give 3-[1-ethyl-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indol-3-yl]-2,2-dimethyl-propan-1-ol (compound G7, 4.5 g) as a colorless gum. MS calculated 596.4 (MH + ), measured value 596.4 (MH + ).

[0162] Step 7: Preparation of methyl (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[1-ethyl-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-5-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylate (Compound G8) 3-[1-ethyl-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indol-3-yl]-2,2-dimethyl-propan-1-ol in toluene (45 mL), 1,4-dioxane (15 mL), and water (15 mL) To a mixture of (compound G7, 4.5 g, 7.56 mmol) and methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (intermediate B, 3.6 g, 7.56 mmol) was added K3PO4 (4.0 g, 18.89 mmol) and Pd(dtbp f) Cl2 (492.5 mg, 0.75 mmol) was added. The mixture was stirred at 70 °C under a nitrogen atmosphere for 12 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 to give methyl (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[1-ethyl-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-5-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylate (compound G8, 3.8 g) as a colorless gum. MS calculated 866.4 (MH + ), measured value 866.4 (MH + ).

[0163] Step 8: Preparation of (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[1-ethyl-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-5-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylic acid (Compound G9) To a mixture of methyl (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[1-ethyl-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-5-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylate (compound G8, 3.8 g, 4.39 mmol) in DCE (76 mL) was added MeSnOH (3.2 g, 17.55 mmol). The mixture was stirred at 60 °C for 48 h. The reaction mixture was concentrated in vacuo to give a residue. EtOAc (200 mL) and water (100 mL) were added to the residue, and the layers were separated. The aqueous phase was extracted with EtOAc (150 mL, 2 times). The combined organic layers were washed with brine (200 mL), dried over NaSO, filtered, and concentrated in vacuo to give (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[1-ethyl-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-5-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylic acid (compound G9, 3.7 g) as a brown solid. MS calculated 852.4 (MH + ), measured value 852.4 (MH + ).

[0164] Step 9: tert-Butyl 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-tetraazapentacyclo[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 G10) To a mixture of (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[1-ethyl-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-5-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylic acid (compound G9, 2.5 g, 2.93 mmol) in DCM (250 mL) was added DIEA (7.58 mL, 58.68 mmol), EDCI (8.4 g, 44.01 mmol) and HOBt (991.2 mg, 0.91 mmol) at 0° C. After stirring at 20° C. for 12 hours, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL, 3×). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated in vacuo to give a residue which was purified by column chromatography to give tert-butyl 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-tetraazapentacyclo[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 G10, 1.2 g) was obtained as a yellow oil. MS calculated 834.4 (MH + ), measured value 834.4 (MH +).

[0165] Step 10: (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-tetraazapentacyclo[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 G) tert-Butyl 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-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 To a solution of ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamate (compound G10, 1.2 g, 1.44 mmol) was added TFA (6.0 mL). The mixture was stirred at 20 °C for 3 hours. After the reaction was complete, the reaction mixture was concentrated in vacuo to give a residue. Saturated aqueous NaHCO3 (60 mL) was added, and the mixture was extracted with EtOAc (80 mL, 3 times). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give (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-tetraazapentacyclo[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 G, 1 g) was obtained as a yellow solid. MS calculated 734.3 (MH +), measured value 734.3 (MH + ).

[0166] 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-tetraazapentacyclo[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 The title compound was prepared in a manner similar to the preparation of TIFF2025525565000046.tif57170 Intermediate C by using 5-bromo-4-fluoro-1H-indole instead of 5-bromo-6-fluoro-1H-indole (compound C2).

[0167] 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-tetraazapentacyclo[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 TIFF2025525565000047.tif57170 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).

[0168] Intermediate J (7S,13S)-7-amino-25-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-tetraazapentacyclo[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 The title compound was prepared in a manner similar to the preparation of TIFF2025525565000048.tif64170 intermediate E by using [3-(5-bromo-4-fluoro-2-iodo-1H-indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound J1) instead of [3-(5-bromo-6-fluoro-2-iodo-1H-indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound C5).

[0169] Compound J1 was prepared in a manner similar to the preparation of compound C5, by using 5-bromo-4-fluoro-1H-indole instead of 5-bromo-6-fluoro-1H-indole (compound C2).

[0170] Example 1 3-(Dimethylamino)-N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N-methyl-azetidine-1-carboxamide The compound TIFF2025525565000049.tif68170 was prepared according to the following scheme: TIFF2025525565000050.tif180170

[0171] Step 1: Preparation of benzyl (2S)-2-[tert-butoxycarbonyl(methyl)amino]-3-methyl-butanoate (Compound 1B) To a mixture of BOC-N-ME-VAL-OH (5.0 g, 21.62 mmol) and potassium carbonate (4.5 g, 32.43 mmol) in DMF (70 mL) was added benzyl bromide (4.1 g, 23.78 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 hours. After the reaction was completed, the reaction mixture was diluted with water (70 mL) and extracted with EtOAc (70 mL, twice). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by reverse-phase column chromatography to give benzyl (2S)-2-[tert-butoxycarbonyl(methyl)amino]-3-methyl-butanoate (compound 1B, 6.7 g) as a yellow oil. 1 H NMR(400MHz,chloroform-d)δ=7.34(br s,5H),5.21-5.10(m,2H),2.88-2.74(m,3H),2.31-2.12(m,1H),1.68-1.64(m,1H),1.44(br d,J=15.0Hz,9H),0.96(d,J=6.6Hz,3H),0.90(br d,J=3.8Hz,3H).MS calculated value 322.2(MH + ), measured value 344.2 (MNa + ).

[0172] Step 2: Preparation of benzyl (2S)-3-methyl-2-(methylamino)butanoate (Compound 1C) A mixture of benzyl (2S)-2-[tert-butoxycarbonyl(methyl)amino]-3-methyl-butanoate (Compound 1B, 6.7 g, 21.47 mmol) in HCl / 1,4-dioxane (50.0 mL, 2 M) was stirred at 25 °C for 1 hour. After the reaction was complete, the reaction mixture was concentrated in vacuo to give a residue. The residue was diluted with saturated NaHCO (40 mL) and extracted with EtOAc (50 mL, 3 times). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated in vacuo to give benzyl (2S)-3-methyl-2-(methylamino)butanoate (Compound 1C, 4.7 g) as a colorless oil. MS calculated 222.1 (MH + ), measured value 222.2 (MH + ).

[0173] Step 3: Preparation of benzyl (2S)-2-[[3-(dimethylamino)azetidine-1-carbonyl]-methyl-amino]-3-methyl-butanoate (Compound 1D) To a mixture of benzyl (2S)-3-methyl-2-(methylamino)butanoate (Compound 1C, 1.0 g, 4.52 mmol) and DIEA (0.9 mL, 4.97 mmol) in DCM (15 mL) was added triphosgene (1.3 g, 4.52 mmol) at 0° C. After stirring for 0.5 h, a solution of N,N-dimethylazetidin-3-amine dihydrochloride (Compound 1D, 782.1 mg, 4.52 mmol) and DIEA (1.97 mL, 11.3 mmol) in DCM (4 mL) was added to the reaction. The reaction mixture was stirred at 20° C. for an additional 1 h. After the reaction was complete, the reaction mixture was quenched with water (40 mL) and extracted with EtOAc (40 mL, twice). The combined organic layers were washed with brine (60 mL), dried over NaSO, filtered, and concentrated in vacuo to provide a residue. The residue was purified by preparative HPLC to give benzyl (2S)-2-[[3-(dimethylamino)azetidine-1-carbonyl]-methyl-amino]-3-methyl-butanoate (compound 1E, 1.0 g) as a yellow oil. MS calculated 348.2 (MH + ), measured value 348.2 (MH + ).

[0174] Step 4: Preparation of (2S)-2-[[3-(dimethylamino)azetidine-1-carbonyl]-methyl-amino]-3-methyl-butanoic acid (Compound 1F) To a mixture of benzyl (2S)-2-[[3-(dimethylamino)azetidine-1-carbonyl]-methyl-amino]-3-methyl-butanoate (Compound 1E, 500.0 mg, 1.44 mmol) in methanol (15 mL) was added Pd(OH)2 on activated carbon (400.0 mg, 0.57 mmol). The reaction mixture was degassed, purged with hydrogen three times, and stirred under a hydrogen atmosphere (15 psi) at 20 °C for 12 h. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give (2S)-2-[[3-(dimethylamino)azetidine-1-carbonyl]-methyl-amino]-3-methyl-butanoic acid (Compound 1F, 370.0 mg) as a yellow oil. MS calculated 258.1 (MH + ), measured value 258.3 (MH + ).

