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WO2025247370A1 - Composé bicyclique et son utilisation pharmaceutique - Google Patents

Composé bicyclique et son utilisation pharmaceutique

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Publication number
WO2025247370A1
WO2025247370A1 PCT/CN2025/098324 CN2025098324W WO2025247370A1 WO 2025247370 A1 WO2025247370 A1 WO 2025247370A1 CN 2025098324 W CN2025098324 W CN 2025098324W WO 2025247370 A1 WO2025247370 A1 WO 2025247370A1
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phenyl
compound
crude product
methyl
replaced
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English (en)
Chinese (zh)
Inventor
孙宏斌
杨建新
李晶
付卓歆
冯志奇
戴量
张元�
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China Pharmaceutical University
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China Pharmaceutical University
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Definitions

  • This invention belongs to the field of biomedicine, specifically relating to a bicyclic compound and its pharmaceutical uses.
  • the Hippo signaling pathway is an evolutionarily conserved signaling cascade pathway, first discovered in Drosophila and highly conserved in mammals, regulating growth and development, cell homeostasis, cell proliferation, and differentiation of organisms or organs (Annu Rev Biochem, 2019, 88:577-604). This pathway may be involved in regulating the self-renewal and differentiation of stem cells and progenitor cells. In addition, the Hippo pathway may also be involved in wound healing and tissue regeneration (Cell Mol Life Sci, 2021, 78(2):497-512; Dev Cell, 2019, 50(3):264-282).
  • the Hippo pathway also crosstalks with other signaling pathways such as Wnt, Notch, Hedgehog, and MAPK/ERK, which may affect a variety of biological events, and its dysfunction may be involved in other human diseases besides cancer (Genes Dev, 2019, 33(21-22): 1491-1505; Cell, 2014, 158(1): 157-70; Oncogene, 2014, 33(40): 4857-66; Cancer Cell, 2020, 37(1): 104-122).
  • the Hippo signaling pathway consists of the following core components: upstream regulators (such as NF2/Merlin, SCRIBBLE, CRUMBS, and GPCRs), a core kinase cascade (MST1/2 and LATS1/2 and their adaptor proteins SAV1 and MOB1), and downstream effector factors (the transcriptional coactivator Yes-associated protein (YAP) and the transcriptional coactivator with the PDZ-binding motif (TAZ)).
  • upstream regulators such as NF2/Merlin, SCRIBBLE, CRUMBS, and GPCRs
  • downstream effector factors the transcriptional coactivator Yes-associated protein (YAP) and the transcriptional coactivator with the PDZ-binding motif (TAZ)
  • YAP transcriptional coactivator Yes-associated protein
  • TEZ transcriptional coactivator with the PDZ-binding motif
  • Phosphorylated LATS1/2 then further phosphorylates YAP/TAZ.
  • Phosphorylated YAP/TAZ remains in the cytoplasm, isolated by the 14-3-3 protein, or degraded by the proteasome via ubiquitin-mediated degradation.
  • dephosphorylated YAP and TAZ are transported to the nucleus and bind to transcription factors TEAD1/2/3/4 of the transcriptional enhancer factor TEF with TEA/ATTS domain (TEAD) family.
  • YAP or TAZ with TEAD induces the expression of multiple genes, including connective tissue growth factor (CTGF), cysteine-rich angiogenesis inducer 61 (CYR61), amphotericin G (AREG), proto-oncogene (MYC), GLI family zinc finger 2 (Gli2), AXL receptor tyrosine kinase (AXL), and B-cell lymphoma-2 gene (Bcl2).
  • CTGF connective tissue growth factor
  • CYR61 cysteine-rich angiogenesis inducer 61
  • AREG amphotericin G
  • MYC proto-oncogene
  • GLI family zinc finger 2 Gli2
  • AXL receptor tyrosine kinase AXL receptor tyrosine kinase
  • Bcl2 B-cell lymphoma-2 gene
  • the closed Hippo pathway may act as an oncogene through unphosphorylated YAP and TAZ, while the open Hippo pathway may act as a tumor suppressor through phosphorylated YAP and TAZ.
  • the Hippo pathway also plays a role in the resistance mechanisms of cancer cells to oncology and immuno-oncology therapies (Cancer Res, 2023, 83(24):4112-4129; Pharmaceuticals (Basel), 2023, 16(4):553).
  • the pro-cancer transcriptional activity of YAP/TAZ-TEAD can be inhibited by suppressing palmitoylation of TEAD protein or by inhibiting the YAP/TAZ-TEAD protein interaction.
  • inhibiting TEAD, YAP/TAZ, or the interaction between YAP/TAZ and TEAD through pharmacology may be a potential, rational, and valuable strategy for the prevention or treatment of cancer, organ fibrosis, metabolic diseases, or inflammatory diseases mediated by TEAD, YAP/TAZ, or the interaction between YAP/TAZ and TEAD.
  • the present invention provides a bicyclic compound and its pharmaceutical uses.
  • the bicyclic compound or its pharmaceutically acceptable salts, esters, stereoisomers, deuterated derivatives or solvates can act as TEAD inhibitors and have excellent therapeutic effects on TEAD-mediated, YAP/TAZ-mediated or YAP/TAZ-TEAD-mediated diseases.
  • the present invention provides a bicyclic compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • X is selected from CR a or N, and Ra is selected from H or halogen; Y is selected from CH or N;
  • Cycle A is selected from C6-10 aryl, 5-10 heteroaryl or C3-6 cycloalkenyl, wherein the 5-10 heteroaryl contains 1-4 heteroatoms independently selected from N, O or S;
  • Each R1 may be the same or different, and each is independently selected from H, D, halogen, -CN, -NO 2 , -NH 2 , -OR b1 , -SR b2 , -SF 5 , substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C3-6 cycloalkyl, or substituted or unsubstituted phenyl, wherein the substituted C1-6 alkyl, C3-6 cycloalkyl and phenyl are optionally substituted by 0 to 3 substituents independently selected from -OH, halogen, -CN, -NO 2 or -NH 2 ;
  • Cycle B is selected from C 6-10 aryl, 5-10 heteroaryl or C 3-6 cycloalkenyl, wherein the 5-10 heteroaryl contains 1-4 heteroatoms independently selected from N, O or S;
  • Each R2 may be the same or different, and each is independently selected from H, D, halogen, -CN, -NO2 , -NH2 , -ORb1 , -SRb2 , substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C3-6 cycloalkyl, or substituted or unsubstituted phenyl, wherein the substituted C1-6 alkyl, C3-6 cycloalkyl and phenyl are optionally substituted by 0 to 3 substituents independently selected from -OH, halogen or -CN;
  • Rb1 and Rb2 may be the same or different each time, and each is independently selected from H, D, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted phenyl, wherein the substituted C1-6 alkyl and phenyl are optionally substituted by 0 to 3 substituents independently selected from halogen, -CN, -NH2 or -OH;
  • R 3 is selected from
  • R4 and R5 may be the same or different each time, and each is independently selected from H, D, -OH, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C3-6 cycloalkyl, or substituted or unsubstituted phenyl, wherein the substituted C1-6 alkyl, C3-6 cycloalkyl and phenyl are optionally substituted by 0 to 3 substituents independently selected from halogen , -ORf or -NRfRg ; Rf and Rg may be the same or different each time, and each is independently selected from H, C1-6 alkyl or C3-6 cycloalkyl;
  • Rc , Rd , and Re may be the same or different each time, and each is independently selected from H, D, halogen, -CN, -OH, or C1-6 halogenated or unhalogenated alkyl groups;
  • n is selected from any integer from 0 to 3;
  • n is any integer from 0 to 3.
  • X is selected from CR a or N, wherein Ra is selected from H; and Y is selected from CH or N.
  • ring A is specifically selected from any of the following structural segments:
  • Each R1 may be the same or different, and each is independently selected from H, halogen, -OR b1 , -SR b2 , -SF 5 , substituted or unsubstituted C1-4 alkyl, or substituted or unsubstituted phenyl, wherein the substituted C1-4 alkyl and phenyl are optionally substituted by 0 to 3 substituents independently selected from -OH or halogen;
  • Rb1 and Rb2 may be the same or different each time, and each is independently selected from H, D, substituted or unsubstituted C1-6 alkyl groups, or substituted or unsubstituted phenyl groups, wherein the substituted C1-6 alkyl groups and phenyl groups are optionally substituted by 0 to 3 substituents independently selected from halogens, -CN, -NH2 , or -OH.
  • ring B is specifically selected from any one of the following structural segments:
  • Each R2 may be the same or different, and each is independently selected from halogens, -OR b1 , -SR b2 , or substituted or unsubstituted C1-3 alkyl groups, wherein the substituted C1-3 alkyl groups are optionally substituted by 0 to 3 substituents independently selected from -OH or halogens.
  • Rb1 and Rb2 may be the same or different each time, and each is independently selected from H, or substituted or unsubstituted C1-3 alkyl groups, wherein the substituted C1-3 alkyl group is optionally substituted by 0 to 3 substituents independently selected from halogens.
  • R3 is selected from any of the following structural segments:
  • R4 and R5 may be the same or different each time, and each is independently selected from H, or substituted or unsubstituted C1-3 alkyl groups, wherein the substituted C1-3 alkyl groups are optionally substituted by 0 to 3 substituents independently selected from halogens;
  • Rc , Rd , and Re may be the same or different each time, and each is independently selected from H, halogen, or C1-3 halogenated or unhalogenated alkyl;
  • n is selected from any integer from 0 to 2;
  • n is any integer from 0 to 2.
