Pan-KRAS inhibitor compounds

Abstract

The present invention provides a pan-KRAS inhibitor compound. The present invention relates to a pan-KRAS inhibitor compound represented by formula (I), as well as pharmaceutical compositions containing the compound, and the use of the compound of formula (I) for the prevention and / or treatment of cancer, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases. JPEG2025530275000185.jpg104170

Description

[Technical Field]

[0001] The present invention relates to compounds, particularly highly active pan-KRAS inhibitors, and uses thereof. [Background technology]

[0002] RAS is one of the most frequently mutated genes in human tumors, with mutations found in approximately 30% of tumor patients. Among these, KRAS accounts for approximately 85% of RAS mutations. KRAS mutations occur in 88% of pancreatic cancers, 50% of colorectal adenocarcinomas, and 32% of lung adenocarcinomas. Therefore, the development of inhibitors targeting KRAS is of great clinical significance and value.

[0003] KRAS is a membrane-bound protein with GTPase activity that cycles between a GDP-bound inactive conformation and a GTP-bound active conformation via nucleotide exchange, functioning as a "molecular switch." In its GTP-bound state, KRAS activates multiple downstream signaling pathways, including RAF-MEK-ERK and PI3K-AKT, to regulate vital processes such as cell growth, proliferation, differentiation, and apoptosis.

[0004] KRAS mutations (e.g., G12C, G12D, G12V, G13D, etc.) inhibit GTP hydrolysis by GTPase-activating proteins (GAPs), resulting in increased levels of GTP-bound, active KRAS, leading to excessive activation of downstream signaling pathways and ultimately to tumor initiation and progression. However, the KRAS protein lacks a hydrophobic pocket suitable for drug binding and has picomolar-level (~20 pM) affinity for GTP and GDP, making it extremely difficult to develop competitive inhibitors. For this reason, KRAS has long been considered an "undruggable target."

[0005] In May 2021, AMG510 was approved by the FDA for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) with the KRASG12C mutation, breaking the history of KRAS being "undruggable." However, the G12C mutation only accounts for a small proportion of KRAS mutations, and there are still no effective inhibitors targeting mutations at other sites in KRAS, leaving many clinical needs unmet. Therefore, the development of effective pan-KRAS inhibitors remains a significant challenge in current technology. Summary of the Invention [Problem to be solved by the invention]

[0006] The present invention provides a pan-KRAS inhibitor, which has a structure similar to that of the existing covalent binding type KRAS. G12C Unlike inhibitors, KRAS acts by forming a ternary complex with chaperone proteins (e.g., cyclophilin A) that are widely present in cells and the KRAS protein. The formation of the ternary complex prevents the binding of KRAS to its downstream effector molecules (e.g., RAF) through steric hindrance, suppressing the activation of MAPK and PI3K-AKT signaling pathways. This suppresses the development and progression of tumors, and exerts a therapeutic effect against tumors and other diseases. [Means for solving the problem]

[0007] In one aspect, the present invention provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof: JPEG2025530275000002.jpg104170 where R1 represents C1-C6 alkyl, -(C1-C6 alkylene)-(C3-C8 cycloalkyl), or -(C1-C6 alkylene)-(3- to 8-membered heterocycloalkyl);

[0008] R2 represents halogen, cyano, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(3-8 membered heterocycloalkyl), which may optionally be substituted with 0, 1, or 2 substituents selected from -ORa, -SRa, or -NRaRa';

[0009] R3 is hydrogen, -O(C0-C6 alkylene)Ra, -S(C0-C6 alkylene)Ra, -N(C0-C6 alkylene)Ra(C0-C6 alkylene)R a ', -O(C2-C6 alkylene)R L , -S(C2-C6 alkylene)R L , -N(C2-C6 alkylene)R L (C2-C6 alkylene)R L ', where R L , R L ' each independently represent -ORa, -SRa, or -NRaRa';

[0010] Cy1 is C3~C 12 represents cycloalkyl or 3- to 12-membered heterocycloalkyl; R4 is hydrogen, halogen, oxo, C1-C6 alkyl, -(C0-C6 alkylene)(C3-C6)cycloalkyl, -(C0-C6 alkylene)(3-8 membered)heterocycloalkyl, -(C0-C6 alkylene)ORa, -(C0-C6 alkylene)SRa, -(C0-C6 alkylene)NRaRa', -(C0-C6 alkylene)-CORa, -(C0-C6 alkylene)COORa, -(C0-C6 alkylene)CONRaRa', -(C0-C6 alkylene)NRaCORa', -(C0-C6 alkylene) OCONRaRa', -(C0-C6 alkylene)NRaCONRaRa', -(C0-C6 alkylene)SORa, -(C0-C6 alkylene)S(O)2Ra, -(C0-C6 alkylene)NRaS(O)2Ra', -(C0-C6 alkylene)CN, -(C0-C6 alkylene)(C6-C 10 -(C0-C6 alkylene)(5-12 membered heteroaryl);

[0011] wherein R4 on two C atoms of Cy1 can form a 3-8 membered ring together with the C atom to which they are bonded and the atom between the two C atoms, and the 3-8 membered ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S;

[0012] or two R4 on the same C atom of Cy1 can form a 3- to 8-membered ring together with the C atom to which they are attached, and the 3- to 8-membered ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S;

[0013] R8 is -Cy2-(R5) q or -NR9R9', where: Cy2 is C3 to C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 represents aryl or 5-12 membered heteroaryl;

[0014] R5 represents hydrogen, halogen, oxo, C1-C6 alkyl, -(C0-C6 alkylene)ORa, -(C0-C6 alkylene)SRa, -(C0-C6 alkylene)NRaRa', or R5 on the two C atoms of Cy2 can form a 3-8 membered ring together with the C atom to which they are bonded and the atom between the two C atoms, and the 3-8 membered ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S;

[0015] or two R5 on the same C atom of Cy2 can form a 3- to 8-membered ring together with the C atom to which they are attached, and the 3- to 8-membered ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; or at least one atom on the Cy2 ring is substituted with S(=O)(=NRa) or S(=O)2;

[0016] R9 and R9' each independently represent a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a 3-8 membered heterocycloalkyl group, or a C6-C 10 represents an aryl group or a 5- to 12-membered heteroaryl group; R6 and R6' each independently represent hydrogen, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, or -(C0-C6 alkylene)CN;

[0017] R7, R7' each independently represent hydrogen, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, or R7, R7' and the C atoms bonded thereto may form a 3-8 membered ring, and the ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O and S;

[0018] wherein p and q each independently represent 0, 1, 2, 3, or 4; m represents 0, 1, 2 or 3; Ra and Ra' each independently represent hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl, and when Ra and Ra' are bonded to the same N atom, Ra and Ra' may form a 4- to 8-membered ring together with the N atom to which they are bonded, and the 4- to 8-membered ring may optionally contain 0, 1, 2, or 3 heteroatoms selected from N, O, and S;

[0019] The alkyl, cycloalkyl, heterocycloalkyl and alkylene groups may each independently be substituted with 0, 1, 2, 3, 4, 5 or 6 halogen atoms.

[0020] The present invention further provides a compound having the structure of formula (I) above, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein R1 represents a C1-C6 alkyl group, preferably a C1-C3 alkyl group.

[0021] The present invention further provides a compound having the structure of formula (I) above, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein R2 represents a C1-C6 alkyl group, optionally substituted by 0, 1, or 2 -ORa substituents; JPEG2025530275000003.jpg22170

[0022] Here, * indicates R2 in formula (I) and the site to which it binds.

[0023] The present invention further provides a compound having the structure of formula (I) above, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein R3 is —O(C1-C6)alkyl, —O(C0-C6 alkylene)(C3-C8)cycloalkyl, —O(C0-C6 alkylene)(3-8 membered)heterocycloalkyl, —O(C2-C6 alkylene))R L , or hydrogen.

[0024] The present invention further provides a compound having the structure of formula (I) above, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein Cy1 represents a C3-C8 cycloalkyl group or a 3-8 membered heterocycloalkyl group.

[0025] The present invention further provides a compound having the structure of formula (I) above, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein: R4 represents hydrogen, halogen, C1-C6 alkyl, -(C0-C6 alkylene)CONRaRa', -(C0-C6 alkylene)NRaCORa', -(C0-C6 alkylene)OCONRaRa', -(C0-C6 alkylene)CN, or -(C0-C6 alkylene)(5-12 membered heteroaryl);

[0026] or R4 on two C atoms of Cy1 can form a 3-8 membered ring together with the C atom to which they are attached and the atom between the two C atoms, and the 3-8 membered ring can optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O, or;

[0027] Alternatively, two R4s on the same C atom of Cy1 can form a 3- to 8-membered ring together with the C atom to which they are attached, and the 3- to 8-membered ring can optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S.

[0028] The present invention further provides a compound having the structure of formula (I) above, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein:

[0029] R4 represents hydrogen, halogen, C1-C6 alkyl, -(C0-C6 alkylene)CONRaRa', -(C0-C6 alkylene)(5-12 membered heteroaryl), or R4 on two C atoms of Cy1 can form a 3- to 8-membered ring together with the C atom to which they are bonded and the atom between the two C atoms, and the 3- to 8-membered ring can optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S, or two R5 on the same C atom of Cy1 can form a 3- to 8-membered ring together with the C atom to which they are bonded, and the 3- to 8-membered ring can optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S.

[0030] The present invention further provides a compound having the structure of formula (I) above, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein Cy2 represents a 3- to 8-membered heterocycloalkyl group or a 5- to 12-membered heteroaryl.

[0031] The present invention further provides a compound having the structure of formula (I) above, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein: R5 represents hydrogen, halogen, C1-C6 alkyl, -(C0-C6 alkylene)ORa, or -(C0-C6 alkylene)NRaRa';

[0032] or R5 on two C atoms of Cy2 can form a 3- to 8-membered ring together with the C atom to which they are bonded and the atom between the two C atoms, and the 3- to 8-membered ring can optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S;

[0033] Alternatively, two R5s on the same C atom of Cy2 can form a 3- to 8-membered ring together with the C atom to which they are attached, and the 3- to 8-membered ring can optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S.

[0034] Furthermore, the present invention provides a compound having the structure of formula (I) above, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein at least one of R9 and R9' represents C1-C6 alkyl substituted with q R5.

[0035] Furthermore, the present invention provides a compound having the structure of formula (I) above, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein R6 and R6' each independently represent hydrogen or C1-C6 alkyl, and more preferably R6 and R6' each independently represent hydrogen or methyl.

[0036] Furthermore, the present invention provides a compound having the structure of the above formula (I), or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein R7 and R7' each independently represent hydrogen or C1-C6 alkyl, or R7, R7' and the C atoms bonded thereto form a 3- to 8-membered ring, which may optionally contain 0, 1, 2, or 3 heteroatoms selected from N, O, and S, and more preferably R7 represents hydrogen. Furthermore, the present invention provides a compound having the structure of formula (I) above, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein m, p, and q are each independently preferably 0, 1, or 2.

[0037] Furthermore, the present invention provides a compound having the structure of formula (I) above, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein the structure of -Cy-(R) in formula (I) is selected from the following: JPEG2025530275000004.jpg117170Here, * indicates -Cy1-(R4)p in formula (I) and the site to which it binds. Furthermore, the present invention provides a compound having the structure of formula (I) above, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein the structure of -Cy2-(R5)q in formula (I) is selected from the following:

[0038] JPEG2025530275000005.jpg228170Here, * indicates -Cy2-(R5)q in formula (I) and the site to which it binds.

[0039] Additionally, the present invention provides a compound having the structure of formula (I) above, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein the compound of formula (I) has the structure of formula (II): JPEG2025530275000006.jpg106163

[0040] In another aspect, the present invention also provides a compound having the structure: JPEG2025530275000007.jpg247170JPEG2025530275000008.jpg255154JPEG20255302750 00009.jpg210170JPEG2025530275000010.jpg204170JPEG2025530275000011.jpg255148

[0041] In yet another aspect, the present invention also provides a pharmaceutical composition comprising any one of the foregoing compounds or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof.

[0042] In one aspect, the present invention also provides the use of the aforementioned compounds or pharmaceutically acceptable salts, isotopic derivatives, stereoisomers and pharmaceutical compositions thereof in the preparation of a medicament for preventing and / or treating cancer, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases.

[0043] It should be noted that when referring to a "compound" having the structural formula of Formula (I) or Formula (II), this generally includes its stereoisomers, diastereoisomers, enantiomers, racemic mixtures and isotopic derivatives, as well as alternative forms thereof, including pharmaceutically acceptable salts, solvates and hydrates.

[0044] It is well known to those skilled in the art that salts, solvates, and hydrates of a compound are alternative forms of the compound, and all of them can be converted into the compound under certain conditions. In addition, when referring to a compound having the structural formula of Formula (I) or Formula (II), the reference generally includes its pharmaceutically acceptable salts, and further includes its solvates and hydrates.

[0045] Similarly, a reference herein to a compound generally includes its prodrugs, metabolites, and nitroxides.

[0046] Pharmaceutically acceptable salts of the present invention can be formed using inorganic or organic acids. They are suitable for use in contact with the tissues of humans or lower animals without excessive toxicity, irritation, allergic reaction, or the like, and are considered to have a reasonable benefit / risk ratio. Salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or separately by reacting the free base or free acid with a suitable reagent, as summarized below. For example, a free base can be reacted with a suitable acid. Furthermore, if the compounds of the present invention contain an acidic moiety, suitable pharmaceutically acceptable salts thereof can include metal salts, such as alkali metal salts (e.g., sodium or potassium salts) and alkaline earth metal salts (e.g., calcium or magnesium salts). Examples of pharmaceutically acceptable non-toxic acid addition salts include salts formed with amino groups and inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by using other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, sodium alginate, ascorbate, aspartate, benzenesulfonic acid, benzoic acid, bisulfate, boric acid, butyric acid, camphoric acid, camphorsulfonic acid, citric acid, cyclopentanepropionate, digluconic acid, lauryl sulfate, ethanesulfonic acid, formic acid, fumaric acid, glucoheptonic acid, glycerin phosphate, gluconate, enanthate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobacillus acid, lactobacillus acid, lactobacillus acid, lactobacillus acid salt ... Salts include hydroxybenzoates, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamate, pectinate, persulfate, 3-phenylpropionate, phosphate, bitter salt, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Representative alkali metal or alkaline earth metal salts include sodium salt, lithium salt, potassium salt, calcium salt, magnesium salt, etc.Other pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts, and ammonium cations formed, where appropriate, with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0047] The pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example, by dissolving the compound of the present invention in a water-miscible organic solvent (acetone, methanol, ethanol, acetonitrile, etc.) and adding an excess of an organic solvent thereto, precipitating the salt from the resulting mixture using an acid or aqueous inorganic acid solution, removing the solvent and remaining free acid therefrom, and then isolating the precipitated salt.

[0048] The precursors or metabolites described in the present invention may be precursors or metabolites known in the art, as long as they are converted into compounds through in vivo metabolism. For example, a "prodrug" refers to a prodrug of a compound of the present invention that, within the scope of reasonable medical judgment, is suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., exhibits a reasonable benefit / risk ratio, and is effective for its intended use. The term "prodrug" refers to a compound that is rapidly converted in vivo to produce the parent compound of the above formula, for example, by metabolism in the body or N-demethylation of the compound of the present invention.

[0049] As used herein, "solvate" refers to a physical association of a compound of the present invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain circumstances, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate may be isolated. The solvent molecules in a solvate may exist in an ordered and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" includes both solution-phase and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation techniques are well known in the art.

[0050] In the present invention, "stereoisomerism" can be divided into structural isomerism and configurational isomerism, which can be further divided into cis-trans isomerism and optical isomerism (optical isomerism). Conformational isomerism is a stereoisomeric phenomenon in which organic molecules with a certain configuration change their spatial arrangement due to the rotation or distortion of carbon atoms or carbon single bonds. Typical examples include the chair and boat conformations found in alkane and cycloalkane compound structures, such as the cyclohexane structure. "Stereoisomer" refers to compounds of the present invention that contain one or more asymmetric centers and are therefore available as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures, and single diastereomers. Compounds of the present invention may contain asymmetric centers, each of which generates two optical isomers. The scope of the present invention includes all possible optical isomers and diastereomeric mixtures, as well as pure or partially pure compounds. Compounds described in the present invention may exist as tautomers with different hydrogen attachment points due to the displacement of one or more double bonds. For example, a ketone and its enol form are keto-enol tautomers. Each tautomer and mixtures thereof are included within the scope of the present invention. All enantiomers, diastereomers, racemates, meso, cis-trans isomers, tautomers, geometric isomers, and epimers of the compounds of Formulas (I) through (III), and mixtures thereof, are included within the scope of the present invention.

[0051] The present invention also relates to the treatment of cancer, tumors, and inflammatory diseases. The term "isotope derivatives" used in the present invention refers to molecules in which the compounds of this patent are isotopically labeled. Isotopes commonly used as isotopic labels include hydrogen isotopes: 2 H and 3 H; Carbon isotopes: 11 C. 13 C and 14 C; Chlorine isotopes: 35 Cl and 37 Cl; Fluorine isotopes: 18 F; Iodine isotopes: 123 I and 125 I; Nitrogen isotope: 13 N and 15 N; Oxygen isotopes: 15 O. 17 O. 18 O and sulfur isotopes 35 These isotopically labeled compounds can be used to study the distribution of drug molecules in tissues. 2 H and carbon 13 C is more widely used because it is easier to label and detect. 2 Substitution of certain heavy isotopes, such as H, can provide therapeutic benefits by increasing metabolic stability and half-life, thereby reducing dosage. Isotopically labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques similar to those used for non-isotopically labeled compounds.

[0052] There is provided the use of a compound of the invention in the manufacture of a medicament for the prevention and / or treatment of an autoimmune disease or an immune-mediated disease.

[0053] The present invention further provides a pharmaceutical composition for the prevention and / or treatment of cancer, tumor, inflammatory disease, autoimmune disease, neurodegenerative disease, attention-related disease or immune-mediated disease, which comprises the compound of the present invention as an active ingredient, and may optionally contain a pharmaceutically acceptable carrier.

[0054] Furthermore, the present invention provides a method for the prevention and / or treatment of cancer, tumors, inflammatory diseases, autoimmune diseases, neurodegenerative diseases, attention-related diseases or immune-mediated diseases, which method comprises administering a compound of the present invention to a mammal to which the method is applied.

[0055] Representative examples of inflammatory, autoimmune, and immune-mediated diseases include arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, juvenile arthritis, other arthritic conditions, lupus, systemic lupus erythematosus (SLE), skin-related diseases, psoriasis, eczema, dermatitis, allergic dermatitis, pain, lung disease, pulmonary inflammation, adult acute respiratory distress syndrome (ARDS), pulmonary sarcoidosis, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease (COPD), cardiovascular disease, atherosclerosis, myocardial infarction, congestive heart failure, myocardial ischemia-reperfusion injury, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, Sjogren's syndrome, autoimmune thyroid disease, urticaria (rubella), multiple sclerosis, and the like. These include, but are not limited to, sclerosis, scleroderma, organ transplant rejection, xenotransplantation, idiopathic thrombocytopenic purpura (ITP), Parkinson's disease, Alzheimer's disease, diabetes-related diseases, inflammation, pelvic inflammatory disease, allergic rhinitis, allergic bronchitis, allergic sinusitis, leukemia, lymphoma, B-cell lymphoma, T-cell lymphoma, myeloma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), hairy cell leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, myelodysplastic syndromes (MDS), myelodysplastic neoplasms (MPN), diffuse large B-cell lymphoma, and follicular lymphoma.

[0056] Representative examples of cancers or tumors include skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neurocytoma, rectal cancer, colon cancer, familial adenomatous polyposis, hereditary non-polyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary system cancer, melanoma, brain tumors (e.g., glioblastoma, astrocytoma, meningioma, medulloblastoma, primitive neuroectomy), These include, but are not limited to, myeloid leukemia (MYC), Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia / lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder cancer, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma.

[0057] When the compound of the present invention or a pharmaceutical salt thereof is administered in combination with other therapeutic agents or immune checkpoint inhibitors for treating cancer or tumors, the compound of the present invention or a pharmaceutical salt thereof exhibits an enhanced anti-cancer effect.

[0058] Representative examples of therapeutic agents for treating cancer or tumors include cell signaling inhibitors, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trametinib, thiazolinone ... Bectedin, dactinomycin, doxorubicin, epirubicin, daunomycin, mitoxantrone, bleomycin, mitomycin C, ixabepilone, tamoxifen, flutamide, gonadorelin analogues, megestrol, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon alpha, leucovorin, sirolimus, temsirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brivanib , cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, danusertib, dasatinib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib ), motesanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, sorafenib, sunitinib, telatinib, tivantinib, tivozanib, tofacitinib,These include, but are not limited to, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, alemtuzumab, bevacizumab, brentuximab vedotin, catumaxomab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panituzumab, rituximab, tositumomab, trastuzumab, PI3K inhibitors, CSF1R inhibitors, A2A and / or A2B receptor antagonists, IDO inhibitors, anti-PD-1 antibodies, LAG3 antibodies, TIM-3 antibodies, anti-CTLA-4 antibodies, or any combination thereof.

[0059] When the compounds of the present invention or pharmaceutical salts thereof are administered in combination with other therapeutic agents for treating inflammatory diseases, autoimmune diseases or immune-mediated diseases, the compounds of the present invention or pharmaceutical salts thereof exhibit enhanced therapeutic effects.

[0060] Representative examples of therapeutic agents for inflammatory diseases, autoimmune diseases, or immune-mediated diseases include, but are not limited to, steroid drugs (e.g., prednisone, prednisolone, methylprednisolone, cortisone, hydroxycortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti-TNFα drugs (e.g., etanercept, infliximab, adalizumab, etc.), calcineurin inhibitors (e.g., tacrolimus, pimecrolimus, etc.), and antihistamines (e.g., diphenhydramine, hydroxyzine, loratadine, ebastine, ketotifen, cetirizine, levocetirizine, fexofenadine, etc.), and at least one therapeutic agent selected from these may be contained in the pharmaceutical composition of the present invention.

[0061] Furthermore, the present invention also provides a method for preventing and / or treating tumors, cancers, viral infections, organ transplant rejection, neurodegenerative diseases, attention-related diseases or autoimmune diseases, which method comprises administering a compound of the present invention or a pharmaceutical composition of the present invention to a mammal in need thereof.

[0062] The compounds or pharmaceutical compositions of the present invention can be formulated in any conventional manner into dosage forms for oral or parenteral administration (including intramuscular, intravenous, subcutaneous, and intratumoral injection), such as tablets, granules, powders, capsules, syrups, emulsions, microemulsions, solutions, or suspensions.

[0063] Pharmaceutical compositions of the present invention for oral administration may be prepared by mixing the active ingredient with a carrier such as cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifying agents, diluents, etc.

[0064] Examples of carriers used in the injectable compositions of the present invention include water, salt solutions, glucose solutions, glucose-like solutions, alcohols, glycols, ethers (e.g., polyethylene glycol 400), oils, fatty acids, fatty acid esters, glycerides, surfactants, suspending agents, and emulsifying agents.

[0065] Other features of the present invention will become apparent from the description of exemplary embodiments, which are merely illustrative of the present invention and are prepared, isolated, and characterized using the methods disclosed in the following examples.

[0066] The compounds of the present invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis, including the methods described below, as well as synthetic methods known in the art of synthetic organic chemistry, or variations thereof known to those skilled in the art to synthesize the compounds of the present invention. Preferred methods include, but are not limited to, those described below. The reactions are carried out in a solvent or solvent mixture appropriate to the kit materials used and the transformations being performed. Those skilled in the art of organic synthesis will understand that the functional groups present in the molecule are consistent with the proposed transformations. Judgment is sometimes required to alter the order of synthetic steps or starting materials to obtain the desired compounds of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0067] term Unless otherwise noted, the terms used in this application (including the specification and claims) are defined as follows: It should be noted that, in this specification and the appended claims, the singular form "a" includes the plural reference unless the context clearly dictates otherwise. Conventional methods of mass spectroscopy, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology were employed unless otherwise indicated. In this application, the use of "or" or "and" means "and / or" unless stated otherwise.

[0068] In the specification and claims, a given chemical formula or name is intended to encompass all stereoisomers and optical isomers, as well as racemates in which such isomers exist. Unless otherwise indicated, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of the present invention. Many geometric isomers of C=C double bonds, C=N double bonds, ring systems, and the like may also be present in the compounds, and all such stable isomers are encompassed by the present invention. The present invention describes cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present invention, which can be separated into mixtures of isomers or into separate isomeric forms. The compounds of the present invention can be isolated in optically active or racemic form. All processes for preparing the compounds of the present invention and intermediates prepared therein are considered to be part of the present invention. When enantiomeric or diastereomeric products are prepared, they can be separated by conventional methods, such as chromatography or fractional crystallization. Depending on the process conditions, the final products of the present invention may be obtained in free (neutral) or salt form. Both the free form and the salts of these final products are within the scope of the present invention. If necessary, one form of a compound can be converted to another form. A free base or acid can be converted to a salt, and the salt can be converted to the free compound or another salt, and a mixture of isomeric compounds of the present invention can be separated into individual isomers. The compounds of the present invention, their free forms and salts, can exist in various tautomeric forms in which hydrogen atoms are transferred to other parts of the molecule, thereby rearranging the chemical bonds between the atoms of the molecule. It should be understood that all possible tautomers are included in the present invention.

[0069] The definitions of the substituents in the present invention are independent of each other unless otherwise specified. For example, R a (or R a ') is independent of the definition of different substituents. Specifically, R a (or R a If one definition is chosen for R '), it must be used in other substituents. a (or R a') have the same definition. More specifically, for example (not exhaustively) NR a R a 'About R a (or R a When the definition of ') is selected from hydrogen, it is -C(O)-NR a R a In 'R' a (or R a It does not mean that R' must be hydrogen. On the other hand, if a substituent has multiple R's, a (or R a '), if there are R a (or R a For example, the substituent -(CR a R b )mO-(CR a R a ')n-, if m+n is 2 or more, R of m+n a (or R a ') are independent and can have the same or different meanings.

[0070] Unless otherwise defined, when a substituent is designated as being "optionally substituted," that substituent can be, for example, alkyl, cycloalkyl, aryl, heterocyclyl, halogen, hydroxyl, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amine group (wherein the two amino substituents are selected from alkyl, aryl, or arylalkyl), alkanoylamino, arolylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thio, alkylthio group, arylthio group, arylalkylthio group, arylthiocarbonyl group, arylalkylthiocarbonyl group, alkyls and the like. The substituents may be selected from the group consisting of alkoxycarbonyl, aryl, substituted aryl, guanidyl, heterocyclyl, such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, homopiperazinyl, and the like, and substituted heterocyclyl.

[0071] As used herein, the term "alkyl" or "alkylene" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C1-C6 alkyl" means an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, and neopentyl. Preferred alkyl groups of the present invention include C1-C6 alkyl or C1-C4 alkyl.

[0072] The term "alkenyl" refers to a straight or branched chain hydrocarbon radical containing one or more double bonds and typically having a length of 2 to 20 carbon atoms. For example, a "C2-C6 alkenyl" contains 2 to 6 carbon atoms. Alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. Preferred alkenyl groups of the present invention include C2-C6 alkenyl groups.

[0073] The term "alkynyl" refers to a straight- or branched-chain hydrocarbon group containing one or more triple bonds and typically having a length of 2 to 20 carbon atoms. For example, "C2-C6 alkynyl" contains 2 to 6 carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, and the like. Preferred alkynyl groups of the present invention include C2-C6 alkynyl groups. The term "alkoxy" or "alkyloxy" refers to -O-alkyl. "C1-C6 alkoxy" (or alkyloxy) is intended to include C1, C2, C3, C4, C5, and C6 alkoxy. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (e.g., N-propoxy and isopropoxy), and tert-butoxy. Similarly, "alkylthio" or "thioalkoxy" refers to a sulfur-bridged alkyl group as defined above having the specified number of carbon atoms, e.g., methyl-S- and ethyl-S-. In the present invention, preferred alkoxy groups include C1 to C6 alkoxy groups and C1 to C4 alkoxy groups.

[0074] The term "carbonyl" refers to an organic functional group consisting of two atoms, carbon and oxygen, joined by a double bond (C=O).

[0075] The term "aryl," alone or as part of a larger moiety such as "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to a monocyclic, bicyclic, or tricyclic ring system having a total of 5 to 12 ring members, where at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. In certain embodiments of the invention, "aryl" refers to aromatic ring systems, including, but not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthyl. The term "aralkyl" or "arylalkyl" refers to an alkyl residue attached to an aryl ring. Non-limiting examples include benzyl, phenethyl, and the like. A fused aryl group can be attached to another group at any suitable position on the cycloalkyl ring or aromatic ring. For example, a dashed line drawn through a ring system indicates that the bond can be attached to any suitable ring atom.

[0076] The term "cycloalkyl" refers to a monocyclic or bicyclic cyclic alkyl group. Monocyclic cyclic alkyl refers to unbranched or branched cyclic alkyl, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, 1-methylcyclopropyl, and 2-methylcyclopropyl. Bicyclic cyclic alkyl groups include bridged, spirocyclic, or fused ring cycloalkyl groups. Preferred cycloalkyl groups of the present invention include C3-C6 cycloalkyl groups.

[0077] As used herein, the term "heterocycloalkyl" or "heterocycle" refers to a monocyclic heterocycloalkyl system or a bicyclic heterocycloalkyl system, including spiroheterocycles or bridged heterocycloalkyl groups. A monocyclic heterocycloalkyl refers to a saturated or unsaturated, but non-aromatic, cyclic alkyl system containing at least one heteroatom selected from O, N, S, and P. A bicyclic heterocycloalkyl system refers to a bicyclic heterocycloalkyl group in which the heterocycloalkyl is fused to a phenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heteroaryl ring system. Preferably, the "heterocycloalkyl" or "heterocycle" contains at least one or two heteroatoms selected from O, N, and S.

[0078] The term "bridged cycloalkyl" as used herein refers to a polycyclic compound that shares two or more carbon atoms. It can be divided into bicyclic bridged cyclic hydrocarbons and polycyclic bridged cyclic hydrocarbons. The former is composed of two alicyclic rings that share two or more carbon atoms, while the latter is composed of three or more rings.

[0079] As used herein, the term "spirocycloalkyl" refers to a polycyclic hydrocarbon that shares one carbon atom (called a spiro atom) between the monocyclic rings.

[0080] The term "bridged cycloheteroyl" as used herein refers to a polycyclic compound that shares two or more carbon atoms, and the rings contain at least one atom selected from O, N, and S. They can be divided into bicyclic bridged heterocycles and polycyclic bridged heterocycles.

[0081] The term "heterospirocyclyl" as used herein refers to a polycyclic hydrocarbon that shares one carbon atom (called a spiroatom) between monocyclic rings and contains at least one heteroatom selected from O, N, and S within the ring.

[0082] As used herein, the term "substituted" means that at least one hydrogen atom is replaced with a non-hydrogen group, provided that normal valence is maintained and the substitution results in a stable compound. As used herein, a cyclic double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0083] The term "cycloalkenyl" refers to a monocyclic or bicyclic cyclic alkenyl group. Monocyclic cyclic alkenyl refers to unbranched or branched cyclic alkenyl, including, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and norbornenyl, 1-methylcyclopropenyl, and 2-methylcyclopropenyl. Bicyclic cyclic alkenyl groups include bridged, spiro, or fused ring cyclic alkenyl groups. Preferred cycloalkenyl groups of the present invention include C3-C6 cycloalkenyl groups.

[0084] "Halo" or "halogen" includes fluorine, chlorine, bromine, and iodine. "Haloalkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoroethylpropyl, and heptachloropropyl. Examples of haloalkyl groups also include "fluoroalkyl groups," which are intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more fluorine atoms.

[0085] "Haloalkoxy" or "haloalkyloxy" refers to a haloalkyl group as defined above having the specified number of carbon atoms attached through an oxygen bridge. For example, "C1-C6 haloalkoxy" is intended to include C1, C2, C3, C4, C5, and C6 haloalkoxy. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" refers to a sulfur-bridged haloalkyl group as defined above having the specified number of carbon atoms, e.g., trifluoromethyl-S- and pentafluoroethyl-S-.

[0086] In this disclosure, C x1 ~C x2 The expression "x" is used when referring to several substituents, which means that the number of carbon atoms in the substituent can be x1 to x2. For example, C0-C8 means that the group contains 0, 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, C1-C8 means that the group contains 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, C2-C8 means that the group contains 2, 3, 4, 5, 6, 7, or 8 carbon atoms, C3-C8 means that the group contains 3, 4, 5, 6, 7, or 8 carbon atoms, and C4-C8 means that the group contains 4, 5, 6, 7, or 8 carbon atoms. 8 means the group contains 4, 5, 6, 7 or 8 carbon atoms, C0-C6 means the group contains 0, 1, 2, 3, 4, 5 or 6 carbon atoms, C1-C6 means the group contains 1, 2, 3, 4, 5 or 6 carbon atoms, C2-C6 means the group contains 2, 3, 4, 5 or 6 carbon atoms, and C3-C6 means the group contains 3, 4, 5 or 6 carbon atoms.