[0175] Step 5: 3-(dimethylamino)-N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N-methyl-azetidine-1-carboxamide (Example 1) To a solution of (2S)-2-[[3-(dimethylamino)azetidine-1-carbonyl]-methyl-amino]-3-methyl-butanoic acid (compound 1F, 32.13 mg, 0.12 mmol) in DMF (2 mL) was added DIEA (0.1 mL, 0.25 mmol), HATU (47.47 mg, 0.12 mmol) and (7S,13S)-7-amino-24-fluoro-17,17-dimethyl-20-[5-(4-methylpiperazin-1-yl)-2-[rac-(1S)-1-methoxyethyl]-3-pyridyl]-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[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, 50.0 mg, 0.06 mmol) was added at 0°C. After stirring at 20°C for 1 hour, the reaction mixture was diluted with water (15 mL) and extracted with EtOAc (15 mL, 3 times). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC to give Example 1 (35.1 mg) as a white solid. MS calculated 1040.5 (MH + ), measured value 1040.8 (MH + ), 1H NMR (400MHz, methanol-d4)δ=8.68(d,J=7.6Hz,1H),8.51(d,J=2.8Hz,1H),7.69(d,J=2.4Hz,1H),7.57-7.44(m,2H),5.79-5.69(m,1H),5. 25-5.11(m,1H),4.97-4.89(m,2H),4.51-4.39(m,2H),4.31-4.12(m,7H),4.12-3.88(m,2H),3.87-3.67(m,3H),3.67-3.52(m,2H),3.47 (d,J=14.8Hz,2H),3.35(s,3H),3.29-3.22(m,2H),3.22-3.10(m,2H),2.99(s,3H),2.92(s,8H),2.87-2.77(m,1H),2.58(d,J=14.4Hz, 1H),2.30-2.16(m,2H),2.03-1.90(m,1H),1.88-1.74(m,1H),1.72-1.58(m,1H),1.45(d,J=6.0Hz,3H),1.03-0.89(m,9H),0.45(s,3H).

[0176] Example 2 3-(Dimethylamino)-N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N-methyl-azetidine-1-carboxamide TIFF2025525565000051.tif57170 In a manner similar to the preparation of Example 1, (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-tetraazapentacyclo[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 H) was reacted with (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-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ] was used instead of octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate C) to prepare the title compound. Example 2 (50.0 mg) was obtained as a yellow solid. MS calculated 1040.5 (MH + ), measured value 1040.8 (MH + ). 1H NMR (400MHz, methanol-d4)δ=8.55-8.49(m,1H),7.63-7.56(m,1H),7.52-7.39(m,3H),6.03-5.81(m,1H),5.20-5.01(m,1H) ),4.70-4.61(m,1H),4.45-4.36(m,2H),4.30-4.23(m,2H),4.17-3.93(m,7H),3.77-3.63(m,3H),3.56-3.48(m,2H),3.4 2-3.34(m,2H),3.29-3.21(m,3H),3.20-3.11(m,3H),3.00-2.98(m,3H),2.94-2.87(m,10H),2.68-2.51(m,2H),2.23-2 .14(m,1H),1.68-1.53(m,1H),1.47-1.41(m,3H),1.35-1.15(m,3H),0.95-0.88(m,6H),0.81(s,3H),0.72-0.58(m,3H).

[0177] Example 3 N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N-methyl-morpholine-4-carboxamide The title compound was prepared in a manner similar to that of Example 1, except that morpholine was used instead of N,N-dimethylazetidin-3-amine dihydrochloride (Compound 1D). Example 3 (25 mg) was obtained as an off-white solid. MS calculated 1027.4 (MH + ), measured value 1027.7(MH + ), 1H NMR (400MHz, methanol-d4) δ=8.71(d,J=7.6Hz,1H),8.49(d,J=2.8Hz,1H),7.72-7.67(m,2H),7.48(d,J=12.8Hz,1H),5.76(d,J=8.8Hz,1H),5.2 6-5.13(m,1H),4.84-4.75(m,1H),4.43(d,J=12Hz,1H),4.30-4.24(m, 1H),4.20(dd,J=12,2.8Hz,1H),4.17-4.03(m,2H),4.00(s,1H),3.85-3 .62(m,8H),3.55-3.44(m,2H),3.42-3.34(m,6H),3.30-3.18(m,5H),3 .15-3.09(m,1H),2.99(s,3H),2.91(s,3H),2.87-2.77(m,1H),2.71-2 .58(m,1H),2.33-2.14(m,2H),2.01-1.90(m,1H),1.87-1.74(m,1H),1 70-1.57(m,1H),1.46(d,J=6.0Hz,3H),1.01-0.87(m,9H),0.50(s,3H).

[0178] Example 4 3-(Dimethylamino)-N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N-methyl-azetidine-1-carboxamide TIFF2025525565000053.tif53170 In a manner similar to the preparation of Example 1, (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-tetraazapentacyclo[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 I) was reacted with (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-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 The title compound was prepared by using 12.9 mg of Example 4 as a yellow solid. MS calculated 1027.5 (MH + ), measured value 1027.5 (MH + ). 1H NMR (400MHz, methanol-d4) δ=8.69(d,J=7.8Hz,1H),8.42(d,J=2.9Hz,1H),7.69(d,J=2.4Hz,1H),7.55(d,J=2.4Hz,1H),7.48(d,J=12.7Hz,1H),5.74(br d,J=9.3Hz,1H),5.18(br dd,J=8.3,16.6Hz,1H),4.87-4.79(m,2H),4.49-4.38(m,2H),4.33-4.11(m,7H),3.87(t,J=4.6Hz,4H),3.78(br d,J=11.2Hz,1H),3.72-3.66(m,1H),3.48(br d,J=14.7Hz,1H),3.39-3.33(m,6H),3.26-3.21(m,1H),3.15-3.10(m,1H),2.97-2.90(m,8H),2.89-2.76(m,2H),2.66-2.60(m,1H) ),2.26-2.17(m,2H),2.01-1.91(m,1H),1.87-1.78(m,1H),1.70-1.60(m,1H),1.49-1.41(m,3H),1.01-0.84(m,9H),0.48(s,3H).

[0179] Example 5 N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N-methyl-morpholine-4-carboxamide TIFF2025525565000054.tif64170 Morpholine and (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-tetraazapentacyclo-[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 G) was reacted with N,N-dimethylazetidin-3-amine dihydrochloride (compound 1D) and (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-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ] was used instead of octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate C) to prepare the title compound. Example 5 (131.3 mg) was obtained as a yellow solid. MS calculated 960.5 (MH + ), measured value 960.3 (MH + ). 1H NMR (400 MHz, chloroform-d) δ = 8.97 (br d, J = 1.6 Hz, 1H), 8.69 (d, J = 7.5 Hz, 1H), 8.14-7.98 (m, 1H), 7.61 (d, J = 1.7 Hz, 1H), 7.38 (d, J = 1.5 Hz, 1H), 7.13 (d, J = 12.5 Hz, 1H), 5.81 (br d,J=17.7Hz,1H),4.68-4.57(m,1H),4.41(d,J=6.5Hz,1H),4.29-4.22(m,1H) ,4.19-4.07(m,2H),4.00-3.88(m,6H),3.84-3.78(m,2H),3.77-3.70(m,3H), 3.49-3.42(m,6H),3.39-3.31(m,6H),3.23-3.14(m,2H),2.91(s,3H),2.77-2 .68(m,1H),2.49-2.42(m,1H),2.38-2.28(m,2H),2.02-1.96(m,2H),1.82(br d,J=12.7Hz,1H),1.69-1.60(m,1H),1.57(d,J=6.2Hz,3H),1.03-0.96(m,9H),0.91(d,J=6.6Hz,3H),0.55-0.43(m,3H).

