3-amino pyridazines containing indole substituted structure, and pharmaceutically acceptable salts and uses thereof

Abstract

The application belongs to the technical field of pharmaceutical chemistry, and particularly relates to a 3-amino pyridazine compound containing an indole substituted structure, a pharmaceutically acceptable salt thereof and application, wherein the structure of the pyridazine compound is shown as formula I. The pyridazine compound provided in the application can effectively degrade SMARCA2 and / or SMARCA4 protein, and can be used for preventing or treating cancer, cell proliferation disorder, inflammation, autoimmune disease or sepsis.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry and relates to a 3-aminopyridazine compound containing an indole-substituted structure, its pharmaceutically acceptable salts, and its applications, particularly to a 3-aminopyridazine compound containing an indole-substituted structure as a protein degrader for SMARCA2 and / or SMARCA4, its pharmaceutically acceptable salts, and its applications. Background Technology

[0002] Epigenetic dysregulation, a common and prominent feature in almost all human cancers, is closely related to abnormalities in the chromatin regulatory network at its core mechanism. The SWI / SNF (mSWI / SNF) complex, as a key ATP-dependent epigenetic regulator, precisely regulates chromatin structure and function, thereby affecting gene expression and regulation. SMARCA2 and SMARCA4 are homologous members of the SNF2 ATPase family and are mutually exclusive enzymatic subunits in the SWI / SNF complex in all mammals, sharing a protein sequence homology of up to 76%, allowing them to substitute for each other in many biological processes. Large-scale cancer genome sequencing studies have shown that genes encoding SWI / SNF complex subunits are mutated in over 20% of cancers, such as hypercalcemic small cell carcinoma of the ovary, uterine sarcoma, undifferentiated sinus carcinoma, and gastrointestinal pleomorphic carcinoma, all of which exhibit functional loss of the SMARCA4 gene. Research indicates a synthetic lethal relationship between SMARCA2 and SMARCA4. In cancer cells with missing or mutated SMARCA4, cell survival is more dependent on SMARCA2.

[0003] PROTACs are a unique class of heterobifunctional molecules that selectively degrade target proteins via the ubiquitin-proteasome system (UPS). The core mechanism of PROTAC's action lies in the chemically induced proximity effect. It acts as a precise "molecular bridge," bringing the target protein (POI) and the E3 ubiquitin ligase to a suitable distance, thereby triggering the UPS-mediated POI degradation process. During this degradation process, the PROTAC molecule itself is not consumed but can be recycled like a catalyst, continuously catalyzing the degradation of the target protein, fully demonstrating its unique non-stoichiometric advantage. More importantly, PROTACs exhibit excellent selectivity for specific proteins; compared to other homologous proteins with similar or identical binding pockets, they can precisely recognize and degrade target proteins.

[0004] In recent years, PROTAC degraders targeting SMARCA2 / 4 have been developed, but no SMARCA2 degrader drugs have yet been marketed. In summary, degraders targeting SMARCA2 and / or SMARCA4 proteins may be beneficial for developing therapeutic strategies targeting cancer, inflammation, and autoimmune diseases. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the present invention aims to provide a 3-aminopyridazine compound containing an indole-substituted structure, its pharmaceutically acceptable salts, and its applications. Particularly, it relates to a 3-aminopyridazine compound containing an indole-substituted structure as a protein degrader for SMARCA2 and / or SMARCA4, its pharmaceutically acceptable salts, and its applications. These compounds are intended for the treatment of diseases or conditions mediated by SMARCA2 and / or SMARCA4, such as cancer, inflammation, and autoimmune diseases.

[0006] To achieve this objective, the present invention adopts the following technical solution: In a first aspect, the present invention provides a 3-aminopyridazine compound containing an indole-substituted structure or a pharmaceutically acceptable salt thereof, the structure of said pyridazine compound being shown in Formula I: Formula I Among them, R 1 Selected from H, CR a NR a R b OR a ;R a R b Each is independently selected from H, C1-C6 alkyl, deuterium, halogen, hydroxyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -C(=O)-C1-C6 alkyl; R 3 R 4 R 5 R 6 R 7 Independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, amino, -COOR a -CON(R) a )2;R a Selected from H, C1-C6 alkyl groups; Y 1 Selected from single key, -R a C(O)R b -、-R a C(O)N(R c )R b -、-R a C(O)OR b-、-R a C(O)SR b - Any one of them; R a R b Independently selected from any one of single-bonded, substituted or unsubstituted C1-C10 alkylene groups, wherein the substituted group is selected from C1-C6 alkyl groups; R c Selected from H or C1-C10 alkyl groups; L is selected from any one or a combination of at least two of the following groups: single bond, ether group, thioether group, ester group, amino group, amide group, carbamate group, urea group, sulfone group, carbonyl group, substituted or unsubstituted C1-C10 alkylene group, substituted or unsubstituted C2-C10 alkenyl group, substituted or unsubstituted C2-C10 alkyne group, substituted or unsubstituted C6-C12 aryl group, substituted or unsubstituted C6-C12 heteroaryl group, substituted or unsubstituted C3-C10 cycloalkyl group, and substituted or unsubstituted C4-C10 heterocyclic group. The substituted group is selected from any one of the following groups: halogen, amino, nitro, carboxyl, cyano, hydroxyl, C1-C5 haloalkyl, and C1-C6 alkyl. Y 2 Selected from -O-, -N(R) d -, -S-, -CH2-, -C(O)N(R) d )- or any of the single bonds; R d Selected from H or C1-C10 alkyl groups; E has the structure shown in either Equation II-1 or Equation II-2, wherein Selected from the group linkage position: Formula II-1 Formula II-2 Among them, Y 3 Selected from -O-, -S-, -CH(R) e -, -C(O)-, -S(O)2-, -N(R) e Any one of the following; R e The group is selected from H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocyclic group, wherein the substituted group is selected from halogen, amino, nitro, carboxyl, cyano, hydroxyl, C1-C5 haloalkyl, C1-C6 alkyl; Y 4 Y 5 Y 6 Y 7 Independently selected from CH or N; T 1 T 2 T 3 Independently selected from O or S; R 8 and R 9 The group is independently selected from any one of H, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 heterocyclic group, wherein the substituted group is selected from any one of halogen, hydroxyl, and C1-C6 alkyl; R 10 The group is selected from any one of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocyclic groups, wherein the substituted group is selected from any one of halogen, hydroxyl, C1-C5 haloalkyl, C1-C6 alkyl, C3-C10 cycloalkyl, and C3-C10 heterocyclic groups; R 11 The group is selected from H, substituted or unsubstituted C1-C10 alkyl groups, and substituted or unsubstituted carboxyl groups, wherein the substituted group is selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. R 12 The group is selected from H, substituted or unsubstituted C1-C10 alkyl groups, wherein the substituted group is selected from any one of halogen, hydroxyl, C1-C6 alkyl, C3-C10 cycloalkyl, and C3-C10 heterocyclic groups; R 13 The group is selected from any one of H, halogen, amino, hydroxyl, cyano, substituted or unsubstituted C1-C10 alkyl, wherein the substituted group is selected from any one of halogen, hydroxyl, and C1-C6 alkyl; R 14 The group is selected from H, halogen, carboxyl, cyano, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, wherein the substituted group is selected from any one of halogen, hydroxyl, and C1-C6 alkyl.

[0007] Alternatively, in the above-mentioned pyridazine compounds or their pharmaceutically acceptable salts, the Y... 4 Y 5 Y 6 Y 7 Independently selected from CH or N; Preferably, the Y 4 Y 5 Y 6 Y 7 Any one of the groups is CH, and the group is attached to the CH; Preferably, the L is selected from any one of the following groups: Indicates the location of the group connection: , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , ; Wherein, n, o, and p are independently selected from positive integers between 1 and 10; m is selected from positive integers between 0 and 10; q is selected from 1 and 3; Y8 is selected from substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 O-containing heterocyclic alkyl, substituted or unsubstituted C1-C10 N-containing heterocyclic alkyl, and substituted or unsubstituted C1-C10 S-containing heterocyclic alkyl; A, B, C, D, U, V, S, and Z are independently selected from CH or N; Preferably, the Y 3 Selected from -CH- or -C(=O)-; Preferably, the T 1 T 2 T 3 Selected from O.

[0008] Alternatively, in the above-mentioned pyridazine compounds or their pharmaceutically acceptable salts, the structure of the pyridazine compounds is shown in Formula III-1 or Formula III-2: Formula III-1 or Formula III-2 Among them, R 8 R 9 R 10 R 12 Y 1 Y 2 Y 3 L has the same limiting range as described above; Preferably, the Y 1Selected from single key, -R a C(O)R b -、-R a C(O)N(R c )R b - any one of them; the R a R b Independently selected from single bonds or C1-C10 alkylene groups; the R c Selected from H or C1-C10 alkyl groups; Preferably, the Y 2 Selected from -O-, -N(R) d )-、-C(O)N(R d () or any one of the single bonds; the R d Selected from H or C1-C10 alkyl groups; Preferably, the Y 3 Selected from -CH2- or -C(O)-; Preferably, the R 8 R 9 Independently selected from H or C1-C10 alkyl groups; Preferably, the R 10 It is selected from C1-C5 alkyl-substituted C1-C6 alkyl and C3-C10 cycloalkyl, preferably any one of isopropyl, tert-butyl, sec-butyl, cyclohexyl, and cyclopentyl; Preferably, the R 12 Independently selected from H or C1-C10 alkyl groups; Preferably, the L is selected from any one of the following groups: Indicates the location of the group connection: , , , , , , , , ... , , ... , , , , , , , , .

[0009] Where n, o, and p are independently selected from positive integers between 1 and 10; m is selected from positive integers between 0 and 10.

[0010] Alternatively, in the above-mentioned pyridazine compounds or their pharmaceutically acceptable salts, the structure of the pyridazine compounds is shown in formula IV-1 or IV-2: Formula IV-1 Formula IV-2 Among them, Y 1 Y 2 L has the same limiting range as described above.

[0011] Alternatively, among the above-mentioned pyridazine compounds or their pharmaceutically acceptable salts, the pyridazine compounds are selected from any one of the structures shown in compounds 1-39 below: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0012] In a second aspect, the present invention provides a pharmaceutical composition comprising a pyridazine compound or a pharmaceutically acceptable salt thereof as described in any one of the first aspects, and at least one pharmaceutically acceptable carrier and / or at least one other therapeutically active agent.

[0013] Thirdly, the present invention provides a SMARCA2 and / or SMARCA4 protein degrading agent, said SMARCA2 and / or SMARCA4 protein degrading agent comprising at least one of the pyridazine compounds as described in any one of the first aspects or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in the second aspect.

[0014] Fourthly, the present invention provides the use of any pyridazine compound as described in any one of the first aspects or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in the second aspect, or a SMARCA2 and / or SMARCA4 protein degrader as described in the third aspect, in the preparation of a medicament for diseases or conditions mediated by SMARCA2 and / or SMARCA4.

[0015] Preferably, the diseases or conditions mediated by SMARCA2 and / or SMARCA4 include cancer, inflammation, and autoimmune diseases.

[0016] The cancers mentioned include, but are not limited to, synovial sarcoma, malignant rhabdoid tumor, leukemia (e.g., acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, mixed leukemia, chronic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia), multiple myeloma, polycythemia vera, cutaneous T-lymphocytoma, lymphoma (Hodgkin's disease, non-Hodgkin's disease), Woldanstrom's macroglobulinemia, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g.,Fibrosarcoma, myxosarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, synovoma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colonoma, colorectal cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary gland carcinoma, cystic adenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, liver cancer, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, and nephroblastoma are all mentioned. The cancers mentioned include: adrenal tumors, acoustic neuroma, acral melanoma, and acral sweat gland carcinoma. Adenoma, Acute eosinophilic leukemia, Acute red leukemia, Acute lymphoblastic leukemia, Acute megakaryocytic leukemia, Acute monocytic leukemia, Acute promyelocytic leukemia, Adenocarcinoma, Adenoid cystic carcinoma, Adipose tissue tumor, Adrenocortical carcinoma, Adult T-cell leukemia / lymphoma, AIDS-related lymphoma, Alveolar rhabdomyosarcoma, Alveolar soft sarcoma, Ameloblastic fibroma, Anaplastic large cell lymphoma, Undifferentiated thyroid carcinoma, Angiomyolipoma, Angiosarcoma, Astrocytoma, Atypical rod tumor, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B... Cellular lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, germ cell tumor, bone tumor, brown tumor, Burkitt lymphoma, breast cancer, brain cancer, carcinoma in situ, chondroma, cementum tumor, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, renal clear cell sarcoma, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colon cancer, small round cell tumor, diffuse B-cell lymphoma, neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine gland tumor, endodermal sinus tumor, esophageal cancer, fibroma, fibrosarcoma, follicular lymphoma, follicular astrocytoma, thyroid cancer, gastrointestinal cancer, germ cell tumors The following are considered cancers: choriocarcinoma of pregnancy, giant cell fibroblastoma, giant cell tumor of bone, glioma, glioblastoma multiforme, glioma, granulosa cell tumor, androgenetic adenomas, gallbladder cancer, gastric cancer, hemangioblastoma, head and neck cancers, hemangiopericytoma, hepatoblastoma, cellular lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, fatal midline carcinoma, leukemia, testicular interstitial cell tumor, liposarcoma, lung cancer, lymphangioma, lymphoepithelioma, lymphoma, acute lymphangiosarcoma, lymphocytic leukemia, chronic lymphocytic leukemia, and liver cancer.Small cell lung cancer, non-small cell lung cancer, malt lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary breast carcinoma, medullary thyroid carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesothelioma, metastatic cell carcinoma, mixed Müllerian tumor, myxoma, multiple myeloma, muscle tissue tumor, mycosis myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, neuroblastoma, neuroma, ocular cancer, eosinophilic, optic nerve sheath meningioma, tumor, oral cancer, osteosarcoma, ovarian cancer, papillary thyroid carcinoma, paraganglioma, pineal tumor Somatic cell tumors, pituitary cell tumors, precursor T-cell lymphoblastic lymphomas, primary central nervous system lymphomas, peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyosarcoma, rhabdomyosarcoma, rectal cancer, sarcoma, seminoma, trophoblastic tumors, skin cancer, small round cell tumors, small cell carcinoma, soft tissue sarcoma, somatostatinoma, spinal cord tumors, marginal zone lymphoma of the spleen, squamous cell carcinoma, synovial sarcoma, small intestinal cancer, squamous cell carcinoma, gastric cancer, T-cell lymphoma, testicular cancer, thyroid cancer, transitional cell carcinoma, laryngeal cancer, urachal cancer, urogenital cancer, uterine cancer, verrucous carcinoma, glioma of the visual pathway, vulvar cancer or vaginal cancer.

[0017] In this invention, the cell proliferation disorder includes: benign soft tissue tumors, brain and spinal cord tumors, eyelid and orbital tumors, granulomas, lipomas, meningiomas, multiple endocrine tumors, nasal polyps, pituitary tumors, prolactinomas, seborrheic keratosis, gastric polyps, thyroid nodules, hepatic hemangiomas, vocal cord nodules, polyps, cysts, pilonidal disease, dermatofibromas, Pilar cysts, or pyogenic granulomas.

[0018] In this invention, the inflammatory diseases include: inflammatory pelvic inflammatory disease, urethritis, sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, pancreatitis, psoriasis, allergies, Crohn's disease, intestinal syndrome, ulcerative colitis, tissue transplant rejection, organ transplant rejection, asthma, allergic rhinitis, chronic obstructive pulmonary disease, autoimmune diseases, autoimmune alopecia, anemia, glomerulonephritis, dermatomyositis, and more. Scleroderma, scleroderma, vasculitis, autoimmune hemolytic anemia and thrombocytopenia, pulmonary hemorrhage and nephritis syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, myasthenia gravis, Hashimoto's thyroiditis, allergic dermatitis, degenerative joint disease, Guillain-Barré syndrome, mycosis fungoides, or acute inflammatory reactions.

[0019] The various aspects and features of the present invention will be further described below.

[0020] The various terms and phrases used in this invention have their general meanings known to those skilled in the art. Nevertheless, this invention still aims to provide a more detailed explanation and interpretation of these terms and phrases. In the event of any inconsistency between the mentioned terms and their known meanings and those of the present invention, the meaning expressed in this invention shall prevail. Below are definitions of various terms used in this invention. These definitions apply to all terms used throughout this specification, unless otherwise specified in the specific context. The following provides definitions of various groups in the compounds of this invention, which, unless otherwise defined, are used consistently in the specification and claims.

[0021] As mentioned in this invention, the terms "halogen", "halogen", "halogen atom", etc., refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0022] As mentioned in this invention, the term "alkyl" refers to an alkyl group having a specified number of carbon atoms, which can be a straight-chain alkyl group or a branched alkyl group. For example, when "C1-C6 alkyl" is mentioned, it refers to a straight-chain alkyl group or a branched alkyl group having 1-6 carbon atoms. Specific groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, etc., and similar groups.

[0023] As mentioned in this invention, the term "cycloalkyl" refers to a cyclic alkyl group having a specified number of cyclic carbon atoms. For example, when "C3-C10 cycloalkyl" is mentioned, it refers to a cycloalkyl group having 3-10 carbon atoms. Specific groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and similar groups.

[0024] As mentioned in this invention, the term "alkenyl" refers to an alkenyl group (a hydrocarbon group having one or more C=C double bonds) having a specified number of carbon atoms. It can be a straight-chain alkyl group or a branched alkenyl group. For example, when "C2-C6 alkenyl" is mentioned, it refers to a straight-chain alkyl group or a branched alkenyl group having 2-6 carbon atoms. Specific groups include vinyl, propenyl, allyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 1,3-pentadienyl, 1-hexenyl, 2-hexenyl, etc., and similar groups.