  • the bicyclic compound further includes its pharmaceutically acceptable salt, tautomer, meso compound, racemic compound, stereoisomer, metabolite, metabolic precursor, prodrug, chelate, non-covalent complex, or solvate.
  • the bicyclic compound of Formula I of the present invention is selected from any one of the compounds shown in Table 1 below:
  • the bicyclic compounds of the present invention can be used as pharmaceutical salts, which can be salts formed by the compounds of the present invention with metal ions (including sodium, potassium, calcium, etc.) or pharmaceutically acceptable amines (including ethylenediamine, tromethamine, diisopropylamine, meglumine, berberine, metformin, etc.) or ammonium ions.
  • metal ions including sodium, potassium, calcium, etc.
  • pharmaceutically acceptable amines including ethylenediamine, tromethamine, diisopropylamine, meglumine, berberine, metformin, etc.
  • ammonium ions including sodium, potassium, calcium, etc.
  • bicyclic compounds or their pharmaceutically acceptable salts, tautomers, meso compounds, racemates, stereoisomers, metabolites, metabolic precursors, prodrugs, chelates, non-covalent complexes or solvates described in this invention in the preparation of TEAD inhibitors.
  • the bicyclic compounds described in this invention can be used as TEAD inhibitors to prepare drugs for the prevention or treatment of TEAD-mediated, YAP/TAZ-mediated, or YAP/TAZ-TEAD-mediated diseases.
  • the compounds of the present invention can be used to prepare medicaments for the prevention or treatment of diseases mediated by TEAD, YAP/TAZ, or by the interaction between YAP/TAZ and TEAD.
  • the compounds of this invention can be used to prevent or treat cancers, including mesothelioma, glioma, medulloblastoma, myeloma, myelodysplastic syndrome, Hodgkin's lymphoma, non-Hodgkin's lymphoma, meningioma, sarcoma, melanoma, germ cell tumor (pineal tumor), astrocytoma, medulloblastoma, ependymoma, head and neck cancer, colorectal cancer, gastric cancer, thyroid cancer, lung cancer, leukemia, pancreatic cancer, hematologic malignancies, esophageal squamous cell carcinoma, bone cancer, vascular cancer, brain cancer, kidney cancer, liver cancer, squamous cell carcinoma, basal cell carcinoma, bladder cancer, prostate cancer, uterine cancer, testicular cancer, interstitial cell carcinoma, ovarian cancer, or breast cancer, etc.
  • cancers including mes
  • the compounds of this invention can be used to prevent or treat organ fibrosis, metabolic diseases, or inflammatory diseases, including liver cirrhosis, liver fibrosis, idiopathic pulmonary fibrosis, renal fibrosis, cystic fibrosis, systemic sclerosis, progressive nephropathy, diabetic nephropathy, cardiovascular fibrosis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, alcoholic fatty liver, cirrhosis, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), interstitial pneumonia, pulmonary tuberculosis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), Behcet's disease, asthma, chronic obstructive pulmonary disease, chronic bronchitis, and pulmonary emphysema.
  • organ fibrosis including liver cirrhosis, liver fibrosis, idiopathic pulmonary fibro
  • This invention also provides a pharmaceutical composition for the prevention or treatment of diseases mediated by TEAD, YAP/TAZ, or by the interaction between YAP/TAZ and TEAD, comprising a therapeutically effective amount of a bicyclic compound of formula (I) or a pharmaceutically acceptable salt thereof, tautomer, meso compound, racemic compound, stereoisomer, metabolite, metabolic precursor, prodrug, chelate, non-covalent complex, or solvate as the active ingredient and a pharmaceutically acceptable carrier.
  • the carrier can be varied depending on the dosage form, administration method, etc. Examples of carriers include excipients, binders, disintegrants, lubricants, flavoring agents, fragrances, colorants, and sweeteners.
  • the pharmaceutical composition may be in pharmaceutically conventional forms such as capsules, powders, tablets, granules, pills, injections, syrups, oral solutions, inhalers, ointments, suppositories, or patches.
  • the pharmaceutical composition of the present invention may contain one or more excipients selected from the following components: fillers, binders, wetting agents, disintegrants, or excipients. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.
  • halogen refers to F, Cl, Br, and I.
  • alkyl refers to a saturated monovalent hydrocarbon group having a straight-chain, branched, or cyclic moiety having 1 to 6 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, and cyclohexyl.
  • aryl refers to a 6- to 10-membered monocyclic or polycyclic system containing a carbon ring atom, whether unsubstituted or substituted. Examples of such aryl groups include, but are not limited to, phenyl and naphthyl groups.
  • heteroaryl refers to an unsubstituted or substituted stable 5- or 6-membered monocyclic aromatic ring system, or an unsubstituted or substituted 8- to 10-membered benzo[a]-fused heteroaromatic ring system, or a bicyclic heteroaromatic ring system, consisting of a carbon atom and 1 to 4 heteroatoms selected from N, O, or S, wherein the N or S heteroatoms may optionally be oxidized, and the N heteroatoms may optionally be quaternized.
  • Heteroaryl groups can be attached to any heteroatom or carbon atom to produce a stable structure.
  • heteroaryl groups include, but are not limited to, pyrrole, thiophene, furanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, azaindolyl, indolyl, azaindolyl, benzimidazolyl, benzofuranyl, benzothiophene, benzoisooxazolyl, benzooxazolyl, benzopyrazolyl, benzothiazolyl, quinolinyl, and isoquinolinyl.
  • cycloalkyl refers to a cyclic saturated alkyl group having 3 to 6 carbon atoms.
  • examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • composition is intended to include products containing specific amounts of specific ingredients, as well as products directly or indirectly produced from combinations of specific amounts of specific ingredients. Therefore, pharmaceutical compositions containing compounds of the present invention as active ingredients, and methods for preparing the compounds of the present invention, are also part of this invention. Furthermore, some compounds can form solvates with water or common organic solvents, and such solvates are also included within the scope of this invention.
  • pharmaceutically acceptable salt refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base.
  • a base addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, aluminum, magnesium, bismuth, and ammonium salts.
  • an acid addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent.
  • Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochlorides, acetates, trifluoroacetates, sulfates, and methanesulfonates.
  • the present invention has the following advantages:
  • the bicyclic compounds provided by the present invention or their pharmaceutically acceptable salts, esters, stereoisomers, deuterated compounds or solvates have strong TEADs inhibitory activity. Multiple compounds show an inhibition rate of more than 80% against TEADs at a concentration of 1 ⁇ M, inhibiting the transcriptional activity of YAP/TAZ and TEAD protein/protein interactions; they can be used to prepare or treat drugs for TEADs-mediated diseases.
  • bicyclic compounds of the present invention or their pharmaceutically acceptable salts, esters, stereoisomers, deuterated compounds or solvates are easy to prepare and inexpensive, and have simple structures, ingenious designs, cheap and readily available raw materials, safe and environmentally friendly synthesis processes, and are easy to scale up for production.
  • Cu(OAc) 2 Copper acetate; NaHCO3: Sodium bicarbonate; NH4Cl : Ammonium chloride; CuI: Cuprous iodide; CuCl: Cuprous chloride; NaNO2 : Sodium nitrite; Cs2CO3 : Cesium carbonate; K2CO3 : Potassium carbonate; MeNH2 ⁇ HCl : Methylamine hydrochloride; LiOH ⁇ H2O : Lithium hydroxide monohydrate; DPPA: Diphenyl azidophosphate; TEA or Et3N : Triethylamine; Py: Pyridine ; 4,4'-Bipyridine: 4,4-Bipyridine; B2 (OH) 4 : Tetrahydroxydiboron; SnCl2 ⁇ 2H2O : Stannous chloride dihydrate; STAB: Sodium triacetoxyborohydride; CDI: N,N'-carbonyldiimidazolium; NaH:
  • reagents and solvents are used in the form obtained from the supplier.
  • Anhydrous solvents and dried glassware are used for synthetic transformations sensitive to moisture and/or oxygen. Yields are not optimized. Reaction times are approximate and not optimized.
  • Column chromatography and thin-layer chromatography (TLC) are performed on silica gel, with 200-300 mesh silica gel from Qingdao Ocean Chemical Plant Branch generally used as the support for column chromatography.
  • the structure of the compound was determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR measurements were performed using a Bruker NMR spectrometer with deuterated dimethyl sulfoxide (DMSO- d6 ) or deuterated chloroform ( CDCl3 ) as the solvent and tetramethylsilane (TMS) as the internal standard.
  • DMSO- d6 deuterated dimethyl sulfoxide
  • CDCl3 deuterated chloroform
  • TMS tetramethylsilane
  • the known starting materials of this invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as Leyan, Bidex Pharmaceuticals, Aladdin, and Anaiji.
  • Iron powder (192 mg, 3.4 mmol) was added to a mixture of 1-1 (330 mg, 0.85 mmol) and NH4Cl (51 mg, 0.95 mmol) in EtOH (2 mL) and water (1 mL), and the mixture was heated and stirred at 80 °C for 4 h.
  • the residue was concentrated under reduced pressure using anhydrous magnesium sulfate pad suction. PE (2.0 mL) and EA (0.2 mL) were added to the residue, and the mixture was stirred at room temperature for 1 h.
