Substituted tricyclic compounds as KRAS degraders

Abstract

The present invention provides substituted tricyclic compound of formula (I), which are therapeutically useful as KRAS degraders. These compounds are useful in the treatment and / or prevention of diseases or disorders dependent upon KRAS. The present invention also provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof thereof.

Description

[0001] SUBSTITUTED TRICYCLIC COMPOUNDS AS KRAS DEGRADERS

[0002] This application claims a benefit of Indian provisional application number 202341067839, filed on October 10, 2023, and Indian provisional application number 202441054021, filed on July 15, 2024, the specifications of which are hereby incorporated by reference in their entirety.

[0003] FIELD OF THE INVENTION

[0004] The present invention relates to substituted tricyclic compounds or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof which are useful as KRAS degraders and for the treatment of diseases or conditions or disorders dependent upon KRAS. The present invention also relates to a method of preparation of the substituted tricyclic compounds and pharmaceutical compositions comprising said compounds.

[0005] BACKGROUND OF THE INVENTION

[0006] Cancer is one of the leading causes of death worldwide. The treatment of cancer is gradually changing from an organ-centred to a pathway-centred approach. Cancer cells often have an addiction to the signals that are generated by the cancer-causing genes. Consequently, targeted cancer drugs that selectively inhibit the products of activated oncogenes can have dramatic effects on cancer cell viability.

[0007] RAS is a family of related proteins which are ubiquitously expressed in all cell lineages and organs. All RAS protein family members (the key human members of which are KRAS, NRAS, and HRAS) belong to a class of protein called small GTPase and are involved in cellular signal transduction).

[0008] RAS represents a group of closely related monomeric globular proteins comprised of 189 amino acids (21 kDa molecular mass) which is associated with the plasma membrane, and which binds either GDP or GTP. RAS acts as a molecular switch. When RAS contains bound GDP, it is in the resting or off position and is “inactive”. In response to exposure of the cell to certain growth promoting stimuli, RAS is induced to exchange its bound GDP for a GTP. When GTP bound, RAS is “switched on” and is able to interact with and activate other proteins (its “downstream targets”). The RAS protein itself has a very low intrinsic ability to hydrolyze GTP back to GDP, to turn into the ‘off state. Switching RAS off requires extrinsic proteins termed GTPase- activating proteins (GAPs) that interact with RAS and accelerate the conversion of GTP to GDP. consequently, in RAS which affects its ability to interact with GAP or to convert GTP back to GDP will result in a prolonged activation of the protein and consequently a prolonged growth signal to the cell. Because these signals result in cell growth and cell division, an overactive RAS signalling may ultimately lead to cancer.

[0009] Activating mutations in the RAS oncogenes (KRAS, NRAS, or HRAS) are found in approximately 30% of all human tumours. Although mutation of any one of the three RAS isoforms (KRAS, NRAS, or HRAS) has been shown to lead to oncogenic transformation, KRAS mutations are by far the most common in human cancer. Oncogenic KRAS mutations occur in 90% of pancreatic, 45% of colorectal and 35% of lung carcinomas (Bos J L., Bos JL. RAS oncogenes in human cancer: a review. Cancer Res. 1989 Sep l;49(17):4682-9. Erratum in: Cancer Res 1990 Feb 15;50(4): 1352 and Downward J., Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003 Jan;3(l): 11-22).

[0010] The well-known role of KRAS in malignancy and the discovery of these frequent mutations in KRAS in various tumour types, made KRAS a highly attractive target of the pharmaceutical industry for cancer therapy. Notwithstanding thirty years of large-scale discovery efforts to develop inhibitors of KRAS for treating cancer.

[0011] Compounds that inhibit KRAS activity are still highly desirable and under investigation, including those that disrupt effectors such as guanine nucleotide exchange factors (Sun Q, Burke JP, Phan J, Bums MC, Olejniczak ET, Waterson AG, Lee T, Rossanese OW, Fesik SW. Discovery of small molecules that bind to KRAS and inhibit Sos-mediated activation. Angew Chem Int Ed Engl. 2012 Jun 18;51(25):6140-3) as well advances in the covalent targeting of an allosteric pocket of KRAS G12C (Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM). KRAS (G12C) inhibitors allosterically control GTP affinity and effector interactions (Nature 2013 Nov 28; 503(7477):548-51). Clearly there is a continued interest in developing inhibitors of KRAS, particularly inhibitors of activating KRAS mutants, especially KRAS G12D.

[0012] In recent years, use of the ubiquitin proteasome pathway to specifically degrade protein substrates with the help of proteolysis-targeting chimeras (PROTAC) has become more impactful than the inhibition. PROTAC which is a compound with two hetero functional ligands linked by a linker: one ligand targets the target protein of interest (POI), while the other ligand specifically recruits E3 ligase. When PROTAC binds to E3 ligase and the protein of interest to form a ternary complex, by hijacking the E3 ligase, PROTAC presents POI with a favourable spatial position to facilitate its ubiquitination, and subsequently the ubiquitinated target protein is recognized by the proteasome and degraded, thereby selectively reducing the level of the target protein within the cell. The advantage of PROTAC technology, compared with the research and development methods of traditional small molecule inhibitors, is that they can catalyse multiple rounds of degradation of target proteins, and complete removal of proteins will also produce more potent efficacy. Least progress has been made in this field, and hence there is a need for potent therapeutic compounds for the treatment of KRAS mutant cancers, as well as to provide therapeutically effective pharmaceutical compositions for use in these KRAS mutant cancers. That is, there remains a need for compounds that are KRAS degraders useful as therapeutic agents. SUMMARY OF THE INVENTION: Provided herein are substituted tricyclic compounds and pharmaceutical compositions thereof that are useful as KRAS degraders and for treating diseases or conditions or disorders that are dependent upon or mediated by KRAS. In one aspect, the present application provides a compound of formula (I): or a pharmaceutically acceptable salt or stereoisomer or a tautomer thereof; wherein, R1 at each occurrence, independently is hydrogen, (C1-C6)alkyl, hydroxy, halo, amino, halo(C1-C6)alkyl, and / or two R1adjacent to each other together with the C atoms to which they are attached form a phenyl or 5- to 6-membered heterocyclyl; wherein the phenyl and heterocyclyl are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of (C1-C6)alkyl, (C2-C4)alkynyl, halo, hydroxy, halo(C1- C6)alkyl, amino, and cyano; p is 1, 2, 3, or 4; X and X’, independently, is C or N; R2 is hydrogen, cyclopropyl or absent; R3 is hydrogen or oxo; R4aand R4b,independently, is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, 5- to 10- membered heteroaryl(C1-C6)alkyl or 4- to 7-membered heterocyloalkyl, wherein the cycloalkyl and heteroarylalkyl are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo, (C1-C6)alkyl and amino; and / or R4aand R4btogether with the nitrogen to which they are attached form a 4- to 14-membered heterocyclyl optionally containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulphur; wherein the heterocyclyl is unsubstituted or substituted with 1, 2 or 3 groups each independently selected from the group consisting of (C1- C6)alkyl, (C3-C6)cycloalkyl, hydroxy, cyano and -C(O)-R4c; wherein said alkyl is unsubstituted or substituted independently with one or more of halo, hydroxy, amino, cyano or (C3- C6)cycloalkyl; and / or R4cis hydrogen, amino, (C1-C6)alkylamino, 4- to 7-membered heterocycloalkyl, (C3- C6)cycloalkyl, (C1-C6)alkyl or (C1-C6)alkylamino(C1-C6)alkyl; wherein the heterocycloalkyl and cycloalkyl are unsubstituted or substituted with 1, 2 or 3 groups each independently selected from the group consisting of halo, hydroxy and (C1-C6)alkyl; L is -O-(CH2)m-*, or -C(O)-*, -C(O)-NH-*; wherein asterisk mark represents the point of attachment with R5; R5is (C1-C6)alkyl, (C1-C6)alkoxy, -(CH2)m-NRcRd, 5- to 14-membered heterocycloalkyl or (C3-C6)cycloalkyl; wherein the heterocycloalkyl and cycloalkyl are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of (C1-C6)alkyl, halo, amino, and -(CH2)mNRyRz; m is 0, 1, 2 or 3; Rcand Rd, independently, is hydrogen or (C1-C6)alkyl; or Rcand Rdtogether with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl; Ry and Rz, independently is hydrogen or (C1-C6)alkyl; or Ry and Rz together with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of (C1-C6)alkyl, halo and (C2-C4)acyl; R6at each occurrence, independently, is hydrogen, amino, (C1-C6)alkyl, (C1-C6)alkoxy or hydroxy; or two R6on the same carbon represent an oxo group; q is 1, 2 or 3; Y1, Y2and Y3,independently, is a bond, C, N, or O; wherein not more than one of Y1, Y2or Y3is a bond; Z1, Z2, Z3 and Z4 independently, is a C, CR7’, NR7, or N; wherein at least two of Z1, Z2, Z3 and Z4 are N; R7and R7’independently, is hydrogen, halo, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1- C6)alkoxy, or halo(C1-C6)alkoxy; M is M1, M2, M3, M4, M5, M6, M7, M8 or M9;

[0013] wherein, R8 is (C1-C6)alkyl, hydroxy, halo, or amino; Z is hydrogen, (C1-C6)alkyl, halo or -CH2OH; Ra’ and Rb’ independently, is hydrogen, halo or (C1-C6)alkyl; or Ra’ and Rb’ together with the C atoms to which they are attached form a 5 to 6 membered heterocyclyl ring optionally containing one or two hetero atoms independently selected from the group consisting of O, S, and N; R9at each occurrence, independently, is hydrogen, 4- to 8-membered heterocycloalkyl, -O-heterocycloalkyl, -O-(C1-C6)alkyl; wherein heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo or (C1- C6)alkyl; wherein the alkyl in -O-(C1-C6)alkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of (C1- C6)alkylamino or 5- to 8-membered heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo, or (C1-C6)alkyl; P1, P2, P3and P4, independently, is C, N or S; wherein at least one of P1, P2, P3and P4, is N; R10 is hydrogen, (C1-C6)alkyl, (C2-C4)alkynyl, hydroxy, 3- to 7-membered heterocycloalkyl, or (C3-C6)cycloalkyl; wherein the alkyl and alkynyl is unsubstituted or substituted with halo, 25 cycloalkyl, -NH-(CO)-NH2, -NRmRn, or 4 to 6 membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of (C1-C6)alkyl, hydroxy, halo or amino; wherein 3- to 7-membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo, hydroxy or (C1-C6)alkyl; Rmand Rnare independently hydrogen or (C1-C6)alkyl; R11 at each occurrence, independently, is hydrogen, hydroxy or (C1-C6)alkyl; wherein the alkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo or hydroxy; R12at each occurrence, independently, is hydrogen or amino; X1 is C or N; R13 is hydrogen or (C1-C6)alkyl; X2, X3, X4and X5, each independently is C, CH or N; wherein one of X3or X4is always N and the other is C; R14 at each occurrence, independently is hydrogen, halo, hydroxy, (C1-C6)alkyl, halo(C1-C6)alkyl or (C2-C6)alkynyl; Cy is (C3-C10)cycloalkyl or 3- to 10-membered heterocycloalkyl; a dotted line [-----] indicates a bond or absent; and n is 1, 2 or 3. In another aspect, 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 an excipient. In another aspect, 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 KRAS. In another aspect, 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 have altered KRAS including mutations and overexpression. In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer for treating diseases or conditions or disorders wherein degradation of KRAS proteins provide a benefit. For example, cancer. In another aspect, the present invention provides 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 of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof. In another aspect, the present invention provides a method of treating a condition or a disease or a disorder dependent upon KRAS 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. The conditions or disease or disorder of interest is treatable by degradation of KRAS, for example, a cancer. 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. 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 KRAS; wherein the disease or disorder is cancer. BRIEF DESCRIPTION OF THE DRAWINGS FIG.1 illustrates the change in tumor volume in mice that received the compound 1d (10 mg / kg or 30 mg / kg) and compound 12d (10 mg / kg or 30 mg / kg) at various treatment days. DETAILED DESCRIPTION OF THE INVENTION The present invention provides substituted tricyclic compounds, referred as a compound of formula (I), which are useful as KRAS degraders and for the treatment of diseases or conditions or disorders dependent upon or mediated by KRAS. The present invention further provides a pharmaceutical composition comprising compound or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof as therapeutic agents. 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 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. In one embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer or a tautomer thereof; wherein, R1at each occurrence, independently is hydrogen, (C1-C6)alkyl, hydroxy, halo, amino, halo(C1-C6)alkyl, and / or two R1 adjacent to each other together with the C atoms to which they are attached form a phenyl or 5- to 6-membered heterocyclyl; wherein the phenyl and heterocyclyl are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of (C1-C6)alkyl, (C2-C4)alkynyl, halo, hydroxy, halo(C1- C6)alkyl, amino, and cyano; p is 1, 2, 3, or 4; X and X’, independently, is C or N; R2 is hydrogen, cyclopropyl or absent; R3is hydrogen or oxo; R4aand R4b,independently, is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, 5- to 10- membered heteroaryl(C1-C6)alkyl or 4- to 7-membered heterocyloalkyl, wherein the cycloalkyl and heteroarylalkyl are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo, (C1-C6)alkyl and amino; and / or R4a and R4b together with the nitrogen to which they are attached form a 4- to 14-membered heterocyclyl optionally containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulphur; wherein the heterocyclyl is unsubstituted or substituted with 1, 2 or 3 groups each independently selected from the group consisting of (C1- C6)alkyl, (C3-C6)cycloalkyl, hydroxy, cyano and -C(O)-R4c; wherein said alkyl is unsubstituted or substituted independently with one or more of halo, hydroxy, amino, cyano or (C3- C6)cycloalkyl; and / or R4c is hydrogen, amino, (C1-C6)alkylamino, 4- to 7-membered heterocycloalkyl, (C3- C6)cycloalkyl, (C1-C6)alkyl or (C1-C6)alkylamino(C1-C6)alkyl; wherein the heterocycloalkyl and cycloalkyl are unsubstituted or substituted with 1, 2 or 3 groups each independently selected from the group consisting of halo, hydroxy and (C1-C6)alkyl; L is -O-(CH2)m-*, or -C(O)-*, -C(O)-NH-*; wherein asterisk mark represents the point of attachment with R5; R5is (C1-C6)alkyl, (C1-C6)alkoxy, -(CH2)m-NRcRd, 5- to 14-membered heterocycloalkyl or (C3-C6)cycloalkyl; wherein the heterocycloalkyl and cycloalkyl are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of (C1-C6)alkyl, halo, amino, and -(CH2)mNRyRz; m is 0, 1, 2 or 3; Rcand Rd, independently, is hydrogen or (C1-C6)alkyl; or Rcand Rdtogether with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl; Ry and Rz, independently is hydrogen or (C1-C6)alkyl; or Ry and Rz together with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of (C1-C6)alkyl, halo and (C2-C4)acyl; R6at each occurrence, independently, is hydrogen, amino, (C1-C6)alkyl, (C1-C6)alkoxy or hydroxy; or two R6on the same carbon represent an oxo group; q is 1, 2 or 3; Y1, Y2 and Y3, independently, is a bond, C, N, or O; wherein not more than one of Y1, Y2or Y3is a bond; Z1, Z2, Z3 and Z4 independently, is a C, CR7’, NR7, or N; wherein at least two of Z1, Z2, Z3 and Z4 are N; R7and R7’independently, is hydrogen, halo, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1- C6)alkoxy, or halo(C1-C6)alkoxy; M is M1, M2, M3, M4, M5, M6, M7, M8 or M9;

[0014] wherein, R8 is (C1-C6)alkyl, hydroxy, halo or amino; Z is hydrogen, (C1-C6)alkyl, halo or -CH2OH; Ra’ and Rb’ independently, is hydrogen, halo or (C1-C6)alkyl; or Ra’ and Rb’ together with the C atoms to which they are attached form a 5 to 6 membered heterocyclyl ring optionally containing one or two hetero atoms independently selected from the group consisting of O, S, and N; R9 at each occurrence, independently, is hydrogen, 4- to 8-membered heterocycloalkyl, -O-heterocycloalkyl, -O-(C1-C6)alkyl; wherein heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo or (C1-15C6)alkyl; wherein the alkyl in -O-(C1-C6)alkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of (C1- C6)alkylamino or 5- to 8-membered heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo, or (C1-C6)alkyl; P1, P2, P3 and P4, independently, is C, N or S; wherein at least one of P1, P2, P3 and P4, is N; R10is hydrogen, (C1-C6)alkyl, (C2-C4)alkynyl, hydroxy, 3- to 7-membered heterocycloalkyl or (C3-C6)cycloalkyl; wherein the alkyl and alkynyl is unsubstituted or substituted with halo, cycloalkyl, -NH-(CO)-NH2, -NRmRn, or 4 to 6 membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of (C1-C6)alkyl, hydroxy, halo or amino; wherein 3- to 7-membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo, hydroxy or (C1-C6)alkyl; Rmand Rnare independently hydrogen or (C1-C6)alkyl; R11 at each occurrence, independently, is hydrogen, hydroxy or (C1-C6)alkyl; wherein the alkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo or hydroxy; R12 at each occurrence, independently, is hydrogen or amino; X1 is C or N; R13is hydrogen or (C1-C6)alkyl; X2, X3, X4 and X5, each independently is C, CH or N; wherein one of X3 or X4 is always N and the other is C; R14at each occurrence, independently is hydrogen, halo, hydroxy, (C1-C6)alkyl, halo(C1-C6)alkyl or (C2-C6)alkynyl; Cy is (C3-C10)cycloalkyl or 3- to 10-membered heterocycloalkyl; a dotted line [-----] indicates a bond or absent; and n is 1, 2 or 3. In one embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer or a tautomer thereof; wherein, R1at each occurrence, independently is hydrogen, (C1-C6)alkyl, hydroxy, halo, amino or halo(C1-C6)alkyl, and / or two R1adjacent to each other together with the C atoms to which they are attached form a phenyl or 5- to 6-membered heterocyclyl; wherein the phenyl and heterocyclyl are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of (C1-C6)alkyl, (C2-C4)alkynyl, halo, hydroxy, halo(C1- C6)alkyl, amino, and cyano; p is 1, 2, 3, or 4; X and X’, independently, is C or N; R2 is hydrogen, cyclopropyl or absent; R3 is hydrogen or oxo; R4aand R4b,independently, is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, 5- to 10- membered heteroaryl(C1-C6)alkyl or 4- to 7-membered heterocyloalkyl, wherein the cycloalkyl 20 and heteroarylalkyl are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo, (C1-C6)alkyl and amino; and / or R4aand R4btogether with the nitrogen to which they are attached form a 4- to 14- membered heterocyclyl optionally containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulphur; wherein the heterocyclyl is unsubstituted or substituted with 1, 2 or 3 groups each independently selected from the group consisting of (C1-C6)alkyl, (C3-C6)cycloalkyl, hydroxy, cyano and -C(O)-R4c; wherein said alkyl is unsubstituted or substituted independently with one or more of hydrogen, halo, hydroxy, amino, cyano or (C3-C6)cycloalkyl; and / or R4cis hydrogen, amino, (C1-C6)alkylamino, 4- to 7-membered heterocycloalkyl, (C3- C6)cycloalkyl, (C1-C6)alkyl or (C1-C6)alkylamino(C1-C6)alkyl; wherein the heterocycloalkyl and cycloalkyl are unsubstituted or substituted with 1, 2 or 3 groups each independently selected from the group consisting of halo, hydroxy and (C1-C6)alkyl; L is -O-(CH2)m-*, or -C(O)-NH-*; wherein asterisk mark represents the point of attachment with R5; R5is (C1-C6)alkyl, (C1-C6)alkoxy, -(CH2)m-NRcRd, 5- to 14-membered heterocycloalkyl or (C3-C6)cycloalkyl; wherein the heterocycloalkyl and cycloalkyl are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of (C1-C6)alkyl, halo, amino and -(CH2)mNRyRz; m is 0, 1, 2 or 3; Rc and Rd, independently, is hydrogen or (C1-C6)alkyl; Ryand Rz, independently is hydrogen or (C1-C6)alkyl; or Ryand Rztogether with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of (C1-C6)alkyl, halo and (C2-C4)acyl; R6at each occurrence, independently, is hydrogen, amino, (C1-C6)alkyl, (C1-C6)alkoxy or hydroxy; or two R6 on the same carbon represent an oxo group; q is 1, 2 or 3; Y1, Y2and Y3,independently, is a bond, C, N, or O; wherein not more than one of Y1, Y2or Y3is a bond; Z1, Z2, Z3 and Z4 independently, is a C, CR7’, NR7, or N; wherein at least two of Z1, Z2, Z3 and Z4 are N; R7and R7’independently, is hydrogen, halo, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1- C6)alkoxy, or halo(C1-C6)alkoxy; M is M1, M2, M3, M4, M5, M6, M7, M8 or M9; wherein, R8is (C1-C6)alkyl, hydroxy, halo or amino; Z is hydrogen, (C1-C6)alkyl, halo or -CH2OH; Ra’and Rb’independently, is hydrogen, halo or (C1-C6)alkyl; or Ra’and Rb’together with the C atoms to which they are attached form a 5 to 6 membered heterocyclyl ring optionally containing one or two hetero atoms independently selected from the group consisting of O, S and N; R9at each occurrence, independently, is hydrogen, 4- to 8-membered heterocycloalkyl, -O-heterocycloalkyl or -O-(C1-C6)alkyl; wherein 4- to 8-membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo or (C1-C6)alkyl; wherein the alkyl in -O-(C1-C6)alkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of (C1- C6)alkylamino or 5- to 8-membered heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo, or (C1-C6)alkyl; P1, P2, P3and P4, independently, is C, N or S; wherein at least one of P1, P2, P3and P4, is N; R10 is hydrogen, (C1-C6)alkyl, (C2-C4)alkynyl, hydroxy, 3- to 7-membered heterocycloalkyl or (C3-C6)cycloalkyl; wherein the alkyl and alkynyl is unsubstituted or substituted with halo, cycloalkyl, NH-(CO)-NH2, NRmRn or 5 to 6 membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of (C1-C6)alkyl, hydroxy, halo or amino; wherein 3- to 7-membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo, hydroxy or (C1-C6)alkyl; Rm and Rn are independently hydrogen or (C1-C6)alkyl; R11at each occurrence, independently, is hydrogen, hydroxy or (C1-C6)alkyl; wherein the alkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo or hydroxy; R12at each occurrence, independently, is hydrogen or amino; X1is C or N; R13 is hydrogen or (C1-C6)alkyl; X2, X3, X4and X5, each independently is C, CH or N; wherein one of X3or X4is always N and the other is C; R14 at each occurrence, independently is hydrogen, halo, hydroxy, (C1-C6)alkyl, halo(C1-C6)alkyl or (C2-C6)alkynyl; Cy is (C3-C10)cycloalkyl or 3- to 10-membered heterocycloalkyl; a dotted line [-----] indicates a bond or absent; and n is 1, 2 or 3. 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, R1at each occurrence, independently is hydrogen, (C1-C6)alkyl, hydroxy, halo, amino or halo(C1-C6) alkyl, and / or two R1adjacent to each other together with the C atoms to which they are attached form a phenyl or 5- to 6-membered heterocyclyl; wherein the phenyl and heterocyclyl are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of (C1-C6)alkyl, (C2-C4)alkyne, halo, hydroxy, halo(C1- C6)alkyl, amino and cyano; p is 1, 2, 3 or 4; X and X’, independently, is C or N; R2is hydrogen, cyclopropyl or absent; R3is hydrogen or an oxo; R4a and R4b, independently, is hydrogen, (C1-C6)alkyl or 4- to 7-membered heterocyloalkyl; or R4a and R4b together with the nitrogen to which they are attached form a 5- to 14-membered heterocyclyl optionally containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulphur; wherein the heterocyclyl is unsubstituted or substituted with 1, 2 or 3 groups each independently selected from the group consisting of (C1-C6)alkyl, hydroxy and -C(O)-amino(C1-C6)alkyl; L is -O-(CH2)m- or -C(O)-NH-; R5 is (C1-C6)alkyl, -(CH2)mNRcRd, 5- to 14-membered heterocycloalkyl or (C3- C6)cycloalkyl; wherein the heterocycloalkyl and cycloalkyl are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of (C1- C6)alkyl, halo, amino and -(CH2)mNRyRz; m is 0, 1, 2 or 3; Rcand Rd, independently, is hydrogen or (C1-C6)alkyl; Ry and Rz, independently is hydrogen or (C1-C6)alkyl; or Ry and Rz together with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with (C1-C6)alkyl, halo or (C2-C4)acyl; R6at each occurrence, independently, is hydrogen, amino, (C1-C6)alkyl, (C1-C6)alkoxy or hydroxy; or two R6 on the same carbon represent an oxo group; q is 1, 2 or 3; Y1, Y2and Y3,independently, is a bond, C, N or O; wherein not more than one of Y1, Y2or Y3 is a bond; Z1, Z2, Z3 and Z4 independently, is a C, CR7’, NR7 or N; wherein at least two of Z1, Z2, Z3and Z4are N; R7 and R7’ independently, is hydrogen, halo, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1- C6)alkoxy or halo(C1-C6)alkoxy; M is M1, M2, M3, M4M5or M6;

