Novel heterocyclic compounds as inhibitors of parg

Abstract

The present invention relates to novel heterocyclic compounds of formula (I) as inhibitors of PARG, their pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, prodrugs, deuterated including other possible isotopes, combinations and use thereof in treating cancer. Formula (I) The present invention also relates to a process for the preparation of novel heterocyclic compounds of Formula (I), pharmaceutical compositions comprising them, and their use in the treatment of cancer.

Description

[0001] NOVEL HETEROCYCLIC COMPOUNDS AS INHIBITORS OF PARG

[0002] This application claims the priority to, and benefit of Indian Patent Application No. 202341082368 filed on April 30, 2024 (Postdated), and Indian Patent Application No. 202441062128 filed on August 16, 2024; the disclosures of which are incorporated herein by reference.

[0003] FIELD OF INVENTION

[0004] The present invention relates to novel heterocyclic compounds of Formula (I) as inhibitors of PARG, their pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, prodrugs, deuterated compounds including other possible isotopes, combinations and use thereof in treating cancer.

[0005] Formula (I)

[0006] The present invention also relates to a process for the preparation of novel heterocyclic compounds of Formula (I), pharmaceutical compositions comprising them, and their use in the treatment of cancer.

[0007] BACKGROUND OF THE INVENTION

[0008] Cancer is the second leading cause of death worldwide after cardiovascular disease (WHO report, 2018). Error in DNA repair mechanism leads to cancer development and progression (Front Genet. 2015; 6: 157). Single strand breaks generated during cellular replication are being primarily repaired by a class of chromatin associated proteins called poly ADP ribose polymerase, PARP (Nature 2005 Apr 14;434 (7035):917-21). PARP enzymes are responsible for modifying a wide variety of target proteins with poly(ADP-ribose) (PAR). PARs are highly negatively charged, branched-chain, posttranslational modification derived from NAD+(D’ Amours et al., 1999, Krishnakumar and Kraus, 2010) that signal the rest of the DNA repair machinery (J Biol Chem 252: 7000-7005, J Biol Chem 255: 10493-10501). 17 family members of PARP are discovered till date (Cell Prolif. 2016 Aug; 49(4): 421-437) of which PARP1 is the major PAR-producing enzyme in eukaryotes. Activation of PARP1 upon acute DNA damage (like single strand break), is one of the earliest cellular responses to genotoxic stress (Polo and Jackson, 2011). This synchronizes DNA damage response signaling, recruitment of DNA repair factors and an efficient modulation of chromatin structure (Durkacz et al., 1980, Schreiber et al., 2006, Chou et al., 2010). Accumulation of PAR chains in the cell are toxic (Molecular Cell 81, 2640-2655, June 17, 2021) and systematic hydrolysis of PAR chains are performed post DNA repair by poly (ADP-ribose) glycohydrolase (PARG) (Biochim. Biophys. ACTA-GENE Struct. Expr. 1219, 342-350, 1994). PARG activity accounts for almost 90% of dePARylation activity in cells and is the primary mediator of PAR catabolism in the cell (Experimental Cell Research, Volume 268, Issue 1, 2001; Front. Biosci. (Landmark Ed) 2009, 14(5), 1619-1626). PARG inhibition results in excessive PAR accumulation and DNA replication fork stalling, that leads to replication arrest and eventual cell death. DNA replication stress bearing background, including BRCA deficiency can result in synthetic lethal interaction with PARG inhibitors and is expected to be particularly sensitive to PARG inhibitors [(Nat Commun 10, 5654 (2019); Sci. Adv.5, eaav4340(2019)]. PARG is a potentially attractive therapeutic target with potential to even treat patients with PARPi resistant tumors (ACS Chem. Biol 2016, 11, 3179-3190).

[0009] Treatment of cancer continues to be a challenge though several drugs that have been approved with different mechanism. In view of this, there is unmet need for new drugs that can treat such diseases more effectively. We herein describe novel heterocyclic compounds as inhibitors of PARG.

[0010] OBJECTIVE OF THE INVENTION

[0011] An objective of the present invention is to provide novel heterocyclic compounds of formula (I) as inhibitors of PARG, their pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, prodrugs, deuterated compounds including other possible isotopes thereof.

[0012] Another objective of the present invention is to provide a process for the preparation of novel heterocyclic compounds of Formula (I).

[0013] Yet another objective of the present invention is to provide a pharmaceutical compositions comprising novel heterocyclic compounds of Formula (I) and process for the preparation thereof. Still another objective of the present invention is to provide novel heterocyclic compounds of Formula (I) and its pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, prodrugs, deuterated compounds including other possible isotopes, combinations and use thereof in treating cancer.

[0014] SUMMARY OF THE INVENTION

[0015] The present invention provides novel heterocyclic compounds of formula (I)

[0016] Formula (I) or its pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, prodrugs, deuterated including other possible isotopes, combinations and use thereof in treating cancer; wherein, Xi, X2, X3 are each independently selected from N, CR5;

[0017] X4, X5 are each independently selected from N or CR4;

[0018] Xf, is independently selected from O, S, NR4, C(R4)2;

[0019] Li is selected from -NR6SO2-, -SO2NR6-, -NR6CO-, substituted or unsubstituted tetrazole, substituted or unsubstituted heterocycle, -NH(CO)NH, -NH(CO)O-, -SO2 and -CONR6;

[0020] R1is absent or selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, haloalkyl, perhaloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, OR7b;

[0021] R2and R3are independently absent or selected from alkyl; or R2and R3together with the carbon atom to which they are attached form substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl;

[0022] R4is selected from hydrogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkylene, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkylheterocycloalkyl;

[0023] R5is selected from hydrogen, cyano, haloalkyl, perhaloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted and substituted or unsubstituted , -OR7, -OR7a, -OR7b, -SO2R7a, -C(=O)OR7b, -C(=O)R7b, -OC(=O)R7a, - OC(=O)OR7a, -C(=O)N(H)R7, -C(=O)N(alkyl)R7, -N(H)C(=O)R7a, -N(H)R7, and - N(alkyl)R7;

[0024] R6is selected from the group consisting of hydrogen, alkyl and alkoxy;

[0025] R7is independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, and substituted or unsubstituted heteroaryl;

[0026] R7ais independently selected from substituted or unsubstituted alkyl, alkenyl, alkynyl, halogen, haloalkyl, perhaloalkyl and cycloalkyl;

[0027] R7bis selected from hydrogen, halogen, substituted or unsubstituted alkyl, alkenyl, haloalkyl, perhaloalkyl, and cycloalkyl;

[0028] R7Cis selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl.

[0029] The present invention also provides a process for the preparation of novel heterocyclic compounds of Formula (I) or its pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, prodrugs, deuterated compounds including other possible isotopes, combinations.

[0030] The present invention also provides a pharmaceutical compositions comprising novel heterocyclic compounds of Formula (I) or its pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, prodrugs, deuterated compounds including other possible isotopes, combinations and process for the preparation thereof.

[0031] The present invention provides use of novel heterocyclic compounds of formula (I) or its pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, prodrugs, deuterated compounds including other possible isotopes, combinations and use thereof in treating cancer. The present invention also provides a method of treating cancer by administering to a subject therapeutically effective amount of a pharmaceutical composition comprising at least one or more of the compounds of Formula (I) or its pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, prodrugs, deuterated compounds including other possible isotopes thereof, wherein the subject is cancer associated with PARG protein.

[0032] Further, the cancer is a solid tumor or hematopoietic tumor; wherein the solid tumor is selected from but not limited to breast cancer, colorectal cancer, endometrial cancer, esophageal cancer, glioblastoma, hepatocellular carcinoma, lung cancer, neuroblastoma, ovarian cancer, prostate cancer, stomach cancer, rhabdomyosarcoma, fibrosarcoma, thyroid follicular cancer or Kaposi's sarcoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoactanthoma or uterine cancer. wherein the hematopoietic tumor is selected from but not limited to the group comprising:

[0033] (a) a hematopoietic tumor of lymphoid lineage selected from leukemia, acute lymphocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-20 lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma or Burkett's lymphoma; and

[0034] (b) a hematopoietic tumor of myeloid lineage selected from acute and chronic myelogenous leukemias, myelodysplastic syndrome or promyelocytic leukemia.

[0035] DETAILED DESCRIPTION OF THE INVENTION

[0036] General terms used in formula can be defined as follows; however, the meaning stated should not be interpreted as limiting the scope of the term per se.

[0037] As used herein, the term “inhibitors” meant to be non-covalent inhibitors or covalent inhibitors of PARG.

[0038] The term “non-covalent inhibitors” meant to be a mechanism involving PARG inhibitors bind reversibly to the enzyme using interactions like hydrogen bonds, ionic bonds, hydrophobic forces, and van der waals forces. They usually target the active site, competing with the natural substrate. Their binding is temporary, allowing dynamic regulation. Because their structure can be fine-tuned, they offer greater selectivity and reduced off-target effects, enabling controlled inhibition of PARG activity.

[0039] The term “covalent inhibitors” meant to be a mechanism involving cysteine in PARG (Poly(ADP-ribose) glycohydrolase) inhibitors primarily requires the formation of either an irreversible or reversible covalent bond between the thiol group of cysteine and an electrophilic moiety on the inhibitor. This covalent interaction is further enhanced by non- covalent binding forces, resulting in effective and sustained inhibition of PARG activity. Importantly, this mechanism allows for the eventual dissociation of the inhibitor, facilitating recovery of PARG function.

[0040] The term “alkyl” is meant to be a branched and unbranched alkyl groups with 1 to 6 carbon atoms and by the term "Ci-3-alkyl" are meant branched and unbranched alkyl groups with 1 to 3 carbon atoms. "Ci-4-alkyl" accordingly denotes branched and unbranched alkyl groups with 1 to 4 carbon atoms. Alkyl groups with 1 to 4 carbon atoms are preferred. Examples of these include: methyl, ethyl, zz-propyl, iso-propyl, zz-butyl, zso-butyl, sec-butyl, tert-butyl, n- pentyl, zso -pentyl, zzeo-pentyl or hexyl. ‘Alkyl’ may be substituted or unsubstituted, when ‘alkyl’ is substituted, it is substituted with 1 to 4 substituents independently selected from oxo (=0), halogen, -CN, alkoxy, hydroxy, haloalkyl, perhaloalkyl, cycloalkyl, substituted or unsubstituted- heterocycloalkyl, substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, -0R7b, -SO2R7a, -C(=0)0R7b, -0C(=0)R7a, -0C(=0)0R7a, - C(=0)N(H)R7, -C(=O)N(alkyl)R7, -N(H)C(=0)R7a, -N(H)R7, and -N(alkyl)R7.

[0041] The term “alkylene” is meant to be a branched and unbranched alkylene groups with 1-6 carbon atoms and by the term “C1-6 alkylene” are meant branched and unbranched alkylene groups with 1 to 6 carbon atoms and by the term “C1-4 alkylene” are meant branched and unbranched alkylene groups with 2 to 4 carbon atoms. Alkylene groups with 2 to 4 carbon atoms are preferred.

[0042] The term “alkenyl” is meant to be 2-6 carbon atoms and by the term “C2-6-alkenyl” (including those which are part of other groups) are meant branched and unbranched alkenyl groups with 2 to 6 carbon atoms and by the term “C2-4-alkenyl” are meant branched and unbranched alkenyl groups with 2 to 4 carbon atoms, provided that they have at least one double bond. Alkenyl groups with 2 to 4 carbon atoms are preferred. Examples include: ethenyl or vinyl, propenyl, butenyl, pentenyl or hexenyl; when ‘alkenyl’ is substituted, it is substituted with 1 to 4 substituents independently selected from substituted- or unsubstituted-alkyl, halogen, - CN, cycloalkyl, substituted- or unsubstituted- heterocycloalkyl, substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, -OR7b, -SO2R7a, -C(=O)OR7b, -OC(=O)R7a, - OC(=O)OR7a, -alkyl-N(R7)2, -C(=O)N(H)R7, -C(=O)N(alkyl)R7, -N(H)C(=O)R7a, -N(H)R7, and -N(alkyl)R7.

[0043] The term “alkenylene” is meant to be a branched and unbranched alkenylene groups with 2-6 carbon atoms and by the term “C2-6 alkenylene” are meant branched and unbranched alkenylene groups with 2 to 6 carbon atoms and by the term “C2-4 alkenylene” are meant branched and unbranched alkylene groups with 2 to 4 carbon atoms. Alkenylene groups with 2 to 4 carbon atoms are preferred, when ‘alkenylene’ is substituted, it is substituted with 1 to 4 substituents independently selected from substituted or unsubstituted alkyl, halogen, alkoxy, hydroxy, haloalkyl, perhaloalkyl, -CN, cycloalkyl, substituted or unsubstituted- heterocycloalkyl, substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl. The term “alkynyl” is meant to be a branched and unbranched alkynyl groups with 1-6 carbon atoms and by the term “C1-6 alkynyl” are meant branched and unbranched alkylene groups with 1 to 6 carbon atoms and by the term “C1-4 alkynyl” are meant branched and unbranched alkynyl groups with 1 to 4 carbon atoms. Alkynyl groups with 1 to 4 carbon atoms are preferred, when ‘alkynyl is substituted, it is substituted with 1 to 4 substituents independently selected from substituted- or unsubstituted-alkyl, halogen, alkoxy, hydroxy, haloalkyl, perhaloalkyl, -CN, cycloalkyl, substituted- or unsubstituted- heterocycloalkyl, substituted- or unsubstituted aryl, substituted- or unsubstituted- heteroaryl.

[0044] The term “alkynylene” is meant to be a branched and unbranched alkynyl ene groups with 1-6 carbon atoms and by the term “C1-6 alkynylene” are meant branched and unbranched alkynylene groups with 1 to 6 carbon atoms and by the term “C1-4 alkynylene” are meant branched and unbranched alkynylene groups with 1 to 4 carbon atoms. Alkynylene groups with 1 to 4 carbon atoms are preferred, when ‘alkynylene’ is substituted, it is substituted with 1 to 4 substituents independently selected from substituted or unsubstituted-alkyl, halogen, alkoxy, hydroxy, haloalkyl, perhaloalkyl, -CN, cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl. As used herein, the term "carbocycle" or “cycloalkyl” refers to a cyclic, saturated, monovalent hydrocarbon group with a specified number of carbon atoms (for example, C3 to C12), which is a monocyclic or polycyclic ring, (bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings), when ‘carbocycle’ or ‘cycloalkyl’ is substituted, it is substituted with 1 to 4 substituents independently selected from oxo (=0), halogen, -CN, alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -0R7b, -SO2R7a, - C(=0)0R7b, -0C(=0)R7a, -0C(=0)0R7a, -C(=0)N(H)R7, -C(=O)N(alkyl)R7, -

[0045] N(H)C(=0)R7a, -N(H)R7, and -N(alkyl)R7.

[0046] The term “heterocycloalkyl” or “heterocycle” are meant to be, unless stated otherwise, three to twelve-membered, saturated, partially saturated or unsaturated heterocyclic rings which may contain one, two or three heteroatoms, selected from among oxygen, sulphur and nitrogen. Although included by the term "heterocyclic rings" or "heterocycles", the term "saturated heterocyclic ring" refers to five-, six- or seven-membered saturated rings. “Heterocycloalkyl” or “heterocycle” may be substituted or unsubstituted. The term "heterocycloalkyl" refers to a group having a specified number of ring atoms and a specified number of heteroatoms (for example, 1, 2 or 3), monocyclic or polycyclic ring (bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings); when ‘heterocycloalkyl’ or ‘heterocycle’ is substituted, it is substituted with 1 to 4 substituents independently selected from oxo (=0), imino (=N), halogen, -CN, alkyl, hydroxyalkyl, alkoxy, haloalkyl, perhaloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -O-C(=O)-aryl, -alkyl-NH(alkyl), -alkyl-N(alkyl)2, -alkyl-OR7a, - alkyl-R7a, -N(alkyl), -N(alkyl)2, -N(alkyl)2, -N(H)alkyl, -NH2, -N(alkyl)C(=O)alkyl, - N(H)C(=O)alkyl, -C(=O)N(alkyl)2, -C(=O)N(H)alkyl, -C(=0)NH2, -SO2N(alkyl)2, - SO2N(H)alkyl, -SO2NH2, SO(alkyl), - SO2(alkyl), - SO2(alkenyl), - SO2(alkynyl), -C(=0)0H, -C(=O)O-alkyl, and -C(=O)-alkyl, -C(=O)-alkylene-N(R7b)2, -C(=O)-alkenylene-N(R7b)2, - C(=O)-alkylene-R7a, -C(=O)-alkenyl, -C(=O)-N(R7)2, -C(=O)-alkenylene-R7a-N(R7b)2, -

[0047] O

[0048] C(=O)-alkenylene-R7a,R7a, -C(=O)-alkynyl, -C(=O)-alkynylene-R7a, C(=O)-cycloalkyl, C(=O)-heterocycloalkyl; -OR7, -0R7a, -0R7b, -SO2R7a, -C(=0)0R7b, -C(=0)R7b, - OC(=O)R7a, -OC(=O)OR7a, -C(=O)N(H)R7, -C(=O)N(alkyl)R7, -N(H)C(=O)R7a, -N(H)R7, and -N(alkyl)R7.

[0049] The term “aryl” is meant to be an aromatic ring system with 6 to 12 carbon atoms. Examples include: phenyl or naphthyl, the preferred aryl group being phenyl. Unless otherwise stated, the aromatic groups may be substituted by one or more groups. “Aryl” may be substituted or unsubstituted, when the ‘aryl’ group is substituted, it is substituted with 1 to 4 substituents selected from halogen, -CN, alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocycloalkyl, -O- alkyl, -O-perhaloalkyl, -O-C(=O)-aryl, -N(alkyl)alkyl, -N(H)alkyl, -OR7b, -NH2, - N(alkyl)C(=O)alkyl, -N(H)C(=O)alkyl, -C(=O)N(alkyl)alkyl, -C(=O)N(H)alkyl, -C(=O)NH2, -SO2N(alkyl)alkyl, -SO2N(H)alkyl, -SO2NH2, -C(=O)OH, -C(=O)-alkyl, and -C(=O)O-alkyl.

[0050] The term “heteroaryl” is meant to be includes three to six-membered heterocyclic aromatic groups or 5-12-membered, bicyclic heteroaryl rings which may contain one, two, three or four heteroatoms selected from among oxygen, sulphur and nitrogen, and contain so many conjugated double bonds that an aromatic system is formed. “Heteroaryl” may be substituted or unsubstituted, when the ‘heteroaryl’ group is substituted, it is substituted with 1 to 4 substituents selected from halogen, -CN, alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocycloalkyl, -O-alkyl, O-perhaloalkyl, -N(alkyl)alkyl, -N(H)alkyl, OR7b-NH2, - N(alkyl)C(=O)alkyl, -N(H)C(=O)alkyl, -C(=O)N(alkyl)alkyl, -C(=O)N(H)alkyl, -C(=O)NH2, -SO2N(alkyl)alkyl, -SO2N(H)alkyl, -SO2NH2, -C(=O)OH, -C(=O)-alkyl, and -C(=O)O-alkyl. each R7is independently selected from hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, and heteroaryl; each R7ais independently selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, perhaloalkyl and cycloalkyl, heterocycloalkyl; each R7bis selected from hydrogen, halogen, alkyl, alkenyl, haloalkyl, perhaloalkyl, and cycloalkyl, heterocycloalkyl, s

[0051] The particular compounds of the present invention without departing from the scope of the definitions given under compounds of formula (I) and particular compounds emanated from formula (I) are summarized herein below table encompassing the entirety of the scope of compounds within compounds of formula (I).

[0052] Few compounds of the present invention were separated into their pure enantiomers which are shown in the below table: Table 1:

[0053]

[0054] The present invention provides a pharmaceutical composition, comprising a pharmaceutically acceptable carrier and one or more safe and effective amounts of the compounds described in the aspect of the present invention or their pharmaceutically acceptable salts, stereoisomers, solvates, geometrical isomers, atropisomers, tautomers, endogenous racemates, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

[0055] Pharmaceutical compositions

[0056] The pharmaceutical preparation of the present invention may be in various oral dosage forms include, but are not limited to tablets, pills, dragees (containing the active ingredient in powder or pellet form), troches, lozenges, ointments, capsules (soft or hard gelatin), syrups, suppositories, pessaries, emulsions, or in parenteral dosage forms such as injections for intramuscular, intravenous, or subcutaneous administration.

[0057] All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses. Exemplary isotopes that can be incorporated in to compounds of the invention include but are not limited to isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as 2H (“D”), 3H, 11C, 13C, 14C, 13N, 15N, 150, 170, 180, 32P, 33P, 35S, 18F, 36C1, 1231 and 1251.

[0058] Methods of Treatment

[0059] The present invention provides a compound described in the above aspect of the present invention or its tautomer, meso, racemate, enantiomer, and diastereomer, or the use of mixture forms thereof, or pharmaceutically acceptable salts thereof, for the preparation of medicaments for the prevention and / or treatment of PARG-mediated related diseases.

[0060] The related disease mediated by PARG is a cancer selected from the group consisting of but not limited to a solid or hematologically derived tumor selected from cancer of the bladder, endometrial, lung squamous cell, breast, colon, kidney, liver, lung, small cell lung cancer, esophagus, gall-bladder, brain, head and neck, ovary, pancreas, stomach, cervix, thyroid, prostate and skin, (b) a hematopoietic tumor of lymphoid lineage selected from leukemia, acute lymphocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-20 lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma, (c) a hematopoietic tumor of myeloid lineage selected from acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia (d) a tumor of mesenchymal origin selected from fibrosarcoma and rhabdomyosarcoma, (e) a tumor of the central and peripheral nervous system selected from astrocytoma, neuroblastoma, glioma and schwannoma, or (f) a melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoactanthoma, thyroid follicular cancer or Kaposi's sarcoma.

[0061] Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. In one embodiment of the present invention provides compounds of formula (I) are irreversible or reversible covalent inhibitors of PARG (Poly(ADP -ribose) glycohydrolase). These compounds form irreversible or reversible covalent bond with the cysteine residue of PARG, primarily through mechanisms such as Michael addition. In addition to this labile covalent binding, the compounds also engage in non-covalent interactions with PARG, including van der waals, hydrogen, hydrophobic, hydrophilic, and electrostatic interactions.

[0062] In another embodiment of the present invention provides irreversible covalent inhibition of PARG involves the formation of a stable covalent bond between a reactive electrophilic group on the inhibitor and a nucleophilic cysteine residue. This binding is permanent, leading to the irreversible inactivation of the enzyme. The process usually includes initial non- covalent interactions that help position the inhibitor for effective covalent modification. Once formed, the covalent adduct cannot be easily reversed, leading to long-term inhibition of PARG activity.

[0063] Compounds disclosed herein and their tautomeric forms, atropisomers, stereoisomers, prodrugs may be prepared, for example, by techniques well known in the organic synthesis and familiar to a practitioner ordinarily skilled in art of this invention. In addition, the processes described herein may enable the synthesis of the compounds of the present invention. However, these may not be the only means by which the compounds described in the invention may be synthesized. Further, the various synthetic steps described herein may be performed in alternate sequences to furnish the desired compounds.

[0064] General Methods:

[0065] Scheme 1:

[0066] Scheme 1 shows a method of preparation of Intermediate (compound 4) from compound 1.

[0067] The compound (4) was prepared as per procedure reported in J. Med. Chem. 2012, 55, 21, 9181-9194

[0068] Scheme 2 shows a method of preparation of Intermediate (compound 8) from compound 5.

[0069] The compound (8) was prepared as per procedure reported in J. Med. Chem. 2021, 64, 16, 12089-12108.50141275A

[0070] Scheme 3 shows a method of preparation of Intermediate (compound 13) from compound 9.

[0071] The compound (11) was prepared by reacting commercially available (9) with compound (10) in presence of HATU in DMF solvent and DIPEA as a base. Cbz deprotection of compound 15 with Palladium on carbon in methanol solvent under hydrogen pressure to afford compound (13).

[0072] Scheme 4 shows a method of preparation of Intermediate (compound 16) from compound 5.

[0073] The compound (16) was prepared by reacting commercially available compound (5) with compound (14) in presence of HATU in dichloromethane solvent and triethylamine as a base. Compound (15) reacted with TFA in dichloromethane solvent to afford compound (16).

[0074]

[0075] Scheme 5 shows a method of preparation of Intermediate (compound 25) from compound 17. The compounds of formula (18) were prepared as per the procedure reported in WO2023154913. Compound (18) reacted with iodine in presence of KOH in DMF solvent to afford compound (19). NH group in compound 19 was protected with trityl chloride in THF solvent using sodium hydride as a base. Compound 21 of prepared by reacting compound 20 with cyclopropane boronic acid using the methods known in the art for Suzuki coupling reaction. Deprotection of trityl group was carried with TFA in dichloromethane to afford compound 22. Compound 22 reacted with 2-bromo-5-(difluoromethyl)-l,3,4- thiadiazole in DMF solvent using cesium carbonate as a base to afford compound 23. Reaction of compound 23 with l,3-Dichloro-5,5-dimethylhydantoin in acetonitrile, acetic acid and water to afford compound 24, which was reacted with cesium carbonate and pyridine as a base in acetonitrile solvent to afford compound 25. Protection of sulfonamide NH with 2-(Trimethylsilyl)ethoxymethyl chloride (SEM-Chloride) in THF solvent using sodium hydride as a base to afford compound 26.

[0076] Scheme 6 shows a method of preparation of the compound of the formula (28) from compounds 27.

[0077] Intermediate 26 and intermediate 4 reacted using the methods known in the art for Buchwald coupling reaction to give compound 27 and finally acid catalyzed deprotection of 2- (Trimethylsilyl)ethoxymethyl group with TFA in dichloromethane solvent afforded compound of formula (28).

[0078] Scheme -7 illustrates the synthesis of compound of formula 16.

[0079] Compound 2 can be synthesized by coupling of 6-bromo-4-chloro-lH-indazole and benzylmercaptan with suitable Pd catalysts such as but not limited to Pd2(dba)3 in presence of ligands such as but not limited to XantPhos and base such as but not limited DIPEA or NEts. Typically these reactions are carried out in ethereal solvents such as 1,4-dioxane, THF or similar solvents at temperatures ranging from 80 °C to 110 °C for about 8 h to 16 h.

[0080] Mitsunobu reaction of compound 2 with compound of formula 3 using various azodicarxylate such as but not limited to DEAD or DIAD in presence of phosphine such as but not limited to PPhs gives the compound of formula 4. Typically these reactions are run in ethereal solvents such as 1,4-dioxane, THF or similar solvents at temperatures ranging from 0 °C to 25 °C for about 3 h to 16 h. The compound of formula 5 is formed upon treatment of compound of formula 4 with reagents such as but not limited to DCDMH in presence of acid such as but not limited to AcOH. Typically these reactions are done in solvents such as acetonitrile at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h. The compound of formula 6 when treated with compound of formula 5 in presence of base such as but not limited to NEts gives compound of formula 7. Typically these reactions are performed in solvents such as but not limited to CH2CI2 at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h. The compound of formula 8 can be synthesized by protection of compound of formula 7 with reagents such as but not limited to SEM-C1 in presence of base such as but not limited to NEts or DIPEA. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0081] Compound of formula 9 can be synthesized by Buchwald coupling of compound of formula 8 and N-Boc -piperazine with suitable Pd catalysts such as but not limited to Pd2(dba)3 in presence of ligands such as but not limited to RuPhos or XantPhos and base such as but not limited CS2CO3 or K2CO3. Typically these reactions are carried out in ethereal solvents such as 1,4-dioxane, THF or similar solvents at temperatures ranging from 80 °C to 110 °C for about 8 h to 16 h. Deprotection of compound of formula 9 with acids such as but not limited to HCl / dioxane or TFA affords the compound of formula 10. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0082] Amidation of the compound of formula 10 with various carboxylic acids of formula 11 such as but not limited to isobutyric acid using various coupling agents such as but not limited to HATU or EDC.HCl / HOBt in presence of base such as but not limited to NEt3 or DIPEA. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0083] Compound of formula 13 can be prepared by hydrogenation of compound of formula 12 with suitable Pd catalysts such as but not limited to Pd / C in protic solvents such as EtOH, MeOH or similar solvents at temperature around 25 °C for about 1 h to 3 h.

[0084] Amidation of the compound of formula 13 with various carboxylic acid of formula 14 such as but not limited to but-2-ynoic acid, propiolic acid, (E)-4-(dimethylamino)but-2-enoic acid, 2-fluoroacrylic acid using various coupling agents such as but not limited to HATU, or EDC.HCl / HOBt in presence of base such as but not limited to NEt3 or DIPEA gives compound of formula 16. Typically these reactions are run in polar aprotic solvents such as DMF, DMAc or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0085] Alternatively, amidation of the compound of formula 13 can also be carried out with various acid chlorides of formula 15 such as but not limited to chloroacetyl chloride, acryloyl chloride, propionyl chloride, vinylsulphonyl chloride in presence of base such as but not limited to NEt? or DIPEA to afford the compound of formula 16. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0086] Compounds at every step may be purified by standard techniques such as column chromatography, crystallization, and reverse phase preparative HPLC or SFC.

[0087] Scheme -8 illustrates the synthesis of compound of formula 21.

[0088] Compound of formula 18 can be synthesized by Buchwald coupling of compound of formula 8 and compound of formula 17 with suitable Pd catalysts such as but not limited to Pd2(dba)3 in presence of ligands such as but not limited to RuPhos or XantPhos and base such as but not limited CS2CO3 or K2CO3. Typically these reactions are carried out in ethereal solvents such as 1,4-dioxane, THF or similar solvents at temperatures ranging from 80 °C to 110 °C for about 8 h to 16 h. Compound of formula 19 can be prepared by hydrogenation of compound of formula 18 with suitable Pd catalysts such as but not limited to Pd / C in protic solvents such as EtOH, MeOH or similar solvents at temperature around 25 °C for about 1 h to 3 h. Amidation of the compound of formula 19 with various carboxylic acid of formula 14 such as but not limited to but-2-ynoic acid, propiolic acid, (E)-4-(dimethylamino)but-2-enoic acid, 2-fluoroacrylic acid using various coupling agents such as but not limited to HATU or EDC.HCl / HOBt in presence of base such as but not limited to NEts or DIPEA gives compound of formula 20. Typically these reactions are run in polar aprotic solvents such as DMF, DMAc or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0089] Alternatively, amidation of the compound of formula 19 can also be carried out with various acid chloride of formula 15 such as but not limited to chloroacetyl chloride, acryloyl chloride, propionyl chloride, vinylsulphonyl chloride in presence of base such as but not limited to NEts or DIPEA to afford compound of formula 20. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0090] Deprotection of compound of formula 20 with acids such as but not limited to HCl / dioxane or TFA affords the compound of formula 21. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0091] Compounds at every step may be purified by standard techniques such as column chromatography, crystallization, and reverse phase preparative HPLC or SFC.

[0092] Scheme -9 illustrates the synthesis of compound of formula 25. Deprotection of compound of formula 18 with acids such as but not limited to HCl / dioxane or TFA affords the compound of formula 22. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0093] Reductive amination of compound of formula 23 can be synthesized from compound of formula 22 by reacting with aldehydes such as but not limited to aq. formaldehyde and reducing agents such as but not limited to NaBH ,CN. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0094] Cbz deprotection of compound of formula 23 with acid such as but not limited TFA affords the compound of formula 24. Typically these reactions are run at temperatures ranging from 40 °C to 60 °C for about 30 min. to 2 h.

[0095] Amidation of the compound of formula 24 with various carboxylic acid of formula 14 such as but not limited to but-2-ynoic acid, propiolic acid, (E)-4-(dimethylamino)but-2-enoic acid, 2-fluoroacrylic acid using various coupling agents such as but not limited to HATU or EDC.HCl / HOBt in presence of base such as but not limited to NEts or DIPEA gives compound of formula 25. Typically these reactions are run in polar aprotic solvents such as DMF, DMAc or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0096] Alternatively, amidation of the compound of formula 24 can also be carried out with various acid chloride of formula 15 such as but not limited to chloroacetyl chloride, acryloyl chloride, propionyl chloride, vinylsulphonyl chloride in presence of base such as but not limited to NEts or DIPEA to afford compound of formula 25. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0097] Scheme -10 illustrates the synthesis of compound of formula 35.

[0098] Mitsunobu reaction of compound 2 with compound of formula 26 using various azodicarxylate such as but not limited to DEAD or DIAD in presence of phosphine such as but not limited to PPI13 gives the compound of formula 27. Typically these reactions are run in ethereal solvents such as 1,4-dioxane, THF or similar solvents at temperatures ranging from 0 °C to 25 °C for about 3 h to 16 h. The compound of formula 28 is formed upon treatment of compound of formula 27 with reagents such as but not limited to DCDMH in presence of acid such as but not limited to AcOH. Typically these reactions are done in solvents such as acetonitrile at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0099] The compound of formula 28 when treated with compound of formula 6 in presence of base such as but not limited to NEts gives compound of formula 29. Typically these reactions are performed in solvents such as but not limited to CH2CI2 at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h. The compound of formula 30 can be synthesized by protection of compound of formula 29 with reagents such as but not limited to SEM-C1 in presence of base such as but not limited to NEts or DIPEA. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0100] Compound of formula 31 can be synthesized by Buchwald coupling of compound of formula 30 and N-Boc -piperazine with suitable Pd catalysts such as but not limited to Pd2(dba)3 in presence of ligands such as but not limited to RuPhos or XantPhos and base such as but not limited CS2CO3 or K2CO3. Typically these reactions are carried out in ethereal solvents such as 1,4-dioxane, THF or similar solvents at temperatures ranging from 80 °C to 110 °C for about 8 h to 16 h. Deprotection of compound of formula 31 with acids such as but not limited to HCl / dioxane or TFA affords the compound of formula 32. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCI3 or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0101] Amidation of the compound of formula 32 with various carboxylic acids of formula 11 such as but not limited to isobutyric acid using various coupling agents such as but not limited to HATU or EDC.HCl / HOBt in presence of base such as but not limited to NEt3 or DIPEA. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCI3 or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0102] Compound of formula 34 can be prepared by hydrogenation of compound of formula 33 with suitable Pd catalysts such as but not limited to Pd / C in protic solvents such as EtOH, MeOH or similar solvents at temperature around 25 °C for about 1 h to 3 h.

[0103] Amidation of the compound of formula 34 with various carboxylic acid of formula 14 such as but not limited to but-2-ynoic acid, propiolic acid, (E)-4-(dimethylamino)but-2-enoic acid, 2-fluoroacrylic acid using various coupling agents such as but not limited to HATU, or EDC.HCl / HOBt in presence of base such as but not limited to NEt3 or DIPEA gives compound of formula 35. Typically these reactions are run in polar aprotic solvents such as DMF, DMAc or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0104] Alternatively, amidation of the compound of formula 34 can also be carried out with various acid chlorides of formula 15 such as but not limited to chloroacetyl chloride, acryloyl chloride, propionyl chloride, vinylsulphonyl chloride in presence of base such as but not limited to NEt? or DIPEA to afford the compound of formula 35. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCI3 or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h. Compounds at every step may be purified by standard techniques such as column chromatography, crystallization, and reverse phase preparative HPLC or SFC.

[0105] Scheme -11 illustrates the synthesis of compound of formula 45. Nucleophilic displacement of compound of formula 2 with compound of formula 36 using various inorganic bases such as but not limited to CS2CO3 or K2CO3 gives the compound of formula 37. Typically these reactions are run in dipolar aprotic solvents such as DMF, DMAc or similar solvents at temperatures ranging from 50 °C to 80 °C for about 8 h to 16 h.

[0106] The compound of formula 38 is formed upon treatment of compound of formula 37 with reagents such as but not limited to DCDMH in presence of acid such as but not limited to AcOH. Typically these reactions are done in solvents such as acetonitrile at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0107] The compound of formula 38 when treated with compound of formula 6 in presence of base such as but not limited to NEts gives compound of formula 39. Typically these reactions are performed in solvents such as but not limited to CH2CI2 at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h. The compound of formula 40 can be synthesized by protection of compound of formula 39 with reagents such as but not limited to SEM-C1 in presence of base such as but not limited to NEts or DIPEA. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0108] Compound of formula 42 can be synthesized by Buchwald coupling of compound of formula 40 and compound of formula 41 with suitable Pd catalysts such as but not limited to Pd2(dba)3 in presence of ligands such as but not limited to RuPhos or XantPhos and base such as but not limited CS2CO3 or K2CO3. Typically these reactions are carried out in ethereal solvents such as 1,4-dioxane, THF or similar solvents at temperatures ranging from 80 °C to 110 °C for about 8 h to 16 h.

[0109] Deprotection of compound of formula 42 with acids such as but not limited to HCl / dioxane or TFA affords the compound of formula 43. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0110] Cbz deprotection of compound of formula 43 with acid such as but not limited TFA affords the compound of formula 44. Typically these reactions are run at temperatures ranging from 40 °C to 60 °C for about 30 min. to 2 h.

[0111] Amidation of the compound of formula 44 with various carboxylic acid of formula 14 such as but not limited to but-2-ynoic acid, propiolic acid, (E)-4-(dimethylamino)but-2-enoic acid, 2-fluoroacrylic acid using various coupling agents such as but not limited to HATU, or EDC.HCl / HOBt in presence of base such as but not limited to NEt3 or DIPEA gives compound of formula 45. Typically these reactions are run in polar aprotic solvents such as DMF, DMAc or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0112] Alternatively, amidation of the compound of formula 44 can also be carried out with various acid chlorides of formula 15 such as but not limited to chloroacetyl chloride, acryloyl chloride, propionyl chloride, vinylsulphonyl chloride in presence of base such as but not limited to NEt? or DIPEA to afford the compound of formula 45. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h. Compounds at every step may be purified by standard techniques such as column chromatography, crystallization, and reverse phase preparative HPLC or SFC.

[0113] Scheme -12 illustrates the synthesis of compound of formula 50. Compound of formula 47 can be synthesized by Buchwald coupling of compound of formula 40 and compound of formula 46 with suitable Pd catalysts such as but not limited to Pd2(dba)3 in presence of ligands such as but not limited to RuPhos or XantPhos and base such as but not limited CS2CO3 or K2CO3. Typically these reactions are carried out in ethereal solvents such as 1,4- dioxane, THF or similar solvents at temperatures ranging from 80 °C to 110 °C for about 8 h to 16 h.

[0114] Deprotection of compound of formula 47 with acids such as but not limited to HCl / dioxane or TFA affords the compound of formula 48. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCI3 or similar solvents at temperatures ranging from 0 °C to 25

[0115] °C for about 30 min. to 2 h.

