Pyridazinone derivatives as pad4 inhibitors

Abstract

The present invention provides compounds of Formula (I) useful as inhibitors of PAD4, compositions thereof, and methods of treating PAD4-related disorders, wherein each of Rings A, B, C, and variables X, and R, along with other variables are as defined herein.

Description

PAD4 INHIBITORS CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application Serial No. 63 / 701,630 filed October 1, 2024 which is incorporated herein in its entirety. BACKGROUND OF THE INVENTION PAD4 is a member of the peptidylarginine deiminase (PAD) family of enzymes capable of catalysing the citrullination of arginine into citrulline within peptide sequences. PAD4 is responsible for the deimination or citrullination of a variety of proteins in vitro and in vivo, with consequences of diverse functional responses in a variety of diseases (Jones J.E. et al, Curr. Opin. Drug Discov. Devel., 12(5), (2009),616-627). Examples of exemplar diseases include rheumatoid arthritis, diseases with neutrophilic contributions to pathogenesis (for example vasculitis, systemic lupus erythematosus, ulcerative colitis) in addition to oncology indications. PAD4 inhibitors also have wider applicability as tools and therapeutics for human disease through epigenetic mechanisms. Inhibitors of PAD4 have utility against Rheumatoid Arthritis (RA). RA is an auto-immune disease affecting approximately 1% of the population (Wegner N. et al, Immunol. Rev., 233(1) (2010), 34-54). It is characterized by inflammation of articular joints leading to debilitating destruction of bone and cartilage. A weak genetic association between PAD4 polymorphisms and susceptibility to RA has been suggested, albeit inconsistently, in a number of population studies (Kochi Y. et al, Ann. Rheum. Dis., 70, (2011),512-515). PAD4 (along with family member PAD2) has been detected in synovial tissue where it is responsible for the deimination of a variety of joint proteins. This process is presumed to lead to a break of tolerance to, and initiation of immune responses to, citrullinated substrates such as fibrinogen, vimentin and collagen in RA joints. These anti-citrullinated protein antibodies (ACPA) contribute to disease pathogenesis and may also be used as a diagnostic test for RA (e.g. the commercially available CCP2 or cyclic citrullinated protein 2 test). In addition, increased citrullination may also offer additional direct contributions to disease pathogenesis through its ability to affect directly the function of several jointand inflammatory mediators (e.g. fibrinogen, anti-thrombin, multiple chemokines). In a smaller subset of RA patients, anti-PAD4 antibodies can be measured and may correlate with a more erosive form of the disease. PAD4 inhibitors are also useful for the reduction of pathological neutrophil activity in a variety of diseases. Studies suggest that the process of Neutrophil Extracellular Trap (NET) formation, an innate defense mechanism by which neutrophils are able to immobilize and kill pathogens, is associated with histone citrullination and is deficient in PAD4 knockout mice (Neeli I. et al, J. Immunol., 180, (2008), 1895-1902 and Li P. et al, J. Exp. Med., 207(9), (2010), 1853-1862). PAD4 inhibitors may therefore have applicability for diseases where NET formation in tissues contributes to local injury and disease pathology. Such diseases include, but are not limited to, small vessel vasculitis (Kessenbrock K. et al, Nat. Med., 15(6), (2009), 623-625), systemic lupus erythematosus (Hakkim A. et al, Proc. Natl. Acad. Sci. USA, 107(21), (2010), 9813-9818 and Villanueva E. et al, J. Immunol., 187(1), (2011), 538-52), ulcerative colitis (Savchenko A. et al, Pathol. Int., 61(5), (2011), 290- 7), cystic fibrosis, asthma (Dworski R. et al, J. Allergy Clin. Immunol., 127(5), (2011), 1260-6), deep vein thrombosis (Fuchs T. et al, Proc. Natl. Acad. Sci. USA, 107(36), (2010), 15880-5), periodontitis (Vitkov L. et al, Ultrastructural Pathol., 34(1), (2010), 25-30), sepsis (Clark S.R. et al, Nat. Med., 13(4), (2007), 463-9), appendicitis (Brinkmann V. et al, Science, 303, (2004), 1532-5), and stroke. In addition, there is evidence that NETs may contribute to pathology in diseases affecting the skin, e.g., in cutaneous lupus erythematosis (Villanueva E. et al, J. Immunol., 187(1), (2011), 538- 52) and psoriasis (Lin A.M. et al., J. Immunol., 187(1), (2011), 490-500), so a PAD4 inhibitor may show benefit to tackle NET skin diseases, when administered by a systemic or cutaneous route. PAD4 inhibitors may affect additional functions within neutrophils and have wider applicability to neutrophilic diseases. Studies have demonstrated efficacy of tool PAD inhibitors (for example chloro- amidine) in a number of animal models of disease, including collagen-induced arthritis (Willis V.C. et al, J. Immunol., 186(7), (2011), 4396-4404), dextran sulfate sodium (DSS)-induced experimental colitis (Chumanevich A.A. et al, Am. J. Physiol. Gastrointest. Liver Physiol., 300(6), (2011), G929–G938), spinal cord repair (Lange S. et al, Dev. Biol., 355(2), (2011), 205-14), and experimental autoimmuneencephalomyelitis (EAE). The DSS colitis report also demonstrates that chloro- amidine drives apoptosis of inflammatory cells both in vitro and in vivo, suggesting that PAD4 inhibitors may be effective more generally in widespread inflammatory diseases. PAD4 inhibitors are also useful in the treatment of cancers (Slack J.L. et al, Cell. Mol. Life Sci., 68(4), (2011), 709-720). Over-expression of PAD4 has been demonstrated in numerous cancers (Chang X. et al, BMC Cancer, 9, (2009), 40). An anti-proliferative role has been suggested for PAD4 inhibitors from the observation that PAD4 citrullinates arginine residues in histones at the promoters of p53-target genes such as p21, which are involved in cell cycle arrest and induction of apoptosis (Li P. et al, Mol. Cell Biol., 28(15), (2008), 4745-4758). The aforementioned role of PAD4 in deiminating arginine residues in histones may be indicative of a role for PAD4 in epigenetic regulation of gene expression. PAD4 is the primary PAD family member observed to be resident in the nucleus as well as the cytoplasm. Early evidence that PAD4 may act as a histone demethyliminase as well as a deiminase is inconsistent and unproven. However, it may reduce histone arginine methylation (and hence epigenetic regulation associated with this mark) indirectly via depletion of available arginine residues by conversion to citrulline. PAD4 inhibitors are useful as epigenetic tools or therapeutics for affecting expression of varied target genes in additional disease settings. Through such mechanisms, PAD4 inhibitors may also be effective in controlling citrullination levels in stem cells and may therefore therapeutically affect the pluripotency status and differentiation potential of diverse stem cells including, but not limited to, embryonic stem cells, neural stem cells, haematopoietic stem cells and cancer stem cells. Accordingly, there remains an unmet need to identify and develop PAD4 inhibitors for the treatment of PAD4-mediated disorders.SUMMARY OF THE INVENTION It has now been found that compounds of Formula (I) are useful as inhibitors of PAD4:or a pharmaceutically acceptable salt thereof, wherein each of Ring A, Ring and Ring C, X, and R, along with other variables is as defined herein. In some embodiments, a provided compound demonstrates selectivity for PAD4 with respect to PAD2. The present invention also provides pharmaceutically acceptable compositions comprising a provided compound. Provided compounds are useful in treatment of various disorders associated with PAD4. Such disorders are described in detail, herein, and include, for example rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosis, and psoriasis. DETAILED DESCRIPTION OF THE INVENTION 1. General Description of Certain Aspects of the Invention In some embodiments, such compounds include those of the formulae described herein, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined herein and described in embodiments. Such compounds have the structure of Formula (I):or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:--- is an optional bond; Q is selected from the group consisting of CH, CR5, and N;is a 6-membered heterocycle of the formula comprising one ortwo nitrogen atoms; X is selected from the group consisting of -S(=O)-, -S(=O)2-, and -S(=O)(=NH)-; R is selected from the group consisting of C2-4alkylene, C2-4alkenylene, and C3-4alkoxylene, each substituted with 1-4 R7; R1is selected from the group consisting of halogen, CN, Ra, NRaRa, and –ORa; R2 is selected from the group consisting of –OR2a, –(CH2)n-NR2aR2a, –(CH2)n-3-10 membered carbocycle substituted with 1-4 of R2b, –(CH2)n-3-10 membered heterocycle substituted with 1-4 of R2b, -O-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R2b, -O-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R2b, -NR2a-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R2b, and -NR2a-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R2b; R2a, at each occurrence, is independently selected from the group consisting of H and C1-6alkyl substituted with 0-4 Rc; R2b, at each occurrence, is independently selected from the group consisting of D, Ra, halogen, =O, CN, -NRaRa, -ORa, S(=O)2NH2, C(=O)Ra, and C(=O)ORa; R3is selected from the group consisting of halogen, CN, Ra, and –ORa; R4is selected from the group consisting of H and =O; R5, at each occurrence, is independently selected from the group consisting of halogen, CN, C1-6alkyl substituted with 0-5 Rc, and –ORa; R6, at each occurrence, is independently selected from the group consisting of halogen, CN, R6a, -(CH2)nNR6aR6a, -(CH2)nOR6a, -(CH2)nCONR6aR6a, - (CH2)nNR6aCONR6aR6a, -(CH2)nNR6aCOR6a, -(CH2)nNR6aSO2R6a, -(CH2)nS(=O)2, -NR6a(CH2)1-3NR6aCOR6a, -NR6a(CH2)1-3NR6aCOOR6a, -O(CR6bR6b)1- 3O(CR6bR6b)1-3OR6a, –(CH2)n-3-10 membered carbocycle substituted with 1-4 of R6b, –(CH2)n-3-10 membered heterocycle substituted with 1-4 of R6b, -O-(CH2)n- 3-10 membered carbocycle substituted with 1-4 of R6b, -O-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R6b, -NR6a-(CH2)n-3-10 membered carbocyclesubstituted with 1-4 of R6b, and -NR6a-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R6b; R6a, at each occurrence, is independently selected from the group consisting of H and C1-6alkyl substituted with 0-5 Rc; R6b, at each occurrence, is independently selected from the group consisting of D, Ra, halogen, =O, CN, -NRaRa, -NRaCORa, -NRaCOORa, -ORa; R7, at each occurrence, is independently selected from the group consisting of =O, Raand –ORa; or R7and R7together with the carbon atom to which they are both attached form a C3-6cycloalkyl; Ra, at each occurrence, is independently selected from the group consisting of H and C1-6alkyl substituted with 0-5 Rc; Rc, at each occurrence, is independently selected from the group consisting of –OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, halogen, =O, CONH2, -COOH, and - COOC1-4 alkyl; n is an integer of 0, 1, 2, 3, 4, or 5;provided is when is .2. Definitions Throughout the specification and the appended claims, a given chemical formula or name shall encompass all stereo and optical isomers and racemates thereof where such isomers exist. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the invention. Many geometric isomers of C=C double bonds, C=N double bonds, ring systems, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. Cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. The present compounds can be isolated in optically active or racemic forms. Optically active forms may be prepared byresolution of racemic forms or by synthesis from optically active starting materials. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention. When enantiomeric or diastereomeric products are prepared, they may be separated by conventional methods, for example, by chromatography or fractional crystallization. Depending on the process conditions the end products of the present invention are obtained either in free (neutral) or salt form. Both the free form and the salts of these end products are within the scope of the invention. If so desired, one form of a compound may be converted into another form. A free base or acid may be converted into a salt; a salt may be converted into the free compound or another salt; a mixture of isomeric compounds of the present invention may be separated into the individual isomers. Compounds of the present invention, free form and salts thereof, may exist in multiple tautomeric forms, in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged. It should be understood that all tautomeric forms, insofar as they may exist, are included within the invention. As used herein, the term "alkyl" or "alkylene" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For examples, "C1to C12alkyl" or "C1-12alkyl" (or alkylene), is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11and C12alkyl groups; "C4to C18alkyl" or "C4-18alkyl" (or alkylene), is intended to include C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, and C18alkyl groups. Additionally, for example, "C1to C6alkyl" or "C1-6alkyl" denotes alkyl having 1 to 6 carbon atoms. Alkyl group can be unsubstituted or substituted with at least one hydrogen being replaced by another chemical group. Example alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). When "C0 alkyl" or "C0 alkylene" is used, it is intended to denote a direct bond. "Alkenyl" or "alkenylene" is intended to include hydrocarbon chains of either straight or branched configuration having the specified number of carbon atoms and one or more, preferably one to two, carbon-carbon double bonds that may occur in any stable point along the chain. For example, "C2 to C6 alkenyl" or "C2-6 alkenyl" (oralkenylene), is intended to include C2, C3, C4, C5, and C6 alkenyl groups. Examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3, pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl. "Alkynyl" or "alkynylene" is intended to include hydrocarbon chains of either straight or branched configuration having one or more, preferably one to three, carbon-carbon triple bonds that may occur in any stable point along the chain. For example, "C2to C6alkynyl" or "C2-6alkynyl" (or alkynylene), is intended to include C2, C3, C4, C5, and C6alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl. The term "alkoxy" or "alkyloxy" refers to an -O-alkyl group. For example, "C1 to C6 alkoxy" or "C1-6alkoxy" (or alkyloxy), is intended to include C1, C2, C3, C4, C5, and C6 alkoxy groups. Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy. Similarly, "alkylthio" or "thioalkoxy" represents an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge; for example methyl-S- and ethyl-S-. "Halo" or "halogen" includes fluoro, chloro, bromo, and iodo. "Haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl also include "fluoroalkyl" that is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more fluorine atoms. The term "cycloalkyl" refers to cyclized alkyl groups, including mono-, bi- or poly-cyclic ring systems. For example, "C3 to C6 cycloalkyl" or "C3-6 cycloalkyl" is intended to include C3, C4, C5, and C6 cycloalkyl groups. Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl". The term"cycloalkenyl" refers to cyclized alkenyl groups. C4-6 cycloalkenyl is intended to include C4, C5, and C6 cycloalkenyl groups. Example cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, and cyclohexenyl. As used herein, "carbocycle", "carbocyclyl", or "carbocyclic residue" is intended to mean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclic hydrocarbon ring, any of which may be saturated, partially unsaturated, unsaturated or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shown above, bridged rings are also included in the definition of carbocycle (e.g., [2.2.2]bicyclooctane). Preferred carbocycles, unless otherwise specified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, indanyl, and tetrahydronaphthyl. When the term "carbocycle" is used, it is intended to include "aryl." A bridged ring occurs when one or more, preferably one to three, carbon atoms link two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge. As used herein, the term "bicyclic carbocycle" or "bicyclic carbocyclic group" is intended to mean a stable 9- or 10-membered carbocyclic ring system that contains two fused rings and consists of carbon atoms. Of the two fused rings, one ring is a benzo ring fused to a second ring; and the second ring is a 5- or 6-membered carbon ring which is saturated, partially unsaturated, or unsaturated. The bicyclic carbocyclic group may be attached to its pendant group at any carbon atom which results in a stable structure. The bicyclic carbocyclic group described herein may be substituted on any carbon if the resulting compound is stable. Examples of a bicyclic carbocyclic group are, but not limited to, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and indanyl. "Carbocycle", "carbocyclyl", or "carbocyclic residue" can also refer to spiro compounds, for example, a spiro[3.3]heptane."Aryl" groups refer to monocyclic or bicyclic aromatic hydrocarbons, including, for example, phenyl, and naphthyl. Aryl moieties are well known and described, for example, in Lewis, R.J., ed., Hawley's Condensed Chemical Dictionary, 15th Edition, John Wiley & Sons, Inc., New York (2007). "C6-10aryl" refers to phenyl and naphthyl. As used herein, the term "heterocycle", "heterocyclyl", or "heterocyclic group" is intended to mean a stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered polycyclic heterocyclic ring that is saturated, partially unsaturated, or fully unsaturated, and that contains carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S; and including any polycyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally beoxidized (i.e., N O and S(O)p, wherein p is 0, 1 or 2). The nitrogen atom may besubstituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined). The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. When the term "heterocycle" is used, it is intended to include heteroaryl. Examples of heterocycles include, but are not limited to, acridinyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazolopyridinyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles. Examples of 5- to 10-membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl, benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl, quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl. Examples of 5- to 6-membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles. As used herein, the term "bicyclic heterocycle" or "bicyclic heterocyclic group" is intended to mean a stable 9- or 10-membered heterocyclic ring system which containstwo fused rings and consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O and S. Of the two fused rings, one ring is a 5- or 6-membered monocyclic aromatic ring comprising a 5-membered heteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, each fused to a second ring. The second ring is a 5- or 6-membered monocyclic ring which is saturated, partially unsaturated, or unsaturated, and comprises a 5-membered heterocycle, a 6-membered heterocycle or a carbocycle (provided the first ring is not benzo when the second ring is a carbocycle). The bicyclic heterocyclic group may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The bicyclic heterocyclic group described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. Examples of a bicyclic heterocyclic group are, but not limited to, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl, 1,2,3,4-tetrahydro-quinoxalinyl, and 1,2,3,4-tetrahydro-quinazolinyl. As used herein, the term "aromatic heterocyclic group" or "heteroaryl" is intended to mean stable monocyclic and polycyclic aromatic hydrocarbons that include at least one heteroatom ring member such as sulfur, oxygen, or nitrogen. Heteroaryl groups include, without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, benzodioxolanyl, and benzodioxane. Heteroaryl groups are substituted or unsubstituted. The nitrogen atom is substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined). The nitrogen and sulfur heteroatoms mayoptionally be oxidized (i.e., N O and S(O)p, wherein p is 0, 1 or 2).Examples of 5- to 6-membered heteroaryls include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, imidazolyl, imidazolidinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxazolidinyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl. Bridged rings are also included in the definition of heterocycle. A bridged ring occurs when one or more, preferably one to three, atoms (i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms. Examples of bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge. The term "counter ion" is used to represent a negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate or a positively charged species such as sodium (Na+), potassium (K+), ammonium (RnNHm+ where n=0-4 and m=0-4) and the like. When a dotted ring is used within a ring structure, this indicates that the ring structure may be saturated, partially saturated or unsaturated. As used herein, the term "amine protecting group" means any group known in the art of organic synthesis for the protection of amine groups which is stable to an ester reducing agent, a disubstituted hydrazine, R4-M and R7-M, a nucleophile, a hydrazine reducing agent, an activator, a strong base, a hindered amine base and a cyclizing agent. Such amine protecting groups fitting these criteria include those listed in Wuts, P.G.M. et al., Protecting Groups in Organic Synthesis, 4th Edition, Wiley (2007) and The Peptides: Analysis, Synthesis, Biology, Vol.3, Academic Press, New York (1981), the disclosure of which is hereby incorporated by reference. Examples of amine protecting groups include, but are not limited to, the following: (1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; (2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); (3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; (4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; (5) alkyl types such astriphenylmethyl and benzyl; (6) trialkylsilane such as trimethylsilane; (7) thiol containing types such as phenylthiocarbonyl and dithiasuccinoyl; and (8) alkyl types such as triphenylmethyl, methyl, and benzyl; and substituted alkyl types such as 2,2,2-trichloroethyl, 2-phenylethyl, and t-butyl; and trialkylsilane types such as trimethylsilane. As referred to herein, the term "substituted" means that at least one hydrogen atom is replaced with a non-hydrogen group, provided that normal valencies are maintained and that the substitution results in a stable compound. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). In cases wherein there are nitrogen atoms (e.g., amines) on compounds of the present invention, these may be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxides) to afford other compounds of this invention. Thus, shown and claimed nitrogen atoms are considered to cover both theshown nitrogen and its N-oxide (N O) derivative.When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R, then said group may optionally be substituted with up to three R groups, and at each occurrence R is selected independently from the definition of R. When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom in which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, and / or other problem or complication, commensurate with a reasonable benefit / risk ratio.As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. 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. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate baseor acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Allen, Jr., L.V., ed., Remington: The Science and Practice of Pharmacy, 22nd Edition, Pharmaceutical Press, London, UK (2012), the disclosure of which is hereby incorporated by reference. In addition, compounds of Formula (I) may have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent (i.e., a compound of Formula (I)) is a prodrug within the scope and spirit of the invention. Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see: a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and Widder, K. et al., eds., Methods in Enzymology, 112:309-396, Academic Press (1985); b) Bundgaard, H., Chapter 5, "Design and Application of Prodrugs", Krosgaard-Larsen, P. et al., eds., A Textbook of Drug Design and Development, pp.113- 191, Harwood Academic Publishers (1991); c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992); d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988); e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984); and f) Rautio, J., ed., Prodrugs and Targeted Delivery (Methods and Principles in Medicinal Chemistry), Vol.47, Wiley-VCH (2011). Compounds containing a carboxy group can form physiologically hydrolyzable esters that serve as prodrugs by being hydrolyzed in the body to yield formula I compounds per se. Such prodrugs are preferably administered orally since hydrolysis in many instances occurs principally under the influence of the digestive enzymes. Parenteral administration may be used where the ester per se is active, or in those instances where hydrolysis occurs in the blood. Examples of physiologically hydrolyzable esters of compounds of formula I include C1-6alkyl, C1-6alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, C1-6alkanoyloxy-C1-6alkyl (e.g., acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl), C1-6alkoxycarbonyloxy-C1-6alkyl (e.g., methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and other well known physiologicallyhydrolyzable esters used, for example, in the penicillin and cephalosporin arts. Such esters may be prepared by conventional techniques known in the art. Preparation of prodrugs is well known in the art and described in, for example, King, F.D., ed., Medicinal Chemistry: Principles and Practice, The Royal Society of Chemistry, Cambridge, UK (2nd Edition, reproduced (2006)); Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, C.G., ed., The Practice of Medicinal Chemistry, 3rd Edition, Academic Press, San Diego, CA (2008). The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium (symbol D or 2H) and tritium (symbol T or 3H). For example, a methyl group may be represented by CH3 or CD3. Isotopes of carbon include13C and14C. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. The term "solvate" means a physical association of a compound of this invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. The solvent molecules in the solvate may be present in a regular arrangement and / or a non-ordered arrangement. The solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules. "Solvate" encompasses both solution-phase and isolable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are generally known in the art. The terms “measurable affinity” and “measurably inhibit,” as used herein, means a measurable change in PAD4 activity between a sample comprising a compound of the present invention, or composition thereof, and PAD4, and an equivalent sample comprising PAD4 in the absence of said compound, or composition thereof.Abbreviations as used herein, are defined as follows: "1 x" for once, "2 x" for twice, "3 x" for thrice, "ºC" for degrees Celsius, "eq" for equivalent or equivalents, "g" for gram or grams, "mg" for milligram or milligrams, "L" for liter or liters, "mL" for milliliter or milliliters, " L" for microliter or microliters, "N" for normal, "M" formolar, "mmol" for millimole or millimoles, "min" for minute or min, "h" for hour or h, "rt" for room temperature, "RT" for retention time, "atm" for atmosphere, "psi" for pounds per square inch, "conc." for concentrate, "aq" for "aqueous", "sat" or "sat'd " for saturated, "MW" for molecular weight, "mp" for melting point, "MS" or "Mass Spec" for mass spectrometry, "ESI" for electrospray ionization mass spectroscopy, "HR" for high resolution, "HRMS" for high resolution mass spectrometry, "LCMS" for liquid chromatography mass spectrometry, "HPLC" for high pressure liquid chromatography, "RP HPLC" for reverse phase HPLC, "TLC" or "tlc" for thin layer chromatography, "NMR" for nuclear magnetic resonance spectroscopy, "nOe" for nuclear Overhauser effect spectroscopy, "1H" for proton, " " for delta, "s" for singlet,"d" for doublet, "t" for triplet, "q" for quartet, "m" for multiplet, "br" for broad, "Hz" for hertz, and " ", " ", "R", "S", "E", "Z" and "ee" are stereochemical designationsfamiliar to one skilled in the art. As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. AcOH or HOAc acetic acid ACN acetonitrile Alk Alkyl AlMe3 TrimethylaluminumBBr3boron tribromideBn benzyl Boc tert-butyloxycarbonylBOP reagent benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate Bu butyl i-Bu isobutyl t-Bu tert-butyl t-BuOH tert-butanol Cbz carbobenzyloxyCDCl3deutero-chloroformCD3ODdeutero-methanolCH2Cl2dichloromethaneCH3CN acetonitrileCHCl3chloroformDCM dichloromethane DIEA, DIPEA or diisopropylethylamine Hunig's base DMF dimethyl formamide DMSO dimethyl sulfoxide Et ethylEt3N or TEAtriethylamineEt2Odiethyl ether EtOAc ethyl acetate EtOH ethanol HCl hydrochloric acid HPLC high-performance liquid chromatographyK2CO3potassium carbonateK2HPO4potassium hydrogenphosphateLCMS liquid chromatography mass spectrometry LiHMDS lithium bis(trimethylsilyl)amide LG leaving group Me methyl MeOH methanolMgSO4magnesium sulfateMsOH or MSA methylsulfonic acid NaCl sodium chloride Na2CO3sodium carbonate NaHCO3sodium bicarbonateNaOH sodium hydroxide Na2SO4sodium sulfateNH3ammoniaNH4Clammonium chloride NH4OAcammonium acetate Pd(OAc)2palladium(II) acetate Pd(dppf)Cl2[1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0) PG protecting group Ph phenyl Pr propyl i-Pr isopropyl i-PrOH or IPA isopropanol Rt retention time SiO2silica oxide SFC supercritical fluid chromatography TBAI Tetrabutylammonium iodide TEA triethylamine TFA trifluoroacetic acid TFAA Trifluoroacetic anhydride THF tetrahydrofuran TiCl4 titanium tetrachloride T3P 1-propanephosphonic acid cyclic anhydride3. Description of Exemplary CompoundsIn a first aspect, the present invention provides a compound of Formula (I): (I), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: is selected from the group consisting of , ,, , ,, , , , , , ,and ;--- is an optional bond; Q is selected from the group consisting of CH, CR5, and N;is selected from the group consisting of , ,and ; is a 6-membered heterocycle of the formula comprising one ortwo nitrogen atoms; X is selected from the group consisting of -S(=O)-, -S(=O)2-, and -S(=O)(=NH)-; R is selected from the group consisting of C2-4alkylene, C2-4alkenylene, and C3-4alkoxylene, each substituted with 1-4 R7; R1 is selected from the group consisting of halogen, CN, Ra, NRaRa, and –ORa; R2 is selected from the group consisting of halogen, –OR2a, –(CH2)n-NR2aR2a, –(CH2)n-3- 10 membered carbocycle substituted with 1-4 of R2b, –(CH2)n-3-10 membered heterocycle substituted with 1-4 of R2b, -O-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R2b, -O-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R2b, -NR2a-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R2b, and -NR2a-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R2b; R2a, at each occurrence, is independently selected from the group consisting of H and C1-6alkyl substituted with 0-4 Rc; R2b, at each occurrence, is independently selected from the group consisting of D, Ra, halogen, =O, CN, -NRaRa, -ORa, S(=O)2NH2, C(=O)Ra, and C(=O)ORa; R3is selected from the group consisting of halogen, CN, Ra, and –ORa; R4is selected from the group consisting of H and =O; R5, at each occurrence, is independently selected from the group consisting of halogen, CN, C1-6alkyl substituted with 0-5 Rc, and –ORa; R6, at each occurrence, is independently selected from the group consisting of halogen, CN, R6a, -(CH2)nNR6aR6a, -(CH2)nOR6a, -(CH2)nCONR6aR6a, -(CH2)nNR6aCONR6aR6a, -(CH2)nNR6aCOR6a, -(CH2)nNR6aSO2R6a, -(CH2)nS(=O)2, -NR6a(CH2)1-3NR6aCOR6a, -NR6a(CH2)1-3NR6aCOOR6a, -O(CR6bR6b)1- 3O(CR6bR6b)1-3OR6a, –(CH2)n-3-10 membered carbocycle substituted with 1-4 of R6b, –(CH2)n-3-10 membered heterocycle substituted with 1-4 of R6b, -O-(CH2)n- 3-10 membered carbocycle substituted with 1-4 of R6b, -O-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R6b, -NR6a-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R6b, and -NR6a-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R6b; R6a, at each occurrence, is independently selected from the group consisting of H and C1-6alkyl substituted with 0-5 Rc; R6b, at each occurrence, is independently selected from the group consisting of D, Ra, halogen, =O, CN, -NRaRa, -NRaCORa, -NRaCOORa, -ORa; R7, at each occurrence, is independently selected from the group consisting of =O, Ra, and –ORa; or R7 and R7 together with the carbon atom to which they are both attached form a C3-6 cycloalkyl; Ra, at each occurrence, is independently selected from the group consisting of H and C1-6alkyl substituted with 0-5 Rc; Rc, at each occurrence, is independently selected from the group consisting of –OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, halogen, =O, CONH2, -COOH, and - COOC1-4alkyl; n is an integer of 0, 1, 2, 3, 4, or 5;provided is when is. In a second aspect, the present invention provides a compound of Formula (I), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, within the scope of the first aspect, wherein: R is selected from the group consisting of -CHR7CR7CH2-, -CH2C(R7)2CH2-, and - CH2C(R7)2CH2O-; andR7 is selected from the group consisting of H, CH3, CH2OH, and OH; or R7 and R7 together with the carbon atom to which they are both attached form a cyclopropyl. In a third aspect, the present invention provides a compound of Formula (II): (II), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, within the scope of the first aspect, wherein: R1is selected from the group consisting of F, Cl, CN, Ra, and –ORa; R2is selected from the group consisting of halogen, –OR2a, –(CH2)n-NR2aR2a, –(CH2)n-3- 10 membered carbocycle substituted with 1-4 of R2b, –(CH2)n-3-10 membered heterocycle substituted with 1-4 of R2b, -O-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R2b, -O-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R2b, -NH-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R2b, and -NH-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R2b; R2a, at each occurrence, is independently selected from H and a C1-6alkyl substituted with 0-4 Rc; R2b, at each occurrence, is independently selected from the group consisting of D, Ra, halogen, =O, CN, -NRaRa, and -ORa; R3 is selected from the group consisting of halogen, CN, and Ra; R5, at each occurrence, is independently selected from the group consisting of halogen, CN, C1-4alkyl substituted with 0-4 Rc, and –ORa; R6, at each occurrence, is independently selected from halogen, CN, R6a, –OR6a, - O(CH2)n(O)n(CH2)nOR6a, -(CH2)nNR6aR6a, -(CH2)nOR6a, -(CH2)nCONR6aR6a, - (CH2)nNR6aCONR6aR6a, -(CH2)nNR6aCOR6a,-NH-(CH2)n-NR6aR6a, –(CH2)n-3-10 membered carbocycle substituted with 1-4 of R6b, –(CH2)n-3-10 memberedheterocycle substituted with 1-4 of R6b, -O-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R6b, -O-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R6b, -NH-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R6b, and -NH-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R6b; R6a, at each occurrence, is independently selected from H and a C1-6alkyl substituted with 0-3 Rc; R6b, at each occurrence, is independently selected from D, Ra, halogen, =O, CN, -NRaRa, and -ORa; R7, at each occurrence, is independently selected from the group consisting of Raand ORa; Ra, at each occurrence, is independently selected from the group consisting of H and C1-6alkyl substituted with 0-3 Rc; Rc, at each occurrence, is independently selected from the group consisting of –OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, halogen, =O, -COOH, and -COOC1-4 alkyl; and n is an integer of 0, 1, 2, or 3. In a fourth aspect, the present invention provides of a compound of formula (III): (III), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, within the scope of the third aspect, wherein: R1is selected from the group consisting of F, Cl, CN, and H; R2is selected from the group consisting of halogen, –OR2a, -NR2aR2a, –(CH2)n-3-10 membered carbocycle substituted with 1-4 of R2b, –(CH2)n-3-10 membered heterocycle substituted with 1-4 of R2b, -O-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R2b, -O-(CH2)n-3-10 membered heterocycle substitutedwith 1-4 of R2b, -NH-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R2b, and -NH-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R2b; R2a, at each occurrence, is independently selected from H and C1-3alkyl substituted with 0-4 Rc; R2b, at each occurrence, is independently selected from the group consisting of D, Ra, and halogen; R3is selected from the group consisting of