Fused heterocyclic compounds and their derivatives as p300 selective degraders

Abstract

The present disclosure provides fused heterocyclic compounds of formula (I) and their derivatives, that are therapeutically useful as p300 degraders. These compounds are useful in the treatment and / or prevention of diseases and / or disorders responsive to the p300 protein degradation. 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 or a stereoisomer thereof.

Description

[0001] FUSED HETEROCYCLIC COMPOUNDS AND THEIR DERIVATIVES AS p300 SELECTIVE DEGRADERS

[0002] The present application claims priority to and the benefit of Indian provisional patent application No. 202441102777, filed on 24thDecember 2024, the contents of which are hereby incorporated by reference in its entirety.

[0003] TECHNICAL FIELD

[0004] The present disclosure is directed to compounds of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or an isomer thereof as degraders of target proteins. 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 cancer, viral infection, autoimmune disease or disorder, inflammatory disease or disorder, neurodegenerative disease and metabolic disorder.

[0005] BACKGROUND 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 coactivator 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.

[0006] 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 itsselective degradation is expected to enhance efficacy in CBP-mutant or p300-dependent malignancies (Ogiwara et al., Ca Discov 2016). In prostate cancer, p300 plays a major role for androgen-dependent and -independent transactivation of the AR (Gong et al., Oncogene 2006: 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., Ca Disc 2021). 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) (Gao et al., Nat Cel Bio 2020; Pardoll and Drake J. Exp. Med. 2012).

[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 tumour 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

[0011] Provided herein are compounds of formula (I) and pharmaceutical compositions thereof, which are capable of degrading p300 protein.

[0012] In one aspect of the present disclosure, it comprises compounds of formula (I):

[0013]

[0014] or a pharmaceutically acceptable salt or a stereoisomer thereof;wherein,

[0015] X1is C, N or O;

[0016] X2is CH or N;

[0017] X3is C, CH or N;

[0018] Y1is C, CH or N;

[0019] Ar is (C3-C12)cycloalkylenyl, 3-12 membered heterocycloalkylenyl, (C6-C10)arylenyl or 5-12 membered heteroarylenyl;

[0020] R1is (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C12)cycloalkyl, 3-12 membered heterocycloalkyl or -NR1aR1b;

[0021] each R1aand R1bis independently hydrogen or (C1-C6)alkyl;

[0022] R2and R3at each occurrence is independently hydrogen, (C1-C6)alkyl, halo or halo(C1-C6)alkyl;

[0023] alternatively, R1band R3together with the atoms to which they are attached get cyclized to form an unsubstituted or substituted 5-7 membered heterocyclyl, wherein the substituent on heterocyclyl is independently selected from one or more (C1-C6)alkyl, halo, halo(C1-C6)alkyl, hydroxy, cyano and amino;

[0024] R4is a bond, -C(R4aR4b)- or -NR4c;

[0025] each R4aand R4bis independently hydrogen, halogen or (C1-C6)alkyl;

[0026] R4cis hydrogen or (C1-C6)alkyl;

[0027] R5is hydrogen, halogen, (C1-C6)alkyl or (C1-C6)alkoxy;

[0028] alternatively, R4b or R4Ctogether with R5 get cyclized to form an unsubstituted or substituted (C3-Ci2)cycloalkyl, an unsubstituted or substituted 3-12 membered heterocycloalkyl, an unsubstituted or substituted (Ce-Cio)aryl or an unsubstituted or substituted 5-12 membered heteroaryl, wherein the substituent on cycloalkyl, heterocycloalkyl, aryl and heteroaryl is one or more Rsa, wherein each Rsais independently selected from (Ci-Ce)alkyl, halo, halo(Ci-Ce)alkyl, hydroxy, cyano and amino;

[0029] Rs is hydrogen, (Ci-Ce)alkyl, halo, halo(Ci-Ce)alkyl, (C3-Ci2)cycloalkyl or 3-12 membered heterocycloalkyl;

[0030] R7 is hydrogen, (Ci-Ce)alkyl, halo, halo(Ci-Ce)alkyl or (C3-Ci2)cycloalkyl;L is a bond or an unsubstituted or substituted (C1-C10)alkylenyl, wherein one or more methylene units of the alkylenyl is optionally and independently replaced with any combination of -C(O)-, -O-, -NH-, (C2-C6)alkenylenyl, (C2-C6)alkynylenyl, an unsubstituted or substituted 3-12 membered heterocycloalkylenyl, an unsubstituted or substituted 5-12 membered heteroarylenyl, an unsubstituted or substituted 6 to 10 membered arylenyl or an unsubstituted or substituted (C3-C6)cycloalkylenyl; wherein the substituent at each occurrence is independently selected from one or more oxo, halo, cyano, hydroxy, (C1-C6)alkyl or (C1-C4)alkoxy;

[0031] M is represented by formula (M-l), (M-2), (M-3), (M-4), (M-5) or (M-6):

[0032]

[0033] wherein the wavy bond represents the point of attachment with L;

[0034] each W1, W2, W3, W4and W5is independently C, CH or N;W6is a bond, *-C(O)NH-, *-NH-C(O)- or -NRW-; wherein the asterisk mark represents the point of attachment with the ring having W5;

[0035] W7is CH2, NH or O;

[0036] Rwis hydrogen or (C1-C6)alkyl;

[0037] RM1at each occurrence is independently hydrogen, (C1-C6)alkyl or halo(C1-C6)alkyl; RM2at each occurrence is independently halo, cyano, (C1-C6)alkyl or (C1-C6)alkoxy; each RM3and RM4is independently hydrogen or (C1-C6)alkyl; or RM3and RM4together with the carbon atom to which they are attached represent an oxo group;

[0038] RM5at each occurrence is independently hydrogen or (C1-C6)alkyl; alternatively, two RM5on the same carbon atom together represent an oxo group; alternatively, RM2and RM5together with the atoms to which they are attached get cyclized to form a fused 4 to 7 membered, carbocyclyl or heterocyclyl ring system;

[0039] subscript ‘m’ is 0, 1, 2 or 3;

[0040] subscript ‘n’ is 0, 1, 2 or 3;

[0041] subscript ‘p’ is 1, 2 or 3;

[0042] subscript ‘q’ is 1, 2 or 3;

[0043] subscript ‘t’ at each occurrence is independently 0, 1, 2 or 3; and

[0044] subscript ‘u’ is 0, 1, 2 or 3.

[0045] In yet another aspect, the present disclosure provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).

[0046] In yet another aspect, the present disclosure relates to the preparation of compounds of formula (I).

[0047] In yet another aspect of the present disclosure, provided herein are compounds of formula (I), that are capable of degrading p300 protein and therapeutic uses thereof.DETAILED DESCRIPTION

[0048] 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 to facilitate the understanding of the present disclosure.

[0049] As used herein, unless otherwise defined the term “alkyl” alone or in combination with other term(s) means saturated aliphatic hydrocarbon chains, including Ci-Cu straight or Ci-Ci4 branched alkyl groups, where “C1-C14” means one to fourteen carbons. Alkyl may also include, for example, a Ci-Ce alkyl group, where “Ci-Ce” means one to six carbons, a C1-C5 alkyl group, where “C1-C5” means one to five carbons, a C1-C4 alkyl group, where “C1-C4” means one to four carbons, a C1-C3 alkyl group, where “C1-C3” means one to three carbons or a C1-C2 alkyl group, where “C1-C2” means one to two carbons. Examples of "alkyl" include but are not limited to methyl, ethyl, 1 -propyl, 2-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3 -pentyl, neo-pentyl, 1 -hexyl, 2-hexyl, 3 -hexyl, 1 -heptyl, 2-heptyl, 3 -heptyl, 4-heptyl, 1 -octyl, 2-octyl, 3 -octyl and 4-octyl and the like. As used herein, the term “alkylenyl” refers to a divalent alkyl group, wherein the “alkyl” group is as defined above. Examples of “alkylenyl” include, but are not limited to, -CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH(CH3)CH2CH2CH2-, -CH2CH(CH3)CH2CH2- and -(CH2)i-i4-.

[0050] As used herein, “alkenyl” refers to an alkyl group having one or more double carboncarbon bonds. Alkenyl groups include, but are not limited to, ethenyl, propenyl, cyclohexenyl, 1 -propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l- propenyl, 1-butenyl, and 2-butenyl. Alkenyl groups may be unsubstituted or substituted by one or more suitable substituents, as defined above.

[0051] The term “alkenylenyl” refers to a divalent “alkenyl” as defined above. An “alkenylenyl” group may be substituted or unsubstituted with one or more substituents as described herein. Representative examples of alkenylenyl groups include, but are not limited to,-C(H)=C(H)-, -C(H)=C(H)-CH2-, -C(H)=C(H)-CH2-CH2-, -CH2-C(H)=C(H)-CH2-, -C(H)=C(H)-CH(CH3)- and -CH2-C(H)=C(H)-CH(CH2CH2)-.

[0052] The term “alkynyl”, as used herein, refers to an alkyl group as described above having at least one carbon-carbon triple bond and is intended to include both “unsubstituted alkynyls” and “substituted alkynyls”, the latter of which refers to alkynyl moieties having substituentsreplacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive. For example, substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl or heteroaryl groups is contemplated. Alkynylenyl groups may be unsubstituted or substituted by one or more suitable substituents, as defined above. Preferably, the “alkynyl” group refers to C2-C6 alkynyl. Examples of “alkynyl” includes, but not limited to ethynyl, propynyl, butynyl and pentynyl.

[0053] As used herein, the term “carbocycle”, “carbocyclic” or “carbocyclyl” is intended to mean any stable 3-, 4-, 5-, 6- or 7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-or 13 -membered bicyclic or tricyclic hydrocarbon ring, any of which may be saturated, partially unsaturated, unsaturated or aromatic. Examples of carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl and tetrahydronaphthyl (tetralin). As shown above, bridged rings are also included in the definition of carbocycle (e.g., [2.2.2]bicyclooctane). Preferred carbocycles, unless otherwise specified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and indanyl. When the term “carbocycle” or “carbocyclyl” is used, it is intended to include “aryl”. A bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.

[0054] The terms “heterocyclyl”, “heterocycle” and “heterocyclic” refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms "heterocyclyl" and "heterocyclic" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls and / or heterocyclyl s. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, 2,3-dihydrobenzo[b] [l,4]dioxine,lactones, lactams and the like. Heterocyclyl groups may be optionally substituted as permitted by valence.

[0055] As used herein, the term “halo” or “halogen” alone or in combination with other term(s) means fluorine, chlorine, bromine or iodine.

[0056] As used herein, the term “oxo” refers to =0 group.

[0057] As used herein, the term “haloalkyl” means alkyl substituted with one or more halogen atoms, wherein the alkyl groups are as defined above. The term “halo” is used herein interchangeably with the term “halogen” means F, Cl, Br or I. Examples of “haloalkyl” include but are not limited to fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and the like. The term “haloalkylenyl”, as used herein, refers to a divalent “haloalkyl” as defined above.

[0058] As used herein, the term “hydroxy” or “hydroxyl” alone or in combination with other term(s) means -OH.

[0059] As used herein, the term “alkoxy” alone or in combination with other term(s) refers to the group alkyl-O- or -O-alkyl, where alkyl groups are as defined above. Exemplary C1-C10 alkoxy includes but are not limited to methoxy, ethoxy, n-propoxy, n-butoxy, t-butoxy and the like. An alkoxy group can be unsubstituted or substituted with one or more suitable groups.

[0060] As used herein, the term “cyano” refers to -CN.

[0061] As used herein the term “cycloalkyl” alone or in combination with other term(s) means C3-C12 saturated cyclic hydrocarbon ring. A cycloalkyl may be a single ring, which typically contains ranging from 3 to 7, 3 to 6, or 5 to 6 carbon ring atoms. Examples of single-ring cycloalkyls include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. A cycloalkyl may alternatively be polycyclic or contain more than one ring. Examples of polycyclic cycloalkyls include bridged, fused and spirocyclic carbocyclyls and the like.

[0062] As used herein, the term “aryl” is unsubstituted or substituted monocyclic, bicyclic or polycyclic aromatic hydrocarbon ring system of about 6 to 14 carbon atoms. Examples of a Ce-C14 aryl group include, but are not limited to phenyl, naphthyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl and acenaphthyl. An aryl group may typically contain 6 to 10 carbon atoms. An aryl group may be unsubstituted or substituted with one or more suitable groups. As used herein, the term “arylenyl” refers to a divalent aryl group, wherein the aryl group is as defined above.The term “heterocycloalkyl” refers to a non-aromatic, saturated or partially saturated monocyclic or polycyclic, fused, bridged or spiro ring system of 3 to 15 members having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O)2 or NH with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen and sulfur. A heterocycloalkyl may typically contain 3 to 12 ring atoms. A monocyclic heterocycloalkyl may typically contain 4 to 7 ring atoms. Examples of “heterocycloalkyl” include, but are not limited to azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, indolinyl, azepanyl and N-oxides thereof. Attachment of a heterocycloalkyl substituent can occur via either a carbon atom or a heteroatom. A heterocycloalkyl group can be unsubstituted or substituted with one or more suitable groups by one or more aforesaid groups. Preferably “heterocycloalkyl” refers to 5- to 10-membered ring. In one embodiment, “heterocycloalkyl” refers to 5- to 6-membered ring selected from the group consisting of imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl and N-oxides thereof. More preferably, “heterocycloalkyl” includes azetidinyl, pyrrolidinyl, morpholinyl and piperidinyl.

[0063] As used herein, the term “heterocycloalkylenyl” refers to a divalent heterocycloalkyl group as defined herein. All “heterocycloalkyl”, “heterocycloalkylenyl” are optionally substituted by one or more aforesaid groups.

[0064] As used herein, the term “cycloalkylenyl” refers to a divalent form of an optionally substituted cycloalkyl group. Examples of ‘cycloalkylenyl include, but not limited to, cyclopropylenyl, cyclobutylenyl, cyclopentylenyl, cyclohexylenyl and cycloheptylenyl.

[0065] As used herein, the term “heteroaryl” alone or in combination with other term(s) means a completely unsaturated ring system containing a total of 5 to 14 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen or sulfur), with the remaining ring atoms / groups being independently selected from the group consisting of carbon, oxygen, nitrogen or sulfur. A heteroaryl may be a single-ring (monocyclic) or polycyclic ring system. Examples of "heteroaryl" include but are not limited to pyridyl, indolyl, benzimidazolyl, benzothiazolyl and the like.

[0066] The term “heteroatom” as used herein designates a sulfur, nitrogen or oxygen atom.As used in the above definitions, the term “optionally substituted” or “substituted” or “optionally substituted with suitable groups” refers to replacement of one or more hydrogen radicals in a given structure with a radical of a specified substituent including, but not limited to halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl, carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl, heteroaryl, heterocyclic and aliphatic. It is understood that any substituent may be further substituted.

[0067] As used herein, the term “compound(s)” comprises the compounds disclosed in the present disclosure.

[0068] As used herein, the term “comprise” or “comprising” is generally used in the sense of include, that is to say permitting the presence of one or more features or components.

[0069] As used herein, the term “or” means “and / or” unless stated otherwise.

[0070] As used herein, the term “including” as well as other forms, such as “include”, “includes” and “included” is not limiting.

[0071] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By “pharmaceutically acceptable” it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0072] As used herein, the term “treat”, “treating” and “treatment” refer to a method of alleviating or abrogating a disease and / or its attendant symptoms.

[0073] As used herein, the terms “prevent”, “preventing” and “prevention” refer to a method of preventing the onset of a disease and / or its attendant symptoms or barring a subject from acquiring a disease. As used herein, “prevent”, “preventing” and “prevention” also include delaying the onset of a disease and / or its attendant symptoms and reducing a subject's risk of acquiring a disease. “Preventing” also includes administration of at least one compound or a composition of the present invention to those subjects thought to be predisposed to the disease or condition due to age, familial history, genetic or chromosomal abnormalities, due to thepresence of one or more biological markers for the disease or condition and / or due to environmental factors. Also, the terms “prevent”, “preventing” and grammatical variations thereof mean to administer a compound or a composition of the present invention to a subject who has not been diagnosed as having the disease or condition at the time of administration, but who could be expected to develop the disease or condition or be at increased risk for the disease or condition.

[0074] As used herein, the terms “ameliorate”, “ameliorating” and grammatical variations thereof mean to decrease the severity of the symptoms of a disease in a subject.

[0075] As used herein, the term “therapeutically effective amount” refers to that amount of the compound being administered sufficient to prevent development of or alleviate to some extent one or more of the symptoms of the condition or disorder being treated.

[0076] “Pharmaceutically acceptable” means that, which is useful in preparing a pharmaceutical 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.

[0077] As used herein, the phrase “pharmaceutically acceptable excipient” refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, solvent or encapsulating material. Excipients or carriers are generally safe, non-toxic and neither biologically nor otherwise undesirable and include excipients or carriers that are acceptable for veterinary use as well as human pharmaceutical use. In one embodiment, each component is “pharmaceutically acceptable” as defined herein. See, e.g., Remington: The Science and Practice of Pharmacy, 21sted.; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients, 6thed.; Rowe et al, Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rded.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nded.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.

[0078] As used herein, “pharmaceutically acceptable salt(s)” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present disclosure include the conventional non-toxic salts of the parent compoundformed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols or acetonitrile (ACN) are preferred.

[0079] The term “stereoisomers” refers to any enantiomers, diastereoisomers or geometrical isomers of the compounds of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (IK) and (IL) wherever they are chiral or when they bear one or more double bonds. When the compounds of the formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (IK) and (IL) are chiral, they can exist in racemic or in optically active form. It should be understood that the disclosure encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric and epimeric forms, as well as d-isomers and l-isomers and mixtures thereof. Individual stereoisomers of compounds 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. Additionally, the compounds of the present disclosure may exist as geometric isomers. The present disclosure includes all cis, trans, syn, anti, R and S, entgegen (E) and zusammen (Z) isomers as well as the appropriate mixtures thereof.

[0080] The p300 degraders as used herein is alternatively referred to as “p300 protein degraders” or “p300 modulators”.

[0081] The present disclosure provides compounds of formula (I), which are useful as p300 degraders.

[0082] The present disclosure further provides pharmaceutical compositions comprising the said compounds of formula (I), and their derivatives as therapeutic agents.

[0083] 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 departingfrom the scope or spirit of various embodiments disclosed herein. For instance, features illustrated or described as part of one embodiment can be applied to another embodiment to yield a still further embodiment. Thus, it is intended that the present disclosure includes such modifications and variations and their equivalents. Other objects, features, and aspects of the present disclosure are disclosed in or are obvious from, the following detailed description. It is to be understood by one of ordinary skill in the art that the present discussion is a description of exemplary embodiments and is not to be construed as limiting the broader aspects of the present disclosure.

[0084] The embodiments below are illustrative of the present disclosure and are not intended to limit the claims to the specific embodiments exemplified.

[0085] In a first embodiment, the present disclosure provides compounds of formula (I),

[0086]

[0087] or a pharmaceutically acceptable salt or a stereoisomer thereof;

[0088] wherein,

[0089] X1is C, N or O;

[0090] X2is CH or N;

[0091] X3is C, CH or N;

[0092] Y1is C, CH or N;

[0093] Ar is (C3-C12)cycloalkylenyl, 3-12 membered heterocycloalkylenyl, (C6-C10)arylenyl or 5-12 membered heteroarylenyl;

[0094] R1is (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C12)cycloalkyl, 3-12 membered heterocycloalkyl or -NR1aR1b;

[0095] each R1aand R1bis independently hydrogen or (C1-C6)alkyl;R2and R3at each occurrence is independently hydrogen, (C1-C6)alkyl, halo or halo(C1-C6)alkyl;

[0096] alternatively, R1band R3together with the atoms to which they are attached get cyclized to form an unsubstituted or substituted 5-7 membered heterocyclyl, wherein the substituent on heterocyclyl is independently selected from one or more (C1-C6)alkyl, halo, halo(C1-C6)alkyl, hydroxy, cyano and amino;

[0097] R4is a bond, -C(R4aR4b)- or -NR4c;

[0098] each R4aand R4bis independently hydrogen, halogen or (C1-C6)alkyl;

[0099] R4cis hydrogen or (C1-C6)alkyl;

[0100] R5is hydrogen, halogen, (C1-C6)alkyl or (C1-C6)alkoxy;

[0101] alternatively, R4bor R4ctogether with R5get cyclized to form an unsubstituted or substituted (C3-C12)cycloalkyl, an unsubstituted or substituted 3-12 membered heterocycloalkyl, an unsubstituted or substituted (C6-C10)aryl or an unsubstituted or substituted 5-12 membered heteroaryl, wherein the substituent on cycloalkyl, heterocycloalkyl, aryl and heteroaryl is one or more R5a, wherein each R5ais independently selected from (C1-C6)alkyl, halo, halo(C1-C6)alkyl, hydroxy, cyano and amino;

[0102] R6is hydrogen, (C1-C6)alkyl, halo, halo(C1-C6)alkyl, (C3-C12)cycloalkyl or 3-12 membered heterocycloalkyl;

[0103] R7is hydrogen, (C1-C6)alkyl, halo, halo(C1-C6)alkyl or (C3-C12)cycloalkyl;

[0104] L is a bond or an unsubstituted or substituted (C1-C10)alkylenyl, wherein one or more methylene units of the alkylenyl is optionally and independently replaced with any combination of -C(O)-, -O-, -NH-, (C2-C6)alkenylenyl, (C2-C6)alkynylenyl, an unsubstituted or substituted 3-12 membered heterocycloalkylenyl, an unsubstituted or substituted 5-12 membered heteroarylenyl, an unsubstituted or substituted 6 to 10 membered arylenyl or an unsubstituted or substituted (C3-C6)cycloalkylenyl; wherein the substituent at each occurrence is independently selected from one or more oxo, halo, cyano, hydroxy, (C1-C6)alkyl or (C1-C4)alkoxy;

[0105] M is represented by formula (M-l), (M-2), (M-3), (M-4), (M-5) or (M-6):or

[0106] (M-6)

[0107]

[0108] wherein the wavy bond represents the point of attachment with L;

[0109] each W1, W2, W3, W4and W5is independently C, CH or N;

[0110] W6is a bond, *-C(O)NH-, *-NH-C(O)- or -NRW-; wherein the asterisk mark represents the point of attachment with the ring having W5;

[0111] W7is CH2, NH or O;

[0112] Rwis hydrogen or (C1-C6)alkyl;

[0113] RM1at each occurrence is independently hydrogen, (C1-C6)alkyl or halo(C1-C6)alkyl; RM2at each occurrence is independently halo, cyano, (C1-C6)alkyl or (C1-C6)alkoxy; each RM3and RM4is independently hydrogen or (C1-C6)alkyl; or RM3and RM4together with the carbon atom to which they are attached represent an oxo group;RM5at each occurrence is independently hydrogen or (C1-C6)alkyl; alternatively, two RM5on the same carbon atom together represent an oxo group; alternatively, RM2and RM5together with the atoms to which they are attached get cyclized to form a fused 4 to 7 membered, carbocyclyl or heterocyclyl ring system;

[0114] subscript ‘m’ is 0, 1, 2 or 3;

[0115] subscript ‘n’ is 0, 1, 2 or 3;

[0116] subscript ‘p’ is 1, 2 or 3;

[0117] subscript ‘q’ is 1, 2 or 3;

[0118] subscript ‘t’ at each occurrence is independently 0, 1, 2 or 3; and

[0119] subscript ‘u’ is 0, 1, 2 or 3.

[0120] In another embodiment, it provides compounds of formula (IA),

[0121]

[0122] or a pharmaceutically acceptable salt or a stereoisomer thereof.

[0123] In another embodiment, it provides compounds of formula (IB),

[0124]

[0125] or a pharmaceutically acceptable salt or a stereoisomer thereof.

[0126] In another embodiment, it provides compounds of formula (IC),

[0127]

[0128] or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

[0129] In another embodiment, it provides compounds of formula (ID),

[0130]

[0131] or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein r is 1, 2 or 3.

[0132] In another embodiment, it provides compounds of formula (IE),

[0133]

[0134] or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein r is 1, 2 or 3.

[0135] In another embodiment, it provides compounds of formula (IF),

[0136]

[0137] or a pharmaceutically acceptable salt or a stereoisomer thereof. In another embodiment, it provides compounds of formula (IG),

[0138]

[0139] or a pharmaceutically acceptable salt or a stereoisomer thereof.

[0140] In another embodiment, it provides compounds of formula (IH),o (R2)m

[0141]

[0142] or a pharmaceutically acceptable salt or a stereoisomer thereof.

[0143] In another embodiment, it provides compounds of formula (IJ),

[0144]

[0145] or a pharmaceutically acceptable salt or a stereoisomer thereof.

[0146] In another embodiment, it provides compounds of formula (IK),

[0147]

[0148] or a pharmaceutically acceptable salt or a stereoisomer thereof.

[0149] In another embodiment, it provides compounds of formula (IL),o (R2)m

[0150]

[0151] (IL)

[0152] or a pharmaceutically acceptable salt or a stereoisomer thereof.

[0153] In another embodiment, M is (M-1) represented by

[0154]

[0155] y o

[0156]

[0157] r

[0158]

[0159] In another embodiment, M is (M-2) represented by

[0160]

[0161]

[0162] In another embodiment, M is (M-3) represented by

[0163]

[0164] In another embodiment, M is (M-4) represented by

[0165] In another embodiment, M is (M-5) represented by

[0166]

[0167] (M-5)

[0168] In another embodiment, M is (M-6) represented b

[0169]

[0170] (RM5)u

[0171] In certain embodiments, M is linked to L.

