Fused bicyclic compounds as smarca2 and / or smarca4 degraders

Abstract

The present invention provides fused bicyclic compounds of formula (I), which are therapeutically useful as SMARCA2 and / or SMARCA4 degraders. These compounds are useful in the treatment and / or delaying progression of disease or disorder dependent upon SMARCA2 and / or SMARCA4 in a subject. The present invention also provides pharmaceutical compositions comprising at least one of the compounds of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.

Description

[0001] FUSED BICYCLIC COMPOUNDS AS SMARCA2 AND / OR SMARCA4 DEGRADERS

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of Indian provisional application number 202441021032, filed on March 20, 2024, and Indian provisional application number 202441071928, filed on September 24, 2024, the specifications of which are hereby incorporated by reference in its entirety.

[0004] FIELD OF THE INVENTION

[0005] The present invention relates to fused bicyclic compounds and a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof which are useful as SMARCA2 / 4 degraders and for the treatment of disease or disorder dependent on SMARCA2 / 4. The present invention also relates to a method of preparation of the fused bicyclic compounds and pharmaceutical compositions comprising the compounds.

[0006] BACKGROUND OF THE INVENTION

[0007] One of the most significant findings from the cancer genome profiling is the discovery of frequent mutations in various subunits of the mammalian SWI / SNF (SWItch / Sucrose Non- Fermentable) chromatin remodelling complex. Approximately 20% of human cancers are associated with somatic mutations in subunits of the SWI / SNF complex, a chromatin remodelling complex that influences gene regulation by disrupting histone-DNA contacts (PNAS February 25, 2014. Ill (8) 3128-3133).

[0008] SWI / SNF complexes contain either of two closely related and evolutionarily conserved catalytic ATPase subunits: Brahma (BRM / SMARCA2) or Brahma-related gene 1 (BRG1 / SMARCA4). They share approximately 75% identity at the protein level. Although BRG1- and BRM-containing complexes show some redundancy, they may function distinctively. In human cancer, BRG1 seems to be one of the most frequently mutated subunit genes, whereas the BRM gene is rarely mutated. BRG1 / SMARCA4 (SWI / SNF related BAF chromatin remodeling complex subunit ATPase 4) mutations occurring in ~ 10-15% of lung adenocarcinomas. BRM / SMARCA2 (SWI / SNF related BAF chromatin remodeling complex subunit ATPase 2) is essential for the growth of tumour cells that harbour loss of function mutations in BRG1 / SMARCA4. Depletion of BRM in BRG1 -deficient cancer cells leads to a cell cycle arrest, induction of senescence, and increased levels of global H3K9me31 (PNAS February 25, 2014, 111 (8), 3128-3133).

[0009] In some tumour types, mutations within the SWI / SNF complex lead to context specific vulnerabilities such as the requirement of SMARCA2 for survival of tumour cells lacking SMARCA4. This finding of SMARCA2 / 4 synthetic lethal relationship translates in vivo which emphasizes SMARCA2 as a promising therapeutic target for the treatment of SMARCA4- deficient cancers. Moreover, the SMARCA4-deficient patient population generally lacks targetable oncogenes (such as mutant EGFR or ALK translocations), which further emphasizes the potential of developing SMARCA2 inhibitors. Characterization of SMARCA4 function in tumours with high SMARCA4 levels, shows effects on signalling pathways that result in increased proliferation and survival. SMARCA4 knockdown in tumours that show elevated levels known to inhibit proliferation and other cancer cell properties. Studies have also shown that SMARCA4 knockdown / modulation increases sensitivity to known chemotherapeutic agents, thereby indicating that SMARCA4 targeting could also be an adjuvant therapy to existing chemotherapeutic approaches (PNAS February 25, 2014. Ill (8) 3128-3133; J Pathol. 2016 Feb; 238(3): 389-400).

[0010] Contrary to genetic silencing of SMARCA2 leading to potent anti -proliferative activity in SMARCA4-deficient cancer cell lines, PFI-3, a selective cell permeable SMARCA2 / 4 bromodomain inhibitor capable of binding to SMARCA2 and SMARCA4 bromodomain, fails to display an antiproliferative phenotype which indicates that bromodomain function of SMARCA2 / 4 is dispensable for tumor cell proliferation, while the catalytic ATPase activity is essential (Cancer Res. 2015 Sep 15; 75(18): 3865-3878). In order to mimic the phenotype achieved by genetic silencing, approaches that lead to reduction or complete elimination of SMARCA2 / 4 may be needed.

[0011] The ubiquitin-proteasome system (UPS) is a major pathway that regulates the levels of intracellular proteins and provides a fine balance between protein synthesis and degradation required for normal maintenance of cellular function, including proliferation, differentiation, and cell death. Ubiquitination is a post-translational modification, where a small protein, ubiquitin, is covalently attached to lysine residues on a substrate protein carried out sequentially by a cascade of enzymatic reactions involving an intimate collaboration between El activating, E2 conjugating and E3 ligating enzymes and subsequent degradation of the tagged proteins (J. Biosci. 31(1), March 2006, 137-155; Expert Opin Ther Targets. 2013 September; 17(9): 1091 1108 and Cell Research (2016) 26:484-498). Proteolysis targeting chimeras are the heterobifunctional molecules containing a ligand for a target protein of interest connected via a linker to a ligand for an E3 ubiquitin ligase. Upon such bi-functional molecule-mediated heterodimerization of the two bound proteins, the target protein is ubiquitinated and degraded by the proteasome in cells. Many such bi-functional molecules have been developed to recruit E3 ubiquitin ligases to a variety of substrates using high-affinity ligands for the protein of interest. Proteins effectively degraded using these approaches include RIPK2 and ERRa, BRD4, BRD9, BCR / Abl and Abl and Era (Cell Chemical Biology 25, 78-87, January 18, 2 18). E3 ubiquitin ligases (of which over 600 are known in humans) confer substrate specificity for ubiquitination and are more attractive therapeutic targets than general proteasome inhibitors due to their specificity for certain protein substrates.

[0012] Small molecule ligands targeting the bromodomains of SMARCA2 and SMARCA4 have been reported (Gerstenberger et al., Journal of Medicinal Chemistry 2016, 59, 4800- 4811; Hoffman et al., PNAS, 2014b, 777, 3128-3133; Sutherell et al., 2016, Journal of Medicinal Chemistry 59, 5095-5101; WO2016138114). Although cells lacking SMARCA4 activity are vulnerable to the loss of SMARCA2 (Hoffman et al., 2014a, PNAS 777, 3128- 3133), SMARCA2 / 4 inhibitors have failed to phenocopy these anti -proliferative effects (Vangamudi et al., 2015, Cancer Research 75, 3865-3878). In agreement with this, reexpression of SMARCA2 variants in cells, where the endogenous protein had been suppressed, showed that an intact bromodomain is not required to maintain proliferation (Vangamudi etal., 2015, Cancer Research 75, 3865-3878). SMARCA2 / 4BD inhibitors are thus precluded from use for the treatment of SMARCA4 mutant cancers but could provide attractive ligands for PROTAC conjugation.

[0013] It is therefore reasoned that a PROTAC targeting the non-functional bromodomain of SMARCA2 / 4 should offer an opportunity to exploit the vulnerability of SMARCA2 in SMARCA4 mutated cancer cells for therapeutic purposes. The principle of conjugation of a suitable SMARCA ligand with an E3 ligase binder has been described in WO 2016 / 105518; W02017 / 007612 and W02017 / 011371. However, in none of the publications a concrete example and corresponding degradation of SMARCA proteins has been demonstrated.

[0014] SUMMARY OF THE INVENTION

[0015] Provided herein fused bicyclic compounds and pharmaceutical compositions thereof that are useful as SMARC A2 / 4 degraders and for the treatment of disease or disorder dependent on or mediated by SMARCA2 / 4. In one aspect, the present invention provides a compound of formula (I): or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof; wherein

[0016] Ri at each occurrence is independently hydrogen, halo, alkyl, haloalkyl, alkoxy or hydroxy;

[0017] R2 at each occurrence, is independently hydrogen, alkyl, halo or haloalkyl; or two R2 attached on the same carbon atom to form an oxo(=O) group;

[0018] Xi, X2 and X3 are independently selected from CH, NH, C or N; wherein at least any one of Xi, X2 or X3 is N; ring A is arylenyl or heteroarylenyl; wherein the arylenyl and heteroaryl enyl are independently unsubstituted or substituted with 1, 2 or 3 groups selected from alkyl, hydroxy, halo or haloalkyl;

[0019] L is , wherein asterisk mark indicates the point of attachment with ring A;

[0020] Li is a bond, heterocycloalkylenyl, -O-heterocycloalkylenyl or cycloalkylenyl; wherein the heterocycloalkylenyl and cycloalkylenyl are independently unsubstituted or substituted with 1, 2 or 3 Ry;

[0021] L2 is a bond, *-C(0)-(CH2)q-, *-C(0)-NR5- or -(CH2)b-; wherein asterisk mark indicates the point of attachment with Li;

[0022] L3 is (heterocycloalkylenyl)p or cycloalkylenyl; wherein the cycloalkylenyl and heterocycloalkylenyl are independently unsubstituted or substituted with 1, 2 or 3 Ryi;

[0023] R5 is hydrogen or alkyl; Ry and Ryiat each occurrence are independently selected from alkyl, halo, hydroxy or haloalkyl; or any of two Ryor Ryiattached on the same carbon atom to form an oxo(=O) group;

[0024] M is selected from Ml, M2, M3, M4, M5, M6 or M7; wherein,

[0025] X and X’ are independently CH, C or N;

[0026] Y and Y’ are independently a bond, -NH-, -C(O)-NH-*, -CH2- or -O-; wherein the asterisk mark indicates the point of attachment with piperidinedione ring;

[0027] Yi is N, NH, O, CH or CH2;

[0028] Y2is N or CH;

[0029] Y3is NH, C(O) or CH2;

[0030] X4, X5 and Xe are independently N or C;

[0031] X7, Xs and X9 are independently N or C; wherein at least one of X7, Xs or X9 is N;

[0032] X10, Xu, Xi2and X13 are independently C or N;

[0033] Zi, Z2and Z3are independently N or C;

[0034] Z4 and Z5 are independently C or N;

[0035] R3and 5 are independently hydrogen, halo, haloalkyl or alkyl;

[0036] R4 at each occurrence is independently hydrogen or alkyl; or two R4 on the same carbon atom together represent an oxo(=O) group;

[0037] ‘m’ and ‘q’ are independently an integer of 1, 2 or 3;

[0038] ‘p’ is integer of 1 or 2; ‘b’ is integer of 0, 1, 2 or 3;

[0039] ‘n’ is integer of 1, 2, 3 or 4; and

[0040] - is a single bond or a double bond.

[0041] In another aspect, the present invention provides a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof, and a pharmaceutically acceptable carrier or an excipient.

[0042] In another aspect, the present invention provides a method of degrading a target protein in a subject, wherein administering to the subject in need thereof, a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.

[0043] In another aspect, the present invention provides a method of treating or delaying the progression of a disease or a disorder dependent upon at least one of SMARCA2 and SMARCA4 in a subject, comprising, administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof to the subject in need thereof. The disease or disorder is treatable by degradation of SMARCA2 / 4, such as a cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis or a viral infection.

[0044] In another aspect, the present invention provides a method of treating or delaying the progression of a disease or a disorder dependent upon at least one of SMARCA2 and SMARCA4 in a subject, comprising, administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof to the subject in need thereof, wherein the disease or disorder is a cancer.

[0045] In another aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, for use as a medicament.

[0046] In another aspect, the present invention provides a use of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, in the manufacture of a medicament for the treatment of a disease or disorder dependent upon SMARCA2 and / or SMARCA4; wherein the disease or disorder is cancer. DETAILED DESCRIPTION OF THE INVENTION

[0047] The present invention provides fused bicyclic compounds, referred as compound of formula (I), which are useful as SMARCA2 / 4 degraders and for the treatment of conditions dependent on / or mediated by SMARCA2 / 4. The present invention further provides pharmaceutical compositions comprising the compound or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof as therapeutic agents.

[0048] Each embodiment is provided by way of explanation of the invention and not by way of limitation of the invention. In fact, it will be apparent to those skilled in the art that various modifications and variations can be made to the compounds, compositions and methods described herein without departing from the scope or spirit of the invention. 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 invention includes such modifications and variations and their equivalents. Other objects, features and aspects of the present invention 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 only and is not to be construed as limiting the broader aspects of the present invention.

[0049] In one embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof; wherein

[0050] Ri at each occurrence is independently hydrogen, halo, alkyl, haloalkyl, alkoxy or hydroxy;

[0051] R2 at each occurrence, is independently hydrogen, alkyl, halo or haloalkyl; or two R2 attached on the same carbon atom to form an oxo(=O) group; Xi, X2 and X3 are independently selected from CH, NH, C or N; wherein at least any one of Xi, X2 or X3 is N; ring A is arylenyl or heteroarylenyl; wherein the arylenyl and heteroaryl enyl are independently unsubstituted or substituted with 1, 2 or 3 groups selected from alkyl, hydroxy, halo or haloalkyl;

[0052] L is , wherein asterisk mark indicates the point of attachment with ring A;

[0053] Li is a bond, heterocycloalkylenyl, -O-heterocycloalkylenyl or cycloalkylenyl; wherein the heterocycloalkylenyl and cycloalkylenyl are independently unsubstituted or substituted with 1, 2 or 3 Ry;

[0054] L2 is a bond, *-C(O)-(CH2)q-, *-C(O)-NR5- or -(CH2)b-; wherein asterisk mark indicates the point of attachment with Li;

[0055] L3 is (heterocycloalkylenyl)p or cycloalkylenyl; wherein the cycloalkylenyl and heterocycloalkylenyl are independently unsubstituted or substituted with 1, 2 or 3 Ryi;

[0056] R5 is hydrogen or alkyl;

[0057] Ryand Ryiat each occurrence are independently selected from alkyl, halo, hydroxy or haloalkyl; or any of two Ryor Ryiattached on the same carbon atom to form an oxo(=O) group;

[0058] M is selected from Ml, M2, M3, M4, M5, M6 or M7; wherein,

[0059] X and X’ are independently CH, C or N; Y and Y’ are independently a bond, -NH-, -C(O)-NH-*, -CH2- or -O-; wherein the asterisk mark indicates the point of attachment with piperidinedione ring;

[0060] Yi is N, NH, O, CH or CH2;

[0061] Y2is N or CH;

[0062] Y3is NH, C(O) or CH2;

[0063] X4, X5 and Xe are independently N or C;

[0064] X7, Xs and X9 are independently N or C; wherein at least one of X7, Xs or X9 is N;

[0065] X10, Xu, Xi2and X13 are independently C or N;

[0066] Zi, Z2and Z3are independently N or C;

[0067] Z4 and Z5 are independently C or N;

[0068] R3and Re are independently hydrogen, halo, haloalkyl or alkyl;

[0069] R4 at each occurrence is independently hydrogen or alkyl; or two R4 on the same carbon atom together represent an oxo(=O) group;

[0070] ‘m’ and ‘q’ are independently an integer of 1, 2 or 3;

[0071] ‘p’ is integer of 1 or 2;

[0072] ‘b’ is integer of 0, 1, 2 or 3;

[0073] ‘n’ is integer of 1, 2, 3 or 4; and

[0074] - is a single bond or a double bond.

[0075] In one embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof; wherein

[0076] Ri at each occurrence is hydrogen, halo, alkyl, haloalkyl, alkoxy or hydroxy; R.2 at each occurrence, is hydrogen, alkyl, halo or haloalkyl; or two R2 attached on the same carbon atom to form an oxo(=O) group;

[0077] Xi, X2 and X3 are independently selected from CH, NH, C or N; wherein at least any one of Xi, X2 or X3 is N; ring A is arylenyl or heteroaryl enyl; wherein arylenyl and heteroaryl enyl are independently unsubstituted or substituted with 1, 2 or 3 groups selected from alkyl, halo or haloalkyl;

[0078] Li is a bond, heterocycloalkylenyl, -O-heterocycloalkylenyl or cycloalkylenyl; wherein heterocycloalkylenyl and cycloalkylenyl are independently unsubstituted or substituted with 1, 2 or 3 Ry;

[0079] L2is a bond, -C(O)-(CH2)q-, -C(O)-NR5- or -(CH2)b-;

[0080] L3 is heterocycloalkylenyl or cycloalkylenyl; wherein cycloalkylenyl and heterocycloalkylenyl are independently unsubstituted or substituted with 1, 2 or 3 Ryi;

[0081] R5 is hydrogen or alkyl;

[0082] Ryand Ryiat each occurrence are independently selected from alkyl, halo or haloalkyl; or any of two Ryor Ryiattached on the same carbon atom to form an oxo(=O) group;

[0083] M is selected from group of formulas Ml, M2 and M3: wherein,

[0084] X and X’ are independently selected from CH, C or N;

[0085] Y and Y’ are independently selected from a bond, NH, CH2 or O;

[0086] Yi is NH, O or CH2;

[0087] Y2is N or CH; Y3is NH, C(0) or CH2;

[0088] X4, X5 and Xe are independently N, C or CH;

[0089] Zi, Z2and Z3are independently selected from NH, N, C or CH;

[0090] R3and Re at each occurrence are independently hydrogen, halo, haloalkyl or alkyl;

[0091] R4 at each occurrence is hydrogen or alkyl; or two R4 attached on the same carbon to form an oxo(=O) group;

[0092] ‘m’ and ‘q’ are independently integer of 1, 2 or 3;

[0093] ‘b’ is integer of 0, 1, 2 or 3;

[0094] ‘n’ is integer of 1, 2, 3 or 4; and

[0095] - is a single bond or a double bond.

[0096] In one embodiment, Ri at each occurrence, is independently halo, (Ci-Ce)alkyl, (Ci- Ce)alkoxy or hydroxy.

[0097] In one embodiment, Ri at each occurrence, is independently halo, (Ci-Ce)alkyl or hydroxy.

[0098] In one embodiment, Ri at each occurrence, is hydroxy.

[0099] In one embodiment, Ri at each occurrence, is halo.

[0100] In one embodiment, R2 at each occurrence, is independently hydrogen, (Ci-Ce)alkyl, halo or halo(Ci-Ce)alkyl; or two R2 attached on the same carbon atom to form an oxo(=O) group.

[0101] In one embodiment, R2 at each occurrence, is independently hydrogen, (Ci-Ce)alkyl, halo or halo(Ci-Ce)alkyl.

[0102] In one embodiment, R2 at each occurrence is independently hydrogen, (Ci-Ce)alkyl or halo(Ci-Ce)alkyl.

[0103] In one embodiment, R2 at each occurrence, is hydrogen.

[0104] In one embodiment, two R2 attached on the same carbon atom to form an oxo(=O) group.

[0105] In one embodiment, Xi, X2and X3are independently selected from CH, NH, C or N; wherein at least any one of Xi, X2or X3is N. In one embodiment, Xi and X3 are CH and X2 is N.

[0106] In one embodiment, X2 and X3 are CH and Xi is N.

[0107] In one embodiment, Xi and X3 are N and X2 is CH.

[0108] In one embodiment, X2 and X3 are N and Xi is CH.

[0109] In one embodiment, X2 and X3 are C and Xi is N.

[0110] In one embodiment, Xi and X2 are N and X3 is CH.

[0111] In one embodiment, Xi is C, X3 is CH and X2 is NH.

[0112] In one embodiment, Xi, X2 and X3 are N.

[0113] In one embodiment, ring A is 6- to 10-membered arylenyl or 5- to 10-membered heteroaryl enyl; wherein arylenyl and heteroaryl enyl are independently unsubstituted or substituted with 1, 2 or 3 groups selected from hydroxy or halo.

[0114] In one embodiment, ring A is unsubstituted or substituted 6- to 10-membered arylenyl.

[0115] In one embodiment, ring A is unsubstituted or substituted phenylenyl.

[0116] In one embodiment, ring A is unsubstituted or substituted 5- to 10-membered heteroaryl enyl.

[0117] In one embodiment, ring A is unsubstituted or substituted pyrazolenyl, pyridazinenyl, pyrazinenyl or pyrimidinenyl. asterisk mark indicates point of attachment to L. In one embodiment, ring A is selected from wherein asterisk mark indicates point of attachment to L.

[0118] In one embodiment, ring A is selected from , wherein the asterisk mark indicates point of attachment to L.

[0119] In one embodiment, ring

[0120] In one embodiment,

[0121] In one embodiment, L is selected from *-3- to 14-membered heterocycloalkylenyl-(3- to 14-membered heterocycloalkylenyl)p-, *-3- to 14-membered heterocycloalkylenyl-C(O)- (CH2)q-3- to 14-membered heterocycloalkylenyl-, *-O-3- to 14-membered heterocycloalkylenyl-C(O)-(CH2)q-3- to 14-membered heterocycloalkylenyl-, *-3- to 14- membered heterocycloalkylenyl-C(O)-NR5-3- to 14-membered heterocycloalkylenyl-, *-3- to 14-membered heterocycloalkylenyl-(CH2)b-3- to 14-membered heterocycloalkylenyl-, *-3- to 14-membered heterocycloalkylenyl-(C3-Ci4)cycloalkylenyl-; wherein heterocycloalkylenyl and cycloalkylenyl are independently unsubstituted or substituted with 1, 2 or 3 Ry; wherein asterisk mark indicates the point of attachment with ring A.

[0122] In one embodiment, L is *-3- to 14-membered heterocycloalkylenyl-(3- to 14- membered heterocycloalkylenyl)p-; wherein heterocycloalkylenyl and cycloalkylenyl are independently unsubstituted or substituted with 1, 2 or 3 Ry; wherein asterisk mark indicates the point of attachment with ring A.

[0123] In one embodiment, L is *-3- to 14-membered heterocycloalkylenyl-C(O)-(CH2)q-3- to 14-membered heterocycloalkylenyl-; wherein heterocycloalkylenyl is unsubstituted or substituted with 1, 2 or 3 Ry; wherein asterisk mark indicates the point of attachment with ring A.

[0124] In one embodiment, L is *-O-3- to 14-membered heterocycloalkylenyl-C(O)-(CH2)q-3- to 14-membered heterocycloalkylenyl-; wherein heterocycloalkylenyl is unsubstituted or substituted with 1, 2 or 3 Ry; wherein asterisk mark indicates the point of attachment with ring A.

[0125] In one embodiment, L is *-3- to 14-membered heterocycloalkylenyl-C(O)-NRs-3- to 14-membered heterocycloalkylenyl-; wherein heterocycloalkylenyl is unsubstituted or substituted with 1, 2 or 3 Ry; wherein asterisk mark indicates the point of attachment with ring A.

[0126] In one embodiment, L is *-3- to 14-membered heterocycloalkylenyl-(CH2)b-3- to 14- membered heterocycloalkylenyl-; wherein heterocycloalkylenyl is unsubstituted or substituted with 1, 2 or 3 Ry; wherein asterisk mark indicates the point of attachment with ring A.

[0127] In one embodiment, L is *-3- to 14-membered heterocycloalkylenyl-(C3- Ci4)cycloalkylenyl-; wherein heterocycloalkylenyl and cycloalkylenyl are independently unsubstituted or substituted with 1, 2 or 3 Ry; wherein asterisk mark indicates the point of attachment with ring A.

[0128] In one embodiment, Li is a bond, -3- to 14-membered heterocycloalkylenyl-, *-0-3- to 14-membered heterocycloalkylenyl- or -(C3-Ci4)cycloalkylenyl-; wherein heterocycloalkylenyl and cycloalkylenyl are independently unsubstituted or substituted with 1, 2 or 3 (Ci-Ce)alkyl, halo, hydroxy or halo(Ci-Ce)alkyl groups; wherein asterisk mark indicates the point of attachment with ring A.

[0129] In one embodiment, Li is a -3- to 14-membered heterocycloalkylenyl-; wherein heterocycloalkylenyl is unsubstituted or substituted with 1, 2 or 3 (Ci-Ce)alkyl, halo or hydroxy.

[0130] In one embodiment, Li is a -5- to 6-membered heterocycloalkylenyl-; wherein heterocycloalkylenyl is unsubstituted or substituted with 1, 2 or 3 (Ci-Ce)alkyl, halo or hydroxy.

[0131] wherein * mark indicates point of attachment to ring A. indicates point of attachment to ring A.