[0087] In the present disclosure, the expression "x1-x2-membered ring" is used when referring to a cyclic group (such as aryl, heteroaryl, cycloalkyl, and heterocycloalkyl), meaning that the number of ring atoms in the group can be x1 to x2. For example, a 3- to 12-membered cyclic group can be a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, and the number of ring atoms can be 3, 4, 5, 6, 7, 8, 9, 10-, 11-, or 12. A 3- to 6-membered ring means that the cyclic group can be a 3-, 4-, 5-, or 6-membered ring, and the number of ring atoms can be 3, 4, 5, or 6. A 3- to 8-membered ring means that the cyclic group can be a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, and the number of ring atoms can be 3, 4, 5, 6, 7, or 8. A 3-9 membered ring means that the cyclic group can be a 3-, 4-, 5-, 6-, 7-, 8-, or 9-membered ring, and the number of ring atoms can be 3, 4, 5, 6, 7, 8, or 9. A 4- to 7-membered ring means that the cyclic group can be a 4-, 5-, 6-, or 7-membered ring, and the number of ring atoms can be 4, 5, 6, or 7. A 5- to 8-membered ring means that the cyclic group can be a 5-, 6-, 7-, or 8-membered ring, and the number of ring atoms can be 5, 6, 7, or 8. A 5- to 12-membered ring means that the cyclic group can be a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, and the number of ring atoms can be 5, 6, 7, 8, 9, 10-, 11-, or 12. A 6- to 12-membered ring means that the cyclic group can be a 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, and the number of ring atoms can be 6, 7, 8, 9, 10-, 11-, or 12. The ring atoms may be carbon atoms or heteroatoms, e.g., heteroatoms selected from N, O, and S. When the ring is a heterocycle, the heterocycle may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more ring heteroatoms, e.g., selected from N, O, and S heteroatoms.

[0088] In the context of the present invention, the one or more halogens may each be independently selected from fluorine, chlorine, bromine and iodine.

[0089] The term "heteroaryl" refers to a stable 5-, 6-, or 7-membered aromatic monocyclic or bicyclic ring, or a 7-, 8-, 9-, 10-, 11-, or 12-membered aromatic polycyclic heterocycle, fully unsaturated, partially unsaturated, containing carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, including any of the following polycyclic groups: The heterocycle defined above is fused to a benzene ring. The nitrogen and sulfur heteroatoms may be optionally oxidized. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R, as defined, is H or another substituent). A heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclyl groups described herein can be substituted on carbon or nitrogen atoms if the resulting compound is stable. A nitrogen in a heterocycle can optionally be quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to one another. Preferably, the total number of S and O atoms in the heterocycle is 1 or less. When the term "heterocycle" is used, it is intended to include heteroaryl groups. Examples of aryl heterogroups include acridinyl, azetidinyl, azecinyl, benzimidazolyl, benzofuryl, benzothiofuranyl, benzothienyl, benzoazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benz, diisothiazolyl, benzimidazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuryl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridyl, pseudoindolenyl, indolenyl, indolinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolyl, isoindolyl, isoquinolyl, isothiazolyl, isothiazopyridyl, isoxazolyl, isoxazolopyridyl, methylenedioxyphenyl, morpholinyl, diazanaphthyl, octahydroisoquinoline base, oxalyl Sadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridyl, oxazolidinyl, naphthyridyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidinonyl, 4-piperidinonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazo Rizinyl, pyrazolinyl, pyrazopyridyl, pyrazolyl, pyridazinyl, pyridoxazolyl, pyrimidazolyl, pyridothiazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydroquinolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4 -Thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thiazolopyridyl, thienothiazolyl, thienoxanylazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthyl, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolyl, 1H-indazolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, 5,6,Examples of heteroaryl include, but are not limited to, 7,8-tetrahydroquinolyl, 2,3-dihydrobenzofuryl, chromanyl, 1,2,3,4-tetrahydroquinoxalinyl, and 1,2,3,4-tetrahydroquinazolinyl. The term "heteroaryl" also includes, but is not limited to, biaryl structures formed by the above-defined "aryl" and monocyclic "heteroaryl," such as "-phenylbipyridyl-," "-phenylbipyrimidinyl," "-pyridylbiphenyl," "-pyridylbipyrimidinyl-," "-pyrimidinylbiphenyl-," and the like. Here, the present invention also includes, for example, fused rings containing the above heterocyclic and spirocyclic compounds.

[0090] When nitrogen atoms (e.g., amines) are present on the compounds of the invention, these nitrogen atoms can be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxide) to provide other compounds of the invention. Thus, the nitrogen atoms shown and claimed are considered to encompass the nitrogen atoms shown and their N-oxides to provide derivatives of the invention.

[0091] When any variable occurs more than one time in any composition or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R, that group may optionally be substituted with up to three R groups, and each occurrence of R is independently selected from the definitions of R. Further, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0092] As used herein, the term "patient" refers to an organism treated by the methods of the present invention, preferably, but not limited to, a mammal (e.g., rodents, apes / monkeys, horses, cows, pigs, dogs, cats, etc.), and most preferably, a human.

[0093] As used herein, the term "effective amount" refers to an amount of a drug or agent (i.e., a compound of the present invention) that elicits the biological or medical response desired, for example, in a tissue, system, animal, or human, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" refers to an amount that results in the treatment, cure, prevention, or improvement of amelioration of a disease, disorder, or side effect, or a reduction in the risk of a disease, disorder, or side effect, compared to a corresponding subject not receiving such an amount or compared to the rate at which symptoms progress. An effective amount can be administered in one or more administrations, doses, or dosages and is not intended to be limited to a particular formulation or route of administration. The term also encompasses within its scope amounts effective to enhance normal physiological function.

[0094] The term "treatment" is used herein in its broadest sense and encompasses therapeutic and / or prophylactic treatment of a subject. In particular, "treatment" includes any treatment that results in the alleviation, suppression, elimination, improvement and / or prevention of symptoms, diseases, disorders, etc., such as the alleviation, reduction, modulation, improvement, elimination, prevention, prophylaxis or amelioration of symptoms.

[0095] The terms "pharmaceutically useful" or "pharmaceutically acceptable" are used herein to refer to compounds, substances, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals, without undue toxicity, irritation, allergic response, and / or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0096] As used herein, the phrase "pharmaceutically acceptable carrier" refers to a pharmaceutical substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium stearate, calcium stearate, zinc stearate, zinc stearate, or stearic acid, etc.), or solvent encapsulating material, which carries or transports the subject compound from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

[0097] The term "pharmaceutical composition" refers to a composition comprising a compound of the present invention and at least one other pharmaceutically acceptable carrier. A "pharmaceutically acceptable carrier" refers to a vehicle generally accepted in the art for delivering a bioactive agent to an animal, particularly a mammal, and includes (i.e.,) adjuvants, excipients, or vehicles (e.g., diluents, preservatives, fillers, flow conditioners, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavorings, aromatic substances, antibacterial agents, antifungal agents, lubricants, dispersing agents, and the like), which will vary depending on the method of administration and the nature of the dosage form.

[0098] Certain pharmaceutical and medical terms As used herein, the term "acceptable" means that the formulation ingredients or active ingredients do not have excessive adverse effects on the health of the typical treated subject.

[0099] The term "cancer," as used herein, refers to an abnormal growth of cells that is uncontrolled and may metastasize (spread) under certain conditions. This type of cancer includes, but is not limited to, solid tumors (bladder, intestine, brain, breast, uterus, heart, kidney, lung, lymphatic tissue (lymphoma), ovary, pancreas, or other endocrine organs (e.g., thyroid), prostate, skin (melanoma), or blood tumors (e.g., non-leukemic leukemia).

[0100] As used herein, the term "administration in combination" or similar terms refers to the administration of several selected therapeutic agents to a patient at the same or different times, in the same or different modes of administration.

[0101] As used herein, the terms "enhance" or "potentiable" mean that a desired result is increased or prolonged, either in potency or duration. Thus, in the context of enhancing the therapeutic effect of a drug, the term "potentiable" refers to the ability of a drug to increase or prolong its potency or duration in a system. As used in this article, "synergy" refers to the ability to maximize the potentiation of another therapeutic agent in an ideal system.

[0102] The term "immune disease" refers to a disease or disorder resulting from an adverse or harmful response to endogenous or exogenous antigens, usually resulting in cellular dysfunction or organ or tissue damage that can lead to immune symptoms.

[0103] The terms "kit" and "product package" are synonymous.

[0104] The terms "subject," "test subject," or "patient" include mammals and non-mammals. Mammals include, but are not limited to, mammals (humans, non-human primates, e.g., orangutans, monkeys, and apes), agricultural animals (e.g., cows, horses, goats, sheep, and pigs), livestock (e.g., rabbits and dogs), and laboratory animals (including rodents such as rats, mice, and guinea pigs). Non-mammals include, but are not limited to, birds, fish, and the like. In a preferred embodiment, the selected mammal is a human.

[0105] As used herein, the terms "treatment," "process of treatment," or "therapy" include alleviating, inhibiting, or ameliorating the symptoms or condition of a disease, ameliorating or preventing the underlying metabolic syndrome, controlling the onset of a disease or condition, alleviating a disease or condition, or alleviating complications caused by a disease or condition, or preventing and / or treating symptoms caused by a disease or condition.

[0106] Certain compounds or pharmaceutical compositions described herein, after administration, result in an improvement in a particular disease, symptom, or condition, particularly a reduction in the severity, delay in onset, slowing of disease progression, or shortening of disease duration, whether administered as a fixed dose or punctually, whether administered continuously or intermittently.

[0107] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transdermal, vaginal, intra-aural, nasal, and topical administration, and illustrative parenteral administration includes intramuscular, subcutaneous, intravenous, intramedullary, ventricular, intraperitoneal, intralymphatic, and intranasal injections.

[0108] The compounds of the present invention may be administered locally. In certain embodiments, long-acting formulations are administered by infusion (e.g., subcutaneous or intramuscular) or intramuscular injection. In another particular embodiment, the drug is administered via a targeted drug delivery system, e.g., a liposome encapsulated with an organ-specific antibody. In such embodiments, the liposome is selectively targeted to and absorbed by a specific organ.

[0109] Pharmaceutical Compositions and Dosages Pharmaceutical compositions of the present invention may comprise a therapeutically effective amount of one or more compounds of the present invention, optionally combined with one or more pharmaceutical carriers (excipients) and / or diluents, and optionally one or more other therapeutic agents. For any of the above uses, the compounds of the present invention can be administered in any suitable manner, for example, orally (e.g., tablets, pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, and spray-dried dispersions), syrups, emulsions), sublingually, bucally, parenterally (e.g., subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., sterile aqueous or non-aqueous solutions or suspensions for injection)), nasally (e.g., administration to the nasal membranes (e.g., inhalation spray)), topically (e.g., creams or ointments), rectally (e.g., suppositories), or intratumoral injection. Compounds of the present invention may also be administered alone, generally with a pharmaceutical carrier selected based on the intended route of administration and standard pharmaceutical experimentation.

[0110] The above-mentioned carriers may contain various ingredients and additives in addition to the active agent, and the other ingredients, such as stabilizers, adhesives, etc., are used in the formulation based on various factors known to those skilled in the art. Many references are available for explanations of suitable pharmaceutical carriers and factors involved in the selection of carriers (e.g., Allen LVJr. et al. Remington: The Science and Practice of Pharmacy (2 volumes), 22nd Edition (2012), Pharmaceutical Press).

[0111] The dosing regimen for the compounds of the present invention varies depending on known factors, such as the pharmacodynamic properties of the drug, the mode and route of administration, the target organism, age, sex, health condition, disease state and weight, characteristics and severity of symptoms, type and frequency of concurrent treatment, route of administration, the patient's renal and hepatic function, and the desired effect. Generally, to achieve the desired effect, the daily oral dose of each active ingredient is about 0.001 mg / day to about 10-5000 mg / day, preferably about 0.01 mg / day to about 1000 mg / day, and most preferably about 0.1 mg / day to about 250 mg / day. When administered by constant rate infusion, the intravenous dose is most preferably about 0.01 mg / kg / min to about 10 mg / kg / min. The compounds of the present invention may be administered in a single daily dose, or in two, three, or four divided doses throughout the day.

[0112] The compounds are generally administered in admixture with pharmaceutical diluents, excipients, and carriers (collectively referred to herein as pharmaceutical carriers) appropriately selected depending on the desired route of administration (e.g., oral tablets, capsules, elixirs, syrups) and on the basis of conventional pharmaceutical experience.

[0113] The dosage form (pharmaceutical composition) for administration has an active ingredient per dosage unit of about 1 mg to about 2000 mg, and in such pharmaceutical compositions, the active ingredient is generally present in an amount of about 0.1 to 95% by weight based on the total weight of the composition.

[0114] The present invention includes pharmaceutical compositions containing a therapeutically effective amount of at least one compound of the present invention as an active ingredient (alone or in combination with a pharmaceutical carrier), optionally used alone or in combination with other compounds of the present invention, or in combination with one or more other therapeutic agents (e.g., anti-cancer agents or other pharmaceutically active substances).

[0115] Regardless of the route of administration selected, the compounds of the present invention (including appropriate hydrates) and / or pharmaceutical compositions of the present invention are formulated in pharmaceutical dosages by conventional methods known to those skilled in the art.

[0116] The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention is adjusted to obtain an amount of the active ingredient that effectively achieves the desired therapeutic response in a particular patient, composition and mode of administration, and is not toxic to the patient.

[0117] The dose level is determined by many factors known in the medical field, such as the activity of the compound of the present invention, its ester, salt or amide used, the route of administration, the duration of administration, the rate of metabolism of the compound used, the rate and extent of absorption, the duration of treatment, other drugs, compounds and / or substances administered in combination with the compound used, the age, sex, weight, condition, underlying health and medical history of the patient being treated, etc.

[0118] A physician or veterinarian skilled in the art can easily determine and prescribe an effective amount of the pharmaceutical composition. For example, to achieve a desired therapeutic effect, a physician or veterinarian can start with a pharmaceutical composition containing a compound of the present invention at a lower amount than the target level and gradually increase the dosage until the desired effect is achieved. In general, an appropriate daily dose of a compound of the present invention is the lowest dose of the compound necessary to achieve a therapeutic effect. The effective dose is generally determined by the factors described above. In general, oral, intravenous, intracerebroventricular, or subcutaneous doses of a compound of the present invention for a patient range from about 0.01 to about 50 mg / kg body weight / day. If necessary, an effective daily dose of the active compound may be administered in two, three, four, five, six, or more divided doses at appropriate intervals throughout the day, or, if desired, in a unit dosage form. In some embodiments of the present invention, the drug is administered once daily.

[0119] While a compound of the present invention may be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition).

[0120] "Kit / product packaging" Kits / product packaging for use in treating the above-mentioned indications are now described. These kits consist of a shipping device, drug pack, or container box, which can be divided into sections to house one or more containers (e.g., vials, test tubes, etc.), each containing one component of the method. Suitable containers include bottles, vials, syringes, test tubes, etc. The containers can be made from acceptable materials such as glass or plastic.

[0121] For example, the container may contain one or more of the compounds, and the compound may be present as a component of a drug or may be present in a mixture with other components described herein. The container may be provided with a single sterile delivery port (e.g., the container may be an intravenous drug bag or bottle with a stopper that can be pierced by the needle tip of a hypodermic syringe). Such product packaging may include the compound and instructions, labels, or manuals for use as described herein.

[0122] A typical product package contains one or more containers, each containing one or more materials (e.g., reagents, concentrated mother liquors, and / or equipment) to meet the marketing and use requirements of the compound. These materials, e.g., buffers, diluents, filters, needle tips, syringes, transfer devices, bags, containers, bottles, and / or test tubes, are provided with a list of contents and / or instructions, and instructions are also provided on the inner packaging. All information provided as instructions must be provided in its entirety.

[0123] A label may be affixed to or associated with a container. When a label is affixed to a container, it may have letters, numbers, or other features affixed, molded, or imprinted onto the container. A label may also be placed inside a container box or shipping box containing multiple containers, for example, as a product description. A label may indicate a specific therapeutic use of the contents. A label may also indicate how to use the contents, as described in the methods above.

[0124] All features described in this specification (including all claims, abstracts, and drawings), and / or all steps associated with any method or procedure, may be present in any combination, unless some features or steps in a combination are mutually inconsistent.

[0125] The above-described features of the present invention or the features of the embodiments thereof can be arbitrarily combined. All features described in this specification can be provided in the form of a suitable composition, and each feature described in the specification may be replaced with an alternative feature that can achieve the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the described feature is merely an example of an equivalent or similar feature.

[0126] The present invention will now be further described in connection with specific examples. It should be noted that these examples are merely illustrative and do not limit the scope of the present invention. Experimental methods not specifically described in the following examples are carried out under standard conditions or under conditions recommended by the manufacturer. Unless otherwise specified, percentages, ratios, proportions, and parts are all by weight.

[0127] In the present invention, the units used to indicate weight-volume percentages are known to those skilled in the art, for example, the weight (g) of solute in 100 mL of solution. Unless otherwise defined, all technical and scientific terms used herein have the ordinary meanings understood by those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are merely exemplary.

[0128] Example General Process Unless a preparation route is described, all raw materials and reagents used in the present invention are known products and can be synthesized according to known methods or purchased commercially. All commercially available reagents were used without further purification.

[0129] Room temperature refers to 20 to 30 degrees Celsius. Unless otherwise specified in the reaction examples, all reactions were carried out under a nitrogen atmosphere, which means that a nitrogen balloon of approximately 1 L was connected to the reaction bottle. The hydrogenation reaction is usually performed by evacuating and then refilling with hydrogen three times. The hydrogen atmosphere refers to a state in which a hydrogen balloon of approximately 1 L is connected to the reaction bottle. For microwave reactions, Biotage (登録商標) An Initiator+ microwave reactor was used.

[0130] The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The NMR shifts (δ) were 10 -6 The units are given in ppm. NMR is (BrukerAscend TM Measurements were performed using a 500 nm nuclear magnetic spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS). The following abbreviations are used for NMR signal multiplicities: s = singlet, brs = broad, d = doublet, t = triplet, and m = multiplet. Coupling constants are listed as J values ​​measured in Hz.

[0131] A Thermo (UltiMate 3000) reversed-phase preparative chromatograph was used for reversed-phase preparative chromatography. An Agela (FS-9200T) automated column system was used for flash column chromatography, and Santai SEPAFLASH® prepacked silica gel columns were used. Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates were used for thin-layer chromatography. The thickness of the thin-layer chromatography separation and purification products was 0.4 mm to 0.5 mm.

[0132] The LC-MS analysis method is as follows: 1) Mass spectrometry: ThermoFisher MSQ PLUS mass spectrometer, ESI source, positive ion mode. Ion source parameters: drying gas temperature 350°C, drying gas flow rate 10 L / min, MS range 120-1000.

[0133] 2) Liquid phase conditions: Column: Waters XBridge (3.5 μm, 50 mm × 4.6 mm); Mobile phase A was 0.1% ammonium bicarbonate aqueous solution, and mobile phase B was acetonitrile solution. Linear gradient elution was performed according to Table 1; Flow rate: 2 mL / min; Column temperature: 30 °C; UV detection wavelengths: 214 nm, 254 nm, 280 nm; Injection volume: 2 μL.

[0134] Table 1. Gradient elution conditions JPEG2025530275000012.jpg73170

[0135] The HPLC analysis method is as follows: Column: Waters XBridge phenyl (3.5 μm, 150 mm × 4.6 mm); mobile phase A was 0.1% ammonium bicarbonate aqueous solution, and mobile phase B was acetonitrile solution. Linear gradient elution was performed according to Table 2; flow rate: 1 mL / min; column temperature: 30 °C; UV detection wavelengths: 214 nm, 254 nm, 280 nm; injection volume: 2 μL.

[0136] Table 2. Gradient elution conditions JPEG2025530275000013.jpg70170

[0137] The synthesis methods of some intermediates in the present invention are as follows.

[0138] Intermediate 1 JPEG2025530275000014.jpg82169

[0139] Intermediate 1 was prepared by the following steps: JPEG2025530275000015.jpg141170

[0140] Step 1: 2,2-Dimethyl-3-hydroxypropionic acid methyl ester INT-1a (100 g, 757 mmol) was dissolved in 1 L of N,N-dimethylformamide, imidazole (129 g, 1.89 mol) was added, and the mixture was stirred to dissolve. tert-Butyldiphenylsilyl chloride (229 g, 832 mmol) was added dropwise at room temperature. After the addition was completed, the mixture was stirred for 4 hours. After the reaction was complete, the reaction mixture was poured into 3 L of ice water, and the suspension was extracted with ethyl acetate (1 L x 2). The organic phase was washed three times with water and concentrated under reduced pressure to give INT-1b as a colorless oil. No purification was required and the product was used directly in the next step. ESI-MS (m / z): 371.2 [M+H] + .

[0141] Step 2: The residual liquid INT-1b obtained in the previous step was added to 2 L of methanol, and 360 g of the prepared 33% aqueous sodium hydroxide solution was added. The mixture was stirred at room temperature for 17 hours. After the reaction was completed, 1 L of water was added, and the methanol was removed by distillation under reduced pressure. The residual liquid was extracted with petroleum ether (1 L x 5). After extraction, the pH of the aqueous phase was adjusted to 4-5 with hydrochloric acid. Stirring was continued for 30 minutes, and the mixture was suction filtered and dried to obtain INT-1c (269 g, 90% yield) as a white solid. ESI-MS (m / z): 357.8 [M+H] + .

[0142] Step 3: INT-1c (130 g, 365 mmol) was dissolved in 500 mL of dichloromethane, and thionyl chloride (130 g, 1.09 mol, 79.4 mL) was added at room temperature. The mixture was stirred at 60 °C for 3 hours. The reaction was completed, and methylene chloride and remaining thionyl chloride were removed under reduced pressure to give INT-1d as a yellow oil. 200 mL of methylene chloride was added and the mixture was stored without further purification.

[0143] Step 4: INT-1e (64.8 g, 331 mmol) was dissolved in 400 mL of dichloromethane and 198 mL of a 2 M diethylaluminum chloride solution (hexane) was added dropwise at 0 °C. The temperature was controlled so that it did not exceed 5 °C. After the addition was completed, the mixture was stirred for 30 min. The resulting dichloromethane solution of INT-1d was added dropwise to the reaction vessel. The temperature during the addition was controlled so that it did not exceed 10 °C. After the addition was completed, the mixture was stirred for 2 h. After the reaction was completed, the reaction solution was poured into 1 L of ice water, stirred for 30 min, and concentrated under reduced pressure to remove methylene chloride. The residual liquid was extracted with ethyl acetate (1 L x 2) and washed with water. The organic phase was evaporated on a rotary evaporator to give a brown oil. This oil was added to 2 L of a 10:1 mixture of petroleum ether and ethyl acetate, stirred to precipitate the solid, and filtered under suction to give a yellow solid, INT-1f (139 g, 78% yield). ESI-MS (m / z): 534.8 [M+H] + .

[0144] Step 5: INT-1f (100 g, 187 mmol) was dissolved in 500 mL of tetrahydrofuran, lithium borohydride (12.2 g, 561 mmol) was added, and the mixture was stirred at 60 °C overnight. After the starting material disappeared, the mixture was quenched with 200 mL of ice water and extracted with ethyl acetate (500 mL × 3). The organic phase was washed with water, dried, and concentrated under reduced pressure. The remaining liquid was dissolved in 500 mL of methylene chloride, and diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate (28.4 g, 112 mmol) and p-toluenesulfonic acid (21.4 g, 112 mmol) were added. The mixture was stirred at room temperature for 3 hours to complete the reaction. The mixture was concentrated under reduced pressure to remove methylene chloride, and the remaining liquid was dissolved in 500 mL of methanol. 14% aqueous lithium hydroxide solution (100 mL) was added and stirred at room temperature for 3 hours. The yellow solid INT-1g (84 g, 86.3% yield) was obtained by suction filtration. ESI-MS (m / z): 520.2 [M+H] + .

[0145] Step 6: INT-1g (50 g, 96 mmol) was dissolved in 250 mL of tetrahydrofuran, tetrabutylammonium fluoride (1 M in THF, 197 mL) was added, and the mixture was stirred at 60 °C overnight until the reaction was complete. The reaction mixture was added to 3 mL of water, extracted with ethyl acetate (200 mL × 3), washed with water, and concentrated under reduced pressure to give a brown oil. The resulting residue was dissolved in 40 mL of methanol, 20 mL of water was added, and the mixture was washed with petroleum ether (40 mL × 5), concentrated under reduced pressure to remove the methanol. The residue was extracted with ethyl acetate (50 mL × 2), and the organic phase was washed with water and dried to give INT-1h (25 g, 90.4% yield) as a pale yellow oil. ESI-MS (m / z): 282.8 [M+H] + .

[0146] Step 7: Compound INT-1h (22 g, 77 mmol) was dissolved in 100 mL of dichloromethane. 4-Dimethylaminopyridine (467 mg, 3.82 mmol) and triethylamine (23.2 g, 230 mmol) were added, and acetic anhydride (7.9 g, 77 mmol) was added dropwise at 0 °C. After the addition, the temperature rose spontaneously and the reaction was stirred overnight until completion. The reaction solution was washed with water, dried, and concentrated to give a brown oil, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give a pale yellow oil, INT-1i (22.5 g, 90.7% yield). ESI-MS (m / z): 324.2 [M+H] + .

[0147] Step 8: Compound INT-1i (40 g, 123 mmol) was dissolved in dioxane (400 mL), potassium acetate (30.3 g, 308.4 mmol), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium (10 g, 12.3 mmol), and bis(pinacolato)diboron (78.3 g, 308 mmol) were added, and the reaction was carried out under nitrogen protection at 90 °C for 3 hours. Completion of the reaction mixture was monitored by LCMS. The reaction solution was directly concentrated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL), washed with water and brine, and the organic phase was purified by silica gel column chromatography to give compound INT-1j (35 g, 76.4% yield) as a white solid. ESI-MS (m / z): 372.5 [M+H] + .

[0148] Step 9: Compound INT-1j (35 g, 94.3 mmol) and compound INT-1k (37.9 g, 104 mmol) were dissolved in dioxane (300 mL) and water (30 mL), and potassium phosphate (50 g, 236 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium (6.89 g, 9.43 mmol) were added. The reaction was allowed to proceed overnight at 90 °C under nitrogen protection. Complete reaction of the starting materials was monitored by LCMS. The reaction solution was directly concentrated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL), washed with water and saturated brine, and the organic phase was purified by silica gel column chromatography to give compound INT-11 (28 g, 56.1% yield) as a yellow oil. ESI-MS (m / z): 530.7 [M+H] + .

[0149] Step 10: Compound INT-11 (28 g, 52.9 mmol) was dissolved in N,N-dimethylformamide (280 mL), N-iodosuccinimide (11.9 g, 52.9 mmol) was added, and the mixture was allowed to react at 50 °C for 2 hours. LCMS confirmed the completion of the reaction of the raw materials. The reaction mixture was poured into water (800 mL) and extracted with ethyl acetate (200 mL * 2). The organic phase was washed with saturated brine, dried, filtered, and purified by silica gel column chromatography to give yellow solid compound INT-1m (22 g, 63.5% yield). ESI-MS (m / z): 656.6 [M+H] + .

[0150] Step 11: Compound INT-1m (5.0 g, 7.63 mmol), 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (939 mg, 2.29 mmol), tris(dibenzylideneacetone)dipalladium (838 mg, 0.915 mmol), and potassium acetate (2.6 g, 26.7 mmol) were dissolved in toluene (100 mL). Pinacolborane (4.9 g, 38.1 mmol) was added under nitrogen protection. After the dropwise addition, the reaction was carried out at 50 °C. The reaction solution was filtered and purified by silica gel column chromatography to obtain compound INT-1 (4.5 g, 90% yield) as a yellow oil. ESI-MS (m / z): 656.5 [M+H] + .

[0151] Intermediate 2 JPEG2025530275000016.jpg69137

[0152] Intermediate 2 was prepared by the following steps: JPEG2025530275000017.jpg79170

[0153] Step 1: Compound INT-1m (12 g, 18.3 mmol) was dissolved in tetrahydrofuran (120 mL) and water (20 mL), lithium hydroxide monohydrate (3.84 g, 91.5 mmol) was added, and the mixture was allowed to react at room temperature overnight. LCMS confirmed the reaction was complete. The reaction mixture was then directly concentrated under reduced pressure. The residue was dissolved in water, and 4 M hydrochloric acid was added to adjust the pH to 4-5. The mixture was extracted with dichloromethane (100 mL). The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound INT-2a (10.6 g, 96.6% yield) as a white solid. ESI-MS (m / z): 600.7 [M+H] + .

[0154] Step 2: Compound INT-2a (9.5 g, 15.9 mmol) and compound INT-2b (11.7 g, 31.7 mmol) were dissolved in acetonitrile (190 mL) and N,N,N',N-tetramethylchloroformamidine hexafluorophosphate (6.67 g, 23.8 mmol) and 1-methylimidazole (6.51 g, 79.2 mmol) were added at 0 °C. The mixture was allowed to react for 1 h at 0 °C. LCMS showed the reaction was complete. The reaction solution was poured into water (200 mL), extracted with dichloromethane (100 mL x 3), and the organic phase was washed with water. The mixture was purified by silica gel column chromatography to give compound INT-2c (9.6 g, 83.5% yield) as a yellow solid. ESI-MS (m / z): 726.3 [M+H] + .

[0155] Step 3: Compound INT-2c (9.6 g, 13.2 mmol) was dissolved in tetrahydrofuran (100 mL) and water (10 mL), and lithium hydroxide monohydrate (1.39 g, 33.1 mmol) was added. The mixture was allowed to react at room temperature for 4 hours. LCMS confirmed the reaction was complete. The reaction solution was directly concentrated under reduced pressure, and the residue was dissolved in water (100 mL). The pH was adjusted to 4–5 with 4 M hydrochloric acid, and a white solid precipitated. The solid was washed with water and dried to give compound INT-2d (8.3 g, 88.2% yield) as a white solid. ESI-MS (m / z): 712.6 [M+H] + .

[0156] Step 4: Compound INT-2d (3.5 g, 4.9 mmol), 1-hydroxybenzotriazole (1.99 g, 14.8 mmol), and 4-dimethylaminopyridine (1.8 g, 14.6 mmol) were dissolved in dichloromethane (170 mL). N,N-diisopropylethylamine (6 mL, 34.4 mmol) was added at 0 °C, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodioxidoamine hydrochloride (4.71 g, 24.6 mmol). The reaction was allowed to proceed at room temperature overnight. Completion of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was washed with saturated aqueous ammonium chloride, dried over sodium sulfate, and purified by silica gel column chromatography to obtain compound INT-2e (2 g, 58.6% yield) as a yellow solid. ESI-MS (m / z): 694.6 [M+H] + .

[0157] Step 5: Compound INT-2e (500 mg, 0.721 mmol), 2-dicyclohexylphosphine-2',6'-dimethyl-biphenyl (88.8 mg, 0.216 mmol), tris(dibenzylideneacetone)dipalladium (79 mg, 0.086 mmol), and potassium acetate (247 mg, 2.52 mmol) were dissolved in tetrahydrofuran (20 mL). Pinacolborane (461 mg, 3.6 mmol) was added dropwise under nitrogen protection to complete the addition. The reaction was carried out at 50 °C for 3 h under nitrogen protection. The reaction completion of the raw material was monitored by LCMS, and the reaction solution was filtered and purified by silica gel column chromatography to obtain a yellow solid compound INT-2 (400 mg, 80% yield). ESI-MS (m / z): 694.6 [M+H] + .

[0158] Intermediate 3 JPEG2025530275000018.jpg72131

[0159] Intermediate 3 was prepared by the following steps: JPEG2025530275000019.jpg86170

[0160] Step 1: Compound INT-2e (1.7 g, 2.45 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (5 mL) was added, and the mixture was allowed to react at room temperature for 2 hours. Completion of the reaction was monitored by LCMS. The reaction solution was directly concentrated under reduced pressure, and the residue was dissolved in DCM (50 mL) and washed twice with saturated aqueous NaHCO3. The organic phase was washed with water, dried over sodium sulfate, filtered, and concentrated to give yellow solid compound INT-3a (1.3 g, 89.4% yield). ESI-MS (m / z): 594.7 [M+H] + .

[0161] Step 2: Compound INT-3a (1.3 g, 2.19 mmol) and compound INT-3b (0.24 g, 2.41 mmol) were dissolved in acetonitrile (30 mL). N,N,N',N-tetramethylchloroformamidine hexafluorophosphate (922 mg, 3.29 mmol) and 1-methylimidazole (414 mg, 5.04 mmol) were added at 0 °C. The mixture was incubated for 1 h at 0 °C. The reaction was monitored by LCMS for completion. The reaction solution was poured into water (50 mL), extracted with dichloromethane (50 mL x 3), washed with water, and the samples were mixed and purified using a column chromatography column to obtain compound INT-3c (1.3 g, 87.9%) as a white solid. ESI-MS (m / z): 675.7 [M+H] + .

[0162] Step 3: Compound INT-3c (1.1 g, 1.63 mmol), 2-dicyclohexylphosphine-2',6'-dimethyl-biphenyl (200 mg, 0.188 mmol), tris(dibenzylideneacetone)dipalladium (179 mg, 0.195 mmol), and potassium acetate (559 mg, 5.7 mmol) were dissolved in toluene (30 mL). Pinacolborane (1.04 g, 8.14 mmol) was added dropwise under nitrogen protection to complete the addition. The reaction was carried out at 50 °C for 3 h under nitrogen protection. The reaction completion of the raw material was monitored by LCMS. The reaction solution was filtered and purified by silica gel column chromatography to give compound INT-3 (990 mg, 90% yield), a yellow solid. ESI-MS (m / z): 676.9 [M+H] + .

[0163] Intermediate 4 JPEG2025530275000020.jpg71129

[0164] Intermediate 4 was prepared by the following steps: JPEG2025530275000021.jpg40170

[0165] Step 1: Compound INT-3a (2.2 g, 3.71 mmol) and compound INT-4a (0.47 g, 4.08 mmol) were dissolved in dichloromethane (50 mL). N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (1.56 g, 5.56 mmol) and 1-methylimidazole (0.70 g, 8.53 mmol) were added at 0 °C and the mixture was allowed to react for 1 h. LCMS confirmed the reaction was complete. The reaction solution was poured into water (50 mL), extracted with dichloromethane (50 mL x 3), and the organic phase was washed with water. The samples were mixed and purified through a column to give compound INT-4b (2.3 g, 90.0% yield) as a white solid. ESI-MS (m / z): 690.2 [M+H] + .