[0180] Example 6 N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N-methyl-morpholine-4-carboxamide TIFF2025525565000055.tif72170 Morpholine and (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-tetraazapentacyclo[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) was reacted with N,N-dimethylazetidin-3-amine dihydrochloride (compound 1D) and (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-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ] was used instead of octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate C) to prepare the title compound. Example 6 (8.8 mg) was obtained as an off-white solid. MS calculated 1095.5 (MH + ), measured value 1095.5 (MH + ). 1H NMR (400 MHz, methanol-d4) δ = 8.71 (d, J = 7.2 Hz, 1H), 8.45-8.38 (m, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.63-7.56 (m, 1H), 7.48 (d, J = 12.8 Hz, 1H), 5.87-5.69 (m, 1H), 5.24-5.11 (m, 1H), 4.49-4.37 (m, 1H), 4.29-4.16 (m, 2H), 4.01 (d, J = 11.2 Hz, 1H), 3.83- 3.57(m,7H),3.50-3.36(m,10H),3.26-3.06(m,5H),2.93-2.77(m,8H),2.71-2.60(m,1H),2.31-2.16(m,2H),2.00-1.91 (m,1H),1.87-1.75(m,1H),1.70-1.58(m,1H),1.46(d,J=6.0Hz,3H),1.34-1.26(m,1H),1.00-0.88(m,9H),0.50(s,3H).

[0181] Example 7 N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-3,3-difluoro-N-methyl-azetidine-1-carboxamide The compound TIFF2025525565000056.tif64170 was prepared according to the following scheme: TIFF2025525565000057.tif115170

[0182] Step 1: tert-butyl N-[(1S)-1-[[(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-tetraazapentacyclo[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]carbamoyl]-2-methyl-propyl]-N-methyl-carbamate (compound 7A) To a solution of BOC-N-ME-VAL-OH (compound 1A, 66.2 mg, 0.29 mmol) in DMF (1 mL) was added DIEA (0.3 mL, 1.90 mmol) and HATU (67.3 mg, 0.29 mmol) at 0° C. After stirring for 15 min at 0° C., the reaction mixture was treated with (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-tetraazapentacyclo-[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 G, 70.0 mg, 0.09 mmol) was added. After stirring the reaction at 20 °C for 0.5 h, the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL, 3 times). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative TLC to give tert-butyl N-[(1S)-1-[[(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-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,267A, 65.1 mg) as a pale yellow solid. MS calculated 947.5 (MH + ), measured value 947.4 (MH + ).

[0183] Step 2: [(1S)-1-[[(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-tetraazapentacyclo[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]carbamoyl]-2-methyl-propyl]-methyl-ammonium;2,2,2-trifluoroacetate (compound 7B) tert-Butyl N-[(1S)-1-[[(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-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26To a mixture of 7A (compound 7A, 40.0 mg, 0.04 mmol) and octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl)carbamoyl-2-methyl-propyl)-N-methyl-carbamate (compound 7A, 40.0 mg, 0.04 mmol), TFA (0.2 mL, 2.7 mmol) was added at 20° C. After stirring at 20° C. for 1 hour, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC to give [(1S)-1-[[(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-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 7B (20.0 mg) was obtained as a white solid. MS calculated 847.5 (MH + ), measured value 847.4 (MH + ). 1H NMR (400 MHz, methanol-d4) δ = 8.68 (d, J = 7.8 Hz, 1H), 8.40 (d, J = 2.8 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.56 (br s,1H),7.35(d,J=12.6Hz,1H),5.95-5.92(m,1H),5.04-4.96(m,1H),4.94-4.91(m,3H),4.45-4.40(m,1H),4.35 -4.05(m,4H),3.88-3.83(m,4H),3.80-3.69(m,3H),3.56-3.50(d,J=14.5Hz,1H),3.35-3.31(m,4H),3.07-2.97 (m,1H),2.90-2.80(m,1H),2.75-2.65(m,4H),2.30-2.15(m,2H),2.03-1.91(m,1H),1.89-1.75(m,1H),1.73-1. 56(m,1H),1.45-1.43(m,3H),1.15-1.09(m,3H),1.09-1.07(m,3H),1.03-1.01(m,3H),0.95(s,3H),0.56(s,3H).

[0184] Step 3: N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-3,3-difluoro-N-methyl-azetidine-1-carboxamide (Example 7) [(1S)-1-[[(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-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .022,26 To a solution of 7B (50.0 mg, 0.06 mmol) and DIEA (45.8 mg, 0.35 mmol), triphosgene (6.1 mg, 0.02 mmol) was added at 0 °C. After stirring at 20 °C for 1 h, 3,3-difluoroazetidine hydrochloride (7C, 7.6 mg, 0.06 mmol) was added to the reaction mixture at 0 °C and stirred at 20 °C for 11 h. After completion of the reaction, the reaction mixture was poured into HO (10 mL) and extracted with EtOAc (10 mL, 3 times). The organic layer was washed with brine (10 mL, 2 times), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC to give Example 7 (13.0 mg) as a pale yellow solid. MS calculated 966.5 (MH + ), measured value 966.4 (MH + ). 1 H NMR (400 MHz, methanol-d4) δ = 8.70-8.64 (m, 1H), 8.49-8.35 (m, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.33 (d, J = 12.8 Hz, 1H), 5.78 (br t,J=8.2Hz,1H),5.02-4.96(m,1H),4.68-4.52(m,1H),4.46-4.43(m,1H),4.42-4.32(m,4H),4.22-4.0 5(m,3H),3.93-3.82(m,4H),3.81-3.66(m,2H),3.50-3.42(m,1H),3.35-3.31(m,6H),3.28-3.21(m,1H) ),3.09-2.96(m,1H),2.88(s,3H),2.84-2.77(m,1H),2.26-2.14(m,2H),1.95-1.90(m,1H),1.87-1.74 (m,1H),1.69-1.59(m,1H),1.43(d,J=6.2Hz,3H),1.36-1.27(m,2H),1.03-0.89(m,12H),0.53(s,3H).

[0185] Example 8 (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]-3-methyl-2-(3-methyl-2-oxo-imidazolidin-1-yl)butanamide TIFF2025525565000058.tif66170 In a manner similar to the preparation of Example 1, (2S)-3-methyl-2-(3-methyl-2-oxo-imidazolidin-1-yl)butanoic acid (compound 8H) and (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-tetraazapentacyclo-[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 G) was reacted with (2S)-2-[[3-(dimethylamino)azetidine-1-carbonyl]-methyl-amino]-3-methyl-butanoic acid (compound 1F) and (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-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ] was used instead of octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate C) to prepare the title compound. Example 8 (50.4 mg) was obtained as a yellow solid. MS calculated 916.5 (MH +), measured value 916.3 (MH + ). 1 H NMR(400MHz,chloroform-d)δ=8.84(br s,1H),8.66(d,J=7.6Hz,1H),7.58(d,J=2.0Hz,1H),7.10(d,J=12.3Hz,1H),7.05(d,J=9.2Hz,1H),5.83(t,J=9.0Hz,1H),4.59(br d,J=11.9Hz,1H),4.39-4.31(m,1H),4.27-4.14(m,2H),4.11-4.03(m,1H),3.95(s,1H),3.93-3.89(m,4H),3.84(br d,J=11.5Hz,1H),3.71(d,J=11.0Hz,1H),3.52-3.46(m,1H),3.42-3.31(m,11H),3.21-3.07(m,3H),2.89(s,3H),2.76-2.59(m,2H),2.46(br d,J=14.4Hz,1H),2.29-2.18(m,2H),2.00-1.91(m,1H),1.80(br d,J=12.2Hz,1H),1.66-1.59(m,1H),1.54-1.50(m,3H),1.00-0.90(m,12H),0.49(s,3H).

[0186] Compound 8H was prepared according to the following scheme: TIFF2025525565000059.tif106170

[0187] Step 1: Preparation of (2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoate (Compound 8B) To a mixture of BOC-L-valine (compound 8A, 1.0 g, 4.6 mmol) and potassium carbonate (763.4 mg, 5.52 mmol) in DMF (10 mL) was added benzyl bromide (0.6 mL, 5.06 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 h. After the reaction was complete, the reaction mixture was diluted with water (70 mL) and extracted with EtOAc (70 mL, 3 times). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give benzyl (2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoate (compound 8B, 1.0 g) as a colorless oil. MS calculated 307.4 (MH + ), measured value 208.0 (M-Boc+H + ).

