WO2024231875A1

WO2024231875A1 - Hpk1 inhibitor for use in the treatment of cancer

Info

Publication number: WO2024231875A1
Application number: PCT/IB2024/054521
Authority: WO
Inventors: Harsha DODDIHAL
Original assignee: Glenmark Specialty SA
Current assignee: Glenmark Specialty SA
Priority date: 2023-05-09
Filing date: 2024-05-09
Publication date: 2024-11-14
Anticipated expiration: 2025-11-09

Abstract

The present invention relates to a method of treating cancer in a subject comprising administering to the subject, a therapeutically dosage effective amount of HPK1 inhibitor. Further, the present invention relates to a method of treating cancer in a subject comprising administering to a subject therapeutically effective amount of HPK1 inhibitor and optionally, one or more chemotherapeutic(s) and/or cancer immunotherapy(ies) sequentially or simultaneously to the subject.

Description

METHOD OF TREATING CANCER USING HPK1 INHIBITOR RELATED APPLICATION This application claims the benefit of Indian Provisional Application No. 202321032854 filed on 9^th May 2023 the contents of which is hereby incorporated by reference in its entirety. BACKGROUND OF THE INVENTION Hematopoietic progenitor kinase 1 (HPK1), is also known as “MAP kinase 1 (MAPK1)”, is a hematopoietic cell-specific Ste20-related serine/threonine kinase, and HPK1 is a negative regulator of signal transduction in immune cells, including T cells, B cells, and dendritic cells (DCs). HPK1 deficiency subverts inhibition of the anti-tumor immune response and is associated with functional augmentation of anti-tumor T cells. The relationship between HPK1 and PGE2 is particularly noteworthy because PGE2 is the predominant eicosanoid product released by cancer cells, including lung, colon, and breast cancer cells. Tumor-produced PGE2 is known to contribute significantly to tumor-mediated immune suppression. Inhibition of HPK1 enhances Th1 cytokine production in T cells and fully reverted immune suppression imposed by the prostaglandin E2 (PGE2) and adenosine pathways in human T cells. International Patent Publication WO 2020/070332 discloses certain oxindole compounds as HPK1 inhibitor(s). International Patent Publication WO 2021/057872 discloses certain PROTAC small molecule compounds as HPK1 degraders. PROTAC refers to protein degradation-targeted chimera (PROTAC) technology. International Patent Publication WO 2022/068848 discloses certain pyrazin-2-amine compounds as HPK1 inhibitor(s). International Patent Publication WO 2023/281417 discloses certain pyrimidine chemical compound(s) as HPK1 inhibitor(s). It was considered probable that blocking the HPK1 kinase activity with pyrimidine chemical compounds may activate the superior antitumor activity of both cell types, resulting in a synergistic amplification of anti-tumor potential. Given that HPK1 is not expressed in any major organs, it is less likely that a selective inhibitor of HPK1 would cause any serious side effects. The inventors of the present patent application found that therapeutically effective dosage amount of HPK1 inhibitor(s) described in WO 2023/281417 and method for using the HPK1 inhibitor(s) as described therein a single agent and/or in combination with one or more other therapy(ies) for effectively treating cancer in a subject(s) in need thereof. SUMMARY OF THE INVENTION In an aspect, the present invention relates to a method of treating cancer by administering a therapeutically effective amount of hematopoietic progenitor kinase-1 inhibitor (HPK1 inhibitor) to a subject in need thereof. In an aspect, the present invention provides a method of treating cancer in a subject in need thereof comprising administering Compound (I) or a tautomer thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the amount of Compound (I) administered to the subject is at least about 12.5mg once daily:

(Compound (I)). DETAILED DESCRIPTION OF THE INVENTION Disclosed herein are detailed descriptions of specific embodiments of the present invention of a method of treating cancer in a subject in need thereof. It will be understood that the disclosed embodiments are merely examples of the way in which certain embodiments of the application can be implemented and do not represent an exhaustive list of all of the ways the application may be embodied. In one embodiment, the present invention provides a method of treating cancer in a subject in need thereof comprising administering Compound (I) or a tautomer thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the amount of Compound (I) administered to the subject is at least about 12.5mg once daily:

In an embodiment, the present invention relates to a method of treating cancer in a subject using multimodal cancer immunotherapy comprising administering a therapeutically effective dosage amount of HPK1 inhibitor and one or more cancer immunotherapy selected a checkpoint inhibitor, cancer vaccine, and adoptive cell therapy; wherein the method optionally comprises one or more cancer therapy selected from surgery, chemotherapy, radiation therapy, and hormone therapy. In an embodiment, the present invention relates to a method of treating cancer in a subject in need thereof comprising administering (i) a therapeutically effective dosage amount of HPK1 compound (I) or its pharmaceutically acceptable salts thereof, structurally represented as

