6-substituted pyridazine compounds as SMARCA2 and / or SMARCA4 degrading agents

Abstract

The present invention provides compounds for treating or slowing the progression of cancers that are dependent on SMARCA2 and / or SMARCA4. [Solution] In one embodiment, a compound represented by the following formula (IB), or a pharmaceutically acceptable salt or stereoisomer thereof, is provided. JPEG2026082834000126.jpg5382

Description

[Technical Field]

[0001] Related applications This application claims the benefits of Indian Provisional Patent Application No. 202041033326, filed on 4 August 2020, the specification of which is incorporated herein by reference in whole.

[0002] Technical field The present invention relates to 6-substituted pyridazine compounds, or pharmaceutically acceptable salts, stereoisomers, tautomers, or prodrugs thereof, which are useful as SMARCA2 and / or SMARCA4 degrading agents in the treatment of diseases or disorders dependent on SMARCA2 and / or SMARCA4. The present invention also relates to such pyridazine compounds and methods for preparing pharmaceutical compositions containing them. [Background technology]

[0003] One of the most significant findings from cancer genome profiling is the discovery that various subunits of the mammalian SWI / SNF (SWitch / Sucrose Non-Fermentable) chromatin remodeling complex frequently undergo mutations. Approximately 20% of human cancers are associated with somatic mutations in subunits of the SWI / SNF complex, a chromatin remodeling complex that influences gene regulation by disrupting histone DNA contact (PNAS February 25, 2014. 111(8)3128-3133).

[0004] The SWI / SNF complex contains either Brahma (BRM / SMARCA2) or Brahma-related gene 1 (BRG1 / SMARCA4), two closely related and evolutionarily conserved catalytic ATPase subunits. These share approximately 75% identity at the protein level. While the BRG1-containing and BRM-containing complexes exhibit some redundancy, they may function independently. In human cancers, BRG1 is considered one of the most frequently mutated subunit genes, while BRM genes rarely mutate. BRG1 / SMARCA4 mutations occur in approximately 10-15% of lung adenocarcinomas. BRM / SMARCA2 is essential for the growth of tumor cells with functional mutation loss in BRG1 / SMARCA4. When BRM deficiency occurs in cancer cells lacking BRG1, cell cycle arrest, induction of senescence, and an overall increase in H3K9me31 levels occur (PNAS February 25, 2014.111(8)3128-3133).

[0005] In some tumor types, mutations within the SWI / SNF complex create situation-specific vulnerabilities, such as SMARCA2 becoming necessary for the survival of tumor cells lacking SMARCA4. This finding regarding the synthetic lethal relationship between SMARCA2 / 4 is transposed in vivo, highlighting the potential of SMARCA2 as a therapeutic target in the treatment of SMARCA4-deficient cancers. Furthermore, since the patient population lacking SMARCA4 generally lacks targetable oncogenes (such as mutant EGFR or ALK translocations), the potential for further development of SMARCA2 inhibitors is emphasized. Characterization of SMARCA4 function in tumors with high SMARCA4 levels reveals effects on signaling pathways that enhance proliferation and survival. SMARCA4 knockdown in tumors exhibiting elevated levels is known to inhibit proliferation and other cancer cell characteristics. The study further demonstrated that knockdown / modification of SMARCA4 increased sensitivity to known chemotherapeutic agents, thus showing that targeting SMARCA4 can also be used as an adjuvant therapy to existing chemotherapy approaches (PNAS February 25, 2014.111(8)3128-3133;J Pathol.2016 Feb;238(3):389-400).

[0006] In contrast to SMARCA2 gene silencing, which elicits potent antiproliferative activity in cancer cell lines deficient in SMARCA4, PFI-3, a selective cell-permeable SMARCA2 / 4 bromodomain inhibitor capable of binding to the bromodomains of SMARCA2 and SMARCA4, fails to produce an antiproliferative phenotype indicating that SMARCA2 / 4 bromodomain function is unnecessary for tumor cell proliferation while catalytic ATPase activity is essential (Cancer Res. 2015 Sep 15;75(18):3865-3878). To mimic the phenotype obtained through gene silencing, approaches that reduce or completely eliminate SMARCA2 / 4 may be necessary.

[0007] The ubiquitin-proteasome system (UPS) is a major pathway that regulates intracellular protein levels, providing a delicate balance between protein synthesis and protein degradation necessary to maintain normal cellular functions, including proliferation, differentiation, and cell death. Ubiquitination is a post-translational modification in which the small protein ubiquitin is covalently bound to a lysine residue on a substrate protein, and is subsequently carried out through a cascade of enzymatic reactions involving close cooperation between E1 activating enzymes, E2 conjugation enzymes, and E3 ligation enzymes, followed by the degradation of the tagged 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] Chimeras targeting proteolysis are heterobifunctional molecules containing a ligand for a target protein of interest, which is linked to the ligand of an E3 ubiquitin ligase via a linker. During this bifunctional molecule-mediated heterodimerization of two binding proteins, 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 various substrates using high-affinity ligands for the target protein. Proteins effectively degraded using these approaches include RIPK2, ERRα, BRD4, BRD9, BCR / Abl, Abl, and Erα (Cell Chemical Biology 25, 1-10, January 18, 2018). E3 ubiquitin ligases (of which over 600 are known to exist in humans) offer substrate specificity for ubiquitination, making them more attractive therapeutic targets than common proteasome inhibitors due to their specificity for particular protein substrates.

[0009] Small molecule ligands targeting the bromodomains of SMARCA2 and SMARCA4 have been reported (Journal of Medicinal Chemistry 2016, 59, 4800-4811 by Gerstenberger et al.; PNAS 2014b, 777, 3128-3133 by Hoffman et al.; Journal of Medicinal Chemistry 59, 5095-5101, 2016 by Sutherell et al.; International Publication No. 2016138114). Cells lacking SMARCA4 activity are vulnerable to SMARCA2 loss (Hoffman et al. 2014a, PNAS 777, 3128-3133), but SMARCA2 / 4 inhibitors were unable to phenotypicly mimic these antiproliferative effects (Vangamudi et al., 2015). Accordingly, in SMARCA2 mutants within cells, endogenous protein production was suppressed, and the intact bromodomain was found not to be necessary for maintaining proliferation (Cancer Research 75, 3865-3878, 2015, by Vangamudi et al.). For this reason, SMARCA2 / 4BD inhibitors are excluded from use in treating SMARCA4 mutant cancers, but they offer attractive ligands for PROTAC conjugations.

[0010] Therefore, it is inferred that PROTACs targeting the non-functional bromodomains of SMARCA2 / 4 should provide an opportunity to exploit the vulnerability of SMARCA2 in SMARCA4-mutated cancer cells for therapeutic purposes. The principles of suitable SMARCA ligand conjugation to E3 ligase binders are described in International Publications 2016 / 105518, 2017 / 007612, and 2017 / 011371. However, none of these publications demonstrate specific examples of SMARCA proteins and their corresponding degradation. [Overview of the project]

[0011] This specification provides 6-substituted pyridazine compounds and their pharmaceutical compositions that are useful as SMARCA2 and / or SMARCA4 degrading agents and for the treatment of diseases or disorders that depend on or are mediated by SMARCA2 and / or SMARCA4.

[0012] In one embodiment, the present invention relates to formula (I):

[0013] [ka] A compound thereof, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or prodrug, During the ceremony, A represents a 5-6 member heteroarylenyl or a 6 member arylenyl, and arylenyls and heteroarylenyls are substituted with one, two, or three occurrences of Ra. Ra is hydrogen, hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, haloalkoxy, amino, alkylamino, or cyano. R1 is a halogen, alkyl, haloalkyl, alkenyl, alkoxy, hydroxy, hydroxyalkyl, -COORb, -CON(Rb)2, 6-10 membered aryl, or 5-10 membered heteroaryl, and the aryl and heteroaryl are optionally substituted with 1, 2, or 3 groups independently selected from oxo, hydroxy, alkoxy, halogen, alkyl, haloalkyl, amino, -ONa, -COORc, and -OCORc. Rb and Rc, when they appear, independently represent hydrogen, alkyl, or aminoalkyl, respectively. R2 is hydrogen, hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, or cyano. L is bonded to -O-(CH2)p-, -O-(CH2)pO-, -C≡C-alkylenyl-, -NRx-(CH2)p-, -NRx-(CH2)pO-, -NRx-(CH2)pC≡C-, -NRx-(3~10-membered heterocycloalkylenyl)-(CRxRy)n-, -(3~10-membered cycloalkylenyl)-(CRxRy)n-, -(3~10-membered heterocycloalkylenyl)-(CRxRy)n-, or -O-(3~10-membered heterocycloalkylenyl)-(CRxRy)n-, where cycloalkylenyl and heterocycloalkylenyl are substituted with 1, 2, or 3 occurrences of Rd, the left side of L is bonded to A, and the right side of L is bonded to M. Rd is independently selected from hydrogen, hydroxyl, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano at the time of its appearance. Rx and Ry are independently selected from hydrogen, alkyl, and halogen at the time of their appearance. M stands for M-1 and M-2:

[0014] [ka] Selected from, During the ceremony, Z is a 5-6 member heteroallyrenyl optionally substituted with 1, 2, or 3 groups independently selected from hydroxy, halogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, and aminoalkynyl, where aminoalkyl and aminoalkynyl are optionally substituted with 1 or 2 substituents selected from alkyl and -COCH3. 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, where alkyl is optionally substituted with -OCOR' or -OP(O)(OR'')2. R' and R'' are independently selected from hydrogen and alkyl, R5, R6, R 10 , and R 11 These independently represent hydrogen, alkyl, halogen, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl-, -CONRuRv, acyl, -Na, -alkyl-heterocycloalkyl, and -heteroalkyl-heterocycloalkyl, where aminoalkyl and heterocycloalkyl are optionally substituted with one or two substituents selected from alkyl and -COCH3, or R5 and R6 combine integrally with the C atom to which they are bonded to form a 4- to 6-membered heterocycloalkyl group that is optionally substituted with alkyl or -COCH3, or R 10 and R 11 These combine integrally with the C atom to which they are bonded, forming a 4-6 member heterocycloalkyl group that is optionally substituted with alkyl or -COCH3. Ru and Rv independently represent hydrogen, alkyl, 4- to 6-membered cycloalkyl, or 6-membered aryl. R7 and R 12 This represents a thiazolyl substituted with alkyl, hydroxy, amino, or haloalkyl. p is an integer selected from 1, 2, 3, and 4. n is an integer selected from 0, 1, 2, and 3. The present invention provides compounds, or pharmaceutically acceptable salts thereof, stereoisomers, tautomers, or prodrugs thereof.

[0015] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or prodrug, and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).

[0016] In another aspect, the present invention relates to the preparation of a compound of formula (I).

[0017] In another embodiment, the present invention provides pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or prodrug, for treating diseases or disorders that depend on or are mediated by SMARCA2 and / or SMARCA4.

[0018] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or prodrug, for treating or slowing the progression of a disease or disorder for which the degradation of SMARCA2 and / or SMARCA4 proteins is beneficial, such as cancer.

[0019] In another aspect, the present invention provides a method for degrading a target protein, comprising the step of administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or prodrug thereof, to a subject in a therapeutically effective dose, wherein the compound is effective in degrading the target protein.

[0020] In another aspect, the present invention provides a method for treating a subject with cancer, comprising the step of administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or prodrug, in a therapeutically effective amount.

[0021] In another aspect, the present invention provides a method for inhibiting tumor growth in a cancerous subject, comprising the step of administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or prodrug, in a therapeutically effective amount.

[0022] In another aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or prodrug, in the manufacture of a drug for treating a disease or disorder that depends on or is mediated by SMARCA2 and / or SMARCA4. [Modes for carrying out the invention]

[0023] The present invention provides a 6-substituted pyridazine compound referred to as the compound of formula (I), which is useful as a SMARCA2 and / or SMARCA4 degradation agent and for the treatment of diseases that depend on or are mediated by SMARCA2 and / or SMARCA4. The present invention further provides pharmaceutical compositions comprising the compound or its stereoisomers, tautomers, or prodrugs as therapeutic agents.

[0024] Each embodiment is provided by the description of the invention, not by any limitation of the invention. Indeed, it will be apparent to those skilled in the art that various modifications and changes can be made to the compounds, compositions, and methods described herein without departing from the scope or spirit of the invention. For example, features exemplified or described as part of one embodiment can be applied to another embodiment to obtain another further embodiment. For this reason, the invention is intended to include such modifications and changes, and their equivalents. Other objects, features, and aspects of the invention are disclosed in or will become apparent from the following detailed description. It will be understood by those skilled in the art that this discussion describes only exemplary embodiments and should not be construed as limiting broader aspects of the invention.

[0025] In one embodiment, the present invention is represented by formula (I):

[0026] [ka] A compound thereof, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or prodrug, During the ceremony, A represents a 5- to 6-membered heteroaryrenyl or a 6-membered aryrenyl, and aryrenyls and heteroaryrenyls are substituted with one, two, or three occurrences of Ra. Ra is hydrogen, hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, haloalkoxy, amino, alkylamino, or cyano. R1 is a halogen, alkyl, haloalkyl, alkenyl, alkoxy, hydroxy, hydroxyalkyl, -COORb, -CON(Rb)2, 6-10 membered aryl, or 5-10 membered heteroaryl, and the aryl and heteroaryl are optionally substituted with 1, 2, or 3 groups independently selected from oxo, hydroxy, alkoxy, halogen, alkyl, haloalkyl, amino, -ONa, -COORc, and -OCORc. Rb and Rc, when they appear, independently represent hydrogen, alkyl, or aminoalkyl, respectively. R2 is hydrogen, hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, or cyano. L is bonded to -O-(CH2)p-, -O-(CH2)pO-, -C≡C-alkylenyl-, -NRx-(CH2)p-, -NRx-(CH2)pO-, -NRx-(CH2)pC≡C-, -NRx-(3~10-membered heterocycloalkylenyl)-(CRxRy)n-, -(3~10-membered cycloalkylenyl)-(CRxRy)n-, -(3~10-membered heterocycloalkylenyl)-(CRxRy)n-, or -O-(3~10-membered heterocycloalkylenyl)-(CRxRy)n-, where cycloalkylenyl and heterocycloalkylenyl are substituted with 1, 2, or 3 occurrences of Rd, the left side of L is bonded to A, and the right side of L is bonded to M. Rd is independently selected from hydrogen, hydroxyl, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano at the time of its appearance. Rx and Ry are independently selected from hydrogen, alkyl, and halogen at the time of their appearance. M stands for M-1 and M-2:

[0027] [ka] Selected from, During the ceremony, Z is a 5- to 6-membered heteroarylenyl optionally substituted with 1, 2, or 3 groups independently selected from hydroxy, halogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, and aminoalkynyl, wherein aminoalkyl and aminoalkynyl are optionally substituted with 1 or 2 substituents selected from alkyl and -COCH3, 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, and alkyl is optionally substituted with -OCOR’ or -OP(O)(OR’’)2, R’ and R’’ are independently selected from hydrogen and alkyl, R5, R6, R 10 、and R 11 independently represent hydrogen, alkyl, halogen, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl-, -CONRuRv, acyl, -Na, -alkyl-heterocycloalkyl, and -heteroalkyl-heterocycloalkyl, wherein aminoalkyl and heterocycloalkyl are optionally substituted with 1 or 2 substituents selected from alkyl and -COCH3, or R5 and R6, when combined together with the C atom to which they are attached, form a 4- to 6-membered heterocycloalkyl optionally substituted with alkyl or -COCH3, or R 10 and R 11 when combined together with the C atom to which they are attached, form a 4- to 6-membered heterocycloalkyl optionally substituted with alkyl or -COCH3, Ru and Rv independently represent hydrogen, alkyl, 4- to 6-membered cycloalkyl, or 6-membered aryl, R7 and R 12 represent thiazolyl substituted with alkyl, hydroxy, amino, or haloalkyl, p is an integer selected from 1, 2, 3, and 4. n is an integer selected from 0, 1, 2, and 3. The present invention provides compounds, or pharmaceutically acceptable salts thereof, stereoisomers, tautomers, or prodrugs thereof.

[0028] In one embodiment, R1 is a halogen, alkyl, haloalkyl, alkoxy, hydroxy, hydroxyalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl, and the aryl and heteroaryl are optionally substituted with 1, 2, or 3 groups independently selected from oxo, hydroxy, alkoxy, halogen, alkyl, haloalkyl, and amino.

[0029] In one embodiment, R1 is a halogen, hydroxyl, -CH2OH, -COOH, -COOCH3, -CONH2, -CONHCH3, a 6-10 membered aryl, or a 5-10 membered heteroaryl, and the aryl and heteroaryl are optionally substituted with 1, 2, or 3 groups independently selected from hydroxyl, alkoxy, halogen, alkyl, and haloalkyl.

[0030] In one embodiment, R1 is a halogen, hydroxyl, 6-10 membered aryl, or 5-10 membered heteroaryl, and the aryl and heteroaryl are optionally substituted with 1, 2, or 3 groups independently selected from hydroxyl, alkoxy, halogen, alkyl, haloalkyl, -OCOCH3, and -CH(NH2)(CH(CH3)2).

[0031] In one embodiment, R1 represents a halogen, hydroxy, hydroxyalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl, and the aryl and heteroaryl are optionally substituted with one or two groups independently selected from alkyl, hydroxy, alkoxy, halogen, and haloalkyl.

[0032] In one embodiment, R1 is a 6-10 membered aryl or a 5-10 membered heteroaryl, and the aryl and heteroaryl are optionally substituted with 1, 2, or 3 groups independently selected from alkyl, hydroxy, alkoxy, halogen, and haloalkyl groups.

[0033] In one embodiment, R1 is a 6-10 membered aryl group optionally substituted with 1, 2, or 3 groups independently selected from alkyl, hydroxy, alkoxy, halogen, and haloalkyl groups.

[0034] In one embodiment, R1 is a phenyl compound optionally substituted with one or two groups independently selected from hydroxy, alkyl, haloalkyl, and halogen.

[0035] In one embodiment, R1 is a 5-10 membered heteroaryl substituted with one, two, or three groups independently selected from alkyl, hydroxy, alkoxy, halogen, and haloalkyl groups.

[0036] In one embodiment, R1 is

[0037] [ka] Each group is optionally substituted with one, two, or three groups independently selected from hydroxy, alkyl, haloalkyl, and halogen groups.

[0038] In one embodiment, R2 is hydrogen, hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, or haloalkyl.

[0039] In one embodiment, R2 is hydrogen, hydroxyl, halogen, alkoxy, alkyl, or haloalkyl.

[0040] In one embodiment, R2 independently represents hydrogen or a halogen.

[0041] In one embodiment, A represents phenylenyl substituted with one or two occurrences of Ra.

[0042] In one embodiment, A represents a 5-6 member heteroary lenyl substituted with one or two occurrences of Ra.

[0043] In one embodiment, A is phenylenyl, furanylenyl, thienylenyl, pyrrolylenyl, imidazolylenyl, oxazolylenyl, isoxazolilenyl, thiazolylenyl, isothiazolilenyl, 1H-tetrazolylenyl, oxadiazolylenyl This represents azolylenyl, triazolilenyl, pyrazolilenyl, pyridylenyl, pyrimidylenyl, pyrazinylenyl, pyrazinylenyl, pyridadinylenyl, 1,2,3-triazinylenyl, 1,2,4-triazinylenyl, or 1,3,5-triazinylenyl, where each group is optionally substituted by the appearance of one or two Ra groups.

[0044] In one embodiment, A represents phenylenyl, pyridylenyl, pyrimidilenyl, pyrazinylenyl, or pyridadinylenyl, and each group is optionally substituted by one, two, or three occurrences of Ra.

[0045] In one embodiment, A represents phenylenyl, furanylenyl, thienylenyl, pyrrolylenyl, imidazolylenyl, oxazolilenyl, isoxazolilenyl, thiazolylenyl, isothiazolilenyl, 1H-tetrazolylenyl, oxadiazolylenyl, triazolilenyl, pyrazolilenyl, pyridylenyl, pyrimidilenyl, pyrazinyl, pyridadinylenyl, 1,2,3-triazinylenyl, 1,2,4-triazinylenyl, or 1,3,5-triazinylenyl, where each of the above groups is substituted with one or two substituents selected from hydrogen, hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, haloalkoxy, amino, alkylamino, or cyano.

[0046] In one embodiment, A represents phenylenyl, pyridylenyl, pyrimidilenyl, or pyridadinylenyl, and phenylenyl, pyridylenyl, pyrimidilenyl, and pyridadinylenyl are optionally substituted with one or two substituents selected from hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, haloalkoxy, amino, alkylamino, or cyano.

[0047] In one embodiment, A is

[0048] [ka] Each ring is optionally substituted by one or two occurrences of Ra, with the left side of A bonded to the pyridazine ring and the right side of the ring bonded to L.

[0049] In one embodiment, A is

[0050] [ka] Each group is optionally substituted with one or two substituents selected from hydrogen, hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, haloalkoxy, amino, alkylamino, and cyano, with the left side of A bonded to the pyridazine ring and the right side of the ring bonded to L.

[0051] In one embodiment, L is a bond, -O-(CH2)p-, -O-(CH2)pO-, -NRx-(CH2)p-, -NRx-(CH2)pO-, -NRx-(3-10 member heterocycloalkylenyl)-(CRxRy)n-, -(3-10 member cycloalkylenyl)-(CRxRy)n-, (3-10 member heterocycloalkylenyl)-(CRxRy)n, or -O-(3-10 member heterocycloalkylenyl)-(CRxRy)n-, where the cycloalkylenyl and heterocycloalkylenyl are substituted with one or two appearances of Rd.

[0052] In one embodiment, L is a bond and M is bonded to A. In one embodiment, L is -O-(CH2)p-. 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-(CH2)pO- or -C≡C-alkylenyl-. In one embodiment, L is -O-CH2CH2CH2CH2-O-. In one embodiment, L is -O-CH2CH2CH2-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≡C-CH2-. In one embodiment, L is -C≡C-CH2CH2-. In one embodiment, L is -C≡C-CH2CH2CH2-. In one embodiment, L is -C≡C-CH2CH2CH2CH2-.

[0053] In one embodiment, L is -NRx-(CH2)p-. In one embodiment, L is -NRx-(CH2) 1-4In 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)-CH2CH2-. In one embodiment, L is -N(CH3)-CH2CH2CH2-. In one embodiment, L is -N(CH3)-CH2CH2CH2CH2-.

[0054] In one embodiment, L is -NRx-(CH2)pO-. In one embodiment, L is -NRx-(CH2) 1-4 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)-CH2CH2CH2-O-. In one embodiment, L is -N(CH3)-CH2CH2CH2CH2-O-.

[0055] A-a-x )-CH2CH2-, -N(CH3)-CH2CH2CH2-, -N(CH3)-CH2CH2CH2CH2-, NH-CH2-O-, -NH-CH2CH2-O-, -NH-CH2CH2CH2-O-, -NH-CH 2CH2CH2CH2-O-, -N(CH3)-CH2-O-, -N(CH3)-CH2CH2-O-, -N(CH3)-CH2CH2CH2-O-, or -N(CH3)-CH2CH2CH2CH2-O-.

[0056] In one embodiment, L is -NRx-(3-10 member heterocycloalkylenyl)-(CRxRy)n-, (3-10 member cycloalkylenyl)-(CRxRy)n-, (3-10 member heterocycloalkylenyl)-(CRxRy)n, or -O-(3-10 member heterocycloalkylenyl)-(CRxRy)n-, where the cycloalkylenyl and heterocycloalkylenyl are substituted with one or two appearances of Rd.

