6-substituted pyridazine compounds as smarca2 and / or smarca4 degraders

Abstract

The present invention provides 6-substituted pyridazine compounds of Formula (I) that are therapeutically useful as SMARCA2 and / or SMARCA4 degraders. These compounds are useful for treating and / or delaying progression of a disease or disorder in a subject that depends on SMARCA2 and / or SMARCA4. The present invention also provides methods of making the compounds and pharmaceutical compositions comprising at least one compound of Formula (I) or a pharmaceutically acceptable salt or stereoisomer or tautomer or prodrug thereof.

Description

[0001] Related applications This application claims the benefit of Indian Provisional Application No. 202041033326, filed on August 4, 2020; the description of which is incorporated herein by reference in its entirety. Technical Field

[0002] This invention relates to 6-substituted pyridazine compounds, their pharmaceutically acceptable salts or stereoisomers or tautomers or prodrugs, used as SMARCA2 and / or SMARCA4 degrading agents for the treatment of diseases or disorders dependent on SMARCA2 and / or SMARCA4. The invention also relates to methods for preparing said pyridazine compounds and pharmaceutical compositions comprising said compounds. Background Technology

[0003] One of the most important discoveries in cancer genomics is the finding of frequent mutations in various subunits of the mammalian SWI / SNF (transfer / sucrose nonfermentation) chromatin remodeling complex. Approximately 20% of human cancers are associated with somatic mutations in the subunits of the SWI / SNF complex, a chromatin remodeling complex that influences gene regulation by disrupting histone-DNA contacts (PNAS February 25, 2014. 111(8) 3128-3133).

[0004] The SWI / SNF complex contains either one of two closely related and evolutionarily conserved ATPase subunits: Brahma (BRM / SMARCA2) or Brahma-associated gene 1 (BRG1 / SMARCA4). They share approximately 75% identity at the protein level. Although complexes containing BRG1 and BRM exhibit some redundancy, they can have different functions. In human cancers, BRG1 appears to be one of the most frequently mutated subunit genes, while the BRM gene is rarely mutated. BRG1 / SMARCA4 mutations are present in approximately 10–15% of lung adenocarcinomas. BRM / SMARCA2 is essential for the growth of tumor cells with hidden functional mutations in BRG1 / SMARCA4. BRM depletion in BRG1-deficient cancer cells leads to cell cycle arrest, induces senescence, and increases overall H3K9me31 levels (PNAS February 25, 2014, 111(8), 3128–3133).

[0005] In some tumor types, mutations within the SWI / SNF complex lead to environment-specific vulnerability; for example, the survival of SMARCA4-deficient tumor cells requires SMARCA2. This finding of the in vivo transformation of the SMARCA2 / 4 synthetic lethal relationship highlights SMARCA2 as a promising therapeutic target for SMARCA4-deficient cancers. Furthermore, the SMARCA4-deficient patient population typically lacks targetable oncogenes (e.g., mutated EGFR or ALK translocations), further emphasizing the potential for developing SMARCA2 inhibitors. SMARCA4 functional characterization in tumors with high SMARCA4 levels reveals its role in signaling pathways leading to increased proliferation and survival. Knockdown of SMARCA4 in tumors shows elevated levels of known inhibitory proliferation and other cancer cell properties. The study also showed that SMARCA4 knockdown / modulation increased sensitivity to known chemotherapeutic agents, suggesting that SMARCA4 targeting could also be an adjunct therapy to existing chemotherapy regimens (PNAS February 25, 2014. 111 (8) 3128-3133; J Pathol. 2016 Feb; 238(3): 389–400).

[0006] In contrast to the potent antiproliferative activity resulting from SMARCA2 gene silencing in SMARCA4-deficient cancer cell lines, PFI-3, a selective, cell-permeable SMARCA2 / 4 bromodomain inhibitor that binds to both SMARCA2 and SMARCA4 bromodomains, failed to exhibit an antiproliferative phenotype. This suggests that SMARCA2 / 4 bromodomain function is not essential for tumor cell proliferation, but rather for catalytic ATPase activity (Cancer Res. 2015 Sep 15; 75(18): 3865–3878). To mimic the phenotype acquired through gene silencing, methods leading to a reduction or complete elimination of SMARCA2 / 4 may be required.

[0007] The ubiquitin-proteasome system (UPS) is a major pathway for regulating intracellular protein levels and provides a delicate balance between protein synthesis and degradation required for normal cellular function, including proliferation, differentiation, and cell death. Ubiquitination is a posttranslational modification in which small protein ubiquitin is covalently linked to lysine residues on substrate proteins, proceeding sequentially through an enzymatic cascade involving close cooperation between E1 activation, E2 conjugation, and E3 ligases, followed by degradation of the labeled protein (J. Biosci. 31(1), March 2006, 137–155; Expert Opin Ther Targets. 2013 September; 17(9): 1091–1108 and Cell Research (2016) 26:484-498).

[0008] Proteolytic targeting chimeras are heterobifunctional molecules containing a ligand for the target protein that is linked to an E3 ubiquitin ligase via a linker. During heterodimerization of the two binding proteins mediated by such bifunctional molecules, the target protein is ubiquitinated and degraded by the proteasome in the cell. Many such bifunctional molecules have been developed to recruit E3 ubiquitin ligases to a variety of substrates using high-affinity ligands for the target protein. Proteins efficiently degraded using these methods include RIPK2 and ERRα, BRD4, BRD9, BCR / Abl, and Erα (Cell Chemical Biology 25, 1–10, January 18, 2018). E3 ubiquitin ligases (of which more than 600 are known in humans) confer substrate specificity to ubiquitination and, due to their specificity for certain protein substrates, are more attractive therapeutic targets than general proteasome inhibitors.

[0009] Small molecule ligands targeting the bromine domains of SMARCA2 and SMARCA4 have been reported (Gerstenberger et al., Journal of Medicinal Chemistry 2016, 59, 4800-4811; Hoffman et al., PNAS, 2014b, 777, 3128-3133; Sutherell et al., 2016, Journal of Medicinal Chemistry 59, 5095-5101; WO2016138114). Although cells lacking SMARCA4 activity are susceptible to SMARCA2 deficiency (Hoffman et al., 2014a, PNAS 777, 3128-3133), SMARCA2 / 4 inhibitors have failed to phenotype these antiproliferative effects (Vangamudi et al., 2015). Consistent with this, reexpression of the SMARCA2 variant in cells where the endogenous protein has been suppressed showed that maintaining proliferation does not require the intact bromodomain (Vangamudi et al., 2015, Cancer Research 75, 3865-3878). SMARCA2 / 4BD inhibitors are therefore not suitable for treating SMARCA4 mutant cancers, but they could provide attractive ligands for PROTAC conjugation.

[0010] Therefore, it can be inferred that PROTACs targeting the nonfunctional bromine domains of SMARCA2 / 4 should offer an opportunity to exploit the vulnerability of SMARCA2 in SMARCA4-mutant cancer cells for therapeutic purposes. The principles of conjugation of suitable SMARCA ligands with E3 ligase binders have been described in WO 2016 / 105518; WO2017 / 007612 and WO2017 / 011371. However, none of these publications demonstrates specific embodiments of the SMARCA protein and its corresponding degradation. Summary of the Invention

[0011] The present invention provides 6-substituted pyridazine compounds and pharmaceutical compositions thereof, which can be used as SMARCA2 and / or SMARCA4 degrading agents and for the treatment of diseases or disorders dependent on or mediated by SMARCA2 and / or SMARCA4.

[0012] On the one hand, the present invention provides a compound of formula (I):

[0013] Or a pharmaceutically acceptable salt or stereoisomer or tautomer or prodrug; in, A represents 5- to 6-membered heteroarylenyl or 6-membered arylenyl; wherein the arylenyl and heteroarylenyl are replaced by 1, 2 or 3 Ra. Ra is hydrogen, hydroxyl, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, haloalkoxy, amino, alkylamino, or cyano; R1 is a halogen, alkyl, haloalkyl, alkenyl, alkoxy, hydroxy, hydroxyalkyl, -COORb, -CON(Rb)2, 6- to 10-aryl, or 5- to 10-heteroaryl; wherein the aryl and heteroaryl are optionally substituted by one, two, or three groups independently selected from oxo, hydroxy, alkoxy, halogen, alkyl, haloalkyl, amino, -ONa, -COORc, and -OCORc. Rb and Rc independently represent hydrogen, alkyl, or aminoalkyl each time they appear; R2 is hydrogen, hydroxyl, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, or cyano; L is a chemical bond, -O-(CH2)p-, -O-(CH2)pO-, -C≡C-alkylene-, -NRx-(CH2)p-, -NRx-(CH2)pO-, -NRx-(CH2)pC≡C-, -NRx-(3- to 10-membered heterocycloalkylene)-(CRxRy)n-, -(3- to 10-membered heterocycloalkylene)-(CRxRy)n-, -(3- to 10-membered heterocycloalkylene)-(CRxRy)n-, or -O-(3- to 10-membered heterocycloalkylene)-(CRxRy)n-; wherein the cycloalkylene and heterocycloalkylene are substituted by 1, 2, or 3 Rds; and wherein the left side of L is connected to A, and the right side of L is connected to M; Rd is independently selected from hydrogen, hydroxyl, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino and cyano groups each time it appears; Rx and Ry are independently selected from hydrogen, alkyl and halogen each time they appear; M is selected from M-1 and M-2: or ; in, Z is a 5- to 6-membered heteroarylene, which is optionally substituted by one, two or three groups independently selected from hydroxyl, halogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl and aminoynyl; wherein the aminoalkyl and aminoynyl are optionally substituted by one or two substituents selected from alkyl and -COH3; R3 and R8 independently represent alkyl, acyl, heteroalkyl, haloalkyl, hydroxyalkyl, or aminoalkyl; R4 and R9 independently represent hydrogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, -CO-aminoalkyl or acyl; wherein the alkyl group is optionally substituted with -OCOR' or -OP(O)(OR″)2; R' and R" are independently selected from hydrogen and alkyl groups; R5, R6, R 10 and R 11 Independently representing hydrogen, alkyl, halogen, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl-, -CONRuRv, acyl, -Na, -alkyl-heterocyclic alkyl, and -heteroalkyl-heterocyclic alkyl; wherein the aminoalkyl and heterocyclic alkyl are optionally substituted with one or two substituents selected from alkyl and -COH3; or R5 and R6, together with the C atoms they are attached to, form 4- to 6-membered heterocyclic alkyl groups, which are optionally substituted with alkyl groups or -COH3; or R 10 and R 11 Together with the C atoms to which they are attached, they form 4- to 6-membered heterocyclic alkyl groups, which are optionally substituted with alkyl groups or -COH3; Ru and Rv independently represent hydrogen, alkyl, 4- to 6-membered cycloalkyl or 6-membered aryl; R7 and R 12 Indicates a thiazolyl group substituted with an alkyl, hydroxyl, amino, or haloalkyl group; p is an integer selected from 1, 2, 3, and 4; and n is an integer selected from 0, 1, 2, and 3.

[0014] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer or tautomer or prodrug thereof, and at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier or diluent).

[0015] In another respect, the present invention relates to the preparation of compounds of formula (I).

[0016] In another aspect, the present invention provides pharmaceutical compositions for treating diseases or disorders dependent on or mediated by SMARCA2 and / or SMARCA4, comprising a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer or tautomer or prodrug thereof.

[0017] In another aspect, the present invention provides pharmaceutical compositions for treating diseases or disorders (e.g., cancer) or delaying the progression of diseases or disorders (e.g., cancer), said pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer or tautomer or prodrug thereof, wherein degradation of SMARCA2 and / or SMARCA4 proteins provides a benefit.

[0018] In another aspect, the present invention provides a method for degrading a target protein, comprising administering to a subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer or tautomer or prodrug thereof, wherein the compound is effective for degrading the target protein.

[0019] On the other hand, the present invention provides a method for treating a subject suffering from cancer, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer or tautomer or prodrug thereof.

[0020] On the other hand, the present invention provides a method for inhibiting tumor growth in a subject suffering from cancer, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer or tautomer or prodrug thereof.

[0021] In another aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer or tautomer or prodrug thereof in the preparation of a medicament for treating diseases or disorders dependent on or mediated by SMARCA2 and / or SMARCA4. Detailed Implementation

[0022] This invention provides 6-substituted pyridazine compounds, designated as compounds of formula (I), which can be used as SMARCA2 and / or SMARCA4 degrading agents and for the treatment of conditions dependent on or mediated by SMARCA2 and / or SMARCA4. This invention also provides pharmaceutical compositions comprising said compound or its stereoisomers or tautomers or prodrugs for use as therapeutic agents.

[0023] Each embodiment is provided by way of explaining the invention and not by way of limiting it. Indeed, it will be apparent to those skilled in the art that various modifications and variations can be made to the compounds, compositions, and methods described herein without departing from the scope or spirit of the invention. For example, features shown or described as part of one embodiment may be applied to another embodiment to produce yet another embodiment. Therefore, the invention is intended to include these modifications and variations and their equivalents. Other objects, features, and aspects of the invention are disclosed in or become apparent from the following detailed description. It should be understood by those skilled in the art that this discussion is merely a description of exemplary embodiments and should not be construed as limiting the broader aspects of the invention.

[0024] In one embodiment, the present invention provides a compound of formula (I),

[0025] Or a pharmaceutically acceptable salt or stereoisomer or tautomer or prodrug; in, A represents a 5- to 6-membered heteroarylene or a 6-membered arylene; wherein the arylene and heteroarylene are replaced by 1, 2 or 3 Ra; Ra is hydrogen, hydroxyl, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, haloalkoxy, amino, alkylamino, or cyano; R1 is a halogen, alkyl, haloalkyl, alkenyl, alkoxy, hydroxy, hydroxyalkyl, -COORb, -CON(Rb)2, 6- to 10-aryl, or 5- to 10-heteroaryl; wherein the aryl and heteroaryl groups are optionally substituted by one, two, or three groups independently selected from oxo, hydroxy, alkoxy, halogen, alkyl, haloalkyl, amino, -ONa, -COORc, and -OCORc. Rb and Rc independently represent hydrogen, alkyl, or aminoalkyl each time they appear; R2 is hydrogen, hydroxyl, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, or cyano; L is a chemical bond, -O-(CH2)p-, -O-(CH2)pO-, -C≡C-alkylene-, -NRx-(CH2)p-, -NRx-(CH2)pO-, -NRx-(CH2)pC≡C-, -NRx-(3-to-10-membered heterocycloalkylene)-(CRxRy)n-, -(3-to-10-membered heterocycloalkylene)-(CRxRy)n-, -(3-to-10-membered heterocycloalkylene)-(CRxRy)n-, or -O-(3-10-membered heterocycloalkylene)-(CRxRy)n-; wherein the cycloalkylene and heterocycloalkylene are substituted by 1, 2, or 3 Rds; and wherein the left side of L is connected to A, and the right side of L is connected to M; Rd is independently selected from hydrogen, hydroxyl, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino and cyano groups each time it appears; Rx and Ry are independently selected from hydrogen, alkyl and halogen each time they appear; M is selected from M-1 and M-2: or ; in, Z is a 5- to 6-membered heteroarylene, which is optionally substituted by one, two or three groups independently selected from hydroxyl, halogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl and aminoynyl; wherein the aminoalkyl and aminoynyl are optionally substituted by one or two substituents selected from alkyl and -COH3; R3 and R8 independently represent alkyl, acyl, heteroalkyl, haloalkyl, hydroxyalkyl, or aminoalkyl; R4 and R9 independently represent hydrogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, -CO-aminoalkyl or acyl; wherein the alkyl group is optionally substituted with -OCOR' or -OP(O)(OR″)2; R' and R" are independently selected from hydrogen and alkyl groups; R5, R6, R 10 and R 11 Independently representing hydrogen, alkyl, halogen, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl-, -CONRuRv, acyl, -Na, -alkyl-heterocyclic alkyl, and -heteroalkyl-heterocyclic alkyl; wherein the aminoalkyl and heterocyclic alkyl are optionally substituted with one or two substituents selected from alkyl and -COH3; or R5 and R6, together with the C atoms they are attached to, form 4- to 6-membered heterocyclic alkyl groups, which are optionally substituted with alkyl groups or -COH3; or R 10 and R 11 Together with the C atoms to which they are attached, they form 4- to 6-membered heterocyclic alkyl groups, which are optionally substituted with alkyl groups or -COH3; Ru and Rv independently represent hydrogen, alkyl, 4- to 6-membered cycloalkyl or 6-membered aryl; R7 and R 12 Indicates a thiazolyl group substituted with an alkyl, hydroxyl, amino, or haloalkyl group; p is an integer selected from 1, 2, 3, and 4; and n is an integer selected from 0, 1, 2, and 3.

[0026] In one embodiment, R1 is a halogen, alkyl, haloalkyl, alkoxy, hydroxyalkyl, 6- to 10-aryl, or 5- to 10-heteroaryl; wherein the aryl and heteroaryl groups are optionally substituted by one, two, or three groups independently selected from oxo, hydroxy, alkoxy, halogen, alkyl, haloalkyl, and amino.

[0027] In one embodiment, R1 is a halogen, hydroxyl group, -CH2OH, -COOH, -COOCH3, -CONH2, -CONHCH3, 6- to 10-aryl, or 5- to 10-heteroaryl; wherein the aryl and heteroaryl groups are optionally substituted by one, two, or three groups independently selected from hydroxyl, alkoxy, halogen, alkyl, and haloalkyl.

[0028] In one embodiment, R1 is a halogen, hydroxyl, 6- to 10-aryl, or 5- to 10-heteroaryl; wherein the aryl and heteroaryl groups are optionally substituted by one, two, or three groups independently selected from hydroxyl, alkoxy, halogen, alkyl, haloalkyl, -OCOCH3, and -CH(NH2)(CH(CH3)2).

[0029] In one embodiment, R1 represents a halogen, a hydroxyl group, a 6- to 10-aryl group, or a 5- to 10-heteroaryl group; wherein the aryl and heteroaryl groups are optionally substituted by one or two groups independently selected from alkyl, hydroxyl, alkoxy, halogen, and haloalkyl groups.

[0030] In one embodiment, R1 is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; wherein the aryl and heteroaryl groups are optionally substituted by one, two, or three groups independently selected from alkyl, hydroxyl, alkoxy, halogen, and haloalkyl groups.

[0031] In one embodiment, R1 is a 6- to 10-aryl group, which is optionally substituted with one, two, or three groups independently selected from alkyl, hydroxyl, alkoxy, halogen, and haloalkyl groups.

[0032] In one embodiment, R1 represents a phenyl group, which is optionally substituted by one or two groups independently selected from hydroxyl, alkyl, haloalkyl and halogen.

[0033] In one embodiment, R1 is a 5- to 10-membered heteroaryl group, which is optionally substituted by one, two, or three groups independently selected from alkyl, hydroxyl, alkoxy, halogen, and haloalkyl groups.

[0034] In one implementation, R1 represents , , , , or Furthermore, each group is optionally substituted by one, two, or three groups independently selected from hydroxyl, alkyl, haloalkyl, and halogen.

[0035] In one embodiment, R2 is hydrogen, hydroxyl, hydroxyalkyl, halogen, alkoxy, alkyl, or haloalkyl.

[0036] In one embodiment, R2 is hydrogen, hydroxyl, halogen, alkoxy, alkyl, or haloalkyl.

[0037] In one implementation, R2 independently represents hydrogen or halogen.

[0038] In one embodiment, A represents a phenlyenyl substituted with one or two Ra atoms.

[0039] In one embodiment, A represents a 5- to 6-membered heteroaryl group substituted by one or two Ra groups.

[0040] In one embodiment, A represents phenylene, furanyl, thiophenyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolylenyl, oxadiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, or 1,3,5-triazinyl; wherein each group is optionally substituted by one or two Ra.

[0041] In one embodiment, A represents phenylene, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl; wherein each group is optionally substituted by one, two, or three Ra groups.

[0042] In one embodiment, A represents phenylene, furanyl, thiophenyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazoleyl, oxadiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, or 1,3,5-triazinyl; wherein each of the groups is substituted with one or two substituents selected from hydrogen, hydroxyl, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, haloalkoxy, amino, alkylamino, or cyano.

[0043] In one embodiment, A represents phenylene, pyridinyl, pyrimidinyl, or pyrazinyl, wherein the phenylene, pyridinyl, pyrimidinyl, and pyrazinyl are optionally substituted with one or two substituents selected from hydroxyl, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, haloalkoxy, amino, alkylamino, or cyano.

[0044] In one implementation, A represents , , , , , or Each ring is optionally replaced by one or two Ra rings; the left side of A is connected to a pyridazine ring, and the right side of A is connected to L.

[0045] In one implementation, A represents , , , , , or Each group is optionally substituted by one or two substituents selected from hydrogen, hydroxyl, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, haloalkoxy, amino, alkylamino and cyano; wherein the left side of A is connected to a pyridazine ring and the right side of A is connected to L.

[0046] In one embodiment, L is a chemical bond, -O-(CH2)p-, -O-(CH2)pO-, -NRx-(CH2)p-, -NRx-(CH2)pO-, -NRx-(3- to 10-membered heterocyclic alkylene)-(CRxRy)n-, (3- to 10-membered heterocyclic alkylene)-(CRxRy)n-, (3- to 10-membered heterocyclic alkylene)-(CRxRy)n-, or -O-(3- to 10-membered heterocyclic alkylene)-(CRxRy)n-; wherein the cycloalkylene and heterocyclic alkylene are substituted by one or two Rds.

[0047] In one embodiment, L is a chemical bond, and M is attached to A. In one embodiment, L is -CH2-(CH2)p-. In one embodiment, L is -O-CH2-. In one embodiment, L is -O-CH2CH2-. In one embodiment, L is -O-CH2CH2CH2-. In one embodiment, L is -O-CH2CH2CH2CH2-. In one embodiment, L is -O-(OCH2)pO- or -C≡C-alkylene-. In one embodiment, L is -O-CH2CH2CH2CH2-O-. In one embodiment, L is -O-CH2CH2CH2-O-. In one embodiment, L is -O-CH2CH2-O-. In one embodiment, L is -O-CH2-O-. In one embodiment, L is -C≡C-(CH2)-. 1-4 - In one embodiment, L is -C≡CCH2-. In one embodiment, L is -C≡C-CH2CH2-. In one embodiment, L is -C≡C-CH2CH2CH2-. In one embodiment, L is -C≡C-CH2CH2CH2CH2-.

[0048] In one implementation, L is -NRx-(CH2)p-. 1-4 In one embodiment, L is -NRx-CH2-. In one embodiment, L is -NRx-CH2CH2-. In one embodiment, L is -NRx-CH2CH2CH2-. In one embodiment, L is -NRx-CH2CH2CH2CH2-. In one embodiment, L is -NH-(CH2) 1-4 - In one embodiment, L is -NH-CH2-. In one embodiment, L is -NH-CH2CH2-. In one embodiment, L is -NH-CH2CH2CH2-. In one embodiment, L is -NH-CH2CH2CH2CH2-. In one embodiment, L is -N(CH3)-CH2-. In one embodiment, L is -N(CH3)-CH2CH2CH2-. In one embodiment, L is -N(CH3)-CH2CH2CH2CH2-.

[0049] In one embodiment, L is -NRx-(CH2)pO-. 1-4-O-. In one embodiment, L is -NRx-CH2-O-. In one embodiment, L is -NRx-CH2CH2-O-. In one embodiment, L is -NRx-CH2CH2CH2-O-. In one embodiment, L is -NRx-CH2CH2CH2CH2-O-. In one embodiment, L is -NH-CH2-O-. In one embodiment, L is -NH-CH2CH2-O-. In one embodiment, L is -NH-CH2CH2CH2-O-. In one embodiment, L is -NH-CH2CH2CH2CH2-O-. In one embodiment, L is -N(CH3)-CH2-O-. In one embodiment, L is -N(CH3)-CH2CH2-O-. In one embodiment, L is -N(CH3)-CH2CH2CH2CH2-O-. In one embodiment, L is -N(CH3)-CH2CH2CH2CH2-O-.

[0050] In one embodiment, L is a chemical bond, -O-CH2-, -O-CH2CH2-, -O-CH2CH2CH2-, -O-CH2CH2CH2CH2-, -O-CH2-O-, -O-CH2CH2-O-, -O-CH2CH2CH2-O-, -O-CH2CH2CH2CH2-O-, -NH-CH2-, -NH-CH2CH2-, -NH-CH2CH2CH2-, -NH-CH2CH2CH2CH2-, -N(CH3)-CH2-, -N( CH3)-CH2CH2-, -N(CH3)-CH2CH2CH2-, -N(CH3)-CH2CH2CH2CH2-, NH-CH2-O-, -NH-CH2CH2-O-, -NH-CH2CH2CH2-O-, - NH-CH2CH2CH2CH2-O-, -N(CH3)-CH2-O-, -N(CH3)-CH2CH2-O-, -N(CH3)-CH2CH2CH2-O-, or -N(CH3)-CH2CH2CH2CH2-O-.

[0051] In one embodiment, L is -NRx-(3-to-10-membered heterocycloalkylene)-(CRxRy)n-, (3-to-10-membered heterocycloalkylene)-(CRxRy)n-, (3-to-10-membered heterocycloalkylene)-(CRxRy)n-, or -O-(3-to-10-membered heterocycloalkylene)-(CRxRy)n-; wherein the cycloalkylene and heterocycloalkylene are substituted by one or two Rds.

[0052] In one embodiment, L is -NRx-(3- to 10-membered heterocyclic alkylene)-(CRxRy). 0-3In one embodiment, L is -NH-(3- to 10-membered heterocyclic alkylene)-(CRxRy). 0-3 In one embodiment, L is -N(CH3)-(3- to 10-membered heterocyclic alkylene)-(CRxRy) 0-3 The heterocyclic alkyl group is optionally substituted by one or two Rd groups.

[0053] In one embodiment, L is (3- to 10-membered cycloalkylene)-(CRxRy). 0-3 ; wherein the cycloalkylene group is optionally substituted by one or two Rd groups.

[0054] In one embodiment, L is a 3- to 10-membered heterocyclic alkylene-(CRxRy). 0-3 -; wherein the heterocycloalkyl group is optionally substituted by 1, 2 or 3 Rds.

[0055] In one embodiment, L is -O-(3- to 10-membered heterocyclic alkylene)-(CRxRy). 0-3 -; wherein the heterocycloalkyl group is optionally substituted by 1, 2 or 3 Rds.

[0056] In one embodiment, L is -NRx-(3-10-membered heterocyclic alkylene)-(CRxRy) 0-3 -NH-(3-10-membered heterocyclic alkylene)-(CRxRy) 0-3 or -N(CH3)-(3-10-membered heterocyclic alkylene)-(CRxRy) 0-3 The heterocyclic alkyl group is selected from piperidinyl, piperazine, azetidinylenyl, pyrrolidine, tetrahydropyridinyl, diazobicyclooctanylenyl, azabicyclooctanylenyl, azaspiroheptanylenyl, tetrahydropyranyl, tetrahydropyridazinyl, morpholinyl, thiomorpholinyl, 1,4-dioxyl, dioxidothiomorpholinyl, oxapiperazinylenyl, oxapiperidinylenyl, tetrahydropyranyl, dihydropyranyl, and dihydropyrimidinyl, with each group substituted by one or two Rd groups.

[0057] In one embodiment, L is (3- to 10-membered cycloalkylene)-(CRxRy). 0-3 The cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0058] In one implementation, L is , , , , , , , , , , , , , , , , , or Each ring is replaced by one or two Rd occurrences; each ring is replaced by one or two Rd occurrences; the left side of L is connected to A, and the right side of L is connected to M.

[0059] In one implementation, L is -O-CH2-, -O-CH2CH2-, -O-CH2CH2CH2-, -O-CH2CH2CH2CH2-, -O-CH2-O-, -O-CH2CH2-O-, -O-CH2CH2CH2-O-, -O-CH2CH2CH2CH2-O-, -NH-CH2-, -NH-CH2CH2-, -NH-CH2CH2CH2-, -NH-CH2CH2CH2CH2-, -N(CH3)-CH2-, -N(CH 3)-CH2CH2-, -N(CH3)-CH2CH2CH2-, -N(CH3)-CH2CH2CH2CH2-, -NH-CH2-O-, -NH-CH2CH2-O-, -NH-CH2CH2CH2-O-, -N H-CH2CH2CH2CH2-O-, -N(CH3)-CH2-O-, -N(CH3)-CH2CH2-O-, -N(CH3)-CH2CH2CH2-O-, -N(CH3)-CH2CH2CH2CH2-O-, , , , , , , , , , , , , , , , , , or Each ring is replaced by one or two occurrences of Rd.