[0015] wherein, R8is (C1-C6)alkyl, hydroxy, halo or amino; Z is hydrogen, (C1-C6)alkyl, halo or CH2OH; Ra’ and Rb’ independently, is hydrogen, halo or (C1-C6)alkyl; or Ra’ and Rb’ together with the C atoms to which they are attached form a 5 to 6 membered heterocyclyl ring optionally containing one or two hetero atoms independently selected from the group consisting of O, S and N; R9 at each occurrence, independently, is hydrogen, 4- to 8-membered heterocycloalkyl, - O- heterocycloalkyl or -O-(C1-C6)alkyl; wherein the alkyl is unsubstituted or substituted with amino(C1-C6)alkyl or 5 to 8 membered heterocycloalkyl; wherein the heterocycloalkyl at each occurrence is unsubstituted or substituted with halo or (C1-C6)alkyl; P1, P2, P3and P4, independently, is C, N or S; wherein at least one of P1, P2, P3and P4, is N; R10 is hydrogen, (C1-C6)alkyl, (C2-C4)alkynyl, hydroxy, 3- to 7-membered heterocycloalkyl or (C3-C6)cycloalkyl; wherein the alkyl and alkynyl is unsubstituted or substituted with halo, cycloalkyl, NH-(CO)-NH2, NRmRnor 5 to 6 membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with (C1-C6)alkyl, hydroxy, halo or amino; Rm and Rn are independently hydrogen or (C1-C6)alkyl; R11at each occurrence, independently, is hydrogen, hydroxy or (C1-C6)alkyl; wherein the alkyl is unsubstituted or substituted with halo or hydroxy; R12 at each occurrence, independently, is hydrogen or amino; X1is C or N; R13is hydrogen or (C1-C6)alkyl; X2, X3, X4 and X5, each independently is C, CH or N; wherein one of X3 or X4 is always N and the other is C; Cy is (C3-C10)cycloalkyl or 3- to 10-membered heterocycloalkyl; a dotted line [-----] indicates a bond or absent; and n is 1, 2 or 3. In one embodiment, R1at each occurrence, independently is (C1-C6)alkyl, halo(C1-C6) alkyl, hydroxy, halo or amino. In one embodiment, R1 at each occurrence is (C1-C6)alkyl, amino, hydroxy or halo. In one embodiment, R1at each occurrence, independently is -CH3, -CH2-CH3, -CH2-CH2- CH3, -CH(CH3)2or -CH2-CH2-CH2-CH3. In one embodiment, R1 is methyl, hydroxy, amino or fluoro. In one embodiment, R1 at each occurrence, independently is -CHF2 or -CF3. In one embodiment, R1at each occurrence, independently is -CH3, -CF3or -NH2. In one embodiment, R1 at each occurrence, independently is -CH3, -OH or F. In one embodiment, two R1 adjacent to each other together with the C atoms to which they are attached form a phenyl or 5- to 6-membered heterocyclyl; wherein the phenyl and heterocyclyl are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from (C1-C6)alkyl, (C2-C4)alkynyl, halo and amino. In one embodiment, two R1adjacent to each other together with the C atoms to which they are attached form In one embodiment, two R1adjacent to each other together with the C atoms to which they are attached form In one embodiment, two R1 adjacent to each other together with the C atoms to which they are attached form a substituted phenyl selected from the group consisting of formula: . In one embodiment, R1 at each occurrence, independently is two R1 adjacent to each other together with the C atoms to which they are attached form a unsubstituted 5- to 6-membered heterocyclyl selected from the group consisting of formula: . In one embodiment, p is 1, 2, 3, or 4. In one embodiment, X and X’, independently, is C or N. In one embodiment, X is C and X’ is N. In one embodiment, X is N and X’ is C. In one embodiment, X and X’ both are C or N. In one embodiment, R2 is hydrogen, cyclopropyl or absent. In one embodiment, R2 is cyclopropyl or absent. In one embodiment, R3is hydrogen. In one embodiment, R3 is oxo. In one embodiment, R4a and R4b, independently, is (C1-C6)alkyl, (C3-C6)cycloalkyl, 5- to 10-membered heteroaryl(C1-C6)alkyl or 4- to 7-membered heterocyloalkyl. In one embodiment, R4aand R4b,independently, is (C1-C6)alkyl or 4- to 7-membered heterocyloalkyl. In one embodiment, R4a and R4b , independently, is methyl, ethyl, cyclopropyl, , In one embodiment, R4aand R4b,independently, is methyl or . In one embodiment, R4aand R4btogether with the nitrogen to which they are attached form a 4- to 14-membered heterocyclyl optionally containing additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur. In one embodiment, the 4- to 14-heterocyclyl is optionally substituted with 1, 2 or 3 groups each independently selected from (C1-C6)alkyl, (C3-C6)cycloalkyl, hydroxy and -C(O)- R4c; wherein said alkyl is substituted independently with one or more of halo, hydroxy or (C3- C6)cycloalkyl. In one embodiment, R4a and R4b together with the nitrogen to which they are attached form a 4- to 14-membered heterocyclyl optionally containing one or two additional nitrogen, wherein the heterocyclyl is unsubstituted. In one embodiment, R4aand R4btogether with the nitrogen to which they are attached form a unsubstituted or substituted heterocyclyl selected from , or 3 groups each independently selected from (C1-C6)alkyl, (C3-C6)cycloalkyl, hydroxy and - C(O)-R4c; wherein said alkyl is substituted independently with one or more of halo, hydroxy or (C3-C6)cycloalkyl. In one embodiment, R4aand R4btogether with the nitrogen to which they are attached In one embodiment R4a and R4b, independently, is methyl or ; or together with the nitrogen to which they are attached form a moiety selected from the group consisting of In one embodiment, R4c is amino, (C1-C6)alkylamino, unsubstituted or substituted 4- to 7-membered heterocycloalkyl, (C3-C6)cycloalkyl, (C1-C6)alkyl or (C1-C6)alkylamino(C1- C6)alkyl; wherein the heterocycloalkyl and cycloalkyl are unsubstituted or substituted with 1, 2 or 3 groups each independently selected from the group consisting of halo, hydroxy and (C1- C6)alkyl. In one embodiment, R4c is amino, (C1-C6)alkylamino, (C1-C6)alkyl or unsubstituted or substituted 4- to 7-membered heterocycloalkyl; wherein the heterocycloalkyl is substituted with (C1-C6)alkyl. In one embodiment, L is -O-, -O-(CH2)m-*, -C(O)-* or -C(O)-NH-*; wherein asterisk mark represents the point of attachment with R5. In one embodiment, L is -O-, -O-(CH2)m-* or -C(O)-NH-*; wherein asterisk mark represents the point of attachment with R5. In one embodiment, L is -O-(CH2)m-* or -C(O)-NH-*; wherein asterisk mark represents the point of attachment with R5.In one embodiment, L is -O-(CH2)m-*; wherein asterisk mark represents the point of attachment with R5. In one embodiment, wherein L is -O- or -O-CH2-* wherein asterisk mark represent the point of attachment with R5. In one embodiment, L is -C(O)-NH-*; wherein asterisk mark represents the point of 25 attachment with R5. In one embodiment, R5is (C1-C6)alkyl, -(CH2)m-NRcRd, 5- to 14-membered heterocycloalkyl or (C3-C6)cycloalkyl, wherein the heterocycloalkyl and cycloalkyl are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of (C1-C6)alkyl, halo, amino and -(CH2)mNRyRz. In one embodiment, R5 is (C1-C6)alkoxy, -(CH2)mNRcRd or 5- to 14-membered heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from (C1-C6)alkyl, halo, amino and -(CH2)m-NRyRz. In one embodiment, R5 is 5- to 14-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from (C1-C6)alkyl, halo and -(CH2)mNRyRz. In one embodiment, R5is (C3-C6)cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of (C1-C6)alkyl, halo, amino and -(CH2)mNRyRz. In one embodiment, Rcand Rdare (C1-C6)alkyl; or Rcand Rdtogether with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl. Ry and Rz, independently is hydrogen or (C1-C6)alkyl; or Ry and Rz together with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from (C1-C6)alkyl, halo or (C2-C4)acyl. In one embodiment, Ry and Rz is (C1-C6)alkyl; or Ry and Rz together with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from (C1-C6)alkyl and (C2-C4)acyl. . . In one embodiment, m is 0, 1, 2 or 3. In one embodiment, R6at each occurrence, independently, is hydrogen, amino, (C1-C6)alkyl, (C1-C6)alkoxy or hydroxy; or two R6 on the same carbon represent an oxo group. In one embodiment, R6is amino, (C1-C6)alkyl, (C1-C6)alkoxy or hydroxy; or two R6on the same carbon represent an oxo group. In one embodiment, R6 is amino, methyl, methoxy, hydroxy or oxo. In one embodiment, two R6on the same carbon represent an oxo group. In one embodiment q is 1, 2 or 3. In one embodiment Y1, Y2 and Y3, independently, is a bond, C, N, or O, wherein not more than one of Y1, Y2or Y3is a bond. In one embodiment Y1, Y2and Y3,are independently, is C or N. In one embodiment Y1, Y2 and Y3, are independently, is C or O. In one embodiment Z1, Z2, Z3 and Z4 are independently, is a C, CR7’, NR7, or N, wherein at least two of Z1, Z2, Z3and Z4are N. In one embodiment Z1, Z2, Z3 and Z4 independently, is a C or N. In one embodiment Z1, Z2, Z3 and Z4 independently, is N, wherein two of Z1, Z2, Z3 and Z4are N. In one embodiment Z1, Z2, Z3and Z4independently, is N, wherein three of Z1, Z2, Z3and Z4 are N. In one embodiment R7 and R7’ independently, is hydrogen, halo, (C1-C6)alkyl, halo(C1- C6)alkyl, (C1-C6)alkoxy or halo(C1-C6)alkoxy. In one embodiment, R7 and R7’ are independently, is halo, (C1-C6)alkyl, halo(C1- C6)alkyl, (C1-C6)alkoxy or halo(C1-C6)alkoxy. In one embodiment, R7and R7’is halo, methyl, trifluoromethyl, methoxy or -O-CF3. In one embodiment, R7 and R7’ independently, is F, Cl or Br. In one embodiment, R7 and R7’ independently, is CHF2 or CF3. In one embodiment, R7and R7’independently, is CH3, -CH2-CH3, -CH2-CH2-CH3, - CH(CH3)2or -CH2-CH2-CH2-CH3. In one embodiment, R7 and R7’ independently is methoxy. In one embodiment, R7 and R7’ independently is -OCF3. In one embodiment, M is M1 . In one embodiment, Ml is In one embodiment, M1 has formula selected from the group consisting of In one embodiment, R8is (C1-C6)alkyl, hydroxy, halo, or amino. In one embodiment, R8is (C1-C6)alkyl. In one embodiment, Z is hydrogen, (C1-C6)alkyl, halo or -CH2OH. In one embodiment, Z is hydrogen or -CH2OH. In one embodiment, Ra’and Rb’independently, is hydrogen. In one embodiment, Ra’ and Rb’ together with the C atoms to which they are attached form a 5 to 6 membered heterocyclyl ring optionally containing one or two hetero atoms independently selected from the group consisting of O, S, and N. In one embodiment, R9at each occurrence, independently, is hydrogen, 4- to 8-membered heterocycloalkyl, -O- heterocycloalkyl, -O-(C1-C6)alkyl, wherein the alkyl is unsubstituted or substituted with amino(C1-C6)alkyl or 5 to 8 membered heterocycloalkyl, wherein the heterocycloalkyl at each occurrence is unsubstituted or substituted with halo, or (C1-C6)alkyl. In one embodiment, R9 at each occurrence, independently is 4- to 8-membered heterocycloalkyl, wherein the heterocycloalkyl at each occurrence is unsubstituted or substituted with halo, or (C1-C6)alkyl. In one embodiment, R9 at each occurrence, independently is 6-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted. In one embodiment, R9at each occurrence, independently is 6-membered heterocycloalkyl, wherein the heterocycloalkyl is substituted with methyl. In one embodiment, R9 at each occurrence, independently is -O-heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted. In one embodiment, R9at each occurrence, independently is -O-heterocycloalkyl, wherein the heterocycloalkyl is substituted with methyl. In one embodiment, R9 at each occurrence, independently is -O-(C1-C6)alkyl, wherein the alkyl is unsubstituted or substituted with amino(C1-C6)alkyl or 5 to 8 membered heterocycloalkyl, wherein the heterocycloalkyl at each occurrence is unsubstituted or substituted with halo, or (C1-C6)alkyl. In one embodiment, R9at each occurrence, independently is -O-(C1-C6)alkyl, wherein the alkyl is substituted with amino(C1-C6)alkyl. In one embodiment, R9at each occurrence, independently is -O-(C1-C6)alkyl, wherein the alkyl is substituted with 5 to 8 membered heterocycloalkyl, wherein the heterocycloalkyl at each occurrence is unsubstituted or substituted with halo, or (C1-C6)alkyl. In one embodiment, R9at each occurrence, independently is -O-(C1-C6)alkyl, wherein the alkyl is substituted with 5 to 8 membered heterocycloalkyl, wherein the heterocycloalkyl is substituted with (C1-C6)alkyl. In one embodiment, R9at each occurrence, independently is -O-(C1-C6)alkyl, wherein the alkyl is substituted with 6 membered heterocycloalkyl, wherein the heterocycloalkyl is substituted with (C1-C6)alkyl. In one embodiment, P1, P2, P3and P4, independently, is C, N or S, wherein at least one of P1, P2, P3and P4, is N. In one embodiment, P1, P2, P3 and P4, independently, is C, N or S, wherein two of P1, P2, P3 and P4, is N. In one embodiment, P1, P2, P3and P4, independently, is C or N. In one embodiment, R10 is hydrogen, (C1-C6)alkyl, (C2-C4)alkynyl, hydroxy, 3- to 7- membered heterocycloalkyl, or (C3-C6)cycloalkyl, wherein the alkyl and alkynyl is unsubstituted or substituted with halo, cycloalkyl, -NH-(CO)-NH2, NRmRn, or 5 to 6 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with (C1-C6)alkyl, hydroxy, halo or amino; and Rm and Rn are independently hydrogen or (C1-C6)alkyl. In one embodiment, R10is (C1-C6)alkyl. In one embodiment, R10 is -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2 or -CH2-CH2- CH2-CH3. In one embodiment, R10is hydroxy. In one embodiment, R10is (C1-C6)alkyl, wherein the alkyl is substituted with -NH-(CO)- NH2. In one embodiment, R10is (C1-C6)alkyl, wherein the alkyl is substituted with halo. In one embodiment, R10is (C1-C6)alkyl, wherein the alkyl is substituted with cycloalkyl, wherein the cycloalkyl is substituted with hydroxy. In one embodiment, R10is (C1-C6)alkyl, wherein the alkyl is substituted with 5 to 6 membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with (C1-C6)alkyl, hydroxy, halo or amino. In one embodiment, R10is (C1-C)alkyl, wherein alkyl is substituted with NRmRn. In one embodiment, R10 is (C2-C4)alkynyl, wherein alkynyl is substituted with NRmRn. In one embodiment, Rm and Rn are independently hydrogen or (C1-C6)alkyl. In one embodiment, . In one embodiment, M2 is In one embodiment, M2has formula selected from the group consisting of In one embodiment, R11at each occurrence, independently, is hydrogen, hydroxy or (C1- C6)alkyl, wherein the alkyl is unsubstituted or substituted with halo or hydroxy. In one embodiment, R11 at each occurrence, independently is hydroxy. In one embodiment, R11 at each occurrence, independently is (C1-C6)alkyl, wherein the alkyl is unsubstituted or substituted with hydroxy. In one embodiment, R11 at each occurrence, independently is methyl or ethyl, wherein the methyl or ethyl is substituted with -OH. In one embodiment, n is 1, 2 or 3. In one embodiment, M is M3 . In one embodiment, M is M3 . In one embodiment, M3 is . In one embodiment, R12 at each occurrence, independently, is hydrogen or amino. In one embodiment, n is 1, 2 or 3. In one embodiment, X1is C or N. In one embodiment, X1is C. In one embodiment, X1 is N. In one embodiment, M is M4 . In one embodiment, R13is hydrogen or (C1-C6)alkyl. In one embodiment, R13 is methyl. In one embodiment, M4is a group of formula . In one embodiment, M is M5: . In one embodiment, X2, X3, X4 and X5, each independently is C, CH or N, wherein one of X3or X4is always N and the other is C; and a dotted line [-----] indicates a bond or absent. In one embodiment, M5 is . In one embodiment, M5 is a group of formula wherein Cy is (C3-C10)cycloalkyl or 3- to 10-membered heterocycloalkyl. In one embodiment M6 is a group of formula represents the point of attachment with pyrazole ring. In one embodiment, M is M7

[0016] In one embodiment, M is M8 . In another embodiment, M8 is . In one embodiment, M is M9 . In another embodiment, M9 is ,

[0017] ; wherein asterisk mark represents the point of attachment with M. , , , , , , wherein asterisk mark represents the point of attachment with M. In one embodiment, the present invention provides a compound of formula (IA) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof: . wherein R4a R4b, L, R5, R6, q, Y1, Y2, Y3, R7, M and same as defined in compound of formula I. In one embodiment, R1is (C1-C6)alkyl, hydroxy or halo. In one embodiment, R4a and R4b independently is (C1-C6)alkyl, (C3-C6)cycloalkyl or 5- to 10-membered heteroaryl(C1-C6)alkyl. In one embodiment, R4aand R4btogether with the nitrogen to which they are attached form a 5- to 14-membered heterocyclyl containing one or two additional heteroatoms selected from the group consisting of nitrogen and oxygen, wherein the heterocyclyl substituted with 2 or groups each independently selected from the group consisting of (C1-C6)alkyl and hydroxy. In another embodiment, R4aand R4b, independently, is methyl, ethyl, cyclopropyl, . In one embodiment, R4aand R4btogether with the nitrogen to which they are attached form a moiety selected from the group consisting . In one embodiment, R4aand R4btogether with the nitrogen to which they are attached form a group of formula, In one embodiment, R 4a and R4b represents formula .In one embodiment, L is -O-, -C(O)-* or -O-CH2-*, wherein asterisk mark represents the point of attachment with R5.In one embodiment, L is -O-(CH2)m- or -C(O)-NH-. In one embodiment, L is -O- or -O-CH2-. In one embodiment, L is -C(O)-NH-. In one embodiment, R5is (C1-C6)alkyl, -(CH2)mNRcRd, 5- to 14-membered heterocycloalkyl or (C3-C6)cycloalkyl, wherein the heterocycloalkyl and cycloalkyl are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of (C1-C6)alkyl, halo, amino and -(CH2)mNRyRz; m is 0, 1, 2 or 3; Rc and Rd, independently, is hydrogen or (C1-C6)alkyl; and Ryand Rz, independently is hydrogen or (C1-C6)alkyl; or Ryand Rztogether with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with (C1-C6)alkyl, halo or (C2-C4)acyl. In one embodiment of the compound of formula (IA), R5is 5- to 14-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of (C1-C6)alkyl, halo, and -(CH2)mNRyRz. m is 0, 1, 2 or 3; and Ryand Rz, independently is hydrogen or (C1-C6)alkyl; or Ryand Rztogether with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with (C1-C6)alkyl, halo or (C2-C4)acyl. In one embodiment of the compound of formula (IA), R5 is , , , . In one embodiment of the compound of formula (IA), R5 is .In one embodiment, . In one embodiment of the compound of formula (IA), R6at each occurrence, independently, is hydrogen, amino, (C1-C6)alkyl, (C1-C6)alkoxy or hydroxy; or two R6 on the same carbon represent an oxo group. In one embodiment, R6is hydrogen, amino, hydroxy or two R6on the same carbon represent an oxo group. In one embodiment of the compound of formula (IA), R6 is hydrogen or two R6 on the same carbon represent an oxo group. In one embodiment of the compound of formula (IA), R6 is methoxy. In one embodiment of the compound of formula (IA), R6 at each occurrence, independently is -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2or -CH2-CH2-CH2-CH3. In one embodiment of the compound of formula (IA), q is 1, 2 or 3. In one embodiment of the compound of formula (IA), Y1, Y2 and Y3, independently, is a bond, C, N, or O, wherein not more than one of Y1, Y2 or Y3 is a bond. In one embodiment of the compound of formula (IA), Y1, Y2and Y3,independently, is C or N. In one embodiment of the compound of formula (IA), Y1, Y2 and Y3, independently, is C or O. In one embodiment of the compound of formula (IA), R7is hydrogen, halo, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, or halo(C1-C6)alkoxy. In one embodiment of the compound of formula (IA), R7 is hydrogen, halo, (C1-C6)alkyl, or halo(C1-C6)alkyl. In one embodiment of the compound of formula (IA), R7 is -F, -Cl or -Br. In one embodiment of the compound of formula (IA), R7 is -CHF2 or -CF3. In one embodiment of the compound of formula (IA), R7is -CH3, -CH2-CH3, -CH2-CH2- CH3, -CH(CH3)2 or -CH2-CH2-CH2-CH3. In one embodiment of the compound of formula (IA), R7 is methoxy. In one embodiment of the compound of formula (IA), R7is -OCF3. In one embodiment, M is M1, M2, M3, M4, M5, M6,M7, M8 or M9; . wherein, R8is (C1-C6)alkyl, hydroxy, halo or amino; Z is hydrogen, (C1-C6)alkyl, halo or -CH2OH; Ra’ and Rb’ independently, is hydrogen, halo or (C1-C6)alkyl; or Ra’ and Rb’ together with the C atoms to which they are attached form a 5 to 6 membered heterocyclyl ring optionally containing one or two hetero atoms independently selected from the group consisting of O, S and N; R9 at each occurrence, independently, is hydrogen, 4- to 8-membered heterocycloalkyl, - O- heterocycloalkyl, -O-(C1-C6)alkyl; wherein the alkyl is unsubstituted or substituted with amino(C1-C6)alkyl or 5 to 8 membered heterocycloalkyl; wherein the heterocycloalkyl at each occurrence is unsubstituted or substituted with halo or (C1-C6)alkyl; P1, P2, P3and P4, independently, is C, N or S; wherein at least one of P1, P2, P3and P4is N; R10 is hydrogen, (C1-C6)alkyl, (C2-C4)alkynyl, hydroxy, 3- to 7-membered heterocycloalkyl, or (C3-C6)cycloalkyl; wherein the alkyl and alkynyl is unsubstituted or substituted with halo, cycloalkyl, -NH-(CO)-NH2, NRmRnor 5 to 6 membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with (C1-C6)alkyl, hydroxy, halo or amino; Rmand Rnare independently hydrogen or (C1-C6)alkyl; R11at each occurrence, independently, is hydrogen, hydroxy or (C1-C6)alkyl; wherein the alkyl is unsubstituted or substituted with halo or hydroxy; R12at each occurrence, independently, is hydrogen or amino; X1is C or N; R13is hydrogen or (C1-C6)alkyl; X2, X3, X4 and X5 each independently is C, CH or N; wherein one of X3 or X4 is always N and the other is C; Cy is (C3-C10)cycloalkyl or 3- to 10-membered heterocycloalkyl; a dotted line [-----] indicates a bond or absent; and n is 1, 2 or 3. In one embodiment, M is selected from the group consisting of In one embodiment, the present invention provides a compound of formula (IB) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof: . wherein R7, R6, q, Y1, Y2, Y3, R9, n, Ra’, Rb’, P1, P2, P3, P4and R10same as defined in compound of formula I. In one embodiment, R1 is (C1-C6)alkyl, hydroxy or halo. In one embodiment of the compound of formula (IB), R7is hydrogen, halo, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, or halo(C1-C6)alkoxy. In one embodiment of the compound of formula (IB), R7 is F, Cl or Br. In one embodiment of the compound of formula (IB), R7is -CHF2or -CF3. In one embodiment of the compound of formula (IB), R7 is -CH3, -CH2-CH3, -CH2-CH2- CH3, -CH(CH3)2 or -CH2-CH2-CH2-CH3. In one embodiment of the compound of formula (IB), R7is methoxy. In one embodiment of the compound of formula (IB), R7is -OCF3. In one embodiment of the compound of formula (IB), R6 at each occurrence, independently, is hydrogen, amino, (C1-C6)alkyl, (C1-C6)alkoxy or hydroxy; or two R6 on the same carbon represent an oxo group. In one embodiment of the compound of formula (IB), R6 is hydrogen, amino, (C1- C6)alkyl, (C1-C6)alkoxy or hydroxy; or two R6 on the same carbon represent an oxo group. In one embodiment, R6is hydrogen, amino, hydroxy or two R6on the same carbon represent an oxo group. In one embodiment of the compound of formula (IB), two R6 on the same carbon represent an oxo group. In one embodiment of the compound of formula (IB), R6is methoxy. In one embodiment of the compound of formula (IB), R6 at each occurrence, independently is -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2 or -CH2-CH2-CH2-CH3. In one embodiment of the compound of formula (IB), q is 1, 2 or 3. In one embodiment of the compound of formula (IB), Y1, Y2 and Y3, independently, is a bond, C, N, or O, wherein not more than one of Y1, Y2 or Y3 is a bond. In one embodiment of the compound of formula (IB), Y1, Y2and Y3,independently, is C or N. In one embodiment of the compound of formula (IB), Y1, Y2and Y3,independently, is C or O. In one embodiment of the compound of formula (IB), R9 is hydrogen or (C1-C6)alkyl. In one embodiment of the compound of formula (IB), n is 0,1, 2 or 3. In one embodiment, Ra’ and Rb’ together with the C atoms to which they are attached form 5- to 6-membered heterocycloalkyl or heteroaryl. In one embodiment of the compound of formula (IB), Ra’and Rb’together with the C atoms to which they are attached form a 5 to 6 membered heterocyclyl ring optionally containing one or two hetero atoms independently selected from the group consisting of O, S, and N; In one embodiment of the compound of formula (IB), P1, P2, P3and P4, independently, is C, N or S, wherein at least one of P1, P2, P3 and P4 is N. In one embodiment of the compound of formula (IB), R10 is hydrogen, (C1-C6)alkyl, (C2- C4)alkynyl, hydroxy, 3- to 7-membered heterocycloalkyl, or (C3-C6)cycloalkyl, wherein the alkyl and alkynyl is unsubstituted or substituted with halo, cycloalkyl, NH-(CO)-NH2, NRmRn, or 5 to 6 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with (C1-C6)alkyl, hydroxy, halo or amino. In one embodiment of the compound of formula (IB), R10is hydrogen, or (C1-C6)alkyl. In one embodiment, the present invention provides a compound of formula (IC) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof: wherein R7, R6, q, Y1, Y2, Y3R11and n same as defined in compound of formula I. In one embodiment of the compound of formula (IC), R7 is hydrogen, halo, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, or halo(C1-C6)alkoxy. In one embodiment of the compound of formula (IC), R7is F, Cl or Br. In one embodiment of the compound of formula (IC), R7 is -CHF2 or -CF3. In one embodiment of the compound of formula (IC), R7 is -CH3, -CH2-CH3, -CH2-CH2- CH3, -CH(CH3)2or -CH2-CH2-CH2-CH3. In one embodiment of the compound of formula (IC), R7 is methoxy. In one embodiment of the compound of formula (IC), R7 is -OCF3. In one embodiment of the compound of formula (IC), R6at each occurrence, independently, is hydrogen, amino, (C1-C6)alkyl, (C1-C6)alkoxy or hydroxy; or two R6on the same carbon represent an oxo group. In one embodiment of the compound of formula (IC), R6 is hydrogen. In one embodiment of the compound of formula (IC), two R6on the same carbon represent an oxo group. In one embodiment of the compound of formula (IC), R6 is methoxy. In one embodiment of the compound of formula (IC), R6at each occurrence, independently is -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2or -CH2-CH2-CH2-CH3. In one embodiment of the compound of formula (IC), q is 1, 2 or 3. In one embodiment of the compound of formula (IC), Y1, Y2 and Y3, independently, is a bond, C, N, or O, wherein not more than one of Y1, Y2or Y3is a bond. In one embodiment of the compound of formula (IC), Y1, Y2 and Y3, independently, is C or N. In one embodiment of the compound of formula (IC), Y1, Y2and Y3,independently, is C or O. In one embodiment of the compound of formula (IC), the compound of R11 at each occurrence, independently, is hydrogen, hydroxy or (C1-C6)alkyl, wherein the alkyl is unsubstituted or substituted with halo or hydroxy. a dotted line [-----] indicates a bond or absent. n is 1, 2 or 3. In one embodiment, the present invention provides a compound of formula (ID) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof: wherein R7, R6, q, Y1, Y2, Y3, Z, R12, n and X1, and same as defined in compound of formula (I). In one embodiment of the compound of formula (IC), R7is hydrogen, halo, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, or halo(C1-C6)alkoxy. In one embodiment of the compound of formula (ID), R7 is F, Cl or Br. In one embodiment of the compound of formula (ID), R7 is -CHF2 or -CF3. In one embodiment of the compound of formula (ID), R7is -CH3, -CH2-CH3, -CH2-CH2- CH3, -CH(CH3)2 or -CH2-CH2-CH2-CH3. In one embodiment of the compound of formula (ID), R7 is methoxy. In one embodiment of the compound of formula (ID), R7is -OCF3. In one embodiment of the compound of formula (ID), R6 at each occurrence, independently, is hydrogen, amino, (C1-C6)alkyl, (C1-C6)alkoxy or hydroxy; or two R6 on the same carbon represent an oxo group. In one embodiment of the compound of formula (ID), two R6on the same carbon represent an oxo group. In one embodiment of the compound of formula (ID), R6is methoxy. In one embodiment of the compound of formula (ID), R6 at each occurrence, independently is -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2 or -CH2-CH2-CH2-CH3. In one embodiment of the compound of formula (ID), q is 1, 2 or 3 In one embodiment of the compound of formula (ID), Y1, Y2 and Y3, independently, is a bond, C, N, or O, wherein not more than one of Y1, Y2 or Y3 is a bond. In one embodiment of the compound of formula (ID), Y1, Y2and Y3,independently, is C or N. In one embodiment of the compound of formula (ID), Y1, Y2 and Y3, independently, is C or O. In one embodiment of the compound of formula (ID), Z is -CH2-OH. In one embodiment, the compound of formula (ID), R12 at each occurrence, independently, is hydrogen or amino. In one embodiment, the compound of formula (ID), n is 1,2 or 3. In one embodiment, the compound of formula (ID), X1, is C or N. In one embodiment, the present invention provides a compound of formula (IE) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof: wherein R7, R6, q, Y1, Y2, Y3, R8and R13are same as defined in compound of formula I. In one embodiment of the compound of formula (IE), R7is hydrogen, halo, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, or halo(C1-C6)alkoxy. In one embodiment of the compound of formula (IE), R7 is F, Cl or Br. In one embodiment of the compound of formula (IE), R7is -CHF2or -CF3. In one embodiment of the compound of formula (IE), R7 is -CF3. In one embodiment of the compound of formula (IE), R7 is -CH3, -CH2-CH3, -CH2-CH2- CH3, -CH(CH3)2or -CH2-CH2-CH2-CH3. In one embodiment of the compound of formula (IE), R7 is methoxy. In one embodiment of the compound of formula (IE), R7 is -OCF3. In one embodiment of the compound of formula (IE), R6at each occurrence, independently, is hydrogen, amino, (C1-C6)alkyl, (C1-C6)alkoxy or hydroxy; or two R6on the same carbon represent an oxo group. In one embodiment of the compound of formula (IE), two R6 on the same carbon represent an oxo group. In one embodiment of the compound of formula (IE), R6 is methoxy. In one embodiment of the compound of formula (IE), R6 at each occurrence, independently is -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2or -CH2-CH2-CH2-CH3. In one embodiment of the compound of formula (IE), q is 1, 2 or 3. In one embodiment of the compound of formula (IE), Y1, Y2 and Y3, independently, is a bond, C, N, or O, wherein not more than one of Y1, Y2 or Y3 is a bond. In one embodiment of the compound of formula (IE), Y1, Y2and Y3,independently, is C or N. In one embodiment of the compound of formula (IE), Y1, Y2 and Y3, independently, is C or O. In one embodiment of the compound of formula (IE), R8 is hydrogen or (C1-C6)alkyl. In one embodiment of the compound of formula (IE), R13 is hydrogen or (C1-C6)alkyl. a dotted line [-----] indicates a bond or absent. In one embodiment, present invention provides a compound of formula (IF), (IG), (IH), (IJ) and (IK) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof: .

