Heterocyclic compounds as p300 degraders

Abstract

The present disclosure provides heterocyclic compounds of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or an isomer thereof as protein degraders. These compounds are useful in the treatment and / or prevention of diseases and / or disorders responsive to the degradation of target protein. Compounds of the present disclosure are especially useful for treating cancer, autoimmune, inflammatory, and neurodegenerative diseases and disorders. The present disclosure also provides processes for preparation of the compounds and pharmaceutical formulations comprising at least one of the compounds of formula (I) or a pharmaceutically acceptable salt, a solvate or an isomer thereof.

Description

[0001] HETEROCYCLIC COMPOUNDS AS P300 DEGRADERS

[0002] This application claims the benefit of Indian provisional application number 202441011166, filed on 17thFeb 2024; the specification of which is hereby incorporated by reference in its entirety.

[0003] FIELD OF THE INVENTION

[0004] The present disclosure provides a heterocyclic compound of formula (I') a pharmaceutically acceptable salt thereof, a solvate thereof or an isomer thereof. The disclosure also provides methods of preparation of the compound of formula (I'). Particularly, the present disclosure provides a compound of formula (I') useful for treating or preventing a disease or disorder responsive to the degradation of target proteins, preferably neurodegenerative disease, cancer, autoimmune and / or inflammatory disease, or disorder.

[0005] BACKGROUND OF THE INVENTION

[0006] EP300 (or p300) acts as histone acetyltransferase (HAT) and transcriptional adapter, thereby regulates transcription via chromatin remodelling and co-activator (Delvecchio et al., Nat Struct Mol Biol. 2013 Sep;20(9): 1040-6). Both histone and non-histone proteins are acetylated by p300. In addition to HAT function, p300 has crotonyl-transferase activities, and that p300-catalyzed histone crotonylation directly stimulates transcription to a greater degree (Sabari et al., Mol Cell. 2015 Apr 16;58(2):203-l). EP300 functions by scaffolding or as co-activator and enhancer of different transcription factors like HIFla, BRCA-1, p53, NFkB, c-Myc, PD-L1, Estrogen receptor (ER) and Androgen receptor (AR) (Pao et al. PNAS USA. 2000, 97, 1020).

[0007] Conventional CBP / p300 inhibitors do not discriminate between CBP and p300 proteins due to high homology. They show lesser than desirable efficacy in various cancer models within very well tolerated doses. A synthetic lethal relationship between these paralogs in cancer set up has been well established recently. Paralog targeting approach in recent time has been proved to be possible with degrader approach due to differentiated ternary complex formation. CBP mutation frequency is reported to be higher in several solid and hematological malignancies, for example, 10% to 15% of non-small cell and small cell lung cancers harbor loss-of-function aberrations in the CBP gene (Kishimoto et al. Clin Cancer Res 2005, 11 : 512 - 9; George et al. Nature 2015, 524:47 - 53). Targeting wild type paralogue, p300, by its selective degradation is expected to enhance efficacy in CBP-mutant or p300-dependent malignancies (Ogiwara et al., Cancer Discov (2016) 6 (4): 430-445). In prostate cancer, p300 plays a major role for androgen-dependent and -independent transactivation of the AR (Oncogene 2006 ;25(14):2011-21). Neuroblastoma cancer cells primarily depend on p300, not CBP, for their survival by regulating enhancer acetylation by interacting with TFAP2β, a transcription factor member of the lineage-defining transcriptional core regulatory circuitry (CRC) of neuroblastoma (Durbin et al., Cancer Discov 2022;12:730-51). By considering the above facts, p300 depletion will have a therapeutic advantage in PTEN-deficient, AR+ prostate, ER+ breast cancers and MYCN-amplified neuroblastoma, and also in the indications which are approved for immune checkpoint blockers (ICB) by governing the acetylation of PD-L1 directly (nuclear localization) and transcription of PD-L1 (histone acetylation at the promoter level) (Nat Cell Biol. 2020; 22(9): 1064-1075.; Pardoll and Drake, J Exp Med 2012; 209(2):201-9).

[0008] Selective degraders of p300 are expected to enhance efficacy of SOC drugs or immune checkpoint blockers by governing the acetylation and transcription of oncogenic factors and co-stimulatory molecules involved in tumor progression.

[0009] Therefore, selective degradation of p300 activity provides a promising route to the treatment of certain cancers. Accordingly, compounds that can degrade the activity of p300 are of interest in cancer therapy.

[0010] SUMMARY OF THE INVENTION

[0011] The present disclosure provides a compound of formula (I'), a pharmaceutically acceptable salt thereof, a solvate thereof or an isomer thereof, a pharmaceutical composition comprising a compound of formula (f) as an active ingredient, methods of production, and methods of use thereof. Particularly, the present disclosure provides a compound of formula (f) useful for treating or preventing a disease or disorder mediated by p300, preferably cancer, immune disorders, inflammatory diseases, viral infections, neurodegenerative diseases or metabolic disorders.

[0012] In one aspect, the present disclosure provides a compound of formula (I'): or pharmaceutically acceptable salts, solvates or isomers thereof, wherein;

[0013] R1represents hydrogen, (C1-C6)alkyl or (C3-C6)cycloalkyl;

[0014] R2and R3independently represents hydrogen or (C1-C6)alkyl;

[0015] R4represents hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, halogen or 5 to 12 membered heterocycloalkyl;

[0016] X1represents CRx1or N;

[0017] X2represents: i) -C(RaRb)-, -NRx2-, -O- or -S-; wherein Raand Rbare independently hydrogen or (C1-C6)alkyl; or ii) -C(Ra)- or N, when the ring having X2is aromatic; wherein Rais hydrogen or (C1-C6)alkyl;

[0018] X3represents C, CH or N;

[0019] X4represents C or N; R5represents hydrogen, halogen, cyano, (C1-C6)alkyl, halo(C1-C6)alkyl or (C1-C6)alkoxy;

[0020] Rx1represents hydrogen or (C1-C6)alkyl;

[0021] Rx2represents hydrogen, (C1-C6)alkyl or (C3-C6)cycloalkyl;

[0022] Ar represents 5- or 6-membered heteroaryl enyl or (C6-C12)arylenyl;

[0023] L1and L3independently represents a bond, -O-, -(CH2)P-, -(CH2)q-C(O)-NRc-, or - C(O)-NRc-(CH2)q-, wherein L1is attached with Ar, L3is attached with E, and any methylene group of -(CH2)qis optionally independently substituted with one or more Ra;

[0024] L2represents -(CH2)m-, 3- to 8- membered heterocycloalkylenyl, phenylenyl or (3- to 8-membered heterocycloalkylenyl)-L4-(3- to 8-membered heterocycloalkylenyl), wherein L4 is a bond, -(CH2)n- or -C(O)-; and one or more methylene group of - (CH2)m- is optionally replaced with -O- or optionally independently substituted with one or more Re;

[0025] Rcrepresents hydrogen or (C1-C6)alkyl;

[0026] Rdat each occurrence represents hydrogen, (C1-C6)alkyl or hydroxyl;

[0027] Reat each occurrence represents (C1-C6)alkyl, hydroxyl, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl or an amino acid sidechain; m is an integer ranging from 1 to 20; n is an integer ranging from 1 to 3; p is an integer ranging from 1 to 5; q is an integer ranging from 1 to 3; r is an integer ranging from 1 to 3;

[0028] E is selected from formulae E1, E2, E3, E4, E5, E6 or E7:

[0029] wherein, the asterisk marks the point of attachment with linker, L3;

[0030] R6represents hydrogen or hydroxyl-protecting group;

[0031] R7represents hydrogen or (C1-C6)alkyl; R8represents hydrogen, (C1-C6)alkyl or hydroxy(C1-C6)alkyl;

[0032] R9and R10independently represent hydrogen, (C1-C6)alkyl or halogen;

[0033] R11represents hydrogen, (C2-C6)alkynyl, halogen, cyano or 5-membered heteroaryl ring, wherein the heteroaryl is optionally substituted with Rf;

[0034] Rf represents (C1-C6)alkyl, halogen, hydroxyl, amino or halo(C1-C6)alkyl; and Z represents 5-6 membered heterocycloalkylenyl or 5-6 membered heteroarylenyl.

[0035] In another aspect, the present disclosure provides a compound of formula (I): or pharmaceutically acceptable salts, solvates or isomers thereof.

[0036] In another aspect, the present disclosure provides heterocyclic compounds of formula (I) or pharmaceutically acceptable salts, solvates or isomers thereof, wherein;

[0037] R1represents hydrogen, (C1-C6)alkyl or (C3-C6)cycloalkyl;

[0038] R2and R3independently represents hydrogen or (C1-C6)alkyl(C1-C6)alkyl; R4represents hydrogen, (C1-C6)alkyl(C1-C6)alkyl, (C1-C6)alkoxy, halogen or 5 to 12 membered heterocycloalkyl; X1 represents CH or N;

[0039] X2 represents -C(RaRb)-, -NRX2-, -O- or -S-; wherein Raand Rbare independently hydrogen or (C1-C6)alkyl; R5represents hydrogen, halogen, cyano, (C1-C6)alkyl, halo(C1-C6)alkyl or (C1- C6)alkoxy; Rx2represents hydrogen, (C1-C6)alkyl or (C3-C6)cycloalkyl;

[0040] Ar represents 5- or 6-membered heteroaryl enyl or (C6-C12)arylenyl;

[0041] L1 and L3 independently represents a bond, -O-, -(CH2)P-, -(CH2)q-C(O)-NRc- or - C(O)-NRc-(CH2)q-, wherein L1 is attached with Ar, L3 is attached with E, and any methylene group of -(CH2)qis optionally substituted with one or more Rd; L2 represents -(CH2)m-, 3- to 8- membered heterocycloalkylenyl, phenylenyl or (3- to 8-membered heterocycloalkylenyl)-L4-(3- to 8-membered heterocycloalkylenyl), wherein L4is a bond, -(CH2)n- or -C(O)-; and one or more methylene group of - (CH2)m- is optionally replaced with -O- or optionally independently substituted with one or more Re;

[0042] Rcrepresents hydrogen or (C1-C6)alkyl;

[0043] Rdrepresents hydrogen or (C1-C6)alkyl;

[0044] Rerepresents (C1-C6)alkyl, hydroxyl, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl or an amino acid side chain; m is an integer ranging from 1 to 20; n is an integer ranging from 1 to 3; p is an integer ranging from 1 to 5; q is an integer ranging from 1 to 3;

[0045] E is selected from formulae E1, E2, E3, E4, E5, E6 or E7:

[0046] wherein, the asterisk marks the point of attachment with Linker, L3; R6represents hydrogen or hydroxyl-protecting group;

[0047] R7represents hydrogen or (C1-C6)alkyl; R8represents hydrogen, (C1-C6)alkyl or hydroxy(C1-C6)alkyl;

[0048] R9and R10independently represent hydrogen or halogen;

[0049] R11represents hydrogen, (C2-C6)alkynyl, halogen, cyano or 5-membered heteroaryl ring wherein the heteroaryl is optionally substituted with Rf;

[0050] Rfrepresents (C1-C6)alkyl, hydroxyl, amino or halo(C1-C6)alkyl, and

[0051] Z represents 5-membered heteroaryl enyl.

[0052] The present disclosure may involve one or more of the following embodiments associated with the compound of formula (I'). For example, in one embodiment, there is provided a compound of formula (I'), a pharmaceutically acceptable salt thereof, a solvate thereof, or an isomer thereof, wherein Ar represents 5- or 6-membered heteroaryl enyl. In another embodiment, Ar represents (C6-C12)arylenyl.

[0053] In another embodiment, the present disclosure provides a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or an isomer thereof, wherein Ar represents 5- or 6-membered heteroarylenyl. In another embodiment, Ar represents (C6-C12)arylenyl.

[0054] In another embodiment, there is provided a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or an isomer thereof, wherein L1-L2-L3represents: -CH2-, -CH(CH(CH3)2)-, -CH2-CH2-, -CH2-CH2- CH2-, -CH2-(CH2)3-CH2-, -CH2-(CH2)4-CH2-, -CH2-(CH2)6-CH2-, -CH2-(CH2)7- CH2-, -CH2-(CH2)5-CH2-, -CH2-(CH2)8-CH2-, -CH2-(CH2)9-CH2-, -CH2-(CH2)12- CH2-, -O-CH2-(CH2)4-CH2-, -O-CH2-(CH2)5-CH2-, -O-CH2-(CH2)6-CH2-, -CH2- (CH2)5-CH2-O-, -CH2-(CH2)6-CH2-O-, -CH2-(CH2)7-CH2-O-, -CH2-CH2-O- (CH2)2-O-CH2-CH2-, -CH2-CO-NH-CH2-CH2-, -CH2-(CH2)7-CO-N(CH3)- CH(CH3)-, -CH2-(CH2)10-CO-N(CH3)-CH(CH3)-, -CH2-CO-NH-(CH2)4-CH2-, - CH2-CO-NH-(CH2)7-CH2-, -CH2-CO-NH-(CH2)10-CH2-, -CH2-CO-NH-(CH2)13- CH2-,

[0055] wherein, the asterisk marks the point of attachment with Ar.

[0056] In another embodiment, there is provided a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or an isomer thereof, wherein R1represents (C1-C6)alkyl.

[0057] In another embodiment, there is provided a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or an isomer thereof, wherein R2represents (C1-C6)alkyl.

[0058] In another embodiment, there is provided a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or an isomer thereof, wherein R3represents hydrogen.

[0059] In another embodiment, there is provided a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or an isomer thereof, wherein R4represents hydrogen.

[0060] In another embodiment, there is provided a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or an isomer thereof, wherein R4represents (C1-C6)alkoxy.

[0061] In another embodiment, there is provided a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or an isomer thereof, wherein R4represents halogen.

[0062] In another embodiment, there is provided a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or an isomer thereof, wherein R4represents 5 to 6 membered heterocycloalkyl. In another embodiment, there is provided a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or an isomer thereof, wherein R5represents hydrogen, halogen, cyano, or halo(C1-C6)alkyl.

[0063] In another embodiment, there is provided a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or an isomer thereof, wherein R5represents halo(C1-C6)alkyl.

[0064] In another embodiment, there is provided a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or an isomer thereof, wherein X1represents CH.

[0065] In another embodiment, there is provided a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or an isomer thereof, wherein X2represents -C(RaRb)-, wherein Raand Rbare hydrogen.

[0066] In another embodiment, there is provided a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or an isomer thereof, wherein X2represents -NRx2- wherein RX2is (C1-C6)alkyl.

[0067] In another embodiment, there is provided a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or an isomer thereof, wherein X2represents -O-.

[0068] In another embodiment, there is provided a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or an isomer thereof, wherein:

[0069] R6represents hydrogen,

[0070] R7represents (C1-C6)alkyl;

[0071] R8represents (C1-C6)alkyl or hydroxy(C1-C6)alkyl;

[0072] R9and R10represent halogen; and

[0073] R11represents 5-membered heteroaryl ring. In another embodiment, there is provided a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or an isomer thereof, wherein Re represents hydrogen.

[0074] In another embodiment, there is provided a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or an isomer thereof, wherein R7represents (C1-C6)alkyl.

[0075] In another embodiment, there is provided a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or an isomer thereof, wherein R8represents (C1-C6)alkyl or hydroxy(C1-C6)alkyl.

[0076] In another embodiment, there is provided a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or an isomer thereof, wherein R8represents hydrogen.

[0077] In another embodiment, there is provided a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or an isomer thereof, wherein R8represents (C1-C6)alkyl.

[0078] In another embodiment, there is provided a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or an isomer thereof, wherein R8represents hydroxy(C1-C6)alkyl.

[0079] In another embodiment, there is provided a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or an isomer thereof, wherein R9and R10independently represent halogen.

[0080] In another embodiment, there is provided a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or an isomer thereof, wherein R11represents (C2-C6)alkynyl.

[0081] In another embodiment, there is provided a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or an isomer thereof, wherein R11represents 5-membered heteroaryl ring. In another embodiment, there is provided a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or an isomer thereof, wherein R11represents halogen or cyano. In another embodiment, there is provided a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or an isomer thereof, wherein R11represents 5-membered heteroaryl ring optionally substituted with Rf, wherein Rf represents (C1-C6)alkyl. In another embodiment, there is provided a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or an isomer thereof, wherein Z represents 5-membered heteroarylenyl.

[0082] In another embodiment, there is provided a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or an isomer thereof, wherein Z represents 5-membered heteroarylenyl selected from:

[0083] One embodiment of the present disclosure provides a compound of formula (I') or (I), selected from the below table 1 :

[0084] Table 1: or a pharmaceutically acceptable salt thereof.

[0085] In an aspect is provided a pharmaceutical composition comprising a compound of formula (I), a pharmaceutically acceptable salt, solvate or isomer thereof and at least one pharmaceutically acceptable excipient. In another aspect, the disclosure provides a pharmaceutical composition comprising a compound of formula (I'), a pharmaceutically acceptable salt, solvate or isomer thereof and at least one pharmaceutically acceptable excipient. In an aspect is provided a pharmaceutical composition comprising a compound of formula (I') or (I), or a pharmaceutically acceptable salt, solvate or isomer thereof for treating a disease or disorder responsive to the degradation of target protein.

