Plpro inhibitors and methods of using the same

Abstract

Disclosed herein is a library of SARS-CoV-2 PLpro inhibitors. The compounds described herein represent potent inhibitors of PLpro with activity translating to live virus assays in mammalian and human host cells. Also provided herein are methods of using the PLpro inhibitors for preventing or treating infections, diseases, and / or symptoms caused by exposure to a coronavirus, such as SARS-CoV-2, SARS-CoV-1, and MERS in a subject in need thereof.

Description

PLPRO INHIBITORS AND METHODS OF USING THE SAMECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U. S. Provisional Application No. 63 / 789,206 filed April 15, 2025, which is herein incorporated by reference in its entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0002] This invention was made with government support under Grant No. AI168165 awarded by the National Institutes of Health. The government has certain rights in the invention.TECHNICAL FIELD

[0003] The invention is generally in the field of SARS-CoV-2 PLpro inhibitors and methods of use thereof.BACKGROUND

[0004] The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused profound socioeconomic challenges for humankind. While most countries have taken strict measures to combat the virus, there were at least 150 million cases and 3 million deaths worldwide as of April 31st, 2021. Many patients recovering from severe COVID-19 infections have been shown to face a higher risk of long-term effects in the respiratory system. The pandemic is particularly detrimental to members of those social groups in the most vulnerable situations. In the USA, fatality rates showed a strong correlation with known health disparities, for example, for African Americans in Chicago and Detroit. COVID- 19 has also significantly undermined the economy. According to the IMF’s latest World Economic Outlook, the recession caused by the pandemic is the deepest since the end of WWII, with a 3.5% output contraction in 2020, and the pathway to recovery may take many years. Furthermore, the combined health and economic impacts have negatively affected many people's mental health with increased stress and anxiety, which could persist for a long tern, even when the pandemic significantly subsides.

[0005] PLpro is a promising antiviral target, but discovery of potent PLpro inhibitors is a challenge because of featureless Pl and P2 recognition sites.-1- 45844530.1BRIEF DESCRIPTION OF THE DRAWINGS

[0006] FIG. 1 is a graph showing the activity of SARS-CoV-2 in A549 ace2 / TMPDRSS2 cells of PLpro inhibitors in vitro.

[0007] FIG. 2A. is a dose-response curves of furafylline against CYP1 A2. FIG. 2B. is a dose-response curves of tranylcypromine against CYP2A6. FIG. 2C. is a dose-response curves of ketoconazole against CYP2B6. FIG. 2D is a dose-response curve of quercetin against CYP2C8. FIG. 2E is a dose-response curve of sulfaphenazole against CYP2C9. FIG. 2F is a dose-response curve of SUN-084 against CYP1 A2. FIG. 2G is a dose-response curve of SUN-084 against CYP2A6. FIG. 2H is a dose-response curve of SUN-084 against CYP2B6. FIG. 21 is a dose-response curve of SUN-084 against CYP2C8. FIG. 2J is a dose-response curve of SUN-084 against CYP2C9. FIG. 2K is a dose-response curve of Tranylcypromine against CYP2C19. FIG. 2L is a dose-response curve of quinidine against CYP2D6. FIG. 2M is a doseresponse curve of quercetin against CYP2E 1. FIG. 2N is a dose-response curve of ketoconazole against CYP3A4-M. FIG. 20 is a dose-response curve of 3A4-T-ketoconazole against CYP3A4-T. FIG. 2P is a dose-response curve of SUN-084 against CYP2C19. FIG. 2Q is a dose-response curve of SUN-084 against CYP2D6. FIG. 2R is a dose-response curve of SUN-084 against CYP2E1. FIG. 2S is a dose-response curve of SUN-084 against CYP3A4-M. FIG.2T is a dose-response curve of SUN-084 against CYP3A4-T.

[0008] FIG. 3 is a plasma concentration vs time profile for SUN-084 after 10 mg / kg PO in C57BL / 6J mouse

[0009] FIG. 4 is a mean plasma concentration vs time profile for SUN-084 10 mg / kg PO in C57BL / 6J mouse.

[0010] FIG. 5 is a plasma concentration vs time profile for SUN-084 after 1 mg / kg IV in SD Rat.

[0011] FIG. 6 is a plasma concentration vs time profile for SUN-084 after 10 mg / kg PO in SD Rat.

[0012] FIG. 7 is a plasma concentration vs time profile for SUN-084 after 1 mg / kg IV; 10 mg / kg PO in SD Rat.

[0013] FIG. 8 is a bar graph showing the viral titer data of mouse efficacy study at 50mg / Kg, 100 mg / kg, 150mg / kg dose.

[0014] FIG. 9 is a table showing the Human Liver Microsomes stability of SUN-084 with NADPH.-2- 45844530.1

[0015] FIG. 10 is a table showing the Human Liver Microsomes stability with NADPH and UDPGA.

[0016] FIG. 11 is a table showing the Metabolic Stability of SUN-084 in Human Hepatocytes at 1 LIM.

[0017] FIG. 12 is a table showing the protein binding results of SUN-084 in mouse plasma.

[0018] FIG. 13 is a table showing the protein binding results of SUN-084 in rat plasma.

[0019] FIG. 14 is a table showing the protein binding results of SUN-084 in human plasma.

[0020] FIG. 15 is a table showing the PO dose of 10 mg / kg of SUN-084 in C57BL / 6J mouse.

[0021] FIG. 16 is a table showing the summary of SUN-084 PO pharmacokinetic parameters.

[0022] FIG. 17 is a table showing the IV Dose of 1 mg / kg of SUN-084 in SD rat.

[0023] FIG. 18 is a table showing the summary of pharmacokinetic parameters (IV Dose 10 mg / kg) in SD rat.

[0024] FIG. 19 is a table showing the PO dose of 10 mg / kg of SUN-084 in SD rat.

[0025] FIG. 20 is a table showing the summary of pharmacokinetic parameters (PO Dose 10 mg / kg) in SD rat.

[0026] FIG. 21 is a table showing the SUN-084 PO (BID 1.5 days) Lung / Plasma ratio pharmacokinetic profile in C57BL / 6J mouse.

[0027] FIG. 22A is a table showing the biological assays for representative compounds SUN-052, SUN-053, SUN-054, SUN-055, SUN-058, SUN-067, SUN-061, SUN-062, SUN-059, and SUN-078. FIG. 22B is a table showing the biological assays for representative compounds SUN-081, SUSN-082, SUN-083, SUN-120, SUN-084, SC1-257, SC1-258, SC1-283, SC1-284, and SC1-285. FIG. 22C is a table showing the biological assays for representative compounds SC1-298, SC1-300, ID-5-4, SC2-072, SC2-055, SC2-009, SC2-090, SC2-087, and SC2-091. FIG. 22D is a table showing the biological assays for representative compounds SC2-040, SC2-133, SC2-142. SC2-144, MR-1-060, MR-I-061, MR-1-081, MR-1-062, MR- 1-115, MR- 1-116, and MR-1-103. FIG. 22Eis a table showing the biological assays for representative compounds MR-1-105, ID-5-71, MR-1-122, MR-1-131, and MR- 1-155.-3- 45844530.1DETAILED DESCRIPTION

[0028] Provided herein is a library of SARS-CoV-2 PLpro inhibitors, designed and synthesized utilizing a structure-based drug design approach. The studies described herein led to the identification of exemplary compounds with low nanomolar potency against SARS-CoV-2 PLpro as well as co-crystal structures of a number of the disclosed inhibitors with SARS-CoV-2 PLpro. Overall, structure-based optimization led to PLpro inhibitors with increased metabolic stability, low nanomolar potency against PLpro enzyme activity, a relatively slow dissociation rate, and low micromolar potency against infectious SARS-CoV-2. The compounds described herein represent potent inhibitors of PLpro with activity translating to live virus assays in mammalian and human host cells.

[0029] Also provided herein are methods of using the PLpro inhibitors for preventing or treating infections, diseases, and / or symptoms caused by exposure to a coronavirus, such as SARS-CoV-2, SARS-CoV-1, and MERS in a subject in need thereof.

[0030] The following description of the invention is merely intended to illustrate various embodiments of the invention. As such, the specific modifications discussed are not to be construed as limitations on the scope of the invention. It will be apparent to one skilled in the art that various equivalents, changes, and modifications may be made without departing from the scope of the invention, and it is understood that such equivalent embodiments are to be included herein.Definitions

[0031] Terms used herein may be preceded and / or followed by a single dash, or a double dash, “=“, to indicate the bond order of the bond between the named substituent and its parent moiety; a single dash indicates a single bond and a double dash indicates a double bond. In the absence of a single or double dash it is understood that a single bond is formed between the substituent and its parent moiety; further, substituents are intended to be read “left to right” unless a dash indicates otherwise. For example, Ci-Ce alkoxycarbonyloxy and -OC(O)Ci-Ce alkyl indicate the same functionality; similarly, arylalkyl and -alkylaryl indicate the same functionality.

[0032] The term “alkyl” refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms unless otherwise specified. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3--4- 45844530.1dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. When an “alkyl” group is a linking group between two other moieties, then it may also be a straight or branched chain; examples include, but are not limited to -CH2-, -CH2CH2-, -CH2CH2CHC(CH3)-, and -CH2CH(CH2CH3)CH2-.