  • Step 4 Preparation of N-(3-(1-methyl-1H-pyrazole-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-yl)methanesulfonamide
  • Step 1 Preparation of N-(3-(1H-imidazol-1-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-5-yl)methanesulfonamide
  • Step 1 employed the same preparation method as Step 1 of Example 1, except that 4-trifluoromethylphenylboronic acid in Step 1 of Example 1 was replaced with 4-methoxyphenylboronic acid (Leyan, 1036309).
  • Step 2 follows the same preparation method as Step 2 of Example 1, except that 1-1 in Step 2 of Example 1 is replaced with 4-1.
  • the residue was concentrated under reduced pressure using anhydrous magnesium sulfate, and PE (5.0 mL) and EA (0.5 mL) were added to the residue.
  • reaction solution 1 SOCl2 (780 ⁇ L, 10.7 mmol; Macklin, T819486) was added dropwise to water (3.5 mL), followed by CuCl (4.5 mg, 0.05 mmol; Adamas, 013385471). The mixture was stirred at room temperature for 3 h to prepare reaction solution 1.
  • an aqueous solution of NaNO2 (163 mg, 2.35 mmol; Macklin, S818033) was added dropwise to a solution of 4-2 (678 mg, 2.14 mmol) dissolved in concentrated HCl (3.0 mL). The mixture was stirred for 30 min to prepare reaction solution 2.
  • the reaction solution was poured into water (30 mL), extracted with EA (20 mL ⁇ 3), the organic layer was washed with saturated brine (20 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 4-3, which was yellow-black oil. The crude product was used directly in the next step of the reaction without purification.
  • Step 5 Preparation of 1-(4-methoxyphenyl)-N-methyl-3-(1-methyl-1H-pyrazol-3-yl)-1H-indazole-5-sulfonamide
  • Step 5 uses the same preparation method as step 4 of Example 1, except that 1-4 in step 4 of Example 1 is replaced with 4-4.
  • Step 2 follows the same preparation method as Step 2 of Example 1, except that 1-1 in Step 2 of Example 1 is replaced with 5-1.
  • the residue was concentrated under reduced pressure using anhydrous magnesium sulfate, and PE (15 mL) and DCM (3.0 mL) were added to the residue.
  • Step 3 uses the same preparation method as Step 3 in Example 4, except that 4-2 in Step 3 of Example 4 is replaced with 5-2.
  • the reaction solution is poured into water (30 mL), extracted with EA (20 mL ⁇ 3), the organic layer is washed with saturated brine (20 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 5-3, which is a yellow-black oil.
  • the crude product is used directly in the next step of the reaction without purification.
  • Step 4 follows the same preparation method as step 4 of Example 4, except that 4-3 in step 4 of Example 4 is replaced with 5-3.
  • Step 5 Preparation of N-methyl-3-(1-methyl-1H-pyrazole-4-yl)-1-(4-(trifluoromethoxy)phenyl)-1H-indazole-5-sulfonamide
  • Step 5 follows the same preparation method as step 4 of Example 1, except that 1-4 in step 4 of Example 1 is replaced with 5-4.
  • Example 6 uses the same preparation method as Example 4, except that 4-methoxyphenylboronic acid in step 1 of Example 4 is replaced with 4-trifluoromethylphenylboronic acid (Adamas, 011468334), and 3-bromo-5-nitro-1H-indazole is replaced with 3-bromo-6-nitro-1H-indazole (Bide, BD4141).
  • Steps 2, 3, and 4 are prepared using the same methods as steps 2, 3, and 4 in Example 1.
  • the starting material is changed from 1-1 to 7-1.
  • Step 3 uses the same preparation method as step 1 in Example 8, except that 1-2 in step 1 of Example 8 is replaced with 9-2.
  • Step 1 Preparation of 3-(1-methyl-1H-pyrazole-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-amine
  • Step 2 Preparation of N-(3-(1-methyl-1H-pyrazole-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-yl)acrylamide
  • Step 1 Preparation of 3-bromo-5-nitro-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridine
  • Step 1 was prepared using the same method as Step 1 of Example 1, except that 3-bromo-5-nitro-1H-indazole in Step 1 of Example 1 was replaced with 3-bromo-5-nitro-1H-pyrazolo[3,4-b]pyridine (Bide, BD224019), and 4-trifluoromethylphenylboronic acid was replaced with 4-trifluoromethoxyphenylboronic acid. After concentration under reduced pressure, the residue was obtained.
  • Step 2 uses the same preparation method as Step 2 of Example 1, except that 1-1 in Step 2 of Example 1 is replaced with 12-1. After concentration under reduced pressure, crude product 12-2, which is a yellow solid, is obtained and used directly in the next reaction without purification.
  • Step 3 Preparation of 3-(1-methyl-1H-pyrazol-4-yl)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridine-5-amine
  • Step 3 uses the same preparation method as step 1 of Example 10, except that 1-2 in step 1 of Example 10 is replaced with 12-2. After concentration under reduced pressure, a yellow gelatinous crude product 12-3 is obtained, which is used directly in the next reaction without purification.
  • Step 4 Preparation of N-(3-(1-methyl-1H-pyrazol-4-yl)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)acrylamide
  • Step 4 follows the same preparation method as step 2 in Example 10.
  • the 10-1 in step 2 of Example 10 is replaced with 12-3.
  • Diethyl ether (2.0 mL) and n-hexane (2.0 mL) are added to the crude product, and the mixture is stirred at room temperature for 1 h. Filtering yields the title compound 12 (2.1 mg, 2% yield) in the form of a pale yellow solid: 1H NMR (400 MHz, DMSO- d6) .
  • Step 1 Preparation of methyl 3-bromo-1-(4-(trifluoromethyl)phenyl)-1H-indazole-6-carboxylate
  • Step 1 was prepared using the same method as Step 1 of Example 1, except that 3-bromo-5-nitro-1H-indazole in Step 1 of Example 1 was replaced with methyl 3-bromo-1H-indazole-6-carboxylate (Bide, BD209901).
  • Step 2 Preparation of methyl 3-(1-methyl-1H-pyrazole-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indazole-6-carboxylate
  • Step 1 Preparation of 3-(1-methyl-1H-pyrazole-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indazole-6-carboxylic acid
  • Step 1 uses the same preparation method as Step 1 in Example 7, except that 3-bromo-6-nitro-1H-indazole in Step 1 of Example 7 is replaced with 3-bromo-5-nitro-1H-indazole, and 4-iodo-1-methylimidazole is replaced with 1-bromo-4-(trifluoromethylthio)benzene (Adamas; 013436328).
  • Step 3 Preparation of 3-(1-methyl-1H-pyrazole-4-yl)-1-(4-((trifluoromethyl)thio)phenyl)-1H-indazole-5-amine
  • Step 3 uses the same preparation method as step 1 of Example 10, except that 1-2 in step 1 of Example 10 is replaced with 15-2. After concentration under reduced pressure, a yellow gelatinous crude product 15-3 is obtained, which is used directly in the next reaction without purification.
  • Step 4 Preparation of N-(3-(1-methyl-1H-pyrazole-4-yl)-1-(4-((trifluoromethyl)thio)phenyl)-1H-indazole-5-yl)acrylamide
  • Step 4 follows the same preparation method as step 2 in Example 10.
  • the 10-1 in step 2 of Example 10 is replaced with 15-3.
  • Diethyl ether 5.0 mL is added to the crude product, and the mixture is stirred at room temperature for 1 h. Filtering yields the title compound 15 (73 mg, 55% yield) in the form of a yellow solid: 1H NMR (400 MHz, CDCl3 ).
  • Example 16 uses the same preparation method as Example 13, except that methyl 3-bromo-1H-indazole-6-carboxylate in step 1 of Example 13 is replaced with methyl 3-bromo-1H-indazole-5-carboxylate (Bide, BD210997), and 4-trifluoromethylphenylboronic acid is replaced with 4-trifluoromethoxyphenylboronic acid.
  • Example 17 uses the same preparation method as Example 14, except that 13 in step 1 of Example 14 is replaced with 16.
  • the residue was concentrated under reduced pressure. 1N HCl was added dropwise to the residue solution dissolved in water (20 mL) to adjust the pH to approximately 1. Extraction was performed using DCM (20 mL ⁇ 3). The organic layer was washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue. Diethyl ether (6.0 mL) was added to the residue, and the mixture was stirred at room temperature for 1 h.
  • Step 1 Preparation of N-methyl-3-(1-methyl-1H-pyrazole-4-yl)-1-(4-(trifluoromethoxy)phenyl)-1H-indazole-5-carboxamide
  • Step 1 Preparation of 3-(1-methyl-1H-pyrazole-4-yl)-1-(4-(trifluoromethoxy)phenyl)-1H-indazole-5-formyl azide
  • Step 2 Preparation of 1-cyclopropyl-3-(3-(1-methyl-1H-pyrazole-4-yl)-1-(4-(trifluoromethoxy)phenyl)-1H-indazole-5-yl)urea
  • Example 21 uses the same preparation method as Example 1, except that 3-bromo-5-nitro-1H-indazole in Example 1 is replaced with 3-bromo-5-nitro-1H-pyrazolo[3,4-b]pyridine, and 4-trifluoromethylphenylboronic acid is replaced with 4-trifluoromethoxyphenylboronic acid.