[0086] In an aspect is provided the use of a compound of formula (I') or (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, in the manufacture of a medicament for the treatment of disease or disorder responsive to the degradation of the target protein.

[0087] In an aspect is provided the use of a compound of formula (I') or (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, in the manufacture of a medicament for the treatment of neurodegenerative disease, cancer, autoimmune and / or inflammatory disease or disorder.

[0088] In an aspect is provided a method of treating or preventing a disease or disorder responsive to the degradation of target protein, which method comprises administering to a subject in need thereof a therapeutically effective amount of a compound formula (I') or (I) or a pharmaceutically acceptable salt, solvate or isomer thereof.

[0089] In an aspect is provided a method of treating or preventing neurodegenerative disease, cancer, autoimmune and / or inflammatory disease or disorder, wherein the degradation of target protein is implicated, which method comprises administering to a subject in need thereof a therapeutically effective amount of a compound formula (I') or (I) or a pharmaceutically acceptable salt, solvate or isomer thereof.

[0090] In an aspect is provided a method for the preparation of a compound of formula (I') or (I).

[0091] DETAILED DESCRIPTION OF THE INVENTION

[0092] The afore mentioned embodiments and other aspects, objects, features, and advantages of the present disclosure will be apparent from the following detailed description. The embodiment provided hereinafter is by way of explanation of the disclosure and not by way of limitation of the disclosure . In fact, 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 disclosure . Thus, it is intended that the present disclosure includes such modifications and variations and their equivalents. It is to be understood by one of ordinary skill in the art that the present discussion is a description of exemplary embodiments only and is not to be construed as limiting the broader aspects of the present disclosure . It should also be understood that unless expressly stated to the contrary, "a compound of general formula (I') or (I)" refers to and includes any and all compounds described by formula (I') or (I), its embodiments, as well as sub-genus(es), inclusive of all salts, solvates and isomers thereof.

[0093] According to first aspect of the present disclosure, there is provided a compound of formula (I'), or pharmaceutically acceptable salts, solvates or isomers thereof, wherein;

[0094] R1represents hydrogen, (C1-C6)alkyl or (C3-C6)cycloalkyl;

[0095] R2and R3independently represents hydrogen or (C1-C6)alkyl; R4represents hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, halogen or 5 to 12 membered heterocycloalkyl; X1represents CRx1or N;

[0096] X2represents: i) -C(RaRb)-, -NRx2-, -O- or -S-; wherein Raand Rbare independently hydrogen or (C1-C6)alkyl; or ii) -C(Ra)- or N, when the ring having X2is aromatic; wherein Rais hydrogen or (C1-C6)alkyl;

[0097] X3represents C, CH or N;

[0098] X4represents C or N;

[0099] R5represents hydrogen, halogen, cyano, (C1-C6)alkyl, halo(C1-C6)alkyl or (C1- C6)alkoxy;

[0100] Rx1 represents hydrogen or (C1-C6)alkyl;

[0101] Rx2 represents hydrogen, (C1-C6)alkyl or (C3-C6)cycloalkyl;

[0102] Ar represents 5- or 6-membered heteroaryl enyl or (C6-C12)arylenyl;

[0103] L1and L3independently represents a bond, -O-, -(CH2)p-, -(CH2)q-C(O)-NRc-, or - C(O)-NRc-(CH2)q-, wherein L1is attached with Ar, L3is attached with E, and any methylene group of -(CH2)qis optionally independently substituted with one or more Rd;

[0104] L2represents -(CH2)m-, 3- to 8- membered heterocycloalkylenyl, phenylenyl or (3- to 8-membered heterocycloalkylenyl)-L4-(3- to 8-membered heterocycloalkylenyl), wherein L4 is a bond, -(CH2)n- or -C(O)-; and one or more methylene group of - (CH2)m- is optionally replaced with -O- or optionally independently substituted with one or more Re;

[0105] Rcrepresents hydrogen or (C1-C6)alkyl;

[0106] Rdat each occurrence represents hydrogen, (C1-C6)alkyl or hydroxyl;

[0107] Reat each occurrence represents (C1-C6)alkyl, hydroxyl, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl or an amino acid sidechain; m is an integer ranging from 1 to 20; n is an integer ranging from 1 to 3; p is an integer ranging from 1 to 5; q is an integer ranging from 1 to 3; r is an integer ranging from 1 to 3; E is selected from formulae E1, E2, E3, E4, E5, E6 or E7: wherein, the asterisk marks the point of attachment with linker, L3;

[0108] R6represents hydrogen or hydroxyl-protecting group; R7represents hydrogen or (C1-C6)alkyl;

[0109] R8represents hydrogen, (C1-C6)alkyl or hydroxy(C1-C6)alkyl;

[0110] R9and R10independently represent hydrogen, (C1-C6)alkyl or halogen;

[0111] R11represents hydrogen, (C2-C6)alkynyl, halogen, cyano or 5-membered heteroaryl ring, wherein the heteroaryl is optionally substituted with Rf; Rf represents (C1-C6)alkyl, halogen, hydroxyl, amino or halo(C1-C6)alkyl; and

[0112] Z represents 5-6 membered heterocycloalkylenyl or 5-6 membered heteroarylenyl.

[0113] According to another aspect of the present disclosure, there is provided a compound of formula (I), or pharmaceutically acceptable salts, solvates or isomers thereof, wherein;

[0114] R1represents hydrogen, (C1-C6)alkyl or (C3-C6)cycloalkyl;

[0115] R2and R3independently represents hydrogen or (C1-C6)alkyl; R4represents hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, halogen or 5 to 12 membered heterocycloalkyl;

[0116] X1represents CH or N;

[0117] X2represents -C(RaRb)-, -NRX2-, -O- or -S-; wherein Raand Rbare independently hydrogen or (C1-C6)alkyl; R5represents hydrogen, halogen, cyano, (C1-C6)alkyl, halo(C1-C6)alkyl or (C1- C6)alkoxy;

[0118] Rx2 represents hydrogen, (C1-C6)alkyl or (C3-C6)cycloalkyl;

[0119] Ar represents 5- or 6-membered heteroaryl enyl or (C6-C12)arylenyl;

[0120] L1and L3independently represents a bond, -O-, -(CH2)p-, -(CH2)q-C(O)-NRc- or - C(O)-NRc-(CH2)q-, wherein L1is attached with Ar, L3is attached with E, and any methylene group of -(CH2)qis optionally substituted with one or more Rd;

[0121] L2represents -(CH2)m-, 3- to 8- membered heterocycloalkylenyl, phenylenyl or (3- to 8-membered heterocycloalkylenyl)-L4-(3- to 8-membered heterocycloalkylenyl), wherein L4is a bond, -(CH2)n- or -C(O)-; and one or more methylene group of - (CH2)m- is optionally replaced with -O- or optionally independently substituted with one or more Re;

[0122] Rcrepresents hydrogen or (C1-C6)alkyl;

[0123] Rdrepresents hydrogen or (C1-C6)alkyl; Rerepresents (C1-C6)alkyl, hydroxyl, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl or an amino acid side chain; m is an integer ranging from 1 to 20; n is an integer ranging from 1 to 3; p is an integer ranging from 1 to 5; q is an integer ranging from 1 to 3;

[0124] E is selected from formulae E1, E2, E3, E4, E5, E6 or E7:

[0125] wherein, the asterisk marks the point of attachment with Linker L3; R6represents hydrogen or hydroxyl-protecting group;

[0126] R7represents hydrogen or (C1-C6)alkyl; R8represents hydrogen, (C1-C6)alkyl or hydroxy(C1-C6)alkyl;

[0127] R9and R10independently represent hydrogen or halogen;

[0128] R11represents hydrogen, (C2-C6)alkynyl, halogen, cyano or 5-membered heteroaryl ring, wherein the heteroaryl is optionally substituted with Rf; Rf represents (C1-C6)alkyl, hydroxyl, amino or halo(C1-C6)alkyl, and

[0129] Z represents 5-membered heteroaryl enyl.

[0130] In some embodiments, the compound of formula (I) has the following formulae: or a pharmaceutically acceptable salt, a solvate or an isomer thereof, wherein: R1, R2, R3, R4, R5, X1, X2, Ar, L1, L2, L3and E are as defined in compounds of formula (I). In some embodiments, the compound of formula (I) has the following formulae: or a pharmaceutically acceptable salt, a solvate or an isomer thereof, wherein: R1, R2, R3, R4, R5, X1, X2, L1, L2, L3and E are as defined in compounds of formula (I).

[0131] In some embodiments, the compound of formula (I) has the following formulae (IA):

[0132] or a pharmaceutically acceptable salt, a solvate or an isomer thereof.

[0133] In some embodiments, the compound of formula (I) has the following formulae (IB): or a pharmaceutically acceptable salt, a solvate or an isomer thereof.

[0134] In some embodiments, the compound of formula (I) has the following formulae (IC):

[0135] or a pharmaceutically acceptable salt, a solvate or an isomer thereof.

[0136] In certain embodiments, formula (IA) has the following formulae:

[0137] or a pharmaceutically acceptable salt, a solvate or an isomer thereof, wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, X1, X2, L1, L2and L3are as defined in compounds of formula (I).

[0138] In certain embodiments, formula (IB) has the following formulae:

[0139]

[0140]

[0141] or a pharmaceutically acceptable salt, a solvate or an isomer thereof, wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, X1, X2, L1, L2and L3are as defined in compounds of formula (I).

[0142] In certain embodiments, the compounds of the present disclosure have the following formulae:

[0143]

[0144] or a pharmaceutically acceptable salt, a solvate or an isomer thereof, wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, X1, X2, L1, L2and L3are as defined in compounds of formula (I).

[0145] According to certain foregoing embodiments, the compounds may involve one or more of the following embodiments.

[0146] In one embodiment, R1represents hydrogen or (C1-C6)alkyl.

[0147] In yet another embodiment, R1represents (C1-C6)alkyl. In yet another embodiment, R1represents (C3-C6)cycloalkyl.

[0148] In another embodiment, R2and R3independently represents hydrogen or (C1-C6)alkyl.

[0149] In yet another embodiment, R2represents (C1-C6)alkyl.

[0150] In yet another embodiment, R3represents hydrogen. In another embodiment, R4represents hydrogen, halogen, (C1-C6)alkyl, (C1- C6)alkoxy or 5 to 12 membered heterocycloalkyl.

[0151] In yet another embodiment, R4represents (C1-C6)alkoxy.

[0152] In one embodiment, R4represents 5 to 10 membered heterocycloalkyl.

[0153] In one embodiment, R4represents 5 to 6 membered heterocycloalkyl.

[0154] In another embodiment, the 5 to 6 membered heterocycloalkyl is tetrahydropyran.

[0155] In one embodiment, R5represents hydrogen.

[0156] In one embodiment, R5represents halogen or cyano. In one embodiment, R5represents (C1-C6)alkyl or (C1-C6)alkoxy.

[0157] In one embodiment, R5represents halo(C1-C6)alkyl.

[0158] According to the preceding embodiment, the halo(C1-C6)alkyl is difluoromethyl or trifluoromethyl.

[0159] In another embodiment, R5represents cyano.

[0160] In another embodiment, R6represents hydrogen.

[0161] In another embodiment, R7represents hydrogen.

[0162] In yet another embodiment, R7represents (C1-C6)alkyl.

[0163] In another embodiment, R8represents hydrogen.

[0164] In yet another embodiment, R8represents (C1-C6)alkyl

[0165] In yet another embodiment, R8represents hydroxy(C1-C6)alkyl.

[0166] In another embodiment, R9and R10represent halogen.

[0167] In another embodiment, R9and R10represent hydrogen.

[0168] In another embodiment, R11represents hydrogen or (C2-C6)alkynyl.

[0169] In some embodiments, R11is ethynyl.

[0170] In another embodiment, R11represents (C2-C6)alkynyl. In yet another embodiment, R11represents halogen or cyano.

[0171] In yet another embodiment, R11represents 5-membered heteroaryl ring optionally substituted with (C1-C6)alkyl.

[0172] In one embodiment, Z represents 5-membered heteroaryl enyl selected from, but not limited to:

[0173] In one embodiment, X1represents CRx1.

[0174] In one embodiment, X1is CH and X2is -C(RaRb)-, -NRx2- or -O-; wherein Ra, Rband Rx2independently represent hydrogen or (C1-C6)alkyl.

[0175] In one embodiment, X1is N and X2is -C(RaRb)-; wherein Ra and Rb are hydrogen.

[0176] In one embodiment, X1represents CH or N.

[0177] In some embodiments, CRx1is CH. In some embodiments, Xi is N.

[0178] In another embodiment, X2represents -C(RaRb)-, wherein Raand Rbare hydrogen.

[0179] In yet another embodiment, Raand Rb are ( C1-C6)alkyl

[0180] In yet another embodiment, X2represents -C(RaRb)-, -NRx2-, -O- or -S-; wherein Raand Rbare independently hydrogen or (C1-C6)alkyl.

[0181] In yet another embodiment, X2represents -C(Ra)- or N, when the ring having X2is aromatic; wherein Rais hydrogen or (C1-C6)alkyl.

[0182] In one embodiment, the ring having X2is aromatic.

[0183] In one embodiment, the ring having X2is not aromatic.

[0184] In one embodiment, the phrase “the ring having X2” and the phrase “the ring having X3” refer to the same ring. In yet another embodiment, X2represents CH and the ring having X2is aromatic. In some embodiments, X2is CH and X3is C when the ring having X2is aromatic. In some embodiments, X2is CH, X3is C and X4is N, when the ring having X2is aromatic.

[0185] In yet another embodiment, X2represents -NRX2, wherein RX2represents (C1-C6)alkyl.

[0186] In yet another embodiment, X2represents -O- or -S-.

[0187] In one embodiment, X3represents CH.

[0188] In one embodiment, X3represents N.

[0189] In one embodiment, X3represents C, and the ring having X3is aromatic.

[0190] In one embodiment, X4represents C. In one embodiment, X4represents N.

[0191] In one embodiment, X4represents C and R5represents (C1-C6)alkyl or (C1- C6)alkoxy. In one embodiment, X4represents C and R5represents (C1-C6)alkoxy.

[0192] In one embodiment, L1and L3independently represents a bond, -O-, - (CH2)p-, -(CH2)q-C(O)-NRc- or -C(O)-NRc-(CH2)q-, wherein L1is attached with Ar, L3is attached with E, and any methylene group of -(CH2)qis optionally substituted with one or more Rd.

[0193] In yet another embodiment, L2represents -(CH2)m-, 3- to 8- membered heterocycloalkylenyl, phenylenyl or (3- to 8-membered heterocycloalkyl enyl)-L4- (3- to 8-membered heterocycloalkylenyl), wherein L4is a bond, -(CH2)n- or -C(O)- ; and one or more methylene group of -(CH2)m- is optionally replaced with -O- or optionally independently substituted with one or more Re.

[0194] In yet another embodiment, L1and L3are each bond.

[0195] In yet another embodiment, when L3is a bond, L2is attached with E.

[0196] In yet another embodiment, when L1is a bond, L2is attached with Ar.

[0197] In one embodiment, L1-L2-L3together represents: -CH2-, -(CH2)2-, -(CH2)3-, -CH2-(CH2)2-CH2-, -CH2-(CH2)3-CH2-, -CH2-(CH2)4- CH2-,-CH2-(CH2)5-CH2-, -CH2-(CH2)6-CH2-, -CH2-(CH2)7-CH2-, -CH2-(CH2)8- CH2-, -CH2-(CH2)9-CH2-, -CH2-(CH2)10-CH2-, -CH2-(CH2)11-CH2-, -CH2-(CH2)12- CH2-, -CH2-(CH2)13-CH2-, -CH2-(CH2)14-CH2-, -CH2-(CH2)15-CH2-, -CH2- (CH2)16-CH2-, -CH2-(CH2)17-CH2-, -CH2-(CH2)18-CH2-, -CH(CH(CH3)2)-, -CH2- CH(CH(CH3)2)-CH2-, -CH2-C(CH(CH3)3)-CH2-, -CH2-CH(CH(CH3)2)-CH2- CH2- , CH(CH3)-(CH(CH3))2-CH(CH3)-, -CH2-CH(C(CH3)3)-CH2-CH2-, -CH2-

[0198] (CH(CH3)2)-(CH2)2-CH2, -CH2-(CH2-CH(CH(CH3)2)CH2)-CH2-, -CH2-(CH(CH3)- CH(CH(CH3)2)-CH(CH3)-CH2-, -CH2-CH(CH(CH3)2)-(CH2)3-CH2-, -CH2-CH2- CH(CH3)2-(CH2)2-CH2-, -CH2-(CH2)2-CH(CH(CH3)2)-CH(CH3)-CH2-, -CH(CH3)- (CH(CH3))5-CH(CH3)-, -CH(CH(CH3)2)-CH(CH3)-(CH2)3-CH2- or -CH2-CH2- CH(CH(CH3)2)-(CH(CH3))2-CH2-CH2-.

