3-Substituted Pyridazine Compounds as SMARCA2 and / or SMARCA4 Degraders

Abstract

The present invention provides 3-substituted pyridazine compounds of formula (I), which are therapeutically useful as SMARCA2 and / or SMARCA4 degraders. These compounds are useful for treating and / or preventing diseases or disorders that depend on SMARCA2 and / or SMARCA4 in a subject. The present invention also provides for the preparation of pharmaceutical compositions comprising the compounds of formula (I) or pharma- ceutically acceptable salts or stereoisomers or tautomers thereof. [Formula 1] TIFF2025506452000148.tif28170

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to Indian Provisional Patent Application No. 202241006964, filed on February 9, 2022, the specification of which is hereby incorporated by reference in its entirety.

[0002] The present invention relates to 3-substituted pyridazine compounds and their pharmacologically acceptable salts or stereoisomers or tautomers, which are useful as SMARCA2 and / or SMARCA4 degraders and for the treatment of diseases or disorders that depend on SMARCA2 and / or SMARCA4. The present invention also relates to methods for preparing said pyridazine compounds and pharmaceutical compositions containing said compounds. [Background technology]

[0003] One of the most important findings from cancer genome profiling is the discovery of frequent mutations in various subunits of the mammalian SWI / SNF (switch / sucrose nonfermenting) chromatin remodeling complex. Approximately 20% of human cancers are associated with somatic mutations in the SWI / SNF complex, a subunit of a chromatin remodeling complex that affects gene regulation by disrupting histone-DNA contacts (PNAS February 25,2014.111(8)3128-3133).

[0004] SWI / SNF complexes contain two closely related and evolutionarily conserved catalytic ATPase subunits: either Bramer (BRM / SMARCA2) or Bramer-related gene 1 (BRG1 / SMARCA4). They share approximately 75% identity at the protein level. BRG1- and BRM-containing complexes show some redundancy, and they may function uniquely. In human cancers, BRG1 appears to be one of the most frequently mutated subunit genes, while BRM genes are rarely mutated. BRG1 / SMARCA4 mutations occur in approximately 10-15% of lung adenocarcinomas. BRM / SMARCA2 is essential for tumor cell proliferation, which masks loss of function mutations in BRG1 / SMARCA4. Depletion of BRM in BRG1-deficient cancer cells leads to cell cycle arrest, induction of senescence and increased levels of globular H3K9me31 (PNAS February 25, 2014. 111(8)3128-3133).

[0005] In several tumor types, mutations within the SWI / SNF complex lead to a unique set of vulnerabilities, such as the requirement of SMARCA2 for survival of tumor cells lacking SMARCA4. The discovery of the lethal relationship of SMARCA2 / 4 synthesis is translatable in vivo, which highlights SMARCA2 as a potential therapeutic target for the treatment of SMARCA4-deficient cancers. Furthermore, SMARCA4-deficient patient populations generally lack targetable oncogenes (such as EGFR or ALK translocations due to mutations), which further highlights the possibility of developing SMARCA2 inhibitors. Characterization of SMARCA4 function in tumors with high SMARCA4 levels shows effects on signaling pathways that lead to increased proliferation and survival. SMARCA4 knockdown in tumors showing high levels known to inhibit proliferation and other cancer cell properties. Studies have also shown that SMARCA4 knockdown / modulation increases sensitivity to known chemotherapeutic drugs, thereby indicating that SMARCA4 targeting may also be an adjunct to existing chemotherapy approaches (PNAS February 25, 2014.111(8)3128-3133; J Pathol. 2016 Feb;238(3):389-400).

[0006] Contrary to the point that genetic silencing of SMARCA2 leads to strong anti-proliferative activity in SMARCA4-deficient cancer cell lines, pharmacological studies of selective cell permeating SMARCA2 / 4 bromodomain inhibitors capable of binding to PFI-3, SMARCA2 and SMARCA4 bromodomains fail to show an anti-proliferative phenotype. This indicates that SMARCA2 / 4 bromodomain function is not critical for tumor cell proliferation, whereas catalytic ATPase activity is absolutely essential (Cancer Res. 2015 Sep 15; 75(18):3865-3878). To mimic the phenotype achieved by genetic silencing, approaches leading to reduction or complete elimination of SMARCA2 / 4 may be required.

[0007] The ubiquitin-proteasome system (UPS) is a major pathway that regulates the levels of intracellular proteins and provides a delicate balance between protein synthesis and degradation required for the normal maintenance of cellular functions, such as proliferation, differentiation, and cell death. Ubiquitination is a post-translational modification in which a small protein, ubiquitin, is covalently attached to lysine residues on substrate proteins, which is carried out in turn by a series of enzymatic reactions involving close cooperation between E1 activation, E2 conjugation, and E3 conjugation enzymes, and the subsequent 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] Protein degradation targeting chimeras (PROTACs) are heterobifunctional molecules that contain a ligand for a target protein of interest that is linked via a linker to a ligand for an E3 ubiquitin ligase. Upon heterodimerization brought about by such a bifunctional molecule of two binding proteins, the target protein is ubiquinated 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 protein of interest. Proteins that are efficiently degraded using these approaches include RIPK2 and ERRα, BRD4, BRD9, BCR / Abl and Abl, and Erα (Cell Chemical Biology 25,1-10,January 18,2018). E3 ubiquitin ligases, of which over 600 are known in humans, confer substrate specificity for ubiquitination and are more attractive therapeutic targets than general proteasome inhibitors due to their specificity for certain protein substrates (Cancer Res. 2017 May 1;77(9):2476-2487).

[0009] Small molecule ligands targeting the SMARCA2 and SMARCA4 bromodomains have been reported in the literature (Journal of Medicinal Chemistry 2016, 59, 4800-4811; Hoffman et al., PNAS, 2014b, 777, 3128-3133; Sutherell et al., 2016, Journal of Medicinal Chemistry 59, 5095-5101 and WO2016138114). However, cells lacking SMARCA4 activity are susceptible to loss of SMARCA2 (2014a, PNAS 777, 3128-3133). SMARCA2 / 4 inhibitors have not been able to phenocopy these antiproliferative effects. Consistent with this, re-expression of SMARCA2 mutants in cells in which the endogenous protein was silenced showed that an intact bromodomain was not required to sustain proliferation (Cancer Res. 2015, Sep 15;75(18):pp.3865-3878). SMARCA2 / 4 bromodomain inhibitors are thus precluded from use for the treatment of SMARCA4 mutant cancers, but could provide attractive ligands for PROTAC conjugation.

[0010] It is therefore concluded that PROTACs targeting non-functional bromodomains of SMARCA2 and / or SMARCA4 should offer the opportunity to exploit the vulnerability of SMARCA2 in SMARCA4 mutant cancer cells for therapeutic purposes. The principles of binding suitable SMARCA ligands with E3 ligase binders are described in WO 2016 / 105518, WO 2016138114, WO 2017007612, WO 2017011371, WO 2019195201, WO 2019207538, WO 2019213005, WO 2020010227, WO 20200 This is described in International Publication No. 78933, International Publication No. 2020251972, International Publication No. 2020251969, International Publication No. 2020251971, International Publication No. 2020251974, International Publication No. 2021083949, International Publication No. 2021133920, International Publication No. 2021133917, International Publication No. 2021142247, and International Publication No. 2021207291. However, none of the published literature demonstrates specific examples of degradation of SMARCA proteins. Summary of the Invention [Means for solving the problem]

[0011] Provided herein are 3-substituted pyridazine compounds and pharmaceutical compositions thereof that are useful as SMARCA2 and / or SMARCA4 degraders and for treating diseases or conditions or disorders dependent on or caused by SMARCA2 and / or SMARCA4.

[0012] In one aspect, the present invention provides a compound of formula (I): [ka] or a pharmacologically acceptable salt or stereoisomer or tautomer thereof; A represents a 5- to 6-membered heteroarylenyl or a 6-membered arylenyl; wherein the arylenyl and heteroarylenyl are unsubstituted or contain one, two or three R a is replaced by; R a represents each occurrence independently hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, or cyano; R 1 is halogen, alkyl, haloalkyl, alkoxy, hydroxy, hydroxyalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein the aryl and heteroaryl groups are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from oxo, hydroxy, alkoxy, halogen, alkyl, haloalkyl, amino, and cyano; R 2 is hydrogen, hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, amino, aminoalkyl, haloalkyl or cyano; Q is amino, aminoalkyl, hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, or cyano; L is a bond, -N(R x )-(CR x R y )pO-, -O-(CR x R y )p-, -O-(CR x R y )pO-, -C≡C-(CR x R y )p-, -heterocycloalkylenyl-heterocycloalkylenyl-, -heterocycloalkylenyl-O-, -heterocycloalkylenyl-C≡C-, -C≡C-heterocycloalkylenyl-, -O-heterocycloalkylenyl-(CR x R y )p-, -N(R x )-Heterocycloalkylenyl-(CR x R y)p-, -cycloalkylenyl-(CR x R y )p-, -heteroaryl-(CR x R y )p-, -heterocycloalkylenyl-(CR x R y )p-, -heterocycloalkylenyl-(CR x R y )p 1 -heterocycloalkylenyl- or -heterocycloalkylenyl-O-heterocycloalkylenyl-; where cycloalkylenyl, heteroarylenyl and heterocycloalkylenyl are unsubstituted or contain one, two or three R d the left side of the L group is attached to A and the right side of the L group is attached to M; R d is, at each occurrence, independently selected from hydroxy, halogen, alkyl and alkoxy; or any two R d the groups together form an oxo group; R x and R y is independently selected at each occurrence from hydrogen and alkyl; M is M-1 and M-2: [ka] (In the formula, Z is a 5- to 6-membered heteroarylenyl or a 5- to 6-membered heterocycloalkylenyl; wherein the heteroarylenyl and heterocycloalkylenyl groups are unsubstituted or substituted with oxo, hydroxy, halogen, alkyl, or alkoxy; R 3 and R 8 independently represents alkyl, haloalkyl, or hydroxyalkyl; R 4 and R 9 independently represents hydrogen, alkyl, haloalkyl, or hydroxyalkyl; R 5 , R 6 , R 10 and R 11is independently selected from hydrogen, alkyl, halogen, heteroalkyl, haloalkyl, hydroxyalkyl, and acyl; R 7 and R 12 independently represents thiazolyl, which is unsubstituted or substituted with alkyl, hydroxy, amino, or haloalkyl. and; "p" is an integer selected from 0, 1, 2, 3, 4, 5, and 6; "p 1 " is an integer selected from 1, 2, 3 and 4; The present invention provides a compound or a pharmacologically acceptable salt or stereoisomer or tautomer thereof.

[0013] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt, or stereoisomer, or tautomer thereof, and at least one pharma- ceutically acceptable excipient, such as a pharma- ceutically acceptable carrier or diluent.

[0014] In yet another aspect, the present invention relates to the preparation of compounds of formula (I).

[0015] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmacologically acceptable salt or stereoisomer or tautomer thereof for treating a disease or condition or disorder dependent on or caused by SMARCA2 and / or SMARCA4.

[0016] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmacologically acceptable salt or stereoisomer or tautomer thereof for treating a disease or condition or disorder altering SMARCA2 and / or SMARCA4, including mutation and overexpression.

[0017] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmacologically acceptable salt or stereoisomer or tautomer thereof for treating a disease or condition or disorder in which degradation of SMARCA2 and / or SMARCA4 protein provides a benefit, such as cancer.

[0018] In another aspect, the present invention provides a method for treating a condition or disease or disorder by administering a therapeutically effective amount of a compound of formula (I) or a pharmacologically acceptable salt or stereoisomer or tautomer thereof to an individual, e.g., a human, in need thereof. The condition or disease or disorder of interest is treatable by degradation of SMARCA2 and / or SMARCA4, e.g., cancer, a chronic autoimmune disease, an inflammatory condition, a proliferative disease, sepsis, or a viral infection.

[0019] In another aspect, the present invention provides a composition of a compound of formula (I) or a pharmacologically acceptable salt or stereoisomer or tautomer thereof for treating a disease or condition or disorder that depends on altered activity of a SWI / SNF complex, with or without chromosome remodeling activity.

[0020] In another aspect, the present invention provides the use of a compound of formula (I) or a pharma- ceutical acceptable salt or stereoisomer or tautomer thereof for the manufacture of a medicament for the treatment of a disease or condition or disorder of interest, such as cancer. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] The present invention provides 3-substituted pyridazine compounds, referred to as compounds of formula (I), which are useful as SMARCA2 and / or SMARCA4 degraders and for the treatment of disorders dependent on or caused by SMARCA2 and / or SMARCA4.The present invention further provides pharmaceutical compositions comprising said compounds or stereoisomers or tautomers thereof as therapeutic agents.

[0022] Each embodiment is provided by way of illustration and not by way of limitation of the invention. Indeed, it will be apparent to those skilled in the art that various modifications and variations can be made to the compounds, compositions, and methods described herein without departing from the scope or spirit of the invention. For example, a feature illustrated or described as part of one embodiment can be applied to another embodiment to produce yet a further embodiment. Thus, the present invention is intended to encompass such modifications and variations and their equivalents. Other objects, features, and aspects of the present invention are disclosed in or are apparent from the following detailed description. It should be understood by those skilled in the art that the present discussion is merely a description of exemplary embodiments and should not be construed as limiting the broader aspects of the present invention.

[0023] In one embodiment, the present invention provides a compound of formula (I), [ka] or a pharmacologically acceptable salt or stereoisomer or tautomer thereof; A represents a 5- to 6-membered heteroarylenyl or a 6-membered arylenyl; wherein the arylenyl and heteroarylenyl are unsubstituted or contain one, two or three R a is replaced by; R a represents each occurrence independently hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, or cyano; R 1 is halogen, alkyl, haloalkyl, alkoxy, hydroxy, hydroxyalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein the aryl and heteroaryl groups are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from oxo, hydroxy, alkoxy, halogen, alkyl, haloalkyl, amino, and cyano; R 2is hydrogen, hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, amino, aminoalkyl, haloalkyl or cyano; Q is amino, aminoalkyl, hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, or cyano; L is a bond, -N(R x )-(CR x R y )pO-, -O-(CR x R y )p-, -O-(CR x R y )pO-, -C≡C-(CR x R y )p-, -heterocycloalkylenyl-heterocycloalkylenyl-, -heterocycloalkylenyl-O-, -heterocycloalkylenyl-C≡C-, -C≡C-heterocycloalkylenyl-, -O-heterocycloalkylenyl-(CR x R y )p-, -N(R x )-Heterocycloalkylenyl-(CR x R y )p-, -cycloalkylenyl-(CR x R y )p-, -heteroaryl-(CR x R y )p-, -heterocycloalkylenyl-(CR x R y )p-, -heterocycloalkylenyl-(CR x R y )p 1 -heterocycloalkylenyl- or -heterocycloalkylenyl-O-heterocycloalkylenyl-; where cycloalkylenyl, heteroarylenyl and heterocycloalkylenyl are unsubstituted or contain one, two or three R d the left side of the L group is attached to A and the right side of the L group is attached to M; R d is, at each occurrence, independently selected from hydroxy, halogen, alkyl and alkoxy; or any two R dthe groups together form an oxo group; R x and R y is independently selected at each occurrence from hydrogen and alkyl; M is M-1 and M-2: [ka] (In the formula, Z is a 5- to 6-membered heteroarylenyl or a 5- to 6-membered heterocycloalkylenyl, where the heteroarylenyl and heterocycloalkylenyl groups are unsubstituted or substituted with oxo, hydroxy, halogen, alkyl, or alkoxy; R 3 and R 8 independently represents alkyl, haloalkyl, or hydroxyalkyl; R 4 and R 9 independently represents hydrogen, alkyl, haloalkyl, or hydroxyalkyl; R 5 , R 6 , R 10 and R 11 is independently selected from hydrogen, alkyl, halogen, heteroalkyl, haloalkyl, hydroxyalkyl, and acyl; R 7 and R 12 independently represents thiazolyl, which is unsubstituted or substituted with alkyl, hydroxy, amino, or haloalkyl. Selected from; "p" is an integer selected from 0, 1, 2, 3, 4, 5, and 6; "p 1 " is an integer selected from 1, 2, 3 and 4; The present invention provides a compound or a pharmacologically acceptable salt or stereoisomer or tautomer thereof.

[0024] In one embodiment, A represents a 5- to 6-membered heteroarylenyl or a 6-membered arylenyl; wherein the arylenyl and heteroarylenyl are unsubstituted or contain one, two or three Ra is replaced by; R a represents each occurrence independently hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, or cyano; R 1 is halogen, alkyl, haloalkyl, alkoxy, hydroxy, hydroxyalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein the aryl and heteroaryl groups are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from oxo, hydroxy, alkoxy, halogen, alkyl, haloalkyl, amino, and cyano; R 2 is hydrogen, hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, amino, aminoalkyl, haloalkyl or cyano; Q is amino, aminoalkyl, hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, or cyano; L is a bond, -N(R x )-(CR x R y )pO-, -O-(CR x R y )p-, -O-(CR x R y )pO-, -C≡C-(CR x R y )p-, -heterocycloalkylenyl-heterocycloalkylenyl-, -heterocycloalkylenyl-O-, -heterocycloalkylenyl-C≡C-, -C≡C-heterocycloalkylenyl-, -O-heterocycloalkylenyl-(CR x R y )p-, -N(R x )-Heterocycloalkylenyl-(CR x R y )p-, -cycloalkylenyl-(CR x R y )p-, -heteroaryl-(CR x R y )p-, -heterocycloalkylenyl-(CR x R y)p-, -heterocycloalkylenyl-(CR x R y ) p-heterocycloalkylenyl- or -heterocycloalkylenyl-O-heterocycloalkylenyl-; where cycloalkylenyl, heteroarylenyl and heterocycloalkylenyl are unsubstituted or substituted with one, two or three R d the left side of the L group is attached to A and the right side of the L group is attached to M; R d is, at each occurrence, independently selected from hydroxy, halogen, alkyl and alkoxy; or any two R d the groups together form an oxo group; R x and R y is independently selected at each occurrence from hydrogen and alkyl; M is M-1 and M-2: [ka] (In the formula, Z is a 5- to 6-membered heteroarylenyl or a 5- to 6-membered heterocycloalkylenyl, where the heteroarylenyl and heterocycloalkylenyl groups are unsubstituted or substituted with oxo, hydroxy, halogen, alkyl, or alkoxy; R 3 and R 8 independently represents alkyl, haloalkyl, or hydroxyalkyl; R 4 and R 9 independently represents hydrogen, alkyl, haloalkyl, or hydroxyalkyl; R 5 , R 6 , R 10 and R 11 is independently selected from hydrogen, alkyl, halogen, heteroalkyl, haloalkyl, hydroxyalkyl, and acyl; R 7 and R 12independently represents thiazolyl, which is unsubstituted or substituted with alkyl, hydroxy, amino, or haloalkyl. and; “p” is an integer selected from 0, 1, 2, 3, 4, 5, and 6.

[0025] In one embodiment, R 1 is halogen, alkyl, haloalkyl, hydroxy, alkoxy, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; where the aryl and heteroaryl groups are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from oxo, hydroxy, alkoxy, halogen, alkyl, haloalkyl, amino, and cyano.

[0026] In one embodiment, R 1 is methoxy, chloro, trifluoromethyl, phenyl, or pyridinyl; where phenyl and pyridinyl are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from oxo, hydroxy, methoxy, fluoro, chloro, difluoromethyl, and trifluoromethyl.

[0027] In one embodiment, R 2 is hydrogen, hydroxy, halogen, alkoxy, alkyl or haloalkyl.

[0028] In one embodiment, R 2 is hydrogen.

[0029] In one embodiment, Q is amino, aminoalkyl, hydroxy, hydroxyalkyl, halogen, alkoxy, or alkyl.

[0030] In one embodiment, Q is amino or alkoxy.

[0031] In one embodiment, Q is -NH 2 , -O-CH 3 or -O-CH 2 CH3 It is.

[0032] In one embodiment, A is unsubstituted or has one or two R a represents phenylenyl substituted with a Each occurrence independently represents hydroxy, halogen, alkoxy, alkyl, or haloalkyl.

[0033] In one embodiment A represents phenylenyl, unsubstituted or substituted with 1 or 2 substituents selected from hydrogen and halogen.

[0034] In one embodiment A represents phenylenyl, which is unsubstituted or substituted with hydrogen or fluoro.

[0035] In one embodiment A represents 5-6 membered heteroarylenyl which is unsubstituted or substituted by one or two R a .

[0036] In one embodiment, A represents phenylenyl, furanylenyl, thienylenyl, pyrrolilenyl, pyrazolilenyl, imidazolylenyl, oxazolilenyl, isoxazolilenyl, thiazolylenyl, isothiazolilenyl, 1H-tetrazolylenyl, oxadiazolylenyl, triazolilenyl, pyridylenyl, pyrimidinylenyl, pyrazinylenyl, pyridazinylenyl, 1,2,3-triazinylenyl, 1,2,4-triazinylenyl, or 1,3,5-triazinylenyl; each group is unsubstituted or substituted with one or two substituents independently selected from hydrogen, hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, and cyano.

[0037] In one embodiment, A represents pyridylenyl, pyrimidinylenyl, or pyrazinylenyl, where the pyridylenyl, pyrimidinylenyl, and pyrazinylenyl groups are unsubstituted or substituted with one or two substituents selected from hydrogen, hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, and cyano.

[0038] In one embodiment, L is a bond. In one embodiment, L is a bond and M is bonded to A.

[0039] In one embodiment, L is -N(R x )-(CR x R y )pO-, -O-(CR x R y )p-, -O-(CR x R y )pO- or -C≡C-(CR x R y In one embodiment, R x and R y is independently selected at each occurrence from hydrogen and alkyl.

[0040] In one embodiment, L is -N(CH 3 )-CH 2 CH 2 -O-, -N(CH 3 )-CH 2 CH 2 CH 2 -O-, -N(CH 3 )-CH 2 CH 2 CH 2 CH 2 -O-, -NH-CH 2 CH 2 -O-, -NH-CH 2 CH 2 CH 2 -O-, -O-CH 2 -, -O-CH 2 -CH 2 -, -O-CH 2 -CH 2 -CH 2 -, -O-CH2 -CH 2 -O-, -O-CH 2 CH 2 CH 2 CH 2 -, -C≡C-CH 2 -, -C≡C-CH 2 CH 2 - or -C≡C-CH 2 CH 2 CH 2 -It is.

[0041] In one embodiment, L is -N(R x )-(CR x R y In one embodiment, L is -N(CH 3 )-CH 2 -CH 2 -O-, -N(CH 3 )-CH 2 CH 2 CH 2 -O-, -N(CH 3 )-CH 2 CH 2 CH 2 CH 2 -O-, -NH-CH 2 -CH 2 -O- or -NH-CH 2 CH 2 CH 2 -O-.

[0042] In one embodiment, L is -O-(CR x R y In one embodiment, L is -O-CH 2 -, -O-CH 2 -CH 2 -, -O-CH 2 -CH 2 -CH 2 -or-O-CH 2 -CH 2 -CH 2 -CH 2 -It is.

[0043] In one embodiment, L is -O-(CR x Ry In one embodiment, L is -O-CH 2 -O- or -O-CH 2 CH 2 -O-.

[0044] In one embodiment, L is -C≡C-(CR x R y In one embodiment, L is -C≡C-(CH 2 ) 1-4 In one embodiment, L is -C≡C-CH 2 -, -C≡C-CH 2 CH 2 - or -C≡C-CH 2 CH 2 CH 2 It is.

[0045] In one embodiment, L is a bond, -heterocycloalkylenyl-heterocycloalkylenyl-, -heterocycloalkylenyl-O-, -heterocycloalkylenyl-C≡C-, -C≡C-heterocycloalkylenyl-, -O-heterocycloalkylenyl-(CR x R y )p-, -N(R x )-Heterocycloalkylenyl-(CR x R y )p-, -cycloalkylenyl-(CR x R y )p-, -heteroaryl-(CR x R y )p-, -heterocycloalkylenyl-(CR x R y )p-, -heterocycloalkylenyl-(CR x R y )p 1 -heterocycloalkylenyl- or -heterocycloalkylenyl-O-heterocycloalkylenyl-; where heterocycloalkylenyl, cycloalkylenyl, or heteroarylenyl is unsubstituted or contains one, two, or three R d has been replaced with.

[0046] In one embodiment, heterocycloalkylenyl is azetidinylenyl, pyrrolidinylenyl, piperidinylenyl, piperazinylenyl, tetrahydropyranyl, tetrahydropyridazinylenyl, morpholinylenyl, thiomorpholinylenyl, 1,4-dioxanylenyl, dioxidothiomorpholinylenyl, oxapiperazinylenyl, oxapiperidinylenyl, tetrahydropyranylenyl, dihydropyranylenyl, or dihydropyrimidinylenyl; each group is unsubstituted or contains one or two R d has been replaced with.

[0047] In one embodiment, cycloalkylenyl is cyclopropylenyl, cyclobutylenyl, cyclopentylenyl, cyclohexylenyl, or cycloheptylenyl. In one embodiment, L is cyclohexylenyl.

[0048] In one embodiment, heteroarylenyl is furanylenyl, thienylenyl, pyrrolilenyl, pyrazolyllenyl, imidazolylenyl, oxazolyllenyl, isoxazolyllenyl, thiazolylenyl, isothiazolyllenyl, 1H-tetrazolylenyl, oxadiazolylenyl, triazolyllenyl, pyridylenyl, pyrimidinylenyl, pyrazinylenyl, pyridazinylenyl, 1,2,3-triazinylenyl, 1,2,4-triazinylenyl or 1,3,5-triazinylenyl.

[0049] In one embodiment, L is piperidinylenyl, piperazinylenyl, oxapiperazinylenyl, oxapiperidinylenyl, dihydropyrimidinylenyl, cyclohexylenyl, bipiperidinylenyl, 1-(piperidin-1-ylmethyl)piperazine, 4,4′-oxydipiperidinylenyl, 4-ethynylpiperidinylenyl, or 1-(azetidin-3-yl)piperazinylenyl; each group is unsubstituted or contains one, two, or three R d has been replaced with.

[0050] In one embodiment, L is -N(CH 3 )-CH 2 CH 2-O-, -NH-CH 2 CH 2 -O-, -O-CH 2 -, -O-CH 2 -CH 2 -O-, -O-CH 2 CH 2 CH 2 CH 2 -, -C≡C-CH 2 -, -C≡C-CH 2 CH 2 -, -C≡C-CH 2 CH 2 CH 2 is.

[0051] In one embodiment, L is -N(CH 3 )-CH 2 CH 2 -O-, -N(CH 3 )-CH 2 CH 2 CH 2 -O-, -N(CH 3 )-CH 2 CH 2 CH 2 CH 2 -O-, -NH-CH 2 CH 2 -O-, -NH-CH 2 CH 2 CH 2 -O-, -O-CH 2 -, -O-CH 2 -CH 2 -, -O-CH 2 -CH 2 -CH 2 -, -O-CH 2 -CH 2 -O-, -O-CH 2 CH 2 CH 2 CH 2 -, -C≡C-CH 2 -, -C≡C-CH 2 CH 2 - or -C≡C-CH 2 CH 2 CH 2 -,

Chemical formula

[0052] In one embodiment, R d is alkyl, hydroxy, halogen or alkoxy; or any two R d The groups together form an oxo group.

[0053] In one embodiment, the left side of the L group is attached to A in the compound of formula (I) and the right side of the L group is attached to M in the compound of formula (I).

[0054] In one embodiment, p represents 0, 1, 2, 3, 4, 5 or 6.

[0055] In one embodiment, M is selected from M-1 and M-2; [ka]

[0056] In one embodiment, M is M-1; in one embodiment, M is M-2; where R 3 , R 4 , R 5 , R 6 , R 7、 R 8 , R 9 , R 10 , R 11 and R 12 is as defined in the compounds of formula (I).

[0057] In one embodiment, M is M-1; 3 (C 1 ~C 4 ) alkyl; R 4 represents hydrogen or alkyl; R 5 and R 6 is independently selected from hydrogen, alkyl, and haloalkyl; R 7is thiazolyl which is unsubstituted or substituted with alkyl, hydroxy, amino or haloalkyl.

[0058] In one embodiment, M is M-1; [ka] During the ceremony, R 3 represents alkyl, haloalkyl, or hydroxyalkyl; R 4 represents hydrogen, alkyl, haloalkyl, or hydroxyalkyl; R 5 and R 6 is independently selected from hydrogen, alkyl, halogen, haloalkyl, and hydroxyalkyl; R 7 represents thiazolyl which is unsubstituted or substituted with alkyl or haloalkyl.

[0059] In one embodiment, M-1 is selected from the group consisting of M-1A and M-1B: [ka] (In the formula, R 4 is hydrogen or alkyl; R 6 is hydrogen, alkyl or haloalkyl; R 7 represents thiazolyl which is unsubstituted or substituted with alkyl or haloalkyl. is selected from.

[0060] In one embodiment, M-1A has the formula: [ka] [ka] Represented by; During the ceremony, R 4is selected from hydrogen and alkyl; R 6 is selected from hydrogen, alkyl, and haloalkyl.

[0061] In one embodiment, M-1B is [ka] and During the ceremony, R 4 is selected from hydrogen and alkyl; R 6 is selected from hydrogen, alkyl, and haloalkyl.

[0062] In certain embodiments, M-1 has the formula: [ka] (In the formula, R 4 and R 6 is the same as defined in the compound of formula (I). It is expressed as:

[0063] In certain embodiments, M-1 is [ka] It is.

[0064] In certain embodiments, M-1 is [ka] It is.

[0065] In one embodiment, M is M-2; 8 is (C 1 ~C 4 ) alkyl; R 9 represents hydrogen or alkyl; R 10 and R 11 is independently selected from hydrogen, alkyl, and haloalkyl; R 12is thiazolyl which is unsubstituted or substituted with alkyl, hydroxy, amino or haloalkyl.

[0066] In one embodiment, M is M-2: [ka] (In the formula, Z is oxazolilenyl, pyrazolilenyl, isoxazolilenyl or piperidinylenyl; R 8 represents alkyl, heteroalkyl, haloalkyl, or hydroxyalkyl; R 9 represents hydrogen, alkyl, haloalkyl, or hydroxyalkyl; R 10 and R 11 is independently selected from hydrogen, alkyl, halogen, heteroalkyl, haloalkyl, and hydroxyalkyl; R 12 represents thiazolyl which is unsubstituted or substituted with alkyl or haloalkyl. It is.

[0067] In one embodiment, M-2 is selected from the group consisting of M-2A and M-2B: [ka] (In the formula, Z represents isoxazolilenyl, oxazolilenyl, pyrazolilenyl or piperidinylenyl; R 9 is hydrogen or alkyl; R 11 is hydrogen, alkyl or haloalkyl; R 12 represents thiazolyl which is unsubstituted or substituted with alkyl or haloalkyl. is selected from.

[0068] In one embodiment, Z represents isoxazolilenyl, oxazolilenyl, or pyrazolilenyl;

[0069] In certain embodiments, M-2 is [ka] (In the formula, R 9 represents hydrogen, alkyl, haloalkyl, or hydroxyalkyl; R 11 is selected from hydrogen, alkyl, halogen, heteroalkyl, haloalkyl, and hydroxyalkyl. It is.

[0070] In one embodiment, M-2 has the formula: [ka] (In the formula, R 8 represents alkyl; R 11 represents hydrogen or alkyl; R 12 represents thiazolyl which is unsubstituted or substituted with alkyl or haloalkyl. It is expressed as:

[0071] In certain embodiments, M is [ka] It is.

[0072] In certain embodiments, when L is a bond, M is bonded to A in the compound of Formula (I).

[0073] In one embodiment, “p” is selected from 0, 1, 2, and 3.

[0074] In one embodiment, "p" is 0.

[0075] In one embodiment, "p" is 1 or 2.

[0076] In one embodiment, "p 1 " is selected from 1, 2 and 3.

[0077] In one embodiment, "p 1 " is either 1 or 2.

[0078] In one embodiment, the present invention provides a compound of formula (IA): [ka] (In the formula, R 1 , R 2 , Q, R a , L and M are as defined in the compounds of formula (I). or a pharmacologically acceptable salt or stereoisomer or tautomer thereof.

[0079] In one embodiment of the compound of formula (IA), R 1 is halogen, alkyl, haloalkyl, alkoxy, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; where the aryl and heteroaryl groups are unsubstituted or substituted with one or two substituents independently selected from oxo, hydroxy, alkoxy, halogen, and haloalkyl.

[0080] In one embodiment of the compound of formula (IA), R 1 is methoxy, chloro, trifluoromethyl, phenyl, or pyridinyl; where phenyl and pyridinyl are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from oxo, hydroxy, alkoxy, halogen, alkyl, haloalkyl, and amino.

[0081] In one embodiment of the compound of formula (IA), R 2 is hydrogen, hydroxy, halogen, alkoxy, alkyl or haloalkyl.

[0082] In one embodiment of the compound of formula (IA), R 2 is hydrogen.

[0083] In one embodiment of the compound of formula (IA), Q is selected from amino and alkoxy.

[0084] In one embodiment of the compound of formula (IA), R a Each occurrence independently represents hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, or cyano.

[0085] In one embodiment of the compound of formula (IA), R a Each occurrence independently represents a halogen.