[0057] In one embodiment, L is -NRx-(3-10 member heterocycloalkylenyl)-(CRxRy) 0-3 In one embodiment, L is -NH-(3-10 member heterocycloalkylenyl)-(CRxRy) 0-3 In one embodiment, L is -N(CH3)-(3-10 member heterocycloalkylenyl)-(CRxRy) 0-3 The heterocycloalkylenyl is optionally substituted by the appearance of one or two Rd groups.

[0058] In one embodiment, L is (3-10 member cycloalkylenyl)-(CRxRy) 0-3The cycloalkylenyl is optionally substituted by the appearance of one or two Rd units.

[0059] In one embodiment, L is a 3-10 member heterocycloalkylenyl-(CRxRy) 0-3 - and the heterocycloalkylenyl is optionally substituted by one, two, or three occurrences of Rd.

[0060] In one embodiment, L is -O-(3-10 member heterocycloalkylenyl)-(CRxRy) 0-3 - and the heterocycloalkylenyl is optionally substituted by one, two, or three occurrences of Rd.

[0061] In one embodiment, L is -NRx-(3-10 member heterocycloalkylenyl)-(CRxRy) 0-3 -NH-(3-10 member heterocycloalkylenyl)-(CRxRy) 0-3 , or -N(CH3)-(3-10 member heterocycloalkylenyl)-(CRxRy) 0-3Heterocycloalkylenyl is a compound of piperidinylenyl, piperazinylenyl, azetidinylenyl, pyrrolidinylenyl, tetrahydropyridinylenyl, diazobicyclooctanylenyl, azabicyclooctanylenyl, azaspiroheptanylenyl, tetrahydropyranyl, tetrahydropyridazinylenyl, and molars. The compounds are selected from morpholinylenyl, thiomorpholinylenyl, 1,4-dioxanylenyl, dioxidothiomorpholinylenyl, oxapiperazinylenyl, oxapiperidinylenyl, tetrahydropyranylenyl, dihydropyranylenyl, and dihydropyrimidinylenyl, with each group being substituted with one or two Rd occurrences.

[0062] In one embodiment, L is (3-10 member cycloalkylenyl)-(CRxRy) 0-3 The cycloalkylenyl is selected from cyclopropyrenyl, cyclobutyrenyl, cyclopentyrenyl, cyclohexylenyl, and cycloheptyrenyl. In one embodiment, L is

[0063] [ka] Each ring is substituted with one or two occurrences of Rd, and each ring is substituted with one or two occurrences of Rd, with the left side of L bonded to A and the right side of L bonded to M.

[0064] In one embodiment, L is -O-CH2-, -O-CH2CH2-, -O-CH2CH2CH2-, -O-CH2CH2-CH2CH2-, -O-CH2O-, -O-CH2CH2-O-, -O-CH2CH2CH 2-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-,

[0065] [ka] Each ring is replaced by one or two occurrences of Rd.

[0066] In one embodiment of the compound of formula (I), A represents a 5- to 6-membered heteroaryrenyl or a 6-membered aryrenyl, and aryrenyls and heteroaryrenyls are substituted with one, two, or three occurrences of Ra. Ra is hydrogen, hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, haloalkoxy, amino, alkylamino, or cyano. R1 is a halogen, alkyl, haloalkyl, alkenyl, alkoxy, hydroxy, hydroxyalkyl, -COORb, -CON(Rb)2, 6-10 membered aryl, or 5-10 membered heteroaryl, and the aryl and heteroaryl are optionally substituted with 1, 2, or 3 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 at the time of their appearance. R2 is hydrogen, hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, or cyano. L is a bond, -O-(CH2)p-, -O-(CH2)pO-, -C≡C-alkylenyl, 6-membered heterocycloalkylenyl, or 6-membered heterocycloalkylenyl-(CRxRy)n-, where the heterocycloalkylenyl is optionally substituted by one, two, or three occurrences of Rd. Rd is independently selected from hydrogen, hydroxyl, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano at the time of its appearance. Rx and Ry are independently selected from hydrogen and alkyl, respectively, upon their appearance. M is

[0067] [ka] Selected from, During the ceremony, Z is a 5-6 member heteroallyrenyl optionally substituted with 1, 2, or 3 groups selected from hydroxy, halogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, and aminoalkynyl, where aminoalkyl and aminoalkynyl are optionally substituted with 1 or 2 substituents selected from alkyl and -COCH3. 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, where alkyl is optionally substituted with -OCOR' or -OP(O)(OR'')2. R' and R'' are independently selected from hydrogen and alkyl, R5, R6, R 10 , and R11 These are independently selected from hydrogen, alkyl, halogen, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, -CONRuRv, acyl, -Na, -alkyl-heterocycloalkyl, and -heteroalkyl-heterocycloalkyl, where aminoalkyl and heterocycloalkyl are optionally substituted with one or two substituents selected from alkyl and -COCH3, or R5 and R6 combine integrally with the C atom to which they are bonded to form a 4- to 6-membered heterocycloalkyl group that is optionally substituted with alkyl or -COCH3, or R 10 and R 11 These combine integrally with the C atom to which they are bonded, forming a 4-6 member heterocycloalkyl group that is optionally substituted with alkyl or -COCH3. Ru and Rv independently represent hydrogen, alkyl, 4- to 6-membered cycloalkyl, or 6-membered aryl. R7 and R 12 These are thiazolyls that are independently substituted with alkyl, hydroxy, amino, or haloalkyl groups. p is an integer selected from 1 and 2. n is an integer selected from 1, 2, and 3.

[0068] In one embodiment, M is M-1:

[0069] [ka] And, In the formula, Z is oxazolirenyl or isoxazolirenyl, R3 represents 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-, and R7 represents alkyl-substituted thiazolyl.

[0070] In one embodiment, M is M-1A, M-1B, and M-1C:

[0071] [ka] Selected from, During the ceremony, R4 is hydrogen, alkyl, acyl, or -Na, and alkyl is optionally substituted with -OCOR' or -OP(O)(OR'')2. R' and R'' are independently selected from hydrogen and alkyl, R6 is hydrogen, alkyl, hydroxyalkyl, aminoalkyl, or haloalkyl, and aminoalkyl is optionally substituted with one or two substituents selected from alkyl and -COCH3.

[0072] In one embodiment, M-1A is

[0073] [ka]

[0074] [ka] And, During the ceremony, R4 is selected from hydrogen, alkyl, acyl, and -Na, and alkyl is optionally substituted with -OCOR' and -OP(O)(OR'')2. R' and R'' are independently selected from hydrogen and alkyl, R6 is selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl, and aminoalkyl is optionally substituted with one or two substituents selected from alkyl and -COCH3.

[0075] In one embodiment, M-1B and M-1C are,

[0076] [ka] And, During the ceremony, R4 is selected from hydrogen, alkyl, acyl, and -Na, and alkyl is optionally substituted with -OCOR' and -OP(O)(OR'')2. R' and R'' are independently selected from hydrogen and alkyl, R6 is selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, and aminoalkyl, and aminoalkyl is optionally substituted with one or two substituents selected from alkyl and -COCH3.

[0077] In one embodiment, M-1A is given by formula:

[0078] [ka] It is represented by, During the ceremony, R4 is selected from hydrogen and alkyl. R6 is selected from hydrogen, hydroxyalkyl, (alkyl)aminoalkyl-, or alkyl.

[0079] In one embodiment, M-1A has the following structure:

[0080] [ka] It is represented by [this].

[0081] In one embodiment, M is M-2:

[0082] [ka] In the formula, R8, R9, R 10 , R 11 , and R 12 This is defined as a compound of formula (I).

[0083] In one embodiment, M is M-2, and in the formula, Z represents a 5-6 member heteroarylenyl optionally substituted with 1, 2, or 3 groups independently selected from hydroxy, halogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, and aminoalkynyl, while aminoalkyl and aminoalkynyl are optionally substituted with 1 or 2 substituents selected from alkyl and -COCH3. R8 represents alkyl, acyl, heteroalkyl, haloalkyl, hydroxyalkyl, or aminoalkyl. R9 represents hydrogen, alkyl, acyl, or -Na. R 10 and R 11 These are independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, and aminoalkyl, and aminoalkyl is optionally substituted with one or two substituents selected from alkyl or -COCH3. R 12 These are 5-6 member heteroaryls substituted with alkyl, hydroxy, amino, or haloalkyl groups.

[0084] In one embodiment, M is M-2, where Z is oxazolirenyl or isoxazolirenyl, R8 represents alkyl, haloalkyl, or hydroxyalkyl, and R9 represents hydrogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, or acyl, R 10 and R 11 R independently represents hydrogen, alkyl, halogen, haloalkyl, hydroxyalkyl, or (alkyl)aminoalkyl-, 12 This represents an alkyl-substituted thiazolyl.

[0085] In one embodiment, M-2 is M-2A, M-2B, and M-2C:

[0086] [ka] Selected from, During the ceremony, Z represents an oxazolirenyl optionally substituted with one, two, or three groups selected from hydroxy, halogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, and aminoalkynyl, while aminoalkyl and aminoalkynyl are optionally substituted with one or two substituents selected from alkyl and -COCH3. R9 is hydrogen, alkyl, acyl, or -Na. R 11 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl, where the aminoalkyl is optionally substituted with one or two substituents selected from alkyl and -COCH3.

[0087] In one embodiment, M is selected from M-1A, M-1B, M-1C, M-2A, M-2B, and M-2C, in the formula, Z represents a 5-6 member heteroarylenyl optionally substituted with 1, 2, or 3 groups independently selected from hydroxy, halogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, and aminoalkynyl, while aminoalkyl and aminoalkynyl are optionally substituted with 1 or 2 substituents selected from alkyl and -COCH3. R4 and R9 are independently hydrogen, alkyl, acyl, or -Na, and the alkyl is optionally substituted with -OCOR' or -OP(O)(OR'')2. R' and R'' are independently selected from hydrogen and alkyl, R6 and R 11 These are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl, where the aminoalkyl is optionally substituted with one or two substituents selected from alkyl and -COCH3.

[0088] In one embodiment, Z represents isoxazolirenyl, oxazolirenyl, or pyrazolirenyl.

[0089] In one embodiment, M-2 has the following structure:

[0090] [ka] It is expressed as follows, where R9 represents hydrogen, and R 11 represents hydrogen or alkyl.

[0091] In one embodiment, M has the structure:

[0092] [ka] It is represented by [this].

[0093] In one embodiment, if L is a bond, M is bonded to A in the compound of formula (I).

[0094] In one embodiment, the present invention is given by formula (IA):

[0095] [ka] We provide compounds, or pharmaceutically acceptable salts, stereoisomers, tautomers, or prodrugs thereof. In the formula, R1, R2, Ra, L, and M are defined as in the compound of formula (I).

[0096] In one embodiment of the compound of formula (IA), R1 is a halogen, hydroxyl, 6-10 membered aryl, or 5-10 membered heteroaryl, and the aryl and heteroaryl are optionally substituted with 1, 2, or 3 groups independently selected from alkyl, hydroxyl, alkoxy, halogen, and haloalkyl.

[0097] In one embodiment of the compound of formula (IA), R1 is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl, and the aryl and heteroaryl are optionally substituted with one, two, or three groups independently selected from alkyl, hydroxy, alkoxy, halogen, and haloalkyl groups.

[0098] In one embodiment of the compound of formula (IA), R1 is -Cl, -OH,

[0099] [ka] Each ring is optionally substituted with one, two, or three groups independently selected from alkyl, hydroxy, alkoxy, halogen, and haloalkyl groups.

[0100] In one embodiment of the compound of formula (IA), R2 is hydrogen, hydroxyl, halogen, alkoxy, alkyl, or haloalkyl.

[0101] In one embodiment of the compound of formula (IA), R2 represents hydrogen or a halogen.

[0102] In one embodiment of the compound of formula (IA), Ra is hydrogen, hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, haloalkoxy, amino, alkylamino, or cyano.

[0103] In one embodiment of the compound of formula (IA), Ra is hydrogen, hydroxy, hydroxyalkyl, halogen, alkoxy, or haloalkyl.

[0104] In one embodiment of the compound of formula (IA), Ra is hydrogen, a halogen, or a haloalkyl.

[0105] In one embodiment of the compound of formula (IA), Ra is hydrogen or a halogen.

[0106] In one embodiment of the compound of formula (IA), L is a bond.

[0107] In one embodiment of the compound of formula (IA), L is a bond, -O-(CH2)p-, -O-(CH2)pO-, -NRx-(CH2)p-, -NRx-(CH2)pO-, -NRx-(3-10 member heterocycloalkylenyl)-(CRxRy)n-, -(3-10 member cycloalkylenyl)-(CRxRy)n-, (3-10 member heterocycloalkylenyl)-(CRxRy)n, or -O-(3-10 member heterocycloalkylenyl)-(CRxRy)n-.

[0108] In one embodiment of the compound of formula (IA), L is -O-CH2CH2CH2CH2-, -O-CH2-CH2CH2-, O-CH2CH2-O-, -O-CH2CH2CH2-O-, -NH-CH2CH2-O-, -N(CH3)-CH2CH2-O-, -NH-CH2CH2CH2CH2-, -N(CH3)-CH2CH2CH2CH2-,

[0109] [ka] Each group is substituted with one or two occurrences of Rd.

[0110] In one embodiment of the compound of formula (IA), M is selected from M-1 and M2, During the ceremony, Z is oxazolilenyl or isoxazolilenyl. 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 These independently represent hydrogen, alkyl, halogen, haloalkyl, hydroxyalkyl, or (alkyl)aminoalkyl-. R7 and R 12 This represents an alkyl-substituted thiazolyl.

[0111] In one embodiment of the compound of formula (IA), M is structured as follows:

[0112] [ka] It is represented by [this].

[0113] In one embodiment of the compound of formula (IA), R1 is a halogen, hydroxyl, 6-10 membered aryl, or 5-10 membered heteroaryl, and the aryl and heteroaryl are optionally substituted with 1, 2, or 3 groups independently selected from hydroxyl, alkoxy, halogen, alkyl, and haloalkyl. R2 is hydrogen or halogen. Each instance of Ra independently represents hydrogen, halogen, or haloalkyl. L is a bond, -O-CH2CH2CH2-, -O-CH2CH2CH2CH2-, -O-CH2CH2-O-, -O-CH2CH2CH2CH2-O-, -NH-CH2CH2CH2CH2-, -N(CH3)-CH2CH2-O-, -N(CH3)-CH2CH2CH2CH2-, -NH-CH2CH2-O-,

[0114] [ka] Each group is substituted with one or two occurrences of Rd, Z is oxazolilenyl or isoxazolilenyl. 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 11These independently represent hydrogen, alkyl, halogen, haloalkyl, hydroxyalkyl, or (alkyl)aminoalkyl-. R7 and R 12 This represents an alkyl-substituted thiazolyl.

[0115] In one embodiment of the compound of formula (IA), R1 is -Cl, -OH,

[0116] [ka] Each ring is optionally substituted with 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-,

[0117] [ka] Each ring is substituted with one or two occurrences of Rd, M is

[0118] [ka] It represents.

[0119] In one embodiment, the present invention is given by formula (IB):

[0120] [ka] We provide compounds, or pharmaceutically acceptable salts, stereoisomers, tautomers, or prodrugs thereof. In the formula, R1, R2, Ra, R3, R4, R5, R6, and R7 are as defined in the compound of formula (I).

[0121] In one embodiment of the compound of formula (IB), R1 is -Cl, -OH,

[0122] [ka] Each ring is optionally substituted with one or two groups independently selected from alkyl, hydroxyl, and halogen groups.

[0123] In one embodiment of the compound of formula (IB), L is a bond, -O-(CH2)p-, -O-(CH2)pO-, -NRx-(CH2)p-, -NRx-(CH2)pO-, -NRx-(3-10 member heterocycloalkylenyl)-(CRxRy)n-, (3-10 member cycloalkylenyl)-(CRxRy)n-, (3-10 member heterocycloalkylenyl)-(CRxRy)n, or -O-(3-10 member heterocycloalkylenyl)-(CRxRy)n-.

[0124] 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-,

[0125] [ka] Each ring is replaced by one or two occurrences of Rd.

[0126] In one embodiment of the compound of formula (IB), R1 is -Cl, -OH,

[0127] [ka] Each ring is optionally substituted with one, two, or three groups independently selected from alkyl, hydroxy, and halogen groups. R2 is hydrogen or halogen. Ra is hydrogen or halogen, L is a bond, -O-CH2CH2CH2-, -O-CH2CH2CH2CH2-, -O-CH2CH2-O-, -O-CH2CH2CH2CH2-O-, -NH-CH2CH2CH2CH2-, -N(CH3)-CH2CH2-O-, -N(CH3)-CH2CH2CH2CH2-, -NH-CH2CH2-O-,

[0128] [ka] Each group is substituted with one or two occurrences of Rd, R3 represents alkyl, R4 represents hydrogen or alkyl, R5 stands for hydrogen. R6 represents alkyl, halogen, haloalkyl, hydroxyalkyl, or (alkyl)aminoalkyl-. R7 represents an alkyl-substituted thiazolyl.

[0129] In one embodiment, the present invention is based on formula (IC):

[0130] [ka] We provide compounds, or pharmaceutically acceptable salts, stereoisomers, tautomers, or prodrugs thereof. In the formula, X1 and X2 are independently N or C, and R1, R2, Ra, Rd, Rx, Ry, X1, X2, n, and M are as defined in the compound of formula (I).

[0131] In one embodiment of the compound of formula (IC), R1 is -Cl, -OH,

[0132] [Chemistry] and each ring is optionally substituted by one or two groups independently selected from alkyl, hydroxy, and halogen.

[0133] In one embodiment of the compound of formula (IC), Rx is hydrogen and Ry is hydrogen or alkyl.

[0134] In one embodiment of the compound of formula (IC), M is

[0135] [Chemistry] represents.

[0136] In one embodiment of the compound of formula (IC), X1 and X2 independently represent N or C, R1 is -Cl, -OH,

[0137] [Chemistry] and each ring is optionally substituted by one or two groups independently selected from alkyl, hydroxy, and halogen, R2 is hydrogen or halogen, Ra represents hydrogen or halogen, Rd is hydrogen or hydroxy, Rx is hydrogen, Ry is hydrogen or alkyl, M is

[0138] [Chemistry] represents, n is 0, 1, 2, or 3.

[0139] In one embodiment, the present invention relates to a compound of formula (ID):

[0140] [ka] We provide compounds, or pharmaceutically acceptable salts, stereoisomers, tautomers, or prodrugs thereof. In the formula, R1, R2, Ra, Rd, R3, R4, R5, R6, R7, and n are as defined in the compound of formula (I).

[0141] In one embodiment of the compound of formula (ID), R1 is a halogen, hydroxyl, 6-10 membered aryl, or 5-10 membered heteroaryl, and the aryl and heteroaryl are optionally substituted hydroxyl, halogen, alkyl, and haloalkyl. R2 is hydrogen or halogen. Ra represents hydrogen or halogen, Rd is either hydrogen or hydroxyl. R3 represents alkyl, acyl, or haloalkyl. R4 represents hydrogen or alkyl, R5 stands for hydrogen. R6 represents hydrogen, alkyl, halogen, haloalkyl, hydroxyalkyl, or (alkyl)aminoalkyl-. R7 is an alkyl-substituted thiazolyl, n is 0, 1, 2, or 3.

[0142] In one embodiment of the compound of formula (ID), R1 is a halogen, hydroxyl, 6-10 membered aryl, or 5-10 membered heteroaryl, and the aryl and heteroaryl are optionally substituted hydroxyl, halogen, alkyl, and haloalkyl. R2 is hydrogen or halogen. Ra represents hydrogen or halogen, Rd is either hydrogen or hydroxyl. R3 represents alkyl, acyl, or haloalkyl. R4 represents hydrogen or alkyl, R5 stands for hydrogen. R6 represents hydrogen, alkyl, halogen, hydroxyalkyl, or (alkyl)aminoalkyl-. R7 is thiazolyl substituted with alkyl, n is 0, 1, 2, or 3.

[0143] In one embodiment, the present invention provides a compound of formula (IE):

[0144]

Chemical formula

[0145] In one embodiment of the compound of formula (IE), R1 is -Cl, -OH,

[0146]

Chemical formula

[0147]

Chemical formula

[0148] In one embodiment, the present invention is as follows:

[0149] [Table 1-1]

[0150] [Table 1-2]

[0151] [Table 1-3]

[0152] [Table 1-4]

[0153] [Table 1-5]

[0154] [Table 1-6]

[0155] [Table 1-7]

[0156] [Table 1-8] The present invention provides compounds selected from, or pharmaceutically acceptable salts, stereoisomers, tautomers, or prodrugs thereof.

[0157] Treatment method In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or prodrug for use as a pharmaceutical agent.

[0158] In one embodiment, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or prodrug, in the manufacture of a drug for treating a disease or disorder dependent on SMARCA2 and / or SMARCA4.

[0159] In one embodiment, the present invention provides compounds of formula (I), pharmaceutically acceptable salts thereof, stereoisomers, tautomers, or prodrugs for use in treating diseases or disorders dependent on SMARCA2 and / or SMARCA4.

[0160] In one embodiment, the disease or disorder that depends on SMARCA2 and / or SMARCA4 is cancer.

[0161] In one embodiment, the present invention provides a method for degrading a target protein, comprising the step of administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or prodrug thereof, to a subject in a therapeutically effective amount, wherein the compound is effective in degrading the target protein.

[0162] In one embodiment, the present invention provides a method for treating or slowing the progression of a disease or disorder dependent on SMARCA2 and / or SMARCA4, comprising the step of administering a therapeutically effective dose of a compound of formula (I), or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or prodrug thereof, to a subject requiring treatment.

[0163] In one embodiment, diseases or disorders that depend on SMARCA2 and / or SMARCA4 include cancer.

[0164] In one embodiment, the present invention provides a method for inhibiting tumor growth in a cancer-affected subject, comprising the step of administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or prodrug, to a subject requiring inhibition.

[0165] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) described herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). The pharmaceutical composition preferably contains at least one of the compounds described herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, in a therapeutically effective amount. The compounds described in the present invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or diluent), diluted by a carrier, or encapsulated in a carrier which can be in the form of a capsule, sachet, paper, or other container.

[0166] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) used to degrade a target protein, wherein the target protein is SMARCA2 and / or SMARCA4.

[0167] In one embodiment, the subject suffers from a disease or disorder that is dependent on SMARCA2 and / or SMARCA4.

[0168] In one embodiment, the subject has cancer mediated by a target protein, which is SMARCA2 and / or SMARCA4.

[0169] In one embodiment, the present invention provides a pharmaceutical composition for use as a pharmacopoeia, comprising a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or prodrug.

[0170] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) for use in treating or slowing the progression of diseases or disorders mediated by SMARCA2 and / or SMARCA4.

[0171] In one embodiment, diseases or disorders dependent on SMARCA2 and / or SMARCA4 include hematological 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, promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granuloleukocyte) leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, and dysproliferative changes. Changes (dysplasia and dysplasia), fetal cancer, endometrial cancer, endotheliosarcoma, ependymoma, epithelial malignancies, 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, liver cancer, hepatocellular carcinoma, hormone-sensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, liver cancer, lymphangiosarcoma, lymphangiosarcoma, lymphocytic leukemia, lymphoma (Hodgkin type, non-Hodgkin type, Burkitt type), bladder, breast, colon, lung, ovary, pancreas, prostate, skin, and uterus Cancers selected from malignant lesions and hyperproliferative disorders, lymphoid neoplasms of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT plagioclase (NMC), oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pineal glandoma, primary polycythemia, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, malignant rhabdoid tumor (MRT), rhabdomyosarcoma, sarcoma, sebaceous carcinoma, seminomas, skin cancer, small cell lung cancer, solid tumors (cytomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synoviomas, sweat gland carcinoma, thyroid cancer, Waldenström macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor.