[0018] In one embodiment, the present invention provides a compound of formula (IL): or a pharmaceutically acceptable salt or stereoisomer or a tautomer thereof; wherein, R1at each occurrence, independently is hydrogen, (C1-C6)alkyl, hydroxy, halo, amino or halo(C1-C6) alkyl, and / or two R1adjacent to each other together with the C atoms to which they are attached form a phenyl or 5- to 6-membered heterocyclyl; wherein the phenyl and heterocyclyl are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of (C1-C6)alkyl, (C2-C4)alkyne, halo, hydroxy, halo(C1- C6)alkyl, amino, and cyano; p is 1, 2, 3, or 4; R4aand R4b,independently, is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, 5- to 10- membered heteroaryl(C1-C6)alkyl or 4- to 7-membered heterocyloalkyl, wherein the cycloalkyl and heteroarylalkyl are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo, alkyl and amino; and / or R4aand R4btogether with the nitrogen to which they are attached form a 4- to 14- membered heterocyclyl optionally containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulphur; wherein the heterocyclyl is unsubstituted or substituted with 1, 2 or 3 groups each independently selected from the group consisting of (C1-C6)alkyl, (C3-C6)cycloalkyl, hydroxy, cyano and -C(O)-R4c; wherein said alkyl is substituted independently with one or more of hydrogen, halo, hydroxy, amino, cyano or (C3- C6)cycloalkyl; and / or R4c is hydrogen, amino, (C1-C6)alkylamino, 4- to 7-membered heterocycloalkyl, (C3- C6)cycloalkyl, (C1-C6)alkyl or (C1-C6)alkylamino(C1-C6)alkyl; wherein the heterocycloalkyl and cycloalkyl are unsubstituted or substituted with 1, 2 or 3 groups each independently selected from the group consisting of halo, hydroxy and (C1-C6)alkyl; R7is hydrogen, halo, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, or halo(C1- C6)alkoxy; Ra’ and Rb’ independently, is hydrogen, halo or (C1-C6)alkyl; or Ra’ and Rb’ together with the C atoms to which they are attached form a 5 to 6 membered heterocyclyl ring optionally containing one or two hetero atoms independently selected from the group consisting of O, S, and N; R9 at each occurrence, independently, is hydrogen, 4- to 8-membered heterocycloalkyl, -O-heterocycloalkyl, -O-(C1-C6)alkyl; wherein 4- to 8-membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo or (C1-C6)alkyl; wherein the alkyl in -O-(C1-C6)alkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of (C1- C6)alkylamino or 5- to 8-membered heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo, or (C1-C6)alkyl; P1, P2, P3 and P4, independently, is C, N or S; wherein at least one of P1, P2, P3 and P4, is N; R10is hydrogen, (C1-C6)alkyl, (C2-C4)alkynyl, hydroxy, 3- to 7-membered heterocycloalkyl, or (C3-C6)cycloalkyl; wherein the alkyl and alkynyl is unsubstituted or substituted with halo, cycloalkyl, NH- (CO)-NH2, NRmRn, or 5 to 6 membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of (C1-C6)alkyl, hydroxy, halo or amino; Wherein; 3- to 7-membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo, hydroxy or (C1-C6)alkyl; Rmand Rnare independently hydrogen or (C1-C6)alkyl; and n is 1, 2 or 3. PHARMACEUTICAL COMPOSITIONS: 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. 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 excipient. Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising one or more compounds of the present disclosure and a pharmaceutically acceptable carrier, such as, but not limited to, a) a diluent, example, 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, example, 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, example, 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, example, starches, agar, methyl cellulose, bentonite, xanthan gum, alginic acid or its sodium salt or effervescent mixtures; e) absorbent, colorant, flavourant 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 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 degrading a target protein in a subject, wherein the target protein is KRAS. In one embodiment, the subject is afflicted with a disease or disorder dependent upon at least one of KRAS, wherein the disease or disorder is cancer. In one embodiment, the subject is afflicted with a disease or disorder dependent upon KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D or KRAS Q61H. 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 biliary tract malignancies, colon cancer, liver cancer, colorectal cancer, non-small cell lung cancer, small-cell lung cancer, pancreatic cancer, appendiceal cancer, melanoma, acute myeloid leukemia, small bowel cancer, ampullary cancer, germ cell cancer, cervical cancer, cancer of unknown primary origin, endometrial cancer, esophagogastric cancer, GI neuroendocrine cancer, ovarian cancer, sex cord stromal tumor cancer, hepatobiliary cancer, bladder cancer, lung cancer, prostate cancer, breast cancer, cervical carcinomas, testicular carcinomas, gastric cancer, head and neck cancer, hepatocellular cancer, laryngeal cancer, oral cancer, thyroid carcinomas, sarcomas, cardiac cancer, angiosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, teratoma, bronchogenic carcinoma, undifferentiated small cell cancer, adenocarcinoma, alveolar carcinoma, bronchiolar carcinoma, bronchial adenoma, lymphoma, chondromatous hamartoma, mesothelioma, gastrointestinal cancer, squamous cell carcinoma, leiomyosarcoma, stomach cancer, carcinoma, pancreas cancer, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, VIPoma, adenocarcinoma, Kaposi's sarcoma, leiomyoma, hemangioma, neurofibroma, tubular adenoma, villous adenoma, hamartoma, genitourinary tract cancer, Wilm's tumor, nephroblastoma, leukemia, urethra cancer, transitional cell carcinoma, testis cancer, seminoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroadenoma, adenomatoid tumors, hepatoma, hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, hepatocellular adenoma, gall bladder carcinoma, ampullary carcinoma, bone cancer, osteogenic sarcoma, osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, reticulum cell sarcoma, multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma, osteocartilaginous exostoses, benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, giant cell tumors, nervous system cancer, skull cancer, granuloma, xanthoma, osteitis deformans, meningioma, meningiosarcoma, gliomatosis, brain cancer, astrocytoma, medulloblastoma, glioma, ependymoma, germinoma, pinealoma, glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal cord neurofibroma, neurofibromatosis type 1, gynecological cancer, uterus cancer, endometrial carcinoma, uterine carcinoma, uterine corpus endometrial carcinoma, pre-tumor cervical dysplasia, ovarian carcinoma, serous cystadenocarcinoma, mucinous cystadenocarcinoma, granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma, intraepithelial carcinoma, clear cell carcinoma, botryoid sarcoma, embryonal rhabdomyosarcoma, fallopian tubes carcinoma, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma, malignant melanoma, basal cell carcinoma, moles dysplastic nevi, dermatofibroma, keloids and neuroblastoma. METHODS and / or USES: 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. In one embodiment, the present invention provides a method of degrading a target protein is KRAS. In one embodiment, the present invention provides a method of degrading a target protein is KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D or KRAS Q61H. In one embodiment, the present invention provides a method of treating or delaying progression of a disease or disorder dependent upon KRAS 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. In one embodiment, the present invention provides a method for treating diseases or disorders dependent upon KRAS 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. In one embodiment, diseases or disorders that are dependent upon KRAS, include cancer. In one embodiment, the present invention provides a method of inhibiting tumour 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. In any one of the preceding embodiments, cancer is selected from the group consisting of biliary tract malignancies, colon cancer, liver cancer, colorectal cancer, non-small cell lung cancer, small-cell lung cancer, pancreatic cancer, appendiceal cancer, melanoma, acute myeloid leukemia, small bowel cancer, ampullary cancer, germ cell cancer, cervical cancer, cancer of unknown primary origin, endometrial cancer, esophagogastric cancer, GI neuroendocrine cancer, ovarian cancer, sex cord stromal tumor cancer, hepatobiliary cancer, bladder cancer, lung cancer, prostate cancer, breast cancer, cervical carcinomas, testicular carcinomas, gastric cancer, head and neck cancer, hepatocellular cancer, laryngeal cancer, oral cancer, thyroid carcinomas, sarcomas, cardiac cancer, angiosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, teratoma, bronchogenic carcinoma, undifferentiated small cell cancer, adenocarcinoma, alveolar carcinoma, bronchiolar carcinoma, bronchial adenoma, lymphoma, chondromatous hamartoma, mesothelioma, gastrointestinal cancer, squamous cell carcinoma, leiomyosarcoma, stomach cancer, carcinoma, pancreas cancer, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, VIPoma, adenocarcinoma, Kaposi's sarcoma, leiomyoma, hemangioma, neurofibroma, tubular adenoma, villous adenoma, hamartoma, genitourinary tract cancer, Wilm's tumor, nephroblastoma, leukemia, urethra cancer, transitional cell carcinoma, testis cancer, seminoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroadenoma, adenomatoid tumors, hepatoma, hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, hepatocellular adenoma, gall bladder carcinoma, ampullary carcinoma, bone cancer, osteogenic sarcoma, osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, reticulum cell sarcoma, multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma, osteocartilaginous exostoses, benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, giant cell tumors, nervous system cancer, skull cancer, granuloma, xanthoma, osteitis deformans, meningioma, meningiosarcoma, gliomatosis, brain cancer, astrocytoma, medulloblastoma, glioma, ependymoma, germinoma, pinealoma, glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal cord neurofibroma, neurofibromatosis type 1, gynecological cancer, uterus cancer, endometrial carcinoma, uterine carcinoma, uterine corpus endometrial carcinoma, pre-tumor cervical dysplasia, ovarian carcinoma, serous cystadenocarcinoma, mucinous cystadenocarcinoma, granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma, intraepithelial carcinoma, clear cell carcinoma, botryoid sarcoma, embryonal rhabdomyosarcoma, fallopian tubes carcinoma, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma, malignant melanoma, basal cell carcinoma, moles dysplastic nevi, dermatofibroma, keloids and neuroblastoma. In one embodiment, the cancer dependent upon KRAS is lung cancer and non-small cell lung cancer. In one embodiment, the cancer dependent upon KRAS is pancreatic cancer. In one embodiment, the present invention provides a compound of (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, for use as a medicament. In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutical acceptable salt or a stereoisomer or a tautomer thereof, for use in the treatment of a disease or disorder dependent upon KRAS. In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutical acceptable salt or a stereoisomer or a tautomer thereof, for use in the treatment of a disease or disorder dependent upon KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D or KRAS Q61H. In one embodiment, a disease or disorder dependent upon KRAS is cancer. In one embodiment, the present invention provides use of 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 KRAS. In one embodiment, the present invention provides a compound represented by formula (I) or a pharmaceutical acceptable salt or a stereoisomer or a tautomer thereof, for use in the treatment of a disease or disorder dependent upon KRAS, wherein the disease or disorder dependent upon KRAS is cancer. In one embodiment, the disease or disorder is cancer selected from the group consisting of biliary tract malignancies, colon cancer, liver cancer, colorectal cancer, non-small cell lung cancer, small-cell lung cancer, pancreatic cancer, appendiceal cancer, melanoma, acute myeloid leukemia, small bowel cancer, ampullary cancer, germ cell cancer, cervical cancer, cancer of unknown primary origin, endometrial cancer, esophagogastric cancer, GI neuroendocrine cancer, ovarian cancer, sex cord stromal tumor cancer, hepatobiliary cancer, bladder cancer, lung cancer, prostate cancer, breast cancer, cervical carcinomas, testicular carcinomas, gastric cancer, head and neck cancer, hepatocellular cancer, laryngeal cancer, oral cancer, thyroid carcinomas, sarcomas, cardiac cancer, angiosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, teratoma, bronchogenic carcinoma, undifferentiated small cell cancer, adenocarcinoma, alveolar carcinoma, bronchiolar carcinoma, bronchial adenoma, lymphoma, chondromatous hamartoma, mesothelioma, gastrointestinal cancer, squamous cell carcinoma, leiomyosarcoma, stomach cancer, carcinoma, pancreas cancer, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, VIPoma, adenocarcinoma, Kaposi's sarcoma, leiomyoma, hemangioma, neurofibroma, tubular adenoma, villous adenoma, hamartoma, genitourinary tract cancer, Wilm's tumor, nephroblastoma, leukemia, urethra cancer, transitional cell carcinoma, testis cancer, seminoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroadenoma, adenomatoid tumors, hepatoma, hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, hepatocellular adenoma, gall bladder carcinoma, ampullary carcinoma, bone cancer, osteogenic sarcoma, osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, reticulum cell sarcoma, multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma, osteocartilaginous exostoses, benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, giant cell tumors, nervous system cancer, skull cancer, granuloma, xanthoma, osteitis deformans, meningioma, meningiosarcoma, gliomatosis, brain cancer, astrocytoma, medulloblastoma, glioma, ependymoma, germinoma, pinealoma, glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal cord neurofibroma, neurofibromatosis type 1, gynecological cancer, uterus cancer, endometrial carcinoma, uterine carcinoma, uterine corpus endometrial carcinoma, pre-tumor cervical dysplasia, ovarian carcinoma, serous cystadenocarcinoma, mucinous cystadenocarcinoma, granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma, intraepithelial carcinoma, clear cell carcinoma, botryoid sarcoma, embryonal rhabdomyosarcoma, fallopian tubes carcinoma, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma, malignant melanoma, basal cell carcinoma, moles dysplastic nevi, dermatofibroma, keloids and neuroblastoma. In one embodiment, the present invention provides a process for the preparation of compound of formula (I). In one embodiment, the present invention provides a method for degrading KRAS protein, comprising contacting a compound of formula or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof with KRAS protein. 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 drug for treating or preventing a KRAS- mediated disease or condition. 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 drug for KRAS- mediated disease or condition. The present invention provides a method for treating or preventing a disease or condition regulated by KRAS (e.g., cancer), comprising administering to a patient 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. The present invention provides a method for treating or preventing a disease or condition regulated by KRAS mutations, wherein the KRAS mutation is in the region selected from KRAS G12C, KRAS G12D, KRAS G12H, KRAS G12V, KRAS G12S, KRAS G13C, KRAS G13D, KRAS Q61, KRAS Q61K and KRAS Q61H, or pan-KRAS degrader comprising administering to a patient 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. In one embodiment, the compounds of the present disclosure are KRAS degraders. In one embodiment, the compounds of the present disclosure are pan-KRAS degraders as the compounds target more than one KRAS mutation. Definitions: 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. The singular forms “a”, “an” and “the” encompass plural references unless the context clearly indicates otherwise. 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. The term “optionally substituted alkyl” can also be referred to as ‘unsubstituted or substituted alkyl’ group, wherein the substituent(s) are as stated therein. As used herein, the term “unsubstituted” means that there is no substituent or that the only substituents are hydrogen. As used herein, 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, example, 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. As used herein, the term “alkyl” refers to saturated aliphatic groups, including but not limited to C1-C10straight-chain alkyl groups or C3-C10branched-chain alkyl groups. Preferably, “alkyl” group refers to C1-C6 straight-chain alkyl groups or C3-C6 branched-chain alkyl groups. In one embodiment, the “alkyl” group refers to C1-C4 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 “alkyl” include, but are not limited to, -CH3, -CH2CH3, -CH(CH3)CH3, - CH2CH2CH2CH3, -CH(CH3)CH2CH2CH3and -CH2CH(CH3)CH2CH3. The “alkyl” group may be optionally substituted. In one embodiment, the term “optionally substituted alkyl” can also be referred to as ‘unsubstituted or substituted alkyl’ group, wherein the substituent(s) are as stated therein. As used herein, the term “alkynyl” refers to straight or branched carbon chains with one or more triple bonds wherein the number atoms are in the range 2 to 6. As used herein, the term “acyl” refers to the general formula RCO-. The carbon atom is double bonded to an oxygen atom, and the R group is a chain of carbon and hydrogen atoms. Examples of “acyl” groups include but are not limited to -C(O)-CH3, -C(O)-C2H5, -C(O)- CH(CH3)2 and the like. As used herein, the term “halogen” is used herein interchangeably with the term “halogen” to mean F, Cl, Br or I atoms. As used herein, the term “cyano” as used herein refers to -CN group. As used herein, the term “oxo” as used herein refers to -O- or =O. As used herein, the term “amino” is art-recognized and refers to –NRxRy, wherein Rxand Ry independently absent, H or (C1-C6)alkyl. Exemplary amino includes an –NH2 group, –NH– , and –N Rx – group. As used herein, the term “alkylamino” refers to an amino group substituted with one or more “alkyl” group, wherein the alkyl group and amino group is as defined above. Examples of “alkylamino” groups include but are not limited to -NHCH3, -NHCH2CH3, -N(CH3)2, - N(CH3)(CH2CH3) and the like. As used herein, the term “haloalkoxy” means alkoxy substituted with one or more halogen atoms, wherein the halo and alkoxy groups are as defined above. The term “halo” is used herein interchangeably with the term “halogen” means F, Cl, Br or I. As used herein, the term “hydroxy” or “hydroxyl” alone or in combination with other term(s), is art-recognized and refers to –OH. As used herein, the term “alkoxy” refers to the group -O-alkyl, where alkyl groups are as defined above. Exemplary C1-C10alkoxy group include but are not limited to methoxy, ethoxy, n-propoxy, n-butoxy or t-butoxy. In one embodiment, the “alkoxy” group refers to C1-C6 alkoxy groups. In another embodiment, the “alkoxy” group refers to C1-C4 alkoxy groups. An alkoxy group can be optionally substituted with one or more suitable groups. In some embodiments, alkoxy group can be unsubstituted or substituted with one or more substituents, wherein the substituents are described herein. As used herein, the term “haloalkyl” refers to alkyl substituted with one or more halogen atoms, wherein the halogen and alkyl groups are as defined above. Preferably (C1-C6) alkyl substituted with one or more halogen atoms. Examples of “haloalkyl” include but are not limited to fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl and 2,2,2- trifluoroethyl. As used herein, the term “cycloalkyl” means C3-C10 saturated cyclic hydrocarbon ring. A cycloalkyl may be a single ring, which typically contains from 3 to 8 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 spiro or bicyclo 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, bicyclo[2.2.2]octane, spiro[3.3]heptane, and cycloheptylenyl. As used herein, the term “heterocycloalkyl” refers to a non-aromatic, saturated or partially saturated, monocyclic or polycyclic ring system of 3 to 15 member having at least one heteroatom or heterogroup selected from the group consisting of O, N, S, S(O), S(O)2, NH and C(O) with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. The term “heterocycloalkyl” also refers to the bridged or spiro or fused bicyclic ring system having at least one heteroatom or heterogroup selected from the group consisting of O, N, S, S(O), S(O)2, NH and C(O). Examples of “heterocycloalkyl” include, but are not limited to azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, dioxidothiomorpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, indolinyl, indolinylmethyl, aza-bicyclooctanyl, azocinyl, chromanyl, xanthenyl, 2- oxabicyclo[2.2.2]octanyl, and N-oxides thereof. Attachment of a heterocycloalkyl substituent can occur via either a carbon atom or a heteroatom. A heterocycloalkyl group can be optionally substituted with one or more suitable groups by one or more aforesaid groups. Preferably “heterocycloalkyl” refers to 5- to 6-membered ring selected from the group consisting of azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, and N-oxides thereof. More preferably, “heterocycloalkyl” includes azetidinyl, pyrrolidinyl, morpholinyl and piperidinyl. All heterocycloalkyl are optionally substituted by one or more aforesaid groups. As used herein, the term “heteroaryl” refers to an aromatic heterocyclic ring system containing 5 to 20 ring atoms, suitably 5 to 10 ring atoms, which 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. The rings may contain from 1 to 4 heteroatoms selected from the group consisting of N, O and S, wherein the N or S atom is optionally oxidized or the N atom is optionally quarternized. Any suitable ring position of the heteroaryl moiety may be covalently linked to the defined chemical structure. Examples of heteroaryl include, but are not limited to: furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, 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, α- carboline, indolizinyl, benzoisothiazolyl, benzoxazolyl, pyrrolopyridyl, pyrazolopyrimidyl, furopyridinyl, purinyl, benzothiadiazolyl, benzooxadiazolyl, benzotriazolyl, benzotriadiazolyl, carbazolyl, dibenzothienyl, acridinyl and the like. Preferably “heteroaryl” refers to 5- to 6- membered ring selected from the group consisting of furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl. More preferably, pyrazolyl, pyridyl, oxazolyl, and furanyl. All heteroaryls are optionally substituted by one or more aforesaid groups. As used herein, the term ‘compound(s)’ comprise(s) the compound(s) disclosed in the present invention. As used herein, the term “heteroaryalkyl” refers to alkyl substituted with one or more heteroaryl groups, wherein the heteroaryl and alkyl groups are as defined above. Preferably (C1-C6) alkyl substituted with one or more heteroaryl groups. Examples of “heteroaryalkyl” include but are not limited to -CH2-Pyridine, -CH2-Pyrazine, -CH2-CH2-Pyridine etc. As used herein, the term “heterocyclyl” refers to heterocycloalkyl or heteroaryl. As used herein, the term “aryl” is optionally substituted monocyclic, bicyclic or polycyclic aromatic hydrocarbon ring system of about 6 to 14 carbon atoms. Examples of a C6- C14 aryl group include, but are not limited to phenyl, naphthyl, biphenyl, anthryl, fluorenyl, indanyl, biphenylenyl and acenaphthyl. Aryl group can be unsubstituted or substituted with one or more suitable groups. The term “acyl” refers to a group R-CO- wherein R is an optionally substituted alkyl group defined above. Examples of ‘acyl’ groups are, but not limited to, CH3CO-, CH3CH2CO- , CH3CH2CH2CO- or (CH3)2CHCO-. The term “heteroatom” as used herein designates a sulfur, nitrogen or oxygen atom. As used herein, the term 'compound(s)' comprises the compounds disclosed in the present invention. As used herein, the term “salt / salts” refers to the salts derived from appropriate bases include alkali metal (example, sodium and potassium), alkaline earth metal (example, magnesium), ammonium and N+(C1-C4 alkyl)4 salts. As used herein, the term “comprises” or “comprising” is generally used in the sense of include, that is to say permitting the presence of one or more features or components. 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. As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By “pharmaceutically acceptable” it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. 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. 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. 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. As used herein, 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 a prodrug derivative or 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. As used herein, the term “carrier” as used in this disclosure, encompasses carriers, excipients and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, 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. As used herein, the term “treat”, “treating” and “treatment” refer to a method of alleviating or abrogating a disease and / or its attendant symptoms. 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. As used herein, the term “subject” that may be interchangeable with ‘patient’, refers to an animal, preferably a mammal and most preferably a human. 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 hereof, 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. As used herein, 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. “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. The present invention also provides methods for formulating the disclosed compounds as for pharmaceutical administration. 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, example, a skin patch. The composition can also be present in a solution suitable for topical administration, such as an eye drop. 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 tumours. Exemplary cancers which may be treated by the present compounds include biliary tract malignancies, bladder cancer, breast cancer, colon cancer, colorectal cancer, cervical cancer, endometrial cancer, liver cancer, lung cancer, non-small cell lung cancer, myeloid leukemia or pancreatic cancer. The term “stereoisomers” refers to any enantiomers, diastereoisomers or geometrical isomers of the compound 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 d-Isomers and l-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 I and zusammen (Z) Isomers as well as the appropriate mixtures thereof. 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. 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 (S)-enantiomer. 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. 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. 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. 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. 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. 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. 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. 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. Liquid formulations include, but are not limited to, syrups, emulsions and sterile injectable liquids, such as suspensions or solutions. 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. The pharmaceutical compositions of the present patent application may be prepared by conventional techniques known in literature. Suitable doses of the compounds for use in treating the diseases or disorders described herein can be determined by those skilled in the relevant art. Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects. Mode of administration, dosage forms and suitable pharmaceutical excipients can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the present patent application. 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 labelled 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 as 2H (“D”), 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 32P, 33P, 35S, 18F, 36Cl, 123I and 125I. Isotopically labelled 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 labelled reagent for a non-isotopically labelled reagent. EXPERIMENTAL: The following general guidelines apply to all experimental procedures described here. Unless otherwise stated, reactions were performed under positive pressure of nitrogen, and temperatures described are external temperatures (oil bath temperature). Reagents and solvents received from vendors were used as such without any further drying or purification. Molarities mentioned here for reagents in solutions are approximate, as they were not verified by a prior titration with a standard. All reactions were stirred with a magnetic stir bar. Cooling to negative temperatures was achieved with acetone / dry ice or ice / salt baths. Magnesium sulfate and sodium sulfate were used as solvent drying agent after reaction work up and are interchangeable. Removal of solvents under reduced pressure / vacuum was conducted using a rotary evaporator. The specifics of the processes for preparing compounds of the present disclosure are detailed in the experimental section. ABBREVIATIONS: The abbreviations used in the entire specification is summarized below with their meaning. DMF-N,N-Dimethylformamide; ACN-Acetonitrile; EtOAc-Ethyl acetate; THF- Tetrahydrofuran; DCM-Dichloromethane; MeOH-Methanol; EtOH-Ethanol; DMSO-dimethyl sulfoxide; THF- Tetrahydrofuran; MeI-Methyl iodide; EtI-Ethyl iodide; TEA (or) Et3N- Triethylamine; DIPEA- N,N-Diisopropylethylamine; KOtBu-potassium tertiary butoxide; K2CO3-Potassium carbonate; Cs2CO3-cesium carbonate; K3PO4- Potassium phosphate; LiOH- Lithium hydroxide; NH3-Ammonia; NaOAc-Sodium acetate; KOAc-Potassium acetate; NH4OH-Ammonium hydroxide; NH4Cl-Ammonium chloride; NIS- N-Iodosuccinimide, CDI- 1,1 carbonyl diimidazole, DDQ - 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone; POCl3- Phosphoryl chloride, PBr3- Phosphorus tribromide; N2H4-hydrazine monohydrate; NaBH4 - sodium borohydride; NaIO4- sodium periodate; OsO4 - osmium tetraoxide DABCO- 1,4- Diazabicyclo[2.2.2]octane, HATU-1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate; RuPhos-2-Dicyclohexylphosphino-2′,6′- diisopropoxybiphenyl; TFA-Trifluoroacetic acid; AcOH-Acetic acid; RT / rt-Room temperature; P-TSA- para-toluene sulfonic acid monohydrate; Ruphos-Pd-G3 - (2- Dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)] palladium (II) methanesulfonate; Pd-C- Palladium on carbon; Pd(dppf)Cl2·DCM-[1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane; LiAlH4- Lithium aluminum hydride; B2pin2-bis(pinacolato)diboron; DMF-DMA- N,N- Dimethylformamide dimethyl acetal; BnOH- benzyl alcohol; MW- microwave; TLC-Thin layer chromatography; LCMS-Liquid chromatography–mass spectrometry; HPLC- High- performance liquid chromatography; CD3OD- Deuterated methanol; DMSO-d6-Deuterated dimethyl sulfoxide; CDCl3-Deuterated chloroform; NMR-Nuclear magnetic resonance; s- Singlet; d-Doublet; t-Triplet; q-Quartet; app. quint-Apparent quintet; dd-doublet of doublets; td-Triplet of doublets; SM-starting material; Int-Intermediate. GENERAL SCHEME – I: The general scheme for the synthesis of compound represented by formula (I’) is depicted in the above scheme. The compound of formula (A2) can be obtained by the reduction reaction of a compound of formula (A1). The compound of formula (A2) upon further reaction with a compound of formula (B1) in a suitable solvent can result in a compound of formula (A3) which can undergo hydrolysis in the presence of a base to yield a compound of formula (A4). The compound of formula (A4) can be coupled with a pyrrolidine nitrogen of M in the presence of a solvent to yield compound of formula (I’). GENERAL SCHEME – II: The general scheme for the synthesis of compound represented by formula (B1) is depicted in the above scheme. The compound of formula (D2) can be obtained from a compound of formula (D1). The compound of formula (D2), upon further reaction with a compound of formula (E1) in the presence of a suitable solvent can yield a compound of formula (B1). Alternatively, the compound of formula (D2’) can be obtained by the coupling reaction of compound of formula (D1’). The compound of formula (D2’) can undergo substitution and coupling to give a compound of formula (D3’). The compound of formula (D3’) can undergo oxidation in the presence of a suitable solvent and reagent to yield a compound of formula (D4’), which can further undergo reduction in the presence of a suitable reagent and solvent to yield the compound of formula (B1). PREPARATION OF INTERMEDIATES (I-1 to XXIV-1) Synthesis of 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (I-1): To a stirred solution of 2-amino-4-bromo-3-fluorobenzoic acid (40.0 g, 0.017 mol, 1.0 equiv.) in DMF (200 mL) was added NIS (46.14 g, 0.02 mol, 1.2 equiv.) at room temperature and the reaction mixture was subsequently stirred at 80 °C for 6 h. The reaction mixture was allowed to cool to room temperature, then poured into ice water (100 mL) and stirred for 30 min. The resulting solid was filtered from the aqueous phase and dried under high vacuum to give acid title compound I-1 (62.0 g), which was sufficiently pure to perform the next reaction.1H NMR (400 MHz, DMSO-d6): ^ 13.30 (bs, 1H), 7.99 (d, J = 2.0 Hz, 1H), 6.7 (bs, 2 H); LC-MS: m / z 357.7 (M-H)+. Synthesis of 2-amino-4-bromo-3-fluoro-5-iodobenzamide (II-1): To a stirred solution of ammonium chloride (2.95 g, 0.055 mol, 2.0 equiv.) and DIPEA (10.8 g, 0.08 mol, 3.0 equiv.) in DMF (0.1 L) was added 2-amino-4-bromo-3-fluoro- 5-iodobenzoic acid (I-1) (10.0 g, 0.028 mol, 1.0 equiv.) and HATU (12.0 g, 0.033 mol, 1.2 equiv.) at room temperature. The mixture was stirred at room temperature for 16 h. The reaction mixture was poured into ice water and stirred for 30 min. The solid was filtered from the aqueous phase and dried under a high vacuum to afford iodobenzamide II-1(10.0 g) which was sufficiently pure to perform the next reaction.1H NMR (400 MHz, DMSO-d6): ^ 8.03 (bs, 2H), 7.94 (s, 1H), 6.85 (s, 2H); LC-MS: m / z 358.60 (M-H)+. Synthesis of 7-bromo-8-fluoro-6-iodoquinazoline-2,4-diol (III-1): To a stirred solution of 2-amino-4-bromo-3-fluoro-5-iodobenzamide (II-1) (30.0 g, 0.083 mol, 1.0 equiv.) in DMF (150 mL) was added potassium carbonate (40.0 g, 0.29 mol, 3 equiv.) and 1,1-carbonyl diimidazole (54.0 g, 0.33 mol, 4 equiv.) at room temperature. Then the reaction mixture was heated to 80 °C and stirred for 16 h. The reaction mixture was allowed to cool to room temperature, then poured into ice water and stirred for 30 min. The solid was filtered from the aqueous phase and dried under high vacuum to provide the title dihydroxy compound III-1 (30.0 g) which was sufficiently pure to perform the next reaction. LC-MS: m / z 382.75 (M-H)+. Synthesis of ethyl 7-bromo-8-fluoro-4-hydroxy-6-iodoquinazoline-2-carboxylate (III-1a) To a stirred solution of ethyl 2-amino-4-bromo-3-fluoro-5-iodobenzoate (27.0 g, 69.59 mmol, 1.0 equiv.) in acetic acid (150 mL) was added ethyl carbonocyanidate (27.58 g, 278.37mmol, 4 equiv.) followed by the addition of concentrated HCl (1 mL) and the reaction mixture was stirred for 16 h at 70 °C. The mixture was allowed to cool to room temperature and quenched with ice-cold water. The obtained solid filtered and dried to get titled crude product (12.1g) which was proceeded to next step without purification; LC-MS: m / z 440.75 (M-H)+. Synthesis of 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (IV-1): To a stirred solution of 7-bromo-8-fluoro-6-iodoquinazoline-2,4-diol (III-1) (60.0 g, 0.155 mol, 1.0 equiv.) in POCl3(0.6 L) was added DIPEA (54.0 g, 0.13 mol, 2.2 equiv.) carefully at 0 °C. The mixture was allowed to reach room temperature and was then heated to 110 °C for 16 h. The reaction mixture was allowed to cool to room temperature, then concentrated under reduced pressure to remove the POCl3. The crude oil was poured into ice cold water carefully and stirred for 10 min. The solid was filtered from the aqueous phase and dried under high vacuum to give a crude title compound IV-1 (65.0 g) which was sufficiently pure to perform the next reaction.1H NMR (400 MHz, DMSO-d6): δ 8.67 (d, J = 1.6 Hz, 1H); LC-MS: m / z 424.3 (M+H)+ Synthesis of Ethyl 7-bromo-4-chloro-8-fluoro-6-iodoquinazoline-2-carboxylate (IV-1a): The above intermediate IV-1a was prepared using procedure similar to the one described in the synthesis of Intermediate IV-1 using POCl3 as chlorinating agent; LC-MS: m / z 459.6 (M+H)+Synthesis of tert-butyl (1S,4S)-5-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (V-1): To a stirred solution of 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (IV-1) (27.0 g, 0.06 mol, 1.0 equiv.) in DCM (280 mL) was added DIPEA (34.0 g, 0.25 mol, 4.0 equiv.) followed by tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (13.0 g, 0.07 mol, 1.05 equiv.) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure. The crude material was poured into ice water and stirred for 10 min. The crude solid was filtered from the aqueous phase and dried under a high vacuum. The crude compound was suspended in 0.15 L of 5% ethyl acetate in hexane and stirred for 2 h. The solid was then filtered and dried under high vacuum to give a crude title compound V-1 (37.0 g) which was sufficiently pure to perform the next reaction.1H NMR (400 MHz, DMSO-d6): ^ 8.37 (d, J = 6.4 Hz, 1H), 5.20 (d, J = 18.4 Hz, 1H), 4.57 (d, J = 16.8 Hz, 1H), 4.40- 4.30 (bs, 1H), 3.90- 3.70 (bs, 1H), 3.60- 3.40 (m, 2H), 2.05- 1.90 (m, 2H), 1.39 (d, J = 13.6 Hz, 9H); LC-MS: m / z 584.90 (M+H)+. The intermediates listed below in Table-1 were prepared by procedures similar to the one described in the synthesis of Intermediate V-1 with 7-bromo-2,4-dichloro-8-fluoro-6- iodoquinazoline (IV-1) and appropriate amine (SM-2) with appropriate variations in reagents, solvents and reaction conditions. The characterization data of the intermediates are summarized herein the below table. Table-1

[0019] Synthesis of ethyl 7-bromo-4-((1S,4S)-5-(tert-butoxycarbonyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-8-fluoro-6-iodoquinazoline-2-carboxylate (V-16): The above reaction was carried out by a procedure similar to the one described in the procedure of Intermediate V-1 with ethyl 7-bromo-4-chloro-8-fluoro-6-iodoquinazoline-2- carboxylate (IV-1a) and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylateto to get desired intermediate V-16; LC-MS: m / z 621.4 [M+H]+ Synthesis of tert-butyl (1S,4S)-5-(7-bromo-8-fluoro-6-iodo-2-((tetrahydro-2H-pyran-4- yl)oxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (VI-1): To a stirred solution of tert-butyl (1S,4S)-5-(7-bromo-2-chloro-8-fluoro-6- iodoquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (V-1) (15.0 g, 0.025mol, 1.0 equiv.) in 120 mL of THF and DMF (3:5) was added DABCO (0.58 g, 0.005 mol, 0.20 equiv.), followed by tetrahydro 4-hydroxypyranol (7.87 g, 0.077 mol, 3.0 equiv.) and cesium carbonate (25.0 g, 0.077 mol, 3.0 equiv.) and stirred for 16 hours at room temperature. The reaction mixture was poured into ice-cold water and stirred for 5 hours. The solid formed was filtered from the aqueous phase and dried under a high vacuum. The crude compound was suspended in 0.15 L of 5% ethyl acetate in hexane solution and stirred for 15 minutes, and the solid was filtered and dried under high vacuum to give a crude title compound VI-1 (15.0 g) which was sufficiently pure to perform the next reaction.1H NMR (400 MHz, DMSO-d6): ^ 8.28 (d, J = 6.0 Hz, 1H), 5.20- 5.10 (m, 2H), 4.55 (d, J = 17.6 Hz, 1H), 4.30- 4.20 (bs, 1H), 3.90- 3.80 (m, 2H), 3.80- 3.70 (m, 1H), 3.60- 3.30 (m, 4H), 2.10- 1.90 (m, 4H), 1.75- 1.60 (m, 2H), 1.35 (d, J = 8.8 Hz, 9H); LC-MS: m / z 649.0 (M+H)+. The intermediates listed below in Table-2 were prepared by procedures similar to the one described in the synthesis of Intermediate VI-1 with chloro quinazoline (SM-1) and appropriate alcohol (SM-2) with appropriate variations in reagents, solvents and reaction conditions. The characterization data of the intermediates are summarized herein the below table. Table-2