[0025] As mentioned in this invention, the term "cycloalkenyl" refers to a cyclic alkenyl group (a hydrocarbon group having one or more C=C double bonds) having a specified number of carbon atoms. For example, "C3-C10 cycloalkenyl" refers to a cyclic alkenyl group having 3-10 carbon atoms. Specific groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and similar groups.

[0026] As mentioned in this invention, the term "alkynyl" refers to an alkynyl group (a hydrocarbon group having one or more C≡C triple bonds) having a specified number of carbon atoms. It can be a straight-chain alkyl or a branched alkynyl group. For example, when "C2-C6 alkynyl" is mentioned, it refers to a straight-chain alkyl or a branched alkynyl group having 2-6 carbon atoms. Specific groups include ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-hexynyl, and similar groups.

[0027] As used in this invention, the term "heterocyclic group" refers to a non-aromatic heterocycle in which one or more of the ring-forming atoms are heteroatoms such as O, N, or S. Heterocyclic groups can include monocyclic or polycyclic ring systems (such as those having 2, 3, or 4 fused rings) and spirocyclic rings. Preferred examples of "heterocyclic" groups include, but are not limited to: azirropropyl, azirrobutyl, tetrahydrofuranyl, tetrahydrothiopheneyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, morpholinyl, thiomorpholinyl, piperazine, piperidinyl, and similar groups. Also included in the definition of heterocyclic groups are those portions having one or more aromatic rings fused to a non-aromatic heterocyclic ring (e.g., sharing a common bond), such as 2,3-dihydrobenzofuranyl, 1,3-benzodioxacyclopentenyl, benzo-1,4-dioxacyclohexyl, phthalimide, naphthalimide, and similar groups. Heterocyclic groups having one or more fused aromatic rings can be linked by either an aromatic or non-aromatic moiety.

[0028] As mentioned in this invention, the term "aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon (e.g., having 2, 3, or 4 fused rings), such as phenyl, naphthyl, anthracene, phenanthryl, indene, and similar groups.

[0029] As used in this invention, the term "heteroaryl" refers to an aromatic heterocycle having at least one heteroatom ring member such as O, N, or S. Heteroaryl groups include monocyclic or polycyclic ring systems (e.g., having 2, 3, or 4 fused rings). Any N atom cyclic in the heterocyclic group can also be oxidized to form an N-oxide. Preferred examples of "heteroaryl" groups include, but are not limited to: furanyl, thiophene, pyrrole, pyrazolyl, imidazolyl, oxazolyl, cenylyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolyl, 1, 1 H Tetraazolyl, oxadiazolyl, triazolyl, pyridyl, 3-fluoropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzoisoxazolyl; benzothiazolyl, benzofuranyl, benzothiophenyl, benzotriazinyl, phthalazinyl, thiaanthryl, dibenzofuranyl, dibenzothiophenyl, benzoimidazolyl, indoleyl, isoindoleyl, indazoleyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purineyl, pteridinyl, 9H Carbazolyl, α Carboline, indazinyl, benzoisothiazolyl, benzoxazolyl, pyrrolopyridyl, furanopyridyl, purinyl, benzothiadiazolyl, benzoxadiazolyl, benzotriazolyl, benzothiadiazolyl, carbolyl, dibenzothiaphenyl, acridineyl, and similar groups.

[0030] As mentioned in this invention, the term "single bond" refers to the direct connection between two groups attached to that position; for example, when Y 1 When it is a single key, L is directly connected to R. 1 Connected, the structure of Equation I can be expressed as: When Y 2 When it is a single bond, L is directly connected to E, and the structure of Equation I can be expressed as: To give a more specific example, Y 2 In the case of single bonds, such as compounds 8 and 9 provided in this invention.

[0031] As used herein, the term "compound" means, as is used herein, all stereoisomers, geometric isomers, tautomers, and isotopes.

[0032] The compounds of this invention can be asymmetric, for example, having one or more stereocenters. Unless otherwise specified, all stereoisomers can be enantiomers and diastereomers. Compounds of this invention containing asymmetrically substituted carbon atoms can be isolated into optically pure or racemic forms. The optically pure form can be prepared by resolving the racemic mixture or by using chiral synthons or chiral reagents.

[0033] The compounds of this invention may also include tautomer forms. New tautomer forms are generated by the exchange of single bonds and adjacent double bonds along with proton migration.

[0034] The compounds of this invention may also include all isotopic forms of atoms present in the intermediates or the final compound. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include deuterium and tritium.

[0035] As used in this invention, the term "pharmaceutical composition" can also refer to a "composition" that can be used in subjects, particularly mammals, to treat and / or prevent the diseases or conditions described in this invention.

[0036] As used in this invention, the term "disease and / or symptom" refers to a physical state of the subject that is related to the disease and / or symptom described in this invention. For example, the disease and / or symptom described in this invention can refer to either a physical state or a disease state. In this document, no distinction is made between physical state and disease state, or the two may refer to each other.

[0037] As mentioned in this invention, the term "pharmaceutically acceptable salt" means that the salt is not only physiologically acceptable to the subject, but also refers to a synthetic substance that has pharmaceutical value, such as a salt formed as an intermediate during chiral resolution, although such intermediate salt cannot be directly given to the subject, but can play a role in obtaining the end product of this invention.

[0038] Pharmaceutically acceptable salts of the compounds shown in Formula I can be formed in two forms: one is a salt formed with an acid; the other is a salt formed with a base or alkali metal. Acids that form pharmaceutically acceptable salts with the compounds shown in Formula I include inorganic acids and organic acids. Suitable inorganic acids include hydrochloric acid, sulfuric acid, and phosphoric acid. Suitable organic acids include aliphatic, cyclic aliphatic, aromatic, heterocyclic carboxylic acids, and sulfonic acid organic acids, examples of which include, but are not limited to, formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, glycine, arginine, citric acid, fumaric acid, alkyl sulfonic acid, and aromatic sulfonic acid. Alkali metals that form pharmaceutically acceptable salts with the compounds shown in Formula I include lithium, sodium, potassium, magnesium, calcium, aluminum, and zinc; bases that form pharmaceutically acceptable salts with the compounds shown in Formula I include choline, diethanolamine, and morpholine.

[0039] As mentioned in this invention, the term "prodrug" refers to derivatives of compounds of Formula I that are converted in vivo (e.g., hydrolyzed, reduced, or oxidized) into compounds of Formula I through in vivo metabolism. For example, compounds of Formula I containing hydroxyl groups can be reacted with acids to prepare the corresponding esters, which are prodrugs that can be hydrolyzed in vivo to produce the parent drug. Suitable acids for preparing "prodrugs" include, but are not limited to: acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, oxalic acid, salicylic acid, succinic acid, fumaric acid, maleic acid, and methylene-bis- β Hydroxynaphthalene acid, gentian acid, hydroxyethyl sulfonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.

[0040] Compared with the prior art, the present invention has the following beneficial effects: This invention provides a pyridazine compound that, by selecting specific functional groups, exhibits excellent anticancer effects. This class of compounds can be used to treat cancer, inflammation, and autoimmune diseases. These compounds can effectively degrade SMARCA2 and / or SMARCA4. Attached Figure Description

[0041] Figure 1 Western blot analysis of the effect of compound 2 on SMARCA2 / 4 protein expression at different concentrations after 24 hours of treatment in MV4-11 cells; Figure 2 Western blot analysis of the effect of compound 3 on SMARCA2 / 4 protein expression at different concentrations after 24 hours of treatment in MV4-11 cells; Figure 3 Study on the inhibitory activity of compounds 2 and 3 on the proliferation of MV4-11 cell line; Figure 4 In vivo antitumor activity of compounds 2 and 3 in the MV4-11 xenograft model. Detailed Implementation

[0042] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments described are not merely helpful in understanding the present invention, but should not be considered as specific limitations of the present invention.

[0043] Unless otherwise stated, temperatures are in Celsius. All reagents purchased are ready for use without further purification, unless otherwise stated.

[0044] Unless otherwise specified, the following reactions shall be carried out under positive pressure of anhydrous solvent, nitrogen or argon or using a drying tube; the reaction flask shall be sealed with a rubber stopper to allow for the addition of substrate and reagents via syringe; glassware shall be heated and dried before use.

[0045] The solvents used for NMR data include CDCl3 and DMSO- d6 etc., using tetramethylsilane (0.00 ppm) or residual solvent peaks as references (CDCl3: 7.26 ppm, DMSO- d6 (2.50 ppm). When indicating peak diversity, the following abbreviations are used to represent different peak types: s (single peak), d (double peak), t (triple peak), q (quartet), m (multiple peak), dd (double double peak). The given coupling constant is in Hertz (Hz).

[0046] Preparation Example 1: This preparation example provides the synthetic steps for the starting material W1 required for the preparation of the pyridazine compound. The synthetic route for compound W1 is shown below: a: Synthesis of 6-chloro-4-(1 H -indol-5-yl)pyridazine-3-amine (1-1) Procedure: 4-Bromo-6-chloropyridazine-3-amine (5.00 g, 24.16 mmol, 1.00 eq.) was placed in a 250 mL round-bottom flask containing dioxane / water (9:1 v / v, 100 mL total). Then, 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-1H-indole (7.05 g, 29.00 mmol, 1.20 eq.), tetraphenylphosphine palladium (2.79 g, 2.40 mmol, 0.10 eq.), and potassium carbonate (6.68 g, 48.33 mmol, 2.00 eq.) were added. Under nitrogen protection, the solution was stirred at 100 °C for 16 hours. After the reaction was detected by TLC, the solid was removed by diatomaceous earth filtration, the filter cake was washed with ethyl acetate, the filtrate was collected, concentrated to remove the organic solvent, then water was added, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate) to give a yellow solid compound 1-1 (5.01 g, yield 85%). 1 H NMR (600 MHz, DMSO- d 6) δ 11.33 (s, 1H),7.75 (d, J = 1.8 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.45 (t, J = 2.7 Hz, 1H),7.33 (s, 1H), 7.24 (dd, J = 8.4, 1.8 Hz, 1H), 6.52 (t, J = 2.6 Hz, 1H), 6.29(s, 2H). b: Synthesize 4-(1 H -indol-5-yl)-6-(2-(methoxymethoxy)phenyl)pyridazine-3-amine (1-2) Procedure: Compound 1-1 (5.00 g, 20.49 mmol, 1.0 eq.) was placed in a 100 mL round-bottom flask containing dioxane / water (5:1 v / v, 50 mL total). Then, (2-(methoxymethoxy)phenyl)boronic acid (4.48 g, 24.59 mmol, 1.2 eq.), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (1.73 g, 2.05 mmol, 0.1 eq.), and potassium carbonate (5.66 g, 40.98 mmol, 2.0 eq.) were added. The resulting solution was stirred at 95 °C for 12 hours. After the reaction was detected by TLC, the solid was removed by diatomaceous earth filtration, the filter cake was washed with ethyl acetate, the filtrate was collected, concentrated to remove the organic solvent, extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate) to give a yellow solid compound 1-2 (4.98 g, yield 69%). 1 H NMR (600 MHz, DMSO- d 6) δ11.29 (s, 1H), 7.76 (s, 1H), 7.72 (dd, J = 7.6, 1.8 Hz, 1H), 7.59 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.44 (t, J = 2.7 Hz, 1H), 7.41 – 7.34 (m, 1H), 7.27(dd, J = 8.4, 1.7 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 7.13 (t, J = 7.5 Hz,1H), 6.52 (t, J = 2.4 Hz, 1H), 6.07 (s, 2H), 5.22 (s, 2H), 3.30 (s, 3H). c: Synthesis of 6-(2-(methoxymethoxy)phenyl)-4-(1-(prop-2-yn-1-yl)-1 H -indol-5-yl)pyridazine-3-amine (1-3) Procedure: Compounds 1-2 (2.00 g, 5.78 mmol, 1.0 eq.) were added to a 200 mL round-bottom flask containing 30 mL of tetrahydrofuran solvent. The reaction mixture was then cooled to 0 °C, and sodium hydride (416 mg, 17.33 mmol, 3.0 eq.) was slowly added. After stirring at 0 °C for 1 hour, compound 3-bromopropyne (0.6 mL, 6.93 mmol, 1.2 eq.) was added. The reaction mixture was brought to room temperature and stirred for another 1 hour. After the reaction was complete as determined by TLC, the mixture was extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. The residue was purified by silica gel column filtration to give the target compounds 1-3 (1.89 g, 85% yield). 1 H NMR (600 MHz, DMSO- d 6) δ 7.82 – 7.79(m, 1H), 7.73 (dd, J = 7.6, 1.8 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.60 (s,1H), 7.50 (d, J = 3.2 Hz, 1H), 7.42 – 7.33 (m, 2H), 7.22 (dd, J = 8.4, 1.1Hz, 1H), 7.13 (td, J = 7.5, 1.1 Hz, 1H), 6.57 (dd, J = 3.2, 0.9 Hz, 1H), 6.12(s, 2H), 5.22 (s, 2H), 5.15 (d, J = 2.5 Hz, 2H), 3.43 (t, J = 2.5 Hz, 1H), 3.35 (s, 3H). d: Synthesis of 2-(6-amino-5-(1-(prop-2-yn-1-yl)-1H-indol-5-yl)pyridazin-3-yl)phenol (W1) Procedure: Compounds 1-3 (1.89 g, 4.92 mmol, 1.0 eq.) were dissolved in methanol. A 4 M dioxane hydrochloric acid solution (4.92 mL, 19.68 mmol, 4.0 eq.) was slowly added while stirring at room temperature. The mixture was stirred for another 3 hours at room temperature. After the reaction was complete as determined by TLC, the reaction mixture was concentrated under reduced pressure to give a yellow solid, compound W1 (1.22 g, 79% yield). 1 H NMR (600 MHz, DMSO- d6) δ 13.79 (s, 1H), 8.02 (s,1H), 7.98 – 7.90 (m, 1H), 7.88 – 7.79 (m, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.52(d, J = 3.2 Hz, 1H), 7.43 (dd, J = 8.4, 1.7 Hz, 1H), 7.29 – 7.21 (m, 1H), 6.97 – 6.91 (m, 1H), 6.88 (ddd, J = 8.2, 7.2, 1.3 Hz, 1H), 6.61 – 6.56 (m,1H), 6.42 (s, 2H), 5.17 (d, J = 2.5 Hz, 2H), 3.43 (q, J = 2.6 Hz, 1H). Preparation Example 2: This preparation example provides the synthetic steps for starting materials X1 and X2 required for the preparation of the pyridazine compounds. The synthetic routes for compounds X1 and X2 are shown below: a: Synthetic tert-butyl ( S 1-(4-bromophenyl)ethylcarbamate (2-1) Procedure: Under 0 °C conditions, di-tert-butyl dicarbonate (3.95 g, 18.09 mmol, 1.2 eq.) was slowly added to a mixture containing ( S The compound was prepared in a mixture of 1-(4-bromophenyl)ethylamine (3.00 g, 15.08 mmol, 1.0 eq.) and sodium bicarbonate (1.01 g, 12.06 mmol, 0.8 eq.) in water (10 mL) and ethyl acetate (10 mL). The reaction was carried out at room temperature for 4 hours. After the reaction was completed by TLC, the mixture was extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent, giving the target compound 2-1 as a white solid (4.37 g, 97% yield). 1 H NMR (400 MHz, DMSO- d 6)δ 7.49 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.2 Hz, 1H), 7.24 (d, J = 8.4 Hz, 2H), 4.58 (q, J = 7.4 Hz, 1H), 1.35 (s, 9H), 1.27 (d, J = 7.1 Hz, 3H). b: Synthetic tert-butyl ( S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethylcarbamate (2-2) Procedure: A mixture of compound 2-1 (4.37 g, 14.61 mmol, 1.0 eq.), 4-methylthiazole (2.89 g, 29.22 mmol, 2.0 eq.), palladium acetate (328 mg, 0.10 mmol, 0.1 eq.), and potassium acetate (2.40 g, 29.22 mmol, 2.0 eq.) was dissolved in... N , N The reaction mixture was prepared in dimethylacetamide (20 mL). Under nitrogen protection, the reaction mixture was stirred at 90 °C for 18 hours. After cooling to room temperature, the reaction was detected by TLC. The mixture was then extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound 2-2 as a grayish-white solid (3.11 g, yield 67%). 1 H NMR (400 MHz, DMSO- d 6) δ 8.98 (s, 1H), 7.41 (d, J = 12.3 Hz, 4H), 7.37(s, 1H), 4.71 – 4.60 (m, 1H), 2.45 (s, 4H), 1.37 (s, 10H), 1.33 (d, J = 7.1Hz, 4H). c: Synthesis ( S )-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethylamine (2-3) Procedure: Compound 2-2 (4.37 g, 13.74 mmol, 1.0 eq.) was dissolved in methanol. A solution of 1,4-dioxane in 4 M hydrochloric acid (5 mL, 20 mmol, 4.0 eq.) was slowly added dropwise under stirring at room temperature. The mixture was stirred for another 3 hours at room temperature. After the reaction was complete as determined by TLC, the reaction solution was concentrated under reduced pressure to give crude compound 2-3 as a yellow solid (2.37 g, 79% yield).