[0060] In one embodiment of the compound of formula (I), A represents a 5- to 6-membered heteroarylene or a 6-membered arylene; wherein the arylene and heteroarylene are replaced by 1, 2 or 3 Ra; Ra is hydrogen, hydroxyl, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, haloalkoxy, amino, alkylamino, or cyano; R1 is a halogen, alkyl, haloalkyl, alkenyl, alkoxy, hydroxy, hydroxyalkyl, -COORb, -CON(Rb)2, 6- to 10-aryl, or 5- to 10-heteroaryl; wherein the aryl and heteroaryl groups are optionally substituted by one, two, or three groups independently selected from oxo, hydroxy, alkoxy, halogen, alkyl, haloalkyl, amino, -ONa, -COORc, and -OCORc. Rb and Rc are independently selected from hydrogen, alkyl, or aminoalkyl in each occurrence; R2 is hydrogen, hydroxyl, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, or cyano; L is a chemical bond, -O-(CH2)p-, -O-(CH2)pO-, -C≡C-alkylene-, 6-membered heterocycloalkylene- or 6-membered heterocycloalkylene-(CRxRy)n-; wherein the heterocycloalkylene is substituted by 1, 2 or 3 Rds; Rd is independently selected from hydrogen, hydroxyl, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino and cyano groups each time it appears; Rx and Ry are independently selected from hydrogen and alkyl groups each time they appear; M is selected from: and ; in, Z is a 5- to 6-membered heteroarylene, which is optionally substituted by one, two or three groups independently selected from hydroxyl, halogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl and aminoynyl; wherein the aminoalkyl and aminoynyl are optionally substituted by one or two substituents selected from alkyl and -COH3; R3 and R8 independently represent alkyl, acyl, heteroalkyl, haloalkyl, hydroxyalkyl, or aminoalkyl; R4 and R9 independently represent hydrogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, -CO-aminoalkyl or acyl; wherein the alkyl group is optionally substituted with -OCOR' or -OP(O)(OR″)2; R' and R" are independently selected from hydrogen and alkyl groups; R5, R6, R 10 and R 11 Independently selected from hydrogen, alkyl, halogen, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl-, -CONRuRv, acyl, -Na, -alkyl-heterocyclic alkyl, and -heteroalkyl-heterocyclic alkyl; wherein the aminoalkyl and heterocyclic alkyl are optionally substituted by one or two substituents selected from alkyl and -COCH3; or R5 and R6, together with the C atoms they are attached to, form 4- to 6-membered heterocyclic alkyl groups, which are optionally substituted with alkyl groups or -COCH3; or R 10 and R 11 Together with the C atoms to which they are attached, they form 4- to 6-membered heterocyclic alkyl groups, which are optionally substituted with alkyl groups or -COCH3; Ru and Rv independently represent hydrogen, alkyl, 4- to 6-membered cycloalkyl or 6-membered aryl; R7 and R 12 It is independently a thiazolyl group substituted with an alkyl, hydroxyl, amino, or haloalkyl group; p is an integer selected from 1 and 2; and n is an integer selected from 1, 2, and 3.

[0061] In one implementation, M is M-1; ; Where Z is an imoxazolyl or imisoxazolyl; R3 represents an alkyl, haloalkyl, or hydroxyalkyl; R4 represents hydrogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, or acyl; R5 and R6 independently represent hydrogen, alkyl, halogen, haloalkyl, hydroxyalkyl, or (alkyl)aminoalkyl; R7 is a thiazolyl group substituted with an alkyl group.

[0062] In one implementation, M is selected from M-1A, M-1B, and M-1C: , , ; in, R4 is hydrogen, alkyl, acyl, or -Na; wherein the alkyl group is optionally substituted with -OCOR' or -OP(O)(OR″)2; R' and R" are independently selected from hydrogen and alkyl groups; and R6 is hydrogen, alkyl, hydroxyalkyl, aminoalkyl, or haloalkyl; wherein the aminoalkyl is optionally substituted with one or two substituents selected from alkyl and -COCH3.

[0063] In one implementation, M-1A is, , , , , , , , , , ; in, R4 is selected from hydrogen, alkyl, acyl and -Na; wherein the alkyl group is optionally replaced by -OCOR' and -OP(O)(OR″)2; R' and R" are independently selected from hydrogen and alkyl groups; and R6 is selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl; wherein the aminoalkyl is optionally substituted by one or two substituents selected from alkyl and -COCH3.

[0064] In one implementation, M-1B and M-1C are, ,

[0065] in, R4 is selected from hydrogen, alkyl, acyl and -Na; wherein the alkyl group is optionally replaced by -OCOR' and -OP(O)(OR″)2; R' and R" are independently selected from hydrogen and alkyl groups; and R6 is selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, and aminoalkyl; wherein the aminoalkyl is optionally substituted by one or two substituents selected from alkyl and -COCH3.

[0066] In one implementation, M-1A is represented by the following formula: ; in, R4 is selected from hydrogen and alkyl groups; and R6 is selected from hydrogen, hydroxyalkyl, (alkyl)aminoalkyl, or alkyl.

[0067] In one implementation, M-1A is represented by the following structure: , .

[0068] In one implementation, M is M-2: Among them, R8, R9, R 10 R 11 and R 12As defined in the compounds of formula (I).

[0069] In one implementation, M is M-2; where Z represents a 5- to 6-membered heteroarylene group, which is optionally substituted by one, two, or three groups independently selected from hydroxyl, halogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, and aminoynyl; wherein the aminoalkyl and aminoynyl groups are optionally substituted by one or two substituents selected from alkyl and -COCH3; R8 indicates alkyl, acyl, heteroalkyl, haloalkyl, hydroxyalkyl, or aminoalkyl; R9 is hydrogen, alkyl, acyl, or -Na; R 10 and R 11 Independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, and aminoalkyl; wherein the aminoalkyl group is optionally substituted with one or two substituents selected from alkyl or -COCH3; and R 12 It is a 5- to 6-membered heteroaryl group substituted with alkyl, hydroxyl, amino, or haloalkyl groups.

[0070] In one embodiment, M is M-2; wherein Z is imoxazolyl or imisooxazolyl; R8 represents alkyl, haloalkyl, or hydroxyalkyl; R9 represents hydrogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, or acyl; R 10 and R 11 Independently representing hydrogen, alkyl, halogen, haloalkyl, hydroxyalkyl, or (alkyl)aminoalkyl; and R 12 It is a thiazolyl group substituted with an alkyl group.

[0071] In one implementation, M-2 is selected from M-2A, M-2B, and M-2C: , in, Z represents an oxazolyl group optionally substituted by one, two, or three groups independently selected from hydroxyl, halogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, and aminoynyl, wherein the aminoalkyl and aminoynyl groups are optionally substituted by one or two substituents selected from alkyl and -COCH3. R9 is hydrogen, alkyl, acyl, or -Na; and R 11 It is hydrogen, alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl; wherein the aminoalkyl is optionally substituted with one or two substituents selected from alkyl and -COCH3.

[0072] In one implementation, M is selected from M-1A, M-1B, M-1C, M-2A, M-2B, and M-2C; wherein, Z represents a 5- to 6-membered heteroarylene group, which is optionally substituted by one, two, or three groups independently selected from hydroxyl, halogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, and aminoynyl; wherein the aminoalkyl and aminoynyl groups are optionally substituted by one or two substituents selected from alkyl and -COCH3; R4 and R9 are independently hydrogen, alkyl, acyl, or -Na; wherein the alkyl group is optionally substituted with -OCOR' or -OP(O)(OR″)2; R' and R" are independently selected from hydrogen and alkyl groups; and R6 and R 11 It is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl; wherein the aminoalkyl is optionally substituted with one or two substituents selected from alkyl and -COCH3.

[0073] In one implementation, Z represents isoxazolyl, pyrrazolylenyl, or pyrrazolylenyl.

[0074] In one implementation, M-2 is represented by the following structure: ; Where R9 represents hydrogen; and R 11 It indicates hydrogen or alkyl.

[0075] In one implementation, M is represented by the following structure: , or .

[0076] In one implementation, if L is a chemical bond, then M is connected to A in the compound of formula (I).

[0077] In one embodiment, the present invention provides a compound of formula (IA) or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof:

[0078] R1, R2, Ra, L and M are as defined in the compound of formula (I).

[0079] In one embodiment of the compound of formula (IA), R1 is a halogen, hydroxyl, 6- to 10-aryl, or 5- to 10-heteroaryl; wherein the aryl and heteroaryl groups are optionally substituted by one, two, or three groups independently selected from alkyl, hydroxyl, alkoxy, halogen, and haloalkyl.

[0080] In one embodiment of the compound of formula (IA), R1 is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; wherein the aryl and heteroaryl groups are optionally substituted by one, two or three groups independently selected from alkyl, hydroxyl, alkoxy, halogen and haloalkyl.

[0081] In one embodiment of the compound of formula (IA), R1 is -Cl, -OH, , , , , or Each ring is optionally substituted by one, two, or three groups independently selected from alkyl, hydroxy, alkoxy, halogen, and haloalkyl groups.

[0082] In one embodiment of the compound of formula (IA), R2 is hydrogen, hydroxyl, halogen, alkoxy, alkyl, or haloalkyl.

[0083] In one embodiment of the compound of formula (IA), R2 represents hydrogen or halogen.

[0084] In one embodiment of the compound of formula (IA), Ra is hydrogen, hydroxyl, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, haloalkoxy, amino, alkylamino, or cyano.

[0085] In one embodiment of the compound of formula (IA), Ra is hydrogen, hydroxyl, hydroxyalkyl, halogen, alkoxy, and haloalkyl.

[0086] In one embodiment of the compound of formula (IA), Ra is hydrogen, halogen, or haloalkyl.

[0087] In one embodiment of the compound of formula (IA), Ra is hydrogen or halogen.

[0088] In one embodiment of the compound of formula (IA), L is a chemical bond.

[0089] In one embodiment of the compound of formula (IA), L is a chemical bond, -O-(CH2)p-, -O-(CH2)pO-, -NRx-(CH2)p-, -NRx-(CH2)pO-, -NRx-(3-to-10-membered heterocyclic alkylene)-(CRxRy)n-, (3-to-10-membered heterocyclic alkylene)-(CRxRy)n-, (3-to-10-membered heterocyclic alkylene)-(CRxRy)n- or -O-(3-to-10-membered heterocyclic alkylene)-(CRxRy)n-.

[0090] In one embodiment of the compound of formula (IA), L is -O-CH2CH2CH2CH2-, -O-CH2CH2CH2-, -O-CH2CH2-O-, -O-CH2CH2CH2-O-, -NH-CH2CH2-O-, -N(CH3)-CH2CH2-O-, -NH-CH2CH2CH2CH2-, -N(CH3)-CH2CH2CH2CH2-, , , , , , , , , , , , , , , , , , or Each group is replaced by one or two Rd groups.

[0091] In one embodiment of the compound of formula (IA), M is selected from M-1 and M-2; wherein Z is an imoxazolyl group or an isoxazolyl group; R3 and R8 independently represent alkyl, haloalkyl, or hydroxyalkyl; R4 and R9 independently represent hydrogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, or acyl; R5 and R6 independently represent hydrogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, or (alkyl)aminoalkyl; R 10 and R 11 Independently representing hydrogen, alkyl, halogen, haloalkyl, hydroxyalkyl, or (alkyl)aminoalkyl; and R7 and R 12 This indicates a thiazolyl group that has been substituted with an alkyl group.

[0092] In one embodiment of the compound of formula (IA), M is represented by the following structure: , or .

[0093] In one embodiment of the compound of formula (IA), R1 is a halogen, hydroxyl, 6- to 10-aryl, or 5- to 10-heteroaryl; wherein the aryl and heteroaryl groups are optionally substituted by one, two, or three groups independently selected from hydroxyl, alkoxy, halogen, alkyl, and haloalkyl. R2 is hydrogen or halogen; Ra independently represents hydrogen, halogen, or haloalkyl each time it appears; L is a chemical bond, -O-CH2CH2CH2-, -O-CH2CH2CH2CH2-, -O-CH2CH2-O-, -O-CH2CH2CH2-O-, -NH-CH2CH2CH2CH2-, -N(CH3)-CH2CH2-O-, -N(CH3)-CH2CH2CH2CH2-, -NH-CH2CH2-O-, , , , , , , , , , , , , , , , , , or Each group is replaced by one or two Rd groups. Z is an imoxazolyl group or an isoxazolyl group; R3 and R8 independently represent alkyl, haloalkyl, or hydroxyalkyl; R4 and R9 independently represent hydrogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, or acyl; R5 and R6 independently represent hydrogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, or (alkyl)aminoalkyl; R 10 and R 11 Independently representing hydrogen, alkyl, halogen, haloalkyl, hydroxyalkyl, or (alkyl)aminoalkyl; and R7 and R 12 This indicates a thiazolyl group that has been substituted with an alkyl group.

[0094] In one embodiment of the compound of formula (IA), R1 is -Cl, -OH, , , , , or Each ring is optionally substituted by one, two, or three groups independently selected from alkyl, hydroxy, alkoxy, halogen, and haloalkyl groups; R2 is hydrogen or halogen; Ra is hydrogen or halogen; L is -O-CH2CH2CH2-, -O-CH2CH2CH2CH2-, -O-CH2CH2-O-, -O-CH2CH2CH2-O-, -NH-CH2CH2CH2CH2-, -N(CH3)-CH2CH2-O-, -N(CH3)-CH2CH2CH2CH2-, -NH-CH2CH2-O-, , , , , , , , , , , , , , , , , , or Each ring is replaced by one or two occurrences of Rd; M represents , or .

[0095] In one embodiment, the present invention provides a compound of formula (IB) or a pharmaceutically acceptable salt or stereoisomer or tautomer or prodrug thereof: ; R1, R2, Ra, R3, R4, R5, R6 and R7 are as defined in the compounds of formula (I).

[0096] In one embodiment of the compound of formula (IB), R1 represents -Cl, -OH, , , , , or Each ring is optionally substituted by one or two groups independently selected from alkyl, hydroxyl and halogen groups.

[0097] In one embodiment of the compound of formula (IB), L is a chemical bond, -O-(CH2)p-, -O-(CH2)pO-, -NRx-(CH2)p-, -NRx-(CH2)pO-, -NRx-(3-to-10-membered heterocyclic alkylene)-(CRxRy)n-, (3-to-10-membered heterocyclic alkylene)-(CRxRy)n-, (3-to-10-membered heterocyclic alkylene)-(CRxRy)n- or -O-(3-to-10-membered heterocyclic alkylene)-(CRxRy)n-.

[0098] In one embodiment of the compound of formula (IA), L is -O-CH2CH2CH2-, -O-CH2CH2CH2CH2-, -O-CH2CH2-O-, -O-CH2CH2CH2-O-, -NH-CH2CH2CH2CH2-, -N(CH3)-CH2CH2-O-, -N(CH3)-CH2CH2CH2CH2-, -NH-CH2CH2-O-, , , , , , , , , , , , , , , , , , or Each ring is replaced by one or two occurrences of Rd.

[0099] In one embodiment of the compound of formula (IB), R1 represents -Cl, -OH, , , , , or Each ring is optionally substituted by one, two, or three groups independently selected from alkyl, hydroxyl, and halogen groups; R2 is hydrogen or halogen; Ra is hydrogen or halogen; L is a chemical bond, -O-CH2CH2CH2-, -O-CH2CH2CH2CH2-, -O-CH2CH2-O-, -O-CH2CH2CH2-O-, -NH-CH2CH2CH2CH2-, -N(CH3)-CH2CH2-O-, -N(CH3)-CH2CH2CH2CH2-, -NH-CH2CH2-O-, , , , , , , , , , , , , , , , , , or Each group is replaced by one or two Rd groups. R3 indicates an alkyl group; R4 indicates hydrogen or alkyl; R5 represents hydrogen; R6 indicates alkyl, halogen, haloalkyl, hydroxyalkyl, or (alkyl)aminoalkyl-; and R7 represents a thiazolyl group substituted with an alkyl group.

[0100] In one embodiment, the present invention provides a compound of formula (IC) or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof: ; Where X1 and X2 independently represent N or C; and R1, R2, Ra, Rd, Rx, Ry, X1, X2, n and M are as defined in the compound of formula (I).

[0101] In one embodiment of the compound of formula (IC), R1 is -Cl, -OH, , , , , or Each ring is optionally substituted by one or two groups independently selected from alkyl, hydroxyl and halogen groups.

[0102] In one embodiment of the compound of formula (IC), Rx is hydrogen; and Ry is hydrogen or alkyl.

[0103] In one embodiment of the compound of formula (IC), M represents... , or .

[0104] In one embodiment of the compound of formula (IC), X1 and X2 independently represent N or C; R1 is -Cl, -OH, , , , , or Each ring is optionally substituted by one or two groups independently selected from alkyl, hydroxyl and halogen groups; R2 is hydrogen or halogen; Ra represents hydrogen or halogen; Rd is either hydrogen or hydroxyl; Rx is hydrogen; Ry is hydrogen or alkyl; M represents , or ; n can be 0, 1, 2, or 3.

[0105] In one embodiment, the present invention provides a compound of formula (ID) or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof: ; R1, R2, Ra, Rd, R3, R4, R5, R6, R7 and n are as defined in the compound of formula (I).

[0106] In one embodiment of the compound of formula (ID), R1 is a halogen, hydroxyl, 6- to 10-aryl or 5- to 10-heteroaryl; wherein the aryl and heteroaryl groups are optionally substituted with hydroxyl, halogen, alkyl and haloalkyl. R2 is hydrogen or halogen; Ra represents hydrogen or halogen; Rd is either hydrogen or hydroxyl; R3 indicates an alkyl, acyl, or haloalkyl group; R4 indicates hydrogen or alkyl; R5 represents hydrogen; R6 represents hydrogen, alkyl, halogen, haloalkyl, hydroxyalkyl, or (alkyl)aminoalkyl; R7 is a thiazolyl group substituted with an alkyl group; and n can be 0, 1, 2, or 3.

[0107] In one embodiment of the compound of formula (ID), R1 is a halogen, hydroxyl, 6- to 10-aryl or 5- to 10-heteroaryl; wherein the aryl and heteroaryl groups are optionally substituted with hydroxyl, halogen, alkyl and haloalkyl. R2 is hydrogen or halogen; Ra represents hydrogen or halogen; Rd is either hydrogen or hydroxyl; R3 indicates an alkyl, acyl, or haloalkyl group; R4 indicates hydrogen or alkyl; R5 represents hydrogen; R6 indicates hydrogen, alkyl, halogen, hydroxyalkyl, or (alkyl)aminoalkyl; R7 is a thiazolyl group substituted with an alkyl group; and n can be 0, 1, 2, or 3.

[0108] In one embodiment, the present invention provides a compound of formula (IE) or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof: ; Among them, R1, R2, R8, R9, R 10 R 11 R 12 A and Z are as defined in compound (I).

[0109] In one embodiment of the compound of formula (IE), R1 represents -Cl, -OH, , , , , or Each ring is optionally substituted by one or two groups independently selected from alkyl, hydroxyl and halogen groups.

[0110] R2 is hydrogen or halogen; A represents , , , , , or Each ring is replaced by one or two hydrogen or halogen atoms. Z represents imoxazole group or imisooxazole group; R8 indicates an alkyl group; R9 represents hydrogen; R 10 It represents hydrogen; R 11 Indicates alkyl; and R 12 This indicates a thiazolyl group that has been substituted with an alkyl group.

[0111] In one embodiment, the present invention provides a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof; wherein the compound is selected from:

[0112] Or a pharmaceutically acceptable salt or stereoisomer or tautomer or prodrug.

[0113] Treatment In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer or tautomer or prodrug thereof, which is used as a drug.

[0114] In one embodiment, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer or tautomer or prodrug thereof in the preparation of a medicament for treating diseases or disorders dependent on SMARCA2 and / or SMARCA4.

[0115] In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer or tautomer or prodrug thereof for the treatment of diseases or disorders dependent on SMARCA2 and / or SMARCA4.

[0116] In one implementation, the disease or disorder that depends on SMARCA2 and / or SMARCA4 is cancer.

[0117] In one embodiment, the present invention provides a method for degrading a target protein, comprising administering to a subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, wherein the compound is effective in degrading the target protein.

[0118] In one embodiment, the present invention provides a method for treating or delaying the progression of a disease or disorder dependent on SMARCA2 and / or SMARCA4 in a subject, the method comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer or tautomer or prodrug thereof.

[0119] In one implementation, diseases or disorders that depend on SMARCA2 and / or SMARCA4 include cancer.

[0120] In one embodiment, the present invention provides a method for inhibiting tumor growth in a subject suffering from cancer, comprising administering to a subject in need a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer or tautomer or prodrug thereof.

[0121] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, or a stereoisomer or tautomer thereof, or a prodrug thereof, and at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof, or a stereoisomer or tautomer thereof, or a prodrug. The compounds described in the present invention may be bound to, or diluted with, a carrier, or encapsulated in a carrier, which may be in the form of a capsule, sachet, paper, or other container.

[0122] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) for degrading a target protein in a subject, wherein the target protein is SMARCA2 and / or SMARCA4.

[0123] In one implementation, the subject suffers from a disease or disorder that depends on SMARCA2 and / or SMARCA4.

[0124] In one implementation, the subject has cancer mediated by a target protein, wherein the target protein is SMARCA2 and / or SMARCA4.

[0125] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer or tautomer or prodrug thereof, which is used as a medicament.

[0126] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) for treating diseases or disorders mediated by SMARCA2 and / or SMARCA4, or delaying the progression of diseases or disorders mediated by SMARCA2 and / or SMARCA4.

[0127] In one implementation, the disease or disorder dependent on SMARCA2 and / or SMARCA4 is selected from the following cancers: blood cancers, lung cancer (NSCLC, i.e., non-small cell lung cancer), acoustic neuroma, acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia (granulocytic leukemia). Leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, proliferative dysplasia (developmental abnormalities and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocytosis, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, head and neck cancer, hemangioblastoma, hepatoma, hepatocellular carcinoma. Cancer), hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, liver cancer, lymphangiosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's; Burkitt's), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, T-cell or B-cell-derived lymphomas, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), oligodendroglioma, oral cancer, osteosarcoma, ovarian cancer Pancreatic cancer, papillary gland cancer, papillary carcinoma, pineal gland tumor, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, malignant rhabdomyosarcoma (MRT), rhabdomyosarcoma, sarcoma, sebaceous gland cancer, seminoma, skin cancer, small cell lung tumor, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovial malformation, sweat gland cancer, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor.

[0128] In one implementation, cancers that depend on SMARCA2 and / or SMARCA4 are lung cancers, such as NSCLC, or non-small cell lung cancer.

[0129] In one implementation, cancers that depend on SMARCA2 and / or SMARCA4 are melanomas.

[0130] In another implementation, the cancer is a SMARCA2 and / or SMARCA4 dependent cancer.

[0131] Orally administered liquid dosage forms include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitol and mixtures thereof. Besides inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatizers.

[0132] Injectable formulations, such as sterile injectable aqueous or oily suspensions, can be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injectable formulations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among acceptable media and solvents, water, Ringer's solution, United States Pharmacopeia (USP), and isotonic sodium chloride solution can be used. Furthermore, sterile, non-volatile oils are commonly used as solvents or suspension media. For this purpose, any mild, non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids (such as oleic acid) are used in injectable formulations.

[0133] To prolong the effect of a drug, it is often necessary to slow down its absorption after subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a poorly water-soluble crystalline or amorphous substance. The absorption rate of the drug depends on its dissolution rate, which in turn depends on the crystal size and crystal shape. Alternatively, delayed absorption of parenteral dosage forms can be achieved by dissolving or suspending the drug in an oil carrier.

[0134] The composition for rectal or vaginal application is preferably a suppository, which can be prepared by mixing the compound of the present application with a suitable non-irritating excipient or carrier (e.g., cocoa butter, polyethylene glycol, or suppository wax) that is solid at ambient temperature but liquid at body temperature, thus melting in the rectal or vaginal cavity and releasing the active compound.

[0135] Similar solid compositions can also be used as fillers in soft and hard filled gelatin capsules that use excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0136] The active compound may also be in microencapsulated form with one or more of the excipients described above. Solid dosage forms of tablets, sugar-coated pills, capsules, pellets, and granules can be prepared using coatings and shells (e.g., enteric coatings, controlled-release coatings, and other coatings known in the field of pharmaceutical formulation). In such solid dosage forms, the active compound may be mixed with at least one inert diluent (e.g., sucrose, lactose, or starch). According to conventional practice, such dosage forms may also contain substances other than inert diluents, including but not limited to tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pellets, the dosage form may also contain a buffer.

[0137] Dosage forms for topical or transdermal application of the compounds of this application include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers, or patches. The active ingredient is mixed under aseptic conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers. Ophthalmic preparations, ear drops, eye ointments, powders, and solutions are also considered within the scope of this application.

[0138] In addition to the active compounds of this application, ointments, pastes, creams and gels may contain excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth gum, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.

[0139] In addition to the compounds of this application, powders and aerosols may contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures thereof. Aerosols may also contain conventional propellants such as chlorofluorocarbons (CFCs).

[0140] Transdermal patches offer the added advantage of providing controlled delivery of compounds into the body. This dosage form can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flow of the compound across the skin. The rate can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0141] The disclosed compounds and pharmaceutical compositions can be administered via any method of therapeutic application. These methods include systemic or local administration, such as oral, nasal, parenteral, intravenous, transdermal, subcutaneous, vaginal, oral, rectal, or topical administration.

[0142] Depending on the intended method of administration, the disclosed compounds or pharmaceutical compositions may be in solid, semi-solid, or liquid dosage forms, such as injections, tablets, suppositories, pills, sustained-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, etc., sometimes in unit doses and consistent with conventional pharmaceutical practice. Similarly, they may be administered intravenously (bolus and infusion), intraperitoneally, subcutaneously, or intramuscularly, as well as in all forms of use known to those skilled in the art of pharmacy.

[0143] Exemplary pharmaceutical compositions are tablets and gelatin capsules comprising one or more compounds disclosed herein and a pharmaceutically acceptable carrier, such as, but not limited to, a) diluents, such as purified water, triglyceride oils (e.g., hydrogenated or partially hydrogenated vegetable oils, or mixtures thereof), corn oil, olive oil, sunflower oil, safflower oil, fish oil (e.g., EPA or DHA, or their esters or triglycerides, or mixtures thereof), omega-3 fatty acids or derivatives thereof, lactose, dextran, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose, and / or glycine; b) lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and / or polyethylene glycol; the same applies to tablets; c) binders, such as magnesium aluminum silicate, starch paste, gelatin, etc. d) Gum, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars (e.g., glucose or β-lactose), corn sweeteners, natural and synthetic gums (e.g., gum arabic, gum arabic, or sodium alginate), waxes and / or polyvinylpyrrolidone, if desired; e) Disintegrants, such as starch, agar, methylcellulose, bentonite, xanthan gum, alginate or its sodium salt, or effervescent mixtures; f) Absorbents, colorants, flavorings, and sweeteners; e) Emulsifiers or dispersants, such as Tween 80, Labrasol, hydroxypropyl methylcellulose (HPMC), DOSS, hexanoyl 909, medium-chain triglycerides (Labrafac), Labrafil, peceol, transcutol, Capmul MCM, Capmul PG-12, Captex 355, glyceryl monostearate (Gelucire), vitamin E TGPS or other acceptable emulsifiers; and / or g) agents that enhance the absorption of the compound, such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, PEG200.

[0144] Liquid compositions, particularly injectable compositions, can be prepared, for example, by dissolution, dispersion, etc. For instance, one or more disclosed compounds can be dissolved in or mixed with a pharmaceutically acceptable solvent, such as water, saline, dextran aqueous solution, glycerol, ethanol, etc., to form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicrons, or serum proteins can be used to dissolve the disclosed compounds.

[0145] One or more disclosed compounds or compositions may be delivered via parenteral administration. Parenteral injection is commonly used for subcutaneous, intramuscular, or intravenous injection and infusion. Injectable preparations may be prepared in conventional forms, as liquid solutions or suspensions, or in solid forms suitable for dissolving in a liquid prior to injection.

[0146] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this subject matter pertains. As used in the specification and appended claims, unless otherwise stated, the following terms have the indicated meanings for the purpose of understanding the invention.

[0147] The singular forms “a”, “an”, and “the” include plural references unless the context explicitly indicates otherwise.

[0148] As used herein, the terms “optional” or “optionally” mean that an event or situation described below may or may not occur, and the description includes examples in which the event or situation occurs as well as examples in which the event or situation does not occur. For example, “optionally substituted alkyl” means an event or situation in which the alkyl group may be substituted as well as an event or situation in which the alkyl group is not substituted.

[0149] The term "substituted" refers to a portion having a substituent that replaces hydrogen on one or more carbons of the skeleton. It should be understood that "substitution" or "substituted" includes the implicit condition that such substitution is consistent with the permissible valence of the substituted atom and the substituent, and that the substitution produces a stable compound, for example, which does not spontaneously transform, for example, through rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For suitable organic compounds, permissible substituents may be one or more, and may be the same or different. For the purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of the organic compounds described herein that satisfy the valence of the heteroatom. Those skilled in the art will understand that the substituent itself may be substituted, if appropriate.

[0150] As used herein, the term "alkylene" refers to a divalent alkyl group as defined herein. The term "alkyl" refers to a saturated aliphatic group, including but not limited to C1-C1 groups. 10 Straight-chain alkyl or C3-C 10 Branched alkyl. Preferably, "alkyl" refers to a C1-C6 straight-chain alkyl or a C3-C6 branched alkyl. Most preferably, "alkyl" refers to a C1-C4 straight-chain alkyl or a C3-C8 branched alkyl. Examples of "alkyl" include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neopentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl, and 4-octyl. Therefore, examples of "alkylene" include, but are not limited to, -CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH(CH3)CH2CH2CH2-, and -CH2CH(CH3)CH2CH2-, wherein the "alkyl" may optionally be substituted.

[0151] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms, wherein the halogen and alkyl group are as defined above. Examples of "haloalkyl" include, but are not limited to, fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl, and 2,2,2-trifluoroethyl.

[0152] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group, wherein the amino group and the alkyl group are as defined above. Examples of "aminoalkyl" include, but are not limited to, -CH3-NH2, -CH2-CH2-NH2, -CH2-CH2-CH2-NH2, -CH(CH3)-CH2-NH2, -CH2-CH2-NH(CH3), and -CH2-CH2-N(CH3)2.