[0166] Step 2: Compound INT-4b (2.1 g, 3.05 mmol), 2-dicyclohexylphosphine-2',6'-dimethyl-biphenyl (375 mg, 0.91 mmol), tris(dibenzylideneacetone)dipalladium (335 mg, 0.365 mmol), and potassium acetate (1.05 g, 10.7 mmol) were dissolved in toluene (30 mL). Pinacolborane (1.95 g, 15.2 mmol) was added dropwise under nitrogen protection. The reaction was carried out at 50 °C for 3 h under nitrogen protection. The reaction was monitored for completion by LCMS. The reaction solution was filtered and purified by silica gel column chromatography to give compound INT-4 (1.8 g, 85.7% yield), a yellow solid. ESI-MS (m / z): 690.3 [M+H] + .

[0167] Intermediate 5 JPEG2025530275000022.jpg50125

[0168] Intermediate 5 was prepared by the following steps: JPEG2025530275000023.jpg53170

[0169] Step 1: (S)-3-Bromo-5-iodo-2-(1-methoxyethyl)pyridine INT-5a (2.0 g, 5.85 mmol) was dissolved in tetrahydrofuran (20 mL) and copper iodide (111 mg, 0.585 mmol), bistriphenylphosphinepalladium dichloride (410 mg, 0.585 mmol), triethylamine (1.18 g, 11.7 mmol), and 4-propyne-1-morpholine INT-5b (878 mg, 7.02 mmol) were added sequentially. The reaction mixture was stirred at room temperature under nitrogen protection for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate = 1 / 1) to give INT-5 (1.8 g, 90.7% yield) as a pale yellow oil. ESI-MS (m / z): 339.4 [M+H] + .

[0170] Intermediate 6 JPEG2025530275000024.jpg53126

[0171] Intermediate 6 was prepared by the following steps: JPEG2025530275000025.jpg43170

[0172] Step 1: (S)-2-Methylmorpholine hydrochloride INT-6a (1.00 g, 9.27 mmol), 3-bromopropyne (1.04 g, 8.72 mmol), and potassium carbonate (3.01 g, 21.8 mmol) were dissolved in N,N-dimethylformamide (15 mL), and the reaction mixture was stirred overnight at room temperature. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic phase was dried and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound INT-6b (450 mg, 44.5% yield) as a pale yellow oil. ESI-MS (m / z): 140.3 [M+H] + .

[0173] Step 2: INT-6b (269 mg, 1.93 mmol), INT-5a (600 mg, 1.75 mmol), copper iodide (33.4 mg, 0.18 mmol), triethylamine (355 mg, 3.51 mmol), and bistriphenylphosphinepalladium dichloride (123 mg, 0.18 mmol) were dissolved in tetrahydrofuran (10 mL) and stirred overnight at room temperature. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound INT-6 (360 mg, 58.1% yield) as a pale yellow oil. ESI-MS (m / z): 353.5 [M+H] + .

[0174] Intermediate 7 JPEG2025530275000026.jpg67128

[0175] Intermediate 7 was prepared by the following steps: JPEG2025530275000027.jpg40170

[0176] Step 1: Compound INT-7a (1.0 g, 4.46 mmol) was dissolved in acetonitrile (10 mL), and morpholine (1.16 g, 13.3 mmol) and potassium carbonate (1.23 g, 8.92 mmol) were added sequentially. The reaction mixture was stirred and reacted at 90 °C for 16 h under nitrogen protection. After completion of the reaction, the reaction mixture was filtered through diatomaceous earth, and the filtrate was washed twice with aqueous ammonium chloride solution and concentrated to give compound INT-7b (450 mg, 72.6% yield) as a yellow oil. ESI-MS (m / z): 140.1 [M+H] + .

[0177] Step 2: (S)-3-Bromo-5-iodo-2-(1-methoxyethyl)pyridine INT-5a (920 mg, 2.69 mmol) was dissolved in tetrahydrofuran (20 mL), and copper iodide (51 mg, 0.27 mmol), triphenylphosphine palladium dichloride (188 mg, 0.27 mmol), triethylamine (540 mg, 5.34 mmol), and INT-7b (450 mg, 3.24 mmol) were added sequentially. The reaction mixture was stirred at room temperature under nitrogen protection for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate = 1 / 1) to give INT-7 (850 mg, 89.2% yield) as a pale yellow oil. ESI-MS (m / z): 353.6 [M+H] + .

[0178] Intermediate 8 JPEG2025530275000028.jpg144149

[0179] Intermediate 8 was prepared by the following steps: JPEG2025530275000029.jpg106170

[0180] Step 1: Dess-Martin reagent (5.08 g, 12.0 mmol) was added to a solution of INT-8a (2.0 g, 9.21 mmol) in dichloromethane (40 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 5 h. After the reaction, saturated aqueous sodium bicarbonate and aqueous sodium thiosulfate were added to quench the reaction. The mixture was extracted with dichloromethane, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude product INT-8b.

[0181] Step 2: The crude product INT-8b and potassium carbonate (3.81 g, 27.60 mmol) were added to methanol (40 mL) and dimethyl (1-diazo-2-oxopropyl)phosphonate (3.53 g, 18.4 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 4 h, and the reaction completion was monitored by TLC. The reaction was quenched with water and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 6:1) to give a colorless, transparent solid, INT-8c (1.20 g, 62.0% yield for two steps). ESI-MS (m / z): 212.3 [M+H] + .

[0182] Step 3: Under a nitrogen atmosphere, (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine INT-5a (300 mg, 0.88 mmol), copper iodide (17 mg, 0.088 mmol), bistriphenylphosphinepalladium dichloride (62 mg, 0.088 mmol), triethylamine (178 mg, 1.75 mmol), compound INT-8c (222 mg, 1.05 mmol), and tetrahydrofuran (10 mL) were sequentially added to a reaction flask. The reaction solution was stirred at room temperature for 4 hours, and the completion of the reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give INT-8d as a pale yellow oily liquid. ESI-MS (m / z): 425.7 [M+H] + .

[0183] Step 4: The above product INT-8d was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (2 mL) was added dropwise. The reaction solution was stirred at room temperature for 30 minutes, and the completion of the reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure to give compound INT-8e. ESI-MS (m / z): 325.5 [M+H] + .

[0184] Step 5: The above product INT-8e was dissolved in 1,2-dichloroethane (10 mL), and aqueous formaldehyde (213 mg, 2.63 mmol, 37% w / w) was added dropwise. After 30 minutes of reaction, sodium triacetoxyborohydride (1.11 g, 5.26 mmol) was added. The reaction solution was stirred at room temperature for 30 minutes, and the completion of the reaction was monitored by LCMS. The reaction was quenched by adding saturated aqueous sodium bicarbonate, extracted with dichloromethane and methanol, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give INT-8 (269 mg, 90.5% yield over three steps) as a pale yellow oil. ESI-MS (m / z): 339.6 [M+H] + .

[0185] Intermediate 9 JPEG2025530275000030.jpg58141

[0186] Intermediate 9 was prepared by the following steps: JPEG2025530275000031.jpg43170

[0187] Step 1: cis-2,6-Dimethylmorpholine INT-9a (1.06 g, 9.20 mmol), 3-bromopropyne (1.09 g, 9.20 mmol), and cesium carbonate (3.82 g, 27.6 mmol) were dissolved in N,N-dimethylformamide (10 mL), and the reaction solution was stirred overnight at room temperature. After completion of the reaction, the reaction solution was extracted with ethyl acetate, and the organic phase was dried and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound INT-9b (600 mg, 42.6% yield) as a pale yellow oil. ESI-MS (m / z): 154.2 [M+H] + .

[0188] Step 2: INT-9b (296 mg, 1.93 mmol), INT-5a (600 mg, 1.75 mmol), copper iodide (33.4 mg, 0.18 mmol), triethylamine (355 mg, 3.51 mmol), and bistriphenylphosphinepalladium dichloride (123.0 mg, 0.18 mmol) were dissolved in tetrahydrofuran (10 mL) and stirred overnight at room temperature. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated and dried by centrifugation to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound INT-9 (600 mg, 93.1% yield) as a pale yellow oil. ESI-MS (m / z): 367.3 [M+H] + .

[0189] Intermediate 10 JPEG2025530275000032.jpg69127

[0190] Intermediate 10 was prepared by the following steps: JPEG2025530275000033.jpg83170

[0191] Step 1: (R)-3-Formylmorpholine-4-carboxylic acid tert-butyl ester INT-10a (4.06 g, 18.9 mmol) and (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (5.44 g, 28.3 mmol) were dissolved in methanol (30 mL). Potassium carbonate was added to the reaction mixture at room temperature. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic phase was dried and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the pale yellow oily compound INT-10b (3.2 g, 80.3% yield). ESI-MS (m / z): 212.4 [M+H] + .

[0192] Step 2: INT-10b (710 mg, 3.36 mmol), INT-5a (1.00 g, 2.92 mmol), triethylamine (592 mg, 5.58 mmol), copper iodide (55.7 mg, 0.29 mmol), and bistriphenylphosphinepalladium dichloride (205 mg, 0.29 mmol) were dissolved in tetrahydrofuran (10 mL) and stirred overnight at room temperature. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound INT-10c (1.05 g, 84.4% yield) as a pale yellow solid. ESI-MS (m / z): 425.5 [M+H] + .

[0193] Step 3: INT-10c (1.20 g, 2.82 mmol) was dissolved in dichloromethane (15 mL), and hydrochloric acid-dioxane (7.05 mL, 4M) was added to the above reaction solution. The reaction solution was stirred at room temperature for 4 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution was added to the reaction solution. The organic phases were combined, dried, and concentrated to give pale yellow solid compound INT-10d (918 mg, 100% yield). ESI-MS (m / z): 325.5 [M+H] + .

[0194] Step 4: INT-10d (917 mg, 2.82 mmol), aqueous formaldehyde (288 mg, 8.46 mmol), and sodium cyanoborohydride (532 mg, 8.46 mmol) were dissolved in methanol (10 mL), and the reaction mixture was stirred overnight at room temperature. After completion of the reaction, saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with dichloromethane. The combined organic phase was dried and concentrated to give the crude product, which was purified by column chromatography (dichloromethane / methanol = 10 / 1) to give the pale yellow oily compound INT-10 (650 mg, 68.0% yield). ESI-MS (m / z): 339.2 [M+H] + .

[0195] Intermediate 11 JPEG2025530275000034.jpg147168

[0196] Intermediate 11 was prepared by the following steps: JPEG2025530275000035.jpg107170

[0197] Step 1: Dess-Martin reagent (5.08 g, 12.0 mmol) was added to a solution of INT-11a (2.0 g, 9.21 mmol) in dichloromethane (40 mL) at 0 °C. After the reaction mixture warmed to room temperature, stirring was continued for 5 h. After the reaction, the reaction was quenched by adding saturated aqueous sodium bicarbonate and aqueous sodium thiosulfate. The mixture was extracted with dichloromethane. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the crude product INT-11b.

[0198] Step 2: The crude product INT-11b and potassium carbonate (3.81 g, 27.60 mmol) were added to methanol (40 mL) and dimethyl (1-diazo-2-oxopropyl)phosphonate (3.53 g, 18.4 mmol) was added dropwise at 0 °C. The reaction solution was stirred at room temperature for 16 h, and the reaction completion was monitored by TLC. The reaction was quenched with water and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 6 / 1) to give the product, a colorless, transparent solid, INT-11c (1.38 g, 70.8% yield for two steps). ESI-MS (m / z): 212.2 [M+H] + .

[0199] Step 3: Under a nitrogen atmosphere, (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine INT-5a (500 mg, 1.46 mmol), copper iodide (28 mg, 0.146 mmol), bistriphenylphosphinepalladium dichloride (103 mg, 0.146 mmol), triethylamine (296 mg, 2.92 mmol), compound INT-11c (402 mg, 1.90 mmol), and tetrahydrofuran (10 mL) were sequentially added to a reaction flask. The reaction solution was stirred at room temperature for 16 hours, and the completion of the reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give INT-11d as a pale yellow oily liquid. ESI-MS (m / z): 425.6 [M+H] + .

[0200] Step 4: The above product INT-11d was dissolved in dichloromethane (9 mL) and trifluoroacetic acid (3 mL) was added dropwise. The reaction solution was stirred at room temperature for 30 minutes, and the completion of the reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure to give compound INT-11e. ESI-MS (m / z): 325.3 [M+H] + .

[0201] Step 5: The above product INT-11e was dissolved in 1,2-dichloroethane (10 mL), and aqueous formaldehyde (356 mg, 4.38 mmol, 37%) was added dropwise. The reaction was allowed to proceed for 30 minutes. Sodium triacetyloxyborohydride (1.86 g, 8.76 mmol) was then added. The reaction solution was stirred at room temperature for 30 minutes, and the completion of the reaction was monitored by LCMS. The reaction was quenched by adding saturated aqueous sodium bicarbonate, extracted with dichloromethane and methanol, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give INT-11 (481 mg, 97.1% yield over three steps) as a pale yellow oily liquid. ESI-MS (m / z): 339.4 [M+H] + .

[0202] Intermediate 12 JPEG2025530275000036.jpg70122

[0203] Intermediate 12 was prepared by the following steps: JPEG2025530275000037.jpg64146

[0204] Compound INT-12 can be obtained by replacing INT-5b in intermediate 5 with INT-12a and using the same method and reaction steps. ESI-MS (m / z): 395.5 [M+H] + .

[0205] Intermediate 13 JPEG2025530275000038.jpg67118

[0206] Intermediate 13 was prepared by the following steps: JPEG2025530275000039.jpg112170

[0207] By replacing INT-8a in intermediate INT-8 with INT-13a, compound INT-13 can be obtained using the same method and reaction steps. ESI-MS (m / z): 395.5 [M+H] + .

[0208] Intermediate 14 JPEG2025530275000040.jpg62125

[0209] Intermediate 14 was prepared by the following steps: JPEG2025530275000041.jpg113170

[0210] By replacing INT-8a in intermediate 8 with INT-14a, compound INT-14 can be obtained using similar methods and reaction steps. ESI-MS (m / z): 395.5 [M+H] + .

[0211] Intermediate 15 JPEG2025530275000042.jpg82147

[0212] Intermediate 15 was prepared by the following steps: JPEG2025530275000043.jpg46170

[0213] Step 1: Compound INT-15a (600 mg, 3.0 mmol) was dissolved in methanol (5 mL), and potassium carbonate (1.25 g, 9.0 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (1.16 g, 6 mmol) were added at room temperature. The reaction solution was stirred at room temperature for 12 hours. TLC confirmed the completion of the reaction. Saturated brine was added to the reaction mixture, and the mixture was extracted with dichloromethane. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound INT-15b (587 mg, 99% yield).

[0214] Step 2: Compound INT-15b (570 mg, 2.92 mmol) and compound INT-5a (1 g, 2.92 mmol) were dissolved in tetrahydrofuran (8 mL), and bistriphenylphosphinepalladium dichloride (204 mg, 0.29 mmol), copper iodide (56 mg, 0.29 mmol), and triethylamine (591 mg, 5.85 mmol) were added. The reaction mixture was purged with nitrogen and stirred at room temperature for 8 hours. LCMS confirmed the completion of the reaction. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give INT-15 (1.08 g, 90% yield) as a yellow oil. ESI-MS (m / z): 409.6 [M+H] + .

[0215] Intermediate 16 JPEG2025530275000044.jpg80120

[0216] Intermediate 16 was prepared by the following steps: JPEG2025530275000045.jpg46170

[0217] Compound INT-16 can be obtained by replacing INT-15a in intermediate INT-15 with INT-16a and using the same method and reaction steps. ESI-MS (m / z): 409.5 [M+H] + .

[0218] Intermediate 17 JPEG2025530275000046.jpg92125

[0219] Intermediate 17 was prepared by the following steps: JPEG2025530275000047.jpg46170

[0220] By replacing INT-15a in intermediate INT-15 with INT-17a, compound INT-17 can be obtained using similar methods and reaction steps. ESI-MS (m / z): 409.3 [M+H] + .

[0221] Intermediate 18 JPEG2025530275000048.jpg71150

[0222] Intermediate 18 was prepared by the following steps: JPEG2025530275000049.jpg53170

[0223] Compound INT-18 can be obtained by replacing INT-5b in intermediate INT-5 with INT-18a and using the same method and reaction steps. ESI-MS (m / z): 354.3 [M+H] + .

[0224] Intermediate 19 JPEG2025530275000050.jpg85164

[0225] Intermediate 19 was prepared by the following steps. Step 1: Compound INT-3 (300 mg, 0.44 mmol) was dissolved in a mixture of 1,4-dioxane (5 mL) and water (1 mL), followed by the addition of INT-18 (170 mg, 0.48 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (32 mg, 0.04 mmol), and potassium phosphate (188 mg, 0.88 mmol). The reaction mixture was stirred at 70 °C for 16 h under nitrogen protection. After completion of the reaction, the reaction mixture was filtered through diatomaceous earth, and the concentrated residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound INT-19a (260 mg, 71.2% yield) as a pale yellow oil. ESI-MS (m / z): 823.1 [M+H] + .

[0226] Step 2: Compound INT-19a (260 mg, 0.31 mmol) was dissolved in N,N-dimethylformamide (4 mL), and cesium carbonate (205 mg, 0.63 mmol) and ethyl iodide (145 mg, 0.93 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound INT-19b (110 mg, 41.0% yield) as a pale yellow solid. ESI-MS (m / z): 851.2 [M+H] + .

[0227] Step 3: Compound INT-19b (110 mg, 0.13 mmol) was dissolved in methanol (3 mL) and p-toluenesulfonic acid monohydrate (123 mg, 0.65 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound INT-19c (80 mg, 80.8% yield) as a pale yellow solid. ESI-MS (m / z): 767.5 [M+H] + .

[0228] Step 4: Compound INT-19c (80 mg, 0.10 mmol) was dissolved in dichloromethane (4 mL), and methanesulfonic anhydride (54 mg, 0.31 mmol) and diisopropylethylamine (68 mg, 0.53 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, dichloromethane (30 mL) was added to the reaction mixture, which was washed with water (15 mL × 2) and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound INT-19 (70 mg, 79.5% yield) as a pale yellow solid. ESI-MS (m / z): 845.5 [M+H] + .

[0229] Intermediate 20 JPEG2025530275000051.jpg139170

[0230] Intermediate 20 was prepared by the following steps: JPEG2025530275000052.jpg61158

[0231] Compound INT-20 can be obtained by replacing INT-5b in intermediate INT-5 with INT-20a and using the same method and reaction steps. ESI-MS (m / z): 317.3 [M+H] + .

[0232] Intermediate 21 JPEG2025530275000053.jpg147168

[0233] Intermediate 21 was prepared by the following steps: JPEG2025530275000054.jpg61150

[0234] By replacing INT-5b in intermediate INT-5 with INT-21a, compound INT-21 can be obtained using the same method and reaction steps. ESI-MS (m / z): 317.3 [M+H] + .

[0235] Intermediate 22 JPEG2025530275000055.jpg136158

[0236] By replacing INT-15a in intermediate INT-15 with (S)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester, compound INT-22 can be obtained using the same method and reaction steps. ESI-MS (m / z): 409.5 [M+H] + .

[0237] Intermediate 23 JPEG2025530275000056.jpg136142

[0238] Intermediate 23 was prepared by the following steps: JPEG2025530275000057.jpg108170

[0239] Step 1: 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.12 g, 5.58 mmol) was added to a solution of INT-23a (1.0 g, 4.65 mmol) and N,N-diisopropylethylamine (13.8 g, 13.9 mmol) in tetrahydrofuran (15 mL) at 0 °C. After stirring at this temperature for 1.5 h, methoxymethylamine hydrochloride (0.50 g, 5.11 mmol) was added to the reaction solution. The mixture was allowed to warm to room temperature and stirred for 16 h. The reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3 / 1) to give INT-23b (1.14 g, 95.0% yield) as a colorless oil. ESI-MS (m / z): 259.5 [M+H] + .

[0240] Step 2: Under a nitrogen atmosphere, lithium aluminum tetrahydride (0.18 g, 4.85 mmol) was added in batches to a solution of compound INT-23b (1.14 g, 4.41 mmol) in tetrahydrofuran (10 mL) at 0 °C. After stirring at this temperature for 1 h, the reaction was monitored by LCMS until completion. The reaction was quenched with water and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a colorless oily liquid, INT-23c, which was used directly in the next step without further purification.

[0241] Step 3: The crude product INT-23c and potassium carbonate (1.22 g, 8.82 mmol) were added to methanol (10 mL), and dimethyl (1-diazo-2-oxopropyl)phosphonate (1.70 g, 8.82 mmol) was added dropwise at 0 °C. The reaction solution was stirred at room temperature for 16 h, and the completion of the reaction was monitored by TLC. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 6 / 1) to give INT-23d (368 mg, 42.7% yield) as a colorless oil. ESI-MS (m / z): 196.4 [M+H] + .

[0242] Step 4: Under a nitrogen atmosphere, (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine INT-5a (300 mg, 0.88 mmol), copper iodide (17 mg, 0.088 mmol), bistriphenylphosphinepalladium dichloride (62 mg, 0.088 mmol), triethylamine (178 mg, 1.75 mmol), compound INT-23d (188 mg, 0.96 mmol), and tetrahydrofuran (2 mL) were sequentially added to a reaction flask. The reaction solution was stirred at room temperature for 16 hours, and the completion of the reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give INT-23 (278 mg, 77.4% yield for two steps) as a pale yellow oily liquid. ESI-MS (m / z): 409.5 [M+H] + .

[0243] Intermediate 24 JPEG2025530275000058.jpg88119

[0244] By replacing INT-5b in intermediate 5 with 5-ethynylpyrimidine, compound INT-24 can be obtained using similar methods and reaction steps. ESI-MS (m / z): 318.4 [M+H] + .

[0245] Intermediate 25 JPEG2025530275000059.jpg84153

[0246] INT-3 can be replaced with INT-4 in the synthesis step of intermediate INT-19, and compound INT-25 can be obtained using similar methods and reaction steps. ESI-MS (m / z): 859.7 [M+H] + .

[0247] Intermediate 26 JPEG2025530275000060.jpg89123

[0248] By replacing INT-5b in intermediate 5 with 2-ethynylpyrazine, compound INT-26 can be obtained using similar methods and reaction steps. ESI-MS (m / z): 318.4 [M+H] + .

[0249] Intermediate 27 JPEG2025530275000061.jpg105123

[0250] Compound INT-27 can be obtained by replacing INT-5b in intermediate INT-5 with 1-Boc-4-ethynylpiperidine and using the same method and reaction steps. ESI-MS (m / z): 423.1 [M+H] + .

[0251] Intermediate 28 JPEG2025530275000062.jpg164170

[0252] Intermediate 28 was prepared by the following steps: JPEG2025530275000063.jpg46170

[0253] Step 1: INT-28a (250 mg, 0.84 mmol), trimethylsilyl acetylene (412 mg, 4.19 mmol), copper iodide (16 mg, 0.084 mmol), and bis(triphenylphosphine)palladium(II) dichloride (59 mg, 0.084 mmol) were dissolved in 1,4-dioxane (1.5 mL) and triethylamine (1.5 mL). The reaction mixture was stirred at 110 °C overnight. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated and dried by centrifugation to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain compound INT-28b (240 mg, 90.7% yield) as a pale yellow solid. ESI-MS (m / z): 316.3 [M+H] + .

[0254] Step 2: INT-28b (240 mg, 0.76 mmol) was dissolved in methanol (5 mL), potassium carbonate (526 mg, 3.8 mmol) was added at room temperature, and the reaction solution was stirred at room temperature for 4 hours. After the reaction, water (30 mL) was added and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and spin-dried to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain compound INT-28c (170 mg, 91.9% yield) as a pale yellow solid. ESI-MS (m / z): 244.3 [M+H] + .

[0255] Step 3: INT-28c (170 mg, 0.7 mmol), INT-5a (239 mg, 0.7 mmol), copper iodide (13 mg, 0.07 mmol), triethylamine (212 mg, 2.1 mmol), and bis(triphenylphosphine)palladium(II) dichloride (49 mg, 0.07 mmol) were dissolved in tetrahydrofuran (5 mL) and stirred overnight at room temperature. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated and dried by centrifugation to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the pale yellow oily compound INT-28 (220 mg, 68.8% yield). ESI-MS (m / z): 457.3 [M+H] + .

[0256] Intermediate 29 JPEG2025530275000064.jpg102137

[0257] Compound INT-29 can be obtained by replacing INT-28a in intermediate INT-28 with 6-bromo-2-tert-butoxycarbonylaminopyridine and using the same method and reaction steps. ESI-MS (m / z): 432.3 [M+H] + .

[0258] Intermediate 30 JPEG2025530275000065.jpg73163

[0259] Compound INT-30 can be obtained by replacing INT-28a in intermediate INT-28 with (6-iodopyridazin-3-yl)carbamate tert-butyl ester using the same method and reaction steps. ESI-MS (m / z): 433.3 [M+H] + .

[0260] Intermediate 31 JPEG2025530275000066.jpg76131

[0261] By replacing INT-28a of intermediate 28 with 4-amino-5-bromopyrimidine, compound INT-31 can be obtained using similar methods and reaction steps. ESI-MS (m / z): 333.3 [M+H] + .

[0262] Intermediate 32 JPEG2025530275000067.jpg72122

[0263] By replacing INT-28a in intermediate 28 with 2-amino-5-bromopyrazine, compound INT-32 can be obtained using similar methods and reaction steps. ESI-MS (m / z): 333.3 [M+H] + .

[0264] Intermediate 33 JPEG2025530275000068.jpg85134

[0265] Intermediate 33 was prepared by the following steps: JPEG2025530275000069.jpg144170

[0266] Step 1: Compound INT-2 (300 mg, 0.43 mmol) was dissolved in a mixture of 1,4-dioxane (5 mL) and water (1 mL), followed by the addition of INT-18 (170 mg, 0.48 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (32 mg, 0.04 mmol), and potassium phosphate (188 mg, 0.88 mmol). The reaction mixture was stirred under nitrogen protection at 70 °C for 16 h. After completion of the reaction, the reaction mixture was filtered through diatomaceous earth, and the concentrated residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give INT-33a (210 mg, 57% yield) as a pale yellow oily solid. ESI-MS (m / z): 841.6 [M+H] + .

[0267] Step 2: Compound INT-33a (200 mg, 0.28 mmol) was dissolved in N,N-dimethylformamide (3 mL), and cesium carbonate (232 mg, 0.71 mmol) and ethyl iodide (185 mg, 1.19 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a pale yellow solid, INT-33b (200 mg, 95% yield). ESI-MS (m / z): 869.8 [M+H] + .

[0268] Step 3: Compound INT-33b (200 mg, 0.23 mmol) was dissolved in methanol (3 mL) and p-toluenesulfonic acid monohydrate (175 mg, 0.92 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound INT-33c (160 mg, 89% yield) as a yellow oil. ESI-MS (m / z): 785.6 [M+H] + .

[0269] Step 4: Compound INT-33c (140 mg, 0.18 mmol) was dissolved in tetrahydrofuran (3 mL) and diethyl ether (3 mL), and p-toluenesulfonyl chloride (68 mg, 0.36 mmol) and potassium hydroxide (20 mg, 0.36 mmol) were added. The reaction mixture was stirred at 0 °C for 2 h. After completion of the reaction, dichloromethane (30 mL) was added to the reaction mixture, which was washed with water (15 mL × 2) and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 20 / 1) to give INT-33 (110 mg, 66% yield). ESI-MS (m / z): 939.9 [M+H] + .

[0270] Intermediate 34 JPEG2025530275000070.jpg85121

[0271] Intermediate 34 was prepared by the following steps: JPEG2025530275000071.jpg40170

[0272] Step 1: Compound INT-18 (500 mg, 1.41 mmol) was dissolved in methanol (5 mL) and p-toluenesulfonic acid monohydrate (537 mg, 2.82 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound INT-34a (210 mg, 55% yield) as a pale yellow solid. ESI-MS (m / z): 270.3 [M+H] + .

[0273] Step 2: Compound INT-34a (350 mg, 1.30 mmol) was dissolved in dichloromethane (5 mL), and methanesulfonic anhydride (1.13 g, 6.48 mmol) and diisopropylethylamine (1.34 g, 10.37 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, water (30 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give compound INT-34b (330 mg, 73% yield) as a pale yellow solid. ESI-MS (m / z): 348.2 [M+H] + .

[0274] Step 3: Compound INT-34b (200 mg, 0.58 mmol) and (S)-3-hydroxymethylmorpholine (87 mg, 0.75 mmol) were dissolved in dichloromethane (5 mL), and N,N-diisopropylethylamine (148 mg, 1.15 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, water (30 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give INT-34 (180 mg, 85% yield) as a colorless oil. ESI-MS (m / z): 369.3 [M+H] + .

[0275] Intermediate 35 JPEG2025530275000072.jpg97124

[0276] By replacing (S)-3-hydroxymethylmorpholine in intermediate INT-34 with (S)-octahydropyrazine[2,1-c][1,4]oxazine dihydrochloride, compound INT-35 can be obtained using similar methods and reaction steps. ESI-MS (m / z): 394.5 [M+H] + .

[0277] Intermediate 36 JPEG2025530275000073.jpg91140

[0278] Compound INT-36 can be obtained by replacing (S)-3-hydroxymethylmorpholine in intermediate INT-34 with 1-acetylpiperazine and using the same method and reaction steps. ESI-MS (m / z): 380.4 [M+H] + .

[0279] Intermediate 37 JPEG2025530275000074.jpg102134

[0280] By replacing INT-28a in intermediate INT-28 with N-Boc-2-amino-5-bromopyrimidine, compound INT-37 can be obtained using the same method and reaction steps. ESI-MS (m / z): 433.4 [M+H] + .

[0281] Intermediate 38 JPEG2025530275000075.jpg82136

[0282] Compound INT-38 can be obtained by replacing INT-5b in intermediate INT-5 with 4-propargylthiomorpholine-1,1-dioxide and using the same method and reaction steps. ESI-MS (m / z): 387.5 [M+H] + .

[0283] Intermediate 39 JPEG2025530275000076.jpg110130

[0284] Using similar methods and reaction steps, INT-28a of intermediate INT-28 can be replaced with 2-chloro-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylic acid tert-butyl ester to give compound INT-39. ESI-MS (m / z): 473.3 [M+H] + .

[0285] Intermediate 40 JPEG2025530275000077.jpg144163

[0286] Intermediate 40 was prepared by the following steps: JPEG2025530275000078.jpg81170

[0287] Step 1: O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.48 g, 3.88 mmol) was added to a solution of INT-40a (800 mg, 3.23 mmol) and N,N-diisopropylethylamine (1.25 g, 9.70 mmol) in tetrahydrofuran (10 mL) at 0 °C. After stirring at this temperature for 1.5 hours, methoxymethylamine hydrochloride (347 mg, 3.56 mmol) was added to the reaction solution. The mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3 / 1) to give INT-40b (696 mg, 74.1% yield) as a colorless oil. ESI-MS (m / z): 291.5 [M+H] + .

[0288] Step 2: Under a nitrogen atmosphere, lithium aluminum tetrahydride (211 mg, 5.56 mmol) was added in batches to a solution of compound INT-40b (1.47 g, 5.06 mmol) in tetrahydrofuran (15 mL) at 0 °C. After stirring at this temperature for 3 h, the reaction was monitored by LCMS until completion. The reaction was quenched with water and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the crude product compound INT-40c, which was used directly in the next reaction without further purification.

[0289] Step 3: The crude product INT-40c and potassium carbonate (1.40 g, 10.1 mmol) were added to methanol (15 mL) and dimethyl (1-diazo-2-oxopropyl)phosphonate was added dropwise at 0 °C. The reaction solution was stirred at room temperature for 16 h, and the completion of the reaction was monitored by TLC. Water was added to quench the reaction, followed by extraction with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 6:1) to obtain compound INT-40d as a colorless, clear oil (767 mg, two-step yield 66.7%).

[0290] Step 4: m-Chloroperoxybenzoic acid (399 mg, 2.31 mmol) and potassium carbonate (319 mg, 2.31 mmol) were added sequentially to a solution of INT-40d (150 mg, 0.66 mmol) in ethanol (6 mL). The reaction solution was stirred at room temperature for 8 hours. The completion of the reaction was monitored by TLC, and the reaction was quenched by adding saturated aqueous sodium bicarbonate and sodium thiosulfate solutions. The mixture was extracted with ethyl acetate, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the crude product of compound INT-40e, which was used directly in the next reaction without further purification.

[0291] Step 5: Under a nitrogen atmosphere, (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine INT-5a (196 mg, 0.57 mmol), copper(I) iodide (11 mg, 0.057 mmol), bistriphenylphosphinepalladium dichloride (40 mg, 0.057 mmol), and triethylamine (116 mg, 1.15 mmol) were added sequentially to a solution of the crude product INT-40e in tetrahydrofuran (5 mL). The reaction mixture was stirred at room temperature for 16 h, and the completion of the reaction was monitored by LCMS. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give INT-40 (227 mg, 83.7% yield) as a yellow solid. ESI-MS (m / z): 473.3 [M+H] + .

[0292] Intermediate 41 JPEG2025530275000079.jpg95163

[0293] Using a similar method and reaction procedure, compound INT-41 was obtained by replacing INT-28a in intermediate INT-28 with tert-butyl-3-bromo-5H,6H,7H-pyrrolo[3,4-b]pyridine-6-carboxylate. ESI-MS (m / z): 458.4 [M+H] + .

[0294] Intermediate 42 JPEG2025530275000080.jpg82155

[0295] By replacing INT-28a in intermediate INT-28 with 1-BOC-7-bromoindole, compound INT-42 can be obtained using the same method and reaction steps. ESI-MS (m / z): 455.3 [M+H] + .

