Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters
[EN ]
PHARMACEUTICAL COMBINATIONS OF SOS1 INHIBITORS FOR TREATING AND/OR PREVENTING CANCER

CROSS-REFERENCE TO RELATED APPLICATIONS

This PCT Application claims priority in and to Indian Provisional Patent Application No. 202121002487 filed January 19, 2021, the contents of which are hereby incorporated by reference herein in their entirety.

FIELD OF INVENTION

The present invention relates to a pharmaceutical combination comprising a SOS1 inhibitor and an additional active ingredient selected from a KRAS inhibitor such as a KRAS G12C inhibitor and a KRASG12D inhibitor, KRAS G13C inhibitor, and panKRAS inhibitor; an EGFR inhibitor; an ERK1/2 inhibitor; a BRAF inhibitor; a pan-RAF inhibitor; a MEK inhibitor; a AKT inhibitor; a SHP2 inhibitor; protein arginine methyltransferases (PRMTs) inhibitor such as a PRMT5 inhibitor and Type 1 PRMT inhibitor; a PI3K inhibitor; a cyclin-dependent kinase (CDK) inhibitor such as CDK4/6 inhibitor; a FGFR inhibitor; a c-Met inhibitor; a RTK inhibitor; a non-receptor tyrosine kinase inhibitor; a histone methyltransferases (HMTs) inhibitor; a DNA methyltransferases (DNMTs) inhibitor; a Focal Adhesion Kinase (FAK) inhibitor; a Bcr-Abl tyrosine kinase inhibitor; a mTOR inhibitor; a PD1 inhibitor; a PD-E1 inhibitor; CTEA4 inhibitor; and chemotherapeutic agents such as gemcitabine, doxorubicin, cisplatin, carboplatin, paclitaxel, docetaxel, topotecan, irinotecan and temozolomide; wherein, the SOS1 inhibitor is selected from compound of formula (I) or compound of formula (II),

their tautomeric form, their stereoisomers, their pharmaceutically acceptable salt, their polymorph, or solvate thereof, for use in the treatment and/or prevention of cancer.

The present invention also relates to the treatment and/or prevention of cancer using a pharmaceutical combination as described hereinabove.

BACKGROUND OF THE INVENTION

Multiple signaling pathways control the initiation, progression, spread, metastasis, immune evasion of cancer. Key signaling pathways include RTK/RAS pathway, PI3K pathway, Wnt pathway, Myc pathway and the cell cycle pathway (Francisco Sanchez-Vega et al., Cell, 2018, 173(2):321-337.el0). RAS-family proteins (KRAS, HRAS and NRAs and their respective mutants) are small GTPases that exist in cells in either GTP-bound (active) or GDP-bound (inactive) states (Siqi Li et al., Nat. Rev. Cancer, 2018, 18(12):767-777). The activity of RAS proteins is modulated by proteins known as GTPase Activating Proteins (GAPs) or Guanine Nucleotide Exchange Factors (GEFs).

The GAP proteins belonging to the RAS family include members such as NF1, TSC2, IQGAP1, etc. which activate the GTPase function of the RAS proteins and thus terminate the signaling by catalyzing the hydrolysis of GTP to GDP. In contrast, the RAS family GEFs include proteins such as SOS1, SOS2, RASGRP, RASGRF2, etc.

which activate the RAS proteins by exchanging GTP for GDP (Biochim Biophys Acta Rev Cancer. 2020, 1874(2):188445; Johannes L. Bos et al., Cell, 2007, 129(5):865-77). SOS proteins has been implicated in the regulation of RAS in multiple cancers, with more impetus on the role of targeting SOS1 for cancer therapy.

Ras-GTP binds to effector proteins such as Raf and PI3K which in turn leads to activation of the RAF-MEK-ERK (MAPK) and PI3K-mT0R-AKT (PI3K) signaling pathways (Suzanne Schubbert et al., Nat. Rev. Cancer, 2007, 7(4):295-308). Triggering of one or more of these cellular signaling pathways leads to the initiation and maintenance of the oncogenic phenotype involving enhanced cell proliferation, increased cell survival, altered metabolism, angiogenesis, migratory potential and immune evasion eventually leading to establishment and metastasis of cancers (Yousef Ahmed Fouad et al., Am. J. Cancer Res., 2017 7(5): 1016-1036; Douglas Hanahan et al., Cell, 2011, 144(5):646-74). RAS proteins undergo point mutations at several amino acid residues - the key hot spots being positions G12, G13 and Q61. These mutations render the RAS proteins constitutively active since the proteins are predominantly in the active GTP -bound form (Ian A. Prior et al., Cancer Res., 2012, 72(10): 2457-2467; Adrienne D. Cox, et al., Nat. Rev. Drug. Discov., 2014, 13(11):828-51). Interaction of RAS proteins with GEFs such as Son of Sevenless 1 (SOS1) plays a crucial role in relaying the signals to downstream effectors. The SOS1 protein harbors several domains such as the Dbl homology domain (DH), a Pleckstrin homology domain (PH), RAS exchanger motif (REM), CDC25 homology domain and a C -terminal proline rich domain (PxxP) (Pradeep Bandaru et al., Cold Spring Harb Perspect Med., 2019, 9(2). pii:a031534). SOS1 has been shown to have a catalytic site as well as an allosteric site. The catalytic site is preferentially bound by RAS-GDP whereas RAS-GTP binds with the allosteric site with better affinity than RAS-GDP (S. Mariana Margarit et al., Cell, 2003, 112(5):685-95; Hao-Hsuan Jeng et al., Nat. Commun., 2012; 3:1168). Furthermore, binding of oncogenic KRAS to SOS1 promotes the activation of wild type HRAS and NRAS (Hao-Hsuan Jeng et al., Nat. Commun., 2012;3: 1168). The

catalytic (guanine nucleotide exchange) function of SOS1 is critical for KRAS oncogenic activity in cancer cells (You X et al., Blood. 2018, 132(24):2575-2579; Erin Sheffels et al., Sci Signal. 2018, 11(546). pii: eaar8371). SOS1 plays a key role in signal transmission following cellular activation by Receptor Tyrosine Kinases (RTKs) (Frank McCormick et al., Nature, 1993, 363(6424):45-51; Stephane Pierre et al., Biochem Pharmacol. 2011 82(9): 1049-56). Additionally, SOS 1 is required for function of receptors on lymphocytes (B cell and T cell receptor) (Mateusz Poltorak et al., Eur J Immunol. 2014, 44(5): 1535-40; Stephen R. Brooks et al., J Immunol. 2000, 164(6):3123-31) and hematopoietic cells (Mario N. Lioubin et al., Mol Cell Biol., 1994, 14(9):5682-91).

The role of SOS1 in the RAS-mediated signaling pathways make it an attractive target for cancer therapy. Pharmacological intervention with SOS1 inhibitors has been shown to attenuate or eliminate the downstream effector events of the RAS-mediated pathways (Roman C. Hillig et al., Proc. Natl. Acad. Sci. U S A. 2019, 116(7):2551-2560; Chris R. Evelyn et al., J Biol Chem., 2015, 290(20): 12879-98).

Furthermore, alterations in SOS1 have been implicated in cancer. SOS1 mutations are found in embryonal rhabdomyosarcomas, sertoli cell testis tumors, granular cell tumors of the skin (Denayer et al. Genes Chromosomes Cancer, 2010, 49(3):242-52) and lung adenocarcinoma (Cancer Genome Atlas Research Network., Nature. 2014,511 (7511):543-50). Meanwhile over-expression of SOS1 has been described in bladder cancer (Watanabe at al. IUBMB Life., 2000, 49(4):317-20) and prostate cancer (Timofeeva et al. Int. J. Oncol., 2009, 35(4):751-60). In addition to cancer, hereditary SOS1 mutations are implicated in the pathogenesis of RASopathies like e.g. Noonan syndrome (NS), cardio-facio-cutaneous syndrome (CFC), hereditary gingival fibromatosis type 1 Noonan Syndrome with Multiple Lentigines (NSML) (LEOPARD syndrome), Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM), Costello Syndrome (CS), Legius Syndrome (NFl-like Syndrome) (Pierre et al., Biochem. Pharmacol., 2011, 82(9): 1049-56).

Pharmaceutical combinations of S0S1 inhibitors are disclosed in WO2018115380, WO2020254451, WO2021259972, Marco H H. et al., Cancer Discov. 2021, 11(1): 142-157

SUMMARY OF THE INVENTION

The invention described and claimed herein has many attributes and aspects, including but not limited to, those set forth or described or referenced in this summary. It is not intended to be all-inclusive and the invention described and claimed herein are not limited to or by features or embodiments identified in this summary, which is included for purposes of illustration only and not restriction.

In consideration above problems, in accordance with the one aspect disclosed herein, the present invention relates to a pharmaceutical combination comprising a SOS1 inhibitor and at least one additional active ingredient selected from a KRAS inhibitor such as a KRAS G12C inhibitor and a KRAS G12D inhibitor, KRAS G13C inhibitor, and panKRAS inhibitor; an EGFR inhibitor; an ERK1/2 inhibitor; a BRAF inhibitor; a pan-RAF inhibitor; a MEK inhibitor; a AKT inhibitor; a SHP2 inhibitor; protein arginine methyltransferases (PRMTs) inhibitor such as a PRMT5 inhibitor and Type 1 PRMT inhibitor; a PI3K inhibitor; a cyclin-dependent kinase (CDK) inhibitor such as CDK4/6 inhibitor; a FGFR inhibitor; a c-Met inhibitor; a RTK inhibitor; a non-receptor tyrosine kinase inhibitor; a histone methyltransferases (HMTs) inhibitor; a DNA methyltransferases (DNMTs) inhibitor; a Focal Adhesion Kinase (FAK) inhibitor; a Bcr-Abl tyrosine kinase inhibitor; a mTOR inhibitor; a PD1 inhibitor; a PD-E1 inhibitor; CTEA4 inhibitor; and chemotherapeutic agents such as gemcitabine, doxorubicin, cisplatin, carboplatin, paclitaxel, docetaxel, topotecan, irinotecan and temozolomide; wherein the SOS1 inhibitor is selected from compound of formula (I) or formula (II),

their tautomeric form, their stereoisomer, their pharmaceutically acceptable salt, their polymorph, or solvate thereof, for use in the treatment and/or prevention of cancer.

R1, R2, R3, R4, R5, Ring A, Ring B, m, n, X, Y are described herein below respectively for each compound.

In accordance with another aspect disclosed herein, the SOS1 inhibitor compound is administered simultaneously, concurrently, sequentially, successively, alternately, or separately with the at least one additional active ingredient.

In accordance with yet another aspect disclosed herein, a method of treating and/or preventing cancer, wherein the method comprises administering to the subject in need the pharmaceutical combination of any one of the pharmaceutical combinations disclosed herein.

In accordance with other aspect disclosed herein, the cancer is selected from glioblastoma multiforme, prostate cancer, pancreatic cancer, mantle cell lymphoma, non-Hodgkin's lymphomas and diffuse large B-cell lymphoma, acute myeloid leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, multiple myeloma, non-small cell lung cancer, small cell lung cancer, breast cancer, triple negative breast cancer, gastric cancer, colorectal cancer, ovarian cancer, bladder cancer, hepatocellular cancer, melanoma, sarcoma, oropharyngeal squamous cell

carcinoma, chronic myelogenous leukemia, epidermal squamous cell carcinoma, nasopharyngeal carcinoma, neuroblastoma, endometrial carcinoma, head and neck cancer, cervical cancer, cancers harboring overexpression, amplification of wild type KRAS, NRAS or HRAS, cancers having amplification, overexpression or mutation of KRAS, NRAS, or HRAS, cancers harboring KRAS mutations such as G12C, G12D, G12V, G12S, G12A, G12R, G12F, G12W, G13C, G13D, GBR, G13V, G13S, G13A, Q61H, Q61R, Q61P, Q61E, Q61K, Q61L, A59S, A59T, R68M, R68S, Q99L, M72I, H95D, H95Q, H95R, Y96D, Y96S, Y96C, cancers harboring NRAS mutations such G12A, G12V, G12D, G12C, G12S, G12R, G13V, G13D, GBR, G13S, G13C, G13A, Q61K, Q61L, Q61H, Q61P, Q61R, A146T, A 146V, cancers harboring HRAS mutations such as G12C, G12V, G12S, G12A, G12R, G12F, G12D, G13C, G13D, GBR, G13V, G13S, G13A, Q61K, Q61L, Q61H, Q61P, Q61R.

BRIEF DESCRIPTION OF FIGURES

The drawing form part of the present specification and are included to further demonstrate certain aspects of embodiments described herein. These embodiments may be better understood by reference to one or more of the following drawings in combination with detailed description.

FIG. 1 shows the in vitro inhibition effect of a representative combination of the invention, Compound 4b with KRAS G12C inhibitor AMG510, in MIA PaCa-2 cells.

FIG. 2 shows the in vitro inhibition effect of a representative combination of the invention, Compound 4b with EGFR inhibitor Afatinib, in MIA PaCa-2 cells.

FIG. 3 shows the in vitro inhibition effect of a representative combination of the invention, Compound 4b with ERK1/2 inhibitor LY3214996, in MIA PaCa-2 cells.

FIG. 4 shows the in vitro inhibition effect of a representative combination of the invention, Compound 4b with ERK1/2 inhibitor BVD-523, in MIA PaCa-2 cells.

FIG. 5 shows the in vitro inhibition effect of a representative combination of the invention, Compound 4b with RAF inhibitor Encorafenib, in MIA PaCa-2 cells.

FIG. 6 shows the in vitro inhibition effect of a representative combination of the invention, Compound 4b with PRMT5 inhibitor Compound 24 of WO 2019116302, in MIA PaCa-2 cells.

FIG. 7 shows the in vitro inhibition effect of a representative combination of the invention, Compound 1 with EGFR inhibitor Afatinib, in MIA PaCa-2 cells.

FIG. 8 shows the in vitro inhibition effect of a representative combination of the invention, Compound 1 with KRAS G12C inhibitor AMG510, in MIA PaCa-2 cells.

FIG. 9 shows the in vitro inhibition effect of a representative combination of the invention, Compound 1 with ERK1/2 inhibitor LY3214996, in MIA PaCa-2 cells.

FIG. 10 shows the in vitro inhibition effect of a representative combination of the invention, Compound 1 with ERK1/2 inhibitor BVD-523, in MIA PaCa-2 cells.

FIG. 11 shows the in vitro inhibition effect of a representative combination of the invention, Compound 1 with RAF inhibitor Encorafenib, in MIA PaCa-2 cells.

FIG. 12 shows the in vitro inhibition effect of a representative combination of the invention, Compound 1 with PRMT5 inhibitor Compound 24 of WO 2019116302 , in MIA PaCa-2 cells.

FIG. 13 shows the in vitro inhibition effect of a representative combination of the invention, Compound 6a with EGFR inhibitor Afatinib, in MIA PaCa-2 cells.

FIG. 14 shows the in vitro inhibition effect of a representative combination of the invention, Compound 6a with KRAS G12C inhibitor AMG510, in MIA PaCa-2 cells.

FIG. 15 shows the in vitro inhibition effect of a representative combination of the invention, Compound 6a with ERK1/2 inhibitor LY3214996, in MIA PaCa-2 cells.

FIG. 16 shows the in vitro inhibition effect of a representative combination of the invention, Compound 6a with ERK1/2 inhibitor BVD-523, in MIA PaCa-2 cells.

FIG. 17 shows the in vitro inhibition effect of a representative combination of the invention, Compound 5 with ERK1/2 inhibitor BVD-523, in MIA PaCa-2 cells.

FIG. 18 shows the in vitro inhibition effect of a representative combination of the invention, Compound 5 with ERK1/2 inhibitor LY3214996, in MIA PaCa-2 cells.

FIG. 19 shows the in vitro inhibition effect of a representative combination of the invention, Compound 5 with EGFR inhibitor Afatinib, in MIA PaCa-2 cells.

FIG. 20 shows the in vitro inhibition effect of a representative combination of the invention, Compound 5 with KRAS G12C inhibitor AMG510, in MIA PaCa-2 cells.

FIG. 21 shows the in vitro inhibition effect of a representative combination of the invention, Compound 5 with Compound 24 of WO 2019116302, in MIA PaCa-2 cells.

FIG. 22 shows the in vitro inhibition effect of a representative combination of the invention, Compound 2 with KRAS G12C inhibitor AMG510, in MIA PaCa-2 cells.

FIG. 23 shows the in vitro inhibition effect of a representative combination of the invention, Compound 3a with KRAS G12C inhibitor AMG510, in MIA PaCa-2 cells.

FIG. 24 shows the in vitro inhibition effect of a representative combination of the invention, Compound 3a with ERK1/2 inhibitor LY3214996, in MIA PaCa-2 cells.

FIG. 25 shows the in vitro inhibition effect of a representative combination of the invention, Compound 3a with RAF inhibitor Encorafenib, in MIA PaCa-2 cells.

FIG. 26 shows the in vitro inhibition effect of a representative combination of the invention, Compound 4b with pan-RAF inhibitor LXH254, in MIA PaCa-2 cells.

FIG. 27 shows the in vitro inhibition effect of a representative combination of the invention, Compound 4b with SHP2 inhibitor TNO155, in MIA PaCa-2 cells.

FIG. 28 shows the in vitro inhibition effect of a representative combination of the invention, Compound 7 with KRAS G12C inhibitor AMG510, in MIA PaCa-2 cells.

FIG. 29 shows the in vitro inhibition effect of a representative combination of the invention, Compound 7 with EGFR inhibitor Afatinib, in MIA PaCa-2 cells.

FIG. 30 shows the in vitro inhibition effect of a representative combination of the invention, Compound 7 with ERK1/2 inhibitor LY3214996, in MIA PaCa-2 cells.

FIG. 31 shows the in vitro inhibition effect of a representative combination of the invention, Compound 7 with ERK1/2 inhibitor BVD-523, in MIA PaCa-2 cells.

FIG. 32 shows the in vitro inhibition effect of a representative combination of the invention, Compound 7 with RAF inhibitor Encorafenib, in MIA PaCa-2 cells.

FIG. 33 shows the in vitro inhibition effect of a representative combination of the invention, Compound 7 with pan-RAF inhibitor LXH254, in MIA PaCa-2 cells.

FIG. 34 shows the in vitro inhibition effect of a representative combination of the invention, Compound 7 with SHP2 inhibitor TNO155, in MIA PaCa-2 cells.

FIG. 35 shows the in vitro inhibition effect of a representative combination of the invention, Compound 7 with KRAS G12C inhibitor MRTX849, in MIA PaCa-2 cells.

FIG. 36 shows the in vitro inhibition effect of a representative combination of the invention, Compound 7 with PI3K inhibitor BYL-719 in MIA PaCa-2 cells.

FIG. 37 shows the in vitro inhibition effect of a representative combination of the invention, Compound 7 with Type I PRMT inhibitor GSK3368715 in MIA PaCa-2 cells.

FIG. 38 shows the in vitro inhibition effect of a representative combination of the invention, Compound 7 with FGFR inhibitor Nintedanib in MIA PaCa-2 cells.

FIG. 39 shows the in vitro inhibition effect of a representative combination of the invention, Compound 7 with CDK4/6 inhibitor Abemaciclib in MIA PaCa-2 cells.

FIG. 40 shows the in vitro inhibition effect of a representative combination of the invention, Compound 7 with MRTX1133 in SW-1990 cells.

FIG. 41 shows the in vitro inhibition effect of a representative combination of the invention, Compound 7 with Gemcitabine in MIA PaCa-2 cells.