[0172] In one embodiment, cancers that depend on SMARCA2 and / or SMARCA4 are lung cancers such as NSCLC (i.e., non-small cell lung cancer).

[0173] In one embodiment, a cancer that depends on SMARCA2 and / or SMARCA4 is melanoma.

[0174] In a further embodiment, the cancer is a SMARCA2 and / or SMARCA4-dependent cancer.

[0175] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may contain, for example, water or other solvents, solubilizers and emulsifiers, such as inert diluents commonly used in the art, including ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (specifically cottonseed oil, peanut oil, corn (com) oil, germ oil, olive oil, castor oil, sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, as well as mixtures thereof. The oral composition may also contain, in addition to the inert diluent, adjuvants such as wetting agents, emulsifiers, suspending agents, sweeteners, flavorings, and fragrances.

[0176] Injectable preparations, such as injectable sterile aqueous or oily suspensions, may also be formulated according to known techniques using appropriate dispersants or wetting agents and suspending agents. Injectable sterile preparations may be injectable sterile solutions, suspensions, or emulsions in parenterally acceptable and non-toxic diluents or solvents, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used are water, Ringer's solution, USP, and isotonic salines. In addition, sterile fixative oils are conventionally used as solvents or suspension media. For this purpose, formulated fixative oils containing synthetic monoglycerides or diglycerides may be used. Furthermore, fatty acids such as oleic acid are used in injectable preparations.

[0177] To extend the effects of a drug, it is often desirable to slow down the absorption of the drug, whether administered subcutaneously or intramuscularly. This can sometimes be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of drug absorption depends on its dissolution rate, which may depend on the size and morphology of the crystals. Alternatively, the absorption of parenterally administered drug forms can be slowed by dissolving or suspending the drug in an oil vehicle.

[0178] The composition for rectal or vaginal administration is preferably a suppository, and can be prepared by mixing the compound of this application with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at ambient temperature but liquid at body temperature, and therefore dissolves in the rectum or sheath lumen to release the active compound.

[0179] Similar types of solid compositions may also be used as fillers in filled soft and hard gelatin capsules, using excipients such as lactose or lactose, as well as high molecular weight polyethylene glycol.

[0180] The active compound may also be in the form of microencapsulated tablets containing one or more excipients as described above. Solid dosage forms such as tablets, draggers, capsules, pills, and granules can be prepared using coatings and shells, such as enteric coatings and controlled-release coatings, which are well known in the pharmaceutical manufacturing industry. In these solid dosage forms, the active compound may also be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms may also contain additional substances other than the inert diluent, as is commonly practiced, such as tableting lubricants, magnesium stearate, and other tableting aids such as microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0181] Dosage forms for topical or transdermal administration of the compounds in this application include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and, if necessary, any preservative or buffer. Ophthalmic formulations, ear drops, ophthalmic ointments, powders, and solutions are also intended to be within the scope of this application.

[0182] The ointments, pastes, creams, and gels may also contain excipients such as animal fats, vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof, in addition to the active compounds of this application.

[0183] The powders and sprays may also contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powders, or mixtures thereof, in addition to the compounds of this application. The sprays may further contain conventional spraying agents such as chlorofluorohydrocarbons.

[0184] Transdermal patches offer the added advantage of controlled delivery of compounds to the body. These dosage forms can be manufactured by dissolving or aliquoting the compound in a suitable medium. Absorption enhancers can also be used to increase the influx of the compound through the skin. The rate can be controlled by providing a rate-limiting membrane or by dispersing the compound in a polymer matrix or gel.

[0185] The compounds and pharmaceutical compositions of this disclosure can be administered by any of the following forms of administration to the therapeutic agent. These forms include systemic administration, or topical administration such as oral, nasal, parenteral, intravenous, transdermal, transvaginal, rectal, and topical administration.

[0186] Depending on the intended mode of administration, the compounds or pharmaceutical compositions of this disclosure may be in solid, semi-solid, or liquid dosage forms, such as injections, tablets, suppositories, pills, time-releasing capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, or suspensions, sometimes in unit doses and conforming to conventional pharmaceutical practices. Similarly, the compounds or pharmaceutical compositions may be administered intravenously (both bolus and infusion), intraperitoneally, subcutaneously, or intramuscularly, and in all forms well known to those skilled in the pharmaceutical art.

[0187] Exemplary pharmaceutical compositions include tablets and gelatin capsules comprising one or more compounds of the present disclosure and a pharmaceutically acceptable carrier, the carrier being a) a diluent, e.g., purified water, triglyceride oils such as hydrogenated or partially hydrogenated vegetable oils, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil or its esters such as EPA and DHA, triglycerides, or mixtures thereof, ω-3 fatty acids or their derivatives, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose, and / or glycine; b) a lubricant in the tablet, e.g., silica, talc, stearic acid, magnesium or calcium salts of stearic acid, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride a) Aluminium and / or polyethylene glycol, if desired, binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose and β-lactose, corn syrup, natural and synthetic gums (such as acacia, tragacanth, or sodium alginate), waxes, and / or polyvinylpyrrolidone, d) Disintegrants, e.g., starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salts, effervescent mixtures, e) Absorbents, colorants, flavorings, and sweeteners, f) Tween80, Labrasol, HPMC, DOSS, Caproyl909, Labrafac, Labrafil, Peceol, Transcutol, Capmul Emulsifiers or dispersants such as MCM, capmul PG-12, captex355, gelucire, vitamin E TGPS, and other acceptable emulsifiers, as well as / or g) agents that enhance the absorption of compounds, such as cyclodextrin, hydroxypropyl cyclodextrin, PEG400, PEG200, etc.

[0188] Liquids, specifically injection compositions, can be prepared by means of dissolution or dispersion, for example. For instance, one or more compounds of the Disclosure may be dissolved or mixed in a pharmaceutically acceptable solvent such as water, saline, dextrose aqueous solution, glycerol, or ethanol to produce an injectionable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the compounds of the Disclosure.

[0189] One or more compounds or compositions of this disclosure can be delivered by parental administration. Injectable parenteral administration is commonly used for subcutaneous, intramuscular, or intravenous injection and infusion. Injectable solutions can be prepared in any conventional form, such as a liquid solution, suspension, or solid form suitable for dissolution in liquid before injection.

[0190] definition Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art in the field to which the inventions described herein belong. Unless otherwise specified, as used herein and in the appended claims, the following terms have the meanings provided for the convenience of understanding the invention.

[0191] The singular forms "a," "an," and "the" refer to multiple objects unless the context clearly indicates otherwise.

[0192] When used herein, the terms “optional” or “optionally” mean that the events or circumstances described below may or may not occur, and that this description includes both cases in which the events or circumstances occur and cases in which they do not occur. For example, “optionally substituted alkyl” means events or circumstances in which alkyl is not substituted, as well as cases in which alkyl is substituted.

[0193] The term “substituted” refers to a portion of a skeleton having substituents that replace hydrogen on one or more carbon atoms. “Substituted” or “substituted with” is understood to imply the implicit condition that such substitution is subject to the acceptable valences of the substituted atom and substituent, and that the substitution results in a stable compound, such as one that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is intended to include all acceptable substituents of an organic compound. In a broad range of embodiments, acceptable substituents of an organic compound include acyclic and cyclic substituents, branched and unbranched substituents, cyclic and heterocyclic substituents, and aromatic and non-aromatic substituents. Acceptable substituents may be one or more identical or different for a given organic compound. For the purposes of the present invention, heteroatoms such as nitrogen may also have hydrogen substituents and / or acceptable substituents of the organic compound as described herein, satisfying the valence of the heteroatom. Where appropriate, it will be understood by those skilled in the art that the substituents themselves are substituteable.

[0194] As used herein, the term "alkylenyl" refers to a divalent alkyl group as defined herein. The term "alkyl" refers to a C1-C 10 Linear alkyl groups and C3-C 10This refers to saturated aliphatic groups, including but not limited to branched alkyl groups. The "alkyl" group preferably refers to a C1-C6 linear alkyl group or a C3-C6 branched alkyl group. The "alkyl" group most preferably refers to a C1-C4 linear alkyl group or a C3-C8 branched alkyl group. 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, neo-pentyl, 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 "alkylenyl" groups include, but are not limited to, -CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH(CH3)CH2CH2CH2-, and -CH2CH(CH3)CH2CH2-. The "alkyl" group may also be optionally substituted.

[0195] As used herein, the term “haloalkyl” refers to an alkyl group substituted with one or more halogen atoms, where the halo group 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.

[0196] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group, where the amino group and 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-CH2N(CH3).

[0197] As used herein, the term "alkylamino" refers to an amino group substituted with one or two alkyl groups, where the amino group and alkyl group are as defined above. Examples of "alkylamino" include, but are not limited to, -NH(CH3), -N(CH3)2, -NH(C2H5), and -NH(C2H5).

[0198] As used herein, the terms "hydroxyalkyl" or "hydroxyalkyl" refer to an alkyl group as defined above, in which one or more hydrogen atoms of the alkyl group are substituted with a hydroxyl group. Examples of hydroxyalkyl moieties include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH(OH)CH2OH, -CH2CH(OH)CH3, and -CH(CH3)CH2OH.

[0199] As used herein, the term "cycloalkylenyl" refers to a divalent cycloalkylenyl as defined herein. The term "cycloalkyl" refers to a C3-C 10 This refers to a saturated cyclic hydrocarbon ring. Cycloalkyls can be monocyclic and typically contain 3 to 7 carbocyclic atoms. Examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyls can also be polycyclic or contain more than one ring. Examples of polycyclic cycloalkyls include crosslinked, condensed, and spirocyclic carbocyclyls. Therefore, examples of "cycloalkylenyl" include, but are not limited to, cyclopropyrenyl, cyclobutyrenyl, cyclopentyrenyl, cyclohexylenyl, and cycloheptyrenyl.

[0200] As used herein, the term “heterocycloalkylenyl” refers to a divalent heterocycloalkyl as defined herein. The term “heterocycloalkyl” refers to a 3- to 15-membered non-aromatic, saturated, or partially saturated bicyclic, spirocyclic, monocyclic, or polycyclic bridging ring system, which, unless otherwise specified, has at least one heteroatom or heterogroup selected from O, N, S, 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 “heterocycloalkyl” also refers to a bicyclic bridging ring system having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O)₂, NH, and C(O). Examples of "heterocycloalkyl" include, but are not limited to, azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, dihydropyridinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, dioxidethiomorpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, indolinyl, indolinylmethyl, isoindolinyl, oxoisoindolinyl, dioxoisoindolinyl, azabicyclooctanyl, diazabicyclooctanyl, azosinyl, chromanyl, isochromanyl, xanthenyl, and 2-oxa-6-azaspiro[3.3]heptanyl. Therefore, examples of "heterocycloalkylenyls" include, but are not limited to, azetidinylenil, oxetanylenil, pyrrolidinylenil, piperidinylenil, piperadinylenil, tetrahydropyridinylenil, diazobicyclooctanylenil, azabicyclooctanylenil, azaspiroheptanylenil, tetrahydropyranil, tetrahydropyridadinylenil, morpholinylenil, thiomorpholinylenil, 1,4-dioxanylenil, dioxidethiomorpholinylenil, oxapiperazinylenil, oxapiperidinylenil, tetrahydropyranylenil, dihydropyranylenil, and dihydropyrimidinylenil.The bonding of heterocycloalkyl substituents may occur via either a carbon atom or a heteroatom. Heterocycloalkyl groups may optionally be substituted with one or more preferred groups, including one or more of the aforementioned groups. Preferably, "heterocycloalkyl" means a 5- to 6-membered ring (unless the ring size is specifically mentioned) selected from imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, and thiomorpholinyl. All heterocycloalkyl groups are optionally substituted with one or more of the aforementioned groups.

[0201] As used herein, the term “heteroarylenyl” refers to a divalent heteroaryl as defined herein. The term “heteroaryl,” alone or in combination with other terms, means a fully unsaturated ring system containing a total of 5 to 14 ring atoms unless the ring size is specifically mentioned. At least one of the ring atoms is a heteroatom (i.e., O, N, or S), and the remaining ring atoms / groups are independently selected from C, N, O, and S. A heteroaryl may be monocyclic (monocyclic formula) or polycyclic (bicyclic, tricyclic, polycyclic) that are integrally condensed or covalently bonded. Unless the ring size is specifically mentioned, a “heteroaryl” is preferably a 5- to 6-membered ring. The ring may contain 1 to 4 additional heteroatoms selected from N, O, and S, and the N atoms are optionally quaternized. Preferred ring positions of the teloaryl moiety may also be covalently bonded to the defined chemical structure. Examples of "heteroaryls" include furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl (pyridinyl), 3-fluoropyridyl, pyrimidinyl, pyrazinyl, pyridadinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, benzotriazinyl, phthalazinyl, thiantrene, dibenzofuranyl, dibenzothi Examples include, but are not limited to, enyl, benzimidazolyl, indol, isoindol, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purinyl, pteridinyl, 9H-carbazoyl, α-carbolinyl, indolidinyl, benzoisothiazolyl, benzoxazolyl, pyrrolopyridyl, phlopyridinyl, purinyl, benzothiadiazolyl, benzoxadiazolyl, benzotriazolyl, benzotriasiazolyl, carbazoyl, dibenzothienyl, and acridinyl.Therefore, examples of heteroaryl lenyls include, but are not limited to, franylenyl, thienylenyl, pyrrolylenenyl, pyrazolilenyl, imidazolylenyl, oxazolilenyl, isoxazolilenyl, thiazolylenyl, isothiazolilenyl, 1H-tetrazolylenyl, oxadiazolylenyl, triazolylenyl, pyridylenyl (pyridinylenyl), pyrimidinylenyl, pyradidinelenyl, and pyridadinylenyl. The heteroaryl group may be further substituted at will.

[0202] As used herein, the term “alkenyl” refers to a carbon chain containing at least one carbon-carbon double bond and which may be linear, branched, or a combination thereof. Examples of “alkenyls” include, but are not limited to, vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, and 2-methyl-2-butenyl.

[0203] As used herein, the term "amino" refers to the -NH2 group.

[0204] As used herein, the terms "halo" or "halogen," alone or in combination with other terms, mean fluorine, chlorine, bromine, or iodine.

[0205] As used herein, the terms "hydroxy" or "hydroxyl," alone or in combination with other terms, mean -OH.

[0206] As used herein, the term "oxo" refers to the O group.

[0207] As used herein, the term "alkoxy" refers to the -O-alkyl group, where alkyl groups are as defined above. Exemplary C1-C 10Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, t-butoxy, or n-pentoxy. The alkoxy group can be optionally substituted with one or more suitable groups. Preferably, the term "alkoxy" refers to a C1-C4 alkoxy group. Some examples of C1-C4 alkoxys include methoxy, ethoxy, n-propoxy, n-butoxy, or t-butoxy.

[0208] The term "aryl," when used herein either alone or as part of another group, means a monocyclic, bicyclic, or polycyclic aromatic hydrocarbon ring system having 6 to 14 carbon atoms. Preferably, "aryl" is (C6-C 10 The term refers to aryl groups. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, indanyl, biphenylenyl, and acenaphthyl. The preferred aryl group is phenyl. The term "alkylene" refers to a divalent aryl group. Therefore, examples of arylenyls include, but are not limited to, phenylenyl, naphthylenyl, biphenylenyl, and anthrylenyl.

[0209] The term "acyl" refers to the group R-CO- or -CO-R, where R is an alkyl group substituted with any choice as defined above. Examples of "acyl" groups include, but are not limited to, CH3CO-, CH3CH2CO-, CH3CH2CH2CO-, or (CH3)2CHCO-.

[0210] As used herein, the term “heteroatom” refers to a sulfur, nitrogen, or oxygen atom.

[0211] As used herein, the term “compound” includes the compounds disclosed in this invention. The term “salt / salts” includes alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., magnesium), ammonium, and N + (C 1-4This refers to a salt derived from a suitable base, including an alkyl(4) salt.

[0212] As used herein, the terms “comprise” or “comprising” generally mean “include,” that is, to allow the presence of one or more functions or components.

[0213] As used herein, the term "or" means "and / or" unless otherwise specified.

[0214] As used herein, the term “including” is not limited to other forms such as “include,” “includes,” and “included.”

[0215] As used herein, the term “composition” is intended to encompass not only products containing specific amounts of specific components, but also all products obtained directly or indirectly from specific combinations of specific components in specific amounts. “Pharmacologically acceptable” means that the carrier, diluent, or excipient must be compatible with the other components of the formulation and must not be harmful to the recipient.

[0216] As used herein, the term "pharmaceutical composition" means a pharmaceutical 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.

[0217] A pharmaceutical composition typically contains about 1% to 99% by weight, for example, about 5% to 75% by weight, about 10% to 50% by weight, or about 10% to 30% by weight, of the 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 can be in the range of about 1 mg to about 1000 mg, about 2.5 mg to about 500 mg, or about 5 mg to about 250 mg, or a wide range of 1 mg to 1000 mg higher or lower than the aforementioned ranges.

[0218] As used herein, the expression “pharmaceutically acceptable carrier, diluent, or excipient” includes, but is not limited to, any adjuvants, carriers, excipients, lubricants, sweeteners, diluents, preservatives, dyes / colorants, flavorings, surfactants, humectants, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers approved by the U.S. Food and Drug Administration as acceptable for use in human or domestic animal.

[0219] As used in this disclosure, the terms “administer,” “administering,” or “administration” refer to directly administering one or more of the compounds of this disclosure, a pharmaceutically acceptable salt thereof, or a composition comprising one or more of the compounds of this disclosure, or indirectly administering a prodrug derivative or analog of the compound, or a pharmaceutically acceptable salt of the compound or composition, thereby generating an equivalent amount of the active compound in the subject’s body.

[0220] As used in this disclosure, the term “carrier” encompasses carriers, excipients, and diluents, and means any material, composition, or vehicle necessary to transport or deliver a pharmaceutical product from one organ or body part to another, including liquid or solid fillers, diluents, excipients, solvents, and encapsulating materials.

[0221] In this specification, the terms “treat,” “treating,” and “treatment” mean a method of alleviating or inhibiting a disease and / or its associated symptoms.

[0222] As used herein, the term “subject” refers to an animal, preferably a mammal, most preferably a human.

[0223] As used herein, “delaying the progression” of a disease means delaying, preventing, slowing, postponing, stabilizing, and / or prolonging the onset of a disease (such as cancer). This delay can be of varying lengths depending on the medical history and / or the history of the individual being treated. As will be apparent to those skilled in the art, a sufficient or significant delay may include prevention in that the individual has not actually developed the disease. For example, late-stage cancers, such as the onset of metastasis, may be delayed.

[0224] As used herein, the term “therapeutic dose” means an amount of the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, or a composition comprising the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, that is effective for use in a specific subject suffering from a disease or disorder, specifically for use in a disease or disorder related to cancer mediated by SMARCA2 and / or SMARCA4. Specifically, the term “therapeutic dose” includes an amount of the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, that is considered sufficient to induce a positive modification to the disease or disorder being treated when administered, or to prevent or moderately mitigate the onset of one or more symptoms of the disease or disorder being treated. With respect to the therapeutic dose of the compound, the amount of the compound used for the treatment of the subject may also be considered within reasonable medical standards, so as to avoid excessive or severe side effects. The therapeutically effective dose of a compound or composition will vary depending on the specific disease being treated, the severity of the disease being treated or prevented, the duration of treatment, the nature of the concurrent therapy, the age and physical condition of the subject, the specific compound or composition used, and the specific pharmaceutically acceptable carrier used.

[0225] "Pharmacologically acceptable" means that it is safe and non-toxic overall and useful in the preparation of a pharmaceutical composition that is biologically or otherwise undesirable, and includes being acceptable for veterinary and human pharmaceutical use.

[0226] The term "pharmaceutically acceptable salt" refers to a product obtained by reacting the compound of the present invention with a suitable acid or base. Examples of pharmaceutically acceptable salts of the compound of the present invention include salts derived from suitable bases such as Li salts, Na salts, K salts, Ca salts, Mg salts, Fe salts, Cu salts, Al salts, Zn salts, and Mn salts. Examples of pharmaceutically acceptable and non-toxic acid addition salts are salts of amino groups formed with inorganic acids, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartaric acid, pantothenate, hydrogen tartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharinate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, 4-methylbenzenesulfonate, or p-toluenesulfonate. Certain compounds of the present invention (compounds of formula (I)) can form pharmaceutically acceptable salts containing various organic bases such as lysine, arginine, guanidine, diethanolamine, or metformin. Suitable basic salts include, but are not limited to, aluminum salts, calcium salts, lithium salts, magnesium salts, potassium salts, sodium salts, or zinc salts.

[0227] Throughout this specification, the term "cancer" means a malignant or malignant neoplasm, a pathological process resulting in the formation and proliferation of abnormal tissue that grows faster than normal by cell proliferation and continues to grow even after stimulation initiated to stop further growth. Malignant neoplasms are characterized by a partial or complete lack of structural organization and functional cooperation between normal tissue and most invasive surrounding tissue, and they can metastasize to various sites, recur after attempted removal, and, if not properly treated, can be fatal to the patient. As used herein, the term neoplasia is used to describe all cancerous disease conditions and encompasses or includes the pathological processes associated with hematopoietic, ascites, and solid malignancies. In one embodiment, cancer is a SMARCA2 and / or SMARCA4-mediated cancer.Examples of cancers include hematological 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, promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granuloleukocyte) leukemia, chronic myeloid leukemia, colon cancer, and colorectal cancer. Cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, abnormal proliferative changes (dysplasia and dysplasia), fetal cancer, endometrial cancer, endosplenomegaly, ependymoma, epithelial malignancy, 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, liver cancer, hepatocellular carcinoma, hormone-sensitive prostate cancer, leiomyosarcoma, leukemia, lipid Liposarcoma, liver cancer, intralymphatic sarcoma, lymphangiosarcoma, lymphocytic leukemia, lymphoma (Hodgkin type, non-Hodgkin type, Burkitt type), malignant lesions and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin, and uterus, T-cell or B-cell origin lymphoid neoplasms, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT plagioclase (NMC), oligodendroglioma, oral cancer, bone cancer This includes, but is not limited to, sarcomas, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pineal gland tumor, primary polycythemia, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, malignant rhabdoid tumor (MRT), rhabdomyosarcoma, sarcoma, sebaceous carcinoma, seminomas, skin cancer, small cell lung cancer, solid tumors (cytomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synoviomas, sweat gland carcinomas, thyroid cancer, Waldenström macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor.

[0228] The term “stereoisomer” refers to any enantiomer, diastereomer, or geometric isomer of the compound of formula (I), in which case they are always chiral or have one or more double bonds. When compounds represented by formula (I) and related formulas are chiral, they can exist in racemic or optically active forms. It should be understood that the present invention encompasses all forms of stereochemical isomers, including diastereomers, enantiomers, and epimers, as well as D and L isomers, and mixtures thereof. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials with chiral centers, or by separation such as preparation of a mixture of enantiomer products, then conversion to a mixture of diastereomers, followed by separation or recrystallization, chromatography, direct separation of enantiomers on a chiral chromatography column, or any other suitable method known in the art. Starting compounds for specific stereochemistrys are commercially available or can be prepared and decomposed by techniques known in the art. In addition, the compounds of the present invention may also exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as suitable mixtures thereof.

