Fused bicyclic heterocyclyl compounds and their derivatives as p300 selective degraders

Abstract

The present disclosure provides fused bicyclic heterocyclyl 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 BICYCLIC HETEROCYCLYL COMPOUNDS AND THEIR DERIVATIVES AS P300 SELECTIVE DEGRADERS

[0002] The present application claims priority to and the benefit of Indian Patent Application No. IN 202441066883, filed on 04thSeptember 2024, which application is incorporated herein by reference in it’s entirety.

[0003] TECHNICAL FIELD

[0004] The present application is directed to compounds of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a stereoisomer thereof as degraders of target proteins. Particularly, the present invention 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

[0006] EP300 (or p300) acts as histone acetyltransferase (HAT) and transcriptional adapter, thereby regulates transcription via chromatin remodelling and co-activator (Delvecchio et cd.. 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. 2000, 97, 1020).

[0007] Conventional CBP / p300 inhibitors do not discriminate between CBP and p300 proteins due to high homology. They show less 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. The paralog targeting approach in recent times has been proven to be possible with the 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 etal., Clin Cancer Res 2005, 11 : 512— 9; George etal. Nature 2015, 524:47-53). Targeting wild-type paralogue, p300, by its selective degradation is expected to enhance efficacy in CBP-mutant or p300-dependent malignancies (Ogiwara et al., Cancer Discov (2016) 6 (4): 430-445). In prostate cancer, p300 plays a major role for androgen-dependent and -independent transactivation of the AR (Gong et al., Oncogene 2006; 25(14):2011-21). Neuroblastoma cancer cells primarily depend on p300, not CBP, for their survival by regulating enhancer acetylation by interacting with TFAP2P, a transcription factor member of the lineage-defining transcriptional core regulatory circuitry (CRC) of neuroblastoma (Durbin et al., Cancer Discov 2022; 12:730-51). By considering the above facts, p300 depletion will have a therapeutic advantage in PTEN-defi cient, AR+ prostate, ER+ breast cancers and ATFGV-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 etal., Nat Cell Biol 2020, 22(9): 1064-1075; Pardoll and Drake J. Exp. Med. 2012; 209(2): 201-9).

[0008] Selective degraders of p300 are expected to enhance the 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): or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; wherein,

[0013] Xi is CR2, N, NR2, S or O;

[0014] X2is CH, N, NH, S or 0;

[0015] Yi is C or N; each Zi, and Z2is independently C or N;

[0016] Ar is (C3-Ci2)cycloalkylenyl, 3-12 membered heterocycloalkylenyl, (Ce-Cio)arylenyl, or 5-12 membered heteroaryl enyl;

[0017] Ri is hydrogen, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, (C3-Ci2)cycloalkyl, 3-12 membered heterocycloalkyl, or NRiaRib;

[0018] R2is hydrogen, (Ci-Ce)alkyl, halo, halo(Ci-Ce)alkyl, (C3-Ci2)cycloalkyl, or 3-12 membered heterocycloalkyl;

[0019] R3 is CR3aR3b, or NR3C;

[0020] R4 is hydrogen, halogen, (Ci-Ce)alkyl, or (Ci-Ce)alkoxy; alternatively, R3a or R3Ctogether with R4 get cyclized to form an unsubstituted or substituted, (C3-Ci2)cycloalkyl, 3-12 membered heterocycloalkyl, (Ce-Cio)aryl, or 5-12 membered heteroaryl wherein the substituents on cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently selected from one or more (Ci-Ce)alkyl, halo, halo(Ci-Ce)alkyl, hydroxy, cyano and amino;

[0021] R5 is hydrogen, (Ci-Ce)alkyl, halo, halo(Ci-Ce)alkyl, (C3-Ci2)cycloalkyl, or 3-12 membered heterocycloalkyl;

[0022] Re at each occurrence is independently hydrogen, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo, hydroxy; or two Re on the same carbon atom together represent an oxo group; each Ria and Rib is independently hydrogen, halogen, or (Ci-Ce)alkyl; each R3a, R3b andR3c is independently hydrogen, halogen, or (Ci-Ce)alkyl;

[0023] M is represented by formula (M-l), (M-2), (M-3), (M-4), (M-5), (M-6), (M-7) or (M- 8): each Wi, W2, Ws and Wn is independently C, CH or N; each W3 W4, W5, We and W7 is independently C or N; wherein at least one of W3, W4 and W5 is C;

[0024] W9 is a bond, *-C(O)NH-, *-NH-C(O)-, or -NRW-; wherein the asterisk mark represents the point of attachment with the ring having Ws; Ww is CH2, NH or O;

[0025] Rwis hydrogen or (Ci-Ce)alkyl;

[0026] RMI at each occurrence is independently hydrogen, (Ci-Ce)alkyl or halo(Ci-Ce)alkyl;

[0027] RM2 at each occurrence is independently hydrogen, halo, cyano, (Ci-Ce)alkyl or (Ci- Ce)alkoxy; each RM3 and RM4 is hydrogen or (Ci-Ce)alkyl; or RM3 and RM4 together represent an oxo group;

[0028] RMS at each occurrence is independently hydrogen or (Ci-Ce)alkyl; alternatively, two RMS on the same carbon atom together represent an oxo (=0) group; subscript ‘p’ and ‘r’ each independently is 0, 1 or 2; subscript ‘q’ is 0 or 1; subscript ‘s’ is 0, 1, 2, 3 or 4; subscript ‘t’ at each occurrence is independently 0, 1, 2 or 3; and subscript ‘u’ is 0, 1, 2 or 3.

[0029] In yet another aspect, the present application 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).

[0030] In yet another aspect, the present application relates to the preparation of compounds of formula (I).

[0031] In yet another aspect of the present application, provided herein are compounds of formula (I), that are capable of degrading p300 protein and therapeutic uses thereof.

[0032] DETAILED DESCRIPTION

[0033] 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. As used herein, unless otherwise defined the term "alkyl" alone or in combination with other term(s) means saturated aliphatic hydrocarbon chains, including C1-C14 straight or Ci- C14 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- .

[0034] As used herein, the term "halo" or "halogen" alone or in combination with other term(s) means fluorine, chlorine, bromine or iodine.

[0035] As used herein, the term “oxo” refers to =0 group.

[0036] 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.

[0037] As used herein, the term "hydroxy" or "hydroxyl" alone or in combination with other term(s) means -OH.

[0038] 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.

[0039] As used herein, the term "cyano" refers to -CN.

[0040] As used herein the term "cycloalkyl" alone or in combination with other term(s) means -C3-C10 saturated cyclic hydrocarbon ring. A cycloalkyl may be a single ring, which typically contains from 3 to 7 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.

[0041] 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.

[0042] 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.

[0043] 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. 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.

[0044] 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.

[0045] The term "heteroatom" as used herein designates a sulfur, nitrogen or oxygen atom.

[0046] 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.

[0047] As used herein, the term 'compound(s)' comprises the compounds disclosed in the present disclosure.

[0048] 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.

[0049] As used herein, the term "or" means "and / or" unless stated otherwise.

[0050] As used herein, the term "including" as well as other forms, such as "include", "includes" and "included" is not limiting.

[0051] 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.

[0052] As used herein, the term "treat", "treating" and "treatment" refer to a method of alleviating or abrogating a disease and / or its attendant symptoms.

[0053] 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 the presence 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.

[0054] 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.

[0055] 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.

[0056] "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.

[0057] 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, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al, Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds. ; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.

[0058] 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 compound formed, 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.

[0059] The term "stereoisomers" refers to any enantiomers, diastereoisomers, or geometrical isomers of the compounds of Formula (I), (IA), (IB), (IC), (ID), (IE), (IE-1), (IF), (IG), (IH), (II), (IJ), (IK), (IL) and (IM) 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), (IE-1), (IF), (IG), (IH), (II), (IJ), (IK), (IL) and (IM) 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 t / -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.