[0047] d: Synthesis (2) S 4 R )-4-hydroxy-2-((( S 1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-tert-butyl ester (2-4) Steps: At room temperature, N,N,N',N '-Tetramethyl- O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (4.13 g, 10.87 mmol, 1.0 eq.) was added to a mixture containing compound 2-3 (2.37 g, 10.87 mmol, 1.0 eq.). N -Boc-cis-4-hydroxy- D -proline (3.01 g, 13.04 mmol, 1.2 eq.) and diisopropylethylamine (9.50 mL, 54.33 mmol, 5.0 eq.) N,N The reaction mixture was stirred in a dimethylformamide solution for 2 hours at room temperature. After the reaction was completed by TLC, the mixture was extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give a white solid compound 2-4 (2.95 g, 63% yield). 1 H NMR (600 MHz, CDCl3) δ 8.67 (s, 1H), 7.39 (t, J = 6.5 Hz, 4H), 5.06 (s, 1H), 4.47 (d, J = 39.5 Hz, 2H), 3.78 – 3.35 (m,2H), 2.51 (s, 3H), 2.24 – 1.91 (m, 3H), 1.58 – 1.18 (m, 10H). e: Synthesis (2) S 4 R )-4-hydroxy- N -(( S )-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (2-5) Procedure: Compound 2-4 (2.95 g, 6.84 mmol, 1.0 eq.) was dissolved in methanol. A 4 mol / L dioxane hydrochloric acid solution (6.84 mL, 27.37 mmol, 4.0 eq.) was slowly added with stirring at room temperature. The mixture was stirred for another 3 hours at room temperature. After the reaction was complete as determined by TLC, the reaction mixture was concentrated under reduced pressure to give a crude, light green solid, compound 2-5 (1.52 g, 67% yield).

[0048] f: Synthesis N -((1 S )-1-((2 S 4 R )-4-hydroxy-2-((( S )-1-(4-(4-methylthiazo-5-yl)phenyl)ethyl)carbamoyl)pyrrolidone-1-yl)-3,3-dimethyl-1-oxobut-2-yl)tert-butyl carbamate (2-6) Steps: At room temperature, N,N,N',N' -Tetramethyl- O -(7-azabenzotriazol-1-yl)hexafluorophosphate urea (1.75 g, 4.59 mmol, 1.0 eq.) was added to a mixture containing compound 2-5 (1.52 g, 4.59 mmol, 1.0 eq.). N -Boc- L -Tertiary leucine (1.27 g, 5.51 mmol, 1.2 eq.) and diisopropylethylamine (4.00 mL, 22.95 mmol, 5.0 eq.) N,N The reaction mixture was stirred in a dimethylformamide solution for 2 hours at room temperature. After the reaction was completed by TLC, the mixture was extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give a white solid compound 2-6 (1.32 g, 53% yield). 1 H NMR (400 MHz, DMSO- d 6) δ 8.98 (s, 1H), 8.39 (d, J =7.7 Hz, 1H), 7.49 – 7.32 (m, 4H), 6.39 (d, J = 9.2 Hz, 1H), 4.90 (p, J = 7.1Hz, 1H), 4.45 (t, J = 8.0 Hz, 1H), 4.28 (t, J = 3.6 Hz, 1H), 4.14 (d, J = 9.3Hz, 1H), 3.63 – 3.52 (m, 2H), 2.45 (s, 3H), 2.08 – 1.72 (m, 2H), 1.38 (s,12H), 0.93 (s, 9H). g: Synthesis (2) S 4 R )-1-(( S )-2-amino-3,3-dimethylbutyryl)-4-hydroxy- N -(( S )-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (X1) Procedure: Compounds 2-6 (1.75 g, 4.60 mmol, 1.0 eq.) were dissolved in methanol. 4 M dioxane hydrochloric acid solution (4.60 mL, 18.41 mmol, 4.0 eq.) was slowly added under stirring at room temperature. The mixture was stirred for another 3 hours at room temperature. After the reaction was complete as detected by TLC, the reaction solution was concentrated under reduced pressure to give a light green solid, compound X1 (1.35 g, 66% yield).1 H NMR (600 MHz, MeOD) δ 8.88 (d, J = 4.5 Hz, 1H), 7.50 – 7.40 (m,4H), 5.00 (q, J = 7.0 Hz, 1H), 4.64 (dd, J = 9.0, 7.7 Hz, 1H), 4.45 (dq, J =4.2, 2.0 Hz, 1H), 3.79 (dt, J = 11.3, 1.8 Hz, 1H), 3.67 (dd, J = 11.2, 3.8Hz, 1H), 3.62 (d, J = 7.7 Hz, 1H), 2.47 (s, 3H), 2.25 (ddt, J = 13.2, 7.8,2.0 Hz, 1H), 1.95 (ddd, J = 13.3, 9.1, 4.4 Hz, 1H), 1.51 (d, J = 7.1 Hz, 3H), 1.05 (d, J = 12.5 Hz, 9H). h: Synthesis (2) S 4 R )-1-(( S )-2-Azide-3,3-dimethylbutyryl)-4-hydroxy- N -(( S )-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (X2) Procedure: Compound X1 (500 mg, 1.13 mmol, 1.0 eq.), 1H-imidazolium-1-sulfonyl azidohydrochloride (283 mg, 1.35 mmol, 1.2 eq.), potassium carbonate (389 mg, 2.81 mmol, 2.5 eq.), and copper sulfate (36 mg, 0.23 mmol, 0.2 eq.) were added sequentially to a reaction flask. Then, 20 mL of methanol was added as a solvent, and the suspension was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with 20 mL of water, and methanol was removed by rotary evaporation under reduced pressure. The pH of the aqueous phase was adjusted to 3 with potassium bisulfate, followed by extraction three times with 50 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound X2 (476 mg, 90% yield). 1 H NMR (400 MHz, Acetone- d6) δ 8.85 (d, J =2.3 Hz, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.56 – 7.42 (m, 4H), 5.10 – 5.07 (m, J= 7.2 Hz, 1H), 4.69 (t, J = 8.1 Hz, 1H), 4.49 – 4.45 (m, 1H), 4.31 (d, J =3.8 Hz, 1H), 3.88 (s, 1H), 3.76 (dt, J = 10.9, 1.9 Hz, 1H), 3.71 – 3.64 (m,1H), 2.48 (d, J = 2.0 Hz, 3H), 2.23 – 2.05 (m, 2H), 1.48 (d, J = 7.0 Hz, 3H), 1.10 (s, 9H). Example 1 a: Synthesis of tert-butyl2-(5-(3-amino-6-chloropyridazin-4-yl)-1 H -Indole-1-yl)acetate (5-1) Procedure: Compound 1-1 (2.00 g, 5.78 mmol, 1.0 eq.) was added to a 200 mL round-bottom flask containing 30 mL of tetrahydrofuran solvent. The reaction mixture was then cooled to 0 °C, and sodium hydride (416 mg, 17.33 mmol, 3.0 eq.) was slowly added. After stirring at 0 °C for 1 hour, tert-butyl 2-bromoacetate (1.43 mL, 6.93 mmol, 1.2 eq.) was added, and the reaction mixture was brought to room temperature and stirred for another hour. After the reaction was complete as determined by TLC, the mixture was extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. The residue was purified by silica gel column filtration to give the target compound 5-1 (2.35 g, 80% yield). 1 H NMR (400 MHz, DMSO- d 6) δ 7.73 (d, J =1.7 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.38 (d, J = 3.2 Hz, 1H), 7.30 (s,1H), 7.25 (dd, J = 8.6, 1.8 Hz, 1H), 6.50 (d, J = 3.2 Hz, 1H), 6.24 (s, 2H), 5.02 (s, 2H), 1.40 (s, 9H). b: Synthesis of tert-butyl-2-(5-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1 H -Indole-1-yl)acetate (5-2) Procedure: Compound 5-1 (5.00 g, 20.49 mmol, 1.0 eq.) was placed in a 100 mL round-bottom flask containing dioxane / water (5:1 v / v, 50 mL total). Then, 2-hydroxyphenylboronic acid (2.31 g, 24.59 mmol, 1.2 eq.), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (1.73 g, 2.05 mmol, 0.1 eq.), and potassium carbonate (5.66 g, 40.98 mmol, 2.0 eq.) were added. The resulting solution was stirred at 95 °C for 12 hours. After the reaction was detected by TLC, the solid was removed by diatomaceous earth filtration, the filter cake was washed with ethyl acetate, the filtrate was collected, concentrated to remove the organic solvent, extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate) to give a yellow solid compound 5-2 (4.24 g, yield 73%). 1 H NMR (400 MHz, DMSO- d 6) δ 13.74 (s, 1H), 7.98 (s, 1H), 7.94 – 7.90 (m, 1H), 7.82 (d, J = 1.6 Hz, 1H), 7.51 (d, J = 8.5Hz, 1H), 7.40 (d, J = 3.2 Hz, 1H), 7.35 (dd, J = 8.6, 1.7 Hz, 1H), 7.21 (t, J= 7.5 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.84 (t, J = 7.5 Hz, 1H), 6.54 (d, J= 3.2 Hz, 1H), 6.37 (s, 2H), 5.05 (s, 2H), 1.41 (s, 9H). c: Synthesis of 2-(5-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1 H -Indole-1-yl)acetic acid (5-3) Procedure: At room temperature, trifluoroacetic acid (1.07 mL, 14.42 mmol, 3.0 eq.) was slowly added dropwise to a stirred solution of compound 5-2 (2.00 g, 4.81 mmol, 1.0 eq.) in dichloromethane (10 mL). The mixture was stirred for 2 hours, and then the solvent was removed under reduced pressure to give crude compound 5-3 (1.44 g, 83% yield).

[0049] d:(2 S 4 R )-1-(( S )-2-(2-(5-(3-amino-6-(2-hydroxyphenyl)pyridazine-4-yl)-1 H -indol-1-yl)acetamido)-3,3-dimethylbutyryl)-4-hydroxy- N -(( S )-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (1) Steps: At room temperature, N,N,N',N' -Tetramethyl- O -(7-azabenzotriazol-1-yl)hexafluorophosphate (171 mg, 0.45 mmol, 1.0 equivalent) was added to a mixture containing Y1 (162 mg, 0.45 mmol, 1.0 equivalent), 5-3 (200 mg, 0.45 mmol, 1.0 equivalent), and... N,N -Diisopropylethylamine (0.40 mL, 2.25 mmol, 5.0 equivalents) N,N - Dimethylformamide solution. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed by TLC, water and ethyl acetate were added for extraction, followed by washing with saturated brine, drying with anhydrous sodium sulfate, concentration under reduced pressure and purification by column chromatography to give a white solid compound (1) (106 mg, yield 30%). 1 H NMR (600 MHz, DMSO- d6) δ 13.80 (s, 1H), 8.98 (s, 1H), 8.42(d, J = 7.8 Hz, 1H), 8.29 (d, J = 9.3 Hz, 1H), 8.02 (s, 1H), 7.96 (dd, J =8.1, 1.6 Hz, 1H), 7.85 (d, J = 1.7 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.46 (d, J = 3.1 Hz, 1H), 7.44 (d, J = 1.8 Hz, 0H), 7.43 (d, J = 2.0 Hz, 1H), 7.40– 7.36 (m, 3H), 7.25 (ddt, J = 10.9, 5.4, 2.7 Hz, 1H), 6.94 – 6.91 (m, 1H), 6.88 (ddd, J = 8.2, 7.2, 1.3 Hz, 1H), 6.56 (dd, J = 3.2, 0.8 Hz, 1H), 6.41(s, 2H), 5.11 – 5.09 (m, 1H), 5.05 (d, J = 31.5 Hz, 1H), 4.92 (q, J = 7.1 Hz,1H), 4.52 (d, J = 9.3 Hz, 1H), 4.44 (t, J = 8.2 Hz, 1H), 4.27 (s, 1H), 3.60(dd, J = 10.6, 4.1 Hz, 1H), 3.55 – 3.49 (m, 1H), 2.45 (s, 3H), 2.01 (q, J =13.5, 12.1 Hz, 1H), 1.78 (ddd, J = 13.0, 8.8, 4.6 Hz, 1H), 1.39 (d, J = 7.0Hz, 3H), 1.38 – 1.32 (m, 1H), 0.97 (s, 9H). Example 2 a:(2 S 4 R )-1-(2-(3-(5-(3-amino-6-(2-hydroxyphenyl)pyridazine-4-yl)-1 H -indol-1-yl)propamido)-3,3-dimethylbutyryl)-4-hydroxy- N -(( S )-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (2) The synthesis method follows the synthesis route of Example 1.

[0050] The only difference is that tert-butyl 2-bromoacetate is replaced with an equimolar amount of tert-butyl 3-bromopropionate.

[0051] Compound 2 is a white solid (145 mg, yield 34%). 1 H NMR (400 MHz, DMSO- d 6) δ 13.78(s, 1H), 8.98 (s, 1H), 8.38 (d, J = 7.7 Hz, 1H), 8.09 (d, J = 9.2 Hz, 1H), 8.00 (s, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.83 (s, 1H), 7.69 (d, J = 8.6 Hz,1H), 7.43 (d, J = 8.3 Hz, 3H), 7.39 (s, 3H), 7.25 (t, J = 7.8 Hz, 1H), 7.00 –6.79 (m, 2H), 6.53 (s, 1H), 6.38 (s, 2H), 5.15 (s, 1H), 4.94 (q, J = 9.9, 7.3Hz, 1H), 4.66 – 4.36 (m, 4H), 4.31 (s, 1H), 3.63 (s, 2H), 2.79 – 2.75 (m,2H), 2.45 (s, 3H), 2.13 – 1.70 (m, 2H), 1.45 – 1.17 (m, 3H), 0.90 (s, 9H). Example 3 a:(2 S 4 R )-1-(2-(4-(5-(3-amino-6-(2-hydroxyphenyl)pyridazine-4-yl)-1 H -indol-1-yl)propamido)-3,3-dimethylbutyryl)-4-hydroxy- N -(( S )-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (3) The synthesis method follows the synthesis route of Example 1.

[0052] The only difference is that tert-butyl 2-bromoacetate is replaced with an equimolar amount of tert-butyl 4-bromobutyrate.

[0053] Compound 3 is a yellow solid (89 mg, yield 30%). 1 H NMR (400 MHz, DMSO-d 6) δ 13.80(s, 1H), 8.98 (s, 1H), 8.37 (d, J = 7.8 Hz, 1H), 8.02 (s, 1H), 7.99 – 7.91(m, 2H), 7.88 – 7.79 (m, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 3.1 Hz, 1H), 7.44 – 7.35 (m, 5H), 7.25 (ddd, J = 8.5, 7.1, 1.6 Hz, 1H), 6.95 – 6.88(m, 1H), 6.91 – 6.84 (m, 1H), 6.55 (d, J = 3.1 Hz, 1H), 6.42 (s, 2H), 5.11(d, J = 3.5 Hz, 1H), 4.94 – 4.91 (m, 1H), 4.54 (t, J = 9.3 Hz, 1H), 4.43 (t,J = 8.1 Hz, 1H), 4.29 (q, J = 3.5 Hz, 1H), 4.23 (t, J = 7.1 Hz, 2H), 3.63 (d,J = 3.1 Hz, 2H), 2.45 (s, 3H), 2.31 – 2.24 (m, 1H), 2.22 – 2.13 (m, 1H), 2.06– 1.93 (m, 3H), 1.79 (ddd, J = 13.0, 8.6, 4.6 Hz, 1H), 1.36 (d, J = 7.0 Hz, 3H), 0.95 (d, J = 5.3 Hz, 9H). Example 4 a:(2 S 4 R )-1-(2-(5-(5-(3-amino-6-(2-hydroxyphenyl)pyridazine-4-yl)-1 H -indol-1-yl)propamido)-3,3-dimethylbutyryl)-4-hydroxy- N -(( S )-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (4) The synthesis method follows the synthesis route of Example 1.

[0054] The only difference is that tert-butyl 2-bromoacetate is replaced with an equimolar amount of tert-butyl 5-bromobutyrate.

[0055] Compound 4 is a yellow solid (100 mg, yield 33%). 1 H NMR (400 MHz, DMSO- d 6) δ 13.74(s, 1H), 8.98 (s, 1H), 8.37 (d, J = 7.8 Hz, 1H), 8.02 (s, 1H), 7.95 (dd, J =8.1, 1.6 Hz, 1H), 7.86 (d, J = 9.4 Hz, 1H), 7.84 (d, J = 1.7 Hz, 1H), 7.67(d, J = 8.5 Hz, 1H), 7.49 (d, J = 3.1 Hz, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.38(td, J = 5.9, 2.7 Hz, 3H), 7.28 – 7.22 (m, 1H), 6.93 (d, , 4.52 (d, J = 9.3 Hz, 1H), 4.42 (t, J= 8.1 Hz, 1H), 4.31 – 4.27 (m, 2H), 4.25 (t, J = 6.9 Hz, 2H), 3.64 – 3.55 (m,2H), 2.45 (s, 3H), 2.33 (dt, J = 14.7, 7.5 Hz, 1H), 2.19 – 2.16 (m 1H), 2.04 – 2.00 (m, 1H), 1.80 – 1.76 (m, 3H), 1.57 – 1.40 (m, 2H), 1.37 (d, J = 7.0Hz, 3H), 1.29 – 1.19 (m, 3H), 0.93 (s, 9H). Example 5 a:(2 S 4 R )-1-(2-(6-(5-(3-amino-6-(2-hydroxyphenyl)pyridazine-4-yl)-1 H -indol-1-yl)propamido)-3,3-dimethylbutyryl)-4-hydroxy- N -(( S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (5) The synthesis method follows the synthesis route of Example 1.

[0056] The only difference is that tert-butyl 2-bromoacetate is replaced with an equimolar amount of tert-butyl 6-bromobutyrate.