[0086] In one embodiment of the compound of formula (IA), L is a bond, -O-CH 2 -, -O-CH 2 CH 2 CH 2 CH 2 -, -O-CH 2 -CH 2 -O-, -NH-CH 2 -CH 2 -O-, -N(CH 3 )-CH 2 CH 2 -O-, -C≡C-CH 2 -, -C≡C-CH 2 CH 2 -, -C≡C-CH 2 CH 2 CH 2 -, [ka] wherein each ring is unsubstituted or has one or two R d (which is replaced by ).

[0087] In one embodiment of formula (IA), Z is oxazolilenyl, pyrazolilenyl, isoxazolilenyl or piperidinylenyl; R 3 and R 8 independently represent alkyl; R4 and R 9 independently represent hydrogen or alkyl; R 5 , R 6 , R 10 and R 11 is independently selected from hydrogen and alkyl; R 7 and R 12 independently represents thiazolyl, which is unsubstituted or substituted with alkyl or haloalkyl.

[0088] In one embodiment of the compound of formula (IA), R a represents each occurrence independently a halogen; R 1 is halogen, haloalkyl, alkoxy, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; wherein the aryl and heteroaryl groups are unsubstituted or substituted with one or two substituents independently selected from oxo, hydroxy, alkoxy, halogen, and haloalkyl; R 2 is hydrogen; Q is amino or alkoxy; L is a bond, -O-CH 2 -, -O-CH 2 CH 2 CH 2 CH 2 -, -O-CH 2 -CH 2 -O-, -NH-CH 2 -CH 2 -O-, -N(CH 3 )-CH 2 CH 2 -O-, -C≡C-CH 2 -, -C≡C-CH 2 CH 2 -, -C≡C-CH 2 CH 2 CH 2 -, [ka] wherein each ring is unsubstituted or has one or two R d substituted with; R d is, at each occurrence, independently selected from alkyl, hydroxy and halogen; or any two R d the groups together form an oxo group; M is selected from M-1 and M-2; Z is oxazolilenyl, pyrazolilenyl, isoxazolilenyl or piperidinylenyl; R 3 and R 8 independently represent alkyl; R 4 and R 9 each independently represents hydrogen; R 5 , R 6 , R 10 and R 11 is independently selected from hydrogen and alkyl; R 7 and R 12 independently represents thiazolyl, which is unsubstituted or substituted with alkyl or haloalkyl.

[0089] In one embodiment, the present invention provides a compound of formula (IB): [ka] (In the formula, R 1、 R a , L and M are as defined in the compounds of formula (I). or a pharmacologically acceptable salt or stereoisomer or tautomer thereof.

[0090] In one embodiment of the compound of formula (IB), R a Each occurrence independently represents a halogen.

[0091] In one embodiment of the compound of formula (IB), R 1is halogen, haloalkyl, alkoxy, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; where the aryl and heteroaryl groups are unsubstituted or substituted with one or two substituents independently selected from oxo, hydroxy, alkoxy, halogen, alkyl, haloalkyl, and amino.

[0092] In one embodiment of formula (IA), R 1 is methoxy, chloro, trifluoromethyl, phenyl, or pyridinyl; where phenyl and pyridinyl are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from oxo, hydroxy, alkoxy, halogen, alkyl, haloalkyl, and amino.

[0093] In one embodiment of the compound of formula (IB), L is a bond, -O-CH 2 -, -O-CH 2 CH 2 CH 2 CH 2 -, -O-CH 2 -CH 2 -O-, -NH-CH 2 -CH 2 -O-, -N(CH 3 )-CH 2 CH 2 -O-, -C≡C-CH 2 -, -C≡C-CH 2 CH 2 -, -C≡C-CH 2 CH 2 CH 2 -, [ka] wherein each ring is unsubstituted or has one or two R d substituted with .

[0094] In one embodiment of the compound of formula (IB), M is selected from M-1 and M-2; Where: Z is oxazolilenyl, pyrazolilenyl, isoxazolilenyl or piperidinylenyl; R 3 and R 8 independently represent alkyl; R 4 and R 9 independently represent hydrogen or alkyl; R 5 , R 6 , R 10 and R 11 is independently selected from hydrogen and alkyl; R 7 and R 12 independently represents thiazolyl, which is unsubstituted or substituted with alkyl or haloalkyl.

[0095] In one embodiment of the compound of formula (IB), R a represents each occurrence independently a halogen; R 1 is halogen, haloalkyl, alkoxy, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein the aryl and heteroaryl groups are unsubstituted or substituted with one or two substituents independently selected from hydroxy, alkoxy, halogen, and haloalkyl; L is a bond, -O-CH 2 -, -O-CH 2 CH 2 CH 2 CH 2 -, -O-CH 2 -CH 2 -O-, -NH-CH 2 -CH 2 -O-, -N(CH 3 )-CH 2 CH 2 -O-, -C≡C-CH 2 -, -C≡C-CH 2 CH 2 -, -C≡C-CH 2 CH 2 CH 2 -, [ka] wherein each ring is unsubstituted or has one or two R d substituted with; R d is, at each occurrence, independently selected from alkyl, hydroxy and halogen; or any two R d the groups together form an oxo group; M is selected from M-1 and M-2; Z is oxazolilenyl, pyrazolilenyl, isoxazolilenyl or piperidinylenyl; R 3 and R 8 independently represent alkyl; R 4 and R 9 independently represent hydrogen or alkyl; R 5 , R 6 , R 10 and R 11 is independently selected from hydrogen and alkyl; R 7 and R 12 independently represents thiazolyl, which is unsubstituted or substituted with alkyl or haloalkyl.

[0096] In one embodiment, the present invention provides a compound of formula (IC): [ka] (In the formula, R a , R 1 , L, R 3 , R 6 and R 7 is as defined in the compounds of formula (I). or a pharmacologically acceptable salt or stereoisomer or tautomer thereof.

[0097] In one embodiment of the compound of formula (IC), R 1is halogen, a 6- to 10-membered aryl, or a 5- to 10-membered heteroaryl; where the aryl and heteroaryl groups are unsubstituted or substituted with one or two substituents independently selected from hydroxy, alkoxy, halogen, and haloalkyl.

[0098] In one embodiment of the compound of formula (IA), R 1 is methoxy, chloro, trifluoromethyl, phenyl, or pyridinyl; where phenyl and pyridinyl are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from oxo, hydroxy, alkoxy, halogen, alkyl, haloalkyl, and amino.

[0099] In one embodiment of the compound of formula (IC), R a represents hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl or haloalkyl.

[0100] In one embodiment of the compound of formula (IC), R a represents a halogen. L is a bond, -O-CH 2 -, -O-CH 2 CH 2 CH 2 CH 2 -, -O-CH 2 -CH 2 -O-, -NH-CH 2 -CH 2 -O-, -N(CH 3 )-CH 2 CH 2 -O-, -C≡C-CH 2 -, -C≡C-CH 2 CH 2 -, -C≡C-CH 2 CH 2 CH 2 -, [ka] wherein each ring is unsubstituted or has one or two R d (which is replaced by ).

[0101] In one embodiment of the compound of formula (IC), R d is, at each occurrence, independently selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl and amino; or any two R d The groups together form an oxo group.

[0102] In one embodiment of the compound of formula (IC), R 3 represents alkyl; R 6 is selected from hydrogen and alkyl; R 7 represents thiazolyl which is unsubstituted or substituted with alkyl or haloalkyl.

[0103] In one embodiment of the compound of formula (IC), R 1 is halogen, haloalkyl, alkoxy, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein the aryl and heteroaryl groups are unsubstituted or substituted with one or two substituents independently selected from hydroxy, alkoxy, halogen, and haloalkyl; R a represents a halogen; L is a bond, -O-CH 2 -, -O-CH 2 CH 2 CH 2 CH 2 -, -O-CH 2 -CH 2 -O-, -NH-CH 2 -CH 2 -O-, -N(CH 3 )-CH 2 CH 2 -O-, -C≡C-CH 2 -, -C≡C-CH 2 CH 2 -, -C≡C-CH 2 CH 2 CH 2 -, [ka] wherein each ring is unsubstituted or has one or two R d substituted with; R d is, for each occurrence, independently selected from alkyl, hydroxy and halogen, or any two R d the groups together form an oxo group; R 3 represents alkyl; R 6 is selected from hydrogen and alkyl; R 7 represents thiazolyl which is unsubstituted or substituted with alkyl or haloalkyl.

[0104] In one embodiment, the present invention provides a compound of formula (ID): [ka] (In the formula, R 1 , L, Z, R 8 , R 11 and R 12 is as defined in the compounds of formula (I). or a pharmacologically acceptable salt or stereoisomer or tautomer thereof.

[0105] In one embodiment of the compound of formula (IC), R 1 is halogen, a 6- to 10-membered aryl, or a 5- to 10-membered heteroaryl; where the aryl and heteroaryl groups are unsubstituted or substituted with one or two substituents independently selected from hydroxy, alkoxy, halogen, and haloalkyl.

[0106] In one embodiment of the compound of formula (IA), R 1is methoxy, chloro, trifluoromethyl, phenyl, or pyridinyl; where phenyl and pyridinyl are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from oxo, hydroxy, alkoxy, halogen, alkyl, haloalkyl, and amino.

[0107] In one embodiment of the compound of formula (ID), L is a bond, -O-CH 2 -CH 2 -O-, -NH-CH 2 -CH 2 -O-, -N(CH 3 )-CH 2 CH 2 -O-, [ka] wherein each ring is unsubstituted or has one or two R d substituted with; R d is, at each occurrence, independently selected from alkyl, hydroxy and halogen; or any two R d The groups together form an oxo group.

[0108] In one embodiment of the compound of formula (ID), Z is oxazolilenyl, pyrazolilenyl, isoxazolilenyl, or piperidinylenyl; R 8 represents alkyl; R 11 is selected from hydrogen and alkyl; R 12 represents thiazolyl which is unsubstituted or substituted with alkyl or haloalkyl.

[0109] In one embodiment of the compound of formula (ID), R 1is halogen, haloalkyl, alkoxy, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein the aryl and heteroaryl groups are unsubstituted or substituted with one or two substituents independently selected from hydroxy, alkoxy, halogen, and haloalkyl; L is a bond, -O-CH 2 -CH 2 -O-, -NH-CH 2 -CH 2 -O-, -N(CH 3 )-CH 2 CH 2 -O-, [ka] wherein each ring is unsubstituted or has one or two R d substituted with; R d is, at each occurrence, independently selected from alkyl, hydroxy and halogen; or any two R d the groups together form an oxo group; Z is oxazolilenyl, pyrazolilenyl, isoxazolilenyl or piperidinylenyl; R 8 represents alkyl; R 11 is selected from hydrogen and alkyl; R 12 independently represents thiazolyl, which is unsubstituted or substituted with alkyl or haloalkyl.

[0110] In one embodiment, the present invention provides a compound of formula (IE): [ka] (In the formula, R 1 , R 2 , A, Q and M are as defined in the compounds of formula (I); X a and X b represents independently CH or N) or a pharmacologically acceptable salt or stereoisomer or tautomer thereof.

[0111] In one embodiment of the compound of formula (IE), A is unsubstituted or contains one or two R a represents a 5- to 6-membered heteroaryl group substituted with

[0112] In one embodiment of a compound of formula (IE), A represents phenylenyl, furanylenyl, thienylenyl, pyrrolilenyl, pyrazolilenyl, imidazolylenyl, oxazolilenyl, isoxazolilenyl, thiazolylenyl, isothiazolilenyl, 1H-tetrazolylenyl, oxadiazolylenyl, triazolilenyl, pyridylenyl, pyrimidinylenyl, pyrazinylenyl, pyridazinylenyl, 1,2,3-triazinylenyl, 1,2,4-triazinylenyl, or 1,3,5-triazinylenyl; each group is unsubstituted or substituted with one or two substituents selected from hydrogen, hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, and cyano.

[0113] In one embodiment of the compound of formula (IE), Q is amino, aminoalkyl, hydroxy, hydroxyalkyl, halogen, alkoxy or alkyl.

[0114] In one embodiment of the compound of formula (IE), R 1 is halogen, alkyl, haloalkyl, alkoxy, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; where the aryl and heteroaryl groups are unsubstituted or substituted with one or two substituents independently selected from oxo, hydroxy, alkoxy, halogen, and haloalkyl.

[0115] In one embodiment of the compound of formula (IE): R 1is methoxy, chloro, trifluoromethyl, phenyl, or pyridinyl; wherein phenyl and pyridinyl are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from oxo, hydroxy, alkoxy, halogen, alkyl, haloalkyl, and amino; R 2 is hydrogen; Q is selected from amino and alkoxy; A is phenylenyl or pyridylenyl; where phenylenyl and pyridylenyl are unsubstituted or contain one, two or three R a is replaced by; X a is CH or N; X b is N.

[0116] In one embodiment, the present invention provides a compound of formula (I) selected from those described herein, or a pharma- ceutical acceptable salt, or stereoisomer, or tautomer thereof.

[0117] Treatment methods In one embodiment, the present invention provides a compound of formula (I) or a pharma- ceutical acceptable salt or stereoisomer or tautomer thereof for use as a medicament.

[0118] In one embodiment, the present invention provides a compound of formula (I) or a pharmacologically acceptable salt or stereoisomer or tautomer thereof for use in the treatment of a disease or disorder dependent on SMARCA2 and / or SMARCA4.

[0119] In one embodiment, the SMARCA2 and / or SMARCA4 dependent disease or disorder is cancer.

[0120] In one embodiment, the present invention provides a method for degrading a target protein in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or a pharmacologically acceptable salt or stereoisomer or tautomer thereof.

[0121] In one embodiment, the present invention provides a method for degrading a target protein, wherein the target protein is SMARCA2 and / or SMARCA4.

[0122] 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 in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmacologically acceptable salt or stereoisomer or tautomer thereof.

[0123] In one embodiment, the present invention provides a method for treating a disease or disorder dependent on SMARCA2 and / or SMARCA4 in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I or a pharmacologically acceptable salt or stereoisomer or tautomer thereof.

[0124] In one embodiment, the disease or disorder dependent on SMARCA2 and / or SMARCA4 includes cancer.

[0125] In one embodiment, the disease or disorder is selected from the group consisting of hematological cancer, lung cancer (i.e., non-small cell lung cancer), acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelogenous (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, head and neck cancer, and / or cerebrovascular and vascular diseases. Ophthalmology, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasia and hair growths), embryonal cancer, endometrial cancer, endothelial sarcoma, ependymoma, epithelial cancer, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, 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 refractory prostate cancer, smooth muscle Myosarcoma, Leukemia, Liposarcoma, Hepatoma, Lymphangiosarcoma-endothelial sarcoma, Lymphangiosarcoma, Lymphoblastic leukemia, Lymphoma (Hodgkin's and non-Hodgkin's; Burkitt's), Malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, Lymphoid malignancies of T-cell or B-cell origin, Medullary carcinoma, Medulloblastoma, Melanoma, Meningioma, Mesothelioma, Multiple myeloma, Myeloid leukemia, Myeloma, Myxosarcoma, Neuroblastoma, NUT Midline Carcinoma (NMC), Oligodendroglioma, Oral cancer , osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, neoplastic erythrocytosis, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, malignant rhabdoid tumor (MRT), hilar myosinoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovial tumor, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, or Wilms' tumor.

[0126] In one embodiment, the present invention provides a method of inhibiting tumor growth in a subject afflicted with cancer, comprising administering to a subject in need thereof a compound of formula (I) or a pharmacologically acceptable salt or stereoisomer or tautomer thereof.

[0127] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmacologically acceptable salt or stereoisomer or tautomer thereof, and at least one pharmacologically acceptable excipient (such as a pharmacologically acceptable carrier or diluent). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound as described herein, or a pharmacologically acceptable salt or stereoisomer or tautomer thereof. The compound as described herein may be combined with or diluted by a pharmacologically acceptable excipient (such as a carrier or diluent), or may be enclosed within a carrier, which may be in the form of a capsule, sachet, paper, or other container.

[0128] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) for use in degrading a target protein in a subject, wherein the target protein is SMARCA2 and / or SMARCA4.

[0129] In one embodiment, the subject is afflicted with a disease or disorder that is dependent on SMARCA2 and / or SMARCA4.

[0130] In one embodiment, the subject is afflicted with a cancer mediated by a target protein, wherein the target protein is SMARCA2 and / or SMARCA4.

[0131] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein or a pharma- ceutically acceptable salt or stereoisomer or tautomer thereof, for use as a medicament.

[0132] In one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula (I) for use in treating or slowing the progression of a disease or disorder mediated by SMARCA2 and / or SMARCA4.

[0133] In one embodiment, the disease or disorder dependent on SMARCA2 and / or SMARCA4 is selected from the group consisting of hematological cancer, lung cancer (i.e., non-small cell lung cancer), acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain tumor, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, and / or chronic myeloid (granulocytic) leukemia. Hemopathy, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, hyperproliferative changes (dysplasia and hair growth), embryonal cancer, endometrial cancer, endothelial sarcoma, ependymoma, epithelial cancer, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, 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 refractory prostate cancer , leiomyosarcoma, leukemia, liposarcoma, hepatocellular carcinoma, lymphangiosarcoma-endothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's; Burkitt's), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), oligodendroglioma, oral The cancer is selected from the group consisting of osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, neoplastic erythrocytosis, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, malignant rhabdoid tumor (MRT), hilar myosinoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovial tumor, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, or Wilms' tumor.

[0134] In one embodiment, the invention provides the use of a compound or a pharma- ceutically acceptable salt or stereoisomer or tautomer thereof in the manufacture of a medicament for the treatment of a disease or disorder dependent on SMARCA2 and / or SMARCA4.

[0135] In one embodiment, the treatment of a disease or disorder dependent on SMARCA2 and / or SMARCA4 is cancer.

[0136] In one embodiment, the cancer is selected from the group consisting of hematological cancer, lung cancer (i.e., non-small cell lung cancer), acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain tumor, breast cancer, bronchial carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelogenous (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, and large intestine cancer. Cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, hyperproliferative changes (dysplasia and hair follicles), embryonal cancer, endometrial cancer, endothelial sarcoma, ependymoma, epithelial cancer, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, 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 refractory prostate cancer, leiomyosarcoma, leukemia, lipid Liposarcoma, Hepatocellular Carcinoma, Lymphangiosarcoma-endothelial sarcoma, Lymphoblastic leukemia, Lymphoma (Hodgkin's and non-Hodgkin's; Burkitt's), Malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, Lymphoid malignancies of T-cell or B-cell origin, Medullary carcinoma, Medulloblastoma, Melanoma, Meningioma, Mesothelioma, Multiple myeloma, Myeloid leukemia, Myeloma, Myxosarcoma, Neuroblastoma, NUT Midline Carcinoma (NMC), Oligodendroglioma, Oral cancer, Bone Selected from sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, neoplastic erythrocytosis, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, malignant rhabdoid tumor (MRT), hilar myosinoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovial tumor, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, or Wilms' tumor.

[0137] In one embodiment, the SMARCA2 and / or SMARCA4 dependent cancer is a lung cancer such as NSCLC, i.e., non-small cell lung cancer.

[0138] In one embodiment, the SMARCA2 and / or SMARCA4 dependent cancer is melanoma.

[0139] In a further embodiment, the cancer is a SMARCA2 and / or SMARCA4 dependent cancer.

[0140] Liquid dosage forms for oral administration include pharmacologic acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, groundnut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan and mixtures thereof. In addition to inert diluents, oral compositions can also contain auxiliary agents, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings and aromatics.

[0141] Injectable preparations, for example, sterile injectable aqueous or oily suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions or emulsions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, USP and isotonic sodium chloride solution. In addition, sterile fixed oils are used in conventional methods as solvents or suspending media. For this purpose, any bland fixed oil can be used, such as synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in injectable preparations.

[0142] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which in turn may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0143] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing a compound of the present application with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, a suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore will melt in the rectal or vaginal cavity and release the active compound.

[0144] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or papillae as well as high molecular weight polyethylene glycols and the like.

[0145] The active compound can be in microencapsulated form with one or more excipients as mentioned above. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings, release control coatings and other coatings well known in pharmaceutical compounding technology. In such solid dosage forms, the active compound can be mixed with at least one inert diluent, such as sucrose, lactose or starch. Such dosage forms can also contain, as is common practice, additional substances other than the inert diluent, including, but not limited to, tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms can also contain buffering agents.

[0146] Dosage forms for topical or transdermal administration of the compounds of the present application include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active compound is mixed under sterile conditions with a pharmacologically acceptable carrier and any necessary preservatives or buffers as required. Ophthalmic preparations, ear drops, eye ointments, powders and solutions are also considered to be within the scope of the present application.

[0147] The ointments, pastes, creams and gels may contain, in addition to the active compounds of the present application, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0148] Powders and sprays can contain, in addition to the compounds of this application, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain conventional propellants such as chlorofluorohydrocarbons.

[0149] Transdermal patches have the added advantage of providing controlled delivery of compounds to the body. Such dosage forms can be prepared by dissolving or dispersing the compounds in a suitable medium. Absorption enhancers can also be used to increase the flux of the compounds through the skin. The rate can be controlled either by providing a rate-controlling membrane or by dispersing the compounds in a polymer matrix or gel.

[0150] Administration of the disclosed compounds and pharmaceutical compositions can be accomplished by any method of administration for therapeutic agents, including systemic or local administration, such as oral, nasal, parenteral, intravenous, transdermal, subcutaneous, vaginal, buccal, rectal or topical methods of administration.

[0151] Depending on the intended method of administration, the disclosed compounds or pharmaceutical compositions can be in solid, semi-solid or liquid dosage forms, sometimes in unit doses and consistent with conventional pharmaceutical practice, such as, for example, injections, tablets, suppositories, pills, sustained release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, etc. Likewise, they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, and all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0152] Exemplary pharmaceutical compositions include one or more compounds of the present disclosure, including, but not limited to, a) a diluent, such as purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oils, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, and the like, fish oils, such as EPA or DHA, or esters or triglycerides thereof, or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose, and / or glycine; b) a lubricant, such as silica, talcum, stearic acid, magnesium or calcium salts thereof, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate ... c) binders, for example magnesium ammonium silicate, starch paste, gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars, for example glucose or beta-lactose, corn syrup, natural and synthetic gums, for example acacia, tragacanth or sodium alginate, if necessary waxes and / or polyvinylpyrrolidone; d) disintegrants, for example starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures; e) absorbents, colorants, flavorings and sweeteners; f) emulsifiers or dispersants, for example Tween and / or g) a pharmacologically acceptable carrier such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG-400, PEG-200, or other acceptable emulsifier.

[0153] Liquid, particularly injectable, compositions can be prepared, for example, by dissolving, dispersing, etc. For example, one or more of the disclosed compounds are dissolved in or mixed with a pharmacologically acceptable solvent, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, etc., to thereby form an injectable isotonic solution or suspension. Proteins, such as albumin, chylomicron particles, or serum proteins, can be used to solubilize the disclosed compounds.

[0154] One or more of the disclosed compounds or compositions can be delivered by parenteral administration. Parenteral injectable administration is generally used for subcutaneous, intramuscular or intravenous injection and infusion. Injectables can be prepared in conventional form, either as liquid solutions or suspensions, or in solid form suitable for dissolving in liquid before injection.

[0155] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter herein belongs. As used in this specification and the appended claims, unless expressly stated to the contrary, the following terms have the meanings indicated to facilitate understanding of the invention.

[0156] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0157] As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where the event or circumstance occurs as well as cases where it does not occur. For example, an "optionally substituted alkyl" refers to an event or circumstance in which the alkyl is substituted as well as an event or circumstance in which the alkyl is not substituted. The term "optionally substituted alkyl" may also be referred to as an "unsubstituted or substituted alkyl" group, where the substituents are as described in the location.

[0158] As used herein, the term "unsubstituted" means that there are no substituents or that the only substituents are hydrogen.

[0159] As used herein, the term "substituted" refers to a moiety having a substituent replacing a hydrogen on one or more carbons of the backbone. It will be understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is in accordance with the permissible valences of the substituted atom and substituent, as well as that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, and the like. As used herein, the term "substituted" is considered to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituent of organic compounds described herein that satisfies the valence of the heteroatom. The substituents may include any of the substituents described herein, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, oxo, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heteroaryl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. It will be understood by those skilled in the art that the substituents may themselves be substituted, where appropriate.

[0160] As used herein, the term "alkyl" includes, but is not limited to, C 1 ~C10 Straight chain alkyl group or C 3 ~C 10 It refers to saturated aliphatic groups, including branched chain alkyl groups. Preferably, the "alkyl" group is 1 ~C 6 Straight chain alkyl group or C 3 ~C 6 In one embodiment, the "alkyl" group is 1 ~C 4 It refers to an 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. Accordingly, examples of "alkylenyl" include, but are not limited to, -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 CH 2 CH 2 - and -CH 2 CH(CH 3 )CH 2 CH 2 "Alkyl" groups can be optionally substituted. In one embodiment, the term "optionally substituted alkyl" can also refer to an "unsubstituted or substituted alkyl" group, where the substituents are as described in the location.

[0161] As used herein, the term "halo" is used interchangeably herein with the term "halogen" to mean an F, Cl, Br, or I atom.

[0162] As used herein, the term "amino" refers to -NH 2 Refers to the base.

[0163] As used herein, the term "haloalkyl" refers to an alkyl substituted with one or more halogen atoms, where the halo and alkyl groups are as defined above. In one embodiment, a haloalkyl is selected from the group consisting of (C 1 ~C 6 ) alkyl, preferably (C 1 ~C 4 ) alkyl. Examples of "haloalkyl" include, but are not limited to, fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl, and 2,2,2-trifluoroethyl.

[0164] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group, where the amino and alkyl groups are as defined above. In one embodiment, the aminoalkyl is 1 ~C 4 Examples of "aminoalkyl" include, but are not limited to, -CH 3 -NH 2 , -CH 2 -CH 2 -NH 2 , -CH 2 -CH 2 -CH 2 -NH 2 , -CH(CH 3 )-CH 2 -NH 2 , -CH 2 -CH 2 -NH(CH 3 ) and -CH 2 -CH 2 -N(CH 3 ) 2 Examples include:

[0165] As used herein, the term "heteroalkyl" refers to a straight or branched chain alkyl group, preferably having 2 to 14 carbons in the chain, more preferably 2 to 10 carbons in the chain, one or more of which are replaced by a heteroatom selected from S, O, P, and N. Exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, amides, alkyl sulfides, and the like. The group can be a terminal group or a bridging group. As used herein, reference to a normal chain, when used in connection with a bridging group, refers to a direct chain of atoms connecting the two terminal positions of the bridging group.

[0166] As used herein, the term "hydroxyalkyl" refers to an alkyl group, as defined above, in which one or more of the alkyl group's hydrogen atoms have been replaced with a hydroxyl group. In one embodiment, a hydroxyalkyl is a hydroxyalkyl group represented by the formula (C 1 ~C 6 ) alkyl, preferably (C 1 ~C 4 ) alkyl. Examples of hydroxyalkyl moieties include, but are not limited to, -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH(OH)CH 2 OH, -CH 2 CH(OH)CH 3 , -CH(CH 3 )CH 2 OH is an example.

[0167] As used herein, the term "cycloalkylenyl" refers to a divalent cycloalkylenyl group, as defined herein. The term "cycloalkyl" refers to a C 3 ~C 10It means a saturated cyclic hydrocarbon ring. Cycloalkyl can be monocyclic, typically containing 3 to 7 carbon ring atoms. Examples of monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyl can alternatively be polycyclic or have two or more rings. Examples of polycyclic cycloalkyl include bridged, fused, and spirocyclic carbocyclyl. Accordingly, examples of cycloalkylenyl include, but are not limited to, cyclopropylenyl, cyclobutylenyl, cyclopentylenyl, cyclohexylenyl, and cycloheptylenyl.

[0168] As used herein, the term "heterocycloalkylenyl" refers to a divalent heterocycloalkyl group as defined herein. The term "heterocycloalkyl" refers to a 3-15 membered non-aromatic, saturated or partially saturated, bridged bicyclic, spirocyclic, monocyclic or polycyclic ring system, unless a ring size is specifically stated, having at least one heteroatom or heterogroup selected from O, N and S, with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen and sulfur. The term "heterocycloalkyl" also refers to a bridged bicyclic ring system having at least one heteroatom or heterogroup selected from O, N and S. 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, dioxidothiomorpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, indolinyl, indolinylmethyl, isoindolinyl, oxoisoindolinyl, dioxoisoindolinyl, aza-bicyclooctanyl, diazabicyclooctanyl, azocinyl, chromanyl, isochromanyl, xanthenyl, and 2-oxa-6-azaspiro[3.3]heptanyl. Accordingly, examples of "heterocycloalkylenyl" include, but are not limited to, azetidinylenyl, oxetanylenyl, pyrrolidinylenyl, piperidinylenyl, and piperazinylenyl. All "heterocycloaryls" and "heterocycloalkylenyls" are optionally substituted with one or more of the above groups.

[0169] As used herein, the term "heteroarylenyl" refers to a divalent heteroaryl group as defined herein. The term "heteroaryl", alone or in combination with other terms, means a fully unsaturated ring system containing a total of 5-14 ring atoms, unless the acid 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, or S. The heteroaryl may be a single ring (monocyclic) or multiple rings (bicyclic, tricyclic, or polycyclic) fused together or covalently linked. Preferably, the "heteroaryl" is a 5-6 membered ring, unless the ring size is specifically mentioned. The ring may contain 1-4 additional heteroatoms selected from N, O, and S, where the N atom is optionally quaternized. Any suitable ring position of the heteroaryl moiety may be covalently linked to the defined chemical structure. Examples of "heteroaryl" include, but are not limited to, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl (pyridinyl), 3-fluoropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, benzotriazinyl, phthalazinyl, thianthrene, dibenzyl, phenyl ... Examples of the alkyl group include benzofuranyl, dibenzothienyl, benzimidazolyl, indolyl, isoindolyl, imidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purinyl, pteridinyl, 9H-carbazolyl, α-carbolinyl, indolizinyl, benzoisothiazolyl, benzoxazolyl, pyrrolopyridyl, furopyridinyl, purinyl, benzothiadiazolyl, benzoxadiazolyl, benzotriazolyl, benzotridiazolyl, carbazolyl, dibenzothienyl, and acridinyl.Accordingly, examples of heteroarylenyl include, but are not limited to, furanylenyl, thienylenyl, pyrrolylenyl, pyrazolyllenyl, imidazolylenyl, oxazolyllenyl, isoxazolyllenyl, thiazolylenyl, isothiazolyllenyl, 1H-tetrazolylenyl, oxadiazolylenyl, triazolyllenyl, pyridylenyl (pyridinylenyl), pyrimidinylenyl, pyrazinylenyl, pyridazinylenyl, 1,2,3-triazinylenyl, 1,2,4-triazinylenyl, and 1,3,5-triazinylenyl. Heteroaryl groups can be optionally further substituted.

[0170] As used herein, the terms "hydroxy" or "hydroxyl," alone or in combination with other terms, mean --OH.

[0171] As used herein, the term "oxo" refers to the group ═O.

[0172] As used herein, the term "alkoxy" refers to the group -O-alkyl, where the alkyl group is as defined above. 1 ~C 10 Alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, or t-butoxy. In one embodiment, an "alkoxy" group is 1 ~C 6 In another embodiment, the "alkoxy" group is 1 ~C 4 "Alkoxy" refers to an alkoxy group. An alkoxy group can be optionally substituted with one or more suitable groups. In some embodiments, an alkoxy group can be unsubstituted or substituted with one or more substituents, where the substituents are described herein.

[0173] As used herein, the term "arylenyl" refers to a divalent aryl group as defined herein. The term "aryl", as used herein as such or as part of another group, refers to a monocyclic, bicyclic or polycyclic aromatic hydrocarbon ring system of 6 to 14 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, biphenylenyl and acenaphthyl. A preferred aryl group is phenyl. The term "arylenyl" refers to a divalent aryl group. Accordingly, examples of arylenyl groups include, but are not limited to, phenylenyl, naphthylenyl, biphenylenyl and anthrylenyl. The term "optionally substituted aryl" may also be referred to as an "unsubstituted or substituted aryl" group, where the substituents are as described therein.

[0174] As used herein, the term "acyl" refers to the group R-CO- or -CO-R, where R is an optionally substituted alkyl group as defined above. Examples of "acyl" groups include, but are not limited to, CH 3 CO-, CH 3 CH 2 CO-, CH 3 CH 2 CH 2 CO- or (CH 3 ) 2 The term "-O-acyl" refers to -O-CO-R, where R is alkyl as defined above.

[0175] The term "heteroatom" as used herein refers to a sulfur, nitrogen, or oxygen atom.

[0176] As used herein, the term "compound" includes compounds disclosed in the present invention.

[0177] As used herein, the term "salt" refers to salts derived from appropriate bases, including alkali metals (e.g., sodium and potassium), alkaline earth metals (e.g., magnesium), ammonium and N + (C 1~4 Alkyl) 4 Contains salt.

[0178] As used herein, the terms "comprise" or "comprising" are used generally in the sense of include, i.e. permitting the presence of one or more features or components.

[0179] As used herein, the term "or" means "and / or" unless otherwise stated.

[0180] As used herein, the term "including" as well as other forms such as "include," "includes," and "included" are not limiting.