[0033] The term “cycloalkyl” refers to a monocyclic or a bicyclic cycloalkyl ring system, having a branched or unbranched group containing 3 or more carbon atoms where one or more of the rings does not have a completely conjugated pi-electron system, and may further be substituted or unsubstituted. Monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups can be saturated or unsaturated, but not aromatic. In certain embodiments, cycloalkyl groups are fully saturated. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems are bridged monocyclic rings or fused bicyclic rings. Bridged monocyclic rings contain a monocyclic cycloalkyl ring where two non-adjacent carbon atoms ofthe monocyclic ring are linked by an alkylene bridge of between one and three additional carbonatoms (z.e., a bridging group of the form -(CH2)W-, where w is 1, 2, or 3). Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octanc, bicyclo[3.2.2]nonanc, bicyclo[3.3.1]nonanc, and bicyclo[4.2.1]nonanc. Fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclicheterocyclyl, or a monocyclic heteroaryl. The bridged or fused bicyclic cycloalkyl is attached tothe parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. Cycloalkyl groups are optionally substituted with one or two groups which are independently oxo or thio. In certain embodiments, the fused bicyclic cycloalkyl is a 5 or 6 membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted by one or two groups which are independently oxoor thio. In certain embodiments of the disclosure, the cycloalkyl is cyclopentyl, cyclohexyl, or cycloheptyl.

[0034] Whenever a numerical range; e.g., "1-10" or “C1-C10”, is stated herein, it implies that the group, in this case the alkyl group, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. In some embodiments, the alkyl is a lower alkyl, including 1-6 or 1-4 carbon atoms. An alkyl can be substituted or unsubstituted.-5- 45844530.1When substituted, the substituent can be, for example, an alkyl (fomiing a branched alkyl), an alkenyl, an alkynyl, a cycloalkyl, an aryl, a heteroaryl, a halo, a hydroxy, an alkoxy and a hydroxyalkyl as these terms are defined hereinbelow. The term "alkyl", as used herein, also encompasses saturated or unsaturated hydrocarbon, hence this term further encompasses alkenyl and alkynyl.

[0035] The term "alkenyl" refers to a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon double bond, e.g., allyl, vinyl, 3-butenyl, 2-butenyl, 2-hexenyl and i-propenyl. The alkenyl may be substituted or unsubstituted by one or more substituents, as described hereinabove.

[0036] The term “alkynyl” refers to a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representativeexamples of alkynyl include, but are not limited, to ethynyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl. In one embodiment the alkynyl is ethynyl. The alkynyl may be substituted or unsubstituted by one or more substituents, as described hereinabove.

[0037] The term “alkoxy” refers an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0038] The terms “cyano” and “nitrile” refer to a -CN group.

[0039] The term "halo" or “halogen” refers to F, Cl, Br and I atoms as substituents.

[0040] The term “haloalkyl” refers to the present of at least one halogen appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2- chloro-3-fluoropentyl. In certain embodiments, each “haloalkyl” is a fluoroalkyl, for example, apolyfluoroalkyl such as a substantially perfluorinated alkyl.

[0041] The term "aryl" describes an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. The aryl group may be substituted or unsubstituted by one or more substituents, as described hereinabove.

[0042] The term "heteroaryl" describes a monocyclic or fused ring i.e., rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms, such as, for -6- 45844530.1example, nitrogen, oxygen and sulfur and, in addition, having a completely conjugated pi-electron system. Examples, without limitation, of heteroaryl groups include pyrrole, furane, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline and purine. The heteroaryl group may be substituted or unsubstituted by one or more substituents, as described hereinabove. Representative examples are thiadiazole, pyridine, pyrrole, oxazole, indole, purine and the like.

[0043] The term “pharmaceutically acceptable salts" refers to salts or zwitterionic forms of the present compounds. Salts of the present compounds can be prepared during the final isolation and purification of the compounds or separately by reacting the compound with an acid having a suitable cation. The pharmaceutically acceptable salts of the present compounds can be acid addition salts formed with pharmaceutically acceptable acids. Examples of acids which can be employed to form pharmaceutically acceptable salts include inorganic acids such as nitric, boric, hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, tartaric, and citric. Nonlimiting examples of salts of compounds of the disclosure include, but are not limited to, the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethansulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerolphosphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, naphthylenesulfonate, nicotinate, 2- naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, paratoluenesulfonate, undecanoate, lactate, citrate, tartrate, gluconate, methanesulfonate, ethanedisulfonate, benzene sulphonate, and p-toluenesulfonate salts. In addition, available aminogroups present in the compounds of the disclosure can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; and benzyl and phenethyl bromides.

[0044] The term “subject” refers to a mammalian subject, preferably a human. A “subject in need thereof’ refers to a subject who has been infected with a coronavirus, has been diagnosed of a disease caused by a coronavirus, or is at an increased risk of infection or developing a severe illness caused by a coronavirus. The phrases “subject” and “patient” are used interchangeably herein.-7- 45844530.1

[0045] The term “treatment” in relation a given disease, disorder or viral infection, includes, but is not limited to, inhibiting the disease, disorder or viral infection, for example, arresting the development of the disease, disorder, or viral infection; relieving the disease, disorder, or viral infection for example, causing regression of the disease, disorder, or viral infection; or relieving a condition caused by or resulting from the disease, disorder, or viral infection for example, relieving or treating symptoms of the disease, disorder, or viral infection. The term “prevention” in relation to a given disease, disorder, or viral infection means: preventing the onset of disease, disorder, or viral infection development if none had occurred, preventing the disease, disorder, or viral infection from occurring in a subject that may be predisposed to the disorder, disease, or viral infection but has not yet been diagnosed as having the disorder, disease, or viral infection and / or preventing further disease / disorder / infection development if already present. In certain embodiments, treatment or prevention of a viral infection is measured or determined by reducing the viral load in a subject infected with a virus.

[0046] The term “therapeutically effective amount” refers to an amount that produces a desired effect in a subject for treating and / or preventing a condition, e.g., a therapeutic effect. In certain embodiments, the therapeutically effective amount is an amount that yields maximum therapeutic effect. In other embodiments, the therapeutically effective amount yields a therapeutic effect that is less than the maximum therapeutic effect. For example, a therapeutically effective amount may be an amount that produces a therapeutic effect while avoiding one or more side effects associated with a dosage that yields maximum therapeutic effect. A therapeutically effective amount for a particular composition will vary based on a variety of factors, including, but not limited to, the characteristics of the therapeutic composition (e.g., activity, pharmacokinetics, pharmacodynamics, and bioavailability), the physiological condition of the subject (e.g., age, body weight, sex, disease type and stage, medical history, general physical condition, responsiveness to a given dosage, and other present medications), the nature of any pharmaceutically acceptable carriers, excipients, and preservatives in the composition, and the route of administration. One skilled in the clinical and pharmacological arts will be able to determine a therapeutically effective amount through routine experimentation, namely, by monitoring a subject’s response to administration of the composition and adjusting the dosage accordingly. For additional guidance, see, for example, Remington: The Science and Practice of Pharmacy, 22nd ed., Pharmaceutical Press, Rondon, 2012, and Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12th ed., McGraw-Hill, New York, NY, 2011, the entire disclosures of which are incorporated by reference herein.-8- 45844530.1Compounds

[0047] In certain embodiments, compounds of the present disclosure include, without limitation, compounds of Formula I:

[0048] In some embodiments, the PLpro inhibitors can have the structure of Formula la or lb:Formula la Formula lb or a pharmaceutically acceptable sale thereof, wherein:• Ar is selected from aryl, heteroaryl, heterocyclyl, cycloalkyl, and cycloalkenyl, wherein the Ar (i.e., aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl) can be substituted with 1, 2, 3, 4, or 5 Rdgroups;• X is independently selected from — H, — CH3, — Ci-Ce alkyl, — (Ci-Ce alkylenyl)NRaRb, — (Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb— (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalky lenyl)Rc;• Y1-Y3 are independently — N or — CR’, and R’ is H or halogen;• Ri is independently selected from — H, — NH2, — CH3, — Ci-Ce alkyl, — heterocyclyl, — (Ci-C6alkylenyl)NRaRb, — ORa, — (Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRh, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb, — (Ci-Ce alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc, — (Ci-Ce alkylenyl)RcRc’, and — Ci-Ce alkyl, — C4-C10 heterocyclyl, — CO heterocyclyl, aryl, a sulfur-containing heteroaryl, an oxygen-containing heteroaryl, or a nitrogen-containing heteroaryl, wherein any said 4-10 membered heterocyclyl optionally contains one, two or three nitrogen, and wherein each aryl, heterocyclyl, or heteroaryl (e.g., — C4-C10 heterocyclyl, — CO heterocyclyl, aryl, sulfur-containing heteroaryl, oxygen-containing -9- 45844530.1heteroaryl, or nitrogen-containing heteroaryl) may be substituted with 1, 2, or 3 substituents independently selected from halogen, — CN, — (Ci-Ce alkylenyl)NRaRb, — ORa, — (Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRb, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb, — (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc, — (Ci-Ce alkylenyl)RcRc, heterocyclyl, or — CO heterocyclyl;• R2and R3 are each independently selected from the group of — H and — C1-C4 alkyl, — C1-C4 aminoalkyl and — C1-C4 alkoxy-Cl-C4 alkyl, or alternatively R2and R3 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl optionally substituted by a 4-8 membered heterocycloalkyl;