[0172] In another embodiment, it provides compounds of formula (IA),

[0173]

[0174] wherein,

[0175] X1is C, N or O;

[0176] X2is CH or N;

[0177] Y1is C, CH or N;

[0178] Ar is (C3-C12)cycloalkylenyl, 3-12 membered heterocycloalkylenyl, (C6-C10)arylenyl or 5-12 membered heteroarylenyl;

[0179] R1ais hydrogen or (C1-C6)alkyl;

[0180] R2and R3at each occurrence is independently hydrogen, (C1-C6)alkyl, halo or halo(C1-C6)alkyl;

[0181] R4is a bond, -C(R4aR4b)- or -NR4c;each R4aand R4bis independently hydrogen, halogen or (C1-C6)alkyl;

[0182] R4cis hydrogen or (C1-C6)alkyl;

[0183] R5is hydrogen, halogen, (C1-C6)alkyl or (C1-C6)alkoxy;

[0184] alternatively, R4bor R4ctogether with R5get cyclized to form an unsubstituted or substituted (C3-C12)cycloalkyl, an unsubstituted or substituted 3-12 membered heterocycloalkyl, an unsubstituted or substituted (C6-C10)aryl or an unsubstituted or substituted 5-12 membered heteroaryl wherein the substituents on cycloalkyl, heterocycloalkyl, aryl and heteroaryl is one or more R5a, wherein each R5ais independently selected from (C1-C6)alkyl, halo, halo(C1-C6)alkyl, hydroxy, cyano and amino;

[0185] R6is hydrogen, (C1-C6)alkyl, halo, halo(C1-C6)alkyl, (C3-C12)cycloalkyl or 3-12 membered heterocycloalkyl;

[0186] R7is hydrogen, (C1-C6)alkyl, halo, halo(C1-C6)alkyl or (C3-C12)cycloalkyl;

[0187] L is a bond or an unsubstituted or substituted (C1-C10)alkylenyl, wherein one or more methylene units of the alkylenyl is optionally and independently replaced with any combination of -C(O)-, -O-, -NH-, (C2-C6)alkenylenyl, (C2-C6)alkynylenyl, an unsubstituted or substituted 3-12 membered heterocycloalkylenyl, an unsubstituted or substituted 5-12 membered heteroarylenyl, an unsubstituted or substituted 6 to 10 membered arylenyl or an unsubstituted or substituted (C3-C6)cycloalkylenyl; wherein the substituent at each occurrence is independently selected from one or more oxo, halo, cyano, hydroxy, (C1-C6)alkyl or (C1-C4)alkoxy;

[0188] M is represented by formula (M-l), (M-2), (M-3), (M-4), (M-5) or (M-6):

[0189]

[0190]

[0191] wherein the wavy bond represents the point of attachment with L;

[0192] each W1, W2, W3, W4and W5is independently C, CH or N;

[0193] W6is a bond, *-C(O)NH-, *-NH-C(O)- or -NRW-; wherein the asterisk mark represents the point of attachment with the ring having W5;

[0194] W7is CH2, NH or O;

[0195] Rwis hydrogen or (C1-C6)alkyl;

[0196] RM1at each occurrence is independently hydrogen, (C1-C6)alkyl or halo(C1-C6)alkyl; RM2at each occurrence is independently halo, cyano, (C1-C6)alkyl or (C1-C6)alkoxy; each RM3and RM4is independently hydrogen or (C1-C6)alkyl; or RM3and RM4together with the carbon atom to which they are attached represent an oxo group;

[0197] RM5at each occurrence is independently hydrogen or (C1-C6)alkyl; alternatively, two RM5on the same carbon atom together represent an oxo group; alternatively, RM2and RM5together with the atoms to which they are attached get cyclized to form a fused 4 to 7 membered, carbocyclyl or heterocyclyl ring system;

[0198] subscript ‘m’ is 0, 1, 2 or 3;

[0199] subscript ‘p’ is 1, 2 or 3;subscript ‘q’ is 1, 2 or 3;

[0200] subscript ‘t’ at each occurrence is independently 0, 1, 2 or 3; and

[0201] subscript ‘u’ is 0, 1, 2 or 3.

[0202] In another embodiment, it provides compounds of formula (IA), wherein,

[0203] X1is C, N or O;

[0204] X2is CH or N;

[0205] Y1is C, CH or N;

[0206] Ar is 3-12 membered heterocycloalkylenyl, (Ce-Cio)arylenyl or 5-12 membered heteroaryl enyl;

[0207] Ria is hydrogen or halo(Ci-C3)alkyl;

[0208] R2and R3at each occurrence is independently hydrogen, (C1-C6)alkyl,

[0209] R4is a bond, -C(R4aR4b)- or -NR4c;

[0210] each R4aand R4bis independently hydrogen, halogen or (C1-C6)alkyl;

[0211] R4cis hydrogen or (C1-C6)alkyl;

[0212] R5 is hydrogen;

[0213] alternatively, R4bor R4ctogether with R5get cyclized to form an unsubstituted or substituted (C3-C12)cycloalkyl, an unsubstituted or substituted 3-12 membered heterocycloalkyl, an unsubstituted or substituted (C6-C10)aryl or an unsubstituted or substituted 5-12 membered heteroaryl wherein the substituents on cycloalkyl, heterocycloalkyl, aryl and heteroaryl is one or more R5a, wherein each R5ais independently selected from (C1-C6)alkyl, halo, halo(C1-C6)alkyl, hydroxy, cyano and amino;

[0214] R6is hydrogen, (C1-C6)alkyl, halo, halo(C1-C6)alkyl, (C3-C12)cycloalkyl or 3-12 membered heterocycloalkyl;

[0215] R7is hydrogen, (C1-C6)alkyl, halo, halo(C1-C6)alkyl or (C3-C12)cycloalkyl;

[0216] L is a bond or an unsubstituted or substituted (C1-C10)alkylenyl, wherein one or more methylene units of the alkylenyl is optionally and independently replaced with any combination of -C(O)-, -O-, -NH-, (C2-C6)alkenylenyl, (C2-C6)alkynylenyl, an unsubstituted or substituted3-12 membered heterocycloalkylenyl, an unsubstituted or substituted 5-12 membered heteroarylenyl, an unsubstituted or substituted 6 to 10 membered arylenyl;

[0217] M is represented by formula (M-l), (M-2), (M-3), (M-4), (M-5) or (M-6):

[0218]

[0219] wherein the wavy bond represents the point of attachment with L;

[0220] each W1, W2, W3, W4and W5is independently C, CH or N;

[0221] W6is a bond, *-C(O)NH-, *-NH-C(O)- or -NRw-; wherein the asterisk mark represents the point of attachment with the ring having W5;

[0222] W7is CH2;

[0223] Rwis hydrogen or (C1-C6)alkyl;

[0224] RMI at each occurrence is independently hydrogen, or (Ci-Ce)alkyl;RM2 at each occurrence is independently halo;

[0225] each RM3and RM4is independently hydrogen or (C1-C6)alkyl; or RM3and RM4together with the carbon atom to which they are attached represent an oxo group;

[0226] RM5at each occurrence is independently hydrogen or (C1-C6)alkyl; alternatively, two RM5on the same carbon atom together represent an oxo group; alternatively, RM2and RM5together with the atoms to which they are attached get cyclized to form a fused 4 to 7 membered, carbocyclyl or heterocyclyl ring system;

[0227] subscript ‘m’ is 0, 1, 2 or 3;

[0228] subscript ‘p’ is 1, 2 or 3;

[0229] subscript ‘q’ is 1, 2 or 3;

[0230] subscript ‘t’ at each occurrence is independently 0, 1, 2 or 3; and

[0231] subscript ‘u’ is 0, 1, 2 or 3.

[0232] In some embodiments, Ar is 3-12 membered heterocycloalkylenyl, (C6-C10)arylenyl or 5-12 membered heteroarylenyl.

[0233] In some embodiments, Ar is 5-12 membered heteroarylenyl.

[0234] In some embodiments, Ar is 5-6 membered heteroarylenyl.

[0235] In some embodiments, Ar is pyridinyl, pyrimidinyl or pyrazolyl.

[0236] In some embodiments, L is -C(O)NH-, -C(O)NHCH2-, -NHC(O)-,

[0237]

[0238]

[0239] In some embodiments, Xi is C.

[0240] In some embodiments, Xi is C, and two R2 are substituted on Xi.

[0241] In some embodiments, Xi is C, and R2 is independently hydrogen or (Ci-Ce)alkyl. In some embodiments, Xi is N or O.

[0242] In some embodiments, Xi is N, and R2 is (Ci-Ce)alkyl.

[0243] In some embodiments, X2 is CH.

[0244] In some embodiments, X2 is CH and X3 is C.

[0245] In some embodiments, X2 is CH and X3 is CH, wherein one of R3 is substituted on X3 by displacing the hydrogen on X3.

[0246] In some embodiments, Yi is N.

[0247] In some embodiments, Yi is CH.

[0248] In some embodiments, Yi is C and one of Rs is substituted on Yi.

[0249] In some embodiments, R1is (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C12)cycloalkyl, 3-12 membered heterocycloalkyl or -NR1aR1b.

[0250] In some embodiments, R1is (C1-C6)alkyl, halo(C1-C6)alkyl or -NR1aR1b.In some embodiments, R1is (C1-C6)alkyl or -NR1aR1b.

[0251] In some embodiments, R1is -NR1aR1b.

[0252] In some embodiments, R2and R3at each occurrence is independently (C1-C6)alkyl or halo.

[0253] In some embodiments, R2and R3at each occurrence is independently (C1-C6)alkyl. In some embodiments, R2at each occurrence is independently (C1-C6)alkyl.

[0254] In some embodiments, R3at each occurrence is independently (C1-C6)alkyl.

[0255] In some embodiments, R2at each occurrence is independently (C1-C6)alkyl or halo. In some embodiments, R3at each occurrence is independently (C1-C6)alkyl or halo. In some embodiments, R1band R3together with the atoms to which they are attached get cyclized to form an unsubstituted or substituted 5-7 membered heterocyclyl, wherein the substituent on heterocyclyl is independently selected from one or more (C1-C6)alkyl, halo, halo(C1-C6)alkyl, hydroxy, cyano and amino.

[0256] In some embodiments, one of R3is substituted on X3by displacing the hydrogen when X3is CH.

[0257] In some embodiments, one of R3is substituted on X3when X3is C.

[0258] In some embodiments, R1band R3together with the atoms to which they are attached get cyclized to form an unsubstituted or substituted 5-7 membered heterocyclyl as shown in formula (IA).

[0259] In some embodiments, R4is -C(R4aR4b)- or -NR4c.

[0260] In some embodiments, R4is -C(R4aR4b)-.

[0261] In some embodiments, R4is -NR4c.

[0262] In some embodiments, R4bor R4ctogether with R5get cyclized to form an unsubstituted or substituted (C5-C6)cycloalkyl, an unsubstituted or substituted 5-7 membered heterocycloalkyl, an unsubstituted or substituted phenyl or an unsubstituted or substituted 5-7 membered heteroaryl, wherein the substituent on cycloalkyl, heterocycloalkyl, aryl and heteroaryl is one or more R5a, wherein each R5ais independently selected from (C1-C6)alkyl, halo, halo(C1-C6)alkyl, hydroxy, cyano and amino.In some embodiments, wherein R4bor R4ctogether with R5get cyclized to form (C5-C6)cycloalkyl, 5-7 membered heterocycloalkyl, phenyl or 5-7 membered heteroaryl.

[0263] In some embodiments, R4is -C(R4aR4b)-, wherein R4btogether with R5get cyclized to form phenyl ring.

[0264] In some embodiments, R4is -NR4c, wherein R4ctogether with R5get cyclized to form an unsubstituted or substituted 5-7 membered heterocycloalkyl, wherein the substituent is one or more R5a, wherein each R5ais independently selected from (C1-C6)alkyl, halo, halo(C1-C6)alkyl, hydroxy, cyano and amino.

[0265] In some embodiments, R4is -NR4c, wherein R4ctogether with R5get cyclized to form a 5-7 membered heterocycloalkyl.

[0266] In some embodiments, R5is hydrogen, (C1-C6)alkyl or (C1-C6)alkoxy.

[0267] In some embodiments, R5is hydrogen or (C1-C6)alkyl.

[0268] In some embodiments, R5is hydrogen.

[0269] In some embodiments, R6is (C1-C6)alkyl, halo, halo(C1-C6)alkyl or (C3-C12)cycloalkyl. In some embodiments, R6is (C1-C6)alkyl or halo(C1-C6)alkyl.

[0270] In some embodiments, R6is halo or halo(C1-C6)alkyl.

[0271] In some embodiments, R6is halo(C1-C6)alkyl.

[0272] In some embodiments, R6is (C1-C6)alkyl.

[0273] In some embodiment, R7is (C1-C6)alkyl, halo or halo(C1-C6)alkyl.

[0274] In some embodiment, R7is (C1-C6)alkyl, halo or halo(C1-C6)alkyl.

[0275] In some embodiment, R7is halo or halo(C1-C6)alkyl.

[0276] In some embodiment, R7is (C1-C6)alkyl or halo(C1-C6)alkyl.

[0277] In some embodiment, R7is (C1-C6)alkyl.

[0278] In some embodiments, L is a bond or unsubstituted or substituted (C1-C6)alkylenyl, wherein one or more methylene units of the alkylenyl is optionally and independently replaced with any combination of -C(O)-, -O-, -C(O)NH-, -NHC(O)-, (C2-C6)alkenylenyl, (C2-C6)alkynylenyl, 5-12 membered heteroarylenyl or 6 to 10 membered arylenyl; wherein the substituent at each occurrence is independently selected from one or more oxo, halo, cyano, hydroxy or (C1-C4)alkoxy.In certain embodiments, the present disclosure provides a compound selected from:

[0279] Comp.

[0280] IUPAC Name

[0281] No.

[0282] 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- 1.

[0283] imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-(4-(2-(2,6- dioxopiperi din-3 -yl)- 1 -oxoisoindolin-4-yl)but-3 -yn- 1 -yl)picolinamide;

[0284] 2. Isomer- 1 of compound- 1;

[0285] 3. Isomer-2 of compound- 1;

[0286] 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- 4. imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-((5-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)isoxazol-3-yl)methyl)picolinamide; 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-((3-(2-(2,6- 5.

[0287] dioxopiperi din-3 -yl)- 1 -oxoisoindolin-4-yl)- 1 -methyl- lH-pyrazol-5- yl)methyl)picolinamide;

[0288] 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- 6. imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-(3-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)benzyl)picolinamide;

[0289] 5-(7-(difluoromethyl)-l-(l,6,6-trimethyl-2-oxo-l,2,5,6-tetrahydro-4H- 7. imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-(4-(2-(2,6- dioxopiperi din-3 -yl)- 1 -oxoisoindolin-4-yl)but-3 -yn- 1 -yl)picolinamide;

[0290] 5-(8-(l,6-dimethyl-2-oxo- 1,2,5, 6-tetrahydro-4H-imidazo[4, 5,1 -ij]quinolin-8- 8. yl)isoquinolin-3-yl)-N-(4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)but-3 -yn- 1 -yl)picolinamide;

[0291] 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[l,5,4-de]quinoxalin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-(4-(2- 9.

[0292] (2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)but-3-yn-l-yl)picolinamide;

[0293]

[0294] 5-(7-(difluoromethyl)-l-(l,6,6-trimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-((5-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)isoxazol-3-yl)methyl)picolinamide;

[0295] 5-(7-(difluoromethyl)-l-(l-methyl-2-oxo-l,2,3,4-tetrahydro-5-oxa-l,2a- diazaacenaphthylen-7-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-((3-(2-(2,6- dioxopiperi din-3 -yl)- 1 -oxoisoindolin-4-yl)- 1 -methyl- lH-pyrazol-5- yl)methyl)picolinamide;

[0296] 5-(7-(difluoromethyl)-l-(l-methyl-2-oxo-l,2,3,4-tetrahydro-5-oxa-l,2a- diazaacenaphthylen-7-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-((5-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)isoxazol-3-yl)methyl)picolinamide;

[0297] 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-((5-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)isoxazol-3-yl)methyl)-3- fluoropicolinamide;

[0298] 7-(difluoromethyl)-6-(6-(((5-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)isoxazol-3-yl)methyl)carbamoyl)pyridin-3-yl)-N,4'-dimethyl-3,3',4,4'- tetrahydro-2H-[l,6'-biquinoline]-l'(2'H)-carboxamide;

[0299] 5-(7-(difluoromethyl)-l-(l,6,6-trimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-((3-(2-(2,6- dioxopiperi din-3 -yl)- 1 -oxoisoindolin-4-yl)- 1 -methyl- lH-pyrazol-5- yl)methyl)picolinamide;

[0300] 5-(7-(difluoromethyl)-l-(l-methyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-(4-(2-(2,6- dioxopiperi din-3 -yl)- 1 -oxoisoindolin-4-yl)but-3 -yn- 1 -yl)picolinamide;

[0301] 5-(7-(difluoromethyl)-l-(l-methyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-((5-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)isoxazol-3-yl)methyl)picolinamide;

[0302]

[0303] 5-(8-(l,6-dimethyl -2-oxo- 1,2,5, 6-tetrahydro-4H-imidazo[4, 5,1 -ij]quinolin-8- yl)isoquinolin-3-yl)-N-((5-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)isoxazol-3-yl)methyl)picolinamide;

[0304] N-((5-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)isoxazol-3- yl)methyl)-5-(8-(l-methyl-2-oxo- 1,2,3, 4-tetrahydro-5-oxa- 1,2a- diazaacenaphthylen-7-yl)isoquinolin-3-yl)picolinamide;

[0305] 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-((5-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)thiazol-2-yl)methyl)picolinamide;

[0306] 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-(4-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)phenethyl)picolinamide;

[0307] 5-(8-(l,6-dimethyl -2-oxo- 1,2,5, 6-tetrahydro-4H-imidazo[4, 5,1 -ij]quinolin-8- yl)isoquinolin-3-yl)-N-((5-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)- l,3,4-thiadiazol-2-yl)methyl)picolinamide;

[0308] 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-(2-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)phenethyl)picolinamide;

[0309] 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-(4-(2-(2,6- dioxopiperi din-3 -yl)- 1 -oxoisoindolin-4-yl)but-3 -yn- 1 -yl)-N- methylpicolinamide;

[0310] 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-(3-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)phenethyl)picolinamide;

[0311] 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-(4-(2-(2,6- dioxopiperi din-3 -yl)- 1 -oxoisoindolin-5-yl)but-3 -yn- 1 -yl)picolinamide;

[0312]

[0313] 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-(4-(2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)but-3-yn-l-yl)picolinamide;

[0314] 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-(4-(3-(2,4- dioxotetrahy dropyrimidin- 1 (2H)-yl)- 1 -methyl - 1 H-indazol-5 -yl)but-3 -yn- 1 - yl)picolinamide;

[0315] 5-(8-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8- yl)isoquinolin-3-yl)-N-(3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)prop-2-yn- 1 -yl)picolinamide;

[0316] 5-(6-(difluoromethyl)-4-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-3,4-dihydro-2H-benzo[b][l,4]oxazin-7-yl)-N- (4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)but-3-yn-l- yl)picolinamide;

[0317] 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-((5-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)pyridin-3-yl)methyl)picolinamide;

[0318] 5-(8-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8- yl)isoquinolin-3-yl)-N-(3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)benzyl)picolinamide;

[0319] 5-(8-(l,6-dimethyl -2-oxo- 1,2,5, 6-tetrahydro-4H-imidazo[4, 5,1 -ij]quinolin-8- yl)isoquinolin-3-yl)-N-(4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)benzyl)picolinamide;

[0320] 5-(8-(l,6-dimethyl -2-oxo- 1,2,5, 6-tetrahydro-4H-imidazo[4, 5,1 -ij]quinolin-8- yl)isoquinolin-3-yl)-N-(3-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)prop-2- yn- 1 -yl)picolinamide;

[0321] 5-(8-(l,6-dimethyl -2-oxo- 1,2,5, 6-tetrahydro-4H-imidazo[4, 5,1 -ij]quinolin-8- yl)isoquinolin-3-yl)-N-(3-(3-(2,4-dioxotetrahydropyrimidin-l(2H)- yl)benzofuran-5-yl)prop-2-yn-l-yl)picolinamide;

[0322]

[0323] 5-(8-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8- yl)isoquinolin-3-yl)-N-(3-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l- methyl-lH-indazol-5-yl)prop-2-yn-l-yl)picolinamide;

[0324] 5-(8-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8- yl)isoquinolin-3-yl)-N-(3-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-4-yl)prop-2-yn-l-yl)picolinamide;

[0325] 5-(8-(l,6-dimethyl -2-oxo- 1,2,5, 6-tetrahydro-4H-imidazo[4, 5,1 -ij]quinolin-8- yl)isoquinolin-3 -yl)-N-(3 -( 1 -(2,6-dioxopiperidin-3 -yl)-lH- benzo[d][l,2,3]triazol-6-yl)prop-2-yn-l-yl)picolinamide;

[0326] 5-(8-(l,6-dimethyl -2-oxo- 1,2,5, 6-tetrahydro-4H-imidazo[4, 5,1 -ij]quinolin-8- yl)isoquinolin-3-yl)-N-(3-(3-(2,4-dioxotetrahydropyrimidin-l(2H)- yl)pyrazolo[ 1,5 -a]pyridin-5-yl)prop-2-yn- 1 -yl)picolinamide;

[0327] 5-(8-(l,6-dimethyl -2-oxo- 1,2,5, 6-tetrahydro-4H-imidazo[4, 5,1 -ij]quinolin-8- yl)isoquinolin-3-yl)-N-(3-(3-((2,6-dioxopiperidin-3-yl)oxy)-4- fluorophenyl)prop-2-yn- 1 -yl)picolinamide;

[0328] 5-(8-(l,6-dimethyl -2-oxo- 1,2,5, 6-tetrahydro-4H-imidazo[4, 5,1 -ij]quinolin-8- yl)isoquinolin-3-yl)-N-(3-(3-(2,6-dioxopiperidin-3-yl)benzofuran-5-yl)prop-2- yn- 1 -yl)picolinamide;

[0329] 5-(8-(l,6-dimethyl -2-oxo- 1,2,5, 6-tetrahydro-4H-imidazo[4, 5,1 -ij]quinolin-8- y 1 )i soquinolin-3 -yl)-N-(( 1 -(2, 6-dioxopiperi din-3 -yl)-2-oxo- 1,2- dihydrobenzo[cd]indol-6-yl)methyl)picolinamide;

[0330] N-(3 -(3 -((2, 6-dioxopiperi din-3 -yl)amino)phenyl)prop-2-yn- 1 -yl)-5-(8-( 1 - methyl-2-oxo- 1,2,5, 6-tetrahydro-4H-imidazo[4, 5,1 -de] [l,5]naphthyri din-8- yl)isoquinolin-3-yl)picolinamide;

[0331] 5-(8-(l,6-dimethyl -2-oxo- 1,2,5, 6-tetrahydro-4H-imidazo[4, 5,1 -ij]quinolin-8- yl)isoquinolin-3 -yl)-N-(3 -( 1 -(2, 6-dioxopiperi din-3 -yl)-2-oxo- 1,2- dihydrobenzo[cd]indol-5-yl)prop-2-yn-l-yl)picolinamide;

[0332]

[0333] N-(3 -(3 -((2,6-dioxopiperidin-3 -yl)amino)phenyl)prop-2-yn- 1 -yl)-5-(8-( 1 - methyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8- yl)isoquinolin-3-yl)picolinamide;

[0334] 5-(8-(l, 6-dimethyl -2-oxo- 1,2, 5, 6-tetrahydro-4H-imidazo[4, 5, l-ij]quinolin-8- yl)isoquinolin-3 -yl)-N-(3 -(3 -(2,6-dioxopiperidin-3 -yl)-4-oxo-3,4- dihydrophthalazin-6-yl)prop-2-yn- 1 -yl)picolinamide;

[0335] 5-((l, 6-dimethyl -2-oxo- 1,2,5, 6-tetrahydro-4H-imidazo[4, 5,1 -ij]quinolin-8- yl)(methyl)amino)-N-(3-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)prop-2- yn-l-yl)-5'-methyl-[2,3'-bipyridine]-6'-carboxamide;

[0336] 5-((l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8- yl)(methyl)amino)-N-(3-(3-(2,4-dioxotetrahydropyrimidin-l(2H)- yl)pyrazolo[l,5-a]pyridin-5-yl)prop-2-yn-l-yl)-5'-methyl-[2,3'-bipyridine]-6'- carboxamide;

[0337] 5-((l, 6-dimethyl -2-oxo- 1,2,5, 6-tetrahydro-4H-imidazo[4, 5,1 -ij]quinolin-8- yl)(methyl)amino)-N-(3-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)prop-2- yn-l-yl)-3-fluoro-5'-methyl-[2,3'-bipyridine]-6'-carboxamide;

[0338] 5-((l, 6-dimethyl -2-oxo- 1,2,5, 6-tetrahydro-4H-imidazo[4, 5,1 -ij]quinolin-8- yl)(methyl)amino)-N-(3-(3-(2,6-dioxopiperidin-3-yl)benzo[d]isoxazol-5- yl)prop-2-yn-l-yl)-5'-methyl-[2,3'-bipyridine]-6'-carboxamide;

[0339] 5-(8-(l, 6-dimethyl -2-oxo- 1,2, 5, 6-tetrahydro-4H-imidazo[4, 5, l-ij]quinolin-8- yl)isoquinolin-3-yl)-N-(3-(4-(2,6-dioxopiperidin-3-yl)pyrazolo[l,5-a]pyridin- 2-yl)prop-2-yn- 1 -yl)picolinamide;

[0340] 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-((3-(2-(2,6- dioxopiperi din-3 -yl)- 1 -oxoisoindolin-4-yl)- 1 -methyl- lH-pyrazol-5- yl)methyl)picolinamide;

[0341] 5-(7-(difluoromethyl)-l-(l,5-dimethyl-2-oxo-l,2-dihydrobenzo[cd]indol-7- yl)- 1,2,3, 4-tetrahydroquinolin-6-yl)-N-(4-(2-(2,6-dioxopiperi din-3 -yl)-l- oxoisoindolin-4-yl)but-3-yn-l-yl)picolinamide;

[0342]

[0343] 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4, 5, 1-ij ]quinolin-8-yl)-2-methyl- 1,2, 3, 4-tetrahy droquinolin-6-yl)-N- (4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)but-3-yn-l- yl)picolinamide;

[0344] 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-2,2-dimethyl-l,2,3,4-tetrahydroquinolin-6-yl)- N-(4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)but-3-yn-l- yl)picolinamide;

[0345] 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4, 5, 1-ij ]quinolin-8-yl)-3-fluoro- 1,2, 3, 4-tetrahy droquinolin-6-yl)-N- (4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)but-3-yn-l- yl)picolinamide;

[0346] 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-3,3-difluoro-l,2,3,4-tetrahydroquinolin-6-yl)- N-(4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)but-3-yn-l- yl)picolinamide;

[0347] 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4, 5, l-ij]quinolin-8-yl)-4-methyl- 1,2, 3, 4-tetrahy droquinoxalin-6-yl)- N-(4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)but-3-yn-l- yl)picolinamide;

[0348] 5-(7-(difluorom ethyl)- 1-(1, 6-dimethyl-2-oxo- 1,2,5, 6-tetrahydro-4H- imidazo[4,5, 1 -de] [ 1,5]naphthyridin-8-yl)- 1,2,3, 4-tetrahy droquinolin-6-yl)-N- (4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)but-3-yn-l- yl)picolinamide;

[0349] 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-(4-(2-(2,6- dioxopiperi din-3 -yl)- 1 -oxoisoindolin-4-yl)but-3 -yn- 1 -yl)pyrimidine-2- carboxamide;

[0350] 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-(4-(2-(2,6-

[0351]

[0352] di oxopiperi din-3 -yl)- 1 -oxoisoindolin-4-yl)but-3 -yn- 1 -y l)-3 - fluoropicolinamide;

[0353] 3-(difluoromethyl)-5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6- tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6- yl)-N-(4-(2-(2,6-di oxopiperi din-3 -yl)- 1 -oxoisoindolin-4-yl)but-3 -yn- 1 - yl)picolinamide;

[0354] 5-(l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8- yl)-l, 2,3, 4-tetrahydro-l, 7-naphthyridin-6-yl)-N-(4-(2-(2,6-di oxopiperi din-3 - yl)- 1 -oxoisoindolin-4-yl)but-3 -yn- 1 -yl)picolinamide;

[0355] 2-(4-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4, 5,1 -ij]quinolin-8-yl)- 1,2,3, 4-tetrahy droquinolin-6-yl)-lH-pyrazol- 1- yl)-N-(4-(2-(2,6-di oxopiperi din-3 -yl)- 1 -oxoisoindolin-4-yl)but-3 -yn- 1 - yl)acetamide;

[0356] 7-(difluoromethyl)-6-(6-((4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)but-3-yn-l-yl)carbamoyl)pyridin-3-yl)-N,4'-dimethyl-3,3',4,4'-tetrahydro- 2H-[l,6'-biquinoline]-l'(2'H)-carboxamide;

[0357] 6-(7-(difluoromethyl)-6-(6-((4-(2-(2,6-di oxopiperi din-3-yl)-l -oxoisoindolin-4- yl)but-3 -yn- 1 -yl)carb amoyl)pyri din-3 -y 1 ) - 3,4-dihy droquinolin- 1 (2H)-yl)-N,4- dimethyl-3,4-dihy dro- 1,8-naphthyridine- 1 (2H)-carboxamide;

[0358] 5-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8-yl)- N-(4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)but-3-yn-l-yl)-[2,3'- bipyridine]-6'-carboxamide;

[0359] 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-(4-(2-(2,6- dioxopiperidin-3-yl)pyridin-4-yl)benzyl)picolinamide;

[0360] 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-(3-(3-((2,6- dioxopiperidin-3-yl)amino)-4-fluorophenyl)prop-2-yn-l-yl)picolinamide;

[0361]

[0362] 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-((5-(3-(2,4- 70.