DETAILED DESCRIPTION OF INVENTION

RAS mutated cancers continue to be dependent on upstream regulators like SOS1 for uninterrupted downstream oncogenic signaling (Bivona T. G., Science. 2019, 363(6433):1280-1281). Thus, concomitant inhibition of SOS1 and RAS may lead to sustained inhibition of the cancer growth signaling pathway resulting in more effective anticancer activity. The KRAS inhibitors that can be used along with SOS1 inhibitors include KRAS-G12C inhibitors (AMG 510, MRTX849 or any other agent that inhibits KRAS-G12C activity) or Pan KRAS inhibitors (inhibiting G12D, G12V, G12S, etc) like BI-2852 (Kessler, Dirk et al., PNAS., 2019, 116(32):15823-15829.). SOS1 is required for 3D spheroid growth of EGFR mutated NSCLC cells. Combined EGFR-and SOS 1 -inhibition markedly inhibited Raf/MEK/ERK and PI3K/AKT signaling and demonstrated strong synergy in mitigating RAS effector signaling (Theard, P. L. et al., eLife, 2020, 9:e58204). SOS1 is positioned proximal to RAS and RAF as downstream effector of RAS in the RAS/RAF/MEK/ERK pathway. Current approved RAF inhibitors, as single agent, demonstrate only modest efficacy in the clinic, and have rapid emergence of resistance (Packer, L.M. et al., Pigment Cell Melanoma Res. 2009, 22, 785-798; Saei, Azad et al., Cancers, 2019, 11(8), 1176). Thus, combination with a proximal regulator of the pathway, like SOS1, is expected to have more effective and sustained anticancer activity. ERK is a kinase positioned downstream in the RAS/RAF/MEK/ERK pathway. Activated ERK triggers the negative-feedback loop formed by inactivation of the Ras activating exchange factor complex Grb2-SOS by SOS1 phosphorylation and inactivation (Sung-Young Shin et al., Journal of Cell Science, 2009, 122(3), 425-435). Phosphatidylinositol 3-kinase (PI3K) is one of the main effector pathways of RAS, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism, and cancer. (Castellano, E. et al., Genes & Cancer, 2011, 2(3):261-74). PI3K mutations that hinder its interaction with RAS are highly resistant to RAS induced mutagenesis. Thus, combination of proximal regulator of RAS pathway, SOS1 with PI3K inhibitors is expected to have enhanced antitumor activity. AKT is an essential downstream effector of the PI3K pathway, having intersection with RAS/RAF pathway during oncogenic signaling. Combination of SOS1 and AKT inhibitors should interfere with both RAS/RAF and PI3K7AKT pathway and thus result in more complete and sustained tumor growth inhibition, c-MET activation stimulates the activity of the RAS guanine nucleotide exchanger son of sevenless (SOS) via binding with SHC and GRB2. This leads to leading to the activation of RAS/RAF/MEK/ERK pathway responsible for regulating a large number

of genes, including those involved in cell proliferation, cell motility and cell cycle progression (Organ, S. L. et al., Ther Adv Med Oncol. 2011,3(1 Suppl):S7-S19). Thus, combined inhibition of c-MET and SOS 1 is expected to have enhanced antitumor effect as compared to indididual treatment. The c-Met inhibitors that can be used along with SOS1 inhibitors include Tivantinib, Cabozantinib, Crizotinib, Capmatinib or antibodies targeting c-Met. SOS1 has also been implicated in hematological malignancies such as CML (Leukemia (2018) 32, 820-827). Combined treatment of CML cells with Brc-Abl kinase inhibitors along with SOS1 inhibitor provides a special opportunity to target both sensitive and resistant versions of CML. Recent reports indicate the emergence of acquired resistance to KRAS -targeted therapies and targeting SOS1 offers a possibility to overcome this resistance (NPJ Precis Oncol. 2021,5(l):98; Sci Signal. 2019,12(583):eaaw9450; J Thorac Oncol. 2021,16(8): 1321-1332).

SOS1 inhibitors can be used in combination with other therapies such as radiation, chemotherapy and/or treatment with a other targeted agents in multiple cancers and their subtypes as mentioned above. The agents that can be used for combination therapy are a KRAS inhibitor such as a KRAS G12C inhibitor and a KRAS G12D inhibitor, KRAS G13C inhibitor, and panKRAS inhibitor; an EGPR inhibitor; an ERK1/2 inhibitor; a BRAE inhibitor; a pan-RAF inhibitor; a MEK inhibitor; a AKT inhibitor; a SHP2 inhibitor; protein arginine methyltransferases (PRMTs) inhibitor such as a PRMT5 inhibitor and Type 1 PRMT inhibitor; a PI3K inhibitor; a cyclin -dependent kinase (CDK) inhibitor such as CDK4/6 inhibitor; a FGFR inhibitor; a c-Met inhibitor; a RTK inhibitor; a non-receptor tyrosine kinase inhibitor; a histone methyltransferases (HMTs) inhibitor; a DNA methyltransferases (DNMTs) inhibitor; a Focal Adhesion Kinase (FAK) inhibitor; a Bcr-Abl tyrosine kinase inhibitor; a mTOR inhibitor; a PD1 inhibitor; a PD-L1 inhibitor; CTLA4 inhibitor; and chemotherapeutic agents such as gemcitabine, doxorubicin, cisplatin, carboplatin, paclitaxel, docetaxel, topotecan, irinotecan and temozolomide.

The KRAS inhibitors that can be used along with S0S1 inhibitors include KRAS-G12C inhibitors such as AMG 510, MRTX849, JDQ443, LY-3537982, JNJ-74699157, JAB-21822, GDC-6036, MK-1084, ZG-19018, D-1553, YL-15293, ICP-915, BI-1823911, BEBT-607, ERAS-3490, BPI-421286, JMX-1899 or KRAS-G12D inhibitors such as MRTX1133 or agents inhibiting multiple oncogenic RAS mutants such as BI-2852 (PNAS 2019; 116:32, 15823-15829), or KRAS G13C inhibitor (as disclosed in the US patent Application 20210130326A1 and US patent Application 20210130369A1), panRAS inhibitors (as disclosed in the US patent Application 20210130326A1 and US patent Application 20210130369A1).

The EGFR inhibitors that can be used along with SOS1 inhibitors include Afatinib, Osimertinib, Erlotinib or Gefitinib or any other agent that inhibits activity of the enzymes EGFR or its oncogenic variants.

The ERK inhibitors that can be used along with SOS1 inhibitors include BVD-523 (Ulixertinib), LY3214996, ASTX029, MK-8353 or ravoxertinib or any other agent that inhibits activity of the ERK 1/2 kinases.

The BRAF inhibitors that can be used along with SOS1 inhibitors include Dabrafenib, Regorafenib, Encorafenib or pan-RAF inhibitors such as LXH254 or any other agent that inhibits activity of the RAF isoforms (ARAF, BRAF and CRAF).

The AKT inhibitors that can be used along with SOS1 inhibitors include GSK690693, AZD5363, Ipatasertib or any other agent that inhibits the activity of one or more AKT isoforms (1, 2 and 3).

The SHP2 inhibitors that can be used along with SOS1 inhibitors include TNG 155, JAB-3068, RMC-4630 or REY-1971 or any other agent that inhibits activity of the SHP2 phosphatase.

The PRMT inhibitors that can be used along with S0S1 inhibitors include JNJ-64619178, PF-06939999, GSK-3326595, PRT543, PRT811, MS023, GSK3368715, Type I PRMT inhibitors or Compound 24 of WO 2019116302 or any other agent that inhibits the activity of PRMT methyltransferases.

SOS1 inhibitors also have the potential to target cancers with class III BRAF mutation (Clin Cancer Res 2019, 25(23), 6896). This includes cancers such as NSCLC, CRC and melanoma (Nature 2017, 548, 234-238).

The PI3K inhibitors that can be used along with SOS1 inhibitors include Alpelisib (BYL719), Copanlisib, Duvelisib, BEZ-235, Gedatolisib, Buparlisib or agents that inhibits the activity of one or more PI3K isoforms (a, 0, 5 and y) or PI3K-mT0R dual inhibitors.

The CDK4/6 inhibitors that can be used along with SOS1 inhibitor is Abemaciclib or any other agent that inhibits activity of the CDK.

The FGFR inhibitors that can be used along with SOS1 inhibitors include Nintedanib, Dovitinib, AZD4547, BGJ398, JNJ 42756493 or any other agent that inhibits the activity of FGFR isoforms (1, 2, 3 and 4).

The c-Met inhibitors that can be used along with SOS1 inhibitors include Tivantinib, Cabozantinib, Crizotinib, Capmatinib or antibodies targeting c-Met.

SOS1 inhibitors can be combined with Bcr-Abl inhibitors that target CML. Examples of such agents include imatinib, dasatinib, nilotinib, ponatinib, etc.

S0S1 inhibitors also have the potential to be combined with immune-oncological (IO) agents such as PD1 inhibitor (Pembrolizumab, Nivolumab), PD-L1 inhibitor (Atezolizumab, Avelumab), CTLA4 inhibitor (Ipilimumab), etc.

The chemotherapeutic agents that can be used along with SOS1 inhibitors include gemcitabine, topotecan, irinotecan, paclitaxel, cisplatin, carboplatin, doxorubicin or any other agent that is classified as chemotherapeutic.

SOS1 is involved in progression of Chronic Myelogenous leukemia (Leukemia 2018, volume 32, 820-827; Science. 2015; 350(6264): 1096-1101) and KRAS-G12D-mediated leukemogenesis (Blood. 2018,;132(24):2575-2579).

Present invention relates to a pharmaceutical combination for treating and/or preventing cancer comprising a SOS1 inhibitor of formula (I) or formula (II), its stereoisomer, or its pharmaceutical acceptable salt, and at least one additional active ingredient selected from a a KRAS inhibitor such as a KRAS G12C inhibitor and a KRASG12D inhibitor, KRAS G13C inhibitor, and panKRAS inhibitor; an EGFR inhibitor; an ERK1/2 inhibitor; a BRAF inhibitor; a pan-RAF inhibitor; a MEK inhibitor; a AKT inhibitor; a SHP2 inhibitor; protein arginine methyltransferases (PRMTs) inhibitor such as a PRMT5 inhibitor and Type 1 PRMT inhibitor; a PI3K inhibitor; a cyclin-dependent kinase (CDK) inhibitor such as CDK4/6 inhibitor; a FGFR inhibitor; a c-Met inhibitor; a RTK inhibitor; a non-receptor tyrosine kinase inhibitor; a histone methyltransferases (HMTs) inhibitor; a DNA methyltransferases (DNMTs) inhibitor; a Focal Adhesion Kinase (FAK) inhibitor; a Bcr-Abl tyrosine kinase inhibitor; a mTOR inhibitor; a PD1 inhibitor; a PD-E1 inhibitor; CTEA4 inhibitor; and chemotherapeutic agents such as gemcitabine, doxorubicin, cisplatin, carboplatin, paclitaxel, docetaxel, topotecan, irinotecan and temozolomide; wherein the SOS1 inhibitor of formula (I) is,

its tautomeric form, its stereoisomers, its pharmaceutically acceptable salt, their polymorph, and solvate thereof,

Wherein,

Ring A is selected from aryl, heteroaryl, and heterocyclyl;

Ring B is selected from substituted or unsubstituted 5 or 6 membered carbocyclic ring and substituted or unsubstituted 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from S, O, and N;

When ring B is carbocyclic ring, it is substituted with 1 to 8 substituents independently selected from Rc and Rd;

when ring B is heterocyclic ring, it is substituted with 1 to 7 substituents; when it is substituted on a ring nitrogen atom, it is substituted with substituents selected from Ra and Rb; and when it is substituted on a ring carbon atom, it is substituted with substituents selected from Rc and Rd;

Ra and Rb are independently selected from hydrogen, -C(=O)Rg, -C(=O)NRh(R1), substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl;

Rc and Rd are independently selected from hydrogen, halogen, oxo, -C(=O)Rg, -NRh(R1)C(=O)NRh(R1), -OR', substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl; optionally Rc and Rd groups together with the carbon atom which they are attached forming a substituted or unsubstituted carbocyclic ring and substituted or unsubstituted heterocycle;

R1 is selected from hydrogen, substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl

R2 and R3 are independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl;

R4 is selected from halogen, cyano, -NReRf, -OR\ -C(=O)Rg, -C(=O)NRh(R‘), substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, cycloalkyl substituted with substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, and heterocyclyl substituted with substituted alkyl;

Re and Rf are independently selected from hydrogen, -C(=O)Rg, -C(=O)NRh(R‘), substituted or unsubstituted alkyl, alkyl substituted with substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl;

Rg is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl;

Rh and R' are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl; optionally Rh and R1 groups together with the nitrogen atom to which they are attached forming a substituted or unsubstituted heterocycle;

RJ is selected from hydrogen, substituted or unsubstituted alkyl, alkyl substituted with substituted or unsubstituted cycloalkyl, and substituted or unsubstituted cycloalkyl;

‘n’ is an integer selected from 0, 1, 2, and 3;

when an alkyl group is substituted, it is substituted with 1 to 5 substituents independently selected from oxo (=0), halogen, cyano, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR5, -C(=O)OH, -C(=O)O(alkyl), -NR6R6a, - NR6C(=O)R7, and -C(=O)NR6R6a;

when an cycloalkyl group is substituted, it is substituted with 1 to 4 substituents independently selected from oxo (=0), halogen, alkyl, hydroxyalkyl, cyano, aryl, heteroaryl, heterocyclyl, -OR5, -C(=0)0H, - C(=O)O(alkyl), -NR6R6a, -NR6C(=O)R7, and -C(=O)NR6R6a;

when the aryl group is substituted, it is substituted with 1 to 4 substituents independently selected from halogen, nitro, cyano, alkyl, perhaloalkyl, cycloalkyl, heterocyclyl, heteroaryl, -OR5, -NR6R6a, -NR6C(=O)R7, - C(=0)R7, -C(=O)NR6R6a, -S02-alkyl, -C(=0)0H, -C(=O)O-alkyl, and haloalkyl;

when the heteroaryl group is substituted, it is substituted with 1 to 4 substituents independently selected from halogen, nitro, cyano, alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR5, -NR6R6a, -NR5C(=O)R7, -C(=0)R7, -C(=O)NR6R6a, -S02-alkyl, -C(=0)0H, and -C(=O)O-alkyl;

when the heterocycle group is substituted, it is substituted either on a ring carbon atom or on a ring hetero atom, and when it is substituted on a ring carbon atom, it is substituted with 1 to 4 substituents independently selected from oxo (=0), halogen, cyano, alkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl, perhaloalkyl, -OR5, -C(=O)NR6R6a, -C(=0)0H, -C(=O)O-alkyl, -N(H)C(=O)(alkyl), -N(H)R6, and -N(alkyl)2; and when the heterocycle group is substituted on a ring nitrogen, it is substituted with substituents independently selected from alkyl, cycloalkyl, aryl,

heteroaryl, -SO2(alkyl), -C(=O)R7, and -C(=O)O(alkyl); when the heterocycle group is substituted on a ring sulfur, it is substituted with 1 or 2 oxo (=0) group(s);

R5 is selected from hydrogen, alkyl, perhaloalkyl, and cycloalkyl;

R6 and R6a are each independently selected from hydrogen, alkyl, and cycloalkyl; or R6 and R6a together with nitrogen to which they are attached form a heterocyclyl ring; and

R7 is selected from alkyl and cycloalkyl;

and wherein the S0S1 inhibitor of formula (II) is,

its tautomeric form, its stereoisomer, its pharmaceutical acceptable salt, its polymorph, or solvate thereof,

wherein

Ring A is selected from aryl, heteroaryl, and heterocyclyl;

‘ ’ is either a single bond or double bond;

X and Y are independently selected from C, O, and NRc, provided that both X and Y cannot be O at the same time;

R1 is selected from hydrogen and substituted or unsubstituted alkyl;

R2 is selected from hydrogen, halogen, alkyl, and cycloalkyl;

R3 is selected from -OR6, -NRaRb, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, alkyl substituted with substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl;

R4 is selected from oxo and substituted or unsubstituted alkyl;

R5 is selected from halogen, cyano, -NRcRd, substituted or unsubstituted alkyl, -C(=O) substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; optionally two R5 groups attached to the adjacent carbon atoms forming substituted or unsubstituted heterocycle;

R6 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl, 5 and alkyl substituted with substituted heterocyclyl;

Ra and Rb are independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted heterocyclyl;

Rc and Rd are independently selected from hydrogen and alkyl;

m is an integer selected from 0, 1, 2, and 3;

n is an integer selected from 0, 1, 2, 3, and 4;

when an alkyl group is substituted, it is substituted with 1 to 5 substituents independently selected from oxo (=0), halogen, cyano, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR7, -C(=O)OH, -C(=O)O(alkyl), -NR8R8a, -NR8C(=O)R9, and -C(=O)NR8R8a;

when an cycloalkyl group is substituted, it is substituted with 1 to 4 substituents independently selected from oxo (=0), halogen, alkyl, hydroxyalkyl, cyano, aryl, heteroaryl, heterocyclyl, -OR7, -C(=0)0H, -C(=O)O(alkyl), -NR8R8a, -NR8C(=O)R9,

and -C(=O)NR8R8a aryl, heteroaryl, -OR7, -NR8R8a, -NR7C(=O)R9, -C(=O)R9, -C(=O)NR8R8a, -SO2-alkyl, -C(=O)OH, and -C(=O)O-alkyl;

when the aryl group is substituted, it is substituted with 1 to 4 substituents independently selected from halogen, nitro, cyano, alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocyclyl, heteroaryl, -OR7, -NR8R8a, -NR8C(=O)R9, -C(=O)R9, -C(=O)NR8R8a, -SO2-alkyl, -C(=O)OH, and -C(=O)O-alkyl;

when the heteroaryl group is substituted, it is substituted with 1 to 4 substituents independently selected from halogen, nitro, cyano, alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR7, -NR8R8a, -NR7C(=O)R9, -C(=O)R9, -C(=O)NR8R8a, -SO2-alkyl, -C(=O)OH, and -C(=O)O-alkyl;

when the heterocycle group is substituted, it is substituted either on a ring carbon atom or on a ring hetero atom, and when it is substituted on a ring carbon atom, it is substituted with 1 to 4 substituents independently selected from oxo (=0), halogen, cyano, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl, perhaloalkyl, -OR7, -C(=O)NR8R8a, -C(=0)0H, -C(=O)O-alkyl, -N(H)C(=O)(alkyl), -N(H)R8, and -N(alkyl)2; and when the heterocycle group is substituted on a ring nitrogen, it is substituted with substituents independently selected from alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, -SO2(alkyl), -C(=0)R9, and -C(=O)O(alkyl); when the heterocycle group is substituted on a ring sulfur, it is substituted with 1 or 2 oxo (=0) group(s);

R7 is selected from hydrogen, alkyl, perhaloalkyl, and cycloalkyl;

R8 and R8a are each independently selected from hydrogen, alkyl, and cycloalkyl; and

R9 is selected from alkyl and cycloalkyl.