[0049] wherein each occurrence of Rdcan be independently selected from the following:• — H, — C4-C10 heterocyclyl, — C(O)heterocyclyl, — N(Ra)heterocyclyl, — C(Ra)heterocyclyl, — O — heterocyclyl, wherein any said 4-10 membered heterocyclyl optionally contains one, two or three nitrogen or oxygen; wherein aryl, a sulfur- containing heteroaryl, an oxygen-containing heteroaryl, or a nitrogen-containing heteroaryl, each of which may be substituted with 1, 2, or 3 substituents independently selected from halogen, — CN, — (Ci-C6alkylenyl)NRaRb, — ORa, — (Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRb, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb, — (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc, — (Ci-Ce alkylenyl)RcRc. — CO heterocyclyl; or• — Ci-Ce heteroaryl, — CO heteroaryl, wherein it can be optionally substituted with 1, 2, 3, 4, or 5 Regroups; — Ci-Ce alkyl, — C2-Ce alkenyl, — C2-Ce alkynyl, halogen, Ci- Ce haloalkyl, — CN, — NO2, — ORe, — S(O)2NReRf, — C(O)Re, — C(O)NReRf, — NReRf, — N(Re)C(O)Rf, — (Ci-C6alkylenyl)-ORe, — (Ci-C6alkylenyl)-C(O)NReRf, — (Ci-C6alkylenyl)-NReRf, or — (Ci-C6alkylenyl)-N(Re)C(O)Rf;

[0050] wherein each occurrence of Raand Rbcan be independently selected from the following:• — H, — Ci-Ce alkenyl, — Ci-Ce alkynyl, — Ci-Ce haloalkyl, — Rc, heterocyclyl, or — Ci-Ce alkyl, wherein the — Ci-Ce alkyl can be substituted with a substituent selected from — ORe, — NReRf, — C(O)ORe, — C(O)NReRf, — S(O)2Re, — S(O)2NReRf, and — Rc;

[0051] wherein each occurrence of Rcand Rccan be independently selected from the following:-10- 45844530.1• aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl, wherein each Rcgroup may be substituted with 1, 2, 3, 4, or 5 Rdgroups; and

[0052] wherein each occurrence of Reand Rfcan be independently selected from the following:• — H, halogen, — CN, — Ci-Ce alkyl, — Ci-Cg cycloalkyl, aryl, heteroaryl or — Ci-Ce haloalkyl

[0053] In some forms, Ri can be any one of the following:

[0054] In other embodiments, compounds of the present disclosure include, without limitation, compounds of Formula II:Formula II-11- 45844530.1or a pharmaceutically acceptable salt thereof, wherein all X, Y and R groups and subgroups (e.g., Y1-Y7, R1-R20, Ra-Rg, R’, etc.) are each independently selected from those disclosed in Formula I above or as additionally indicated below:• Y i-Ye are independently — N or — CR’, and R’ is H or halogen;• R4, Rs, Re, R7, and Rs can each be independently selected from — H, — C4-C10 heterocyclyl, — heteroaryl, — C(O)heterocyclyl, — N(Ra)heterocyclyl, — C(Ra)heterocyclyl, — O-heterocyclyl, — C(O)heteroaryl, — N(Ra)heteroaryl, — C(Ra)heteroaryl, — O-heteroaryl, aryl, a sulfur-containing heteroaryl, an oxygencontaining heteroaryl, or a nitrogen-containing heteroaryl, wherein any said 4-10 membered heterocycle optionally contains one, two or three nitrogen or oxygen, and wherein each aryl, heterocyclyl, or heteroaryl (e.g., — C4-C10 heterocyclyl, — CO heterocyclyl, aryl, sulfur-containing heteroaryl, oxygen-containing heteroaryl, or nitrogen-containing heteroaryl) may be substituted with 1, 2, or 3 substituents independently selected from halogen, -alkyl, — CN, — (Ci-Ce alkylenyl)NRaRb, — ORa, — (Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRb, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb, — (Ci-C6alkylenyl)Rc, — (Ci- C3 cycloalkylenyl)Rc, — (Ci-Ce alkylenyl)RcRc, — CO heterocyclyl;• Alternatively:o R7 and Rs together with the carbon atom to which they are attached form a C3- C.6 cycloalkyl, a C3-C6 heterocycl, a C3-C6 aryl, or a C3-C6 heteroaryl, each of which may be optionally substituted with 1, 2, or 3 substituents independently selected from halogen, — CN, — (Ci-C6alkylenyl)NRaRb, — ORa, — (Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRb, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb, — (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc, — (Ci-CY alkylenyl)RcRc, — CO heterocyclyl;o R4 and R5 together with the carbon atom to which they are attached form a C3- Ce cycloalkyl, a C3-C6 heterocycl, a C -C6 aryl, or a C3-C6 heteroaryl, each of which may be optionally substituted with 1, 2, or 3 substituents independently selected from halogen, — CN, — (Ci-Ce alkylenyl)NRaRb, — ORa, — (Ci-Ce alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRb, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb, — (Ci-C6-12- 45844530.1alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc, — (Ci-Ce alkylenyl)RcRc— CO heterocyclyl;

[0055] In certain embodiments, compounds of the present disclosure include, without limitation, compounds of Formula Illa or Illb:or a pharmaceutically acceptable salt thereof, wherein:• X is independently selected from — C1-C6 alkyl, — (C1-C6 alkylenyl)NRaRb, — (Cl- C6 alkylenyl)NC(O)Ra, — (C1-C6 alkylenyl) C(O)NRa, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb, — (C1-C6 alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc, • Y 1-Y4 are independently selected from — N or — CR’, and R’ is H or halogen;• Ri, R5, and R7 are each independently selected from:o — H, — C4-C10 heterocyclyl, — heteroaryl, — C(O)heterocyclyl, — N(Ra)heterocyclyl, — C(Ra)heterocyclyl, — O-heterocyclyl, — C(O)heteroaryl, — N(Ra)heteroaryl, — C(Ra)heteroaryl, — O-heteroaryl wherein any said 4-10 membered heterocycle optionally contains one, two or three nitrogen or oxygen, or an aryl, a heterocyclyl, a sulfur-containing heteroaryl, an oxygen-containing heteroaryl, or a nitrogen-containing heteroaryl, each of which may be substituted with 1, 2, or 3 substituents independently selected from halogen, - alkyl, — CN, — (Ci-C6alkylenyl)NRaRb, — ORa, — (Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRb, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb— (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc, and — (Ci-Ce alkylenyl)RcRc, heterocyclyl, — CO heterocyclyl;-13- 45844530.1• R2and Ra are each independently selected from — H, — C1-C4 alkyl, — C1-C4 aminoalkyl, and — C1-C4 alkoxy, -C1-C4 alkyl, or alternatively, R2 and R3 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl optionally substituted by a 4-8 membered heterocycloalkyl;

[0056] wherein each occurrence of Raand Rbcan be independently — H, — Ci-Ce alkenyl, — Ci-Ce alkynyl, — C i-Ce haloalkyl, — Rc, heterocyclyl, or — Ci-Ce alkyl, wherein the — Ci-Ce alkyl can be substituted with a substituent selected from — ORe, — NReRf, — C(O)ORe, — C(O)NReRf, — S(O)2Re, — S(O)2NReRf, and — Rc;

[0057] wherein each occurrence of Rcand Rccan be independently aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl, wherein each Rcgroup may be substituted with 1, 2, 3, 4, or 5 Rdgroups;

[0058] wherein each occurrence of Rdcan be independently — Ci-Ce heteroaryl, — CO heteroaryl, wherein it can be optionally substituted with 1, 2, 3, 4, or 5 Regroups; — Ci-Ce alkyl, — C2-C6alkenyl, — C2-Ce alkynyl, halogen, Ci-Ce haloalkyl, — CN, — NO2, — ORe, — S(O)2NReRf, — C(O)Re, — C(O)NReRf, — NRcRf, — N(Re)C(O)Rf, — (Ci-C6alkylenyl)-ORe, — (Ci-C6alkylenyl)-C(O)NReRf, — (Ci-C6alkylenyl)-NReRf, or — (Ci-C6alkylenyl)-N(Re)C(O)Rf; and

[0059] wherein each occurrence of Reand Rfcan be independently — H, halogen, — CN, — Ci-Ce alkyl, — Ci-Ce cycloalkyl, aryl, heteroaryl or — Ci-Ce haloalkyl.

[0060] In some forms, Ri can be any one of the following:-14- 45844530.1

[0061] In certain embodiments, compounds of the present disclosure include, without limitation, compounds of Formula IV:Formula IV

[0062] or a pharmaceutically acceptable salt thereof, wherein all X, Y and R groups and subgroups (e.g., Y1-Y7, R1-R20, Ra-R8, R’, etc.) are each independently selected from those identified and disclosed in Formula II, and / or Illa-b above.

[0063] In certain embodiments, compounds of the present disclosure include, without limitation, compounds of Formula Va, Vb, or Vc:-15- 45844530.1Formula Va Formula Vb Formula Vc

[0064] or a pharmaceutically acceptable salt thereof, wherein all X, Y and R groups and subgroups (e.g., Yi-Yn, R1-R20, Ra-Rs, R’, etc.) are each independently selected from those identified and disclosed in Formula II, and / or Illa-b and / or IV above or as additionally indicated below:• Y2, and Ys-Yn arc independently selected from — N or — CR’, and R’ is H or halogen;and• Rn, R12, and R13 are independently selected from — H, halogen, — CN, — (Ci-Ce alkylenyl)NRaRb. — ORa, — (Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRb, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb’ — (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc, and — (Ci-C6alkylenyl)RcRc, —CO heterocyclyl.