[0363] dioxotetrahydropyrimidin-l(2H)-yl)-6-fluoro-l-methyl-lH-indazol-5- yl)isoxazol-3-yl)methyl)picolinamide;

[0364] 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-((5-(3-(2,6- 71.

[0365] dioxopiperi din-3-yl)-l -methyl -2-oxo-2, 3 -dihydro- lH-benzo[d]imidazol-5- yl)isoxazol-3-yl)methyl)picolinamide;

[0366] 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-((5-(4-(2,6- 72.

[0367] dioxopiperidin-3-yl)-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)isoxazol-3- yl)methyl)picolinamide;

[0368] 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-((5-(l-(2,6- 73.

[0369] dioxopiperidin-3-yl)-2-oxo-l,2-dihydrobenzo[cd]indol-7-yl)isoxazol-3- yl)methyl)picolinamide;

[0370] 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- 74. imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-((5-(3-(2,6- dioxopiperidin-3-yl)phenyl)isoxazol-3-yl)methyl)picolinamide; and

[0371] 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- 75. imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-((5-(2-(2,6- dioxopiperidin-3-yl)pyridin-4-yl)isoxazol-3-yl)methyl)picolinamide;

[0372]

[0373] or a pharmaceutically acceptable salt or a stereoisomer thereof.

[0374] In certain embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof or a stereoisomer thereof as described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein. The compounds described in the present disclosure may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrieror enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.

[0375] In yet another embodiment, the compounds of the present disclosure are p300 degraders.

[0376] In yet another embodiment, the compound of formula (I) is a p300 degrader.

[0377] In another embodiment, the present disclosure provides pharmaceutical composition for use in treating and / or ameliorating a disease and / or disorder responsive to the modulation of p300 protein and its activity.

[0378] In another embodiment, the present disclosure provides pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, for use in the manufacture of a medicament for treating and / or ameliorating a disease and / or disorder responsive to the modulation of p300 protein and its activity.

[0379] In yet another embodiment, the compounds of the present disclosure are a pharmaceutical acceptable salt or a stereoisomer thereof, for use as a medicament.

[0380] In an embodiment, the present disclosure provides pharmaceutical composition comprising the compound of formula (I), for use as a medicament.

[0381] In yet another embodiment, the compounds of the present disclosure are a pharmaceutical acceptable salt or a stereoisomer thereof, for the manufacture of a medicament for the treatment of cancer.

[0382] In yet another embodiment, the compounds of the present disclosure are a pharmaceutical acceptable salt or a stereoisomer thereof, for use in degrading the target protein in a subject, wherein the target protein is p300.

[0383] In yet another embodiment, the compounds of the present disclosure are a pharmaceutical acceptable salt or a stereoisomer thereof, for use in the treatment of p300 mediated disorder.

[0384] In an embodiment, the present disclosure provides pharmaceutical composition comprising the compound of formula (I), for use in the manufacture of a medicament for the treatment of cancer.In another embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof and at least one pharmaceutically acceptable carrier or excipient.

[0385] In an embodiment, the present disclosure provides pharmaceutical composition comprising the compound of formula (I), for use in treating a subject suffering from a disease or condition associated with p300.

[0386] In an embodiment, the compounds of the disclosure are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared using procedures well known in the pharmaceutical art and comprise at least one compound of the present disclosure. The pharmaceutical composition of the present disclosure comprises one or more compounds described herein and one or more pharmaceutically acceptable excipients. Typically, the pharmaceutically acceptable excipients are approved by regulatory authorities or are generally regarded as safe for human or animal use. The pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents, viscosifying agents, solvents and the like.

[0387] In an embodiment, the pharmaceutical composition can be administered by oral, parenteral or inhalation routes. Examples of the parenteral administration include administration by injection, percutaneous, transmucosal, transnasal and transpulmonary administrations.

[0388] In an embodiment, examples of suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, peanut oil, olive oil, gelatine, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, fatty acid esters and polyoxyethylene.

[0389] In an embodiment, the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, suspending agents, preserving agents, buffers, sweetening agents, flavouring agents, colorants or any combination of the foregoing.

[0390] In an embodiment, the pharmaceutical compositions may be in conventional forms, for example, tablets, capsules, solutions, suspensions, injectables or products for topicalapplication. Further, the pharmaceutical composition of the present disclosure may be formulated to provide desired release profile.

[0391] In an embodiment, administration of the compounds of the disclosure, in pure form or in an appropriate pharmaceutical composition, can be carried out using any of the accepted routes of administration of pharmaceutical compositions. The route of administration may be any route which effectively transports the active compound of the present disclosure to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, buccal, dermal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, intramuscular or topical.

[0392] In an embodiment, solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges.

[0393] In an embodiment, liquid formulations include, but are not limited to, syrups, emulsions and sterile injectable liquids, such as suspensions or solutions.

[0394] In an embodiment, topical dosage forms of the compounds include ointments, pastes, creams, lotions, powders, solutions, eye or ear drops, impregnated dressings and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration.

[0395] In an embodiment, the pharmaceutical compositions of the present disclosure may be prepared by conventional techniques known in literature.

[0396] In an embodiment, suitable doses of the compounds for use in treating the diseases or disorders described herein can be determined by those skilled in the relevant art. Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects. Mode of administration, dosage forms and suitable pharmaceutical excipients can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the present disclosure.

[0397] In one embodiment, the compounds as disclosed in the present disclosure are formulated for pharmaceutical administration.Yet another embodiment of the present disclosure provides use of the compounds as disclosed in the present disclosure in the treatment and prevention of diseases and / or disorder responsive to the p300 degraders activity.

[0398] Yet another embodiment of the present disclosure provides use of the compounds as disclosed in the present application in the manufacture of a medicament for the treatment of disease or disorder responsive to the p300 degradation.

[0399] Yet another embodiment of the present disclosure provides use of the compounds as disclosed in the present application 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.

[0400] Yet another embodiment of the present disclosure provides use of the compound or a pharmaceutically acceptable salt thereof, in treating and / or preventing a disease for which the symptoms thereof are treated, improved, diminished and / or prevented by p300 degraders.

[0401] According to above mentioned embodiments, the present disclosure provides use of the compound 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, neuroplastoma, angiosarcoma, chondrosarcoma, Ewing’s sarcoma, fibroblastic sarcoma, gynecological 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.According to yet another embodiment, the disease and / or disorder responsive to p300 degraders or condition is cancer, viral infection and autoimmune disease or disorder, inflammatory disease or disorder, neurodegenerative disease and metabolic disorder.

[0402] According to yet another embodiment, the disease and / or disorder responsive to p300 degraders or condition is cancer.

[0403] Yet another embodiment of the present disclosure, provides the pharmaceutical acceptable salt or a stereoisomer thereof, for use in degrading the target protein in a subject, wherein the target protein is p300.

[0404] In yet another aspect of an embodiment, 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, neuroplastoma, angiosarcoma, chondrosarcoma, Ewing’s sarcoma, fibroblastic sarcoma, gynecological 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.

[0405] In yet another aspect of an embodiment, a method of treating or preventing disease and / or disorder responsive to p300 degraders in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof.In yet another embodiment, the present disclosure provides compounds for use as a medicament for treating a subject suffering from diseases and / or disorder responsive to the responsive to the p300 degradation activity.

[0406] 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 anti-proliferative agents, anti-cancer agents, immunosuppressant agents and pain-relieving agents.

[0407] 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-viral agents and drugs used in the treatment of autoimmune disease or disorder.

[0408] In an embodiment, the method(s) of treatment of the present disclosure comprises administering a safe and therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient (particularly a human) in need thereof.

[0409] In certain embodiments, the present disclosure provides a method of treating or preventing a disease and / or disorder responsive to p300 degraders in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof.

[0410] According to the preceding embodiment, the disease or disorder is cancer, viral infection and autoimmune disease or disorder, inflammatory disease or disorder, neurodegenerative disease and metabolic disorder.

[0411] According to yet another embodiment, the disease or disorder is cancer.

[0412] In certain embodiments, the present disclosure provides a method of modulating p300 in a subject, comprising contacting p300 protein with a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0413] In certain embodiments, the present disclosure provides a method of treating or preventing a disease or disorder mediated by p300 protein, the disease or disorder is cancer, viral infection, autoimmune disease or disorder, inflammatory disease or disorder, neurodegenerative disease and metabolic disorder.According to certain foregoing embodiments, the present disclosure provides a method wherein the disease or disorder is cancer.

[0414] According to certain foregoing embodiments, the present disclosure provides a method 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, lymphoma or lymphoid malignancy or metastatic cancer.

[0415] In certain embodiments, the present disclosure provides a method of treating or preventing viral infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0416] In certain embodiments, the present disclosure provides a method of treating or preventing autoimmune or inflammatory disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0417] According to certain foregoing embodiments, the present disclosure provides a method wherein the 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, prurigo nodularis, Addison'sdisease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, bullous skin diseases, chronic obstructive pulmonary disease, Crohn's disease, eczema, giant cell arteritis, fibrosis, glomerulonephritis, hepatic vascular occlusion, hepatitis, hypophysitis, immunodeficiency syndrome, Kawasaki disease, lupus nephritis, myocarditis, myositis, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, Polyarteritis nodosa, pneumonitis, primary biliary cirrhosis, psoriatic arthritis, scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, Takayasu's Arteritis, toxic shock, thyroiditis, ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener's granulomatosis.

[0418] In certain embodiments, the present disclosure provides a method of treating or preventing neurodegenerative disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0419] According to certain foregoing embodiments, the present disclosure provides a method wherein the neurodegenerative disease is selected from Alzheimer’s disease, Parkinson’s disease, dementia, Huntington’s disease or amyotrophic lateral sclerosis.

[0420] According to certain foregoing embodiments, the present disclosure provides a method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of the present disclosure along with one or more chemotherapeutic agents, anti-viral agents, anti-inflammatory agent, immunosuppressant agents or pain-relieving agents.

[0421] In certain embodiments, the present disclosure provides a method of treating or preventing an autoimmune disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0422] In certain embodiments, the present disclosure provides a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0423] In an embodiment, Compounds of the disclosure are indicated both in the therapeutic and / or prophylactic treatment of the above-mentioned conditions. For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder or disease indicated.The compounds of the present disclosure may be used as single drug or as a pharmaceutical composition in which the compound is mixed with various pharmacologically acceptable materials.

[0424] According to one embodiment, the present disclosure provides compounds for use in combination with other compounds or biologic entities for treatment of cancer. Suitable combinations and doses of compounds for combination therapy used in treating the diseases or disorders described herein can be determined by those skilled in the relevant art. Combination therapies for compounds of the present disclosure can be used for treatment of cancer.

[0425] According to one embodiment, the compounds of the present disclosure can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the present disclosure also embraces isotopically-labeled variants of the present disclosure which are identical to those recited herein, but for the fact that one or more atoms of the compound are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the disclosure and their uses. Exemplary isotopes that can be incorporated in to compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as2H (“D”),3H,11C,13C,14C,13N,15N,15O,17O,18O,32P,33P,35S,18F,36Cl,123I and125I. Isotopically labeled compounds of the present disclosure can generally be prepared by following procedures analogous to those disclosed in the schemes and / or in the examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0426] EXPERIMENTAL

[0427] The present disclosure provides methods for the preparation of compound of formula (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.

[0428] 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 solventsreceived 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.

[0429] 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.

[0430] The specifics of the process for preparing compounds of the present disclosure are detailed in the experimental section.

[0431] 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.

[0432] 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.

[0433] 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.

[0434] 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.General Scheme 1:

[0435] o ovo ^Nv(R2)m°s NJR2>- Cyclization, A f —

[0436] Halogenation X Nitration GS-1a step-1 GS-1c step-2 GS-1d step-3 GS-1e

[0437] oR3 HXN 1—^ / N- Az(R2)mN-Alkylation GS-1h Halogenation using R1a-halide Buchwald coupling X GS-1i step-7

[0438] Hydrolysis

[0439]

[0440] Formula 1A' X= Halogen;

[0441] X1, X2, Y1, R2, R3, R6, R7, Ar, are as defined in the specification.

[0442] Some intermediates of the present disclosure may be generally synthesized utilizing the process outlined in General Scheme-1. The intermediate GS-1b was reacted with GS-la under suitable reaction conditions to afford GS-1c, which further undergoes halogenation by reacting with an appropriate halogenating agent under suitable conditions to afford GS-ld. GS-ld underwent nitration by reacting with a nitrating agent to afford GS-le. GS-le gets cyclized to form GS-lf in the presence of suitable reagents and conditions (Reductive Cyclization). GS-lf further gets alkylated to form GS-lg under suitable reaction conditions like (N-Alkylation). GS-lg upon coupling with GS-lh under suitable Buchwald coupling conditions affords GS-li followed by halogenation of GS-li under suitable conditions afforded GS-lj. GS-lj undergoes coupling with GS-lk under suitable Suzuki coupling conditions (Suzuki or other Pd-Catalyzed Cross-Coupling) to afford GS-11, which further upon ester hydrolysis forms intermediate of Formula-1A'.General Scheme 1A:

[0443] CRBN-amine Acid amine coupling

[0444]

[0445] step-1

[0446]

[0447] Some compounds of the present disclosure may be generally synthesized utilizing the process outlined in General Scheme-1 A. The carboxylic acid intermediate of Formula 1A" reacts with an appropriate CRBN-amine (as disclosed in the present disclosure) under suitable acid-amine coupling conditions to afford compound of Formula (1A").

[0448] General Scheme 2:

[0449] Buchwald coupling step-2 GS-2a

[0450] Halogenation GS-2f Suzuki coupling step-3 GS-2d step-4

[0451]

[0452] X= Halogen;

[0453] X1fX2, Yi, R1a, R2, R3, Re. R7, Ar are as defined in the specification.

[0454] Some intermediates of the present disclosure may be generally synthesized utilizing the process outlined in General Scheme-2. The intermediate GS-2a upon reacting with a halogenating agent under suitable halogenation conditions affords GS-2b. GS-2b uponBuchwald coupling with GS-2c in appropriate reaction conditions affords GS-2d, which upon halogenation under suitable conditions affords GS-2e. GS-2e on undergoing Suzuki coupling with GS-2f under suitable reaction conditions affords GS-2g, which further on ester hydrolysis forms intermediate of Formula- ID'.

[0455] General Scheme 2A:

[0456] o

[0457] CRBN-amine Acid-amine coupling

[0458]

[0459] Formula 1D' step-1

[0460]

[0461] Some compounds of the present disclosure may be generally synthesized utilizing the process outlined in General Scheme-2A. The intermediate Formula ID' upon acid-amine coupling with an appropriate CRBN amine (as provided in the present disclosure) affords compound of Formula (ID).

[0462] ABBREVIATIONS DMF - Dimethylformamide; h - hour; NBS - N-Bromosuccinimide; TFA - Trifluoroacetic acid; THF - Tetrahydrofuran; DCM - Dichloromethane; ACN - Acetonitrile; NCS - N-Chlorosuccinimide; XPhos Pd G2 - Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl)[2-(2'-amino-l,r-biphenyl)]palladium(II) RuPhos - Organic Phosphorus Compounds (including phosphines) Ligands; RuPhos Pd G2 - Chloro(2-dicy clohexylphosphino-2 6 ' -di i sopropoxy- 1, 1 '-biphenyl) [2-(2 '-amino- 1,1'-biphenyl)]palladium(II); RM - reaction mixture; Cs2CO3-Cesium carbonate; K2CO3-potassium carbonate; NaH-sodium hydride; Fe / AcOH- Iron / Acetic acid; 0C -degree Celsius; Mel-Methyl Iodide; LiOH-Lithium Hydroxide; MeOH-methanol; EA- ethylacetate; n-buli - n-Butyllithium; ti(oEt) - Titanium ethoxide; KoAc -Potassium acetate; NaOtBu -Sodium tert-butoxide; dppf - l,l'-Bis(diphenylphosphino)ferrocene; KNO3-Potassium nitrate; NH2OH-Hydroxylamine; HATU-l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; N, N-Diisopropylethylamine; RT / rt-Room temperature; TLC-Thin layer chromatography; LC-MS-Liquid chromatography-mass spectrometry; HPLC-High performance liquid chromatography; DMSO-d6-Deuterated dimethyl sulfoxide; NMR-Nuclear magnetic resonance, s-Singlet, d-Doublet, t-Triplet, q-Quartet, app. quint-Apparent quintet, dd-doublet of doublets, td-Triplet of doublets, SM-starting material, Int-Intermediate, Comp. -Compound, RT-Room temperature; and temptemperature.

[0463] SYNTHESIS OF INTERMEDIATES

[0464] Intermediate— 1 A:

[0465] Mel, NaH THF, RT, 3h

[0466]

[0467] step-5 lntermediate-1A Step-1: methyl 4-methyl-3,4-dihydroquinoline-l(2H)-carboxylate

[0468] To a stirred solution of 4-methyl-l,2,3,4 tetrahydroquinoline (1.5g, 10.18mmol) in DMF (20ml) was added potassium carbonate (5.63g, 40.75mmol) at 0°C. The reaction mixture was stirred for 5 min. and methyl carbonochloridate (2.8g, 30.56mmol) was the added dropwise and reaction mixture was stirred at RT for 10 min. Reaction mixture was then stirred at 60°C for 16h. Reaction progress was monitored by TLC. The reaction mixture was quenched with water and extracted with ethyl acetate to afford crude product. The crude was purified by normal phase chromatography using (0-6%) EA / Hexane to afford intermediate la (2.0g, 95.6%). LC-MS: 206.20 [M+H]+.

[0469] Step-2: methyl 6-bromo-4-methyl-3,4-dihydroquinoline-l(2H)-carboxylate

[0470] To a stirred solution of intermediate la (2.0g, 9.74mmol) in DMF (30ml) was added NBS (1.73 g, 9.74mmol) at 0°C. Reaction mixture was stirred at RT for 3h. Reaction progress was monitored by TLC. The reaction mixture was quenched with water and extracted with ethyl acetate to afford intermediate lb. (3.4g, crude). LC-MS: 284.00 [M+H]+.

[0471] Step-3: methyl 6-bromo-4-methyl-8-nitro-3,4-dihydroquinoline-l(2H)-carboxylateTo a stirred solution of intermediate lb (3.4g, 11.96mmol) in TFA (30ml) was added potassium nitrate (1.81g, 17.94mmol) at 0°C. The reaction mixture was stirred at same 0°C for 20 min. Reaction progress was monitored by TLC. The reaction mixture was quenched with saturated sodium bicarbonate and extracted with ethyl acetate to afford intermediate 1c. (3.8g, crude). LC-MS: 329.90 [M+H]+.

[0472] Step-4: 8-bromo-6-methyl-5,6-dihydro-4H-imidazo[4,5,l-ij]quinolin-2(lH)-one

[0473] To a stirred solution of Iron (4.5g, 80.81mmol) in acetic acid (40ml), was added intermediate 1c (3.8g, 11.54mmol) at 80°C. Reaction mixture was stirred at 80°C for 2h. Reaction progress was monitored by TLC. The reaction mixture was filtered through celite and the filtrate was quenched with saturated sodium bicarbonate and extracted with ethyl acetate to afford intermediate Id. (3.6g, crude). LC-MS: 269.00 [M+H]+.

[0474] Step-5: 8-bromo-l,6-dimethyl-5,6-dihydro-4H-imidazo[4,5,l-ij]quinolin-2(lH)-one To a stirred solution of intermediate Id (3.6g, 13.47mmol) in THF (40ml) was added sodium hydride (0.37g, 16.17mmol) at RT. Reaction mixture was stirred for 5 min. The methyl iodide (3.07g, 20.21mmol) was added dropwise. Reaction mixture was stirred at RT for 3h. Reaction progress was monitored by TLC. Reaction mixture was quenched with water and extracted with ethyl acetate to afford crude compound. The crude compound was purified by normal phase chromatography using ethyl acetate / Hexane (0-30%) to afford pure intermediate -1A (2.8g, 73.9%).

[0475] LC-MS: 283.00 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) 57.24 (s, 1H), 7.09 (s, 1H), 3.83-3.82 (m,lH), 3.79-3.70 (m, 1H), 3.32 (s, 3H), 3.01 -3.00 (m, 1H), 2.10-2.09 (m, 1H), 1.73-1.72 (m, 1H), 1.29-1.27 (d, 3H).

[0476] Intermediate-IB:

[0477] AICI3, DCM H LAH, THF, RT, 3h ° 0 °C-60 °C, 3h TEA, DCM Br RT, 3h step-2 Bb step-3 Be

[0478] K2CO3, DMF, 60 °C, 6 h

[0479]

[0480] step-4 Bd step-5Step-1: N-(4-bromophenyl)-3-methylbut-2-enamide

[0481] To a stirred solution of 4-bromoaniline (5g, 29.06mmol) in DCM (50ml) was added 3-methylbut-2-enoyl chloride (4.13g, 34.87mmol) at 0 °C and the RM was stirred at RT for 30 min and TEA (2.2g, 21.79mmol) was added and total reaction mixture was stirred at RT for 3h. Reaction progress was monitored by TLC. Reaction mixture was quenched with ice water and extracted with DCM and organic layer was concentrated to afford intermediate Ba (7.5g, crude). LC-MS: 255.90 [M+H]+.

[0482] Step-2: 6-bromo-4,4-dimethyl-3,4-dihydroquinolin-2(lH)-one

[0483] To intermediate Ba (3g, 11.80mmol) in DCM (50ml) under ice-cold condition AlCh (2.36g, 17.70mmol) was added and the resultant solution stirred vigorously for 3h at RT. The reaction was then cooled to 0 °C quenched slowly with H2O and extracted with DCM., affords Bb(3g, crude). LC-MS: 255.80 [M+H]+.

[0484] Step-3: 6-bromo-4,4-dimethyl-l,2,3,4-tetrahydroquinoline

[0485] To a stirred solution of Intermediate Bb (2.5g, 9.83mmol) in THF (50ml) was added LiAlFL (2M) (1.12g, 29.51mmol) at 0 °C and the reaction mixture was stirred at 60 °C for 3h. Progress of the reaction was monitored by TLC. Reaction Mixture was quenched slowly by pouring it in to crushed ice and extracted with EtOAc for two times. The organic layer was dried over on sodium sulphate and concentrated under reduced pressure to get intermediate Be.

[0486] (3g, crude). LC-MS: 241.85 [M+H]+.

[0487] Step-4: methyl 6-bromo-4,4-dimethyl-3,4-dihydroquinoline-l(2H)-carboxylate

[0488] To a stirred solution of intermediate Be (5.5g, 22.90mmol) in DMF (100ml) was added K2CO3 (12.6g, 91.61mmol) followed by methyl chloroformate (6.49g, 68.70mmol) at 0 °C. Reaction mixture was stirred at 60 °C for 6h in sealed tube. Reaction progress was monitored by TLC. Reaction mixture was quenched with ice water and extracted with ethyl acetate and concentrated to afford crude material. Purification was done by combi flash column chromatography to afford intermediate Bd (5.5g, 80.54%). LC-MS: 299.02 [M+H]+.

[0489] Step-5: methyl 6-bromo-4,4-dimethyl-8-nitro-3,4-dihydroquinoline-l(2H)-carboxylate To a stirred solution of intermediate Bd (3.3g, 11.06mmol) in TFA (35ml) was added KNO3 (1 67g, 16.60mmol) at 0 °C and the reaction mixture was stirred at 0 °C for 20 min. Progress of the reaction was monitored by TLC. RM was quenched with ice water andSaturated bi carbonate solution extracted with EtOAc for two times. The organic layer was dried over on sodium sulphate and concentrated under reduced pressure to get intermediate Be (4g, crude). LC-MS: 344.90 [M+H]+.

[0490] Step-6: 8-bromo-6,6-dimethyl-5,6-dihydro-4H-imidazo[4,5,l-ij]quinolin-2(lH)-one To a stirred solution of Fe powder (4.5g, 81.59mmol) in AcOH (40ml) at 80° C was added Intermediate Be (4g, 11.65mmol) and the reaction mixture was stirred at 80 °C for 2h. Progress of the reaction was monitored by TLC. RM was quenched with saturated bi carbonate solution and extracted with EtOAc for two times. The organic layer was dried over on sodium sulphate and concentrated under reduced pressure to get intermediate Bf. (3.5g, crude). LC-MS: 282.90 [M+H]+.