[0181] As used herein, the term "composition" is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product resulting, directly or indirectly, from the combination of the specified ingredients in the specified amounts. "Pharmacologically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0182] As used herein, the term "pharmaceutical composition" refers to a composition containing a therapeutically effective amount of at least one compound of formula (I) or a pharmacologiciy acceptable salt thereof; and a pharmacologiciy acceptable carrier.

[0183] The pharmaceutical composition usually contains about 1% to 99% by weight, for example, about 5% to 75% by weight or about 10% to about 30% by weight of the compound of formula (I) or (II) or a pharmacologically acceptable salt thereof. The amount of the compound of formula (I) or a pharmacologically acceptable salt thereof in the pharmaceutical composition can be about 1 mg to about 1000 mg, about 2.5 mg to about 500 mg, about 5 mg to about 250 mg, or any range falling within a broader range of 1 mg to 1000 mg, or a range higher or lower than the aforementioned ranges.

[0184] The term "tautomer" refers to a compound in which a hydrogen atom is replaced by another part of the molecule, and the chemical bonds between the atoms of the molecule are consequently rearranged. The compounds of the present invention, in free form and salts thereof, can exist in a number of tautomeric forms. It is understood that all tautomeric forms are included within the present invention insofar as they may exist. For example, pyridine or pyridyl can be optionally substituted by oxo to form the respective pyridone or pyridon-yl, and can include its tautomeric forms such as the respective hydroxy-pyridine or hydroxy-pyridyl, provided that said tautomeric forms may be obtainable.

[0185] As used herein, a "pharmacologically acceptable carrier, diluent, or excipient" includes, without limitation, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, surface active agent, or emulsifier approved by the U.S. Food and Drug Administration as acceptable for human or veterinary use.

[0186] As used herein, the terms "administer," "administering," or "administration," as used in this disclosure, refer to either directly administering to a subject one or more of the disclosed compounds or a pharmacologically acceptable salt of one or more of the disclosed compounds, or a composition comprising one or more of the disclosed compounds, or administering to a subject a prodrug derivative or analog or composition of the compound or a pharmacologically acceptable salt of the compound, which is capable of forming an equivalent amount of the active compound in the subject's body.

[0187] As used herein, the term "carrier" as used in this disclosure encompasses carriers, excipients and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, that is involved in carrying or transporting a pharmaceutical agent from one organ or part of a subject's body to another organ or part of the body.

[0188] As used herein, the terms "treat," "treating," and "treatment" refer to a method of alleviating or ending a disease and / or its attendant symptoms.

[0189] As used herein, the terms "prevent", "preventing" and "prevention" refer to a method of preventing the onset of a disease and / or its associated symptoms or precluding a subject from acquiring a disease. As used herein, the terms "prevent", "preventing" and "prevention" also refer to a method of delaying the onset of a disease and / or its associated symptoms and reducing a subject's risk of acquiring a disease.

[0190] As used herein, the term "subject", which may be synonymous with "patient", refers to an animal, preferably a mammal, and most preferably a human.

[0191] As used herein, the term "therapeutically effective amount" refers to an amount of a compound of formula (I) or a pharmacologically acceptable salt or stereoisomer or tautomer thereof; or a composition containing a compound of formula (I) or a pharmacologically acceptable salt or stereoisomer or tautomer thereof, effective to produce a desired therapeutic response in a particular patient suffering from the disease or disorder, particularly in its use in diseases or disorders related to cancer. In particular, the term "therapeutically effective amount" includes an amount of a compound of formula (I) or a pharmacologically acceptable salt or stereoisomer or tautomer thereof, which, when administered, is sufficient to induce a positive change in the disease or disorder being treated, or to prevent the progression of one or more symptoms or to alleviate to some extent one or more symptoms of the disease or disorder being treated in a subject. For a therapeutic amount of a compound, the amount of the compound used for the treatment of a subject is low enough to avoid excessive or serious side effects, within the bounds of sound medical judgment. The therapeutically effective amount of a compound or composition will vary with the particular condition being treated, the severity of the condition being treated or prevented, the duration of treatment, the nature of any concurrent therapy, the age and physical condition of the end user, the specific compound or composition employed, and the particular pharmacologiciZably acceptable carrier employed.

[0192] As used herein, the term "pharmacologically acceptable salt" refers to the product obtained by reacting the compound of the present invention with a suitable acid or base.The pharmacologically acceptable salt of the compound of the present invention includes those derived from suitable inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn and Mn salts;Examples of pharmacologically acceptable, 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, tartrate, pantothenate, acid tartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, 4-methylbenzenesulfonate, i.e. p-toluenesulfonate, etc. Certain compounds of the present invention (compounds of formula (I)) can form pharmacologically acceptable salts with various organic bases such as lysine, arginine, guanidine, diethanolamine or metformin. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium or zinc salts.

[0193] "Pharmacologically acceptable" means useful in preparing pharmaceutical compositions that are generally safe, non-toxic, and not biologically or otherwise undesirable, and includes those suitable for veterinary as well as human pharmaceutical use.

[0194] The present invention also provides methods for formulating the disclosed compounds for pharmaceutical administration.

[0195] In a preferred embodiment, when such pharmaceutical compositions are for human administration, especially for invasive routes of administration (i.e., routes such as injection or implantation that avoid transport or diffusion through epithelial barriers), the aqueous solution is pyrogen-free or substantially pyrogen-free. Excipients can be selected, for example, to achieve delayed release of the agent or to selectively target one or more cells, tissues or organs. The pharmaceutical compositions can be in dosage unit forms such as tablets, capsules (such as sprinkle capsules and gelatin capsules), granules, lyophilisates for reconstitution, powders, solutions, syrups, suppositories, injections, etc. The compositions can also be present in transdermal delivery systems, e.g., skin patches. The compositions can also be present in solutions suitable for topical administration, such as eye drops.

[0196] The term "cancer" is used throughout this specification to refer to a pathological process that results in the formation and growth of cancerous or malignant neoplasms, i.e., pathological tissues that grow by cellular proliferation, often faster than normal tissues, and continue to grow after the stimuli that initiated the new growth have ceased. Malignant neoplasms exhibit partial or complete lack of structural organization and functional coordination with normal tissues, among other things, invade surrounding tissues, metastasize to several sites, recur despite attempts at removal, and are likely to cause the death of the patient unless properly treated. As used herein, the term neoplasia is used to describe all cancer disease states and includes or encompasses the pathological processes associated with malignant hematopoietic, ascites, and solid tumors. Exemplary cancers that may be treated by the compounds, either alone or in combination with at least one additional anti-cancer agent, include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, hematological and renal cell carcinoma, bladder, intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate and stomach cancer; leukemia; benign and malignant lymphomas, particularly Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative disorders; Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma. sarcomas, such as liposarcoma, myosarcoma, acral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma, and schwannoma; intestinal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor, and teratocarcinoma. Additional cancers that may be treated using the compounds according to the invention include, for example, T-lineage acute lymphoblastic leukemia (T-ALL), T-lineage lymphoblastic lymphoma (T-LL), acute T-cell lymphoma, adult T-cell leukemia, Pre-B ALL, Pre-B lymphoma, Large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, and Philadelphia chromosome positive CML.

[0197] The term "stereoisomer" refers to any enantiomer, diastereoisomer or geometric isomer of the compounds of formula (I) whenever they are chiral or when they have one or more double bonds. When a compound of formula (I) and related formulae is chiral, it can exist in racemic or optically active form. It should be understood that the present invention encompasses all stereochemical isomers, such as diastereomers, enantiomers and epimers, as well as d- and 1-isomers and mixtures thereof. Individual stereoisomers of the compounds can be prepared by synthesis from commercially available starting materials containing chiral centers, or by separation, such as preparation of a mixture of enantiomers, followed by conversion to a mixture of diastereomers, followed by separation or recrystallization, chromatographic methods, chiral chromatographic columns, or any other suitable method known in the art for direct separation of the enantiomers. Starting compounds of a particular stereochemistry are commercially available or can be prepared and resolved by techniques known in the art. Additionally, the compounds of the present invention can exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen I and zusammen (Z) isomers as well as the appropriate mixtures thereof.

[0198] The term "enantiomers" refers to a pair of stereoisomers that are non-superimposable mirror images of one another. The term "enantiomer" refers to a single member of this pair of stereoisomers. The term "racemic" refers to a 1:1 mixture of a pair of enantiomers. The present disclosure includes the enantiomers of the compounds described herein. Each compound disclosed herein includes all enantiomers that conform to the general structure of the compound. The compounds may be in racemic or enantiomerically pure form or any other form in terms of stereochemistry. In some embodiments, the compounds are (S)-enantiomers.

[0199] The term "diastereomer" refers to a set of stereoisomers that cannot be made superimposable by rotation around a single bond. For example, compounds containing cis- and trans-double bonds, endo- and exo-substitution in a bicyclic ring system, and multiple stereocenters of different relative configurations are considered to be diastereomers. The term "diastereomer" refers to any member of this set of compounds. In some examples presented, the synthetic route may produce a single diastereomer or a mixture of diastereomers. The present disclosure includes diastereomers of the compounds described herein.

[0200] The compounds of the present invention can be used as single agents or as pharmaceutical compositions in which the compounds are mixed with various pharmacologically acceptable substances.

[0201] 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 arts and contain at least one compound of the present invention. The pharmaceutical compositions of this patent application contain one or more compounds described herein and one or more pharmacologically acceptable excipients. Typically, pharmacologically acceptable excipients are approved by regulatory agencies or considered safe for human or animal use. Pharmacologically acceptable excipients include, but are not limited to, carriers, diluents, glidants and lubricants, preservatives, buffers, chelating agents, polymers, gelling agents, viscosifiers and solvents.

[0202] The pharmaceutical compositions can be administered by oral, parenteral or inhalation routes. Examples of parenteral administration include administration by injection, transdermal, transmucosal, intranasal and pulmonary administration.

[0203] Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohol, polyethylene glycol, peanut oil, olive oil, gelatin, lactose, terra alba, 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 mono- and diglycerides, fatty acid esters and polyoxyethylene.

[0204] The pharmaceutical compositions may also include one or more pharmacologically acceptable auxiliary agents, wetting agents, suspending agents, preservatives, buffers, sweetening agents, flavoring agents, coloring agents, or any combination of the foregoing.

[0205] The pharmaceutical compositions may be in conventional forms, such as tablets, capsules, solutions, suspensions, injections or products for topical application. Further, the pharmaceutical compositions of the present invention may be formulated to provide a desired release profile.

[0206] The administration of the compounds of the present invention, either in pure form or in a suitable pharmaceutical composition, can be carried out by any of the accepted routes for administration of pharmaceutical compositions.The route of administration can be any route that effectively transports the active compounds of the present patent application to the appropriate or desired site of action.Suitable routes of administration include, but are not limited to, oral, nasal, buccal, dermal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, ​​intramuscular or topical.

[0207] Solid oral preparations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges.

[0208] Liquid formulations include, but are not limited to, sterile injectable liquids such as syrups, emulsions and suspensions or solutions.

[0209] Topical dosage forms of the compounds include ointments, pastes, creams, lotions, powders, solutions, eye or ear drops, impregnated dressings, and may contain appropriate conventional additives such as preservatives, solvents to aid drug permeation, and the like.

[0210] The pharmaceutical compositions of this patent application may be prepared by conventional techniques known in the literature.

[0211] Suitable doses of the compounds for use in treating the diseases or disorders described herein can be determined by those skilled in the relevant art. Therapeutic doses are generally identified by human dose-ranging studies based on preliminary evidence from animal studies. The dose should be sufficient to provide the desired therapeutic benefit without causing undesirable side effects. Methods of administration, dosage forms and suitable pharmaceutical excipients can also be used and adjusted by those skilled in the art. All changes and modifications are contemplated within the scope of this patent application.

[0212] The term "prodrug" is intended to denote a compound that can be converted under physiological conditions or by solvolysis to a biologically active compound described herein (e.g., a compound of structure (I)). Thus, the term "prodrug" refers to a pharmacologically acceptable precursor of a biologically active compound. In some embodiments, a prodrug is inactive when administered to a subject, but is converted in vivo, e.g., by hydrolysis, to an active compound. Prodrug compounds often offer advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems", ACS Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1999). Press, 1987, both of which are fully incorporated herein by reference. The term "prodrug" is also intended to include any covalently bonded carrier that releases an active compound in vivo when such a prodrug is administered to a mammalian subject. Prodrugs of active compounds as described herein are typically prepared by modifying functional groups present in the active compound in such a way that the modification is cleaved, either by routine manipulation or in vivo. Prodrugs include compounds in which a hydroxy, amino or mercapto group is bonded to any group that is cleaved to form a free hydroxy, free amino or free mercapto group, respectively, when the prodrug of the active compound is administered to a mammalian subject.Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of hydroxy functional groups, or acetamide, formamide and benzamide derivatives of amine functional groups in the active compounds.

[0213] In some embodiments, prodrugs include compounds of structure (I) having phosphate, phosphoalkoxy, ester, or boronic ester substituents. Without being bound by theory, it is believed that such substituents are converted to hydroxyl groups under physiological conditions. Accordingly, embodiments include any of the compounds of the invention in which a hydroxyl group is replaced with a phosphate, phosphoalkoxy, ester, or boronic ester group, e.g., a phosphate or phosphoalkoxy group. For example, in some embodiments, R 4 or R 8 A hydroxyl group on the moiety is replaced with a phosphate, phosphoalkoxy, ester, or boronic ester group, such as a phosphate or alkoxyphosphate group.

[0214] According to one embodiment, the compounds of the present invention can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.For example, the present invention also encompasses the isotopically labeled variants of the present invention that are identical to those listed herein, but which relate to the fact that one or more atoms of the compounds are replaced by atoms that have atomic masses or mass numbers different from the predominant atomic masses or mass numbers that are usually found in nature for that atom.All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the present invention and their use.Exemplary isotopes that can be incorporated into the compounds of the present invention include: 2 H("D"), 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 32 P,33 P, 35 S, 18 F, 36 Cl, 123 I and 125 and isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as I. Isotopically labeled compounds of the invention can generally be prepared by following procedures similar to those disclosed in the schemes and / or examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. EXAMPLES

[0215] The abbreviations used throughout this specification are summarized below along with their meanings. MeOH-methanol, EtOH-ethanol, DCM-dichloromethane, DMF-N,N-dimethylformamide, EtOAc-ethyl acetate, THF-tetrahydrofuran, DME-1,2-dimethoxyethane, DMSO-dimethylsulfoxide, 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, Na 2 SO 4 -Sodium sulfate, Na 2 CO 3 -Sodium carbonate, K 2 CO 3 - Potassium carbonate, Cs 2 CO 3 -Cesium carbonate, KO t Bu-Potassium tert-butoxide, Pd(dppf)Cl 2 ·DCM-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex, NaOMe-sodium methoxide, BINAP-(2,2'-bis(diphenylphosphino)-1,1'-binaphthyl), H 2 SO 4 -Sulfuric acid, NaHCO 3-Sodium bicarbonate, TEA-triethylamine; DEA-diethylamine, LiOH · H 2 O-Lithium hydroxide monohydrate; EDC·HCl-1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; DAST-Diethylaminosulfur trifluoride; PPTs-Pyridinium p-toluenesulfonate; NaH-Sodium hydride; NH 4 OH-Ammonium hydroxide, NaOH-Sodium hydroxide, HCl-Hydrogen acid, Pd(pph 3 ) 2 Cl 2 DCM-Bis(triphenylphosphine)palladium(II) dichloride dichloromethane complex; Pd(OAc) 2 - palladium(II) acetate, mL - milliliters, TLC - thin layer chromatography, RT - room temperature, h - hours, N - normality, M - molarity, 1 HNMR - Proton nuclear magnetic resonance, DMSO-d 6 -Deuterated dimethyl sulfoxide, CDCl 3 - Deuterated chloroform, CD 3 OD-deuterated methanol, s-singlet, d-doublet, t-triplet, m-multiplet, H-proton, MHz-megahertz, Hz-hertz, Ppm-parts per million, Bs-broad singlet, HPLC-high performance liquid chromatography, LCMS-liquid chromatography mass spectrometry, g-grams, mmol-millimole and °C-degrees Celsius.

[0216] General Scheme-I [ka] A general scheme for the synthesis of intermediate compounds of formula (A7) is shown in the scheme above. Compounds of formula (A1) can be reacted with hydroxylamine derivatives to give compounds of formula (A2), which can be further cyclized in the presence of a base to give compounds of formula (A3). Compounds of formula (A3) can be oxidized in the presence of a metal oxide to give the respective acid derivatives of formula (A4), which can be esterified in the presence of an acid and a solvent to give formula (A5), which can be further alkylated in the presence of a suitable reagent to give alkyl derivatives of formula (A6). Compounds of formula (A6) can be Suzuki-coupled to give intermediate compounds of formula (A7).

[0217] General Scheme-II [ka] The general scheme for the synthesis of the compound of formula (I') is shown in the scheme above. The compound of formula (B1) can be obtained by reacting the compound of formula (A7) with a suitable pyridazine derivative in a solvent. The compound of formula (B1) can be further reacted with an aryl or heteroaryl boronic acid derivative in a suitable solvent to give the compound of formula (B2), which can be hydrolyzed in the presence of a base to give the compound of formula (B3). The compound of formula (B3) can be coupled with the VHL derivative of M2 in the presence of a solvent to give the compound of formula (I').

[0218] General Scheme-III [ka] A general scheme for the synthesis of compounds of formula (II') is shown in the scheme above. Compounds of formula (V-2) can be prepared by reacting an appropriate pyridazine derivative (V-1) with an aryl or heteroaryl borane derivative ((Boc)-L'-AB(OH) in a suitable solvent and reagent. 2The resulting compound of formula (V-2) can be deprotected by hydrolysis in the presence of a solvent to give a compound of formula (V-3), which upon further reaction with the corresponding protected acid derivative at elevated temperature can give a compound of formula (V-4). Compounds of formula (V-4) can be prepared by reacting aryl or heteroaryl borane derivatives (R1-B(OH) 2 ) to provide a compound of formula (V-5), which can be hydrolyzed in the presence of an acid to give a compound of formula (V-6). The compound of formula (V-6) can be reacted with a VHL-derivative of M1' to provide a compound of formula (II').

[0219] General Scheme-IV-A [ka] A general scheme for the synthesis of a compound represented by formula (I') is shown in Scheme IV-A above. A compound of formula (D2) can be obtained by treating a suitable pyridazine derivative (D1) with a compound of formula (H-1) or (H-2) in a suitable solvent. The compound of formula (D2) can be further reacted with a compound of formula (H-3) in a suitable solvent and at elevated temperature to provide a compound of formula (D3). The compound of formula (D3) can also be obtained by reacting a compound of formula (D1) with tributylchlorostannane in a suitable solvent to give a compound of formula (D8) and further reacting the thus obtained compound of formula (D8) with a compound of formula (H-6) in a suitable solvent. The compound of formula (D1) can also be reacted with a compound of formula (H-5) in a suitable solvent and at elevated temperature to give a compound of formula (D4). The compound of formula (D3) thus obtained can be reacted with an aryl or heteroaryl boron derivative in the presence of a suitable solvent to provide a compound of formula (D6). The compound of formula (D4) can also be reacted with an aryl or heteroaryl boron derivative in the presence of a suitable solvent to provide a compound of formula (D5), which can also be reduced in the presence of a suitable solvent to provide a compound of formula (D6). The compound of formula (D6) can further be hydrolyzed in the presence of an acid to provide a compound of formula (D7). The compound of formula (D7) can be reacted with the VHL-derivative of M1' by acid-amine coupling to provide a compound of formula (I').

[0220] General Scheme-IV-B [ka] Another general scheme for the synthesis of compounds of formula (I') is shown in Scheme IV-B above. Compounds of formula (G1) can be obtained by treating compounds of formula (D2) with compounds of formula (H-7) in a suitable base and catalyst. Compounds of formula (G1) can be further reacted with aryl- or heteroarylborane derivatives in a suitable solvent and reagent to provide compounds of formula (G2), which upon hydrolysis in the presence of acid can give compounds of formula (D7). Compounds of formula (D7) can be further subjected to an acid-amine coupling reaction with VHL-derivatives of M1' to provide compounds of formula (I'). Alternatively, compounds of formula (G3) can be obtained by treating compounds of formula (D2) with 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonic acid derivatives in the presence of base, which can be further reacted with compounds of formula (H-8) at higher temperatures in a suitable base and solvent to provide compounds of formula (G4). The resulting compound of formula (G4) upon acid-amine coupling reaction with a VHL-derivative of M1' provides a compound of formula (G5), which can undergo a coupling reaction with an aryl or heteroaryl borane derivative to provide a compound of formula (I').

[0221] General Scheme-IV-C [ka] A general scheme for the synthesis of a compound of formula (I') is shown in Scheme IV-C above. A compound of formula (J1) can be obtained by treating a compound of formula (D2) with a compound of formula (H-9) in a suitable solvent, which can further undergo a deprotection reaction to provide a compound of formula (J2). The obtained compound of formula (J2) can be reacted with a compound of formula (H-7) in a suitable solvent and reagent to give a compound of formula (J3). The obtained compound of formula (J3) can be reacted with an aryl- or heteroaryl borane derivative in a suitable solvent and reagent to give a compound of formula (J4), which can further undergo a hydrolysis reaction to give a compound of formula (D7). The compound of formula (D7) can be reacted with a VHL-derivative of M1' by acid-amine coupling to give a compound of formula (I').

[0222] General scheme - VA [ka] A general scheme for the synthesis of a compound of formula (I') is shown in Scheme VA above. A compound of formula (B1) can be obtained by reaction of a compound of formula (G3) with a compound of formula (G6) derivative in a suitable solvent. The compound of formula (B1) can be further reacted with an aryl or heteroaryl boronic acid derivative in a suitable solvent to give a compound of formula (B2). The compounds of formula (B2) and (B1) can be hydrolyzed in the presence of a base to give a compound of formula (B3). The compound of formula (B3) can be coupled with a VHL-derivative of M2' in the presence of a solvent to provide a compound of formula (I').

[0223] General Scheme - VB [ka] A general scheme for the synthesis of a compound represented by formula (I') is shown in scheme VB above. A compound of formula (W2) can be obtained by reacting a compound of formula (D2) with 1,2-dibromoethane in a solvent, and the compound of formula (W2) can be further reacted with a compound of formula (G7) derivative in a suitable solvent to give a compound of formula (W3). The compound of formula (W3) can be reacted with an aryl or heteroaryl boronic acid derivative in a suitable solvent and at a suitable temperature to give a compound of formula (B2'). The compounds of formula (B2') and (W3) can be hydrolyzed in the presence of a base to give a compound of formula (B3'), which can be further coupled with a VHL derivative of M2' in the presence of a solvent to give a compound of formula (I').

[0224] Intermediate-1: tert-butyl 2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-yl)acetate [ka] Step a: Synthesis of 1-(4-bromophenyl)piperazine hydrochloride To a stirred solution of tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate (5.0 g, 14.7 mmol) in DCM (50 mL) was added 4N dioxane HCl (50 mL) at 0° C. and the reaction mixture was stirred at RT under nitrogen atmosphere for 16 h. The reaction mixture was concentrated under vacuum to give the crude product. The crude product was triturated with pentane and then dried under reduced pressure to give the pure title compound as a pale yellow solid (5 g, crude yield). 1 H NMR (400MHz, DMSO-d 6 ):δ 9.29(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 240.03(M+H).

[0225] Step b: Synthesis of tert-butyl 2-(4-(4-bromophenyl)piperazin-1-yl)acetate To a stirred solution of 1-(4-bromophenyl)piperazine hydrochloride (5.0 g, 18.1 mmol) in DMF (50 mL) was added DIPEA (4.66 g, 36.2 mmol) at RT and the mixture was stirred for 15 min. Then tert-butyl 2-bromoacetate (5.3 g, 27.15 mmol) was added to the reaction mixture and stirred at RT for 4 h under nitrogen atmosphere. The reaction mixture was quenched with cold water and stirred for 1 h. The solid was filtered and dried under vacuum to give the title compound as an off-white solid (4.5 g, 70%). 1 H NMR (400MHz, DMSO-d 6 ):δ 7.29(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).

[0226] Step c: Synthesis of tert-butyl 2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-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) was added bis(pinacolato)diboron (4.52 g, 17.8 mmol) and KOAc (2.33 g, 23.7 mmol) at RT. The reaction mixture was degassed with nitrogen for 5 min and then diluted with Pd(dppf)Cl. 2 ·DCM (0.89 g, 1.18 mmol) was added into the reaction mixture and heated at 100 °C for 4 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound as an off-white solid (5 g, 100%). 1 H NMR (400MHz, DMSO-d 6):δ 7.50(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).

[0227] Intermediate-2: Ethyl 2-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-yl)acetate [ka] Step a: Synthesis of ethyl 2-(1-(4-bromo-2-nitrophenyl)piperidin-4-yl)acetate To a stirred solution of 4-bromo-1-fluoro-2-nitrobenzene (2.0 g, 9.1 mmol) in DMF (20 mL) was added ethyl 2-(piperidin-4-yl)acetate (1.87 g, 10.9 mmol) and DIPEA (3.7 g, 27.4 mmol) at RT and the mixture was stirred at 100 °C for 4 h. The reaction mixture was quenched with cold water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product. The crude product was purified by combiflash column chromatography using 20-25% ethyl acetate in hexane as eluent to give the title compound as a yellow solid (1.3 g, 38%). 1 H NMR (400MHz, DMSO-d 6 ):δ 7.99(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,2H),2.82-2. 76(m,2H),2.26(d,J=7.2Hz,2H),1.84-1.79(m,1H),1.69(d,J=12.4Hz,2H),1.32-1.22(m,2H),1.17(t,J=7.4Hz,3H);LC-MS:m / z 371.0(M+H).

[0228] Step b: Synthesis of ethyl 2-(1-(2-amino-4-bromophenyl)piperidin-4-yl)acetate To a stirred solution of ethyl 2-(1-(4-bromo-2-nitrophenyl)piperidin-4-yl)acetate (1.30 g, 3.5 mmol) in a mixture of methanol (10 mL) and water (3 mL) was added iron (3.1 g, 28 mmol) and NH 4 OH (1.5 g, 28 mmol) was added and the mixture was stirred at RT for 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with methanol and filtered. The filtrate was concentrated, diluted with EtOAc, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound as an off-white solid (1.2 g, 100%). 1 H NMR (400MHz, DMSO-d 6 ):δ 6.80-6.78(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=1 1.6Hz,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).

[0229] Step c: Synthesis of ethyl 2-(1-(4-bromophenyl)piperidin-4-yl)acetate To a stirred solution of ethyl 2-(1-(2-amino-4-bromophenyl)piperidin-4-yl)acetate (1.0 g, 2.9 mmol) in THF (10 mL) was added tert-butyl nitrite (0.58 g, 5.1 mmol) and stirred at RT for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the crude product. The crude product was purified by combiflash column chromatography using 20% ​​ethyl acetate in hexane as eluent to give the title compound as an off-white solid (0.37 g, 34%). 1 H NMR (400MHz, DMSO-d 6):δ 7.30(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).

[0230] Step d: Synthesis of ethyl 2-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-yl)acetate To a stirred solution of ethyl 2-(1-(4-bromophenyl)piperidin-4-yl)acetate (0.37 g, 1.13 mmol) in dioxane (10 mL) was added bis(pinacolato)diboron (0.45 g, 1.7 mmol) and KOAc (0.22 g, 2.27 mmol) at RT. The reaction mixture was degassed with nitrogen for 5 min. Pd(dppf)Cl 2 ·DCM (0.09 g, 0.11 mmol) was added into the reaction mixture and heated at 100 °C for 6 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by combiflash column chromatography using 10-15% ethyl acetate in hexane as eluent to give the title compound as a yellow solid (0.25 g, 58%). 1 H NMR (400MHz, DMSO-d 6 ):δ 7.48(d,J=8.4Hz,2H),6.87(d,J=8.4Hz,2H),4.06(q,J=14.4Hz,2H),3.78(d,J=12.4Hz,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).

[0231] Intermediate-3: Ethyl 3-methyl-2-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)butanoate [ka] Step a: Synthesis of 4-bromobenzaldehyde oxime To a solution of 4-bromobenzaldehyde (30 g, 162.16 mmol) and hydroxylamine hydrochloride (14.64 g, 210.8 mmol) in ethanol (300 mL), pyridine (19.21 mL, 243.2 mmol) was added to the reaction mixture and stirred at RT for 6 h. The reaction mixture was quenched with ice-cold water and stirred for 20 min. The resulting solid was further washed with water and dried under vacuum to 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-d 6 ):δ 11.37(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).

[0232] Step b: Synthesis of 2-(3-(4-bromophenyl)isoxazol-5-yl)ethan-1-ol To a solution of 4-bromobenzaldehyde oxime (15 g, 75 mmol) in DCM (300 mL) was added NCS (12.01 g, 90 mmol) and heated at 45° C. for 30 min. The reaction mixture was cooled to RT. But-3-yn-1-ol (6.3 g, 90 mmol) and TEA (10.52 mL, 75 mmol) were added dropwise into the reaction mixture over a period of 15 min. The reaction mixture was again heated at 45° C. for 7 h. The reaction mixture was quenched with ice-cold water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by combiflash column chromatography using 10% ethyl acetate in hexane as eluent to give the title compound as a white solid (7.5 g, 37%). 1 H NMR (400MHz, DMSO-d 6 ):δ 7.80(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).

[0233] 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) at 0° C., Jones reagent (15 mL) was added dropwise and the temperature was allowed to reach RT over a period of 2 h. After completion of the reaction, the reaction mixture was diluted with acetone and filtered. The filtrate was concentrated under vacuum to give 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 (400MHz, DMSO-d 6 ):δ 7.82(d,J=8.8Hz,2H),7.71(d,J=8.4Hz,2H),6.96(s,1H),3.96(s,2H);LC-MS:m / z 283.09(M+H).

[0234] 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) at 0° C. was added H 2 SO 4 (7 mL) was added dropwise and heated at 80° C. for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated and diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by combiflash column chromatography using 7% ethyl acetate in hexane as eluent to give the title compound as an off-white solid (5.8 g, 76%). 1 H NMR (400MHz, DMSO-d 6 ):δ 7.82(d,J=8.4Hz,2H),7.72(d,J=8.4Hz,2H),6.99(s,1H),4.17(q,J=14.4Hz,2H),4.08(s,2H),1.22(t,J=14.4Hz,3H);LC-MS:m / z 309.9(M+H).

[0235] Step e: Synthesis of ethyl 2-(3-(4-bromophenyl)isoxazol-5-yl)-3-methylbutanoate To a solution of ethyl 2-(3-(4-bromophenyl)isoxazol-5-yl)acetate (5.8 g, 18.77 mmol) in THF (80 mL), KO t Bu 1M solution (28.1 mL, 28.1 mmol) was added dropwise at 0° C. and stirred for 15 min. 2-Iodopropane (2.25 mL, 22.5 mmol) was added into the reaction mixture and stirred at RT for 16 h. After completion of the reaction, the reaction mixture was quenched with ice-cold water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by combiflash column chromatography using 4-5% ethyl acetate in hexane as eluent to give the title compound as a colorless liquid (3.8 g, 57%).1 H NMR (400MHz, DMSO-d 6 ):δ 7.84(d,J=8.8Hz,2H),7.72(d,J=8.0Hz,2H),7.05(s,1H),4.16(q,J=7.2Hz,2H),3.85(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).

[0236] Step f: Synthesis of ethyl 3-methyl-2-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)butanoate To a stirred solution of ethyl 2-(3-(4-bromophenyl)isoxazol-5-yl)-3-methylbutanoate (3.8 g, 10.82 mmol) in dioxane (50 mL) was added bis-pinacolatodiboron (4.12 g, 16.2 mmol) and KOAc (2.12 g, 21.6 mmol) at RT and degassed with nitrogen for 5 min. Pd(dppf)Cl 2 ·DCM (0.88 g, 1.08 mmol) was added into the reaction mixture and stirred at 100 °C for 2 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound as a colorless liquid (4.1 g, 94%). 1 H NMR (400MHz, DMSO-d 6 ):δ 7.90(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=8.0Hz,1H),2.4 4-2.33(m,1H),1.31(s,12H),1.20(t,J=7.2Hz,3H),0.98(d,J=6.8Hz,3H),0.89(d,J=6.4Hz,3H);LC-MS:m / z 400.2(M+H).

[0237] Intermediate-4: (4-bromo-6-(trifluoromethyl)pyridazin-3-amine [ka] Step a: Synthesis of 6-(trifluoromethyl)pyridazin-3-amine A stirred solution of 3-chloro-6-(trifluoromethyl)pyridazine (1.0 g, 5.47 mmol) in methanolic ammonia (10 mL) was heated in a sealed tube at 100 °C for 16 h. The reaction mixture was concentrated under vacuum to give the crude product. The residue was purified by combiflash column chromatography using 50-60% ethyl acetate in hexanes as eluent to give the title compound as an off-white solid (0.3 g, 34%). 1 H NMR (400MHz, DMSO-d 6 ):δ 7.66(d,J=9.2Hz,1H),7.13(bs,2H),6.88(d,J=9.2Hz,1H).