[0188] Step 2: Preparation of benzyl (2S)-2-amino-3-methyl-butanoate (compound 8C) To a mixture of benzyl (2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoate (compound 8B, 1.0 g, 3.11 mmol) in THF (5 mL) was added HCl / dioxane (20.0 mL, 80.0 mmol, 4N) at 0 °C. After stirring the reaction at 25 °C for 1 h, the reaction mixture was concentrated in vacuo to give a yellow gum. The gum was diluted with aqueous NaHCO (40 mL) and extracted with EtOAc (50 mL, 3 times). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated in vacuo to give benzyl (2S)-2-amino-3-methyl-butanoate (compound 8C, 600.0 mg) as a colorless oil, which was used in the next step without purification.

[0189] Step 3: Preparation of benzyl (2S)-2-[2-[tert-butoxycarbonyl(methyl)amino]-ethylamino]-3-methyl-butanoate (Compound 8E) To a solution of benzyl (2S)-2-amino-3-methylbutanoate (Compound 8C, 600.0 mg, 2.89 mmol) and N-BOC-(methylamino)acetaldehyde (Compound 8D, 601.7 mg, 3.47 mmol) in methanol (20 mL) was added MgSO (2.1 g, 14.47 mmol). After stirring at 20 °C for 1 h, NaBH(OAc) (1.2 g, 5.79 mmol) was added to the reaction mixture and stirred at 20 °C for an additional 1 h. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a colorless oil. The oil was purified by column chromatography to give benzyl (2S)-2-[2-[tert-butoxycarbonyl(methyl)amino]-ethylamino]-3-methylbutanoate (Compound 8E, 700.0 mg) as a colorless gum. MS calculated value 365.2 (MH + ), measured value 365.1 (MH + ).

[0190] Step 4: Preparation of benzyl (2S)-3-methyl-2-[2-(methylamino)ethylamino]butanoate; hydrochloride salt (Compound 8F) To a solution of benzyl (2S)-2-[2-[tert-butoxycarbonyl(methyl)amino]-ethylamino]-3-methyl-butanoate (Compound 8E, 700.0 mg, 1.92 mmol) in THF (5 mL) at 0 °C was added HCl / dioxane (15.0 mL, 60.0 mmol, 4N). After stirring at 25 °C for 2 h, the reaction mixture was concentrated in vacuo to give a white solid. Residual solvent was removed twice by azeotropic distillation with THF to give benzyl (2S)-3-methyl-2-[2-(methylamino)ethylamino]butanoate; hydrochloride salt (Compound 8F, 600.0 mg) as a white solid, which was used directly in the next step without further purification. MS calculated 265.2 (MH + ), measured value 265.2 (MH + ).

[0191] Step 5: Preparation of benzyl (2S)-3-methyl-2-(3-methyl-2-oxo-imidazolidin-1-yl)butanoate (compound 8G) To a solution of benzyl (2S)-3-methyl-2-[2-(methylamino)ethylamino]butanoate; hydrochloride salt (compound 8F, 600.0 mg, 1.99 mmol) and DIEA (772.5 mg, 5.98 mmol) in ACN (50 mL) was added CDI (646.4 mg, 3.99 mmol). After stirring at 0 °C for 2 h, water (10 mL) was added to the reaction mixture and extracted with EA (40 mL, twice). The combined organic layers were washed with brine (20 mL), dried (NaSO), and concentrated in vacuo to give a yellow gum. The gum was purified by reverse-phase column chromatography to give benzyl (2S)-3-methyl-2-(3-methyl-2-oxo-imidazolidin-1-yl)butanoate (compound 8G, 300.0 mg) as a colorless gum. MS calculated 291.2 (MH + ), measured value 291.2 (MH + ).

[0192] Step 6: Preparation of (2S)-3-methyl-2-(3-methyl-2-oxo-imidazolidin-1-yl)butanoic acid (compound 8H) To a solution of benzyl (2S)-3-methyl-2-(3-methyl-2-oxo-imidazolidin-1-yl)butanoate (compound 8G, 280.0 mg, 0.96 mmol) in methanol (10 mL) was added Pd(OH)2 on activated carbon (0.2 g, 10% purity). The reaction mixture was hydrogenated at room temperature for 5 hours. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give (2S)-3-methyl-2-(3-methyl-2-oxo-imidazolidin-1-yl)butanoic acid (compound 8H, 150.0 mg) as a colorless gum. MS calculated 201.1 (MH + ), measured value 201.0 (MH + ).

[0193] Example 9 N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N-methyl-morpholine-4-carboxamide TIFF2025525565000060.tif72170 Morpholine and (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-tetraazapentacyclo[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) was reacted with N,N-dimethylazetidin-3-amine dihydrochloride (compound 1D) and (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-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ] was used in place of octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate C) to prepare the title compound. Example 9 (26.8 mg) was obtained as an off-white solid. MS calculated 1041.5 (MH + ), measured value 1041.7(MH+ ). 1 H NMR (400MHz, methanol-d4) δ=8.71(d,J=7.6Hz,1H),8.38(d,J=2.8Hz,1H),7.87(d,J=2.8Hz,1H),7.64(d,J=2.4Hz,1H),7.36(d,J=12.8 Hz,1H),5.86(d,J=8.4Hz,1H),4.48-4.32(m,2H),4.30-4.19(m,1H),4.18-4.11(m,1H),4.08-3.97(m,2H),3.80-3.67(m,6H),3.51-3 .47(m,4H),3.39-3.33(m,5H),3.29-3.08(m,6H),3.03-2.96(m,1H),2.93-2.84(m,7H),2.84-2.70(m,2H),2.28-2.14(m,2H),1.99- 1.92(m,1H),1.86-1.74(m,1H),1.70-1.58(m,1H),1.48-1.43(d,J=6.0Hz,3H)1.03(t,J=6.8Hz,3H),0.96-0.89(m,9H),0.61(s,3H).

[0194] Example 10 N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N-methyl-morpholine-4-carboxamide TIFF2025525565000061.tif68170 In a manner similar to the preparation of Example 1, morpholine 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-tetraazapentacyclo[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) was reacted with N,N-dimethylazetidin-3-amine dihydrochloride (compound 1D) and (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-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ] was used instead of octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate C) to prepare the title compound. Example 10 (10.3 mg) was obtained as a yellow solid. MS calculated 973.5 (MH + ), measured value 973.5 (MH + ). 1H NMR (400MHz, methanol-d4) δ=8.67(d,J=7.6Hz,1H),8.49(d,J=2.8Hz,1H),7.70-7.60(m,2H),7.34(d,J=12.4Hz,1H),5.80(d,J=8. 8Hz,1H),4.43(d,J=10.8Hz,1H),4.36-4.28(m,1H),4.27-4.05(m,4H),4.01(d,J=10.8Hz,1H),3.81-3.62(m,8H),3.49-3.43(m, 2H),3.42-3.33(m,7H),3.29-3.17(m,4H),3.07-3.02(m,1H),2.99(s,3H),2.89(s,3H),2.86-2.79(m,1H),2.67-2.63(m,1H),2. 30-2.15(m,2H),2.01-1.91(m,1H),1.86-1.74(m,1H),1.70-1.57m,1H),1.44(d,J=6.0Hz,3H),1.03-0.88(m,13H),0.53(s,3H).

[0195] Example 11 N-[(1S)-1-[[(7S,13S)-24-fluoro-20-(20M)-[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]carbamoyl]-2-methyl-propyl]-N-methyl-morpholine-4-carboxamide TIFF2025525565000062.tif64170 Morpholine and (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-tetraazapentacyclo[17.5.2.1 2,5 .19,13 .0 22,26 ]octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (intermediate I) was reacted with N,N-dimethylazetidin-3-amine dihydrochloride (compound 1D) and (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-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ] was used instead of octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate C) to prepare the title compound. Example 11 (26.3 mg) was obtained as a white solid. MS calculated 1013.5 (MH + ), measured value 1013.8 (MH + ). 1 H NMR (400MHz, methanol-d4) δ=8.71(d,J=7.6Hz,1H),8.49-8.35(d,J=2.8,1H),7.73-7.69(d,J=2.4,1H),7.66-7.59(d,J=2.4,1H),7.53-7.43(d,J=12 .4,1H),5.88-5.70(d,J=8.8,1H),5.25-5.13(m,1H),4.53-4.38(m,1H),4 .31-4.15(m,2H),4.07-3.98(d,J=10.8,1H),3.91-3.84(t,J=4.8,4H),3. 83-3.67(m,6H),3.52-3.45(m,1H),3.43-3.34(m,10H),3.30-3.18(m,3H ),3.11(m,1H),2.99-2.89(s,3H),2.88-2.78(m,1H),2.72-2.60(d,J=14. 8,1H),2.34-2.15(m,2H),2.01-1.91(m,1H),1.90-1.74(m,1H),1.72-1.5 7(m,1H),1.52-1.42(d,J=6.0,3H),1.05-0.88(m,9H),0.57-0.45(s,3H).