[0065] In certain embodiments, compounds of the present disclosure include, without limitation, compounds of Formula Via, VIb, Vic:Formula Via Formula VIb Formula Vic-16- 45844530.1or a pharmaceutically acceptable salt thereof, wherein all X, Y and R groups and subgroups (e.g., Y1-Y7, R1-R20, Ra-Rg, R’, etc.) are each independently selected from those identified and disclosed in Formula II, and / or Illa-b and / or IV and / or Va-c above.

[0066] In certain embodiments, compounds of the present disclosure include, without limitation, compounds of Formula Vila, Vllb, Vile:Formula Vila Formula Vllb Formula Vile

[0067] or a pharmaceutically acceptable salt thereof, wherein all X, Y and R groups and subgroups (e.g., Y1-Y7, R1-R20, Ra-Rg, R’, etc.) are each independently selected from those identified and disclosed in Formula II, and / or Illa-b and / or IV and / or Va-c and / or Vile above.

[0068] In certain embodiments, compounds of the present disclosure include, without limitation, compounds of Formula Villa or VUIb:Formula Villa Formula Vlllb

[0069] or a pharmaceutically acceptable salt thereof, wherein all X, Y and R groups and subgroups (e.g., Y1-Y7, R1-R20, Ra-Rg, R’, etc.) are each independently selected from those-17- 45844530.1identified and disclosed in Formula II, and / or Illa-b and / or IV and / or Va-c and / or Vile and / or Vllla-c above or as additionally indicated below:• Y2, and Y4-Y7 are independently selected from — N or — CR’, and R’ is H or halogen;and• R15 is selected from — H, halogen, — CN, — (Ci-Ce alkylenyl)NRaRb, — ORa, — (Ci- C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRb, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb— (Ci-C6alkylenyl)Rc, — (Ci- C3 cycloalkylenyl)Rc, and — (Ci-Ce alkylenyl)RcRc’, — CO heterocyclyl.

[0070] In some forms, the PLpro inhibitors can have the structure of Formula IX:Formula IXor a pharmaceutically acceptable salt thereof, wherein:• X is independently selected from — Ci-Ce alkyl, — (Ci-Ce alkylenyl)NRaRb, — (Ci-Ce alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl) C(O)NRa, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb- — (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc;• n is selected from 1-3;• Y 1-Y3 are independently selected from — N or — CR’, and R’ is H or halogen;• Ri and R2are each independently selected from the group of — H, — C4-C10 heterocyclyl, -heteroaryl, — C(O)heterocyclyl, — N(Ra)heterocyclyl, — C(Ra)heterocyclyl, — O-heterocyclyl, — (CO)heteroaryl, — (NRa)heteroaryl, — (CRa)heteroaryl, — O-heteroaryl, wherein any said 4-10 membered heterocycle optionally contains one, two or three nitrogen or oxygen; wherein a aryl, a sulfur- containing heteroaryl, an oxygen-containing heteroaryl, or a nitrogen-containing heteroaryl, each of which may be substituted with 1, 2, or 3 substituents independently-18- 45844530.1selected from halogen, -CN, -alkyl, — (Ci-C6alkylenyl)NRaRb, — ORa, — (Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRb, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb’ — (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc, and — (Ci-Ce alkylenyl)RcRc; — CO heterocyclyl;• Ra and R4 are each independently selected from the group of H and C1-C4 alkyl, C1-C4 aminoalkyl and C1-C4 alkoxy-Ci-C4 alkyl, or alternatively R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl optionally substituted by a 4-8 membered heterocycloalkyl;• R9 and Rio are each independently selected from the group of — C4-C10 heterocyclyl, — CO heterocyclyl, wherein any said 4-10 membered heterocycle optionally contains one, two or three nitrogen, wherein each occurrence of Raand Rbcan be independently — H, — Ci-Ce alkenyl, — Ci-Ce alkynyl, — Ci-Ce haloalkyl, — Rc, heterocyclyl, or — Ci-Ce alkyl, wherein the — Ci-Ce alkyl can be substituted with a substituent selected from — ORe, — NReRf, — C(O)ORe, — C(O)NReRf, — S(O)2Re, — S(O)2NReRf, and — Rc, or R9 and Rio with the carbon atom to which they are attached form one or more aryl groups, heteroaryl groups, polyaryls groups, heterocyclyl groups, cycloalkyl groups, and / or cycloalkenyl groups, optionally substituted with one or more Ragroups;

[0071] wherein each occurrence of Raand Rbcan be independently — H, — Ci-Ce alkenyl, — Ci-Ce alkynyl, — Ci-Ce haloalkyl, — Rc, heterocyclyl, or — Ci-Ce alkyl, wherein the — Ci-Ce alkyl can be substituted with a substituent selected from — ORe, — NReRf, — C(O)ORe, C(O)NReRf, — S(O)2Re, — S(O)2NReRf, and Rc;

[0072] wherein each occurrence of Rcand Rccan be independently aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl, wherein each Rcgroup may be substituted with 1, 2, 3, 4, or 5 Rdgroups;

[0073] wherein each occurrence of Rdcan be independently — Ci-Ce heteroaryl, — CO heteroaryl, wherein it can be optionally substituted with 1, 2, 3, 4, or 5 Rcgroups; — Ci-Ce alkyl, — C2-Ce alkenyl, — C2-Ce alkynyl, halogen, Ci-Ce haloalkyl, — CN, — NO2, — ORe, — S(O)2NReRf, — C(O)Re, — C(O)NReRf, — NReRf, — N(Re)C(O)Rf, — (Ci-C6alkylenyl)-ORe, — (Ci-C6alkylenyl)-C(O)NReRf, — (Ci-C6alkylenyl)-NReRf, or — (Ci-C6alkylenyl)-N(Re)C(O)Rf; and

[0074] wherein each occurrence of Reand Rfcan be independently — H, halogen, — CN, — Ci-Ce alkyl, — Ci-Ce cycloalkyl, aryl, heteroaryl or — Ci-Cg haloalkyl.-19- 45844530.1

[0075] In some forms, the PLpro inhibitors can have the structure of Formula X or Formula X’:Formula X Formula X’

[0076] or a pharmaceutically acceptable salt thereof, wherein:• X is independently — Ci-C6alkyl, — (Ci-C6alkylenyl)NRaRb(Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl) C(O)NRa, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb— (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc• Y 1-Y4 are independently, N or — CR’, and R' is H or halogen; Y5-Y7 are independently, N or — CR’, and R’ is H, — Ci-Ce alkyl• Z is independently -O, -CO, -NH, -NRa- -CH2, — Ci-C6alkyl, — C(O)NRaRb, — N(Ra)C(O)Rb• R2and R5 is selected from the group of — H, — C4-C10 heterocyclyl, -heteroaryl, — C(O)heterocyclyl, — N(Ra)heterocyclyl, — C(Ra)heterocyclyl, — O-heterocyclyl, — (CO)heteroaryl, — (NRa)heteroaryl, — (CRa)heteroaryl, — O-heteroaryl, wherein any said 4-10 membered heterocycle optionally contains one, two or three nitrogen or oxygen; wherein aryl, heterocyclyl, a sulfur-containing heteroaryl, an oxygencontaining heteroaryl, or a nitrogen-containing heteroaryl, each of which may be substituted with 1, 2, or 3 substituents independently selected from halogen, heterocyclyl, alkyl, -CN, — (Ci-C6alkylenyl)NRaRb, — ORa, — (Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRb, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb— (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc, and — (C1-C.6 alkylenyl)RcRc; — CO heterocyclyl• R3 and R4 are each independently selected from the group of H and C1-C4 alkyl, C1-C4 aminoalkyl and C1-C4 alkoxy-Ci-C4 alkyl, or alternatively R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl optionally substituted by a 4-8 membered heterocycloalkyl-20- 45844530.1• R' is selected from the group of — C4-C10 heterocyclyl, — CO heterocyclyl, wherein any said 4-10 membered heterocycle optionally contains one, two or three nitrogen;

[0077] wherein each occurrence of Raand Rbcan be independently — H, — Ci-Ce alkenyl, — Ci-Ce alkynyl, — Ci-Ce haloalkyl, — Rc, heterocyclyl, or — Ci-Ce alkyl, wherein the — Ci-Ce alkyl can be substituted with a substituent selected from — ORe, — NReRf, — C(O)ORe, — C(O)NReRf, — S(O)2Re, — S(O)2NReRf, and — Rc;

[0078] wherein each occurrence of Rcand Rccan be independently aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl, wherein each Rcgroup may be substituted with 1, 2, 3, 4, or 5 Rdgroups;

[0079] wherein each occurrence of Rdcan be independently — Ci-Ce heteroaryl, — CO heteroaryl, wherein it can be optionally substituted with 1, 2, 3, 4, or 5 Regroups; — Ci-Ce alkyl, — C2-Ce alkenyl, — C2-Ce alkynyl, halogen, Ci-Ce haloalkyl, — CN, — NO2, — ORe, — S(O)2NReRf, — C(O)Re, — C(O)NReRf, — NReRf, — N(Re)C(O)Rf, — (Ci-C6alkylenyl)-ORe, — (Ci-Ce alkylenyl)-C(O)NReRf, — (Ci-Ce alkylenyl)-NReRf, or — (Ci-Ce alkylenyl)-N(Rc)C(O)Rr;

[0080] and wherein each occurrence of Rcand Rfcan be independently — H, halogen, — CN, — Ci-Ce alkyl, — Ci-Ce cycloalkyl, aryl, heteroaryl or — Ci-Ce haloalkyl.