[0132] In one embodiment, Li is ; wherein * mark indicates point of attachment to ring A.

[0133] In one embodiment, L2 is a bond, *-C(O)-CH2-, *-C(O)-N(CH3)- or -CH2-; wherein asterisk mark indicates the point of attachment with Li.

[0134] In one embodiment, L2 is a bond or -CH2-. In one embodiment, L2 is a bond.

[0135] In one embodiment, L2 is *-C(O)-CH2-; wherein the asterisk mark indicates the point of attachment with Li. In one embodiment, L2 is *-C(O)-N(CH )-; wherein asterisk mark indicates the point of attachment with Li.

[0136] In one embodiment, L3 is -3- to 14-membered (heterocycloalkylenyl)p- or -(C3- Ci4)cycloalkylenyl-; wherein cycloalkylenyl and heterocycloalkylenyl are independently unsubstituted or substituted with 1, 2 or 3 (Ci-Ce)alkyl, halo, hydroxy or halo(Ci-Ce)alkyl groups.

[0137] In one embodiment, L3 is -5- to 6-membered (heterocycloalkylenyl)p- or -(C5- C6)cycloalkylenyl-; wherein cycloalkylenyl and heterocycloalkylenyl are independently unsubstituted or substituted with 1, 2 or 3 (Ci-Ce)alkyl, halo, hydroxy or halo(Ci-Ce)alkyl groups.

[0138] In one embodiment, L3 is selected from wherein * mark indicates point of attachment to M.

[0139] In one embodiment, L3 is selected from ; wherein * mark indicates point of attachment to M. 0+ es point of attachment to M. In one embodiment, L3 is ; wherein * mark indicates point of attachment to M.

[0140] In one embodiment, Ryat each occurrence is independently selected from (Ci-Ce)alkyl, halo, hydroxy or halo(Ci-Ce)alkyl; or two Ryattached on the same carbon atom to form an oxo(=O) group.

[0141] In one embodiment, Ryat each occurrence is independently selected from (Ci-Ce)alkyl, halo or hydroxy.

[0142] In one embodiment, two Ryattached on the same carbon atom to form an oxo(=O) group.

[0143] In one embodiment, Ryis an oxo(=O).

[0144] In one embodiment, Ryis an alkyl.

[0145] In one embodiment, Ryis a halo.

[0146] In one embodiment, Ryiat each occurrence is independently selected from (Ci-Ce)alkyl, halo, hydroxy or halo(Ci-Ce)alkyl; or two Ryiattached on the same carbon atom to form an oxo(=O) group.

[0147] In one embodiment, Ryiat each occurrence is independently selected from (Ci-Ce)alkyl and halo.

[0148] In one embodiment, Ryiis (Ci-Ce)alkyl.

[0149] In one embodiment, two Ryiattached on the same carbon atom to form an oxo(=O) group.

[0150] In one embodiment, M is a group of formula of Ml, M2, M3, M4, M5 M6 or M7:

[0151]

[0152] In one embodiment, M is a group of formula of Ml, M2, M3, M4, M5 M6 or M7:

[0153] In one embodiment, M is a group of formula of Ml: wherein, X4, X5 and Xe are independently N, C or CH;

[0154] Zi, Z2 and Z3 are independently selected from NH, N, C or CH;

[0155] R3 at each occurrence is independently hydrogen, halo, halo(Ci-Ce)alkyl or (Ci- Ce)alkyl; and R.4 at each occurrence is hydrogen or (Ci-Ce)alkyl; or two R4 attached on the same carbon to form an oxo(=O) group.

[0156] In one embodiment, M is a represented by a formula M2:

[0157] Wherein,

[0158] X and X’ are independently selected from CH, C or N;

[0159] Y is selected from bond, -NH-, -C(O)-NH-*, -CH2- or -O-; wherein asterisk mark indicates the point of attachment with piperidinedione ring, and

[0160] Rs at each occurrence are independently hydrogen, halo, halo(Ci-Ce)alkyl or (Ci- Ce)alkyl.

[0161] In one embodiment, M is represented by a formula M3:

[0162] Wherein,

[0163] Yi is N, NH, O, CH or CH2;

[0164] Y2is N or CH;

[0165] Y3is NH, C(O) or CH2;

[0166] Y’ is selected from bond, -NH-, -C(O)-NH-*, -CH2- or -O-; wherein asterisk mark indicates the point of attachment with piperidinedione ring;

[0167] X’ is CH, C or N; and

[0168] Rs at each occurrence are independently hydrogen, halo, halo(Ci-Ce)alkyl or (Ci- Ce)alkyl.

[0169] In one embodiment, M is represented by a formula M3: wherein,

[0170] Yi is N, NH, O, CH or CH2;

[0171] Y2is N or CH;

[0172] Y3is NH, C(O) or CH2;

[0173] Y’ is selected from bond, -NH-, -C(O)-NH-*, -CH2- or -O-; wherein asterisk mark indicates the point of attachment with piperidinedione ring; and

[0174] Re at each occurrence is independently hydrogen, halo, halo(Ci-Ce)alkyl or (Ci- Ce)alkyl.

[0175] In one embodiment, M is represented by a formula M4: wherein,

[0176] Yi is N, NH, O, CH or CH2;

[0177] Y2is N or CH;

[0178] Y3is NH, C(O) or CH2;

[0179] Y’ is selected from bond, -NH-, -C(O)-NH-*, -CH2- or -O-; wherein asterisk mark indicates the point of attachment with piperidinedione ring; and

[0180] Rs at each occurrence is independently hydrogen, halo, halo(Ci-Ce)alkyl or (Ci- Ce)alkyl.

[0181] In one embodiment, M is represented by a formula M5: wherein,

[0182] Yi is N, NH, 0, CH or CH2;

[0183] Y2is N or CH;

[0184] Y3is NH, C(0) or CH2;

[0185] Y’ is selected from bond, -NH-, -C(O)-NH-*, -CH2- or -O-; wherein asterisk mark indicates the point of attachment with piperidinedione ring; and

[0186] Re at each occurrence is independently hydrogen, halo, halo(Ci-Ce)alkyl or (Ci- Ce)alkyl;

[0187] X7, Xs and X9 are independently N, C or CH; wherein at least any one of X7, Xs or X9 is N.

[0188] In one embodiment, M is represented by a formula M6:

[0189] Wherein,

[0190] X10, Xu, Xi2and X13 are independently CH, C or N;

[0191] Z4 and Z5 are independently CH, CH2, N or NH;

[0192] R3and Re at each occurrence are independently hydrogen, halo, halo(Ci-Ce)alkyl or (Ci-Ce)alkyl; and

[0193] R4 at each occurrence is hydrogen or (Ci-Ce)alkyl; or two R4 attached on the same carbon to form an oxo(=O) group.

[0194] In one embodiment, M is represented by a formula M7:

[0195] Wherein,

[0196] Xio, Xu, X12 and Xu are independently CH, C or N;

[0197] Z4 and Z5 are independently CH, CH2, N or NH; R3 and Re at each occurrence are independently hydrogen, halo, halo(Ci-Ce)alkyl or

[0198] (Ci-Ce)alkyl; and

[0199] R4 at each occurrence is hydrogen or (Ci-Ce)alkyl; or two R4 attached on the same carbon to form an oxo(=O) group.

[0200] In one embodiment, M is selected from

[0201]

[0202] In one embodiment, R3 and Re at each occurrence are independently hydrogen, halo or (Ci-Ce)alkyl.

[0203] In one embodiment, R3 and Rs at each occurrence are independently halo or (Ci- Ce)alkyl.

[0204] In one embodiment, R3 and Rs at each occurrence are independently (Ci-Ce)alkyl.

[0205] In one embodiment, wherein R4 is (Ci-Ce)alkyl; or two R4 attached on the same carbon to form an oxo(=O) group. In one embodiment, wherein two R4 attached on the same carbon to form an oxo(=O) group.

[0206] In one embodiment, ‘m’ and ‘q’ are independently an integer of 1, 2 or 3.

[0207] In one embodiment, ‘b’ is integer of 0, 1, 2 or 3.

[0208] In one embodiment, ‘n’ is integer of 1, 2, 3 or 4.

[0209] In one embodiment, ‘n’ is integer of 1, 2 or 3.

[0210] In one embodiment, - indicates a single bond.

[0211] In one embodiment, - indicates a double bond.

[0212] In one embodiment, the present invention provides a compound of formula (IA), or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.

[0213] In one embodiment, Ri at each occurrence, is halo, (Ci-Ce)alkyl, (Ci-Ce)alkoxy or hydroxy.

[0214] In one embodiment, Ri is hydrogen or halo.

[0215] In one embodiment, R2 at each occurrence is hydrogen, (Ci-Ce)alkyl or halo(Ci-C- e)alkyl.

[0216] In one embodiment, R2 at each occurrence is hydrogen or (Ci-Ce)alkyl.

[0217] In one embodiment, two R2 attached on the same carbon atom to form an oxo(=O) group.

[0218] In one embodiment, Xi and X2 is N.

[0219] In one embodiment, Xi and X2 is CH.

[0220] In one embodiment, ring A is unsubstituted or substituted 6- to 10-membered arylenyl.

[0221] In one embodiment, ring A is unsubstituted or substituted phenylenyl.

[0222] In one embodiment, ring A is unsubstituted or substituted 5- to 10-membered heteroarylenyl. wherein * mark indicates point of attachment to L.

[0223] In one embodiment, ring A is selected from wherein * mark indicates point of attachment to L.

[0224] In one embodiment ring wherein * mark indicates point of attachment to L.

[0225] In one embodiment, ring

[0226] In one embodiment, Li is a bond, 3- to 14-membered heterocycloalkylenyl, *-O-(3- to

[0227] 14-membered) heterocycloalkylenyl- or -(C3-Ci4)cycloalkylenyl-; wherein heterocycloalkylenyl and cycloalkylenyl are independently unsubstituted or substituted with 1, 2 or 3 (Ci-Ce)alkyl, halo, hydroxy or halo(Ci-Ce)alkyl groups; wherein asterisk mark indicates the point of attachment with ring A.

[0228] In one embodiment, Li is a -3- to 14-membered heterocycloalkylenyl-; wherein heterocycloalkylenyl is unsubstituted or substituted with 1, 2 or 3 (Ci-Ce)alkyl, halo or hydroxy. attachment to ring A.

[0229] In one embodiment, Li is selected from ; wherein * mark indicates point of attachment to A.

[0230] In one embodiment, Li is ; wherein * mark indicates point of attachment to A.

[0231] In one embodiment, L2 is a bond, *-C(O)-CH2-, *-C(O)-N(CH3)- or -CH2-; wherein asterisk mark indicates the point of attachment with Li.

[0232] In one embodiment, L2 is a bond.

[0233] In one embodiment, L2 is a bond or -CH2-.

[0234] In one embodiment, L3 is -5- to 6-membered (heterocycloalkylenyl)p- or -(C5- C6)cycloalkylenyl-; wherein cycloalkylenyl and heterocycloalkylenyl are independently unsubstituted or substituted with 1, 2 or 3 halo, (Ci-Ce)alkyl or hydroxy. X 0X

[0235] In one embodiment, L3 is selected from wherein * mark indicates point of attachment to M.

[0236] mark indicates point of attachment to M.

[0237] In one embodiment, Ryis (Ci-Ce)alkyl, halo, hydroxy or halo(Ci-Ce)alkyl; or any of two Ryattached on the same carbon atom to form an oxo(=O) group.

[0238] In one embodiment, Ryis (Ci-Ce)alkyl or halo; or any of two Ryattached on the same carbon atom to form an oxo(=O) group.

[0239] In one embodiment, two Ryattached on the same carbon atom to form an oxo(=O) group.

[0240] In one embodiment, Ryis (Ci-Ce)alkyl.

[0241] In one embodiment, Ryis halo.

[0242] In one embodiment, Ryiis (Ci-Ce)alkyl, hydroxy or halo; or any of two Ryiattached on the same carbon atom to form an oxo(=O) group.

[0243] In one embodiment, two Ryiattached on the same carbon atom to form an oxo(=O) group.

[0244] In one embodiment, Ryiis (Ci-Ce)alkyl.

[0245] In one embodiment, Ryiis halo. 1

[0246] In one embodiment, the present invention provides a compound of formula (IB), or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.

[0247] In one embodiment, Ri at each occurrence, is halo, (Ci-Ce)alkyl, (Ci-Ce)alkoxy or hydroxy. In one embodiment, Ri is hydrogen or halo.

[0248] In one embodiment, X2 is CH or N.

[0249] In one embodiment, X2 is CH.

[0250] In one embodiment, X2 is N.

[0251] wherein * mark indicates point of attachment to L.

[0252] In one embodiment, ring A is selected from wherein * mark indicates point of attachment to L.

[0253] In one embodiment ring wherein * mark indicates point of attachment to L. In one embodiment, Li is a -3- to 14-membered heterocycloalkylenyl-; wherein heterocycloalkylenyl is unsubstituted or substituted with 1, 2 or 3 (Ci-Ce)alkyl, halo or hydroxy. attachment to A. In one embodiment, Li is selected from ; wherein * mark indicates point of attachment to ring A.

[0254] In one embodiment, Li is selected from wherein * mark indicates point of attachment to ring A.

[0255] In one embodiment, Li ; wherein * mark indicates point of attachment to ring A.

[0256] In one embodiment, L2 is a bond, *-C(O)-CH2-, *-C(0)-N(CH3)- or -CH2-; wherein asterisk mark indicates the point of attachment with Li.

[0257] In one embodiment, L2 is a bond or -CH2-.

[0258] In one embodiment, L2 is a bond.

[0259] In one embodiment, L2 is -CH2-.

[0260] In one embodiment, L3 is 6-membered heterocycloalkylenyl or (C5-Ce)membered cycloalkylenyl.

[0261] In one embodiment, L3 is selected from wherein * mark indicates point of attachment to M. In one embodiment, L3 is selected from , , wherein * mark indicates point of attachment to M.

[0262] In one embodiment, Ryis (Ci-Ce)alkyl, halo, hydroxy or halo(Ci-Ce)alkyl; or any of two Ryattached on the same carbon atom to form an oxo(=O) group. In one embodiment, Ryis (Ci-Ce)alkyl or halo; or any of two Ryattached on the same carbon atom to form an oxo(=O) group.

[0263] In one embodiment, two Ryattached on the same carbon atom form an oxo(=O) group.

[0264] In one embodiment, Ryis (Ci-Ce)alkyl.

[0265] In one embodiment, Ryis halo. In one embodiment, Ryiis (Ci-Ce)alkyl, hydroxy or halo; or any of two Ryiattached on the same carbon atom to form an oxo(=O) group.

[0266] In one embodiment, two Ryiattached on the same carbon atom form an oxo(=O) group.

[0267] In one embodiment, Ryiis (Ci-Ce)alkyl. In one embodiment, Ryiis halo.

[0268] In one embodiment, Re is hydrogen, halo or (Ci-Ce)alkyl.

[0269] In one embodiment, Re is hydrogen or halo.

[0270] In one embodiment, Re is (Ci-Ce) alkyl. In one embodiment, Re is hydrogen.

[0271] In one embodiment, X is CH, C or N.

[0272] In one embodiment, Y is a bond, NH, CH2 or O.

[0273] In one embodiment, the present invention provides a compound of formula (IC), or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.

[0274] In one embodiment, p, q, r and s are independently selected from CH, C or N.

[0275] In one embodiment, Ri at each occurrence is halo, (Ci-Ce)alkyl, (Ci-Ce)alkoxy or hydroxy.

[0276] In one embodiment, Ri is hydrogen or halo. In one embodiment, X2 is CH or N.

[0277] In one embodiment, X2 is CH.

[0278] In one embodiment, X2 is N. wherein * mark indicates point of attachment to L.

[0279] In one embodiment, ring A is selected from wherein * mark indicates point of attachment to L.

[0280] In one embodiment ring wherein * mark indicates point of attachment to L.

[0281]

[0282] In one embodiment, the present invention provides a compound of formula (ID), or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.

[0283] In one embodiment, p, q, r and s are independently selected from CH, C or N.

[0284] In one embodiment, Ri at each occurrence is halo, (Ci-Ce)alkyl, (Ci-Ce)alkoxy or hydroxy.

[0285] In one embodiment, Ri is hydrogen or halo. In one embodiment, X2 is CH or N.

[0286] In one embodiment, X2 is CH.

[0287] In one embodiment, X2 is N. wherein * mark indicates point of attachment to L. In one embodiment, ring A is selected from wherein * mark indicates point of attachment to L.

[0288] In one embodiment, the present invention provides a compound of formula (IE), or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.

[0289] In one embodiment, Ri at each occurrence, is halo, (Ci-Ce)alkyl, (Ci-Ce)alkoxy or hydroxy.

[0290] In one embodiment, Ri is hydrogen or halo. In one embodiment, Xi and X2 are independently CH or N.

[0291] In one embodiment, Xi and X2 are independently CH.

[0292] In one embodiment, Xi and X2 are independently N. wherein * mark indicates point of attachment to L. In one embodiment, ring A is selected from wherein * mark indicates point of attachment to L.

[0293] In one embodiment, the present invention provides a compound of formula (IF), or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof. In one embodiment, Ri at each occurrence is halo, (Ci-Ce)alkyl, (Ci-Ce)alkoxy or hydroxy.

[0294] In one embodiment, Ri at each occurrence is hydrogen or halo.

[0295] In one embodiment, Xi and X2 are independently CH or N.

[0296] In one embodiment, Xi and X2 are independently CH. In one embodiment, Xi and X2 are independently N.

[0297] wherein * mark indicates point of attachment to L.

[0298] In one embodiment, ring A is selected from wherein * mark indicates point of attachment to L.

[0299] In one embodiment, Li is a -3- to 14-membered heterocycloalkylenyl-; wherein heterocycloalkylenyl is unsubstituted or substituted with 1, 2 or 3 (Ci-Ce)alkyl, halo or hydroxy.

[0300] In one embodiment, Li is selected from wherein * mark indicates point of attachment to A.

[0301] In one embodiment, Li is selected from In one embodiment, Li is selected from • -NO wherein * mark indicates point of attachment to ring A.

[0302] In one embodiment, Li is ; wherein * mark indicates point of attachment to ring A.

[0303] In one embodiment, L2 is a bond, *-C(O)-CH2-, *-C(0)-N(CH3)- or -CH2-; wherein asterisk mark indicates the point of attachment with Li.

[0304] In one embodiment, L2 is a bond or -CH2-.

[0305] In one embodiment, L2 is a bond.

[0306] In one embodiment, L2 is -CH2-.

[0307] In one embodiment, L3 is -5- to 6-membered heterocycloalkylenyl or -(C5-

[0308] Ce)membered cycloalkylenyl-.

[0309] In one embodiment, L3 is selected from wherein * mark indicates point of attachment to M.

[0310] In one embodiment, L3 is selected from wherein * mark indicates point of attachment to M. In one embodiment, ; wherein * mark indicates point of attachment to M.

[0311] In one embodiment, X7, Xs and X9 are independently N or C; wherein at least one of X7, Xs or X9is N. In one embodiment, Re is independently hydrogen, halo, haloalkyl or alkyl.

[0312] In one embodiment, Yi is N, NH, O, CH or CH2.

[0313] In one embodiment, Y2 is N or CH.

[0314] In one embodiment, Y3 is NH, C(O) or CH2.

[0315] In one embodiment, the present invention provides a compound of formula (IG), or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.

[0316]

[0317] In one embodiment, the present invention provides a compound of formula (IH), or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.

[0318] In one embodiment, the present invention provides a compound of formula (IJ),

[0319] or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof. In one embodiment, the present invention provides a compound or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof; wherein the compound is selected from:

[0320]

[0321] or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.

[0322] PHARMACEUTICAL COMPOSITIONS

[0323] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.

[0324] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, and a pharmaceutically acceptable carrier or excipient.

[0325] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, and at least one pharmaceutically acceptable carrier or pharmaceutically acceptable excipients. In one embodiment, the pharmaceutically acceptable excipients (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.

[0326] In one embodiment, liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

[0327] Injectable preparations, for example, sterile injectable aqueous, or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0328] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0329] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this application with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatine capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0330] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, draggers, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, including but not limited to tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0331] Dosage forms for topical or transdermal administration of a compound of this application include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this application.

[0332] The ointments, pastes, creams and gels may contain, in addition to an active compound of this application, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0333] Powders and sprays can contain, in addition to the compounds of this application, excipients such as lactose, talc, silicic acid, aluminium hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.

[0334] Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0335] Administration of the disclosed compounds and pharmaceutical compositions can be accomplished via any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral, intravenous, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes.

[0336] Depending on the intended mode of administration, the disclosed compounds or pharmaceutical compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices. Likewise, they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form and all using forms well known to those skilled in the pharmaceutical arts.

[0337] Illustrative pharmaceutical compositions are tablets and gelatine capsules comprising one or more compounds of the present disclosure and a pharmaceutically acceptable carrier, such as, but not limited to, a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and / or polyethylene glycol; for tablets also; c) a binder, e.g., magnesium aluminium silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes and / or polyvinylpyrrolidone, if desired; d) a disintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures; e) absorbent, colorant, flavorant and sweetener; f) an emulsifier or dispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifier; and / or g) an agent that enhances absorption of the compound such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, PEG200.

[0338] Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc. For example, one or more disclosed compound is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds. One or more disclosed compounds or compositions can be delivered by parental administration. The parental injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.

[0339] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I), for use in degrading a target protein in a subject, wherein the target protein is SMARCA2 and / or SMARCA4.

[0340] In one embodiment, the subject is afflicted with a disease or disorder dependent upon SMARCA2 and / or SMARCA4, wherein the disease or disorder is cancer.

[0341] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, for use in treating or preventing cancers selected from the group consisting of hematologic cancers, lung cancer, non-small cell lung cancer, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic leukemia, promyelocytic leukemia, acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, granulocytic leukemia, chronic granulocytic leukemia chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes, dysplasias, metaplasias, embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, head and neck cancer, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, liver cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma, Hodgkin's lymphoma and nonHodgkin's lymphoma, Burkitt's lymphoma, malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, malignant rhabdoid tumor (MRT), rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors, carcinomas, sarcomas, small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer or Wilms' tumor.

[0342] In one embodiment the cancer is selected from the hematologic cancers, lung cancer, acoustic neuroma, astrocytoma, bladder cancer, brain cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, craniopharyngioma, dysplasias and metaplasias, endometrial cancer, ependymoma, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, head and neck cancer, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leukemia, liposarcoma, liver cancer, lymphoma, malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, neuroblastoma, non-small cell lung cancer, oligodendroglioma, oral cancer, ovarian cancer, pancreatic cancer, pinealoma, polycythemia vera, prostate cancer, rectal cancer, retinoblastoma, sarcoma, seminoma, skin cancer, small cell lung cancer, carcinoma, stomach cancer, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor.

[0343] In one embodiment, the leukemia is selected from acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, monocytic leukemia, myeloblastic leukemia, myelomonocytic leukemia, promyelocytic leukemia, acute T-cell leukemia, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, granulocytic leukemia, chronic myelogenous leukemia, erythroleukemia, and myelogenous leukemia.

[0344] In one embodiment, the lymphoma is selected from diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, and Burkitt's lymphoma. In one embodiment, the angiosarcoma, chondrosarcoma, chordoma, endotheliosarcoma, fibrosarcoma, leiomyosarcoma, liposarcoma, lymphagioendotheliosarcoma, lymphangiosarcoma, myxosarcoma, osteogenic sarcoma, malignant rhabdoid tumor (MRT), rhabdomyosarcoma, and synovioma.

[0345] In one embodiment, the carcinoma is selected from adenocarcinoma, basal cell carcinoma, bile duct carcinoma, bronchogenic carcinoma, choriocarcinoma, cystadenocarcinoma, embryonal carcinoma, epithelial carcinoma, medullary carcinoma, NUT midline carcinoma (NMC), papillary adenocarcinomas, papillary carcinoma, renal cell carcinoma, sebaceous gland carcinoma, squamous cell carcinoma, and sweat gland carcinoma.

[0346] In one embodiment, the present invention provides a pharmaceutical composition for use in degrading a target protein in a subject, wherein the target protein is SMARCA2 and / or SMARCA4.