[0116] Cbz deprotection of compound of formula 48 with acid such as but not limited TFA affords the compound of formula 49. Typically these reactions are run at temperatures ranging from 40 °C to 60 °C for about 30 min. to 2 h.

[0117] Amidation of the compound of formula 49 with various carboxylic acid of formula 14 such as but not limited to but-2-ynoic acid, propiolic acid, (E)-4-(dimethylamino)but-2-enoic acid, 2-fluoroacrylic acid using various coupling agents such as but not limited to HATU, or EDC.HCl / HOBt in presence of base such as but not limited to NEt3 or DIPEA gives compound of formula 50. Typically these reactions are run in polar aprotic solvents such as DMF, DMAc or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0118] Alternatively, amidation of the compound of formula 49 can also be carried out with various acid chlorides of formula 15 such as but not limited to chloroacetyl chloride, acryloyl chloride, propionyl chloride, vinylsulphonyl chloride in presence of base such as but not limited to NEt? or DIPEA to afford the compound of formula 50. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0119] Compounds at every step may be purified by standard techniques such as column chromatography, crystallization, and reverse phase preparative HPLC or SFC.

[0120] Scheme -13 illustrates the synthesis of compound of formula 54. Compound of formula 51 can be synthesized by Buchwald coupling of compound of formula 40 and compound of formula 17 with suitable Pd catalysts such as but not limited to Pd2(dba)3 in presence of ligands such as but not limited to RuPhos or XantPhos and base such as but not limited CS2CO3 or K2CO3. Typically these reactions are carried out in ethereal solvents such as 1,4- dioxane, THF or similar solvents at temperatures ranging from 80 °C to 110 °C for about 8 h to 16 h.

[0121] Compound of formula 52 can be prepared by hydrogenation of compound of formula 51 with suitable Pd catalysts such as but not limited to Pd / C in protic solvents such as EtOH, MeOH or similar solvents at temperature around 25 °C for about 1 h to 3 h.

[0122] Amidation of the compound of formula 52 with various carboxylic acid of formula 14 such as but not limited to but-2-ynoic acid, propiolic acid, (E)-4-(dimethylamino)but-2-enoic acid, 2-fluoroacrylic acid using various coupling agents such as but not limited to HATU, or EDC.HCl / HOBt in presence of base such as but not limited to NEts or DIPEA gives compound of formula 53. Typically these reactions are run in polar aprotic solvents such as DMF, DMAc or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0123] Alternatively, amidation of the compound of formula 52 can also be carried out with various acid chlorides of formula 15 such as but not limited to chloroacetyl chloride, acryloyl chloride, propionyl chloride, vinylsulphonyl chloride in presence of base such as but not limited to NEt? or DIPEA to afford the compound of formula 53. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0124] Deprotection of compound of formula 53 with acids such as but not limited to HCl / dioxane or TFA affords the compound of formula 54. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0125] Compounds at every step may be purified by standard techniques such as column chromatography, crystallization, and reverse phase preparative HPLC or SFC.

[0126] Scheme -14 illustrates the synthesis of compound of formula 56. Nucleophilic displacement of compound of formula 19 with aryl halides such as but not limited to trichloropyrimidine using various inorganic bases such as but not limited to CS2CO3 or K2CO3 gives the compound of formula 55. Typically these reactions are run in solvents such as CH3CN or similar solvents at temperatures ranging from 50 °C to 80 °C for about 1 h to 3 h. Deprotection of compound of formula 55 with acids such as but not limited to HCl / dioxane or TFA affords the compound of formula 56. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0127] Compounds at every step may be purified by standard techniques such as column chromatography, crystallization, and reverse phase preparative HPLC or SFC.

[0128] Scheme -15 illustrates the synthesis of compound of formula 57. Nucleophilic displacement of compound of formula 13 with aryl halides such as but not limited to trichloropyrimidine using various inorganic bases such as but not limited to CS2CO3 or K2CO3 gives the compound of formula 57. Typically these reactions are run in solvents such as CH3CN or similar solvents at temperatures ranging from 50 °C to 80 °C for about 1 h to 3 h.

[0129] Compounds at every step may be purified by standard techniques such as column chromatography, crystallization, and reverse phase preparative HPLC or SFC.

[0130] Scheme -16 illustrates the synthesis of compound of formula 61. Compound of formula 58 can be prepared by hydrogenation of compound of formula 9 with suitable Pd catalysts such as but not limited to Pd / C in protic solvents such as EtOH, MeOH or similar solvents at temperature around 25 °C for about 1 h to 3 h.

[0131] Amidation of the compound of formula 58 with various carboxylic acid of formula 14 such as but not limited to but-2-ynoic acid, propiolic acid, (E)-4-(dimethylamino)but-2-enoic acid, 2-fluoroacrylic acid using various coupling agents such as but not limited to HATU, or EDC.HCl / HOBt in presence of base such as but not limited to NEt3 or DIPEA gives compound of formula 59. Typically these reactions are run in polar aprotic solvents such as DMF, DMAc or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0132] Alternatively, amidation of the compound of formula 58 can also be carried out with various acid chlorides of formula 15 such as but not limited to chloroacetyl chloride, acryloyl chloride, propionyl chloride, vinylsulphonyl chloride in presence of base such as but not limited to NEt? or DIPEA to afford the compound of formula 59. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0133] Deprotection of compound of formula 59 with acids such as but not limited to HCl / dioxane or TFA affords the compound of formula 60. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0134] Amidation of the compound of formula 60 with various amino acids such as but not limited to Boc glycine, N-Boc using various coupling agents such as but not limited to HATU, or EDC.HCl / HOBt in presence of base such as but not limited to NEts or DIPEA gives compound of formula 61. Typically these reactions are run in polar aprotic solvents such as DMF, DMAc or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0135] Compounds at every step may be purified by standard techniques such as column chromatography, crystallization, and reverse phase preparative HPLC or SFC. Scheme -17 illustrates the synthesis of compound of formula 72. Mitsunobu reaction of compound 2 with compound of formula 62 using various azodicarxylate such as but not limited to DEAD or DIAD in presence of phosphine such as but not limited to PPhs gives the compound of formula 63. Typically these reactions are run in ethereal solvents such as 1,4- dioxane, THF or similar solvents at temperatures ranging from 0 °C to 25 °C for about 3 h to 16 h. Deprotection of compound of formula 63 with acids such as but not limited to HCl / dioxane or TFA affords the compound of formula 64. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0136] Compound of formula 65 can be synthesized by protection of compound of formula 64 with suitable reagents such as but not limited to CbzCl in presence of base such as but not limited NaHCC or K2CO3. Typically these reactions are carried out in ethereal solvents such as 1,4- dioxane, THF or similar solvents at temperatures ranging from 0 °C to 25 °C for about 8 h to 16 h.

[0137] The compound of formula 66 is formed upon treatment of compound of formula 65 with reagents such as but not limited to DCDMH in presence of acid such as but not limited to AcOH. Typically these reactions are done in solvents such as acetonitrile at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0138] The compound of formula 66 when treated with compound of formula 6 in presence of base such as but not limited to NEt3 gives compound of formula 67. Typically these reactions are performed in solvents such as but not limited to CH2CI2 at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0139] The compound of formula 68 can be synthesized by protection of compound of formula 67 with reagents such as but not limited to SEM-C1 in presence of base such as but not limited to NEt3 or DIPEA. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0140] Compound of formula 69 can be synthesized by Buchwald coupling of compound of formula 68 and compound of formula 17 with suitable Pd catalysts such as but not limited to Pd2(dba)3 in presence of ligands such as but not limited to RuPhos or XantPhos and base such as but not limited CS2CO3 or K2CO3. Typically these reactions are carried out in ethereal solvents such as 1,4-dioxane, THF or similar solvents at temperatures ranging from 80 °C to 110 °C for about 8 h to 16 h.

[0141] Compound of formula 70 can be prepared by hydrogenation of compound of formula 69 with suitable Pd catalysts such as but not limited to Pd / C in solvents such as EtOAc, EtOH, MeOH or similar solvents at temperature around 25 °C for about 1 h to 3 h.

[0142] Amidation of the compound of formula 70 with various carboxylic acid of formula 14 such as but not limited to but-2-ynoic acid, propiolic acid, (E)-4-(dimethylamino)but-2-enoic acid, 2-fluoroacrylic acid using various coupling agents such as but not limited to HATU, or EDC.HCl / HOBt in presence of base such as but not limited to NEt3 or DIPEA gives compound of formula 71. Typically these reactions are run in polar aprotic solvents such as DMF, DMAc or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0143] Alternatively, amidation of the compound of formula 70 can also be carried out with various acid chlorides of formula 15 such as but not limited to chloroacetyl chloride, acryloyl chloride, propionyl chloride, vinylsulphonyl chloride in presence of base such as but not limited to NEt? or DIPEA to afford the compound of formula 71. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCI3 or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h. Deprotection of compound of formula 71 with acids such as but not limited to HCl / dioxane or TFA affords the compound of formula 72. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0144] Compounds at every step may be purified by standard techniques such as column chromatography, crystallization, and reverse phase preparative HPLC or SFC.

[0145] Scheme -18 illustrates the synthesis of compound of formula 81. Nucleophilic displacement of compound of formula 2 with compound of formula 73 (synthesis mentioned in scheme-14) using various inorganic bases such as but not limited to CS2CO3 or K2CO3 gives the compound of formula 74. Typically these reactions are run in dipolar aprotic solvents such as DMF, DMAc or similar solvents at temperatures ranging from 50 °C to 80 °C for about 8 h to 16 h.

[0146] The compound of formula 75 is formed upon treatment of compound of formula 74 with reagents such as but not limited to DCDMH in presence of acid such as but not limited to AcOH. Typically these reactions are done in solvents such as acetonitrile at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0147] The compound of formula 75 when treated with compound of formula 6 in presence of base such as but not limited to NEt3 gives compound of formula 76. Typically these reactions are performed in solvents such as but not limited to CH2CI2 at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0148] The compound of formula 77 can be synthesized by protection of compound of formula 76 with reagents such as but not limited to SEM-C1 in presence of base such as but not limited to NEt3 or DIPEA. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2h.

[0149] Compound of formula 78 can be synthesized by Buchwald coupling of compound of formula 77 and compound of formula 17 with suitable Pd catalysts such as but not limited to Pd2(dba)3 in presence of ligands such as but not limited to RuPhos or XantPhos and base such as but not limited CS2CO3 or K2CO3. Typically these reactions are carried out in ethereal solvents such as 1,4-dioxane, THF or similar solvents at temperatures ranging from 80 °C to 110 °C for about 8 h to 16 h.

[0150] Compound of formula 79 can be prepared by hydrogenation of compound of formula 78 with suitable Pd catalysts such as but not limited to Pd / C in solvents such as EtOAc, EtOH, MeOH or similar solvents at temperature around 25 °C for about 1 h to 3 h.

[0151] Amidation of the compound of formula 79 with various carboxylic acid of formula 14 such as but not limited to but-2-ynoic acid, propiolic acid, (E)-4-(dimethylamino)but-2-enoic acid, 2-fluoroacrylic acid using various coupling agents such as but not limited to HATU, or EDC.HCl / HOBt in presence of base such as but not limited to NEts or DIPEA gives compound of formula 80. Typically these reactions are run in polar aprotic solvents such as DMF, DMAc or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0152] Alternatively, amidation of the compound of formula 79 can also be carried out with various acid chlorides of formula 15 such as but not limited to chloroacetyl chloride, acryloyl chloride, propionyl chloride, vinylsulphonyl chloride in presence of base such as but not limited to NEt? or DIPEA to afford the compound of formula 80. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h. Deprotection of compound of formula 80 with acids such as but not limited to HCl / dioxane or TFA affords the compound of formula 81. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h. Compounds at every step may be purified by standard techniques such as column chromatography, crystallization, and reverse phase preparative HPLC or SFC.

[0153] Scheme -19 illustrates the synthesis of compound of formula 92. Nucleophilic displacement of compound of formula 82 (synthesis mentioned in scheme- 15) with compound of formula 2 using various inorganic bases such as but not limited to CS2CO3 or K2CO3 gives the compound of formula 83. Typically these reactions are run in dipolar aprotic solvents such as DMF, DMAc or similar solvents at temperatures ranging from 50 °C to 80 °C for about 8 h to 16 h. Deprotection of compound of formula 83 with acids such as but not limited to HCl / dioxane or TFA affords the compound of formula 84. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0154] Compound of formula 85 can be synthesized by protection of compound of formula 84 with suitable reagents such as but not limited to CbzCl in presence of base such as but not limited NaHCCh or K2CO3. Typically these reactions are carried out in ethereal solvents such as 1,4- dioxane, THF or similar solvents at temperatures ranging from 0 °C to 25 °C for about 8 h to 16 h.

[0155] The compound of formula 86 is formed upon treatment of compound of formula 85 with reagents such as but not limited to DCDMH in presence of acid such as but not limited to AcOH. Typically these reactions are done in solvents such as acetonitrile at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0156] The compound of formula 86 when treated with compound of formula 6 in presence of base such as but not limited to NE ? gives compound of formula 87. Typically these reactions are performed in solvents such as but not limited to CH2CI2 at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0157]

[0158] The compound of formula 88 can be synthesized by protection of compound of formula 87 with reagents such as but not limited to SEM-C1 in presence of base such as but not limited to NEt3 or DIPEA. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCI3 or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min to 2 h.

[0159] Compound of formula 89 can be synthesized by Buchwald coupling of compound of formula 88 and compound of formula 17 with suitable Pd catalysts such as but not limited to Pd2(dba)3 in presence of ligands such as but not limited to RuPhos or XantPhos and base such as but not limited CS2CO3 or K2CO3. Typically these reactions are carried out in ethereal solvents such as 1,4-dioxane, THF or similar solvents at temperatures ranging from 80 °C to 110 °C for about 8 h to 16 h.

[0160] Compound of formula 90 can be prepared by hydrogenation of compound of formula 89 with suitable Pd catalysts such as but not limited to Pd / C in solvents such as EtOAc, EtOH, MeOH or similar solvents at temperature around 25 °C for about 1 h to 3 h.

[0161] Amidation of the compound of formula 90 with various carboxylic acid of formula 14 such as but not limited to but-2-ynoic acid, propiolic acid, (E)-4-(dimethylamino)but-2-enoic acid, 2-fluoroacrylic acid using various coupling agents such as but not limited to HATU, or EDC.HCl / HOBt in presence of base such as but not limited to NEt3 or DIPEA gives compound of formula 91. Typically these reactions are run in polar aprotic solvents such as DMF, DMAc or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0162] Alternatively, amidation of the compound of formula 90 can also be carried out with various acid chlorides of formula 15 such as but not limited to chloroacetyl chloride, acryloyl chloride, propionyl chloride, vinylsulphonyl chloride in presence of base such as but not limited to NEt? or DIPEA to afford the compound of formula 91. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0163] Deprotection of compound of formula 91 with acids such as but not limited to HCl / dioxane or TFA affords the compound of formula 92. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0164] Compounds at every step may be purified by standard techniques such as column chromatography, crystallization, and reverse phase preparative HPLC or SFC.

[0165] Scheme -20 illustrates the synthesis of compound of formula 36 and 73. Protection of the 1- benzyl 2-methyl-4-hydroxypyrrolidine-l,2-dicarboxylate can also be carried out with various protecting agents such as but not limited to DHP to afford the compound of formula a. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 2 h to 8 h. Reduction of the compound of formula a can also be carried out with various reducing agents such as but not limited to lithium borohydride, sodium borohydride, lithium aluminum hydride to afford the compound of formula b. Typically these reactions are run in etheral solvents such as THF, dioxane or similar solvents at temperatures ranging from 0 °C to 25 °C for about 2 h to 16 h. Mesylation of the compound of formula b can be carried out with various sulphonyl chlorides such as but not limited to mesyl chloride in presence of base such as but not limited to NEts or DIPEA to afford the compound of formula c. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0166] Compound of formula d can be synthesized by nucleophilic dispt. of compound of formula c with suitable reagents such as but not limited to TBAF. Typically these reactions are carried out in ethereal solvents such as 1,4-dioxane, THF or similar solvents at temperatures ranging from 70 °C to 110 °C for about 8 h to 16 h.

[0167] Selective deprotection of compound of formula d can be achieved with suitable reagents such as but not limited to AcOH to afford compound of formula e. Typically these reactions are carried out in solvents such as water at temperatures ranging from 40 °C to 60 °C for about 2 h to 8 h.

[0168] Mesylation of the compound of formula e can be carried out with various sulphonyl chlorides such as but not limited to mesyl chloride in presence of base such as but not limited to NEts or DIPEA to afford the compound of formula 36. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0169] Alkylation of the compound of formula b can be carried out with various alkylating agents such as but not limited to methyl iodide in presence of base such as but not limited to NaH or KO'Bu to afford the compound of formula f. Typically these reactions are carried out in ethereal solvents such as 1,4-dioxane, THF or similar solvents at temperatures ranging from 0 °C to 25 °C for about 2 h to 8 h.

[0170] Selective deprotection of compound of formula f can be achieved with suitable reagents such as but not limited to AcOH to afford compound of formula g.. Typically these reactions are carried out in solvents such as water at temperatures ranging from 40 °C to 60 °C for about 2 h to 8 h. Mesylation of the compound of formula g can be carried out with various sulphonyl chlorides such as but not limited to mesyl chloride in presence of base such as but not limited to NEts or DIPEA to afford the compound of formula 73. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h. Compounds at every step may be purified by standard techniques such as column chromatography, crystallization, and reverse phase preparative HPLC or SFC.

[0171] Scheme -21 illustrates the synthesis of compound of formula 82. Protection of the 1 -(tert- butyl) 2-methyl 4-hydroxypyrrolidine-l,2-dicarboxylate can also be carried out with various protecting agents such as but not limited to TBDMSC1 in presence of base such as but not limited to imidazole to afford the compound of formula h. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 2 h to 16 h. Reduction of the compound of formula h can also be carried out with various reducing agents such as but not limited to lithium borohydride, sodium borohydride, lithium aluminum hydride to afford the compound of formula i. Typically these reactions are run in etheral solvents such as THF, dioxane or similar solvents at temperatures ranging from 0 °C to 25 °C for about 2 h to 16 h.

[0172] Oxidation of the compound of formula i can also be carried out with various oxidising agents such as but not limited to Dess-Martin periodinane to afford the compound of formula j. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 2 h to 16 h.

[0173] Fluorination of the compound of formula j can be carried out with various fluorinatiing agents such as but not limited to DAST to afford the compound of formula k. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from -60 °C to 25 °C for about 2 h to 16 h. Deprotection of the compound of formula k can be carried out with various agents such as but not limited to TBAF to afford the compound of formula 1. Typically these reactions are run in halogenated solvents such as THF, dioxane or similar solvents at temperatures ranging from 0 °C to 25 °C for about 2 h to 16 h.

[0174] Mesylation of the compound of formula 1 can be carried out with various sulphonyl chlorides such as but not limited to mesyl chloride in presence of base such as but not limited to NEts or DIPEA to afford the compound of formula 82. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h. Compounds at every step may be purified by standard techniques such as column chromatography, crystallization, and reverse phase preparative HPLC or SFC.

[0175] Scheme -22 illustrates the synthesis of compound of formula 97. Compound of formula 93 can be synthesized by Buchwald coupling of compound of formula 40 and compound of formula 17 with suitable Pd catalysts such as but not limited to Pd2(dba)3 in presence of ligands such as but not limited to RuPhos or XantPhos and base such as but not limited CS2CO3 or K2CO3. Typically these reactions are carried out in ethereal solvents such as 1,4- dioxane, THF or similar solvents at temperatures ranging from 80 °C to 110 °C for about 8 h to 16 h.

[0176] Deprotection of compound of formula 93 with acids such as but not limited to HCl / dioxane or TFA affords the compound of formula 94. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0177] Reductive amination of compound of formula 94 can be done to give compound of formula 95 by reacting with aldehydes such as but not limited to aq. formaldehyde and reducing agents such as but not limited to NaBHsCN. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0178] Compound of formula 96 can be prepared by hydrogenation of compound of formula 95 with suitable Pd catalysts such as but not limited to Pd / C in solvents such as EtOAc, EtOH, MeOH or similar solvents at temperature around 25 °C for about 1 h to 3 h.

[0179] Amidation of the compound of formula 96 with various carboxylic acid of formula 14 such as but not limited to but-2-ynoic acid, propiolic acid, (E)-4-(dimethylamino)but-2-enoic acid, 2-fluoroacrylic acid using various coupling agents such as but not limited to HATU or EDC.HCl / HOBt in presence of base such as but not limited to NEts or DIPEA gives compound of formula 97. Typically these reactions are run in polar aprotic solvents such as DMF, DMAc or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0180] Alternatively, amidation of the compound of formula 96 can also be carried out with various acid chloride of formula 15 such as but not limited to chloroacetyl chloride, acryloyl chloride, propionyl chloride, vinylsulphonyl chloride in presence of base such as but not limited to NEts or DIPEA to afford compound of formula 97. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0181] Compounds at every step may be purified by standard techniques such as column chromatography, crystallization, and reverse phase preparative HPLC or SFC.

[0182] Scheme -23 illustrates the synthesis of compound of formula 102. The compound of formula 93 can be treated with brominating agents such as but not limited to NBS, dibromantin etc. to afford the compound of formula 98. Typically these reactions are carried out in halogenated solvents such as CCU, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 1 h to 4 h.

[0183] Compound of formula 99 can be synthesized by Suzuki coupling of compound of formula 98 and various cycloalkylboronic acid such as but not limited to cyclopropylboronic acid, cyclobutylboronic acid etc. with suitable Pd catalysts such as but not limited to PdChdppf.CHiCh in presence of base such as but not limited K3PO4.. Typically these reactions are carried out in ethereal solvents such as 1,4-dioxane, THF or similar solvents at temperatures ranging from 80 °C to 110 °C for about 8 h to 16 h.

[0184] Compound of formula 100 can be prepared by hydrogenation of compound of formula 99 with suitable Pd catalysts such as but not limited to Pd / C in solvents such as EtOAc, EtOH, MeOH or similar solvents at temperature around 25 °C for about 1 h to 3 h.

[0185] Amidation of the compound of formula 100 with various carboxylic acid of formula 14 such as but not limited to but-2-ynoic acid, propiolic acid, (E)-4-(dimethylamino)but-2-enoic acid, 2-fluoroacrylic acid using various coupling agents such as but not limited to HATU or EDC.HCl / HOBt in presence of base such as but not limited to NEts or DIPEA gives compound of formula 101. Typically these reactions are run in polar aprotic solvents such as DMF, DMAc or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0186] Alternatively, amidation of the compound of formula 100 can also be carried out with various acid chloride of formula 15 such as but not limited to chloroacetyl chloride, acryloyl chloride, propionyl chloride, vinylsulphonyl chloride in presence of base such as but not limited to NEts or DIPEA to afford compound of formula 101. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0187] Deprotection of compound of formula 101 with acids such as but not limited to HCl / dioxane or TFA affords the compound of formula 102. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0188] Compounds at every step may be purified by standard techniques such as column chromatography, crystallization, and reverse phase preparative HPLC or SFC.

[0189] Scheme -24 illustrates the synthesis of compound of formula 114. Mitsunobu reaction of compound 2 with compound of formula 103 using various azodicarxylate such as but not limited to DEAD or DIAD in presence of phosphine such as but not limited to PPI13 gives the compound of formula 104. Typically these reactions are run in ethereal solvents such as 1,4- dioxane, THF or similar solvents at temperatures ranging from 0 °C to 25 °C for about 3 h to 16 h. Deprotection of compound of formula 104 with acids such as but not limited to HCl / dioxane or TFA affords the compound of formula 105. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0190] Compound of formula 106 can be synthesized by protection of compound of formula 105 with suitable reagents such as but not limited to CbzCl in presence of base such as but not limited NaHCO, or K2CO3. Typically these reactions are carried out in ethereal solvents such as 1,4-dioxane, THF or similar solvents at temperatures ranging from 0 °C to 25 °C for about 8 h to 16 h.

[0191] The compound of formula 107 is formed upon treatment of compound of formula 106 with reagents such as but not limited to DCDMH in presence of acid such as but not limited to AcOH. Typically these reactions are done in solvents such as acetonitrile at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h. The compound of formula 107 when treated with compound of formula 6 in presence of base such as but not limited to NEts gives compound of formula 108. Typically these reactions are performed in solvents such as but not limited to CH2CI2 at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0192] The compound of formula 109 can be synthesized by protection of compound of formula 108 with reagents such as but not limited to SEM-C1 in presence of base such as but not limited to NEt3 or DIPEA. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCI3 or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0193] Compound of formula 110 can be synthesized by Buchwald coupling of compound of formula 109 and compound of formula 17 with suitable Pd catalysts such as but not limited to Pd2(dba)3 in presence of ligands such as but not limited to RuPhos or XantPhos and base such as but not limited CS2CO3 or K2CO3. Typically these reactions are carried out in ethereal solvents such as 1,4-dioxane, THF or similar solvents at temperatures ranging from 80 °C to 110 °C for about 8 h to 16 h.

[0194] Compound of formula 111 can be prepared by reduction of compound of formula 110 with suitable reducing agents such as but not limited to LiBPE in solvents such as EtOAc, EtOH, MeOH or similar solvents at temperature around 25 °C for about 1 h to 3 h. Compound of formula 112 can be prepared by hydrogenation of compound of formula 111 with suitable Pd catalysts such as but not limited to Pd / C in solvents such as EtOAc, EtOH, MeOH or similar solvents at temperature around 25 °C for about 1 h to 3 h.

[0195] Amidation of the compound of formula 112 with various carboxylic acid of formula 14 such as but not limited to but-2-ynoic acid, propiolic acid, (E)-4-(dimethylamino)but-2-enoic acid, 2-fluoroacrylic acid using various coupling agents such as but not limited to HATU, or EDC.HCl / HOBt in presence of base such as but not limited to NEts or DIPEA gives compound of formula 113. Typically these reactions are run in polar aprotic solvents such as DMF, DMAc or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0196] Alternatively, amidation of the compound of formula 112 can also be carried out with various acid chlorides of formula 15 such as but not limited to chloroacetyl chloride, acryloyl chloride, propionyl chloride, vinylsulphonyl chloride in presence of base such as but not limited to NEts or DIPEA to afford the compound of formula 113. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0197] Deprotection of compound of formula 113 with acids such as but not limited to HCl / dioxane or TFA affords the compound of formula 114. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0198] Compounds at every step may be purified by standard techniques such as column chromatography, crystallization, and reverse phase preparative HPLC or SFC.

[0199] Scheme -25 illustrates the synthesis of compound of formula 119. The compound of formula 115 can be synthesized by reacting compound of formula 111 with reagents such as but not limited to MsCl in presence of base such as but not limited to NEt3 or DIPEA. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0200] The compound of formula 116 can be synthesized by reacting compound of formula 115 with reagents such as but not limited to HNMe2. Typically these reactions are run in alcoholic solvents such as EtOH, or similar solvents at temperatures ranging from 50 °C to 80 °C for about 8 h to 16 h.

[0201] Compound of formula 117 can be prepared by hydrogenation of compound of formula 116 with suitable Pd catalysts such as but not limited to Pd / C in solvents such as EtOAc, EtOH, MeOH or similar solvents at temperature around 25 °C for about 1 h to 3 h.

[0202] Amidation of the compound of formula 117 with various carboxylic acid of formula 14 such as but not limited to but-2-ynoic acid, propiolic acid, (E)-4-(dimethylamino)but-2-enoic acid, 2-fluoroacrylic acid using various coupling agents such as but not limited to HATU, or EDC.HCl / HOBt in presence of base such as but not limited to NEts or DIPEA gives compound of formula 118. Typically these reactions are run in polar aprotic solvents such as DMF, DMAc or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0203] Alternatively, amidation of the compound of formula 117 can also be carried out with various acid chlorides of formula 15 such as but not limited to chloroacetyl chloride, acryloyl chloride, propionyl chloride, vinylsulphonyl chloride in presence of base such as but not limited to NEb, or DIPEA to afford the compound of formula 118. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0204] Deprotection of compound of formula 118 with acids such as but not limited to HCl / dioxane or TFA affords the compound of formula 119. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0205] Compounds at every step may be purified by standard techniques such as column chromatography, crystallization, and reverse phase preparative HPLC or SFC.

[0206] Scheme -26 illustrates the synthesis of compound of formula 123. Compound of formula 120 can be prepared by addition of Grignard reagent such as but not limited to MeMgBr. Typically these reactions are run in ethereal solvents such as Et2O, THF or similar solvents at temperatures ranging from 10 °C to 25 °C for about 1 h to 4 h. Compound of formula 121 can be prepared by hydrogenation of compound of formula 120 with suitable Pd catalysts such as but not limited to Pd / C in solvents such as EtOAc, EtOH, MeOH or similar solvents at temperature around 25 °C for about 1 h to 3 h.

[0207] Amidation of the compound of formula 121 with various carboxylic acid of formula 14 such as but not limited to but-2-ynoic acid, propiolic acid, (E)-4-(dimethylamino)but-2-enoic acid, 2-fluoroacrylic acid using various coupling agents such as but not limited to HATU, or EDC.HCl / HOBt in presence of base such as but not limited to NEts or DIPEA gives compound of formula 122. Typically these reactions are run in polar aprotic solvents such as DMF, DMAc or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0208] Alternatively, amidation of the compound of formula 121 can also be carried out with various acid chlorides of formula 15 such as but not limited to chloroacetyl chloride, acryloyl chloride, propionyl chloride, vinylsulphonyl chloride in presence of base such as but not limited to NEb, or DIPEA to afford the compound of formula 122. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0209] Deprotection of compound of formula 122 with acids such as but not limited to HCl / dioxane or TFA affords the compound of formula 123. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0210] Compounds at every step may be purified by standard techniques such as column chromatography, crystallization, and reverse phase preparative HPLC or SFC.

[0211] Scheme -27 illustrates the synthesis of compound of formula 124. Fluorination of compound of formula 122 with fluorinating agents such as but not limited to DAST affords the compound of formula 124. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0212] Deprotection of compound of formula 124 with acids such as but not limited to HCl / dioxane or TFA affords the compound of formula 125. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0213] Compounds at every step may be purified by standard techniques such as column chromatography, crystallization, and reverse phase preparative HPLC or SFC.

[0214] Scheme -28 illustrates the synthesis of compound of formula 129. Dehydration of compound of formula 120 with reagents such as but not limited to SOCI2 in presence of organic bases such as but not limited pyridine affords the compound of formula 126. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 8h. to 16 h.

[0215]

[0216] Compound of formula 127 can be prepared by hydrogenation of compound of formula 126 with suitable Pd catalysts such as but not limited to Pd / C in solvents such as EtOAc, EtOH, MeOH or similar solvents at temperature around 25 °C for about 1 h to 3 h. Amidation of the compound of formula 127 with various carboxylic acid of formula 14 such as but not limited to but-2-ynoic acid, propiolic acid, (E)-4-(dimethylamino)but-2-enoic acid, 2-fluoroacrylic acid using various coupling agents such as but not limited to HATU, or EDC.HCl / HOBt in presence of base such as but not limited to NEt3 or DIPEA gives compound of formula 128. Typically these reactions are run in polar aprotic solvents such as DMF, DMAc or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0217] Alternatively, amidation of the compound of formula 127 can also be carried out with various acid chlorides of formula 15 such as but not limited to chloroacetyl chloride, acryloyl chloride, propionyl chloride, vinylsulphonyl chloride in presence of base such as but not limited to NEts or DIPEA to afford the compound of formula 128. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0218] Deprotection of compound of formula 128 with acids such as but not limited to HCl / dioxane or TFA affords the compound of formula 129. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0219] Compounds at every step may be purified by standard techniques such as column chromatography, crystallization, and reverse phase preparative HPLC or SFC. Scheme -29 illustrates the synthesis of compound of formula 132. Compound of formula 130 can be prepared by hydrogenation of compound of formula 110 with suitable Pd catalysts such as but not limited to Pd / C in solvents such as EtOAc, EtOH, MeOH or similar solvents at temperature around 25 °C for about 1 h to 3 h.

[0220] Amidation of the compound of formula 130 with various carboxylic acid of formula 14 such as but not limited to but-2-ynoic acid, propiolic acid, (E)-4-(dimethylamino)but-2-enoic acid, 2-fluoroacrylic acid using various coupling agents such as but not limited to HATU, or EDC.HCl / HOBt in presence of base such as but not limited to NEt3 or DIPEA gives compound of formula 131. Typically these reactions are run in polar aprotic solvents such as DMF, DMAc or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0221] Alternatively, amidation of the compound of formula 130 can also be carried out with various acid chlorides of formula 15 such as but not limited to chloroacetyl chloride, acryloyl chloride, propionyl chloride, vinylsulphonyl chloride in presence of base such as but not limited to NEts or DIPEA to afford the compound of formula 131. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0222] Deprotection of compound of formula 131 with acids such as but not limited to HCl / dioxane or TFA affords the compound of formula 132. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h. Compounds at every step may be purified by standard techniques such as column chromatography, crystallization, and reverse phase preparative HPLC or SFC.

[0223] Scheme -30 illustrates the synthesis of compound of formula 136. The compound of formula 133 can be synthesized by reacting compound of formula 115 with reagents such as but not limited to TBAC1. Typically these reactions are run in solvents such as DMF, or similar solvents at temperatures ranging from 50 °C to 90 °C for about 8 h to 16 h.

[0224] Compound of formula 134 can be prepared by hydrogenation of compound of formula 133 with suitable Pd catalysts such as but not limited to Pd / C in solvents such as EtOAc, EtOH, MeOH or similar solvents at temperature around 25 °C for about 1 h to 3 h.

[0225] Amidation of the compound of formula 134 with various carboxylic acid of formula 14 such as but not limited to but-2-ynoic acid, propiolic acid, (E)-4-(dimethylamino)but-2-enoic acid, 2-fluoroacrylic acid using various coupling agents such as but not limited to HATU, or EDC.HCl / HOBt in presence of base such as but not limited to NEb, or DIPEA gives compound of formula 135. Typically these reactions are run in polar aprotic solvents such as DMF, DMAc or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0226] Alternatively, amidation of the compound of formula 134 can also be carried out with various acid chlorides of formula 15 such as but not limited to chloroacetyl chloride, acryloyl chloride, propionyl chloride, vinylsulphonyl chloride in presence of base such as but not limited to NEb, or DIPEA to afford the compound of formula 135. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0227] Deprotection of compound of formula 135 with acids such as but not limited to HCl / dioxane or TFA affords the compound of formula 136. Typically these reactions are run in halogenated solvents such as CH2CI2, CHCh or similar solvents at temperatures ranging from 0 °C to 25 °C for about 30 min. to 2 h.

[0228] Compounds at every step may be purified by standard techniques such as column chromatography, crystallization, and reverse phase preparative HPLC or SFC.

[0229] Intermediates: tert-Butyl 3-(piperazine-l-carbonyl)azetidine-l-carboxylate

[0230] To a stirred solution of 1 -(tert-butoxycarbonyl) azetidine-3 -carboxylic acid (5.0g, 0.024 mol.) in DMF (10ml) was added HATU (17.26g, 0.045mol.) and DIPEA (7.33g, 0.056mol.) at room temperature. After 30 min was added benzyl piperazine- 1 -carboxylate (5.0g, 0.22mol.) and stirred for 16 h. at room temperature. The reaction mass was quenched with water (50ml) and extracted with ethyl acetate (2 X 50 mL). Organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give crude compound (10g). Crude compound dissolved in methanol (150ml) and added 10 % Pd / C (4g) and hydrogenated for 12 hrs. Filtered the reaction mass thorough celite bed and washed with methanol (20ml). Filtrate concentrated to afford the title compound (4.5 g).LCMS m / z = 292.10 (M+ Na, 20%).

[0231] Oxetan-3-yl (piperazin-l-yl) methanone To a stirred solution of oxetane-3 -carboxylic acid (0.783g, 7.68mmol) in dichloromethane (10ml) was added triethylamine (3.1ml 22.73mmol), HATU (2.91g, 7.68mmol) and tert -butyl piperazine- 1 -carboxylate (1.3g, 6.98mmol) at room temperature and stirred for 16hrs. The reaction mass was quenched with water (25 ml) and separated the layers, aqueous layer extracted with dichloromethane (25ml). Combined organic layer was dried over anhydrous NaiSCU, filtered, and concentrated in vacuo to give crude compound. Crude compound dissolved in dichloromethane (10ml) and added TFA (1.5ml) and stirred at room temperature for 2 hrs. Concentrated the reaction mass in vacuo and purified by column chromatography eluting with 0-10% methanol in dichloromethane to afford the title compound (500mg).

[0232] LCMS m / z =171.10 (M+ H, 50%).

[0233] 6-(Benzylthio)-4-chloro-lH-indazole

[0234] BnS^^^N

[0235] Cl (18)

[0236] The compound (18) was prepared as per procedure reported in WO2021055744 A.

[0237] 6-(Benzylthio)-4-chloro-3-iodo-lH-indazole XX Cl(19)1

[0238] To a stirred solution of 6-(benzylthio)-4-chloro-lH-indazole (200mg, 0.72mmol) in DMF (3ml) was added potassium hydroxide (151mg, 2.70mmol) and cooled to 0-5°C. Added iodine portion wise at 0-5°C, allowed the reaction mass temperature to room temperature and stirred for 1 hr. The reaction mass was quenched with water (200ml) and extracted with ethyl acetate (2X20ml). Organic layer was washed with brine solution and dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give crude compound which was purified by column chromatography eluting with 0-30% ethyl acetate in hexane to afford the title compound (250 mg). LCMS m / z =400.90 (M+ H, 100%).

[0239] 6-(Benzylthio)-4-chloro-3-iodo-l-trityl-lH-indazole

[0240] To a stirred solution of 6-(benzylthio)-4-chloro-3-iodo-lH-indazole (300mg, 0.75mmol) in THF (5ml) was added 60 % sodium hydride (39mg, 0.97mmol) at 0-5°C. After stirring for lOmin at 0-5°C was added trityl chloride and stirred at RT for 16 hrs. The reaction mass was quenched with water (200ml) and extracted with ethyl acetate (2 X 20ml). Organic layer was washed with brine solution and dried over anhydrous NaiSO^ filtered, and concentrated in vacuo to give crude compound which was purified by column chromatography eluting with 0-30% ethyl acetate in hexane to afford the title compound (250 mg). LCMS m / z =400.90 (M+ H, 100%).