[0057] Compound 5 is a yellow solid (107 mg, yield 35%). 1 H NMR (400 MHz, DMSO- d 6) δ 13.78(s, 1H), 8.98 (s, 1H), 8.37 (d, J = 7.8 Hz, 1H), 8.02 (s, 1H), 7.96 (dd, J =8.1, 1.6 Hz, 1H), 7.85 (d, J = 1.6 Hz, 1H), 7.82 (d, J = 9.3 Hz, 1H), 7.68 (dd, J = 18.1, 8.8 Hz, 1H), 7.48 (d, J = 3.1 Hz, 1H), 7.46 – 7.32 (m, 5H), 7.29 – 7.20 (m, 1H), 6.94 (dd, J = 8.2, 1.2 Hz, 1H), 6.92 – 6.85 (m, 1H), 6.55 (d, J = 3.1 Hz, 1H), 6.41 (s, 2H), 5.13 (d, J = 3.5 Hz, 1H), 4.98 – 4.84(m, 1H), 4.53 (d, J = 9.4 Hz, 1H), 4.44 (t, J = 8.1 Hz, 1H), 4.30 (q, J = 3.5Hz, 1H), 4.23 (t, J = 7.0 Hz, 2H), 3.62 (d, J = 3.4 Hz, 2H), 2.54 – 2.50 (m,2H), 2.26 (dt, J = 14.6, 7.6 Hz, 1H), 2.17 – 2.14 (m, 1H), 2.05 – 2.01 (m,1H), 1.84 – 1.80 (m, 3H), 1.56 – 1.53 (m, 2H), 1.38 (d, J = 7.0 Hz, 3H), 1.33– 1.16 (m, 4H), 0.94 (s, 9H), 0.90 – 0.81 (m, 1H). Example 6 a:(2S 4 R )-1-(2-(7-(5-(3-amino-6-(2-hydroxyphenyl)pyridazine-4-yl)-1 H -indol-1-yl)propamido)-3,3-dimethylbutyryl)-4-hydroxy- N -(( S )-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (6) The synthesis method follows the synthesis route of Example 1.

[0058] The only difference is that 2-hydroxyphenylboronic acid is replaced with an equimolar amount of 3-hydroxyphenylboronic acid.

[0059] Compound 6 is a yellow solid (99 mg, yield 34%). 1 H NMR (400 MHz, DMSO- d 6) δ 9.52(s, 1H), 8.99 (s, 1H), 8.39 (d, J = 7.8 Hz, 1H), 8.09 (d, J = 9.3 Hz, 1H), 7.81 (d, J = 1.7 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.63 (s, 1H), 7.54 – 7.47(m, 2H), 7.46 – 7.42 (m, 4H), 7.41 – 7.36 (m, 3H), 7.26 (t, J = 7.8 Hz, 1H), 6.81 (dd, J = 8.0, 2.5 Hz, 1H), 6.51 (d, J = 3.1 Hz, 1H), 6.20 (s, 2H), 5.15(d, J = 3.5 Hz, 1H), 4.99 – 4.88 (m, 1H), 4.57 (d, J = 9.3 Hz, 1H), 4.47 –4.43 (m, 3H), 4.30 (p, J = 3.5 Hz, 1H), 3.67 – 3.57 (m, 2H), 2.84 (dt, J =14.6, 7.3 Hz, 1H), 2.70 (dt, J = 14.4, 6.7 Hz, 1H), 2.46 (s, 3H), 2.07 – 1.95(m, 2H), 1.81 (ddd, J = 12.9, 8.5, 4.6 Hz, 1H), 1.38 (d, J = 7.0 Hz, 3H), 0.90 (s, 9H). Example 7 a:(2 S 4 R )-1-(2-(8-(5-(3-amino-6-(2-hydroxyphenyl)pyridazine-4-yl)-1 H -indol-1-yl)propamido)-3,3-dimethylbutyryl)-4-hydroxy- N -(( S )-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (7) The synthesis method follows the synthesis route of Example 2.

[0060] The only difference is that ethyl acrylate is replaced with an equimolar amount of ethyl 2-bromopropionate.

[0061] Compound 7 is a yellow solid (96 mg, yield 33%). 1 H NMR (400 MHz, DMSO- d6) δ 13.71(s, 1H), 8.98 (d, J = 2.6 Hz, 1H), 8.43 (d, J = 7.8 Hz, 1H), 8.31 (d, J = 9.1Hz, 1H), 8.02 (d, J = 3.6 Hz, 1H), 8.00 – 7.91 (m, 1H), 7.84 (dd, J = 8.1,1.7 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.64 (d, J = 3.3 Hz, 1H), 7.48 – 7.41(m, 2H), 7.40 – 7.35 (m, 2H), 7.31 – 7.22 (m, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.89 (t, J = 7.6 Hz, 1H), 6.59 (d, J = 3.3 Hz, 1H), 6.46 (s, 2H), 5.61 (q, J= 6.7 Hz, 1H), 5.15 (d, J = 3.3 Hz, 1H), 4.95 – 4.92 (m, 1H), 4.46 (d, J =9.0 Hz, 1H), 4.27 (d, J = 24.8 Hz, 1H), 3.67 – 3.49 (m, 2H), 2.45 (d, J = 4.2Hz, 3H), 2.11 – 1.92 (m, 1H), 1.80 (ddd, J = 13.0, 8.7, 4.6 Hz, 1H), 1.65 (d,J = 7.0 Hz, 3H), 1.38 (t, J = 6.7 Hz, 3H), 1.24 (d, J = 7.1 Hz, 3H), 0.88 (s,9H). Example 8 a:(2 S 4 R )-1-(( S )-2-(4-((5-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1H-indol-1-yl)methyl)-1 H -1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxy- N -(( S )-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (8) Procedure: Compound X2 (100 mg, 0.21 mmol, 1.0 eq.), compound W1 (72 mg, 0.21 mmol, 1.0 eq.), sodium ascorbate (4 mg, 0.10 mmol, 0.1 eq.), and copper sulfate pentahydrate (5 mg, 0.10 mmol, 0.1 eq.) were added sequentially to a 100 mL round-bottom flask. Then, a mixed solvent of methanol / dichloromethane / water (2:2:1, 5 mL, v / v) was added to the flask. The suspension was stirred at room temperature for 1 hour. After the reaction was complete as determined by TLC, the mixture was extracted with water and dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give compound 8 (91 mg, 53% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 13.76 (s, 1H), 8.98 (s, 1H), 8.50 (d, J = 7.6 Hz, 1H), 8.38 (s, 1H), 8.02 (s, 1H), 7.95 (dt, J = 8.1, 2.1Hz, 1H), 7.86 – 7.80 (m, 2H), 7.61 (d, J = 3.2 Hz, 1H), 7.49 – 7.40 (m, 3H), 7.40 – 7.32 (m, 3H), 7.25 (ddd, J = 8.5, 7.2, 1.6 Hz, 1H), 6.93 (dd, J = 8.2,1.3 Hz, 1H), 6.91 – 6.83 (m, 1H), 6.58 (d, J = 3.1 Hz, 1H), 6.45 (s, 2H), 5.56 (d, J = 6.7 Hz, 2H), 5.50 (d, J = 5.8 Hz, 1H), 5.12 (d, J = 3.6 Hz, 1H), 4.97 – 4.86 (m, 1H), 4.39 (t, J = 8.3 Hz, 1H), 4.28 (s, 1H), 3.65 (d, J = 4.2Hz, 2H), 2.45 (d, J = 3.7 Hz, 3H), 2.02 (ddd, J = 23.8, 11.4, 6.9 Hz, 1H),1.75 (ddd, J = 13.1, 9.1, 4.4 Hz, 1H), 1.38 (d, J = 7.0 Hz, 3H), 0.96 (s,9H). Example 9 a: 6-(2-(methoxymethoxy)phenyl)-4-(1-(pent-4-yn-1-yl)-1 H -indol-5-yl)pyridazin-3-amine(6-1) Procedure: Compounds 1-2 (2.00 g, 5.78 mmol, 1.0 eq.) were added to a 200 mL round-bottom flask containing 30 mL of tetrahydrofuran solvent. The reaction mixture was then cooled to 0 °C, and sodium hydride (416 mg, 17.33 mmol, 3.0 eq.) was slowly added. After stirring at 0 °C for 1 hour, compound 5-bromopentyne (0.6 mL, 6.93 mmol, 1.2 eq.) was added. The reaction mixture was brought to room temperature and stirred for another 1 hour. After the reaction was complete as determined by TLC, the mixture was extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. The residue was purified by silica gel column filtration to give the target compound 6-1 (1.91 g, 80% yield). 1 H NMR (400 MHz, DMSO- d 6) δ 7.79 (d, J =1.7 Hz, 1H), 7.73 (dd, J = 7.6, 1.8 Hz, 1H), 7.67 – 7.63 (m, 1H), 7.60 (s,1H), 7.46 (d, J = 3.1 Hz, 1H), 7.41 – 7.32 (m, 2H), 7.22 (dd, J = 8.3, 1.1Hz, 1H), 7.14 (td, J = 7.5, 1.1 Hz, 1H), 6.58 – 6.52 (m, 1H), 6.12 (s, 2H),5.23 (s, 2H), 4.30 (t, J = 7.0 Hz, 2H), 3.42 – 3.34 (m, 3H), 2.90 (t, J = 2.6Hz, 1H), 2.16 (td, J = 7.1, 2.7 Hz, 2H), 1.97 – 1.95 (m, 2H). b: 2-(6-amino-5-(1-(pent-4-yn-1-yl)-1 H -indol-5-yl)pyridazin-3-yl)phenol (6-2) Procedure: Compound 6-1 (1.91 g, 4.92 mmol, 1.0 eq.) was dissolved in methanol. A 4 M dioxane hydrochloric acid solution (4.92 mL, 19.68 mmol, 4.0 eq.) was slowly added while stirring at room temperature. The mixture was stirred for another 3 hours at room temperature. After the reaction was complete as determined by TLC, the reaction mixture was concentrated under reduced pressure to give a yellow solid, compound 6-2 (1.23 g, 72% yield). 1 H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.87 (t, J =2.0 Hz, 1H), 7.75 – 7.71 (m, 2H), 7.45 (dd, J = 7.0, 2.2 Hz, 1H), 7.30 (d, J= 4.9 Hz, 1H), 7.25 (td, J = 7.9, 1.3 Hz, 1H), 7.01 (ddd, J = 9.0, 7.7, 1.5Hz, 1H), 6.95 (dd, J = 8.2, 1.4 Hz, 1H), 6.57 (dd, J = 5.2, 2.0 Hz, 1H), 6.01(s, 2H), 4.04 (t, J = 5.8 Hz, 2H), 2.52 (td, J = 5.7, 3.0 Hz, 2H), 2.05 (t, J= 3.0 Hz, 1H), 1.89 (p, J = 5.7 Hz, 2H). c:(2 S 4 R )-1-(( S )-2-(4-(3-(5-(3-amino-6-(2-hydroxyphenyl)pyridazine-4-yl)-1 H -indol-1-yl)propyl)-1 H -1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxy- N -(( S )-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (9) Procedure: Compound 6-2 (100 mg, 0.21 mmol, 1.0 eq.), compound W1 (72 mg, 0.21 mmol, 1.0 eq.), sodium ascorbate (4 mg, 0.10 mmol, 0.1 eq.), and copper sulfate pentahydrate (5 mg, 0.10 mmol, 0.1 eq.) were added sequentially to a 100 mL round-bottom flask. Then, a mixed solvent of methanol / dichloromethane / water (2:2:1, 5 mL, v / v) was added to the flask. The suspension was stirred at room temperature for 1 hour. After the reaction was complete as determined by TLC, the mixture was extracted with water and dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain a white solid compound 9 (64 mg, 50% yield). 1 H NMR (400 MHz, DMSO- d 6) δ 13.76 (s, 1H), 8.01 (s, 1H), 7.95 (dd, J = 8.1, 1.6 Hz, 1H), 7.85 (d, J = 1.7 Hz, 1H), 7.66 (d, J = 8.5Hz, 1H), 7.48 (d, J = 3.1 Hz, 1H), 7.39 (dd, J = 8.5, 1.7 Hz, 1H), 7.25 (td,J = 7.7, 7.1, 1.5 Hz, 1H), 6.93 (dd, J = 8.2, 1.3 Hz, 1H), 6.88 (t, J = 7.6Hz, 1H), 6.56 (d, J = 3.1 Hz, 1H), 6.41 (s, 2H), 4.31 (t, J = 6.8 Hz, 2H), 2.89 (dt, J = 2.7, 1.8 Hz, 1H), 2.14 (td, J = 7.2, 2.6 Hz, 2H), 1.99 – 1.95 (m, 3H). Example 10 a: 2-Bromo- N -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)acetamide (7-1) Procedure: At 0 °C, oxalyl chloride (8.7 mL, 8.70 mmol, 1.2 eq.) and N,NDimethylformamide (30 μL) was added to a solution of anhydrous dichloromethane (10 mL) containing 2-bromoacetic acid (1.00 g, 7.25 mmol, 1.0 eq.). The reaction mixture was brought to room temperature and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure. The resulting product was dissolved in anhydrous tetrahydrofuran (10 mL) and pomalidomide (1.58 g, 5.80 mmol, 0.8 eq.) was added. The reaction mixture was stirred at 75 °C for 12 hours. After the reaction was completed by TLC, the product was extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent, giving a white crude compound 7-1 (1.80 g, 63% yield).

[0062] b: 2-Azide- N -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)acetamide (7-2) Procedure: Compound 7-1 (1.80 g, 4.58 mmol, 1.0 eq.) and sodium azide (0.89 g, 13.74 mmol, 3.0 eq.) were added to a 100 mL round-bottom flask, followed by the addition of dimethyl sulfoxide (20 mL). The reaction mixture was stirred overnight at 70 °C. After the reaction solution cooled to room temperature, the reaction was detected by TLC. The mixture was then extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent, yielding a white crude compound 7-2 (1.47 g, 90% yield).

[0063] c: 2-(4-((5-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1 H -indole-1-yl)methyl)-1 H -1,2,3-triazol-1-yl)- N -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)acetamide (10) Procedure: Compound W1 (476 mg, 1.01 mmol, 1.0 eq.), compound 7-2 (155 mg, 1.01 mmol, 1 eq.), sodium ascorbate (20 mg, 0.10 mmol, 0.1 eq.), and copper sulfate pentahydrate (25 mg, 0.10 mmol, 0.1 eq.) were added sequentially to a 100 mL round-bottom flask. A mixed solvent of methanol / dichloromethane / water (2:2:1, 5 mL total) was then added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete as determined by TLC, the mixture was extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent, yielding a white solid, compound 10 (486 mg, 77% yield). 1 H NMR (600 MHz, DMSO- d 6) δ 13.79 (s, 1H), 11.17 (s, 1H),10.20 (s, 1H), 8.34 (dd, J = 8.4, 0.8 Hz, 1H), 8.15 (s, 1H), 8.00 (s, 1H),7.95 (dd, J = 8.1, 1.6 Hz, 1H), 7.88 – 7.79 (m, 3H), 7.71 – 7.64 (m, 1H), 7.60 (d, J = 3.2 Hz, 1H), 7.40 (dd, J = 8.5, 1.7 Hz, 1H), 7.25 (ddd, J = 8.4,7.1, 1.6 Hz, 1H), 6.93 (dd, J = 8.2, 1.2 Hz, 1H), 6.88 (ddd, J = 8.2, 7.1,1.3 Hz, 1H), 6.58 (dd, J = 3.1, 0.9 Hz, 1H), 6.40 (s, 2H), 5.59 (s, 2H), 5.53(s, 2H), 5.16 (dd, J = 12.9, 5.5 Hz, 1H), 2.91 (ddd, J = 17.1, 13.9, 5.4 Hz, 1H), 2.66 – 2.59 (m, 1H), 2.58 – 2.52 (m, 1H), 2.12 – 1.95 (m, 1H). Example 11 a: 3-(4-((5-(3-amino-6-(2-hydroxyphenyl)pyridazine-4-yl)-1 H -indole-1-yl)methyl)-1 H -1,2,3-triazol-1-yl)- N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)propionamide (11) The synthesis method follows the synthesis route of Example 10.

[0064] The only difference is that 2-bromoacetic acid is replaced with an equimolar amount of 3-bromopropionic acid.

[0065] Compound 11 is a yellow solid (102 mg, yield 34%). 1 H NMR (600 MHz, DMSO- d 6) δ 13.77(s, 1H), 11.15 (s, 1H), 9.89 (s, 1H), 8.33 (d, J = 8.4 Hz, 1H), 8.12 (s, 1H),7.97 (s, 1H), 7.93 (dd, J = 8.1, 1.6 Hz, 1H), 7.85 – 7.79 (m, 2H), 7.75 (d, J= 8.5 Hz, 1H), 7.62 (d, J = 7.3 Hz, 1H), 7.55 (d, J = 3.1 Hz, 1H), 7.34 (dd,J = 8.4, 1.7 Hz, 1H), 7.25 (ddd, J = 8.4, 7.1, 1.5 Hz, 1H), 6.92 (dd, J =8.2, 1.2 Hz, 1H), 6.91 – 6.85 (m, 1H), 6.56 – 6.51 (m, 1H), 6.37 (s, 2H),5.51 (s, 2H), 5.13 (dd, J = 12.9, 5.5 Hz, 1H), 4.64 (t, J = 6.6 Hz, 2H), 3.13 (t, J = 6.7 Hz, 2H), 2.89 (ddd, J = 17.1, 13.9, 5.5 Hz, 1H), 2.64 – 2.57 (m,1H), 2.10 – 1.95 (m, 2H). Example 12 a: 4-(4-((5-(3-amino-6-(2-hydroxyphenyl)pyridazine-4-yl)-1 H -indole-1-yl)methyl)-1 H -1,2,3-triazol-1-yl)- N -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)butyramide (12) The synthesis method follows the synthesis route of Example 10.

[0066] The only difference is that 2-bromoacetic acid is replaced with an equimolar amount of 4-bromobutyric acid.