[0347] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof for treating diseases or conditions or disorders that are dependent upon or mediated by SMARCA2 and / or SMARCA4.

[0348] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof for treating a disease that has altered SMARCA2 / 4 including mutations and overexpression.

[0349] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof for treating a disease wherein degradation of SMARCA2 / 4 proteins provides a benefit, e.g., cancer.

[0350] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof for treating a disease dependent upon altered activity of SWI / SNF complex with or without chromatic remodeling activities.

[0351] METHODS and / or USES:

[0352] In one embodiment, the present invention provides a method of degrading a target protein in a subject comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.

[0353] In one embodiment, the present invention provides a method of degrading a target protein, wherein target protein is SMARCA2 and / or SMARCA4.

[0354] In one embodiment, the present invention provides, a method of treating or delaying progression of a disease or disorder dependent upon SMARCA2 and / or SMARCA4 in a subject comprising administering to the subject, in need thereof, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.

[0355] In one embodiment, the present invention provides a method for treating diseases or disorders dependent upon at least one of SMARCA2 and SMARCA4 in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.

[0356] In one embodiment, diseases or disorders dependent upon SMARCA2 and / or SMARCA4, include cancer.

[0357] In one embodiment, the present invention provides a method of inhibiting tumor growth in a subject afflicted with cancer comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof to the subject, in need thereof.

[0358] In one embodiment, cancer is selected from hematologic cancers, lung cancer, non-small cell lung cancer, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic leukemia, promyelocytic leukemia, acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, granulocytic leukemia, chronic granulocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes, dysplasias, metaplasias, embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, head and neck cancer, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, liver cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma, Hodgkin's lymphoma, nonHodgkin's lymphoma, Burkitt's lymphoma, malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, malignant rhabdoid tumor (MRT), rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors, carcinomas, sarcomas, small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer or Wilms' tumor.

[0359] In one embodiment the cancer is selected from the hematologic cancers, lung cancer, acoustic neuroma, astrocytoma, bladder cancer, brain cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, craniopharyngioma, dysplasias and metaplasias, endometrial cancer, ependymoma, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, head and neck cancer, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leukemia, liposarcoma, liver cancer, lymphoma, malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, neuroblastoma, non-small cell lung cancer, oligodendroglioma, oral cancer, ovarian cancer, pancreatic cancer, pinealoma, polycythemia vera, prostate cancer, rectal cancer, retinoblastoma, sarcoma, seminoma, skin cancer, small cell lung cancer, carcinoma, stomach cancer, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor.

[0360] In one embodiment, the leukemia is selected from acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, monocytic leukemia, myeloblastic leukemia, myelomonocytic leukemia, promyelocytic leukemia, acute T-cell leukemia, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, granulocytic leukemia, chronic myelogenous leukemia, erythroleukemia, and myelogenous leukemia.

[0361] In one embodiment, the lymphoma is selected from diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, and Burkitt's lymphoma.

[0362] In one embodiment, the sarcoma is selected from angiosarcoma, chondrosarcoma, chordoma, endotheliosarcoma, fibrosarcoma, leiomyosarcoma, liposarcoma, lymphagioendotheliosarcoma, lymphangiosarcoma, myxosarcoma, osteogenic sarcoma, malignant rhabdoid tumor (MRT), rhabdomyosarcoma, and synovioma.

[0363] In one embodiment, the carcinoma is selected from adenocarcinoma, basal cell carcinoma, bile duct carcinoma, bronchogenic carcinoma, choriocarcinoma, cystadenocarcinoma, embryonal carcinoma, epithelial carcinoma, medullary carcinoma, NUT midline carcinoma (NMC), papillary adenocarcinomas, papillary carcinoma, renal cell carcinoma, sebaceous gland carcinoma, squamous cell carcinoma, and sweat gland carcinoma.

[0364] In one embodiment, the cancer dependent upon SMARCA2 and / or SMARCA4 is lung cancer such as NSCLC, i.e., non-small cell lung cancer.

[0365] In one embodiment, the cancer dependent upon SMARCA2 and / or SMARCA4 is melanoma.

[0366] In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, for use as a medicament.

[0367] In one embodiment, the present invention provides, a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, for use in the treatment of a disease or disorder dependent upon SMARCA2 and / or SMARCA4.

[0368] In one embodiment, a disease or disorder dependent upon SMARCA2 and / or SMARCA4 is cancer.

[0369] In one embodiment, the present invention provides use of a compound of formula (I) or a pharmaceutical acceptable salt or a stereoisomer or a tautomer thereof, in the manufacture of a medicament for the treatment of a disease or disorder dependent upon SMARCA2 and / or SMARCA4. In one embodiment, the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, for use in the treatment of a disease or disorder dependent upon SMARCA2 and / or SMARCA4, wherein the disease or disorder dependent upon SMARCA2 and / or SMARCA4 is cancer.

[0370] In one embodiment, the disease or disorder is cancer selected from hematologic cancers, lung cancer, non-small cell lung cancer, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic leukemia, promyelocytic leukemia, acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, granulocytic leukemia, chronic granulocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes, dysplasias, metaplasias, embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, head and neck cancer, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, liver cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma, Hodgkin's lymphoma, non -Hodgkin's, Burkitt's lymphoma, malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, malignant rhabdoid tumor (MRT), rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors, carcinomas, sarcomas, small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer or Wilms' tumor. In one embodiment the cancer is selected from the hematologic cancers, lung cancer, acoustic neuroma, astrocytoma, bladder cancer, brain cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, craniopharyngioma, dysplasias and metaplasias, endometrial cancer, ependymoma, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, head and neck cancer, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leukemia, liposarcoma, liver cancer, lymphoma, malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, neuroblastoma, non-small cell lung cancer, oligodendroglioma, oral cancer, ovarian cancer, pancreatic cancer, pinealoma, polycythemia vera, prostate cancer, rectal cancer, retinoblastoma, sarcoma, seminoma, skin cancer, small cell lung cancer, carcinoma, stomach cancer, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor.

[0371] In one embodiment, the leukemia is selected from acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, monocytic leukemia, myeloblastic leukemia, myelomonocytic leukemia, promyelocytic leukemia, acute T-cell leukemia, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, granulocytic leukemia, chronic myelogenous leukemia, erythroleukemia, and myelogenous leukemia.

[0372] In one embodiment, the lymphoma is selected from diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, and Burkitt's lymphoma.

[0373] In one embodiment, the sarcoma is selected from angiosarcoma, chondrosarcoma, chordoma, endotheliosarcoma, fibrosarcoma, leiomyosarcoma, liposarcoma, lymphagioendotheliosarcoma, lymphangiosarcoma, myxosarcoma, osteogenic sarcoma, malignant rhabdoid tumor (MRT), rhabdomyosarcoma, and synovioma.

[0374] In one embodiment, the carcinoma is selected from adenocarcinoma, basal cell carcinoma, bile duct carcinoma, bronchogenic carcinoma, choriocarcinoma, cystadenocarcinoma, embryonal carcinoma, epithelial carcinoma, medullary carcinoma, NUT midline carcinoma (NMC), papillary adenocarcinomas, papillary carcinoma, renal cell carcinoma, sebaceous gland carcinoma, squamous cell carcinoma, and sweat gland carcinoma. In one embodiment, SMARCA2 refers to SWI / SNF related BAF chromatin remodeling complex subunit ATPase 2.

[0375] In one embodiment, SMARCA4 refers to SWI / SNF related BAF chromatin remodeling complex subunit ATPase 4.

[0376] In one embodiment, the present invention provides, a preparation of compound of formula (I).

[0377] Definitions

[0378] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in art to which the subject matter herein belongs. As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated in order to facilitate the understanding of the present invention.

[0379] The singular forms “a”, “an” and “the” encompass plural references unless the context clearly indicates otherwise.

[0380] As used herein, the terms “optional” or “optionally” mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not. For example, “optionally substituted alkyl” refers to an event or circumstance where the alkyl is substituted as well as the event or circumstance where the alkyl is not substituted.

[0381] The term “substituted” refers to moieties having substituents replacing hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched, and unbranched, carbocyclic, and heterocyclic, aromatic, and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl or an acyl), a thiocarbonyl (such as a thioester, a thioacetate or a thioformate), an alkoxyl, an oxo, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heteroaryl, a heterocyclyl, an aralkyl or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate.

[0382] As used herein, the term “alkyl” refers to saturated aliphatic groups, including but not limited to C1-C10 straight-chain alkyl groups or C3-C10 branched-chain alkyl groups. Preferably, “alkyl” group refers to Ci-Ce straight-chain alkyl groups or C3-C6 branched-chain alkyl groups. In one embodiment, the “alkyl” group refers to C1-C4 straight-chain alkyl groups. Examples of “alkyl” include, but are not limited to, methyl, ethyl, 1 -propyl, 2-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 1-hexyl, 2- hexyl, 3 -hexyl, 1 -heptyl, 2-heptyl, 3 -heptyl, 4-heptyl, 1 -octyl, 2-octyl, 3 -octyl and 4-octyl. Accordingly, examples of “alkylenyl” include, but are not limited to, -CH2-, -CH2CH2-, - CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH(CH3)CH2CH2CH2- and -CH2CH(CH3)CH2CH2-, The “alkyl” group may be optionally substituted.

[0383] The term “halo” is used herein interchangeably with the term “halogen” to mean F, Cl, Br or I atoms.

[0384] As used herein, the term “haloalkyl” refers to alkyl substituted with one or more halogen atoms, wherein the halo and alkyl groups are as defined above. In one embodiment, haloalkyl contains (Ci-Ce)alkyl and preferably (Ci-C4)alkyl. Examples of “haloalkyl” include but are not limited to fluoromethyl, difluor omethyl, chloromethyl, trifluoromethyl and 2,2,2- trifluoroethyl.

[0385] As used herein, the term “cycloalkylenyl” refers to a divalent cycloalkyl group as defined herein. The term “cycloalkyl” 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 and cycloheptyl. A cycloalkyl may alternatively be polycyclic or contain more than one ring. Examples of polycyclic cycloalkyls include bridged, fused and spirocyclic carbocyclyls. Accordingly, examples of ‘cycloalkylenyl’ include, but not limited to, cyclopropylenyl, cyclobutylenyl, cyclopentylenyl, cyclohexylenyl and cycloheptylenyl.

[0386] As used herein, the term “heterocycloalkylenyl” refers to a divalent heterocycloalkyl group as defined herein. The term “heterocycloalkyl” refers to a non-aromatic, saturated or partially saturated, bridged bicyclic, spirocyclic, monocyclic or polycyclic ring system of 3 to 15 member, unless the ring size is specifically mentioned, having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O)2, NH or C(O) with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen and sulfur. The term “heterocycloalkyl” or “heterocyclyl” also refers to the bridged bicyclic ring system having at least one heteroatom or hetero group selected from O, N, S, S(O), S(O)2, NH and C(O). Examples of “heterocycloalkyl” include, but not limited to, azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, dihydropyridinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, dioxidothiomorpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, indolinyl, indolinylmethyl, isoindolinyl, oxoisoindolinyl, dioxoisoindolinyl, aza-bicyclooctanyl, diazabicyclooctanyl, azocinyl, chromanyl, isochromanyl, xanthenyl and 2-oxa-6-azaspiro[3.3]heptanyl. Accordingly, examples of ‘heterocycloalkylenyl’ include, but not limited to, azetidinyl enyl, oxetanylenyl, pyrrolidinylenyl, piperidinylenyl and piperazinylenyl. Attachment of a heterocyclyl substituent can occur via either a carbon atom or a heteroatom.

[0387] As used herein, the term “heteroarylenyl” refers to a divalent heteroaryl group as defined 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, unless the ring size is specifically mentioned. At least one of the ring atoms is a heteroatom (i.e., O, N or S), with the remaining ring atoms / groups being independently selected from C, N, O or S. A heteroaryl may be a single-ring (monocyclic) or multiple rings (bicyclic, tricyclic or polycyclic) fused together or linked covalently. Preferably, “heteroaryl” is a 5- to 6-membered ring, unless the ring size is specifically mentioned. The rings may contain from 1 to 4 additional heteroatoms selected from N, O and S, wherein the N atom is optionally quartemized. Any suitable ring position of the heteroaryl moiety may be covalently linked to the defined chemical structure. Examples of “heteroaryl” include but not limited to furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, IH-tetrazolyl, oxadiazolyl, triazolyl, pyridyl (pyridinyl), 3 -fluoropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, benzotriazinyl, phthalazinyl, thianthrene, dibenzofuranyl, dibenzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purinyl, pteridinyl, 9H- carbazolyl, a-carbolinyl, indolizinyl, benzoisothiazolyl, benzoxazolyl, pyrrol opyridyl, furopyridinyl, purinyl, benzothiadiazolyl, benzooxadiazolyl, benzotri azolyl, benzotriadiazolyl, carbazolyl, dibenzothienyl, acridinyl and the like. Accordingly, examples of ‘ heteroaryl enyl’ include, but not limited to, furanylenyl, thienylenyl, pyrrolylenyl, pyrazolylenyl, imidazolylenyl, oxazolylenyl, isoxazolylenyl, thiazolyl enyl, isothiazolyl enyl, 1H- tetrazolylenyl, oxadi azolyl enyl, tri azolyl enyl, pyridylenyl (pyridinylenyl), pyrimidinylenyl, pyrazinylenyl, pyridazinylenyl, 1,2,3-triazinylenyl, 1,2,4-triazinylenyl and 1,3,5-triazinylenyl. Heteroaryl group may be optionally further substituted.

[0388] A heterocyclyl group can be heterocycloalkyl or heteroaryl groups optionally substituted with one or more suitable groups by aforesaid groups.

[0389] As used herein, the term “hydroxy” or “hydroxyl” alone or in combination with other term(s) means -OH.

[0390] As used herein, the term “oxo” refers to =0 group.

[0391] As used herein, the term “alkoxy” refers to the group -O-alkyl, where alkyl groups are as defined above. Exemplary C1-C10 alkoxy group include but are not limited to methoxy, ethoxy, n-propoxy, n-butoxy or t-butoxy. An alkoxy group can be optionally substituted with one or more suitable groups.

[0392] The term “aryl”, as employed herein as such or as part of another group, refers to a monocyclic, bicyclic or polycyclic aromatic hydrocarbon ring system of 6 to 14 carbon atoms. Examples of aryl groups include, but are not limited to phenyl, naphthyl, biphenyl, anthryl, biphenylenyl and acenap hthyl. Preferred aryl group is phenyl.

[0393] As used herein, the term “arylenyl” refers to a divalent aryl group as defined herein. The term “aryl”, as employed herein as such or as part of another group, refers to a monocyclic, bicyclic or polycyclic aromatic hydrocarbon ring system of 6 to 14 carbon atoms. Examples of aryl groups include, but are not limited to phenyl, naphthyl, biphenyl, anthryl, biphenylenyl and acenaphthyl.

[0394] The term “heteroatom” as used herein designates a sulfur, nitrogen or oxygen atom.

[0395] As used herein, the term 'compound(s)' comprise(s) the compound(s) disclosed in the present invention.

[0396] The term “salt / salts” refers to the salts derived from appropriate bases include alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., magnesium), ammonium and N+(CI-4 alkyl)4 salts.

[0397] 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.

[0398] As used herein, the term “or” means “and / or” unless stated otherwise. As used herein, the term “including” as well as other forms, such as “include”, “includes” and “included” is not limiting.

[0399] 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.

[0400] As used herein, the term “pharmaceutical composition” refers to a composition(s) containing a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0401] The pharmaceutical composition(s) usually contain(s) about 1% to 99%, for example, about 5% to 75% or from about 10% to about 30% by weight of the compound of formula (I) or (II) or pharmaceutically acceptable salts thereof. The amount of the compound of formula (I) or pharmaceutically acceptable salts thereof in the pharmaceutical composition(s) can range from about 1 mg to about 1000 mg or from about 2.5 mg to about 500 mg or from about 5 mg to about 250 mg or in any range falling within the broader range of 1 mg to 1000 mg or higher or lower than the aforementioned range.

[0402] The term “tautomer” refers to compounds in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged. Compounds of the present invention, free form and salts thereof, may exist in multiple tautomeric forms. It is understood that all tautomeric forms, insofar as they may exist, are included within the invention. For example, pyridine or pyridyl can be optionally substituted by oxo to form a respective pyridone or pyridon-yl and may include its tautomeric form such as a respective hydroxy -pyridine or hydroxy-pyridyl, provided said tautomeric form may be obtainable.

[0403] As used herein, “pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, surfactant or emulsifier that has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[0404] The term “administer,” “administering,” or “administration” as used in this disclosure refers to either directly administering one or more disclosed compounds or a pharmaceutically acceptable salt of one or more disclosed compounds or a composition comprising one or more disclosed compounds to a subject or administering an analog of the compound or a pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body.

[0405] The term “carrier” as used in this disclosure, encompasses carriers, excipients and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ or portion of the body to another organ or portion of the body of a subject.

[0406] As used herein, the term “treat”, “treating” and “treatment” refer to a method of alleviating or abrogating a disease and / or its attendant symptoms.

[0407] As used herein, the term “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.

[0408] As used herein, the term “subject” that may be interchangeable with ‘patient’, refers to an animal, preferably a mammal and most preferably a human.

[0409] As used herein, the term, “therapeutically effective amount” refers to an amount of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof; or a composition comprising the compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, effective in producing the desired therapeutic response in a particular patient suffering from a diseases or disorder, in particular their use in diseases or disorder associated with cancer. Particularly, the term “therapeutically effective amount” includes the amount of the compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, when administered, that induces a positive modification in the disease or disorder to be treated or is sufficient to prevent development of or alleviate to some extent, one or more of the symptoms of the disease or disorder being treated in a subject. In respect of the therapeutic amount of the compound, the amount of the compound used for the treatment of a subject is low enough to avoid undue or severe side effects, within the scope of sound medical judgment can also be considered. The therapeutically effective amount of the compound or composition will be varied with the particular condition being treated, the severity of the condition being treated or prevented, the duration of the treatment, the nature of concurrent therapy, the age and physical condition of the end user, the specific compound or composition employed the particular pharmaceutically acceptable carrier utilized. The term “pharmaceutically acceptable salt” refers to a product obtained by reaction of the compound of the present invention with a suitable acid or a base. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn and Mn salts; Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, 4-methylbenzenesulfonate or p-toluenesulfonate salts and the like. Certain compounds of the invention (compound of formula (I)) can form pharmaceutically acceptable salts with various organic bases such as lysine, arginine, guanidine, diethanolamine or metformin. Suitable base salts include, but are not limited to, aluminium, calcium, lithium, magnesium, potassium, sodium or zinc salts.

[0410] “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.

[0411] The present invention also provides methods for formulating the disclosed compounds as for pharmaceutical administration.

[0412] In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as an eye drop.

[0413] The term “cancer” is used throughout the specification to refer to the pathological process that results in the formation and growth of a cancerous or malignant neoplasm, i.e., abnormal tissue that grows by cellular proliferation, often more rapidly than normal and continues to grow after the stimuli that initiated the new growth cease. Malignant neoplasms show partial or complete lack of structural organization and functional coordination with the normal tissue and most invade surrounding tissues, metastasize to several sites and are likely to recur after attempted removal and to cause the death of the patient unless adequately treated. As used herein, the term neoplasia is used to describe all cancerous disease states and embraces or encompasses the pathological process associated with malignant hematogenous, ascitic and solid tumors. Exemplary cancers which may be treated by the present compounds either alone or in combination with at least one additional anti-cancer agent include squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, hematologic cancers and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratocarcinomas. Additional cancers which may be treated using compounds according to the present invention include, for example, T-lineage Acute lymphoblastic Leukemia (T-ALL), T- lineage lymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cell Leukemia, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, Burkitts Lymphoma, B-cell ALL, Philadelphia chromosome positive ALL and Philadelphia chromosome positive CML.

[0414] The term “stereoisomers” refers to any enantiomers, diastereoisomers or geometrical isomers of the compounds of formula (I), wherever they are chiral or when they bear one or more double bonds. When the compounds of the formula (I) and related formulae are chiral, they can exist in racemic or in optically active form. It should be understood that the invention encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric and epimeric forms, as well as t / -Isomers and / -Isomers and mixtures thereof. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centres 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 invention may exist as geometric Isomers. The present invention includes all cis, trans, syn, anti, entgegen (E) and zusammen (Z) Isomers as well as the appropriate mixtures thereof.

[0415] The term “enantiomers” refers to a pair of stereoisomers which are non-superimposable mirror images of one another. The term “enantiomer” refers to a single member of this pair of stereoisomers. The term “racemic” refers to a 1 : 1 mixture of a pair of enantiomers. The disclosure includes enantiomers of the compounds described herein. Each compound herein disclosed includes all the enantiomers that conform to the general structure of the compound. The compounds may be in a racemic or enantiomerically pure form or any other form in terms of stereochemistry. In some embodiments the compounds are the (R,S)-enantiomer.

[0416] The term “diastereomers” refers to the set of stereoisomers which cannot be made superimposable by rotation around single bonds. For example, cis- and trans- double bonds, endo- and exo- substitution on bicyclic ring systems and compounds containing multiple stereogenic centres with different relative configurations are considered to be diastereomers. The term “diastereomer” refers to any member of this set of compounds. In some examples presented, the synthetic route may produce a single diastereomer or a mixture of diastereomers. The disclosure includes diastereomers of the compounds described herein.

[0417] The compounds of the present invention may be used as single drug or as a pharmaceutical composition in which the compound is mixed with various pharmacologically acceptable materials.

[0418] The compounds of the invention 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 invention. The pharmaceutical composition of the present patent application 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 and solvents. 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.

[0419] Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, fatty acid esters and polyoxyethylene.

[0420] 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.

[0421] 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 invention may be formulated so as to provide desired release profile.

[0422] Administration of the compounds of the invention, 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 patent application to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to oral, nasal, buccal, dermal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, intramuscular or topical.

[0423] 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.

[0424] Liquid formulations include, but are not limited to, syrups, emulsions and sterile injectable liquids, such as suspensions or solutions.

[0425] 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.

[0426] The pharmaceutical compositions of the present patent application may be prepared by conventional techniques known in literature.

[0427] Suitable doses of the compounds for use in treating the disease or disorder 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 patent application.

[0428] According to one embodiment, the compounds of the present invention can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the present invention also embraces isotopically-labeled variants of the present invention 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 invention and their uses. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as2H (“D”),3H,nC,13C,14C,13N,15N,15O,17O,18O,32P,33P,35S,18F,36C1,123I and125I. Isotopically labeled compounds of the present inventions 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.

[0429] EXPERIMENTAL

[0430] The abbreviations used in the entire specification is summarized below with their meaning.

[0431] MeOH - Methanol, EtOH - Ethanol, DCM - Dichloromethane, DMF - N,N- Dimethylformamide, EtOAc - Ethyl acetate, THF - Tetrahydrofuran, DME- 1,2- Dimethoxy ethane, DMSO- Dimethyl sulfoxide DIPEA- N,N-Diisopropylethylamine, NCS- N- chloro succinimide, HATU - (l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluoro phosphate), KOAc - Potassium acetate, Na2SO4 - Sodium sulphate, Na2CO3 - Sodium carbonate, K2CO3 - Potassium carbonate, Cs2CO3-Cesium carbonate, KO'Bu- Potassium tert-butoxide, TEA - Triethyl amine; DEA- Diethyl amine, LiOHFEO - Lithium hydroxide monohydrate; EDC.HC1 - l-(3-Dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride, DAST- diethylaminosulfur trifluoride, PPTs- Pyridinium p- toluenesulfonate, NaH - Sodium hydride, NH4OH- Ammonium hydroxide, NaOH - Sodium hydroxide, HC1 - Hydrochloric acid, Pd(pph3)2C12. DCM -Bis(triphenylphosphine)- palladium(II) dichloride Dichloromethane complex; Pd(OAc)2 - Palladium (II) acetate, mL - Milliliter, TLC - Thin layer chromatography, RT - Room temperature, h - Hour, N - Normality, M - Molarity,1HNMR - Proton nuclear magnetic resonance, DMSO-de - Deuterated Dimethyl sulfoxide, CDCh - Deuterated chloroform, CD3OD- Deuterated Methanol, s - Singlet, d - Doublet, t -Triplet, m - Multiplet, H - Proton, MHz - Mega hertz, Hz - Hertz, Ppm - Parts per million, Bs - Broad singlet, HPLC - High-performance liquid chromatography, LCMS - Liquid chromatography Mass spectroscopy, g - Gram, mmol - Milli mol and °C - degree centigrade.