[0296] Intermediate 43 JPEG2025530275000081.jpg80149

[0297] Intermediate 43 was prepared by the following steps: By replacing (S)-3-hydroxymethylmorpholine in intermediate INT-34 with 4-methyl-1,4-azaphosphine 4-oxide, compound INT-43 can be obtained using similar methods and reaction steps. ESI-MS (m / z): 386.2 [M+H] + .

[0298] Intermediate 44 JPEG2025530275000082.jpg82145

[0299] Using similar methods and reaction steps, (S)-3-hydroxymethylmorpholine in intermediate INT-34 is replaced with 2-tert-butoxycarbonyl-2,7-diazaspiro[3.5]nonane hydrochloride to give compound INT-44. ESI-MS (m / z): 478.4 [M+H]+.

[0300] Intermediate 45 JPEG2025530275000083.jpg85153

[0301] Compound INT-45 can be obtained by replacing (S)-3-hydroxymethylmorpholine in intermediate INT-34 with 1-tert-butoxycarbonylpiperazine using the same method and reaction steps. ESI-MS (m / z): 437.4 [M+H] + .

[0302] Intermediate 46 JPEG2025530275000084.jpg98151

[0303] Intermediate 46 was prepared by the following steps: JPEG2025530275000085.jpg75170

[0304] Step 1: Compound INT-40d (485 mg, 2.31 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (1.5 mL) was added dropwise. The reaction solution was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure to give compound INT-46a. ESI-MS (m / z): 128.3 [M+H] + .

[0305] Step 2: The above product INT-46a was dissolved in 1,2-dichloroethane (7 mL), and aqueous formaldehyde (519 mg, 6.39 mmol, 37% w / w) was added dropwise. After 20 minutes of reaction, sodium triacetoxyborohydride (1.81 g, 8.52 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes, and the reaction completion was monitored by LCMS. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give INT-46b (211 mg, 70.1% yield for the two steps) as a colorless oil. ESI-MS (m / z): 142.1 [M+H] + .

[0306] Step 3: Sodium periodate (479 mg, 2.24 mmol) was added to a solution of INT-46b (211 mg, 1.49 mmol) in a mixture of methanol (6 mL) and water (2 mL). The reaction solution was stirred at room temperature for 6 hours. The completion of the reaction was monitored by TLC, and the reaction was quenched by adding aqueous sodium thiosulfate solution. The mixture was extracted with ethyl acetate, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified using silica gel column chromatography (dichloromethane / methanol = 15 / 1) to give INT-46c (171 mg, 72.8% yield) as a colorless oil. ESI-MS (m / z): 158.3 [M+H] + .

[0307] Step 4: tert-Butyl carbamate (255 mg, 2.18 mmol), rhodium acetate (15 mg, 0.054 mmol), magnesium oxide (175 mg, 4.35 mmol), iodobenzene acetate (525 mg, 1.63 mmol), compound INT-46c (171 mg, 1.09 mmol), and 1,2-dichloroethane (5 mL) were added to a reaction flask. The reaction solution was stirred at 80 °C for 48 h. The reaction solution was filtered through diatomaceous earth, and the filtrate was extracted with a mixture of dichloromethane and methanol. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 15 / 1) to give compound INT-46d (219 mg, 73.9% yield). ESI-MS (m / z): 273.4 [M+H] + .

[0308] Step 5: (S)-3-Bromo-5-iodo-2-(1-methoxyethyl)pyridine INT-5a (212 mg, 0.62 mmol), copper iodide (12 mg, 0.062 mmol), bistriphenylphosphine palladium dichloride (44 mg, 0.062 mmol), triethylamine (125 mg, 1.24 mmol), compound INT-46d (219 mg, 0.80 mmol), and tetrahydrofuran (5 mL) were added to a reaction bottle. The reaction mixture was purged with nitrogen and stirred at room temperature for 16 hours. The completion of the reaction was monitored by LCMS. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give INT-46 (179 mg, 59.5% yield) as a yellow solid. ESI-MS (m / z): 486.3 [M+H] + .

[0309] Intermediate 47 JPEG2025530275000086.jpg88150

[0310] By replacing INT-28a in intermediate INT-28 with 1-BOC-4-bromoindole, compound INT-47 can be obtained using the same method and reaction steps. ESI-MS (m / z): 455.3 [M+H] + .

[0311] Intermediate 48 JPEG2025530275000087.jpg88163

[0312] Intermediate 48 was prepared by the following steps: JPEG2025530275000088.jpg79170

[0313] Step 1: Thiomorpholine INT-48a (4.0 g, 38.8 mmol), benzyl chloroformate (7.94 g, 46.5 mmol), and N,N-diisopropylethylamine (15.0 g, 116 mmol) were dissolved in dichloromethane (40 mL), and the reaction mixture was stirred overnight at room temperature. After completion of the reaction, the reaction mixture was extracted with dichloromethane, and the organic phase was dried and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the pale yellow oily compound INT-48b (9.0 g, 97.8% yield). ESI-MS (m / z): 238.3 [M+H] + .

[0314] Step 2: Compound INT-48b (1.0 g, 38.8 mmol) was dissolved in a mixture of methanol (10 mL) and water (5 mL). Sodium periodate (1.17 g, 5.5 mmol) was added in an ice bath, and the reaction mixture was stirred overnight at room temperature. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic phase was dried and concentrated to give the crude product INT-48c (900 mg, 84.3% yield). The crude product was used directly in the next reaction without further purification. ESI-MS (m / z): 254.3 [M+H] + .

[0315] Step 3: Compound INT-48c (850 mg, 3.36 mmol) was dissolved in 1,2-dichloroethane (15 mL). tert-Butyl carbamate (1.97 g, 16.8 mmol), rhodium acetate (94 mg, 0.34 mmol), magnesium oxide (541 mg, 13.4 mmol), and (diacetoxyiodo)benzene (3.24 g, 10.1 mmol) were added at room temperature, and the reaction solution was stirred at 80 °C overnight. After completion of the reaction, the reaction solution was concentrated. The crude product was purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound INT-48d (1.0 g, 80.9% yield) as a pale yellow solid. ESI-MS (m / z): 369.3 [M+H] + .

[0316] Step 4: Compound INT-48d (850 mg, 2.31 mmol) was dissolved in methanol (10 mL) and palladium hydroxide on carbon (85 mg, 10% w / w) was added. The reaction solution was stirred overnight at room temperature under a hydrogen atmosphere. After completion of the reaction, the filtrate was filtered through diatomaceous earth and concentrated to give compound INT-48e (410 mg, 75.9% yield) as a pale yellow oil. ESI-MS (m / z): 235.3 [M+H] + .

[0317] Step 5: Compound INT-48e (150 mg, 0.64 mmol) was dissolved in N,N-dimethylformamide (3 mL), and cesium carbonate (626 mg, 1.92 mmol) and 3-bromopropyl ether (114 mg, 0.96 mmol) were added at room temperature. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic phase was dried and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound INT-48f (135 mg, 77.4% yield) as a pale yellow solid. ESI-MS (m / z): 273.3 [M+H]+.

[0318] Step 6: Compound INT-48f (140 mg, 0.51 mmol) was dissolved in tetrahydrofuran (5 mL). INT-5a (176 mg, 0.51 mmol), copper iodide (10 mg, 0.051 mmol), bistriphenylphosphinepalladium dichloride (36 mg, 0.051 mmol), and triethylamine (104 mg, 1.03 mmol) were added at room temperature. The reaction solution was stirred overnight at room temperature. After completion of the reaction, the reaction solution was concentrated. The crude product was purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound INT-48 (60 mg, 24.0% yield) as a pale yellow solid. ESI-MS (m / z): 486.5 [M+H] + .

[0319] Intermediate 49 JPEG2025530275000089.jpg118170

[0320] Piperidine can be used to replace INT-6a in intermediate INT-6, and similar methods and reaction steps can be used to obtain compound INT-49. ESI-MS (m / z): 337.4 [M+H] + . The synthesis methods of the example compounds of the present invention are as follows. Example 1

[0321] (1S,2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl))pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1 (5,3)-indra-6(1,3)-pyridazin-4-yl)-2-methylcyclopropane-1-carboxamide

[0322] Example 1 was prepared by the following steps: JPEG2025530275000090.jpg175170

[0323] Step 1: Compound INT-5 (600 mg, 1.77 mmol) was dissolved in a mixture of 1,4-dioxane (10 mL) and water (1 mL), followed by the addition of INT-1 (1.16 g, 1.77 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (129.3 mg, 0.177 mmol), and potassium carbonate (1.18 g, 4.42 mmol). The reaction mixture was stirred at 80 °C for 16 h under nitrogen protection. After completion of the reaction, the reaction solution was filtered through diatomaceous earth and concentrated to give crude compound 1a (1.39 g, 100%) as a black solid. This was used directly in the next reaction without further purification. ESI-MS (m / z): 788.1 [M+H] + .

[0324] Step 2: Crude compound 1a (1.39 g, 1.77 mmol) was dissolved in a mixture of tetrahydrofuran (3 mL) and water (3 mL), and lithium hydroxide (211 mg, 8.82 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was adjusted to pH 6 with 6N aqueous hydrochloric acid and extracted with ethyl acetate (40 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give compound 1b (1.0 g, 77.3% yield) as a pale yellow solid. ESI-MS (m / z): 732.1 [M+H] + .

[0325] Step 3: Compound 1b (1.0 g, 1.37 mmol) was dissolved in dichloromethane (20 mL) and INT-2b (1.01 g, 2.73 mmol, TFA salt), 1-(3-dimethylamino)(propyl)-3-ethylcarbodiimide hydrochloride (524 mg, 2.73 mmol), 1-hydroxybenzotriazole (369 mg, 2.73 mmol), and N,N-diisopropylethylamine (883 mg, 6.83 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, water (50 mL) was added to the reaction mixture, followed by extraction with dichloromethane (50 mL × 2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give compound 1c (700 mg, 59.7% yield) as a pale yellow solid. ESI-MS (m / z): 858.2 [M+H] + .

[0326] Step 4: Compound 1c (700 mg, 0.815 mmol) was dissolved in a mixture of tetrahydrofuran (3 mL) and water (3 mL), and lithium hydroxide (195 mg, 8.16 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction mixture was adjusted to pH 6 with 6N aqueous hydrochloric acid and extracted with ethyl acetate (40 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 1d (640 mg, 93.0% yield) as a pale yellow solid. ESI-MS (m / z): 844.2 [M+H] + .

[0327] Step 5: Compound 1d (370 mg, 0.44 mmol) was dissolved in dichloromethane (8 mL) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (840 mg, 4.4 mmol), 1-hydroxybenzotriazole (296 mg, 2.2 mmol), 4-dimethylaminopyridine (268 mg, 2.2 mmol), and N,N-diisopropylethylamine (850 mg, 6.6 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, water (30 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give compound 1e as a pale yellow solid (120 mg, 33.1% yield). ESI-MS (m / z): 826.2 [M+H] + .

[0328] Step 6: Compound 1e (150 mg, 0.18 mmol) was dissolved in N,N-dimethylformamide (3 mL), and cesium carbonate (118 mg, 0.36 mmol) and iodoethane (42.5 mg, 0.27 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 1f (150 mg, 96.7% yield) as a pale yellow solid. ESI-MS (m / z): 854.2 [M+H] + .

[0329] Step 7: Compound 1f (120 mg, 0.14 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, saturated aqueous sodium bicarbonate (30 mL) was added to the reaction mixture in an ice bath, and the mixture was extracted with dichloromethane (30 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 1g (100 mg, 94.4% yield) as a pale yellow solid. ESI-MS (m / z): 754.2 [M+H]+ .

[0330] Step 8: Compound 1g (70 mg, 0.093 mmol) was dissolved in N,N-dimethylformamide (3 mL), and (1S,2S)-2-methylcyclopropanecarboxylic acid INT-3b (18.6 mg, 0.186 mmol), diisopropylethylamine (36.0 mg, 0.278 mmol), and (2-oxime-ethyl cyanoacetate)-N,N-dimethyl-morpholinourea hexafluorophosphate (79.5 mg, 0.186 mmol) were added. The reaction mixture was stirred in an ice bath for 1 h. After the reaction was completed, water (20 mL) was added to the reaction mixture and extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative liquid chromatography to give compound 1 (15 mg, 19.3% yield) and epimer 1' (20 mg, 25.8% yield) as a white solid. The absolute configurations of the two compounds were empirically assumed. In the current analytical method, 1 is a compound with relatively low polarity and a relatively long retention time by LC-MS and HPLC, while 1' is a compound with relatively high polarity and a relatively short retention time by LC-MS and HPLC.

[0331] Compound 1:

[0332] ESI-MS (m / z): 836.5 [M+H] + ;LC-MS retention time RT=1.80 min. HPLC retention time RT=11.63 min.

[0333] 1H NMR (500 MHz, DMSO-d6) δ 8.81 (d, J = 2.0 Hz, 1H), 8.54-8.48 (m, 2H), 7.86 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.77-7.73 (m, 1H), 7.58 (m, 1H), 5.56 (t, J = 9.0 Hz, 1H), 5.10-5.04 (m, 1H), 4.36-4.15 (m, 4H), 4.14-4.01 (m, 1H), 3.61 (t, J = 5.0 Hz, 4H), 3.59-3.53 (m, 4H), 3.32-3.29 (m, 1H), 3.25 (s, 3H), 3.18-3.11 (m, 1H), 3.00-2.94 (m, 1H), 2.79-2.73 (m, 1H), 2.56-2.52 (m, 4H), 2.40-2.35 (m, 1H), 2.11-2.06 (m, 1H), 1.85-1.73 (m, 2H), 1.57-1.47 (m, 2H), 1.35 (d, J = 6.0 Hz, 3H), 1.11-1.03 (m, 4H), 0.91 (s, 3H), 0.90-0.85 (m, 4H), 0.59-0.53 (m, 1H), 0.34 (s, 3H).

[0334] Compound 1': ESI-MS (m / z): 836.5 [M+H] + ; LC-MS retention time RT = 1.77 min. HPLC retention time RT = 11.27 min.

[0335] 1H NMR (500 MHz, DMSO-d6) δ 8.83 (d, J = 2.0 Hz, 1H), 8.56-8.51 (m, 2H), 8.00 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.77-7.71 (m,1H), 7.57-7.52 (m, 1H), 5.55 (t, J = 9.0 Hz, 1H), 5.10-5.04 (m, 1H), 4.28-4.17 (m, 2H), 4.00-3.91 (m, 2H), 3.88-3.79 (m, 1H), 3.69-3.53 (m, 9H), 3.18-3.13 (m, 1H), 3.10 (s, 3H), 3.07-3.02 (m, 1H), 2.81-2.74 (m, 1H), 2.57-2.52 (m, 4H), 2.35-2.29 (m, 1H), 2.16-2.07 (m, 1H), 1.84-1.76 (m, 2H), 1.56-1.48 (m, 2H), 1.22 (d, J = 6.0 Hz, 3H), 1.11 (t, J = 7.0 Hz, 3H), 1.08-1.05 (m, 4H), 0.98-0.92 (m, 3H), 0.90-0.85 (m, 1H), 0.58-0.54 (m, 1H), 0.50 (s, 3H).

[0336] Example 2 (1r,2R,3S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazinacycloundecaphan-4-yl)-2,3-dimethylcyclopropane-1-carboxamide

[0337] Example 2 was prepared by the following steps: JPEG2025530275000091.jpg102170

[0338] Step 1: Compound 1g (30 mg, 0.04 mmol) was dissolved in N,N-dimethylformamide (3 mL) and (2R,3S)-2,3-dimethylcyclopropanecarboxylic acid 2a (9.1 mg, 0.08 mmol), N,N-diisopropylethylamine (15.4 mg, 0.12 mmol), and (2-oxime-cyanoacetic acid ethyl ester)-N,N-dimethyl-morpholineurea hexafluorophosphate (34.1 mg, 0.08 mmol) were added. The reaction mixture was stirred in an ice bath for 1 h. After completion of the reaction, water (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative liquid chromatography to afford compound 2 (10 mg, 29.6% yield) and epimer 2' (15 mg, 44.4% yield) as a white solid. The absolute configurations of the two compounds were empirically assumed. In the current analytical method, 2 is a compound with relatively low polarity and a relatively long retention time in LC-MS and HPLC, while 2' is a compound with relatively high polarity and a relatively short retention time in LC-MS and HPLC.

[0339] Compound 2: ESI-MS (m / z): 850.6 [M+H] + ;LC-MS retention time RT=1.86 min. HPLC retention time RT=12.10 min. 1H NMR (500 MHz, DMSO-d6) δ 8.81 (d, J = 2.0 Hz, 1H), 8.51-8.49 (m, 1H), 8.39 (d, J = 9.0 Hz, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.82 (s, 1H), 7.77-7.73 (m, 1H), 7.58 (d, J = 9.0 Hz, 1H), 5.56 (t, J = 9.0 Hz, 1H), 5.10-5.04 (m, 1H), 4.36-4.04 (m, 5H), 3.63-3.59 (m, 4H), 3.59-3.55 (m, 4H), 3.31-3.29 (m, 1H), 3.25 (s, 3H), 3.18-3.12 (m, 1H), 2.99-2.92 (m, 1H), 2.79-2.72 (m, 1H), 2.56-2.52 (m, 4H), 2.42-2.36 (m, 1H), 2.11-2.05 (m, 1H), 1.83-1.70 (m, 2H), 1.56-1.47 (m, 1H), 1.35 (d, J = 6.0 Hz, 3H), 1.26-1.13 (m, 4H), 1.10-1.04 (m, 5H), 0.91 (s, 3H), 0.88 (t, J = 7.0 Hz, 3H), 0.34 (s, 3H).

[0340] Compound 2': ESI-MS (m / z): 850.6 [M+H] + ; LC-MS retention time RT = 1.83 min. HPLC retention time RT = 11.76 min.

[0341] 1H NMR (500 MHz, DMSO-d6) δ 8.82 (d, J = 2.0 Hz, 1H), 8.54-8.51 (m, 1H), 8.41 (d, J = 9.0 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.82 (s, 1H), 7.76-7.71 (m, 1H), 7.54 (d, J = 9.0 Hz, 1H), 5.53 (t, J = 9.0 Hz, 1H), 5.07-5.02 (m, 1H), 4.26-4.18 (m, 2H), 4.00-3.91 (m, 2H), 3.87-3.79 (m, 1H), 3.69-3.65 (m, 1H), 3.61 (t, J = 5.0 Hz, 4H), 3.59-3.52 (m, 3H), 3.31-3.29 (m, 1H), 3.19-3.12 (m, 1H), 3.09 (s, 3H), 3.06-3.02 (m, 1H), 2.81-2.73 (m, 1H), 2.56-2.52 (m, 4H), 2.34-2.30 (m, 1H), 2.15-2.06 (m, 1H), 1.84-1.75 (m, 2H), 1.57-1.47 (m, 1H), 1.25-1.20 (m, 4H), 1.20-1.15 (m, 2H), 1.13-1.08 (m, 6H), 1.08-1.05 (m, 3H), 0.93 (s, 3H), 0.49 (s, 3H).

[0342] Example 3 (1S,2S)-N-((6 3 S,4S,Z)-1 2 -(2-((S)-1-Methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 -(2,2,2-trifluoroethylethyl)-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000092.jpg93158

[0343] Example 3 was prepared by the following steps: Step 1: Compound 1g (30 mg, 0.036 mmol) was dissolved in N,N-dimethylformamide (2 mL), and cesium carbonate (23.7 mg, 0.072 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (12.6 mg, 0.054 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin-layer chromatography (DCM:MeOH = 30 / 1) to give compound 3a (10 mg, 30.2% yield) as a pale yellow solid. ESI-MS (m / z): 908.2 [M+H] + .

[0344] Step 2: Compound 3a (10 mg, 0.011 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, saturated aqueous sodium bicarbonate (30 mL) was added to the reaction mixture in an ice bath, and the mixture was extracted with dichloromethane (30 mL × 2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 3b (7.0 mg, 78.7% yield) as a pale yellow solid. ESI-MS (m / z): 808.2 [M+H] + .

[0345] Step 3: Compound 3b (7.0 mg, 0.011 mmol) was dissolved in N,N-dimethylformamide (2 mL) and (1S,2S)-2-methylcyclopropanecarboxylic acid INT-3b (2.2 mg, 0.022 mmol), N,N-diisopropylethylamine (4.2 mg, 0.033 mmol), and (2-oxime-cyanoacetic acid ethyl ester)-N,N-dimethylmorpholineurea hexafluorophosphate (9.4 mg, 0.022 mmol) were added. The reaction mixture was stirred in an ice bath for 1 h. After completion of the reaction, water (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative liquid chromatography to afford compound 3 (0.25 mg, 4.5% yield) and epimer 3' (0.25 mg, 4.5% yield) as a white solid. The absolute configurations of the three compounds were empirically assumed. In the current analytical method, 3 is a compound with relatively low polarity and a relatively long retention time in LC-MS and HPLC, and 3' is a compound with relatively high polarity and a relatively short retention time in LC-MS and HPLC.

[0346] Compound 3: ESI-MS (m / z): 890.2 [M+H] + ;LC-MS retention time RT=1.84 min. HPLC retention time RT=13.37 min. 1H NMR (500 MHz, DMSO-d6) δ 8.85-8.82 (m, 1H), 8.55-8.50 (m, 2H), 7.87 (s, 1H), 7.86-7.81 (m, 2H), 7.79-7.75 (m, 1H), 5.63-5.51 (m, 2H), 5.09-5.04 (m, 1H), 4.89-4.81 (m, 1H), 4.27-4.20 (m, 3H), 3.63-3.56 (m, 8H), 3.30-3.27 (m, 1H), 3.19-3.11 (m, 2H), 3.06-3.00 (m, 1H), 2.79-2.72 (m, 1H), 2.55-2.52 (m, 2H), 2.40-2.36 (m, 1H), 2.12-2.08 (m, 1H), 2.03-1.97 (m, 1H), 1.82-1.78 (m, 2H), 1.54-1.49 (m, 2H), 1.36 (d, J = 6.0 Hz, 3H), 1.27-1.19 (m, 2H), 1.10-1.05 (m, 4H), 0.94 (s, 3H), 0.89-0.84 (m, 2H), 0.58-0.53 (m, 1H), 0.29 (s, 3H).

[0347] Compound 3': ESI-MS (m / z):890.2 [M+H] + LC-MS retention time RT = 1.80 min. HPLC retention time RT = 12.95 min. 1H NMR (500 MHz, DMSO-d6) δ 8.82 (d, J = 2.0 Hz, 1H), 8.55-8.51 (m, 2H), 7.95 (d, J = 2.0 Hz, 1H), 7.87 (s, 1H), 7.84-7.80 (m, 1H), 7.71-7.67 (m, 1H), 5.54 (t, J = 9.0 Hz, 1H), 5.07-5.02 (m, 1H), 4.98-4.79 (m, 2H), 4.27-4.19 (m, 2H), 3.93-3.88 (m, 1H), 3.68-3.65 (m, 1H), 3.64-3.59 (m, 4H), 3.58 (s, 2H), 3.53-3.47 (m, 1H), 3.19-3.12 (m, 1H), 3.09 (s, 3H), 3.07-2.98 (m, 1H), 2.80-2.73 (m, 1H), 2.56-2.52 (m, 4H), 2.47-2.42 (m, 1H), 2.16-2.09 (m, 1H), 1.84-1.77 (m, 2H), 1.54-1.49 (m, 2H), 1.24 (d, J = 6.0 Hz, 3H), 1.09-1.06 (m, 4H), 0.93 (s, 3H), 0.90-0.83 (m, 2H), 0.58-0.54 (m, 1H), 0.46 (s, 3H). Example 4

[0348] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-Methoxyethyl)-5-(3-((S)-2-methylmorpholino)prop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000093.jpg95154

[0349] Example 4 was prepared by the following steps: JPEG2025530275000094.jpg156170

[0350] Step 1: Compound INT-2 (102 mg, 0.15 mmol) was dissolved in a mixture of 1,4-dioxane (3 mL) and water (0.3 mL). INT-6 (40 mg, 0.11 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (8.3 mg, 0.011 mmol), and potassium phosphate (72.1 mg, 0.33 mmol) were added sequentially. The reaction mixture was stirred at 70 °C for 16 h under nitrogen protection. After completion of the reaction, water (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 20:1) to obtain compound 4a (60 mg, 63.1% yield) as a pale yellow solid. ESI-MS (m / z): 840.2 [M+H] + .

[0351] Step 2: Compound 4a (60 mg, 0.071 mmol) was dissolved in N,N-dimethylformamide (2 mL), and cesium carbonate (46.3 mg, 0.142 mmol) and ethyl iodide (16.6 mg, 0.106 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 30 / 1) to give compound 4b (50 mg, 81.2% yield) as a pale yellow solid. ESI-MS (m / z): 868.6 [M+H] + .

[0352] Step 3: Compound 4b (50 mg, 0.058 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, saturated aqueous sodium bicarbonate (30 mL) was added to the reaction mixture in an ice bath, and the mixture was extracted with dichloromethane (30 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 4c (40 mg, 90.4% yield) as a pale yellow solid. ESI-MS (m / z): 768.4 [M+H] + .

[0353] Step 4: Compound 4c (40 mg, 0.052 mmol) was dissolved in N,N-dimethylformamide (2 mL) and (1S,2S)-2-methylcyclopropanecarboxylic acid INT-3b (10.4 mg, 0.104 mmol), N,N-diisopropylethylamine (20.2 mg, 0.156 mmol), and (2-oxime-cyanoacetic acid ethyl ester)-N,N-dimethylmorpholineurea hexafluorophosphate (55.8 mg, 0.104 mmol) were added. The reaction mixture was stirred in an ice bath for 1 h. After completion of the reaction, water (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative liquid chromatography to give compound 4 (6 mg, 13.6% yield) and epimer 4' (9 mg, 20.3% yield) as a white solid. The absolute configurations of the four compounds were empirically assumed. In the current analytical method, 4 is a compound with relatively low polarity and a relatively long retention time in LC-MS and HPLC, and 4' is a compound with relatively high polarity and a relatively short retention time in LC-MS and HPLC.

[0354] Compound 4: ESI-MS (m / z): 850.4 [M+H] + ;LC-MS retention time RT=1.88 min. HPLC retention time RT=13.62 min.

[0355] 1H NMR (500 MHz, DMSO-d6) δ 8.81 (d, J = 2.0 Hz, 1H), 8.53-8.48 (m, 2H), 7.86 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.77-7.73 (m, 1H), 7.58 (d, J = 8.5 Hz, 1H), 5.56 (t, J = 9.0 Hz, 1H), 5.10-5.06 (m, 1H), 4.36-4.13 (m, 4H), 4.12-4.02 (m, 1H), 3.80-3.75 (m, 1H), 3.61-3.48 (m, 6H), 3.25 (s, 3H), 3.18-3.11 (m, 1H), 2.99-2.94 (m, 1H), 2.81-2.70 (m, 3H), 2.40-2.36 (m, 1H), 2.30-2.24 (m, 1H), 2.11-2.05 (m, 1H), 2.00-1.94 (m, 2H), 1.83-1.75 (m, 2H), 1.53-1.47 (m, 2H), 1.35 (d, J = 6.0 Hz, 3H), 1.08-1.04 (m, 7H), 0.92-0.85 (m, 8H), 0.57-0.53 (m, 1H), 0.34 (s, 3H).

[0356] Compound 4': ESI-MS (m / z):850.4 [M+H] + LC-MS retention time RT = 1.85 min. HPLC retention time RT = 13.25 min.

[0357] 1H NMR (500 MHz, DMSO-d6) δ 8.82 (d, J = 2.0 Hz, 1H), 8.56-8.49 (m, 2H), 7.99 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.76-7.72 (m, 1H), 7.54 (d, J = 8.5 Hz, 1H), 5.55 (t, J = 9.0 Hz, 1H), 5.07-5.02 (m, 1H), 4.28-4.17 (m, 2H), 4.00-3.91 (m, 2H), 3.87-3.75 (m, 2H), 3.70-3.64 (m, 1H), 3.60-3.48 (m, 4H), 3.20-3.02 (m, 5H), 2.81-2.68 (m, 3H), 2.35-2.24 (m, 2H), 2.15-2.09 (m, 1H), 2.03-1.93 (m, 2H), 1.84-1.75 (m, 2H), 1.56-1.47 (m, 2H), 1.42-1.38 (m, 1H), 1.27-1.19 (m, 7H), 1.14-1.05 (m, 6H), 0.93 (s, 3H), 0.89-0.82 (m, 2H), 0.59-0.53 (m, 1H), 0.50 (s, 2H). Example 5

[0358] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-Methoxyethyl)-5-(4-morpholinobut-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000095.jpg101147

[0359] Example 5 was prepared by the following steps: JPEG2025530275000096.jpg171170

[0360] Step 1: Compound INT-2 (100 mg, 0.14 mmol) was dissolved in a mixture of 1,4-dioxane (5 mL) and water (1 mL), followed by the addition of INT-7 (51 mg, 0.14 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (10 mg, 0.01 mmol), and potassium phosphate (60 mg, 0.28 mmol). The reaction mixture was stirred and reacted at 70 °C for 16 h under nitrogen protection. After completion of the reaction, the reaction mixture was filtered through diatomaceous earth, and the concentrated residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 5a (65 mg, 53.7% yield) as a pale yellow oil. ESI-MS (m / z): 840.1 [M+H] + ;

[0361] Step 2: Compound 5a (60 mg, 0.07 mmol) was dissolved in N,N-dimethylformamide (2 mL), and cesium carbonate (46 mg, 0.14 mmol) and iodoethane (22 mg, 0.14 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, water (15 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 5b (25 mg, 40.3% yield) as a pale yellow solid. ESI-MS (m / z): 868.2 [M+H] + ;

[0362] Step 3: Compound 5b (25 mg, 0.03 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, saturated aqueous sodium bicarbonate (20 mL) was added to the reaction mixture in an ice bath, and the mixture was extracted with dichloromethane (20 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 5c (20 mg, 90.9% yield) as a pale yellow solid. ESI-MS (m / z): 768.2 [M+H] + ;

[0363] Step 4: Compound 5c (20 mg, 0.03 mmol) was dissolved in N,N-dimethylformamide (1 mL) and (1S,2S)-2-methylcyclopropanecarboxylic acid INT-3b (5.0 mg, 0.05 mmol), N,N-diisopropylethylamine (10 mg, 0.07 mmol), and (2-oxime-cyanoacetic acid ethyl ester)-N,N-dimethylmorpholineurea hexafluorophosphate (11 mg, 0.03 mmol) were added. The reaction mixture was stirred in an ice bath for 1 h. After completion of the reaction, water (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative liquid chromatography to give compound 5 (5 mg, 22.7% yield) and epimer 5' (7 mg, 31.8% yield) as a white solid. The absolute configurations of the five compounds were empirically assumed. In the current analytical method, 5 is a compound with relatively low polarity and a relatively long retention time in LC-MS and HPLC, and 5' is a compound with relatively high polarity and a relatively short retention time in LC-MS and HPLC.

[0364] Compound 5: ESI-MS (m / z): 850.6 [M+H] + ;LC-MS retention time RT=1.89 min. HPLC retention time RT=13.37 min.

[0365] 1H NMR (500 MHz, DMSO-d6) δ 8.75 (d, J = 2.0 Hz, 1H), 8.55-8.48 (m, 2H), 7.81 (s, 1H), 7.78-7.73 (m, 2H), 7.58 (d, J = 8.5 Hz, 1H), 5.56 (t, J = 9.0 Hz, 1H), 5.10-5.06 (m, 1H), 4.37-4.04 (m, 5H), 3.60-3.54 (m, 6H), 3.25 (s, 3H), 3.18-3.11 (m, 1H), 2.98-2.94 (m, 1H), 2.80-2.72 (m, 1H), 2.69-2.57 (m, 4H), 2.47-2.42 (m, 4H), 2.39-2.35 (m, 1H), 2.11-2.07 (m, 1H), 1.83-1.76 (m, 2H), 1.53- 1.46 (m, 2H), 1.34 (d, J = 6.0 Hz, 3H), 1.07 (s, 3H), 0.91 (s, 3H), 0.87 (t, J = 7.0 Hz, 3H), 0.57-0.53 (m, 1H), 0.33 (s, 3H). Compound 5': ESI-MS (m / z):850.6 [M+H] + LC-MS retention time RT = 1.83 min. HPLC retention time RT = 13.01 min.

[0366] 1H NMR (500 MHz, DMSO-d6) δ 8.76 (d, J = 2.0 Hz, 1H), 8.56-8.50 (m, 2H), 7.91 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.74 (dd, J = 8.5, 1.5 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 5.54 (t, J = 9.0 Hz, 1H), 5.10-5.06 (m, 1H), 4.27-4.15 (m, 2H), 3.97-3.88 (m, 2H), 3.84-3.77 (m, 1H), 3.70-3.66 (m, 1H), 3.59-3.55 (m, 5H), 3.18-3.14 (m, 1H), 3.08 (s, 3H), 3.07-3.02 (m, 1H), 2.80-2.73 (m, 1H), 2.68-2.57 (m, 5H), 2.47-2.42 (m, 4H), 2.34-2.28 (m, 1H), 2.15-2.10 (m, 1H), 1.84-1.77 (m, 2H), 1.56-1.47 (m, 2H), 1.21 (d, J = 6.0 Hz, 3H), 1.10 (t, J = 7.0 Hz, 3H), 1.07 (s, 3H), 0.93 (s, 3H), 0.90-0.84 (m, 2H), 0.55 (d, J = 6.0 Hz, 1H), 0.49 (s, 3H). Example 6

[0367] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-Methoxyethyl)-5-(((S)-4-methylmorpholin-2-yl)ethynyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000097.jpg95150

[0368] Example 6 was prepared by the following steps: JPEG2025530275000098.jpg163170

[0369] Step 1: Compound INT-2 (120 mg, 0.172 mmol) was dissolved in a mixture of 1,4-dioxane (3 mL) and water (0.3 mL), followed by the addition of INT-8 (45 mg, 0.133 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (9.7 mg, 0.013 mmol), and potassium phosphate (84.5 mg, 0.399 mmol). The reaction mixture was stirred at 70 °C for 16 h under nitrogen protection. After completion of the reaction, water (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin-layer chromatography to give compound 6a (65 mg, 59.3% yield) as a pale yellow solid. ESI-MS (m / z): 826.2 [M+H] + .