[0060] The p300 degraders as used herein is alternatively referred to as “p300 protein degraders” or ‘p300 modulators”.

[0061] The present disclosure provides compounds of formula (I), which are useful as p300 degraders.

[0062] The present disclosure further provides pharmaceutical compositions comprising the said compounds of formula (I), and their derivatives as therapeutic agents.

[0063] It will be apparent to those skilled in the art that various modifications and variations can be made to the compounds, compositions, and methods described herein without departing from the scope or spirit of 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 application includes such modifications and variations and their equivalents. Other objects, features, and aspects of the present application 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.

[0064] The embodiments below are illustrative of the present disclosure and are not intended to limit the claims to the specific embodiments exemplified.

[0065] In a first embodiment, the present application provides a compound of formula (I): or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; wherein,

[0066] Xi is CR2, N, NR2, S or O;

[0067] X2is CH, N, NH, S or 0;

[0068] Yi is C or N; each Zi, and Z2is independently C or N;

[0069] Ar is (C3-Ci2)cycloalkylenyl, 3-12 membered heterocycloalkylenyl, (Ce-Cio)arylenyl, or 5-12 membered heteroaryl enyl;

[0070] Ri is hydrogen, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, (C3-Ci2)cycloalkyl, 3-12 membered heterocycloalkyl, or NRiaRib;

[0071] R2is hydrogen, (Ci-Ce)alkyl, halo, halo(Ci-Ce)alkyl, (C3-Ci2)cycloalkyl, or 3-12 membered heterocycloalkyl;

[0072] R3 is CR3aR3b, or NR3C;

[0073] R4 is hydrogen, halogen, (Ci-Ce)alkyl, or (Ci-Ce)alkoxy; alternatively, R3a or R3Ctogether with R4 get cyclized to form an unsubstituted or substituted, (C3-Ci2)cycloalkyl, 3-12 membered heterocycloalkyl, (Ce-Cio)aryl, or 5-12 membered heteroaryl wherein the substituents on cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently selected from one or more (Ci-Ce)alkyl, halo, halo(Ci-Ce)alkyl, hydroxy, cyano and amino;

[0074] R5 is hydrogen, (Ci-Ce)alkyl, halo, halo(Ci-Ce)alkyl, (C3-Ci2)cycloalkyl, or 3-12 membered heterocycloalkyl;

[0075] Re at each occurrence is independently hydrogen, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo, hydroxy; or two Re on the same carbon atom together represent an oxo group; each Ria and Rib is independently hydrogen, halogen, or (Ci-Ce)alkyl; each R3a, R3b andR3c is independently hydrogen, halogen, or (Ci-Ce)alkyl;

[0076] M is represented by formula (M-l), (M-2), (M-3), (M-4), (M-5), (M-6), (M-7) or (M- 8): each Wi, W2, Ws and Wn is independently C, CH or N; each W3 W4, W5, We and W7 is independently C or N; wherein at least one of W3, W4 and W5 is C;

[0077] W9 is a bond, *-C(O)NH-, *-NH-C(O)-, or -NRW-; wherein the asterisk mark represents the point of attachment with the ring having Ws; Ww is CH2, NH or O;

[0078] Rwis hydrogen or (Ci-Ce)alkyl;

[0079] RMI at each occurrence is independently hydrogen, (Ci-Ce)alkyl or halo(Ci-Ce)alkyl;

[0080] RM2 at each occurrence is independently hydrogen, halo, cyano, (Ci-Ce)alkyl or (Ci- Ce)alkoxy; each RM3 and RM4 is hydrogen or (Ci-Ce)alkyl; or RM3 and RM4 together represent an oxo group;

[0081] RMS at each occurrence is independently hydrogen or (Ci-Ce)alkyl; alternatively, two RMS on the same carbon atom together represent an oxo (=0) group; subscript ‘p’ and ‘r’ each independently is 0, 1 or 2; subscript ‘q’ is 0 or 1; subscript ‘s’ is 0, 1, 2, 3 or 4; subscript ‘t’ at each occurrence is independently 0, 1, 2 or 3; and subscript ‘u’ is 0, 1, 2 or 3.

[0082] In another embodiment of the present application, it provides a compound of formula (I): or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; wherein,

[0083] Xi is CR2, NR2, S or O; X2is CH, NH, S or 0;

[0084] Yi is C or N; each Zi, and Z2is independently C or N;

[0085] Ar is (C3-Ci2)cycloalkylenyl, 3-12 membered heterocycloalkylenyl, (Ce-Cio)arylenyl, or 5-12 membered heteroaryl enyl;

[0086] Ri is hydrogen, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, (C3-Ci2)cycloalkyl, 3-12 membered heterocycloalkyl, or NRiaRib;

[0087] R2is hydrogen, (Ci-Ce)alkyl, halo, halo(Ci-Ce)alkyl, (C3-Ci2)cycloalkyl, or 3-12 membered heterocycloalkyl;

[0088] R3 is CR3aR3b, or NR3C;

[0089] R4 is hydrogen, halogen, (Ci-Ce)alkyl, or (Ci-Ce)alkoxy; alternatively, R3a or R3Ctogether with R4 get cyclized to form an unsubstituted or substituted, (C3-Ci2)cycloalkyl, 3-12 membered heterocycloalkyl, (Ce-Cio)aryl, or 5-12 membered heteroaryl wherein the substituents on cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently selected from one or more (Ci-Ce)alkyl, halo, halo(Ci-Ce)alkyl, hydroxy, cyano and amino;

[0090] R5 is hydrogen, (Ci-Ce)alkyl, halo, halo(Ci-Ce)alkyl, (C3-Ci2)cycloalkyl, or 3-12 membered heterocycloalkyl;

[0091] Re is hydrogen, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo, hydroxy; or two Re on the same carbon atom together represent an oxo group; each Ria and Rib is independently hydrogen, halogen, or (Ci-Ce)alkyl; each R3a, R3b andR3c is independently hydrogen, halogen, or (Ci-Ce)alkyl;

[0092] M is represented by formula (M-l), (M-2), (M-3), (M-4), (M-5), (M-6), (M-7) or (M- 8):

[0093] each Wi, W2, Ws and Wn is independently C, CH or N; each W3 W4, W5, We and W7 is independently C or N; wherein at least one of W3, W4 and W5 is C;

[0094] W9 is a bond, *-C(O)NH-, *-NH-C(O)-, or -NRW-; wherein the asterisk mark represents the point of attachment with the ring having Ws; Ww is CH2, NH or O; Rwis hydrogen or (Ci-Ce)alkyl;

[0095] RMI at each occurrence is independently hydrogen, (Ci-Ce)alkyl or halo(Ci-Ce)alkyl;

[0096] RM2 at each occurrence is independently hydrogen, halo, cyano, (Ci-Ce)alkyl or (Ci- Ce)alkoxy; each RM3 and RM4 is hydrogen or (Ci-Ce)alkyl; or RM3 and RM4 together represent an oxo group;

[0097] RMS at each occurrence is independently hydrogen or (Ci-Ce)alkyl; alternatively, two RMS on the same carbon atom together represent an oxo group; subscript ‘p’, ‘q’, ‘r’ and ‘s’ each independently is 0, 1 or 2; subscript ‘t’ at each occurrence is independently 0, 1, 2 or 3; and subscript ‘u’ is 0, 1, 2 or 3.