[0432] General scheme - 1:

[0433] The general scheme-I for the synthesis of the compound represented by formula (T) is depicted in the above scheme. The compound of formula (Ai) is reacted with the compound of formula (Bi) in a suitable solvent and suitable coupling reagent to yield compound of formula (A2) which upon further reaction with compound of formula (B2) in presence of suitable coupling reagent and solvent can provide compound of formula (A3). The compound of formula (A3) undergo deprotection to result in compound of formula (A4). The compound of formula (A4) reacts with the compound of formula (B3) with suitable solvent in high temperature to result the compound of formula (T). General Scheme - II:

[0434] The general scheme-II for the synthesis of compound represented by formula (I) is depicted in above scheme. The compound of formula (Ai) is reacted with the compound of formula (B4) in suitable solvent and suitable coupling reagent to yield compound of formula (A5) which upon further reaction with compound of formula (B2) in presence of suitable coupling reagent and solvent to provide compound of formula (Ae). The compound of formula (Ae) undergoes deprotection to result in compound of formula (A7). The compound of formula (A7) reacts with the compound of formula (B5) with suitable solvent at high temperature to result the compound of formula (I).

[0435] PREPARATION OF INTERMEDIATES AND COMPOUNDS:

[0436] Intermediate 1: Synthesis of 3-chloro-5H-pyrrolo[3,2-c]pyridazine lnt-1

[0437] Step-a: Synthesis of 6-chloro-3-((triisopropylsilyl)ethynyl) pyridazin-4-amine

[0438] To a stirred solution of 3,6-dichloropyridazin-4-amine (10.0 g, 60.97 mmol) and Bis(triphenylphosphine)palladium(II)dichloride (1.28 g, 1.82 mmol) in acetonitrile (100 mL) was added copper(II)iodide (0.69 g, 3.65 mmol) at RT in sealed tube and the reaction mixture was degassed with nitrogen for 10 min followed by the addition of ethynyl triisopropyl silane (10.0 g, 54.88 mmol) and triethylamine (30.85 g, 304.89 mmol). Then reaction mixture was heated for 4 h at 120°C in a sealed tube. Once the reaction was completed (monitored by TLC), the reaction mixture was diluted with EtOAc, filter through celite and concentrated under vacuum to give the residue which was purified by combi flash column chromatography using 40% ethyl acetate in hexane as eluent to afford the title compound as off-white solid (10.0 g, 53%).XH NMR (400 MHz, DMSO-d6): 8 6.90 (s, 1H), 6.59 (bs, 2H), 1.21-1.11 (m, 3H), 1.09 (s, 18H); LC-MS: m / z 310.1 (M+H)+.

[0439] Step-b: Synthesis of 6-chloro-3-ethynylpyridazin-4-amine

[0440] To a stirred solution of 6-chloro-3-((triisopropylsilyl)ethynyl) pyridazin-4-amine (8.9 g, 28.72 mmol) in THF (90 mL) was added tetrabutylammonium bromide (TBAB) (9.76 g, 37.33 mmol) at 0°C and then reaction mixture slowly brought to RT and stirred for 1 h. Once the reaction was completed (monitored by TLC), the reaction mixture was diluted with EtOAc and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under vacuum to give the residue which was purified by combi flash column chromatography using 60-70% ethyl acetate in hexane as eluent to afford the title compound as off-white solid (4.1 g, 97 %). flT NMR (400 MHz, DMSO-d6): 6 6.94 (bs, 2H), 6.81 (s, H), 4.92 (s, 1H); LC-MS: m / z 154.1 (M+H)+.

[0441] Step-c: Synthesis of 3-chloro-5H-pyrrolo[3,2-c]pyridazine

[0442] To a stirred solution of 6-chloro-3-ethynylpyridazin-4-amine (2.2 g, 14.32 mmol) in THF (50 mL) was added potassium tertiary butoxide (3.21g, 28.65 mmol) at 0°C and then reaction mixture slowly brought to RT and stirred at RT for 16 h. Once the reaction was completed (monitored by TLC), the reaction mixture was diluted with EtOAc, washed with water, brine, dried over anhydrous sodium sulphate and concentrated under vacuum to give titled compound as off-white solid (1.8 g, 82 %). 'H NMR (400 MHz, DMSO-d6): 5 11.91 (bs, 1H), 7.91 (d, J = 3.2 Hz, 1H), 7.80 (d, J = 3.2 Hz, 1H), 6.88 (dd, J = 7.2, 1.2 Hz, 1H); LC-MS: m / z 154.0 (M+H)+.

[0443] Intermediate 2: Synthesis of 8-(4-bromophenyl)-l,4-dioxa-8-azaspiro[4.5]decane lnt-2 To a stirred solution of l-bromo-4-iodobenzene (10 g, 35.3 mmol) and l,4-dioxa-8- azaspiro[4.5]decane (5.06 g, 35.3 mmol) in DMSO (100 mL) were added K2CO3 (9.77 g, 70.69 mmol) and L-proline (1.62 g, 14.1 mmol) and degassed with nitrogen for 10 min. Further Cui (1.34 g, 7.06 mmol) was added to the reaction mixture and the reaction mixture was heated at 90°C for 16 h in a sealed tube with continuous stirring. Once the reaction was completed (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated under vacuum to give the residue which was purified by combi flash column chromatography using 10% ethyl acetate in hexane as eluent to afford the titled compound as off-white solid (7 g, 66%). 'H NMR (400 MHz, DMSO-d6): 8 7.31 (d, J= 9.2 Hz, 2H), 6.90 (d, J= 92 Hz, 2H), 3.90 (s, 4H), 3.27-3.24 (m, 4H), 1.68-1.65 (m, 4H); LC-MS: m / z 297.9 (M+H)+.

[0444] Intermediate-3: Synthesis of l-(4-(3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-5- yl)phenyl)piperidin-4-one

[0445] Step a: Synthesis of 8-(4-(3-chloro-5H-pyrrolo[3,2-c]pyridazin-5-yl)phenyl)-l,4-dioxa-8- azaspiro [4.5] decane

[0446] To a stirred solution of 3-chloro-5H-pyrrolo[3,2-c]pyridazine (3.4 g, 22.14 mmol) in DMSO (50 mL) were added 8-(4-bromophenyl)-l,4-dioxa-8-azaspiro[4.5]decane (6.60 g, 22.14 mmol) and CS2CO3 (21.64 g, 66.42 mmol) at RT. The reaction mixture was degassed with nitrogen for 5 min, then pyrrolidine-2-carboxylic acid (0.510 g, 4.42 mmol) and copper(I)iodide (0.843 g, 4.42 mmol) was added into the reaction mixture and the reaction mixture was stirred at 140°C for 16 h. Once the reaction was completed (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulphate and concentrated under vacuum to give the residue which was purified by combi flash column chromatography using 50-60% ethyl acetate in hexane as eluent to afford the title compound as solid (3.6 g, 43.8 %). 'H NMR (400 MHz, DMSO-de): 8 8.19 (d, J= 3.6 Hz, 1H), 7.82 (d, J= 0.8 Hz, 1H), 7.47 (d, J= 92 Hz, 2H), 7.16-7.13 (m, 3H), 3.93 (s, 4H), 3.40-3.37 (m, 4H), 1.75-1.72 (m, 4H); LC-MS: m / z 371.1 (M+H)+.

[0447] Step b: Synthesis of 2-(5-(4-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)-5H-pyrrolo[3,2- c] pyridazin-3-yl)phenol

[0448] To a stirred solution of 8-(4-(3-chloro-5H-pyrrolo[3,2-c]pyridazin-5-yl)phenyl)-l,4- dioxa-8-azaspiro[4.5]decane (3.5 g, 9.44 mmol) and (2-hydroxyphenyl)boronic acid (1.95 g, 14.15 mmol) in 1,4-dioxane (30 mL) and water (8 mL) was added K2CO3 (3.91g, 28.31 mmol) and degassed with nitrogen for 10 min. Further, X-phosPdGs (0.79 g, 0.94 mmol) was added and the reaction mixture was stirred for 4h at 120°C in sealed tube. Once the reaction was completed (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated under vacuum to give the residue which was purified by combi flash column chromatography using 50-80% ethyl acetate in hexane to afford the title compound as off white solid (1.8 g, 44%). 'H NMR (400 MHz, DMSO-d6): 6 13.85 (s, 1H), 8.32 (d, J= 0.8 Hz, 1H), 8.24 (d, .7= 3.2 Hz, 1H), 8.07 (dd, J= 8.0, 1.6 Hz, 1H), 7.54 (dd, J= 7.6, 2.0 Hz, 2H), 7.31 (dt, J = 7.6, 1.6 Hz, 1H), 7.20-7.17 (m, 3H), 7.00-6.92 (m, 2H), 3.94 (s, 4H), 3.41-3.36 (m, 4H), 1.76-1.71 (m, 4H); LC-MS: m / z 429.2 (M+H)+.

[0449] Step c: Synthesis of l-(4-(3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-5- yl)phenyl)piperidin-4-one

[0450] To a stirred solution of 2-(5-(4-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)-5H- pyrrolo[3,2-c]pyridazin-3-yl)phenol (1.3 g, 3.03 mmol) in THF (20 mL) was added 3(N) aq. HC1 (10 mL) at 0°C and then slowly brought to RT and the reaction mixture was stirred for 1 h at 60 °C. Once the reaction was completed (monitored by TLC), the reaction mixture was basified with NaHCOs and extracted with EtOAc. The combined organic layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated under vacuum to give title compound as white solid (1.1 g, 95%). 'H NMR (400 MHz, DMSO-de): 6 13.84 (s, 1H), 8.32 (d, J= 0.4 Hz, 1H), 8.25 (d, = 3.6 Hz, 1H), 8.06 (dd, J= 8.0, 1.2 Hz, 1H), 7.59 (dd, J= 12, 2.0 Hz, 2H), 7.32 (dt, J= 12, 1.6 Hz, 1H), 7.25 (dd, J= 12, 2.0 Hz, 2H), 7.20 (dd, J = 3.2, 0.8 Hz, 1H), 7.00-6.92 (m, 2H), 3.73 (t, J = 6.0 Hz, 4H), 2.48 (t, J = 6.0 Hz, 4H); LC- MS: m / z 385.2 (M+H)+.

[0451] The intermediates 4 to 21 listed in below Table-1 were prepared by procedure similar to the one described in intermediate-3 with appropriate variations in reactants, quantities of reagents, protections and deprotections, solvents, and reaction conditions. The characterization data of the compounds are summarized herein the below table.

[0452] Table-1

[0453] Intermediate 22: Synthesis of l-(4-(3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-5- yl)phenyl) piperazin-2-one

[0454] Step-a: Synthesis of tert-butyl 4-(4-bromophenyl)-3-oxopiperazine-l-carboxylate

[0455] Tert-butyl 3 -oxopiperazine- 1 -carboxylate (3.53 g, 17.67 mmol), l-bromo-4-iodobenzene (5 g, 17.67 mmol) and K3PO4 (11.25 g, 53 mmol) was dissolved in DMF (50 mL) with continuous stirring. The resultant solution was purged with argon for 10 minutes. After that Cui (0.67 g, 3.53 mmol) and N,N-dimethyl ethylenediamine (0.31 g, 3.53 mmol) were added and the reaction mixture was stirred at 100 °C for 16 h. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed, and the filtrate was diluted with EtOAc and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue which was purified by combi flash column chromatography using 90% ethyl acetate in hexane as eluent to afford the title compound as white solid (2.5 g, 39%). LCMS: m / z 356.2 (M+H)+.

[0456] Step-b: Synthesis of tert-butyl 4-(4-(3-chloro-5H-pyrrolo[3,2-c]pyridazin-5-yl)phenyl)-3- oxopiperazine-l-carboxylate

[0457] Tert-butyl 4-(4-bromophenyl)-3 -oxopiperazine- 1 -carboxylate (3 g, 8.46 mmol), 3-chloro-5H- pyrrolo[3,2-c]pyridazine (1.3 g, 8.46 mmol) and CS2CO3 (5.51 g, 16.93 mmol) was dissolved in DMSO (25 mL) with continuous stirring. The resultant solution was purged with argon for 10 minutes followed by Cui (0.32 g, 1.69 mmol) and pyrrolidine-2-carboxylic acid (0.39 g, 3.38 mmol) addition, and the reaction mixture was stirred at 120 °C for 16 h. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed, and the filtrate was diluted with EtOAc and extracted with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue which was purified by combi flash column chromatography using 90% ethyl acetate in hexane as eluent to afford the title compound as light brown solid (1.3 g, 35%).1HNMR (DMSO d6, 400 MHz): 8.32 (d, J= 3.6 Hz, 1H), 8.00 (d, J = 1.2 Hz, 1H), 7.74 (dd, J= 6.8, 2.4 Hz, 2H), 7.60 (dd, J= 6.8, 2.4 Hz, 2H), 7.23 (dd, J= 3.6, 1.2 Hz, 1H), 4.12 (s, 2H), 3.82-3.79 (m, 2H), 3.74-3.71 (m, 2H); LCMS: m / z 428.3 (M+H)+.

[0458] Step-c: Synthesis of tert-butyl 4-(4-(3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-5- yl)phenyl)-3-oxopiperazine-l-carboxylate

[0459] Tert-butyl4-(4-(3-chloro-5H-pyrrolo[3,2-c]pyridazin-5-yl)phenyl)-3-oxopiperazine-l- carboxylate (1.3 g, 3.03 mmol), (2-hydroxyphenyl)boronic acid (0.46 g, 3.31 mmol) and K2CO3 (1.26 g, 9.11 mmol) was dissolved in 1,4-dioxane (20 mL) and H2O (4 ml) with continuous stirring. The resultant solution was purged with argon for 15 minutes followed by X-PhosPdG3 (0.12 g, 0.15 mmol) addition and the reaction mixture was stirred at 95 °C for 16 h. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed, and the filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was diluted with EtOAc and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure which further was purified by combi flash column chromatography using 3% MeOH in DCM as eluent to afford the pure titled compound as yellow solid (0.7 g, 47%). LCMS: m / z 486.1 (M+H)+.

[0460] Step-d: Synthesis of l-(4-(3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-5- yl)phenyl)piperazin-2-one

[0461] To a stirred solution of tert-butyl 4-(4-(3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-5- yl)phenyl)-3 -oxopiperazine- 1 -carboxylate (0.7 g, 1.44 mmol) in Dioxane (5 mL) was added 4M HC1 in dioxane (1 mL) and the reaction mixture was stirred at r.t. for 16 h. Upon completion, checked by TLC, the reaction mixture concentrated under reduced pressure to give the crude compound. The crude compound was triturated with n-pentane and then dried under vacuum to afford Int-22 as pale-yellow solid (0.4 g). 'H NMR (DMSO d6, 400 MHz): 5 9.97 (bs, 2H), 8.63-8.62 (d, J= 3.2 Hz, 1H), 8.57 (s, 1H), 7.91-7.89 (m, 3H), 7.65-7.61 (m, 2H), 7.45- 7.39 (m, 2H), 7.10-7.10 (d, J= 0.8 Hz, 1H), 7.08 (s, 1H), 4.01-3.98 (t, J= 5.2 Hz, 2H), 3.92-3.91 (m, 2H), 3.58 (s, 2H); LCMS: m / z 386.2 (M+H)+; HPLC: 96.7%.

[0462] The intermediates 23-26A listed in below Table-2 were prepared by procedure similar to the one described in Intermediate-22 with appropriate variations in reactants, quantities of reagents, protections and deprotections, solvents and reaction conditions. The characterization data of the compounds are summarized herein the below table. Table-2

[0463] Intermediate 27: Synthesis of l-(6-(3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-5- yl)pyridin-3-yl)piperazin-2-one

[0464] Step-a: Synthesis of 3-chloro-5-(5-iodopyridin-2-yl)-5H-pyrrolo[3,2-c]pyridazine

[0465] To a stirred solution of 3-chloro-5H-pyrrolo[3,2-c]pyridazine (5.16 g, 33.6 mmol) and 2- fluoro-5-iodopyridine (7.49 g, 33.6 mmol) in DMF (70 mL) was added K2CO3 (13.93 g, 100 mmol) and the reaction mixture was stirred at 90 °C for 16 h. Once the reaction was completed (monitored by TLC), ice-cold water was added to the reaction mixture and the resultant solid was filtered, dried under reduced pressure to give title compound as light yellow solid (11.2 g, 92%). LCMS: m / z 357.1 (M+H)+.

[0466] Step-b: Synthesis of Tert-butyl 4-(6-(3-chloro-5H-pyrrolo[3,2-c]pyridazin-5-yl)pyridin- 3-yl)-3-oxopiperazine-l-carboxylate 3-chloro-5-(5-iodopyridin-2-yl)-5H-pyrrolo[3,2-c]pyridazine (9.1 g, 25.5 mmol), tert-butyl 3- oxopiperazine-1 -carboxylate (5.11 g, 25.56 mmol) and CS2CO3 (20.8 g, 63.9 mmol) was dissolved in PhMe (150 mL) under continuous stirring. The resultant solution was purged with argon for 10 minutes followed by the addition of Pd2dba3 (2.34 g, 2.55 mmol) and Xantphos (1.47 g, 2.55 mmol) and the reaction mixture was stirred at 100 °C for 16 h. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed and the filtrate was diluted with EtOAc and extracted with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue which was purified by combi flash column chromatography using 1.2% MeOH in DCM as eluent to afford the title compound as light brown solid (4.5 g, 41%). LCMS: m / z 429.05 (M+H)+.

[0467] Step-c: Synthesis of tert-butyl 4-(6-(3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-5- yl)pyridin-3-yl)-3-oxopiperazine-l-carboxylate

[0468] Tert-butyl 4-(6-(3-chloro-5H-pyrrolo[3,2-c]pyridazin-5-yl)pyridin-3-yl)-3-oxopiperazine-l- carboxylate (4.44 g, 10.36 mmol), (2-hydroxyphenyl)boronic acid (1.71g, 12.43 mmol) and K2CO3 (4.29g, 31.09 mmol) was dissolved in 1,4-dioxane (20 mL) and H2O (4 ml) under continuous stirring. The resultant solution was purged with argon for 15 minutes followed by the addition of X-PhosPdG3 (0.43 g, 0.51 mmol). The reaction mixture was stirred at 120 °C for 16 h. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed, and the filtrate was concentrated under reduced pressure to give the crude compound. The crude was diluted with EtOAc and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue which was purified by combi flash column chromatography using 3% MeOH in DCM as eluent to afford the title compound as white solid (1.37 g, 27%). LCMS: m / z 487.03 (M+H)+.

[0469] Step-d: Synthesis of l-(6-(3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-5-yl)pyridin- 3-yl)piperazin-2-one

[0470] To a stirred solution of tert-butyl 4-(6-(3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-5- yl)pyri din-3 -yl)-3 -oxopiperazine- 1 -carboxylate 1.37 g, 2.81 mmol) in DCM (15 mL) was added 4M HC1 in dioxane (15 mL) and the reaction mixture was stirred at r.t. for 2 h. Once the reaction was completed (monitored by TLC), the reaction mixture was concentrated under reduced pressure to give the crude compound. The crude compound was triturated with n- pentane, Et2O and then dried under vacuum to afford title compound as pale-yellow solid (1 g, 99% yield). 'H NMR (DMSO-d6, 400MHz): 5 9.82(bs, 2H), 9.248-9.246(d, 1H, J=0.8 Hz), 8.909-8.900(d, 1H, J=3.6 Hz), 8.72-8.70(dd, 1H, J=1.46 Hz, J=4 Hz), 8.16-8.11(m, 2H), 7.94- 7.92(d, 1H, J=7.2 Hz), 7.45-7.44(m, 2H), 7.12-7.03(m, 2H), 4.05-4.02(t, 2H, J=5.2 Hz), 3.97(s, 2H,), 3.60(s, 2H); LCMS: m / z 387.10 (M+H)+. HPLC:88.76%.

[0471] The intermediates 27A-27F listed in below Table-2A were prepared by procedure similar to the one described in Intermediate-27 with appropriate variations in reactants, quantities of reagents, protections and deprotections, solvents and reaction conditions. The characterization data of the compounds are summarized herein the below table.

[0472] Table-2A:

[0473] Intermediate 28: Synthesis of 2-(5-(l-(piperidin-4-yl)-l / / -pyrazol-3-yl)-5 / / -pyrrolo|3.2- c] pyridazin-3-yl)phenol Step-a: Synthesis of tert-butyl 4-(tosyloxy)piperidine-l-carboxylate

[0474] To a stirred solution of tert-butyl 4-hydroxypiperidine-l -carboxylate (10 g, 49.6 mmol) in

[0475] DCM (100 mL) was added EtsN (20 g, 198.7 mmol). After stirred at r.t. for 15 mins, -toluene sulfonyl chloride (18.9 g, 99.37 mmol) was added to the reaction mixture and stirred at r.t. for

[0476] 20 h. Once the reaction was completed (monitored by TLC), ice-cold water was added to the reaction mixture and extracted with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue. Pentane (100 mL) was added to the residue and stirred at r.t. for 2 h. The resultant solid formed was filtered and dried under reduced pressure to give the title compound as white solid (12 g, 67% yield). LCMS: m / z 356.01 (M+H)+.

[0477] Step-b: Synthesis of tert-butyl 4-(3-iodo-lH-pyrazol-l-yl)piperidine-l-carboxylate

[0478] To a stirred solution of tert-butyl 4-(tosyloxy)piperidine-l -carboxylate (6.1 g, 8.43 mmol) and 3-iodo-lH-pyrazole (1.63 g, 8.43 mmol) in DMA (30 mL) was added CS2CO3 (4.12 g, 12.6 mmol) and reaction mixture was stirred at 100 °C for 3 h. Once the reaction was completed (monitored by TLC), ice-cold water was added to the reaction mixture and stirred at r.t. for 2 h. The solid precipitated out was filtered and dried under reduced pressure to give the title compound as a white solid (4.4 g). LCMS: m / z 378.2 (M+H)+.

[0479] Step-c: Synthesis of tert-butyl 4-(3-(3-chloro-5H-pyrrolo[3,2-c]pyridazin-5-yl)-lH- pyrazol-l-yl)piperidine-l-carboxylate

[0480] A stirred solution of tert-butyl 4-(3-iodo-lH-pyrazol-l-yl)piperidine-l-carboxylate (1.47 g, 3.90 mmol), 3-chloro-5H-pyrrolo[3,2-c]pyridazine (0.51 g, 3.25 mmol) and CS2CO3 (3.18 g, 9.76 mmol) in DMSO (15 mL) was purged with argon for 10 minutes. After that Cui (0.126 g, 0.65 mmol) and N,N-dimethyl ethylenediamine (0.14 g, 1.65 mmol) were added and the reaction mixture was stirred at 120 °C for 18 h. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed, and the filtrate was diluted with EtOAc and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue which was purified by combi flash column chromatography using 3% MeOH in DCM as eluent to afford the title compound as white solid (0.8 g, 60%). LCMS: m / z 403.5 (M+H)+.

[0481] Step-d: Synthesis of tert-butyl 4-(3-(3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-5- yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate

[0482] Tert-butyl 4-(3-(3-chloro-5H-pyrrolo[3,2-c]pyridazin-5-yl)-lH-pyrazol-l-yl)piperidine-l- carboxylate (0.79 g, 1.97 mmol), (2-hydroxyphenyl)boronic acid (0.35 g, 2.56 mmol) and K2CO3 (0.81 g, 5.91 mmol) was dissolved in 1,4-dioxane (10 mL) and H2O (2 ml) with continuous stirring. The resultant solution was purged with argon for 15 minutes followed by the addition of X-PhosPdG3 (0.084 g, 0.09 mmol). The reaction mixture was stirred at 120 °C for 16 h. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed, and the filtrate was concentrated under reduced pressure to give the crude residue. The crude residue was diluted with EtOAc and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the crude compound which was purified by combi flash column chromatography using 3% MeOH in DCM as eluent to afford the pure title compound as white solid (0.77 g, 84%). LCMS: m / z 461 (M+H)+.