[0238] Step b: Synthesis of (4-bromo-6-(trifluoromethyl)pyridazin-3-amine) To a stirred solution of 6-(trifluoromethyl)pyridazin-3-amine (0.3 g, 1.8 mmol) in methanol (20 mL) was added NaHCO 3 (0.3 g, 3.6 mmol) was added at 0° C. and stirred for 5 min. Bromine (0.44 g, 2.7 mmol) was added dropwise and stirred at RT under nitrogen atmosphere for 16 h. The reaction mixture was quenched with cold water, stirred for 1 h, and the solid so formed was filtered and dried under vacuum to give the title compound as an off-white solid (0.25 g, 56%). 1 H NMR (400 MHz, CDCl 3 ):δ 7.79(s,1H),5.67(bs,2H),LC-MS:m / z 242.0(M+H).

[0239] Intermediate-5: Ethyl 3-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)butanoate [ka] Step a: Synthesis of ethyl 3-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)butanoate To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 g, 5.15 mmol) and ethyl 2-bromo-3-methylbutanoate (1.28 mL, 6.18 mmol) in DMF (10 mL) was added Cs 2 CO 3 (5.05 g, 15.45 mmol) was added and heated at 100° C. and stirred for 4 h. The reaction mixture was quenched with ice-cold water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue which was purified by combiflash column chromatography using 30-35% ethyl acetate in hexane as eluent to give the title compound as a grey solid (0.45 g, 27%). LC-MS: m / z 323.1 (M+H).

[0240] Intermediate-6: (2S,4R)-1-(L-valyl)-N-(4-(4-(difluoromethyl)thiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide hydrochloride [ka] Step a: Synthesis of tert-butyl (4-bromobenzyl)carbamate To a solution of (4-bromophenyl)methanamine (5.0 g, 22.52 mmol) in DCM (50 mL) was added triethylamine (6.82 g, 67.56 mmol) dropwise at 0° C. and stirred for 5 min. Boc anhydride (8.18 mL, 33.78 mmol) was added into the reaction mixture and stirred at RT for 16 h. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue which was stirred in hexane at RT and filtered on a Buchner funnel to give the title compound as an off-white solid (6 g, 57%). 1 H NMR (400MHz, DMSO-d 6 ):δ 7.50(d,J=8Hz,2H),7.43(s,1H),7.18(d,J=8Hz,2H),4.07(d,J=4Hz,2H),1.38(s,9H);LC-MS:m / z 230(M-56).

[0241] Step b: Synthesis of tert-butyl (4-(4-(1,3-dioxolan-2-yl)thiazol-5-yl)benzyl)carbamate To a stirred solution of tert-butyl (4-bromobenzyl)carbamate (0.5 g, 1.75 mmol) in DMF (10 mL) was added 4-(1,3-dioxolan-2-yl)thiazole (0.27 g, 1.75 mmol) and KOAc (0.34 g, 3.50 mmol) at RT and degassed with nitrogen for 10 min. Pd(OAc) 2 (0.02 g, 0.08 mmol) was added into the reaction mixture and heated at 100° C. for 16 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the crude product. The crude product was purified by combiflash column chromatography using 40% ethyl acetate in hexane as eluent to give the title compound as a pale yellow solid (0.14 g, 17%). 1 H NMR (400MHz, DMSO-d 6):δ 9.07(s,1H),7.47-7.42(m,3H),7.34(d,J=8Hz,2H),5.86(s,1H),4.18-4.10(m,4H),3.95-3.93(m,2H),1.40(s,9H);LC-MS:m / z 363.1(M+H).

[0242] Step c: Synthesis of tert-butyl (4-(4-formylthiazol-5-yl)benzyl)carbamate To a stirred solution of tert-butyl (4-(4-(1,3-dioxolan-2-yl)thiazol-5-yl)benzyl)carbamate (0.55 g, 1.51 mmol) in acetone (5.5 mL) was added PPTs (0.762 g, 3.03 mmol) at RT and heated at 50° C. for 16 h. The reaction mixture was evaporated, diluted with EtOAc, the organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product. The crude product was purified by combiflash column chromatography using 45% ethyl acetate in hexane as eluent to give the title compound as a yellow sticky material (0.28 g, 63%). 1 H NMR (400MHz, DMSO-d 6 ):δ 9.90(s,1H),9.19(s,1H),7.62(d,J=8Hz,2H),7.49(s,1H),7.37(d,J=8Hz,2H),4.19(d,J=4Hz,2H),1.40(s,9H).LC-MS:m / z 263(M-56).

[0243] Step d: Synthesis of tert-butyl (4-(4-(difluoromethyl)thiazol-5-yl)benzyl)carbamate To a stirred solution of tert-butyl (4-(4-formylthiazol-5-yl)benzyl)carbamate (0.57 g, 1.79 mmol) in DCM (15 mL) was added DAST (0.72 g, 4.48 mmol) at 0° C. and the reaction mixture was stirred at the same temperature for 2 h. The reaction mixture was diluted with DCM and diluted with saturated NaHCO 3The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product, which was purified by combiflash column chromatography using 40% ethyl acetate in hexane as eluent to give the title compound as a pale yellow sticky material (0.34 g, 55%). 1 H NMR (400MHz, DMSO-d 6 ):δ 9.20(s,1H),7.47-7.36(m,5H),7.00(s,1H),4.18(d,J=4Hz,2H),1.40(s,9H);LC-MS:m / z 341.1(M+H).

[0244] Step e: Synthesis of (4-(4-(difluoromethyl)thiazol-5-yl)phenyl)methanamine hydrochloride To a stirred solution of tert-butyl (4-(4-(difluoromethyl)thiazol-5-yl)benzyl)carbamate (0.34 g, 1.41 mmol) in DCM (2 mL) was added 4M HCl in 1,4-dioxane (2.0 mL) at RT and stirred for 16 h. The reaction mixture was evaporated under reduced pressure and the resulting residue was washed with diethyl ether and dried under vacuum to give the title compound as an off-white solid (0.29 g, crude yield). 1 H NMR (400MHz, DMSO-d 6 ):δ 9.25(d,J=8Hz,1H),8.37(bs,2H),7.68-7.57(m,4H),7.05(s,1H),4.12-4.08(m,2H);LC-MS:m / z 241.1(M+H).

[0245] Step f: Synthesis of tert-butyl ((S)-1-((2S,4R)-2-((4-(4-(difluoromethyl)thiazol-5-yl)benzyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate To a solution of (4-(4-(difluoromethyl)thiazol-5-yl)phenyl)methanamine hydrochloride (0.41 g, 1.26 mmol), (2S,4R)-1-((tert-butoxycarbonyl)-L-valyl)-4-hydroxypyrrolidine-2-carboxylic acid (WO 2012 / 37259) (0.29 g, 1.05 mmol) and HATU (0.6 g, 0.57 mmol) in DMF (10 mL), DIPEA (0.94 mL, 5.25 mmol) was added dropwise at 0° C. and slowly brought to RT. The reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with ethyl acetate, washed with cold brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product. The crude product was purified by combiflash column chromatography using 2.5% methanol in DCM as eluent to give the title compound as an off-white solid (0.5 g, 83%). 1 H NMR (400MHz, DMSO-d 6 ):δ 9.20(s,1H),8.54(t,J=12Hz,1H),7.45-7.40(m,4H),7.00(t,J=53.2Hz,1H),5.13(d,J=3.2Hz,1H),4.42-4.31(m,3H),4.03(t, LC-MS:m / z 497.1(M-56).

[0246] Step g: Synthesis of (2S,4R)-1-(L-valyl)-N-(4-(4-(difluoromethyl)thiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide hydrochloride To a stirred solution of tert-butyl ((S)-1-((2S,4R)-2-((4-(4-(difluoromethyl)thiazol-5-yl)benzyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (0.5 g, 0.95 mmol) in DCM (2 mL) was added 4M HCl in 1,4-dioxane (2.0 mL) at RT and stirred for 16 h. The reaction mixture was evaporated under reduced pressure and the resulting residue was washed with diethyl ether and dried under vacuum to give the title compound as a pale yellow solid (0.45 g, 96%). 1 H NMR (400MHz, DMSO-d 6 ):δ 9.21(s,1H),8.96(t,J=12Hz,1H),8.07(bs,2H),7.43(bs,3H),7.03(t,J=52.8Hz,1H),4.52(m,1H),4.41-4.32(m,2H),4.04(b s,1H),3.67-3.58(m,2H),2.73(s,2H),2.04-1.89(m,2H),1.90(m,1H),1.01(d,J=6.8Hz,3H),0.93(d,J=6.8Hz,3H);LC-MS:m / z 453.2(M+1).

[0247] Intermediate-7: (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-(difluoromethyl)thiazol-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide hydrochloride [ka] Step a: Synthesis of tert-butyl (S)-(1-(4-(4-(1,3-dioxolan-2-yl)thiazol-5-yl)phenyl)ethyl)carbamate To a stirred solution of tert-butyl (S)-(1-(4-bromophenyl)ethyl)carbamate (1.5 g, 5 mmol) in DMF (20 mL) was added 4-(1,3-dioxolan-2-yl)thiazole (0.94 g, 6 mmol) and KOAc (0.98 g, 10 mmol) at RT and degassed with nitrogen for 10 min. Pd(OAc) 2(0.056 g, 0.25 mmol) was added into the reaction mixture and stirred at 90° C. for 16 h. Once the reaction was complete (monitored by TLC), all the batches were combined and diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the crude product. The crude product was purified by combiflash column chromatography using 40% ethyl acetate in hexane as eluent to give the title compound as a sticky material (0.32 g, 17%). LC-MS: m / z 377.1 (M+H).

[0248] Step b: Synthesis of tert-butyl (S)-(1-(4-(4-formylthiazol-5-yl)phenyl)ethyl)carbamate To a stirred solution of tert-butyl S)-(1-(4-(4-(1,3-dioxolan-2-yl)thiazol-5-yl)phenyl)ethyl)carbamate (0.3 g, 0.79 mmol) in acetone (20 mL) was added PPTs (0.4 g, 1.59 mmol) at RT and heated at 50° C. for 16 h. The reaction mixture was quenched with cold water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product. The crude product was purified by combiflash column chromatography using 20% ​​ethyl acetate in hexane as eluent to give the title compound as a pale yellow solid (0.15 g, 56%). LC-MS: m / z 333.1 (M+H).

[0249] Step c: Synthesis of tert-butyl (S)-1-(4-(4-(difluoromethyl)thiazol-5-yl)phenyl)ethylcarbamate To a stirred solution of tert-butyl (S)-(1-(4-(4-formylthiazol-5-yl)phenyl)ethyl)carbamate (0.15 g, 0.45 mmol) in DCM (20 mL) was added DAST (0.18 g, 1.12 mmol) at 0° C. and the reaction mixture was stirred at the same temperature for 3 h. The reaction mixture was diluted with DCM and saturated NaHCO 3The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product, which was purified by combiflash column chromatography using 1.5% methanol in DCM as eluent to give the title compound as an orange solid (0.115 g, 72%). 1 H NMR (400MHz, DMSO-d 6 ):δ 9.20(s,1H),7.42-7.50(m,5H),7.01(t,J=52.8Hz,1H),4.68(m,1H),1.37(s,9H),1.32(d,J=7.2Hz,1H).

[0250] Step d: Synthesis of (S)-1-(4-(4-(difluoromethyl)thiazol-5-yl)phenyl)ethan-1-amine hydrochloride To a stirred solution of tert-butyl (S)-1-(4-(4-(difluoromethyl)thiazol-5-yl)phenyl)ethylcarbamate (0.15 g, 0.42 mmol), 4 M HCl in 1,4-dioxane (2.0 mL) was added at RT and stirred for 2 h. The reaction mixture was evaporated under reduced pressure and the resulting residue was washed with diethyl ether and dried under vacuum to give the title compound as an off-white solid (0.1 g, 81%). 1 H NMR (400MHz, DMSO-d 6 ):δ 9.24(s,1H),8.46(bs,1H),7.66-7.48(m,4H),7.05(t,J=53.2Hz,1H),4.49(m,1H),1.52(d,J=6.8Hz,3H),LC-MS:m / z 255.1(M+H).

[0251] Step e: Synthesis of tert-butyl ((S)-1-((2S,4R)-2-(((S)-1-(4-(4-(difluoromethyl)thiazol-5-yl)phenyl)ethyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate To a solution of (S)-1-(4-(4-(difluoromethyl)thiazol-5-yl)phenyl)ethanamine hydrochloride (0.10 g, 0.29 mmol), (2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid (WO 2012 / 37259) (0.1 g, 0.34 mmol) and HATU (0.16 g, 0.43 mmol) in DCM (5 mL) was added DIPEA (0.26 mL, 1.45 mmol) dropwise at 0° C. and slowly brought to RT. The reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with ethyl acetate, washed with cold brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product. The crude product was purified by combiflash column chromatography using 2.5% methanol in DCM as eluent to afford the title compound as an off-white solid (0.1 g, 98%). 1 H NMR (400MHz, DMSO-d 6 ):δ 9.19(s,1H)8.42(d,J=7.2Hz,1H),7.47-7.40(m,4H),7.01(t,J=53.2Hz,1H),6.34(d,J=9.2Hz,1H),5.12(d,J =3.6Hz,1H),4.93(m,1H),4.45(m,1H),4.28(bs,1H),4.13(d,J=8.8Hz,1H),3.57(m,2H),2.03(m,1H),1.78(m ,1H),1.39(s,9H),1.37(d,J=8Hz,3H),0.92(s,9H);LC-MS:m / z 481.2(M-100).

[0252] Step f: Synthesis of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-(difluoromethyl)thiazol-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide hydrochloride To a stirred solution of tert-butyl ((S)-1-((2S,4R)-2-(((S)-1-(4-(4-(difluoromethyl)thiazol-5-yl)phenyl)ethyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (0.1 g, 0.17 mmol) in DCM (2 mL) was added 4 M HCl in 1,4-dioxane (2.0 mL) at RT and stirred for 1 h. The reaction mixture was evaporated under reduced pressure and the resulting residue was washed with diethyl ether and dried under vacuum to give the title compound as an off-white solid (0.08 g, 89%). LC-MS: m / z 481.5 (M+1).

[0253] Intermediate 8: Ethyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-4-carboxylate [ka] Intermediate-8 was prepared by procedures similar to those described for Intermediate-2 with appropriate changes in reactants, amounts of reagents, protection and deprotection, solvents and reaction conditions. 1 H NMR(400MHz,DMSO-d6):δ 7.48(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(t d,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).

[0254] Intermediate 9: tert-Butyl 2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)acetate [ka] Step-a: Synthesis of tert-butyl 4-(4-bromophenyl)-3,6-dihydropyridine-1(2H)-carboxylate To a stirred solution of 1-bromo-4-iodobenzene (1 g, 3.53 mmol), 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) in 1,4-dioxane (10 mL) and water (2.5 mL) was added K 2 CO 3 (1.22 g, 8.83 mmol) was added and degassed with nitrogen for 15 min. 2 ·DCM (0.3 g, 0.35 mmol) was added into the reaction mixture and heated in a sealed tube at 100 °C for 16 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by combiflash column chromatography using 50% ethyl acetate in hexane as eluent to give the title compound as an off-white solid (1.3 g, 83%). 1 H NMR(400MHz,DMSO-d6):δ 7.53(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).

[0255] 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) at 0° C. was added 4M HCl in 1,4-dioxane (5 mL). The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure and washed with diethyl ether to give the title compound (0.8 g, 98%). 1H NMR(400MHz,DMSO-d6):δ 9.35(bs,1H),7.57(d,J=8Hz,2H),7.43(d,J=8Hz,2H),6.24(s,1H),3.72(bs,2H),3.28(bs,2H),2.66(bs,2H).LC-MS:m / z 238(M+1).

[0256] 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 RT and stirred for 15 min. tert-Butyl 2-bromoacetate (0.56 g, 2.91 mmol) was added to the reaction mixture and stirred at RT for 4 h under nitrogen atmosphere. The reaction mixture was quenched with cold water and stirred for 1 h. The solid so formed was filtered and dried under vacuum to give the title compound as a yellow solid (1.3 g, 97%). 1 H NMR (400MHz, DMSO-d 6 ):δ 7.51(d,J=8Hz,2H),7.38(d,J=8Hz,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).

[0257] Step-d: Synthesis of tert-butyl 2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)acetate To a stirred solution of tert-butyl 2-(4-(4-bromophenyl)-3,6-dihydropyridin-1(2H)-yl)acetate (0.5 g, 1.41 mmol) in dioxane (20 mL) was added bis(pinacolato)diboron (0.43 g, 1.70 mmol) and KOAc (0.28 g, 2.83 mmol) at RT and the mixture was degassed with nitrogen for 5 min. Pd(dppf)Cl2 ·DCM (0.11 g, 0.14 mmol) was added into the reaction mixture and heated at 100 °C for 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound as an off-white solid (0.5 g, 88%). 1 H NMR (400MHz, DMSO-d 6 ):δ 7.63(d,J=10.8Hz,2H),7.43(d,J=10.8Hz,2H),6.22(s,1H),3.22(bs,4H),2.73(m,2H),2.46(bs,2H),1.42(s,9H),1.28(s,12H):LC-MS:m / z 400.4(M+H).

[0258] The intermediate compounds listed in Table-1 below were prepared by procedures similar to those described in Intermediate-9 with appropriate changes in reactants, amounts of reagents, protection and deprotection, solvents and reaction conditions. The characterization data of the compounds are summarized herein in the table below.

[0259] [Table 1]

[0260] Intermediate 10: tert-Butyl 4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate [ka] Step-a: Synthesis of tert-butyl 4-(4-bromo-3-fluorophenyl)piperazine-1-carboxylate To a stirred solution of 4-bromo-2-fluoro-1-iodobenzene (5 g, 16.72 mmol), N-Boc piperazine (1.24 g, 6.6 mmol) in toluene (50 mL) was added Cs 2 CO 3(8.68 g, 26.6 mmol) was added and degassed with nitrogen for 10 min., followed by Pd 2 (dba) 3 (0.6 g, 0.66 mmol) and BINAP (0.41 g, 0.66 mmol) were added and the reaction mixture was heated in a sealed tube at 100° C. for 16 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by combiflash column chromatography using 40% ethyl acetate in hexane as eluent to give the title compound as a yellow solid (1.6 g, 26%). 1 H NMR (400 MHz, CDCl 3 ):δ 7.45(t,J=8.8Hz 1H),6.95(dd,J=8.8,2.8Hz,1H),6.75(dd,J=8.8,2.8Hz,1H),3.42(m,4H),3.15(m,4H),1.41(s,9H);LC-MS:m / z 361.0(M+H).

[0261] Step-b: Synthesis of tert-butyl 4-(3-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-3-fluorophenyl)piperazine-1-carboxylate (1.6 g, 4.46 mmol) in dioxane (10 mL) was added bis(pinacolato)diboron (1.69 g, 6.69 mmol) and KOAc (1.3 g, 13.4 mmol) at RT and degassed with nitrogen for 5 min. Pd(dppf)Cl 2 ·DCM (0.36 g, 0.44 mmol) was added into the reaction mixture and heated at 90 °C for 16 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound as a yellow solid (0.9 g, 50%). 1 H NMR (400MHz, DMSO-d 6):δ 7.44(2,J=8.4Hz,1H),6.72(dd,J=8.4,2Hz,1H),6.64(dd,J=9.2,2Hz,1H),3.42(m,4H),3.24(m,4H),1.41(s,9H),1.25(s,12H);LC-MS:m / z 406.9(M+H).

[0262] Intermediate 11: Ethyl 2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)propanoate [ka] Step-a: Synthesis of ethyl 2-(4-(4-bromophenyl)-3,6-dihydropyridin-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) was added DIPEA (2.35 g, 18.2 mmol) at RT and stirred for 15 min. Ethyl 2-bromopropanoate (0.79 g, 4.37 mmol) was added to the reaction mixture and stirred at RT for 4 h under nitrogen atmosphere. The reaction mixture was quenched with cold water, stirred for 1 h and the solid so formed was filtered and dried under vacuum to give the title compound as an off-white solid (0.8 g, 56%). 1 H NMR (400MHz, DMSO-d 6 ):δ 7.46(d,J=8Hz,2H),7.33(d,J=8Hz,2H),6.15(s,1H),4.07(m,2H),3.39(q,J =6.8Hz,H),3.22(bs,2H),2.78(m,2H),2.38(bs,2H),1.18(m,6H):LC-MS:m / z 338(M+H).

[0263] Step-b: Synthesis of ethyl 2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)propanoate To a stirred solution of ethyl 2-(4-(4-bromophenyl)-3,6-dihydropyridin-1(2H)-yl)propanoate (0.8 g, 2.36 mmol) in dioxane (15 mL) was added bis(pinacolato)diboron (0.9 g, 3.54 mmol) and KOAc (0.69 g, 7.09 mmol) at RT and degassed with nitrogen for 5 min. Pd(dppf)Cl 2 ·DCM (0.19 g, 0.23 mmol) was added to the reaction mixture and heated at 80 °C for 16 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound as an off-white solid (0.9 g, 98%). 1 H NMR (400MHz, DMSO-d 6 ):δ 7.62(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).

[0264] Intermediate 12: 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 [ka] Step-a: Synthesis of ethyl 2-(4'-bromo-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)acetate To a stirred solution of 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)cyclohex-3-en-1-yl)acetate (0.99 g, 3.39 mmol) in 1,4-dioxane (8 mL) and water (1 mL) was added K 2 CO3 (0.97 g, 7.07 mmol) was added and degassed with nitrogen for 15 min, followed by Pd(dppf)Cl 2 ·DCM (0.23 g, 0.28 mmol) was added and the reaction mixture was heated in a sealed tube at 100 °C for 6 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by combiflash column chromatography using 50% ethyl acetate in hexane as eluent to give the title compound as a colorless liquid (0.48 g, 52%). 1 H NMR (400MHz, DMSO-d 6 ):δ 7.49(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).

[0265] 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)diboron (0.58 g, 2.32 mmol) and KOAc (0.38 g, 3.86 mmol) were added at RT and degassed with nitrogen for 5 min. Pd(dppf)Cl 2 ·DCM (0.12 g, 0.15 mmol) was added into the reaction mixture and heated at 100 °C for 3 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound as a colorless sticky material (0.48 g, 83%). 1 H NMR (400MHz, DMSO-d 6 ):δ 7.61(d,J=8Hz,2H),7.41(d,J=8Hz,2H),6.19(bs,1H),4.07(q,J=6.8Hz,2H),2.41(bs,2H),2.31(m,3H),1.85- 2.04(m,3H),1.40(m,1H),1.28(s,12H),1.22(t,J=6.8Hz,3H).

[0266] Intermediate 13: Ethyl 4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-carboxylate [ka] Intermediate-13 was prepared by procedures similar to those described for Intermediate-12 with appropriate changes in reactants, amounts of reagents, protection and deprotection, solvents and reaction conditions. 1 H NMR (400MHz, DMSO-d 6 ):δ 7.61(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).

[0267] Intermediate 14: Methyl 5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)pentanoate [ka] Step-a: Synthesis of methyl 5-((4-bromophenyl)amino)pentanoate To a stirred solution of 4-bromoaniline (0.5 g, 2.90 mmol) in DMF (5 mL) was added K 2 CO 3(0.14 g, 2.90 mmol) was added at RT and stirred for 15 min. Methyl 2-bromopropanoate (1.13 g, 5.81 mmol) was added into the reaction mixture and stirred at 60° C. under nitrogen atmosphere for 24 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with ice-cold water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by combiflash column chromatography using 10% ethyl acetate in hexane as eluent to give the title compound as an off-white solid (0.28 g, 33%). 1 H NMR (400MHz, DMSO-d 6 ):δ 7.22(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).

[0268] 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) was added bis(pinacolato)diboron (0.32 g, 1.26 mmol) and KOAc (0.29 g, 2.93 mmol) at RT and degassed with nitrogen for 5 min. Pd(dppf)Cl 2 ·DCM (0.08 g, 0.09 mmol) was added into the reaction mixture and heated at 80 °C for 16 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was filtered through Celite and washed with EtOAc. The combined organic layers were concentrated under vacuum to give a residue, which was purified by combiflash column chromatography using 10% ethyl acetate in hexane as eluent to give the title compound as a yellow solid (0.15 g, 46%). 1 H NMR (400MHz, DMSO-d6 ):δ 7.41(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).

[0269] Intermediate 15: tert-Butyl 2-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidin-1-yl)acetate [ka] Step-a: Synthesis of tert-butyl 3-(2-((4-methoxyphenyl)sulfonyl)hydrazinylidene)azetidine-1-carboxylate To a stirred solution of 4-methoxybenzenesulfonohydrazide (2 g, 11.68 mmol) and tert-butyl 3-oxoazetidine-1-carboxylate (2.36 g, 11.68 mmol) in toluene (40 mL) and the reaction mixture was heated in a sealed tube at 50° C. for 16 h. Upon completion of the reaction (monitored by TLC), the reaction mass was concentrated under vacuum to give a residue which was purified by combiflash column chromatography using 40% ethyl acetate in hexane as eluent to give the title compound as a white solid (1.75 g, 42%). 1 H NMR (400MHz, DMSO-d 6 ):δ 10.81(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).

[0270] Step-b: Synthesis of tert-butyl 3-(4-bromophenyl)azetidine-1-carboxylate To a stirred solution of tert-butyl 3-(2-((4-methoxyphenyl)sulfonyl)hydrazinylidene)azetidine-1-carboxylate (1.2 g, 3.37 mmol), (4-bromophenyl)boronic acid (1.01 g, 5.06 mmol) in dioxane (35 mL) was added Cs 2 CO 3 (1.65 g, 5.06 mmol) was added and degassed with nitrogen for 30 min. The reaction mixture was heated in a sealed tube at 110° C. for 16 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc and filtered. The filtrate was concentrated under vacuum to give a residue, which was purified by combiflash column chromatography using 20% ​​ethyl acetate in hexane as eluent to give the title compound as a colorless liquid (0.36 g, 34%). 1 H NMR (400 MHz, CDCl 3 ):δ 7.47(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).

[0271] Step-c: Synthesis of 3-(4-bromophenyl)azetidine To a stirred solution of tert-butyl 3-(4-bromophenyl)azetidine-1-carboxylate (0.36 g, 1.15 mmol) in DCM (3 mL) was added trifluoroacetic acid (0.3 mL) at 0° C., then slowly brought to RT and stirred at RT for 1 h. The reaction mixture was evaporated under reduced pressure and the resulting residue was washed with diethyl ether and dried under vacuum to give the title compound (0.28 g, 97.7%) as an off-white solid. 1 H NMR (400 MHz, CDCl 3 ):δ 9.85(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).

[0272] Step-d: Synthesis of tert-butyl 2-(3-(4-bromophenyl)azetidin-1-yl)acetate To a stirred solution of 3-(4-bromophenyl)azetidine (0.28 g, 1.12 mmol) in DMF (5 mL) was added DIPEA (0.72 g, 5.63 mmol) at RT and stirred for 15 min. tert-Butyl 2-bromoacetate (0.24 g, 1.24 mmol) was added to the reaction mixture and stirred at RT for 2 h under nitrogen atmosphere. The reaction mixture was quenched with cold water, stirred for 1 h and the solid so formed was filtered and dried under vacuum to give the title compound as a pale yellow sticky solid (0.28 g, 76%). 1 H NMR (400 MHz, CDCl 3 ):δ 7.40(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).

[0273] Step-e: Synthesis of tert-butyl 2-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidin-1-yl)acetate To a stirred solution of tert-butyl 2-(3-(4-bromophenyl)azetidin-1-yl)acetate (0.28 g, 0.85 mmol) in dioxane (5 mL) was added bis(pinacolato)diboron (0.32 g, 1.28 mmol) and KOAc (0.21 g, 2.14 mmol) at RT and degassed with nitrogen for 5 min. Pd(dppf)Cl 2 ·DCM (0.07 g, 0.08 mmol) was added into the reaction mixture and stirred at 110 °C for 16 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound as a white sticky solid (0.3 g, 93%). 1 H NMR (400 MHz, CDCl 3):δ 7.76(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).

[0274] Intermediate 16: tert-Butyl 6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-azaspiro[3.3]heptane-2-carboxylate [ka] Step-a: Synthesis of tert-butyl 6-(2-((4-methoxyphenyl)sulfonyl)hydrazinylidene)-2-azaspiro[3.3]heptane-2-carboxylate To a stirred solution of 4-methoxybenzenesulfonohydrazide (1.5 g, 7.41 mmol) and tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (1.56 g, 7.41 mmol) in toluene (30 mL), the reaction mixture was heated in a sealed tube at 50° C. for 16 h. Upon completion of the reaction (monitored by TLC), the reaction mass was concentrated under vacuum to give a residue which was purified by combiflash column chromatography using 35% ethyl acetate in hexane as eluent to give the title compound as a white solid (2.8 g, 95%). 1 H NMR (400MHz, DMSO-d 6 ):δ 10.21(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).

[0275] Step-b: Synthesis of tert-butyl 6-(4-bromophenyl)-2-azaspiro[3.3]heptane-2-carboxylate To a 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 (60 mL) was added Cs 2 CO 3 (4.6 g, 14.16 mmol) was added and degassed with nitrogen for 30 min. The reaction mixture was heated in a sealed tube at 110° C. for 16 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc and filtered. The filtrate was concentrated under vacuum to give a residue, which was purified by combiflash column chromatography using 20% ​​ethyl acetate in hexane as eluent to give the title compound as a colorless liquid (1.3 g, 52%). 1 H NMR (400MHz, DMSO-d 6 ):δ 7.38(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).

[0276] 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)diboron (1.4 g, 5.53 mmol) and KOAc (0.90 g, 9.22 mmol) were added at RT and degassed with nitrogen for 5 min. Pd(dppf)Cl 2·DCM (0.30 g, 0.36 mmol) was added to the reaction mixture and heated at 110 °C for 16 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound as a creamy sticky solid (0.3 g, 93%). 1 H NMR (400MHz, DMSO-d 6 ):δ 7.74(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 300.3(M+H-100).

[0277] Intermediate 17: Methyl 3,3-dimethyl-2-(4-oxopiperidin-1-yl)butanoate [ka] Step-a: Synthesis of methyl 3,3-dimethyl-2-(4-oxopiperidin-1-yl)butanoate To a stirred solution of methyl (S)-2-amino-3,3-dimethylbutanoate (3.7 g, 25.48 mmol) in acetonitrile (40 mL), DIPEA (9.88 g, 76.44 mmol) was added dropwise followed by 1,5-dichloropentan-3-one (3.16 g, 20.38 mmol) into the reaction mixture. The reaction mixture was then heated at a temperature of 70° C. for 16 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate, then the combined organic layers were dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified by combiflash column chromatography using 20-30% ethyl acetate in hexane to give the title compound as a pale yellow liquid (1.95 g, 39%). 1 H NMR (400MHz, DMSO-d 6):3.63(s,3H),3.08(s,1H),3.03-2.97(m,2H),2.70-2.64(m,2H),2.36-2.30(m,4H),1.00(s,9H);LCMS:m / z 228.2(MH).

[0278] Intermediate-18: Methyl 3-methyl-2-(3-(4-oxopiperidin-1-yl)isoxazol-5-yl)butanoate [ka] Step-a: Synthesis of methyl 2-(3-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)isoxazol-5-yl)-3-methylbutanoate To a stirred solution of methyl 3-methyl-2-(3-(((perfluorobutyl)sulfonyl)oxy)isoxazol-5-yl)butanoate (0.4 g, 0.83 mmol) and 1,4-dioxa-8-azaspiro[4.5]decane (0.18 g, 1.24 mmol) in DMF (6 mL), DIPEA (0.32 g, 2.5 mmol) was added and the reaction mass was heated at a temperature of 80° C. for 16 h. After completion of the reaction, the reaction mixture was poured into ice-cold water, extracted with ethyl acetate and evaporated. The obtained crude product was first purified by combiflash column chromatography using 25% ethyl acetate in hexane to obtain the title compound as a colorless solid (0.16 g, 59.3%). 1 H NMR (400MHz, DMSO-d 6 ):δ 5.93(s,1H),4.00(s,4H),3.74(s,3H),3.49(d,J=7.2Hz,1H),3.41(m,4H),2.37- 2.32(m,1H),1.80(m,4H),1.02(d,J=6.8Hz,3H),0.95(d,J=6.8Hz,3H);LCMS:m / z 325.2(MH).

[0279] Step-b: Synthesis of methyl 3-methyl-2-(3-(4-oxopiperidin-1-yl)isoxazol-5-yl)butanoate To a stirred solution of methyl 2-(3-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)isoxazol-5-yl)-3-methylbutanoate (0.1 g, 0.81 mmol) in THF (4 mL) was added 4N hydrogen chloride in dioxane (0.4 mL) and slowly heated at 90° C. for 6 h. The reaction mixture was evaporated under reduced pressure and the resulting residue was washed with diethyl ether and dried under vacuum to give the title compound as a yellowish solid (0.05 g, 57.9%). 1 H NMR (400MHz, DMSO-d 6 ):6.03(s,1H),3.76(s,3H),3.66(m,4H),3.54(d,J=8.8Hz,1H),3.55(m,4H) ),2.40-2.34(m,1H),1.03(d,J=6.8Hz,3H),0.96(d,J=6.8Hz,3H);LCMS:m / z 281.1(M+H).