  • Example 22 uses the same preparation method as Example 1, except that the 3-bromo-5-nitro-1H-indazole in Example 1 is replaced with 3-bromo-5-nitro-1H-pyrazolo[3,4-b]pyridine.
  • Example 25 uses the same preparation method as Example 1, except that 4-trifluoromethylphenylboronic acid in step 1 of Example 1 is replaced with 3-trifluoromethylphenylboronic acid (Adamas, 01022844).
  • Example 31 uses the same preparation method as Example 1, except that 1-methyl-1H-pyrazole-4-boronic acid in step 4 of Example 1 is replaced with cyclopenten-1-ylboronic acid (BYD, BD122948).
  • Example 33 uses the same preparation method as Example 1, except that 1-methyl-1H-pyrazole-4-boric acid in step 4 of Example 1 is replaced with 5-pyrimidineboric acid (Leyan, 1016490).
  • Example 36 uses the same preparation method as Example 1, except that 1-methyl-1H-pyrazole-4-boronic acid in step 4 of Example 1 is replaced with 2-naphthoboronic acid (Bide, BD0424).
  • Example 38 uses the same preparation method as Example 1, except that 1-methyl-1H-pyrazole-4-boric acid in step 4 of Example 1 is replaced with 1-methyl-1H-pyrazole-5-boric acid (BYD, BD164764).
  • Example 39 uses the same preparation method as Example 1, except that 1-methyl-1H-pyrazole-4-boronic acid in step 4 of Example 1 is replaced with 1-methylsulfonyl-4-(tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-pyrazole (Bide, BD01416355).
  • Example 41 uses the same preparation method as Example 1, except that 4-trifluoromethylphenylboronic acid in step 1 of Example 1 is replaced with 4-trifluoromethoxyphenylboronic acid.
  • Example 42 uses the same preparation method as Example 1, except that 4-trifluoromethylphenylboronic acid in step 1 of Example 1 is replaced with 4-cyclohexylphenylboronic acid (Bide, BD01391414).
  • Example 43 uses the same preparation method as Example 1, except that 4-trifluoromethylphenylboronic acid in step 1 of Example 43 is replaced with 4-methoxyphenylboronic acid.
  • Step 1 Preparation of 1,1,1-trifluoro-N-(3-(1-methyl-1H-pyrazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-yl)methanesulfonamide
  • Step 1 was prepared using the same method as Step 3 of Example 1, except that 1-2 in Step 3 of Example 1 was replaced with 10-1 prepared in Step 1 of Example 10, and the methanesulfonic anhydride was replaced with trifluoromethanesulfonic anhydride (Adamas, 01065791).
  • Example 48 uses the same preparation method as step 3 of Example 1, except that 1-2 in step 3 of Example 1 is replaced with 19-1 prepared in step 1 of Example 19, and methanesulfonic anhydride is replaced with trifluoromethanesulfonic anhydride.
  • Example 49 uses the same preparation method as Example 10, except that 1-2 in step 1 of Example 10 is replaced with 5-2 prepared in step 2 of Example 5, and acryloyl chloride in step 2 is replaced with 1-propylsulfonyl chloride (Bide, BD60318).
  • Example 50 uses the same preparation method as Example 10, except that 1-2 in step 1 of Example 10 is replaced with 5-2 prepared in step 2 of Example 5, and acryloyl chloride in step 2 is replaced with 2-chloroethanesulfonyl chloride (Bide, BD73577).
  • Example 53 uses the same preparation method as Example 10, except that 1-2 in step 1 of Example 10 is replaced with 5-2 prepared in Example 5, and acryloyl chloride in step 2 is replaced with ethylsulfonyl chloride.
  • Step 1 Preparation of methyl 1-(4-(trifluoromethoxy)phenyl)-1H-indole-5-carboxylate
  • Step 2 Preparation of methyl 3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-indole-5-carboxylate
  • Step 3 Preparation of methyl 3-(1-methyl-1H-pyrazole-4-yl)-1-(4-(trifluoromethoxy)phenyl)-1H-indole-5-carboxylate
  • Example 55 uses the same preparation method as Example 14, except that compound 13 in step 1 of Example 14 is replaced with compound 54.
  • the residue was concentrated under reduced pressure. 1N HCl was added dropwise to the residue solution dissolved in water (20 mL) to adjust the pH to approximately 1. Extraction was performed using DCM (20 mL ⁇ 5). The organic layer was washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue. Diethyl ether (6.0 mL) was added to the residue, and the mixture was stirred at room temperature for 1 h.
  • Example 57 was prepared using the same method as Example 14, except that compound 13 in step 1 of Example 14 was replaced with compound 56. After concentration under reduced pressure, a residue was obtained. 1N HCl was added dropwise to the residue solution dissolved in water (20 mL) to adjust the pH to approximately 1. Extraction was performed using DCM (20 mL ⁇ 5). The organic layer was washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue. Diethyl ether (6.0 mL) was added to the residue, and the mixture was stirred at room temperature for 1 h. Filtering yielded the title compound 57 (55 mg, 63% yield) as a pale yellow solid.
  • Step 2 Preparation of 3-(1-methyl-1H-pyrazole-4-yl)-5-nitro-1-(4-(trifluoromethoxy)phenyl)-1H-indole
  • Step 2 follows the same preparation method as Step 1 in Example 54, except that methyl 1H-indole-5-carboxylate in Step 1 of Example 54 is replaced with 58-1.
  • the reaction solution is poured into water (30 mL), extracted with EA (30 mL ⁇ 3), the organic layer is washed with saturated brine (20 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow, gelatinous crude product 58-2, which is used directly in the next reaction without purification.
  • Step 3 Preparation of 3-(1-methyl-1H-pyrazole-4-yl)-1-(4-(trifluoromethoxy)phenyl)-1H-indole-5-amine
  • Step 4 Preparation of N-(3-(1-methyl-1H-pyrazole-4-yl)-1-(4-(trifluoromethoxy)phenyl)-1H-indole-5-yl)methanesulfonamide
  • Step 4 follows the same preparation method as Step 3 of Example 1, except that steps 1-2 in Step 3 of Example 1 are replaced with 58-3.
  • Example 60 uses the same preparation method as Example 10, except that 1-2 in step 1 of Example 10 is replaced with 19-2 prepared in step 2 of Example 19, and acryloyl chloride in step 2 is replaced with methacryloyl chloride (Adamas, 01124709).
  • 1-2 in step 1 of Example 10 is replaced with 19-2 prepared in step 2 of Example 19, and acryloyl chloride in step 2 is replaced with methacryloyl chloride (Adamas, 01124709).
  • Diethyl ether (4.0 mL) was added to the crude product, and the mixture was stirred at room temperature for 1 h.
  • Example 64 uses the same preparation method as Example 1, except that 1-methyl-1H-pyrazole-4-boric acid in step 4 of Example 1 is replaced with 1-isopropylpyrazole-4-boric acid.
  • Example 65 uses the same preparation method as Example 1, except that 1-methyl-1H-pyrazole-4-boronic acid in step 4 of Example 1 is replaced with 1-ethyl-1H-pyrazole-4-boronic acid pinacol ester (Leyan, 1052797).
  • Step 1 Preparation of methyl 3-nitro-4-((4-(trifluoromethyl)phenyl)amino)benzoate
  • Step 2 Preparation of methyl 3-amino-4-((4-(trifluoromethyl)phenyl)amino)benzoate
  • Step 3 Preparation of methyl 3-(((1H-imidazol-4-yl)methyl)amino)-4-((4-(trifluoromethyl)phenyl)amino)benzoate
  • reaction solution was poured into water (30 mL), extracted with DCM (30 mL ⁇ 3), the organic layer was washed with saturated brine (20 mL ⁇ 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was obtained.
  • Step 4 Preparation of methyl 3-((1H-imidazol-4-yl)methyl)-2-oxo-1-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-5-carboxylate
  • Step 5 3-((1H-imidazol-4-yl)methyl)-2-oxo-1-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-5-carboxylic acid
  • Step 5 uses the same preparation method as in Example 14, except that compound 13 in step 1 of Example 14 is replaced with 68-4. After concentration under reduced pressure, a residue was obtained. 1N HCl was added dropwise to the residue solution dissolved in water (5.0 mL) to adjust the pH to approximately 7.
  • Step 1 Preparation of methyl 3-((1-methyl-1H-imidazol-4-yl)methyl)-2-oxo-1-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-5-carboxylate
  • Step 2 Preparation of 3-((1-methyl-1H-imidazol-4-yl)methyl)-2-oxo-1-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-5-carboxylic acid
  • Step 2 uses the same preparation method as step 1 of Example 14, except that compound 13 in Example 14 is replaced with 69-1. After concentration under reduced pressure, a residue was obtained. 1N HCl was added dropwise to the residue solution dissolved in water (3 mL) to adjust the pH to approximately 1.
  • Step 2 uses the same preparation method as Step 2 of Example 1, except that 1-1 in Step 2 of Example 1 is replaced with 70-1. After vacuum concentration using anhydrous magnesium sulfate, a crude product 70-2 in the form of yellow oil is obtained. The crude product is used directly in the next reaction without purification.
  • Step 3 followed the same preparation method as in Step 3 of Example 1, except that 1-2 in Step 3 of Example 1 was replaced with 70-2.
  • Step 4 Preparation of N-(3-(1-methyl-1H-pyrazole-4-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indazole-5-yl)methanesulfonamide
  • Step 4 uses the same preparation method as step 4 in Example 1, except that 1-3 in step 4 of Example 1 is replaced with 70-3.