[0199] In another embodiment, L1-L2-L3together represents:

[0200] -O-, *-O(CH2)-, *-O(CH2)2-, *-O(CH2)3-, *-OCH2-(CH2)2-CH2-, *-OCH2-(CH2)3- CH2-, *-OCH2-(CH2)4-CH2-,*-OCH2-(CH2)5-CH2-, *-OCH2-(CH2)6-CH2-, *- OCH2-(CH2)7-CH2-, *-OCH2-(CH2)8-CH2-, *-OCH2-(CH2)9-CH2-, *-OCH2- (CH2)10-CH2-, *-OCH2-(CH2)11-CH2-, *-OCH2-(CH2)12-CH2-, *-OCH2-(CH2)13- CH2-, *-OCH2-(CH2)14-CH2-, *-OCH2-(CH2)15-CH2-, *-OCH2-(CH2)16-CH2-, *- OCH2-(CH2)17-CH2-, *-OCH2-(CH2)18-CH2-, *-CH2O-, *-CH2-CH2-O-, *-CH2- (CH2)2-O-, *-CH2-(CH2)3-O-, *-CH2-(CH2)4-O-, *-CH2-(CH2)5-O-,*-CH2-(CH2)6- O-, *-CH2-(CH2)7-O-, *-CH2-(CH2)8-O, *-CH2-(CH2)9-O-, *-CH2-(CH2)10-O -, *- CH2-(CH2)11-O-, *-CH2-(CH2)12-O-, *-CH2-(CH2)13-O-, *-CH2-(CH2)14-O-, *- CH2-(CH2)15-O-, *-CH2-(CH2)17-O-, *-CH2-(CH2)18-O-, *-CH2-O-CH2-, *-CH2- CH2-O-CH2-, *-CH2-CH2-O-CH2-CH2-, *-CH2-CH2-O-CH2-CH2-O-, -CH2-CH2- O-(CH2)2-O-CH2-, *-CH2-CH2-O-(CH2)2-O-CH2-CH2-, *-CH2-CH2-O-(CH2)2-O- (CH2)2-O-, *-CH2-CH2-O-(CH2)2-O-(CH2)2-O-CH2-, *-CH2-CH2-O-(CH2)2-O- (CH2)2-O-CH2-CH2-,* -CH2-CH2-O-(CH2)2-O-(CH2)2-O-CH2-CH2-O-, *-CH2- CH2-O-(CH2)2-O-(CH2)2-O-(CH2)2-O-CH2-, *-CH2-CH2-O-(CH2)2-O-(CH2)2-O- (CH2)2-O-CH2-CH2, *-CH2-CH2-O-(CH2)2-O-(CH2)2-O-(CH2)2-O-CH2-CH2-O-, *-CH2-CH2-O-(CH2)2-O-(CH2)2-O-(CH2)2-O-CH2-CH2-O-CH2, *-CH2-CH2-O- (CH2)2-O-(CH2)2-O-(CH2)2-O-CH2-CH2-O-CH2-CH2-, *-CH2-CH2-O-(CH2)2-O- (CH2)2-O-(CH2)2-O-CH2-CH2-O-(CH2)2O-, *-CH2-CH2-O-(CH2)2-O-(CH2)2-O-

[0201] (CH2)2-O-CH2-CH2-O-(CH2)2O-CH2- or *-CH2-CH2-O-(CH2)2-O-(CH2)2-O- (CH2)2-O-CH2-CH2-O-(CH2)2O-CH2-CH2-. wherein, the asterisk marks the point of attachment with Ar.

[0202] In yet another embodiment, L1-L2-L3together represents:

[0203] *-CH2-CO-NH-CH2-, *-CH2-CO-NH-CH2-CH2-, *-CH2-CO-NH-(CH2)2-CH2-, *- CH2-CO-NH-(CH2)3-CH2-, *-CH2-CO-NH-(CH2)4-CH2-, *-CH2-CO-NH-(CH2)5- CH2-, *-CH2-CO-NH-(CH2)6-CH2-, *-CH2-CO-NH-(CH2)6-CH2-, *-CH2-CO-NH- (CH2)7-CH2-, *-CH2-CO-NH-(CH2)8-CH2-, *-CH2-CO-NH-(CH2)9-CH2-, *-CH2- CO-NH-(CH2)10-CH2-,*-CH2-CO-NH-(CH2)1 1-CH2-,*-CH2-CO-NH-(CH2)12- CH2-, *-CH2-CO-NH-(CH2)13-CH2-,*-CH2-CO-NH-(CH2)14-CH2-, *-CH2-CO- NH-(CH2)15-CH2-, *-CH2-CO-NH-(CH2)16-CH2-, *-CH2-CO-NH-(CH2)17-CH2-, *- CH2-CO-NH-(CH2)18-CH2-, *-CH2-CO-NH-(CH2)19-CH2-, *-CH2-CH2-CO-NH- CH2-, *-CH2-CH2-CO-NH-CH2-CH2-, *-CH2-CH2-CO-NH-(CH2)2-CH2-, *-CH2- CH2-CO-NH-(CH2)3-CH2-, *-CH2-CH2-CO-NH-(CH2)4-CH2-, *-CH2-CH2-CO- NH-(CH2)5-CH2-, *-CH2-CH2-CO-NH-(CH2)6-CH2-, *-CH2-CH2-CO-NH-(CH2)6- CH2-, *-CH2-CH2-CO-NH-(CH2)7-CH2-, *-CH2-CH2-CO-NH-(CH2)8-CH2-, *- CH2-CH2-CO-NH-(CH2)9-CH2-, *-CH2-CH2-CO-NH-(CH2)10-CH2-, *-CH2-CH2- CO-NH-(CH2)11-CH2-, *-CH2-CH2-CO-NH-(CH2)12-CH2-, *-CH2-CH2-CO-NH- (CH2)13-CH2-, *-CH2-CH2-CO-NH-(CH2)14-CH2-, *-CH2-CH2-CO-NH-(CH2)15- CH2-, *-CH2-CH2-CO-NH-(CH2)16-CH2-,* -CH2-CH2-CO-NH-(CH2)17-CH2-, *- CH2-CH2-CO-NH-(CH2)18-CH2-, *-CH2-CH2-CO-NH-(CH2)19-CH2-, *-CH2-

[0204] (CH2)2-CO-NH-CH2-, *-CH2-(CH2)2-CO-NH-CH2-CH2-, *-CH2-(CH2)2-CO-NH- (CH2)2-CH2-, *-CH2-(CH2)2-CO-NH-(CH2)3-CH2-, *-CH2-(CH2)2-CO-NH-(CH2)4- CH2-, *-CH2-(CH2)2-CO-NH-(CH2)5-CH2-, *-CH2-(CH2)2-CO-NH-(CH2)6-CH2-, *-CH2-(CH2)2-CO-NH-(CH2)6-CH2-, *-CH2-(CH2)2-CO-NH-(CH2)7-CH2-, *-CH2- (CH2)2-CO-NH-(CH2)8-CH2-, *-CH2-(CH2)2-CO-NH-(CH2)9-CH2-, *-CH2-(CH2)2- CO-NH-(CH2)10-CH2-, *-CH2-(CH2)2-CO-NH-(CH2)11-CH2-, *-CH2-(CH2)2-CO- NH-(CH2)12-CH2-, *-CH2-(CH2)2-CO-NH-(CH2)13-CH2-, *-CH2-(CH2)2-CO-NH- (CH2)14-CH2-, *-CH2-(CH2)2-CO-NH-(CH2)15-CH2-, *-CH2-(CH2)2-CO-NH-

[0205] (CH2)16-CH2-, *-CH2-(CH2)2-CO-NH-(CH2)17-CH2-, *-CH2-(CH2)2-CO-NH-

[0206] (CH2)18-CH2-, *-CH2-(CH2)2-CO-NH-(CH2)19-CH2-, wherein, the asterisk marks the point of attachment with Ar.

[0207] In yet another embodiment, Li-L2-L3represents:

[0208] *-CH2-CO-N(CH3)-CH2-, *-CH2-CH2-CO-N(CH3)-CH2-, *-CH2-(CH2)2-CO-

[0209] N(CH3)-CH2-, *-CH2-(CH2)3-CO-N(CH3)-CH2-, *-CH2-(CH2)4-CO-N(CH3)-CH2-,

[0210] *-CH2-(CH2)5-CO-N(CH3)-CH2-, *-CH2-(CH2)6-CO-N(CH3)-CH2-, *-CH2-

[0211] (CH2)7-CO-N(CH3)-CH2-, *-CH2-(CH2)8-CO-N(CH3)-CH2-, *-CH2-(CH2)9-CO- N(CH3)-CH2-, *-CH2-(CH2)10-CO-N(CH3)-CH2-, *-CH2-(CH2)1 1-CO-N(CH3)- CH2-, *-CH2-(CH2)12-CO-N(CH3)-CH2-, *-CH2-(CH2)13-CO-N(CH3)-CH2-, *- CH2-(CH2)14-CO-N(CH3)-CH2-, *-CH2-(CH2)15-CO-N(CH3)-CH2-, *-CH2-

[0212] (CH2)16-CO-N(CH3)-CH2-, *-CH2-(CH2)17-CO-N(CH3)-CH2-, *-CH2-(CH2)18-CO-

[0213] N(CH3)-CH2-, *-CH2-(CH2)19-CO-N(CH3)-CH2-, *-CH2-CO-N(CH3)-CH2-CH2

[0214] *-CH2-CH2-CO-N(CH3)-CH2-CH2-, *-CH2-(CH2)2-CO-N(CH3)-CH2-CH2-, *-

[0215] CH2-(CH2)3-CO-N(CH3)-CH2-CH2-, *-CH2-(CH2)4-CO-N(CH3)-CH2-CH2-, *-

[0216] CH2-(CH2)5-CO-N(CH3)-CH2-CH2-, *-CH2-(CH2)6-CO-N(CH3)-CH2-CH2-, *-

[0217] CH2-(CH2)7-CO-N(CH3)-CH2-CH2-, *-CH2-(CH2)8-CO-N(CH3)-CH2-CH2-, *-

[0218] CH2-(CH2)9-CO-N(CH3)-CH2-CH2-, *-CH2-(CH2)10-CO-N(CH3)-CH2-CH2-, *-

[0219] CH2-(CH2)11-CO-N(CH3)-CH2-CH2-, *-CH2-(CH2)12-CO-N(CH3)-CH2-CH2-, *-

[0220] CH2-(CH2)13-CO-N(CH3)-CH2-CH2-, *-CH2-(CH2)14-CO-N(CH3)-CH2-CH2-, *-

[0221] CH2-(CH2)15-CO-N(CH3)-CH2-CH2-, *-CH2-(CH2)16-CO-N(CH3)-CH2-CH2-, *-

[0222] CH2-(CH2)17-CO-N(CH3)-CH2-CH2-, *-CH2-(CH2)18-CO-N(CH3)-CH2-CH2-, *-

[0223] CH2-(CH2)19-CO-N(CH3)-CH2-CH2-, -CH2-CO-N(CH3)-(CH2)2-CH2-, *-CH2-

[0224] CH2-CO-N(CH3)-(CH2)2-CH2-, *-CH2-(CH2)2-CO-N(CH3)-(CH2)2-CH2-, *-CH2- (CH2)3-CO-N(CH3)-(CH2)2-CH2-, *-CH2-(CH2)4-CO-N(CH3)-(CH2)2-CH2-, *- CH2-(CH2)5-CO-N(CH3)-(CH2)2-CH2-, *-CH2-(CH2)6-CO-N(CH3)-(CH2)2-CH2-, *-CH2-(CH2)7-CO-N(CH3)-(CH2)2-CH2, *-CH2-(CH2)8-CO-N(CH3)-(CH2)2-CH2-, *-CH2-(CH2)9-CO-N(CH3)-(CH2)2-CH2, *-CH2-(CH2)10-CO-N(CH3)-(CH2)2-CH2- , *-CH2-(CH2)11-CO-N(CH3)-(CH2)2-CH2-, *-CH2-(CH2)12-CO-N(CH3)-(CH2)2- CH2-, *-CH2-(CH2)13-CO-N(CH3)-(CH2)2-CH2-, *-CH2-(CH2)14-CO-N(CH3)- (CH2)2-CH2-, *-CH2-(CH2)15-CO-N(CH3)-(CH2)2-CH2-, *-CH2-(CH2)16-CO-

[0225] N(CH3)-(CH2)2-CH2-, *-CH2-(CH2)17-CO-N(CH3)-(CH2)2-CH2-, *-CH2-(CH2)18- CO-N(CH3)-(CH2)2-CH2-, *-CH2-(CH2)19-CO-N(CH3)-(CH2)2-CH2-,*-CH2-CO- N(CH3)-CH(CH3)-CH2-, *-CH2-CH2-CO-N(CH3)-CH(CH3)-CH2-, *-CH2-(CH2)2- CO-N(CH3)-CH(CH3)-CH2-, *-CH2-(CH2)3-CO-N(CH3)-CH(CH3)-CH2-, *-CH2- (CH2)4-CO-N(CH3)-CH(CH3)-CH2-, *-CH2-(CH2)5-CO-N(CH3)-CH(CH3)-CH2-, *-CH2-(CH2)6-CO-N(CH3)-CH(CH3)-CH2-, *-CH2-(CH2)7-CO-N(CH3)-CH(CH3)- CH2-, *-CH2-(CH2)8-CO-N(CH3)-CH(CH3)-CH2-, *-CH2-(CH2)9-CO-N(CH3)- CH(CH3)-CH2-, *-CH2-(CH2)IO-CO-N(CH3)-CH(CH3)-CH2-, *-CH2-(CH2)1 1-CO- N(CH3)-CH(CH3)-CH2-, *-CH2-(CH2)12-CO-N(CH3)-CH(CH3)-CH2-, *-CH2- (CH2)13-CO-N(CH3)-CH(CH3)-CH2-, *-CH2-(CH2)14-CO-N(CH3)-CH(CH3)-CH2-, *-CH2-(CH2)15-CO-N(CH3)-CH(CH3)-CH2-, *-CH2-(CH2)16-CO-N(CH3)-

[0226] CH(CH3)-CH2-, *-CH2-(CH2)17-CO-N(CH3)-CH(CH3)-CH2-, *-CH2-(CH2)18-CO- N(CH3)-CH(CH3)-CH2-, *-CH2-(CH2)19-CO-N(CH3)-CH(CH3)-CH2-, *-CH2-CO- N(CH3)-CH2-CH(CH3)-, *-CH2-CH2-CO-N(CH3)-CH2-CH(CH3)-, *-CH2-(CH2)2- CO-N(CH3)-CH2-CH(CH3)-, *-CH2-(CH2)3-CO-N(CH3)-CH2-CH(CH3)-, *-CH2- (CH2)4-CO-N(CH3)-CH2-CH(CH3)-, *-CH2-(CH2)5-CO-N(CH3)-CH2-CH(CH3)-, *-CH2-(CH2)6-CO-N(CH3)-CH2-CH(CH3)-, *-CH2-(CH2)7-CO-N(CH3)-CH2-

[0227] CH(CH3)-, *-CH2-(CH2)8-CO-N(CH3)-CH2-CH(CH3)-, *-CH2-(CH2)9-CO-

[0228] N(CH3)-CH2-CH(CH3)-, *-CH2-(CH2)10-CO-N(CH3)-CH2-CH(CH3)-, *-CH2- (CH2)1 1-CO-N(CH3)-CH2-CH(CH3)-, *-CH2-(CH2)i2-CO-N(CH3)-CH2-CH(CH3)-, *-CH2-(CH2)13-CO-N(CH3)-CH2-CH(CH3)-, *-CH2-(CH2)14-CO-N(CH3)-CH2-

[0229] CH(CH3)-, *-CH2-(CH2)15-CO-N(CH3)-CH2-CH(CH3)-, *-CH2-(CH2)16-CO-

[0230] N(CH3)-CH2-CH(CH3)-, *-CH2-(CH2)17-CO-N(CH3)-CH2-CH(CH3)-, *-CH2- (CH2)18-CO-N(CH3)-CH2-CH(CH3)-, *-CH2-(CH2)19-CO-N(CH3)-CH2-CH(CH3)- wherein, the asterisk marks the point of attachment with Ar.

[0231] In yet another embodiment, L1-L2-L3together represents:

[0232] wherein, the asterisk marks the point of attachment with Ar.

[0233] In yet another embodiment, L1-L2-L3together represents:

[0234] wherein, the asterisk marks the point of attachment with Ar.

[0235] In yet another embodiment, L1-L2-L3together represents: wherein, the asterisk marks the point of attachment with Ar. In a preferred embodiment, L1-L2-L3together represents: -CH2-, -CH(CH(CH3 )2)-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-(CH2)3-CH2-, -CH2- (CH2)4-CH2-, -CH2-(CH2)6-CH2-, -CH2-(CH2)7-CH2-, -CH2-(CH2)5-CH2-, -CH2- (CH2)8-CH2-, -CH2-(CH2)9-CH2-, -CH2-(CH2)12-CH2-, *-O-CH2-(CH2)4-CH2-, *- O-CH2-(CH2)5-CH2-, *-O-CH2-(CH2)6-CH2-, *-CH2-(CH2)5-CH2-O-, *-CH2- (CH2)6-CH2-O-, *-CH2-(CH2)7-CH2-O-, *-CH2-CH2-O-(CH2)2-O-CH2-CH2-, *- CH2-CO-NH-CH2-CH2-, *-CH2-(CH2)7-CO-N(CH3)-CH(CH3)-, *-CH2-(CH2)10- CO-N(CH3)-CH(CH3)-, *-CH2-CO-NH-(CH2)4-CH2-, *-CH2-CO-NH-(CH2)7- CH2-, *-CH2-CO-NH-(CH2)10-CH2-, *-CH2-CO-NH-(CH2)13-CH2-, wherein, the asterisk marks the point of attachment with Ar.