and optionally, (ii) one or more cancer immunotherapy selected from checkpoint inhibitors, cancer vaccine, and adoptive cell therapy; wherein the method optionally comprises one or more cancer therapy selected from surgery, chemotherapy, radiation therapy, and hormone therapy. In an embodiment, the present invention relates to a method of treating cancer in a subject in need thereof, comprising administering (i) a therapeutically effective dosage amount of compound (I) or its pharmaceutically acceptable salts thereof, and (ii) one or more cancer immunotherapy selected a checkpoint inhibitor, cancer vaccine, and adoptive cell therapy. In some embodiments, the duration of method of the present invention is from at least about 1 week to about 150 weeks. In some embodiments, the duration of method of the present invention is from at least about 1 week to about 96 weeks. In some embodiments, the duration of method of the present invention is from at least about 1 week to about 52 weeks. In some embodiments, the duration of method is divided into treatment cycle(s), and a treatment cycle comprises at least about 1 week to about 30 days. In some embodiments, a treatment cycle according to the present invention may be about 2 weeks. In some embodiments, a treatment cycle according to the present invention may be about 14 days to about 30 days. In some embodiments, the cancer is one or more solid tumor(s). In some embodiments, one or more solid tumor is selected from the group comprising biliary duct cancer, nasopharyngeal cancer, breast cancer, prostate cancer, colorectal cancer, ovarian cancer, pancreatic cancer, liver cancer, renal cancer, and any combination of any of the foregoing thereof. In an embodiment, the present invention relates to a method of treating cancer by orally administering therapeutically effective dosage amount of compound (I) or its pharmaceutically acceptable salts thereof. In some embodiments, the therapeutically effective dosage amount is from about 1mg to about 500 mg of compound (I). In some embodiments, the therapeutically effective dosage amount is from about 10mg to about 400 mg of compound (I). In some embodiments, the therapeutically effective dosage amount is from about 10mg to about 200 mg of compound (I). In a specific embodiment, the present invention relates to a method of treating cancer in a subject in need thereof by administering a therapeutically effective dosage amount of compound (I) or its pharmaceutically acceptable salts thereof; wherein the therapeutically effective amount of compound (I) is selected from about 1 mg to about 500 mg. In one embodiment, the amount of Compound (I) administered to the subject is about 25mg once daily. In one embodiment, the amount of Compound (I) administered to the subject is about 37.5mg once daily. In one embodiment, the amount of Compound (I) administered to the subject is about 50mg once daily. In one embodiment, the amount of Compound (I) administered to the subject is about 75mg once daily. In one embodiment, the amount of Compound (I) administered to the subject is about 100mg once daily. In a specific embodiment, the present invention relates to a method of treating cancer in a subject in need thereof by administering a combination therapy comprising: (i) a therapeutically effective dosage amount of compound (I) or its pharmaceutically acceptable salts thereof and (ii) one or more chemotherapeutic(s); wherein the combination therapy is selected from simultaneous administration of component (i) and component (ii); or sequential administration of component (i) and component (ii). In some embodiments, one or more chemotherapeutic is selected from cancer immunotherapies, paclitaxel, platinum based therapeutics, vascular endothelial growth factor (VEGF) inhibitors / tyrosine kinase inhibitors which block VEGF such as sorafenib, lenvatinib, axitinib, sunitinib, bevacizumab, aflibercept, ramucirumab, pazopanib, regorafenib, cabozantinib, vandetanib, radiotherapy, surgery (adjuvant/ neoadjuvant), CAR-T-cell therapy, conventional chemotherapy, any targeted therapy, hormonal therapy, and the like. In a specific embodiment, the present invention relates to a method of treating cancer in a subject in need thereof by administering a combination therapy comprising: (i) a therapeutically effective dosage amount of compound (I) or its pharmaceutically acceptable salts thereof and (ii) a therapeutically effective amount of a checkpoint inhibitor; wherein the combination therapy is selected from simultaneous administration of component (i) and component (ii); or sequential administration of component (i) and component (ii). In some embodiments, the checkpoint inhibitor is Anti-PD1 antibody and/or Anti-PD- L1 antibody. In some embodiments, one or more checkpoint inhibitor is selected from the group comprising of: pembrolizumab, nivolumab, atezolizumab, duralumab, toripalimab, cemiplimab, spartalizumab, sasanlimab (PF-06801591), durvalumab, avelumab, MPDL3280A, and ipilimumab. In a specific embodiment, the checkpoint inhibitor is an Anti-PD1 antibody and is pembrolizumab. In a specific embodiment, the checkpoint inhibitor is an Anti-PD1 antibody and is nivolumab. In a specific embodiment, the checkpoint inhibitor is an Anti-PD1 antibody and is durvalumab. In a specific embodiment, the checkpoint inhibitor is an Anti-PD-L1 antibody and is atezolizumab. In a specific embodiment, the present invention relates to a method of treating cancer in a subject in need thereof by administering a combination therapy comprising: (i) a therapeutically effective dosage amount of compound (I) or its pharmaceutically acceptable salts thereof and (ii) a therapeutically dosage effective amount of a checkpoint inhibitor; wherein the method comprising initially administering the component (i) therapeutically effective dosage amount of compound (I) or its pharmaceutically acceptable salts thereof for a period of at least about 1 week to about 1 month, and simultaneously administering fixed dose of component (ii) via intravenous route for a period of at least about 1 week to about 1 month. In a specific embodiment, the present invention relates to a method of treating cancer in a subject in need thereof by administering a combination therapy comprising: (i) a therapeutically effective dosage amount of compound (I) or its pharmaceutically acceptable salts thereof and (ii) a therapeutically dosage effective amount of a checkpoint inhibitor; wherein the method comprising initially administering the component (i) therapeutically effective dosage amount of compound (I) or its pharmaceutically acceptable salts thereof for a period of at least about 1 week to about 1 month, and sequentially administering a fixed dose of component (ii) via intravenous route once in every 21-day treatment cycle. DEFINITIONS As used herein, the term “about” when used to refer to weight % in composition or other numeral amounts means plus or minus up to 20% (alternatively, up to 10% or 5%) of the reported value. The term “about” when used with days/ weeks, it is referred to ±7 days. The term “Anti-PD1 antibody” as used herein refers to an antibody or antigen-binding fragment thereof that binds to PD-1 receptor, blocking the binding of PD-L1 expressed on cancer cells with PD-1 expressed on immune cells (T, B, NK cells) and preferably It can also block any chemical compound or biological molecule that binds PD-L2 expressed on cancer cells and PD-1 expressed on immune cells. Alternative nouns or synonyms for PD-1 and its ligands include: for PD-1, there are PDCD1, PD1, CD279, and SLEB2; for PD-L1, there are PDCD1L1, PDL1, B7-H1, B7H1, B7-4, CD274 and B7-H; and for PD-L2 there are PDCD1L2, PDL2, B7-DC and CD273. In any of the treatment methods, drugs and uses of the present invention for treating human individuals, the PD-1 antibody blocks the binding of human PD- L1 and human PD-1, and preferably blocks both human PD-L1 and PD-L2 and human PD1 binding. The amino acid sequence of human PD-1 can be found in NCBI locus number: NP_005009. The amino acid sequences of human PD-L1 and PD-L2 can be found in NCBI locus numbers: NP_054862 and NP_079515, respectively. In some embodiments, the anti-PD-1 antibodies used in any of the uses, therapies, drugs, and kits described in the present invention include monoclonal antibodies (mAb) or antigen-binding fragments thereof, which specifically bind to PD-1, and it preferably specifically binds to human PD-1. The mAb can be a human antibody, a humanized antibody, or a chimeric antibody, and can include a human constant region. In some embodiments, the constant region is selected from the group consisting of human IgG1, IgG2, IgG3, and IgG4 constant regions; preferably, the anti-PD-1 antibody suitable for any use, therapy, drug, and kit of the present invention or its antigen-binding fragment comprises a heavy chain constant region of human IgG1 or IgG4 isotype, more preferably a human IgG4 constant region. As used herein, the term "cancer" refers to a wide range of diseases characterized by the uncontrolled growth of abnormal cells in the body. Unregulated cell division, growth division, and growth lead to the formation of malignant tumors, which invade adjacent tissues and can also metastasize to remote parts of the body through the lymphatic system or bloodstream. Examples of cancers that are suitable for the treatment or prevention of the methods, drugs, and kits of the present invention include, but are not limited to, carcinoma, lymphoma, leukemia, blastoma, and sarcoma. More specific examples of cancer include adenocarcinomas of any organ, nasopharyngeal cancer, squamous cell carcinoma (such as cutaneous squamous cell carcinoma, Bowen’s disease, verrucous squamous cell carcinoma, metastatic squamous cell carcinoma, cervical squamous cell carcinoma and the likes), myeloma, lung cancer (such as small cell lung cancer, non-small cell lung cancer, adenocarcinoma and the likes), glioma (such as glioblastoma multiforme, mixed gliomas, ependymomas, oligodendrogliomas, astrocytomas and the likes), Hodgkin's lymphoma (such as nodular lymphocyte-predominant hodgkin's lymphoma, lymphocyte-depleted hodgkin's lymphoma and the likes), non-Hodgkin's lymphoma (such as B-cell lymphomas such as diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma; T-cell lymphomas, Burkitt lymphoma and the likes), acute myelogenous leukemia, multiple myeloma , Gastrointestinal (tract) cancer, kidney cancer (i.e., various type of renal cell carcinoma), ovarian cancer (i.e., granulosa cell tumor, dysgerminoma and the likes), liver cancer (such as hepatoblastoma, angioblastoma, hepatocellular carcinoma, fibrolamellar carcinoma and the likes), lymphoblastic leukemia, lymphocytic leukemia, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, melanoma, chondrosarcoma, neuroblastoma, pancreatic cancer, glioblastoma multiforme, cervical cancer, brain cancer, stomach cancer, bladder cancer, hepatocytoma, breast cancer, colon cancer and head neck cancer, and any cancers irrespective of histology which are either PD-L1 positive, microsatellite instability high, high tumor mutational burden or mismatch repair genes. In a specific embodiment, the cancer is selected from one or more solid tumor(s) such as biliary duct cancer, breast cancer, buccal mucosa cancer, cervical carcinoma, colon cancer, and ovarian cancer. In a specific embodiment, the cancer is selected from hodgkin’s lymphoma. In a specific embodiment, the cancer is selected from non-hodgkin’s lymphoma. The term “cancer immunotherapy” as used herein refers to cancer therapeutics that work by activating the body’s immune system to fight cancer cells. The cancer immunotherapies are designed to stimulate the immune system. Examples of cancer immunotherapies are checkpoint inhibitors, CAR-T cell therapy, cancer vaccines, adoptive cell transfer, and the like. The term “cancer immunotherapy” can alternatively be referred as “Immuno-Oncology (IO) therapy”. The term “checkpoint inhibitor” as used herein refers to Anti-PD1 antibody and/or Anti-PD-L1 antibody. For example, an anti-PD1 antibody may be pembrolizumab, nivolumab, atezolizumab, duralumab, toripalimab, cemiplimab, spartalizumab, sasanlimab (PF- 06801591), durvalumab, avelumab, MPDL3280A and ipilimumab. The term “combination therapy” as used to refer when two or more therapeutic agents are administered to a subject in need thereof. Each therapeutic agent can be present in single therapeutic composition or in two different therapeutic compositions, and/or the same or different dosage form(s). For example, one therapeutic agent may be in a tablet and a second therapeutic agent may be in the form of an intravenous injection. Further, the term combination therapy refers to two or more therapeutic agents are administered to a subject in need thereof in the form of fixed-dose combination in a single dosage unit, or simultaneously administered or sequentially administered (with or without a treatment gap). In an embodiment, the combination therapy is administering HPK1 inhibitor to a subject in combination with one or more cancer immunotherapies, paclitaxel, platinum based therapeutics, vascular endothelial growth factor (VEGF) inhibitors / tyrosine kinase inhibitors which block VEGF such as sorafenib, lenvatinib, axitinib, sunitinib, bevacizumab, aflibercept, ramucirumab, pazopanib, regorafenib, cabozantinib, vandetanib, radiotherapy, surgery (adjuvant/ neoadjuvant), CAR-T-cell therapy, conventional chemotherapy, any targeted therapy, hormonal therapy, and the like. The term “HPK1” as used herein referred as hematopoietic progenitor kinase-1. HPK1 is also referred as MAP4K1 (Mitogen-activated protein kinase kinase kinase kinase 1). HPK1 is a protein kinase that belongs to the family of MAP kinase kinase kinases (MAP4Ks). MAP4K1 plays a role in regulating a variety of cellular processes, including cell growth, differentiation, apoptosis, and immune responses. The term “HPK1 inhibitor” as used herein refers to a chemical and/or biological molecule that has been shown to inhibit hematopoietic progenitor kinase-1 enzyme activity in FRET assay with IC50 value of less than about 500 nM, or less than about 400 nM, or less than about 300 nM, or less than about 200 nM, or preferably less than about 100 nM. Preferably, the term “HPK1 inhibitor” as used herein refers to one or more pyrimidine chemical compound(s) that are disclosed in PCT/US2017/063633. More preferably, the term “HPK1 inhibitor” as used herein refers to “compound (I)” as used herein refers to Formula I and it is chemically known as 4-((5-Chloro-2-((6-methoxy- 2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)-3- (dimethylphosphoryl)phenylsulfurofluoridate.