[0153] As used herein, the term "alkylamino" refers to an amino group substituted with one or two alkyl groups, wherein the amino and alkyl groups are as defined above. Examples of "alkylamino" include, but are not limited to, -NH(CH3), -N(CH3)2, -NH(C2H5)2, and -NH(C2H5)2.

[0154] As used herein, the term "hydroxylalkyl" or "hydroxyalkyl" refers to an alkyl group as defined above, wherein one or more hydrogen atoms of the alkyl group have been replaced by hydroxyl groups. Examples of hydroxyalkyl moiety include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CHOHCH2OH, -CH2CH(OH)CH3, and -CH(CH3)CH2OH.

[0155] As used herein, the term "cycloalkylene" refers to a divalent cycloalkylene group as defined herein. The term "cycloalkyl" refers to a C3-C... 10 Saturated cyclic hydrocarbon rings. Cycloalkyl groups can be monocyclic, typically containing 3 to 7 carbon ring atoms. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Alternatively, cycloalkyl groups can be polycyclic or contain more than one ring. Examples of polycyclic cycloalkyl groups include bridged, fused, and spirocyclic carbocyclic groups. Therefore, examples of "cycloalkylene" include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, and cycloheptylene.

[0156] As used herein, the term "heterocyclic alkyl" refers to a divalent heterocyclic alkyl group as defined herein. The term "heterocyclic alkyl" refers to a 3- to 15-membered non-aromatic, saturated or partially saturated, bridged bicyclic, spirocyclic, monocyclic, or polycyclic cyclic system having at least one heteroatom or heterogroup selected from O, N, S(O), S(O)₂, NH, and C(O), with the remaining ring atoms independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. The term "heterocyclic alkyl" also refers to a bridged bicyclic system having at least one heteroatom or heterogroup selected from O, N, S(O), S(O)₂, NH, and C(O). Examples of “heterocyclic alkyl” include, but are not limited to, azacyclic butyl, oxacyclic butyl, imidazoalkyl, pyrrolidinyl, oxazolidinyl, thiazoalkyl, pyrazolyl, tetrahydrofuranyl, piperidinyl, dihydropyridinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-oxacyclohexyl, dioxothiomorpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopheneyl, dihydropyranyl, indololinyl, indololinylmethyl, isoindololinyl, oxoisoindololinyl, dioxoisoindololinyl, azabicyclooctyl, diazabicyclooctyl, azocinyl, chromiumyl, isochoryl stantonyl and 2-oxa-6-azaspiro[3.3]heptyl. Therefore, examples of "heterocyclic alkyl" include, but are not limited to, aza-heterocyclic butyl, oxocyclic butyl, pyrrolidine, piperidinyl, piperazine, tetrahydropyridinyl, diazobicyclooctyl, azabicyclooctyl, azaspiroheptyl, tetrahydropyranyl, tetrahydropyridazine, morpholinyl, thiomorpholinyl, 1,4-dioxane, dioxothiomorpholinyl, oxopiperazine, oxopiperidinyl, tetrahydropyranyl, dihydropyranyl, and dihydropyrimidinyl. The linkage of the heterocyclic alkyl substituent can occur via a carbon atom or a heteroatom. The heterocyclic alkyl group may optionally be substituted with one or more suitable groups, said suitable groups being one or more of the groups described above. Preferably, "heterocyclic alkyl" refers to a 5- to 6-membered ring selected from the group consisting of imidazoalkyl, pyrrolidinyl, oxazolidinyl, thiazoalkyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, and thiomorpholinyl (unless otherwise specified). All heterocyclic alkyl groups are optionally substituted with one or more of the above groups.

[0157] As used herein, the term "hybrid aryl" refers to a divalent heteroaryl as defined herein. The term "heteroaryl," alone or in combination with other terms, refers to a fully unsaturated ring system containing a total of 5 to 14 ring atoms, unless specifically mentioned in relation to ring size. At least one ring atom is a heteroatom (i.e., O, N, or S), and the remaining ring atoms / groups are independently selected from C, N, O, and S. The heteroaryl can be single-ring (monocyclic) or polycyclic (bicyclic, tricyclic, or polycyclic) fused together or covalently linked. Preferably, "heteroaryl" is a 5- to 6-membered ring, unless specifically mentioned in relation to ring size. The ring may contain 1 to 4 additional heteroatoms selected from N, O, and S, wherein the N atom is optionally quaternized. Any suitable ring position of the heteroaryl moiety may be covalently linked to the defined chemical structure. Examples of "heteroaryl" groups include, but are not limited to, furanyl, thiophene, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazoleyl, oxadiazolyl, triazolyl, pyridyl, 3-fluoropyridyl, pyrimidinyl, pyrazinyl, pyrazinyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzofuranyl, benzothiaphenyl, benzotriazinyl, phthalazinyl, and thiazolyl. Anthrayl, dibenzofuranyl, dibenzothiophenyl, benzimidazolyl, indolyl, isoindolyl, indazoleyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxolinyl, purineyl, pteridinyl, 9H-carbazoyl, α-carbazoyl, inazinyl, benzisothiazolyl, benzoxazolyl, pyrrolopyridyl, furanpyridyl, purineyl, benzothiadiazolyl, benzoxadiazolyl, benzotriazolyl, benzotriadiazolyl, carbazoyl, dibenzothiophenyl, acridineyl, etc. Therefore, examples of heteroaryl groups include, but are not limited to, furanyl, thiopheneyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazoleyl, oxadiazolyl, triazolyl, pyridylenyl (pyridinylenyl), pyrimidinyl, pyrazinyl, and pyridazinyl. The heteroaryl group may optionally be further substituted.

[0158] As used herein, the term "alkenyl" refers to a carbon chain containing at least one carbon-carbon double bond, which may be straight-chain or branched, or a combination thereof. Examples of "alkenyl" include, but are not limited to, vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, and 2-methyl-2-butenyl.

[0159] The term "amino" as used in this article refers to the -NH2 group.

[0160] The terms “halogenated” or “halogen” used in this article, alone or in combination with other terms, refer to fluorine, chlorine, bromine, or iodine.

[0161] The term "hydroxyl" or "hydroxyl" as used herein, alone or in combination with other terms, represents -OH.

[0162] The term "oxo" as used in this article refers to the =O group.

[0163] As used herein, the term "alkoxy" refers to the -O-alkyl group, wherein the alkyl group is as defined above. Exemplary C1-C 10 Alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, tert-butoxy, or n-pentoxy. Alkoxy groups may optionally be substituted with one or more suitable groups. Preferably, the term "alkoxy" refers to a C1-C4 alkoxy group. A few examples of C1-C4 alkoxy groups include methoxy, ethoxy, n-propoxy, n-butoxy, or tert-butoxy groups.

[0164] As used herein, the term "aryl" (either by itself or as part of another group) refers to a monocyclic, bicyclic, or polycyclic aromatic hydrocarbon ring system with 6 to 14 carbon atoms. Preferably, "aryl" refers to (C6-C4) aromatic hydrocarbons. 10 Aryl groups. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthraceneyl, biphenyl, and acenaphthene. A preferred aryl group is phenyl. The term "arylene" refers to a divalent aryl group. Therefore, examples of arylene groups include, but are not limited to, phenylene, naphthylene, biphenylene, and anthracene.

[0165] The term "acyl" refers to a group R-CO- or -CO-R, where R is an optionally substituted alkyl group as defined above. Examples of "acyl" groups are, but are not limited to, CH3CO-, CH3CH2CO-, CH3CH2CH2CO-, or (CH3)2CHCO-.

[0166] The term "heteroatom" as used in this article refers to sulfur, nitrogen, or oxygen atoms.

[0167] The term "compound" as used herein includes the compounds disclosed herein.

[0168] The term "salt" refers to a salt derived from a suitable base, including alkali metals (e.g., sodium and potassium), alkaline earth metals (e.g., magnesium), ammonium, and nitrogen. + (C 1-4 Alkyl)4 salt.

[0169] The terms “comprise” or “comprising” as used in this article are generally used in the sense of inclusion, that is, allowing the presence of one or more features or components.

[0170] Unless otherwise stated, the term "or" as used herein means "and / or".

[0171] The term "including" as used herein, as well as other forms such as "include," "includes," and "included," are not restrictive.

[0172] As used herein, the term "composition" is intended to include products containing specific amounts of specific ingredients, and any products directly or indirectly produced from combinations of specific amounts of specific ingredients. "Pharmaceutically acceptable" means that the carrier, diluent, or excipient must be compatible with the other components of the formulation and harmless to its recipients.

[0173] As used herein, the term "pharmaceutical composition" refers to a composition comprising a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof and a pharmaceutically acceptable carrier.

[0174] Pharmaceutical compositions typically contain about 1% to 99% (e.g., about 5% to 75%, or about 10% to about 50%, or about 10% to about 30%) by weight of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof. The amount of the compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof in the pharmaceutical composition may be about 1 mg to about 1000 mg, or about 2.5 mg to about 500 mg, or about 5 mg to about 250 mg, or any range within the wider range of 1 mg to 1000 mg or above or below the foregoing range.

[0175] The term "pharmaceutically acceptable carrier, diluent, or excipient" as used herein includes, but is not limited to, any adjuvant, carrier, excipient, gliding agent, sweetener, diluent, preservative, dye / coloring agent, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, surfactant, or emulsifier approved by the U.S. Food and Drug Administration for acceptable use in humans or livestock.

[0176] As used in this disclosure, the terms “administer,” “administering,” or “administration” mean the direct administration to a subject of one or more of the disclosed compounds or pharmaceutically acceptable salts or stereoisomers of one or more of the disclosed compounds or a composition comprising one or more of the disclosed compounds, or the administration to a subject of a prodrug derivative or analog of the compound or a pharmaceutically acceptable salt of the compound or composition, which may form an equivalent amount of the active compound in the subject’s body.

[0177] As used in this disclosure, the term "carrier" encompasses carriers, excipients, and diluents, and means a material, composition, or medium involved in carrying or transporting a pharmaceutical agent from one organ or part of a subject to another organ or part of a subject, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material.

[0178] As used in this article, the terms “treat,” “treating,” and “treatment” refer to methods for alleviating or eliminating a disease and / or its accompanying symptoms.

[0179] The term "subject" as used in this article refers to animals, preferably mammals, and most preferably humans.

[0180] As used herein, “delayed progression” refers to postponing, hindering, slowing, stabilizing, and / or delaying the development of a disease (such as cancer). This delay can be of varying lengths, depending on the history of the disease and / or the individual being treated. As will be apparent to those skilled in the art, sufficient or significant delay can indeed include prevention, as the individual does not develop the disease. For example, the development of advanced cancer, such as metastasis, may be delayed.

[0181] As used herein, the term "therapeuticly effective amount" refers to a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, or a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, which, in a specific subject suffering from a disease or disorder (particularly in its use in a disease or disorder associated with SMARCA2 and / or SMARCA4-mediated cancer), effectively produces the desired therapeutic response. Specifically, the term "therapeuticly effective amount" includes, upon administration, an amount of a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof that induces a positive alteration in the disease or disorder to be treated, or is sufficient to delay the progression of one or more symptoms of the disease or disorder to be treated in a subject, or is sufficient to prevent its development, or alleviates its symptoms to some extent. Regarding the therapeutic amount of a compound, the amount of the compound used to treat the subject may be sufficiently low to avoid excessive or serious side effects, within the bounds of reasonable medical judgment. The therapeutically effective amount of a compound or composition will vary depending on the specific condition being treated, the severity of the condition being treated or prevented, the duration of treatment, the nature of concurrent treatments, the age and physical condition of the subject, the specific compound or composition used, and the specific pharmaceutically acceptable carrier used.

[0182] "Pharmaceutical acceptable" means that it can be used to prepare pharmaceutical compositions that are generally safe, non-toxic and not biologically or otherwise undesirable, and include that they are acceptable for veterinary and human pharmaceutical use.

[0183] The term "pharmaceutically acceptable salt" refers to the product obtained by reacting the compounds of the present invention with a suitable acid or base. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic bases, such as Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn, and Mn salts; examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids, such as hydrochlorides, hydrobroms, hydroiodates, nitrates, sulfates, hydrogen sulfates, phosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, pantothenates, hydrogen tartrate, ascorbic acid salts, succinates, maleates, gentianates, fumarates, gluconates, glucono-diates, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, 4-methylbenzenesulfonates, or p-toluenesulfonates, etc. Certain compounds of the present invention (compounds of formula (I)) can form pharmaceutically acceptable salts with various organic bases such as lysine, arginine, guanidine, diethanolamine, or metformin. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, or zinc salts.

[0184] The term "cancer" is used throughout this specification to refer to the pathological process that leads to cancerous or malignant growths, namely, the formation and growth of abnormal tissue through cell proliferation, typically faster than normal, and continuing to grow after the stimuli that initiated new growth cease. Malignant tumors are characterized by a partial or complete lack of structural tissue and functional coordination with normal tissue, and most invade surrounding tissues, metastasize to several sites, and may recur after attempted removal, leading to patient death unless adequately treated. The term tumor formation, as used herein, is used to describe all cancerous disease states and includes or covers the pathological processes associated with malignant hematogenous tumors, ascites tumors, and solid tumors. In one embodiment, cancer is SMARCA2- and / or SMARCA4-mediated cancer. Exemplary cancers include, but are not limited to, blood cancers, lung cancer (NSCLC, i.e., non-small cell lung cancer), acoustic neuroma, acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia (CML), and chronic myeloid leukemia (CML). Granulocytic leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, proliferative dysplasia (developmental abnormalities and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocytosis, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, brain glioma, neuroglioma, heavy chain disease, head and neck cancer, hemangioblastoma, hepatocellular carcinoma, hormones Insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, liver cancer, lymphangiosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's; Burkitt's disease), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, T-cell or B-cell-derived lymphomas, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT Non-malignant glioma, oligodendroglioma, oral cancer, osteoblastic sarcoma, ovarian cancer, pancreatic cancer, papillary gland carcinoma, papillary carcinoma, pineal tumor, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, malignant rhabdomyosarcoma (MRT), rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung tumor, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovial tumor, sweat gland carcinoma, thyroid cancer, Waldenström macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor.

[0185] The term "stereoisomer" refers to any enantiomer, diastereomer, or geometric isomer of a compound of formula (I), whether chiral or when they contain one or more double bonds. When the compounds of formula (I) and related formulas are chiral, they may exist in racemic or optically active forms. It should be understood that this invention covers all stereochemical isomers, including diastereomers, enantiomers, and epimers, as well as... d -Isomers and l - Isomerics and mixtures thereof. Individual stereoisomers of the compound may be prepared synthetically from commercially available starting materials containing a chiral center, or by preparing a mixture of enantiomers followed by separation (e.g., conversion to a diastereomer mixture), followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on a chiral column, or any other suitable method known in the art. Starting compounds having a specific stereochemistry may be commercially available or may be prepared and resolved by techniques known in the art. Additionally, the compounds of the present invention may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, engegen (E), and trans (Z) isomers and suitable mixtures thereof.

[0186] The term "enantiomer" refers to a pair of stereoisomers that are mirror images of each other that do not overlap. The term "enantiomer" also refers to a single member of this pair of stereoisomers. The term "racemic" refers to a 1:1 mixture of a pair of enantiomers. This disclosure includes enantiomers of the compounds described herein. Each compound disclosed herein includes all enantiomers conforming to the general structure of the compound. The compound may be in racemic or enantiomerically pure form, or any other form according to stereochemistry. In some embodiments, the compound is an (S)-enantiomer.

[0187] The term "diastereomer" refers to a set of stereoisomers that cannot overlap by rotation around a single bond. For example, cis and trans double bonds, internal and external substitutions in bicyclic systems, and compounds containing multiple stereocenters with different relative configurations are considered diastereomers. The term "diastereomer" refers to any member of this group of compounds. In some of the examples given, synthetic routes can produce a single diastereomer or a mixture of diastereomers. This disclosure includes diastereomers of the compounds described herein.

[0188] Pharmaceutical Composition The compounds of the present invention can be used as a single drug or as a pharmaceutical composition in which the compounds are mixed with a variety of pharmacologically acceptable materials.

[0189] The compounds of this invention are typically administered in the form of pharmaceutical compositions. Such compositions can be prepared using methods well known in the pharmaceutical field and comprise at least one compound of this invention. The pharmaceutical compositions of this patent application comprise one or more of the compounds described herein and one or more pharmaceutically acceptable excipients. Generally, pharmaceutically acceptable excipients are approved by regulatory authorities or are generally considered safe for use in humans or animals. Pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, flow aids and lubricants, preservatives, buffers, chelating agents, polymers, gelling agents, thickeners, and solvents.

[0190] The pharmaceutical composition may be administered orally, parenterally, or by inhalation. Examples of parenterally administration include injection, transdermal, transmucosal, nasal, and transpulmonary administration.

[0191] Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycol, peanut oil, olive oil, gelatin, lactose, gypsum powder, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, gelatin, agar, pectin, gum arabic, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, mono- and diglycerides of fatty acids, fatty acid esters, and polyoxyethylene.

[0192] The pharmaceutical composition may also include one or more pharmaceutically acceptable adjuvants, wetting agents, suspending agents, preservatives, buffers, sweeteners, flavoring agents, coloring agents, or any combination thereof.

[0193] The pharmaceutical compositions can be in conventional forms, such as tablets, capsules, solutions, suspensions, injections, or products for topical application. Furthermore, the pharmaceutical compositions of the present invention can be formulated to provide a desired release profile.

[0194] The compounds of this invention, in their pure form or in suitable pharmaceutical composition form, can be administered using any acceptable route of administration. The route of administration can be any method that efficiently delivers the active compound of this patent application to a suitable or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, oral, skin, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, ​​intramuscular, or topical administration.

[0195] Solid oral dosage forms include, but are not limited to, tablets, capsules (soft or hard gelatin), sugar-coated pills (containing active ingredients in powder or pill form), sugar tablets, and tablets.

[0196] Liquid formulations include, but are not limited to, syrups, emulsions, and sterile injectable liquids, such as suspensions or solutions.

[0197] Topical dosage forms of compounds include ointments, pastes, creams, lotions, powders, solutions, eye drops or ear drops, and impregnated dressings, and may contain appropriate conventional additives, such as preservatives and solvents, to aid drug penetration.

[0198] The appropriate dosage of the compound used to treat the disease or disorder described herein can be determined by a person skilled in the art. Therapeutic dosages are typically determined based on preliminary evidence derived from animal studies through studies of dosage ranges in humans. The dosage must be sufficient to produce the desired therapeutic benefit without causing unwanted side effects. A person skilled in the art can also readily use and adjust the method of administration, dosage form, and suitable pharmaceutical excipients. All variations and modifications are contemplated within the scope of this patent application.

[0199] The term "prodrug" refers to a compound that, under physiological conditions or by solvent degradation, can be converted into the bioactive compound described herein (e.g., a compound of structure (I)). Therefore, the term "prodrug" refers to a precursor of a pharmaceutically acceptable bioactive compound. In some embodiments, the prodrug is inactive when administered to a subject, but is converted into the active compound in vivo, for example, by hydrolysis. Prodrug compounds generally offer advantages in mammalian organisms such as solubility, tissue compatibility, or delayed release (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). Discussions of prodrugs are provided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” ACS Symposium Series, Vol. 14 and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entirety. The term "prodrug" also refers to any covalently bonded carrier that, when administered to a mammalian subject, releases the active compound in vivo. As described herein, prodrugs of active compounds are generally prepared by modifying the functional groups present in the active compound such that the modification cleaves into the parent active compound under normal operating conditions or in vivo. Prodrugs include compounds in which a hydroxyl, amino, or thiol group is bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free thiol group, respectively. Examples of prodrugs include, but are not limited to, acetic acid, formic acid, and benzoic acid derivatives with hydroxyl functional groups, or acetamide, formamide, and benzamide derivatives with amine functional groups in the active compound.

[0200] In some embodiments, the prodrug comprises a compound having a phosphate, phosphoalkoxy, ester, or borate ester substituent (I). Without being bound by theory, it is believed that such substituents convert to hydroxyl groups under physiological conditions. Therefore, embodiments include any compound of the present invention wherein the hydroxyl group has been replaced by a phosphate, phosphoalkoxy ester, or borate ester group (e.g., a phosphate or phosphoalkoxy group). For example, in some embodiments, the hydroxyl group on the R4 or R9 moiety is replaced by a phosphate, phosphoalkoxy, ester, or borate ester group (e.g., a phosphate or alkoxyphosphate group).

[0201] According to one embodiment, the compounds of the present invention may also contain atomic isotopes in non-natural proportions at one or more atoms constituting such compounds. For example, the invention also includes isotopically labeled variants of the invention that are consistent with those described herein, but in fact, one or more atoms of the compound are replaced by atoms having atomic masses or mass numbers different from the principal atomic mass or mass number of atoms normally found in nature. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the present invention and their uses. Exemplary isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, for example... 2 H(“D”), 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 32 P, 33 P, 35 S, 18 F, 36 Cl、 123 I and 125 I. The isotopically labeled compounds of the present invention can generally be prepared by means of replacing non-isotopically labeled reagents with isotopically labeled reagents, similar to those disclosed in the schemes and / or examples below.

[0202] experiment The abbreviations used throughout the instruction manual are summarized below with their meanings.

[0203] MeOH – Methanol, EtOH – Ethanol, DCM – Dichloromethane, DMF – N,N-Dimethylformamide, EtOAc – Ethyl acetate, ACN – Acetonitrile, THF – Tetrahydrofuran, DMSO – Dimethyl sulfoxide, DIPEA – N,N-Diisopropylethylamine, NCS – N-Chlorosuccinimide, HATU – (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), KOAc – Potassium acetate, Na2SO4 – Sodium sulfate, Na2CO3 – Sodium carbonate, K2CO3 – Potassium carbonate, KO t Bu – Potassium tert-butoxide, TEA – Triethylamine; LiOH .H2O – Lithium hydroxide monohydrate; EDC.HCl – 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; HOBt – Hydroxybenzotriazole; NaH – Sodium hydride; NH4OH – Ammonium hydroxide; NaOH – Sodium hydroxide; HCl – Hydrochloric acid; Pd(pph3)2Cl2. DCM – Bis(triphenylphosphine)palladium(II) dichloromethane complex; Pd(OAc)2 – Palladium(II) acetate; Pd2(dba)3 – Tris(dibenzylideneacetone)dipalladium(O); mL – Milliliters; TLC – Thin-layer chromatography; RT – Room temperature; h – Hour; N – Equivalent concentration; M – Molar concentration; 1 HNMR – Proton NMR, DMSO-d6 – Deuterated dimethyl sulfoxide, CDCl3 – Deuterated chloroform, s – Singlet, d – Doublet, t – Triplet, m – Multiplet, H – Proton, MHz – Megahertz, Hz – Hertz, Ppm – Parts per million, Bs – Broad singlet, HPLC – High Performance Liquid Chromatography, LCMS – Liquid Chromatography-Mass Spectrometry, g – Gram, mmol – Millimole.

[0204] Intermediate 1: 5-Bromo-3-chloropyridazine Step a: Synthesis of 5-bromo-3-chloropyridazine (1a) Under RT, tert-butyl nitrite (9.8 g, 82.12 mmol, 1.7 eq) was added to a stirred solution of 4-bromo-6-chloropyridazine-3-amine (10.0 g, 48.30 mmol) in 100 mL of THF. The reaction mixture was heated at 80 °C for 3 h in a sealed tube. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the residue, which was purified by Combiflash column chromatography using a hexane solution of 50-60% ethyl acetate as eluent to give the title compound as a grayish-white solid (5.3 g, 57%). 1 HNMR (400 MHz, DMSO-d6): δ 9.50 (d, J = 2.0 Hz, 1H), 8.48 (d, J = 2.0 Hz, 1H); LC-MS: m / z 192.8 (M+H). Intermediate 2: 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)phenyl)piperazine-1-yl)tert-butyl acetate Step a: Synthesis of 1-(4-bromophenyl)piperazine hydrochloride At 0 °C, 50 mL of 4N dioxane hydrochloride was added to a stirred solution of 5.0 g (14.7 mmol) of tert-butyl piperazine-1-carboxylic acid in DCM. The mixture was stirred for 16 h under RT and nitrogen atmosphere. The reaction mixture was then concentrated under vacuum to obtain a crude product. The crude product was ground with n-pentane and then dried under vacuum to give the pure title compound (5 g) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.29 (bs, 1H), 7.38 (d, J = 9.2Hz, 2H), 6.94 (d, J = 9.2 Hz, 2H), 5.06 (m, 4H), 3.35 (m, 4H); LC-MS: m / z354.8 (M+H). Step b: Synthesis of 2-(4-(4-bromophenylpiperazin-1-yl)tert-butyl acetate) DIPEA (4.66 g, 36.2 mmol) was added to a stirred solution of 1-(4-bromophenyl)piperazine hydrochloride (5.0 g, 18.1 mmol) in 50 mL of DMF under RT, and the mixture was stirred for 15 min. Then, tert-butyl 2-bromoacetate (5.3 g, 27.15 mmol) was added, and the mixture was stirred for 4 h under RT and a nitrogen atmosphere. The reaction mixture was quenched with cold water and stirred for 1 h. The solid thus formed was filtered and dried under vacuum to give the title compound as a grayish-white solid (4.5 g, 70%).

[0205] 1 H NMR (400 MHz, DMSO-d6): δ 7.29 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.4Hz, 2H), 3.11 (s, 2H), 3.07 (m, 4H), 2.58 (m, 4H), 1.37 (s, 9H); LC-MS: m / z340.8 (M+H). Step c: 2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)piperazine- Synthesis of 1-yl)tert-butyl acetate Under RT, bispinacol diborone (4.52 g, 17.8 mmol) and KOAc (2.33 g, 23.7 mmol) were added to a solution of tert-butyl 2-(4-(4-bromophenylpiperazin-1-yl)acetate) (4.2 g, 11.8 mmol) in dioxane (80 mL) under stirring, and the mixture was degassed with nitrogen for 5 min. Then, Pd(dppf)Cl2·DCM (0.89 g, 1.18 mmol) was added to the reaction mixture, and the mixture was heated at 100 °C for 4 h. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound as a grayish-white solid (5 g, 100%). 1 H NMR (400 MHz, DMSO-d6): δ 7.50 (d, J = 8.0 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 3.20 (bs, 4H), 3.15 (s, 2H), 2.62 (d, J = 4.4 Hz, 4H), 1.41 (s, 9H), 1.26 (s, 12H); LC-MS: m / z 402.7 (M+H). Intermediate 3: 2-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)piperyl Acetyl 4-pyridyl) Step a: Synthesis of ethyl 2-(1-(4-bromo-2-nitrophenyl)piperidin-4-yl) Under RT, ethyl 2-(piperidin-4-yl)acetate (1.87 g, 10.9 mmol) and DIPEA (3.7 g, 27.4 mmol) were added to a stirred DMF (20 mL) solution of 4-bromo-1-fluoro-2-nitrobenzene (2.0 g, 9.1 mmol) and heated at 100 °C for 4 h. The reaction mixture was quenched with cold water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the crude product. The crude product was purified by Combiflash column chromatography using a 20–25% ethyl acetate solution in hexane as eluent to give the title compound as a yellow solid (1.3 g, 38%). 1 H NMR (400MHz, DMSO-d6): δ 7.99 (d, J = 2.4 Hz, 1H), 7.70 (dd, J = 2.4, 6.4 Hz, 1H), 7.24(d, J = 8.8 Hz, 1H), 4.05 (q, J = 5.4 Hz, 2H), 3.12 (d,J = 12.4 Hz, 2H), 2.82-2.76 (m, 2H), 2.26 (d, J = 7.2 Hz, 2H), 1.84-1.79 (m, 1H), 1.69 (d, J = 12.4Hz, 2H), 1.32-1.22 (m, 2H), 1.17 (t, J = 7.4 Hz, 3H); LC-MS: m / z 371.0 (M+H). Step b: Synthesis of ethyl 2-(1-(2-amino-4-bromophenyl)piperidin-4-yl) Iron (3.1 g, 28 mmol) and NH4OH (1.5 g, 28 mmol) were added to a stirred solution of ethyl 2-(1-(4-bromo-2-nitrophenyl)piperidin-4-yl)acetate (1.3 g, 3.5 mmol) in methanol (10 mL) and water (3 mL). The mixture was stirred at RT for 4 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with methanol and filtered. The filtrate was concentrated, diluted with EtOAc, washed with water and saline solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound as a grayish-white solid (1.2 g, 100%). 1 H NMR (400 MHz, DMSO-d6): δ 6.80-6.78 (m, 2H), 6.63 (dd, J = 2.4&6.0 Hz, 1H), 4.91 (s, 2H), 4.06 (q, J = 7.0 Hz, 2H), 2.97 (d, J = 11.6Hz, 2H), 2.27 (d, J = 6.8 Hz, 2H), 1.73-1.69 (m, 5H), 1.40-1.36 (m, 2H), 1.19(t, J = 7.0 Hz, 3H).