  • 1-3 in step 4 of Example 1 is replaced with 70-3.
  • Step 3 Preparation of 3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indazole-5-amine
  • Step 3 follows the same preparation method as Step 2 of Example 1, except that 1-1 in Step 2 of Example 1 is replaced with 71-2.
  • Step 4 N-(3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indazole-5-yl)methanesulfonamide
  • Step 4 uses the same preparation method as step 3 of Example 1, except that 1-2 in step 3 of Example 1 is replaced with 71-3.
  • 1-2 in step 3 of Example 1 is replaced with 71-3.
  • Example 72 uses the same preparation method as Example 4, except that 4-2 in step 3 of Example 4 is replaced with 70-2 prepared in Example 70.
  • After purification by column chromatography (DCM:MeOH 75:1), a crude product in the form of a pale yellow gel was obtained. Diethyl ether (5.0 mL) was added to the crude product, and the mixture was stirred at room temperature for 1 h.
  • Step 1 employs the same preparation method as Step 1 in Example 70, except that 1-(bromomethyl)-4-(trifluoromethyl)benzene in Step 1 of Example 70 is replaced with 1-(bromomethyl)-3-(trifluoromethyl)benzene (BYD, BD33580).
  • the reaction solution is poured into water (100 mL), extracted with EA (50 mL ⁇ 3), the organic layer is washed with saturated brine (30 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 73-1, which is a yellow solid.
  • the crude product is used directly in the next reaction without purification.
  • Step 2 uses the same preparation method as Step 2 of Example 1, except that 1-1 in Step 2 of Example 1 is replaced with 73-1. After filtration through anhydrous magnesium sulfate pad and concentration under reduced pressure, crude product 73-2, which is a brownish-yellow solid, is obtained. The crude product is used directly in the next reaction without purification.
  • Step 3 uses the same preparation method as Step 3 in Example 4, except that 4-2 in Step 3 of Example 4 is replaced with 73-2.
  • the reaction solution is poured into water (30 mL), extracted with EA (20 mL ⁇ 3), the organic layer is washed with saturated brine (20 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 73-3, which is a yellow solid.
  • the crude product is used directly in the next step of the reaction without purification.
  • Step 4 follows the same preparation method as Step 4 of Example 4, except that 4-3 in Step 4 of Example 4 is replaced with 73-3.
  • Step 5 Preparation of N-methyl-3-(1-methyl-1H-pyrazole-4-yl)-1-(3-(trifluoromethyl)benzyl)-1H-indazole-5-sulfonamide
  • Step 5 follows the same preparation method as step 4 of Example 1, except that 1-3 in step 4 of Example 1 are replaced with 73-4.
  • a crude product in the form of a pale yellow solid was obtained.
  • Diethyl ether (5.0 mL) was added to the crude product, and the mixture was stirred at room temperature for 1 h. Filtering yielded the title compound 73 (25 mg, 71% yield) in the form of a white solid.
  • Example 75 uses the same preparation method as Example 72, except that the 1-methyl-1H-pyrazole-4-boric acid in Example 72 is replaced with 71-1 prepared in step 1 of Example 71.
  • Example 77 uses the same preparation method as Example 4, except that 4-methoxyphenylboronic acid in step 1 of Example 4 is replaced with 3-chloro-4-trifluoromethylphenylboronic acid (BYD, BD4275).
  • Example 78 uses the same preparation method as Example 4, except that 4-methoxyphenylboronic acid in step 1 of Example 4 is replaced with 2-trifluoromethyl-5-pyridineboronic acid (Adamas, 01233453).
  • Example 82 uses the same preparation method as Example 1, except that the 4-trifluoromethylphenylboronic acid in step 1 of Example 1 is replaced with 2-trifluoromethylphenylboronic acid (Leyan, 1021256).
  • Example 83 uses the same preparation method as Example 1, except that 4-trifluoromethylphenylboronic acid in step 1 of Example 1 is replaced with 2-trifluoromethyl-5-pyridineboronic acid.
  • Example 85 uses the same preparation method as Example 1, except that 4-trifluoromethylphenylboronic acid in step 1 of Example 1 is replaced with 4-ethylphenylboronic acid (Bide, BD10663).
  • Example 86 uses the same preparation method as Example 1, except that the 4-trifluoromethylphenylboronic acid in step 1 of Example 1 is replaced with 4-methylphenylboronic acid (Leyan, 1036307).
  • Example 88 uses the same preparation method as Example 7, except that 4-iodo-1-methylimidazolium in step 1 of Example 7 is replaced with 5-bromo-2-trifluoromethylpyrimidine (Leyan, 1050316), and 4-trifluoromethylphenylboronic acid in step 4 is replaced with 1-methyl-1H-pyrazole-4-boronic acid.
  • Example 89 was prepared using the same method as Example 7, except that 4-iodo-1-methylimidazolium in step 1 of Example 7 was replaced with 4-bromocyclopropylbenzene (BYD, BD96719), and 4-trifluoromethylphenylboronic acid in step 4 was replaced with 1-methyl-1H-pyrazole-4-boronic acid.
  • Example 90 uses the same preparation method as Example 4, except that 4-methoxyphenylboronic acid in step 1 of Example 4 is replaced with 4-trifluoromethylphenylboronic acid, and 1-methyl-1H-pyrazole-4-boronic acid in step 5 is replaced with pyridine-4-boronic acid.
  • Example 91 was prepared using the same method as Example 4, except that 4-methoxyphenylboronic acid in step 1 of Example 4 was replaced with 4-trifluoromethylphenylboronic acid, and 1-methyl-1H-pyrazole-4-boronic acid in step 5 was replaced with cyclohexene-1-ylboronic acid.
  • Example 92 uses the same preparation method as Example 4, except that 4-methoxyphenylboronic acid in step 1 of Example 4 is replaced with 4-trifluoromethylphenylboronic acid, and 1-methyl-1H-pyrazole-4-boronic acid in step 5 is replaced with phenylboronic acid.
  • Step 1 uses the same preparation method as Step 1 of Example 1, except that 3-bromo-5-nitro-1H-indazole in Step 1 of Example 1 is replaced with 5-bromo-3-methyl-1H-indazole (Leyan, 1048785). After concentration under reduced pressure, crude product 93-1, which is dark green and gelatinous, is obtained and used directly in the next reaction without purification.
  • NCS 133 mg, 0.82 mmol; Biotin, BD40870
  • 93-2 86 mg, 0.2 mmol
  • CH3CN 3.0 mL
  • AcOH 140 ⁇ L
  • water 94 ⁇ L
  • reaction solution was poured into water (10 mL), extracted with EA (10 mL ⁇ 3), the organic layer was washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude 93-3, which was a yellow-black gel and used directly in the next reaction without purification.
  • Step 4 uses the same preparation method as step 4 of Example 4, except that 4-3 in step 4 of Example 4 is replaced with 93-3.
  • Example 94 was prepared using the same method as Example 4, except that 4-methoxyphenylboronic acid in step 1 of Example 4 was replaced with 4-trifluoromethylphenylboronic acid, and 1-methyl-1H-pyrazole-4-boronic acid in step 5 was replaced with 1-cyclopentenylboronic acid (Bide, BD122948).
  • Example 95 uses the same preparation method as Example 4, except that 4-methoxyphenylboronic acid in step 1 of Example 4 is replaced with 4-trifluoromethylphenylboronic acid, and 1-methyl-1H-pyrazole-4-boronic acid in step 5 is replaced with 4-biphenylboronic acid (Leyan, 1034198).
  • Example 96 was prepared using the same method as Example 4, except that 4-methoxyphenylboronic acid in step 1 of Example 4 was replaced with 4-trifluoromethylphenylboronic acid, and 1-methyl-1H-pyrazole-4-boronic acid in step 5 was replaced with 4-cyclohexylphenylboronic acid.
  • Example 97 uses the same preparation method as Example 93, except that 5-bromo-3-methyl-1H-indazole in step 1 of Example 93 is replaced with 5-bromo-3-chloro-1H-indazole (Leyan, 1121243).
  • Example 99 was prepared using the same method as Example 4, except that 4-methoxyphenylboronic acid in step 1 of Example 4 was replaced with 4-trifluoromethylphenylboronic acid, and 1-methyl-1H-pyrazole-4-boronic acid in step 5 was replaced with 1-naphthylboronic acid.
  • Diethyl ether (5.0 mL) was added to the crude product, and the mixture was stirred at room temperature for 1 h. Filtering yielded the title compound 99 (48 mg, 83% yield) in the form of a white solid: 1H NMR (400 MHz, DMSO- d6) .
  • Step 1 Preparation of methyl 3-bromo-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-carboxylate
  • Step 1 was prepared using the same method as Step 1 of Example 1, except that 3-bromo-5-nitro-1H-indazole in Step 1 of Example 1 was replaced with methyl 3-bromo-1H-indazole-5-carboxylate. After concentration under reduced pressure, a residue was obtained.
  • Step 2 Preparation of methyl 3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-carboxylate
  • Step 3 Preparation of 3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-carboxylic acid
  • Step 3 followed the same preparation method as in Example 14, except that compound 13 in step 1 of Example 14 was replaced with 101-2. After concentration under reduced pressure, a residue was obtained. 1N HCl was added dropwise to the residue solution dissolved in water (20 mL) to adjust the pH to approximately 1. Extraction was performed using DCM (20 mL ⁇ 3). The organic layer was washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue. Diethyl ether (5.0 mL) was added to the residue, and the mixture was stirred at room temperature for 1 h. Filtration yielded the title compound 101 (29 mg, 66% yield) as a white solid.