[0081] In some forms R5 of Formula X and X’ can be any one of the following:

[0082] In some forms, the PLpro inhibitors can have the structure of Formula XI or -21- 45844530.1Formula XI’:

[0083] or a pharmaceutically acceptable salt thereof, wherein:• X is independently — Ci-Ce alkyl, — (Ci-Ce alkylenyl)NRaRb, — (Ci-Ce alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl) C(O)NRa, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb— (C1-C& alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc,• Y1-Y4 are independently, NR’ or — CR’, and R’ is H or halogen; Y5-Y7 are independently, NR’ or — CR’, and R’ is independently H, — Ci-Ce alkyl, — Ci-Ce cycloalkyl;• R4 is selected from the group of — H, — C4-C10 heterocyclyl, — CO heterocyclyl, wherein any said 4-10 membered heterocycle contains one, two or three nitrogen; wherein aryl, a sulfur-containing heteroaryl, an oxygen-containing heteroaryl, or a nitrogen-containing heteroaryl, each of which may be substituted with 1, 2, or 3 substituents independently selected from halogen, -CN, — (Ci-Ce alkylenyl) NRaRb, — ORa, — (Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRb, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb- — (Ci-C6alkylenyl)Rc, — (Ci- C3 cycloalkylenyl)Rc, and — (Ci-Cg alkylenyl)RcRc; — CO heterocyclyl.• R2and R3 are each independently selected from the group of H and C1-C4 alkyl, C1-C4 aminoalkyl and C1-C4 alkoxy-Ci-C4 alkyl, or alternatively R2and Raogciher with the carbon atom to which they are attached form a C3-C5 cycloalkyl optionally substituted by a 4-8 membered heterocycloalkyl.In some forms, R4in Formula XI and XI’ is — C4-C10 heterocyclyl, or — CO heterocyclyl, wherein any said 4-10 membered heterocyclyl contains one, two or three nitrogen.-22- 45844530.1

[0084] In some forms, R4 of Formula XI or XI’ can be any one of the following:

[0085] wherein each occurrence of Raand Rbcan be independently — H, — Ci-Ce alkenyl, — Ci-Ce alkynyl, — Ci-Ce haloalkyl, — Rc, heterocyclyl, or — Ci-Ce alkyl, wherein the — Ci-Cc, alkyl can be substituted with a substituent selected from — ORe, — NReRf, — C(O)ORe, — C(O)NReRf, — S(O)2Re, — S(O)2NReRf, and — Rc;

[0086] wherein each occurrence of Rcand Rccan be independently aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl, wherein each Rcgroup may be substituted with 1, 2, 3, 4, or 5 Rdgroups;

[0087] wherein each occurrence of Rdcan be independently — Ci-Ce heteroaryl, — CO heteroaryl, wherein it can be optionally substituted with 1, 2, 3, 4, or 5 Regroups; — Ci-Ce alkyl, — C2-C6 alkenyl, — C2-C6 alkynyl, halogen, Ci-Cc, haloalkyl, — CN, — NO2, — ORe, — S(O)2NReRf, — C(O)Re, — C(O)NReRf, — NReRf, — N(Re)C(O)Rf, — (Ci-C6alkylenyl)-ORe, — (C1-C6 alkylenyl)-C(O)NReRf, — (C1-C6 alkylenyl)-NReRf, or — (Ci-Ce alkylenyl)-N(Re)C(O)Rf;

[0088] and wherein each occurrence of Reand Rfcan be independently — H, halogen, — CN, — Ci-Ce alkyl, — Ci-Ce cycloalkyl, aryl, heteroaryl or — Ci-Ce haloalkyl.-23- 45844530.1Table 1. Exemplary Compounds of Formulas la, lb, II, Illa, Illb, IV, Va, Vb, Vc, Via, VIb, and / or Vic and Chemical Characterization-24- 45844530.1-25- 45844530.1-26- 45844530.1-27- 45844530.1-28- 45844530.1-29- 45844530.1-30- 45844530.1-31- 45844530.1-32- 45844530.1-33- 45844530.1-34- 45844530.1-35- 45844530.1-36- 45844530.1-37- 45844530.1-38- 45844530.1

[0089] In some embodiments, the compounds of Formula lb, II, Illa, Illb, Vila, Vllb, VIIc, and / or IX include, but are not limited to, one or more compounds of Table 2.Table 2. Exemplary Compounds of Formulas lb, II, Illa, Illb, Vila, Vllb, Vile, and / or IX and Chemical Characterization-39- 45844530.1-40- 45844530.1-41- 45844530.1-42- 45844530.1-43- 45844530.1

[0090] In some embodiments, the compounds of Formula la, lb, II, Villa, and / or Vlllb include, but are not limited to, one or more compounds of Table 3.-44- 45844530.1Table 3. Exemplary Compounds of Formulas la, lb, II, Villa, and / or Vlllb and Chemical Characterization-45- 45844530.1-46- 45844530.1-47- 45844530.1-48- 45844530.1-49- 45844530.1-50- 45844530.1-51- 45844530.1-52- 45844530.1-53- 45844530.1-54- 45844530.1-55- 45844530.1-56- 45844530.1-57- 45844530.1-58- 45844530.1Compositions Comprising Compounds Described Herein

[0091] In some respects, the present disclosure provides pharmaceutical compositions comprising one or more compounds described herein and / or derivatives thereof. The pharmaceutical compositions of the present disclosure can have various formulations for different routes of administration, including, but not limited to, oral formulations, injectable formulations, and liquid formulations.

[0092] In some embodiments, the pharmaceutical compositions comprising one or more compounds described herein and / or derivatives thereof have injectable formulations or are formulated for injections through various administration routes, including, but not limited to, intranasal administration, subcutaneous administration, intravenous administration, intraperitoneal administration, intramuscular administration, intradermal administration, and intrathecal administration. In some embodiments, the pharmaceutical compositions comprising one or more compounds described herein and / or derivatives thereof is in a liquid formulation, for example, in the form of an emulsion, for intravenous administration.

[0093] In some embodiments, the pharmaceutical compositions comprising one or more compounds described herein and / or derivatives thereof are formulated for oral administration or are orally deliverable. The terms “orally deliverable” or “oral administration” herein include any form of delivery of a therapeutic agent or a composition thereof to a subject wherein the agent or composition is placed in the mouth of the subject, whether or not the agent or -59- 45844530.1composition is swallowed. Thus “oral administration” includes buccal and sublingual as well as esophageal administration.

[0094] In some embodiments, the pharmaceutical compositions comprising one or more compounds described herein and / or derivatives thereof are in the form of solid, semi-solid, or liquid dosage forms. Non-limiting examples of suitable solid, semi-solid, or liquid dosage forms include tablets (e.g. suspension tablets, bite suspension tablets, rapid dispersion tablets, chewable tablets, melt tablets, effervescent tablets, bilayer tablets, etc.), caplets, capsules (e.g. a soft or a hard gelatin capsule filled with solid and / or liquids), powder (e.g. a packaged powder, a dispensable powder or an effervescent powder), lozenges, sachets, cachets, troches, pellets, granules, microgranules, encapsulated microgranules, powder aerosol formulations, solutions, suspension, elixirs, syrups, liquid aerosol formulations, or any other solid, semisolid, or liquid dosage form reasonably adapted for oral administration. In some embodiments, the orally deliverable pharmaceutical compositions comprising one or more compounds described herein and / or derivatives thereof can be ingested directly, or they can be mixed with food or beverage prior to ingestion.

[0095] In some embodiments, the orally deliverable pharmaceutical compositions arc a tablet, capsule, softgel, or an aqueous or nonaqueous solution, suspension, or syrup. In some embodiments, the orally deliverable pharmaceutical compositions comprise one or more carriers, e.g., lactose and / or corn starch. In some embodiments, the orally deliverable compositions comprise one or more lubricating agents such as magnesium stearate. In some embodiments, the orally deliverable pharmaceutical composition comprises an oral, non-toxic, pharmaceutically acceptable, inert carrier. Non-limiting examples of inert carriers include lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, and sorbitol.

[0096] In some embodiments, the compositions optionally comprise one or more nontoxic solid carriers. Non-limiting examples of non-toxic solid carries include pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, and magnesium carbonate.

[0097] In some embodiments, the pharmaceutical compositions comprising one or more compounds described herein and / or derivatives thereof encapsulated in a capsule shell. In some embodiments, the capsule is a hard gelatin capsule. In some embodiments, the capsule is a soft gelatin capsule.-60- 45844530.1

[0098] In some embodiments, the pharmaceutical compositions comprising one or more compounds described herein and / or derivatives thereof are liquid pharmaceutically administrable compositions. In some embodiments, the liquid pharmaceutically administrable compositions by dissolving, dispersing, and the like, one or more compounds described herein and / or derivatives thereof and optionally, pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. In some embodiments, the pharmaceutical compositions comprise minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and the like.

[0099] In some embodiments, the pharmaceutical compositions comprising one or more compounds described herein and / or derivatives thereof optionally comprise one or more pharmaceutically acceptable excipients. The term “pharmaceutically acceptable excipient” herein means any substance, not itself a therapeutic agent, used as a carrier or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a unit dose of the composition, and that does not produce unacceptable toxicity or interaction with other components in the composition.