[0229] The term "enantiomer" refers to a pair of stereoisomers that are mirror images of each other but cannot be superimposed. The term "enantiomer" also refers to a single part of this pair of stereoisomers. The term "racemic compound" refers to a 1:1 mixture of a pair of enantiomers. This disclosure includes enantiomers of the compounds described herein. The compounds disclosed herein include all enantiomers that correspond to the overall structure of each compound. Compounds may be in racemic form, enantiomerically pure form, or any other form from a stereochemical standpoint. In some embodiments, the compounds are (S)-enantiomers.

[0230] The term “diastereomer” refers to a set of stereoisomers that cannot be superimposed by rotation around a single bond. For example, compounds with cis and trans double bonds, endo and exo substitutions on bicyclic ring systems, and multiple stereocenters with different relative configurations are considered diastereomers. The term “diastereomer” refers to any member of this set of compounds. In some of the examples presented, this synthetic route may also yield a single diastereomer or a mixture of diastereomers. This disclosure includes diastereomers of compounds described herein.

[0231] Pharmaceutical composition The compounds of the present invention may be used as single drugs or as pharmaceutical compositions in which the compounds are mixed with various pharmacologically acceptable materials.

[0232] The compounds of the present invention are typically administered in the form of pharmaceutical compositions. Such compositions can be prepared using procedures well known in the pharmaceutical field and contain at least one of the compounds of the present invention. The pharmaceutical compositions of this patent application comprise one or more of the compounds described herein and one or more pharmaceutically acceptable excipients. Typically, pharmaceutically acceptable excipients are approved by regulatory authorities or are generally considered safe for use in humans or animals. Examples of pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, lubricants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents, viscosifying agents, and solvents.

[0233] Pharmaceutical compositions can be administered orally, parenterally, or by inhalation. Examples of parenteral administration include injection, transdermal administration, transmucosal administration, nasal administration, and transpulmonary administration.

[0234] Examples of suitable carriers include, but are not limited to, water, saline solution, alcohols, polyethylene glycol, peanut oil, olive oil, gelatin, lactose, clay, sucrose, dextrin, magnesium carbonate, sugars, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, fatty acid esters, and polyoxyethylenes.

[0235] The pharmaceutical composition may also contain one or more pharmaceutically acceptable excipients, humectants, suspending agents, preservatives, buffers, sweeteners, flavorings, colorants, or any combination thereof.

[0236] The pharmaceutical composition may be in conventional forms, such as tablets, capsules, solutions, suspensions, injections, or products for topical administration. Furthermore, the pharmaceutical composition of the present invention may be formulated to provide desired release characteristics.

[0237] The compound of the present invention, in its pure form or in a suitable pharmaceutical composition, can be administered using any route of administration accepted for the pharmaceutical composition. The route of administration may be any route that effectively delivers the active compound of this application to a suitable or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, buccal, cutaneous, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, ​​intramuscular, or topical administration.

[0238] Examples of solid oral preparations include, but are not limited to, tablets, capsules (soft or hard gelatin), sugar-coated tablets (containing the active ingredient in powder or pellet form), lozenges, and troches.

[0239] Liquid formulations include, but are not limited to, suspensions and solutions such as syrups, emulsions, and sterile injection solutions.

[0240] Topical dosage forms of the compound include ointments, pastes, creams, lotions, powders, solutions, eye drops, ear drops, and impregnated dressings, which may contain conventional appropriate additives such as preservatives and solvents that aid drug penetration.

[0241] The preferred doses of the compounds for use in treating the diseases or disorders described herein can be determined by those skilled in the art. The therapeutic dose is generally determined by dose-range studies in humans based on prior evidence derived from animal studies. The dose must be sufficient to produce the desired therapeutic benefit without causing unwanted side effects. The dosage form, formulation, and preferred excipients can also be readily used and modified by those skilled in the art. Any changes and modifications are conceived within the scope of this application.

[0242] The term “prodrug” is intended to indicate a compound that can be converted under physiological conditions or biologically by solvolysis to a bioactive compound described herein (e.g., the compound of structure (I)). Thus, the term “prodrug” means a precursor of a pharmaceutically acceptable bioactive compound. In some embodiments, a prodrug is inactive when administered to a subject but is converted in vivo to an active compound, for example, by hydrolysis. Prodrug compounds often offer advantages in mammals such as solubility, tissue compatibility, or delayed release (see, for example, Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam) by Bundgard, H.). The discussion of prodrugs is provided in "Pro-drugs as Novel Delivery Systems" by Higuchi, T. et al., ACSSymposium Series, Vol. 14, and in "Bioreversible Carriers in Drug Design," ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are fully incorporated herein by reference. The term "prodrug" is also intended to include any covalent carrier that, when administered to a mammalian subject, releases an active compound in vivo. Prodrugs of active compounds described herein are typically prepared by modifying a functional group present in the active compound, either through conventional procedures or in vivo, such that the modification is cleaved back to the parent active compound. A prodrug is a compound in which a hydroxyl group, an amino group, or a mercapto group is cleaved when the prodrug of the active compound is administered to a mammalian subject, forming a free hydroxyl group, a free amino group, or a free mercapto group, respectively.Examples of prodrugs include, but are not limited to, derivatives of acetate, formate, and benzoate salts of hydroxyl functional groups, or acetamide derivatives, formamide derivatives, and benzamide derivatives of amine functional groups in active compounds.

[0243] In some embodiments, the prodrug comprises a compound of structure (I) having substituents of phosphate, phosphoalkoxy, ester, or boronic acid ester. While not theoretically bound, such substituents are thought to be converted to hydroxyl groups under physiological conditions. Thus, embodiments include any of the compounds of the present invention, in which the hydroxyl group is substituted with a phosphate, phosphoalkoxy, ester, or boronic acid ester group, such as a phosphate group or a phosphoalkoxy group. For example, in some embodiments, the hydroxyl group on the R4 or R9 moiety is substituted with a phosphate, phosphoalkoxy, ester, or boronic acid ester group, such as a phosphate group or a phosphate alkoxy group.

[0244] According to one embodiment, the compounds of the present invention may also contain atomic isotopes in an unnatural ratio in one or more of the atoms constituting such compounds. Except for the fact that one or more atoms of a compound are substituted with atoms having an atomic mass or mass number different from the dominant atomic mass or mass number normally found naturally for a given atom, the present invention also encompasses isotopically labeled variants of the present invention that are identical to those enumerated herein. All isotopes of specific atoms or elements defined are intended to fall within the scope of the compounds of the present invention and their use. As isotopes that can be incorporated into the compounds of the present invention, 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, 125 Examples of isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfuric acid, fluorine, chlorine, and iodine, such as I. The isotope-labeled compounds of the present invention can generally be prepared by replacing the isotope-labeling reagent with a non-isotope-labeling reagent, following a procedure similar to that disclosed in the following scheme and examples.

[0245] experiment The abbreviations used throughout this specification, along with their meanings, are summarized below.

[0246] MeOH - methanol, EtOH - ethanol, DCM - dichloromethane, DMF - N,N-dimethylformamide, siRNA - 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) dichloride dichloromethane complex, Pd(OAc)2- Palladium(II) acetate, Pd2(dba)3- Tris(dibenzylideneacetone)dipalladium(O), mL - Milliliter, TLC - Thin-layer chromatography, RT - Room temperature, h - Time, N - Normality, M - Molar concentration 1HNMR - Proton nuclear magnetic resonance, 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 - Broadband singlet, HPLC - High-performance liquid chromatography, LCMS - Liquid chromatography-mass spectrometry, g - Gram, mmol - Millimole.

[0247] Intermediate 1: 5-bromo-3-chloropyrazine Step a: Synthesis of 5-bromo-3-chloropyrazine (1a) 4-bromo-6-chloropyridazine-3-amine (10.0 g, 48.30 mmol) was added to a stirred solution of THF (100 mL) with tert-butylnitrile (9.8 g, 82.12 mmol, 1.7 eq) at room temperature. The reaction mixture was heated in a sealed tube at 80°C for 3 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with RINKAN. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the residue. The residue was purified by combiflash column chromatography using 50-60% ethyl acetate in hexane as an eluent to obtain the title compound as an off-white solid (5.3 g, 57%). 1 H NMR (400MHz, DMSO-d6): δ9.50 (d, J = 2.0 Hz, 1H), 8.48 (d, J = 2.0 Hz, 1H); LC-MS: m / z 192.8 (M + H).

[0248] Intermediate 2: Tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-yl)acetate Step a: Synthesis of 1-(4-bromophenyl)piperazine hydrochloride A 50 mL solution of tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate (5.0 g, 14.7 mmol) in DCM was mixed with 50 mL of 4N dioxane HCl at 0°C and stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction mixture was then concentrated under vacuum to obtain the crude product. The crude product was triturated with n-pentane and dried under vacuum to obtain the pure title compound as a pale yellow solid (5 g). 1 H NMR (400MHz, DMSO-d6): δ9.29(bs,1H),7.38(d,J=9.2Hz,2H),6.94(d,J=9.2Hz,2H),5.06(m,4H),3.35(m,4H);LC-MS:m / z 354.8(M+H).

[0249] Step b: Synthesis of Tert-butyl 2-(4-(4-bromophenylpiperazin-1-yl)acetate 1-(4-bromophenyl)piperazine hydrochloride (5.0 g, 18.1 mmol) was mixed in 50 mL of DMF with DIPEA (4.66 g, 36.2 mmol) at room temperature and stirred for 15 minutes. Then, Tert-butyl 2-bromoacetate (5.3 g, 27.15 mmol) was added and the mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction mixture was quenched with cold water and stirred for 1 hour to produce a solid. This solid was filtered and dried under vacuum to obtain the title compound as an off-white solid (4.5 g, 70%).

[0250] 1 H NMR (400MHz, DMSO-d6): δ7.29(d,J=8.4Hz,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 / z 340.8(M+H).

[0251] Step c: Synthesis of tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-yl) acetate To a stirred solution of tert-butyl 2-(4-(4-bromophenylpiperazin-1-yl)acetate) (4.2 g, 11.8 mmol) in dioxane (80 mL), bis-pinacolato-diborone (4.52 g, 17.8 mmol) and KOAc (2.33 g, 23.7 mmol) were added at room temperature. After degassing with nitrogen for 5 minutes, 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 hours. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with siRNA. The combined organic layer was washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the title compound as an off-white solid (5 g, 100%). 1 H NMR(400MHz,DMSO-d6):δ7.50(d,J=8.0Hz,2H),6.89(d,J=8.8Hz,2H),3.20(bs ,4H),3.15(s,2H),2.62(d,J=4.4Hz,4H),1.41(s,9H),1.26(s,12H);LC-MS:m / z 402.7(M+H).

[0252] Intermediate 3: Ethyl 2-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-4-yl)acetate Step a: Synthesis of ethyl 2-(1-(4-bromo-2-nitrophenyl)piperidine-4-yl)acetate To a stirred solution of 4-bromo-1-fluoro-2-nitrobenzene (2.0 g, 9.1 mmol) in DMF (20 mL), ethyl 2-(piperidine-4-yl) acetate (1.87 g, 10.9 mmol) and DIPEA (3.7 g, 27.4 mmol) were added at room temperature, and the mixture was heated at 100 °C for 4 hours. The reaction mixture was quenched with cold water and extracted with siRNA. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. The crude product was purified by combiflash column chromatography using 20-25% ethyl acetate in hexane as an eluent to obtain the title compound as a yellow solid (1.3 g, 38%). 1H NMR(400MHz,DMSO-d6):δ7.99(d,J=2.4Hz,1H),7.70(dd,J=2.4,6.4Hz,1H),7.24(d,J=8.8Hz,1H),4.05(q,J=5.4Hz,2H),3.12(d,J=12.4Hz, LC-MS: m / z 371.0(M+H).

[0253] Step b: Synthesis of ethyl 2-(1-(2-amino-4-bromophenyl)piperidine-4-yl)acetate Ethyl 2-(1-(4-bromo-2-nitrophenyl)piperidine-4-yl)acetate (1.3 g, 3.5 mmol) was dissolved in methanol (10 mL) and water (3 mL). To this mixed and stirred solution, iron (3.1 g, 28 mmol) and NH4OH (1.5 g, 28 mmol) were added, and the mixture was stirred at room temperature for 4 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with methanol and filtered. The filtrate was concentrated, diluted with siRNA, washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the title compound as an off-white solid (1.2 g, 100%). 1 H NMR(400MHz,DMSO-d6):δ6.80-6.78(m,2H),6.63(dd,J=2.4&6.0Hz,1H),4.91(s,2H),4.06(q,J=7.0Hz,2H) ,2.97(d,J=11.6Hz,2H),2.27(d,J=6.8Hz,2H),1.73-1.69(m,5H),1.40-1.36(m,2H),1.19(t,J=7.0Hz,3H).

[0254] Step c: Synthesis of ethyl 2-(1-(4-bromophenyl)piperidine-4-yl)acetate To a stirred solution of ethyl 2-(1-(2-amino-4-bromophenyl)piperidine-4-yl)acetate (1.0 g, 2.9 mmol) in THF (10 mL), tert-butylnitrile (0.58 g, 5.1 mmol) was added and the mixture was stirred at room temperature for 3 hours. After the completion of the reaction (monitored by TLC), the reaction mixture was diluted with siRNA. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. The crude product was purified by combiflash column chromatography using 20% ​​ethyl acetate in hexane as an eluent to obtain the title compound as an off-white solid (0.37 g, 34%). 1 H NMR(400MHz,DMSO-d6):δ7.30(d,J=8.8Hz,2H),6.87(d,J=9.2Hz,2H),4.06(q,J=14.4Hz,2H),3.64(d,J=12.8Hz ,2H),2.67-2.62(m,2H),2.25(d,J=7.2Hz,2H),1.70(d,J=12.4Hz,3H),1.28-1.25(m,2H),1.17(t,J=7.2Hz,3H). LC-MS: m / z 326.1 (M+H).

[0255] Step d: Synthesis of ethyl 2-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-4-yl) acetate To a stirred solution of ethyl 2-(1-(4-bromophenyl)piperidine-4-yl)acetate (0.37 g, 1.13 mmol) in dioxane (10 mL), bis-pinacolato-diborone (0.45 g, 1.7 mmol) and KOAc (0.22 g, 2.27 mmol) were added at room temperature, and the mixture was degassed under nitrogen for 5 minutes. 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 hours. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with ethyl acetate. The combined organic layer was washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the residue. The residue was purified by combiflash column chromatography using 10-15% ethyl acetate in hexane as an eluent to obtain the title compound as a yellow solid (0.25 g, 58%). 1 H NMR (400MHz, DMSO-d6): δ7.48(d,J=8.4Hz,2H),6.87(d,J=8.4Hz,2H),4.06(q,J=14.4Hz,2H),3.78(d,J=12.4H) z,2H),2.75-2.66(m,1H),2.24(d,J=6.8Hz,2H),1.87(t,J=7.2Hz,1H),1.72-1.68(m,2H),1.29-1.16(m,18H). LC-MS: m / z 373.9 (M+H).

[0256] Intermediate 4: Ethyl 3-methyl-2-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazole-5-yl)butanoate Step a: Synthesis of 4-bromobenzaldehyde oxime 4-bromobenzaldehyde (30 g, 162.16 mmol) and hydroxylamine hydrochloride (14.64 g, 210.8 mmol) were dissolved in ethanol (300 mL). Pyridine (19.21 mL, 243.2 mmol) was added to the reaction mixture and the mixture was stirred at room temperature for 6 hours. After the reaction was complete, the reaction mixture was quenched with ice-cold water and stirred for 20 minutes. The resulting solid was further washed with water and dried under vacuum to obtain the crude compound. The crude compound was washed with hexane and dried under vacuum to obtain the title compound as a white solid (24 g, 74%). 1 H NMR (400MHz, DMSO-d6): δ11.37(s,1H),8.13(s,1H),7.60(d,J=10.8Hz,2H),7.54(d,J=10.4Hz,2H);LC-MS:m / z 199.9(M+H).

[0257] Step b: Synthesis of 2-(3-(4-bromophenyl)isoxazole-5-yl)ethane-1-ol 4-bromobenzaldehyde oxime (15 g, 75 mmol) was dissolved in DCM (300 mL) and NCS (12.01 g, 90 mmol) was added, and the mixture was heated at 45 °C for 30 minutes. The reaction mixture was cooled to room temperature, and buta-3-in-1-ol (6.3 g, 90 mmol) and TEA (10.52 mL, 75 mmol) were added dropwise to the reaction mixture over 15 minutes. The reaction mixture was heated again at 45 °C for 7 hours. After the reaction was complete, the reaction mixture was quenched with ice-cold water and extracted with RINKAN. The combined organic layer was washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the residue. The residue was purified by combiflash column chromatography using 10% ethyl acetate in hexane as the eluent to obtain the title compound as a white solid (7.5 g, 37%). 1 H NMR(400MHz,DMSO-d6):δ7.80(d,J=6.4Hz,2H),7.71(d,J=6.8Hz,2H),6.86(s,1H) ,4.92(t,J=10.8Hz,1H),3.75(q,J=11.6Hz,2H),2.94(t,J=12.8Hz,2H);LC-MS:m / z 267.90(M+H).

[0258] Step c: Synthesis of 2-(3-(4-bromophenyl)isoxazol-5-yl)acetic acid To a stirred solution of 2-(3-(4-bromophenyl)isoxazol-5-yl)ethan-1-ol (7.5 g, 27.9 mmol) in acetone (150 mL) was added Jones reagent (15 mL) dropwise at 0 °C, and the temperature was brought to room temperature over 2 hours. After completion of the reaction, the reaction mass was diluted with acetone and filtered. The filtrate was concentrated under vacuum to obtain the crude product. The crude product was triturated with hexane and dried under vacuum to give the pure title compound as an off-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).

[0259] Step d: Synthesis of ethyl 2-(3-(4-bromophenyl)isoxazol-5-yl)acetate To a stirred solution of 2-(3-(4-bromophenyl)isoxazol-5-yl)acetic acid (7 g, 24.9 mmol) in ethanol (140 mL) was added H2SO4 (7 mL) dropwise at 0 °C, and then the mixture was heated at 80 °C for 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated and then diluted with EtOAc. The combined organic layers were washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a residue, which was purified by combiflash column chromatography using 7% ethyl acetate in hexane as the eluent to give the title compound as an off-white solid (5.8 g, 76%).

[0260] 1 H NMR (400 MHz, DMSO-d6): δ 7.82 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 6.99 (s, 1H), 4.17 (q, J = 14.4 Hz, 2H), 4.08 (s, 2H), 1.22 (t, J = 14.4 Hz, 3H); LC-MS: m / z 309.9 (M+H).​

[0261] Step e: Synthesis of ethyl 2-(3-(4-bromophenyl)isoxazole-5-yl)-3-methylbutanoate In a solution of ethyl 2-(3-(4-bromophenyl)isoxazole-5-yl) acetate (5.8 g, 18.77 mmol) in THF (80 mL), KO t A 1M Bu solution (28.1 mL, 28.1 mmol) was added dropwise at 0°C and the mixture was stirred for 15 minutes. Then, 2-iodopropane (2.25 mL, 22.5 mmol) was added to the reaction mixture and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was quenched with ice-cold water and extracted with RINKAN. The combined organic layer was washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a residue. The residue was purified by combiflash column chromatography using 4-5% ethyl acetate in hexane as an eluent to obtain the title compound as a colorless liquid (3.8 g, 57%). 1 H NMR (400MHz, DMSO-d6): δ7.84(d,J=8.8Hz,2H),7.72(d,J=8.0Hz,2H),7.05(s,1H),4.16(q,J=7.2Hz,2H),3.8 5(d,J=8.0Hz,1H),2.38(m,1H),1.19(t,J=14.4Hz,3H),0.98(d,J=6.4Hz,3H)0.89(d,J=6.8Hz,3H);LC-MS:m / z 351.9(M+H).

[0262] Step f: Synthesis of ethyl 3-methyl-2-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazole-5-yl)butanoate To a stirred solution of ethyl 2-(3-(4-bromophenyl)isoxazole-5-yl)-3-methylbutanoate (3.8 g, 10.82 mmol) in dioxane (50 mL), bis-pinacolate diborone (4.12 g, 16.2 mmol) and KOAc (2.12 g, 21.6 mmol) were added at room temperature, and the mixture was degassed under nitrogen for 5 minutes. 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 hours with stirring. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with ethyl acetate. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the title compound as a colorless liquid (4.1 g, 94%). 1 H NMR (400MHz, DMSO-d6): δ7.90(d,J=8.0Hz,2H),7.79(d,J=7.6Hz,2H),7.05(s,1H),4.18(q,J=11.2Hz,2H),3.85(d,J=8. LC-MS:m / z 400.2(M+H).

[0263] Intermediate 5: 4-(6-chloropyridazine-4-yl)phenol Step a: Synthesis of 4-(6-chloropyridazine-4-yl)phenol 5-bromo-3-chloropyrazine (5 g, 26.04 mmol) and (4-hydroxyphenyl)boronic acid (3.3 g, 23.4 mmol) were dissolved in 1,4-dioxane (70 mL) and water (15 mL). To a stirred solution, Na2CO3 (7 g, 65.1 mmol) was added, and the mixture was degassed under nitrogen for 15 minutes. 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 hours. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with ethyl acetate. The combined organic layer was washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a residue. The residue was purified by combiflash column chromatography using 60% ethyl acetate in hexane as an eluent to obtain the title compound as an off-white solid (0.5 g, 23%). 1 H NMR (400MHz, CDCl3): δ10.19(s,1H),9.61(d,J=2Hz,1H),8.15(d,J=2Hz,1H),7.89(d,J=8.8Hz,2H),6.95(d,J=8.8Hz,2H);LC-MS:m / z 206.9(M+H).

[0264] Intermediate 6: Ethyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-4-carboxylate Intermediate 6 was prepared by following the same procedure as described for intermediate 3, with appropriate modifications to the reactants, reagent quantities, protection and deprotection, solvent, and reaction conditions.

[0265] 1H NMR(400MHz,DMSO-d6):δ7.48(d,J=8.4Hz,2H),6.88(d,J=8.4Hz,2H),4.05(q,J=7.2Hz,2H)3.73(d,J=13.2Hz, 2H), 2.83(td,J=13.2,2.4Hz,2H),2.54(m,1H),1.86(m,2H),1.60(m,2H),1.24(s,12H),1.17(t,J=7.2Hz,3H).

[0266] Intermediate 7: Tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-yl)acetate Step a: Synthesis of tert-butyl 4-(4-bromophenyl)-3,6-dihydropyridine-1(2H)-carboxylate 1-Bromo-4-iodobenzene (1 g, 3.53 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.87 g, 2.82 mmol) were dissolved in 1,4-dioxane (10 mL) and water (2.5 mL). K2CO3 (1.22 g, 8.83 mmol) was added to the stirred solution, and the mixture was degassed under nitrogen for 15 minutes. 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 hours. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with ethyl acetate. The combined organic layers were washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a residue. The residue was then purified by combiflash column chromatography using 50% ethyl acetate in hexane as an eluent to obtain the title compound as an off-white solid (1.3 g, 83%). 1 H NMR(400MHz,DMSO-d6):δ7.53(d,J=8Hz,2H),7.39(d,J=8Hz,2H),6.20(s,1H),3.98(bs,2H),3.52(t,J=5.2Hz,2H),2.43(bs,2H),1.42(s,9H);LC-MS:m / z 338.0(M+H).

[0267] Step b: Synthesis of 4-(4-bromophenyl)-1,2,3,6-tetrahydropyridine hydrochloride To a stirred solution of tert-butyl 4-(4-bromophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (1 g, 2.95 mmol) in DCM (15 mL) was added a solution of 4M HCl in 1,4-dioxane (5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure and washed with diethyl ether to afford the title compound (0.8 g, 98%).

[0268] 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).