[0241] 6-(Benzylthio)-4-chloro-3-cyclopropyl-l-trityl-lH-indazole

[0242] To a mixture of 6-(benzylthio)-4-chloro-3-iodo-l-trityl-lH-indazole (5 g, 0.008 mmol) and cyclopropyl boronic acid (1.7 g, 0.0194 mmol) was added 1,4-dioxan (50 mL) followed by addition of K2CO3 (3..3 g, 0.0233 mmol) was completed at rt, then the solution was degassed under Ar / N atmosphere for 20 min, then PdCh(dppf).DCM complex (1.2 g, 0.0016 mmol) was added into the reaction mass, then the reaction mass was degassed for additional 10 minutes under Ar / N atmosphere. After that the reaction mass was stirred at 90 °C for 18 hr. The progress of the reaction was monitored by TLC as well as LCMS of the crude reaction mixture. After completion of reaction, the reaction mass was filtered through celite bed and the residue was washed with EtOAc. The solvents were removed under reduced pressure and the crude residue was dissolved in EtOAc and extracted with water followed by washing with saturated solution of brine was completed. The organic solvent was collected, dried over anhydrous NaiSO^ filtered and concentrated to get gummy crude material which was then purified over silica-gel column chromatography using 10% EtOAc / Hexane as eluent to get the pure tile compound (6 g). The title compound was used as-is for the next step as there was no ionization in LCMS.

[0243] 6-(Benzylthio)-4-chloro-3-cyclopropyl-lH-indazole

[0244] To a well stirred solution of 6-(benzylthio)-4-chloro-3-iodo-l -trityl- IH-indazole (6 g, 0.0107 mmol) in 60 ml anhydrous DCM was added 10 mL TFA under cooling condition (0 °C) and the reaction mass was allowed to warm slowly at rt, the reaction was stirred at rt until there is no starting material (reaction progress monitored by TLC). After completion of the reaction, the solvent and TFA was removed under reduced pressure, then the crude gummy residue was dissolved in EtOAc and quenched with saturated NaHCOs solution, the organic solvent was dried over anhydrous NaiSCU, filtered and concentrated under reduced pressure to get the tile compound (1.5 g). LCMS m / z =337.00 (M+ Na)

[0245] 2-(6-(Benzylthio)-4-chloro-3-cyclopropyl-lH-indazol-l-yl)-5-(difluoromethyl)-l,3,4- thiadiazole

[0246] To a well stirred solution of 6-(benzylthio)-4-chloro-3-cyclopropyl-lH-indazole (1.4 g, 0.0044 mmol) in anhydrous DMF (20 mL) was added CS2CO3 (1.45 g, 0.0044 mmol) at rt and the suspension was stirred at rt for 20 minutes, then 2-bromo-5-(difluoromethyl)-l,3,4- thiadiazole (1.45 g, 0.0066 mmol) was added into it and the reaction mass was stirred at 60 °C, the reaction progress was monitored by TLC. After completion of reaction, the reaction mass was cooled to rt and then poured into water and extracted with EtOAc, the organic solvents were washed with brine solution, then the organic solvent was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure and the crude material was purified over silica gel column chromatography to get the pure title compound (1.3 g). The title compound was used as-is for the next step as there was no ionization in LCMS.

[0247] 4-Chloro-3-cyclopropyl-l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-lH-indazole-6- sulfonyl chloride

[0248] To a well stirred solution of 2-(6-(benzylthio)-4-chloro-3-cyclopropyl-lH-indazol-l-yl)-5- (difluoromethyl)-l,3,4-thiadiazole (1.3 g, 0.0029 mmol) in ACN (15 mL) and water (0.4 mL) and AcOH (0.2 mL) was added into it under cooling condition (0 °C). After that dichloro dimethyl hydantoin (DCDMH) (0.9 g) was added into the reaction mass under cooling condition, then the reaction mass was stirred at rt until there is no starting material, the progress of the reaction was monitored by TLC. After completion of reaction the solvents were removed under reduced pressure to get the title compound in solid form. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0249] 4-Chloro-3-cyclopropyl-l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide

[0250] To a well stirred solution of 1-methylcyclopropan-l -amine hydrochloride (300 mg, 3.76 mmol) in anhydrous DCM (10 mL) was added Et3N (0.8 mL, 5.643 mmol) at -10 °C, after stirring for 10 minutes at the same temperature, 4-chloro-3-cyclopropyl-l-(5- (difluoromethyl)-l,3,4-thiadiazol-2-yl)-lH-indazole-6-sulfonyl chloride (800 mg, 1.881 mmol) was added into the reaction mass and then the reaction mass was allowed to warm up to rt slowly and the progress of the reaction was monitored by TLC. After completion of reaction, the reaction mass was poured into water and extracted with DCM. The organic solvent was dried over anhydrous NaiSC , filtered and concentrated under reduced pressure to get crude residue which was purified over silica-gel column chromatography to get the tile compound (200 mg). LCMS m / z =474.80 (M+ H)

[0251] 4-Chloro-3-cyclopropyl-l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-methyl cyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole-6-sulfonamide

[0252] To a well stirred solution of 4-chloro-3-cyclopropyl-l-(5-(difluoromethyl)-l,3,4-thiadiazol-2- yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide (150 mg, 0.318 mmol) in a mixture of THF and DMF (2 mL, 1: 1), was added NaH (80 mg, 1.272 mmol) (60% oil dispersion) under cooling condition, after stirring the reaction mass for 10 minutes at the same temperature, SEM-C1 (0.2 mL, 0.637 mmol) was added under cooling condition, the progress of the reaction was monitored by TLC. After completion of reaction, the reaction mass was acidified and then extracted with EtOAc, the organic solvent was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to get a crude residue, which was purified over silica-gel column chromatography to get the pure title compound (200 mg). The title compound was used as-is for the next step as there was no ionization in LCMS.

[0253] 1-Benzyl 2-methyl (2S,4S)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidine-l,2- dicarboxylate

[0254] To a stirred solution of 1-benzyl 2-methyl (2S,4S)-4-hydroxypyrrolidine-l,2-dicarboxylate (17g, 60.93 mmol) in CH2CI2 (200 mL) was added pTSA (0.35g, 1.83 mmol) and stirred for 10 mins. 3,4-Dihydro-2H-pyran (16.7 mL, 182.79 mmol) at 25 °C under N2 atmosphere. Stirred the reaction mixture at 25 °C for 2 h. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (100 mL x 2). Layers were separated and the organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous NaiSCL. filtered, and concentrated in vacuo to give 21 g of a crude compound. This crude residue was purified by combiflash instrument onto a redisep® column with a gradient elution of 0 to 100% of EtOAc in hexane to afford the title compound (17 g) as a yellow solid. LCMS m / z = 364.

[0255] 1-Benzyl 2-methyl (2R,4R)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidine-l,2- dicarboxylate

[0256] The title compound was prepared by following the same reaction protocol as described in the synthesis 1 -benzyl 2-methyl (2S,4S)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidine-l,2- dicarboxylate using appropriate starting materials. LCMS m / z = 364.

[0257] 1-Benzyl 2-methyl (2S,4R)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidine-l,2- dicarboxylate

[0258] The title compound was prepared by following the same reaction protocol as described in the synthesis 1 -benzyl 2-methyl (2S,4S)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidine-l,2- dicarboxylate using appropriate starting materials. LCMS m / z = 364.

[0259] 1-Benzyl 2-methyl (2R,4S)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidine-l,2- dicarboxylate The title compound was prepared by following the same reaction protocol as described in the synthesis 1 -benzyl 2-methyl (2S,4S)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidine-l,2- dicarboxylate using appropriate starting materials. LCMS m / z = 364.

[0260] Benzyl (2S,4S)-2-(hydroxymethyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidine-l- carboxylate

[0261] To a stirred mixture of 1 -benzyl 2-methyl (2S,4S)-4-((tetrahydro-2H-pyran-2- yl)oxy)pyrrolidine-l,2-dicarboxylate (5g, 14.92 mmol in THF (50 mL) was added IM LiBH4 in THF (67 ml, 67 mmol) at 0 °C under N2 atmosphere. Stirred the reaction mixture at 25 °C for 16 h. The reaction mixture was diluted with water (20 mL) and quenched with sat.aq.NH4C! (50 mL). The aqueous layer was extracted with EtOAc (50 mL x 2). Layers were separated and the organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous NaiSCL, filtered, and concentrated in vacuo to give 4.5 g of a crude compound. This crude residue was purified by combiflash instrument onto a redisep® column with a gradient elution of 0 to 100% of EtOAc in hexane to afford the title compound (2.5 g) as a yellow solid LCMS m / z = 336.

[0262] Benzyl (2R,4R)-2-(hydroxymethyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidine-l- carboxylate

[0263] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl (2S,4S)-2-(hydroxymethyl)-4-((tetrahydro-2H-pyran-2- yl)oxy)pyrrolidine-l-carboxylate_using appropriate starting materials. LCMS m / z = 336.

[0264] Benzyl (2S,4R)-2-(hydroxymethyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidine-l- carboxylate

[0265] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl (2S, 4S)-2-(hydroxymethyl)-4-((tetrahydro-2H-pyran-2- yl)oxy)pyrrolidine-l-carboxylate_using appropriate starting materials. LCMS m / z = 336.

[0266] Benzyl (2R,4S)-2-(hydroxymethyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidine-l- carboxylate

[0267] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl (2S,4S)-2-(hydroxymethyl)-4-((tetrahydro-2H-pyran-2- yl)oxy)pyrrolidine-l-carboxylate_using appropriate starting materials. LCMS m / z = 336.

[0268] Benzyl (2S,4S)-2-(((methylsulfonyl)oxy)methyl)-4-((tetrahydro-2H-pyran-2- yl)oxy)pyrrolidine-l-carboxylate

[0269] To a stirred mixture of benzyl (2S,4S)-2-(hydroxymethyl)-4-((tetrahydro-2H-pyran-2- yl)oxy)pyrrolidine-l -carboxylate (5g, 14.92 mmol in CH2CI2 (50 mL) was added NEts (7.3 ml, 52.23 mmol) at 0 °C under N2 atmosphere. Mesyl chloride (2.5 mL, 29.85 mmol) was added and stirred the reaction mixture at 25 °C for 3 h. The reaction mixture was diluted with CH2CI2 (50 mL) and washed with water (50 mL). Layers were separated and the organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous Na2SC>4, filtered, and concentrated in vacuo to give 6.5 g of a crude compound. LCMS m / z = 414.

[0270] Benzyl (2R,4R)-2-(((methylsulfonyl)oxy)methyl)-4-((tetrahydro-2H-pyran-2- yl)oxy)pyrrolidine-l-carboxylate

[0271] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl (2S,4S)-2-(((methylsulfonyl)oxy)methyl)-4-((tetrahydro-2H-pyran-2- yl)oxy)pyrrolidine-l-carboxylate_using appropriate starting materials. LCMS m / z = 414.

[0272] Benzyl (2S,4R)-2-(((methylsulfonyl)oxy)methyl)-4-((tetrahydro-2H-pyran-2- yl)oxy)pyrrolidine-l-carboxylate

[0273] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl (2S,4S)-2-(((methylsulfonyl)oxy)methyl)-4-((tetrahydro-2H-pyran-2- yl)oxy)pyrrolidine-l-carboxylate_using appropriate starting materials. LCMS m / z = 414.

[0274] Benzyl (2R,4S)-2-(((methylsulfonyl)oxy)methyl)-4-((tetrahydro-2H-pyran-2- yl)oxy)pyrrolidine-l-carboxylate

[0275] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl (2S,4S)-2-(((methylsulfonyl)oxy)methyl)-4-((tetrahydro-2H-pyran-2- yl)oxy)pyrrolidine-l-carboxylate_using appropriate starting materials. LCMS m / z = 414.

[0276] Benzyl (2S,4S)-2-(fluoromethyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidine-l- carboxylate

[0277] The mixture of benzyl (2S,4S)-2-(((methylsulfonyl)oxy)methyl)-4-((tetrahydro-2H-pyran-2- yl)oxy)pyrrolidine-l -carboxylate (6.5g, 15.73 mmol) in THF (50 mL) was added IM TBAF in THF (61 mL) and heated to reflux for 6 h. The reaction mixture was concentrated in vacuo, diluted with water (100 mL) and extracted with EtOAc (50 mL x 2). The organic layer was washed with 5% aq.citric acid followed by aq.sat.NaHCOs solution. Layers were separated and the organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous NaiSCL. filtered, and concentrated in vacuo to give 2.8 g of a crude compound. This crude residue was purified by combiflash instrument onto a redisep® column with a gradient elution of 0 to 30%) of EtOAc in hexane to afford the title compound (2.3 g) as a yellow solid. LCMS m / z = 338.

[0278] Benzyl (2R,4R)-2-(fluoromethyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidine-l- carboxylate

[0279] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl (2S,4S)-2-(fluoromethyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidine- l-carboxylate_using appropriate starting materials. LCMS m / z = 338.

[0280] Benzyl (2S,4R)-2-(fluoromethyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidine-l- carboxylate

[0281] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl (2S,4S)-2-(fluoromethyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidine- l-carboxylate_using appropriate starting materials. LCMS m / z = 338.

[0282] Benzyl (2R,4S)-2-(fluoromethyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidine-l- carboxylate The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl (2S,4S)-2-(fluoromethyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidine- l-carboxylate_using appropriate starting materials. LCMS m / z = 338.

[0283] Benzyl (2S,4S)-2-(methoxymethyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidine-l- carboxylate

[0284] To a stirred solution of benzyl (2S,4S)-2-(hydroxymethyl)-4-((tetrahydro-2H-pyran-2- yl)oxy)pyrrolidine-l -carboxylate (5 g, 14.98 mmol) in THF (10 mL) was added NaH (1.5g, 31.46 mmol) at 0 °C and stirred for 15 mins. Methyl iodide (5.5g, 89.55 mmol) was added at 0 °C and stirred for 2 h. The reaction mixture was quenched with aq.sat.NH4C! (50 mL) and extracted with EtOAc (50 mL). Layers were separated and the organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 3.5 g of a crude compound. This crude residue was purified by combiflash instrument onto a redisep® column with a gradient elution of 0 to 30% of EtOAc in hexane to afford the title compound (2 g) as a yellow solid. LCMS m / z = 350.20.

[0285] Benzyl (2S,4S)-2-(fluoromethyl)-4-hydroxypyrrolidine-l-carboxylate

[0286] The mixture of benzyl (2S,4S)-2-(fluoromethyl)-4-((tetrahydro-2H-pyran-2- yl)oxy)pyrrolidine-l -carboxylate (2.3g, 6.81 mmol in AcOH (14 mL) and water (14 mL) was stirred at 40 °C for 2 h. The reaction mixture was basified with aq.sat.NaHCOs and extracted with EtOAc (50 mL). Layers were separated and the organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous NaiSCL, filtered, and concentrated in vacuo to give 1.5 g of a crude compound. This crude residue was purified by combiflash instrument onto a redisep® column with a gradient elution of 0 to 30% of EtOAc in hexane to afford the title compound (1.2 g) as a yellow solid. LCMS m / z = 254.

[0287] Benzyl (2R,4R)-2-(fluoromethyl)-4-hydroxypyrrolidine-l-carboxylate

[0288] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl (2S,4S)-2-(fluoromethyl)-4-hydroxypyrrolidine-l-carboxylate using appropriate starting materials. LCMS m / z = 254.

[0289] Benzyl (2S,4R)-2-(fluoromethyl)-4-hydroxypyrrolidine-l-carboxylate

[0290] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl (2S,4S)-2-(fluoromethyl)-4-hydroxypyrrolidine-l-carboxylate using appropriate starting materials. LCMS m / z = 254.

[0291] Benzyl (2R,4S)-2-(fluoromethyl)-4-hydroxypyrrolidine-l-carboxylate

[0292] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl (2S,4S)-2-(fluoromethyl)-4-hydroxypyrrolidine-l-carboxylate using appropriate starting materials. LCMS m / z = 254.

[0293] Benzyl (2S,4S)-4-hydroxy-2-(methoxymethyl)pyrrolidine-l-carboxylate

[0294] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl (2S,4S)-2-(fluoromethyl)-4-hydroxypyrrolidine-l-carboxylate using appropriate starting materials. LCMS m / z = 266.

[0295] Benzyl (2S,4S)-2-(fluoromethyl)-4-((methylsulfonyl)oxy)pyrrolidine-l-carboxylate

[0296] To a stirred mixture of benzyl (2S,4S)-2-(fluoromethyl)-4-hydroxypyrrolidine-l-carboxylate (1.1g, 4.35 mmol in CH2CI2 (10 mL) was added NEts (0.9 ml, 6.52 mmol) at 0 °C under N2 atmosphere. Mesyl chloride (0.49 mL, 4.78 mmol) was added and stirred the reaction mixture at 25 °C for 2 h. The reaction mixture was diluted with CH2CI2 (50 mL) and washed with water (50 mL). Layers were separated and the organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous Na2SC>4, filtered, and concentrated in vacuo to give 1.5 g of a crude compound. LCMS m / z = 332.

[0297] Benzyl (2R,4R)-2-(fluoromethyl)-4-((methylsulfonyl)oxy)pyrrolidine-l-carboxylate

[0298] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl (2S,4S)-2-(fluoromethyl)-4-((methylsulfonyl)oxy)pyrrolidine-l- carboxylate_ using appropriate starting materials. LCMS m / z = 332.

[0299] Benzyl (2S,4R)-2-(fluoromethyl)-4-((methylsulfonyl)oxy)pyrrolidine-l-carboxylate

[0300] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl (2S,4S)-2-(fluoromethyl)-4-((methylsulfonyl)oxy)pyrrolidine-l- carboxylate_ using appropriate starting materials. LCMS m / z = 332.

[0301] Benzyl (2R,4S)-2-(fluoromethyl)-4-((methylsulfonyl)oxy)pyrrolidine-l-carboxylate cbz The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl (2S,4S)-2-(fluoromethyl)-4-((methylsulfonyl)oxy)pyrrohdine-l- carboxylate_ using appropriate starting materials. LCMS m / z = 332.

[0302] Benzyl (2S,4S)-2-(methoxymethyl)-4-((methylsulfonyl)oxy)pyrrolidine-l-carboxylate

[0303] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl (2S,4S)-2-(fluoromethyl)-4-((methylsulfonyl)oxy)pyrrolidine-l- carboxylate_using appropriate starting materials. LCMS m / z = 344. tert-Butyl (2S,4S)-2-(difluoromethyl)-4-((methylsulfonyl)oxy)pyrrolidine-l-carboxylate

[0304] The title compound was prepared by following the same reaction protocol as described in W02010016005 Al.

[0305] 6-(Benzylthio)-4-chloro-lH-indazole

[0306] To a stirred mixture of 6-bromo-4-chloro-lH-indazole (5g, 21.60mmol) and phenylmethanethiol (7.6 mL, 64.80 mmol) in 1, 4-dioxane (75 mL) was added DIPEA (11.14 ml, 64.80 mmol) at 25 °C in a sealed tube. The reaction mixture was degassed by purging nitrogen gas for 30 min. XantPhos (2.5 g, 4.32 mmol) and Pdi(dba)3 (1.97 g, 2.16 mmol) were added in portions. The reaction mixture was again degassed by purging nitrogen gas for 30 min. The resulting mixture was stirred for additional 16 h at 100 °C. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (100 mL). Layers were separated and the organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous NaiSCU, filtered, and concentrated in vacuo to give 7.2 g of a crude compound. This crude residue was purified by combiflash instrument onto a redisep® column with a gradient elution of 0 to 20% of EtOAc in hexane to afford the title compound (5.23 g) as a yellow solid. LCMS m / z = 275, 277

[0307] Benzyl 3-(6-(benzylthio)-4-chloro-lH-indazol-l-yl)pyrrolidine-l-carboxylate

[0308] To a stirred mixture of 6-(benzylthio)-4-chloro-lH-indazole (2.1 g, 7.643 mmol) and benzyl- 3 -hydroxypyrrolidine- 1 -carboxylate (4.05 g, 18.30 mmol) in THF (20 mL) was added TPP (4.81 g, 18.30 mmol) and 40% DIAD in toluene (9.85 mL, 18.30 mmol) at 0 °C under N2 atmosphere. The resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (50 mL). Layers were separated and the organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 2.7 g of a crude compound. This crude residue was purified by combiflash instrument onto a redisep® column with a gradient elution of 0 to 20% of EtOAc in hexane to afford the title compound (2.5 g) as a yellow liquid.JH NMR (400 MHz, DMSO-ifc) 3 8.09 (s, 1H), 7.72 (d, J = 6.4 Hz, 1H), 7.45-7.25 (m, 11H), 5.55-5.45 (m, 1H), 5.11 (d, J = 4 Hz, 1H), 5.09 (s, 1H), 4.39 (d, J = 3.2 Hz, 2H), 3.90-3.80 (m, 1H), 3.70-3.60 (m, 2H), 3.60-3.50 (m, 1H), 2.45-2.25 (m, 2H).

[0309] Benzyl 4-(6-(benzylthio)-4-chloro-lH-indazol-l-yl)piperidine-l-carboxylate Cbz

[0310] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(6-(benzylthio)-4-chloro-lH-indazol-l-yl)pyrrolidine-l-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0311] Benzyl 3-(6-(benzylthio)-4-chloro-lH-indazol-l-yl)piperidine-l-carboxylate

[0312] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(6-(benzylthio)-4-chloro-lH-indazol-l-yl)pyrrolidine-l-carboxylate using appropriate starting materials.JH NMR (400 MHz, DMSO-de) 3 8.08 (s, 1H), 7.73 (s, 1H), 7.46-7.18 (m, 11H), 5.20-5.50 (m, 2H), 4.85-4.75 (m, 1H), 4.45-4.35 (m, 2H), 4.40-4.00 (m, 2H), 3.30-3.20 (m, 1H), 3.05-2.95 (m, 1H), 2.10-2.00 (m, 2H), 1.95-1.60 (m, 2H).

[0313] Benzyl 3-((6-(benzylthio)-4-chloro-lH-indazol-l-yl)methyl)pyrrolidine-l-carboxylate

[0314] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(6-(benzylthio)-4-chloro-lH-indazol-l-yl)pyrrolidine-l-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2R,4R)-4-(6-(benzylthio)-4-chloro-lH-indazol-l-yl)-2-methylpyrrolidine-l- carboxylate

[0315] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(6-(benzylthio)-4-chloro-lH-indazol-l-yl)pyrrolidine-l-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,4R)-4-(6-(benzylthio)-4-chloro-lH-indazol-l-yl)-2-methylpyrrolidine-l- carboxylate

[0316] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(6-(benzylthio)-4-chloro-lH-indazol-l-yl)pyrrolidine-l-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. l-(tert-Butyl) 2-methyl (2S,4R)-4-(6-(benzylthio)-4-chloro-lH-indazol-l-yl)pyrrolidine- 1,2-dicarboxylate

[0317] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(6-(benzylthio)-4-chloro-lH-indazol-l-yl)pyrrolidine-l-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0318] 6-(Benzylthio)-4-chloro-l-((3R,5R)-5-methylpyrrolidin-3-yl)-lH-indazole

[0319] To a stirred solution of tert-butyl (2R,4R)-4-(6-(benzylthio)-4-chloro-lH-indazol-l-yl)-2- methylpyrrolidine-1 -carboxylate (700 mg) in CH2CI2 (10 mL) was added trifluoroacetic acid (5.8 mL) at 0 °C and stirred at 25 °C for 30 mins. The reaction mixture was concentrated in vacuo at 35 °C and diluted the residue with CH2CI2 (50 mL). The organic layer was washed with sat.aq.NaHCOs (50 mL). Layers were separated and the organic layer was washed with water (25 ml x 2) and finally with brine (50 mL). The organic layer was dried over anhydrous Na2SC>4, filtered, and concentrated in vacuo to give 800 mg of a title compound, which was used as-is for the next step as there was no ionization in LCMS. 6-(Benzylthio)-4-chloro-l-((3R,5S)-5-methylpyrrolidin-3-yl)-lH-indazole

[0320] The title compound was prepared by following the same reaction protocol as described in the synthesis of 6-(benzylthio)-4-chloro-l-((3R,5R)-5-methylpyrrolidin-3-yl)-lH-indazole using appropriate starting materials. The title compound was used as-isfor the next step as there was no ionization in LCMS.

[0321] Methyl (2S,4R)-4-(6-(benzylthio)-4-chloro-lH-indazol-l-yl)pyrrolidine-2-carboxylate

[0322] The title compound was prepared by following the same reaction protocol as described in the synthesis of 6-(benzylthio)-4-chloro-l-((3R,5R)-5-methylpyrrolidin-3-yl)-lH-indazole using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0323] Benzyl (2R,4R)-4-(6-(benzylthio)-4-chloro-lH-indazol-l-yl)-2-methylpyrrolidine-l- carboxylate

[0324] 6-(Benzylthio)-4-chloro-l-((3R,5R)-5-methylpyrrolidin-3-yl)-lH-indazole (1.5 g, 3.30 mmol) was dissolved in a mixture of aq.sat.NaHCCL (0.7g, 25 ml) and dioxane (25 ml) and cooled to 0 °C. Benzyl chloroformate in toluene (50%, 1.15 ml) was added slowly at 0 °C under N2 atmosphere. The resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was acidified slowly with 3N HC1 and extracted with EtOAc (50 mL). Layers were separated and the organic layer was washed with water (25 ml x 2) and finally with brine (50 mL). The organic layer was dried over anhydrous NaiSCL, filtered, and concentrated in vacuo to give 1.8 g of a crude compound. This crude residue was purified by combiflash instrument onto a redisep® column with a gradient elution of 0 to 30% of EtOAc in hexane to afford the title compound (1.4 g) as a yellow oil, which was used as-is for the next step as there was no ionization in LCMS.

[0325] Benzyl (2S,4R)-4-(6-(benzylthio)-4-chloro-lH-indazol-l-yl)-2-methylpyrrolidine-l- carboxylate

[0326] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl (2R,4R)-4-(6-(benzylthio)-4-chloro-lH-indazol-l-yl)-2- methylpyrrolidine-1 -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0327] 1-Benzyl 2-methyl (2S,4R)-4-(6-(benzylthio)-4-chloro-lH-indazol-l-yl)pyrrolidine-l,2- dicarboxylate

[0328] To a stirred solution of methyl (2S,4R)-4-(6-(benzylthio)-4-chloro-lH-indazol-l- yl)pyrrolidine-2-carboxylate (3.2 g, 8.73 mmol) in CH2CI2 (35 mL) was added NEts (2.43 mL, 17.45 mmol) and cooled the reaction mixture to 0 °C. Cbz-Cl (4.42 mL, 13.09 mmol) was added and stirred at 25°C for 16 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (50 mL). Layers were separated and the organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 3.8 g of a crude compound. This crude residue was purified by combiflash instrument onto a redisep® column with a gradient elution of 0 to 15% of EtOAc in hexane to afford the title compound (3.5 g) as a light reddish liquid. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0329] Benzyl (2S,4R)-4-(6-(benzylthio)-4-chloro-lH-indazol-l-yl)-2-(fluoromethyl)pyrrolidine- 1-carboxylate

[0330] To a stirred mixture of 6-(benzylthio)-4-chloro-lH-indazole (1.5 g, 4.54 mmol) in DMF (10 mL) was added cesium carbonate (2.22 g, 6.81 mmol) and stirred at 25°C for 10 mins. Benzyl (2S,4S)-2-(fluoromethyl)-4-((methylsulfonyl)oxy)pyrrolidine-l-carboxylate (996 mg, 3.63 mmol) was dissolved in DMF (5 mL) and added to above reaction mixture. The resulting mixture was stirred at 80 °C for 16 h under N2 atmosphere. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (50 mL). Layers were separated and the organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous NaiSCL, filtered, and concentrated in vacuo to give 1.7 g of a crude compound. This crude residue was purified by combiflash instrument onto a redisep® column with a gradient elution of 0 to 20% of EtOAc in hexane to afford the title compound (non polar spot, 900 mg) as a pale yellow solid. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0331] Benzyl (2R,4S)-4-(6-(benzylthio)-4-chloro-lH-indazol-l-yl)-2-(fluoromethyl)pyrrolidine- 1-carboxylate

[0332] The title compound was prepared by following the same reaction protocol as described in the synthesis benzyl (2S ,4R)-4-(6-(benzylthio)-4-chloro- IH-indazol- 1 -yl)-2-

[0333] (fluoromethyl)pyrrolidine-l -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0334] Benzyl (2S,4S)-4-(6-(benzylthio)-4-chloro-lH-indazol-l-yl)-2-(fluoromethyl)pyrrolidine- 1-carboxylate The title compound was prepared by following the same reaction protocol as described in the synthesis benzyl (2S ,4R)-4-(6-(benzylthio)-4-chloro- IH-indazol- 1 -yl)-2-

[0335] (fluoromethyl)pyrrolidine-l -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0336] Benzyl (2R,4R)-4-(6-(benzylthio)-4-chloro-lH-indazol-l-yl)-2-

[0337] (fluoromethyl)pyrrolidine-l-carboxylate

[0338] The title compound was prepared by following the same reaction protocol as described in the synthesis benzyl (2S ,4R)-4-(6-(benzylthio)-4-chloro- IH-indazol- 1 -yl)-2-

[0339] (fluoromethyl)pyrrolidine-l -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0340] Benzyl (2S,4R)-4-(6-(benzylthio)-4-chloro-lH-indazol-l-yl)-2-

[0341] (methoxymethyl)pyrrolidine-l-carboxylate

[0342] The title compound was prepared by following the same reaction protocol as described in the synthesis benzyl (2S ,4R)-4-(6-(benzylthio)-4-chloro- IH-indazol- 1 -yl)-2-

[0343] (fluoromethyl)pyrrolidine-l -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,4R)-4-(6-(benzylthio)-4-chloro-lH-indazol-l-yl)-2-

[0344] (difluoromethyl)pyrrolidine-l-carboxylate

[0345] The title compound was prepared by following the same reaction protocol as described in the synthesis benzyl (2S ,4R)-4-(6-(benzylthio)-4-chloro- IH-indazol- 1 -yl)-2- (fluoromethyl)pyrrolidine-l -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0346] 6-(Benzylthio)-4-chloro-l-((3R,5S)-5-(difluoromethyl)pyrrolidin-3-yl)-lH-indazole

[0347] The title compound was prepared by following the same reaction protocol as described in the synthesis of 6-(benzylthio)-4-chloro-l-((3R,5R)-5-methylpyrrolidin-3-yl)-lH-indazole using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0348] Benzyl (2S,4R)-4-(6-(benzylthio)-4-chloro-lH-indazol-l-yl)-2-

[0349] (difluoromethyl)pyrrolidine-l-carboxylate

[0350] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl (2R,4R)-4-(6-(benzylthio)-4-chloro-lH-indazol-l-yl)-2- methylpyrrolidine-1 -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0351] Benzyl 3-(4-chloro-6-(chlorosulfonyl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate

[0352] To a stirred solution of benzyl 3-(6-(benzylthio)-4-chloro-lH-indazol-l-yl)pyrrolidine-l- carboxylate (0.25 g, 0.52 mmol) in acetonitrile (3 mL) was added acetic acid (0.055 mL) and water (0.105 mL) at 0 °C and stirred for 5 mins. DCDMH (154.5 mg, 0.78 mmol) was added and the resulting mixture was stirred at 0 °C for 30 mins.. The reaction mixture was concentrated in vacuo at 38° C and then co-distilled with toluene (15 mL x 5) to afford the title compound (0.26 g) as a yellow liquid. LCMS m / z = 455.20

[0353] Benzyl 4-(4-chloro-6-(chlorosulfonyl)-lH-indazol-l-yl)piperidine-l-carboxylate

[0354] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(chlorosulfonyl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate using appropriate starting materials. LCMS m / z = 468.10

[0355] Benzyl 3-(4-chloro-6-(chlorosulfonyl)-lH-indazol-l-yl)piperidine-l-carboxylate

[0356] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(chlorosulfonyl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate using appropriate starting materials. LCMS m / z = 468, 470

[0357] Benzyl 3-((4-chloro-6-(chlorosulfonyl)-lH-indazol-l-yl)methyl)pyrrolidine-l- carboxylate

[0358] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(chlorosulfonyl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate using appropriate starting materials. LCMS m / z = 468, 470. Benzyl (2S,4R)-4-(4-chloro-6-(chlorosulfonyl)-lH-indazol-l-yl)-2-

[0359] (fluoromethyl)pyrrolidine-l-carboxylate

[0360] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(chlorosulfonyl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0361] Benzyl (2R,4S)-4-(4-chloro-6-(chlorosulfonyl)-lH-indazol-l-yl)-2-

[0362] (fluoromethyl)pyrrolidine-l-carboxylate

[0363] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(chlorosulfonyl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0364] Benzyl (2S,4S)-4-(4-chloro-6-(chlorosulfonyl)-lH-indazol-l-yl)-2-

[0365] (fluoromethyl)pyrrolidine-l-carboxylate

[0366] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(chlorosulfonyl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. Benzyl (2R,4R)-4-(4-chloro-6-(chlorosulfonyl)-lH-indazol-l-yl)-2-

[0367] (fluoromethyl)pyrrolidine-l-carboxylate

[0368] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(chlorosulfonyl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0369] Benzyl (2R,4R)-4-(4-chloro-6-(chlorosulfonyl)-lH-indazol-l-yl)-2-methylpyrrolidine-l- carboxylate

[0370] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(chlorosulfonyl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0371] Benzyl (2S,4R)-4-(4-chloro-6-(chlorosulfonyl)-lH-indazol-l-yl)-2-methylpyrrolidine-l- carboxylate

[0372] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(chlorosulfonyl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. 1-Benzyl 2-methyl (2S,4R)-4-(4-chloro-6-(chlorosulfonyl)-lH-indazol-l-yl)pyrrolidine- 1,2-dicarboxylate

[0373] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(chlorosulfonyl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0374] Benzyl (2S,4R)-4-(4-chloro-6-(chlorosulfonyl)-lH-indazol-l-yl)-2-

[0375] (difluoromethyl)pyrrolidine-l-carboxylate

[0376] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(chlorosulfonyl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0377] Benzyl (2S,4R)-4-(4-chloro-6-(chlorosulfonyl)-lH-indazol-l-yl)-2-

[0378] (methoxymethyl)pyrrolidine-l-carboxylate

[0379] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(chlorosulfonyl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. Benzyl 3-(4-chloro-6-(N-(l-methylcyclopropyl)sulfamoyl)-lH-indazol-l-yl)pyrrolidine- 1-carboxylate

[0380] To a stirred solution of benzyl 3-(4-chloro-6-(chlorosulfonyl)-lH-indazol-l-yl)pyrrolidine-l- carboxylate (2.5 g, 5.5 mmol) in CH2CI2 (20 mL) was added NEts (2.29 ml, 16.5 mmol) at 0 °C and stirred for 5 mins. 1-Methylcyclopropan-l -amine hydrochloride (0.71 g, 6.6 mmol) was added and the resulting mixture was stirred at 25 °C for 30 mins. The reaction mixture was diluted with CH2CI2 (50 mL) and washed with water (50 mL). Layers were separated and the organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 1.8 g of a crude compound. This crude residue was purified by combiflash instrument onto a redisep® column with a gradient elution of 0 to 50% of EtOAc in hexane to afford the title compound (1.3 g) as a yellow semisolid. LCMS m / z = 489, 491

[0381] Benzyl 4-(4-chloro-6-(N-(l-methylcyclopropyl)sulfamoyl)-lH-indazol-l-yl)piperidine-l- carboxylate

[0382] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(N-(l-methylcyclopropyl)sulfamoyl)-lH-indazol-l- yl)pyrrolidine-l -carboxylate using appropriate starting materials. LCMS m / z = 503, 505

[0383] Benzyl 3-(4-chloro-6-(N-(l-methylcyclopropyl)sulfamoyl)-lH-indazol-l-yl)piperidine-l- carboxylate

[0384] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(N-(l-methylcyclopropyl)sulfamoyl)-lH-indazol-l- yl)pyrrolidine-l -carboxylate using appropriate starting materials. LCMS m / z = 503, 505

[0385] Benzyl 3-((4-chloro-6-(N-(l-methylcyclopropyl)sulfamoyl)-lH-indazol-l- yl)methyl)pyrrolidine-l-carboxylate

[0386] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(N-(l-methylcyclopropyl)sulfamoyl)-lH-indazol-l- yl)pyrrolidine-l -carboxylate using appropriate starting materials. LCMS m / z = 503, 505

[0387] Benzyl (2S,4R)-4-(4-chloro-6-(N-(l-methylcyclopropyl)sulfamoyl)-lH-indazol-l-yl)-2-

[0388] (fluoromethyl)pyrrolidine-l-carboxylate

[0389] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(N-(l-methylcyclopropyl)sulfamoyl)-lH-indazol-l- yl)pyrrolidine-l -carboxylate using appropriate starting materials. LCMS m / z = 521, 523.

[0390] Benzyl (2R,4S)-4-(4-chloro-6-(N-(l-methylcyclopropyl)sulfamoyl)-lH-indazol-l-yl)-2- (fluoromethyl)pyrrolidine-l-carboxylate

[0391] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(N-(l-methylcyclopropyl)sulfamoyl)-lH-indazol-l- yl)pyrrolidine-l -carboxylate using appropriate starting materials. LCMS m / z = 521, 523.

[0392] Benzyl (2S,4S)-4-(4-chloro-6-(N-(l-methylcyclopropyl)sulfamoyl)-lH-indazol-l-yl)-2- (fluoromethyl)pyrrolidine-l-carboxylate

[0393] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(N-(l-methylcyclopropyl)sulfamoyl)-lH-indazol-l- yl)pyrrolidine-l -carboxylate using appropriate starting materials. LCMS m / z = 521, 523.

[0394] Benzyl (2R,4R)-4-(4-chloro-6-(N-(l-methylcyclopropyl)sulfamoyl)-lH-indazol-l-yl)-2- (fluoromethyl)pyrrolidine-l-carboxylate

[0395] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(N-(l-methylcyclopropyl)sulfamoyl)-lH-indazol-l- yl)pyrrolidine-l -carboxylate using appropriate starting materials. LCMS m / z = 521, 523.

[0396] Benzyl (2R,4R)-4-(4-chloro-6-(N-(l-methylcyclopropyl)sulfamoyl)-lH-indazol-l-yl)-2- methylpyrrolidine- 1 -carboxylate

[0397] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(N-(l-methylcyclopropyl)sulfamoyl)-lH-indazol-l- yl)pyrrolidine-l -carboxylate using appropriate starting materials. LCMS m / z = 503, 505.

[0398] Benzyl (2S,4R)-4-(4-chloro-6-(N-(l-methylcyclopropyl)sulfamoyl)-lH-indazol-l-yl)-2- methylpyrrolidine- 1 -carboxylate

[0399] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(N-(l-methylcyclopropyl)sulfamoyl)-lH-indazol-l- yl)pyrrolidine-l -carboxylate using appropriate starting materials. LCMS m / z = 503, 505.