[0098] In another embodiment of the present application, it provides compounds of formula (IA), or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

[0099] In another embodiment of the present application, it provides compounds of formula (IB),

[0100] or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

[0101] In another embodiment of the present application, it provides compounds of formula (IC), or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

[0102] In another embodiment of the present application, it provides compounds of formula (ID), or a pharmaceutically acceptable salt thereof or a stereoisomer thereof. In another embodiment of the present application, it provides compounds of formula

[0103] (IE), or a pharmaceutically acceptable salt thereof or a stereoisomer thereof. In another embodiment of the present application, it provides compounds of formula

[0104] (IF), or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

[0105] In another embodiment of the present application, it provides compounds of formula (IG),

[0106] or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

[0107] In another embodiment of the present application, it provides compounds of formula (IH), or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

[0108] In another embodiment of the present application, it provides compounds of formula (II), or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

[0109] In another embodiment of the present application, it provides compounds of formula (U), or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

[0110] In another embodiment of the present application, it provides compounds of formula (IK), or a pharmaceutically acceptable salt thereof or a stereoisomer thereof. In another embodiment of the present application, it provides compounds of formula

[0111] (IL), or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

[0112] In another embodiment of the present application, it provides compounds of formula (IM), or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

[0113] (M-l)

[0114] In certain embodiments, M is,

[0115] In certain embodiments, M is,

[0116] In certain embodiments, M is,

[0117] (M-5)

[0118] In certain embodiments, M is,

[0119] In certain embodiments, M is,

[0120] In certain embodiments, M is, In certain embodiments, M is,

[0121] In another embodiment of the present application, it provides compounds of formula (I), wherein M is represented by: In certain embodiments, M is linked to the ring having Zi and Z2.

[0122] In certain embodiments, M is substituted on Z2.

[0123] In certain embodiments, M is substituted on Zi.

[0124] In certain embodiments, M is substituted on Zi, and Zi is N.

[0125] In certain embodiments, M is substituted on Z2 and Z2 is N.

[0126] In certain embodiments, M is substituted on Z2 and Z2 is C.

[0127] In certain embodiments, Zi is C and two Re substituted on Zi together form an oxo group.

[0128] In certain embodiments, Zi is C and two Re substituted on Zi together form an oxo group.

[0129] In certain embodiments, Zi is CH2; wherein two Re substituted on Zi are each hydrogen.

[0130] In certain embodiments, Zi is -C(Re)M-; wherein Re is hydrogen.

[0131] In certain embodiments, Z2 is CH2; wherein two R6 substituted on Z2 are each hydrogen.

[0132] In certain embodiments, Z2 is -C(Re)M-; wherein Re is hydrogen.

[0133] In certain embodiments, subscript ‘r’ is 1.

[0134] In certain embodiments, subscript ‘r’ is 0. In certain embodiments, when subscript ‘r’ is 0, ring having Zi and Z2 is directly linked to the ring having Yi.

[0135] In certain embodiments, subscript ‘s’ is 2.

[0136] In certain embodiments, subscript ‘s’ is 3.

[0137] In certain embodiments, subscript ‘s’ is 4.

[0138] In one embodiment of the present application, Xi is NR2 and X2 is CH.

[0139] In one embodiment of the present application, Xi is N and X2 is N.

[0140] In one embodiment of the present application, Xi is CR2 and X2 is CH.

[0141] In one embodiment of the present application, Xi is CR2 and X2 is N.

[0142] In one embodiment of the present application, Xi is NR2 and X2 is O.

[0143] In one embodiment of the present application, Xi is O and X2 is N.

[0144] In one embodiment of the present application, Xi is S and X2 is CH.

[0145] In one embodiment of the present application, Xi is CR2 and X2 is S.

[0146] In one embodiment of the present application, Xi is O and X2 is CH.

[0147] In one embodiment of the present application, Xi is CR2 and X2 is O.

[0148] In some embodiments, Xi is NR2 and q is 0 or 1.

[0149] In some embodiments, Xi is CR2 and q is 0 or 1.

[0150] In some embodiments, Xi is NR2 and q is 0.

[0151] In some embodiments, Xi is S or O, and q is 0.

[0152] In some embodiments, X2 is S or O, and q is 0.

[0153] In some embodiments, Xi is NR2 and q is 0.

[0154] In one embodiment of the present application, Ri is hydrogen, (Ci-Ce)alkyl, halo(Ci- Ce)alkyl or NRiaRib.

[0155] In one embodiment of the present application, Ri is hydrogen, (Ci-Ce)alkyl or NRiaRib.

[0156] In one embodiment of the present application, Ri is (Ci-C4)alkyl or NRiaRib.

[0157] In one embodiment of the present application, Ri is (Ci-C4)alkyl or NRiaRib. In one embodiment of the present application, Ri is (Ci-C4)alkyl or NRiaRib, wherein each Ria and Rib is independently hydrogen or (Ci-Ce)alkyl.

[0158] In another embodiment of the present application, R2 is hydrogen, (Ci-Ce)alkyl, (C3- Ci2)cycloalkyl, or 3-12 membered heterocycloalkyl.

[0159] In another embodiment of the present application, R2 is hydrogen, (Ci-Ce)alkyl.

[0160] In another embodiment of the present application, R2 is (C3-Ci2)cycloalkyl, or 3-12 membered heterocycloalkyl.

[0161] In another embodiment of the present application, R2 is (Ci-Ce)alkyl or (C3-C12) cycloalkyl.

[0162] In another embodiment of the present application, R2 is 3-12 membered heterocycloalkyl.

[0163] In another embodiment of the present application, R2 is 3-6 membered heterocycloalkyl.

[0164] In another embodiment of the present application, R2 is a 6-membered heterocycloalkyl.

[0165] In another embodiment of the present application, R2 is (C3-Ci2)cycloalkyl.

[0166] In another embodiment of the present application, R3 is CR3aR3b, or NR3c, wherein each R3a, R3b andR3c is independently hydrogen, halogen, or (Ci-Ce)alkyl.

[0167] In another embodiment of the present application, R3 is NR3c, wherein R3Cis hydrogen, halogen, or (Ci-Ce)alkyl.

[0168] In another embodiment of the present application, R3 is NR3c, wherein R3Cis hydrogen.

[0169] In one embodiment of the present application, R4 is hydrogen, halogen, (Ci-Ce)alkyl, or (Ci-Ce)alkoxy.

[0170] In one embodiment of the present application, R4 is hydrogen or halogen.

[0171] In one embodiment of the present application, R3a or R3Ctogether with R4 get cyclized to form an unsubstituted or substituted, (C3-Ci2)cycloalkyl, 3-12 membered heterocycloalkyl, (Ce-Cio)aryl, or 5-12 membered heteroaryl wherein the substituents on cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently selected from one or more (Ci- Ce)alkyl, halo, halo(Ci-Ce)alkyl, hydroxy, cyano and amino.

[0172] In one embodiment of the present application, R3a together with R4 get cyclized to form an unsubstituted or substituted, (C3-Ci2)cycloalkyl, 3-12 membered heterocycloalkyl, (Ce- Cio)aryl, or 5-12 membered heteroaryl wherein the substituents on cycloalkyl, 1 heterocycloalkyl, aryl and heteroaryl are independently selected from one or more (Ci- Ce)alkyl, halo, halo(Ci-Ce)alkyl, hydroxy, cyano and amino.

[0173] In one embodiment of the present application, Rae together with R4 get cyclized to form an unsubstituted or substituted, (C3-Ci2)cycloalkyl, 3-12 membered heterocycloalkyl, (Ce- Cio)aryl, or 5-12 membered heteroaryl wherein the substituents on cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently selected from one or more (Ci- Ce)alkyl, halo, halo(Ci-Ce)alkyl, hydroxy, cyano and amino.

[0174] In one embodiment of the present application, Rja or Rae together with R4 get cyclized to form an unsubstituted or substituted, 3-12 membered heterocycloalkyl, (Ce-Cio)aryl, or 5-12 membered heteroaryl wherein the substituents on heterocycloalkyl, aryl and heteroaryl are independently selected from one or more (Ci-Ce)alkyl, halo, halo(Ci-Ce)alkyl and hydroxy.

[0175] In one embodiment of the present application, Yi is C.