halogen, CN, and H; R5, at each occurrence, is independently selected from the group consisting of halogen, CN, C1-3alkyl substituted with 0-3 Rc, and -ORa; R6, at each occurrence, is independently selected from halogen, CN, R6a, –OR6a, - O(CH2)n(O)n(CH2)nOR6a, -(CH2)nNR6aR6a, -(CH2)nOR6a, -(CH2)nCONR6aR6a, - (CH2)nNR6aCONR6aR6a, -(CH2)nNR6aCOR6a,-NH-(CH2)n-NR6aR6a, –(CH2)n-3-10 membered carbocycle substituted with 1-4 of R6b, –(CH2)n-3-10 membered heterocycle substituted with 1-4 of R6b, -O-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R6b, -O-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R6b, -NH-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R6b, and -NH-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R6b; R6a, at each occurrence, is independently selected from H and a C1-6alkyl substituted with 0-3 Rc; R6b, at each occurrence, is independently selected from D, Ra, halogen, =O, CN, -NRaRa, and -ORa; R7is selected from the group consisting of H and CH3. Ra, at each occurrence, is independently selected from the group consisting of H and C1-6alkyl substituted with 0-3 Rc; Rc, at each occurrence, is independently selected from the group consisting of –OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, halogen, =O, -COOH, and -COOC1-4 alkyl; and n is an integer of 0, 1, 2, 3, or 4. In a fifth aspect, the present invention provides a compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof thereof, within the scope of the fourth aspect, wherein:R2 is selected from the group consisting of –OCH3, –NH-CH3, –NH-CH2CH3, and – N(CH3)2. In a sixth aspect, the present invention provides a compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, within the scope of the fourth aspect, wherein: R2is –(CH2)n-3-10 membered heterocycle substituted with 1-4 of R2b. In a seventh aspect, the present invention provides a compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, within the scope of the fourth aspect, wherein: R2 is selected from the group consisting of –O-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R2b, and –O-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R2b. In an eighth aspect, the present invention provides a compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, within the scope of the fourth aspect, wherein: R2is selected from the group consisting of –NH-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R2b, and –NH-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R2b. In a ninth aspect, the present invention provides a compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, within the scope of the fourth aspect, wherein: R2 is selected from the group consisting of –O(CH2)2-3NH2, –OCH3, –NH-CH3, –NH- CH2CH3, –N(CH3)2, , , , ,, , , , , ,, , , , , ,, , , ,, , , , , ,, , , , ,CH3NH N ,, , , CH3 , ,, , , , ,, , ,, , , , ,, , , ,, , , , , ,, and .In a tenth aspect, the present invention provides a compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, within the scope of the fourth aspect, wherein: R3is selected from the group consisting of F, Cl, CN, and H. In an eleventh aspect, the present invention provides a compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, within the scope of the fourth aspect, wherein: R5, at each occurrence, is independently selected from the group consisting of F, Cl, CH3, CF3, -OCH3, and -OCF3. In a twelfth aspect, the present invention provides a compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, within the scope of the fourth aspect, wherein: R6, at each occurrence, is independently selected from the group consisting of F, H, -CH2- NH2, -CH2CH2-CO-NH2, -CH2-NH-CO-CH2, -CH2-NH-SO2-C(CH3)3, NH2, -NH- CH3, -NH-CH2-CO-NH2, -NH-CH(CH3)-CO-NH2, -NH-CH2-CH2-NH2, -NH- CH2CH2CH2-NH2, -NH-CH2CH2CH2CH2-NH2, -NH-CH2-CH(OH)-CH2-NH2, - NH-CH2-CH(CH3)-CH2-NH2, -NH-CH2-CH(F)-CH2-NH2, -NH-CH2CH2CH2-NH- CH3, -NH-CH2-C(CH3)2-CH2-NH2, -CH2CH2CH2-NH2, -NH-CH2-CH(CH3)-NH2, -NH-CH2-CH(F)-NH2, -NH-CH(CH3)-CH2-NH2, -NH-CH2-CHF-CH2-NH2, -NH- CH2-CF2-CH2-NH2, -NH-CH2CH2-CH(NH2)-COOH, -O-CH2CH2-NH2, -O- CH2CH2CH2-NH2, -O-CH2-CF2-CH2-NH2, -O-CH2CH2-OH, ,, , , , ,, , , , ,, , , ,, , , , ,, , , , ,, , and . In a thirteenth aspect, the present invention provides a compound of Formula (IV): (IV), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, within the scope of the first aspect, wherein: R2 is selected from the group consisting of 3-10 membered heterocycle substituted with 1-4 of R2b, -O-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R2b, -O- (CH2)n-3-10 membered heterocycle substituted with 1-4 of R2b, -NH-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R2b, and -NH-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R2b; R2a, at each occurrence, is independently selected from H and a C1-6alkyl substituted with 0-4 Rc; R2b, at each occurrence, is independently selected from the group consisting of D, Ra, halogen, =O, CN, -NRaRa, and -ORa; R3 is selected from the group consisting of halogen and CN; R5, at each occurrence, is independently selected from the group consisting of halogen, CN, C1-4 alkyl, and –ORa;R6, at each occurrence, is independently selected from halogen, CN, R6a, –OR6a, - O(CH2)n(O)n(CH2)nOR6a, -(CH2)nNR6aR6a, -(CH2)nOR6a, -(CH2)nCONR6aR6a, - (CH2)nNR6aCONR6aR6a, -(CH2)nNR6aCOR6a,-NH-(CH2)n-NR6aR6a, –(CH2)n-3-10 membered carbocycle substituted with 1-4 of R6b, –(CH2)n-3-10 membered heterocycle substituted with 1-4 of R6b, -O-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R6b, -O-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R6b, -NH-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R6b, and -NH-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R6b; R6a, at each occurrence, is independently selected from H and a C1-6alkyl substituted with 0-3 Rc; R6b, at each occurrence, is independently selected from D, Ra, halogen, =O, CN, -NRaRa, and -ORa; R7 is selected from the group consisting of H and CH3; Ra, at each occurrence, is independently selected from the group consisting of H and C1-6alkyl substituted with 0-3 Rc; Rc, at each occurrence, is independently selected from the group consisting of –OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, halogen, =O, -COOH, and -COOC1-4 alkyl; and n is an integer of 0, 1, 2, 3, or 4. In a fourteenth aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, within the scope of the twelfth and thirteenth aspects, wherein: R1is Cl;R2 is selected from the group consisting of –NH-CH3, , ,, and ;R5, at each occurrence, is independently selected from the group consisting of F, Cl, and CH3;R6, at each occurrence, is independently selected from the group consisting of –O(CH2)2- 3NH2, -NH-CH2-CH2-NH2, -NH-CH2-CH(CH3)-NH2, -NH-CH2-CH(F)-NH2, - NH-CH2-CH(F)-CH2-NH2, -O-CH2CH2-OH, , , ,, , , and; and R7, at each occurrence, is independently selected from the group consisting of H and CH3. In a fifteenth aspect, the present invention provides a compound of Formula (V): (V), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, within the scope of the first aspect, wherein: is selected from the group consisting of ,, , ,, , , , and , ; R1is Cl;R2 is selected from the group consisting of –NH-CH3, , ,, and ;R5, at each occurrence, is independently selected from the group consisting of F, Cl, and CH3; and R7is selected from the group consisting of H and CH3. In a sixteenth aspect, the present invention provides a compound of Formula (VI): R1R2(R6)1-4OR7C S R O3R4(R5)1-4(VI) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, within the scope of the first aspect wherein:is selected from the group consisting of and ; R1is selected from the group consisting of halogen, CN, Raand –ORa;R2 is selected from the group consisting of , , ,, , and ;R5, at each occurrence, is independently selected from the group consisting of halogen and C1-3alkyl substituted with 0-3 Rc; Ra, at each occurrence, is independently selected from the group consisting of H and C1-4 alkyl substituted with 0-3 Rc; R6, at each occurrence, is independently selected from the group consisting of H, F, -NH- CH2-CH2-NH2, and ; and R7 is selected from the group consisting of H and CH3. In a seventeenth aspect, the present invention provides a compound of Formula (VII): (VII), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof within the scope of the first aspect, wherein: R1 is selected from the group consisting of halogen, CN, Ra and –ORa;R2 is selected from the group consisting of , , ,, , and ;R5, at each occurrence, is independently selected from the group consisting of halogen and C1-4alkyl substituted with 0-3 Rc; Ra, at each occurrence, is independently selected from the group consisting of H and C1-4alkyl substituted with 0-5 Rc; R6, at each occurrence, is independently selected from the group consisting of H, F, -NH- CH2-CH2-NH2, and ; and R7is selected from the group consisting of H and CH3. In an eighteenth aspect, the present invention provides a compound of Formula (VIII): (VIII), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, within the scope of the first aspect, wherein:is selected from the group consisting of , , and ; R1is selected from the group consisting of halogen, CN, Ra, and –ORa;R2 is selected from the group consisting of , . ,, , , , and ;R5, at each occurrence, is independently selected from the group consisting of halogen and C1-3alkyl substituted with 0-3 Rc; R3is H and C1-3alkyl; Ra, at each occurrence, is independently selected from the group consisting of H and C1-4alkyl substituted with 0-5 Rc; and R6, at each occurrence, is independently selected from the group consisting of H, F, -NH- CH2-CH2-NH2, and ; and R7 is selected from the group consisting of H and CH3. In a nineteenth aspect, the present invention provides a compound of Formula (IX):(IX), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, within the scope of the first aspect, wherein: R2is 3-10 membered heterocycle substituted with 1-4 of R2b; R2b, at each occurrence, is independently selected from the group consisting of D, Ra, halogen, =O, CN, -NRaRa, and -ORa; R5, at each occurrence, is independently selected from the group consisting of halogen, CN, C1-4alkyl, and –ORa; R6, at each occurrence, is independently selected from -CH2NR6aR6a; R6a, at each occurrence, is independently selected from H and a C1-6alkyl substituted with 0-3 Rc; R7, at each occurrence, is selected from the group consisting of H and CH3; Ra, at each occurrence, is independently selected from the group consisting of H and C1-6alkyl substituted with 0-3 Rc; and Rc, at each occurrence, is independently selected from the group consisting of –OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, halogen, =O, -COOH, and -COOC1-4 alkyl. As defined above and described herein, R1 is selected from group consisting of halogen, CN, Ra and –ORa, wherein Ra is selected from the group consisting of H and C1-6alkyl substituted with 0-5 Rc. In some embodiments, R1is Cl. In some embodiments, R1is Rawherein Rais H or C1-3alkyl. Preferably, R1is H or Cl. As defined above and described herein, R2is NR2aR2a, wherein R2ais selected from the group consisting of H and a C1-6alkyl substituted with 0-4 Rc, wherein Rcis selected from the group consisting of –OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, halogen, =O, CONH2, -COOH, and -COOC1-4alkyl. As defined above and described herein, R2 is 3-10 membered heterocycle substituted with 1-4 of R2b, wherein R2bis selected from the group consisting of D, Ra, halogen, =O, CN, -NRaRa, -ORa S(=O)2NH2, C(=O)Ra, and C(=O)ORa, wherein Ra is selected from the group consisting of H and C1-6alkyl substituted with 0-5 Rc, wherein Rc is selected from the group consisting of –OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, halogen, =O, CONH2, -COOH, and -COOC1-4 alkyl.In some embodiments, R2 is , , ,, or . In some embodiments, R2 is , , or .In some embodiments, R2 is , , or .In some embodiments, R2 is ,In some embodiments, R2 is , , or .In some embodiments, R2 is or .In some embodiments, R2is , , , , , , ,or .As defined above and described herein, R2 is -(CH2)1-3-3-10 membered heterocycle substituted with 1-4 of R2b, wherein R2bis selected from the group consisting of is independently selected from the group consisting of D, Ra,halogen, =O, CN, -NRaRa, -ORa S(=O)2NH2, C(=O)Ra, and C(=O)ORa, wherein Ra is selected from the group consisting of H and C1-6alkyl substituted with 0-5 Rc, wherein Rc is selected from the group consisting of –OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, halogen, =O, CONH2, -COOH, and -COOC1-4alkyl. In some embodiments, R2 is . As defined above and described herein, R2 is -NR2a-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R2b, wherein R2bis selected from the group consisting of is independently selected from the group consisting of D, Ra, halogen, =O, CN, -NRaRa, -ORa S(=O)2NH2, C(=O)Ra, and C(=O)ORa, wherein Ra is selected from the group consisting of H and C1-6alkyl substituted with 0-5 Rc, wherein Rcis selected from the group consisting of –OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, halogen, =O, CONH2, -COOH, and -COOC1-4alkyl. In some embodiments, R2is , , . As defined above and described herein, R2is -NR2a-3-10 membered carbocycle substituted with 1-4 of R2b, wherein R2bis selected from the group consisting of is independently selected from the group consisting of D, Ra, halogen, =O, CN, -NRaRa, -ORa S(=O)2NH2, C(=O)Ra, and C(=O)ORa, wherein Ra is selected from the group consisting of H and C1-6alkyl substituted with 0-5 Rc, wherein Rc is selected from the group consisting of –OH, -CN, -NH2, -NH(C1- 6 alkyl), -N(C1-6alkyl)2, halogen, =O, CONH2, -COOH, and -COOC1-4 alkyl. In some embodiments, R2is . In certain embodiments, R2is selected from those functional groups depicted in the examples below. As defined above and described herein, R3is selected from the group consisting of halogen, CN, Ra, and –ORa, wherein Rais selected from the group consisting of H and C1-3alkyl. In some embodiments, R3 is Cl. In some embodiments, R3 is CN. In some embodiments, R1 is H and R3 is Cl. In some embodiments, R1 is H and R2 is CN. In certain embodiments, R3 is selected from those functional groups depicted in the examples below.As defined above and described herein, R4 is selected from the group consisting of H and =O. Preferably, R4is =O. As defined above and described herein, R5is selected from the group consisting of halogen and C1-6alkyl substituted with 0-5 Rc. In some embodiments, R5is F or Cl. In some embodiments, R5is CH3or CF3. In certain embodiments, R5is selected from those functional groups depicted in the examples below. As defined above and described herein, R6is selected from the group consisting of halogen, CN, R6a, -(CH2)nNR6aR6a, -(CH2)nOR6a, -(CH2)nCONR6aR6a, - (CH2)nNR6aCONR6aR6a, -(CH2)nNR6aCOR6a, -(CH2)nNR6aSO2R6a, -(CH2)nS(=O)2, - NR6a(CH2)1-3NR6aCOR6a, -NR6a(CH2)1-3NR6aCOOR6a, -O(CR6bR6b)1-3O(CR6bR6b)1-3OR6a, –(CH2)n-3-10 membered carbocycle substituted with 1-4 of R6b, –(CH2)n-3-10 membered heterocycle substituted with 1-4 of R6b, -O-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R6b, -O-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R6b, -NR6a-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R6b, and -NR6a-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R6b. In some embodiments, R6is H. In some embodiments, R6is F or Cl. In some embodiments, R6is NR6aR6a, wherein R6ais H or C1-3alkyl subsitued with 0-3 Rc, wherein Rcis -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2. In some embodiments, R6is -NHCH2CH2NH2. In some embodiments, R6is -NHCH2CHFCH2NH2. In some embodiments, R6is -NHCH2CFFCH2NH2. In some embodiments, R6is - NHCH2CH2(CH3)NH2. In some embodiments, R6is -CH2NR6aR6a, wherein R6ais H. In some embodiments, R6is -OR6a, wherein R6ais C1-3alkyl subsitued with 0-3 Rc, wherein Rcis -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2. In some embodiments, R6is - OCH2CH2NH2. In some embodiments, R6is -OCH2CFFCH2NH2. In some embodiments, R6is -OCH2CH2CH2OR6a. In some embodiments, R6is -O(CH2)2-5OR6a, wherein R6ais H or C1-3alkyl. In some embodiments, R6is -O(CH2)1-3O(CH2)1-3OR6a, wherein R6ais C1-3alkyl. In some embodiments, R6is NH-(CH2)1-2-3- to 6-membered carbocycle substituted with 1-4 of R6b.In some embodiments, R6 is , , , , or . In In some embodiments, R6is -O-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R6b. In some embodiments, R6 is , , , or . In In some embodiments, R6 is -O-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R6b. In In some embodiments, R6is . In certain embodiments, R6is selected from those functional groups depicted in the examples below. As defined above and described herein, R is selected from the group consisting of C2-4 alkylene, C2-4 alkenylene, and C3-4 alkoxylene, each substituted with 1-4 R7.In some embodiments, R is , , or .As defined above and described herein, R7is is Ra, =O, or –ORa. In some embodiments, R7is CH3.In some embodiments, R7is CH2CH3. In some embodiments, the compound of Formula (I) is selected from examples depicted below. In certain embodiments, the present invention provides any compound described above and herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides any compound described above and herein in isolated form.4. Uses, Formulation and Administration Pharmaceutically acceptable compositions According to another embodiment, the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in compositions of this invention is such that is effective to measurably inhibit PAD4, in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this invention is such that is effective to measurably inhibit PAD4, in a biological sample or in a patient. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient. The term “subject,” as used herein, is used interchangeably with the term “patient” and means an animal, preferably a mammal. In some embodiments, a subject or patient is a human. In other embodiments, a subject (or patient) is a veterinary subject (or patient). In some embodiments, a veterinary subject (or patient) is a canine, a feline, or an equine subject. The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.Compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non- toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3- butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation. Pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying andsuspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. Alternatively, pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. Pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically- transdermal patches may also be used. For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, thepharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum. Pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents. Most preferably, pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food. Pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg / kg to about 50 mg / kg and preferably from about 1 mg / kg to about 25 mg / kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect. Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues. Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or asuppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar--agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like. The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulatingart. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. The amount of compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01 - 100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions. A compound of the current invention can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic compounds being staggered or given independentlyof one another, or the combined administration of fixed combinations and one or more other therapeutic compounds. Exemplary of such other therapeutic agents include corticosteroids, rolipram, calphostin, cytokine-suppressive anti-inflammatory drugs (CSAIDs), Interleukin-10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressants; nuclear translocation inhibitors, such as deoxyspergualin (DSG); non-steroidal antiinflammatory drugs (NSAIDs) such as ibuprofen, celecoxib and rofecoxib; steroids such as prednisone or dexamethasone; antiviral agents such as abacavir; antiproliferative agents such as methotrexate, leflunomide, FK506 (tacrolimus, Prograf); cytotoxic drugs such as azathiprine and cyclophosphamide; TNF-^ inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus or Rapamune) or derivatives thereof. A compound of the current invention can besides or in addition be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk. Those additional agents may be administered separately from an inventive compound-containing composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another. As used herein, the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a compound of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising a compound of the current invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.The amount of both an inventive compound and additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, compositions of this invention should be formulated so that a dosage of between 0.01 - 100 mg / kg body weight / day of an inventive compound can be administered. In those compositions which comprise an additional therapeutic agent, that additional therapeutic agent and the compound of this invention may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent. The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent. It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition. Uses of Compounds and Pharmaceutically Acceptable Compositions Compounds and compositions described herein are generally useful for the inhibition of PAD4. The activity of a compound utilized in this invention as an inhibitor of PAD4, may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine the inhibition of PAD4. Detailed conditions for assaying a compoundutilized in this invention as an inhibitor of PAD4 are set forth in the Examples below. In some embodiments, a provided compound inhibits PAD4 selectively as compared to PAD2. As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence. Provided compounds are inhibitors of PAD4and are therefore useful for treating one or more disorders associated with activity of PAD4. Thus, in certain embodiments, the present invention provides a method for treating a PAD4-mediated disorder comprising the step of administering to a patient in need thereof a compound of the present invention, or pharmaceutically acceptable composition thereof. In one embodiment, a PAD4-mediated disorder is a disease, condition, or disorder mediated by inappropriate PAD4 activity. In some embodiments, a PAD4-mediated disorder is selected from the group consisting of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosis, and psoriasis. In a further embodiment, the disorder mediated by inappropriate PAD4 activity is rheumatoid arthritis. In a further embodiment, the disorder mediated by inappropriate PAD4 activity is systemic lupus. In a further embodiment, the disorder mediated by inappropriate PAD4 activity is vasculitis. In a further embodiment, the disorder mediated by inappropriate PAD4 activity is cutaneous lupus erythematosis. In a further embodiment, the disorder mediated by inappropriate PAD4 activity is psoriasis. In one embodiment there is provided a method of treatment of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosis, or psoriasis, which method comprisesadministering to a human subject in need thereof, a therapeutically effective amount of a provided compound or a pharmaceutically acceptable salt thereof. In one embodiment there is provided a method of treatment of rheumatoid arthritis, which method comprises administering to a human subject in need thereof, a therapeutically effective amount of a provided compound, or a pharmaceutically acceptable salt thereof. In one embodiment there is provided a method of treatment of systemic lupus, which method comprises administering to a human subject in need thereof, a therapeutically effective amount of a provided compound, or a pharmaceutically acceptable salt thereof. In one embodiment there is provided a method of treatment of vasculitis, which method comprises administering to a human subject in need thereof, a therapeutically effective amount of a provided compound, or a pharmaceutically acceptable salt thereof. In one embodiment there is provided a method of treatment of cutaneous lupus erythematosis, which method comprises administering to a human subject in need thereof, a therapeutically effective amount of a provided compound, or a pharmaceutically acceptable salt thereof. In one embodiment there is provided a method of treatment of psoriasis, which method comprises administering to a human subject in need thereof, a therapeutically effective amount of a provided compound, or a pharmaceutically acceptable salt thereof. In some embodiments, a PAD4-mediated disorder is selected from the group consisting of acid-induced lung injury, acne (PAPA), acute lymphocytic leukemia, acute, respiratory distress syndrome, Addison’s disease, adrenal hyperplasia, adrenocortical insufficiency, ageing, AIDS, alcoholic hepatitis, alcoholic hepatitis, alcoholic liver disease, allergen induced asthma, allergic bronchopulmonary, aspergillosis, allergic conjunctivitis, alopecia, Alzheimer’s disease, amyloidosis, amyotropic lateral sclerosis, and weight loss, angina pectoris, angioedema, anhidrotic ecodermal dysplasia-ID, ankylosing spondylitis, anterior segment, inflammation, antiphospholipid syndrome, aphthous stomatitis, appendicitis, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune diseases, autoimmune hepatitis, bee sting-induced inflammation, behcet’s disease, Behcet’s syndrome, Bells Palsey, berylliosis, Blau syndrome, bone pain, bronchiolitis, burns, bursitis, cancer, cardiac hypertrophy, carpal tunnel syndrome, catabolic disorders, cataracts, cerebral aneurysm, chemical irritant-induced inflammation, chorioretinitis, chronic heart failure, chroniclung disease of prematurity, chronic lymphocytic leukemia, chronic obstructive pulmonary disease, colitis, complex regional pain syndrome, connective tissue disease, corneal ulcer, crohn’s disease, cryopyrin-associated periodic syndromes, cyrptococcosis, cystic fibrosis, deficiency of the interleukin-1–receptor antagonist (DIRA), dermatitis, dermatitis endotoxemia, dermatomyositis, diffuse intrinsic pontine glioma, endometriosis, endotoxemia, epicondylitis, erythroblastopenia, familial amyloidotic polyneuropathy, familial cold urticarial, familial Mediterranean fever, fetal growth retardation, glaucoma, glomerular disease, glomerular nephritis, gout, gouty arthritis, graft-versus-host disease, gut diseases, head injury, headache, hearing loss, heart disease, hemolytic anemia, Henoch-Scholein purpura, hepatitis, hereditary periodic fever syndrome, herpes zoster and simplex, HIV-1, Hodgkin’s disease, Huntington’s disease, hyaline membrane disease, hyperammonemia, hypercalcemia, hypercholesterolemia, hyperimmunoglobulinemia D with recurrent fever (HIDS), hypoplastic and other anemias, hypoplastic anemia, idiopathic thrombocytopenic purpura, incontinentia pigmenti, infectious mononucleosis, inflammatory bowel disease, inflammatory lung disease, inflammatory neuropathy, inflammatory pain, insect bite-induced inflammation, iritis, irritant-induced inflammation, ischemia / reperfusion, juvenile rheumatoid arthritis, keratitis, kidney disease, kidney injury caused by parasitic infections, kidney injury caused by parasitic infections, kidney transplant rejection prophylaxis, leptospiriosis, leukemia, Loeffler’s syndrome, lung injury, lung injury, lupus, lupus, lupus nephritis, lymphoma, meningitis, mesothelioma, mixed connective tissue disease, Muckle-Wells syndrome (urticaria deafness amyloidosis), multiple sclerosis, muscle wasting, muscular dystrophy, myasthenia gravis, myocarditis, mycosis fungiodes, mycosis fungoides, myelodysplastic syndrome, myositis, nasal sinusitis, necrotizing enterocolitis, neonatal onset multisystem inflammatory disease (NOMID), nephrotic syndrome, neuritis, neuropathological diseases, non-allergen induced asthma, obesity, ocular allergy, optic neuritis, organ transplant, osterarthritis, otitis media, paget’s disease, pain, pancreatitis, Parkinson’s disease, pemphigus, pericarditis, periodic fever, periodontitis, peritoneal endometriosis, pertussis, pharyngitis and adenitis (PFAPA syndrome), plant irritant- induced inflammation, pneumonia, pneumonitis, pneumosysts infection, poison ivy / urushiol oil-induced inflammation, polyarteritis nodosa, polychondritis, polycystickidney disease, polymyositis, psoriasis, psoriasis, psoriasis, psoriasis, psychosocial stress diseases, pulmonary disease, pulmonary hypertension, pulmonayr fibrosis, pyoderma gangrenosum, pyogenic sterile arthritis, renal disease, retinal disease, rheumatic carditis, rheumatic disease, rheumatoid arthritis, sarcoidosis, seborrhea, sepsis, severe pain, sickle cell, sickle cell anemia, silica-induced disease, Sjogren’s syndrome, skin diseases, sleep apnea, solid tumors, spinal cord injury, Stevens- Johnson syndrome, stroke, subarachnoid hemorrhage, sunburn, temporal arteritis, tenosynovitis, thrombocytopenia, thyroiditis, tissue transplant, TNF receptor associated periodic syndrome (TRAPS), toxoplasmosis, transplant, traumatic brain injury, tuberculosis, type 1 diabetes, type 2 diabetes, ulcerative colitis, urticarial, uveitis, and Wegener’s granulomatosis. In one embodiment, the invention provides a provided compound, or a pharmaceutically acceptable salt thereof, for use in therapy. In another embodiment, the invention provides a provided compound, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disorder mediated by inappropriate PAD4 activity. In another embodiment, the invention provides a provided compound, or a pharmaceutically acceptable salt thereof, for use in the treatment of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosis, or psoriasis. In another embodiment, the invention provides a provided compound, or a pharmaceutically acceptable salt thereof, for use in the treatment of rheumatoid arthritis. In another embodiment, the invention provides a provided compound, or a pharmaceutically acceptable salt thereof, for use in the treatment of systemic lupus. In another embodiment, the invention provides a provided compound, or a pharmaceutically acceptable salt thereof, for use in the treatment of vasculitis. In another embodiment, the invention provides a provided compound, or a pharmaceutically acceptable salt thereof, for use in the treatment of cutaneous lupus erythematosis. In another embodiment, the invention provides a provided compound, or a pharmaceutically acceptable salt thereof, for use in the treatment of psoriasis. In another embodiment, the invention provides the use of a provided compound, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a disorder mediated by inappropriate PAD4 activity. In another embodiment, the inventionprovides the use of a provided compound, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosis, or psoriasis. In another embodiment, the invention provides the use of a provided compound, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of rheumatoid arthritis. In another embodiment, the invention provides the use of a provided compound, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of systemic lupus. In another embodiment, the invention provides the use of a provided compound, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of vasculitis. In another embodiment, the invention provides the use of a provided compound, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of cutaneous lupus erythematosis. In another embodiment, the invention provides the use of a provided compound, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of psoriasis. In a further embodiment, the invention provides a pharmaceutical composition for the treatment or prophylaxis of a disorder mediated by inappropriate PAD4 activity comprising a provided compound, or a pharmaceutically acceptable salt thereof. In a further embodiment, the invention provides a pharmaceutical composition for the treatment or prophylaxis of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosis, or psoriasis, comprising a provided compound, or a pharmaceutically acceptable salt thereof. In a further embodiment, the invention provides a pharmaceutical composition for the treatment or prophylaxis of rheumatoid arthritis comprising a provided compound, or a pharmaceutically acceptable salt thereof. In a further embodiment, the invention provides a pharmaceutical composition for the treatment or prophylaxis of systemic lupus comprising a provided compound, or a pharmaceutically acceptable salt thereof. In a further embodiment, the invention provides a pharmaceutical composition for the treatment or prophylaxis of vasculitis comprising a provided compound, or a pharmaceutically acceptable salt thereof. In a further embodiment, the invention provides a pharmaceuticalcomposition for the treatment or prophylaxis of cutaneous lupus erythematosis comprising a provided compound, or a pharmaceutically acceptable salt thereof. In a further embodiment, the invention provides a pharmaceutical composition for the treatment or prophylaxis of psoriasis comprising a provided compound, or a pharmaceutically acceptable salt thereof All features of each of the aspects of the invention apply to all other aspects mutatis mutandis. In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner. As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present invention, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein. VI. EXAMPLES The following Examples are offered as illustrative, as a partial scope and particular embodiments of the invention and are not meant to be limiting of the scope of the invention. Abbreviations and chemical symbols have their usual and customary meanings unless otherwise indicated. Unless otherwise indicated, the compounds described herein have been prepared, isolated and characterized using the schemes and other methods disclosed herein or may be prepared using the same. AcOH or HOAc acetic acid ACN acetonitrile Alk Alkyl AlMe3Trimethylaluminum BBr3boron tribromideBn benzyl Boc tert-butyloxycarbonyl BOP reagent benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate Bu butyl i-Bu isobutyl t-Bu tert-butyl t-BuOH tert-butanol Cbz carbobenzyloxyCDCl3deutero-chloroformCD3ODdeutero-methanolCH2Cl2dichloromethaneCH3CN acetonitrileCHCl3chloroformDCM dichloromethane DIEA, DIPEA or Hunig's diisopropylethylamine base DMF dimethyl formamide DMSO dimethyl sulfoxide Et ethylEt3N or TEAtriethylamineEt2Odiethyl ether EtOAc ethyl acetate EtOH Ethanol HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate HCl hydrochloric acid HPLC high-performance liquid chromatography Ir(dF(CF3)ppy)2(dtbbpy)PF6 (4,4’-Di-t-butyl-2,2’-bipyridine)bis[3,5-difluoro-2-(5- trifluoromethyl-2-pyridinyl-kN)phenyl-kC]iridum(III) hexafluorophosphateK2CO3potassium carbonateK2HPO4potassium hydrogenphosphateK3PO4potassium phosphate, tribasic LCMS liquid chromatography mass spectrometry LiHMDS lithium bis(trimethylsilyl)amide LG leaving group Me methyl MeOH methanolMgSO4magnesium sulfateMsOH or MSA methylsulfonic acid NaCl sodium chlorideNa2CO3sodium carbonateNaHCO3sodium bicarbonateNaOH sodium hydroxideNa2SO4sodium sulfateNH3ammoniaNH4Clammonium chlorideNH4OAcammonium acetatePd(OAc)2palladium(II) acetatePd(dppf)Cl2[1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0) PG protecting group Ph phenyl Pr propyl i-Pr isopropyl i-PrOH or IPA isopropanol Rt retention timeSiO2silica oxideSi-pyridineSiliaBond©PyridineSFC supercritical fluid chromatography TBAI Tetrabutylammonium iodide TEA triethylamine TFA trifluoroacetic acid TFAA Trifluoroacetic anhydride THF tetrahydrofuran TiCl4titanium tetrachlorideT3P 1-propanephosphonic acid cyclic anhydrideDescription of Prep HPLC and analytical LCMS methods Method A: Column: Xselect CSH Prep C18 Column, 30*150 mm, 5 m; Mobile Phase A: Water / 0.05% TFA, Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 17% B to 47 % B in 10 min; Wavelength: 254nm / 220nm Method B: Column: Shim-pack Scepter C18-120 Column 3*33 mm, 3.0 m; [Mobile Phase]; Flow rate: 1.5000 mL / min; [Gradient]; Wavelength: 254 / 220 nm Method Mobile Phase Gradient Method B1 A: 0.05% NH4HCO3in water 10% B to 95% B in 1.2 min, hold at 95% for B: 0.05% NH4HCO3in acetonitrile 0.6 min, 95% B to 10% B in 0.02 min Method B2 A: 5 mM NH4HCO3in water 0% B to 95% B in 1.20 min, hold at 95% for B: ACN 0.6 min, 95% B to 10% B in 0.02 min Method C: Column: SunFire C18 OBD Prep Column, 19*250 mm, 5 m; Mobile Phase A: 0.05% TFA in water, Mobile Phase B: ACN; [Flow Rate]; [Gradient]; Wavelength: 254 / 210 nm Method Flow Rate Gradient Method C1 25 mL / min 27% B to 33% B in 6.5 min, 33% B Method C2 60 mL / min 30% B to 50% B in 7 min, 50% BMethod D: Column: HALO C18 Column 3.0*30 