[0020] Synthesis of tert-butyl (1S,4S)-5-(7-bromo-8-fluoro-6-iodo-2-((1- (morpholinomethyl)cyclopropyl)methoxy)quinazolin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (VI-21) Step-i: Synthesis of tert-butyl (1S,4S)-5-(7-bromo-8-fluoro-6-iodo- 2((1(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)quinazolin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate To a solution of tert-butyl (1S,4S)-5-(7-bromo-8-fluoro-2-((1- (hydroxymethyl)cyclopropyl)methoxy)-6-iodoquinazolin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (VI-15) (4.0g, 6.16 mmol, 1.0 eq) in DCM (40 mL) was added DIPEA (3.98 g, 30.80 mmol, 5.0 eq) and the reaction mixture was stirred at room temperature for 5 min. Then methanesulfonic anhydride (1.41g, 12.31mmol, 2.0 eq) was added to the reaction mixture at 0 °C and stirred at room temperature for 1 h. After completion of reaction, the reaction mixture was diluted with water and extracted with DCM (40 mL x 3). The combined organic phase was washed with brine (40 mL), dried over Na2SO4and concentrated to give tert-butyl (1S,4S)-5-(7-bromo-8-fluoro-6-iodo- 2((1(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)quinazolin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate(4.50g, crude) as a yellow solid, which was directly used in the next step without purification; LC-MS: m / z 728.90 [M+H]+Step-ii; Synthesis of tert-butyl (1S,4S)-5-(7-bromo-8-fluoro-6-iodo-2-((1- (morpholinomethyl)cyclopropyl)methoxy)quinazolin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate To a stirred solution of tert-butyl (1S,4S)-5-(7-bromo-8-fluoro-6-iodo-2-((1- (((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)quinazolin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (4.2 g, 5.774mmol, 1.0 equiv.) in 40 mL of DMF was added morpholine (0.654g, 7.50 mmol, 1.3equiv.), potassium carbonate (2.394 g, 17.32 mmol, 3.0 equiv.) and potassium iodide(0.096g, 0.57mmol, 0.1equiv.) and stirred for 2 hours at 60oC. The reaction mixture was cooled to room temperature and poured into ice-cold water, The mixture was diluted and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with brine (40 mL), dried over Na2SO4 and concentrated to give a residue. The crude was purified by combi-flash column chromatography using 30% ethyl acetate in hexane to afford the compound VI-21 (1.7 g) LC-MS: m / z 718.05 [M+H]+. Synthesis of tert-butyl (1S,4S)-5-(7-bromo-8-fluoro-6-iodo-2-(methylthio)quinazolin-4- yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (VI-22): Step-i: Synthesis of tert-butyl (1S,4S)-5-(7-bromo-2,8-difluoro-6-iodoquinazolin-4-yl)- 2,5-diazabicyclo [2.2.1] heptane-2-carboxylate To a mixture of tert-butyl (1S,4S)-5-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4- yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (V-1) (1.0 g, 1.71 mmol) in DMSO (5 mL) was added KF (0.99 g, 17.13 mmol) and the reaction mixture was stirred at 120 °C for 12 h. After the completion of reaction, the mixture was quenched with ice cold water and the product was extracted with ethyl acetate (3 X 15 mL). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated to a give crude product. Crude product was purified by Combiflash using 10%-30% ethyl acetate in hexane to get titled compound as off white solid (0.81 g, 83%), LC-MS: m / z 568.90 [M+H]+Step-ii: Synthesis of tert-butyl (1S,4S)-5-(7-bromo-8-fluoro-6-iodo-2- (methylthio)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate To a solution of tert-butyl (1S,4S)-5-(7-bromo-2,8-difluoro-6-iodoquinazolin-4-yl)- 2,5-diazabicyclo [2.2.1] heptane-2-carboxylate (0.8 g, 1.41 mmol, 1.0 eq.) in THF (5 mL) was added NaSMe (0.198 g, 2.82 mmol, 2.0 eq.)) at 0 °C. The reaction mixture was stirred at room temperature for 12 h. After the completion of reaction, the reaction mixture was quenched with ice cold water and extracted with ethyl acetate (20 mLx3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Combiflash, eluting with 10%-20% ethyl acetate in hexane to get titled compound (VI-22) as off white solid (0.38 g, 45%), LC-MS: m / z 594.95 [M+H]+ Synthesis of tert-butyl (1S,4S)-5-(7-bromo-2-(ethylthio)-8-fluoro-6-iodoquinazolin-4-yl)- 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (VI-23) To a stirred solution of tert-butyl (1S,4S)-5-(7-bromo-2-chloro-8-fluoro-6- iodoquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (V-1) (15.0 g, 0.025mol, 1.0 equiv.) in 120 mL of THF and DMF (3:5) was added DABCO (0.58 g, 0.005 mol, 0.20 equiv.), followed by the addition of ethanethiol (4.80 g, 0.077 mol, 3.0 equiv.) and cesium carbonate (25.0 g, 0.077 mol, 3.0 equiv.) and stirred for 16 hours at room temperature. After the completion of reaction, the mixture was quenched with ice cold water and the product was extracted with ethyl acetate, combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated to a give crude product. The crude was purified by Combiflash, eluting with 10%-20% ethyl acetate in hexane to get titled compound as off white solid VI-23 (9.40 g, 60%); LC-MS: m / z 609.90 [M+H]+Synthesis of tert-butyl (1S,4S)-5-(8-(benzyloxy)-7-bromo-6-iodo-2-((tetrahydro-2H- pyran-4-yl)oxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (VII-1): To a stirred solution of benzyl alcohol (7.25 g, 0.066 mol, 1.5 equiv.) in THF (150 mL) was added potassium tertiary butoxide (7.5 g, 0.066 mol, 1.5 equiv.) at 0oC, and the reaction mixture was stirred for 10 min, followed by the addition of starting material tert-butyl (1S,4S)-5-(7-bromo-8-fluoro-6-iodo-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (VI-1) (29.0 g, 0.044 mol, 1.0 equiv.). The mixture was allowed to warm to room temperature and stirred for 12 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (200 mL) and poured into ice cold ammonium chloride solution (100 mL) and stirred for 0.5 h. The organic layer was collected, dried over anhydrous sodium sulphate, and concentrated under reduced pressure afforded the titled crude compound VII-1 (32.0 g) which was sufficiently pure to perform next step.1H NMR (400 MHz, DMSO-d6): ^ 8.26 (d, J = 8.4 Hz, 1H), 7.58 (dd, J = 8.4 Hz, 1.2 Hz, 2H), 7.46- 7.30 (m, 3H), 5.30- 5.10 (m, 4H), 4.54 (d, J = 20.0 Hz, 1H), 4.30- 4.20 (bs, 1H), 4.03 (d, J = 7.2 Hz, 2H), 3.85- 3.82 (m, 1H), 3.50- 3.40 (m, 2H), 2.10- 1.90 (m, 5H), 1.80- 1.60 (m, 2H), 1.38 (d, J = 14.0 Hz, 9H); LC-MS: m / z 739.0 (M+H)+. The intermediates listed below in Table-3 were prepared by procedures similar to the one described in the synthesis of Intermediate VII-1 with fluro quinazoline (SM-1) and (S)- 1-phenylethan-1-ol or benzyl alcohol (SM-2) with appropriate variations in reagents, solvents and reaction conditions. The characterization data of the intermediates are summarized herein the below table. Table-3

[0021]

[0022] Synthesis of tert-butyl (75',45)-5-(8-(benzyloxy)-7-bromo-6-cyclopropyl-2-((tetrahydro- 2H-pyran-4-yl)oxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (VIII- 1):

[0023] A mixture of tert-butyl (AS',-AS’)-5-(8-(benzyloxy)-7-bromo-6-iodo-2-((tetrahydro-2H- pyran-4-yl)oxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2. l]heptane-2-carboxylate (VII-1) (17.0 g, 0.023 mol, 1.0 equiv.), cyclopropyl boronic acid (11.8 g, 0.14 mol, 6.0 equiv.) and potassium phosphate (12.2 g, 0.06 mol, 2.5 equiv.) in 170 mL of toluene and water (4: 1) was transferred to a sealed tube and degassed with argon for 30 min. Pd(dppf)C12-DCM was added to the reaction mixture, which was then degassed for another 5 min. The reaction mixture was then heated at 80 °C for 4 h. The reaction mixture was allowed to cool to room temperature, then diluted with ethyl acetate (0.25 L) and filtered through a pad of Celite®. The organic layer was separated from the aqueous layer and dried over anhydrous sodium sulphate, then concentrated under reduced pressure to get crude product. The crude was purified by combi -flash column chromatography using 30% ethyl acetate in hexane to afford the titled compound of VIII-1 (14.0 g) along with des-bromo compound (49%); LC-MS: m / z 653.1 (M+H)+.

[0024] The intermediates listed below in Table-4 were prepared by procedures similar to the one described in the synthesis of Intermediate VIII-1 with iodo quinazoline (SM-1) and cyclopropyl boronic acid (SM-2) with appropriate variations in reagents, solvents and reaction conditions. The characterization data of the intermediates are summarized herein the below table.

[0025] Table-4

[0026] Synthesis of tert-butyl (lS,4S)-5-(7-bromo-6-cyclopropyl-2-((2-

[0027] (dimethylamino)ethyl)carbamoyl)-8-fluoroquinazolin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (VIII-24a):

[0028] Boc Boc VIII-24 Vlll-24a

[0029] To a solution of 7-bromo-4-((lS,4S)-5-(tert-butoxycarbonyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-8-fluoro-6-iodoquinazoline-2-carboxylic acid (VIII-24) (8.7 g, 14.66 mmol, 1.0 equiv.) in DMF (50 mL), diisopropylethylamine (5.68 g, 43.99 mmol, 3.0 equiv.) was added at 0 °C, and the reaction mixture was stirred for 10 mins at rt. Then N1,N1- dimethylethane- 1,2-diamine (1.55 g, 17.59mmol, 1.2 equiv.) followed by HATU (5.17g, 21.99 mmol, 1.5 equiv.) were added to the reaction mixture, and the reaction mixture was stirred for 12 h. The reaction mixture extracted with EtOAc (2x100 mL). Organic layers were collected and washed with brine (100 mL), dried over anhydrous, sodium sulphate, filtered, and concentrated under reduced pressure to get the crude product which was purified by column chromatography (silica gel, 230-400 mesh, 5% MeOH in DCM) to get the pure titled compound

[0030] VIII-24a (9.1g, 91%); LC-MS: m / z 577.7 (M+H)+.

[0031] The intermediates listed below in Table-4A were prepared by procedures similar to the one described in the synthesis of Intermediate VIII-24a using 7-bromo-4-((lS,4S)-5-(tert- butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-8-fluoroquinazoline-2- carboxylic acid (SM-1) and appropriate amine (SM-2) with appropriate variations in reagents, solvents and reaction conditions. The characterization data of the intermediates are summarized herein the below table.

[0032] Table-4A Synthesis of 5-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-((2-

[0033] (trimethylsilyl)ethoxy)methyl)-lH-indazole (IX-la):

[0034] IX-1a

[0035] Step-i: Synthesis of 4-bromo-5-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole

[0036] To a stirred solution of 4-bromo-5-methyl-lH-indazole (20 g, 0.094 mol, 1.0 equiv.) in DCM (600 mL, 30V) was added DIPEA (24.4 g, 0.188 mol, 2.0 equiv.) at room temperature, followed by addition of SEM-C1 (23.5g,0.141mol, 1.5eq), and then reaction mixture was stirred for 2h at room temperature. After completion of the reaction, the reaction mixture was quenched with ice cold water and extracted with ethyl acetate (150 mLx3). The combined organic layers were dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Combi-flash, eluting with by 2-10% ethyl acetate in hexane to afford titled compound (18 g); LC-MS: m / z 554.00 [M+H]+.

[0037] Step-ii: Synthesis of 5-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-((2- (trimethylsilyl)ethoxy)methyl)-2H-indazole

[0038] A mixture of 4-bromo-5-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H- indazole(34.0 g, 0.0946 mol, 1.0 equiv.), B2Pin2(48 g, 0.1892 mol, 2.0 equiv.) and potassium acetate (27.0 g, 0.2838 mol, 3.0 equiv.) in 680 mL of dioxane in 2.0 L RBF was degassed with argon for 20 min. Pd(dppf)C12-DCM (3.8 g, 0.0047 mmol, 0.05 eq) was added to the reaction mixture at room temperature and subsequently heated to 100 °C and stirred for 12 h. After the completion of the reaction, the mixture was filtered through a pad of celite, and the filtrate was quenched with ice cold water and extracted with ethyl acetate (40 mL x 3). The combined organic layers were dried over anhydrous ISfeSCU, then filtered and concentrated under reduced pressure to give a residue. The residue was purified by Combi-flash, eluting with 3-10% ethyl acetate in hexane to get titled compound IX-la (30 g); LC-MS: m / z 250.2 [M+H]+. Synthesis of tert-butyl (7X,45)-5-(8-(benzyloxy)-6-cyclopropyl-7-(5-methyl-l-(tetrahydro- 2H-pyran-2-yl)-lH-indazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (IX-1):

[0039] A mixture of tert-butyl (75,45)-5-(8-(benzyloxy)-7-bromo-6-cyclopropyl-2- ((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate (VIII-1) (14.0 g, 0.021 mol, 1.0 equiv.), 5 -methyl- l-(tetrahydro-2H-pyran-2-yl)- 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazole (8.82 g, 0.025 mol, 1.2 equiv.) and potassium phosphate (13.7 g, 0.06 mol, 3 equiv.) was dissolved in 150 mL of toluene and water (4: 1) using sealed tube and then degassed for 30 min with argon. Ruphos (1.0 g, 0.001 mol, O.lequiv.) and Ruphos-Pd-G3 (1.8 g, 0.001 mol, O.lequiv.) were added to the reaction mixture, which was degassed for another 5 min. Then the reaction mixture was heated to 100 °C for 7 h. The reaction mixture was cooled to room temperature and then diluted with ethyl acetate (0.25 L) and filtered through a pad of Celite®. The organic layer was separated from the aqueous layer and dried over anhydrous sodium sulphate, then concentrated under reduced pressure to provide the crude product. The crude product was purified by combi-flash column chromatography using 50% ethyl acetate in hexane to provide pure titled compound IX-1 (8.0 g; yield 46%); LC-MS: m / z 787.35 (M+H)+

[0040] The intermediates listed below in Table-5 were prepared by procedures similar to the one described in the synthesis of Intermediate IX-1 with bromo quinazoline (SM-1) and indazole boronated ester (SM-2) with appropriate variations in reagents, solvents and reaction conditions. The characterization data of the intermediates are summarized herein the below table. Table-5

[0041] Ill

[0042] Synthesis of tert-butyl (lS,4S)-5-(6-cyclopropyl-7-(5-methyl-l-(tetrahydro-2H-pyran-2- yl)-lH-indazol-4-yl)-2-(methylsulfonyl)-8-((S)-l-phenylethoxy)quinazolin-4-yl)-2,5- diazabicyclo [2.2.1] heptane-2-carboxylate (IX-26a) :

[0043] To a stirred solution of compound tert-butyl (lS,4S)-5-(6-cyclopropyl-7-(5-methyl-l- (tetrahydro-2H-pyran-2-yl)-lH-indazol-4-yl)-2-(methylthio)-8-((S)-l- phenylethoxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2. l]heptane-2-carboxylate (IX-26) (460 mg, 0.616 mmol, leq.) in DCM (20mL) at 0 °C under nitrogen, 3 -chloroperoxybenzoic acid (319mg, 1.84 mmol, 3.0 eq.) in DCM was added slowly. The mixture was stirred at room temperature for 3h. After completion of reaction, the reaction mixture was partitioned between water (20 mL) and DCM (20 mL X 2). The layers were separated and organic layer was concentrated in vacuo and the residue obtained was purified by Combiflash, eluting with 10%- 20% ethyl acetate in hexane to get titled compound IX-26a as off white solid (0.23 g, 44.14%), LC-MS: 779.30 [M+H]+.

[0044] The intermediates listed below in Table- 5A were prepared by procedures similar to the one described in the synthesis of Intermediate IX-26a with m-CPBA as oxidative reagent and DCM as solvent. The characterization data of the intermediates are summarized herein the below table. Table-5A

[0045] Synthesis of tert-butyl (lS,4S)-5-(8-(benzyloxy)-6-cyclopropyl-7-(2-fluoro-6- (methoxymethoxy)phenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (IX-32):

[0046] To a solution of tert-butyl (lS,4S)-5-(8-(benzyloxy)-6-cyclopropyl-7-(2-fluoro-6- hydroxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate IX-22 (0.90 g, 1.31 mmol, 1.0 eq.) in DCM (20mL) at 0° C were added DIPEA (0.045g, 1.97 mmol, 1.5 eq.) and MOM-CI (0.318 g ,3.954 mmol, 3.0 eq.). The mixture was stirred at 40 °C for 2h. After completion of the reaction, the reaction was quenched with water and extracted with DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by combi flash (0- 20% ethyl acetate in hexanes) to provide the titled compound IX-32 as a white solid (7.9 g, 68%); LC-MS: m / z 727.4 [M+H]+

[0047] Synthesis of tert-butyl (lS,4S)-5-(6-cyclopropyl-7-(5-methyl-l-(tetrahydro-2H-pyran-2- yl)-lH-indazol-4-yl)-8-((S)-l-phenylethoxy)-2-((tetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (IX-33):

[0048] To a solution of (tetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol) (119 mg, 0.846 mmol, 3.0 eq.) in DMF (21 mL) was added NaH (0.019 mg, 0.840 mmol, 3.0 eq.) (60% in mineral oil) at 0 °C under N2. The mixture was stirred at 0 °C for 10 min, then tert-butyl tert-butyl (1S,4S)- 5-(6-cyclopropyl-7-(5-methyl-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-4-yl)-2- (methylsulfonyl)-8-((S)-l-phenylethoxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate (IX-26a) (220 mg, 0.282 mmol, 1.0 eq.) in DMF (1 mL) was added to the above reaction mixture, and the resulting reaction mixture was stirred at 55 °C for 1 h. The reaction mixture was quenched with water and extracted with EtOAc (3 X 30 mL). The organic layer was dried over ISfeSCU, filtered and the residue was purified by Combiflash, eluting with 10%- 20% ethyl acetate in hexane to get titled compound IX-33 as off white solid (0.15 g,), LC-MS: 840.45 [M+H]+

[0049] The intermediates listed below in Table-5B were prepared by procedures similar to the one described in Intermediate IX-33 using sulfone intermediate (SM-1) with appropriate alcohol. The characterization data of the intermediates are summarized herein the below table. Table-5B

[0050] Synthesis of tert-butyl (lS,4S)-5-(6-cyclopropyl-2-((2-(dimethylamino)ethyl)carbamoyl)- 8-fluoro-7-(5-methyl-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-4-yl)quinazolin-4-yl)- 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (IX-37):

[0051] The above intermediate IX-37 prepared by procedures similar to the one described in the synthesis of Intermediate VII-1 with Fluro quinazoline amide (SM-1) and phenyl methanol (SM-2) with appropriate variations in reagents, solvents and reaction conditions; LC- MS: m / z 801.20[M+H]+. Similarly, the compounds listed in Table-5C also followed the same synthesis procedure as Intermediate VII-1 with fluro quinazoline amide (SM-1) and phenyl methanol (SM-2) with appropriate variations in reagents, solvents and reaction conditions. The characterization data of the intermediates are summarized herein the below table.

[0052] Table-5C

[0053] Synthesis of tert-butyl (75',45)-5-(6-cyclopropyl-8-hydroxy-7-(5-methyl-l-(tetrahydro- 2H-pyran-2-yl)-lH-indazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-yl)-2,5- diazabicyclo [2.2.1] heptane-2-carboxylate (X- 1) :