In accordance with another aspect the invention compound 1 of the Pharmaceutical combination of the present invention is selected from the group consisting of:

(R)-4-((l-(3-(l,l-Difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,6,8,8-tetramethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 1);

(R/S)-4-(( 1 -(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)phenyl)ethyl)amino)-2, 6,8,8-tetramethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 2);

4-(((R)-l-(3-((R&S)-l,l-Difluoro-2,3-dihydroxy-2-methylpropyl)-2-fluorophenyl) ethyl)amino)-2,6,8,8-tetramethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 3);

4-(((R)- l-(3-((R/S)- 1 , 1 -difluoro-2,3-dihydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,6,8,8-tetramethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 3a);

4-(((R)- 1 -(3-((S/R)- 1 , 1 -difluoro-2,3-dihydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,6,8,8-tetramethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 3b);

(R&S)-4-(((R)-l-(3-(l,l-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl) ethyl) amino)-8-methoxy-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 4);

(S/R)-4-(((R)-l-(3-(l,l-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-8-methoxy-2,6,8-trimethyl-6H-pyrrolo[2,3-g]quinazolin-7(8H)-one (Compound 4a);

(R/S)-4-(((R)-l-(3-(l,l-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl) amino)-8-methoxy-2,6,8-trimethyl-6H-pyrrolo[2,3-g]quinazolin-7(8H)-one

(Compound 4b);

(R&S)-4-(((R)-l-(3-(l,l-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 6);

(S/R)-4-(((R)-l-(3-(l,l-dmuoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 6a);

(R/S)-4-(((R)-l-(3-(l,l-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 6b); and

(S)-4-(((R)-l-(3-amino-5-(trifluoromethyl) phenyl) ethyl)amino)-8-methoxy-2,6,8-trimethyl-6, 8-dihydro-7H-pyrrolo [2,3 -g] quinazolin-7 -one (Compound 7) ;

or a pharmaceutically acceptable salt, a hydrate, or a stereoisomer thereof.

In accordance with yet another aspect the invention compound II of the pharmaceutical combination of the present invention is

(R)-5-(4-((l-(3-amino-5-(trifluoromethyl) phenyl) ethyl) amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)- 1 -methylpyridin-2( lH)-one (Compound 5);

or a pharmaceutically acceptable salt, a hydrate, or a stereoisomer thereof.

In some embodiments of the invention, the pharmaceutical combination comprising SOS 1 inhibitor selected from formula (I) or formula (II) and an additional active ingredient selected from KRAS, inhibitor, KRASG12C inhibitor, KRAS-G12D inhibitors, KRAS G13C inhibitor, and pan KRAS inhibitor. In some embodiments, KRASG12C inhibitor is selected from Sotorasib (AMG510) 4-((S)-4-acryloyl-2-methylpiperazin- 1 -yl)-6-fluoro-7 -(2-fluoro-6-hydroxyphenyl)- 1 -(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(lH)-one, (Hong DS. et al. New England Journal of Medicine 2020, 383(13): 1207-17); MRTX849 (l-(4-(7-(8-chloronaphthalen- 1 -yl)-2-(( 1 -methylpyrrolidin-2-yl)methoxy)-5, 6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-methylpiperazin- 1 -yl)-2-fluoroprop-2-en- 1 -one), (Hallin J., et al. Cancer discovery. 2020 10( l):54-71); JDQ443 (Brachmann SM, et. al. Mol Cancer Ther. 2021, 20 (12):P124); LY-3537982 (Peng, Sheng-Bin, et al. Cncer Res. 2021, 81(13): 1259-1259); JNJ-74699157, (Nagasaka M,. et. al. Cancer treatment reviews 2020, 84:101974); JAB-21822 (Li Y. et al. Current Opinion in Oncology 2022, 34(l):66-76); GDC-6036 (Chen H., et al. Journal of medicinal chemistry, 2020 63(23): 14404-24); D-1553 (Zhe Shi. et al. Cancer Res 2021

81(13):932), YL-15293 (Herdeis L., et al. Current opinion in structural biology. 2021

71: 136-47), BI-1823911 (Nagasaka M. et al. Cancer treatment reviews. 2021

101: 102309) BEBT-607:

In some embodiments, KRASG12D inhibitor is selected from MRTX1133 (4-(4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2S)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol ) (Wang X,. et al. Journal of medicinal chemistry, 2021 , 71 : 136-147) and BI-2852 ((3S)-5-hydroxy-3-(2-((((l-((l-methyl-lH-pyrrol-3-yl)methyl)-lH-inden-5-yl)methyl)amino)methyl)-lH-inden-3-yl)isoindolin-l-one) (Tran TH et al., Proceedings of the National Academy of Sciences. 2020, 17(7):3363-4):

In some embodiments of the invention, the pharmaceutical combination comprises SOS 1 inhibitor selected from formula (I) or formula (II) and additional active ingredient is an EGFR inhibitor; wherein EGFR inhibitor is selected from Afatinib ((S,E)-N-(4-((3-chloro-4-fhiorophenyl)amino)-7-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide) (Dungo RT. et al., Drugs.

2013, 73(13): 1503-15), Osimertinib (N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(l -methyl- lH-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide) (Greig SL. Et al., Drugs. 2016, 76(2):263-73), Erlotinib (N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine) (Dowell, J. et al., Nature Reviews Drug Discovery, 2005 4(1)); and Gefitinib (N-(3-chloro-4-fhrorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine) (Sanford M., et al. Drugs 2009, 69(16):2303-28):

In some embodiments the invention, the pharmaceutical combination comprises SOS 1 inhibitor selected from formula (I) or formula (II) and additional active ingredient is an ERK1/2 inhibitor, wherein, the ERK1/2 inhibitor is selected from LY -3214996 (6,6-Dimethyl-2-[2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-5-(2-morpholin-4-ylethyl)thieno[2,3-c]pyrrol-4-one), (Yan Q., et al. Journal of Biomedical Nanotechnology 2021, 17(7): 1380-91), BVD-523 (Ulixertinib) ((S)-4-(5-chloro-2-(isopropylamino)pyridin-4-yl)-N-(l-(3-chlorophenyl)-2-hydroxyethyl)-lH-pyrrole-2-carboxamide) (Sullivan RJ., et al. Cancer discovery. 2018, 8(2): 184-95), ASTX-029 (Moon H., et al. Cancers. 2021, 13(12):3026), MK-8353 ((3S)-3-methylsulfanyl-l-[2-[4- [4-( 1 -methyl- 1 ,2,4-triazol-3-yl)phenyl] -3 ,6-dihydro-2H-pyridin- 1 -yl] -2-oxoethyl] -N-[3-(6-propan-2-yloxypyridin-3-yl)-lH-indazol-5-yl]pyrrolidine-3-carboxamide) (Moschos SJ., et al. JCI insight 2018, 3(4):e92352) and ravoxertinib ((S)-l-(l-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-(( 1 -methyl- lH-pyrazol-5-

yl)amino)pyrimidin-4-yl)pyridin-2(lH)-one) (Park SJ., et al. Annals of Oncology.

2020, 31:S1281):

In some embodiments of the invention, the pharmaceutical combination comprising SOS 1 inhibitor selected from formula (I) or formula (II) and an additional active ingredient is a pan-RAF, wherein the pan-RAF inhibitor is selected from Dabrafenib (N-(3-(5-(2-aminopyrimidin-4-yl)-2-(tert-butyl)thiazol-4-yl)-2-fluorophenyl)-2,6- difluorobenzenesulfonamide) (Menzies AM., et al. Drug design, development and therapy 2012, 6:391);, Regorafenib (4-(4-(3-(4-chloro-3- (trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)-N-methylpicolinamide) (Grothey A., et al. The Lancet 2013, 381(9863):303-12);, Encorafenib (methyl (S)-(l-((4-(3-(5- chloro-2-fluoro-3-(methylsulfonamido)phenyl)-l-isopropyl-lH-pyrazol-4- yl)pyrimidin-2-yl)amino)propan-2-yl)carbamate) (Dummer R., et al. The Lancet Oncology 2018, 19(5):603-15.); and LXH254 N-(3-(2-(2-hydroxyethoxy)-6- morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide

(Monaco KA., et al. Clinical cancer research 2021, 27(7):2061-73):

In some embodiments of the invention, the pharmaceutical combination comprising SOS 1 inhibitor selected from formula (I) or formula (II) and additional active ingredient is AKT inhibitor, wherein, the AKT inhibitor is selected from GSK690693 ((S)-4-(2-(4-amino-l,2,5-oxadiazol-3-yl)-l-ethyl-7-(piperidin-3-ylmethoxy)-lH-imidazo[4,5-c]pyridin-4-yl)-2-methylbut-3-yn-2-ol), Levy DS., et al. The Journal of the American Society of Hematology. 2009, 113(8): 1723-9); AZD5363 (S)-4-amino-N-(l-(4-chlorophenyl)-3-hydroxypropyl)-l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (Davies BR., et al. Molecular cancer therapeutics 2012, 11(4):873-87) and Ipatasertib ((S)-2-(4-chlorophenyl)-l-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-l-yl)-3-(isopropylamino)propan-l-one) (Kim SB., et al., The Lancet Oncology. 2017, 18(10):1360-72):

In some embodiments of the invention, the pharmaceutical combination comprises SOS1 inhibitor selected from formula (I) and formula (II) and an additional active ingredient is a SHP2 inhibitor, wherein, the SHP2 inhibitor is selected from TNO155 ((3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl- 2-oxa-8-azaspiro[4.5]decan-4-amine) (LaMarche MJ., et al. Journal of Medicinal Chemistry 2020, 63(22): 13578-94); JAB-3068, (Liu Q., et al. Pharmacological research. 2020, 152:104595); RMC-4630 (Ou, S.I., et al. Journal of Thoracic Oncology, 15(2), 15-16) and RLY-1971 (Tang, Kai, et al. European Journal of

Medicinal Chemistry 2020, 204:112657):

In some embodiments of the invention, the pharmaceutical combination comprising SOS 1 inhibitor selected from formula (I) or formula (II) and an additional active ingredient is PRMT inhibitor, wherein the PRMT inhibitor is selected from JNJ- 64619178 ((lS,2R,3S,5R)-3-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-l,2-diol) (Tongfei Wu. et al Cancer Res. 2018, 78(13):4859); PF-06939999 (Jensen-Pergakes K, et al. Molecular cancer therapeutics. 2022, 21 ( 1):3- 15); GSK-3326595((R)-6-((l-acetylpiperidin-4-yl)amino)- N-(3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)pyrimidine-4-carboxamide) (Zhu K., et al Bioorganic & medicinal chemistry letters. 2018, 28(23-24):3693-9);

PRT543, (Bhagwat N„ et al. In Cancer Research 2020, 80(16) 19106-44040); PRT811,

(Falchook, Gerald S., et al. 2021 20(12):P044-P044); MS023 (Nx-((4-(4- isopropoxyphenyl)- lH-pyrrol-3-yl)methyl)-N 1 -methylethane- 1 ,2-diamine), (Eram

MS., et al. ACS chemical biology. 2016 11(3):772-81); GSK3368715 (Nx-((3-(4,4- bis(ethoxymethyl)cyclohexyl)- 1 H-pyrazol-4-yl)methyl)-N 1 ,N2-dimethylethane- 1 ,2- diamine), (Fedoriw A., et al. Cancer Cell 2019 36(1): 100-14) and Compound 24 of WO2019116302 ((lS,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5- (4-amino-7H-pyrrolo[2, 3 -d]pyrimidin-7 -yl)cyclopent-3-ene- 1 ,2-diol) :

In some embodiments of the invention, the pharmaceutical combination comprising SOS 1 inhibitor selected from formula (I) or formula (II) and an additional active ingredient is PI3K inhibitor, wherein, the PI3K inhibitor is selected from Alpelisib ((S)-N 1 -(4-methyl-5-(2-( 1,1,1 -trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-l,2-dicarboxamide), (Andre F, et al. New England Journal of Medicine 201,9 380(20): 1929-40) Copanlisib (2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[ 1 ,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide), (Dreyling M., et al. Journal of Clinical Oncology 2017, 35(35):3898-905) Duvelisib ((S)-3-( l-((7H-purin-6-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one), (Flinn IW., et al., The Journal of the American Society of Hematology 2018, 131(8):877-87); BEZ-235 (2-methyl-2-(4-(3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-lH-imidazo[4,5-c]quinolin-l-yl)phenyl)propanenitrile), (Chen J., et al. Clinical and Experimental Pharmacology and Physiology. 2015, 42(12): 1317-26);Gedatolisib (l-(4-(4-(dimethylamino)piperidine-l-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-l,3,5-triazin-2-yl)phenyl)urea) (Del Campo JM., et al. Gynecologic oncology 2016, 142(l):62-9) and Buparlisib (5-(2,6-dimorpholinopyrimidin-4-yl)-4-(trifhioromethyl)pyridin-2-amine) (Baselga J., et al. The Lancet Oncology. 2017, 18(7):904-16):

In some embodiments of the invention, the pharmaceutical combination comprising SOS 1 inhibitor selected from formula (I) or formula (II) and an additional active ingredient is CDK4/6 inhibitor, wherein, the CDK4/6 inhibitor is Abemaciclib (N-(5- ((4-ethylpiperazin- 1 -yl)methyl)pyridin-2-yl)-5-fluoro-4-(4-fluoro- 1 -isopropyl-2- methyl-lH-benzo[d]imidazol-6-yl)pyrimidin-2-amine) (Patnaik A., et al. Cancer discovery. 2016 6(7):740-53):

In some embodiments of the invention, the pharmaceutical combination comprising SOS 1 inhibitor selected from formula (I) or formula (II) and an additional active ingredient is the FGFR inhibitor, wherein, the FGFR inhibitor is selected from Nintedanib (methyl (Z)-3-(((4-(N-methyl-2-(4-methylpiperazin-l-yl)acetamido)phenyl)amino)(phenyl)methylene)-2-oxoindoline-6-carboxylate), (Richeldi L., et al. New England Journal of Medicine 2014, 370(22):2071-82) Dovitinib (4-amino-5-fluoro-3-(6-(4-methylpiperazin-l-yl)-lH-benzo[d]imidazol-2-yl)-4a,8a-dihydroquinolin-2(lH)-one), (Andre F., et al. Clinical cancer research 2013,

19( 13) : 3693 -702) ; JNJ 42756493 (N1 -(3 ,5 -dimethoxyphenyl)-N2-isopropyl-N 1 -(3 -( 1 -methyl- lH-pyrazol-4-yl)quinoxalin-6-yl)ethane-l,2-diamine), (Loriot, Yohann, et al. New England Journal of Medicine 2019, 381(4) 338-348); AZD4547 (N-(5-(3,5-dimethoxyphenethyl)-lH-pyrazol-3-yl)-4-((3R,5S)-3,5-dimethylpiperazin-l-yl)benzamide), (Gavine PR., et al. Cancer research. 2012, 72(8):2045-56) and BGJ398 (3-(2,6-dichloro-3,5-dimethoxyphenyl)-l-(6-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-l -methylurea), (Guagnano V. et al. Journal of medicinal chemistry 2011, 54(20):7066-83):

In some embodiments of the invention, the pharmaceutical combination comprising SOS 1 inhibitor selected from formula (I) or formula (II) and an additional active ingredient is c-Met inhibitor, wherein, the c-Met inhibitor is selected from Tivantinib ((3R,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,l-ij]quinolin-l-yl)-4-(lH-indol-3- yl)pyrrolidine-2, 5-dione) (Santoro A., et al. The lancet oncology 2013, 14(l):55-63);

Cabozantinib (N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-N-(4- fhrorophenyl)cyclopropane- 1,1 -dicarboxamide), (Abou-Alfa GK., et al. New England Journal of Medicine 2018, 379(l):54-63); Crizotinib ((R)-3-(l-(2,6-dichloro-3- fluorophenyl)ethoxy)-5-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)pyridin-2-amine) (Shaw AT., et al. New England Journal of Medicine 2013, 368(25):2385-94) and Capmatinib (2-fhroro-N-methyl-4-(7 -(quinolin-6-ylmethyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-2- yl)benzamide) (Wolf J., et al. New England Journal of Medicine 2020, 383(10):944- 57):

Crizotinib Capmatinib

In some embodiments of the invention, the pharmaceutical combination comprising S0S1 inhibitor selected from formula (I) or formula (II) and additional active ingredient is Bcr-Abl kinase inhibitor, wherein, the Bcr-Abl kinase inhibitor is selected from imatinib (N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)-4-((4-methylpiperazin-l-yl)methyl)benzamide); (Peng B., et al. Clinical pharmacokinetics 2005, 44(9):879-94) Dasatinib (N-(2-chloro-6-methylphenyl)-2-((6-(4-(2-hydroxyethyl)piperazin-l-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide) (Kantarjian H., et al. Nature reviews Drug discovery 2006, 5(9):717-9.); nilotinib (4-methyl-N-(3-(4-methyl-lH-imidazol-l-yl)-5-(trifluoromethyl)phenyl)-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)benzamide) (Weisberg E., et al. British journal of cancer 2006 94(12): 1765-9) and ponatinib (3-(imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin- 1 -yl)methyl)-3-(trifluoromethyl)phenyl)benzamide) (Cortes JE., et al. New England Journal of Medicine 2012 367(22):2075-88):

In some embodiments of the invention, the pharmaceutical combination comprising SOS 1 inhibitor selected from formula (I) or formula (II) and additional active ingredient is PD-1 inhibitor, wherein, the PD1 inhibitor is selected from Pembrolizumab (Garon EB., et al. New England Journal of Medicine 2015, 372(21):2018-28) and Nivolumab (Wolchok JD., et al. N Engl J Med. 2013, 369: 122- 33). In some embodiments of the invention, the pharmaceutical combination comprising SOS 1 inhibitor selected from formula (I) or formula (II) and additional active ingredient is PD-L1 inhibitor, wherein, the PD-L1 inhibitor is selected from Atezolizumab (Schmid P., et al. New England Journal of Medicine 2018, 379(22):2108-21) and Avelumab (Motzer RJ., et al. New England Journal of Medicine 2019, 380(12):l 103-15).

In some embodiments of the invention, the pharmaceutical combination comprising SOS 1 inhibitor selected from formula (I) or formula (II) and additional active ingredient is CTLA-4 inhibitor, wherein, the CTLA-4 inhibitor is Ipilimumab ((Hodi FS., et al., New England Journal of Medicine. 2010, 363(8):711-23).

In some embodiments of the invention, the pharmaceutical combination comprising SOS 1 inhibitor selected from formula (I) or formula (II) and an additional active ingredient is gemcitabine(4-amino- 1 -((2R,4R,5R)-3 ,3-difhioro-4-hydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(lH)-one), (Plunkett W., Anticancer drugs. 1995, 6:7-13); Topotecan ((S)-10-((dimethylamino)methyl)-4-ethyl-4,9-dihydroxy- 1 , 12-dihydro- 14H-pyrano [3' ,4' : 6,7]indolizino[ 1 ,2-b] quinoline-3 , 14(4H)-dione), (Herben VM., et al. Clinical pharmacokinetics 1996, 31(2):85-102); Irinotecan ((S)-4, 11 -diethyl-4-hydroxy-3 , 14-dioxo-3 ,4,12,14-tetrahydro- 1 H-pyrano[3',4':6,7]indolizino[l,2-b]quinolin-9-yl [l,4'-bipiperidine]-l'-carboxylate), (Vanhoefer U., et al. Journal of clinical oncology 2001, 19(5): 1501-18); Paclitaxel ((2aR,4S,4aS,6R,9S,l lS,12S,12aR,12bS)-9-(((2R,3S)-3-benzamido-2-hydroxy-3-phenylpropanoyl)oxy)- 12-(benzoyloxy)-4, 11 -dihydroxy-4a,8, 13, 13-tetramethyl-5-oxo-3 ,4, 4a, 5, 6, 9, 10, 11, 12,12a-decahydro- 1 H-7, 11 -methanocyclodeca[3 ,4]benzo [1,2-b]oxete-6,12b(2aH)-diyl diacetate), (Rowinsky EK,, et al. New England journal of medicine 1995, 332(15): 1004-14.); Cisplatin (diaminoplatinum(IV) chloride), carboplatin, (LOEHRER PJ., et al. Annals of internal medicine 1984, 100(5):704- 13) doxorubicin ((8S,10S)-10-(((2R,4S,5R,6S)-4-amino-5-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-6,8,l l-trihydroxy-8-(2-hydroxyacetyl)-l-methoxy-7,8,9,10-tetrahydrotetracene-5, 12-dione), (Weiss RB., et al. In Seminars in oncology 1992, 19(6):670-686) and Temozolomide (3-methyl-4-oxo-3,4-dihydroimidazo[5,l-d][l,2,3,5]tetrazine-8-carboxamide) (Friedman HS., et al. Clinical cancer research.