[0206] Step c: Synthesis of ethyl 2-(1-(4-bromophenyl)piperidin-4-yl)acetate To a stirred solution of ethyl 2-(1-(2-amino-4-bromophenyl)piperidin-4-yl)acetate (1.0 g, 2.9 mmol) in 10 mL of THF, tert-butyl nitrite (0.58 g, 5.1 mmol) was added. The mixture was stirred at RT for 3 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the crude product. The crude product was purified by Combiflash column chromatography using a 20% ethyl acetate solution in hexane as eluent to give the title compound as a grayish-white solid (0.37 g, 34%). 1 H NMR (400 MHz, DMSO-d6): δ 7.30 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 9.2 Hz, 2H), 4.06 (q, J =14.4 Hz, 2H), 3.64 (d, J = 12.8 Hz, 2H), 2.67-2.62 (m, 2H), 2.25 (d, J = 7.2Hz, 2H), 1.70 (d, J = 12.4 Hz, 3H), 1.28-1.25 (m, 2H), 1.17 (t, J = 7.2 Hz,3H). LC-MS: m / z 326.1 (M+H). Step d: 2-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)piperidine- Synthesis of 4-yl)ethyl acetate Under RT, bispinacol diborone (0.45 g, 1.7 mmol) and KOAc (0.22 g, 2.27 mmol) were added to a stirred solution of ethyl 2-(1-(4-bromophenyl)piperidin-4-yl)acetate (0.37 g, 1.13 mmol) in dioxane (10 mL), and the mixture was degassed with nitrogen for 5 min. Then, Pd(dppf)Cl2·DCM (0.09 g, 0.11 mmol) was added to the reaction mixture, and the mixture was heated at 100 °C for 6 h. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a residue, which was purified by Combiflash column chromatography using a 10–15% ethyl acetate solution in hexane as eluent to give the title compound as a yellow solid (0.25 g, 58%). 1H NMR (400 MHz, DMSO-d6): δ 7.48 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 4.06 (q, J = 14.4 Hz, 2H), 3.78 (d, J = 12.4 Hz, 2H),2.75-2.66 (m, 1H), 2.24 (d, J = 6.8 Hz, 2H), 1.87 (t, J = 7.2 Hz, 1H), 1.72-1.68 (m, 2H), 1.29-1.16 (m, 18H). LC-MS: m / z 373.9 (M+H). Intermediate 4: 3-Methyl-2-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzene ethyl isoxazol-5-yl)butyrate Step a: Synthesis of 4-bromobenzaldehyde oxime Pyridine (19.21 mL, 243.2 mmol) was added to an ethanol (300 mL) solution of 4-bromobenzaldehyde (30 g, 162.16 mmol) and hydroxylamine hydrochloride (14.64 g, 210.8 mmol), and the reaction mixture was stirred at RT for 6 h. After the reaction was complete, the reaction mixture was quenched with ice-cold water and stirred for 20 min. The resulting solid was further washed with water and dried under vacuum to give the crude compound. The crude compound was washed with hexane and dried under vacuum to give the title compound as a white solid (24 g, 74%). 1 H NMR (400 MHz, DMSO-d6): δ 11.37 (s, 1H), 8.13 (s, 1H), 7.60(d, J = 10.8 Hz, 2H), 7.54 (d, J = 10.4 Hz, 2H); LC-MS: m / z 199.9 (M+H). Step b: Synthesis of 2-(3-(4-bromophenyl)isoxazo-5-yl)ethanol-1-ol To a solution of 4-bromobenzaldehyde oxime (15 g, 75 mmol) in DCM (300 mL), NCS (12.01 g, 90 mmol) was added, and the mixture was heated at 45 °C for 30 min. The reaction mixture was cooled to RT, and but-3-yn-1-ol (6.3 g, 90 mmol) and TEA (10.52 mL, 75 mmol) were added dropwise to the reaction mixture over 15 min. The reaction mixture was heated again at 45 °C for 7 h. After the reaction was complete, the reaction mixture was quenched with ice-cold water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the residue, which was purified by Combiflash column chromatography using a hexane solution of 10% ethyl acetate as eluent to give the title compound as a white solid (7.5 g, 37%). 1 H NMR (400 MHz, DMSO-d6): δ 7.80 (d, J = 6.4 Hz, 2H), 7.71 (d, J = 6.8 Hz, 2H), 6.86 (s, 1H), 4.92 (t, J = 10.8 Hz, 1H), 3.75 (q, J = 11.6 Hz, 2H), 2.94 (t, J =12.8 Hz, 2H); LC-MS: m / z 267.90 (M+H). Step c: Synthesis of 2-(3-(4-bromophenyl)isoxazol-5-yl)acetic acid Jones' reagent (15 mL) was added dropwise to a stirred solution of 2-(3-(4-bromophenyl)isoxazol-5-yl)ethanol-1-ol (7.5 g, 27.9 mmol) in 150 mL of acetone at 0 °C, and the temperature was raised to RT over 2 h. After the reaction was complete, the reactants were diluted with acetone and filtered. The filtrate was concentrated under vacuum to give a crude product. The crude product was ground with hexane and dried under vacuum to give the pure title compound as a grayish-white solid (7 g, 88%). 1 H NMR (400 MHz, DMSO-d6): δ 7.82 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 6.96 (s, 1H), 3.96 (s, 2H); LC-MS: m / z 283.09 (M+H). Step d: Synthesis of ethyl 2-(3-(4-bromophenyl)isoxazo-5-yl)ethyl acetate At 0 °C, 7 mL of H₂SO₄ was added dropwise to a stirred solution of 2-(3-(4-bromophenyl)isoxazol-5-yl)acetic acid (7 g, 24.9 mmol) in 140 mL of ethanol, followed by heating at 80 °C for 2 h. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated and diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by Combiflash column chromatography using a hexane solution of 7% ethyl acetate as eluent to give the title compound as a grayish-white solid (5.8 g, 76%).

[0207] 1 H NMR (400 MHz, DMSO-d6): δ 7.82 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.4Hz, 2H), 6.99 (s, 1H), 4.17 (q, J = 14.4 Hz, 2H), 4.08 (s, 2H), 1.22 (t, J = 14.4Hz, 3H); LC-MS: m / z 309.9 (M+H). Step e: Synthesis of ethyl 2-(3-(4-bromophenyl)isoxazol-5-yl)-3-methylbutyrate At 0°C, 1 M KO was added dropwise to an 80 mL solution of 5.8 g (18.77 mmol) of ethyl 2-(3-(4-bromophenyl)isoxazol-5-yl)ethyl acetate in THF. t Bu solution (28.1 mL, 28.1 mmol) was added and stirred for 15 min. Then 2-iodopropane (2.25 mL, 22.5 mmol) was added to the reaction mixture, and the mixture was stirred at RT for 16 h. After the reaction was complete, the reaction mixture was quenched with ice-cold water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the residue, which was purified by Combiflash column chromatography using a 4-5% ethyl acetate solution in hexane as eluent to give the title compound as a colorless liquid (3.8 g, 57%). 1 H NMR (400 MHz, DMSO-d6): δ 7.84(d, J = 8.8 Hz, 2H), 7.72 (d, J = 8.0 Hz, 2H), 7.05 (s, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.85 (d, J= 8.0 Hz, 1H), 2.38 (m, 1H), 1.19 (t, J = 14.4 Hz, 3H), 0.98 (d, J = 6.4 Hz, 3H) 0.89 (d, J = 6.8 Hz, 3H); LC-MS: m / z 351.9 (M+H). Step f: 3-Methyl-2-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzene Synthesis of ethyl isoxazol-5-yl)butyrate Under RT, bispinacol diborone (4.12 g, 16.2 mmol) and KOAc (2.12 g, 21.6 mmol) were added to a stirred solution of ethyl 2-(3-(4-bromophenyl)isoxazol-5-yl)-3-methylbutyrate (3.8 g, 10.82 mmol) in dioxane (50 mL), and the mixture was degassed with nitrogen for 5 min. Pd(dppf)Cl2·DCM (0.88 g, 1.08 mmol) was added to the reaction mixture, and the mixture was heated at 100 °C for 2 h with stirring. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound as a colorless liquid (4.1 g, 94%). 1 H NMR (400 MHz, DMSO-d6): δ 7.90 (d, J = 8.0 Hz, 2H), 7.79(d, J = 7.6 Hz, 2H), 7.05 (s, 1H), 4.18 (q, J = 11.2 Hz, 2H), 3.85 (d, J = 8.0 Hz,1H), 2.44-2.33 (m, 1H), 1.31 (s, 12H), 1.20 (t, J = 7.2 Hz, 3H), 0.98 (d, J = 6.8Hz, 3H), 0.89 (d, J = 6.4 Hz, 3H); LC-MS: m / z 400.2 (M+H). Intermediate 5: 4-(6-chloropyridazine-4-yl)phenol Step a: Synthesis of 4-(6-chloropyridazine-4-yl)phenol To a stirred solution of 5-bromo-3-chloropyridazine (5 g, 26.04 mmol), (4-hydroxyphenyl)boronic acid (3.3 g, 23.4 mmol) in 1,4-dioxane (70 mL) and water (15 mL), Na₂CO₃ (7 g, 65.1 mmol) was added, and the mixture was degassed with nitrogen for 15 min. Pd(dppf)Cl₂·DCM (1.3 g, 1.56 mmol) was added, and the reaction mixture was heated in a sealed tube at 110 °C for 16 h. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a residue, which was purified by Combiflash column chromatography using a hexane solution of 60% ethyl acetate as eluent to give the title compound as a grayish-white solid (0.5 g, 23%). 1 H NMR (400 MHz, CDCl3): δ 10.19 (s, 1H), 9.61 (d, J = 2 Hz, 1H), 8.15 (d, J = 2 Hz, 1H), 7.89 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H); LC-MS: m / z206.9 (M+H). Intermediate 6: 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)piperidine-4- Ethyl carboxylate Intermediate 6 is prepared by appropriately changing the reactants, reagent amounts, protecting and deprotecting agents, solvents, and reaction conditions, similar to the method described in intermediate 3.

[0208] 1H NMR (400 MHz, DMSO-d6): δ 7.48 (d, J = 8.4 Hz, 2H), 6.88 (d, J =8.4 Hz, 2H), 4.05 (q, J = 7.2 Hz, 2H) 3.73 (d, J = 13.2 Hz, 2H), 2.83 (td, J= 13.2, 2.4 Hz, 2H), 2.54 (m, 1H), 1.86 (m, 2H), 1.60 (m, 2H), 1.24 (s, 12H), 1.17 (t, J = 7.2 Hz, 3H).

[0209] Intermediate 7: 2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)-3, 6-Dihydropyridine-1(2H)-yl)tert-butyl acetate Step a: Synthesis of tert-butyl 4-(4-bromophenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid K₂CO₃ (1.22 g, 8.83 mmol) was added to a stirred solution of 1-bromo-4-iodobenzene (1 g, 3.53 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (0.87 g, 2.82 mmol) in 1,4-dioxane (10 mL) and water (2.5 mL), and the mixture was degassed with nitrogen for 15 min. Pd(dppf)Cl₂·DCM (0.3 g, 0.35 mmol) was added, and the reaction mixture was heated in a sealed tube at 100 °C for 16 h. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and salt water, dried with anhydrous sodium sulfate and concentrated under vacuum to obtain the residue, which was purified by Combiflash column chromatography using a hexane solution of 50% ethyl acetate as the eluent to give the title compound as a grayish-white solid (1.3 g, 83%). 1 H NMR (400 MHz, DMSO-d6): δ 7.53 (d, J = 8 Hz, 2H), 7.39 (d, J = 8 Hz, 2H), 6.20 (s,1H), 3.98 (bs, 2H), 3.52 (t, J = 5.2 Hz, 2H), 2.43 (bs, 2H), 1.42 (s, 9H); LC-MS: m / z 338.0 (M+H). Step b: Synthesis of 4-(4-bromophenyl)-1,2,3,6-tetrahydropyridine hydrochloride At 0 °C, a solution of 1,4-dioxane in 4 M HCl (5 mL) was added to a stirred solution of 1 g (2.95 mmol) of tert-butyl 4-(4-bromophenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid in 15 mL of DCM. The reaction mixture was stirred at RT for 2 h. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under reduced pressure and washed with diethyl ether to give the title compound (0.8 g, 98%).

[0210] 1 H NMR (400 MHz, DMSO-d6): δ 9.35 (bs, 1H), 7.57 (d, J = 8 Hz, 2H), 7.43 (d, J= 8 Hz, 2H), 6.24 (s, 1H), 3.72 (bs, 2H), 3.28 (bs, 2H), 2.66 (bs,2H). LC-MS: m / z 238 (M+1).

[0211] Step c: Synthesis of tert-butyl 2-(4-(4-bromophenyl)-3,6-dihydropyridine-1(2H)-yl)acetate Under RT, DIPEA (1.12 g, 8.73 mmol) was added to a stirred DMF (10 mL) solution of 4-(4-bromophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (0.8 g, 2.91 mmol) and stirred for 15 min. Then, tert-butyl 2-bromoacetate (0.56 g, 2.91 mmol) was added, and the mixture was stirred for 4 h under RT and a nitrogen atmosphere. The reaction mixture was quenched with cold water and stirred for 1 h. The solid thus formed was filtered and dried under vacuum to give the title compound as a yellow solid (1.3 g, 97%).

[0212] 1 H NMR (400 MHz, DMSO-d6): δ 7.51 (d, J = 8 Hz, 2H), 7.38 (d, J = 8 Hz, 2H), 6.19 (s, 1H), 3.22 (s, 2H), 3.20 (m, 2H), 2.74 (m, 2H), 2.44 (bs, 2H), 1.42 (s, 9H): LC-MS: m / z 352.2 (M+H). Step d: 2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)-3,6- Synthesis of dihydropyridine-1(2H)-yl)tert-butyl acetate Under RT, bispinacol diborone (0.43 g, 1.70 mmol) and KOAc (0.28 g, 2.83 mmol) were added to a stirred solution of tert-butyl 2-(4-(4-bromophenyl)-3,6-dihydropyridin-1(2H)-yl)acetate (0.5 g, 1.41 mmol) in dioxane (20 mL), and the mixture was degassed with nitrogen for 5 min. Then, Pd(dppf)Cl2·DCM (0.11 g, 0.14 mmol) was added to the reaction mixture, and the mixture was heated at 100 °C for 4 h. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound as a grayish-white solid (0.5 g, 88%). 1 H NMR (400 MHz, DMSO-d6): δ 7.63 (d, J= 10.8Hz, 2H), 7.43 (d, J = 10.8 Hz, 2H), 6.22 (s, 1H), 3.22 (bs, 4H), 2.73 (m, 2H), 2.46 (bs, 2H), 1.42 (s, 9H), 1.28 (s, 12H): LC-MS: m / z 400.4 (M+H). The compounds listed in Table 1 were prepared by means of a method similar to that described in Intermediate 7, with appropriate modifications to the reactants, reagent amounts, protecting and deprotecting agents, solvents, and reaction conditions. Characterization data for the compounds are summarized in the table below.

[0213]

[0214] Intermediate 8: 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester Step i: Synthesis of tert-butyl 4-(4-bromo-2-fluorophenyl)piperazine-1-carboxylic acid NaO was added to a stirred solution of 4-bromo-2-fluoro-1-iodobenzene (1 g, 3.23 mmol) and N-Boc piperazine (0.63 g, 3.39 mmol) in toluene (20 mL). t Bu (0.93 g, 9.63 mmol) was added and degassed with nitrogen for 15 min. Pd₂(dba)₃ (0.146 g, 0.16 mmol) and Xantphos (0.09 g, 0.16 mmol) were then added, and the reaction mixture was heated in a sealed tube at 120 °C for 6 h. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the residue, which was purified by Combiflash column chromatography using a hexane solution of 60% ethyl acetate as eluent to give the title compound as a grayish-white solid (0.65 g, 54%).

[0215] 1 H NMR (400 MHz, CDCl3): δ 7.44 (d, J = 11.6 Hz 1H), 7.30 (d, J = 8.8Hz, 1H), 7.00 (t, J= 8.8 Hz, 1H), 3.45 (m, 4H), 2.94 (m, 4H), 1.44 (s, 9H); LC-MS: m / z 358.9 (M+H). Step ii: 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)piperyl Synthesis of tert-butyl aziridine-1-carboxylic acid Under RT, bispinalol diborone (0.55 g, 2.17 mmol) and KOAc (0.53 g, 5.43 mmol) were added to a stirred solution of tert-butyl piperazine-1-carboxylic acid (0.65 g, 1.81 mmol) in dioxane (10 mL), and the mixture was degassed with nitrogen for 5 min. Then, Pd(dppf)Cl2·DCM (0.15 g, 0.18 mmol) was added to the reaction mixture and the mixture was heated at 90 °C for 16 h. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound as a grayish-white solid (0.65 g, 88%). 1 H NMR (400 MHz, DMSO-d6): δ 7.43 (dd, J = 8.0, 1.2 Hz, 1H), 7.37(dd, J = 8.0, 1.2 Hz, 1H), 6.82 (t, J = 8.8 Hz, 1H), 3.52 (m, 4H), 3.00 (m,4H), 1.41 (s, 9H), 1.25 (s, 12H); LC-MS: m / z 407.1 (M+H). Intermediate 9: 2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)-3, Ethyl 6-dihydropyridine-1(2H)-yl)propionate Step a: Synthesis of ethyl 2-(4-(4-bromophenyl)-3,6-dihydropyridine-1(2H)-yl)propionate Under RT, DIPEA (2.35 g, 18.2 mmol) was added to a stirred DMF (10 mL) solution of 4-(4-bromophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (1 g, 3.64 mmol), and the mixture was stirred for 15 min. Then, ethyl 2-bromopropionate (0.79 g, 4.37 mmol) was added, and the mixture was stirred for 4 h under RT and a nitrogen atmosphere. The reaction mixture was quenched with cold water and stirred for 1 h. The solid thus formed was filtered and dried under vacuum to give the title compound as a grayish-white solid (0.8 g, 56%). 1 H NMR (400MHz, DMSO-d6): δ 7.46 (d, J = 8 Hz, 2H), 7.33 (d,J = 8 Hz, 2H), 6.15 (s, 1H), 4.07 (m, 2H), 3.39 (q, J = 6.8 Hz, 1H), 3.22 (bs, 2H), 2.78 (m, 2H), 2.67 (m,1H), 2.38 (bs, 2H), 1.18 (m, 6H): LC-MS: m / z 338 (M+H). Step b: 2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)-3,6- Synthesis of ethyl dihydropyridine-1(2H)-yl)propionate Under RT, bispinalol diboron (0.9 g, 3.54 mmol) and KOAc (0.69 g, 7.09 mmol) were added to a stirred solution of ethyl 2-(4-(4-bromophenyl)-3,6-dihydropyridine-1(2H)-yl)propionate (0.8 g, 2.36 mmol) in dioxane (15 mL). The mixture was degassed with nitrogen for 5 min, and then Pd(dppf)Cl2·DCM (0.19 g, 0.23 mmol) was added to the reaction mixture. The mixture was heated at 80 °C for 16 h. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound as a grayish-white solid (0.9 g, 98%).

[0216] 1 H NMR (400 MHz, DMSO-d6): δ 7.62 (d, J = 10.8 Hz, 2H), 7.42 (d, J = 10.8Hz, 2H), 6.22 (s, 1H), 4.11 (m, 2H), 3.43 (q, J = 6.8 Hz, 1H), 3.28 (bs, 2H), 2.84 (m, 2H), 2.45 (bs, 2H), 1.28 (s, 12H), 1.21 (m 6H): LC-MS: m / z 386.3 (M+H). Intermediate 10: 2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)piperyl Ethyl azinon-1-yl)propionate Intermediate 10 was prepared by appropriately varying the reactants, reagent amounts, protecting and deprotecting agents, solvents, and reaction conditions, similar to the method described for intermediate 9. LC-MS: M / z 389.3 (M+H). Intermediate 11: 2-(4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2,3,4,5- Ethyl tetrahydro-[1,1'-biphenyl]-4-yl)ethyl acetate Step a: Synthesis of ethyl 2-(4'-bromo-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl) K₂CO₃ (0.97 g, 7.07 mmol) was added to a stirred solution of 1-bromo-4-iodobenzene (0.8 g, 2.82 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)cyclohex-3-en-1-yl)ethyl acetate (0.99 g, 3.39 mmol) in 1,4-dioxane (8 mL) and water (1 mL), and the mixture was degassed with nitrogen for 15 min. Pd(dppf)Cl₂·DCM (0.23 g, 0.28 mmol) was added, and the reaction mixture was heated at 100 °C for 6 h in a sealed test tube. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and salt water, dried with anhydrous sodium sulfate and concentrated under vacuum to obtain the residue, which was purified by Combiflash column chromatography using a hexane solution of 50% ethyl acetate as the eluent to give the title compound as a colorless liquid (0.48 g, 52%). 1 H NMR (400MHz, DMSO-d6): δ 7.49 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 6.16 (d, J=2 Hz, 1H), 4.08 (q, J = 6.8 Hz, 2H), 2.39 (bs, 2H), 2.31 (d, J= 7.2 Hz, 2H), 2.28 (m, 1H), 1.83- 2.05 (m, 3H), 1.38 (m, 1H), 1.19 (t, J = 6.8 Hz, 3H).

[0217] Step b: 2-(4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2,3,4 ... Synthesis of ethyl(hydro-[1,1'-biphenyl]-4-yl) Under RT, bispinalol diboron (0.58 g, 2.32 mmol) and KOAc (0.38 g, 3.86 mmol) were added to a stirred solution of ethyl 2-(4'-bromo-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)acetate (0.5 g, 1.54 mmol) in dioxane (5 mL), and the mixture was degassed with nitrogen for 5 min. Then, Pd(dppf)Cl2·DCM (0.12 g, 0.15 mmol) was added to the reaction mixture, and the mixture was heated at 100 °C for 3 h. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound as a colorless, viscous solid (0.48 g, 83%). 1H NMR (400 MHz, DMSO-d6): δ 7.61 (d, J = 8 Hz, 2H), 7.41 (d, J = 8 Hz, 2H), 6.19 (bs, 1H), 4.07 (q, J = 6.8 Hz, 2H), 2.41 (bs,2H), 2.31 (m, 3H), 1.85- 2.04 (m, 3H), 1.40 (m, 1H), 1.28 (s, 12H), 1.22 (t,J = 6.8 Hz, 3H).

[0218] Intermediate 12: 4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2,3,4 ... Ethyl hydrogen-[1,1'-biphenyl]-4-carboxylate Intermediate 12 is prepared by appropriately changing the reactants, reagent amounts, protecting and deprotecting agents, solvents, and reaction conditions, similar to the method described in intermediate 11. 1 H NMR (400 MHz, DMSO-d6): δ 7.61 (d, J = 8 Hz, 2H), 7.41 (d, J = 8 Hz, 2H), 6.22 (bs, 1H), 4.09 (q, J = 6.8 Hz, 2H), 2.57 (m,1H), 2.30-2.50 (m, 4H), 2.08 (m, 1H), 1.71 (m, 1H), 1.28 (s, 12H), 1.20 (t, J= 6.8 Hz, 3H); LC-MS: m / z 357.3 (M+H). Intermediate 13: 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)-8-nitrogen Heterobicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester Intermediate 13 was prepared by appropriately changing the reactants, reagent amounts, protecting and deprotecting agents, solvents, and reaction conditions, similar to the method described in intermediate 11. 1 H NMR (400 MHz, DMSO-d6): δ 7.62 (d, J = 7.6Hz, 2H), 7.41 (d, J = 7.6 Hz, 2H), 6.61 (d, JLC-MS: m / z 312.3 (M+H). Intermediate 14: (1R,5S)-8-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzene 3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester Step a: Synthesis of (1R,5S)-8-(4-bromophenyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester To a stirred solution of 1-bromo-4-iodobenzene (1.6 g, 5.65 mmol) and 3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (1.43 g, 6.78 mmol) in toluene (30 mL), KOtBu (1.55 g, 13.89 mmol) was added, followed by degassing with nitrogen for 15 min. Then, Pd2(dba)3 (0.25 g, 0.28 mmol) and xanthones (0.16 g, 0.28 mmol) were added, and the reaction mixture was heated in a sealed tube at 110 °C for 16 h. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and salt water, dried with anhydrous sodium sulfate and concentrated under vacuum to obtain the residue, which was purified by Combiflash column chromatography using a hexane solution of 50% ethyl acetate as the eluent to give the title compound as a grayish-white solid (1.1 g, 53%). 1 H NMR (400 MHz, DMSO-d6): δ 7.24 (d, J = 8 Hz, 2H), 6.59 (d, J = 8 Hz, 2H), 4.08 (m, 2H), 3.65 (d, J = 12.8 Hz, 1H), 3.51 (d, J =12.8 Hz, 1H), 3.08-3.25 (m, 2H), 1.95 (m, 2H), 1.77 (m, 2H), 1.35 (s, 9H); LC-MS: m / z 367 (M+H). Step b: (1R,5S)-8-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)- Synthesis of tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid Under RT, 1.14 g (4.49 mmol) and KOAc (0.88 g (8.9 mmol) were added to a stirred solution of (1R,5S)-8-(4-bromophenyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (1.1 g, 2.99 mmol) in dioxane (5 mL), and the mixture was degassed with nitrogen for 5 min. Then, Pd(dppf)Cl2·DCM (0.24 g, 0.29 mmol) was added to the reaction mixture, and the mixture was heated at 100 °C for 4 h. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound as a pale yellow solid (0.5 g, 40%). 1 H NMR (400 MHz, DMSO-d6): δ 7.49(d, J = 8 Hz, 2H), 6.83 (d, J = 8 Hz, 2H), 4.34 (m, 2H), 3.42-3.58 (m, 2H), 3.12(m, 1H), 2.98 (m, 1H), 1.91 (m, 2H), 1.69 (m, 2H), 1.38 (s, 9H), 1.25 (s,12H).; LC-MS: m / z 415.2 (M+H). Intermediate 15: (1'-(tert-butoxycarbonyl)-1',2',3',6'-tetrahydro-[2,4'-bipyridine]-5-yl)boronic acid Intermediate 15 is prepared by appropriately changing the reactants, reagent amounts, protecting and deprotecting agents, solvents, and reaction conditions, similar to the method described in intermediate 11. 1 H NMR (400 MHz, DMSO-d6): δ 8.72 (s, 1H), 7.96(m,2H), 7.55 (d, J = 8 Hz, 1H), 6.78 (bs, 1H), 4.05 (m, 2H), 3.53 (m, 2H), 2.55(m, 2H), 1.32 (s, 9H); LC-MS: m / z 305.1 (M+H). Intermediate 16: 5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)amino) Methyl valerate Step a: Synthesis of methyl 5-((4-bromophenyl)amino)valerate Under RT, K₂CO₃ (0.14 g, 2.90 mmol) was added to a stirred DMF (5 mL) solution of 4-bromoaniline (0.5 g, 2.90 mmol), and the mixture was stirred for 15 min. Then, methyl 2-bromopropionate (1.13 g, 5.81 mmol) was added, and the mixture was stirred at 60 °C under a nitrogen atmosphere for 24 h. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with ice-cold water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the residue, which was purified by Combiflash column chromatography using a hexane solution of 10% ethyl acetate as eluent to give the title compound as a grayish-white solid (0.28 g, 33%). 1 H NMR (400 MHz, DMSO-d6): δ 7.22 (dd, J = 8.8, 1.6 Hz, 2H), 6.53 (dd, J = 8.8, 1.6 Hz, 2H), 3.61 (s, 3H), 3.00 (m, 2H), 2.37 (t, J =7.6 Hz, 2H), 1.52-1.68 (m, 4H): LC-MS: m / z 288.0 (M+H). Step b: 5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)amino)pentane Synthesis of methyl ester Under RT, bispinaldiboron (0.32 g, 1.26 mmol) and KOAc (0.29 g, 2.93 mmol) were added to a stirred solution of methyl 5-((4-bromophenyl)amino)valerate (0.28 g, 0.97 mmol) in dioxane (5 mL), and the mixture was degassed with nitrogen for 5 min. Then, Pd(dppf)Cl2·DCM (0.08 g, 0.09 mmol) was added to the reaction mixture, and the mixture was heated at 80 °C for 16 h. Once the reaction was complete (monitored by TLC), the reaction mixture was filtered through diatomaceous earth and washed with EtOAc. The combined organic layers were concentrated under vacuum to obtain a residue, which was purified by Combiflash column chromatography using a hexane solution of 10% ethyl acetate as eluent to give the title compound as a yellow solid (0.15 g, 46%).

[0219] 1 H NMR (400 MHz, DMSO-d6): δ 7.41 (d, J = 8 Hz, 2H), 6.54 (d, JLC-MS: m / z 334.05 (M+H). Intermediate 17: 2-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)nitrogen Heterocyclic butane-1-yl)tert-butyl acetate Step a: 3-(2-((4-methoxyphenyl)sulfonyl)hydrazineylidene)azacyclobutane- Synthesis of tert-butyl 1-carboxylic acid The reaction mixture was added to a stirred solution of 4-methoxybenzenesulfonyl hydrazine (2 g, 11.68 mmol) and tert-butyl 3-oxozyne-1-carboxylate (2.36 g, 11.68 mmol) in toluene (40 mL), and the reaction mixture was heated in a sealed tube at 50 °C for 16 h. Once the reaction was complete (monitored by TLC), the reactants were concentrated under vacuum to obtain a residue, which was purified by Combiflash column chromatography using a hexane solution of 40% ethyl acetate as eluent to give the title compound as a white solid (1.75 g, 42%).

[0220] 1 H NMR (400 MHz, DMSO-d6): δ 10.81 (bs, 1H), 7.78 (dd, J = 6.8, 2 Hz, 2H), 7.16 (dd, J = 6.8, 2 Hz, 2H), 4.50 (bs, 4H), 3.88 (s, 3H), 1.41 (s, 9H); LC-MS: m / z 353.9 (MH).