mm, 2.0 m; mobile phase A: 0.05% TFA in water, mobile phase B: 0.05% TFA in acetonitrile; [Flow Rate]; [Gradient]; Wavelength: 220 / 254 nm Method Flow Rate Gradient Method D1 1.5000 mL / min 5% B to 50% B in 1.69 min, 50% B to 100% B in 0.6 min, hold at 100% for 0.5 min, 100% B to 5% B in 0.03 min Method D2 1.5000 mL / min 5% B to 95% B in 1.19 min, hold at 95% for 0.6 min, 95% B to 5% B in 0.02 min Method D3 1.5000 mL / min 5% B to 60% B in 1.69 min, 60% B to 100% B in 0.6 min, hold at 100% for 0.5 min, 100% B to 5% B in 0.03 min Method D4 1.5000 mL / min 5% B to 50% B in 1.70 min, 50% B to 95% B in 0.6 min, hold at 95% for 0.5 min, 95% B to 5% B in 0.03 min Method D5 1.5000 mL / min 5% B to 100% B in 1.20 min, hold at 100% for 0.6 min, 100% B to 5% B in 0.02 min Method D6 1.2000 mL / min 5% B to 40% B in 1.69 min, 40% B to 95% B in 0.6 min, hold at 95% for 0.5 min, 95% B to 5% B in 0.03 min Method E: Column: Ultimate XB-C18, 50*250 mm, 10 m; Mobile Phase A: 10mM NH4HCO3in water, Mobile Phase B: ACN; Flow rate: 90 mL / min; Gradient: 5% B to 15% B in 35 min; Wavelength: 254 nm Method F: Column: XBridge C18, 19*200 mm, 5 μm; Mobile Phase A: 0.05% TFA in water / ACN 95:5, Mobile Phase B: 0.05% TFA in water / ACN 5:95; Flow Rate: 20 mL / min; Gradient: 15% B to 55% B in 20 min, 55% B to 100% B in 0.1 min, hold at 100% B for 3.9 min; Wavelength: 220 / 254 nm Method G: Column: XBridge C18, 2.1*50 mm, 1.7 m; Mobile Phase A: 0.05% TFA in water / ACN 95:5, Mobile Phase B: 0.05% TFA in water / ACN 5:95; Flow rate: 1.0 mL / min; Gradient: 0% B to 100% B in 3.0 min, hold at 100% B for 0.5 min; Wavelength: 220 nm Method H: Column: XBridge C18, 2.1*50 mm, 1.7 m; Mobile Phase A: 10 mM NH4OAc in water / ACN 95:5, Mobile Phase B: 10 mM NH4OAc in water / ACN 5:95; Flow rate: 1.0 mL / min; Gradient: 0% B to 100% B in 3.0 min, hold at 100% B for 0.5 min; Wavelength: 220 nmMethod L: Ascentis Express C18 (2.1 x 50 mm) 2.7 micron; Solvent A: 95% water, 5% acetonitrile with 10 mM ammonium acetate; Solvent B: 95% acetonitrile, 5% water with 10 mM ammonium acetate; Temperature: 50 ºC; Gradient: 0-100% B over 3 minutes, then 1 minute hold at 100% B; Flow: 1.1 mL / min, UV 220 nm. Method M: Kinetex, XB C18 (2.6 m x 75.3 mm); Solvent A: 10 mM NH4CO2H in 98% water, 2% acetonitrile; Solvent B: 10 mM NH4CO2H in 2% water, 98% acetonitrile, Gradient: 20-100% B over 4 minutes, then 0.6 minute hold at 100% B; Flow: 1.1 mL / min, UV 220 nm. Method O: Acquity UPLC BEH C18 (3 x 50 mm) 1.7 micron; Solvent A: 5 mM ammonium acetate in 95% water, 5% acetonitrile; Solvent B: 5 mM ammonium acetate in 5% water, 95% acetonitrile, Gradient: 20-90% B over 1.1 minutes, then 0.6 minute hold at 90% B; Flow: 0.7 mL / min, UV 220 nm. Method P: Luna 3.0 C18 (2) 100 A° LC (4 x 20 mm) Mercury MS TM; Solvent A: 0.1% TFA in water; Solvent B: 0.1% TFA in ACN; Gradient: 20 % B to 100 % B over 2.5 min, hold at 100% B for 0.3 min, 100 % B to 20 % B over 0.2 min; Flow: 1.5- 2.0 mL / min; UV 220 nm. Method R: XBridge BEH XP C18 (2.1 x 50 mm) 2.5 micron; Solvent A: 0.1 % TFA in 95% water, 5% acetonitrile; Solvent B: 0.1 % TFA in 5% water, 95% acetonitrile, Gradient: 0-100% B over 3 minutes; Flow: 1.1 mL / min, UV 220 nm. Method S: XBridge BEH XP C18 (2.1 x 50 mm) 2.5 micron; Solvent A: 10 mM ammonium acetate in 95% water, 5% acetonitrile; Solvent B: 10 mM ammonium acetate in 5% water, 95% acetonitrile, Gradient: 0-100% B over 3 minutes; Flow: 1.1 mL / min, UV 220 nm. Synthetic Examples Example 1: 4-chloro-2-(3-((3',4'-dichloro-[1,1'-biphenyl]-3-yl)sulfonyl)propyl)-5- (piperazin-1-yl)pyridazin-3(2H)-oneIntermediate 1A: To a stirred solution of 3-bromobenzenethiol (2.00 g, 10.58 mmol) in DMF (30 mL) was added Cs2CO3(6.89 g, 21.16 mmol) followed by 3-bromopropan-1-ol (1.91 g, 13.75 mmol) and the resulting reaction mixture was heated at 50 °C for 12 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulphate, and evaporated under reduced pressure to obtain the title compound (2.50 g) as a gummy liquid. The crude product was taken to the next step without purification. Intermediate 1B: To a stirred solution of intermediate 1A (1.50 g, 6.07 mmol) in DCM (20 mL) was added m-CPBA (3.14 g, 18.21 mmol) and the resulting reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was diluted with ice cold water (40 mL), basified by aq. sodium bicarbonate, and extracted with DCM (2 x 40 mL). The combined organic layer was washed with brine (30 mL), dried over sodium sulphate, and evaporated under reduced pressure to afford the title compound. The crude product was taken to the next step without purification. Intermediate 1C: To a stirred solution of intermediate 1B (1.50 g, 5.37 mmol) and 4,5- dichloropyridazin-3(2H)-one (0.89 g, 5.37 mmol) in THF (20 mL) was added triphenylphosphine (1.51 g, 5.37 mmol) followed by diethyl azodicarboxylate (0.94mL, 5.91 mmol) and the resulting reaction mixture was stirred at ambient temperature for 24 h. THF was evaporated under reduced pressure and the residue was purified by column chromatography (Redisep-40 g, 25-30% EtOAc / n-hexane) to obtain the title compound (2 g) as a gummy liquid. LCMS (Method-O): retention time 1.27 min, [M+H]+425.3. Intermediate 1D: To a stirred solution of intermediate 1C (2.00 g, 4.69 mmol) in EtOH (20 mL) was added DIPEA (1.07 mL, 6.13 mmol) followed by tert-butyl piperazine-1-carboxylate (1.75 g, 9.39 mmol) and the resulting mixture was heated at 90 °C for 16 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulphate, and evaporated under reduced pressure to obtain the title compound (2.10 g) as a gummy liquid. LCMS (Method-S): retention time 1.36 min, [M+H]+577.1. Intermediate 1E: To a stirred solution of intermediate 1D (0.08 g, 0.14 mmol) in a mixture of dioxane (1 mL): water (0.5 mL) was added (3,4-dichlorophenyl)boronic acid (0.040 g, 0.21 mmol) followed by potassium carbonate (0.03 g, 0.18 mmol) and the resulting reaction mixture was degassed with nitrogen for 5 min. PdCl2(dppf)2CH2Cl2(0.004 g, 5 μmol) was added and the resulting reaction mixture was degassed again for 5 min and stirred at 80 °C for 24 h. The reaction was cooled to ambient temperature, filtered through Celite® and the filtrate was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (30 mL), washed with water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to obtain Intermediate 1E (0.08 g) as a brown solid. LCMS (Method-O): retention time 1.58 min, [M+H]+641.6.Example 1: To a stirring solution of intermediate 1E (0.08 g, 0.13 mmol) in DCM (1.00 mL) was added TFA (0.05 mL, 0.62 mmol) and the resulting reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by Prep- HPLC (Column: Waters XBridge C18, 19 x 150 mm, 5 m; Mobile Phase A: 10 mM ammonium acetate in water, Mobile Phase B: acetonitrile; Gradient: 15-50% B over 25 min, then hold at 100% B for 5 min; Flow rate: 15 mL / min), and the purified material was diluted with a 2:1 mixture of dichloromethane and methanol, treated with Si-pyridine, and shaken 2 h. The mixture was then filtered and concentrated to obtain the title compound.1H NMR (400 MHz, CDCl3) ppm 8.08 (s, J = 1.50 Hz, 1H), 7.92 (d, J = 8.00 Hz, 1H), 7.87 - 7.79 (m, 1H), 7.73 (d, J = 2.50 Hz, 1H), 7.69 - 7.61 (m, 1H), 7.61 - 7.52 (m, 2H), 7.50 - 7.43 (m, 1H), 4.25 (t, J = 6.50 Hz, 2H), 3.47 - 3.31 (m, 4H), 3.28 - 3.17 (m, 2H), 3.13 - 2.98 (m, 4H), 2.36 - 2.19 (m, 2H). LCMS (Method-S): retention time 1.67 min, [M+H]+541.1. Examples given in the below table were prepared in a similar manner like Example 1 using appropriate substrates. Ret. Time Example Structure Name [M+H]+(min) and method 4-chloro-2-(3-((2'- methyl-[1,1'-biphenyl]-3- 2 yl)sulfonyl)propyl)-5-487.2 1.48(piperazin-1-yl)pyridazin-(Method S)3(2H)-one 4-chloro-2-(3-((3'-fluoro- [1,1'-biphenyl]-3- 3 yl)sulfonyl)propyl)-5-491.1 1.39(piperazin-1-yl)pyridazin-(Method S)3(2H)-one4-chloro-2-(3-((3'-chloro- [1,1'-biphenyl]-3- 4 yl)sulfonyl)propyl)-5-507.2 1.52(piperazin-1-yl)pyridazin-(Method S)3(2H)-one 4-chloro-2-(3-((3'-fluoro- 2'-methyl-[1,1'-biphenyl]- 5 3-yl)sulfonyl)propyl)-5-505.2 1.52(piperazin-1-yl)pyridazin-(Method S)3(2H)-one 4-chloro-2-(3-((2',3'- dimethyl-[1,1'-biphenyl]- 6 3-yl)sulfonyl)propyl)-5-501.2 1.607(piperazin-1-(Method S)yl)pyridazin-3(2H)-one 4-chloro-2-(3-((5'-fluoro- 2'-methyl-[1,1'-biphenyl]- 7 3-yl)sulfonyl)propyl)-5-505.2 1.51(piperazin-1-yl)pyridazin-(Method S)3(2H)-one 4-chloro-2-(3-((3'-chloro- 4'-fluoro-[1,1'-biphenyl]- 8 3-yl)sulfonyl)propyl)-5-525.1 1.57(piperazin-1-yl)pyridazin-(Method S)3(2H)-one Example 9: 2-(3-((4-amino-3'-fluoro-[1,1'-biphenyl]-3-yl)sulfonyl)propyl)-4-chloro-5- (piperazin-1-yl)pyridazin-3(2H)-oneIntermediate 9A: To a stirred solution of 4-bromo-2-fluoro-1-nitrobenzene (5.00 g, 22.7 mmol) in DMF (80 mL) was added Cs2CO3 (14.81 g, 45.50 mmol) followed by 2-methyl-2- propanethiol (3.07 g, 34.1 mmol) and the resulting reaction mixture was heated at 60 °C for 24 h. The reaction mixture was concentrated under reduced pressure, diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulphate, and evaporated under reduced pressure to obtain the title compound (4.80 g) as a gummy liquid.1H NMR (400 MHz, DMSO-d6) ppm 7.97 - 7.89 (m, 1H), 7.82 (d, J = 1.50 Hz, 1H), 7.77 - 7.73 (m, 1H), 1.30 (s, 9H). Intermediate 9B: To a stirred solution of intermediate 9A in DCM (20 mL) was added TFA (5.31 mL, 68.90 mmol) and stirred at ambient temperature overnight. The reaction mixture was evaporated under reduced pressure to obtain the title compound (1.30 g) as a yellow liquid. LCMS (Method-O): retention time 0.74 min, [M+H]+234.0. The compound was advanced to the subsequent step without further purification.Intermediate 9C: Intermediate 9C was prepared as a gummy liquid by using a similar synthetic protocol as that of intermediate 1A and starting from intermediate 9B and 3- bromopropan-1-ol.1H NMR (400 MHz, CDCl3) ppm 8.15 (d, J = 8.40 Hz, 1H), 7.55 (d, J = 8.40 Hz, 1H), 7.36 (dd, J = 2.00, 8.40 Hz, 1H), 3.88 - 3.82 (m, 2H), 3.08 (m, 2H), 2.05 - 1.97 (m, 2H). Intermediate 9D: Intermediate 9D was prepared as a gummy liquid by using a similar synthetic protocol as that of Intermediate 1C and starting from intermediate 9C and 4,5- dichloropyridazin-3(2H)-one. LCMS (Method-O): retention time 1.49 min, [M+H]+438.0. The compound was advanced to the subsequent step without further purification. Intermediate 9E: Intermediate 9E was prepared as a gummy liquid by using a similar synthetic protocol as that of intermediate 1B starting from intermediate 9D and m-CPBA. LCMS (Method-O): retention time 1.28 min, [M+H]+470.0. The compound was advanced to the subsequent step without further purification. Intermediate 9F: Intermediate 9F was prepared as a gummy liquid by using a similar synthetic protocol as that of intermediate 1D and starting from intermediate 9E and tert-butyl piperazine-1-carboxylate. LCMS (Method-O): retention time 1.36 min, [M+H]+620.3. Intermediate 9G: To a stirred solution of intermediate 9F (0.06 g, 0.097 mmol) in EtOH (3 mL) was added iron (0.030 g, 0.48 mmol) and ammonium chloride (0.031 g, 0.58 mmol) and the resulting reaction mixture was stirred at 80 °C 24 h. The reaction mixture was cooled to ambient temperature, filtered through Celite®, washed with ethyl acetate (30 mL) and the filtrate was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organiclayer was washed with brine (20 mL), dried over anhydrous sodium sulphate, and evaporated under reduced pressure to obtain Intermediate 9G (0.05 g). LCMS (Method-O): retention time 1.31 min, [M+H]+589.1 Intermediate 9H: Intermediate 9H was prepared as a gummy liquid by using a similar synthetic protocol as that of Intermediate 1E and starting from Intermediate 9G and (3- fluorophenyl)boronic acid. LCMS (Method O): retention time 1.40 min, [M+H]+606.4. Example 9: Example 9 was prepared by using a similar synthetic protocol as that of Example 1 and starting from Intermediate 9H and TFA.1H NMR (400 MHz, DMSO-d6) ppm 7.96 (s, 1H), 7.91 - 7.81 (m, 1H), 7.80 - 7.64 (m, 2H), 7.55 -7.38 (m, 2H), 7.18 - 7.07 (m, 1H), 6.98 (d, J = 9.30 Hz, 1H), 6.30 (s, 2H), 4.13 (t, J = 6.80 Hz, 2H), 3.37 (m, J = 5.60 Hz, 8H), 2.74 (m, 2H), 2.08 - 1.95 (m, 2H), LCMS (Method S): retention time 1.39 min, [M+H]+506.1. Example 10: 3-((3-(5-chloro-6-oxo-4-(piperazin-1-yl)pyridazin-1(6H)yl)propyl)sulfonyl)- 3'-fluoro-2'-methyl-[1,1'-biphenyl]-4-carbonitrile Intermediate 10A: To a stirred solution of 4-bromo-2-fluorobenzonitrile (2.00 g, 10.0 mmol) in DMF (10 mL) was added sodium sulfide (1.56 g, 20.0 mmol) and the resulting reaction mixture was stirred at 90 °C for 3 h. Then 3-bromopropan-1-ol (2.09 g, 15.0 mmol)was added and the reaction mixture was heated at same temperature for 12 h. The reaction mixture was cooled to ambient temperature, concentrated under reduced pressure, diluted with water (30 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulphate, and evaporated under reduced pressure to obtain Intermediate 10A (1.20 g) as a gummy liquid. LCMS (Method-O): retention time 1.33 min, [M+H]+272.0. The compound was advanced to the subsequent step without further purification. Intermediate 10B: Intermediate 10B was prepared as a gummy liquid by using a similar synthetic protocol as that of Intermediate 1C and starting from Intermediate 10A and 4,5- dichloropyridazin-3(2H)-one. LCMS (Method-O): retention time 1.45 min, [M+H]+418.1 Intermediate 10C: Intermediate 10C was prepared by using a similar synthetic protocol as that of Intermediate 1B and starting from Intermediate 10B and m-CPBA. LCMS (Method-O): retention time 1.23 min, [M+H]+450.0. The compound was advanced to the subsequent step without further purification. Intermediate 10D: Intermediate 10D was prepared as a gummy liquid by using a similar synthetic protocol as that of Intermediate 1D and starting from intermediate 10C and tert-butyl piperazine-1-carboxylate. LCMS (Method-O): retention time 1.34 min, [M+H]+600.3. Intermediate 10E: Intermediate 10E was prepared as gummy liquid by using a similar synthetic protocol as that of intermediate 1E and starting from intermediate 10D and (3-fluoro-2- methylphenyl)boronic acid. LCMS (Method-O): retention time 1.50 min, [M+H]+630.5.Example 10: Example 10 was prepared by using a similar synthetic protocol as that of Example 1 and starting from intermediate 10E and TFA.1H NMR (400 MHz, DMSO-d6) ppm 8.28 (d, J = 7.80 Hz, 1H), 8.06 - 7.94 (m, 2H), 7.92 - 7.84 (m, 1H), 7.47 - 7.36 (m, 1H), 7.36 - 7.28 (m, 1H), 7.24 (d, J = 7.60 Hz, 1H), 4.12 (t, J = 6.70 Hz, 2H), 3.66 - 3.59 (m, 2H), 3.36 - 3.34 (m, 4H), 2.94 - 2.79 (m, 4H), 2.15 (d, J = 2.20 Hz, 3H), 2.05 (dd, J = 15.00, 7.40 Hz, 2H). LCMS (Method S): retention time 1.52 min, [M+H]+530.2. Example given in the below table was prepared in a similar manner like Example 10 using appropriate substrates. Ret.Time Example Structure Name [M+H]+(min) and method 3',4'-dichloro-3-((3-(5- chloro-6-oxo-4- (piperazin-1- 11 yl)pyridazin-1(6H)-566.1 1.69yl)propyl)sulfonyl)-(Method S)[1,1'-biphenyl]-4- carbonitrile Example 12: 4-chloro-2-(3-((3'-fluoro-2'-methyl-[1,1'-biphenyl]-3-yl)sulfonyl)-2- methylpropyl)-5-(piperazin-1-yl)pyridazin-3(2H)-one Intermediate 12A: To a stirred solution of 2-methylpropane-1,3-diol (0.57 g, 6.35 mmol) and 3- bromobenzenethiol (1.00 g, 5.29 mmol) in THF (20 mL) was addedtriphenylphosphine (1.66 g, 6.35 mmol) followed by di-tert-butyl azodicarboxylate (1.34 g, 5.82 mmol) and the resulting reaction mixture was stirred at ambient temperature for 24 h. The volatile component was evaporated under reduced pressure and the residue was purified by column chromatography (Redisep-24 g, 40% EtOAc / n- hexane) to obtain Intermediate 12A (1.10 g) as a colorless gummy liquid.1H NMR (400 MHz, DMSO-d6) ppm 8.13 (s, 1H), 7.50 - 7.44 (m, 2H), 7.36 - 7.19 (m, 1H), 4.65 (t, J = 5.30 Hz, 1H), 3.17 - 3.08 (m, 2H), 2.76 (dd, J = 7.80, 12.80 Hz, 2H), 1.81 - 1.70 (m, 1H), 0.96 (d, J = 7.19 Hz, 3H). Intermediate 12B: To a stirred solution of intermediate 12A (1.10 g, 4.21 mmol) and 4,5- dichloropyridazin-3(2H)-one (0.69 g, 4.21 mmol) in THF (20 mL) was added triphenylphosphine (1.21 g, 4.63 mmol) followed by diethyl azodicarboxylate (0.81 g, 4.63 mmol) and the resulting reaction mixture was stirred at ambient temperature for 24 h. The volatile component was evaporated and the residue was purified by column chromatography (Redisep-40 g, 25-30% EtOAc / n-hexane) to obtain intermediate 12B (1.30 g) as a gummy liquid. LCMS (Method-O): retention time 1.62 min, [M+H]+407.3. Intermediate 12C: To a stirred solution of intermediate 12B (1.10 g, 2.70 mmol) in DCM (20 mL) was added m-CPBA (1.39 g, 8.09 mmol) and the resulting reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was diluted with ice cold water (40 mL), basified by aq. sodium bicarbonate, and extracted with DCM (2 x 40 mL). The combined organic layer was washed with brine (30 mL), dried over sodium sulfate and evaporated under reduced pressure to obtain Intermediate 12C (1.00 g). LCMS (Method-O): retention time 1.27 min, [M+H]+439.3. The compound was advanced to the subsequent step without further purification. Intermediates 12D and 12E: To a stirred solution of intermediate 12C (0.90 g, 2.0 mmol) in EtOH (20 mL) was added DIPEA (1.07 mL, 6.13 mmol) followed by tert-butyl piperazine-1-carboxylate(0.95 g, 5.11 mmol) and the resulting mixture was heated at 90 °C for 16 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-40 g, 40-45% EtOAc / n-hexane) and enantiomers were separated by SFC [Column: Luxcellulose-421.5*250 mm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: 0.2% NH4OH in ACN : MeOH (1:1); Flow rate: 70 mL / min; Gradient: isocratic 25% B; Back pressure: 100 bar; Column temperature: 30 °C; Detection: UV (240 nm)]. First eluted isomer (retention time 6.00 min) was designated as intermediate 12D (0.34 g) and the second eluted isomer (retention time 7.50 min) was designated as intermediate 12E (0.29 g). LCMS (Method-O): retention time 1.34 min, [M+H]+589.5. Intermediate 12F: To a stirred solution of intermediate 12D (0.04 g, 0.060 mmol) in a mixture of dioxane (1 mL) and water (0.5 mL) was added (3-fluoro-2-methylphenyl)boronic acid (0.01 g, 0.09 mmol) followed by potassium carbonate (0.03 g, 0.18 mmol) and the resulting reaction mixture was degassed with nitrogen for 5 min. PdCl2(dppf)2CH2Cl2(0.004 g, 5 μmol) was added and the resulting reaction mixture was degassed again for 5 min and stirred at 80 °C for 24 h. The reaction was cooled to ambient temperature, filtered through Celite® and the filtrate was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (30 mL), washed with water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford brown solid. LCMS (Method-O): retention time 1.54 min, [M+H] 619.7. The compound was advanced to the subsequent step without further purification. Example 12: To a stirring solution of intermediate 12F (0.04 g, 0.06 mmol) in DCM (1.00 mL) was added TFA (0.02 mL, 0.28 mmol) and the resulting reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was concentrated to dryness underreduced pressure. The residue was purified by Prep-HPLC [Column: XBridge C18 (19 x 150 mm) 5 μm; Solvent A: 10-mM ammonium acetate in water; Solvent B: acetonitrile; Gradient: 10-50% B over 25 min, then a 5-min hold at 100% B; Flow: 15 mL / min, UV 250 nm]. To the purified material were added a mixture of DCM: MeOH (2:1) and 20% poly(4-vinylpyridine) which is the 2% cross-linked resin and the resulting mixture was agitated at ambient temperature for 2 h on shaker. The mixture was filtered through a 25 mm syringe filter, evaporated and dried to obtain the title compound (0.03 g).1H NMR (400 MHz, DMSO-d6) ppm 7.91 (dt, J = 7.1, 1.8 Hz, 1H), 7.87 - 7.80 (m, 2H), 7.79 - 7.66 (m, 2H), 7.42 - 7.31 (m, 1H), 7.30 - 7.22 (m, 1H), 7.18 (d, J = 7.3Hz, 1H), 4.05 - 3.93 (m, 2H), 3.46 - 3.43 (m, 2H), 3.33 - 3.30 (m, 4H), 2.94 - 2.76 (m, 4H), 2.49 - 2.43 (m, 1H), 2.13 (d, J = 2.2Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H) LCMS (Method-S): retention time 1.55 min, [M+H]+519.2. Examples given in the below table were prepared in a similar manner like Example 12 using intermediate 12D or intermediate 12D / E mixture and appropriate substrates. Compounds are single enantiomers unless noted otherwise. Ret.Time + Example Structure Name [M+H] (min) and method 4-chloro-2-(3-((3'-fluoro- [1,1'-biphenyl]-3- 13 yl)sulfonyl)-2-1.39methylpropyl)505.2-5-(Method S)(piperazin-1-yl)pyridazin- 3(2H)-one 4-chloro-2-(3-((3'-chloro- [1,1'-biphenyl]-3- yl)sulfonyl)-2-1.5814521.2methylpropyl)-5-(Method S)(piperazin-1-yl)pyridazin- 3(2H)-one4-chloro-2-(3-((4'-fluoro- [1,1'-biphenyl]-3- 15 yl)sulfonyl)-2-1.43methylpropyl)-5-505.2(Method S)(piperazin-1-yl)pyridazin- 3(2H)-one 4-chloro-2-(3-((3'-chloro- 2'-methyl-[1,1'-biphenyl]- 3-yl)sulfonyl)-2-1.7416535.1methylpropyl)-5-(Method S)(piperazin-1-yl)pyridazin- 3(2H)-one 4-chloro-2-(3-((2',3'- difluoro-[1,1'-biphenyl]- 3-yl)sulfonyl)-2-1.4417523.2methylpropyl)-5-(Method S)(piperazin-1-yl)pyridazin- 3(2H)-one 4-chloro-2-(3-((2',3'- dimethyl-[1,1'-biphenyl]- 3-yl)sulfonyl)-2-1.6318515.3methylpropyl)-5-(Method S)(piperazin-1-yl)pyridazin- 3(2H)-one 4-chloro-2-(3-((2',3'- dichloro-[1,1'-biphenyl]- 3-yl)sulfonyl)-2-1.6419555.1methylpropyl)-5-(Method S)(piperazin-1-yl)pyridazin- 3(2H)-one 4-chloro-2-(3-((3'-chloro- [1,1'-biphenyl]-3- yl)sulfonyl)-2-1.5420521.2methylpropyl)-5-(Method S)(piperazin-1-yl)pyridazin- 3(2H)-one 4-chloro-2-(3-((3'-fluoro- 2'-methyl-[1,1'-biphenyl]- 3-yl)sulfonyl)-2-1.5621519.2methylpropyl)-5-(Method S)(piperazin-1-yl)pyridazin- 3(2H)-one4-chloro-2-(3-((3',4'- dichloro-[1,1'-biphenyl]- 22 3-yl)sulfonyl)-2-1.71methylpropyl)-5-555.2(Method S)(piperazin-1-yl)pyridazin- 3(2H)-one Examples given in the below table were prepared in a similar manner like Example 12 using intermediate 12E and appropriate substrates. Ret.Time + Example Structure Name [M+H] (min) and method 4-chloro-2-(3-((3'- fluoro-[1,1'-biphenyl]-3- yl)sulfonyl)-2-1.4223505.2methylpropyl)-5-(Method S)(piperazin-1- yl)pyridazin-3(2H)-one 4-chloro-2-(3-((3'- chloro-[1,1'-biphenyl]- 3-yl)sulfonyl)-2-1.5624521.2methylpropyl)-5-(Method S)(piperazin-1- yl)pyridazin-3(2H)-one 4-chloro-2-(3-((3'- fluoro-2'-methyl-[1,1'- biphenyl]-3- 1.5825 yl)sulfonyl)-2-519.2(Method S)methylpropyl)-5- (piperazin-1- yl)pyridazin-3(2H)-one 4-chloro-2-(3-((2',3'- dimethyl-[1,1'- biphenyl]-3- 1.6726 yl)sulfonyl)-2-515.2(Method S)methylpropyl)-5- (piperazin-1- yl)pyridazin-3(2H)-one4-chloro-2-(3-((2',3'- dichloro-[1,1'- biphenyl]-3- 27 yl)sulfonyl)-2-555.1 1.66methylpropyl)-5-(Method S)(piperazin-1- yl)pyridazin-3(2H)-one 4-chloro-2-(3-((3',4'- dichloro-[1,1'- biphenyl]-3- 28 yl)sulfonyl)-2-555.1 1.73methylpropyl)-5-(Method S)(piperazin-1- yl)pyridazin-3(2H)-one Example 29: (R)-4-chloro-2-(3-((3'-fluoro-2'-methyl-[1,1'-biphenyl]-3-yl)sulfonyl)-2- methylpropyl)-5-(piperazin-1-yl-2,2-d2)pyridazin-3(2H)-one Intermediate 29A: To a stirred solution of 2-methylpropane-1,3-diol (2.86 g, 31.7 mmol) and 3- bromobenzenethiol (5.0 g, 26.4 mmol) in THF (100 mL) was added triphenylphosphine (8.32 g, 31.7 mmol) and di-tert-butyl azodicarboxylate (6.70 g, 29.1 mmol) at ambient temperature and stirred for 16h. The volatiles were evaporated to dryness under reduced pressure. The crude compound obtained was purified by column chromatography (Redisep-80 g, 40% EtOAc / n-hexane) to afford a colourless gummy liquid (6.5 g). The enantiomers were separated by SFC [Column: Chiralpak AD-H, 4.6*250 mm, 5 m; Mobile Phase A: CO2, Mobile Phase B: 0.2% NH4OH in ACN:IPA (1:1); Flow rate: 3 mL / min; Gradient: isocratic 25% B; Column Temperature: 30 °C; Back pressure: 100 bar; Detection: UV (240 nm)]. First elutedcompound (retention time 5.62 min), designated as intermediate 29A (1.3 g), was identified as R-isomer by comparison with a standard sample prepared from a chiral alcohol. LCMS (Method M): retention time 2.84 min, [M+H]+261.1. Intermediate 29B: To a stirred solution of 4,5-dichloropyridazin-3(2H)-one (1.0 g, 6.06 mmol) and intermediate 29A (1.58 g, 6.06 mmol) in THF (30 mL) was added triphenyl phosphine (1.75 g, 6.67 mmol) and diethyl azodicarboxylate (1.16 g, 6.67 mmol) at ambient temperature and the reaction mixture was stirred for 16h. The volatile component was removed in vacuo and the residue was purified by column chromatography (Redisep-24 g, 40% EtOAc / n-hexane) to obtain the title compound (1.3 g) as a white solid. LCMS (Method-O): retention time 1.69 min, [M+H]+407.1. Intermediate 29C: To a stirred solution of intermediate 29B (1.3 g, 3.19 mmol) in DCM (20 mL) was added m-CPBA (1.47 g, 6.37 mmol) at ambient temperature and the reaction mixture was stirred for 2 hr. The reaction mixture was diluted with 10% sodium bicarbonate solution and extracted with DCM (2X40 mL). The combined organic layer was washed with water and brine, dried over anhydrous sodium sulphate and evaporated in vacuo to afford the title compound (1.3 g) as white solid. LCMS (Method-O): retention time 1.33 min, [M+H]+439.1. Intermediate 29D: To a stirred solution of intermediate 29C (1.3 g) in ethanol (10 mL) was added DIPEA (0.24 mL, 1.36 mmol) and 1-(4-methoxybenzyl)piperazine-3,3-d2 (0.12 g, 0.59 mmol) at ambient temperature and stirred at 90 °C for 16 hr. The volatile component was removed in vacuo, and the residue was partitioned between water and ethyl acetate (20 mL) and the aqueous layer was extracted with ethylacetate (20 mL). The combined organic layer was washed with water and brine, dried over anhydrous sodium sulphate and evaporated in vacuo. The crude product was purified by silica gel columnchromatography (Redisep-12 g, 40% EtOAc / n-hexane) to afford the title compound (0.25 g). LCMS (Method-O): retention time 1.45 min, [M+H]+ 611.4. Intermediate 29E: To a stirred solution of intermediate 29D (0.08 g, 0.131 mmol) and (3-fluoro-2- methylphenyl) boronic acid (0.030 g, 0.196 mmol) in 1,4-dioxane (1 mL) was added potassium carbonate (0.05g, 0.39mmol) in water (0.05 mL), PdCl2(dppf)2CH2Cl2(8.5 mg, 10.5 μmol) at ambient temperature, purged with nitrogen for 5 min and heated at 85 °C for 16 h. Reaction mixture was filtered through Celite using ethyl acetate and the filtrate was concentrated under reduced pressure to afford the title compound (0.075 g). LCMS (Method-O): retention time 1.62 min, [M+H]+641.5. Example 29: To a stirred solution of intermediate 29E (0.08g, 0.13 mmol) in THF (1 mL) was added 1-chloroethyl chloroformate (0.027 mL, 0.25 mmol) at 0 °C and stirred at 70 °C for 2 hr. The reaction mixture was quenched with MeOH and heated to 70 °C for 1h. The volatiles were evaporated to dryness under reduced pressure. The residue was diluted with 10% aqueous sodium bicarbonate solution and extracted with DCM (2x10mL). The combined organic layer was washed with water, brine, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The crude residue was purified by prep-HPLC to afford the title compound (5.7 mg).1H NMR (400 MHz, DMSO-d6) ppm 7.91 (d, J=7.1 Hz, 1H), 7.82 (s, 2H), 7.78 - 7.65 (m, 2H), 7.41- 7.32 (m, 1H), 7.30 - 7.22 (m, 1H), 7.18 (d, J=7.8 Hz, 1H), 4.06 - 3.93 (m, 2H), 3.46 - 3.43 (m, 4H), 2.86 - 2.72 (m, 4H), 2.13 (s, J=2.2 Hz, 3H), 1.91 (m, 1H), 1.24 (s, 1H),0.96 (d, J=6.8 Hz, 3H). LCMS (Method-S): retention time 1.81 min, [M+H]+521.2 Examples given in the below table were prepared in a similar manner like Example 29 using appropriate substrates.Ret. Time Example Structure Name [M+H]+(min) and method 4-chloro-2-(3-((3'-chloro- [1,1'-biphenyl]-3- 31 yl)sulfonyl)-2-1.58methylpropyl)-5-523.1(Method S)(piperazin-1-yl-2,2- d2)pyridazin-3(2H)-one 4-chloro-2-(3-((3'-fluoro- 2'-methyl-[1,1'-biphenyl]- 3-yl)sulfonyl)-2-1.5932523.2methylpropyl)-5-(Method S)(piperazin-1-yl-2,2,5,5- d4)pyridazin-3(2H)-one 4-chloro-2-(3-((3',4'- dichloro-[1,1'-biphenyl]- 3-yl)sulfonyl)-2-1.7630557.2methylpropyl)-5-(Method S)(piperazin-1-yl-2,2- d2)pyridazin-3(2H)-one Cl4-chloro-2-(3-((3'-chloro-HO N [1,1'-biphenyl]-3-O O NHS N yl)sulfonyl)-2- N1.4833 methylpropyl)-5-(((R)-521.2(Method S)pyrrolidin-3- yl)amino)pyridazin- Cl 3(2H)-one 4-chloro-2-(3-((3'-fluoro- 2'-methyl-[1,1'-biphenyl]- 3-yl)sulfonyl)-2- 1.5134 methylpropyl)-5-(((R)-519.2(Method S)pyrrolidin-3- yl)amino)pyridazin- 3(2H)-one 4-chloro-2-(3-((3',4'- dichloro-[1,1'-biphenyl]- 3-yl)sulfonyl)-2- 1.6535 methylpropyl)-5-(((R)-555.1(Method S)pyrrolidin-3- yl)amino)pyridazin- 3(2H)-one4-chloro-2-(3-((3'-chloro- [1,1'-biphenyl]-3- yl)sulfonyl)-2- 36 methylpropyl)-5-(((S)-521.1 1.57pyrrolidin-3-(Method S)yl)amino)pyridazin- 3(2H)-one 4-chloro-2-(3-((3'-fluoro- 2'-methyl-[1,1'-biphenyl]- 3-yl)sulfonyl)-2- 37 methylpropyl)-5-(((S)-519.2 1.47pyrrolidin-3-(Method R)yl)amino)pyridazin- 3(2H)-one 5-((azetidin-3- ylmethyl)amino)-4- chloro-2-(3-((3'-chloro- 38 [1,1'-biphenyl]-3-521.2 1.37yl)sulfonyl)-2-(Method S)methylpropyl)pyridazin- 3(2H)-one 5-((azetidin-3- ylmethyl)amino)-4- chloro-2-(3-((3'-fluoro-2'- 39 methyl-[1,1'-biphenyl]-3-519.2 1.39yl)sulfonyl)-2-(Method S)methylpropyl)pyridazin- 3(2H)-one Example 40: (R)-4-chloro-2-(3-((3',4'-dichloro-[1,1'-biphenyl]-3-yl)sulfonyl)-2- methylpropyl)-5-(piperazin-1-yl)pyridazin-3(2H)-oneIntermediate 40A: To a stirred solution of 3-bromobenzenethiol (12.00 g, 63.50 mmol) and methyl (S)-3-hydroxy-2-methylpropanoate (8.25 g, 69.80 mmol) in THF (250 mL) was added triphenylphosphine (19.98 g, 76.00 mmol), diethyl azodicarboxylate (10.05 mL, 63.50 mmol) and the resulting reaction mixture was stirred at ambient temperature for 32 h. The volatile component was evaporated under reduced pressure and the residue was purified by column chromatography (Redisep-80 g, 10-15% EtOAc / n-hexane) to afford Intermediate 40A (11.50 g) as a gummy liquid.1H NMR (300 MHz, CDCl3) ppm 7.53 (t, J = 5.60 Hz, 1H), 7.35 - 7.22 (m, 2H), 7.22 - 7.10 (m, 1H), 3.588 (s, 3H), 3.23 (dd, J = 8.0, 23.60 Hz, 2H), 2.77 - 2.64 (m, 1H), 1.18 (d, J = 7.20 Hz, 3H). Intermediate 40B: To a stirring solution of intermediate 40A (10.00 g, 34.60 mmol) in THF (200 mL) was added 4M solution of LiBH4 in THF (19.02 mL, 38.00 mmol) and the resulting reaction mixture was stirred at ambient temperature for 12 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-120 g, 60-65% EtOAc / n-hexane) to obtain intermediate 40B (8.60 g) as a gummy liquid. LCMS (Method-O): retention time 1.63 min, [M+H]+260.9. Intermediate 40C: Intermediate 40C was prepared as a gummy liquid by using a similar synthetic protocol as that of intermediate 12B and starting from intermediate 40B and 4,5- dichloropyridazin-3(2H)-one. LCMS (Method-O): retention time 2.16 min, [M+H]+406.9. Intermediate 40D: Intermediate 40D was prepared as a white solid by using a similar synthetic protocol as that of intermediate 12C and starting from intermediate 40C and m-CPBA. LCMS (Method-O): retention time 1.65 min, [M+H]+438.8.Intermediate 40E: Intermediate 40E was prepared as a gummy liquid by using a similar synthetic protocol as that of intermediate 12D and starting from intermediate 40D and tert-butyl piperazine-1-carboxylate. LCMS (Method-O): retention time 0.79 min, [M+H]+590.1. Intermediate 40F: Intermediate 40F was prepared by using a similar synthetic protocol as that of intermediate 12F and starting from intermediate 40E and (3,4-dichlorophenyl)boronic acid. LCMS (Method-O): retention time 2.14 min, [M+H]+655.1. The compound was advanced to the subsequent step without further purification. Example 40: Example 40 was prepared by using a similar synthetic protocol as that of example 12 and starting from intermediate 40F and TFA.1H NMR (400 MHz, DMSO-d6) ppm 8.20 (s, 1H), 8.10 - 8.03 (m, 2H), 7.89 (d, J = 8.30 Hz, 1H), 7.80 - 7.69 (m, 4H), 4.06 (dd, J = 13.10, 7.00 Hz, 1H), 3.91 (dd, J = 13.00, 7.30 Hz, 1H), 3.48 -3.42 (m, 2H), 3.25 (d, J = 3.20 Hz, 4H), 2.85 - 2.71 (m, 4H), 2.48 - 2.39 (m, 1H), 0.98 (d, J = 6.80 Hz, 3H). LCMS (Method M): retention time 2.50 min, [M+H]+555.1. Examples given in the below table were prepared in a similar manner like Example 40 using appropriate substrates. Ret.Time Example Structure Name [M+H]+(min) and method Cl O NH (R)-4-chloro-2-(2- OON methyl-3-((3'- SNN (trifluoromethyl)-[1,1'- 41 biphenyl]-3-555.1 1.51yl)sulfonyl)propyl)-5-(Method R)(piperazin-1- CF3yl)pyridazin-3(2H)-one(R)-4-chloro-2-(2- methyl-3-((4'- (trifluoromethyl)-[1,1'- 42 biphenyl]-3-555.2 1.54yl)sulfonyl)propyl)-5-(Method R)(piperazin-1- yl)pyridazin-3(2H)-one Cl O NH OON (R)-4-chloro-2-(3-((4'- SNN chloro-[1,1'-biphenyl]- 3-yl)sulfonyl)-2- 43 met521.1 1.48hylpropyl)-5-(Method R)(piperazin-1- yl)pyridazin-3(2H)-one Cl Cl O NH OON (R)-3'-((3-(5-chloro-6- SNoxo-4-(piperazin-1- N yl)pyridazin-1(6H)-yl)- 44 2-512.2 1.55methylpropyl)sulfonyl)-(Method S)[1,1'-biphenyl]-4- CN carbonitrile (R)-4-chloro-2-(3-((4'- fluoro-3'-methyl-[1,1'- biphenyl]-3- 45 yl)sulfonyl)-2-519.2 1.48methylpropyl)-5-(Method R)(piperazin-1- yl)pyridazin-3(2H)-one (R)-4-chloro-2-(3-((4'- fluoro-3'- (trifluoromethyl)-[1,1'- 46 biphenyl]-3-1.57yl)sulfonyl)-2-573.1(Method R)methylpropyl)-5- (piperazin-1- yl)pyridazin-3(2H)-one (R)-4-chloro-2-(3-((3'- chloro-4'-fluoro-[1,1'- biphenyl]-3- 47 yl)sulfonyl)-2-539.1 1.50methylpropyl)-5-(Method R)(piperazin-1- yl)pyridazin-3(2H)-one(R)-4-chloro-2-(3- ((2',4'-difluoro-[1,1'- biphenyl]-3- 48 yl)sulfonyl)-2-523.1 1.71methylpropyl)-5-(Method S)(piperazin-1- yl)pyridazin-3(2H)-one (R)-4-chloro-2-(3-((2'- chloro-4'-fluoro-[1,1'- biphenyl]-3- 49 yl)sulfonyl)-2-539.1 1.81methylpropyl)-5-(Method S)(piperazin-1- yl)pyridazin-3(2H)-one (R)-4-chloro-2-(3-((4'- fluoro-2'-methyl-[1,1'- biphenyl]-3- 50 yl)sulfonyl)-2-519.2 1.48methylpropyl)-5-(Method R)(piperazin-1- yl)pyridazin-3(2H)-one (R)-4-chloro-2-(3- ((2',4'-dichloro-[1,1'- biphenyl]-3- 51 yl)sulfonyl)-2-555.1 1.84methylpropyl)-5-(Method S)(piperazin-1- yl)pyridazin-3(2H)-one (R)-4-chloro-2-(3- ((2',5'-dichloro-[1,1'- biphenyl]-3- 52 yl)sulfonyl)-2-555.1 1.58methylpropyl)-5-(Method R)(piperazin-1- yl)pyridazin-3(2H)-one (R)-4-chloro-2-(3- ((3',5'-dichloro-[1,1'- biphenyl]-3- 53 yl)sulfonyl)-2-555.1 1.66methylpropyl)-5-(Method R)(piperazin-1- yl)pyridazin-3(2H)-one(R)-4-chloro-2-(3-((3'- fluoro-5'-methoxy-[1,1'- biphenyl]-3- 54 yl)sulfonyl)-2-535.2 1.38methylpropyl)-5-(Method R)(piperazin-1- yl)pyridazin-3(2H)-one (R)-4-chloro-2-(3-((3- (2,3-dihydrobenzofuran- 55 5-yl)phenyl)sulfonyl)-2- methylpropyl)-5-529.1 1.28(Method R)(piperazin-1- yl)pyridazin-3(2H)-one (R)-4-chloro-2-(2- methyl-3-((3-(2- methylfuran-3- 1.24 56 yl)phenyl) 491.1 (Method R) sulfonyl)propyl)-5- (piperazin-1- yl)pyridazin-3(2H)-one (R)-4-chloro-2-(2- methyl-3-((3-(5- methylthiophen-2- 57 yl)phenyl)507.1 1.37sulfonyl)propyl)-5-(Method R)(piperazin-1- yl)pyridazin-3(2H)-one (R)-5-(3-((3-(5-chloro- 6-oxo-4-(piperazin-1- 58 yl)pyridazin-1(6H)-yl)-1.272-methylpropyl)517.9(Method R)sulfonyl)phenyl)thiophe ne-2-carbonitrile (R)-4-chloro-2-(2- methyl-3-((3-(pyridin-4- 59 yl)phenyl)sulfonyl)488.1 0.64propyl)-5-(piperazin-1-(Method R)yl)pyridazin-3(2H)-one(R)-4-chloro-2-(3-((3- (2-chloropyridin-4- yl)phenyl)sulfonyl)-2- 60 methylpropyl)-5-1.10(piperazin-1-522.1(Method R)yl)pyridazin-3(2H)- onemethylamino)pyrida zin-3(2H)-one (R)-4-chloro-2-(3-((3- (6-fluoropyridin-2- yl)phenyl)sulfonyl)-2-1.1661506.1methylpropyl)-5-(Method R)(piperazin-1- yl)pyridazin-3(2H)-one (R)-4-chloro-2-(3-((3- (6-methoxypyridin-2- yl)phenyl)sulfonyl)-2-1.2862518.2methylpropyl)-5-(Method R)(piperazin-1- yl)pyridazin-3(2H)-one (R)-4-chloro-2-(3-((3- (5-chlorothiophen-2- yl)phenyl)sulfonyl)-2-1.4864527.1methylpropyl)-5-(Method R)(piperazin-1- yl)pyridazin-3(2H)-one (R)-2-(3-((3-(1H- indazol-4- yl)phenyl)sulfonyl)-2-1.065527.1methyl propyl)-4-(Method R)chloro-5-(piperazin-1- yl)pyridazin-3(2H)-one (R)-4-chloro-2-(2- methyl-3-((3- (naphthalen-1- 1.5766 yl)phenyl)537.2(Method R)sulfonyl)propyl)-5- (piperazin-1- yl)pyridazin-3(2H)-one(R)-4-chloro-5-(1,4- diazepan-1-yl)-2-(3-((3'- fluoro-2'-methyl-[1,1'- 67 biphenyl]-3-533.2 1.50yl)sulfonyl)-2-(Method S)methylpropyl)pyridazin- 3(2H)-one (R)-4-chloro-2-(3-((3'- chloro-2'-methyl-[1,1'- biphenyl]-3- 68 yl)sulfonyl)-2-549.2 1.63methylpropyl)-5-(1,4-(Method S)diazepan-1- yl)pyridazin-3(2H)-one (R)-4-chloro-5-(1,4- diazepan-1-yl)-2-(3- ((3',4'-dichloro-[1,1'- 69 biphenyl]-3-569.2 1.63yl)sulfonyl)-2-(Method S)methylpropyl)pyridazin- 3(2H)-one (R)-4-chloro-2-(3-((3'- chloro-4'-fluoro-[1,1'- biphenyl]-3- 70 yl)sulfonyl)-2-553.2 1.52methylpropyl)-5-(1,4-(Method S)diazepan-1- yl)pyridazin-3(2H)-one 4-chloro-2-((R)-3-((3'- chloro-2'-methyl-[1,1'- biphenyl]-3- 71 yl)sulfonyl)-2-1.68methylpropyl)-5-(6-565.2(Method S)hydroxy-1,4-diazepan- 1-yl)pyridazin-3(2H)- one 4-chloro-2-((R)-3- ((3',4'-dichloro-[1,1'- biphenyl]-3- 72 yl)sulfonyl)-2-587.2 1.92methylpropyl)-5-(6-(Method S)fluoro-1,4-diazepan-1- yl)pyridazin-3(2H)-one(R)-4-chloro-2-(3- ((3',4'-dichloro-[1,1'- biphenyl]-3- 73 yl)sulfonyl)-2-583.1 1.65methylpropyl)-5-(2,2-(Method R)dimethylpiperazin-1- yl)pyridazin-3(2H)-one 4-chloro-2-((R)-3-((3'- fluoro-2'-methyl-[1,1'- biphenyl]-3- 74 yl)sulfonyl)-2-533.2 1.46methylpropyl)-5-((R)-3-(Method R)methylpiperazin-1- yl)pyridazin-3(2H)-one 4-chloro-2-((R)-3-((3'- fluoro-2'-methyl-[1,1'- biphenyl]-3- 75 yl)sulfonyl)-2-533.2 1.48methylpropyl)-5-((S)-3-(Method R)methylpiperazin-1- yl)pyridazin-3(2H)-one 4-chloro-5-((3R,5R)- 3,5-dimethylpiperazin- 