2000, 6(7):2585-97):

temozolomide

According to a feature of the present invention, the SOS1 inhibitor formula (I) and formula (II),

wherein all the symbols are as defined earlier, can be prepared by methods illustrated in the schemes and examples provided herein below. However, the disclosure should not be construed to limit the scope of the invention arriving at compound of formula (I) as disclosed hereinabove. Further, in the following schemes, where specific bases, acids, reagents, solvents, coupling agents, etc., are mentioned, it is understood that other bases, acids, reagents, solvents, coupling agents etc., known in the art may also be used and are therefore included within the scope of the present invention. Variations in reaction conditions, for example, temperature and/or duration of the reaction, which may be used as known in the art, are also within the scope of the present invention. All the isomers of the compound of formula in described in these schemes, unless otherwise specified, are also encompassed within the scope of this invention.

General Synthetic procedures for SOS1 inhibitor of formula I,

SOS1 inhibitor of formula I

The corresponding a-methyl amine derivatives represented as formula (A5) could be prepared by following the sequential transformations as depicted in Scheme - A herein below-

The compound of formula (Al) undergoes a metal catalyzed cross coupling with alkoxy vinyl stannane, e.g. tributyl( 1 -ethoxy vinyl)tin in presence of palladium catalysts such as Pd(Ph3P)2Ch, Pd2(dba)3 and like; optionally using bases such as triethylamine, N,N-Diisopropylethylamine and like, in hydrocarbon solvents like toluene or ether solvents like 1,4-dioxane to furnish the alkoxy vinyl intermediate which in turn provide compound of formula (A2) in acidic condition by employing aqueous mineral acids such as hydrochloric acid in ether solvent such as THF, 1,4-dioxane and like. The similar transformation can be carried out by reaction of compound of formula (Al) with n-alkylvinyl ether using catalysts such as palladium (II) acetate and like, ligands such as 1,3-Bis(diphenylphosphino)propane and like, in presence of organic bases such as DIPEA, TEA and like in alcoholic solvents such as ethylene glycol and at elevated temperatures ,in solvents such as 1,4-dioxane, THF and mixtures thereof to give alkoxy vinyl intermediate which in turn provide compound of formula (A2) in acidic condition by employing aqueous mineral acids such as hydrochloric acid in ether solvent such as THF, 1 ,4-dioxane and like

The compound of formula (A2) was then reacted with corresponding chirally pure t-butanesulfinamide in presence of Lewis acid such as Titanium alkoxides e.g. titanium tetraethoxide, titanium isopropoxide and the like, in ether solvents such as 1,4-dioxane, THF and like, to obtain the compound of formula (A3).

The compound of formula (A3) reacted with reducing agent such as metal hydrides e.g. sodium borohydride, L-selectride and like, in solvents such as THF, 1,4- dioxane, methanol and the like, optionally in presence of water to provide sulfinamide of formula (A4). Major diastereoisomer in the compound of formula (A4) after reduction was separated or taken ahead as such.

The compound of formula (A4) under acidic condition undergoes cleavage of reduced ketimine derivative to generate amine of formula (A5) as a free base or salt. The acids employed for the transformation may involve mineral acids such as hydrochloric acid, organic acids like trifluoroacetic acid and thereof.

The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme-B herein below-

SCHEME - B

Compound of formula (B2) can be synthesized from compound of formula (Bl) by following the reaction protocol as mentioned in EP2243779 (Ra = Rb = CH3) and WO2015164480 (Ra and Rb together forms a ring). Compound of formula (B2) was converted to corresponding cyclic amide of formula (B3) through selective reduction of nitro group by using different reducing agents. Although not limited, such reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like. Such reduction of the compound of formula (B2) can be carried out in one or more solvents, e.g., ethers such as THF, 1,4-dioxane, and the like; alcohol such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and mixtures thereof. Nitration of compound of formula (B3) with nitrating reagents such as, although not limited to fuming nitric acid, potassium nitrate, and the like in acids such as, although not limited to tin (IV) chloride, sulphuric acid, trifluroacetic acid, acetic acid and the like, anhydrides like acetic anhydride, trifluroacetic anhydride and the like, or mixture(s) thereof to provide compound of formula (B4). Compound of formula (B4) can be further alkylated by using corresponding alkyl halide in presence of bases such as Na2CC>3, K2CO3, CS2CO3 etc. in polar aprotic solvents like DMF, DMSO etc. at temperature 20 °C - 60 °C leading to compound of formula (B5). An alternative synthetic route towards the compound of formula (B5) is the transformation of intermediate of compound of formula (B4) via Mitsunobu reaction with corresponding alcohol, using different reagents such as but not limited to DEAD, DIAD etc. Such reactions can be carried out in aprotic solvents like, e.g., ethers such as THF, Dioxane and the like; hydrocarbons, e.g., toluene or mixtures thereof, at temperature 25°C -90°C. Compound of formula (B5) was converted to corresponding aniline derivative compound of formula (B6) through selective reduction of nitro group by using different reducing agents. Although not limited, such reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like. Such reduction of the compound of formula (B5) can be carried out in one or more solvents, e.g., ethers such as THF, 1,4-dioxane, and the like; alcohol such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and the like mixtures thereof. Compound of formula (B6) upon treatment with corresponding alkylnitriles using acids such as but not limited to

Methane sulfonic acid, HC1 etc. at 25 C-120 C to afford compound of formula (B7), which could be further coupled with different chiral benzyl amine (A5) derivatives using different coupling reagents such as but not limited to BOP, PyBop etc. and organic bases such as DBU, DIPEA etc. in a polar aprotic solvent like DMF, DMSO etc. at 0°-120°C to afford a compound of formula (I).

Alternatively, compound of formula (I) can be prepared from compound of formula (B7) by reacting with phosporyl halides such as POCI3 or POBn optionally in solvents such as toluene, xylene, chlorobenzene or the like or the mixtures thereof, optionally using organic base such as triethylamine, diisopropylethylamine or the like to provide compound of formula (B8).

Compound of formula (B8) undergoes a nucleophilic substitution reaction with different chiral benzylic amines (A5) leading to the final compound of formula (I) using organic basic reagents such as but not limited to DIPEA, TEA etc. optionally neat or in a polar aprotic solvents like dioxane, THF etc. at 0°C -130°C. Carbonyl functional group in Compound of formula (I) on further reduction using different reducing reagents such as but not limited to borane DMS, borane THF, LiAlH4 in polar aprotic solvents like THF, dioxane etc. at temperature 70 - 90°C leading to final compound of formula (I).

Compound of formula (I) allowed to react with fluorinating reagent such as DAST, martin sulfurane in solvents such as DCM, chloroform, THF, ether, 1,4-dioxane to provide compound of formula (B9).

Compound of formula (B9) undergoes epoxidation reaction to provide compound of formula (BIO). This reaction is effected by hydrogen peroxide in presence of acidic medium using organic acids such as formic acid and like.

Compound of formula (BIO) on epoxide opening by nucleophilic reagent provide compound of formula (I). Such transformations can be effected by reaction of epoxide compound with various nucleophilic reagents such as sodium alkoxides, primary or

secondary amines in alcohol solvents like ethanol, methanol, and like and at room temperature or elevated temperature.

The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme-C herein below-

Compound of formula (C2) is prepared by following a procedure reported in Chemistry - A European Journal, 2015, vol. 21, # 4, p. 1482 - 1487. The compound of formula (C2) is converted to corresponding 4-oxo chromene carboxylic ester derivative of compound of formula (C3) using corresponding alpha diketo ester and basic reagents such as but not limited to NaOMe, NaOEt, K'OBLI etc. in a polar aprotic solvents like DMF, DMA etc. at 0 C - 75 C. Halogenation of compound of formula (C3) using N-halosuccinamide reagent such as but not limited to NBS , NIS and NCS gives corresponding dihalo compound of formula (C4) via e.g. benzylic halogenation in a aprotic halogenated solvents like CCI4, DCM etc. at 0°-80°C. The compound of formula (C5) aldehyde derivative can be synthesized by oxidation of compound of formula (C4). Compound of formula (C5) undergoes an acidic hydrolysis leading to compound of formula (C6), that can be further functionalized to corresponding amide of compound of formula (C7) using coupling reagent such as but not limited to PyBop in a polar aprotic solvents like DMF, DMSO etc. at temperature ranging from 0°C -30°C for about l-16h. Compound of formula (C8) can be achieved by oxidation of compound of formula (C7) with suitable oxidizing reagent such as but not limited to sulphamic acid and sodium chlorite. Compound of formula (C8) when condensed with corresponding amidine by coupling reaction affords a quinazoline enone derivative of compound of formula (C9). Reduction of enone compound of formula (C9) using reagents such as but not limited to H2-Pd/C leading to corresponding compound of formula (CIO). The compound of formula (CIO) can be transformed to the corresponding compound of formula (Cl l) via halogenation using reagents such as phosphorus oxyhalide, thionyl chloride and like, in aprotic solvents like chlorobenzene, toluene and mixtures thereof. Compound of formula (Cl l) undergoes a coupling with different chiral benzylic amines (A5 ) leading to the final compound of formula (I). This reaction can be effected by organic base such as DIPEA, TEA, DBU or the like, or using coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like; optionally neat or in etheral solvents such as THF, 1 ,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and thereof at temperature ranging from 20-130°C. The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme - D herein below.

The compound of formula (DI) is converted to corresponding acetyl derivative of compound of formula (D2) via N-acylation reaction using acetyl chloride & using organic basic reagents such as but not limited to pyridine, DIPEA, TEA etc in halogenated solvents such as, although not limited chloroform, dichloromethane, and the like mixtures thereof. Nitration of compound of formula (D2) with nitrating reagents such as, although not limited to fuming nitric acid, potassium nitrate, and the like in acids such as, although not limited to tin (IV) chloride, sulphuric acid, trifluroacetic acid, acetic acid and the like, anhydrides like acetic anhydride, trifluroacetic anhydride and the like, or mixture(s) thereof to provide compound of formula (D3).

Acetyl deprotection of compound of formula (D3) using inorganic bases such as Na2CC>3, K2CO3, CS2CO3, etc in polar protic solvents like methanol, ethanol etc at appropriate temperature afforded compound of formula (D4).

Compound of formula (D4) can be further alkylated by using alkyl halides and bases such as NaH, Na2COs, K2CO3, CS2CO3 etc. in polar aprotic solvents like THF, DMF, and DMSO etc. at temperature 20°C - 60°C leading to compound of formula (D5).

Compound of formula (D5) can be converted to corresponding aniline derivative, compound of formula (D6) through selective reduction of nitro group by using different reducing agents. Although not limited, such reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like. Such reduction of the compound of formula (D6) can be carried out in one or more solvents, such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and the like mixtures thereof.

Compound of formula (D6) allowed to react with alkylnitrile in presence of the acidic reagents such as methane sulfonic acid, sulfuric acid, hydrochloric acid or the like to obtain compound of formula (D7).

Compound of formula (D7) was reacted with POCI3 or POBn optionally in solvents such as toluene, xylene or the like or the mixtures thereof, optionally using organic base such as triethylamine, diisopropylethylamine or the like to provide compound of formula (D8).

Compound of formula (D8) was reacted with compound of formula (A5) in the presence DIPEA, TEA, DBU or the like, or using coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like; optionally neat or in etheral solvents such as THF, 1,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and thereof at temperature ranging from 20-130°C. to provide compound of formula (I). The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme - E herein below.

SCHEME - E

Compound of formula (El) can be synthesized following a reaction protocol described in WO200879759.Compound of formula (E2) can be synthesized by appropriate displacement of aromatic halogen with corresponding alkyl amine using appropriate bases such as TEA, NaH, Na2COs, K2CO3, CS2CO3 etc. in polar aprotic solvents like

THF, DMF, DMSO etc. at temperature 20°C - 120°C.

Compound of formula (E2) can be converted to corresponding cyclic amide of formula

(E3) through selective reduction of nitro group by using different reducing agents.

Although not limited, such reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like. Such reduction of the compound of formula (E2) can be carried out in one or more solvents, alcohol such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and the like mixtures thereof. Compound of formula (E3) can be further alkylated by using bases such as NaH, Na2CC>3, K2CO3, CS2CO3 etc. in polar aprotic solvents like THF, DMF, and DMSO etc. at temperature 20°C - 60°C

leading to compound of formula (E4). Compound of formula (E5) can be synthesized by ester hydrolysis of compound of formula (E4) using bases such as NaOH, LiOH and KOH etc.Compound of formula (E5) which on coupling with different amidines such as acetamidine, formamidine etc. in polar aprotic solvents like DMF, DMSO etc. at temperature 80°C - 100°C leading to compound of formula (E6).Compound of formula

(E6) can be converted to the corresponding compound of formula (E7) by halogenation using reagents such as POCh, POBr3, SOCh etc.

Compound of formula (E7) undergoes a nucleophilic substitution reaction with different chiral benzyl amine (A5) leading to compound of formula (I) using aprotic solvents like dioxane, THF and like, at temperature 0°C -130°C and bases such as but limited to DIPEA, TEA and thereof.

The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme -F herein below.

SCHEME - F

Compound of formula (F2) can be synthesized by following the reaction protocol as mentioned in EP2243779 (Rc = Rd = CH3) and WO2015164480 (Rc and Rd together

forms a ring). Compound of formula (F2) was converted to corresponding cyclic amide of formula (F3) through selective reduction of nitro group by using different reducing agents. Although not limited, such reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like. Such reduction of the compound of formula (F2) can be carried out in one or more solvents, such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and the like mixtures thereof. Nitration of compound of formula (F3) with nitrating reagents such as, although not limited to fuming nitric acid, potassium nitrate, and the like in acids such as, although not limited to tin (IV) chloride, sulphuric acid, trifluroacetic acid, acetic acid and the like, anhydrides like acetic anhydride, trifluroacetic anhydride and the like, or mixture(s) thereof to provide compound of formula (F4).

Compound of formula (F4) can be treated with SOCh , POCI3, POBn and thereof using DMF to give an intermediate (Halogenation reaction intermediate), which undergoes a nucleophilic substitution reaction with appropriate amines leading to the compound of formula (F5), using organic basic reagents such as but not limited to DIPEA, TEA etc. in a polar aprotic solvent like dioxane, THF etc. at appropriate temperature.

Compound of formula (F5) can be converted to corresponding aniline derivative, compound of formula (F6) through selective reduction of nitro group by using different reducing agents. Although not limited, such reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like. Such reduction of the compound of formula (F5) can be carried out in one or more solvents, such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and mixtures thereof. Compound of formula (F6) upon treatment with corresponding nitrile solvents such as but not limited to acetonitrile using acids such as but not limited to methane sulfonic acid, HC1 etc. at 25°C-120°C to afford compound of formula (F7), which can be transformed to intermediate (F8), via e.g. triflate or halogenation etc. of the corresponding compound of formula (F7). Compound of formula (F8) undergoes a nucleophilic substitution

reaction with different chiral benzyl amine (A5), using aprotic solvents like dioxane, THF etc., at temperature 0°C-130°C and bases such as but limited to DIPEA, TEA etc. leading to final compound of formula (I).

The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme - G herein below.

SCHEME - G

Compound of formula (Gl) was allowed to react with corresponding carbamate in the presence of catalyst such as (tris(dibenzylideneacetone)dipalladium(O), palladium(II) acetate, Bis(dibenzylideneacetone)2 Pd(0), rac 2,2'-Bis(diphenylphosphino)-l,l'- binaphthyl, 2,5 bis(tri-t-butylphosphine) palladium (0) and the like; in presence of ligands such as RuPhos, Xanthphos, Davephos, BINAP, or the like; using a suitable base such as sodium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert- butoxide, DIPEA, Potassium triphosphate and thereof; in a suitable solvent selected from THF, 1,4-dioxane, dime thoxye thane, DMF, DMA, toluene and the like to provide compound of formula (G2)

Cyclization of compound of formula(G2) provided compound of formula (G3), in the presence of suitable base, preferably inorganic bases such as alkali metal carbonates, e.g., Na2COs, K2CO3, CS2CO3, NaO'Bu, Potassium phosphate, or mixture thereof. Such reactions can be carried out in solvents like, e.g., ethers such as THF, Dioxane and the like; hydrocarbons, e.g., toluene; amides such as DMF, DMA or mixtures thereof.

Nitration of compound of formula (G3) with nitrating reagents such as, although not limited to fuming nitric acid, potassium nitrate, and the like in acids such as, although not limited to tin (IV) chloride, sulphuric acid, trifluroacetic acid, acetic acid and the like, anhydrides like acetic anhydride, trifluroacetic anhydride and the like, or mixture(s) thereof to provide compound of formula (G4).

The compound of formula (G4) was alkylated to give compound of formula (G5). This conversion was effected in presence alkali hydrides like sodium hydride and like; or bases such as potassium carbonate and like; and alkylating reagents alkyl halides e.g. Methyl iodide and like; in presence of solvents such as THF, DMF or mixture(s) thereof.

Compound of the formula (G6) was obtained from compound of formula (G5) using by metal reductions using iron, tin or tin chloride or the like in solvents selected from THF, 1,4-dioxane methanol, ethanol or the like or mixtures thereof under acidic condition using ammonium chloride, acetic acid, hydrochloric acid or the like or mixture(s) thereof. This transformation can also be carried out by catalytic hydrogenation using Pd/C and thereof in solvents ethyl acetate, Methanol or mixture(s) thereof.

Compound of formula (G6) reacted with alkylnitriles in presence of the reagent such as methane sulfonic acid, sulfuric acid, hydrochloric acid or the like to obtain compound of formula (G7).

Compound of formula (G7) was reacted with POCI3 or POBn optionally in solvents such as toluene, xylene or the like or the mixtures thereof, optionally using organic base such as triethylamine, diisopropylethylamine or the like to provide compound of formula (G8).

Compound of formula (G8) was reacted with compound of formula (A5) in the presence of triethyl amine, N,N-ethyldiisopropyl amine, pyridine, DBU or the like in solvents such as THF , 1,4-Dioxane, toluene, DCM, DMSO or mixture(s) thereof to provide compound of formula (I).

The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme - H herein below.

sis

(') SCHEME - H

Compound of formula (Hl) can be synthesized by reaction protocol as mentioned in (WO243823). Compound of formula (H2) can be synthesized from compound of formula (Hl) by using oxidizing agents like MnCh, H2O2, AgNCh, DDQ and thereof. Compound of formula (H2) undergoes alkylation reaction using alkyl halides in presence of bases such as K2CO3, Na2COs, CS2CO3 and like; in polar aprotic solvents like DMF, DMSO and thereof; at temperature 20 C - 60 C afforded compound of formula (H3).

An alternative synthetic route towards the compound of formula (H3) is the transformation of intermediate of compound of formula (H2) via Mitsunobu reaction with corresponding alcohol, using different reagents such as but not limited to DEAD, DIAD etc. Such reactions can be carried out in aprotic solvents like, e.g., ethers such as THF, Dioxane and the like; hydrocarbons, e.g., toluene or mixtures thereof, at temperature 25°C - 90°C.