[0176] In one embodiment of the present application, Yi is C, and R5 is substituted on Yi.

[0177] In one embodiment of the present application, Yi is C, and R5 is substituted on Yi, wherein R5 is hydrogen.

[0178] In some embodiments, R5 is substituted on Yi.

[0179] In one embodiment of the present application, Yi is N.

[0180] In one embodiment of the present application, R5 is hydrogen, (Ci-Ce)alkyl, halo or halo(Ci-Ce)alkyl.

[0181] In one embodiment of the present application, R5 is hydrogen or (Ci-Ce)alkyl.

[0182] In one embodiment of the present application, R5 is halo or halo(Ci-Ce)alkyl.

[0183] In one embodiment of the present application, Ar is (C3-Ci2)cycloalkylenyl, 3-12 membered heterocycloalkylenyl, (Ce-Cio)arylenyl, or 5-12 membered heteroarylenyl.

[0184] In another embodiment of the present application, Ar is 3-12 membered heterocycloalkylenyl, (Ce-Cio)arylenyl, or 5-12 membered heteroarylenyl.

[0185] In another embodiment of the present application, Ar is (Ce-Cio)arylenyl or 5-12 membered heteroarylenyl.

[0186] In another embodiment of the present application, Ar is (Ce-Cio)arylenyl or 5 membered heteroarylenyl.

[0187] In another embodiment of the present application, Ar is 5-12 membered heteroaryl enyl.

[0188] In another embodiment of the present application, Ar is 5 membered heteroaryl enyl. In another embodiment of the present application, Zi and Z2 are each C.

[0189] In another embodiment of the present application, Zi and Z2 are each C, and substituted by Re.

[0190] In another embodiment of the present application, Zi and Z2 are each C, and substituted by Rs, wherein Re at each occurrence is hydrogen.

[0191] In another embodiment of the present application, Zi is N and Z2 is C.

[0192] In another embodiment of the present application, Zi is C and Z2 is N.

[0193] In some embodiments, the valency of Zi and Z2 is balanced by the substitution of Re on each of them, independently.

[0194] In another embodiment of the present application, Re is hydrogen, (Ci-Ce)alkyl, (Ci- Ce)alkoxy, halo, hydroxy; or two Re on the same carbon atom together represent an oxo group.

[0195] In another embodiment of the present application, Re is hydrogen, (Ci-Ce)alkyl, halo, hydroxy; or two Re on the same carbon atom together represent an oxo group.

[0196] In another embodiment of the present application, the compound having formula (IA): or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; wherein,

[0197] Xi is CR2, NR2, S or O;

[0198] X2is CH, N, NH, S or O;

[0199] Yi is C or N; each Zi, and Z2 is independently C or N;

[0200] Ar is (C3-Ci2)cycloalkylenyl, 3-12 membered heterocycloalkylenyl, (Ce-Cio)arylenyl, or 5-12 membered heteroaryl enyl;

[0201] Ri is hydrogen, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl orNRiaRib; R.2 is hydrogen, (Ci-Ce)alkyl, (C3-Ci2)cycloalkyl, or 3-12 membered heterocycloalkyl;

[0202] R3 is CR3aR3b, or NR3C;

[0203] R4 is hydrogen, halogen, (Ci-Ce)alkyl, or (Ci-Ce)alkoxy; alternatively, R3a or R3Ctogether with R4 get cyclized to form an unsubstituted or substituted, (C3-Ci2)cycloalkyl, 3-12 membered heterocycloalkyl, (Ce-Cio)aryl, or 5-12 membered heteroaryl wherein the substituents on cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently selected from one or more (Ci-Ce)alkyl, halo, halo(Ci-Ce)alkyl, hydroxy, cyano and amino;

[0204] R5 is hydrogen, (Ci-Ce)alkyl, halo or halo(Ci-Ce)alkyl; Re is hydrogen, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo, hydroxy; or two Re on the same carbon atom together represent an oxo group; each Ria and Rib is independently hydrogen, or (Ci-Ce)alkyl; and each R3a, R3b andR3c is independently hydrogen, halogen, or (Ci-Ce)alkyl.

[0205] In certain embodiments, the present application provides a compound selected from: or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

[0206] 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 carrier or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.

[0207] In yet another embodiment, the compounds of the present disclosure are p300 degraders.

[0208] In yet another embodiment, the compound of formula (I) is a p300 degrader.

[0209] 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.

[0210] 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.

[0211] In yet another embodiment, the compounds of the present disclosure are a pharmaceutically acceptable salt or a stereoisomer thereof, for use as a medicament.

[0212] In yet another embodiment, the compounds of the present disclosure are a pharmaceutically acceptable salt or a stereoisomer thereof, for use as a medicament, medicament for the treatment of cancer, an inflammatory disease or disorder, autoimmune disease or disorder, neurodegenerative disease or metabolic disorder.

[0213] In an embodiment, the present disclosure provides a pharmaceutical composition comprising the compound of formula (I), for use as a medicament.

[0214] In yet another embodiment, the compounds of the present disclosure are a pharmaceutically acceptable salt or a stereoisomer thereof, for the manufacture of a medicament for the treatment of cancer.

[0215] In an embodiment, the present disclosure provides a pharmaceutical composition comprising the compound of formula (I), for use in the manufacture of a medicament for the treatment of cancer.

[0216] 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.

[0217] In an embodiment, the present disclosure provides a pharmaceutical composition comprising the compound of formula (I), for use in treating a subject suffering from a disease or condition associated with p300.

[0218] 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.

[0219] 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.

[0220] 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.

[0221] 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.

[0222] In an embodiment, the pharmaceutical compositions may be in conventional forms, for example, tablets, capsules, solutions, suspensions, injectables or products for topical application. Further, the pharmaceutical composition of the present disclosure may be formulated to provide desired release profile.

[0223] 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.

[0224] 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.

[0225] In an embodiment, liquid formulations include, but are not limited to, syrups, emulsions and sterile injectable liquids, such as suspensions or solutions. 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.

[0226] In an embodiment, the pharmaceutical compositions of the present disclosure may be prepared by conventional techniques known in literature.

[0227] 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.

[0228] In one embodiment, the compounds as disclosed in the present disclosure are formulated for pharmaceutical administration.

[0229] Yet another embodiment of the present disclosure provides use of the compounds as disclosed in the present application in the treatment and prevention of diseases and / or disorder responsive to the p300 degraders activity.

[0230] 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.

[0231] 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.

[0232] Yet another embodiment of the present disclosure provides use of the compounds, pharmaceutically acceptable salt or a stereoisomer thereof, as disclosed in the present application in the treatment of P300 mediated disorder.

[0233] In another embodiment, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof, for use in the treatment of P300 mediated disorder. According to yet another embodiment, the disease and / or disorder responsive to p300 degraders or condition is cancer.

[0234] Yet another embodiment of the present disclosure, provides the pharmaceutically acceptable salt or a stereoisomer thereof, for use in degrading the target protein in a subject, wherein the target protein is P300.

[0235] In yet another aspect of an embodiment, the cancer is 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, uveal melanoma, lymphoma, leukemia or lymphoid malignancy or metastatic cancer.

[0236] 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.

[0237] In yet another embodiment, the present application 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. 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.

[0238] 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.

[0239] 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.

[0240] 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.

[0241] 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.

[0242] According to yet another embodiment, the disease or disorder is cancer.

[0243] 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.

[0244] 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.

[0245] According to certain foregoing embodiments, the present disclosure provides a method wherein the disease or disorder is cancer. 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.

[0246] 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.

[0247] 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.

[0248] 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'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.

[0249] 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.

[0250] 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.

[0251] 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.

[0252] 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.

[0253] In certain embodiments, the present disclosure provides a method of treating or preventing 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.

[0254] 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.

[0255] 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.

[0256] 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.

[0257] 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.