[0483] Step-e: Synthesis of 2-(5-(l-(piperidin-4-yl)-lH-pyrazol-3-yl)-5H-pyrrolo[3,2- c] pyridazin-3-yl)phenol

[0484] To a stirred solution of tert-butyl 4-(3-(3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-5- yl)-lH-pyrazol-l-yl)piperidine-l -carboxylate (0.77 g, 1.67 mmol) in dioxane (10 mL) was added 4M HC1 in dioxane (7 mL) and the reaction mixture was stirred at r.t. for 2 h. Once the reaction was completed (monitored by TLC), the reaction mixture concentrated under reduced pressure to give the crude compound. The crude compound was triturated with n-pentane, Et2O and then dried under vacuum to afford Int-28 as pale-yellow solid (0.9 g). NMR (DMSO- D6, 400MHz): 5 9.16-9.12(m, 1H), 9.07-9.02(m, 2H), 8.75-8.74(d, 1H, J=3.6), 8.08-8.07(d, 1H, J=2.4), 7.89-7.86(d, , 1H, J=6.8), 7.49-7.43(m, 1H), 7.20-7.18(m, 1H), 7.11-7.07(m, 1H) 6.948-6.942(d, 1H, J=2.4), 4.67-4.58(m, 1H), 3.46-3.43(d, 2H, J=12 Hz), 3.17-3.02(m, 3H), 2.30-2.27(m, 3H), 2.17-2.12(m, 1H); LCMS m z 361.10 (M+H)+; HPLC: 97.34 %, rt: 4.97 min.

[0485] Intermediate 29: Synthesis of 2-(5-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-5H-pyrrolo[3,2- c] pyridazin-3-yl)phenol

[0486] Step-a: Synthesis of tert-butyl 4-(tosyloxy)piperidine-l-carboxylate

[0487] To a stirred solution of tert-butyl 4-hydroxypiperidine-l -carboxylate (10 g, 49.6 mmol) in DCM (100 mL) was added EtsN (20 g, 198.7 mmol). After stirring at r.t. for 15 mins, / ?-toluene sulfonyl chloride (18.9 g, 99.37 mmol) was added, and the reaction mixture was stirred at r.t. for 20 h. Once the reaction was completed (monitored by TLC), ice-cold water was added to the reaction mixture and extracted with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue. Pentane (100 mL) was added to the residue, and it was stirred at r.t. for 2 h. The solid formed was filtered and dried under reduced pressure to give the title compound as white solid (12 g, 67% yield). LCMS: m / z 356.1 (M+H)+.

[0488] Step-b: Synthesis of tert-butyl 4-(3-iodo-lH-pyrazol-l-yl)piperidine-l-carboxylate

[0489] To a stirred solution of tert-butyl 4-(tosyloxy)piperidine-l -carboxylate (3 g, 8.43 mmol) and 4- iodo-lH-pyrazole (1.63 g, 8.43 mmol) in DMA (30 mL) was added CS2CO3 (4.12 g, 12.6 mmol) and reaction mixture was stirred at 100 °C for 3 h. Once the reaction was completed (monitored by TLC), ice-cold water was added to the reaction mixture, and it was stirred at r.t. for 2 h. The solid precipitated out was filtered and dried under reduced pressure to give the title compound as white solid (1.9 g). LCMS: m / z 378.2 (M+H)+.

[0490] Step-c: Synthesis of tert-butyl 4-(4-(3-chloro-5H-pyrrolo[3,2-c]pyridazin-5-yl)-lH- pyrazol-l-yl)piperidine-l-carboxylate

[0491] A stirred solution of tert-butyl 4-(3-iodo-lH-pyrazol-l-yl)piperidine-l-carboxylate (1.5 g, 3.90 mmol) and 3-chloro-5H-pyrrolo[3,2-c]pyridazine (0.51 g, 3.32 mmol) and CS2CO3 (3.24 g, 9.96 mmol) in DMSO (10 mL) was purged with argon for 10 minutes. After that Cui (0.126 g, 0.66 mmol) and N,N-dimethyl ethylenediamine (0.14 g, 1.65 mmol) were added and the reaction mixture was stirred at 120 °C for 18 h. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed, and the filtrate was diluted with EtOAc and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue which was purified by combi flash column chromatography using 3% MeOH in DCM as eluent to afford the title compound as white solid (0.99 g, 73%). LCMS: m / z 403.02 (M+H)+.

[0492] Step-d: Synthesis of tert-butyl 4-(4-(3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-5- yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate

[0493] Tert-butyl 4-(4-(3-chloro-5H-pyrrolo[3,2-c]pyridazin-5-yl)-lH-pyrazol-l-yl)piperidine-l- carboxylate (0.99 g, 2.45 mmol), (2-hydroxyphenyl)boronic acid (0.37 g, 2.70 mmol) and K2CO3 (1.01 g, 7.3 mmol) was dissolved in 1,4-dioxane (10 mL) and H2O (2 ml) with continuous stirring. The resultant solution was purged with argon for 15 minutes followed by X-PhosPdG3 (0.10 g, 0.12 mmol) addition. The reaction mixture was stirred at 120 °C for 16 h. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed, and the filtrate was concentrated under reduced pressure to give the crude residue. The crude residue was diluted with EtOAc and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the crude compound which was purified by combi flash column chromatography using 3% MeOH in DCM as eluent to afford the pure title compound as white solid (0.9 g, 79%). LCMS: m / z 461 (M+H)+.

[0494] Step-e: Synthesis of 2-(5-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-5H-pyrrolo[3,2- c] pyridazin-3-yl)phenol

[0495] To a stirred solution of tert-butyl 4-(3-(3-chloro-5J / -pyrrolo[3,2-c]pyridazin-5-yl)-U / -pyrazol- l-yl)piperidine-l -carboxylate (0.9 g, 1.95 mmol) in dioxane (10 mL) was added 4M HC1 in dioxane (7 mL) and the reaction mixture was stirred at r.t. for 2 h. Once the reaction was completed (monitored by TLC), the reaction mixture concentrated under reduced pressure to give the crude compound. The crude compound was triturated with n-pentane, Et2O and then dried under vacuum to afford title compound as pale-yellow solid (1.5 g).TH NMR (DMSO- d6, 400MHz): 5 9.36-9.34(d, 1H, J = 7.2Hz), 9.17-9.15(d, 1H, J = 8.4 Hz), 8.64-8.62(m, 3H), 8.183-8.181(d, 1H, J = 0.8 Hz), 7.81-7.78(d, 1H, J = 12 Hz), 7.49-7.47(m, 2H), 7.18-7.16(d, 1H, J = 7.6 Hz), 7.06-7.06 (t, 1H, J = 0.4 Hz), 4.65-4.55 (m, 1H), 3.40-3.38 (m, 2H), 3.12-3.09 (d, 2H, J = 11.6 Hz), 2.29-2.26 (m, 4H); LCMS m z 361.10 (M+H)+; HPLC: 96.83 %, rt: 4.986 min.

[0496] Intermediate 30: Synthesis of 2-(5-(4-(piperazin-l-yl)-lH-pyrazol-l-yl)-7H-pyrrolo[2,3- c] pyridazin-3-yl)phenol

[0497] Step a: Synthesis of 4-iodo-l-(4-methoxybenzyl)-lH-pyrazole

[0498] To a stirred solution of 4-iodo-lH-pyrazole (3 g, 15.4 mmol) and l-(chloromethyl)-4- methoxybenzene (3.63, 23.19 mmol) in DMF (30 mL) was added CS2CO3 (7.56 g, 23.1 mmol) and the reaction mixture was stirred at 50 °C for 2 h. Once the reaction was completed (monitored by TLC), ice-cold water was added, and the resulted solid was filtered. The solid was further dried under reduced pressure to give the crude off-white solid compound (5 g). LCMS: m / z 315.2 (M+H)+.

[0499] Step b: Synthesis of tert-butyl 4-(l-(4-methoxybenzyl)-lH-pyrazol-4-yl)piperazine-l- carboxylate

[0500] A stirred solution of 4-iodo-l-(4-methoxybenzyl)-lH-pyrazole (5.8 g, 18.4 mmol) and tertbutyl piperazine- 1 -carboxylate (5.15 g, 27.69 mmol) and CS2CO3 (18 g, 55.3 mmol) in DMSO (70 mL) was purged with argon for 10 minutes. After that Cui (0.70 g, 3.69 mmol) and L- proline (0.425 g, 3.69 mmol) were added, and the reaction mixture was stirred at 120 °C for 18 h. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed, and the filtrate was diluted with EtOAc and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue which was purified by combi flash column chromatography using 50% ethyl acetate in hexane as eluent to afford the title compound as white solid (1.6 g, 23% yield). LCMS: m / z 373.01 (M+H)+.

[0501] Step-c: Synthesis of l-(lH-pyrazol-4-yl)piperazine

[0502] To a stirred solution of tert-butyl 4-(l-(4-methoxybenzyl)-lH-pyrazol-4-yl)piperazine-l- carboxylate (1.6 g, 4.26 mmol) in DCM (5 mL) was added TFA (20 mL) and the reaction mixture was stirred at 80 °C for 18 h. Once the reaction was completed (monitored by TLC), the reaction mixture concentrated under reduced pressure to give the crude compound. The crude compound was triturated with n-pentane, Et2O and then dried under vacuum to afford title compound as pale-yellow solid (1.3 g). LCMS: m / z 153.3 (M+H)+.

[0503] Step d: Synthesis of tert-butyl 4-(lH-pyrazol-4-yl)piperazine-l-carboxylate

[0504] To a stirred solution of l-(lH-pyrazol-4-yl)piperazine (1 g, 6.57 mmol) in DCM (20 mL) was added EtsN (1.33 g, 13.14 mmol) and resultant reaction mixture stirred at r.t. for 15 mins. Then BOC2O (18.9 g, 99.37 mmol) was added to the reaction mixture, and it was stirred at r.t. for 20 h. Once the reaction was completed (monitored by TLC), ice-cold water was added to the reaction mixture and extracted with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the crude residue. Et2O (100 mL) was added to the crude residue, and it was stirred at r.t. for 2 h. The solid formed was filtered and dried under reduced pressure to give the title compound as white solid (0.4 g, 24% yield). LCMS: m / z 253.02 (M+H)+.

[0505] Step e: Synthesis of tert-butyl 4-(l-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-5-yl)-lH- pyrazol-4-yl)piperazine-l-carboxylate A stirred solution of tert-butyl 4-(lH-pyrazol-4-yl)piperazine-l-carboxylate (0.352 g, 1.39 mmol) and 3-chloro-5-iodo-7H-pyrrolo[2,3-c]pyridazine (0.352 g, 1.39 mmol) and CS2CO3 (1.364 g, 4.18 mmol) in DMSO (6 mL) was purged with argon for 10 minutes. After that Cui (0.053 g, 0.27 mmol) and N,N-dimethyl ethylenediamine (0.025 g, 0.27 mmol) were added and the reaction mixture was stirred at 80 °C for 18 h. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed and the filtrate was diluted with EtOAc and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue which was purified by combi flash column chromatography using 5% MeOH in DCM as eluent to afford the title compound as white solid (0.27 g, 48% yield). LCMS: m / z 404.03 (M+H)+.

[0506] Step f: Synthesis of tert-butyl 5-(4-(4-(tert-butoxycarbonyl)piperazin-l-yl)-lH-pyrazol-l- yl)-3-chloro-7H-pyr rolo [2 ,3-c] pyridazine-7 -carboxylate

[0507] To a stirred solution of tert-butyl 4-(l-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-5-yl)-lH-pyrazol- 4-yl)piperazine-l -carboxylate (0.27 g, 0.678 mmol) in DMF (5 mL) was added NaH (60% dispersion) (0.041 g, 1.69 mmol) at 0 °C as portion wise. After 15 mins, BOC2O (0.29 g, 1.35 mmol) was added to the reaction mixture, and it was stirred at r.t. for 30 mins. Once the reaction was completed (monitored by TLC), ice-cold water was added to the reaction mixture and extracted with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the crude residue which was purified by combi flash column chromatography using 3% MeOH in DCM as eluent to afford the title compound as white solid (0.31 g, 91% yield). LCMS: m / z 505 (M+H)+.

[0508] Step-g: Synthesis of tert-butyl 5-(4-(4-(tert-butoxycarbonyl)piperazin-l-yl)-lH-pyrazol- l-yl)-3-(2-hydroxyphenyl)-7H-pyrrolo[2,3-c]pyridazine-7-carboxylate

[0509] A stirred solution of tert-butyl 5-(4-(4-(tert-butoxycarbonyl)piperazin-l-yl)-lH-pyrazol-l-yl)- 3-chloro-7H-pyrrolo[2,3-c]pyridazine-7-carboxylate (0.31 g, 0.62 mmol), (2- hydroxyphenyl)boronic acid (0.129 g, 0.934 mmol) and K2CO3 (0.215 g, 1.55 mmol) in 1,4- di oxane (6 mL) and H2O (1 ml) was purged with argon for 15 minutes followed by X- PhosPdG3 (0.053 g, 0.06 mmol) addition. The reaction mixture was stirred at 100 °C for 16 h. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed and the filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was diluted with EtOAc and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue which was purified by combi flash column chromatography using 3% MeOH in DCM as eluent to afford the title compound as off-white solid (0.17 g, 49%). LCMS: m / z 562 (M+H)+. Step-h: Synthesis of 2-(5-(4-(piperazin-l-yl)-lH-pyrazol-l-yl)-7H-pyrrolo[2,3- c] pyridazin-3-yl)phenol

[0510] To a stirred solution of tert-butyl 5-(4-(4-(tert-butoxycarbonyl)piperazin-l-yl)-lH-pyrazol-l- yl)-3-(2-hydroxyphenyl)-7H-pyrrolo[2,3-c]pyridazine-7-carboxylate (0.17 g, 0.30 mmol) in dioxane (2 mL) was added 4M HC1 in dioxane (2 mL) and the reaction mixture was stirred at r.t. for 2 h. Once the reaction was completed (monitored by TLC), the reaction mixture concentrated under reduced pressure to give the crude compound. The crude compound was triturated with n-pentane, Et2O and then dried under vacuum to afford Int-30 as pale-yellow solid (0.15 g). LCMS: m / z 362.2 (M+H)+.

[0511] Intermediate 31: Synthesis of 2-(5-(4-(piperidin-4-yl)-l / / -pyrazol-l-yl)-7 / / -pyrrolo|2.3- c] pyridazin-3-yl)phenol

[0512] Step a: Synthesis of 3-Chloro-5-iodo-7H-pyrrolo[2,3-c]pyridazine

[0513] To a stirred solution of 3-chloro-7H-pyrrolo[2,3-c]pyridazine (3.5 g, 22.79 mmol) in DCM (50 mL) was added NIS (6.6 g, 29.62 mmol) and the reaction mixture was stirred at r.t. for 4 h. Once the reaction was completed (monitored by TLC), the reaction mixture concentrated under reduced pressure to give the crude compound. The crude compound was diluted with EtOAc and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the title compound as yellow solid (5 g). LCMS: m / z 280 (M+H)+.

[0514] Step b: Synthesis of Tert-butyl 4-(l-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-5-yl)-lH- pyrazol-4-yl)piperidine-l-carboxylate

[0515] A stirred solution of 3-chloro-5-iodo-7H-pyrrolo[2,3-c]pyridazine (0.5 g, 1.788 mmol) and tert-butyl 4-(17 / -pyrazol-4-yl)piperidine-l -carboxylate (0.446 g, 1.78 mmol) and CS2CO3 (1.457 g, 4.47 mmol) in DMF (5 mL) was purged with argon for 10 minutes. After that Cui (0.17 g, 0.89 mmol) and N,N-dimethyl ethylenediamine (0.095 g, 1.07 mmol) were added and the reaction mixture was stirred at 80 °C for 18 h. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed, and the filtrate was diluted with EtOAc and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue which was purified by combi flash column chromatography using 50% EtOAc in hexane as eluent to afford the title compound as brown solid (0.35 g, 48% yield). LCMS: m / z 403.1 (M+H)+.

[0516] Step-c: Synthesis of Tert-butyl 4-(l-(3-(2-hydroxyphenyl)-7H-pyrrolo[2,3-c]pyridazin-5- yl)-lH-pyrazol-4-yl)piperidine-l-carboxylate

[0517] A stirred solution of tert-butyl 4-(l-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-5-yl)-lH-pyrazol-4- yl)piperidine-l -carboxylate (0.25 g, 0.499mmol), (2-hydroxyphenyl)boronic acid (0.083 g, 0.599 mmol) and K2CO3 (0.138 g, 0.99 mmol) in 1,4-dioxane (4 mL) and H2O (1.2 ml) was purged with argon for 15 minutes. After that X-PhosPdG3 (0.021 g, 0.020 mmol) was added and the reaction mixture was stirred at 80 °C for 16 h. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed, and the filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was diluted with EtOAc and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue which was purified by combi flash column chromatography using 3% MeOH in DCM as eluent to afford the title compound as light brown solid (0.2 g, 71%). LCMS: m / z 461.2 (M+H)+.

[0518] Step-d: Synthesis of 2-(5-(4-(Piperidin-4-yl)-lH-pyrazol-l-yl)-7H-pyrrolo[2,3- c] pyridazin-3-yl)phenol

[0519] To a stirred solution of tert-butyl 4-(l-(3-(2-hydroxyphenyl)-7H-pyrrolo[2,3-c]pyridazin-5- yl)-lH-pyrazol-4-yl)piperidine-l -carboxylate (0.08 g, 0.17 mmol) in dioxane (2 mL) was added 4M HC1 in dioxane (1 mL) and the reaction mixture was stirred at r.t. for 3 h. Once the reaction was completed (monitored by TLC), the reaction mixture concentrated under reduced pressure to give the crude compound. The crude product was triturated with n-pentane, Et2O and then dried under vacuum to afford Int-31 as pale-yellow solid (0.07 g). LCMS: m / z 361.15 (M+H)+. Intermediate 32: Synthesis of l-(l-(3-(2-hydroxyphenyl)-7H-pyrrolo[2,3-c]pyridazin-5- yl)-lH-pyrazol-4-yl)piperazin-2-one

[0520] Step a: Synthesis of tert-butyl 3-oxo-4-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4- yl)piperazine-l-carboxylate

[0521] A stirred solution of 4-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole (1 g, 3.59 mmol), tertbutyl 3 -oxopiperazine- 1 -carboxylate (0.72 g, 3.59 mmol) and CS2CO3 (3.51 g, 10.78 mmol) in DMSO (70 mL) was purged with argon for 10 minutes. After that Cui (0.068 g, 0.36 mmol) and pyridine-2-carboxylic acid (0.041 g, 0.36 mmol) were added and the reaction mixture was stirred at 100 °C for 12 h. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed, and the filtrate was diluted with EtOAc and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue which was purified by combi flash column chromatography using 40% ethyl acetate in hexane as eluent to afford the title compound as white solid (2.2 g). LCMS: m / z 351 (M+H)+.

[0522] Step-b: Synthesis of l-(lH-pyrazol-4-yl)piperazin-2-one

[0523] To a stirred solution of tert-butyl 3-oxo-4-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4- yl)piperazine-l -carboxylate (2 g, 5.70 mmol) in dioxane (10 mL) was added 4M HC1 in dioxane (10 mL) and the reaction mixture was stirred at 60 °C for 24 h. Once the reaction was completed (monitored by TLC), the reaction mixture concentrated under reduced pressure to give the crude compound. The crude compound was triturated with n-pentane, Et2O and then dried under vacuum to afford title compound as yellow solid (2.2 g). LCMS: m / z 167 (M+H)+.

[0524] Step c: Synthesis of tert-butyl 3-oxo-4-(lH-pyrazol-4-yl)piperazine-l-carboxylate

[0525] To a stirred solution of l-(lH-pyrazol-4-yl)piperazin-2-one (1.5 g, 9.02 mmol) in THF (20 mL) was added EtsN (2.74 g, 27.07 mmol). After stirred at r.t. for 15 mins, BOC2O (1.97 g, 9.02 mmol) was added to the reaction mixture, and it was stirred at r.t. for 24 h. Once the reaction was completed (monitored by TLC), ice-cold water was added to the reaction mixture and extracted with DCM (2X100 mL). Finally organic layer washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the crude compound which was purified by combi flash column chromatography using 50% ethyl acetate in hexane as eluent to afford the title compound as white solid (1.6 g, 66% yield). LCMS: m / z 267.2 (M+H)+.

[0526] Step d: Synthesis of tert-butyl 4-(l-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-5-yl)-lH- pyrazol-4-yl)-3-oxopiperazine-l-carboxylate

[0527] A stirred solution of tert-butyl 3-oxo-4-(lH-pyrazol-4-yl)piperazine-l-carboxylate (0.75 g, 2.68 mmol), 3-chloro-5-iodo-7H-pyrrolo[2,3-c]pyridazine (0.715 g, 2.68 mmol) and CS2CO3 (2.18 g, 6.71 mmol) in DMF (15 mL) was purged with argon for 10 minutes, followed by Cui (0.051 g, 0.26 mmol) and N,N-dimethyl ethylenediamine (0.026 g, 0.26 mmol) addition and the reaction mixture was stirred at 80 °C for 12 h. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed and the filtrate was diluted with EtOAc and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue which was purified by combi flash column chromatography using 40% ethyl acetate in hexane as eluent to afford the title compound as light brown solid (0.45 g, 40% yield). LCMS: m / z 418 (M+H)+.

[0528] Step e: Synthesis of tert-butyl 5-(4-(4-(tert-butoxycarbonyl)-2-oxopiperazin-l-yl)-lH- pyrazol-l-yl)-3-chloro-7H-pyrrolo[2,3-c]pyridazine-7-carboxylate

[0529] To a stirred solution of tert-butyl 4-(l-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-5-yl)-lH-pyrazol- 4-yl)-3 -oxopiperazine- 1 -carboxylate (0.5 g, 1.197 mmol) in DMF (15 mL) was added NaH (60% dispersion) (0.072 g, 3 mmol) at 0 °C as portion wise. After 15 mins, BOC2O (0.29 g, 1.35 mmol) was added to the reaction mixture, and reaction mixture was stirred at r.t. for 30 mins. Once the reaction was completed (monitored by TLC), ice-cold water was added to the reaction mixture and extracted with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the crude residue which was purified by combi flash column chromatography using 50% ethyl acetate in hexane as eluent to afford the title compound as white solid (0.2 g, 32% yield). LCMS: m / z 519.2 (M+H)+.

[0530] Step-f: Synthesis of tert-butyl 5-(4-(4-(tert-butoxycarbonyl)-2-oxopiperazin-l-yl)-lH- pyrazol-l-yl)-3-(2-hydroxyphenyl)-7H-pyrrolo[2,3-c]pyridazine-7-carboxylate

[0531] A stirred solution of tert-butyl 5-(4-(4-(tert-butoxycarbonyl)-2-oxopiperazin-l-yl)-lH- pyrazol-l-yl)-3-chloro-7H-pyrrolo[2,3-c]pyridazine-7-carboxylate (0.25 g, 0.48 mmol), (2- hydroxyphenyl)boronic acid (0.08 g, 0.58 mmol) and K2CO3 (0.134 g, 0.97 mmol) in 1,4- di oxane (7 mL) and H2O (3 ml) was purged with argon for 15 minutes followed by the addition of X-PhosPdG3 (0.056 g, 0.04 mmol). The reaction mixture was stirred at 90 °C for 24 h. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed, and the filtrate was concentrated under reduced pressure to give the crude compound. The crude was diluted with EtOAc and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue which was purified by combi flash column chromatography using 70% ethyl acetate in hexane as eluent to afford the title compound as off-white solid (0.22 g, 79%). LCMS: m / z 517 (M+H)+. Step-g: Synthesis of l-(l-(3-(2-hydroxyphenyl)-7H-pyrrolo[2,3-c]pyridazin-5-yl)-lH- pyrazol-4-yl)piperazin-2-one

[0532] To a stirred solution of tert-butyl 5-(4-(4-(tert-butoxycarbonyl)-2-oxopiperazin-l-yl)-lH- pyrazol-l-yl)-3-(2-hydroxyphenyl)-7H-pyrrolo[2,3-c]pyridazine-7-carboxylate (0.22 g, 0.30 mmol) in dioxane (7 mL) was added 4M HC1 in dioxane (4 mL) and the reaction mixture was stirred at r.t. for 48h. Once the reaction was completed (monitored by TLC), the reaction mixture concentrated under reduced pressure to give the crude compound. The crude compound was triturated with n-pentane, Et2O and then dried under vacuum to afford Int-32 as pale-yellow solid (0.14 g). LCMS: m / z 376.2 (M+H)+.