Compound of formula (H4) can be synthesized by ester hydrolysis of formula (H3) using bases such as NaOH, LiOH, KOH and like; in polar protic solvents such as methanol, ethanol and like.

Compound of formula (H4) on reaction with acetamidine, formamidine and like; in polar aprotic solvents like DMF, DMSO and thereof at temperature elevated temperatures afforded compound of formula (H5).

Compound of formula (H7) was reacted with POCI3 or POBn optionally in solvents such as toluene, xylene or the like or the mixtures thereof, optionally using organic base such as triethylamine, diisopropylethylamine or the like to provide compound of formula (H6).

Compound of formula (H6) was reacted with compound of formula (A5) in the presence of triethyl amine, N,N-ethyldiisopropyl amine, pyridine, DBU or the like in solvents such as THF , 1,4-Dioxane, toluene, DCM, DMSO or mixture(s) thereof to provide compound of formula (I).

The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme - 1 herein below.

SCHEME - 1

The compound of the formula (12) obtained by treating compound of the formula (II) with oxidizing agent potassium permanganate, potassium dichromate, sodium dichromate in presence of acids like sulphuric acid, acetic acid and like, in 1 : 1 mixture of t-butanol and Water as Solvent.

The compound of formula (12) was subjected to esterification in alcoholic solvents like methanol ethanol and thereof in presence of chlorinating agents such as thionyl chloride, oxalyl chloride and thereof, or in presence of acidic reagents such as sulfuric and methane sulfonic acid thereof to provide the compound of formula (13).

The compound of formula (13) was subjected to C-N coupling reaction e.g. Buchwald reaction with 1 -methylurea provided compound of formula (14). This reaction can mediated by a suitable catalyst such as, e.g., Pd(PPh3)2C12, Pd2dba3, Pd(PPh3)4, Pd(OAc)2 or mixtures thereof; a suitable ligand such as Xantphos, BINAP, Ru-Phos, XPhos, or mixtures thereof; in the presence of suitable base, preferably inorganic bases such as alkali metal carbonates, e.g., K2CO3, Na2CC>3, CS2CO3, NaCfBu, Potassium phosphate, or mixture thereof. Such reactions can be carried out in solvents like, e.g., ethers such as THF, Dioxane and the like; hydrocarbons, e.g., toluene; amides such as DMF, DMA or mixtures thereof.

Nitration of compound of formula (14) with nitrating reagents such as, although not limited to fuming nitric acid, potassium nitrate, and the like in acids such as, although not limited to tin (IV) chloride, sulphuric acid, trifluroacetic acid, acetic acid and the like, anhydrides like acetic anhydride, trifluroacetic anhydride and the like, or mixture(s) thereof to provide compound of formula (15).

The compound of formula (15) was alkylated to give compound of formula (16). This conversion was effected in presence alkali hydrides like sodium hydride and like; or bases such as potassium carbonate and like; and alkylating reagents alkyl halides e.g. Methyl iodide and like; in presence of solvents such as THF, DMF or mixture(s) thereof.

Compound of the formula (17) was obtained from compound of formula (16) using by metal reductions using iron, tin or tin chloride or the like in solvents selected from THF, 1,4-dioxane methanol, ethanol or the like or mixtures thereof under acidic condition using ammonium chloride, acetic acid, hydrochloric acid or the like or mixture(s) thereof. This transformation can also be carried out by catalytic hydrogenation using Pd/C and thereof in solvents ethyl acetate, Methanol or mixture(s) thereof.

Compound of formula (17) reacted with acetonitrile in presence of the reagent such as methane sulfonic acid, sulfuric acid, hydrochloric acid or the like to obtain compound of formula (18).

Compound of formula (18) was reacted with POCI3 or POBn optionally in solvents such as toluene, xylene or the like or the mixtures thereof, optionally using organic base such as triethylamine, diisopropylethylamine or the like to provide compound of formula (19).

Compound of formula (19) was reacted with compound of formula (A5) in the presence of triethyl amine, N,N-ethyldiisopropyl amine, pyridine, DBU or the like in solvents such as THF , 1,4-Dioxane, toluene, DCM, DMSO or mixture(s) thereof to provide compound of formula (I).

The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme - J herein below.

Compound of formula (J2) can be synthesized from compound of formula (JI) by following the reaction protocol as mentioned in ACS Medicinal Chemistry Letters, 2018, vol. 9, # 8, p. 827 - 831 (Rb = Rc = CH3). Upon thermal cyclization at elevated temperature(s) the compound of the formula (J2) can undergo ring cyclization to produce compound of formula (J3). Such reaction can be carried out by using Lewis acids such as, although not limited to AICI3, BF3, etc., either neat or by using solvents such as DCM, DCE, chlrobenzene, toluene, xylene, etc. and the like or mixture(s) thereof. Nitration of compound of formula (J3) with nitrating reagents such as, although not limited to fuming nitric acid, potassium nitrate, and the like in acids such as, although not limited to tin (IV) chloride, sulphuric acid, trifluroacetic acid, acetic acid and the like, anhydrides like acetic anhydride, trifluroacetic anhydride and the like, or mixture(s) thereof to provide compound of formula (J4). Compound of formula (J4) can be further alkylated by using bases such as NaH, K2CO3, Na2COs, CS2CO3 etc. in polar aprotic solvents like THF, DMF, DMSO etc. at appropriate temperature leading to compound of formula (J5). Compound of formula (J5) was converted to corresponding aniline derivative compound of formula (J6) through selective reduction of nitro group by using different reducing agents. Such reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like. Such reduction can be carried out in one or more solvents, e.g., ethers such as THF, 1,4-dioxane, and the like; alcohol such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and the like mixtures thereof. Compound of formula (J6) upon treatment with corresponding alkylnitriles using acids such as but not limited to Methane sulfonic acid, HC1 etc. at appropriate temperature to afford compound of formula (J7). The halogenation of compound of formula (J7) to produce the compound of formula (J8). Such reaction can be carried out by using neat halogenating reagents, such as but not limited to POCI3, POBr3, SOC12 and the like at appropriate temperature. This reaction can also be caried out by using combination of halogenating reagents and organic bases such as POCI3, POBr3, SOCh and the like; and organic bases like DIPEA, TEA, N,N-Dimethylaniline and the like; using solvents such as DCE, DCM, chlorobenzene, toluene and the like or mixture(s) thereof at appropriate temperature. The compound of formula (I) can be obtained by using nucleophilic substitution of benzyl amines (A5) with the compound of the formula (J8). Such reaction can be carried out at appropriate temperature in presence of bases like DIPEA, TEA and the like; in solvents such as THF, 1,4-Dioxane, DCE, ACN, DMSO, etc., and the like or mixture(s) thereof.

The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme -K herein below.

The compound of formula (KI) was subjected to esterification in alcoholic solvents like methanol ethanol and thereof in presence of chlorinating agents such as thionyl chloride, oxalyl chloride and thereof, or in presence of acidic reagents such as sulfuric and methane sulfonic acid thereof to provide the compound of formula (K2).

Compound of formula (K3) can be synthesized by appropriate displacement of aromatic halogen with corresponding alkyl amine in alcoholic solvents like methanol ethanol and thereof.

Compound of formula (K3) was reacted with oxalyl chloride in the presence of bases like triethyl amine, N,N-ethyldiisopropyl amine, pyridine, DBU or the like in solvents such as THF , 1,4-Dioxane, toluene, DCM, or mixture(s) thereof to provide compound of formula (K4).

Compound of formula (K4) was subjected to cyclisation using di thionate salts in the presence of mixture of solvents such as THF , 1,4-Dioxane , in alcoholic solvents like methanol ethanol and water, mixture(s) thereof to provide compound of formula (K5).

The compound of formula (K5) was alkylated to give compound of formula (K6). This conversion was effected in presence alkali hydrides like sodium hydride and like; or bases such as potassium carbonate and like; and alkylating reagents alkyl halides e.g.

Methyl iodide and like; in presence of solvents such as THF, DMF or mixture(s) thereof.

The compound of formula (K6) was subjected to C-N coupling reaction e.g. Buchwald reaction with tert-butyl carbamate provided compound of formula (K7). This reaction can mediated by a suitable catalyst such as, e.g., Pd(PPh3)2Ch, Pd2dba3, Pd(PPh3)4, Pd(OAc)2 or mixtures thereof; a suitable ligand such as Xantphos, BINAP, Ru-Phos, XPhos, or mixtures thereof; in the presence of suitable base, preferably inorganic bases such as alkali metal carbonates, e.g., K2CO3, Na2CC>3, CS2CO3, NaOtBu, Potassium phosphate, or mixture thereof. Such reactions can be carried out in solvents like, e.g., ethers such as THF, Dioxane and the like; hydrocarbons, e.g., toluene; amides such as DMF, DMA or mixtures thereof.

Compound of formula (K7) undergoes deprotection using acids like organic acids such as trifluoroacetic acid, Methane sulfonic acid and like, mineral acids like hydrochloric acid, acetic acid (Aqueous or in etheral solvents), sulfuric acid and the like; using solvents like dichloromethane, dichloroethane, THF, 1,4-dioxane and like thereof to provide compound of formula (K8).

Compound of formula (K8) reacted with alkyl nitriles in presence of the reagent such as methane sulfonic acid, sulfuric acid, hydrochloric acid, or the like to obtain compound of formula (K9).

Compound of formula (K9) was reacted with POCI3 or POBr3 optionally in solvents such as toluene, xylene or the like or the mixtures thereof, optionally using organic base such as triethylamine, diisopropylethylamine or the like to provide compound of formula (K10).

Compound of formula (K10) was reacted with compound of formula (A5) in the presence of triethyl amine, N,N-ethyldiisopropyl amine, pyridine, DBU or the like in solvents such as THF , 1,4-Dioxane, toluene, DCM, DMSO or mixture(s) thereof to provide compound of formula (I).

The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme - L herein below.

Compound of formula (LI) allowed to react with N-hydroxy acetamide in presence of the bases such as K2CO3, Na2COs, CS2CO3 etc. in polar aprotic solvents like DMF, DMSO etc. at temperature 20°C - 80°C leading to compound of formula (L2). Nitration of compound of formula (L2) with nitrating reagents such as, although not limited to fuming nitric acid, potassium nitrate, and the like in acids such as, although not limited to tin (IV) chloride, sulphuric acid, trifluroacetic acid, acetic acid and the like, anhydrides like acetic anhydride, trifluroacetic anhydride and the like, or mixture(s) thereof to provide compound of formula (L3). Compound of formula (L3) was converted to corresponding aniline derivative compound of formula (L4) through selective reduction of nitro group by using different reducing agents. Although not limited, such reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like. Such reduction of the compound of formula (L3) can be carried out in one or more solvents, e.g., ethers such as THF, 1,4-dioxane, and the like; alcohol such as methanol, ethanol and the like; under acidic

conditions involving ammonium chloride, acetic acid, hydrochloric acid and the like mixtures thereof. Compound of formula (L4) allowed to react with corresponding acyl halide in presence of the organic basic reagents such as but not limited to DIPEA, TEA etc. in polar aprotic solvents like DMF, DMSO etc. at temperature 20°C - 80°C leading to compound of formula (L5). Compound of formula (L5) can be further alkylated by using bases such as K2CO3, Na2COs, CS2CO3 etc. in polar aprotic solvents like DMF, DMSO etc. at temperature 20°C - 60°C leading to compound of formula (L6). Compound of formula (L6) which on coupling with different amidines such as acetamidine, formamidine etc. in polar aprotic solvents like DMF, DMSO etc. at temperature 80°C - 100°C leading to compound of formula (E7).

Compound of formula (E8) can be prepared from compound of formula (E7) by reacting with phosporyl halides such as POCI3 or PC) Bn optionally in solvents such as toluene, xylene, chlorobenzene or the like or the mixtures thereof, optionally using organic base such as triethylamine, diisopropylethylamine or the like to provide compound of formula (E8).

Compound of formula (E8) undergoes a nucleophilic substitution reaction with different chiral benzylic amines (A5) leading to the final compound of formula (I) using organic basic reagents such as but not limited to DIPEA, TEA etc. in a polar aprotic solvents like dioxane, THF etc. at 0°C -130°C.

The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme - M herein below.

SCHEME ■ M

Carbonyl functional group in Compound of formula (Ml) on further reduction using different reducing reagents such as but not limited to triethyl silane, borane DMS, borane THF, LiAlH4 in polar aprotic solvents like THF, dioxane etc or like in acids such as, although not limited to trifluroacetic acid, sulphuric acid, acetic acid and the like, or mixture(s) thereof to provide compound of formula (M2).

Compound of formula (M2) converted to compound of formula (M3) using Friedel craft acylation. This transformation was carried out by reaction of Compound of formula (M2) with corresponding acyl halide in presence of Lewis acids such as aluminum trichloride, zinc chloride, boron trifluoride etherate and like, in halogenated solvents like dichloromethane, dichloroethane and like.

Compound of formula (M3) was allowed to react with mixture of bromine & aqueous metal hydroxides like NaOH, KOH or the like or mixtures thereof to provide compound of formula (M4).

Compound of formula (M4) which on coupling with different amidines such as acetamidine, formamidine etc. in polar aprotic solvents like DMF, DMSO etc. at temperature 80°C - 100°C leading to compound of formula (M5).

Compound of formula (M6) can be prepared from compound of formula (M5) by reacting with phosporyl halides such as POCI3 or PC) Bn optionally in solvents such as toluene, xylene, chlorobenzene or the like or the mixtures thereof, optionally using organic base such as triethylamine, diisopropylethylamine or the like to provide compound of formula (M6).

Compound of formula (M6) undergoes a nucleophilic substitution reaction with different chiral benzylic amines (A5) leading to the final compound of formula (I) using organic basic reagents such as but not limited to DIPEA, TEA etc. in a polar aprotic solvents like dioxane, THF etc. at 0°C -130°C.

The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme - N herein below.

Compound of the formula (N2) was obtained by oxidation of compound of the formula (Nl). This transformation can be effected by oxidizing reagents such as potassium permanganate, potassium dichromate, sodium dichromate and like; in presence of acids like H2SO4, acetic acid and like.

Compound of the formula (N3) was obtained from compound of the formula (N2) by esterification reaction. This transformation can be effected by reaction of alcohols such as methanol, ethanol and like; in presence of mineral acids like sulfuric acid, organic acids like methane sulfonic acid and like, or in presence of chloride reagents like thionyl chloride, oxalyl chloride and thereof. This transformation can also be effected by Mitsonobu reaction between acid (N3) and corresponding alcohols in presence of Triaryl phosphines and azo carboxylates such as DEAD, DIAD and like.

The reaction between compound of formula (N3) and substituted dialkyl dicarboxylates (compound of the formula (N4)) in presence of base provided compound of the formula (N5). This type of transformations can be carried out either at room temperature or at elevated temperatures using alkali bases such as NaOH, KOH and like; carbonates such as potassium carbonate, cesium carbonate and like; or organic bases like Triethylamine, diisopropylethyl amine and thereof; in amidic solvents like DMF, DMA and like; etheral solvents like 1, 4-dioxane, THF and thereof.

Compound of formula (N5) undergo reductive cyclization to provide compound of formula (N6). The reduction of nitro group was carried out using different reagents; although not limited, such reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like. These reactions are carried out in one or more solvents, e.g., ethers such as THF, 1, 4-dioxane, and the like; alcohol such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and mixtures thereof.

Compound of formula (N6) undergoes N-alkylation using alkyl halides and bases such as K2CO3, Na2CC>3, CS2CO3; organic bases like diisopropylethyl amine, DBU, DABCO and so on; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1,4-dioxane and like, at room temperature or elevated temperatures provide compound of formula (N7).

Compound of formula (N7) allowed to react with tert -butyl carbamate in the presence of catalyst such as (tris(dibenzylideneacetone) dipalladium(O), palladium (II) acetate, Bis(dibenzylideneacetone)2 Pd(0), racemic 2,2'-Bis(diphenylphosphino)-l,l'-binaphthyl, 2,5 bis(tri-t-butylphosphine) palladium (0) and the like; in presence of ligands such as RuPhos, Xanthphos, Davephos, BINAP, or the like; using a suitable base such as sodium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, DIPEA, Potassium triphosphate and thereof; in a suitable solvent selected from THF, 1,4-dioxane, dime thoxye thane, DMF, DMA, toluene and the like to provide compound of formula (N8).

Compound of formula (N8) undergoes deprotection using acids like organic acids such as trifluoroacetic acid, Methane sulfonic acid and like, mineral acids like hydrochloric acid, acetic acid (aqueous or in etheral solvents), sulfuric acid and the like; using solvents like dichloromethane, dichloroethane, THF, 1,4-dioxane and like thereof to provide compound of formula (N9).

Compound of formula (N9) allowed to react with alkylnitrile in presence of the acidic reagents such as methane sulfonic acid, sulfuric acid, hydrochloric acid or the like to obtain compound of formula (N10). The same transformation can be carried out using trialkyl orthoacetate in presence of ammonium acetate, in corresponding polar protic solvents like ethanol, methanol and thereof.

Alternatively, compound of formula (N8) on reaction with alkylnitrile in presence of the acidic reagents such as methane sulfonic acid, sulfuric acid, hydrochloric acid or the like can directly give compound of formula (N10)

Compound of formula (N10) can also be obtained directly from compound of formula (N8) by reaction alkylnitrile in presence of the acidic reagents such as methane sulfonic acid, sulfuric acid, hydrochloric acid and thereof.

Compound of formula (N 10) allowed to react with phosporyl halides such as POCI3 or POBrs optionally in solvents such as toluene, xylene, chlorobenzene or the like or the mixtures thereof, optionally using organic base such as tnethylamine, diisopropylethylamine or the like to provide compound of formula (Ni l).

Compound of formula (Ni l) allowed to react with compound of formula (A5) in presence of suitable coupling reagent to provide compound of formula (N12). The reaction can be carried out in presence of organic base such as diisopropylethylamine, triethylamine, DBU or the like, or using coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like; in etheral solvents such as THF, 1,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and thereof.

Compound of formula (N12) converted to compound of formula (I) in presence of alkali hydroxides such as NaOH, EiOH and thereof, in solvents like methanol, ethanol and thereof or using tetrabutyl ammonium halide in etheral solvents like THF, 1,4-dioxane and thereof.

Compound of formula (N12) undergoes decarboxylation reaction to furnish compound of the formula (N13). This transformation can be effected by acidic reagents such as mineral acids like sulfuric acid, organic acids like trifluoroacetic acid and thereof; similar transformation can be achieved using sodium chloride, lithium chloride and thereof, in solvents such as dimethyl sulfoxide and like; at elevated temperatures.

Compound of formula (N13) converted to compound of formula (I) using ceric ammonium nitrate, thallium nitrate and thereof in present of alcoholic solvents like methanol, ethanol and thereof.

Further, Compound of formula (N7) undergoes decarboxylation reaction to furnish compound of the formula (N14). This transformation can be achieved using sodium chloride, lithium chloride and thereof, in solvents such as dimethyl sulfoxide and like, at elevated temperatures. Similar transformation can be effected by acidic reagents such as mineral acids like sulfuric acid, organic acids like trifluoroacetic acid and thereof.

Compound of formula (N14) undergoes C-alkylation reaction with alkyl halides in presence of bases such as NaH, sodium/potassium alkoxides, K2CO3, Na2COs, CS2CO3;

organic bases like diisopropylethyl amine, DBU, DABCO and so on; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1, 4-dioxane and like, at room temperature or elevated temperatures provide compound of formula (N15)

Compound of formula (N15) can be converted to compound of formula (I) in five steps by employing analogous protocol mentioned above in scheme -N for the conversion of compound of formula (N7) to compound of formula (N12).

The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme-O herein below.