[0100] In some embodiments, the pharmaceutical compositions comprising one or more compounds and / or derivatives thereof can be formulated to have modified rates of release. Suitable modified-release formulations include those that exhibit a delayed- or extended-release. An “extended-release” formulation can extend the period over which the pharmaceutically active compound is released or targeted to the desired site. A “delayed-release” formulation can be designed to delay the release of the pharmaceutically active compound for a specified period. Mechanisms can be dependent or independent of local pH in the stomach and / or intestine and can also rely on local enzymatic activity to achieve the desired effect. Examples of modified-release formulations are known in the art and are described, for example, in U. S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,733,566; The Handbook of Pharmaceutical Controlled Release Technology, D. L. Wise (ed.), Marcel Decker, Inc., New York (2000); and also in Treatise on Controlled Drug Delivery: Fundamentals, Optimization, and Applications, A. Kydonieus (ed.), Marcel Decker, Inc., New York, (1992), the relevant contents of each of which are hereby incorporated by reference for this purpose.-61- 45844530.1

[0101] In some embodiments, the compositions optionally comprise one or more pharmaceutically acceptable diluents as excipients. Non-limiting examples of suitable diluents include, either individually or in combination, lactose, including anhydrous lactose and lactose monohydrate; starches, including directly compressible starch and hydrolyzed starches (e.g., Celutab™ and Emdex™); mannitol; sorbitol; xylitol; dextrose (e.g., Cerelose™ 2000) and dextrose monohydrate; dibasic calcium phosphate dihydrate; sucrose-based diluents; confectioner’s sugar; monobasic calcium sulfate monohydrate; calcium sulfate dihydrate; granular calcium lactate trihydrate; dextrates; inositol; hydrolyzed cereal solids; amylose; celluloses including microcrystalline cellulose, food grade sources of amorphous cellulose (e.g., Rexcel™) and powdered cellulose; calcium carbonate; glycine; bentonite; polyvinylpyrrolidone; and the like. Such diluents, if present, constitute in total about 5% to about 99%, about 10% to about 85%, or about 20% to about 80%, of the total weight of the composition.

[0102] In some embodiments, the compositions optionally comprise one or more pharmaceutically acceptable disintegrants as excipients. Non-limiting examples of suitable disintegrants include, either individually or in combination, starches, including sodium starch glycolate (e.g., Explotab™ of PenWest) and pregelatinized corn starches (e.g., National™ 1551, National™ 1550, and Colocorn™ 1500), clays (e.g., Veegum™ HV), celluloses such as purified cellulose, microcrystalline cellulose, methylcellulose, carboxymethylcellulose and sodium carboxymethylcellulose, croscarmellose sodium (e.g., Ac-Di-Sol™ of FMC), alginates, crospovidone, and gums such as agar, guar, xanthan, locust bean, karaya, pectin and tragacanth gums. Such disintegrants, if present, typically comprise in total about 0.2% to about 30%, about 0.2% to about 10%, or about 0.2% to about 5%, of the total weight of the composition.

[0103] In some embodiments, the compositions optionally comprise one or more antioxidants. Non-limiting examples of antioxidants include sodium ascorbate, vitamin E (tocopherol), ascorbic acid, palmitic acid, ascorbyl palmitate, a-tocopherol, idebenone, ubiquinone, ferulic acid, coenzyme Q10, lycopene, green tea, catechins, epigallocatechin 3-gallate (EGCG), green tea polyphenols (GTP), silymarin, coffeeberry, resveratrol, grape seed, pomegranate extracts, genisten, pycnogenol, niacinamide, and the like. One or more antioxidants, if present, are typically present in a composition in an amount of about 0.001% to about 5%, about 0.005% to about 2.5%, or about 0.01% to about 1%, by weight.-62- 45844530.1

[0104] In some embodiments, the compositions optionally comprise one or more pharmaceutically acceptable binding agents or adhesives as excipients. Such binding agents and adhesives can impart sufficient cohesion to a powder being tableted to allow for normal processing operations such as sizing, lubrication, compression and packaging, but still allow the tablet to disintegrate and the composition to be absorbed upon ingestion. Non-limiting examples of suitable binding agents and adhesives include, either individually or in combination, acacia; tragacanth; sucrose; gelatin; glucose; starches such as, but not limited to, pregelatinized starches (e.g., National™ 1511 and National™ 1500); celluloses such as, but not limited to, methylcellulose and carmellose sodium (e.g., Tylose™); alginic acid and salts of alginic acid; magnesium aluminum silicate: PEG; guar gum; polysaccharide acids; bentonites; povidone, for example povidone K-15, K-30 and K 29 / 32; poly methacrylates; HPMC; hydroxypropylcellulose (e.g., Klucel™); and ethylcellulose (e.g., Ethocel™). Such binding agents and / or adhesives, if present, constitute in total about 0.5% to about 25%, about 0.75% to about 15%, or about 1% to about 10%, of the total weight of the composition.

[0105] In some embodiments, the compositions optionally comprise one or more pharmaceutically acceptable wetting agents as excipients. Non- limiting examples of surfactants that can be used as wetting agents in compositions include quaternary ammonium compounds, for example benzalkonium chloride, benzethonium chloride and cetylpyridinium chloride, dioctyl sodium sulfosuccinate, polyoxyethylene alkylphenyl ethers, for example nonoxynol 9, nonoxynol 10, and octoxynol 9, poloxamers (polyoxyethylene and polyoxypropylene block copolymers), polyoxyethylene fatty acid glycerides and oils, for example polyoxyethylene (8) caprylic / capric mono- and diglycerides (e.g., Labrasol™ of Gattefosse), polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castor oil; polyoxyethylene alkyl ethers, for example polyoxyethylene (20) cetostearyl ether, polyoxyethylene fatty acid esters, for example polyoxyethylene (40) stearate, polyoxyethylene sorbitan esters, for example polysorbate 20 and polysorbate 80 (e.g., Tween™ 80 of ICI), propylene glycol fatty acid esters, for example propylene glycol laurate (e.g., Lauroglycol™ of Gattefosse), sodium lauryl sulfate, fatty acids and salts thereof, for example oleic acid, sodium oleate and triethanolamine oleate, glyceryl fatty acid esters, for example glyceryl monostearate, sorbitan esters, for example sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate and sorbitan monostearate, tyloxapol, and mixtures thereof. Such wetting agents, if present, constitute in total about 0.25% to about 15%, about 0.4% to about 10%, or about 0.5% to about 5%, of the total weight of the composition.-63- 45844530.1

[0106] In some embodiments, the compositions optionally comprise one or more pharmaceutically acceptable lubricants (including anti-adherents and / or glidants) as excipients. Non-limiting examples of suitable lubricants include, either individually or in combination, glyceryl behapate (e.g., Compritol™ 888); stearic acid and salts thereof, including magnesium (magnesium stearate), calcium and sodium stearates; hydrogenated vegetable oils (e.g., Sterotex™); colloidal silica; talc; waxes; boric acid; sodium benzoate; sodium acetate; sodium fumarate; sodium chloride; DL-leucine; PEG (e.g., Carbowax™ 4000 and Carbowax™ 6000); sodium oleate; sodium lauryl sulfate; sodium chloride; and magnesium lauryl sulfate. Such lubricants, if present, constitute in total about 0.1% to about 10%, about 0.2% to about 8%, or about 0.25% to about 5%, of the total weight of the composition.

[0107] In some embodiments, the compositions optionally comprise one or more permeation enhancer excipients. Non-limiting examples of permeation enhancer excipients include polymers such as: polycations (chitosan and its quaternary ammonium derivatives, poly-L-arginine, aminated gelatin); polyanions (N-carboxymethyl chitosan, poly-acrylic acid); and thiolated polymers (carboxymethyl cellulose-cysteine, polycarbophil-cysteine, chitosanthiobutylamidine, chitosan- thioglycolic acid, chitosan-glutathione conjugates).

[0108] In some embodiments, the compositions optionally comprise one or more binders. Non-limiting examples of binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, and waxes.

[0109] In some embodiments, the compositions optionally comprise one or more flavoring agents, sweetening agents, and / or colorants. Non-limiting examples of flavoring agents include acacia syrup, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, blackcurrant, butter, butter pecan, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, citrus, citrus punch, citrus cream, cocoa, coffee, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, MagnaSweet®, maltol, mannitol, maple, menthol, mint, mint cream, mixed berry, nut, orange, peanut butter, pear, peppermint, peppermint cream, Prosweet® Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, Swiss cream, tagatose, tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry, Wintergreen, xylitol, and combinations thereof, for example, anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon,-64- 45844530.1chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, etc. Flavoring agents, sweetening agents, and / or colorants can be present in the compositions in any suitable amount, for example about 0.01% to about 10%, about 0.1% to about 8%, or about 1% to about 5%, by weight.

[0110] In some embodiments, the composition is formulated for parenteral administration. Non-limiting examples of parenteral administration include intraarticular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous administration. In some embodiments, the compositions are an aqueous and non-aqueous, isotonic sterile injection solution optionally comprising antioxidants, buffers, bacteriostats, and solutes that renderthe formulation isotonic with the blood of the intended recipient. In another embodiment, the compositions are aqueous and non-aqueous sterile suspensions that can optionally include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.

[0111] In some embodiments, parenteral administration comprises administration the composition to a subject via a needle or a catheter, sterile syringe, or other mechanical device such as a continuous infusion system. In some embodiments, parenteral administration includes introducing the composition to the subject via a syringe, injector, or pump.

[0112] In some embodiments, the composition is a sterile injectable suspension comprising a suitable carrier, dispersing, or wetting agents, and suspending agents. In some embodiments, the sterile injectable suspension comprises a nontoxic parenterally acceptable diluent or solvent. Non-limiting examples of suitable diluent or solvents include water, Ringer’s solution, and isotonic sodium chloride solution. In some embodiments, the sterile injectable suspension comprises fixed oils, fatty esters, or polyols.