[0258] 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,UC,13C,14C,13N,15N,15O,17O,18O,32P,33P,35S,18F,36C1,123I 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.

[0259] EXPERIMENTAL

[0260] The present application 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. Following general guidelines apply to all experimental procedures described here. Until otherwise stated, experiments are performed under positive pressure of nitrogen, temperature described are the external temperature (i.e. oil bath temperature). Reagents and solvents received from vendors are used as such without any further drying or purification. Molarities mentioned here for reagents in solutions are approximate as it was not verified by a prior titration with a standard. All reactions are stirred under magnetic stir bar. Cooling to minus temperature was done by acetone / dry ice or wet ice / salts. Magnesium sulfate and sodium sulfate were used as solvent drying agent after reaction work up and are interchangeable. Removing of solvents under reduced pressure or under vacuum means distilling of solvents in rotary evaporator.

[0261] 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.

[0262] The specifics of the process for preparing compounds of the present disclosure are detailed in the experimental section.

[0263] 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.

[0264] 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.

[0265] 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.

[0266] 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.

[0267] GENERAL SCHEME-1: Some compounds of the present invention may be generally synthesized utilizing the process outlined in General Scheme-1. The intermediate GS-1 was reacted with GS-la a boronic ester, with suitable reaction conditions (K2CO3, Pd(dppf)C12.DCM, 1,4-Dioxane, H2O, 110 °C, 16 h), to afford GS-lb, which further undergoes Buchwald coupling with GS-lc under suitable conditions (BrettPhos, XPhos Pd G2, NaOtBu, 1,4-di oxane, 110 °C, 16 h) to afford GS-ld. GS-ld undergoes acid hydrolysis with suitable conditions (6N HC1, THF, RT, 3 h) to afford GS-le. GS-le on reacting with GS-1 fin the presence of suitable reagents and conditions (CS2CO3, DMF, 100 °C, 2 h) affords GS-lg. GS-lg further reacts with GS-lh to afford formula (I) under suitable reaction conditions like (i) Pd-PEPPSI-iHeptCl, CS2CO3. DMSO, 100 °C, 3 h or ii) DIPEA, DMSO, 100 °C, 3 h). ABBREVATIONS

[0268] MeOH - Methanol; EtOH - Ethanol; DCM - Dichloromethane; THF - Tetrahydrofuran; EtOAc - Ethyl acetate; ACN - Acetonitrile; DMF - N,N- Dimethylformamide; DMSO - Dimethyl sulfoxide; Pd(dppf)C12.DCM - 1,1'- Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex; BrettPhos - 2-Dicyclohexylphosphino-3,6-dimethoxy- 2',4',6'-triisopropyl-l,r-biphenyl; XPhos Pd G2 - Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,r-biphenyl)[2-(2'- amino-l,l'-biphenyl)]palladium(ii); Pd-PEPPSI-iHeptCl - [1,3-Bis(2,6- diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride ; TEA - Triethylamine; DIPEA - A,A-Diisopropylethylamine; py-Pyridine; HC1 - Hydrochloride; CDCh - Deuterated chloroform; CD3OD - Deuterated methanol; TLC - Thin-layer chromatography; HPLC - High-performance liquid chromatography; rt : Retention time; LCMS - Liquid chromatography -mass spectrometry; NMR - Nuclear Magnetic Resonance; RT - Room temperature; MsCl - Mesyl chloride; K2CO3 - Potassium carbonate; K3PO4 - Tripotassium phosphate; CS2CO3 - Caesium carbonate;t-BuONa - Sodium terLbutoxide; ppm - parts per million; h - Hour; MHz - Megahertz.

[0269] SYNTHESIS OF INTERMEDIATES

[0270] Intermediate-I-1: Synthesis of 7-(difluoromethyl)-6-(l-(tetrahydro-2Z / -pyran-2-yl)-lH- pyrazol-4-yl)- 1 ,2,3,4-tetrahydroquinoline (I- 1) .

[0271] Reagents and conditions: i) K2CO3, Pd(dppf)C12.DCM, l,4-Dioxane.H2O, 110 °C, 16 h.

[0272] Step-i: Synthesis of 7-(difluoromethyl)-6-(l-(tetrahydro-2Z / -pyran-2-yl)-lH-pyrazol-4- yl)-l,2,3,4-tetrahydroquinoline

[0273] To a degassed solution of 6-bromo-7-(difhioromethyl)-l,2,3,4-tetrahydroquinoline (29 g, 110.64 mmol), l-(tetrahydro-2J7-pyran-2-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-U / -pyrazole (33.8 g, 278.16 mmol) and K2CO3 (30.5 g, 221.29 mmol) in 1,4-dioxane: water (430 mL: 110 mL) were added Pd(dppf)C12.DCM (8.09 g, 11.06 mmol) again degassed with argon for 5 min at RT and stirred at 110 °C for 16 h. Reaction mass was dissolved in EtOAc and filtered through celite bed. Obtained filtrate was washed with water, dried over anhydrous Na2SO4 and concentrated to get the crude compound. Obtained crude was purified by combi flash chromatography using 15-20% EtOAc in hexane as an eluent to get the intermediate 1-1 (29 g, 78.62%). LCMS m / z: 334.15 (M+H)+.

[0274] The intermediates listed in Table-A were prepared by a procedure similar to the one described in the synthesis of Intermediate 1-1 with appropriate variations in reactants / reagents. The characterization data of the intermediates are summarized herein the below table.

[0275] Table-A Intermediate 1-2: Synthesis of l-(3-(7-(difluoroniethyl)-6-(l-(piperidin-4-yl)-l / / -pyrazol-

[0276] 4-yl)-3,4-dihydroquinolin- 1 (2Z / )-yl)-l-methyl- 1 ,4,6,7-tetrahydro-5Z / -pyrazolo [4,3- c]pyridin-5-yl)ethan-l-one (1-2)

[0277]

[0278] Reagents and conditions: i) BrettPhos, XPhos Pd G2, NaOtBu, 1,4-di oxane, 110 °C, 16 h; ii) 6N HC1, THF, RT, 3 h; iii) Cs2CO3, DMF, 100 °C, 2 h; iv) 10%Pd / C, H2, EtOH, RT,16 h.

[0279] Step-i: Synthesis of l-(3-(7-(difluoromethyl)-6-(l-(tetrahydro-2Z / -pyran-2-yl)-lH- pyrazol-4-yl)-3,4-dihydroquinolin-l(2Z / )-yl)-l-methyl-l,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridin-5-yl)ethan-l-one (1-2.2)

[0280] To a degassed solution of l-(3-bromo-l-methyl-l,4,6,7-tetrahydro-5H-pyrazolo[4,3- c]pyridin-5-yl)ethan-l-one (2 g, 7.74 mmol), 7-(difluoromethyl)-6-(l-(tetrahydro-2H-pyran-2- yl)-U / -pyrazol-4-yl)-l,2,3,4-tetrahydroquinoline (3.1 g, 9.29 mmol) and sodium tertiary butoxide (2.2 g, 23.24 mmol) in dioxane (30 mL) were added Brettphos (0.41 g, 0.77 mmol) and XPhos Pd G2(0.6 g, 0.77 mmol) degassed with argon again for 5 mins. The reaction mixture was stirred at 110 °C for 16 h. The progress of reaction was monitored by TLC, after completion of starting material reaction mixture was cool to RT, diluted with EtOAc and filtered through celite pad. Obtained filtrate was washed with water, dried over anhydrous Na2SO4 and concentrated to get the crude compound. Obtained crude was purified by combi flash chromatography using 5-10% MeOH in DCM as an eluent to get the intermediateI-2.2 (2 g, 50.56%). LCMS m / z: 511.2 (M+H)+.