[0533] Intermediate 33: Synthesis of 2-(5-(3-(piperidin-4-yloxy)phenyl)-5H-pyrrolo[3,2- c] pyridazin-3-yl)phenol

[0534] Step a: Synthesis of tert-butyl 4-(3-(3-chloro-5H-pyrrolo[3,2-c]pyridazin-5- yl)phenoxy)piperidine-l-carboxylate

[0535] A stirred solution of tert-butyl 4-(3 -brom ophen oxy )piperi dine- 1 -carboxylate (0.69 g, 1.95 mmol), 3-chloro-5H-pyrrolo[3,2-c]pyridazine (0.3 g, 1.95 mmol) and CS2CO3 (1.27 g, 3.90 mmol) in DMF (20 mL) was purged with argon for 10 minutes. After that Cui (0.037 g, 0.19 mmol) and N,N-dimethyl ethylenediamine (0.034 g, 0.39 mmol) were added and the reaction mixture was stirred at 80 °C for 12 h. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed and the filtrate was diluted with EtOAc and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue which was purified by combi flash column chromatography using 40% ethyl acetate in hexane as eluent to afford the title compound as light brown solid (0.35 g, 41% yield). LCMS: m / z 430 (M+H)+.

[0536] Step-b: Synthesis of tert-butyl 4-(3-(3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-5- yl)phenoxy)piperidine-l-carboxylate

[0537] A stirred solution of tert-butyl 4-(3-(3-chloro-5H-pyrrolo[3,2-c]pyridazin-5- yl)phenoxy)piperidine-l -carboxylate (0.30 g, 0.699 mmol), (2-hydroxyphenyl)boronic acid (0.096 g, 0.699 mmol) and K2CO3 (0.193 g, 1.39 mmol) in 1,4-dioxane (10 mL) and H2O (3 ml) was purged with argon for 15 minutes followed by the addition of X-PhosPdG3 (0.059 g, 0.04 mmol). The reaction mixture was stirred at 90 °C for 24 h. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed, and the filtrate was concentrated under reduced pressure to give the crude residue. The crude residue was diluted with EtOAc and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the crude compound which was purified by combi flash column chromatography using 70% ethyl acetate in hexane as eluent to afford the title compound as off-white solid (0.23 g, 88%). LCMS: m / z 487.1 (M+H)+.

[0538] Step-c: Synthesis of 2-(5-(3-(piperidin-4-yloxy)phenyl)-5H-pyrrolo[3,2-c]pyridazin-3- yl)phenol

[0539] To a stirred solution of tert-butyl 4-(3-(3-(2-hydroxyphenyl)-5H-pyrrolo[3,2-c]pyridazin-5- yl)phenoxy)piperidine-l -carboxylate (0.25 g, 0.51 mmol) in dioxane (10 mL) was added 4M HC1 in dioxane (5 mL) and the reaction mixture was stirred at r.t. for 48 h. Once the reaction was completed (monitored by TLC), the reaction mixture concentrated under reduced pressure to give the crude compound. The crude compound was triturated with n-pentane, Et2O and then dried under vacuum to afford title compound as pale-yellow solid (0.149 g). LCMS: m / z 387.03 (M+H)+. Intermediate 34: Synthesis of 3-(4-(piperazin-l-yl)phenyl)piperidine-2, 6-dione hydrochloride lnt-34

[0540] Step-a: Synthesis of tert-butyl 4-(4-(2-ethoxy-2-oxoethyl)phenyl)piperazine-l- carboxylate

[0541] To a stirred solution of ethyl 2-(4-bromophenyl)acetate (2 g, 8.22 mmol), tert-butyl piperazine- 1 -carboxylate (1.53 g, 8.22 mmol) in toluene (15 mL) was added CS2CO3 (5.36 g, 16.45 mmol) and degassed with nitrogen for 10 min followed by Ru-Phos Pd-G2 (0.32g, 0.41 mmol) addition and the reaction mixture was heated for 12 h at 110 °C in sealed tube. Once the reaction was completed (monitored by TLC), the reaction mixture was dissolved in 10% MeOH / DCM and passed through celite. The filtrate was concentrated under reduced pressure to obtain crude compound. The crude compound was purified by combi flash column chromatography using 20-25% ethyl acetate in hexane as eluent to afford the title compound as off-white solid (2.1 g, 73.2%).XH NMR (400 MHz, DMSO-d6): 8 7.10 (d, J= 8.4 Hz, 2H), 6.89 (d, J= 8.4 Hz, 2H), 4.04 (q, J = 7.2 Hz, 2H), 3.52 (s, 2H), 3.43 (m, 4H), 3.05 (m, 4H), 1.41 (s, 9H), 1.16 (t, J = 7.2 Hz, 3H); LC-MS: m / z 349.2 (M+H)+.

[0542] Step-b: Synthesis of tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-l- carboxylate

[0543] To a stirred solution of tert-butyl 4-(4-(2-ethoxy-2-oxoethyl)phenyl)piperazine-l -carboxylate (2 g, 5.74 mmol) and acrylamide (0.36 g, 5.16 mmol) were taken in THF (20 mL) was added KO’Bu (0.70 g, 6.31 mmol) and the reaction mixture was heated for 12 h at 50 °C. Once the reaction was completed (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with EtOAc. The combined organic layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated under vacuum to give the residue which was purified by combi flash column chromatography using 40-60% ethyl acetate in hexane as eluent to afford the title compound as off-white solid (0.82 g, 38%). 'H NMR (400 MHz, DMSO-de): 6 10.77 (s, 1H), 7.06 (d, J= 8.8 Hz, 2H), 6.90 (d, J= 8.8 Hz, 2H), 3.73 (m, 1H), 3.44 (m, 4H), 3.06 (m, 4H), 2.69-2.54 (m, 1H), 2.48-2.42 (m, 1H), 2.18-2.07 (m, 1H), 2.03-1.95 (m, 1H), 1.41 (s, 9H); LC-MS: m / z 374.3 (M+H)+.

[0544] Step-c: Synthesis of 3-(4-(piperazin-l-yl)phenyl)piperidine-2, 6-dione hydrochloride

[0545] To a stirred solution of tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-l- carboxylate (0.82 g, 2.19 mmol) in DCM (10 mL) was added 4(N) dioxane HC1 (10 mL) at 0

[0546] °C and then slowly brought to RT and stirred for 16 h. The reaction mixture was evaporated under reduced pressure, and the resultant residue was washed with diethyl ether, then dried under vacuum to afford the title compound as yellowish solid (0.8 g, crude).TH NMR (400 MHz, DMSO-d6): d 10.78 (s, 1H), 9.35 (bs, 2H), 7.10 (d, J= 8.4 Hz, 2H), 6.96 (d, J= 8.4 Hz, 2H), 3.78-3.74 (m, 1H), 3.37 (m, 4H), 3.19 (m, 4H), 2.69-2.56 (m, 1H), 2.47-2.41 (m, 1H),

[0547] 2.21-2.09 (m, 1H), 2.05-1.95 (m, 1H); LC-MS: m / z 274.2 (M+H)+.

[0548] The intermediates 35 to 40A listed in below Table-3 were prepared by procedure similar to the one described in intermediate-34 with appropriate variations in reactants, quantities of reagents, protections and deprotections, solvents and reaction conditions. The characterization data of the compounds are summarized herein the below table:

[0549] Table-3

[0550] Intermediate 41: Synthesis of 3-((3-fluoro-4-(piperidin-4-yl)phenyl)amino)piperidine-

[0551] 2,6-dione hydrochloride Step-a: Synthesis of tert-butyl 4-(4-amino-2-fluorophenyl)-3,6-dihydropyridine-l(2H)- carboxylate

[0552] 4-bromo-3 -fluoroaniline (25.0 g, 131.56 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (44.75 g, 144.72 mmol) and potassium carbonate (54.5 g, 394.69 mmol) were dissolved in 1,4-dioxane (200 mL) and water (50 ml) with continuous stirring. The resultant solution was purged with nitrogen for 10 minutes followed by Pd(dppf)C12.DCM (8.05 g, 816.60 mmol) addition. The reaction mixture was stirred at 110°C for 16 h. Once the reaction was completed (monitored by TLC), the reaction mixture was diluted with EtOAc and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under vacuum to give the residue which was purified by combi flash column chromatography using 20-30% ethyl acetate in hexane as eluent to afford the title compound as yellow solid (38 g, 98.8%).XH NMR (400 MHz, DMSO-d6): 5 6.98 (t, J= 8.4 Hz, 1H), 6.35-6.27 (m, 2H), 5.78 (bs, 1H), 5.41 (s, 2H), 3.92 (bs, 2H), 3.48 (t, J= 5.6 Hz, 2H), 2.34 (bs, 2H), 1.42 (s, 9H); LC-MS: m / z 293.1 (M+H)+.

[0553] Step-b: Synthesis of tert-butyl 4-(4-amino-2-fluorophenyl)piperidine-l-carboxylate To a stirred solution of tert-butyl 4-(4-amino-2-fluorophenyl)-3,6-dihydropyridine- l(2H)-carboxylate (10.0g, 34.20 mmol) in ethanol (100 mL) and THF (10 mL) were added 10% Pd / C (3.64g, 34.2 mmol) and the reaction mixture was stirred for 16 h under hydrogen atmosphere. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed and washed with EtOAc, concentrated under vacuum to give the compound as yellow solid (10 g, crude).TH NMR (400 MHz, CDCL): 8 6.89 (t, J= 8.4 Hz, 1H), 6.33-6.25 (m, 2H), 5.18 (bs, 1H), 4.04 (d, J = 10.8 Hz, 2H), 3.93 (s, 1H), 2.78-2.72 (m, 2H), 1.63 (d, J = 12.0 Hz, 2H), 1.50-1.42 (m, 2H), 1.41 (s, 9H); LC-MS: m / z 195.2 (M+H- 100).

[0554] Step-c: Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2- fluorophenyl)piperidine-l-carboxylate

[0555] To a stirred solution of tert-butyl 4-(4-amino-2-fluorophenyl)piperidine-l -carboxylate (2.0 g, 6.79 mmol) and 3 -brom opiperidine-2, 6-dione (1.95 g, 10.19 mmol) in 1,4-dioxane (20 mL) was added DIPEA (3.51 g, 27.17 mmol). The reaction mixture was stirred at 110°C for 16 h. Once the reaction was completed (monitored by TLC), the reaction mixture was diluted with EtOAc, washed with water, brine, dried over anhydrous sodium sulphate and concentrated under vacuum to give the residue which was purified by combi flash column chromatography using 40-50% ethyl acetate in hexane as eluent to afford the title compound as yellow solid (0.350 g, 13%). 'H NMR (400 MHz, CDCh): 6 10.78 (s, 1H), 6.98 (t, J= 8.4 Hz, 1H), 6.46- 6.42 (m, 2H), 6.02 (d, J = 8.0 Hz, 2H), 4.32-4.29 (m, 1H), 4.05 (d, J = 11.2 Hz, 2H), 2.82-2.67 (m, 3H), 2.62-2.52 (m, 2H), 2.12-2.05 (m, 1H), 1.91- 1.82 (m, 1H), 1.65 (d, J = 10 Hz, 2H), 1.53-1.43 (m, 2H), 1.41 (s, 9H); LC-MS: m / z 306.2 (M+H-100).

[0556] Step-d: Synthesis of 3-((3-fluoro-4-(piperidin-4-yl)phenyl)amino)piperidine-2, 6-dione hydrochloride

[0557] To a stirred solution of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2- fluorophenyl)piperidine-l -carboxylate (1.2 g, 2.96 mmol) in DCM (12 mL) was added 4N dioxane HC1 (12 mL) at 0°C and stirred for 16 h at RT under nitrogen atmosphere. Then the reaction mixture was concentrated under vacuum to get crude product. The crude product was triturated with n-pentane and then dried under vacuum to afford pure title compound as paleyellow solid (1 g). 'H NMR (400 MHz, DMSO-d6): 10.79 (s, 1H), 8.89 (bs, 1H), 8.68 (bs, 1H), 6.94 (t, J= 8.8 Hz, 1H), 6.50-6.45 (m, 2H), 4.34-4.30 (m, 1H), 3.24 (d, J = 15.2 Hz, 2H), 3.05- 2.89 (m, 3H), 2.79-2.67 (m, 1H), 2.63-2.55 (m, 1H), 2.12-2.04 (m, 1H), 1.93- 1.77 (m, 5H); LC-MS: m / z 306.1 (M+H)+. The intermediates 42 to 43 listed in below Table-4 were prepared by procedure similar to the one described in intermediate-41 with appropriate variations in reactants, quantities of reagents, protections and deprotections, solvents and reaction conditions. The characterization data of the compounds are summarized herein the below table: Table-4

[0558] Intermediate 44: Synthesis of 3-(4-(4-oxopiperidin-l-yl)indolin-l-yl)piperidine-2, 6-dione Step a: Synthesis of benzyl 4-bromoindoline-l-carboxylate

[0559] To a stirred solution of 4-bromoindoline (4 g, 20.19 mmol) in DCM (50 mL) was added DIPEA (5.22 g, 40.33 mmol). After stirred at r.t. for 15 mins, benzyl chloroformate (4.13 g, 24.2 mmol) was added to the reaction mixture and it was stirred at r.t. for 16 h. Once the reaction was completed (monitored by TLC), ice-cold water was added and the solid formed was filtered. This was further dried under reduced pressure to give the crude off-white solid compound. (4.2 g). LCMS: m / z 333 (M+H)+.

[0560] Step-b: Synthesis of benzyl 4-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)indoline-l- carboxylate

[0561] A stirred solution of benzyl 4-bromoindoline-l-carboxylate (1 g, 3.01 mmol), l,4-dioxa-8- azaspiro[4.5]decane (0.862 g, 6.01 mmol) and CS2CO3 (2.94 g, 9.03 mmol) in PhMe (15 mL) was purged with argon for 15 minutes. After that X-Phos (0.143 g, 0.3 mmol) and Pd2dba3 were added to the reaction mixture. The reaction mixture was stirred at 90 °C for 16 h. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed, and the filtrate was concentrated under reduced pressure to give the crude compound. The crude was diluted with EtOAc and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue which was purified by combi flash column chromatography using 30% ethyl acetate and hexane as eluent to afford the title compound as light brown solid (0.4 g, 33%). LCMS: m / z 395.2 (M+H)+.

[0562] Step-c: Synthesis of 8-(indolin-4-yl)-l,4-dioxa-8-azaspiro[4.5]decane

[0563] To a stirred solution of benzyl 4-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)indoline-l-carboxylate (0.35 g, 0.887 mmol) in EtOAc (4 mL) and THF (4 mL) were added 10% Pd / C (0.189 g, 1.77 mmol) and the reaction mixture was stirred for 6 h under hydrogen atmosphere. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed and washed with EtOAc:THF (100 mL: 100 mL). The filtrate was concentrated under reduced pressure to give the compound as yellow solid (0.25 g, crude). LCMS: m / z 261 (M+H)+.

[0564] Step-d: Synthesis of 8-(l-(2,6-bis(benzyloxy)pyridin-3-yl)indolin-4-yl)-l,4-dioxa-8- azaspiro [4.5] decane

[0565] A stirred solution of 8-(Indolin-4-yl)-l,4-dioxa-8-azaspiro[4.5]decane (1.2 g, 4.60 mmol), 2,6- bis(benzyloxy)-3-bromopyridine (1.877 g, 5.07 mmol) and Cs2CO3 (3.75 g, 11.52 mmol) in PhMe (15 mL) was purged with argon for 15 minutes followed by X-Phos (0.22 g, 0.46 mmol) and Pd2dba3 (0.422, 0.46 mmol) addition. The reaction mixture was stirred at 90 °C for 16 h. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed, and the filtrate was concentrated under reduced pressure to give the crude residue. The crude residue was diluted with EtOAc and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the crude compound which was purified by combi flash column chromatography using 40% ethyl acetate and hexane as eluent to afford the title compound as light brown solid (1.3 g, 51% yield). LCMS: m / z 550.02 (M+H)+.

[0566] Step-e: Synthesis of 3-(4-(l,4-Dioxa-8-azaspiro[4.5]decan-8-yl)indolin-l-yl)piperidine- 2, 6-dione

[0567] To a stirred solution of 8-(l-(2,6-bis(benzyloxy)pyridin-3-yl)indolin-4-yl)-l,4-dioxa-8- azaspiro[4.5]decane (1.2 g, 2.18 mmol) in EtOAc (6 mL) and THF (6 mL) were added 10% Pd / C (0.465 g, 4.36 mmol) and PtO2 (0.050 g, 0.21 mmol). The reaction mixture was stirred for 16 h under hydrogen atmosphere. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed and washed with EtOAc:THF (100 mL: 100mL). The filtrate was concentrated under reduced pressure to give the compound as yellow solid (0.35 g, crude). LCMS: m / z 371 (M+H)+.

[0568] Step-f: Synthesis of 3-(4-(4-oxopiperidin-l-yl)indolin-l-yl)piperidine-2, 6-dione

[0569] To a stirred solution of 3-(4-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)indolin-l-yl)piperidine-2,6- dione (0.2 g, 0.53 mmol) in THF (3 mL) was added IN H2SO4 (3 mL) and the reaction mixture was stirred at 60 °C for 16 h. Once the reaction was completed (monitored by TLC), the reaction mixture concentrated under reduced pressure to give the crude compound. The crude compound was washed with sat. NaHCOs solution (20 mL) and extracted with EtOAc (3 X 100 mL). The extracted solvent was dried over Na2SO4, and the solvent was removed under reduced pressure to give the crude compound (0.2 g). LCMS: m / z 328.10 (M+H)+.

[0570] Intermediate 45: Synthesis of 3-(4-(4-(Methylamino)piperidin-l-yl)indolin-l- yl)piperidine-2, 6-dione

[0571] Step-a: Synthesis of benzyl-4-(4-((tert-butoxycarbonyl)(methyl)amino)piperidin-l- yl)indoline-l-carboxylate

[0572] A stirred solution of benzyl 4-bromoindoline-l -carboxylate (1.5 g, 4.51 mmol), tert-butyl methyl(piperidin-4-yl)carbamate (1.16 g, 5.41 mmol) and CS2CO3 (4.41 g, 13.5 mmol) in PhMe (15 mL) was purged with argon for 15 minutes followed by X-Phos (0.215g, 0.45 mmol) and Pd2dba3 (0.365, 0.45 mmol) addition. The reaction mixture was stirred at 90 °C for 16 h. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed, and the filtrate was concentrated under reduced pressure to give the crude compound. The crude was diluted with EtOAc and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue which was purified by combi flash column chromatography using 40% ethyl acetate and hexane as eluent to afford the title compound as light brown solid (1.5 g, 71%). LCMS: m / z 466 (M+H)+.

[0573] Step-b: Synthesis of tert-butyl (l-(indolin-4-yl)piperidin-4-yl)(methyl)carbamate

[0574] To a stirred solution of benzyl 4-(4-((tert-butoxycarbonyl)(methyl)amino)piperidin-l- yl)indoline- 1 -carboxylate (1.50 g, 3.21 mmol) in EtOAc (10 mL) and THF (lO mL) were added 10% Pd / C (0.51 g, 4.83 mmol) and the reaction mixture was stirred for 6 h under hydrogen atmosphere. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed and washed with EtOAc:THF (100 mL: 100 mL). The filtrate was concentrated under reduced pressure to give the compound as yellow solid (1 g, crude). LCMS: m / z 332 (M+H)+.

[0575] Step-c: Synthesis of tert-butyl (l-(l-(2,6-bis(benzyloxy)pyridin-3-yl)indolin-4- yl)piperidin-4-yl)(methyl)carbamate A stirred solution of tert-butyl (l-(indolin-4-yl)piperidin-4-yl)(methyl)carbamate (1 g, 3.01 mmol), 2,6-bis(benzyloxy)-3-bromopyridine (1.22 g, 5.07 mmol) and CS2CO3 (2.45 g, 7.54 mmol) in PhMe (15 mL) was purged with argon for 15 minutes followed by X-Phos (0.144 g, 0.31 mmol) and Pd2dba3 (0.276, 0.3 mmol) addition. The reaction mixture was stirred at 90 °C for 16 h. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed, and the filtrate was concentrated under reduced pressure to give the crude compound. The crude was diluted with EtOAc and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue which was purified by combi flash column chromatography using 30% ethyl acetate and hexane as eluent to afford the title compound as light brown solid (0.8 g, 42% yield). LCMS: m / z 621 (M+H)+.

[0576] Step-d: Synthesis of tert-butyl (l-(l-(2,6-dioxopiperidin-3-yl)indolin-4-yl)piperidin-4- yl)(methyl)carbamate

[0577] To a stirred solution of tert-butyl (l-(l-(2,6-bis(benzyloxy)pyridin-3-yl)indolin-4-yl)piperidin- 4-yl)(methyl)carbamate (0.8 g, 1.28 mmol) in EtOAc (6 mL) and THF (6 mL) were added 10% Pd / C (0.27 g, 2.57 mmol) and PtO2 (0.029 g, 0.12 mmol). The reaction mixture was stirred for 16 h under hydrogen atmosphere. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed and washed with EtOAc:THF (100 mL: 100mL). The filtrate was concentrated under reduced pressure to give the compound as brown solid (0.25 g, crude). LCMS: m / z 443.1 (M+H)+.

[0578] Step-e: Synthesis of 3-(4-(4-(methylamino)piperidin-l-yl)indolin-l-yl)piperidine-2,6- dione

[0579] To a stirred solution of tert-butyl (l-(l-(2,6-dioxopiperidin-3-yl)indolin-4-yl)piperidin-4- yl)(methyl)carbamate (0.22 g, 0.49 mmol) in dioxane (3 mL) was added 4M HC1 in dioxane (2 mL) and the reaction mixture was stirred at r.t. for 6 h. Once the reaction was completed (monitored by TLC), the reaction mixture concentrated under reduced pressure to give the crude compound. The crude compound was washed with pentane (20 mL) and Et2O (20 mL) and decanted. The resulted solid was dried under reduced pressure to give the titled compound. (0.18 g). LCMS: m / z 343.15 (M+H)+. Intermediate 46: Synthesis of 3-(8-(4-oxopiperidin-l-yl)-2,3-dihydro-4H- benzo[b][l,4]oxazin-4-yl)piperidine-2, 6-dione

[0580] Step a: Synthesis of benzyl 8-bromo-2,3-dihydro-4H-benzo[b][l,4]oxazine-4-carboxylate To a stirred solution of 8-bromo-3,4-dihydro-2H-benzo[b][l,4]oxazine (3.2 g, 14.94 mmol) in JLdTHF (10:30 mL) was added NaHCCh (3.76 g, 44.8 mmol). After stirring at r.t. for 15 mins, benzyl chloroformate (4.13 g, 24.2 mmol) was added to the reaction mixture and it was stirred at r.t. for 2 h. Once the reaction was completed (monitored by TLC), it was diluted with EtOAc and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue which was purified by combi flash column chromatography using 5% ethyl acetate and hexane as eluent to afford the title compound as light brown solid (4 g, 76%). LCMS: m / z 349 (M+H)+.

[0581] Step-b: Synthesis of benzyl-8-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-2,3-dihydro-4H- benzo[b][l,4]oxazine-4-carboxylate

[0582] A stirred solution of benzyl 8-bromo-2,3-dihydro-4H-benzo[b][l,4]oxazine-4-carboxylate (2.7 g, 7.75 mmol), l,4-dioxa-8-azaspiro[4.5]decane (3.88 g, 27.1 mmol) and Cs2CO3 (6.31 g, 19.3 mmol) in PhMe (35 mL) was purged with argon for 15 minutes followed by X-Phos (0.37 g, 0.77 mmol) and Pd2dba3 (0.71, 0.77 mmol) addition. The reaction mixture was stirred at 100 °C for 12 h. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed, and the filtrate was concentrated under reduced pressure to give the crude compound as light brown solid (2.8 g). LCMS: m / z 411.3 (M+H)+.