[0113] In some embodiments, the composition is a sterile aqueous or non-aqueous solution, suspension, or emulsion. Non-limiting examples of non-aqueous solvents include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil and com oil), gelatin, and injectable organic esters such as ethyl oleate. In some embodiments, the composition comprises adjuvants such as preserving, wetting, emulsifying, and dispersing agents. In some embodiments, the composition is sterilized, for example, by filtering the composition through a bacterium retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. In some embodiments, the composition is formulated from sterile water, or some other sterile injectable medium, immediately before use.-65- 45844530.1

[0114] In some embodiments, the composition is formulated for rectal administration. A composition for rectal administration can be prepared by mixing the one or more compounds of the present disclosure and / or derivatives thereof with a suitable nonirritating excipient which is solid at room temperature but liquid at the rectal temperature. As such, the formulation will melt in the rectum to release the drug. Non- limiting examples of nonirritating excipients include (mibuller. beeswax, and polyethylene glycols.

[0115] In some embodiments, the composition is formulated for aerosol administration. In some embodiments, the aerosol administration includes intranasal administration. In some embodiments, the composition comprises one or more of a preservative, absorption promoter, or propellant. Non-limiting examples of propellants include chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In some embodiments, one or more compounds of the present disclosure and / or derivatives thereof is a dry powder that can form a gel in a nasal cavity. In some embodiments, the dry powder includes one or more compounds of the present disclosure and / or derivatives thereof mixed with a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP).

[0116] In some embodiments, the composition comprises a therapeutically effective amount of one or more compounds of the present disclosure and / or derivatives thereof, where the therapeutically effective amount includes about 0.01 mg / kg to about 250 mg / kg body weight. For example, about 0.1 mg / kg, about 10 mg / kg, about 20 mg / kg, about 30 mg / kg, about 40 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 110 mg / kg, about 120 mg / kg, about 130 mg / kg, about 140 mg / kg, about 150 mg / kg, about 160 mg / kg, about 170 mg / kg, about 180 mg / kg, about 190 mg / kg, about 200 mg / kg, about 210 mg / kg, about 220 mg / kg, about 230 mg / kg, about 240 mg / kg, or about 250 mg / kg.Additional Therapeutic Agents

[0117] In some aspects, the pharmaceutical compositions comprising one or more compounds described herein and / or derivatives thereof according to various embodiments of the present disclosure comprise one or more additional therapeutic agents or are used for coadministration regimens with one or more additional therapeutic agents.

[0118] In some embodiments, the one or more additional therapeutic agents may be formulated into the same pharmaceutical composition comprising one or more compounds described herein and / or derivatives thereof, for example, as a single dosage unit or as multiple -66- 45844530.1dosage units for coordinated, combination, or concomitant administration, or into separate pharmaceutical compositions for combinational therapy.

[0119] In some embodiments, the one or more additional therapeutic agents may be formulated as separate pharmaceutical compositions, for example, as a single dosage unit or as multiple dosage units, for co-administration with the pharmaceutical composition comprising one or more compounds described herein and / or derivatives thereof.

[0120] Non-limiting examples of classes of additional therapeutic agents suitable for use in accordance with the present invention include: antiviral agents; anti-inflammatory agents; antimalaria agents; and biological agents.

[0121] In some embodiments, the one or more additional therapeutic agents comprise an antiviral agent. Non- limiting examples of an antiviral agent include remdesivir (e.g., Veklury®), favipiravir (e.g., Avigan®), lopinavir / ritonavir (e.g., Kaletra®, Aluvia®), nitazoxanide (e.g., Alinia®), danoprevir (e.g., Ganovo®), ASC-09, umifenovir (e.g., Arbidol®), nafamostat, brequinar, AT-527, ABX464, merimepodib, molnupiravir, opaganib (e.g., Yeliva®), ivermectin (e.g., Soolantra®, Stromectol®, Skiice®), and hydroxychloroquine.

[0122] In some embodiments, the one or more additional therapeutic agents comprise an antimalaria agent. Non-limiting examples of an antimalaria agent include hydroxychloroquine and chloroquine.

[0123] In some embodiments, the one or more additional therapeutic agents comprise a biologic agent. In some embodiments, the biological agent is an antibody, for example, an antibody recognizing at least a portion of the SARS-CoV-2 coronaviruse, such as an epitope on a spike protein.

[0124] In some embodiments, the biological agent is a vaccine, for example, a vaccine against the SARS-CoV-2 coronavimse. In some embodiments, the vaccine is BNT162b2 (Pfizer / BioNTech), mRNA-1273 (Modema), AZD1222 / ChAdOxl (AstraZeneca / Oxford Univ), Ad5-vectored CO VID- 19 vaccine (CanSino Biologies), CoronaVac (Sinovac), and / or NVX-COV2373 (Novavax).

[0125] In some embodiments, the one of more additional therapeutic agents may be formulated in various formulations, for example, injectable formulations, lyophilized formulations, liquid formulations, or oral formulations. The formulation can be selected based upon the suitable administration route.-67- 45844530.1Treatment and / or Prevention of SARS-COV-2 Infections

[0126] In some aspects, the pharmaceutical compositions comprising one or more compounds described herein and / or derivatives thereof according to various embodiments of the present disclosure may be used in the treatment and / or prevention of infections and / or diseases caused by coronaviruses, including COVID-19 caused by SARS-CoV-2. In some embodiments, the present disclosure also provides methods for treatment and / or prevention of a disease or symptoms associated thereof caused by a coronaviral infection in a subject. In other embodiments, the present disclosure also provides methods for reducing the viral load in a subject infected with a virus, including in a subject infected with a coronavirus (e.g., SARS-CoV-2). See, e.g., FIG. 2 - FIG. 22 showing that SUN-084 is effective at reducing viral load in a subject. In some embodiments, the compounds (e.g., SUN-084) are shown to be more effective at reducing viral load than current treatments available Nirmatrelvir. Id.

[0127] In some embodiments, the present disclosure provides methods for treatment, prevention, or amelioration of one or more symptoms and / or diseases associated with a coronavirus. In some embodiments, methods for the treatment and / or prevention of COVID-19 associated with infection of the SARS-CoV-2 virus are provided. As used herein, the terms “SARS-CoV-2”, “coronavirus”, “corona”, “2019 novel coronavirus,” “201 -nCoV”, and “COVID-19” are used interchangeably throughout the present disclosure.

[0128] In some embodiments, the present disclosure provides methods for the treatment and / or prevention of infections and / or diseases caused by coronaviruses in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds described herein and / or derivatives thereof according to various embodiments of the present disclosure.

[0129] In some embodiments, the methods further comprise administering the subject a therapeutic effect amount of one or more additional therapeutic agents according to various embodiments of the present disclosure. The pharmaceutical composition comprising one or more compounds described herein and / or derivatives thereof can be used in combination with one or more additional therapeutic agents to obtain improved or synergistic therapeutic effects. In some embodiments, the one or more additional therapeutic agents comprise an antiviral agent, an antimalaria agent, and / or a biologic agent. In some embodiments, the antiviral agent is remdesivir (e.g., Veklury®), favipiravir (e.g., Avigan®), lopinavir / ritonavir (e.g., Kaletra®, Aluvia®), nitazoxanide (e.g., Alinia®), danoprevir(e.g., Ganovo®), ASC-09, umifenovir (e.g., Arbidol®), nafamostat, brequinar, AT-527, ABX464, merimepodib, molnupiravir, opaganib -68- 45844530.1(e.g., Yeliva®), ivermectin (e.g., Soolantra®, Stromectol®, Skiice®), and / or hydroxychloroquine. In some embodiments, the antimalaria agent is hydroxychloroquine or chloroquine. In some embodiments, the biologic agent is an antibody, for example, an antibody recognizing the SARS-CoV-2 coronaviruse. In some embodiments, the biological agent is a vaccine, for example, a vaccine for the SARS-CoV-2 coronavirus. In some embodiments, the vaccine is BNT162b2 (Pfizer / BioNTech), mRNA-1273 (Modema), AZD1222 / ChAdOxl (AstraZeneca / Oxford Univ), Ad5-vectored COVID- 19 vaccine (CanSino Biologies), CoronaVac (Sinovac), and / or NVX-CoV2373 (Novavax).

[0130] In some embodiments, the subject is administered the one or more additional therapeutic agents before administration of the pharmaceutical composition comprising one or more compounds described herein and / or derivatives thereof. In some embodiments, the subject is co-administered the one or more additional therapeutic agents and the pharmaceutical composition comprising one or more compounds described herein and / or derivatives thereof. In some embodiments, the subject is administered the one or more additional therapeutic agents before after administration of the pharmaceutical composition comprising one or more compounds described herein and / or derivatives thereof.

[0131] It is within the purview of one of ordinary skill in the art to select a suitable administration route, such as oral administration, subcutaneous administration, intravenous administration, intramuscular administration, intradermal administration, intrathecal administration, or intraperitoneal administration, for the one or more additional therapeutic agents.

[0132] As one of ordinary skill in the art would understand, the pharmaceutical composition comprising one or more compounds described herein and / or derivatives thereof and the one or more additional therapeutic agents can be administered to a subject in need thereof one or more times at the same or different doses, depending on the diagnosis and prognosis of the subject. One skilled in the art would be able to combine one or more of these therapies in different orders to achieve the desired therapeutic results. In some embodiments, the combinational therapy achieves improved or synergistic effects in comparison to any of the treatments administered alone.