[0236] In certain embodiments, halogen (or halo) represents F, Cl, Br or I.

[0237] In certain embodiments, (C1-C6)alkyl as used herein (as in R1, R2, R3, R4, R5, R7, R8R11, Ra, Rb, Rc, Rd, Reand Rf) represents -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH(CH3)2, -C(CH3)3, - CH2CH(CH3)2, -CH2CH2CH(CH3)2, -CH2C(CH3)2CH3, - CH2CH2CH2CH(CH3)2, -CH2CH2C(CH3)2CH3or -CH2C(CH3)2CH2CH3.

[0238] In certain embodiments, halo(C1-C6)alkyl as used herein (as in R5, Reand Rf) represents -CH2X, -CHX2, -CX3, -CH(X)CH3, -CH2CH2(X), -C(X)2CH3, - CH2CH(X)2, -CH2C(X)3,-CH(X)CH2CH3, -CH2CH(X)CH3, -CH2CH2CH2(X), - C(X)2CH2CH3, -CH2C(X)2CH3, -CH2CH2C(X)3, -CH(X)CH2CH2CH3, - CH2CH(X)CH2CH3, -CH2CH2CH(X)CH3, -CH2CH2CH2CH2(X), C(X)2CH2CH2CH3, -C(X)2CH2CH2CH3, -CH2C(X)2CH2CH3, -CH2CH2C(X)2CH3, -CH2CH2CH2CH(X)2, -C(X)2CH2CH2C(X)3, -CH(X)CH2CH2CH2CH3, CH2CH(X)CH2CH2CH3, -CH2CH2CH(X)CH2CH3, -CH2CH2CH2CH(X)CH3, - CH2CH2CH2CH2CH2(X), -C(X)2CH2CH2CH2CH3, -CH2C(X)2CH2CH2CH3, - CH2CH2C(X)2CH2CH3, -CH2CH2CH2C(X)2CH3, -CH2CH2CH2CH2CH(X)2, -

[0239] CH2CH2CH2CH2C(X)3,-CH(X)CH2CH2CH2CH2CH3,

[0240] CH2CH(X)CH2CH2CH2CH3, -CH2CH2CH(X)CH2CH2CH3,

[0241] CH2CH2CH2CH(X)CH2CH3, -CH2CH2CH2CH2CH(X)CH3,

[0242] CH2CH2CH2CH2CH2CH2(X), -C(X)2CH2CH2CH2CH2CH3,

[0243] CH2C(X)2CH2CH2CH2CH3, -CH2CH2C(X)2CH2CH2CH3,

[0244] CH2CH2CH2C(X)2CH2CH3, -CH2CH2CH2CH2C(X)2CH3,

[0245] CH2CH2CH2CH2CH2CH(X)2or -CH2CH2CH2CH2CH2C(X)3, wherein X represents F, Cl, Br or I.

[0246] In certain embodiments, (C1-C6)alkoxy as used herein (as in R4and R5) represents -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3, -OCH(CH3)CH2CH3, -OCH2CH(CH3)CH3, -OC(CH3)2CH3,

[0247] OCH2CH2CH2CH2CH3, -OCH(CH3)CH2CH2CH3, OCH2CH(CH3)CH2CH3, - OCH2CH2CH(CH3)CH3, -OC(CH3)2CH2CH3, OCH2C(CH3)2CH3,

[0248] OCH2CH2CH2CH2CH2CH3, -OCH(CH3)CH2CH2CH2CH3,

[0249] OCH2CH(CH3)CH2CH2CH3, -OCH2CH2CH(CH3)CH2CH3,

[0250] OC(CH3)2CH2CH2CH3, -OCH2C(CH3)2CH2CH3, -OCH2CH2C(CH3)2CH3, or the like.

[0251] In certain embodiments, hydroxyl(C1-C6)alkyl represents alkyl group such as -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, - CH2CH2CH2CH2CH2CH3, -CH(CH3)2, -C(CH3)3, - CH2CH(CH3)2, - CH2CH2CH(CH3)2, -CH2C(CH3)2CH3, -CH2CH2CH2CH(CH3)2, -CH2CH2C(CH3)2CH3or -CH2C(CH3)2CH2CH3, wherein one or more of hydrogen atom(s) is / are replaced by hydroxyl group, for example -CH2OH.

[0252] In certain embodiments, hydroxyl-protecting group represents acetyl, benzoyl, benzyl, methoxymethyl ether, methoxy trityl, p-methoxybenzyl ether, methylthiomethyl ether, pivaloyl, tetrahydropyranyl, trityl or the like.

[0253] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in art to which the subject matter herein belongs. As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated in order to facilitate the understanding of the present disclosure.

[0254] The singular forms "a" "an" and "the" include plural reference unless the context clearly dictates otherwise.

[0255] As used herein, a “bond” refers to a single bond joining two groups.

[0256] As used herein, the term “cycloalkyl” means 3 to 12 membered saturated cyclic hydrocarbon rings. A cycloalkyl may be a single ring, which typically contains from 3 to 7 carbon ring atoms. Cycloalkyl includes, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

[0257] The term “heterocycloalkyl” as used herein, refers to any 3- to 18- membered non-aromatic radical monocyclic or polycyclic (e.g., bicyclic or tricyclic) moiety comprising at least one ring heteroatom selected from nitrogen, oxygen, phosphorous, and sulfur, and wherein a heterocycloalkyl ring systems can be a fused, bridged or spiro ring system. The heterocycloalkyl ring systems can include one or more heteroatoms in one or more rings. A heterocycloalkyl group can be saturated or partially unsaturated. Whenever it appears herein, a numerical range such as “5 to 12” refers to each integer in the given range; e.g., “5 to 12 ring atoms” means that the heterocycloalkyl group can consist of 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, 10 ring atoms, 11 ring atoms and 12 ring atoms. An N-containing heterocycloalkyl moiety refers to a non-aromatic group in which at least one of the ring atoms is a nitrogen atom. The heteroatom(s) in the heterocycloalkyl radical can be optionally oxidized. One or more nitrogen atoms, if present, can be optionally quaternized. Heterocycloalkyl also includes ring systems substituted with one or more nitrogen oxide substituents, such as piperidinyl N-oxides. The heterocycloalkyl is attached to the parent molecular structure through any atom of any of the ring(s). Heterocycloalkyl also includes ring systems wherein the heterocycloalkyl ring, as defined above, is fused with one or more aryl or heteroaryl groups. In some embodiments, a heterocycloalkyl group is a 3- to 12-membered nonaromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous, and sulfur.

[0258] In some embodiments, a heterocycloalkyl group is a 5- to 8-membered nonaromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous, and sulfur.

[0259] In some embodiments, a heterocycloalkyl group is a 5- to 6-membered nonaromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous, and sulfur. In some embodiments, the 5 to 6-membered heterocycloalkyl has 1 to 3 ring heteroatoms independently selected from nitrogen, oxygen, phosphorous, and sulfur. In some embodiments, the 5- to 6-membered heterocycloalkyl has 1 to 2 ring heteroatoms independently selected from nitrogen, oxygen, phosphorous, and sulfur. In some embodiments, the 5- to 6-membered heterocycloalkyl has 1 ring heteroatom selected from nitrogen, oxygen, phosphorous, and sulfur, preferably nitrogen or oxygen.

[0260] Heterocycloalkyl includes, but not limited to, aziridinyl, oxiranyl, thiorenyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, dihydrofuranyl, imidazolidinyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, pyrrolyl-2, 5-dione, dioxolanyl, oxathiolanyl, dithiolanyl, triazolinyl, oxadiazolinyl, thiadiazolinyl, piperidinyl, tetrahydropyranyl, dihydropyridinyl, thianyl, piperazinyl, morpholinyl, dithianyl, dioxanyl, triazinanyl, azepanyl, oxepanyl, thiepanyl, azocanyl, oxecanyl, thiocanyl, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, indolinyl, phthalimidyl, chromanyl, chromenyl, aza-bicyclooctanyl, diazabicyclooctanyl, azocinyl or 2-oxa-6-azaspiro[3.3]heptanyl.

[0261] Unless stated otherwise, heterocycloalkyl moieties are optionally substituted by one or more substituents which independently include: halogen, alkyl, alkoxy, haloalkyl, amino, substituted amino, hydroxyl, cyano, nitro, amido, imino, azide, carbonate or carbamate.

[0262] As used herein, the term “heterocycloalkylenyl” refers to a divalent heterocycloalkyl group as defined herein.

[0263] The term “heteroaryl” as used herein, refers to a radical of a 5- to 18- membered monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen or sulfur. Whenever it appears herein, a numerical range such as “5 to 12” refers to each integer in the given range; e.g., “5 to 12 ring atoms” means that the heteroaryl group can consist of 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, 10 ring atoms, 11 ring atoms or 12 ring atoms. One or more heteroatom(s) in the heteroaryl radical can be optionally oxidized. One or more nitrogen atoms, if present, can also be optionally quaternized. Heteroaryl also includes ring systems substituted with one or more nitrogen oxide substituents, such as pyridinyl N-oxides. The heteroaryl is attached to the parent molecular structure through any atom of the ring(s).

[0264] “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment to the parent molecular structure is either on the aryl or on the heteroaryl ring.

[0265] In some embodiments, a heteroaryl group is a 5 to 12 membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each hetero atom is independently selected from nitrogen, oxygen or sulfur (“5- to 10-membered heteroaryl”). In some embodiments, a heteroaryl group is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen or sulfur (“5- to 8-membered heteroaryl”).

[0266] In some embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen or sulfur (“5- to 6-membered heteroaryl”).

[0267] In some embodiments, the 5- to 6-membered heteroaryl has 1 to 3 ring heteroatoms independently selected from nitrogen, oxygen or sulphur, preferably nitrogen. In some embodiments, the 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms independently selected from nitrogen, oxygen or sulfur, preferably nitrogen atom. In some embodiments, the 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen or sulfur, preferably nitrogen.

[0268] Examples of heteroaryl include, but not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3 -benzodi oxolyl, benzofuranyl, benzodthiazolyl, benzothiadiazolyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl, carbazolyl, cinnolinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, 1,6- naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl (e.g., 1,2,4 triazinyl) or thienyl.

[0269] Unless stated otherwise, heteroaryl moieties are optionally substituted by one or more substituents which independently include: halogen, alkyl, alkoxy, haloalkyl, amino, substituted amino, hydroxyl, cyano, nitro, amido, imino, azide, carbonate or carbamate. As used herein, the term “heteroarylenyl” refers to a divalent heteroaryl group as defined herein.

[0270] The term “alkyl” as used herein, refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having, in some embodiments, from one to twenty carbon atoms (e.g., C1-20alkyl) and in some embodiments, from one to ten carbon atoms (e.g., C1-10alkyl). Whenever it appears herein, a numerical range such as "1 to 10” refers to each integer in the given range; e.g., " 1 to 10 carbon atoms” means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up to and including 10 carbon atoms. In some embodiments, alkyl groups have 1 to 10, 1 to 6, 1 to 4, or 1 to 3 carbon atoms, preferably 1 to 3 or 1 to 6 carbon atoms.

[0271] Examples of alkyl groups include, but are not limited to, methyl, ethyl, n- propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3 -methylbutyl, 2-methylpentyl, 3 -methylpentyl, 4- methylpentyl, 2-methylhexyl, 3 -methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3- dimethylbutyl, and the like.

[0272] The term “haloalkyl” as used herein refers to an alkyl group in which one or more of the hydrogen atoms have been replaced with a halogen independently selected from fluoro, chloro, bromo, and iodo.

[0273] The term “alkoxy” as used herein refers to the group -O-alkyl (in some embodiments, including from 1 to 10 carbon atoms), of a straight, branched, cyclic configuration and combinations thereof, attached to the parent molecular structure through an oxygen. Preferably, alkoxy refers to alkoxy groups containing one to six carbons, which encompasses both straight and branched chain alkyls of from 1 to 6 carbon atoms. Unless stated otherwise in the specification, an alkoxy group is optionally substituted by one or more substituents which independently include: amino, hydroxy, cyano, halo, and the like. The term “alkynyl” as used herein refers to straight or branched chain hydrocarbon moieties containing at least one carbon-carbon triple bonds. Examples of “alkynyl” include, but not limited to, ethynyl, propynyl, butynyl, pentynyl or hexynyl.

[0274] The term “aryl”, as employed 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. The term “arylenyl” refers to a divalent aryl group. Examples include, but are not limited to phenylenyl, naphthylenyl, biphenylenyl and anthrylenyl.

[0275] The term “pharmaceutically acceptable salt” as used herein refers to those salts which are within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19.

[0276] In some embodiments, the pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminium or zinc.

[0277] In some embodiments, pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, guanidine or metformin. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0278] The term “solvate” as used herein, refers to compounds that further include a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. The solvate can be of a disclosed compound or a pharmaceutically acceptable salt thereof. Where the solvent is water, the solvate is a “hydrate”. Pharmaceutically acceptable solvates and hydrates are complexes that, for example, can include 1 to about 100, or 1 to about 10, or one to about 2, about 3 or about 4, solvent or water molecules.

[0279] The term “isomers or stereoisomers” as used herein, refers to compounds having the same number and kind of atoms and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms. In such cases, the compound can adopt either an (S)- or (R)- stereochemical configuration. The compounds may be in a racemic or enantiomerically pure form, or any other form in terms of stereochemistry.

[0280] In some embodiments, the compounds as described herein are racemic mixture of (S)- and (R )-isomers in 1 : 1 ratio.

[0281] In some embodiments, the compounds as described herein have (S)- stereochemical configuration.

[0282] In some embodiments, the compounds as described herein have (R)- stereochemical configuration.

[0283] In other embodiments, provided herein is a mixture, wherein individual compound of the mixture exists predominately in an (S - or (R )-isomeric configuration. For example, in one embodiment, the compound mixture has an (S)- enantiomeric excess of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or more. In another embodiment, the compound mixture has an ( S) nantiomeric excess of greater than about 10%, greater than about 20%, greater than about 30%, greater than about 40%, greater than about 50%, greater than about 55%, greater than about 60%, greater than about 65%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, greater than about 96%, greater than about 97%, greater than about 98%, greater than about 99%, greater than about 99.5%, or more. In other embodiments, the compound mixture has an CS')-enantiomeric excess of about 10% to about 99.5%, about 20% to about 99.5%, about 30% to about 99.5%, about 40% to about 99.5%, about 50% to about 99.5%, about 55% to about 99.5%, about 60% to about 99.5%, about 65% to about 99.5%, about 70% to about 99.5%, about 75% to about 99.5%, about 80% to about 99.5%, about 85% to about 99.5%, about 90% to about 99.5%, about 95% to about 99.5%, about 96% to about 99.5%, about 97% to about 99.5%, about 98% to about 99.5%, about 99% to about 99.5%, or more.

[0284] In other embodiments of a compound of formula (I') or (I), the compound mixture has an (R)-enantiomeric excess of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or more at chiral centre. In one embodiment, the compound mixture has an (R)-enantiomeric excess of greater than about 10%, greater than about 20%, greater than about 30%, greater than about 40%, greater than about 50%, greater than about 55%, greater than about 60%, greater than about 65%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, greater than about 96%, greater than about 97%, greater than about 98%, greater than about 99%, greater than about 99.5%, or more, at chiral centre. In other embodiments, the compound mixture has an (R)-enantiomeric excess of about 10% to about 99.5%, about 20% to about 99.5%, about 30% to about 99.5%, about 40% to about 99.5%, about 50% to about 99.5%, about 55% to about 99.5%, about 60% to about 99.5%, about 65% to about 99.5%, about 70% to about 99.5%, about 75% to about 99.5%, about 80% to about 99.5%, about 85% to about 99.5%, about 90% to about 99.5%, about 95% to about 99.5%, about 96% to about 99.5%, about 97% to about 99.5%, about 98% to about 99.5%, about 99% to about 99.5%, or more. In certain embodiments, the individual isomer (S or (R) can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art.

[0285] The compound alone or in the form of a pharmaceutical composition will typically be used in therapy for human subjects. However, they may also be used to prevent or treat similar indications in other animal subjects. Thus, for therapy a suitable dosage form may be required. Suitable dosage forms will depend upon the use or the route of administration. It should be understood that such dosage forms should allow the compound to reach target cells. Other factors are well known in the art and include considerations such as toxicity and dosage forms that retard the compound or composition from exerting its effect. Techniques and formulations generally may be found in The Science and Practice of Pharmacy, 21stedition, Lippincott, Wiliams and Wilkins, Philadelphia, Pa., 2005 (incorporated herein by reference).

[0286] Thus, in another aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound as disclosed herein or a pharmaceutically acceptable salt, solvate or isomer thereof, and one or more pharmaceutically acceptable excipient(s).

[0287] The compound of formula (I') or (I), a pharmaceutically acceptable salt thereof, a solvate thereof or an isomer thereof, may be administered as a formulation, i.e., pharmaceutical composition, in association with one or more pharmaceutically acceptable excipient(s).