FORMULA I The compound (I) referred herein may be available in any suitable pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” includes salts prepared from pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids. Examples of such salts include but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate, diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Examples of salts derived from inorganic bases include, but are not limited to, aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, and zinc. In a specific embodiment, the pharmaceutically acceptable salt of compound (I) is hydrochloride salt. In a specific embodiment, term “compound (I)” as used herein refers to Formula IA and chemically referred as 4-((5-Chloro-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7- yl)amino)pyrimidin-4-yl)amino)-3-(dimethylphosphoryl)phenylsulfurofluoridate dihydrochloride.

FORMULA IA The term “subject” as used herein refers to a mammal, preferably human. In some embodiments, the term subject referred is a human patient in need of cancer therapy. More preferably, the subject is a human patient in need of cancer therapy whose PD1 expression or PD-L1 expression is positive in peripheral blood or tumor tissue. In some embodiment, the term subject referred is a human patient in need of cancer therapy. In some embodiment, the term subject referred is a human patient aged ≥ 18 years in need of cancer therapy with histologically or cytologically confirmed advanced, metastatic, unresectable solid tumors or lymphomas who have previously received standard systemic therapy. The term “therapeutically effective dosage amount” as used herein refers to the total amount of drug present in a unit dosage form for treating a given disease condition in a subject. The therapeutically effective dosage amount is generally referred in milligram units. For example, if the dosage form is a tablet, and the amount of drug present in the dosage form is 100 mg, the therapeutically effective dosage amount is 100 mg/tablet. Precisely, the therapeutically effective dosage amount is the amount of drug required in the dosage form for release in the biological system and exert its therapeutic activity in the biological system. Preferably, the therapeutically effective dosage amount refers to the amount of drug required in the dosage to deliver an effective amount of the drug into the biological system of the human subject, particularly in a cancer patient. The term “therapeutically effective dosage amount” as used herein referred on a free base basis of compound (I). For example, therapeutically effective dosage amount of 100mg refers to 100mg of compound (I) as a free base. In some embodiments, the therapeutically effective dosage amount of compound (I) for oral administration is from about 1 mg to about 1000 mg. In a preferred embodiment, the therapeutically effective dosage amount of compound (I) is from about 1 mg to about 800 mg. In a preferred embodiment, the therapeutically effective dosage amount of compound (I) is from about 1 mg to about 500 mg. In some embodiments, the therapeutically effective dosage amount of compound (I) for oral administration is selected from about 1mg to about 200mg. In a specific embodiment, the therapeutically effective dosage amount of compound (I) for oral administration is selected from about 10mg, about 10.5mg, about 11mg, about 11.5mg, about 12mg, about 12.5mg, about 13mg, about 13.5mg, about 14mg, about 14.5mg, about 15mg, about 15.5mg, about 16mg, about 16.5mg, about 17mg, about 17.5mg, about 18mg, about 18.5mg, about 19mg, about 19.5mg, about 20mg, about 20.5mg, about 21mg, about 21.5mg, about 22mg, about 22.5mg, about 23mg, about 23.5mg, about 24mg, about 24.5mg, about 25mg, about 25.5mg, about 26mg, about 26.5mg, about 27mg, about 27.5mg, about 28mg, about 28.5mg, about 29mg, about 29.5mg, about 30mg, about 30.5mg, about 31mg, about 31.5mg, about 32mg, about 32.5mg, about 33mg, about 33.5mg, about 34mg, about 34.5mg, about 35mg, about 35.5mg, about 36mg, about 36.5mg, about 37mg, about 37.5mg, about 38mg, about 38.5mg, about 39mg, about 39.5mg, about 40mg, about 40.5mg, about 41mg, about 41.5mg, about 42mg, about 42.5mg, about 43mg, about 43.5mg, about 44mg, about 44.5mg, about 45mg, about 45.5mg, about 46mg, about 46.5mg, about 47mg, about 47.5mg, about 48mg, about 48.5mg, about 49mg, about 49.5mg, about 50mg, about 50.5mg, about 51mg, about 51.5mg, about 52mg, about 52.5mg, about 53mg, about 53.5mg, about 54mg, about 54.5mg, about 55mg, about 55.5mg, about 56mg, about 56.5mg, about 57mg, about 57.5mg, about 58mg, about 58.5mg, about 59mg, about 59.5mg, about 60mg, about 60.5mg, about 61mg, about 61.5mg, about 62mg, about 62.5mg, about 63mg, about 63.5mg, about 64mg, about 64.5mg, about 65mg, about 65.5mg, about 66mg, about 66.5mg, about 67mg, about 67.5mg, about 68mg, about 68.5mg, about 69mg, about 69.5mg, about 70mg, about 70.5mg, about 71mg, about 71.5mg, about 72mg, about 72.5mg, about 73mg, about 73.5mg, about 74mg, about 74.5mg, about 75mg, about 75.5mg, about 76mg, about 76.5mg, about 77mg, about 77.5mg, about 78mg, about 78.5mg, about 79mg, about 79.5mg, about 80mg, about 80.5mg, about 81mg, about 81.5mg, about 82mg, about 82.5mg, about 83mg, about 83.5mg, about 84mg, about 84mg, about 85.0mg, about 85.5mg, about 86.0mg, about 86.5mg, about 87.0mg, about 87.5mg, about 88.0mg, about 88.5mg, about 89.0mg, about 89.5mg, about 90.0mg, about 90.5mg, about 91.0mg, about 91.5mg, about 92.0mg, about 92.5mg, about 93.0mg, about 93.5mg, about 94.0mg, about 94.5mg, about 95.0mg, about 95.5mg, about 96.0mg, about 96.5mg, about 97.0mg, about 97.5mg, about 98.0mg, about 98.5mg, about 99.0mg, about 99.5mg, about 100.0mg, a bout 101.0mg, about 101.5mg, about 102.0mg, about 102.5mg, about 103.0mg, about 103.5mg, about 104.0mg, about 104.5mg, about 105.0mg, about 105.5mg, about 106.0mg, about 106.5mg, about 107.0mg, about 107.5mg, about 108.0mg, about 108.5mg, about 109.0mg, about 109.5mg, about 110.0mg, about 110.5mg, about 111.0mg, about 111.5mg, about 112.0mg, about 112.5mg, about 113.0mg, about 113.5mg, about 114.0mg, about 114.5mg, about 115.0mg, about 115.5mg, about 116.0mg, about 116.5mg, about 117.0mg, about 117.5mg, about 118.0mg, about 118.5mg, about 119.0mg, about 119.5mg, about 120.0mg, about 120.5mg, about 121.0mg, about 121.5mg, about 122.0mg, about 122.5mg, about 123.0mg, about 123.5mg, about 124.0mg, about 124.5mg, about 125.0mg, about 125.5mg, about 126.0mg, about 126.5mg, about 127.0mg, about 127.5mg, about 128.0mg, about 128.5mg, about 129.0mg, about 129.5mg, about 130.0mg, about 130.5mg, about 131.0mg, about 131.5mg, about 132.0mg, about 132.5mg, about 133.0mg, about 133.5mg, about 134.0mg, about 134.5mg, about 135.0mg, about 135.5mg, about 136.0mg, about 136.5mg, about 137.0mg, about 137.5mg, about 138.0mg, about 138.5mg, about 139.0mg, about 139.5mg, about 140.0mg, about 140.5mg, about 141.0mg, about 141.5mg, about 142.0mg, about 142.5mg, about 143.0mg, about 143.5mg, about 144.0mg, about 144.5mg, about 145.0mg, about 145.5mg, about 146.0mg, about 146.5mg, about 147.0mg, about 147.5mg, about 148.0mg, about 148.5mg, about 149.0mg, about 149.5mg, and about 150.0mg. In a specific embodiment, the therapeutically effective dosage amount of compound (I) for oral administration is about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, and about 100mg. The therapeutically effective dosage amount may be reduced/ adjusted when administered in combination with cancer immunotherapy. The term “pharmaceutically acceptable dosage form” as used herein refers to any suitable dosage form known to the person skilled in the art. For example, oral tablet, oral hard gelatin capsule, oral soft gelatin capsule, oral solution, oral suspension, intravenous injection, subcutaneous injection, intramuscular injection, inhalation and the like. The term “progression-free survival” as used herein refers to a period of time during which a patient's disease does not progress or worsen. For example, in cancer treatment, progression-free survival (PFS) is a measure of how long a patient's cancer does not progress after treatment. The term “partial response” as used herein refers to describe a reduction in the size or extent of a tumor or cancer. This partial response may be determined by imaging studies such as computed tomography (CT) scans or magnetic resonance imaging (MRI). The term “stable disease state” as used herein refers to a situation where the size of a tumor does not significantly increase or decrease over a period of time. The present invention relates to a method of treating cancer in a subject in need thereof comprising administering one or more therapeutically effective dosage amount of HPK1 inhibitor to the subject. In an embodiment, the present invention relates to a method of treating cancer in a subject in need thereof comprising administering a therapeutically effective dosage amount of HPK1 inhibitor or its pharmaceutically acceptable salts thereof. In an embodiment, the present invention relates to a method of treating cancer in a subject in need thereof comprising administering a therapeutically effective dosage amount of HPK1 inhibitor or its pharmaceutically acceptable salts thereof in a pharmaceutically acceptable dosage form; wherein the pharmaceutically acceptable dosage form is selected from oral tablet, oral hard gelatin capsule, oral soft gelatin capsule, oral solution, oral suspension, intravenous injection, subcutaneous injection, intramuscular injection and the like. The pharmaceutically acceptable dosage form refers to any suitable dosage form that can be used to administer the drug into the biological system of the subject effectively. In an embodiment, the present invention relates to a method of treating cancer in a subject in need thereof comprising administering a therapeutically effective dosage amount of HPK1 inhibitor or its pharmaceutically acceptable salts thereof in combination with one or more cancer immunotherapy. In an embodiment, the present invention relates to a method of treating cancer in a subject in need thereof comprising administering a therapeutically effective dosage amount of compound (I) or its pharmaceutically acceptable salts thereof to the subject for a period of at least about 1 week. In some embodiments, the HPK1 inhibitor is compound (I)

or its pharmaceutically acceptable salts thereof. In a specific embodiment, the HPK1 inhibitor is compound (I) . In an embodiment, the present invention relates to a method of administering a HPK1 inhibitor to a subject in need thereof for the treatment of cancer, comprising orally administering a therapeutically dosage effective amount of HPK1 inhibitor to the subject once daily or twice daily. In an embodiment, the present invention relates to a method of administering a HPK1 inhibitor to a subject in need thereof for the treatment of cancer, comprising orally administering a therapeutically dosage effective amount of HPK1 inhibitor to the subject once daily; wherein the HPK1 inhibitor is compound (I) or its pharmaceutically acceptable salts and the therapeutically effective dosage amount of compound (I) is from about 1mg to about 200 mg. In a specific embodiment, the present invention relates to a method of treating cancer in a subject in need thereof comprising administering (i) a therapeutically effective dosage amount of compound (I) or its pharmaceutically acceptable salts thereof, structurally represented as