[0196] Example 12 3-(Dimethylamino)-N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N-methyl-azetidine-1-carboxamide TIFF2025525565000063.tif63170 In a manner similar to the preparation of Example 1, (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-tetraazapentacyclo[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) was reacted with (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-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26] was used instead of octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate C) to prepare the title compound. Example 12 (45.3 mg) was obtained as a white solid. MS calculated 1108.5 (MH + ), measured value 1108.5 (MH + ). 1 H NMR (400MHz, methanol-d4) δ=8.68(d,J=7.6Hz,1H),8.42(d,J=2.8Hz,1H),7.70(d,J=2.4Hz,1H),7.45(d,J=12.8Hz,1H),7.32- 7.27(m,1H),5.74-5.68(m,1H),5.18-5.06(m,2H),4.93-5.00(m,2H),4.58-4.56(m,5H),4.32-4.23(m,1H),4.22-4.14(m,2 H),4.14-4.07(m,1H),4.00-3.89(m,1H),3.87-3.67(m,2H),3.53-3.39(m,1H),3.34-3.32(m,4H),3.19-3.09(m,4H),2.90- 2.79(m,8H),2.63-2.54(m,1H),2.26-2.15(m,8H),1.57-1.98(m,3H),1.43(d,J=6.0Hz,3H),0.99-0.89(m,9H),0.44(s,3H).

[0197] Example 13 (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]-3-methyl-2-[methyl(2,2,2-trifluoroethylcarbamoyl)amino]butanamide TIFF2025525565000064.tif62170 In a manner similar to the preparation of Example 1, 2,2,2-trifluoroethylamine and (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-tetraazapentacyclo-[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 G) was reacted with N,N-dimethylazetidin-3-amine dihydrochloride (compound 1D) and (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-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ] was used in place of octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate C) to prepare the title compound. Example 13 (13.4 mg) was obtained as a white solid. MS calculated 972.4 (MH + ), measured value 972.4 (MH + ). 1H NMR (400MHz, chloroform-d) δ=8.64(d,J=7.6Hz,1H),8.47(d,J=2.8Hz,1H),7.55(d ,J=1.7Hz,1H),7.10(s,1H),7.08-7.03(m,2H),5.84(t,J=9.1Hz,1H),5.21(br s,1H),4.58(br d,J=12.1Hz,1H),4.32-4.21(m,3H),4.08-4.02(m,2H),3.92-3.88(m,4H),3.84(br d,J=11.0Hz,1H),3.73-3.70(m,1H),3.38(s,3H),3.27-3.21(m,4H),3.17-3.04(m,2H),2.97(s,3H),2.74-2.65(m,1H),2.46(br d,J=14.4Hz,1H),2.31-2.21(m,5H),1.96(br d,J=13.7Hz,1H),1.85-1.72(m,1H),1.66-1.54(m,1H),1.44(d,J=6.1Hz,3H),1.25(t,J=7.0Hz,1H),0.99-0.86(m,12H),0.45(s,3H).

[0198] Example 14 N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N-methyl-3-(trifluoromethyl)azetidine-1-carboxamide TIFF2025525565000065.tif64170 In a manner similar to the preparation of Example 1, 3-(trifluoromethyl)azetidine and (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-tetraazapentacyclo-[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 G) was reacted with N,N-dimethylazetidin-3-amine dihydrochloride (compound 1D) and (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-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ] was used instead of octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate C) to prepare the title compound. Example 14 (3.1 mg) was obtained as a white solid. MS calculated 998.5 (MH + ), measured value 998.5 (MH + ). 1H NMR (400MHz, chloroform-d) δ=8.64(d,J=7.5Hz,1H),8.47(d,J=2.4Hz,1H),7.58(s,1H),7.32(br d,J=9.6Hz,1H),7.11-7.04(m,2H),5.81(br t,J=8.8Hz,1H),4.59(br d,J=9.8Hz,1H),4.35(br t,J=8.7Hz,1H),4.30-4.21(m,4H),4.13(br dd,J=7.9,15.0Hz,3H),4.08-3.99(m,3H),3.90(br s,4H),3.84(br d,J=11.3Hz,1H),3.43(br d,J=14.6Hz,1H),3.37(s,3H),3.24(br d,J=4.3Hz,4H),3.18-3.13(m,1H),2.84(s,3H),2.75-2.62(m,1H),2.47(br d,J=14.4Hz,1H),2.31-2.17(m,2H),2.05(s,3H),1.94(br d,J=1.8Hz,1H),1.51(br s,2H),1.46-1.46(m,1H),1.44-1.44(m,1H),1.15(td,J=6.4,13.0Hz,12H),0.46(s,3H).

[0199] Example 15 (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]-3-methyl-2-(3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[5,1-c][1,4]oxazin-2-yl)butanamide TIFF2025525565000066.tif59170 In a manner similar to the preparation of Example 1, (2S)-3-methyl-2-(3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[5,1-c][1,4]oxazin-2-yl)butanoic acid (compound 15g) and (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-tetraazapentacyclo-[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 G) was reacted with (2S)-2-[[3-(dimethylamino)azetidine-1-carbonyl]-methyl-amino]-3-methyl-butanoic acid (compound 1F) and (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-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ] was used instead of octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate C) to prepare the title compound. Example 15 (37.5 mg) was obtained as a white solid. MS calculated 958.5 (MH + ), measured value 958.5 (MH + ). 1H NMR (400MHz, methanol-d4)δ=8.70-8.61(m,1H),8.53-8.30(m,1H),7.64-7.59(m,1H),7.38-7.27(m,2H),5.86-5.72(m,1H),5.03-4.92(m,1H) ,4.82-4.78(m,1H),4.67-4.53(m,3H),4.47-4.36(d,J=12.8Hz,1H),4.29-4.12(m,4H),4.10-4.01(d,J=10.8Hz,1H),3.89-3.84(m,4H),3. 79-3.68(m,4H),3.65-3.54(m,1H),3.50-3.36(m,4H),3.28(m,4H),3 .20-3.10(m,2H),3.03-2.95(m,1H),2.88-2.75(m,1H),2.69-2.58(m, 1H),2.24-2.07(m,2H),2.01-1.89(m,1H),1.87-1.71(m,1H),1.70-1 .56(m,1H),1.51-1.37(m,3H),1.03-0.87(m,12H),0.62-0.42(m,3H).

[0200] Compound 15g was prepared according to the following scheme: TIFF2025525565000067.tif98170

[0201] Step 1: tert-Butyl 3-[[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]carbamoyl]-morpholine-4-carboxylate (Compound 15c) To a solution of 4-tert-butoxycarbonylmorpholine-3-carboxylic acid (compound 15b, 2.8 g, 12.31 mmol) and L-valine benzyl ester hydrochloride (compound 15a, 3.0 g, 12.31 mmol) in DMF (30 mL) was added DIEA (4.29 mL, 24.62 mmol) and HATU (5.1 g, 13.54 mmol). After stirring at 25 °C for 1 h, EtOAc (40 mL) and water (40 mL) were added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with EtOAc (30 mL, twice). The combined organic layers were washed with brine (60 mL), dried over NaSO, filtered, and concentrated in vacuo to give tert-butyl 3-[[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]carbamoyl]morpholine-4-carboxylate (compound 15c, 7.5 g) as a white oil. MS calculated 420.23 (MH + ), measured value 321.2 (M-Boc+H + ).