[0288] The term “pharmaceutically acceptable” as used herein refers to a compound of formula (I') or (I) or pharmaceutical composition thereof is suitable for administration to humans. Preferably, this term means approved by a regulatory agencies such as EMEA (Europe) and / or FDA and / or any other National Regulatory Agency for use in animals, preferably humans. In the context of excipients, it refers to materials useful in preparing a composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.

[0289] The term “excipient” as used herein refers to any ingredient in the formulation other than the compound of formula (I') or (I). The example of an excipient includes, but are not limited to, carrier, vehicle, solvent, adjuvant, lubricant, surfactant, binder, buffer, diluent, flavouring agent, coloring agent, disintegrant, emulsifying agent, suspending agent, plasticizer, solubilizer, filler or bulking agent. The choice of excipient(s) will largely depend on factors such as the particular mode of administration, the effect of the excipients on solubility, stability, and release profile, and the nature of the dosage form. The compound of formula (I') or (I) may be generally referred to as the active ingredient(s) in a formulation or pharmaceutical composition. A pharmaceutical composition suitable for the delivery of a compound of formula (I') or (I) and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington's Pharmaceutical Sciences, 19thed., (Mack Publishing Company, 1995).

[0290] The compounds can be administered by different routes including, for example intravenous, intraperitoneal, subcutaneous, intramuscular, oral, transmucosal, rectal, transdermal, or inhalant. For oral administration, for example, the compounds can be formulated into conventional oral dosage forms such as a tablet, capsule (hard or soft filled), pill, dispersible powder, granules, emulsions, syrups, microbeads, sustain or immediate release formulations, elixirs, aqueous or non-aqueous solutions or suspensions; the parenteral administration includes intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion as, for example, a sterile solution or suspension or sustained-release formulation; and the topical administration includes, for example an ointment or cream. The present disclosure contemplates the administration of a compound described herein in the form of suppositories for rectal administration. The compounds described herein may be in the form of any other suitable pharmaceutical composition (e.g., sprays for nasal or inhalation use).

[0291] In certain embodiments, the tablets, capsules and the like suitable for oral administration may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action.

[0292] The amount of active ingredient(s) and excipient(s) to be present in formulation or pharmaceutical composition can be determined by standard procedures taking into account factors such as the compound IC50, the biological half-life of the compound, the age, size, and weight of the patient, and the disorder associated with the patient. Generally, a dose will be between about 0.01 and 100 mg / Kg, preferably 0.1 to 50 mg / Kg, even more preferably 0.1 to 20 mg / Kg of the patient being treated. Multiple doses may be used. Accordingly, while certain dose and administration regimens are exemplified herein, however, these do not in any way limit the dose and administration regimen that may be provided to the patient in practicing the present invention.

[0293] In some embodiments, a pharmaceutical composition described herein includes a second active agent such as an additional therapeutic agent, (e.g., a chemotherapeuti c) .

[0294] As shown in the specification, the compounds of the present disclosure were tested for their biological activity and have been found to significantly degrade the target proteins as envisaged by the inventors of the present disclosure . As a result of these findings, the compounds of the present disclosure are considered to be useful for the prevention and / or treatment of a disease and / or a disorder responsive to the degradation of target protein, for example cancer, immune disorders, inflammatory diseases, viral infections, neurodegenerative diseases and metabolic disorders. Thus, another object of the present disclosure is to provide a method for treating or preventing a disease, condition or disorder associated with the degradation of target protein by compound of formula (I') or (I) of the present disclosure.

[0295] In certain embodiments, the present disclosure provides a method for treating or preventing a disease, condition, or disorder responsive to the degradation of target protein in a patient comprising the steps of administering to the said patient a therapeutically effective amount of a compound of formula (I') or (I), a pharmaceutically acceptable salt thereof, a solvate thereof, an isomer thereof or a pharmaceutical composition thereof.

[0296] In certain embodiments, the present disclosure provides a compound of formula (I') or (I), or a pharmaceutically acceptable salt thereof, a solvate thereof or an isomer thereof or a pharmaceutical composition thereof for use in a method of treating or preventing disease, condition or disorder associated with degradation of the target protein.

[0297] In certain embodiments, the present disclosure provides a use of a compound of formula (I') or (I), or a pharmaceutically acceptable salt thereof, a solvate thereof or an isomer thereof for the manufacture of a medicament for treating or preventing disease, condition or disorder associated with the degradation of target protein.

[0298] In certain embodiments, the present disclosure provides a method for treating or preventing cancer, immune disorders, inflammatory diseases, viral infections, neurodegenerative diseases, or metabolic disorders in a patient comprising the steps of administering to the said patient a therapeutically effective amount of a compound of formula (I') or (I), a pharmaceutically acceptable salt thereof, a solvate thereof, an isomer thereof or a pharmaceutical composition thereof.

[0299] In certain embodiments, the present disclosure provides a compound of formula (I') or (I), or a pharmaceutically acceptable salt thereof, a solvate thereof or an isomer thereof or a pharmaceutical composition thereof for use in a method of treating or preventing cancer, immune disorders, inflammatory diseases, viral infections, neurodegenerative diseases or metabolic disorders.

[0300] In certain embodiments, the present disclosure provides a use of a compound of formula (I') or (I) or a pharmaceutically acceptable salt thereof, a solvate thereof or an isomer thereof, in the manufacture of a medicament for the treatment of disease or disorder responsive to the degradation of target protein.

[0301] In certain embodiments, the present disclosure provides a use of a compound of formula (I') or (I) or a pharmaceutically acceptable salt thereof, a solvate thereof or an isomer thereof, for the manufacture of a medicament for treating or preventing cancer, immune disorders, inflammatory diseases, viral infections, neurodegenerative diseases or metabolic disorders.

[0302] In certain embodiments, the present disclosure provides a use of a compound of formula (I') or (I) or a pharmaceutically acceptable salt thereof, a solvate thereof or an isomer thereof, for the manufacture of a medicament for treatment of cancer, an inflammatory disease or disorder, autoimmune disease or disorder, neurodegenerative disease or metabolic disorder.

[0303] The term “patient” as used herein refers to human subjects and other animal subjects. In this context, the terms “subject”, “animal subject”, and the like refer to human such as men and women, and non-human vertebrates, for example mammals such as non-human primates, sports and commercial animals, and pets (e.g., canines and felines). Preferably, the patient is a human subject.

[0304] The term “therapeutically effective amount” as used herein refers to an amount of a compound of formula (I') or (I) sufficient to treat or prevent a specific disease, disorder, condition or one or more of its symptoms. The amount of a compound which constitutes an effective amount will vary depending on the various factors including for example, the compound being used, the disease state and its severity, the age of the patient to be treated, and the like. The said effective amount can be determined routinely by a person of ordinary skill in the art. The term “treat”, “treating” or “treatment” refer to amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being.

[0305] In one embodiment, the compounds as disclosed in the present disclosure are formulated for pharmaceutical administration.

[0306] Yet another embodiment of the present disclosure provides use of the compounds as disclosed in the present application in the treatment and prevention of diseases and / or disorder responsive to the degradation of target proteins.

[0307] According to yet another embodiment, the target protein targeted by the compounds of the present disclosure can be a protein related to cancer, an autoimmune disease or disorder, inflammatory disease or disorder or a neurodegenerative disease.

[0308] According to yet another embodiment, the target protein targeted by the compounds of the present disclosure can be a protein related to cancer.

[0309] In yet another embodiment, the cancer is selected from prostate cancer, neuroendocrine prostate cancer, breast cancer, colorectal cancer, colon cancer, pancreatic cancer, intestinal cancer, chronic lymphocytic leukemia, lymphoma, glioblastoma, myeloid leukemia, acute myeloid leukemia, acute T-cell lymphoma, T-cell lymphoma, leukemia, lympho-plasmacytoid B-cell lymphoma, glioma, small cell lung cancer, neuroblastoma, angiosarcoma, chondrosarcoma, Ewing’s sarcoma, fibroblastic sarcoma, gynaecological sarcoma, liposarcoma, osteosarcoma, rhabdomyosarcoma, soft tissue sarcoma or synovial sarcoma.

[0310] In yet another embodiment, the cancer is selected from cancer of prostate adenocarcinoma, breast invasive carcinoma, bladder urothelial carcinoma, lung adenocarcinoma, liver hepatocellular carcinoma, cervical squamous cell carcinoma and endocervical adenocarcinoma, cholangiocarcinoma, lung squamous cell carcinoma, colon adenocarcinoma, rectum adenocarcinoma, pancreatic adenocarcinoma, uterine corpus endometrial carcinoma, uterine carcinosarcoma, head and neck squamous cell carcinoma, mesothelioma, testicular germ cell tumors, ovarian serous cystadenocarcinoma, thyroid carcinoma, sarcoma, skin cutaneous melanoma, adrenocortical carcinoma, kidney renal clear cell carcinoma, pheochromocytoma and paraganglioma, kidney renal papillary cell carcinoma, lymphoid neoplasm diffuse large B-cell lymphoma, thymoma, brain lower grade glioma, kidney chromophobe, glioblastoma multiforme, acute myeloid leukemia or uveal melanoma.

[0311] In some embodiments, a target protein targeted by compounds of the present disclosure can be a protein related to a carcinoma or a haematological cancer, for example lymphoma, leukemia or lymphoid malignancy.

[0312] In some embodiments, a target protein targeted by compounds of the present disclosure can be a protein related to a metastatic cancer.

[0313] According to yet another embodiment, the target protein targeted by the compounds of the present disclosure can be a protein related to an autoimmune or inflammatory disease or disorder.

[0314] In certain embodiments, the present disclosure provides a method of treating disease or disorder, wherein the disease or disorder is autoimmune or inflammatory disease or disorder.

[0315] In yet another embodiment, the autoimmune or inflammatory disease or disorder is selected from, but not limited to, diabetes, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, fatty liver disease, HIV / AIDS, systemic lupus erythematosus, psoriasis, dermatitis or prurigo nodularis.

[0316] In yet another embodiment, the target protein targeted by the compounds of the present disclosure can be a protein related to neurodegenerative disease. In certain embodiments, the present disclosure provides a method of treating disease or disorder, wherein the disease or disorder is neurodegenerative disease.

[0317] In yet another embodiment, the neurodegenerative disease is selected from, but not limited to, Alzheimer’s disease, Parkinson’s disease, dementia, Huntington’s disease or amyotrophic lateral sclerosis.

[0318] According to yet another embodiment, the present disclosure provides a compound of formula (I') or (I), for use in the treatment of cancer, autoimmune disease, inflammatory disease or disorder or neurodegenerative disease.

[0319] According to yet another embodiment, the present disclosure provides a pharmaceutically acceptable salt, a solvate or an isomer thereof, for use in the treatment of disease or disorder responsive to the degradation of target protein. According to yet another embodiment, the present disclosure provides a compound of formula (I') or (I), or pharmaceutically acceptable salts or stereoisomers thereof, for use as a medicament.

[0320] According to yet another embodiment, the present disclosure provides a pharmaceutically acceptable salt, a solvate or an isomer thereof, for use as a medicament. According to yet another embodiment, the present disclosure provides the use of a compound of formula (I') or (I), in the manufacture of a medicament.

[0321] According to yet another embodiment, the present disclosure provides the use of a compound of formula (I') or (I), in the manufacture of a medicament for the treatment of diseases and / or disorder responsive to degradation of target protein.

[0322] According to yet another embodiment, the present disclosure provides the use of a compound of formula (I') or (I), in the manufacture of a medicament for the treatment of cancer, autoimmune disease, and inflammatory disease or disorder or neurodegenerative disease.

[0323] In certain embodiments, the present disclosure provides a method of treating disease and / or disorder responsive to degradation of target protein in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I') or (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

[0324] In certain embodiments, the present disclosure provides a method of treating disease and / or disorder responsive to degradation of p300 in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to compound of formula (I') or (I), a pharmaceutically acceptable salt thereof, a solvate or an isomer thereof.

[0325] In certain embodiments, the present disclosure provides a method of treating disease and / or disorder responsive to degradation of p300 in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I') or (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof.In certain embodiments, the present disclosure provides a method of degrading a human kinase in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I') or (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

[0326] In an embodiment, the human kinase is selected from, but not limited to, tyrosine kinase (RTK), TKL kinase (TKL), STE kinase (STE), CAMK kinase (CAMK), and AGC kinase (AGC), CMGC kinase group (CMGC), atypical protein kinase group (atypical), CK1 kinase group, and the like.

[0327] In certain embodiments, the present disclosure provides a method of treating cancer, immune disorder, inflammatory disease, viral infection, neurodegenerative disease and metabolic disorder in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula (f) or (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

[0328] In certain embodiments, the present disclosure provides a method of treating disease and / or disorder responsive to degradation of p300 wherein disease or disorder is cancer, autoimmune disease, inflammatory disease, viral infection, neurodegenerative disease, and metabolic disorder. In certain embodiments, the present disclosure provides a method of treating cancer, autoimmune disease, inflammatory disease, viral infection, neurodegenerative disease, and metabolic disorder.In certain embodiments, the present disclosure provides a method of treating disease or disorder, wherein the disease or disorder is cancer.

[0329] In certain embodiments, the present disclosure provides a method of treating cancer, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I') or (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein the cancer is prostate cancer, neuroendocrine prostate cancer, breast cancer, colorectal cancer, colon cancer, pancreatic cancer, intestinal cancer, chronic lymphocytic leukemia, lymphoma, glioblastoma, myeloid leukemia, acute myeloid leukemia, acute T-cell lymphoma, T-cell lymphoma, leukemia, lympho-plasmacytoid B-cell lymphoma, glioma, small cell lung cancer, neuroblastoma, angiosarcoma, chondrosarcoma, Ewing’s sarcoma, fibroblastic sarcoma, gynaecological sarcoma, liposarcoma, osteosarcoma, rhabdomyosarcoma, soft tissue sarcoma, synovial sarcoma, cancer of prostate adenocarcinoma, breast invasive carcinoma, bladder urothelial carcinoma, lung adenocarcinoma, liver hepatocellular carcinoma, cervical squamous cell carcinoma and endocervical adenocarcinoma, cholangiocarcinoma, lung squamous cell carcinoma, colon adenocarcinoma, rectum adenocarcinoma, pancreatic adenocarcinoma, uterine corpus endometrial carcinoma, uterine carcinosarcoma, head and neck squamous cell carcinoma, mesothelioma, testicular germ cell tumors, ovarian serous cystadenocarcinoma, thyroid carcinoma, sarcoma, skin cutaneous melanoma, adrenocortical carcinoma, kidney renal clear cell carcinoma, pheochromocytoma and paraganglioma, kidney renal papillary cell carcinoma, lymphoid neoplasm diffuse large B-cell lymphoma, thymoma, brain lower grade glioma, kidney chromophobe, glioblastoma multiforme, acute myeloid leukemia, uveal melanoma, lymphoma, leukemia or lymphoid malignancy or metastatic cancer. In certain embodiments, the present disclosure provides a method of treating cancer, wherein the cancer is prostate cancer, neuroendocrine prostate cancer, breast cancer, colorectal cancer, colon cancer, pancreatic cancer, intestinal cancer, chronic lymphocytic leukemia, lymphoma, glioblastoma, myeloid leukemia, acute myeloid leukemia, acute T-cell lymphoma, T-cell lymphoma, leukemia, lympho- plasmacytoid B-cell lymphoma, glioma, small cell lung cancer, neuroblastoma, angiosarcoma, chondrosarcoma, Ewing’s sarcoma, fibroblastic sarcoma, gynaecological sarcoma, liposarcoma, osteosarcoma, rhabdomyosarcoma, soft tissue sarcoma, synovial sarcoma, cancer of prostate adenocarcinoma, breast invasive carcinoma, bladder urothelial carcinoma, lung adenocarcinoma, liver hepatocellular carcinoma, cervical squamous cell carcinoma and endocervical adenocarcinoma, cholangiocarcinoma, lung squamous cell carcinoma, colon adenocarcinoma, rectum adenocarcinoma, pancreatic adenocarcinoma, uterine corpus endometrial carcinoma, uterine carcinosarcoma, head and neck squamous cell carcinoma, mesothelioma, testicular germ cell tumors, ovarian serous cystadenocarcinoma, thyroid carcinoma, sarcoma, skin cutaneous melanoma, adrenocortical carcinoma, kidney renal clear cell carcinoma, pheochromocytoma and paraganglioma, kidney renal papillary cell carcinoma, lymphoid neoplasm diffuse large B-cell lymphoma, thymoma, brain lower grade glioma, kidney chromophobe, glioblastoma multiforme, uveal melanoma, or lymphoid malignancy or metastatic cancer.In certain embodiments, the present disclosure provides a method of treating autoimmune or inflammatory disease or disorder, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I') or (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein the autoimmune or inflammatory disease or disorder is diabetes, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, fatty liver disease, HIV / AIDS, systemic lupus erythematosus, psoriasis, dermatitis or prurigo nodularis.

[0330] In certain embodiments, the present disclosure provides a method of treating a neurodegenerative disease, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I') or (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein neurodegenerative disease is Alzheimer’s disease, Parkinson’s disease, dementia, Huntington’s disease or amyotrophic lateral sclerosis.