[0370] Step 2: Compound 6a (65 mg, 0.079 mmol) was dissolved in N,N-dimethylformamide (2 mL), and cesium carbonate (51.3 mg, 0.157 mmol) and ethyl iodide (18.4 mg, 0.118 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 30 / 1) to give compound 6b (50 mg, 74.4% yield) as a pale yellow solid. ESI-MS (m / z): 854.4 [M+H] + .

[0371] Step 3: Compound 6b (50 mg, 0.059 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, saturated aqueous sodium bicarbonate (30 mL) was added to the reaction mixture in an ice bath, and the mixture was extracted with dichloromethane (30 mL × 2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 6c (40 mg, 90.6% yield) as a pale yellow solid. ESI-MS (m / z): 754.4 [M+H] + .

[0372] Step 4: Compound 6c (40 mg, 0.053 mmol) was dissolved in N,N-dimethylformamide (2 mL) and (1S,2S)-2-methylcyclopropanecarboxylic acid INT-3b (10.6 mg, 0.106 mmol), N,N-diisopropylethylamine (20.6 mg, 0.159 mmol), and (2-oxime-cyanoacetic acid ethyl ester)-N,N-dimethylmorpholineurea hexafluorophosphate (45.4 mg, 0.106 mmol) were added. The reaction mixture was stirred in an ice bath for 1 h. After completion of the reaction, water (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative liquid chromatography to give compound 6 (8 mg, 18.0% yield) and epimer 6' (10 mg, 22.5% yield) as a white solid. The absolute configurations of the six compounds were empirically assumed. In the current analytical method, 6 is a compound with relatively low polarity and a relatively long retention time in LC-MS and HPLC, while 6' is a compound with relatively high polarity and a relatively short retention time in LC-MS and HPLC.

[0373] Compound 6: ESI-MS (m / z): 836.4 [M+H] + ;LC-MS retention time RT=1.80 min. HPLC retention time RT=13.34 min.

[0374] 1H NMR (500 MHz, DMSO-d6) δ 8.81 (d, J = 2.0 Hz, 1H), 8.54-8.48 (m, 2H), 7.86 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.77-7.74 (m, 1H), 7.58 (d, J = 8.5 Hz, 1H), 5.56 (t, J = 9.0 Hz, 1H), 5.10-5.05 (m, 1H), 4.63-4.57 (m, 1H), 4.37-4.16 (m, 4H), 4.11-4.04 (m, 1H), 3.90-3.83 (m, 1H), 3.61-3.54 (m, 3H), 3.25 (s, 3H), 3.18-3.11 (m, 1H), 3.00-2.93 (m, 1H), 2.80-2.72 (m, 2H), 2.48-2.44 (m, 1H), 2.40-2.36 (m, 1H), 2.34-2.28 (m, 1H), 2.22-2.17 (m, 4H), 2.11-2.04 (m, 1H), 1.83-1.75 (m, 2H), 1.53-1.47 (m, 2H), 1.35 (d, J = 6.0 Hz, 3H), 1.10-1.04 (m, 5H), 0.92 (s, 3H), 0.90-0.85 (m, 4H), 0.57-0.52 (m, 1H), 0.33 (s, 3H).

[0375] Compound 6': ESI-MS (m / z):836.4 [M+H] + LC-MS retention time RT = 1.76 min. HPLC retention time RT = 12.94 min.

[0376] 1H NMR (500 MHz, DMSO-d6) δ 8.82 (d, J = 2.0 Hz, 1H), 8.56-8.50 (m, 2H), 8.00 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.76-7.71 (m, 1H), 7.54 (d, J = 8.5 Hz, 1H), 5.54 (t, J = 9.0 Hz, 1H), 5.07-5.02 (m, 1H), 4.64-4.58 (m, 1H), 4.28-4.18 (m, 2H), 3.98-3.91 (m, 2H), 3.88-3.79 (m, 2H), 3.71-3.64 (m, 1H), 3.62-3.50 (m, 2H), 3.31-3.27 (m, 1H), 3.18-3.12 (m, 1H), 3.09 (s, 3H), 3.07-3.02 (m, 1H), 2.80-2.74 (m, 2H), 2.48-2.43 (m, 1H), 2.34-2.26 (m, 2H), 2.21 (s, 3H), 2.19-2.09 (m, 2H), 1.85-1.75 (m, 2H), 1.54-1.48 (m, 2H), 1.21 (d, J = 6.0 Hz, 3H), 1.13-1.06 (m, 7H), 0.93 (s, 3H), 0.90-0.86 (m, 1H), 0.58-0.54 (m, 1H), 0.49 (s, 3H).

[0377] Example 7 (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-Methoxyethyl)-5-(((R)-4-methylmorpholin-3-yl)ethynyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000099.jpg95138

[0378] Example 7 was prepared by the following steps: JPEG2025530275000100.jpg156170

[0379] Step 1: Intermediate INT-2 (98 mg, 0.14 mmol) and intermediate INT-10 (40 mg, 0.12 mmol) were dissolved in a mixture of 1,4-dioxane (2 mL) and water (0.2 mL), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride and potassium phosphate (75 mg, 0.35 mmol) were added. The reaction mixture was purged with nitrogen and heated to 70 °C and stirred for 12 h. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 30 / 1) to give compound 7a (92 mg, 94% yield). ESI-MS (m / z): 826.5 [M+H] + .

[0380] Step 2: Compound 7a (92 mg, 0.11 mmol) was dissolved in N,N-dimethylformamide (2 mL), cesium carbonate (73 mg, 0.22 mmol) was added, and then ethyl iodide (35 mg, 0.22 mmol) was added dropwise to the reaction solution. The reaction solution was stirred at 50 °C for 6 hours. After the reaction solution was cooled to room temperature, saturated brine (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound 7b (80 mg, 84% yield). ESI-MS (m / z): 854.5 [M+H] + .

[0381] Step 3: Compound 7b (80 mg, 0.09 mmol) was dissolved in dichloromethane (1 mL), the reaction solution was cooled to 0 °C, and then trifluoroacetic acid (53 mg, 0.47 mmol) was added dropwise to the reaction solution. The reaction was stirred at 0 °C for 1 hour. The reaction solution was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound 7c (70 mg, 99% yield). ESI-MS (m / z): 754.4 [M+H] + .

[0382] Step 4: Compound 7c (70 mg, 0.09 mmol) and intermediate INT-3b (18 mg, 0.19 mmol) were dissolved in N,N-dimethylformamide (3 mL), and N,N-dimethylformamide (36 mg, 0.28 mmol) and (2-oxime-ethyl cyanoacetate)-N,N-dimethyl-morpholinourea hexafluorophosphate (36 mg, 0.19 mmol) were added. The reaction solution was stirred at 0 °C for 30 min. Saturated brine (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative liquid chromatography to give compound 7 (7 mg, 9% yield) and epimer 7' (10 mg, 12.9% yield) as a white solid. The absolute configurations of the seven compounds were empirically assumed. In the current analytical method, 7 is a compound with relatively low polarity and a relatively long retention time in LC-MS and HPLC, while 7' is a compound with relatively high polarity and a relatively short retention time in LC-MS and HPLC.

[0383] Compound 7: ESI-MS (m / z): 836.6 [M+H] + . LC-MS retention time RT=2.09 min. HPLC retention time RT=13.10 min.

[0384] 1H NMR (500 MHz, DMSO) δ 8.81 (d, J = 2.0 Hz, 1H), 8.53-8.48 (m, 2H), 7.85 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.75 (dd, J = 8.5, 2.0 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 5.56 (t, J = 9.0 Hz, 1H), 5.09-5.05 (m, 1H), 4.35-4.16 (m, 4H), 4.10-4.05 (m, 1H), 3.79-3.75 (m, 1H), 3.72-3.56 (m, 5H), 3.53-3.48 (m, 1H), 3.32-3.28 (m, 2H), 3.25 (s, 3H), 3.17-3.08 (m, 2H), 3.00-2.95 (m, 1H), 2.79-2.72 (m, 1H), 2.68-2.62 (m, 1H), 2.40-2.33 (m, 4H), 2.32-2.27 (m, 1H), 2.11-2.07 (m, 1H), 1.83-1.74 (m, 2H), 1.54-1.46 (m, 2H), 1.35 (d, J = 6.0 Hz, 3H), 1.10-1.02 (m, 4H), 0.92 (s, 3H), 0.87 (t, J = 7.0 Hz, 3H), 0.58-0.52 (m, 1H), 0.34 (s, 3H).

[0385] Compound 7': ESI-MS (m / z): 836.6 [M+H] + LC-MS retention time RT = 2.06 min. HPLC retention time RT = 12.76 min.

[0386] 1H NMR (500 MHz, DMSO) δ 8.84-8.80 (m, 1H), 8.53 (d, J = 9.0 Hz, 2H), 7.99 (d, J = 1.5 Hz, 1H), 7.81 (s, 1H), 7.74 (dd, J = 9.0, 1.5 Hz, 1H), 7.54 (d, J = 9.0 Hz, 1H), 5.54 (t, J = 9.0 Hz, 1H), 5.07-5.02 (m, 1H), 4.25-4.20 (m, 1H), 3.98-3.92 (m, 1H), 3.86-3.82 (m, 1H), 3.78-3.72 (m, 1H), 3.70-3.65 (m, 3H), 3.63-3.59 (m, 1H), 3.57-3.49 (m, 2H), 3.33-3.28 (m, 2H), 3.18-3.12 (m, 1H), 3.09 (s, 3H), 3.07-3.02 (m, 1H), 2.79-5.75 (m, 1H), 2.68-2.61 (m, 1H), 2.36-2.31 (m, 3H), 2.32-2.25 (m, 2H), 2.14-2.09 (m, 1H), 1.85-1.75 (m, 2H), 1.54-1.48 (m, 2H), 1.21 (d, J = 6.0 Hz, 3H), 1.11 (t, J = 7.0 Hz, 3H), 1.10-1.05 (m, 4H), 0.93 (s, 3H), 0.90-0.85 (m, 1H), 0.60-0.52 (m, 1H), 0.50 (s, 3H).

[0387] Example 8 (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-Methoxyethyl)-5-(((R)-4-methylmorpholin-2-yl)ethynyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000101.jpg98144

[0388] Example 8 was prepared by the following steps: JPEG2025530275000102.jpg168170

[0389] Step 1: Intermediate INT-2 (98 mg, 0.14 mmol) and intermediate INT-11 (40 mg, 0.12 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.2 mL), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (9 mg, 0.01 mmol) and potassium phosphate (75 mg, 0.35 mmol) were added. The reaction mixture was purged with nitrogen and heated to 70 °C and stirred for 12 h. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 30 / 1) to give compound 8a (37 mg, 38% yield). ESI-MS (m / z): 826.5 [M+H] + .

[0390] Step 2: Compound 8a (37 mg, 0.05 mmol) was dissolved in N,N-dimethylformamide (2 mL), cesium carbonate (29 mg, 0.09 mmol) was added, and then ethyl iodide (14 mg, 0.09 mmol) was added dropwise to the reaction solution. The reaction solution was stirred at 50 °C for 6 hours. After the reaction solution was cooled to room temperature, saturated brine (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound 8b (30 mg, 78% yield). ESI-MS (m / z): 854.3 [M+H] + .

[0391] Step 3: Compound 8b (30 mg, 0.04 mmol) was dissolved in dichloromethane (1 mL), the reaction solution was cooled to 0 °C, and then trifluoroacetic acid (20 mg, 0.18 mmol) was added dropwise to the reaction solution. The reaction was stirred at 0 °C for 1 hour. The reaction solution was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound 8c (26 mg, 99% yield). ESI-MS (m / z): 754.5 [M+H] + .

[0392] Step 4: Compound 8c (26 mg, 0.04 mmol) and intermediate INT-3 (7 mg, 0.07 mmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-dimethylformamide (13 mg, 0.10 mmol) and (2-oxime-ethyl cyanoacetate)-N,N-dimethyl-morpholinourea hexafluorophosphate (14 mg, 0.07 mmol) were added. The reaction solution was stirred at 0 °C for 30 min. Saturated brine (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative liquid chromatography to give compound 8 (3 mg, 10% yield) and epimer 8' (5 mg, 17.8% yield) as a white solid. The absolute configurations of the eight compounds were empirically assumed. In the current analytical method, 8 is a compound with relatively low polarity and a relatively long retention time in LC-MS and HPLC, while 8' is a compound with relatively high polarity and a relatively short retention time in LC-MS and HPLC.

[0393] Compound 8: ESI-MS (m / z): 836.2 [M+H] + . LC-MS retention time RT=1.81 min. HPLC retention time RT=13.43 min.

[0394] 1H NMR (500 MHz, DMSO) δ 8.81 (d, J = 2.0 Hz, 1H), 8.55-8.50 (m, 2H), 7.85 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 5.56 (t, J = 9.0 Hz, 1H), 5.09-5.05 (m, 1H), 4.64-4.58 (m, 1H), 4.38-4.15 (m, 5H), 4.10-4.04 (m, 1H), 3.88-3.83 (m, 1H), 3.61-3.54 (m, 3H), 3.32-3.31 (m, 2H), 3.25 (s, 3H), 3.17-3.08 (m, 2H), 2.99-2.95 (m, 1H), 2.80-2.72 (m, 2H), 2.40-2.35 (m, 1H), 2.32-2.28 (m, 1H), 2.20 (s, 3H), 2.11-2.05 (m, 1H), 1.81-1.76 (m, 2H), 1.53-1.46 (m, 2H), 1.35 (d, J = 6.0 Hz, 3H), 1.10-1.05 (m, 4H), 0.91 (s, 3H), 0.87 (t, J = 7.0 Hz, 3H), 0.58-0.52 (m, 1H), 0.33 (s, 3H).

[0395] Compound 8': ESI-MS (m / z): 836.2 [M+H] + LC-MS retention time RT = 1.78 min. HPLC retention time RT = 13.01 min.

[0396] 1H NMR (500 MHz, DMSO) δ 8.82 (d, J = 2.0 Hz, 1H), 8.53 (d, J = 9.0 Hz, 2H), 8.00 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.74 (dd, J = 9.0, 2.0 Hz, 1H), 7.54 (d, J = 9.0 Hz, 1H), 5.54 (t, J = 9.0 Hz, 1H), 5.07-5.02 (m, 1H), 4.64-4.58 (m, 1H), 4.25-4.20 (m, 2H), 4.00-3.90 (m, 2H), 3.88-3.79 (m, 2H), 3.68-3.62 (m, 1H), 3.60-3.57 (m, 1H), 3.58-3.50 (m, 1H), 3.34-3.28 (m, 2H), 3.18-3.14 (m, 1H), 3.09 (s, 3H), 3.08-3.02 (m, 1H), 2.78-2.73 (m, 2H), 2.50-3.45 (m, 1H), 2.32-2.25 (m, 2H), 2.24-2.18 (m, 3H), 2.19-2.06 (m, 2H), 1.83-1.77 (m, 2H), 1.56-1.47 (m, 2H), 1.21 (d, J = 6.0 Hz, 3H), 1.12-1.17 (m, 6H), 0.93 (s, 3H), 0.89-0.85 (m, 1H), 0.58-0.52 (m, 1H), 0.49 (s, 3H).

[0397] Example 9 (1S,2S)-N-((6 3 S,4S,Z)-1 2 -(5-(3-((2S,6R)-2,6-ジメチルmorpholino)prop-1-yn-1-yl)-2-((S)-1-メトキシエチル)ピリジン-3-イル)-1 1 -エチル-10,10-ジメチル-5,7-ジオキソ-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -ヘキサヒドロ-11 H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000103.jpg99149

[0398] Example 9 was prepared by the following steps: JPEG2025530275000104.jpg163170

[0399] Step 1: INT-3 (85.0 mg, 0.12 mmol), INT-9 (30 mg, 0.08 mmol), 1,1-bis(diphenylphosphine)diphenyliron dichloride palladium (6.0 mg, 0.008 mmol), and potassium phosphate (52.0 mg, 0.25 mmol) were dissolved in a mixture of 1,4-dioxane (5 mL) and water (1 mL). The reaction solution was stirred overnight at 70 °C under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound 9a (69.8 mg, 100% yield) as a brown oil. ESI-MS (m / z): 854.3 [M+H] + ;

[0400] Step 2: Compound 9a (60.0 mg, 0.07 mmol), cesium carbonate (45.8 mg, 0.14 mmol), and ethyl iodide (21.9 mg, 0.14 mmol) were dissolved in N,N-dimethylformamide (2 mL), and the reaction solution was stirred overnight at room temperature. After completion of the reaction, the reaction solution was extracted with ethyl acetate. The organic phases were then combined, dried, and concentrated to give compound 9b (62.0 mg, 100% yield) as a pale yellow oil. ESI-MS (m / z): 882.5 [M+H] + ;

[0401] Step 3: Compound 9b (60 mg, 0.07 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (78 mg, 0.68 mmol) was added to the reaction solution, and the reaction solution was stirred at room temperature overnight. After the reaction was completed, saturated aqueous sodium bicarbonate solution was added to the reaction solution. The neutralized reaction solution was extracted with dichloromethane, and the combined organic phase was dried and concentrated to give compound 9c (53.2 mg, 100% yield). ESI-MS (m / z): 782.5 [M+H] + ;

[0402] Step 4: Compound 9c (60 mg, 0.08 mmol), INT-3b (15.4 mg, 0.15 mmol), and N,N-diisopropylethylamine (49.6 mg, 0.38 mmol) were dissolved in N,N-bismethylformamide (2 mL). To the reaction mixture was added (2-oxime-ethyl cyanoacetate)-N,N-dimethyl-morpholinourea hexafluorophosphate (2-oxime-ethyl cyanoacetate) (65.7 mg, 0.15 mmol) at 0 °C. The reaction mixture was allowed to react for 2 hours. After the reaction, the reaction mixture was extracted with ethyl acetate. The organic phases were combined, dried, and concentrated. The resulting crude product was purified by preparative liquid chromatography to give compound 9 (4 mg, 6.0% yield) and epimer 9' (6 mg, 9.0% yield). The absolute configurations of the nine compounds were empirically assumed. In the current analytical method, 9 is a compound with relatively low polarity and a relatively long retention time in LC-MS and HPLC, while 9' is a compound with relatively high polarity and a relatively short retention time in LC-MS and HPLC.

[0403] Compound 9: ESI-MS (m / z): 864.6 [M+H] + ;LC-MS retention time RT = 1.95 min. HPLC retention time RT = 14.28 min.

[0404] 1H NMR (500 MHz, DMSO-d6) δ 8.81 (d, J = 2.0 Hz, 1H), 8.53-8.49 (m, 2H), 7.85 (d, J = 2.5 Hz, 1H), 7.81 (s, 1H), 7.76-7.74 (m, 1H), 7.59-7.57 (m, 1H), 5.56 (t, J = 9.0 Hz, 1H), 5.10-5.05 (m, 1H), 4.40-4.15 (m, 5H), 4.12-4.05 (m, 1H), 3.62-3.55 (m, 7H), 3.25 (s, 3H), 3.17-3.12 (m, 1H), 2.98-2.95 (m, 1H), 2.78-2.75 (m, 3H), 2.40-2.35 (m, 1H), 2.09-2.07 (m, 1H), 1.93-1.88 (m, 2H), 1.79-1.76 (m, 2H), 1.60-1.45 (m, 3H), 1.35 (d, J = 6.0 Hz, 3H), 1.27-1.22 (m, 1H), 1.10-1.02 (m, 6H), 0.91 (s, 3H), 0.90-0.85 (m, 5H), 0.56-0.52 (m, 1H), 0.34 (s, 3H).

[0405] Compound 9': ESI-MS (m / z): 864.6 [M+H] + LC-MS retention time RT = 1.87 min. HPLC retention time RT = 13.84 min. Example 10

[0406] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -エチル-1 2 -(2-((S)-1-メトキシエチル)-5-(((R)-1-メチルピロリジン-2 -yl)エチニル)ピリジン-3-イル)-10,10-ジメチル-5,7-ジオキソ-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6-Hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000105.jpg95147

[0407] Example 10 was prepared by the following steps: JPEG2025530275000106.jpg154170

[0408] Step 1: Intermediate INT-3 (55 mg, 0.08 mmol) and intermediate INT-15 (30 mg, 0.08 mmol) were dissolved in a mixture of 1,4-dioxane (3 mL) and water (0.2 mL), and 1,1-bis(diphenylphosphine)ferrocene]dichloropalladium (6 mg, 0.01 mmol) and potassium phosphate (47 mg, 0.02 mmol) were added. The reaction mixture was purged with nitrogen and heated to 70 °C and stirred for 12 h. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 30 / 1) to give compound 10a (62 mg, 96% yield). ESI-MS (m / z): 879.2 [M+H] + .

[0409] Step 2: Compound 10a (62 mg, 0.07 mmol) was dissolved in DMF (2 mL), and cesium carbonate (47 mg, 0.14 mmol) was added. Iodoethane (23 mg, 0.14 mmol) was then added dropwise to the reaction solution, and the reaction solution was stirred at room temperature for 6 hours. LCMS confirmed the completion of the reaction. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound 10b (64 mg, 99% yield). ESI-MS (m / z): 908.3 [M+H] + .

[0410] Step 3: Compound 10b (64 mg, 0.07 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (41 mg, 0.36 mmol) was added dropwise to the reaction solution at 0 °C. The reaction solution was stirred at 0 °C for 1 hour. LCMS confirmed the completion of the reaction. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound 10c (57 mg, 99% yield). ESI-MS (m / z): 807.6 [M+H] + .

[0411] Step 4: The crude product of compound 10c (57 mg, 0.07 mmol) was dissolved in methanol (2 mL). Aqueous formaldehyde solution (0.05 mL, 37% w / w) was added dropwise to the reaction solution at room temperature and stirred for 10 minutes. Sodium cyanoborohydride (14 mg, 0.21 mmol) was then slowly added to the reaction solution, and the reaction solution was stirred at room temperature for 3 hours. LCMS showed the reaction was complete. The reaction was quenched with saturated aqueous ammonium chloride solution, extracted with methylene chloride, and the combined organic phase was concentrated. The residue was purified by preparative liquid chromatography to give compound 10 (3.0 mg, 5.2% yield) and the corresponding isomer 10' (4.0 mg, 6.9% yield) as a white solid. The absolute configurations of the 10 compounds were empirically assumed. In the current analytical method, 10 is a compound with relatively low polarity and a relatively long retention time in LC-MS and HPLC, and 10' is a compound with relatively high polarity and a relatively short retention time in LC-MS and HPLC.

[0412] Compound 10: ESI-MS (m / z): 820.0 [M+H] + . LC-MS retention time RT = 1.97 min. HPLC retention time RT = 14.55 min.

[0413] 1H NMR (500 MHz, DMSO) δ 8.79 (d, J = 2.0 Hz, 1H), 8.55-8.47 (m, 2H), 7.82 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.75 (dd, J = 8.5, 2.0 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 5.56 (t, J = 9.0 Hz, 1H), 5.10-5.05 (m, 1H), 4.36-4.15 (m, 4H), 4.12-4.03 (m, 1H), 3.57 (s, 2H), 3.41-3.35 (m, 1H), 3.25 (s, 3H), 3.17-3.11 (m, 1H), 3.00-2.94 (m, 1H), 2.83-2.72 (m, 2H), 2.41-2.31 (m, 5H), 2.19-2.11 (m, 1H), 2.13-2.05 (m, 1H), 1.94-1.68 (m, 6H), 1.56-1.46 (m, 2H), 1.35 (d, J = 6.0 Hz, 3H), 1.26-1.20 (m, 1H), 1.06 (s, 3H), 0.91 (s, 3H), 0.93-0.88 (m, 4H), 0.57-0.52 (m, 1H), 0.34 (s, 3H).

[0414] Compound 10': ESI-MS (m / z): 820.0 [M+H] + LC-MS retention time RT = 1.90 min. HPLC retention time RT = 13.87 min.

[0415] 1H NMR (500 MHz, DMSO) δ 8.80 (d, J = 2.0 Hz, 1H), 8.53 (dd, J = 9.0, 2.0 Hz, 2H), 7.96 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.74 (dd, J = 8.5, 1.5 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 5.54 (t, J = 9.0 Hz, 1H), 5.07-5.02 (m, 1H), 4.27-4.18 (m, 2H), 3.99-3.90 (m, 2H), 3.85-3.80 (m, 1H), 3.70-3.66 (m, 1H), 3.57-3.52 (m, 1H), 3.42-3.37 (m, 1H), 3.31 (s, 2H), 3.19-3.01 (m, 5H), 2.80-2.75 (m, 2H), 2.40-2.28 (m, 5H), 2.18-2.12 (m, 2H), 1.92-1.69 (m, 5H), 1.57-1.47 (m, 2H), 1.21 (d, J = 6.0 Hz, 3H), 1.10 (t, J = 7.0 Hz, 3H), 1.07 (s, 3H), 0.93 (s, 3H), 0.90-0.85 (m, 1H), 0.59-1.47 (m, 2H), , 0.50 (s, 3H). Example 11

[0416] (1r,2R,3S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-Methoxyethyl)-5-(((S)-1-methylpyrrolidin-2-yl)ethynyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4, 6 5 ,6 6 -Hexahydro-1 1H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2,3-dimethylcyclopropane-1-carboxamide JPEG2025530275000107.jpg101150

[0417] Example 11 was prepared by the following steps: JPEG2025530275000108.jpg155170

[0418] Step 1: Intermediate INT-4 (93 mg, 0.14 mmol) and intermediate INT-16 (50 mg, 0.12 mmol) were dissolved in a mixture of 1,4-dioxane (3 mL) and water (0.2 mL), and 1,1-bis(diphenylphosphine)diphenyliron dichloride palladium (9 mg, 0.01 mmol) and potassium phosphate (78 mg, 0.37 mmol) were added. The reaction mixture was purged with nitrogen, heated to 70 °C, and stirred for 12 h. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 30 / 1) to give compound 11a (105 mg, 96% yield). ESI-MS (m / z): 892.4 [M+H] + .

[0419] Step 2: Compound 11a (105 mg, 0.12 mmol) was dissolved in DMF (2 mL), and cesium carbonate (115 mg, 0.35 mmol) was added. Iodoethane (55 mg, 0.35 mmol) was added dropwise to the reaction solution, and the reaction solution was stirred at room temperature for 6 hours. LCMS confirmed the completion of the reaction. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound 11b (108 mg, 99% yield). ESI-MS (m / z): 920.5 [M+H] + .

[0420] Step 3: Compound 11b (108 mg, 0.12 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (67 mg, 0.59 mmol) was added dropwise to the reaction solution at 0 °C. The reaction solution was stirred at 0 °C for 1 hour. LCMS confirmed the completion of the reaction. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound 11c (96 mg, 99% yield). ESI-MS (m / z): 820.4 [M+H] + .

[0421] Step 4: The crude product of compound 11c (96 mg, 0.12 mmol) was dissolved in methanol (2 mL). Aqueous formaldehyde solution (0.05 mL) was added dropwise to the reaction solution at room temperature, and the reaction solution was stirred at room temperature for 10 minutes. Subsequently, sodium cyanoborohydride (22 mg, 0.35 mmol) was slowly added to the reaction solution, and the reaction solution was stirred at room temperature for 3 hours. LCMS showed that the reaction was complete. The reaction was quenched with saturated aqueous ammonium chloride solution, extracted with dichloromethane, and the combined organic phase was concentrated. The residue was purified by preparative liquid chromatography to give compound 11 (3.0 mg, 3% yield) and epitope 11' (5.0 mg, 5% yield) as a white solid. The absolute configurations of the two compounds were empirically assumed. In the current analytical method, 11 is a compound with relatively low polarity and a relatively long retention time in LC-MS and HPLC, while 11' is a compound with relatively high polarity and a relatively short retention time in LC-MS and HPLC.

[0422] Compound 11: ESI-MS (m / z): 834.5 [M+H] + . LC-MS retention time RT = 2.07 min. HPLC retention time RT = 15.25 min. 1H NMR (500 MHz, DMSO) δ 8.79 (d, J = 2.0 Hz, 1H), 8.50 (s, 1H), 8.39 (d, J = 8.5 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.75 (dd, J = 8.5 Hz, 2.0 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 5.55 (t, J = 9.0 Hz, 1H), 5.09-5.02 (m, 1H), 4.37 - 4.13 (m, 5H), 4.12 - 4.02 (m, 1H), 3.57 (s, 2H), 3.24 (s, 3H), 3.18 - 3.10 (m, 1H), 2.99-2.92 (m, 1H), 2.82-2.77 (m, 1H), 2.76 - 2.71 (m, 1H), 2.36 (s, 3H), 2.35-2.31 (m, 1H), 2.19-2.12 (m, 1H), 2.10 - 2.05 (m, 1H), 1.94-1.72 (m, 6H), 1.55 - 1.46 (m, 1H), 1.35 (d, J = 6.0 Hz, 3H), 1.26-1.20 (m, 1H), 1.19-1.16 (m, 2H), 1.11-1.04 (m, 6H), 0.91 (s, 3H), 0.88 (t, J = 7.0 Hz, 3H), 0.35 (s, 3H).

[0423] Compound 11': ESI-MS (m / z): 834.5 [M+H] + LC-MS retention time RT = 2.01 min. HPLC retention time RT = 14.61 min. Example 12

[0424] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -エチル-1 2 -(2-((S)-1-メトキシエチル)-5-((1-メチルアゼチジン-3-イル)エチニル)ピリジン-3-イル)-10,10-ジメチル-5,7-ジオキソ-61 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000109.jpg100152

[0425] Example 12 was prepared by the following steps: JPEG2025530275000110.jpg161170

[0426] Compound 12 and epimer 12' can be obtained using the same method and reaction steps by replacing INT-15 with INT-12 in Example 10. The absolute configurations of the two compounds are empirically assumed, and in the current analytical method, 12 is a compound with relatively low polarity and a relatively long retention time in LC-MS and HPLC, while 12' is a compound with relatively high polarity and a relatively short retention time in LC-MS and HPLC.

[0427] Compound 12: ESI-MS (m / z): 806.5 [M+H] + ;LC-MS retention time RT = 1.88 min. HPLC retention time RT = 13.59 min.

[0428] 1H NMR (500 MHz, DMSO-d6) δ 8.77 (d, J = 2.0 Hz, 1H), 8.55-8.46 (m, 2H), 7.83-7.77 (m, 2H), 7.75 (dd, J = 8.5, 2.0 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 5.56 (t, J = 9.0 Hz, 1H), 5.10-5.05 (m, 1H), 4.36-4.16 (m, 4H), 4.10-4.05 (m, 1H), 3.61-3.52 (m, 4H), 3.48-3.40 (m, 1H), 3.25 (s, 3H), 3.18-3.06 (m, 3H), 2.99-2.94 (m, 1H), 2.79-2.72 (m, 1H), 2.40-2.35 (m, 1H), 2.22 (s, 3H), 2.12-2.05 (m, 1H), 1.84-1.75 (m, 2H), 1.54-1.46 (m, 2H), 1.35 (d, J = 6.0 Hz, 3H), 1.09-1.05 (m, 4H), 0.93-0.85 (m, 7H), 0.58-0.52 (m, 1H), 0.33 (s, 3H).

[0429] Compound 12': ESI-MS (m / z):806.5 [M+H] + LC-MS retention time RT = 1.83 min. HPLC retention time RT = 12.92 min.

[0430] 1H NMR (500 MHz, DMSO-d6) δ 8.77 (d, J = 2.0 Hz, 1H), 8.55-8.46 (m, 2H), 7.83-7.77 (m, 2H), 7.75 (dd, J = 8.5, 2.0 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 5.56 (t, J = 9.1 Hz, 1H), 5.10-5.05 (m, 1H), 4.36-4.16 (m, 4H), 4.12-4.05 (m, 1H), 3.61-3.52 (m, 4H), 3.48-3.42 (m, 1H), 3.25 (s, 3H), 3.18-3.06 (m, 3H), 2.99-2.94 (m, 1H), 2.79-2.72 (m, 1H), 2.40-2.35 (m, 1H), 2.22 (s, 3H), 2.12-2.05 (m, 1H), 1.84-1.75 (m, 2H), 1.54-1.46 (m, 2H), 1.35 (d, J = 6.0 Hz, 3H), 1.09-1.05 (m, 4H), 0.93-0.85 (m, 7H), 0.58-0.52 (m, 1H), 0.33 (s, 3H).

[0431] Example 13 (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-Methoxyethyl)-5-(((S)-1-methylazetidin-2-yl)ethynyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000111.jpg95147

[0432] Example 13 was prepared by the following steps: JPEG2025530275000112.jpg156170

[0433] Compound 13 and epimer 13' can be obtained using the same method and reaction steps by replacing INT-15 with INT-13 in Example 10. The absolute configurations of the two compounds are empirically assumed, and in the current analytical method, 13 is a compound with relatively low polarity and a relatively long retention time in LC-MS and HPLC, while 13' is a compound with relatively high polarity and a relatively short retention time in LC-MS and HPLC.

[0434] Compound 13: ESI-MS (m / z): 806.5 [M+H] + ;LC-MS retention time RT = 1.88 min. HPLC retention time RT = 13.92 min.

[0435] Compound 13': ESI-MS (m / z): 806.5 [M+H] + ;LC-MS retention time RT = 1.82 min. HPLC retention time RT = 13.32 min.