1-yl)-2-((R)-3-((3'- 76 fluoro-2'-methyl-[1,1'-1.75biphenyl]-3-547.2(Method R)yl)sulfonyl)-2- methylpropyl)pyridazin- 3(2H)-one 4-chloro-2-((R)-3-((3'- fluoro-2'-methyl-[1,1'- biphenyl]-3- yl)sulfonyl)-2- 771.59methylpropyl)-5-((R)-3-549.2(Method R)(hydroxymethyl) piperazin-1-yl) pyridazin-3(2H)-one 4-chloro-5-((2S,5R)-5- ethyl-2- methylpiperazin-1-yl)- 78 2-((R)-3-((3'-fluoro-2'-1.53methyl-[1,1'-biphenyl]-561.2(Method R)3-yl)sulfonyl)-2- methylpropyl)pyridazin- 3(2H)-one4-chloro-2-((R)-3-((3'- fluoro-2'-methyl-[1,1'- biphenyl]-3- 79 yl)sulfonyl)-2-1.59methylpropyl)-5-575.2(Method R)((2S,5R)-2-methyl-5- propylpiperazin-1- yl)pyridazin-3(2H)-one 4-chloro-2-((R)-3- ((3',4'-dichloro-[1,1'- biphenyl]-3- 80 yl)sulfonyl)-2-583.1 1.69methylpropyl)-5-(2,6-(Method R)dimethylpiperazin-1- yl)pyridazin-3(2H)-one 4-chloro-2-((R)-3- ((3',4'-dichloro-[1,1'- biphenyl]-3- 81 yl)sulfonyl)-2- 583.1 1.71 methylpropyl)-5- (Method R) ((2R,5S)-2,5- dimethylpiperazin-1- yl)pyridazin-3(2H)-one 4-chloro-5-((2S,5R)-2,5- dimethyl piperazin-1- yl)-2-((R)-3-((3'-fluoro- 82 2'-methyl-[1,1'- biphenyl]-3-547.2 1.79(Method S)yl)sulfonyl)-2-methyl propyl)pyridazin-3(2H)- one 4-chloro-2-((R)-3- ((3',4'-dichloro-[1,1'- biphenyl]-3- yl)sulfonyl)-2- 831.9methylpropyl)-5-583.1 8(Method S)((2S,5R)-2,5- dimethylpiperazin-1- yl)pyridazin-3(2H)-one 4-chloro-2-((R)-3-((3'- chloro-4'-fluoro-[1,1'- biphenyl]-3- 84 yl)sulfonyl)-2-1.84methylpropyl)-5-567.1(Method S)((2S,5R)-2,5- dimethylpiperazin-1- yl)pyridazin-3(2H)-one5-((1S,4S)-2,5- diazabicyclo[2.2.1]hepta n-2-yl)-4-chloro-2-((R)- 85 3-((3'-fluoro-2'-methyl- [1,1'-biphenyl]-3-531.1 1.84(Method S)yl)sulfonyl)-2- methylpropyl) pyridazin-3(2H)-one 5-(3,8- diazabicyclo[3.2.1]octan -3-yl)-4-chloro-2-((R)- 86 3-((3'-fluoro-2'-methyl-1.49[1,1'-biphenyl]-3-545.2(Method R)yl)sulfonyl)-2- methylpropyl) pyridazin-3(2H)-one 5-(3,8- diazabicyclo[3.2.1]octan -8-yl)-4-chloro-2-((R)- 3-((3'-fluoro-2'-methyl- 871.49[1,1'-biphenyl]-3-542.2(Method R)yl)sulfonyl)-2- methylpropyl) pyridazin-3(2H)-one 5-(2,5- diazabicyclo[2.2.2]octan -2-yl)-4-chloro-2-((R)- 88 3-((3'-fluoro-2'-methyl- [1,1'-biphenyl]-3-545.1 1.66(Method S)yl)sulfonyl)-2- methylpropyl) Diastereomer-I pyridazin-3(2H)-one 5-(2,5- diazabicyclo[2.2.2]octan -2-yl)-4-chloro-2-((R)- 89 3-((3'-fluoro-2'-methyl-1.74[1,1'-biphenyl]-3-545.1(Method S)yl)sulfonyl)-2- methylpropyl) Diastereomer-II pyridazin-3(2H)-one (R)-4-chloro-2-(3-((3'- fluoro-2'-methyl-[1,1'- biphenyl]-3- 90 yl)sulfonyl)-2-559.2 1.54methylpropyl)-5-(5,8-(Method R)diazaspiro[3.5]nonan-8- yl)pyridazin-3(2H)-one(R)-4-chloro-2-(3-((3'- fluoro-2'-methyl-[1,1'- biphenyl]-3- 91 yl)sulfonyl)-2-545.2 1.47methylpropyl)-5-(2,6-(Method R)diazaspiro[3.4]octan-6- yl)pyridazin-3(2H)-one 4-chloro-2-((R)-3- ((3',4'-dichloro-[1,1'- biphenyl]-3- yl)sulfonyl)-2- 92 methylpropyl)-5-595.1 1.71(octahydro-5H-(Method R)pyrrolo[3,4-c] pyridin- 5-yl)pyridazin-3(2H)- one 4-chloro-2-((R)-3- ((3',4'-dichloro-[1,1'- biphenyl]-3- yl)sulfonyl)-2- 931.5methylpropyl)-5-581.1 9(Method R)(hexahydropyrrolo[3,4- c]pyrrol-2(1H)- yl)pyridazin-3(2H)-one (R)-4-chloro-2-(3- ((3',4'-dichloro-[1,1'- biphenyl]-3- 94 yl)sulfonyl)-2-567.1 1.60methylpropyl)-5-(2,6-(Method R)diazaspiro[3.3]heptan-2- yl)pyridazin-3(2H)-one 4-chloro-2-((R)-3- ((3',4'-dichloro-[1,1'- biphenyl]-3- 95 yl)sulfonyl)-2-595.1 1.64methylpropyl)-5-(2,7-(Method R)diazaspiro[4.4]nonan-2- yl)pyridazin-3(2H)-one (R)-4-chloro-2-(3- ((3',4'-dichloro-[1,1'- biphenyl]-3- 96 yl)sulfonyl)-2-609.1 1.70methylpropyl)-5-(2,8-(Method R)diazaspiro[4.5]decan-8- yl)pyridazin-3(2H)-oneNH 4-chloro-2-((R)-3- Cl O ((3',4'-dichloro-[1,1'- OON biphenyl]-3- SNN yl)sulfonyl)-2- 97 methylpropyl)-5-595.2 1.64(octahydro-2H-(Method R)pyrrolo[3,4-c] pyridin- Cl Cl 2-yl)pyridazin-3(2H)- one 4-chloro-2-((R)-3- ((3',4'-dichloro-[1,1'- biphenyl]-3- yl)sulfonyl)-2- 98 methylpropyl)-5-595.1 1.67(octahydro-1H-(Method R)pyrrolo[3,2-c] pyridin- 1-yl)pyridazin-3(2H)- one (R)-4-chloro-2-(3- ((3',4'-dichloro-[1,1'- biphenyl]-3- 99 yl)sulfonyl)-2-581.1 1.64methylpropyl)-5-(2,6-(Method R)diazaspiro[3.4]octan-2- yl)pyridazin-3(2H)-one (R)-4-chloro-2-(3- ((3',4'-dichloro-[1,1'- biphenyl]-3- 100 yl)sulfonyl)-2-581.1 1.62methylpropyl)-5-(2,6-(Method R)diazaspiro[3.4]octan-6- yl)pyridazin-3(2H)-one (R)-4-chloro-2-(3-((3'- fluoro-2'-methyl-[1,1'- biphenyl]-3- 101 yl)sulfonyl)-2-573.2 1.48methylpropyl)-5-(2,8-(Method R)diazaspiro[4.5]decan-2- yl)pyridazin-3(2H)-one(R)-4-chloro-2-(3-((3'- fluoro-2'-methyl-[1,1'- biphenyl]-3- 102 yl)sulfonyl)-2-545.2 1.48methylpropyl)-5-(2,6-(Method R)diazaspiro[3.4]octan-2- yl)pyridazin-3(2H)-one (R)-4-chloro-2-(3- ((3',4'-dichloro-[1,1'- biphenyl]-3- yl)sulfonyl)-2- 103 methylpropyl)-5-592.2 1.79(2,4,6,7-tetrahydro-5H-(Method R)pyrazolo[4,3-c]pyridin- 5-.2yl)pyridazin-3(2H)- one 5-((S)-3- aminopiperidin-1-yl)-4- chloro-2-((R)-3-((3'- 104 fluoro-[1,1'-biphenyl]-3-519.1 1.48yl)sulfonyl)-2-(Method S)methylpropyl)pyridazin- 3(2H)-one 5-((S)-3- aminopiperidin-1-yl)-4- chloro-2-((R)-3-((4'- 105 fluoro-[1,1'-biphenyl]-3-519.1 1.48yl)sulfonyl)-2-(Method S)methylpropyl)pyridazin- 3(2H)-one NH2Cl 5-((S)-3- O N O O aminopiperidin-1-yl)-4- SNN chloro-2-((R)-2-methyl- 106 3-((4'-methyl-[1,1'-515.1 1.59biphenyl]-3-(Method S)yl)sulfonyl)propyl)pyrid azin-3(2H)-one CH35-((S)-3- aminopiperidin-1-yl)-4- chloro-2-((R)-3-((2',3'- 107 difluoro-[1,1'-biphenyl]-537.1 1.933-yl)sulfonyl)-2-(Method S)methylpropyl)pyridazin- 3(2H)-one 5-((S)-3- aminopiperidin-1-yl)-4- chloro-2-((R)-3-((2'- 108 chloro-3'-fluoro-[1,1'-1.58biphenyl]-3-555.1(Method S)yl)sulfonyl)-2- methylpropyl) pyridazin-3(2H)-one 5-((S)-3- aminopiperidin-1-yl)-4- chloro-2-((R)-3-((3'- 109 fluoro-2'-methyl-[1,1'-1.91biphenyl]-3-533.1(Method S)yl)sulfonyl)-2- methylpropyl) pyridazin-3(2H)-one 5-((S)-3- aminopiperidin-1-yl)-4- chloro-2-((R)-3-((3'- 110 chloro-2'-methyl-[1,1'- biphenyl]-3-549.1 1.75(Method S)yl)sulfonyl)-2- methylpropyl) pyridazin-3(2H)-one 5-((S)-3- aminopiperidin-1-yl)-4- chloro-2-((R)-3-((4'- chloro-2'-fluoro-[1,1'- 1112.12biphenyl]-3-553.1(Method S)yl)sulfonyl)-2- methylpropyl) pyridazin-3(2H)-one 5-((S)-3- aminopiperidin-1-yl)-4- chloro-2-((R)-3-((3',4'- 112 dichloro-[1,1'-2.09biphenyl]-3-569.1(Method S)yl)sulfonyl)-2- methylpropyl)pyridazin- 3(2H)-one5-((S)-3- aminopiperidin-1-yl)-4- chloro-2-((R)-3-((4'- chloro-3'-fluoro-[1,1'- 1131.6biphenyl]-3-553.1 6(Method L)yl)sulfonyl)-2- methylpropyl) pyridazin-3(2H)-one 5-((S)-3- aminopiperidin-1-yl)-4- chloro-2-((R)-3-((2'- 114 chloro-4'-fluoro-[1,1'-2.05biphenyl]-3-553.0(Method S)yl)sulfonyl)-2- methylpropyl) pyridazin-3(2H)-one 5-((S)-3- aminopiperidin-1-yl)-4- chloro-2-((R)-2-methyl- 115 3-((3',4',5'-trifluoro-555.1 1.63[1,1'-biphenyl]-3-(Method S)yl)sulfonyl)propyl)pyrid azin-3(2H)-one NH25-((R)-3- Cl ONaminopiperidin-1-yl)-4- OOchloro-2-((R)-3-((3',4'- S N 116 N dichloro-[1,1'- biphenyl]-3-569.2 1.94(Method R)yl)sulfonyl)-2- methylpropyl)pyridazin- Cl Cl 3(2H)-one 5-((3R,5R)-3-amino-5- fluoropiperidin-1-yl)-4- chloro-2-((R)-3-((3',4'- 117 dichloro-[1,1'-1.67biphenyl]-3-587.0(Method R)yl)sulfonyl)-2- methylpropyl)pyridazin- 3(2H)-one(R)-5-(3-aminoazetidin- 1-yl)-4-chloro-2-(3- ((3',4'-dichloro-[1,1'- 118 biphenyl]-3-541.1 1.58yl)sulfonyl)-2-(Method R)methylpropyl)pyridazin- 3(2H)-one 4-chloro-2-((R)-3- ((3',4'-dichloro-[1,1'- biphenyl]-3- yl)sulfonyl)-2- 1191.7methylpropyl)-5-(3-569.1 5(Method S)(methylamino)pyrrolidi n-1-yl)pyridazin-3(2H)- Diastereomeric mixture one 4-chloro-2-((R)-3-((3'- fluoro-2'-methyl-[1,1'- biphenyl]-3- 120 yl)sulfonyl)-2-1.67methylpropyl)-5-((S)-3-547.2(Method S)(methylamino)piperidin- 1-yl)pyridazin-3(2H)- one 5-((7R)-7-amino-2- azabicyclo [2.2.1]heptan-2-yl)-4- chloro-2-((R)-3-((3'- 1211.17fluoro-[1,1'-biphenyl]-3-531.2(Method R)yl)sulfonyl)-2- methylpropyl) pyridazin-3(2H)-one 5-((7R)-7-amino-2- azabicyclo [2.2.1]heptan-2-yl)-4- 122 chloro-2-((R)-3-((3'-1.19fluoro-[1,1'-biphenyl]-3-531.2(Method R)yl)sulfonyl)-2- methylpropyl) pyridazin-3(2H)-one 5-((7R)-7-amino-2- azabicyclo [2.2.1]heptan-2-yl)-4- chloro-2-((R)-3-((3'- 123 chloro-2'-methyl-[1,1'-561.1 1.46biphenyl]-3-(Method R)yl)sulfonyl)-2- methylpropyl)pyridazin- 3(2H)-one5-((7R)-7-amino-2- azabicyclo [2.2.1]heptan-2-yl)-4- chloro-2-((R)-3-((3'- 124 chloro-4'-fluoro-[1,1'-565.1 1.35biphenyl]-3-(Method R)yl)sulfonyl)-2- methylpropyl)pyridazin- 3(2H)-one 4-chloro-2-((R)-3- ((3',4'-dichloro-[1,1'- biphenyl]-3- 125 yl)sulfonyl)-2-1.57methylpropyl)-5-(2-585.1(Method R)(hydroxymethyl)piperaz in-1-yl)pyridazin-3(2H)- one Diastereomeric mixture (R)-4-chloro-5- (cyclopropyl amino)-2- (3-((3',4'-dichloro-[1,1'- 126 biphenyl]-3-526.1 2.14yl)sulfonyl)-2-(Method S)methylpropyl)pyridazin- 3(2H)-one Cl H (R)-5-((2-(1H-imidazol- O N OONH 4-yl)ethyl)amino)-4- S N N N chloro-2-(3-((3',4'- 127 dichloro-[1,1'- 580 1.56biphenyl]-3-.1(Method R)yl)sulfonyl)-2- Cl methylpropyl) Cl pyridazin-3(2H)-one Example 128: (R)-4-chloro-2-(3-((2',3'-dichloro-[1,1'-biphenyl]-3-yl)sulfonyl)-2- methylpropyl)-5-(piperazin-1-ylmethyl)pyridazin-3(2H)-oneIntermediate 128A: To a stirred solution of Intermediate 40D (0.30 g, 0.68 mmol) in DMF (5 mL) was added sodium iodide (0.31 g, 2.04 mmol) and the resulting reaction mixture was heated at 120 °C for 16 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was diluted with water (40 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic layer was washed with brine (40 mL), dried over anhydrous sodium sulphate, and evaporated under reduced pressure to obtain the title compound (0.33 g) as a brown solid. LCMS (Method-O): retention time 1.65 min, [M+H]+530.4. Intermediate 128B: Intermediate 128B was prepared as a gummy liquid by using a similar synthetic protocol as that of intermediate 12F starting from intermediate 128A and 4,4,5,5- tetramethyl-2-vinyl-1,3,2-dioxaborolane. LCMS (Method-O): retention time 1.57 min, [M+H]+430.8. Intermediate 128C: To a stirred solution of intermediate 128B (0.50 g, 1.16 mmol) in a mixture of dioxane (6 mL) and water (6 mL) was added osmium tetroxide (0.54 mL, 1.74 mmol) followed by sodium periodate (0.37 g, 1.74 mmol) at 0 °C and the resulting reactionmixture was stirred at ambient temperature 16 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulphate, and evaporated under reduced pressure to obtain the title compound (0.42 g) as a gummy liquid. LCMS (Method-O): retention time 1.23 min, [M+H]+432.8. The compound was advanced to the subsequent step without further purification. Intermediate 128D: To a stirred solution of intermediate 128C (0.15 g, 0.34 mmol) in MeOH (5 mL) was added NaBH4(0.03 g, 0.69 mmol) at 0°C and the resulting reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was concentrated under reduced pressure, diluted with water (30 mL) and extracted with DCM (2 x 30 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulphate, and evaporated under reduced pressure to afford the title compound (0.14 g) as a gummy liquid. LCMS (Method-O): retention time 1.25 min, [M+H]+435.1. The compound was advanced to the subsequent step without further purification. Intermediate 128E: To a stirred solution of intermediate 128D (0.15 g, 0.34 mmol) in DCM (2 mL) was added TEA (0.10 mL, 0.69 mmol) followed by methane sulfonyl chloride (0.04 mL, 0.52 mmol) and the resulting reaction mixture was stirred at ambient temperature for 1h. The reaction mixture was diluted with water (20 mL) and extracted with DCM (2 x 30 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulphate, and evaporated under reduced pressure to obtain desired compound (0.14 g) as a gummy liquid. LCMS (Method-O): retention time 1.45 min, [M+H]+512.8. The compound was advanced to the subsequent step without further purification. Intermediate 128F: To a stirred solution of intermediate 128E (0.08 g, 0.156 mmol) in DCM (1 mL) was added tert-butyl piperazine-1-carboxylate (0.03 g, 0.16 mmol) followed by TEA(0.04 mL, 0.31 mmol) and the resulting reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with water (20 mL) and extracted with DCM (2 x 30 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-4 g, 30% EtOAc / n-hexane) to obtain the desired intermediate (0.09 g). LCMS (Method-O): retention time 1.92 min, [M+H]+602.9. The compound was advanced to the subsequent step without further purification. Intermediate 128G: Intermediate 128G was prepared as gummy liquid by using a similar synthetic protocol as that of intermediate 12F starting from intermediate 128F and 2-(2,3- dichlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. LCMS (Method-O): retention time 2.24 min, [M+H]+669.4. The compound was advanced to the subsequent step without further purification. Example 128: Example 128 was prepared by using a similar synthetic protocol as that of example 12 starting from intermediate 128G and TFA.1H NMR (400 MHz, DMSO-d6) ppm 7.88 - 7.99 (m, 3H), 7.81 - 7.86 (m, 1H), 7.68 - 7.79 (m, 2H), 7.41 - 7.56 (m, 2H), 4.10 - 4.16 (m, 1H), 4.02 - 4.08 (m, 1H), 3.52 (s, 2H), 3.45 - 3.50 (m, 2H), 2.74 - 2.91 (m, 4H), 2.35 - 2.48 (m, 5H), 1.03 (d, J = 6.50 Hz, 3H). LCMS (Method S): retention time 1.69 min, [M+H]+569.1. Example 129: (R)-6-chloro-2-(3-((3',4'-dichloro-[1,1'-biphenyl]-3-yl)sulfonyl)-2- methylpropyl)-5-(piperazin-1-yl)pyridazin-3(2H)-oneIntermediate 129A: Intermediate 129A was prepared by using a similar synthetic protocol as that of intermediate 12B and starting from intermediate 40B and 5,6-dichloropyridazin-3(2H)- one. LCMS (Method-O): retention time 2.20 min, [M+H]+406.8. Intermediate 129B: Intermediate 129B was prepared by using a similar synthetic protocol as that of intermediate 12C and starting from intermediate 129A and m-CPBA. LCMS (Method- O): retention time 1.68 min, [M+H]+438.8. The compound was advanced to the subsequent step without further purification. Intermediate 129C: Intermediate 129C was prepared as a gummy liquid by using a similar synthetic protocol as that of intermediate 12D starting from intermediate 129B and 1-Boc- piperazine. LCMS (Method O): retention time 1.89 min, [M+H]+588.9. The compound was advanced to the subsequent step without further purification. Intermediate 129D: Intermediate 129D was prepared as a gummy liquid by using a similar synthetic protocol as that of intermediate 12F starting from intermediate 129C and (3,4- dichlorophenyl)boronic acid. LCMS (Method-O): retention time 2.21 min, [M+H]+655.4. The compound was advanced to the subsequent step without further purification.Example 129: To a stirred solution of intermediate 129D (0.03 g, 0.05 mmol) in DCM (3 mL) was added 4M solution of HCl in dioxane (0.11 mL, 0.45 mmol) and the resulting reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by HPLC [Column: Waters XBridge C18 (19 x 250 mm) 5 micron; Solvent A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Solvent B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid, Gradient: 20-100% B over 17 min, Flow: 15 mL / min, UV 250 nm] to obtain pure material. To the purified material in a mixture of DCM: MeOH (2:1) was added 20% poly(4-vinylpyridine) and the resulting mixture was agitated at ambient temperature for 2 h on shaker. Then filtered through a 25 mm syringe filter and evaporated and dried to obtain Example 129 (0.015 g).1H NMR (400 MHz, DMSO-d6) ppm 8.19 (t, J = 1.80 Hz, 1H), 8.15 - 8.06 (m, 2H), 7.91 (d, J = 8.30 Hz, 1H), 7.83 - 7.68 (m, 3H), 6.16 (s, 1H), 4.02 (dd, J = 13.10, 7.20 Hz, 1H), 3.89 - 3.82 (m, 1H), 3.45 - 3.50 (m, 2H), 2.93 - 3.01 (m, 4H), 2.77 - 2.87 (m, 4H), 2.45 - 2.50 (m, 1H), 1.00 (d, J = 6.80 Hz, 3H). LCMS (Method-S): retention time 1.87 min, [M+H]+555.1. Examples given in the below table were prepared in a similar manner like Example 129 using appropriate substrates. Ret.Time Example Structure Name [M+H]+(min) and method (R)-6-chloro-2-(3-((2'- chloro-[1,1'-biphenyl]-3- 130 yl)sulfonyl)-2-1.79methylpropyl)-5-521.1(Method S)(piperazin-1-yl)pyridazin- 3(2H)-one (R)-6-chloro-2-(3-((3'- chloro-[1,1'-biphenyl]-3- 131 yl)sulfonyl)-2-1.84methylpropyl)-5-521.1(Method S)(piperazin-1-yl)pyridazin- 3(2H)-oneO NH OON (R)-6-chloro-2-(3-((4'- SNN chloro-[1,1'-biphenyl]-3- Cl 132 yl)sulfonyl)-2- methylprop521.1 1.86yl)-5-(Method S)(piperazin-1-yl)pyridazin- 3(2H)-one Cl (R)-6-chloro-2-(3-((3'- fluoro-2'-methyl-[1,1'- 134 biphenyl]-3-yl)sulfonyl)-1.722-methylpropyl)-5-521.2(Method S)(piperazin-1-yl)pyridazin- 3(2H)-one (R)-6-chloro-2-(3-((2',3'- dichloro-[1,1'-biphenyl]- 3-yl)sulfonyl)-2- 1351.92methylpropyl)-5-555.1(Method S)(piperazin-1-yl)pyridazin- 3(2H)-one (R)-6-chloro-2-(3-((2',5'- dichloro-[1,1'-biphenyl]- 3-yl)sulfonyl)-2-1.94136 methylpropyl)-5-555.1(Method S)(piperazin-1-yl)pyridazin- 3(2H)-one (R)-6-chloro-2-(3-((2',6'- dichloro-[1,1'-biphenyl]- 137 3-yl)sulfonyl)-2-1.85methylpropyl)-5-555.1(Method S)(piperazin-1-yl)pyridazin- 3(2H)-one (R)-6-chloro-2-(3-((3',4'- dichloro-[1,1'-biphenyl]- 138 3-yl)sulfonyl)-2-1.67methylpropyl)-5-555.1(Method R)(piperazin-1-yl)pyridazin- 3(2H)-one (R)-6-chloro-2-(3-((3',5'- dichloro-[1,1'-biphenyl]- 139 3-yl) sulfonyl)-2-1.79methylpropyl)-5-555.1(Method R)(piperazin-1-yl)pyridazin- 3(2H)-one6-chloro-2-(3-((3'-fluoro- 2'-methyl-[1,1'-biphenyl]- 133 3-yl) sulfonyl)-2-1.54methylpropyl)-5-521.2(Method R)(piperazin-1-yl)pyridazin- 3(2H)-one Racemic mixture Examples given in the below table were prepared in a similar manner like Example 129 using (S)-3-((3-bromophenyl)thio)-2-methylpropan-1-ol (isolated in the synthesis of Intermediate 29A) and appropriate substrates. Ret.Time + Example Structure Name [M+H] (min) and method (S)-6-chloro-2-(3-((3'- fluoro-2'-methyl-[1,1'- biphenyl]-3-yl)sulfonyl)-1.94140519.12-methylpropyl)-5-(Method R)(piperazin-1-yl)pyridazin- 3(2H)-one NH O N (S)-6-chloro-2-(3-((3',4'-O OS Ndichloro-[1,1'-biphenyl]- N Cl 3-yl)sulfonyl)-2-2.04141555.1methylpropyl)-5-(Method S)(piperazin-1-yl)pyridazin- Cl 3(2H)-one Cl Example 142: 1-(3-((3',4'-dichloro-[1,1'-biphenyl]-3-yl)sulfonyl)-2- methylpropyl)-6-oxo-4-(piperazin-1-yl)-1,6-dihydropyridazine-3-carbonitrileIntermediates 142A and 142B: Intermediates 142A and 142B were prepared using a similar synthetic protocol as that of intermediate 12B and starting from 5,6-dichloropyridazin-3(2H)-one (1.00g, 6.06 mmol) and 2-methylpropane-1,3-diol (0.59 mL, 6.67 mmol). The product mixture was separated by supercritical fluid chromatography (SFC) [Column: Lux Cellulose-2 30*250 mm, 5.0 μm; Mobile Phase A: CO2,Mobile Phase B: MeOH, Flow rate: 120 g / min; Gradient: isocratic 15% B; Column temperature: 30 °C; Detection: UV (220 nm)]. First eluted compound (retention time 6.30 min) was designated as intermediate 142A (0.90 g) and the second eluted compound (retention time 8.80 min) was designated as intermediate 142B (0.34 g). LCMS (Method-O): retention time 1.02 min, [M+H]+237.2. Intermediate 142C: Intermediate 142C was prepared by using a similar synthetic protocol as that of intermediate 12D and starting from intermediate 142A and 1-Boc-piperazine. LCMS (Method-O): retention time 1.44 min [M+H]+387.4. Intermediate 142D: To a stirred solution of intermediate 142C (1.40 g, 3.62 mmol) in DMF (14 mL) was added Zn (0.024 g, 0.36 mmol), Zn(CN)2(0.63 g, 5.43 mmol) and the resulting reaction mixture was degassed with nitrogen for 5 min. Tris(dibenzylideneacetone)dipalladium(0) (0.33 g, 0.36 mmol) followed by 1,1'- Bis(diphenylphosphino)ferrocene (0.321 g, 0.579 mmol) was added and the resulting reaction mixture was degassed again for 5 min and stirred 100 °C for 16 h. The reaction was cooled to ambient temperature, filtered through Celite® and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (Redisep-24 g, 40-45% EtOAc / n-hexane) to obtain the title compound (1.20 g). LCMS (Method-O): retention time 1.32 min, [M+H]+378.1. Intermediate 142E: To a stirred solution of intermediate 142D (0.85 g, 2.25 mmol) in THF (8 mL) was added triphenylphosphine (1.18 g, 4.50 mmol) followed by NBS (0.80 g, 4.50mmol) and the resulting reaction mixture was stirred at ambient temperature for 30 min. The reaction mixture was evaporated under reduced pressure. The residue was purified by combi flash chromatography (Redisep-24 g, 15-20% EtOAc / n-hexane) to obtain the title compound (0.50 g). LCMS (Method O): retention time 1.78 min, [M- tBu+H]+384.2. Intermediate 142F: To a stirred solution of 3-bromobenzenethiol (0.22 mL, 2.12 mmol) in acetone (5 mL) was added K2CO3(0.88 g, 6.35 mmol) followed by intermediate 142E (0.93 g, 2.12 mmol) and the resulting reaction mixture was heated at 56 °C for 16 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was diluted with water (40 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layer was washed with brine (40 mL), dried over anhydrous sodium sulphate, and evaporated under reduced pressure to obtain the title compound (1.10 g). LCMS (Method-O): retention time 2.19 min, [M+H]+548.0. Intermediate 142G: Intermediate 142G was prepared by using a similar synthetic protocol as that of intermediate 12C starting from intermediate 142F and m-CPBA. LCMS (Method-O): retention time 1.79 min, [M+H]+580.3. The compound was advanced to the subsequent step without further purification. Intermediate 142H: Intermediate 142H was prepared by using a similar synthetic protocol as that of intermediate 12F starting from intermediate 142G and 3,4-dichlorophenyl)boronic acid. LCMS (Method-O): retention time 2.11 min, [M+H]+646.0. The compound was advanced to the subsequent step without further purification. Example 142: Example 142 was prepared by using a similar synthetic protocol as that of example 129 and starting from intermediate 142H and 4M solution of HCl in dioxane. 1H NMR (400 MHz, DMSO-d6) ppm 8.21 (t, J = 1.70 Hz, 1H), 8.17 - 8.03 (m, 2H),7.92 (d, J = 8.60 Hz, 1H), 7.84 - 7.69 (m, 3H), 6.08 (s, 1H), 4.14 (dd, J = 13.0, 7.1Hz, 1H), 3.93 (dd, J = 13.10, 7.50 Hz, 1H), 3.53 - 3.49 (m, 1H), 3.45-3.40 (m, 1H), 3.15 - 3.04 (m, 4H), 2.89 - 2.69 (m, 4H), 2.45 (dd, J = 11.70, 6.80 Hz, 1H), 1.01 (d, J = 6.80 Hz, 3H). LCMS (Method-R): retention time 1.72 min, [M+H]+546.1. Examples given in the below table were prepared in a similar manner like Example 142 using appropriate substrates. Ret.Time Example Structure Name [M+H]+(min) and method 1-(3-((3'-chloro-2'- methyl-[1,1'-biphenyl]-3- yl)sulfonyl)-2- 1.99143 methylpropyl)-6-oxo-4-526.2(piperazin-1-yl)-1,6-(Method S)dihydropyridazine-3- carbonitrile 1-(3-((2',3'-dichloro-[1,1'- biphenyl]-3-yl)sulfonyl)- 2-methylpropyl)-6-oxo-4-1.94144 (piperazin-1-yl)-1,6-546.1(Method S)dihydropyridazine-3- carbonitrile 1-(3-((3',4'-dichloro-[1,1'- biphenyl]-3-yl)sulfonyl)- 145 2-methylpropyl)-6-oxo-4-1.72(piperazin-1-yl)-1,6-546.1(Method R)dihydropyridazine-3- carbonitrile 1-(3-((3'-chloro-2'- methyl-[1,1'-biphenyl]-3- yl)sulfonyl)-2- 1.70146 methylpropyl)-6-oxo-4-526.2(Method R)(piperazin-1-yl)-1,6- dihydropyridazine-3- carbonitrile1-(3-((2',3'-dichloro-[1,1'- biphenyl]-3-yl)sulfonyl)- 2-methylpropyl)-6-oxo-4- 1.65 147 (piperazin-1-yl)-1,6- 546.1 ([Method dihydropyridazine-3- R) carbonitrile Example 148: 5-chloro-1-(3-((3',4'-dichloro-[1,1'-biphenyl]-3-yl)sulfonyl)-2- methylpropyl)-6-oxo-4-(piperazin-1-yl)-1,6-dihydropyridazine-3-carbonitrile Intermediate 148A: To a stirred solution of intermediate 142H (0.09 g, 0.139 mmol) in ACN (3 mL) was added NCS (0.02 g, 0.14 mmol) and the resulting reaction mixture was stirred at 50 °C for 1 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulphate, and evaporated under reduced pressure to obtain intermediate 148A (0.09 g). LCMS (Method-O): retention time 2.21 min, [M+H]+680.3. Example 148: Example 148 was prepared by using a similar synthetic protocol as that of example 12 starting from intermediate 148A and TFA.1H NMR (400 MHz, DMSO-d6) ppm 8.24 (t, J = 1.70 Hz, 1H), 8.15 - 8.11 (m, 2H), 7.93 (d, J = 7.80 Hz, 1H), 7.84 - 7.74 (m, 3H), 4.21 (dd, J = 7.20, 13.10 Hz, 1H), 3.97 (dd, J = 7.50, 13.10 Hz, 1H), 3.71 - 3.49 (m, 1H), 3.48 - 3.40 (m, 1H), 3.31 - 3.23 (m, 4H), 2.87 - 2.79 (m, 4H), 2.50 -2.40 (m, 1H), 1.02 (d, J = 6.80 Hz, 3H). LCMS (Method-R): retention time 1.74 min, [M+H]+580.1Example given in the below table was prepared in a similar manner like Example 148 using appropriate substrates. Ret.Time Example Structure Name [M+H]+(min) and method 5-chloro-1-(3-((3',4'- dichloro-[1,1'-biphenyl]- 3-yl)sulfonyl)-2- 149 methylpropyl)-6-oxo-4-580.1 1.77(piperazin-1-yl)-1,6-(Method R)dihydropyridazine-3- carbonitrile Example 150 & Example 151: 4-chloro-2-(3-((3'-fluoro-2'-methyl-[1,1'-biphenyl]-3- yl)sulfonyl)-2-(hydroxymethyl)propyl)-5-(piperazin-1-yl)pyridazin-3(2H)-one Intermediate 150A: Intermediate 150A was prepared as a gummy liquid by using a similar synthetic protocol as that of intermediate 12A starting from 3-bromobenzenethiol and 2- (hydroxymethyl)propane-1,3-diol. LCMS (Method M): retention time 2.09 min, [M+H]+277.0. The compound was taken to the subsequent step without further purification. Intermediate 150B: Intermediate 150B was prepared as a gummy liquid by using a similar synthetic protocol as that of intermediate 12B starting from intermediate 150A, 4,5- dichloropyridazin-3(2H)-one, and diethyl azodicarboxylate (0.03 mL, 0.20 mmol).LCMS (Method M): retention time 3.06 min, [M+2H]+423.0. The compound was advanced to the subsequent step without further purification. Intermediate 150C: Intermediate 150C was prepared by using a similar synthetic protocol as that of intermediate 12C and starting from intermediate 150B and m-CPBA. LCMS (Method M): retention time 3.21 min, [M+H]+455.0. The compound was advanced to the subsequent step without further purification. Intermediate 150D: Intermediate 150D was prepared by using a similar synthetic protocol as that of intermediate 12D starting from intermediate 150C and tert-butyl piperazine-1- carboxylate. LCMS (Method-O): retention time 1.25 min, [M+H]+605.3. The compound was advanced to the subsequent step without further purification. Intermediate 150E: Intermediate 150E was prepared as a gummy liquid by using a similar synthetic protocol as that of intermediate 12F starting from intermediate 150D and (3-fluoro-2- methylphenyl)boronic acid. LCMS (Method M): retention time 3.04 min, [M+H]+635.2. Examples 150 and 151: To a stirred solution of intermediate 150E (0.040 g, 0.06 mmol) in dioxane (2 mL) was added 4M solution of HCl in dioxane (0.16 mL, 0.63 mmol) and the resulting reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was evaporated under reduced pressure. The enantiomer was separated into individual isomers by Chiral HPLC [Cellulose C5 (250 x 30 mm) 5 micron; 0.1% DEA in ACN + MeOH (1:1), Flow: 30 mL / min. Temperature: 25°C, UV: 220 nm]. First eluted compound (retention time 12.24 min), designated as example 150 (0.005 g).1H NMR (400MHz, DMSO-d6) d = 7.88 - 7.83 (m, 1H), 7.81 (s, 1H), 7.80 - 7.77 (m, 1H), 7.77 - 7.68 (m, 2H), 7.36 (dd, J=6.1, 7.8 Hz, 1H), 7.26 (t,J=9.0 Hz, 1H), 7.18 (d, J=7.3 Hz, 1H), 4.85 (br s, 1H), 4.11 (br d, J=6.4 Hz, 2H), 3.58 - 3.47 (m, 3H), 3.55 - 3.30 (m, 8H), 2.95- 2.86 (m, 3H), 2.49 - 2.38 (m, 1H), 2.13 (d, J=2.4 Hz, 3H). LCMS (Method- R): retention time 1.31 min, [M+H]+535.2. Second eluted compound (retention time 14.28 min), designated as example 151 (0.004 g).1H NMR (400 MHz, DMSO-d6) ppm 7.89 - 7.83 (m, 1H), 7.82 - 7.65 (m, 4H), 7.41 - 7.32 (m, 1H), 7.30 -7.22 (m, 1H), 7.18 (d, J = 7.3Hz, 1H), 4.84 (br. s., 1H), 4.10 (d, J = 7.30 Hz, 2H), 3.55 - 3.30 (m, 8 H), 2.92 - 2.75 (m, 3H) 2.47 - 2.39 (m, 1H), 2.17 (s, 3H). LCMS (Method-R): retention time 1.30 min, [M+H]+535.2. Example 152: 4-chloro-2-(3-((3',4'-dichloro-[1,1'-biphenyl]-3-yl)sulfonyl)-2- hydroxypropyl)-5-(piperazin-1-yl)pyridazin-3(2H)-one Intermediate 152A: To a stirred solution of 3-bromobenzenethiol (2.00 g, 10.58 mmol) in ACN (40 mL) was added Cs2CO3(6.89 g, 21.16 mmol) followed by 1,3-dibromopropan-2-ol (3.46 g, 15.87 mmol) and the resulting reaction mixture was stirred at ambient temperature for 12 h. ACN was evaporated under reduced pressure and the mixture was diluted with water (40 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine (40 mL), dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-40 g, 25-30% EtOAc / n-hexane) to afford the title compound (0.72 g) as a gummy liquid.1H NMR (400 MHz, DMSO-d6) ppm 7.59 (t, J = 2.40 Hz, 1H), 7.45-7.35 (m, 2H), 7.27 (dd, J = 10.40, 12.00 Hz, 1H), 3.30 - 3.20 (m, 1H), 3.20-3.10 (m, 2H), 2.80 - 2.70 (m, 1H), 2.65 - 2.55 (m, 1H).Intermediate 152B: To a stirred solution of intermediate 152A (0.98 g, 3.03 mmol) in THF (10 mL) was added 4,5-dichloropyridazin-3(2H)-one (0.5 g, 3.03 mmol) followed by DIPEA (1.59 mL, 9.09 mmol) and the resulting reaction mixture was stirred at ambient temperature for 48 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-12 g, 40-45% EtOAc / n-hexane) to afford the title compound (0.35 g) as a gummy liquid. LCMS (Method-O) retention time 1.33 min, [M+H]+409.1. The compound was advanced to the subsequent step without further purification. Intermediate 152C: Intermediate 152C was prepared as a gummy liquid by using a similar synthetic protocol as that of intermediate 12C and starting from intermediate 152B and m- CPBA. LCMS (Method-O) retention time 1.12 min, [M+H]+441.0. Intermediate 152D and 152E: Intermediate 152D and 152E were prepared by using a similar synthetic protocol as that of intermediate 12D starting from intermediate 152C and tert-butyl piperazine- 1-carboxylate. The product mixture was separated by supercritical fluid chromatography (SFC) [Column: Cellulose C44.6*250 mm, 5 μm; Mobile Phase: 0.2% NH4OH in ACN : MeOH (1:1), Flow rate: 30 mL / min; Column temperature: 25°C; Detection: UV (220 nm)]. First eluted isomer (retention time 7.37 min) was designated as intermediate 152D (0.08g) and the second eluted isomer (retention time 8.42 min) was designated as intermediate 152E (0.09 g). LCMS (Method M): retention time 2.54 min, [M+H]+591.0. Intermediate 152F: Intermediate 152F was prepared as a gummy liquid by using a similar synthetic protocol as that of intermediate 12F and starting from intermediate 152E and (3,4- dichlorophenyl)boronic acid. LCMS (Method-O) retention time 1.52 min, [M+H]657.3. The compound was advanced to the subsequent step without further purification. Example 152: Example 152 was prepared by using a similar synthetic protocol as that of example 12 starting from intermediate 152F and TFA.1H NMR (400 MHz, DMSO-d6) ppm 8.19 (s, 1H), 8.14 - 8.03 (m, 2H), 7.92 (d, J = 8.30 Hz, 1H), 7.86 (s, 1H), 7.83 - 7.67 (m, 3H), 5.33 (br.s., 1H), 4.40 – 4.50 (m.1H), 4.12 - 4.02 (m, 2H), 3.66 - 3.61(m, 2H), 3.31 - 3.27 (m, 4H), 2.85 - 2.75 (m, 4H). LCMS (Method-S) retention time 1.58 min, [M+H]+557.1. Examples given in the below table were prepared in a similar manner like Example 152 using Intermediate 152E and appropriate substrates. Ret.Time Example Structure Name [M+H]+(min) and method 4-chloro-2-(3-((3'-fluoro- 2'-methyl-[1,1'-biphenyl]- 3-yl)sulfonyl)-2- 1531.41hydroxypropyl)-5-521.1(Method S)(piperazin-1-yl)pyridazin- 3(2H)-one 4-chloro-2-(3-((2',3'- dimethyl-[1,1'-biphenyl]- 154 3-yl)sulfonyl)-2-1.41hydroxypropyl)-5-517.2(Method S)(piperazin-1-yl)pyridazin- 3(2H)-one Examples given in the below table were prepared in a similar manner like Example 152 using Intermediate 152D and appropriate substrates.Ret.Time Example Structure Name [M+H]+(min) and method 4-chloro-2-(3-((3',4'- dichloro-[1,1'- biphenyl]-3- 155 yl)sulfonyl)-2-557.1 1.58(Method S)hydroxypropyl)-5- (piperazin-1- yl)pyridazin-3(2H)-one 4-chloro-2-(3-((3'- fluoro-[1,1'-biphenyl]-3- 156 yl)sulfonyl)-2-1.27hydroxypropyl)-5-507.1(Method S)(piperazin-1- yl)pyridazin-3(2H)-one Example 157: 3-((3-(5-chloro-6-oxo-4-(piperazin-1-yl)pyridazin- 1(6H)yl)propyl)sulfonyl)-3'-fluoro-2'-methyl-[1,1'-biphenyl]-4-carbonitrile Intermediate 157A: To a stirred solution of intermediate 152C (0.05 g, 0.11 mmol) in DCM (1 mL) was added DAST (0.02 mL, 0.16 mmol) at -10 °C and the resulting reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with 10% aq. sodium bicarbonate solution (10 mL) and extracted with DCM (2 x 20 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulphate, and evaporated under reduced pressure to afford the title compound (0.04 g)as a gummy liquid. The compound was taken to the subsequent step without further purification. Intermediate 157B: Intermediate 157B was prepared as a gummy liquid by using a similar synthetic protocol as that of intermediate 12D starting from intermediate 157A and tert-butyl piperazine-1-carboxylate. LCMS (Method-O): retention time 1.72 min, [M+H]+573.3. Intermediate 157C: Intermediate 157C was prepared as a gummy liquid by using a similar synthetic protocol as that of intermediate 12F starting from intermediate 157B and (3,4dichlorophenyl)boronic acid. LCMS (Method-O): retention time 2.14 min, [M+H]+639.3. The compound was taken to the subsequent step without further purification. Example 157: Example 157 was prepared by using a similar synthetic protocol as that of example 12 and starting from intermediate 157C and TFA.1H NMR (400 MHz, DMSO-d6) ppm 8.15 - 8.06 (m, 3H), 8.04 (d, J = 1.70 Hz, 1H),7.88 (d, J = 8.10 Hz, 1H), 7.80 - 7.69 (m, 3H), 7.52 (d, J = 13.90 Hz, 1H), 6.05 -5.95 (m, 1H), 4.46 (d, J = 8.10 Hz, 2H), 3.72 - 3.60 (m, 4H), 3.30 – 3.20( m, 4H). LCMS (Method-S): retention time 1.74 min, [M+H]+539.0. Example 158: 4-chloro-2-((R)-3-((3',4'-dichloro-[1,1'-biphenyl]-3-yl)sulfonyl)-2- methylpropyl)-5-(6-fluoro-1,4-diazepan-1-yl)pyridazin-3(2H)-oneIntermediate 158A: Intermediate 158A was prepared by using a similar synthetic protocol as that of intermediate 12F and starting from intermediate 40D and (3,4-dichlorophenyl)boronic acid. LCMS (Method-O): retention time 2.08 min, [M+H]+505.0. The compound was advanced to the subsequent step without further purification. Intermediate 158B: Intermediate 158B was prepared by using a similar synthetic protocol as that of intermediate 12D and starting from 1,4-diazepan-6-ol and intermediate 158A. The compound was advanced to the subsequent step without further purification. Intermediates 158C and 158D: To a stirred solution of intermediate 158B (0.79 g, 1.35 mmol) in DCM (20 mL) was added DIPEA (0.47 mL, 2.70 mmol) followed by Boc-anhydride (0.31 mL, 1.35 mmol) and the resulting reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine (100 mL), dried over sodium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-40 g, 70-75% EtOAc / n-hexane) to obtain mixture of diastereomer (0.70 g). The diastereomers were separated into individual isomers by supercritical fluid chromatography (SFC) [Column: Chiralpak AD-H 4.6*250, 5 μm;Mobile Phase: 0.2% ammonia in ACN : MeOH (1:1), Flow rate: 4 mL / min; Column temperature: 23.8 °C; Detection: UV (220 nm)]. First eluted compound (retention time 15.20 min) was designated as intermediate 158C (0.07 g). LCMS (Method-O): retention time 1.88 min, [M+H] 685.3. Second eluted compound (retention time 19.50 min) was designated as intermediate 158D (0.08 g). LCMS (Method-O): retention time 1.89 min, [M+H]+685.3. Intermediate 158E: To a stirred solution of intermediate 158C (0.07 g, 0.11 mmol) in DCM (5 mL) was added DAST (0.03 mL, 0.22 mmol) at 0 °C and the resulting reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was diluted with water (15 mL), basified with 10% NaHCO3 solution and extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulphate, and evaporated under reduced pressure to afford the intermediate (0.07 g). LCMS (Method-O): retention time 2.09 min, [M+H]+687.3. Example 158: Example 158 was prepared by using a similar synthetic protocol as that of example 12 and starting from intermediate 158E and TFA.1H NMR (400 MHz, DMSO-d6) ppm 8.18 (t, J = 1.7 Hz, 1H), 8.14 - 8.05 (m, 2H), 7.91 (td, J = 1.30, 7.80 Hz, 1H), 7.87 - 7.72 (m, 3H), 4.95 - 4.78 (m, 1H), 4.10 -3.97 (m, 2H), 3.95 - 3.83 (m, 2H), 3.69 - 3.51 (m, 2H), 3.50 - 3.40 (m, 3H), 3.07 - 2.82 (m, 4H), 0.96 (d, J = 6.40 Hz, 3H). LCMS (Method-S): retention time 1.91 min, [M+H]+587.2. Examples given in the below table were prepared in a similar manner like Example 158 using appropriate substrates.Ret. Time Example Structure Name [M+H]+(min) and method 4-chloro-2-((R)-3-((3'- chloro-2'-methyl-[1,1'- biphenyl]-3-yl)sulfonyl)- 1592.02-methylpr567.2 7opyl)-5-(6-(Method L)fluoro-1,4-diazepan-1- yl)pyridazin-3(2H)-one 4-chloro-2-((R)-3-((3'- chloro-2'-methyl-[1,1'- 160 biphenyl]-3-yl)sulfonyl)- 2-methylpr565.2 1.68opyl)-5-(6-(Method L)hydroxy-1,4-diazepan-1- yl)pyridazin-3(2H)-one Example 161: (R)-4-chloro-2-(3-((3'-fluoro-2'-methyl-[1,1'-biphenyl]-3-yl)sulfonyl)-2- methylpropyl)-5-(piperidin-4-yloxy)pyridazin-3(2H)-one Intermediate 161A: To a stirred solution of intermediate 40D (0.05 g, 0.12 mmol) and tert-butyl 4- hydroxypiperidine-1-carboxylate (0.04 g, 0.17 mmol) in DMF (1 mL) was added Cs2CO3(0.07 g, 0.23 mmol) and the resulting reaction mixture was heated at 80 °C for 12 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulphate, and evaporated under reduced pressure to obtain Intermediate 161A (0.05 g) as colourless liquid. LCMS (Method M): retention time 3.6 min, [M+H]+604.1.Intermediate 161B: Intermediate 161B was prepared by using a similar synthetic protocol as that of intermediate 12F and starting from intermediate 161A and (3-fluoro-2- methylphenyl)boronic acid. LCMS (Method-O): retention time 2.10 min, [M+H]+634.5. Example 