[0280] Example-1: (2S,4R)-1-((S)-2-(2-(4-(3-amino-6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-yl)phenoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 1) [ka] Step i: Synthesis of 4-(3-amino-6-chloropyridazin-4-yl)phenol To a stirred solution of 4-bromo-6-chloropyridazin-3-amine (3 g, 14.39 mmol) and (4-hydroxyphenyl)boronic acid (2.97 g, 21.58 mmol) in 1,4-dioxane (45 mL) and water (15 mL) was added Na 2 CO 3 (3.81 g, 35.9 mmol) was added. The reaction mixture was degassed with nitrogen for 15 min and then Pd(dppf)Cl 2This was followed by the addition of .DCM (1.17 g, 1.43 mmol) and heating in a sealed tube at 120 °C for 18 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue which was purified by combiflash column chromatography using 35% ethyl acetate in hexanes as eluent to give the title compound as an off-white solid (1.3 g, 40%). 1 H NMR (400MHz, DMSO-d 6 ):δ 9.85(s,1H),7.38(d,J=8.4Hz,2H),7.27(s,1H),6.89(d,J=8.4Hz,2H),6.26(bs,2H).LC-MS:m / z 222(M+H).

[0281] Step II: Synthesis of tert-butyl 2-(4-(3-amino-6-chloropyridazin-4-yl)phenoxy)acetate To a stirred solution of 4-(3-amino-6-chloropyridazin-4-yl)phenol (0.4 g, 1.8 mmol) and tert-butyl 2-bromoacetate (0.42 g, 2.17 mmol) in DMF (10 mL) was added K 2 CO 3 (0.37 mL, 2.7 mmol) was added at RT and heated at 50° C. for 1 h. The reaction mixture was quenched with cold water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a brown solid (0.2 g, 33%). 1 H NMR (400MHz, DMSO-d 6 ):δ 7.23(d,J=9.6Hz,2H),7.04(d,J=8.8Hz,2H),6.79(s,1H),6.29(s,2H),4.70(s,2H),1.42(s,9H).LC-MS:m / z 336.1(M+H).

[0282] Step III: Synthesis of tert-butyl 2-(4-(3-amino-6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-yl)phenoxy)acetate To a stirred solution of tert-butyl 2-(4-(3-amino-6-chloropyridazin-4-yl)phenoxy)acetate (0.08 g, 0.23 mmol) and (4-fluoro-2-hydroxyphenyl)boronic acid (0.07 g, 0.47 mmol) in 1,4-dioxane (1.6 mL) and water (0.4 mL) was added K 2 CO 3 (0.1 g, 0.69 mmol) was added. The reaction mixture was degassed with nitrogen for 15 min. Pd(dppf)Cl 2 ·DCM (0.02 g, 0.023 mmol) was added to the reaction mixture and heated in a microwave at 120 °C for 1 h. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by combiflash column chromatography using 35% ethyl acetate in hexane as eluent to give the title compound as an off-white solid (0.025 g, 25%). LC-MS: m / z 412.2 (M+H).

[0283] Step iv: Synthesis of 2-(4-(3-amino-6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-yl)phenoxy)acetic acid To a stirred solution of tert-butyl 2-(4-(3-amino-6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-yl)phenoxy)acetate (0.025 g, 0.21 mmol) in DCM (2 mL) was added 4N hydrogen chloride in dioxane (0.25 mL) at 0° C. Then the reaction mixture was slowly brought to RT and stirred for 3 h. The reaction mixture was evaporated under reduced pressure and the resulting residue was washed with diethyl ether and dried under vacuum to give the title compound as a brown solid (0.02 g, 92%). LC-MS: m / z 356 (M+H).

[0284] Step v: Synthesis of (2S,4R)-1-((S)-2-(2-(4-(3-amino-6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-yl)phenoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide To a stirred solution of 2-(4-(3-amino-6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-yl)phenoxy)acetic acid (0.02 g, 0.056 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (WO2019207538) (0.03 g, 0.06 mmol) and HATU (0.04 g, 0.076 mmol) in DMF (2 mL), DIPEA (0.04 mL, 0.2 mmol) was added dropwise at 0° C. and slowly brought to RT. The reaction mixture was stirred at RT for 2 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product, which was purified by combiflash column chromatography using 3% methanol in DCM as eluent to give the title compound as an off-white solid (0.020 g, 45%). 1 H NMR (400MHz, DMSO-d 6):δ 13.5(s,1H),8.98(s,1H),8.43(d,J=7.2Hz,1H),8.03(s,1H),7.95(d,J=9.2Hz,1H),7.88-7.85(m,1H),7.6 1(d,J=8.8Hz,2H),7.45-7.36(m,4H),7.13-7.09(m,3H),6.94-6.90(m,1H),6.51(s,2H),5.14(d,J=2.3Hz, 1H),4.93(t,J=14.4Hz,1H),4.72(s,2H),4.60(d,J=9.2Hz,1H),4.47(t,J=17.6Hz,1H),4.29(s,1H),3.61( t,J=7.6Hz,2H),2.50-2.30(m,3H),2.04(s,1H),1.78(s,1H),1.39(d,J=6.8Hz,3H),0.96(s,9H).LC-MS:m / z 782.25(M+H).

[0285] Example-2: (2S,4R)-1-((S)-2-(2-(4-(3-amino-6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-yl)phenoxy)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-(difluoromethyl)thiazol-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide (compound 2) [ka] Compound 2 was synthesized using the same procedure as described in step v of Example 1 by using (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-(difluoromethyl)thiazol-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide hydrochloride to give the title compound as a light brown solid (0.02 g, 32%). 1 H NMR (400MHz, DMSO-d 6):δ 13.47(s,1H),9.20(s,1H),8.48(d,J=8.0Hz,1H),8.04(s,1H),7.96(d,J=9.6Hz,1H),7.87(dd,J=7.6Hz & 3.2Hz,1H),7.61(d,J=8.8Hz,2H),7.47-7.41(m,4H),7.13-7.10(m,3H),7.01(t,J= 52.8Hz,1H),6.94-6.91(m,1H),6.52(s,2H),5.16(d,J=3.2Hz,1H),4.94(s,1H),4. 72(s,2H),4.59(d,J=9.6Hz,1H),4.46(s,1H),4.29(s,1H),3.61(d,J=6.0Hz,2H),2 .10-2.02(m,1H),1.83-1.75(m,1H),1.39(d,J=6.8Hz,3H),0.92(s,9H).LC-MS:m / z 818.2(M+H).

[0286] Example-3: (2S,4R)-1-((2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)acetyl)-L-valyl)-N-(4-(4-(difluoromethyl)thiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide (compound 3) [ka] Step I: Synthesis of tert-butyl 2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)acetate To a stirred solution of tert-butyl 2-(4-(3-amino-6-chloropyridazin-4-yl)phenoxy)acetate (0.27 g, 0.8 mmol) and (2-hydroxyphenyl)boronic acid (0.22 g, 1.6 mmol) in 1,4-dioxane (3.6 mL) and water (1.2 mL) was added K 2 CO 3 (0.33 g, 2.4 mmol) was added. The reaction mixture was degassed with nitrogen for 15 min. Pd(dppf)Cl 2·DCM (0.065 g, 0.08 mmol) was added to the reaction mixture and heated in a microwave at 120 °C for 1 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by combiflash column chromatography using 35% ethyl acetate in hexane as eluent to give the title compound as an off-white solid (0.12 g, 38%). 1 H NMR 1 H NMR (400MHz, DMSO-d 6 ):δ 13.62(s,1H),7.98(s,1H),7.95(d,J=8.0Hz,1H),7.59(d,J=8.8Hz,2H),7.24(d,J=7.2Hz,1H ),7.07(d,J=8.4Hz,2H),6.93-6.83(m,2H),6.42(s,1H),4.74(s,2H),1.46(s,9H).LC-MS:m / z 394.3(M+H).

[0287] Step ii: Synthesis of 2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)acetic acid To a stirred solution of tert-butyl 2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)acetate (0.12 g, 0.35 mmol) in DCM (2 mL) was added 4N hydrogen chloride in dioxane (2 mL) at 0° C., slowly brought to RT and stirred for 3 h. The reaction mixture was evaporated under reduced pressure and the resulting residue was washed with diethyl ether and dried under vacuum to give the title compound as a yellow solid (0.08 g, 77%). 1 H NMR (400MHz, DMSO-d 6):δ 13.15(s,1H),8.09(s,1H),7.80(s,2H),7.68(d,J=7.6Hz,1H),7.59(d,J=8.4Hz,2H),7.34(d,J=7.6 Hz,1H),7.12(t,J=8.0Hz,2H),7.02(d,J=8.0Hz,1H),6.96(t,J=7.2Hz,1H),4.78(s,1H).LC-MS:m / z 338.1(M+H).

[0288] Step iii: Synthesis of (2S,4R)-1-((2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)acetyl)-L-valyl)-N-(4-(4-(difluoromethyl)thiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide To a solution of 2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)acetic acid (0.04 g, 0.10 mmol), (2S,4R)-1-(L-valyl)-N-(4-(4-(difluoromethyl)thiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide hydrochloride (0.06 g, 0.12 mmol) and HATU (0.06 g, 0.16 mmol) in DMF (2 mL) was added DIPEA (0.1 mL, 0.53 mmol) dropwise at 0° C. and slowly brought to RT. The reaction mixture was stirred at RT for 2 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product, which was purified by combiflash column chromatography using 2-3% methanol in DCM as eluent to give the title compound as a light brown solid (0.02 g, 22%). 1 H NMR (400MHz, DMSO-d 6):δ 13.62(s,1H),9.19(s,1H),8.57(s,1H),8.18(d,J=8.8Hz,1H),7.95(t,J=8.0Hz,2H),7.58(d, J=8.4Hz,2H),7.43(s,4H),7.25(s,1H),7.11(d,J=8.8Hz,2H),6.93-6.86(m,2H),6.42(s,2H) ,5.15(d,J=2.8Hz,1H),4.68(s,2H),4.49-4.37(m,3H),4.37-4.33(m,3H),3.67-3.65(m,2H), 2.11-2.02(m,2H),1.94-1.85(m,1H),0.92(d,J=6.4Hz,3H),0.85(d,J=6.8Hz,3H).LC-MS:m / z 772.2(M+H).

[0289] Example-4: (2S,4R)-1-(2-(3-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 4) [ka] Step i: Synthesis of ethyl 2-(3-(4-(3-amino-6-chloropyridazin-4-yl)phenyl)isoxazol-5-yl)-3-methylbutanoate To a stirred solution of ethyl 3-methyl-2-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)butanoate (0.2 g, 0.50 mmol) and 4-bromo-6-chloropyridazin-3-amine (0.15 g, 0.75 mmol) in 1,4-dioxane (8 mL) and water (0.8 mL) was added K 2 CO 3 (0.17 g, 1.25 mmol) was added. The reaction mixture was degassed with nitrogen for 15 min, followed by Pd(dppf)Cl 2·DCM (0.04 g, 0.05 mmol) was added and heated in a microwave at 100 °C for 1 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by combiflash column chromatography using 35% ethyl acetate in hexane as eluent to give the title compound as an off-white solid (0.12 g, 60%). 1 H NMR (400MHz, DMSO-d 6 ):δ 8.02(d,J=8Hz,2H),7.68(d,J=8Hz,2H),7.43(s,1H),7.11(s,1H),6.45(bs,2H),4.17(q,J=8Hz,2H),3. 87(d,J=8Hz,1H),2.40(m,1H),1.22(t,J=12Hz,3H),0.99(d,J=4Hz,3H),0.90(d,J=4Hz,3H);LC-MS:m / z 401.1(M+H).

[0290] Step ii: Synthesis of ethyl 2-(3-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)isoxazol-5-yl)-3-methylbutanoate To a stirred solution of ethyl 2-(3-(4-(3-amino-6-chloropyridazin-4-yl)phenyl)isoxazol-5-yl)-3-methylbutanoate (0.11 g, 0.27 mmol) and (2-hydroxyphenyl)boronic acid (0.075 g, 0.54 mmol) in 1,4-dioxane (9 mL) and water (2 mL) was added K 2 CO 3 (0.11 g, 0.82 mmol) was added. The reaction mixture was degassed with nitrogen for 15 min. Pd(dppf)Cl 2·DCM (0.02 g, 0.027 mmol) was added into the reaction mixture and heated in a microwave at 120 °C for 1 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by combiflash column chromatography using 50% ethyl acetate in hexane as eluent to give the title compound as an off-white solid (0.085 g, 67%). 1 H NMR (400MHz, DMSO-d 6 ):δ 13.55(s,1H),8.06(d,J=12Hz,3H),7.97(d,J=4Hz,1H),7.77(d,J=8Hz,2H),7.26(m,1H),7.14(s,1H),6.94-6.90(m,2H),6. 57(bs,2H),4.19-4.16(m,2H),3.88(d,J=12Hz,1H),1.21(t,J=16Hz,3H),1.00(d,J=8Hz,3H),0.91(d,J=4Hz,3H);LC-MS:m / z 459.1(M+H).

[0291] Step iii: Synthesis of 2-(3-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)isoxazol-5-yl)-3-methylbutanoic acid THF (0.5 mL) and H 2 To a stirred solution of ethyl 2-(3-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)isoxazol-5-yl)-3-methylbutanoate (0.08 g, 0.18 mmol) in 20HO (0.5 mL) was added LiOH H 2 O (0.023 g, 0.55 mmol) was added at 0° C. The reaction mixture was stirred at RT for 1 h. The reaction mixture was evaporated under reduced pressure and the resulting residue was diluted with methanol, acidified to pH-6 using Amberlite® IT120 and filtered. The filtrate was concentrated under vacuum to give the title compound as a brown solid (0.05 g, 66%). 1 H NMR (400MHz, DMSO-d 6):δ 8.09-7.96(m,4H),7.74(d,J=8Hz,2H),7.25(d,J=20Hz,1H),6.94-6.89(m,2H),6.79(bs,1H),6. 56(bs,2H),3.20(d,J=12Hz,1H),2.32(m,1H),0.97(d,J=8Hz,3H),0.79(d,J=4Hz,3H);LC-MS:m / z 431.15(M+H).

[0292] Step-iv: Synthesis of (2S,4R)-1-(2-(3-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide To a solution of 2-(3-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)isoxazol-5-yl)-3-methylbutanoic acid (0.05 g, 0.11 mmol), (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.05 g, 0.14 mmol) and HATU (0.06 g, 0.17 mmol) in DMF (5 mL) was added DIPEA (0.1 mL, 0.58 mmol) dropwise at 0° C. and slowly brought to RT. The reaction mixture was stirred at RT for 2 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product, which was purified by combiflash column chromatography using 3% methanol in DCM as eluent to give the title compound as an off-white solid (0.025 g, 29%). 1 H NMR (400MHz, DMSO-d 6):δ 13.55(t,J=12Hz,1H),8.96(d,J=4Hz,1H),8.44(d,J=8Hz,1H),8.08-7.98(m,4H),7.78-7.72(m,2H),7.46(d,J=4Hz) ,1H),7.38(d,J=8Hz,2H),7.31(m,2H),7.04(d,J=12Hz,1H),6.94-6.88(m,2H),6.57(bs,2H),5.14(q,J=8Hz,1H),4 .96-4.91(m,1H),4.46-4.38(m,1H),4.31(bs,1H),3.98(d,J=8Hz,1H),3.75(m,2H),2.47(s,3H),2.07(t,J=12Hz,1 LC-MS:m / z 744.2(M+H).

[0293] Example-5: (2S,4R)-1-((S)-2-(3-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 5) and (2S,4R)-1-((R)-2-(3-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 6) Compounds 5 and 6 were obtained by chiral HPLC of compound 4 using the following method: Chiral HPLC Method Dilution: IPA:DCM (90:10); Mobile phase A: 0.1% TFA in MTBE; Mobile phase B: 100% ethanol; Isocratic: A:B (80:20); Flow rate: 15 mL / min, Column: Chiralpak IA (250 x 20 x 5 μm). (2S,4R)-1-((S)-2-(3-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 5): 1 H NMR (400MHz, DMSO-d 6 ):δ 8.98(s,1H),8.42(d,J=8Hz,1H),8.04(d,J=8Hz,4H),7.96(d,J=8Hz,1H),7.44(d,J=8Hz,2H),7.38(d, J=8Hz,2H),7.25(bs,1H),7.04(s,1H),6.91-6.88(m,2H),6.53(bs,2H),4.93(t,J=12Hz,1H),4.41(t,J =16Hz,1H),4.31(bs,1H),3.89(d,J=12Hz,1H),3.76(d,J=4Hz,1H),3.70-3.50(m,2H),2.44(s,3H),2. 05(d,J=12Hz,1H),1.81(s,1H),1.39(d,J=8Hz,3H),1.03(d,J=8Hz,3H),0.86(d,J=8Hz,3H);LC-MS:m / z 744.2(M+H). (2S,4R)-1-((R)-2-(3-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 6): 1 H NMR (400MHz, DMSO-d 6):δ 13.54(s,1H),8.93(s,1H),8.31(d,J=8Hz,1H),8.06-7.96(m,4H),7.76(d,J=16Hz,2H),7.49(q,J=16Hz,1H),7.36 (d,J=8Hz,2H),7.31-7.24(m,2H),7.01(d,J=8Hz,1H),6.92(d,J=16Hz,2H),6.53(bs,2H),5.12(d,J=4Hz,1H),4.87 (t,J=12Hz,1H),4.46(t,J=16Hz,1H),4.29(bs,1H),3.97(d,J=12Hz,1H),3.65-3.45(m,2H),2.32(s,3H),2.07(s,1 LC-MS:m / z 745.0(M+H).

[0294] The compounds listed in Table-2 below were prepared by procedures similar to those described in Example-4, with appropriate changes in reactants, amounts of reagents, protection and deprotection, solvents and reaction conditions. The characterization data of the compounds are summarized herein in the table below.

[0295] [Table 2]

[0296] [Table 3]

[0297] Example-6: (2S,4R)-1-(2-(3-(4-(3-amino-6-methoxypyridazin-4-yl)phenyl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 10) [ka] Step-i: Synthesis of 2-(3-(4-(3-amino-6-methoxypyridazin-4-yl)phenyl)isoxazol-5-yl)-3-methylbutanoic acid To a stirred solution of ethyl 2-(3-(4-(3-amino-6-chloropyridazin-4-yl)phenyl)isoxazol-5-yl)-3-methylbutanoate (0.05 g, 0.12 mmol) in methanol (3 mL) was added NaOMe (0.02 g, 0.36 mmol) and the reaction mixture was heated in a microwave at 120° C. for 1 h. The reaction mixture was evaporated under reduced pressure and the resulting residue was diluted with methanol, acidified to pH-6 using Amberlite® IT120 (acidic resin) and filtered. The filtrate was concentrated under vacuum to give the title compound as a yellow solid (0.04 g, 87%). 1 H NMR (400MHz, DMSO-d 6 ):δ 7.95(d,J=8.0Hz,2H),7.64(d,J=8.0Hz,2H),6.90(s,1H),6.69(s,1H),5.63(bs,2H) ),3.91(s,3H),2.25(m,1H),0.96(d,J=6.8Hz,3H),0.87(d,J=6.8Hz,3H).LC-MS:m / z 369.2(M+H).

[0298] Step-ii: Synthesis of (2S,4R)-1-(2-(3-(4-(3-amino-6-methoxypyridazin-4-yl)phenyl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide To a stirred solution of 2-(3-(4-(3-amino-6-methoxypyridazin-4-yl)phenyl)isoxazol-5-yl)-3-methylbutanoic acid (0.04 g, 0.11 mmol), (2R,4S)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.05 g, 0.14 mmol) and HATU (0.06 g, 0.17 mmol) in DMF (3 mL) was added DIPEA (0.1 mL, 0.58 mmol) dropwise at 0° C. and slowly brought to RT. The reaction mixture was stirred at RT for 2 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product, which was purified by combiflash column chromatography using 3% methanol in DCM as eluent to give the title compound as an off-white solid (0.01 g, 13%). 1 H NMR (400MHz, DMSO-d 6 ):δ 8.99-8.93(m,1H),8.42-8.29(m,1H),7.99(d,J=20Hz,2H),7.67-7.62(m,2H),7.48-7.36(m,3H),7.3 0(d,J=8Hz,1H),6.99(d,J=8Hz,1H),6.90(d,J=8Hz,1H),5.65(bs,2H),5.11(bs,1H),4.95-4.85(m,1 H),4.48-4.38(m,1H),4.29(bs,1H),3.97(d,1H),3.91(s,3H),3.64-3.44(m,2H),2.43(s,3H),2.04( LC-MS:m / z 682.3(M+H).

[0299] Example-7: (2S,4R)-1-(2-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)-1H-pyrazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 11) [ka] Step i: Synthesis of ethyl 2-(4-(4-(3-amino-6-chloropyridazin-4-yl)phenyl)-1H-pyrazol-1-yl)-3-methylbutanoate 4-(3-amino-6-chloropyridazin-4-yl)phenyl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (0.2 g, 0.39 mmol), (1-(1-ethoxy-3-methyl-1-oxobutan-2-yl)-1H-pyrazol-4-yl)boronic acid (0.15 g, 0.44 mmol), Na in toluene (6 mL), ethanol (3 mL) and water (mL). 2 CO 3 (0.12 g, 1.19 mmol) and lithium chloride (0.02 g, 0.47 mmol). The reaction mixture was degassed with nitrogen for 15 min and subsequently Pd(PPh 3 ) 4 (0.045 g, 0.04 mmol) was added and heated in a sealed tube at 130° C. for 1 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by combiflash column chromatography using 60% ethyl acetate in hexane as eluent to give the title compound as a yellow solid (0.1 g, 63%). 1 H NMR (400 MHz, CDCl 3):δ 8.01(s,1H),7.83(s,1H),7.65(d,J=8.4Hz,2H),7.48(d,J=8.4Hz,2H)7.17(s,1H),4.90(bs,2H),4.70(d,J=9.2Hz,1 LC-MS:m / z 400.2(M+H).

[0300] Step ii: Synthesis of ethyl 2-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)-1H-pyrazol-1-yl)-3-methylbutanoate Ethyl 2-(4-(4-(3-amino-6-chloropyridazin-4-yl)phenyl)-1H-pyrazol-1-yl)-3-methylbutanoate (0.1 g, 0.25 mmol), 2-hydroxyphenylboronic acid (0.04 g, 0.3 mmol) and Na in 1,4-dioxane (5 mL) and water (0.5 mL). 2 CO 3 (0.08 g, 0.75 mmol). The reaction mixture was degassed with nitrogen for 15 min and subsequently Pd(dppf)Cl 2 ·DCM (0.02 g, 0.025 mmol) was added and heated in a sealed tube at 130 °C for 4 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue. The residue was purified by combiflash column chromatography using 45% ethyl acetate in hexane as eluent to give the title compound as a yellow solid (0.055 g, 48%). 1 H NMR (400 MHz, CDCl 3):δ 8.03(s,1H),7.85(s,1H),7.77(s,1H),7.69(d,J=8.4Hz,2H),7.63-7.65(m,1H ),7.56(d,J=8.4Hz,2H)7.28-7.33(m,1H),7.08(d,J=8Hz,1H),6.94-6.89(m,1H ),4.96(bs,2H),4.71(d,J=9.6Hz,1H),4.26(q,J=7.2Hz,2H),2.54-2.57(m,1H) ,1.31(t,J=7.2Hz,3H),1.07(d,J=6.8Hz,3H),0.90(d,J=6.8Hz,3H);LC-MS:m / z 458.2(M+H).

[0301] Step iii: Synthesis of 2-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)-1H-pyrazol-1-yl)-3-methylbutanoic acid Methanol:THF:H 2 To a stirred solution of ethyl 2-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)-1H-pyrazol-1-yl)-3-methylbutanoate (0.05 g, 0.11 mmol) in a mixture of 2H2O (3 mL:3 mL:0.5 mL), LiOH H 2 O (0.01 g, 0.22 mmol) was added at 0° C. The reaction mixture was stirred at RT for 3 h. The reaction mixture was evaporated under reduced pressure and 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 give the title compound as an off-white solid (0.04 g, 85%). LC-MS: m / z 4 30.2 (M+H).

[0302] Step iv: Synthesis of (2S,4R)-1-(2-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)-1H-pyrazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide To a solution of 2-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)-1H-pyrazol-1-yl)-3-methylbutanoic acid (0.04 g, 0.093 mmol) and (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.04 g, 0.10 mmol) in DMF (2 mL) at 0° C. was added HATU (0.05 g, 0.14 mmol), followed by dropwise addition of DIPEA (0.05 mL, 0.27 mmol) and the reaction mixture was stirred at RT for 4 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product, which was purified by combiflash column chromatography using 5% methanol in DCM as eluent to give the title compound as an off-white solid (0.018 g, 26%). 1 H NMR (400MHz, DMSO-d 6 ):δ 13.64(s,1H),8.99(s,1H),8.39(d,J=12Hz,1H),8.05-7.96(m,3H),7.79(d,J=8Hz,2H),7.63(d,J=8Hz,2H), 7.44(d,J=12Hz,1H)7.30-7.36(m,4H),7.27(m,1H),6.94-6.88(m,2H),6.48(bs,2H),5.15(d,J=12Hz,1H)5. 01-4.85(m,1H),4.46-4.22(m,2H),3.99-3.75(m,2H),3.61(d,J=8Hz,1H),2.46(s,3H),2.10-1.97(m,1H),1 .75-1.85(m,1H),1.55-1.64(m,1H),1.39(d,J=8Hz,3H),1.04(d,J=8Hz,3H),0.73(d,J=12Hz,3H);LC-MS:m / z 743.3(M+H).

[0303] Example-8: (2S,4R)-1-((S)-2-(2-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 12) [ka] Step i: Synthesis of tert-butyl 4-(4-(3-amino-6-chloropyridazin-4-yl)phenyl)piperazine-1-carboxylate To a stirred solution of 4-bromo-6-chloropyridazin-3-amine (0.21 g, 1.0 mmol) and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (0.58 g, 1.5 mmol) in 1,4-dioxane (4 mL) and water (2 mL) was added Na 2 CO 3 (0.32 g, 3.0 mmol) was added. The reaction mixture was degassed with nitrogen for 15 min. Pd(dppf)Cl 2 ·DCM (0.08 g, 0.1 mmol) was added to the reaction mixture and heated in a sealed tube at 100 °C for 16 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by combiflash column chromatography using 70% ethyl acetate in hexanes as eluent to give the title compound as an off-white solid (0.18 g, 46%). 1 H NMR (400MHz, DMSO-d 6 ):δ 7.45(d,J=8.8Hz,2H),7.29(s,1H),7.05(d,J=8.8Hz,2H),6.28(s,2H),3.47(t,J=5.2Hz,4H),3.22(t,J=5.2Hz,4H),1.42(s,9H).LC-MS:m / z 390.1(M+H).

[0304] Step ii: Synthesis of 6-chloro-4-(4-(piperazin-1-yl)phenyl)pyridazin-3-amine hydrochloride To a stirred solution of tert-butyl 4-(4-(3-amino-6-chloropyridazin-4-yl)phenyl)piperazine-1-carboxylate (0.24 g, 0.61 mmol) in DCM (5 mL) was added 4N hydrogen chloride in dioxane (1 mL) at 0° C., slowly brought to RT and stirred for 4 h. The reaction mixture was evaporated under reduced pressure and the resulting residue was washed with diethyl ether and dried under vacuum to give the title compound as a sticky material (0.23 g, crude yield). 1 H NMR (400MHz, DMSO-d 6 ):δ 9.32(s,2H),7.67(s,1H),7.50(d,J=8.8Hz,2H),7.15(d,J=8.0Hz,2H),3.57-3.52(m,4H),3.21(s,4H).LC-MS:m / z 290.1(M+H).

[0305] Step iii: Synthesis of tert-butyl 2-(4-(4-(3-amino-6-chloropyridazin-4-yl)phenyl)piperazin-1-yl)acetate To a stirred solution of 6-chloro-4-(4-(piperazin-1-yl)phenyl)pyridazin-3-amine hydrochloride (0.23 g, 0.7 mmol) in DMF (2 mL) was added tert-butyl 2-bromoacetate (0.15 mL, 1.05 mmol) and DIPEA (0.36 mL, 2.11 mmol) at RT and stirred at RT for 16 h. The reaction mixture was quenched with cold water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a pale yellow solid (0.28 g, 98%). 1 H NMR (400MHz, DMSO-d 6):δ 7.43(d,J=9.2Hz,2H),7.28(s,1H),7.05(d,J=8.8Hz,2H),6.27(s,2H),3.24 (t,J=5.2Hz,4H),3.17(s,2H),2.65(t,J=5.2Hz,4H),1.43(s,9H).LC-MS:m / z 404.05(M+H).

[0306] Step iv: Synthesis of tert-butyl 2-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetate A mixture of 1,4-dioxane (4 mL) and water (2 mL) was taken in a microwave vial and degassed with nitrogen for 5 minutes. tert-Butyl 2-(4-(4-(3-amino-6-chloropyridazin-4-yl)phenyl)piperazin-1-yl)acetate (0.27 g, 0.71 mmol) and (2-hydroxyphenyl)boronic acid (0.2 g, 1.42 mmol) were added to the reaction mixture, which was then cooled to 100° C. 2 CO 3 (0.2 g, 3.51 mmol) and Pd(dppf)Cl 2 This was followed by the addition of .DCM (0.06 g, 0.071 mmol). The reaction mixture was heated in a microwave at 120 °C for 1 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue which was purified by combiflash column chromatography using 60% ethyl acetate in hexane as eluent to give the title compound (0.1 g, 32%) as an off-white solid. 1 H NMR (400MHz, DMSO-d 6 ):δ 13.74(s,1H),7.94(d,J=3.6Hz,2H),7.53(d,J=8.4Hz,2H),7.25(s,1H),7.09(d,J=8.8Hz,2H),6 .91(t,J=7.6Hz,2H),6.38(s,2H),3.26(s,4H),3.19(s,2H),2.67(s,4H),1.43(s,9H).LC-MS:m / z 462.3(M+H).

[0307] Step v: Synthesis of 2-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetic acid To a stirred solution of tert-butyl 2-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetate (0.1 g, 0.21 mmol) in dioxane (2 mL) was added 4N hydrogen chloride in dioxane (0.5 mL) at 0° C., slowly brought to RT and stirred for 16 h. The reaction mixture was evaporated under reduced pressure and the resulting residue was washed with diethyl ether and dried under vacuum to give the title compound as a yellow solid (0.08 g, 84%). 1 H NMR (400MHz, DMSO-d 6 ):δ 10.8(s,1H),8.08(s,2H),7.66-7.56(m,3H),7.36(t,J=7.6Hz,1H),7.19(d,J=8.8Hz,2H),7.07-6.95(m,2H),4.23(s,2H),3.57(s,8H).

[0308] Step vi: Synthesis of (2S,4R)-1-((S)-2-(2-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide To a solution of 2-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetic acid (0.08 g, 0.18 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.13 g, 0.27 mmol) and HATU (0.1 g, 0.27 mmol) in DMF (2 mL), DIPEA (0.16 mL, 0.9 mmol) was added dropwise at 0° C. and slowly brought to RT, and the reaction mixture was stirred at RT for 1 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product, which was purified by combiflash column chromatography using 5% methanol in DCM as eluent to give the title compound as a brown solid (0.04 g, 26%). 1 H NMR (400MHz, DMSO-d 6 ):δ 13.74(s,1H),8.98(s,1H),8.42(d,J=7.6Hz,1H),7.94(d,J=8.4Hz,2H),7.79(d,J=9.2Hz,1H),7.54(d,J=8.4 Hz,2H),7.42-7.35(m,4H),7.25(t,J=8.0Hz,1H),7.13(d,J=8.0Hz,2H),6.89(q,J=8.0Hz,2H),6.37(s,2H),5 .12(d,J=2.4Hz,1H),4.89(t,J=6.8Hz,1H),4.54-4.42(m,2H),4.29(s,1H),3.59(s,2H),3.18-3.02(m,2H),2 .67(bs,4H),2.45(bs,7H),2.03-2.10(m,1H),1.72-1.80(m,1H),1.37(d,J=8Hz,3H),0.96(s,9H).LC-MS:m / z 832.4(M+H).

[0309] Example-9: (2S,4R)-1-((S)-2-(2-(4-(4-(3-amino-6-chloropyridazin-4-yl)phenyl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 13) [ka] Step i: Synthesis of 2-(4-(4-(3-amino-6-chloropyridazin-4-yl)phenyl)piperazin-1-yl)acetic acid To a stirred solution of tert-butyl 2-(4-(4-(3-amino-6-chloropyridazin-4-yl)phenyl)piperazin-1-yl)acetate (0.3 g, 0.74 mmol) in DCM (10 mL) was added 4N hydrogen chloride in dioxane (2 mL) at 0° C., then slowly brought to RT and stirred for 16 h. The reaction mixture was evaporated under reduced pressure and the resulting residue was washed with diethyl ether and dried under vacuum to give the title compound as a sticky material (0.3 g, crude yield). 1 H NMR (400MHz, DMSO-d 6 ):δ 11.0(s,1H),7.72(s,1H),7.51(d,J=8.8Hz,2H),7.16(d,J=8.8Hz,2H),4.38(s,4H),4.24(s,4H),3.56(s,2H).