[0436] Example 14 (1r,2R,3S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-Methoxyethyl)-5-(((S)-1-methylpyrrolidin-3-yl)ethynyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2,3-dimethylcyclopropane-1-carboxamide JPEG2025530275000113.jpg96141

[0437] Example 14 was prepared by the following steps: JPEG2025530275000114.jpg160170

[0438] Compound 14 and epimer 14' can be obtained using the same method and reaction steps as in Example 10, replacing INT-15 with INT-17. The absolute configurations of the two compounds are empirically assumed, and in the current analytical method, 14 is a compound with relatively low polarity and a relatively long retention time in LC-MS and HPLC, while 14' is a compound with relatively high polarity and a relatively short retention time in LC-MS and HPLC.

[0439] Compound 14: ESI-MS (m / z): 834.5 [M+H] + ;LC-MS retention time RT = 2.02 min. HPLC retention time RT = 14.80 min.

[0440] 1H NMR (500 MHz, DMSO) δ 8.74 (d, J = 2.0 Hz, 1H), 8.49 (d, J = 1.5 Hz, 1H), 8.39 (d, J = 9.0 Hz, 1H), 7.81 (s, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.75 (dd, J = 9.0, 1.5 Hz, 1H), 7.57 (d, J = 9.0 Hz, 1H), 5.55 (t, J = 9.0 Hz, 1H), 5.10-5.05 (m, 1H), 4.35 - 4.29 (m, 1H), 4.27-4.20 (m, 1H), 4.24-4.20 (m, 1H), 4.20-4.15 (m, 1H), 4.09 - 4.03 (m, 1H), 3.57 (s, 2H), 3.24 (s, 3H), 3.17-3.11 (m, 2H), 2.98-2.92 (m, 1H), 2.85-2.80 (m, 1H), 2.76-2.72 (m, 1H), 2.48-2.45 (m, 1H), 2.40-2.35 (m, 1H), 2.26 (s, 3H), 2.24-2.20 (m, 1H), 2.10-2.05 (m, 1H), 2.03-1.99 (m, 1H), 1.91 - 1.83 (m, 2H), 1.80-1.78 (m, 1H), 1.34 (d, J = 6.0 Hz, 3H), 1.23 (s, 3H), 1.19-1.06 (m, 6H), 1.05-1.00 (m, 3H), 0.91 (s, 3H), 0.88 (d, J = 7.0 Hz, 3H), 0.34 (s, 3H).

[0441] Compound 14': ESI-MS (m / z):834.5 [M+H] + LC-MS retention time RT = 1.95 min. HPLC retention time RT = 14.11 min.

[0442] 1H NMR (500 MHz, DMSO) δ 8.76 (d, J = 2.0 Hz, 1H), 8.52 (s, 1H), 8.40 (d, J = 9.0 Hz, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.82 (s, 1H), 7.73 (dd, J = 8.5, 2.0 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 5.53 (t, J = 9.0 Hz, 1H), 5.10-5.05 (m, 1H), 4.27-4.20 (m, 2H), 3.97-3.89 (m, 2H), 3.85-3.77 (m, 1H), 3.70-3.65 (m, 1H), 3.56-3.51 (m, 1H), 3.26-3.21 (m, 2H), 3.19 - 3.12 (m, 2H), 3.08 (s, 3H), 3.07-3.02 (m, 1H), 2.86-2.82 (m, 1H), 2.81-2.71 (m, 2H), 2.56-2.53 (m, 1H), 2.48-2.42 (m, 1H), 2.34-2.29 (m, 1H), 2.26 (s, 3H), 2.25-2.19 (m, 1H), 2.14-2.10 (m, 1H), 2.03-1.96 (m, 1H), 1.88-1.84 (m, 1H), 1.81-1.79 (m, 1H), 1.56-1.43 (m, 3H), 1.23 (s, 3H), 1.20 (d, J = 6.0 Hz, 3H), 1.21-1.16 (m, 1H), 1.13-1.10 (m, 1H), 1.09-1.05 (m, 6H), 0.93 (s, 3H), 0.85 (t, J = 6.0 Hz, 1H).

[0443] Example 15 (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-Methoxyethyl)-5-(3-((R)-3-methylmorpholino)prop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,62 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000115.jpg89156

[0444] Example 15 was prepared by the following steps: JPEG2025530275000116.jpg95170

[0445] Step 1: Compound INT-19 (20 mg, 0.02 mmol) was dissolved in dichloromethane (5 mL), and (R)-3-methylmorpholine hydrochloride (10 mg, 0.07 mmol) and diisopropylethylamine (18 mg, 0.14 mmol) were added. The reaction mixture was stirred at 50 °C for 16 h. After completion of the reaction, the reaction mixture was concentrated, and the residue was purified by preparative liquid chromatography to give compound 15 (3.0 mg, 15.0% yield) and epimer 15' (5.0 mg, 25.0% yield) as a white solid. The absolute configurations of the two compounds were empirically assumed. In the current analytical method, 15 is a compound with relatively low polarity and a relatively long retention time by LC-MS and HPLC, while 15' is a compound with relatively high polarity and a relatively short retention time by LC-MS and HPLC.

[0446] Compound 15: ESI-MS (m / z): 850.6 [M+H] + ;LC-MS retention time RT =1.90 min. HPLC retention time RT=13.50 min.

[0447] 1H NMR (500 MHz, DMSO-d6) δ 8.80 (d, J = 2.0 Hz, 1H), 8.54-8.48 (m, 2H), 7.85 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.75 (dd, J = 8.5, 2.0 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 5.56 (t, J = 9.0 Hz, 1H), 5.10-5.05 (m, 1H), 4.38-4.15 (m, 4H), 4.12-4.04 (m, 1H), 3.78-3.61 (m, 4H), 3.58 (s, 2H), 3.52-3.47 (m, 1H), 3.25 (s, 3H), 3.19-3.02 (m, 3H), 3.00-2.95 (m, 1H), 2.80-2.69 (m, 2H), 2.41-2.36 (m, 1H), 2.11-2.05 (m, 1H), 1.84-1.74 (m, 2H), 1.57-1.46 (m, 2H), 1.35 (d, J = 6.0 Hz, 3H), 1.07 (s, 3H), 0.94-0.91 (m, 6H), 0.88 (t, J = 7.0 Hz, 3H), 0.58-0.52 (m, 1H), 0.34 (s, 3H).

[0448] Compound 15': ESI-MS (m / z): 850.6 [M+H] + LC-MS retention time RT = 1.86 min. HPLC retention time RT = 13.14 min.

[0449] 1H NMR (500 MHz, DMSO-d6) δ 8.82 (d, J = 2.0 Hz, 1H), 8.58-8.48 (m, 2H), 7.99 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.74 (dd, J = 8.5, 2.0 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 5.55 (t, J = 9.0 Hz, 1H), 5.10-5.05 (m, 1H), 4.28-4.16 (m, 2H), 4.01-3.89 (m, 2H), 3.87-3.73 (m, 3H), 3.71-3.60 (m, 3H), 3.57-3.45 (m, 2H), 3.18-3.12 (m, 1H), 3.09 (s, 3H), 3.07-3.02 (m, 2H), 2.83-2.67 (m, 2H), 2.63-2.53 (m, 2H), 2.35-2.30 (m, 1H), 2.15-2.0 (m, 1H), 1.85-1.74 (m, 2H), 1.58-1.45 (m, 2H), 1.22 (d, J = 6.0 Hz, 3H), 1.11 (t, J = 7.0 Hz, 3H), 1.07 (s, 3H), 0.95-0.91 (m, 6H), 0.90-0.84 (m, 1H), 0.58-0.53 (m, 1H), 0.50 (s, 3H). Example 16

[0450] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-Methoxyethyl)-5-(pyridin-2-ylethynyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000117.jpg94150

[0451] Example 16 was prepared by the following steps: JPEG2025530275000118.jpg139170

[0452] Compound 16 and epimer 16' can be obtained using the same method and reaction steps as in Example 10, replacing INT-15 with INT-20. The absolute configurations of the two compounds are empirically assumed, and in the current analytical method, 16 is a compound with relatively low polarity and a relatively long retention time in LC-MS and HPLC, while 16' is a compound with relatively high polarity and a relatively short retention time in LC-MS and HPLC.

[0453] Compound 16: ESI-MS (m / z): 814.5 [M+H] + ;LC-MS retention time RT = 1.89 min. HPLC retention time RT = 14.05 min.

[0454] 1H NMR (500 MHz, DMSO-d6) δ 8.92 (dd, J = 7.5, 2.0 Hz, 1H), 8.63-8.54 (m, 1H), 8.50-8.39 (m, 2H), 7.99 (d, J = 2.0 Hz, 1H), 7.86-7.81 (m, 1H), 7.74 (s, 1H), 7.71-7.65 (m, 2H), 7.53 (d, J = 8.5 Hz, 1H), 7.42-7.37 (m, 1H), 5.49 (t, J = 9.0 Hz, 1H), 5.10-5.05 (m, 1H), 4.33-4.21 (m, 2H), 4.20-4.09 (m, 2H), 4.07-4.02 (m, 1H), 3.52 (s, 2H), 3.26-3.23 (m, 2H), 3.21 (s, 3H), 3.10-3.05 (m, 1H), 2.95-2.88 (m, 1H), 2.73-2.65 (m, 1H), 2.40-2.35 (m, 1H), 2.05-2.00 (m, 1H), 1.72 (s, 3H), 1.51-1.40 (m, 2H), 1.32 (t, J = 6.0 Hz, 3H), 1.17 (s, 2H), 1.02-0.99 (m, 3H), 0.89-0.80 (m, 6H), 0.52-0.45 (m, 1H), 0.29 (s, 3H).

[0455] Compound 16': ESI-MS (m / z): 814.5 [M+H] + ; LC-MS retention time RT = 1.86 min. HPLC retention time RT = 13.61 min.

[0456] 1H NMR (500 MHz, DMSO-d6) δ 9.00 (d, J = 2.0 Hz, 1H), 8.67-8.60 (m, 1H), 8.57-8.48 (m, 2H), 8.20 (d, J = 2.0 Hz, 1H), 7.93-7.88 (m, 1H), 7.82 (s, 1H), 7.77-7.70 (m, 2H), 7.56 (d, J = 8.5 Hz, 1H), 7.50-7.45 (m, 1H),5.55 (t, J = 9.0 Hz, 1H), 5.10-5.05 (m, 1H), 4.25-4.20 (m, 2H), 4.03-3.93 (m, 2H), 3.89-3.84 (m, 1H), 3.70-3.65 (m, 1H), 3.60-3.55 (m, 1H), 3.36-3.30 (m, 1H), 3.19-3.14 (m, 1H), 3.12 (s, 3H), 3.08-3.03 (m, 1H), 2.80-2.75 (m, 1H), 2.38-2.32 (m, 1H), 2.15-2.10 (m, 1H), 1.85-1.77 (m, 1H), 1.57-1.45 (m, 2H), 1.24 (d, J = 6.0 Hz, 3H), 1.14 (t, J = 7.0 Hz, 3H), 1.09-1.06 (m, 4H), 0.94 (s, 3H), 0.88 (d, J = 6.0 Hz, 1H), 0.60-0.56 (m, 1H), 0.53 (s, 3H). Example 17

[0457] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-Methoxyethyl)-5-(pyridin-3-ylethynyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000119.jpg98147

[0458] Example 17 was prepared by the following steps: JPEG2025530275000120.jpg135170

[0459] Compound 17 and epimer 17' can be obtained using the same method and reaction steps as in Example 10, replacing INT-15 with INT-21. The absolute configurations of the two compounds are empirically assumed, and in the current analytical method, 17 is a compound with relatively low polarity and a relatively long retention time in LC-MS and HPLC, while 17' is a compound with relatively high polarity and a relatively short retention time in LC-MS and HPLC.

[0460] Compound 17: ESI-MS (m / z): 814.5 [M+H] + ;LC-MS retention time RT = 1.91 min. HPLC retention time RT = 14.20 min.

[0461] 1H NMR (500 MHz, DMSO-d6) δ 8.97 (d, J = 2.0 Hz, 1H), 8.86-8.81 (m, 1H), 8.66-8.60 (m, 1H), 8.56-8.48 (m, 2H), 8.10-8.02 (m, 1H), 7.82 (s, 1H), 7.77 (dd, J = 8.5, 2.0 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.53-7.48 (m, 1H), 5.56 (t, J = 9.0 Hz, 1H), 5.10-5.05 (m, 1H), 4.40-4.29 (m, 2H), 4.28-4.14 (m, 2H), 4.12-4.07 (m, 1H), 3.59 (s, 2H), 3.36-3.31 (m, 1H), 3.28 (s, 3H), 3.18-3.13 (m, 1H), 3.00-2.95 (m, 1H), 2.80-2.74 (m, 1H), 2.45-2.40 (m, 1H), 2.12-2.07 (m, 1H), 1.79 (s, 2H), 1.56-1.47 (m, 2H), 1.38 (d, J = 6.0 Hz, 3H), 1.11-1.05 (m, 4H), 0.93 (s, 3H), 0.93-0.88 (m, 5H), 0.57-0.51 (m, 1H), 0.36 (s, 3H).

[0462] Compound 17': ESI-MS (m / z):814.5 [M+H] + ;LC-MS retention time RT = 1.86 min. HPLC retention time RT = 13.67 min.

[0463] 1H NMR (500 MHz, DMSO-d6) δ 8.98 (d, J = 2.0 Hz, 1H), 8.86-8.81 (m, 1H), 8.66-8.60 (m, 1H), 8.58-8.50 (m, 2H), 8.18 (d, J = 2.0 Hz, 1H), 8.08-8.04 (m, 1H), 7.82 (s, 1H), 7.75 (dd, J = 8.5, 2.0 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.53-7.47 (m, 1H), 5.55 (t, J = 9.0 Hz, 1H), 5.10-5.05 (m, 1H), 4.29-4.13 (m, 2H), 4.00-3.95 (m, 2H), 3.90-3.85 (m, 1H), 3.70-3.65 (m, 1H), 3.58-3.53 (m, 1H), 3.36-3.31 (m, 1H), 3.19-3.14 (m, 1H), 3.12 (s, 3H), 3.10-3.05 (m, 1H), 2.81-2.74 (m, 1H), 2.40-2.35 (m, 1H), 2.16-2.11 (m, 1H), 1.84-1.79 (m, 2H), 1.58-1.42 (m, 2H), 1.24 (d, J = 6.0 Hz, 3H), 1.13 (t, J = 7.0 Hz, 3H), 1.09-1.05 (m, 4H), 0.94 (s, 3H), 0.90-0.85 (m, 1H), 0.60-0.55 (m, 1H), 0.52 (s, 3H). Example 18

[0464] (1r,2R,3S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(((R)-1-methylpyrrolidin-3-yl)ethynyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazinacyclodecaphan-4-yl)-2,3-dimethylcyclopropane-1-carboxamide JPEG2025530275000121.jpg102138

[0465] Example 18 was prepared by the following steps. JPEG2025530275000122.jpg115170

[0466] Compound 18 can be obtained by replacing INT-16 with compound INT-22 in the synthesis of compound 11 and using the same method and reaction steps. 18 is a compound with relatively low polarity and relatively long LC-MS and HPLC retention times. Experience has shown that the in vitro cellular activity of compound 18 is far superior to that of its epimer 18', so the structural characterization of the epimer was not performed in the following examples.

[0467] Compound 18: ESI-MS (m / z): 834.7 [M+H] + ;LC-MS retention time RT= 1.95 min. HPLC retention time RT= 14.85 min.

[0468] 1H NMR (500 MHz, DMSO) δ 8.74 (d, J = 2.0 Hz, 1H), 8.49 (d, J = 1.0 Hz, 1H), 8.39 (d, J = 9.0 Hz, 1H), 7.81 (s, 1H), 7.77 - 7.73 (m, 2H), 7.57 (d, J = 9.0 Hz, 1H), 5.55 (t, J = 9.5 Hz, 1H), 5.08-5.04 (m, 1H), 4.35 - 4.15 (m, 5H), 4.11 - 4.02 (m, 1H), 3.57 (s, 2H), 3.24 (s, 3H), 3.17-3.11 (m, 2H), 2.98 - 2.92 (m, 1H), 2.83 (t, J = 8.0 Hz, 1H), 2.79 - 2.70 (m, 1H), 2.40 - 2.35 (m, 1H), 2.25 (s, 3H), 2.24-2.19 (m, 1H), 2.10-2.05 (m, 1H), 1.91-1.83 (m, 2H), 1.82-1.76 (m, 2H), 1.56 - 1.47 (m, 2H), 1.34 (d, J = 6.0 Hz, 3H), 1.25 - 1.22 (m, 2H), 1.18 - 1.15 (m, 2H), 1.09 - 1.05 (m, 6H), 0.91 (s, 3H), 0.87 (t, J = 7.0 Hz, 3H), 0.33 (s, 3H). Example 19

[0469] (1r,2R,3S)-N-((6 3 S,4S,Z)-1 2 -(5-((1,3-dimethylazetidin-3-yl)ethynyl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2,3-dimethylcyclopropane-1-carboxamide JPEG2025530275000123.jpg100140

[0470] Compound 19 can be obtained by replacing INT-16 with compound INT-23 in the synthesis step of compound 11 and using the same method and reaction steps. ESI-MS (m / z): 834.6 [M+H] + ;LC-MS retention time RT = 1.95 min. HPLC retention time RT = 14.62 min.

[0471] 1H NMR (500 MHz, DMSO-d6) δ 8.76 (d, J = 2.0 Hz, 1H), 8.50 (d, J = 1.5 Hz, 1H), 8.39 (d, J = 9.0 Hz, 1H), 7.82 (s, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.75 (dd, J = 8.5, 1.5 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 5.55 (t, J = 9.0 Hz, 1H), 5.10-5.01 (m, 1H), 4.35-4.16 (m, 4H), 4.11-4.02 (m, 1H), 3.57 (s, 2H), 3.30-3.28 (m, 2H), 3.25 (s, 3H), 3.22-3.19 (m, 2H), 3.18-3.11 (m, 1H), 3.00-2.93 (m, 1H), 2.79-2.72 (m, 1H), 2.41-2.35 (m, 1H), 2.24 (s, 3H), 2.11-2.05 (m, 1H), 2.03-1.95 (m, 1H), 1.83-1.74 (m, 2H), 1.56 (s, 3H), 1.54-1.43 (m, 2H), 1.35 (d, J = 6.0 Hz, 3H), 1.18-1.15 (m, 2H), 1.10-1.05 (m, 6H), 0.92 (s, 3H), 0.89-0.85 (m, 3H), 0.34 (s, 3H). Example 20

[0472] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(5-(3-((R)-2-(hydroxymethyl)morpholino)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000124.jpg91157

[0473] In the synthesis of compound 15, compound (R)-morpholine-2-methanol hydrochloride is used instead of (R)-3-methylmorpholine hydrochloride, and compound 20 can be obtained using the same method and reaction steps. ESI-MS (m / z): 866.6 [M+H] + ;LC-MS retention time RT = 1.63 min. Example 21

[0474] (1r,2R,3S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(5-(3-((R)-3-fluoropyrrolidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2,3-dimethylcyclopropane-1-carboxamide JPEG2025530275000125.jpg85170

[0475] By using compound 3-(R)-fluoropyrrolidine instead of (R)-3 methylmorpholine hydrochloride and INT-25 instead of INT-19 in the synthesis of compound 15, compound 21 can be obtained using the same method and reaction steps. ESI-MS (m / z): 852.6 [M+H] +;LC-MS retention time RT= 1.91 min.

[0476] 1 H NMR (500 MHz, DMSO-d6) δ 8.82 (d, J = 2.0 Hz, 1H), 8.51-8.49 (m, 1H), 8.39 (d, J = 9.0 Hz, 1H), 7.89-7.84 (m, 1H), 7.82 (s, 1H), 7.77-7.74 (m, 1H), 7.58 (d, J = 9.0 Hz, 1H), 5.56 (t, J = 9.1 Hz, 1H), 5.09-5.03 (m, 1H), 4.36-4.04 (m, 5H), 3.95-3.74 (m, 2H), 3.57 (s, 2H), 3.25 (s, 3H), 3.18-3.12 (m, 2H), 2.95-2.92 (m, 1H), 2.79-2.72 (m, 1H), 2.41-2.35 (m, 1H), 2.22-1.16 (m, 1H), 2.11- 2.04 (m, 1H), 1.86-1.70 (m, 3H), 1.55-1.48 (m, 1H), 1.35 (d, J = 6.0 Hz, 3H), 1.26-1.22 (m, 2H), 1.17-1.15 (m, 2H), 1.10-1.05 (m, 6H), 1.04-0.97 (m, 2H), 0.92-0.86 (m, 6H), 0.72-0.63 (m, 2H), 0.34 (s, 3H). Example 22

[0477] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-Methoxyethyl)-5-(pyrimidin-5-ylethynyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000126.jpg96137

[0478] Compound 22 can be obtained by replacing INT-15 with compound INT-24 in the synthesis step of compound 10 and using the same method and reaction steps. ESI-MS (m / z): 815.8 [M+H] + ;LC-MS retention time RT = 1.84 min. HPLC retention time RT = 13.73 min.

[0479] 1 H NMR (500 MHz, DMSO-d6) δ 9.23-9.22 (m, 1H), 9.09-9.07 (m, 2H), 8.99-8.98 (m, 1H), 8.53-8.50 (m, 2H), 8.08-8.06 (m, 1H), 7.81 (s, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.60 (d, J = 8.6 Hz, 1H), 5.56 (t, J = 9.1 Hz, 1H), 5.09-5.05 (m, 1H), 4.39-4.31 (m, 2H), 4.25-4.17 (m, 2H), 4.13-4.07 (m, 1H), 3.58 (s, 2H), 3.31-3.30 (m, 1H), 3.27 (s, 3H), 3.17-3.12 (m, 1H), 3.01-2.97 (m, 1H), 2.78-2.74 (m, 1H), 2.44-2.40 (m, 1H), 2.10-2.06 (m, 1H), 1.82-1.76 (m, 2H), 1.53-1.48 (m, 2H), 1.38 (d, J = 6.0 Hz, 3H), 1.08-1.05 (m, 4H), 0.93 (s, 3H), 0.91-0.86 (m, 4H), 0.56-0.53 (m, 1H), 0.35 (s, 3H). Example 23

[0480] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-Methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-phenylcyclopropane-1-carboxamide JPEG2025530275000127.jpg91167

[0481] Compound 23 can be obtained using the same method and reaction steps by using compound (1S,2S)-2-phenylcyclopropylcarboxylic acid instead of INT-3b in the synthesis step of compound 1. ESI-MS (m / z): 898.7 [M+H] + ;LC-MS retention time RT = 1.92 min. HPLC retention time RT = 14.35 min.

[0482] 1H NMR (500 MHz, DMSO-d6) δ 8.81 (d, J = 2.0 Hz, 1H), 8.70 (d, J = 9.0 Hz, 1H), 8.53-8.49 (m, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.83 (s, 1H), 7.78-7.75 (m, 1H), 7.61-7.57 (m, 1H), 7.33-7.28 (m, 2H), 7.22-7.17 (m, 1H), 7.16-7.12 (m, 2H), 5.61 (t, J = 9.0 Hz, 1H), 5.15-5.09 (m, 1H), 4.37-4.17 (m, 4H), 4.12-4.05 (m, 1H), 3.63-3.57 (m, 8H), 3.37-3.34 (m, 1H), 3.26 (s, 3H), 3.13-3.08 (m, 1H), 3.00-2.95 (m, 1H), 2.80-2.73 (m, 1H), 2.56-2.52 (m, 4H), 2.41-2.36 (m, 1H), 2.22-2.16 (m, 1H), 2.12-2.06 (m, 2H), 1.82-1.76 (m, 2H), 1.56-1.50 (m, 1H), 1.39-1.34 (m, 3H), 1.29-1.23 (m, 2H), 0.92 (s, 3H), 0.88 (t, J = 7.0 Hz, 3H), 0.34 (s, 3H). Example 24

[0483] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-Methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-fluorocyclopropane-1-carboxamide JPEG2025530275000128.jpg91144

[0484] Compound 24 can be obtained using the same method and reaction steps by using compound (1S,2S)-2-fluorocyclopropanecarboxylic acid instead of INT-3b in the synthesis step of compound 1. ESI-MS (m / z): 840.7 [M+H] + ;LC-MS retention time RT = 1.69 min. HPLC retention time RT = 12.20 min.

[0485] 1 H NMR (500 MHz, DMSO-d6) δ 8.83-8.80 (m, 1H), 8.67-8.62 (m, 1H), 8.52-8.47 (m, 1H), 7.88-7.85 (m, 1H), 7.83 (s, 1H), 7.78-7.74 (m, 1H), 7.61-7.55 (m, 1H), 5.57 (t, J = 9.0 Hz, 1H), 5.14-5.07 (m, 1H), 4.96-4.76 (m, 1H), 4.36-4.18 (m, 4H), 4.12-4.04 (m, 1H), 3.64-3.55 (m, 8H), 3.26 (s, 3H), 3.20-3.13 (m, 1H), 3.02-2.93 (m, 1H), 2.81-2.73 (m, 1H), 2.57-2.53 (m, 4H), 2.40-2.35 (m, 1H), 2.12-2.06 (m, 1H), 1.96-1.89 (m, 1H), 1.84-1.75 (m, 2H), 1.55-1.44 (m, 3H), 1.35 (d, J = 6.0 Hz, 3H), 1.07-1.02 (m, 1H), 0.92 (s, 3H), 0.87 (t, J = 7.0 Hz, 3H), 0.34 (s, 3H). Example 25

[0486] (1r,2R,3S)-N-((63S,4S,Z)-1 1 -ethyl-1 2 -(5-(3-((S)-3-(hydroxymethyl)morpholino)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2,3-dimethylcyclopropane-1-carboxamide JPEG2025530275000129.jpg91154

[0487] In the synthesis step of compound 15, compound (S)-3-hydroxymethylmorpholine was used instead of (R)-3-methylmorpholine hydrochloride, and INT-25 was used instead of INT-19, to obtain compound 25. ESI-MS (m / z): 880.6 [M+H] + ;LC-MS retention time RT= 1.68 min.

[0488] 1H NMR (500 MHz, DMSO-d6) δ 8.81 (d, J = 2.0 Hz, 1H), 8.51-8.48 (m, 1H), 8.39 (d, J = 8.5 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.77-7.73 (m, 1H), 7.58 (d, J = 8.5 Hz, 1H), 5.55 (t, J = 9.0 Hz, 1H), 5.10-5.02 (m, 1H), 4.60 (t, J = 5.5 Hz, 1H), 4.38-4.04 (m, 5H), 3.83-3.78 (m, 2H), 3.76-3.71 (m, 2H), 3.62-3.56 (m, 3H), 3.25 (s, 3H), 3.17-3.11 (m, 2H), 2.99-2.93 (m, 1H), 2.79-2.68 (m, 2H), 2.64-2.59 (m, 2H), 2.42-2.35 (m, 1H), 2.11-2.04 (m, 1H), 1.83-1.75 (m, 2H), 1.58-1.44 (m, 2H), 1.36 (d, J = 6.0 Hz, 3H), 1.25-1.15 (m, 5H), 1.11-1.04 (m, 6H), 0.94-0.87 (m, 6H), 0.39-0.31 (s, 3H).

[0489] Example 26 N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-Methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-yl)cycloundecaphan-4-yl-1-(trifluoromethyl)cyclopropane-1-carboxamide JPEG2025530275000130.jpg91159

[0490] Compound 26 can be obtained using the same method and reaction steps by using compound 1-trifluoromethylcyclopropane-1-carboxylic acid instead of INT-3b in the synthesis step of compound 1. ESI-MS (m / z): 890.6 [M+H] + ;LC-MS retention time RT = 1.71 min. HPLC retention time RT=14.19 min.

[0491] 1 H NMR (500 MHz, DMSO-d6) δ 8.81 (d, J = 2.0 Hz, 1H), 8.50 (d, J = 1.5 Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.83 (s, 1H), 7.76 (dd, J = 8.5, 1.5 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 5.58-5.48 (m, 1H), 5.15-5.09 (m, 1H), 4.39-4.26 (m, 2H), 4.25-4.16 (m, 2H), 4.15-4.04 (m, 1H), 3.64-3.59 (m, 4H), 3.59-3.54 (m, 4H), 3.45-3.39 (m, 1H), 3.30-3.28 (m, 1H), 3.26 (s, 3H), 3.01-2.91 (m, 1H), 2.80-2.73 (m, 1H), 2.57-2.52 (m, 4H), 2.41-2.34 (m, 1H), 2.14-2.05 (m, 1H), 1.86-1.73 (m, 2H), 1.57-1.43 (m, 2H), 1.39-1.30 (m, 6H), 0.93 (s, 3H), 0.87 (t, J = 7.0 Hz, 3H), 0.34 (s, 3H). Example 27

[0492] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-Methoxyethyl)-5-(pyrazin-2-ylethynyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000131.jpg100142

[0493] Compound 27 can be obtained using the same method and reaction steps by using compound INT-26 instead of compound INT-15 in the synthesis step of compound 10. ESI-MS (m / z): 815.7 [M+H] + ;LC-MS retention time RT = 1.86 min. HPLC retention time RT= 13.80 min.

[0494] 1H NMR (500 MHz, DMSO-d6) δ 9.03 (d, J = 2.0 Hz, 1H), 8.96 (d, J = 1.5 Hz, 1H), 8.74-8.73 (m, 1H), 8.69 (d, J = 2.0 Hz, 1H), 8.53-8.50 (m, 2H), 8.12 (d, J = 2.0 Hz, 1H), 7.82 (s, 1H), 7.77 (dd, J = 8.5, 1.5 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 5.56 (t, J = 9.0 Hz, 1H), 5.09-5.05 (m, 1H), 4.39-4.30 (m, 2H), 4.26-4.13 (m, 2H), 4.13-4.06 (m, 1H), 3.59 (s, 2H), 3.32-3.29 (m, 1H), 3.28 (s, 3H), 3.17-3.12 (m, 1H), 3.00-2.98 (m, 1H), 2.79-2.73 (m, 1H), 2.46-2.43 (m, 1H), 2.10-2.07 (m, 1H), 1.82-1.75 (m, 2H), 1.54-1.48 (m, 2H), 1.39 (d, J = 6.0 Hz, 3H), 1.28 -1.24 (m, 1H), 1.07-1.06 (m, 4H), 0.93 (s, 3H), 0.90 (t, J = 7.0 Hz, 3H), 0.57-0.54 (m, 1H), 0.36 (s, 3H). Example 28

[0495] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-Methoxyethyl)-5-(((R)-4-methylmorpholin-3-yl)ethynyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000132.jpg98148

[0496] Example 28 was prepared by the following steps: JPEG2025530275000133.jpg88170

[0497] Compound 28 can be obtained using the same method and reaction steps by using compound INT-8d instead of INT-15 in the synthesis step of compound 10. ESI-MS (m / z): 836.7 [M+H] + ;LC-MS retention time RT= 1.81 min. HPLC retention time RT= 13.37 min.

[0498] 1H NMR (500 MHz, DMSO) δ 8.81 (d, J = 2.0 Hz, 1H), 8.54-8.49 (m, 2H), 7.86-7.83 (m, 1H), 7.81 (s, 1H), 7.77-7.74 (m, 1H), 7.58 (d, J = 8.5 Hz, 1H), 5.56 (t, J = 9.5 Hz, 1H), 5.09-5.05 (m, 1H), 4.36-4.27 (m, 2H), 4.26-4.22 (m, 1H), 4.22-4.16 (m, 1H), 4.11-4.03 (m, 1H), 3.79-3.74 (m, 1H), 3.72-3.63 (m, 2H), 3.62-3.59 (m, 1H), 3.58 (s, 2H), 3.53-3.49 (m, 1H), 3.25 (s, 3H), 3.20-3.11 (m, 2H), 3.00-2.94 (m, 1H), 2.79-2.73 (m, 1H), 2.68-2.63 (m, 1H), 2.41-2.36 (m, 1H), 2.34 (s, 3H), 2.33-2.27 (m, 1H), 2.11 - 2.05 (m, 1H), 1.83-1.75 (m, 2H), 1.53-1.47 (m, 2H), 1.36 (d, J = 6.0 Hz, 3H), 1.10-1.05 (m, 4H), 0.92 (s, 3H), 0.90-0.83 (m, 4H), 0.57-0.52 (m, 1H), 0.35 (s, 3H). Example 29

[0499] (1S,2S)-N-((63S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-Methoxyethyl)-5-((1-methylpiperidin-4-yl)ethynyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000134.jpg104147

[0500] Compound 29 can be obtained by replacing INT-15 with compound INT-27 in the synthesis step of compound 10 and using the same method and reaction steps. ESI-MS (m / z): 834.8 [M+H] + ;LC-MS retention time RT= 1.90 min. HPLC retention time RT=14.59 min.

[0501] 1 H NMR (500 MHz, DMSO) δ 8.75 (d, J = 2.0 Hz, 1H), 8.53-8.48 (m, 2H), 7.80 (s, 1H), 7.76-7.73 (m, 2H), 7.57 (d, J = 8.5 Hz, 1H), 5.56 (t, J = 9.0 Hz, 1H), 5.09-5.05 (m, 1H), 4.36-4.29 (m, 1H), 4.27-4.16 (m, 4H), 4.11-4.02 (m, 1H), 3.57 (s, 2H), 3.24 (s, 3H), 3.17-3.11 (m, 2H), 2.99-2.93 (m, 1H), 2.79-2.74 (m, 1H), 2.64-2.61 (m, 2H), 2.39-2.35 (m, 1H), 2.15 (s, 3H), 2.10-2.03 (m, 2H), 1.90-1.85 (m, 3H), 1.82-1.78 (m, 2H), 1.67-1.62 (m, 2H), 1.51-1.47 (m, 2H), 1.34 (d, J = 6.0 Hz, 3H), 1.24-1.22 (m, 1H), 1.09-1.04 (m, 4H), 0.91 (s, 3H), 0.87 (t, J = 7.0 Hz, 3H), 0.56-0.53 (m, 1H), 0.33 (s, 3H). Example 30

[0502] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-Methoxyethyl)-5-((2-methylisoindolin-4-yl)ethynyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000135.jpg102162

[0503] Compound 30 can be obtained by replacing INT-15 with compound INT-28 in the synthesis step of compound 10 and using the same method and reaction steps. ESI-MS (m / z): 868.7 [M+H] + ;LC-MS retention time RT = 2.08 min.