161: Example 161 was prepared by using a similar synthetic protocol as that of example 12 starting from intermediate 161B and TFA.1H NMR (400 MHz, DMSO-d6) ppm 8.24 (d, J = 6.00 Hz, 1H), 7.92-7.85 (m, 1H), 7.82 (s, 1H), 7.80-7.70 (m, 2H), 7.35 (dd, J = 8.00, 13.80 Hz, 1H), 7.25 (t, J = 9.20 Hz, 1H), 7.16 (d, J = 7.60 Hz, 1H), 4.87 (m, 1H), 4.14 - 3.97 (m, 2H), 3.51 - 3.44 (m, 2H), 3.00 (d, J = 12.50 Hz, 2H), 2.72 (d, J = 13.4Hz, 2H), 2.1 ( s, 3H), 2.00 – 1.91 (m, 3H), 1.91 (s, 3H), 1.66 - 1.41 (m, 2H), 0.97(d, J = 6.80 Hz, 3H). LCMS (Method-R): retention time 1.56 min, [M+H]+534.2. Examples given in the below table were prepared in a similar manner like Example 161 using appropriate substrates. Ret.Time Example Structure Name [M+H]+(min) and method (R)-4-chloro-2-(3-((2'- fluoro-[1,1'-biphenyl]- 3-yl)sulfonyl)-2- 162 methylpropyl)-5-520.2 1.83(piperidin-4-(Method S)yloxy)pyridazin- 3(2H)-one (R)-4-chloro-2-(3-((2'- chloro-[1,1'-biphenyl]- 3-yl)sulfonyl)-2- 163 methylpropyl)-5-536.1 1.91(piperidin-4-(Method S)yloxy)pyridazin- 3(2H)-one(R)-4-chloro-2-(3-((3'- fluoro-[1,1'-biphenyl]- 3-yl)sulfonyl)-2- 164 methylpropyl)-5-520.2 1.82(piperidin-4-(Method S)yloxy)pyridazin- 3(2H)-one (R)-4-chloro-2-(3-((3'- chloro-[1,1'-biphenyl]- 3-yl)sulfonyl)-2- 165 methylpropyl)-5-536.2 2.06(piperidin-4-(Method S)yloxy)pyridazin- 3(2H)-one (R)-4-chloro-2-(3-((4'- fluoro-[1,1'-biphenyl]- 3-yl)sulfonyl)-2- 166 methylpropyl)-5-520.2 1.58(piperidin-4-(Method R)yloxy)pyridazin- 3(2H)-one (R)-4-chloro-2-(3-((4'- chloro-[1,1'-biphenyl]- 3-yl)sulfonyl)-2- 167 methylpropyl)-5-536.2 1.70(piperidin-4-(Method R)yloxy)pyridazin- 3(2H)-one (R)-4-chloro-2-(3- ((2',3'-difluoro-[1,1'- biphenyl]-3- yl)sulfonyl)-2- 1681.6methylpropyl)-5-538.2 1(Method S)(piperidin-4- yloxy)pyridazin- 3(2H)-one (R)-4-chloro-2-(3-((3'- chloro-2'-fluoro-[1,1'- biphenyl]-3- 169 yl)sulfonyl)-2-1.72methylpropyl)-5-554.2(Method S)(piperidin-4- yloxy)pyridazin- 3(2H)-one(R)-4-chloro-2-(3-((3'- chloro-2'-methyl-[1,1'- biphenyl]-3- 170 yl)sulfonyl)-2-1.57methylpropyl)-5-550.2(Method S)(piperidin-4- yloxy)pyridazin- 3(2H)-one (R)-4-chloro-2-(3- ((2',3'-dichloro-[1,1'- biphenyl]-3- yl)sulfonyl)-2-1.80171570.1methylpropyl)-5-(Method S)(piperidin-4- yloxy)pyridazin- 3(2H)-one (R)-4-chloro-2-(3- ((3',4'-difluoro-[1,1'- biphenyl]-3- yl)sulfonyl)-2-1.63172538.2methylpropyl)-5-(Method R)(piperidin-4- yloxy)pyridazin- 3(2H)-one (R)-4-chloro-2-(3-((3'- chloro-4'-fluoro-[1,1'- biphenyl]-3- yl)sulfonyl)-2-1.47173555.2methylpropyl)-5-(Method S)(piperidin-4- yloxy)pyridazin- 3(2H)-one (R)-4-chloro-2-(3-((4'- chloro-3'-fluoro-[1,1'- biphenyl]-3- yl)sulfonyl)-2-1.73174554.2methylpropyl)-5-(Method R)(piperidin-4- yloxy)pyridazin- 3(2H)-one (R)-4-chloro-2-(3- ((3',4'-dichloro-[1,1'- biphenyl]-3- yl)sulfonyl)-2-1.59175570.1methylpropyl)-5-(Method S)(piperidin-4- yloxy)pyridazin- 3(2H)-one(R)-4-chloro-2-(3- ((2',4'-difluoro-[1,1'- biphenyl]-3- 176 yl)sulfonyl)-2-1.62methylpropyl)-5-538.2(Method R)(piperidin-4- yloxy)pyridazin- 3(2H)-one (R)-4-chloro-2-(3-((2'- chloro-4'-fluoro-[1,1'- biphenyl]-3- yl)sulfonyl)-2-1.71177554.2methylpropyl)-5-(method R)(piperidin-4- yloxy)pyridazin- 3(2H)-one (R)-4-chloro-2-(3- ((2',4'-dichloro-[1,1'- biphenyl]-3- yl)sulfonyl)-2-1.85178570.2methylpropyl)-5-(Method R)(piperidin-4- yloxy)pyridazin- 3(2H)-one (R)-4-chloro-2-(3-((4'- chloro-2'-methyl-[1,1'- biphenyl]-3- yl)sulfonyl)-2-1.69179534.2methylpropyl)-5-(Method R)(piperidin-4- yloxy)pyridazin- 3(2H)-one (R)-4-chloro-2-(3- ((2',5'-dichloro-[1,1'- biphenyl]-3- yl)sulfonyl)-2-1.80180570.2methylpropyl)-5-(Method R)(piperidin-4- yloxy)pyridazin- 3(2H)-one (R)-4-chloro-2-(3-((2'- chloro-6'-fluoro-[1,1'- biphenyl]-3- yl)sulfonyl)-2-1.65181554.2methylpropyl)-5-(Method R)(piperidin-4- yloxy)pyridazin- 3(2H)-one(R)-4-chloro-2-(3- ((3',5'-dichloro-[1,1'- biphenyl]-3- 182 yl)sulfonyl)-2-1.86methylpropyl)-5-570.2(Method R)(piperidin-4- yloxy)pyridazin- 3(2H)-one (R)-5-(azetidin-3- ylmethoxy)-4-chloro-2- (3-((2'-chloro-[1,1'- 1.55183 biphenyl]-3-522.1(Method S)yl)sulfonyl)-2- methylpropyl)pyridazin- 3(2H)-one (R)-5-(azetidin-3- ylmethoxy)-4-chloro-2- (3-((3'-chloro-[1,1'- 1.59184 biphenyl]-3-522.1(Method S)yl)sulfonyl)-2- methylpropyl)pyridazin- 3(2H)-one (R)-5-(azetidin-3- ylmethoxy)-4-chloro-2- (3-((4'-chloro-[1,1'- 1.60185 biphenyl]-3-522.1(Method S)yl)sulfonyl)-2- methylpropyl)pyridazin- 3(2H)-one (R)-5-(azetidin-3- ylmethoxy)-4-chloro-2- (3-((3'-fluoro-2'-methyl- 1.41186 [1,1'-biphenyl]-3-520.1(Method S)yl)sulfonyl)-2- methylpropyl)pyridazin- 3(2H)-one (R)-5-(azetidin-3- ylmethoxy)-4-chloro-2- (3-((2',3'-difluoro-[1,1'- 1.49187 biphenyl]-3-524.1(Method S)yl)sulfonyl)-2- methylpropyl)pyridazin- 3(2H)-one(R)-5-(azetidin-3- ylmethoxy)-4-chloro-2- (3-((3'-chloro-2'-fluoro- 188 [1,1'-biphenyl]-3-540.1 1.61yl)sulfonyl)-2-(Method S)methylpropyl)pyridazin- 3(2H)-one (R)-5-(azetidin-3- ylmethoxy)-4-chloro-2- (3-((3'-chloro-2'-methyl- 189 [1,1'-biphenyl]-3-536.2 1.49yl)sulfonyl)-2-(Method S)methylpropyl)pyridazin- 3(2H)-one (R)-5-(azetidin-3- ylmethoxy)-4-chloro-2- (3-((3',4'-difluoro-[1,1'- 190 biphenyl]-3-524.1 1.52yl)sulfonyl)-2-(Method S)methylpropyl)pyridazin- 3(2H)-one (R)-5-(azetidin-3- ylmethoxy)-4-chloro-2- (3-((3',4'-dichloro-[1,1'- 191 biphenyl]-3-556.1 1.52yl)sulfonyl)-2-(Method S)methylpropyl)pyridazin- 3(2H)-one (R)-5-(azetidin-3- ylmethoxy)-4-chloro-2- (3-((3'-chloro-4'-fluoro- 192 [1,1'-biphenyl]-3-540.1 1.41yl)sulfonyl)-2-(Method S)methylpropyl)pyridazin- 3(2H)-one (R)-5-(azetidin-3- ylmethoxy)-4-chloro-2- (3-((2',3'-dichloro-[1,1'- 193 biphenyl]-3-556.1 1.69yl)sulfonyl)-2-(Method S)methylpropyl)pyridazin- 3(2H)-one(R)-5-(azetidin-3- ylmethoxy)-4-chloro-2- (3-((2',5'-dichloro-[1,1'- 194 biphenyl]-3-556.1 1.72yl)sulfonyl)-2-(Method S)methylpropyl)pyridazin- 3(2H)-one (R)-5-(azetidin-3- ylmethoxy)-4-chloro-2- (3-((2'-chloro-4'-fluoro- 195 [1,1'-biphenyl]-3-540.1 1.61yl)sulfonyl)-2-(Method S)methylpropyl)pyridazin- 3(2H)-one (R)-5-(azetidin-3- ylmethoxy)-4-chloro-2- (3-((2',4'-dichloro-[1,1'- 196 biphenyl]-3-556.1 1.77yl)sulfonyl)-2-(Method S)methylpropyl)pyridazin- 3(2H)-one Example 197: (R)-4-chloro-2-(3-((3'-fluoro-2'-methyl-[1,1'-biphenyl]-3-yl)sulfonyl)-2- methylpropyl)-5-((3-methylazetidin-3-yl)methoxy)pyridazin-3(2H)-one Intermediate 197A: To a stirred solution of 1-(tert-butyl) 3-methyl azetidine-1,3-dicarboxylate (3.00 g, 13.94 mmol) in THF (50 mL) was added potassium bis(trimethylsilyl)amide (13.94 mL, 13.94 mmol) at -70 °C and the resulting reaction mixture was stirred at same temperature for 30 min. Methyl iodide (1.74 mL, 27.9 mmol) was added and the resulting reaction mixture was stirred at ambient temperature for 12 h. The reaction mixture was diluted with water (30 mL), aq. NH4Cl solution (20 mL) and extractedwith ethyl acetate (2 x 100 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by combi flash chromatography (Redisep-12 g, 25- 30% EtOAc / n-hexane) to obtain intermediate 197A (1.10 g) as a gummy liquid.1H NMR (400 MHz, DMSO-d6) ppm 4.11 - 4.01 (m, 2H), 3.67 (s, 3H), 3.65 - 3.58 (m, 2H), 1.43 (s, 3H), 1.37 (s, 9 H). The compound was advanced to the subsequent step without further purification. Intermediate 197B: To a stirring solution of intermediate 197A (0.50 g, 2.18 mmol) in THF (10 mL) was added 4M solution of LiBH4 in THF (1.2 mL, 2.40 mmol) and the resulting reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulphate, and evaporated under reduced pressure to obtain intermediate 197B (0.34 g) as a gummy liquid.1H NMR (400 MHz, DMSO-d6) ppm 4.87 (t, J = 5.20 Hz, 1H), 3.64 (br. d, J = 2.50 Hz, 2H), 3.36 (br. d, J = 3.50 Hz, 2H), 3.32 -3.30 ( m, 2H) 1.36 (s, 9 H), 1.13 (s, 3H). The compound was advanced to the subsequent step without further purification. Intermediate 197C: Intermediate 197C was prepared as a gummy liquid by using a similar synthetic protocol as that of intermediate 161A and starting from intermediate 40D and intermediate 197B.1H NMR (400 MHz, DMSO-d6) ppm 8.19 (s, 1H), 8.04 (t, J = 1.80 Hz, 1H), 7.98 - 7.94 (m, 1H), 7.91 - 7.87 (m, 1H), 7.58 (m, 1H), 4.32 (s, 2H), 4.14 - 4.00 (s, 3H), 3.48 - 3.43 (s, 2H), 2.69 - 2.66 (m, 2H), 2.35 - 2.32 (m, 1H), 2.01 - 1.99 (m, 1H), 1.39 (s, 9H), 1.38 (s, 3H), 0.98 (d, J = 7.0 Hz, 3H). The compound was advanced to the subsequent step without further purification. Intermediate 197D: Intermediate 197D was prepared as a gummy liquid by using a similar synthetic protocol as that of intermediate 12F and starting from intermediate 197C and (3,4-dichlorophenyl)boronic acid. LCMS (Method-O): retention time 2.29 min, [M+H]+634.2. The compound was advanced to the subsequent step without further purification. Example 197: Example 197 was prepared by using a similar synthetic protocol as that of example 12 starting from intermediate 197D and TFA.1H NMR (400 MHz, DMSO- d6) ppm 8.21 (s, J = 10.27 Hz, 1H), 7.91 (dt, J = 6.42, 2.17 Hz, 1H), 7.83 (d, J = 1.22Hz, 1H), 7.79 - 7.69 (m, 2H), 7.40 - 7.30 (m, 1H), 7.25 (t, J = 9.05Hz, 1H), 7.21 - 7.13 (m, 1H), 4.41 - 4.27 (m, 2H), 4.16 -3.99 (m, 4H), 3.85 - 3.75 (m, 2H), 3.55 - 3.53 (m, 3H), 2.13 (s, 3H), 1.90 (s, 3H), 0.97 (d, J = 6.80 Hz, 3H). LCMS (Method-S): retention time 1.55 min, [M+H]+534.2 Examples given in the below table were prepared in a similar manner like Example 197 using appropriate substrates. Ret.Time Example Structure Name [M+H]+(min) and method (R)-4-chloro-2-(3-((3'- chloro-2'-methyl-[1,1'- biphenyl]-3-yl)sulfonyl)- 198 2-methylpropyl)-5-((3-550.1 1.73methylazetidin-3-(Method S)yl)methoxy)pyridazin- 3(2H)-one (R)-4-chloro-2-(3-((2',3'- dichloro-[1,1'-biphenyl]- 3-yl)sulfonyl)-2- 199 methylpropyl)-5-((3-570.1 2.03methylazetidin-3-(Method S)yl)methoxy)pyridazin- 3(2H)-one (R)-4-chloro-2-(3-((3',4'- dichloro-[1,1'-biphenyl]- 3-yl)sulfonyl)-2- 200 methylpropyl)-5-((3-570.1 2.02methylazetidin-3-(Method S)yl)methoxy)pyridazin- 3(2H)-one(R)-4-chloro-2-(3-((2',3'- dichloro-[1,1'-biphenyl]- 3-yl)sulfonyl)-2- 201 methylpropyl)-5-((3-574.1 1.63fluoroazetidin-3-(Method R)yl)methoxy)pyridazin- 3(2H)-one 4-chloro-2-((R)-3-((3'- fluoro-2'-methyl-[1,1'- biphenyl]-3-yl)sulfonyl)- 202 2-methylpropyl)-5-(((S)-534.1 1.56piperidin-3-(Method R)yl)oxy)pyridazin-3(2H)- one 4-chloro-2-((R)-3-((3'- fluoro-2'-methyl-[1,1'- biphenyl]-3-yl)sulfonyl)- 203 2-methylpropyl)-5-(((R)-534.1 1.56piperidin-3-(Method R)yl)oxy)pyridazin-3(2H)- one 4-chloro-2-((R)-3-((2'- chloro-3'-fluoro-[1,1'- biphenyl]-3-yl)sulfonyl)- 204 2-methylpropyl)-5-(((S)-554.1 1.59piperidin-3-(Method S)yl)oxy)pyridazin-3(2H)- one 4-chloro-2-((R)-3-((3'- fluoro-2'-methyl-[1,1'- biphenyl]-3-yl)sulfonyl)- 205 2-methylpropyl)-5-(((R)-520.2 1.52pyrrolidin-3-(Method S)yl)oxy)pyridazin-3(2H)- one 4-chloro-2-((R)-3-((3'- fluoro-2'-methyl-[1,1'- biphenyl]-3-yl)sulfonyl)- 206 2-methylpropyl)-5-(((S)-520.2 1.52pyrrolidin-3-(Method S)yl)oxy)pyridazin-3(2H)- one 4-chloro-2-((R)-3-((3'- chloro-2'-methyl-[1,1'- 207 biphenyl]-3-yl)sulfonyl)-536.2 1.652-methylpropyl)-5-(((S)-(Method S)pyrrolidin-3-yl)oxy)pyridazin-3(2H)- one 4-chloro-2-((R)-3-((3',4'- dichloro-[1,1'-biphenyl]- 3-yl)sulfonyl)-2- 208 methylpropyl)-5-(((R)-556.1 1.66pyrrolidin-3-(Method S)yl)oxy)pyridazin-3(2H)- one 4-chloro-2-((R)-3-((3',4'- dichloro-[1,1'-biphenyl]- 3-yl)sulfonyl)-2- 209 methylpropyl)-5-(((S)-556.1 1.67pyrrolidin-3-(Method S)yl)oxy)pyridazin-3(2H)- one 4-chloro-2-((R)-3-((3'- fluoro-2'-methyl-[1,1'- biphenyl]-3-yl)sulfonyl)- 210 2-methylpropyl)-5-534.2 1.61(pyrrolidin-3-(Method S)ylmethoxy)pyridazin- Diastereomer-I 3(2H)-one 4-chloro-2-((R)-3-((3'- fluoro-2'-methyl-[1,1'- biphenyl]-3-yl)sulfonyl)- 211 2-methylpropyl)-5-534.2 1.60(pyrrolidin-3-(Method S)ylmethoxy)pyridazin- Diastereomer-II 3(2H)-one 4-chloro-2-((R)-3-((3',4'- dichloro-[1,1'-biphenyl]- 3-yl)sulfonyl)-2- 212 methylpropyl)-5-570.1 1.75(pyrrolidin-3-(Method S)ylmethoxy)pyridazin- 3(2H)-one Diasteroemer-I 4-chloro-2-((R)-3-((3',4'- dichloro-[1,1'-biphenyl]- 3-yl)sulfonyl)-2- 213 methylpropyl)-5-570.1 1.72(pyrrolidin-3-(Method S)ylmethoxy)pyridazin- 3(2H)-oneDiastereomer-II 4-chloro-2-((R)-3-((3'- chloro-4'-fluoro-[1,1'- biphenyl]-3-yl)sulfonyl)- 214 2-methylpropyl)-5-554.1 1.62(pyrrolidin-3-(Method S)ylmethoxy)pyridazin- 3(2H)-one Diastereomer-I 4-chloro-2-((R)-3-((3'- chloro-4'-fluoro-[1,1'- biphenyl]-3-yl)sulfonyl)- 215 2-methylpropyl)-5-554.1 1.63(pyrrolidin-3-(Method S)ylmethoxy)pyridazin- 3(2H)-one Diastereomer-II (R)-4-chloro-2-(3-((3'- fluoro-2'-methyl-[1,1'- biphenyl]-3-yl)sulfonyl)- 216 2-methylpropyl)-5-548.2 1.44(piperidin-4-(Method S)ylmethoxy)pyridazin- 3(2H)-one (R)-4-chloro-2-(3-((3'- chloro-2'-methyl-[1,1'- biphenyl]-3-yl)sulfonyl)- 217 2-methylpropyl)-5-564.2 1.55(piperidin-4-(Method S)ylmethoxy)pyridazin- 3(2H)-one (R)-4-chloro-2-(3-((3',4'- dichloro-[1,1'-biphenyl]- 3-yl)sulfonyl)-2- 218 methylpropyl)-5-584.2 1.55(piperidin-4-(Method S)ylmethoxy)pyridazin- 3(2H)-one (R)-4-chloro-2-(3-((3'- chloro-4'-fluoro-[1,1'- biphenyl]-3-yl)sulfonyl)- 219 2-methylpropyl)-5-568.2 1.44(piperidin-4-(Method S)ylmethoxy)pyridazin- 3(2H)-one(R)-5-((2- azaspiro[3.3]heptan-6- yl)oxy)-4-chloro-2-(3- 220 ((3'-fluoro-2'-methyl-1.46[1,1'-biphenyl]-3-546.2(Method R)yl)sulfonyl)-2- methylpropyl)pyridazin- 3(2H)-one (R)-5-((2- azaspiro[3.3]heptan-6- yl)oxy)-4-chloro-2-(3- ((3',4'-dichloro-[1,1'-1.68221582.1biphenyl]-3-yl)sulfonyl)-(Method R)2- methylpropyl)pyridazin- 3(2H)-one (R)-5-(azetidin-3-yloxy)- 4-chloro-2-(3-((3'-fluoro- 2'-methyl-[1,1'-biphenyl]-1.54222506.23-yl)sulfonyl)-2-(Method S)methylpropyl)pyridazin- 3(2H)-one (R)-5-(azetidin-3-yloxy)- 4-chloro-2-(3-((3',4'- dichloro-[1,1'-biphenyl]-1.69223542.13-yl)sulfonyl)-2-(Method S)methylpropyl)pyridazin- 3(2H)-one (R)-5-(3-aminopropoxy)- 4-chloro-2-(3-((3'-fluoro- 2'-methyl-[1,1'-biphenyl]-1.57224508.13-yl)sulfonyl)-2-(Method S)methylpropyl)pyridazin- 3(2H)-one (R)-5-(3-aminopropoxy)- 4-chloro-2-(3-((3'-chloro- 2'-methyl-[1,1'-biphenyl]-1.71225524.13-yl)sulfonyl)-2-(Method S)methylpropyl)pyridazin- 3(2H)-one(R)-5-(3-aminopropoxy)- 4-chloro-2-(3-((3',4'- 226 dichloro-[1,1'-biphenyl]- 3-yl)sulfonyl)-2-544.0 1.71(Method S)methylpropyl)pyridazin- 3(2H)-one (R)-5-(3-aminopropoxy)- 4-chloro-2-(3-((3'-chloro- 227 4'-fluoro-[1,1'-biphenyl]-1.613-yl)sulfonyl)-2-528.1(Method S)methylpropyl)pyridazin- 3(2H)-one Cl F F (R)-5-(3-amino-2,2- OO NH2O Odifluoropropoxy)-4- S N N chloro-2-(3-((3'-fluoro-2'- 228 methyl-[1,1'-biphenyl]-3-544.2 1.75yl)sulfonyl)-2-(Method R)methylpropyl)pyridazin- F 3(2H)-one 5-(azepan-4-yloxy)-4- chloro-2-((R)-3-((3'- fluoro-2'-methyl-[1,1'- 229 biphenyl]-3-yl)sulfonyl)-548.2 1.492-(Method R)methylpropyl)pyridazin- 3(2H)-one 5-(((1R,3r,5S)-8- azabicyclo[3.2.1]octan-3- yl)oxy)-4-chloro-2-((R)- 230 3-((3'-fluoro-2'-methyl- [1,1'-biphenyl]-3-560.1 1.71(Method S)yl)sulfonyl)-2- methylpropyl)pyridazin- 3(2H)-one 5-(((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3- yl)oxy)-4-chloro-2-((R)- 231 3-((3'-fluoro-2'-methyl-2.06[1,1'-biphenyl]-3-560.2(Method R)yl)sulfonyl)-2- methylpropyl)pyridazin- 3(2H)-oneExample 232: (R)-4-chloro-2-(3-((4'-fluoro-[1,1'-biphenyl]-3-yl)sulfonyl)-2- methylpropyl)-5-hydroxypyridazin-3(2H)-one Intermediate 232A: Intermediate 232A was prepared as gummy liquid by using a similar synthetic protocol as that of intermediate 161A and starting from intermediate 40D and (1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methanol. LCMS (Method-O): retention time 1.89 min, [M+H]+630.9. Intermediate 232B: Intermediate 232B was prepared as a gummy liquid by using a similar synthetic protocol as that of intermediate 12F starting from intermediate 232A and (4- fluorophenyl)boronic acid. LCMS (Method-O): retention time 2.05 min, [M+H]+647.1. The compound was advanced to the subsequent step without further purification. Example 232: Example 232 was prepared by using a similar synthetic protocol as that of example 129 starting from intermediate 232B and 4M solution of HCl in dioxane.1H NMR (400 MHz, DMSO-d6) ppm 8.09 (s, 1H), 8.02 (d, J = 7.60 Hz, 1H), 7.92 - 7.76 (m, 3H), 7.75- 7.69 (m, 1H), 7.51 (s, 1H), 7.36 (t, J = 8.80 Hz, 2H), 7.22 (s, 1H), 4.08 - 4.02 (m, 1H), 3.90 (dd, J = 13.10, 7.50 Hz, 1H), 3.49 - 3.40 (m, 2H), 2.50 – 2.40 (m, 1H), 0.95 (d, J = 6.60 Hz, 3H). LCMS (Method-S): retention time 1.37 min, [M+H]+437.1. Example given in the below table was prepared in a similar manner like Example 232 using appropriate substrates.Ret. Time Example Structure Name [M+H]+(min) and method (R)-4-chloro-2-(3- ((3',4'-dichloro-[1,1'- biphenyl]-3- 233 yl)sulfonyl)-2-487.0 1.91methylpropyl)-5-(Method R)hydroxypyridazin- 3(2H)-one Example 234: (R)-4-chloro-2-(3-((3'-fluoro-2'-methyl-[1,1'-biphenyl]-3-yl)sulfonyl)-2- methylpropyl)-5-(methylthio)pyridazin-3(2H)-one Cl Cl O Cl O S OS OOH OS ON ONS ONN 40C 234A 234BExample 234F F F Intermediate 234A: Intermediate 234A was prepared by using a similar synthetic protocol as that of intermediate 12F starting from intermediate 40C and (3-fluoro-2- methylphenyl)boronic acid. LCMS (Method-O): retention time 1.49 min, [M+H]+323.1. Intermediate 234B: Intermediate 234B was prepared by using a similar synthetic protocol as that of intermediate 12B and starting from intermediate 234A and 4,5-dichloropyridazin- 3(2H)-one. LCMS (Method-O): retention time 1.92 min, [M+18]+469.0. Example 234: To a stirred solution of intermediate 234C (0.07 g, 0.15 mmol) in EtOH (1 mL) was added sodium thiomethoxide (0.010 g, 0.18 mmol), DIPEA (0.08 mL, 0.45 mmol) and the resulting reaction mixture was stirred at 80°C for 16 h. The reaction mixture was concentrated under reduced pressure, diluted with water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulphate, and evaporated under reduced pressure.The residue was purified by HPLC to afford the title compound (0.02 g).1H NMR (400 MHz, DMSO-d6) ppm 8.05 (s, 1H), 7.92 - 7.85 (m, 1H), 7.80 (s, 1H), 7.72 - 7.60 (m, 2H), 7.29 (dd, J = 6.0, 7.8 Hz, 1H), 7.16 - 7.02 (m, 2H), 4.18 - 4.07 (m, 2H), 3.43 (dd, J = 4.1, 14.9 Hz, 1H), 3.35 ( s, 3H), 3.28 - 3.20 (m, 1H), 2.65 - 2.59 (m, 1H), 2.15 (d, J = 2.5Hz, 3H), 1.11 (d, J = 7.0 Hz, 3H). LCMS (Method-R): retention time 1.98 min, [M+1]+481.0. Example 235: (R)-4-chloro-2-(3-((2',3'-dichloro-[1,1'-biphenyl]-3-yl)sulfonyl)-2- methylpropyl)-5-(piperidin-4-yl)pyridazin-3(2H)-one Intermediate 235A and 235B: To a stirred solution of 2-methylpropane-1,3-diol (30 g, 333 mmol) in DCM (500 mL) was added pyridine (26.90 mL, 333 mmol) followed by p-toluenesulfonyl chloride (63.50 g, 333 mmol) and the resulting reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with water (200 mL) and extracted with DCM (3 x 200 mL). The combined organic layer was washed with brine (200 mL), dried over anhydrous sodium sulphate and evaporated under reduced pressure to obtain racemic compound. The product mixture was separated by SFC [Column: Chiralpak AD-H 50*250, 5 μm; Mobile Phase A: CO2, Mobile Phase B: 0.2% ammonia in ACN : IPA (1:1); Flow rate: 200 mL / min; Gradient: isocratic 10% B; Back pressure: 100 bar; Column temperature: 30 °C; Detection: UV (220 nm)]. First eluted compound (retention time 7.9 min) was designated as intermediate 235A(18.0 g). LCMS (Method M): retention time 1.21 min, [M+H]+245.1. Intermediate 235A was found to be S-isomer by comparing with authentic sample. Second eluted compound (retention time 9.3 min) was designated as intermediate 235B (19.0 g). Intermediate 235C: To a stirred solution of intermediate 235A (44 g, 18.00 mmol) in acetone (400 mL) was added sodium iodide (54.00 g, 36.00 mmol) and the resulting reaction mixture was heated at 50 °C for 2 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was diluted with water (200 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulphate, and evaporated under reduced pressure to obtain intermediate 235C (34.00 g) as a pale brown syrup. The compound was advanced to the subsequent step without further purification. Intermediate 235D: To a stirred solution of 4-chloro-5-iodopyridazin-3(2H)-one (3.85 g, 15 mmol) in DMF (15 mL) was added K2CO3 (2.07 g, 15.00 mmol) followed by intermediate 235C (3.00 g, 15.00 mmol) and the resulting mixture was heated at 85 °C for 1 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was diluted with water (40 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by combi flash chromatography (Redisep-80 g, 50-55% EtOAc / n-hexane) to obtain intermediate 235D (4.50 g) as a colourless oil. LCMS (Method-O): retention time 0.96 min, [M+H]+328.9. Intermediate 235E: Intermediate 235E was prepared by using a similar synthetic protocol as that of intermediate 12F starting from intermediate 235D and tert-butyl 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate. LCMS (Method-O): retention time 1.47 min, [M+H]+384.3.Intermediate 235F: To a stirred solution of intermediate 235E (4.10 g, 10.68 mmol) in ethyl acetate (15 mL) was added platinum (IV) oxide (0.97 g, 4.27 mmol) and the resulting reaction mixture was stirred under H2gas pressure atmosphere at ambient temperature for 2 h. The reaction mixture was filtered through Celite® and washed with ethyl acetate (30 mL). The filtrate was evaporated under reduced pressure. The residue was purified by combi flash chromatography (Redisep-80 g, 80-82% EtOAc / n-hexane) to obtain intermediate 235F (1.50 g). LCMS (Method-O): retention time 1.52 min, [M-H]- 384.4. Intermediate 235G: To a stirred solution of intermediate 235F (0.40 g, 1.04 mmol) in THF (8 mL) was added triphenylphosphine (0.54 g, 2.07 mmol) followed by NBS (0.37 g, 2.07 mmol) and the resulting reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by combi flash chromatography (Redisep-24 g, 45-50% EtOAc / n-hexane) to obtain intermediate 235G (0.4 g). The compound was advanced to the subsequent step without further purification. Intermediate 235H: To a stirred solution of 3-bromobenzenethiol (0.169 g, 0.89 mmol) in DMF (5 mL) was added potassium carbonate (0.31 g, 2.23 mmol), sodium formaldehydesulfoxylate dehydrate (0.14 g, 0.89 mmol) followed by intermediate 235G (0.40 g, 0.89 mmol) and the resulting reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with ice cold water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over sodium sulphate, and evaporated under reduced pressure. The residue was purified by combi flash chromatography (Redisep-12 g, 70-75% EtOAc / n-hexane) to obtain Intermediate 235H (0.44 g), LCMS (Method-O): retention time 2.36 min, [M+H]+556.5.Intermediate 235I: To a stirred solution of intermediate 235H (0.44 g, 0.79 mmol) in DCM (10 mL) was added m-CPBA (0.41 g, 2.37 mmol) and the resulting reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was diluted with water (30 mL), basified with 10% NaHCO3solution and extracted with DCM (2 x 30 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure to afford the title compound (0.45 g). LCMS (Method M): retention time 2.02 min, [M-H]- 586.4. The compound was advanced to the subsequent step without further purification. Intermediate 235J: Intermediate 235J was prepared by using a similar synthetic protocol as that of intermediate 12F starting from intermediate 235I and 2,3-dichlorophenylboronic acid. LCMS (Method-I): retention time 2.26 min, [M-H]- 652.5. The compound was advanced to the subsequent step without further purification. Example 235: Example 235 was prepared by using a similar synthetic protocol as that of example 12 starting from intermediate 235J and TFA.1H NMR (400 MHz, DMSO-d6) ppm 8.00 - 7.89 (m, 3H), 7.87 - 7.81 (m, 1H), 7.80 - 7.68 (m, 2H), 7.56 - 7.44 (m, 2H), 4.15 - 4.08 (m, 1H), 4.06 - 3.96 (m, 1H), 3.47 - 3.46 (m, 3H), 2.99 - 2.93 (m, 1H), 2.66 - 2.57 (m, 2H), 1.95 - 1.84 (m, 2H), 1.72 - 1.52 (m, 4H), 0.97 (d, J = 6.60 Hz, 3H). LCMS (Method- R): retention time 1.59 min, [M+H]+554.1. Examples given in the below table were prepared in a similar manner like Example 235 using appropriate substrates. Ret.Time Example Structure Name [M+H]+(min) and method ClONH(R)-4-chloro-2-(3-((3'- OOS Nfluoro-2'-methyl-[1,1'- N 236 biphenyl]-3-yl)sulfonyl)- 2-methylpropyl)-518.2 1.515-(Method R)(piperidin-4-yl)pyridazin- F 3(2H)-one(R)-4-chloro-2-(3-((3'- chloro-2'-methyl-[1,1'- 237 biphenyl]-3-yl)sulfonyl)- 2-methylpropyl)-5-534.2 1.64(Method R)(piperidin-4-yl)pyridazin- 3(2H)-one ClONHO O(R)-4-chloro-2-(3-((2'- SNN chloro-4'-fluoro-[1,1'- 238 biphenyl]-3-yl)sulfonyl)- 2-methy538.2 1.52Cl lpropyl)-5-(Method R)(piperidin-4-yl)pyridazin- 3(2H)-one F (R)-4-chloro-2-(3-((2',4'- dichloro-[1,1'-biphenyl]- 239 3-yl)sulfonyl)-2-1.65methylpropyl)-5-554.1(Method R)(piperidin-4-yl)pyridazin- 3(2H)-one (R)-4-chloro-2-(3-((3',4'- dichloro-[1,1'-biphenyl]- 3-yl)sulfonyl)-2- 2401.65methylpropyl)-5-554.1(Method R)(piperidin-4-yl)pyridazin- 3(2H)-one Example 241: (R)-4-chloro-2-(3-((3',4'-dichloro-[1,1'-biphenyl]-3-yl)sulfonyl)-2- methylpropyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3(2H)-one Intermediate 241A: Intermediate 241A was prepared as a gummy liquid by using a similar synthetic protocol as that of intermediate 12F starting from intermediate 128A and 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate. LCMS (Method-O): + retention time 1.94 min, [M+H] 586.3.Intermediate 241B: Intermediate 241B was prepared by using a similar synthetic protocol as that of intermediate 12F and starting from intermediate 241A and (3,4-dichlorophenyl) boronic acid. LCMS (Method-O): retention time 2.24 min, [M+H]+652.3. The compound was advanced to the subsequent step without further purification. Example 241: Example 241 was prepared by using a similar synthetic protocol as that of example 12 and starting from intermediate 241B and TFA.1H NMR (400 MHz, DMSO-d6) ppm 8.20 (d, J = 1.5Hz, 1H), 8.14 - 7.98 (m, 1H), 7.92 (d, J = 8.3Hz,1H), 7.84 - 7.54 (m, 2H), 7.40 (d, J = 8.8 Hz, 1H), 6.99 (d, J = 2.7 Hz, 1H), 6.78 (dd, J = 8.8, 2.7 Hz, 1H), 6.03 (br. s., 1H), 4.19 - 4.13 (m, 1H), 4.01 (dd, J = 12.7, 7.3 Hz, 1H), 3.56 - 3.42 (m, 4H), 2.98 (t, J = 5.6 Hz, 2H), 2.91 (d, J = 7.3 Hz, 1H), 2.38 - 2.28 (m, 2H), 1.1 (d, J = 6.8 Hz, 3H). LCMS (Method-S): retention time 1.62 min, [M+H]+552.1. Example given in the below table was prepared in a similar manner like Example 241 using appropriate substrates. Ret.Time Example Structure Name [M+H]+(min) and method (R)-4-chloro-2-(3-((3'- fluoro-2'-methyl-[1,1'- biphenyl]-3-yl)sulfonyl)- 1.57 242 2-methylpropyl)-5- 516.2 (Method (1,2,3,6- S) tetrahydropyridin-4- yl)pyridazin-3(2H)-one Example 243: (R)-4-chloro-2-(3-((3'-fluoro-2'-methyl-[1,1'-biphenyl]-3- yl)sulfonyl)-2-methylpropyl)-5-(1H-pyrazol-4-yl)pyridazin-3(2H)-oneIntermediate 243A: Intermediate 243A was prepared as a gummy liquid by using a similar synthetic protocol as that of intermediate 12F starting from intermediate 128A and 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole. LCMS (Method-O): retention time 2.00 min, [M+H]+600.9. Intermediate 243B: Intermediate 243B was prepared by using a similar synthetic protocol as that of intermediate 12F starting from intermediate 243A and (3-fluoro-2-methylphenyl)boronic acid. LCMS (Method-O): retention time 2.20 min, [M+H]+631.1. The compound was advanced to the subsequent step without further purification. Example 243: Example 243 was prepared by using a similar synthetic protocol as that of example 12 and starting from intermediate 243B and TFA.1H NMR (400 MHz, DMSO-d6) ppm 8.64 (s, 1H), 8.32 (s, 1H), 8.30 (d, J = 1.00 Hz, 1H), 7.90 (td, J = 1.70, 7.50 Hz, 1H), 7.82 (t, J = 1.60 Hz, 1H), 7.77 - 7.65 (m, 2H), 7.40 – 7.30 (m, 1H), 7.24 (t, J = 8.40 Hz, 1H), 7.15 (d, J = 7.60 Hz, 1H), 4.16 - 4.01 (m, 2H), 3.56 - 3.41 (m, 3H), 2.12 (s, 3H), 1.00 (d, J = 6.80 Hz, 3H). LCMS (Method-S): retention time 1.77 min, [M+H]+501.1. Examples given in the below table were prepared in a similar manner like Example 243 using appropriate substrates. Ret.Time Example Structure Name [M+H]+(min) and method (R)-4-chloro-2-(3-((2'- chloro-[1,1'-biphenyl]- 3-yl)sulfonyl)-2- 2441.69methylpropyl)-5-(1H-503.0(Method R)pyrazol-4-yl)pyridazin- 3(2H)-oneCl N O NH (R)-4-chloro-2-(3-((3'- OOS Nchloro-[1,1'-biphenyl]- N 245 3-yl)sulfonyl)-2- methylpropyl)-5-(1H-503.1 1.69(Method S)pyrazol-4-yl)pyridazin- Cl 3(2H)-one (R)-4-chloro-2-(3-((4'- chloro-[1,1'-biphenyl]- 246 3-yl)sulfonyl)-2-1.71methylpropyl)-5-(1H-503.1(Method R)pyrazol-4-yl)pyridazin- 3(2H)-one N (R)-4-chloro-2-(3- Cl NH O ((2',3'-dichloro-[1,1'-OObiphenyl]-3- S N N1.83247 yl)sulfonyl)-2-537.1(Method S)methylpropyl)-5-(1H- Cl pyrazol-4-yl)pyridazin- Cl 3(2H)-one Cl (R)-4-chloro-2-(3- N O NH ((2',5'-dichloro-[1,1'-O OS Nbiphenyl]-3- N1.84248 yl)sulfonyl)-2-537(Method S)methylpropyl)-5-(1H- Cl pyrazol-4-yl)pyridazin- Cl 3(2H)-one (R)-4-chloro-2-(3- ((2',4'-dichloro-[1,1'- biphenyl]-3- 1.89249 yl)sulfonyl)-2-537.0(Method S)methylpropyl)-5-(1H- pyrazol-4-yl)pyridazin- 3(2H)-one (R)-4-chloro-2-(3- ((3',4'-dichloro-[1,1'- biphenyl]-3- 1.84250 yl)sulfonyl)-2-537.1(Method S)methylpropyl)-5-(1H- pyrazol-4-yl)pyridazin- 3(2H)-one(R)-4-chloro-2-(3- ((3',4'-dichloro-4-fluoro- [1,1'-biphenyl]-3- 1.95 251 yl)sulfonyl)-2- 555.1 (Method S) methylpropyl)-5-(1H- pyrazol-4-yl)pyridazin- 3(2H)-one Cl N (R)-4-chloro-2-(3- O FNHO O((2',3'-dichloro-4-fluoro- SNN [1,1'-biphenyl]-3- 1.90 252 yl)sulfonyl)-2- 555.1 (Method S) Cl methylpropyl)-5-(1H- pyrazol-4-yl)pyridazin- Cl 3(2H)-one Example 253: (R)-5-(2-aminopyridin-4-yl)-4-chloro-2-(3-((3'-fluoro-2'-methyl-[1,1'- biphenyl]-3-yl)sulfonyl)-2-methylpropyl)pyridazin-3(2H)-one Intermediate 253A: Intermediate 253A was prepared as a gummy liquid by using a similar synthetic protocol as that of intermediate 12F and starting from intermediate 128A and 5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine. LCMS (Method-O): retention time 1.24 min, [M+H]+495.2. Example 253: Example 253 was prepared by using a similar synthetic protocol as that of example 12 and starting from intermediate 253A and (3-fluoro-2-methylphenyl)boronic acid.1H NMR (400MHz, DMSO-d6) ppm 8.05 (s, 1H), 7.93 (dt, J = 7.30, 1.70 Hz, 1H), 7.89 (s, 1H), 7.85 (t, J = 1.50 Hz, 1H), 7.79 - 7.67 (m, 2H), 7.41 - 7.29 (m, 1H), 7.28 - 7.20 (m, 1H), 7.17 (d, J = 7.30 Hz, 1H), 6.57 (dd, J = 5.30, 1.60 Hz, 1H), 6.55 - 6.48 (m, 1H), 6.22 (s, 2H), 4.17 (dd, J = 13.00, 7.10 Hz, 1H), 4.09 (dd, J = 13.10, 7.70 Hz, 1H), 3.56 (dd, J = 14.60, 4.50 Hz, 1H), 3.46 (dd, J = 14.70, 7.60 Hz, 1H), 2.62 - 2.53 (m, 1H), 2.13 (s, 3H),1.03 (d, J = 6.80 Hz, 3H). LCMS (Method-S): retention time 1.74 min, [M+H]+ 527.2.Example 254: (R)-4-chloro-2-(3-((6-(3,4-dichlorophenyl)pyridin-2-yl)sulfonyl)-2- methylpropyl)-5-(piperazin-1-yl)pyridazin-3(2H)-one Intermediate 254A: To a stirred solution of 2,6-dichloropyridine (10 g, 67.60 mmol) in TFA (15.62 mL, 203.0 mmol) was added H2O2(13.80 mL, 135.0 mmol) and resulting reaction mixture was stirred at resulting mixture was heated at 80 °C for 7 h. The reaction mixture was cooled to ambient temperature, the resulting solid was filtered. The filtrate was diluted with CHCl3 (50 mL) and basified by solid Na2CO3, diluted with water (30 mL) and extracted with CHCl3 (2 x 40 mL). The combined organic layer was washed with brine (40 mL), dried over anhydrous sodium sulphate, and evaporated under reduced pressure to obtain intermediate 254A (1.60 g). LCMS (Method-O): retention time 0.51 min, [M+H]+164.2. Intermediate 254B: To a stirred solution of intermediate 254A (1.50 g, 9.15 mmol) in EtOH (20.0 mL) was added thiourea (0.69 g, 9.15 mmol) and the resulting reaction mixture was heated at 80 °C for 3 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure and diluted with aq.10 % sodium hydroxide (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulphate, and evaporated under reduced pressure. Theresidue was purified by column chromatography (Redisep-12 g, 30-35% EtOAc / n- hexane) to obtain intermediate 254B (0.68 g). LCMS (Method-O): retention time 1.95 min, [M+H]+289.9. Intermediate 254C: Intermediate 254C was prepared as a white solid by using a similar synthetic protocol as that of intermediate 12D and starting from intermediate 235C and 1-Boc-piperazine. LCMS (Method-O): retention time 1.29 min, [M+H]+387.4. Intermediate 254D: Intermediate 254D was prepared by using a similar synthetic protocol as that of intermediate 142E and starting from intermediate 254C and NBS. LCMS (Method-O): retention time 2.09 min, [M+H]+449.2. Intermediate 254E: Intermediate 254E was prepared by using a similar synthetic protocol as that of intermediate 235H and starting from intermediate 254B and intermediate 254D. LCMS (Method-O): retention time 1.99 min, [M+H]+514.2. The compound was advanced to the subsequent step without further purification. Intermediate 254F: Intermediate 254F was prepared by using a similar synthetic protocol as that of intermediate 12C and starting from intermediate 254E and m-CPBA. LCMS (Method M): retention time 2.81 min, [M+H]+548.0. Intermediate 254G: Intermediate 254G was prepared as a gummy liquid by using a similar synthetic protocol as that of intermediate 12F starting from intermediate 254F and (3,4- dichlorophenyl)boronic acid. LCMS (Method-O): retention time 1.98 min, [M+H]+656.2. The compound was advanced to the subsequent step without further purification.Example 254: Example 254 was prepared by using a similar synthetic protocol as that of example 1 and starting from intermediate 254G and TFA.1H NMR (400 MHz, DMSO-d6) ppm 8.47 - 8.41 (m, 1H), 8.39 (d, J = 2.20 Hz, 1H), 8.28 (t, J = 7.80 Hz, 1H), 8.15 (dd, J = 8.40, 2.10 Hz, 1H), 8.06 (dd, J = 7.60, 0.70 Hz, 1H), 7.91 (s, 1H), 7.83 (d, J = 8.60 Hz, 1H), 4.12 - 3.97 (m, 2H), 3.74 - 3.65 (m, 1H), 3.62 - 3.56 (m, 1H), 3.56 - 3.45 (m, 4H), 3.27 - 3.13 (m, 4H), 2.62 - 2.54 (m, 1H), 1.00 (d, J = 6.80 Hz, 3H). LCMS (Method-S): retention time + 1.45 min, [M+H] 556.1. Examples given in the below table were prepared in a similar manner like Example 254 using appropriate substrates. Ret.Time + Example Structure Name [M+H] (min) and method (R)-4-chloro-2-(3-((6-(3- chlorophenyl)pyridin-2- 255 yl)sulfonyl)-2-1.54methylpropy522.1l)-5-(Method S)(piperazin-1-yl)pyridazin- 3(2H)-one (R)-4-chloro-2-(3-((6-(3- fluoro-2- methylphenyl)pyridin-2- 1.29256 yl)sulfonyl)-2-520.2(Method S)methylpropyl)-5- (piperazin-1-yl)pyridazin- 3(2H)-one (R)-4-chloro-2-(3-((6-(3- chloro-2- methylphenyl)pyridin-2- 1.41257 yl)sulfonyl)-2-536.1(Method S)methylpropyl)-5- (piperazin-1-yl)pyridazin- 3(2H)-one (R)-4-chloro-2-(3-((6-(4- chloro-3- fluorophenyl)pyridin-2- 1.48258 yl)sulfonyl)-2-540.1(Method S)methylpropyl)-5- (piperazin-1-yl)pyridazin- 3(2H)-oneExample 259: (R)-1-(3-((3'-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)sulfonyl)-2- methylpropyl)-6-oxo-4-(piperazin-1-yl)-1,6-dihydropyridazine-3-carboxamide Intermediate 259A: Intermediate 259A was prepared by using a similar synthetic protocol as that of intermediate 235D and starting from intermediate 235C and 5,6-dichloropyridazin-3(2H)- one. LCMS (Method-O): retention time 0.98 min, [M+H]+237.0. Intermediate 259B: Intermediate 259B was prepared by using a similar synthetic protocol as that of intermediate 12D and starting from intermediate 259A and 1-Boc-piperazine. LCMS (Method-O): retention time 1.42 min, [M+H]+387.2. Intermediate 259C: Intermediate 259C was prepared by using a similar synthetic protocol as that of intermediate 142D and starting from intermediate 259B and Zn(CN)2. LCMS (Method- V): retention time 1.28 min, [M+H]+378.0. Intermediate 259D: Intermediate 259D was prepared by using a similar synthetic protocol as that of intermediate 235G and starting from intermediate 259C and NBS. LCMS (Method-O): retention time 1.80 min, [M+H]+441.1.Intermediate 259E: Intermediate 259E was prepared by using a similar synthetic protocol as that of intermediate 235H and starting from intermediate 259D and 3-bromobenzenethiol. LCMS (Method-O): retention time 2.20 min, [M+H]+548.2. Intermediate 259F: Intermediate 259F was prepared by using a similar synthetic protocol as that of intermediate 12C and starting from intermediate 259E and m-CPBA. LCMS (Method-O): retention time 1.80 min, [M+H]+580.2. Intermediate 259G: Intermediate 259G was prepared by using a similar synthetic protocol as that of intermediate 12F and starting from intermediate 259F and (3-chloro-2- methylphenyl)boronic acid. LCMS (Method-O): retention time 2.14 min, [M+H]+626.4. The compound was advanced to the subsequent step without further purification. Example 259: To a stirred solution of intermediate 259G (0.09 g, 0.137 mmol) in MeOH (2 mL) was added aq. NaOH (1 mL, 0.137 mmol) followed by H2O2(4.21 μL, 0.137 mmol) at 0oC and the resulting reaction mixture was stirred at ambient temperature for 3 h. The reaction mass concentred under reduced pressure. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by prep-HPLC to obtain example 259 (0.02 g).1H NMR (400 MHz, DMSO-d6) ppm 7.94 - 7.88 (m, 2H), 7.79 (s, 1H), 7.75 - 7.70 (m, 2H), 7.65 (s, 1H), 7.53 (d, J = 6.8 Hz, 1H), 7.38 - 7.31 (m, 1H), 7.30 -7.26 (m, 1H), 5.88 (s, 1H), 3.98 - 3.86 (m, 2H), 3.60 – 3.50 (m, 4H), 3.07 - 2.96 (m, 4H), 2.79 - 2.71 (m, 3H), 2.23 (s, 3H), 0.95 (d, J = 6.8 Hz, 3H). LCMS (Method-R): retention time 1.49 min, [M+H]+544.0. Example given in the below table was prepared in a similar manner like Example 259 using appropriate substrates.Ret.Time Example Structure Name [M+H]+(min) and method (R)-1-(3-((3',4'-dichloro- [1,1'-biphenyl]-3- yl)sulfonyl)-2- 260 methylpropyl)-6-oxo-4-564.1 1.52(piperazin-1-yl)-1,6-(Method R)dihydropyridazine-3- carboxamide Example 261: (R)-6-chloro-2-(3-((3',4'-dichloro-[1,1'-biphenyl]-3-yl)sulfonyl)-2- methylpropyl)-5-(piperidin-4-yloxy)pyridazin-3(2H)-one Intermediate 261A: Intermediate 261A was prepared by using a similar synthetic protocol as that of intermediate 161A and starting from intermediated 129B and tert-butyl 4- hydroxypiperidine-1-carboxylate. LCMS (Method-O): retention time 1.96 min, [M+H]+605.8. The compound was advanced to the subsequent step without further purification. Intermediate 261B: Intermediate 261B was prepared as a brown solid by using a similar synthetic protocol as that of intermediate 12F and starting from intermediate 261A and (3,4- dichlorophenyl)boronic acid. LCMS (Method-O): retention time 2.28 min, [M+H]+670.9. The compound was advanced to the subsequent step without further purification. Example 261: Example 261 was prepared by using a similar synthetic protocol as that of example 129 and starting from intermediate 261B and 4M solution of HCl in dioxane.1H NMR (400MHz, DMSO-d6) ppm 8.53 (br. s., 1H), 8.19 (s, 1H), 8.14 - 8.03 (m, 1H), 7.92 (d, J = 7.80 Hz, 1H), 7.83 - 7.69 (m, 3H), 6.62 (s, 1H), 4.80 - 4.75 (m, 1H), 4.05 (dd, J = 13.30, 7.00 Hz, 1H), 3.88 (dd, J = 13.60, 7.50 Hz, 1H), 3.53 - 3.38 (m, 2H), 3.20 – 3.15(m, 2H), 3.15 -3.05 (m, 2H), 2.40 - 2.30 (m.1H), 2.10 - 2.05 (m, 2H), 1.90 - 1.85 (m, 2H), 0.99 (d, J = 6.80 Hz, 3H). LCMS (Method-S): retention time 1.86 min, [M+H]+570.1. Examples given in the below table were prepared in a similar manner like Example 261 using appropriate substrates. Ret.Time Example Structure Name [M+H]+(min) and method (R)-6-chloro-2-(3-((3'- fluoro-2'-methyl-[1,1'- 262 biphenyl]-3-yl)sulfonyl)-2-1.83methylpropyl)-5-534.2(Method S)(piperidin-4- yloxy)pyridazin-3(2H)-one (R)-5-(azetidin-3- ylmethoxy)-6-chloro-2-(3- 263 ((3',4'-dichloro-[1,1'-1.71biphenyl]-3-yl)sulfonyl)-2-556.1(Method S)methylpropyl)pyridazin- 3(2H)-one (R)-5-(azetidin-3- ylmethoxy)-6-chloro-2-(3- 264 ((3'-fluoro-2'-methyl-[1,1'- biphenyl]-3-yl)sulfo520.2 1.76nyl)-2-(Method S)methylpropyl)pyridazin- 3(2H)-one Example 265: 4-chloro-2-((2R)-3-(3'-fluoro-2'-methyl-[1,1'-biphenyl]-3-sulfonimidoyl)-2- methylpropyl)-5-(piperazin-1-yl)pyridazin-3(2H)-oneIntermediate 265A: To a stirred solution of intermediate 40D (0.30 g, 0.74 mmol) in MeOH (10 mL) was added ammonium carbamate (0.23 g, 2.94 mmol) and (diacetoxyiodo)benzene (0.59 g, 1.84 mmol) at 0°C and the resulting reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by combi flash chromatography (Redisep-12 g, 70% EtOAc / n-hexane) to obtain intermediate 265A (0.26 g) as a gummy liquid. LCMS (Method-O) retention time 1.38 min, [M+H]+438.1. Intermediate 265B and 265C: Intermediates 265B and 265C was prepared by using a similar synthetic protocol as that of intermediate 12D and starting from intermediate 265A and tert-butyl piperazine-1- carboxylate. The product mixtre was separated by supercritical fluid chromatography (SFC) [Column: Chiralpak IC 4.6*250 mm, 5 μm; Mobile Phase: 0.2% NH4OH in MeOH : ACN (1:1); Flow rate: 200 mL / min; Back pressure: 100 bar; Column temperature: 30 °C; Detection: UV (220 nm)]. First eluted compound (retention time 6.31 min) was designated as intermediate 265B (0.08 g). LCMS (Method-O): retention time 1.52 min, [M+H]+588.4. Second eluted compound (retention time 7.52 min) was designated as intermediate 265C (0.16 g). LCMS (Method-O): retention time 1.55 min, [M+H]+588.4. Intermediate 265D: Intermediate 265D was prepared by using a similar synthetic protocol as that ofintermediate 12F starting from intermediate 265B and (3-fluoro-2-methylphenyl)boronic acid. LCMS (Method-O): retention time 1.81 min, [M+H]+618.5. The compound was advanced to the subsequent step without further purification. Example 265: Example 265 was prepared by using a similar synthetic protocol as that of example 12 and starting from intermediate 265D and TFA.1H NMR (400 MHz, DMSO-d6) ppm 8.86 (br. d, J = 1.20 Hz, 1H), 7.89 (s, 1H), 7.79 (s, 1H), 7.67 - 7.62 (m, 1H), 7.40 - 7.32 (m, 1H), 7.27 - 7.22 (m, 2H), 7.17 - 7.13 (m, 1H), 4.07 - 3.92 (m, 2H), 3.58 - 3.49 (m, 4H), 3.26 - 3.19 (m, 6H), 2.5 - 2.4 ( m, 1H) 2.13 (s, 3H), 0.91 (d, J = 6.80 Hz, 3H). LCMS (Method-S): retention time 1.23 min, [M+H]+518.2. Examples given in the below table were prepared in a similar manner like Example 265 using appropriate substrates. Ret. Time Example Structure Name [M+H]+(min) and method 4-chloro-2-((2R)-3-(3'- chloro-4'-fluoro-[1,1'- biphenyl]-3- 266 sulfonimidoyl)-2-538.1 1.27(Method S)methylpropyl)-5- (piperazin-1-yl)pyridazin- 3(2H)-one 4-chloro-2-((2R)-3-(3',4'- dichloro-[1,1'-biphenyl]- 3-sulfonimidoyl)-2- 2671.3methylpropyl)-5-554.1 6(Method S)(piperazin-1-yl)pyridazin- 3(2H)-one 4-chloro-2-((2R)-3-(3'- fluoro-2'-methyl-[1,1'- biphenyl]-3- 268 sulfonimidoyl)-2- 518.3 1.26 (Method S) methylpropyl)-5- (piperazin-1-yl)pyridazin- 3(2H)-one4-chloro-2-((2R)-3-(3',4'- dichloro-[1,1'-biphenyl]- 269 3-sulfonimidoyl)-2-1.39methylpropyl)-5-554.1(Method S)(piperazin-1-yl)pyridazin- 3(2H)-one 4-chloro-2-((2R)-3-(3',4'- dichloro-[1,1'-biphenyl]- 270 3-sulfonimidoyl)-2-1.49methylpropyl)-5-554.1(Method S)(piperazin-1-yl)pyridazin- 3(2H)-one Diastereomeric mixture Example 271: 4-chloro-2-(3-(3',4'-dichloro-[1,1'-biphenyl]-3-sulfonimidoyl)propyl)-5- (piperazin-1-yl)pyridazin-3(2H)-one Intermediate 271A: Intermediate 271A was prepared by using a similar synthetic protocol as that of intermediate 12B and starting from intermediate 1A and 4,5-dichloropyridazin-3(2H)- one. LCMS (Method-O): retention time 1.04 min, [M+H]+395.1. Intermediate 271B: To a stirred solution of intermediate 271A (0.50 g, 1.27 mmol) in DCM (10 mL) was added m-CPBA (0.22 g, 1.27 mmol) and the resulting reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was dissolved in DCM (100 mL) and washed with sodium bicarbonate (2 x 50 mL) and combined organic layer was washedwith brine (50 mL) and dried over sodium sulphate, filtered and volatiles were concentrated under reduced pressure to obtain intermediate 271B (0.35 g). LCMS (Method-O): retention time 1.44 min, [M+H]+409.1. The compound was advanced to the subsequent step without further purification. Intermediate 271C: To a stirred solution of intermediate 271B (0.35 g, 0.85 mmol) in Eaton's reagent (1.00 mL, 0.85 mmol) was added sodium azide (0.11 g, 1.71 mmol) and the resulting reaction mixture was stirred at 50 °C for 30 min. The pH of the reaction mixture was adjusted as pH 7 using 10% of aq. NaHCO3and the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-40 g, 45-50% EtOAc / n-hexane) to obtain intermediate 271C (0.150 g). LCMS (Method-O): retention time 1.31 min, [M+H]+424.1. The compound was advanced to the subsequent step without further purification. Intermediate 271D: Intermediate 271D was prepared by using a similar synthetic protocol as that of intermediate 12D and starting from intermediate 271C and tert-butyl piperazine-1- carboxylate. LCMS (Method-O): retention time 1.52 min, [[M+H]+574.3. Intermediate 271E: Intermediate 271E was prepared by using a similar synthetic protocol as that of intermediate 12F and starting from intermediate 271D and (3,4-dichlorophenyl)boronic acid. LCMS (Method-O): retention time 1.90 min, [M+H]+640.4. Example 271: Example 271 was prepared by using a similar synthetic protocol as that of example 12 and starting from intermediate 271E and TFA.1H NMR (400 MHz, DMSO-d6) ppm 8.15 (s, 1H), 8.07 (s, 1H), 8.03 (d, J = 8.30 Hz, 1H), 7.91 (d, J = 8.30 Hz, 1H), 7.87 (s, 1H), 7.78 (s, 2H), 7.71 (t, J = 7.8 Hz, 1H), 4.08 (t, J = 6.7 Hz, 2H), 3.02 - 2.80 (m, 4H),3.2 - 3.33 (m, 4H), 2.93 - 2.95 (m, 2H) 2.00 - 1.90 (m, 2H). LCMS (Method-R): retention time 1.36 min, [M+H]+540.1. Example 274: 4-chloro-2-((2R)-3-((3'-fluoro-2'-methyl-[1,1'-biphenyl]-3-yl)sulfinyl)-2- methylpropyl)-5-(piperazin-1-yl)pyridazin-3(2H)-one Intermediate 274A: Intermediate 274A was prepared as a white solid by using a similar synthetic protocol as that of intermediate 271B and starting from intermediate 29B and m-CPBA. LCMS (Method-O): retention time 1.20 min, [M+H]+423.1. The compound was advanced to the subsequent step without further purification. Intermediate 274B: Intermediate 274B was prepared as a gummy liquid by using a similar synthetic protocol as that of intermediate 12D and starting from intermediate 274A and tert-butyl piperazine-1-carboxylate. LCMS (Method-O): retention time 1.66 min, [M+H]+573.3. Intermediate 274C: Intermediate 274C was prepared as a gummy liquid by using a similar synthetic protocol as that of intermediate 12F and starting from intermediate 274B and (3-fluoro-2- methylphenyl)boronic acid. LCMS (Method-O): retention time 1.92 min, [M+H]+603.6. The compound was advanced to the subsequent step without further purification.Example 274: Example 274 was prepared by using a similar synthetic protocol as that of example 12 and starting from intermediate 274C and TFA.1H NMR (400 MHz, DMSO-d6) ppm 7.89 (d, J = 15.9 Hz, 1H), 7.73 - 7.62 (m, 2H), 7.61 (s, 1H), 7.54 (d, J = 4.9 Hz, 1H), 7.38 - 7.29 (m, 1H), 7.27 - 7.18 (m, 1H), 7.14 (d, J = 8.8 Hz, 1H ), 4.18 - 3.98 (m, 2H), 350 - 3.40 (m, 4H), 3.03 (m, 1H), 2.96 - 2.90 (m, 1H), 2.88 - 2.78 (m, 5H), 2.14 (d, J = 2.0 Hz, 3H), 1.11 (d, J = 6.8 Hz, 2H), 0.97 (d, J = 6.8 Hz, 1H). LCMS (Method-S): retention time 1.49 min, [M+H]+503.2. Examples given in the below table were prepared in a similar manner like Example 274 using appropriate substrates. Ret. Time Example Structure Name [M+H]+(min) and method 4-chloro-2-((2R)-3-((3'- chloro-[1,1'-biphenyl]- 3-yl)sulfinyl)-2- 2751.5methylpropyl)-5-505.1 0(Method S)(piperazin-1- yl)pyridazin-3(2H)-one 4-chloro-2-((2R)-3- ((3',4'-dichloro-[1,1'- 276 biphenyl]-3-yl)sulfinyl)- 2-methylpropyl)-5-539.1 1.66(Method S)(piperazin-1- yl)pyridazin-3(2H)-one Example 277: 4-chloro-2-(2-(((3'-fluoro-2'-methyl-[1,1'-biphenyl]-3- yl)sulfonyl)methyl)allyl)-5-(piperazin-1-yl)pyridazin-3(2H)-oneIntermediate 277A: Intermediate 277A was prepared as a brown solid by using a similar synthetic protocol as that of intermediate 12A starting from 3-bromobenzenethiol and 2-methylenepropane- 1,3-diol.1H NMR (400 MHz, CD3OD) ppm 7.51 (t, J = 2.00 Hz, 1H), 7.31 - 7.37 (m, 2H), 7.16 - 7.26 (m, 1H), 5.13 (d, J = 1.50 Hz, 1H), 5.01 (d, J = 1.20 Hz, 1H), 4.17 (s, 2H), 3.68 (s, 2H). Intermediate 277B: Intermediate 277B was prepared as a brown solid by using a similar synthetic protocol as that of intermediate 12B starting from intermediate 277A and 4,5-dichloropyridazin- 3(2H)-one. The crude product was advanced to the subsequent step without further purification. Intermediate 277C: Intermediate 277C was prepared as a brown solid by using a similar synthetic protocol as that of intermediate 12C starting from intermediate 277B and m-CPBA. LCMS (Method M): retention time 2.90 min, [M+H]+436.8. The crude product was advanced to the subsequent step without further purification. Intermediate 277D: Intermediate 277D was prepared as a brown solid by using a similar synthetic protocol as that of intermediate 12D starting from intermediate 277C and 1-Boc-piperazine. LCMS (Method M): retention time 3.17 min, [M+H]+587.0. The crude product was advanced to the subsequent step without further purification.Intermediate 277E: Intermediate 277E was prepared as brown solid by using a similar synthetic protocol as that of intermediate 12F starting from intermediate 277D and (3-fluoro-2- methylphenyl)boronic acid. LCMS (Method M): retention time 3.67 min, [M+H]+617.2. The compound was advanced to the subsequent step without further purification. Example 277: Example 277 was prepared as an off-white solid by using a similar synthetic protocol as that of example 129 starting from intermediate 277E and 4M solution of HCl in dioxane.1H NMR (400 MHz, DMSO-d6) ppm 7.97 - 7.87 (m, 2H), 7.77 - 7.67 (m, 2H), 7.67 - 7.56 (m, 2H), 7.39 - 7.18 (m, 1H), 6.61 (br. s., 1H), 4.83 - 4.70 (m, 1H), 4.40-4.30 (m, 1H), 4.00 (s, 2H), 3.45 (s, 2H), 3.44 -3.40 (m, 4H), 3.002.90 (m, 4H), 2.54 (s, 3H). LCMS (Method-S): retention time 1.59 min, [M+H]+517.2 Example 278 and 279: 4-chloro-2-(3-((3',4'-dichloro-[1,1'-biphenyl]-3-yl)sulfonyl)butyl)- 5-(piperazin-1-yl)pyridazin-3(2H)-one Intermediate 278A: Intermediate 278A was prepared by using a similar synthetic protocol as that of intermediate 12A starting from 4,5-dichloropyridazin-3(2H)-one and butane-1,3-diol.1HNMR (300 MHz, DMSO-d6) ppm 8.20 (s, 1H), 4.58 (d, J = 4.80 Hz, 1H), 4.30 - 4.15 (m, 2H), 3.70 - 3.60 (m, 1H), 1.79 - 1.70 (m, 2H), 1.05 (d, J = 6.80 Hz, 3H). LCMS (Method-O): retention time 0.95 min, [M+H]+237.2. Intermediate 278B: Intermediate 278B was prepared by using a similar synthetic protocol as that of intermediate 12D starting from intermediate 278A and tert-butyl piperazine-1- carboxylate. LCMS (Method-O): retention time 1.26 min, [M+H]+387.4. Intermediate 278C: Intermediate 278C was prepared by using a similar synthetic protocol as that of intermediate 142E starting from intermediate 278B and NBS. LCMS (Method-O): retention time 1.83 min, [M+2]+449.3. Intermediate 278D: Intermediate 278D was prepared by using a similar synthetic protocol as that of intermediate 235H starting from intermediate 278C and 3-bromobenzenethiol. LCMS (Method-O): retention time 2.26 min, [M+2]+557.3. The crude product was advanced to the subsequent step without further purification. Intermediate 278E: Intermediate 278E was prepared by using a similar synthetic protocol as that of Intermediate 12C starting from Intermediate 278D and m-CPBA. LCMS (Method-O): retention time 1.84 min, [M+2]+589.4. Intermediate 278F: Intermediate 278F was prepared by using a similar synthetic protocol as that of intermediate 12F starting from intermediate 278E and (3,4-dichlorophenyl)boronic acid. LCMS (Method-O): retention time 2.19 min, [M+H]+655.4. The compound was advanced to the subsequent step without further purification.Example 278 and 279: Examples 278 and 279 were prepared by using a similar synthetic protocol as that of example 12 starting from intermediate 278F and TFA. The product mixture was separated by SFC [Column: Chiralcel IG 4.6*250 mm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: 0.2% NH4OH in MeOH : ACN (1:1); Flow rate: 80 g / min; Gradient: isocratic 50% B; Column temperature: 30 °C; Detection: UV (242 nm)]. First eluted compound (retention time 18.30 min) was designated as Example 278 (0.01 g)1H NMR (400MHz, DMSO-d6) ppm 8.18 - 8.10 (m, 2H), 8.09 (d, J = 1.20 Hz, 1H), 7.93 - 7.86 (m, 1H), 7.84 - 7.71 (m, 3H), 7.54 (d, J = 4.60 Hz, 1H), 4.23 - 4.07 (m, 2H), 3.55 -3.50 (m, 2H), 3.2 (m, 2H), 2.5- 2.76 (m, 1H), 2.30 - 2.20 (m, 1H), 2.1 (s,3 H), 1.80 - 1.70 (m, 1H), 1.28 (d, J = 6.80 Hz, 3H). LCMS (Method-R): retention time 1.64 min, [M+H]+555. The second eluted compound (retention time 23.50 min) was designated as Example 279 (0.05 g).1H NMR (400MHz, DMSO-d6) ppm 8.18 - 8.10 (m, 2H), 8.09 (d, J = 1.20 Hz, 1H), 7.93 - 7.86 (m, 1H), 7.84 - 7.71 (m, 3H), 7.54 (d, J = 4.60 Hz, 1H), 7.40 (d, J = 9.0 Hz, 1H), 4.23 - 4.07 (m, 2H), 3.55 -3.50 (m, 1H), 3.50 - 3.40 (m, 4H), 3.00 - 2.76 (m, 4H), 2.30 - 2.20 (m, 1H),1.80 - 1.70 (m, 1H), 1.28 (d, J = 6.80 Hz, 3H). LCMS (Method-R): retention time 1.44 min, [M+H]+555. Examples given in the below table were prepared in a similar manner like Example 278 and 279 using appropriate substrates. Ret. Time Example Structure Name [M+H]+(min) and method 4-chloro-2-(3-((3',4'- dichloro-[1,1'-biphenyl]-3- 280 yl)sulfonyl)butyl)-5-555.1 1.77(piperazin-1-yl)pyridazin-(Method S)3(2H)-one Racemic mixture 4-chloro-2-(3-((3'-chloro-2'- methyl-[1,1'-biphenyl]-3- 281 yl)sulfonyl)butyl)-5-535.2 1.74(piperazin-1-yl)pyridazin-(Method S)3(2H)-one Racemic mixture4-chloro-2-(3-((3'-chloro-4'- fluoro-[1,1'-biphenyl]-3- 282 yl)sulfonyl)butyl)-5-539.1 1.53(piperazin-1-yl)pyridazin-(Method R)3(2H)-one Racemic mixture 4-chloro-2-(3-((3'-chloro-4'- fluoro-[1,1'-biphenyl]-3- 283 yl)sulfonyl)butyl)-5-593.2 1.32(piperazin-1-yl)pyridazin-(Method R)3(2H)-one Enantiomer-I 4-chloro-2-(3-((3'-chloro-4'- fluoro-[1,1'-biphenyl]-3- 284 yl)sulfonyl)butyl)-5-539.2 1.32(piperazin-1-yl)pyridazin-(Method R)3(2H)-one Enantiomer-II Example 285: 4-chloro-5-(1H-pyrazol-4-yl)-2-(3-((3',4,4',5'-tetrafluoro-[1,1'-biphenyl]-3- yl)sulfonyl)propyl)pyridazin-3(2H)-one Intermediate 285A: Intermediate 285A was prepared by using a similar synthetic protocol as that of intermediate 12A and starting from 5-bromo-2-fluorobenzenethiol and 3-bromopropan-1-ol.1H NMR (300 MHz, DMSO-d6) ppm 7.57 (dd, J = 2.60, 6.80 Hz, 1H), 7.48 - 7.37 (m, 1H), 7.27 - 7.16 (m, 1H), 4.64 (t, J = 5.30 Hz, 1H), 3.50 (q, J = 6.00 Hz, 2H), 3.05 (t, J = 7.40 Hz, 2H), 1.79 - 1.64 (m, 2H). Intermediate 285B: Intermediate 285B was prepared as an off white solid by using a similar synthetic protocol as that of intermediate 12B and starting from intermediate 285A and 4-chloro-5- iodopyridazin-3(2H)-one. LCMS (Method-O): retention time 1.06 min, [M+H]+502.8. Intermediate 285C: Intermediate 285C was prepared by using a similar synthetic protocol as that of Intermediate 12C and starting from intermediate 285B and m-CPBA. LCMS (Method-O): retention time 0.70 min, [M+H]+534.9. The crude product was advanced to the subsequent step without further purification. Intermediate 285D: Intermediate 285D was prepared by using a similar synthetic protocol as that of intermediate 12F and starting from intermediate 285C and 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole. LCMS (Method- O): retention time 2.07 min, [M+H]+605.2. The crude product was advanced to the subsequent step without further purification. Intermediate 285E: Intermediate 285E was prepared by using a similar synthetic protocol as that of intermediate 12F starting from intermediate 285D and 4,4,5,5-tetramethyl-2-(3,4,5- trifluorophenyl)-1,3,2-dioxaborolane. LCMS (Method-O): retention time 2.26 min, [M+H]+657.3. Example 285: Example 285 was prepared by using a similar synthetic protocol as that of example 12 starting from intermediate 285E and TFA.1H NMR (400 MHz, DMSO-d6) ppm 13.56 (br. s, 1H), 8.63 (s, 1H), 8.32 (s, 1H), 8.29 (s, 1H), 8.14 (ddd, J = 2.60, 4.60, 8.60 Hz,1H), 8.05 (dd, J = 2.50, 6.50 Hz, 1H), 7.80 (dd, J = 6.70, 9.30 Hz, 2H), 7.69 - 7.53 (m, 1H), 4.21 (t, J = 6.90 Hz, 2H), 3.59 (t, J = 8.00 Hz, 2H), 2.21 - 2.03 (m, 2H). LCMS (Method-R): retention time 1.65 min, [M+H]+527.1. Example 286: (R)-5-chloro-1-(3-((3',4'-dichloro-[1,1'-biphenyl]-3-yl)sulfonyl)-2- methylpropyl)-4-(piperazin-1-yl)pyrimidin-2(1H)-one Intermediate 286A: Intermediate 286A was prepared by using a similar synthetic protocol as that of intermediate 235F and starting from intermediate 40B and NBS.1H NMR (400 MHz, DMSO-d6) ppm 7.55 (t, J = 2.00 Hz, 1H), 7.38 (t, J = 8.70 Hz, 2H), 7.28 (t, J = 7.90 Hz, 1H), 3.63 (dd, J = 1.50, 5.00 Hz, 2H), 3.21 - 3.08 (m, 1H), 2.98 (dd, J = 7.30, 13.30 Hz, 1H), 2.05-1.95 (m, 1H), 1.08 (d, J = 6.50 Hz, 3H). Intermediate 286B: To a stirred solution of intermediate 286A (3.40 g, 10.49 mmol) in DMF (5 mL) was added pyrimidine-2,4(1H,3H)-dione (1.53 g, 13.64 mmol), potassium carbonate (1.88 g, 13.64 mmol) followed by tetrabutylammonium bromide (0.17 g, 0.52 mmol) and the resulting reaction mixture was stirred at 80 °C for 36 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-24 g, 70% EtOAc / n-hexane) to afford the title compound (1.10 g). LCMS (Method M): retention time 2.36 min, [M+H]+355.0.Intermediate 286C: Intermediate 286C was prepared by using a similar synthetic protocol as that of intermediate 12C and starting from intermediate 286B and m-CPBA. LCMS (Method M): retention time 1.79 min, [M+H]+387.0. The compound was advanced to the subsequent step without further purification. Intermediate 286D: To a stirred solution of intermediate 286C (0.62 g, 1.60 mmol) in DCM (15 mL) was added TEA (0.67 mL, 4.80 mmol), DMAP (0.02 g, 0.160 mmol) followed by tosyl chloride (0.37 g, 1.92 mmol) and the resulting reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was concentrated under reduced pressure. To the resulted residue in EtOH (5 mL) was added tert-butyl piperazine-1-carboxylate (0.36 g, 1.92 mmol) and the reaction mixture was stirred at 80 °C for 1 h. The reaction mixture was concentrated under reduced pressure, diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-24 g, 5% MeOH / CHCl3) to obtain intermediate 286D (0.51g). LCMS (Method M): retention time 2.55 min, [M+H]+555.0. Intermediate 286E: Intermediate 286E was prepared by using a similar synthetic protocol as that of intermediate 12F and starting from intermediate 286D and (3,4-dichlorophenyl)boronic acid. LCMS (Method O): retention time 1.79 min, [M+H]+621.3. The compound was advanced to the subsequent step without further purification. Intermediate 286F: To a stirred solution of intermediate 286E (0.08 g, 0.13 mmol) in ACN (3 mL) was added NCS (0.03 g, 0.19 mmol) and the resulting reaction mixture was stirred at 75 °C for 3 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with ethyl acetate (2x 20 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulphate, and evaporated under reduced pressure to obtain intermediate 286F (0.06 g). LCMS (Method-O): retention time 2.09 min, [M+H]+655.3. The compound was advanced to the subsequent step without further purification. Example 286: Example 286 was prepared by using a similar synthetic protocol as that of example 12 starting from intermediate 286F.1H NMR (400 MHz, DMSO-d6) ppm 8.17 (s, 1H), 8.14 - 8.07 (m, 2H), 8.02 - 7.98 (m, 1H), 7.93 - 7.87 (m, 1H), 7.82 - 7.69 (m, 3H), 3.88 - 3.81 (m, 1H), 3.72 -3.68 (m, 1H), 3.59 (br. dd, J = 3.90, 5.10 Hz, 4H), 3.50 - 3.46 (m, 4H), 2.94 - 2.76 (m, 2H), 2.47 - 2.35 (m, 1H), 0.96 (d, J = 7.00 Hz, 3H), LCMS (Method- S): retention time 1.70 min, [M+H]+555.1. Example 287: 4-chloro-2-((1-(((3'-fluoro-2'-methyl-[1,1'-biphenyl]-3- yl)sulfonyl)methyl)cyclopropyl)methyl)-5-(piperazin-1-yl)pyridazin-3(2H)-one Intermediate 287A: Intermediate 287A was prepared as a brown liquid by using a similar synthetic protocol as that of intermediate 12A starting from 3-bromobenzenethiol and cyclopropane-1,1- diyldimethanol.1H NMR (400 MHz, CD3OD) ppm 7.53 (t, J = 1.80 Hz, 1H), 7.33 (t, J = 8.00 Hz, 2H), 7.17 - 7.22 (m, 1H), 3.53 (s, 2H), 3.15 (s, 2H), 0.48 - 0.57 ppm (m, 4H). Intermediate 287B:Intermediate 287B was prepared as a brown solid by using a similar synthetic protocol as that of intermediate 12B and starting from intermediate 287A and 4,5-dichloropyridazin- 3(2H)-one. LCMS (Method M): retention time 3.87 min, [M+H]+418.8. Intermediate 287C: Intermediate 287C was prepared as an off-white solid by using a similar synthetic protocol as that of intermediate 12C and starting from intermediate 287B and m-CPBA. LCMS (Method M): retention time 3.08 min, [M+H]+450.8. Intermediate 287D: Intermediate 287D was prepared as brown solid by using a similar synthetic protocol as that of intermediate 12D and starting from intermediate 287C and 1-Boc-piperazine. LCMS (Method M): retention time 3.12 min, [M+H]+601.2. Intermediate 287E: Intermediate 287E was prepared as brown solid by using a similar synthetic protocol as that of intermediate 12F and starting from intermediate 287D and (3-fluoro-2- methylphenyl)boronic acid. LCMS (Method M): retention time 3.56 min, [M+H]+631.2. The compound was advanced to the subsequent step without further purification. Example 287: Example 287 was prepared as an off-white solid by using a similar synthetic protocol as that of example 129 starting from intermediate 287E and 4M solution of HCl in dioxane.1H NMR (400 MHz, DMSO-d6) ppm 8.01 - 7.93 (m, 1H), 7.92 - 7.84 (m, 2H), 7.78 (d, J = 5.10 Hz, 2H), 7.41 - 7.31 (m, 1H), 7.30 - 7.23 (m, 1H), 7.19 (d, J = 7.80 Hz, 1H), 4.18 (s, 2H), 3.58 (s, 2H), 3.40 -3.38 (m., 4H), 2.96 - 2.84 (m, 4H), 2.15 (d, J = 2.4Hz, 3H), 0.79 - 0.65 (m, 2H), 0.61 - 0.49 (m, 2H). LCMS (Method-S): retention time 1.67 min, [M+H]+531.2 Examples given in the below table were prepared in a similar manner like Example 287 using appropriate substrates.Ret. Time Example Structure Name [M+H]+(min) and method 4-chloro-2-((1-(((3'- chloro-[1,1'-biphenyl]-3- 288 yl)sulfonyl)methyl)cyclop1.56ropyl)methyl)-5-533.2(Method R)(piperazin-1-yl)pyridazin- 3(2H)-one Cl O NH 4-chloro-2-((1-(((3'- OON SNchloro-4'-fluoro-[1,1'- N biphenyl]-3- 289 yl)sulfonyl)methyl)cyclop550.1 1.59ropyl)methyl)-5-(Method R)Cl (piperazin-1-yl)pyridazin- F 3(2H)-one 4-chloro-2-((1-(((3',4'- dichloro-[1,1'-biphenyl]- 3- 290 yl)sulfonyl)methyl)cyclop567.2 1.71ropyl)methyl)-5-(Method R)(piperazin-1-yl)pyridazin- 3(2H)-one Example 291: 4-chloro-2-(2-((3',4'-dichloro-[1,1'-biphenyl]-3-yl)sulfonyl)ethyl)-5- (piperazin-1-yl)pyridazin-3(2H)-one Intermediate 291A: Intermediate 291A was prepared as a brown oil, by using a similar synthetic protocol as that of intermediate 1A and starting from 3-bromobenzenethiol and 2-bromoethanol.1HNMR (400 MHz, CD3OD) ppm 7.54 (t, J = 2.00 Hz, 1H), 7.33 - 7.37 (m, 2H), 7.19 - 7.25 (m, 1H), 3.72 (t, J = 6.80 Hz, 2H), 3.10 (t, J = 6.50 Hz, 2H). Intermediate 291B: Intermediate 291B was prepared as a brown semisolid by using a similar synthetic protocol as that of intermediate 12B and starting from intermediate 291A and 4,5- dichloropyridazin-3(2H)-one. LCMS (Method M): retention time 3.44 min, [M+H]+378.8. Intermediate 291C: Intermediate 291C was prepared as an off white solid by using a similar synthetic protocol as that of intermediate 12C and starting from intermediate 291B and m-CPBA. The compound was advanced to the subsequent step without further purification. LCMS (Method M): retention time 2.6 min, [M+2H]+412.4. Intermediate 291D: Intermediate 291D was prepared as brown solid by using a similar synthetic protocol as that of intermediate 12D and starting from intermediate 291C and 1-Boc-piperazine. LCMS (Method M): retention time 2.99 min, [M+H]+561.2. Intermediate 291E: Intermediate 291E was prepared as a brown solid by using a similar synthetic protocol as that of intermediate 12F and starting from intermediate 291D and (3,4- dichlorophenyl)boronic acid. LCMS (Method M): retention time 3.51 min, [M+H]+627.1. The compound was advanced to the subsequent step without further purification. Example 291: Example 291 was prepared as an off-white solid by using a similar synthetic protocol as that of example 129 and starting from intermediate 291E and 4M solution of HCl in dioxane.1H NMR (400 MHz, DMSO-d6) ppm 8.07 - 7.98 (m, 3H), 7.81 (d, J = 8.10 Hz, 1H), 7.78 - 7.75 (m, 1H), 7.74 - 7.65 (m, 2H), 7.63 (s, 1H), 4.37 (t, J = 6.40 Hz, 2H), 3.97(t, J = 6.00 Hz, 2H), 3.21 - 3.13 (m, 4H), 2.73 - 2.68 (m, 4H). LCMS (Method-S): retention time 1.56 min, [M+H]+527.1. Example 292: 2-(3-((4-((azetidin-3-ylmethyl)amino)-2',3'-dichloro-[1,1'-biphenyl]-3- yl)sulfonyl)propyl)-4-chloro-5-(piperazin-1-yl)pyridazin-3(2H)-one Intermediate 292A: To a stirred solution of intermediate 320A (1g, 3.77 mmol), 4,5-dichloropyridazin-3(2H)- one (0.684 g, 4.15 mmol) triphenylphosphine (1.08 g, 4.15 mmol) in THF (25 ml) was added the DEAD (0.657 ml, 4.15 mmol) at 30 °C and the reaction mixture was stirred at 30 °C for 16h. Reaction mixture was quenched with brine (25 mL) and extracted with DCM (2 X 50 mL). The combined organic extracts were dried over sodium sulphate, filtered, and the filtrate evaporated under reduced pressure to afford the crude material. The crude material was loaded onto a silica gel column (12 g) and purified using ethyl acetate in hexanes (0-100%) in a gradient manner to afford intermediate 292A (1.2 g). LCMS (Method-O): retention time 2.05 min., [M+H]+410.9. Intermediate 292B: Intermediate 292B was prepared by using a similar synthetic procedure as that of intermediate 12D starting from intermediate 292A and tert-butyl piperazine-1- carboxylate. LCMS (Method-O): retention time 2.10 min, [M+H]+561.1 Intermediate 292C:Intermediate 292C was prepared by using a similar synthetic procedure as that of intermediate 12C starting from intermediate 292B and mCPBA. LCMS (Method-O): retention time 1.74 min, [M+H]+593.1. Intermediate 292D: To a stirred solution of intermediate 292C (200 mg, 0.38 mmol), DIPEA (0.18 mL, 1.01 mmol) in 1,4-dioxane (5 mL) was added tert-butyl 3-(aminomethyl)azetidine-1- carboxylate (82 mg, 0.438 mmol) at 30 °C and the reaction mixture was stirred at 120 °C for 16 h. Reaction mixture was quenched with brine (25 mL) and extracted with DCM (2 X 50 mL). The combined organic extracts were dried over sodium sulphate, filtered and the filtrate evaporated under reduced pressure to afford the crude material. The crude material was loaded onto a silica gel column (12g) and purified using ethyl acetate in hexanes (0-100%) in a gradient manner to afford the title compound (195 mg). LCMS (Method-O): retention time 2.08 min, [M-H] 757.2 Intermediate 292E: Intermediate 292E was prepared by using a similar synthetic procedure as that of intermediate 12F starting from intermediate 292D and (2,3-dichlorophenyl)boronic acid. LCMS (Method-O): retention time 2.31 min, [M-H] 823.4 Example 292: Example 292 was prepared by using a similar synthetic procedure as that of example 12 starting from intermediate 292E and TFA.1H NMR (400 MHz, DMSO-d6) ppm 7.96 (s, 1H) 7.57 - 7.68 (m, 3H) 7.37 - 7.50 (m, 2H) 7.03 (d, J=9.05Hz, 1H) 6.56 (t, J=5.87 Hz, 1H) 4.10 - 4.17 (m, 2H) 3.96 - 4.07 (m, 2H) 3.75 - 3.85 (m, 2H) 3.51 - 3.61 (m, 6H) 3.36 - 3.39 (m, 2H) 3.21 - 3.27 (m, 4H) 3.20 -3.15 (m, 1H) 1.95 - 2.06 (m, 2H). LCMS (Method-O): retention time 1.346 min, [M+H]+625.1. Examples given in the below table were prepared in a similar manner like Example 292 using appropriate substrates.Ret.Time Example Structure Name [M+H]+(min) and method 2-(3-((4-((azetidin-3- ylmethyl) amino)-2'- (trifluoromethyl)-[1,1'- 293 biphenyl]-3-625.2 1.188yl)sulfonyl)propyl)-4-(Method R)chloro-5-(piperazin-1- yl)pyridazin-3(2H)-one 2-(3-((4-((azetidin-3- ylmethyl) amino)-3'- fluoro-2'-methyl-[1,1'- 294 biphenyl]-3-589.3 1.186yl)sulfonyl)propyl)-4-(Method R)chloro-5-(piperazin-1- yl)pyridazin-3(2H)-one H N 2-(3-((4-((azetidin-3- Cl NH ylmethyl) amino)-3'- O N NH O O chloro-2'-methyl-[1,1'- 295S NN biphenyl]-3-605.2 1.276yl)sulfonyl)propyl)-4-(Method R)chloro-5-(piperazin-1- yl)pyridazin-3(2H)-one Cl H N 2-(3-((4-((azetidin-3- Cl NH ylmethyl) amino)-3'- O N NH O O chloro-2'-fluoro-[1,1'- 296S NN biphenyl]-3-609.2 1.21yl)sulfonyl)propyl)-4-(Method R)F chloro-5-(piperazin-1- yl)pyridazin-3(2H)-one Cl H N Cl NH 2-(3-((4-((azetidin-3- O N NH O O ylmethyl) amino)-2',4'- SN297 N difluoro-[1,1'-biphenyl]-1.133-yl)sulfonyl)propyl)-4-593.2(Method R)F chloro-5-(piperazin-1- yl)pyridazin-3(2H)-one F2-(3-((4-((azetidin-3- ylmethyl) amino)-2'- chloro-4'-fluoro-[1,1'- 298 biphenyl]-3-609.2 1.20yl)sulfonyl)propyl)-4-(Method R)chloro-5-(piperazin-1- yl)pyridazin-3(2H)-one H N Cl NH 2-(3-((4-((azetidin-3- O N ylmethyl) amino)-4'- NH O O SNchloro-2'-fluoro-[1,1'- 299 N biphenyl]-3-609.2 1.24yl)sulfonyl)propyl)-4-(Method R)F chloro-5-(piperazin-1- yl)pyridazin-3(2H)-one Cl H N Cl NH 2-(3-((4-((azetidin-3- O N ylmethyl) amino)-2',4'- NH O O SNdichloro-[1,1'- 300 N biphenyl]-3-625.1 1.41yl)sulfonyl)propyl)-4-(Method S)Cl chloro-5-(piperazin-1- yl)pyridazin-3(2H)-one Cl H N Cl NH 2-(3-((4-((azetidin-3- O N ylmethyl) amino)-3',4'- NH O O SNdichloro-[1,1'- 301 N biphenyl]-3-625.2 1.33yl)sulfonyl)propyl)-4-(Method R)chloro-5-(piperazin-1- Cl yl)pyridazin-3(2H)-one Cl 2-(3-((4-((azetidin-3- ylmethyl) amino)-4'- chloro-3'-fluoro-[1,1'- 302 biphenyl]-3-609.2 1.25yl)sulfonyl)propyl)-4-(Method R)chloro-5-(piperazin-1- yl)pyridazin-3(2H)-one2-(3-((4-((azetidin-3- ylmethyl) amino)- 3',4',5'-trifluoro-[1,1'- 303 biphenyl]-3-611.2 1.22yl)sulfonyl)propyl)-4-(Method R)chloro-5-(piperazin-1- yl)pyridazin-3(2H)-one Example 304: 4-chloro-2-(3-((2',3'-dichloro-4-((3-fluoroazetidin-3-yl)methoxy)-[1,1'- biphenyl]-3-yl)sulfonyl)propyl)-5-(piperazin-1-yl)pyridazin-3(2H)-one Intermediate 304A: To a stirred solution of intermediate 292C (0.08 g, 0.13 mmol), tert-butyl 3-fluoro-3- (hydroxymethyl)azetidine-1-carboxylate (0.03 g, 0.15 mmol) in THF (2 mL) was added the KOtBu (0.19 mL, 0.19 mmol) at 30 °C and the reaction mixture was stirred at 60 °C for 4 h. The reaction mixture was quenched with brine (25 mL) and extracted with DCM (2 X 50mL). The combined organic extracts were dried over sodium sulphate, filtered and the filtrate evaporated under reduced pressure to afford the crude material. The crude material was loaded onto a silica gel column (12g) and purified using ethyl acetate in hexanes (0-100%) in a gradient manner to afford the title compound (75 mg). LCMS (Method-O): retention time 1.99 min, [M+H]+778.3. Intermediate 304B: To a stirred solution of intermediate 304A (70 mg, 0.090 mmol), (2,3- dichlorophenyl)boronic acid (20.57 mg, 0.108 mmol) and K2CO3(18.63 mg, 0.14 mmol) in 1,4-dioxane (3mL) was added the PdCl2(dppf) (6.57 mg, 8.98 μmol) at RT and the reaction mixture was heated and stirred at 120 °C for 16h. The reaction mixture was quenched with brine (25 mL) and extracted with DCM (2 X 50 mL). The combined organic extracts were dried over sodium sulphate, filtered and the filtrate evaporatedunder reduced pressure to afford the crude material. The crude material was loaded onto a silica gel column (12g) and purified using ethyl acetate in hexanes (0-100%) in a gradient manner to afford the title compound (70 mg). LCMS (Method-O): retention time 2.21 min, [M+H]+844.3. Example 304: Example 304 was prepared by using a similar synthetic procedure as that of example 12 starting from intermediate 304B.1H NMR (400 MHz, DMSO-d6) ppm 7.96 (s, 1H), 7.88 (dd, J = 2.4, 8.8 Hz, 1H), 7.81 (d, J = 2.2Hz, 1H), 7.72 (dd, J = 2.4, 7.1Hz, 1H), 7.51 - 7.42 (m, 3H), 4.68 (s, 2H), 4.44 - 4.25 (m, 4H), 4.12 (br t, J = 7.0 Hz, 2H), 3.61 - 3.52 (m, 4H), 3.50 - 3.43 (m, 2H), 3.28 - 3.19 (m, 4H), 2.07 - 1.94 (m, 2H). LCMS (Method- S): retention time 1.488 min, [M+H]+645.2. Examples given in the below table were prepared in a similar manner like Example 304 using appropriate substrates. Ret.Time Example Structure Name [M+H]+(min) and method H N 4-chloro-2-(3-((2',4'- F Cl NH dichloro-4-((3- O O N O fluoroazetidin-3- SONN yl)methoxy)-[1,1'- 1.565 305 biphenyl]-3- 644.2 (Method S) Cl yl)sulfonyl)propyl)-5- (piperazin-1- yl)pyridazin-3(2H)-one Cl 5-amino-2-(3-((4-(2- aminoethoxy)-3',4',5'- trifluoro-[1,1'- 1.399 306 biphenyl]-3- 517 (Method yl)sulfonyl)propyl)-4- S) chloropyridazin-3(2H)- one Example 307: 2-(3-((4-((azetidin-3-ylmethyl)amino)-2',3'-dichloro-[1,1'-biphenyl]-3- yl)sulfonyl)propyl)-4-chloro-5-(piperidin-4-yloxy)pyridazin-3(2H)-oneIntermediate 307 A: Intermediate 307A was prepared by using a similar synthetic procedure as that of intermediate 161A starting from intermediate 292A and tert-butyl 4-hydroxypiperidine-1- carboxylate. LCMS (Method-O): retention time 2.14 min, [M-tBu+H]+520.0 Intermediate 307B: Intermediate 307B was prepared by using a similar synthetic procedure as that of intermediate 12C starting from intermediate 307A. LCMS (Method O): retention time 1.82 min, [M-tBu+H]+552.1. Intermediate 307C: Intermediate 307C was prepared by using a similar synthetic procedure as that of intermediate 292D starting from intermediate 307B. LCMS (Method-O): retention time 2.13 min, [M-H] 772.3 Intermediate 307D: Intermediate 307D was prepared by using a similar synthetic procedure as that of intermediate 12F starting from intermediate 307C and (2,3-dichlorophenyl)boronic acid. LCMS (Method-O): retention time 2.33 min, [M-Boc+H]+740.3.Example 307: Example 307 was prepared by using a similar synthetic procedure as that of example 12 starting from intermediate 307D.1H NMR (400 MHz, DMSO-d6) ppm 8.87 - 8.56 (m, 2H), 8.28 (s, 1H), 7.71 - 7.56 (m, 3H), 7.51 - 7.36 (m, 2H), 7.03 (d, J = 9.0 Hz, 1H), 6.56 (t, J = 5.7 Hz, 1H), 5.08 - 4.99 (m, 1H), 4.22 - 4.12 (m, 2H), 4.09 - 3.95 (m, 2H), 3.87 - 3.75 (m, 2H), 3.56 (t, J = 6.5Hz, 2H), 3.43 - 3.36 (m, 2H), 3.26 - 3.06 (m, 4H), 2.15 - 1.99 (m, 4H), 1.95 - 1.85 (m, 2H). LCMS (Method-S): retention time 1.36 min, [M+H]+640.1. Examples given in the below table were prepared in a similar manner like Example 307 using appropriate substrates. Ret.Time Example Structure Name [M+H]+(min) and method 2-(3-((4-((azetidin-3- ylmethyl)amino)-2'- fluoro-[1,1'-biphenyl]-3- 308 yl)sulfonyl)propyl)-4-590.2 1.11chloro-5-(piperidin-4-(Method R)yloxy)pyridazin-3(2H)- one 2-(3-((4-((azetidin-3- ylmethyl) amino)-2'- (trifluoromethyl)-[1,1'- 309 biphenyl]-3-1.23yl)sulfonyl)propyl)-4-640.3(Method R)chloro-5-(piperidin-4- yloxy)pyridazin-3(2H)- one 2-(3-((4-((azetidin-3- ylmethyl)amino)-2',3'- difluoro-[1,1'-biphenyl]- 310 3-yl)sulfonyl) propyl)-4-608.2 1.15chloro-5-(piperidin-4-(Method R)yloxy)pyridazin-3(2H)- one2-(3-((4-((azetidin-3- ylmethyl) amino)-3'- chloro-2'-fluoro-[1,1'- 311 biphenyl]-3-1.24yl)sulfonyl)propyl624.2)-4-(Method R)chloro-5-(piperidin-4- yloxy)pyridazin-3(2H)- one 2-(3-((4-((azetidin-3- ylmethyl) amino)-2',4'- difluoro-[1,1'-biphenyl]- 1.16312 3-yl)sulfonyl)propyl)-4-608.2(Method R)chloro-5-(piperidin-4- yloxy)pyridazin-3(2H)- one 2-(3-((4-((azetidin-3- ylmethyl) amino)-2'- chloro-4'-fluoro-[1,1'- biphenyl]-3-1.25313624.2yl)sulfonyl)propyl)-4-(Method