[0491] Step-7: 8-bromo-l,6,6-trimethyl-5,6-dihydro-4H-imidazo[4,5,l-ij]quinolin-2(lH)-one To a stirred solution of intermediate Bf (2.5g, 8.89mmol) in THF (50ml) at 0°C was added sodium hydride (0.4g, 17.78mmol) then stirred for lOmins followed by iodo methane (2.52g, 17.78mmol) added to the RM. This reaction mixture was stirred at 2h at RT. Then progress of the reaction mixture was monitored by TLC. The reaction mixture was quenched with ice cold water and extracted with ethyl acetate. Purification was done by combi flash column chromatography to afford intermediate-lB. (2.5g, 95.25%). LC-MS: 296.95 [M+H]+.

[0492] 1H-NMR (400 MHz, DMSO-d6) 57.23 (s, 1H), 7.15 (s, 1H), 3.77-3.75 (m,2H), 3.32-3.30 (m, 3H), 1.84-1.83 (m, 2H), 1.28 (s, 6H).

[0493] Inter m ediate- 1 C:

[0494] Br2, AcOH Zn / NH4CI RT, 16h RT, 2h K2CO3, DMF, 100 °C, 5h step-1 step-2 Cb step-3

[0495] CDI, DMF 100 °C, 6h

[0496]

[0497] step-4 Cd step-5 Intermediate-1 C Step-1: 2-amino-5-bromo-3-nitrophenolTo a stirred solution of 2-amino-3 -nitrophenol (5g, 32.44mmol) in AcOH (50ml) was added Bn (2.59g, 32.44mmol) at 0 °C and the reaction mixture was stirred at RT for 16h. Progress of the reaction was monitored by TLC. Water was added to RM and the precipitated solid was filtered and dried to afford intermediate Ca. (6.5g, crude). LC-MS: 233.9 [M+H]+.

[0498] Step-2: 7-bromo-5-nitro-3,4-dihydro-2H-benzo[b][l,4]oxazine

[0499] To a stirred solution of intermediate Ca (4g, 17.16mmol) in DMF (40ml) was added K2CO3 (7.1g, 51.49mmol) heated the RM for 100 °C and was added dropwise, 1,2-dibromoethane (3.22g, 17.16mmol). Reaction mixture was stirred at 100 °C for 5h. Reaction progress was monitored by TLC. Reaction mixture was quenched with ice water and solid was obtained and filtered, dried to afford intermediate Cb. (4.3g, crude). LC-MS: 260.2 [M+H]+.

[0500] Step-3: 7-bromo-3,4-dihydro-2H-benzo[b] [l,4]oxazin-5-amine

[0501] To a stirred solution of intermediate Cb (0.5g, 1.93mmol) in THF (5ml) and water (2ml) was added NH4CI (L03g, 19.3mmol) followed by Zn powder (1g, 15.44mmol) at 0 °C and total reaction mixture was stirred at RT for 2h. Progress of the reaction was monitored by TLC. RM was quenched with water and extracted with EtOAc for two times. The organic layer was dried over on sodium sulphate and concentrated under reduced pressure to get intermediate Cc. (0.4g, crude). LC-MS: 230.6 [M+H]+.

[0502] Step-4: 7-bromo-3,4-dihydro-5-oxa-l,2a-diazaacenaphthylen-2(lH)-one Intermediate Cc (0.1g, 0.43mmol) was taken in DMF (3ml). CDI (0.14g, 0.87mmol) was added to it and heated at 100°C for 6h. Reaction progress was monitored through TLC. After completion of starting material, the RM was quenched with water and extracted with EtOAc. Org layer was concentrated to get the crude. Purified by 40-50% EtOAc: Hexane using Flash Chromatography to afford intermediate Cd. (80mg, 71.85%). LC-MS: 254.90 [M+H]+.

[0503] Step-5: 7-bromo-l-methyl-3,4-dihydro-5-oxa-l,2a-diazaacenaphthylen-2(lH)-one To a stirred solution of intermediate Cd (0.1g, 0.39mmol) in DMF (2ml) was added sodium hydride (13mg, 0.58mmol) at ice cold condition. Reaction mixture was stirred for 15 min. The methyl iodide (83mg, 0.58mmol) was added dropwise. Reaction mixture was stirred at RT for 2h. Reaction progress was monitored by TLC. Reaction mixture was quenched with water and extracted with ethyl acetate to afford intermediate-lC. (0.1g, crude). LC-MS: 270.95 [M+H]+.Intermediate-ID:

[0504] Br2, AcOH SnCI2, con. HCI 120 °C, 3h NH2-10 °C, RT, 16htNO2EtOH, RT, 1h step-1 Da step-2 Db step-3 De

[0505] NaBH4, TFA CDI, DMF, Mel, NaH, THF, 0 °C, RT, 3h RT, 6 h DMF, 0 °C to RT, 3h

[0506] Br

[0507]

[0508] step-4 Dd step-5 step-6 Intermediate-1 D

[0509] Step-1: 4-bromo-2,6-dinitroaniline

[0510] To a stirred solution of 2,6-dinitroaniline (5g, 27.30mmol) in AcOH (50ml) was added Bn (2.4g, 30mmol) at 0 °C and total reaction mixture was stirred at 120 °C for 3h. Progress of the reaction was monitored by TLC. RM was quenched with water and precipitated and solid was filtered and dried to afford intermediate Da. (4.5g, crude). LC-MS: 261.9 [M-H]+.

[0511] Step-2: 5-bromobenzene-l,2,3-triamine

[0512] To a stirred solution of intermediate Da (2g, 7.63mmol) in conc. HCl (40ml) was added SnCh. 2H2O (10.3g, 45.79mmol) at -10 °C and total reaction mixture was stirred at RT for 16h. Progress of the reaction was monitored by TLC. RM was quenched with ice water extracted with EtOAc for two times. The Aqueous layer was basified with 25% NaOH aqueous solution and extracted with Ethyl acetate for two times and dried over on sodium sulphate and concentrated under reduced pressure to get intermediate Db. (1.5g, crude). LC-MS: 203.65 [M+H]+.

[0513] Step-3: 7-bromoquinoxalin-5-amine

[0514] To a stirred solution of intermediate Db (0.1g, 0.49mmol) in EtOH (2ml) was added oxalaldehyde (28mg, 0.49mmol) at 0 °C. Then total reaction mixture was stirred at RT for 2h. Reaction progress was monitored by TLC. Reaction mixture was quenched with ice water and extracted with ethyl acetate and organic layer was dried and concentrated to get intermediate Dc(1.5g, crude). LC-MS: 225.7 [M+H]+.

[0515] Step-4: 7-bromo-l,2,3,4-tetrahydroquinoxalin-5-amineTo a stirred solution of intermediate Dc(0.3g, 1.33mmol) in THF (10ml) was added NaBHj (0.25g, 6.69mmol) at 0 °C and total reaction mixture was stirred at 0 °C for 30min. After 30 min TFA (0.38g, 3.34mmol) was added at 0 °C and the RM was stirred at RT for 3h. Progress of the reaction was monitored by TLC. RM was quenched with water and extracted with EtOAc for two times. The organic layer was dried over on sodium sulphate and concentrated under reduced pressure to get intermediate Dd. (0.23g, crude). LC-MS: 227.85 [M+H]+.

[0516] Step-5: 8-bromo-5,6-dihydro-4H-imidazo[l,5,4-de]quinoxalin-2(lH)-one

[0517] To a stirred solution of intermediate Dd(0.38g, 1.66mmol) in DMF (10ml) was added CDI (0.6g, 3.74mmol) at 0 °C. Reaction mixture was stirred at RT for 6h. Reaction progress was monitored by TLC. Reaction mixture was quenched with ice water and extracted with ethyl acetate and concentrated to afford intermediate De(0.23g, crude). LC-MS: 253.8 [M]+.

[0518] Step-6: 8-bromo-l,6-dimethyl-5,6-dihydro-4H-imidazo[l,5,4-de]quinoxalin-2(lH)-one To a stirred solution of Intermediate De (0.15g, 0.59mmol) in DMF (5ml) was added NaH (27mg, 1.18mmol) follwed by Mel (0.41g, 2.95mmol) at 0 °C. Reaction mixture was stirred at RT for 3h. Reaction progress was monitored by TLC. Reaction mixture was quenched with ice water and extracted with ethyl acetate and concentrated to afford intermediate-lD. (0.17g, crude). LC-MS: 283.8 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) 5 6.66 (s, 1H), 6.55 (s, 1H), 4.02-4.01 (t, 2H), 3.38 (s, 3H), 3.33-3.3 l(t, 2H), 2.93 (s, 3H).

[0519] Intermediate-IE:

[0520] KNO3, TFA, 0 °C, 20min K2CO3, DMF, 60 °C, 16 h step-1 step-3

[0521]

[0522] Step-1: methyl 3,4-dihydroquinoline-l(2H)-carboxylate

[0523] To a stirred solution of 1,2,3,4-tetrahydroquinoline (1.5g, 10.18mmol) in DMF (20ml) was added potassium carbonate (5.63g, 40.75mmol) at 0°C. The reaction mixture was stirred for 5 min. and methyl carb onochlori date (2.8g, 30.56mmol) was the added dropwise and reaction mixture was stirred at RT for 10 min. Reaction mixture was then stirred at 60°C for 16h. Reaction progress was monitored by TLC. The reaction mixture was quenched with water and extracted with ethyl acetate to afford crude product. The crude was purified by normal phase chromatography using (0-6%) EA / Hexane to afford intermediate Ea (2.0g, 95.6%). LC-MS: 206.20 [M+H]+.

[0524] Step-2: methyl 6-bromo-3,4-dihydroquinoline-l(2H)-carboxylate

[0525] To a stirred solution of intermediate Ea(2.0g, 9.74mmol) in DMF (30ml) was added NBS (1.73 g, 9.74mmol) at 0°C. Reaction mixture was stirred at RT for 3h. Reaction progress was monitored by TLC. The reaction mixture was quenched with water and extracted with ethyl acetate to afford intermediate Eb. (3.4g, crude). LC-MS: 284.00 [M+H]+.

[0526] Step-3: methyl 6-bromo-8-nitro-3,4-dihydroquinoline-l(2H)-carboxylate

[0527] To a stirred solution of intermediate Eb. (3.4g, 11.96mmol) in TFA (30ml) was added potassium nitrate (1.81g, 17.94mmol) at 0°C. The reaction mixture was stirred at same 0°C for 20 min. Reaction progress was monitored by TLC. The reaction mixture was quenched with saturated sodium bicarbonate and extracted with ethyl acetate to afford intermediate Ec. (3.8g, crude). LC-MS: 329.90 [M+H]+.

[0528] Step-4: 8-bromo-5,6-dihydro-4H-imidazo[4,5,l-ij]quinolin-2(lH)-one

[0529] To a stirred solution of Iron (4.5g, 80.81mmol) in acetic acid (40ml) was added intermediate Ec(3.8g, 11.54mmol) at 80°C. Reaction mixture was stirred at 80°C for 2h. Reaction progress was monitored by TLC. The reaction mixture was filtered through celite and the filtrate was quenched with saturated sodium bicarbonate and extracted with ethyl acetate to afford intermediate Ed (3.6g, crude). LC-MS: 269.00 [M+H]+.

[0530] Step-5: 8-bromo-l-methyl-5,6-dihydro-4H-imidazo[4,5,l-ij]quinolin-2(lH)-one

[0531] To a stirred solution of intermediate Ed (3.6g, 13.47mmol) in THF (40ml) was added sodium hydride (0.37g, 16.17mmol) at RT. Reaction mixture was stirred for 5 min. The methyl iodide (3.07g, 20.21mmol) was added dropwise. Reaction mixture was stirred at RT for 3h.Reaction progress was monitored by TLC. Reaction mixture was quenched with water and extracted with ethyl acetate to afford crude compound. The crude compound was purified by normal phase chromatography using ethyl acetate / Hexane (0-30%) to afford pure intermediate-1E (2.8g, 73.9%).

[0532] LC-MS: 283.00 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ 7.24 (s, 1H), 7.09 (s, 1H), 3.83-3.82 (m,1H), 3.79-3.70 (m, 1H), 3.32 (s, 3H), 3.01 -3.00 (m, 1H), 2.10-2.09 (m, 1H), 1.73-1.72 (m, 2H).

[0533] Intermediate-1F:

[0534] NBS, DMF, RT, 3 h KNO3, TFA,

[0535] 0 °C. 20min,

[0536] step-1 Fa Fb step-3 Fc step-4

[0537]

[0538] Intermediate-1 F

[0539] Step-1 and Step-2 procedures and workup same as Intermediate-IE.

[0540] Step-3: 2-bromo-5-(methoxycarbonyl)-5,6,7,8-tetrahydro-l,5-naphthyridine 1-oxide

[0541] To a stirred solution Intermediate Fb(2.2g, 9.14mmol) in DCM (100ml) cooled at 0° C was added mCPBA (4.73g, 27.42mmol) under argon atmosphere for 3h. then progress of the reaction mixture monitored by TLC. Then reaction mixture was quenched with sodium bicarbonate solution and extracted with DCM to afford intermediate Fc. (1.7g, 72.46%). LC-MS: 288.20 [M+H]+.

[0542] Step-4, Step-5 and Step-6 procedures and workup same as step-5 and step-6 of Intermediate-IE.

[0543] LC-MS: 269.21 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ 7.23 (s, 1H), 3.85-3.84 (m,1H), 3.83-3.82 (m, 1H), 3.32 (s, 3H), 2.20 -2.19 (m, 1H), 1.84-1.83 (m, 1H), 1.28-1.24 (d, 3H).Intermediate-1: 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)picolinic acid

[0544]

[0545] Intermediate-1A step-1 1f step-2

[0546]

[0547]

[0548] Intermediate-1 Step-1: 8-(7-(difluoromethyl)-3,4-dihydroquinolin-l(2H)-yl)-l,6-dimethyl-5,6-dihydro-4H-imidazo[4,5,l-ij]quinolin-2(lH)-one

[0549] To a stirred solution of intermediate 1A (1.9g, 6.75mmol) in 1, 4 dioxane (50ml) was added 7-(difluoromethyl)-l,2,3,4tetrahydroquinoline (1.48g, 8.11mmol) at RT. The reaction mixture was purged with argon for 5 min. The Sodium tert-butoxide (1.94g, 20.27mmol) was added and again purged for 5 min. Finally, RuPhos (0.64g, 1.38mmol) and RuPhosPdG2 (0.53g, 0.68mmol) was added and reaction mixture purged for 5 min. The reaction mixture was stirred under 100°C for 2h. Reaction progress was monitored by TLC. The reaction mixture as such evaporated to afford crude compound. The crude compound was purified by normal phase chromatography using (0-100%) EA / Hexane to afford pure intermediate-lf. (2.5g, 96.48%). LC-MS: 384.20 [M+H]+.

[0550] Step-2: 8-(6-bromo-7-(difluoromethyl)-3,4-dihydroquinolin-l(2H)-yl)-l,6-dimethyl-5,6-dihydro-4H-imidazo[4,5,l-ij]quinolin-2(lH)-one

[0551] To a stirred solution of intermediate-lf (2.3g, 5.99 mmol) in Acetonitrile (30ml) and DCM (150ml) was added NBS (0.96g, 5.39mmol) at 0°C. Reaction mixture was stirred at RT for Ih. Reaction progress was monitored by TLC. The reaction mixture was quenched with water and extracted with ethyl acetate to afford pure intermediate-lg. (2.9g, crude). LC-MS: 462.00 [M+H]+.Step-3: methyl 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro- 4H-imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)picolinate

[0552] To a stirred solution of intermediate-lg (2.8g, 6.05mmol) and methyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)picolinate (2.4g, 9.08mmol) in dioxane (56ml) and water (4ml) was added potassium carbonate (2.51g, 18.21mmol) at RT. The reaction mixture was purged with argon for 10 min. Pd(dppf)C12. DCM (0.44g, 0.60mmol) was then added and reaction mixture was again purged for 5 min. The reaction mixture was stirred at 100°C for 2h. Reaction progress was monitored by TLC. The reaction mixture as such evaporated to afford crude. The crude compound was purified twice by normal phase chromatography using (0-100%) EA / Hexane to afford pure intermediate-lh. (1.5g, 47.76%). LC-MS: 519.20 [M+H]+.

[0553] Step-4: 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)picolinic acid

[0554] To a stirred solution of intermediate-lh (1.5g, 2.89 mmol) in MeOH (5ml), THF (20ml) and water (5ml) was added Lithium hydroxide (0.34g, 14.46 mmol) at RT. Reaction mixture was stirred at RT for Ih. Reaction progress was monitored by TLC. The reaction mixture was acidified with IN HCI and extracted with DCM to afford pure Intermdiate-1. (1.0g, crude). LC-MS: 505.10 [M+H]+.

[0555] Intermediate-2: 3-(4-(3-(aminomethyl)isoxazol-5-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione

[0556] NH2OH. HCI K2CO3, EtOH NCS, DMF RT, 16h RT, 3h SnBu3BocHN BocHN ^^ 'OH BocHN RT, 16h step-1 2a step-2 2b step-3 2c

[0557] Dioxane-HCI DCM, RT, 1h Pd(dppf)CI2DCM, Dioxane 100 °C, 16 h

[0558]

[0559] step-4 step-5 Intermediate-2 Step-1: tert-butyl (E)-(2-(hydroxyimino)ethyl)carbamateTo a stirred solution tert-butyl (2-oxoethyl)carbamate (4.5g, 28.26mmol) in Ethanol (50ml) was added potassium carbonate (7.7g, 56.53mmol) hydroxylamine hydrochloride (3.9g, 56.53mmol) at RT. Resulting reaction mixture was stirred at RT for 16h. Then reaction mixture was quenched with water and extracted with ethyl acetate to afford intermediate-2a. (5.0g, crude).

[0560] Step-2: tert-butyl (Z)-(2-chloro-2-(hydroxyimino)ethyl)carbamate

[0561] To a stirred solution of intermediate-2a (2.5g, 14.35 mmol) in DMF (25ml) at RT was added NCS (1.9g, 14.35 mmol) under argon atmosphere. Then the resulting reaction mixture was stirred for 3h. Progress of the reaction mixture monitored by TLC. Then the reaction mixture was quenched with ice cold water and extracted with ethyl acetate to afford intermediate-2b. (3.0g, crude).

[0562] Step-3: tert-butyl ((5-(tributylstannyl)isoxazol-3-yl)methyl)carbamate

[0563] To a stirred solution of intermediate-2b (3g, 14.37 mmol) in DCM (60 ml) was added potassium carbonate (5.9g, 43.13mmol) and tributyl(ethynyl)stannane (13.59g, 43.13mmol) at RT for 16h. Progress of the reaction monitored by TLC. Then reaction mixture was quenched with water and extracted with DCM. Purification was done by combi flash column chromatography to afford intermediate-2c. (0.6g, 8.56%). LC-MS: 489.20 [M+H]+.

[0564] Step-4: tert-butyl ((5-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)isoxazol-3-yl)methyl)carbamate

[0565] To a stirred solution of intermediate-2c (0.55g, 1.12 mmol) and 3-(4-bromo-l-oxoisoindolin-2 -yl)piperidine-2, 6-dione (0.36g, 1.12mmol) in dioxane (10ml) solvent degassed by argon atmosphere. After degassing Pd(dppf)C12. DCM complex (92mg, O.llmmol) added to the reaction mixture and again degassed. Then reaction mixture stirred at 100° C for 16h. Progress of the reaction mixture was monitored by TLC. Reaction mixture was quenched with water and extracted with ethyl acetate. Purification was done by combi flash column chromatography to afford intermediate-2d. (0.3g, 60.34%). LC-MS: 441.10 [M+H]+.

[0566] Step-5: 3-(4-(3-(aminomethyl)isoxazol-5-yl)-l-oxoisoindolin-2-yl)piperidine-2,6-dione

[0567] To a stirred solution of intermediate-2d (0.3g, 0.68mmol) in DCM (6ml) at 0° C were added Dioxane HC1 (2ml) under argon atmosphere. Then reaction mixture was stirred at RT for Ih.Progress of the reaction mixture was monitored by TLC. Reaction mixture was concentrated and dried to afford Intermediate-2. (0.2g, crude salt). LC-MS: 341.10 [M+H]+.

[0568] Intermediate-3: 3-(4-(5-(aminomethyl)-l-methyl-lH-pyrazol-3-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione

[0569] Mel, K2CO3, THF, -78 °C, 1h DMF, RT, 2h RT, 2h Ti(OEt)4, THF RT, 3h step-1 3a step-2 3b step-3 3c step-4

[0570] Pd(dppf)CI2DCM, CsF DME-H2O 100 °C, 3h

[0571]

[0572] step-5 3e step-6 Intermediate-3 Step-1: 3,5-dibromo-l-methyl-lH-pyrazole

[0573] To a stirred solution of 3,5-dibromo-lH-pyrazole (5g, 22.13mmol) in DMF (50ml) at 0°C was added potassium carbonate (7.65g, 55.34mmol) then stirred for 10 mins followed by methyl iodide (6.28g, 44.27mmol) added to the RM. This reaction mixture was stirred at 2h at RT. Then progress of the reaction mixture was monitored by TLC. Then reaction mixture was quenched with ice cold water and extracted with ethyl acetate. Purification was done by combi flash column chromatography to afford intermediate-3a. (4.5g, 84.74%). LC-MS: 240.85 [M+H]+.

[0574] Step-2: 3-bromo-l-methyl-lH-pyrazole-5-carbaldehyde

[0575] To a stirred solution of intermediate-3a (4.2g, 17.50mmol) in THF (50ml) at -78° C was added n-BuLi (1.68g, 26.26mmol) under argon atmosphere. Then resulting reaction mixture was stirred at same temperature for Ih then DMF (1.92g, 26.26mmol) added to the reaction mixture and stirred for another 2h. Then reaction mixture was quenched with ammonium chloride solution and extracted with ethyl acetate. Purification was done by combi flash column chromatography to afford intermediate-3b. (3g, 90.66%). LC-MS: 293.95 [M+H]+.

[0576] Step-3: (E)-N-((3-bromo-l-methyl-lH-pyrazol-5-yl)methylene)-2-methylpropane-2-sulfinamideTo a stirred solution of intermediate-3b (2.8g, 14.81mmol) in THF (45ml) was added Ethyl titanate (6.7g, 29.62mmol) followed by 2-methylpropane-2-sulfinamide (2.1g, 17.77mmol) at RT. Reaction mixture was stirred at RT for 3h. Reaction progress was monitored by TLC. The reaction mixture was quenched with water and extracted with ethyl acetate to afford intermediate-3c. (4.5g, crude). LC-MS: 294.2 [M+H]+.

[0577] Step-4: N-((3-bromo-l-methyl-lH-pyrazol-5-yl)methyl)-2-methylpropane-2-sulfinamide

[0578] To a stirred solution of intermediate-3c (4g, 13.68mmol) in MeOH (80ml) was added sodium borohydride (3.1g, 82.13mmol) and reaction mixture was stirred at RT for 2h. Then progress of the reaction was monitored by TLC. Reaction mixture was quenched with water and extracted with ethyl acetate to afford intermediate-3d. (4g, crude). LC-MS: 294.2 [M+H]+. Step-5: N-((3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)-l-methyl-lH-pyrazol-5-yl)methyl)-2-methylpropane-2-sulfinamide

[0579] To s stirred solution of intermediate-3d (0.25g, 0.84mmol) and Intermediate-4 (0.55g, 1.48mmol) in dimethoxy ethane (1ml) and water (0.5ml) solvent degassed by argon atmosphere. Cesium fluoride (0.38g, 2.54mmol) was added. After degassing Pd(dppf)C12. DCM complex (69mg, 0.085mmol) added to the reaction mixture and again degassed. Then reaction mixture stirred at 100° C for 3h. Progress of the reaction mixture was monitored by TLC. Reaction mixture was quenched with water and extracted with ethyl acetate. Purification was done by combi flash column chromatography to afford intermediate-3e. (0.3g, 78.12%). LC-MS: 458.15 [M+H]+.

[0580] Step-6: 3-(4-(5-(aminomethyl)-l-methyl-lH-pyrazol-3-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione

[0581] To intermediate-3 e (0.3g, 0.65mmol) at 0° C was added Dioxane HC1 (3ml) under argon atmosphere. Then reaction mixture was stirred at RT for 2h. Progress of the reaction mixture was monitored by TLC. Reaction mixture was concentrated and dried to afford Intermediate-3. (0.2g, crude salt). LC-MS: 354.10 [M+H]+.

[0582] Intermediate-4: 3-(l-oxo-4-(4,4,5,5-tetramethyll,3,2-dioxaborolan-2-yl)isoindolin- 2yl)piperidine-2, 6-dione

[0583]

[0584] Step-1: 3-(l-oxo-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2, 6-dione

[0585] To s stirred solution of 3 -(4-bromo-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (1g, 3.09mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.5g, 6.18mmol) in Dioxane (10ml) solvent degassed by argon atmosphere. Potassium acetate (0.6g, 6.18mmol) was added. After degassing Pd(dppf)C12. DCM complex (0.25g, 0.30mmol) added to the reaction mixture and again degassed. Then reaction mixture stirred at 90° C for Ih. Progress of the reaction mixture was monitored by TLC. Reaction mixture was quenched with water and extracted with ethyl acetate. Purification was done by combi flash column chromatography to afford Intermediate-4. (0.55g, 48.12%). LC-MS: 371.05 [M+H]+.

[0586] Intermediate-5: 3-(4-(3-(aminomethyl)phenyl)-l-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride

[0587]

[0588] Step-1: Synthesis of tert-butyl (3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)benzyl)carbamate

[0589] tert-butyl (3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) benzyl) carbamate (0.61g, 1.85mmol) and 3-(4-bromo-l-oxoisoindolin-2-yl) piperidine-2, 6-dione (0.5g, 1.54mmol) in dioxane(lOml) and water (1ml) was purged with Ar for 5 mins. To this Cesium fluoride (0.7g, 4.64mmol) and Pd(dppf)C12. DCM (0.12g, 0.15mmol) was added and purged again with Ar. Seal tube was closed and heated at 100°C for 4h. Progress of the reaction mixture was monitored by TLC. Reaction mixture was quenched with water and extracted with ethylacetate. Purification was done by combi flash column chromatography to afford Intermediate-5a. (0.55g, 78.57%). LC-MS: 449.4 [M+H]+.

[0590] Step-2: 3-(4-(3-(aminomethyl)phenyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochloride

[0591] To a stirred solution if Intermediate-5a (0.5g, l.llmmol) in DCM (5ml) at 0° C were added Dioxane HC1 (5ml) under argon atmosphere. Then reaction mixture was stirred at RT for Ih. Progress of the reaction mixture was monitored by TLC. Reaction mixture was concentrated and dried to afford Intermediate-5. (0.55g, crude salt). LC-MS: 350.3 [M+H]+.