[0269] Step c: Synthesis of tert-butyl 2-(4-(4-bromophenyl)-3,6-dihydropyridin-1(2H)-yl)acetate To a stirred solution of (4-(4-bromophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (0.8 g, 2.91 mmol) in DMF (10 mL) was added DIPEA (1.12 g, 8.73 mmol) at room temperature. After stirring for 15 minutes, tert-butyl 2-bromoacetate (0.56 g, 2.91 mmol) was added and the mixture was stirred at room temperature for 4 hours under a nitrogen atmosphere. The reaction mixture was quenched with cold water, stirred for 1 hour, and the resulting solid was filtered and dried under vacuum to afford the title compound as a yellow solid (1.3 g, 97%).

[0270] 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).

[0271] Step d: Synthesis of tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-yl) acetate To a stirred solution of tert-butyl 2-(4-(4-bromophenyl)-3,6-dihydropyridine-1(2H)-yl) acetate (0.5 g, 1.41 mmol) in dioxane (20 mL), bis-pinacolato-diborone (0.43 g, 1.70 mmol) and KOAc (0.28 g, 2.83 mmol) were added at room temperature. After degassing with nitrogen for 5 minutes, 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 hours. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with ethyl acetate. The combined organic layer was washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the title compound as an off-white solid (0.5 g, 88%). 1 H NMR(400MHz,DMSO-d6):δ7.63(d,J=10.8Hz,2H),7.43(d,J=10.8Hz,2H),6.22(s,1 H),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).

[0272] The compounds listed in Table 1 were prepared using the same procedure as described in Intermediate 7, with appropriate modifications to the reactants, reagent quantities, protection and deprotection, solvent, and reaction conditions. The characteristic analysis data for each compound is summarized in the table below.

[0273] [Table 2-1]

[0274] [Table 2-2]

[0275] Intermediate 8: Tert-butyl 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate Step i: Synthesis of tert-butyl 4-(4-bromo-2-fluorophenyl)piperazine-1-carboxylate In a toluene (20 mL) stirred solution of 4-bromo-2-fluoro-1-iodobenzene (1 g, 3.23 mmol) and N-Boc piperazine (0.63 g, 3.39 mmol), NaO t Bu (0.93 g, 9.63 mmol) was added, and the mixture was stirred under nitrogen for 15 minutes. Then Pd2(dba)3 (0.146 g, 0.16 mmol) and Xantphos (0.09 g, 0.16 mmol) were added, and the reaction mixture was heated in a sealed tube at 120°C for 6 hours. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with RINKAN. The combined organic layer was washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the residue. The residue was purified by combiflash column chromatography using 60% ethyl acetate in hexane as an eluent to obtain the title compound as an off-white solid (0.65 g, 54%).

[0276] 1 H NMR (400MHz, CDCl3): δ7.44(d,J=11.6Hz 1H),7.30(d,J=8.8Hz,1H),7.00(t,J=8.8Hz,1H),3.45(m,4H),2.94(m,4H),1.44(s,9H);LC-MS:m / z 358.9(M+H).

[0277] Step ii: Synthesis of tert-butyl 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate To a stirred solution of tert-butyl 4-(4-bromo-2-fluorophenyl)piperazine-1-carboxylate (0.65 g, 1.81 mmol) in dioxane (10 mL), bis-pinacolato-diborone (0.55 g, 2.17 mmol) and KOAc (0.53 g, 5.43 mmol) were added at room temperature. After degassing with nitrogen for 5 minutes, 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 hours. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with ethyl acetate. The combined organic layer was washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the title compound as an off-white solid (0.65 g, 88%). 1 H NMR (400MHz, DMSO-d6): δ7.43(dd,J=8.0,1.2Hz,1H),7.37(dd,J=8.0,1.2Hz,1H),6. 82(t,J=8.8Hz,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).

[0278] Intermediate 9: Ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-yl)propanoate Step a: Synthesis of ethyl 2-(4-(4-bromophenyl)-3,6-dihydropyridine-1(2H)-yl)propanoate To a stirred solution of 4-(4-bromophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (1 g, 3.64 mmol) in DMF (10 mL), DIPEA (2.35 g, 18.2 mmol) was added at room temperature and the mixture was stirred for 15 minutes. Then, ethyl 2-bromopropanoate (0.79 g, 4.37 mmol) was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. The reaction mixture was quenched with cold water and stirred for 1 hour. The resulting solid was filtered and dried under vacuum to obtain the title compound as an off-white solid (0.8 g, 56%). 1H NMR (400MHz, DMSO-d6): δ7.46(d,J=8Hz,2H),7.33(d,J=8Hz,2H),6.15(s,1H),4.07(m,2H),3.39 (q,J=6.8Hz,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).

[0279] Step b: Synthesis of ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-yl)propanoate To a stirred solution of ethyl 2-(4-(4-bromophenyl)-3,6-dihydropyridine-1(2H)-yl)propanoate (0.8 g, 2.36 mmol) in dioxane (15 mL), bis-pinacolato-diborone (0.9 g, 3.54 mmol) and KOAc (0.69 g, 7.09 mmol) were added at room temperature. After degassing with nitrogen for 5 minutes, Pd(dppf)Cl2.DCM (0.19 g, 0.23 mmol) was added to the reaction mixture and the mixture was heated at 80 °C for 16 hours. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with ethyl

[0280] 1 H NMR(400MHz,DMSO-d6):δ7.62(d,J=10.8Hz,2H),7.42(d,J=10.8Hz,2H),6.22(s,1H),4.11( m,2H),3.43(q,J=6.8Hz,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).

[0281] Intermediate 10: Ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-yl)propanoate Intermediate 10 was prepared using the same procedure as described for intermediate 9, with appropriate modifications to the reactants, reagent quantities, protection and deprotection, solvent, and reaction conditions. LC-MS: m / z 389.3 (M+H).

[0282] Intermediate 11: Ethyl 2-(4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl) acetate Step a: Synthesis of ethyl 2-(4'-bromo-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)acetate 1-Bromo-4-iodobenzene (0.8 g, 2.82 mmol) and ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexa-3-en-1-yl) acetate (0.99 g, 3.39 mmol) were dissolved in 1,4-dioxane (8 mL) and water (1 mL). K2CO3 (0.97 g, 7.07 mmol) was added to the stirred solution, and the mixture was degassed with nitrogen for 15 minutes. Pd(dppf)Cl2.DCM (0.23 g, 0.28 mmol) was added, and the reaction mixture was heated in a sealed tube at 100°C for 6 hours. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with ethyl acetate. The combined organic layers were washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a residue. The residue was then purified by combiflash column chromatography using 50% ethyl acetate in hexane as an eluent to obtain the title compound as a colorless liquid (0.48 g, 52%). 1 H NMR(400MHz,DMSO-d6):δ7.49(d,J=8.4Hz,2H),7.36(d,J=8.4Hz,2H),6.16(d,J=2Hz,1H),4.08(q,J=6.8Hz, 2H),2.39(bs,2H),2.31(d,J=7.2Hz,2H),2.28(m,1H),1.83-2.05(m,3H),1.38(m,1H),1.19(t,J=6.8Hz,3H).

[0283] Step b: Synthesis of ethyl 2-(4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl) acetate 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), bis-pinacolato-diborone (0.58 g, 2.32 mmol) and KOAc (0.38 g, 3.86 mmol) were added at room temperature. After degassing with nitrogen for 5 minutes, 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 hours. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with ethyl acetate. The combined organic layer was washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the title compound as a colorless, viscous solid (0.48 g, 83%). 1 H NMR (400MHz, DMSO-d6): δ7.61(d,J=8Hz,2H),7.41(d,J=8Hz,2H),6.19(bs,1H),4.07(q,J=6.8Hz,2 H),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=6.8Hz,3H).

[0284] Intermediate 12: Ethyl 4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-carboxylate Intermediate 12 was prepared using the same procedure as described for intermediate 11, with appropriate modifications to the reactants, reagent quantities, protection and deprotection, solvent, and reaction conditions. 1H NMR(400MHz,DMSO-d6):δ7.61(d,J=8Hz,2H),7.41(d,J=8Hz,2H),6.22(bs,1H),4.09(q,J=6.8Hz,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=6.8Hz,3H);LC-MS:m / z 357.3(M+H).

[0285] Intermediate 13: Tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-8-azabicyclo[3.2.1]octa-2-ene-8-carboxylate Intermediate 13 was prepared using the same procedure as described for intermediate 11, with appropriate modifications to the reactants, reagent quantities, protection and deprotection, solvent, and reaction conditions. 1 H NMR (400MHz, DMSO-d6): δ7.62(d,J=7.6Hz,2H),7.41(d,J=7.6Hz,2H),6.61(d,J=5.2Hz,1H),4.38(m, 2H),2.95(m,1H),2.05-2.33(m,2H),1.85(m,2H),1.63(m,1H),1.37(s,9H),1.28(s,12H);LC-MS:m / z 312.3(M+H).

[0286] Intermediate 14: Tert-butyl(1R,5S)-8-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate Step a: Synthesis of tert-butyl(1R,5S)-8-(4-bromophenyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate To a 30 mL stirred solution of 1-bromo-4-iodobenzene (1.6 g, 5.65 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1.43 g, 6.78 mmol) in toluene, KOtBu (1.55 g, 13.89 mmol) was added and the mixture was stirred under nitrogen for 15 minutes. Then, Pd2(dba)3 (0.25 g, 0.28 mmol) and Xantphos (0.16 g, 0.28 mmol) were added, and the reaction mixture was heated in a sealed tube at 110 °C for 16 hours. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with RINKAN. The combined organic layers were washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a residue. The residue was then purified by combiflash column chromatography using 50% ethyl acetate in hexane as an eluent to obtain the title compound as an off-white solid (1.1 g, 53%). 1 H NMR(400MHz,DMSO-d6):δ7.24(d,J=8Hz,2H),6.59(d,J=8Hz,2H),4.08(m,2H),3.65(d,J=12.8Hz, 1H),3.51(d,J=12.8Hz,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).

[0287] Step b: Synthesis of tert-butyl(1R,5S)-8-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate To a stirred solution of tert-butyl(1R,5S)-8-(4-bromophenyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1.1 g, 2.99 mmol) in dioxane (5 mL), bis-pinacolato-diborone (1.14 g, 4.49 mmol) and KOAc (0.88 g, 8.9 mmol) were added at room temperature. After degassing with nitrogen for 5 minutes, 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 hours. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with ethyl acetate. The combined organic layer was washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the title compound as a pale yellow solid (0.5 g, 40%). 1 H NMR (400MHz, DMSO-d6): δ7.49(d,J=8Hz,2H),6.83(d,J=8Hz,2H),4.34(m,2H),3.42-3.5 8(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).

[0288] Intermediate 15: (1'-(Tert-butoxycarbonyl)-1',2',3',6'-tetrahydro-[2,4'-bipyridine]-5-yl)boronic acid Intermediate 15 was prepared using the same procedure as described for intermediate 11, with appropriate modifications to the reactants, reagent quantities, protection and deprotection, solvent, and reaction conditions. 1 H NMR(400MHz,DMSO-d6):δ8.72(s,1H),7.96(m,2H),7.55(d,J=8Hz,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).

[0289] Intermediate 16: Methyl 5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)pentanoate Step a: Synthesis of methyl 5-((4-bromophenyl)amino)pentanoate 4-bromoaniline (0.5 g, 2.90 mmol) was mixed in DMF (5 mL) with K2CO3 (0.14 g, 2.90 mmol) at room temperature and stirred for 15 minutes. Then, methyl-2-bromopropanoate (1.13 g, 5.81 mmol) was added, and the mixture was stirred at 60°C for 14 hours under a nitrogen atmosphere. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with ice-cold water and extracted with RINKAN. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the residue. The residue was purified by combiflash column chromatography using 10% ethyl acetate in hexane as an eluent to obtain the title compound as an off-white solid (0.28 g, 33%). 1 H NMR(400MHz,DMSO-d6):δ7.22(dd,J=8.8,1.6Hz,2H),6.53(dd,J=8.8,1.6Hz,2H ),3.61(s,3H),3.00(m,2H),2.37(t,J=7.6Hz,2H),1.52-1.68(m,4H):LC-MS:m / z 288.0(M+H).

[0290] Step b: Synthesis of methyl 5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)pentanoate To a stirred solution of methyl 5-((4-bromophenyl)amino)pentanoate (0.28 g, 0.97 mmol) in dioxane (5 mL), bis-pinacolato-diborone (0.32 g, 1.26 mmol) and KOAc (0.29 g, 2.93 mmol) were added at room temperature. After degassing with nitrogen for 5 minutes, 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 hours. Once the reaction was complete (monitored by TLC), the reaction mixture was filtered through Celite and washed with ethyl acetate. The combined organic layer was concentrated under vacuum to obtain the residue, and the residue was purified by combiflash column chromatography using 10% ethyl acetate in hexane as the eluent to obtain the title compound as a yellow solid (0.15 g, 46%).

[0291] 1 H NMR (400MHz, DMSO-d6): δ7.41(d,J=8Hz,2H),6.54(d,J=8Hz,2H),6.04(m,1H),3.61(s ,3H),3.05(m,2H),2.37(t,J=7.6Hz,2H),1.56-1.68(m,4H):1.28(s,12H);LC-MS:m / z 334.05(M+H).

[0292] Intermediate 17: Tert-butyl 2-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidine-1-yl)acetate Step a: Synthesis of Tert-butyl 3-(2-((4-methoxyphenyl)sulfonyl)hydrazineylidene)azetidine-1-carboxylate The reaction mixture of 4-methoxybenzene sulfonohydrazide (2 g, 11.68 mmol) and tert-butyl 3-oxoazetidine-1-carboxylate (2.36 g, 11.68 mmol) was stirred in toluene (40 mL), and the reaction mixture was heated in a sealed tube at 50°C for 16 hours. Once the reaction was complete (monitored by TLC), the reaction mass was concentrated under vacuum to obtain the residue, and the residue was purified by combiflash column chromatography using 40% ethyl acetate in hexane as the eluent to obtain the title compound as a white solid (1.75 g, 42%).

[0293] 1 H NMR(400MHz,DMSO-d6):δ10.81(bs,1H),7.78(dd,J=6.8,2Hz,2H),7.16(dd,J=6.8,2Hz,2H),4.50(bs,4H),3.88(s,3H),1.41(s,9H);LC-MS:m / z 353.9(MH).

[0294] Step b: Synthesis of tert-butyl 3-(4-bromophenyl)azetidine-1-carboxylate 1.2 g, 3.37 mmol) tert-butyl 3-(2-((4-methoxyphenyl)sulfonyl)hydrazinylidene)azetidine-1-carboxylate (1.2 g, 3.37 mmol) and (4-bromophenyl)boronic acid (1.01 g, 5.06 mmol) were stirred in dioxane (35 mL), to which Cs2CO3 (1.65 g, 5.06 mmol) was added, and the mixture was degassed under nitrogen for 30 minutes. The reaction mixture was then heated in a sealed tube at 110 °C for 16 hours. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated under vacuum to obtain a residue, and the residue was purified by combiflash column chromatography using 20% ​​ethyl acetate in hexane as an eluent to obtain the title compound as a colorless liquid (0.36 g, 34%). 1H NMR (400MHz, CDCl3): δ7.47(d,J=8.4Hz,2H),7.19(d,J=8.8Hz,2H),4.32(m,2H),3.92(m,2H),3.67(m,1H),1.46(s,9H);LC-MS:m / z 212(M-100).

[0295] Step c: Synthesis of 3-(4-bromophenyl)azetidine Trifluoroacetic acid (0.3 mL) was added at 0°C to a stirred solution of tert-butyl 3-(4-bromophenyl)azetidine-1-carboxylate (0.36 g, 1.15 mmol) in DCM (3 mL), and the mixture was gradually brought to room temperature and stirred at room temperature for 1 hour. The reaction mixture was evaporated under reduced pressure, and the resulting residue was washed with diethyl ether and dried under vacuum to obtain the title compound as an off-white solid (0.28 g, 97.7%). 1 H NMR (400MHz, CDCl3): δ9.85(bs,1H),7.53(d,J=7.6Hz,2H),7.25(d,J=7.6Hz,2H),4.35(m,2H),4.20(m,3H);LC-MS:m / z 212(M+H).

[0296] Step d: Synthesis of tert-butyl 2-(3-(4-bromophenyl)azetidine-1-yl)acetate 3-(4-bromophenyl)azetidine (0.28 g, 1.12 mmol) was mixed in DMF (5 mL) with DIPEA (0.72 g, 5.63 mmol) at room temperature and stirred for 15 minutes. Then, Tert-butyl 2-bromoacetate (0.24 g, 1.24 mmol) was added and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction mixture was quenched with cold water and stirred for 1 hour. The resulting solid was filtered and dried under vacuum to obtain the title compound as a pale yellow, viscous solid (0.28 g, 76%). 1 H NMR (400MHz, CDCl3): δ7.40(d,J=7.6Hz,2H),7.14(d,J=7.6Hz,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).

[0297] Step e: Synthesis of tert-butyl 2-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidine-1-yl)acetate To a stirred solution of tert-butyl 2-(3-(4-bromophenyl)azetidine-1-yl) acetate (0.28 g, 0.85 mmol) in dioxane (5 mL), bis-pinacolato-diborone (0.32 g, 1.28 mmol) and KOAc (0.21 g, 2.14 mmol) were added at room temperature. After degassing with nitrogen for 5 minutes, 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 hours. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with siRNA. The combined organic layer was washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the title compound as a white, viscous solid (0.3 g, 93%).

[0298] 1 H NMR (400MHz, CDCl3): δ7.76(d,J=8Hz,2H),7.28(d,J=8Hz,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).

[0299] Intermediate 18: Tert-butyl 6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-azaspiro[3,3]heptane-2-carboxylate Step a: Synthesis of tert-butyl 6-(2-((4-methoxyphenyl)sulfonyl)hydrazinylidene)-2-azaspiro[3.3]heptane-2-carboxylate The reaction mixture of 4-methoxybenzene sulfonohydrazide (1.5 g, 7.41 mmol) and Tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (1.56 g, 7.41 mmol) was stirred in toluene (30 mL), and the reaction mixture was heated in a sealed tube at 50°C for 16 hours. Once the reaction was complete (monitored by TLC), the reaction mass was concentrated under vacuum to obtain the residue, and the residue was purified by combiflash column chromatography using 35% ethyl acetate in hexane as the eluent to obtain the title compound as a white solid (2.8 g, 95%). 1 H NMR(400MHz,DMSO-d6):δ10.21(bs,1H),7.68(d,J=8.4Hz,2H),7.05(d,J=8.4Hz,2H),3.82(bs,4H),3.78(s,3H),2.95(m,4H),1.31(s,9H);LC-MS:m / z 394.1(MH).

[0300] Step b: Synthesis of tert-butyl 6-(4-bromophenyl)-2-azaspiro[3.3]heptane-2-carboxylate To a 60 mL stirred solution of tert-butyl 6-(2-((4-methoxyphenyl)sulfonyl)hydrazinylidene)-2-azaspiro[3.3]heptane-2-carboxylate (2.8 g, 7.08 mmol) and (4-bromophenyl)boronic acid (2.13 g, 10.6 mmol) in dioxane, Cs2CO3 (4.6 g, 14.16 mmol) was added, and the mixture was degassed under nitrogen for 30 minutes. The reaction mixture was then heated in a sealed tube at 110 °C for 16 hours. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with ELISA and filtered. The filtrate was concentrated under vacuum to obtain a residue, and the residue was purified by combiflash column chromatography using 20% ​​ethyl acetate in hexane as an eluent to obtain the title compound as a colorless liquid (1.3 g, 52%). 1H NMR (400MHz, DMSO-d6): δ7.38(d,J=8.4Hz,2H),7.01(d,J=8.4Hz,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).

[0301] Step c: Synthesis of tert-butyl 6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-azaspiro[3.3]heptane-2-carboxylate To a stirred solution of tert-butyl 6-(4-bromophenyl)-2-azaspiro[3.3]heptane-2-carboxylate (1.3 g, 3.69 mmol) in dioxane (35 mL), bis-pinacolato-diborone (1.4 g, 5.53 mmol) and KOAc (0.90 g, 9.22 mmol) were added at room temperature. After degassing with nitrogen for 5 minutes, 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 hours. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with RINKAN. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the title compound as a cream-colored viscous solid (0.3 g, 93%). 1 H NMR(400MHz,DMSO-d6):δ7.74(d,J=8Hz,2H),7.16(d,J=8Hz,2H),4.05(s,2H), 3.83(s,2H),3.38(m,1H),2.56(m,2H),2.58(m,2H),1.33(s,9H),1.25(s,12H). LC-MS: m / z 374.05 (M+H).

[0302] Intermediate 19: (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride Step a: Synthesis of tert-butyl(2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl) carbamate 1.49 g, 15.89 mmol and 0.34 g, 1.51 mmol were added to a stirred solution of tert-butyl(1-(4-bromophenyl)-2-hydroxyethyl)carbamate (2.4 g, 7.59 mmol) and 4-methylthiazole (0.9 g, 9.11 mmol) in DMF (12 mL). The reaction mixture was heated at 90 °C for 3 hours. After the reaction was complete (monitored by TLC), the reaction mixture was cooled to room temperature and poured into ice-cold water. The resulting mixture was extracted with ethyl acetate (twice with 50 mL). The combined organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the residue. The residue was purified by combiflash column chromatography using 50% ethyl acetate in hexane as the eluent to obtain the title compound (0.5 g, 30%). 1 H NMR(400MHz,DMSO-d6):δ8.98(s,1H),7.44(d,J=7.6Hz,2H),7.38(d,J=7.6Hz,2H),7.30(d,J=8.4 Hz,1H),4.83(t,J=6Hz,1H),4.56(m,1H),3.51(t,J=6Hz,2H),2.45(s,3H),1.37(s,9H),LC-MS:m / z 335.0(M+1).

[0303] Step b: Synthesis of 2-amino-2-(4-(4-methylthiazole-5-yl)phenyl)ethane-1-ol hydrochloride To a stirred solution of tert-butyl(2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl) carbamate (0.3 g, 0.89 mmol) in DCM (2 mL), a solution of 1,4-dioxane (1.5 mL) in 4 M HCl at 0 °C was added. The reaction mixture was stirred at room temperature for 2 hours. After the completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure and washed with diethyl ether to obtain the title compound (0.2 g, 95%).

[0304] 1H NMR (400MHz, DMSO-d6): δ9.04 (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).

[0305] Step c: Synthesis of tert-butyl((2S)-1-((2S,4R)-4-hydroxy-2-((2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate 2-amino-2-(4-(4-methylthiazole-5-yl)phenyl)ethane-1-ol hydrochloride (0.2 g, 0.85 mmol) and (2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid (0.35 g, 1.02 mmol) were dissolved in DMF (3 mL) at 0°C. HATU (0.48 g, 1.28 mmol) was added, followed by dropwise addition of DIPEA (0.5 mL, 2.56 mmol), and the mixture was stirred at room temperature for 2 hours. After the reaction was complete (monitored by TLC), the reaction mixture was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ELISA (twice with 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. The crude product was purified by combiflash column chromatography using 5% MeOH in DCM as the eluent to obtain the title compound (0.17 g, 53%). LC-MS: m / z 561.2 (M+1).

[0306] Step d: Synthesis of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride To a stirred solution of tert-butyl((2S)-1-((2S,4R)-4-hydroxy-2-((2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (0.17 g, 0.30 mmol) in DCM (2 mL), a solution of 1,4-dioxane (1.5 mL) in 4 M HCl at 0 °C was added. The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure, and the residue was washed with diethyl ether to obtain 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).