[0067] Compound 12 is a yellow solid (100 mg, yield 30%). 1 H NMR (600 MHz, DMSO- d 6) δ 11.15(s, 1H), 9.76 (s, 1H), 8.37 (d, J = 8.4 Hz, 1H), 8.15 (s, 1H), 8.11 (s, 0H),8.02 (d, J = 3.6 Hz, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.83 (d, J = 1.7 Hz, 1H), 7.79 (dd, J = 18.8, 8.3 Hz, 2H), 7.62 (d, J = 7.3 Hz, 1H), 7.57 (d, J = 3.3Hz, 1H), 7.37 (dd, J = 8.5, 1.7 Hz, 1H), 7.29 – 7.24 (m, 1H), 6.95 (d, J =8.2 Hz, 1H), 6.90 (td, J = 7.5, 3.6 Hz, 1H), 6.57 (d, J = 3.0 Hz, 1H), 5.52(s, 3H), 5.13 (dd, J = 12.9, 5.5 Hz, 1H), 4.41 (t, J = 7.1 Hz, 2H), 2.94 –2.82 (m, 2H), 2.79 (s, 1H), 2.65 – 2.57 (m, 1H), 2.57 – 2.51 (m, 2H), 2.48(d, J = 7.6 Hz, 2H), 2.26 (t, J = 7.1 Hz, 1H), 2.15 – 2.12 (m, J = 7.2 Hz,2H), 2.07 – 2.05 (m, 1H), 2.03 – 1.93 (m, 2H). Example 13 a: 5-(4-((5-(3-amino-6-(2-hydroxyphenyl)pyridazine-4-yl)-1 H -indole-1-yl)methyl)-1 H -1,2,3-triazol-1-yl)- N -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)pentanamide (13) The synthesis method follows the synthesis route of Example 10.

[0068] The only difference is that 2-bromoacetic acid is replaced with an equimolar amount of 5-bromopentanoic acid.

[0069] Compound 13 is a yellow solid (99 mg, yield 32%). 1 H NMR (600 MHz, DMSO- d 6) δ 13.77(s, 1H), 11.15 (s, 1H), 9.70 (s, 1H), 8.42 (d, J = 8.4 Hz, 1H), 8.12 (s, 1H),7.98 (s, 1H), 7.93 (dd, J = 8.1, 1.6 Hz, 1H), 7.82 (d, J = 1.7 Hz, 1H), 7.80 (dd, J = 8.4, 7.3 Hz, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.60 (dd, J = 7.3, 0.8Hz, 1H), 7.56 (d, J = 3.2 Hz, 1H), 7.37 (dd, J = 8.5, 1.8 Hz, 1H), 7.24 (ddd,J = 8.5, 7.2, 1.6 Hz, 1H), 6.92 (dd, J = 8.2, 1.3 Hz, 1H), 6.87 (ddd, J =8.2, 7.2, 1.3 Hz, 1H), 6.55 (dd, J = 3.1, 0.8 Hz, 1H), 6.38 (s, 2H), 5.52 (s,2H), 5.13 (dd, J = 12.9, 5.5 Hz, 1H), 4.36 (t, J = 7.0 Hz, 2H), 2.94 – 2.83(m, 1H), 2.64 – 2.57 (m, 1H), 2.56 – 2.51 (m, 2H), 2.49 (s, 1H), 2.11 – 1.92 (m, 1H), 1.87 – 1.84 (m, 2H), 1.56 (dd, J = 10.7, 4.5 Hz, 2H). Example 14 a: 5-(4-((5-(3-amino-6-(2-hydroxyphenyl)pyridazine-4-yl)-1 H -indole-1-yl)methyl)-1 H -1,2,3-triazol-1-yl)- N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)pentanamide)(14) The synthesis method follows the synthesis route of Example 10.

[0070] The only difference is that 2-bromoacetic acid is replaced with an equimolar amount of 6-bromohexanoic acid.

[0071] Compound 14 is a yellow solid (101 mg, yield 28%). 1 H NMR (600 MHz, DMSO- d 6) δ 13.76(s, 1H), 11.15 (s, 1H), 9.67 (s, 1H), 8.43 (d, J = 8.4 Hz, 1H), 8.10 (s, 1H),7.98 (s, 1H), 7.93 (dd, J = 8.0, 1.6 Hz, 1H), 7.82 (d, J = 1.9 Hz, 1H), 7.81– 7.78 (m, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 7.3 Hz, 1H), 7.55 (d,J = 3.2 Hz, 1H), 7.38 (dd, J = 8.5, 1.7 Hz, 1H), 7.24 (ddd, J = 8.5, 7.2, 1.6Hz, 1H), 6.91 (dd, J = 8.1, 1.2 Hz, 1H), 6.89 – 6.83 (m, 1H), 6.55 (d, J =3.2 Hz, 1H), 6.38 (s, 2H), 5.51 (s, 2H), 5.13 (dd, J = 12.9, 5.5 Hz, 1H), 4.32 (t, J = 7.1 Hz, 2H), 2.89 (ddd, J = 17.1, 13.9, 5.5 Hz, 1H), 2.60 (dd, J= 16.9, 3.0 Hz, 1H), 2.57 – 2.45 (m, 1H), 2.43 (t, J = 7.4 Hz, 2H), 2.12 –2.03 (m, 1H), 1.20 – 1.97 (m, 1H), 1.81 (p, J = 7.1 Hz, 2H), 1.64 – 1.61 (m,2H), 1.39 – 1.25 (m, 1H). Example 15 a: 7-(4-((5-(3-amino-6-(2-hydroxyphenyl)pyridazine-4-yl)-1 H -indole-1-yl)methyl)-1 H -1,2,3-triazol-1-yl)- N -(1,3-dioxo-2-(6-oxopiperidin-3-yl)isoindolin-4-yl)heptamide)(15) The synthesis method follows the synthesis route of Example 10.

[0072] The only difference is that 2-bromoacetic acid is replaced with an equimolar amount of 7-bromoheptanoic acid.

[0073] Compound 15 is a yellow solid (105 mg, yield 32%). 1 H NMR (400 MHz, DMSO- d6) δ 13.50(s, 1H), 11.15 (s, 1H), 9.66 (s, 1H), 8.44 (d, J = 8.4 Hz, 1H), 8.11 (s, 1H),8.00 (s, 1H), 7.89 (dd, J = 8.1, 1.7 Hz, 1H), 7.85 – 7.81 (m, 1H), 7.78 (dd,J = 10.2, 8.3 Hz, 2H), 7.59 (d, J = 7.3 Hz, 1H), 7.57 (d, J = 3.2 Hz, 1H), 7.38 (dd, J = 8.5, 1.7 Hz, 1H), 7.29 – 7.20 (m, 1H), 6.93 (dd, J = 8.2, 1.2Hz, 1H), 6.88 (t, J = 7.3 Hz, 1H), 6.60 (s, 2H), 6.56 (d, J = 3.2 Hz, 1H), 5.52 (s, 2H), 5.14 (dd, J = 12.8, 5.4 Hz, 1H), 4.31 (t, J = 7.0 Hz, 2H), 4.03(q, J = 7.1 Hz, 1H), 2.89 (ddd, J = 16.8, 13.7, 5.3 Hz, 1H), 2.67 – 2.57 (m,1H), 2.56 – 2.51 (m, 1H), 2.42 (t, J = 7.4 Hz, 2H), 2.06 (ddd, J = 14.4, 6.2,4.0 Hz, 1H), 1.99 (s, 1H), 1.80 – 1.77 (m, 2H), 1.58 (p, J = 7.4 Hz, 2H), 1.32 (p, J = 7.4 Hz, 1H), 1.28 – 1.20 (m, 2H), 1.17 (t, J = 7.1 Hz, 1H). Example 16 a: 8-(4-((5-(3-amino-6-(2-hydroxyphenyl)pyridazine-4-yl)-1 H -indole-1-yl)methyl)-1 H -1,2,3-triazol-1-yl)- N -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)octamide)(16) The synthesis method follows the synthesis route of Example 10.

[0074] The only difference is that 2-bromoacetic acid is replaced with an equimolar amount of 8-bromooctanoic acid.

[0075] Compound 16 is a yellow solid (105 mg, yield 30%). 1 H NMR (600 MHz, DMSO- d 6) δ 13.77(s, 1H), 11.16 (s, 1H), 9.66 (s, 1H), 8.45 (d, J = 8.4 Hz, 1H), 8.10 (s, 1H),7.98 (s, 1H), 7.93 (dd, J = 8.1, 1.6 Hz, 1H), 7.83 (d, J = 1.7 Hz, 1H), 7.81 (dd, J = 8.4, 7.3 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 7.3 Hz,1H), 7.56 (d, J = 3.2 Hz, 1H), 7.39 (dd, J = 8.5, 1.7 Hz, 1H), 7.24 (ddd, J =8.4, 7.1, 1.6 Hz, 1H), 6.92 (dd, J = 8.2, 1.2 Hz, 1H), 6.90 – 6.86 (m, 1H), 6.56 (d, J = 3.3 Hz, 1H), 6.39 (s, 2H), 5.52 (s, 2H), 5.14 (dd, J = 12.9, 5.5Hz, 1H), 4.31 (t, J = 7.1 Hz, 2H), 2.90 (ddd, J = 17.1, 13.9, 5.5 Hz, 1H), 2.61 (dt, J = 17.3, 3.3 Hz, 1H), 2.55 (dd, J = 13.1, 4.5 Hz, 2H), 2.43 (t, J= 7.4 Hz, 2H), 2.11 – 2.00 (m, 1H), 1.79 – 1.76 (m, 2H), 1.60 – 1.57 (m, 2H), 1.30 – 1.28 (m, 4H), 1.26 – 1.11 (m, 1H). Example 17 a: 9-(4-((5-(3-amino-6-(2-hydroxyphenyl)pyridazine-4-yl)-1 H -indole-1-yl)methyl)-1 H -1,2,3-triazol-1-yl)- N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)nonanoamide)(17) The synthesis method follows the synthesis route of Example 10.

[0076] The only difference is that 2-bromoacetic acid is replaced with an equimolar amount of 9-bromononanoic acid.

[0077] Compound 17 is a yellow solid (108 mg, yield 31%). 1 H NMR (600 MHz, DMSO- d 6) δ 13.77(s, 1H), 11.16 (s, 1H), 9.67 (s, 1H), 8.46 (d, J = 8.4 Hz, 1H), 8.10 (d, J =1.9 Hz, 1H), 7.99 (d, J = 3.5 Hz, 1H), 7.94 (dt, J = 8.0, 2.6 Hz, 1H), 7.85 –7.80 (m, 2H), 7.76 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 7.3 Hz, 1H), 7.56 (d, J= 3.1 Hz, 1H), 7.38 (dd, J = 8.5, 1.7 Hz, 1H), 7.29 – 7.20 (m, 1H), 6.93 (ddd, J = 8.1, 6.1, 1.3 Hz, 1H), 6.90 – 6.84 (m, 1H), 6.62 – 6.52 (m, 1H), 6.38 (s, 2H), 5.52 (d, J = 3.1 Hz, 2H), 5.14 (dd, J = 12.9, 5.5 Hz, 1H), 4.30(t, J = 7.1 Hz, 2H), 2.94 – 2.85 (m, 1H), 2.78 (s, 0H), 2.67 – 2.58 (m, 1H),2.58 – 2.53 (m, 1H), 2.43 (t, J = 7.4 Hz, 2H), 2.11 – 1.95 (m, 1H), 1.79 –1.76 (m, 2H), 1.58 (q, J = 7.3 Hz, 2H), 1.32 – 1.22 (m, 4H), 1.20 (s, 4H). Example 18 a: 10-(4-((5-(3-amino-6-(2-hydroxyphenyl)pyridazine-4-yl)-1 H-indole-1-yl)methyl)-1 H -1,2,3-triazol-1-yl)- N -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)decanoamide)(18) The synthesis method follows the synthesis route of Example 10.

[0078] The only difference is that 2-bromoacetic acid is replaced with an equimolar amount of 10-bromodecanoic acid.

[0079] Compound 18 is a yellow solid (109 mg, yield 30%). 1 H NMR (600 MHz, DMSO- d6) δ 13.77(s, 1H), 11.16 (s, 1H), 9.67 (s, 1H), 8.46 (d, J = 8.4 Hz, 1H), 8.10 (s, 1H),7.98 (s, 1H), 7.93 (dd, J = 8.0, 1.6 Hz, 1H), 7.85 – 7.79 (m, 2H), 7.76 (d, J= 8.5 Hz, 1H), 7.73 – 7.70 (m, 1H), 7.68 (dt, J = 5.3, 3.7 Hz, 1H), 7.60 (d,J = 7.3 Hz, 1H), 7.56 (d, J = 3.2 Hz, 1H), 7.38 (dd, J = 8.5, 1.7 Hz, 1H),7.24 (ddd, J = 8.4, 7.1, 1.6 Hz, 1H), 6.92 (dd, J = 8.2, 1.2 Hz, 1H), 6.90 –6.84 (m, 1H), 6.59 – 6.53 (m, 1H), 6.39 (s, 2H), 5.52 (s, 2H), 5.14 (dd, J =12.9, 5.4 Hz, 1H), 4.30 (t, J = 7.1 Hz, 2H), 4.19 – 4.10 (m, 2H), 2.90 (ddd,J = 17.1, 13.9, 5.4 Hz, 1H), 2.65 – 2.53 (m, 1H), 2.43 (t, J = 7.4 Hz, 2H), 2.10 – 1.96 (m, 1H), 1.78 – 1.75 (m, 2H), 1.63 – 1.59 (m, 2H), 1.40 – 1.33(m, 1H), 1.33 – 1.21 (m, 3H), 0.87 (d, J = 7.7 Hz, 5H). Example 19 a: 2-(4-((5-(3-amino-6-(2-hydroxyphenyl)pyridazine-4-yl)-1 H -indole-1-yl)methyl)-1 H -1,2,3-triazol-1-yl)- N -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)acetamide)(19) The synthesis method follows the synthesis route of Example 10.

[0080] The only difference is that pomalidomide is replaced with an equimolar amount of 5-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[0081] Compound 19 is a yellow solid (100 mg, yield 34%). 1 H NMR (500 MHz, CDCl3) δ 9.95(s, 1H), 9.80 (s, 1H), 7.94 (d, J = 2.2 Hz, 1H), 7.87 (dd, J = 6.2, 1.7 Hz,3H), 7.77 (s, 1H), 7.76 – 7.72 (m, 2H), 7.71 (d, J = 6.9 Hz, 1H), 7.44 (dd, J= 7.0, 2.2 Hz, 1H), 7.28 (d, J = 4.9 Hz, 1H), 7.25 (td, J = 7.9, 1.3 Hz, 1H), 7.01 (ddd, J = 9.0, 7.7, 1.5 Hz, 1H), 6.95 (dd, J = 8.2, 1.5 Hz, 1H), 6.64 (dd, J = 4.9, 2.0 Hz, 1H), 6.01 (s, 2H), 5.47 (d, J = 1.6 Hz, 2H), 5.39 (t, J= 3.7 Hz, 1H), 5.20 (s, 2H), 2.68 – 2.47 (m, 2H), 2.19 – 2.15 (m, 1H), 1.80 –1.75 (m, 1H). Example 20 a: 3-(4-((5-(3-amino-6-(2-hydroxyphenyl)pyridazine-4-yl)-1 H -indole-1-yl)methyl)-1 H -1,2,3-triazol-1-yl)- N -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)propionamide)(20) The synthesis method follows the synthesis route of Example 10.

[0082] The difference lies in replacing 2-bromoacetic acid with an equimolar amount of 3-bromopropionic acid. Pomalidomide was replaced with an equimolar amount of 5-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[0083] Compound 20 is a yellow solid (105 mg, yield 34%).1 H NMR (400 MHz, DMSO- d 6) δ 13.78(s, 1H), 11.11 (s, 1H), 10.71 (s, 1H), 8.22 (d, J = 1.8 Hz, 1H), 8.11 (s,1H), 7.97 (s, 1H), 7.93 (dd, J = 8.2, 1.6 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.81 (td, J = 4.6, 4.2, 1.8 Hz, 2H), 7.76 (d, J = 8.6 Hz, 1H), 7.53 (d, J =3.2 Hz, 1H), 7.34 (dd, J = 8.5, 1.7 Hz, 1H), 7.25 (ddd, J = 8.6, 7.3, 1.6 Hz, 1H), 6.93 (dd, J = 8.2, 1.2 Hz, 1H), 6.91 – 6.84 (m, 1H), 6.53 (dd, J = 3.1, 0.8 Hz, 1H), 6.37 (s, 2H), 5.51 (s, 2H), 5.11 (dd, J = 12.8, 5.4 Hz, 1H), 4.65 (t, J = 6.5 Hz, 2H), 3.51 (s, 1H), 3.05 (t, J = 6.6 Hz, 2H), 2.88 (ddd,J = 16.7, 13.6, 5.3 Hz, 1H), 2.64 – 2.52 (m, 1H), 2.10 – 1.92 (m, 1H). Example 21 a: 4-(4-((5-(3-amino-6-(2-hydroxyphenyl)pyridazine-4-yl)-1 H -indole-1-yl)methyl)-1 H -1,2,3-triazol-1-yl)- N -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)butyramide)(21) The synthesis method follows the synthesis route of Example 10.

[0084] The difference is that 2-bromoacetic acid is replaced with an equimolar amount of 4-bromobutyric acid. Replace pomalidomide with an equimolar amount of 5-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. Compound 21 is a yellow solid (99 mg, yield 30%). 1 H NMR (400 MHz, DMSO- d 6) δ 13.77(s, 1H), 11.11 (s, 1H), 10.58 (s, 1H), 8.23 ​​(s, 1H), 8.15 (s, 1H), 7.98 (s,1H), 7.94 (dd, J = 8.0, 1.6 Hz, 1H), 7.85 (s, 2H), 7.83 (d, J = 1.6 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 3.2 Hz, 1H), 7.38 (dd, J = 8.5, 1.7Hz, 1H), 7.29 – 7.21 (m, 1H), 6.92 (d, J = 8.1 Hz, 1H), 6.88 (t, J = 7.6 Hz, 1H), 6.56 (d, J = 3.1 Hz, 1H), 6.38 (s, 2H), 5.53 (s, 2H), 5.12 (dd, J =12.8, 5.4 Hz, 1H), 4.41 (t, J = 6.9 Hz, 2H), 2.88 (ddd, J = 17.0, 13.8, 5.4Hz, 1H), 2.69 – 2.52 (m, 2H), 2.42 (t, J = 7.3 Hz, 2H), 2.15 – 2.12 (m, 2H), 2.09 – 1.97 (m, 1H). Example 22 a: 5-(4-((5-(3-amino-6-(2-hydroxyphenyl)pyridazine-4-yl)-1 H -indole-1-yl)methyl)-1 H -1,2,3-triazol-1-yl)- N -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)pentanamide)(22) The synthesis method follows the synthesis route of Example 10.