[0592] A

[0593] The intermediates listed in Table-A were prepared by a procedure similar to the one described in the synthesis of Intermediate-1 with appropriate variations in reactants / reagents. The characterization data of the intermediates are summarized herein the below table.Table-A:Int. No. Starting material (SM1) Starting material (SM2) Structure Characterisation data

[0594] Int- IB

[0595] & LCMS m / z: 519.26 Int-6 7 OH

[0596] H I (M+H)+ cX / F

[0597] Int-lC

[0598] & LCMS m / z: 493.1 Int-7

[0599] H I (M+H)+ O^F

[0600] Int- ID

[0601] LCMS m / z: 506.35 &

[0602] Int- 8 (M+H)+

[0603] H I

[0604] C^F

[0605] O^N j ” F. p LCMS m / z: 523.2 Int-9 Int-IA xn XcU (M+H)+

[0606] XzO. \-V / A==NOH

[0607] NiT

[0608] 0

[0609]

[0610] &

[0611] H I

[0612] Int-1A

[0613] LCMS m / z: 519.32 &

[0614] Int-10 H (M+H)+

[0615] I N-V / \=N0HcX / 'F

[0616] Int-1E O CD- 7^0

[0617] & LCMS m / z: 492.32 Int-11

[0618] H I A

[0619] o (M+H)+ 0YF0 /

[0620] o / / /

[0621] o o

[0622] \°= to to

[0623] B C oz / —

[0624] p> < ^N^ / X LCMS m / z: 451.7 Int-12 Int-IA 5 Ooo- / (M+H)+

[0625] A7\oo^-~ ~ 0

[0626] °< Y'N / □

[0627] LCMS m / z: 439.21 Int-13 Int-lC y_v=yyyA

[0628] Q^ \= / A> H (M+H)+

[0629] 0^NZN— LCMS m / z: 452.32 ^N^ / X

[0630] Int-14 Int-ID ^yv=yyyy (M+H)+

[0631] < Q^ \=Nn>H

[0632] Int-IA & °^N \ - LCMS m / z: 507.1

[0633] J j=\ VF

[0634] Int-15 (M+H)+

[0635] fVtM

[0636] CA - ^0H

[0637] Int-IF

[0638] & LCMS m / z: 492.65 Int-16

[0639] H T Aynj OH (M+H)+

[0640] 0

[0641]

[0642] C^FThe intermediates listed in Table-B were prepared by a procedure similar to the one described in the synthesis of Intermediate-5 with appropriate variations in reactants / reagents. The characterization data of the intermediates are summarized herein the below table.

[0643] Table-B:Int. No. Starting material (SM1) Starting material (SM2) Structure Characterisation data

[0644] VNH

[0645] Br o b 4 d

[0646] NH WW O O-- C^0LCMS m / z: Int- 17 W O- “ vN_,

[0647] 0 (l tHCI364.01 (M+H)+ iTj

[0648] 0

[0649] LCMS m / Int QBA / C iT Oj~C >-'N^=o z: - 18 I z\ H

[0650] > °~7\ oZ364.26 (M+H)+ NHBoc X)

[0651] 0 LCMS m / z:

[0652] Br o

[0653] NH O

[0654] Int- 19 C^CN~C^=°

[0655] J il. o ^~NH 351.67 (M+H)+ 0

[0656] C|H

[0657] 0

[0658] A / “ LCMS m / z:

[0659] BocHN^CLBn

[0660] Int-20 C 1JC / N~

[0661] Jv0 / CT~^NH=O 350.32 (M+H)+ CH H2N^X I|

[0662] 0

[0663] C^C / N~ LCM ^(~~y=o S m / z: Int-21 J. o NH

[0664] 350.21 (M+H)+ o

[0665] ^NH2. HCI

[0666] 0 o LCMS m / z:

[0667] CIH H2N. / — \

[0668] Int-22 3 BocHN^x-^b^B'°'y / 1 11 LN\ /

[0669] ^-NH=<364.42 (M+H)+ 00

[0670]

[0671] Intermediate-23:

[0672]

[0673] Step-1: methyl 5-((tert-butoxycarbonyl)amino)-5'-methyl-[2,3'-bipyridine]-6'-carboxylate

[0674] To tert-butyl (6-brom opyri din-3 -yl)carbamate (8g, 27.76 mmol) and methyl 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) picolinate (11.5g, 41.64 mmol) in dioxane (180 ml) and water (20 ml) was added K2CO3 (11.5g, 83.29 mmol) and purged with Argon for 2mins. To this Pd(dppf)C12. DCM (2.03g, 2.77 mmol) was added and purged again with Argon. Seal tube was closed and heated at 100°C for 3h. Worked up using EtOAc and water. Org layer was concentrated to get the crude. Purified by 50-60% EtOAc: Hex using Flash Chromatography to afford Intermediate 23a. (9.5g, 95.47%). LC-MS: 344.32 [M+H]+.

[0675] Step-2: methyl 5-((tert-butoxycarbonyl)(methyl)amino)-5'-methyl-[2,3'-bipyridine]-6'-carboxylate

[0676] Intermediate 23a (10g, 36.48 mmol) was taken in DMF (100 ml) and NaH (1.67g, 72.96 mmol) was added to it in ice cold condition and the RM was stirred at RT for 30mins. After 30mins Mel (10.35g, 72.96 mmol) was added to it and stirred at RT for 3h. After completion of reaction, it was quenched with water and extracted with ETOAc. Org layer was concentrated to afford desired intermediate 23b. (10g, crude). LC-MS: 358.42 [M+H]+.

[0677] Step-3: methyl 5-(5-((tert-butoxycarbonyl)(methyl)amino)pyrimidin-2-yl)-3-methylpicolinate

[0678] Intermediate 23b (0.9g, 2.51 mmol) was taken in DCM (15 ml). TFA (5 ml) was added to it and stirred at RT for 3h. Reaction progress was monitored through TLC. After SM was over RM was directly concentrated and neutralised with sat bicarbonate soln, and then extractedwith DCM. Org layer was concentrated to get the crude intermediate 23c. (0.5g, crude). LC-MS: 258.45 [M+H]+.

[0679] Step-4: methyl 5-((l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8-yl)(methyl)amino)-5'-methyl-[2,3'-bipyridine]-6'-carboxylate

[0680] Intermediate 23c (0.75g, 2.90 mmol) and Intermediate- 1 A (0.81g, 2.90 mmol) ware taken in toluene (15 ml) and CS2CO3 (2.36g, 7.26 mmol) was added under Argon gas atmosphere in a seal tube. Then RuPhos (0.13g, 0.29 mmol) was added and reaction mixture was purged with Argon and Pd2dba3 (0.13g, 0.14 mmol) catalyst was added and once again purging was continued for another 5 minutes and heated at 100°C for 5h. The progress was monitored by TLC. RM was quenched with water and extracted with EtOAc. Org layer was concentrated to get the crude. Purified by 70-80% EtOAc: Hex using Flash Chromatography to afford intermediate 23d. (0.6g, 45.05%). LC-MS: 458.5 [M+H]+.

[0681] Step-5: 5-((l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8-yl)(methyl)amino)-5'-methyl-[2,3'-bipyridine]-6'-carboxylic acid

[0682] To a stirred solution Intermediate 23d (0.2g, 0.43 mmol) in THF (3 ml), MeOH (2 ml) and water (2 ml) was added LiOH. H2O (91 mg, 2.18 mmol) in water to the reaction mixture at RT. The resulting reaction mixture was stirred at RT for 3h. RM was evaporated directly and then reaction mixture was acidified with IN HC1 and precipitated solid was filtered out and dried to afford the Intermediate-23. (0.18g, crude). LC-MS: 444.21 [M+H]+.

[0683] Intermediate-24:

[0684] step-3 24c

[0685]

[0686] Intermediate-24 was synthesized in similar way via Procedure and workup same as Intermediate-23.Intermediate-25:

[0687]

[0688] Step-1: N,4-dimethyl-3,4-dihydroquinoline-l(2H)-carboxamide

[0689] To a stirred solution of 4-methyl-l,2,3,4-tetrahydroquinoline (1g, 6.79 mmol) in DCM (10 ml), was added triethyl amine (2.74g, 27.17 mmol) at 0°C. The reaction mixture was stirred for 5 min. N-methyl-lH-imidazole-1 -carboxamide (1.7g, 13.58 mmol) was then added and reaction mixture was stirred at RT for 2h. Reaction progress was monitored by TLC. The reaction mixture was quenched with water and extracted with ethyl acetate to afford crude compound. The crude compound was purified by normal phase chromatography using (0-100%) EA / Hexane to afford intermediate 25a. (0.44g, 31.71%). LC-MS: 205.2 [M+H]+.

[0690] Step-2: 6-bromo-N,4-dimethyl-3,4-dihydroquinoline-l(2H)-carboxamide

[0691] To a stirred solution of Intermediate 25a (4.4g, 2.15 mmol) in DMF (10 ml), was added NBS (0.38g, 2.15 mmol) at 0°C. Reaction mixture was stirred at RT for 3h. Reaction progress was monitored by TLC. The reaction mixture was quenched with water and extracted with ethyl acetate to afford intermediate 25b. (0.6g, crude). LC-MS: 284.95 [M+H]+.

[0692] Step-3: methyl 5-(7-(difluoromethyl)-4'-methyl-l'-(methylcarbamoyl)-l',2',3,3\4,4'-hexahydro-2H-[l,6'-biquinolin]-6-yl)picolinate

[0693] To a stirred solution of Intermediate 25b (0.6g, 2.11 mmol) in Toluene (15 ml), was added methyl 5-(7-(difluoromethyl)-l,2,3,4-tetrahydroquinolin-6-yl) picolinate (0.8g, 2.54 mmol) at RT. Reaction mixture was purged with argon for 5min. The tripotassium phosphate (1.12g, 5.29 mmol) was added and purged for 5min. Finally, Pd-PEPPSI (0.2g, 0.21 mmol) was added and purged for 5 min. Reaction mixture was stirred at 100°C for 16h. Reaction progress was monitored by TLC. Reaction mixture as such evaporated to afford crude compound. The crude compound was purified by normal phase chromatography using(0-60%)EA / Hexane to afford intermediate 25c. (70mg, 6.35%). LC-MS: 521.2 [M+H]+.

[0694] Step-4: 5-(7-(difluoromethyl)-4'-methyl-l'-(methylcarbamoyl)-l',2',3,3\4,4'-hexahydro-2H-[l,6'-biquinolin]-6-yl)picolinic acidTo a stirred solution Intermediate 25c (70mg, 0.13 mmol) in THF (3 ml), MeOH (0.3 ml) and water (0.3 ml) was added LiOH. H2O (16 mg, 0.67 mmol) in water to the reaction mixture at RT. The resulting reaction mixture was stirred at RT for Ih. RM was evaporated directly and then reaction mixture was acidified with IN HC1 and precipitated solid was filtered out and dried to afford intermediate-25. (30mg, crude). LC-MS: 507.15 [M+H]+.

[0695] The commercially available (or synthesized) CRBN, (CRBN-1 to CRBN-29), which are used

[0696] in the synthesis of compounds of the present disclosure are listed in the following Table-C:

[0697] Table-C:

[0698] CRBN No. Structure

[0699] 0

[0700] HN^\ CRBN-6

[0701] (AJ

[0702] CRBN-1

[0703] 1 A0

[0704] H YN A > CRBN-7 / L

[0705] CRBN-2?r0

[0706] NH

[0707] [j? N ^=0 I>< P

[0708] O 0

[0709] 0

[0710] HN'^N CRBN-8 £

[0711] cr y rz°\ / ^X ( CRBN-3

[0712] 0 CRBN-9

[0713] HN^X

[0714] CRBN-4 O^J

[0715] O HN— «

[0716] F o=f \

[0717] CRBN- 10

[0718] 0

[0719] N"O\ / ~A, HN'^'T £ \ \= / 7NCRBN-5 0

[0720] Z^N HNA

[0721] o-y

[0722] CRBN-11

[0723] F

[0724]

[0725] H2N

[0726]

[0727] 0 o V. - HN

[0728] HNA

[0729] oXp tr CRBN-12 CRBN-21 A" N'N)— / A' Y^siOX 0

[0730] z HN" \ \ zz UQi A ° CRBN-22

[0731] CRBN-13

[0732] Me [ 7=°

[0733] X z CMM C z z

[0734] ( o ox

[0735] J^ Cc>°zn H

[0736] °VNyO

[0737] o

[0738] CRBN-14 CRBN-23

[0739] H2N--^^~£y-Ao

[0740] CRBN-15

[0741] CRBN-24

[0742] 0

[0743] A X X z

[0744] O V. O C V z-— N N> K> z z z

[0745] CRBN-16 O^HT

[0746] CRBN-25

[0747] \aa / ~ N\ V CM CM z z z

[0748] z vy=\ ( o o\ z z

[0749] o 7 A X — ^< °= zz- CRBN-17

[0750] CRBN-26

[0751] OxH ■^N CRBN-18

[0752] CRBN-27 7^0

[0753] PU

[0754] H2N^^<

[0755] 0 CRBN-19 HN-P oX J? CRBN-28 H2N'X'>.,NifTS ^ / ~-N \ HN ) H2N.

[0756] CRBN-20 d N- >'

[0757] A 1

[0758] |Q| CRBN-29

[0759] (

[0760]

[0761] 0

[0762]

[0763] Example-1: 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-(4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)but-3-yn-l-yl)picolinamide

[0764] CRBN-1 HATU, DIPEA, DMF O C to RT, 1h

[0765]

[0766] step-1 Step-1: 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-(4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)but-3-yn-l-yl)picolinamide

[0767] To a stirred solution of Intermediate-1 (0.16g, 0.31mmol) in DMF (5ml) was added HATU (0.18g, 0.47mmol) at 0°C. The reaction mixture was stirred for 15 min. Diisopropylethylamine amine (0.2g, 1.58mmol) followed by CRBN-1 (0.14g, 0.47mmol) was then added respectively. The reaction mixture was stirred at RT for Ih. Reaction progress was monitored by TLC. The reaction mixture was quenched with water and extracted with 10% MeOH / DCM to afford crude compound. The crude compound was purified by normal phase chromatography using (0-5%) MeOH / DCM to afford pure compound-1. (0.1g, 39.54%).

[0768] LCMS: 798.15; HPLC: 96.89%; 1H-NMR (400 MHz, DMSO-d6) 5 11.02 (s, IH), 9.10-9.07 (t, IH), 8.54-8.53 (d, IH), 8.08-8.06 (d, IH), 7.90-7.88 (m, IH), 7.73-7.72 (d, IH), 7.65-7.64 (m, IH), 7.53-7.50 (m, IH), 7.09 (s, IH), 7.00 (s, IH), 6.89 (s, IH), 6.80-6.52 (m, 2H), 5.16-5.10 (dd, IH), 4.46-4.28 (m, 2H), 3.90-3.84 (m, IH), 3.76-3.71 (m, IH), 3.64-3.59 (m, 6H), 3.16-3.14 (m, 2H), 3.09-3.06 (m, IH), 2.91-2.87 (m, 3H), 2.80-2.78 (t, 2H), 2.67-2.64 (m, 2H), 2.58 (s, IH), 2.49-2.33 (m, IH), 2.19-2.14 (m, IH), 2.07-2.04 (m, 3H), 1.80-1.73 (m, IH). Chiral separation was done for compound- 1 using column REGIS, I-Cellulose-C and mobile phase acetonitrile-ethanol to afford two isomers Compound-2 and Compound-3.o o

[0769] Compound-3

[0770]

[0771] Isomer-1 isomer-2

[0772] Compound-2 (Isomer-1 of compound-1): LCMS: 798.05; HPLC: 97.83%; Chiral HPLC: 99.32% 1H-NMR (400 MHz, DMSO-d6) 5 11.02 (s, 1H), 9.10-9.07 (t, 1H), 8.54-8.53 (d, 1H), 8.07-8.05 (d, 1H), 7.91-7.90 (d, 1H), 7.72-7.70 (d, 1H), 7.65-7.63 (d, 1H), 7.53-7.50 (t, 1H), 7.07 (s, 1H), 7.00 (s, 1H), 6.89 (s, 1H), 6.80-6.52 (m, 2H), 5.16-5.10 (dd, 1H), 4.46-4.28 (m, 2H), 3.90-3.84 (m, 1H), 3.76-3.71 (m, 1H), 3.64-3.59 (m, 3H), 3.36 (s, 3H), 3.09-3.06 (m, 1H), 2.91-2.87 (m, 2H), 2.80-2.78 (t, 2H), 2.67-2.64 (m, 2H), 2.58 (s, 3H), 2.49-2.33 (m, 1H), 2.19-2.14 (m, 1H), 2.07-2.04 (m, 3H), 1.80-1.73 (m, 2H).

[0773] Compound-3 (Isomer-2 of compound-1): LCMS: 798.10; HPLC: 98.36%; Chiral HPLC: 95.25% 1H-NMR (400 MHz, DMSO-d6) 5 11.02 (s, 1H), 9.10-9.07 (t, 1H), 8.54-8.53 (d, 1H), 8.07-8.05 (d, 1H), 7.91-7.90 (d o, 1H), 7.72-7.70 (d, 1H), 7.65-7.63 (d, 1H), 7.53-7.50 (t, 1H), 7.07 (s, 1H), 7.00 (s, 1H I),

[0774] 6.89 (s, 1H), 6.80-6.52 (m, 2H), 5.16-5.10 (dd, 1H), 4.42-4.28 (m, 2H), 3.90-3.84 (m, 1H), 3.76-3.71 (m, 1H), 3.64-3.59 (m, 3H), 3.36 (s, 3H), 3.09-3.06 (m, 1H), 2.91-2.87 (m, 2H), 2.80-2.78 (t, 2H), 2.67-2.64 (m, 2H), 2.58 (s, 3H), 2.49-2.33 (m, 1H), 2.19-2.14 (m, 1H), 2.07-2.04 (m, 3H), 1.80-1.73 (m, 2H).

[0775] /

[0776] The compounds listed in below Table-D were prepared by reacting the corresponding intermediates and CRBN amines using a procedure as described in Example-1 with appropriate

[0777] variations in quantities of reagents, solvents and reaction conditions. The characterization data of the compounds are summarized herein the Table-D below.

[0778] Table-D:

[0779] Compound structure /

[0780] Characterization data Intermediates used

[0781] LCMS: 827.25; HPLC: 92.55%; 1H-NMR (400 MHz, DMSO-d6) 5 11.03 (s, 1H), 9.47-9.44 (t, 1H), 8.58-8.57 (d, 1H), 8.17-8.09 (m, 2H), 7.93- 7.87 (m, 2H), 7.71-7.67 (t, 1H), 7.10-7.06 (m, 2H), 7.00 (s, 1H), 6.89 (s, 1H), 6.81-6.54 (m, 2H), 5.21-5.17 (dd, 1H), 4.78-4.60 (m, 4H), 3.90-

[0782]

[0783] Compound 4 3.84 (m, 1H), 3.76-3.71 (m, 1H), 3.64-3.59 (m,

[0784] 2H), 3.16-3.14 (m, 2H), 2.91-2.87 (m, 3H), 2.80- Intermediates used

[0785] 2.78 (t, 1H), 2.13-2.11 (m, 1H), 2.07-2.04 (m, Intermediate- 1 & Intermediate-2 3H), 1.80-1.73 (m, 1H). 1.34-1.29 (m, 3H), 1.27- 1.25 (m, 3H),

[0786] LCMS: 840.30; HPLC: 92.41%; 1H-NMR (400 MHz, DMSO-d6) 5 11.01 (s, 1H), 9.44-9.41 (t, 1H), 8.57-8.56 (d, 1H), 8.15-8.11 (m, 1H), 7.93- 7.87 (m, 1H), 7.71-7.67 (d, 1H), 7.57-7.53 (m, C XAF\ r V°

[0787] H rV / X 2H), 7.10-7.06 (m, 2H), 7.00 (s, 1H), 6.89 (s,

[0788] 1H), 6.81-6.54 (m, 2H), 5.19-5.14 (dd, 1H), 4.69- Compound 5 4.56 (m, 4H), 3.96 (s, 3H), 3.90-3.84 (m, 1H),

[0789] 3.76-3.71 (m, 1H), 3.64-3.59 (m, 5H), 3.17-3.12 Intermediates used

[0790] (m, 3H), 2.91-2.87 (m, 3H), 2.80-2.78 (t, 1H), Intermediate- 1 & Intermediate-3 2.13-2.11 (m, 1H), 2.08-2.07 (m, 1H), 2.05-2.04

[0791] (m, 3H). 1.84-1.79 (m, 2H).

[0792] LCMS: 836.3; HPLC: 98.17%; 1H-NMR (400 MHz, DMSO-d6) 5 10.99 (s, 1H), 9.47-9.44 (t, 1H), 8.54-8.53 (d, 1H), 8.08-8.06 (d, 1H), 7.90- 7.88 (m, 1H), 7.73-7.72 (d, 1H), 7.65-7.64 (m, VFl

[0793] NVXFn. XX02H), 7.53-7.50 (m, 1H), 7.48-7.44 (m, 2H), 7.46

[0794] (s, 1H), 7.09 (s, 1H), 7.00 (s, 1H), 6.89 (s, 1H), 6.80-6.52 (m, 2H), 5.16-5.11 (dd, 1H), 4.60-4.57 Compound 6 (m, 2H), 4.41-4.37 (m, 1H), 3.90-3.84 (m, 1H), Intermediates used 3.76-3.71 (m, 1H), 3.64-3.59 (m, 2H), 3.16-3.14

[0795] (m, 1H), 2.91-2.87 (m, 3H), 2.67-2.64 (m, 2H), Intermediate- 1 & Intermediate-5

[0796] 2.58 (s, 3H), 2.49-2.33 (m, 1H), 2.19-2.14 (m, 1H), 2.07-2.04 (m, 3H), 1.80-1.73 (m, 1H). 1.30- 1.24 (m, 3H).

[0797]

[0798] LCMS: 812.25; HPLC: 88.62%; 1H-NMR (400

[0799] HNA MHz, DMSO-d6) 5 11.02 (s, 1H), 9.10-9.07 (t, V 1H), 8.54 (s, 1H), 8.08-8.06 (d, 1H), 7.90-7.88

[0800] (m, 1H), 7.72-7.70 (d, 1H), 7.65-7.64 (d, 1H), 7.54-7.50 (t, 1H), 7.09 (s, 1H), 6.99-6.95 (d, 2H), Compound 7 6.80-6.52 (m, 2H), 5.15-5.10 (dd, 1H), 4.47-4.28

[0801] (m, 2H), 3.82-3.80 (t, 2H), 3.66-3.63 (m, 4H), Intermediates used

[0802] 2.92-2.89 (m, 3H), 2.80-2.77 (t, 2H), 2.68-2.67 Intermediate-6 & CRBN-1 (m, 2H), 2.49-2.33 (m, 3H), 2.08-2.06 (m, 3H),

[0803] 1.90-1.87 (t, 2H). 1.29 (s, 6H).

[0804] LCMS: 786.2; HPLC: 99.14%; 1H-NMR (400 HNA MHz, DMSO-d6) 5 11.02 (s, 1H), 9.10-9.07 (t, °YNf~1N- oAj

[0805] 1H), 8.54 (s, 1H), 8.08-8.06 (d, 1H), 7.91-7.88 v? fy

[0806] (m, 1H), 7.72-7.70 (d, 1H), 7.64-7.62 (d, 1H), 7.53-7.50 (t, 1H), 7.09 (s, 1H), 6.82-6.81 (d, 2H), Compound 8 6.68-6.54 (m, 2H), 5.12-5.08 (dd, 1H), 4.46-4.42

[0807] (m, 3H), 4.32-4.28 (d, 1H), 3.98-3.96 (t, 2H), Intermediates used 3.63-3.58 (m, 4H), 2.89-2.88 (m, 3H), 2.80-2.77 Intermediate- 14 & CRBN-1 (t, 2H), 2.58-2.58 (m, 2H), 2.42-2.33 (m, 2H),

[0808] 2.05-1.98 (m, 4H).

[0809] LCMS: 745.2; HPLC: 90.05%; 1H-NMR (400 MHz, DMSO-d6) 5 11.02 (s, 1H), 9.47 (s, 1H), 9.46 (s, 1H), 9.15-9.12 (t, 1H), 8.78-8.76 (d, 1H), V rV°

[0810] 8.71 (s, 1H), 8.20-8.18 (d, 1H), 8.08-8.06 (d, 1H), 7.91-7.87 (t, 1H), 7.71-7.70 (m, 3H), 7.57-7.50 Compound 9 (t, 1H), 6.84 (s, 1H), 6.62 (s, 1H), 5.11-5.06 (dd,

[0811] 1H), 4.39 (s, 1H), 4.30 (s, 1H), 4.00-3.97 (t, 2H), Intermediates used

[0812] 3.65-3.60 (m, 2H), 3.20 (s, 1H), 2.93 (s, 1H), Intermediate-7 & CRBN-1 2.83-2.80 (t, 2H), 2.63 (s, 1H), 2.57 (s, 1H). 2.33

[0813] (m, 1H), 2.01-1.97 (m, 2H), 1.35-1.27 (m, 4H).

[0814]

[0815] o

[0816] — N 1 0 LCMS: 841.3; HPLC: 95.66%; 1H-NMR (400

[0817] MHz, DMSO-d6) 5 11.03 (s, 1H), 9.47-9.44 (t, & * 1H), 8.58 (s, 1H), 8.17-8.10 (m, 3H), 7.93-7.86 r X iFrNx°

[0818] (m, 2H), 7.71-7.67 (t, 1H), 7.11-7.07 (d, 2H), 0 6.99-6.95 (d, 1H), 6.67 (m, 2H), 5.20-5.15 (dd,

[0819] 1H), 4.74 (d, 1H), 4.67-4.60 (m, 3H), 3.82-3.80 Compound 10

[0820] (t, 2H), 3.66-3.60 (m, 5H), 3.31 (s, 3H), 3.17- Intermediates used 3.13 (m, 3H), 2.93-2.90 (m, 3H), 2.68-2.67 (m,

[0821] 2H). 2.07-2.05 (m, 3H), 1.90-1.89 (t, 2H).

[0822] Intermediate-6 & Intermediate-2

[0823] o LCMS: 828.25; HPLC: 94.79%; 1H-NMR (400

[0824] MHz, DMSO-d6) 5 11.01 (s, 1H), 9.45-9.41 (t, 1H), 8.56 (s, 1H), 8.10-8.09 (d, 1H), 7.99-7.99 (d, C X^LFfNy° 1H), 7.92-7.91 (d, 1H), 7.67-7.65 (d, 1H), 7.57- 7.53 (t, 1H), 7.09 (s, 1H), 6.82 (s, 1H), 6.76 (s, o

[0825] 1H), 6.67 (s, 1H), 6.61-6.54 (d, 2H), 5.20-5.12 Compound 11 (dd, 1H), 4.65-4.61 (m, 4H), 4.45-4.42 (t, 2H),

[0826] 3.98 (s, 5H), 3.61-3.58 (t, 2H), 3.51 (s, 1H), 2.91- Intermediates used

[0827] 2.88 (t, 3H), 2.68-2.67 (t, 2H), 2.33 (s, 1H), 2.03- Intermediate-7 & Intermediate-3 2.01 (m, 4H).