[0221] Step b: Synthesis of tert-butyl 3-(4-bromophenyl)azacyclobutane-1-carboxylic acid Cs₂CO₃ (1.65 g, 5.06 mmol) was added to a solution of tert-butyl 3-(2-((4-methoxyphenyl)sulfonyl)hydrazine)azacyclobutane-1-carboxylic acid (1.2 g, 3.37 mmol), (4-bromophenyl)boronic acid (1.01 g, 5.06 mmol), and dioxane (35 mL) was added, followed by degassing with nitrogen for 30 min. The reaction mixture was then heated in a sealed tube at 110 °C for 16 h. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc and filtered. The filtrate was concentrated under vacuum to obtain a residue, which was purified by Combiflash column chromatography using a hexane solution of 20% ethyl acetate as eluent to give the title compound as a colorless liquid (0.36 g, 34%). 1H NMR (400 MHz, CDCl3): δ 7.47 (d, J =8.4Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H), 4.32 (m, 2H), 3.92 (m, 2H), 3.67 (m, 1H), 1.46 (s, 9H); LC-MS: m / z 212 (M-100).

[0222] Step c: Synthesis of 3-(4-bromophenyl)azacyclobutane At 0 °C, trifluoroacetic acid (0.3 mL) was added to a stirred solution of tert-butyl 3-(4-bromophenyl)azacyclobutane-1-carboxylic acid (0.36 g, 1.15 mmol) in DCM (3 mL). The solution was then slowly heated to RT and stirred at RT for 1 h. The reaction mixture was evaporated under reduced pressure. The residue was washed with diethyl ether and dried under vacuum to give the title compound as a grayish-white solid (0.28 g, 97.7%). 1 H NMR (400 MHz, CDCl3): δ 9.85 (bs, 1H), 7.53 (d, J = 7.6 Hz, 2H), 7.25 (d, J = 7.6 Hz, 2H), 4.35 (m, 2H), 4.20 (m, 3H); LC-MS: m / z 212 (M+H). Step d: Synthesis of tert-butyl 2-(3-(4-bromophenyl)azacyclobutane-1-yl)acetate Under RT, DIPEA (0.72 g, 5.63 mmol) was added to a stirred DMF (5 mL) solution of 3-(4-bromophenyl)azacyclobutane (0.28 g, 1.12 mmol) and stirred for 15 min. Then, tert-butyl 2-bromoacetate (0.24 g, 1.24 mmol) was added and stirred for 2 h under RT and a nitrogen atmosphere. The reaction mixture was quenched with cold water and stirred for 1 h. The solid thus formed was filtered and dried under vacuum to give the title compound as a pale yellow viscous solid (0.28 g, 76%). 1 H NMR (400 MHz, CDCl3): δ 7.40 (d, J = 7.6 Hz, 2H), 7.14 (d, J = 7.6 Hz, 2H), 3.85 (m,2H), 3.70 (m, 1H), 3.22 (m, 4H), 1.44 (s, 9H); LC-MS: m / z 326.1 (M+H). Step e: 2-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborheptan-2-yl)phenyl)aza-heterocyclic ring Synthesis of butane-1-yl)tert-butyl acetate Under RT, bispinacol diborone (0.32 g, 1.28 mmol) and KOAc (0.21 g, 2.14 mmol) were added to a stirred solution of tert-butyl 2-(3-(4-bromophenyl)azacyclobutan-1-yl)acetate (0.28 g, 0.85 mmol) in dioxane (5 mL), and the mixture was degassed with nitrogen for 5 min. Then, Pd(dppf)Cl2·DCM (0.07 g, 0.08 mmol) was added to the reaction mixture and the mixture was heated at 110 °C for 16 h. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound as a white viscous solid (0.3 g, 93%).

[0223] 1 H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 8 Hz, 2H), 7.28 (d, J = 8 Hz, 2H), 3.93 (m, 2H), 3.83 (m, 1H), 3.28 (m, 2H), 3.24 (s, 2H), 1.33 (s, 9H), 1.25(s, 12H); LC-MS: m / z 374.4 (M+H). Intermediate 18: 6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)-2-nitrogen Spiro[3.3]heptane-2-carboxylic acid tert-butyl ester Step a: 6-(2-((4-methoxyphenyl)sulfonyl)hydrazinyl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl Ester Synthesis The reaction mixture was added to a toluene (30 mL) solution of 4-methoxybenzenesulfonyl hydrazine (1.5 g, 7.41 mmol) and tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylic acid (1.56 g, 7.41 mmol) under stirring, and the reaction mixture was heated in a sealed tube at 50 °C for 16 h. Once the reaction was complete (monitored by TLC), the reactants were concentrated under vacuum to obtain a residue, which was purified by Combiflash column chromatography using a hexane solution of 35% ethyl acetate as eluent to give the title compound as a white solid (2.8 g, 95%). 1 H NMR (400 MHz, DMSO-d6): δ 10.21 (bs, 1H), 7.68 (d, J =8.4 Hz, 2H), 7.05 (d, J= 8.4 Hz, 2H), 3.82 (bs, 4H), 3.78 (s, 3H), 2.95 (m,4H), 1.31 (s, 9H); LC-MS: m / z 394.1 (MH).

[0224] Step b: Synthesis of tert-butyl 6-(4-bromophenyl)-2-azaspiro[3.3]heptane-2-carboxylic acid Cs₂CO₃ (4.6 g, 14.16 mmol) was added to a stirred solution of tert-butyl 6-(2-((4-methoxyphenyl)sulfonyl)hydrazinyl)-2-azaspiro[3.3]heptane-2-carboxylic acid (tert-butyl ester, 2.8 g, 7.08 mmol) and (4-bromophenyl)boronic acid (2.13 g, 10.6 mmol) in dioxane (60 mL), and the mixture was degassed with nitrogen for 30 min. The reaction mixture was then heated in a sealed tube at 110 °C for 16 h. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc and filtered. The filtrate was concentrated under vacuum to obtain a residue, which was purified by Combiflash column chromatography using a hexane solution of 20% ethyl acetate as eluent to give the title compound as a colorless liquid (1.3 g, 52%). 1 H NMR (400 MHz, DMSO-d6): δ 7.38(d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 4.02 (s, 2H), 3.81 (s, 2H), 3.18(m, 1H), 2.54 (m, 2H), 2.21 (m, 2H), 1.42 (s, 9H).

[0225] Step c: 6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)-2-azaspiro [3.3] Synthesis of heptane-2-carboxylic acid tert-butyl ester Under RT, bispinalol diboron (1.4 g, 5.53 mmol) and KOAc (0.90 g, 9.22 mmol) were added to a stirred solution of tert-butyl 6-(4-bromophenyl)-2-azaspiro[3.3]heptane-2-carboxylic acid (tert-butyl ester, 1.3 g, 3.69 mmol) in dioxane (35 mL), and the mixture was degassed with nitrogen for 5 min. Then, Pd(dppf)Cl2·DCM (0.30 g, 0.36 mmol) was added to the reaction mixture and the mixture was heated at 110 °C for 16 h. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound as a creamy, viscous solid (0.3 g, 93%). 1H NMR (400 MHz, DMSO-d6): δ 7.74 (d, J = 8 Hz, 2H), 7.16 (d, J LC-MS: m / z 374.05 (M+H). Intermediate 19: (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-(2-hydroxy-1- (4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride Step a: Synthesis of tert-butyl (2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamate To a stirred solution of tert-butyl carbamate (2.4 g, 7.59 mmol) and 4-methylthiazole (0.9 g, 9.11 mmol) in DMF (12 mL), KOAc (1.49 g, 15.89 mmol) and Pd(OAC)₂ (0.34 g, 1.51 mmol) were added. The reaction mixture was heated at 90 °C for 3 h. After the reaction was complete (monitored by TLC), the reaction mixture was cooled to RT and poured into ice-cold water. The resulting mixture was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by Combiflash column chromatography using a hexane solution of 50% ethyl acetate as eluent to give the title compound (0.5 g, 30%). 1 H NMR (400 MHz, DMSO- d 6): δ 8.98 (s, 1H), 7.44 (d, J = 7.6 Hz, 2H), 7.38 (d, J = 7.6 Hz, 2H), 7.30 (d, J = 8.4 Hz, 1H), 4.83 (t, J = 6 Hz, 1H),4.56 (m, 1H), 3.51 (t, J = 6 Hz, 2H), 2.45 (s, 3H), 1.37 (s, 9H), LC-MS: m / z335.0 (M+1).

[0226] Step b: Synthesis of 2-amino-2-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl-1-ol hydrochloride At 0 °C, a 1.5 mL solution of 1,4-dioxane in 4 M HCl was added to a stirred solution of tert-butyl (2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamate (0.3 g, 0.89 mmol) in DCM (2 mL). The reaction mixture was stirred at RT for 2 h. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under reduced pressure and washed with diethyl ether to give the title compound (0.2 g, 95%).

[0227] 1 H NMR (400 MHz, DMSO- d 6): δ 9.04 (s, 1H), 8.48 (bs, 2H), 7.57 (m,4H), 4.34 (m, 1H), 3.72 (m, 2H), 2.46 (s, 3H), LC-MS: m / z 335.0 (M+1).

[0228] Step c: ((2S)-1-((2S,4R)-4-hydroxy-2-((2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl) Synthesis of tert-butyl carbamate (ethyl)carbamoyl)pyrrolidone-1-yl)-3,3-dimethyl-1-oxobut-2-yl)carbamate At 0 °C, HATU (0.48 g, 1.28 mmol) was added to a DMF (3 mL) solution of 2-amino-2-(4-(4-methylthiazol-5-yl)phenyl)ethyl-1-ol hydrochloride (0.2 g, 0.85 mmol) and (2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxylic acid (0.35 g, 1.02 mmol) followed by dropwise addition of DIPEA (0.5 mL, 2.56 mmol), and the mixture was stirred at RT for 2 h. After the reaction was complete (monitored by TLC), the reaction mixture was cooled to RT and poured into ice-cold water. The resulting mixture was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. This crude product was purified by Combiflash column chromatography using a 5% MeOH DCM solution as the eluent to give the title compound (0.17 g, 53%). LC-MS: M / z 561.2 (M + 1).

[0229] Step d: (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-(2-hydroxy-1-(4- Synthesis of (4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride At 0 °C, a solution of 1,4-dioxane in 4 M HCl was added to a stirred solution of ((2S)-1-((2S,4R)-4-hydroxy-2-((2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobut-2-yl)carbamate (0.17 g, 0.30 mmol) in DCM (2 mL). The reaction mixture was stirred at RT for 16 h. The solvent was evaporated under reduced pressure, and the residue was washed with diethyl ether to give the title compound (0.16 g, 100%), which was used in the next step without further purification. LC-MS: M / z 461.1 (M+1).

[0230] Intermediate 20: (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-N-(2-(dimethylamino)-1- (4-(4-methylthiazolyl-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide hydrochloride Step a: Ethyl 2-((tert-butoxycarbonyl)amino)-2-(4-(4-methylthiazolyl-5-yl)phenyl)methanesulfonate synthesis At 0 °C, methanesulfonyl chloride (0.2 mL, 2.69 mmol) was added to a stirred solution of tert-butyl (2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamate (0.6 g, 1.79 mmol) in DCM (10 mL), followed by TEA (0.64 mL, 4.49 mmol). The reaction mixture was stirred at RT for 2 h. After the reaction was complete (monitored by TLC), the reaction mixture was cooled to RT and poured into ice-cold water. The resulting mixture was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give a crude product. This crude product was purified by Combiflash column chromatography using a 2% MeOH solution in DCM as the eluent to give the title compound (0.48 g, 64%). 1 H NMR (400 MHz, DMSO- d 6): δ 9.01 (d, J = 2 Hz, 1H), 7.75 (d, J = 8.8 Hz,1H), 7.50 (m, 4H), 4.94 (m, 1H), 4.24-4.33 (m, 2H), 3.18 (s, 3H), 2.46 (s,3H), 1.39 (s, 9H): LC-MS: m / z 413.0 (M+1).

[0231] Step b: tert-butyl (2-(dimethylamino)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamate Synthesis DIPEA (0.6 mL) was added to a stirred solution of ethyl 2-((tert-butoxycarbonyl)amino)-2-(4-(4-methylthiazolyl-5-yl)phenyl)methanesulfonate (0.480 g, 0.89 mmol) in acetonitrile (2 mL), and the mixture was cooled to 0 °C. N,N-dimethylamine gas was then passed through the reaction mixture for 15 min, and the reaction mixture was stirred for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the crude title compound as a brown liquid (0.300 g crude). 1 HNMR (400 MHz, DMSO- d 6): δ 8.98 (d, J LC-MS: m / z 362.1 (M+1).

[0232] Step c: Synthesis of N1,N1-dimethyl-2-(4-(4-methylthiazo-5-yl)phenyl)ethane-1,2-diamine hydrochloride N1,N1-dimethyl-2-(4-(4-methylthiazolyl-5-yl)phenyl)ethane-1,2-diamine hydrochloride was prepared by a method similar to that described in step b of intermediate 19. LC-MS: M / z 262.0 (M+1).

[0233] Step d: ((2S)-1-((2S,4R)-2-((2-(dimethylamino)-1-(4-(4-methylthiazolyl-5-yl)phenyl) ethyl(carbamoyl)-4-hydroxypyrrolidone-1-yl)-3,3-dimethyl-1-oxobut-2-yl)tert-butyl carbamate synthesis ((2S)-1-((2S,4R)-2-((2-(dimethylamino)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamoyl)-4-hydroxypyrrolidone-1-yl)-3,3-dimethyl-1-oxobut-2-yl)carbamate tert-butyl ester was prepared by a method similar to that described in step c of intermediate 19. LC-MS: M / z 588.3 (M+1).

[0234] Step -e: (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-N-(2-(dimethylamino)-1- Synthesis of (4-(4-methylthiazolyl-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide hydrochloride (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-N-(2-(dimethylamino)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide hydrochloride was prepared by a method similar to that described in step d of intermediate 19. LC-MS: M / z 488.2 (M+1).

[0235] Example 1: (2S,4R)-4-hydroxy-1-(2-(3-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)isoxazol-5-yl)-3-methylbutyryl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 1, racemic)

[0236] step Synthesis of ethyl 2-(3-(4-(6-chloropyridazin-4-yl)phenyl)isoxazol-5-yl)-3-methylbutyrate A mixture of 1,4-dioxane (13 mL) and water (2 mL) was placed in a microwave-safe vial and degassed with nitrogen for 5 minutes. 5-Bromo-3-chloropyridazine (0.91 g, 4.72 mmol) and ethyl 3-methyl-2-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)isoxazol-5-yl)butyrate (1.42 g, 3.63 mmol) were added, followed by K₂CO₃ (1 g, 7.26 mmol) and Pd(dppf)Cl₂·DCM (0.29 g, 0.36 mmol). The reaction mixture was heated in a microwave at 110 °C for 1 h. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and salt water, dried with anhydrous sodium sulfate and concentrated under vacuum to obtain the residue, which was purified by Combiflash column chromatography using a hexane solution of 50-60% ethyl acetate as the eluent to give the title compound as a grayish-white solid (1 g, 71%).

[0237] 1 H NMR (400 MHz, DMSO-d6): δ 9.76 (d, J = 2.0 Hz, 1H), 8.38 (d, J = 2.0Hz, 1H), 8.17 (d, J = 8.4 Hz, 2H), 8.09 (d, J = 8.4 Hz, 2H), 7.18 (s, 1H), 4.17(d, J = 2.8 Hz, 2H), 3.88 (d,J = 8.4 Hz, 1H), 2.45-2.38 (m, 1H), 1.22 (t, J = 7.2Hz, 3H), 1.00 (d, J = 6.8 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H); LC-MS: m / z 386.1 (M+H). Step ii: 2-(3-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)isoxazol-5-yl)-3-methylbutyric acid Synthesis of ethyl ester A mixture of 1,4-dioxane (15 mL) and water (3 mL) was placed in a microwave-safe vial and degassed with nitrogen for 5 minutes. Ethyl 2-(3-(4-(6-chloropyridazin-4-yl)phenyl)isoxazol-5-yl)-3-methylbutyrate (0.95 g, 2.46 mmol) and (2-hydroxyphenyl)boronic acid (0.68 g, 4.9 mmol) were added, followed by K₂CO₃ (0.85 g, 6.1 mmol) and Pd(dppf)Cl₂·DCM (0.2 g, 0.24 mmol). The reaction mixture was heated in a microwave-safe environment at 120 °C for 1 h. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and salt water, dried with anhydrous sodium sulfate and concentrated under vacuum to obtain the residue, which was purified by Combiflash column chromatography using a hexane solution of 50-60% ethyl acetate as the eluent to give the title compound as a yellow solid (0.75 g, 69%).

[0238] 1 H NMR (400 MHz, DMSO-d6): δ 13.05 (s, 1H), 9.69 (d, J = 2.0 Hz, 1H), 8.79 (d, J = 2.0 Hz, 1H), 8.24 (d, J = 8.4 Hz, 3H), 8.12 (d, J = 8.4 Hz, 2H), 7.44-7.40 (m, 1H), 7.19 (s, 1H), 7.03 (d, J = 7.2 Hz, 2H), 4.19-4.16 (m, 2H), 3.34(d, J = 8.4 Hz, 1H), 2.46-2.41 (m, 1H), 1.20 (t, J = 14 Hz, 3H), 1.01 (d,J = 6.8Hz, 3H), 0.92 (d, J = 6.4 Hz, 3H); LC-MS: m / z 444.1 (M+H). Step iii: 2-(3-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)isoxazol-5-yl)-3-methylbutyric acid Synthesis At 0 °C, LiOH·H2O (0.21 g, 5.07 mmol) was added to a stirred solution of ethyl 2-(3-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)isoxazol-5-yl)-3-methylbutyrate (0.75 g, 1.69 mmol) in 5 ml of THF and 5 ml of H2O. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then evaporated under reduced pressure, and the residue was diluted with methanol, acidified to pH 6 with Amberlite IT120 (acidic resin), filtered, and the filtrate was concentrated under vacuum to give the title compound as a dark brown solid (0.65 g, 93%).

[0239] 1 H NMR (400 MHz, DMSO-d6): δ 9.66 (s, 1H), 8.78 (s, 1H), 8.23 ​​(s, 1H), 8.20 (d, J = 8.4 Hz, 2H), 8.06 (d, J = 8.4 Hz, 2H), 7.39 (t, J = 14.4 Hz, 1H), 7.00(t, J = 15.2 Hz, 2H), 6.82 (s, 1H), 3.17 (d, J = 8.8 Hz, 1H), 2.32-2.27 (m, 1H), 0.98 (d, J = 6.4 Hz, 3H), 0.80 (d, J = 6.8 Hz, 3H); LC-MS: m / z 416.1 (M+H). Step iv: ((2S,4R)-4-hydroxy-1-(2-(3-(4-(6-(2-hydroxyphenyl)pyridazine-4-yl)phenyl)isoxane (-5-yl)-3-methylbutyryl)-N-((S)-1-(4-(4-methylthiazolyl)phenyl)ethyl)pyrrolidine-2-carboxamide Synthesis At 0 °C, DIPEA (0.21 mL, 1.2 mmol) was added dropwise to a DMF (5 mL) solution of 2-(3-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)isoxazol-5-yl)-3-methylbutyric acid (0.1 g, 0.24 mmol), (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.11 g, 0.28 mmol), and HATU (0.14 g, 0.36 mmol). The solution was slowly raised to RT, and the reaction mixture was stirred at RT for 1 h. The reaction mixture was then poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and salt water, dried with anhydrous sodium sulfate and concentrated under vacuum to obtain a crude product, which was purified by preparative HPLC to obtain the title compound as a grayish-white solid (0.025 g, 14%).

[0240] 1 H NMR (400 MHz, DMSO-d6): δ 13.12 (bs, 1H), 9.69 (d, J = 2.4 Hz, 1H),8.99 (t, J = 8 Hz, 1H), 8.90 (s, 1H), 8.79 (d, J = 2 Hz, 1H), 8.19-8.26 (m,3H), 8.06-8.11 (m, 2H), 7.46-7.37 (m, 5H), 7.10-7.01 (m, 3H), 5.12 (m, 1H),4.95-4.92 (m, 1H), 4.46-4.38 (m, 1H), 4.31 (bs, 1H), 3.89-4.04 (m, 1H), 3.55-3.76 (m, 2H), 2.47 (s, 2H), 2.37 (s, 1H), 2.06 (d, J = 12 Hz, 1H), 1.82-1.76 (m, 1H), 1.50 (d, J = 4.4 Hz, 1H), 1.39 (d, J = 4.4 Hz, 3H), 1.03 (d, J = 6.4Hz, 3H), 0.90 (d, J = 3.2 Hz, 3H); LC-MS: m / z 729.3 (M+H). Example 2: (2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetamyl)-3,3-dimethylbutyryl)-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 2)

[0241] Step i: Synthesis of 2-(4-(4-(6-chloropyridazine-4-yl)phenyl)piperazine-1-yl)tert-butyl acetate K₂CO₃ (1.77 g, 16.7 mmol) was added to a stirred solution of 5-bromo-3-chloropyridazine (1.6 g, 8.3 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)piperazin-1-yl)tert-butyl acetate (2.78 g, 6.9 mmol), d-1,4-dioxane (30 mL), and water (3 mL), and the mixture was degassed with nitrogen for 5 min. Pd(dppf)Cl₂·DCM (0.68 g, 0.83 mmol) was added, and the reaction mixture was heated in a sealed tube at 120 °C for 4 h. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and salt water, dried with anhydrous sodium sulfate and concentrated under vacuum to obtain the residue, which was purified by Combiflash column chromatography using a hexane solution of 40-80% ethyl acetate as the eluent to obtain the title compound as a viscous substance (1.7 g, 63%).

[0242] 1 H NMR (400 MHz, DMSO-d6): 9.62 (d, J = 1.6 Hz, 1H), 8.15 (d, J = 2.0Hz, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 3.34 (s, 2H), 3.31(bs, 4H), 2.64 (d, J = 4.4 Hz, 4H), 1.42 (s, 9H); LC-MS: m / z 389.0 (M+H). Step ii: Synthesis of 2-(4-(4-(6-(2-hydroxyphenyl)pyridazine-4-yl)phenyl)piperazine-1-yl)tert-butyl acetate To a stirred solution of tert-butyl 2-(4-(4-(6-chloropyridazin-4-yl)phenyl)piperazin-1-yl)acetate (0.5 g, 1.28 mmol), (2-hydroxyphenyl)boronic acid (0.27 g, 1.93 mmol) in 1,4-dioxane (10 mL) and water (3 mL), Na₂CO₃ (0.54 g, 5.18 mmol) was added, and the mixture was degassed with nitrogen for 5 min. Pd(dppf)Cl₂·DCM (0.1 g, 0.13 mmol) was added, and the reaction mixture was heated in a sealed test tube at 130 °C for 3 h. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and salt water, dried with anhydrous sodium sulfate and concentrated under vacuum to obtain the residue, which was purified by Combiflash column chromatography using a hexane solution of 60% ethyl acetate as the eluent to give the title compound as a viscous substance (0.35 g, 60%).

[0243] 1 H NMR (400 MHz, DMSO-d6): 13.53 (s, 1H), 9.57 (d, J = 2.0 Hz, 1H), 8.62 (d, J = 2.0 Hz, 1H), 8.25 (d, J = 7.2 Hz, 1H), 8.01 (d, J = 8.8 Hz, 2H), 7.40 (t, J = 6.8 Hz, 1H), 7.11 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 6.0 Hz, 2H),3.18 (s, 2H), 2.66 (d, J = 4.4 Hz, 4H), 2.50 (d, J = 4.4 Hz, 4H), 1.43 (s, 9H). LC-MS: m / z 447.15 (M+H). Step iii: Synthesis of 2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetic acid At 0 °C, 7 mL of 4N dioxane hydrochloride was added to a stirred solution of 0.7 g (1.56 mmol) of tert-butyl acetate in DCM (10 mL), and the solution was slowly brought to RT and stirred for 6 h. The reaction mixture was evaporated under reduced pressure, the residue was washed with diethyl ether and dried under vacuum to give the title compound as an orange solid (0.5 g, 74%).1 H NMR (400 MHz, DMSO-d6): 10.6 (bs, 1H), 9.67 (d, J = 2.0 Hz, 1H), 8.70 (s, 1H), 8.15 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 8.8 Hz,2H), 7.46-7.45 (m, 1H), 7.20 (d, J = 9.2 Hz, 2H), 7.07-7.01 (m, 2H), 4.24 (s,2H), 3.64-3.57 (m, 8H); LC-MS: m / z 391.1 (M+H). Step -iv: (2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(4-(6-(2-hydroxyphenyl)pyridazine-4-yl)benzene) (S)-1-(4-(4-methylthiazolyl-5-yl)phenyl) Synthesis of pyrrolidine-2-carboxamide At 0 °C, HATU (0.73 g, 1.92 mmol) was added to a DMF (3 mL) solution of 2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetic acid (0.5 g, 1.28 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.62 g, 1.28 equivalents), followed by dropwise addition of DIPEA (0.7 mL, 3.84 mmol). The reaction mixture was stirred at RT for 4 hours. The reaction mixture was then poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and salt water, dried with anhydrous sodium sulfate, and concentrated under vacuum to obtain a crude product. This crude product was purified by Combiflash column chromatography using a 5% methanol DCM solution as the eluent to obtain the title compound as a yellow solid (0.11 g, 11%).

[0244] 1 H NMR (400 MHz, DMSO-d6): 13.53 (s, 1H), 9.58 (d, J = 2.0 Hz, 1H),8.98 (s, 1H), 8.62 (d, J = 2.0 Hz, 1H), 8.45 (d, J = 8.0 Hz, 1H), 8.26 (d, J =6.8 Hz, 1H), 8.03 (d, J= 8.8 Hz, 2H), 7.79 (d, J = 9.2 Hz, 1H), 7.44-7.35 (m,5H), 7.15 (d, J = 9.2 Hz, 2H), 7.00 (t, J = 8.0 Hz, 2H), 5.14 (d, J = 3.2 Hz, 1H), 4.88 (t, J = 7.2 Hz, 1H), 4.53 (d, J = 9.6 Hz, 1H), 4.44 (t, J = 8.4 Hz,1H), 4.29 (bs, 1H), 3.59 (s, 2H), 3.38 (s, 4H), 3.16 (d, J = 16.0 Hz, 1H), 3.03 (d, J = 16.0 Hz, 1H), 2.67-2.66 (m, 4H), 2.45 (s, 3H), 2.32 (t, J = 2.0Hz, 1H), 1.76-1.70 (m, 1H), 1.36 (d, J = 6.8 Hz, 3H), 0.96 (s, 9H); LC-MS: m / z817.45 (M+H). Example 3: (2S,4R)-1-((S)-2-(2-(4-(4-(6-chloropyridazin-4-yl)phenyl)piperazin-1-yl)acetamyl)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 3)

[0245] Compound 3 Step i: Synthesis of 2-(4-(4-(6-chloropyridazin-4-yl)phenyl)piperazin-1-yl)acetic acid At 0 °C, 2 mL of 4N-dioxane hydrochloride was added to a stirred solution of 0.07 g (0.179 mmol) of tert-butyl 2-(4-(4-(6-chloropyridazin-4-yl)phenyl)piperazin-1-yl)acetate in DCM (5 mL), and the solution was slowly brought to RT and stirred for 16 h. The reaction mixture was evaporated under reduced pressure, and the resulting residue was washed with diethyl ether and dried under vacuum to give the title compound as an orange solid (0.065 g, 99%). LC-MS: M / z 333.1 (M+H). Step ii: (2S,4R)-1-((S)-2-(2-(4-(4-(6-chloropyridazin-4-yl)phenyl)piperazin-1-yl)acetamide (3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazo-5-yl)phenyl)ethyl)pyrrolidine-2- Synthesis of formamide At 0 °C, HATU (0.09 g, 0.24 mmol) was added to a DMF (2 mL) solution of 2-(4-(4-(6-chloropyridazin-4-yl)phenyl)piperazin-1-yl)acetic acid (0.07 g, 0.20 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.09 g, 0.20 equivalents), followed by dropwise addition of DIPEA (0.06 mL, 0.4 mmol). The reaction mixture was stirred at RT for 4 h. The reaction mixture was then poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and salt water, dried with anhydrous sodium sulfate and concentrated under vacuum to obtain a crude product, which was purified by preparative HPLC to obtain the title compound as a yellow solid (0.014 g, 8%).

[0246] 1 H NMR (400 MHz, DMSO-d6): 9.60 (d, J = 1.2 Hz, 1H), 8.94 (s, 1H), 8.38(d, J = 7.6 Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H), 7.89 (d, J = 8.8 Hz, 2H), 7.74(d, J = 9.6 Hz, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 7.07(d, J = 8.8 Hz, 2H), 5.09 (d, J = 3.2 Hz, 1H), 4.86 (t, J = 14.0 Hz, 1H), 4.49(d, J = 9.2 Hz, 1H), 4.42 (t, J= 4.2 Hz, 1H), 4.26 (s, 1H), 3.56 (s, 1H), 3.18-3.06 (m,2H), 2.64-2.58 (m, 6H), 2.42 (s, 4H), 2.30 (s, 2H), 1.88 (s,1H), 1.74 (s, 1H), 1.34 (d, J = 6.8 Hz, 3H), 0.93 (s, 9H). LC-MS: m / z 759.35(M+H). Example 4: (2S,4R)-1-((S)-2-(2-(4-(4-(6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetamyl)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 4)

[0247] Step-i: 2-(4-(4-(6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)tert-butyl acetate Ester Synthesis To a stirred solution of tert-butyl 2-(4-(4-(6-chloropyridazin-4-yl)phenyl)piperazin-1-yl)acetate (0.1 g, 0.26 mmol), (4-fluoro-2-hydroxyphenyl)boronic acid (0.06 g, 0.38 mmol) in 1,4-dioxane (1.6 mL) and water (0.4 mL), Na₂CO₃ (0.08 g, 0.77 mmol) was added, and the mixture was degassed with nitrogen for 15 min. Pd(dppf)Cl₂·DCM (0.02 g, 0.026 mmol) was added, and the reaction mixture was heated in a microwave at 130 °C for 1.2 h. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and salt water, dried with anhydrous sodium sulfate and concentrated under vacuum to obtain the residue, which was purified by Combiflash column chromatography using a hexane solution of 60% ethyl acetate as the eluent to give the title compound as a pale yellow solid (0.06 g, 50%).