[0085] The difference lies in replacing 2-bromoacetic acid with an equimolar amount of 5-bromopentanoic acid. Pomalidomide was replaced with an equimolar amount of 5-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[0086] Compound 22 is a yellow solid (109 mg, yield 34%).1 H NMR (400 MHz, DMSO- d 6) δ 13.77(s, 1H), 11.11 (s, 1H), 10.56 (s, 1H), 8.23 ​​(d, J = 1.7 Hz, 1H), 8.12 (s,1H), 7.98 (s, 1H), 7.93 (dd, J = 8.1, 1.6 Hz, 2H), 7.88 (dd, J = 8.3, 1.7 Hz, 1H), 7.86 (s, 1H), 7.83 (d, J = 1.7 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 3.2 Hz, 1H), 7.38 (dd, J = 8.6, 1.8 Hz, 1H), 7.25 (ddd, J = 8.5, 7.1,1.6 Hz, 1H), 6.92 (dd, J = 8.2, 1.2 Hz, 1H), 6.87 (td, J = 7.6, 1.2 Hz, 1H), 6.56 (d, J = 3.4 Hz, 1H), 6.38 (s, 2H), 5.53 (s, 2H), 5.12 (dd, J = 12.8, 5.4Hz, 1H), 4.36 (t, J = 7.0 Hz, 2H), 2.89 (ddd, J = 16.8, 13.7, 5.3 Hz, 1H), 2.58 (td, J = 15.5, 14.8, 4.1 Hz, 1H), 2.43 (t, J = 7.3 Hz, 2H), 2.05 (ddd, J= 15.1, 6.6, 4.3 Hz, 1H), 1.87 – 1.84 (m, 2H), 1.58 – 1.55 (m, 2H). Example 23 a: (2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)ethyl)tert-butyl carbamate (8-1) Procedure: Compound 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (1.00 g, 3.62 mmol, 1.0 eq.), compound Ntert-butyl 2-(2-aminoethyl)carbamate (580 mg, 4.00 mmol, 1.1 eq.) and diisopropylethylamine (1.26 mL, 7.25 mmol, 2.0 eq.) were dissolved in dimethyl sulfoxide. The reaction mixture was stirred and heated at 80 °C for 12 hours. After the reaction was completed by TLC, the mixture was extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and purified by silica gel column chromatography to give a yellow oily compound 8-1 (573 mg, yield 38%). 1 H NMR (600 MHz, DMSO- d 6) δ 11.09 (s, 1H), 7.58 (dd, J = 8.6,7.1 Hz, 1H), 7.14 (d, J = 8.6 Hz, 1H), 7.02 (dd, J = 10.8, 6.2 Hz, 2H), 6.71(t, J = 6.2 Hz, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 3.37 (d, J = 6.2 Hz, 3H), 3.12 (q, J = 6.1 Hz, 2H), 2.89 (ddd, J = 17.3, 14.0, 5.4 Hz, 1H), 2.66 –2.43 (m, 2H), 2.05 – 2.01 (m, 1H), 1.36 (s, 8H). b: 4-((2-aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (8-2) Procedure: At room temperature, trifluoroacetic acid (0.1 mL, 1.44 mmol, 3.0 eq.) was slowly added dropwise to a solution of compound 8-1 (200 mg, 0.48 mmol, 1.0 eq.) in dichloromethane (3 mL) while stirring. After stirring the mixture for 2 hours, the solvent was removed under reduced pressure to give crude compound 8-2 (132 mg, 87% yield).

[0087] c: 2-(5-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1 H -indol-1-yl)- N -(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)ethyl)acetamide (23) Steps: Under room temperature conditions, N,N,N',N '-Tetramethyl- O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (159 mg, 0.42 mmol, 1.0 eq.) was added to a solution containing compound 5-3 (180 mg, 0.50 mmol, 1.2 eq.), compound 8-2 (132 mg, 0.42 mmol, 1.0 eq.), and diisopropylethylamine (0.36 mL, 2.09 mmol, 5.0 eq.). N,N - Dimethylformamide (2 mL) was added to a 25 mL round-bottom flask. The resulting reaction solution was stirred for 2 hours at room temperature. After the reaction was completed by TLC, the mixture was extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and purified by silica gel column chromatography to give compound 23 (96 mg, yield 35%) as a white solid. 1 HNMR (600 MHz, DMSO- d 6) δ 13.78 (s, 1H), 11.10 (s, 1H), 8.47 (t, J = 5.6 Hz,1H), 7.99 (s, 1H), 7.95 (dd, J = 8.0, 1.6 Hz, 1H), 7.84 (d, J = 1.7 Hz, 1H), 7.59 (dd, J = 8.6, 7.0 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.43 (d, J = 3.2Hz, 1H), 7.35 (dd, J = 8.5, 1.7 Hz, 1H), 7.25 (ddd, J = 8.5, 7.2, 1.6 Hz,1H), 7.19 (d, J = 8.6 Hz, 1H), 7.05 (d, J = 7.0 Hz, 1H), 6.93 (dd, J = 8.2,1.2 Hz, 1H), 6.93 – 6.83 (m, 1H), 6.79 (t, J = 6.2 Hz, 1H), 6.56 (d, J = 3.1Hz, 1H), 6.39 (s, 2H), 5.07 (dd, J = 12.7, 5.4 Hz, 1H), 4.89 (s, 2H), 3.44(q, J = 6.3 Hz, 2H), 3.33 (t, J = 9.2 Hz, 1H), 2.88 (ddd, J = 17.0, 13.4, 5.4Hz, 1H), 2.62 – 2.44 (m, 2H), 2.03 – 2.19 (m, 1H). Example 24 a: 2-(5-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1 H -indol-1-yl)- N -(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)propyl)acetamide)(24) The synthesis method follows the synthesis route of Example 23.

[0088] The only difference is: N -(2-aminoethyl)carbamate tert-butyl ester was replaced with an equimolar amount of N-(3-aminopropyl)carbamate tert-butyl ester. Compound 24) is a yellow solid (97 mg, yield 34%). 1 H NMR (400 MHz, DMSO- d 6) δ 13.75(s, 1H), 11.06 (s, 1H), 8.30 (t, J = 5.7 Hz, 1H), 7.96 (s, 1H), 7.91 (dd, J =8.0, 1.6 Hz, 1H), 7.82 (d, J = 1.7 Hz, 1H), 7.54 (dd, J = 8.6, 7.4 Hz, 2H), 7.42 (d, J = 3.2 Hz, 1H), 7.35 (dd, J = 8.5, 1.7 Hz, 1H), 7.22 (ddd, J = 8.4,7.2, 1.6 Hz, 1H), 7.05 (d, J = 8.6 Hz, 1H), 6.99 (d, J = 7.0 Hz, 1H), 6.90(dd, J = 8.2, 1.2 Hz, 1H), 6.90 – 6.81 (m, 1H), 6.66 (t, J = 6.3 Hz, 1H), 6.54 (d, J = 3.1 Hz, 1H), 6.37 (s, 2H), 5.02 (dd, J = 12.9, 5.4 Hz, 1H), 4.88 (s, 2H), 3.34 (d, J = 7.1 Hz, 2H), 3.18 (q, J = 6.4 Hz, 2H), 2.84 (ddd, J =19.0, 14.9, 6.2 Hz, 1H), 2.61 – 2.49 (m, 1H), 1.96 (td, J = 13.8, 12.5, 6.6Hz, 2H), 1.70 – 1.66 (m, 2H). Example 25 a: 2-(5-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1 H -indol-1-yl)- N -(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)butyl)acetamide)(25) The synthesis method follows the synthesis route of Example 23.

[0089] The only difference is: N -(2-aminoethyl)carbamate tert-butyl ester was replaced with an equimolar amount. N -(4-aminobutyl)carbamate tert-butyl ester raw material; Compound 25 is a yellow solid (99 mg, yield 35%). 1 H NMR (400 MHz, DMSO- d 6) δ 13.78(s, 1H), 11.09 (s, 1H), 8.26 (t, J = 5.7 Hz, 1H), 7.99 (s, 1H), 7.94 (dd, J =8.1, 1.6 Hz, 1H), 7.84 (d, J = 1.7 Hz, 1H), 7.60 – 7.55 (m, 1H), 7.55 – 7.49(m, 1H), 7.43 (d, J = 3.2 Hz, 1H), 7.36 (dd, J = 8.5, 1.7 Hz, 1H), 7.25 (ddd,J = 8.4, 7.2, 1.6 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H), 7.01 (d, J = 7.0 Hz, 1H), 6.93 (dd, J = 8.2, 1.2 Hz, 1H), 6.88 (td, J = 7.6, 1.2 Hz, 1H), 6.56 (t,J = 5.0 Hz, 2H), 6.39 (s, 2H), 5.04 (dd, J = 12.8, 5.3 Hz, 1H), 4.88 (s, 2H), 3.31 (s, 1H), 3.15 (q, J = 6.4 Hz, 2H), 2.87 (ddd, J = 17.6, 14.1, 5.5 Hz,1H), 2.76 (s, 1H), 2.64 – 2.52 (m, 1H), 2.01 (dt, J = 13.1, 4.5 Hz, 3H), 1.59– 1.54 (m, 3H). Example 26 a: 2-(5-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1 H -indol-1-yl)- N -(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)pentyl)acetamide (26) The synthesis method follows the synthesis route of Example 23.

[0090] The only difference is that N-(2-aminoethyl)carbamate tert-butyl ester is replaced with an equimolar amount of N tert-butyl (5-aminopentyl)carbamate raw material; Compound 26 is a yellow solid (99 mg, yield 34%). 1 H NMR (400 MHz, DMSO- d 6) δ 13.75(s, 1H), 11.07 (s, 1H), 8.21 (t, J = 5.6 Hz, 1H), 7.96 (s, 1H), 7.90 (dd, J =8.2, 1.6 Hz, 1H), 7.82 (d, J = 1.7 Hz, 1H), 7.52 (dt, J = 8.6, 3.6 Hz, 2H), 7.41 (d, J = 3.2 Hz, 1H), 7.35 (dd, J = 8.4, 1.7 Hz, 1H), 7.27 – 7.19 (m,1H), 7.03 (d, J = 8.6 Hz, 1H), 6.97 (d, J = 7.0 Hz, 1H), 6.90 (dd, J = 8.2,1.2 Hz, 1H), 6.88 – 6.81 (m, 1H), 6.53 (d, J = 3.2 Hz, 1H), 6.50 (t, J = 6.0Hz, 1H), 6.37 (s, 2H), 5.02 (dd, J = 12.9, 5.4 Hz, 1H), 4.85 (s, 2H), 3.24(q, J = 6.7 Hz, 2H), 3.10 (q, J = 6.5 Hz, 2H), 2.84 (ddd, J = 17.5, 14.0, 5.4Hz, 1H), 2.62 – 2.39 (m, 2H), 2.05 – 1.90 (m, 1H), 1.59 – 1.56 (m, 2H), 1.49 – 1.46 (m, 2H), 1.39 – 1.28 (m, 2H). Example 27 a: 2-(5-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1H-indol-1-yl)- N -(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)hexyl)acetamide (27) The synthesis method follows the synthesis route of Example 23.

[0091] The only difference is: N -(2-aminoethyl)carbamate tert-butyl ester was replaced with an equimolar amount. N -(6-aminohexyl)carbamate tert-butyl ester raw material; Compound 27 is a yellow solid (98 mg, yield 32%). 1 H NMR (400 MHz, DMSO-d6) δ 13.72(s, 1H), 11.04 (s, 1H), 8.16 (t, J = 5.6 Hz, 1H), 7.93 (s, 1H), 7.88 (dd, J =8.1, 1.6 Hz, 1H), 7.79 (d, J = 1.7 Hz, 1H), 7.55 – 7.43 (m, 2H), 7.38 (d, J =3.2 Hz, 1H), 7.32 (dd, J = 8.5, 1.7 Hz, 1H), 7.19 (td, J = 7.7, 7.0, 1.5 Hz,1H), 7.01 (d, J = 8.6 Hz, 1H), 6.95 (d, J = 7.0 Hz, 1H), 6.87 (dd, J = 8.2,1.2 Hz, 1H), 6.85 – 6.77 (m, 1H), 6.50 (d, J = 3.1 Hz, 1H), 6.47 (t, J = 6.0Hz, 1H), 6.33 (s, 2H), 4.98 (dd, J = 12.8, 5.4 Hz, 1H), 4.81 (s, 2H), 3.24 –3.21 (m, 2H), 3.05 (q, J = 6.5 Hz, 2H), 2.82 (ddd, J = 17.9, 13.8, 5.3 Hz,1H), 2.57 – 2.38 (m, 1H), 2.02 – 1.83 (m, 2H), 1.56 – 1.45 (m, 2H), 1.39 (q,J = 6.7 Hz, 2H), 1.35 – 1.23 (m, 4H). Example 28 a: 2-(5-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1 H -indol-1-yl)- N -(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)heptyl)acetamide (28) The synthesis method follows the synthesis route of Example 23.

[0092] The only difference is: N -(2-aminoethyl)carbamate tert-butyl ester was replaced with an equimolar amount. N tert-butyl (7-aminoheptyl)carbamate raw material; Compound 28 is a yellow solid (100 mg, yield 33%). 1 H NMR (400 MHz, DMSO- d6) δ 13.76(s, 1H), 11.09 (s, 1H), 8.30 (t, J = 5.6 Hz, 1H), 7.99 (s, 1H), 7.94 (dd, J =8.1, 1.6 Hz, 1H), 7.84 (d, J = 1.7 Hz, 1H), 7.55 (dt, J = 8.6, 3.6 Hz, 2H), 7.44 (d, J = 3.1 Hz, 1H), 7.37 (dd, J = 8.5, 1.7 Hz, 1H), 7.29 – 7.19 (m,1H), 7.05 (d, J = 8.7 Hz, 1H), 7.00 (d, J = 7.0 Hz, 1H), 6.92 (d, J = 8.1 Hz,1H), 6.87 (t, J = 7.5 Hz, 1H), 6.55 (d, J = 3.1 Hz, 1H), 6.50 (t, J = 5.9 Hz,1H), 6.39 (s, 2H), 5.04 (dd, J = 12.9, 5.4 Hz, 1H), 4.88 (s, 2H), 3.59 (p, J= 6.8 Hz, 1H), 3.27 (q, J = 6.7 Hz, 2H), 3.10 (p, J = 6.3 Hz, 3H), 2.88 (ddd,J = 17.4, 14.4, 5.4 Hz, 1H), 2.63 – 2.47 (m, 2H), 2.015 –2.00 (m, 2H), 1.56 (p, J = 7.1 Hz, 2H), 1.46 – 1.41 (m, 2H), 1.22 (s, 3H). Example 29 a: 2-(5-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1 H -indol-1-yl)- N -(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)octyl)acetamide (29) The synthesis method follows the synthesis route of Example 23.

[0093] The only difference is: N -(2-aminoethyl)carbamate tert-butyl ester was replaced with an equimolar amount. N -(8-aminooctyl)carbamate tert-butyl ester raw material; Compound 29 is a yellow solid (97 mg, yield 30%).1 H NMR (400 MHz, DMSO- d 6) δ 13.75(s, 1H), 11.09 (s, 1H), 8.21 (d, J = 5.6 Hz, 1H), 7.99 (s, 1H), 7.93 (d, J =7.9 Hz, 1H), 7.84 (s, 1H), 7.55 (t, J = 8.7 Hz, 2H), 7.43 (d, J = 3.1 Hz,1H), 7.38 (d, J = 8.5 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.03 (dd, J = 19.1,7.8 Hz, 2H), 6.97 – 6.83 (m, 2H), 6.55 (d, J = 3.1 Hz, 1H), 6.50 (d, J = 5.9Hz, 1H), 6.40 (s, 2H), 5.04 (dd, J = 12.9, 5.4 Hz, 1H), 4.87 (s, 2H), 3.26(q, J = 6.8 Hz, 2H), 3.09 (q, J = 6.6 Hz, 2H), 2.87 (ddd, J = 18.5, 14.0, 5.4Hz, 1H), 2.64 – 2.44 (m, 1H), 2.01 (dq, J = 15.2, 8.5, 7.7 Hz, 2H), 1.56 (p,J = 7.8, 7.2 Hz, 2H), 1.43 (t, J = 6.9 Hz, 2H), 1.25 (d, J = 19.9 Hz, 9H). Example 30 a: 2-(5-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1 H -indol-1-yl)- N -(9-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)nonyl)acetamide (30) The synthesis method follows the synthesis route of Example 23.