[0828] 0

[0829] LCMS: 815.20; HPLC: 98.27%; 1H-NMR (400 MHz, DMSO-d6) 5 11.02 (s, 1H), 9.47-9.44 (t, V,

[0830] 1H), 8.58 (s, 1H), 8.17-8.15 (d, 1H), 9.11-8.09 (d, ( X i ^FKI-0 r ) -V [ °

[0831] 1H), 7.93-7.86 (m, 2H), 7.71-7.67 (t, 1H), 7.10 0 (s, 1H), 7.06 (s, 1H), 6.82-6.55 (m, 4H), 5.15- 5.13 (m, 1H), 4.77 (s, 1H), 4.73 (s, 1H), 4.67- Compound 12

[0832] 4.65 (t, 3H), 4.45-4.43 (t, 2H), 3.98-3.36 (t, 2H), Intermediates used 3.62-3.59 (t, 3H), 2.90 (s, 3H), 2.68-2.67 (m,

[0833] 1H), 2.04 (m, 5H).

[0834] Intermediate-7 & Intermediate-2

[0835]

[0836] LCMS: 845.25; HPLC: 95.92%; 1H-NMR (400

[0837] 0

[0838] HN' \ MHz, DMSO-d6) 5 11.03 (s, 1H), 9.39-9.36 (t, O. / - 1 L /

[0839] y-N A 1H), 8.42 (s, 1H), 8.18-8.16 (d, 1H), 7.89-7.87 (d, ^NAA N^O

[0840] V?F\ VT 1H), 7.81-7.78 (d, 1H), 7.72-7.69 (d, 1H), 7.11 ' z=ZFF N'°\A /

[0841] < \NY (s, 1H), 7.06 (s, 1H), 7.00 (s, 1H), 6.90 (s, 1H), KAAXf Y \\, Hn~~^

[0842] 6.76 (s, 1H), 6.60 (s, 1H), 5.22-5.17 (dd, 1H), 4.79-4.74 (d, 1H), 4.65-4.60 (q, 3H), 3.89-3.86 Compound 13

[0843] (m, 1H), 3.72-3.65 (m, 1H), 3.65-3.61 (m, 3H), Intermediates used 3.31 (s, 5H), 3.05-3.04 (m, 1H), 2.92-2.91 (m,

[0844] 3H). 2.64-2.54 (m, 1H), 2.134 (m, 1H), 2.07-2.01 Intermediate-9 & Intermediate-2

[0845] (m, 3H), 1.31-1.24 (m, 1H), 0.95-0.86 (m, 1H).

[0846] LCMS: 829.25; HPLC: 93.75%; 1H-NMR (400 ° A

[0847] "-N'SZH7 1 MHz, DMSO-d6): 5 11.03 (s, 1H), 9.48-9.45 (t, H A / -- < A /

[0848] CY °A

[0849] MFA° 1H), 8.60-8.58 (d, 1H), 8.18-8.15 (d, 1H), 8.12- 8.08 (d, 1H), 7.95-7.91 (dd, 1H), 7.89-7.87 (d, I AAA H L / \=J

[0850] 1H), 7.72-7.68 (t, 1H), 7.55-7.51 (d, 1H), 7.15- 0

[0851] 7.10 (m, 2H), 7.08-7.01 (m, 2H), 6.90-6.60 (m, Compound 14 3H), 5.21-5.15 (m, 1H), 4.79-4.72 (d, 1H), 4.69- Intermediates used 4.59 (m, 3H), 3.70-3.55 (m, 4H), 3.30 (s, 3H),

[0852] 2.95-2.8 (m, 3H), 2.70-2.60 (m, 2H), 2.10-1.95 Intermediate-25 & Intermediate-2

[0853] (m, 4H), 1.60-1.50 (m, 1H), 1.12-0.90 (m, 4H).

[0854] LCMS: 854.3; HPLC: 96.67%; 1H-NMR (400 o

[0855] / ~NY MHz, DMSO-d6): 5 11.03 (s, 1H), 9.45-9.40 (t, " VLZ j?

[0856] 1H), 8.55-8.53 (d, 1H), 8.13-8.10 (d, 1H), 8.00- A 7.98 (d, 1H), 7.93-7.88 (m, 1H), 7.68-7.62 (d,

[0857] H YV / A 1H), 7.60-7.52 (t, 1H), 7.10 (s, 1H), 6.98-6.95 0 (m, 1H), 6.92 (s, 1H), 6.80-6.50 (m, 3H), 5.20- 5.12 (m, 1H), 4.70-4.58 (m, 4H), 3.95 (s, 3H), Compound 15

[0858] 3.73-3.71 (t, 3H), 3.68-3.61 (t, 3H), 2.95-2.88 Intermediates used (m, 3H), 2.68-2.55 (m, 2H), 2.48-2.43 (m, 1H),

[0859] 2.10-2.02 (m, 3H), 1.92-1.88 (m, 2H), 1.29 (s, Intermediate-6 & Intermediate-3

[0860] 6H).

[0861]

[0862] LCMS: 784.3; HPLC: 93.31%; 1H-NMR (400

[0863] 0 MHz, DMSO-d6): 5 11.03 (s, 1H), 9.12-9.06 (t, 1H), 8.56-8.52 (d, 1H), 8.10-8.05 (d, 1H), 7.92- 7.88 (dd, 1H), 7.72-7.68 (d, 1H), 7.65-7.61 (d, 1H), 7.53-7.48 (t, 1H), 7.1 (s, 1H), 7.00-6.98 (d,V' / "^ o

[0864] 1H), 6.83-6.80 (m, 1H), 6.70-6.52 (m, 2H), 5.18- Compound 16 5.10 (m, 1H), 4.48-4.41 (d, 1H), 4.31-4.27 (d, Intermediates used 1H), 3.82-3.65 (t, 2H), 3.85-3.65 (m, 4H), 2.92- 2.87 (m, 3H), 2.85-2.75 (m, 4H), 2.62-2.51 (m, Intermediate- 11 & CRBN-1 1H), 2.50-2.30 (m, 1H), 2.10-1.92 (m, 5H), 1.30- 1.20 (m, 3H).

[0865] o LCMS: 813.3; HPLC: 93.21%; 1H-NMR (400

[0866] MHz, DMSO-d6): 5 11.03 (s, 1H), 9.47-9.44 (t, 1H), 8.58-8.57 (d, 1H), 8.17-8.15 (d, 1H), 8.12- C Y iFrV° 8.09 (d, 1H), 7.95-7.85 (m, 2H), 7.72-7.68 (t,

[0867] 1H), 7.11 (s, 1H), 7.09 (s, 1H), 6.98 (d, 1H), 6.82 o

[0868] (s, 1H), 6.68 (s, 1H), 6.59 (s, 1H), 5.23-5.18 (m, Compound 17 1H), 4.81-4.71 (d, 1H), 4.68-4.60 (m, 3H), 3.81- 3.73 (t, 2H), 3.62-3.58 (t, 2H), 3.20-3.10 (m, 1H), Intermediates used

[0869] 2.95-2.90 (m, 3H), 2.88-2.80 (m, 2H), 2.62-2.52 Intermediate- 11 & Intermediate-2 (m, 1H), 2.10-1.98 (m, 5H), 1.40-1.30 (m, 3H).

[0870] LCMS: 773.25; HPLC: 99.85%; 1H-NMR (400 0

[0871] MHz, DMSO-d6): 5 11.03 (s, 1H), 9.55-9.49 (m, 2H), 9.42 (s, 1H), 8.89-8.88 (m, 1H), 8.73 (s, zN^°

[0872] 1H), 8.24-8.21 (d, 1H), 8.19-8.16 (d, 1H), 8.12- NA_ / A

[0873] \ H L / W 8.08 (d, 1H), 7.95-7.85 (m, 2H), 7.75-7.65 (m,

[0874] N «

[0875] O 2H), 7.28 (s, lH), 7.15 (s, 1H), 7.10 (s, 1H), 5.23- 5.17 (m, 1H), 4.81-4.61 (m, 4H), 3.98-3.90 (m, Compound 18

[0876] 1H), 3.82-3.75 (m, 1H), 3.4 (s, 3H), 3.20-3.10 Intermediates used (m, 1H), 2.98-2.87 (m, 1H), 2.52-2.42 (m, 1H),

[0877] 2.25-2.15 (m, 1H), 2.08-1.99 (m, 2H), 1.88-1.78 Intermediate- 12 & Intermediate-2

[0878] (m, 1H), 1.38-1.36 (d, 3H).

[0879]

[0880] 0

[0881] LCMS: 761.25; HPLC: 99.26%; 1H-NMR (400 -°W > &

[0882] , NOMHz, DMSO-d6): 5 11.02 (s, 1H), 9.53-9.51 (m, J-ZA NA / A 2H), 9.494 (s, 1H), 8.82-8.78 (m, 2H), 8.25-8.22

[0883] A / ^

[0884] N V (d, 2H), 8.21-8.19 (d, 1H), 7.95-7.85 (m, 2H), 0

[0885] 7.72-7.62 (m, 2H), 7.12-7.08 (d, 2H), 6.83 (s, Compound 19 1H), 5.23-5.17 (m, 1H), 4.80-4.60 (m, 4H), 4.52- 4.47 (t, 2H), 4.15-3.98 (t, 2H), 3.41 (s, 3H), 3.0- Intermediates used

[0886] 2.9 (m, 1H), 2.65-2.5 (m, 2H), 2.1-1.95 (m, 1H). Intermediate- 13 & Intermediate-2

[0887] LCMS: 843.15; HPLC: 94.09%; 1H-NMR (400 0 MHz, DMSO-d6): 5 11.03 (s, 1H), 9.55-9.49 (m,

[0888] 2H), 9.42 (s, 1H), 8.89-8.88 (m, 1H), 8.73 (s, A R

[0889] 1H), 8.24-8.21 (d, 1H), 8.19-8.16 (d, 1H), 8.12- rW - Xo

[0890] 8.08 (d, 1H), 7.95-7.85 (m, 2H), 7.75-7.65 (m, 0 2H), 7.28 (s, lH), 7.15 (s, 1H), 7.10 (s, 1H), 5.23- Compound 20 5.17 (m, 1H), 4.81-4.61 (m, 4H), 3.98-3.90 (m,

[0891] 1H), 3.82-3.75 (m, 1H), 3.4 (s, 3H), 3.20-3.10 Intermediates used

[0892] (m, 1H), 2.98-2.87 (m, 1H), 2.52-2.42 (m, 1H), Intermediate- 1 & CRBN-11 2.25-2.15 (m, 1H), 2.08-1.99 (m, 2H), 1.88-1.78

[0893] (m, 1H), 1.38-1.36 (d, 3H).

[0894] LCMS: 850.25; HPLC: 97.14%; 1H-NMR (400 0 MHz, DMSO-d6) 5 10.99 (s, 1H), 9.47-9.44 (t, 1H), 8.54-8.53 (d, 1H), 8.08-8.06 (d, 1H), 7.90- > R- ■ R

[0895] fr 7.88 (m, 1H), 7.73-7.72 (d, 1H), 7.65-7.64 (m,N0 2H), 7.53-7.50 (m, 1H), 7.48-7.44 (m, 2H), 7.46

[0896] (s, 1H), 7.09 (s, 1H), 7.00 (s, 1H), 6.89 (s, 1H), Compound 21

[0897] 6.80-6.52 (m, 2H), 5.16-5.11 (dd, 1H), 4.60-4.57 Intermediates used (m, 2H), 4.41-4.37 (m, 1H), 3.90-3.84 (m, 1H),

[0898] 3.76-3.71 (m, 1H), 3.64-3.59 (m, 4H), 3.16-3.14 Intermediate- 1 & Intermediate- 17

[0899] (m, 1H), 2.91-2.87 (m, 3H), 2.67-2.64 (m, 2H), 2.58 (s, 3H), 2.49-2.33 (m, 1H), 2.19-2.14 (m,

[0900]

[0901] 1H), 2.07-2.04 (m, 3H), 1.80-1.73 (m, 1H). 1.30- 1.24 (m, 3H).

[0902] LCMS: 844.20; HPLC: 91.28%; 1H-NMR (400 MHz, DMSO-d6): 5 11.02 (s, 1H), 9.55-9.49 (m, _ N O

[0903] 2H), 9.42 (s, 1H), 8.89-8.88 (m, 1H), 8.73 (s, T X 1H), 8.24-8.21 (d, 1H), 8.19-8.16 (d, 1H), 8.12- MPT N-N r L_V_ / ®

[0904] 8.08 (d, 1H), 7.95-7.85 (m, 2H), 7.75-7.65 (m, 0 2H), 7.28 (s, 1H), 7.15 (s, 1H), 5.23-5.17 (m, Compound 22 1H), 4.81-4.61 (m, 4H), 3.98-3.90 (m, 1H), 3.82- 3.75 (m, 1H), 3.4 (s, 3H), 3.20-3.10 (m, 1H), Intermediates used

[0905] 2.98-2.87 (m, 1H), 2.52-2.42 (m, 1H), 2.25-2.15 Intermediate- 12 & CRBN-12 (m, 1H), 2.08-1.99 (m, 2H), 1.88-1.78 (m, 1H),

[0906] 1.38-1.36 (d, 3H).

[0907] LCMS: 850.40; HPLC: 96.81%; 1H-NMR (400 MHz, DMSO-d6) 5 10.99 (s, 1H), 9.47-9.44 (t, 1H), 8.54-8.53 (d, 1H), 8.08-8.06 (d, 1H), 7.90- 7.88 (m, 1H), 7.73-7.72 (d, 1H), 7.65-7.64 (m, 2H), 7.53-7.50 (m, 1H), 7.48-7.44 (m, 2H), 7.46 L I T L I M A°

[0908] (s, 1H), 7.09 (s, 1H), 7.00 (s, 1H), 6.89 (s, 1H), ix»--'Ar

[0909] 06.80-6.52 (m, 2H), 5.16-5.11 (dd, 1H), 4.60-4.57 Compound 23 (m, 2H), 4.41-4.37 (m, 1H), 3.90-3.84 (m, 1H),

[0910] 3.76-3.71 (m, 1H), 3.64-3.59 (m, 4H), 3.16-3.14 Intermediates used

[0911] (m, 1H), 2.91-2.87 (m, 3H), 2.67-2.64 (m, 2H), Intermediate- 1 & Intermediate- 18 2.58 (s, 3H), 2.49-2.33 (m, 1H), 2.19-2.14 (m,

[0912] 1H), 2.07-2.04 (m, 3H), 1.80-1.73 (m, 1H). 1.30- 1.24 (m, 3H).

[0913] LCMS: 812.25; HPLC: 94.79%; 1H-NMR (400 V< V HNA

[0914] MHz, DMSO-d6) 5 11.02 (s, 1H), 9.10-9.07 (t, '“■0 °v

[0915] _ Me L / ° 1H), 8.54-8.53 (d, 1H), 8.08-8.06 (d, 1H), 7.90- N X 7.88 (m, 1H), 7.73-7.72 (d, 1H), 7.65-7.64 (m, Compound 24 1H), 7.53-7.50 (m, 1H), 7.09 (s, 1H), 7.00 (s,

[0916] 1H), 6.89 (s, 1H), 6.80-6.52 (m, 1H), 5.16-5.10

[0917]

[0918] Intermediates used (dd, 1H), 4.46-4.28 (m, 2H), 3.90-3.84 (m, 1H),

[0919] 3.76-3.71 (m, 1H), 3.64-3.59 (m, 3H), 3.16-3.14 Intermediate- 1 & CRBN-13

[0920] (m, 2H), 3.09-3.06 (m, 3H), 2.91-2.87 (m, 3H), 2.80-2.78 (t, 2H), 2.67-2.64 (m, 2H), 2.58 (s, 1H), 2.49-2.33 (m, 1H), 2.19-2.14 (m, 2H), 2.07- 2.04 (m, 3H), 1.38-1.36 (d, 3H).

[0921] LCMS: 850.30; HPLC: 97.44%; 1H-NMR (400 MHz, DMSO-d6) 5 10.99 (s, 1H), 9.47-9.44 (t, 1H), 8.54-8.53 (d, 1H), 8.08-8.06 (d, 1H), 7.90- 7.88 (m, 1H), 7.73-7.72 (d, 1H), 7.65-7.64 (m, \\ \Fi J nt V I-N y=°

[0922] M i £>N< Z2H), 7.53-7.50 (m, 1H), 7.48-7.44 (m, 2H), 7.46

[0923] (s, 1H), 7.09 (s, 1H), 7.00 (s, 1H), 6.89 (s, 1H), 6.80-6.52 (m, 2H), 5.16-5.11 (dd, 1H), 4.60-4.57 Compound 25

[0924] (m, 2H), 4.41-4.37 (m, 1H), 3.90-3.84 (m, 1H), Intermediates used 3.76-3.71 (m, 1H), 3.64-3.59 (m, 4H), 3.16-3.14

[0925] (m, 1H), 2.91-2.87 (m, 3H), 2.67-2.64 (m, 2H), Intermediate- 1 & Intermediate-22

[0926] 2.58 (s, 3H), 2.49-2.33 (m, 1H), 2.19-2.14 (m, 1H), 2.07-2.04 (m, 3H), 1.80-1.73 (m, 1H). 1.30- 1.24 (m, 3H).

[0927] LCMS: 798.25; HPLC: 97.62%; 1H-NMR (400 MHz, DMSO-d6) 5 11.02 (s, 1H), 9.10-9.07 (t, °V'( 1— 1H), 8.54-8.53 (d, 1H), 8.08-8.06 (d, 1H), 7.90- 7.88 (m, 1H), 7.73-7.72 (d, 1H), 7.65-7.64 (m, 1H), 7.53-7.50 (m, 1H), 7.09 (s, 1H), 7.00 (s, 1H), 6.89 (s, 1H), 6.80-6.52 (m, 2H), 5.16-5.10 Compound 26

[0928] (dd, 1H), 4.46-4.28 (m, 2H), 3.90-3.84 (m, 1H), Intermediates used 3.76-3.71 (m, 1H), 3.64-3.59 (m, 3H), 3.16-3.14

[0929] (m, 2H), 3.09-3.06 (m, 1H), 2.91-2.87 (m, 3H), Intermediate- 1 & CRBN-14

[0930] 2.80-2.78 (t, 2H), 2.67-2.64 (m, 2H), 2.58 (s, 1H), 2.49-2.33 (m, 1H), 2.19-2.14 (m, 2H), 2.07- 2.04 (m, 3H), 1.38-1.36 (d, 3H).

[0931]

[0932] LCMS: 812.25; HPLC: 91.54%; 1H-NMR (400

[0933] MHz, DMSO-d6) 5 11.12 (s, 1H), 9.10-9.07 (t, 0

[0934] 1H), 8.54-8.53 (d, 1H), 8.08-8.06 (d, 1H), 7.90- °VrO—HNA

[0935] >o°v 7.88 (m, 1H), 7.73-7.72 (d, 1H), 7.65-7.64 (m,

[0936] 1H), 7.53-7.50 (m, 1H), 7.09 (s, 1H), 7.00 (s, CvN HNA = Q

[0937] 1H), 6.89 (s, 1H), 6.80-6.52 (m, 2H), 5.16-5.10 Compound 27 (dd, 1H), 4.46-4.28 (m, 2H), 3.90-3.84 (m, 1H),

[0938] 3.76-3.71 (m, 1H), 3.64-3.59 (m, 3H), 3.16-3.14 Intermediates used

[0939] (m, 2H), 3.09-3.06 (m, 1H), 2.91-2.87 (m, 3H), Intermediate- 1 & CRBN-15 2.80-2.78 (t, 2H), 2.67-2.64 (m, 2H), 2.58 (s,

[0940] 1H), 2.49-2.33 (m, 1H), 2.19-2.14 (m, 2H), 2.07- 2.04 (m, 1H), 1.38-1.36 (d, 3H).

[0941] LCMS: 798.25; HPLC: 95.26%; 1H-NMR (400 MHz, DMSO-d6) 5 10.56 (s, 1H), 9.10-9.07 (t, V-N V o 1H), 8.54-8.53 (d, 1H), 8.08-8.06 (d, 1H), 7.90- '"'Q \ O i 7.88 (m, 1H), 7.73-7.72 (d, 1H), 7.65-7.64 (m,

[0942] ^NS

[0943] ZN-< A 7^ H A

[0944] 1H), 7.53-7.50 (m, 1H), 7.09 (s, 1H), 7.00 (s,N / 1 \

[0945] 1H), 6.89 (s, 1H), 6.80-6.52 (m, 2H), 4.46-4.28 Compound 28 (m, 2H), 3.90-3.84 (m, 1H), 3.76-3.71 (m, 1H),

[0946] 3.64-3.59 (m, 3H), 3.16-3.14 (m, 5H), 3.09-3.06 Intermediates used

[0947] (m, 1H), 2.91-2.87 (m, 3H), 2.80-2.78 (t, 2H), Intermediate- 1 & CRBN-16 2.67-2.64 (m, 2H), 2.58 (s, 1H), 2.49-2.33 (m,

[0948] 1H), 2.19-2.14 (m, 2H), 2.07-2.04 (m, 2H), 1.38- 1.36 (d, 3H).

[0949] ()

[0950] LCMS: 730.25; HPLC: 95.40%; 1H-NMR (400 MHz, DMSO-d6): 5 10.58 (s, 1H), 9.51 (s, 1H), T 0 N—

[0951] 9.41 (s, 1H), 9.39-9.37 (t, 1H), 8.82-8.77 (m, uCu. n

[0952] 2H), 8.25-8.23 (d, 1H), 8.10-8.08 (d, 1H), 7.93- o

[0953] 7.89 (t, 1H), 7.79 (s, 1H), 7.68-7.63 (m, 2H), 7.26 Compound 29 (s, 1H), 7.14-7.12 (m, 2H), 5.17-5.12 (m, 1H),

[0954] 4.39-4.38 (d, 1H), 3.99 (s, 3H), 3.95-3.91 (m, Intermediates used

[0955] 1H), 3.85-3.80 (m, 1H), 3.66-3.61 (m, 2H), 3.38

[0956]

[0957] Intermediate- 12 & CRBN-29 (s, 3H), 3.20-3.10 (m, 1H), 2.52-2.42 (m, 1H),

[0958] 2.25-2.15 (m, 1H), 2.08-1.99 (m, 1H), 1.88-1.78 (m, 1H), 1.38-1.36 (d, 3H).

[0959] LCMS: 800.25; HPLC: 98.02%; 1H-NMR (400 MHz, DMSO-d6): 5 11.02 (s, 1H), 9.51 (s, 1H), ye- 9.41 (s, 1H), 9.39-9.37 (t, 1H), 8.82-8.77 (m,

[0960] 1H), 8.25-8.23 (d, 1H), 8.10-8.08 (d, 1H), 7.93- N'- / \ H J"- /

[0961] <07.89 (t, 1H), 7.79 (s, 1H), 7.68-7.63 (m, 2H), 7.26

[0962] (s, 1H), 7.14-7.12 (m, 1H), 5.17-5.12 (m, 1H), Compound 380 4.39-4.38 (d, 2H), 3.99 (s, 3H), 3.95-3.91 (m, Intermediates used 1H), 3.85-3.80 (m, 4H), 3.66-3.61 (m, 4H), 3.38

[0963] (s, 3H), 3.20-3.10 (m, 1H), 2.52-2.42 (m, 1H), Intermediate- 15 & CRBN-1

[0964] 2.25-2.15 (m, 1H), 2.08-1.99 (m, 1H), 1.88-1.78 o

[0965] \= o /

[0966] (m, 1H), 1.38-1.36 (d, 3H).

[0967] Vw

[0968] / o

[0969] G LCMS: 837.6; HPLC: 80.89%; 1H-NMR (400 V < MHz, DMSO-d6) 5 10.99 (s, 1H), 9.47-9.44 (t,

[0970] 0 1H), 8.54-8.53 (d, 1H), 8.08-8.06 (d, 1H), 7.90- °^-NZHN^X

[0971] 7.88 (m, 1H), 7.73-7.72 (d, 1H), 7.65-7.64 (m, M

[0972] v? kFy

[0973] \ / =< M c Y=° 1H), 7.53-7.50 (m, 1H), 7.48-7.44 (m, 2H), 7.46 y AO

[0974] (s, 1H), 7.09 (s, 1H), 7.00 (s, 1H), 6.89 (s, 1H), HN~Z ~ / \= /

[0975] 6.80-6.52 (m, 2H), 5.16-5.11 (dd, 1H), 4.60-4.57 Compound 381 (m, 2H), 4.41-4.37 (m, 1H), 3.90-3.84 (m, 1H), Intermediates used 3.76-3.71 (m, 1H), 3.64-3.59 (m, 2H), 3.16-3.14

[0976] (m, 1H), 2.91-2.87 (m, 3H), 2.67-2.64 (m, 2H), Intermediate- 1 & Intermediate- 19

[0977] 2.58 (s, 3H), 2.49-2.33 (m, 1H), 2.19-2.14 (m, 1H), 2.07-2.04 (m, 3H), 1.80-1.73 (m, 1H). 1.30- 1.24 (m, 3H).

[0978] LCMS: 782.25; HPLC: 95.45%; 1H-NMR (400 MHz, DMSO-d6): 5 10.99 (s, 1H), 9.55-9.49 (m, 2H), 9.42 (s, 1H), 8.89-8.88 (m, 1H), 8.73 (s, 1H), 8.24-8.21 (d, 1H), 8.19-8.16 (d, 1H), 7.95- 7.85 (m, 4H), 7.75-7.65 (m, 2H), 7.62-7.49 (m,

[0979]

[0980] Compound 382 2H), 7.28(s, 1H), 7.15 (s, 1H), 7.10 (s, 1H), 5.13- 5.11 (m, 1H), 4.63-4.57 (m, 2H), 4.41-4.37 (m, Intermediates used

[0981] 2H), 3.98-3.90 (m, 1H), 3.82-3.75 (m, 1H), 3.4 Intermediate- 12 & Intermediate- 16 (s, 3H), 3.20-3.10 (m, 1H), 2.98-2.87 (m, 1H),

[0982] 2.52-2.42 (m, 1H), 2.25-2.15 (m, 1H), 2.08-1.99 (m, 2H), 1.88-1.78 (m, 1H), 1.38-1.36 (d, 3H).