[0248] 1 H NMR (400 MHz, DMSO-d6): 13.30 (s, 1H), 9.60 (d, J = 1.2 Hz, 1H), 8.64 (d, J = 1.2 Hz, 1H), 8.16 (dd, J = 2.8 & 10.0 Hz, 1H), 8.03 (d,J = 8.8 Hz, 2H), 7.25 (t, J = 4.0 Hz, 1H), 7.11 (d, J = 8.8 Hz, 2H), 7.04-7.00 (m, 1H), 3.18 (s,2H), 2.66 (bs, 4H), 2.40 (bs, 4H), 1.43 (s, 9H). LC-MS: m / z 465.2 (M+H). Step ii: Synthesis of 2-(4-(4-(6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetic acid At 0 °C, 1.2 mL of 4N dioxane hydrochloride was added to a stirred solution of 0.16 g (0.34 mmol) of tert-butyl acetate in DCM (4 mL), followed by slow heating to RT and stirring at RT for 6 h. The reaction mixture was evaporated under reduced pressure, the residue was washed with diethyl ether and dried under vacuum to give the title compound as an orange solid (0.15 g, 98%). LC-MS: M / z 407.1 (MH).

[0249] Step iii: (2S,4R)-1-((S)-2-(2-(4-(4-(6-(5-fluoro-2-hydroxyphenyl)pyridazine-4-yl)phenyl) Piperazine-1-yl)acetamyl)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)benzene Synthesis of 2-carboxamide (ethyl)pyrrolidine-2-carboxamide At 0 °C, HATU (0.07 g, 0.19 mmol) was added to a DMF (2 mL) solution of 2-(4-(4-(6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetic acid (0.07 g, 0.16 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.08, 0.16 equivalents), followed by dropwise addition of DIPEA (0.05 mL, 0.31 mmol). The reaction mixture was stirred at RT for 3 h. The reaction mixture was then poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and salt water, dried with anhydrous sodium sulfate and concentrated under vacuum to obtain a crude product, which was purified by preparative HPLC to obtain the title compound as a yellow solid (0.014 g, 10%).

[0250] 1 H NMR (400 MHz, DMSO-d6): 13.30 (s, 1H), 9.61 (s, 1H), 8.97 (s, 1H),8.65 (s, 1H), 8.49 (d, J= 7.6 Hz, 1H), 8.16 (t, J = 10.0 Hz, 1H), 8.04 (d, J =8.8 Hz, 2H), 7.78 (d, J = 9.6 Hz, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.36 (d, J =7.6 Hz, 2H), 7.26 (t, J = 7.2 Hz, 1H), 7.14 (d, J = 4.4 Hz, 2H), 7.04-7.00 (m,1H), 5.12 (s, 1H), 4.89 (t, J = 7.4 Hz, 1H), 4.53 (d, J = 10.0 Hz, 1H), 4.45(t, J = 8.0 Hz, 1H), 4.29 (s, 1H), 3.60 (s, 2H), 3.38-3.05 (m, 2H), 2.66-2.60(m, 6H), 2.55-2.45 (m, 4H), 2.06 (t, J = 9.8 Hz, 1H), 1.78 (s, 2H), 1.36 (d, J = 6.8 Hz, 3H), 0.96 (s, 9H). LC-MS: m / z 835.3 (M+H). Example 5: (2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(5-(6-(2-hydroxyphenyl)pyridazin-4-yl)pyridin-2-yl)piperazin-1-yl)acetamyl)-3,3-dimethylbutyryl)-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 5)

[0251] Step i: Synthesis of 5-(6-bromopyridin-3-yl)-3-chloropyridazine To a stirred solution of 5-bromo-3-chloropyridazine (0.5 g, 2.48 mmol), (6-bromopyridin-3-yl)boronic acid (0.47 g, 2.48 mmol) in 1,4-dioxane (15 mL), 4 mL of 2M Na₂CO₃ (1 g, 9.9 mmol) was added, and the mixture was degassed with nitrogen for 15 min. Pd(dppf)Cl₂·DCM (0.04 g, 0.05 mmol) was added, and the reaction mixture was heated in a microwave at 80 °C for 1 h. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a residue, which was purified by Combiflash column chromatography using a hexane solution of 60% ethyl acetate as eluent to give the title compound as a yellow solid (0.45 g, 64%).

[0252] 1 H NMR (400 MHz, DMSO-d6): δ 9.75 (d, J = 2.0 Hz, 1H), 9.01 (d, J = 2.4Hz, 1H), 8.43 (d, J = 2.0 Hz, 1H), 8.36 (dd, J = 2.8 Hz, 2.4 Hz 1H), 7.90 (d, J =8.4 Hz, 1H); LC-MS: m / z 272 (M+H). Step ii: Synthesis of 2-(4-(5-(6-chloropyridazin-4-yl)pyridin-2-yl)piperazin-1-yl)tert-butyl acetate Under RT, 2-(piperazin-1-yl)tert-butyl acetate (0.35 g, 1.78 mmol) and DIPEA (0.85 g, 4.72 mmol) were added to a stirred solution of 5-(6-bromopyridin-3-yl)-3-chloropyridazine (0.32 g, 1.18 mmol) in DMSO (10 mL), and the mixture was heated at 120 °C for 16 h. The reaction mixture was then quenched with cold water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the residue, which was purified by Combiflash column chromatography using a hexane solution of 45–50% ethyl acetate as eluent to give the title compound as a yellow solid (0.2 g, 40%).

[0253] 1 H NMR (400 MHz, DMSO-d6): δ 9.31 (d, J = 2.0 Hz, 1H), 8.54 (d,J = 2.4Hz, 1H), 7.76 (dd, J = 2.8 Hz, 2.4 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 6.74 (d, J =9.2 Hz, 1H), 3.74 (t, J = 4.8 Hz, 4H), 3.19 (s, 2H), 2.70 (t, J = 4.8 Hz, 4H),1.47 (s, 9H); LC-MS: m / z 390.2 (M+H). Step iii: 2-(4-(5-(6-(2-hydroxyphenyl)pyridazin-4-yl)pyridin-2-yl)piperazin-1-yl)tert-butyl acetate Ester Synthesis To a stirred solution of tert-butyl acetate (0.25 g, 0.64 mmol) and (2-hydroxyphenyl)boronic acid (0.13 g, 0.96 mmol) in 1,4-dioxane (10 mL), 1.2 mL of 2M Na₂CO₃ (0.27 g, 2.56 mmol) was added, followed by degassing with nitrogen for 15 min. Pd(dppf)Cl₂·DCM (0.05 g, 0.06 mmol) was added, and the reaction mixture was heated in a microwave at 120 °C for 2 h. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and salt water, dried with anhydrous sodium sulfate and concentrated under vacuum to obtain the residue, which was purified by Combiflash column chromatography using a hexane solution of 60% ethyl acetate as the eluent to give the title compound as a yellow solid (0.18 g, 62%).

[0254] 1 H NMR (400 MHz, DMSO-d6): δ 13.78 (s, 1H), 9.26 (d, J = 2.0 Hz, 1H), 8.62 (d, J = 2.8 Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H), 7.85-7.80 (m, 2H), 7.40-7.39(m, 1H), 7.13-7.11 (m, 1H), 7.01 (t, J = 8.0 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 3.76 (t, J= 4.8 Hz, 4H), 3.2 (s, 2H), 2.72 (t, J = 4.8 Hz, 4H), 1.47 (s, 9H); LC-MS: m / z 448.25 (M+H). Step-iv: Synthesis of 2-(4-(5-(6-(2-hydroxyphenyl)pyridazin-4-yl)pyridin-2-yl)piperazin-1-yl)acetic acid At 0 °C, 5 mL of 4N dioxane hydrochloride was added to a stirred solution of 0.15 g (0.33 mmol) of tert-butyl acetate in DCM (10 mL). The solution was then slowly brought to RT and stirred at RT for 2 h. The reaction mixture was evaporated under reduced pressure, and the residue was washed with diethyl ether and dried under vacuum to give the title compound as an orange solid (0.1 g, 63%). LC-MS: M / z 392.1 (M+H). Step v: (2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(5-(6-(2-hydroxyphenyl)pyridazine-4-yl)pyridine- 2-yl)piperazin-1-yl)acetamyl)-3,3-dimethylbutyryl)-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl) Synthesis of ethylpyrrolidine-2-carboxamide At 0 °C, HATU (0.14 g, 0.37 mmol) was added to a DMF (3 mL) solution of 2-(4-(5-(6-(2-hydroxyphenyl)pyridazin-4-yl)pyridin-2-yl)piperazin-1-yl)acetic acid (0.1 g, 0.25 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.13, 0.28 eq.), followed by dropwise addition of DIPEA (0.18 mL, 1 mmol). The reaction mixture was stirred at RT for 4 hours. The reaction mixture was then poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and salt water, dried with anhydrous sodium sulfate and concentrated under vacuum to obtain a crude product, which was purified by preparative HPLC to obtain the title compound as a yellow solid (0.03 g, 16%).

[0255] 1 H NMR (400 MHz, DMSO-d6): δ 13.5 (bs, 1H), 9.61 (s, 1H), 8.97 (s,1H), 8.90 (s, 1H), 8.66 (s, 1H), 8.42 (d, J = 8.0 Hz, 1H), 8.31 (d, J = 8.8 Hz, 1H), 8.25 (d, J = 8.0 Hz, 1H), 7.79 (d,J = 9.6 Hz, 1H), 7.44-7.35 (m, 5H), 7.07-6.99 (m, 3H), 5.12 (bs, 1H), 4.89 (t, J = 6.8 Hz, 1H), 4.53 (d, J = 9.6 Hz, 1H), 4.45 (t, J = 7.6 Hz, 1H), 4.29 (bs, 1H), 3.71-3.60 (m, 5H), 3.16-3.02 (m, 2H), 2.61 (bs, 4H), 2.45 (m, 3H), 2.08-2.03 (m, 1H), 1.84 (s, 1H), 1.77-1.75 (m,1H), 1.37 (d, J = 6.8 Hz, 3H), 096 (s, 9H); LC-MS: m / z 818.2 (M+H). Example 6: (2S,4R)-4-hydroxy-1-((S)-2-(2-(1-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperidin-4-yl)acetamyl)-3,3-dimethylbutyryl)-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 6)

[0256] Step i: Synthesis of 2-(1-(4-(6-chloropyridazin-4-yl)phenyl)piperidin-4-yl)acetic acid Add the mixture to a stirred solution of 5-bromo-3-chloropyridazine (0.13 g, 0.67 mmol), 2-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)phenyl)piperidin-4-yl)ethyl acetate (0.25 g, 0.67 mmol), and Na₂CO₃ (0.28 g, 2.68 mmol) in 1,4-dioxane (5 mL) and water (2 mL), and degas with nitrogen for 15 min. Add Pd(dppf)Cl₂·DCM (0.055 g, 0.0067 mmol), and microwave the reaction mixture in a sealed tube at 120 °C for 6 h. Once the reaction is complete (monitored by TLC), dilute the reaction mixture with EtOAc. The combined organic layers were washed with water and salt water, dried with anhydrous sodium sulfate, and concentrated under vacuum to obtain the residue. The residue was purified by Combiflash column chromatography using 8-12% methanol in DCM solution as eluent to obtain the title compound as a viscous substance (0.09 g, 40%).

[0257] 1 H NMR (400 MHz, DMSO-d6): δ 12.11 (s, 1H), 9.61 (d, J = 2.0 Hz, 1H), 8.14 (d, J = 2.0 Hz, 1H), 7.89 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 9.2 Hz, 2H),3.95-3.89 (m, 2H), 2.83 (t, J = 6.0 Hz, 2H), 2.18 (d, J = 6.8 Hz, 2H), 1.91-1.86 (m, 1H), 1.76-1.73 (m, 1H), 1.29-1.20 (m, 2H). LC-MS: m / z 331.9 (MH).

[0258] Step ii: (2S,4R)-1-((S)-2-(2-(1-(4-(6-chloropyridazin-4-yl)phenyl)piperidin-4-yl)acetamide (3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazo-5-yl)phenyl)ethyl)pyrrolidine-2- Synthesis of formamide At 0 °C, HATU (0.155 g, 0.40 mmol) was added to a DMF (2 mL) solution of 2-(1-(4-(6-chloropyridazin-4-yl)phenyl)piperidin-4-yl)acetic acid (0.09 g, 0.27 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.13 g, 0.27 eq.), followed by dropwise addition of DIPEA (0.14 mL, 0.81 mmol), and the reaction mixture was stirred at RT for 4 h. The reaction mixture was then poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and salt water, dried with anhydrous sodium sulfate and concentrated under vacuum to obtain a crude product, which was purified by Combiflash column chromatography using a 5% methanol DCM solution as the eluent to obtain the title compound as a grayish-white solid (0.125 g, 61%).

[0259] 1 H NMR (400 MHz, DMSO-d6): δ 9.61 (d, J = 2.0 Hz, 1H), 8.99 (s, 1H), 8.40 (d, J = 7.6 Hz, 1H), 8.13 (d, J= 1.6 Hz, 1H), 7.90-7.85 (m, 3H), 7.48-7.36 (m, 4H), 7.05 (d, J = 9.2 Hz, 2H), 5.12 (d, J = 3.6 Hz, 1H), 4.92 (t, J =7.2 Hz, 1H), 4.54-4.28 (m, 2H), 4.21 (s, 1H), 3.93-3.89 (m, 2H), 3.61 (s,2H), 2.95-2.79 (m, 2H), 2.45 (s, 3H), 2.24-2.21 (m, 1H), 2.13-2.12 (m, 1H),2.01-1.67 (m, 5H), 1.37 (d, J = 7.2 Hz, 3H), 1.23-1.21 (m, 2H), 0.95 (s, 9H). LC-MS: m / z 756.3 (MH).

[0260] Step iii: (2S,4R)-4-hydroxy-1-((S)-2-(2-(1-(4-(6-(2-hydroxyphenyl)pyridazine-4-yl)benzene) (S)-1-(4-(4-methylthiazolyl-5-yl)phenyl) Synthesis of pyrrolidine-2-carboxamide Add 1,4-dioxane (4 mL) and water (1 mL) to a stirred solution of (2S,4R)-1-((S)-2-(2-(1-(4-(6-chloropyridazin-4-yl)phenyl)piperidin-4-yl)acetamyl)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (0.12 g, 0.15 mmol), (2-hydroxyphenyl)boronic acid (0.033 g, 0.23 mmol), and K₂CO₃ (0.07 g, 0.48 mmol), and degas with nitrogen for 5 min. Add Pd(dppf)Cl₂.DCM (0.013 g, 0.016 mmol), and microwave the reaction mixture at 120 °C for 1 h. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the residue, which was purified by Combiflash column chromatography using 8–12% methanol in DCM solution as eluent to give the title compound as a pale yellow solid (0.015 g, 11%).

[0261] 1 H NMR (400 MHz, DMSO-d6): 13.58 (s, 1H), 9.56 (d,J = 2.0 Hz, 1H),8.99 (s, 1H), 8.60 (d, J = 2.0 Hz, 1H), 8.40 (d, J = 7.6 Hz, 1H), 8.25 (d, J =7.2 Hz, 1H), 7.99 (d, J = 8.8 Hz, 2H), 7.87 (d, J = 9.2 Hz, 1H), 7.45-7.37 (m,5H), 7.09 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.0 Hz, 2H), 5.12 (d, J = 3.6 Hz,1H), 4.91-4.89 (m, 1H), 4.53 (d, J = 9.2 Hz, 1H), 4.43-4.42 (m, 1H), 4.28 (d, J = 2.4 Hz, 1H), 3.90 (d, J = 6.4 Hz, 2H), 3.62 (d, J = 1.6 Hz, 2H), 2.83 (t, J =12.4 Hz, 2H), 2.45 (s, 3H), 2.14-2.13 (m, 1H), 2.13-2.12 (m, 1H), 2.11-1.78(m, 2H), 1.77-1.69 (m, 3H), 1.37 (d, J = 7.2 Hz, 3H), 1.26-1.21 (m, 2H), 0.95(s, 9H). LC-MS: m / z 816.4 (M+H). Example 7: (2S,4R)-1-((S)-2-(2-(4-(4-(6-(2-fluorophenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetamyl)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 7)

[0262] Step i: Synthesis of 2-(4-(4-(6-(2-fluorophenyl)pyridazine-4-yl)phenyl)piperazine-1-yl)tert-butyl acetate To a stirred solution of tert-butyl 2-(4-(6-chloropyridazin-4-yl)phenyl)piperazin-1-yl)acetate (0.25 g, 0.64 mmol), 2-fluorophenylboronic acid (0.13 g, 0.96 mmol), 1,4-dioxane (10 mL), and water (1 mL), K₂CO₃ (0.35 g, 2.57 mmol) was added, and the mixture was degassed with nitrogen for 5 min. Pd(dppf)Cl₂·DCM (0.05 g, 0.064 mmol) was added, and the reaction mixture was heated in a sealed test tube at 130 °C for 4 h. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and salt water, dried with anhydrous sodium sulfate and concentrated under vacuum to obtain the residue, which was purified by Combiflash column chromatography using a hexane solution of 50-60% ethyl acetate as the eluent to obtain the title compound as a viscous substance (0.22 g, 76%).

[0263] 1 H NMR (400 MHz, DMSO-d6): 9.39 (d, J = 2.0 Hz, 1H), 8.18 (ddd, J = 8.0Hz, 1H), 8.05 (t, J = 4.4 Hz, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.47-7.46 (m, 1H),7.36 (ddd, J = 7.6 Hz, 1H), 7.23 (d, J = 12.0 Hz, 1H), 7.03 (d, J = 9.2 Hz, 2H), 3.38 (t, J = 4.8 Hz, 4H), 3.20 (s, 2H), 2.76 (t, J = 5.2 Hz, 4H), 1.48 (s, 9H). LC-MS: m / z 449.45 (M+H). Step ii: Synthesis of 2-(4-(4-(6-(2-fluorophenyl)pyridazine-4-yl)phenyl)piperazine-1-yl)acetate hydrochloride At 0 °C, 2 mL of 4N dioxane hydrochloride was added to a stirred solution of 0.22 g (0.48 mmol) of tert-butyl acetate in DCM (5 mL). The solution was then slowly brought to RT and stirred at RT for 6 h. The reaction mixture was evaporated under reduced pressure, and the residue was washed with diethyl ether and dried under vacuum to give the title compound as an orange solid (0.2 g, 87%). LC-MS: M / z 393.1 (M+H). Step iii: (2S,4R)-1-((S)-2-(2-(4-(4-(6-(2-fluorophenyl)pyridazine-4-yl)phenyl)piperazine-1- (S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl) Synthesis of pyrrolidine-2-carboxamide At 0 °C, HATU (0.13 g, 0.36 mmol) was added to a DMF (3 mL) solution of 2-(4-(4-(6-(2-fluorophenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetate hydrochloride (0.1 g, 0.24 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.115, 0.24 equivalents). Then, DIPEA (0.12 mL, 0.72 mmol) was added dropwise, and the reaction mixture was stirred at RT for 4 h. The reaction mixture was then poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and salt water, dried with anhydrous sodium sulfate and concentrated under vacuum to obtain a crude product, which was purified by Combiflash column chromatography using a 5% methanol DCM solution as the eluent to obtain the title compound as a pale yellow solid (0.07 g, 37%).

[0264] 1 H NMR (400 MHz, DMSO-d6): 9.61 (d, J = 2.4 Hz, 1H), 8.96 (s, 1H), 8.44(d, J = 7.6 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 7.96-7.95 (m, 2H), 7.90 (d, J =8.8 Hz, 1H), 7.77 (d, J = 10.0 Hz, 1H), 7.59-7.57 (m, 1H), 7.44-7.34 (m, 6H),7.12 (d, J = 8.8 Hz, 2H), 5.13 (d, J= 3.2 Hz, 1H), 4.87 (t, J = 7.2 Hz, 1H),4.53-4.43 (m, 2H), 4.27 (s, 1H), 3.58-3.55 (m, 2H), 3.14 (d, J = 16.0 Hz, 1H), 3.01 (d, J = 16.0 Hz, 1H), 2.66-2.64 (m, 4H), 2.45 (t, J = 1.6 Hz, 4H), 2.07-2.02 (m, 1H), 1.77-1.75 (m, 1H), 1.46 (d, J = 6.8 Hz, 1H), 1.35 (d, J = 7.2 Hz,3H), 1.20 (s, 2H), 0.94 (s, 9H). LC-MS: m / z 819.4 (M+H). Example 8: (2S,4R)-4-hydroxy-1-((S)-2-(3-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)propamido)-3,3-dimethylbutyryl)-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 8)

[0265] Step i: Synthesis of tert-butyl 4-(4-(6-chloropyridazine-4-yl)phenyl)piperazine-1-carboxylic acid To a stirred solution of 5-bromo-3-chloropyridazine (0.72 g, 3.8 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (1 g, 2.57 mmol) in 1,4-dioxane (20 mL) and water (4 mL), Na₂CO₃ (0.82 g, 7.73 mmol) was added, and the mixture was degassed with nitrogen for 15 min. Pd(dppf)Cl₂·DCM (0.31 g, 0.38 mmol) was added, and the reaction mixture was heated in a sealed tube at 130 °C for 16 h. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and salt water, dried with anhydrous sodium sulfate and concentrated under vacuum to obtain the residue, which was purified by Combiflash column chromatography using a hexane solution of 60% ethyl acetate as the eluent to give the title compound as a pale yellow solid (0.5 g, 72%).

[0266] 1 H NMR (400 MHz, CDCl3): δ 9.32 (d, J = 1.6 Hz, 1H), 7.61 (d, J = 8.8 Hz,2H), 7.25 (s, 1H), 7.0 (d, J = 8.8 Hz, 2H), 3.60 (m, 4H), 3.30 (m 4H), 1.49 (s,9H); LC-MS: m / z 375.0 (M+H). Step ii: Synthesis of tert-butyl 4-(4-(6-(2-hydroxyphenyl)pyridazine-4-yl)phenyl)piperazine-1-carboxylic acid To a stirred solution of tert-butyl 4-(4-(6-chloropyridazin-4-yl)phenyl)piperazine-1-carboxylic acid (0.5 g, 1.33 mmol), (2-hydroxyphenyl)boronic acid (0.22 g, 1.60 mmol) in 1,4-dioxane (10 mL) and water (2 mL), Na₂CO₃ (0.42 g, 4.01 mmol) was added, and the mixture was degassed with nitrogen for 5 min. Pd(dppf)Cl₂·DCM (0.11 g, 0.13 mmol) was added, and the reaction mixture was heated in a sealed test tube at 130 °C for 6 h. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and salt water, dried with anhydrous sodium sulfate and concentrated under vacuum to obtain the residue, which was purified by Combiflash column chromatography using a hexane solution of 50-60% ethyl acetate as the eluent to give the title compound as a grayish-white solid (0.25 g, 43%).

[0267] 1 H NMR (400 MHz, DMSO-d6): δ 13.45 (s, 1H), 9.58 (d, J = 2.4 Hz, 1H), 8.62 (d, J = 2.0 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.03 (d, J =9.2 Hz, 2H), 7.40(m, 1H), 7.12 (d, J = 8.8 Hz, 2H), 7.0 (t, J = 8.4 Hz, 2H), 3.48 (m, 4H), 3.31(m, 4H), 1.43 (s, 9H); LC-MS: m / z 433.10 (M+H). Step iii: Synthesis of 2-(5-(4-(piperazin-1-yl)phenyl)pyridazin-3-yl)phenol At 0 °C, 0.8 mL of 4N dioxane hydrochloride was added to a stirred solution of tert-butyl 4-(4-(6-(2-hydroxyphenyl)pyridazine-4-yl)phenyl)piperazine-1-carboxylic acid (0.25 g, 0.66 mmol) in DCM (5 mL). The solution was then slowly brought to RT and stirred at RT for 6 h. The reaction mixture was evaporated under reduced pressure, and the residue was washed with diethyl ether and dried under vacuum to give the title compound as an orange solid (0.21 g, 98%).

[0268] 1 H NMR (400 MHz, DMSO-d6): δ 9.78 (s, 1H), 9.60 (bs, 1H), 8.80 (s,1H), 8.15 (d, J = 8.8 Hz, 2H), 7.94 (d, 1H), 7.47 (t, J = 15.2 Hz 1H), 7.18-7.45(m, 3H), 7.05 (t, J = 14.8 Hz 1H), 3.56 (bs, 4H), 3.20 (bs, 4H); LC-MS: m / z333.0 (M+H). Step-iv: Synthesis of ethyl 3-(4-(4-(6-(2-hydroxyphenyl)pyridazine-4-yl)phenyl)piperazine-1-yl)propionate At RT, ethyl 3-bromopropionate (0.12 g, 0.65 mmol) and DIPEA (0.3 g, 1.63 mmol) were added to a stirred DMF (40 mL) solution of 2-(5-(4-(piperazin-1-yl)phenyl)pyridazin-3-yl)phenol (0.2 g, 0.54 mmol), and the mixture was stirred at RT for 16 h. The reaction mixture was then quenched with cold water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the residue, which was purified by Combiflash column chromatography using 3-5% methanol in DCM solution as eluent to give the title compound as a viscous solid (0.09 g, 38%). LC-MS: M / z 433.15 (M+H). Step v: Synthesis of 3-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)propionic acid At 0 °C, LiOH·H₂O (0.02 g, 0.41 mmol) was added to a stirred solution of ethyl 3-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)propionate (0.09 g, 0.20 mmol) in methanol:THF:H₂O (2 mL:4 mL:1 mL). The reaction mixture was stirred at RT for 16 h. The reaction mixture was then evaporated under reduced pressure, and the resulting residue was diluted with methanol and treated with Amberlite. ® Acidified to pH 6 with IT120, filtered, and the filtrate was concentrated under vacuum to give the title compound as a viscous solid (0.05 g, 59%). LC-MS: M / z 405.1 (M+H). Step vi: (2S,4R)-4-hydroxy-1-((S)-2-(3-(4-(4-(6-(2-hydroxyphenyl)pyridazine-4-yl)benzene) (S)-1-(4-(4-methylthiazolyl-5-yl)phenyl) 2-pyrrolidine-2-carboxamide At 0 °C, HATU (0.14 g, 0.37 mmol) was added to a DMF (2 mL) solution of 3-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)propionic acid (0.05 g, 0.12 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.09 g, 0.18 equivalents). Then, DIPEA (0.07 mL, 0.37 mmol) was added dropwise, and the reaction mixture was stirred at RT for 3 h. The reaction mixture was then poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and salt water, dried with anhydrous sodium sulfate and concentrated under vacuum to obtain a crude product. This crude product was purified by Combiflash column chromatography using 8-10% methanol in DCM solution as eluent to obtain the title compound as a pale yellow solid (0.015 g, 15%).

[0269] 1 H NMR (400 MHz, DMSO-d6): δ 13.51 (s, 1H), 9.57 (s, 1H), 8.96 (s,1H), 8.61 (s, 1H), 8.42-8.36 (m, 2H), 8.24 (d, J = 8.0 Hz, 1H), 8.01 (d, J = 8.4Hz, 2H), 7.42-7.34 (m, 5H), 7.12 (d, J = 8.4 Hz, 2H), 7.01 (d, J= 7.6 Hz, 2H), 5.12 (d, J = 3.2 Hz 1H), 4.91-4.80 (m, 1H), 4.54 (d, J = 9.6 Hz, 1H), 4.42 (t,1H), 4.28 (bs, 1H), 3.64-3.48 (m, 4H), 2.3-2.7 (m, 9H), 2.08 (m, 2H), 1.78(m, 1H), 1.45 (m, 1H), 1.34 (m, 4H); 1.23 (bs, 1H), 0.95 (s, 9H); LC-MS: m / z831.40 (M+H). Example 9: (2S,4R)-1-((S)-3,3-dimethyl-2-(2-(4-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetamyl)butyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 9)

[0270] Step -i: (2S,4R)-1-((S)-3,3-dimethyl-2-(2-(4-(4-(6-(1-methyl-1H-pyrazol-4-yl)) (pyridazine-4-yl)phenyl)piperazine-1-yl)acetamyl)butyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-) Synthesis of 2-carboxamide (phenyl)ethylpyrrolidine-2-carboxamide Add K2CO3 (0.22 g, 1.59 mmol) to a stirred solution of (2S,4R)-1-((S)-2-(2-(4-(4-(6-chloropyridazin-4-yl)phenyl)piperazin-1-yl)acetamyl)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (0.3 g, 0.39 mmol), 1-methyl-1H-pyrazole-4-yl-4-boronic acid (0.123 g, 0.58 mmol) in 1,4-dioxane (10 mL) and water (1 mL), and degas with nitrogen for 5 minutes. Pd(dppf)Cl2·DCM (0.03 g, 0.034 mmol) was added, and the reaction mixture was heated in a sealed test tube at 130 °C for 6 hours. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the residue, which was purified by preparative HPLC to give the title compound as a pale yellow solid (6 mg, 2%).