Compound of formula (01) converted to compound of formula (02) using Friedel craft acylation. This transformation was carried out by reaction of Compound of formula (01) with corresponding acyl halide in presence of Lewis acids such as aluminum trichloride, zinc chloride, boron trifluoride etherate and like, in halogenated solvents like dichloromethane, dichloroethane and like.

Compound of formula (02) was allowed to react with pyridine, optionally in solvents such as THF, toluene, xylene or the like or the mixtures thereof, followed by treatment of aqueous metal hydroxides like NaOH, KOH or the like or mixtures thereof to provide compound of formula (03).

Compound of formula (03) acid derivative undergoes esterification reaction to corresponding compound of formula (04) using solvents such as methanol, ethanol, propanol, tert-butanol using acidic conditions like hydrochloric acid, sulfuric acid, thionyl chloride or the like or mixture(s) thereof.

Compound of formula (04) was undergoes coupling with alkyl/substituted alkyl halide/dihalides to the corresponding formula (05) using bases like Lithium diisopropylamide, butyl lithium, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, sodium tert-butoxide, potassium tertbutoxide, sodium ethoxide, sodium methoxide, cesium carbonate, potassium carbonate or the like possibly in the presence of additives such as N,N,N',N' -Tetramethylethane- 1,2-diamine in solvents selected from THF, 1 ,4-dioxane, DMF and like.

Alternatively, the compound of formula (01) undergoes alkylation/acylation reaction to give compound of formula (Oi l) the reaction was carried out using alkyl halides/ acyl halide and bases like Lithium diisopropylamide, butyl lithium, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, sodium tert-butoxide, potassium tertbutoxide, sodium ethoxide, sodium methoxide, cesium carbonate, potassium carbonate or the like possibly in the presence of additives such as N,N,N',N'-Tetramethylethane-l,2-diamine in solvents selected from THF, 1,4-dioxane, DMF and like

Compound of formula (Oi l) was converted to compound of formula (013) by employing similar protocol mentioned above for conversion of compound of formula (01) to compound of formula (03).

Compound of formula (013) undergoes esterification reaction to corresponding compound of formula (05) using solvents such as methanol, ethanol, propanol, tertbutanol using acidic conditions like hydrochloric acid, sulfuric acid, thionyl chloride or the like or mixture(s) thereof.

Compound of formula (05) can be further reacted with alkyl halide, acyl chlorides using bases such as K2CO3, Na2COs, CS2CO3 etc. in polar aprotic solvents like DMF, DMS0 etc. at elevated temperatures leading to compound of formula (06) Compound of formula (06) allowed to react with tert -butyl carbamate in the presence of catalyst such as (tris(dibenzylideneacetone) dipalladium(O), palladium (II) acetate, Bis(dibenzylideneacetone)2 Pd(O), racemic 2,2'-Bis(diphenylphosphino)-l,l'-binaphthyl, 2,5 bis(tri-t-butylphosphine) palladium (0) and the like; in presence of ligands such as RuPhos, Xanthphos, Davephos, BINAP, or the like; using a suitable base such as sodium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, DIPEA, Potassium triphosphate and thereof; in a suitable solvent selected from THF, 1,4-dioxane, dime thoxye thane, DMF, DMA, toluene and the like to provide compound of formula (07).

Compound of formula (07) undergoes deprotection using acids like organic acids such as trifluoroacetic acid, Methane sulfonic acid and like, mineral acids like hydrochloric acid, acetic acid (aqueous or in etheral solvents), sulfuric acid and the like; using solvents like dichloromethane, dichloroethane, THF, 1,4-dioxane and like, to provide compound of formula (08).

Compound of formula (08) allowed to react with alkylnitrile in presence of the acidic reagents such as methane sulfonic acid, sulfuric acid, hydrochloric acid and the like to obtain compound of formula (09). The same transformation can be carried out using trialkyl orthoacetate in presence of ammonium acetate, in corresponding polar protic solvents like ethanol, methanol and thereof.

Further, compound of formula (07) on reaction with alkylnitrile in presence of the acidic reagents such as methane sulfonic acid, sulfuric acid, hydrochloric acid or the like can directly give compound of formula (09)

Compound of formula (09) allowed to react with phosporyl halides such as POCI3 or POBrs optionally in solvents such as toluene, xylene, chlorobenzene or the like or the mixtures thereof, optionally using organic base such as triethylamine, diisopropylethylamine or the like to provide compound of formula (010).

Compound of formula (010) allowed to react with compound of formula (A5) in presence of suitable coupling reagent to provide compound of formula (I). The reaction can be carried out in presence of organic base such as diisopropylethylamine, triethylamine, DBU or the like, or using coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like; in etheral solvents such as THF, 1,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and thereof.

Further, compound of formula (010) converted to compound of formula (014) using halogenating reagents such as NBS, NCS, bromine and like, in polar solvents such as DMF, AcOH, DCM and like.

Compound of formula (015) was prepared from compound of formula (014) using C-C coupling reactions such as Suzuki coupling reaction using corresponding boronic acid in presence of Pd catalyst such as tris(dibenzylideneacetone) dipalladium(O), palladium(II)acetate, Bis(dibenzylideneacetone)2Pd(0), rac 2,2'-Bis(diphenylphosphino)-l,l'-binaphthyl, 2,5 bis(tri-t-butylphosphine) palladium (0), Pd(PPh3)4 and like in base such as K2CO3, Na2CO3, CS2CO3, Potassium phosphate and like; in solvents such as toluene, 1,4-dioxane , DMA, DMF and like

The compound of formula (014) can be converted to compound of formula (I) using similar protocol used earlier for conversion of compound of formula (09) to compound of formula (I) in two steps.

The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme - P herein below.

SCHEME - P

Compound of the formula (P2) was obtained by oxidation of compound of the formula

(Pl). This transformation can be effected by oxidizing reagents such as potassium permanganate, potassium dichromate, sodium dichromate and like; in presence of acids like H2SO4, acetic acid and like.

Compound of formula (P2) undergoes N-alkylation using alkyl halides in presence of bases such as NaH, Potassium/sodium alkoxides, K2CO3, Na2COs, CS2CO3 organic bases like diisopropylethyl amine, DBU, DABCO and so on; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1,4-dioxane and like, at room temperature or elevated temperatures provide compound of formula (P3). Compound of formula (P3) undergoes reaction with organometallic reagents such as grignard reagent, dialkyl zinc , alkyl lithiums, and thereof; silane reagents such as trifluromethyl trimethyl silane and thereof; in etheral solvents such as THF, MTBE and like to provide compounds of formula (P4)

Compound of formula (P4)undergoes O-alkylation using alkyl halides in presence of bases such as sodium hydride, potassium /sodium alkoxide K2CO3, Na2CC>3, CS2CO3, NaH and thereof; organic bases like diisopropylethyl amine, DBU, DABCO and so on; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1,4-dioxane and like, at room temperature or elevated temperatures provide compound of formula (P5).

Compound of formula (P5) converted to compound of formula (P6) in presence of alkali hydroxides such as NaOH, LiOH and thereof, in solvents like methanol, ethanol and thereof or using solvents like THF, 1 ,4-dioxane and thereof.

Compound of formula (P6) on reaction with acetamidine, formamidine and like; in polar aprotic solvents like DMF, DMSO and metals like copper, thereof at temperature elevated temperatures afforded compound of formula (P7).

Alternatively, Compound of formula (P5) allowed to react with tert-butyl carbamate in the presence of catalyst such as (tris(dibenzylideneacetone) dipalladium(O), palladium (II) acetate, Bis(dibenzylideneacetone)2 Pd(0), racemic 2,2'-Bis(diphenylphosphino)-1,1' -binaphthyl, 2,5 bis(tri-t-butylphosphine) palladium (0) and the like; in presence of ligands such as RuPhos, Xanthphos, Davephos, BINAP, or the like; using a suitable base such as sodium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert- butoxide, DIPEA, Potassium triphosphate and thereof; in a suitable solvent selected from THF, 1,4-dioxane, dime thoxye thane, DMF, DMA, toluene and the like to provide compound of formula (P9).

Compound of formula (P9) undergoes deprotection using acids like organic acids such as trifluoroacetic acid, Methane sulfonic acid and like, mineral acids like hydrochloric acid, acetic acid (aqueous or in etheral solvents), sulfuric acid and the like; using solvents like dichloromethane, dichloroethane, THF, 1,4-dioxane and like thereof to provide compound of formula (PIO).

Compound of formula (PIO) allowed to react with alkylnitrile in presence of the acidic reagents such as methane sulfonic acid, sulfuric acid, hydrochloric acid or the like to obtain compound of formula (P7). The same transformation can be carried out using trialkyl orthoacetate in presence of ammonium acetate, in corresponding polar protic solvents like ethanol, methanol and thereof.

Alternatively, compound of formula (P9) on reaction with alkylnitrile in presence of the acidic reagents such as methane sulfonic acid, sulfuric acid, hydrochloric acid or the like can directly give compound of formula (P7)

Compound of formula (P7) allowed to react with phosporyl halides such as POCI3 or POBrs optionally in solvents such as toluene, xylene, chlorobenzene or the like or the mixtures thereof, optionally using organic base such as triethylamine, diisopropylethylamine or the like to provide compound of formula (P8).

Compound of formula (P8) allowed to react with compound of formula (A5) in presence of suitable coupling reagent to provide compound of formula (I). The reaction can be carried out in presence of organic base such as diisopropylethylamine, triethylamine, DBU or the like, or using coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like; in etheral solvents such as THF, 1,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and thereof.

The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme-Q herein below

The reaction between compound of formula (QI) and substituted dialkyl dicarboxylates in presence of base provided compound of the formula (Q2). This type of transformations can be carried out at appropriate temperature using alkali bases such as NaOH, KOH and like; carbonates such as potassium carbonate, cesium carbonate and like; or organic bases like Triethylamine, diisopropyl ethyl amine and the like; in amidic solvents like DMF, DMA and like; etheral solvents like 1, 4-dioxane, THF and mixtures thereof.

Compound of formula (Q2) undergoes decarboxylation reaction to furnish compound of formula (Q3). This transformation was carried out in polar solvents like DMSO, DMF, and like, using sodium chloride, lithium chloride and like. Similar transformation can be done using acids such as sulfuric acid, trifluoroacetic acid and like, at appropriate temperature.

Reductive cyclization of compound of the formula (Q3) provide compound of formula (Q4). The reduction of nitro group was carried out using different reagents; although not limited, such reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like. These reactions are carried out in one or more solvents, e.g., ethers such as THF, 1, 4-dioxane, and the like; alcohol such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and the like mixtures thereof.

Compound of formula (Q4) undergoes alkylation reaction by reacting with corresponding alkyl halide in presence of bases such as sodium hydride, potassium tert butoxide, K2CO3, Na2COs, CS2CO3; organic bases like diisopropyl ethyl amine, DBU, DABCO and the like; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1, 4-dioxane and like, at appropriate temperature provided compound of formula (Q5).

Alternatively, Compound of formula (Q3) undergoes C-alkylation reaction by reacting with corresponding alkyl halide in presence of bases such as sodium hydride, potassium tert butoxide and like; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1 , 4-dioxane and like, to provide compound of formula (QI 1). Compound of formula (QI 1) undergoes reductive cyclization similar to conversion of compound of formula (Q3) to compound of formula (Q4) to provide compound of formula (Q12). Compound of formula (Q12) undergoes N-alkylation reaction with alkyl halides in presence of bases such as NaH, Potassium/sodium alkoxides, K2CO3, Na2COs, CS2CO3 organic bases like diisopropylethyl amine, DBU, DABCO and so on; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1,4-dioxane and like, at room temperature or elevated temperatures provide compound of formula (Q5)

Alternatively, Compound of formula (Q2) undergoes C-alkylation using corresponding alkyl halide in presence of bases such as sodium hydride, potassium tert butoxide , K2CO3, Na2CC>3, CS2CO3 and like; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1,4-dioxane and like to provide compound of formula (Q13).

The compound of formula (Q13) was converted to compound of formula (Q15) in two steps viz. reductive cyclization and N-alkylation by following similar reactions employed for conversion of compound of formula (Q3) to compound of formula (Q5). Compound of formula (QI 5) undergoes decarboxylation reaction to furnish compound of formula (QI 6). This transformation was carried out in polar solvents like DMSO, DMF, and like, using sodium chloride, lithium chloride and like. Similar transformation can be done using acids such as sulfuric acid, trifluoroacetic acid and like, at elevated temperatures.

Compound of formula (QI 6) undergoes C-alkylation using corresponding alkyl halide in presence of bases such as sodium hydride, potassium tert butoxide , K2CO3, Na2CO3, CS2CO3 and like; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1,4-dioxane and like to provide compound of formula (Q5).

Compound of formula (Q5) allowed to react with tert -butyl carbamate in the presence of catalyst such as (tris(dibenzylideneacetone)dipalladium(O), palladium(II) acetate, Bis(dibenzylideneacetone)2 Pd(0), rac 2,2'-Bis(diphenylphosphino)-l,r-binaphthyl, 2,5 bis(tri-t-butylphosphine) palladium (0) and the like; in presence of ligands such as RuPhos, Xanthphos, Davephos, BINAP, or the like; using a suitable base such as sodium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, DIPEA, Potassium triphosphate and thereof; in a suitable solvent selected from THF, 1 ,4-dioxane, dimethoxyethane, DMF, DMA, toluene and the like to provide compound of formula (Q6).

Compound of formula (Q6) undergoes deprotection using acids like organic acids such as trifluoroacetic acid, Methane sulfonic acid and like, mineral acids like hydrochloric acid, acetic acid (Aqueous or in etheral solvents), sulfuric acid and the like; using solvents like dichloromethane, dichloroethane, THF, 1,4-dioxane and like thereof to provide compound of formula (Q7).

Compound of formula (Q7) allowed to react with alkylnitrile in presence of the acidic reagents such as methane sulfonic acid, sulfuric acid, hydrochloric acid or the like to obtain compound of formula (Q8). The same transformation can be carried out using trialkyl orthoacetate in presence of ammonium acetate, in corresponding polar protic solvents like ethanol, methanol and thereof.

Alternatively, compound of formula (Q6) on reaction with alkylnitrile in presence of the acidic reagents such as methane sulfonic acid, sulfuric acid, hydrochloric acid or the like can directly give compound of formula (Q8)

Compound of formula (Q8) allowed to react with phosporyl halides such as POCI3 or POBrs optionally in solvents such as toluene, xylene, chlorobenzene or the like or the mixtures thereof, optionally using organic base such as triethylamine, diisopropylethylamine or the like to provide compound of formula (Q9).

Compound of formula (Q9) allowed to react with compound of formula (A5) in presence of suitable coupling reagent to provide compound of formula (I). The reaction can be carried out in presence of organic base such as diisopropylethylamine, triethylamine, DBU or the like, or using coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like; in etheral solvents such as THF, 1,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and thereof.

Compound of formula (Q9) allowed to react with l-(3-(l-aminoethyl)-2-fluorophenyl)- 1 , 1 -difluoro-2-methylpropan-2-ol hydrochloride in presence of suitable coupling reagent to provide compound of formula (I). The reaction can be carried out in presence of organic base such as diisopropylethylamine, triethylamine, DBU or the like, or using coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like; in etheral solvents such as THF, 1,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and thereof.

Compound of formula (I) allowed to react with fluorinating reagent such as DAST, martin sulfurane in solvents such as DCM, chloroform, THF, ether, 1,4-dioxane to provide compound of formula (Q10).

Compound of formula (Q10) allowed to react with osmium tetra oxide, potassium osmate dihydrate (Sharpless asymmetric dihydroxylation method) using potassium chlorate, hydrogen peroxide, potassium ferricyanide, N-methylmorpholine N-oxide, chiral quinine or the like, in solvents like acetone, tert butanol water system to provide compound of formula (I).

Compound of formula (I) undergoes mesylation, tosylation and thereof , reactions in presence of organic bases such as TEA, DIPEA, Pyridine and like, in solvents such as THF, DCM and mixtures thereof, to provide compound of formula (Q17)

Compound of formula (QI 7) undergoes displacement reaction with primary or secondary amines in presence of alcohol solvents such as ethanol, IPA and mixtures thereof to provide compound of formula (I).

Compound of formula (Q10) undergoes epoxidation reaction to provide compound of formula (QI 8). This reaction is effected by hydrogen peroxide in presence of acidic medium using organic acids such as formic acid and like.

Compound of formula (QI 8) on epoxide opening by nucleophilic reagent provide compound of formula (I). Such transformations can be effected by reaction of epoxide compound with various nucleophilic reagents such as sodium alkoxides, primary or

secondary amines in alcohol solvents like ethanol, methanol, and like and at room temperature or elevated temperature.

The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme-R herein below

The reaction between compound of formula (Rl) and substituted dialkyl dicarboxylates (compound of the formula (R2) in presence of base provided compound of the formula (R3). This type of transformations can be carried out either at room temperature or at elevated temperatures using alkali bases such as NaOH, KOH and like; carbonates such as potassium carbonate, cesium carbonate and like; or organic bases like triethylamine, diisopropylethyl amine and thereof; in amidic solvents like DMF, DMA and like; etheral solvents like dioxane, THF and thereof.

Compound of formula (R3) undergoes alkylation using alkyl halides in presence of bases such as sodium hydride, potassium /sodium alkoxide bases such as K2CO3, Na2COs, CS2CO3; organic bases like diisopropylethyl amine, DBU, DABCO and so on; in polar aprotic solvents like DMF, DMSO and like, at room temperature or elevated temperatures provide compound of formula (R4).

Compound of formula (R4) allowed to react with tert-butyl carbamate in the presence of catalyst such as (tris(dibenzylideneacetone) dipalladium(O), palladium (II) acetate, Bis(dibenzylideneacetone)2 Pd(0), rac 2,2'-Bis(diphenylphosphino)-l,l'-binaphthyl,2,5 bis(tri-t-butylphosphine) palladium (0) and the like; in presence of ligands such as RuPhos, Xanthphos, Davephos, BINAP, or the like; using a suitable base such as sodium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, DIPEA, Potassium triphosphate and thereof; in a suitable solvent selected from THF, 1,4-dioxane, dimethoxyethane, DMF, DMA, toluene and the like to provide compound of formula (R5).

Compound of formula (R5) undergo reductive cyclization to provide compound of formula (R6). This nitro reduction can be achieved by reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like. These reactions are carried out in one or more solvents, e.g., ethers such as THF, 1,4-dioxane, and the like; alcohol such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and the like mixtures thereof.

Compound of formula (R6) undergoes N-alkylation using alkyl halides in presence of bases such as sodium hydride, potassium /sodium alkoxide bases such as K2CO3, Na2CC>3, CS2CO3; organic bases like diisopropylethyl amine, DBU, DABCO and so on; in polar aprotic solvents like DMF, DMSO and like, at room temperature or elevated temperatures provide compound of formula (R7).

Compound of formula (R7) can be converted to the compound of formula (Rl l) by employing 4 step protocol mentioned in conversion of compound of formula (N8) to compound of formula (N12)

Compound of formula (Rl l) undergoes decarboxylation reaction to furnish compound of the formula (R12). This transformation can be effected by acidic reagents such as mineral acids like sulfuric acid, organic acids like trifluoroacetic acid and thereof; similar transformation can be achieved using sodium chloride, lithium chloride and thereof, in solvents such as dimethyl sulfoxide and like; at elevated temperatures. Compound of formula (R12) converted to compound of formula (I) using ceric ammonium nitrate, thallium nitrate and thereof in present of alcoholic solvents like methanol, ethanol and thereof.