[0054] To a stirred solution of tert-butyl (75,4,S)-5-(8-(benzyloxy)-6-cyclopropyl-7-(5- methyl- l -(tetrahydro-2H-pyran-2-yl)- l / / -indazol-4-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (IX-1) (7.0 g, 0.008 mol, 1.0 equiv.) in ethanol (0.07 L) was added Pd-C (wet 50%, 7.0 g.) at 0 °C. The reaction mixture was stirred at rt under 70 psi in hydrogen atmosphere for 4 h. The reaction mixture was filtered through a pad of Celite®and washed the Celite®pad with ethyl acetate (4x50 mL). The ethyl acetate was evaporated under reduced pressure to give a crude compound X-1 (6.0 g) which was sufficiently pure to perform the next step.1H NMR (400 MHz, DMSO-d6): ^ 7.64 (d, J = 8.4 Hz, 1H), 7.41 (t, J = 4.4 Hz, 1H), 7.05 (s, 1H), 5.85 (dd, J = 9.6 Hz, 2.0 Hz, 1H), 5.39- 5.33 (m, 1H), 5.18 (d, J = 8.0 Hz, 1H ), 4.55 (d, J = 20.0 Hz, 2H), 4.35 (d, J = 20.0 Hz, 2H), 3.90- 3.70 (m, 5H), 3.55- 3.40 (m, 4H), 3.17 (d, J = 5.2 Hz, 2H), 2.14 (d, J = 5.6 Hz, 3H), 2.10- 1.90 (m, 7H), 1.75- 1.55 (m, 4H), 1.39 (d, J = 7.6 Hz, 9H), 0.62 (m, 4H); LC-MS: m / z 697.30 (M+H)+. The intermediates listed below in Table-6 were prepared by procedures similar to the one described in the synthesis of Intermediate X-1 with Pd / C catalyst and ethanol as solvent. The characterization data of the intermediates are summarized herein the below table. Table-6 Synthesis of (3-amino-4-bromophenyl) methanol (XI-1): To a mixture of methyl 3-amino-4-bromobenzoate (5.0 g, 21.73 mmol, 1.0 equiv.) in THF (50 mL) was added LiAlH4(0.83 g, 17.13 mmol, 0.8 equiv.) at 0 °C, and the resulting mixture was stirred at same temperature for 2.5 h. After completion of the reaction, the reaction mixture was quenched with ice cold saturated ammonium chloride solution (50 mL), and the product was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude titled compound XI-1 (5.0 g) which was sufficiently pure to perform the next step.1H NMR (400 MHz, DMSO-d6): ^ 7.25 (d, J = 8.4 Hz, 1H), 6.78 (t, J = 0.8 Hz, 1H), 6.43 (dd, J = 8.0, 2.0 Hz, 1H), 5.24 (s, 2H), 5.11 (t, J = 6.0 Hz, 1H), 4.34 (d, J = 5.6 Hz, 2H); LC-MS: m / z 201.85 (M+H)+. Synthesis of (3-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (XII-1): A mixture of (3-amino-4-bromophenyl)methanol (XI-1) (4.1 g, 20.3 mmol, 1.0 equiv.), bis(pinacolato)diboron (6.18 g, 24.35 mmol, 1.2 equiv.) and potassium acetate (3.88 g, 40.50 mmol, 2.0 equiv.) in 1, 4 dioxane (130 mL) was degassed with argon for 15 min. Pd(dppf)Cl2·DCM (1.26 g, 1.72 mmol, 0.008 equiv.) was added to the reaction mixture at room temperature and subsequently heated to 90 °C for 12 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite®, and the filtrate was quenched with ice cold water and extracted with ethyl acetate (40 mL x 3). The combined organic layers were dried over anhydrous Na2SO4then filtered and concentrated under reduced pressure to give a residue. The residue was purified by Combi-flash, eluting with 60% ethyl acetate in hexane to get the title compound XII-1 (3.4 g, 67%) as an off-white semi solid.1H NMR (400 MHz, DMSO-d6): ^ 7.62 (d, J = 7.6 Hz, 1H), 6.69- 6.64 (m, 2H), 4.62 (s, 2H), 1.32- 1.27 (m, 12H); LC-MS: m / z 250.2 [M+H]+Synthesis of methyl 5-(hydroxymethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzoate (XII-2): The above reaction was carried out according to the procedure similarly to the one described in the synthesis of Intermediate XII-1 using methyl 2-bromo-5- (hydroxymethyl)benzoate as starting material; LC-MS: m / z 293.10 [M+H]+. Synthesis of methyl 4-bromo-1-(1-ethoxy-3-methyl-1-oxobutan-2-yl)-1H-pyrazole-3- carboxylate (XIII-1): To a stirred solution of methyl 4-bromo-1H-pyrazole-3-carboxylate (5.0 g, 24.38 mmol) in DMF (100 mL) was added K2CO3(8.42 g, 60.97 mmol) and ethyl 2-bromo-3- methylbutanoate (6.10 g, 29.26 mmol) at room temperature. Then the reaction mixture was heated to 100 °C and stirred for 12 h. After completion of the reaction, the reaction mixture was allowed to cool to room temperature and was quenched with ice cold water (50 mL). The product was then extracted with ethyl acetate (2x500 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure to give a residue. The residue was purified by combi-flash, eluting with 40% ethyl acetate in hexane to provide the title compound XIII-1 (7.5 g, 92%) as colorless sticky liquid;1H NMR (400 MHz, DMSO-d6): ^ 7.87 (s, 1H), 4.8 (d, J = 9.2 Hz, 1H), 4.32- 4.19 (m, 2H), 3.97 (s, 3H), 2.49- 2.40 (m, 1H), 1.33- 1.28 (m, 3H), 1.45 (d, J = 6.8 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H); LC-MS: m / z 333.1 [M+H]+. Synthesis of ethyl 2-(3-amino-4-bromo-1H-pyrazol-1-yl)-3-methylbutanoate (XIII-2): The reaction was carried out according to the procedure similarly to the one described in the synthesis of Intermediate XIII-1 using 4-bromo-1H-pyrazol-3-amine as starting material.1H NMR (400 MHz, CDCl3): ^ 7.46 (s, 1H), 4.33 (d, J = 9.6 Hz, 1H), 4.30- 4.18 (m, 2H), 2.45- 2.39 (m, 1H), 1.3 (t, J = 7.2 Hz, 3H), 1.02 (d, J = 6.4 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H); LC-MS: m / z 290.0 [M+H]+. Synthesis of ethyl 2-(7-(hydroxymethyl)-4-oxo-4,5-dihydro-2H-pyrazolo[3,4-c]quinolin- 2-yl)-3-methylbutanoate (XIV-1): To a stirred solution of methyl 4-bromo-1-(1-methoxy-3-methyl-1-oxobutan-2-yl)-1H- pyrazole-3-carboxylate (XIII-1) (0.96 g, 2.89 mmol) in 1, 4 dioxane (20 mL) and water (3 mL) was added (3-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (XII-1) (0.60 g, 2.40 mmol) and potassium phosphate (1.53 g, 7.20 mmol). The vessel was then purged with argon for 15 min. Then Pd(dppf)Cl2·DCM (0.20 g, 0.24 mmol) was added, and the mixture was stirred at 100 °C for 1 hour under microwave irradiation. After completion of the reaction, the mixture was filtered through Celite®pad and quenched with ice cold water and extracted with ethyl acetate (15 mLx3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Combi-flash, eluting with 7% methanol in dichloromethane to afford the title compound XIV-1 (0.3 g, 36%) as light brown color solid;1H NMR (400 MHz, DMSO-d6): ^ 11.38 (s, 1H), 8.80 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.32 (s, 1H), 7.12 (d, J = 7.6 Hz, 1H), 5.29 (t, J = 5.6 Hz, 1H), 5.10 (d, J = 9.6 Hz, 1H), 4.55 (d, J = 5.6 Hz, 2H), 4.25- 4.14 (m, 2H), 2.69- 2.63 (m, 1H), 1.24- 1.16 (m, 3H), 1.11- 1.04 (m, 3H), 0.83 (d, J = 8.0 Hz, 3H); LC-MS: m / z 344.00 [M+H]+. Synthesis of ethyl 2-(7-(hydroxymethyl)-5-oxo-4,5-dihydro-2H-pyrazolo[3,4- c]isoquinolin-2-yl)-3-methylbutanoate (XIV-2): The above reaction was carried out according to the procedure similarly to the one described in the synthesis of Intermediate XIV-1 using XIII-2 and XII-2 as starting materials.1H NMR (400 MHz, CDCl3): ^ 8.93 (s, 1H), 8.40 (d, J = 0.8 Hz, 1H), 8.13 (s, 1H), 7.80- 7.70 (m, 2H), 4.84 (d, J = 5.6 Hz, 2H), 4.69 (d, J = 9.6 Hz, 1H), 4.31- 4.26 (m, 2H), 2.63- 2.57 (m, 1H), 1.91 (t, J = 6.0 Hz, 1H), 1.33 (t, J = 7.2 Hz, 3H), 1.11 (d, J = 6.4 Hz, 3H), 0.93 (d, J = 6.4 Hz, 3H); LC-MS: m / z 344.2 [M+H]+. Synthesis of (Z)-6-bromo-1-((dimethylamino)methylene)-3,4-dihydronaphthalen-2(1H)- one (XV-1): To a stirred solution of 6-bromo-3,4-dihydronaphthalen-2(1H)-one (25.0 g, 111.07 mmol, 1 equiv.) in DMF-DMA (133.47g, 120.17mmol, 10.0 equiv.) was added para-toluene sulfonic acid monohydrate (0.423g, 2.220 mmol, 0.02 equiv.), and the reaction mixture was stirred at room temperature for 1h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by Combi-flash column using 50% ethyl acetate in hexane to give pure titled compound of XV- 1 (2.05 g; yield 66 %) as a pale brown solid.;1H NMR (400 MHz, DMSO-d6): ^ 7.81 (s, 1H), 7.40- 7.20 (m, 2H), 6.75 (d, J = 8.0 Hz, 1H), 2.94 (s, 6H), 2.74 (d, J = 6.0 Hz, 2H), 2.25 (d, J = 6.0 Hz, 2H); LC-MS: m / z 282.0 [M+2H]+. Synthesis of 7-bromo-4,5-dihydro-3H-benzo[e]indazole (XV-2): To a stirred solution of (Z)-6-bromo-1- ((dimethylamino)methylene)-3,4- dihydronaphthalen-2(1H)one (XV-1) (20.0 g, 71.39 mmol, 1 equiv.) in MeOH (200 mL) was added hydrazine monohydrate (8.934g, 17.840, 2.5 equiv.) The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to give crude residue. The crude residue was purified by Combi-flash column chromatography using 50% ethyl acetate in hexane to afford pure titled compound of XV-2 (17.5 g; yield 98 %) as brown solid;1H NMR (400 MHz, DMSO-d6): ^ 12.64 (s, 1H), 8.09 (s, 1H), 7.43- 7.34 (m, 3H), 2.94- 2.91 (m, 2H), 2.76 (m, 2H); LC-MS: m / z 250.9 [M+H]+. Synthesis of ethyl 2-(7-bromo-4,5-dihydro-2H-benzo[e]indazol-2-yl)-3-methylbutanoate (XV-3a) and methyl 2-(7-bromo-4,5-dihydro-3H-benzo[e]indazol-3-yl)-3- methylbutanoate (XV-3b): The above reaction was carried out according to the procedure similar to the one described in the synthesis of Intermediate XIII-1 using Intermediate XV-2 as starting material to obtain inseparable mixture of 2:1 ratio of regio-isomers of Intermediate XV-3a and Intermediate XV-3b. LC-MS: m / z 378 [M+H]+Synthesis of ethyl 3-methyl-2-(7-vinyl-4,5-dihydro-2H-benzo[e]indazol-2-yl)butanoate (XV-4a) and ethyl 3-methyl-2-(7-vinyl-4,5-dihydro-3H-benzo[e]indazol-3-yl)butanoate (XV-4b): In a sealed tube, ethyl 2-(7-bromo-4,5-dihydro-3H-benzo[e]indazol-3-yl)-3- methylbutanoate (XV-3a) (5.4 g, 14.313 mmol, 1.0 equiv.), ethyl 2-(7-bromo-4,5-dihydro-2H- benzo[e]indazol-2-yl)-3-methylbutanoate (XV-3b), potassium vinyl trifluoroborate (3.834g, 28.620 mmol, 2.0 equiv.) and potassium carbonate (3.956 g, 28.620 mmol, 2.0 equiv.) was taken up and dissolved in 1,4-dioxane (96 mL) and water (16 mL), after which the vessel was purged with argon for 30 min. Then Pd(dppf)Cl2·CH2Cl2(0.209 g, 0.280 mmol, 0.020 equiv.) was added, and the mixture was heated at 100 °C for 12 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through a Celite®bed, after which the filtrate was diluted with water. The organic layer was then separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give crude product. The crude product was purified by combi-flash column chromatography using 50% ethyl acetate in hexane to give inseparable mixture of titled compound XV-4a and XV-4b (6.2 g; yield 72 %) as brown semi solid. LC-MS: m / z 325.05 [M+H]+. Synthesis of ethyl 2-(7-formyl-4,5-dihydro-2H-benzo[e]indazol-2-yl)-3-methylbutanoate (XV-5a) and ethyl 2-(7-formyl-4,5-dihydro-3H-benzo[e]indazol-3-yl)-3-methylbutanoate (XV-5b): To a stirred solution of ethyl 3-methyl-2-(7-vinyl-4,5-dihydro-2H-benzo[e]indazol- 2-yl)butanoate (XV-4a) and ethyl 3-methyl-2-(7-vinyl-4,5-dihydro-3H-benzo[e]indazol-3- yl)butanoate (XV-4b) (4.0 g, 12.33 mmol, 1.0 equiv.) in THF (100 mL) and water (5 mL) were added sodium periodate (7.912 g , 36.990 mmol, 3.0 equiv.), 2,6-dimethylpyridine (1.321 g, 12.330 mmol, 1.0 equiv.) and osmium tetraoxide (1.254 g, 4.930 mmol, 0.4 equiv.) at room temperature. The reaction mixture was stirred at room temperature for 5 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to give crude product. The crude product was purified by combi-flash column using 50% ethyl acetate in hexane to provide mixture of compound of XV-5a and XV-5b (3.8 g; yield 94%) as colorless liquid. LC-MS: m / z 327.05 [M+H]+. Synthesis of ethyl 2-(7-(hydroxymethyl)-4,5-dihydro-2H-benzo[e]indazol-2-yl)-3- methylbutanoate (XV-6a) and ethyl 2-(7-(hydroxymethyl)-4,5-dihydro-3H- benzo[e]indazol-3-yl)-3-methylbutanoate (XV-6b): To a stirred solution of 2-(7-formyl-4,5-dihydro-3H-benzo[e]indazol-3-yl)-3- methylbutanoate (XV-5a) and ethyl 2-(7-formyl-4,5-dihydro-2H-benzo[e]indazol-2-yl)-3- methylbutanoate (XV-5b) (3.8 g, 11.64 mmol, 1.0 equiv.) in methanol (40 mL) was added sodium borohydride (0.925 g , 24.440 mmol, 2.1 equiv.) at 0°C. After stirring at 0 °C for 10 minutes, the reaction mixture was warmed to room temperature and stirred for 3 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with dichloromethane (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by chiral HPLC to afford all four isomers of titled compounds as colorless liquids. XV-6aa (isomer-1 of XV-6a):1H NMR (400 MHz, DMSO-d6): ^ 7.84 (s, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.18 (s, 1H), 7.14 (d, J = 7.6 Hz, 1H), 5.10 (t, J = 6.0 Hz, 1H), 4.75 (d, J = 9.2 Hz, 1H), 4.44 (d, J = 5.6Hz, 2H), 4.15- 4.09 (m, 2H), 2.95- 2.92 (m, 3H), 2.87- 2.82 (m, 1H), 2.64- 2.60 (m, 1H), 1.14 (t, J = 7.2 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H), 0.76 (d, J = 6.4 Hz, 3H); LC- MS: m / z 329.05 [M+H]+. XV-6ab (isomer-2 of XV-6a):1H NMR (400 MHz, DMSO-d6): ^ 7.84 (s, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.18 (s, 1H), 7.14 (d, J = 7.6 Hz, 1H), 5.10 (t, J = 6.0 Hz, 1H), 4.75 (d, J = 9.2 Hz, 1H), 4.44 (d, J = 5.6Hz, 2H), 4.15- 4.09 (m, 2H), 2.95- 2.92 (m, 3H), 2.87- 2.82 (m, 1H), 2.64- 2.60 (m, 1H), 1.14 (t, J = 7.2 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H), 0.76 (d, J = 6.4 Hz, 3H); LC- MS: m / z 329.05 [M+H]+. XV-6ba (isomer-1 of XV-6b):1H NMR (400 MHz, DMSO-d6): ^ 8.13 (s, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.17 (s, 1H), 7.14 (d, J = 8.0 Hz, 1H), 5.10 (t, J = 5.6 Hz, 1H), 4.66 (d, J = 9.6 Hz, 1H), 4.45 (d, J = 5.6Hz, 2H), 4.21- 4.16 (m, 2H), 2.90 (t, J = 7.2 Hz, 2H), 2.74 (t, J = 7.6 Hz, 2H), 2.55- 2.53 (m, 1H), 1.21 (t, J = 9.2 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H), 0.81 (d, J = 6.8 Hz, 3H); LC-MS: m / z 329.05 [M+H]+. XV-6bb (isomer-2 of XV-6b):1H NMR (400 MHz, DMSO-d6): ^ 8.13 (s, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.17 (s, 1H), 7.14 (d, J = 8.0 Hz, 1H), 5.10 (t, J = 5.6 Hz, 1H), 4.66 (d, J = 9.6 Hz, 1H), 4.45 (d, J = 5.6Hz, 2H), 4.21- 4.16 (m, 2H), 2.90 (t, J = 7.2 Hz, 2H), 2.74 (t, J = 7.6 Hz, 2H), 2.55- 2.53 (m, 1H), 1.21 (t, J = 9.2 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H), 0.81 (d, J = 6.8 Hz, 3H); LC-MS: m / z 329.05 [M+H]+. Synthesis of ethyl (S)-2-(7-(hydroxymethyl)-4,5-dihydro-3H-naphtho[1,2- d][1,2,3]triazol-3-yl)-3-methylbutanoate(XVI-5): Step-i: Synthesis of methyl (S)-2-(7-bromo-4,5-dihydro-3H-naphtho[1,2-d][1,2,3]triazol- 3-yl)-3-methylbutanoate (XVI-1) To a stirred solution of 6-bromo-3,4-dihydronaphthalen-2(1H)-one (6.0 g, 26.65 mmol, 1 equiv.) in toluene (20 mL) was added methyl L-valinate (4.55 g, 34.65 mmol, 1.3 equiv.) and 1-azido-4-nitrobenzene (5.69 g, 34.65 mmol, 1.3 equiv.) at room temperature. The mixture was heated to 60 °C and stirred for 16 h. After completion of reaction, the reaction mixture was allowed to cool to room temperature and was poured into ice water and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to give the crude product. The crude product was purified by combi-flash column using 10% ethyl acetate in hexane to give titled compound methyl (S)- 2-(7-bromo-4,5-dihydro-3H-naphtho[1,2-d][1,2,3]triazol-3-yl)-3-methylbutanoate XVI-1 (7.5 g; yield 77 %) as brown semi solid.;1H NMR (400 MHz, DMSO-d6): ^ 7.67 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 1.6 Hz, 1H), 7.50 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 5.26 (d, J = 8.4 Hz, 1H), 3.71 (s, 3H), 3.10- 2.90 (m, 4H), 2.75- 2.65 (m, 1H), 1.03 (d, J = 6.8 Hz, 3H), 0.84 (d, J = 6.8 Hz, 3H); LC-MS: m / z 364.1 [M+H]+. Step-ii: Synthesis of (S)-3-methyl-2-(7-vinyl-4,5-dihydro-3H-naphtho[1,2- d][1,2,3]triazol-3-yl)butanoic acid (XVI-2) To a stirred solution of methyl (R)-2-(7-bromo-4,5-dihydro-3H-naphtho[1,2- d][1,2,3]triazol-3-yl)-3-methylbutanoate (XVI-1) (3.50 g, 9.61 mmol, 1 equiv.) in a 1,4 dioxane / water mixture (4:1) (25 mL) was added vinyl boronic acid pinacol ester (2.22 g, 14.41 mmol, 1.5 equiv.) and sodium carbonate (3.06 g, 28.82 mmol, 3 equiv.). The vessel was then purged with argon for 10 min and Pd(dppf)Cl2·CH2Cl2(0.78 g, 0.96 mmol, 0.1 equiv.) was added, and the reaction mixture was heated at 100 °C for 12 hours. The reaction mixture was poured into ice water, the pH was adjusted to 2-3, and the reaction mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to give the crude product (-SR)-3-methyl-2-(7-vinyl-4,5- dihydro-3H-naphtho[1,2-d][1,2,3]triazol-3-yl)butanoic acid (XVI-2) (7.0 g) as brown gummy solid; LC-MS: m / z 298.2 [M+H]+. Step-iii: Synthesis of ethyl (S)-3-methyl-2-(7-vinyl-4,5-dihydro-3H-naphtho[1,2- d][1,2,3]triazol-3-yl)butanoate(XVI-3): To a stirred solution of (S)-3-methyl-2-(7-vinyl-4,5-dihydro-3H-naphtho[1,2- d][1,2,3]triazol-3-yl)butanoic acid (XVI-2) (7.0 g, 23.54 mmol, 1.0 equiv.) in DMF was added K2CO3 (9.76 g, 70.62 mmol, 3.0 equiv.) at room temperature, and the reaction mixture was stirred for 5 min. Then iodoethane (7.34 g, 47.08 mmol, 2.0 equiv.) was added to the mixture at 0 °C, and the contents of the vessel were stirred for 16 hours at room temperature. The mixture was poured in ice cold water and exacted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to give the crude product. The crude product was purified by combi-flash column using 20% ethyl acetate in hexane to afford titled compound (S)-3-methyl-2-(7-vinyl-4,5-dihydro-3H-naphtho[1,2- d][1,2,3]triazol-3-yl)butanoate (XVI-3) (2.35 g; yield 31%) as brown solid;1H NMR (400 MHz, DMSO-d6): ^ 7.71 (d, J = 8.0 Hz, 1H), 7.45 (s, 1H), 7.41 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 6.80- 6.75 (m, 1H), 5.85 (dd, J = 17.6 Hz, 0.80 Hz, 1H), 5.30- 5.20 (m, 2H), 4.25- 4.10 (m, 2H), 3.15- 2.90 (m, 4H), 2.75- 2.65 (m, 1H), 1.19 (t, J = 7.2 Hz, 3H), 1.05 (d, J = 6.4 Hz, 3H), 0.84 (d, J = 6.8 Hz, 3H); LC-MS: m / z 326.2 [M+H]+. Step-iv: Synthesis of ethyl (S)-2-(7-formyl-4,5-dihydro-3H-naphtho[1,2-d][1,2,3]triazol- 3-yl)-3-methylbutanoate (XVI-4) To a stirred solution of (S)-3-methyl-2-(7-vinyl-4,5-dihydro-3H-naphtho[1,2- d][1,2,3]triazol-3-yl)butanoate XVI-3 (2.25 g, 6.91 mmol, 1.0 equiv.) in THF / water (6:1) mixture (70 mL), were added NaIO4 (4.44 g, 20.74 mmol, 3.0 equiv.) and 2,6 dimethyl pyridine (0.74 g, 6.91 mmol, 1 equiv.) at 0 °C. After 10 min, OsO4(0.87 g, 3.45 mmol, 0.5 equiv.) was added to the mixture at 0 °C, and the reaction mixture was stirred for 3 h at the same temperature. After completion of reaction, the reaction mixture was poured in ice cold water and exacted with EtOAc. Then the organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford crude compound ethyl (R)-2-(7- formyl-4,5-dihydro-3H-naphtho[1,2-d][1,2,3]triazol-3-yl)-3-methylbutanoate (XVI-4) (3.8 g) as brown solid; LC-MS: m / z 328.2 [M+H]+. Step-v: Synthesis of ethyl (S)-2-(7-(hydroxymethyl)-4,5-dihydro-3H-naphtho[1,2- d][1,2,3]triazol-3-yl)-3-methylbutanoate (XVI-5): To a stirred solution of (S)-2-(7-formyl-4,5-dihydro-3H-naphtho[1,2-d][1,2,3]triazol- 3-yl)-3-methylbutanoate (XVI-4) (3.8 g, 11.6 mmol, 1.0 equiv.) in MeOH (20 mL) was added NaBH4 (0.88 g, 23.2 mmol, 2 equiv.) at 0 °C. The reaction mixture was allowed to warm to room temperature and was stirred for 2 hours. After completion of reaction, the reaction mixture was poured into ice-cold water and exacted with DCM. Then the organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the crude product. The crude product was purified by combi-flash column using 60% ethyl acetate in hexane to provide titled compound (ethyl (R)-2-(7-(hydroxymethyl)-4,5- dihydro-3H-naphtho[1,2-d][1,2,3]triazol-3-yl)-3-methylbutanoate (XVI-5) (1.65 g; yield 43%) as brown gummy solid.1H NMR (400 MHz, DMSO-d6): ^ 7.69 (d, J = 7.6 Hz, 1H), 7.30- 7.20 (m, 2H), 5.27- 5.15 (m, 2H), 4.49 (d, J = 5.6 Hz, 2H), 4.25- 4.10 (m, 2H), 3.15- 2.90 (m, 4H), 2.75- 2.60 (m, 1H), 1.18 (t, J = 6.8 Hz, 3H), 1.05 (d, J = 6.8 Hz, 3H), 0.85 (d, J = 6.4 Hz, 3H); LC-MS: m / z 330.1 [M+H]+. Synthesis of ethyl 2-(7-formyl-2H-benzo[e]indazol-2-yl)-3-methylbutanoate (XVII-1): To a stirred solution of ethyl 2-(7-(hydroxymethyl)-4,5-dihydro-2H-benzo[e]indazol- 2-yl)-3-methylbutanoate (XV-6a) (0.5 g, 1.52 mmol, 1 equiv.) in toluene (30 mL) was added DDQ (1.04 g, 4.56 mmol, 3.0 equiv.) at room temperature., The mixture was heated to 100 °C and stirred for 12 hours. After completion of reaction, the reaction mixture was allowed to cool to room temperature and filtered through a pad of Celite®. The organic layer was concentrated under reduced pressure to give the crude product. The crude product was purified by combi- flash column using 50% ethyl acetate in hexane to provide the pure compound ethyl 2-(7- formyl-2H-benzo[e]indazol-2-yl)-3-methylbutanoate (XVII-1) (0.27 g; yield 55 %) as pale brown semi solid.1H NMR (400 MHz, DMSO-d6): ^ 10.14 (s, 1H), 9.17 (s, 1H), 8.52 (s, 1H), 8.47 (d, J = 8.4 Hz, 1H), 8.05 (dd, J = 8.4 Hz, 1.6 Hz, 2H), 7.83 (d, J = 9.2 Hz, 1H), 7.74 (d, J = 9.2 Hz, 1H), 7.33 (s, 2H), 5.16 (d, J = 9.2 Hz, 1H), 4.22- 4.13 (m, 1H), 2.85- 2.65 (m, 1H), 1.19 (t, J = 7.2 Hz, 3H), 1.07 (d, J = 6.4 Hz, 3H), 0.82 (d, J = 6.8 Hz, 3H); LC-MS: m / z 325.3 [M+H]+. Synthesis of ethyl 2-(7-(hydroxymethyl)-2H-benzo[e]indazol-2-yl)-3-methylbutanoate (XVII-2): The above reaction was carried out by a procedure similar to the one described in the step-5 of Intermediate XVI-5 using sodium borohydride as reducing agent; LC-MS: m / z 327.2 [M+H]+. Synthesis of ethyl 2-(4-bromo-3-(2-ethoxy-2-oxoethyl)-1H-pyrazol-1-yl)-3- methylbutanoate(XVII-3): Step-i: Synthesis of (4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl methanesulfonate To a stirred solution of (4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3- yl)methanol (9.4 g, 36.0 mmol, 1.0 equiv.) in DCM (100 mL) was added DIPEA (13.3 g, 107.9 mmol, 3.0 equiv.) at 20° C. Methanesulfonyl chloride (8.3 g, 71.9 mmol 2.0 equiv.) was added dropwise in the reaction mixture at 0° C and the reaction mixture was stirred at 20° C for 4 hours. TLC showed the reaction was completed. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by combi- flash column using 60% ethyl acetate in hexane to provide titled compound (4.6 g, 37.67%), LC-MS: 341.2[M+H]+ Step-ii: Synthesis of 2-(4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3- yl)acetonitrile To a solution of (4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl methanesulfonate (4.1 g, 12.1 mmol, 1.0 equiv.) in DCM (80 mL) was added KCN (1.6 g, 24.17 mmol, 2.0 equiv.) and hexaoxacyclooctadecane (3.2 g, 12.1 mmol, 1.0 equiv.) at room temperature. The mixture was stirred at rt for 3 h. The reaction mixture was diluted with ice cold water and extracted into DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by combi-flash column using 30% ethyl acetate in hexane to provide titled compound (2.45g, 75.04%), LC-MS: 272.1[M+H]+ Step-iii: Synthesis of ethyl 2-(4-bromo-1H-pyrazol-3-yl)acetate Concentrated sulphuric acid (5mL) was added to a stirred solution of 2-(4-bromo-1- (tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)acetonitrile (2.0 g, 7.4 mmol, 1.0 equiv.) in EtOH (20 mL) at RT. The mixture was stirred at 110 °C for 16 h. The methanol was removed in vacuo and the remaining aqueous suspension was quenched with sat aq. NaHCO3 drop-wise to pH 8. EtOAc (50 mL) was added, and the organic layer was collected. The aqueous layer was extracted with EtOAc (50 mL) and the combined organic layers were concentrated in vacuo to afford a white solid which was triturated with diethyl ether to give a title compound (0.65 g, 37.67%);LC-MS: m / z 235.0 [M+H]+Step-iv: Synthesis of ethyl 2-(4-bromo-3-(2-ethoxy-2-oxoethyl)-1H-pyrazol-1-yl)-3- methylbutanoate The procedure for the Step-iv was carried out similarly to the one described in the synthesis of Intermediate XIII-1 to obtain titled compound;LC-MS: m / z 361.05 [M+H]+Step-v: Synthesis of ethyl 2-(8-(hydroxymethyl)-5-oxo-5,6-dihydrobenzo[b]pyrazolo[4,3- d]azepin-2(4H)-yl)-3-methylbutanoate The step-v was carried out by a procedure similar to the one described in the synthesis of Intermediate XIV-1 to obtain titled compound Intermediate XVII-3; LC-MS: m / z 358.15 [M+H] +.

[0055] Synthesis of ethyl 2-(8-(hydroxymethyl)-5-oxo-5,6-dihydrobenzo[d]pyrazolo[4,3- f][1,3]diazepin-2(4H)-yl)-3-methylbutanoate (XVII-4): Step-i: Synthesis of ethyl 2-(3-amino-4-(2-amino-4-(hydroxymethyl)phenyl)-1H-pyrazol- 1-yl)-3-methylbutanoate To a stirred solution of methyl 4-bromo-1-(1-methoxy-3-methyl-1-oxobutan-2-yl)-1H- pyrazole-3-carboxylate (XIII-2) (3.30 g, 11.37 mmol) in 1, 4 dioxane (24 mL) and water (6 mL) was added (3-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (0.60 g, 2.83 mmol) and potassium phosphate (4.71 g, 34.11 mmol). The vessel was then purged with argon for 15 min. Then Pd(dppf)Cl2·DCM (0.92 g, 1.13 mmol) was added, and the mixture was stirred at 110 °C for 1 hour under microwave irradiation. After the completion of the reaction, the mixture was filtered through Celite®and quenched with ice cold water and extracted with ethyl acetate (25 mLx3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Combi-flash, eluting with 7% methanol in dichloromethane to afford the title compound (1.6 g, 42.33%) as light brown color solid; LC-MS: m / z 333.20 [M+H]+Step-ii: Synthesis of ethyl 2-(8-(hydroxymethyl)-5-oxo-5,6-dihydrobenzo[d]pyrazolo[4,3- f][1,3]diazepin-2(4H)-yl)-3-methylbutanoate To a stirred solution of ethyl 2-(3-amino-4-(2-amino-4-(hydroxymethyl)phenyl)-1H- pyrazol-1-yl)-3-methylbutanoate (0.80 g, 2.40 mmol) in ACN (10 mL) was added DIPEA (0.93 g, 7.22 mmol, followed by triphosgene (0.71 g, 2.40 mol) at 0 °C. The reaction temperature was allowed to warm to room temperature and stirred for 2 h. After completion of the reaction, the reaction mixture was quenched with ice cold water and extracted with ethyl acetate (25 mLx3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Combi- flash, eluting with 5% methanol in dichloromethane to afford the title compound XVII-4 (0.6 g, 69.55%); LC-MS: m / z 359.20 (M+H)+. Synthesis of methyl 2-(7-(((tert-butyldiphenylsilyl)oxy)methyl)-2H-pyrazolo[3,4- c]quinolin-2-yl)-3-methylbutanoate (XVII-5a) and methyl 2-(7-(((tert- butyldiphenylsilyl)oxy)methyl)-3H-pyrazolo[3,4-c]quinolin-3-yl)-3-methylbutanoate (XVII-5b) Step-i: Synthesis of (4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methanol To a stirred solution of methyl 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole- 3-carboxylate (7.5 g, 25.9 mmol, 1.0 equiv.) in THF (80mL) was added LiBH4(0.88 g, 25.9 mmol, 1.0equiv.) at 0 °C. The reaction mixture was allowed to warm to room temperature and was stirred for 12 hours. After completion of reaction, the reaction mixture was poured into ice-cold water and exacted with EtOAc. Then the organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the crude product. The crude product was purified by combi-flash column using 50% ethyl acetate in hexane to provide titled compound (5.7 g, 84.15%), LC-MS: 263.0 [M+H]+. Step-ii: Synthesis of 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3- carbaldehyde To a stirred solution of (4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3- yl)methanol (3.0 g, 11.5 mmol, 1.0 equiv.) in DCM (30mL) was added DMP (9.75 g, 23.0 mmol, 2equiv.) at 0 °C. The reaction mixture was allowed to warm to room temperature and was stirred for 12 hours. After completion of reaction, the reaction mixture was poured into ice-cold water and exacted with DCM. Then the organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the crude product. The crude product was purified by combi-flash column using 50% ethyl acetate in hexane to provide titled compound (2.7 g, 90.7%), LC-MS: 260.10 [M+H]+. Step-iii: Synthesis of (2-(tetrahydro-2H-pyran-2-yl)-2H-pyrazolo[3,4-c]quinolin-7- yl)methanol The step-iii was carried out by a procedure similar to the one described in the synthesis of Intermediate XIV-1 to obtain titled compound; LC-MS: m / z 284.2 [M+H]+. Step-iv: Synthesis of (2H-pyrazolo[3,4-c]quinolin-7-yl)methanol 4M HCl in 14-dioxane (5mL) was added to stirred solution of (2-(tetrahydro-2H- pyran-2-yl)-2H-pyrazolo[3,4-c]quinolin-7-yl)methanol (0.70g, 2.5 mmol, 1.0 equiv.) in MeOH (2.0 mL) and DCM (10mL) at RT. The reaction mixture was stirred at RT for 4 h. After completion of reaction, the methanol was removed in vacuo and the remaining aqueous suspension was quenched with TEA drop-wise to pH 8. EtOAc (50 mL) was added, and the organic layer was collected. The aqueous layer was extracted with EtOAc (50 mL) and the combined organic layers were concentrated in vacuo to afford a white solid which was triturated with diethyl ether to give a title compound (0.7 g, );LC-MS: m / z 200.1 [M+H]+. Step-v: Synthesis of 7-(((tert-butyldiphenylsilyl)oxy)methyl)-2H-pyrazolo[3,4- c]quinoline To a stirred solution of (2H-pyrazolo[3,4-c]quinolin-7-yl)methanol (0.70 g, 3.51 mmol, 1.0 equiv.) in DCM (10mL) was added imidazole (0.24 g, 68.08 mmol, 1.0 equiv) and TBDPS-Cl (0.97 g, 3.51 mmol, 1.0 equiv) at 0 °C. Reaction mixture was stirred at room temperature for 12 h. After completion of reaction, saturated aqueous NH4Cl / H2O was added to the reaction mixture and the aqueous phase was extracted with diethyl ether (3200 mL), then the organic phase was washed with brine (2 *500 mL) before drying (Na2SO4) and removal of solvent under reduced pressure. The crude product was purified by combi-flash column using 5% methanol in DCM provide titled compound (0.80 g, 52.02%), LC-MS: 438.2 [M+H]+ Step-vi: Synthesis of methyl 2-(7-(((tert-butyldiphenylsilyl)oxy)methyl)-2H-pyrazolo[3,4- c]quinolin-2-yl)-3-methylbutanoate (XVII-5a) and methyl 2-(7-(((tert- butyldiphenylsilyl)oxy)methyl)-3H-pyrazolo[3,4-c]quinolin-3-yl)-3-methylbutanoate (XVII-5b) The procedure for the Step-vi was carried out similarly to the one described in the synthesis of Intermediate XIII-1 obtain two regio-isomers Intermediate XVII-5a and Intermediate XVII-5b; LC-MS: m / z 566.25 [M+H]+. Synthesis of methyl 2-(7-(hydroxymethyl)-2H-pyrazolo[3,4-c]quinolin-2-yl)-3- methylbutanoate (XVII-6) To a stirred solution of methyl 2-(7-(((tert-butyldiphenylsilyl)oxy)methyl)-2H- pyrazolo[3,4-c]quinolin-2-yl)-3-methylbutanoate (XVII-5a) (0.40 g, 0.7 mmol, 1.0 equiv.) in THF (10mL) was added TBAF (0.28 g, 1.1 mmol, 1.50equiv.) at 0 °C. The reaction mixture was allowed to warm to room temperature and was stirred for 3 hours. After completion of reaction, the reaction mixture was poured into ice-cold water and exacted with DCM. Then the organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the crude product. The crude product was purified by combi-flash column using 5% methanol in DCM to provide titled compound (XVII-6) (0.23 g, 99.18%), LC-MS: 329.1 [M+H]+. Synthesis of methyl 2-(7-(hydroxymethyl)-3H-pyrazolo[3,4-c]quinolin-3-yl)-3- methylbutanoate(XVII-7): The above Intermediate XVII-7 synthesis carried out by a procedure similar to the one described in the synthesis of Intermediate XVII-6; LC-MS: 329.1 [M+H]+. Synthesis of ethyl 2-(4-chloro-7-(chloromethyl)-2H-pyrazolo[3,4-c]quinolin-2-yl)-3- methylbutanoate (XVIII-1): Ethyl 2-(7-(hydroxymethyl)-4-oxo-4,5-dihydro-2H-pyrazolo[3,4-c]quinolin-2-yl)-3- methylbutanoate (XIV-1) (0.45 g, 1.31 mmol) in POCl3(10 mL) was heated to 75 °C for 2 h. After completion of the reaction, the reaction mixture was allowed to cool to room temperature and was quenched with ice-cold water carefully, neutralized with sodium bicarbonate saturated solution, and extracted with ethyl acetate (15 mLx3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by combi flash, eluting with 30% ethyl acetate in hexane to get title compound as off-white sticky solid XVIII-1 (0.34 g, 68%);1H NMR (400 MHz, DMSO-d6): ^ 8.7 (s, 1H), 8.09- 8.07 (m, 2H), 7.67 (dd, J = 8.0, 1.6 Hz, 1H), 5.17 (d, J = 9.6 Hz, 1H), 4.79 (s, 2H), 4.40- 4.25 (m, 2H), 2.70- 2.64 (m, 1H), 1.35 (t, J = 6.8 Hz, 3H), 1.15 (d, J = 6.8 Hz, 3H), 0.90 (dd, J = 4.4 Hz, 2.8 Hz, 3H); LC-MS: m / z 379.95 [M]- Synthesis of ethyl 2-(5-chloro-7-(chloromethyl)-2H-pyrazolo[3,4-c]isoquinolin-2-yl)-3- methylbutanoate (XVIII-2): The above Intermediate XVIII-2 was prepared by a procedure similar to the one described in the synthesis of Intermediate XVIII-1 using phosphorous oxychloride as a reagent;1H NMR (400 MHz, DMSO-d6): ^ 9.08 (s, 1H), 8.46-8.43 (m, 2H), 8.02 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 5.18 (d, J = 8.8 Hz, 1H), 5.06 (s, 2H), 4.23- 4.14 (m, 2H), 2.71- 2.68 (m, 1H), 1.19 (t, J = 6.8 Hz, 3H), 1.06 (d, J = 6.4 Hz, 3H), 0.83 (d, J = 6.8 Hz, 3H); LC-MS: m / z 380.1 [M+H]+. Synthesis of ethyl 2-(7-(bromomethyl)-4,5-dihydro-2H-benzo[e]indazol-2-yl)-3- methylbutanoate (XVIII-3): To a stirred solution of ethyl 2-(7-(hydroxymethyl)-4,5-dihydro-2H-benzo[e]indazol- 2-yl)-3-methylbutanoate (XV-6a) (0.375 g, 1.141 mmol, 1.0 equiv.) in THF (25mL) was added phosphorus tribromide (0.371 g, 1.370 mmol, 1.2 equiv.) at 0°C. The reaction mixture was stirred at 0°C for 2 hours. After completion of reaction, the reaction mixture was concentrated under vacuum, cooled to 0 °C, neutralized with triethyl amine, and concentrated again under vacuum. The crude product was purified by flash column using 50% ethyl acetate in hexane to get titled compound (0.31 g; yield 83%) as colorless liquid (XVIII-3). The resulting product was directly taken into the next reaction, as the bromo compound is not stable. The intermediates XVIII-4 to XVIII-8 listed in below Table-7 were prepared by a procedure similar to the one described in the synthesis of Intermediate XVIII-3 with appropriate starting material (SM) and appropriate variations to get the corresponding bromo product. The characterization data of the intermediates are summarized in Table-7. Table-7

[0056] Synthesis of ethyl 2-(7-(bromomethyl)-4-oxo-4,5-dihydro-2H-pyrazolo[3,4-c]quinolin-2- yl)-3-methylbutanoate (XVIII-7): To a stirred solution of ethyl 2-(7-(hydroxymethyl)-4-oxo-4,5-dihydro-2H- pyrazolo[3,4-c]quinolin-2-yl)-3-methylbutanoate (XIV-1) (10 g, 29.12 mmol, 1.0 equiv.) in DCM (25mL) was added N-bromo succinimide ( 7.7 g, 43.68 mmol, 1.5 equiv.) at 0 °C and triphenyl phosphine (11.4 g, 43.68 mmol, 1.5 eq) . The reaction mixture was stirred at 0 °C for 2 hours. After completion of reaction, the reaction mixture was concentrated under vacuum, cooled to 0 °C, neutralized with triethyl amine, and concentrated again under vacuum. The crude product was purified by flash column using 50% ethyl acetate in hexane to get titled compound (0.31 g; yield 83%) as colorless liquid (XVIII-7). The resulting product was directly taken into the next reaction. Synthesis of ethyl 2-(8-(hydroxymethyl)-5-oxo-5,6-dihydrobenzo[b]pyrazolo[4,3- d]azepin-2(4H)-yl)-3-methylbutanoate (XVIII-9): To a solution of ethyl 2-(8-(hydroxymethyl)-5-oxo-5,6- dihydrobenzo[b]pyrazolo[4,3-d]azepin-2(4H)-yl)-3-methylbutanoate XVII-3 (0.16 g, 0.49 mmol, 1.0 equiv.) in DCM (5mL) was added triethylamine (0.14 g, 1.34 mmol, 3.0 equiv.) at 20° C. Methanesulfonyl chloride (0.11 g, 0.94 mmol 2.1 equiv) was added dropwise at 0° C. The reaction mixture was stirred at 20 °C. for 16 hours. TLC showed the reaction was completed. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by combi-flash column using 60% ethyl acetate in hexane to provide desired product XVIII-9 (0.2 g), LC-MS: 376.10 [M+H]+. The intermediates listed below in Table-8 were prepared by a procedure similar to the one described in the synthesis of Intermediate XVIII-9 with appropriate starting material (SM) and appropriate variations to get the corresponding choro product. The characterization data of the intermediates are summarized in Table-8. Table-8 Synthesis of tert-butyl (1S,4S)-5-(8-((4-chloro-2-(1-ethoxy-3-methyl-1-oxobutan-2-yl)-2H- pyrazolo[3,4-c]quinolin-7-yl)methoxy)-6-cyclopropyl-7-(5-methyl-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (XIX-1): To a stirred solution of ethyl 2-(4-chloro-7-(hydroxymethyl)-2H-pyrazolo[3,4- c]147uinoline-2-yl)-3-methylbutanoate (XVIII-1) (0.33 g, 0.86 mmol) and compound (X-1) (0.60 g, 0.86 mmol) in DMF (10 mL) was added cesium carbonate (0.84 g, 2.58 mmol), and the resulting reaction mixture was heated to 60 °C for 1.5 h. After completion of the reaction, the reaction mixture was quenched with ice cold water and extracted with ethyl acetate (15 mLx3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by Combi flash, eluting with 7% MeOH in DCM to get title compound as off-white sticky solid XIX-1 (0.60 g, 67%);1H NMR (400 MHz, DMSO-d6): ^ 9.18 (d, J = 2.8 Hz, 1H), 8.08- 8.04 (m, 1H), 7.67 (dd, J = 25.2, 8.4 Hz, 1H), 7.52- 7.39 (m, 4H), 7.21- 7.15 (m, 1H), 7.05- 6.93 (m, 1H), 5.855.70 (m, 1H), 5.50- 5.4 (m, 1H), 5.32 (d, J = 8.8 Hz, 1H), 5.30- 5.20 (m, 2H), 5.20- 5.19 (m, 1H), 4.54 (d, J = 23.6 Hz, 1H), 4.36- 4.15 (m, 3H), 3.17- 3.72 (m, 8H), 3.51 (s, 2H), 3.30- 3.26 (m, 3H), 2.74- 2.67 (m, 2H), 2.16 (s, 3H), 2.09- 1.95 (m, 5H), 1.75- 1.65 (m, 6H), 1.45- 1.37 (m, 9H), 1.27- 1.16 (m, 3H), 1.07- 1.05 (m, 3H), 0.87- 0.81 (m, 3H); LC-MS: m / z 1040.5 [M+H]+. The intermediates XIX-2 to XIX-40 listed below in Table-9 were prepared by procedures similar to the one described in the synthesis of Intermediate XIX-1 with appropriate benzyl halide (SM-1) and hydroxy quinazoline (SM-2) with appropriate variations. The characterization data of the intermediates are summarized in Table-9. Table-9