and optionally, (ii) one or more cancer immunotherapy selected a checkpoint inhibitor, cancer vaccine, and adoptive cell therapy; wherein the method optionally comprises one or more cancer therapy selected from surgery, chemotherapy, radiation therapy, and hormone therapy. In a specific embodiment, the present invention relates to a method of treating cancer in a subject in need thereof comprising administering orally to the subject a therapeutically effective dosage amount of compound (I) or its pharmaceutically acceptable salts thereof, once or twice daily for at least about 1 week. In a specific embodiment, the present invention relates to a method of treating cancer in a subject in need thereof comprising administering orally to the subject a therapeutically effective dosage amount of compound (I) or its pharmaceutically acceptable salts thereof, once or twice daily for at least about 2 weeks. In a specific embodiment, the present invention relates to a method of treating cancer in a subject in need thereof comprising administering orally to the subject a therapeutically effective dosage amount of compound (I) or its pharmaceutically acceptable salts thereof, once or twice daily for a treatment cycle of about 21 days. In some embodiments, the present invention relates to use of the compound (I) or a pharmaceutically acceptable salt thereof for the treatment of cancer in a subject in need thereof. In some embodiments, the present invention relates to use of the compound (I) or a pharmaceutically acceptable salt thereof for the treatment of cancer in a subject in need thereof; wherein the compound (I) is administered to the subject in an oral pharmaceutically acceptable dosage form. In some embodiments, the present invention relates to use of the compound (I) or its pharmaceutically acceptable salts thereof in the manufacture of a medicament comprises orally administering a subject, a pharmaceutical composition comprising a therapeutically effective dosage amount of compound (I) for the treatment of cancer. In some embodiments, the present invention relates to use of the compound (I) or its pharmaceutically acceptable salts thereof in the manufacture of a medicament comprises orally administering a subject, a pharmaceutical composition comprising a therapeutically effective dosage amount of compound (I) for the treatment of cancer; wherein the therapeutically effective amount of compound (I) is selected from about 1mg to about 500mg. In some embodiments, the present invention relates to use of the compound (I) or its pharmaceutically acceptable salts thereof in the manufacture of a medicament comprises orally administering a subject, a pharmaceutical composition comprising a therapeutically effective dosage amount of compound (I) for the treatment of cancer; wherein the therapeutically effective amount of compound (I) is selected from about 5mg to about 200mg. In some embodiments, the present invention relates to use of the compound (I) or its pharmaceutically acceptable salts thereof in the manufacture of a medicament comprises orally administering a subject, a pharmaceutical composition comprising a therapeutically effective dosage amount of compound (I) for the treatment of cancer; characterized in that the pharmaceutical composition is administered once or twice daily to the subject, and wherein the therapeutically effective amount of compound (I) is selected from about 5mg to about 200mg. In some embodiments, the present invention relates to use of the compound (I) or its pharmaceutically acceptable salts thereof in the manufacture of a medicament comprises orally administering a subject, a pharmaceutical composition comprising a therapeutically effective dosage amount of compound (I) for the treatment of cancer; characterized in that the pharmaceutical composition is administered once or twice daily to the subject, and wherein the therapeutically effective amount of compound (I) is selected from about 5mg to about 200mg. In some embodiments, the method of present invention results in one or more of the following: (a) progression-free survival for at least 21 days; (b) partial response at about 6 weeks; and (c) stable disease state for at least 2 weeks. In a specific embodiment, the present invention relates to a method of treating cancer in a subject in need thereof comprising administering orally to the subject a therapeutically effective dosage amount of compound (I) or its pharmaceutically acceptable salts thereof, once or twice daily for a treatment cycle of about 21 days; wherein the method results in one or more of the following: (a) progression-free survival for at least 21 days; (b) partial response at about 6 weeks; and (c) stable disease state for at least 2 weeks. In a specific embodiment, the present invention relates to a method of treating cancer in a subject in need thereof comprising administering orally to the subject from about 10mg to about 150mg of compound (I) or its pharmaceutically acceptable salts thereof, once or twice daily for a treatment cycle of about 21 days; wherein the method results one or more of the following: (a) progression-free survival for at least 21 days; (b) partial response at about 6 weeks; and (c) stable disease state for at least 2 weeks. In a specific embodiment, the present invention relates to a method of treating cancer in a subject in need thereof comprising administering orally to the subject from about 50mg of compound (I) or its pharmaceutically acceptable salts thereof, once or twice daily for a treatment cycle of about 21 days; wherein the method results in one or more of the following: (a) progression-free survival for at least 21 days; (b) partial response at about 6 weeks; and (c) stable disease state for at least 2 weeks. In a specific embodiment, the present invention relates to a method of treating cancer in a subject in need thereof comprising administering orally to the subject from about 75mg to about 150mg of compound (I) or its pharmaceutically acceptable salts thereof, once or twice daily for a treatment cycle of about 21 days; wherein the method results in one or more of the following: (a) progression-free survival for at least 21 days; (b) partial response at about 6 weeks; and (c) stable disease state for at least 2 weeks. In a specific embodiment, the present invention relates to a method of treating cancer in a subject in need thereof comprising administering orally to the subject from about 100 mg of compound (I) or its pharmaceutically acceptable salts thereof, once or twice daily for a treatment cycle of about 21 days; wherein the method results in one or more of the following: (a) progression-free survival for at least 21 days; (b) partial response at about 6 weeks; and (c) stable disease state for at least 2 weeks. In a specific embodiment, the present invention relates to a method of treating cancer in a subject in need thereof comprising administering (i) a therapeutically effective dosage amount of compound (I) or its pharmaceutically acceptable salts thereof, and (ii) one or more cancer immunotherapy selected from sorafenib, lenvatinib, axitinib, sunitinib, bevacizumab, aflibercept, ramucirumab, pazopanib, regorafenib, cabozantinib, vandetanib, radiotherapy, surgery (adjuvant/ neoadjuvant), CAR-T-cell therapy, conventional chemotherapy, any targeted therapy, and hormonal therapy. In a specific embodiment, the present invention relates to a method of treating cancer in a subject in need thereof comprising administering (i) a therapeutically effective dosage amount of compound (I) or its pharmaceutically acceptable salts thereof, and (ii) one or more checkpoint inhibitor. In some embodiments, the checkpoint inhibitor is selected from the group comprising of: pembrolizumab, nivolumab, atezolizumab, duralumab, toripalimab, cemiplimab, spartalizumab, sasanlimab (PF-06801591), durvalumab, avelumab, MPDL3280A, and ipilimumab. In some embodiments, the checkpoint inhibitor is pembrolizumab. In some embodiments, the checkpoint inhibitor is atezolizumab. In some embodiments, the checkpoint inhibitor is nivolumab. In some embodiments, the checkpoint inhibitor is toripalimab. In a specific embodiment, the present invention relates to a method of treating cancer in a subject in need thereof comprising administering (i) a therapeutically effective dosage amount of compound (I) or its pharmaceutically acceptable salts thereof, and (ii) one or more checkpoint inhibitor selected from pembrolizumab, nivolumab, atezolizumab, duralumab, toripalimab, cemiplimab, spartalizumab, PF-06801591, durvalumab, avelumab, MPDL3280A and ipilimumab. In a specific embodiment, the present invention relates to a method of treating cancer in a subject in need thereof comprising administering (i) a therapeutically effective dosage amount of compound (I) or its pharmaceutically acceptable salts thereof, and (ii) one or more checkpoint inhibitor selected from pembrolizumab, nivolumab, atezolizumab, duralumab, toripalimab, MPDL3280A and ipilimumab; wherein therapeutically effective dosage amount of compound (I) is selected from about 1mg to about 500mg. In a specific embodiment, the present invention relates to a method of treating cancer in a subject in need thereof comprising administering (i) a therapeutically effective dosage amount of compound (I) or its pharmaceutically acceptable salts thereof, and (ii) one or more checkpoint inhibitor selected from pembrolizumab, nivolumab, atezolizumab, duralumab, toripalimab, cemiplimab, spartalizumab, sasanlimab (PF-06801591), durvalumab, avelumab, MPDL3280A and ipilimumab; wherein therapeutically effective dosage amount of compound (I) is selected from about 5mg to about 200mg. In a specific embodiment, the present invention relates to a method of treating cancer in a subject in need thereof comprising administering (i) a therapeutically effective dosage amount of compound (I) or its pharmaceutically acceptable salts thereof, and (ii) one or more checkpoint inhibitor selected from pembrolizumab, nivolumab, atezolizumab, duralumab, toripalimab, MPDL3280A, and ipilimumab; wherein therapeutically effective dosage amount of compound (I) is orally administered at least for about 2 weeks. In some