  • Step 1 Preparation of methyl 3-bromo-1-(4-(trifluoromethyl)benzyl)-1H-indazole-5-carboxylate
  • Step 1 was prepared using the same method as Step 1 of Example 70, except that 3-bromo-5-nitro-1H-indazole in Step 1 of Example 70 was replaced with methyl 3-bromo-1H-indazole-5-carboxylate. After concentration under reduced pressure, a residue was obtained.
  • Step 2 Preparation of methyl 3-(1-methyl-1H-pyrazole-4-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indazole-5-carboxylate
  • Step 3 Preparation of 3-(1-methyl-1H-pyrazole-4-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indazole-5-carboxylic acid
  • Step 3 followed the same preparation method as in Example 14, except that compound 13 in step 1 of Example 14 was replaced with 102-2. After concentration under reduced pressure, a residue was obtained. 1N HCl was added dropwise to the residue solution dissolved in water (20 mL) to adjust the pH to approximately 1. Extraction was performed using DCM (20 mL ⁇ 3). The organic layer was washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue. Diethyl ether (5.0 mL) was added to the residue, and the mixture was stirred at room temperature for 1 h. Filtering yielded the title compound 102 (36 mg, 60% yield) as a white solid.
  • Step 1 Preparation of 3-(1-methyl-1H-pyrazol-4-yl)-5-nitro-1-(4-((trifluoromethyl)thio)phenyl)-1H-indole
  • Step 1 uses the same preparation method as Step 2 in Example 58, except that 1-iodo-4-(trifluoromethoxy)benzene in Step 2 of Example 58 is replaced with 1-bromo-4-(trifluoromethylthio)benzene.
  • Step 2 Preparation of 3-(1-methyl-1H-pyrazol-4-yl)-1-(4-((trifluoromethyl)thio)phenyl)-1H-indole-5-amine
  • Step 2 follows the same preparation method as Step 3 of Example 58, except that 58-2 in Step 3 of Example 58 is replaced with 105-1.
  • Step 3 Preparation of N-(3-(1-methyl-1H-pyrazol-4-yl)-1-(4-((trifluoromethyl)thio)phenyl)-1H-indole-5-yl)methanesulfonamide
  • Step 3 follows the same preparation method as in Step 3 of Example 1, except that steps 1-2 in Step 3 of Example 1 are replaced with 105-2.
  • PE:EA 4:1
  • Step 1 Preparation of methyl 3-(cyclopenten-1-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-carboxylate
  • Step 1 employs the same preparation method as Step 4 of Example 1, except that 1-3 in Step 4 of Example 1 is replaced with 101-1, and 1-methyl-1H-pyrazole-4-boric acid is replaced with cyclopenten-1-ylboric acid. After concentration under reduced pressure, crude product 108-1, a yellow solid, is obtained and used directly in the next reaction without purification.
  • Step 2 Preparation of 3-(cyclopent-1-en-1-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-carboxylic acid
  • Step 2 uses the same preparation method as in Example 14, except that compound 13 in step 1 of Example 14 is replaced with 108-1.
  • the residue was concentrated under reduced pressure. 1N HCl was added dropwise to the residue solution dissolved in water (20 mL) to adjust the pH to approximately 1. Extraction was performed using DCM (20 mL ⁇ 3). The organic layer was washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue. Diethyl ether (4.0 mL) was added to the residue, and the mixture was stirred at room temperature for 1 h.
  • Step 1 Preparation of methyl 1-(4-(trifluoromethyl)phenyl)-1H-indole-5-carboxylate
  • Step 1 followed the same preparation method as Step 1 in Example 54, except that 1-iodo-4-(trifluoromethoxy)benzene in Step 1 of Example 54 was replaced with 4-iodotrifluorotoluene (BYD, BD10289).
  • Step 2 Preparation of methyl 3-bromo-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-carboxylate
  • Step 2 adopts the same preparation method as step 2 of Example 54, except that 54-1 in step 2 of Example 54 is replaced with 109-1.
  • Step 3 Preparation of methyl 3-(cyclopent-1-en-1-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-carboxylate
  • Step 4 Preparation of 3-(cyclopent-1-en-1-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-carboxylic acid
  • Step 4 follows the same preparation method as in Example 14, except that compound 13 in step 1 of Example 14 is replaced with 109-3. After concentration under reduced pressure, a residue was obtained. 1N HCl was added dropwise to the residue solution dissolved in water (20 mL) to adjust the pH to approximately 1. Extraction was performed using DCM (20 mL ⁇ 5). The organic layer was washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue. Diethyl ether (1.5 mL) and n-hexane (1.5 mL) were added to the residue, and the mixture was stirred at room temperature for 1 h.
  • Example 110 was prepared using the same method as Example 108, except that cyclopenten-1-ylboronic acid in step 1 of Example 108 was replaced with thiophene-2-boronic acid. After concentration under reduced pressure, a residue was obtained. 1N HCl was added dropwise to the residue solution dissolved in water (20 mL) to adjust the pH to approximately 1. Extraction was performed using DCM (20 mL ⁇ 5). The organic layer was washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue. Diethyl ether (4.0 mL) was added to the residue, and the mixture was stirred at room temperature for 1 h.
  • Example 111 uses the same preparation method as Example 108, except that thiophene-2-boronic acid in step 1 of Example 108 is replaced with 3-thiopheneboronic acid.
  • the residue was concentrated under reduced pressure. 1N HCl was added dropwise to the residue solution dissolved in water (20 mL) to adjust the pH to approximately 1. Extraction was performed using DCM (20 mL ⁇ 5). The organic layer was washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue. Diethyl ether (4.0 mL) was added to the residue, and the mixture was stirred at room temperature for 1 h.
  • Example 112 was prepared using the same method as Example 109, except that cyclopent-1-ene-1-boric acid in step 3 of Example 109 was replaced with 3-thiopheneboric acid. After concentration under reduced pressure, a residue was obtained. 1N HCl was added dropwise to the residue solution dissolved in water (20 mL) to adjust the pH to approximately 1. Extraction was performed using DCM (20 mL ⁇ 5). The organic layer was washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue. Diethyl ether (5.0 mL) was added to the residue, and the mixture was stirred at room temperature for 1 h.
  • Example 113 uses the same preparation method as Example 58, except that 1-methyl-4-pyrazoleboronic acid pinacol ester in step 1 of Example 58 is replaced with thiophene-2-boronic acid, and 1-iodo-4-(trifluoromethoxy)benzene in step 2 is replaced with 4-iodotrifluorotoluene.
  • Example 115 was prepared using the same method as Example 1, except that 3-bromo-5-nitro-1H-indazole in step 1 of Example 1 was replaced with 3-bromo-6-nitro-1H-indazole, 4-trifluoromethylphenylboronic acid was replaced with cyclopenten-1-ylboronic acid, and 1-methyl-1H-pyrazole-4-boronic acid in step 4 was replaced with 4-trifluoromethylphenylboronic acid.
  • Step 1 Preparation of methyl 3-bromo-1-(4-((trifluoromethyl)thio)phenyl)-1H-indazole-5-carboxylate
  • reaction mixture was poured into water (50 mL), extracted with DCM (30 mL ⁇ 3), the organic layer was washed with saturated brine (30 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a brownish-black gelatinous crude product 117-1, which was used directly in the next reaction without purification.
  • Step 2 Preparation of methyl 3-(1-methyl-1H-pyrazole-4-yl)-1-(4-((trifluoromethyl)thio)phenyl)-1H-indazole-5-carboxylate
  • Step 3 Preparation of 3-(1-methyl-1H-pyrazole-4-yl)-1-(4-((trifluoromethyl)thio)phenyl)-1H-indazole-5-carboxylic acid
  • Step 3 was prepared using the same method as in Example 14, except that compound 13 in step 1 of Example 14 was replaced with 117-2. After concentration under reduced pressure, a residue was obtained. 1N HCl was added dropwise to the residue solution dissolved in water (20 mL) to adjust the pH to approximately 1. Extraction was performed using DCM (20 mL ⁇ 5). The organic layer was washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue. Diethyl ether (5.0 mL) and n-hexane (0.5 mL) were added to the residue, and the mixture was stirred at room temperature for 1 h.
  • Example 118 uses the same preparation method as Example 117, except that 1-methyl-1H-pyrazole-4-boric acid in step 2 of Example 117 is replaced with thiophene-3-boric acid.
  • the residue was concentrated under reduced pressure. 1N HCl was added dropwise to the residue solution dissolved in water (20 mL) to adjust the pH to approximately 1. Extraction was performed using DCM (20 mL ⁇ 5). The organic layer was washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue. Diethyl ether (5.0 mL) was added to the residue, and the mixture was stirred at room temperature for 1 h.
  • Example 119 was prepared using the same method as Example 117, except that 1-methyl-1H-pyrazole-4-boric acid in step 2 of Example 117 was replaced with thiophene-2-boric acid. After concentration under reduced pressure, a residue was obtained. 1N HCl was added dropwise to the residue solution dissolved in water (20 mL) to adjust the pH to approximately 1. Extraction was performed using DCM (20 mL ⁇ 5). The organic layer was washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue.