[0400] 1-Benzyl 2-methyl (2S,4R)-4-(4-chloro-6-(N-(l-methylcyclopropyl)sulfamoyl)-lH- indazol-l-yl)pyrrolidine-l,2-dicarboxylate

[0401] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(N-(l-methylcyclopropyl)sulfamoyl)-lH-indazol-l- yl)pyrrolidine-l -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0402] Benzyl (2S,4R)-4-(4-chloro-6-(N-(l-methylcyclopropyl)sulfamoyl)-lH-indazol-l-yl)-2- (difluoromethyl)pyrrolidine-l-carboxylate

[0403] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(N-(l-methylcyclopropyl)sulfamoyl)-lH-indazol-l- yl)pyrrolidine-l -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0404] Benzyl (2S,4R)-4-(4-chloro-6-(N-(l-methylcyclopropyl)sulfamoyl)-lH-indazol-l-yl)-2-

[0405] (methoxymethyl)pyrrolidine-l-carboxylate

[0406] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(N-(l-methylcyclopropyl)sulfamoyl)-lH-indazol-l- yl)pyrrolidine-l -carboxylate using appropriate starting materials. LCMS m / z = 533, 535.

[0407] Benzyl 3-(4-chloro-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl) sulfamoyl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate

[0408] To a stirred solution of benzyl 3-(4-chloro-6-(N-(l-methylcyclopropyl) sulfamoyl)- 1H- indazol-l-yl)pyrrolidine-l -carboxylate (1.3 g, 2.6 mmol) in THF (15 mL) was added NaH (0.192 g, 7.8 mmol) at 0 °C and stirred for 30 mins. 2-(Trimethylsilyl) ethoxymethyl chloride (0.68 mL, 3.9 mmol) was added and the resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (50 mL). Layers were separated and the organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous NaiSCL, filtered, and concentrated in vacuo to give 1.5 g of a crude compound. This crude residue was purified by combiflash instrument onto a redisep® column with a gradient elution of 0 to 20% of EtOAc in hexane to afford the title compound (1.2 g) as a yellow liquid. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0409] Benzyl 4-(4-chloro-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl) sulfamoyl)-lH-indazol-l-yl)piperidine-l-carboxylate

[0410] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy) methyl)sulfamoyl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0411] Benzyl 3-(4-chloro-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl) sulfamoyl)-lH-indazol-l-yl)piperidine-l-carboxylate

[0412] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy) methyl)sulfamoyl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0413] Benzyl 3-((4-chloro-6-(N-(l-methylcyclopropyl)-N-((2-

[0414] (trimethylsilyl)ethoxy)methyl)sulfamoyl) - IH-indazol- l-yl)methyl)pyrrolidine- 1- carboxylate

[0415] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy) methyl)sulfamoyl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0416] Benzyl (2S,4R)-4-(4-chloro-6-(N-(l-methylcyclopropyl)-N-((2-

[0417] (trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-l-yl)-2-(fluoromethyl)pyrrolidine-

[0418] 1-carboxylate

[0419] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy) methyl)sulfamoyl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0420] Benzyl (2S,4R)-4-(4-chloro-6-(N-(l-cyanocyclopropyl)-N-((2-

[0421] (trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-l-yl)-2-(fluoromethyl)pyrrolidine- 1-carboxylate The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy) methyl)sulfamoyl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0422] Benzyl (2R,4S)-4-(4-chloro-6-(N-(l-methylcyclopropyl)-N-((2-

[0423] (trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-l-yl)-2-(fluoromethyl)pyrrolidine- 1-carboxylate

[0424] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy) methyl)sulfamoyl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0425] Benzyl (2S,4S)-4-(4-chloro-6-(N-(l-methylcyclopropyl)-N-((2-

[0426] (trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-l-yl)-2-(fluoromethyl)pyrrolidine- 1-carboxylate

[0427] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy) methyl)sulfamoyl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. Benzyl (2R,4R)-4-(4-chloro-6-(N-(l-methylcyclopropyl)-N-((2-

[0428] (trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-l-yl)-2-(fluoromethyl)pyrrolidine-

[0429] 1-carboxylate

[0430] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy) methyl)sulfamoyl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0431] Benzyl (2R,4R)-4-(4-chloro-6-(N-(l-methylcyclopropyl)-N-((2-

[0432] (trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-l-yl)-2-methylpyrrolidine-l- carboxylate

[0433] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy) methyl)sulfamoyl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0434] Benzyl (2S,4R)-4-(4-chloro-6-(N-(l-methylcyclopropyl)-N-((2-

[0435] (trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-l-yl)-2-methylpyrrolidine-l- carboxylate The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy) methyl)sulfamoyl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0436] 1-Benzyl 2-methyl (2S,4R)-4-(4-chloro-6-(N-(l-methylcyclopropyl)-N-((2-

[0437] (trimethylsilyl)ethoxy)methyl)sulfamoyl) - IH-indazol- l-yl)pyrrolidine- 1,2-dicarboxylate

[0438] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy) methyl)sulfamoyl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0439] Benzyl (2S,4R)-4-(4-chloro-6-(N-(l-methylcyclopropyl)-N-((2-

[0440] (trimethylsilyl)ethoxy)methyl)sulfamoyl) - IH-indazol- l-yl)-2-

[0441] (difluoromethyl)pyrrolidine-l-carboxylate

[0442] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy) methyl)sulfamoyl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. Benzyl (2S,4R)-4-(4-chloro-6-(N-(l-methylcyclopropyl)-N-((2-

[0443] (trimethylsilyl)ethoxy)methyl)sulfamoyl) - IH-indazol- l-yl)-2- (methoxymethyl)pyrrolidine-l-carboxylate

[0444] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-chloro-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy) methyl)sulfamoyl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl 4-(l-(l-((benzyloxy)carbonyl)pyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N- ((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)piperazine-l-carboxylate

[0445] To a stirred mixture of benzyl 3-(4-chloro-6-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy )methyl) sulfamoyl) - 1 H-indazol- 1 -yl)pyrrolidine- 1 -carboxylate (1.2 g, 1.9 mmol) and N-Boc-piperazine (1.44 g, 7.7 mmol) in 1, 4-dioxane (20 mL) was added CS2CO3 (2.47 g, 7.6 mmol) at 25 °C in a sealed tube. The reaction mixture was degassed by purging nitrogen gas for 30 min. RuPhos (0.35 g, 0.76 mmol) and Pd2(dba)3 (0.34 g, 0.38 mmol) were added in portions. The reaction mixture was again degassed by purging nitrogen gas for 30 min. The resulting mixture was stirred for additional 16 h at 110 °C. The reaction mixture was filtered through celite, diluted with EtOAc (75 mL) and washed with water (75 mL). Layers were separated and the organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 1.5 g of a crude compound. This crude residue was purified by combiflash instrument onto a redisep® column with a gradient elution of 0 to 30% of EtOAc in hexane to afford the title compound (1.6 g) as a yellow semi-solid. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl 4-(l-(l-((benzyloxy)carbonyl)piperidin-4-yl)-6-(N-(l-methylcyclopropyl)-N-

[0446] ((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)piperazine-l-carboxylate

[0447] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl 4-(l-(l-((benzyloxy)carbonyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4- yl)piperazine-l -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl 4-(l-(l-((benzyloxy)carbonyl)piperidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-

[0448] ((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)piperazine-l-carboxylate

[0449] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl 4-(l-(l-((benzyloxy)carbonyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4- yl)piperazine-l -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl tert-butyl (2R,6S)-4-(l-(l-((benzyloxy)carbonyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)- 2,6-dimethylpiperazine-l-carboxylate

[0450] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl 4-(l-(l-((benzyloxy)carbonyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4- yl)piperazine-l -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl 4-(l-((l-((benzyloxy)carbonyl)pyrrolidin-3-yl)methyl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4- yl)piperazine-l-carboxylate

[0451] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl 4-(l-(l-((benzyloxy)carbonyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4- yl)piperazine-l -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-(l-((benzyloxy)carbonyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-

[0452] 2,6-dimethylpiperazine-l-carboxylate The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl 4-(l-(l-((benzyloxy)carbonyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4- yl)piperazine-l -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-l-((benzyloxy)carbonyl)-5-(fluoromethyl)pyrrolidin-3- yl)-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH- indazol-4-yl)-2,6-dimethylpiperazine-l-carboxylate

[0453] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl 4-(l-(l-((benzyloxy)carbonyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4- yl)piperazine-l -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-l-((benzyloxy)carbonyl)-5-(fluoromethyl)pyrrolidin-3- yl)-6-(N-(l-cyanocyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH- indazol-4-yl)-2,6-dimethylpiperazine-l-carboxylate

[0454] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl 4-(l-(l-((benzyloxy)carbonyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4- yl)piperazine-l -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. Benzyl (2S,4R)-2-(fluoromethyl)-4-(4-(4-isobutyrylpiperazin-l-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-l- yl)pyrrolidine- 1-carboxylate

[0455] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl 4-(l-(l-((benzyloxy)carbonyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4- yl)piperazine- 1-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0456] Benzyl (2R,4S)-2-(fluoromethyl)-4-(4-(4-isobutyrylpiperazin-l-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-l- yl)pyrrolidine- 1-carboxylate

[0457] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl 4-(l-(l-((benzyloxy)carbonyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4- yl)piperazine- 1-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0458] Benzyl (2R,4S)-2-(fluoromethyl)-4-(4-((3R,5S)-4-isobutyryl-3,5-dimethylpiperazin-l-yl)- 6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol- l-yl)pyrrolidine-l-carboxylate

[0459] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl 4-(l-(l-((benzyloxy)carbonyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4- yl)piperazine- 1-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0460] Benzyl (2S,4S)-2-(fluoromethyl)-4-(4-(4-isobutyrylpiperazin-l-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-l- yl)pyrrolidine- 1-carboxylate

[0461] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl 4-(l-(l-((benzyloxy)carbonyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4- yl)piperazine- 1-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0462] Benzyl (2R,4R)-2-(fluoromethyl)-4-(4-(4-isobutyrylpiperazin-l-yl)-6-(N-(l- methylcyclopropyl)sulfamoyl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl 4-(l-(l-((benzyloxy)carbonyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4- yl)piperazine-l -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5R)-l-((benzyloxy)carbonyl)-5-methylpyrrolidin-3-yl)-6-(N- (l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)- 2,6-dimethylpiperazine-l-carboxylate

[0463] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl 4-(l-(l-((benzyloxy)carbonyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4- yl)piperazine-l -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-l-((benzyloxy)carbonyl)-5-methylpyrrolidin-3-yl)-6-(N-

[0464] (l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-

[0465] 2,6-dimethylpiperazine-l-carboxylate

[0466] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl 4-(l-(l-((benzyloxy)carbonyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4- yl)piperazine-l -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. 1-Benzyl 2-methyl (2S,4R)-4-(4-((3S,5S)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin- l-yl)-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH- indazol-l-yl)pyrrolidine-l,2-dicarboxylate

[0467] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl 4-(l-(l-((benzyloxy)carbonyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4- yl)piperazine-l -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-l-((benzyloxy)carbonyl)-5-(difluoromethyl)pyrrolidin-

[0468] 3-yl)-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH- indazol-4-yl)-2,6-dimethylpiperazine-l-carboxylate

[0469] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl 4-(l-(l-((benzyloxy)carbonyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4- yl)piperazine-l -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-l-((benzyloxy)carbonyl)-5-(methoxymethyl)pyrrolidin-

[0470] 3-yl)-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH- indazol-4-yl)-2,6-dimethylpiperazine-l-carboxylate

[0471] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl 4-(l-(l-((benzyloxy)carbonyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4- yl)piperazine- 1-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0472] Benzyl 3-(4-((3R,5S)-3,5-dimethyl-4-(oxetan-3-yl)piperazin-l-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-l- yl)pyrrolidine- 1-carboxylate

[0473] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl 4-(l-(l-((benzyloxy)carbonyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4- yl)piperazine- 1-carboxylate using benzyl 3-(4-chloro-6-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy )methyl) sulfamoyl) - 1 H-indazol- 1 -yl)pyrrolidine- 1 -carboxylate and

[0474] (2R,6S)-2,6-dimethyl-l-(oxetan-3-yl)piperazine (synthesized as described in WO2019079373 Al) as a starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0475] Benzyl 3-(4-((3R,5S)-4-ethyl-3,5-dimethylpiperazin-l-yl)-6-(N-(l-methylcyclopropyl)-N- ((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate

[0476] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl 4-(l-(l-((benzyloxy)carbonyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4- yl)piperazine- 1-carboxylate using benzyl 3-(4-chloro-6-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy )methyl) sulfamoyl) - 1 H-indazol- 1 -yl)pyrrolidine- 1 -carboxylate and

[0477] (2R,6S)-l-ethyl-2,6-dimethylpiperazine (synthesized as described in W02019020657 Al) as a starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0478] Benzyl 3-(4-((3R,5S)-4-cyclopropyl-3,5-dimethylpiperazin-l-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-l- yl)pyrrolidine- 1-carboxylate

[0479] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl 4-(l-(l-((benzyloxy)carbonyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4- yl)piperazine- 1-carboxylate using benzyl 3-(4-chloro-6-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy )methyl) sulfamoyl) - 1 H-indazol- 1 -yl)pyrrolidine- 1 -carboxylate and

[0480] (2R,6S)-l-cyclopropyl-2,6-dimethylpiperazine (synthesized as described in W02020035464 Al ) as a starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-l-((benzyloxy)carbonyl)-5-(fluoromethyl)pyrrolidin-3- yl)-3-bromo-6-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-2,6-dimethylpiperazine-l- carboxylate

[0481] To a stirred solution of tert-butyl (2S,6S)-4-(l-((3R,5S)-l-((benzyloxy)carbonyl)-5- (fluoromethyl)pyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl) sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine- 1 - carboxylate (500 mg, 0.604 mmol) in CCU (5 mL) was added NBS (107 mg, 0.604 mmol) at 0 °C and stirred at 25 °C for 1 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (50 mL). Layers were separated and the organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous NaiSCL, filtered, and concentrated in vacuo to give 480mg of a crude compound. This crude residue was purified by combiflash instrument onto a redisep® column with a gradient elution of 0 to 20% of EtOAc in hexane to afford the title compound (440 mg) as an off white solid. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0482] Benzyl 3-(6-(N-(l-methylcyclopropyl)sulfamoyl)-4-(piperazin-l-yl)-lH-indazol-l- yl)pyrrolidine- 1-carboxylate

[0483] To a stirred solution of tert-butyl 4-(l-(l-((benzyloxy)carbonyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4- yl)piperazine- 1-carboxylate (1.6 g, 2.1 mmol) in CH2CI2 (10 mL) was added trifluoroacetic acid (8.28 mL, 108 mmol) at 0 °C and stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuo at 25 °C and co-distilled with toluene (15 mL x 5) to afford the title compound (1.5 g) as a yellow liquid. LCMS m / z = 539.20 Benzyl 4-(6-(N-(l-methylcyclopropyl)sulfamoyl)-4-(piperazin-l-yl)-lH-indazol-l- yl)piperidine- 1-carboxylate

[0484] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(6-(N-(l-methylcyclopropyl)sulfamoyl)-4-(piperazin-l-yl)-lH-indazol- l-yl)pyrrolidine- 1-carboxylate using appropriate starting materials. LCMS m / z =553.

[0485] Benzyl 3-(6-(N-(l-methylcyclopropyl)sulfamoyl)-4-(piperazin-l-yl)-lH-indazol-l- yl)piperidine- 1-carboxylate

[0486] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(6-(N-(l-methylcyclopropyl)sulfamoyl)-4-(piperazin-l-yl)-lH-indazol- l-yl)pyrrolidine- 1-carboxylate using appropriate starting materials. LCMS m / z = 553.20

[0487] Benzyl 3-((6-(N-(l-methylcyclopropyl)sulfamoyl)-4-(piperazin-l-yl)-lH-indazol-l- yl)methyl)pyrrolidine-l-carboxylate

[0488] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(6-(N-(l-methylcyclopropyl)sulfamoyl)-4-(piperazin-l-yl)-lH-indazol- l-yl)pyrrolidine- 1-carboxylate using appropriate starting materials. LCMS m / z = 553

[0489] Benzyl 3-(4-((3R,5S)-3,5-dimethylpiperazin-l-yl)-6-(N-(l-methylcyclopropyl)sulfamoyl)- lH-indazol-l-yl)pyrrolidine-l-carboxylate

[0490] To a stirred solution of tert-butyl (2R,6S)-4-(l-(l-((benzyloxy)carbonyl)pyrrolidin-3-yl)-6- (N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)- 2,6-dimethylpiperazine-l -carboxylate (1 g, 1.35 mmol) in CH2CI2 (10 mL) was added TFA (5.1 mL, 67.6 mmol) at 25 °C and stirred the resulting mixture for 1 h. The resulting mixture was concentrated in vacuo, basified with sat.aq. NaHCOs and extracted with CH2CI2 (50 mL x 2). Layers were separated and the combined organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 700 mg of the title compound as a pale yellow solid. LCMS m / z = 567.

[0491] Benzyl 3-(4-((3S,5S)-3,5-dimethylpiperazin-l-yl)-6-(N-(l-methylcyclopropyl)sulfamoyl)- lH-indazol-l-yl)pyrrolidine-l-carboxylate

[0492] The title compound was prepared by following the same reaction protocol as described in the synthesis benzyl 3-(4-((3R, 5S)-3,5-dimethylpiperazin-l-yl)-6-(N-(l- methylcyclopropyl)sulfamoyl)- IH-indazol- 1 -yl)pyrrolidine- 1 -carboxylate using appropriate starting materials. LCMS m / z = 567.

[0493] Benzyl (2S,4R)-4-(4-((3S,5S)-3,5-dimethylpiperazin-l-yl)-6-(N-(l- methylcyclopropyl) sulfamoyl) - IH-indazol- 1 -yl) -2- (fluoromethyl)pyrrolidine- 1 - carboxylate

[0494] The title compound was prepared by following the same reaction protocol as described in the synthesis benzyl 3-(4-((3R, 5S)-3, 5-dimethylpiperazin-l-yl)-6-(N-(l- methylcyclopropyl)sulfamoyl)- IH-indazol- 1 -yl)pyrrolidine- 1 -carboxylate using appropriate starting materials. LCMS m / z = 599.

[0495] Benzyl 3-(4-((3R,5S)-3,5-dimethyl-4-(oxetan-3-yl)piperazin-l-yl)-6-(N-(l- methylcyclopropyl)sulfamoyl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate

[0496] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-((3R,5S)-3,5-dimethylpiperazin-l-yl)-6-(N-(l- methylcyclopropyl) sulfamoyl)- IH-indazol- 1 -yl)pyrrolidine- 1 -carboxylate using appropriate starting materials. LCMS m / z = 623.

[0497] Benzyl 3-(4-((3R,5S)-4-ethyl-3,5-dimethylpiperazin-l-yl)-6-(N-(l- methylcyclopropyl)sulfamoyl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate

[0498] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-((3R,5S)-3,5-dimethylpiperazin-l-yl)-6-(N-(l- methylcyclopropyl) sulfamoyl)- IH-indazol- 1 -yl)pyrrolidine- 1 -carboxylate using appropriate starting materials. LCMS m / z = 595.

[0499] Benzyl 3-(4-((3R,5S)-4-cyclopropyl-3,5-dimethylpiperazin-l-yl)-6-(N-(l- methylcyclopropyl)sulfamoyl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate

[0500] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-((3R,5S)-3,5-dimethylpiperazin-l-yl)-6-(N-(l- methylcyclopropyl) sulfamoyl)- IH-indazol- 1 -yl)pyrrolidine- 1 -carboxylate using appropriate starting materials. LCMS m / z = 608.

[0501] Benzyl 3-(4-(4-isobutyrylpiperazin-l-yl)-6-(N-(l-methylcyclopropyl)sulfamoyl)-lH- indazol-l-yl)pyrrolidine-l-carboxylate

[0502] To a stirred solution of isobutyric acid (0.2 mL, 2.3 mmol) in CH2CI2 (10 mL) was added NEt3(0.35 mL, 2.5 mmol), EDC.HC1 (0.44 g, 2.3 mmol), and HOBt (0.31 g, 2.3 mmol) at 0 °C under N2 atmosphere and stirred for 30 mins. Benzyl 3 -(6-(N-(l -methylcyclopropyl) sulfamoyl)-4-(piperazin-l-yl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate (1.525 g, 2.3 mmol) was added and the resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with CH2CI2 (50 mL) and washed with water (50 mL). Layers were separated and the organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous Na2SC>4, filtered, and concentrated in vacuo to give 1.5 g of a crude compound. This crude residue was purified by combiflash instrument onto a redisep® column with a gradient elution of 0 to 70% of EtOAc in hexane to afford the title compound (0.7 g) as a yellow solid. LCMS m / z = 609. Benzyl 4-(4-(4-isobutyrylpiperazin-l-yl)-6-(N-(l-methylcyclopropyl)sulfamoyl)-lH- indazol-l-yl)piperidine-l-carboxylate

[0503] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-(4-isobutyrylpiperazin-l-yl)-6-(N-(l-methylcyclopropyl)sulfamoyl)- lH-indazol-l-yl)pyrrolidine-l-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0504] Benzyl 3-(4-(4-isobutyrylpiperazin-l-yl)-6-(N-(l-methylcyclopropyl)sulfamoyl)-lH- indazol-l-yl)piperidine-l-carboxylate

[0505] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-(4-isobutyrylpiperazin-l-yl)-6-(N-(l-methylcyclopropyl)sulfamoyl)- lH-indazol-l-yl)pyrrolidine-l-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0506] Benzyl 3-((4-(4-isobutyrylpiperazin-l-yl)-6-(N-(l-methylcyclopropyl)sulfamoyl)-lH- indazol-l-yl)methyl)pyrrolidine-l-carboxylate

[0507] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(4-(4-isobutyrylpiperazin-l-yl)-6-(N-(l-methylcyclopropyl)sulfamoyl)- lH-indazol-l-yl)pyrrolidine-l-carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0508] Benzyl 3-(6-(N-(l-methylcyclopropyl)sulfamoyl)-4-((3R,5S)-3,4,5-trimethylpiperazin-l- yl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate

[0509] To a stirred solution of benzyl 3-(4-((3R,5S)-3,5-dimethylpiperazin-l-yl)-6-(N-(l- methylcyclopropyl)sulfamoyl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate (530 mg, 0.936 mmol) in MeOH (5 mL) was added aq. formaldehyde (0.45 mL, 5.62 mmol), followed by portion-wise addition of NaBHsCN (176 mg, 2.80 mmol) at 25 °C and stirred the resulting mixture for 3 h. The resulting mixture was basified with sat.aq. NaHCOs and extracted with CH2CI2 (25 mL x 2). Layers were separated and the combined organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 390 mg of the title compound as a pale yellow solid. LCMS m / z = 581.

[0510] Benzyl 3-(6-(N-(l-methylcyclopropyl)sulfamoyl)-4-((3S,5S)-3,4,5-trimethylpiperazin-l- yl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate

[0511] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(6-(N-(l-methylcyclopropyl)sulfamoyl)-4-((3R,5S)-3,4,5- trimethylpiperazin- 1 -yl)- IH-indazol- 1 -yl)pyrrolidine- 1 -carboxylate using appropriate starting materials. LCMS m / z = 581. Benzyl (2S,4R)-2-(fluoromethyl)-4-(6-(N-(l-methylcyclopropyl)sulfamoyl)-4-((3S,5S)-

[0512] 3,4,5-trimethylpiperazin-l-yl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate

[0513] The title compound was prepared by following the same reaction protocol as described in the synthesis of benzyl 3-(6-(N-(l-methylcyclopropyl)sulfamoyl)-4-((3R,5S)-3,4,5- trimethylpiperazin- 1 -yl)- IH-indazol- 1 -yl)pyrrolidine- 1 -carboxylate using appropriate starting materials. LCMS m / z = 613. tert-Butyl (2S,6S)-4-(l-((3R,5S)-l-((benzyloxy)carbonyl)-5-(fluoromethyl)pyrrolidin-3- yl)-3-cyclopropyl-6-(N-(l-methylcyclopropyl)-N-((2-

[0514] (trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-2,6-dimethylpiperazine-l- carboxylate

[0515] To a stirred solution of tert-butyl (2S,6S)-4-(l-((3R,5S)-l-((benzyloxy)carbonyl)-5- (fluoromethyl)pyrrolidin-3-yl)-3-bromo-6-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl) sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine- 1 - carboxylate (440 mg, 0.485 mmol) and cyclopropylboronic acid (125 mg, 1.45 mmol) in dioxane (10 mL) was added K3PO4 (207 mg, 0.969 mmol) and PdChdppf.CHiCh 40 mg, 0.048 mmol) at 25 °C and purged with N2 for 10 mins. The resulting mixture was stirred for 90 °C for 16 h. The reaction mixture was filtered through celite washed with EtOAc (20 mL). This organic layer was washed with water (50 mL). Layers were separated and the organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous NaiSCL, filtered, and concentrated in vacuo to give 500 mg of a crude compound. This crude residue was purified by combiflash instrument onto a redisep® column with a gradient elution of 0 to ill 20% of EtOAc in hexane to afford the title compound (0.4 g) as a yellow solid. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-l-((benzyloxy)carbonyl)-5-(hydroxymethyl)pyrrolidin-

[0516] 3-yl)-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH- indazol-4-yl)-2,6-dimethylpiperazine-l-carboxylate

[0517] To a stirred solution of 1-benzyl 2-methyl (2S,4R)-4-(4-((3S,5S)-4-(tert-butoxycarbonyl)-3,5- dimethylpiperazin- l-yl)-6-(N-( 1 -methylcyclopropyl)-N-((2-

[0518] (trimethylsilyl)ethoxy)methyl) sulfamoyl) - IH-indazol- l-yl)pyrrolidine- 1 ,2-dicarboxylate (520 mg, 0.878 mmol) in THF (5 mL) was added LiBH4 (1.83 mL, 2M in THF) at 0 °C and stirred at 25 °C for 2 h. The reaction mixture was quenched with sat.aq.NH4C! (50 mL) and extracted with EtOAc (50 mL). Layers were separated and the organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 400 mg of a crude compound. This crude residue was purified by combiflash instrument onto a redisep® column with a gradient elution of 0 to 50% of EtOAc in hexane to afford the title compound (0.23 g) as a yellow liquid. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-l-((benzyloxy)carbonyl)-5-

[0519] (((methylsulfonyl)oxy)methyl)pyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2-

[0520] (trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-2,6-dimethylpiperazine-l- carboxylate To a stirred solution of tert-butyl (2S,6S)-4-(l-((3R,5S)-l-((benzyloxy)carbonyl)-5-

[0521] (hydroxymethyl)pyrrohdin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl) sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine- 1 - carboxylate (600 mg, 0.725 mmol) in CH2CI2 (5 mL) was added NEls (0.15 mL, 1.088 mmol) at 0 °C. MsCl (91.3 mg, 0.798 mmol) was added slowly and stirred at 25 °C for 1 h. The reaction mixture was diluted with CH2CI2 (50 mL) and washed with H2O (50 mL). Layers were separated and the organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the title compound (0.65 g) as a brown liquid. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-l-((benzyloxy)carbonyl)-5-

[0522] ((dimethylamino)methyl)pyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-2,6-dimethylpiperazine-l- carboxylate

[0523] Bo

[0524] The stirred solution of tert-butyl (2S,6S)-4-(l-((3R,5S)-l-((benzyloxy)carbonyl)-5- (((methylsulfonyl)oxy)methyl)pyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl) sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine- 1 - carboxylate (650 mg, 0.718 mmol) and 2M HNMei in EtOH (0.78 mL, 0.789 mmol) was stirred at 80 °C for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL). Layers were separated and the organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous NaiSCh, filtered, and concentrated in vacuo to afford the title compound (0.65 g) as a yellow liquid. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-l-((benzyloxy)carbonyl)-5-(chloromethyl)pyrrolidin-3- yl)-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH- indazol-4-yl)-2,6-dimethylpiperazine-l-carboxylate

[0525] The stirred solution of tert-butyl (2S,6S)-4-(l-((3R,5S)-l-((benzyloxy)carbonyl)-5- (((methylsulfonyl)oxy)methyl)pyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl) sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine- 1 - carboxylate (1g, 1.1 mmol) in DMF (5 mL) was added tetra-n-butylammonium chloride (160 mg, 0.57 mmol) at 25 °C and was stirred at 90 °C for 16 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with sat.aq.NaHCOs (50 mL). Layers were separated and the organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous NaiSO^ filtered, and concentrated in vacuo to afford the title compound (0.65 g) as a yellow liquid. This crude residue was purified by combiflash instrument onto a redisep® column with a gradient elution of 0 to 50% of EtOAc in hexane to afford the title compound (0.35 g) as a yellow solid. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-l-((benzyloxy)carbonyl)-5-(2-hydroxypropan-2- yl)pyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2-

[0526] (trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-2,6-dimethylpiperazine-l- carboxylate

[0527] To a stirred solution of 1-benzyl 2-methyl (2S,4R)-4-(4-((3S,5S)-4-(tert-butoxycarbonyl)-3,5- dimethylpiperazin- l-yl)-6-(N-( 1 -methylcyclopropyl)-N-((2-

[0528] (trimethylsilyl)ethoxy )methyl) sulfamoyl) - 1 H-indazol- 1 -yl)pyrrolidine- 1 ,2-dicarboxylate (750 mg, 0.877 mmol) in diethyl ether ( 10 mL) was added 2M MeMgBr in THF (1.31 mL, 2.631 mmol) at 25 °C and stirred for 3 h. The reaction mixture was quenched with sat.aq. NH4CI (50 mL) and extracted with EtOAc (50 mL). Layers were separated and the organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous NaiSC , filtered, and concentrated in vacuo to afford the title compound (0.85 g) as a yellow liquid. This crude residue was purified by combiflash instrument onto a redisep® column with a gradient elution of 0 to 50% of EtOAc in hexane to afford the title compound (0.65 g) as a yellow liquid. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-l-((benzyloxy)carbonyl)-5-(prop-l-en-2-yl)pyrrolidin-3- yl)-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH- indazol-4-yl)-2,6-dimethylpiperazine-l-carboxylate

[0529] To a stirred solution of tert-butyl (2S,6S)-4-(l-((3R,5S)-l-((benzyloxy)carbonyl)-5-(2- hydroxypropan-2-yl)pyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl) sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine- 1 - carboxylate (510 mg, 0.596 mmol) in chloroform ( 15 mL) was added pyridine (91.96 mg, 1.193 mmol) followed by thionyl chloride (106.4 mg, 0.894 mmol) at 25 °C and stirred for 16 h. The reaction mixture was diluted with CH2CI2 (50 mL) and washed with aq.sat.NaHCOs (50 mL). Layers were separated and the organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the crude compound (0.56 g). This residue was purified by combiflash instrument onto a redisep® column with a gradient elution of 0 to 20% of EtOAc in hexane to afford the title compound (0.26 g) as a brown solid. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0530] 4-(4-Isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)-l-(pyrrolidin-3-yl)-lH-indazole- 6-sulfonamide To a stirred solution of benzyl 3-(4-(4-isobutyrylpiperazin-l-yl)-6-(N-(l- methylcyclopropyl)sulfamoyl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate (0.7 g) in EtOAc (3.5 mL) and MeOH (3.5 mL) was added Pd / C (10% wet, 0.35 g) at 25 °C. The resulting mixture was stirred at 25 °C for 16 h under hydrogen atmosphere with balloon. The reaction mixture was filtered through celite under vacuum, washed with EtOAc (10 mL) and the filtrate was evaporated to provide 0.42 g of sufficiently pure compound as an off white solid. LCMS m / z = 475.

[0531] 4-(4-Isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)-l-(piperidin-4-yl)-lH-indazole-

[0532] 6-sulfonamide

[0533] The title compound was prepared by following the same reaction protocol as described in the synthesis of 4-(4-isobutyrylpiperazin- 1 -yl)-N-( 1 -methylcyclopropyl)- 1 -(pyrrolidin-3-yl)- 1H- indazole-6-sulfonamide using appropriate starting materials. LCMS m / z = 489.

[0534] 4-(4-Isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)-l-(piperidin-3-yl)-lH-indazole-

[0535] 6-sulfonamide

[0536] The title compound was prepared by following the same reaction protocol as described in the synthesis of 4-(4-isobutyrylpiperazin- 1 -yl)-N-( 1 -methylcyclopropyl)- 1 -(pyrrolidin-3-yl)- 1H- indazole-6-sulfonamide using appropriate starting materials. LCMS m / z = 489. tert-Butyl (2R,6S)-2,6-dimethyl-4-(6-(N-(l-methylcyclopropyl)-N-((2-

[0537] (trimethylsilyl)ethoxy)methyl)sulfamoyl)-l-(pyrrolidin-3-yl)-lH-indazol-4- yl)piperazine-l-carboxylate

[0538] The title compound was prepared by following the same reaction protocol as described in the synthesis of 4-(4-isobutyrylpiperazin- 1 -yl)-N-( 1 -methylcyclopropyl)- 1 -(pyrrolidin-3-yl)- 1H- indazole-6-sulfonamide using appropriate starting material. LCMS m / z = 664. tert-Butyl (2S,6S)-4-(l-((3R,5S)-5-(fluoromethyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-

[0539] 2,6-dimethylpiperazine-l-carboxylate

[0540] The title compound was prepared by following the same reaction protocol as described in the synthesis of 4-(4-Isobutyrylpiperazin- 1 -yl)-N-( 1 -methylcyclopropyl)- l-(pyrrolidin-3-yl)- 1H- indazole-6-sulfonamide using appropriate starting material. LCMS m / z = 695 tert-Butyl (2S,6S)-4-(6-(N-(l-cyanocyclopropyl)-N-((2-

[0541] (trimethylsilyl)ethoxy)methyl)sulfamoyl)-l-((3R,5S)-5-(fluoromethyl)pyrrolidin-3-yl)- lH-indazol-4-yl)-2,6-dimethylpiperazine-l-carboxylate

[0542] The title compound was prepared by following the same reaction protocol as described in the synthesis of 4-(4-Isobutyrylpiperazin- 1 -yl)-N-( 1 -methylcyclopropyl)- l-(pyrrolidin-3-yl)- 1H- indazole-6-sulfonamide using appropriate starting material. LCMS m / z = 706. 4-(4-Isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)-l-(pyrrolidin-3-ylmethyl)-lH- indazole-6-sulfonamide

[0543] The title compound was prepared by following the same reaction protocol as described in the synthesis of 4-(4-isobutyrylpiperazin- 1 -yl)-N-( 1 -methylcyclopropyl)- 1 -(pyrrolidin-3-yl)- 1H- indazole-6-sulfonamide using appropriate starting material. LCMS m / z = 489 tert-Butyl (2S,6S)-2,6-dimethyl-4-(6-(N-(l-methylcyclopropyl)-N-((2-

[0544] (trimethylsilyl)ethoxy)methyl)sulfamoyl)-l-((3R,5R)-5-methylpyrrolidin-3-yl)-lH- indazol-4-yl)piperazine-l-carboxylate

[0545] The title compound was prepared by following the same reaction protocol as described in the synthesis of 4-(4-isobutyrylpiperazin- 1 -yl)-N-( 1 -methylcyclopropyl)- 1 -(pyrrolidin-3-yl)- 1H- indazole-6-sulfonamide using appropriate starting material. The title compound was used as- is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-2,6-dimethyl-4-(6-(N-(l-methylcyclopropyl)-N-((2-

[0546] (trimethylsilyl)ethoxy)methyl)sulfamoyl)-l-((3R,5S)-5-methylpyrrolidin-3-yl)-lH- indazol-4-yl)piperazine-l The title compound was prepared by following the same reaction protocol as described in the synthesis of 4-(4-isobutyrylpiperazin- 1 -yl)-N-( 1 -methylcyclopropyl)- 1 -(pyrrolidin-3-yl)- 1H- indazole-6-sulfonamide using appropriate starting material. The title compound was used as- is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-5-(difluoromethyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-

[0547] 2,6-dimethylpiperazine-l-carboxylate

[0548] The title compound was prepared by following the same reaction protocol as described in the synthesis of 4-(4-isobutyrylpiperazin- 1 -yl)-N-( 1 -methylcyclopropyl)- 1 -(pyrrolidin-3-yl)- 1H- indazole-6-sulfonamide using appropriate starting material. The title compound was used as- is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-5-(methoxymethyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-

[0549] 2,6-dimethylpiperazine-l-carboxylate

[0550] The title compound was prepared by following the same reaction protocol as described in the synthesis of 4-(4-isobutyrylpiperazin- 1 -yl)-N-( 1 -methylcyclopropyl)- 1 -(pyrrolidin-3-yl)- 1H- indazole-6-sulfonamide using appropriate starting material. The title compound was used as- is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(3-cyclopropyl-l-((3R,5S)-5-(fluoromethyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-

[0551] 2,6-dimethylpiperazine-l-carboxylate

[0552] The title compound was prepared by following the same reaction protocol as described in the synthesis of 4-(4-isobutyrylpiperazin- 1 -yl)-N-( 1 -methylcyclopropyl)- 1 -(pyrrolidin-3-yl)- 1H- indazole-6-sulfonamide using appropriate starting material. The title compound was used as- is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-

[0553] 2,6-dimethylpiperazine-l-carboxylate

[0554] The title compound was prepared by following the same reaction protocol as described in the synthesis of 4-(4-isobutyrylpiperazin- 1 -yl)-N-( 1 -methylcyclopropyl)- 1 -(pyrrolidin-3-yl)- 1H- indazole-6-sulfonamide using appropriate starting material. The title compound was used as- is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-5-((dimethylamino)methyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-

[0555] 2,6-dimethylpiperazine-l-carboxylate The title compound was prepared by following the same reaction protocol as described in the synthesis of 4-(4-isobutyrylpiperazin- 1 -yl)-N-( 1 -methylcyclopropyl)- 1 -(pyrrolidin-3-yl)- 1H- indazole-6-sulfonamide using appropriate starting material. The title compound was used as- is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-5-(chloromethyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-

[0556] 2,6-dimethylpiperazine-l-carboxylate

[0557] The title compound was prepared by following the same reaction protocol as described in the synthesis of 4-(4-isobutyrylpiperazin- 1 -yl)-N-( 1 -methylcyclopropyl)- 1 -(pyrrolidin-3-yl)- 1H- indazole-6-sulfonamide using appropriate starting material. The title compound was used as- is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-5-(2-hydroxypropan-2-yl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-

[0558] 2,6-dimethylpiperazine-l-carboxylate

[0559] The title compound was prepared by following the same reaction protocol as described in the synthesis of 4-(4-isobutyrylpiperazin- 1 -yl)-N-( 1 -methylcyclopropyl)- 1 -(pyrrolidin-3-yl)- 1H- indazole-6-sulfonamide using appropriate starting material. The title compound was used as- is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-5-isopropylpyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-

[0560] N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-2,6- dimethylpiperazine-l-carboxylate

[0561] The title compound was prepared by following the same reaction protocol as described in the synthesis of 4-(4-isobutyrylpiperazin- 1 -yl)-N-( 1 -methylcyclopropyl)- 1 -(pyrrolidin-3-yl)- 1H- indazole-6-sulfonamide using tert-butyl (2S,6S)-4-(l-((3R,5S)-l-((benzyloxy)carbonyl)-5- (prop-l-en-2-yl)pyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl) sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine- 1 - carboxylate as a starting material. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-5-(methoxycarbonyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-

[0562] 2,6-dimethylpiperazine-l-carboxylate

[0563] The title compound was prepared by following the same reaction protocol as described in the synthesis of 4-(4-isobutyrylpiperazin- 1 -yl)-N-( 1 -methylcyclopropyl)- 1 -(pyrrolidin-3-yl)- 1H- indazole-6-sulfonamide using tert-butyl (2S,6S)-4-(l-((3R,5S)-l-((benzyloxy)carbonyl)-5- (prop-l-en-2-yl)pyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl) sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine- 1 - carboxylate as a starting material. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0564] N-(l-Methylcyclopropyl)-l-(pyrrolidin-3-yl)-4-((3R,5S)-3,4,5-trimethylpiperazin-l-yl)- lH-indazole-6-sulfonamide

[0565] The stirred solution of benzyl 3 -(6-(N-(l -methylcyclopropyl) sulfamoyl)-4-((3R, 5S)-3,4,5- trimethylpiperazin-l-yl)-lH-indazol-l-yl)pyrrolidine-l-carboxylate (50 mg) in TFA (1.5 mL) was heated at 60 °C for 2 h. The resulting mixture was basified with sat.aq. NaHCOs and extracted with EtOAc (25 mL x 2). Layers were separated and the combined organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous NaiSCL. filtered, and concentrated in vacuo to give 40 mg of the title compound as a yellow solid. LCMS m / z = 447.