Further, Compound of formula (Rl l) on reaction with alkalis such as NaOH, LiOH and like, in alcoholic solvents like methanol ethanol and thereof, provide compound of formula (I) where (Rd= -OH)

Compound of formula (RIO) undergoes nucleophilic substitution along with air oxidation in presence of bases like LiOH and like, in alcoholic solvent such as methanol in presence of air, provide compound of formula (R13).

Compound of formula (R13) on O-alkylation using corresponding alkyl halide in presence of bases such as sodium hydride, potassium tert butoxide , K2CO3, Na2CO3, CS2CO3 and like; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1,4-dioxane and like to provide compound of formula (R14). This reaction Yielded decarboxylation product viz. compound of formula (R15).

Compound of formula (R14) undergoes coupling reaction with compound of formula (A5) to furnish compound of formula (I). The reaction can be carried out in presence of organic base such as diisopropylethylamine, triethylamine, DBU or the like, or using coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like; either neat reaction in base or in etheral solvents such as THF, 1 ,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and thereof.

Compound of formula (R15) undergoes fluorination reaction by fluorinating reagents such as DAST, selectflour and thereof, or C-alkylation reaction with various alkyl halides in presence of bases such as sodium hydride, potassium tert butoxide , K2CO3, Na2CC>3, CS2CO3 and like; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1 ,4-dioxane and like to give compound of formula (R16).

Compound of formula (R16) can be converted to compound of formula (I) by analogous protocol mentioned above for the conversion of (R14) to compound of formula (I).

The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme S:

Compound of formula (S2) was prepared from compound of formula (S 1) by oxidation reaction followed by N-alkylation reaction. This oxidation was effected by reagents like tertiary butyl hydroperoxide, selenium dioxide, manganese dioxide and like; in presence of catalytic Cui, Cu(I) reagents and thereof. Further the N-alkylation was carried out by using alkyl halides in presence of bases such as sodium hydride, potassium /sodium alkoxide bases such as K2CO3, Na2COs, CS2CO3; organic bases like diisopropylethyl amine, DBU, DABCO and so on; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1,4-dioxane and like, at room temperature or elevated temperatures provide compound of formula (S2)

Compound of formula (S2) undergoes reaction with organometallic reagents such as Grignard reagent, dialkyl zinc , alkyl lithiums, and thereof; silane reagents such as trifluoromethyl trimethyl silane and thereof; in etheral solvents such as THF, MTBE and like to provide compounds of formula (S3)

Compound of formula (S3) undergoes O-alkylation to provide compound of formula (S4). This transformation can be effected by using alkyl halides in presence of bases such as sodium hydride, potassium /sodium alkoxide K2CO3, Na2CC>3, CS2CO3, sodium hydride; organic bases like diisopropylethyl amine, DBU, DABCO and so on; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1,4-dioxane and like, at room temperature or elevated temperatures.

Compound of formula (S5) can be prepared from compound of formula (S4) by employing halogenation reaction. Such reactions can be carried out in presence of halogenating reagents such as N-halo succinamide, hydrohaloic acid and likes; in solvents like DMF, Acetic acid and thereof; optionally in presence additives such as trifluoroacetic acid and like, in catalytic or molar proportions; and at room temperature or at elevated temperatures.

Compound of formula (S5) undergoes hydrolysis of ester group to provide compound of formula (S6). This transformation can be effected in presence of alkali hydroxides such as NaOH, LiOH and thereof, in solvents like methanol, ethanol and thereof or using solvents like THF, 1 ,4-dioxane and thereof

Compound of formula (S6) on reaction with acetarmdine, formamidine and like; in polar aprotic solvents like DMF, DMSO and metals copper and like; optionally in presence of additives like proline and thereof, at room temperature or elevated temperatures afforded compound of formula (S7).

Alternatively compound of formula (S7) can be prepared in three steps. Compound of formula (S4) undergoes nitration reaction to provide compound of formula (S9). This reaction was carried out in presence of nitrating reagents such as potassium nitrate, sodium nitrate nitric acid and like; in acidic solvents such as sulfuric acid and thereof. Compound of formula (S9) undergoes reduction reaction to provide compound of formula (S10). These transformations can be carried out using reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like. These reactions are carried out in one or more solvents, e.g., ethers such as THF, 1,4-dioxane, and the like; alcohol such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and the like mixtures thereof

Compound of formula (S10) allowed to react with alkylnitrile in presence of the acidic reagents such as methane sulfonic acid, sulfuric acid, hydrochloric acid or the like to obtain compound of formula (S7). The same transformation can be carried out using trialkyl orthoacetate in presence of ammonium acetate, in corresponding polar protic solvents like ethanol, methanol and thereof.

Compound of formula (S7) allowed to react with phosporyl halides such as POCI3 or POBrs optionally in solvents such as toluene, xylene, chlorobenzene or the like or the mixtures thereof, optionally using organic base such as triethylamine, diisopropylethylamine or the like to provide compound of formula (S8).

Compound of formula (S8) allowed to react with compound of formula (A5) in presence of suitable coupling reagent to provide compound of formula (I). The reaction can be carried out in presence of organic base such as diisopropylethylamine, triethylamine, DBU or the like, or using coupling reagents such as DCC, EDC, BOP,

pyBOP, HBTU or the like; either neat or in etheral solvents such as THF, 1,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and thereof

Further, compound of formula (S2) undergoes difluorination reaction with reagents such as DAST, selectfluor and like, in chlorinated solvent like dichloromethane and like; provided compound of formula (S 11) ( Rc, Rd = F)

Also, compound of formula (SI) undergoes c-alkylation and N-alkylation simultaneously in presence of alkyl halides in presence of bases such as sodium hydride, potassium /sodium alkoxide, K2CO3, Na2COs, CS2CO3; organic bases like diisopropylethyl amine, DBU, DABCO and so on; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1,4-dioxane and like, at room temperature or elevated temperatures provide compound of formula (Si l) ( Rc, Rd = alkyl)

Compound of formula (Si l) can be converted to compound of formula (I) by employing analogous five step protocol as mentioned above for conversion of compound of formula (S4) to compound of formula (I).

Further, Compound of formula (Si l) can be converted to compound of formula (S14) by employing analogous three step protocol as mentioned above for conversion of compound of formula (S4) to compound of formula (S7) via compound of formula (S5) followed by compound of formula (S6).

Compound of formula (SI 4) can be converted to compound of formula (I) by employing analogous two step protocol as mentioned above for conversion of compound of formula (S7) to compound of formula (I).

Compound of formula (I) further on reaction with various organometallic reagents like LiAlH4,BH3-DMS and like provide compound of formula (I) These reactions are carried out in one or more solvents, e.g., ethers such as THF, 1,4-dioxane, and the like The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme T :

R1 = Alkyl

R' = Alkyl

Rb= alkyl , Cycloalkyl

Ra= Alkyl, Cycloalkyl

X, X1= Halogen SCHEME - T

Nitration of compound of formula (Tl) with nitrating reagents such as, although not limited to fuming nitric acid, potassium nitrate, and the like in acids such as, although not limited to tin (IV) chloride, sulphuric acid, trifluoracetic acid, acetic acid and the like, anhydrides like acetic anhydride, trifluoracetic anhydride and the like, or mixture(s) thereof to provide compound of formula (T2).

Compound of formula (T2) undergoes esterification reaction to corresponding compound of formula (T3) using solvents such as methanol, ethanol, propanol, tertbutanol using acidic conditions like hydrochloric acid, sulfuric acid, thionyl chloride or the like or mixture(s) thereof.

Compound of formula (T3) derivative undergoes N-alkylation reaction to corresponding compound of formula (T4) using alkylamine and solvents such as methanol, ethanol, propanol, tert-butanol.

Compound of the formula (T4) on reduction of nitro group to corresponding amlimc compound of formula (T5). The reduction of nitro group was carried out using different reagents; although not limited, such reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like. These reactions are carried out in one or more solvents, e.g., ethers such as THF, 1,4-dioxane, and the like; alcohol such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and the like mixtures thereof.

Cyclization of compound of the formula (T5) using CDI in polar aprotic solvents like DMF, DMSO, halogenated solvents like DCM, chloroform, ethereal solvents like THF, 1,4-dioxane, at room temperature or elevated temperatures provided compound of formula (T6).

Compound of formula (T6) undergoes N-alkylation using alkyl halides in presence of bases such as sodium hydride, potassium /sodium alkoxide K2CO3, Na2COs, CS2CO3; organic bases like diisopropylethyl amine, DBU, DABCO and so on; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1,4-dioxane and like, at room temperature or elevated temperatures provide compound of formula (T7).

Compound of formula (T7) allowed to react with tert -butyl carbamate in the presence of catalyst such as (tris(dibenzylideneacetone)dipalladium(O), palladium(II) acetate, Bis(dibenzylideneacetone)2 Pd(0), rac 2,2'-Bis(diphenylphosphino)-l,r-binaphthyl, 2,5 bis(tri-t-butylphosphine) palladium (0) and the like; in presence of ligands such as RuPhos, Xanthphos, Davephos, BINAP, or the like; using a suitable base such as sodium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, DIPEA, Potassium triphosphate and thereof; in a suitable solvent selected from THF, 1 ,4-dioxane, dimethoxy ethane, DMF, DMA, toluene and the like to provide compound of formula (T8).

Compound of formula (T8) undergoes deprotection using acids like organic acids such as trifluoroacetic acid, Methane sulfonic acid and like, mineral acids like hydrochloric acid, acetic acid (Aqueous or in etheral solvents), sulfuric acid and the like; using solvents like dichloromethane, dichloroethane, THF, 1,4-dioxane and like thereof to provide compound of formula (T9).

Compound of formula (T9) allowed to react with alkyl nitrile in presence of the acidic reagents such as methane sulfonic acid, sulfuric acid, hydrochloric acid or the like to obtain compound of formula (T10). The same transformation can be carried out using trialkyl orthoacetate in presence of ammonium acetate, in corresponding polar protic solvents like ethanol, methanol and thereof.

Compound of formula (T10) allowed to react with phosporyl halides such as POCI3 or POBrs optionally in solvents such as toluene, xylene, chlorobenzene or the like or the mixtures thereof, optionally using organic base such as triethylamine, diisopropylethylamine or the like to provide compound of formula (Ti l).

Compound of formula (Ti l) allowed to react with compound of formula (A5) in presence of suitable coupling reagent to provide compound of formula (I). The reaction can be carried out in presence of organic base such as diisopropylethylamine, triethylamine, DBU or the like, or using coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like; in etheral solvents such as THF, 1,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and thereof.

The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme U :

SCHEME - U

Compound of formula (T4) on reaction with acetamidine, formamidine and like; in polar aprotic solvents like DMF, DMSO and thereof at temperature elevated temperatures afforded compound of formula (U2).

Compound of formula (U2) allowed to react with phosporyl halides such as POCI3 or POBrs optionally in solvents such as toluene, xylene, chlorobenzene or the like or the mixtures thereof, optionally using organic base such as triethylamine, diisopropylethylamine or the like to provide compound of formula (U3).

Compound of formula (U3) allowed to react with compound of formula (A5) in presence of suitable coupling reagent to provide compound of formula (U4). The reaction can be carried out in presence of organic base such as diisopropylethylamine, triethylamine, DBU or the like, or using coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like; in etheral solvents such as THF, 1,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and thereof.

Reduction of compound of the formula (U4) provide compound of formula (U5). The reduction of nitro group was carried out using different reagents; although not limited, such reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like. These reactions are carried out in one or more solvents, e.g., ethers such as THF, 1,4-dioxane, and the like; alcohol such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and the like mixtures thereof.

Cyclization of compound of the formula (U5) using corresponding ketone in acid catalyst like pTsOH, Benzene sulphonic acid, sulfuric acid and acetic acid at room temperature or elevated temperatures provided compound of formula (U6).

Compound of formula (U6) undergoes N-alkylation using alkyl halides in presence of bases such as sodium hydride, potassium /sodium alkoxide K2CO3, Na2COs, CS2CO3; organic bases like diisopropylethyl amine, DBU, DABCO and so on; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1,4-dioxane and like, at room temperature or elevated temperatures provide compound of formula (I).

The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme V :

SCHEME - V

Compound of formula (V2) can be prepared from compound of formula (VI) via reductive cyclization reaction. This transformations can be carried out using reducing reagents such as contact hydrogenation in presence of Raney nickel, Pd/C, Pt/C and like; in etheral solvents such as 1,4-dioxane and like; optionally at room temperature or at elevated temperatures.

Compound of formula (V2) undergoes diazotization reaction using tert-butyl nitrite, isoamyl nitrite, sodium nitrite and like; followed by reaction with copper halides and like; can provide compound of formula (V3)

Compound of formula (V3) undergoes C-alkylation and N-alkylation simultaneously in presence of alkyl halides in presence of bases such as sodium hydride, potassium /sodium alkoxide K2CO3, Na2COs, CS2CO3; organic bases like diisopropylethyl amine, DBU, DABCO and so on; in polar aprotic solvents like DMF, DMSO, acetone and

like, etheral solvents such as THF, 1,4-dioxane and like, at room temperature or elevated temperatures provide compound of formula (V4)

Compound of formula (V4) can be converted to compound of formula (I) by employing analogous 3 step protocol mentioned in scheme-P for conversion of compound of formula (P6) to compound of formula (I).

The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme W :

SCHEME - W

Compound of formula (Wl) undergoes esterification reaction to provide compound of formula (W2). This transformation can be effected by reaction of alcohols such as methanol, ethanol and like; in presence of mineral acids like sulfuric acid, organic acids like methane sulfonic acid and like, or in presence of chloride reagents like thionyl chloride, oxalyl chloride and thereof. This transformation can also be effected by Mitsonobu reaction between acid (Wl) and corresponding alcohols in presence of Triaryl phosphines and azocarboxylates such as DEAD, DIAD and like.

Compound of formula (W2) undergoes benzylic halogenation reaction using halogenating reagents like N-halo succinimide and thereof; in presence of initiators such as benzoyl peroxide, AIBN and like; in solvents such as carbon tetrachloride and thereof; at elevated temperature provide compound of formula (W3).

Compound of formula (W3) on reaction with ammonium hydroxide at room temperature or at elevated temperatures in alcoholic solvents like methanol, ethanol and like; undergoes cyclization reaction to provide compound of formula (W4).

Compound of formula (W4) undergoes C-alkylation and N-alkylation simultaneously in presence of alkyl halides in presence of bases such as sodium hydride, potassium /sodium alkoxide K2CO3, Na2COs, CS2CO3; organic bases like diisopropylethyl amine, DBU, DABCO and so on; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1,4-dioxane and like, at room temperature or elevated temperatures provide compound of formula (W5).

Compound of formula (W5) on reaction with metal cyanides such as Copper(I) cyanide and like in polar aprotic solvent such as DMF and like at elevated temperatures afford compound of formula (W6).

Compound of formula (W6) undergoes hydrolysis reaction to furnish compound of formula (W7). This transformation can be carried out in presence of alkali hydroxides such as NaOH, LiOH and thereof, in solvents like methanol, ethanol and thereof or using solvents like DMF, THF, 1,4-dioxane.

Compound of formula (W7) can be converted to compound of formula (I) by employing analogous 3 step protocol mentioned in scheme P for conversion of compound of formula (P6) to compound of formula (I).

The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme-Y herein below

Compound of formula (Yl) undergoes reaction with bases such as K2CO3, Na2COs, CS2CO3 and like; in solvents such as DMF, DMSO and thereof, at elevated temperatures to afford compound of formula (Y2)

Compound of formula (Y2) undergoes reduction reaction to furnish compound of formula (Y3). Such reductions of nitro group were carried out using different reagents; although not limited, such reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like. These reactions are carried out in one or more solvents, e.g., ethers such as THF, 1,4-dioxane, and the like; alcohol such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and the like mixtures thereof.

Cyclization of compound of the formula (Y3) using CDI in polar aprotic solvents like DMF, DMSO, halogenated solvents like DCM, chloroform, ethereal solvents like THF,

1,4-dioxane, at room temperature or elevated temperatures provided compound of formula (Y4).

Compound of formula (Y4) undergoes N-alkylation using alkyl halides in presence of bases such as NaH, Potassium/sodium alkoxides, K2CO3, Na2COs, CS2CO3; organic bases like diisopropylethyl amine, DBU, DABCO and so on; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1,4-dioxane and like, at room temperature or elevated temperatures provide compound of formula (Y5). Compound of formula (Y5) allowed to react with tert-butyl carbamate in the presence of catalyst such as (tris(dibenzylideneacetone) dipalladium(O), palladium (II) acetate, Bis(dibenzylideneacetone)2 Pd(0), racemic 2,2'-Bis(diphenylphosphino)-l,l'-binaphthyl, 2,5 bis(tri-t-butylphosphine) palladium (0) and the like; in presence of ligands such as RuPhos, Xanthphos, Davephos, BINAP, or the like; using a suitable base such as K2CO3, Na2CC>3, CS2CO3, sodium tert-butoxide, potassium tert-butoxide, DIPEA, Potassium triphosphate and thereof; in a suitable solvent selected from THF, 1 ,4-dioxane, dimethoxy ethane, DMF, DMA, toluene and the like to provide compound of formula (Y6).

Compound of formula ( Y 6) undergoes deprotection in acidic conditions using organic acids such as trifluoroacetic acid, Methane sulfonic acid and like, mineral acids like hydrochloric acid, acetic acid (aqueous or in etheral solvents), sulfuric acid and the like; using solvents like dichloromethane, dichloroethane, THF, 1,4-dioxane and like thereof to provide compound of formula (Y7).

Compound of formula (Y7) allowed to react with alkylnitrile in presence of the acidic reagents such as methane sulfonic acid, sulfuric acid, hydrochloric acid or the like to obtain compound of formula (Y8). The same transformation can be carried out using trialkyl orthoacetate in presence of ammonium acetate, in corresponding polar protic solvents like ethanol, methanol and thereof.

Compound of formula (Y8) allowed to react with phosporyl halides such as POCI3 or POBr3 optionally in solvents such as toluene, xylene, chlorobenzene or the like or the mixtures thereof, optionally using organic base such as triethylamine,

diisopropylethylamine or the like at room temperature or elevated temperatures to provide compound of formula (Y9).

Compound of formula (Y9) allowed to react with compound of formula (A5) in presence of suitable coupling reagent to provide compound of formula (I). The reaction can be carried out in presence of organic base such as diisopropylethylamine, triethylamine, DBU or the like, or using coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like; in etheral solvents such as THF, 1,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and like, at elevated temperatures.