  • Example 120 uses the same preparation method as Example 7, except that the 4-iodo-1-methylimidazole in step 1 of Example 7 is replaced with 4-iodo-1-methyl-1H-pyrazole (Bide, BD59498).
  • Example 122 uses the same preparation method as Example 10, except that 1-methyl-1H-pyrazole-4-boric acid in step 1 of Example 10 is replaced with thiophene-3-boric acid, and acryloyl chloride in step 2 is replaced with ethylsulfonyl chloride.
  • Example 124 uses the same preparation method as Example 10, except that 1-2 in step 1 of Example 10 is replaced with 5-2 prepared in step 2 of Example 5, and 1-methyl-1H-pyrazole-4-boric acid is replaced with thiophene-3-boric acid.
  • Step 1 Preparation of methyl 3-bromo-1-(cyclohex-1-en-1-yl)-1H-indazole-6-carboxylate
  • Step 2 Preparation of methyl 1-(cyclohexyl-1-en-1-yl)-3-(4-(trifluoromethyl)phenyl)-1H-indazole-6-carboxylate
  • Step 3 Preparation of 1-(cyclohexyl-1-en-1-yl)-3-(4-(trifluoromethyl)phenyl)-1H-indazole-6-carboxylic acid
  • Step 3 followed the same preparation method as in Example 14, except that compound 13 in step 1 of Example 14 was replaced with 128-2. After concentration under reduced pressure, a residue was obtained. 1N HCl was added dropwise to the residue solution dissolved in water (20 mL) to adjust the pH to approximately 1. Extraction was performed using DCM (20 mL ⁇ 3). The organic layer was washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue. Diethyl ether (2.5 mL) and n-hexane (2.0 mL) were added to the residue, and the mixture was stirred at room temperature for 1 h.
  • Example 129 was prepared using the same method as Example 128, except that cyclohexen-1-ylboronic acid in step 1 of Example 128 was replaced with cyclopenten-1-ylboronic acid. After concentration under reduced pressure, a residue was obtained. 1N HCl was added dropwise to the residue solution dissolved in water (20 mL) to adjust the pH to approximately 1. Extraction was performed using DCM (20 mL ⁇ 5). The organic layer was washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue.
  • Example 130 was prepared using the same method as Example 10, except that 1-2 in step 1 of Example 10 was replaced with 5-2 prepared in step 2 of Example 5, 1-methyl-1H-pyrazole-4-boric acid was replaced with 3-thiopheneboric acid, and acryloyl chloride in step 2 was replaced with ethylsulfonyl chloride.
  • PE:EA 4:1
  • P:EA 2:1
  • Example 133 uses the same preparation method as Example 1, except that 1-methyl-1H-pyrazole-4-boric acid in step 4 of Example 1 is replaced with 3-thiopheneboric acid.
  • Example 134 uses the same preparation method as Example 1, except that 1-methyl-1H-pyrazole-4-boric acid in step 4 of Example 1 is replaced with 4-methyl-2-thiopheneboric acid (Bide, BD2775).
  • Example 135 uses the same preparation method as Example 1, except that 1-methyl-1H-pyrazole-4-boric acid in step 4 of Example 1 is replaced with 2-aldehydethiophene-4-boric acid (Bide, BD8087).
  • DCM:MeOH 500:1
  • Example 138 uses the same preparation method as Example 1, except that 1-methyl-1H-pyrazole-4-boric acid in step 4 of Example 1 is replaced with 4-methyl-3-thiopheneboric acid (Bide, BD98883).
  • Example 139 uses the same preparation method as Example 1, except that 1-methyl-1H-pyrazole-4-boric acid in step 4 of Example 1 is replaced with 2-methyl-3-thiopheneboric acid (Bide, BD161868).
  • Example 140 uses the same preparation method as Example 1, except that 1-methyl-1H-pyrazole-4-boric acid in step 4 of Example 1 is replaced with 2-aldehydethiophene-3-boric acid (Bide, BD2643).
  • Example 141 uses the same preparation method as Example 1, except that 1-methyl-1H-pyrazole-4-boric acid in step 4 of Example 1 is replaced with 2,5-dimethylthiophene-3-boric acid (Bide, BD260481).
  • Example 142 uses the same preparation method as Example 1, except that 1-methyl-1H-pyrazole-4-boric acid in step 4 of Example 1 is replaced with benzothiophene-2-boric acid (Bide, BD6032).
  • Example 143 uses the same preparation method as Example 1, except that 1-methyl-1H-pyrazole-4-boric acid in step 4 of Example 1 is replaced with 3-methylthiophene-2-boric acid (BYD, BD2774).
  • PE:EA 4:1
  • Step 1 was prepared using the same method as Step 1 of Example 1, except that 3-bromo-5-nitro-1H-indazole in Step 1 of Example 1 was replaced with 3-bromo-5-nitro-1H-pyrazolo[3,4-b]pyridine. After concentration under reduced pressure, a residue was obtained.
  • Step 2 uses the same preparation method as step 3 in Example 58, except that 58-2 in step 3 of Example 58 is replaced with 145-1. After concentration under reduced pressure, crude product 145-2, which is a yellow solid, is obtained and used directly in the next reaction without purification.
  • Step 3 Preparation of N-(3-bromo-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)acrylamide
  • Step 1 uses the same preparation method as Step 1 of Example 145, except that 3-bromo-5-nitro-1H-pyrazolo[3,4-b]pyridine in Step 1 of Example 145 is replaced with 5-nitro-1H-pyrrole[2,3-b]pyridine (Bide, BD104973), 4-trifluoromethylphenylboronic acid is replaced with 4-trifluoromethoxyphenylboronic acid, and Py is replaced with DBU.
  • Step 2 uses the same preparation method as Step 2 of Example 145, except that 145-1 in Step 2 of Example 145 is replaced with 146-1. After concentration under reduced pressure, crude product 146-2, which is brownish-black and oily, is obtained and used directly in the next reaction without purification.
  • Example 147 uses the same preparation method as Example 11, except that 9-2 in step 1 of Example 11 is replaced with 146-2 prepared in step 2 of Example 146.
  • Diethyl ether (1.0 mL) and n-hexane (2.5 mL) were added to the crude product, and the mixture was stirred at room temperature for 1 h.
  • PE:EA 2:1
  • Step 1 Preparation of methyl 3-bromo-1-(thiophen-3-yl)-1H-indazole-6-carboxylate
  • Step 1 uses the same preparation method as Step 1 in Example 54, except that methyl 1H-indole-5-carboxylate in Step 1 of Example 54 is replaced with methyl 3-bromo-1H-indazole-6-carboxylate, and 1-iodo-4-(trifluoromethoxy)benzene is replaced with 3-iodothiophene.
  • Step 2 Preparation of methyl 1-(thiophene-3-yl)-3-(4-(trifluoromethyl)phenyl)-1H-indazole-6-carboxylate
  • Step 2 followed the same preparation method as Step 4 of Example 1, except that 1-3 in Step 4 of Example 1 were replaced with 149-1, and 1-methyl-1H-pyrazole-4-boric acid was replaced with 4-trifluoromethylphenylboronic acid.
  • Step 3 Preparation of 1-(thiophene-3-yl)-3-(4-(trifluoromethyl)phenyl)-1H-indazole-6-carboxylic acid
  • Step 3 followed the same preparation method as in Example 14, except that compound 13 in step 1 of Example 14 was replaced with 149-2. After concentration under reduced pressure, a residue was obtained. 1N HCl was added dropwise to the residue solution dissolved in water (20 mL) to adjust the pH to approximately 1. Extraction was performed using DCM (20 mL ⁇ 3). The organic layer was washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue. Diethyl ether (1.5 mL) and n-hexane (2.5 mL) were added to the residue, and the mixture was stirred at room temperature for 1 h.
  • Example 150 uses the same preparation method as Example 149, except that the 3-iodothiophene in step 1 of Example 149 is replaced with 2-iodothiophene.
  • the residue was concentrated under reduced pressure. 1N HCl was added dropwise to the residue solution dissolved in water (20 mL) to adjust the pH to approximately 1. Extraction was performed using DCM (20 mL ⁇ 3). The organic layer was washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue. Diethyl ether (2.0 mL) and n-hexane (1.0 mL) were added to the residue, and the mixture was stirred at room temperature for 1 h.
  • Step 1 was prepared using the same method as Step 1 of Example 146, except that 5-nitro-1H-pyrrolo[2,3-b]pyridine in Step 1 of Example 146 was replaced with 3-bromo-5-nitro-1H-pyrrolo[2,3-b]pyridine (Bide, BD561411).
  • Step 2 uses the same preparation method as Step 2 of Example 146, except that 146-1 in Step 2 of Example 146 is replaced with 151-1. After concentration under reduced pressure, crude product 151-2, which is a pale yellow solid, is obtained and used directly in the next reaction without purification.
  • Step 3 Preparation of N-(3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acrylamide
  • P:EA 3:1
  • Example 155 was prepared using the same method as Example 108, except that cyclopenten-1-ylboronic acid in step 1 of Example 108 was replaced with 1-ethyl-1H-pyrazole-4-boronic acid pinacol ester. After concentration under reduced pressure, a residue was obtained. The pH was adjusted to approximately 1 by dropwise addition of 1N HCl to a solution of the residue dissolved in water (20 mL). Extraction was performed using DCM (20 mL ⁇ 3). The organic layer was washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue.