[0566] N-(l-Methylcyclopropyl)-l-(pyrrolidin-3-yl)-4-((3S,5S)-3,4,5-trimethylpiperazin-l-yl)- lH-indazole-6-sulfonamide

[0567] The title compound was prepared by following the same reaction protocol as described in the synthesis of N-(l-methylcyclopropyl)-l-(pyrrolidin-3-yl)-4-((3R,5S)-3,4,5- trimethylpiperazin-l-yl)-lH-indazole-6-sulfonamide using appropriate starting materials. LCMS m / z = 447. l-((3R,5S)-5-(Fluoromethyl)pyrrolidin-3-yl)-N-(l-methylcyclopropyl)-4-((3S,5S)-3,4,5- trimethylpiperazin-l-yl)-lH-indazole-6-sulfonamide The title compound was prepared by following the same reaction protocol as described in the synthesis of l-((3R,5S)-5-(fluoromethyl)pyrrolidin-3-yl)-4-(4-isobutyrylpiperazin-l-yl)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide using appropriate starting materials. LCMS m / z = 479. l-((3R,5S)-5-(Fluoromethyl)pyrrolidin-3-yl)-4-(4-isobutyrylpiperazin-l-yl)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide

[0568] The stirred solution of benzyl (2S,4R)-2-(fluoromethyl)-4-(4-(4-isobutyrylpiperazin-l-yl)-6- (N-( 1 -methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl) sulfamoyl) - IH-indazol- 1 - yl)pyrrolidine-l -carboxylate (125 mg, 0.162 mmol) in CH2CI2 (2 mL) was added TFA (0.8 mL, 8.103 mmol) was stirred at 25 °C for 2 h. The resulting mixture was concentrated in vacuo to afford the residue, which was dissolved in TFA (2 mL) and heated at 60 °C for 2 h. The reaction mixture was basified with sat.aq. NaHCOs and extracted with CH2CI2 (25 mL x 2). Layers were separated and the combined organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 120 mg of the title compound as a yellow solid. LCMS m / z = 507. l-((3S,5R)-5-(Fluoromethyl)pyrrolidin-3-yl)-4-(4-isobutyrylpiperazin-l-yl)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide

[0569] The title compound was prepared by following the same reaction protocol as described in the synthesis of 1-((3R, 5S)-5-(fluoromethyl)pyrrolidin-3-yl)-4-(4-isobutyrylpiperazin-l-yl)-N- (l-methylcyclopropyl)-lH-indazole-6-sulfonamide using appropriate starting materials. LCMS m / z = 507. l-((3S,5S)-5-(Fluoromethyl)pyrrolidin-3-yl)-4-(4-isobutyrylpiperazin-l-yl)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide

[0570] The title compound was prepared by following the same reaction protocol as described in the synthesis of l-((3R,5S)-5-(fluoromethyl)pyrrolidin-3-yl)-4-(4-isobutyrylpiperazin-l-yl)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide using appropriate starting materials. LCMS m / z = 507. l-((3R,5R)-5-(Fluoromethyl)pyrrolidin-3-yl)-4-(4-isobutyrylpiperazin-l-yl)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide

[0571] The title compound was prepared by following the same reaction protocol as described in the synthesis of l-((3R,5S)-5-(fluoromethyl)pyrrolidin-3-yl)-4-(4-isobutyrylpiperazin-l-yl)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide using appropriate starting materials. LCMS m / z = 507. l-((3S,5R)-5-(Fluoromethyl)pyrrolidin-3-yl)-4-((3R,5S)-4-isobutyryl-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide The title compound was prepared by following the same reaction protocol as described in the synthesis of l-((3R,5S)-5-(fluoromethyl)pyrrolidin-3-yl)-4-(4-isobutyrylpiperazin-l-yl)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide using appropriate starting materials. LCMS m / z = 535.

[0572] 4-((3R,5S)-3,5-Dimethyl-4-(oxetan-3-yl)piperazin-l-yl)-N-(l-methylcyclopropyl)-l-

[0573] (pyrrolidin-3-yl)-lH-indazole-6-sulfonamide

[0574] The title compound was prepared by following the same reaction protocol as described in the synthesis of 1-((3R, 5S)-5-(fluoromethyl)pyrrolidin-3-yl)-4-(4-isobutyrylpiperazin-l-yl)-N- (l-methylcyclopropyl)-lH-indazole-6-sulfonamide using appropriate starting materials. LCMS m / z = 489.

[0575] 4-((3R,5S)-4-Ethyl-3,5-dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-l-(pyrrolidin-

[0576] 3-yl)-lH-indazole-6-sulfonamide

[0577] The title compound was prepared by following the same reaction protocol as described in the synthesis of l-((3R,5S)-5-(fluoromethyl)pyrrolidin-3-yl)-4-(4-isobutyrylpiperazin-l-yl)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide using appropriate starting materials. LCMS m / z = 461.

[0578] 4-((3R,5S)-4-Cyclopropyl-3,5-dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-l-

[0579] (pyrrolidin-3-yl)-lH-indazole-6-sulfonamide

[0580] The title compound was prepared by following the same reaction protocol as described in the synthesis of l-((3R,5S)-5-(fluoromethyl)pyrrolidin-3-yl)-4-(4-isobutyrylpiperazin-l-yl)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide using appropriate starting materials. LCMS m / z = 473. tert-Butyl (2R,6S)-4-(l-(l-(2-chloroacetyl)pyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-

[0581] N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-2,6- dimethylpiperazine-l-carboxylate

[0582] To a stirred solution of tert-butyl (2R,6S)-2,6-dimethyl-4-(6-(N-(l-methylcyclopropyl)-N- ((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-l-(pyrrolidin-3-yl)-lH-indazol-4-yl)piperazine- 1 -carboxylate (150 mg, 0.226 mmol) in CH2CI2 (2 mL) was added NE ? (0.063 mL, 0.453 mmol) at 0 °C under N2 atmosphere and stirred for 5 mins. Chloroacetyl chloride (0.027 mL, 0.3398 mmol) was added and the resulting mixture was stirred at 0 °C for 30 mins. The reaction mixture was diluted with CH2CI2 (50 mL) and washed with water (50 mL). Layers were separated and the organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 90 mg of sufficiently pure compound as an off white solid. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl 4-(l-(l-acryloylpyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2-

[0583] (trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)piperazine-l-carboxylate

[0584] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl (2R,6S)-4-(l-(l-(2-chloroacetyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-2,6- dimethylpiperazine-1 -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2R,6S)-4-(l-(l-acryloylpyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2-

[0585] (trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-2,6-dimethylpiperazine-l- carboxylate

[0586] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl (2R,6S)-4-(l-(l-(2-chloroacetyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-2,6- dimethylpiperazine-1 -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2R,6S)-2,6-dimethyl-4-(6-(N-(l-methylcyclopropyl)-N-((2-

[0587] (trimethylsilyl)ethoxy)methyl)sulfamoyl)-l-(l-propioloylpyrrolidin-3-yl)-lH-indazol-4- yl)piperazine-l-carboxylate The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl (2R,6S)-4-(l-(l-(2-chloroacetyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-2,6- dimethylpiperazine-1 -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-l-acryloyl-5-(fluoromethyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-

[0588] 2,6-dimethylpiperazine-l-carboxylate

[0589] The title compound was prepared by following the same reaction protocol as described in the synthesis of 1 -( 1 -(2-chloroacetyl)pyrrolidin-3 -yl)-4-(4-isobutyrylpiperazin- 1 -yl) -N-( 1 - methylcyclopropyl)- lH-indazole-6- sulfonamide using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-l-acryloyl-5-(fluoromethyl)pyrrolidin-3-yl)-6-(N-(l- cyanocyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-2,6- dimethylpiperazine-l-carboxylate

[0590] The title compound was prepared by following the same reaction protocol as described in the synthesis of 1 -( 1 -(2-chloroacetyl)pyrrolidin-3 -yl)-4-(4-isobutyrylpiperazin- 1 -yl) -N-( 1 - methylcyclopropyl)- lH-indazole-6- sulfonamide using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-5-(fluoromethyl)-l-propionylpyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)- 2,6-dimethylpiperazine-l-carboxylate

[0591] The title compound was prepared by following the same reaction protocol as described in the synthesis of 1 -( 1 -(2-chloroacetyl)pyrrolidin-3 -yl)-4-(4-isobutyrylpiperazin- 1 -yl) -N-( 1 - methylcyclopropyl)- lH-indazole-6- sulfonamide using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2R,6S)-4-(l-(l-(2,5-dichloropyrimidin-4-yl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-

[0592] 2,6-dimethylpiperazine-l-carboxylate

[0593] To a stirred solution of tert-butyl (2R,6S)-2,6-dimethyl-4-(6-(N-(l-methylcyclopropyl)-N- ((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-l-(pyrrolidin-3-yl)-lH-indazol-4-yl)piperazine- 1 -carboxylate (50 mg, 0.069 mmol) in acetonitrile (1 mL) was added potassium carbonate (15 mg, 0.105 mmol) at 0 °C under N2 atmosphere and stirred for 5 mins. 2,4,5- Trichloropyrimidine (13 mg, 0.069 mmol) was added and the resulting mixture was stirred at 80 °C for 1 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (50 mL). Layers were separated and the organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous NaiSCL, filtered, and concentrated in vacuo to give 70 mg of the title compound as an off white solid, which was used as-is for the next step as there was no ionization in LCMS. l-(l-Acryloylpyrrolidin-3-yl)-N-(l-methylcyclopropyl)-4-(piperazin-l-yl)-lH-indazole-

[0594] 6-sulfonamide hydrochloride

[0595] To a stirred solution of tert-butyl 4-(l-(l-acryloylpyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4- yl)piperazine-l -carboxylate (800 mg) in CH2CI2 (3 mL) was added 4N HC1 in dioxane (3 mL) at 25 °C under N2 atmosphere and stirred for 2 h. The reaction mixture was concentrated in vacuo at 35 °C and co-distilled with ethyl acetate (5 mL x 2) to give 600 mg of the title compound as an off white solid. LCMS m / z = 496. tert-Butyl (2S)-2-(4-(l-(l-acryloylpyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)sulfamoyl)-lH-indazol-4-yl)piperazine-l-carbonyl)pyrrolidine-l- carboxylate

[0596] To a stirred solution of l-(l-acryloylpyrrolidin-3-yl)-N-(l-methylcyclopropyl)-4-(piperazin- l-yl)-lH-indazole-6-sulfonamide hydrochloride (60 mg, 0.13 mmol) and (tert- butoxycarbonyl)-L-proline (42.24 mg, 0.19 mmol) in DMF (2 mL) was added HATU (74.1 mg, 0.19 mmol) at 25 °C under N2 atmosphere and stirred for 5 mins. DIPEA (0.08 mL, 0.52 mmol) was added and stirred for 30 mins. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (50 mL). Layers were separated and the organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous Na2SC>4, filtered, and concentrated in vacuo to give 130 mg of a crude compound. This crude residue was purified by reverse phase preparative HPLC to afford the title compound (18 mg) as an off white solid. LCMS m / z = 556. tert-Butyl (2S,6S)-4-(l-((3R,5S)-l-(2-fluoroacryloyl)-5-(fluoromethyl)pyrrolidin-3-yl)-6- (N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4- yl)-2,6-dimethylpiperazine-l-carboxylate

[0597] To a stirred solution of tert-butyl (2S,6S)-4-(l-((3R,5S)-5-(fluoromethyl)pyrrolidin-3-yl)-6- (N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)- 2,6-dimethylpiperazine-l -carboxylate (200 mg, 0.288 mmol), 2-fluoroacrylic acid (39 mg, 0.433 mmol) in DMF (2 mL) was added HATU (164 mg, 0.431 mmol) at 25 °C and stirred for 10 mins. DIPEA (0.15 mL, 0.864 mmol) was added under N2 atmosphere and stirred at 25 °C for 10 mins. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (20 mL). Layers were separated and the organic layer was washed with brine (20 mL). The organic layer was dried over anhydrous NaiSCU, filtered, and concentrated in vacuo to give 240 mg of a crude compound. This crude residue was purified by combiflash instrument onto a redisep® column with a gradient elution of 0 to 50% of EtOAc in hexane to afford the title compound (0.2 g) as an off white solid. The title compound was used as -is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-l-((E)-4-(dimethylamino)but-2-enoyl)-5-

[0598] (fluoromethyl)pyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2-

[0599] (trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-2,6-dimethylpiperazine-l- carboxylate

[0600] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl (2S,6S)-4-(l-((3R,5S)-l-(2-fluoroacryloyl)-5-(fluoromethyl)pyrrolidin- 3-yl)-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH- indazol-4-yl)-2,6-dimethylpiperazine-l -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-l-(but-2-ynoyl)-5-(fluoromethyl)pyrrolidin-3-yl)-6-(N- (l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)- 2,6-dimethylpiperazine-l-carboxylate

[0601] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl (2S,6S)-4-(l-((3R,5S)-l-(2-fluoroacryloyl)-5-(fluoromethyl)pyrrolidin- 3-yl)-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH- indazol-4-yl)-2,6-dimethylpiperazine-l -carboxylate using appropriate starting materials.

[0602] The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-5-(fluoromethyl)-l-((Z)-2-methylbut-2- enoyl)pyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2-

[0603] (trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-2,6-dimethylpiperazine-l- carboxylate

[0604] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl (2S,6S)-4-(l-((3R,5S)-l-(2-fluoroacryloyl)-5-(fluoromethyl)pyrrolidin- 3-yl)-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH- indazol-4-yl)-2,6-dimethylpiperazine-l -carboxylate using appropriate starting materials.

[0605] The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-5-(fluoromethyl)-l-((E)-4,4,4-trifluorobut-2- enoyl)pyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2-

[0606] (trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-2,6-dimethylpiperazine-l- carboxylate

[0607] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl (2S,6S)-4-(l-((3R,5S)-l-(2-fluoroacryloyl)-5-(fluoromethyl)pyrrolidin- 3-yl)-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH- indazol-4-yl)-2,6-dimethylpiperazine-l -carboxylate using appropriate starting materials.

[0608] The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-l-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-

[0609] 2,6-dimethylpiperazine-l-carboxylate

[0610] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl (2S,6S)-4-(l-((3R,5S)-5-(fluoromethyl)-l-methacryloylpyrrolidin-3- yl)-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol- 4-yl)-2,6-dimethylpiperazine-l -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-5-(fluoromethyl)-l-(pent-2-ynoyl)pyrrolidin-3-yl)-6-(N- (l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)- 2,6-dimethylpiperazine-l-carboxylate

[0611] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl (2S,6S)-4-(l-((3R,5S)-5-(fluoromethyl)-l-methacryloylpyrrolidin-3- yl)-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol- 4-yl)-2,6-dimethylpiperazine-l -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-5-(fluoromethyl)-l-methacryloylpyrrolidin-3-yl)-6-(N- (l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-

[0612] 2,6-dimethylpiperazine-l-carboxylate

[0613] To a stirred solution of tert-butyl (2S,6S)-4-(l-((3R,5S)-5-(fluoromethyl)pyrrolidin-3-yl)-6- (N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)- 2,6-dimethylpiperazine-l -carboxylate (150 mg, 0.216 mmol) in CH2CI2 (2 mL) was added NEts (0.06 mL, 0.432 mmol) at 0 °C under N2 atmosphere and stirred for 5 mins. Methacryloyl chloride (0.02 mL, 0.237 mmol) was added and the resulting mixture was stirred at 25 °C for 30 mins. The reaction mixture was diluted with CH2CI2 (50 mL) and washed with water (50 mL). Layers were separated and the organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 120 mg of sufficiently pure compound as an off white solid. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-l-((E)-but-2-enoyl)-5-(fluoromethyl)pyrrolidin-3-yl)-6- (N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4- yl)-2,6-dimethylpiperazine-l-carboxylate

[0614] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl (2S,6S)-4-(l-((3R,5S)-5-(fluoromethyl)-l-methacryloylpyrrolidin-3- yl)-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol- 4-yl)-2,6-dimethylpiperazine-l -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-5-(fluoromethyl)-l-((E)-2-methylbut-2- enoyl)pyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2-

[0615] (trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-2,6-dimethylpiperazine-l- carboxylate

[0616] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl (2S,6S)-4-(l-((3R,5S)-5-(fluoromethyl)-l-methacryloylpyrrolidin-3- yl)-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol- 4-yl)-2,6-dimethylpiperazine-l -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5R)-l-acryloyl-5-methylpyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-

[0617] 2,6-dimethylpiperazine-l-carboxylate

[0618] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl (2S,6S)-4-(l-((3R,5S)-5-(fluoromethyl)-l-methacryloylpyrrolidin-3- yl)-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol- 4-yl)-2,6-dimethylpiperazine-l -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-l-acryloyl-5-methylpyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-

[0619] 2,6-dimethylpiperazine-l-carboxylate

[0620] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl (2S,6S)-4-(l-((3R,5S)-5-(fluoromethyl)-l-methacryloylpyrrolidin-3- yl)-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol- 4-yl)-2,6-dimethylpiperazine-l -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-l-acryloyl-5-(difluoromethyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-

[0621] 2,6-dimethylpiperazine-l-carboxylate The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl (2S,6S)-4-(l-((3R,5S)-5-(fluoromethyl)-l-methacryloylpyrrohdin-3- yl)-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol- 4-yl)-2,6-dimethylpiperazine-l -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-l-acryloyl-5-(fluoromethyl)pyrrolidin-3-yl)-3- cyclopropyl-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine-l-carboxylate

[0622] Bo

[0623] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl (2S,6S)-4-(l-((3R,5S)-5-(fluoromethyl)-l-methacryloylpyrrolidin-3- yl)-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol- 4-yl)-2,6-dimethylpiperazine-l -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-l-acryloyl-5-(hydroxymethyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)- 2,6-dimethylpiperazine-l-carboxylate

[0624] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl (2S,6S)-4-(l-((3R,5S)-5-(fluoromethyl)-l-methacryloylpyrrolidin-3- yl)-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol- 4-yl)-2,6-dimethylpiperazine-l -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-l-acryloyl-5-((dimethylamino)methyl)pyrrolidin-3-yl)-

[0625] 6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-

[0626] 4-yl)-2,6-dimethylpiperazine-l-carboxylate

[0627] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl (2S,6S)-4-(l-((3R,5S)-5-(fluoromethyl)-l-methacryloylpyrrolidin-3- yl)-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol- 4-yl)-2,6-dimethylpiperazine-l -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-l-acryloyl-5-(chloromethyl)pyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-

[0628] 2,6-dimethylpiperazine-l-carboxylate

[0629] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl (2S,6S)-4-(l-((3R,5S)-5-(fluoromethyl)-l-methacryloylpyrrolidin-3- yl)-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol- 4-yl)-2,6-dimethylpiperazine-l -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-l-acryloyl-5-(2-hydroxypropan-2-yl)pyrrolidin-3-yl)-6- (N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4- yl)-2,6-dimethylpiperazine-l-carboxylate

[0630] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl (2S,6S)-4-(l-((3R,5S)-5-(fluoromethyl)-l-methacryloylpyrrolidin-3- yl)-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol- 4-yl)-2,6-dimethylpiperazine-l -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-l-acryloyl-5-(2-fluoropropan-2-yl)pyrrolidin-3-yl)-6-(N-

[0631] (l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-

[0632] 2,6-dimethylpiperazine-l-carboxylate

[0633] To a stirred solution of tert-butyl (2S,6S)-4-(l-((3R,5S)-l-acryloyl-5-(2-hydroxypropan-2- yl)pyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2-

[0634] (trimethylsilyl)ethoxy)methyl) sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine- 1 - carboxylate (260 mg, 0.335 mmol) in CH2CI2 (5 mL) was added DAST (65 pL) at 0 °C under N2 atmosphere and stirred for 2 h at 25 °C. The reaction mixture was diluted with CH2CI2 (50 mL) and washed with aq.sat.NaHCOs (50 mL). Layers were separated and the organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous Na2SC>4, filtered, and concentrated in vacuo to give 150 mg of a crude compound. This crude residue was purified by combiflash instrument onto a redisep® column with a gradient elution of 0 to 10% of methanol in dichloromethane to afford the title compound (0.1 g) as yellow sticky solid. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-l-acryloyl-5-isopropylpyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-

[0635] 2,6-dimethylpiperazine-l-carboxylate

[0636] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl (2S,6S)-4-(l-((3R,5S)-5-(fluoromethyl)-l-methacryloylpyrrolidin-3- yl)-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol- 4-yl)-2,6-dimethylpiperazine-l -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS. tert-Butyl (2S,6S)-4-(l-((3R,5S)-l-acryloyl-5-(methoxycarbonyl)pyrrolidin-3-yl)-6-(N- (l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-

[0637] 2,6-dimethylpiperazine-l-carboxylate

[0638] The title compound was prepared by following the same reaction protocol as described in the synthesis of tert-butyl (2S,6S)-4-(l-((3R,5S)-5-(fluoromethyl)-l-methacryloylpyrrolidin-3- yl)-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol- 4-yl)-2,6-dimethylpiperazine-l -carboxylate using appropriate starting materials. The title compound was used as-is for the next step as there was no ionization in LCMS.

[0639] EXAMPLES

[0640] Although the invention has been illustrated by certain of the preceding examples, it is not to be construed as being limited thereby; but rather, the invention encompasses the generic area as hereinbefore disclosed. Various modifications and embodiments can be made without departing from the spirit and scope thereof. General procedure 1:

[0641] To a stirred solution of SEM compound (1 eqv.) in CH2CI2 (1-2 mL) was added TFA (2 eqv.) at 0 °C under N2 atmosphere and stirred for 1 h. The reaction mixture was concentrated in vacuo and diluted with CH2CI2 (25 mL) and washed with aq.sat. NaHCOs (25 mL). Layers were separated and the organic layer was washed with brine (25 mL). The organic layer was dried over anhydrous Na2SC>4, filtered, and concentrated in vacuo to give a crude compound. This crude residue was purified by reverse phase preparative HPLC to afford the title compound.

[0642] General procedure 2:

[0643] To a stirred mixture of chloro compound (1 eqv.) and amine (2 eqv.) in 1, 4-dioxane (2-4 mL) was added CS2CO3 (3.5 eqv.) at 25 °C in a sealed tube. The reaction mixture was degassed by purging nitrogen gas for 30 min. RuPhos (0.8 eqv.) and RuPhos-Pd-G3 (0.4 eqv.)) were added in portions. The reaction mixture was again degassed by purging nitrogen gas for 30 min. The resulting mixture was stirred for additional 16 h at 100 °C. The reaction mixture was diluted with EtOAc (50 mL), filtered through celite, and concentrated in vacuo to give a crude compound. This crude residue was purified by combiflash instrument onto a redisep® column with a gradient elution of 0 to 50% of EtOAc in hexane to afford the title compound.

[0644] General procedure 3:

[0645] To a stirred solution of amine (1 eqv.) in CH2CI2 (1 mL) was added NEI3 (1.1 eqv.) at 0 °C under N2 atmosphere and stirred for 5 mins. Acid chloride (2 eqv.) was added and the resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with CH2CI2 (50 mL) and washed with water (50 mL). Layers were separated and the organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a crude compound. This crude residue was purified by reverse phase preparative HPLC to afford the title compound.

[0646] General procedure 4:

[0647] To a stirred solution of amine (1 eqv.), carboxylic acid (1.5 eqv.) in DMF (2 mL) was added HATU (1.5 eqv.) at 25 °C and stirred for 10 mins. DIPEA (3 eqv.) was added under N2 atmosphere and stirred at 25 °C for 10 mins. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (20 mL). Layers were separated and the organic layer was washed with brine (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a crude compound. This crude residue was purified by reverse phase preparative HPLC to afford the title compound.

[0648] General procedure 5:

[0649] To a stirred solution of Boc and SEM protected compound (1 eqv.) in CH2CI2 (1.5 mL) was added trifluoroacetic acid (30 eqv.) at 0 °C and stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuo at 25 °C and co-distilled with toluene (15 mL x 5) to afford the crude compound. This crude residue was purified by reverse phase preparative HPLC to afford the title compound.

[0650] Example 1: 4-(4-(Cyclopropanecarbonyl)piperazin-l-yl)-3-cyclopropyl-l-(5-

[0651] (difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-methylcyclopropyl)-lH-indazole-6- sulfonamide

[0652] Following the General procedure 1, 4-(4-(cyclopropanecarbonyl)piperazin-l-yl)-3- cyclopropyl- 1 -(5-(difluoromethyl)- 1 ,3 ,4-thiadiazol-2-yl)-N-( 1 -methylcyclopropyl)-N-((2-

[0653] ( trimethylsilyl) ethoxy)methyl)-lH-indazole-6-sulfonamide (100 mg) was treated with TFA (0.2mL) to afford the title compound (13mg) as an off white solid. LCMS m / z = 576;JH NMR (400MHz, DMSO-t / 6) 8 8.59 (s, 1H), 8.35 (s, 1H), 7.57 (t, 1H, J = 53.2 Hz), 7.35 (s, 1H), 3.98 (brs, 2H), 3.75 (brs, 2H), 3.23 (brs, 3H), 3.15 (brs, 3H), 2.67 (t, 1H, J = 1.6 Hz), 2.33 (t, 1H, J = 1.6 Hz), 1.23-1.15 (m, 6H), 1.06 (s, 3H), 0.64 (t, 2H, J = 6.4 Hz), 0.40 (t, 2H, 7 = 6.4 Hz).

[0654] Example 2: 4-(4-(Cyclopropanecarbonyl)piperazin-l-yl)-3-cyclopropyl-l-(5-

[0655] (difluoromethyl) -1,3, 4 -thiadiazol-2-yl)-N-(oxetan-3-yl)-lH-indazole-6-sulfonamide

[0656]

[0657] Following the General procedure 2, 4-chloro-3-cyclopropyl-l-(5-(difluoromethyl)-l,3,4- thiadiazol-2-yl)-N-(oxetan-3-yl)-lH-indazole-6-sulfonamide (lOOmg) was treated with cyclopropyl(piperazin-l-yl)methanone (67mg) to afford the title compound (20mg) as an off white solid. LCMS m / z = 580 (M+H); 'H NMR (400MHz, DMSO-de) 8 8.85 (s, 1H), 8.54 (s, 1H), 7.58 (t, 1H, J = 53.2 Hz), 7.29 (s, 1H), 4.50 (t, 3H, J = 6.4 Hz), 4.27 (s, 2H), 3.98 (brs, 2H), 3.76 (brs, 2H), 3.26-3.17 (m, 5H), 2.72-2.67 (m, 1H), 2.08 (s, 1H), 1.23-1.06 (m, 6H). Example 3: N-(l-Cyanocyclopropyl)-4-(4-(cyclopropanecarbonyl)piperazin-l-yl)-3- cyclopropyl-l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-lH-indazole-6-sulfonamide

[0658] Following the General procedure 1, N-(l-cyanocyclopropyl)-4-(4- (cyclopropanecarbonyl)piperazin- 1 -yl)-3 -cyclopropyl- 1 -(5-(difluoromethyl)- 1 ,3 ,4-thiadiazol- 2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole-6-sulfonamide (300 mg) was treated with TFA (3mL) to afford the title compound (lOmg) as an off white solid. LCMS m / z = 589.20 (M+l, 100%);JH NMR (400MHz, DMSO-t6) 8 9.38 (brs, 1H), 8.64 (s, 1H), 7.57 (s, 1H, J = 53.2 Hz), 7.38m(s, 1H), 3.98 (brs, 2H), 3.39-3.18 (m, 6H), 2.73-2.67 (m, 2H), 1.45 (t, 3H, J = 8.8 Hz), 1.33 (t, 2H, J = 8.8 Hz), 0.85-0.74 (m, 5H). Example 4: 4-(4-(Cyclopropanecarbonyl)piperazin-l-yl)-3-cyclopropyl-l-(5- (difluoromethyl) -1,3,4 -thiadiazol-2-yl)-N-(l-methylcyclobutyl)-lH-indazole-6- sulfonamide

[0659] Following the General procedure 1, 4-(4-(cyclopropanecarbonyl)piperazin-l-yl)-3- cyclopropyl- 1 -(5-(difluoromethyl)- 1 ,3 ,4-thiadiazol-2-yl)-N-( 1 -methylcyclobutyl)-N-((2- (trimethylsilyl)ethoxy)methyl)-lH-indazole-6-sulfonamide (300 mg) was treated with TFA (3mL) to afford the title compound (lOmg) as an off white solid. LCMS (No ionization); 'H NMR (400MHz, DMSO-t / 6) 8 8.59 (s, 1H), 8.14 (s, 1H), 7.57 (t, 1H, J = 53.2 Hz), 7.39 (s, 1H), 3.94 (brs, 2H), 3.75 (brs, 2H), 3.23 (brs, 2H), 3.15 (brs, 2H), 2.14-2.07 (m, 4H), 1.67- 1.59 (m, 5H), 1.28 (s, 3H), 1.23-1.17 (m, 7H).

[0660] Example 5: N-(l-Cyanocyclopropyl)-4-(4-(cyclobutanecarbonyl)piperazin-l-yl)-3- cyclopropyl-l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-lH-indazole-6-sulfonamide

[0661] Following the General procedure 1, N-(l-cyanocyclopropyl)-4-(4- (cyclobutanecarbonyl)piperazin- 1 -yl)-3 -cyclopropyl- 1 -(5-(difluoromethyl)- 1 ,3 ,4-thiadiazol- 2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole-6-sulfonamide (300 mg) was treated with TFA (3mL) to afford the title compound (lOmg) as an off white solid. LCMS (No ionization), m / z = 479.20 (M+l, 100%); H NMR (400MHz, DMSO-t / 6) 8.59 (s, 1H), 7.57

[0662] (t, 1H, J = 53.2 Hz), 7.33 (s, 1H), 3.73 (brs, 2H), 3.60 (brs, 2H), 3.16-3.15 (m, 4H), 2.72-2.55 (m, 1H), 2.33-2.08 (m, 4H), 1.95-1.87 (m, 1H), 1.79-1.74 (m, 1H), 1.33 (brs, 2H), 1.23-1.16 (m, 7H).

[0663] Example 6: 4-(4-(Cyclobutanecarbonyl)piperazin-l-yl)-3-cyclopropyl-l-(5-

[0664] (difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-methylcyclopropyl)-lH-indazole-6- sulfonamide

[0665] Following the General procedure 1, 4-(4-(cyclobutanecarbonyl)piperazin-l-yl)-3- cyclopropyl- 1 -(5-(difluoromethyl)- 1 ,3 ,4-thiadiazol-2-yl)-N-( 1 -methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl)-lH-indazole-6-sulfonamide (200 mg) was treated with TFA (2mL) to afford the title compound (18mg) as an off white solid. LCMS m / z = 591.80 (M+l, 100%);JH NMR (400MHz, DMSO-t6) 8 8.59 (s, 1H0, 8.36 (s, 1H), 7.57 (t, 1H, J = 53.2 Hz), 7.33 (s, 1H), 3.73 (brs, 2H), 3.60 (brs, 3H), 3.24 (brs, 5H), 2.68-2.67 (m, 2H), 2.45-2.33 (m, 2H), 1.95-1.87 (m, 1H), 1.79-1.74 (m, 1H), 1.33 (brs, 2H), 1.12-1.16 (m, 9H).

[0666] Example 7: 3-Cyano-N-(l-cyanocyclopropyl)-4-(4-(cyclopropanecarbonyl)piperazin-l- yl)-l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-lH-indazole-6-sulfonamide

[0667] Following the General procedure 1, 3-cyano-N-(l-cyanocyclopropyl)-4-(4- (cyclopropanecarbonyl)piperazin-l-yl)-l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-((2- (trimethylsilyl)ethoxy)methyl)-lH-indazole-6-sulfonamide (300 mg) was treated with TFA (5mL) to afford the title compound (3mg) as an off white solid. LCMS m / z = 574.2 (M+l, 100%);JH NMR (400MHz, DMSO-t / 6) 8 9.58 (s, 1H), 8.75 (s, 1H), 7.66 (t, 1H, J = 53.2

[0668] Hz), 7.47 (s, 1H), 4.02 (brs, 2H), 3.78 (brs, 2H), 2.67 (t, 2H, J = 1.6 Hz), 2.33 (t, 2H, J = 1.6 Hz), 1.49-1.46 (m, 3H), 1.33-1.30 (m, 3H), 0.85-0.75 (m, 3H).

[0669] Example 8: 4-(4-(Azetidine-3-carbonyl)piperazin-l-yl)-N-(l-cyanocyclopropyl)-3- cyclopropyl-l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-lH-indazole-6-sulfonamide

[0670] Following the General procedure 1, tert-butyl 3-(4-(6-(N-(l-cyanocyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl)sulfamoyl)-3-cyclopropyl-l-(5-(difluoromethyl)-l,3,4- thiadiazol-2-yl)- lH-indazol-4-yl)piperazine- 1 -carbonyl)azetidine- 1 -carboxylate (300 mg) was treated with TFA (3mL) to afford the title compound (5mg) as an off white solid. LCMS m / z = 604 (M+l, 100%); ' H NMR (400MHz, DMSO-t6) 8 8.59 (s, 1H), 7.58 (t, 1H, J = 53.2 Hz), 7.34 (s, 1H), 3.82-3.68 (m, 9H), 3.53 (brs, 4H), 3.17 (brs, 5H), 2.72-2.67 (m, 1H), 1.35-1.33 (m, 2H).

[0671] Example 9: N-(l-Cyanocyclopropyl)-3-cyclopropyl-l-(5-(difluoromethyl)-l,3,4- thiadiazol-2-yl)-4-(4-(oxetane-3-carbonyl)piperazin-l-yl)-lH-indazole-6-sulfonamide

[0672] Following the General procedure 1, N-(l-cyanocyclopropyl)-3-cyclopropyl-l-(5- (difluoromethyl)-l,3,4-thiadiazol-2-yl)-4-(4-(oxetane-3-carbonyl)piperazin-l-yl)-N-((2- (trimethylsilyl)ethoxy)methyl)-lH-indazole-6-sulfonamide (100 mg) was treated with TFA (0.2mL) to afford the title compound (13mg) as an off white solid. LCMS m / z = 605.20 (M+l, 100%);JH NMR (400MHz, DMSO-t / 6) 8 9.39 (s, 1H), 8.64 (s, 1H), 7.58 (t, 1H, J = 53.2 Hz), 7.36 (s, 1H), 4.76-4.69 (m, 4H), 4.23-4.19 (m, 1H), 3.78 (brs, 2H), 3.47 (brs, 2H), 3.19 (brs, 4H), 1.47-1.44 (m, 2H), 1.34-1.31 (m, 2H), 1.23-1.15 (m, 6H).

[0673] Example 10: l-(l-(2-Chloroacetyl)pyrrolidin-3-yl)-4-(4-isobutyrylpiperazin-l-yl)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide

[0674] Following the General procedure 3, 4-(4-isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)- l-(pyrrolidin-3-yl)-lH-indazole-6-sulfonamide (50 mg, 0.105 mmol) was treated with chloroacetyl chloride (13.1 mg) to afford the title compound (lOmg) as an off white solid. LCMS m / z = 551, 553.

[0675] This racemic compound was purified by chiral preparative HPLC to give two enantiomers as shown below.

[0676] Example 11: Isomer I:1H NMR (400 MHz, DMSO-t / 6) 8 8.35 (d, J = 8.8 Hz, 1H), 8.08 (s, 1H), 7.74 (d, J = 8.8 Hz, 1H), 6.85 (s, 1H), 5.69-5.57 (m, 1H), 4.39-4.31 (m, 1H), 4.08-3.80 (m, 2H), 3.78-3.68 (m, 6H), 3.64-3.50 (m, 2H), 3.30-3.26 (m, 2H), 2.98-2.90 (m, 1H), 2.43- 2.28 (m, 2H), 1.06-1.02 (m, 9H), 0.65-0.61 (m, 2H), 0.39-0.35 (m, 2H); LCMS m / z = 551, 553.