[0057] Synthesis of 2-(7-(((4-((75',45)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2- yl)-6-cyclopropyl-7-(5-methyl-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-4-yl)-2- ((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-8-yl)oxy)methyl)-4-chloro-2H-pyrazolo[3,4- c]quinolin-2-yl)-3-methylbutanoic acid (XX-1):

[0058] XIX-1 XX-1

[0059] To a solution of ester (XIX-1) (0.60 g, 0.58 mmol) in methanol and water (5:2) mixture (7 mL) was added LiOH (0.07 g, 2.8 mmol), and the mixture was stirred for 3 h at rt. After completion of the reaction, the solvent was distilled off, and the crude mixture was acidified with IN HC1 and extracted with ethyl acetate (3x15 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a light brown sticky solid (XX-1) (0.55 g, crude);1H NMR (400 MHz, DMSO-d6): ^ 13.60-13.40 (bs, 1H), 9.15 (d, J = 3.2 Hz, 1H), 8.06 (t, J = 8.4 Hz, 1H), 7.62 (dd, J = 27.2, 8.4 Hz, 2H), 7.51- 7.39 (m, 4H), 7.21- 7.03 (m, 1H), 7.01- 6.92 (m, 1H), 5.90- 5.70 (m, 1H), 5.20 (d, J = 8.8 Hz, 4H), 5.10- 5.00 (m, 1H), 4.65- 4.30 (m, 3H), 3.82- 3.51 (m, 6H), 3.50 (s, 2H), 3.32- 3.20 (bs, 2H), 2.75- 2.65 (m, 1H), 2.15 (s, 3H), 2.10- 1.91 (m, 6H), 1.78- 1.50 (m, 6H), 1.45- 1.35 (bs, 9H), 1.07 (dd, J = 6.8 Hz, 2.0 Hz, 3H), 0.65- 0.70 (bs, 4H); LC-MS: m / z 1012.45 [M]+. The intermediates XX-2 to XX-40 listed in below Table-10 were prepared by a procedure similar to the one described in the synthesis of Intermediate XX-1 with appropriate ester (SM) compound and appropriate variations to get corresponding hydrolyzed product. The characterization data of the intermediates are summarized in Table-10. Table-10 Synthesis of tert-butyl (R)-(1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2- hydroxyethyl)carbamate (XXI-1): To a stirred solution of tert-butyl (R)-(1-(4-bromophenyl)-2-hydroxyethyl)carbamate (10.0 g, 31.63 mmol, 1.0 equiv.) and 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazole (8.43 g, 37.951 mmol, 1.2 equiv.) in 1, 4-dioxane (80.0 mL) and water (8.0 mL), was added potassium carbonate (13.11g, 94.87 mmol, 1.0 equiv.), and the mixture was purged with argon gas for 15 mins. Then Pd(dppf)Cl2·DCM (2.61 g 3.190 mmol, 0.1 equiv.) was added, and the mixture was degassed again (5 min) and stirred at 100 °C for 5 h. After completion of reaction, the reaction mixture was cooled to RT, filtered through Celite®bed, and washed with EtOAc (2x30 mL). The filtrate was concentrated under reduced pressure, diluted with water (50 mL), and extracted with EtOAc (3x50 mL).The organic layers were collected, washed with brine (30 mL), dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to get the crude product which was purified by column chromatography (silica gel, 230-400 mesh, 50% EtOAc in hexane) to get the pure compound XXI-1 (9.0 g; yield 86%).1H NMR (400 MHz, DMSO-d6): ^ 7.29(d, J = 8.4 Hz, 1H), 7.41(s, 4H), 7.49 (s, 1H), 6.32(d, J = 1.6 Hz, 1H), 4.834 (t, J = 6.0 Hz, 1H), 4.60 - 4.58(m, 1H), 4.11(q, J = 7.2 Hz, 2H), 3.53 (t, J = 6.4 Hz, 2H), 1.38 (s, 9H), 1.293 (t, J = 7.2 Hz, 3H); LC-MS: m / z 332.2 [M+H]+. Synthesis of (R)-2-amino-2-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)ethan-1-ol (XXI-2): To a stirred solution of XXI-1 (8.5 g, 25.65 mmol, 1.0 equiv.) in DCM (15.0 mL) and MeOH (15 mL) at 00C was added 4.0 M HCl in 1,4- dioxane (25 mL), and the resulting mixture was stirred at rt for 5 h. The reaction mixture was concentrated directly under reduced pressure to get the crude product. Residual acid was stripped off by the addition of diethyl ether (2x10 mL), and the mixture was dried and concentrated to get the crude compound XXI-2 (9.5 g) which was used in the next step without further purification.1H NMR (400 MHz, DMSO-d6): ^ 8.71 (s, 2H), 7.66(d, J = 8.4 Hz, 2H), 7.54-7.51(m, 3H), 6.38(s,1H), 4.36 -4.32(m, 1H), 4.14(q, J = 7.2 Hz, 2H), 3.78(d, J = 5.6 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H); LC-MS: m / z 232.1 [M+H]+Step 3: Synthesis of tert-butyl (2S,4R)-2-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2- hydroxyethyl)carbamoyl)-4-hydroxypyrrolidine-1-carboxylate (XXI-3): To a stirred solution of XXI-2 (7.5 g, 28.01 mmol, 1.0 equiv.) in DMF (80 mL), diisopropylethylamine (7.24 g, 56.02 mmol, 2.0 equiv.) was added at 0 °C, and the reaction mixture was stirred for 30 mins at rt. Then (2S,4R)-1-(tert-butoxycarbonyl)-4- hydroxypyrrolidine-2-carboxylic acid (6.48 g, 28.01mmol, 1.0 equiv.) followed by HATU (9.88g, 42.01 mmol, 1.5 equiv.) were added to the reaction mixture, and the contents of the vessel were stirred for 3 h. After completion of reaction, the reaction mixture was quenched with ice-cold water (50 mL) and extracted with DCM (2x100 mL). The organic layers were collected washed with brine (50 mL), dried over anhydrous. sodium sulphate, filtered, and concentrated under reduced pressure to get the crude product which was purified by column chromatography (silica gel, 230-400 mesh, 5% MeOH in DCM) to get the pure compound XXI-3 (9.5 g; yield 76%).1H NMR (400 MHz, DMSO-d6): 8.29 - 8.25 (m, 1H), 7.49(d, J = 1.6 Hz, 1H), 7.44 -7.37(m, 4H), 6.31(d, J = 2.0 Hz, 1H), 4.99 - 4.98 (m, 1H), 4.90 - 4.86(m, 2H), 4.26 - 4.21 (m, 2H), 4.14 -4.08 (m, 2H), 3.65 -3.61 (m, 3H), 3.37- 3.34 (m, 1H), 3.33- 3.30 (m, 1H), 3.27 -3.09 (m, 1H), 2.05 – 2.15(m, 1H), 1.78 -1.85 (m, 1H), 1.26(s, 9H); LC- MS: m / z 445.3 [M+H]+ Synthesis of (2S,4R)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4- hydroxypyrrolidine-2-carboxamide (XXI-4): To a stirred solution of XXI-3 (9.5 g 21.37 mmol, 1.0 equiv.) in DCM (20.0 mL) and MeOH (20.0 mL) at 00C was added 4.0 M HCl in 1,4- dioxane (40.0 mL), and the resulting mixture was stirred at rt for 5 h. The reaction mixture was concentrated directly under reduced pressure to get the crude product. The residual acid was stripped-off by the addition of diethyl ether (2x30 mL), and the mixture was dried and concentrated to get the crude compound XXI- 4 (9.0 g) which was directly forwarded for the next step without further purification. NMR (400 MHz, DMSO-d6): ^ 8.030(s, 1H), 6.655(s,1H), 5.153-5.121(m, 1H), 4.641-4.596(m, 2H), 4.378-4.324(m,2H), 3.896-3.736(m,3H), 3.379-3.325(m,1H), 2.002(m, 1H), 1.464-1.403(m, 1H) 1.403-1.399(m,3H), 1.387-1.381(m, 6H); LC-MS: m / z 345.2[M+H]+. Synthesis of tert-butyl (R)-(2-hydroxy-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamate (XXII-1): To a stirred solution of tert-butyl (R)-(1-(4-bromophenyl)-2-hydroxyethyl)carbamate (10.0 g, 31.62 mmol, 1.0 equiv.) and 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)thiazole (9.25 g, 41.11 mmol, 1.2 equiv.) in 1, 4-dioxane (80.0 mL) and water (8.0 mL), potassium carbonate (13.11g, 94.87 mmol, 3.0 equiv.) was added and the reaction mixture was purged with argon gas for 15 mins. Then Pd(dppf)Cl2·DCM (2.58 g 3.16 mmol, 0.1 equiv.) was added, and the reaction mixture was degassed again (5 min) and subsequently stirred at 100 °C for 5 h. The reaction mixture was cooled to RT, filtered through a Celite®bed, and washed with EtOAc (2x30 mL). The filtrate was concentrated under reduced pressure, diluted with water (50 mL), and extracted with EtOAc (3x50 mL). The organic layers were collected, washed with brine (30 mL), dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to get the crude product which was purified by column chromatography (silica gel, 230-400 mesh, 50% EtOAc in hexane) to get the pure compound XXII-1 (8.9g; yield 84%).1H NMR (400 MHz, CDCl3): ^ 8.70 (s,1H), 7.47-7.44 (m, 2H), 7.40-7.38(m, 2H) 5.32 - 5.31 (m, 1H), 4.84 (bs,1H), 3.94 -3.89(m, 2H), 2.55 (s, 3H), 2.12 -2.22(m,1H), 1.47 (s, 9H); LC-MS: m / z 335.3 [M+H]+Synthesis of (R)-2-amino-2-(4-(4-methylthiazol-5-yl)phenyl)ethan-1-ol (XXII-2): To a stirred solution of XXII-1 (8.9 g, 26.61 mmol, 1.0 equiv.) in DCM (15.0 mL) and MeOH (15 mL) at 00C, was added 4.0 M HCl in 1,4- dioxane (25 mL), and the mixture was stirred at rt for 5 h. The reaction mixture was concentrated directly under reduced pressure to get the crude product. The residual acid was stripped off by the addition of diethyl ether (2x10 mL), and the mixture was dried to get the crude compound XXII-2 (5.3 g) which was directly forwarded for the next step without further purification. LC-MS: m / z 235.3[M+H]+Synthesis of tert-butyl (2S,4R)-4-hydroxy-2-(((R)-2-hydroxy-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate (XXII-3): To a stirred solution of XXII-2 (5.2 g, 19.20 mmol, 1.0 equiv.) in DMF (50 mL), diisopropylethylamine (4.96 g, 38.40 mmol, 2.0 equiv.) was added at 0 °C, and the reaction mixture was stirred for 30 mins at rt. Then (2S,4R)-1-(tert-butoxycarbonyl)-4- hydroxypyrrolidine-2-carboxylic acid (6.48 g, 28.01mmol, 1.5 equiv.) followed by HATU (6.77g, 28.80 mmol, 1.5 equiv.) were added to the reaction mixture, and the contents of the vessel were stirred for 3 h. After completion of reaction, the reaction mixture was quenched with ice-cold water (50 mL) and extracted with DCM (2x100 mL). The organic layers were collected, washed with brine (50 mL), dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to get the crude product which was purified by column chromatography (silica gel, 230-400 mesh, 5% MeOH in DCM) to get the pure compound XXII-3 (5.3g; yield 62%).1H NMR (400 MHz, DMSO-d6): ^ 8.98 (s, 1H), 8.27- 8.23 (m, 1H), 7.45 - 7.38 (m, 4H), 5.01-4.99(m,1H), 4.88 - 4.83 (m, 2H) 4.25 - 4.20 (m, 2H) 3.66 - 3.61(m, 2H) 3.36- 3.32 (m, 1H) 2.45(s, 3H) 2.09-2.07(m, 2H) 1.79-1.77(m, 1H) 1.41(m, 9H); LC-MS: m / z 448.3[M+H]+The compounds listed in below Table-12 were prepared by reacting appropriate amine with (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid with appropriate variations in reagents, solvents and reaction conditions using a procedure similar to the one described in Intermediate XXII-3 to obtain desired amide product. The characterization data of the compounds are summarized herein the below table Table-12

[0060] Synthesis of tert-butyl (2S,4R)-2-(((S)-6-(1-ethyl-1H-pyrazol-5-yl)-1-(hydroxymethyl)- 1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-4-hydroxypyrrolidine-1-carboxylate and tert-butyl (2S,4R)-2-(((S)-6-(1-ethyl-1H-pyrazol-5-yl)-1-(hydroxymethyl)-1,2,3,4- tetrahydronaphthalen-1-yl)carbamoyl)-4-hydroxypyrrolidine-1-carboxylate (XXII-3k and XXII-3l): Step-i: Synthesis of 6-(1-ethyl-1H-pyrazol-5-yl)-3,4-dihydronaphthalen-1(2H)-one (XXII-3e) To a stirred solution of 6-bromo-3,4-dihydronaphthalen-1(2H)-one (5.00 g, 22.21 mmol, 1.0 equiv.) and 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.92 g, 26.65 mmol, 1.2 equiv.) in 1, 4-dioxane (40 mL) and water (10 mL), was added potassium carbonate (9.21 g, 66.63 mmol, 3.0 equiv.) and the reaction mixture was purged with argon gas for 15 mins. Then Pd(dppf)Cl2·DCM (1.81 g, 2.22 mmol, 0.1 equiv.) was added, and the reaction mixture was degassed again (5 min) and stirred at 70 °C for 4 h. After completion of reaction, the reaction mixture was cooled to RT, filtered through celite bed, and washed with EtOAc (2x20 mL). The filtrate was concentrated under reduced pressure, diluted with water (50 mL), and extracted with EtOAc (3x25 mL). Organic layers were collected, washed with brine (30 mL), dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to get the crude product which was purified by column chromatography (silica gel, 230-400 mesh, 50% EtOAc in hexane) to get the pure titled compound XXII-3e (5.3g); LC- MS: m / z 241.1 (M+H)+Step-ii: Synthesis of 6'-(1-ethyl-1H-pyrazol-5-yl)-3',4'-dihydro-2'H-spiro[imidazolidine- 4,1'-naphthalene]-2,5-dione (XXII-3f) A suspension of 6-(1-ethyl-1H-pyrazol-5-yl)-3,4-dihydronaphthalen-1(2H)-one (XXII-3e) (3.5 g, 14.56 mmol, 1.0 equiv.),TMSCN (6.21 g, 62.62 mmol, 4.3 equiv.), (NH4)2CO3 (15.47 g, 161.08 mmol, 11.06equiv) and NH4F(9.55 g, 167.49 mmol, 11.50 equiv.) in ethanol(100 mL) and 30% aqueous NH3(45 mL) were heated at 60 °C for 6 h. After cooling to the room temperature, the reaction mixture was diluted with water and then compound was extracted with EtOAc. The organic layer was dried over Na2SO4and then concentrated under reduced pressure to obtain titled compound XXII-3f (3.5g); LC-MS: m / z 311.1 (M+H)+Step-iii: Synthesis of 1-amino-6-(1-ethyl-1H-pyrazol-5-yl)-1,2,3,4- tetrahydronaphthalene-1-carboxylic acid (XXII-3g) To a suspension of 6'-(1-ethyl-1H-pyrazol-5-yl)-3',4'-dihydro-2'H-spiro[imidazolidine- 4,1'-naphthalene]-2,5-dione (XXII-3f) (3.5 g, 11.27 mmol, 1.0 equiv) in 50 mL of water was added barium hydroxide octahydrate (11.59 g, 67.66 mmol, 6.0 equiv.). The reaction was heated at 100oC for 72 h. After completion of reaction, the reaction mixture was acidified with 1M H2SO4 and then reaction mixture was filtered. The filtrate obtained was concentrated and lyophilized for 48 hr to obtain titled compound XXII-3g (2.3g); LC-MS: m / z 286.1 (M+H)+Step-iv: Synthesis of ethyl 1-amino-6-(1-ethyl-1H-pyrazol-5-yl)-1,2,3,4- tetrahydronaphthalene-1-carboxylate (XXII-3h) To a suspension of 1-amino-6-(1-ethyl-1H-pyrazol-5-yl)-1,2,3,4- tetrahydronaphthalene-1-carboxylic acid (XXII-3g) (1.0 g, 3.50 mmol, 1.0 equiv) in EtOH (50 mL) was added SOCl2(0.3 mL, 4.20 mmol, 1.2 equiv) at 0 °C. The reaction mixture was heated to reflux for 12 h before being evaporated to dryness. After completion of reaction, the reaction mixture was filtered over celite, water and brine wash were given to the filtrate and then dried over Na2SO4and then concentrated under reduced pressure to obtain crude product. The crude was purified by combi flash by combi flash eluting it with 0-40% EtOAc / Hexane to give pure compound XXII-3h (0.56g); LC-MS: m / z 313.1(M+H)+Step-v: Synthesis of (1-amino-6-(1-ethyl-1H-pyrazol-5-yl)-1,2,3,4-tetrahydronaphthalen- 1-yl)methanol (XXII-3i) To a suspension of lithium aluminum hydride (0.34 g, 8.93 mmol, 5 equiv) in 6 mL of THF at 0°C was added ethyl 1-amino-6-(1-ethyl-1H-pyrazol-5-yl)-1,2,3,4- tetrahydronaphthalene-1-carboxylate (XXII-3h) (0.56 g, 1.78 mmol, 1.0 equiv.). The mixture was stirred at -780C for 3 hr. After completion of reaction, the reaction mixture was quenched with saturated NH4Cl solution and then compound was extracted with 10% MeOH-DCM. The organic layer was dried over Na2SO4, filtered and then concentrated under reduced pressure to give a residue. The residue was purified by Combi flash, eluting it with 5-10% MeOH in DCM to get the titled compound XXII-3i (0.48g ); LC-MS: m / z 272.1 (M+H)+. Step-vi: Synthesis of tert-butyl (2S,4R)-2-((6-(1-ethyl-1H-pyrazol-5-yl)-1- (hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-4-hydroxypyrrolidine- 1-carboxylate (XXII-3k and XXII-3l) To a stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2- carboxylic acid (XXII-3i) (0.41 g, 1.76 mmol, 1.0 equiv.) in DMF (10 mL) was added DIPEA (0.45 g, 3.53 mmol, 2.0 equiv.) and HATU (0.62 g, 2.65 mmol, 1.5 equiv.) while keeping the reaction mixture in an ice bath. After 15 min, (1-amino-6-(1-ethyl-1H-pyrazol-5-yl)-1,2,3,4- tetrahydronaphthalen-1-yl)methanol (0.48 g, 1.76 mmol, 1.0 equiv.) was added, and the reaction was stirred overnight at rt for 12 hr. After completion of the reaction, the reaction mixture was diluted with ice cold water and extracted with ethyl acetate (15 mLx3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Combi flash, eluting with 7- 10% MeOH in DCM to get the titled racemic compound XXII-3j (0.47 g); Isomers (isomer- 1(XXII-3k) and isomer-2 (XXII-3l)) were separated by using Regis 250 x 21.2mm , 5 micron column and Hexane / 0.1% DEA in Ethanol as solvent; LC-MS: m / z 484.1(M+H)+. Synthesis of Synthesis of tert-butyl (2S,4R)-2-((2-(1-ethyl-1H-pyrazol-5-yl)-6,7,8,9- tetrahydro-5H-benzo[7]annulen-5-yl)carbamoyl)-4-hydroxypyrrolidine-1-carboxylate (XXII-3t) and tert-butyl (2S,4R)-2-((2-(1-ethyl-1H-pyrazol-5-yl)-6,7,8,9-tetrahydro-5H- benzo[7]annulen-5-yl)carbamoyl)-4-hydroxypyrrolidine-1-carboxylate (XXII-3u): Step-i: Synthesis of 2-chloro-4-(1-ethyl-1H-pyrazol-5-yl)benzaldehyde (XXII-3m): To a stirred solution of methyl 4-bromo-2-chlorobenzaldehyde (5.0 g, 22.78 mmol) in 1, 4 dioxane (50 mL) and water (20 mL) was added 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole (7.6 g, 34.17 mmol), potassium carbonate (9.44 g, 68.34 mmol) and reaction mixture was purged with argon for 15 min. Then Pd(dppf)Cl2·DCM (1.66 g, 2.27 mmol) was added, and reaction mixture was stirred at 90 °C for 5 hours. After completion of reaction, the reaction mixture was filtered through celite bed and quenched with ice cold water and extracted with ethyl acetate (15 mLx3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Combi-flash, eluting with 50% ethyl acetate in hexane to afford titled compound XXII-3m (2.7 g, 50%) as light yellow color solid.1H NMR (400 MHz, DMSO-d6): ^ 10.37 (d, J = 0.8 Hz, 1H), 7.97 (d, J = 28.4 Hz, 1H), 7.7 (s, 1 H), 7.67 (dd, J = 1.6 Hz, 0.8 Hz, 2H), 7.57 (s, 1H), 6.58 (s, 1H), 4.21 (q, J = 7.2 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H),; LC-MS: m / z 234.95 (M+H)+Step-ii: Synthesis of 4-(1-ethyl-1H-pyrazol-5-yl)-2-vinylbenzaldehyde (XXII-3n) To a stirred solution of 2-chloro-4-(1-ethyl-1H-pyrazol-5-yl)benzaldehyde (XXII- 3m) (2.8 g, 26.8 mmol) in 1, 4 dioxane (16 mL) and water (4 mL) was added 4,4,5,5- tetramethyl-2-vinyl-1,3,2-dioxaborolane (2.07 g, 13.4 mmol), potassium carbonate (2.89 g, 26.85 mmol) and purged with argon for 15 min. Then Pd(dppf)Cl2·DCM (0.65 g, 0.9 mmol) was added, and reaction mixture was stirred at 90 °C for 6 hour. After completion of reaction, the reaction mixture was filtered through celite bed and quenched with ice cold water and extracted with ethyl acetate (15 mLx3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Combi-flash, eluting with 50% ethyl acetate in hexane to afford titled compound XXII-3n (1.5 g, 74%) as light yellow color solid.1H NMR (400 MHz, DMSO-d6): ^ 7.97 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 0.8 Hz, 1H), 7.69 – 7.63 (m, 2 H), 7.56 (d, J = 2.0 Hz, 1H), 6.54 (d, J = 2.0 Hz, 1H), 5.96 (dd, d, J = 17.6 Hz, 1.2 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H). Step-iii: Synthesis of 1-(4-(1-ethyl-1H-pyrazol-5-yl)-2-vinylphenyl)pent-4-en-1-ol (XXII- 3o) To a stirred solution of 4-(1-ethyl-1H-pyrazol-5-yl)-2-vinylbenzaldehyde (2.4 g, 10.6 mmol) in THF was added but-3-en-1-ylmagnesium bromide (XXII-3n) (3.38 g, 21.21 mmol), mixture was stirred at rt for 6 hours. After the completion of reaction, the reaction mixture was quenched with ice cold ammonium chloride solution and extracted with ethyl acetate (15 mLx3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Combi- flash, eluting with 50% ethyl acetate in hexane to afford titled compound XXII-3o (1.2 g, 40%) as light-yellow color solid.1H NMR (400 MHz, DMSO-d6): ^ 7.60 (d, J = 8.0 Hz, 1H), 7.51 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.38 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.13 – 7.606 (m, 1 H), 6.37 (d, J = 1.0 Hz, 1H), 5.85 – 5.74 (m, 2H), 5.38- 5.36 (m, 1H), 5.31 (d, J = 4.4 Hz, 1H), 5.04- 4.90 (m, 3H), 4.13 (q, J = 7.2 Hz, 2H), 2.18 – 2.08 (m, 2H), 1.67 – 1.61 (m, 2H), 1.31 (t, J = 7.2 Hz, 3H). Step-iv: Synthesis of 2-(1-ethyl-1H-pyrazol-5-yl)-6,7-dihydro-5H-benzo[7]annulen-5-ol (XXII-3p) To a stirred solution of 1-(4-(1-ethyl-1H-pyrazol-5-yl)-2-vinylphenyl)pent-4-en-1-ol (XXII-3o) (2.4 g, 10.6 mmol) in toluene was added grubbs 2ndgeneration initiator (0.15 g, 0.050 mmol), and reaction mixture was stirred at 50 °C for 6 hours. After the completion of reaction, the reaction mixture was passed through celite bed and organic layer was concentrated under reduced pressure to give a residue. The residue was purified by Combi-flash, eluting with 40% ehyl acetate in hexane to afford titled compound XXII-3p (0.8 g, 88%) as off-white color solid.1H NMR (400 MHz, DMSO-d6): ^ 7.62 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.32 – 7.25 (m, 2H), 6.47 – 6.44 (m, 1H), 6.33 (d, J = 1.6 Hz ,1 H), 5.98 – 5.93 (m, 1H), 5.42 (d, J = 4.8 Hz 2H), 4.68 (q, J = 4.4 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 4.02 (dd, J = 7.2 Hz, 1.6 Hz, 2H), 2.45 – 2.42 (m, 2H), 2.10 - 1.90 (m, 2H), 1.31 (t, J = 7.2 Hz, 3H), 1.07 (s, 2H);LC-MS: m / z 255.15 (M+H)+. Step-v: Synthesis of 2-(1-ethyl-1H-pyrazol-5-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen- 5-ol (XXII-3q) To a stirred solution of 2-(1-ethyl-1H-pyrazol-5-yl)-6,7-dihydro-5H- benzo[7]annulen-5-ol (XXII-3p) (0.25g, 0.98 mmol) in EtOH was added Pd-C 20% (0.335 g, 3.14 mmol), and the reaction mixture was stirred at rt for 16 hour. After the completion of reaction, the reaction mixture was passed through celite bed and organic layer was concentrated under reduced pressure to give a titled compound XXII-3q (0.23 g, 91%) as off-white color solid.1H NMR (400 MHz, DMSO-d6): ^ 7.56 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.25 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.17 (d, J = 1.6 Hz, 1H ), 6.30 (s,1 H), 5.29 (s, 1H), 4.79 (d, J = 9.6 Hz, 1H), 4.11 (q, J = 7.2 Hz, 2H), 2.91 -2.86 (m, 2H), 2.76 – 2.71 (m, 2H), 1.97 – 1.91 (m, 2H), 1.80 – 1.72 (m, 2H), 1.57 – 1.49 (m, 2H), 1.30 (t, J = 7.2 Hz, 3H).; LC-MS: m / z 257.20 (M+H)+. Step-vi: Synthesis of 2-(1-ethyl-1H-pyrazol-5-yl)-6,7,8,9-tetrahydro-5H- benzo[7]annulen-5-one (XXII-3r) To a stirred solution of 2-(1-ethyl-1H-pyrazol-5-yl)-6,7,8,9-tetrahydro-5H- benzo[7]annulen-5-ol (XXII-3q) (0.5g, 1.95 mmol) in DCM was added Dess–Martin periodinane (1.6 g, 3.75 mmol), and the reaction mixture was stirred at rt for 16 hour. After the completion of reaction, the reaction mixture was passed through celite bed and organic layer was washed with water and concentrated under reduced pressure to give a titled compound XXII-3r (0.22 g, 44%) as off-white color solid.LC-MS: m / z 255.10 (M+H)+. Step-vii: Synthesis of 2-(1-ethyl-1H-pyrazol-5-yl)-6,7,8,9-tetrahydro-5H- benzo[7]annulen-5-amine (XXII-3s) To a stirred solution of 2-(1-ethyl-1H-pyrazol-5-yl)-6,7,8,9-tetrahydro-5H- benzo[7]annulen-5-one (XXII-3r) (0.05g, 0.19 mmol) in 10 mL of 7M Ammonia in MeOH was added titanium ethoxide (0.112 g, 0.5 mmol), and the reaction mixture was stirred at rt for 48 hour. After that NaBH4(0.03 g; 0.78 mmol) was added and stirred for 60 h at rt. After the completion of reaction, the reaction mixture was poured in ice cold 2M HCl solution and extracted by EtOAc. Then acidic aqueous layer was basified by saturated sodium bicarbonate solution and extracted in EtOAc. Organic layer was concentrated under reduced pressure to give a titled compound XXII-3s (0.05 g, Crude) as yellow-white color solid.; LC-MS: m / z 256.20 (M+H)+. Step-viii: Synthesis of tert-butyl (2S,4R)-2-((2-(1-ethyl-1H-pyrazol-5-yl)-6,7,8,9- tetrahydro-5H-benzo[7]annulen-5-yl)carbamoyl)-4-hydroxypyrrolidine-1-carboxylate (XXII-3t) and tert-butyl (2S,4R)-2-((2-(1-ethyl-1H-pyrazol-5-yl)-6,7,8,9-tetrahydro-5H- benzo[7]annulen-5-yl)carbamoyl)-4-hydroxypyrrolidine-1-carboxylate (XXII-3u) To a stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2- carboxylic acid (0.05g, 0.22 mmol) in 10 mL of DMF was added DIPEA (0.08 g, 0.58 mmol), followed by HATU (0.07 g; 0.3 mmol) and the reaction mixture was stirred at rt for 0.5 hour. After that 2-(1-ethyl-1H-pyrazol-5-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5- amine(XXII-3s) (0.05 g; 0.0.19 mmol) was added and stirred overnight in rt. After the completion of reaction, the reaction mixture was poured in ice cold water and extracted by EtOAc. Organic layer was concentrated under reduced pressure and purified by 10% MeOH in DCM to give a titled compound (0.055 g, 60%) as yellow-white color solid. Isomer’s (isomer- 1(XXII-3t) and isomer-2 (XXII-3u)) were separated by using Regis 250 x 21.2mm , 5 micron column and Hexane / 0.1% DEA in Ethanol as solvent.LC-MS: m / z 469.20 (M+H)+. Synthesis of tert-butyl (2S,4R)-4-hydroxy-2-(5-(4-(4-methylthiazol-5-yl)phenyl)-1H- imidazol-2-yl)pyrrolidine-1-carboxylate (XXII-3v) A mixture of tert-butyl (2S,4R)-4-hydroxy-2-(5-(4-(4-methylthiazol-5-yl)phenyl)- 1H-imidazol-2-yl)pyrrolidine-1-carboxylate (1.5 g, 3.673 mmol, 1.0 equiv.), 4-methylthiazole (1.0 g, 11.020 mmol, 3.0 equiv.) and potassium acetate (0.721 g, 7.340mmol, 2.0 equiv.) in 15 mL of DMA was transferred to a sealed tube and degassed with argon for 30 min. Pd(OAc)2(0.082 g, 0.360 mmol, 0.09 equiv.) was added to the reaction mixture, which was then degassed for another 5 min. The reaction mixture was then heated at 90 °C for 12 h. After completion of reaction, the reaction mixture was allowed to cool to room temperature then diluted with ethyl acetate and filtered through a pad of celite. The organic layer was separated from the aqueous layer and dried over anhydrous sodium sulphate then concentrated under reduced pressure to get crude product. The crude was purified by combi-flash column chromatography using 30% ethyl acetate in hexane to afford the titled compound XXII-3v (1.5g). LC-MS: m / z 427.1 (M+H)+. Synthesis of (3R,5S)-5-(5-(4-(2,4-dimethylthiazol-5-yl)phenyl)-1H-imidazol-2- yl)pyrrolidin-3-ol (XXII-3w): The intermediate XXII-3w was prepared by reacting tert-butyl (2S,4R)-2-(5-(4- bromophenyl)-1H-imidazol-2-yl)-4-hydroxypyrrolidine-1-carboxylate with 2,4- dimethylthiazole using a procedure similar to the one described in Intermediate XXII-3v. LC- MS: m / z 441.1 (M+H)+Synthesis of tert-butyl (2S,4R)-2-(5-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-1H-imidazol-2- yl)-4-hydroxypyrrolidine-1-carboxylate (XXII-3x): To a stirred solution of tert-butyl (2S,4R)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-4- hydroxypyrrolidine-1-carboxylate (0.600 g, 1.47 mmol, 1.0 equiv.) and 1-ethyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.392 g, 1.760 mmol, 1.2 equiv.) in 1, 4- dioxane (8 mL) and water (1.0 mL), potassium carbonate (0.609g, 4.40 mmol, 2.99 equiv.) was added and purged with argon gas for 15 mins. Then Pd(dppf)Cl2·DCM (0.120 g 0.140 mmol, 0.1 equiv.) was added, and the reaction mixture was degassed again (5 min) and subsequently stirred at 100 °C for 3 h. The reaction mixture was cooled to RT, filtered through a celite bed, and washed with EtOAc (2x30 mL). The filtrate was concentrated under reduced pressure, diluted with water (50 mL), and extracted with EtOAc (3x50 mL). Organic layers were collected, washed with brine (30 mL), dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to get the crude product which was purified by column chromatography (silica gel, 230-400 mesh, 50% EtOAc in hexane) to get the pure compound XXII-3x (0.58 g; yield 93.16%). The compounds listed in below Table-13 were prepared by reacting 1-ethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewith appropriate bromo compound with reagents, solvents and reaction conditions using a procedure similar to the one described in Intermediate XXII-3x. The characterization data of the compounds are summarized herein the below table. Table-13