[0310] Step ii: Synthesis of (2S,4R)-1-((S)-2-(2-(4-(4-(3-amino-6-chloropyridazin-4-yl)phenyl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide To a solution of 2-(4-(4-(3-amino-6-chloropyridazin-4-yl)phenyl)piperazin-1-yl)acetic acid (0.04 g, 0.10 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.06 g, 0.12 mmol) and HATU (0.05 g, 0.12 mmol) in DMF (5 mL) was added DIPEA (0.1 mL, 0.52 mmol) dropwise at 0° C., slowly brought to RT and the reaction mixture was stirred for 1 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product, which was purified by combiflash column chromatography using 6-7% methanol in DCM as eluent to give the title compound as a pale yellow solid (0.02 g, 22%). 1 H NMR (400MHz, DMSO-d 6 ):δ 8.98(s,1H),8.44(d,J=7.6Hz,1H),7.79(d,J=9.6Hz,1H),7.45-7.42(m,4H),7.36(d,J=8.0Hz,2H) ,7.29(s,1H),7.08(d,J=8.8Hz,2H),6.28(s,2H),5.13(d,J=3.6Hz,1H),4.88-4.78(m,1H),4.52(d, J=10.0Hz,1H),4.44(s,1H),4.29(s,1H),3.59(d,J=3.6Hz,2H),3.36-3.29(m,4H),2.67-2.64(m,6H ),2.45(s,3H),2.03-2.10(m,1H),1.72-1.80(m,1H),1.23(d,J=9.2Hz,3H),0.95(s,9H).LC-MS:m / z 774.3(M+H).

[0311] Example-10: (2S,4R)-1-((S)-2-(2-(4-(4-(3-amino-6-(trifluoromethyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 14) [ka] Step i: Synthesis of tert-butyl 2-(4-(4-(3-amino-6-(trifluoromethyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetate 4-Bromo-6-(trifluoromethyl)pyridazin-3-amine (0.15 g, 0.61 mmol), tert-butyl 2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-yl)acetate (0.027 g, 0.68 mmol) and K in 1,4-dioxane (4 mL) and water (1 mL). 2 CO 3 (0.25 g, 1.85 mmol). The reaction mixture was degassed with nitrogen for 15 min. Pd(dppf)Cl 2 ·DCM (0.05 g, 0.0061 mmol) was added to the reaction mixture and heated in a sealed tube at 110 °C for 1 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by combiflash column chromatography using 45% ethyl acetate in hexane as eluent to give the title compound (0.15 g, 96%) as an off-white solid. 1 H NMR (400MHz, DMSO-d 6 ):δ 7.49(s,1H),7.46-7.44(m,2H),7.05(d,J=8.8Hz,2H),6.83(s,2H),3.91(s,2H),3.25-3.23(m,4H),2.66-2.64(m,4H),1.42(s,9H);LC-MS:m / z 438.2(M+H).

[0312] Step ii: Synthesis of 2-(4-(4-(3-amino-6-(trifluoromethyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetic acid hydrochloride To a stirred solution of tert-butyl 2-(4-(4-(3-amino-6-(trifluoromethyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetate (0.15 g, 0.34 mmol) in DCM (10 mL) was added 4N hydrogen chloride in dioxane (0.75 mL) at 0° C., then slowly brought to RT and stirred for 16 h. The reaction mixture was evaporated under reduced pressure and the resulting residue was washed with diethyl ether and dried under vacuum to give the title compound as a gummy material (0.11 g, crude yield). LC-MS: m / z 382.1 (M+H).

[0313] Step iii: Synthesis of ((2S,4R)-1-((S)-2-(2-(4-(4-(3-amino-6-(2-methoxypyridin-3-yl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide To a solution of 2-(4-(4-(3-amino-6-(trifluoromethyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetic acid hydrochloride (0.05 g, 0.11 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.07 g, 0.14 equiv.) in DMF (2 mL) at 0° C. was added HATU (0.055 g, 0.14 mmol), followed by dropwise addition of DIPEA (0.1 mL, 0.59 mmol) and the reaction mixture was stirred at RT for 4 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give the title compound as an off-white solid (0.015 g, 11%).1 H NMR (400MHz, DMSO-d 6 ):δ 8.95(s,1H),8.39(d,J=7.2Hz,1H),7.76(d,J=10.0Hz,1H),7.48-7.33(m,7H),7.07(d,J=8.8Hz,2H ),6.82(s,2H),5.10(s,1H),4.86(t,J=7.2Hz,1H),4.5(d,J=10.0Hz,1H),4.42(t,J=8.4Hz,1H),4. 26(s,1H),3.58-3.57(m,2H),3.14-3.1(m,1H),3.02-2.98(m,1H),2.63(bs,6H),2.47-2.43(m,2H) ,2.42(s,3H),2.03-2.02(m,1H),1.75-1.74(m,1H),1.34(d,J=8.0Hz,3H),0.93(s,9H);LC-MS:m / z 808.3(M+H).

[0314] Example-11: (2S,4R)-1-((S)-2-(2-(4-(4-(3-amino-6-(2-methoxypyridin-3-yl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 15) [ka] Step i: Synthesis of tert-butyl 2-(4-(4-(3-amino-6-(2-methoxypyridin-3-yl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetate To a stirred solution of tert-butyl 2-(4-(4-(3-amino-6-chloropyridazin-4-yl)phenyl)piperazin-1-yl)acetate (0.22 g, 0.54 mmol) and (2-methoxypyridin-3-yl)boronic acid (0.17 g, 1.08 mmol) in DME (10 mL) and water (1 mL) was added K 2 CO 3 (0.22 g, 1.63 mmol) was added. The reaction mixture was degassed with nitrogen for 15 min. Pd(dppf)Cl2 ·DCM (0.045 g, 0.054 mmol) was added into the reaction mixture and heated in a sealed tube at 120 °C for 6 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by combiflash column chromatography using 2-3% methanol in DCM as eluent to give the title compound as a yellow solid (0.22 g, 84%). 1 H NMR (400MHz, DMSO-d 6 ):δ 8.24-8.22(m,1H),8.15-8.13(m,1H),7.77(s,1H),7.39-7.37(m,2H),6.97-6.95(m,3H),4.91( bs,2H),3.91(s,3H),3.29-3.26(m,4H),3.13(s,2H),2.71-2.68(m,4H),1.42(s,9H);LC-MS:m / z 477.2(M+H).

[0315] Step ii: Synthesis of 2-(4-(4-(3-amino-6-(2-methoxypyridin-3-yl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetic acid To a stirred solution of tert-butyl 2-(4-(4-(3-amino-6-(2-methoxypyridin-3-yl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetate (0.11 g, 0.23 mmol) in DCM (10 mL) was added 4N hydrogen chloride in dioxane (0.33 mL) at 0° C., slowly brought to RT and stirred for 2 h. The reaction mixture was evaporated under reduced pressure and the resulting residue was washed with diethyl ether and dried under vacuum to give the title compound as a gummy material (0.1 g, crude yield). LC-MS: m / z 421.2 (M+H).

[0316] Step iii: Synthesis of ((2S,4R)-1-((S)-2-(2-(4-(4-(3-amino-6-(2-methoxypyridin-3-yl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide To a solution of 2-(4-(4-(3-amino-6-(2-methoxypyridin-3-yl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetic acid (0.1 g, 0.22 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.13 g, 0.27 mmol) in DMF (2 mL) at 0° C. was added HATU (0.1 g, 0.27 mmol), followed by dropwise addition of DIPEA (0.2 mL, 1.12 mmol) and the reaction mixture was stirred at RT for 2 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give the title compound as a yellow solid (0.02 g, 10%). 1 H NMR (400MHz, DMSO-d 6):δ 8.98(s,1H),8.45(d,J=8.0Hz,1H),8.24-8.22(m,1H),8.17-8.14(m,1H),7.79(d,J=9.2Hz,1H),7.61(s,1H),7.47-7 .37(m,6H),7.16-7.09(m,3H),6.19(s,2H),5.15(d,J=3.2Hz,1H),4.88(t,J=7.2Hz,1H),4.52(d,J=9.6Hz,1H),4.44( t,J=8.4Hz,1H),4.28(s,1H),3.90(s,3H),3.60-3.59(m,2H),3.31-3.30(m,4H),3.17-3.13(m,1H),3.04-3.00(m,1H) ,2.67-2.66(m,4H),2.45(s,3H),2.05-2.03(m,1H),1.80-1.75(m,1H),1.36(d,J=7.2Hz,3H),0.95(s,9H);LC-MS:m / z 847.40(M+H).

[0317] Example-12: (2S,4R)-1-((S)-2-(2-(4-(4-(3-amino-6-(2-hydroxypyridin-3-yl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 16) [ka] Step i: Synthesis of 2-(4-(4-(3-amino-6-(2-hydroxypyridin-3-yl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetic acid To a stirred solution of tert-butyl 2-(4-(4-(3-amino-6-(2-methoxypyridin-3-yl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetate (0.11 g, 0.23 mmol) in DCM (10 mL) was added 4N hydrogen chloride in dioxane (1 mL) at 0° C., slowly brought to RT and stirred for 16 h. The reaction mixture was evaporated under reduced pressure and the resulting residue was washed with diethyl ether and dried under vacuum to give the title compound as a gummy material (0.1 g, crude yield). LC-MS: m / z 407.1 (M+H).

[0318] Step ii: Synthesis of (2S,4R)-1-(2-(3-(4-(3-amino-6-(2-oxo-1,2-dihydropyridin-3-yl)pyridazin-4-yl)phenyl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide To a solution of 2-(4-(4-(3-amino-6-(2-hydroxypyridin-3-yl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetic acid (0.1 g, 0.22 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.13 g, 0.27 mmol) in DMF (2 mL) at 0° C. was added HATU (0.1 g, 0.27 mmol), followed by dropwise addition of DIPEA (0.2 mL, 1.12 mmol). The reaction mixture was stirred at RT for 4 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give the title compound as a yellow solid (0.02 g, 10%). 1 H NMR (400MHz, DMSO-d 6):δ 11.91(s,1H),8.97(s,1H),8.42(d,J=7.2Hz,1H),8.25(d,J=5.6Hz,1H),8.13(s,1H),7.78(d,J=10.0Hz,1H), 7.46-7.35(m,7H),7.10(d,J=8.8Hz,2H),6.38(t,J=6.0Hz,1H),6.06(s,2H),5.12(d,J=2.4Hz,1H),4.89(t,J =6.8Hz,1H),4.53-4.30(m,2H),4.29(bs,1H),3.59-3.56(m,2H),2.66-2.61(m,6H),3.16-3.03(m,2H),2.5-2 .45(m,5H),2.32(s,2H),2.08-2.03(m,1H),1.79-1.74(m,1H),1.36(d,J=6.8Hz,3H),0.96(s,9H);LC-MS:m / z 833.35(M+H)

[0319] Example-13: ((2S,4R)-1-(2-(3-(4-(3-amino-6-(2-oxo-1,2-dihydropyridin-3-yl)pyridazin-4-yl)phenyl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 17) [ka] Step i: Synthesis of ethyl 2-(3-(4-(3-amino-6-(2-methoxypyridin-3-yl)pyridazin-4-yl)phenyl)isoxazol-5-yl)-3-methylbutanoate To a stirred solution of ethyl 2-(3-(4-(3-amino-6-chloropyridazin-4-yl)phenyl)isoxazol-5-yl)-3-methylbutanoate (0.12 g, 0.29 mmol) and (2-methoxypyridin-3-yl)boronic acid (0.09 g, 0.59 mmol) in DME (4 mL) and water (2 mL) was added K 2 CO 3 (0.08 g, 0.59 mmol) was added. The reaction mixture was degassed with nitrogen for 15 min. Pd(dppf)Cl 2·DCM (0.024 g, 0.029 mmol) was added to the reaction mixture and heated in a microwave at 120 °C for 1 h. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by combiflash column chromatography using 3% methanol in DCM as eluent to give the title compound as an off-white solid (0.05 g, 35%). LC-MS: m / z 474.3 (M+H).

[0320] Step ii: Synthesis of ethyl 2-(3-(4-(3-amino-6-(2-oxo-1,2-dihydropyridin-3-yl)pyridazin-4-yl)phenyl)isoxazol-5-yl)-3-methylbutanoate To a stirred solution of compound ethyl 2-(3-(4-(3-amino-6-(2-methoxypyridin-3-yl)pyridazin-4-yl)phenyl)isoxazol-5-yl)-3-methylbutanoate (0.05 g, 0.1 mmol) mixture in DMF (2 mL), PTSA (0.09 g, 0.5 mmol) and LiCl (0.02 g, 0.5 mmol) were added and the reaction mixture was heated at 120° C. for 1 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by combiflash column chromatography using 6% methanol in DCM as eluent to give the title compound as a yellow solid (0.04 g, 83%). 1 H NMR (400MHz, DMSO-d 6):δ 11.97(s,1H),8.27-8.29(m,1H),8.22(s,1H),8.04(d,J=8.0Hz,1H),7.6 7(d,J=8.0Hz,2H),7.51(bs,1H),7.11(s,1H),6.4(d,J=6.4Hz,1H),6.30 (bs,2H),4.16(q,J=8.0Hz,2H),3.88(d,J=8.4Hz,1H),2.41(m,1H),1.22(t,J=3.6Hz,3H),1.00(d,J=6.4Hz,3H),0.91(d,J=6.4Hz,3H);LC-MS:m / z 460.2(M+H).

[0321] Step iii: Synthesis of 2-(3-(4-(3-amino-6-(2-oxo-1,2-dihydropyridin-3-yl)pyridazin-4-yl)phenyl)isoxazol-5-yl)-3-methylbutanoic acid Methanol:THF:H 2 To a stirred solution of the compound ethyl 2-(3-(4-(3-amino-6-(2-oxo-1,2-dihydropyridin-3-yl)pyridazin-4-yl)phenyl)isoxazol-5-yl)-3-methylbutanoate (0.04 g, 0.087 mmol) in a 1 mL:2 mL:1 mL mixture of LiOH H 2 O (0.01 g, 0.26 mmol) was added at 0° C. The reaction mixture was stirred at RT for 16 h. The reaction mixture was evaporated under reduced pressure and the resulting residue was diluted with methanol, acidified to pH 6 using amberlite IT120 (acidic resin) and filtered. The filtrate was concentrated under vacuum to give the title compound as a sticky solid (0.04 g, crude yield). LC-MS: m / z 432.1 (M+H).

[0322] Step iv: Synthesis of ((2S,4R)-1-(2-(3-(4-(3-amino-6-(2-oxo-1,2-dihydropyridin-3-yl)pyridazin-4-yl)phenyl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide To a solution of 2-(3-(4-(3-amino-6-(2-oxo-1,2-dihydropyridin-3-yl)pyridazin-4-yl)phenyl)isoxazol-5-yl)-3-methylbutanoic acid (0.038 g, 0.086 mmol) and (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.038 g, 0.1 mmol) in DMF (5 mL) at 0° C. was added HATU (0.04 g, 0.1 mmol), followed by dropwise addition of DIPEA (0.08 mL, 0.4 mmol) and the reaction mixture was stirred at RT for 4 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product, which was purified by combiflash column chromatography using 12% methanol in DCM as the eluent to give the title compound (0.005 g, 7%) as an off-white solid. 1 H NMR (400MHz, DMSO-d 6 ):δ 11.96(bs,1H),8.98(s,1H),8.28(d,J=7.2Hz,2H),8.23(s,1H),8.02(d,J=8.0Hz,1H),7.98-7.95(m,1H),7. 68-7.62(m,2H),7.48-7.29(m,5H),7.00(d,J=7.2Hz,1H),6.41-6.38(m,1H),6.30(bs,2H),5.13-5.1(m,1H) ,4.95-4.93(m,1H),4.46-4.41(m,1H),4.3(bs,1H),3.99-3.88(m,1H),3.62-3.51(m,2H),2.44(s,3H),2.06 -2.04(m,1H),1.85-1.80(m,1H),1.49(d,J=6.8Hz,1H),1.02(d,J=6.4Hz,3H),0.88-0.80(m,6H);LC-MS:m / z 745.2(M+H).

[0323] Example-14: (2S,4R)-1-((S)-2-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)propanamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 18) [ka] Step i: Synthesis of tert-butyl 4-(4-(3-amino-6-chloropyridazin-4-yl)phenyl)piperazine-1-carboxylate To a stirred solution of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (2.0 g, 5.15 mmol) and 4-bromo-6-chloropyridazin-3-amine (1.6 g, 7.7 mmol) in dioxane (20 mL) and water (10 mL) was added K 2 CO 3 (1.6 g, 15.4 mmol). The reaction mixture was degassed with nitrogen for 15 min. Pd(dppf)Cl 2 ·DCM (0.42 g, 0.51 mmol) was added to the reaction mixture and heated in a sealed tube at 120 °C for 16 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by combiflash column chromatography using 80% ethyl acetate in hexane as eluent to give the title compound as an off-white solid (1 g, 50%). 1 H NMR (400MHz, DMSO-d 6 ):δ 7.45(d,J=8.8Hz,2H),7.29(s,1H),7.05(d,J=8.8Hz,2H),6.28(s,2H),3.47(t,J=5.2Hz,4H),3.22(t,J=5.2Hz,4H),1.42(s,9H).LC-MS:m / z 390.2(M+H).

[0324] Step ii: Synthesis of tert-butyl 4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazine-1-carboxylate To a stirred solution of ethyl tert-butyl 4-(4-(3-amino-6-chloropyridazin-4-yl)phenyl)piperazine-1-carboxylate (1.0 g, 2.56 mmol) and (2-hydroxyphenyl)boronic acid (0.7 g, 5.1 mmol) in dioxane (20 mL) and water (10 mL) was added K 2 CO 3 (0.7 g, 0.59 mmol) was added and degassed with nitrogen for 15 min. 2 ·DCM (0.024 g, 0.029 mmol) was added to the reaction mixture and heated in a sealed tube at 120 °C for 6 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by combiflash column chromatography using 60% ethyl acetate in hexane as eluent to give the title compound as a yellow solid (0.2 g, 17%). 1 H NMR (400MHz, DMSO-d 6 ):δ 13.72(s,1H),7.93(d,J=4.4Hz,2H),7.54(d,J=8.8Hz,2H),7.24(m,1H),7.10(d,J=8.8Hz,2H),7. 86-7.92(m,2H),6.36(s,2H),3.48(t,J=5.2Hz,4H),3.23(t,J=5.2Hz,4H),1.43(s,9H).LC-MS:m / z 448.2(M+H).

[0325] Step iii: Synthesis of 2-(6-amino-5-(4-(piperazin-1-yl)phenyl)pyridazin-3-yl)phenol To a stirred solution of tert-butyl 4-(4-(3-amino-6-chloropyridazin-4-yl)phenyl)piperazine-1-carboxylate (0.2 g, 0.41 mmol) in DCM (5 mL) was added 4N hydrogen chloride in dioxane (1 mL) at 0° C., slowly brought to RT, and stirred for 2 h. The reaction mixture was evaporated under reduced pressure and the resulting residue was washed with diethyl ether and dried under vacuum to give the title compound as a gummy material (0.2 g, crude yield). LC-MS: m / z 348.2 (M+H).

[0326] Step iv: Synthesis of tert-butyl (E)-3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acrylate A stirred solution of 2-(6-amino-5-(4-(piperazin-1-yl)phenyl)pyridazin-3-yl)phenol (0.2 g, 0.52 mmol) in DMF (5 mL) was cooled to 0° C. and stirred for 5 min. DIPEA (0.45 g, 2.6 mmol) and tert-butyl propiolate (0.14 g, 1.04 mmol) were added to the reaction mixture and stirred at RT under nitrogen atmosphere for 16 h. The reaction mixture was quenched with cold water and stirred for 1 h; the solid so formed was filtered and dried under vacuum to give the title compound as an off-white solid (0.15 g, 60%). 1 H NMR (400MHz, DMSO-d 6 ):δ 13.79(s,1H),7.94(d,J=5.2Hz,2H),7.55(d,J=8.8Hz,2H),7.33(d,J=13.2Hz,1H),7.25(t,J=7.6Hz,1H),7 .12(d,J=8.4Hz,2H),6.90(q,J=8.4Hz,2H),6.38(s,2H),3.39(s,4H),3.29(s,4H),1.39(s,9H).LC-MS:m / z 474.3(M+H).

[0327] Step v: Synthesis of tert-butyl 3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)propanoate To a stirred solution of tert-butyl (E)-3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acrylate (0.15 g, 0.31 mmol) in methanol (10 mL) was added Pd-C (0.1 g) at RT and stirred under hydrogen atmosphere for 4 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with methanol and filtered through Celite®. The filtrate was concentrated under vacuum to give the title compound as an off-white solid (0.03 g, 20%). LC-MS: m / z 476.25 (M+H).

[0328] Step vi: Synthesis of 3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)propanoic acid To a stirred solution of tert-butyl 3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)propanoate (0.03 g, 0.063 mmol) in DCM (5 mL) was added 4N hydrogen chloride in dioxane (1 mL) at 0° C., slowly brought to RT and stirred for 16 h. The reaction mixture was evaporated under reduced pressure and the resulting residue was washed with diethyl ether and dried under vacuum to give the title compound as a sticky material (0.025 g, crude yield).

[0329] Step vii: Synthesis of (2S,4R)-1-((S)-2-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide To a solution of 3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)propanoic acid (0.025 g, 0.059 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.034 g, 0.071 mmol) and HATU (0.027 g, 0.071 mmol) in DMF (5 mL), DIPEA (0.05 mL, 0.29 mmol) was added dropwise at 0° C. and slowly brought to RT and the reaction mixture was stirred at RT for 1 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product, which was purified by combiflash column chromatography using 6-7% methanol in DCM as eluent to give the title compound as a pale yellow solid (0.01 g, 20%). 1 H NMR (400MHz, DMSO-d 6 ):δ 13.77(s,1H),8.97(s,1H),8.45-8.31(m,2H),7.93(d,J=4.4Hz,2H),7.53(d,J=8.4Hz,2H),7.43-7. 35(m,4H),7.29-7.20(m,1H),7.11(d,J=8.4Hz,2H),6.91(t,J=9.6Hz,2H),6.37(s,2H),5.10(d,J=2. 8Hz,1H),4.59-4.51(m,1H),4.48-4.41(m,1H),4.32-4.28(m,1H),3.59(s,3H),3.21-3.40(m,6H),2. 60-2.42(m,9H),2.06-1.98(m,1H),1.83-1.75(m,1H),1.36(d,J=7.2Hz,3H),0.95(s,9H).LC-MS:m / z 846.45(M+H).

[0330] Example-15: (2S,4R)-1-((S)-2-(6-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)hex-5-ynamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 19) [ka] Step i: Synthesis of 4-(3-amino-6-chloropyridazin-4-yl)phenyl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate To a stirred solution of 4-(3-amino-6-chloropyridazin-4-yl)phenol (0.6 g, 2.71 mmol), nonafluorobutanesulfonyl fluoride (1.2 ml, 2 vol) in THF (10 mL) was added K 2 CO 3 (0.75 g, 5.42 mmol) was added and the reaction mixture was stirred at RT for 16 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue. The residue was purified by combiflash column chromatography using 40% ethyl acetate in hexane as eluent to give the title compound (1.2 g, 88%) as an off-white solid. 1 H NMR (400MHz, DMSO-d 6 ):δ 7.74-7.72(m,2H),7.55(d,J=8.8Hz,2H),7.45(s,1H),6.51(s,2H);LC-MS:m / z 503.9(M+H).

[0331] Step ii: Synthesis of 6-(4-(3-amino-6-chloropyridazin-4-yl)phenyl)hex-5-yn-1-ol To a stirred solution of 4-(3-amino-6-chloropyridazin-4-yl)phenyl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (1.2 g, 2.38 mmol), hex-5-yn-1-ol (2.33 g, 23.8 mmol) and TEA (0.8 g, 5.95 mmol) in DMF (15 mL). The reaction mixture was degassed with nitrogen for 5 min. Pd(PPh 3 ) 2 Cl 2 (0.08 g, 0.119 mmol) and CuI (0.045 g, 0.238 mmol) were added and heated in a microwave at 120° C. for 2 h. After completion of the reaction, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue. The residue was purified by combiflash column chromatography using 50% ethyl acetate in hexane as eluent to give the title compound yellow solid (0.45 g, 63%). 1 H NMR (400MHz, DMSO-d 6 ):δ 7.79-7.72(m,2H),7.52-7.46(m,4H),7.36(s,1H),6.41(s,2H),4.45-4.39(m ,1H),3.45-3.36(m,2H),3.15(d,J=5.2Hz,2H),2.51-2.45(m,2H).LC-MS:m / z 301.9(M+H).

[0332] Step iii: Synthesis of 6-(4-(3-amino-6-chloropyridazin-4-yl)phenyl)hex-5-ynoic acid To a stirred solution of 6-(4-(3-amino-6-chloropyridazin-4-yl)phenyl)hex-5-yn-1-ol (0.45 g, 1.49 mmol) in acetone (4 mL) at 0° C., Jones reagent (0.5 mL) was added dropwise and the temperature was allowed to reach RT over a period of 2 h. After completion of the reaction, the reaction mixture was diluted with acetone and filtered. The filtrate was concentrated under vacuum. The residue was added with 1 mL of water, extracted with 5% methanol in DCM, and the organic layer was concentrated to give the crude product. The crude product was triturated with diethyl ether and dried under vacuum to give the title compound as an off-white solid (0.35 g, 94%). LC / MS: m / z 315.9 (M+1).

[0333] Step iv: Synthesis of (2S,4R)-1-((S)-2-(6-(4-(3-amino-6-chloropyridazin-4-yl)phenyl)hex-5-ynamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide To a solution of 6-(4-(3-amino-6-chloropyridazin-4-yl)phenyl)hex-5-ynoic acid (0.38 g, 1.2 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.58 g, 1.2 mmol) in DMF (4 mL) at 0° C., HATU (0.54 g, 1.44 mmol) was added, followed by dropwise addition of DIPEA (0.4 mL, 2.4 mmol) and the reaction mixture was stirred at RT for 2 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product, which was purified by combiflash column chromatography using 5% methanol in DCM as the eluent to give the title compound a pale yellow solid (0.24 g, 27%). 1 H NMR (400MHz, DMSO-d 6):δ 8.97(s,1H),8.32(s,1H),7.82(s,1H),7.51(s,3H),7.43-7.41(m,3H),7.37 -7.34(m,3H0,6.40(s,2H),5.15-5.09(m,1H),4.54(d,J=9.2Hz,1H),4.43(t, J=8.0Hz,1H),4.28(s,1H),3.60(s,2H),2.66-2.44(m,6H),2.01(s,1H),1.79 (t,J=7.6Hz,3H),1.37(d,J=6.8Hz,3H),1.23(s,1H),0.95(s,9H).LC / MS:m / z 742.3(M+1).

[0334] Step v: Synthesis of (2S,4R)-1-((S)-2-(6-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)hex-5-ynamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide A mixture of 1,4-dioxane (4 mL) and water (2 mL) was taken in a microwave vial and degassed with nitrogen for 5 minutes. (2S,4R)-1-((S)-2-(6-(4-(3-amino-6-chloropyridazin-4-yl)phenyl)hex-5-ynamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (0.24 g, 0.32 mmol) and (2-hydroxyphenyl)boronic acid (0.067 g, 0.48 mmol) were added to the reaction mixture, which was then cooled to 100° C. for 5 minutes. 2 CO 3 (0.09 g, 3.51 mmol) and Pd(dppf)Cl 2This was followed by the addition of .DCM (0.065 g, 0.08 mmol). The reaction mixture was heated in a microwave at 120 °C for 1 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue. The residue was purified by combiflash column chromatography using 5-7% methanol in DCM as the eluent to give the title compound pale yellow solid (0.08 g, 31%). 1 H NMR (400MHz, DMSO-d 6 ):δ 13.5(s,1H),8.34(d,J=8.0Hz,1H),8.01(s,1H),7.93(d,J=8.4Hz,2H),7.61(d,J=8.4Hz,3H),7.56(d,J=8.4H) z,2H),7.43(d,J=8.4Hz,2H),7.37(d,J=8.4Hz,2H),7.25(t,J=7.6Hz,1H),6.93-6.86(m,2H),6.48(s,2H),5. 09(d,J=3.6Hz,1H),4.92(t,J=7.6Hz,1H),4.54(d,J=9.2Hz,1H),4.43(t,J=8.0Hz,1H),4.28(s,1H),3.81(s, 2H),2.66-2.45(m,5H),2.01(m,1H),1.79(m,3H),1.37(d,J=6.8Hz,3H),1.23(bs,2H),0.95(s,9H).LC / MS:m / z 800.4(M+1).

[0335] The intermediate compounds listed in Table-3 below were prepared by procedures similar to those described in Example-15, with appropriate changes in reactants, amounts of reagents, protection and deprotection, solvents and reaction conditions. The characterization data of the compounds are summarized herein in the tables below.

[0336] [Table 4]

[0337] [Table 5]

[0338] [Table 6]

[0339] Example-16: (2S,4R)-1-(2-(3-(2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 24) [ka] Step i: Synthesis of 4-(4-(2-bromoethoxy)phenyl)-6-chloropyridazin-3-amine To a stirred solution of 4-(3-amino-6-chloropyridazin-4-yl)phenol (1 g, 4.52 mmol) in ethanol (20 mL) was added K 2 CO 3 (3.8 g, 27.14 mmol) and 1,2-dibromoethane (2 mL, 22.6 mmol) were added at RT and the reaction mixture was heated at 100° C. for 12 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product, which was purified by combiflash column chromatography using 60-70% ethyl acetate in hexane as eluent to give the title compound as a pale yellow solid (0.5 g, 33%). 1 H NMR (400MHz, DMSO-d 6 ):δ 7.51(d,J=8.4Hz,2H),7.31(s,1H),7.11(d,J=8.8Hz,2H),6.31(s,2H),4.40(t,J=10.8Hz,2H),3.84(t,J=10.4Hz,2H).LC-MS:m / z 330.0(M+H).

[0340] Step ii: Synthesis of methyl 2-(3-(2-(4-(3-amino-6-chloropyridazin-4-yl)phenoxy)ethoxy)isoxazol-5-yl)-3-methylbutanoate To a stirred solution of 4-(4-(2-bromoethoxy)phenyl)-6-chloropyridazin-3-amine (0.35 g, 1.06 mmol) and methyl 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoate (0.21 g, 2.06 mmol) in DMF (8 mL) was added K 2 CO 3 (0.44 g, 3.18 mmol) was added at RT and the reaction mixture was stirred at RT for 16 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product, which was purified by combiflash column chromatography using 75% ethyl acetate in hexane as eluent to give the title compound as an off-white solid (0.35 g, 73%). 1 H NMR (400MHz, DMSO-d 6 ):δ 7.51(d,J=8.4Hz,2H),7.31(s,1H),7.12(d,J=8.8Hz,2H),6.30(d,J=14.0Hz,3H),4.51(t,J=3.6Hz,2H),4. 38(d,J=2.0Hz,2H),3.67(s,3H),2.33-2.27(m,1H),0.94(d,J=6.4Hz,3H),0.86(d,J=6.4Hz,3H).LC-MS:m / z 447.2(M+H).

[0341] Step iii: Synthesis of methyl 2-(3-(2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)ethoxy)isoxazol-5-yl)-3-methylbutanoate A mixture of 1,4-dioxane (13 mL), water (2 mL) was placed in a microwave vial and degassed with nitrogen for 5 minutes. Methyl 2-(3-(2-(4-(3-amino-6-chloropyridazin-4-yl)phenoxy)ethoxy)isoxazol-5-yl)-3-methylbutanoate (0.3 g, 0.67 mmol) and 2-hydroxyphenylboronic acid (0.19 g, 1.34 mmol) were added to the reaction mixture, which was then cooled to 100° C. 2 CO 3 (0.28 g, 2.01 mmol) and Pd(dppf)Cl 2 This was followed by the addition of .DCM (0.055 g, 0.067 mmol). The reaction mixture was heated in a microwave at 120° C. for 1 min. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue which was purified by combiflash column chromatography using 60% ethyl acetate in hexane as eluent to give the title compound as an off-white solid (0.14 g, 41%). LC-MS: m / z 505.2 (M+H).

[0342] Step iv: Synthesis of 2-(3-(2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)ethoxy)isoxazol-5-yl)-3-methylbutanoic acid THF:H 2 To a stirred solution of methyl 2-(3-(2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)ethoxy)isoxazol-5-yl)-3-methylbutanoate (0.14 g, 0.27 mmol) in a mixture of LiOH H2O (6 mL:1 mL), 2 O (0.035 g, 0.83 mmol) was added at 0° C. The reaction mixture was stirred at RT for 12 h. The reaction mixture was evaporated under reduced pressure and 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 give the title compound as a brown solid (0.12 g, 88%). LC-MS: m / z 491.2 (M+H).