embodiments, the duration of method of the present invention is from at least about 1 week to about 150 weeks. In some embodiments, the duration of method of the present invention is from at least about 1 week to about 96 weeks. In some embodiments, the duration of method of the present invention is from at least about 1 week to about 52 weeks. In some embodiments, the duration of method is divided into treatment cycle(s), and a treatment cycle comprises at least about 1 week to about 30 days. In some embodiments, a treatment cycle according to the present invention may be about 2 weeks. In some embodiments, a treatment cycle according to the present invention may be about 14 days to about 30 days. In some embodiments, the method of the present invention comprises a treatment cycle of at least 1 week to 10 weeks with or without dosing intervals. In some embodiments, the method of the present invention comprises a 21-days treatment cycle. In a specific embodiment, the present invention relates to a method of treating cancer in a subject in need thereof comprising administering (i) a therapeutically effective dosage amount of compound (I) or its pharmaceutically acceptable salts thereof, and (ii) atezolizumab; wherein the method comprises 21 days as a treatment cycle, and the compound (I) is administered orally once or twice daily; and atezolizumab is administered at 1200mg once in every 21 days. In a specific embodiment, the present invention relates to a method of treating cancer in a subject in need thereof comprising administering (i) a therapeutically effective dosage amount of compound (I) or its pharmaceutically acceptable salts thereof, and (ii) atezolizumab; wherein the method comprises 21 days as a treatment cycle; and atezolizumab is administered at 1200mg once in every 21 days, and the therapeutically effective dosage amount of compound (I) is selected from about 5mg to about 200mg. In a specific embodiment, the present invention relates to a method of treating cancer in a subject in need thereof comprising administering (i) a therapeutically effective dosage amount of compound (I) or its pharmaceutically acceptable salts thereof, and (ii) pembrolizumab; wherein the compound (I) is administered orally once or twice daily for at least 2 weeks; and pembrolizumab is administered at 200mg every 21-days interval intravenously. In a specific embodiment, the present invention relates to a method of treating cancer in a subject in need thereof comprising administering (i) a therapeutically effective dosage amount of compound (I) or its pharmaceutically acceptable salts thereof, and (ii) toripalimab; wherein the compound (I) is administered orally once or twice daily for at least 2 weeks; and toripalimab is administered at 240mg every 2-week interval intravenously. In a specific embodiment, the present invention relates to a method of treating cancer in a subject in need thereof comprising administering (i) a therapeutically effective dosage amount of compound (I) or its pharmaceutically acceptable salts thereof, and (ii) a checkpoint inhibitor; wherein the method results one or more of the following: (a) progression-free survival for at least 21 days; (b) partial response at about 6 weeks; and (c) stable disease state for at least 2 weeks. In a specific embodiment, the present invention relates to a method of treating cancer in a subject in need thereof comprising administering (i) a therapeutically effective dosage amount of compound (I) or its pharmaceutically acceptable salts thereof, and (ii) a checkpoint inhibitor; wherein the subject is having cancer that is selected from hodgkin’s lymphoma, colon cancer, cholangio carcinoma, genitourinary melanoma, metastatic gallbladder adenocarcinoma, biliary duct cancer, metastatic breast cancer, squamous cell carcinoma, metastatic renal cell carcinoma and ovarian granulosa cell tumor; and the method results in one or more of the following: (a) progression-free survival for at least 21 days; (b) partial response at about 6 weeks; and (c) stable disease state for at least 2 weeks. In a specific embodiment, the present invention relates to a method of treating cancer in a subject in need thereof comprising administering (i) a therapeutically effective dosage amount of compound (I) or its pharmaceutically acceptable salts thereof, and (ii) a checkpoint inhibitor is selected from pembrolizumab and atezolizumab; wherein the subject is having cancer that is selected from hodgkin’s lymphoma, colon cancer, cholangio carcinoma, genitourinary melanoma, metastatic gallbladder adenocarcinoma, biliary duct cancer, metastatic breast cancer, squamous cell carcinoma, metastatic renal cell carcinoma and ovarian granulosa cell tumor; and the method results one or more of the following: (a) progression-free survival for at least 21 days; (b) partial response at about 6 weeks; and (c) stable disease state for at least 2 weeks. In a specific embodiment, the present invention relates to a method of treating cancer in a subject in need thereof comprising administering (i) a therapeutically effective dosage amount of compound (I) or its pharmaceutically acceptable salts thereof, and (ii) a checkpoint inhibitor is selected from pembrolizumab and atezolizumab; wherein the subject was having cancer that is selected from hodgkin’s lymphoma, colon cancer, cholangio carcinoma, genitourinary melanoma, metastatic gallbladder adenocarcinoma, biliary duct cancer, metastatic breast cancer, squamous cell carcinoma, metastatic renal cell carcinoma and ovarian granulosa cell tumor; and the method results one or more of the following: (a) progression-free survival for at least 21 days; (b) partial response at about 6 weeks; and (c) stable disease state for at least 2 weeks. In a specific embodiment, the present invention relates to a method of treating cancer in a subject in need thereof comprising administering (i) from about 10mg to about 150mg of compound (I) or its pharmaceutically acceptable salts thereof, and (ii) a checkpoint inhibitor is selected from pembrolizumab and atezolizumab; wherein the subject was having cancer that is selected from hodgkin’s lymphoma, colon cancer, cholangio carcinoma, genitourinary melanoma, metastatic gallbladder adenocarcinoma, biliary duct cancer, metastatic breast cancer, squamous cell carcinoma, metastatic renal cell carcinoma and ovarian granulosa cell tumor; and the method results one or more of the following: (a) progression-free survival for at least 21 days; (b) partial response at about 6 weeks; and (c) stable disease state for at least 2 weeks. In a specific embodiment, the present invention relates to a method of treating cancer in a subject in need thereof comprising administering (i) from about 50mg of compound (I) or its pharmaceutically acceptable salts thereof, and (ii) a checkpoint inhibitor is selected from pembrolizumab and atezolizumab; wherein the subject was having cancer that is selected from hodgkin’s lymphoma, colon cancer, cholangio carcinoma, genitourinary melanoma, metastatic gallbladder adenocarcinoma, biliary duct cancer, metastatic breast cancer, squamous cell carcinoma, metastatic renal cell carcinoma, and ovarian granulosa cell tumor; and the method results in one or more of the following: (a) progression-free survival for at least 21 days; (b) partial response at about 6 weeks; and (c) stable disease state for at least 2 weeks. In a specific embodiment, the present invention relates to a method of treating cancer in a subject in need thereof comprising administering (i) from about 75 mg of compound (I) or its pharmaceutically acceptable salts thereof, and (ii) a checkpoint inhibitor is selected from pembrolizumab and atezolizumab; wherein the subject was having cancer that is selected from hodgkin’s lymphoma, colon cancer, cholangio carcinoma, genitourinary melanoma, metastatic gallbladder adenocarcinoma, biliary duct cancer, metastatic breast cancer, squamous cell carcinoma, metastatic renal cell carcinoma and ovarian granulosa cell tumor; and the method results in one or more of the following: (a) progression-free survival for at least 21 days; (b) partial response at about 6 weeks; and (c) stable disease state for at least 2 weeks. In a specific embodiment, the present invention relates to a method of treating cancer in a subject in need thereof comprising administering (i) from about 100mg of compound (I) or its pharmaceutically acceptable salts thereof, and (ii) a checkpoint inhibitor is selected from pembrolizumab and atezolizumab; wherein the subject was having cancer that is selected from hodgkin’s lymphoma, colon cancer, cholangio carcinoma, genitourinary melanoma, metastatic gallbladder adenocarcinoma, biliary duct cancer, metastatic breast cancer, squamous cell carcinoma, metastatic renal cell carcinoma and ovarian granulosa cell tumor; and the method results in one or more of the following: (a) progression-free survival for at least 21 days; (b) partial response at about 6 weeks; and (c) stable disease state for at least 2 weeks. In one embodiment, the present invention provides Compound (I) or a tautomer thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in the treatment of cancer in a subject in need thereof wherein the Compound (I) is administered to the subject at least about 12.5mg once daily: In one embodiment, the Compound (I) administered to the subject is about 25mg once daily. In one embodiment, the Compound (I) administered to the subject is about 37.5mg once daily. In one embodiment, the Compound (I) administered to the subject is about 50mg once daily. In one embodiment, the Compound (I) administered to the subject is about 75mg once daily. In one embodiment, the Compound (I) administered to the subject is about 100mg once daily. In one embodiment, the subject is administered with an additional anti-cancer agent selected from anti-PD1 antibody and anti-PD-L1 antibody. In one embodiment, the anticancer agent is pembrolizumab or atezolizumab. In one embodiment, the amount of atezolizumab administered to the subject is about 1200mg. In one embodiment, wherein the amount of pembrolizumab administered to the subject is about 200mg. In one embodiment, the Compound (I) is a di-hydrochloride salt:

. EXAMPLES Example 1: Preparation of Compound (I) The synthetic procedure for the preparation of compound I or a pharmaceutically acceptable salt thereof described in the present invention was described in PCT application PCT/IB2022/056248 which was published as WO2023281417, the contents of which are hereby incorporated by reference in their entirety. Example 1: Phase 1 Clinical Trial study of Compound (I) as single agent and in combination with Anti-PD1 or Anti-PD-L1 antibody First in human (FIH) study evaluating the safety, tolerability, pharmacokinetic and efficacy of compound (I) as a single agent and in combination with Anti-PD1 antibody as well as Anti-PD-L1 antibody was undertaken. Part 1 of the dose escalation trial had a traditional 3+3 design consisting of part 1a (monotherapy of compound (I)) and part 1b (combination with Atezolizumab or Pembrolizumab). Inclusion Criteria: 1. Subjects (≥18 years of age) with histologically or cytologically confirmed advanced, metastatic, unresectable solid tumors or lymphomas who have previously received standard systemic therapy or for whom treatment is not accessible, not tolerated or refused, have progressed after ≥1 of systemic therapies for recurrent/metastatic disease and who have not received prior therapy targeting HPK1. 2. At least 1 measurable lesion as defined per RECIST 1.1. The target lesion(s) selected have not been previously treated with local therapy or the target lesion(s) selected that are within the field of prior local therapy have subsequently progressed as defined by RECIST 1.1. 3. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1 measured within 72 hours of treatment. 4. Predicted life expectancy of ≥3 months. 5. Adequate organ function as indicated by the following laboratory values up to first dose of study drug: Hemoglobin ≥9.0 g/dL, Absolute neutrophil count ≥1.5 x 109/L, Serum total bilirubin ≤1.5 x ULN (<3 x ULN for participants with Gilbert syndrome), AST and ALT ≤2.5 x ULN (≤5 x ULNs for participants with hepatocellular carcinoma or liver metastases). 6. Adequate renal function as indicated by creatinine clearance of ≥60mL/min calculated using Cokroft-Gault method. 7. Adequate cardiac function, left ventricular ejection fraction (LVEF) of ≥50% as assessed by multi-gated acquisition (MUGA) or ultrasound/echocardiography (ECHO). For Part 2, dose expansion cohorts inclusion criteria specific to tumor types is to be updated after completion of Part 1. Exclusion Criteria: 1. Any condition that, in the opinion of the Investigator, would interfere with evaluation of the study drug or interpretation of subject safety or study results. 2. Subjects with uncontrolled or untreated brain metastasis or leptomeningeal disease. Subjects with equivocal findings or with confirmed brain metastases are eligible provided that they are asymptomatic and radiologically stable without the need for corticosteroid treatment for at least 4 weeks prior to the first dose of study drug(s) 3. Any active malignancy ≤2 years before the first dose of study drug(s) except for the specific cancer under investigation in this study and any locally recurring cancer that has been treated with curative intent (e.g., resected basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast) 4. Any condition that required systemic treatment with either corticosteroids (>10 mg daily of prednisone or equivalent) or other immunosuppressive medication ≤14 days before the first dose of study drug(s), with the following exceptions: 1. Adrenal replacement steroid (dose ≤10 mg daily of prednisone or equivalent) 2. Topical, ocular, intra-articular, intranasal, or inhalational corticosteroid with minimal systemic absorption 3. Short course (≤7 days) of corticosteroid prescribed prophylactically (e.g., for contrast dye allergy) or for the treatment of a non-autoimmune condition (e.g., delayed-type hypersensitivity reaction caused by contact allergen) 5. Pregnant/planning to be pregnant or breast-feeding women. 6. Any important medical illness or abnormal laboratory finding that would increase the risk of participating in this study (based on the investigator's judgment). 7. Any known severe allergic reaction to pembrolizumab/atezolizumab or its excipients. In the Phase I clinical Trial, 28 (n=28) human subjects were enrolled in Part 1a design and were orally administered Compound I at doses of 50 mg (n=21), 75 mg (n=3), 100 mg (n=4). Refer to Table – 1. Table – 1: Cohort Mono 50 mg Mono 75 Mono 100 mg mg Recruited human subjected (total n = 28) 21 3 4 Further, 20 (n=20) human subjects were enrolled in Part 1b combination arm design and were orally administered Compound I at doses of 12.5 mg, 25 mg and 37.5 mg in combination with Pembrolizumab and Atezolizumab separately which were administered intravenously Refer to Table – 2. Table – 2: Cohort – 1 Cohort – 2 Cohort – 3 Compound-I Compound-I Compound-I (12.5 mg) (25 mg) (37.5 mg) Cohort + Pembro + Atezo + Pembro + Atezo + Pembro + Atezo (200 mg, (1200 (200 mg, (1200 mg, (200 mg, (1200 mg, IV) mg, IV) IV) IV) IV) IV) Recruited human subjects 3 3 4 3 4 3 (total n = 20) Table – 3: Tumor types of human subjects enrolled in the study Tumor Types Part 1a Part 1b Head and Neck (2 Parotid) (1 Nasopharyngeal) 7 3 Breast cancer 3 - Lung cancer - 2 Ovarian cancer 1 2 Melanoma 3 (Rectal, Anal canal 3 (Buccal, Skin & & Cervix) Acral) Colorectal cancer 2 2 Cervix cancer 2 - Hodgkin’s Lymphoma 2 - Hepatobiliary + one pancreas 2 3 Renal Cell Carcinoma 5 1 Small Round Blue Cell Tumor - 2 (Esthesioneuroblastoma & Ewings) Endometrium cancer (Leiomyosarcoma + HG 1 1 serous) Sarcoma - 1 Mean duration of treatment was 59.5 days (range:07-126) in Part 1a and 63.63 in Part 1b (range: 7-126). Results:

A total of 339 treatment-emergent adverse events (TEAEs) were reported in 25 (89.3%) subjects who were enrolled in Part-1a of the trial where the subjects were exposed to Compound I as monotherapy. 47 severe (≥Grade 3) TEAEs have been reported in 50 mg cohort, 6 severe (≥Grade 3) TEAEs reported in 2 subjects in 75 mg cohort and 5 severe (≥Grade 3) TEAEs reported in 2 subjects in 100 mg cohort. Few relevant related treatment emergent adverse events seen are: 50 mg - hyponatremia and fatigue.75 mg - increased blood pressure. 100 mg - right heart failure, breathlessness, and pulmonary hypertension. No dose limiting toxicities (DLTs) in the DLT observation period were observed in any of the aforesaid cohorts. One subject of Hodgkin’s lymphoma had partial response at 6 weeks and progressed at 18 weeks. Part – 1b (Compound I in combination with Pembrolizumab or Atezolizumab) A total of 167 TEAEs were reported in 19 subjects in Part- 1b of the trial in which the subjects were exposed to Compound I in combination with pembrolizumab or atezolizumab. There were 10 TEAEs reported in 3 subjects in Cohort 1 (Pembro), 9 TEAEs were reported in 3 subjects in Cohort 1 (Atezo), 49 TEAEs were reported in 4 subjects in Cohort 2 (Pembro), 31 TEAEs were reported in 3 subjects in Cohort 2 (Atezo), 30 TEAEs reported in 3 subjects in Cohort 3 (Pembro) and 38 TEAEs reported in 3 subjects in Cohort 3 (Atezo). There were no severe (≥Grade 3) TEAEs reported in Cohort 1 (Pembro), Cohort 1 (Atezo) and Cohort 3 (Pembro), 8 severe (≥Grade 3) TEAEs were reported in 2 subjects in Cohort 2 (Pembro), 2 severe (≥Grade 3) TEAEs were reported in 1 subject in Cohort 2 (Atezo), and 4 severe (≥Grade 3) TEAEs were reported in 2 subjects in Cohort 3 (Atezo). Further, one subject of Head and Neck cancer in the part-1b combination arm at 25 mg of Compound I once daily with Atezolizumab 1200 mg every 21 days, was reported to have Complete Response and stable disease. One subject of NSCLC, Squamous cell carcinoma treated in cohort of 12.5 mg Compound I once daily with Pembrolizumab 200 mg every 21 days were found to have stable disease till 26 weeks. Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above. All publications and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.