R2 and R3 are independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl;

R4 is selected from halogen, cyano, -NR'Ti OR’, -C(=O)Rg, -C(=O)NRh(R1), substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, cycloalkyl substituted with substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, and heterocyclyl substituted with substituted alkyl;

Re and Rf are independently selected from hydrogen, -C(=O)Rg, -C(=O)NRh(R‘), substituted or unsubstituted alkyl, alkyl substituted with substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl;

Rg is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl;

Rh and R' are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl;

optionally Rh and R1 groups together with the nitrogen atom to which they are attached forming a substituted or unsubstituted heterocycle;

RJ is selected from hydrogen, substituted or unsubstituted alkyl, alkyl substituted with substituted or unsubstituted cycloalkyl, and substituted or unsubstituted cycloalkyl;

‘n’ is an integer selected from 0, 1, 2, and 3;

when an alkyl group is substituted, it is substituted with 1 to 5 substituents independently selected from oxo (=0), halogen, cyano, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR5, -C(=0)0H, -C(=O)O(alkyl), -NR6R6a, -NR6C(=O)R7, and -C(=O)NR6R6a;

when an cycloalkyl group is substituted, it is substituted with 1 to 4 substituents independently selected from oxo (=0), halogen, alkyl, hydroxyalkyl, cyano, aryl, heteroaryl, heterocyclyl, -OR5, -C(=0)0H, -C(=O)O(alkyl), -NR6R6a, -NR6C(=O)R7, and -C(=O)NR6R6a;

when the aryl group is substituted, it is substituted with 1 to 4 substituents independently selected from halogen, nitro, cyano, alkyl, perhaloalkyl, cycloalkyl, heterocyclyl, heteroaryl, -OR5, -NR6R6a, -NR6C(=O)R7, -C(=0)R7, -C(=O)NR6R6a, -SO2-alkyl, -C(=0)0H, -C(=O)O-alkyl, and haloalkyl;

when the heteroaryl group is substituted, it is substituted with 1 to 4 substituents independently selected from halogen, nitro, cyano, alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR5, -NR6R6a, -NR5C(=O)R7, -C(=0)R7, -C(=O)NR6R6a, -SO2-alkyl, -C(=0)0H, and -C(=O)O-alkyl;

when the heterocycle group is substituted, it is substituted either on a ring carbon atom or on a ring hetero atom, and when it is substituted on a ring carbon atom, it is substituted with 1 to 4 substituents independently selected from oxo (=0), halogen, cyano, alkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl, perhaloalkyl, -OR5, -C(=O)NR6R6a, -C(=0)0H, -C(=O)O-alkyl, -N(H)C(=O)(alkyl), -N(H)R6, and -N(alkyl)2; and when the heterocycle group is substituted on a ring nitrogen, it is substituted with substituents independently selected from alkyl, cycloalkyl, aryl, heteroaryl, -SO2(alkyl), -C(=0)R7, and - C(=O)O(alkyl); when the heterocycle group is substituted on a ring sulfur, it is substituted with 1 or 2 oxo (=0) group(s);

R5 is selected from hydrogen, alkyl, perhaloalkyl, and cycloalkyl;

R6 and R6a are each independently selected from hydrogen, alkyl, and cycloalkyl;

or R6 and R6a together with nitrogen to which they are attached form a heterocyclyl ring; and

R7 is selected from alkyl and cycloalkyl;

and wherein the S0S1 inhibitor of formula (II), its tautomeric form, its stereoisomer, its pharmaceutical acceptable salt, its polymorph, or solvate thereof,

Wherein

Ring A is selected from aryl, heteroaryl, and heterocyclyl;

‘ ’ is either a single bond or double bond;

X and Y are independently selected from C, O, and NR , provided that both X and Y cannot be O at the same time;

R1 is selected from hydrogen and substituted or unsubstituted alkyl;

R2is selected from hydrogen, halogen, alkyl, and cycloalkyl;

R3 is selected from -OR6, -NRaRb, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, alkyl substituted with substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl;

R4is selected from oxo and substituted or unsubstituted alkyl;

R5 is selected from halogen, cyano, -NRcRd, substituted or unsubstituted alkyl, -C(=O) substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; optionally two R5 groups attached to the adjacent carbon atoms forming substituted or unsubstituted heterocycle;

R6 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl, and alkyl substituted with substituted heterocyclyl;

Ra and Rb are independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted heterocyclyl;

Rc and Rd are independently selected from hydrogen and alkyl;

m is an integer selected from 0, 1, 2, and 3;

n is an integer selected from 0, 1, 2, 3, and 4;

when an alkyl group is substituted, it is substituted with 1 to 5 substituents independently selected from oxo (=0), halogen, cyano, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR7, -C(=0)0H, -C(=O)O(alkyl), -NR8R8a, -NR8C(=O)R9, and -C(=O)NR8R8a;

when an cycloalkyl group is substituted, it is substituted with 1 to 4 substituents independently selected from oxo (=0), halogen, alkyl, hydroxyalkyl, cyano, aryl, heteroaryl, heterocyclyl, -OR7, -C(=0)0H, -C(=O)O(alkyl), -NR8R8a, -NR8C(=O)R9, and -C(=O)NR8R8a;

when the aryl group is substituted, it is substituted with 1 to 4 substituents independently selected from halogen, nitro, cyano, alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocyclyl, heteroaryl, -OR7, -NR8R8a, -NR8C(=O)R9, -C(=0)R9, -C(=O)NR8R8a, -SO2-alkyl, -C(=0)0H, and -C(=O)O-alkyl;

when the heteroaryl group is substituted, it is substituted with 1 to 4 substituents independently selected from halogen, nitro, cyano, alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR7, -NR8R8a, -NR7C(=O)R9, -C(=0)R9, -C(=O)NR8R8a, -SO2-alkyl, -C(=0)0H, and -C(=O)O-alkyl;

when the heterocycle group is substituted, it is substituted either on a ring carbon atom or on a ring hetero atom, and when it is substituted on a ring carbon atom, it is substituted with 1 to 4 substituents independently selected from oxo (=0), halogen, cyano, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl, perhaloalkyl, -OR7, -C(=O)NR8R8a, -C(=0)0H, -C(=O)O-alkyl, - N(H)C(=O)(alkyl), -N(H)R8, and -N(alkyl)2; and when the heterocycle group is substituted on a ring nitrogen, it is substituted with substituents independently selected from alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, -SO2(alkyl), -

C(=O)R9, and -C(=O)O(alkyl); when the heterocycle group is substituted on a ring sulfur, it is substituted with 1 or 2 oxo (=0) group(s);

R7 is selected from hydrogen, alkyl, perhaloalkyl, and cycloalkyl;

R8 and R8a are each independently selected from hydrogen, alkyl, and cycloalkyl; and

R9 is selected from alkyl and cycloalkyl.

2. The Pharmaceutical combination as claimed in claim 1, wherein the S0S1 inhibitor of is selected from the group consisting of:

(R)-4-((l-(3-(l,l-Difluoro-2-hydroxy-2-methylpropyl)-2- fhiorophenyl)ethyl)amino)-2,6,8,8-tetramethyl-6,8-dihydro-7H-pyrrolo[2,3- g]quinazolin-7-one (Compound 1);

R/S)-4-(( 1 -(3-( 1 ,l-difluoro-2-hydroxy-2-methylpropyl)phenyl)ethyl)amino)- 2,6,8,8-tetramethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 2);

-(((R)- 1 -(3-((R&S)- 1 , 1 -Difhroro-2,3-dihydroxy-2-methylpropyl)-2- fluorophenyl) ethyl)amino)-2,6,8,8-tetramethyl-6,8-dihydro-7H-pyrrolo[2,3- g]quinazolin-7-one (Compound 3);

4-(((R)- l-(3-((R/S)- 1 , 1 -difhroro-2,3-dihydroxy-2-methylpropyl)-2- fhiorophenyl)ethyl)amino)-2,6,8,8-tetramethyl-6,8-dihydro-7H-pyrrolo[2,3- g]quinazolin-7-one (Compound 3a);

4-(((R)- 1 -(3-((S/R)- 1 , 1 -difhroro-2,3-dihydroxy-2-methylpropyl)-2- fhiorophenyl)ethyl)amino)-2,6,8,8-tetramethyl-6,8-dihydro-7H-pyrrolo[2,3- g]quinazolin-7-one (Compound 3b);

(R&S)-4-(((R)-l-(3-(l,l-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl) ethyl) amino)-8-methoxy-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 4);

(S/R)-4-(((R)- 1 -(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethy 1) amino) - 8-methoxy-2 ,6,8 -trimethy l-6H-pyrrolo [2,3-g]quinazolin-7(8H)-one (Compound 4a);

(R/S)-4-(((R)- 1 -(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl) amino)-8-methoxy-2,6,8-trimethyl-6H-pyrrolo[2,3-g]quinazolin-7(8H)-one (Compound 4b);

(R)-5-(4-((l-(3-amino-5-(trifluoromethyl) phenyl) ethyl) amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)- 1 -methylpyridin-2( 1 H)-one (Compound 5);

(R&S)-4-(((R)-l-(3-(l,l-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 6);

(S/R)-4-(((R)- 1 -(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 6a);

(R/S)-4-(((R)- 1 -(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 6b); and

(S)-4-(((R)-l -(3 -amino-5 -(trifluoromethyl) phenyl) ethyl)amino)-8-methoxy-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 7);

or a pharmaceutically acceptable salt, a hydrate, or a stereoisomer thereof.

3. The pharmaceutical combination as claimed in anyone of claims 1 to 2, wherein the additional active ingredient selected from a KRAS inhibitor, KRASG12C inhibitor, and KRAS-G12D inhibitors.

. The pharmaceutical combination as claimed in claim 3, wherein the additional active ingredient is selected from Sotorasib (AMG510), MRTX849, JDQ443, LY-3537982, JNJ-74699157, JAB-21822, GDC-6036, D-1553, YL-15293, BI- 1823911, BEBT-607, MRTX1133 and BI-2852.

5. The pharmaceutical combination as claimed in anyone of claims 1 to 3, wherein the additional active ingredient is an EGFR inhibitor.

6. The pharmaceutical combination as claimed in claim 5, wherein the EGFR inhibitor is selected from Afatinib, Osimertinib, Erlotinib and Gefitinib . The pharmaceutical combination as claimed in any of claims 1 to 3, wherein the additional active ingredient is an ERK1/2 inhibitor.

8. The pharmaceutical combination as claimed in claim 7, wherein the ERK1/2 inhibitor is selected from LY-3214996, BVD-523 (Ulixertinib), MK-8353 and ravoxertinib.

. The pharmaceutical combination as claimed in anyone of claims 1 to 3, wherein the additional active ingredient is a pan-RAF inhibitor.

10. The pharmaceutical combination as claimed in claim 9, wherein the pan-RAF inhibitor is selected from Dabrafenib, Regorafenib Encorafenib, and LXH254.

11. The pharmaceutical combination as claimed in anyone of claims 1 to 3, wherein the additional active ingredient is selected from an AKT inhibitor.

12. The pharmaceutical combination as claimed in claim 11, wherein the AKT inhibitor is selected from GSK690693, AZD5363 and Ipatasertib.

13. The pharmaceutical combination as claimed in anyone of claims 1 to 3, wherein the additional active ingredient is a SHP2 inhibitor.

14. The pharmaceutical combination as claimed in claim 13, wherein the SHP2 inhibitor is TNO155, JAB-3068, RMC-4630 or RLY-1971 or any other agent that inhibits activity of the SHP2 phosphatase.

15. The pharmaceutical combination as claimed in anyone of claims 1 to 3, wherein the additional active ingredient is a PRMT inhibitor.

16. The pharmaceutical combination as claimed in claim 15, wherein the PRMT inhibitor is JNJ-64619178, PF-06939999, GSK-3326595, PRT543, PRT811, MS023, GSK3368715, Type I PRMT inhibitors or (lS,2R,5R)-3-(2-(2-amino- 3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3- d]pyrimidin-7-yl)cyclopent-3-ene-l,2-diol (Compound 24 WO 2019116302).

17. The pharmaceutical combination as claimed in any of claims 1 to 3, wherein the additional active ingredient is a PI3K inhibitor.

18. The pharmaceutical combination as claimed in claim 17, wherein PI3K inhibitor is selected from Alpelisib, Copanlisib, Duvelisib, BEZ-235, Gedatolisib, Buparlisib.

19. The pharmaceutical combination as claimed in any of claims 1 to 3, wherein the additional active ingredient is a CDK4/6 inhibitor.

20. The pharmaceutical combination as claimed in claim 19, wherein CDK4/6 inhibitor is Abemaciclib.

21. The pharmaceutical combination as claimed in anyone of claims 1 to 3, wherein the additional active ingredient is selected from a FGFR inhibitor.

22. The pharmaceutical combination as claimed in claim 21, wherein the FGFR inhibitor is selected from Dovitinib, AZD4547, BGJ398 and JNJ 42756493.

23. The pharmaceutical combination as claimed in anyone of claims 1 to 3, wherein the additional active ingredient is selected from a c-Met inhibitor.

24. The pharmaceutical combination as claimed in claim 23, wherein the c-Met inhibitor is selected from Tivantinib, Cabozantinib, Crizotinib and Capmatinib.

25. The pharmaceutical combination as claimed in anyone of claims 1 to 3, wherein the additional active ingredient is selected from a Bcr-Abl kinase inhibitor.

26. The pharmaceutical combination as claimed in claim 25, wherein the Bcr-Abl kinase inhibitor is selected from imatinib, Dasatinib, nilotinib and ponatinib.

27. The pharmaceutical combination as claimed in anyone of claims 1 to 3, wherein the additional active ingredient is a PD 1 inhibitor.

28. The pharmaceutical combination as claimed in claim 27, wherein the PD1 inhibitor is selected from Pembrolizumab and Nivolumab.

29. The pharmaceutical combination as claimed in anyone of claims 1 to 3, wherein the additional active ingredient is selected from a PD-L1 inhibitor.

30. The pharmaceutical combination as claimed in claim 29, wherein the PD-L1 inhibitor is selected from Atezolizumab and Avelumab.

31. The pharmaceutical combination as claimed in anyone of claims 1 to 3, wherein the additional active ingredient is a CTLA-4 inhibitor.

32. The pharmaceutical combination as claimed in claim 31, wherein the CTLA-4 inhibitor is Ipilimumab.

33. The pharmaceutical combination as claimed in anyone of claims 1 to 3, wherein the additional active ingredient is a gemcitabine, topotecan, irinotecan, paclitaxel, cisplatin, carboplatin, doxorubicin or any other agent that is classified as chemotherapeutic.

34. The pharmaceutical combination as claimed in claim 1, wherein, an additional therapeutic agent is selected from EGFR inhibitor, KRAS G12C inhibitor, ERK1/2 inhibitor, RAF inhibitor, PRMT5 inhibitor, pan-RAF inhibitor, SHP2 inhibitor, PI3K inhibitor, Type I PRMT inhibitor, FGFR inhibitor, CDK4/6 inhibitor, and Chemotherapeutic agent.

35. The pharmaceutical combination as claimed in claim 1, wherein, an additional therapeutic agent is selected from Afatinib, AMG510, LY3214996, BVD-523, Encorafenib, Compound 24 of WO 2019116302, LXH254, TNO155, MRTX849, MRTX1133, BYL-719, GSK3368715, Nintedanib, Abemaciclib, and Gemcitabine.

36. The pharmaceutical combination as claimed in claim 1, wherein, SOS1 inhibitor is selected from (R)-4-((l-(3-(l,l-Difluoro-2-hydroxy-2-

methylpropyl)-2-fluorophenyl)ethyl)amino) -2,6,8,8-tetramethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 1), (R/S)-4-((l-(3-(l,l-difluoro-2-hydroxy-2-methylpropyl)phenyl)ethyl)amino)-2,6,8,8-tetramethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 2), 4-(((R)-l-(3-((R/S)- 1 , 1 -difluoro-2,3-dihydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,6,8,8-tetramethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 3a), (R/S)-4-(((R)-l-(3-(l,l-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl) amino)-8-methoxy-2,6,8-trimethyl-6H-pyrrolo[2,3-g]quinazolin-7(8H)-one (Compound 4b), (R)-5-(4-((1 -(3 -amino-5 -(trifluoromethyl) phenyl) ethyl) amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)- 1 -methylpyridin-2( 1 H)-one (Compound 5), (S/R)-4-(((R)- 1 -(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 6a), and (S)-4-(((R)-l-(3-amino-5-(trifluoromethyl) phenyl) ethyl)amino)-8-methoxy-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 7); and an additional therapeutic agent is selected from EGFR inhibitor, KRAS G12C inhibitor, ERK1/2 inhibitor, RAF inhibitor, PRMT5 inhibitor, pan-RAF inhibitor, SHP2 inhibitor, PI3K inhibitor, Type I PRMT inhibitor, FGFR inhibitor, CDK4/6 inhibitor, and Chemotherapeutic agent.

The pharmaceutical combination as claimed in claim 1, wherein, SOS1 inhibitor is selected from (R)-4-((l-(3-(l,l-Difluoro-2-hydroxy-2-methylpropyl)-2-fhiorophenyl)ethyl)amino)-2,6,8,8-tetramethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 1), (R/S)-4-((l-(3-(l,l-difluoro-2-hydroxy-2-methylpropyl)phenyl)ethyl)amino)-2,6,8,8-tetramethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 2), 4-(((R)-l-(3-((R/S)- 1 , 1 -difluoro-2,3-dihydroxy-2-methylpropyl)-2-fhiorophenyl)ethyl)amino)-2,6,8,8-tetramethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 3a), (R/S)-4-(((R)-l-(3-(l,l-difluoro-2-

hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl) amino)-8-methoxy-2,6,8-trimethyl-6H-pyrrolo[2,3-g]quinazolin-7(8H)-one (Compound 4b), (R)-5-(4-((1 -(3 -amino-5 -(trifluoromethyl) phenyl) ethyl) amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)- 1 -methylpyridin-2( 1 H)-one (Compound 5), (S/R)-4-(((R)- 1 -(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 6a), and (S)-4-(((R)-l-(3-amino-5-(trifluoromethyl) phenyl) ethyl)amino)-8-methoxy-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 7); and an additional therapeutic agent is selected from Afatinib, AMG510, LY3214996, BVD-523, Encorafenib, Compound 24 of WO 2019116302, LXH254, TNO155, MRTX849, MRTX1133, BYL-719, GSK3368715, Nintedanib, Abemaciclib, and Gemcitabine.

A pharmaceutical combination comprising a S0S1 inhibitor (S)-4-(((R)-l-(3-amino-5-(trifluoromethyl) phenyl) ethyl)amino)-8-methoxy-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 7), and an additional therapeutic agent selected from Afatinib, AMG510, LY3214996, BVD-523, Encorafenib, LXH254, TNO155, MRTX849, MRTX1133, BYL-719, GSK3368715, Nintedanib, Abemaciclib, and Gemcitabine.

The pharmaceutical combination as claimed in any of claims 1 to 38, wherein the S0S1 inhibitor is administered simultaneously, concurrently, sequentially, successively, alternately or separately with the additional active ingredient. A method of treating or preventing cancer, wherein the method comprising administering to the subject in need with pharmaceutical combination of any one of claims 1 to 38.

The method of claim 40, wherein the cancer is glioblastoma multiforme, prostate cancer, pancreatic cancer, mantle cell lymphoma, non-Hodgkin's lymphomas and diffuse large B-cell lymphoma, acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma, non-small cell lung cancer, small cell lung cancer, breast cancer, triple negative breast cancer, gastric cancer, colorectal cancer, ovarian cancer, bladder cancer, hepatocellular cancer, melanoma, sarcoma, oropharyngeal squamous cell carcinoma, chronic myelogenous leukemia, epidermal squamous cell carcinoma, nasopharyngeal carcinoma, neuroblastoma, endometrial carcinoma, head and neck cancer, cervical cancer, or cancers harboring overexpression, amplification of wild type KRAS, NRAS or HRAS, cancers having amplification, overexpression or mutation of KRAS, NRAS, or HRAS, cancers harboring KRAS mutations such as G12C, G12D, G12V, G12S, G12A, G12R, G12F, G12W, G13C, G13D, GBR, G13V, G13S, G13A, Q61H, Q61R, Q61P, Q61E, Q61K, Q61L, A59S,

A59T, R68M, R68S, Q99L, M72I, H95D, H95Q, H95R, Y96D, Y96S, Y96C, cancers harboring NRAS mutations such G12A, G12V, G12D, G12C, G12S, GBR, G13V, G13D, GBR, G13S, G13C, G13A, Q61K, Q61L, Q61H, Q61P, Q61R, A146T, A 146V, cancers harboring HRAS mutations such as G12C, G12V, G12S, G12A, GBR, G12F, G12D, G13C, G13D, GBR, G13V, G13S,

G13A, Q61K, Q61L, Q61H, Q61P, Q61R..