R)chloro-5-(piperidin-4- yloxy)pyridazin-3(2H)- one 2-(3-((4-((azetidin-3- ylmethyl) amino)-2',4'- dichloro-[1,1'-biphenyl]- 1.42314 3-yl)sulfonyl)propyl)-4-640.2(Method S)chloro-5-(piperidin-4- yloxy)pyridazin-3(2H)- one 2-(3-((4-((azetidin-3- ylmethyl) amino)-3',4'- dichloro-[1,1'-biphenyl]- 1.45315 3-yl)sulfonyl)propyl)-4-640.2(Method S)chloro-5-(piperidin-4- yloxy)pyridazin-3(2H)- one2-(3-((4-((azetidin-3- ylmethyl) amino)-2',3'- dichloro-[1,1'-biphenyl]- 316 3-yl)sulfonyl)propyl)-4- chloro-5-((3-644.1 1.54(Method S)fluoroazetidin-3- yl)methoxy)pyridazin- 3(2H)-one 2-(3-((4-((azetidin-3- ylmethyl) amino)-2',4'- dichloro-[1,1'-biphenyl]- 317 3-yl)sulfonyl)propyl)-4- chloro-5-((3-644.2 1.61(Method S)fluoroazetidin-3- yl)methoxy)pyridazin- 3(2H)-one 2-(3-((4-((azetidin-3- ylmethyl) amino)-2'- chloro-4'-fluoro-[1,1'- biphenyl]-3- 318 yl)sulfonyl)propyl)-4-628.2 1.46chloro-5-((3-(Method S)fluoroazetidin-3- yl)methoxy)pyridazin- 3(2H)-one 2-(3-((4-((azetidin-3- ylmethyl) amino)-2'- chloro-4'-fluoro-[1,1'- biphenyl]-3- 3191.5yl)sulfonyl)propyl)-4-555.2 4(Method R)chloro-5- methoxypyridazin-3(2H)- one Example 320: 2-(3-((4-((azetidin-3-ylmethyl)amino)-3'-fluoro-2'-methyl-[1,1'-biphenyl]- 3-yl)sulfonyl)propyl)-4-chloro-5-(1H-pyrazol-4-yl)pyridazin-3(2H)-oneIntermediate 320A: To a stirred solution of 5-bromo-2-fluorobenzenethiol (5 g, 24.15 mmol), potassium carbonate (6.67 g, 48.3 mmol) and sodium formaldehyde sulfoxylate (2.85 g, 24.15 mmol) in DMF (30 mL) was added 3-bromopropan-1-ol (3.36 g, 24.15 mmol) and the reaction mixture was stirred at RT for 4 h. The volatiles were evaporated to dryness, the residue was added water (150 mL) and extracted with EtOAc (2 x 150 mL). Combined organic extracts were washed with water (100 mL), brine (100 mL), dried over sodium sulphate, filtered and volatiles were evaporated to dryness under reduced pressure to afford crude product. The crude product obtained was purified by silica gel column chromatography using a gradient of EtOAc in hexanes. Product was isolated at 25% EtOAc in hexanes, required fractions were collected and volatiles were evaporated to dryness under reduced pressure to afford the title compound (4.3 g).1H NMR (400MHz, DMSO-d6) ppm 7.56 (dd, J=2.5, 6.5Hz, 1H), 7.42 (ddd, J=2.5, 4.5, 8.5Hz, 1H), 7.20 (dd, J=8.8, 9.8 Hz, 1H), 3.57 (t, J=6.5Hz, 2H), 3.04 (t, J=7.3Hz, 2H), 1.93 (quin, J=6.3Hz, 2H). Intermediate 320B: Intermediate 320B was prepared by using a similar synthetic procedure as that of intermediate 12B starting from intermediate 320A, 4-chloro-5-iodopyridazin-3(2H)-one,triphenylphosphine, and diethyl azodicarboxylate. LCMS (Method-O): retention time 2.07 min, [M+H]+503.0. Intermediate 320C: Intermediate 320C was prepared by using a similar synthetic procedure as that of intermediate 12C starting from intermediate 320B and m-CPBA. LCMS (Method-O): retention time 1.61 min, [M+H]+535.8. Intermediate 320D: Intermediate 320D was prepared by using a similar synthetic procedure as that of intermediate 12F starting from intermediate 320C and 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole. LCMS (Method- O): retention time 2.07 min, [M+H]+605.3. Intermediate 320E: Intermediate 320E was prepared by using a similar synthetic procedure as that of intermediate 292D starting from intermediate 320D and tert-butyl 3- (aminomethyl)azetidine-1-carboxylate. LCMS (Method-O): retention time 2.24 min, [M- Boc+H]+671.3. Intermediate 320F: Intermediate 320F was prepared by using a similar synthetic procedure as that of intermediate 12F starting from intermediate 320E and (3-fluoro-2-methylphenyl)boronic acid. LCMS retention time 2.52 min, [M+H]+801.0. Example 320: Example 320 was prepared by using a similar synthetic procedure as that of example 12 starting from intermediate 320F.1H NMR (400MHz, DMSO-d6) ppm 13.66 - 13.50 (br, 1H), 8.79 - 8.46 (m, 2H), 8.32 (s, 1H), 7.58 - 7.45 (m, 1H), 7.34 - 7.21 (m, 1H), 7.20 - 7.13 (m,1H), 7.08 (d, J=7.6 Hz, 1H), 7.02 - 6.94 (m, 1H), 6.51 - 6.39 (m, 1H), 4.24 - 4.11 (m, 2H), 4.06 - 3.93 (m, 2H), 3.85 - 3.70 (m, 2H), 3.52 (br t, J=6.5Hz, 2H), 3.40 (br d,J=6.8 Hz, 3H), 3.19 - 2.92 (m, 2H), 2.16 - 1.99 (m, 3H). LCMS (Method-S): retention time 1.52 min, [M+H]+571.2. Examples given in the below table were prepared in a similar manner like Example 320 using appropriate substrates. Ret.Time Example Structure Name [M+H]+(min) and method 2-(3-((4-((azetidin-3- ylmethyl) amino)-2'- 321 fluoro-[1,1'-biphenyl]-3- yl)sulfonyl)propyl)-557.2 1.284-(Method R)chloro-5-(1H-pyrazol-4- yl)pyridazin-3(2H)-one 2-(3-((4-((azetidin-3- ylmethyl) amino)-2'- (trifluoromethyl)-[1,1'- 1.42322 biphenyl]-3-607.2yl)sulfonyl)propyl)-4-(Method R)chloro-5-(1H-pyrazol-4- yl)pyridazin-3(2H)-one 2-(3-((4-((azetidin-3- ylmethyl) amino)-3'- 323 fluoro-[1,1'-biphenyl]-3-1.29yl)sulfonyl)propyl)-4-557.2(Method R)chloro-5-(1H-pyrazol-4- yl)pyridazin-3(2H)-one 2-(3-((4-((azetidin-3- ylmethyl) amino)-2',3'- 324 difluoro-[1,1'-biphenyl]- 3-yl)sulfonyl)propyl575.2 1.32)-4-(Method R)chloro-5-(1H-pyrazol-4- yl)pyridazin-3(2H)-one2-(3-((4-((azetidin-3- ylmethyl) amino)-2',3'- 325 dichloro-[1,1'-biphenyl]- 3-yl)sulfonyl)prop607.0 1.60yl)-4-(Method S)chloro-5-(1H-pyrazol-4- yl)pyridazin-3(2H)-one 2-(3-((4-((azetidin-3- ylmethyl) amino)-3'- chloro-2'-methyl-[1,1'- 326 biphenyl]-3-587.2 1.51yl)sulfonyl)propyl)-4-(Method R)chloro-5-(1H-pyrazol-4- yl)pyridazin-3(2H)-one 2-(3-((4-((azetidin-3- ylmethyl) amino)-2',4'- 327 difluoro-[1,1'-biphenyl]-1.333-yl)sulfonyl)propyl)-4-575.2(Method R)chloro-5-(1H-pyrazol-4- yl)pyridazin-3(2H)-one 2-(3-((4-((azetidin-3- ylmethyl) amino)-2'- chloro-4'-fluoro-[1,1'- 328 biphenyl]-3-593.1 1.43yl)sulfonyl)propyl)-4-(Method S)chloro-5-(1H-pyrazol-4- yl)pyridazin-3(2H)-one 2-(3-((4-((azetidin-3- ylmethyl) amino)-4'- chloro-2'-fluoro-[1,1'- 329 biphenyl]-3-591.1 1.46yl)sulfonyl)propyl)-4-(Method R)chloro-5-(1H-pyrazol-4- yl)pyridazin-3(2H)-one2-(3-((4-((azetidin-3- ylmethyl) amino)-2',4'- 330 dichloro-[1,1'-biphenyl]- 3-yl)sulfonyl)propy607.1 1.55l)-4-(Method R)chloro-5-(1H-pyrazol-4- yl)pyridazin-3(2H)-one H N 2-(3-((4-((azetidin-3- Cl NH ylmethyl) amino)-3'- NHO OONS chloro-4'-fluoro-[1,1'- 331 N N biphenyl]-3-591.1 1.38yl)sulfonyl)propyl)-4-(Method S)chloro-5-(1H-pyrazol-4- Cl yl)pyridazin-3(2H)-one F 2-(3-((4-((azetidin-3- ylmethyl) amino)-3',4'- 332 dichloro-[1,1'-biphenyl]-1.653-yl)sulfonyl)propyl)-4-607.1(Method S)chloro-5-(1H-pyrazol-4- yl)pyridazin-3(2H)-one H N Cl NH 2-(3-((4-((azetidin-3- NHO OONylmethyl) amino)-3',4'- S 333 N difluoro-[1,1'-biphenyl]- N 3-yl)sulf575.2 1.45onyl)propyl)-4-(Method S)chloro-5-(1H-pyrazol-4- yl)pyridazin-3(2H)-one F F 2-(3-((4-((azetidin-3- ylmethyl) amino)-4'- chloro-3'-fluoro-[1,1'- 334 biphenyl]-3-591.1 1.45yl)sulfonyl)propyl)-4-(Method R)chloro-5-(1H-pyrazol-4- yl)pyridazin-3(2H)-one2-(3-((4-((azetidin-3- ylmethyl) amino)-3',4',5'- trifluoro-[1,1'-biphenyl]- 3351.433-yl)sulfonyl)propyl)-4-593.1(Method S)chloro-5-(1H-pyrazol-4- yl)pyridazin-3(2H)-one H2NCl N NH2-(3-((4-((2- 531.1 1.26 O NHO Oaminoethyl)amino)-2'- SNfluoro-[1,1'-biphenyl]-3- (Method S) 336 N yl)sulfonyl)propyl)-4- F chloro-5-(1H-pyrazol-4- yl)pyridazin-3(2H)-one H2NCl N NH2-(3-((4-((2- 581.2 1.38 O NHO Oaminoethyl)amino)-2'- SNN (trifluoromethyl)-[1,1'- (Method R) 337 biphenyl]-3- CF3yl)sulfonyl)propyl)-4- chloro-5-(1H-pyrazol-4- yl)pyridazin-3(2H)-one 2-(3-((4-((2- 531.1 1.27 aminoethyl)amino)-3'- fluoro-[1,1'-biphenyl]-3- (Method S) 338 yl)sulfonyl)propyl)-4- chloro-5-(1H-pyrazol-4- yl)pyridazin-3(2H)-one 2-(3-((4-((2- 547.1 1.40 aminoethyl)amino)-3'- (Method S) chloro-[1,1'-biphenyl]-3- 339 yl)sulfonyl)propyl)-4- chloro-5-(1H-pyrazol-4- yl)pyridazin-3(2H)-one 2-(3-((4-((2- 565.1 1.41 aminoethyl)amino)-3'- chloro-2'-fluoro-[1,1'- (Method S) 340 biphenyl]-3- yl)sulfonyl)propyl)-4- chloro-5-(1H-pyrazol-4- yl)pyridazin-3(2H)-one2-(3-((4-((2- aminoethyl)amino)-3'- fluoro-2'-methyl-[1,1'- 1.4141 biphenyl]-3- 545.2 (Method S) yl)sulfonyl)propyl)-4- chloro-5-(1H-pyrazol-4- yl)pyridazin-3(2H)-one 2-(3-((4-((2- aminoethyl)amino)-3'- chloro-2'-methyl-[1,1'- 1.5242 biphenyl]-3- 561.1 yl)sulfonyl)propyl)-4- (Method S) chloro-5-(1H-pyrazol-4- yl)pyridazin-3(2H)-one 2-(3-((4-((2- aminoethyl)amino)-2',3'- 1.4943 dichloro-[1,1'-biphenyl]- 581.1 3-yl)sulfonyl)propyl)-4- (Method S) chloro-5-(1H-pyrazol-4- yl)pyridazin-3(2H)-one 2-(3-((4-((2- aminoethyl)amino)-2',4'- 1.3244 difluoro-[1,1'-biphenyl]- 549.1 3-yl)sulfonyl)propyl)-4- (Method S) chloro-5-(1H-pyrazol-4- yl)pyridazin-3(2H)-one 2-(3-((4-((2- aminoethyl)amino)-2'- chloro-4'-fluoro-[1,1'- 1.3945 biphenyl]-3- 565.1 yl)sulfonyl)propyl)-4- (Method R) chloro-5-(1H-pyrazol-4- yl)pyridazin-3(2H)-one 2-(3-((4-((2- aminoethyl)amino)-2',4'- 1.5446 dichloro-[1,1'-biphenyl]- 581.1 3-yl)sulfonyl)propyl)-4- (Method S) chloro-5-(1H-pyrazol-4- yl)pyridazin-3(2H)-one2-(3-((4-((2- aminoethyl)amino)-4'- chloro-2'-fluoro-[1,1'- 1.4147 biphenyl]-3- 565.1 (Method R) yl)sulfonyl)propyl)-4- chloro-5-(1H-pyrazol-4- yl)pyridazin-3(2H)-one H2NCl NH NHO OON2-(3-((4-((2- S N aminoethyl)amino)-3',4'- N 48 difluoro-[1,1'-biphenyl]- 1.34 549.2 3-yl)sulfonyl)propyl)-4- (Method S) chloro-5-(1H-pyrazol-4- F yl)pyridazin-3(2H)-one F 2-(3-((4-((2- aminoethyl)amino)-3',4'- 1.5449 dichloro-[1,1'-biphenyl]- 581.1 3-yl)sulfonyl)propyl)-4- (Method S) chloro-5-(1H-pyrazol-4- yl)pyridazin-3(2H)-one 2-(3-((4-((2- aminoethyl)amino)-3'- chloro-4'-fluoro-[1,1'- 1.4350 biphenyl]-3- 565.2 yl)sulfonyl)propyl)-4- (Method S) chloro-5-(1H-pyrazol-4- yl)pyridazin-3(2H)-one 2-(3-((4-((2- aminoethyl)amino)-4'- chloro-3'-fluoro-[1,1'- 1.4151 biphenyl]-3- 565.1 yl)sulfonyl)propyl)-4- (Method R) chloro-5-(1H-pyrazol-4- yl)pyridazin-3(2H)-one2-(3-((4-((2- aminoethyl)amino)- 3',4',5'-trifluoro-[1,1'- 2.0952 biphenyl]-3- 567.1 (Method M) yl)sulfonyl)propyl)-4- chloro-5-(1H-pyrazol-4- yl)pyridazin-3(2H)-one NH2HO Cl N (S)-2-amino-4-((3-((3-(5- O O NH chloro-6-oxo-4-(1H- NHOSON pyrazol-4-yl)pyridazin- N 1.9153 1(6H)- 625.1 yl)propyl)sulfonyl)- (Method M) 3',4',5'-trifluoro-[1,1'- F F biphenyl]-4- F yl)amino)butanoic acid Example 354: 2-(3-((4-(azetidin-3-ylmethoxy)-3'-chloro-2'-methyl-[1,1'-biphenyl]-3- yl)sulfonyl)propyl)-4-chloro-5-(1H-pyrazol-4-yl)pyridazin-3(2H)-one Intermediate 354A: Intermediate 354A was prepared by using a similar synthetic procedure as that of intermediate 12C starting from intermediate 320A.1H NMR (300 MHz, DMSO-d6) ppm 8.05 (ddd,J=8.78, 4.25, 2.46 Hz, 1H), 7.91 (dd, J=6.04, 2.64Hz, 1H), 7.56 (dd, J=9.82, 9.07 Hz, 1H), 4.98 (br, 1H) 3.31 - 3.59 (m, 4H) 1.59 - 1.87 (m, 2H).Intermediate 354B: To a stirred solution of intermediate 354A (3.0 g, 10.1 mmol) in dichloromethane (30 mL) was added imidazole (1.03 g, 15.14 mmol) followed by tert-butyldimethylsilyl chloride (2.28 g, 15.14 mmol) and the reaction mixture was stirred at RT for 14 h. The reaction mixture was added water (50 mL) and extracted with DCM (2 x 100 mL). The combined organic extract was washed with water (100 mL), brine (100 mL), dried over sodium sulphate, filtered and and evaporated to dryness under reduced pressure to afford the title compound (3.8 g). LCMS (Method-O): retention time 1.45 min, [M+H]+411.1. Intermediate 354C: To a stirred solution of intermediate 354B (1.0 g, 2.43 mmol) and tert-butyl 3- (hydroxymethyl)azetidine-1-carboxylate (0.46 g, 2.43 mmol) in THF (22 mL) was added NaH (0.194 g, 4.86 mmol) in portion and the reaction mixture was stirred at RT for 2 h. The volatiles were evaporated to dryness under reduced pressure, water (15 mL) was added and extracted with EtOAc (2 x 15 mL). The combined organic extract was washed with water (20 mL) and brine (20 mL), dried over sodium sulphate, filtered and volatile component was removed under reduced pressure. The crude product obtained was purified by silica gel column chromatography (45% EtOAc in hexanes) to afford the title compound (690 mg). LCMS (Method-O): retention time 1.64 min, 480 [M-tBu+H]+. Intermediate 354D: To a stirred solution of intermediate 354C (680 mg, 1.18 mmol) in THF (20 mL) was added TBAF (1 M in THF) (2.35 mL, 2.35 mmol) and the reaction mixture was stirred under nitrogen for 14 h. The volatile component was removed under reduced pressure, water (50 mL) was added and the mixture was extracted with EtOAc (2 x 50 mL). The combined organic extract was washed with water (100 mL) and brine (100 mL), dried over sodium sulphate, filtered and volatiles were removed under reduced pressure. Residue obtained was purified by silica gel column chromatography (45% EtOAc in hexanes) to afford the title compound (520 mg). LCMS (Method-O): retention time 0.7 min, [M-Boc+H]+364.0Intermediate 354E: Intermediate 354E was prepared by using a similar synthetic procedure as that of intermediate 12B starting from intermediate 354D, 4-chloro-5-iodopyridazin-3(2H)-one and triphenylphosphine. LCMS (Method-O): retention time 1.03 min, [M-Boc+H]+601.8. Intermediate 354F: Intermediate 354F was prepared from intermediate 354E and 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole using a similar synthetic procedure as that of intermediate 12F. LCMS (Method-O): retention time 1.35 min, [M-Boc+H]+672.1. Intermediate 354G: Intermediate 354G was prepared by using a similar synthetic procedure as that of intermediate 12F starting from intermediate 354F and 2-(3-chloro-2-methylphenyl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane. LCMS (Method-O): retention time 1.37 min, [M-Boc+H]+718.2. Example 354: Example 354 was prepared by using a similar synthetic procedure as that of Example 12 starting from intermediate 354G.1H NMR (400 MHz, DMSO-d6) ppm13.59 (br s, 1H), 8.51 (br s, 1H), 8.31 (s, 2H), 7.72 (dd, J = 2.3, 8.5Hz, 1H),7.67 (d, J = 2.4Hz, 1H), 7.50 (dd, J = 1.1, 7.9 Hz, 1H), 7.39 - 7.28 (m, 2H), 7.23 (dd, J = 1.1, 7.6 Hz, 1H), 4.34 (d, J = 5.9 Hz, 2H), 4.19 (t, J = 6.8Hz, 2H), 4.12 - 3.89 (m, 4H), 3.57 - 3.49 (m, 2H), 2.24 (s, 3H), 2.13 - 1.98 (m, 2H). LCMS (Method-S): retention time 1.57 min, [M+H]+588.0. Examples given in the below table were prepared in a similar manner like Example 354 using appropriate substrates.Ret.Time Example Structure Name [M+H]+(min) and method 2-(3-((4-(azetidin-3- ylmethoxy)-3'-fluoro- 1.32 [1,1'-biphenyl]-3- 355 yl)sulfonyl)propyl)-4- 560 (Method chloro-5-(1H-pyrazol- S) 4-yl)pyridazin-3(2H)- one 2-(3-((4-(azetidin-3- ylmethoxy)-3'-fluoro- 2'-methyl-[1,1'- 1.44 356 biphenyl]-3- 572.1 (Method yl)sulfonyl)propyl)-4- chloro-5-(1H-pyrazol- S) 4-yl)pyridazin-3(2H)- one 2-(3-((4-(azetidin-3- ylmethoxy)-2',3'- dichloro-[1,1'- 1.52 358 biphenyl]-3- 608.0 (Method yl)sulfonyl)propyl)-4- chloro-5-(1H-pyrazol- S) 4-yl)pyridazin-3(2H)- one 2-(3-((4-(azetidin-3- ylmethoxy)-4'-chloro- 2'-fluoro-[1,1'- 1.49 359 biphenyl]-3- 592.1 (Method yl)sulfonyl)propyl)-4- chloro-5-(1H-pyrazol- S) 4-yl)pyridazin-3(2H)- one 2-(3-((4-(azetidin-3- ylmethoxy)-2'-chloro- 4'-fluoro-[1,1'- 1.44 360 biphenyl]-3- 592.1 (Method yl)sulfonyl)propyl)-4- chloro-5-(1H-pyrazol- S) 4-yl)pyridazin-3(2H)- one2-(3-((4-(azetidin-3- ylmethoxy)-3',4'- dichloro-[1,1'- 1.60 361 biphenyl]-3- 608.1 (Method yl)sulfonyl)propyl)-4- chloro-5-(1H-pyrazol- S) 4-yl)pyridazin-3(2H)- one 2-(3-((4-(azetidin-3- ylmethoxy)-3',4',5'- trifluoro-[1,1'- 1.46 362 biphenyl]-3- 594.0 (Method yl)sulfonyl)propyl)-4- chloro-5-(1H-pyrazol- S) 4-yl)pyridazin-3(2H)- one 2-(3-((4-(2- aminoethoxy)-3'- 1.68 fluoro-[1,1'-biphenyl]- 363 3-yl)sulfonyl)propyl)-4- 532.1 (Method chloro-5-(1H-pyrazol- M) 4-yl)pyridazin-3(2H)- one 2-(3-((4-(2- aminoethoxy)-2'- 1.30 chloro-4'-fluoro-[1,1'- 364 biphenyl]-3- 532.1 (Method yl)sulfonyl)propyl)-4- S) chloro-5-(1H-pyrrol-3- yl)pyridazin-3(2H)-one 2-(3-((4-(2- aminoethoxy)-3'- fluoro-2'-methyl-[1,1'- 1.23 365 biphenyl]-3- 546.2 (Method yl)sulfonyl)propyl)-4- chloro-5-(1H-pyrazol- R) 4-yl)pyridazin-3(2H)- one2-(3-((4-(2- aminoethoxy)-3'- chloro-2'-methyl-[1,1'- 1.53 366 biphenyl]-3- 562.0 (Method yl)sulfonyl)propyl)-4- chloro-5-(1H-pyrazol- S) 4-yl)pyridazin-3(2H)- one 2-(3-((4-(2- aminoethoxy)-2',3'- difluoro-[1,1'- 1.32 367 biphenyl]-3- 550.1 (Method yl)sulfonyl)propyl)-4- chloro-5-(1H-pyrazol- S) 4-yl)pyridazin-3(2H)- one 2-(3-((4-(2- aminoethoxy)-2'- chloro-4'-fluoro-[1,1'- 1.41 368 biphenyl]-3- 566.0 (Method yl)sulfonyl)propyl)-4- chloro-5-(1H-pyrazol- S) 4-yl)pyridazin-3(2H)- one 2-(3-((4-(2- aminoethoxy)-2',4'- dichloro-[1,1'- 1.37 369 biphenyl]-3- 582.1 (Method yl)sulfonyl)propyl)-4- chloro-5-(1H-pyrazol- R) 4-yl)pyridazin-3(2H)- one 2-(3-((4-(2- aminoethoxy)-3',4'- dichloro-[1,1'- 2.03 370 biphenyl]-3- 581.95 (Method yl)sulfonyl)propyl)-4- chloro-5-(1H-pyrazol- M) 4-yl)pyridazin-3(2H)- one2-(3-((4-(2- aminoethoxy)-3',4',5'- trifluoro-[1,1'- 1.85 371 biphenyl]-3- 568.05 (Method yl)sulfonyl)propyl)-4- chloro-5-(1H-pyrazol- M) 4-yl)pyridazin-3(2H)- one Example 372: (R)-2-(3-((4-((azetidin-3-ylmethyl)amino)-3'-fluoro-2'-methyl-[1,1'- biphenyl]-3-yl)sulfonyl)-2-methylpropyl)-4-chloro-5-(piperazin-1-yl)pyridazin-3(2H)-one Intermediate 372A: Ethylxanthic acid potassium salt (31.6 g, 197 mmol) was added into the stirring solution of sodium carbonate (20.92 g, 197 mmol) in water (100 mL) and the resulting reaction mixture was stirred at ambient temperature for 15 h. In another round bottom flask, to a stirred suspension of 5-bromo-2-fluoroaniline (25.0 g, 132 mmol) in water (100 mL) was added conc. HCl (100 mL, 3291 mmol) followed by sodium nitrite (13.62 g, 197 mmol) in water (10.0 mL) at 0oC and the resulting reaction mixture was stirred at 10 °C for 30 min. The freshly prepared diazonium salt was added to the first reaction mixture at 0 °C and stirred at RT for 1 h and at 55 °C for 1 h. The reaction mixture was cooled to ambient temperature, basified with 10% NaHCO3solution and extracted with ethylacetate (2 x 100 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulphate, and evaporated under reduced pressure to obtain the title compound (38 g).1H NMR (400 MHz, DMSO-d6) ppm 7.92 - 7.85 (m, 1H), 7.85 - 7.77 (m, 1H), 7.48 - 7.39 (m, 1H), 4.75 (q, J = 3.60 Hz, 2H), 1.24 (t, J = 5.20 Hz, 3H). Intermediate 372B: To a stirred solution of intermediate 372A (38 g, 129 mmol) in ethanol (100 mL) was added KOH (14.45 g, 257 mmol) and the resulting reaction mixture was heated at 90 °C for 16 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was diluted with water (40 mL), acidified with 5 N HCl solution and extracted with ethyl acetate (3 x 100 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep- 120 g, 25-30% EtOAc / n-hexane) to obtain the title compound (20 g).1H NMR (300 MHz, CDCl3) ppm 7.70 (dd, J = 2.30, 6.60 Hz, 2H), 7.39 (ddd, J = 2.50, 4.40, 8.70 Hz, 2H), 6.97 (t, J = 8.80 Hz, 2H). Intermediate 372C: Intermediate 372C was prepared by using a similar synthetic procedure as that of intermediate 235H starting from intermediate 372B and (R)-3-hydroxy-2-methylpropyl 4- methylbenzenesulfonate.1H NMR (400 MHz, DMSO-d6) ppm 7.58 (dd, J = 2.5, 6.50 Hz, 1H), 7.44 - 7.39 (m, 1H), 7.21 (t, J = 9.30 Hz, 1H), 4.68 (t, J = 5.30 Hz, 1H), 3.39 - 3.33 (m, 2H), 3.15 (dd, J = 5.50, 12.50 Hz, 1H), 2.79 (dd, J = 7.80, 12.80 Hz, 1H), 1.76 (dd, J = 6.80, 12.3Hz, 1H), 0.96 (d, J = 7.00 Hz, 3H). Intermediate 372D: Intermediate 372D was prepared by using a similar synthetic procedure as that of intermediate 12B starting from intermediate 372C, 4,5-dichloropyridazin-3(2H)-one, triphenylphosphine and DEAD. LCMS (Method M): retention time 3.72 min, [M+H]+425.8.Intermediate 372E: Intermediate 372E was prepared as a gummy liquid by using a similar synthetic protocol as that of intermediate 12D and starting from intermediate 372D and tert- butylpiperazine-1-carboxylate. LCMS (Method-O): retention time 2.22 min, [M+H]+575.2. Intermediate 372F: Intermediate 372F was prepared as a gummy liquid by using a similar synthetic protocol as that of intermediate 12C and starting from intermediate 372E and m-CPBA . LCMS (Method-O): retention time 1.84 min, [M+H]+607.2. Intermediate 372G: Intermediate 372G was prepared by using a similar synthetic procedure as that of intermediate 292D starting from intermediate 372F and tert-butyl 3- (aminomethyl)azetidine-1-carboxylate. LCMS (Method-O): retention time 1.14 min, [M- Boc+H]+673.3 Intermediate 372H: Intermediate 372H was prepared by using a similar synthetic procedure as that of intermediate 12F starting from intermediate 372G and (3-fluoro-2-methylphenyl)boronic acid. LCMS (Method-O): retention time 1.29 min, [M-Boc+H]+703.2. The compound was advanced to the subsequent step without further purification. Example 372: Example 372 was prepared by using a similar synthetic procedure as that of Example 12 starting from intermediate 372H.1H NMR (400 MHz, CD3OD) ppm 7.70 (s, 1H), 7.53 (s, 1H), 7.45 (br. d, J = 8.5Hz, 1H), 7.28 - 7.22 (m, 1H), 7.07 - 7.02 (m, 2H), 6.89 (d, J = 8.5Hz, 1H), 4.10 - 4.06 (m, 1H), 3.93 (dd, J = 5.5, 13.0 Hz, 1H), 3.84 (dt, J = 3.5, 8.3Hz, 1H), 3.60 - 3.53 (m, 1H), 3.48 - 3.36 (m, 8H), 3.29 - 3.07 (m, 2H), 2.95-2.90 (m, 4H), 2.60- 2.50 (m, 1H), 2.17 (s, 3H), 1.14 (d, J = 7.0 Hz, 3H). LCMS (Method M): retention time 1.49 min, [M+H]+603.3.Examples given in the below table are prepared in a similar manner like Example 372 using appropriate substrates. Ret. Time Example Structure Name [M+H]+(min) and method (R)-2-(3-((4-((azetidin-3- ylmethyl)amino)-2'- fluoro-[1,1'-biphenyl]-3- 1.13 373 yl)sulfonyl)-2- 589.3 methylpropyl)-4-chloro- (Method R) 5-(piperazin-1- yl)pyridazin-3(2H)-one H N (R)-2-(3-((4-((azetidin-3- Cl NH O N ylmethyl)amino)-3'- NHO Ofluoro-[1,1'-biphenyl]-3- 1.13 374S NN yl)sulfonyl)-2- 589.3 methylpropyl)-4-chloro- (Method R) 5-(piperazin-1- F yl)pyridazin-3(2H)-one (R)-2-(3-((4-((azetidin-3- ylmethyl)amino)-2'- chloro-[1,1'-biphenyl]-3- 1.35 375 yl)sulfonyl)-2- 605.2 methylpropyl)-4-chloro- (Method S) 5-(piperazin-1- yl)pyridazin-3(2H)-one (R)-2-(3-((4-((azetidin-3- ylmethyl)amino)-3'- chloro-[1,1'-biphenyl]-3- 1.36 376 yl)sulfonyl)-2- 605.2 methylpropyl)-4-chloro- (Method S) 5-(piperazin-1- yl)pyridazin-3(2H)-one (R)-2-(3-((4-((azetidin-3- ylmethyl)amino)-2'- (trifluoromethyl)-[1,1'- 1.26 377 biphenyl]-3-yl)sulfonyl)- 639.3 (Method R) 2-methylpropyl)-4- chloro-5-(piperazin-1- yl)pyridazin-3(2H)-one(R)-2-(3-((4-((azetidin-3- ylmethyl)amino)-3'- (trifluoromethyl)-[1,1'- 1.53 378 biphenyl]-3-yl)sulfonyl)- 639.2 2-methylpropyl)-4- (Method S) chloro-5-(piperazin-1- yl)pyridazin-3(2H)-one (R)-2-(3-((4-((azetidin-3- ylmethyl)amino)-2',3'- difluoro-[1,1'-biphenyl]- 1.32 379 3-yl)sulfonyl)-2- 607.2 methylpropyl)-4-chloro- (Method S) 5-(piperazin-1- yl)pyridazin-3(2H)-one (R)-2-(3-((4-((azetidin-3- ylmethyl)amino)-2',3'- dichloro-[1,1'-biphenyl]- 1.48 380 3-yl)sulfonyl)-2- 639.2 methylpropyl)-4-chloro- (Method S) 5-(piperazin-1- yl)pyridazin-3(2H)-one (R)-2-(3-((4-((azetidin-3- ylmethyl)amino)-3'- chloro-2'-methyl-[1,1'- 1.54 381 biphenyl]-3-yl)sulfonyl)- 619.2 2-methylpropyl)-4- (Method S) chloro-5-(piperazin-1- yl)pyridazin-3(2H)-one H N Cl NH (R)-2-(3-((4-((azetidin-3- O N ylmethyl)amino)-3'- NHO Ochloro-2'-fluoro-[1,1'- 1.25 382S NN biphenyl]-3-yl)sulfonyl)- 623.2 2-methylpropyl)-4- (Method R) F chloro-5-(piperazin-1- Cl yl)pyridazin-3(2H)-one(R)-2-(3-((4-((azetidin-3- ylmethyl)amino)-2'- chloro-4'-fluoro-[1,1'- 1.40 383 biphenyl]-3-yl)sulfonyl)- 623.2 2-methylpropyl)-4- (Method S) chloro-5-(piperazin-1- yl)pyridazin-3(2H)-one H N Cl NH (R)-2-(3-((4-((azetidin-3- O N NHO Oylmethyl)amino)-4'- SNchloro-2'-fluoro-[1,1'- 1.29 384 N biphenyl]-3-yl)sulfonyl)- 623.2 F 2-methylpropyl)-4- (Method R) chloro-5-(piperazin-1- yl)pyridazin-3(2H)-one Cl (R)-2-(3-((4-((azetidin-3- ylmethyl)amino)-2',4'- dichloro-[1,1'-biphenyl]- 1.51 385 3-yl)sulfonyl)-2- 639.3 methylpropyl)-4-chloro- (Method S) 5-(piperazin-1- yl)pyridazin-3(2H)-one (R)-2-(3-((4-((azetidin-3- ylmethyl)amino)-3',4'- difluoro-[1,1'-biphenyl]- 1.34 386 3-yl)sulfonyl)-2- 607.2 methylpropyl)-4-chloro- (Method S) 5-(piperazin-1- yl)pyridazin-3(2H)-one (R)-2-(3-((4-((azetidin-3- ylmethyl)amino)-4'- chloro-3'-fluoro-[1,1'- 1.41 387 biphenyl]-3-yl)sulfonyl)- 623.2 2-methylpropyl)-4- (Method S) chloro-5-(piperazin-1- yl)pyridazin-3(2H)-one(R)-2-(3-((4-((azetidin- 3-ylmethyl)amino)-3',4'- dichloro-[1,1'-biphenyl]- 1.50 388 3-yl)sulfonyl)-2- 639.3 methylpropyl)-4-chloro- (Method S) 5-(piperazin-1- yl)pyridazin-3(2H)-one (R)-2-(3-((4-((azetidin-3- ylmethyl)amino)-3',4',5'- trifluoro-[1,1'-biphenyl]- 1.26 389 3-yl)sulfonyl)-2- 625.2 methylpropyl)-4-chloro- (Method R) 5-(piperazin-1- yl)pyridazin-3(2H)-one 2-((R)-3-((4-((azetidin- 3-ylmethyl)amino)-3'- fluoro-2'-methyl-[1,1'- 1.26 390 biphenyl]-3-yl)sulfonyl)- 617.3 2-methylpropyl)-4- (Method R) chloro-5-((S)-3- methylpiperazin-1- yl)pyridazin-3(2H)-one 2-((R)-3-((4-((azetidin- 3-ylmethyl)amino)-3'- fluoro-2'-methyl-[1,1'- 1.24 391 biphenyl]-3-yl)sulfonyl)- 617.3 2-methylpropyl)-4- (Method R) chloro-5-((R)-3- methylpiperazin-1- yl)pyridazin-3(2H)-one 2-((R)-3-((4-((azetidin- 3-ylmethyl)amino)-3'- chloro-2'-methyl-[1,1'- 1.34 392 biphenyl]-3-yl)sulfonyl)- 633.3 2-methylpropyl)-4- (Method R) chloro-5-((R)-3- methylpiperazin-1- yl)pyridazin-3(2H)-one2-((R)-3-((4-((azetidin- 3-ylmethyl)amino)-2',3'- dichloro-[1,1'-biphenyl]- 1.31 393 3-yl)sulfonyl)-2- 653.3 methylpropyl)-4-chloro- (Method R) 5-((R)-3- methylpiperazin-1- yl)pyridazin-3(2H)-one 2-((R)-3-((4-((azetidin- 3-ylmethyl)amino)-3',4'- dichloro-[1,1'-biphenyl]- 1.37 394 3-yl)sulfonyl)-2- 653.2 methylpropyl)-4-chloro- (Method R) 5-((S)-3- methylpiperazin-1- yl)pyridazin-3(2H)-one 2-((R)-3-((4-((azetidin- 3-ylmethyl)amino)-3',4'- dichloro-[1,1'-biphenyl]- 1.35 395 3-yl)sulfonyl)-2- 653.3 methylpropyl)-4-chloro- (Method R) 5-((R)-3- methylpiperazin-1- yl)pyridazin-3(2H)-one 2-((R)-3-((4-((azetidin- 3-ylmethyl)amino)-2',4'- dichloro-[1,1'-biphenyl]- 1.38 396 3-yl)sulfonyl)-2- 653.2 methylpropyl)-4-chloro- (Method R) 5-((S)-3- methylpiperazin-1- yl)pyridazin-3(2H)-one 2-((R)-3-((4-((azetidin- 3-ylmethyl)amino)-2',4'- dichloro-[1,1'-biphenyl]- 1.36 397 3-yl)sulfonyl)-2- 653.2 methylpropyl)-4-chloro- (Method R) 5-((R)-3- methylpiperazin-1- yl)pyridazin-3(2H)-one2-((R)-3-((4-((azetidin- 3-ylmethyl)amino)-4'- chloro-2'-fluoro-[1,1'- 1.28 398 biphenyl]-3-yl)sulfonyl)- 637.3 2-methylpropyl)-4- (Method R) chloro-5-((R)-3- methylpiperazin-1- yl)pyridazin-3(2H)-one 2-((R)-3-((4-((azetidin- 3-ylmethyl)amino)-2'- chloro-4'-fluoro-[1,1'- 1.25 399 biphenyl]-3-yl)sulfonyl)- 637.3 2-methylpropyl)-4- (Method R) chloro-5-((R)-3- methylpiperazin-1- yl)pyridazin-3(2H)-one 2-((R)-3-((4-((azetidin- 3-ylmethyl)amino)-3'- fluoro-2'-methyl-[1,1'- 1.20 400 biphenyl]-3-yl)sulfonyl)- 617.3 2-methylpropyl)-4- (Method R) chloro-5-((R)-2- methylpiperazin-1- yl)pyridazin-3(2H)-one 2-((R)-3-((4-((azetidin- 3-ylmethyl)amino)-2',4'- dichloro-[1,1'-biphenyl]- 1.31 401 3-yl)sulfonyl)-2- 653.2 methylpropyl)-4-chloro- (Method R) 5-((R)-2- methylpiperazin-1- yl)pyridazin-3(2H)-one 2-((R)-3-((4-((azetidin- 3-ylmethyl)amino)-3',4'- dichloro-[1,1'-biphenyl]- 1.31 402 3-yl)sulfonyl)-2- 653.2 methylpropyl)-4-chloro- (Method R) 5-((R)-2- methylpiperazin-1- yl)pyridazin-3(2H)-one(R)-4-chloro-2-(3-((3'- fluoro-4-(((3- fluoroazetidin-3- yl)methyl)amino)-2'- 1.28 403 methyl-[1,1'-biphenyl]- 621.3 3-yl)sulfonyl)-2- (Method R) methylpropyl)-5- (piperazin-1- yl)pyridazin-3(2H)-one (R)-4-chloro-2-(3- ((2',3'-dichloro-4-(((3- fluoroazetidin-3- yl)methyl)amino)-[1,1'- 1.58 404 biphenyl]-3- 657.1 (Method S) yl)sulfonyl)-2- methylpropyl)-5- (piperazin-1- yl)pyridazin-3(2H)-one (R)-4-chloro-2-(3- ((2',4'-dichloro-4-(((3- fluoroazetidin-3- yl)methyl)amino)-[1,1'- 1.73 405 biphenyl]-3- 657.2 (Method M) yl)sulfonyl)-2- methylpropyl)-5- (piperazin-1- yl)pyridazin-3(2H)-one (R)-4-chloro-2-(3- ((3',4'-dichloro-4-(((3- fluoroazetidin-3- yl)methyl)amino)-[1,1'- 1.80 406 biphenyl]-3- 656.8 yl)sulfonyl)-2- (Method S) methylpropyl)-5- (piperazin-1- yl)pyridazin-3(2H)-one (R)-4-chloro-2-(3-((2'- chloro-4'-fluoro-4-(((3- fluoroazetidin-3- yl)methyl)amino)-[1,1'- 1.72 407 biphenyl]-3- 641.2 (Method R) yl)sulfonyl)-2- methylpropyl)-5- (piperazin-1- yl)pyridazin-3(2H)-one(R)-4-chloro-2-(3-((4'- chloro-3'-fluoro-4-(((3- fluoroazetidin-3- yl)methyl)amino)-[1,1'- 1.29 408 biphenyl]-3- 641.3 yl)sulfonyl)-2- (Method R) methylpropyl)-5- (piperazin-1- yl)pyridazin-3(2H)-one (R)-4-chloro-2-(3-((3'- fluoro-4-(((3- hydroxyazetidin-3- yl)methyl)amino)-2'- 1.36 409 methyl-[1,1'-biphenyl]-3- 619.2 yl)sulfonyl)-2- (Method R) methylpropyl)-5- (piperazin-1-yl)pyridazin- 3(2H)-one (R)-4-chloro-2-(3-((3'- chloro-4-(((3- hydroxyazetidin-3- yl)methyl)amino)-2'- 1.29 410 methyl-[1,1'-biphenyl]-3- 635.3 yl)sulfonyl)-2- (Method R) methylpropyl)-5- (piperazin-1-yl)pyridazin- 3(2H)-one (R)-4-chloro-2-(3-((2',3'- dichloro-4-(((3- hydroxyazetidin-3- 1.30 411 yl)methyl)amino)-[1,1'- 655.2 biphenyl]-3-yl)sulfonyl)- (Method R) 2-methylpropyl)-5- (piperazin-1-yl)pyridazin- 3(2H)-one (R)-4-chloro-2-(3-((3',4'- dichloro-4-(((3- hydroxyazetidin-3- 1.34 412 yl)methyl)amino)-[1,1'- 655.2 biphenyl]-3-yl)sulfonyl)- (Method R) 2-methylpropyl)-5- (piperazin-1-yl)pyridazin- 3(2H)-one(R)-4-chloro-2-(3-((2',4'- dichloro-4-(((3- hydroxyazetidin-3- 1.53 413 yl)methyl)amino)-[1,1'- 655.2 biphenyl]-3-yl)sulfonyl)- (Method S) 2-methylpropyl)-5- (piperazin-1-yl)pyridazin- 3(2H)-one (R)-4-chloro-2-(3-((2'- chloro-4'-fluoro-4-(((3- hydroxyazetidin-3- 1.36 414 yl)methyl)amino)-[1,1'- 639.1 biphenyl]-3-yl)sulfonyl)- (Method S) 2-methylpropyl)-5- (piperazin-1-yl)pyridazin- 3(2H)-one (R)-4-chloro-2-(3-((4'- chloro-3'-fluoro-4-(((3- hydroxyazetidin-3- 1.16 415 yl)methyl)amino)-[1,1'- 639.2 biphenyl]-3-yl)sulfonyl)- (Method R) 2-methylpropyl)-5- (piperazin-1-yl)pyridazin- 3(2H)-one (R)-4-chloro-2-(3-((3'- fluoro-2'-methyl-4- ((piperidin-4- 1.11 416 ylmethyl)amino)-[1,1'- 631.4 biphenyl]-3-yl)sulfonyl)- (Method R) 2-methylpropyl)-5- (piperazin-1-yl)pyridazin- 3(2H)-one (R)-4-chloro-2-(3-((3',4'- dichloro-4-((piperidin-4- ylmethyl)amino)-[1,1'- 1.44 417 biphenyl]-3-yl)sulfonyl)- 667.2 2-methylpropyl)-5- (Method R) (piperazin-1-yl)pyridazin- 3(2H)-one5-((R)-3-aminopyrrolidin- 1-yl)-2-((R)-3-((4- ((azetidin-3- ylmethyl)amino)-2'- 1.13 418 fluoro-[1,1'-biphenyl]-3- 589.2 yl)sulfonyl)-2- (Method R) methylpropyl)-4- chloropyridazin-3(2H)- one 5-((R)-3-aminopyrrolidin- 1-yl)-2-((R)-3-((4- ((azetidin-3- ylmethyl)amino)-2'- 1.27 419 (trifluoromethyl)-[1,1'- 639.3 biphenyl]-3-yl)sulfonyl)- (Method R) 2-methylpropyl)-4- chloropyridazin-3(2H)- one 5-((R)-3-aminopyrrolidin- 1-yl)-2-((R)-3-((4- ((azetidin-3- ylmethyl)amino)-3'- 1.09 420 fluoro-[1,1'-biphenyl]-3- 589.3 (Method R) yl)sulfonyl)-2- methylpropyl)-4- chloropyridazin-3(2H)- one 5-((R)-3-aminopyrrolidin- 1-yl)-2-((R)-3-((4- ((azetidin-3- ylmethyl)amino)-3'- 1.24 421 chloro-2'-fluoro-[1,1'- 623.2 biphenyl]-3-yl)sulfonyl)- (Method R) 2-methylpropyl)-4- chloropyridazin-3(2H)- one 5-((R)-3-aminopyrrolidin- 1-yl)-2-((R)-3-((4- ((azetidin-3- ylmethyl)amino)-3'- 1.21 422 fluoro-2'-methyl-[1,1'- 603.3 biphenyl]-3-yl)sulfonyl)- (Method R) 2-methylpropyl)-4- chloropyridazin-3(2H)- one5-((R)-3-aminopyrrolidin- 1-yl)-2-((R)-3-((4- ((azetidin-3- ylmethyl)amino)-2',3'- 1.28 423 dichloro-[1,1'-biphenyl]- 639.3 3-yl)sulfonyl)-2- (Method R) methylpropyl)-4- chloropyridazin-3(2H)- one 5-((R)-3-aminopyrrolidin- 1-yl)-2-((R)-3-((4- ((azetidin-3- ylmethyl)amino)-3'- 1.32 424 chloro-2'-methyl-[1,1'- 619.3 (Method R) biphenyl]-3-yl)sulfonyl)- 2-methylpropyl)-4- chloropyridazin-3(2H)- one 5-((R)-3-aminopyrrolidin- 1-yl)-2-((R)-3-((4- ((azetidin-3- ylmethyl)amino)-2'- 1.27 425 chloro-4'-fluoro-[1,1'- 623.2 (Method R) biphenyl]-3-yl)sulfonyl)- 2-methylpropyl)-4- chloropyridazin-3(2H)- one 5-((S)-3-aminopyrrolidin- 1-yl)-2-((R)-3-((4- ((azetidin-3- ylmethyl)amino)-2',4'- 1.64 426 dichloro-[1,1'-biphenyl]- 639.2 (Method S) 3-yl)sulfonyl)-2- methylpropyl)-4- chloropyridazin-3(2H)- one 5-(®-3-aminopyrrolidin- 1-yl)-2-(®-3-((4- ((azetidin-3- ylmethyl)amino)-2’,4’- 1.63 427 dichloro-[1,1’-biphenyl]- 639.2 3-yl)sulfonyl)-2- (Method S) methylpropyl)-4- chloropyridazin-3(2H)- one5-((R)-3-aminopyrrolidin- 1-yl)-2-((R)-3-((4- ((azetidin-3- ylmethyl)amino)-4'- 1.28 428 chloro-3'-fluoro-[1,1'- 623.2 biphenyl]-3-yl)sulfonyl)- (Method R) 2-methylpropyl)-4- chloropyridazin-3(2H)- one 5-((R)-3-aminopyrrolidin- 1-yl)-2-((R)-3-((4- ((azetidin-3- ylmethyl)amino)-3',4'- 1.32 429 dichloro-[1,1'-biphenyl]- 639.2 3-yl)sulfonyl)-2- (Method R) methylpropyl)-4- chloropyridazin-3(2H)- one 2-((R)-3-((4-((azetidin-3- ylmethyl)amino)-2',4'- dichloro-[1,1'-biphenyl]- 1.39 430 3-yl)sulfonyl)-2- 653.2 methylpropyl)-4-chloro- (Method R) 5-(3- (methylamino)pyrrolidin- 1-yl)pyridazin-3(2H)-one H NNH25-((R)-3-aminopiperidin- Cl 1-yl)-2-((R)-3-((4- NHO N OO((azetidin-3- S N N ylmethyl)amino)-2'- 1.44 431 chloro-4'-fluoro-[1,1'- 637.3 (Method S) Cl biphenyl]-3-yl)sulfonyl)- 2-methylpropyl)-4- chloropyridazin-3(2H)- F one 5-((3R,5R)-3-amino-5- fluoropiperidin-1-yl)-2- ((R)-3-((4-((azetidin-3- ylmethyl)amino)-3'- 1.37 432 chloro-2'-methyl-[1,1'- 651.4 biphenyl]-3-yl)sulfonyl)- (Method S) 2-methylpropyl)-4- chloropyridazin-3(2H)- one5-((3R,5R)-3-amino-5- fluoropiperidin-1-yl)-2- ((R)-3-((4-((azetidin-3- ylmethyl)amino)-2',3'- 1.33 433 dichloro-[1,1'-biphenyl]- 671.2 3-yl)sulfonyl)-2- (Method S) methylpropyl)-4- chloropyridazin-3(2H)- one 5-((3R,5R)-3-amino-5- fluoropiperidin-1-yl)-2- ((R)-3-((4-((azetidin-3- ylmethyl)amino)-3'- 1.26 434 fluoro-2'-methyl-[1,1'- 635.3 (Method R) biphenyl]-3-yl)sulfonyl)- 2-methylpropyl)-4- chloropyridazin-3(2H)- one 5-((3R,5R)-3-amino-5- fluoropiperidin-1-yl)-2- ((R)-3-((4-((azetidin-3- ylmethyl)amino)-2',4'- 1.68 435 dichloro-[1,1'-biphenyl]- 671.2 (Method S) 3-yl)sulfonyl)-2- methylpropyl)-4- chloropyridazin-3(2H)- one 5-((3R,5R)-3-amino-5- fluoropiperidin-1-yl)-2- ((R)-3-((4-((azetidin-3- ylmethyl)amino)-2'- 1.28 436 chloro-4'-fluoro-[1,1'- 655.4 biphenyl]-3-yl)sulfonyl)- (Method R) 2-methylpropyl)-4- chloropyridazin-3(2H)- one 5-((3R,5R)-3-amino-5- fluoropiperidin-1-yl)-2- ((R)-3-((4-((azetidin-3- ylmethyl)amino)-3',4'- 1.69 437 dichloro-[1,1'-biphenyl]- 671.2 3-yl)sulfonyl)-2- (Method S) methylpropyl)-4- chloropyridazin-3(2H)- one2-((R)-3-((4-((azetidin-3- ylmethyl)amino)-2'- chloro-4'-fluoro-[1,1'- 1.28 438 biphenyl]-3-yl)sulfonyl)- 663.4 2-methylpropyl)-4- (Method R) chloro-5-(octahydro-5H- pyrrolo[3,4-c]pyridin-5- yl)pyridazin-3(2H)-one 2-((R)-3-((4-((azetidin-3- ylmethyl)amino)-2'- chloro-4'-fluoro-[1,1'- 1.26 439 biphenyl]-3-yl)sulfonyl)- 663.4 2-methylpropyl)-4- (Method R) chloro-5-(octahydro-1H- pyrrolo[3,2-c]pyridin-1- yl)pyridazin-3(2H)-one H NHN (R)-2-(3-((4-((azetidin-3- Cl ylmethyl)amino)-2'- O N NH O S O N chloro-4'-fluoro-[1,1'- 1.2 440 N biphenyl]-3-yl)sulfonyl)- 2 649.4 2-methylpropyl)-4- (Method R) Cl chloro-5-(2,6- diazaspiro[3.4]octan-6- yl)pyridazin-3(2H)-one F (R)-2-(3-((4-((azetidin-3- ylmethyl)amino)-2'- chloro-4'-fluoro-[1,1'- 1.23 biphenyl]-3-yl)sulfonyl)- 441 635.3 2-methylpropyl)-4- (Method R) chloro-5-(2,6- diazaspiro[3.3]heptan-2- yl)pyridazin-3(2H)-one 5-((3-amino-2- fluoropropyl)amino)-2- ((R)-3-((4-((azetidin-3- ylmethyl)amino)-2'- 1.42 442 629.1 chloro-4'-fluoro-[1,1'- Method S) biphenyl]-3-yl)sulfonyl)- 2-methylpropyl)-4- chloropyridazin-3(2H)- one4-chloro-2-((R)-3-((3'- fluoro-2'-methyl-4-((((S)- pyrrolidin-3- 1.25 443 yl)methyl)amino)-[1,1'- 617.3 biphenyl]-3-yl)sulfonyl)- (Method R) 2-methylpropyl)-5- (piperazin-1-yl)pyridazin- 3(2H)-one 4-chloro-2-((R)-3-((2',3'- dichloro-4-((((S)- pyrrolidin-3- 1.32 444 yl)methyl)amino)-[1,1'- 653.3 biphenyl]-3-yl)sulfonyl)- (Method R) 2-methylpropyl)-5- (piperazin-1-yl)pyridazin- 3(2H)-one 4-chloro-2-((R)-3-((3',4'- dichloro-4-((((S)- pyrrolidin-3- 1.36 445 yl)methyl)amino)-[1,1'- 653.3 biphenyl]-3-yl)sulfonyl)- (Method R) 2-methylpropyl)-5- (piperazin-1-yl)pyridazin- 3(2H)-one NH Cl NH 4-chloro-2-((R)-3-((2'- O N chloro-4'-fluoro-4-((((S)- NH O O S N pyrrolidin-3- 446 N yl)methyl)amino)-[1,1'- 1.21 637.2 biphenyl]-3-yl)sulfonyl)- (Method R) Cl 2-methylpropyl)-5- (piperazin-1-yl)pyridazin- F 3(2H)-one NH Cl NH 4-chloro-2-((R)-3-((2',4'- O N dichloro-4-((((S)- NH O O S N pyrrolidin-3- 447 N yl)methyl)amino)-[1,1'- 1.37 653.3 biphenyl]-3-yl)sulfonyl)- (Method R) Cl 2-methylpropyl)-5- (piperazin-1-yl)pyridazin- Cl 3(2H)-one4-chloro-2-((2R)-3-((3'- fluoro-4-(((3- fluoropyrrolidin-3- yl)methyl)amino)-2'- 1.27 448 methyl-[1,1'-biphenyl]-3- 635.3 yl)sulfonyl)-2- (Method R) methylpropyl)-5- (piperazin-1-yl)pyridazin- 3(2H)-one 4-chloro-2-((2R)-3-((3'- fluoro-4-(((3- fluoropyrrolidin-3- yl)methyl)amino)-2'- 1.26 449 methyl-[1,1'-biphenyl]-3- 635.3 (Method R) yl)sulfonyl)-2- methylpropyl)-5- (piperazin-1-yl)pyridazin- 3(2H)-one 4-chloro-2-((2R)-3-((2',3'- dichloro-4-(((3- fluoropyrrolidin-3- 1.33 450 yl)methyl)amino)-[1,1'- 671.4 biphenyl]-3-yl)sulfonyl)- (Method R) 2-methylpropyl)-5- (piperazin-1-yl)pyridazin- 3(2H)-one 4-chloro-2-((2R)-3-((2',3'- dichloro-4-(((3- fluoropyrrolidin-3- 1.33 451 yl)methyl)amino)-[1,1'- 671.4 biphenyl]-3-yl)sulfonyl)- (Method R) 2-methylpropyl)-5- (piperazin-1-yl)pyridazin- 3(2H)-one (R)-2-(3-((4-((2- aminoethyl)amino)-2'- fluoro-[1,1'-biphenyl]-3- 1.09 452 yl)sulfonyl)-2- 563.3 methylpropyl)-4-chloro- (Method R) 5-(piperazin-1- yl)pyridazin-3(2H)-oneH2NCl NH (R)-2-(3-((4-((2- O N NHO Oaminoethyl)amino)-3'- SNfluoro-[1,1'-biphenyl]-3- 1.10 453 N yl)sulfonyl)-2- 563.2 (Method R) methylpropyl)-4-chloro- 5-(piperazin-1- F ...