[0061] Synthesis of tert-butyl (2S,4R)-2-(1H-benzo[d]imidazol-2-yl)-4-hydroxypyrrolidine-1- carboxylate (XXII-3ya): To a stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2- carboxylic acid (1.026, 4.62 mmol, 1.0 equiv.) in DMF (10 mL) was added DIPEA (1.79 g, 13.87 mmol, 3.0 equiv.) and T3P (50% solution DMF) (1.76 g, 5.54 mmol, 1.2 equiv.) while keeping the reaction mixture in an ice bath. After 15 min, benzene-1,2-diamine (0.500 g, 4.62 mmol, 1.0 equiv.) was added, and the reaction was stirred overnight at 100 °C. After the completion of reaction, the reaction mixture was diluted with ice cold water and extracted with ethyl acetate (15 mLx3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Combi flash, eluting with 7-10% MeOH in DCM to get the titled compound (XXII-3ya) as brown sticky solid (0.70 g, 49.91%); LC-MS: m / z 304.1 (M+H)+. The compounds listed in below Table-14 were prepared by reacting (2S,4R)-1- (tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid with appropriate amine with reagents, solvents and reaction conditions using a procedure similar to the one described in the synthesis of Intermediate XXII-3ya. The characterization data of the compounds are summarized herein the below table. Table-14 Synthesis of (2S,4R)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl) ethyl)pyrrolidine-2-carboxamide (XXII-4): To a stirred solution of XXII-3 (0.75 g 1.67 mmol, 1.0 equiv.) in DCM (5.0 mL) and MeOH (5 mL) at 00C was added 4.0 M HCl in 1,4- dioxane (10.0 mL), and the reaction mixture was stirred at rt for 5h. After completion of reaction, the reaction mixture was concentrated directly under reduced pressure to get the crude product. The residual acid was striped-off by the addition of diethyl ether (2x10 mL), and the mixture was dried to get the crude compound XXII-4 (0.6 g). LC-MS: m / z 348.1 [M+H]+. The intermediate listed in below Table-15 were prepared by a procedure similar to the one described in Intermediate XXII-4 with 4N HCl in 1,4-dioxane as deprotecting reagent. The characterization data of the intermediate is summarized herein the below table. Table-15 Synthesis of tert-butyl (1S,4S)-5-(8-((4-chloro-2-((S)-1-((2S,4R)-2-(((R)-1-(4-(1-ethyl-1H- pyrazol-5-yl)phenyl)-2-hydroxyethyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3-methyl-1- oxobutan-2-yl)-2H-pyrazolo[3,4-c]quinolin-7-yl)methoxy)-6-cyclopropyl-7-(5-methyl-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (XXIII-1): To a stirred solution of acid (XX-1) (0.525 g, 0.52 mmol, 1.0 equiv.) in DMF (10 mL) was added DIPEA (0.27 g, 2.1 mmol, 4.0 equiv.) and HATU (0.25 g, 1.03 mmol, 2.0 equiv.) while keeping the reaction mixture in an ice bath. After 15 min, amine (XXI-4) (0.22 g, 0.62 mmol, 1.2 equiv.) was added, and the reaction was continued overnight at rt. After the completion of reaction, the reaction mixture was diluted with ice cold water and extracted with ethyl acetate (15 mLx3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by Combi flash, eluting with 7-10% MeOH in DCM to get the title compound (XXIII-1) as brown sticky solid (0.55 g, 75%);1H NMR (400 MHz, DMSO-d6): ^ 9.21- 9.10 (m, 1H), 8.52- 8.48 (m, 1H), 8.25-8.19 (m, 1H), 8.19- 8.05 (m, 1H), 7.96 (s, 1H), 7.80- 7.60 (m, 2H), 7.51- 7.30 (m, 7H), 7.21- 7.16 (m, 2H), 5.83- 5.76 (m, 1H), 5.50- 5.38 (m, 1H), 5.35- 5.20 (m, 4H), 5.10- 4.95 (m, 1H), 4.90- 4.60 (m, 2H), 4.60- 4.40 (m, 3H), 4.40- 4.30 (m, 2H), 4.15- 3.95 (m, 2H), 3.90- 3.60 (m, 8H), 3.58- 3.45 (bs, 3H), 3.30-3.20 (m, 2H), 2.62- 2.55 (bs, 2H), 2.15 (s, 3H), 2.10- 1.90 (m, 5H), 1.75- 1.60 (bs, 3H), 1.60- 1.50 (bs, 3H), 1.48- 1.40 (bs, 9H), 1.40- 1.30 (m, 3H), 1.30- 1.20 (m, 3H), 1.10- 1.05 (m, 3H), 0.80- 0.65 (m, 5H); LC-MS: m / z 1339.6 [M+H]+. The intermediates XXIII-2 to XXIII-56 listed below in Table-16 were prepared by procedures similar to the one described in the synthesis of Intermediate XXIII-1 with appropriate acid (SM-1) and amine (SM-2) with appropriate variations in reagents, solvents and catalyst. The characterization data of the intermediates are summarized in Table-16. Table-16

[0062]

[0063] Synthesis of tert-butyl (lS,4S)-5-(8-((4-amino-2-(l-((2S,4R)-2-(((R)-l-(4-(l-ethyl-lH- pyrazol-5-yl)phenyl)-2-hydroxyethyl)carbamoyl)-4-hydroxypyrrolidin-l-yl)-3-methyl-l- oxobutan-2-yl)-2H-pyrazolo[3,4-c]quinolin-7-yl)methoxy)-6-cyclopropyl-7-(5-methyl-l- (tetrahydro-2H-pyran-2-yl)-lH-indazol-4-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (XXIV-I):

[0064] A stirred solution of chloro intermediate XXIII-1 (0.25 g, 0.187 mmol, 1.0 equiv.) in 7.0M NH3 in MeOH (10 mL) was heated 100 °C for 120 h. After completion of reaction, the reaction mixture was concentrated under vacuum to get the titled crude product XXIV-1 (0.25 g). LC-MS: m / z 1320.2 [M+H]+.

[0065] Synthesis of (2S,4R)-l-(2-(7-(((6-cyclopropyl-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-2-

[0066] ((S)-2-methoxypropoxy)-4-(piperazin-l-yl)quinazolin-8-yl)oxy)methyl)-4-oxo-4,5- dihydro-2H-pyrazolo[3,4-c]quinolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-2- hydroxy-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (XXV-1): To a stirred solution of XXIII-43 (0.50 g, 0.37 mmol, 1.0 equiv.) in MeOH was added 4.0 M HC1 in 1, 4 dioxane (5 mL), and the mixture was stirred for 2h at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was precipitated with diethyl ether to get the title compound XXV-1 (0.40 g) as a mixture of four diastereomers; LC-MS: m / z 1133.30[M+H]+

[0067] Synthesis of (2S,4R)-l-(2-(7-(((4-((lS,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6- cyclopropyl-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-2-((S)-2- methoxypropoxy)quinazolin-8-yl)oxy)methyl)-4-oxo-4,5-dihydro-2H-pyrazolo[3,4- c]quinolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy-l-(4-(4-methylthiazol- 5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (XXV-2):

[0068] The above intermediate XXV-2 was prepared using procedure similar to the one described in the synthesis of Intermediate XXV-1 using XXIII-47 as starting material; LC- MS: m / z 1145.30[M+H]+

[0069] PREPARATION OF COMPOUNDS Example-1: Synthesis of (2S,4R)-1-(2-(7-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2- yl)-6-cyclopropyl-7-(5-methyl-1H-indazol-4-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)quinazolin-8-yl)oxy)methyl)-4-hydroxy-2H-pyrazolo[3,4-c]quinolin-2-yl)-3- methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4- hydroxypyrrolidine-2-carboxamide (Compound-1) To a stirred solution of XXIII-1 (0.50 g, 0.37 mmol, 1.0 equiv.) in MeOH was added 4.0 M HCl in 1, 4 dioxane (5 mL), and the mixture was stirred for 2h at room temperature. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was precipitated with diethyl ether to get the title compound 1 (0.40 g) as a mixture of four diastereomers. The mixture was purified by Prep- HPLC to provide the four pure diastereomers as formate salts (Prep HPLC condition: Column- Luna omega C18 (250 x 21.2mm, 5 micron), Mobile Phase-Formic acid in water(A), Acetonitrile (B). 1a (Isomer-1 of 1)1H NMR (400 MHz, CD3OD): ^ 8.64 (s, 1H), 8.56- 8.48 (m, 2H), 7.60- 7.12 (m, 11H), 6.93 (s, 1H), 6.53 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 6.02 (d, J = 2.0 Hz, 1H), 5.34- 5.20 (m, 4H), 5.00- 4.93 (m, 1H), 4.50- 4.40 (m, 4H), 3.95- 3.85 (m, 4H), 3.79 (d, J = 6.0 Hz, 1H), 3.76- 3.60 (m, 3H), 3.45- 3.40 (m, 3H), 2.82- 2.72 (m, 1H), 2.40- 2.30 (m, 2H), 2.19 (s, 3H), 2.18- 2.0 (m, 5H), 1.85- 1.75 (m, 2H), 1.50- 1.40 (m, 1H), 1.25 (t, J = 7.6 Hz, 3H), 1.20 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H), 0.67- 0.60 (m, 4H); LC-MS: m / z 1136.60 [M+H]+1b (Isomer-2 of 1)1H NMR (400 MHz, CD3OD): ^ 8.65 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.50- 7.36 (m, 12H), 6.99 (s, 1H), 6.60 (d, J = 8.04Hz, 1H), 6.33 (d, J = 1.6 Hz, 1H), 5.34 (s, 2H), 5.24- 5.19 (m, 2H), 5.10 (s, 1H), 4.60- 4.40 (m, 6H), 4.2 (q, J = 7.2 Hz, 3H), 4.05- 3.90 (m, 7H), 3.88 (d, J = 6.8 Hz, 3H), 3.65- 3.60 (m, 1H), 3.45- 3.40 (m, 3H), 2.82- 2.72 (m, 1H), 2.20 (s, 5H), 2.15- 2.00 (m, 6H), 1.85- 1.80 (m, 2H), 1.25- 1.20 (m, 3H), 0.86 (d, J = 6.4 Hz, 3H), 0.70- 0.60 (m, 4H); LC-MS: m / z 1136.69 [M+H]+1c (Isomer-3 of 1)1H NMR (400 MHz, CD3OD): ^ 8.55 (s, 1H), 7.56- 7.37 (m, 8H), 7.28 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.11 (s, 1H), 6.44 (dd, J = 8.04 Hz, 1.6 Hz, 1H), 6.04 (d, J = 2.0 Hz, 1H), 5.40- 5.20 (m, 5H), 5.05 (t, J = 7.6 Hz, 1H), 4.71 (t, J = 8.4 Hz, 1H), 4.50- 4.40 (m, 4H), 4.05- 3.90 (m, 6H), 3.84 (d, J = 6.4 Hz, 3H), 3.70- 3.60 (m, 2H), 3.50- 3.40 (m, 2H), 2.40- 2.30 (m, 2H), 2.24 (s, 4H), 2.20- 2.10 (m, 4H), 1.90- 1.78 (m, 3H), 1.40- 1.35 (m, 3H), 1.21 (d, J = 7.2 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H), 0.65- 0.56 (m, 4H); LC-MS: m / z 1136.60 [M+H]+1d (Isomer-4 of 1)1H NMR (400 MHz, DMSO-d6): ^ 11.27 (s, 1H), 8.76 (s, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.51- 7.43 (m, 8H), 7.37- 7.22 (m, 6H), 7.08 (s, 1H), 6.34 (d, J = 2.0 Hz, 1H), 6.27 (d, J = 7.6 Hz, 1H), 6.13 (d, J = 1.6 Hz, 1H), 5.25- 5.20 (m, 6H), 4.85- 4.60 (m, 2H), 4.32-4.20 (m, 3H), 4.02 (q, J = 7.2 Hz, 2H), 3.85- 3.60 (m, 13H), 2.12- 1.95 (m, 6H), 1.90- 1.87 (m, 1H), 1.85- 1.6 (m, 3H), 1.06 (d, J = 6.8Hz, 3H), 0.71 (d, J = 6.4Hz, 4H), 0.62- 0.60 (m, 4H); LC-MS: m / z 1136.6 [M+H]+The Examples listed in below Table-17 were prepared by a procedure similar to the one described in Example 1 with 4N HCl in 1,4-dioxane as deprotecting reagent. The characterization data of the intermediates are summarized in Table-17. Table-17

[0070] Example-2: Synthesis (2S,4R)-1-(2-(7-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6- cyclopropyl-7-(5-methyl-1H-indazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin- 8-yl)oxy)methyl)-4-amino-2H-pyrazolo[3,4-c]quinolin-2-yl)-3-methylbutanoyl)-N-((R)-1- (4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2- carboxamide (Compound 8) Step-1: Synthesis of tert-butyl (1S,4S)-5-(8-((4-amino-2-(1-((2S,4R)-2-(((R)-1-(4-(1-ethyl- 1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3- methyl-1-oxobutan-2-yl)-2H-pyrazolo[3,4-c]quinolin-7-yl)methoxy)-6-cyclopropyl-7-(5- methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (XXIV-I) A stirred solution of chloro intermediate XXIII-1 (0.25 g, 0.187 mmol, 1.0 equiv.) in 7.0M NH3 in MeOH (10 mL) was heated to 100 °C for 120 h. After completion of reaction, the reaction mixture was concentrated under vacuum to get the titled crude product XXIV-1 (0.25 g) as a white gummy solid. LC-MS: m / z 1320.2 [M+H]+. Step-2: Synthesis of Synthesis (2S,4R)-1-(2-(7-(((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(5-methyl-1H-indazol-4-yl)-2- ((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-8-yl)oxy)methyl)-4-amino-2H-pyrazolo[3,4- c]quinolin-2-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2- hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide (Compound 8) Compound 8 was prepared by a procedure similar to the one described in Example-1 with 4.0 M HCl in 1,4-dioxane as deprotecting reagent. The isolated product was purified by Prep-HPLC to provide the four pure diastereomers as formate salts (Prep HPLC condition: Column- Luna omega C18 (250 x 21.2mm, 5 micron), Mobile phase-Formic acid in water(A), Acetonitrile (B). The characterization data of the compounds are summarized below. 8a (Isomer 1 of compound 8) :1H NMR (400 MHz, CD3OD): ^ 8.80 (s, 1H), 8.38 (bs, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.60-7.18 (m, 10H), 6.72 (d, J = 9.2 Hz, 1H), 6.15 (d, J = 1.6 Hz, 1H), 5.38- 5.20 (m, 4H), 4.72 (t, J = 8.4 Hz, 1H), 4.64- 4.49 (m, 5H), 4.10- 4.00 (m, 3H), 3.95- 3.86 (m, 4H), 3.80- 3.70 (m, 6H), 3.34 (s, 2H), 2.90- 2.75 (m, 1H), 2.50- 2.40 (m, 1H), 2.38- 2.22 (m, 4H), 2.15- 2.00 (m, 5H), 1.90- 1.75 (m, 3H), 1.22 (d, J = 6.8 Hz, 3H), 0.85 (d, J = 8.8 Hz, 3H), 0.71- 0.60 (m, 5H) ; LC-MS: m / z 1135.0 [M+H]+8b (Isomer 2 of compound 8) :1H NMR (400 MHz, CD3OD): ^ 8.79 (s, 1H), 8.45 (bs, 1H), 7.75- 7.36 (m, 10H), 7.26 (s,1H), 6.71 (dd, J = 8.4 Hz, 1.6Hz, 1H), 6.33 (d, J = 1.6 Hz, 1H), 5.40- 5.25 (m, 5H), 5.10 (t, J = 7.2 Hz, 1H), 4.64- 4.59 (m, 3H), 4.52- 4.50 (m, 3H), 4.19 (q, J = 7.2 Hz, 2H), 4.06 (d, J = 11.2 Hz, 2H), 3.98- 3.85 (m, 5H), 3.70- 3.65 (m, 2H), 3.50- 3.40 (m, 1H), 2.85- 2.75 (m, 1H), 2.45- 2.40 (m, 2H), 2.25- 2.04 (m, 11H), 1.85- 1.75 (m, 3H), 1.65- 1.60 (m, 1H), 1.50- 1.44 (m, 1H), 1.21 (d, J = 6.4 Hz, 3H), 0.85 (d, J = 6.0 Hz, 3H), 0.71- 0.63 (m, 4H) ; LC-MS: m / z 1133.55 [M-H]+8c (Isomer 3 of compound 8):1H NMR (400 MHz, CD3OD): ^ 8.65 (s, 1H), 8.46 (bs, 1H), 7.55- 7.20 (m, 9H), 7.04- 7.00 (m,1H), 6.60 (d, J = 8.4 Hz, 1H), 6.14 (d, J = 2.0 Hz, 1H), 5.40- 5.20 (m, 4H), 5.10- 5.00 (m, 2H), 4.55- 4.45 (m, 3H), 4.25- 4.15 (m, 2H), 4.10- 3.80 (m, 7H), 3.70- 3.60 (m, 2H), 3.50 (s, 3H), 2.90- 2.70 (m, 1H), 2.25- 1.95 (m, 11H), 1.90- 1.75 (m, 2H), 1.40- 1.20 (m, 6H), 0.90- 0.80 (m, 3H), 0.70- 0.55 (m, 4H) ; LC-MS: m / z 1135.50 [M+H]+. 8d (Isomer 4 of compound 8) : LC-MS: m / z 1134.90 [M-H]+Example-3: Synthesis of (2S,4R)-1-(2-(7-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H- indazol-4-yl)-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-((tetrahydro-2H- pyran-4-yl)oxy)quinazolin-8-yl)oxy)methyl)-4-oxo-4,5-dihydro-2H-pyrazolo[3,4- c]quinolin-2-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2- hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide (Compound-182)

[0071] To a stirred solution of (2S,4R)-1-(2-(7-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2- yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)quinazolin-8-yl)oxy)methyl)-4-oxo-4,5-dihydro-2H-pyrazolo[3,4-c]quinolin-2-yl)-3- methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4- hydroxypyrrolidine-2-carboxamide (Compound-12d) (0.10 g, 0.09 mmol, 1.0 equiv.) in MeOH (20 mL) was added formaldehyde (0.005 g, 0.17 mmol, 2.0 equiv.) and the reaction was continued for 6 h at rt. After that STAB (0.074 g, 0.34 mmol, 4.0 equiv.) was added and reaction mixture was stirred at rt for 16 h. After completion of reaction, the reaction mixture was diluted with ice cold water and extracted with 10% MeOH in ethyl acetate (15 mLx3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep TLC plate, eluting with 7-10% MeOH in DCM to get the titled compound -182 as white solid (0.015 g, 15%).1H NMR (400 MHz, CD3OD): ^ 8.64 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.55-7.35 (m, 5H), 7.36 (s, 1H), 7.18 (d, J = 6.0 Hz, 1H), 6.98- 6.97 (m, 1H), 6.60 (dd, J = 8.0 Hz, 0.8 Hz, 1H), 6.33 (d, J = 0.8 Hz, 1H), 5.36- 5.08 (m, 7H), 4.65 – 4.58 (m, 1H), 4.54 - 4.50 (bs, 1H), 4.25- 4.10 (m, 4H), 4.05 – 3.91 (m, 4H), 3.88 (d, J = 6.0 Hz, 2H), 3.52-3.39 (m, 4H), 3.10-3.05 (m, 2H), 2.80-2.70 (m, 2H), 2.55 (s, 3H), 2.21 (t, J = 8.0 Hz, 2H), 2.18-2.00 (m, 8H), 1.90- 1.77 (m, 2H), 1.65 – 1.60 (m, 2H), 1.41 - 1.36 (m, 9H), 1.19 (dd, J = 10.8 Hz, 6.4 Hz, 3H), 0.82 (d, J = 6.8 Hz, 3H), 0.67- 0.58 (m, 4H); LC-MS: m / z 1166.20 [M+H]+The compounds listed in below Table-18 were prepared by a procedure similar to the one described in Example-2 reacting appropriate aldehyde / keto regent with compound-1 to get desired reductive aminated product. The characterization data of the intermediates are summarized herein the below table. Table-18

[0072] 185

[0073]

[0074] Example-4: Synthesis of (2S,4R)-1-((2S)-2-(7-(((6-cyclopropyl-4-((1S,4S)-5-cyclopropyl- 2,5-diazabicyclo[2.2.1]heptan-2-yl)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2- ((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-8-yl)oxy)methyl)-4-oxo-4,5-dihydro-2H- pyrazolo[3,4-c]quinolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound-192) To a stirred solution of (2S,4R)-1-(2-(7-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2- yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)quinazolin-8-yl)oxy)methyl)-4-oxo-4,5-dihydro-2H-pyrazolo[3,4-c]quinolin-2-yl)-3- methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4- hydroxypyrrolidine-2-carboxamide (13A) (0.40 g, 0.35 mmol, 1.0 equiv.) in MeOH (2.5 mL) and acetic acid (0.04 g, 0.7 mmol, 2 eq) was added (1-Ethoxycyclopropyloxy) trimethyl silane (0.18 g, 1.05 mmol, 3.0 equiv.) and the reaction was continued for 6 h at RT. After that sodium triacetoxyborohydride (0.043 g, 0.7 mmol, 2.0 equiv.) was added and reaction mix was stirred at rt for 5 h at 60oC. After completion of reaction, the reaction mixture was diluted with ice cold water and extracted with 10% MeOH in ethyl acetate (15 mLx3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep HPLC, to get the two isomers of titled compound (compound-192) as white solid Isomer I (0.06 g, 10%) and Isomer II (0.06 g; 10%). Compound-192a (isomer-1):1H NMR (400 MHz, CD3OD): ^ 8.72 (s, 1H), 8.48 (s, 1H), 7.53 (s, 1H), 7.49 (bs, 1H), 7.31 (d, J =8.0, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 7.1 -7.05 (m, 2 H),6.73 (s, 1H), 6.40 (dd, J = 8.4 Hz, 1.2 Hz, 1H), 5.40 – 5.30 (m, 2H), 5.36- 5.15 (m, 5H), 5.07 (t, J = 6.0 Hz, 1H), 5.03 – 4.99 (m, 2H ) 4.4 (t, J = 8.4 Hz, 1H), 4.47 (bs, 1H), 4.24 – 4.21 (m, 1H), 3.99 – 3.97 (m, 3H), 3.89 – 3.84 (m, 4H), 3.54 (d, 3H), 3.23 – 3.22 (m, 2H), 2.80 – 2.70 (m, 1H), 2.40- 2.30 (m, 1H), 2.28 (s, 3H), 2.20 – 2.07 (m, 8H), 1.90 – 1.80 (m, 2H), 1.35 – 1.30 (m, 2H), 1.20 (d, J = 6.4 Hz, 3H), 0.84 (d, J = 6.4 Hz, 3H), 0.65 – 0.50 (m, 8H) ; LC-MS: m / z 1197.45 [M+H]+Compound-192b (isomer-2):1H NMR (400 MHz, CD3OD): ^ 8.89 (s, 1H), 8.63 (s, 1H), 8.38 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.54-7.53 (m, 2H), 7.49 (s, 3H), 7.44 (s, 1H), 7.35 (dd, J = 4.4 Hz, 0.8 Hz, 1H), 7.18 (d, J = 9.2 Hz, 1H), 6.96 (bs, 1H), 6.58 (dd, J = 8.0 Hz, 1.2 Hz, 2H), 5.36- 5.08 (m, 6H), 4.65 – 4.58 (m, 3H), 4.25 – 3.85 (m, 8H), 3.50 – 3.47 (m, 2H), 3.23 (bs, 2H), 2.80 – 2.70 (m, 1H), 2.50 (s, 3H), 2.20- 2.0 (m, 6H), 1.19 (d, J = 6.8 Hz, 3H), 0.85 (d, J = 8.8 Hz, 3H), 0.63- 0.54 (m, 7H); LC-MS: m / z 1197.45 [M+H]+Example-5: Synthesis of (2S,4R)-1-((2S)-2-(7-(((4-((1S,4S)-5-acetyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2- ((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-8-yl)oxy)methyl)-4-oxo-4,5-dihydro-2H- pyrazolo[3,4-c]quinolin-2-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5- yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide (Compound-193) To a stirred solution of Compound-12d (0.02 g, 0.017 mmol) in DCM (5 mL) was added acetic anhydride (0.002 g, 0.02 mmol), and mixture was stirred at rt for 2 hours. After the completion of reaction, organic solvent was removed by high vacuum. Then the mixture was treated with LiOH (0.002 g; 0.04 mmol) in MeOH and water solution. After 2 h reaction was quenched with ice cold water and extracted with 2 butanol (5 mLx3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep TLC, eluting with 10% MeOH in DCM to afford titled compound (0.007 g, 36%) as off-white color solid.1H NMR (400 MHz, CD3OD): ^ 8.64 (s, 1H), 8.40 (bs 1H), 7.59-7.32 (m, 10H), 7.18 (d, J = 9.6 Hz, 1H), 6.96 (dd, J = 6.4, 0.8 Hz, 1H), 6.61-6.57 (m, 1H), 6.32 (d, J = 2.0 Hz, 1H), 5.40- 5.28 (m, 3H), 5.22- 5.05 (m, 3H), 4.62- 4.28 (m, 6H), 4.22-4.15 (m, 2H), 4.05-3.80 (m, 10H), 3.65-3.60 (m, 1H), 3.52-3.49 (m, 2H), 2.80-2.70 (m, 1H), 2.30-2.03 (m, 11H), 1.88-1.79 (m, 2H), 1.36 (t, J = 7.6 Hz, 3H), 1.20 (d, J = 6.8 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H), 0.67- 0.58 (m, 4H); LC-MS: m / z 1194.25 [M+H]+Example-6: Synthesis of (2S,4R)-1-((2S)-2-(7-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H- indazol-4-yl)-4-((1S,4S)-5-(1-methylazetidine-3-carbonyl)-2,5-diazabicyclo[2.2.1]heptan- 2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-8-yl)oxy)methyl)-4-oxo-4,5-dihydro- 2H-pyrazolo[3,4-c]quinolin-2-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5- yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide (Compound 194) To a stirred solution of 12d (0.03 g, 0.026 mmol) in DCM (5 mL) and diethyl amine (0.010 gm) was added 1-methylazetidine-3-carboxylic acid (0.015 g, 0.13 mmol), and mixture was stirred at rt for 48 hour. After the completion of reaction, the mixture was quenched with ice cold water and extracted with 2 butanol (5 mLx3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep TLC, eluting with10% MeOH in DCM to afford titled compound 194 (0.007 g, 23%) as off-white color solid. LC-MS: m / z 1251.25 [M+H]+. Example-7: Synthesis of (1S,4S)-5-(6-cyclopropyl-8-((2-((S)-1-((2S,4R)-2-(((R)-1-(4-(1- ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3- methyl-1-oxobutan-2-yl)-4-oxo-4,5-dihydro-2H-pyrazolo[3,4-c]quinolin-7-yl)methoxy)- 7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4- yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (Compound-195) To a stirred solution of Compound-12d (0.03 g, 0.026 mmol) in DCM (5 mL) and diethyl amine (0.010 gm) was added isocyanato trimethyl silane (0.015 g, 0.13 mmol), and mixture was stirred at rt for 48 hours. After the completion of reaction, the mixture was quenched with ice cold water and extracted with 2 butanol (5 mLx3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep TLC, eluting with 10% MeOH in DCM to afford titled compound (0.007 g, 23%) as off-white colour solid.1H NMR (400 MHz, CD3OD): ^ 8.65 (s, 1H), 7.60-7.41 (m, 10H), 7.14 (d, J = 8.8 Hz, 1H), 6.89 (s, 1H), 6.59 (d, J = 8.0 Hz, 1H), 6.33 (d, J = 2.0 Hz, 1H), 5.45- 5.36 (m, 4H), 5.22- 5.05 (m, 3H), 4.62- 4.40 (m, 5H), 4.22-4.15 (m, 2H), 4.05-3.80 (m, 10H), 3.65-3.60 (m, 2H), 3.52- 3.49 (m, 2H), 2.80-2.70 (m, 1H), 2.30-2.03 (m, 9H), 1.88-1.80 (m, 2H), 1.36 (t, J = 7.6 Hz, 3H), 1.20 (d, J = 6.8 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H), 0.67- 0.58 (m, 4H); LC-MS: m / z 1197.50 [M+H]+ Although the present invention has been illustrated by certain of the preceding examples, it is not to be construed as being limited thereby; but rather, the present invention 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 given 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 invention.

[0075]

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084] or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.

[0085] Biological Data:

[0086] Example 8: Determination of KRAS degradation in SW1990 cell lines by HiBit degradation assay

[0087] SW1990 HiBiT-KRAS G12D cells were plated at 7000 cells / well in a 96-well plate. Compounds of the present disclosure and positive controls were diluted in 10% DMEM complete media and applied to the plated cells resulting in a final concentration titration of 10 pM to 4 nM in 1% DMSO. All assays were performed in triplicate. Cells were treated with compounds for 24 hours at 37 °C in an incubator containing 5% CO2. Following treatment, 20 pL of CellTiter-Fluor™ Cell Viability Assay (Promega cat. No. G6081) was added to the cells and incubated for 30 minutes at 37 °C to determine if compounds treatment led to a loss in cell viability after 24 hours, by capturing fluorescence on the BMG Labtech Clariostar instrument. After completion of the fluorescence read, Nano-Gio® HiBiT detection reagent (Promega cat. No. PRN3040) was prepared according to the manufacturer’s instructions and 100 pL reagent was added to each well followed by incubation at room temperature for 30 minutes. The luminescence was read in the BMG Labtech Clariostar instrument.