[0271] 1H NMR (400 MHz, DMSO-d6): 9.40 (s, 1H), 8.98 (s, 1H), 8.53 (s, 1H), 8.45 (d, J = 7.2 Hz, 1H), 8.24 (s, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.92 (d, J =8.0 Hz, 2H), 7.79-7.77 (m, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.8 Hz, 2H), 5.14 (d, J = 2.8 Hz, 1H), 4.95-4.85 (m, 1H), 4.44-4.42 (m, 2H), 4.29-4.28 (m, 1H), 3.94 (bs, 3H), 3.59 (m, 2H), 3.14 (bs,1H), 3.05 (bs, 1H), 2.67-2.66 (m, 5H), 2.45 (bs, 6H), 2.08-2.01 (m, 1H), 1.80-1.70 (m, 1H), 1.36 (d, J = 6.8 Hz, 3H), 0.96 (s, 9H). LC-MS: m / z 805.4 (M+H). The compounds listed in Table 2 below were prepared by means of methods similar to those described in Example 2, with appropriate changes to the reactants, reagent amounts, protecting and deprotecting agents, solvents, and reaction conditions. Characterization data for the compounds are summarized in the table below.

[0272]

[0273] The compounds listed in Table 3 below were prepared by means of methods similar to those described in Example 8, with appropriate changes to the reactants, reagent amounts, protecting and deprotecting agents, solvents, and reaction conditions. Characterization data for the compounds are summarized in the table below.

[0274]

[0275] Example 10: (2S,4R)-4-hydroxy-1-((S)-2-(5-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)pentamido)-3,3-dimethylbutyryl)-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 34)

[0276] Step i: Synthesis of methyl 5-(4-(6-chloropyridazine-4-yl)phenoxy)valerate Under RT, methyl 5-bromopentanoate (0.52 mL, 3.64 mmol), K₂CO₃ (1 g, 7.28 mmol), and sodium iodide (0.05 g, 0.24 mmol) were added to a stirred solution of 4-(6-chloropyridazin-4-yl)phenol (0.5 g, 2.42 mmol) in acetone (10 mL), and the reaction mixture was heated at 90 °C and sealed for 16 h. Once the reaction was complete (monitored by TLC), the reaction mixture was concentrated and then diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a residue, which was purified by preparative HPLC to give the title compound as a pale yellow solid (0.5 g, 64%).

[0277] 1 H NMR (400 MHz, CDCl3): δ 9.65 (d, J = 2 Hz, 1H), 8.21 (d, J = 2 Hz, 1H), 7.98 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H), 4.07 (t, J = 6 Hz, 2H), 3.58(s, 3H), 2.39 (t, J = 6.8 Hz, 2H), 1.66-1.77 (m, 4H); LC-MS: m / z 320.9 (M+H). Step ii: Synthesis of methyl 5-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)valerate To a stirred solution of methyl 5-(4-(6-chloropyridazin-4-yl)phenoxy)valerate (0.5 g, 1.56 mmol), (2-hydroxyphenyl)boronic acid (0.43 g, 3.12 mmol), 1,4-dioxane (10 mL), and water (3 mL), Na₂CO₃ (0.50 g, 4.68 mmol) was added, and the solution was degassed with nitrogen for 5 minutes. Pd(dppf)C₂ was then added. l2 DCM (0.13 g, 0.15 mmol) was added, and the reaction mixture was heated at 130 °C for 6 hours in a sealed test tube. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the residue, which was purified by Combiflash column chromatography using a hexane solution of 50-60% ethyl acetate as eluent to give the title compound as a grayish-white solid (0.19 g, 32%).

[0278] 1 H NMR (400 MHz, CDCl3): δ 13.18 (bs, 1H), 9.29 (d, J = 2.4 Hz, 1H), 8.16 (d, J = 2 Hz, 1H), 7.83 (dd, J = 8, 1.2 Hz, 1H), 7.70 (d, J = 8.8 Hz, 2H), 7.38 (t, J = 7.2 Hz, 1H), 7.14 (dd, J = 8.4, 0.8 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H), 6.99 (t, J = 8.4 Hz, 1H), 4.07 (t, J = 5.6 Hz, 2H), 3.69 (s, 3H), 2.43 (t, J = 6.8Hz, 2H), 1.85-1.88 (m, 4H); LC-MS: m / z 379.05 (M+H). Step iii: Synthesis of 5-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)valerate At 0 °C, LiOH·H₂O (0.03 g, 1.51 mmol) was added to a stirred solution of methyl 5-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)valerate (0.19 g, 0.50 mmol) in methanol:THF:H₂O (3 mL:4 mL:3 mL). The reaction mixture was stirred at RT for 16 h. The reaction mixture was then evaporated under reduced pressure, and the resulting residue was diluted with methanol and treated with Amberlite. ® Acidified to pH 6 with IT120, filtered, and the filtrate was concentrated under vacuum to give the title compound as a viscous solid (0.17 g, 92.8%). LC-MS: M / z 365.0 (M+H). Step -iv: (2S,4R)-4-hydroxy-1-((S)-2-(5-(4-(6-(2-hydroxyphenyl)pyridazine-4-yl)phenoxy (S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine- Synthesis of 2-formamide At 0 °C, HATU (0.27 g, 0.70 mmol) was added to a DMF (3 mL) solution of 5-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)valerate (0.17 g, 0.467 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.27 g, 0.56 eq.), followed by dropwise addition of DIPEA (0.25 mL, 1.4 mmol). The reaction mixture was stirred at RT for 3 h. The reaction mixture was then poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and salt water, dried with anhydrous sodium sulfate, and concentrated under vacuum to obtain a crude product. This crude product was purified by Combiflash column chromatography using 8-10% methanol in DCM solution as eluent to obtain the title compound as a pale yellow solid (0.09 g, 24%).

[0279] 1H NMR (400 MHz, DMSO-d6): δ 13.33 (s, 1H), 9. 60 (d, J = 1.6 Hz,1H), 8.98 (s, 1H), 8.66 (d, J = 2 Hz, 1H), 8.38 (d, J = 8 Hz, 1H), 8.25 (d, J= 7.6 Hz, 1H), 8.08 (d, J = 8.8 Hz, 2H), 7.87 (d, J = 9.2 Hz, 1H), 7.36-7.44(m, 5H), 7.15 (d, J = 9.2 Hz, 2H), 7.02 (d, J = 8 Hz, 2H), 5.11 (d, J = 3.6Hz, 1H), 4.90 (t, J = 7.2 Hz, 1H), 4.54 (d, J = 8.8 Hz, 1H), 4.43 (t, J = 7.2Hz, 1H), 4.28 (bs, 1H), 4.09 (d, J = 6 Hz, 2H), 3.61 (bs, 2H), 2.45(s, 3H), 2.23 (m, 1H), 2.17-2.23 (m, 1H), 1.97-2.07 (m, 1H), 1.62-1.83 (m, 5H), 1.47(d, J = 7.2 Hz, 3H), 0.95 (s, 9H); LC-MS: m / z 791.35 (M+H). Example 11: (2S,4R)-4-hydroxy-1-((S)-2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)butyramido)-3,3-dimethylbutyryl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 35)

[0280] Compound 35 was prepared by appropriately changing the reactants, reagent amounts, protecting and deprotecting agents, solvents, and reaction conditions, similar to the method described in Example 10.

[0281] 1H NMR (400 MHz, DMSO-d6): δ 13.35 (s, 1H), 9.60 (s, 1H), 8.98 (s,1H), 8.67 (s, 1H), 8.39 (d, J = 8 Hz, 1H), 8.25 (d, J = 8 Hz, 1H), 8.08 (d, J = 8 Hz, 2H), 7.96 (d, J = 8 Hz, 1H), 7.36-7.44 (m, 5H), 7.14 (d, J = 12 Hz, 2H), 7.02 (d, J = 8 Hz, 2H), 5.13 (s, 1H), 4.89-4.93 (m, 1H), 4.54 (d, J =8.8 Hz, 1H), 4.41-4.45 (m, 1H), 4.28 (bs, 1H), 4.08 (bs, 2H), 3.62 (s, 2H), 2.45 (s, 3H), 2.38-2.42 (m, 2H), 2.04-1.97 (m, 3H), 1.87-1.79 (m, 1H), 1.45(d, J = 8 Hz, 3H), 0.94 (s, 9H); LC-MS: m / z 776.8 (M+H). Example 12: (2S,4R)-4-hydroxy-1-((S)-2-(5-((4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)amino)pentamido)-3,3-dimethylbutyryl)-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 36)

[0282] Compound 36 was prepared by appropriately changing the reactants, reagent amounts, protecting and deprotecting agents, solvents, and reaction conditions, similar to the method described in Example 10.

[0283] 1H NMR (400 MHz, DMSO-d6): δ 13.72(bs, 1H), 9.51 (d, J = 2.4 Hz, 1H), 8.98 (s, 1H), 8.53(d, J = 2 Hz, 1H), 8.38 (d, J = 7.2 Hz, 1H), 8.24 (d, J =6.8 Hz, 1H), 7.92 (d, J = 8.8 Hz, 2H), 7.84 (d, J = 9.6 Hz, 1H), 7.36-7.44(m, 5H), 6.99 (d, J = 8.8 Hz, 2H), 6.73 (d, J = 8.8 Hz, 2H), 6.38 (t, J = 5.6Hz, 1H), 5.11 (d, J = 3.6 Hz, 1H), 4.91 (t, J = 7.2 Hz, 2H), 4.53 (d, J = 9.2Hz, 1H), 4.42 (t, J = 8.4 Hz, 1H), 4.28 (bs, 1H), 3.60 (bs, 2H), 3.11 (d, J =6.0 Hz, 2H), 2.45 (s, 3H), 2.33 (m, 1H), 2.18 (m, 1H), 2.00 (m, 1H), 1.81 (m,1H), 1.57 (m, 3H), 1.37(d, J = 6.8 Hz, 3H), 0.94(s, 9H). LCMS m / z 790.6 (M+H). The compounds listed in Table 4 below were prepared by means of methods similar to those described in Example 7, with appropriate changes to the reactants, reagent amounts, protecting and deprotecting agents, solvents, and reaction conditions. Characterization data for the compounds are summarized in the table below.

[0284]

[0285] Example 13: (2S,4R)-4-hydroxy-1-(2-(3-(2-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)ethoxy)isoxazo-5-yl)-3-methylbutyryl)-N-((S)-1-(4-(4-methylthiazo-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 42, racemic)

[0286] Step i: Synthesis of 5-(4-(2-bromoethoxy)phenyl)-3-chloropyridazine Under RT, 1,2-dibromoethane (0.82 g, 9.7 mmol) and K₂CO₃ (1.4 g, 9.7 mmol) were added to a stirred ethanol (10 mL) solution of 4-(6-chloropyridazin-4-yl)phenol (0.5 g, 2.42 mmol), and the reaction mixture was heated at 100 °C for 16 h under a sealed environment. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by Combiflash column chromatography using a hexane solution of 40% ethyl acetate as eluent to give the title compound as a brown solid (0.4 g, 52.4%).

[0287] 1 H NMR (400 MHz, CDCl3): δ 9.34 (bs, 1H), 7.66 (s, 1H), 7.65 (d, J = 8.8Hz, 2H), 7.08 (d, J = 8.8 Hz, 2H), 4.37 (t, J = 6 Hz, 2H), 3.68 (t, J = 6.8 Hz, 2H); LC-MS: m / z 314.8 (M+H). Step ii: 2-(3-(2-(4-(6-chloropyridazin-4-yl)phenoxy)ethoxy)isoxazo-5-yl)-3-methylbutane Synthesis of methyl ester Under RT, methyl 2-(3-hydroxyisoxazol-5-yl)-3-methylbutyrate (0.2 g, 1 mmol) and K₂CO₃ (0.30 g, 2.2 mmol) were added to a DMF (5 mL) solution of 5-(4-(2-bromoethoxy)phenyl)-3-chloropyridazine (0.38 g, 1.2 mmol) under stirring. The reaction mixture was heated at 70 °C for 12 h under sealed conditions. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by Combiflash column chromatography using a hexane solution of 60% ethyl acetate as eluent to give the title compound as a brown solid (0.16 g, 37%).

[0288] 1H NMR (400 MHz, CDCl3): δ 9.34 (d, J = 2 Hz, 1H), 7.65 (m, 3H), 7.10(d, J = 8.8 Hz, 2H), 5.95 (s, 1H), 4.63 (t, J = 4.4 Hz, 2H), 4.39 (t, J = 4.4 Hz, 2H), 3.73 (s, 3H), 3.51 (d, J = 8.8 Hz, 1H), 2.35 (m, 1H), 1.01 (d, J = 8.6 Hz, 3H), 0.93 (d, J = 8.6 Hz, 3H); LC-MS: m / z 432.05 (M+H). Step iii: 2-(3-(2-(4-(6-(2-hydroxyphenyl)pyridazine-4-yl)phenoxy)ethoxy)isoxazole-5- Synthesis of methyl 3-methylbutyrate K₂CO₃ (0.15 g, 1.11 mmol) was added to a stirred solution of methyl 2-(3-(2-(4-(6-chloropyridazin-4-yl)phenoxy)ethoxy)isoxazol-5-yl)-3-methylbutyrate (0.16 g, 0.37 mmol), (2-hydroxyphenyl)boronic acid (0.1 g, 0.74 mmol) in 1,4-dioxane (3 mL) and water (1 mL), and the mixture was degassed with nitrogen for 5 min. Pd(dppf)Cl₂·DCM (0.03 g, 0.03 mmol) was added, and the reaction mixture was microwaved at 130 °C for 1 h. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and salt water, dried with anhydrous sodium sulfate and concentrated under vacuum to obtain the residue, which was purified by Combiflash column chromatography using a hexane solution of 50% ethyl acetate as the eluent to give the title compound as a grayish-white solid (0.08 g, 43.9%).

[0289] 1 H NMR (400 MHz, DMSO-d6): δ 13.32 (bs, 1H), 9.61 (d, J = 2 Hz, 1H), 8.68 (d, J = 2 Hz, 1H), 8.25 (d, J = 7.6 Hz, 1H), 8.10 (d, J = 8.4 Hz, 2H), 7.40 (t, J = 8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 2H), 7.02 (d, J= 8.4 Hz, 2H), 6.29 (s, 1H), 4.53 (t, J = 3.2 Hz, 2H), 4.44 (t, J = 3.2 Hz, 2H), 3.71 (d, J = 8.4Hz, 1H), 3.66 (s, 3H), 2.32 (m, 1H), 0.92 (d, J = 6.8 Hz, 3H), 0.86(d, J = 6.8Hz, 3H): LC-MS: m / z 490.1 (M+H). Step-iv: 2-(3-(2-(4-(6-(2-hydroxyphenyl)pyridazine-4-yl)phenoxy)ethoxy)isoxazole-5- Synthesis of 3-methylbutyric acid At 0 °C, LiOH·H₂O (0.022 g, 0.49 mmol) was added to a stirred solution of methyl 2-(3-(2-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)ethoxy)isoxazol-5-yl)-3-methylbutyrate (0.08 g, 0.16 mmol) in methanol:THF:H₂O (1 mL:1 mL:1 mL). The reaction mixture was stirred at RT for 16 h. The reaction mixture was then evaporated under reduced pressure, and the resulting residue was diluted with methanol and treated with Amberlite. ® Acidified to pH 6 with IT120, filtered, and the filtrate was concentrated under vacuum to give the title compound as a viscous solid (0.06 g, 77%). 1 H NMR (400 MHz, DMSO-d6): δ 13.19(bs, 1H), 12.95 (bs, 1H), 9.61 (d, J = 2 Hz, 1H), 8.68 (d, J = 2 Hz, 1H), 8.25 (d, J = 7.6 Hz, 1H), 8.10 (d, J = 8.4 Hz, 2H), 7.40 (t, J = 8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.4 Hz, 2H), 6.24 (s, 1H), 4.53 (t, J =3.2 Hz, 2H), 4.44 (t, J = 3.2 Hz, 2H), 3.53 (d, J = 8.8 Hz, 1H), 2.37 (m, 1H), 0.95 (d, J = 6.8 Hz, 3H), 0.85 (d,J = 6.8 Hz, 3H); LC-MS: m / z 476.1 (M+H). Step v: (2S,4R)-4-hydroxy-1-(2-(3-(2-(4-(6-(2-hydroxyphenyl)pyridazine-4-yl)phenoxy)ethyl (Oxy)isoxazo-5-yl)-3-methylbutyryl)-N-((S)-1-(4-(4-methylthiazo-5-yl)phenyl)ethyl)pyrrole Synthesis of alkyl-2-carboxamide At 0 °C, HATU (0.018 g, 0.047 mmol) was added to a DMF (3 mL) solution of 2-(3-(2-(2-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)ethoxy)isoxazol-5-yl)-3-methylbutyric acid (0.015 g, 0.031 mmol) and (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.014 g, 0.037 mmol) followed by dropwise addition of DIPEA (0.017 mL, 0.094 mmol), and the reaction mixture was stirred at RT for 3 h. The reaction mixture was then poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and salt water, dried with anhydrous sodium sulfate, and concentrated under vacuum to obtain a crude product. This crude product was purified by Combiflash column chromatography using 8-10% methanol in DCM solution as the eluent to obtain the title compound as a pale yellow solid (0.005 g, 20%).

[0290] 1 H NMR (400 MHz, DMSO-d6): δ 13.33 (s, 1H), 9.61(d, J = 2 Hz, 1H), 8.97 (s, 1H), 8.68 (bs, 1H), 8.25 (d, J = 7.6 Hz, 1H), 8.11(d, J = 8.8 Hz,2H), 7.30-7.44(m, 6H), 7.21 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 7.6 Hz, 2H), 6.16 (d, J = 9.2 Hz, 1H), 5.11 (bs, 1H), 4.91 (m, 1H), 4.38-4.58 (m, 5H),4.27 (m, 1H), 3.55-3.78 (m, 2H), 3.47 (m, 1H), 2.45 (s, 3H), 2.22-2.30 (m,1H), 2.01-2.09 (m, 1H), 1.71-1.79 (m, 1H), 1.33- 1.40 (m, 3H), 0.97 (m, 3H), 0.83 (m, 3H); LC-MS: 789.3. Example 14: (2S,4R)-4-hydroxy-1-(2-(3-(3-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)propoxy)isoxazo-5-yl)-3-methylbutyryl)-N-((S)-1-(4-(4-methylthiazo-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 43, racemic)

[0291] Compound 43 was prepared by appropriately changing the reactants, reagent amounts, protecting and deprotecting agents, solvents, and reaction conditions, similar to the method described in Example 13.

[0292] 1 H NMR (400 MHz, DMSO-d6): δ 13.33(s, 1H), 9.59(m, 1H), 8.97(m, 1H),8.67 (bs, 1H), 8.24 (d, J = 8 Hz, 1H), 8.06-8.10 (m, 2H), 7.30-7.44 (m, 6H),7.15-7.19 (m, 2H), 6.99-7.03 (m, 2H), 6.10 (d, J = 4 Hz, 1H), 5.12 (bs, 1H),4.90 (m, 1H), 4.32-4.36 (m, 3H), 4.20-4.24 (m, 3H), 3.64 (m, 2H), 3.44-3.50(m, 1H), 2.45 (m, 3H), 2.22 (m, 3H), 2.01 (m, 1H), 1.75 (m, 1H), 1.35-1.38(m, 3H), 0.95-096 (m, 3H), 0.78-0.84 (m, 3H): LC-MS: m / z 803.7 (M+H). Example 15: (2S,4R)-4-hydroxy-1-(2-(3-(2-((4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)(methyl)amino)ethoxy)isoxazo-5-yl)-3-methylbutyryl)-N-((S)-1-(4-(4-methylthiazo-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 44, racemic)

[0293] Compound 44 was prepared by appropriately changing the reactants, reagent amounts, protecting and deprotecting agents, solvents, and reaction conditions, similar to the method described in Example 13.

[0294] 1H NMR (400 MHz, DMSO-d6): δ 13.66 (d, J = 4.8 Hz, 1H), 9.56 (dd, J =5.6Hz, 2.0Hz, 1H), 8.98 (d, J = 5.6Hz, 1H), 8.58 (brs, 1H), 8.26-8.17 (m,3H), 8.01-7.97 (m, 2H), 7.43-7.28 (m, 4H), 7.02-6.90 (m, 2H), 6.07 (d, J =3.2Hz, 1H), 5.10-5.08 (m, 1H), 5.80-5.74 (m, 1H), 4.37-4.33 (m, 2H), 3.86-3.84 (m, 2H), 3.65-3.59 (m, 3H), 3.32-3.10 (m, 2H), 2.45 (s, 3H), 2.26-2.21(m, 1H), 2.04-2.00 (m, 1H), 1.78-1.74 (m, 1H), 1.43-1.31 (m, 4H), 0.95-0.93(m, 2H), 0.81-0.77 (m, 3H). LC-MS: m / z 802.4 (M+H). Example 16: (2S,4R)-4-hydroxy-1-((S)-2-(2-(4-((4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)amino)piperidin-1-yl)acetamyl)-3,3-dimethylbutyryl)-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 45)

[0295] Compound 45 Step i: Synthesis of 4-(6-chloropyridazine-4-yl)aniline K₂CO₃ (4.28 g, 31.02 mmol) was added to a stirred solution of 5-bromo-3-chloropyridazine (2 g, 10.3 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)aniline (2.49 g, 11.3 mmol) in 1,4-dioxane (40 mL) and water (4 mL), and the mixture was degassed with nitrogen for 15 min. Pd(dppf)Cl₂·DCM (0.84 g, 1.03 mmol) was added, and the reaction mixture was heated in a sealed tube at 100 °C for 16 h. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and salt water, dried with anhydrous sodium sulfate and concentrated under vacuum to obtain the residue, which was purified by Combiflash column chromatography using a hexane solution of 40% ethyl acetate as the eluent to give the title compound as a light brown solid (0.7 g, 33%). 1 H NMR (400 MHz, CDCl3): δ 9.57 (d, J = 2 Hz, 1H), 8.06 (d, J = 2 Hz, 1H), 7.79 (d, J = 8.8 Hz, 2H), 6.71 (d, J = 8.8Hz, 2H), 5.92 (bs, 2H); LC-MS: m / z 206.1 (M+H). Step ii: Synthesis of tert-butyl 4-((4-(6-chloropyridazine-4-yl)phenyl)amino)piperidine-1-carboxylic acid Acetic acid (0.05 mL) was added to a stirred ethanol (10 mL) solution of 4-(6-chloropyridazin-4-yl)aniline (0.5 g, 2.43 mmol) and 4-oxopiperidin-1-carboxylic acid tert-butyl ester (0.96 g, 4.86 mmol) and stirred at RT for 2 h. Sodium cyanoborohydride (0.96 g, 4.86 mmol) was then added to the reaction mixture and stirred at RT for 12 h (new spots formed on TLC). The concentrated reaction mixture under reduced pressure was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a residue, which was purified by Combiflash column chromatography using a hexane solution of 40% ethyl acetate as eluent to give the title compound as a yellow solid (0.2 g, 21%).

[0296] 1 H NMR (400 MHz, CDCl3): δ 9.59 (d, J = 2 Hz, 1H), 8.07 (d, J= 2 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H), 6.76 (d, J = 8.8 Hz, 2H), 6.37 (d, J = 8.8 Hz, 1H), 3.93(m, 2H), 3.58 (m, 1H), 2.97 (bs, 2H), 1.94 (m, 2H), 1.44 (s, 9H), 1.30 (m,2H),; LC-MS: m / z 389.2 (M+H). Step iii: Synthesis of N-(4-(6-chloropyridazin-4-yl)phenyl)piperidine-4-amine hydrochloride At 0 °C, dioxane hydrochloride (1 mL) was added to a stirred solution of 0.1 g (0.25 mmol) of tert-butyl 4-((4-(6-chloropyridazin-4-yl)phenyl)amino)piperidine-1-carboxylic acid tert-butyl ester (DCM) in 1 mL, and the solution was slowly brought to RT and stirred at RT for 1 h. The reaction mixture was evaporated under reduced pressure, the residue was washed with diethyl ether, and dried under vacuum to give the title compound as a faint red solid (0.08 g, 95%). 1 H NMR (400 MHz, CDCl3): δ 9.61 (d, J = 2 Hz, 1H),8.84 (bs, 1H), 8.76 (bs, 1H), 8.01 (d, J = 2 Hz, 1H), 7.86 (d, J = 8.8 Hz, 2H), 6.79 (d, J = 8.8 Hz, 2H), 3.72 (m, 1H), 3.32 (m, 2H), 3.03 (m, 2H), 2.09 (m,2H), 1.65 (m, 2H); LC-MS: m / z 289.1 (M+H). Step-iv: Synthesis of 2-(4-((4-(6-chloropyridazin-4-yl)phenyl)amino)piperidin-1-yl)tert-butyl acetate Under RT, DIPEA (0.16 g, 1.23 mmol) was added to a stirred DMF (2 mL) solution of N-(4-(6-chloropyridazin-4-yl)phenyl)piperidine-4-amine hydrochloride (0.08 g, 0.24 mmol) and stirred for 15 min. Then, tert-butyl 2-bromoacetate (0.06 g, 0.295 mmol) was added, and the mixture was stirred for 2 h under RT and a nitrogen atmosphere. The reaction mixture was quenched with cold water and stirred for 1 h. The solid thus formed was filtered and dried under vacuum to give the title compound as a brown solid (0.08 g, 80%).

[0297] 1 H NMR (400 MHz, CDCl3): δ 9.58 (d, J = 2 Hz, 1H), 8.06 (d, J = 2 Hz, 1H), 7.83 (d, J = 8.8 Hz, 2H), 6.74 (d, J = 8.8 Hz, 2H), 6.36 (d, J = 8.8 Hz, 1H), 4.59(m, 1H), 3.95 (m, 1H), 3.74 (m, 1H), 3.14 (s, 2H), 2.85 (m, 2H), 2.36 (m,2H), 1.93 (m, 2H), 1.47 (s, 9H); LC-MS: m / z 403.3 (M+H). Step v: 2-(4-((4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)amino)piperidin-1-yl)tert-butyl acetate Ester Synthesis To a stirred solution of tert-butyl 2-(4-((4-(6-chloropyridazin-4-yl)phenyl)amino)piperidin-1-yl)acetate (0.08 g, 0.199 mmol), 2-hydroxyphenylboronic acid (0.04 g, 0.298 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL), K₂CO₃ (0.08 g, 0.59 mmol) was added, and the mixture was degassed with nitrogen for 10 min. Pd(dppf)Cl₂·DCM (0.016 g, 0.02 mmol) was added, and the reaction mixture was heated in a sealed tube at 110 °C for 16 h. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and salt water, dried with anhydrous sodium sulfate and concentrated under vacuum to obtain the residue, which was purified by Combiflash column chromatography using a hexane solution of 40% ethyl acetate as the eluent to give the title compound as a pale yellow solid (0.04 g, 43%).

[0298] 1 H NMR (400 MHz, DMSO-d6): δ 13.73 (s, 1H), 9.54 (d, J = 2 Hz, 1H), 8.57 (d, J = 2 Hz, 1H), 8.27 (d, J = 8.8 Hz, 1H), 7.94 (d, J = 8.8 Hz, 2H), 7.42(m, 1H), 7.04 (m, 2H), 6.78 (d,J = 8.8 Hz, 2H), 6.31 (d, J LC-MS: m / z 461.3 (M+H). Step vi: 2-(4-((4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)amino)piperidin-1-yl)acetic acid hydrochloric acid Salt synthesis At 0°C, the stirring... 2-(4-((4-(6-(2-hydroxyphenyl)pyridazine-4-yl)phenyl)amino)piperidine-1- tert-butyl acetate 0.4 mL of 4N dioxane hydrochloride was added to a 1 mL solution of DCM (0.04 g, 0.48 mmol), and the solution was slowly brought to RT and stirred at RT for 16 h. The reaction mixture was evaporated under reduced pressure, and the residue was washed with diethyl ether and dried under vacuum to give the title compound as an orange solid (0.04 g, crude).

[0299] 1 H NMR (400 MHz, DMSO-d6): δ 10.28 (s, 1H), 9.68 (d, J = 2 Hz, 1H), 8.66 (d, J = 2 Hz, 1H), 8.06 (d, J = 8.4 Hz, 2H), 7.49 (m, 1H), 7.05-7.15 (m,2H), 6.91 (m, 2H), 4.18 (bs, 2H), 3.65 (m, 2H), 3.15 (s, 2H), 3.25 (m, 2H),2.17 (m, 2H), 1.95 (m, 2H); LC-MS: m / z 405.2 (M+H). Step vii: (2S,4R)-4-hydroxy-1-((S)-2-(2-(4-((4-(6-(2-hydroxyphenyl)pyridazine-4-yl)benzene) (S)-1-(4-(4-methylthiazolyl-5-yl)benzene Synthesis of 2-carboxamide (ethyl)pyrrolidine-2-carboxamide At 0 °C, HATU (0.04 g, 0.11 mmol) was added to a DMF (2 mL) solution of 2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)amino)piperidin-1-yl)acetic acid hydrochloride (0.03 g, 0.074 mmol) and ((2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.04 g, 0.089 mmol) h. The reaction mixture was then poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and salt water, dried over anhydrous sodium sulfate and concentrated under vacuum to give a crude product, which was purified by Combiflash chromatography using 8-10% methanol in DCM solution as eluent to give the title compound as a yellow solid (0.018 g, 29%).