[0307] Intermediate 20: (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-N-(2-(dimethylamino)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide hydrochloride Step a: Synthesis of 2-((tert-butoxycarbonyl)amino)-2-(4-(4-methylthiazole-5-yl)phenyl)ethylmethanesulfonate To a 10 mL stirred solution of tert-butyl(2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl) carbamate (0.6 g, 1.79 mmol) in DCM, methanesulfonic chloride (0.2 mL, 2.69 mmol) was added at 0°C, followed by TEA (0.64 mL, 4.49 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature and poured into ice-cold water. The resulting mixture was extracted with RINKAN (50 mL twice). The combined organic layer was washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. The crude product was purified by combiflash column chromatography using 2% MeOH in DCM as an eluent to obtain the title compound (0.48 g, 64%). 1H NMR(400MHz,DMSO-d6):δ9.01(d,J=2Hz,1H),7.75(d,J=8.8Hz,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).

[0308] Step b: Synthesis of tert-butyl(2-(dimethylamino)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamate 2-((tert-butoxycarbonyl)amino)-2-(4-(4-methylthiazole-5-yl)phenyl)ethylmethanesulfonate (0.480 g, 0.89 mmol) was mixed with acetonitrile (2 mL) and DIPEA (0.6 mL) was added. After cooling to 0°C, N,N dimethylamine gas was passed through the reaction mixture for 15 minutes, and the reaction mixture was stirred for 16 hours. After the completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure and extracted with RINKAN (50 mL twice). The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude title compound as a brown liquid (0.300 g, crude). 1 H NMR(400MHz,DMSO-d6):δ8.98(d,J=2Hz,1H),7.30-7.45(m,5H),4.68(m,1H) ,3.46(m,2H),2.46(s,3H),2.17(s,3H),2.09(s,3H),1.30(s,9H):LC-MS:m / z 362.1(M+1).

[0309] Step c: Synthesis of N1,N1-dimethyl-2-(4-(4-methylthiazole-5-yl)phenyl)ethane-1,2-diamine hydrochloride N1,N1-dimethyl-2-(4-(4-methylthiazole-5-yl)phenyl)ethane-1,2-diamine hydrochloride was prepared by the same procedure as described in step b of intermediate 19. LC-MS: m / z 262.0 (M+1).

[0310] Step d: Synthesis of tert-butyl((2S)-1-((2S,4R)-2-((2-(dimethylamino)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate Tert-butyl((2S)-1-((2S,4R)-2-((2-(dimethylamino)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate was prepared by the same procedure as described in step c of intermediate 19. LC-MS: m / z 588.3 (M+1).

[0311] Process e: (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-N-(2-(dimethylamino)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide hydrochloride (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-N-(2-(dimethylamino)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide hydrochloride was prepared by the same procedure as described in step d of intermediate 19. LC-MS: m / z 488.2 (M+1). [Examples]

[0312] Example 1: (2S,4R)-4-hydroxy-1-(2-(3-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 1, racemic mixture)

[0313] [ka]

[0314] Step i: Synthesis of ethyl 2-(3-(4-(6-chloropyridazine-4-yl)phenyl)isoxazole-5-yl)-3-methylbutanoate A mixture of 1,4-dioxane (13 mL) and water (2 mL) was obtained in a microwave vial and degassed with nitrogen for 5 minutes. 5-bromo-3-chloropyrazine (0.91 g, 4.72 mmol) and ethyl 3-methyl-2-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazole-5-yl)butanoate (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 under microwave at 110°C for 1 hour. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with ELISA. The combined organic layers were washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a residue. The residue was then purified by combiflash column chromatography using 50-60% ethyl acetate in hexane as an eluent to obtain the title compound as an off-white solid (1 g, 71%).

[0315] 1 H NMR (400MHz, DMSO-d6): δ9.76(d,J=2.0Hz,1H),8.38(d,J=2.0Hz,1H),8.17(d,J=8.4Hz,2H),8.09(d,J=8.4Hz,2H),7.18(s,1H),4.17(d ,J=2.8Hz,2H),3.88(d,J=8.4Hz,1H),2.45-2.38(m,1H),1.22(t,J=7.2Hz,3H),1.00(d,J=6.8Hz,3H),0.91(d,J=6.8Hz,3H);LC-MS:m / z 386.1(M+H).

[0316] Step ii: Synthesis of ethyl 2-(3-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)isoxazole-5-yl)-3-methylbutanoate A mixture of 1,4-dioxane (15 mL) and water (3 mL) was obtained in a microwave vial and degassed with nitrogen for 5 minutes. Ethyl 2-(3-(4-(6-chloropyridazin-4-yl)phenyl)isoxazole-5-yl)-3-methylbutanoate (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 under microwave at 120°C for 1 hour. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with ELISA. The combined organic layers were washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a residue. The residue was then purified by combiflash column chromatography using 50-60% ethyl acetate in hexane as an eluent to obtain the title compound as a yellow solid (0.75 g, 69%).

[0317] 1 H NMR(400MHz,DMSO-d6):δ13.05(s,1H),9.69(d,J=2.0Hz,1H),8.79(d,J=2.0Hz, 1H),8.24(d,J=8.4Hz,3H),8.12(d,J=8.4Hz,2H),7.44-7.40(m,1H),7.19(s,1H) ,7.03(d,J=7.2Hz,2H),4.19-4.16(m,2H),3.34(d,J=8.4Hz,1H),2.46-2.41(m,1 H),1.20(t,J=14Hz,3H),1.01(d,J=6.8Hz,3H),0.92(d,J=6.4Hz,3H);LC-MS:m / z 444.1 (M+H).

[0318] Step iii: Synthesis of 2-(3-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)isoxazole-5-yl)-3-methylbutyrate Ethyl 2-(3-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)isoxazole-5-yl)-3-methylbutanoate (0.75 g, 1.69 mmol) was dissolved in a mixture of THF (5 mL) and H2O (5 mL) and stirred. LiOH.H2O (0.21 g, 5.07 mmol) was added at 0°C to this stirred solution. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then evaporated under reduced pressure, the resulting residue was diluted with methanol, acidified to pH 6 using Amberlite IT120 (acidic resin), filtered, and the filtrate was concentrated under vacuum to obtain the title compound as a dark brown solid (0.65 g, 93%).

[0319] 1 H NMR(400MHz,DMSO-d6):δ9.66(s,1H),8.78(s,1H),8.23(s,1H),8.20(d,J=8.4Hz,2H),8.06(d,J=8.4Hz,2H),7.39(t,J=14.4Hz,1H), 7.00(t,J=15.2Hz,2H),6.82(s,1H),3.17(d,J=8.8Hz,1H),2.32-2.27(m,1H),0.98(d,J=6.4Hz,3H),0.80(d,J=6.8Hz,3H);LC-MS:m / z 416.1(M+H).

[0320] Step iv: Synthesis of ((2S,4R)-4-hydroxy-1-(2-(3-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide To a solution of 2-(3-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)isoxazole-5-yl)-3-methylbutyrate (0.1 g, 0.24 mmol), (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.11 g, 0.28 mmol), and HATU (0.14 g, 0.36 mmol) in DMF (5 mL), DIPEA (0.21 mL, 1.2 mmol) was added dropwise at 0°C, and the mixture was gradually brought to room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a crude product. This crude product was then purified by preparative HPLC to obtain the title compound as an off-white solid (0.025 g, 14%).

[0321] 1 H NMR(400MHz,DMSO-d6):δ13.12(bs,1H),9.69(d,J=2.4Hz,1H),8.99(t,J=8Hz,1H),8.90(s,1H),8.79(d,J=2Hz,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=12Hz,1H),1.8 2-1.76(m,1H),1.50(d,J=4.4Hz,1H),1.39(d,J=4.4Hz,3H),1.03(d,J=6.4Hz,3H),0.90(d,J=3.2Hz,3H);LC-MS:m / z 729.3(M+H).

[0322] Example 2: (2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetamide)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 2)

[0323] [ka]

[0324] Step i: Synthesis of Tert-butyl 2-(4-(4-(6-chloropyridazine-4-yl)phenyl)piperazine-1-yl)acetate 5-bromo-3-chloropyrazine (1.6 g, 8.3 mmol) and Tert-butyl 2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-yl) acetate (2.78 g, 6.9 mmol) were dissolved in 1,4-dioxane (30 mL) and water (3 mL). K2CO3 (1.77 g, 16.7 mmol) was added to the stirred solution, and the mixture was degassed with nitrogen for 5 minutes. Pd(dppf)Cl2.DCM (0.68 g, 0.83 mmol) was added, and the reaction mixture was stirred in a sealed tube at 120°C for 4 hours. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with ethyl acetate. The combined organic layers were washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a residue. The residue was then purified by combiflash column chromatography using 40-80% ethyl acetate in hexane as an eluent to obtain the title compound as an adhesive material (1.7 g, 63%).

[0325] 1H NMR(400MHz,DMSO-d6):9.62(d,J=1.6Hz,1H),8.15(d,J=2.0Hz,1H),7.91(d,J=8.8Hz,2H),7. 07(d,J=8.8Hz,2H),3.34(s,2H),3.31(bs,4H),2.64(d,J=4.4Hz,4H),1.42(s,9H);LC-MS:m / z 389.0(M+H).

[0326] Step ii: Synthesis of Tert-butyl 2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)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) and (2-hydroxyphenyl)boronic acid (0.27 g, 1.93 mmol) dissolved in 1,4-dioxane (10 mL) and water (3 mL), Na2CO3 (0.54 g, 5.18 mmol) was added, and the mixture was degassed under nitrogen for 5 minutes. Pd(dppf)Cl2.DCM (0.1 g, 0.13 mmol) was added, and the reaction mixture was stirred in a sealed tube at 130°C for 3 hours. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with ELISA. The combined organic layers were washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a residue. The residue was then purified by combiflash column chromatography using 60% ethyl acetate in hexane as an eluent to obtain the title compound as an adhesive material (0.35 g, 60%).

[0327] 1H NMR(400MHz,DMSO-d6):13.53(s,1H),9.57(d,J=2.0Hz,1H),8.62(d,J=2.0Hz,1H),8.25(d,J=7.2Hz,1H),8.01(d,J=8.8Hz,2H),7.40 (t,J=6.8Hz,1H),7.11(d,J=8.8Hz,2H),7.01(d,J=6.0Hz,2H),3.18(s,2H),2.66(d,J=4.4Hz,4H),2.50(d,J=4.4Hz,4H),1.43(s,9H). LC-MS: m / z 447.15 (M+H).

[0328] Step iii: Synthesis of 2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetic acid To a 10 mL stirred solution of tert-butyl 2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl) acetate (0.7 g, 1.56 mmol) in DCM, 7 mL of 4N dioxane hydrochloride was added at 0°C, and the mixture was then gradually brought to room temperature and stirred for 6 hours. The reaction mixture was evaporated under reduced pressure, and the resulting residue was washed with diethyl ether and dried under vacuum to obtain the title compound as an orange solid (0.5 g, 74%). 1 H NMR(400MHz,DMSO-d6):10.6(bs,1H),9.67(d,J=2.0Hz,1H),8.70(s,1H),8.15(d,J=8.0Hz,1H),8.10(d,J=8.8 Hz,2H),7.46-7.45(m,1H),7.20(d,J=9.2Hz,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).

[0329] Step iv: Synthesis of (2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetamide)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide To a 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-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.62 g, 1.28 eq.) in DMF (3 mL), HATU (0.73 g, 1.92 mmol) was added at 0°C, followed by dropwise addition of DIPEA (0.7 mL, 3.84 mmol). The reaction mixture was stirred at room temperature 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 brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by combiflash column chromatography using 5% methanol in DCM as the eluent to obtain the title compound as a yellow solid (0.11 g, 11%).

[0330] 1 H NMR(400MHz,DMSO-d6):13.53(s,1H),9.58(d,J=2.0Hz,1H),8.98(s,1H),8.62(d,J=2.0Hz,1H),8.45(d,J=8.0Hz,1H),8.26(d,J=6.8Hz, 1H),8.03(d,J=8.8Hz,2H),7.79(d,J=9.2Hz,1H),7.44-7.35(m,5H),7.15(d,J=9.2Hz,2H),7.00(t,J=8.0Hz,2H),5.14(d,J=3.2Hz,1H),4 .88(t,J=7.2Hz,1H),4.53(d,J=9.6Hz,1H),4.44(t,J=8.4Hz,1H),4.29(bs,1H),3.59(s,2H),3.38(s,4H),3.16(d,J=16.0Hz,1H),3.03( d,J=16.0Hz,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=6.8Hz,3H),0.96(s,9H);LC-MS:m / z 817.45(M+H).

[0331] Example 3: (2S,4R)-1-((S)-2-(2-(4-(4-(6-chloropyridazin-4-yl)phenyl)piperazin-1-yl)acetamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 3)

[0332] [ka]

[0333] Step i: Synthesis of 2-(4-(4-(6-chloropyridazine-4-yl)phenyl)piperazine-1-yl)acetic acid To a stirred solution of tert-butyl 2-(4-(4-(6-chloropyridazin-4-yl)phenyl)piperazin-1-yl) acetate (0.07 g, 0.179 mmol) in DCM (5 mL), 4N-dioxane hydrochloride (2 mL) was added at 0°C, and the mixture was then gradually brought to room temperature and stirred for 16 hours. The reaction mixture was evaporated under reduced pressure, and the resulting residue was washed with diethyl ether and dried under vacuum to obtain the title compound as an orange solid (0.065 g, 99%). LC-MS: m / z 333.1 (M+H).

[0334] Step ii: Synthesis of (2S,4R)-1-((S)-2-(2-(4-(4-(6-chloropyridazin-4-yl)phenyl)piperazin-1-yl)acetamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide To a 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-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.09 g, 0.20 eq.) in DMF (2 mL), HATU (0.09 g, 0.24 mmol) was added at 0°C, followed by dropwise addition of DIPEA (0.06 mL, 0.4 mmol). The reaction mixture was stirred at room temperature 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 brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a crude product. This crude product was then purified by preparative HPLC to obtain the title compound as a yellow solid (0.014 g, 8%).

[0335] 1 H NMR(400MHz,DMSO-d6):9.60(d,J=1.2Hz,1H),8.94(s,1H),8.38(d,J=7.6Hz,1H),8.12(d,J=2.0Hz,1H),7.89(d,J= 8.8Hz,2H),7.74(d,J=9.6Hz,1H),7.40(d,J=8.0Hz,2H),7.33(d,J=8.4Hz,2H),7.07(d,J=8.8Hz,2H),5.09(d,J=3. 2Hz,1H),4.86(t,J=14.0Hz,1H),4.49(d,J=9.2Hz,1H),4.42(t,J=4.2Hz,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=6.8Hz,3H),0.93(s,9H). LC-MS: m / z 759.35 (M+H).

[0336] Example 4: (2S,4R)-1-((S)-2-(2-(4-(4-(6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 4)

[0337] [ka]

[0338] Step i: Synthesis of Tert-butyl 2-(4-(4-(6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetate Tert-butyl 2-(4-(4-(6-chloropyridazin-4-yl)phenyl)piperazin-1-yl) acetate (0.1 g, 0.26 mmol) and (4-fluoro-2-hydroxyphenyl)boronic acid (0.06 g, 0.38 mmol) were dissolved in 1,4-dioxane (1.6 mL) and water (0.4 mL). To this stirred solution, Na2CO3 (0.08 g, 0.77 mmol) was added, and the mixture was degassed under nitrogen for 15 minutes. Pd(dppf)Cl2.DCM (0.02 g, 0.026 mmol) was added, and the reaction mixture was heated under microwave at 130°C for 1.2 hours. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with ELISA. The combined organic layers were washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a residue. The residue was then purified by combiflash column chromatography using 60% ethyl acetate in hexane as an eluent to obtain the title compound as a pale yellow solid (0.06 g, 50%).

[0339] 1H NMR(400MHz,DMSO-d6):13.30(s,1H),9.60(d,J=1.2Hz,1H),8.64(d,J=1.2Hz,1H),8.16(dd,J=2.8&10.0Hz,1H),8.03(d,J=8.8 Hz,2H),7.25(t,J=4.0Hz,1H),7.11(d,J=8.8Hz,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).

[0340] Step ii: Synthesis of 2-(4-(4-(6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetic acid To a stirred solution of tert-butyl 2-(4-(4-(6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl) acetate (0.16 g, 0.34 mmol) in DCM (4 mL), 1.2 mL of 4 N dioxane hydrochloride was added at 0°C, and the mixture was gradually brought to room temperature and stirred at room temperature for 6 hours. The reaction mixture was evaporated under reduced pressure, and the resulting residue was washed with diethyl ether and dried under vacuum to obtain the title compound as an orange solid (0.15 g, 98%). LC-MS: m / z 407.1 (MH).

[0341] Step iii: Synthesis of (2S,4R)-1-((S)-2-(2-(4-(4-(6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide 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-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride compound (0.08, 0.16 eq.) were mixed in DMF (2 mL) at 0°C with HATU (0.07 g, 0.19 mmol), followed by dropwise addition of DIPEA (0.05 mL, 0.31 mmol). The reaction mixture was stirred at room temperature for 3 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 brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a crude product. This crude product was then purified by preparative HPLC to obtain the title compound as a yellow solid (0.014 g, 10%).

[0342] 1 H NMR(400MHz,DMSO-d6):13.30(s,1H),9.61(s,1H),8.97(s,1H),8.65(s,1H),8.49(d,J=7.6Hz,1H),8.16(t,J=10.0Hz,1H),8.04 (d,J=8.8Hz,2H),7.78(d,J=9.6Hz,1H),7.43(d,J=8.0Hz,2H),7.36(d,J=7.6Hz,2H),7.26(t,J=7.2Hz,1H),7.14(d,J=4.4Hz,2H ),7.04-7.00(m,1H),5.12(s,1H),4.89(t,J=7.4Hz,1H),4.53(d,J=10.0Hz,1H),4.45(t,J=8.0Hz,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=9.8Hz,1H),1.78(s,2H),1.36(d,J=6.8Hz,3H),0.96(s,9H). LC-MS: m / z 835.3 (M+H).

[0343] Example 5: (2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(5-(6-(2-hydroxyphenyl)pyridazin-4-yl)pyridine-2-yl)piperazine-1-yl)acetamide)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 5)

[0344] [ka]

[0345] Step i: Synthesis of 5-(6-bromopyridine-3-yl)-3-chloropyrazine 5-bromo-3-chloropyrazine (0.5 g, 2.48 mmol) and (6-bromopyridine-3-yl)boronic acid (0.47 g, 2.48 mmol) were mixed in 1,4-dioxane (15 mL) and 4 mL of 2 M Na2CO3 (1 g, 9.9 mmol) were added, and the mixture was degassed under nitrogen for 15 minutes. Pd(dppf)Cl2.DCM (0.04 g, 0.05 mmol) was added, and the reaction mixture was heated under microwave at 80°C for 1 hour. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with RINKAN. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the residue. The residue was purified by combiflash column chromatography using 60% ethyl acetate in hexane as an eluent to obtain the title compound as a yellow solid (0.45 g, 64%).

[0346] 1 H NMR(400MHz,DMSO-d6):δ9.75(d,J=2.0Hz,1H),9.01(d,J=2.4Hz,1H),8.43(d,J=2.0Hz,1H),8.36(dd,J=2.8Hz,2.4Hz 1H),7.90(d,J=8.4Hz,1H);LC-MS:m / z 272(M+H).

[0347] Step ii: Synthesis of Tert-butyl 2-(4-(5-(6-chloropyridazine-4-yl)pyridine-2-yl)piperazine-1-yl) acetate To a 10 mL stirred solution of 5-(6-bromopyridine-3-yl)-3-chloropyrazine (0.32 g, 1.18 mmol) in DMSO (10 mL), Tert-butyl 2-(piperazin-1-yl) acetate (0.35 g, 1.78 mmol) and DIPEA (0.85 g, 4.72 mmol) were added at room temperature, and the mixture was heated at 120 °C for 16 hours. The reaction mixture was then quenched with cold water and extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the residue. The residue was purified by combiflash column chromatography using 45-50% ethyl acetate in hexane as an eluent to obtain the title compound as a yellow solid (0.2 g, 40%).

[0348] 1 H NMR (400MHz, DMSO-d6): δ9.31(d,J=2.0Hz,1H),8.54(d,J=2.4Hz,1H),7.76(dd,J=2.8Hz,2.4Hz,1H),7.58(d,J=2. LC-MS:m / z 390.2(M+H).

[0349] Step iii: Synthesis of Tert-butyl 2-(4-(5-(6-(2-hydroxyphenyl)pyridazin-4-yl)pyridine-2-yl)piperazin-1-yl) acetate To a 10 mL stirred solution of tert-butyl 2-(4-(5-(6-chloropyridazin-4-yl)pyridine-2-yl)piperazin-1-yl) 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 2 M Na2CO3 (0.27 g, 2.56 mmol) was added, and the mixture was degassed under nitrogen for 15 minutes. Pd(dppf)Cl2.DCM (0.05 g, 0.06 mmol) was added, and the reaction mixture was heated under microwave at 120 °C for 2 hours. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with ELISA. The combined organic layers were washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a residue. The residue was then purified by combiflash column chromatography using 60% ethyl acetate in hexane as an eluent to obtain the title compound as a yellow solid (0.18 g, 62%).

[0350] 1 H NMR(400MHz,DMSO-d6):δ13.78(s,1H),9.26(d,J=2.0Hz,1H),8.62(d,J=2.8Hz,1H),8.11(d,J=2.4Hz,1H),7.85-7.80(m,2H),7.40-7.39(m,1H), 7.13-7.11(m,1H),7.01(t,J=8.0Hz,1H),6.78(d,J=8.8Hz,1H),3.76(t, J=4.8Hz,4H),3.2(s,2H),2.72(t,J=4.8Hz,4H),1.47(s,9H);LC-MS:m / z 448.25(M+H).

[0351] Step iv: Synthesis of 2-(4-(5-(6-(2-hydroxyphenyl)pyridazin-4-yl)pyridine-2-yl)piperazin-1-yl)acetic acid To a 10 mL stirred solution of tert-butyl 2-(4-(5-(6-(2-hydroxyphenyl)pyridazin-4-yl)pyridine-2-yl)piperazin-1-yl) acetate (0.15 g, 0.33 mmol) in DCM, 5 mL of 4N dioxane hydrochloride was added at 0°C, and the mixture was gradually brought to room temperature and stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure, and the resulting residue was washed with diethyl ether and dried under vacuum to obtain the title compound as an orange solid (0.1 g, 63%). LC-MS: m / z 392.1 (M+H).

[0352] Step v: Synthesis of (2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(5-(6-(2-hydroxyphenyl)pyridazin-4-yl)pyridine-2-yl)piperazin-1-yl)acetamide)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide To a solution of 2-(4-(5-(6-(2-hydroxyphenyl)pyridazin-4-yl)pyridine-2-yl)piperazin-1-yl)acetic acid (0.1 g, 0.25 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.13, 0.28 eq.) in DMF (3 mL), HATU (0.14 g, 0.37 mmol) was added at 0°C, followed by dropwise addition of DIPEA (0.18 mL, 1 mmol). The reaction mixture was stirred at room temperature 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 brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a crude product. This crude product was then purified by preparative HPLC to obtain the title compound as a yellow solid (0.03 g, 16%).