[0331] In yet another embodiment, the present disclosure comprises administering to the subject in need thereof a therapeutically effective amount of a compound of the present disclosure along with one or more additional chemotherapeutic agents independently selected from anticancer agents, anti-inflammatory agent or immunosuppressant agents or pain-relieving agents.

[0332] In yet another embodiment, the present disclosure comprises administering to the subject in need thereof a therapeutically effective amount of a compound of the present disclosure along with one or more additional anti-inflammatory agents and / or pain-relieving agents.

[0333] In yet another embodiment, the present disclosure comprises administering to the subject in need thereof a therapeutically effective amount of a compound of the present disclosure along with one or more additional anti-cancer agents and / or pain-relieving agents.

[0334] EXPERIMENTAL

[0335] The present application provides methods for the preparation of compound of formula (I') or (I), according to the description provided herein using appropriate methods and / or materials. It is to be understood by those skilled in the art that known variations of the conditions and processes of the following procedures can be used to prepare these intermediates and compounds. Moreover, by utilizing the procedures described in detail, one of ordinary skill in the art can prepare additional compounds of the present disclosure.

[0336] Following general guidelines apply to all experimental procedures described here. Until otherwise stated, experiments are performed under positive pressure of nitrogen, temperature described are the external temperature (i.e. oil bath temperature). Reagents and solvents received from vendors are used as such without any further drying or purification. Molarities mentioned here for reagents in solutions are approximate as it was not verified by a prior titration with a standard. All reactions are stirred under magnetic stir bar. Cooling to minus temperature was done by acetone / dry ice or wet ice / salts. Magnesium sulfate and sodium sulfate were used as solvent drying agent after reaction work up and are interchangeable. Removing of solvents under reduced pressure or under vacuum means distilling of solvents in rotary evaporator.

[0337] Compounds of this disclosure may be made by synthetic chemical processes, examples of which are shown herein. It is meant to be understood that the order of the steps in the processes may be varied, that reagents, solvents and reaction conditions may be substituted for those specifically mentioned and that vulnerable moieties may be protected and deprotected, as necessary.

[0338] The specifics of the process for preparing compounds of the present disclosure are detailed in the experimental section.

[0339] The present disclosure shall be illustrated by means of some examples, which are not construed to be viewed as limiting the scope of the disclosure.

[0340] Unless otherwise stated, work-up includes distribution of the reaction mixture between the organic and aqueous phases, separation of layers and drying the organic layer over anhydrous sodium sulphate, filtration and evaporation of the solvent. Purification, unless otherwise mentioned, includes purification by silica gel chromatographic techniques, generally using ethyl acetate / petroleum ether mixture of a suitable polarity as the mobile phase or by combi-flash, generally using EtOAc- Hexane or methanol- dichloromethane as solvent system.

[0341] Analysis for the compounds of the present disclosure unless mentioned, was conducted in general methods well known to a person skilled in the art. Having described the disclosure with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The disclosure is further defined by reference to the following examples, describing in detail the analysis of the compounds of the disclosure. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the disclosure. Some of the intermediates were taken to next step based on TLC results, without further characterization, unless otherwise specified.

[0342] Abbreviations:

[0343] HC1- Hydrochloric Acid; DMF-N,N-Dimethylformamide; EtOAc-Ethyl acetate; THF-Tetrahydrofuran; DBU- 1,8-Diazabicyclo[5.4. 0]undec-7-ene DCM- Dichloromethane; MeOH-Methanol; NaOH - Sodium hydroxide; C12H26S- Dodecanethiol; (CH3)3CONa - Sodium tert-butoxide; NaHCCE-Sodium bicarbonate; TEA (or) Et3N-Triethylamine; MTBE- Methyl tert-butyl ether; DIPEA- N,N-Diisopropylethylamine; K2CO3 -Potassium carbonate; (CF3SO2)2O- Triflic anhydride; NaHCO3- sat. Sodium bicarbonate; platinum (II) oxide; HATU- l-[Bis(dimethylamino)methylene]-1H- 1,2,3-triazolo[4,5-b ]pyridinium 3-oxide hexafluorophosphate; KI - Potassium iodide; Pd(dppf)Cl2 DCM-[1,1'- Bis(diphenylphosphino)ferrocene] dichloro palladium(II), complex with dichloromethane; CH2Cl2-dichloromethane; Na2SO4- Sodium Sulfate; LiOH- Lithium hydroxide; C30H43O2P - RuPhos; RT / rt-Room temperature; RM-Reaction mixture; TLC-Thin layer chromatography; LCMS-Liquid chromatography-mass spectrometry; HPLC-High performance liquid chromatography.

[0344] GENERAL SYNTHETIC SCHEMES:

[0345] Certain intermediates and compounds of the present disclosure are made by following the processes as given in General scheme-1 (Schemes 1A to 1D) and General scheme-2.

[0346] GENERAL SCHEME-1:

[0347] Scheme- 1A:

[0348] X = Halogen;

[0349] PG = Protecting group

[0350] Scheme-1B:

[0351] Scheme-ID:

[0352] X = Halogen;

[0353] L' = -CH2-Ph-CH2-

[0354] GENERAL SCHEME -2:

[0355] R' = alkyl;

[0356] X = Halogen

[0357] SYNTHESIS OF INTERMEDIATES:

[0358] Intermediate-1: 7-(difluoromethyl)-7'-methoxy-l',3'-dimethyl-6-(1H-pyrazol- 4-yl)-3,4-dihydro-2H-[1,5'-biquinolin]-2'(1'H)-one

[0359] Step-1: Synthesis of 7-(difluoromethyl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline

[0360] To a mixture of 6-bromo-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (29 g, 110.64 mmol) (US2019308978) and 1-(tetrahydro-2H-pyran-2-yl)-4-(4, 4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (33.8 g, 278.16 mmol) (W02018201006 A1, Page-40, Example 1A) in water (110 ml) and dioxane (430 ml), was added K2CO3(30.5 g, 221.29 mmol) and purged with argon for 5 mins. To this Pd(dppf)Cl2.DCM (8.09 g, 11.06 mmol) was added and purged argon again for 5 mins. The reaction mixture was heated at 110°C for 16 hours. Reaction mixture was dissolved in ethyl acetate and filtered through celite bed. Water was added to the filtrate and the organic layer was separated and concentrated under reduced pressure to afford crude. Purification was done using combi flash in EtOAc-Hexane system. Product eluted at 15-20% EtOAc-Hexane to afford the pure title intermediate-la (29 g, 78.62%).

[0361] Step-2: Synthesis of 7-(difluoromethyl)-7'-methoxy-l',3'-dimethyl-6-(1- (tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-3,4-dihydro-2H-[1 5'- biquinolin]-2'(1'H)-one

[0362] 5-bromo-7-methoxy-1,3-dimethylquinolin-2(1H )-one (5 g, 17.72 mmol) (WO202253967, 2022 Al, Page-63, step-5, N11) and intermediate- la (7.6 g, 23.03 mmol) were taken in 1,4-di oxane (50 ml) and sodium tert-butoxide (4.25 g, 44.3 mmol) was added under argon gas atmosphere in a seal tube. Then RuPhos (0.99 g, 2.12 mmol) and RuPhos Pd G2 (0.2 g, 0.26 mmol) were added and once again purging continued for another 5 mins. Then the seal tube was closed and heated at 110 °C for 16 hours. The progress was monitored by TLC. TLC showed completion of the starting materials. Then RM was cooled to RT and filtered through celite using ethyl acetate. Ethyl acetate layer was washed with water and brine solution. Organic layer was concentrated under reduced pressure to afford crude. Crude was purified by using combi flash in Ethyl acetate-Hexane system. Desired product eluted at 40-70% ethyl acetate-hexane to afford the pure intermediate-1 b(4 g, 42.2%).

[0363] Step-3: Synthesis of 7-(difluoromethyl)-7'-methoxy-1',3'-dimethyl-6-(1H- pyrazol-4-yl)-3,4-dihydro-2H-[1,5'-biquinolin]-2'(1'H)-one

[0364] Intermediate 1b(4 g, 7.48 mmol) was taken in THF (80 ml) and added 6N HCl (40 ml) then the reaction mixture was heated to 70°C for 16h. The reaction mixture was evaporated and basified with sat. sodium bicarbonate in ice cold conditions. The resultant solid was vacuum filtered and washed with hexane to get the title Intermediate-1 (4 g).

[0365] The Intermediates listed in below Table-A were prepared by reacting the corresponding starting material and using a procedure similar to the one described in synthesis of Intermediate- 1 with appropriate variations in quantities of reagents, solvents and reaction conditions. The characterization data of the compounds are summarized herein the below table.

[0366] Table-A:

[0367] Intermediate-2: 7-(difluoromethyl)-1',3'-dimethyl-6-(1H-pyrazol-4-yl)-7'-

[0368] (tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-[1,5'-biquinolin]-2'(1'H)-one

[0369] Step-1: Synthesis of 7-(difluoromethyl)-7'-hydroxy-1',3'-dimethyl-6-(1-

[0370] (tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-3,4-dihydro-2H-[1,5'- biquinolin]-2'(1'H)-one

[0371] To the Intermediate -lb (3.7 g, 6.92 mmol) inNMP (15 ml), was added NaOH (0.83 g, 20.76 mmol) and dodecanethiol (2.1 g, 10.38 mmol). The reaction mixture was heated at 100°C for 16 hours. RM was acidified with IN HC1, precipitated solid was filtered and dried. Solid was washed with MTBE and dried to afford the title intermediate-2a (3.4 g, crude).

[0372] Step-2: Synthesis of 7-(difluoromethyl)-1',3'-dimethyl-2'-oxo-6-(1-

[0373] (tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1',2',3,4-tetrahydro-2H-[1,5'- biquinolin]-7'-yl trifluoromethanesulfonate

[0374] To the intermediate-2a (0.5 g, 0.93 mmol) in DCM (20 ml), was added triethylamine (0.47 g, 4.67 mmol) and triflic anhydride (0.79 g, 2.80 mmol). The reaction mixture was heated at 100 °C stirred at RT for 16 hours. Water was added and extracted with dichloromethane and concentrated under reduced pressure to afford the title intermediate-2b (0.8 g, crude).

[0375] Step-3: Synthesis of 7-(difluoromethyl)-7'-(3,6-dihydro-2H-pyran-4-yl)-

[0376] 1',3'-dimethyl-6-(l-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-3,4-dihydro- 2H-[1,5'-biquinolin]-2'(1'H)-one The mixture of intermediate-2b (1.4 g, 2.14 mmol) and 2-(3,6-dihydro-2H-pyran- 4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.6 g, 3.21 mmol) were taken in DMF (30 ml) and was added K2CO3(0.88 g, 6.43 mmol). The reaction mixture was purged with Ar gas for 5 mins and [1,1'-Bis(diphenylphosphino)ferrocene] palladium(II)dichloride was added (0.26 g, 0.32 mmol). The reaction mixture was heated at 80°C for 16 hours. Progress of the reaction was monitored by analysis then the reaction mixture was extracted with ethyl acetate and water. The organic layer was dried and concentrated under reduced pressure. Crude material was purified by combi flash column chromatography using 24 g column and elutes at 50-60% ethyl acetate hexane and concentrated under reduced pressure to afford the title intermediate-2c (1 g, 79.47%).

[0377] Step-4: Synthesis of 7-(difluoromethyl)-1',3'-dimethyl-6-(1-(tetrahydro-2H- pyran-2-yl)-1H-pyrazol-4-yl)-7'-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H- [1,5'-biquinolin]-2'(1'H)-one

[0378] To intermediate-2c (1 g, 1.70 mmol) in THF (8 ml) and ethyl acetate (4 ml), was added platinum oxide (0.19 g, 0.85 mmol). The reaction mixture was stirred under hydrogen for 16 hours. Progress of the reaction was monitored by LCMS analysis then reaction mixture was filtered through celite and concentrated under reduced pressure to afford the title intermediate-2d (0.8 g, crude).

[0379] Step-5: Synthesis of 7-(difluoromethyl)-1',3'-dimethyl-6-(1H-pyrazol-4-yl)-7'- (tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-[1,5'-biquinolin]-2'(1'H)-one

[0380] Intermediate-2d (0.8 g, 1.35 mmol) was taken in THF (20 ml) and added 6N HC1 (7 ml) then the reaction mixture was heated to 70°C for 4 hours. Reaction mixture was evaporated and basified with saturated sodium bicarbonate in ice cold conditions. The resultant solid was vacuum filtered and washed with hexane to afford the title Intermediate-2 (0.6 g).

[0381] The Intermediates listed in below Table-B were prepared by reacting the corresponding starting material and using a procedure similar to the one described in step 1 and 2 of Intermediate- 1 followed by step 1 to step 5 of Intermediate-2 with appropriate variations in quantities of reagents, solvents and reaction conditions. The characterization data of the compounds are summarized herein the below table.

[0382] Table-B:

[0383] Step-1: Synthesis of 7-chloro-5-(7-(difluoromethyl)-6-(1-(tetrahydro-2H- pyran-2-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,3-dimethyl-1,6- naphthyridin-2(1H)-one.

[0384] A solution of 5,7-dichloro-1,3-dimethyl-1,6-naphthyridin-2(1H)-one (1g, 4.11m. mol) and 7-(difluoromethyl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol- 4-yl)-1,2,3,4- tetrahydroquinoline (1.6g, 4.93mmol) in 1,4-dioxane (20ml) was taken in a biotage vial and added potassium carbonate (1.1g, 8.22mmol) and palladium acetate (92mg, 0.41 Immol) followed by xantphos (118mg, 0.20mmol).

[0385] The reaction mixture was stirred for 16 hours at 72°C. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to RT. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was passed through sodium sulphate and evaporated to afford crude. Crude was purified by silica gel column chromatography to afford intermediate-3a(0.6g, 28%). LC- MS: 540.3 [M+H]+.

[0386] Step-2: Synthesis of 5-(7-(difluoromethyl)-6-(l-(tetrahydro-2H-pyran-2-yl)- 1H-pyrazol-4-yl)-3,4-dihydroquinolin-l (2H)-yl)- 1,3-dim ethyl- 1 ,6- naphthyridin-2(1H)-one

[0387] To a solution of 7-chloro-5-(7-(difluoromethyl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,3-dimethyl-1,6-naphthyridin- 2(1H)-one(0.6g, 1.11mmol) in Ethanol (20ml) was added Pd / C (100mg) and the reaction mixture was stirred under hydrogen for 16h. Filtered through celite and evaporated to afford desired intermediate-3b(0.5g, crude). LC-MS: 506.21 [M+H]+.

[0388] Step-3: Synthesis of 5-(7-(difluoromethyl)-6-(1H-pyrazol-4-yl)-3,4- dihydroquinolin-1(2H)-yl)-1,3-dimethyl-1,6-naphthyridin-2(1H)-one

[0389] The Intermediate-3 was synthesized from intermediate-3b by following step-5 of Intermediate-2 Synthesis.

[0390] LC-MS: 422.46 [M+H]+.

[0391] Intermediate-4:

[0392] Step-1: Synthesis of 7-chloro-5-(7-(difluoromethyl)-6-(1H-pyrazol-4-yl)-3,4- dihydroquinolin-1(2H)-yl)-1,3-dimethyl-1,6-naphthyridin-2(1H)-one The Intermediate-4 was synthesized from intermediate-3 a by following step-5 of Intermediate-2 Synthesis.

[0393] LC-MS: 456.31 [M+H]+.

[0394] Intermediate-5:

[0395] Step-1: Synthesis of 5-(7-(difluoromethyl)-6-(1-(tetrahydro-2H-pyran-2-yl)- 1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-7-(3,6-dihydro-2H-pyran-4- yl)-1,3-dimethyl-1,6-naphthyridin-2(1H)-one

[0396] A solution of 7-chloro-5-(7-(difluoromethyl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazol-4-yl)-3 ,4-dihydroquinolin- 1 (2H)-yl)- 1 ,3 -dimethyl- 1 ,6-naphthyridin- 2(1H)-one (0.34g, 0.63mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4, 4,5,5- tetramethyl-1,3,2-dioxaborolane (0.17g, 0.81mmol) in dioxane (7ml) and water (2ml) was taken in a biotage vial and added pd(amphos)Cl2(45mg, 0.06mmol) followed by K2CO3(0.26g, 1.89mmol). The reaction mixture was stirred at 80° C for 16 hours. The progress of the reaction was monitored by checking TLC. Reaction mixture was cooled to RT, diluted with water, and extracted with ethyl acetate. The organic layer was concentrated on rota and carried for purification to afford the intermediate-5a (0.3g, 81%). LC-MS: 588.25 [M+H]+.

[0397] Step-2: Synthesis of 5-(7-(difluoromethyl)-6-(1-(tetrahydro-2H-pyran-2-yl)- 1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-l,3-dimethyl-7-(tetrahydro- 2H-pyran-4-yl)-1,6-naphthyridin-2(1H)-one

[0398] A solution of 5-(7-(difluoromethyl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol- 4-yl)-3,4-dihydroquinolin-1(2H)-yl)-7-(3,6-dihydro-2H-pyran-4-yl)-1,3-dimethyl- 1,6-naphthyridin-2(1H)-one (0.3g, 0.51 mmol) in ethanol (10ml) was taken in an RBF and added platinum oxide (58mg, 0.25mmol). The reaction was carried under hydrogen atmosphere. The reaction mixture was stirred at RT for 16 hours. The progress of the reaction was monitored by checking TLC. After completion of the reaction, the reaction mixture was filtered through celite bed, filtrate was concentrated on rota to afford intermediate-5b (0.3g, crude). LC-MS: 590.3 [M+H]+.