[0677] Example 12: Isomer II:1H NMR (400 MHz, DMSO-t / 6) 8 8.35 (d, J = 8.8 Hz, 1H), 8.08 (s, 1H), 7.74 (d, J = 8.8Hz, 1H), 6.85 (s, 1H), 5.69-5.57 (m, 1H), 4.39-4.31 (m, 1H), 4.08-3.80 (m, 2H), 3.78-3.68 (m, 6H), 3.64-3.50 (m, 2H), 3.30-3.26 (m, 2H), 2.98-2.90 (m, 1H), 2.43- 2.28 (m, 2H), 1.06-1.02 (m, 9H), 0.65-0.61 (m, 2H), 0.39-0.35 (m, 2H); LCMS m / z = 551, 553.

[0678] Example 13: l-(l-Acryloylpyrrolidin-3-yl)-4-(4-isobutyrylpiperazin-l-yl)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide

[0679] Following the General procedure 3, 4-(4-Isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)- l-(pyrrolidin-3-yl)-lH-indazole-6-sulfonamide (50mg) was treated with acryloyl chloride (llmg) to afford the title compound (7mg) as an off white solid.JH NMR (400 MHz, DMSO-de) 8 8.35 (d, J = 6.8 Hz, 1H), 8.07(s, 1H), 7.74 (d, J = 10 Hz, 1H), 6.86 (s, 1H), 6.70-6.54 (m, 1H), 6.20-6.12 (m, 1H), 5.77-5.56 (m, 2H), 4.16-4.11 (m, 1H), 3.95-3.88 (m, 1H), 3.87-3.64 (m, 6H), 3.63-3.54 (m, 1H), 3.28-3.22 (m, 3H), 2.98-2.88 (m, 1H), 2.44-2.24 (m, 2H), 1.08-1.00 (m, 9H), 0.66-0.60 (m, 2H), 0.40-0.34 (m, 2H); LCMS m / z = 529.

[0680] Example 14: 4-(4-Isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)-l-(l- propionylpyrrolidin-3-yl)-lH-indazole-6-sulfonamide

[0681] Following the General procedure 3, 4-(4-Isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)- l-(pyrrolidin-3-yl)-lH-indazole-6-sulfonamide (50mg) was treated with propionyl chloride (10.7mg) to afford the title compound (12.5mg) as an off white solid. 'H NMR (400 MHz, DMSO-t6) 8 8.34 (d, J = 6.8 Hz, 1H), 8.07 (s, 1H), 7.73 (d, J = 12.8 Hz, 1H), 6.85 (s, 1H), 5.65-5.50 (m, 1H), 4.05-3.95 (m, 1H), 3.90-3.80 (m, 1H), 3.78-3.68 (m, 6H), 3.65-3.55 (m, 1H), 3.28-3.22 (m, 3H), 3.00-2.90 (m, 1H), 2.40-2.20 (m, 4H), 1.08-1.00 (m, 9H), 1.05-0.95 (m, 3H), 0.70-0.60 (m, 2H), 0.40-0.30 (m, 2H); LCMS m / z = 531. Example 15: 4-(4-Isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)-l-(l-

[0682] (vinylsulfonyl)pyrrolidin-3-yl)-lH-indazole-6-sulfonamide

[0683] Following the General procedure 3, 4-(4-Isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)- l-(pyrrolidin-3-yl)-lH-indazole-6-sulfonamide (30mg) was treated with vinylsulphonyl chloride (lOmg) to afford the title compound (14mg) as an off white solid.JH NMR (400 MHz, DMSO-de) 8 8.37 (s, 1H), 8.08 (s, 1H), 7.73 (s, 1H), 6.81 - 6.94 (m, 2H), 6.05 - 6.18 (m, 2H), 5.53 - 5.67 (m, 1H), 3.67 - 3.84 (m, 5H), 3.38 - 3.61 (m, 4H), 3.30 (br. s., 3H), 2.94 (td, J = 6.55, 13.43 Hz, 1H), 2.28 - 2.46 (m, 2H), 0.94 - 1.08 (m, 9H), 0.63 (br. s., 2H), 0.27 - 0.44 (m, 2H); LCMS m / z = 565.

[0684] Example 16: l-(l-(2-Chloroacetyl)piperidin-4-yl)-4-(4-isobutyrylpiperazin-l-yl)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide

[0685] Following the General procedure 3, 4-(4-isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)- l-(piperidin-4-yl)-lH-indazole-6-sulfonamide (50mg) was treated with chloroacetyl chloride (13mg) to afford the title compound (9mg) as an off white solid. ' H NMR (400 MHz, DMSO-t / 6) 5 8.32 (s, 1H), 8.06 (s, 1H), 7.77 (s, 1H), 6.83 (s, 1H), 5.08 (br. s., 1H), 4.39 - 4.53 (m, 3H), 3.99 (d, J = 12.94 Hz, 1H), 3.73 (d, J = 15.35 Hz, 4H), 3.29 (br. s., 3H), 2.87 - 3.03 (m, 2H), 2.04 - 2.16 (m, 2H), 1.98 (d, J = 12.72 Hz, 2H), 1.89 (d, J = 12.94 Hz, 2H), 1.04 (d, J = 6.14 Hz, 9H), 0.63 (br. s., 2H), 0.36 (s, 2H); LCMS m / z = 565, 567.

[0686] Example 17: 4-(4-Isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)-l-(l- propionylpiperidin-4-yl)-lH-indazole-6-sulfonamide

[0687] Following the General procedure 3, 4-(4-isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)- l-(piperidin-4-yl)-lH-indazole-6-sulfonamide (50mg) was treated with propionyl chloride (13mL) to afford the title compound (l lmg) as an off white solid.JH NMR (400 MHz, DMSO-t / 6) 8.31 (s, 1H), 8.06 (s, 1H), 7.77 (s, 1H), 6.83 (s, 1H), 4.99 - 5.12 (m, 1H), 4.54 (d, J = 14.47 Hz, 1H), 4.01 (d, J = 11.84 Hz, 1H), 3.73 (d, J = 15.79 Hz, 4H), 3.36 - 3.42 (m, 2H), 3.28 (d, J = 4.60 Hz, 3H), 2.78 - 3.00 (m, 2H), 2.34 - 2.43 (m, 2H), 1.90 - 2.08 (m, 3H), 1.86 (d, J = 7.89 Hz, 1H), 1.00 - 1.07 (m, 12H), 0.59 - 0.68 (m, 2H), 0.32 - 0.41 (m, 2H); LCMS m / z = 545.

[0688] Example 18: l-(l-(2-Chloroacetyl)piperidin-3-yl)-4-(4-isobutyrylpiperazin-l-yl)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide

[0689] Following the General procedure 3, 4-(4-isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)- l-(piperidin-3-yl)-lH-indazole-6-sulfonamide (50mg) was treated with chloroacetyl chloride (13mg) to afford the title compound (l lmg) as an off white solid. ' H NMR (400 MHz, DMSO-de) 8 8.35 (d, J = 3.2 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.71-7.82 (m, 1H), 6.84 (s, 1H), 4.75-4.98 (m, 1H), 4.46-4.49 (m, 2H), 4.30-4.37 (m, 1H), 3.87-3.98 (m, 1H), 3.72-3.76 (m, 4H), 3.30-3.40 (m, 4H), 3.07-3.18 (m, 2H), 2.81-2.97 (m, 2H), 2.07-2.16 (m, 2H), 1.63- 1.88 (m, 2H), 1.04 (d, J = 6.8 Hz, 9H), 0.57-0.62 (m, 2H), 0.36-0.37 (m, 2H); LCMS m / z = 565, 567.

[0690] Example 19: l-(l-Acryloylpiperidin-3-yl)-4-(4-isobutyrylpiperazin-l-yl)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide

[0691] Following the General procedure 3, 4-(4-isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)- l-(piperidin-3-yl)-lH-indazole-6-sulfonamide (50mg) was treated with acryloyl chloride (llmg) to afford the title compound (7mg) as an off white solid. 'H NMR (400 MHz, DMSO-de) 8 8.348 (s, 1H), 8.03-8.05 (m, 1H), 7.74-7.78 (m, 1H), 6.67-6.92 (m, 2H), 6.04- 6.18 (m, 1H), 5.55-5.74 (m, 2H), 4.54-4.90 (m, 3H), 4.32-4.10 (m, 2H), 3.72-3.76 (m, 4H), 2.87-3.21 (m, 4H), 2.30-2.10 (m, 2H), 1.88-1.93 (m, 1H), 1.68-1.71 (m, 1H), 1.04 (d, J = 6.8 Hz, 9H), 0.63 (s, 2H), 0.37 (s, 2H); LCMS m / z = 543.

[0692] Example 20: 4-(4-Isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)-l-(l- propionylpiperidin-3-yl)-lH-indazole-6-sulfonamide

[0693] Following the General procedure 3, 4-(4-isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)- l-(piperidin-3-yl)-lH-indazole-6-sulfonamide (50mg) was treated with propionyl chloride (0.013mL) to afford the title compound (llmg) as an off white solid.JH NMR (400 MHz, DMSO-de) 8 8.34 (s, 1H), 7.70-8.05 (m, 1H), 6.84 (s, 1H), 4.66-4.93 (m, 1H), 4.30-4.56 (m, 1H), 3.89-3.96 (m, 1H), 3.72-3.76 (m, 4H), 3.28-3.53 (m, 4H), 3.07-3.13 (m, 1H), 2.76-2.78 (m, 1H), 2.36-2.45 (m, 2H), 2.10-2.32 (m, 2H), 1.71-1.88 (m, 2H), 1.04 (d, J = 6.8 Hz, 12H), 0.95 (t, J = 6.8 Hz, 2H), 0.59-0.62 (m, 2H), 0.35-0.39 (m, 2H); LCMS m / z = 545.

[0694] Example 21: l-((l-Acryloylpyrrolidin-3-yl)methyl)-4-(4-isobutyrylpiperazin-l-yl)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide

[0695] Following the General procedure 3, 4-(4-isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)- l-(pyrrolidin-3-ylmethyl)-lH-indazole-6-sulfonamide (lOOmg) was treated with acryloyl chloride (0.025mL) to afford the title compound (25mg) as an off white solid.1H NMR (400 MHz, DMSO-de) 8 8.33 (s, 1H), 8.04 (d, J = 10Hz, 1H), 7.74 (s, 1H), 6.82 (s, 1H), 6.60- 6.42 (m, 1H), 6.13-6.06 (m, 1H), 5.67-5.59 (m, 1H), 4.60-4.51 (m, 2H), 3.81-3.65 (m, 4H), 3.64-3.59 (m, 1H), 3.55-3.40 (m, 3H), 3.20-3.12 (m, 1H), 3.00-2.90 (m, 1H), 2.88-2.78 (m, 1H), 2.75-2.65 (m, 1H), 2.00-1.79 (m, 1H), 1.78-1.60 (m, 2H), 1.30-1.20 (m, 1H), 1.10-0.95 (m, 9H), 0.64-0.58 (m, 2H), 0.40-0.30 (m, 2H); LCMS m / z = 543.

[0696] Example 22: l-((l-(2-Chloroacetyl)pyrrolidin-3-yl)methyl)-4-(4-isobutyrylpiperazin-l- yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0697] Following the General procedure 3, 4-(4-isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)- l-(pyrrolidin-3-ylmethyl)-lH-indazole-6-sulfonamide (lOOmg) was treated with chloroacetyl chloride (0.024mL) to afford the title compound (30mg) as an off white solid.JH NMR (400 MHz, DMSO-de) 8 8.34 (d, J = 2.8 Hz, 1H), 8.03 (d, J 11.6 Hz, 1H), 7.74 (s, 1H), 6.82 (s, 1H), 4.54 (d, J = 6.4 Hz, 1H), 4.27 (s, 1H), 4.22 (s, 1H), 3.80-3.69 (m, 4H), 3.64-3.56 (m, 1H), 3.50-3.35 (m, 2H), 3.34-3.24 (m, 4H), 3.19-3.11 (m, 1H), 3.00-2.90 (m, 1H), 2.88-2.66 (m, 1H), 1.97-1.80 (m, 2H), 1.77-1.58 (m, 1H), 1.08-0.99 (m, 9H), 0.65-0.58 (m, 2H), 0.39- 0.31 (m, 2H).; LCMS m / z = 565, 567.

[0698] Example 23: l-((3R,5S)-l-Acryloyl-5-(fluoromethyl)pyrrolidin-3-yl)-4-(4- isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0699] Following the General procedure 3, l-((3R,5S)-5-(fluoromethyl)pyrrolidin-3-yl)-4-(4- isobutyrylpiperazin- 1 -yl)-N -( 1 -methylcyclopropyl)- lH-indazole-6-sulfonamide ( 150mg) was treated with acryloyl chloride (0.03mL) to afford the title compound (5mg) as an off white solid.1H NMR (400 MHz, DMSO-t6) 8 8.36 (s, 1H), 8.08 (s, 1H), 7.75 (s, 1H), 6.85 (s, 1H), 6.60-6.51 (m, 1H), 6.15 (d, J = 16 Hz, 1H), 5.72-5.63 (m, 2H), 4.70-4.49 (m, 2H), 4.13-4.05 (m, 1H), 3.96-3.87 (m, 1H), 3.79-3.65 (m, 5H), 2.98-2.89 (m, 1H), 1.27-1.20 (m, 4H), 1.10- 0.99 (m, 10H), 0.90-0.80 (m, 1H), 0.66-0.58 (m, 2H), 0.40-0.31 (m, 2H); LCMS m / z = 561.

[0700] Example 24: l-((3R,5S)-l-(2-Chloroacetyl)-5-(fluoromethyl)pyrrolidin-3-yl)-4-(4- isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0701] Following the General procedure 3, l-((3R,5S)-5-(fluoromethyl)pyrrolidin-3-yl)-4-(4- isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide (250mg) was treated with chloroacetyl chloride (61.38mL) to afford the title compound (24mg) as an off white solid.JH NMR (400 MHz, DMSO-t / 6) 8 8.37 (s, 1H), 8.08 (s, 1H), 7.75 (s, 1H), 6.86 (s, 1H), 5.71-5.65 (m, 1H), 4.72-4.63 (m, 1H), 4.55-4.42 (m, 2H), 4.07-3.99 (m, 1H), 3.90- 3.82 (m, 1H), 3.79-3.66 (m, 4H), 3.32-3.25 (m, 4H), 2.93 (septet, J = 6.4Hz, 1H), 1.26-1.21 (m, 2H), 1.04 (d, J =6.4Hz, 6H), 1.03-1.01 (m, 4H), 0.88-0.82 (m, 1H), 0.66-0.60 (m, 2H), 0.40-0.34 (m, 2H); LCMS m / z = 583, 585.

[0702] Example 25: l-((3S,5R)-l-Acryloyl-5-(fluoromethyl)pyrrolidin-3-yl)-4-(4- isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0703] Following the General procedure 3, 1-((3S, 5R)-5-(fluoromethyl)pyrrolidin-3-yl)-4-(4- isobutyrylpiperazin- 1 -yl)-N -( 1 -methylcyclopropyl)- lH-indazole-6-sulfonamide (200mg) was treated with acryloyl chloride (35mL) to afford the title compound (14mg) as an off white solid.JH NMR (400 MHz, DMSO-t / 6) 8 8.36 (s, 1H), 8.08 (s, 1H), 7.75 (s, 1H), 6.85 (s, 1H), 6.60-6.51 (m, 1H), 6.15 (d, J = 16 Hz, 1H), 5.72-5.63 (m, 2H), 4.70-4.49 (m, 2H), 4.13-4.05 (m, 1H), 3.96-3.87 (m, 1H), 3.79-3.65 (m, 5H), 2.98-2.89 (m, 1H), 1.27-1.20 (m, 4H), 1.10- 0.99 (m, 10H), 0.90-0.80 (m, 1H), 0.66-0.58 (m, 2H), 0.40-0.31 (m, 2H); LCMS m / z = 561.

[0704] Example 26: l-((3S,5R)-l-(2-Chloroacetyl)-5-(fluoromethyl)pyrrolidin-3-yl)-4-(4- isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0705] Following the General procedure 3, 1-((3S, 5R)-5-(fluoromethyl)pyrrolidin-3-yl)-4-(4- isobutyrylpiperazin- 1 -yl)-N -( 1 -methylcyclopropyl)- lH-indazole-6-sulfonamide (200mg) was treated with chloroacetyl chloride (34mL) to afford the title compound (18.8mg) as an off white solid. ' H NMR (400 MHz, DMSO-t6) 8 8.37 (s, 1H), 8.08 (s, 1H), 7.75 (s, 1H), 6.86 (s, 1H), 5.71-5.65 (m, 1H), 4.72-4.63 (m, 1H), 4.55-4.42 (m, 2H), 4.07-3.99 (m, 1H), 3.90- 3.82 (m, 1H), 3.79-3.66 (m, 4H), 3.32-3.25 (m, 4H), 2.93 (septet, J = 6.4Hz, 1H), 1.26-1.21 (m, 2H), 1.04 (d, J=6.4Hz, 6H), 1.03-1.01 (m, 4H), 0.88-0.82 (m, 1H), 0.66-0.60 (m, 2H), 0.40-0.34 (m, 2H); LCMS m / z = 583, 585.

[0706] Example 27: l-((3S,5R)-l-Acryloyl-5-(fluoromethyl)pyrrolidin-3-yl)-4-((3R,5S)-4- isobutyryl-3,5-dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6- sulfonamide

[0707] Following the General procedure 3, l-((3S,5R)-5-(fluoromethyl)pyrrolidin-3-yl)-4-((3R,5S)- 4-isobutyryl-3 ,5-dimethylpiperazin- 1 -yl)-N -( 1 -methylcyclopropyl)- lH-indazole-6- sulfonamide (45mg) was treated with acryloyl chloride (8mL) to afford the title compound (3mg) as an off white solid. 'H NMR (400 MHz, DMSO-t / 6) 8 8.17 (s, 1H), 8.11 (s, 1H), 6.89 (s, 1H), 6.61-6.51 (m, 1H), 6.21-6.13 (m 2H), 5.25-5.13 (m, 2H), 4.85-4.49 (m, 4H), 4.35-4.22 (m, 1H), 4.13-4.06 (m, 1H), 3.98-3.91 (m, 1H), 3.69-3.58 (m, 2H), 3.08-2.98 (m, 1H), 2.94-2.82 (m, 2H), 1.47-1.40 (m, 2H), 1.39-1.29 (m, 2H), 1.24-1.20 (m, 2H), 1.50-1.00 (m, 11H), 0.68-0.60 (m, 2H), 0.42-0.36 (m, 2H).; LCMS m / z = 589.

[0708] Example 28: l-((3S,5S)-l-Acryloyl-5-(fluoromethyl)pyrrolidin-3-yl)-4-(4- isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0709] Following the General procedure 3, l-((3S,5S)-5-(fluoromethyl)pyrrolidin-3-yl)-4-(4- isobutyrylpiperazin- 1 -yl)-N -( 1 -methylcyclopropyl)- lH-indazole-6-sulfonamide (200mg) was treated with acryloyl chloride (35mg) to afford the title compound (6mg) as an off white solid.1H NMR (400 MHz, DMSO-t / 6) 8 8.39 (s, 1H), 8.07 (s, 1H), 7.79 (s, 1H), 6.85 (s, 1H),

[0710] 6.70-6.60 (m, 1H), 6.25-6.15 (m, 1H), 5.77-5.70 (m, 1H), 5.62-5.50 (m, 1H), 4.70-4.62 (m, 1H), 4.45-4.35 (m, 1H), 3.85-3.78 (m, 1H), 3.76-3.68 (m, 4H), 2.94 (septet, J = 6.4 Hz, 1H), 1.38-1.32 (m, 5H), 1.10-1.00 (m, 10H), 0.88-0.82 (m, 2H), 0.66-0.60 (m, 2H), 0.40-0.34 (m, 2H); LCMS m / z = 561.

[0711] Example 29: l-((3R,5R)-l-Acryloyl-5-(fluoromethyl)pyrrolidin-3-yl)-4-(4- isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0712] Following the General procedure 3, l-((3R,5R)-5-(fluoromethyl)pyrrolidin-3-yl)-4-(4- isobutyrylpiperazin- 1 -yl)-N -( 1 -methylcyclopropyl)- lH-indazole-6-sulfonamide (220mg) was treated with acryloyl chloride (38.6mL) to afford the title compound (13mg) as an off white solid.JH NMR (400 MHz, DMSO-t / 6) 8 8.40 (s, 1H), 8.07 (s, 1H), 7.79 (s, 1H), 6.85 (s, 1H), 6.70-6.60 (m, 1H), 6.25-6.15 (m, 1H), 5.77-5.70 (m, 1H), 5.62-5.50 (m, 1H), 4.70-4.62 (m, 1H), 4.45-4.35 (m, 1H), 3.85-3.78 (m, 1H), 3.76-3.68 (m, 4H), 2.94 (septet, J = 6.4 Hz, 1H), 1.38-1.32 (m, 5H), 1.10-1.00 (m, 10H), 0.88-0.82 (m, 2H), 0.66-0.60 (m, 2H), 0.40-0.34 (m, 2H); LCMS m / z = 561.

[0713] Example 30: l-(l-Acryloylpyrrolidin-3-yl)-N-(l-methylcyclopropyl)-4-((3R,5S)-3,4,5- trimethylpiperazin-l-yl)-lH-indazole-6-sulfonamide

[0714] Following the General procedure 3, N-(l-methylcyclopropyl)-l-(pyrrolidin-3-yl)-4-((3R,5S)- 3,4,5-trimethylpiperazin-l-yl)-lH-indazole-6-sulfonamide (50mg) was treated with acryloyl chloride (11.16mg) to afford the title compound (4mg) as an off white solid. ' H NMR (400 MHz, DMSO-de) 8 8.30 (d, J = 6 Hz, 1H), 8.10 (s, 1H), 7.70 (d, J = 8.8 Hz, 1H), 6.80 (s, 1H), 6.70-6.53 (m, 1H), 6.21-6.12 (m, 1H), 5.74-5.62 (m, 1H), 5.59-5.53 (m, 1H), 4.16-4.10 (m, 1H), 3.94-3.74 (m, 4H), 3.65-3.55 (m, 4H), 2.65-2.55 (m, 2H), 2.45-2.32 (m, 4H), 1.10 (d, J = 6 Hz, 6H), 1.03 (s, 3H), 0.65-0.58 (m, 2H), 0.40-0.32 (m, 2H); LCMS' m / z = 501.

[0715] Example 31: l-(l-Acryloylpyrrolidin-3-yl)-N-(l-methylcyclopropyl)-4-((3S,5S)-3,4,5- trimethylpiperazin-l-yl)-lH-indazole-6-sulfonamide

[0716] Following the General procedure 3, N-(l-methylcyclopropyl)-l-(pyrrolidin-3-yl)-4-((3S,5S)- 3,4,5-trimethylpiperazin-l-yl)-lH-indazole-6-sulfonamide (135mg) was treated with acryloyl chloride (27mL) to afford the title compound (7mg) as an off white solid.JH NMR (400 MHz, DMSO-de) 8 8.30 (d, J = 6 Hz, 1H), 8.10 (s, 1H), 7.70 (d, J = 8.8 Hz, 1H), 6.80 (s, 1H), 6.70-6.53 (m, 1H), 6.21-6.12 (m, 1H), 5.74-5.62 (m, 1H), 5.59-5.53 (m, 1H), 4.16-4.10 (m, 1H), 3.94-3.74 (m, 4H), 3.65-3.55 (m, 4H), 2.65-2.55 (m, 2H), 2.45-2.32 (m, 4H), 1.10 (d, J = 6 Hz, 6H), 1.03 (s, 3H), 0.65-0.58 (m, 2H), 0.40-0.32 (m, 2H).; LCMS' m / z = 501.

[0717] Example 32: l-(l-(2-Chloroacetyl)pyrrolidin-3-yl)-N-(l-methylcyclopropyl)-4-((3S,5S)-

[0718] 3,4,5-trimethylpiperazin-l-yl)-lH-indazole-6-sulfonamide

[0719] Following the General procedure 3, N-(l-methylcyclopropyl)-l-(pyrrolidin-3-yl)-4-((3S,5S)- 3,4,5-trimethylpiperazin-l-yl)-lH-indazole-6-sulfonamide (135mg) was treated with chloroacetyl chloride (25.34mL) to afford the title compound (3.5mg) as an off white solid. ' H NMR (400 MHz, DMSO-t6) 8 8.31 (d, J = 6 Hz, 1H), 8.10 (s, 1H), 7.81 (d, J = 7.2 Hz, 1H), 5.71-5.55 (m, 1H), 4.37 (d, J = 2 Hz, 1H), 4.30 (s, 1H), 4.10-4.03 (m, 1H), 3.92-3.80 (m, 2H), 3.78-3.64 (m, 4H), 3.61-3.52 (m, 2H), 2.80-2.71 (m, 3H), 1.44-1.31 (m, 6H), 1.26-1.20 (m, 4H), 1.04 (s, 3H), 0.70-0.59 (m, 2H), 0.41-0.34 (m, 2H); LCMS' m / z = 523, 525.

[0720] Example 33: l-(l-Acryloylpyrrolidin-3-yl)-4-((3R,5S)-3,5-dimethyl-4-(oxetan-3- yl)piperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0721] Following the General procedure 3, 4-((3R,5S)-3,5-dimethyl-4-(oxetan-3-yl)piperazin-l-yl)- N-( 1 -methylcyclopropyl)- 1 -(pyrrolidin-3-yl)- lH-indazole-6-sulfonamide ( 150mg) was treated with acryloyl chloride (0.025mL) to afford the title compound (14mg) as an off white solid.JH NMR (400 MHz, DMSO-t / 6) 8 8.25 (d, J = 6 Hz, 1H), 8.04 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 6.72 (s, 1H), 6.69-6.53 (m, 1H), 6.19-6.11 (m, 1H), 5.72-5.60 (m, 1H), 5.54-5.48 (m, 1H), 4.61-4.52 (m, 4H), 4.17-4.09 (m, 1H), 3.93-3.74 (m, 2H), 3.70-3.55 (m, 1H), 3.45- 3.39 (m, 2H), 3.30-3.22 (m, 3H), 2.98-2.88 (m, 2H), 2.41-2.22 (m, 2H), 1.10-1.08 (m, 9H), 0.66-0.58 (m, 2H), 0.40-0.33 (m, 2H); LCMS' m / z = 543.

[0722] Example 34: l-(l-(2-Chloroacetyl)pyrrolidin-3-yl)-4-((3R,5S)-3,5-dimethyl-4-(oxetan-3- yl)piperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0723] Following the General procedure 3, 4-((3R,5S)-3,5-dimethyl-4-(oxetan-3-yl)piperazin-l-yl)- N-( 1 -methylcyclopropyl)- 1 -(pyrrolidin-3-yl)- lH-indazole-6-sulfonamide (200mg) was treated with chloroacetyl chloride (36mL) to afford the title compound (19mg) as an off white solid.1H NMR (400 MHz, DMSO-t6) 8 8.26 (d, J = 8.4 Hz, 1H), 8.05 (s, 1H), 7.60 (d, J = 9.6 Hz, 1H), 5.65-5.50 (m, 1H), 4.61-4.52 (m, 4H), 4.40-4.38 (m, 1H), 4.31 (s, 1H), 4.18-4.14 (m, 3H), 3.90-3.70 (m, 2H), 3.46-3.39 (m, 3H), 3.30-3.22 (m, 3H), 2.98-2.88 (m, 2H), 1.12- 1.02 (m, 10H), 0.68-0.62 (m, 2H), 0.40-0.34 (m, 2H).; LCMS' m / z = 565, 567.

[0724] Example 35: l-(l-Acryloylpyrrolidin-3-yl)-4-((3R,5S)-4-ethyl-3,5-dimethylpiperazin-l- yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0725] Following the General procedure 3, 4-((3R, 5S)-4-ethyl-3,5-dimethylpiperazin-l-yl)-N-(l- methylcyclopropyl)-l-(pyrrolidin-3-yl)-lH-indazole-6-sulfonamide (230mg) was treated with acryloyl chloride (44.4mL) to afford the title compound (8mg) as an off white solid.1H NMR (400 MHz, DMSO-de) 8.37-8.34 (m, 1H), 8.12 (s, 1H), 8.09 (s, 1H), 7.76- 7.72 (m, 1H), 6.80 (s, 1H), 6.70-6.53 (m, 1H), 6.21-6.12 (m, 1H), 5.74-5.62 (m, 1H), 5.59-5.53 (m, 1H), 4.16-4.10 (m, 1H), 3.94-3.74 (m, 4H), 3.65-3.55 (m, 4H), 2.65-2.55 (m, 2H), 2.45-2.32 (m, 2H), 1.10 (d, J = 6 Hz, 6H), 1.03 (s, 3H), 1.02-1.00 (m, 3H), 0.65-0.58 (m, 2H), 0.40-0.32 (m, 2H); LCMS m / z = 515.

[0726] Example 36: l-(l-(2-Chloroacetyl)pyrrolidin-3-yl)-4-((3R,5S)-4-ethyl-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0727] Following the General procedure 3, 4-((3R,5S)-4-ethyl-3,5-dimethylpiperazin-l-yl)-N-(l- methylcyclopropyl)-l-(pyrrolidin-3-yl)-lH-indazole-6-sulfonamide (230mg) was treated with chloroacetyl chloride (43.74mL) to afford the title compound (8mg) as an off white solid.JH NMR (400 MHz, DMSO-t / 6) 8 8.37-8.34 (m, 1H), 8.12 (s, 1H), 8.09 (s, 1H), 7.76- 7.72 (m, 1H), 6.80 (s, 1H), 5.59-5.53 (m, 1H), 4.16-4.10 (m, 1H), 3.94-3.74 (m, 2H), 3.65-3.55 (m, 4H), 2.65-2.55 (m, 3H), 2.45-2.32 (m, 4H), 1.10 (d, J = 6 Hz, 6H), 1.03 (s, 3H), 1.02-1.00 (m, 3H), 0.90-0.80 (m, 1H), 0.65-0.58 (m, 2H), 0.40-0.32 (m, 2H); LCMS m / z = 537, 539.

[0728] Example 37: l-(l-Acryloylpyrrolidin-3-yl)-4-((3R,5S)-4-cyclopropyl-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0729] Following the General procedure 3, 4-((3R,5S)-4-cyclopropyl-3,5-dimethylpiperazin-l-yl)-N- (l-methylcyclopropyl)-l-(pyrrolidin-3-yl)-lH-indazole-6-sulfonamide (300mg) was treated with acryloyl chloride (0.056mL) to afford the title compound (5mg) as an off white solid.1H NMR (400 MHz, DMSO-de) 8 8.30 (s, 1H), 8.08 (s, 1H), 7.68 (d, J = 8 Hz, 1H), 7.36-7.29

[0730] (m, 1H), 7.28-7.21 (m, 1H), 6.78 (bs, 1H), 6.70-6.52 (m, 1H), 6.21-6.13 (m, 1H), 5.76-5.52 (m, 2H), 4.29-4.21 (m, 1H), 4.36-4.30 (m, 1H), 3.96-3.84 (m, 2H), 3.83-3.74 (m, 2H), 3.62- 3.50 (m, 4H), 2.84-2.76 (m, 2H), 2.75-2.64 (m, 2H), 1.56-1.48 (m, 1H), 1.34-1.20 (m, 9H), 0.66-0.58 (m, 2H), 0.40-0.34 (m, 2H); LCMS m / z = 527 .

[0731] Example 38: l-(l-(2-Chloroacetyl)pyrrolidin-3-yl)-4-((3R,5S)-4-cyclopropyl-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0732] Following the General procedure 3, 4-((3R,5S)-4-cyclopropyl-3,5-dimethylpiperazin-l-yl)-N- (l-methylcyclopropyl)-l-(pyrrolidin-3-yl)-lH-indazole-6-sulfonamide (300mg) was treated with chloroacetyl chloride (0.0556mL) to afford the title compound (6mg) as an off white solid.JH NMR (400 MHz, DMSO-t / 6) 8 8.32 (d, J = 7.6 Hz, 1H), 8.08 (s, 1H), 7.68 (d, J = 9.2 Hz, 1H), 6.78 (s, 1H), 5.69-5.52 (m, 1H), 4.37 (bs, 1H), 4.31 (s, 1H), 3.92-3.80 (m, 1H), 3.79-3.64 (m, 1H), 3.60-3.52 (m, 2H), 2.84-2.66 (m, 3H), 2.60-2.56 (m, 2H), 2.41-2.24 (m, 3H), 1.30-1.20 (m, 10H), 0.64-0.61 (m, 2H), 0.61-0.56 (m, 2H), 0.50-0.42 (m, 2H), 0.32-0.38 (m, 2H); LCMS m / z = 549, 551.

[0733] Example 39: l-((3R,5S)-l-Acryloyl-5-(fluoromethyl)pyrrolidin-3-yl)-N-(l- methylcyclopropyl)-4-((3S,5S)-3,4,5-trimethylpiperazin-l-yl)-lH-indazole-6- sulfonamide

[0734] Following the General procedure 3, l-((3R,5S)-5-(fluoromethyl)pyrrolidin-3-yl)-N-(l- methylcyclopropyl)-4-((3S,5S)-3,4,5-trimethylpiperazin-l-yl)-lH-indazole-6-sulfonamide (275mg) was treated with acryloyl chloride (0.05mL) to afford the title compound (16.7mg) as an off white solid. ' H NMR (400 MHz, DMSO-t6) 8 8.20 - 8.27 (m, 1H), 8.12 - 8.17 (m, 1H), 8.09 (s, 1H), 7.68 - 7.77 (m, 1H), 6.82 (s, 1H), 6.74 (dd, J = 10.19, 16.55 Hz, 1H), 6.56 (dd, J = 10.19, 16.33 Hz, 1H), 6.09 - 6.23 (m, 1H), 5.59 - 5.74 (m, 1H), 4.73 - 4.89 (m, 1H), 4.66 (d, J = 11.40 Hz, 1H), 4.45 - 4.60 (m, 2H), 4.27 (t, J = 6.14 Hz, 1H), 4.09 (dd, J = 6.80, 11.62 Hz, 1H), 3.92 (dd, J = 5.04, 11.84 Hz, 1H), 3.26 (br. s., 4H), 2.61 (t, J = 6.25 Hz, 1H), 2.24 - 2.34 (m, 3H), 1.07 - 1.16 (m, 6H), 1.05 (s, 3H), 0.55 - 0.72 (m, 2H), 0.37 (s, 2H); LCMS m / z = 533.

[0735] Example 40: l-(l-(But-2-ynoyl)pyrrolidin-3-yl)-4-(4-isobutyrylpiperazin-l-yl)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide

[0736] Following the General procedure 4, 4-(4-isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)- l-(pyrrolidin-3-yl)-lH-indazole-6-sulfonamide (50mg) was treated with but-2-ynoic acid (14mg) to afford the title compound (l lmg) as an off white solid.JH NMR (400 MHz, DMSO-de) 8 8.36 (d, J = 2.4 Hz, 1H), 8.07 (s, 1H), 7.73 (d, J = 10 Hz, 1H), 6.85 (s, 1H), 5.65-5.55 (m, 1H), 4.15-4.05 (m, 1H), 3.95-3.68 (m, 6H), 3.66-3.45 (m, 2H), 3.28-3.25 (m, 3H), 3.00-2.90 (m, 1H), 2.48-2.25 (m, 2H), 2.10-1.90 (m, 3H), 1.10-0.95 (m, 9H), 0.65-0.55 (m, 2H), 0.40-0.30 (m, 2H); LCMS m / z = 541.

[0737] Example 41: 4-(4-Isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)-l-(l- propioloylpyrrolidin-3-yl)-lH-indazole-6-sulfonamide

[0738] Following the General procedure 4, 4-(4-isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)- l-(pyrrolidin-3-yl)-lH-indazole-6-sulfonamide (lOOmg) was treated with propiolic acid (22mg) to afford the title compound (8mg) as an off white solid.JH NMR (400 MHz, DMSO-t / 6) 8.36 (s, 1H), 8.07 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 6.85 (s, 1H), 5.65-5.58 (m, 1H), 4.55-4.44 (m, 1H), 4.20-3.95 (m, 1H), 3.90-3.80 (m, 2H), 3.80-3.50 (m, 6H), 3.80-3.25 (m, 3H), 3.00-2.88 (m, 1H), 2.48-2.25 (m, 2H), 1.10-1.00 (m, 9H), 0.68-0.60 (m, 2H), 0.40- 0.34 (m, 2H); LCMS m / z = 527.

[0739] Example 42: (E)-l-(l-(4-(Dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-4-(4- isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0740] Following the General procedure 4, 4-(4-isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)- l-(pyrrolidin-3-yl)-lH-indazole-6-sulfonamide (50mg) was treated with (E)-4- (dimethylamino)but-2-enoic acid (26.2mg) to afford the title compound (5.2mg) as an off white solid.1H NMR (400 MHz, DMSO-t6) 8 8.34 (d, J = 6.8 Hz, 1H), 8.22 (s, 1H), 8.08 (s, 1H), 7.74 (d, J = 10.8 Hz, 1H), 6.85 (s, 1H), 6.70-6.58 (m, 1H), 6.46-6.33 (m, 1H), 5.68-5.52 (m, 1H), 4.16-4.06 (m, 1H), 3.96-3.82 (m, 2H), 3.80-3.56 (m, 6H), 3.38-3.24 (m, 2H), 3.08- 2.98 (m, 2H), 2.96-2.90 (m, 1H), 2.44-2.26 (m, 2H), 2.17 (s, 3H), 2.13 (s, 3H), 1.06-1.02 (m, 9H), 0.66-0.60 (m, 2H), 0.40-0.34 (m, 2H); LCMS m / z = 586.

[0741] Example 43: l-(l-(2-Fluoroacryloyl)pyrrolidin-3-yl)-4-(4-isobutyrylpiperazin-l-yl)-N- (l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0742] Following the General procedure 4, 4-(4-isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)- l-(pyrrolidin-3-yl)-lH-indazole-6-sulfonamide (50mg) was treated with 2-fluoroacrylic acid (14.2mg) to afford the title compound (8mg) as an off white solid. 'H NMR (400 MHz, DMSO-t / 6) 8.36 (s, 1H), 8.06 (s, 1H), 7.74 (s, 1H), 6.85 (s, 1H), 5.65-5.55 (m, 1H), 5.50- 5.32 (m, 2H), 4.20-3.84 (m, 3H), 3.78-3.68 (m, 4H), 3.68-3.58 (m, 2H), 3.28-3.24 (m, 3H), 2.98-2.90 (m, 1H), 2.44-2.24 (m, 2H), 1.06-1.02 (m, 9H), 0.66-0.60 (m, 2H), 0.38-0.32 (m, 2H); LCMS m / z = 547.