[0202] Step 2: Benzyl (2S)-3-methyl-2-(morpholine-3-carbonylamino)-butanoate; Hydrochloride (Compound 15d) To a solution of tert-butyl 3-[[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]carbamoyl]morpholine-4-carboxylate (Compound 15c, 7.2 g, 17.16 mmol) in 1,4-dioxane (10 mL) was added 1,4-dioxane / HCl (4 M, 15.0 mL, 60.0 mmol). The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated in vacuo to give benzyl (2S)-3-methyl-2-(morpholine-3-carbonylamino)-butanoate; hydrochloride (Compound 15d, 6.7 g) as a white oil. MS calculated 321.2 (MH + ), measured value 321.2 (MH + ).

[0203] Step 3: Benzyl (2S)-2-(1,3-dioxo-5,6,8,8a-tetrahydroimidazo[5,1-c][1,4]oxazin-2-yl)-3-methyl-butanoate (Compound 15e) To a solution of benzyl (2S)-3-methyl-2-(morpholine-3-carbonylamino)butanoate (Compound 15d, 6.5 g, 20.29 mmol) in THF (1 mL) was added TEA (8.5 mL, 60.87 mmol) and N,N'-carbonyldiimidazole (3.9 g, 24.35 mmol). After stirring at 25 °C for 2 h, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by reverse-phase chromatography to give benzyl (2S)-2-(1,3-dioxo-5,6,8,8a-tetrahydroimidazo[5,1-c][1,4]oxazin-2-yl)-3-methylbutanoate (Compound 15e, 2.36 g) as a white oil. MS calculated 346.4 (MH + ), measured value 369.4 (MNa + ).

[0204] Step 4: Benzyl (2S)-3-methyl-2-(1-oxo-5,6,8,8a-tetrahydro-3H-imidazo[5,1-c][1,4]oxazin-2-yl)butanoate (Compound 15e) To a solution of benzyl (2S)-2-(1,3-dioxo-5,6,8,8a-tetrahydroimidazo[5,1-c][1,4]oxazin-2-yl)-3-methyl-butanoate (compound 15e, 1 g, 2.89 mmol) in THF (5 mL) was added boron trifluoride diethyl etherate (1 M, 1.2 mL, 1.2 mmol) and borane-THF (5.77 mL, 5.77 mmol) at 0 °C. After stirring at 20 °C for 18 h, the reaction was quenched with water (40 mL). The aqueous phase was extracted with EtOAc (30 mL, 2 times). The combined organic layers were washed with brine (60 mL), dried over MgSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by reverse-phase column chromatography to give benzyl (2S)-3-methyl-2-(1-oxo-5,6,8,8a-tetrahydro-3H-imidazo[5,1-c][1,4]oxazin-2-yl)butanoate (compound 15f, 220.0 mg) as a colorless oil. MS calculated 333.2 (MH + ), measured value 333.2 (MH + ).

[0205] Step 5: (2S)-3-methyl-2-(3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[5,1-c][1,4]oxazin-2-yl)butanoic acid (compound 15f) To a solution of benzyl (2S)-3-methyl-2-(1-oxo-5,6,8,8a-tetrahydro-3H-imidazo[5,1-c][1,4]oxazin-2-yl)butanoate (Compound 15e, 130.0 mg, 0.39 mmol) in THF (1 mL) was added Pd / C (40.0 mg, 0.78 mmol). The reaction mixture was stirred under a hydrogen atmosphere at 25 °C for 1 hour. The mixture was filtered, and the filtrate was concentrated in vacuo to give (2S)-3-methyl-2-(3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[5,1-c][1,4]oxazin-2-yl)butanoic acid (Compound 15g, 62.0 mg) as a colorless oil. MS calculated 243.1 (MH + ), measured value 243.2 (MH + ).

[0206] Example 16 (3R)-N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-3-hydroxy-N,3-dimethyl-piperidine-1-carboxamide TIFF2025525565000068.tif56170 In a manner similar to the preparation of Example 1, (3R)-3-methylpiperidin-3-ol; hydrochloride and (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-tetraazapentacyclo[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 I) was reacted with N,N-dimethylazetidin-3-amine dihydrochloride (compound 1D) and (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-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ] was used instead of octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate C) to prepare the title compound. Example 16 (13.9 mg) was obtained as a white solid. MS calculated 1042.5 (MH + ), measured value 1042.5 (MH + ). 1H NMR (400 MHz, methanol-d4) δ = 8.73-8.69 (d, J = 7.2 Hz, 1H), 8.44-8.39 (d, J = 2.8 Hz, 1H), 7.70-7.67 (d, J = 2.8 Hz, 1H), 7.67-7.64 (d, J = 2.4 Hz, 1H), 7.51-7.45 (d, J = 12.4 Hz, 1H), 5.80-5.74 (d, J = 8.4 Hz, 1H), 5.23-5. 13(m,1H),4.83-4.76(m,1H),4.47-4.40(m,1H),4.29-4.23(q,J=6.4Hz,J=12.0Hz,1H),4.23-4.17(dd, J=2.4,11.6Hz,1H),4.05-3.99(d,J=10.8Hz,1H),3.89-3.85(t,J=4.4Hz,4H),3.82-3.78(d,J=11.2Hz, 1H),3.74-3.69(d,J=11.2Hz,1H),3.56-3.45(m,2H),3.39-3.36(m,6H),3.29-3.19(m,2H),3.14-3.06( m,1H),3.03-2.96(d,J=12.8Hz,2H),2.91-2.89(s,3H),2.87-2.78(m,1H),2.71-2.63(m,1H),2.29-2.1 6(m,2H),2.00-1.90(m,3H),1.88-1.76(m,1H),1.74-1.68(m,1H),1.67-1.53(m,3H),1.49-1.45(d,J=6 .4Hz,3H),1.34-1.27(m,1H),1.25-1.21(s,3H),0.99-0.93(dd,J=6.0,12.0Hz,9H),0.56-0.49(s,3H).

[0207] Example 17 N-[(1S)-1-[[(7S,13S)-25-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]carbamoyl]-2-methyl-propyl]-N-methyl-morpholine-4-carboxamide TIFF2025525565000069.tif64170 In a manner similar to the preparation of Example 1, morpholine and (7S,13S)-7-amino-25-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-tetraazapentacyclo[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 J) was reacted with N,N-dimethylazetidin-3-amine dihydrochloride (compound 1D) and (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-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ] was used instead of octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate C) to prepare the title compound. Example 17 (12.9 mg) was obtained as a yellow solid. MS calculated 1094.5 (MH + ), measured value 1094.5 (MH + ). 1H NMR (400MHz, methanol-d4) δ=8.49-8.39(m,1H),7.74(br s,1H),7.53-7.44(m,3H),5.97(br d,J=5.9Hz,1H),5.18-5.11(m,1H),4.67-4.58(m,1H),4.42-4.33(m,1H),4.10-3.97(m,1H),3.94 -3.80(m,2H),3.76-3.63(m,5H),3.58-3.42(m,7H),3.26-3.14(m,8H),3.13-2.99(m,2H),2.93(br d,J=14.4Hz,8H),2.62-2.53(m,1H),2.30-2.14(m,1H),1.61-1.49(m,1H),1.43(br d,J=6.1Hz,3H),1.34-1.15(m,3H),0.92(br t,J=7.3Hz,6H),0.85-0.69(m,6H).

[0208] Example 18 N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N,4-dimethyl-piperazine-1-carboxamide TIFF2025525565000070.tif67170 In a manner similar to the preparation of Example 1, 1-methylpiperazine and (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-tetraazapentacyclo[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 (intermediate E) was reacted with N,N-dimethylazetidin-3-amine dihydrochloride (compound 1D) and (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-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ] was used instead of octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate C) to prepare the title compound. Example 18 (10.8 mg) was obtained as a white solid. MS calculated 1108.5 (MH + ), measured value 1108.5 (MH + ). 1H NMR (400MHz, methanol-d4) δ=8.70-8.65(d,J=7.6Hz,1H),8.45-8.40(d,J=2.8Hz,1H),7.70-7.65(d,J=2.4Hz,1H),7.50-7.43(d,J=12.8Hz,1H),7.33-7. 28(d,J=2.8Hz,1H),5.78-5.70(d,J=9.2Hz,1H),5.20-5.05(m,1H),4.62-4 .61(s,1H),4.46-4.40(m,1H),4.28-4.20(m,1H),4.19-4.13(m,1H),4.06- 3.99(d,J=11.2Hz,1H),3.83-3.65(m,3H),3.53-3.40(m,4H),3.27-3.07(m ,6H),2.94-2.81(m,9H),2.63-2.45(m,6H),2.37-2.34(s,3H),2.29-2.17( m,3H),2.00-1.93(m,1H),1.90-1.75(m,2H),1.71-1.56(m,1H),1.46-1.41 (d,J=6.4Hz,3H),1.33-1.15(m,1H),0.98-0.91(m,9H),0.47-0.42(s,3H).