[0281] Step-ii: Synthesis of l-(3-(7-(difluoromethyl)-6-(lH-pyrazol-4-yl)-3,4-dihydroquinolin- l(2Z / )-yl)-l-methyl-l,4,6,7-tetrahydro-5Z / -pyrazolo[4,3-c]pyridin-5-yl)ethan-l-one (I- 2.3)

[0282] To a stirred solution of 1-2.2 (2 g, 3.91 mmol) in THF (10 mL) were added 6N HC1 (10 mL) at RT and stirred for 3 h. The reaction mixture was concentrated and basified with saturated sodium bicarbonate solution in cold conditions. The resultant solid was filtered through vacuum and washed with hexane to get the intermediate 1-2.3 (1.6 g, crude). LC-MS: 427.1 (M+H)+.

[0283] Step-iii: Synthesis of benzyl 4-(4-(l-(5-acetyl-l-niethyl-4.5.6.7-tetrahydro-l / / - pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-l,2,3,4-tetrahydroquinolin-6-yl)-lH- pyrazol-l-yl)piperidine-l-carboxylate (1-2.5)

[0284] To a stirred solution of 1-2.3 (1.6 g, 3.75 mmol) in DMF (20 mL) was added cesium carbonate (3.05 g, 9.38 mmol) and benzyl 4-((methylsulfonyl)oxy)piperidine-l -carboxylate I- 2.4 (2.35 g, 7.50 mmol) at RT and stirred at 100 °C for 2 h. Progress of the reaction was monitored by TLC. After completion of starting material reaction mixture was cool to RT and quenched with water, extracted with ethyl acetate, dried over anhydrous Na2SO4 and concentrated to get the crude compound. Obtained crude was purified by combi flash chromatography using 4-6% MeOH in DCM as an eluent to get the intermediateI-2.5 (1 g, 41.40%). LCMS m / z: 644.3 (M+H)+.

[0285] Step-iv: Synthesis of l-(3-(7-(difluoromethyl)-6-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-3,4- dihydroquinolin-l(2H)-yl)-l-methyl-l,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5- yl)ethan-l-one (1-2)

[0286] To a stirred solution of 1-2.5 (1 g, 1.55 mmol) in ethanol (30 ml) was added 10% Pd / C (0.5 g, 4.65 mmol) at inert atmosphere and stirred the reaction mixture at RT for 16 h under H2 atmosphere. The progress of reaction was monitored by TLC. After completion of starting material reaction mixture was filtered through celite bed and concentrated to afford crude. Obtained crude was washed with diethyl ether to get the intermediate 1-2 (0.7 g, crude). LCMS m / z: 510.2 (M+H)+.

[0287] The intermediates listed in Table-B were prepared by a procedure similar to the one described in the synthesis of Intermediate 1-2 with appropriate variations in reactants / reagents. The characterization data of the intermediates are summarized herein the below table. Table-B

[0288] Intermediate 1-10:

[0289] Reagents and conditions: i) TEA, DCM, 0 °C-RT, 3 h; ii) Pd(dppfCh).DCM, K3PO4, Dioxane-EEO, 75 °C, 3h; iii) Xphos Pd G2, KOAc 1,4-dioxane, 100 °C, 5h; iv) Pd(dppfCl2).DCM, K2CO3, Dioxane-H2O, 90 °C, 5h; v) 6N HC1, THF, RT, 3 h; vi) CS2CO3, DMF, 100 °C, 2 h; vii) 10%Pd / C, H2, EtOH, RT,16 h.

[0290] Step-i: Synthesis of 8-chloroisoquinolin-3-yl trifluoromethanesulfonate To 8-chloroisoquinolin-3-ol (4.65g, 25.89 mmol) in DMF (50 ml) was added TEA

[0291] (7.86g, 77.67 mmol) followed by N-Phenyl-trifhroromethanesulfonamide (13.87g, 38.83 mmol) and reaction mixture was stirred at for 3h. TLC showed completion of SM and formation of new non-polar spot. Ice-cold water was added to RM and stirred. Resultant precipitate was vacuum filtered and dried to get desired product. (6g, crude). LC-MS: 312.26 [M+H]+.

[0292] Step-ii: Synthesis of 8-chloro-3-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)isoquinoline

[0293] To 8-chloroisoquinolin-3-yl trifluoromethanesulfonate (5.9g, 18.93 mmol) and 1- (tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (6.31g, 22.71 mmol) in di oxane :water (3: 1, 120ml) was added K2CO3 (5.23 g, 37.86 mmol) and purged with Ar for 5mins. Pd(dppf)C12.DCM (1.54g, 1.89 mmol) was added and purged with Ar again. Seal tube was closed and heated at 75 °C for 3h. On completion of SM, EtOAc was added to reaction mixture and washed with water. Organic layer was separated and concentrated to afford crude. Purification was done by combi flash column chromatography (4g, 67.8%). LC-MS: 314.36 [M+H]+.

[0294] Step-iii: Synthesis of 3-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)-8-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinoline

[0295] In a seal tube 8-chloro-3-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)isoquinoline (3.7g, 11.79 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (3.6g, 14.14 mmol) and XPhos (0.56g, 1.18 mmol) were dissolved in dioxane (75 ml) and purged with Ar for 5mins. To this KOAc (3.47g, 35.37 mmol) and XPhos Pd G2 (0.92g, 1.18 mmol) was added and purged again with Ar. The seal tube was closed and stirred at 100 °C for 5h. TLC showed formation of new spot. RM was dissolved in EtOAc and filtered through celite bed twice. Filtrate was washed with water followed by brine. Organic layer was concentrated to afford crude. (4g, crude). LC-MS: 406.1 [M+H]+.

[0296] Step-iv: Synthesis of l-(l-methyl-3-(3-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3- yl)isoquinolin-8-yl)-l,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-l-one

[0297] In a seal tube 3-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)-8-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinoline (0.5g, 1.23 mmol), and l-(3-bromo-l- methyl-l,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-l-one (0.38g, 1.48 mmol) was dissolved in dioxane:water (3: 1, 5ml) and K2CO3 (0.34g, 2.46 mmol), was added to it and purged with Ar for 5mins. Pd(dppf)C12.DCM (90mg, 0.123 mmol), was added and purged with Ar again. The seal tube was closed and heated at 90°C for 5h. TLC showed completion of SM and formation of new spot. RM was dissolved in water and extracted with EtOAc and 10% MeOH-DCM. Organic layers were concentrated to afford crude. Purification was done by combi flash column chromatography. (0.5g, 87%). LC-MS: 457.32 [M+H]+.

[0298] Step-v, Step-vi, Step-vii were followed similar to the procedure followed in step ii, step iii, and step iv of Intermediate 1-2 respectively.

[0299] Intermediate 1-11:

[0300] Reagents and conditions: i)DIPEA, DMF, 80 °C, 2 h; ii) Zn, NH4CI, THF, H2O, RT,3h;

[0301] Step-1 : Synthesis of l-(3-(7-(difluoromethyl)-6-(l-(l-(2-fluoro-4-nitrophenyl)piperidin-4- yl)-lH-pyrazol-4-yl)-3,4-dihydroquinolin-l(2H)-yl)-l-methyl-l,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridin-5-yl)ethan-l-one l-(3-(7-(difluoromethyl)-6-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-3,4-dihydroquinolin- l(2H)-yl)-l -methyl- 1,4, 6, 7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-l -one (0.15g, 0.28mmol) was taken in DMF (3ml) and added l,2-difluoro-4-nitrobenzene (54mg, 0.337mmol) and DIPEA (73mg, 0.56mmol) at RT, RM was stirred at 80 °C for 2h. Progress of the reaction was monitored by TLC, SM was consumed. RM was extracted with EA and water, organic layer was concentrated and dried. Crude material was purified by combi flash column chromatography using 12g column and elutes at 40-50% EA-Heaxane to obtain title compound I- 11.1. LC-MS: 649.26 [M+H]+.