[0088] Selected compounds of the present invention were screened in the above-mentioned assay procedures for determination of Dmax values and the results are summarized in below table A. Table-A: Example 9: Determination of KRAS degradation in MIAPaCa-2 cell lines by HiBit degradation assay MIAPaCa-2 HiBiT-KRAS G12C cells were seeded at 4000 cells / well in a 96-well plate. Compounds of the present disclosure and positive controls were diluted in 10% DMEM complete media and applied to the plated cells resulting in a final concentration range ranging from 10 µM to 4 nM at 1% DMSO. All assays were performed in triplicate. Cells were incubated with compounds for 24 hours at 37 °C in an incubator containing 5% CO2. Following treatment, 20 µL of CellTiter-Fluor™ Cell Viability Assay (Promega cat. No. G6081) was added on the cells and incubated for 30 minutes at 37 °C to determine if compounds treatment led to a loss in cell viability after 24 hours, by capturing fluorescence on the BMG Labtech Clariostar instrument. Post completion of the fluorescence read, Nano-Glo® HiBiT detection reagent (Promega cat. No. PRN3040) was prepared according to the manufacturer’s instructions and 100 µL reagent was added to each well followed by incubation at room temperature for 30 minutes. The resultant luminescence was read in the BMG Labtech Clariostar instrument. Selected compounds of the present invention were screened in the above-mentioned assay procedures for determination of Dmaxvalues and the results are summarized in below table B. Table-B: Example 10: Determination of KRAS degradation in SW620 (G12V) cell degradation assay by western blot SW620 cells were seeded at 0.6*106cells / well in 6-well plates. Compounds of the present disclosure and positive controls were diluted in 10% RPMI complete media and applied to the plated cells resulting in a final concentration range of 10 µM to 2 nM at 1% DMSO. Cells were treated with compounds for 24 hours at 37 °C in an incubator containing 5% CO2. Following treatment, PBS was added to the treated cells which were then scraped using a cell scraper and centrifuged at 12500 rpm for 15 min at 4oC. After centrifugation, the pellets were resuspended with 1X RIPA lysis buffer for 60 min with intermediate vortex and centrifuged at 12500 rpm for 15 min at 4oC. After this, the supernatant was collected and estimated protein concentration was determined using BCA kit. Twenty micrograms of protein were loaded per lane and resolved at 80 V for 2 hours. After the protein resolved, the gel was equilibrated in 1X transfer buffer with 20% methanol and processed for wet transfer by setting up the blotting paper, gel, nitrocellulose membrane (0.2 µm) and blotting paper in a transfer cassette and set up the transfer for 1 hour at 80 V under cold conditions. Post transfer, the membrane was blocked using Intercept® blocking buffer (TBS) (Licor, Cat # 972-60001) for 1 hour at RT after which the primary antibody using K-RAS recombinant rabbit monoclonal antibody (Invitrogen :11H35L14 Ref# 703345) (1:1500) with housekeeping antibody β-Actin (Santa Cruz Biotechnology Cat# sc69879) (1:10000) was added for incubation overnight at 4oC in the rocker. Primary antibody was then removed from the blots and washed twice with 1X TBST for 5 minutes. After washing, blots were incubated with the secondary antibody using Goat anti-Rabbit IgG (Licor; IRDye 800CW, Cat # 926-32211) (1:10000) and Goat anti-Mouse IgG (Licor; IRDye 680RD, Cat # 926-68070) for 1 hour at RT. After secondary antibody incubation, the blots were washed thrice with 1X TBST at 15 mins interval. Then, the blots were dried and scanned by LICOR Odyssey™ infrared scanner in the 800 and 700 channels. Selected compounds of the present invention were screened in the above-mentioned assay procedures for determination of Dmax values and the results are summarized in below table C. Table-C: Example 11: Determination of KRAS degradation in NCI-H460 (Q61H) cell degradation by western blot NCI-H460 cells were seeded at 0.2*106cells / well in 6-well plates. Compounds of the present disclosure and positive controls were diluted in 10% RPMI complete media and applied to the plated cells resulting in a final concentration range of 10 µM to 2 nM at 1% DMSO. Cells were treated with compounds for 24 hours at 37 °C in an incubator containing 5% CO2. Following treatment, PBS was added to the treated cells and were scraped using cell scraper and centrifuged at 12500 rpm for 15 min at 4oC. After centrifugation, the pellets were resuspended with 1X RIPA lysis buffer for 60 min with intermediate vortex and centrifuged at 12500 rpm for 15 min at 4oC. The supernatant was then collected, and protein concentration estimated by BCA kit. Twenty micrograms of protein were loaded per lane and resolved at 80 V for 2 hours. After resolution of protein, the gel was equilibrated in 1X transfer buffer (cat# 1610734 Biorad) with 20% methanol and processed for wet transfer by setting up the blotting paper, gel, nitrocellulose membrane (0.2 µM) and blotting paper in a transfer cassette and set up the transfer for 1 hour at 80 V under cold conditions. Post transfer, the membrane was blocked using Intercept® blocking buffer (TBS) (Licor, Cat # 972-60001) for 1 hour incubation at RT and primary antibody added which included K-RAS recombinant rabbit monoclonal antibody (Invitrogen :11H35L14 Ref# 703345) (1:1500) as well as housekeeping antibody β- Actin (Santa Cruz Biotechnology Cat# sc69879) (1:10000) and incubated overnight at 4oC in the rocker. Primary antibody was then removed from the blots and washed twice with 1X TBST for 5 minutes. After these rinses, blots were incubated with the secondary antibody using Goat anti-Rabbit IgG (Licor; IRDye 800CW, Cat # 926-32211) (1:10000) and Goat anti-Mouse IgG (Licor; IRDye 680RD, Cat # 926-68070) for 1 hour at RT. After secondary antibody incubation, the blots were washed thrice with 1X TBST at 15 mins interval. Then, the blots were dried and scanned by LICOR Odyssey™ infrared scanner in the 800 and 700 channels. Selected compounds of the present invention were screened in the above-mentioned assay procedures for determination of Dmaxvalues and the results are summarized below table D. Table-D: Example 12: Determination of KRAS degradation in HCT-116 (G13D) cell degradation by western blot HCT-116 cells were seeded at 0.4*106cells / well in 6-well plates. Compounds of the present disclosure and positive controls were diluted in the 10% RPMI complete media and applied to the plated cells resulting in a final concentration range of 10 µM to 1 nM 1% DMSO. Cells were treated with compounds for 24 hours at 37 °C in an incubator containing 5% CO2. Following treatment, PBS was added to the treated cells and were scraped using cell scraper and centrifuged at 12500 rpm for 15 min at 4oC. After centrifugation, the pellets were resuspended with 1X RIPA lysis buffer for 60 min with intermediate vortex and centrifuged at 12500 rpm for 15 min at 4oC. After that the supernatant was collected and estimated protein concentration by BCA kit. 20 µg of protein were loaded per lane and resolved at 80 V for 2 hours. Once the protein resolved, the gel is equilibrated in 1X transfer buffer with 20% methanol and processed for wet transfer by setting up the blotting paper, gel, nitrocellulose membrane (0.2 µm) and blotting paper in a transfer cassette and set up the transfer for 1 hour at 80 V under cold conditions. Post transfer, the membrane was blocked using Intercept® blocking buffer (TBS) (Licor, Cat # 972-60001) for 1 hour incubation at RT and added the primary antibody i.e. RAS (G13D MUTANT) ANTIBODY 100 UL cat# PA578088 R (1:500) with housekeeping antibody β-Actin (Santa Cruz Biotechnology Cat# sc69879) (1:10000) and incubated overnight at 4oC in the rocker. Next day, primary antibody was removed from the blots and washed twice with 1X TBST for 5 mins. After washes, blots were incubated with the secondary antibody using Goat anti-Rabbit IgG (Licor; IRDye 800CW, Cat # 926-32211) (1:10000) and Goat anti-Mouse IgG (Licor; IRDye 680RD, Cat # 926-68070) for 1 hour at RT. After secondary incubation, the blots were washed thrice with 1X TBST at 15 mins intervals. Then, the blots were dried and scanned by LICOR Odyssey™ infrared scanner in the 800 and 700 channels. Selected compounds of the present invention were screened in the above-mentioned assay procedures for determination of Dmaxvalues and the results are summarized in below table E. Table-E: Example 13: Study on efficacy of compounds in AsPC-1 pancreatic adeno carcinoma xenograft model Five to six weeks-old female athymic nude mice were inoculated with 2 million AsPC- 1 cells on the right flank region. Mice were randomized based on the tumor volume and dosing was initiated when the mean tumor volumes were ~216 mm3. Compounds 1d and 12d were dosed intravenously at a once-a-week interval for three weeks. Animals were monitored daily for body weight loss and clinical signs of toxicity while the tumor volumes were measured twice weekly. Compounds 1d (Isomer-4 of compound 1) and 12d (Isomer-4 of compound 12) were well tolerated at 10 mg / kg and 30 mg / kg once-weekly doses. Compound 1d treatment demonstrated dose dependent anti-tumor efficacy with %TGI values of 78% and 100% at 10 mg / kg and 30 mg / kg, respectively, illustrated in Figure 1. Compound 12d treatment demonstrated dose dependent anti-tumor efficacy with %TGI values of 70% and 94% at 10 mg / kg and 30 mg / kg, respectively, illustrated in Figure 1. % Tumor growth inhibition by Compound 1d and 12d in AsPC-1 pancreatic adeno carcinoma xenograft model is summarized in below table F. Table F: Brown-Forsythe & Welch ANOVA tests: -*p<0.05; **p<0.01** compared to vehicle controls. Incorporation by Reference 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. Equivalents 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 their full scope of equivalents and the specification, along with such variations.

Claims

CLAIMS:

1. A compound of Formula (I)or a pharmaceutically acceptable salt or stereoisomer or a tautomer thereof; wherein, R1 at each occurrence, independently is hydrogen, (C1-C6)alkyl, hydroxy, halo, amino, halo(C1-C6)alkyl, and / or two R1 adjacent to each other together with the C atoms to which they are attached form a phenyl or 5- to 6-membered heterocyclyl; wherein the phenyl and heterocyclyl are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of (C1-C6)alkyl, (C2-C4)alkynyl, halo, hydroxy, halo(C1- C6)alkyl, amino and cyano; p is 1, 2, 3, or 4; X and X’, independently, is C or N; R2 is hydrogen, cyclopropyl or absent; R3is hydrogen or oxo; R4a and R4b, independently, is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, 5- to 10- membered heteroaryl(C1-C6)alkyl or 4- to 7-membered heterocyloalkyl, wherein the cycloalkyl and heteroarylalkyl are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo, (C1-C6)alkyl and amino; and / orR4aand R4btogether with the nitrogen to which they are attached form a 4- to 14-membered heterocyclyl optionally containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur; wherein the heterocyclyl is unsubstituted or substituted with 1, 2 or 3 groups each independently selected from the group consisting of (C1- C6)alkyl, (C3-C6)cycloalkyl, hydroxy, cyano and -C(O)-R4c; wherein said alkyl is unsubstituted or substituted independently with one or more of halo, hydroxy, amino, cyano or (C3- C6)cycloalkyl; and / or R4cis hydrogen, amino, (C1-C6)alkylamino, 4- to 7-membered heterocycloalkyl, (C3- C6)cycloalkyl, (C1-C6)alkyl or (C1-C6)alkylamino(C1-C6)alkyl; wherein the heterocycloalkyl and cycloalkyl are unsubstituted or substituted with 1, 2 or 3 groups each independently selected from the group consisting of halo, hydroxy and (C1-C6)alkyl; L is -O-(CH2)m-*, -C(O)-* or -C(O)-NH-*; wherein asterisk mark represents the point of attachment with R5; R5is (C1-C6)alkyl, (C1-C6)alkoxy, -(CH2)m-NRcRd, 5- to 14-membered heterocycloalkyl or (C3-C6)cycloalkyl; wherein the heterocycloalkyl and cycloalkyl are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of (C1-C6)alkyl, halo, amino and -(CH2)mNRyRz; m is 0, 1, 2 or 3; Rc and Rd, independently, is hydrogen or (C1-C6)alkyl; or Rc and Rd together with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl; Ryand Rz, independently is hydrogen or (C1-C6)alkyl; or Ryand Rztogether with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of (C1-C6)alkyl, halo and (C2-C4)acyl; R6 at each occurrence, independently, is hydrogen, amino, (C1-C6)alkyl, (C1-C6)alkoxy or hydroxy; or two R6 on the same carbon represent an oxo group; q is 1, 2 or 3; Y1, Y2and Y3,independently, is a bond, C, N or O; wherein not more than one of Y1, Y2 or Y3 is a bond;Z1, Z2, Z3and Z4independently, is a C, CR7’, NR7, or N; wherein at least two of Z1, Z2, Z3 and Z4 are N; R7 and R7’ independently, is hydrogen, halo, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1- C6)alkoxy or halo(C1-C6)alkoxy; M is M1, M2, M3, M4, M5, M6, M7, M8 or M9;wherein, R8 is (C1-C6)alkyl, hydroxy, halo or amino; Z is hydrogen, (C1-C6)alkyl, halo or -CH2OH;Ra’and Rb’independently, is hydrogen, halo or (C1-C6)alkyl; or Ra’and Rb’together with the C atoms to which they are attached form a 5 to 6 membered heterocyclyl ring optionally containing one or two hetero atoms independently selected from the group consisting of O, S and N; R9 at each occurrence, independently, is hydrogen, 4- to 8-membered heterocycloalkyl, -O-heterocycloalkyl, -O-(C1-C6)alkyl; wherein heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo or (C1- C6)alkyl; wherein the alkyl in -O-(C1-C6)alkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of (C1- C6)alkylamino or 5- to 8-membered heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo or (C1-C6)alkyl; P1, P2, P3 and P4, independently, is C, N or S; wherein at least one of P1, P2, P3 and P4 is N; R10is hydrogen, (C1-C6)alkyl, (C2-C4)alkynyl, hydroxy, 3- to 7-membered heterocycloalkyl or (C3-C6)cycloalkyl; wherein the alkyl and alkynyl is unsubstituted or substituted with halo, cycloalkyl, -NH-(CO)-NH2, -NRmRnor 4 to 6 membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of (C1-C6)alkyl, hydroxy, halo or amino; wherein 3- to 7-membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo, hydroxy or (C1-C6)alkyl; Rmand Rnare independently hydrogen or (C1-C6)alkyl; R11at each occurrence, independently, is hydrogen, hydroxy or (C1-C6)alkyl; wherein the alkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo or hydroxy;R12at each occurrence, independently, is hydrogen or amino; X1 is C or N; R13 is hydrogen or (C1-C6)alkyl; X2, X3, X4and X5, each independently is C, CH or N; wherein one of X3or X4is always N and the other is C; R14 at each occurrence, independently is hydrogen, halo, hydroxy, (C1-C6)alkyl, halo(C1-C6)alkyl or (C2-C6)alkynyl; Cy is (C3-C10)cycloalkyl or 3- to 10-membered heterocycloalkyl; a dotted line [-----] indicates a bond or absent; and n is 1, 2 or 3.

2. The compound of claim 1, wherein R1at each occurrence is (C1-C6)alkyl, amino, hydroxy or halo.

3. The compound of claim 1, wherein two R1 adjacent to each other together with the C atoms to which they are attached form a phenyl or 5- to 6-membered heterocyclyl; wherein the phenyl and heterocyclyl are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from (C1-C6)alkyl, (C2-C4)alkynyl, halo and amino.

4. The compound of claims 1 and 3, wherein two R1adjacent to each other together with the C atoms to which they are attached form a, , ,.

5. The compound of claim 1, wherein R2 is cyclopropyl or absent.

6. The compound of claim 1, wherein R4aand R4b, independently, is (C1-C6)alkyl, (C3- C6)cycloalkyl, 5- to 10-membered heteroaryl(C1-C6)alkyl or 4- to 7-membered heterocyloalkyl.

7. The compound of claims 1 and 6, wherein R4aand R4bindependently, is methyl, ethyl, cyclopropyl,8. The compound of claim 1, wherein R4a and R4b together with the nitrogen to which they are attached form a unsubstituted or substituted heterocyclyl selected from,9. The compound of claim 8, wherein the heterocyclyl is substituted with 1, 2 or 3 groups each independently selected from (C1-C6)alkyl, (C3-C6)cycloalkyl, hydroxy and -C(O)- R4c; wherein said alkyl is substituted independently with one or more of halo, hydroxy or (C3-C6)cycloalkyl.

10. The compound of claim 9, wherein R4cis amino, (C1-C6)alkylamino, (C1-C6)alkyl or unsubstituted or substituted 4- to 7-membered heterocycloalkyl; wherein the heterocycloalkyl is substituted with (C1-C6)alkyl.

11. The compound of claim 1, wherein L is -O-, -O-(CH2)m-*, -C(O)-* or -C(O)-NH-*; wherein asterisk mark represents the point of attachment with R5.

12. The compound of claims 1 and 11, wherein L is -O-(CH2)m-* wherein the asterisk mark represents the point of attachment with R5.

13. The compound of claim 1, wherein R5is (C1-C6)alkoxy, -(CH2)m-NRcRdor 5- to 14- membered heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from (C1-C6)alkyl, halo, and -(CH2)m-NRyRz.

14. The compound of claim 13, wherein Rc and Rd are (C1-C6)alkyl; or Rc and Rd together with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl.

15. The compound of claim 13, wherein Ry and Rz is (C1-C6)alkyl; or Ry and Rz together with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl;wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from (C1-C6)alkyl and (C2-C4)acyl.

17. The compound of claim 1, wherein R6 is hydrogen, amino, (C1-C6)alkoxy, or hydroxy; or two R6 on the same carbon represent an oxo group.

18. The compound of claim 1, wherein R7and R7’are independently halo, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, or halo(C1-C6)alkoxy.

19. The compound of claim 1, wherein M1 is.

20. The compound of claims 1 and 19, wherein M1 is, , , , ,22. The compound of claims 1 and 21, wherein M2 is23. The compound of claim 1, wherein M3 is.

24. The compound of claims 1 and 23, wherein M3 is.

25. The compound of claim 1, wherein M4 is.

26. The compound of claim 1, wherein M5 is27. The compound of claims 1 and 26, wherein M5 is28. The compound of claim 1, wherein M6 is.

29. The compound of claim 1, wherein M7 is.

30. The compound of formula 1, wherein M8 is.

31. The compound of formula 1, wherein M9 is32.,, , , ,wherein the asterisk mark represents the point of attachment with M.

33. The compound of claim 1, having a formula (IA):or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.

34. The compound of claim 33, wherein R1 is (C1-C6)alkyl, hydroxy or halo.

35. The compound of claim 33, wherein the R4aand R4bindependently is (C1-C6)alkyl, (C3- C6)cycloalkyl or 5- to 10-membered heteroaryl(C1-C6)alkyl.

36. The compound of claims 33 and 35, wherein R4a and R4b , independently, is methyl, ethyl, cyclopropyl,.

37. The compound of claim 33, wherein R4aand R4btogether with the nitrogen to which they are attached form a moiety selected from the group consisting of, ,38. The compound of claim 33, wherein L is -O-, -C(O)-* or -O-CH2-*; wherein asterisk mark represents the point of attachment with R5. , ,40. The compound of claim 33, wherein R6 is hydrogen, amino, hydroxy or two R6 on the same carbon represent an oxo group.

41. The compound of claim 33, wherein R7 is hydrogen, halo, (C1-C6)alkyl or halo(C1-C6)alkyl.

42. The compound of claim 33, wherein M is M1, M2, M3, M4, M5, M6, M7, M8 or M9;.

43. The compound of claim 1, having formula (IB):or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.

44. The compound of claim 43, wherein R1 is (C1-C6)alkyl, hydroxy or halo.

45. The compound of claim 43, wherein R6is hydrogen, amino, hydroxy or two R6on the same carbon represent an oxo group.

46. The compound of claim 43, wherein R9 is hydrogen or (C1-C6)alkyl.

47. The compound of claim 43, wherein Ra’and Rb’together with the C atoms to which they are attached form 5- to 6-membered heterocycloalkyl or heteroaryl.

48. The compound of claim 43, wherein R10 is hydrogen or (C1-C6)alkyl.

49. The compound of claim 1, having formula (IC):or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.

50. The compound of claim 1, having formula (ID):or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.

51. The compound of claim 1, having formula (IE)or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.

52. The compound of claim 1, having structure of formula (IF), (IG), (IH), (IJ) and (IK):,.

53. The compound of claim 1, having structure of formula (IL):or a pharmaceutically acceptable salt or stereoisomer or a tautomer thereof; wherein, R1at each occurrence, independently is hydrogen, (C1-C6)alkyl, hydroxy, halo, amino, halo(C1-C6) alkyl and / or two R1adjacent to each other together with the C atoms to which they are attached form a phenyl or 5- to 6-membered heterocyclyl; wherein the phenyl and heterocyclyl are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of (C1-C6)alkyl, (C2-C4)alkyne, halo, hydroxy, halo(C1- C6)alkyl, amino and cyano; p is 1, 2, 3, or 4;R4aand R4b,independently, is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, 5- to 10- membered heteroaryl(C1-C6)alkyl or 4- to 7-membered heterocyloalkyl, wherein the cycloalkyl and heteroarylalkyl are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo, alkyl and amino; and / or R4a and R4b together with the nitrogen to which they are attached form a 4- to 14- membered heterocyclyl optionally containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulphur; wherein the heterocyclyl is unsubstituted or substituted with 1, 2 or 3 groups each independently selected from the group consisting of (C1-C6)alkyl, (C3-C6)cycloalkyl, hydroxy, cyano and -C(O)-R4c; wherein said alkyl is unsubstituted or substituted independently with one or more of halo, hydroxy, amino, cyano or (C3-C6)cycloalkyl; and / or R4c is hydrogen, amino, (C1-C6)alkylamino, 4- to 7-membered heterocycloalkyl, (C3- C6)cycloalkyl, (C1-C6)alkyl or (C1-C6)alkylamino(C1-C6)alkyl; wherein the heterocycloalkyl and cycloalkyl are unsubstituted or substituted with 1, 2 or 3 groups each independently selected from the group consisting of halo, hydroxy and (C1-C6)alkyl; R7 is hydrogen, halo, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy or halo(C1- C6)alkoxy; Ra’and Rb’independently, is hydrogen, halo or (C1-C6)alkyl; or Ra’and Rb’together with the C atoms to which they are attached form a 5 to 6 membered heterocyclyl ring optionally containing one or two hetero atoms independently selected from the group consisting of O, S, and N; R9 at each occurrence, independently, is hydrogen, 4- to 8-membered heterocycloalkyl, -O-heterocycloalkyl or -O-(C1-C6)alkyl; wherein heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo or (C1-C6)alkyl; wherein the alkyl in -O-(C1-C6)alkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of (C1-C6)alkylamino or 5- to 8-membered heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo or (C1-C6)alkyl;P1, P2, P3and P4independently, is C, N or S; wherein at least one of P1, P2, P3and P4is N; R10 is hydrogen, (C1-C6)alkyl, (C2-C4)alkynyl, hydroxy, 3- to 7-membered heterocycloalkyl or (C3-C6)cycloalkyl; wherein the alkyl and alkynyl is unsubstituted or substituted with halo, cycloalkyl, NH- (CO)-NH2, NRmRn, or 4 to 6 membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of (C1-C6)alkyl, hydroxy, halo or amino; wherein 3- to 7-membered heterocycloalkyl is unsubstituted or substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halo, hydroxy or (C1- C6)alkyl; Rm and Rn are independently hydrogen or (C1-C6)alkyl; a dotted line [-----] indicates a bond or absent; and n is 1, 2 or 3.

54. The compound of claims 1 to 53, wherein the compound is selected from:or a pharmaceutically acceptable salt or stereoisomer or a tautomer thereof.

55. A pharmaceutical composition comprising the compound of any one of claims 1 to 54 or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, and pharmaceutically acceptable carrier or an excipient.

56. The pharmaceutical composition of claim 55, for use in degrading a target protein in a subject, wherein the target protein is KRAS.

57. The pharmaceutical composition for use of claim 56, wherein the subject is afflicted with a disease or disorder dependent upon KRAS.

58. The pharmaceutical composition for use of claim 56, wherein the subject is afflicted with a disease or disorder dependent upon KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D or KRAS Q61H.

59. The pharmaceutical composition for use of claim 57, wherein the disease or disorder is a cancer selected from the group consisting of biliary tract malignancies, colon cancer, liver cancer, colorectal cancer, non-small cell lung cancer, small-cell lung cancer, pancreatic cancer, appendiceal cancer, melanoma, acute myeloid leukemia, small bowel cancer, ampullary cancer, germ cell cancer, cervical cancer, cancer of unknown primary origin, endometrial cancer, esophagogastric cancer, GI neuroendocrine cancer, ovarian cancer, sex cord stromal tumor cancer, hepatobiliary cancer, bladder cancer, lung cancer, prostate cancer, breast cancer, cervical carcinomas, testicular carcinomas, gastric cancer, head and neck cancer, hepatocellular cancer, laryngeal cancer, oral cancer, thyroid carcinomas, sarcomas, cardiac cancer, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, teratoma, bronchogenic carcinoma, undifferentiated small cell cancer, adenocarcinoma, alveolar carcinoma, bronchiolar carcinoma, bronchial adenoma, lymphoma, chondromatous hamartoma, mesothelioma, gastrointestinal cancer, squamous cell carcinoma, leiomyosarcoma, stomach cancer, carcinoma, pancreas cancer, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vasoactive intestinal peptide tumors (VIPoma), Kaposi's sarcoma, leiomyoma, hemangioma, neurofibroma, tubular adenoma, villous adenoma, hamartoma, genitourinary tract cancer, Wilm's tumor, nephroblastoma, leukemia, urethra cancer, transitional cell carcinoma, testis cancer, seminoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, interstitial cell carcinoma, fibroadenoma, adenomatoid tumors, hepatoma, hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, gallbladder carcinoma, ampullary carcinoma, bone cancer, osteogenic sarcoma, osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, reticulum cell sarcoma, multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma, osteocartilaginous exostoses, benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, giant cell tumors, nervous system cancer, skull cancer, granuloma, xanthoma, osteitis deformans, meningioma, meningiosarcoma, gliomatosis, brain cancer, astrocytoma, medulloblastoma, glioma, ependymoma, germinoma, pinealoma, glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal cord neurofibroma, neurofibromatosis type 1, gynecological cancer, uterus cancer, endometrial carcinoma, uterine carcinoma, uterine corpus endometrial carcinoma, pretumor cervical dysplasia, ovarian carcinoma, serous cystadenocarcinoma, mucinous cystadenocarcinoma, granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma, intraepithelial carcinoma, clear cell carcinoma, botryoid sarcoma, embryonal rhabdomyosarcoma, fallopian tubes carcinoma, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, myelodysplastic syndrome, Hodgkin's disease, nonHodgkin's lymphoma, malignant melanoma, basal cell carcinoma, moles dysplastic nevi, dermatofibroma, keloids and neuroblastoma.

60. 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 54 or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.

61. The method of claim 60, wherein the target protein is KRAS.

62. The method of claim 60, wherein the target protein is KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D or KRAS Q61H.

63. A method of treating a disease or a disorder dependent upon KRAS in a subject comprising administering to the subject in need thereof, a therapeutically effective amount of a compound according to any one of claims 1 to 54 or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.

64. The method of claim 63, wherein the disease or disorder dependent upon KRAS is a cancer selected from the group consisting of biliary tract malignancies, colon cancer, liver cancer, colorectal cancer, non-small cell lung cancer, small-cell lung cancer, pancreatic cancer, appendiceal cancer, melanoma, acute myeloid leukemia, small bowel cancer, ampullary cancer, germ cell cancer, cervical cancer, cancer of unknown primary origin, endometrial cancer, esophagogastric cancer, GI neuroendocrine cancer, ovarian cancer, sex cord stromal tumor cancer, hepatobiliary cancer, bladder cancer, lung cancer, prostate cancer, breast cancer, cervical carcinomas, testicular carcinomas, gastric cancer, head and neck cancer, hepatocellular cancer, laryngeal cancer, oral cancer, thyroid carcinomas, sarcomas, cardiac cancer, angiosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, teratoma, bronchogenic carcinoma, undifferentiated small cell cancer, adenocarcinoma, alveolar carcinoma, bronchiolar carcinoma, bronchial adenoma, lymphoma, chondromatous hamartoma, mesothelioma, gastrointestinal cancer, squamous cell carcinoma, leiomyosarcoma, stomach cancer, carcinoma, pancreas cancer, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, VIPoma, adenocarcinoma, Kaposi's sarcoma, leiomyoma, hemangioma, neurofibroma, tubular adenoma, villous adenoma, hamartoma, genitourinary tract cancer, Wilm's tumor, nephroblastoma, leukemia, urethra cancer, transitional cell carcinoma, testis cancer, seminoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroadenoma, adenomatoid tumors, hepatoma, hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, hepatocellular adenoma, gall bladder carcinoma, ampullary carcinoma, bone cancer, osteogenic sarcoma, osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, reticulum cell sarcoma, multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma, osteocartilaginous exostoses, benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, giant cell tumors, nervous system cancer, skull cancer, granuloma, xanthoma, osteitis deformans, meningioma, meningiosarcoma, gliomatosis, brain cancer, astrocytoma, medulloblastoma, glioma, ependymoma, germinoma, pinealoma, glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal cord neurofibroma, neurofibromatosis type 1, gynecological cancer, uterus cancer, endometrial carcinoma, uterine carcinoma, uterine corpus endometrial carcinoma, pre-tumor cervical dysplasia, ovarian carcinoma, serous cystadenocarcinoma, mucinous cystadenocarcinoma, granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma, intraepithelial carcinoma, clear cell carcinoma, botryoid sarcoma, embryonal rhabdomyosarcoma, fallopian tubes carcinoma, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma, malignant lymphoma, malignant melanoma, basal cell carcinoma, moles dysplastic nevi, dermatofibroma, keloids and neuroblastoma.

65. The method of claim 64, wherein the cancer is pancreatic cancer.

66. The method of claim 64, wherein the cancer is lung cancer and non-small cell lung cancer.

67. A compound of claims 1 to 54, for use as a medicament.

68. A compound according to any one of claims 1 to 54, for use in the treatment of a disease or disorder dependent upon KRAS, wherein the disease or disorder dependent upon KRAS is a cancer.

69. A compound according to any one of claims 1 to 54, for use in the treatment of a disease or disorder dependent upon KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D or KRAS Q61H.

70. Use of a compound of formula (I) or a pharmaceutical acceptable salt or a stereoisomer or a tautomer thereof according to any one of claims 1 to 54, in the manufacture of a medicament for the treatment of a disease or disorder dependent upon KRAS; wherein the disease or disorder is a cancer selected from the group consisting of biliary tract malignancies, colon cancer, liver cancer, colorectal cancer, non-small cell lung cancer, small-cell lung cancer, pancreatic cancer, appendiceal cancer, melanoma, acute myeloid leukemia, small bowel cancer, ampullary cancer, germ cell cancer, cervical cancer, cancer of unknown primary origin, endometrial cancer, esophagogastric cancer, GI neuroendocrine cancer, ovarian cancer, sex cord stromal tumor cancer, hepatobiliary cancer, bladder cancer, lung cancer, prostate cancer, breast cancer, cervical carcinomas, testicular carcinomas, gastric cancer, head and neck cancer, hepatocellular cancer, laryngeal cancer, oral cancer, thyroid carcinomas, sarcomas, cardiac cancer, angiosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, teratoma, bronchogenic carcinoma, undifferentiated small cell cancer,adenocarcinoma, alveolar carcinoma, bronchiolar carcinoma, bronchial adenoma, lymphoma, chondromatous hamartoma, mesothelioma, gastrointestinal cancer, squamous cell carcinoma, leiomyosarcoma, stomach cancer, carcinoma, pancreas cancer, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, VIPoma, adenocarcinoma, Kaposi's sarcoma, leiomyoma, hemangioma, neurofibroma, tubular adenoma, villous adenoma, hamartoma, genitourinary tract cancer, Wilm's tumor, nephroblastoma, leukemia, urethra cancer, transitional cell carcinoma, testis cancer, seminoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroadenoma, adenomatoid tumors, hepatoma, hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, hepatocellular adenoma, gall bladder carcinoma, ampullary carcinoma, bone cancer, osteogenic sarcoma, osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, reticulum cell sarcoma, multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma, osteocartilaginous exostoses, benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, giant cell tumors, nervous system cancer, skull cancer, granuloma, xanthoma, osteitis deformans, meningioma, meningiosarcoma, gliomatosis, brain cancer, astrocytoma, medulloblastoma, glioma, ependymoma, germinoma, pinealoma, glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal cord neurofibroma, neurofibromatosis type 1, gynecological cancer, uterus cancer, endometrial carcinoma, uterine carcinoma, uterine corpus endometrial carcinoma, pre-tumor cervical dysplasia, ovarian carcinoma, serous cystadenocarcinoma, mucinous cystadenocarcinoma, granulosa- thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma, intraepithelial carcinoma, clear cell carcinoma, botryoid sarcoma, embryonal rhabdomyosarcoma, fallopian tubes carcinoma, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma, malignant melanoma, basal cell carcinoma, moles dysplastic nevi, dermatofibroma, keloids and neuroblastoma.