[0209] Example 19 N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N-methyl-4-(2,2,2-trifluoroethyl)piperazine-1-carboxamide TIFF2025525565000071.tif67170 In a manner similar to the preparation of Example 1, 1-(2,2,2-trifluoroethyl)piperazine and (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-tetraazapentacyclo[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) was reacted with N,N-dimethylazetidin-3-amine dihydrochloride (compound 1D) and (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-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ] was used instead of octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate C) to prepare the title compound. Example 19 (12.1 mg) was obtained as a white solid. MS calculated 1176.5 (MH + ), measured value 1176.5 (MH + ). 1H NMR (400 MHz, methanol-d4) δ = 8.82-8.63 (d, J = 7.2 Hz, 1H), 8.48-8.38 (d, J = 2.8 Hz, 1H), 7.75-7.67 (d, J = 2.0 Hz, 1H), 7.54-7.43 (d, J = 12.4 Hz, 1H), 7.35-7.28 (d, J = 2.4 Hz, 1H), 5.86-5.72 (d, J = 8.8 Hz,1H),5.26-5.03(m,1H),4.98-4.90(m,3H),4.66-4.56(m,1H),4.51-4.41(m,1H),4.32-4.13 (m,2H),4.07-4.03(d,J=11.3Hz,1H),3.86-3.77(d,J=11.6Hz,1H),3.76-3.69(d,J=11.2Hz,1H) ,3.57-3.48(m,1H),3.48-3.41(m,2H),3.39-3.35(d,J=3.1Hz,4H),3.29-3.23(m,1H),3.22-3. 10(m,6H),2.96-2.92(s,3H),2.91-2.86(t,J=4.8Hz,4H),2.85-2.76(m,3H),2.76-2.69(m,2H), 2.67-2.57(d,J=14.4Hz,1H),2.33-2.19(m,2H),2.03-1.94(m,1H),1.92-1.79(m,1H),1.73-1. 59(m,1H),1.50-1.41(d,J=6.0Hz,3H),1.35-1.30(m,1H),1.00-0.92(m,9H),0.54-0.41(s,3H).

[0210] Biological Examples Compound A555 of WO2021091956 (Table 1 on page 158) is cited as a reference compound of the present invention. TIFF2025525565000072.tif58170(A555)

[0211] Example 20 Single-dose pharmacokinetic (PK) study in female BALB / c mice The purpose of this study was to determine the pharmacokinetics of selected compounds after a single intravenous bolus or oral gavage administration in female BALB / c mice. Briefly, two groups of female BALB / c mice (available from Shanghai Lingchang Biotechnology Co., Ltd.) (N = 3 / group) were treated with a single dose of compound at 3 mg / kg intravenously (IV) or 30 mg / kg orally (PO). Blood samples were collected 5 minutes (IV only), 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 7 hours, and 24 hours after administration. Blood samples were kept on ice until centrifugation to obtain plasma samples. Compound concentrations in plasma samples were determined using an LC-MS / MS method. Pharmacokinetic parameters were calculated by noncompartmental analysis. [Table 1]

[0212] From Table 1, Example 6 has a higher C max almost 7 times higher, AUC 0-last It has been shown to have superior pharmacokinetic properties in mouse models, including a 15-fold increase in potency, improved bioavailability, and significantly lower clearance.

[0213] Example 21 Human hepatocyte stability assay The hepatocyte stability assay measures the rate of compound disappearance from incubation with cryopreserved suspension hepatocytes of human origin. Positive controls containing midazolam, raloxifene, and dextromethorphan are included in all experiments. Incubations are performed with 1 μM test compound and human hepatocytes (1 x 10 cells) in supplemented Williams' E medium containing 10% FBS and 0.5% penicillin-streptomycin. 6The hepatocyte suspension consisted of a suspension of 1000 cells / mL. The hepatocyte suspension was incubated in a 5% CO2 incubator at 37°C with intermittent shaking at 900 rpm. The reaction was stopped by adding methanol containing an internal standard (2 μM tolbutamide) at 2, 10, 20, 40, 60, and 120 min after compound addition, and the depletion of the parent compound was monitored by LC-MS / MS analysis. [Table 2]

[0214] The above results clearly show that in the human hepatocyte stability assay, the reference compound (A555) had a much higher clearance, while Example 6 maintained a low clearance. Achieving low clearance is advantageous for improving the in vivo performance of a compound, such as dose reduction, enhanced exposure, and extended half-life.

[0215] Example 22 Cell viability assay The purpose of this cellular 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.

[0216] 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-OD650) was read using EnVision. IC 50was determined by fitting a four-parameter sigmoidal concentration-response model. [Table 3]

[0217] Example 23 KRAS-BRAF interaction assay with 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. Compounds were added to the plate wells as a 16-point, 3-fold dilution series starting at a final concentration of 10 μM and 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 promote disruption of the KRAS-BRAF complex were identified as compounds that induce a decrease in the TR-FRET ratio compared to DMSO control wells. [Table 4]

[0218] Example 24 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 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 1:10 with phosphate-buffered saline Tween (PBST)) for at least 1 hour at room temperature.

[0219] 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. The cells were washed five times for 5 minutes with PBST. 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 at room temperature for 1–2 hours. The cells were washed five times for 5 minutes with PBST, 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 by EnVision.

[0220] I C 50 was determined by fitting a four-parameter sigmoidal concentration-response model. [Table 5]

[0221] Example 25 Stable KRAS mutant cell lines and cell viability assays The purpose of this study was to determine the potency and efficacy of compounds on cell proliferation using the CellTiter-Glo® (CTG) Luminescent Cell Viability Assay (Promega Corp., Madison, WI). We identified 14 KRAS mutants with secondary mutations (V8A, V9Y, S17E, T58I, A59T, S65W, R68S, D69P, M72I, D92R, H95N, Y96D, Q99F, Q99W, Y96H, and F156L). G12CThe mutant sequences were cloned into Miapaca-2. A total of 14 stable Miapaca-2 mutant cell lines were established by lentiviral infection. For cell viability assays, cells were treated with compounds in a nine-point dose response using a 4-fold dilution series with the highest dose at 10 μM. KRAS mutant cells were maintained in DMEM + 10% FBS + 2.5% HI horse serum + 1% PS + 1 μg / mL puromycin and seeded at 800–1,500 cells / well in 96-well plates 24 h before compound addition. After 3 days of compound incubation, viability was assayed (CellTiter-Glo, Promega). Assays were performed in biological replicates. Nonlinear regression curves were fitted using Xfit. The IC50 (absolute IC50) is the dose at which estimated viability is 50% relative to untreated wells. The inhibition rate of the compound is calculated according to the following formula: % inhibition=100−100×(luminescence value−HPE) / (ZPE−HPE). HPE: luminescence values from wells containing medium only Luminescence values from wells containing ZPE:DMSO [Table 8]

Claims

1. Formula (I) (In the formula, R １ teeth, , 3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[5,1-c][1,4]oxazinyl or (C １～６ alkyl)oxoimidazolidinyl, R ８ is C １～６ is alkyl, R ９ is ((C １～６ alkyl) ２ Amino)azetidinyl, C １～６ Alkylpiperazinyl, haloazetidinyl, halo C １～６ Alkylamino, HaloC １～６ Alkylaminoazetidinyl, halo C １～６ Alkylpiperazinyl, hydroxy(C １～６ alkyl)piperidinyl or morpholinyl; R ２ is C １～６ is alkyl, R ３ is H or a halogen, R ４ is H or a halogen, R ５ is C １～６ Alkyl or halo C １～６ is alkyl, R ６ is C １～６ Alkoxy C １～６ is alkyl, R ７ 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 ３ and R ４ is not H at the same time) or a pharmaceutically acceptable salt thereof.