[0399] Step-3: Synthesis of 5-(7-(difluoromethyl)-6-(1H-pyrazol-4-yl)-3,4- dihydroquinolin-1(2H)-yl)-1,3-dimethyl-7-(tetrahydro-2H-pyran-4-yl)-1,6- naphthyridin-2(1H)-one

[0400] The Intermediate-5 was synthesized from intermediate-5b by following step-5 of Intermediate-2 Synthesis.

[0401] LC-MS: 506.23 [M+H]+.

[0402] Intermediate-6:

[0403] Step-1: Synthesis of methyl 9-(4-(7-(difluoromethyl)-7’-methoxy-1’,3’- dimethyl-2’-oxo-1’,2’,3,4-tetrahydro-2H-[l,5’-biquinolin]-6-yl)-1H-pyrazol-1- yl)nonanoate

[0404] To a mixture of Intermediate- 1(3 g, 6.658 mmol) and methyl 9-bromononanoate (5.017 g, 19.977 mmol) (JP2020 / 83876, 2020, A; Paragraph 0069) in dimethyl sulfoxide (30 ml), were added K2CO3(5.52 g, 39.95 mmol) and KI (0.22 g, 1.33 mmol). The reaction mixture was heated at 100°C for 16 h. Progress of the reaction was monitored by TLC. After completion of the reaction mixture, was quenched with water and extracted with ethyl acetate and organic part was washed with water, brine, dried over Na2SO4 and concentrated under reduced pressure to afford crude. Purification was done by using combi flash in methanol- dichloromethane system. Product eluted at 3-4% methanol-di chloromethane to afford the pure intermediate- 6a (3.2 g, 77.43%). Step-2: Synthesis of 9-(4-(7-(difluoromethyl)-7'-methoxy-1',3'-dimethyl-2'- oxo-1',2',3,4-tetrahydro-2H-[1,5'-biquinolin]-6-yl)-1H-pyrazol-1-yl) nonanoic acid

[0405] To intermediate-6a (2.1 g, 3.383 mmol) in THF: MeOH: H2O (36 ml, 4: 1 :1), was added lithium hydroxide (0.24 g, 10.14 mmol). The reaction mixture was stirred at RT for 16 hours. Acidified with IN HCl, precipitated solid was filtered and dried to afford Intermediate-6 (1.5 g, crude).

[0406] The Intermediates listed in below Table-C were prepared by reacting the corresponding starting material and using a procedure similar to the one described in synthesis of Intermediate-6 with appropriate variations in quantities of reagents, solvents and reaction conditions. The characterization data of the compounds are summarized herein the below table.

[0407] Table-C:

[0408]

[0409] Intermediate-7: step-1 step-2 7b steps

[0410] Step-1: Synthesis of 4-(7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl) phenol The starting material 6-bromo-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (2.5 g, 9.53mmol) and (4-hydroxyphenyl) boronic acid (1.44 g, 10.49 mmol) were taken in dioxane: H2O (50 ml, 4: 1) and K2CO3(2.63 g, 19.07 mmol) was added. The reaction mixture was purged with Ar gas for 5 mins. and Bis(diphenylphosphino)ferrocenedichloropalladium(II)catalyst (0.55 g, 0.76 mmol) was added, purging was continued again for another 5 mins.. The seal tube was closed and heated at 110 ° C for 16 hours. RM was cooled to RT and filtered through celite. The filtrate was diluted with excess of EtOAc and washed with cold water multiple times followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Crude material was purified by combi flash column chromatography by using 40 g column and eluted at 40-50% ethyl acetate and hexane to afford intermediate-7a (2.4 g, 91.4%). LC-MS: 276.0 [M+H]+.

[0411] Step-2: Synthesis of 7-(difluoromethyl)-6-(4-hydroxyphenyl)-7'-methoxy-1',3'- dimethyl-3,4-dihydro-2H-[1,5'-biquinolin]-2'(1'H)-one

[0412] The intermediate-7b was synthesized from intermediate-7a by following the procedure as in step-2 of Intermediate- 1 synthesis.

[0413] LC-MS: 477.1 [M+H]+.

[0414] Step-3: Synthesis of ethyl 8-(4-(7-(difluoromethyl)-7'-methoxy-l',3'-dimethyl- 2'-oxo-1',2',3,4-tetrahydro-2H-[l,5'-biquinolin]-6-yl) phenoxy) octanoate

[0415] The intermediate-7c was synthesized from intermediate-7b by following the procedure as in step- 1 of Intermediate-6 Synthesis.

[0416] LC-MS: 647.2 [M+H]+.

[0417] Step-4: Synthesis of 8-(4-(7-(difluoromethyl)-7'-methoxy-1',3'-dimethyl-2'- oxo-1',2',3,4-tetrahydro-2H-[1,5'-biquinolin]-6-yl) phenoxy)octanoic acid

[0418] The Intermediate-7 was synthesized from intermediated by following the procedure as in step-2 of Intermediate-6. The Intermediates listed in below Table-D were prepared by reacting the corresponding starting material with intermediate 7b and using a procedure similar to the one described in step 3 and step 4 of the synthesis of Intermediate-7 with appropriate variations in quantities of reagents, solvents and reaction conditions. The characterization data of the compounds are summarized herein the below table.

[0419] Table- D:

[0420] Intermediate-8: Step-1: Synthesis of benzyl 4-(4-(7-(difluoromethyl)-7'-methoxy-1',3'- dimethyl-2'-oxo-1',2',3,4-tetrahydro-2H-[1,5'-biquinolin]-6-yl)-1H-pyrazol-1- yl)piperidine-l-carboxylate

[0421] To a solution of Intermediate- 1 (4g, 8.87mmol) in DMSO (40ml) was added CS2CO31 1.5g, 35.51mmol). Stirred for 15min followed by addition of benzyl 4- ((methylsulfonyl)oxy)piperidine-l-carboxylate ( 5.54g, 17.75mmol). RM was heated to 100 °C for 2 hours. Progress of the reaction was monitored by TLC, SM was consumed. RM was extracted with ethyl acetate and water. The organic layers were concentrated and washed with pentane to afford the intermediate-8a(6g, crude). LC-MS: 668.5 [M+H]+.

[0422] Step-2: Synthesis of 7-(difluoromethyl)-7'-methoxy-1',3'-dimethyl-6-(1- (piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydro-2H-[1,5'-biquinolin]-2'(1'H)- one

[0423] To the intermediate-8a (5g, 7.48mmol) in EtOH (50 ml) was added Pd / C (0.5g, 4.69mmol) at inert atm then RM was stirred at RT for 16 hours under H2 atm. Progress of the reaction was monitored by TLC. SM was consumed, RM was filtered through cellite and washed with methanol filtrate was concentrated. The crude was washed with diethyl ether to afford the intermediate-8b (2.7g, crude). LC-MS: 534.2 [M+H]+.

[0424] Step-3: Synthesis of tert-butyl 4-(4-(4-(7-(difluoromethyl)-7'-methoxy-1',3'- dimethyl-2'-oxo-1',2',3,4-tetrahydro-2H-[1,5'-biquinolin]-6-yl)-1H-pyrazol-1- yl)piperidine-1-carbonyl)piperidine-l-carboxylate

[0425] To a solution of 7-(difluoromethyl)-7'-methoxy-1',3'-dimethyl-6-(1-(piperidin-4- yl)-1H-pyrazol-4-yl)-3,4-dihydro-2H-[1,5'-biquinolin]-2'(1'H)-one (0.15g, 0.28mmol) in DMF (2ml), HATU (0.1g. 0.42mmol) was added at RT and then the mixture was stirred at RT for 15min. Then 1-(tert-butoxycarbonyl)piperidine- 4carboxylic acid (77mg. 0.33mmol) and DIPEA (0.1g, 0.84mmol) was added and allowed to stir at RT for 16 hours. The progress of the reaction was monitored by checking the TLC. TLC showed the absence of starting material. Ice was added to the reaction mixture and precipitated solid was filtered and dried to afford the intermediate-8c (0.13g, crude). LC-MS: 745.4 [M+H]+.

[0426] Step-4: Synthesis of 7-(difluoromethyl)-7'-methoxy-1',3'-dimethyl-6-(1-(1- (piperidine-4-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydro-2H- [1,5'-biquinolin]-2'(1'H)-one

[0427] 4M HCl in 1 4 -dioxane (2ml) was added to a stirred solution of tert-butyl 4-(4-(4- (7-(difluoromethyl)-7'-methoxy-T,3'-dimethyl-2'-oxo 1',2',3,4 -tetrahydro-2H- [1,5'-biquinolin]-6-yl)-1H-pyrazol-1-yl)piperidine-l-carbonyl)piperidine-1- carboxylate (0.13g, 0.17mmol) in DCM (2ml) at 0°C. Then the reaction mixture was allowed to stir at RT for 2 hours. The progress of the reaction was monitored by checking the TLC. TLC showed the absence of starting material. The RM was concentrated under reduced pressure to afford intermediate-8d (0.13g, crude). LC- MS: 645.3 [M+H]+.

[0428] Step-5: Synthesis of tert-butyl 2-(4-(4-(4-(7-(difluoromethyl)-7'-methoxy-1',3'- dimethyl-2'-oxo-l',2',3,4-tetrahydro-2H-[1,5'-biquinolin]-6-yl)-1H-pyrazol-1- yl)piperidine-1-carbonyl)piperidin-1-yl)acetate tert-butyl 2-bromoacetate (40mg, 0.20mmol) was added to stirred solution of 7- (difluoromethyl)-7'-methoxy- 1',3'-dimethyl-6-(1-(1-(piperidine-4- carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydro-2H-[1,5'-biquinolin]- 2'(1'H)-one (0.13g, 0.20mmol), DIPEA (78mg, 0.60mmol) in DMF (2ml) and stirred for 1.5 hours at RT. The progress of the reaction was monitored by TLC. TLC showed the absence of Rl. in the RM ice cold water was added precipitated solid was filtered and dried to affordintermediate-8e(0.09g, crude). LC-MS: 759.35 [M+H]+.

[0429] Step-6: Synthesis of 2-(4-(4-(4-(7-(difluoromethyl)-7'-methoxy-1',3'-dimethyl- 2'-oxo-1',2',3,4-tetrahydro-2H-[1,5'-biquinolin]-6-yl)-1H-pyrazol-1- yl)piperidine-1-carbonyl)piperidin-1-yl)acetic acid 4M 1Cl in 1 4 -dioxane (2ml) was added to a stirred solution of tert-butyl 2-(4-(4- (4-(7-(difluorornethyl)-7'-methoxy-1,3'-dirnethyl-2'-oxo- 1',2',3,4-tetrahydro-2H- [ 1 ,5'-biquinolin]-6-yl)- 1H-pyrazol- 1 -yl)piperidine- 1 -carbonyl)piperidin- 1 - yl)acetate (0.09g, 0.1 Immol) in DCM (2ml) at 0°C. Then the reaction mixture was allowed to stir at RT for 2 hours. The progress of the reaction was monitored by checking the TLC. TLC showed the absence of starting material. The RM was concentrated under reduced pressure to afford the crude Intermediate-8(0.09g, crude). LC-MS: 703.3 [M+H]+.

[0430] Intermediate-9:

[0431] Step-1: Synthesis of 2-(4-(7-(difluoromethyl)-7'-methoxy-1',3'-dimethyl-2'- oxo-1',2',3,4-tetrahydro-2H-[1,5'-biquinolin]-6-yl)-1H-pyrazol-l-yl)-N-(14- hydroxytetradecyl)acetamide The synthesis of intermediate-9a was done from intermediate C-1 by following the procedure as in step-3 of Intermediate-8 Synthesis.

[0432] LC-MS: 720.4 [M+H]+.

[0433] Step-2: Synthesis of 14-(2-(4-(7-(difluoromethyl)-7'-methoxy-1',3'-dimethyl- 2'-oxo-1',2',3,4-tetrahydro-2H-[1,5'-biquinolin]-6-yl)-1H-pyrazol-1- yl)acetamido)tetradecyl methanesulfonate

[0434] Methanesulfonylchloride (0.19g, 1.66mmol) was added to stirred solution of 2-(4- (7-(difluoromethyl)-7'-methoxy-T,3'-dimethyl-2'-oxo-1',2',3,4-tetrahydro-2H- [1,5'-biquinolin]-6-yl)-1H-pyrazol-1-yl)-N-(14-hydroxytetradecyl)acetamide (1g, 1.39mmol), TEA (0.42g, 4.17mmol) in DCM (20ml) and stirred for 1.5 hours at

[0435] RT. The progress of the reaction was monitored by TLC showed the absence of R1. in the RM. ice cold water was added,, precipitated solid was filtered and dried to afford the Intermediate-9(0.9g, crude). LC-MS: 799.32 [M+H]+.

[0436] The Intermediates listed in below Table-E were prepared by reacting the corresponding starting material with intermediate C-1 and using a procedure similar to the one described in step 1 and step 2 of the synthesis of Intermediate-9 with appropriate variations in quantities of reagents, solvents and reaction conditions. The characterization data of the compounds are summarized herein the below table.

[0437] Table- E:

[0438] Intermediate-10

[0439] Step-1: Synthesis of 6-(l-(4-(bromomethyl)benzyl)-1H-pyrazol-4-yl)-7- (difluoromethyl)-7'-methoxy-1',3'-dimethyl-3,4-dihydro-2H-[1,5'-biquinolin]-

[0440] 2'(l'H)-one

[0441] Potassium carbonate (92mg, 0.66mmol) was added to stirred solution of 7- (difluorornethyl)-7'-methoxy- 1',3'-dirnethyl-6-(1H-pyrazol-4-yl)-3,4-dihydro-2H- [1,5'-biquinolin]-2'(1'H)-one (0.3g, 0.66mmol) in DMF (3ml) and stirred for 15 min. l,4-bis(bromomethyl)benzene (0.19g, 0.73mmol) was added and the reaction mixture was stirred at RT for 16 hours. The progress of the reaction was monitored by TLC. RM was quenched with ice cold water was precipitated solid was filtered and dried. Purification was done by column chromatography to afford the pure intermediate: Intermediate-10(0.16g, 37.92%) LC-MS: 634.8 [M+H]+. List of commercially available VHL amines which were used herein are summarized in the below table-F:

[0442] Table F:

[0443]

[0444] Step-1: Synthesis of (2S,4S)-1-((S)-2-(9-(4-(7-(difluoromethyl)-7'-methoxy- 1',3'-dimethyl-2'-oxo-1',2',3,4-tetrahydro-2H-[1,5'-biquinolin]-6-yl)-1H- pyrazol-1-yl)nonanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide. To Intermediate-6 (0.1 g, 0.165 mmol) in DMF (2ml), was added VHL-24 (72mg, 0.15 mmol), HATU (53 mg, 0.22 mmol) and DIPEA (0.97 g, 0.75 mmol). The reaction mixture stirred at RT for 2h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice water and extracted with 5% MeOH-DCM. Organic layer was concentrated under reduced pressure to afford crude. Purification was done by using combi-flash in methanol-dichloromethane system. Product eluted at 4-5% methanoldichloromethane to afford the pure title compound Compound-1(0.06 g, 38.7%).

[0445] LC-MS: 1005.3 [M+H]+; 1H-NMR (400 MHz, DMSO-D6) δ 8.98 (s, 1H), 8.37- 8.35 (d, 1H), 7.74-7.76 (m, 3H), 7.59 (s, 1H), 7.49 (s, 1H), 7.42-7.37 (m, 4H), 7.15 (s, 1H), 6.96 (s, 1H), 6.97-6.96 (d, 1H), 6.18 (s, 1H), 5.09-5.08 (d, 1H), 4.52-4.50 (t, 1H), 4.49-4.45 (d, 1H), 4.42-4.39 (t, 1H), 4.35 (s, 1H), 4.15-4.05 (t, 2H), 3.95 (s, 3H), 3.65 (s, 3H), 3.55-3.50 (m, 5H), 3.49 (m, 1H), 2.94 (s, 2H), 2.59-2.49 (m, 6H), 2.45 (s, 1H), 2.25-2.20 (m, 3H), 2.15-2.05 (m, 4H), 2.06-1.79 (m, 1H), 1.75-1.65 (m, 3H), 1.55-1.45 (m, 3H), 0.93 (m, 9H).

[0446] The compounds listed in below Table-G were prepared by reacting the corresponding intermediates and VHL- amines using a procedure as described in Example- 1 with appropriate variations in quantities of reagents, solvents and reaction conditions. The characterization data of the compounds are summarized herein the Table-G below.

[0447] Table-G: mixture extracted

[0448] Ill

[0449] Example-2:

[0450]

[0451] Synthesis of (2S,4R)-N-(2-((14-(2-(4-(7-(difluoromethyl)-7'-methoxy-1',3'- dimethyl-2'-oxo-1',2',3,4-tetrahydro-2H-[l,5'-biquinolin]-6-yl)-1H-pyrazol-1- yl)acetamido)tetradecyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1- ((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide.