[0504] 1H NMR (500 MHz, DMSO-d6) δ 8.98-8.91 (m, 1H), 8.55-8.48 (m, 2H), 8.00 (d, J = 2.0 Hz, 1H), 7.85-7.80 (m, 1H), 7.79-7.74 (m, 1H), 7.64-7.57 (m, 1H), 7.44-7.38 (m, 1H), 7.34-7.24 (m, 2H), 5.56 (t, J = 9.0 Hz, 1H), 5.12-5.03 (m, 1H), 4.40-4.08 (m, 5H), 4.06-3.99 (m, 2H), 3.92-3.83 (m, 1H), 3.59 (s, 2H), 3.29-3.27 (m, 4H), 3.17-3.12 (m, 2H), 3.01-2.97 (m, 1H), 2.80-2.74 (m, 1H), 2.45-2.41 (m, 1H), 2.12-2.05 (m, 1H), 1.83-1.74 (m, 2H), 1.55-1.46 (m, 2H), 1.40-1.36 (m, 3H), 1.25- 1.22 (m, 1H), 1.20-1.15 (m, 2H), 1.10-1.03 (m, 4H), 0.95-0.85 (m, 7H), 0.58-0.52 (m, 1H), 0.36 (s, 3H). Example 31

[0505] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(5-((6-(ethylamino)pyridin-2-yl)ethynyl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000136.jpg118163

[0506] By replacing INT-15 with INT-29 in the synthesis steps of Example 10 and using the same method and reaction steps, compound 31 can be obtained. ESI-MS (m / z): 857.7 [M+H] + ;LC-MS retention time RT= 1.98 min. HPLC retention time RT= 15.11 min.

[0507] 1H NMR (500 MHz, DMSO) δ 8.93 (d, J = 2.0 Hz, 1H), 8.53 - 8.50 (m, 2H), 7.99 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.78 - 7.74 (m, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.43 - 7.38 (m, 1H), 6.82 (d, J = 6.5 Hz, 1H), 6.74 - 6.69 (m, 1H), 6.52 - 6.49 (m, 1H), 5.56 (t, J = 9.5 Hz, 1H), 5.09-5.05 (m, 1H), 4.38 - 4.32 (m, 1H), 4.31 - 4.27 (m, 1H), 4.27-4.21 (m, 2H), 4.20 - 4.16 (m, 1H), 4.14 - 4.07 (m, 1H), 3.58 (s, 2H), 3.27 (s, 3H), 3.25-3.22 (m, 2H), 3.18-3.14 (m, 1H), 3.01 - 2.95 (m, 1H), 2.80 - 2.73 (m, 1H), 2.46 - 2.41 (m, 1H), 2.12-2.05 (m, 1H), 1.82-1.77 (m, 2H), 1.55 - 1.47 (m, 2H), 1.38 (d, J = 6.0 Hz, 3H), 1.25 - 1.22 (m, 1H), 1.13 (t, J = 7.0 Hz, 3H), 1.08 - 1.05 (m, 4H), 0.93 (s, 3H), 0.90 (t, J = 7.0 Hz, 3H), 0.57 - 0.52 (m, 1H), 0.36 (s, 3H). Example 32

[0508] (1r,2R,3S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(5-((6-(ethylamino)pyridazin-3-yl)ethynyl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2,3-dimethylcyclopropane-1-carboxamide JPEG2025530275000137.jpg100170

[0509] Compound 32 and 32' can be obtained by using the same method and reaction steps as compound 11, replacing compound INT-16. Neither thin-layer chromatography nor conventional preparative liquid chromatography can separate compound 32 and its epimer 32', so this compound exhibits cellular activity as a racemate. ESI-MS (m / z): 872.6 [M+H] + ;LC-MS retention time RT = 1.81 min. HPLC retention time RT= 11.92 min. Example 33

[0510] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(5-(((R)-4-(2-hydroxyethyl)morpholin-3-yl)ethynyl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000138.jpg106170

[0511] Example 33 was prepared by the following steps: JPEG2025530275000139.jpg42170

[0512] Step 1: Compound 28c (40 mg, 0.05 mmol) was dissolved in N,N-dimethylformamide (1 mL), followed by the addition of potassium carbonate (21 mg, 0.15 mmol), potassium iodide (25 mg, 0.15 mmol), and (2-bromoethoxy)-tert-butyldimethylsilane (24 mg, 0.10 mmol). The reaction mixture was stirred at 50 °C for 8 h. After LCMS showed the reaction was complete, water (10 mL) was added to the mixture, followed by extraction with dichloromethane (10 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 33a (22 mg, 43% yield). ESI-MS (m / z): 980.7 [M+H] + ;

[0513] Step 2: Compound 33a (22 mg, 0.02 mmol) was dissolved in tetrahydrofuran (1 mL), followed by the addition of tetrabutylammonium fluoride (0.1 mL, 1 M in THF). The reaction solution was stirred at room temperature for 2 hours. After LCMS showed the reaction was complete, saturated aqueous ammonium chloride (10 mL) was added to the reaction mixture, followed by extraction with dichloromethane (10 mL*2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative liquid chromatography to give compound 33 (1.0 mg, 7% yield) as a white solid. ESI-MS (m / z): 866.8 [M+H] + ;LC-MS retention time RT = 1.64 min. HPLC retention time RT = 11.64 min.

[0514] 1H NMR (500 MHz, DMSO) δ 8.82 (d, J = 2.0 Hz, 1H), 8.55-8.51 (m, 2H), 7.97 (s, 1H), 7.81 (s, 1H), 7.76-7.72 (m, 1H), 7.54 (d, J = 8.5 Hz, 1H), 5.57-5.52 (m, 1H), 5.07-5.03 (m, 1H), 4.49-4.43 (m, 1H), 4.26-4.19 m, 2H), 3.98-3.92 (m, 2H), 3.86-3.82 (m, 1H), 3.79-3.75 (m, 2H), 3.73-3.69 (m, 1H), 3.68-3.64 (m, 1H), 3.56-3.52 (m, 2H), 3.18-3.14 (m, 3H), 3.09 (s, 2H), 3.06-3.01 (m, 1H), 2.65-2.63 (m, 1H), 2.59-2.55 (m, 1H), 2.38-2.36 (m, 1H), 2.34-2.29 (m, 1H), 2.14-2.09 (m, 1H), 1.82-1.78 (m, 2H), 1.58-1.54 (m, 3H), 1.34-1.28 (m, 4H), 1.22 (d, J = 6.0 Hz, 2H), 1.11 (t, J = 7.0 Hz, 3H), 1.07 (s, 3H), 0.96-0.91 (m, 5H), 0.88-0.86 (m, 1H), 0.57-0.54 (m, 1H), 0.50 (s, 3H). Example 34

[0515] (1r,2R,3S)-N-((6 3 S,4S,Z)-1 2 -(5-((4-aminopyrimidin-5-yl)ethynyl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2,3-dimethylcyclopropane-1-carboxamide JPEG2025530275000140.jpg99149

[0516] By using compound INT-31 instead of compound INT-16 in the synthesis step of compound 11, compound 34 can be obtained using the same method and reaction steps. ESI-MS (m / z): 844.7 [M+H] + ;LC-MS retention time RT = 1.70 min.

[0517] 1 H NMR (500 MHz, DMSO-d6) δ 8.97-8.94 (m, 1H), 8.53-8.47 (m, 1H), 8.42-8.39 (m, 2H), 8.39-8.37 (m, 1H), 8.20-8.18 (m, 1H), 7.83 (s, 1H), 7.78-7.75 (m, 1H), 7.62-7.58 (m, 1H), 7.23-7.19 (m, 2H), 5.55 (t, J = 9.0 Hz, 1H), 5.10-5.00 (m, 1H), 4.39-4.07 (m, 5H), 3.58 (s, 2H), 3.3-3.30 (m, 1H), 3.27 (s, 3H), 3.18-3.11 (m, 1H), 3.04-2.96 (m, 1H), 2.80-2.71 (m, 1H), 2.47-2.41 (m, 1H), 2.12-2.04 (m, 1H), 1.83-1.73 (m, 2H), 1.55-1.48 (m, 1H), 1.38 (d, J = 6.0 Hz, 3H), 1.21-1.14 (m, 3H), 1.11-1.05 (m, 6H), 0.96-0.86 (m, 6H), 0.36 (s, 3H). Example 35

[0518] (1S,2S)-N-((6 3 S,4S,Z)-12 -(5-((5-aminopyrazin-2-yl)ethynyl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000141.jpg109141

[0519] Compound 35 can be obtained using the same method and reaction steps by using compound INT-32 instead of compound INT-15 in the synthesis step of compound 10. ESI-MS (m / z): 830.7 [M+H] + ;LC-MS retention time RT=1.70 min. Example 36

[0520] (1r,2R,3S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-Methoxyethyl)-5-(3-(methyl(tetrahydro-2H-pyran-4-yl)amino)prop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2,3-dimethylcyclopropane-1-carboxamide JPEG2025530275000142.jpg95170

[0521] Example 36 was prepared by the following steps: JPEG2025530275000143.jpg120170

[0522] Step 1: Compound INT-33 (90 mg, 0.10 mmol) was dissolved in dichloromethane (5 mL), and N-methyltetrahydro-2H-pyran-4-amine (55 mg, 0.48 mmol) and diisopropylethylamine (62 mg, 0.48 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL × 2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 20 / 1) to give compound 36a (60 mg, 71% yield). ESI-MS (m / z): 882.7 [M+H] + ;

[0523] Step 2: Compound 36a (50 mg, 0.06 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) was added. The reaction mixture was stirred at 0 °C for 1 hour. LCMS showed that the reaction was complete. Saturated sodium bicarbonate solution (10 mL) was added to the reaction mixture in an ice bath, and the mixture was extracted with dichloromethane (20 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound 36b (37 mg, 83% yield). ESI-MS (m / z): 782.8 [M+H] + ;

[0524] Step 3: Compound 36b (37 mg, 0.05 mmol) was dissolved in acetonitrile (2 mL), and INT-4a (5 mg, 0.05 mmol), N,N-diisopropylethylamine (30 mg, 0.24 mmol), methylimidazole (6 mg, 0.07 mmol), and (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (19 mg, 0.07 mmol) were added. The reaction mixture was stirred in an ice bath for 1 h. After completion of the reaction, water (20 mL) was added to the reaction mixture, followed by extraction with dichloromethane (20 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative liquid chromatography to give compound 36 (3.0 mg, 7% yield) as a white solid. ESI-MS (m / z): 878.6 [M+H] + ;LC-MS retention time RT= 1.85 min. HPLC retention time RT= 13.67 min.

[0525] 1H NMR (500 MHz, DMSO-d6) δ 8.80 (d, J = 2.0 Hz, 1H), 8.52-8.48 (m, 1H), 8.39 (d, J = 9.0 Hz, 1H), 7.85-7.80 (m, 2H), 7.77-7.73 (m, 1H), 7.58 (d, J = 8.5 Hz, 1H), 5.56 (t, J = 9.0 Hz, 1H), 5.10-5.04 (m, 1H), 4.39-4.02 (m, 5H), 3.91-3.84 (m, 2H), 3.70-3.65 (m, 2H), 3.58 (s, 2H), 3.30-3.29 (m, 2H), 3.25 (s, 3H), 3.18-3.11 (m, 2H), 2.98-2.91 (m, 1H), 2.79-2.71 (m, 1H), 2.42-2.35 (m, 2H), 2.32 (s, 3H), 2.14-2.02 (m, 2H), 1.82-1.74 (m, 4H), 1.55-1.46 (m, 1H), 1.43-1.32 (m, 5H), 1.18-1.14 (m, 2H), 1.10-1.04 (m, 6H), 0.93-0.84 (m, 6H), 0.35 (s, 3H). Example 37

[0526] (1r,2R,3S)-N-((6 3 S,4S,Z)-12-(5-(3-((S)-3-(ethoxymethyl)morpholino)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2,3-dimethylcyclopropane-1-carboxamide JPEG2025530275000144.jpg91155

[0527] Example 37 was prepared by the following steps: JPEG2025530275000145.jpg82170

[0528] Step 1: INT-2 (350 mg, 0.51 mmol), INT-34 (186 mg, 0.51 mmol), 1,1-bis(diphenylphosphine)diphenyliron dichloride palladium (37 mg, 0.05 mmol), and potassium phosphate (214 mg, 1.08 mmol) were dissolved in a mixture of 1,4-dioxane (5 mL) and water (1 mL). The reaction mixture was stirred overnight at 70 °C under a nitrogen atmosphere. After completion of the reaction was confirmed by LCMS, the reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated, and the residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 20 / 1) to give 37a (400 mg, 93% yield) as a brown solid. ESI-MS (m / z): 856.7 [M+H] + ;

[0529] Step 2: Compound 37a (300 mg, 0.35 mmol), cesium carbonate (228 mg, 0.70 mmol), and ethyl iodide (109 mg, 0.70 mmol) were dissolved in N,N-dimethylformamide (10 mL), and the reaction solution was stirred at room temperature overnight. LCMS detection indicated the reaction was complete. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL × 2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 30 / 1) to give 37b (280 mg, 88% yield). ESI-MS (m / z): 913.0 [M+H] + ;

[0530] Step 3: Compound 37b (280 mg, 0.31 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (5 mL) was added. The reaction mixture was stirred at 0 °C for 1 hour. LCMS showed that the reaction was complete. Saturated sodium bicarbonate solution (30 mL) was added to the reaction mixture in an ice bath, and the mixture was extracted with dichloromethane (20 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound 37c (220 mg, 88% yield). ESI-MS (m / z): 813.0 [M+H] + ;

[0531] Step 3: Compound 37c (40 mg, 0.05 mmol) was dissolved in acetonitrile (2 mL), and INT-4a (5 mg, 0.05 mmol), N,N-diisopropylethylamine (30 mg, 0.24 mmol), methylimidazole (6 mg, 0.07 mmol), and (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (19 mg, 0.07 mmol) were added. The reaction mixture was stirred in an ice bath for 1 h. After completion of the reaction, water (20 mL) was added to the reaction mixture, followed by extraction with dichloromethane (20 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative liquid chromatography to give compound 37 (7.0 mg, 15% yield) as a white solid. ESI-MS (m / z): 909.1 [M+H] + ;LC-MS retention time RT = 1.94 min. HPLC retention time RT = 14.41 min.

[0532] 1H NMR (500 MHz, DMSO-d6) δ 8.80 (d, J = 2.0 Hz, 1H), 8.51-8.48 (m, 1H), 8.39 (d, J = 9.0 Hz, 1H), 7.87-7.80 (m, 2H), 7.77-7.73 (m, 1H), 7.58 (d, J = 8.5 Hz, 1H), 5.56 (t, J = 9.0 Hz, 1H), 5.10-5.03 (m, 1H), 4.40-4.02 (m, 5H), 3.85-3.78 (m, 1H), 3.77-3.67 (m, 3H), 3.59-3.51 (m, 3H), 3.23-3.19 (m, 3H), 3.18-3.11 (m, 2H), 2.98-2.92 (m, 1H), 2.79-2.56 (m, 5H), 2.41-2.35 (m, 1H), 2.11-1.97 (m, 2H), 1.82-1.74 (m, 2H), 1.57-1.42 (m, 1H), 1.36 (d, J = 6.0 Hz, 3H), 1.26-1.22 (m, 3H), 1.18-1.15 (m, 2H), 1.10-1.05 (m, 9H), 0.93-0.83 (m, 6H), 0.35 (s, 3H). Example 38

[0533] (1r,2R,3S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(5-(3-((R)-3-(hydroxymethyl)morpholino)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2,3-dimethylcyclopropane-1-carboxamide JPEG2025530275000146.jpg90170

[0534] Substituting (R)-3-hydroxymethylmorpholine for N-methyltetrahydro-2H-pyran-4-amine in Example 36, compound 38 can be obtained using similar methods and reaction steps. ESI-MS (m / z): 881.1 [M+H] + ;LC-MS retention time RT = 1.67 min.

[0535] 1 H NMR (500 MHz, DMSO-d6) δ 8.81 (d, J = 2.0 Hz, 1H), 8.51-8.49 (m, 1H), 8.39 (d, J = 9.0 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.82 (s, 1H), 7.77-7.73 (m, 1H), 7.58 (d, J = 8.5 Hz, 1H), 5.56 (t, J = 9.0 Hz, 1H), 5.09-5.03 (m, 1H), 4.59 (t, J = 5.5 Hz, 1H), 4.38-4.03 (m, 5H), 3.87-3.66 (m, 4H), 3.63-3.55 (m, 3H), 3.51-3.43 (m, 1H), 3.31-3.28 (m, 2H), 3.25 (s, 3H), 3.22-3.07 (m, 2H), 2.99-2.93 (m, 1H), 2.78-2.68 (m, 2H), 2.64-2.57 (m, 1H), 2.56-2.52 (m, 1H), 2.42-2.35 (m, 1H), 2.11 - 2.04 (m, 1H), 1.83-1.74 (m, 2H), 1.57-1.46 (m, 1H), 1.36 (d, J = 6.0 Hz, 3H), 1.24-1.15 (m, 4H), 1.10-1.04 (m, 6H), 0.95-0.85 (m, 6H), 0.35 (s, 3H). Example 40

[0536] (1r,2R,3S)-N-((63 S,4S,Z)-1 1 -ethyl-1 2 -(5-(3-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2,3-dimethylcyclopropane-1-carboxamide JPEG2025530275000147.jpg94170

[0537] Compound 40 can be obtained by replacing INT-16 with INT-35 in Example 11 and using the same method and reaction steps. ESI-MS (m / z): 906.3 [M+H] + ;LC-MS retention time RT = 1.74 min. HPLC retention time RT = 12.56 min.

[0538] 1H NMR (500 MHz, DMSO-d6) δ 8.81 (d, J = 2.0 Hz, 1H), 8.51-8.48 (m, 1H), 8.41 (d, J = 9.0 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.83 (s, 1H), 7.77-7.73 (m, 1H), 7.59 (d, J = 8.5 Hz, 1H), 5.55 (t, J = 9.0 Hz, 1H), 5.11-5.04 (m, 1H), 4.39-3.97 (m, 5H), 3.75-3.68 (m, 1H), 3.75-3.68 (m, 1H), 3.58-3.54 (m, 4H), 3.50-3.43 (m, 1H), 3.31-3.29 (m, 1H), 3.25 (s, 3H), 3.22-3.04 (m, 2H), 2.99-2.93 (m, 1H), 2.83-2.56 (m, 6H), 2.43-2.33 (m, 2H), 2.23-2.04 (m, 4H), 1.96-1.90 (m, 1H), 1.84-1.74 (m, 2H), 1.53-1.47 (m, 1H), 1.35 (d, J = 6.0 Hz, 3H), 1.19-1.12 (m, 2H), 1.11-1.05 (m, 6H), 0.91 (s, 3H), 0.88 (t, J = 7.0 Hz, 3H), 0.34 (s, 3H). Example 41

[0539] (1r,2R,3S)-N-((6 3 S,4S,Z)-1 2 -(5-(3-(4-acetylpiperazin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2,3-dimethylcyclopropane-1-carboxamide JPEG2025530275000148.jpg86170

[0540] By using compound INT-36 instead of INT-16 in the synthesis step of compound 11, compound 41 can be obtained using the same method and reaction steps. ESI-MS (m / z): 891.3 [M+H] + ;LC-MS retention time RT=1.68 min. HPLC retention time RT=12.18 min.

[0541] 1 H NMR (500 MHz, DMSO-d6) δ 8.81 (d, J = 2.0 Hz, 1H), 8.50 (d, J = 1.5 Hz, 1H), 8.41 (d, J = 9.0 Hz, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.82 (s, 1H), 7.75 (dd, J = 8.5, 1.5 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 5.55 (t, J = 9.0 Hz, 1H), 5.12-5.03 (m, 1H), 4.38-4.03 (m, 5H), 3.65-3.55 (m, 4H), 3.51-3.42 (m, 4H), 3.33-3.29 (m, 2H), 3.25 (s, 3H), 3.18-3.11 (m, 1H), 2.99-2.91 (m, 1H), 2.80-2.70 (m, 1H), 2.58-2.53 (m, 2H), 2.49-2.46 (m, 2H), 2.42-2.34 (m, 1H), 2.11-2.04 (m, 1H), 1.99 (s, 3H), 1.84-1.71 (m, 2H), 1.56-1.46 (m, 1H), 1.35 (d, J = 6.0 Hz, 3H), 1.19-1.14 (m, 2H), 1.10-1.04 (m, 6H), 0.93-0.83 (m, 6H), 0.34 (s, 3H). Example 42

[0542] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(5-((2-(ethylaminopyrimidin-5-yl)ethynyl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000149.jpg119139

[0543] Using the same method and reaction steps, compound 42 can be obtained by using INT-37 instead of INT-15 in Example 10. ESI-MS (m / z): 859.5 [M+H] + ;LC-MS retention time RT= 1.93 min. HPLC retention time RT = 14.59 min.

[0544] 1H NMR (500 MHz, DMSO) δ 8.87 (d, J = 2.0 Hz, 1H), 8.56-8.46 (m, 4H), 7.91 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.79-7.74 (m, 2H), 7.59 (d, J = 8.5 Hz, 1H), 5.56 (t, J = 9.5 Hz, 1H), 5.10 - 5.05 (m, 1H), 4.38-4.05 (m, 6H), 3.58 (s, 2H), 3.26 (s, 3H), 3.17-3.10 (m, 2H), 3.00-2.95 (m, 1H), 2.80-2.71 (m, 1H), 2.44-2.38 (m, 1H), 2.11-2.06 (m, 1H), 1.84-1.73 (m, 2H), 1.54-1.47 (m, 2H), 1.37 (d, J = 6.0 Hz, 3H), 1.25-1.22 (m, 1H), 1.12 (t, J = 7.0 Hz, 3H), 1.09-1.03 (m, 4H), 0.93 (s, 3H), 0.88 (t, J = 7.0 Hz, 3H), 0.86-0.84 (m, 1H), 0.57-0.52 (m, 1H), 0.35 (s, 3H). Example 43

[0545] (1S,2S)-N-((6 3 S,4S,Z)-1 2 -(5-(3-(1,1-dioxidethiomorpholino)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000150.jpg89169

[0546] Using INT-38 instead of INT-15 in Example 10, compound 43 can be obtained using the same method and reaction steps. ESI-MS (m / z): 884.8 [M+H] + ;LC-MS retention time RT = 1.70 min. HPLC retention time RT =12.44 min.

[0547] 1 H NMR (500 MHz, DMSO-d6) δ 8.81 (d, J = 2.0 Hz, 1H), 8.53-8.48 (m, 2H), 7.86 (d, J = 2.0 Hz, 1H), 7.80 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 5.56 (t, J = 9.0 Hz, 1H), 5.09-5.05 (m, 1H), 4.34-4.32 (m, 1H), 4.29-4.25 (m, 2H), 4.21-4.15 (m, 2H), 4.09-4.06 (m, 1H), 3.77-3.75 (m, 2H), 3.58-3.57 (m, 2H), 3.31-3.30 (m, 2H), 3.25 (s, 3H), 3.18-3.14 (m, 5H), 3.06-3.03 (m, 3H), 2.98-2.94 (m, 1H), 2.79-2.74 (m, 1H), 2.41-2.36 (m, 1H), 2.10-2.06 (m, 1H), 1.82-1.77 (m, 2H), 1.52-1.47 (m, 2H), 1.35 (d, J = 6.0 Hz, 3H), 1.08-1.05 (m, 4H), 0.91 (s, 3H), 0.90-0.86 (m, 4H), 0.57-0.53 (m, 1H), 0.34 (s, 3H). Example 44

[0548] (1S,2S)-N-((6 3 S,4S,Z)-1 1-ethyl-1 2 -(2-((S)-1-Methoxyethyl)-5-((6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)ethynyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000151.jpg109168

[0549] Using the same method and reaction steps, compound 44 can be obtained by using INT-39 instead of INT-15 in Example 10. ESI-MS (m / z): 883.7 [M+H] + ;LC-MS retention time RT = 1.75 min. HPLC retention time RT = 12.64 min.

[0550] 1H NMR (500 MHz, DMSO-d6) δ 9.02 (d, J = 2.0 Hz, 1H), 8.58 (s, 1H), 8.56-8.51 (m, 2H), 8.09 (d, J = 2.0 Hz, 1H), 7.82 (s, 1H), 7.79-7.75 (m, 1H), 7.60 (d, J = 8.5 Hz, 1H), 5.56 (t, J = 9.0 Hz, 1H), 5.12-5.06 (m, 1H), 4.39-4.29 (m, 2H), 4.27-4.17 (m, 2H), 4.14-4.07 (m, 1H), 3.60-3.54 (m, 4H), 3.28 (s, 3H), 3.17-3.11 (m, 1H), 3.01-2.96 (m, 1H), 2.93-2.89 (m, 2H), 2.78-2.71 (m, 3H), 2.46-2.42 (m, 1H), 2.38 (s, 3H), 2.12-2.05 (m, 1H), 1.83-1.76 (m, 2H), 1.54-1.47 (m, 2H), 1.38 (d, J = 6.0 Hz, 3H), 1.09-1.05 (m, 4H), 0.93 (s, 3H), 0.92-0.84 (m, 5H), 0.58-0.52 (m, 1H), 0.35 (s, 3H). Example 45

[0551] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-Methoxyethyl)-5-(((S)-4-methyl-1,1-dioxidethiomorpholin-2-yl)ethynyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000152.jpg104143

[0552] By replacing INT-15 in Example 10 with INT-40, compound 45 can be obtained using the same method and reaction steps. ESI-MS (m / z): 883.7 [M+H] + ;LC-MS retention time RT =1.75 min. HPLC retention time RT =12.64 min.

[0553] 1 H NMR (500 MHz, DMSO-d6) δ 8.87-8.80 (m, 1H), 8.54 (d, J = 9.0 Hz, 1H), 8.51-8.49 (m, 1H), 7.88-7.85 (m, 1H), 7.82 (s, 1H), 7.76 (dd, J = 8.5, 1.5 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 5.56 (t, J = 9.0 Hz, 1H), 5.12-5.07 (m, 1H), 4.35-4.18 (m, 5H), 4.11-4.04 (m, 1H), 3.59-3.55 (m, 2H), 3.48-3.41 (m, 2H), 3.26 (s, 3H), 3.20-3.12 (m, 4H), 3.01-2.95 (m, 1H), 2.89-2.83 (m, 1H), 2.79-2.73 (m, 1H), 2.47-2.46 (m, 2H), 2.40-2.35 (m, 1H), 2.11-2.06 (m, 1H), 2.03-1.96 (m, 1H), 1.82-1.75 (m, 2H), 1.55-1.46 (m, 3H), 1.36 (d, J = 6.0 Hz, 3H), 1.08-1.05 (m, 4H), 0.92 (s, 3H), 0.89-0.85 (m, 4H), 0.57-0.53 (m, 1H), 0.34 (s, 3H). Example 46

[0554] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-Methoxyethyl)-5-((6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)ethynyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000153.jpg96158

[0555] By replacing INT-15 in Example 10 with INT-41, compound 46 can be obtained using the same method and reaction steps. ESI-MS (m / z): 869.3 [M+H] + ;LC-MS retention time RT = 1.86 min. HPLC retention time RT =13.81 min.

[0556] 1H NMR (500 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.59 (s, 1H), 8.53-8.49 (m, 2H), 8.01 (s, 1H), 7.89 (s, 1H), 7.81 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 5.57 (t, J = 9.0 Hz, 1H), 5.09-5.05 (m, 1H), 4.37-4.30 (m, 2H), 4.26-4.19 (m, 2H), 4.12-4.08 (m, 1H), 3.89-3.85 (m, 4H), 3.58 (s, 2H), 3.27 (s, 3H), 3.18-3.12 (m, 2H), 3.01-2.97 (m, 1H), 2.79-2.74 (m, 1H), 2.44-2.41 (m, 1H), 2.10-2.07 (m, 1H), 1.82-1.77 (m, 2H), 1.53-1.48 (m, 2H), 1.40-1.36 (m, 3H), 1.25-1.23 (m, 2H), 1.08-1.05 (m, 4H), 0.93 (s, 3H), 0.91-0.86 (m, 5H), 0.56-0.53 (m, 1H), 0.36 (s, 3H). Example 47

[0557] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-Methoxyethyl)-5-((1-methyl-1H-indol-7-yl)ethynyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000154.jpg91145

[0558] By replacing INT-15 in Example 10 with INT-42, compound 47 can be obtained using the same method and reaction steps. ESI-MS (m / z): 867.0 [M+H] + ;LC-MS retention time RT = 2.28 min. HPLC retention time RT = 17.46 min.

[0559] 1 H NMR (500 MHz, DMSO-d6) δ 8.98 (d, J = 2.0 Hz, 1H), 8.53-8.50 (m, 2H), 8.03 (d, J = 2.0 Hz, 1H), 7.82 (s, 1H), 7.78-7.75 (m, 1H), 7.65 (d, J =8.0 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.41-7.37 (m, 2H), 7.08-7.05 (m, 1H), 6.51 (d, J = 3.0 Hz, 1H), 5.57 (t, J = 9.0 Hz, 1H), 5.11-5.06 (m, 1H), 4.39-4.30 (m, 2H), 4.25-4.20 (m, 4H), 4.16-4.11 (m, 1H), 3.59 (s, 2H), 3.36-3.34 (m, 1H), 3.31-3.30 (m, 1H), 3.28 (s, 3H), 3.18-3.13 (m, 1H), 3.01-2.96 (m, 1H), 2.79-2.74 (m, 1H), 2.48-2.44 (m, 1H), 2.11-2.06 (m, 1H), 1.82-1.76 (m, 2H), 1.54-1.48 (m, 2H), 1.39 (d, J = 6.0 Hz, 3H), 1.07 (s, 4H), 0.94-0.89 (m, 6H), 0.88-0.85 (m, 1H), 0.57-0.53 (m, 1H), 0.38 (s, 3H). Example 48

[0560] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-Methoxyethyl)-5-(piperidin-4-ylethynyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000155.jpg98149

[0561] Example 48 was prepared by the following steps: JPEG2025530275000156.jpg129170

[0562] Compound 48 can be obtained by replacing INT-15 with compound INT-27 in the synthesis step of compound 10 and using the same method and reaction steps. ESI-MS (m / z): 820.5 [M+H] + ;LC-MS retention time RT= 1.68 min. HPLC retention time RT = 12.19 min.

[0563] 1H NMR (500 MHz, DMSO) δ 8.75 (d, J = 2.0 Hz, 1H), 8.53-8.48 (m, 2H), 7.81 (s, 1H), 7.78-7.73 (m, 2H), 7.57 (d, J = 8.5 Hz, 1H), 5.58-5.53 (m, 1H), 5.10-5.05 (m, 1H), 4.36-4.28 (m, 2H), 4.26 (d, J = 6.0 Hz, 1H), 4.27-4.15 (m, 3H), 4.09-4.04 (m, 1H), 3.57 (s, 2H), 3.25 (s, 3H), 3.19-3.14 (m, 2H), 2.98-2.94 (m, 2H), 2.78-2.74 (m, 1H), 2.65-2.59 (m, 2H), 2.39-2.34 (m, 2H), 2.12-2.06 (m, 1H), 2.01-1.97 (m, 1H), 1.86-1.82 (m, 2H), 1.82-1.77 (m, 2H), 1.58-1.54 (m, 1H), 1.51-1.48 (m, 1H), 1.34 (d, J = 6.0 Hz, 3H), 1.27-1.20 (m, 4H), 1.06 (s, 3H), 0.91 (s, 3H), 0.89-0.85 (m, 3H), 0.56-0.53 (m, 1H), 0.33 (s, 3H). Example 49

[0564] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-Methoxyethyl)-5-(3-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)prop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000157.jpg89150

[0565] Substituting INT-43 for INT-15 in Example 10, compound 49 can be obtained using similar methods and reaction steps. ESI-MS (m / z): 882.5 [M+H] + ;LC-MS retention time RT= 1.51 min. HPLC retention time RT = 10.62 min.

[0566] 1H NMR (500 MHz, DMSO) δ 8.81 (d, J = 2.0 Hz, 1H), 8.53 (d, J = 9.0 Hz, 1H), 8.49 (d, J = 1.5 Hz, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.77-7.73 (m, 1H), 7.58 (d, J = 9.0 Hz, 1H), 5.56 (t, J = 9.0 Hz, 1H), 5.11-5.06 (m, 1H), 4.37-4.30 (m, 1H), 4.29-4.22 (m, 2H), 4.12-4.03 (m, 1H), 4.12-4.03 (m, 1H), 3.66 (s, 2H), 3.57 (s, 2H), 3.32-3.29 (m, 1H), 3.25 (s, 3H), 3.17-3.13 (m, 1H), 3.00-2.90 (m, 3H), 2.78-2.70 (m, 3H), 2.40-2.35 (m, 1H), 2.12-2.04 (m, 1H), 1.93-1.83 (m, 3H), 1.83-1.76 (m, 3H), 1.54-1.47 (m, 2H), 1.44-1.40 (m, 3H), 1.35 (d, J = 6.0 Hz, 3H), 1.09-1.02 (m, 4H), 0.91 (s, 3H), 0.89-0.83 (m, 4H), 0.57-0.52 (m, 1H), 0.33 (s, 3H). Example 50

[0567] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-Methoxyethyl)-5-(3-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)prop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000158.jpg91170

[0568] Substituting INT-44 for INT-15 in Example 10, and using similar methods and reaction steps, compound 50 can be obtained. ESI-MS (m / z): 889.6 [M+H] + ;LC-MS retention time RT=1.65 min. HPLC retention time RT=12.62 min.