2. Formula (Ia) (In the formula, R １ teeth, , 3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[5,1-c][1,4]oxazinyl or (C １～６ alkyl)oxoimidazolidinyl, R ８ is C １～６ is alkyl, R ９ is ((C １～６ alkyl) ２ Amino)azetidinyl, C １～６ Alkylpiperazinyl, haloazetidinyl, halo C １～６ Alkylamino, HaloC １～６ Alkylaminoazetidinyl, halo C １～６ Alkylpiperazinyl, hydroxy(C １～６ alkyl)piperidinyl or morpholinyl; R ２ is C １～６ is alkyl, R ３ is H or a halogen, R ４ is H or a halogen, R ５ is C １～６ Alkyl or halo C １～６ is alkyl, R ６ is C １～６ Alkoxy C １～６ is alkyl, R ７ 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 ３ and R ４ is not H at the same time) or a pharmaceutically acceptable salt thereof.

3. R １ but, and R ８ But C １～６ alkyl, and R ９ But C １～６ Alkylpiperazinyl, HaloC １～６ 3. The compound of claim 1 or 2, which is alkylpiperazinyl or morpholinyl.

4. R １ but, and R ８ is methyl, and R ９ The compound according to any one of claims 1 to 3, wherein is 4-methylpiperazin-1-yl, 4-(2,2,2-trifluoroethyl)piperazin-1-yl or morpholinyl.

5. R １ is methyl-(4-methylpiperazine-1-carbonyl)amino, methyl-[4-(2,2,2-trifluoroethyl)piperazine-1-carbonyl]amino or methyl(morpholine-4-carbonyl)amino.

6. R ２ The compound according to any one of claims 1 to 5, wherein is isopropyl.

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

8. R ３ The compound of any one of claims 1 to 7, wherein is fluoro.

9. R ４ The compound of any one of claims 1 to 8, wherein is H or fluoro.

10. R ４ The compound of any one of claims 1 to 9, wherein is H.

11. R ５ But, Haro C １～６ The compound of any one of claims 1 to 10, which is alkyl.

12. R ５ The compound according to any one of claims 1 to 11, wherein is 2,2,2-trifluoroethyl.

13. R ６ The compound of any one of claims 1 to 12, wherein is 1-methoxyethyl.

14. R ７ However, (Haro C １～６ The compound of any one of claims 1 to 13, which is a (alkyl)piperazinyl.

15. R ７ The compound according to any one of claims 1 to 14, wherein is 4-(2,2,2-trifluoroethyl)piperazin-1-yl.

16. A １ but, 16. The compound of any one of claims 1 to 15, wherein bond "a" connects to the indole ring.

17. A ２ The compound according to any one of claims 1 to 16, wherein is dimethylmethylene.

18. R １ but, and R ８ But C １～６ alkyl, and R ９ But C １～６ Alkylpiperazinyl, HaloC １～６ alkylpiperazinyl or morpholinyl, R ２ But C １～６ is alkyl, R ３ is a halogen, R ４ is H, R ５ But, Haro C １～６ is alkyl, R ６ But C １～６ Alkoxy C １～６ is alkyl, R ７ However, (Haro C １～６ alkyl)piperazinyl, A １ but wherein bond "a" connects to the indole ring; A ２ But C １～６ is alkylene, 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

19. R １ is methyl-(4-methylpiperazine-1-carbonyl)amino, methyl-[4-(2,2,2-trifluoroethyl)piperazine-1-carbonyl]amino or methyl(morpholine-4-carbonyl)amino, R ２ is isopropyl, R ３ But it is fluoro, R ４ is H, R ５ is 2,2,2-trifluoroethyl, R ６ is (1S)-1-methoxyethyl, R ７ is 4-(2,2,2-trifluoroethyl)piperazin-1-yl, A １ but wherein bond "a" connects to the indole ring; A ２ is dimethylmethylene, 19. The compound of claim 18, or a pharmaceutically acceptable salt thereof.

20. below: 3-(Dimethylamino)-N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N-methyl-azetidine-1-carboxamide; 3-(Dimethylamino)-N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N-methyl-azetidine-1-carboxamide; N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N-methyl-morpholine-4-carboxamide; 3-(Dimethylamino)-N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N-methyl-azetidine-1-carboxamide; N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N-methyl-morpholine-4-carboxamide; N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N-methyl-morpholine-4-carboxamide; N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-3,3-difluoro-N-methyl-azetidine-1-carboxamide; (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]-3-methyl-2-(3-methyl-2-oxo-imidazolidin-1-yl)butanamide; N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N-methyl-morpholine-4-carboxamide; N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N-methyl-morpholine-4-carboxamide; N-[(1S)-1-[[(7S,13S)-24-fluoro-20-(20M)-[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]carbamoyl]-2-methyl-propyl]-N-methyl-morpholine-4-carboxamide; 3-(Dimethylamino)-N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N-methyl-azetidine-1-carboxamide; (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]-3-methyl-2-[methyl(2,2,2-trifluoroethylcarbamoyl)amino]butanamide; N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N-methyl-3-(trifluoromethyl)azetidine-1-carboxamide; (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]-3-methyl-2-(3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[5,1-c][1,4]oxazin-2-yl)butanamide; (3R)-N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-3-hydroxy-N,3-dimethyl-piperidine-1-carboxamide; N-[(1S)-1-[[(7S,13S)-25-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]carbamoyl]-2-methyl-propyl]-N-methyl-morpholine-4-carboxamide; N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N,4-dimethyl-piperazine-1-carboxamide; and N-[(1S)-1-[[(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]carbamoyl]-2-methyl-propyl]-N-methyl-4-(2,2,2-trifluoroethyl)piperazine-1-carboxamide 1. A compound selected from:

21. A process for the preparation of a compound according to any one of claims 1 to 20, comprising the following steps: a) reacting a compound of formula (II), in the presence of a coupling reagent and a base, to form a compound of formula (I), with an acid (III), Coupling reaction with Including, In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , A １ and A ２ is defined as in any one of claims 1 to 19, and the coupling reagent is T ３ P, HATU, PyBOP or EDCI / HOBt, and the base is TEA, DIEPA or DMAP.

22. 21. A compound or a pharmaceutically acceptable salt according to any one of claims 1 to 20 for use as a therapeutically active substance.

23. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 and a pharmaceutically acceptable excipient.

24. Use of a compound according to any one of claims 1 to 20 for treating a KRAS G12C protein-related disease.

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

26. Use of a compound according to any one of claims 1 to 20 for inhibiting RAS interaction with downstream effectors, wherein said downstream effectors are RAF and PI3K.

27. Use of a compound according to any one of claims 1 to 20 for inhibiting propagated oncogenic MAPK and PI3K signalling.

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

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

30. 21. The compound or pharmaceutically acceptable salt of any one of claims 1 to 20, 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.

31. 21. Use of a compound according to any one of claims 1 to 20 for the treatment or prevention of a KRAS mutation-driven cancer, wherein said cancer comprises a first mutation which is G12C and a second mutation at a position selected from V8A, V9Y, S17E, T58I, A59T, S65W, R68S, D69P, M72I, D92R, H95N, Y96D, Q99F, Q99W, Y96H and F156L.

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

33. 20. Use of a compound according to any one of claims 1 to 18 for the preparation of a medicament for the treatment or prevention of a KRAS mutation-driven cancer, wherein said cancer comprises a first mutation which is G12C and a second mutation at a position selected from V8A, V9Y, S17E, T58I, A59T, S65W, R68S, D69P, M72I, D92R, H95N, Y96D, Q99F, Q99W, Y96H and F156L.

34. 21. A method for the treatment or prevention of KRAS mutation-driven cancer, wherein said cancer is selected from pancreatic adenocarcinoma, colorectal cancer and non-small cell lung cancer, said method comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 20.

35. 1. A method for the treatment or prevention of a KRAS mutation-driven cancer, wherein said cancer comprises a first mutation that is G12C and a second mutation at a position selected from V8A, V9Y, S17E, T58I, A59T, S65W, R68S, D69P, M72I, D92R, H95N, Y96D, Q99F, Q99W, Y96H and F156L.

36. 22. A compound or a pharmaceutically acceptable salt according to any one of claims 1 to 20 when prepared according to the method of claim 21.

37. The invention as hereinbefore described.

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