[0343] Step v: Synthesis of (2S,4R)-1-(2-(3-(2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide To a solution of 2-(3-(2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)ethoxy)isoxazol-5-yl)-3-methylbutanoic acid (0.12 g, 0.24 mmol), (2R,4S)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.09 g, 0.244 mmol) in DMF (5 mL) at 0° C. was added HATU (0.14 g, 0.36 mmol), which was followed by dropwise addition of DIPEA (0.21 mL, 3.84 mmol) and the reaction mixture was stirred at RT for 3 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product, which was purified by combiflash column chromatography using 5-7% methanol in DCM as the eluent to give the title compound as a pale yellow solid (0.05 g, 25%). 1 H NMR (400MHz, DMSO-d 6):δ 13.80(s,1H),8.96(d,J=11.6Hz,1H),8.41-8.32(m,1H),7.97-7.93(m,2H),7.58(t,J=7.2Hz,2H),7.47-7.23(m,5H),7. 14(t,J=10.0Hz,2H),6.96-6.83(m,2H),6.40(s,2H),6.16(d,J=8.0Hz,1H),5.09(s,1H),4.91-4.88(m,1H),4.52-4.49( m,2H),4.45-4.36(m,3H),4.27(s,1H),3.77(d,J=8.8Hz,1H),3.68-3.46(m,1H),2.45(s,3H),2.29-2.26(m,1H),2.07-2 .03(m,1H),1.80-1.47(m,1H),1.46(d,J=6.8Hz,1H),1.38-1.34(m,3H),0.98-0.96(m,3H),0.85-0.76(m,3H).LC-MS:m / z 804.3(M+H).

[0344] Example-17: (2S,4R)-1-((S)-2-(2-(4-(5-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)pyridin-2-yl)piperazin-1-yl)acetamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 25) [ka] Step i: Synthesis of 6-chloro-4-(6-fluoropyridin-3-yl)pyridazin-3-amine 4-Bromo-6-chloropyridazin-3-amine (1.5 g, 7.24 mmol), tert-butyl 6-fluoropyridin-3-yl-3-boronic acid (1.6 g, 7.99 mmol) and Na in 1,4-dioxane (30 mL) and water (14 mL). 2 CO 3 (3.09 g, 29.16 mmol). The reaction mixture was degassed with nitrogen for 15 min. Pd(dppf)Cl 2·DCM (0.6 g, 0.72 mmol) was added and the reaction mixture was heated in a microwave at 120 °C for 1 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue. The residue was purified by combiflash column chromatography using 45% ethyl acetate in hexane as eluent to give the title compound brown solid (0.75 g, 46%). 1 H NMR (400MHz, DMSO-d 6 ):δ 8.37(d,J=1.6Hz,1H),8.14(dt,J=8.4,2.4Hz,1H),7.47(s,1H),7.33(dd,J=8.4,2.4Hz,1H),6.53(bs,2H);LC-MS:m / z 225.1(M+H).

[0345] Step ii: Synthesis of tert-butyl 2-(4-(5-(3-amino-6-chloropyridazin-4-yl)pyridin-2-yl)piperazin-1-yl)acetate To a stirred solution of 6-chloro-4-(6-fluoropyridin-3-yl)pyridazin-3-amine (0.55 g, 2.44 mmol) in DMF (10 mL) was added DIPEA (1.74 mL, 9.76 mmol) at RT and stirred for 15 min, then tert-butyl 2-(piperazin-1-yl)acetate (0.97 g, 4.88 mmol) was added and the reaction mixture was heated at 120° C. for 16 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product, which was purified by combiflash column chromatography using 3-4% methanol in DCM as eluent to give the title compound brown solid (0.3 g, 30%). 1 H NMR (400MHz, DMSO-d 6):δ 8.29(d,J=2.4Hz,1H),7.72(dd,J=8.8,2Hz,1H),7.33(s,1H),6.93(d,J=8.8Hz,1 H),6.36(bs,2H)3.58(bs,4H),3.17(s,2H),2.60(bs,4H),1.42(s,9H);LC-MS:m / z 405.2(M+H).

[0346] Step iii: Synthesis of tert-butyl 2-(4-(5-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)pyridin-2-yl)piperazin-1-yl)acetate tert-Butyl 2-(4-(5-(3-amino-6-chloropyridazin-4-yl)pyridin-2-yl)piperazin-1-yl)acetate (0.15 g, 0.37 mmol), 2-hydroxyphenylboronic acid (0.08 g, 0.55 mmol) and Na in 1,4-dioxane (5 mL) and water (1 mL). 2 CO 3 (0.15 g, 1.48 mmol). The reaction mixture was degassed with nitrogen for 15 min. Pd(dppf)Cl 2 ·DCM (0.03 g, 0.037 mmol) was added to the reaction mixture and heated in a sealed tube at 120 °C for 2 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by combiflash column chromatography using 5% methanol in DCM as eluent to give the title compound as a brown solid (0.09 g, 52%). 1 H NMR (400MHz, DMSO-d 6):δ 13.64(s,1H),8.39(s,1H),7.99(s,1H),7.94-7.98(m,1H),7.81(d,J=8.4Hz,1H),7.24(d,J=7.6Hz,1H),6.97(d ,J=9.2Hz,1H),6.87-6.98(m,1H),6.48(bs,2H)3.60(bs,4H),3.18(s,2H),2.62(bs,4H),1.42(s,9H);LC-MS:m / z 463.2(M+H).

[0347] Step iv: Synthesis of 2-(4-(5-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)pyridin-2-yl)piperazin-1-yl)acetic acid To a stirred solution of tert-butyl 2-(4-(5-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)pyridin-2-yl)piperazin-1-yl)acetate (0.09 g, 0.15 mmol) in DCM (3 mL) was added 4N hydrogen chloride in dioxane (1 mL) at 0° C., then slowly brought to RT and stirred for 3 h. The reaction mixture was evaporated under reduced pressure and the resulting residue was washed with diethyl ether and dried under vacuum to give the title compound as a brown solid (0.08 g, crude yield). LC-MS: m / z 407.0 (M+H).

[0348] Step v: Synthesis of (2S,4R)-1-((S)-2-(2-(4-(5-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)pyridin-2-yl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide To a solution of 2-(4-(5-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)pyridin-2-yl)piperazin-1-yl)acetic acid (0.04 g, 0.096 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.05 g, 0.096 mmol) in DMF (3 mL) at 0° C. was added HATU (0.054 g, 0.144 mmol), followed by dropwise addition of DIPEA (0.07 mL, 0.38 mmol) and the reaction mixture was stirred at RT for 16 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product, which was purified by combiflash column chromatography using 5-6% methanol in DCM as the eluent to give the title compound as a brown solid (0.02 g, 24%). 1 H NMR (400MHz, DMSO-d 6 ):δ 11.91(s,1H),8.97(s,1H),8.42(d,J=7.2Hz,1H),8.25(d,J=5.6Hz,1H),8.13(s,1H),7.78(d,J=10.0Hz,1H), 7.46-7.35(m,7H),7.10(d,J=8.8Hz,2H),6.38(t,J=6.0Hz,1H),6.06(s,2H),5.12(d,J=2.4Hz,1H),4.89(t,J =6.8Hz,1H),4.53-4.30(m,2H),4.29(bs,1H),3.59-3.56(m,2H),2.66-2.61(m,6H),3.16-3.03(m,2H),2.5-2 .45(m,5H),2.32(s,2H),2.08-2.03(m,1H),1.79-1.74(m,1H),1.36(d,J=6.8Hz,3H),0.96(s,9H);LC-MS:m / z 833.35(M+H).

[0349] Example-18: (2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(4-(6-(2-hydroxyphenyl)-3-methoxypyridazin-4-yl)phenyl)piperazin-1-yl)acetamide)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 26) [ka] Step i: Synthesis of 4-(tributylstannyl)-6-chloro-3-methoxypyridazine To a solution of LDA (2M) (8.3 mL, 16.66 mmol) in THF (30 mL) at −78° C. under nitrogen atmosphere, a solution of 3-chloro-6-methoxypyridazine (2 g, 13.88 mmol) and tributyltin chloride (4.51 g, 13.88 mmol) in tetrahydrofuran (20 ml) was added dropwise at −78° C. and the mixture was stirred for 1 h. Then, water was added to it and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to obtain a crude residue. The residue was purified by combiflash column chromatography using 10% ethyl acetate in hexane to obtain the title compound as a pale yellow oil (0.4 g, 6%). 1 H-NMR (400MHz, CDCl 3 );δ(ppm)0.89(s,9H),1.10-1.15(m,6H),1.27-1.36(m,6H),1.48-1.53(m,6H),4.06(s,3H),7.38(s,1H).

[0350] Step ii: Synthesis of tert-butyl 2-(4-(4-(6-chloro-3-methoxypyridazin-4-yl)phenyl)piperazin-1-yl)acetate To a stirred solution of 4-(tributylstannyl)-6-chloro-3-methoxypyridazine (0.2 g, 0.46 mmol), tert-butyl 2-(4-(4-bromophenyl)piperazin-1-yl)acetate (0.21 g, 0.59 mmol) in xylene (15 mL) was added CuI (0.01 g, 0.046). The reaction mixture was degassed with nitrogen for 15 min. Pd(PPh 3 ) 4 (0.053 g, 0.046 mmol) was added to the reaction mixture and heated in a sealed tube at 140° C. for 4 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by combiflash column chromatography using 40-50% ethyl acetate in hexane as eluent to give the title compound as a yellow solid (0.03 g, 15%). LC-MS: m / z 419.2 (M+H).

[0351] Step III: Synthesis of tert-butyl 2-(4-(4-(6-(2-hydroxyphenyl)-3-methoxypyridazin-4-yl)phenyl)piperazin-1-yl)acetate tert-Butyl 2-(4-(4-(6-chloro-3-methoxypyridazin-4-yl)phenyl)piperazin-1-yl)acetate (0.06 g, 0.143 mmol), 2-hydroxyphenylboronic acid (0.025 g, 0.186 mmol) and Na in 1,4-dioxane (10 mL) and water (0.5 mL). 2 CO 3 (0.045 g, 0.43 mmol) was stirred and degassed with nitrogen for 15 min. 2·DCM (0.011 g, 0.014 mmol) was added to the reaction mixture and the reaction mixture was heated in a sealed tube at 140 °C for 5 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by combiflash column chromatography using 50% ethyl acetate in hexane as eluent to give the title compound as an off-white solid (0.017 g, 25%). 1 H NMR (400MHz, DMSO-d 6 ):δ 7.95(s,1H),7.66(d,J=8.8Hz,2H),7.36-7.31(m,1H),7.21(d,J=7.2Hz,1H),7.11(d,J=7.6Hz,2H),6.99-6. 92(m,4H),4.29(s,3H),3.39(t,J=10.4Hz,4H),3.19(s,2H),2.77(t,J=10.0Hz,4H),1.49(s,9H).LC-MS:m / z 477.2(M+H).

[0352] Step iv: Synthesis of 2-(4-(4-(6-(2-hydroxyphenyl)-3-methoxypyridazin-4-yl)phenyl)piperazin-1-yl)acetic acid To a stirred solution of tert-butyl 2-(4-(4-(6-(2-hydroxyphenyl)-3-methoxypyridazin-4-yl)phenyl)piperazin-1-yl)acetate (0.015 g, 0.031 mmol) in DCM (2 mL) was added 4N hydrogen chloride in dioxane (0.5 mL) at 0° C., slowly brought to RT and stirred for 16 h. The reaction mixture was evaporated under reduced pressure and the resulting residue was washed with diethyl ether and dried under vacuum to give the title compound as a gummy material (0.015 g, crude yield). LC-MS: m / z 421.1 (M+H).

[0353] Step v: Synthesis of (2S,4R)-1-((S)-2-(2-(4-(5-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)pyridin-2-yl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide To a solution of 2-(4-(4-(6-(2-hydroxyphenyl)-3-methoxypyridazin-4-yl)phenyl)piperazin-1-yl)acetic acid (0.015 g, 0.035 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.02 g, 0.039 mmol) in DMF (1 mL) at 0° C. was added HATU (0.02 g, 0.052 mmol), followed by dropwise addition of DIPEA (0.02 mL, 0.1 mmol) and the reaction mixture was stirred at RT for 4 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give the title compound as a yellow solid (0.008 g, 26%). 1 H NMR (400MHz, DMSO-d 6):δ 8.99(s,1H),8.88(s,1H),8.43(d,J=8.0Hz,1H),8.34(s,1H),8.09(d,J=8.0Hz,1H),7.80(d,J=9.2Hz, 2H),7.44(d,J=8.0Hz,2H),7.39-7.33(m,4H),7.13(d,J=9.2Hz,2H),6.99-6.95(m,2H),4.92(s,1H),4 .60(d,J=8.8Hz,1H),4.40(s,1H),4.31(s,1H),4.12(d,J=3.2Hz,5H),4.05(s,3H),3.67-3.61(m,4H), 2.47-2.46(m,7H),2.09-2.04(m,1H),1.90-1.80(m,1H),1.39(d,J=7.2Hz,3H),0.98(s,9H).LC-MS:m / z 847.45(M+H).

[0354] Example-19: (2S,4R)-1-((S)-2-(2-(4-(4-(3-amino-6-(2-fluorophenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 27) [ka] Compound-27 was prepared by procedures similar to those described in Example-8 with appropriate changes in reactants, amounts of reagents, protection and deprotection, solvents and reaction conditions. 1 H NMR (400MHz, DMSO-d 6):δ 8.98(s,1H),8.44(d,J=7.6Hz,1H),7.91(t,J=6.4Hz,1H),7.79(d,J=9.6Hz,1H),7.78-7.42(m,6H),7.37-7.30(m ,4H),7.15(d,J=8.8Hz,2H),6.26(bs,2H),5.14(d,J=3.2Hz,1H),4.89(d,J=8.0Hz,1H),4.52(d,J=9.6Hz,1H),4.4 3(d,J=7.6Hz,1H),4.35(d,J=1.2Hz,1H),3.59(d,J=3.6Hz,2H),3.36(m,4H),3.13(d,J=16.0Hz,1H),3.02(d,J=16 .0Hz,1H),2.67-2.26(m,4H),2.52(s,3H),1.90(m,1H),1.75(m,1H),1.36(d,J=7.2Hz,3H),0.95(s,9H).LCMS:m / z 834.4(M+H)

[0355] Example-20: (2S,4R)-1-((S)-2-(2-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3-fluorophenyl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 28) [ka] Compound-28 was prepared by procedures similar to those described in Example-8 with appropriate changes in reactants, amounts of reagents, protection and deprotection, solvents and reaction conditions. 1 H NMR (400MHz, DMSO-d 6):δ 13.6(s,1H),8.90(s,1H),8.42(d,J=7.2Hz,1H),7.99(s,1H),7.89(d,J=8Hz,1H),7.78(d,J=8.8Hz,1H),7.44-7. 33(m,5H),7.42(t,J=7.2Hz,1H),6.96-6.85(m,4H),6.40(bs,2H),5.13(d,J=3.6Hz,1H),4.89(t,J=8.0Hz,1H),4. 53(d,J=10Hz,1H),4.44(t,J=8.4Hz,1H),4.29(bs,1H),3.59(bs,2H),3.35(s,4H),3.16(d,J=15.6Hz,1H),3.03(d ,J=15.6Hz,1H),2.66(m,4H),2.45(s,3H),2.04(m,1H),1.76(m,1H),1.46(d,J=6.8Hz,3H),0.96(s,9H).LCMS:m / z 850.7(M+H)

[0356] Example-21: (2S,4R)-1-((S)-2-(2-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperidin-1-yl)acetamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 29) [ka] Step-i: Synthesis of tert-butyl 2-(4-(4-(3-amino-6-chloropyridazin-4-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)acetate To a stirred solution of 4-bromo-6-chloropyridazin-3-amine (0.7 g, 1.75 mmol), tert-butyl 2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)acetate (0.43 g, 2.1 mmol) in 1,4-dioxane (15 mL) and water (2.5 mL) was added K 2 CO 3(0.72 g, 5.25 mmol) was added and degassed with nitrogen for 10 min. 2 ·DCM (0.14 g, 0.17 mmol) was added to the reaction mixture and heated in a sealed tube at 100 °C for 16 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by combiflash column chromatography using 40-80% ethyl acetate in hexanes as eluent to give the title compound (0.3 g, 42%) as an off-white solid. 1 H NMR (400MHz, DMSO-d 6 ):δ 7.57(d,J=8.8Hz,2H),7.52(d,J=8.8Hz,2H),7.36(s,1H),6.38(bs,2H),6 .26(s,1H),3.23(s,4H),2.77(m,2H),2.50(m,2H),1.42(s,9H);LC-MS:m / z 401.2(M+H).

[0357] Step-ii: Synthesis of tert-butyl 2-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)acetate To a stirred solution of tert-butyl 2-(4-(4-(3-amino-6-chloropyridazin-4-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)acetate (0.3 g, 0.74 mmol) and (2-hydroxyphenyl)boronic acid (0.12 g, 0.89 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was added K 2 CO 3 (0.31 g, 2.24 mmol) was added and degassed with nitrogen for 10 min. 2·DCM (0.06 g, 0.07 mmol) was added to the reaction mixture and heated in a sealed tube at 110 °C for 16 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by combiflash column chromatography using 60% ethyl acetate in hexane as eluent to give the title compound (0.18 g, 52%) as an off-white solid. 1 H NMR (400MHz, DMSO-d 6 ):δ 13.62(s,1H),8.01(s,1H),7.95(d,J=7.2Hz,1H),7.61(s,4H),7.25(m,1H),6.91(m,2H), 6.48(bs,2H),6.27(s,1H),3.25(s,4H),2.29(m,2H),2.55(m,2H),1.43(s,9H).LC-MS:m / z 459.3(M+H).

[0358] Step-iii: tert-Butyl 2-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperidin-1-yl)acetate To a stirred solution of tert-butyl 2-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)acetate (0.18 g, 0.39 mmol) in ethanol (5 mL) was added Pd-C (7 mL) at 0° C., then slowly brought to RT and stirred for 6 h. The reaction mixture was evaporated under reduced pressure and the resulting residue was washed with diethyl ether and dried under vacuum to give the title compound pale yellow solid (0.15 g, 83%). 1 H NMR (400MHz, DMSO-d 6):δ 13.65(s,1H),8.00(s,1H),7.95(d,J=7.6Hz,1H),7.57(d,J=8Hz,2H),7.43(d,J=8Hz,2H),7.24(m,1H),6.89( LC-MS:m / z 461.1(M+H).

[0359] Step-iv: 2-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperidin-1-yl)acetic acid hydrochloride To a stirred solution of tert-butyl 2-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperidin-1-yl)acetate (0.12 g, 0.26 mmol) in DCM (5 mL) was added 4N hydrogen chloride in dioxane (1 mL) at 0° C., slowly brought to RT and stirred for 1 h. The reaction mixture was evaporated under reduced pressure and the resulting residue was washed with diethyl ether and dried under vacuum to give the title compound orange solid (0.1 g, 94%). 1 H NMR (400MHz, DMSO-d 6 ):δ 8.11(s,1H),8.02(bs,1H),7.66(m,3H),7.46(m,2H),7.33(m,1H),7.04(d,J=6.8Hz,1H),6.9 4(m,1H),4.16(bs,2H),3.62(m,2H),3.21(m,2H),2.91(m,1H),1.92-2.18(m,4H);LC-MS:m / z 405.2(M+H).

[0360] Step-v: (2S,4R)-1-((S)-2-(2-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperidin-1-yl)acetamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide To a solution of 2-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperidin-1-yl)acetic acid hydrochloride (0.07 g, 0.17 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.08 g, 0.17 mmol) in DMF (5 mL) at 0° C. was added HATU (0.1 g, 0.25 mmol), followed by dropwise addition of DIPEA (0.067 mL, 0.51 mmol) and the reaction mixture was stirred at RT for 4 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product, which was first purified by combiflash column chromatography using an 8% methanol in DCM system followed by HPLC, and the pure fractions were dried under lyophilization to give the title compound off-white solid (0.04 g, 27.8%). 1 H NMR (400MHz, DMSO-d 6 ):δ 13.69(bs,1H),8.97(s,1H),8.45(d,J=7.6Hz,1H),8.00(s,1H),7.94(d,J=8.0Hz,1H),7.80(d,J=9.6Hz,1H),7.59(d,J=8.4Hz, 2H),7.47-7.42(m,4H),7.36(d,J=8.4Hz,2H),7.24(t,J=8Hz,1H),6.93-6.86(m,2H),6.44(bs,2H),5.13(d,J=3.6Hz,1H),4.89 (d,J=8.8Hz,1H),4.53(d,J=9.6Hz,1H),4.44(t,J=8Hz,1H),4.28(bs,2H),3.59(bs,2H),3.12(d,J=16.0Hz,1H),2.96(m,3H),2 .64(m,1H),2.44(s,3H),2.36-2.23(m,1H),2.06(m,1H),1.87(m,2H),1.75(m,3H),1.37(d,J=6.8Hz,3H),0.96(s,9H);LCMS:m / z 831.7(M+H).

[0361] The compounds listed in Table-4 below were prepared by procedures similar to those described in Example-21, with appropriate changes in reactants, amounts of reagents, protection and deprotection, solvents and reaction conditions. The characterization data of the compounds are summarized herein in the table below.

[0362] [Table 7]

[0363] [Table 8]

[0364] [Table 9]

[0365] [Table 10]

[0366] [Table 11]

[0367] [Table 12]

[0368] [Table 13]

[0369] [Table 14]

[0370] [Table 15]

[0371] [Table 16]

[0372] [Table 17]

[0373] [Table 18]

[0374] Example-22: Chiral separation of (2S,4R)-1-((2S)-2-(2-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperidin-1-yl)propanamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 32) Compound 33 (isomer-1 of compound 32) and 34 (isomer-2 of compound 32) were obtained by chiral HPLC of compound 32 by using the following method: Chiral HPLC method Mobile phase: A = acetonitrile B = 0.1% DEA in ethanol Flow rate: 15 ml / min Column: Chiral pak-IG (250 mm x 21.2 mm x 5.0 μ)

[0375] Example-23: Chiral separation of (2S,4R)-1-((2S)-2-(2-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)-2-methylpiperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 35) Compound 36 (isomer-1 of compound 35) and 37 (isomer-2 of compound 35) were obtained by chiral HPLC of compound 35 by using the following method: Chiral HPLC Method Mobile phase: A: n-Hexane, B=0.1% DEA in ethanol Flow rate: 17 ml / min Column: Regis, Reflect, i-Cellulose-C (250 x 20.2 mm), 5 μm. Similarly, compounds 41 (isomer-1 of compound 40), 42 (isomer-2 of compound 40), 44 (isomer-1 of compound 43) and 45 (isomer-2 of compound 43) were separated according to the procedure described in Example 23.

[0376] Example-24: (2S,4R)-1-((S)-2-(2-(4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)amino)piperidin-1-yl)acetamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 54) [ka] Step-i: Synthesis of 4-(4-aminophenyl)-6-chloropyridazin-3-amine To a stirred solution of 4-bromo-6-chloropyridazin-3-amine (2 g, 9.61 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.3 g, 10.5 mmol) in 1,4-dioxane (40 mL) and water (4 mL) was added K 2 CO 3 (3.97 g, 28.8 mmol) was added and degassed with nitrogen for 15 min. 2·DCM (0.78 g, 0.96 mmol) was added to the reaction mixture and heated in a sealed tube at 100 °C for 16 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by combiflash column chromatography using 35% ethyl acetate in hexane as eluent to give the title compound as a light brown solid (1.3 g, 64%). 1 H NMR(400MHz,DMSO-d6):δ 7.29(d,J=8.8Hz,2H),7.24(s,1H),6.69(d,J=8.8Hz,2H),6.23(bs,2H),5.59(bs,2H);LC-MS:m / z 221.0(M+H).

[0377] Step-ii: Synthesis of tert-butyl 4-((4-(3-amino-6-chloropyridazin-4-yl)phenyl)amino)piperidine-1-carboxylate To a stirred solution of 4-(4-aminophenyl)-6-chloropyridazin-3-amine (0.4 g, 1.81 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (0.72 g, 3.62 mmol) in methanol (30 mL) was added acetic acid (0.2 mL) and stirred at RT for 2 h. Sodium cyanoborohydride (0.22 g, 3.6 mmol) was added into the reaction mixture and stirred at RT for 18 h (checked by TLC). The reaction mixture concentrated under reduced pressure was diluted with EtOAc, and the combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by combiflash column chromatography using 40% ethyl acetate in hexane as eluent to give the title compound as a pale yellow solid (0.45 g, 61%). 1 H NMR (400MHz, DMSO-d 6):δ 7.36(d,J=8.8Hz,2H),7.26(s,2H),6.74(d,J=8.8Hz,2H),6.25(s,2H),6.15(d,J= 8.8Hz,1H)3.90(m,2H),3.54(m,1H),2.96(bs,2H),1.90(m,2H),1.44(s,9H),1.26(m,2H);LC-MS:m / z 404.0(M+H).

[0378] Step-iii: Synthesis of 6-chloro-4-(4-(piperidin-4-ylamino)phenyl)pyridazin-3-amine To a stirred solution of tert-butyl 4-((4-(3-amino-6-chloropyridazin-4-yl)phenyl)amino)piperidine-1-carboxylate (0.25 g, 0.61 mmol) in DCM (2 mL) was added HCl dioxane (5 mL) at 0° C., then slowly brought to RT and stirred at RT for 3 h. The reaction mixture was evaporated under reduced pressure and the resulting residue was washed with diethyl ether and dried under vacuum to give the title compound reddish solid (0.25 g, crude). 1 H NMR(400MHz,DMSO-d6):δ 9.23(bs,2H),8.41(bs,1H),7.79(s,1H),7.42(d,J=8.8Hz,2H),6.87(d,J=8.8Hz ,2H),3.71(m,1H),3.35(m,2H),3.06(m,2H),2.08(m,2H),1.72(m,2H);LC-MS:m / z 304.2(M+H).

[0379] Step-iv: Synthesis of tert-butyl 2-(4-((4-(3-amino-6-chloropyridazin-4-yl)phenyl)amino)piperidin-1-yl)acetate To a stirred solution of 6-chloro-4-(4-(piperidin-4-ylamino)phenyl)pyridazin-3-amine (0.25 g, 0.82 mmol) in DMF (5 mL) was added DIPEA (0.53 g, 4.11 mmol) at RT and stirred for 15 min. tert-Butyl 2-bromoacetate (0.16 g, 0.82 mmol) was added to the reaction mixture and stirred at RT for 4 h under nitrogen atmosphere. The reaction mixture was quenched with cold water, stirred for 1 h and the solid so formed was filtered and dried under vacuum to give the title compound as a brown solid (0.21 g, 61%). 1 H NMR (400 MHz, CDCl 3 ):δ 7.30(d,J=8.8Hz,2H),7.21(s,1H),6.67(d,J=8.8Hz,2H),6.20(bs,2H),5.95(d,J=8.8Hz,1H),3.2 4(m,1H),3.09(s,2H),2.81(m,2H),2.30(m,2H),1.89(m,2H),1.41(s,9H),1.36(n,2H);LC-MS:m / z 418.2(M+H).

[0380] Step-v: Synthesis of tert-butyl 2-(4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)amino)piperidin-1-yl)acetate To a stirred solution of tert-butyl 2-(4-((4-(3-amino-6-chloropyridazin-4-yl)phenyl)amino)piperidin-1-yl)acetate (0.16 g, 0.38 mmol), 2-hydroxyphenylboronic acid (0.06 g, 0.46 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was added K 2 CO 3 (0.16 g, 1.14 mmol) was added and degassed with nitrogen for 10 min. 2·DCM (0.03 g, 0.03 mmol) was added to the reaction mixture and heated in a sealed tube at 120 °C for 16 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by combiflash column chromatography using 50% ethyl acetate in hexane as eluent to give the title compound as a pale yellow solid (0.06 g, 33%). LC-MS: m / z 476.4 (M+H).

[0381] Step-vi: Synthesis of 2-(4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)amino)piperidin-1-yl)acetic acid To a stirred solution of tert-butyl 2-(4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)amino)piperidin-1-yl)acetate (0.06 g, 0.12 mmol) in DCM (1 mL) was added 4N hydrogen chloride in dioxane (3 mL) at 0° C., then slowly brought to RT and stirred at RT for 3 h. The reaction mixture was evaporated under reduced pressure and the resulting residue was washed with diethyl ether and dried under vacuum to give the title compound as a brownish solid (0.06 g, crude). m / z 420.8 (M+H).

[0382] Step-vii: Synthesis of (2S,4R)-1-((S)-2-(2-(4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)amino)piperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide To a solution of 2-(4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)amino)piperidin-1-yl)acetic acid (0.04 g, 0.095 mmol) and ((2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.046 g, 0.10 mmol) in DMF (1 mL) at 0° C. was added HATU (0. To the reaction mixture was added 100 ml of ethyl acetate (0.05 g, 0.14 mmol), followed by dropwise addition of DIPEA (0.08 g, 0.66 mmol) and the reaction mixture was stirred at RT for 2 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product, which was purified by combiflash column chromatography using 8-10% methanol in DCM as eluent to give the title compound light brown solid (0.03 g, 37%). 1 H NMR (400MHz, DMSO-d 6 ):δ 13.64(bs,1H),8.98(s,1H),8.45-8.44(m,1H),7.94-7.80(m,3H),7.42-7.35(m,6H),7.25-7.23(m,1H),6. 92-6.88(m,2H),6.74(d,J=8.8Hz,2H),6.33(bs,2H),5.14(bs,1H),4.92-4.89(m,1H),4.52-4.42(m,2H),4 .29(bs,1H),3.58(bs,2H),3.13-3.04(m,1H),2.96-2.94(m,1H),2.88-2.79(bs,2H),2.45(s,3H),2.38-2. 26(m,3H),2.10-1.93(m,3H),1.79-1.76(m,1H),1.51(bs,3H),1.38(d,J=6.4Hz,3H),0.95(s,9H);LCMS:m / z 846.6(M+1).

[0383] Example-25: (2S,4R)-1-((S)-2-(2-(4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)(methyl)amino)piperidin-1-yl)acetamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 55) [ka] Example-55 was prepared by a procedure similar to that described in Example-24 with appropriate changes in reactants, amounts of reagents, protection and deprotection, solvents and reaction conditions. δ 13.33 (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,2H),2.45(m,H),2.22(m,3H),2.01(m,1H), 1.7(s,1H),1.67(s,1H),1.45(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).

[0384] Example-26: (2S,4R)-1-(2-(3-(2-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)amino)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 56) [ka] Step-i: Synthesis of (2S,4R)-1-(2-(3-(2-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)amino)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide To a stirred solution of 2-(6-amino-5-(4-aminophenyl)pyridazin-3-yl)phenol (10 mg, 0.036 mmol), (2S,4R)-4-hydroxy-1-(3-methyl-2-(3-(2-oxoethoxy)isoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (prepared according to reference US Patent Application Publication No. 2019 / 300521, 2019, A1) (20 mg, 0.036 mmol) in methanol (1 mL), acetic acid (0.1 mL) was added at 0 ° C. and stirred at RT for 2 h. Sodium cyanohydride (5 mg, 0.070 mmol) was added to the reaction mixture at 0 ° C. and stirred at RT for 2 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was quenched with sodium bicarbonate and diluted with water. The reaction mass was extracted with EtOAc and the combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue which was purified by preparative TLC using 5% methanol in DCM as eluent to give the title compound as a pale yellow solid (10 g, 34%). 1 H NMR (400MHz, DMSO-d 6):δ 13.85(br,1H),8.99-8.96(m,1H),8.41-8.36(m,1H),7.96-7.82(m,1H),7.90(s,1H),7.42-7.39(m,3H),7.38-7. 30(m,2H),7.27-7.22(m,2H),6.92-6.87(m,2H),6.82-6.77(m,2H),6.34(br,3H),6.02(br,1H),5.21(br,1H)4.9 3-4.85(m,1H),4.44-4.37(m,1H),4.35-4.25(m,2H),3.79-3.75(m,2H),3.55-3.45(m,3H),2.44(s,3H),2.05-1. 96(m,2H),1.80-1.72(m,1H),1.48-1.42(m,1H),1.49-1.42(m,3H),0.957(br,3H),0.88-0.78(m,3H);LC-MS:m / z 804.3(M+H).

[0385] Example-27: (2S,4R)-1-(2-(3-(2-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)(methyl)amino)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 57) [ka] Compound-57 was prepared by procedures similar to those described in Example-26 with appropriate changes in reactants, amounts of reagents, protection and deprotection, solvents and reaction conditions. 1H NMR(400MHz,CDCl3):δ 8.85(brs,1H),7.85(brs,1H),7.60-7.56(m,1H),7.53-7.48(m,1H),7.38-7.36(m,3H),7.36-7.35(m,1H),7.35-7.34(m,1H) ,7.33-7.34(m,1H),7.09-7.05(m,2H),6.98-6.93(m,1H),6.83-6.71(m,2H),5.72(brs,1H)5.45-5.40(m,1H),4.99-4.92(m, 1H),4.71-4.68(m,1H),4.62-4.58(m,1H),4.48-4.42(m,2H),3.91-3.85(m,1H),3.72-3.68(m,1H),3.55-3.49(m,2H),3.05( bs,3H),2.50(m,3H),2.42-1.98(m,3H),1.61(m,1H),1.37(d,J=6.8Hz,3H),1.02-0.95(m,3H),0.91-0.85(m,3H);LC-MS:m / z 817.5(M+H).