[0300] 1H NMR (400 MHz, DMSO-d6): δ 13.72 (s, 1H), 9.55 (d, J = 2.0 Hz, 1H), 9.02 (s, 1H), 8.56 (d, J = 2.0 Hz, 1H), 8.45 (d, J = 2.0 Hz, 1H), 8.34 (s,1H), 7.95 (d, J = 8.8 Hz, 2H), 7.96 (s, 1H), 7.48-7.39 (m, 5H), 7.05-7.02 (m,2H), 6.80 (d, J = 8.8 Hz, 2H), 6.40 (d, J = 12.0 Hz, 1H), 5.17 (d, J = 3.6Hz, 1H), 4.98-4.81 (m, 1H), 4.79-4.70 (m, 1H), 4,59-4.43 (m, 1H), 4.32-4.21(m, 1H), 3.72-3.61 (m, 2H), 3.36 (s, 1H), 3.26-3.09 (m, 2H), 3.01-2.81 (m,2H), 2.49 (s, 3H), 2.46-2.22 (m, 2H), 2.19-1.92 (m, 3H), 1.85-1.72 (m, 1H),1.61-1.50 (m, 2H), 1.42 (d, J = 6.8 Hz, 3H), 0.99 (s, 9H). LC-MS: m / z 831.5 (M+H). Example 17: (2S,4R)-4-hydroxy-1-((S)-2-(2-(4-((4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)(methyl)amino)piperidin-1-yl)acetamyl)-3,3-dimethylbutyryl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 46)

[0301] Compound 46 was prepared by appropriately changing the reactants, reagent amounts, protecting and deprotecting agents, solvents, and reaction conditions, similar to the method described in Example 16.

[0302] 1H NMR (400 MHz, DMSO-d6): δ 13.69 (s, 1H), 9.56-9.54 (m, 1H), 8.98(s, 1H), 8.57-8.49 (m, 1H), 8.50-8.41 (m, 1H), 8.39-827 (m, 1H), 7.99 (d, J =12.0 Hz, 2H), 7.80-7.72 (m, 1H), 7.45-7.39 (m, 2H), 7.38-7.36 (m, 3H), 7.02-6.95 (m, 4H), 5.13-5.01 (m, 1H), 4.91-4.82 (m, 1H), 4.54 (s, 1H), 4.49-4.31(m, 1H), 4.29-4.10 (m, 1H), 3.90-3.81 (m, 1H), 3.58 (s, 2H), 3.09 (s, 1H),2.99 (s, 2H), 2.87 (s, 3H), 2.50-2.49 LC-MS: m / z 845.3 (M+H). Example 18: (2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(4-(6-hydroxypyridazin-4-yl)phenyl)piperazin-1-yl)acetamyl)-3,3-dimethylbutyryl)-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 47)

[0303] Step-i: (2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(4-(6-hydroxypyridazine-4-yl)phenyl)piperazine-1- (S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine- Synthesis of 2-formamide To a stirred solution of (2S,4R)-1-((S)-2-(2-(4-(4-(6-chloropyridazin-4-yl)phenyl)piperazin-1-yl)acetamyl)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl)phenyl)ethyl)pyrrolidine-2-carboxamide (0.2 g, 0.26 mmol) in 1,4-dioxane (4 mL) and water (0.5 mL), K₂CO₃ (0.07 g, 0.52 mmol) was added, and the mixture was degassed with nitrogen for 5 min. Pd(dppf)Cl₂·DCM (0.02 g, 0.02 mmol) was added, and the reaction mixture was microwaved at 120 °C for 1 h. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and salt water, dried with anhydrous sodium sulfate, concentrated under vacuum, and the residue was purified by preparative HPLC to obtain the title compound as a pale yellow solid (10 mg, 5%).

[0304] 1 H NMR (400 MHz, DMSO-d6): δ 12.9 (s, 1H), 8.98 (s, 1H), 8.44 (d, J =7.6 Hz, 1H), 8.30 (d, J = 7.6 Hz, 1H), 7.71-7.79 (m, 2H), 7.33-7.45 (m, 4H),7.06 (d, J = 8.8 Hz, 2H), 7.01 (bs, 1H), 5.13 (d, J = 3.2 Hz, 1H), 4.88 (t, J= 8 Hz, 1H), 4.52 (d, J = 9.6 Hz, 1H), 4.44 (t, J = 8.4 Hz, 1H), 4.28 (bs, 1H), 3.59 (bs, 2H), 3.35 (m, 4H), 3.14 (d, J = 16hz, 1H), 3.02 (d, J = 16hz,1H), 2.64 (m, 4H), 2.45 (s, 3H), 2.03 (m, 1H), 1.76 (m, 1H), 1.36 (d, J = 7.2Hz, 3H), 0.9 (s, 9H); LC-MS: m / z 741.3 (M+H). Example 19: (2S,4R)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)-1-((S)-2-(2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetamyl)-3,3-dimethylbutyryl)pyrrolidine-2-carboxamide (Compound 48)

[0305] Step -i: (2S,4R)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)- 1-((S)-2-(2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetamyl)-3,3-dimethyl Synthesis of (butyryl)pyrrolidine-2-carboxamide At 0 °C, HATU (0.19 g, 0.51 mmol) was added to a DMF (5 mL) solution of 2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetic acid (0.13 g, 0.411 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-(2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.17 g, 0.34 mmol) followed by dropwise addition of DIPEA (0.2 mL, 1.02 mmol). The reaction mixture was stirred at RT for 4 h. The reaction mixture was then poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and salt water, dried with anhydrous sodium sulfate and concentrated under vacuum to obtain a crude product, which was purified by Combiflash column chromatography using 5% methanol DCM solution as eluent to obtain the title compound as a yellow solid (10 mg, 3.5%).

[0306] 1H NMR (400 MHz, DMSO-d6): δ 13.54 (bs, 1H), 9.59 (d, J = 2 Hz, 1H), 8.98 (s, 1H), 8.63 (d, J = 2 Hz, 1H), 8.46 (d, J = 8 Hz, 1H), 8.26 (d, J =7.2 Hz, 1H), 8.03 (d, J = 8.8 Hz, 2H), 7.80 (d, J = 9.6 Hz, 2H), 7.36-7.44(m, 5H), 7.15 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8 Hz, 2H), 5.15 (d, J = 2.8Hz, 1H), 4.80-4.86 (m, 2H), 4.47-4.54 (m, 2H), 4.29 (bs, 1H), 3.52-3.65 (m,4H), 3.40 (m, 4H), 3.16 (d, J = 16hz, 1H), 3.04 (d, J = 16hz, 1H), 2.67 (m,4H), 2.46 (s, 3H), 2.08 (m, 1H), 1.79 (m, 1H), 0.96 (s, 9H). LC-MS: m / z833.4. Example 20: (2S,4R)-N-(2-(dimethylamino)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)-4-hydroxy-1-((S)-2-(2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetamyl)-3,3-dimethylbutyryl)pyrrolidine-2-carboxamide (Compound 49)

[0307] Compound 49 Compound 49 was prepared by appropriately changing the reactants, reagent amounts, protecting and deprotecting agents, solvents, and reaction conditions, similar to the method described in Example 15.

[0308] 1H NMR (400 MHz, DMSO-d6): δ 13.53 (s, 1H), 9.58 (d, J = 2.0 Hz, 1H), 8.98-8.96 (m, 1H), 8.62 (s, 1H), 8.32-8.24 (m, 1H), 8.03 (t, J = 3.2 Hz, 2H),7.78-7.75 (m, 2H), 7.43-7.33 (m, 5H), 7.15 (t, J = 6.4 Hz, 2H), 7.02 (t, J =6.4 Hz, 2H), 5.13-5.05 (m, 1H), 4.51-4.47 (m, 1H), 4.32-4.18 (m, 1H), 3.58-3.39 (m, 3H), 3.14-3.00 (m, 3H), 2.67-2.64 (m, 6H), 2.46 (s, 5H), 2.16-2.10(m, 8H), 1.80 (s, 1H), 1.75-1.71 (m, 1H), 0.95 (s, 9H). LCMS: 860.7 (M+H). Example 21: (2S,4R)-4-hydroxy-1-(2-(3-(2-((4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)amino)ethoxy)isoxazo-5-yl)-3-methylbutyryl)-N-((S)-1-(4-(4-methylthiazo-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 50, racemic)

[0309] Compound 50 Compound 50 was prepared by appropriately changing the reactants, reagent amounts, protecting and deprotecting agents, solvents, and reaction conditions, similar to the method described in Example 13.

[0310] 1H NMR (400 MHz, DMSO-d6): δ 13.68 (br, 1H), 9.52 (brs, 1H), 8.96 (d,J = 5.6 Hz, 1H), 8.55 (s, 1H), 8.42-8.35 (m, 1H), 8.26-8.24 (m, 1H), 7.95-7.91 (m, 2H), 7.42-7.32 (m, 4H), 7.01 (d, J = 7.6 Hz, 2H), 6.55-6.52 (m, 2H), 6.63 (m, 1H), 6.11 (d, J = 1.6 Hz, 1H), 5.10 (d, J = 3.2 Hz, 1H), 4.92-4.87(m, 1H), 4.45-4.26 (m, 4H), 3.77-3.58 (m, 2H), 3.53 (br, 2H), 3.47-3.42 (m,1H), 2.45 (d, J = 4.4 Hz, 3H), 2.28-2.23 (m, 1H), 2.06-1.98 (m, 1H), 1.80-1.76 (m, 1H), 1.45-1.43 (m, 1H), 1.38-1.32 (m, 3H), 0.97-0.94 (m, 3H), 0.83-0.79 (m, 3H). LCMS: 786.2 (M-1). Example P1: via Cell TiteRglo ® (Promega) assay to determine the antiproliferative activity of compounds in cell line A549 A549 (ATCCCCL-185) cells were seeded in 96-well plates with a flat black transparent base (Corning, catalog number 3904) using complete F-12K medium. The next day, the compounds of the present invention were added to cells from a 10 mM stock solution prepared in DMSO (Sigma catalog number D2650). The concentration of each compound was tested in triplicate, with the final percentage of DMSO in the cells not exceeding 0.3%. After incubation with the compounds (8 days for A549), the cells were inoculated with 50 μl of CellTiteRGlo. ® The assay was terminated with the reagent (Promega, catalog number G7572). Quantification was performed based on the presence of ATP via CellTiter-Globe assay. ®The luminescent reagent was used to determine the number of viable cells, and ATP quantification is an indicator of cell number and metabolic activity. The luminescence readings were taken using a Victor-3 instrument. The percentage inhibition of proliferation was calculated using the formula: %inhibition = 100 - (tested luminescence value / DMSO control luminescence value) * 100. DMSO control (0%) = cells in complete culture medium containing DMSO; blank = culture medium containing only DMSO. IC50 was calculated using GraphPad Prism software. 50 .

[0311] From the experiments described in Example P1, the IC of the compound selected in this invention was found to be... 50 The value is less than 1 μM.

[0312] Example P2: Degradation of SMARCA2 and SMARCA4 in VCaP cells determined by Western blotting VCaP (ATCCCRL-2876) was seeded in 6-well plates using Dulbecco's Modified Eagle's Medium. On day 3, the compounds of this invention were added to cells from a 10 mM stock solution prepared in DMSO (Sigma, catalog number D2650). The concentration of each compound was tested, with the final percentage of DMSO in the cells not exceeding 0.3%. Cells were cultured with the compounds for 16 hours, and then harvested using 1X RIPA lysis buffer (Thermo Fischer, catalog number #89900) containing a mixture of protease inhibitors (Sigma, catalog number #P-8340). Equal volumes of protein were loaded onto an SDS-PAGE gel for electrophoresis. Western blotting was performed to detect SMARCA2 (Cell Signalling Technologies, catalog number #11966) or SMARCA4 antibody (Cell Signalling Technologies, catalog number #52251). β-tubulin antibody (Cell Signaling Technologies, catalog number #86298) was used as a loading control. The percentage of SMARCA2 or SMARCA4 degradation was calculated using the formula: %degradation = 100 - (normalized band intensity in the treated sample / normalized band intensity in the DMSO sample) * 100.

[0313]

[0314] Example P3: via Cell Titer Glo ® (Promega) assay determined the antiproliferative activity of the compound. Cells were seeded into 96-well plates and incubated overnight at 37°C. The next day, the compound was diluted 3-fold to cover the 9-point concentration range in DMSO. Intermediate plate dilutions were prepared in culture medium, followed by cell treatment with the compound. Cells were retreated with the compound dilutions on day 4, and the SK-MEL-5 cell assay was terminated on day 8 with CellTiter-Glo, and the plates were held at RT for 20 minutes on a track-shaker. On day 6, no further compound treatment was performed, and the RERF-LC-A1 assay was terminated. (VICTOR) 3 The instrument records the luminescence signal. The percentage of proliferation inhibition at each concentration is calculated, and a graph showing the relationship between the percentage of proliferation inhibition and the compound concentration is plotted. EC is calculated using GraphPad software. 50 value.

[0315] In the above determination of EC 50 The selected compounds of this invention were screened using the (SK-MEL-5) value test method, and the results are summarized in groups A, B, and C of the table below. Here, group "A" refers to EC 50 Values ​​below 250 nM, group "B" refers to EC 50 Values ​​between 250.01 nM and 500 nM (inclusive), and group "C" refers to EC. 50 The value is greater than 500 nM.

[0316]

[0317] Furthermore, the RERF-LC-A1 cell line data for the compounds selected in this invention are summarized in the table below. Here, group "++" refers to EC 50 (RERF-LC-A1) values ​​below 100 nM, and group "+" indicates EC 50 The (RERF-LC-A1) value is greater than 100 nM.

[0318] .

Claims

1. Compound of formula (I): Or its pharmaceutically acceptable salts or stereoisomers; in, A represents a 5- to 6-membered heteroarylene or a 6-membered arylene; wherein the arylene and heteroarylene are replaced by 1, 2 or 3 Ra; Ra is hydrogen, halogen, or (C1-C6) alkyl; R1 is a halogen, (C1-C6)alkyl, hydroxyl, 6-to-10-aryl or 5-to-10-heteroaryl; wherein the aryl and heteroaryl are optionally substituted by one, two or three groups independently selected from hydroxyl, halogen, (C1-C6)alkyl and halo(C1-C6)alkyl; R2 is hydrogen or halogen; L is a chemical bond, -O-(CH2)p-, -O-(CH2)pO-, -NRx-(CH2)p-, -NRx-(CH2)pO-, -NRx-(CH2)pC≡C-, -NRx-(3-to-10-membered heterocycloalkylene)-(CRxRy)n-, -(3-to-10-membered heterocycloalkylene)-(CRxRy)n-, -(3-to-10-membered heterocycloalkylene)-(CRxRy)n-, or -O-(3-10-membered heterocycloalkylene)-(CRxRy)n-; wherein the cycloalkylene and heterocycloalkylene are substituted by 1, 2, or 3 Rds; and wherein the left side of L is connected to A, and the right side of L is connected to M; Rd is independently selected from hydrogen, hydroxyl and (C1-C6) alkyl in each occurrence; Rx and Ry are independently selected from hydrogen, (C1-C6) alkyl and halogen each time they appear; M is selected from M-1 and M-2: or ; in, Z is a 5- to 6-membered heteroarylene, which is optionally substituted by 1, 2 or 3 groups independently selected from hydroxyl, halogen and (C1-C6) alkyl; R3 and R8 independently represent (C1-C6) alkyl or halo(C1-C6) alkyl; R4 and R9 independently represent hydrogen or (C1-C6) alkyl; R5, R6, R 10 and R 11 Independently representing hydrogen, (C1-C6)alkyl, hydroxy(C1-C6)alkyl or amino(C1-C6)alkyl; wherein the amino(C1-C6)alkyl is optionally substituted with one or two substituents selected from (C1-C6)alkyl and -COCH3; R7 and R 12 This indicates a thiazolyl group that has been substituted with a methyl group; p is an integer selected from 1, 2, 3, and 4; and n is an integer selected from 0, 1, 2, and 3.

2. The compound according to claim 1, wherein R1 is a halogen, hydroxyl, 6- to 10-aryl, or 5- to 10-heteroaryl; wherein the aryl and heteroaryl are optionally substituted by one or two groups independently selected from (C1-C6)alkyl, hydroxyl, halogen, and halo(C1-C6)alkyl.

3. The compound according to claim 1, wherein R1 represents a phenyl group, which is optionally substituted by one or two groups independently selected from hydroxyl, (C1-C6)alkyl, halo(C1-C6)alkyl and halogen.

4. The compound according to claim 1, wherein R1 represents a 5- to 10-membered heteroaryl group, which is optionally substituted by one, two or three groups independently selected from (C1-C6)alkyl, hydroxyl, halogen and halo(C1-C6)alkyl.

5. The compound according to claim 1, wherein R1 represents... , , , , or Each ring is optionally substituted by one, two, or three groups independently selected from hydroxyl, (C1-C6)alkyl, halo(C1-C6)alkyl, and halogen.

6. The compound according to claim 1, wherein R2 represents hydrogen.

7. The compound according to claim 1, wherein A represents a phenylene substituted with one or two Ra atoms.

8. The compound according to claim 1, wherein A represents a 5- to 6-membered heteroaryl group substituted by one or two Ra groups.

9. The compound according to claim 1, wherein A represents phenylene, furanyl, thiopheneyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazoleyl, oxadiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl or 1,3,5-triazinyl; wherein each group is substituted by one or two substituents selected from hydrogen, halogen, or (C1-C6) alkyl.

10. The compound according to claim 1, wherein A represents... , , , , , or Each ring is optionally replaced by one or two Ra rings; and the left side of the ring is connected to the pyridazine ring, and the right side of the ring is connected to L.

11. The compound according to claim 1, wherein L is a chemical bond, -O-(CH2)p-, -O-(CH2)pO-, -NRx-(CH2)p-, -NRx-(CH2)pO-, -NRx-(3- to 10-membered heterocyclic alkylene)-(CRxRy)n-, (3- to 10-membered heterocyclic alkylene)-(CRxRy)n-, (3- to 10-membered heterocyclic alkylene)-(CRxRy)n- or -O-(3- to 10-membered heterocyclic alkylene)-(CRxRy)n-; wherein the cycloalkylene and heterocyclic alkylene are substituted by one or two Rds.

12. The compound according to claim 11, wherein L is a chemical bond, -O-CH2-, -O-CH2CH2-, -O-CH2CH2CH2-, -O-CH2CH2CH2CH2-, -O-CH2O-, -O-CH2CH2-O-, -O-CH2CH2CH2-O-, -O-CH2CH2CH2CH2-O-, -NH-CH2-, -NH-CH2CH2-, -NH-CH2CH2CH2-, -NH-CH2CH2CH2CH2-, -N(CH3)-CH2-, -N(CH3)-CH2CH2-, -N(CH3)-CH2CH2CH2-, -N(CH3)-CH2CH2CH2CH2-, -NH-CH2-O-, -NH-CH2CH2-O-, -NH-CH2CH2CH2-O-, -NH-CH2CH2CH2CH2-O-, -NH-CH2CH2CH2CH2-O-, -N(CH3)-CH2-O-, -N(CH3)-CH2CH2-O-, -N(CH3)-CH2CH2CH2-O-, or -N(CH3)-CH2CH2CH2CH2-O-.

13. The compound according to claim 11, wherein the heterocyclic alkyl group is selected from piperidinyl, piperazineyl, azacyclobutane, pyrrolidinyl, tetrahydropyridinyl, diazobicyclooctyl, azabicyclooctyl, azaspiroheptyl, tetrahydropyranyl, tetrahydropyridazineyl, morpholinyl, thiomorpholinyl, 1,4-dioxane, dioxothiomorpholinyl, oxapirazineyl, oxapiridinyl, tetrahydropyranyl, dihydropyranyl, and dihydropyrimidinyl.

14. The compound of claim 11, wherein the cycloalkylene group is selected from cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, and cycloheptylene.

15. The compound according to claim 11, wherein L is -O-CH2-, -O-CH2CH2-, -O-CH2CH2CH2-, -O-CH2CH2CH2CH2-, -O-CH2O-, -O-CH2CH2-O-, -O-CH2CH2CH2-O-, -O-CH2CH2CH2CH2-O-, -NH-CH2-, -NH-CH2CH2-, -NH-CH2CH2CH2-, -NH-CH2CH2CH2CH2-, -N(CH3)-CH2-, - N(CH3)-CH2CH2-, -N(CH3)-CH2CH2CH2-, -N(CH3)-CH2CH2CH2CH2-, NH-CH2-O-, -NH-CH2CH2-O-, -NH-CH2CH2CH2-O-, -NH-CH2CH2CH2CH2-O-, -N(CH3)-CH2-O-, -N(CH3)-CH2CH2-O-, -N(CH3)-CH2CH2CH2-O-, -N(CH3)-CH2CH2CH2CH2-O-, , , , , , , , , , , , , , , , , or Each ring is replaced by one or two occurrences of Rd.

16. The compound according to claim 1, wherein M is M-1; wherein R3 indicates (C1-C6) alkyl or halo(C1-C6) alkyl; R4 represents hydrogen or (C1-C6) alkyl; R5 and R6 independently represent hydrogen, (C1-C6)alkyl, halogen, hydroxy(C1-C6)alkyl or ((C1-C6)alkyl)amino(C1-C6)alkyl; and R7 represents a thiazolyl group substituted with a methyl group.

17. The compound according to claim 16, wherein M-1 is represented by formula M-1A: 。 18. The compound according to claim 17, wherein M-1A is represented by the following formula: ； in, R4 is selected from hydrogen and (C1-C6) alkyl groups; and R6 is selected from hydrogen, hydroxy(C1-C6)alkyl, ((C1-C6)alkyl)amino(C1-C6)alkyl-, and (C1-C6)alkyl.

19. The compound according to claim 18, wherein M-1A is represented by the following formula: 、 。 20. The compound according to claim 1, wherein M is M-2; wherein Z is an imoxazolyl group or an isoxazolyl group; R8 indicates (C1-C6) alkyl or halo(C1-C6) alkyl; R9 indicates hydrogen or (C1-C6) alkyl; R 10 and R 11 Independently representing hydrogen, (C1-C6)alkylhydroxy(C1-C6)alkyl or ((C1-C6)alkyl)amino(C1-C6)alkyl-; and R 12 This indicates a thiazolyl group that has been substituted with a methyl group.

21. The compound according to claim 20, wherein M-2 is represented by the following formula: ； R9 represents hydrogen; and R 11 Independently represents hydrogen or (C1-C6) alkyl.

22. The compound according to claim 1, represented by a compound of formula (IA): 。 23. The compound of claim 22, wherein R1 represents a halogen, a hydroxyl group, a 6- to 10-aryl group, or a 5- to 10-heteroaryl group; wherein the aryl and heteroaryl groups are optionally substituted by one or two groups independently selected from (C1-C6) alkyl, hydroxyl, and halogen groups.

24. The compound according to claim 22, wherein R1 represents -Cl, -OH, , , , , or Each ring is optionally substituted by one, two, or three groups independently selected from (C1-C6) alkyl, hydroxyl, halogen, and halo(C1-C6) alkyl groups.

25. The compound according to claim 22, wherein L is a chemical bond, -O-(CH2)p-, -O-(CH2)pO-, -NRx-(CH2)p-, -NRx-(CH2)pO-, -NRx-(3- to 10-membered heterocyclic alkylene)-(CRxRy)n-, (3- to 10-membered heterocyclic alkylene)-(CRxRy)n-, (3- to 10-membered heterocyclic alkylene)-(CRxRy)n- or -O-(3- to 10-membered heterocyclic alkylene)-(CRxRy)n-.

26. The compound according to claim 22, wherein L is -O-CH2-CH2CH2-, -O-CH2CH2CH2CH2-, -O-CH2CH2-O-, -O-CH2CH2CH2-O-, -NH-CH2CH2CH2CH2-, -N(CH3)-CH2CH2-O-, -N(CH3)-CH2CH2CH2CH2-, -NH-CH2CH2-O-, , , , , , , , , , , , , , , , , , or Each ring is replaced by one or two occurrences of Rd.

27. The compound according to claim 22, wherein M represents... , or .

28. The compound according to claim 22, wherein... R1 is -Cl, -OH, , , , , or Each ring is optionally substituted by one, two, or three groups independently selected from (C1-C6) alkyl, hydroxyl, halogen, and halo(C1-C6) alkyl groups; R2 is hydrogen or halogen; Ra is hydrogen or halogen; L is -O-CH2CH2CH2-, -O-CH2CH2CH2CH2-, -O-CH2CH2-O-, -O-CH2CH2CH2-O-, -NH-CH2CH2CH2CH2-, -N(CH3)-CH2CH2-O-, -N(CH3)-CH2CH2CH2CH2-, -NH-CH2CH2-O-, , , , , , , , , , , , , , , , , , or Each ring is replaced by one or two occurrences of Rd; M represents , or .

29. The compound according to claim 1, wherein the compound is represented by a compound of formula (IB): 。 30. The compound according to claim 29, wherein R1 represents -Cl, -OH, , , , , or Each ring is optionally substituted by one or two groups independently selected from (C1-C6) alkyl, hydroxyl and halogen groups.

31. The compound according to claim 29, wherein L is a chemical bond, -O-(CH2)p-, -O-(CH2)pO-, -NRx-(CH2)p-, -NRx-(CH2)pO-, -NRx-(3- to 10-membered heterocyclic alkylene)-(CRxRy)n-, (3- to 10-membered heterocyclic alkylene)-(CRxRy)n-, (3- to 10-membered heterocyclic alkylene)-(CRxRy)n- or -O-(3- to 10-membered heterocyclic alkylene)-(CRxRy)n-.

32. The compound according to claim 29, wherein L is -O-CH2CH2CH2-, -O-CH2CH2CH2CH2-, -O-CH2CH2-O-, -O-CH2CH2CH2-O-, -NH-CH2CH2CH2CH2-, -N(CH3)-CH2CH2-O-, -N(CH3)-CH2CH2CH2CH2-, -NH-CH2CH2-O-, , , , , , , , , , , , , , , , , , or Each ring is replaced by one or two occurrences of Rd.

33. The compound according to claim 29, wherein... R1 represents -Cl, -OH, , , , , or Each ring is optionally substituted by one or two groups independently selected from (C1-C6) alkyl, hydroxyl and halogen groups; R2 is hydrogen or halogen; Ra is hydrogen or halogen; L is -O-CH2CH2CH2-, -O-CH2CH2CH2CH2-, -O-CH2CH2-O-, -O-CH2CH2CH2-O-, -NH-CH2CH2CH2CH2-, -N(CH3)-CH2CH2-O-, -N(CH3)-CH2CH2CH2CH2-, -NH-CH2CH2-O-, , , , , , , , , , , , , , , , , , or Each ring is replaced by one or two occurrences of Rd; R3 indicates (C1-C6) alkyl; R4 represents hydrogen or (C1-C6) alkyl; R5 represents hydrogen; R6 represents (C1-C6)alkyl, hydroxy(C1-C6)alkyl, or ((C1-C6)alkyl)amino(C1-C6)alkyl; and R7 represents a thiazolyl group substituted with a methyl group.

34. The compound according to claim 1, wherein the compound is represented by a compound of formula (IC): ; Where X1 and X2 independently represent N or C.

35. The compound according to claim 34, wherein R1 is -Cl, -OH, , , , , or Each ring is optionally substituted by one or two groups independently selected from (C1-C6) alkyl, hydroxyl and halogen groups.

36. The compound of claim 34, wherein Rx is hydrogen; and Ry is hydrogen or (C1-C6) alkyl.

37. The compound according to claim 34, wherein M represents... 、 or .

38. The compound according to claim 34, wherein... X1 and X2 independently represent N or C; R1 is -Cl, -OH, , , , , or Each ring is optionally substituted by one or two groups independently selected from (C1-C6) alkyl, hydroxyl and halogen groups; R2 is hydrogen or halogen; Ra represents hydrogen or halogen; Rd is either hydrogen or hydroxyl; Rx is hydrogen; Ry is hydrogen or (C1-C6) alkyl; M represents 、 or ;as well as n can be 0, 1, 2, or 3.

39. The compound according to claim 1, represented by the compound of formula (ID). 。 40. The compound according to claim 39, wherein... R1 is a halogen, hydroxyl group, 6- to 10-aryl group, or 5- to 10-heteroaryl group; wherein... The aryl and heteroaryl groups are optionally substituted with hydroxyl, halogen, (C1-C6)alkyl, and halo(C1-C6)alkyl groups; R2 is hydrogen or halogen; Ra represents hydrogen or halogen; Rd is either hydrogen or hydroxyl; R3 represents (C1-C6)alkyl, (C1-C6)acyl, or halo(C1-C6)alkyl; R4 represents hydrogen or (C1-C6) alkyl; R5 represents hydrogen; R6 represents hydrogen, (C1-C6)alkyl, halogen, hydroxy(C1-C6)alkyl, or ((C1-C6)alkyl)amino(C1-C6)alkyl-; R7 is a thiazolyl group substituted with a methyl group; and n can be 0, 1, 2, or 3.

41. The compound according to claim 1, wherein the compound is selected from... Or its pharmaceutically acceptable salts or stereoisomers.

42. A pharmaceutical composition comprising the compound of any one of claims 1 to 41 or a pharmaceutically acceptable salt or stereoisomer thereof and a pharmaceutically acceptable carrier.

43. Use of the compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt or stereoisomer thereof, in the preparation of a medicament for treating SMARCA2-dependent cancers selected from non-small cell lung cancer, lung adenocarcinoma, melanoma, prostate cancer, and squamous cell carcinoma of the lung.

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