[0743] Example 44: l-(l-Acryloylpiperidin-4-yl)-4-(4-isobutyrylpiperazin-l-yl)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide

[0744] Following the General procedure 4, 4-(4-isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)- l-(piperidin-4-yl)-lH-indazole-6-sulfonamide (45mg) was treated with acrylic acid (lOmL) to afford the title compound (15mg) as an off white solid.JH NMR (400 MHz, DMSO-de) 5 8.31 (s, 1H), 8.06 (s, 1H), 7.774 (s, 1H), 6.85-6.92 (m, 1H), 6.83 (s, 1H), 6.12-6.16 (m, 1H), 5.68-5.77 (m, 1H), 5.08-5.10 (m, 1H), 4.56 (d, J = 12.4 Hz, 2H), 4.21 (d, J = 12.8 Hz, 1H), 3.70-3.75 (m, 4H), 3.27-3.40 (m, 4H), 2.90-2.97 (m, 2H), 1.92-1.98 (m, 4H), 1.03-1.04 (m, 9H), 0.63 (s, 2H), 0.36 (s, 2H); LCMS m / z = 543.

[0745] Example 45: (E)-l-(l-(4-(Dimethylamino)but-2-enoyl)piperidin-3-yl)-4-(4- isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0746] Following the General procedure 4, 4-(4-isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)- l-(piperidin-3-yl)-lH-indazole-6-sulfonamide (50mg) was treated with (E)-4- (dimethylamino)but-2-enoic acid (24.84mg) to afford the title compound (16mg) as an off white solid.JH NMR (400 MHz, DMSO-t / 6) 8 8.34 (s, 1H), 8.19 (s, 1H), 8.05 (s, 1H), 7.74- 7.77 (m, 1H), 6.85 (s, 1H), 6.51-6.68 (m, 2H), 4.76-4.90 (m, 1H), 4.54-4.57 (m, 1H), 4.27- 4.30 (m, 1H), 4.08-4.16 (m, 2H), 3.72-3.76 (m, 4H), 3.29-3.39 (m, 4H), 3.06-3.96 (m, 3H), 2.91-2.99 (m, 3H), 2.20 (s, 2H), 2.10 (s, 2H), 1.88-1.91 (m, 1H), 1.67 (br s, 1H), 1.04 (d, J = 6.4 Hz, 9H), 0.64 (s, 2H), 0.37 (s, 2H); LCMS m / z = 600.

[0747] Example 46: l-(l-(2-Fluoroacryloyl)piperidin-3-yl)-4-(4-isobutyrylpiperazin-l-yl)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide

[0748] Following the General procedure 4, 4-(4-isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)- l-(piperidin-3-yl)-lH-indazole-6-sulfonamide (50mg) was treated with 2-fluoroacrylic acid (13.8mg) to afford the title compound (7mg) as an off white solid. 'H NMR (400 MHz, DMSO-t / 6) 8.35 (s, 1H), 8.04 (s, 1H), 7.75 (s, 1H), 6.85 (s, 1H), 5.13-5.32 (m, 3H), 3.95 (br s, 2H), 3.58-3.75 (m, 4H), 2.91-2.97 (m, 4H), 2.09-2.33 (m, 3H), 1.92-1.98 (m, 2H), 1.73 (br s, 2H), 1.04 (d, J = 6.4 Hz, 9H), 0.58-0.66 (m, 2H), 0.36 (s, 2H); LCMS m / z = 561.

[0749] Example 47: l-(l-(But-2-ynoyl)piperidin-3-yl)-4-(4-isobutyrylpiperazin-l-yl)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide

[0750] Following the General procedure 4, 4-(4-isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)- l-(piperidin-3-yl)-lH-indazole-6-sulfonamide (50mg) was treated with but-2-ynoic acid (13mg) to afford the title compound (18mg) as an off white solid. 'H NMR (400 MHz, DMSO-de) 8 8.35 (s, 1H), 8.06 (d, J = 12.4 Hz, 1H), 7.75 (d, J = 14.4 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 4.82-4.94 (m, 1H), 4.15-4.32 (m, 2H), 3.71-3.75 (m, 4H), 3.56-3.62 (m, 2H), 3.37-3.39 (m, 1H), 3.16-3.32 (m, 1H), 2.91-2.99 (m, 2H), 2.22-2.32 (m, 2H), 2.13-2.18 (m, 1H), 2.06-2.10 (m, 2H), 1.85 (s, 3H), 1.04 (d, J = 7.2 Hz, 9H), 0.64 (s, 2H), 0.39 (s, 2H); LCMS m / z = 555.

[0751] Example 48: 4-(4-Isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)-l-((l- propioloylpyrrolidin-3-yl)methyl)-lH-indazole-6-sulfonamide

[0752] Following the General procedure 4, 4-(4-isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)- l-(pyrrolidin-3-ylmethyl)-lH-indazole-6-sulfonamide (lOOmg) was treated with propiolic acid (22mg) to afford the title compound (20mg) as an off white solid.JH NMR (400 MHz, DMSO-de) 8 8.35 (d, J = 5.6 Hz, 1H), 8.03 (d, J = 5.6 Hz, 1H), 7.77 (d, J = 4.4 Hz, 1H), 6.82 (s, 1H), 4.60-4.54 (m, 4H), 3.80-3.68 (m, 5H), 3.49-3.39 (m, 1H), 3.31-3.22 (m, 4H), 3.10-3.17 (m, 1H), 2.94 (septet, J = 6.4 Hz, 1H), 2.83-2.71 (m, 1H), 1.96-1.84 (m, 1H), 1.78- 1.62 (m, 1H), 1.04 (d, J = 6.4 Hz, 6H), 1.01 (s, 3H), 0.62-0.59 (m, 2H), 0.38-0.32 (m, 2H).;

[0753] LCMS m / z = 541.

[0754] Example 49: l-((3R,5S)-5-(Fluoromethyl)-l-propioloylpyrrolidin-3-yl)-4-(4- isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0755] Following the General procedure 4, l-((3R,5S)-5-(fluoromethyl)pyrrolidin-3-yl)-4-(4- isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide (50mg) was treated with propiolic acid (10.38mg) to afford the title compound (7mg) as an off white solid. ' H NMR (400 MHz, DMSO-t6) 8 8.37 (s, 1H), 8.08 (s, 1H), 7.75 (s, 1H), 6.85 (s, 1H), 5.72-5.60 (m, 1H), 4.82-4.62 (m, 3H), 4.60-4.41 (m, 3H), 4.09-4.01 (m, 2H), 3.78-3.68 (m, 5H), 2.93 (septet, J = 6.4Hz, 1H), 1.26-1.20 (m, 2H), 1.04 (d, J = 6.4Hz, 6H), 1.03 (s, 3H), 0.88-0.82 (m, 1H), 0.66-0.60 (m, 2H), 0.40-0.34 (m, 2H); LCMS m / z = 559.

[0756] Example 50: l-((3S,5R)-5-(Fluoromethyl)-l-propioloylpyrrolidin-3-yl)-4-(4- isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0757] Following the General procedure 4, l-((3S,5R)-5-(fluoromethyl)pyrrolidin-3-yl)-4-(4- isobutyrylpiperazin- 1 -yl)-N -( 1 -methylcyclopropyl)- lH-indazole-6-sulfonamide (200mg) was treated with propiolic acid (36mL) to afford the title compound (16.8mg) as an off white solid.JH NMR (400 MHz, DMSO-t / 6) 8 8.37 (s, 1H), 8.08 (s, 1H), 7.75 (s, 1H), 6.85 (s, 1H), 5.72-5.60 (m, 1H), 4.82-4.62 (m, 3H), 4.60-4.41 (m, 3H), 4.09-4.01 (m, 2H), 3.78-3.68 (m, 5H), 2.93 (septet, J = 6.4Hz, 1H), 1.26-1.20 (m, 2H), 1.04 (d, J = 6.4Hz, 6H), 1.03 (s, 3H), 0.88-0.82 (m, 1H), 0.66-0.60 (m, 2H), 0.40-0.34 (m, 2H); LCMS m / z = 559.

[0758] Example 51: l-(l-(2-Chloroacetyl)pyrrolidin-3-yl)-4-((3R,5S)-3,5-dimethylpiperazin-l- yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0759] Following the General procedure 4, tert-butyl (2R,6S)-4-(l-(l-(2-chloroacetyl)pyrrolidin-3- yl)-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol- 4-yl)-2,6-dimethylpiperazine-l -carboxylate (90mg) was treated with trifluoroacetic acid (0.28mL) to afford the title compound (17 mg) as an off white solid. ' H NMR (400 MHz, DMSO-t / 6) 5 9.09 (br s, 1H), 8.47 (d, J = 6.0 Hz, 1H), 8.10 (s, 1H), 7.83 (d, J = 8.8 Hz, 1H), 6.91 (s, 1H), 5.61-5.69 (m, 1H), 4.37 (s, 2H), 3.73-3.91 (m, 4H), 3.59-3.72 (m, 4H), 2.80 (t, J = 10.0 Hz, 2H), 2.40-2.20 (m, 2H), 1.31 (d, J = 6.4 Hz, 6H), 1.03 (s, 3H), 0.63 (s, 2H), 0.38 (s, 2H); LCMS m / z = 509, 511.

[0760] Example 52: l-(l-Acryloylpyrrolidin-3-yl)-4-((3R,5S)-3,5-dimethylpiperazin-l-yl)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide

[0761] Following the General procedure 4, tert-butyl (2R,6S)-4-(l-(l-acryloylpyrrolidin-3-yl)-6-(N- (l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-lH-indazol-4-yl)-2,6- dimethylpiperazine-1 -carboxylate (90mg) was treated with trifluoroacetic acid (0.28mL) to afford the title compound (9mg) as an off white solid.JH NMR (400 MHz, DMSO-de) 5 9.09 (br s, 1H), 8.45 (d, J = 5.2 Hz, 1H), 8.09 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 6.91 (s, 1H), 6.54-6.68 (m, 1H), 6.13-6.18 (m, 1H), 5.67-5.75 (m, 1H), 3.78-3.89 (m, 4H), 3.58-3.66 (m, 4H), 2.79 (t, J = A Hz, 2H), 1.30 (d, J = 6.4 Hz, 6H), 1.17 (s, 3H), 1.03 (s, 3H), 0.63 (s, 2H), 0.38 (s, 2H); LCMS m / z = 487.

[0762] Example 53: 4-((3R,5S)-3,5-Dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-l-(l- propioloylpyrrolidin-3-yl)-lH-indazole-6-sulfonamide

[0763] Following the General procedure 5, tert-butyl (2R,6S)-2,6-dimethyl-4-(6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-l-(l- propioloylpyrrolidin-3-yl)-lH-indazol-4-yl)piperazine-l -carboxylate (lOOmg) was treated with trifluoroacetic acid (0.35mL) to afford the title compound (20mg) as an off white solid..JH NMR (400 MHz, DMSO-t / 6) 8 8.47 (s, 2H), 8.09 (s, 1H), 7.83 (d, J = 7.2 Hz, 1H), 6.91 (s, 1H), 5.64 (br s, 1H), 4.56-4.52 (m, 1H), 3.83-3.86 (m, 4H), 3.59 (br s, 4H), 2.80 (t, J = A Hz, 2H), 2.32 (s, 2H), 1.31 (d, J = 6.0 Hz, 6H), 1.03 (s, 3H), 0.64 (s, 2H), 0.37 (s, 2H); LCMS m / z = 485.

[0764] Example 54: l-(l-(2,5-Dichloropyrimidin-4-yl)pyrrolidin-3-yl)-4-((3R,5S)-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0765] Following the General procedure 5, tert-butyl (2R,6S)-4-(l-(l-(2,5-dichloropyrimidin-4- yl)pyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2-

[0766] (trimethylsilyl)ethoxy)methyl) sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine- 1 - carboxylate (74mg) was treated with trifluoroacetic acid (0.2 ImL) to afford the title compound (lOmg) as an off white solid.1H NMR (400 MHz, DMSO-de) 88.38 (s, 1H), 8.21 (s, 1H), 8.10 (s, 1H), 7.77 (s, 1H), 6.86 (s, 1H), 5.70-5.62 (m, 1H), 4.38-4.30 (m, 1H), 4.20- 4.11 (m, 1H), 4.06-3.98 (m, 1H), 3.78-3.70 (m, 4H), 3.30-3.20 (m, 2H), 2.65-2.55 (m, 2H), 1.29-1.22 (m, 2H), 1.21-1.15 (m, 6H), 1.08 (s, 3H), 0.66-0.61 (m, 2H), 0.40-0.35 (m, 2H); LCMS (m / z) = 579, 581.

[0767] Example 55: l-((3R,5S)-l-Acryloyl-5-(fluoromethyl)pyrrolidin-3-yl)-4-((3S,5S)-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0768] Following the General procedure 5, tert-butyl (2S,6S)-4-(l-((3R,5S)-l-acryloyl-5- (fluoromethyl)pyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl) sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine- 1 - carboxylate (650mg) was treated with trifluoroacetic acid (3.5mL) to afford the title compound (103mg) as an off white solid. ' H NMR (400 MHz, DMSO-de) 8 8.31 (bs, 1H), 8.21 (s, 1H), 8.11 (s, 1H), 7.72 (s, 1H), 6.83 (s, 1H), 6.60-6.52 (m, 1H), 6.20-6.13 (m, 1H), 5.74-5.62 (m, 2H), 4.82-4.74 (m, 1H), 4.71-4.61 (m, 1H), 4.60-4.48 (m, 2H), 4.12-4.06 (m, 1H), 3.97-3.90 (m, 1H), 3.86-3.78 (m, 1H), 3.42-3.36 (m, 2H), 3.32-3.24 (m, 2H), 3.10-3.00 (m, 2H), 1.26-1.20 (m, 9H), 0.68-0.60 (m, 2H), 0.40-0.34 (m, 2H); LCMS m / z = 519.

[0769] Example 56: 4-((3S,5S)-3,5-Dimethylpiperazin-l-yl)-l-((3R,5S)-5-(fluoromethyl)-l- propionylpyrrolidin-3-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0770] Following the General procedure 5, tert-butyl (2S,6S)-4-(l-((3R,5S)-5-(fluoromethyl)-l- propionylpyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl) sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine- 1 - carboxylate (444mg) was treated with trifluoroacetic acid (2.3mL) to afford the title compound (30mg) as an off white solid.JH NMR (400 MHz, DMSO-de) 8 8.25 (d, J = 8.33 Hz, 1H), 8.12 (br. s., 1H), 7.77 (br. s., 1H), 6.86 (br. s., 1H), 5.70-5.60 (m, 1H), 4.80-4.30 (m, 5H), 3.39-3.35 (m, 2H), 3.25-3.15 (m, 2H), 2.70-2.60 (m, 2H), 2.40-2.20 (m, 2H), 2.20-2.10 (m, 2H), 1.32 (d, J = 5.48 Hz, 6H), 1.05 (s, 3H), 0.93 (t, J = 7.34 Hz, 3H), 0.64 (d, J = 10.52 Hz, 2H), 0.38 (br. s., 2H); LCMS m / z = 521. Example 57 : 4-((3S,5S)-3,5-Dimethylpiperazin-l-yl)-l-((3R,5S)-l-(2-fluoroacryloyl)-5-

[0771] (fluoromethyl)pyrrolidin-3-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0772] Following the General procedure 5, tert-butyl (2S,6S)-4-(l-((3R,5S)-l-(2-fluoroacryloyl)-5- (fluoromethyl)pyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl) sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine- 1 - carboxylate (200mg) was treated with trifluoroacetic acid (0.99mL) to afford the title compound (7.5mg) as an off white solid.1H NMR (400 MHz, DMSO-de) § 8.27 (br. s., 1H), 8.20 (br. s., 1H), 8.10 (s, 1H), 7.70 (br. s., 1H), 6.84 (s, 1H), 5.60 (br. s., 1H), 5.40 (br. s., 1H), 5.02 (br. s., 1H), 4.73 (br. s., 1H), 4.62 (br. s., 1H), 4.53 (br. s., 2H), 3.81 - 4.03 (m, 2H), 3.48 (br. s., 2H), 3.32 (d, J = 8.99 Hz, 2H), 3.10 (br. s., 2H), 1.88-1.68 (m, 2H), 1.16 - 1.33 (m, 6H), 1.03 (s, 3H), 0.62 (br. s., 2H), 0.36 (s, 2H); LCMS m / z = 537.

[0773] Example 58: l-((3R,5S)-l-((E)-4-(Dimethylamino)but-2-enoyl)-5-

[0774] (fluoromethyl)pyrrolidin-3-yl)-4-((3S,5S)-3,5-dimethylpiperazin-l-yl)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide

[0775] Following the General procedure 5, tert-butyl (2S,6S)-4-(l-((3R,5S)-l-((E)-4- (dimethylamino)but-2-enoyl)-5-(fluoromethyl)pyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)- N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine- 1 - carboxylate (230mg) was treated with trifluoroacetic acid (l.lmL) to afford the title compound (7mg) as an off white solid.1H NMR (400 MHz, DMSO-de) 5 8.25 (br. s., 2H), 8.12 (br. s., 1H), 7.70 - 7.88 (m, 1H), 6.87 (s, 1H), 6.58 - 6.71 (m, 1H), 6.34 (d, J = 14.47 Hz, 1H), 5.70-5.60 (m, 1H), 4.80-4.30 (m, 5H), 3.39-3.35 (m, 2H), 3.25-3.15 (m, 2H), 2.99 (d, J = 5.70 Hz, 1H), 2.50 (s, 6H), 2.58-2.48 (m, 2H), 2.20-2.10 (m, 2H), 1.33 (d, J = 5.04 Hz, 6H), 1.05 (s, 3H), 0.64 (d, J = 10.74 Hz, 2H), 0.38 (br. s., 2H); LCMS m / z = 288.

[0776] Example 59: 4-((3S,5S)-3,5-Dimethylpiperazin-l-yl)-l-((3R,5S)-5-(fluoromethyl)-l- methacryloylpyrrolidin-3-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0777] Following the General procedure 5, tert-butyl (2S,6S)-4-(l-((3R,5S)-5-(fluoromethyl)-l- methacryloylpyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2-

[0778] (trimethylsilyl)ethoxy)methyl) sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine- 1 - carboxylate (120mg) was treated with trifluoroacetic acid (0.6mL) to afford the title compound (3mg) as an off white solid.1H NMR (400 MHz, DMSO-de) 5 8.27 (br. s., 1H), 8.20 (br. s., 1H), 8.10 (s, 1H), 7.70 (br. s., 1H), 6.84 (s, 1H), 5.54 (br. s., 1H), 5.20 (br. s., 1H), 5.02 (br. s., 1H), 4.73 (br. s., 1H), 4.62 (br. s., 1H), 4.53 (br. s., 2H), 3.81 - 4.03 (m, 2H), 3.48 (br. s., 2H), 3.32 (d, J = 8.99 Hz, 2H), 3.10 (br. s., 2H), 1.88-1.68 (m, 2H), 1.68 (br. s., 3H), 1.16 - 1.33 (m, 6H), 1.03 (s, 3H), 0.62 (br. s., 2H), 0.36 (s, 2H); LCMS m / z = 533.

[0779] Example 60: l-((3R,5S)-l-((E)-But-2-enoyl)-5-(fluoromethyl)pyrrolidin-3-yl)-4-((3S,5S)- 3,5-dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0780] Following the General procedure 5, tert-butyl (2S,6S)-4-(l-((3R,5S)-l-((E)-but-2-enoyl)-5- (fluoromethyl)pyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl) sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine- 1 - carboxylate (250mg) was treated with trifluoroacetic acid (1.33mL) to afford the title compound (26mg) as an off white solid.JH NMR (400 MHz, DMSO-de) 8 8.23 (br. s., 2H), 8.11 (br. s., 1H), 7.75 (br. s., 1H), 6.85 (br. s., 1H), 6.70 (br. s., 1H), 6.24 (d, J = 16.22 Hz, 1H), 5.67 (br. s., 1H), 4.76 (br. s., 1H), 4.64 (br. s., 1H), 4.51 (br. s., 1H), 4.05 (br. s., 1H), 3.89 (br. s., 1H), 3.79 (br. s., 1H), 3.51 (br. s., 2H), 3.34 (d, J = 8.55 Hz, 2H), 2.96 - 3.22 (m, 2H), 2.70-2.50 (m, 2H), 1.86 (d, J = 6.36 Hz, 3H), 1.28 (br. s., 6H), 1.04 (br. s., 3H), 0.62 (br. s., 2H), 0.37 (br. s., 2H); LCMS m / z = 533.

[0781] Example 61: 4-((3S,5S)-3,5-Dimethylpiperazin-l-yl)-l-((3R,5S)-5-(fluoromethyl)-l-((E)- 2-methylbut-2-enoyl)pyrrolidin-3-yl)-N-(l-methylcyclopropyl)-lH-indazole-6- sulfonamide

[0782] Following the General procedure 5, tert-butyl (2S,6S)-4-(l-((3R,5S)-5-(fluoromethyl)-l-((E)- 2-methylbut-2-enoyl)pyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl) sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine- 1 - carboxylate (280mg) was treated with trifluoroacetic acid (1.37mL) to afford the title compound (24mg) as an off white solid. ' H NMR (400 MHz, DMSO-de) 8 8.28 (br. s., 1H), 8.18 (s, 1H), 8.09 (s, 1H), 7.68 (s, 1H), 6.83 (s, 1H), 5.62 (br. s., 1H), 5.53 (br. s., 1H), 4.68 (br. s., 1H), 4.57 (br. s., 1H), 4.51 (br. s., 2H), 3.87 (br. s., 2H), 3.80 (d, J = 11.18 Hz, 2H), 3.43 (br. s., 2H), 3.30 (d, J = 10.96 Hz, 2H), 3.02 - 3.13 (m, 2H), 1.57 (br. s., 6H), 1.25 (d, J = 6.58 Hz, 6H), 0.93 - 1.09 (m, 3H), 0.62 (d, J = 6.14 Hz, 2H), 0.36 (s, 2H); LCMS m / z = 547.

[0783] Example 62: l-((3R,5S)-l-(But-2-ynoyl)-5-(fluoromethyl)pyrrolidin-3-yl)-4-((3S,5S)-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0784] Following the General procedure 5, tert-butyl (2S,6S)-4-(l-((3R,5S)-l-(but-2-ynoyl)-5- (fluoromethyl)pyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl) sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine- 1 - carboxylate (200mg) was treated with trifluoroacetic acid (1.07mL) to afford the title compound (25mg) as an off white solid.JH NMR (400 MHz, DMSO-de) § 8.25 (s, 2H), 8.11 (d, J = 3.73 Hz, 1H), 7.74 (s, 1H), 6.85 (br. s., 1H), 5.63 (br. s., 1H), 4.79 (d, J = 4.38 Hz, 1H), 4.58 - 4.70 (m, 1H), 4.02 (d, J = 5.04 Hz, 2H), 3.87 (d, J = 12.94 Hz, 1H), 3.69 (d, J = 5.70 Hz, 2H), 3.50 (br. s., 2H), 3.34 (d, J = 11.40 Hz, 2H), 3.12 (br. s., 2H), 2.68 (br. s., 1H), 1.92 (s, 3H), 1.25 - 1.48 (m, 6H), 1.05 (s, 3H), 0.50 - 0.75 (m, 2H), 0.37 (s, 2H); LCMS m / z = 531.

[0785] Example 63: 4-((3S,5S)-3,5-Dimethylpiperazin-l-yl)-l-((3R,5S)-5-(fluoromethyl)-l-((Z)-

[0786] 2-methylbut-2-enoyl)pyrrolidin-3-yl)-N-(l-methylcyclopropyl)-lH-indazole-6- sulfonamide

[0787] Following the General procedure 5, tert-butyl (2S,6S)-4-(l-((3R,5S)-5-(fluoromethyl)-l-((Z)- 2-methylbut-2-enoyl)pyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl) sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine- 1 - carboxylate (290mg) was treated with trifluoroacetic acid (1.42mL) to afford the title compound (31mg) as an off white solid. ' H NMR (400 MHz, DMSO-de) § 8.22 (s, 1H), 8.10 (s, 1H), 7.73 (s, 1H), 6.87 (s, 1H), 5.57 (br. s., 1H), 5.19 - 5.31 (m, 1H), 4.83 (dd, J = 4.17, 9.21 Hz, 1H), 4.64 - 4.77 (m, 1H), 4.48 - 4.62 (m, 2H), 3.76 - 3.85 (m, 1H), 3.63 (d, J = 12.06 Hz, 3H), 3.40-3.20 (m, 2H), 3.15 (dd, J = 6.58, 12.50 Hz, 3H), 2.60 - 2.73 (m, 1H), 2.54 (d, J = 7.23 Hz, 1H), 1.49 - 1.54 (m, 3H), 1.26 - 1.39 (m, 9H), 1.03 (s, 3H), 0.55 - 0.70 (m, 2H), 0.29 - 0.45 (m, 2H); LCMS m / z = 547.

[0788] Example 64: 4-((3S,5S)-3,5-Dimethylpiperazin-l-yl)-l-((3R,5S)-5-(fluoromethyl)-l-((E)-

[0789] 4,4,4-trifluorobut-2-enoyl)pyrrolidin-3-yl)-N-(l-methylcyclopropyl)-lH-indazole-6- sulfonamide

[0790] Following the General procedure 5, tert-butyl (2S,6S)-4-(l-((3R,5S)-5-(fluoromethyl)-l-((E)- 4,4,4-trifluorobut-2-enoyl)pyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl) sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine- 1 - carboxylate (l lOmg) was treated with trifluoroacetic acid (0.54mL) to afford the title compound (14mg) as an off white solid. ' H NMR (400 MHz, DMSO-de) § 8.23 (br. s., 2H), 8.11 (br. s., 1H), 7.75 (br. s., 1H), 6.85 (br. s., 1H), 6.70 (br. s., 1H), 6.24 (d, J = 16.22 Hz, 1H), 5.67 (br. s., 1H), 4.76 (br. s., 1H), 4.64 (br. s., 1H), 4.51 (br. s., 1H), 4.05 (br. s., 1H), 3.89 (br. s., 1H), 3.79 (br. s., 1H), 3.51 (br. s., 2H), 3.34 (d, J = 8.55 Hz, 2H), 2.96 - 3.22 (m, 2H), 2.70-2.50 (m, 2H), 1.28 (br. s., 6H), 1.04 (br. s., 3H), 0.62 (br. s., 2H), 0.37 (br. s., 2H); LCMS m / z = 587.

[0791] Example 65: l-((3R,5R)-l-Acryloyl-5-methylpyrrolidin-3-yl)-4-((3S,5S)-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0792] Following the General procedure 5, tert-butyl (2S,6S)-4-(l-((3R,5R)-l-acryloyl-5- methylpyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2-

[0793] (trimethylsilyl)ethoxy)methyl) sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine- 1 - carboxylate (210mg) was treated with trifluoroacetic acid (ImL) to afford the title compound (13mg) as an off white solid.JH NMR (400 MHz, DMSO-t / 6) 8 8.20 (s, 2H), 8.09 (s, 1H), 7.80 (s, 1H), 6.83 (s, 1H), 6.66 (d, J = 9.87 Hz, 1H), 6.48 - 6.60 (m, 1H), 6.15 (t, J = 17.76 Hz, 1H), 5.72 (br. s., 2H), 5.62 (d, J = 10.52 Hz, 1H), 4.53 (br. s., 1H), 4.36 (br. s., 1H), 4.11 (s, 1H), 3.87 (br. s., 2H), 3.79 (br. s., 2H), 2.55 (br. s., 2H), 1.24 (br. s., 9H), 1.05 (s, 3H), 0.65 (br. s., 2H), 0.37 (br. s., 2H); LCMS m / z = 501.

[0794] Example 66: l-((3R,5S)-l-Acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-4-((3S,5S)-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0795] Following the General procedure 5, tert-butyl (2S,6S)-4-(l-((3R,5S)-l-acryloyl-5- (methoxymethyl)pyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl) sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine- 1 - carboxylate (lOOmg) was treated with trifluoroacetic acid (0.5mL) to afford the title compound (14mg) as an off white solid. ' H NMR (400 MHz, DMSO-de) 5 8.28 (br. s., 1H), 8.21 (s, 1H), 8.09 - 8.12 (m, 1H), 7.73 (d, J = 7.23 Hz, 1H), 6.84 (s, 1H), 6.74 (dd, J = 10.41, 16.55 Hz, 1H), 6.53 (dd, J = 10.09, 16.66 Hz, 1H), 6.14 (ddd, J = 2.30, 7.13, 16.66 Hz, 1H), 5.60 - 5.70 (m, 2H), 4.60-4.44 (m, 2H), 4.07 (dd, J = 6.80, 10.74 Hz, 2H), 3.76 - 3.91 (m, 2H), 3.41 - 3.64 (m, 2H), 3.33 (d, J = 7.02 Hz, 3H), 3.08 (dd, J = 5.92, 11.84 Hz, 2H), 2.61 - 2.73 (m, 1H), 2.36 - 2.45 (m, 1H), 1.24 - 1.37 (m, 6H), 1.05 (s, 3H), 0.59 - 0.70 (m, 2H), 0.38 (s, 2H); LCMS m / z = 531.

[0796] Example 67: 4-((3S,5S)-3,5-Dimethylpiperazin-l-yl)-l-((3R,5S)-5-(fluoromethyl)-l- (pent-2-ynoyl)pyrrolidin-3-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0797] Following the General procedure 5, tert-butyl (2S,6S)-4-(l-((3R,5S)-5-(fluoromethyl)-l- (pent-2-ynoyl)pyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl) sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine- 1 - carboxylate (250mg) was treated with trifluoroacetic acid (1.23mL) to afford the title compound (3mg) as an off white solid.JH NMR (400 MHz, DMSO-de) § 8.25 (s, 2H), 8.11 (d, J = 3.73 Hz, 1H), 7.74 (s, 1H), 6.85 (br. s., 1H), 5.63 (br. s., 1H), 4.79 (d, J = 4.38 Hz, 1H), 4.58 - 4.70 (m, 1H), 4.02 (d, J = 5.04 Hz, 2H), 3.87 (d, J = 12.94 Hz, 1H), 3.69 (d, J = 5.70 Hz, 2H), 3.50 (br. s., 2H), 3.34 (d, J = 11.40 Hz, 2H), 3.12 (br. s., 2H), 2.25-2.22 (m, 2H), 1.92 (s, 3H), 1.25 - 1.48 (m, 6H), 1.05-1.00 (m, 3H), 0.50 - 0.75 (m, 2H), 0.37 (s, 2H); LCMS m / z = 545.

[0798] Example 68: l-((3R,5S)-l-Acryloyl-5-methylpyrrolidin-3-yl)-4-((3S,5S)-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0799] Following the General procedure 5, tert-butyl (2S,6S)-4-(l-((3R,5S)-l-acryloyl-5- methylpyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl) sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine- 1 - carboxylate (300mg) was treated with trifluoroacetic acid (1.56mL) to afford the title compound (22mg) as an off white solid. ' H NMR (400 MHz, DMSO-de) § 8.20 (s, 2H), 8.09 (s, 1H), 7.80 (s, 1H), 6.83 (s, 1H), 6.66 (d, J = 9.87 Hz, 1H), 6.48 - 6.60 (m, 1H), 6.15 (t, J = 17.76 Hz, 1H), 5.72 (br. s., 2H), 5.62 (d, J = 10.52 Hz, 1H), 4.53 (br. s., 1H), 4.36 (br. s., 1H), 4.11 (s, 1H), 3.87 (br. s., 2H), 3.79 (br. s., 2H), 2.55 (br. s., 2H), 1.24 (br. s., 9H), 1.05 (s, 3H), 0.65 (br. s., 2H), 0.37 (br. s., 2H); LCMS m / z = 501. Example 69: l-((3R,5S)-l-Acryloyl-5-(difluoromethyl)pyrrolidin-3-yl)-4-((3S,5S)-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0800] Following the General procedure 5, tert-butyl (2S,6S)-4-(l-((3R,5S)-l-acryloyl-5- (difluoromethyl)pyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl) sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine- 1 - carboxylate (60mg) was treated with trifluoroacetic acid (446mg) to afford the title compound (7mg) as an off white solid. 'H NMR (400 MHz, DMSO-de) 8 'H NMR (400 MHz, DMSO-de) 8 8.31 (bs, 1H), 8.21 (s, 1H), 8.11 (s, 1H), 7.72 (s, 1H), 6.83 (s, 1H), 6.60- 6.52 (m, 1H), 6.42 (t, J = 56 Hz, 1H), 6.20-6.13 (m, 1H), 5.74-5.62 (m, 1H), 4.82-4.74 (m, 1H), 4.71-4.61 (m, 1H), 4.60-4.48 (m, 2H), 4.12-4.06 (m, 1H), 3.97-3.90 (m, 1H), 3.86-3.78 (m, 1H), 3.42-3.36 (m, 2H), 3.32-3.24 (m, 2H), 3.10-3.00 (m, 2H), 1.26-1.20 (m, 9H), 0.68- 0.60 (m, 2H), 0.40-0.34 (m, 2H); LCMS m / z = 537.

[0801] Example 70: l-((3R,5S)-l-Acryloyl-5-(fluoromethyl)pyrrolidin-3-yl)-3-cyclopropyl-4-

[0802] ((3S,5S)-3,5-dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6- sulfonamide

[0803] Following the General procedure 5, tert-butyl (2S,6S)-4-(l-((3R,5S)-l-acryloyl-5- (fluoromethyl)pyrrolidin-3-yl)-3-cyclopropyl-6-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl) sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine- 1 - carboxylate (llOmL) was treated with trifluoroacetic acid (ImL) to afford the title compound (20mg) as an off white solid.JH NMR (400 MHz, DMSO-t / 6) 8 8.21 (br.s., 2H), 8.11 (s, 1H), 7.72 (s, 1H), 6.83 (s, 1H), 6.60-6.52 (m, 1H), 6.20-6.13 (m, 1H), 5.74-5.62 (m, 2H), 4.82-4.74 (m, 1H), 4.71-4.61 (m, 1H), 4.60-4.48 (m, 2H), 4.12-4.06 (m, 2H), 3.97-3.90 (m, 1H), 3.86-3.78 (m, 1H), 3.42-3.36 (m, 2H), 3.10-3.00 (m, 2H), 2.20-2.00 (m, 1H), 1.26-1.20 (m, 9H), 1.20-0.99 (m, 4H), 0.68-0.60 (m, 2H), 0.40-0.34 (m, 2H); LCMS m / z = 559.

[0804] Example 71: l-((3R,5S)-l-Acryloyl-5-(hydroxymethyl)pyrrolidin-3-yl)-4-((3S,5S)-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0805] Following the General procedure 5, tert-butyl (2S,6S)-4-(l-((3R,5S)-l-acryloyl-5- (hydroxymethyl)pyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl) sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine- 1 - carboxylate (170mg) was treated with trifluoroacetic acid (0.87mL) to afford the title compound (5mg) as an off white solid.JH NMR (400 MHz, DMSO-de) § 8.20 (s, 2H), 8.09 (s, 1H), 7.80 (s, 1H), 6.83 (s, 1H), 6.66 (d, J = 9.87 Hz, 1H), 6.48 - 6.60 (m, 1H), 6.15 (t, J = 17.76 Hz, 1H), 5.72 (br. s., 2H), 5.62 (d, J = 10.52 Hz, 1H), 5.00-4.96 (m, 1H), 4.53 (br. s., 1H), 4.36 (br. s., 1H), 4.11 (br.s., 2H), 3.87 (br. s., 2H), 3.79 (br. s., 2H), 3.55-3.45 (m, 2H), 2.55 (br. s., 2H), 1.24 (br. s., 9H), 0.65 (br. s., 2H), 0.37 (br. s., 2H); LCMS m / z = 517.

[0806] Example 72: l-((3R,5S)-l-Acryloyl-5-((dimethylamino)methyl)pyrrolidin-3-yl)-4-

[0807] ((3S,5S)-3,5-dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6- sulfonamide

[0808] Following the General procedure 5, tert-butyl (2S,6S)-4-(l-((3R,5S)-l-acryloyl-5- ((dimethylamino)methyl)pyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl) sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine- 1 - carboxylate (200mg) was treated with trifluoroacetic acid (0.98mL) to afford the title compound (3.6mg) as an off white solid.JH NMR (400 MHz, DMSO-de) 8 8.20 (s, 2H), 8.09 (s, 1H), 7.80 (s, 1H), 6.83 (s, 1H), 6.66 (d, J = 9.87 Hz, 1H), 6.48 - 6.60 (m, 1H), 6.15 (t, J = 17.76 Hz, 1H), 5.72 (br. s., 2H), 5.62 (d, J = 10.52 Hz, 1H), 5.00-4.96 (m, 1H), 4.36 (br. s., 1H), 4.11 (br.s., 2H), 3.87 (br. s., 2H), 3.79 (br. s., 2H), 2.69-2.20 (m, 2H), 2.55 (br. s., 2H), 2.25 (s, 6H), 1.24 (br. s., 9H), 0.65 (br. s., 2H), 0.37 (br. s., 2H); LCMS m / z = 544.

[0809] Example 73: l-((3R,5S)-l-Acryloyl-5-(2-hydroxypropan-2-yl)pyrrolidin-3-yl)-4-((3S,5S)-

[0810] 3,5-dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0811] Following the General procedure 5, tert-butyl (2S,6S)-4-(l-((3R,5S)-l-acryloyl-5-(2- hydroxypropan-2-yl)pyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl) sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine- 1 - carboxylate (130mg) was treated with trifluoroacetic acid (0.64mL) to afford the title compound (19.8mg) as an off white solid. ' H NMR (400 MHz, DMSO-de) 8 8.29 (br. s., 1H), 8.14 - 8.22 (m, 1H), 8.11 (s, 1H), 7.63 (s, 1H), 6.79 - 6.95 (m, 1H), 6.53 (dd, J = 10.30, 16.66 Hz, 1H), 6.03 - 6.16 (m, 1H), 5.57 - 5.66 (m, 1H), 4.45 (br. s., 1H), 4.39 (d, J = 6.80 Hz, 1H), 3.95 - 4.17 (m, 4H), 3.77 (d, J = 7.23 Hz, 1H), 3.68 (d, J = 10.30 Hz, 1H), 3.43 (br. s., 3H), 3.29 (d, J = 9.21 Hz, 2H), 3.07 (dd, J = 6.25, 11.51 Hz, 2H), 1.25 (d, J = 6.58 Hz, 6H), 1.12 (d, J = 9.43 Hz, 6H), 1.04 (s, 3H), 0.58 - 0.69 (m, 2H), 0.38 (br. s., 2H); LCMS m / z = 545.