  • Example 156 was prepared using the same method as Example 108, except that cyclopenten-1-ylboronic acid in step 1 of Example 108 was replaced with pinacol 1-cyclopropylpyrazole-4-boronic acid (Bide, BD210594). After concentration under reduced pressure, a residue was obtained. 1N HCl was added dropwise to the residue solution dissolved in water (20 mL) to adjust the pH to approximately 1. Extraction was performed using DCM (20 mL ⁇ 3). The organic layer was washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue.
  • pinacol 1-cyclopropylpyrazole-4-boronic acid Bide, BD210594
  • Example 157 uses the same preparation method as Example 1, except that 4-trifluoromethylphenylboronic acid in step 1 of Example 1 is replaced with 2,4-bis(trifluoromethyl)phenylboronic acid (BYD, BD27613).
  • BYD 2,4-bis(trifluoromethyl)phenylboronic acid
  • Step 1 was prepared using the same method as in Step 1 of Example 58, except that 1-methyl-4-pyrazoleboronic acid pinacol ester in Step 1 of Example 58 was replaced with 2-thiopheneboronic acid. After cooling to room temperature and concentration under reduced pressure, the residue was obtained.
  • Step 2 uses the same preparation method as Step 2 of Example 58, except that 58-1 in Step 2 of Example 58 is replaced with 158-1.
  • the reaction solution is poured into water (30 mL), extracted with EA (30 mL ⁇ 3), the organic layer is washed with saturated brine (20 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 158-2, which is yellow-orange gelatinous and used directly in the next reaction without purification.
  • Step 3 uses the same preparation method as Step 3 in Example 58, except that 58-2 in Step 3 of Example 58 is replaced with 158-2.
  • the reaction solution is poured into water (50 mL), extracted with DCM (30 mL ⁇ 3), the organic layer is washed with saturated brine (30 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 158-3, which is yellow-black oily and used directly in the next reaction without purification.
  • Step 4 Preparation of N-(3-(thiophen-2-yl)-1-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)acrylamide
  • Step 4 follows the same preparation method as in Example 10, except that 10-1 in step 2 of Example 10 is replaced with 158-3.
  • Step 1 Preparation of 3-bromo-5-nitro-1-(4-(pentafluoro- ⁇ 6 -thioalkyl)phenyl)-1H-indazole
  • Step 1 was prepared using the same method as Step 1 in Example 7, except that 3-bromo-6-nitro-1H-indazole in Step 1 of Example 7 was replaced with 3-bromo-5-nitro-1H-indazole, and 4-iodo-1-methylimidazolium was replaced with 4-iodobenzenepentafluoride (Adamas, 014159623).
  • Step 2 Preparation of 3-bromo-1-(4-(pentafluoro- ⁇ 6 -thioalkyl)phenyl)-1H-indazole-5-amine
  • Step 2 uses the same preparation method as Step 2 of Example 145, except that 145-1 in Step 2 of Example 145 is replaced with 159-1. After concentration under reduced pressure, crude product 159-2, which is a pale yellow solid, is obtained and used directly in the next reaction without purification.
  • Step 3 Preparation of 3-(1-methyl-1H-pyrazole-4-yl)-1-(4-(pentafluoro- ⁇ 6 -thioalkyl)phenyl)-1H-indazole-5-amine
  • Step 3 uses the same preparation method as step 1 of Example 10, except that 1-2 in step 1 of Example 10 is replaced with 159-2. After concentration under reduced pressure, crude product 159-3, which is a pale yellowish-brown gel, is obtained and used directly in the next reaction without purification.
  • Step 4 Preparation of N-(3-(1-methyl-1H-pyrazole-4-yl)-1-(4-(pentafluoro- ⁇ 6 -thioalkyl)phenyl)-1H-indazole-5-yl)acrylamide
  • Step 4 uses the same preparation method as step 2 in Example 10.
  • the 10-1 in step 2 of Example 10 is replaced with 159-3.
  • Step 1 Preparation of N-(3-(1-methyl-1H-pyrazole-4-yl)-1-(4-(pentafluoro- ⁇ 6 -thioalkyl)phenyl)-1H-indazole-5-yl)methanesulfonamide
  • Example 164 was prepared using the same method as Example 149, except that 3-iodothiophene in step 1 of Example 149 was replaced with 2-bromothiazole. After concentration under reduced pressure, a residue was obtained. 1N HCl was added dropwise to the residue solution dissolved in water (20 mL) to adjust the pH to approximately 1. Extraction was performed using DCM (20 mL ⁇ 3). The organic layer was washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue. Diethyl ether (4.0 mL) was added to the residue, and the mixture was stirred at room temperature for 1 h.
  • Example 165 uses the same preparation method as Example 149, except that 3-iodothiophene in step 1 of Example 149 is replaced with 4-bromothiazole.
  • the residue was obtained after concentration under reduced pressure. 1N HCl was added dropwise to the residue solution dissolved in water (20 mL) to adjust the pH to approximately 1. Extraction was performed using DCM (20 mL ⁇ 3). The organic layer was washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue. Diethyl ether (4.0 mL) was added to the residue, and the mixture was stirred at room temperature for 1 h.
  • Example 166 was prepared using the same method as Example 149, except that 3-iodothiophene in step 1 of Example 149 was replaced with 5-bromothiazole (Bide, BD20089). After concentration under reduced pressure, a residue was obtained. 1N HCl was added dropwise to the residue solution dissolved in water (20 mL) to adjust the pH to approximately 1. Extraction was performed using DCM (20 mL ⁇ 3). The organic layer was washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue.
  • 3-iodothiophene in step 1 of Example 149 was replaced with 5-bromothiazole (Bide, BD20089). After concentration under reduced pressure, a residue was obtained. 1N HCl was added dropwise to the residue solution dissolved in water (20 mL) to adjust the pH to approximately 1. Extraction was performed using DCM (20 mL ⁇ 3). The organic layer was washed with saturated brine (10
  • Example 170 uses the same preparation method as Example 1, except that 1-methyl-1H-pyrazole-4-boronic acid in step 4 of Example 1 is replaced with pinacol 1,5-dimethyl-1H-pyrazole-4-boronic acid (Bide, BD213101).
  • Example 172 uses the same preparation method as Example 1, except that 1-methyl-1H-pyrazole-4-boronic acid in step 4 of Example 1 is replaced with pinacol 1-phenyl-1H-pyrazole-4-boronic acid (Adamas, 013652405).
  • Example 175 uses the same preparation method as Example 1, except that 1-methyl-1H-pyrazole-4-boronic acid in step 4 of Example 1 is replaced with 1-(difluoromethyl)-1H-pyrazole-4-boronic acid pinacol ester (Adamas, 011146182).
  • Example 176 uses the same preparation method as Example 1, except that 1-methyl-1H-pyrazole-4-boronic acid in step 4 of Example 1 is replaced with pinacol 1-methyl-3-trifluoromethyl-1H-pyrazole-5-boronic acid (Adamas, 013553880).
  • Diethyl ether (3.0 mL) and n-hexane (1.0 mL) were added to the crude product, and the mixture was stirred at room temperature for 1 h.
  • Example 177 uses the same preparation method as Example 1, except that 1-methyl-1H-pyrazole-4-boronic acid in step 4 of Example 1 is replaced with pinacol 1-trifluoromethyl-1H-pyrazole-4-boronic acid (Bide, BD01488893).
  • Example 178 uses the same preparation method as Example 7, except that 4-iodo-1-methylimidazole in step 1 of Example 7 is replaced with 4-bromoisothiazol (Adamas, 013650314).
  • Step 1 uses the same preparation method as Step 1 of Example 1, except that 3-bromo-5-nitro-1H-indazole in Step 1 of Example 1 is replaced with 5-bromo-3-nitro-1H-indazole (BYD, BD00798336). After concentration under reduced pressure, crude product 179-1, which is a yellow-green solid, is obtained and used directly in the next reaction without purification.
  • Step 3 Preparation of 5-(1-methyl-1H-pyrazole-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indazole-3-amine
  • Step 4 Preparation of N-(5-(1-methyl-1H-pyrazole-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indazole-3-yl)methanesulfonamide
  • Example 181 uses the same preparation method as Example 1, except that 1-methyl-1H-pyrazole-4-boronic acid in step 4 of Example 1 is replaced with 2-acetyl-3-thiopheneboronic acid (Bide, BD250313).

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé bicyclique et son utilisation pharmaceutique. La présente invention concerne un composé bicyclique représenté par la formule (I) ou un sel, un ester, un stéréoisomère, une substance deutérée ou un solvate pharmaceutiquement acceptable de celui-ci. Le composé décrit dans la présente invention a un puissant effet inhibiteur sur TEAD, de telle sorte que le composé ou un tautomère, mésomère, racémate, stéréoisomère, métabolite, précurseur métabolique, promédicament, solvate ou sel pharmaceutiquement acceptable de celui-ci peut être utilisé pour préparer un inhibiteur de TEAD, et peut être utilisé pour préparer un médicament destiné à prévenir ou traiter des maladies médiées par TEAD, médiées par YAP/TAZ, ou médiées par l'interaction entre YAP/TAZ et TEAD.
PCT/CN2025/098324 2024-06-01 2025-05-30 Composé bicyclique et son utilisation pharmaceutique Pending WO2025247370A1 (fr)

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