[0353] 1H NMR(400MHz,DMSO-d6):δ13.5(bs,1H),9.61(s,1H),8.97(s,1H),8.90(s,1H),8.66(s,1H),8.42(d,J=8.0Hz,1H),8.31 (d,J=8.8Hz,1H),8.25(d,J=8.0Hz,1H),7.79(d,J=9.6Hz,1H),7.44-7.35(m,5H),7.07-6.99(m,3H),5.12(bs,1H),4.89 (t,J=6.8Hz,1H),4.53(d,J=9.6Hz,1H),4.45(t,J=7.6Hz,1H),4.29(bs,1H),3.71-3.60(m,5H),3.16-3.02(m,2H),2.6 1(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=6.8Hz,3H),096(s,9H);LC-MS:m / z 818.2(M+H).

[0354] Example 6: (2S,4R)-4-hydroxy-1-((S)-2-(2-(1-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperidine-4-yl)acetamide)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 6)

[0355] [ka]

[0356] Step i: Synthesis of 2-(1-(4-(6-chloropyridazine-4-yl)phenyl)piperidine-4-yl)acetic acid A stirred solution of 5-bromo-3-chloropyrazine (0.13 g, 0.67 mmol), ethyl 2-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-4-yl) acetate (0.25 g, 0.67 mmol), and Na2CO3 (0.28 g, 2.68 mmol) dissolved in 1,4-dioxane (5 mL) and water (2 mL) was degassed with nitrogen for 15 minutes. Pd(dppf)Cl2.DCM (0.055 g, 0.0067 mmol) was added, and the reaction mixture in a sealed tube was microwaved at 120°C for 6 hours. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with ethyl acetate. The combined organic layers were washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a residue. The residue was then purified by combiflash column chromatography using 8-12% methanol in DCM as an eluent to obtain the title compound as an adhesive material (0.09 g, 40%).

[0357] 1 H NMR(400MHz,DMSO-d6):δ12.11(s,1H),9.61(d,J=2.0Hz,1H),8.14(d,J=2.0Hz,1H),7.89(d,J=8.8Hz,2H),7.05(d,J=9.2Hz, 2H),3.95-3.89(m,2H),2.83(t,J=6.0Hz,2H),2.18(d,J=6.8Hz,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).

[0358] Step ii: Synthesis of (2S,4R)-1-((S)-2-(2-(1-(4-(6-chloropyridazine-4-yl)phenyl)piperidine-4-yl)acetamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide To a solution of 2-(1-(4-(6-chloropyridazin-4-yl)phenyl)piperidine-4-yl)acetic acid (0.09 g, 0.27 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.13 g, 0.27 eq.) in DMF (2 mL), HATU (0.155 g, 0.40 mmol) was added at 0°C, followed by dropwise addition of DIPEA (0.14 mL, 0.81 mmol). The reaction mixture was stirred at room temperature 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 brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. The crude product was purified by combiflash column chromatography using 5% methanol in DCM as an eluent to obtain the title compound as an off-white solid (0.125 g, 61%).

[0359] 1 H NMR(400MHz,DMSO-d6):δ9.61(d,J=2.0Hz,1H),8.99(s,1H),8.40(d,J=7.6Hz,1H),8.13(d,J=1.6Hz,1H) ,7.90-7.85(m,3H),7.48-7.36(m,4H),7.05(d,J=9.2Hz,2H),5.12(d,J=3.6Hz,1H),4.92(t,J=7.2Hz,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=7.2Hz,3H),1.23-1.21(m,2H),0.95(s,9H). LC-MS: m / z 756.3 (MH).

[0360] Step iii: Synthesis of (2S,4R)-4-hydroxy-1-((S)-2-(2-(1-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperidine-4-yl)acetamide)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (2S,4R)-1-((S)-2-(2-(1-(4-(6-chloropyridazine-4-yl)phenyl)piperidine-4-yl)acetamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-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) were dissolved in 1,4-dioxane (4 mL) and water (1 mL). A stirred solution was degassed with nitrogen for 5 minutes. Pd(dppf)Cl2.DCM (0.013 g, 0.016 mmol) was added, and the reaction mixture was microwaved at 120°C for 1 hour. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with ₹150. The combined organic layer was washed with water and brine solution, dried over 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 as the eluent to obtain the title compound as a pale yellow solid (0.015 g, 11%).

[0361] 1H NMR(400MHz,DMSO-d6):13.58(s,1H),9.56(d,J=2.0Hz,1H),8.99(s,1H),8.60(d,J=2.0Hz,1H),8.40(d,J=7.6Hz,1H),8.25(d,J=7.2Hz,1H), 7.99(d,J=8.8Hz,2H),7.87(d,J=9.2Hz,1H),7.45-7.37(m,5H),7.09(d,J=8.8Hz,2H),6.99(d,J=8.0Hz,2H),5.12(d,J=3.6Hz,1H),4.91-4.89 (m,1H),4.53(d,J=9.2Hz,1H),4.43-4.42(m,1H),4.28(d,J=2.4Hz,1H),3.90(d,J=6.4Hz,2H),3.62(d,J=1.6Hz,2H),2.83(t,J=12.4Hz,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=7.2Hz,3H),1.26-1.21(m,2H),0.95(s,9H). LC-MS: m / z 816.4 (M+H).

[0362] Example 7: (2S,4R)-1-((S)-2-(2-(4-(4-(6-(2-fluorophenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 7)

[0363] [ka]

[0364] Step i: Synthesis of Tert-butyl 2-(4-(4-(6-(2-fluorophenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)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) and 2-fluorophenyl)boronic acid (0.13 g, 0.96 mmol) dissolved in 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 minutes. Pd(dppf)Cl2.DCM (0.05 g, 0.064 mmol) was added, and the reaction mixture was heated in a sealed tube at 130°C for 4 hours. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with ethyl acetate. The combined organic layers were washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a residue. The residue was then purified by combiflash column chromatography using 50-60% ethyl acetate in hexane as an eluent to obtain the title compound as an adhesive material (0.22 g, 76%).

[0365] 1 H NMR(400MHz,DMSO-d6):9.39(d,J=2.0Hz,1H),8.18(ddd,J=8.0Hz,1H),8.05(t,J=4.4Hz,1H),7.67(d,J=8.0Hz,2H),7.47-7.46(m,1H),7.3 6(ddd,J=7.6Hz,1H),7.23(d,J=12.0Hz,1H),7.03(d,J=9.2Hz,2H),3.38(t,J=4.8Hz,4H),3.20(s,2H),2.76(t,J=5.2Hz,4H),1.48(s,9H). LC-MS: m / z 449.45 (M+H).

[0366] Step ii: Synthesis of 2-(4-(4-(6-(2-fluorophenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetic acid hydrochloride To a stirred solution of tert-butyl 2-(4-(4-(6-(2-fluorophenyl)pyridazin-4-yl)phenyl)piperazin-1-yl) acetate (0.22 g, 0.48 mmol) in DCM (5 mL), 4N dioxane hydrochloride (2 mL) was added at 0°C, and the mixture was then gradually brought to room temperature and stirred at room temperature for 6 hours. The reaction mixture was evaporated under reduced pressure, and the resulting residue was washed with diethyl ether and dried under vacuum to obtain the title compound as an orange solid (0.2 g, 87%). LC-MS: m / z 393.1 (M+H).

[0367] Step iii: Synthesis of (2S,4R)-1-((S)-2-(2-(4-(4-(6-(2-fluorophenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide To a 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-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.115, 0.24 eq.) in DMF (3 mL), HATU (0.13 g, 0.36 mmol) was added at 0°C, followed by dropwise addition of DIPEA (0.12 mL, 0.72 mmol). The reaction mixture was stirred at room temperature 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 brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. The crude product was purified by combiflash column chromatography using 5% methanol in DCM as an eluent to obtain the title compound as a pale yellow solid (0.07 g, 37%).

[0368] 1H NMR(400MHz,DMSO-d6):9.61(d,J=2.4Hz,1H),8.96(s,1H),8.44(d,J=7.6Hz,1H),8.18(d,J=2.0Hz,1H),7.96-7.95(m,2H),7.90(d ,J=8.8Hz,1H),7.77(d,J=10.0Hz,1H),7.59-7.57(m,1H),7.44-7.34(m,6H),7.12(d,J=8.8Hz,2H),5.13(d,J=3.2Hz,1H),4.87(t,J =7.2Hz,1H),4.53-4.43(m,2H),4.27(s,1H),3.58-3.55(m,2H),3.14(d,J=16.0Hz,1H),3.01(d,J=16.0Hz,1H),2.66-2.64(m,4H), 2.45(t,J=1.6Hz,4H),2.07-2.02(m,1H),1.77-1.75(m,1H),1.46(d,J=6.8Hz,1H),1.35(d,J=7.2Hz,3H),1.20(s,2H),0.94(s,9H). LC-MS: m / z 819.4 (M+H).

[0369] Example 8: (2S,4R)-4-hydroxy-1-((S)-2-(3-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)propanamide)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 8)

[0370] [ka]

[0371] Step i: Synthesis of Tert-butyl 4-(4-(6-chloropyridazine-4-yl)phenyl)piperazine-1-carboxylate 5-bromo-3-chloropyrazine (0.72 g, 3.8 mmol) and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (1 g, 2.57 mmol) were dissolved in 1,4-dioxane (20 mL) and water (4 mL). To this stirred solution, Na2CO3 (0.82 g, 7.73 mmol) was added, and the mixture was degassed under nitrogen for 15 minutes. 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 hours. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with ethyl acetate. The combined organic layers were washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a residue. The residue was then purified by combiflash column chromatography using 60% ethyl acetate in hexane as an eluent to obtain the title compound as a pale yellow solid (0.5 g, 72%).

[0372] 1 H NMR (400MHz, CDCl3): δ9.32(d,J=1.6Hz,1H),7.61(d,J=8.8Hz,2H),7.25(s,1H),7.0(d,J=8.8Hz,2H),3.60(m,4H),3.30(m 4H),1.49(s,9H);LC-MS:m / z 375.0(M+H).

[0373] Step ii: Synthesis of Tert-butyl 4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazine-1-carboxylate To a stirred solution of tert-butyl 4-(4-(6-chloropyridazin-4-yl)phenyl)piperazine-1-carboxylate (0.5 g, 1.33 mmol) and (2-hydroxyphenyl)boronic acid (0.22 g, 1.60 mmol) dissolved 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 minutes. Pd(dppf)Cl2.DCM (0.11 g, 0.13 mmol) was added, and the reaction mixture was heated in a sealed tube at 130°C for 6 hours. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with ELISA. The combined organic layers were washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a residue. The residue was then purified by combiflash column chromatography using 50-60% ethyl acetate in hexane as an eluent to obtain the title compound as an off-white solid (0.25 g, 43%).

[0374] 1 H NMR(400MHz,DMSO-d6):δ13.45(s,1H),9.58(d,J=2.4Hz,1H),8.62(d,J=2.0Hz,1H),8.25(d,J=8.4Hz,1H),8.03(d,J= LC-MS:m / z 433.10(M+H).

[0375] Step iii: Synthesis of 2-(5-(4-(piperazin-1-yl)phenyl)pyridazin-3-yl)phenol To a stirred solution of tert-butyl 4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazine-1-carboxylate (0.25 g, 0.66 mmol) in DCM (5 mL), 4N dioxane hydrochloride (0.8 mL) was added at 0°C, and the mixture was then gradually brought to room temperature and stirred at room temperature for 6 hours. The reaction mixture was evaporated under reduced pressure, and the resulting residue was washed with diethyl ether and dried under vacuum to obtain the title compound as an orange solid (0.21 g, 98%).

[0376] 1 H NMR (400MHz, DMSO-d6): δ9.78(s,1H),9.60(bs,1H),8.80(s,1H),8.15(d,J=8.8Hz,2H),7.94(d,1H),7.47(t,J=15.2Hz) 1H),7.18-7.45(m,3H),7.05(t,J=14.8Hz 1H),3.56(bs,4H),3.20(bs,4H);LC-MS:m / z 333.0(M+H).

[0377] Step iv: Synthesis of ethyl 3-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)propanoate To a stirred solution of 2-(5-(4-(piperazin-1-yl)phenyl)pyridazin-3-yl)phenol (0.2 g, 0.54 mmol) in DMF (40 mL), ethyl 3-bromopropanoate (0.12 g, 0.65 mmol) and DIPEA (0.3 g, 1.63 mmol) were added at room temperature, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was then quenched with cold water and extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the residue. The residue was purified by combiflash column chromatography using 3-5% methanol in DCM as an eluent to obtain the title compound as a sticky solid (0.09 g, 38%). LC-MS: m / z 433.15 (M+H).

[0378] Process v: 3-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)propanoic acid The compound ethyl 3-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)propanoate (0.09 g, 0.20 mmol) was dissolved in a methanol:THF:H2O (2 mL:4 mL:1 mL) mixture and stirred. LiOH.H2O (0.02 g, 0.41 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then evaporated under reduced pressure, the resulting residue was diluted with methanol, acidified to pH 6 using Amberlite® IT120, filtered, and the filtrate was concentrated under vacuum to obtain the title compound as a viscous solid (0.05 g, 59%). LC-MS: m / z 405.1 (M+H).

[0379] Step vi: (2S,4R)-4-hydroxy-1-((S)-2-(3-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)propanamide)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide To a solution of 3-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)propanoic acid (0.05 g, 0.12 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.09 g, 0.18 eq.) in DMF (2 mL), HATU (0.14 g, 0.37 mmol) was added at 0°C, followed by dropwise addition of DIPEA (0.07 mL, 0.37 mmol). The reaction mixture was stirred at room temperature for 3 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 brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. The crude product was purified by combiflash column chromatography using 8-10% methanol in DCM as an eluent to obtain the title compound as a pale yellow solid (0.015 g, 15%).

[0380] 1 H NMR (400MHz, DMSO-d6): δ13.51(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=8.4Hz,2H),7.01(d,J=7.6Hz,2H),5.12(d,J=3.2Hz) 1H),4.91-4.80(m,1H),4.54(d,J=9.6Hz,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 / z 831.40(M+H).

[0381] Example 9: (2S,4R)-1-((S)-3,3-dimethyl-2-(2-(4-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetamide)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 9)

[0382] [ka]

[0383] Step i: Synthesis of (2S,4R)-1-((S)-3,3-dimethyl-2-(2-(4-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetamide)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (2S,4R)-1-((S)-2-(2-(4-(4-(6-chloropyridazin-4-yl)phenyl)piperazin-1-yl)acetamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (0.3 g, 0.39 mmol) and 1-methyl-1H-pyrazole-4-yl-4-boronic acid (0.123 g, 0.58 mmol) were dissolved in 1,4-dioxane (10 mL) and water (1 mL). K2CO3 (0.22 g, 1.59 mmol) was added to the stirred solution, and the mixture was degassed 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 tube at 130°C for 6 hours. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with RINKAN. The combined organic layer was washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a residue. The residue was purified by preparative HPLC to obtain the title compound as a pale yellow solid (6 mg, 2%).

[0384] 1 H NMR(400MHz,DMSO-d6):9.40(s,1H),8.98(s,1H),8.53(s,1H),8.45(d,J=7.2Hz,1H),8.24(s,1H),8.16(d,J=2.0Hz,1 H),7.92(d,J=8.0Hz,2H),7.79-7.77(m,1H),7.43(d,J=8.0Hz,2H),7.36(d,J=8.0Hz,2H),7.13(d,J=8.8Hz,2H),5.14( d,J=2.8Hz,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=6.8Hz,3H),0.96(s,9H). LC-MS: m / z 805.4 (M+H).

[0385] The compounds listed in Table 2 below were prepared using the same procedure as described in Example 2, with appropriate modifications to the reactants, reagent quantities, protection and deprotection, solvent, and reaction conditions. The characteristic analysis data for each compound is summarized in the table below.

[0386] [Table 3-1]

[0387] [Table 3-2]

[0388] [Table 3-3]

[0389] [Table 3-4]

[0390] [Table 3-5]

[0391] [Table 3-6]

[0392] The compounds listed in Table 3 below were prepared using the same procedure as described in Example 8, with appropriate modifications to the reactants, reagent quantities, protection and deprotection, solvent, and reaction conditions. The characteristic analysis data for each compound is summarized in the table below.

[0393] [Table 4-1]

[0394] [Table 4-2]

[0395] [Table 4-3]

[0396] [Table 4-4]

[0397] Example 10: (2S,4R)-4-hydroxy-1-((S)-2-(5-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)pentanamide)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 34)

[0398] [ka]

[0399] Step i: Synthesis of methyl 5-(4-(6-chloropyridazine-4-yl)phenoxy)pentanoate To a stirred solution of compound 4-(6-chloropyridazine-4-yl)phenol (0.5 g, 2.42 mmol) in acetone (10 mL), 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 at room temperature. The reaction mixture was heated in a sealed tube at 90°C for 16 hours. Once the reaction was complete (monitored by TLC), the reaction mixture was concentrated and then diluted with ethyl acetate. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the residue. The residue was purified by preparative HPLC to obtain the title compound as a pale yellow solid (0.5 g, 64%).

[0400] 1 H NMR (400MHz, CDCl3): δ9.65(d,J=2Hz,1H),8.21(d,J=2Hz,1H),7.98(d,J=8.8Hz,2H),7.10(d,J= LC-MS:m / z 320.9(M+H).

[0401] Step ii: Synthesis of methyl 5-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)pentanoate Methyl 5-(4-(6-chloropyridazin-4-yl)phenoxy)pentanoate (0.5 g, 1.56 mmol) and (2-hydroxyphenyl)boronic acid (0.43 g, 3.12 mmol) were dissolved in 1,4-dioxane (10 mL) and water (3 mL). To this stirred solution, Na2CO3 (0.50 g, 4.68 mmol) was added, and the mixture was degassed under nitrogen for 5 minutes. Pd(dppf)Cl2.DCM (0.13 g, 0.15 mmol) was added, and the reaction mixture was heated in a sealed tube at 130°C for 6 hours. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with ethyl acetate. The combined organic layers were washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a residue. The residue was then purified by combiflash column chromatography using 50-60% ethyl acetate in hexane as an eluent to obtain the title compound as an off-white solid (0.19 g, 32%).

[0402] 1 H NMR (400MHz, CDCl3): δ13.18(bs,1H),9.29(d,J=2.4Hz,1H),8.16(d,J=2Hz,1H ),7.83(dd,J=8,1.2Hz,1H),7.70(d,J=8.8Hz,2H),7.38(t,J=7.2Hz,1H),7.14 (dd,J=8.4,0.8Hz,1H),7.07(d,J=8.8Hz,2H),6.99(t,J=8.4Hz,1H),4.07(t,J =5.6Hz,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).

[0403] Step iii: Synthesis of 5-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)pentanoic acid The compound methyl 5-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)pentanoate (0.19 g, 0.50 mmol) was dissolved in a methanol:THF:H2O (3 mL:4 mL:3 mL) mixture. LiOH.H2O (0.03 g, 1.51 mmol) was added to the stirred solution at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then evaporated under reduced pressure, the resulting residue was diluted with methanol, acidified to pH 6 using Amberlite® IT120, filtered, and the filtrate was concentrated under vacuum to obtain the title compound as a viscous solid (0.17 g, 92.8%). LC-MS: m / z 365.0 (M+H).

[0404] Step iv: Synthesis of (2S,4R)-4-hydroxy-1-((S)-2-(5-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)pentanamide)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide To a solution of 5-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)pentanoic acid (0.17 g, 0.467 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.27 g, 0.56 eq.) in DMF (3 mL), HATU (0.27 g, 0.70 mmol) was added at 0°C, followed by the dropwise addition of DIPEA (0.25 mL, 1.4 mmol). The reaction mixture was stirred at room temperature for 3 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 brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. The crude product was purified by combiflash column chromatography using 8-10% methanol in DCM as an eluent to obtain the title compound as a pale yellow solid (0.09 g, 24%).

[0405] 1H NMR(400MHz,DMSO-d6):δ13.33(s,1H),9. 60(d,J=1.6Hz,1H),8.98(s,1H),8.66(d,J=2Hz,1H),8.38(d,J=8Hz,1H),8.25(d,J=7.6Hz,1H),8.08(d,J=8.8Hz,2H) ,7.87(d,J=9.2Hz,1H),7.36-7.44(m,5H),7.15(d,J=9.2Hz,2H),7.02(d,J=8Hz,2H),5.11(d,J=3.6Hz,1H),4.90(t,J =7.2Hz,1H),4.54(d,J=8.8Hz,1H),4.43(t,J=7.2Hz,1H),4.28(bs,1H),4.09(d,J=6Hz,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=7.2Hz,3H),0.95(s,9H);LC-MS:m / z 791.35(M+H).

[0406] Example 11: (2S,4R)-4-hydroxy-1-((S)-2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)butanamide)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 35)

[0407] [ka]

[0408] Compound 35 was prepared using the same procedure as described in Example 10, with appropriate modifications to the reactants, reagent quantities, protection and deprotection, solvent, and reaction conditions.

[0409] 1H NMR (400MHz, DMSO-d6): δ13.35(s,1H),9.60(s,1H),8.98(s,1H),8.67(s,1H),8.39(d,J=8Hz,1H),8.25(d,J=8H) z,1H),8.08(d,J=8Hz,2H),7.96(d,J=8Hz,1H),7.36-7.44(m,5H),7.14(d,J=12Hz,2H),7.02(d,J=8Hz,2H),5.13 (s,1H),4.89-4.93(m,1H),4.54(d,J=8.8Hz,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=8Hz,3H),0.94(s,9H);LC-MS:m / z 776.8(M+H).

[0410] Example 12: (2S,4R)-4-hydroxy-1-((S)-2-(5-((4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)amino)pentanamide)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 36)

[0411] [ka]

[0412] Compound 36 was prepared using the same procedure as described in Example 10, with appropriate modifications to the reactants, reagent quantities, protection and deprotection, solvent, and reaction conditions.

[0413] 1H NMR (400MHz, DMSO-d6): δ13.72(bs,1H),9.51(d,J=2.4Hz,1H),8.98(s,1H),8.53(d,J=2Hz,1H),8.38(d,J=7.2Hz,1H),8.24(d,J=6. 8Hz,1H),7.92(d,J=8.8Hz,2H),7.84(d,J=9.6Hz,1H),7.36-7.44(m,5H),6.99(d,J=8.8Hz,2H),6.73(d,J=8.8Hz,2H),6.38(t,J=5. 6Hz,1H),5.11(d,J=3.6Hz,1H),4.91(t,J=7.2Hz,2H),4.53(d,J=9.2Hz,1H),4.42(t,J=8.4Hz,1H),4.28(bs,1H),3.60(bs,2H),3.1 1(d,J=6.0Hz,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=6.8Hz,3H),0.94(s,9H). LCMS m / z 790.6(M+H).

[0414] The compounds listed in Table 4 below were prepared using the same procedure as described in Example 7, with appropriate modifications to the reactants, reagent quantities, protection and deprotection, solvent, and reaction conditions. The characteristic analysis data for the compounds are summarized in the table below.

[0415] [Table 5-1]

[0416] [Table 5-2]

[0417] [Table 5-3]

[0418] Example 13: (2S,4R)-4-hydroxy-1-(2-(3-(2-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 42, racemic mixture)

[0419] [ka]

[0420] Step i: Synthesis of 5-(4-(2-bromoethoxy)phenyl)-3-chloropyrazine 4-(6-chloropyridazine-4-yl)phenol (0.5 g, 2.42 mmol) was mixed with ethanol (10 mL) and 1,2-dibromoethane (0.82 g mL, 9.7 mmol) and K2CO3 (1.4 g, 9.7 mmol) were added at room temperature. The reaction mixture was heated in a sealed tube at 100 °C for 16 hours. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the residue. The residue was purified by combiflash column chromatography using 40% ethyl acetate in hexane as an eluent to obtain the title compound as a brown solid (0.4 g, 52.4%).