[0302] Step-2: Synthesis of l-(3-(6-(l-(l-(4-amino-2-fluorophenyl)piperidin-4-yl)-lH-pyrazol-4- yl)-7-(difluoromethyl)-3,4-dihydroquinolin-l(2H)-yl)-l-methyl-l,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridin-5-yl)ethan-l-one

[0303] To 1 -(3 -(7-(difluoromethyl)-6-( 1 -(1 -(2-fluoro-4-nitrophenyl)piperidin-4-yl)- 1 H- pyrazol-4-yl)-3,4-dihydroquinolin-l(2H)-yl)-l-methyl-l,4,6,7-tetrahydro-5H-pyrazolo[4,3- c]pyridin-5-yl)ethan-l-one (0.12g, 0.17mm01) was taken in THF (2ml), water (1ml) and added ammonium chloride (95mg, 1.78mmol) then zinc (93mg, 1.42mmol) at ice cold condition, RM was stirred at RT for 3h. Progress of the reaction was monitored by TLC, SM was consumed. Then RM was filtered, and filtrate was extracted with EA and water. Organic layers were washed with bicarbonate solution, brine, dried over Na2SO4, concentrated to afford 1-11. LC- MS: 619.02 [M+H]+.

[0304] List of commercially available CRBN analogues were used with appropriate variations and summarized herein the below table C.

[0305] Table-C

[0306] Example-1: Synthesis of 3-(5-(4-(4-(l-(5-acetyl-l-methyl-4,5,6,7-tetrahydro-lH- pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-l,2,3,4-tetrahydroquinolin-6-yl)-lH- pyrazol-l-yl)piperidin-l-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (Compound-1)

[0307] Reagents and conditions: i) Pd-PEPPSI-iHeptCl, CS2CO3. DMSO, 100 °C, 3 h.

[0308] To a degassed solution of intermediate 1-2 (0.15 g, 0.29 mmol), 3-(6-bromo-l- oxoisoindolin-2-yl)piperidine-2, 6-dione (0.19 g, 0.588 mmol) and cesium carbonate (0.28 g, 0.88 mmol) in DMSO (3 mL) was added Pd-PEPPSI-iHept-Cl (29 mg, 0.03 mmol) continued purging for another 5 min at RT and stirred at 100 °C for 3 h. The progress of reaction was monitored by TLC. After completion of starting material reaction mixture was cooled to RT and filtered through celite bed and washed with ethyl acetate. Filtrate was washed with water, dried over anhydrous Na2SO4 and concentrated to get the crude compound. Obtained crude was purified by combi flash chromatography using 2-3% MeOH in DCM as an eluent to get the title Compound-1 (88 mg, 39.81%) 'H-NMR (400 MHz, DMSO-t / 6): 8 10.95 (s, 1H), 7.90 (s, 1H), 7.55 (d, 1H), 7.13 (t, 3H), 6.68-6.98 (m, 2H), 5.08-5.03 (m, 1H), 4.50-4.48 (m, 1H), 4.45- 4.33 (m, 1H), 4.33-4.24 (m, 1H), 4.11-4.01 (m, 4H), 3.72 (t, 1H), 3.69 (s, 5H), 3.65-3.55 (m, 2H), 3.06 (t, 2H), 2.95-2.88 (m, 4H), 2.61-2.58 (m, 2H), 2.42-2.39 (m, 1H), 2.18-2.12 (m, 2H), 2.07-2.04 (m, 4H), 1.96-1.92 (m, 3H); LCMS m / z: 750 (M-H)+; HPLC: 95.09%.

[0309] The compounds listed in below Table-D were prepared by reacting appropriate Intermediates using a procedure similar to the one described in Example-1 with appropriate variations. The characterization data of the compounds are summarized herein the below table. Table-D: Example-2: Synthesis of 5-(4-(4-(l-(5-acetyl-l-methyl-4,5,6,7-tetrahydro-lH- pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-l,2,3,4-tetrahydroquinolin-6-yl)-LH- pyrazol-l-yl)piperidin-l-yl)-2-(2,6-dio opiperidin-3-yl)isoindoline-l, 3-dione (Compound-7) Compound-07

[0310] Reagent and conditions: i) DIPEA, DMSO, 100 °C, 3 h.

[0311] To a stirred solution of 1-2 (0.1 g, 0.19 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5- fluoroisoindoline-1, 3-dione (0.1 g, 0.39 mmol) in DMSO (2 mL) was added diisopropylethylamine (0.12 g, 0.97 mmol) at RT and stirred at 100 °C for 3 h. The progress of the reaction was monitored by TLC. After completion of starting material reaction mixture was cool to RT and quenched with ice-cold water, solid precipitated out was filtered and dried to get the crude compound. Obtained crude was purified by combi flash chromatography using 2- 3% MeOH in DCM as an eluent to get the title Compound-7 (18 mg, 11.99%). 'H-NMR (400 MHz, DMSO- e): 8 11.15 (s, 1H), 7.88 (s, 1H), 7.69 (d, 1H), 7.54 (d, 1H), 7.42 (s, 1H), 7.34 (d, 1H), 7.14 (s, 1H), 6.89-6.83 (m, 3H), 5.10-5.08 (m, 1H), 4.54 - 4.51 (m, 1H), 4.23-4.21 (d, 2H), 4.09-4.06 (d, 2H), 3.72-3.71 (m, 1H), 3.70-3.68 (m, 4H), 3.66-3.64 (m, 1H), 3.36-3.32 (t, 2H), 2.85-2.82 (m, 4H), 2.71-2.69 (m, 1H), 2.54-2.49 (m, 1H), 2.23-2.19 (m, 2H), 2.06-2.03 (m, 2H), 2.02-1.96 (m, 7H); LCMS m / z: 766.3 (M+H)+; HPLC: 97.12%

[0312] Example-3: Synthesis of 3-((4-(4-(4-(l-(5-acetyl-l-methyl-4,5,6,7-tetrahydro-lH- pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-l,2,3,4-tetrahydroquinolin-6-yl)-lH- pyrazol-l-yl)piperidin-l-yl)-3-fluorophenyl)amino)piperidine-2, 6-dione (Compound-41)

[0313] Reagents and conditions: i) NaHCO3, ACN, 80°C, 16 h. To a stirred solution of 1-10 (0.1 g, 0.16 mmol) and 2-(2,6-dioxopiperi din-3 -yl)-5- fluoroisoindoline-1, 3-dione (62 mg, 0.32 mmol) in acetonitrile (2 mL) was added sodium bicarbonate (40 mg, 0.48 mmol) at RT and stirred at 80 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of starting material reaction mixture was cool to RT and quenched with ice-cold water, solid precipitated out was filtered and dried to get the crude compound. Obtained crude was purified by combi flash chromatography using 2- 3% MeOH in DCM as an eluent to get the title Compound-41 (55 mg, 46.6%).

[0314] Although the present application has been illustrated by certain of the preceding examples, it is not to be construed as being limited thereby; but rather, the present application encompasses the generic area as hereinbefore disclosed. For example, the compounds below which can be prepared by following 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 application:

[0315] BIOLOGICAL ASSAY

[0316] Targeted protein degradation controls the amount of a harmful cellular protein rather than modulation or inhibition of its function. This novel therapeutic approach also offers many opportunities to differentiate from inhibitor-based therapies. First, by catalysing the destruction of their target protein, degrader molecules may also disrupt scaffolding functions of proteins otherwise not addressed by small 1 molecule inhibitors, allowing for drug properties that are unlike other classes of drugs. Second, degraders may offer higher potency and differentiated cellular pharmacology. Unlike inhibitors, which must remain bound to a single target protein, degrader molecules can catalyse the ubiquitination and destruction of multiple copies of the same protein since the degraders themselves are not degraded in the proteasome. 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.