[0569] 1H NMR (500 MHz, DMSO) δ 8.78 (d, J = 2.0 Hz, 1H), 8.52 (d, J = 9.0 Hz, 1H), 8.49 (d, J = 1.5 Hz, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.77-7.73 (m, 1H), 7.58 (d, J = 9.0 Hz, 1H), 5.56 (t, J = 9.0 Hz, 1H), 5.11-5.06 (m, 1H), 4.37-4.30 (m, 1H), 4.28-4.22 (m, 2H), 4.21-4.13 (m, 2H), 4.11-4.03 (m, 1H), 3.60-3.54 (m, 2H), 3.50 (s, 2H), 3.25 (s, 3H), 3.17-3.11 (m, 2H), 2.98 - 2.93 (m, 4H), 2.78-2.72 (m, 1H), 2.65-2.61 (m, 1H), 2.44-2.40 (m, 3H), 2.37-2.35 (m, 1H), 2.24 (s, 3H), 2.09 - 2.04 (m, 1H), 1.82-1.76 (m, 2H), 1.70-1.64 (m, 4H), 1.56-1.47 (m, 3H), 1.35 (d, J = 6.0 Hz, 3H), 1.26-1.21 (m, 2H), 1.09-1.03 (m, 4H), 0.91 (s, 3H), 0.89-0.84 (m, 4H), 0.57-0.52 (m, 1H), 0.33 (s, 3H). Example 51

[0570] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(5-(((2S)-1-imino-4-methyl-1-oxide-1 6 -thiomorpholin-2-yl)ethynyl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4,6 5 ,6 6 -Hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000159.jpg106141

[0571] By replacing INT-15 in Example 10 with INT-46, compound 51 can be obtained using the same method and reaction steps. ESI-MS (m / z): 883.5 [M+H] + ;LC-MS retention time RT = 1.56 min. HPLC retention time RT = 11.07 min.

[0572] 1 H NMR (500 MHz, DMSO-d6) δ 8.87-8.79 (m, 1H), 8.57-8.48 (m, 2H), 7.93-7.88 (m, 1H), 7.81 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.59 (d, J = 9.0 Hz, 1H), 5.56 (t, J = 9.0 Hz, 1H), 5.13-5.06 (m, 1H), 4.36-4.17 (m, 4H), 4.10-4.02 (m, 2H), 4.00 (s, 1H), 3.57 (s, 2H), 3.32-3.30 (m, 2H), 3.29-3.24 (m, 4H), 3.17-2.94 (m, 6H), 2.81-2.73 (m, 2H), 2.45 (s, 3H), 2.41-2.36 (m, 1H), 2.11-2.05 (m, 1H), 1.83-1.76 (m, 2H), 1.54-1.47 (m, 2H), 1.36 (d, J = 6.0 Hz, 3H), 1.09-1.03 (m, 4H), 0.92 (s, 3H), 0.90-0.84 (m, 4H), 0.57-0.52 (m, 1H), 0.34 (s, 3H). Example 52

[0573] (1r,2R,3S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-Methoxyethyl)-5-(3-(4-methylpiperazin-1-yl)prop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2,3-dimethylcyclopropane-1-carboxamide JPEG2025530275000160.jpg87154

[0574] Compound 52 can be obtained using the same method and reaction steps by using compound INT-45 instead of INT-16 in the synthesis step of compound 11. ESI-MS (m / z): 863.6 [M+H] + ;LC-MS retention time RT=1.78 min. HPLC retention time RT=12.82 min.

[0575] 1H NMR (500 MHz, DMSO-d6) δ 8.80 (d, J = 2.0 Hz, 1H), 8.55-8.47 (m, 1H), 8.39 (d, J = 9.0 Hz, 1H), 7.87-7.78 (m, 2H), 7.75 (dd, J = 8.5, 1.5Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 5.55 (t, J = 9.0 Hz, 1H), 5.12-5.00 (m, 1H), 4.35-4.17 (m, 4H), 4.12-4.04 (m, 1H), 3.59-3.55 (m, 4H), 3.25 (s, 3H), 3.17-3.13 (m, 1H), 2.99-2.93 (m, 1H), 2.79-2.71 (m, 2H), 2.59-2.54 (m, 4H), 2.40-2.36 (m, 2H), 2.16 (s, 3H), 2.09-2.06 (m, 1H), 1.82-1.75 (m, 2H), 1.55-1.45 (m, 2H), 1.35 (d, J = 6.0 Hz, 3H), 1.26-1.22 (m, 2H), 1.18-1.15 (m, 2H), 1.09-1.04 (m, 6H), 0.92-0.86 (m, 6H), 0.34 (s, 3H). Example 53 JPEG2025530275000161.jpg103153

[0576] Compound 53 can be obtained by replacing INT-15 with compound INT-47 in the synthesis step of compound 10 and using the same method and reaction steps. ESI-MS (m / z): 852.7 [M+H] + ;LC-MS retention time RT = 2.15 min. HPLC retention time RT = 16.48 min.

[0577] 1H NMR (500 MHz, DMSO-d6) δ 11.42 (s, 1H), 9.03 (d, J = 2.0 Hz, 1H), 8.60-8.47 (m, 2H), 8.18 (d, J = 2.0 Hz, 1H), 7.82 (s, 1H), 7.78 (dd, J = 8.5, 1.5 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.45 (t, J = 3.0 Hz, 1H), 7.36 (d, J = 7.0 Hz, 1H), 7.07 (t, J = 8.0Hz, 1H), 6.57-6.54 (m, 1H), 5.56 (t, J = 9.0 Hz, 1H), 5.12-5.05 (m, 1H), 4.42-4.32 (m, 2H), 4.27-4.13 (m, 3H), 3.60 (s, 2H), 3.36-3.34 (m, 1H), 3.29 (s, 3H), 3.17-3.12 (m, 1H), 3.05-3.00 (m, 1H), 2.80-2.74 (m, 1H), 2.47-2.43 (m, 1H), 2.12-2.05 (m, 1H), 1.82-1.75 (m, 2H), 1.54-1.47 (m, 2H), 1.40 (d, J = 6.0 Hz, 3H), 1.110-1.04 (m, 4H), 0.96-0.91 (m, 6H), 0.88-0.84 (m, 1H), 0.58-0.54 (m, 1H), 0.38 (s, 3H).

[0578] Example 54 N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-Methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)cyclopropanecarboxamide JPEG2025530275000162.jpg89139

[0579] Compound 54 can be obtained by replacing INT-3b with cyclopropylcarboxylic acid in the synthesis step of compound 1 and using the same method and reaction steps. ESI-MS (m / z): 822.8 [M+H] + ;LC-MS retention time RT=1.73 min. HPLC retention time RT=12.40 min.

[0580] 1 H NMR (500 MHz, DMSO-d6) δ 8.84-8.79 (m, 1H), 8.58 (d, J = 9.0 Hz, 1H), 8.52-8.47 (m, 1H), 7.88-7.85 (m, 1H), 7.82 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 5.57 (t, J = 9.0 Hz, 1H), 5.11-5.05 (m, 1H), 4.38-4.15 (m, 4H), 4.12-4.06 (m, 1H), 3.64-3.59 (m, 4H), 3.59-3.56 (m, 4H), 3.29-3.26 (m, 1H), 3.26-3.23 (m, 3H), 3.19-3.12 (m, 1H), 3.00-2.95 (m, 1H), 2.79-2.73 (m, 1H), 2.55-2.52 (m, 4H), 2.41-2.35 (m, 2H), 2.12-2.06 (m, 1H), 1.81-1.72 (m, 3H), 1.55-1.47 (m, 1H), 1.35 (d, J = 6.0 Hz, 3H), 0.92 (s, 3H), 0.88 (t, J = 7.0 Hz, 3H), 0.73-0.67 (m, 3H), 0.64-0.60 (m, 1H), 0.34 (s, 3H). Example 55

[0581] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(5-((1-(2-hydroxyethyl)piperidin-4-yl)ethynyl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000163.jpg121146

[0582] Example 55 was prepared by the following steps: JPEG2025530275000164.jpg68170

[0583] Step 1: Compound 48 (60 mg, 0.073 mmol) was dissolved in acetonitrile (2 mL), and potassium carbonate (20 mg, 0.146 mmol), potassium iodide (24 mg, 0.146 mmol), and 2-bromoethanol (9 mg, 0.073 mmol) were added. The reaction mixture was stirred at room temperature for 8 hours. After LCMS showed the reaction was complete, water (10 mL) was added to the mixture, and the mixture was extracted with dichloromethane (10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative liquid chromatography to give compound 55 (6 mg, 9.5% yield). ESI-MS (m / z): 864.7 [M+H] + ;LC-MS retention time RT=1.73 min.

[0584] 1H NMR (500 MHz, DMSO) δ 8.78-8.73 (m, 1H), 8.52-8.48 (m, 2H), 7.80 (s, 1H), 7.78-7.73 (m,2H), 7.57 (d, J = 8.5 Hz, 1H), 5.56 (t, J = 9.0 Hz, 1H), 5.10-5.05 (m, 1H), 4.36-4.15 (m, 5H), 4.11 - 4.02 (m, 1H), 3.57 (s, 2H), 3.50 - 3.45 (m, 2H), 3.24 (s, 3H), 3.19 - 3.11 (m, 1H), 3.00-2.94 (m, 1H), 2.80 - 2.72 (m, 3H), 2.71-2.63 (m, 2H), 2.42-2.34 (m, 3H), 2.23-2.14 (m, 2H), 2.10-2.05 (m, 1H), 1.89-1.85 (m, 2H), 1.82-1.75 (m, 2H), 1.67 - 1.59 (m, 2H), 1.56-1.47 (m, 2H), 1.35 (d, J = 6.0 Hz, 3H), 1.11 - 1.02 (m, 4H), 0.91 (s, 3H), 0.90-0.85 (m, 4H), 0.57-0.52 (m, 1H), 0.34 (s, 3H). Example 56

[0585] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-Methoxyethyl)-5-((1-methyl-1H-indol-4-yl)ethynyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000165.jpg103141

[0586] Compound 56 can be obtained using the same method and reaction steps by using compound INT-48 instead of compound INT-15 in the synthesis step of compound 10. ESI-MS (m / z): 865.7 [M+H] + ;LC-MS retention time RT = 2.15 min. HPLC retention time RT=16.44 min.

[0587] 1 H NMR (500 MHz, DMSO-d6) δ 8.99 (d, J = 2.5 Hz, 1H), 8.56-8.49 (m, 2H), 8.07 (d, J = 2.0 Hz, 1H), 7.82 (s, 1H), 7.77 (dd, J = 8.5, 2.0 Hz, 1H), 7.61-7.56 (m, 2H), 7.48 (d, J = 2.5 Hz, 1H), 7.33 (d, J = 7.0 Hz, 1H), 7.21 (t, J = 7.0 Hz, 1H), 6.73 (d, J = 2.0 Hz, 1H), 5.56 (t, J = 9.0 Hz, 1H), 5.10-5.05 (m, 1H), 4.38-4.29 (m, 2H), 4.26-4.10 (m, 3H), 3.84 (s, 3H), 3.59 (s, 2H), 3.37-3.33 (m, 1H), 3.28 (s, 3H), 3.17-3.12 (m, 1H), 3.03-2.97 (m, 1H), 2.79-2.73 (m, 1H), 2.49-2.35 (m, 1H), 2.10-2.07 (m, 1H), 1.85-1.76 (m, 2H), 1.57-1.46 (m, 2H), 1.39 (d, J = 6.0 Hz, 3H), 1.10-1.04 (m, 4H), 0.97-0.90 (m, 6H), 0.89-0.84 (m, 1H), 0.58-0.52 (m, 1H), 0.38 (s, 3H). Example 57

[0588] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(5-(3-(1-Imino-1-oxide-1,6-thiomorpholino)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000166.jpg82162

[0589] By using compound INT-48 instead of INT-15 in the synthesis step of compound 10, compound 57 can be obtained using the same method and reaction steps. ESI-MS (m / z): 883.7 [M+H] + ;LC-MS retention time RT = 1.56 min. HPLC retention time RT = 10.93 min.

[0590] 1H NMR (500 MHz, DMSO-d6) δ 8.81 (d, J = 2.0 Hz, 1H), 8.53-8.49 (m, 2H), 7.85 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.76-7.74 (m, 1H), 7.59-7.57 (m, 1H), 5.56 (t, J = 9.0 Hz, 1H), 5.12-5.07 (m, 1H), 4.39-4.16 (m, 4H), 4.12-4.03 (m, 1H), 3.72 (s, 2H), 3.65 (s, 1H), 3.57 (s, 2H), 3.31-3.28 (m, 1H), 3.25 (s, 3H), 3.18-3.07 (m, 2H), 3.06-3.02 (m, 3H), 3.02-2.94 (m, 5H), 2.79-2.73 (m, 1H), 2.42-2.35 (m, 1H), 2.09-2.07 (m, 1H), 1.82-1.76 (m, 2H), 1.55-1.47 (m, 2H), 1.35 (d, J = 6.0 Hz, 3H), 1.07-1.06 (m, 4H), 0.91 (s, 3H), 0.89-0.86 (m, 4H), 0.56-0.54 (m, 1H), 0.34 (s, 3H). Example 58

[0591] (1r,2R,3S)-N-((6 3 S,4S,Z)-1 2 -(5-(3-(dimethylamino)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2,3-dimethylcyclopropane-1-carboxamide JPEG2025530275000167.jpg90141

[0592] Using the same method and reaction steps, compound 58 can be obtained by using dimethylamine instead of N-methyltetrahydro-2H-pyran-4-amine in the synthesis step of compound 36. ESI-MS (m / z): 808.6 [M+H] + ;LC-MS retention time RT = 1.96 min. HPLC retention time RT= 14.23 min.

[0593] 1 H NMR (500 MHz, DMSO-d6) δ 8.81 (d, J = 2.0 Hz, 1H), 8.53-8.47 (m, 1H), 8.41 (d, J = 9.0 Hz, 1H), 7.88-7.81 (m, 2H), 7.76 (dd, J = 8.5, 1.5 Hz, 1H), 7.59 (d, J = 8.5Hz, 1H), 5.55 (t, J = 9.0 Hz, 1H), 5.13-5.04 (m, 1H), 4.36-4.07 (m, 5H), 3.57 (s, 2H), 3.51 (s, 2H), 3.32-3.29 (m, 1H), 3.25 (s, 3H), 3.17-3.11 (m, 1H), 2.99-2.93 (m, 1H), 2.80-2.72 (m, 1H), 2.41-2.33 (m, 2H), 2.26 (s, 6H), 2.11-2.03 (m, 1H), 1.82-1.74 (m, 2H), 1.56-1.46 (m, 1H), 1.35 (d, J = 6.0Hz, 3H), 1.17-1.14 (m, 2H), 1.09-1.05 (m, 6H), 0.91-0.83 (m, 6H), 0.34 (s, 3H).

[0594] Example 59

[0595] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2-(2-((S)-1-Methoxyethyl)-5-(3-(piperidin-1-yl)prop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000168.jpg89154

[0596] Compound 59 can be obtained by replacing INT-15 with INT-49 in Example 10 and using the same method and reaction steps. ESI-MS (m / z): 835.1 [M+H] + ;LC-MS retention time RT = 2.06 min.

[0597] 1H NMR (500 MHz, DMSO) δ 8.80 (d, J = 2.0 Hz, 1H), 8.52 (d, J = 9.0 Hz, 1H), 8.50 (d, J = 1.0 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.77 - 7.73 (m, 1H), 7.58 (d, J = 8.5 Hz, 1H), 5.56 (t, J = 9.5 Hz, 1H), 5.11 - 5.06 (m, 1H), 4.36-4.16 (m, 5H), 4.12 - 4.03 (m, 1H), 3.57 (s, 2H), 3.51 (s, 2H), 3.25 (s, 3H), 3.17-3.08 (m, 2H), 2.99 - 2.93 (m, 1H), 2.78-2.72 (m, 1H), 2.40 - 2.34 (m, 2H), 2.10 - 2.05 (m, 1H), 1.82 - 1.73 (m, 2H), 1.56-1.47 (m, 7H), 1.40 - 1.36 (m, 2H), 1.35 (d, J = 6.0 Hz, 3H), 1.10 - 1.02 (m, 5H), 0.91 (s, 3H), 0.89 - 0.85 (m, 4H), 0.58 - 0.52 (m, 1H), 0.33 (s, 3H). Example 60

[0598] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-Methoxyethyl)-5-(3-(4-methylpiperazin-1-yl)prop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000169.jpg89156

[0599] If compound INT-45 is used instead of INT-15 in the synthesis step of compound 10, compound 60 can be obtained using the same method and reaction steps. ESI-MS (m / z): 849.9 [M+H] + ;LC-MS retention time RT = 1.70 min.

[0600] 1 H NMR (500 MHz, DMSO-d6) δ 8.81 (d, J = 2.0 Hz, 1H), 8.57-8.48 (m, 2H), 7.85 (d, J = 2.0 Hz, 1H), 7.82 (s, 1H), 7.76 (dd, J = 8.5, 1.5 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 5.56 (t, J = 9.0 Hz, 1H), 5.15-5.01 (m, 1H), 4.38-4.16 (m, 4H), 4.12-4.04 (m, 1H), 3.67-3.53 (m, 4H), 3.33-3.29 (m, 4H), 3.26 (s, 3H), 3.17-3.11 (m, 1H), 3.00-2.93 (m, 1H), 2.80-2.72 (m, 1H), 2.66-2.55 (m, 4H), 2.40-2.35 (m, 2H), 2.34-2.24 (m, 3H), 2.11-2.03 (m, 1H), 1.83-1.72 (m, 2H), 1.55-1.45 (m, 2H), 1.35 (d, J = 6.0 Hz, 3H), 1.09-1.02 (m, 4H), 0.92 (s, 3H), 0.89-0.85 (m, 3H), 0.58-0.52 (m, 1H), 0.33 (s, 3H).

[0601] Example 61

[0602] (1S,2S)-N-((6 3 S,4S,Z)-1 2 -(5-(3-(dimethylamino)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indra-6(1,3)-pyridazin-2-cycloundecaphan-4-yl)-2-methylcyclopropane-1-carboxamide JPEG2025530275000170.jpg92140

[0603] In the synthesis step of compound 15, dimethylamine is used instead of (R)-3-methylmorpholine hydrochloride, and the same method and reaction steps can be used to obtain compound 61. ESI-MS (m / z): 794.8 [M+H] + ;LC-MS retention time RT = 1.83 min. HPLC retention time RT = 13.71 min.

[0604] 1H NMR (500 MHz, DMSO-d6) δ 8.81 (d, J = 2.0 Hz, 1H), 8.55-8.49 (m, 2H), 7.84 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.78-7.74 (m, 1H), 7.58 (d, J = 8.5 Hz, 1H), 5.56 (t, J = 9.0 Hz, 1H), 5.12-5.06 (m, 1H), 4.35-4.06 (m, 5H), 3.57 (s, 2H), 3.50 (s, 2H), 3.33-3.30 (m, 1H), 3.25 (s, 3H), 3.18-3.11 (m, 1H), 2.99-2.93 (m, 1H), 2.80-2.73 (m, 1H), 2.42-2.35 (m, 1H), 2.25 (s, 6H), 2.11-2.05 (m, 1H), 1.83-1.74 (m, 2H), 1.55-1.47 (m, 2H), 1.35 (d, J = 6.0 Hz, 3H), 1.09-1.04 (m, 4H), 0.93-0.84 (m, 7H), 0.57-0.52 (m, 1H), 0.34 (s, 3H).

[0605] Biological screening and results of RAS inhibitors Test Example 1: In vitro cell proliferation inhibition test Considering the diversity of RAS mutations and to evaluate the activity of compounds in different RAS mutant cell lines, we WT , KRAS G12C , KRAS G12D , KRAS G12 and BRAF-mutated cell lines (see the table below) were selected for in vitro activity evaluation and screening of compounds. JPEG2025530275000171.jpg87170

[0606] Experimental protocol: CellTiter-Glo® Luminescent Cell Viability Assay (Promega) Depending on the doubling time of different cell lines, different numbers of cells (1,000–5,000 cells / well) were seeded into 96-well plates containing 180 μl of the corresponding medium and cultured overnight in a cell culture incubator at 37°C with 5% CO2. The next day, the compounds to be tested were pre-diluted 3-fold with medium to create a 10-point concentration gradient, with the highest concentration being 100 μM. Then, 20 μl of medium containing different concentrations of compound was added to the cells in the 96-well plate to achieve a final compound concentration of up to 10 μM, creating a 10-point 3-fold dilution gradient. After incubating the cells and compounds for 72 hours, the 96-well plate was removed from the incubator and allowed to equilibrate at room temperature for 30 minutes. Then, 25 μl of CellTiter-Glo® Reagent was added to each well, mixed thoroughly, and incubated at room temperature for 10 minutes. Next, 100 μl of the sample was transferred to a white 96-well plate (OptiPlate™-96, PerkinElmer), and the fluorescence signal was measured using a multifunction microplate reader (SpectraMax® i3x, Molecular Devices). The signal was then normalized, and the half maximal inhibitory concentration (IC50) of the compound against the cell line was calculated using a four-parameter regression equation for curve fitting.

[0607] Table 3: Antiproliferative activity of compounds of the invention against KRAS mutant cell lines JPEG2025530275000172.jpg205170

Claims

1. A compound having the structure of formula (I), or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof: Here, R １ is C １ ~C ６ Alkyl, -(C １ ~C ６ alkylene)-(C ３ ~C ８ cycloalkyl), or -(C １ ~C ６ alkylene)-(3- to 8-membered heterocycloalkyl); R ２ is halogen, cyano, C １ ~C ６ Alkyl, -(C ０ ~C ６ alkylene)-(C ３ ~C ８ cycloalkyl), or -(C ０ ~C ６ alkylene)-(3- to 8-membered heterocycloalkyl), which is optionally substituted with 0, 1, or 2 substituents selected from -ORa, -SRa, or -NRaRa'; R ３ is hydrogen, —O(C ０ ~C ６ alkylene)Ra, -S(C ０ ~C ６ alkylene)Ra, -N(C ０ ~C ６ alkylene)Ra(C ０ ~C ６ alkylene)Ra′, —O(C ２ ~C ６ alkylene) R Ｌ , -S(C ２ ~C ６ alkylene) R Ｌ , -N(C ２ ~C ６ alkylene) R Ｌ (C ２ ~C ６ alkylene) R Ｌ ', or -N(C ２ ~C ６ alkylene)Ra(C ２ ~C ６ alkylene) R Ｌ where R Ｌ , R Ｌ ' each independently represent -ORa, -SRa, or -NRaRa'; Cy １ is C ３ ~C １２ represents cycloalkyl or 3- to 12-membered heterocycloalkyl; R ４ is hydrogen, halogen, oxo, C １ ~C ６ Alkyl, -(C ０ ~C ６ alkylene) (C ３ ~C ６ ) cycloalkyl, -(C ０ ~C ６ alkylene)(3- to 8-membered)heterocycloalkyl, -(C ０ ~C ６ alkylene) ORa, -(C ０ ~C ６ alkylene)SRa, -(C ０ ~C ６ alkylene)NRaRa', -(C ０ ~C ６ alkylene)CORa, -(C ０ ~C ６ alkylene)COORa, -(C ０ ~C ６ alkylene)CONRaRa', - (C ０ ~C ６ alkylene) NRaCORa', -(C ０ ~C ６ alkylene) OCONRaRa', -(C ０ ~C ６ alkylene) NRaCONRaRa', -(C ０ ~C ６ alkylene)SORa, -(C ０ ~C ６ alkylene)S(O) ２ Ra, -(C ０ ~C ６ alkylene)NRaS(O) ２ Ra', -(C ０ ~C ６ alkylene)CN, -(C ０ ~C ６ alkylene) (C ６ ~C １０ aryl), or -(C ０ ~C ６ alkylene)(5-12 membered heteroaryl); Here, Cy １ R on two C atoms of ４ can form a 3- to 8-membered ring together with the C atom to which they are attached and the atom between said two C atoms, said 3- to 8-membered ring optionally containing 0, 1, 2 or 3 heteroatoms selected from N, O or S, or Cy １ Two R on the same C atom of ４ can form a 3- to 8-membered ring together with the C atom to which they are attached, said 3- to 8-membered ring optionally containing 0, 1, 2 or 3 heteroatoms selected from N, O or S; R ８ is -Cy ２ - (R ５ ) q or -R ９ R ９ ', where Cy ２ is C ３ ~C １２ cycloalkyl, 3- to 12-membered heterocycloalkyl, C ６ ~C １０ represents aryl or 5-12 membered heteroaryl; R ５ is hydrogen, halogen, oxo, C １ ~C ６ Alkyl, -(C ０ ~C ６ alkylene) ORa, -(C ０ ~C ６ alkylene)SRa, -(C ０ ~C ６ alkylene)NRaRa', -(C ０ ~C ６ alkylene)CORa, -(C ０ ~C ６ alkylene)COORa, -(C ０ ~C ６ alkylene)CONRaRa', -(C ０ ~C ６ alkylene)NRaCORa', -(C ０ ~C ６ alkylene)OCONRaRa', -(C ０ ~C ６ alkylene)NRaCONRaRa', - (C ０ ~C ６ alkylene)SORa, -(C ０ ~C ６ alkylene)S(O) ２ Ra or -(C ０ ~C ６ alkylene) NRaS(O) ２ Ra', or Cy ２ R on two C atoms of ５ can form a 3- to 8-membered ring together with the C atom to which they are attached and the atom between the two C atoms, said 3- to 8-membered ring optionally containing 0, 1, 2 or 3 heteroatoms selected from N, O or S, or Cy ２ Two R on the same C atom of ５ can form a 3- to 8-membered ring together with the C atom to which they are attached, said 3- to 8-membered ring optionally containing 0, 1, 2 or 3 heteroatoms selected from N, O or S, Or, Cy ２ At least one atom on the ring is S(=O)(=NRa) or S(=O) ２ is replaced by R ９ , R ９ ' are each independently q R ５ C optionally substituted with １ ~C ６ Alkyl group, C ３ ~C ８ Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, C ６ ~C １０ represents an aryl group or a 5- to 12-membered heteroaryl group; R ６ , R ６ ' are each independently hydrogen, halogen, C １ ~C ６ Alkyl, C ３ ~C ８ Cycloalkyl or -(C ０ ~C ６ alkylene)CN; R ７ , R ７ ' are each independently hydrogen, halogen, C １ ~C ６ Alkyl, C ３ ~C ８ cycloalkyl, 3- to 8-membered heterocycloalkyl, or R ７ , R ７ ' and the C atoms attached thereto may form a 3- to 8-membered ring, said ring optionally containing 0, 1, 2 or 3 heteroatoms selected from N, O and S; wherein p and q each independently represent 0, 1, 2, 3, or 4; m represents 0, 1, 2 or 3; Ra and Ra' are each independently hydrogen, C １ ~C ６ Alkyl, C ３ ~C ８ represents cycloalkyl, and when Ra and Ra' are bound to the same N atom, said Ra and Ra' can form a 4- to 8-membered ring together with the N atom to which they are bound, and said 4- to 8-membered ring optionally contains 0, 1, 2 or 3 heteroatoms selected from N, O or S; The alkyl, cycloalkyl, heterocycloalkyl and alkylene groups may each independently be substituted with 0, 1, 2, 3, 4, 5 or 6 halogen atoms.

2. R １ is C １ ~C ６ Alkyl group, preferably C １ ~C ３ 10. A compound having the structure of formula (I) according to claim 1, or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof, wherein R represents an alkyl group.

3. R ２ is C １ ~C ６ represents an alkyl group, which is optionally substituted by 0, 1 or 2 -ORa substituents; more preferably, where * is R in formula (I). ２ and the site that binds to it, 10. A compound having the structure of formula (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof.

4. R ３ -O(C １ ~C ６ ) alkyl, —O(C ０ ~C ６ alkylene) (C ３ ~C ８ ) cycloalkyl, —O(C ０ ~C ６ alkylene) (3-8 membered) heterocycloalkyl, —O(C ２ ~C ６ alkylene) R Ｌ , or hydrogen, 10. A compound having the structure of formula (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof.

5. Cy １ is C ３ ~C ８ 2. A compound having the structure of formula (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof, wherein: R represents cycloalkyl or 3-8 membered heterocycloalkyl.

6. R ４ is hydrogen, halogen, C １ ~C ６ Alkyl, -(C ０ ~C ６ alkylene)CONRaRa', -(C ０ ~C ６ alkylene)NRaCORa', -(C ０ ~C ６ alkylene)OCONRaRa', -(C ０ ~C ６ alkylene)CN, -(C ０ ~C ６ alkylene) (5-12 membered heteroaryl), or Cy １ R on two C atoms of ４ can form a 3- to 8-membered ring together with the C atom to which they are attached and the atom between the two C atoms, said 3- to 8-membered ring optionally containing 0, 1, 2 or 3 heteroatoms selected from N, O or S, or Cy １ Two R on the same C atom of ４ can form a 3- to 8-membered ring together with the C atom to which they are attached, said 3- to 8-membered ring optionally containing 0, 1, 2 or 3 heteroatoms selected from N, O or S, 10. A compound having the structure of formula (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof.

7. R ４ is hydrogen, halogen, C １ ~C ６ Alkyl, -(C ０ ~C ６ alkylene)CONRaRa', -(C ０ ~C ６ alkylene)(5-12 membered heteroaryl), or Cy １ R on the two C atoms of ４ can form a 3- to 8-membered ring together with the C atom to which they are attached and the atom between the two C atoms, said 3- to 8-membered ring optionally containing 0, 1, 2 or 3 heteroatoms selected from N, O or S, or Cy １ Two R on the same C atom of ４ can form a 3- to 8-membered ring together with the C atom to which they are attached, said 3- to 8-membered ring optionally containing 0, 1, 2 or 3 heteroatoms selected from N, O or S, 10. A compound having the structure of formula (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof.

8. Cy ２ 4. A compound having the structure of formula (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein: represents a 3- to 8-membered heterocycloalkyl group or a 5- to 12-membered heteroaryl group.

9. R ５ is hydrogen, halogen, C １ ~C ６ Alkyl, -(C ０ ~C ６ alkylene) ORa, -(C ０ ~C ６ alkylene)NRaRa', -(C ０ ~C ６ alkylene)CORa, -(C ０ ~C ６ alkylene)COORa, -(C ０ ~C ６ alkylene)CONRaRa', -(C ０ ~C ６ alkylene)NRaCORa', or Cy ２ R on two C atoms of ５ can form a 3- to 8-membered ring together with the C atom to which they are attached and the atom between said two C atoms, said 3- to 8-membered ring optionally containing 0, 1, 2 or 3 heteroatoms selected from N, O or S, or Cy ２ Two R on the same C atom of ５ can form a 3- to 8-membered ring together with the C atom to which they are attached, said 3- to 8-membered ring optionally containing 0, 1, 2 or 3 heteroatoms selected from N, O or S, Or, Cy ２ At least one atom on the ring is S(=O)(=NRa) or S(=O) ２ can be replaced by A compound having the structure of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof.

10. R ５ is hydrogen, halogen, or C １ ~C ６ Alkyl, -(C ０ ~C ６ alkylene) ORa, -(C ０ ~C ６ alkylene)NRaRa', or Cy ２ R on two C atoms of ５ can form a 3- to 8-membered ring together with the C atom to which they are attached and the atom between the two C atoms, said 3- to 8-membered ring optionally containing 0, 1, 2 or 3 heteroatoms selected from N, O and S, or Cy ２ Two R on the same atom ５ can form a 3- to 8-membered ring together with the C atom bonded thereto, said 3- to 8-membered ring optionally containing 0, 1, 2 or 3 heteroatoms selected from N, O or S, A compound having the structure of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof.

11. R ９ , R ９ At least one of q R ５ C substituted with １ ~C ６ 10. A compound having the structure of formula (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof, wherein:

12. R ６ , R ６ ' are each independently hydrogen or C １ ~C ６ alkyl, and more preferably R ６ , R ６ 10. A compound having the structure of formula (I) according to any preceding claim, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein each ' represents independently hydrogen or methyl.

13. R ７ , R ７ ' are each independently hydrogen, C １ ~C ６ represents alkyl, or R ７ , R ７ and the C atoms attached thereto form a 3- to 8-membered ring, which may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O, S, more preferably R ７ represents hydrogen, 10. A compound having the structure of formula (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof.

14. 10. A compound having the structure of formula (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof, wherein m, p, and q are each independently preferably 0, 1, or 2.

15. -Cy in formula (I) １ - (R ４ ) p has a structure selected from the following: Here, * represents -Cy in formula (I). １ - (R ４ ) p and the site to which it binds, A compound having the structure of formula (I) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof.

16. -Cy in formula (I) １ - (R ４ ) p has a structure selected from: Here, * represents -Cy in formula (I). １ - (R ４ ) p and the site to which it binds, A compound having the structure of formula (I) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof.

17. -Cy in formula (I) ２ - (R ５ ) the structure of q is selected from: Here, * represents -Cy in formula (I). ２ - (R ５ ) q and the site to which it binds; 10. A compound having the structure of formula (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof.

18. -Cy in formula (I) ２ - (R ５ ) the structure of q is selected from: Here, * represents -Cy in formula (I). ２ - (R ５ ) q and the site to which it binds; A compound having the structure of formula (I) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof.

19. 10. A compound having the structure of formula (I) according to any one of the preceding claims, wherein the compound of formula (I) has the structure of formula (II): or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof.

20. A compound having the following structure:

21. 10. A pharmaceutical composition comprising a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof.

22. Use of the compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, and the pharmaceutical composition according to claim 21, in the preparation of a medicament for preventing and / or treating cancer, tumor, inflammatory disease, autoimmune disease, or immune-mediated disease.

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