Claims

We Claim: 1. A method of treating cancer in a subject in need thereof comprising administering Compound (I) or a tautomer thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount of Compound (I) administered to the subject is at least about 12.5mg once daily:

(Compound (I)).

2. The method of claim 1, wherein the therapeutically effective amount of Compound (I) administered to the subject is about 25mg once daily.

3. The method of claim 1, wherein the therapeutically effective amount of Compound (I) administered to the subject is about 37.5mg once daily.

4. The method of claim 1, wherein the therapeutically effective amount of Compound (I) administered to the subject is about 50mg once daily.

5. The method of claim 1, wherein the therapeutically effective amount of Compound (I) administered to the subject is about 75mg once daily.

6. The method of claim 1, wherein the therapeutically effective amount of Compound (I) administered to the subject is about 100mg once daily.

7. The method of claim 1, wherein the cancer is selected from carcinoma, lymphoma, leukemia, blastoma, and sarcoma.

8. The method of claim 1, wherein the cancer is selected from adenocarcinoma of any organ, nasopharyngeal cancer, squamous cell carcinoma (i.e. cutaneous squamous cell carcinoma, Bowen’s disease, verrucous squamous cell carcinoma, metastatic squamous cell carcinoma, cervical squamous cell carcinoma), myeloma, lung cancer (i.e. small cell lung cancer, non-small cell lung cancer, adenocarcinoma), glioma (i.e. glioblastoma multiforme, mixed gliomas, ependymomas, oligodendrogliomas, astrocytomas), Hodgkin's lymphoma (i.e., nodular lymphocyte-predominant hodgkin's lymphoma, lymphocyte-depleted hodgkin's lymphoma), non-Hodgkin's lymphoma (i.e. B-cell lymphomas such as diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma; T-cell lymphomas, Burkitt lymphoma), acute myelogenous leukemia, multiple myeloma, Gastrointestinal (tract) cancer, kidney cancer (i.e. various type of renal cell carcinoma), ovarian cancer (i.e., granulosa cell tumor, dysgerminoma), liver cancer (i.e. hepatoblastoma, angioblastoma, hepatocellular carcinoma, fibrolamellar carcinoma), lymphoblastic leukemia, lymphocytic leukemia, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, melanoma, chondrosarcoma, neuroblastoma, pancreatic cancer, glioblastoma multiforme, cervical cancer, brain cancer, stomach cancer, bladder cancer, hepatocytoma, breast cancer, colon cancer and head neck cancer, and any cancers irrespective of histology which are either PD-L1 positive, microsatellite instability high, high tumor mutational burden or mismatch repair genes.

9. The method of any one of claims 1 to 6, wherein the Compound (I) is administered to the subject for a treatment cycle of 21 days.

10. The method of claim 1, wherein the subject is administered with an additional anti- cancer agent selected from anti-PD1 antibody and anti-PD-L1 antibody.

11. The method of claim 2, wherein the subject is administered with an additional anti- cancer agent selected from anti-PD1 antibody and anti-PD-L1 antibody.

12. The method of claim 3, wherein the subject is administered with an additional anti- cancer agent selected from anti-PD1 antibody and anti-PD-L1 antibody.

13. The method of claim 11, wherein the anticancer agent is pembrolizumab or atezolizumab.

14. The method of claim 14, wherein the anticancer agent is pembrolizumab.

15. The method of claim 14, wherein the anticancer agent is atezolizumab.

16. The method of any one of claims 11 to 14, wherein the amount of atezolizumab administered to the subject is about 1200mg.

17. The method of claim 17, wherein the atezolizumab is administered to the subject once in every 21 days.

18. The method of any one of claims 11 to 14, wherein the amount of pembrolizumab administered to the subject is about 200mg.

19. The method of claim 19, wherein the pembrolizumab is administered to the subject once in every 21 days.

20. The method of claim 11, comprising administering (i) a therapeutically effective amount of compound (I) or its pharmaceutically acceptable salt thereof, and (ii) atezolizumab; wherein the method comprises 21 days as a treatment cycle; and atezolizumab is administered at 1200mg once in every 21 days intravenously, and the therapeutically effective amount of compound (I) is selected from 12.5mg daily, about 25mg daily and about 37.5mg daily.

21. The method of claim 11, comprising administering (i) a therapeutically effective amount of compound (I) or its pharmaceutically acceptable salts thereof, and (ii) pembrolizumab; wherein the method comprises 21 days as a treatment cycle; and pembrolizumab is administered at 200mg in every 21-days intravenously, and the therapeutically effective amount of compound (I) is selected from 12.5mg daily, about 25mg daily and about 37.5mg daily.

22. The method of any one of claims 1 to 22, wherein the Compound (I) is a di- hydrochloride salt:

.

23. Compound (I) or a tautomer thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in the treatment of cancer in a subject in need thereof wherein the Compound (I) is administered to the subject at least about 12.5mg once daily: (Compound (I)).

24. The compound for use of claim 23, wherein the administered to the subject is about 25mg once daily.

25. The compound for use of claim 23, wherein the Compound (I) administered to the subject is about 37.5mg once daily.

26. The compound for use of claim 23, wherein the Compound (I) administered to the subject is about 50mg once daily.

27. The compound for use of claim 23, wherein the Compound (I) administered to the subject is about 75mg once daily.

28. The compound for use of claim 23, wherein the Compound (I) administered to the subject is about 100mg once daily.

29. The compound for use of claim 23, wherein the subject is administered with an additional anti-cancer agent selected from anti-PD1 antibody and anti-PD-L1 antibody.

30. The compound for use of claim 29, wherein the anticancer agent is pembrolizumab or atezolizumab.

31. The compound for use of claim 29 or 30, wherein the amount of atezolizumab administered to the subject is about 1200mg.

32. The compound for use of claim 29 or 30, wherein the amount of pembrolizumab administered to the subject is about 200mg.