[0983] LCMS: 782.25; HPLC: 96.01%; 1H-NMR (400 MHz, DMSO-d6): 5 10.94 (s, 1H), 9.54-9.50 (m, OK

[0984] 7N\ \ 2H), 9.40 (s, 1H), 8.80-8.78 (m, 1H), 8.75 (s,

[0985] HN\f0

[0986] 1H), 8.23-8.21 (d, 1H), 8.19-8.16 (d, 1H), 7.95- 7.85 (m, 3H), 7.83-7.79 (m, 2H), 7.75-7.65 (m, N \ f L,l / 2H), 7.56-7.48 (m, 2H), 7.28 (s, 1H), 7.15 (s,

[0987] 1H), 5.13-5.11 (m, 1H), 4.63-4.57 (m, 2H), 4.41- Compound 383

[0988] 4.37 (m, 2H), 3.98-3.90 (m, 1H), 3.82-3.75 (m, Intermediates used 1H), 3.4 (s, 3H), 3.20-3.10 (m, 1H), 2.98-2.87

[0989] (m, 1H), 2.52-2.42 (m, 1H), 2.25-2.15 (m, 1H), Intermediate- 12 & Intermediate-21

[0990] 2.08-1.99 (m, 2H), 1.88-1.78 (m, 1H), 1.38-1.36 (d, 3H).

[0991] LCMS: 690.2; HPLC: 93.07%; 1H-NMR (400 MHz, DMSO-d6): δ 10.77 (s, 1H), 9.49 (s, 1H), — \ JL JL H

[0992] °yNy° 9.40 (s, 1H), 9.33-9.30 (t, 1H), 8.81-8.76 (m,

[0993] 2H), 8.23-8.20 (d, 1H), 8.10-8.07 (d, 1H), 7.92- dcu, 6 7.88 (t, 1H), 7.67-7.65 (d, 1H), 7.25 (s, 1H), 7.14

[0994] o (s, 1H), 7.08-7.04 (t, 1H), 6.72 (s, 1H), 6.70-6.67 Compound 384 (m, 2H), 6.01-5.99 (d, 1H), 4.63-4.57 (m, 2H),

[0995] 4.41-4.37 (m, 2H), 3.98-3.90 (m, 1H), 3.82-3.75 Intermediates used

[0996] (m, 1H), 3.42 (s, 3H), 3.20-3.10 (m, 1H), 2.52- Intermediate- 12 & CRBN-17 2.42 (m, 1H), 2.25-2.15 (m, 1H), 2.08-1.99 (m,

[0997] 2H), 1.88-1.78 (m, 1H), 1.38-1.36 (d, 3H).

[0998]

[0999] LCMS: 716.15; HPLC: 94.08%; 1H-NMR (400 \NX MHz, DMSO-d6): 5 10.51 (s, 1H), 9.50 (s, 1H), -CLA VN 9.40 (s, 1H), 9.37-9.34 (t, 1H), 8.81-8.77 (m, tx tr

[1000] 2H), 8.24-8.22 (d, 1H), 8.18 (s, 2H), 8.10-8.08 (d, &x A

[1001] Qr» X ' 1H), 7.93-7.91 (t, 1H), 7.73 (s, 1H), 7.68-7.67 (d, 0

[1002] 1H), 7.66-7.65 (d, 1H), 7.42-7.40 (m, 1H), 7.26 Compound 385 (s, 1H), 7.15 (s, 1H), 4.39-4.38 (d, 1H), 3.95-3.91

[1003] (m, 1H), 3.85-3.80 (m, 1H), 3.66-3.61 (m, 2H), Intermediates used

[1004] 3.38 (s, 3H), 3.20-3.10 (m, 1H), 2.52-2.42 (m, Intermediate- 12 & CRBN-18 1H), 2.25-2.15 (m, 2H), 2.08-1.99 (m, 1H), 1.88- 1.78 (m, 1H), 1.38-1.36 (d, 3H).

[1005] LCMS: 730.15; HPLC: 93.3%; 1H-NMR (400 MHz, DMSO-d6): 5 10.58 (s, 1H), 9.51 (s, 1H), 9.41 (s, 1H), 9.39-9.37 (t, 1H), 8.82-8.77 (m, XX tr

[1006] I 2H), 8.25-8.23 (d, 1H), 8.10-8.08 (d, 1H), 7.93- 7.89 (t, 1H), 7.79 (s, 1H), 7.68-7.63 (m, 2H), 7.26 X / X'- 0 (s, 1H), 7.14-7.12 (m, 2H), 4.39-4.38 (d, 1H), Compound 386 3.99 (s, 3H), 3.95-3.91 (m, 2H), 3.85-3.80 (m,

[1007] 1H), 3.66-3.61 (m, 2H), 3.38 (s, 3H), 3.20-3.10 Intermediates used

[1008] (m, 1H), 2.52-2.42 (m, 1H), 2.25-2.15 (m, 1H), Intermediate- 12 & CRBN-28 2.08-1.99 (m, 1H), 1.88-1.78 (m, 1H), 1.38-1.36

[1009] (d, 3H).

[1010] LCMS: 745.0; HPLC: 96.31%; 1H-NMR (400 -Al »- /

[1011] Y i °=< \ MHz, DMSO-d6): 5 10.58 (s, 1H), 9.51 (s, 1H),

[1012] 9.41 (s, 1H), 9.39-9.37 (t, 1H), 8.82-8.77 (m, XX 'X

[1013] O / X" 2H), 8.25-8.23 (d, 1H), 8.10-8.08 (d, 1H), 7.93- 0

[1014] 7.89 (t, 1H), 7.79 (s, 1H), 7.68-7.63 (m, 2H), 7.26 Compound 387

[1015] (s, 1H), 7.14-7.12 (m, 2H), 5.40-5.36 (m, 1H), Intermediates used 4.39-4.38 (d, 1H), 3.95-3.91 (m, 2H), 3.85-3.80

[1016] (m, 1H), 3.66-3.61 (m, 2H), 3.63 (s, 3H), 3.38 (s, Intermediate- 12 & CRBN-19

[1017] 3H), 3.20-3.10 (m, 1H), 2.52-2.42 (m, 1H), 2.25-

[1018]

[1019] 2.15 (m, 1H), 2.08-1.99 (m, 1H), 1.88-1.78 (m,

[1020] 1H), 1.38-1.36 (d, 3H).

[1021] LCMS: 716.2; HPLC: 98.41%; 1H-NMR (400 MHz, DMSO-d6): 5 11.30 (s, 1H), 9.51 (s, 1H), — % _

[1022] M HN ) 9.41 (s, 1H), 9.39-9.37 (t, 1H), 8.82-8.77 (m, o r" 2H), 8.25-8.23 (d, 1H), 8.10-8.08 (d, 1H), 7.93- £ Y 7.89 (t, 1H), 7.79 (s, 1H), 7.68-7.63 (m, 2H), 7.26

[1023] (s, 1H), 7.14-7.12 (m, 2H), 6.26-6.23 (m, 1H), o

[1024] 4.39-4.38 (d, 1H), 3.95-3.91 (m, 2H), 3.85-3.80 Compound 38

[1025] (m, 1H), 3.66-3.61 (m, 2H), 3.38 (s, 3H), 3.20- Intermediates used 3.10 (m, 1H), 2.52-2.42 (m, 1H), 2.25-2.15 (m,

[1026] 1H), 2.08-1.99 (m, 1H), 1.88-1.78 (m, 1H), 1.38- Intermediate- 12 & CRBN-20

[1027] 1.36 (d, 3H).

[1028] LCMS: 716.2; HPLC: 98.87%; 1H-NMR (400 MHz, DMSO-d6): 5 10.41 (s, 1H), 9.51 (s, 1H), -N£Q| O H

[1029] 9.50-9.40 (m, 2H), 8.82-8.79 (m, 2H), 8.62-8.60 x£ t"r

[1030] (d, 1H), 8.24-8.22 (d, 1H), 8.13-8.08 (m, 2H), OX-, c? 7.93-7.91 (t, 1H), 7.89 (s, 1H), 7.68-7.63 (m,

[1031] 0 1H), 7.26 (s, 1H), 7.15 (s, 1H), 6.87-6.86 (m, Compound 389 1H), 4.39-4.38 (d, 1H), 3.95-3.91 (m, 2H), 3.85- 3.80 (m, 1H), 3.66-3.61 (m, 2H), 3.38 (s, 3H), Intermediates used

[1032] 3.20-3.10 (m, 1H), 2.52-2.42 (m, 1H), 2.25-2.15 Intermediate- 12 & CRBN-21 (m, 1H), 2.08-1.99 (m, 1H), 1.88-1.78 (m, 1H),

[1033] 1.38-1.36 (d, 3H).

[1034] LCMS: 709.25; HPLC: 98.10%; 1H-NMR (400 — \ 1 1 H MHz, DMSO-d6): 5 10.96 (s, 1H), 9.50 (s, 1H), [I l 9.49-9.40 (m, 2H), 8.82-8.79 (m, 2H), 8.62-8.60 X

[1035] (d, 1H), 8.24-8.22 (d, 1H), 8.13-8.08 (m, 1H), XL, J&

[1036] 7.93-7.91 (t, 1H), 7.89 (s, 1H), 7.68-7.63 (m, 0

[1037] lH), 7.26(s, lH), 7.15 (s, 1H), 7.08 (s, 1H), 5.39- Compound 40 5.35 (m,lH), 4.37-4.35 (d, 1H), 3.95-3.91 (m,

[1038] 2H), 3.85-3.80 (m, 1H), 3.66-3.61 (m, 2H), 3.38

[1039]

[1040] Intermediates used (s, 3H), 3.20-3.10 (m, 1H), 2.52-2.42 (m, 1H),

[1041] 2.25-2.15 (m, 1H), 2.08-1.99 (m, 1H), 1.88-1.78 Intermediate- 12 & CRBN-22

[1042] (m, 1H), 1.38-1.36 (d, 3H).

[1043] LCMS: 715.20; HPLC: 97.85%; 1H-NMR (400 MHz, DMSO-d6): δ 10.88 (s, 1H), 9.50 (s, 1H), 9.40 (s, 1H), 9.37-9.34 (t, 1H), 8.81-8.77 (m, 2H), 8.24-8.22 (d, 1H), 8.18 (s, 1H), 8.10-8.08 (d, Jex X

[1044] 1H), 7.93-7.91 (t, 1H), 7.73 (s, 1H), 7.68-7.67 (d, 0

[1045] 1H), 7.66-7.65 (d, 1H), 7.42-7.40 (m, 1H), 7.26 Compound 41 (s, 1H), 7.15 (s, 1H), 4.39-4.38 (d, 2H), 3.95-3.91

[1046] (m, 1H), 3.85-3.80 (m, 1H), 3.66-3.61 (m, 2H), Intermediates used

[1047] 3.38 (s, 3H), 3.20-3.10 (m, 1H), 2.52-2.42 (m, Intermediate- 12 & CRBN-23 1H), 2.25-2.15 (m, 2H), 2.08-1.99 (m, 1H), 1.88- 1.78 (m, 1H), 1.38-1.36 (d, 3H).

[1048] LCMS: 742.25; HPLC: 96.77%; 1H-NMR (400 MHz, DMSO-d6): δ 11.13 (s, 1H), 9.50 (s, 1H),N^ O

[1049] HNX 9.40 (s, 1H), 9.37-9.34 (t, 1H), 8.81-8.77 (m, ° 2H), 8.24-8.22 (d, 1H), 8.18 (s, 1H), 8.10-8.08 (d, H kA- / 1H), 7.93-7.91 (t, 1H), 7.73 (s, 1H), 7.68-7.67 (d, ZLNXY 1

[1050] ^•N « XZ

[1051] 0 1H), 7.66-7.65 (d, 1H), 7.42-7.40 (m, 1H), 7.55

[1052] (s, 1H), 7.25 (s, 2H), 5.48-5.43 (m, 1H), 4.97- Compound 42

[1053] 4.96 (d, 2H), 3.95-3.91 (m, 1H), 3.85-3.80 (m, Intermediates used 1H), 3.66-3.61 (m, 2H), 3.38 (s, 3H), 3.20-3.10

[1054] (m, 1H), 2.52-2.42 (m, 1H), 2.25-2.15 (m, 1H), Intermediate- 12 & CRBN-24

[1055] 2.08-1.99 (m, 1H), 1.88-1.78 (m, 1H), 1.38-1.36 (d, 3H).

[1056] LCMS: 677.25; HPLC: 96.14%; 1H-NMR (400 VNX

[1057] — N JL J MHz, DMSO-d6): δ 10.77 (s, 1H), 9.49 (s, 1H),

[1058] 9.40 (s, 1H), 9.33-9.30 (t, 1H), 8.81-8.76 (m, OOx Ti ^ % n _ NH 2H), 8.23-8.20 (d, 1H), 8.10-8.07 (d, 1H), 7.92- 0 7.88 (t, 1H), 7.67-7.65 (d, 1H), 7.25 (s, 1H), 7.08- 7.04 (t, 1H), 6.72 (s, 1H), 6.70-6.67 (m, 2H),

[1059]

[1060] Compound 43 6.01-5.99 (d, 1H), 4.41-4.37 (m, 3H), 3.98-3.90

[1061] (m, 1H), 3.82-3.75 (m, 1H), 3.42 (s, 3H), 3.20- Intermediates used

[1062] 3.10 (m, 2H), 2.52-2.42 (m, 2H), 2.25-2.15 (m, Intermediate- 16 & CRBN-17 1H), 2.08-1.99 (m, 2H), 1.88-1.78 (m, 1H).

[1063] LCMS: 766.10; HPLC: 95.63%; 1H-NMR (400 o MHz, DMSO-d6): δ 11.13 (s, 1H), 9.50 (s, 1H),

[1064] 9.40 (s, 1H), 9.37-9.34 (t, 1H), 8.81-8.77 (m, CJ °" P

[1065] 2H), 8.24-8.22 (d, 1H), 8.18 (s, 1H), 8.10-8.08 (d, w ° 1H), 7.93-7.91 (t, 1H), 7.73 (s, 1H), 7.68-7.67 (d,

[1066] 1H), 7.66-7.65 (d, 1H), 7.42-7.40 (m, 1H), 7.55 o

[1067] (s, 1H), 7.25 (s, 2H), 5.48-5.43 (m, 1H), 4.97- Compound 44 4.96 (d, 2H), 3.95-3.91 (m, 1H), 3.85-3.80 (m,

[1068] 1H), 3.66-3.61 (m, 2H), 3.38 (s, 3H), 3.20-3.10 Intermediates used

[1069] (m, 1H), 2.52-2.42 (m, 1H), 2.25-2.15 (m, 1H), Intermediate- 12 & CRBN-25 2.08-1.99 (m, 1H), 1.88-1.78 (m, 1H), 1.38-1.36

[1070] (d, 3H).

[1071] LCMS: 676.2; HPLC: 99.75%; 1H-NMR (400 — N T l )o=

[1072] MHz, DMSO-d6): δ 10.77 (s, 1H), 9.49 (s, 1H), Cz

[1073] 9.40 (s, 1H), 9.33-9.30 (t, 1H), 8.81-8.76 (m, OtX^ n r^° 2H), 8.23-8.20 (d, 1H), 8.10-8.07 (d, 1H), 7.92- 1 S 7.88 (t, 1H), 7.67-7.65 (d, 1H), 7.25 (s, 1H), 7.08- 0

[1074] 7.04 (t, 2H), 6.72 (s, 1H), 6.70-6.67 (m, 2H), Compound 45

[1075] 6.01-5.99 (d, 1H), 4.41-4.37 (m, 3H), 3.98-3.90 Intermediates used (m, 1H), 3.82-3.75 (m, 1H), 3.42 (s, 3H), 3.20- 3.10 (m, 2H), 2.52-2.42 (m, 2H), 2.25-2.15 (m, Intermediate- 12 & CRBN-17

[1076] 1H), 2.08-1.99 (m, 2H), 1.88-1.78 (m, 1H).

[1077] LCMS: 743.20; HPLC: 90.84%; 1H-NMR (400 MHz, DMSO-d6): δ 11.06 (s, 1H), 9.50 (s, 1H), 9.40 (s, 1H), 9.37-9.34 (t, 1H), 8.81-8.77 (m, 2H), 8.24-8.22 (d, 1H), 8.18 (s, 1H), 8.10-8.08 (d, 1H), 7.93-7.91 (t, 1H), 7.73 (s, 1H), 7.68-7.67 (d, 1H), 7.66-7.65 (d, 1H), 7.42-7.40 (m, 1H), 7.55

[1078]

[1079] Compound 46 (s, 1H), 7.25 (s, 1H), 5.88-5.86 (m, 1H), 4.46- 4.45 (d, 2H), 3.95-3.91 (m, 1H), 3.85-3.80 (m, Intermediates used

[1080] 1H), 3.66-3.61 (m, 2H), 3.38 (s, 3H), 3.20-3.10 Intermediate- 12 & CRBN-26 (m, 1H), 2.52-2.42 (m, 1H), 2.25-2.15 (m, 1H),

[1081] 2.08-1.99 (m, 1H), 1.88-1.78 (m, 1H), 1.38-1.36 (d, 3H).

[1082] LCMS: 683.23; HPLC: 93.00%; 1H-NMR (400 o

[1083] MHz, DMSO-d6): δ 10.77 (s, 1H), 9.06-9.03 (m,

[1084] 2H), 8.25 (s, 1H), 8.15-8.14 (d, 1H), 7.95-7.91 U ' Y'l

[1085] HYT (m, 1H), 7.15-7.12 (d, 1H), 7.08-7.04 (t, 1H),

[1086] 6.99 (s, 1H), 6.87 (s, 1H), 6.71-6.62 (m, 3H), 6.01-5.99 (d, 1H), 4.63-4.57 (m, 2H), 4.41-4.37 o

[1087] (m, 2H), 3.98-3.90 (m, 1H), 3.82-3.75 (m, 1H), Compound 47

[1088] 3.42 (s, 3H), 3.32 (s, 3H), 3.20-3.10 (m, 1H), Intermediates used 2.64 (s, 3H), 2.52-2.42 (m, 1H), 2.25-2.15 (m,

[1089] 1H), 2.08-1.99 (m, 2H), 1.88-1.78 (m, 1H), 1.38- Intermediate-23 & CRBN-17

[1090] 1.36 (d, 3H).

[1091] LCMS: 709.25; HPLC: 97.83%; 1H-NMR (400 _? X1 VHMHz, DMSO-d6): δ 10.41 (s, 1H), 9.15-9.12 (t, YJ r Y°

[1092] 1H), 9.04 (s, 1H), 8.62-8.60 (d, 1H), 8.26 (s, 1H), zNx^ JXl

[1093] I JL^ ii i' 8.15 (s, 1H), 8.08 (s, 1H), 7.93-7.91 (d, 1H), 7.77

[1094] (s, 1H), 7.15-7.12 (d, 1H), 6.99 (s, 1H), 6.87-6.84 o

[1095] (m, 2H), 4.36-4.35 (m, 2H), 3.98-3.90 (m, 1H), Compound 48 3.82-3.75 (m, 2H), 3.42 (s, 3H), 3.32 (s, 3H),

[1096] 3.20-3.10 (m, 1H), 2.64 (s, 3H), 2.52-2.42 (m, Intermediates used

[1097] 1H), 2.25-2.15 (m, 1H), 2.08-1.99 (m, 2H), 1.88- Intermediate-23 & CRBN-21 1.78 (m, 1H), 1.38-1.36 (d, 3H).

[1098]

[1099] LCMS: 701.25; HPLC: 93.14%; 1H-NMR (400 MHz, DMSO-d6): δ 10.77 (s, 1H), 9.06-9.03 (m, 2H), 8.25 (s, 1H), 8.15-8.14 (d, 1H), 7.95-7.91 (m, 1H), 7.15-7.12 (d, 1H), 7.08-7.04 (t, 1H), 6.99 (s, 1H), 6.87 (s, 1H), 6.71-6.62 (m, 2H), 6.01-5.99 (d, 1H), 4.63-4.57 (m, 2H), 4.41-4.37 (m, 2H), 3.98-3.90 (m, 1H), 3.82-3.75 (m, 1H), Compound 49

[1100] 3.42 (s, 3H), 3.32 (s, 3H), 3.20-3.10 (m, 1H), Intermediates used 2.64 (s, 3H), 2.52-2.42 (m, 1H), 2.25-2.15 (m,

[1101] 1H), 2.08-1.99 (m, 2H), 1.88-1.78 (m, 1H), 1.38- Intermediate-24 & CRBN-17

[1102] 1.36 (d, 3H).

[1103] LCMS: 709.25; HPLC: 97.99%; 1H-NMR (400 MHz, DMSO-d6): δ 11.07 (s, 1H), 9.06-9.03 (m, 2H), 8.25 (s, 1H), 8.15-8.14 (d, 1H), 7.95-7.91 (m, 1H), 7.15-7.12 (d, 1H), 7.08-7.04 (t, 1H), 6.99 (s, 1H), 6.87 (s, 1H), 6.71-6.62 (m, 2H), 4.63-4.57 (m, 1H), 4.35-4.33 (m, 2H), 3.98-3.90 Compound 50 (m, 1H), 3.82-3.75 (m, 1H), 3.42 (s, 3H), 3.32 (s,

[1104] 3H), 3.20-3.10 (m, 1H), 2.64 (s, 3H), 2.52-2.42 Intermediates used

[1105] (m, 1H), 2.25-2.15 (m, 2H), 2.08-1.99 (m, 2H), Intermediate-23 & CRBN-27 1.88-1.78 (m, 1H), 1.38-1.36 (d, 3H).

[1106]

[1107] Although the present disclosure has been illustrated by certain of the preceding examples, it is not to be construed as being limited thereby; but rather, the present disclosure encompasses the generic area as hereinbefore disclosed. For example, the compounds listed below in table-E which can be prepared by following a similar procedure as described in above Schemes / Examples with suitable modifications known to the one ordinary skilled in the art are also included in the scope of the present disclosure:

[1108] Table-E:

[1109] Comp. Comp.

[1110] Compound Structure Compound Structure No. No.

[1111]

[1112] 0 52. 0 o o 0.w / \ HNAA \^xs A o= JT >=xMeA<n i °o<O~ "F\ / °. N z~-z ’F / / 1 / 1 )==° <

[1113] \ o X \. X <N

[1114] \ o x- XX wZ~*Y 0 rX°'IZIZXx pxzrz

[1115] u.

[1116] 54.

[1117] C Vm- s N z

[1118] J ( /

[1119] x <

[1120] SS" T ■” f "" / X

[1121] X z - rAAOz"zlY C^

[1122] \\ X x

[1123] z /

[1124] O II X XK o

[1125] OXr- o o 56.

[1126] o

[1127] \^x A- OcX

[1128] ) wX <

[1129] o

[1130] o

[1131] 1

[1132] >xf\ \

[1133] O \o o o.

[1134] yy.°

[1135] X AFIzIH58. ^z*~

[1136] ^ / ^XXszzs r z^- I Z. z Z AX

[1137] O u. X Xf'xj u.j ) r'

[1138] FX - 'N0

[1139] F )G x

[1140] x x, <

[1141] SSST ■” " H '" / / / / /

[1142] yTY X cVVO XzZ H>£ < J Jxx

[1143] \ o ^^^ ° O OzxzzZI \ O 60.

[1144] i X o ^ GM Qtrr-- 0 HA o o o VNX-0T 62. ^NxXxF\ F fNys0

[1145] K / =>F3-F / -®-XC XX7X X

[1146] 0

[1147] °> K HN-A

[1148] BA °V vQr YFA V rNy=° 64.

[1149] Xc-zz z Xx HNA 0 0

[1150] X V. 1 66.

[1151] x~7'^ S00

[1152]

[1153]

[1154] BIOLOGICAL ASSAY

[1155] 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 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.

[1156] There are various technologies now currently available to directly measure the degradation of target proteins induced by PROTACs, for example Western Blot and Capillary Electrophoresis Immunoassays, High-Throughput Flow Cytometry and In-Cell Western, AlphaLISA SureFire Technology, Time-Resolved Fluorescence Energy Transfer-Based Assays or Nano-Gio HiBiT Technology.

[1157] Determination of Degradation of Protein in HiBiT Assay:

[1158] U2OS-HiBiT Assay Protocol:

[1159] U2OS-p300 HiBiT cells were seeded and incubated overnight at 37°C in a CO2 incubator 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 0.2pM were determined.

[1160] Exemplary compounds of the present disclosure were screened by the above-mentioned assay. For certain exemplary compounds of the present disclosure, the % p300 degradation @0.2pM is given in the below Table-F.

[1161] Table-F: % p300 degradation @0.2pM of exemplary compounds Comp. % p300 degradation Comp. % p300 degradation No. @0.2pM No. @0.2pM

[1162] 1 69 30 42

[1163] 2 57 31 18

[1164] 3 54 32 39

[1165] 4 93 33 96

[1166] 5 89 34 92

[1167] 7 66 35 93

[1168] 8 41 37 34

[1169] 10 84 38 89

[1170] 12 84 39 87

[1171]

[1172] 15 72 40 85

[1173] 16 84 41 90

[1174] 17 83 43 81

[1175] 18 86 45 82

[1176] 19 81 46 24

[1177] 20 91 47 83

[1178] 22 87 48 88

[1179] 25 18 49 30

[1180] 27 49 50 96

[1181] 29 94 - -

[1182]

[1183] Incorporation by Reference

[1184] 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 disclosure, including any definitions herein, will control.