[0386] Example-28: (2S,4R)-1-((S)-2-(5-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)pentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 58) [ka] Step-i: Synthesis of methyl 5-(4-(3-amino-6-chloropyridazin-4-yl)phenoxy)pentanoate To a stirred solution of the compound 4-(3-amino-6-chloropyridazin-4-yl)phenol (0.25 g, 1.13 mmol) in acetone (10 mL), methyl 5-bromopentanoate (0.25 mL, 1.69 mmol), K 2 CO 3(0.47 g, 3.39 mmol) was added at RT and the reaction mixture was heated in a shield at 90° C. for 16 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was concentrated and diluted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by preparative HPLC to give the title compound as a pale yellow solid (0.3 g, 79%). 1 H NMR (400MHz, DMSO-d 6 ):δ 7.48(d,J=8.4Hz,1H),7.31(s,1H),7.05(d,J=8.4Hz,2H),6.31(bs,2H),4.03( t,J=6Hz,2H),3.59(s,3H),2.39(t,J=6.8Hz,2H),1.76-1.69(m,4H);LC-MS:m / z 335.9(M+H).

[0387] Step-ii: Synthesis of methyl 5-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)pentanoate To a stirred solution of methyl 5-(4-(3-amino-6-chloropyridazin-4-yl)phenoxy)pentanoate (0.3 g, 0.895 mmol), (2-hydroxyphenyl)boronic acid (0.19 g, 1.34 mmol) in 1,4-dioxane (6 mL) and water (1.5 mL) was added Na 2 CO 3 (0.28 g, 2.68 mmol) was added and degassed with nitrogen for 5 min, followed by Pd(dppf)Cl 2 ·DCM (0.04 g, 0.04 mmol) was added and the reaction mixture was heated in a microwave at 130 °C for 1 h. Once the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by combiflash column chromatography using 40-50% ethyl acetate in hexane as eluent to give the title compound as an off-white solid (0.05 g, 14%). LC-MS: m / z 394.1 (M+H).

[0388] Step-iii: Synthesis of 5-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)pentanoic acid Methanol:THF:H 2 To a stirred solution of the compound, methyl 5-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)pentanoate (0.05 g, 0.127 mmol) in 1 mL:1 mL:1 mL mixture of LiOH H 2 O (0.01 g, 0.25 mmol) was added at 0° C. The reaction mixture was stirred at RT for 16 h. The reaction mixture was then evaporated under reduced pressure and the resulting residue was diluted with methanol, acidified to pH 6 using Amberlite® IT120, filtered and the filtrate was concentrated under vacuum to give the title compound as a sticky solid (0.04 g, 81%). LC-MS: m / z 380.05 (M+H).

[0389] Step-iv: Synthesis of (2S,4R)-1-((S)-2-(5-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)pentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(thiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide To a solution of 5-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)pentanoic acid (0.04 g, 0.101 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.06 g, 0.121 equiv.) in DMF (2 mL) at 0° C. was added HATU (0.06 g, 0.151 mmol), followed by dropwise addition of DIPEA (0.05 mL, 0.303 mmol) and the reaction mixture was stirred at RT for 2 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product, which was purified by combiflash column chromatography using 5-5% methanol in DCM as eluent to give the title compound as a white solid (0.02 g, 24%). 1 H NMR (400MHz, DMSO-d 6 ):δ 13.71(s,1H),8.99(s,1H),8.40(d,J=7.8Hz,1H),7.97(s,1H),7.95-7.90(m,1H),7.89(d,J=9.3Hz,1H),7.58(d,J=8.8H z,2H),7.45-7.37(m,5H),7.25(t,J=7.6Hz,1H),7.10(d,J=8.8Hz,2H),6.93-6.87(m,2H),6.44(bs,2H),5.12(d,J=3.4H) z,1H),4.91(d,J=7.4Hz,1H),4.54(d,J=9.3Hz,1H),4.42(t,J=8.0Hz,1H),4.28(s,1H),4.05(d,J=6.4Hz,2H),3.61(bs, 2H),2.45(s,3H),2.23-2.22(m,1H),2.08-1.99(m,1H),1.78-1.65(m,5H),1.37(d,J=6.8Hz,3H),0.95(s,9H);LCMS:m / z 806.3(M+H).

[0390] Example-29: (2S,4R)-1-(2-(3-(4-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 59) [ka] Step-i: Synthesis of methyl 2-(3-(4-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)isoxazol-5-yl)-3-methylbutanoate To a stirred solution of 2-(6-amino-5-(4-(piperazin-1-yl)phenyl)pyridazin-3-yl)phenol hydrochloride (0.01 g, 0.357 mmol) and methyl 3-methyl-2-(3-(4-oxopiperidin-1-yl)isoxazol-5-yl)butanoate (0.15 g, 0.428 mmol) in 6 mL of THF:DMSO (2:1) mixture, KOAc (0.105 g, 1.07 mmol) and acetic acid (0.2 mL) and molecular sieves (4 Å) were added and the reaction mixture was stirred at 70° C. for 16 h. The reaction mixture was then cooled to 0° C. and sodium cyanoborohydride (0.23 g, 1.07 mmol) was added and the reaction mixture was stirred at RT for 6 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured into ice water and the resulting solid was filtered and washed with water to obtain the crude material. The crude product was purified by combiflash column chromatography using 5% methanol in DCM as eluent to obtain the title compound as a pale yellow solid (0.20 g, 91.5%). LCMS: m / z 612.4 (M+H).

[0391] Step-ii: Synthesis of 2-(3-(4-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)isoxazol-5-yl)-3-methylbutanoic acid THF:H 2 To a stirred solution of methyl 2-(3-(4-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)isoxazol-5-yl)-3-methylbutanoate (0.2 g, 0.327 mmol) in 1 mL:1 mL mixture of LiOH H 2 0 (0.04 g, 1.63 mmol) was added at 0° C. The reaction mixture was stirred at RT for 2 h. The reaction mixture was then evaporated under reduced pressure and the residue obtained was diluted with water (3 mL) and acidified to pH 6 using 1N HCl solution at 0° C. and stirred for 30 min. The solid so formed was filtered and dried under vacuum to give the title compound as a pale yellow solid (0.2 g, crude); LCMS: m / z 598.4 (M+H).

[0392] Step-iii: Synthesis of (2S,4R)-1-(2-(3-(4-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide To a solution of 2-(3-(4-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)isoxazol-5-yl)-3-methylbutanoic acid (0.2 g, 0.335 mmol) and (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.136 g, 0.369 mmol) in DMF (5 mL) at 0° C., HATU (0.19 g, 0.5 mmol) was added, followed by dropwise addition of DIPEA (0.216 mL, 1.67 mmol) and the reaction mixture was stirred at RT for 2 h. The reaction mixture was then poured into ice-cold water and stirred for 30 min. The solid so formed was filtered and dried under vacuum to give the crude product. The crude product was first purified by combiflash column chromatography using 3% methanol in DCM, followed by preparative HPLC purification to give the title compound as an off-white solid (0.010 g, 44%). LC-MS: 911.6 (M+H).

[0393] Example-30: (2S,4R)-1-(2-(4-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 60) [ka] Compound-60 was prepared by procedures similar to those described in Example-29 with appropriate changes in reactants, amounts of reagents, protection and deprotection, solvents and reaction conditions. LC-MS: m / z 858.6 (M+H).

[0394] Although the present application is illustrated by some of the above-mentioned examples, it should not be construed as being limited thereby; rather, the present application encompasses the generic domain as disclosed hereinabove. Various modifications and embodiments can be made without departing from the spirit and scope thereof. For example, the following compounds can be prepared by following similar procedures as described above with suitable modifications known to those skilled in the art:

[0395] [Table 19]

[0396] [Table 20]

[0397] [Table 21] or pharmacologically acceptable salts, or stereoisomers, or tautomers thereof are also included within the scope of this application.

[0398] Example - P1: Determination of the antiproliferative activity of compounds in the cell line VCaP by the Cell Titer Glo® (Promega) assay VCaP (ATCC CRL-2876) cells were seeded in 96-well flat black clear bottom plates (Corning, Cat. No 3904) using complete DMEM medium. The following day, compounds listed in this invention were added to the cells from 10 mM stocks made in DMSO (Sigma Cat no. D2650). Each concentration of compound was tested in triplicate with DMSO concentration at a final percentage not exceeding 0.3 in the cells. After culturing VCaP cells with compounds for 8 days, the assay was terminated using 50 μl of CellTiter Glo® Reagent (Promega, Cat. no G7572). CellTiter-Glo® Luminescence Reagent determines the number of viable cells based on quantification of ATP present, which is an indicator of cell number and metabolic activity. Luminescence readings were taken on a Victor-3 instrument. Percent inhibition of proliferation was calculated using the formula: % inhibition = 100 - (luminescence value of test / luminescence value of DMSO control) x 100. DMSO control (0%) = cells in complete medium with DMSO; blank = medium containing DMSO exclusively. EC 50 was calculated using graph pad prism software.

[0399] Selected compounds of the present invention are 50 The results are summarized in the following table into groups A, B, and C. In this specification, group "A" refers to a group with an EC value lower than 10 nM. 50 Group "B" refers to EC values ​​between 10 nM and 100 nM (inclusive). 50 Group "C" refers to EC values ​​greater than 100 nM. 50 Points to a value.

[0400] [Table 22]

[0401] Example - P2: Measurement of SMARCA2 and SMARCA4 degradation in VCaP cells by Western blot VCaP (ATCC CRL-2876) were plated in 6-well plates using complete Dulbecco's modified Eagle's medium. On day 3, compounds of the invention were added to the cells from 10 mM stocks made in DMSO (Sigma Cat no. D2650). Each compound was tested at 100 nM concentration with DMSO not exceeding a final percentage of 0.3 in the cells. Cells were cultured with compounds for 16 hours and subsequently harvested with 1X RIPA lysis buffer (Thermo Fischer, Cat no. #89900) containing a protease inhibitor cocktail (Sigma Cat no. #P-8340). Equal amounts of protein were loaded onto SDS PAGE gels for electrophoresis. Western blots were performed for detection of either SMARCA2 antibody (Cell signalling technologies, Cat no. #11966) or SMARCA4 antibody (Cell signalling technologies, Cat no. #52251). β-tubulin antibody (Cell signalling technologies, Catalog #86298) was used as a loading control. The percentage of SMARCA2 or SMARCA4 degradation was calculated using the formula: % Degradation = 100 - (normalized band intensity in treated sample / normalized band intensity in DMSO sample) x 100 It was calculated by using The results are shown below.

[0402] [Table 23]

[0403] Incorporation by Reference All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0404] equivalent While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those of skill in the art upon review of this specification and the claims that follow. The full scope of the invention should be determined by reference to the claims, together with such variations, along with their full scope of equivalents and the present specification.

Claims

1. Formula (I): 【Chemistry 1】 or a pharmacologically acceptable salt or stereoisomer or tautomer thereof; A represents a 5- to 6-membered heteroarylenyl or a 6-membered arylenyl; wherein the arylenyl and heteroarylenyl are unsubstituted or contain one, two or three R ａ is substituted with; R ａ represents each occurrence independently hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, or cyano; R １ is halogen, alkyl, haloalkyl, alkoxy, hydroxy, hydroxyalkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; wherein said aryl and heteroaryl groups are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from oxo, hydroxy, alkoxy, halogen, alkyl, haloalkyl, amino, and cyano; R ２ is hydrogen, hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, amino, aminoalkyl, haloalkyl or cyano; Q is amino, aminoalkyl, hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, or cyano; L is a bond, -N(R ｘ )-(CR ｘ R ｙ ) p-O-, -O-(CR ｘ R ｙ )p-, -O-(CR ｘ R ｙ )p-O-, -C≡C-(CRxRy)p-, -heterocycloalkylenyl-heterocycloalkylenyl-, -heterocycloalkylenyl-O-, -heterocycloalkylenyl-C≡C-, -C≡C-heterocycloalkylenyl-, -O-heterocycloalkylenyl-(CR ｘ R ｙ ) p-, -N(R ｘ )-heterocycloalkylenyl-(CR ｘ R ｙ ) p-, -cycloalkylenyl-(CR ｘ R ｙ ) p-, -heteroarylenyl-(CR ｘ R ｙ ) p-, -heterocycloalkylenyl-(CR ｘ R ｙ ) p-, -heterocycloalkylenyl-(CR ｘ R ｙ ) p １ -heterocycloalkylenyl- or -heterocycloalkylenyl-O-heterocycloalkylenyl-; wherein the cycloalkylenyl, heteroarylenyl and heterocycloalkylenyl are unsubstituted or contain one, two or three R ｄ the left side of the L group is attached to A and the right side of the L group is attached to M; R ｄ is, at each occurrence, independently selected from hydroxy, halogen, alkyl and alkoxy; or any two R ｄ the groups together form an oxo group; R ｘ and R ｙ is independently selected at each occurrence from hydrogen and alkyl; M is M-1 and M-2: 【Chemistry 2】 (In the formula, Z is a 5- to 6-membered heteroarylenyl or a 5- to 6-membered heterocycloalkylenyl; wherein said heteroarylenyl and heterocycloalkylenyl groups are unsubstituted or substituted with oxo, hydroxy, halogen, alkyl, or alkoxy; R ３ and R ８ independently represents alkyl, haloalkyl, or hydroxyalkyl; R ４ and R ９ independently represent hydrogen, alkyl, haloalkyl, or hydroxyalkyl; R ５ , R ６ , R １０ and R １１ is independently selected from hydrogen, alkyl, halogen, heteroalkyl, haloalkyl, hydroxyalkyl, and acyl; R ７ and R １２ independently represent thiazolyl, which is unsubstituted or substituted with alkyl, hydroxy, amino, or haloalkyl. Selected from: "p" is an integer selected from 0, 1, 2, 3, 4, 5, and 6; "p １ " is an integer selected from 1, 2, 3 and 4; A compound or a pharma- ceutically acceptable salt or stereoisomer or tautomer thereof.

2. R １ is halogen, alkyl, haloalkyl, alkoxy, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein said aryl and heteroaryl groups are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from oxo, hydroxy, alkoxy, halogen, alkyl, haloalkyl, amino, and cyano.

3. R １ is methoxy, chloro, trifluoromethyl, phenyl or pyridinyl; said phenyl and pyridinyl are unsubstituted or substituted with one, two or three substituents independently selected from oxo, hydroxy, methoxy, fluoro, chloro, difluoromethyl and trifluoromethyl.

4. R ２ The compound according to any one of claims 1 to 3, wherein is hydrogen.

5. A is unsubstituted or contains one or two R ａ 5. A compound according to claim 1, which represents phenylenyl substituted with

6. A is unsubstituted or contains one or two R ａ 6. A compound according to claim 1, which represents a 5-6 membered heteroarylenyl substituted with

7. 7. The compound of any one of claims 1 to 6, wherein A represents phenylenyl, furanylenyl, thienylenyl, pyrrolilenyl, pyrazolilenyl, imidazolylenyl, oxazolilenyl, isoxazolilenyl, thiazolylenyl, isothiazolilenyl, 1H-tetrazolylenyl, oxadiazolylenyl, triazolilenyl, pyridylenyl, pyrimidinylenyl, pyrazinylenyl, pyridazinylenyl, 1,2,3-triazinylenyl, 1,2,4-triazinylenyl, or 1,3,5-triazinylenyl; each group is unsubstituted or substituted with one or two substituents independently selected from hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, and cyano.

8. A compound according to any one of claims 1 to 7, wherein Q represents amino or alkoxy.

9. The compound of any one of claims 1 to 8, wherein L is a bond.

10. L is -N(R ｘ )-(CR ｘ R ｙ ) p-O-, -O-(CR ｘ R ｙ )p-, -O-(CR ｘ R ｙ )p-O- or -C≡C-(CR ｘ R ｙ 10. The compound according to claim 1, wherein

11. L is -N(CH ３ )-CH ２ CH ２ -O-, -N(CH ３ )-CH ２ CH ２ CH ２ -O-, -N(CH ３ )-CH ２ CH ２ CH ２ CH ２ -O-, -NH-CH ２ CH ２ -O-, -NH-CH ２ CH ２ CH ２ -O-, -O-CH ２ --, --O-CH ２ CH ２ --, --O-CH ２ CH ２ CH ２ --, --O-CH ２ CH ２ -O-, -O-CH ２ CH ２ CH ２ CH ２ -, -C≡C-CH ２ -, -C≡C-CH ２ CH ２ - or -C≡C-CH ２ CH ２ CH ２ The compound according to claim 10, wherein

12. L is -heterocycloalkylenyl-heterocycloalkylenyl-, -heterocycloalkylenyl-O-, -heterocycloalkylenyl-C≡C-, -C≡C-heterocycloalkylenyl-, -O-heterocycloalkylenyl-(CR ｘ R ｙ ) p-, -N(R ｘ )-heterocycloalkylenyl-(CR ｘ R ｙ ) p-, -cycloalkylenyl-(CR ｘ R ｙ ) p-, -heteroarylenyl-(CR ｘ R ｙ ) p-, -heterocycloalkylenyl-(CR ｘ R ｙ ) p-, -heterocycloalkylenyl-(CR ｘ R ｙ ) p １ The compound according to any one of claims 1 to 11, which is -heterocycloalkylenyl- or -heterocycloalkylenyl-O-heterocycloalkylenyl-.

13. The heterocycloalkylenyl is azetidinylenyl, pyrrolidinylenyl, piperidinylenyl, piperazinylenyl, tetrahydropyranyl, tetrahydropyridazinylenyl, morpholinylenyl, thiomorpholinylenyl, 1,4-dioxanylenyl, dioxidethiomorpholinylenyl, oxapiperazinylenyl, oxapiperidinylenyl, tetrahydropyranylenyl, dihydropyranylenyl, or dihydropyrimidinylenyl; each group is unsubstituted or substituted with one or two R ｄ 13. The compound of claim 12 substituted with:

14. The compound of claim 12, wherein the cycloalkylenyl is cyclopropylenyl, cyclobutylenyl, cyclopentylenyl, cyclohexylenyl, or cycloheptylenyl.

15. Lは、-N(CH ３ )-CH ２ CH ２ -O-、-N(CH ３ )-CH ２ CH ２ CH ２ -O-、-N(CH ３ )-CH ２ CH ２ CH ２ CH ２ -O-、-NH-CH ２ CH ２ -O-、-NH-CH ２ CH ２ CH ２ -O-、-O-CH ２ -、-O-CH ２ CH ２ -、-O-CH ２ CH ２ CH ２ -、-O-CH ２ CH ２ CH ２ CH ２ -、-O-CH ２ CH ２ -O-、-C≡C-CH ２ -、-C≡C-CH ２ CH ２ -、-C≡C-CH ２ CH ２ CH ２ - 【Chemistry 3】 wherein each ring is unsubstituted or contains one or two R ｄ 15. The compound according to any one of claims 9 to 14, wherein

16. M is represented by formula M-1; 【Chemistry 4】 During the ceremony, R ３ represents alkyl, haloalkyl or hydroxyalkyl; R ４ represents hydrogen, alkyl, haloalkyl, or hydroxyalkyl; R ５ and R ６ is independently selected from hydrogen, alkyl, halogen, haloalkyl, and hydroxyalkyl; R ７ represents thiazolyl which is unsubstituted or substituted with alkyl or haloalkyl, The compound of claim 1.

17. M-1 is represented by the formula M-1A or M-1B: 【Chemistry 5】 The compound according to claim 16, represented by:

18. M-1 is, 【Chemistry 6】 【Chemistry 7】 (In the formula, R ４ represents hydrogen; R ６ represents alkyl) 18. The compound according to claim 16 or 17, selected from:

19. M is represented by formula M-2; 【Chemistry 8】 During the ceremony, Z is oxazolilenyl, pyrazolilenyl, isoxazolilenyl or piperidinylenyl; R ８ represents alkyl, heteroalkyl, haloalkyl, or hydroxyalkyl; R ９ represents hydrogen, alkyl, haloalkyl, or hydroxyalkyl; R １０ and R １１ is independently selected from hydrogen, alkyl, halogen, heteroalkyl, haloalkyl, and hydroxyalkyl; R １２ represents thiazolyl which is unsubstituted or substituted with alkyl or haloalkyl, The compound of claim 1.

20. M-2 has the formula M-2A or M-2B: 【Chemistry 9】 The compound according to claim 19 ,

21. M-2 has the formula: 【Chemistry 10】 (In the formula, R ８ represents alkyl; R １１ represents hydrogen or alkyl; R １２ represents thiazolyl which is unsubstituted or substituted with alkyl or haloalkyl; 21. The compound according to claim 19 or 20,

22. M-2 is, 【Chemistry 11】 The compound according to any one of claims 19 to 21,

23. Formula (IA): 【Chemistry 12】 The compound according to claim 1 , wherein the compound is represented by the formula:

24. 24. The compound of claim 23, wherein Q is selected from amino and alkoxy.

25. R １ is halogen, alkyl, haloalkyl, alkoxy, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein said aryl and heteroaryl groups are unsubstituted or substituted with one or two substituents independently selected from oxo, hydroxy, alkoxy, halogen, and haloalkyl.

26. R ２ The compound according to any one of claims 23 to 25, wherein is hydrogen.

27. R ａ 27. The compound of any one of claims 23 to 26, wherein each occurrence independently represents a halogen.

28. L is a bond, -N(CH ３ )-CH ２ CH ２ -O-, -NH-CH ２ CH ２ -O-, -O-CH ２ -, -O-CH ２ -CH ２ -O-, -O-CH ２ CH ２ CH ２ CH ２ -C≡C-CH ２ -C≡C-CH ２ CH ２ -C≡C-CH ２ CH ２ CH ２ - 【Chemistry 13】 wherein each ring is unsubstituted or contains one or two R ｄ 28. The compound according to any one of claims 23 to 27, wherein

29. M is selected from M-1 and M-2; Z is oxazolilenyl, pyrazolilenyl, isoxazolilenyl or piperidinylenyl; R ３ and R ８ independently represents alkyl; R ４ and R ９ independently represent hydrogen or alkyl; R ５ , R ６ , R １０ and R １１ is independently selected from hydrogen and alkyl; R ７ and R １２ independently represents thiazolyl, which is unsubstituted or substituted with alkyl or haloalkyl; A compound according to any one of claims 23 to 28.

30. R ａ represents each occurrence independently a halogen; R １ is halogen, haloalkyl, alkoxy, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; wherein said aryl and heteroaryl groups are unsubstituted or substituted with one or two substituents independently selected from oxo, hydroxy, alkoxy, halogen, and haloalkyl; R ２ is hydrogen; Q is amino or alkoxy; L is a bond, -O-CH ２ -, -O-CH ２ CH ２ CH ２ CH ２ -, -O-CH ２ CH ２ -O-, -NH-CH ２ CH ２ -O-, -N(CH ３ )-CH ２ CH ２ -O-, -C≡C-CH ２ -, -C≡C-CH ２ CH ２ -, -C≡C-CH ２ CH ２ CH ２ - 【Chemistry 14】 wherein each ring is unsubstituted or contains one or two R ｄ substituted with; R ｄ is independently selected at each occurrence from alkyl, hydroxy and halogen; or any two R ｄ the groups together form an oxo group; M is selected from M-1 and M-2; Z is oxazolilenyl, pyrazolilenyl, isoxazolilenyl or piperidinylenyl; R ３ and R ８ independently represents alkyl; R ４ and R ９ independently represent hydrogen; R ５ , R ６ , R １０ and R １１ is independently selected from hydrogen and alkyl; R ７ and R １２ independently represents thiazolyl, which is unsubstituted or substituted with alkyl or haloalkyl; 30. The compound according to any one of claims 23 to 29.

31. Formula (IB): 【Chemistry 15】 The compound according to claim 1 , wherein the compound is represented by the formula:

32. R ａ 32. The compound of claim 31 , wherein each occurrence independently represents a halogen.

33. L is a bond, -O-CH ２ -, -O-CH ２ CH ２ CH ２ CH ２ -, -O-CH ２ CH ２ -O-, -NH-CH ２ CH ２ -O-, -N(CH ３ )-CH ２ CH ２ -O-, -C≡C-CH ２ -, -C≡C-CH ２ CH ２ -, -C≡C-CH ２ CH ２ CH ２ -, 【Chemistry 16】 wherein each ring is unsubstituted or contains one or two R ｄ 33. The compound of claim 31 or 32, wherein

34. M is selected from M-1 and M-2; Z is oxazolilenyl, pyrazolilenyl, isoxazolilenyl or piperidinylenyl; R ３ and R ８ independently represents alkyl; R ４ and R ９ independently represent hydrogen or alkyl; R ５ , R ６ , R １０ and R １１ is independently selected from hydrogen and alkyl; R ７ and R １２ independently represents thiazolyl, which is unsubstituted or substituted with alkyl or haloalkyl; A compound according to any one of claims 31 to 33.

35. R ａ represents each occurrence independently a halogen; R １ is halogen, haloalkyl, alkoxy, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; wherein said aryl and heteroaryl groups are unsubstituted or substituted with one or two substituents independently selected from hydroxy, alkoxy, halogen, and haloalkyl; L is a bond, -O-CH ２ -, -O-CH ２ CH ２ CH ２ CH ２ -, -O-CH ２ CH ２ -O-, -NH-CH ２ CH ２ -O-, -N(CH ３ )-CH ２ CH ２ -O-, -C≡C-CH ２ -, -C≡C-CH ２ CH ２ -, -C≡C-CH ２ CH ２ CH ２ - 【Chemistry 17】 wherein each ring is unsubstituted or contains one or two R ｄ substituted with; R ｄ is independently selected at each occurrence from alkyl, hydroxy and halogen; or any two R ｄ the groups together form an oxo group; M is selected from M-1 and M-2; Z is oxazolilenyl, pyrazolilenyl, isoxazolilenyl or piperidinylenyl; R ３ and R ８ independently represents alkyl; R ４ and R ９ independently represent hydrogen; R ５ , R ６ , R １０ and R １１ is independently selected from hydrogen and alkyl; R ７ and R １２ independently represents thiazolyl, which is unsubstituted or substituted with alkyl or haloalkyl; A compound according to any one of claims 31 to 34.

36. Formula (IC): 【Chemistry 18】 The compound according to claim 1 , wherein the compound is represented by the formula:

37. R ａ 37. The compound of claim 36, wherein represents a halogen.

38. L is a bond, -O-CH ２ -, -O-CH ２ CH ２ CH ２ CH ２ -, -O-CH ２ CH ２ -O-, -NH-CH ２ CH ２ -O-, -N(CH ３ )-CH ２ CH ２ -O-, -C≡C-CH ２ -, -C≡C-CH ２ CH ２ -, -C≡C-CH ２ CH ２ CH ２ -, 【Chemistry 19】 wherein each ring is unsubstituted or contains one or two R ｄ substituted with 38. A compound according to claim 36 or 37.

39. R ３ represents alkyl; R ６ is selected from hydrogen and alkyl; R ７ represents thiazolyl which is unsubstituted or substituted with alkyl or haloalkyl, 37. The compound of claim 36.

40. R １ is halogen, a 6- to 10-membered aryl, or a 5- to 10-membered heteroaryl; wherein said aryl and heteroaryl groups are unsubstituted or substituted with one or two substituents independently selected from hydroxy, alkoxy, halogen, and haloalkyl; R ａ represents alkyl; L is a bond, -O-CH ２ -, -O-CH ２ CH ２ CH ２ CH ２ -, -O-CH ２ CH ２ -O-, -NH-CH ２ CH ２ -O-, -N(CH ３ )-CH ２ CH ２ -O-, -C≡C-CH ２ -, -C≡C-CH ２ CH ２ -, -C≡C-CH ２ CH ２ CH ２ -, 【Chemistry 20】 wherein each ring is unsubstituted or contains one or two R ｄ substituted with; R ｄ is selected at each occurrence from alkyl, hydroxy and halogen; or any two R ｄ the groups together form an oxo group; R ３ represents alkyl; R ６ is selected from hydrogen and alkyl; R ７ represents thiazolyl which is unsubstituted or substituted with alkyl or haloalkyl, 40. The compound according to any one of claims 36 to 39.

41. Formula (ID): 【Chemistry 21】 The compound according to claim 1 , wherein the compound is represented by the formula:

42. L is a bond, -O-CH ２ CH ２ -O-, -NH-CH ２ CH ２ -O-, -N(CH ３ )-CH ２ CH ２ -O-, 【Chemical 22】 wherein each ring is unsubstituted or contains one or two R ｄ substituted with; R ｄ is independently selected at each occurrence from alkyl, hydroxy and halogen; or any two R ｄ The groups together form an oxo group, 42. The compound of claim 41.

43. Z is oxazolilenyl, pyrazolilenyl, isoxazolilenyl or piperidinylenyl; R ８ represents alkyl; R １１ is selected from hydrogen and alkyl; R １２ represents thiazolyl which is unsubstituted or substituted with alkyl or haloalkyl, 43. A compound according to claim 41 or 42.

44. R １ is halogen, a 6- to 10-membered aryl, or a 5- to 10-membered heteroaryl; wherein said aryl and heteroaryl groups are unsubstituted or substituted with one or two substituents independently selected from hydroxy, alkoxy, halogen, and haloalkyl; L is a bond, -O-CH ２ CH ２ -O-, -NH-CH ２ CH ２ -O-, -N(CH ３ )-CH ２ CH ２ -O-, 【Chemistry 23】 wherein each ring is unsubstituted or contains one or two R ｄ substituted with; R ｄ is independently selected from alkyl, hydroxy and halogen at each occurrence, or any two R ｄ the groups together form an oxo group; Z is oxazolilenyl, pyrazolilenyl, isoxazolilenyl or piperidinylenyl; R ８ represents alkyl; R １１ is selected from hydrogen and alkyl; R １２ represents thiazolyl which is unsubstituted or substituted with alkyl or haloalkyl, A compound according to any one of claims 41 to 43.

45. The compound according to any one of claims 1 to 44, 【Table 1】 【Table 2】 【Table 3】 【Table 4】 【Table 5】 【Table 6】 【Table 7】 【Table 8】 【Table 9】 【Table 10】 【Table 11】 【Table 12】 【Table 13】 【Table 14】 or a pharma- ceutically acceptable salt, or stereoisomer, or tautomer thereof.

46. 46. ​​A pharmaceutical composition comprising a compound according to any one of claims 1 to 45, or a pharma- ceutically acceptable salt or stereoisomer or tautomer thereof, and a pharmacologically acceptable carrier or excipient.

47. 47. The pharmaceutical composition of claim 46, for use in degrading a target protein in a subject, wherein the target protein is SMARCA2 and / or SMARCA4.

48. 48. The pharmaceutical composition for use according to claim 47, wherein the subject is afflicted with a disease or disorder dependent on at least one of SMARCA2 and SMARCA4.

49. The disease or disorder may include blood cancer, lung cancer (i.e., non-small cell lung cancer), acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain tumor, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cyst adenocarcinoma, leukemia, cyst adenocarcinoma ... Cancer, diffuse large B-cell lymphoma, hyperproliferative changes (dysplasia and hair growth), embryonal cancer, endometrial cancer, endothelial sarcoma, ependymoma, epithelial cancer, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, 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 refractory prostate cancer, leiomyosarcoma, leukemia, liposarcoma, liver cancer, lymphangiosarcoma endothelial sarcoma lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's; Burkitt's), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), oligodendroglioma, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary adenocarcinoma, 49. The pharmaceutical composition for use according to claim 47 or 48, wherein the cancer is selected from pinealoma, neoplastic erythrocytosis, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, malignant rhabdoid tumor (MRT), hilar myosinoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovial tumor, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer or Wilms' tumor.

50. 46. ​​A compound according to any one of claims 1 to 45, or a pharmacologically acceptable salt or stereoisomer or tautomer thereof, for use as a medicament.

51. 46. ​​A method for degrading a target protein in a subject, comprising administering to said subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 45, or a pharmacologically acceptable salt, or stereoisomer, or tautomer thereof.

52. 52. The method of claim 51 , wherein the target protein is SMARCA2 and / or SMARCA4.

53. A method for treating a disease or disorder dependent on at least one of SMARCA2 and SMARCA4 in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound described in any one of claims 1 to 45 or a pharmacologically acceptable salt, stereoisomer or tautomer thereof.

54. The diseases or disorders that are dependent on SMARCA2 and / or SMARCA4 include hematological cancers, lung cancer (i.e., non-small cell lung cancer), acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain tumor, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, Hematologic malignancies, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, hyperproliferative changes (dysplasia and hair loss), embryonal cancer, endometrial cancer, endothelial sarcoma, ependymoma, epithelial cancer, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, 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 refractory prostate cancer, leiomyosarcoma, leukemia , liposarcoma, liver cancer, lymphangiosarcoma endothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's; Burkitt's), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), oligodendroglioma, oral cancer, osteosarcoma, ovarian cancer, 54. The method of claim 53, wherein the cancer is selected from pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, neoplastic erythrocytosis, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, malignant rhabdoid tumor (MRT), hilar myosinoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovial tumor, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, or Wilms' tumor.

55. A compound according to any one of claims 1 to 45 for use in the treatment of a disease or disorder dependent on SMARCA2 and / or SMARCA4.

56. 56. The compound for use according to claim 55, wherein the disease or disorder dependent on SMARCA2 and / or SMARCA4 is cancer.

57. 50. Use of a compound according to any one of claims 1 to 45 or a pharma- ceutically acceptable salt or stereoisomer or tautomer thereof in the manufacture of a medicament for the treatment of a disease or disorder dependent on SMARCA2 and / or SMARCA4; wherein the disease or disorder is cancer.

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