[0317] Determination of Degradation of Protein in HiBiT Assay:

[0318] U2OS-HiBiT Assay Protocol:

[0319] U2OS-CBP HiBiT and U20S-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 invention were screened in the above-mentioned assay procedure and the percentage of p300 degradation in HiBiT assay at 0.2pM were determined.

[0320] Compounds of the present application were screened by the above-mentioned assay and for certain exemplary compounds, the % p300 degradation at 0.2pM is greater than 50%.

[0321] Incorporation by Reference

[0322] All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0323] Equivalents

[0324] 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:A compound of formula (I):or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; wherein,Xi is CR2, N, NR2, S or O;X2is CH, N, NH, S or O;Yi is C or N; each Zi, and Z2is independently C or N;Ar is (C3-Ci2)cycloalkylenyl, 3-12 membered heterocycloalkylenyl, (Ce-Cio)arylenyl, or 5-12 membered heteroaryl enyl;Ri is hydrogen, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, (C3-Ci2)cycloalkyl, 3-12 membered heterocycloalkyl, or NRiaRib;R2is hydrogen, (Ci-Ce)alkyl, halo, halo(Ci-Ce)alkyl, (C3-Ci2)cycloalkyl, or 3-12 membered heterocycloalkyl;R3 is CR3aR3b, or NR3C;R4 is hydrogen, halogen, (Ci-Ce)alkyl, or (Ci-Ce)alkoxy; alternatively, R3a or R3Ctogether with R4 get cyclized to form an unsubstituted or substituted, (C3-Ci2)cycloalkyl, 3-12 membered heterocycloalkyl, (Ce-Cio)aryl, or 5-12 membered heteroaryl wherein the substituents on cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently selected from one or more (Ci-Ce)alkyl, halo, halo(Ci-Ce)alkyl, hydroxy, cyano and amino;R5 is hydrogen, (Ci-Ce)alkyl, halo, halo(Ci-Ce)alkyl, (C3-Ci2)cycloalkyl, or 3-12 membered heterocycloalkyl;Re at each occurrence is independently hydrogen, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo, hydroxy; or two Re on the same carbon atom together represent an oxo group; each Ria and Rib is independently hydrogen, halogen, or (Ci-Ce)alkyl; each Rsa, Rsb andRsc is independently hydrogen, halogen, or (Ci-Ce)alkyl;M is represented by formula (M-l), (M-2), (M-3), (M-4), (M-5), (M-6), (M-7) or (M- 8):(M-5)each Wi, W2, Ws and Wn is independently C, CH or N; each W3 W4, Ws, We and W7 is independently C or N; wherein at least one of W3, W4 and W5 is C;W9 is a bond, *-C(O)NH-, *-NH-C(O)-, or -NRW-; wherein the asterisk mark represents the point of attachment with the ring having Ws;W10 is CH2, NH or O;Rwis hydrogen or (Ci-Ce)alkyl; RMI at each occurrence is independently hydrogen, (Ci-Ce)alkyl or halo(Ci-Ce)alkyl;RM2 at each occurrence is independently hydrogen, halo, cyano, (Ci-Ce)alkyl or (Ci- Ce)alkoxy; each RM3 and RM4 is hydrogen or (Ci-Ce)alkyl; or RM3 and RM4 together represent an oxo group; RMS at each occurrence is independently hydrogen or (Ci-Ce)alkyl; alternatively, two RMS on the same carbon atom together represent an oxo (=0) group; subscript ‘p’ and ‘r’ each independently is 0, 1 or 2; subscript ‘q’ is 0 or 1; subscript ‘s’ is 0, 1, 2, 3 or 4;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 thereof or a stereoisomer thereof.

3. The compound as claimed in claim 1, having formula (IB):or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

4. The compound as claimed in claim 1, having formula (IC):or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

5. The compound as claimed in claim 1, having formula (ID):or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

6. The compound as claimed in claim 1, having formula (IE), (IF), (IG), (IH), (II), (IJ),(IK), or (IL):or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

7. The compound as claimed in claims 1 to 6, wherein M is represented byThe compound as claimed in claim 1, having formula (IA):or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; wherein,Xi is CR2, N, NR2, S or O;X2is CH, N, NH, S or O;Yi is C or N; each Zi, and Z2 is independently C or N;Ar is (C3-Ci2)cycloalkylenyl, 3-12 membered heterocycloalkylenyl, (Ce-Cio)arylenyl, or 5-12 membered heteroaryl enyl;Ri is hydrogen, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl orNRiaRib;R2 is hydrogen, (Ci-Ce)alkyl, (C3-Ci2)cycloalkyl, or 3-12 membered heterocycloalkyl;R3 is CR3aR3b, or NR3C;R4 is hydrogen, halogen, (Ci-Ce)alkyl, or (Ci-Ce)alkoxy; alternatively, R3a or R3Ctogether with R4 get cyclized to form an unsubstituted or substituted, (C3-Ci2)cycloalkyl, 3-12 membered heterocycloalkyl, (Ce-Cio)aryl, or 5-12 membered heteroaryl wherein the substituents on cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently selected from one or more (Ci-Ce)alkyl, halo, halo(Ci-Ce)alkyl, hydroxy, cyano and amino;R5 is hydrogen, (Ci-Ce)alkyl, halo or halo(Ci-Ce)alkyl;Re is hydrogen, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo, hydroxy; or two Re on the same carbon atom together represent an oxo group;Ria is hydrogen, or (Ci-Ce)alkyl;Rib is hydrogen, or (Ci-Ce)alkyl; and each R3a, R3b andR3c is independently hydrogen, halogen, or (Ci-Ce)alkyl.

9. The compound as claimed in any one of claims 1 to 8, wherein the Ar is 3-12 membered heterocycloalkylenyl, (Ce-Cio)arylenyl, or 5-12 membered heteroarylenyl.

10. The compound as claimed in any one of claims 1 to 8, wherein the Ar is 5-12 membered heteroarylenyl.

11. A compound selected from:or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

12. A pharmaceutical composition comprising a compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt or a stereoisomer thereof and at least one pharmaceutically acceptable carrier or excipient.

13. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt or a stereoisomer thereof, for use as a medicament.

14. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt or a stereoisomer thereof, for the manufacture of a medicament for the treatment of cancer.

15. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt or a stereoisomer thereof, for use in degrading the target protein in a subject, wherein the target protein is P300.

16. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt or a stereoisomer thereof, for use in the treatment of P300 mediated disorder.

17. 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 11, or a pharmaceutically acceptable salt thereof.

18. The method of claim 17, wherein the disease or disorder is cancer, viral infection and autoimmune disease or disorder, inflammatory disease or disorder, neurodegenerative disease and metabolic disorder.

19. The method of claim 18, wherein the disease or disorder is cancer.

20. The method of claim 19, 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, uveal melanoma, lymphoma, or lymphoid malignancy or metastatic cancer.

21. The method of claim 18, 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.

22. The method of claim 18, wherein neurodegenerative disease is selected from Alzheimer’s disease, Parkinson’s disease, dementia, Huntington’s disease or amyotrophic lateral sclerosis.

23. The method of any one of the claims 17 to 22, 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.

24. 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 11, or a pharmaceutically acceptable salt thereof.

25. A method of treating or preventing autoimmune disease or disorder in a subj ect in need thereof, comprising administering to the subject a therapeutically effective amount of the compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

26. 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 11, or a pharmaceutically acceptable salt thereof.

27. The method of claim 26, 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, testiculargerm 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.

28. Use of a compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt or a stereoisomer thereof, in the manufacture of a medicament for the treatment of disease or disorder responsive to the p300 degradation.

29. Use of a compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt or a stereoisomer thereof, in the manufacture of a medicament for the treatment of cancer, an inflammatory disease or disorder, autoimmune disease or disorder, neurodegenerative disease or metabolic disorder.

30. The use of claim 29, 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, uveal melanoma, lymphoma, or lymphoid malignancy or metastatic cancer.

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