[0094] The only difference is: N -(2-aminoethyl)carbamate tert-butyl ester was replaced with an equimolar amount. N -(9-aminononyl)carbamate tert-butyl ester raw material; Compound 30 is a yellow solid (108 mg, yield 34%). 1H NMR (400 MHz, DMSO- d 6) δ 13.78(s, 1H), 11.09 (s, 1H), 8.20 (t, J = 5.6 Hz, 1H), 8.00 (s, 1H), 7.94 (d, J =7.9 Hz, 1H), 7.85 (s, 1H), 7.61 – 7.50 (m, 2H), 7.44 (d, J = 3.2 Hz, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.02 (dd, J = 15.0, 7.8Hz, 2H), 6.99 – 6.81 (m, 2H), 6.55 (d, J = 3.1 Hz, 1H), 6.52 – 6.45 (m, 1H), 6.39 (s, 2H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 4.87 (s, 2H), 3.25 (q, J = 6.7Hz, 2H), 3.09 (q, J = 6.5 Hz, 2H), 2.88 (ddd, J = 18.1, 14.1, 5.4 Hz, 1H), 2.65 – 2.45 (m, 1H), 2.08 – 1.95 (m, 1H), 1.54 (p, J = 7.2 Hz, 2H), 1.42 (t,J = 6.9 Hz, 2H), 1.28 (d, J = 15.1 Hz, 11H). Example 31 a: 2-(5-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1 H -indol-1-yl)- N -(10-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)decyl)acetamide (31) The synthesis method follows the synthesis route of Example 23.

[0095] The only difference is: N -(2-aminoethyl)carbamate tert-butyl ester was replaced with an equimolar amount. N -(10-aminodecyl) tert-butyl carbamate raw material; Compound 31 is a yellow solid (110 mg, yield 34%). 1 H NMR (400 MHz, DMSO- d6) δ 13.78(s, 1H), 11.09 (s, 1H), 8.20 (t, J = 5.6 Hz, 1H), 8.00 (s, 1H), 7.94 (dd, J =8.1, 1.6 Hz, 1H), 7.85 (d, J = 1.6 Hz, 1H), 7.60 – 7.50 (m, 2H), 7.43 (d, J =3.1 Hz, 1H), 7.37 (dd, J = 8.4, 1.7 Hz, 1H), 7.29 – 7.19 (m, 1H), 7.03 (dd, J= 17.2, 7.8 Hz, 2H), 6.96 – 6.83 (m, 2H), 6.55 (d, J = 3.1 Hz, 1H), 6.49 (t,J = 5.9 Hz, 1H), 6.39 (s, 2H), 5.04 (dd, J = 12.9, 5.4 Hz, 1H), 4.87 (s, 2H), 3.25 (q, J = 6.7 Hz, 2H), 3.09 (q, J = 6.5 Hz, 2H), 2.88 (ddd, J = 17.6,14.1, 5.4 Hz, 1H), 2.64 – 2.45 (m, 1H), 2.08 – 1.93 (m, 2H), 1.54 (p, J = 7.1Hz, 2H), 1.42 (t, J = 6.9 Hz, 2H), 1.25 (s, 12H). Example 32 a: 6-Chloro-4-(1-(3-chloropropyl)-1 H -indol-5-yl)pyridazine-3-amine)(9-1) Procedure: Compound 1-1 (2.00 g, 5.78 mmol, 1.0 eq.) was added to a 200 mL round-bottom flask containing 30 mL of tetrahydrofuran solvent. The reaction mixture was then cooled to 0 °C, and sodium hydride (416 mg, 17.33 mmol, 3.0 eq.) was slowly added. After stirring at 0 °C for 1 hour, 1-chloro-3-iodopropane (0.6 mL, 6.93 mmol, 1.2 eq.) was added, and the reaction mixture was then brought to room temperature and stirred for 1 hour. After the reaction was completed by TLC, the mixture was extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and purified by silica gel column chromatography to give compound 9-1 (1.84 g, 70% yield) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 7.77 (d, J = 1.7 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.48 (d, J = 3.1 Hz, 1H), 7.34 (s, 1H), 7.31 (dd, J = 8.5, 1.8 Hz, 1H), 6.58 – 6.53 (m, 1H), 6.31 (s, 2H), 4.36 (t, J =6.8 Hz, 2H), 3.58 (t, J = 6.4 Hz, 2H), 2.23 – 2.20 (m, 2H). b: 2-(6-amino-5-(1-(3-chloropropyl)-1 H -indol-5-yl)pyridazin-3-yl)phenol (9-2) Procedure: A solution of compound 9-1 (3.00 g, 9.37 mmol, 1.0 eq.) in dioxane / water (5:1 v / v, 60 mL) was added to a 250 mL round-bottom flask. Then, 2-hydroxyphenylboronic acid (1.55 g, 11.25 mmol, 1.2 eq.), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (790 mg, 0.94 mmol, 0.1 eq.), and potassium carbonate (2.59 g, 18.75 mmol, 2.0 eq.) were added sequentially. The resulting mixture was stirred at 95 °C for 12 hours. After the reaction was detected by TLC, the mixture was extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove organic solvent, and purified by silica gel column chromatography to finally obtain a yellow solid compound 9-2 (2.37 g, yield 67%). 1 H NMR (400 MHz, DMSO- d6) δ 13.76(s, 1H), 8.03 (s, 1H), 7.96 (dd, J = 8.0, 1.6 Hz, 1H), 7.86 (d, J = 1.7 Hz,1H), 7.69 (d, J = 8.5 Hz, 1H), 7.51 (d, J = 3.1 Hz, 1H), 7.41 (dd, J = 8.5,1.8 Hz, 1H), 7.30 – 7.22 (m, 1H), 6.94 (dd, J = 8.3, 1.2 Hz, 1H), 6.92 – 6.83(m, 1H), 6.59 (d, J = 3.1 Hz, 1H), 6.46 (s, 2H), 4.39 (t, J = 6.7 Hz, 2H), 3.60 (t, J = 6.4 Hz, 2H), 2.25 – 2.22 (m, J = 6.6 Hz, 2H). c: 2-(6-amino-5-(1-(3-azidopropyl)-1 H -indol-5-yl)pyridazin-3-yl)phenol (9-3) Procedure: Compound 9-2 (2.00 g, 5.29 mmol, 1.0 eq.) and sodium azide (1.03 g, 15.87 mmol, 3.0 eq.) were added to a 100 mL round-bottom flask, followed by the addition of dimethyl sulfoxide (5 mL). The reaction mixture was stirred overnight at 70 °C. After the reaction was complete as determined by TLC, the mixture was extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and purified by silica gel column chromatography to give crude compound 9-3 (1.79 g, 88% yield). 1 H NMR (600 MHz, DMSO- d6) δ 13.81 (s, 1H), 8.03 (s, 1H), 7.96 (dd, J= 8.1, 1.6 Hz, 1H), 7.86 (d, J = 1.7 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.50(d, J = 3.1 Hz, 1H), 7.41 (dd, J = 8.5, 1.8 Hz, 1H), 7.29 – 7.21 (m, 1H), 6.95 (dd, J = 8.2, 1.2 Hz, 1H), 6.92 – 6.82 (m, 1H), 6.58 (d, J = 3.1 Hz,1H), 6.44 (s, 2H), 4.32 (t, J = 6.9 Hz, 2H), 3.34 (t, J = 6.7 Hz, 2H), 2.05 –2.00 (m, 2H). d: 2-(2,6-dioxopiperidin-3-yl)-4-(prop-2-yn-1-ylamino)isoindoline-1,3-dione (9-4) Procedure: Compounds 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (1.00 g, 3.62 mmol, 1.0 eq.), propargylamine (219 mg, 3.98 mmol, 1.1 eq.), and diisopropylethylamine (1.26 mL, 7.25 mmol, 2.0 eq.) were added to a solution containing... N,N In a 100 mL round-bottom flask containing dimethylformamide, the reaction mixture was heated to 80 °C and stirred for 12 hours. After the reaction was completed by TLC, the mixture was extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and purified by silica gel column chromatography to give a green solid compound 9-4 (856 mg, yield 76%). 1 H NMR (600 MHz, DMSO- d6) δ 11.10 (s, 1H), 7.65 (dd, J =8.5, 7.1 Hz, 1H), 7.16 (d, J = 8.5 Hz, 1H), 7.12 (d, J = 7.1 Hz, 1H), 6.93(t, J = 6.2 Hz, 1H), 5.07 (dd, J = 12.9, 5.4 Hz, 1H), 4.17 (dd, J = 6.2, 2.5Hz, 2H), 3.17 (t, J = 2.3 Hz, 1H), 2.89 (ddd, J = 17.3, 14.0, 5.4 Hz, 1H), 2.65 – 2.53 (m, 1H), 2.10 – 2.00 (m, 1H), 1.18 (t, J = 7.1 Hz, 1H). e:4-(((1-(3-(5-(3-amino-6-(2-hydroxyphenyl)pyridazine-4-yl)-1 H -indol-1-yl)propyl)-1 H -1,2,3-triazol-4-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (32) Procedure: Compound 9-3 (1.06 g, 2.75 mmol, 1.0 eq.), compound 9-4 (856 mg, 2.75 mmol, 1 eq.), sodium ascorbate (55 mg, 0.10 mmol, 0.1 eq.), and copper sulfate pentahydrate (69 mg, 0.10 mmol, 0.1 eq.) were added sequentially to a 100 mL round-bottom flask. Then, a mixed solvent of methanol / dichloromethane / water (2:2:1, total 10 mL) was added to the flask, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete as detected by TLC, the mixture was extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and purified by silica gel column chromatography to give a white solid compound 32 (824 mg, 43% yield). 1 H NMR (600 MHz, DMSO- d6) δ13.91 – 13.57 (m, 1H), 11.11 (s, 1H), 8.08 (s, 1H), 8.02 (s, 1H), 7.96 (dd, J= 8.0, 1.6 Hz, 1H), 7.85 (d, J = 1.7 Hz, 1H), 7.65 – 7.54 (m, 2H), 7.49 (d, J= 3.1 Hz, 1H), 7.38 (dd, J = 8.5, 1.8 Hz, 1H), 7.26 (ddd, J = 8.4, 7.2, 1.6Hz, 1H), 7.18 (d, J = 8.6 Hz, 1H), 7.10 (t, J = 6.1 Hz, 1H), 7.06 (d, J = 7.1Hz, 1H), 6.94 (dd, J = 8.2, 1.2 Hz, 1H), 6.92 – 6.85 (m, 1H), 6.57 (d, J =3.1 Hz, 1H), 6.43 (s, 2H), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 4.62 (d, J = 6.0Hz, 2H), 4.37 (t, J = 7.1 Hz, 2H), 4.27 (t, J = 7.0 Hz, 2H), 2.88 (ddd, J =17.0, 13.8, 5.4 Hz, 1H), 2.63 – 2.48 (m, 2H), 2.37 – 2.34 (m, 2H), 2.05 –2.02 (m, 1H). Example 33 a: 4-(((1-(4-(5-(3-amino-6-(2-hydroxyphenyl)pyridazine-4-yl)-1 H -indol-1-yl)butyl)-1 H -1,2,3-triazol-4-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (33) The synthesis method follows the synthesis route of Example 32.

[0096] The only difference is that 1-chloro-3-iodopropane is replaced with an equimolar amount of 1-chloro-4-iodobutane. Compound 33 is a yellow solid (820 mg, 40% yield). 1 H NMR (400 MHz, DMSO- d6) δ 13.77(s, 1H), 11.09 (s, 1H), 8.00 (d, J = 5.8 Hz, 2H), 7.95 (dd, J = 8.1, 1.6 Hz,1H), 7.83 (d, J = 1.7 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.54 (dd, J = 8.6,7.1 Hz, 1H), 7.44 (d, J = 3.1 Hz, 1H), 7.37 (dd, J = 8.5, 1.7 Hz, 1H), 7.25(ddd, J = 8.5, 7.1, 1.6 Hz, 1H), 7.14 (d, J = 8.6 Hz, 1H), 6.40 (s, 2H), 5.05 (dd, J = 12.9, 5.3Hz, 1H), 4.58 (d, J = 6.1 Hz, 2H), 4.36 (t, J = 6.6 Hz, 2H), 4.24 (t, J = 6.5Hz, 2H), 2.88 (ddd, J = 17.4, 14.1, 5.4 Hz, 1H), 2.63 – 2.44 (m, 1H), 2.06 –1.95 (m, 2H), 1.84 – 1.68 (m, 4H). Example 34 a: 4-(((1-(5-(5-(3-amino-6-(2-hydroxyphenyl)pyridazine-4-yl)-1 H -indol-1-yl)pentyl)-1 H -1,2,3-triazol-4-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (34) The synthesis method follows the synthesis route of Example 32.

[0097] The only difference is that 1-chloro-3-iodopropane is replaced with an equimolar amount of 1-chloro-5-iodopentane. Compound 34 is a yellow solid (825 mg, yield 41%). 1 H NMR (400 MHz, DMSO- d6) δ 13.79(s, 1H), 11.09 (s, 1H), 8.00 (d, J = 6.6 Hz, 2H), 7.95 (dd, J = 8.1, 1.6 Hz,1H), 7.83 (d, J = 1.7 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.56 (dd, J = 8.5,7.1 Hz, 1H), 7.44 (d, J = 3.1 Hz, 1H), 7.37 (dd, J = 8.5, 1.7 Hz, 1H), 7.25(ddd, J = 8.4, 7.1, 1.6 Hz, 1H), 7.14 (d, J = 8.6 Hz, 1H), 7.06 (dd, J = 8.1,6.4 Hz, 2H), 6.93 (dd, J = 8.2, 1.2 Hz, 1H), 6.91 – 6.84 (m, 1H), 6.52 (d, J= 3.1 Hz, 1H), 6.40 (s, 2H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 4.58 (d, J =6.0 Hz, 2H), 4.31 (t, J = 7.0 Hz, 2H), 4.19 (t, J = 7.0 Hz, 2H), 2.88 (ddd, J= 17.3, 14.0, 5.4 Hz, 1H), 2.63 – 2.51 (m, 2H), 2.05 – 2.01 (m, 1H), 1.84 –1.80 (m, 4H), 1.25 – 1.15 (m, 3H). Example 35 a: 4-(((1-(6-(5-(3-amino-6-(2-hydroxyphenyl)pyridazine-4-yl)-1 H -indol-1-yl)hexyl)-1 H -1,2,3-triazol-4-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (35) The synthesis method follows the synthesis route of Example 32.

[0098] The only difference is that 1-chloro-3-iodopropane is replaced with an equimolar amount of 1-chloro-6-iodohexane. Compound 35 is a yellow solid (840 mg, yield 45%). 1 H NMR (400 MHz, DMSO- d6) δ 13.79(s, 1H), 11.05 (s, 1H), 8.00 (d, J = 3.3 Hz, 2H), 7.95 (dd, J = 8.1, 1.6 Hz,1H), 7.83 (d, J = 1.7 Hz, 1H), 7.62 (d, J = 8.6 Hz, 1H), 7.60 – 7.53 (m, 2H), 7.45 (d, J = 3.2 Hz, 1H), 7.38 (dd, J = 8.5, 1.7 Hz, 1H), 7.25 (ddd, J = 8.4,7.2, 1.6 Hz, 1H), 7.06 (d, J = 2.1 Hz, 1H), 6.94 (ddd, J = 8.2, 3.3, 1.7 Hz, 2H), 6.88 (td, J = 7.6, 1.2 Hz, 1H), 6.53 (d, J = 3.1 Hz, 1H), 6.40 (s, 2H), 5.02 (dd, J = 12.9, 5.4 Hz, 1H), 4.46 (d, J = 5.7 Hz, 2H), 4.32 (t, J = 7.0Hz, 2H), 4.20 (t, J = 7.0 Hz, 2H), 2.86 (ddd, J = 17.3, 14.0, 5.4 Hz, 1H), 2.61 – 2.42 (m, 2H), 2.04 – 1.93 (m, 1H), 1.83 – 1.80 (m, 4H), 1.39 – 1.14 (m, 4H). Example 36 a: 5-(((1-(3-(5-(3-amino-6-(2-hydroxyphenyl)pyridazine-4-yl)-1 H -indol-1-yl)propyl)-1 H -1,2,3-triazol-4-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (36) The synthesis method follows the synthesis route of Example 32.

[0099] The only difference is that 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione is replaced with an equimolar amount of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione. Compound 36 is a yellow solid (826 mg, yield 44%). 1 H NMR (400 MHz, DMSO-d 6) δ 13.79(s, 1H), 11.06 (s, 1H), 8.09 (s, 1H), 8.01 (s, 3H), 7.96 (d, J = 7.8 Hz, 1H), 7.85 (d, J = 1.7 Hz, 1H), 7.60 (t, J = 8.5 Hz, 3H), 7.48 (d, J = 3.1 Hz, 1H), 7.42 – 7.30 (m, 1H), 7.30 – 7.21 (m, 1H), 7.07 (d, J = 2.1 Hz, 1H), 7.00 –6.84 (m, 3H), 6.58 (d, J = 3.2 Hz, 1H), 6.40 (s, 2H), 5.02 (dd, J = 12.8, 5.4Hz, 1H), 4.49 (d, J = 5.7 Hz, 2H), 4.37 (t, J = 7.1 Hz, 2H), 4.27 (t, J = 6.9Hz, 2H), 2.96 – 2.78 (m, 1H), 2.56 (d, J = 17.8 Hz, 1H), 2.35 (t, J = 7.0 Hz, 2H), 2.05 – 1.87 (m, 2H). Example 37 a: 5-(((1-(4-(5-(3-amino-6-(2-hydroxyphenyl)pyridazine-4-yl)-1 H -indol-1-yl)butyl)-1 H -1,2,3-triazol-4-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (37) The synthesis method follows the synthesis route of Example 32.