[0583] Step-c: Synthesis of 8-(3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)-l,4-dioxa-8- azaspiro [4.5] decane To a stirred solution of benzyl 8-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-2,3-dihydro-4H- benzo[b][l,4]oxazine-4-carboxylate (0.1 g, 0.244 mmol) in EtOAc (1 mL) and THF (1 mL) were added 10% Pd / C (0.026 g, 0.24 mmol) and the reaction mixture was stirred for 16 h under hydrogen atmosphere. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed and washed with EtOAc:THF (100 mL: 100 mL). The filtrate was concentrated under reduced pressure to give the compound as yellow solid (0.07 g, crude LCMS: m / z 111 (M+H)+.

[0584] Step-d: Synthesis of 8-(4-(2,6-Bis(benzyloxy)pyridin-3-yl)-3,4-dihydro-2H- benzo[b][l,4]oxazin-8-yl)-l,4-dioxa-8-azaspiro[4.5]decane

[0585] A stirred solution of 8-(3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)-l,4-dioxa-8- azaspiro[4.5]decane (2.4 g, 4.60 mmol), 2,6-bis(benzyloxy)-3-bromopyridine (4.18 g, 11.2 mmol) and NaOt-Bu (2.5 g, 26 mmol) in PhMe (40 mL) was purged with argon for 15 minutes followed by xantphos (0.50 g, 0.86 mmol) and Pd2dba3 (0.795, 0.86 mmol) addition. The reaction mixture was stirred at 100°C for 12 h. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed, and the filtrate was concentrated under reduced pressure to give the crude residue. The crude residue was diluted with EtOAc and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the crude compound which was purified by combi flash column chromatography using 40% ethyl acetate and hexane as eluent to afford the title compound as light brown solid (3.6 g, 73% yield LCMS: m / z 566 (M+H)+.

[0586] Step-e: Synthesis of 3-(8-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-2,3-dihydro-4H- benzo[b][l,4]oxazin-4-yl)piperidine-2, 6-dione

[0587] To a stirred solution of 8-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,4-dihydro-2H- benzo[b][l,4]oxazin-8-yl)-l,4-dioxa-8-azaspiro[4.5]decane (1.8 g, 3.18 mmol) in EtOAc (10 mL) and THF (10 mL) were added 10% Pd / C (0.50 g, 4.77 mmol) and PtO2 (0.144 g, 0.63 mmol). The reaction mixture was stirred for 16 h under hydrogen atmosphere. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed and washed with EtOAc:THF (100 mL: 100 mL). The filtrate was concentrated under reduced pressure to give the compound as yellow solid (1.2 g, crude). LCMS: m / z 388 (M+H)+. Step-f: Synthesis of 3-(8-(4-oxopiperidin-l-yl)-2,3-dihydro-4H-benzo[b][l,4]oxazin-4- yl)piperidine-2, 6-dione

[0588] To a stirred solution of 3-(8-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-2,3-dihydro-4H- benzo[b][l,4]oxazin-4-yl)piperidine-2, 6-dione (0.2 g, 0.53 mmol) in THF (2 mL) was added IN H2SO4 (2 mL) and the reaction mixture was stirred at 75 °C for 4 h. Once the reaction was completed (monitored by TLC), the reaction mixture concentrated under reduced pressure to give the crude compound. The crude compound was washed with sat. NaHCCh solution (20 mL) and extracted with 5% MeOH in DCM (3 X 100 mL). The extracted solvent was dried over Na2SO4, and the solvent was removed under reduced pressure to give the titled compound. (0.15 g). LCMS: m / z 344.34 (M+H)+.

[0589] Intermediate 47: Synthesis of 2-(4-(l-(2,6-dioxopiperidin-3-yl)indolin-4-yl)piperazin-l- yl)aceticacid

[0590] Step-a: Synthesis of benzyl 4-(4-(2-(tert-butoxy)-2-oxoethyl)piperazin-l-yl)indoline-l- carboxylate

[0591] A stirred solution of benzyl-4-bromoindoline-l-carboxylate (2 g, 6.01 mmol), tert-butyl 2- (piperazin-l-yl)acetate (1.80 g, 9.02 mmol) and Cs2CO3 (5.88 g, 18.06 mmol) in PhMe (25 mL) was purged with argon for 15 minutes. After that X-Phos (0.28 g, 0.60 mmol) and Pd2dba3 (0.55, 0.60 mmol) were added to the reaction mixture. The reaction mixture was stirred at 100°C for 12 h. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed, and the filtrate was concentrated under reduced pressure to give the crude residue. The crude residue was diluted with EtOAc and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the crude compound which was purified by combi flash column chromatography using 40% ethyl acetate and hexane as eluent to afford the title compound as light brown solid (2 g, 73%). LCMS: m / z 452 (M+H)+.

[0592] Step-b: Synthesis of tert-butyl 2-(4-(indolin-4-yl)piperazin-l-yl)acetate

[0593] To a stirred solution of benzyl 4-(4-(2-(tert-butoxy)-2-oxoethyl)piperazin-l-yl)indoline-l- carboxylate (2 g, 4.42 mmol) in EtOAc (15 mL) and THF (15 mL) were added 10% Pd / C (0.47 g, 4.42 mmol) and the reaction mixture was stirred for 12 h under hydrogen atmosphere. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed and washed with EtOAc:THF (100 mL: 100 mL). The filtrate was concentrated under reduced pressure to give the compound as yellow solid (2 g, crude). LCMS: m / z 318 (M+H)+.

[0594] Step-c: Synthesis of tert-butyl 2-(4-(l-(2,6-dioxopiperidin-3-yl)indolin-4-yl)piperazin-l- yl)acetate

[0595] To a stirred solution of tert-butyl 2-(4-(indolin-4-yl)piperazin-l-yl)acetate (1 g, 3.14 mmol), 3- bromopiperidine-2, 6-dione (0.66 g, 3.46 mmol) in DMF (10 mL) was added NaHCOs (0.52 g, 6.29 mmol) and the reaction mixture was stirred at 80 °C for 24 h. Once the reaction was completed (monitored by TLC), the reaction mixture was quenched with ice-cold water and diluted with EtOAc followed by washing with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue. The residue was triturated with n-pentane, Et2O and then dried under vacuum to afford the title compound as pale-yellow solid (0.3 g). LCMS: m / z 429 (M+H)+.

[0596] Step-d: Synthesis of 2-(4-(l-(2,6-dioxopiperidin-3-yl)indolin-4-yl)piperazin-l-yl)acetic acid

[0597] To a stirred solution of tert-butyl 2-(4-(l-(2,6-dioxopiperidin-3-yl)indolin-4-yl)piperazin-l- yl)acetate (0.25 g, 0.58 mmol) in DCM (8 mL) was added TFA (0.5 mL) and the reaction mixture was stirred at r.t. for 16 h. Once the reaction was completed (monitored by TLC), the reaction mixture concentrated under reduced pressure to give the crude compound. The crude compound was washed with pentane (20 mL) and Et2O (20 mL) and decanted. The resulted solid was dried under reduced pressure to give the title compound (0.19 g). LCMS: m / z 373.4 (M+H)+.

[0598] Intermediate 48: Synthesis of 3-(8-(4-oxocyclohexyl)-2,3-dihydro-4H-benzo[b] [1,4] oxazin-4-yl)piperidine-2, 6-dione lnt-48 Step-a: Synthesis of 2-amino-6-bromophenol

[0599] To a stirred solution of 2-bromo-6-nitrophenol (20 g, 91.73 mmol) in MeOH (200 mL) was added Zn dust (59.9 g, 917.39 mmol) followed by portion wise addition of NH4CI (49 g, 917.39 mmol) over 5 min. The resultant reaction mixture stirred for 1-2 h at RT under nitrogen atmosphere. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed, and the filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was triturated with n-pentane and then dried under vacuum to afford title compound as pale-yellow solid (24 g). LCMS: m / z 189.1 (M+H)+.

[0600] Step-b: Synthesis of 8-bronio-3.4-dihydro-2 / / -benzo| / ?|| 1.41 oxazine

[0601] To a stirred solution of 2-amino-6-bromophenol (20 g, 106.37 mmol) and 1,2-dibromoethane (23.9 g, 127.64 mmol) in DMF (200 mL) was added K2CO3 (44.1 g, 319 mmol). The reaction mixture was stirred for 18 h at 125 °C under nitrogen atmosphere. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed, and the filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was triturated with n-pentane and then dried under vacuum to afford title compound as pale-yellow solid (24 g).1HNMR (DMSO d6, 400 MHz): 5 6.69 (dd, J = 7.6, 1.6 Hz, 1H), 6.60-6.53 (m, 2H), 6.05 (bs, 1H), 4.19-4.17 (m, 2H), 3.30-3.28 (m, 2H); LCMS: m / z 215.3 (M+H)+.

[0602] Step-c: Synthesis of 8-(1.4-dioxaspiro|4.5|dec-7-en-8-yl)-3.4-dihydro-2 / / - benzo[ / >] [l,4]oxazine

[0603] 8-Bromo-3,4-dihydro-2J / -benzo[Z>][l,4]oxazine (5.3 g, 24.75 mmol), 4,4,5,5-tetramethyl-2- (l,4-dioxaspiro[4.5]dec-7-en-8-yl)-l,3,2-dioxaborolane (7.9 g, 29.71 mmol) and KaPCU (15.76 g, 74.27 mmol) was dissolved in 1,4-dioxane (55 mL) and H2O (11 ml). The resultant solution was purged with nitrogen for 10 minutes followed by Pd(dppf)C12.DCM (2.02 g, 2.47 mmol) addition. The reaction mixture was stirred at 95°C for 16 h. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed, and the filtrate was concentrated under reduced pressure to give the crude compound. The crude was diluted with EtOAc and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue which was purified by combi flash column chromatography using 20-30% ethyl acetate in hexane as eluent to afford the title compound as yellow solid (6.6 g, 97.5%).1HNMR (DMSO d6, 400 MHz): 5 6.57 (t, J = 7.6 Hz, 1H), 6.44 (dd, J = 8.0, 1.6 Hz, 1H), 6.29 (t, J = 7.6, 1.6 Hz, 1H), 5.69 (bs, 1H), 5.54-5.52 (m, 1H), 4.09- 4.07 (m, 2H), 3.92 (s, 4H), 3.27-3.24 (m, 2H), 2.46 (t, J = 6.4 Hz, 1H), 2.31-2.29 (m, 2H), 1.72 (t, J = 6.4

[0604] Step-d: Synthesis of 8-(l,4-dioxaspiro[4.5]decan-8-yl)-3,4-dihydro-2H- benzo[b] [l,4]oxazine

[0605] To a stirred solution of 8-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)-3,4-dihydro-2J7- benzo[Z>][l,4]oxazine (6.6 g, 24.14 mmol) in EtOH (60 mL) purged with N2 for 10-15 min was added Pd / C (5.13 g, 48.29 mmol). The reaction mixture was stirred under H2 atmosphere for 4 h. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed and washed the bed with MeOH (3 X 100 mL). The filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was triturated with n-pentane and then dried under vacuum to afford the title compound as pale-yellow solid (5.2 g). LCMS: m / z 276.1 (M+H)+.

[0606] Step-e: Synthesis of 3-(8-(l,4-dioxaspiro[4.5]decan-8-yl)-2,3-dihydro-4H- benzo[b][l,4]oxazin-4-yl)piperidine-2, 6-dione

[0607] To a stirred solution of 8-(l,4-dioxaspiro[4.5]decan-8-yl)-3,4-dihydro-2H- benzo[b][l,4]oxazine (6.9 g, 25.05 mmol) and 3 -bromopiperidine-2, 6-dione (9.62 g, 50.11 mmol) in DMF (70 mL) was added NaHCCL (6.31 g, 75.17 mmol). The reaction mixture was stirred for 18 h at 70 °C. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed and washed the bed with EtOAc (3 X 100 mL). The filtrate was diluted with EtOAc and washed with ice-cold water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue which was purified by combi flash column chromatography using 80% ethyl acetate in hexane as eluent to afford the title compound as yellow solid (2.5 g, 26% yield). LCMS: m / z 387.3 (M+H)+.

[0608] Step-f: Synthesis of 3-(8-(4-oxocyclohexyl)-2,3-dihydro-4H-benzo[b][l,4]oxazin-4- yl)piperidine-2, 6-dione

[0609] To a stirred solution of 3-(8-(l,4-dioxaspiro[4.5]decan-8-yl)-2,3-dihydro-4H- benzo[b][l,4]oxazin-4-yl)piperidine-2, 6-dione (1.6 g, 4.13 mmol) in THF (20 mL) was added 6M HC1 (24 mL) and the reaction mixture was stirred at r.t. for 4 h. Once the reaction was completed (monitored by TLC), the reaction mixture concentrated under reduced pressure to give the residue which was basified using sat. NaHCOs solution. The resultant solid was then filtered and dried under reduced pressure to give the Int-48 as yellow solid (1.4 g).1HNMR (DMSO d6, 400 MHz): 5 10.83 (s, 1H), 6.71-6.68 (m, 2H), 6.52-6.50 (m, 1H), 4.92-4.88 (m, 1H), 4.22-4.19 (t, J= 4.4 Hz, 2H), 3.37-3.35 (m, 1H), 3.28-3.21 (m, 2H), 2.85-2.85 (m, 1H), 2.59-2.53 (m, 3H), 2.34-2.23 (m, 3H), 2.03-2.00 (m, 2H), 1.83-1.76 (m, 3H); LCMS: m / z 343.4 (M+H)+; HPLC: 98.14 %.

[0610] Intermediate 49: Synthesis of 3-(4-(4-oxocyclohexyl)-3,4-dihydroquinoxalin-l(2H)- yl)piperidine-2, 6-dione

[0611] Intermediate 49 was prepared by procedure similar to the one described in Intermediate 48 with appropriate variations in reactants, quantities of reagents, protections and deprotections, solvents and reaction conditions. 1H NMR (400 MHz, DMSO-d6): 5 10.79 (bs, 1H), 6.77 (d, J = 7.2 Hz, 1H), 6.61-6.55 (m, 2H), 6.51-6.47 (m, 1H), 4.83-4.79 (m, 1H), 4.19-

[0612] 4.15 (m, 1H), 3.20-3.10 (m, 4H), 2.84-2.79 (m, 1H), 2.69-2.54 (m, 3H), 2.30-2.24 (m, 3H), 1.99-1.86 (m, 5H) ; LCMS: m / z 342.1 (M+H)+, HPLC: 97.88 %.

[0613] Intermediate 50: Synthesis of l-(8-(4-oxocyclohexyl)chroman-4-yl)dihydropyrimidine- 2,4(lH,3H)-dione lnt-50

[0614] Step-a: Synthesis of 8-bromochroman-4-amine

[0615] To a stirred solution of 8-bromochroman-4-one (1.65 g, 7.276 mmol) in MeOH (20 mL) was added ammonium acetate (8.41 g, 109.14 mmol) followed by addition of NaCNBH4 (0.686 g, 62.84 mmol) and resultant reaction mixture was stirred at 80°C for 16h. Once the reaction was completed (monitored by TLC), the methanol was removed under reduced pressure and crude was diluted with ethyl acetate and basified with 2M NaOH solution up to pH>10, separated the organic layer and dried over Na2SO4 and concentrated to afford title compound as pale-yellow solid (1.6 g, 100%). LCMS: m / z 228.1 (M+H)+.

[0616] Step-b: Synthesis of l-(8-bromochroman-4-yl)dihydropyrimidine-2,4(lH,3H)-dione

[0617] To a stirred solution of 8-bromochroman-4-amine (3 g, 13.15 mmol) in toluene (25 mL) was added acrylic acid (1.23 g, 17.09 mmol) and resulting mixture was stirred at 110°C for 2h. Once the reaction was completed (monitored by TLC), the toluene was removed under reduced pressure. The crude was dissolved in acetic acid (25 mL) and added urea (2.37 g, 39.45 mmol) and resultant reaction mixture was stirred at 120°C for 16h. After the completion of reaction (monitored by TLC) removed acetic acid completely under reduced pressure. The crude was diluted with EtOAc and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue which was purified by combi flash column chromatography using 50-60% ethyl acetate in hexane as eluent to afford the title compound as a yellow solid (2 g, 46.7%). LCMS: m / z 325.01 (M+H)+.

[0618] Step-c: Synthesis of l-(8-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)chroman-4- yl)dihydropyrimidine-2,4(lH,3H)-dione l-(8-bromochroman-4-yl)dihydropyrimidine-2,4(lH,3H)-dione (1.98 g, 6.08 mmol), 4, 4, 5, 5- tetramethyl-2-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)-l,3,2-dioxaborolane (1.94 g, 7.30 mmol) and K3PO4 (3.87 g, 18.26 mmol) was dissolved in 1,4-dioxane (25 mL) and H2O (5 ml). The resultant solution was purged with nitrogen for 10 minutes followed by Pd(dppf)C12.DCM (0.497 g, 0.609 mmol) addition. The reaction mixture was stirred at 100°C for 4 h. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed, and the filtrate was concentrated under reduced pressure to give the crude compound. The crude was diluted with EtOAc and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue which was purified by combi flash column chromatography using 60-70% ethyl acetate in hexane as eluent to afford the title compound as yellow solid (1.5 g, 65.2%). LCMS: m / z 385.1 (M+H)+.

[0619] Step-d: Synthesis of l-(8-(l,4-dioxaspiro[4.5]decan-8-yl)chroman-4- yl)dihydropyrimidine-2,4(lH,3H)-dione

[0620] To a stirred solution of 8-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)-3,4-dihydro-2J7- benzo[Z>][l,4]oxazine (1.52 g, 3.97 mmol) in EtOH (40 mL) purged with ISh for 10-15 min was added Pd / C (0.549 g, 5.16 mmol). The reaction mixture was stirred under H2 atmosphere for 4 h. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed and washed the bed with MeOH (3 X 100 mL). The filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was triturated with n-pentane and then dried under vacuum to afford title compound as pale-yellow solid (1.5 g). LCMS: m / z 387.1 (M+H)+.

[0621] Step-e: Synthesis of l-(8-(4-oxocyclohexyl)chroman-4-yl)dihydropyrimidine-

[0622] 2,4(lH,3H)-dione

[0623] To a stirred solution of l-(8-(l,4-dioxaspiro[4.5]decan-8-yl)chroman-4-yl)dihydropyrimidine- 2,4(lH,3H)-dione (1.7 g, 4.399 mmol) in THF (17 mL) was added 6M HC1 (17 mL) and the reaction mixture was stirred at r.t. for 2 h. Once the reaction was completed (monitored by TLC), the reaction mixture concentrated under reduced pressure to give the residue which was basified using sat. NaHCOs solution. The resultant solid was then filtered and dried under reduced pressure to give the Int-50 as yellow solid (0.900 g); 1H NMR (400 MHz, DMSO-d6):

[0624] 5 10.25 (bs, 1H), 7.11 (d, J = 7.2 Hz, 1H), 6.99 (d, J= 7.2 Hz, 1H), 6.89-6.85 (m, 1H), 5.62- 5.58 (m, 1H), 4.40-4.36 (m, 1H), 4.27-4.25 (m, 1H), 3.38-3.32 (m, 2H), 3.25-3.15 (m, 2H), 2.91-2.85 (m, 1H), 2.62-2.54 (m, 1H), 2.48-2.42 (m, 1H), 2.25 (bs, 1H), 2.22 (bs, 1H), 2.05- 1.98 (m, 4H), 1.85-1.77 (m, 2H); LCMS: m / z 343.1 (M+H)+.

[0625] Intermediate 51: Synthesis of 3-(2-oxo-6-(4-oxocyclohexyl)benzo[cd]indol-l(2H)- yl)piperidine-2, 6-dione

[0626] Step-a: Synthesis of 6-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)benzo[cd]indol-2(lH)-one

[0627] 6-bromobenzo[cd]indol-2(lH)-one (1 g, 4.03 mmol), 4,4,5,5-tetramethyl-2-(l,4- dioxaspiro[4.5]dec-7-en-8-yl)-l,3,2-dioxaborolane (1.60 g, 6.04 mmol) and K3PO4 (2.56 g, 12.09 mmol) was dissolved in 1,4-dioxane (10 mL) and H2O (2 ml). The resultant solution was purged with nitrogen for 10 minutes followed by Pd(dppf)C12.DCM (0.329 g, 0.4 mmol) addition. The reaction mixture was heated to 100 °C for 6 h. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed, and the filtrate was concentrated under reduced pressure to give the crude compound. The crude was diluted with EtOAc and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue which was purified by combi flash column chromatography using 50-60% ethyl acetate in hexane as eluent to afford the title compound as yellow solid (1.0 g, 80.74%). LCMS: m / z 308.12 (M+H)+.

[0628] Step-b: Synthesis of 6-(l,4-dioxaspiro[4.5]decan-8-yl)benzo[cd]indol-2(lH)-one

[0629] To a stirred solution of 6-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)benzo[cd]indol-2(lH)-one (1.0 g, 3.25 mmol) in EtOAc (5 mL) and MeOH (30 mL) purged with N2 for 10-15 min was added PtO2 (0.739 g, 3.253 mmol). The reaction mixture was stirred under H2 atmosphere for 4 h. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed and washed the bed with MeOH (3 X 100 mL). The filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was triturated with n-pentane and then dried under vacuum to afford title compound as pale-yellow solid (0.900 g). LCMS: m / z 310.1 (M+H)+.

[0630] Step-c: Synthesis of 3-(2-oxo-6-(l,4-dioxaspiro[4.5]decan-8-yl)benzo[cd]indol-l(2H)- yl)piperidine-2, 6-dione

[0631] To a stirred solution of 6-(l,4-dioxaspiro[4.5]decan-8-yl)benzo[cd]indol-2(lH)-one (0.900 g, 2.909 mmol) and 3-bromopiperidine-2, 6-dione ( 2.79g, 14.54 mmol) in DMF (15 mL) and THF (15 mL) was added NaH (0.743 g, 32.32 mmol). The reaction mixture was stirred for 18 h at 70°C. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed and washed the bed with EtOAc (3 X 100 mL). The filtrate was diluted with EtOAc and washed with ice-cold water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue which was purified by combi flash column chromatography using 80% ethyl acetate in hexane as eluent to afford the title compound as yellow solid (0.450 g, 36.79% yield). LCMS: m / z 421.1 (M+H)+.

[0632] Step-d: Synthesis of 3-(2-oxo-6-(4-oxocyclohexyl)benzo[cd]indol-l(2H)-yl)piperidine- 2, 6-dione

[0633] To a stirred solution of 3-(2-oxo-6-(l,4-dioxaspiro[4.5]decan-8-yl)benzo[cd]indol-l(2H)- yl)piperidine-2, 6-dione (0.450 g, 1.07 mmol) in THF (5 mL) was added 6M HC1 (5 mL) and the reaction mixture was stirred at r.t. for 4 h. Once the reaction was completed (monitored by TLC), the reaction mixture concentrated under reduced pressure to give the residue which was basified using sat. NaHCOs solution. The resultant solid was then filtered and dried under reduced pressure to give the Int-51 as yellow solid (0.300 g).1HNMR (DMSO d6, 400 MHz): 5 11.12 (s, 1H), 8.56 (d, J= 5.6 Hz, 1H), 8.12 (d, J= 6.8 Hz, 1H), 7.92-7.88 (m, 1H), 7.42 (d, .7= 7.2 Hz, 1H), 7.11 (d, .7= 4.6 Hz, 1H), 5.47-5.42 (m, 1H), 3.93-3.87 (m, 1H), 2.93-2.81 (m, 1H), 2.78-2.71 (m, 3H), 2.68-2.62 (m, 2H), 2.36-2.33 (m, 2H), 2.28-2.27 (m, 2H), 2.25-2.24 (m, 2H); LCMS: m / z 377.1 (M+H)+.