[0812] Example 74: l-((3R,5S)-l-Acryloyl-5-(2-fluoropropan-2-yl)pyrrolidin-3-yl)-4-((3S,5S)-

[0813] 3,5-dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide Following the General procedure 5, tert-butyl (2S,6S)-4-(l-((3R,5S)-l-acryloyl-5-(2- fluoropropan-2-yl)pyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl) sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine- 1 - carboxylate (lOOmg) was treated with trifluoroacetic acid (0.5mL) to afford the title compound (4mg) as an off white solid.JH NMR (400 MHz, DMSO-de) 5 8.29 (br. s., 1H), 8.14 - 8.22 (m, 1H), 8.11 (s, 1H), 7.63 (s, 1H), 6.79 - 6.95 (m, 1H), 6.53 (dd, J = 10.30, 16.66 Hz, 1H), 6.03 - 6.16 (m, 1H), 4.45 (br. s., 1H), 4.39 (d, J = 6.80 Hz, 1H), 3.95 - 4.17 (m, 4H), 3.77 (d, J = 7.23 Hz, 1H), 3.68 (d, J = 10.30 Hz, 1H), 3.43 (br. s., 3H), 3.29 (d, J = 9.21 Hz, 2H), 3.07 (dd, J = 6.25, 11.51 Hz, 2H), 1.37-1.35 (m, 6H), 1.12 (d, J = 9.43 Hz, 6H), 1.04 (s, 3H), 0.58 - 0.69 (m, 2H), 0.38 (br. s., 2H); LCMS m / z = 547.

[0814] Example 75: l-((3R,5S)-l-Acryloyl-5-isopropylpyrrolidin-3-yl)-4-((3S,5S)-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0815] Following the General procedure 5, tert-butyl (2S,6S)-4-(l-((3R,5S)-l-acryloyl-5- isopropylpyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl) sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine- 1 - carboxylate (lOOmg) was treated with trifluoroacetic acid (750mg) to afford the title compound (12mg) as an off white solid. ' H NMR (400 MHz, DMSO-de) § 8.27 (br. s., 1H), 8.16 (s, 1H), 8.09 (s, 1H), 7.70 (d, J = 7.24 Hz, 1H), 6.82 (s, 1H), 6.71 (dd, J = 10.41, 15.90 Hz, 1H), 6.52 (dd, J = 10.19, 16.77 Hz, 1H), 6.02 - 6.18 (m, 1H), 5.68 (d, J = 10.30 Hz, 1H), 5.52 - 5.62 (m, 1H), 4.26 - 4.40 (m, 2H), 3.94 - 4.04 (m, 2H), 3.38 (br. s., 2H), 3.27 (d, J = 11.84 Hz, 2H), 3.01 - 3.09 (m, 2H), 2.37 - 2.46 (m, 1H), 2.32 (d, J = 6.36 Hz, 1H), 1.23 (d, J = 6.14 Hz, 6H), 1.04 (s, 3H), 0.81 - 0.94 (m, 6H), 0.64 (d, J = 9.21 Hz, 2H), 0.37 (s, 2H); LCMS m / z = 529.

[0816] Example 76: l-(l-(2,5-Dichloropyrimidin-4-yl)pyrrolidin-3-yl)-4-(4-isobutyrylpiperazin- l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0817] To a stirred solution of 4-(4-isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)-l- (pyrrolidin-3-yl)-lH-indazole-6-sulfonamide (55 mg, 0.115 mmol) in acetonitrile (1 mL) was added potassium carbonate (24 mg, 0.105 mmol) at 0 °C under N2 atmosphere and stirred for 5 mins. 2,4,5-Trichloropyrimidine (13.3 mg, 138.21 mmol) was added and the resulting mixture was stirred at 80 °C for 1 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (50 mL). Layers were separated and the organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous NaiSCL, filtered, and concentrated in vacuo to give 130 mg of a crude compound. This crude residue was purified by reverse phase preparative HPLC to afford the title compound (20 mg) as an off white solid.JH NMR (400 MHz, DMSO-t / 6) 8 8.36 (s, 1H), 8.21 (s, 1H), 8.08 (s, 1H), 7.76 (bs, 1H), 5.70-5.62 (m, 1H), 4.38-4.28 (m, 1H), 4.20-4.10 (m, 1H), 4.07-3.96 (m, 2H), 3.70-3.66 (m, 4H), 3.33-3.23 (m, 4H), 2.93 (septet, J = 6.4Hz, 1H), 2.44-2.32 (m, 2H), 1.10-0.99 (m, 9H), 0.69-0.60 (m, 2H), 0.40-0.32 (m, 2H); LCMS m / z = 621, 623.

[0818] Example 77: l-(l-Acryloylpyrrolidin-3-yl)-4-(4-(dimethylglycyl)piperazin-l-yl)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide

[0819] To a stirred solution of l-(l-acryloylpyrrolidin-3-yl)-N-(l-methylcyclopropyl)-4-(piperazin- l-yl)-lH-indazole-6-sulfonamide hydrochloride (200 mg, 43.61 mmol) and dimethylglycine hydrochloride (67.4mg, 65.41 mmol) in DMF (2 mL) was added HATU (248.7 mg, 65.41 mmol) at 25 °C under N2 atmosphere and stirred for 5 mins. DIPEA (0.4 mL, 2.18 mmol) was added and stirred for 30 mins. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (50 mL). Layers were separated and the organic layer was washed with brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 130 mg of a crude compound. This crude residue was purified by reverse phase preparative HPLC to afford the title compound (12 mg) as an off white solid.JH NMR (400 MHz, DMSO-t / 6) 8 8.35 (d, J = 6.8 Hz, 1H), 8.17 (s, 1H), 8.06 (s, 1H), 7.74 (d, J = 10 Hz, 1H), 6.85 (m, 1H), 6.20-6.12 (m, 1H), 5.73-5.51 (m, 2H), 3.95-3.80 (m, 3H), 3.81-3.74 (m, 4H), 3.71-3.65 (m, 4H), 3.38-3.28 (m, 3H), 2.44-2.30 (m, 2H), 2.29 (s, 6H), 1.04 (s, 3H), 0.68-0.60 (m, 2H), 0.40-0.32 (m, 2H); LCMS m / z = 544.

[0820] Example 78: 4-(4-(L-Prolyl)piperazin-l-yl)-l-(l-acryloylpyrrolidin-3-yl)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide hydrochloride

[0821] To a stirred solution of tert-butyl (2S)-2-(4-(l-(l-acryloylpyrrolidin-3-yl)-6-(N-(l- methylcyclopropyl) sulfamoyl)- lH-indazol-4-yl)piperazine- 1 -carbonyl)pyrrolidine- 1 - carboxylate (18 mg) in CH2CI2 (1 mL) was added 4M HC1 in dioxane (0.3mL) at 0 °C under N2 atmosphere and stirred for 2 h. The reaction mixture was concentrated in vacuo and codistilled with diethyl ether to give 12 mg of the title compound as an off white solid.1H NMR (400 MHz, DMSO-t6) 8 10.02 (bs, 1H), 8.53-8.48 (m, 1H), 8.37 (d, J = 6.4 Hz, 1H) 8.12 (s, 1H), 7.77 (d, J = 9.2 Hz, 1H), 6.88 (s, 1H), 6.70-6.54 (m, 1H), 6.20-6.12 (m, 2H), 5.74-5.56 (m, 2H), 4.71-4.63 (m, 2H), 3.98-3.85 (m, 3H), 3.53-3.46 (m, 2H), 3.39-3.31 (m, 4H), 3.30- 3.18 (m, 3H), 2.00-1.80 (m, 4H), 1.55-1.42 (m, 2H), 1.05 (s, 3H), 0.68-0.60 (m, 2H), 0.41- 0.34 (m, 2H); LCMS m / z = 556.

[0822] Example 79: Methyl (2S,4R)-l-acryloyl-4-(4-((3S,5S)-3,5-dimethylpiperazin-l-yl)-6-(N-

[0823] (l-methylcyclopropyl)sulfamoyl)-lH-indazol-l-yl)pyrrolidine-2-carboxylate Following the General procedure 5, tert-butyl (2S,6S)-4-(l-((3R,5S)-l-acryloyl-5- (methoxycarbonyl)pyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl) sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine- 1 - carboxylate (150mg) was treated with trifluoroacetic acid (0.74 mL) to afford the title compound (33mg) as an off white solid.1!! NMR (400 MHz, DMSO-de) § 8.28 (s, 1H), 8.15 (s, 1H), 7.74 - 7.80 (m, 1H), 6.89 (s, 1H), 6.59 (dd, J = 10.41, 16.77 Hz, 1H), 6.15 (dd, J = 2.08, 16.77 Hz, 1H), 5.70 (dd, J = 2.19, 10.30 Hz, 1H), 4.73 (t, J = 7.67 Hz, 1H), 4.21 (dd, J = 6.36, 11.18 Hz, 1H), 3.98 (dd, J = 3.51, 11.18 Hz, 1H), 3.89 (d, J = 5.70 Hz, 1H), 3.69 (s, 3H), 3.64 (br. s., 2H), 3.28 - 3.47 (m, 2H), 3.14 - 3.24 (m, 2H), 2.65 - 2.79 (m, 1H), 2.43 - 2.48 (m, 1H), 1.37 (d, J = 6.36 Hz, 6H), 1.04 (s, 3H), 0.56 - 0.73 (m, 2H), 0.30 - 0.45 (m, 2H); LCMS m / z = 545.

[0824] Example 80: l-((3R,5S)-l-Acryloyl-5-(chloromethyl)pyrrolidin-3-yl)-4-((3S,5S)-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide

[0825] Following the General procedure 5, tert-butyl (2S,6S)-4-(l-((3R,5S)-l-acryloyl-5- (chloromethyl)pyrrolidin-3-yl)-6-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl) sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine- 1 - carboxylate (270mg) was treated with trifluoroacetic acid (1.34 mL) to afford the title compound ( 30 mg) as an off white solid. ' H NMR (400 MHz, DMSO-de) 5 8.18 - 8.34 (m, 2H), 8.05 - 8.15 (m, 1H), 7.81 (br. s., 1H), 6.83 - 6.93 (m, 1H), 6.55 (dd, J = 10.19, 15.89 Hz, 1H), 6.16 (d, J = 17.10 Hz, 1H), 5.67 (d, J = 8.55 Hz, 1H), 4.57 (br. s., 1H), 4.05 (br. s., 2H), 3.91 (d, J = 8.33 Hz, 2H), 3.85 (br. s., 1H), 3.66 (br. s., 1H), 3.57 (br. s., 2H), 3.37 (d, J = 10.52 Hz, 2H), 3.15 (br. s., 2H), 2.33 (br. s., 1H), 2.05 (br. s., 1H), 1.33 (br. s., 6H), 1.05 (br. s., 3H), 0.62 (br. s., 2H), 0.38 (br. s., 2H); LCMS m / z = 535, 537.

[0826] Example 81: l-((3R,5S)-l-Acryloyl-5-(fluoromethyl)pyrrolidin-3-yl)-N-(l- cyanocyclopropyl)-4-((3S,5S)-3,5-dimethylpiperazin-l-yl)-lH-indazole-6-sulfonamide

[0827] Following the General procedure 5, tert-butyl (2S,6S)-4-(l-((3R,5S)-l-acryloyl-5- (fluoromethyl)pyrrolidin-3-yl)-6-(N-(l-cyanocyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl) sulfamoyl)- lH-indazol-4-yl)-2,6-dimethylpiperazine- 1 - carboxylate (550mg) was treated with trifluoroacetic acid ( 2.8mL) to afford the title compound (60mg) as an off white solid.1H NMR (400 MHz, DMSO-de) 5 8.28 (s, 1H),

[0828] 8.22 (br. s., 1H), 7.85 (d, J = 7.45 Hz, 1H), 6.86 (br. s., 1H), 6.71 (s, 1H), 6.54 (d, J = 6.80 Hz, 1H), 6.18 (br. s., 1H), 5.67 (d, J = 9.87 Hz, 2H), 4.80 (br. s., 1H), 4.65 (br. s., 1H), 4.54 (br. s., 2H), 4.08 (br. s., 1H), 3.92 (d, J = 10.96 Hz, 1H), 3.54 (br. s., 2H), 3.39 (d, J = 9.43 Hz, 2H), 3.15 (br. s., 2H), 2.68 (br. s., 2H), 1.42 (br. s., 2H), 1.30 (d, J = 5.26 Hz, 6H), 1.24 (br. s., 2H); LCMS m / z = 530.

[0829] Abbreviations

[0830] °C = degree Celsius

[0831] DMSO = Dimethyl sulphoxide h = hour

[0832] 1H NMR = Proton nuclear magnetic resonance m / z = mass to charge ratio mg = milligram ml = milliliter

[0833] Na2SO4= Sodium sulphate

[0834] PdChdppf .CH2CI2 = [l,r-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethanePd2(dba)3 = Tris(dibenzylideneacetone)dipalladium (0) DIPEA = N, N-Diisopropylethylamine NEts = Triethylamine THF = Tetrahydrofuran

[0835] DEAD = Diethylazodicarboxylate DIAD = Diisopropylazodicarboxylate PPI13 (TPP) = Triphenylphosphine DCDMH = 1 ,3-Dichloro-5,5-di methyl hydantoin

[0836] AcOH = Acetic acid

[0837] CH2CI2 = Dichloromethane

[0838] SEM-C1 = 2-(Trimethylsilyl)ethoxymethyl chloride

[0839] RuPhos = 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl

[0840] XantPhos = 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

[0841] CS2CO3 = Cesium carbonate

[0842] K2CO3 = Potassium carbonate

[0843] TFA = Trifluoroacetic acid

[0844] H ATU = N - [(Dimethylamino) - 1 H- 1 ,2 , 3 -triazolo- [4 , 5 -b] pyridin- 1 -y Imethy lene] -N- methylmethanaminium hexafluorophosphate N-oxide

[0845] EDC.HC1 = N-Ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0846] HOBt = 1 -Hydroxy benzotri azo le

[0847] Pd / C = Palladium on carbon

[0848] EtOH = Ethanol

[0849] MeOH = Methanol

[0850] EtOAc = Ethyl acetate

[0851] DMF = N,N-Dimethylformamide

[0852] DMAc = N,N-Dimethylacetamide

[0853] LCMS = Liquid chromatography -mass spectrometry

[0854] HPLC = High Performance Liquid Chromatography

[0855] SFC = Supercritical fluid chromatography

[0856] PHARMACOLOGICAL ACTIVITY:

[0857] PARG biochemical assay of Non-Covalent compounds:

[0858] Compounds were screened for inhibition of PARG protein using fluorescence assay kit (BPS biosciences # 78858-1). 2 pl of 5X compound was prepared in an assay buffer and added to the corresponding wells in 384 well plate. Next, PARG full length enzyme was diluted in assay buffer to a working concentration of 0.25 ng / pl and 4pl added to each well. The plate was then incubated for 15 minutes at room temperature. Post incubation, 4 pl of Anorogenic PARG substrate was added to corresponding wells to a final concentration of 2 pM. The plate was further incubated for 1 hour at room temperature protected from light. The Auorescence was measured in a plate reader with excitation at 390 nm ± 20 nm and emission at 515 ± 30 nm. “Blank” value was subtracted from all other values. Blank well contains only Anorogenic probe and buffer, but not PARG protein

[0859] % inhibition was calculated using the formula 100-(Auorescence value of treatment / Fluorescence value of DMSO control)* 100

[0860] *** >80%; ** 50-80%; * <50%

[0861] PARG biochemical assay of Covalent compounds:

[0862] Compounds were screened for inhibition of PARG protein using Auorescence assay kit (BPS biosciences # 78858-1). 2 pL of 5X compound was prepared in an assay buffer and added to the corresponding wells in 384 well plate. Next, 4pL of PARG full length enzyme was added to respective wells and incubated for 15 min at room temperature. Post incubation, the reaction was initiated by adding 4 pL of lOpM substrate to all the wells and incubated for 60 min at RT with gentle rocking. The Auorescence was measured in a plate reader with excitation at 390 nm ± 20 nm and emission at 515 ± 30 nm. “Blank” value was subtracted from all other values. Blank well contains only Auorogenic probe and buffer, but not PARG enzyme.

[0863] % inhibition was calculated using the formula 100- (Auorescence value of treatment / Fluorescence value of DMSO control) *100

[0864] % inhibition: > 80% = ***; 50% -80% = **; < 50% = *

[0865] The covalent inhibitors exhibit increase in % inhibition with time.

[0866]

Claims

We Claim:

1. Novel heterocyclic compounds of formula (I)Formula (I) or its pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, prodrugs, deuterated including other possible isotopes, combinations and use thereof in treating cancer; wherein, Xi, X2, X3 are each independently selected from N, CR5;X4, X5 are each independently selected from N or CR4;Xf, is independently selected from O, S, NR4, C(R4)2;Li is selected from -NR6SO2-, -SO2NR6-, -NR6CO-, substituted or unsubstituted tetrazole, substituted or unsubstituted heterocycle, -NH(CO)NH, -NH(CO)O-, -SO2 and -CONR6;R1is absent or selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, haloalkyl, perhaloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, OR7b;R2and R3are independently absent or selected from alkyl; or R2and R3together with the carbon atom to which they are attached form substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl;R4is selected from hydrogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkylene, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkyl-heterocycloalkyl;R5is selected from hydrogen, cyano, haloalkyl, perhaloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted orHN / / y / unsubstituted heterocycloalkyl, substituted or unsubstituted — and substituted or unsubstituted, -OR7a, -OR7b, -SO2R7a, -C(=O)OR7b, -C(=O)R7b, -OC(=O)R7a, -OC(=O)OR7a, -C(=O)N(H)R7, -C(=O)N(alkyl)R7, -N(H)C(=O)R7a, -N(H)R7, and -N(alkyl)R7;R6is selected from the group consisting of hydrogen, alkyl and alkoxy;R7is independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, and substituted or unsubstituted heteroaryl;R7ais independently selected from substituted or unsubstituted alkyl, alkenyl, alkynyl, halogen, haloalkyl, perhaloalkyl and cycloalkyl;R7bis selected from hydrogen, halogen, substituted or unsubstituted alkyl, alkenyl, haloalkyl, perhaloalkyl, and cycloalkyl;R7Cis selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl.

2. A novel heterocyclic compound selected from the group consisting of1. 4-(4-(cyclopropanecarbonyl)piperazin- 1 -y 1) -3 -cyclopropyl- 1 -(5- (difluoromethyl)- 1 ,3 ,4-thiadiazol-2-yl)-N -( 1 -methylcyclopropyl)- IH-indazole- 6-sulfonamide2. 4-(4-(cyclopropanecarbonyl)piperazin-l-yl)-3-cyclopropyl-l-(5- (difluoromethyl)-l,3,4 -thiadiazol-2-yl)-N-(oxetan-3-yl)-lH-indazole-6- sulfonamide3. N-( 1 -cyanocyclopropyl)-4-(4-(cyclopropanecarbonyl)piperazin- 1 -yl)-3 - cyclopropyl- 1 -(5-(difluoromethyl)- 1 ,3 ,4-thiadiazol-2-yl)- 1 H-indazole-6- sulfonamide4. 4-(4-(cyclopropanecarbonyl)piperazin-l-yl)-3-cyclopropyl-l-(5- (difluoromethyl)- 1,3,4 -thiadiazol-2-yl)-N -( 1 -methylcyclobutyl)- IH-indazole- 6-sulfonamide5. N-(l-cyanocyclopropyl)-4-(4-(cyclobutanecarbonyl)piperazin-l-yl)-3- cyclopropyl- 1 -(5-(difluoromethyl)- 1 ,3 ,4-thiadiazol-2-yl)- 1 H-indazole-6- sulfonamide6. 4-(4-(cyclobutanecarbonyl)piperazin- 1 -yl)-3 -cyclopropyl- 1 -(5- (difluoromethyl)- 1 ,3 ,4-thiadiazol-2-yl)-N -( 1 -methylcyclopropyl)- IH-indazole- 6-sulfonamide7. 3-cyano-N-(l-cyanocyclopropyl)-4-(4-(cyclopropanecarbonyl)piperazin-l-yl)- l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-lH-indazole-6-sulfonamide8. 4-(4-(azetidine-3-carbonyl)piperazin-l-yl)-N-(l-cyanocyclopropyl)-3- cyclopropyl- 1 -(5-(difluoromethyl)- 1 ,3 ,4-thiadiazol-2-yl)- 1 H-indazole-6- sulfonamide9. N-(l-cyanocyclopropyl)-3-cyclopropyl-l-(5-(difluoromethyl)-l,3,4-thiadiazol- 2-yl)-4-(4-(oxetane-3-carbonyl)piperazin-l-yl)-lH-indazole-6-sulfonamide10. 1 -( 1 -(2-Chloroacetyl)pyrrolidin-3 -yl)-4-(4-isobutyrylpiperazin- 1 -yl)-N -( 1 - methylcyclopropyl)- lH-indazole-6- sulfonamide11. 1 -( 1 -(2-Chloroacetyl)pyrrolidin-3 -yl)-4-(4-isobutyrylpiperazin- 1 -yl)-N -( 1 - methylcyclopropyl)- lH-indazole-6- sulfonamide (Isomer I)12. 1 -( 1 -(2-Chloroacetyl)pyrrolidin-3-yl)-4-(4-isobutyrylpiperazin- 1 -yl)-N -( 1 - methylcyclopropyl)- lH-indazole-6- sulfonamide (Isomer II)13. 1 -( 1 -Acryloylpyrrolidin-3-yl)-4-(4-isobutyrylpiperazin- 1 -yl)-N-( 1 - methylcyclopropyl)- lH-indazole-6- sulfonamide14. 4-(4-Isobutyrylpiperazin- 1 -yl)-N -( 1 -methylcyclopropyl)- 1 -( 1 - propionylpyrrolidin-3 -yl)- 1 H-indazole-6- sulfonamide15. 4-(4-Isobutyrylpiperazin- 1 -yl)-N -( 1 -methylcyclopropyl)- 1 -( 1 - (vinylsulfonyl)pyrrolidin-3-yl)-lH-indazole-6-sulfonamide16. 1 -( 1 -(2-Chloroacetyl)piperidin-4-yl)-4-(4-isobutyrylpiperazin- 1 -yl)-N -( 1 - methylcyclopropyl)- 1 H-indazole-6- sulfonamide17. 4-(4-Isobutyrylpiperazin- 1 -yl)-N -(1 -methylcyclopropyl)- 1 -( 1 - propionylpiperidin-4-yl)-lH-indazole-6-sulfonamide18. 1 -( 1 -(2-Chloroacetyl)piperidin-3-yl)-4-(4-isobutyrylpiperazin- 1 -yl)-N -( 1 - methylcyclopropyl)- 1 H-indazole-6- sulfonamide19. 1 -( 1 - Acryloylpiperidin-3 -yl) -4-(4-isobutyrylpiperazin- 1 -yl) -N-( 1 - methylcyclopropyl)- 1 H-indazole-6- sulfonamide20. 4-(4-Isobutyrylpiperazin- 1 -yl)-N -( 1 -methylcyclopropyl)- 1 -( 1 - propionylpiperidin-3-yl)-lH-indazole-6-sulfonamide21. 1 -(( 1 -acryloylpyrrolidin-3-yl)methyl)-4-(4-isobutyrylpiperazin- 1 -yl)-N -( 1 - methylcyclopropyl)- 1 H-indazole-6- sulfonamide22. l-((l-(2-chloroacetyl)pyrrolidin-3-yl)methyl)-4-(4-isobutyrylpiperazin-l-yl)- N-( 1 -methylcyclopropyl)- 1 H-indazole-6- sulfonamide23. l-((3R,5S)-l-acryloyl-5-(fluoromethyl)pyrrolidin-3-yl)-4-(4- isobutyrylpiperazin- 1 -yl)-N -( 1 -methylcyclopropyl)- lH-indazole-6-sulfonamide24. l-((3R,5S)-l-(2-chloroacetyl)-5-(fluoromethyl)pyrrolidin-3-yl)-4-(4- isobutyrylpiperazin- 1 -yl)-N -( 1 -methylcyclopropyl)- lH-indazole-6- sulfonamide25. l-((3S,5R)-l-acryloyl-5-(fluoromethyl)pyrrolidin-3-yl)-4-(4- isobutyrylpiperazin- 1 -yl)-N -( 1 -methylcyclopropyl)- lH-indazole-6- sulfonamide26. l-((3S,5R)-l-(2-chloroacetyl)-5-(fluoromethyl)pyrrolidin-3-yl)-4-(4- isobutyrylpiperazin- 1 -yl)-N -( 1 -methylcyclopropyl)- lH-indazole-6- sulfonamide27. l-((3S,5R)-l-acryloyl-5-(fluoromethyl)pyrrolidin-3-yl)-4-((3R,5S)-4- isobutyryl-3,5-dimethylpiperazin- 1 -yl)-N-( 1 -methylcyclopropyl)- IH-indazole- 6-sulfonamide28. l-((3S,5S)-l-acryloyl-5-(fluoromethyl)pyrrolidin-3-yl)-4-(4- isobutyrylpiperazin- 1 -yl)-N -( 1 -methylcyclopropyl)- lH-indazole-6- sulfonamide29. l-((3R,5R)-l-acryloyl-5-(fluoromethyl)pyrrolidin-3-yl)-4-(4- isobutyrylpiperazin- 1 -yl)-N -( 1 -methylcyclopropyl)- lH-indazole-6- sulfonamide30. l-(l-acryloylpyrrolidin-3-yl)-N-(l-methylcyclopropyl)-4-((3R,5S)-3,4,5- trimethylpiperazin-l-yl)-lH-indazole-6-sulfonamide31. l-(l-acryloylpyrrolidin-3-yl)-N-(l-methylcyclopropyl)-4-((3S,5S)-3,4,5- trimethylpiperazin-l-yl)-lH-indazole-6-sulfonamide32. l-(l-(2-chloroacetyl)pyrrolidin-3-yl)-N-(l-methylcyclopropyl)-4-((3S,5S)-3,4,5 -trimethy Ipiperazin- 1 -y 1) - 1 H-indazole-6 - sulfonamide33. l-(l-acryloylpyrrolidin-3-yl)-4-((3R,5S)-3,5-dimethyl-4-(oxetan-3- yl)piperazin- 1 -yl)-N -( 1 -methylcyclopropyl)- lH-indazole-6-sulfonamide34. l-(l-(2-chloroacetyl)pyrrolidin-3-yl)-4-((3R,5S)-3,5-dimethyl-4-(oxetan-3- yl)piperazin- 1 -yl)-N -( 1 -methylcyclopropyl)- lH-indazole-6-sulfonamide35. l-(l-acryloylpyrrolidin-3-yl)-4-((3R,5S)-4-ethyl-3,5-dimethylpiperazin-l-yl)- N-( 1 -methylcyclopropyl)- 1 H-indazole-6- sulfonamide36. l-(l-(2-chloroacetyl)pyrrolidin-3-yl)-4-((3R,5S)-4-ethyl-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide37. l-(l-acryloylpyrrolidin-3-yl)-4-((3R,5S)-4-cyclopropyl-3,5-dimethylpiperazin- l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide38. l-(l-(2-chloroacetyl)pyrrolidin-3-yl)-4-((3R,5S)-4-cyclopropyl-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide39. 1 -((3R,5S)- 1 -acryloyl-5 -(fluoromethyl)pyrrolidin-3-yl)-N -( 1 - methylcyclopropyl)-4-((3S,5S)-3,4,5-trimethylpiperazin-l-yl)-lH-indazole-6- sulfonamide40. 1 -( 1 -(But-2-ynoyl)pyrrolidin-3-yl)-4-(4-isobutyrylpiperazin- 1 -yl)-N-( 1 - methylcyclopropyl)- lH-indazole-6- sulfonamide41. 4-(4-Isobutyrylpiperazin- 1 -yl)-N -( 1 -methylcyclopropyl)- 1 -( 1 - propioloylpyrrolidin-3-yl)-lH-indazole-6-sulfonamide42. (E)- 1 -( 1 -(4-(Dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-4-(4- isobutyrylpiperazin- 1 -yl)-N -( 1 -methylcyclopropyl)- lH-indazole-6- sulfonamide43. 1 -( 1 -(2-Fluoroacryloyl)pyrrolidin-3-yl)-4-(4-isobutyrylpiperazin- 1 -yl)-N -( 1 - methylcyclopropyl)- lH-indazole-6- sulfonamide44. 1 -( 1 - Acryloylpiperidin-4-yl) -4-(4-isobutyrylpiperazin- 1 -yl) -N-( 1 - methylcyclopropyl)- lH-indazole-6- sulfonamide45. (E)-l-(l-(4-(Dimethylamino)but-2-enoyl)piperidin-3-yl)-4-(4- isobutyrylpiperazin- 1 -yl)-N -( 1 -methylcyclopropyl)- lH-indazole-6- sulfonamide46. 1 -( 1 -(2-Fluoroacryloyl)piperidin-3-yl)-4-(4-isobutyrylpiperazin- 1 -yl)-N -( 1 - methylcyclopropyl)- lH-indazole-6- sulfonamide47. l-(l-(But-2-ynoyl)piperidin-3-yl)-4-(4-isobutyrylpiperazin-l-yl)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide48. 4-(4-isobutyrylpiperazin- 1 -yl)-N -( 1 -methylcyclopropyl)- 1 -(( 1 - propioloylpyrrolidin-3-yl)methyl)-lH-indazole-6-sulfonamide49. l-((3R,5S)-5-(fluoromethyl)-l-propioloylpyrrolidin-3-yl)-4-(4- isobutyrylpiperazin- 1 -yl)-N -( 1 -methylcyclopropyl)- lH-indazole-6- sulfonamide50. l-((3S,5R)-5-(fluoromethyl)-l-propioloylpyrrolidin-3-yl)-4-(4- isobutyrylpiperazin- 1 -yl)-N -( 1 -methylcyclopropyl)- lH-indazole-6- sulfonamide51. l-(l-(2-Chloroacetyl)pyrrolidin-3-yl)-4-((3R,5S)-3,5-dimethylpiperazin-l-yl)- N-( 1 -methylcyclopropyl)- 1 H-indazole-6- sulfonamide52. l-(l-Acryloylpyrrolidin-3-yl)-4-((3R,5S)-3,5-dimethylpiperazin-l-yl)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide53. 4-((3R,5S)-3 ,5-dimethylpiperazin- 1 -yl)-N -( 1 -methylcyclopropyl)- 1 -( 1 - propioloylpyrrolidin-3-yl)-lH-indazole-6-sulfonamide54. l-(l-(2,5-dichloropyrimidin-4-yl)pyrrolidin-3-yl)-4-((3R,5S)-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide55. l-((3R,5S)-l-acryloyl-5-(fluoromethyl)pyrrolidin-3-yl)-4-((3S,5S)-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide56. 4-((3S,5S)-3,5-dimethylpiperazin-l-yl)-l-((3R,5S)-5-(fluoromethyl)-l- propionylpyrrolidin-3-yl)-N-(l-methylcyclopropyl)-lH-indazole-6- sulfonamide57. 4-((3S,5S)-3,5-dimethylpiperazin-l-yl)-l-((3R,5S)-l-(2-fluoroacryloyl)-5- (fluoromethyl)pyrrolidin-3-yl)-N-( 1 -methylcyclopropyl)- lH-indazole-6- sulfonamide58. l-((3R,5S)-l-((E)-4-(dimethylamino)but-2-enoyl)-5-(fluoromethyl)pyrrolidin- 3-yl)-4-((3S,5S)-3,5-dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH- indazole-6 - sulfonamide59. 4-((3S,5S)-3,5-dimethylpiperazin-l-yl)-l-((3R,5S)-5-(fluoromethyl)-l- methacryloylpyrrolidin-3-yl)-N-(l-methylcyclopropyl)-lH-indazole-6- sulfonamide60. l-((3R,5S)-l-((E)-but-2-enoyl)-5-(fluoromethyl)pyrrolidin-3-yl)-4-((3S,5S)- 3 ,5-dimethylpiperazin- 1 -yl)-N -( 1 -methylcyclopropyl)- lH-indazole-6- sulfonamide61. 4-((3S,5S)-3,5-dimethylpiperazin-l-yl)-l-((3R,5S)-5-(fluoromethyl)-l-((E)-2- methylbut-2-enoyl)pyrrolidin-3 -yl)-N -(1 -methylcyclopropyl)- 1 H-indazole-6- sulfonamide62. l-((3R,5S)-l-(but-2-ynoyl)-5-(fluoromethyl)pyrrolidin-3-yl)-4-((3S,5S)-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide63. 4-((3S,5S)-3,5-dimethylpiperazin-l-yl)-l-((3R,5S)-5-(fluoromethyl)-l-((Z)-2- methylbut-2-enoyl)pyrrolidin-3 -yl)-N -(1 -methylcyclopropyl)- 1 H-indazole-6- sulfonamide64. 4-((3S,5S)-3,5-dimethylpiperazin-l-yl)-l-((3R,5S)-5-(fluoromethyl)-l-((E)- 4,4,4-trifluorobut-2-enoyl)pyrrolidin-3-yl)-N-( 1 -methylcyclopropyl)- 1H- indazole-6 - sulfonamide65. l-((3R,5R)-l-acryloyl-5-methylpyrrolidin-3-yl)-4-((3S,5S)-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide66. l-((3R,5S)-l-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-4-((3S,5S)-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide67. 4-((3S,5S)-3,5-dimethylpiperazin-l-yl)-l-((3R,5S)-5-(fluoromethyl)-l-(pent-2- ynoyl)pyrrolidin-3-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide68. l-((3R,5S)-l-acryloyl-5-methylpyrrolidin-3-yl)-4-((3S,5S)-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide69. l-((3R,5S)-l-acryloyl-5-(difluoromethyl)pyrrolidin-3-yl)-4-((3S,5S)-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide70. l-((3R,5S)-l-acryloyl-5-(fluoromethyl)pyrrolidin-3-yl)-3-cyclopropyl-4- ((3S,5S)-3,5-dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6- sulfonamide71. l-((3R,5S)-l-acryloyl-5-(hydroxymethyl)pyrrolidin-3-yl)-4-((3S,5S)-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide72. l-((3R,5S)-l-Acryloyl-5-((dimethylamino)methyl)pyrrolidin-3-yl)-4-((3S,5S)- 3 ,5-dimethylpiperazin- 1 -yl)-N -( 1 -methylcyclopropyl)- lH-indazole-6- sulfonamide73. l-((3R,5S)-l-acryloyl-5-(2-hydroxypropan-2-yl)pyrrolidin-3-yl)-4-((3S,5S)- 3 ,5-dimethylpiperazin- 1 -yl)-N -( 1 -methylcyclopropyl)- lH-indazole-6- sulfonamide74. l-((3R,5S)-l-acryloyl-5-(2-fluoropropan-2-yl)pyrrolidin-3-yl)-4-((3S,5S)-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide75. l-((3R,5S)-l-acryloyl-5-isopropylpyrrolidin-3-yl)-4-((3S,5S)-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide76. l-(l-(2,5-dichloropyrimidin-4-yl)pyrrolidin-3-yl)-4-(4-isobutyrylpiperazin-l- yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide77. 1 -( 1 -acryloylpyrrolidin-3-yl)-4-(4-(dimethylglycyl)piperazin- 1 -yl)-N -( 1 - methylcyclopropyl)- lH-indazole-6- sulfonamide78. 4-(4-(L-prolyl)piperazin- 1 -yl)- 1 -( 1 -acryloylpyrrolidin-3 -yl)-N -( 1 -methylcyclopropyl)- lH-indazole-6- sulfonamide hydrochloride79. methyl (2S,4R)-l-acryloyl-4-(4-((3S,5S)-3,5-dimethylpiperazin-l-yl)-6-(N-(l- methylcyclopropyl)sulfamoyl)- IH-indazol- 1 -yl)pyrrolidine-2-carboxylate80. l-((3R,5S)-l-acryloyl-5-(chloromethyl)pyrrolidin-3-yl)-4-((3S,5S)-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide81. 1 -((3R,5S)- 1 -acryloyl-5 -(fluoromethyl)pyrrolidin-3-yl)-N -( 1 - cyanocyclopropyl)-4-((3S,5S)-3,5-dimethylpiperazin-l-yl)-lH-indazole-6- sulfonamide or its pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, prodrugs, deuterated including other possible isotopes, combinations and use thereof.

3. Novel heterocyclic pure enantiomer compounds selected from1 -( 1 -(2-Chloroacetyl)pyrrolidin-3 -yl)-4-(4-isobutyrylpiperazin- 1 -yl)-N -( 1 - methylcyclopropyl)- lH-indazole-6- sulfonamide (Isomer- 1)1 -( 1 -(2-Chloroacetyl)pyrrolidin-3 -yl)-4-(4-isobutyrylpiperazin- 1 -yl)-N -( 1 - methylcyclopropyl)- lH-indazole-6- sulfonamide (Isomer- II)4. The compounds according to any of claim 1-3 or its pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, prodrugs, deuterated compounds including other possible isotopes, combinations thereof are non-covalent or covalent inhibitors of PARG; wherein the covalent inhibitors are irreversible or reversible covalent inhibitors of PARG.

5. A process for the preparation of novel heterocyclic compounds of Formula (I) or its pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, prodrugs, deuterated compounds including other possible isotopes, combinations.

6. A pharmaceutical composition comprising at least one compound according to claim 1-3 or its pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, prodrugs, deuterated compounds including other possible isotopes, combinations thereof and a pharmaceutically acceptable carrier or excipient.

7. The compound according to any of claim 1-3 or its pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, prodrugs, deuterated compounds including other possible isotopes, combinations thereof for use in treating cancer.

8. A method of treating cancer by administering to a subject therapeutically effective amount of a pharmaceutical composition comprising at least one or more of the compounds as claimed in claims 1-3 or its pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, prodrugs, deuterated compounds including other possible isotopes thereof.

9. The method as claimed in claim 8, wherein the cancer is associated with PARG protein.

10. The method as claimed in claims 8 to 9, wherein the cancer is a solid tumor or hematopoietic tumor.

11. The method as claimed in claim 10, wherein the solid tumor is selected from breast cancer, colorectal cancer, endometrial cancer, esophageal cancer, glioblastoma, hepatocellular carcinoma, lung cancer, neuroblastoma, ovarian cancer, prostate cancer, stomach cancer, rhabdomyosarcoma, fibrosarcoma, thyroid follicular cancer or Kaposi's sarcoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoactanthoma or uterine cancer.

12. The method as claimed in claim 10, wherein the hematopoietic tumor is selected from the group comprising:(a) a hematopoietic tumor of lymphoid lineage selected from leukemia, acute lymphocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-20 lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma or Burkett's lymphoma; and(b) a hematopoietic tumor of myeloid lineage selected from acute and chronic myelogenous leukaemia’s, myelodysplastic syndrome or promyelocytic leukemia.

Images