[0452] Potassium carbonate (35mg, 0.25mmol) was added to stirred solution of 2-(4-(7- (difluoromethyl)-7'-methoxy- 1',3'-dimethyl-2'-oxo-T,2',3,4-tetrahydro-2H-[1,5'- biquinolin]-6-yl)-1H-pyrazol-1-yl)-N-(14-hydroxytetradecyl)acetamide (0.1g, 0.12mmol) in DMF (3ml) and stirred for 3h at 80°C. The progress of the reaction was monitored by TLC. RM was quenched with ice cold water was precipitated solid was filtered and dried. Purification was done by column chromatography to afford the title compound Compound-92(0.1g, 74%).

[0453] LC-MS: 1250.45 [M+H]+; 1H-NMR (400 MHz, DMSO-D6) δ 8.98 (s, 1H), 8.38- 8.36 (m, 1H), 8.04-8.01 (t, 1H), 7.75-7.62 (s, 1H), 7.61-7.59 (d, 1H), 7.58-7.49 (m, 5H), 7.49-7.48 (d, 1H), 7.25 (s, 1H), 7.05-6.98 (m, 3H), 6.95-6.89 (m, 1H), 6.86- 6.58 (m, 1H), 6.25-6.20 (m, 1H), 5.25-5.15 (m, 1H), 4.78 (s, 2H), 4.73-4.70 (d, 1H), 4.53-4.51 (s, 1H), 4.48-4.43 (m, 2H), 4.23-4.20 (m, 1H), 4.06-4.02 (m, 2H), 3.89 (s, 3H), 3.77-3.74 (m, 1H), 3.69 (s, 4H), 3.55-3.50 (m, 2H), 3.10-3.06 (m, 2H), 2.95 (s, 2H), 2.65-2.64 (m, 2H), 2.58-2.54 (m, 3H), 2.51-2.49 (s, 3H), 2.45-2.40 (m, 3H), 2.24-2.21 (m, 1H), 2.20-2.15 (m, 5H), 1.95-1.89 (m, 1H) 1.75-1.73 (m, 2H), 1.45-1.43 (m, 4H), 1.39-1.35 (m, 13H), 0.97-0.95 (d, 3H), 0.74-0.71 (d, 3H).

[0454] The compounds listed in below Table-H were prepared by reacting the corresponding intermediates and VHL- amines using a procedure as described in Step 1 and 2 of intermediate-9 and Step 1 of Example-2 with appropriate variations in quantities of reagents, solvents and reaction conditions. The characterization data of the compounds are summarized herein the Table-H below.

[0455] Table-H: Step-1: Synthesis of (2S,4R)-1-((S)-3-((4-((4-(7-(difluoromethyl)-7'-methoxy- 1',3'-dimethyl-2'-oxo-1',2',3,4-tetrahydro-2H-[1,5'-biquinolin]-6-yl)-1H- pyrazol-1-yl)methyl)benzyl)thio)-2-(1-fluorocyclopropane-l-carboxamido)-3- methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0456] DBU (14mg, 0.09mmol) was added to stirred solution of 6-(1-(4- (bromomethyl)benzyl)-1H-pyrazol-4-yl)-7-(difluoromethyl)-7'-methoxy-1',3'- dimethyl-3,4-dihydro-2H-[1,5'-biquinolin]-2'(1'H)-one (50mg, 0.07mmol) and VHL-23 (52mg, 0.09mmol) in DMF (2ml) and stirred for 16 hours atRT. The progress of the reaction was monitored by TLC. RM was quenched with ice cold water was precipitated solid was filtered and dried. Purification was done by column chromatography to afford the title compound: Compoud-96 (25mg, 25.29%).

[0457] LC-MS: 551.3 [M / 2+H]+; 1H-NMR (400 MHz, DMSO-D6) δ 8.98 (s, 1H), 8.48- 8.47 (d, 1H), 7.89-7.88 (s, 1H), 7.58-7.56 (d, 1H), 7.53-7.51 (m, 2H), 7.50-7.45 (m, 4H), 7.44-7.25 (m, 4H), 7.15 (s, 1H), 6.96-6.95 (d, 1H), 6.85-6.55 (m, 1H), 6.25- 6.15 (s, 1H), 5.31 (s, 2H), 4.89-4.85 (d, 2H), 4.50-4.49 (t, 1H), 4.35-4.32 (m, 1H), 3.95 (s, 3H), 3.85-3.82 (s, 2H), 3.68-3.58 (s, 3H), 3.57-3.51 (m, 3H), 3.50-3.49 (m, 1H), 2.95 (s, 2H), 2.45-2.40 (m, 3H), 2.34-2.30 (m, 2H), 2.25-2.20 (m, 1H), 2.05- 2.00 (m, 3H), 1.85-1.75 (m, 1H), 1.49-1.45 (m, 3H), 1.41-1.39 (m, 1H), 1.26 (s, 4H), 1.26-1.24 (m, 7H).

[0458] BIOLOGICAL ASSAY

[0459] Targeted protein degradation controls the amount of a harmful cellular protein rather than modulation or inhibition of its function. This novel therapeutic approach also offers many opportunities to differentiate from inhibitor-based therapies. First, by catalysing the destruction of their target protein, degrader molecules may also disrupt scaffolding functions of proteins otherwise not addressed by small 1 molecule inhibitors, allowing for drug properties that are unlike other classes of drugs. Second, degraders may offer higher potency and differentiated cellular pharmacology. Unlike inhibitors, which must remain bound to a single target protein, degrader molecules can catalyse the ubiquitination and destruction of multiple copies of the same protein since the degraders themselves are not degraded in the proteasome.

[0460] Determination of Degradation of Protein in HiBiT Assay: U2OS-HiBiT Assay Protocol:

[0461] U2OS-CBP HiBiT and U2OS-p300 HiBiT cells were seeded and incubated overnight at 37°C in a CO2incubator for adherence. Next day, both the cells were pretreated with various concentrations of degrader for 24 hrs in the incubator. Working HiBiT-lytic reagent was added to the cells and incubated on orbital shaker at room temperature for 20 mins. Post incubation, the chemiluminescent signal was read using a luminometer. Selected compounds of the present disclosure were screened in the above-mentioned assay procedure and the percentage of p300 degradation in HiBiT assay at 0.2μM were determined.

[0462] Exemplary compounds of the present application were screened by the above-mentioned assay. For certain exemplary compounds of the present application, the % p300 degradation @0.2μM is given in the below Table G where in “A” refers to % degradation value of greater than 50, “B” refers to % degradation value between 20-50(both inclusive), and “C” refers to % degradation value of less than 20.

[0463] Table G:

[0464] Incorporation by Reference

[0465] All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0466] Equivalents

[0467] While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the disclosure will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

We claim:

1. A compound of formula (I'):or pharmaceutically acceptable salts, solvates or isomers thereof, wherein; R1represents hydrogen, (C1-C6)alkyl or (C3-C6)cycloalkyl;R2and R3independently represents hydrogen or (C1-C6)alkyl; R4represents hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, halogen or 5 to 12 membered heterocycloalkyl;X1 represents CRx1or N; X2 represents: i) -C(RaRb)-, -NRx2-, -O- or -S-; wherein Raand Rbare independently hydrogen or (C1-C6)alkyl; or ii) -C(Ra)- or N, when the ring having X2is aromatic; wherein Rais hydrogen or (C1-C6)alkyl; X3 represents C, CH or N;X4 represents C or N;R5represents hydrogen, halogen, cyano, (C1-C6)alkyl, halo(C1-C6)alkyl or (C1- C6)alkoxy;Rx1 represents hydrogen or (C1-C6)alkyl;Rx2 represents hydrogen, (C1-C6)alkyl or (C3-C6)cycloalkyl;Ar represents 5- or 6-membered heteroaryl enyl or (C6-C12)arylenyl;L1 and L3 independently represents a bond, -O-, -(CH2)p-, -(CH2)q-C(O)-NRc-, or - C(O)-NRc-(CH2)q-, wherein Li is attached with Ar, L3 is attached with E, and any methylene group of -(CH2)qis optionally independently substituted with one or more Ra;L2 represents -(CH2)m-, 3- to 8- membered heterocycloalkylenyl, phenylenyl or (3- to 8-membered heterocycloalkylenyl)-L4-(3- to 8-membered heterocycloalkylenyl), wherein L4 is a bond, -(CH2)n- or -C(O)-; and one or more methylene group of - (CH2)m- is optionally replaced with -O- or optionally independently substituted with one or more Re;Rcrepresents hydrogen or (C1-C6)alkyl;Rdat each occurrence represents hydrogen, (C1-C6)alkyl or hydroxyl;Reat each occurrence represents (C1-C6)alkyl, hydroxyl, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl or an amino acid sidechain; m is an integer ranging from 1 to 20; n is an integer ranging from 1 to 3; p is an integer ranging from 1 to 5; q is an integer ranging from 1 to 3; r is an integer ranging from 1 to 3;E is selected from formulae El, E2, E3, E4, E5, E6 or E7:wherein, the asterisk marks the point of attachment with linker, L3;R6represents hydrogen or hydroxyl-protecting group;R7represents hydrogen or (C1-C6)alkyl; R8represents hydrogen, (C1-C6)alkyl or hydroxy(C1-C6)alkyl;R9and R10independently represent hydrogen, (C1-C6)alkyl or halogen;R11represents hydrogen, (C2-C6)alkynyl, halogen, cyano or 5-membered heteroaryl ring, wherein the heteroaryl is optionally substituted with Rf;Rf represents (C1-C6)alkyl, halogen, hydroxyl, amino or halo(C1-C6)alkyl; and Z represents 5-6 membered heterocycloalkylenyl or 5-6 membered heteroarylenyl.

2. The compound according to claim 1, having the formula (I):or pharmaceutically acceptable salts, solvates or isomers thereof.

3. The compound according to any one of the claims 1 or 2, having the formula(IA):or a pharmaceutically acceptable salt, a solvate or an isomer thereof.

4. The compound according to any one of the claims 1 or 2, having the formula(IB):or a pharmaceutically acceptable salt, a solvate or an isomer thereof.

5. The compound according to any one of the claims 1 or 2, having the formula (IC):or a pharmaceutically acceptable salt, a solvate or an isomer thereof.The compound according to any one of the claims 1 to 4, wherein R1represents hydrogen or (C1-C6)alkyl.

7. The compound according to any one of the claims 1 to 4, wherein R2represents (C1-C6)alkyl.

8. The compound according to any one of the claims 1 to 4, wherein R3represents hydrogen.

9. The compound according to any one of the claims 1 to 4, wherein R4represents hydrogen, halogen, (C1-C6)alkyl, (C1-C6)alkoxy or 5 to 12 membered heterocycloalkyl.

10. The compound according to claim 9, wherein R4represents (C1-C6)alkoxy.

11. The compound according to claim 9, wherein R4represents 5 to 6 membered heterocycloalkyl.

12. The compound according to any one of the claims 1 to 4, wherein R5represents hydrogen, halogen, cyano or halo(C1-C6)alkyl.

13. The compound according to claim 12, wherein R5is halo(C1-C6)alkyl.

14. The compound according to any one of the claims 1 to 4, wherein X1is CH and X2is -C(RaRb)-, -NRx2- or -O-; wherein Ra, Rband RX2independently represent hydrogen or (C1-C6)alkyl.

15. The compound according to any one of the claims 1 to 4, wherein X1is N and X2is -C(RaRb)-; wherein Raand Rbare hydrogen.

16. The compound according to any one of the claims 1 to 4, wherein:R6represents hydrogen;R7represents (C1-C6)alkyl;R8represents (C1-C6)alkyl or hydroxy(C1-C6)alkyl;R9and R10represent halogen; andR11represents 5-membered heteroaryl ring.

17. The compound according to any one of the claims 1 to 4, wherein Z represents 5-membered heteroaryl enyl selected from:

18. The compound according to any one of the claims 1 to 17, wherein L1-L2- L3 together represents:-CH2-, -CH(CH(CH3 )2)-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-(CH2)3-CH2-, -CH2- (CH2)4-CH2-, -CH2-(CH2)6-CH2-, -CH2-(CH2)7-CH2-, -CH2-(CH2)5-CH2-, -CH2- (CH2)8-CH2-, -CH2-(CH2)9-CH2-, -CH2-(CH2)12-CH2-, *-O-CH2-(CH2)4-CH2-, *- O-CH2-(CH2)5-CH2-, *-O-CH2-(CH2)6-CH2-, *-CH2-(CH2)5-CH2-O-, *-CH2- (CH2)6-CH2-O-, *-CH2-(CH2)7-CH2-O-, *-CH2-CH2-O-(CH2)2-O-CH2-CH2-, *- CH2-CO-NH-CH2-CH2-, *-CH2-(CH2)7-CO-N(CH3)-CH(CH3)-, *-CH2-(CH2)10- CO-N(CH3)-CH(CH3)-, *-CH2-CO-NH-(CH2)4-CH2-, *-CH2-CO-NH-(CH2)7- CH2-, *-CH2-CO-NH-(CH2)10-CH2-, *-CH2-CO-NH-(CH2)13-CH2-,wherein, the asterisk marks the point of attachment with Ar.

19. A compound selected from:or a pharmaceutically acceptable salt, a solvate or an isomer thereof.

20. A pharmaceutical composition comprising a compound of any one of the claims 1 to 19, or a pharmaceutically acceptable salt, a solvate or an isomer thereof and at least one pharmaceutically acceptable excipient.

21. The compound according to any one of the claims 1 to 19 or a pharmaceutically acceptable salt, a solvate or an isomer thereof, for use as a medicament.

22. The compound of any one of the claims 1 to 19, or a pharmaceutically acceptable salt, a solvate or an isomer thereof, for use in the treatment of disease or disorder responsive to the degradation of target protein.

23. A method of treating disease and / or disorder responsive to degradation of p300 in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to any one of the claims 1 to 19, a pharmaceutically acceptable salt thereof, a solvate or an isomer thereof.

24. The method according to claim 23, wherein disease or disorder is cancer, autoimmune disease, inflammatory disease, viral infection, neurodegenerative disease, and metabolic disorder.

25. The method according to claim 24, wherein the disease or disorder is cancer.

26. The method of claim 25, wherein the cancer is prostate cancer, neuroendocrine prostate cancer, breast cancer, colorectal cancer, colon cancer, pancreatic cancer, intestinal cancer, chronic lymphocytic leukemia, lymphoma, glioblastoma, myeloid leukemia, acute myeloid leukemia, acute T-cell lymphoma, T-cell lymphoma, leukemia, lympho-plasmacytoid B-cell lymphoma, glioma, small cell lung cancer, neuroblastoma, angiosarcoma, chondrosarcoma, Ewing’s sarcoma, fibroblastic sarcoma, gynaecological sarcoma, liposarcoma, osteosarcoma, rhabdomyosarcoma, soft tissue sarcoma, synovial sarcoma, cancer of prostate adenocarcinoma, breast invasive carcinoma, bladder urothelial carcinoma, lung adenocarcinoma, liver hepatocellular carcinoma, cervical squamous cell carcinoma and endocervical adenocarcinoma, cholangiocarcinoma, lung squamous cell carcinoma, colon adenocarcinoma, rectum adenocarcinoma, pancreatic adenocarcinoma, uterine corpus endometrial carcinoma, uterine carcinosarcoma, head and neck squamous cell carcinoma, mesothelioma, testicular germ cell tumors, ovarian serous cystadenocarcinoma, thyroid carcinoma, sarcoma, skin cutaneous melanoma, adrenocortical carcinoma, kidney renal clear cell carcinoma, pheochromocytoma and paraganglioma, kidney renal papillary cell carcinoma, lymphoid neoplasm diffuse large B-cell lymphoma, thymoma, brain lower grade glioma, kidney chromophobe, glioblastoma multiforme, uveal melanoma, or lymphoid malignancy or metastatic cancer.

27. The method according to claim 24, wherein the disease or disorder is autoimmune or inflammatory disease or disorder.

28. The method according to claim 27, wherein autoimmune or inflammatory disease or disorder is selected from diabetes, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, fatty liver disease, HIV / AIDS, systemic lupus erythematosus, psoriasis, dermatitis and prurigo nodularis.

29. The method according to claim 24, wherein the disease or disorder is neurodegenerative disease.

30. The method according to claim 29, wherein neurodegenerative disease is selected from Alzheimer’s disease, Parkinson’s disease, dementia, Huntington’s disease, or amyotrophic lateral sclerosis.

31. The method of any one of the claims 23 to 30, further comprising administering to the subject a therapeutically effective amount of one or more anticancer agents, anti-inflammatory agent, immunosuppressant agents, or pain- relieving agents.

32. Use of a compound according to any one of the claims 1 to 19, or a pharmaceutically acceptable salt, a solvate thereof or an isomer thereof, in the manufacture of a medicament for the treatment of disease or disorder responsive to the degradation of target protein.

33. Use of a compound according to any one of the claims 1 to 19, or a pharmaceutically acceptable salt or a stereoisomer thereof, in the manufacture of a medicament for the treatment of cancer, an inflammatory disease or disorder, autoimmune disease or disorder, neurodegenerative disease or metabolic disorder.

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