[0634] Intermediate 52: Synthesis of 3-(2-oxo-6-(4-oxopiperidin-l-yl)benzo[cd]indol-l(2H)- yl)piperidine-2, 6-dione

[0635] Step-a: Synthesis of 6-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)benzo[cd]indol-2(lH)-one

[0636] A stirred solution of 6-bromobenzo[cd]indol-2(lH)-one (1.0 g, 4.03 mmol), l,4-dioxa-8- azaspiro[4.5]decane (0.577 g, 4.03 mmol) and K3PO4 (2.13 g, 10.07 mmol) in 1,4-Dioxane (10 mL) was purged with argon for 15 minutes followed by PEPPSI (0.31 g, 0.40 mmol) addition. The reaction mixture was stirred at 100 °C for 12 h. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed, and the filtrate was concentrated under reduced pressure to give the residue which was purified by combi flash column chromatography using 30-40% ethyl acetate in hexane as eluent to afford the title compound as yellow solid (0.800 g, 64% yield).1HNMR (DMSO d6, 400 MHz): 5 10.59 (s, 1H), 8.21 (d, J = 6.8 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.80-7.76 (m, 1H), 6.94 (d, J = 7.2 Hz, 1H), 6.84 (d, J = 6.8 Hz, 1H), 3.94 (s, 4H), 3.18-3.13 (m, 4H), 1.92-1.90 (m, 4H); LCMS: m / z 311.0 (M+H)+.

[0637] Step-b: Synthesis of 3-(2-oxo-6-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)benzo[cd]indol- l(2H)-yl)piperidine-2, 6-dione

[0638] To a stirred solution of 6-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)benzo[cd]indol-2(lH)-one (0.600 g, 1.93 mmol) and 3-bromopiperidine-2, 6-dione ( 1.85g, 9.66 mmol) in DMF (30 mL) and THF (30 mL) was added NaH (0.444 g, 19.33 mmol). The reaction mixture was stirred for 18 h at 70°C. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed and washed the bed with EtOAc (3 X 100 mL). The filtrate was diluted with EtOAc and washed with ice-cold water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue which was purified by combi flash column chromatography using 60% ethyl acetate in hexane as eluent to afford the title compound as yellow solid (0.280 g, 40.33% yield).1HNMR (DMSO d6, 400 MHz): 5 11.11 (s, 1H), 8.28 (d, J = 7.2 Hz, 1H), 7.84-7.80 (m, 1H), 7.02-6.97 (m, 2H), 5.44-5.39 (m, 1H), 3.95 (s, 4H), 3.18-3.14 (m, 4H), 2.98-2.91 (m, 2H), 2.78-2.72 (m, 1H), 2.68-2.61 (m, 1H), 2.11-2.05 (m, 1H), 1.93-1.91 (m, 4H); LCMS: m / z 422.1 (M+H)+.

[0639] Step-c: Synthesis of 3-(2-oxo-6-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)benzo[cd]indol- l(2H)-yl)piperidine-2, 6-dione

[0640] To a stirred solution of 3-(2-oxo-6-(l,4-dioxaspiro[4.5]decan-8-yl)benzo[cd]indol-l(2H)- yl)piperidine-2, 6-dione (0.130 g, 0.308 mmol) in THF (3 mL) was added IM H2SO4 (2 mL) and the reaction mixture was stirred at 50°C for 16 h. Once the reaction was completed (monitored by TLC), the reaction mixture concentrated under reduced pressure to give the residue which was basified using sat. NaHCOs solution followed by extract with 5% methanol in DCM to give the Int-52 as yellow solid (0.110 g).1HNMR (DMSO d6, 400 MHz): 5 11.12 (s, 1H), 8.40 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 6.8 Hz, 1H), 7.88-7.84 (m, 1H), 7.06-7.02 (m, 2H), 5.46-5.41 (m, 1H), 3.42-3.32 (m, 4H), 2.70-2.67 (m, 4H), 2.68-2.61 (m, 2H), 2.11-2.05 (m, 2H); LCMS: m / z 378.1 (M+H)+.

[0641] Intermediate 53: Synthesis of l-(4-(3-(2-hydroxyphenyl)-7H-pyrrolo[2,3-c]pyridazin-5- yl)phenyl)piperazin-2-one

[0642] Step a: Synthesis of tert-butyl 4-(4-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-5-yl)phenyl)-3- oxopiperazine-l-carboxylate

[0643] 3-chloro-5-iodo-7H-pyrrolo[2,3-c]pyridazine (1.3 g, 3.584 mmol), tert-butyl 3-oxo-4-(4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)piperazine-l-carboxylate (1.58 g, 3.942 mmol) and potassium carbonate (0.991 g, 7.16 mmol) were dissolved in 1,4-dioxane (20 mL) and water (4 ml) with continuous stirring. The resultant solution was purged with nitrogen for 10 minutes followed by Pd(PPh3)4 (0.414 g, 0.35 mmol) addition. The reaction mixture was stirred at 100°C for 16 h. Once the reaction was completed (monitored by TLC), the reaction mixture was diluted with EtOAc and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under vacuum to give the residue which was purified by combi flash column chromatography using 20-30% ethyl acetate in hexane as eluent to afford the title compound as yellow solid (0.4 g, 22%); LC-MS: m / z 428.1 (M+H)+.

[0644] Step-b: Synthesis of tert-butyl 4-(4-(3-(2-hydroxyphenyl)-7H-pyrrolo[2,3-c]pyridazin-5- yl)phenyl)-3-oxopiperazine-l-carboxylate

[0645] A stirred solution of tert-butyl 4-(4-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-5-yl)phenyl)-3- oxopiperazine-1 -carboxylate (0.700 g, 1.25 mmol), (2-hydroxyphenyl)boronic acid (0.208 g, 1.505 mmol) and K2CO3 (0.520 g, 3.762 mmol) in 1,4-dioxane (10 mL) and H2O (2 ml) was purged with argon for 15 minutes followed by the addition of X-PhosPdG3 (0.106 g, 0.125 mmol). The reaction mixture was stirred at 100°C for 5 h. Once the reaction was completed (monitored by TLC), the reaction mixture was filtered through celite bed, and the filtrate was concentrated under reduced pressure to give the crude compound. The crude was diluted with EtOAc and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue which was purified by combi flash column chromatography using 40% ethyl acetate in hexane as eluent to afford the title compound as off-white solid (0.48 g, 62%). LCMS: m / z 486.2 (M+H)+.

[0646] Step-c: Synthesis of l-(4-(3-(2-hydroxyphenyl)-7H-pyrrolo[2,3-c]pyridazin-5- yl)phenyl)piperazin-2-one

[0647] To a stirred solution of tert-butyl 4-(4-(3-(2-hydroxyphenyl)-7H-pyrrolo[2,3-c]pyridazin-5- yl)phenyl)-3 -oxopiperazine- 1 -carboxylate (0.100 g, 0.162 mmol) in trifluoro acetic acid (1 mL) was added and stirred for 16 h at RT. The solvents were removed under reduced pressure and directly used for next step (0.060 g);TH NMR (DMSO d6, 400 MHz): 5 13.64 (s, 1H), 12.35 (s, 1H), 8.83 (s, 1H), 8.51 (s, 1H), 8.21 (d, J = 7.6 Hz, 1H), 7.93-7.90 (m, 2H), 7.34-7.32 (m, 2H), 7.01-6.97 (m, 3H), 3.79-3.76 (m, 2H), 3.34-3.32 (m, 3H), 3.01 (s, 2H); LCMS: m / z 386.1 (M+H)+.

[0648] General Procedure A for reductive amination:

[0649] To a stirred solution of ketone and amine. HC1 in methanol was added ZnCh and sodium cyanoborohydride and the reaction mixture was stirred at RT for 12 h. Once the reaction was completed (monitored by TLC), solvents were evaporated completely, followed by quenching by ice water and solid formed was filtered and dried. The filtrate was taken and washed with ethyl acetate and purified by prep HPLC, pure fractions were dried under lyophilization to afford the title compound.

[0650] General Procedure B for reductive amination:

[0651] To a stirred solution of corresponding amine.HCl and ketone in DMSO:THF : AcOH was added sodium acetate and the reaction mixture was stirred at 65°C for 18 h. After 18 h, the reaction mixture was cooled to 0°C and sodium triacetoxy borohydride was added. Furthermore, it was stirred at r.t. for 18h. Once the reaction was completed (monitored by TLC), the reaction mixture was concentrated under reduced pressure to remove THF and ice-cold water was added. The solid formed was filtered and dried under reduced pressure to give the crude compound. The crude compound was purified by prep HPLC, pure fractions were dried under lyophilization to afford the title compound.

[0652] General procedure C for acid and amine coupling to form amide:

[0653] To a stirred solution of corresponding amine.HCl and acid in DMF was added DIPEA and HATU. The reaction mixture was stirred at r.t. for 18 h. Once the reaction was completed (monitored by TLC), ice-cold water was added to the reaction mixture and the solid formed was filtered and dried under reduced pressure to give the crude compound. The crude compound was purified by prep HPLC, pure fractions were dried under lyophilization to afford the title amide compound.

[0654] General procedure D for urea formation:

[0655] To a stirred solution of corresponding reactant amine.HCl in DCM was added DIPEA and stirred for 10 min. Followed by triphosgene was added at 0°C and it was stirred for 30 min. After 30 mins, reactant 2 amine.HCl was added, and the reaction mixture was stirred at r.t. for 18 h. Once the reaction was completed (monitored by TLC), the solvent was removed under reduced pressure to give the crude compound. The crude compound was purified by prep HPLC, pure fractions were dried under lyophilization to afford the title urea compound.

[0656] The compounds listed in below Table-5 were prepared by procedure similar to the one described in general procedure A-D with appropriate variations in reactants, quantities of reagents, protections and deprotections, solvents and reaction conditions. The isomers were separated by Prep HPLC chromatography using PORO SHELL 120 C18 (150mmx4.6mm,5p): Mobile phase: A: 10 mM Ammonium Acetate pH: 5 B: CAN: Flow rate: 1.0 ml\min. TEMP: 40°C GRADIENT: 0 / 10,2 / 20,10 / 60,15 / 100,17 / 100,18 / 20,22 / 10 Diluent: ACN:water. The characterization data of the compounds are summarized herein the below table. Table-5

[0657] Although the present disclosure has been illustrated by certain of the preceding examples, it is not to be construed as being limited thereby; but rather, the present disclosure encompasses the generic area as hereinbefore disclosed. Various modifications and embodiments can be made without departing from the spirit and scope thereof. 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 disclosure. Example-Pl: Determination of Anti proliferative activity of compounds in cell line SK- MEL-5 by Cell Titer Glo®(Promega) assay

[0658] Cells were seeded into 96-well plates and the plate was incubated at 37 °C in incubator overnight. The next day, compounds were diluted 3 -fold to cover the 9-point concentration range in DMSO. Intermediate plate dilution was prepared in media followed with compound treatment in cells. Retreatment of cells with compound dilutions was performed on Day 4 and assay was terminated on day 8 for SK-MEL-5 cells using 100 pl of CellTiter-Glo and the plate was kept on orbital shaker for 20 minutes at RT. Luminescence signal was recorded on VICTORS instrument. Percent inhibition of proliferation was calculated at each concentration and plotted against the compound concentration. ECso value was calculated using GraphPad® software.

[0659] Selected compounds of the present invention were screened in the above-mentioned assay procedures for determination of ECso (SK-MEL-5) and the values are summarized into groups A, B and C in the Table-6. Herein the group “A” refers to ECso values lower than 10 nM, group “B” refers to ECso values between 10.01 nM to 100 nM (both inclusive) and group “C” refers to ECso values greater than 100 nM.

[0660] Table-6:

[0661] Example-P2: Determination of Anti proliferative activity of compounds in cell lines MV- 4-11 by Cell Titer Glo®(promega) assay

[0662] MV-4-11 (CRL-9591™) cells were seeded in 96 well plate flat black clear bottom plates using complete DMEM Medium. Next day, compounds listed in the present invention were added to cells from 10 mM stocks made in DMSO. Each concentration of compound was tested in triplicate with DMSO concentration at a final percentage not exceeding 0.3 in the cells. After the incubation of MV-4-11 cells with compound for 3 days; assay was terminated using 100 pl of CellTiter Gio® reagent. Luminescence readings were taken in Victor-5 instrument. Percent inhibition of proliferation was calculated using formula, % inhibition =100 -(luminescence value of test / luminescence value of DMSO control) * 100. EC50 was calculated using graph pad prism software. Selected compounds of the present invention were screened in the above-mentioned assay procedures and the inhibition data is presented in the Table-7 below.

[0663] Table-7:

[0664] Example-P3: Determination of SMARCA2 and SMARCA4 degradation in MV-4-11 cells by Western blot

[0665] MV-4-11 (CRL-9591™) cells were plated in 6 well plates using complete Iscove's Modified Dulbecco's Medium. On the third day, compounds of present invention were added to cells from 10 mM stocks made in DMSO (Sigma Cat no. D2650). Compound were tested at 100 nM with DMSO not exceeding final percentage of 0.1 in the cells. Cells were incubated with the compound for 16 hours followed by harvesting with IX RIPA lysis buffer (Thermo Fischer, catalogue number# 89900) containing protease inhibitor cocktail (Sigma catalogue number #P-8340). Equal amount of protein was loaded on SDS PAGE gel for electrophoresis.

[0666] Western blot was carried out for detection of either SMARCA2 (Cell signalling technologies, catalogue number #11966) or SMARCA4 antibody (Cell signalling technologies, catalogue 5 number #52251). Beta-Tubulin antibody (Cell signalling technologies, catalogue number #86298) was used as loading control. Percentage of SMARCA2 or SMARCA4 degradation was calculated using formula % Degradation = 100-(normalized band intensity in treated sample / normalized band intensity in DMSO sample) * 100.

[0667] Selected compounds of the present invention were screened in the above-mentioned assay procedures for determination of SMARCA2 / 4 degradation (MV-4-11) and the values, and the results are summarized into groups A, B and C in Table-8. Herein the group “A” refers to >80% degradation, group “B” refers to >50% to <80% degradation, group “C” refers to <50% to >10% degradation and “ND” refers to either “no degradation” or <10% degradation.

[0668] Table-8:

[0669] Incorporation by Reference

[0670] 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.

[0671] Equivalents

[0672] While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with such variations.

Claims

Claims:

1. A compound of formula (I):or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof; whereinRi at each occurrence is independently hydrogen, halo, alkyl, haloalkyl, alkoxy or hydroxy;R2 at each occurrence, is independently hydrogen, alkyl, halo or haloalkyl; or two R2 attached on the same carbon atom to form an oxo(=O) group;Xi, X2 and X3 are independently selected from CH, NH, C or N; wherein at least any one of Xi, X2 or X3 is N; ring A is arylenyl or heteroarylenyl; wherein the arylenyl and heteroaryl enyl are independently unsubstituted or substituted with 1, 2 or 3 groups selected from alkyl, hydroxy, halo or haloalkyl;L is, wherein asterisk mark indicates the point of attachment with ring A;Li is a bond, heterocycloalkylenyl, -O-heterocycloalkylenyl or cycloalkylenyl; wherein the heterocycloalkylenyl and cycloalkylenyl are independently unsubstituted or substituted with 1, 2 or 3 Ry;L2 is a bond, *-C(0)-(CH2)q-, *-C(0)-NR5- or -(CH2)b-; wherein asterisk mark indicates the point of attachment with Li;L3 is (heterocycloalkylenyl)p or cycloalkylenyl; wherein the cycloalkylenyl and heterocycloalkylenyl are independently unsubstituted or substituted with 1, 2 or 3 Ryi;R5 is hydrogen or alkyl;Ry and Ryiat each occurrence are independently selected from alkyl, halo, hydroxy or haloalkyl; or any of two Ryor Ryiattached on the same carbon atom to form an oxo(=O) group;M is selected from Ml, M2, M3, M4, M5, M6 or M7;wherein,X and X’ are independently CH, C or N;Y and Y’ are independently a bond, -NH-, -C(O)-NH-*, -CH2- or -O-; wherein the asterisk mark indicates the point of attachment with piperidinedione ring;Yi is N, NH, O, CH or CH2;Y2is N or CH;Y3is NH, C(O) or CH2;X4, X5 and Xe are independently N or C;X7, Xs and X9 are independently N or C; wherein at least one of X7, Xs or X9 is N;X10, Xu, Xi2and X13 are independently C or N;Zi, Z2and Z3are independently N or C;Z4 and Z5 are independently C or N;R3and 5 are independently hydrogen, halo, haloalkyl or alkyl;R4 at each occurrence is independently hydrogen or alkyl; or two R4 on the same carbon atom together represent an oxo(=O) group;‘m’ and ‘q’ are independently an integer of 1, 2 or 3;‘p’ is integer of 1 or 2;‘b’ is integer of 0, 1, 2 or 3;‘n’ is integer of 1, 2, 3 or 4; and- is a single bond or a double bond.

2. The compound of claim 1, wherein Ri at each occurrence, is independently halo, (Ci- Ce)alkyl, (Ci-Ce)alkoxy or hydroxy.

3. The compound of claim 1, wherein R2 at each occurrence is independently hydrogen, (Ci-Ce)alkyl or halo(Ci-Ce)alkyl.

4. The compound of claim 1, wherein ring A is selected fromindicates point of attachment to L.

5. The compound of claim 1, wherein L is selected from *-3- to 14-membered heterocycloalkylenyl-(3- to 14-membered heterocycloalkylenyl)p-, *-3- to 14-membered heterocycloalkylenyl-C(O)-(CH2)q-3- to 14-membered heterocycloalkylenyl-, *-O-3- to 14-membered heterocycloalkylenyl-C(O)-(CH2)q-3- to 14-membered heterocycloalkylenyl-, *-3- to 14-membered heterocycloalkylenyl-C(O)-NRs-3- to 14- membered heterocycloalkylenyl-, *-3- to 14-membered heterocycloalkylenyl-(CH2)b-3- to 14-membered heterocycloalkylenyl-, *-3- to 14-membered heterocycloalkylenyl-(C3- Ci4)cycloalkylenyl-; wherein heterocycloalkylenyl and cycloalkylenyl are independently unsubstituted or substituted with 1, 2 or 3 Ry; wherein asterisk mark indicates the point of attachment with ring A.

6. The compound of claim 1, wherein Li is selected fromring A.

7. The compound of claim 1, wherein L2 is a bond, *-C(O)-CH2-, *-C(0)-N(CH3)- or -CH2- ; wherein asterisk mark indicates the point of attachment with Li.

8. The compound of claim 1, wherein L3 is selected from9. The compound of claim 1, wherein M is a group of formula of Ml, M2, M3, M4, M5,M6 or M7 :

10. The compound of claim 9, wherein M is selected from11. The compound of claim 1, wherein R3 and Re at each occurrence are independently hydrogen, halo or (Ci-Ce)alkyl.

12. The compound of claim 1, wherein R4 is (Ci-Ce)alkyl, or two R4 attached on the same carbon to form an oxo(=O) group.

13. The compound of claim 1, represented by compound of formula (IA)or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.

14. The compound of claim 13, wherein Ri is hydrogen or halo.

15. The compound of claim 13, wherein R2 is hydrogen or (Ci-Ce)alkyl.

16. The compound of claim 13, wherein ring A is; wherein * mark indicates point of attachment to L.

17. The compound of claim 13, wherein Li is selected fromwherein * mark indicates point of attachment to ring A.

18. The compound of claim 13, wherein L2 is a bond, *-C(O)-CH2-, *-C(O)-N(CH3)- or -CH2-; wherein asterisk mark indicates the point of attachment with Li.

19. The compound of claim 13, wherein L3 is selected fromwherein * mark indicates point of attachment to M.

20. The compound of formula 13, wherein M is selected from21. The compound of claim 1, represented by compound of formula (IB)or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.

22. The compound of claim 21, wherein Li is selected from; wherein * mark indicates point of attachment to ring A.

23. The compound of claim 21, wherein L2 is a bond or -CH2-.

24. The compound of claim 21, wherein L3 is selected from; wherein * mark indicates point of attachment to M.

25. The compound of claim 21, wherein Re is hydrogen or halo.

26. The compound of claim 1, represented by compound of formula (IC)or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof; wherein p, q, r and s are independently selected from CH, C or N.

28. The compound of claim 1, represented by compound of formula (ID)or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof; wherein, p, q, r, s are independently selected from CH, C or N.

29. The compound of claim 1, represented by compound of formula (IE)or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.

30. The compound of claim 1, represented by compound of formula (IF)or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.

31. The compound of claim 1, represented by compound of formula (IG)or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.

32. The compound of claim 1, represented by compound of formula (IH)or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.

33. The compound of claim 1, represented by compound of formula (IJ)or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.

34. The compound of claims 1 to 33, wherein the compound is selected fromor a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.

35. A pharmaceutical composition comprising the compound of any one of claims 1 to 34 or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, and a pharmaceutically acceptable carrier or an excipient.

36. The pharmaceutical composition of claims 1 to 34, for use in degrading a target protein in a subject, wherein the target protein is SMARCA2 and / or SMARCA4.

37. The pharmaceutical composition of claim 36, for use in a subject, wherein the subject is afflicted with a disease or disorder dependent upon at least one of SMARCA2 and SMARCA4.

38. The pharmaceutical composition of claim 37, wherein the disease or disorder is cancer selected from hematologic cancers, lung cancer, non-small cell lung cancer, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic leukemia, promyelocytic leukemia, acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breastcancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, granulocytic leukemia, chronic granulocytic leukemia chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes, dysplasias, metaplasias, embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, head and neck cancer, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, liver cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma Hodgkin's lymphoma, nonHodgkin's lymphoma, Burkitt's lymphoma, malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, malignant rhabdoid tumor (MRT), rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors, carcinomas, sarcomas, small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer or Wilms' tumor.

39. A method of degrading a target protein in a subject, comprising administering to the subject in need thereof, a therapeutically effective amount of the compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.

40. The method of claim 39, wherein the target protein is SMARCA2 and / or SMARCA4.

41. A method of treating or delaying progression of a disease or a disorder dependent upon at least one of SMARCA2 and SMARCA4 in a subject, comprising administering to the subjectin need thereof, a therapeutically effective amount of a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt or a stereoisomer or tautomer thereof.

42. The method of claim 41, wherein the disease or disorder dependent upon SMARCA2 and / or SMARCA4 is cancer, selected from hematologic cancers, lung cancer, non-small cell lung cancer, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic leukemia, promyelocytic leukemia, acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, granulocytic leukemia, chronic granulocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes, dysplasias, metaplasias, embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, head and neck cancer, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, liver cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma Hodgkin's lymphoma and nonHodgkin's lymphoma, Burkitt's lymphoma, malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, malignant rhabdoid tumor (MRT), rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors, carcinomas, sarcomas, small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer or Wilms' tumor.

43. A compound of claims 1 to 34, for use as a medicament.

44. A compound according to any one of claims 1 to 34, for use in the treatment of a disease or disorder dependent upon SMARCA2 and / or SMARCA4, wherein the disease or disorder dependent upon SMARCA2 and / or SMARCA4 is cancer.

45. The use of claim 44, wherein the cancer is, selected from hematologic cancers, lung cancer, non-small cell lung cancer, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic leukemia, promyelocytic leukemia, acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, granulocytic leukemia, chronic granulocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes, dysplasias, metaplasias, embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, head and neck cancer, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, liver cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma Hodgkin's lymphoma and non-Hodgkin's lymphoma, Burkitt's lymphoma, malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, malignant rhabdoid tumor (MRT), rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors, carcinomas, sarcomas, small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer or Wilms' tumor.

46. Use of a compound of formula (I) or a pharmaceutical acceptable salt or a stereoisomer or tautomer thereof according to any one of claims 1 to 34, in the manufacture of a medicamentfor the treatment of a disease or disorder dependent upon SMARCA2 and / or SMARCA4; wherein the disease or disorder is cancer.

47. The use of claim 46, wherein the cancer is, selected from hematologic cancers, lung cancer, non-small cell lung cancer, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic leukemia, promyelocytic leukemia, acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, granulocytic leukemia, chronic granulocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes, dysplasias, metaplasias, embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, head and neck cancer, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, liver cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma Hodgkin's lymphoma and non-Hodgkin's lymphoma, Burkitt's lymphoma, malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, malignant rhabdoid tumor (MRT), rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors, carcinomas, sarcomas, small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer or Wilms' tumor.

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