[0100] The difference is that 1-chloro-3-iodopropane is replaced with an equimolar amount of 1-chloro-4-iodobutane. Replace 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione with an equimolar amount of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione. Compound 37 is a yellow solid (820 mg, yield 41%). 1 H NMR (400 MHz, DMSO- d6) δ 13.72(s, 1H), 11.06 (s, 1H), 8.01 (d, J = 2.9 Hz, 2H), 7.94 (d, J = 7.9 Hz, 1H), 7.83 (d, J = 1.6 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.60 – 7.49 (m, 3H), 7.45(d, J = 3.1 Hz, 1H), 7.37 (dd, J = 8.5, 1.7 Hz, 1H), 7.26 (t, J = 7.7 Hz,1H), 7.05 (d, J = 2.0 Hz, 1H), 6.93 (d, J = 8.2 Hz, 2H), 6.89 (t, J = 7.6 Hz,1H), 6.54 (d, J = 3.1 Hz, 1H), 6.47 (s, 2H), 6.18 (dd, J = 17.2, 10.0 Hz,1H), 6.06 (dd, J = 17.2, 2.4 Hz, 1H), 5.59 (dd, J = 2.87 (td, J = 17.2, 15.4, 5.2 Hz, 1H), 2.55(s, 1H), 1.75 (s, 4H). Example 38 a: 5-(((1-(6-(5-(3-amino-6-(2-hydroxyphenyl)pyridazine-4-yl)-1 H -indol-1-yl)pentyl)-1 H -1,2,3-triazol-4-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (38) The synthesis method follows the synthesis route of Example 32.

[0101] The difference is that 1-chloro-3-iodopropane is replaced with an equimolar amount of 1-chloro-5-iodopentane. Replace 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione with an equimolar amount of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione. Compound 38 is a yellow solid (825 mg, yield 43%). 1 H NMR (400 MHz, DMSO- d 6) δ 13.79(s, 1H), 11.09 (s, 1H), 8.01 (d, J = 1.3 Hz, 2H), 7.95 (dd, J = 8.1, 1.6 Hz,1H), 7.83 (d, J = 1.8 Hz, 1H), 7.62 (d, J = 8.6 Hz, 1H), 7.55 (dd, J = 8.6,7.1 Hz, 1H), 7.46 (d, J = 3.1 Hz, 1H), 7.37 (dd, J = 8.5, 1.7 Hz, 1H), 7.25(ddd, J = 8.4, 7.1, 1.6 Hz, 1H), 7.14 (d, J = 8.6 Hz, 1H), 7.10 – 7.00 (m,2H), 6.93 (dd, J = 8.2, 1.2 Hz, 1H), 6.88 (ddd, J = 8.2, 7.3, 1.3 Hz, 1H), 6.53 (d, J = 3.0 Hz, 1H), 6.39 (s, 2H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 4.58(d, J = 6.0 Hz, 2H), 4.29 (t, J = 7.0 Hz, 2H), 4.19 (t, J = 7.0 Hz, 2H), 2.88(ddd, J = 17.3, 14.0, 5.4 Hz, 1H), 2.64 – 2.43 (m, 2H), 2.02 – 2.19 (m, 2H), 1.78 – 1.75 (m, 4H). Example 39 a: 5-(((1-(6-(5-(3-amino-6-(2-hydroxyphenyl)pyridazine-4-yl)-1 H -indol-1-yl)hexyl)-1 H -1,2,3-triazol-4-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (39) The synthesis method follows the synthesis route of Example 32.

[0102] The difference is that 1-chloro-3-iodopropane is replaced with an equimolar amount of 1-chloro-6-iodohexane. Replace 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione with an equimolar amount of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione. Compound 39 is a yellow solid (833 mg, yield 46%). 1 H NMR (400 MHz, DMSO- d 6) δ 13.76(s, 1H), 11.06 (s, 1H), 8.01 (s, 2H), 7.95 (dd, J = 8.0, 1.7 Hz, 1H), 7.83(d, J = 1.7 Hz, 1H), 7.62 (d, J = 8.6 Hz, 1H), 7.59 – 7.52 (m, 2H), 7.46 (d,J = 3.1 Hz, 1H), 7.38 (dd, J = 8.4, 1.8 Hz, 1H), 7.29 – 7.21 (m, 1H), 7.05(d, J = 2.1 Hz, 1H), 6.94 (dt, J = 8.2, 2.1 Hz, 2H), 6.89 (t, J = 7.6 Hz, 1H), 6.53 (d, J = 3.1 Hz, 1H), 6.41 (s, 2H), 5.03 (dd, J = 12.9, 5.4 Hz, 1H), 4.46 (d, J = 5.7 Hz, 2H), 4.35 – 4.26 (m, 2H), 4.25 – 4.13 (m, 2H), 2.99 –2.74 (m, 1H), 2.55 (s, 2H), 2.06 – 1.89 (m, 2H), 1.75 (q, J = 9.5, 8.3 Hz,5H), 0.95 – 0.76 (m, 2H). Test Example 1: Western Blot Experiment Total protein sample collection: MV4-11 cells (1 × 10⁶ cells per well) 6Cells were seeded in 6-well or 12-well plates and treated with solvent control (DMSO) or different concentrations of the compound (0.8 nM / 4 nM / 20 nM / 100 nM / 300 nM / 500 nM / 1000 nM) for specified time periods. Cells were washed with ice-cold PBS, and lysed in RIPA lysis buffer containing 1% protease inhibitor and 1% PMSF for 30 minutes on ice. The lysis buffer was then centrifuged at 4 °C, 12,000 rpm for 20 minutes to remove insoluble debris, and the supernatant was collected. An equal volume of protein extract was separated by SDS-PAGE gel electrophoresis and then transferred to a PVDF membrane. The membrane was blocked at room temperature with TBST (Tris buffer solution containing 0.1% Tween-20) containing 5% skim milk powder for 2 hours. The membrane was incubated overnight at 4 °C with the following primary antibodies: SMARCA2, SMARCA4, and... β -actin. After washing with TBST, the membrane was incubated with HRP-labeled goat anti-rabbit IgG (H+L) or anti-mouse IgG HRP-conjugated antibody at room temperature for 1 hour. Protein bands were developed on a Mini Chemi imaging system using ECL reagent, and the band gray values ​​were quantitatively analyzed using ImageJ software. The experimental results are shown in Table 1 below. Figure 1 and Figure 2 As shown.

[0103] Table 1: Note: A: Dmax > 70%, high activity; B: 70% > Dmax > 40%, moderate activity; C: Dmax < 40%, weak activity. NA: No activity. NT: Not tested.

[0104] According to the results in Table 1, the compounds of the present invention in Examples 1-9 and 13-16 exhibited strong degradation activity against MV4-11 cells, while those in Examples 11-12 and 20-25 exhibited moderate degradation activity against MV4-11 cells.

[0105] Test Example 2: In vitro cell proliferation inhibition experiment In the cell viability assay, cells were seeded at a density of 1000 cells per well in 384-well plates, with a total culture medium volume of 20 mL. μ L. After incubation at 37 °C and 5% CO2 for 12 hours, the specified concentration of the test compound was added to each well to bring the final volume of each well to 30. μ L. The plate was then incubated for another 96 hours. Next, 25 μL of [unspecified substance] was added to each well. μL Cell Titer-GLO® 2.0 reagent. Place the plate on a track shaker and shake for 10 minutes, then let it stand at room temperature for 10 minutes to allow the luminescence signal to stabilize. Measure the luminescence value using an EnVision 2105 multi-plate reader (PerkinElmer) according to the manufacturer's instructions. In vitro half-maximum inhibition concentration (IC50) 50 The calculations were performed using GraphPad Prism software. The experimental results are as follows: Figure 3 As shown, the results indicate that compounds 2 and 3 exhibit significant growth-inhibiting effects in the MV4-11 cell line.

[0106] Test Example 3: In vivo anti-xenograft tumor experiment A batch of 5-week-old male BALB / c-nude mice was procured to establish a xenograft tumor model. All BALB / c-nude mice were placed in a sterile environment and subcutaneously inoculated with 5 × 10⁵ lbs / mL of xenograft solution in the flank. 6 MV4-11 tumor cells. The cells were uniformly suspended in a 1:1 mixture of phosphate-buffered saline (PBS) and Matrigel, with each mouse receiving 100 mg of the mixture. μ L. When the tumor volume grows to approximately 100 mm 3 Mice were randomly assigned to groups of six each using a randomized method. A 24-day dosing experiment was then initiated. Mice were administered the drug daily via oral gavage (po) at doses of 10 mg / kg or 20 mg / kg, with some mice serving as solvent controls. To ensure adequate dissolution and pharmacological effect, the compound was dissolved in a carefully prepared mixed solvent consisting of 15% Cremophor EL (Calbiochem), 82.5% PBS, and 2.5% dimethyl sulfoxide (DMSO). Tumor dimensions were measured using calipers, and the major diameter (L) and minor diameter (W) of the tumor were determined using the formula V = (π / 6) × L × W. 2 Tumor volume was calculated to monitor its growth dynamics. In addition, changes in animal body weight were monitored periodically to assess the potential toxicity of the compounds. Tumor growth inhibition rate (TGI, %) was calculated using the following formula: TGI = [1 (T T0) / (C [C0)] × 100, where T and T0 represent the tumor volume of the drug-treated group at the end and beginning of the experiment, respectively, and C and C0 represent the tumor volume of the solvent control group, respectively. Experimental results are as follows: Figure 4As shown, the results indicated that compound 2 induced a 25% tumor growth inhibition rate at a dose of 10 mg / kg; when the dose was increased to 20 mg / kg, the tumor growth inhibition rate significantly increased to 51%, exhibiting a clear dose-dependent antitumor effect. Under the same dosing regimen, compound 3, administered at a dose of 20 mg / kg, showed a 25% tumor growth inhibition rate, indicating relatively weak in vivo antitumor activity.

[0107] The applicant declares that this invention illustrates the indole-substituted 3-aminopyridazine compounds, their preparation methods, and applications through the above embodiments. However, this invention is not limited to the above embodiments, meaning that this invention does not necessarily rely on the above embodiments for implementation. Those skilled in the art should understand that any improvements to this invention, equivalent substitutions of raw materials, additions of auxiliary components, and selection of specific methods, etc., all fall within the protection and disclosure scope of this invention.

[0108] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0109] It should also be noted that the various specific technical features described in the above embodiments can be combined in any suitable manner without contradiction. To avoid unnecessary repetition, the present invention will not describe the various possible combinations separately. The applicant declares that the present invention illustrates the arylimidazolyl isoxazole compounds and their applications through the above embodiments, but the present invention is not limited to the above process steps, that is, it does not mean that the present invention must rely on the above process steps to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions of the raw materials selected in the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A 3-aminopyridazine compound containing an indole-substituted structure or a pharmaceutically acceptable salt thereof, characterized in that, The structure of the pyridazine compounds is shown in Formula I: Formula I Among them, R 1 Selected from H, CR a NR a R b OR a ;R a R b Each is independently selected from H, C1-C6 alkyl, deuterium, halogen, hydroxyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -C(=O)-C1-C6 alkyl; R 3 R 4 R 5 R 6 R 7 Independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, amino, -COOR a -CON(R) a )2;R a Selected from H, C1-C6 alkyl groups; Y 1 Selected from single key, -R a C(O)R b -、-R a C(O)N(R c )R b -、-R a C(O)OR b -、-R a C(O)SR b - Any one of them; R a R b Independently selected from any one of single-bonded, substituted or unsubstituted C1-C10 alkylene groups, wherein the substituted group is selected from C1-C6 alkyl groups; R c Selected from H or C1-C10 alkyl groups; L is selected from any one or a combination of at least two of the following groups: single bond, ether group, thioether group, ester group, amino group, amide group, carbamate group, urea group, sulfone group, carbonyl group, substituted or unsubstituted C1-C10 alkylene group, substituted or unsubstituted C2-C10 alkenyl group, substituted or unsubstituted C2-C10 alkyne group, substituted or unsubstituted C6-C12 aryl group, substituted or unsubstituted C6-C12 heteroaryl group, substituted or unsubstituted C3-C10 cycloalkyl group, and substituted or unsubstituted C4-C10 heterocyclic group. The substituted group is selected from any one of the following groups: halogen, amino, nitro, carboxyl, cyano, hydroxyl, C1-C5 haloalkyl, and C1-C6 alkyl. Y 2 Selected from -O-, -N(R) d -, -S-, -CH2-, -C(O)N(R) d )- or any of the single bonds; R d Selected from H or C1-C10 alkyl groups; E has the structure shown in either Equation II-1 or Equation II-2, wherein Selected from the group linkage position: Formula II-1 Formula II-2 Among them, Y 3 Selected from -O-, -S-, -CH(R) e -, -C(O)-, -S(O)2-, -N(R) e Any one of the following; R e The group is selected from H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocyclic group, wherein the substituted group is selected from halogen, amino, nitro, carboxyl, cyano, hydroxyl, C1-C5 haloalkyl, C1-C6 alkyl; Y 4 Y 5 Y 6 Y 7 Independently selected from CH or N; T 1 T 2 T 3 Independently selected from O or S; R 8 and R 9 The group is independently selected from any one of H, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 heterocyclic group, wherein the substituted group is selected from any one of halogen, hydroxyl, and C1-C6 alkyl; R 10 The group is selected from any one of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocyclic groups, wherein the substituted group is selected from any one of halogen, hydroxyl, C1-C5 haloalkyl, C1-C6 alkyl, C3-C10 cycloalkyl, and C3-C10 heterocyclic groups; R 11 The group is selected from H, substituted or unsubstituted C1-C10 alkyl groups, and substituted or unsubstituted carboxyl groups, wherein the substituted group is selected from halogens, hydroxyl groups, and C1-C6 alkyl groups. R 12 The group is selected from H, substituted or unsubstituted C1-C10 alkyl groups, wherein the substituted group is selected from any one of halogen, hydroxyl, C1-C6 alkyl, C3-C10 cycloalkyl, and C3-C10 heterocyclic groups; R 13 The group is selected from any one of H, halogen, amino, hydroxyl, cyano, substituted or unsubstituted C1-C10 alkyl, wherein the substituted group is selected from any one of halogen, hydroxyl, and C1-C6 alkyl; R 14 The group is selected from H, halogen, carboxyl, cyano, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, wherein the substituted group is selected from any one of halogen, hydroxyl, and C1-C6 alkyl.

2. The pyridazine compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The Y 4 Y 5 Y 6 Y 7 Independently selected from CH or N; Preferably, the Y 4 Y 5 Y 6 Y 7 Any one of the groups is CH, and the group is attached to the CH; Preferably, the L is selected from any one of the following groups: Indicates the location of the group connection: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； Wherein, n, o, and p are independently selected from positive integers between 1 and 10; m is selected from positive integers between 0 and 10; q is selected from 1 and 3; Y8 is selected from substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 O-containing heterocyclic alkyl, substituted or unsubstituted C1-C10 N-containing heterocyclic alkyl, and substituted or unsubstituted C1-C10 S-containing heterocyclic alkyl; A, B, C, D, U, V, S, and Z are independently selected from CH or N; Preferably, the Y 3 Selected from -CH- or -C(=O)-; Preferably, the T 1 T 2 T 3 Selected from O.

3. The pyridazine compound or a pharmaceutically acceptable salt thereof according to claim 1 or claim 2, characterized in that, The structures of the pyridazine compounds are shown in Formula III-1 or Formula III-2: Formula III-1 or Formula III-2 Among them, R 8 R 9 R 10 R 12 Y 1 Y 2 Y 3 L has the same scope as claim 1 or claim 2; Preferably, the Y 1 Selected from single key, -R a C(O)R b -、-R a C(O)N(R c )R b - any one of them; the R a R b Independently selected from single bonds or C1-C10 alkylene groups; the R c Selected from H or C1-C10 alkyl groups; Preferably, the Y 2 Selected from -O-, -N(R) d )-、-C(O)N(R d () or any one of the single bonds; the R d Selected from H or C1-C10 alkyl groups; Preferably, the Y 3 Selected from -CH2- or -C(O)-; Preferably, the R 8 R 9 Independently selected from H or C1-C10 alkyl groups; Preferably, the R 10 It is selected from C1-C5 alkyl-substituted C1-C6 alkyl and C3-C10 cycloalkyl, preferably any one of isopropyl, tert-butyl, sec-butyl, cyclohexyl, and cyclopentyl; Preferably, the R 12 Independently selected from H or C1-C10 alkyl groups; Preferably, the L is selected from any one of the following groups: Indicates the location of the group connection: 、 、 、 、 、 、 、 、 、、 、 、 、、 、 、 、 、 、 、 、 、 、 Where n, o, and p are independently selected from positive integers between 1 and 10; m is selected from positive integers between 0 and 10.

4. The pyridazine compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, characterized in that, The structures of the pyridazine compounds are shown in formula IV-1 or IV-2: Formula IV-1 Formula IV-2 Among them, Y 1 Y 2 L has the same scope as any one of claims 1-3.

5. The pyridazine compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The pyridazine compounds are selected from any one of the structures shown in compounds 1-39 below: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 6. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises an active ingredient and pharmaceutically acceptable excipients; wherein the active ingredient comprises at least one pyridazine compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-5.

7. A SMARCA2 and / or SMARCA4 protein degrading agent, characterized in that, The SMARCA2 and / or SMARCA4 protein degraders comprise at least one of the pyridazine compounds as described in any one of claims 1-5 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described in claim 6.

8. The use of any one of the pyridazine compounds of claims 1-5 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 6, or the SMARCA2 and / or SMARCA4 protein degrader of claim 7, in the preparation of a medicament for a disease or condition mediated by SMARCA2 and / or SMARCA4.

9. The use of any one of the pyridazine compounds of claims 1-5 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 6, or the SMARCA2 and / or SMARCA4 protein degraders of claim 7, in the preparation of a medicament for the prevention or treatment of cancer, cell proliferation disorders, inflammation, autoimmune diseases, or sepsis.

10. The application according to claim 9, characterized in that, The cancer includes sarcoma, solid tumor, or hematologic cancer. Preferably, the hematologic cancer includes leukemia, lymphoma, myeloma, myelodysplastic syndrome (MDS), myelofibrosis, polycythemia vera, or essential thrombocythemia.

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