[0421] 1 H NMR(400MHz,CDCl3):δ9.34(bs,1H),7.66(s,1H),7.65(d,J=8.8Hz,2H),7.08(d,J=8.8Hz,2H),4.37(t,J=6Hz,2H),3.68(t,J=6.8Hz,2H);LC-MS:m / z 314.8(M+H).

[0422] Step ii: Synthesis of methyl 2-(3-(2-(4-(6-chloropyridazine-4-yl)phenoxy)ethoxy)isoxazole-5-yl)-3-methylbutanoate To a stirred solution of methyl 2-(3-hydroxyisoxazole-5-yl)-3-methylbutanoate (0.2 g, 1 mmol) and 5-(4-(2-bromoethoxy)phenyl)-3-chloropyrazine (0.38 g, 1.2 mmol) in DMF (5 mL), methyl 2-(3-hydroxyisoxazole-5-yl)-3-methylbutanoate (0.2 g, 1 mmol) and K2CO3 (0.30 g, 2.2 mmol) (0.2 g, mmol) were added at room temperature, and the reaction mixture was heated in a sealed tube at 70°C for 12 hours. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with water and extracted with ELISA. The combined organic layers were washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a residue. The residue was then purified by combiflash column chromatography using 60% ethyl acetate in hexane as an eluent to obtain the title compound as a brown solid (0.16 g, 37%).

[0423] 1 H NMR (400MHz, CDCl3): δ9.34(d,J=2Hz,1H),7.65(m,3H),7.10(d,J=8.8Hz,2H),5.95(s,1H),4.63(t,J=4.4Hz,2H),4.39( t,J=4.4Hz,2H),3.73(s,3H),3.51(d,J=8.8Hz,1H),2.35(m,1H),1.01(d,J=8.6Hz,3H),0.93(d,J=8.6Hz,3H);LC-MS:m / z 432.05(M+H).

[0424] Step iii: Synthesis of methyl 2-(3-(2-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)ethoxy)isoxazole-5-yl)-3-methylbutanoate Methyl 2-(3-(2-(4-(6-chloropyridazin-4-yl)phenoxy)ethoxy)isoxazole-5-yl)-3-methylbutanoate (0.16 g, 0.37 mmol) and (2-hydroxyphenyl)boronic acid (0.1 g, 0.74 mmol) were dissolved in 1,4-dioxane (3 mL) and water (1 mL). K2CO3 (0.15 g, 1.11 mmol) was added to the stirred solution, and the mixture was degassed with nitrogen for 5 minutes. Pd(dppf)Cl2.DCM (0.03 g, 0.03 mmol) was added, and the reaction mixture was microwaved at 130°C for 1 hour. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with water and extracted with ELISA. The combined organic layers were washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a residue. The residue was then purified by combiflash column chromatography using 50% ethyl acetate in hexane as an eluent to obtain the title compound as an off-white solid (0.08 g, 43.9%).

[0425] 1 H NMR(400MHz,DMSO-d6):δ13.32(bs,1H),9.61(d,J=2Hz,1H),8.68(d,J=2Hz,1H),8.25(d ,J=7.6Hz,1H),8.10(d,J=8.4Hz,2H),7.40(t,J=8Hz,1H),7.21(d,J=8.8Hz,2H),7.02(d, J=8.4Hz,2H),6.29(s,1H),4.53(t,J=3.2Hz,2H),4.44(t,J=3.2Hz,2H),3.71(d,J=8.4H) z,1H),3.66(s,3H),2.32(m,1H),0.92(d,J=6.8Hz,3H),0.86(d,J=6.8Hz,3H):LC-MS:m / z 490.1(M+H).

[0426] Step iv: Synthesis of 2-(3-(2-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)ethoxy)isoxazole-5-yl)-3-methylbutyrate Methyl 2-(3-(2-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)ethoxy)isoxazole-5-yl)-3-methylbutanoate (0.08 g, 0.16 mmol) was dissolved in a methanol:THF:H2O (1 mL:1 mL:1 mL) mixture and stirred. LiOH.H2O (0.022 g, 0.49 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then evaporated under reduced pressure, the resulting residue was diluted with methanol, acidified to pH 6 using Amberlite® IT120, filtered, and the filtrate was concentrated under vacuum to obtain the title compound as a sticky solid (0.06 g, 77%). 1 H NMR(400MHz,DMSO-d6):δ13.19(bs,1H),12.95(bs,1H),9.61(d,J=2Hz,1H),8.68(d,J=2H) z,1H),8.25(d,J=7.6Hz,1H),8.10(d,J=8.4Hz,2H),7.40(t,J=8Hz,1H),7.21(d,J=8.8Hz ,2H),7.02(d,J=8.4Hz,2H),6.24(s,1H),4.53(t,J=3.2Hz,2H),4.44(t,J=3.2Hz,2H),3. 53(d,J=8.8Hz,1H),2.37(m,1H),0.95(d,J=6.8Hz,3H),0.85(d,J=6.8Hz,3H);LC-MS:m / z 476.1(M+H).

[0427] Step v: Synthesis of (2S,4R)-4-hydroxy-1-(2-(3-(2-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide To a solution of 2-(3-(2-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)ethoxy)isoxazole-5-yl)-3-methylbutyrate (0.015 g, 0.031 mmol) and (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.014 g, 0.037 mmol) in DMF (3 mL), HATU (0.018 g, 0.047 mmol) was added at 0°C, followed by the dropwise addition of DIPEA (0.017 mL, 0.094 mmol). The reaction mixture was stirred at room temperature for 3 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 brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. The crude product was purified by combiflash column chromatography using 8-10% methanol in DCM as an eluent to obtain the title compound as a pale yellow solid (0.005 g, 20%).

[0428] 1 H NMR(400MHz,DMSO-d6):δ13.33(s,1H),9.61(d,J=2Hz,1H),8.97(s,1H),8.68(bs,1H),8.25(d,J=7.6Hz,1H), 8.11(d,J=8.8Hz,2H),7.30-7.44(m,6H),7.21(d,J=8.8Hz,2H),7.03(d,J=7.6Hz,2H),6.16(d,J=9.2Hz,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.

[0429] Example 14: (2S,4R)-4-hydroxy-1-(2-(3-(3-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)propoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 43, racemic mixture)

[0430] [ka]

[0431] Compound 43 was prepared using the same procedure as described in Example 13, with appropriate modifications to the reactants, reagent quantities, protection and deprotection, solvent, and reaction conditions.

[0432] 1 H NMR (400MHz, DMSO-d6): δ13.33(s,1H),9.59(m,1H),8.97(m,1H),8.67(bs,1H),8.24(d,J=8Hz,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=4Hz,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).

[0433] Example 15: (2S,4R)-4-hydroxy-1-(2-(3-(2-((4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)(methyl)amino)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 44, racemic mixture)

[0434] [ka]

[0435] Compound 44 was prepared using the same procedure as described in Example 13, with appropriate modifications to the reactants, reagent quantities, protection and deprotection, solvent, and reaction conditions.

[0436] 1 H NMR(400MHz,DMSO-d6):δ13.66(d,J=4.8Hz,1H),9.56(dd,J=5.6Hz,2.0Hz,1H),8.98(d,J=5.6Hz,1H),8.58(brs,1 H),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).

[0437] Example 16: (2S,4R)-4-hydroxy-1-((S)-2-(2-(4-((4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)amino)piperidine-1-yl)acetamide)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 45)

[0438] [ka]

[0439] Step i: Synthesis of 4-(6-chloropyridazine-4-yl)aniline 5-bromo-3-chloropyrazine (2 g, 10.3 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.49 g, 11.3 mmol) were dissolved in 1,4-dioxane (40 mL) and water (4 mL). K2CO3 (4.28 g, 31.02 mmol) was added to the stirred solution, and the mixture was degassed under nitrogen for 15 minutes. 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 hours. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with ethyl acetate. The combined organic layers were washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a residue. The residue was then purified by combiflash column chromatography using 40% ethyl acetate in hexane as an eluent to obtain the title compound as a light brown solid (0.7 g, 33%). 1 H NMR (400MHz, CDCl3): δ9.57(d,J=2Hz,1H),8.06(d,J=2Hz,1H),7.79(d,J=8.8Hz,2H),6.71(d,J=8.8Hz,2H),5.92(bs,2H);LC-MS:m / z 206.1(M+H).

[0440] Step ii: Synthesis of Tert-butyl 4-((4-(6-chloropyridazine-4-yl)phenyl)amino)piperidine-1-carboxylate 4-(6-chloropyridazine-4-yl)aniline (0.5 g, 2.43 mmol) and Tert-butyl 4-oxopiperidine-1-carboxylate (0.96 g, 4.86 mmol) were mixed in ethanol (10 mL) and acetic acid (0.05 mL) was added, and the mixture was stirred at room temperature for 2 hours. Then sodium borohydride (0.96 g, 4.86 mmol) was added to the reaction mixture and the mixture was stirred at room temperature for 12 hours. A new spot was formed on the TLC. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. The combined organic layer was washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a residue. The residue was purified by combiflash column chromatography using 40% ethyl acetate in hexane as an eluent to obtain the title compound as a yellow solid (0.2 g, 21%).

[0441] 1 H NMR (400MHz, CDCl3): δ9.59(d,J=2Hz,1H),8.07(d,J=2Hz,1H),7.84(d,J=8.8Hz,2H),6.76(d,J=8.8Hz,2H),6. 37(d,J=8.8Hz,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).

[0442] Step iii: Synthesis of N-(4-(6-chloropyridazine-4-yl)phenyl)piperidine-4-amine hydrochloride To a stirred solution of tert-butyl 4-((4-(6-chloropyridazine-4-yl)phenyl)amino)piperidine-1-carboxylate (0.1 g, 0.25 mmol) in DCM (1 mL), dioxane HCl (1 mL) was added at 0°C, and the mixture was then gradually brought to room temperature and stirred at room temperature for 1 hour. The reaction mixture was evaporated under reduced pressure, and the resulting residue was washed with diethyl ether and dried under vacuum to obtain the title compound as a reddish-brown solid (0.08 g, 95%). 1H NMR (400MHz, CDCl3): δ9.61(d,J=2Hz,1H),8.84(bs,1H),8.76(bs,1H),8.01(d,J=2Hz,1H),7.86(d,J=8.8 Hz,2H),6.79(d,J=8.8Hz,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).

[0443] Step iv: Synthesis of Tert-butyl 2-(4-((4-(6-chloropyridazine-4-yl)phenyl)amino)piperidine-1-yl)acetate To a stirred solution of N-(4-(6-chloropyridazine-4-yl)phenyl)piperidine-4-amine hydrochloride (0.08 g, 0.24 mmol) in DMF (2 mL), DIPEA (0.16 g, 1.23 mmol) was added at room temperature and stirred for 15 minutes. Then, tert-butyl 2-bromoacetate (0.06 g, 0.295 mmol) was added and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction mixture was quenched with cold water and stirred for 1 hour. The resulting solid was filtered and dried under vacuum to obtain the title compound as a brown solid (0.08 g, 80%).

[0444] 1 H NMR (400MHz, CDCl3): δ9.58(d,J=2Hz,1H),8.06(d,J=2Hz,1H),7.83(d,J=8.8Hz,2H),6.74(d,J=8.8Hz,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).

[0445] Step v: Synthesis of Tert-butyl 2-(4-((4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)amino)piperidine-1-yl)acetate Tert-butyl 2-(4-((4-(6-chloropyridazin-4-yl)phenyl)amino)piperidine-1-yl) acetate (0.08 g, 0.199 mmol) and 2-hydroxyphenylboronic acid (0.04 g, 0.298 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.2 mL). K2CO3 (0.08 g, 0.59 mmol) was added to the stirred solution, and the mixture was degassed with nitrogen for 10 minutes. 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 hours. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with ELISA. The combined organic layers were washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a residue. The residue was then purified by combiflash column chromatography using 40% ethyl acetate in hexane as an eluent to obtain the title compound as a pale yellow solid (0.04 g, 43%).

[0446] 1 H NMR (400MHz, DMSO-d6): δ13.73(s,1H),9.54(d,J=2Hz,1H),8.57(d,J=2Hz,1H),8.27(d,J=8.8Hz,1H),7.94(d,J=8.8Hz,2H),7.42(m,1H),7.04(m,2H) ),6.78(d,J=8.8Hz,2H),6.31(d,J=8.8Hz,1H),3.3(m,1H),3.15(s,2H),2 .86(m,2H),2.50(m,2H),2.36(m,2H),1.94(m,2H),1.46(s,9H);LC-MS:m / z 461.3(M+H).

[0447] Step vi: Synthesis of 2-(4-((4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)amino)piperidine-1-yl)acetic acid hydrochloride To a stirred solution of tert-butyl 2-(4-((4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)amino)piperidine-1-yl) acetate (0.04 g, 0.48 mmol) in DCM (1 mL), 4N dioxane hydrochloride (0.4 mL) was added at 0°C, and the mixture was then gradually brought to room temperature and stirred at room temperature for 16 hours. The reaction mixture was evaporated under reduced pressure, and the resulting residue was washed with diethyl ether and dried under vacuum to obtain the title compound as an orange solid (0.04 g, crude).

[0448] 1 H NMR(400MHz,DMSO-d6):δ10.28(s,1H),9.68(d,J=2Hz,1H),8.66(d,J=2Hz,1H),8.06(d,J=8.4Hz,2H),7.49(m,1H),7.0 5-7.15(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).

[0449] Step vii: Synthesis of (2S,4R)-4-hydroxy-1-((S)-2-(2-(4-((4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)amino)piperidine-1-yl)acetamide)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide 2-(4-((4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)amino)piperidine-1-yl) acetate hydrochloride (0.03 g, 0.074 mmol) and ((2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.04 g, 0.089 mmol) are dissolved in DMF (2 mL) at 0°C, and HATU (0.04 g, 0.11 mmol) was added, followed by dropwise addition of DIPEA (0.05 mL, 0.37 mmol), and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then poured into ice-cold water and extracted with ethyl acetate. The combined organic layer was washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. The crude product was purified by combiflash column chromatography using 8-10% methanol in DCM as an eluent to obtain the title compound as a pale yellow solid (0.018 g, 29%).

[0450] 1H NMR(400MHz,DMSO-d6):δ13.72(s,1H),9.55(d,J=2.0Hz,1H),9.02(s,1H),8.56(d,J=2.0Hz,1H),8.45(d,J=2.0Hz,1H),8.34(s,1H),7.9 5(d,J=8.8Hz,2H),7.96(s,1H),7.48-7.39(m,5H),7.05-7.02(m,2H),6.80(d,J=8.8Hz,2H),6.40(d,J=12.0Hz,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=6.8Hz,3H),0.99(s,9H). LC-MS: m / z 831.5 (M+H).

[0451] Example 17: (2S,4R)-4-hydroxy-1-((S)-2-(2-(4-((4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)(methyl)amino)piperidine-1-yl)acetamide)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 46)

[0452] [ka]

[0453] Compound 46 was prepared using the same procedure as described in Example 16, with appropriate modifications to the reactants, reagent quantities, protection and deprotection, solvent, and reaction conditions.

[0454] 1H NMR (400MHz, DMSO-d6): δ13.69(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=12.0Hz,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),4.91-4.8 2(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,3 H),2.50-2.49(m,4H),2.45(s,2H),2.11-1.95(m,1H),1.82-1.71(m,3H),1.70-1.61(m,2H),1.38(d,J=8.0Hz,3H),0.96(s,9H). LC-MS: m / z 845.3 (M+H).

[0455] Example 18: (2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(4-(6-hydroxypyridazin-4-yl)phenyl)piperazin-1-yl)acetamide)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 47)

[0456] [ka]

[0457] Step i: Synthesis of (2S,4R)-4-Hhydroxy-1-((S)-2-(2-(4-(4-(6-hydroxypyridazin-4-yl)phenyl)piperazin-1-yl)acetamide)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (2S,4R)-1-((S)-2-(2-(4-(4-(6-chloropyridazin-4-yl)phenyl)piperazin-1-yl)acetamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (0.2 g, 0.26 mmol) was dissolved in 1,4-dioxane (4 mL) and water (0.5 mL). K2CO3 (0.07 g, 0.52 mmol) was added to the stirred solution, and the mixture was degassed with nitrogen for 5 minutes. Pd(dppf)Cl2.DCM (0.02 g, 0.02 d mmol) was added, and the reaction mixture was microwaved at 120 °C for 1 hour. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with ELISA. The combined organic layers were washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a residue. The residue was then purified by preparative HPLC to obtain the title compound as a pale yellow solid (10 mg, 5%).

[0458] 1 H NMR (400MHz, DMSO-d6): δ12.9(s,1H),8.98(s,1H),8.44(d,J=7.6Hz,1H),8.30(d,J=7.6Hz,1H),7.71-7.79(m ,2H),7.33-7.45(m,4H),7.06(d,J=8.8Hz,2H),7.01(bs,1H),5.13(d,J=3.2Hz,1H),4.88(t,J=8Hz,1H),4.52( d,J=9.6Hz,1H),4.44(t,J=8.4Hz,1H),4.28(bs,1H),3.59(bs,2H),3.35(m,4H),3.14(d,J=16hz,1H),3.02(d, LC-MS:m / z 741.3(M+H).

[0459] Example 19: (2S,4R)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)-1-((S)-2-(2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetamide)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamide (Compound 48)

[0460] [ka]

[0461] Step i: Synthesis of (2S,4R)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)-1-((S)-2-(2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetamide)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamide To a 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-dimethylbutanoyl)-4-hydroxy-N-(2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.17 g, 0.34 mmol) in DMF (5 mL), HATU (0.19 g, 0.51 mmol) was added at 0°C, followed by the dropwise addition of DIPEA (0.2 mL, 1.02 mmol), and the reaction mixture was stirred at room temperature 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 brine solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a crude product. The crude product was purified by combiflash column chromatography using 5% methanol in DCM as an eluent to obtain the title compound as a yellow solid (10 mg, 3.5%).

[0462] 1H NMR(400MHz,DMSO-d6):δ13.54(bs,1H),9.59(d,J=2Hz,1H),8.98(s,1H),8.63(d,J=2Hz,1H),8.46(d,J=8Hz,1H), 8.26(d,J=7.2Hz,1H),8.03(d,J=8.8Hz,2H),7.80(d,J=9.6Hz,2H),7.36-7.44(m,5H),7.15(d,J=8.8Hz,2H),7.02( d,J=8Hz,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 / z 833.4

[0463] Example 20: (2S,4R)-N-(2-(dimethylamino)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)-4-hydroxy-1-((S)-2-(2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetamide)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamide (Compound 49)

[0464] [ka]

[0465] Compound 49 was prepared using the same procedure as described in Example 15, with appropriate modifications to the reactants, reagent quantities, protection and deprotection, solvent, and reaction conditions.

[0466] 1H NMR (400MHz, DMSO-d6): δ13.53(s,1H),9.58(d,J=2.0Hz,1H),8.98-8.96(m,1H),8.62(s,1H),8.32-8. 24(m,1H),8.03(t,J=3.2Hz,2H),7.78-7.75(m,2H),7.43-7.33(m,5H),7.15(t,J=6.4Hz,2H),7.02(t, J=6.4Hz,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).

[0467] Example 21: (2S,4R)-4-hydroxy-1-(2-(3-(2-((4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)amino)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 50, racemic mixture)

[0468] [ka]

[0469] Compound 50 was prepared using the same procedure as described in Example 13, with appropriate modifications to the reactants, reagent quantities, protection and deprotection, solvent, and reaction conditions.

[0470] 1H NMR(400MHz,DMSO-d6):δ13.68(br,1H),9.52(brs,1H),8.96(d,J=5.6Hz,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=7.6Hz,2H),6.55-6.52(m,2H),6.63(m,1H),6.11(d,J=1.6Hz,1H),5.10(d,J=3 .2Hz,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=4.4Hz,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).

[0471] Example P1: Determination of the antiproliferative activity of a compound against cell line A549 using the Cell Titer Glo® (promega) assay. A549 (ATCC CCL-185) cells were seeded in a 96-well plate with a black bottom (Corning, catalog number 3904) using complete F-12K medium. The following day, the compound of the present invention was added to a 10 mM stock of cells prepared with DMSO (Sigma, catalog number D2650). Three different concentrations of the compound were tested, and the final percentage of DMSO concentration in the cells did not exceed 0.3. After incubation of the compound (8 days with A549), the assay was completed using 50 μl of CellTiter Glo® reagent (Promega, catalog number G7572). The number of viable cells was determined by quantifying the cell number and the amount of ATP, an indicator of metabolic activity, using the CellTiter-Glo® luminescence reagent. Luminescence was read using a Victor-3 instrument. Inhibition % = 100 - (luminescence value of test substance / luminescence value of DMSO control) *The growth inhibition rate was calculated using formula 100. DMSO control (0%) = cells in complete medium containing DMSO, blank = medium containing only DMSO. IC was performed using GraphPad Prism software. 50 The result was calculated.

[0472] From the experiment described in Example P1, the IC of the selected compound of the present invention 50 The value was found to be less than 1 μM.

[0473] Example P2: Determination of SMARCA2 and SMARCA4 degradation in VCaP cells by Western blotting. VCaP (ATCC CRL-2876) was seeded in 6-well plates using fully modified Dulbecco's Eagle medium. On day 3, the compounds disclosed herein were added to 10 mM stock cells prepared with DMSO (Sigma catalog number D2650). The concentrations of each compound were tested, and the final proportion of DMSO in the cells did not exceed 0.3. The cells were incubated with the compounds for 16 hours and then collected in 1X RIPA lysis buffer (Thermo Fischer, catalog number 89900) containing a protease inhibitor cocktail (Sigma catalog number #P-8340). Equivalent amounts of protein were loaded onto an SDS-PAGE gel and subjected to electrophoresis. Western blotting was performed to detect either SMARCA2 antibody (Cell signalling technologies, catalog number #11966) or SMARCA4 antibody (Cell signalling technologies, catalog number #52251). A β-tubulin antibody (Cell signalling technologies, catalog number #86298) was used as a loading control. The degradation rate of SMARCA2 or SMARCA4 was calculated as follows: Degradation % = 100 - (Normalized band intensity of treated sample / Normalized band intensity of DMSO control) * It was calculated using formula 100.

[0474] [Table 6]

[0475] Example P3: Determination of the antiproliferative activity of the compound using the Cell Titer Glo® (promega) assay. Cells were seeded in a 96-well plate, and the plate was incubated overnight at 37°C in an incubator. The following day, the compound was diluted 3-fold to cover a 9-point concentration range in DMSO. After preparing an intermediate plate dilution in culture medium, the cells were treated with the compound. On day 4, the cells were treated again with the compound dilution, and the assay for SK-MEL-5 cells was completed using CellTiter-Glo. The plate was then kept at room temperature on an orbital shaker for 20 minutes. On day 6, the assay for RERF-LC-A1 cells that had not been treated with the compound was completed. The luminescence signal was VICTOR 3 The data was recorded using the instrument. The growth inhibition rate at each concentration was calculated and plotted against the compound concentration. GraphPad software was used for IC analysis. 50 The result was calculated.

[0476] The selected compounds of the present invention are screened in the assay procedure described above and EC 50 The (SK-MEL-5) values ​​were determined and grouped into A, B, and C in the table below. Here, group "A" is defined as EC less than 250 nM. 50 The value, "B," is an EC between 250.01 nM and 500 nM (both are included). 50 The value, "C", represents an EC of over 500 nM. 50 Represents a value.

[0477] [Table 7]

[0478] Furthermore, the data for the RERF-LC-A1 cell line for the selected compounds of the present invention are summarized in the table below. Here, the group "++" indicates an EC of less than 100 nM. 50 (RERF-LC-A1) value, "+" indicates an EC greater than 100nM 50 (RERF-LC-A1) represents the value.

[0479] Table 8

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