Claims

What is claimed is:

1. A compound of formula (I): (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: is selected from the group consisting of , ,, , ,, , , , , , ,and ;--- is an optional bond; Q is selected from the group consisting of CH, CR5, and N;is selected from the group consisting of , ,and ; is a 6-membered heterocycle of the formula comprising one ortwo nitrogen atoms; X is selected from the group consisting of -S(=O)-, -S(=O)2-, and -S(=O)(=NH)-; R is selected from the group consisting of C2-4alkylene, C2-4alkenylene, and C3-4alkoxylene, each substituted with 1-4 R7; R1 is selected from the group consisting of halogen, CN, Ra -NRaRa, and –ORa; R2 is selected from the group consisting of –OR2a, –(CH2)n-NR2aR2a, –(CH2)n-3-10 membered carbocycle substituted with 1-4 of R2b, –(CH2)n-3-10 membered heterocycle substituted with 1-4 of R2b, -O-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R2b, -O-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R2b, -NR2a-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R2b, and -NR2a-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R2b; R2a, at each occurrence, is independently selected from the group consisting of H and a C1-6alkyl substituted with 0-4 Rc; R2b, at each occurrence, is independently selected from the group consisting of D, Ra, halogen, =O, CN, -NRaRa, -ORaS(=O)2NH2, C(=O)Ra, and C(=O)ORa; R3is selected from the group consisting of halogen, CN, Ra, and –ORa; R4is selected from the group consisting of H and =O; R5, at each occurrence, is independently selected from the group consisting of halogen, CN, C1-6alkyl substituted with 0-5 Rc, and –ORa; R6, at each occurrence, is independently selected from the group consisting of halogen, CN, R6a, -(CH2)nNR6aR6a, -(CH2)nOR6a, -(CH2)nCONR6aR6a, -(CH2)nNR6aCONR6aR6a, -(CH2)nNR6aCOR6a, -(CH2)nNR6aSO2R6a, -(CH2)nS(=O)2, -NR6a(CH2)1-3NR6aCOR6a, -NR6a(CH2)1-3NR6aCOOR6a, -O(CR6bR6b)1- 3O(CR6bR6b)1-3OR6a, –(CH2)n-3-10 membered carbocycle substituted with 1-4 of R6b, –(CH2)n-3-10 membered heterocycle substituted with 1-4 of R6b, -O-(CH2)n- 3-10 membered carbocycle substituted with 1-4 of R6b, -O-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R6b, -NR6a-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R6b, and -NR6a-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R6b; R6a, at each occurrence, is independently selected from the group consisting of H and a C1-6alkyl substituted with 0-5 Rc; R6b, at each occurrence, is independently selected from the group consisting of D, Ra, halogen, =O, CN, -NRaRa, -NRaCORa, -NRaCOORa, -ORa; R7, at each occurrence, is independently selected from the group consisting of =O, Ra and –ORa; or R7 and R7 together with the carbon atom to which they are both attached form a C3-6 cycloalkyl; Ra, at each occurrence, is independently selected from the group consisting of H and C1-6alkyl substituted with 0-5 Rc; Rc, at each occurrence, is independently selected from the group consisting of –OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, halogen, =O, CONH2, -COOH, and - COOC1-4alkyl; n is an integer of 0, 1, 2, 3, 4, or 5;provided is when is.

2. The compound of claim 1, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R is selected from the group consisting of -CHR7CR7CH2-, -CH2C(R7)2CH2-, and -CH2C(R7)2CH2O-; and R7is selected from the group consisting of H, CH3, CH2OH, and OH; or R7and R7together with the carbon atom to which they are both attached form a cyclopropyl.

3. The compound of claim 1, of formula (II): (II) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R1is selected from the group consisting of F, Cl, CN, Ra, and –ORa; R2is selected from the group consisting of halogen, –OR2a, –(CH2)n-NR2aR2a, –(CH2)n-3- 10 membered carbocycle substituted with 1-4 of R2b, –(CH2)n-3-10 membered heterocycle substituted with 1-4 of R2b, -O-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R2b, -O-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R2b, -NH-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R2b, and -NH-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R2b; R2a, at each occurrence, is independently selected from H and a C1-6alkyl substituted with 0-4 Rc; R2b, at each occurrence, is independently selected from the group consisting of D, Ra, halogen, =O, CN, -NRaRa, and -ORa; R3 is selected from the group consisting of halogen, CN, and Ra; R5, at each occurrence, is independently selected from the group consisting of halogen, CN, C1-4alkyl substituted with 0-4 Rc, and –ORa; R6, at each occurrence, is independently selected from halogen, CN, R6a, –OR6a, - O(CH2)n(O)n(CH2)nOR6a, -(CH2)nNR6aR6a, -(CH2)nOR6a, -(CH2)nCONR6aR6a, - (CH2)nNR6aCONR6aR6a, -(CH2)nNR6aCOR6a,-NH-(CH2)n-NR6aR6a, –(CH2)n-3-10 membered carbocycle substituted with 1-4 of R6b, –(CH2)n-3-10 membered heterocycle substituted with 1-4 of R6b, -O-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R6b, -O-(CH2)n-3-10 membered heterocycle substitutedwith 1-4 of R6b, -NH-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R6b, and -NH-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R6b; R6a, at each occurrence, is independently selected from H and a C1-6alkyl substituted with 0-3 Rc; R6b, at each occurrence, is independently selected from D, Ra, halogen, =O, CN, -NRaRa, and -ORa; R7, at each occurrence, is independently selected from the group consisting of Raand ORa; Ra, at each occurrence, is independently selected from the group consisting of H and C1-6alkyl substituted with 0-3 Rc; Rc, at each occurrence, is independently selected from the group consisting of –OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, halogen, =O, -COOH, and -COOC1-4 alkyl; and n is an integer of 0, 1, 2, or 3.

4. The compound of claim 3, of formula (III): (III) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from the group consisting of F, Cl, CN, and H; R2is selected from the group consisting of halogen, –OR2a, -NR2aR2a, –(CH2)n-3-10 membered carbocycle substituted with 1-4 of R2b, –(CH2)n-3-10 membered heterocycle substituted with 1-4 of R2b, -O-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R2b, -O-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R2b, -NH-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R2b, and -NH-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R2b;R2a, at each occurrence, is independently selected from H and C1-3alkyl substituted with 0-4 Rc; R2b, at each occurrence, is independently selected from the group consisting of D, Ra, and halogen; R3is selected from the group consisting of halogen, CN, and H; R5, at each occurrence, is independently selected from the group consisting of halogen, CN, C1-3alkyl substituted with 0-3 Rc, and -ORa; R6, at each occurrence, is independently selected from halogen, CN, R6a, –OR6a, - O(CH2)n(O)n(CH2)nOR6a, -(CH2)nNR6aR6a, -(CH2)nOR6a, -(CH2)nCONR6aR6a, - (CH2)nNR6aCONR6aR6a, -(CH2)nNR6aCOR6a,-NH-(CH2)n-NR6aR6a, –(CH2)n-3-10 membered carbocycle substituted with 1-4 of R6b, –(CH2)n-3-10 membered heterocycle substituted with 1-4 of R6b, -O-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R6b, -O-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R6b, -NH-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R6b, and -NH-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R6b; R6a, at each occurrence, is independently selected from H and a C1-6alkyl substituted with 0-3 Rc; R6b, at each occurrence, is independently selected from D, Ra, halogen, =O, CN, -NRaRa, and -ORa; R7is selected from the group consisting of H and CH3. Ra, at each occurrence, is independently selected from the group consisting of H and C1-6alkyl substituted with 0-3 Rc; Rc, at each occurrence, is independently selected from the group consisting of –OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, halogen, =O, -COOH, and -COOC1-4alkyl; and n is an integer of 0, 1, 2, 3, or 4.

5. The compound of claim 4, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R2 is selected from the group consisting of –OCH3, –NH-CH3, –NH-CH2CH3, and – N(CH3)2.

6. The compound of claim 4, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R2 is –(CH2)n-3-10 membered heterocycle substituted with 1-4 of R2b.

7. The compound of claim 4, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R2is selected from the group consisting of –O-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R2b, and –O-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R2b.

8. The compound of claim 4, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R2 is selected from the group consisting of –NH-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R2b, and –NH-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R2b.

9. The compound of claim 4, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R2is selected from the group consisting of –O(CH2)2-3NH2, –OCH3, –NH-CH3, –NH- CH2CH3, –N(CH3)2, , , , ,, , , , , ,, , , , , ,, , , ,, , , , , ,, , , , ,, , , , , ,, , , , ,, , ,, , , , ,, , , ,, , , , , and.

10. The compound of claim 4, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R3 is selected from the group consisting of F, Cl, CN, and H.

11. The compound of claim 4, or a stereoisomer, an enantiomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:R5, at each occurrence, is independently selected from the group consisting of F, Cl, CH3, CF3, -OCH3 and -OCF3.

12. The compound of claim 4, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R6, at each occurrence, is independently selected from the group consisting of F, H, -CH2- NH2, -CH2CH2-CO-NH2, -CH2-NH-CO-CH2, -CH2-NH-SO2-C(CH3)3, NH2, -NH- CH3, -NH-CH2-CO-NH2, -NH-CH(CH3)-CO-NH2, -NH-CH2-CH2-NH2, -NH- CH2CH2CH2-NH2, -NH-CH2CH2CH2CH2-NH2, -NH-CH2-CH(OH)-CH2-NH2, - NH-CH2-CH(CH3)-CH2-NH2, -NH-CH2-CH(F)-CH2-NH2, -NH-CH2CH2CH2-NH- CH3, -NH-CH2-C(CH3)2-CH2-NH2, -CH2CH2CH2-NH2, -NH-CH2-CH(CH3)-NH2, -NH-CH2-CH(F)-NH2, -NH-CH(CH3)-CH2-NH2, -NH-CH2-CHF-CH2-NH2, -NH- CH2-CF2-CH2-NH2, -NH-CH2CH2-CH(NH2)-COOH, -O-CH2CH2-NH2, -O- CH2CH2CH2-NH2, -O-CH2-CF2-CH2-NH2, -O-CH2CH2-OH, ,, , , , ,, , , , ,, , , ,, , , , ,, , , , ,, and .

13. The compound of claim 1, of formula (IV):(IV) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R2 is selected from the group consisting of 3-10 membered heterocycle substituted with 1-4 of R2b, -O-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R2b, -O- (CH2)n-3-10 membered heterocycle substituted with 1-4 of R2b, -NH-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R2b, and -NH-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R2b; R2a, at each occurrence, is independently selected from H and a C1-6alkyl substituted with 0-4 Rc; R2b, at each occurrence, is independently selected from the group consisting of D, Ra, halogen, =O, CN, -NRaRa, and -ORa; R3is selected from the group consisting of halogen and CN; R5, at each occurrence, is independently selected from the group consisting of halogen, CN, C1-4 alkyl, and –ORa; R6, at each occurrence, is independently selected from halogen, CN, R6a, –OR6a, - O(CH2)n(O)n(CH2)nOR6a, -(CH2)nNR6aR6a, -(CH2)nOR6a, -(CH2)nCONR6aR6a, - (CH2)nNR6aCONR6aR6a, -(CH2)nNR6aCOR6a,-NH-(CH2)n-NR6aR6a, –(CH2)n-3-10 membered carbocycle substituted with 1-4 of R6b, –(CH2)n-3-10 membered heterocycle substituted with 1-4 of R6b, -O-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R6b, -O-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R6b, -NH-(CH2)n-3-10 membered carbocycle substituted with 1-4 of R6b, and -NH-(CH2)n-3-10 membered heterocycle substituted with 1-4 of R6b; R6a, at each occurrence, is independently selected from H and a C1-6alkyl substituted with 0-3 Rc; R6b, at each occurrence, is independently selected from D, Ra, halogen, =O, CN, -NRaRa, and -ORa;R7 is selected from the group consisting of H and CH3; Ra, at each occurrence, is independently selected from the group consisting of H and C1-6alkyl substituted with 0-3 Rc; Rc, at each occurrence, is independently selected from the group consisting of –OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, halogen, =O, -COOH, and -COOC1-4alkyl; and n is an integer of 0, 1, 2, 3, or 4.

14. The compound of claim 12 or 13, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is Cl; R2 is selected from the group consisting of –NH-CH3, , ,, and ;R5, at each occurrence, is independently selected from the group consisting of F, Cl, and CH3; R6, at each occurrence, is independently selected from the group consisting of – O(CH2)2-3NH2, -NH-CH2-CH2-NH2, -NH-CH2-CH(CH3)-NH2, -NH-CH2-CH(F)-NH2, - NH-CH2-CH(F)-CH2-NH2, -O-CH2CH2-OH, , , ,, , , and ; andR7, at each occurrence, is independently selected from the group consisting of H and CH3.

15. The compound of claim 1, of formula (V):ĨV) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: is selected from the group consisting of ,, , ,, , , , and , ; R1 is Cl;R2 is selected from the group consisting of –NH-CH3, , ,, and ;R5, at each occurrence, is independently selected from the group consisting of F, Cl, and CH3; and R7 is selected from the group consisting of H and CH3.

16. The compound of claim 1, of formula (VI): R1R2(R6)1-4OR7C S R O3R4(R5)1-4(VI) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: is selected from the group consisting of and ; R1 is selected from the group consisting of halogen, CN, Ra and –ORa;R2 is selected from the group consisting of , ,, , , and ;R5, at each occurrence, is independently selected from the group consisting of halogen and C1-3alkyl substituted with 0-3 Rc; Ra, at each occurrence, is independently selected from the group consisting of H and C1-4alkyl substituted with 0-3 Rc; R6, at each occurrence, is independently selected from the group consisting of H, F, -NH- CH2-CH2-NH2, and ; and R7is selected from the group consisting of H and CH3.

17. The compound of claim 1, of formula (VII): (VII) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R1is selected from the group consisting of halogen, CN, Raand –ORa; R2 is selected from the group consisting of , ,, , , and ;R5, at each occurrence, is independently selected from the group consisting of halogen and C1-4 alkyl substituted with 0-3 Rc;Ra, at each occurrence, is independently selected from the group consisting of H and C1-4 alkyl substituted with 0-5 Rc; R6, at each occurrence, is independently selected from the group consisting of H, F, -NH- CH2-CH2-NH2, and ; and R7 is selected from the group consisting of H and CH3.

18. The compound of claim 1, of formula (VIII): (VIII) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of , , and ; R1 is selected from the group consisting of halogen, CN, Ra, and –ORa;R2 is selected from the group consisting of , . ,, , , , and ;R5, at each occurrence, is independently selected from the group consisting of halogen and C1-3alkyl substituted with 0-3 Rc; R3 is H and C1-3alkyl; Ra, at each occurrence, is independently selected from the group consisting of H and C1-4alkyl substituted with 0-5 Rc; and R6, at each occurrence, is independently selected from the group consisting of H, F, -NH- CH2-CH2-NH2, and ; and R7 is selected from the group consisting of H and CH3.

19. The compound of claim 1, of formula (IX): (IX) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R2is 3-10 membered heterocycle substituted with 1-4 of R2b; R2b, at each occurrence, is independently selected from the group consisting of D, Ra, halogen, =O, CN, -NRaRa, and -ORa; R5, at each occurrence, is independently selected from the group consisting of halogen, CN, C1-4 alkyl, and –ORa; R6, at each occurrence, is independently selected from -CH2NR6aR6a; R6a, at each occurrence, is independently selected from H and a C1-6alkyl substituted with 0-3 Rc; R7, at each occurrence, is selected from the group consisting of H and CH3; Ra, at each occurrence, is independently selected from the group consisting of H and C1-6alkyl substituted with 0-3 Rc; and Rc, at each occurrence, is independently selected from the group consisting of –OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, halogen, =O, -COOH, and -COOC1-4 alkyl.

20. The compound of claim 1, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, selected from the exemplified compounds.

21. A pharmaceutical composition comprising a compound of any one of the claims 1-20, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

22. A method for treating a disease or a disorder associated with PAD4 enzyme activity, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one compound of any one of the claims 1-20, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

23. Use of a compound of any one of claims 1-20, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or a disorder associated with PAD4 enzyme activity.

24. The method of claim 22 or the use of claim 23, wherein the disease or the disorder associated with PAD4 enzyme activity is selected from rheumatoid arthritis, Alzheimer’s disease, multiple sclerosis, lupus, Parkinson’s disease, and cancer.

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