[1185] Equivalents

[1186] 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):(I)or a pharmaceutically acceptable salt or a stereoisomer thereof;wherein,X1is C, N or O;X2is CH or N;X3is C, CH or N;Y1is C, CH or N;Ar is (C3-C12)cycloalkylenyl, 3-12 membered heterocycloalkylenyl, (C6-C10)arylenyl or 5-12 membered heteroarylenyl;R1is (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C12)cycloalkyl, 3-12 membered heterocycloalkyl or -NR1aR1b;each R1aand R1bis independently hydrogen or (C1-C6)alkyl;R2and R3at each occurrence is independently hydrogen, (C1-C6)alkyl, halo or halo(C1-C6)alkyl;alternatively, R1band R3together with the atoms to which they are attached get cyclized to form an unsubstituted or substituted 5-7 membered heterocyclyl, wherein the substituent on heterocyclyl is independently selected from one or more (C1-C6)alkyl, halo, halo(C1-C6)alkyl, hydroxy, cyano and amino;R4is a bond, -C(R4aR4b)- or -NR4c;each R4aand R4bis independently hydrogen, halogen or (C1-C6)alkyl;R4cis hydrogen or (C1-C6)alkyl;R5is hydrogen, halogen, (C1-C6)alkyl or (C1-C6)alkoxy;alternatively, R4bor R4ctogether with R5get cyclized to form an unsubstituted or substituted (C3-C12)cycloalkyl, an unsubstituted or substituted 3-12 membered heterocycloalkyl, an unsubstituted or substituted (C6-C10)aryl or an unsubstituted or substituted 5-12 membered heteroaryl, wherein the substituent on cycloalkyl, heterocycloalkyl, aryl and heteroaryl is one or more R5a, wherein each R5ais independently selected from (C1-C6)alkyl, halo, halo(C1-C6)alkyl, hydroxy, cyano and amino;R6is hydrogen, (C1-C6)alkyl, halo, halo(C1-C6)alkyl, (C3-C12)cycloalkyl or 3-12 membered heterocycloalkyl;R7is hydrogen, (C1-C6)alkyl, halo, halo(C1-C6)alkyl or (C3-C12)cycloalkyl;L is a bond or an unsubstituted or substituted (C1-C10)alkylenyl, wherein one or more methylene units of the alkylenyl is optionally and independently replaced with any combination of -C(O)-, -O-, -NH-, (C2-C6)alkenylenyl, (C2-C6)alkynylenyl, an unsubstituted or substituted 3-12 membered heterocycloalkylenyl, an unsubstituted or substituted 5-12 membered heteroarylenyl, an unsubstituted or substituted 6 to 10 membered arylenyl or an unsubstituted or substituted (C3-C6)cycloalkylenyl; wherein the substituent at each occurrence is independently selected from one or more oxo, halo, cyano, hydroxy, (C1-C6)alkyl or (C1-C4)alkoxy;M is represented by formula (M-l), (M-2), (M-3), (M-4), (M-5) or (M-6):wherein the wavy bond represents the point of attachment with L;each W1, W2, W3, W4and W5is independently C, CH or N;W6 is a bond, *-C(O)NH-, *-NH-C(O)- or -NRw-; wherein the asterisk mark represents the point of attachment with the ring having W5;W7is CH2, NH or O;Rwis hydrogen or (C1-C6)alkyl;RM1at each occurrence is independently hydrogen, (C1-C6)alkyl or halo(C1-C6)alkyl; RM2at each occurrence is independently halo, cyano, (C1-C6)alkyl or (C1-C6)alkoxy; each RM3and RM4is independently hydrogen or (C1-C6)alkyl; or RM3and RM4together with the carbon atom to which they are attached represent an oxo group;RM5at each occurrence is independently hydrogen or (C1-C6)alkyl; alternatively, two RM5on the same carbon atom together represent an oxo group; alternatively, RM2and RM5together with the atoms to which they are attached get cyclized to form a fused 4 to 7 membered, carbocyclyl or heterocyclyl ring system;subscript ‘m’ is 0, 1, 2 or 3;subscript ‘n’ is 0, 1, 2 or 3;subscript ‘p’ is 1, 2 or 3;subscript ‘q’ is 1, 2 or 3;subscript ‘t’ at each occurrence is independently 0, 1, 2 or 3; and subscript ‘u’ is 0, 1, 2 or 3.

2. The compound as claimed in claim 1, having formula (IA):or a pharmaceutically acceptable salt or a stereoisomer thereof.

3. The compound as claimed in claim 1, having formula (IB):or a pharmaceutically acceptable salt or a stereoisomer thereof.

4. The compound as claimed in claim 1, having formula (IC):o (R2)mor a pharmaceutically acceptable salt or a stereoisomer thereof.

5. The compound as claimed in claim 1, having formula (ID):or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein r is 1, 2 or 3.

6. The compound as claimed in claim 1, having formula (IE):or a pharmaceutically acceptable salt or a stereoisomer thereof;wherein r is 1, 2 or 3.

7. The compound as claimed in claim 1, having formula (IF), (IG), (IH), (II), (IK) or (IL):(IJ)(IL)or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

8. The compound as claimed in claim 1, wherein M is (M-1) represented byThe compound as claimed in claim 1, wherein M is (M-2) represented by10. The compound as claimed in claim 1, wherein M is (M-3) represented by11. The compound as claimed in claim 1, wherein M is (M-4) represented by12. The compound as claimed in claim 1, wherein M is (M-5) represented by(M-5)13. The compound as claimed in claim 1, wherein M is (M-6) represented by14. The compound as claimed in claim 2, having formula (IA) wherein,X1is C, N or O;X2is CH or N;Y1is C, CH or N;Ar is 3-12 membered heterocycloalkylenyl, (Ce-Cio)arylenyl or 5-12 membered heteroaryl enyl;Ria is hydrogen or halo(Ci-C3)alkyl;R2and R3at each occurrence is independently hydrogen, (C1-C6)alkyl,R4is a bond, -C(R4aR4b)- or -NR4c;each R4aand R4bis independently hydrogen, halogen or (C1-C6)alkyl;R4cis hydrogen or (C1-C6)alkyl;Rs is hydrogen;alternatively, R4b or R4c together with R5 get cyclized to form an unsubstituted or substituted (C3-C12)cycloalkyl, an unsubstituted or substituted 3-12 membered heterocycloalkyl, an unsubstituted or substituted (C6-C10)aryl or an unsubstituted or substituted 5-12 membered heteroaryl wherein the substituents on cycloalkyl, heterocycloalkyl, aryl and heteroaryl is one or more R5a, wherein each R5ais independently selected from (C1-C6)alkyl, halo, halo(C1-C6)alkyl, hydroxy, cyano and amino;Re is hydrogen, (Ci-Ce)alkyl, halo, halo(Ci-Ce)alkyl, (C3-Ci2)cycloalkyl or 3-12 membered heterocycloalkyl;R7is hydrogen, (C1-C6)alkyl, halo, halo(C1-C6)alkyl or (C3-C12)cycloalkyl;L is a bond or an unsubstituted or substituted (Ci-Cio)alkylenyl, wherein one or more methylene units of the alkylenyl is optionally and independently replaced with any combination of -C(O)-, -O-, -NH-, (C2-Ce)alkenylenyl, (C2-Ce)alkynylenyl, an unsubstituted or substituted 3-12 membered heterocycloalkylenyl, an unsubstituted or substituted 5-12 membered heteroarylenyl, an unsubstituted or substituted 6 to 10 membered arylenyl;M is represented by formula (M-l), (M-2), (M-3), (M-4), (M-5) or (M-6):wherein the wavy bond represents the point of attachment with L;each W1, W2, W3, W4and W5is independently C, CH or N;W6is a bond, *-C(O)NH-, *-NH-C(O)- or -NRW-; wherein the asterisk mark represents the point of attachment with the ring having W5;W7is CH2;Rwis hydrogen or (C1-C6)alkyl;RMI at each occurrence is independently hydrogen, or (Ci-Ce)alkyl;RM2 at each occurrence is independently halo;each RM3and RM4is independently hydrogen or (C1-C6)alkyl; or RM3and RM4together with the carbon atom to which they are attached represent an oxo group;RM5at each occurrence is independently hydrogen or (C1-C6)alkyl; alternatively, two RM5on the same carbon atom together represent an oxo group; alternatively, RM2and RM5together with the atoms to which they are attached get cyclized to form a fused 4 to 7 membered, carbocyclyl or heterocyclyl ring system;subscript ‘m’ is 0, 1, 2 or 3;subscript ‘p’ is 1, 2 or 3;subscript ‘q’ is 1, 2 or 3;subscript ‘t’ at each occurrence is independently 0, 1, 2 or 3; andsubscript ‘u’ is 0, 1, 2 or 3.

15. The compound as claimed in any one of claims 1 to 14, wherein the Ar is 3-12 membered heterocycloalkylenyl, (Ce-Cio)arylenyl or 5-12 membered heteroaryl enyl.

16. The compound as claimed in any one of claims 1 to 14, wherein the Ar is 5-12 membered heteroaryl enyl.

17. The compound as claimed in any one of claims 1 to 14, wherein Ar is pyridinyl, pyrimidinyl or pyrazolyl.

18. The compound as claimed in any one of claims 1 to 14, wherein Ri is (Ci-Ce)alkyl or -NRlaRlb- 19. The compound as claimed in any one of claims 1 to 14, wherein Ri is -NRiaRib.

20. The compound as claimed in any one of claims 1 to 14, wherein R4 is -C(R4aR4b)- or - NR4C- 21. The compound as claimed in any one of claims 1 to 14, wherein R4 is -NR4C.

22. The compound as claimed in any one of claims 1 to 14, wherein R5 is hydrogen.

23. The compound as claimed in any one of claims 1 to 14, wherein R4b or R4Ctogether with Rs get cyclized to form an unsubstituted or substituted (C5-Ce)cycloalkyl, an unsubstituted or substituted 5-7 membered heterocycloalkyl, an unsubstituted or substituted phenyl or an unsubstituted or substituted 5-7 membered heteroaryl, wherein the substituent on cycloalkyl, heterocycloalkyl, aryl and heteroaryl is one or more Rsa, wherein each Rsais independently selected from (Ci-Ce)alkyl, halo, halo(Ci-Ce)alkyl, hydroxy, cyano and amino.

24. The compound as claimed in any one of claims 1 to 14, wherein R4b or R4Ctogether with Rs get cyclized to form (C5-Ce)cycloalkyl, 5-7 membered heterocycloalkyl, phenyl or 5-7 membered heteroaryl.

25. The compound as claimed in any one of claims 1 to 14, wherein R4 is -C(R4aR4b)-, wherein R4b together with R5 get cyclized to form phenyl ring.

26. The compound as claimed in any one of claims 1 to 14, wherein R4 is -NR4c, wherein R4c together with R5 get cyclized to form a 5-7 membered heterocycloalkyl.

27. The compound as claimed in any one of claims 1 to 14, wherein Re is halo or halo(Ci-Ce)alkyl.

28. The compound as claimed in any one of claims 1 to 14, wherein R7 is (C1-C6)alkyl, halo or halo(C1-C6)alkyl.

29. The compound as claimed in any one of claims 1 to 14, wherein L is -C(O)NH-, -30. A compound selected from:Comp.IUPAC NameNo.

1. 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-(4-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)but-3-yn-l-yl)picolinamide; 2. Isomer- 1 of compound- 1;3. Isomer-2 of compound- 1;5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- 4. imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-((5-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)isoxazol-3-yl)methyl)picolinamide;5. 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-((3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)-l-methyl-lH-pyrazol-5- yl)methyl)picolinamide;5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- 6. imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-(3-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)benzyl)picolinamide;5-(7-(difluoromethyl)-l-(l,6,6-trimethyl-2-oxo-l,2,5,6-tetrahydro-4H- 7. imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-(4-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)but-3-yn-l-yl)picolinamide;5-(8-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8- 8. yl)isoquinolin-3-yl)-N-(4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)but-3 -yn- 1 -yl)picolinamide;5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- 9. imidazo[l,5,4-de]quinoxalin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-(4-(2- (2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)but-3-yn-l-yl)picolinamide; 5-(7-(difluoromethyl)-l-(l,6,6-trimethyl-2-oxo-l,2,5,6-tetrahydro-4H- 10. imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-((5-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)isoxazol-3-yl)methyl)picolinamide;5-(7-(difluoromethyl)-l -(1 -methyl-2-oxo- 1,2,3,4-tetrahydro-5-oxa- 1,2a- diazaacenaphthylen-7-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-((3-(2-(2,6- 11.dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)-l-methyl-lH-pyrazol-5- yl)methyl)picolinamide;5-(7-(difluoromethyl)-l -(1 -methyl-2-oxo- 1,2,3,4-tetrahydro-5-oxa- 1,2a- 12. diazaacenaphthylen-7-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-((5-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)isoxazol-3-yl)methyl)picolinamide;5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-((5-(2-(2,6- 13.dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)isoxazol-3-yl)methyl)-3- fluoropicolinamide;7-(difluoromethyl)-6-(6-(((5-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- 14. yl)isoxazol-3-yl)methyl)carbamoyl)pyridin-3-yl)-N,4'-dimethyl-3,3',4,4'- tetrahydro-2H-[ 1,6'-biquinoline]- 1 '(2'H)-carboxamide;5-(7-(difluoromethyl)-l-(l,6,6-trimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-((3-(2-(2,6- 15.dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)-l-methyl-lH-pyrazol-5- yl)methyl)picolinamide;5-(7-(difluoromethyl)-l-(l-methyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l- 16. ij ]quinolin-8-yl)- 1,2,3, 4-tetrahydroquinolin-6-yl)-N-(4-(2-(2,6-dioxopiperidin- 3 -yl)- 1 -oxoi soindolin-4-yl)but-3 -yn- 1 -yl)picolinamide;5-(7-(difluoromethyl)-l-(l-methyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l- 17. ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-((5-(2-(2,6-dioxopiperidin- 3-yl)-l-oxoisoindolin-4-yl)isoxazol-3-yl)methyl)picolinamide;5-(8-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8- 18. yl)isoquinolin-3-yl)-N-((5-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)isoxazol-3-yl)methyl)picolinamide;N-((5-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)isoxazol-3-yl)methyl)- 19. 5-(8-(l-methyl-2-oxo-l,2,3,4-tetrahydro-5-oxa-l,2a-diazaacenaphthylen-7- yl)isoquinolin-3-yl)picolinamide;5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- 20. imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-((5-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)thiazol-2-yl)methyl)picolinamide;5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- 21. imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-(4-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)phenethyl)picolinamide;5-(8-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8- 22. yl)isoquinolin-3-yl)-N-((5-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)- l,3,4-thiadiazol-2-yl)methyl)picolinamide;5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- 23. imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-(2-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)phenethyl)picolinamide;5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-(4-(2-(2,6- 24.dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)but-3-yn-l-yl)-N- methylpicolinamide;5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- 25. imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-(3-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)phenethyl)picolinamide;5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- 26. imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-(4-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)but-3-yn-l-yl)picolinamide;5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- 27. imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-(4-(2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)but-3-yn-l-yl)picolinamide;5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-(4-(3-(2,4- 28.dioxotetrahydropyrimidin- 1 (2H)-yl)- 1 -methyl- lH-indazol-5-yl)but-3 -yn- 1 - yl)picolinamide;5-(8-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8- 29. yl)isoquinolin-3-yl)-N-(3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)prop-2-yn-l-yl)picolinamide;5-(6-(difluoromethyl)-4-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-3,4-dihydro-2H-benzo[b][l,4]oxazin-7-yl)-N- 30.(4-(2-(2,6-dioxopiperi din-3 -yl)- 1 -oxoisoindolin-4-yl)but-3 -yn- 1 - yl)picolinamide;5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- 31. imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-((5-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)pyridin-3-yl)methyl)picolinamide;5-(8-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8- 32. yl)isoquinolin-3-yl)-N-(3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)benzyl)picolinamide;5-(8-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8- 33. yl)isoquinolin-3-yl)-N-(4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)benzyl)picolinamide;5-(8-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8- 34. yl)isoquinolin-3 -yl)-N-(3 -(3 -((2,6-dioxopiperidin-3 -yl)amino)phenyl)prop-2- yn-l-yl)picolinamide;5-(8-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8- 35. yl)isoquinolin-3-yl)-N-(3-(3-(2,4-dioxotetrahydropyrimidin-l(2H)- yl)benzofuran-5-yl)prop-2-yn-l-yl)picolinamide;5-(8-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8- 36. yl)isoquinolin-3-yl)-N-(3-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l- methyl-lH-indazol-5-yl)prop-2-yn-l-yl)picolinamide;5-(8-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8- 37. yl)isoquinolin-3-yl)-N-(3-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-4-yl)prop-2-yn-l-yl)picolinamide;5-(8-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8- 38. yl)isoquinolin-3-yl)-N-(3-(l-(2,6-dioxopiperidin-3-yl)-lH- benzofd] [ 1,2,3 ]triazol-6-yl)prop-2-yn- 1 -yl)picolinamide;5-(8-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8- 39. yl)isoquinolin-3-yl)-N-(3-(3-(2,4-dioxotetrahydropyrimidin-l(2H)- yl)pyrazolo[l,5-a]pyridin-5-yl)prop-2-yn-l-yl)picolinamide;5-(8-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8- 40. yl)isoquinolin-3-yl)-N-(3-(3-((2,6-dioxopiperidin-3-yl)oxy)-4- fluorophenyl)prop-2-yn- 1 -yl)picolinamide;5-(8-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8- 41. yl)isoquinolin-3-yl)-N-(3-(3-(2,6-dioxopiperidin-3-yl)benzofuran-5-yl)prop-2- yn-l-yl)picolinamide;5-(8-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8- 42. yl)isoquinolin-3-yl)-N-((l-(2,6-dioxopiperidin-3-yl)-2-oxo-l,2- dihydrobenzo[cd]indol-6-yl)methyl)picolinamide;N-(3-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)prop-2-yn-l-yl)-5-(8-(l- 43. methyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-de][l,5]naphthyridin-8- yl)isoquinolin-3-yl)picolinamide;5-(8-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8- 44. yl)isoquinolin-3-yl)-N-(3-(l-(2,6-dioxopiperidin-3-yl)-2-oxo-l,2- dihydrobenzo[cd]indol-5-yl)prop-2-yn-l-yl)picolinamide;N-(3-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)prop-2-yn-l-yl)-5-(8-(l- 45. methyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8-yl)isoquinolin- 3-yl)picolinamide;5-(8-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8- 46. yl)isoquinolin-3-yl)-N-(3-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4- dihydrophthalazin-6-yl)prop-2-yn-l-yl)picolinamide;5-((l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8- 47. yl)(methyl)amino)-N-(3-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)prop-2-yn- l-yl)-5'-methyl-[2,3'-bipyridine]-6'-carboxamide;5-((l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8- yl)(methyl)amino)-N-(3-(3-(2,4-dioxotetrahydropyrimidin-l(2H)- 48.yl)pyrazolo[l,5-a]pyridin-5-yl)prop-2-yn-l-yl)-5'-methyl-[2,3'-bipyridine]-6'- carboxamide;5-((l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8- 49. yl)(methyl)amino)-N-(3-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)prop-2-yn- l-yl)-3-fluoro-5'-methyl-[2,3'-bipyridine]-6'-carboxamide;5-((l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8- 50. yl)(methyl)amino)-N-(3-(3-(2,6-dioxopiperidin-3-yl)benzo[d]isoxazol-5- yl)prop-2-yn-l-yl)-5'-methyl-[2,3'-bipyridine]-6' -carboxamide;5-(8-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8- 51. yl)isoquinolin-3-yl)-N-(3-(4-(2,6-dioxopiperidin-3-yl)pyrazolo[l,5-a]pyridin-2- yl)prop-2-yn-l-yl)picolinamide;5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-((3-(2-(2,6- 52.dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)-l-methyl-lH-pyrazol-5- yl)methyl)picolinamide;5 -(7 -(difluoromethyl)- 1 -( 1, 5 -dimethyl -2-oxo- 1,2-dihydrobenzo[cd]indol-7-yl)- 53. l,2,3,4-tetrahydroquinolin-6-yl)-N-(4-(2-(2,6-dioxopiperidin-3-yl)-l- oxoisoindolin-4-yl)but-3-yn-l-yl)picolinamide;5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- 54. imidazo[4, 5, 1 -ij ]quinolin-8-yl)-2-methyl- 1,2,3,4-tetrahydroquinolin-6-yl)-N-(4- (2-(2, 6-dioxopiperi din-3 -yl)- 1 -oxoi soindolin-4-yl)but-3 -yn- 1 -yl)picolinami de;5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4, 5, 1 -ij ]quinolin-8-yl)-2,2-dimethyl- 1,2,3,4-tetrahydroquinolin-6-yl)- 55.N-(4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)but-3-yn-l- yl)picolinamide;5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- 56. imidazo[4,5,l-ij]quinolin-8-yl)-3-fluoro-l,2,3,4-tetrahydroquinolin-6-yl)-N-(4- (2-(2, 6-dioxopiperi din-3 -yl)- 1 -oxoi soindolin-4-yl)but-3 -yn- 1 -yl)picolinami de;57. 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-3,3-difluoro-l,2,3,4-tetrahydroquinolin-6-yl)-N-(4-(2-(2,6-dioxopiperi din-3 -yl)- 1 -oxoisoindolin-4-yl)but-3 -yn- 1 - yl)picolinamide;5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4, 5, 1 -ij ]quinolin-8-yl)-4-methyl- 1,2,3,4-tetrahydroquinoxalin-6-yl)-N- 58.(4-(2-(2,6-dioxopiperi din-3 -yl)- 1 -oxoisoindolin-4-yl)but-3 -yn- 1 - yl)picolinamide;5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- 59. imidazo[4,5,l-de][l,5]naphthyridin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-(4- (2-(2, 6-dioxopiperi din-3 -yl)- 1 -oxoi soindolin-4-yl)but-3 -yn- 1 -yl)picolinami de;5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-(4-(2-(2,6- 60.dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)but-3-yn-l-yl)pyrimidine-2- carboxamide;5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- 61. imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-(4-(2-(2,6- dioxopiperi din-3 -yl)- 1 -oxoisoindolin-4-yl)but-3-yn- 1 -y l)-3 -fluoropicolinamide;3-(difluoromethyl)-5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6- tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)- 62.N-(4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)but-3-yn-l- yl)picolinamide;5-(l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8- 63. yl)-l,2,3,4-tetrahydro-l,7-naphthyridin-6-yl)-N-(4-(2-(2,6-dioxopiperidin-3-yl)- 1 -oxoisoindolin-4-yl)but-3 -yn- 1 -yl)picolinamide;2-(4-(7-(difluorom ethyl)- 1 -(1,6-dimethyl-2-oxo- 1,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-lH-pyrazol-l- 64.yl)-N-(4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)but-3-yn-l- yl)acetamide;7-(difluoromethyl)-6-(6-((4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- 65. yl)but-3-yn-l-yl)carbamoyl)pyridin-3-yl)-N,4'-dimethyl-3,3',4,4'-tetrahydro- 2H-[ 1,6'-biquinoline]- 1 '(2'H)-carboxamide;6-(7-(difluoromethyl)-6-(6-((4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- 66. yl)but-3-yn-l-yl)carbamoyl)pyridin-3-yl)-3,4-dihydroquinolin-l(2H)-yl)-N,4- dimethyl-3,4-dihydro-l,8-naphthyridine-l(2H)-carboxamide;5-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H-imidazo[4,5,l-ij]quinolin-8-yl)-N- 67. (4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)but-3-yn-l-yl)-[2,3'- bipyridine]-6'-carboxamide;5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- 68. imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-(4-(2-(2,6- dioxopiperidin-3-yl)pyridin-4-yl)benzyl)picolinamide;5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- 69. imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-(3-(3-((2,6- dioxopiperidin-3-yl)amino)-4-fluorophenyl)prop-2-yn-l-yl)picolinamide;5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-((5-(3-(2,4- 70.dioxotetrahydropyrimidin-l(2H)-yl)-6-fluoro-l-methyl-lH-indazol-5- yl)isoxazol-3-yl)methyl)picolinamide;5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-((5-(3-(2,6- 71.dioxopiperidin-3-yl)-l-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5- yl)isoxazol-3-yl)methyl)picolinamide;5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-((5-(4-(2,6- 72.dioxopiperidin-3-yl)-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)isoxazol-3- yl)methyl)picolinamide;73. 5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-((5-(l-(2,6-dioxopiperidin-3-yl)-2-oxo-l,2-dihydrobenzo[cd]indol-7-yl)isoxazol-3- yl)methyl)picolinamide;5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- 74. imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-((5-(3-(2,6- dioxopiperidin-3-yl)phenyl)isoxazol-3-yl)methyl)picolinamide; and5-(7-(difluoromethyl)-l-(l,6-dimethyl-2-oxo-l,2,5,6-tetrahydro-4H- 75. imidazo[4,5,l-ij]quinolin-8-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-N-((5-(2-(2,6- dioxopiperidin-3-yl)pyridin-4-yl)isoxazol-3-yl)methyl)picolinamide;or a pharmaceutically acceptable salt or a stereoisomer thereof.

31. A pharmaceutical composition comprising a compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt or a stereoisomer thereof and at least one pharmaceutically acceptable carrier or excipient.

32. The compound according to any one of claims 1 to 30 or a pharmaceutical acceptable salt or a stereoisomer thereof, for use as a medicament.

33. The compound according to any one of claims 1 to 30 or a pharmaceutical acceptable salt or a stereoisomer thereof, for the manufacture of a medicament for the treatment of cancer.

34. The compound of any one of claims 1 to 30, or a pharmaceutical acceptable salt or a stereoisomer thereof, for use in degrading the target protein in a subject, wherein the target protein is p300.

35. The compound of any one of claims 1 to 30, or a pharmaceutical acceptable salt or a stereoisomer thereof, for use in the treatment of p300 mediated disorder.

36. A method of treating or preventing disease and / or disorder responsive to p300 degraders in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof.

37. The method of claim 36, wherein the disease or disorder is cancer, viral infection and autoimmune disease or disorder, inflammatory disease or disorder, neurodegenerative disease and metabolic disorder.

38. The method of claim 37, wherein the disease or disorder is cancer.

39. The method of claim 38, 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 myeloidleukemia, acute T-cell lymphoma, T-cell lymphoma, leukemia, lympho-plasmacytoid B-cell lymphoma, glioma, small cell lung cancer, neuroplastoma, 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.

40. The method of claim 37, 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, prurigo nodularis, Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, bullous skin diseases, chronic obstructive pulmonary disease, Crohn's disease, eczema, giant cell arteritis, fibrosis, glomerulonephritis, hepatic vascular occlusion, hepatitis, hypophysitis, immunodeficiency syndrome, Kawasaki disease, lupus nephritis, myocarditis, myositis, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, Polyarteritis nodosa, pneumonitis, primary biliary cirrhosis, psoriatic arthritis, scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, Takayasu's Arteritis, toxic shock, thyroiditis, ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener's granulomatosis.

41. The method of claim 37, wherein neurodegenerative disease is selected from Alzheimer’s disease, Parkinson’s disease, dementia, Huntington’s disease or amyotrophic lateral sclerosis.

42. The method of any one of the claims 36 to 41, further comprising administering to the subject a therapeutically effective amount of a compound of claim 1 along with one or more chemotherapeutic agents, anti-viral agents, anti-inflammatory agent, immunosuppressant agents or pain-relieving agents.

43. A method of treating or preventing viral infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof.

44. A method of treating or preventing an autoimmune disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof.

45. A method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof.

46. The method of claim 45, 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, neuroplastoma, angiosarcoma, chondrosarcoma, Ewing’s sarcoma, fibroblastic sarcoma, gynecological 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.

47. Use of a compound of any one of claims 1 to 30, or a pharmaceutical acceptable salt or a stereoisomer thereof, in the manufacture of a medicament for the treatment of disease or disorder responsive to the p300 degradation.

48. Use of a compound of any one of claims 1 to 30, or a pharmaceutical 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.

49. The use of claim 48, 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, neuroplastoma, angiosarcoma, chondrosarcoma, Ewing’s sarcoma, fibroblastic sarcoma, gynecological 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.

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