[0133] In some embodiments, methods for treatment and / or prevention of a disease or symptoms associated thereof caused by SARS-CoV-2 in a subject are provided, wherein the subject is elderly (e.g., 65 years or greater), an infant, or an immunocompromised subject. In some embodiments, the subject has one or more underlying medical conditions resulting an -69- 45844530.1increased risk of severe illness from CO VID-19. Non-limiting examples of underlying medical conditions that render a subject at increased risk of severe illness from COVID-19 include cancer, cardiovascular disease, chronic kidney disease, chronic obstructive pulmonary disease (COPD), immunocompromised state, obesity (i.e., body mass index (BMI) of 30 or higher), serious heart conditions (e.g., heart failure, coronary artery disease, cardiomyopathy), sickle cell disease, Type 2 diabetes mellitus, asthma, cerebrovascular disease, cystic fibrosis, hypertension or high blood pressure, neurologic conditions (e.g., dementia), liver disease, pregnancy, pulmonary fibrosis, smoking, thalassemia, and Type 1 diabetes mellitus.Kits

[0134] Provided herein in certain embodiments are kits for carrying out the methods disclosed herein. In certain embodiments, the kits comprise one or more compounds of the present disclosure and / or derivatives thereof, or one or more pharmaceutical formulations comprising such compounds and / or derivatives thereof. In certain embodiments, the kits further comprise one or more additional therapeutic agents (e.g., anti-viral agent) or pharmaceutical formulations thereof. In those embodiments wherein the kits comprise two or more compounds of the present disclosure and / or derivatives thereof and an additional therapeutic agent, the two or more compounds may be present in the kit in a single composition or in separate compositions. In certain embodiments, the kits comprise instructions in a tangible medium.

[0135] The foregoing and the following working examples are merely intended to illustrate various embodiments of the present invention. The specific modifications discussed above are not to be construed as limitations on the scope of the invention. It will be apparent to one skilled in the art that various equivalents, changes, and modifications may be made without departing from the scope of the invention, and it is understood that such equivalent embodiments are to be included herein. All references cited herein are incorporated by reference as if fully set forth herein.

[0136] The disclosed compounds, pharmaceutical compositions, and methods can be further understood through the following numbered paragraphs.Paragraph 1. A compound of Formula la or lb:-70- 45844530.1Formula la Formula lbor a pharmaceutically acceptable salt thereof, wherein:• Ar is selected from aryl, heteroaryl, heterocyclyl, cycloalkyl, and cycloalkenyl, wherein the Ar (i.e., aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl) can be substituted with 1, 2, 3, 4, or 5 Rdgroups;• X is independently selected from — H, — CH3, — Ci-Ce alkyl, — (Ci-Ce alkylenyl)NRaRb, — (Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb— (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc;• Y 1-Y3 are independently — N or — CR’, and R’ is H or halogen;• Ri is independently selected from — H, — NH2, — CH3, — Ci-Ce alkyl, — heterocyclyl, — (Ci-C6alkylenyl)NRaRb, — ORa, — (Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRh, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb, — (Ci-Ce alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc, — (Ci-Ce alkylenyl)RcRc’, and — Fi-C'e alkyl, — C4-C10 heterocyclyl, — CO heterocyclyl, aryl, a sulfur-containing hetcroaryl, an oxygcn-containing heteroaryl, or a nitrogcn-containing heteroaryl, wherein any said 4-10 membered heterocyclyl optionally contains one, two or three nitrogen, and wherein each aryl, heterocyclyl, or heteroaryl (e.g., — C4-C10 heterocyclyl, — CO heterocyclyl, aryl, sulfur-containing heteroaryl, oxygen-containing heteroaryl, or nitrogen-containing heteroaryl) may be substituted with 1, 2, or 3 substituents independently selected from halogen, — CN, — (Ci-Ce alkylenyl)NRaRb, — ORa, — (Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRb, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb, — (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc, — (Ci-C6alkylenyl)RcRc’, heterocyclyl, or —CO heterocyclyl;-71- 45844530.1• R2 and R3 are each independently selected from the group of — H and — C1-C4 alkyl, — C1-C4 aminoalkyl and — C1-C4 alkoxy-Cl-C4 alkyl, or alternatively R2 and R3 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl optionally substituted by a 4-8 membered heterocycloalkyl;wherein each occurrence of Rdcan be independently selected from the following:• — H, — C4-C10 heterocyclyl, — C(O)heterocyclyl, — N(Ra)heterocyclyl, — C(Ra)heterocyclyl, — O-heterocyclyl, — C(O)heteroaryl, — N(Ra)heteroaryl, — C(Ra)heteroaryl, — O-heteroaryl, wherein any said 4-10 membered heterocyclyl optionally contains one, two or three nitrogen or oxygen; wherein aryl, a sulfur- containing heteroaryl, an oxygen-containing heteroaryl, or a nitrogen-containing heteroaryl, each of which may be substituted with 1, 2, or 3 substituents independently selected from halogen, — CN, — (Ci-C6alkylenyl)NRaRb, — ORa, — (Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRb, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb, — (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc, — (Ci-Ce alkylenyl)RcRc, — CO heterocyclyl; or• — Ci-Ce heteroaryl, — CO heteroaryl, wherein it can be optionally substituted with 1, 2, 3, 4, or 5 Regroups; — Ci-Ce alkyl, — C2-Ce alkenyl, — C2-Ce alkynyl, halogen, Ci- C6haloalkyl, — CN, — NO2, — ORe, — S(O)2NReRf, — C(O)Re, — C(O)NReRf, — NReRf, — N(Re)C(O)Rf, — (Ci-C6alkylenyl)-ORe, — (Ci-C6alkylenyl)-C(O)NReRf, — (Ci-C6alkylenyl)-NReRf, or — (Ci-C6alkylenyl)-N(Re)C(O)Rf;wherein each occurrence of Raand Rbcan be independently selected from the following:• — H, — Ci-Ce alkenyl, — Ci-Ce alkynyl, — Ci-Ce haloalkyl, — Rc, heterocyclyl, or — Ci-Ce alkyl, wherein the — Ci-Ce alkyl can be substituted with a substituent selected from — ORe, — NReRf, — C(O)ORe, — C(O)NReRf, — S(O)2Re, — S(O)2NReRf, and — Rc;wherein each occurrence of Rcand Rccan be independently selected from the following:• aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl, wherein each Rcgroup may be substituted with 1, 2, 3, 4, or 5 Rdgroups; andwherein each occurrence of Reand Rfcan be independently selected from the following:• — H, halogen, — CN, — Ci-Ce alkyl, — Ci-Ce cycloalkyl, aryl, heteroaryl or — Ci-Ce haloalkyl-72- 45844530.1Paragraph 2. The compound of paragraph 1, wherein said compound has the following Formula II:Formula IIor a pharmaceutically acceptable salt thereof, wherein all X, Y and R groups and subgroups (e.g., Y1-Y7, RI-R2O, Ra-Rg, R’, etc.) are each independently selected from those disclosed in Formula I above or as additionally indicated below:Yi-Ye are independently — N or — CR’, and R’ is H or halogen;R4, Rs, Re, R7, and Rs can each be independently selected from — H, — C4- C10 heterocyclyl, — C(O)heterocyclyl, — N(Ra)heterocyclyl, — C(Ra)heterocyclyl, — O-heterocyclyl, — C(O)heteroaryl, — N(Ra)heteroaryl, — C(Ra)heteroaryl, — O-heteroaryl, aryl, a sulfur- containing heteroaryl, an oxygen-containing heteroaryl, or a nitrogen- containing heteroaryl, wherein any said 4-10 membered heterocycle is optionally substituted with one, two or three nitrogen, and wherein each aryl, heterocyclyl, or heteroaryl (e.g., — C4-C10 heterocyclyl, — CO heterocyclyl, aryl, sulfur-containing heteroaryl, oxygen-containing heteroaryl, or nitrogen-containing heteroaryl) may be substituted with 1, 2, or 3 substituents independently selected from halogen, — CN, — (Ci-CY alkylenyl)NRaRb, — ORa, — (Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRb, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb, — (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc, — (Ci-Ce alkylenyl)RcRc, — CO heterocyclyl; alternatively:-73- 45844530.1o R7 and Rs together with the carbon atom to which they are attached form a C3-C6 cycloalkyl, a C3-C6 heterocycl, a C3-C6 aryl, or a C3- Ce heteroaryl, each of which may be optionally substituted with 1, 2, or 3 substituents independently selected from halogen, — CN, — (Ci-C6alkylenyl)NRaRb, — ORa, — (Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRb, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb, — (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc, — (Ci-Cf, alkylenyl)RcRc, — CO heterocyclyl;o R4 and Rs together with the carbon atom to which they are attached form a C3-C6 cycloalkyl, a C3-C6 heterocycl, a C3-C6 aryl, or a C3- C<> heteroaryl, each of which may be optionally substituted with 1, 2, or 3 substituents independently selected from halogen, — CN, — (Ci-C6alkylenyl)NRaRb, — ORa, — (Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRb, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb, — (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc, — (Ci-Ce alkylenyl)RcRc, — CO heterocyclyl;Paragraph 3. The compound of paragraph 2, wherein said compound has the following Formula Illa or Illb:or a pharmaceutically acceptable salt thereof, wherein:-74- 45844530.1• X is independently selected from — C 1 -C6 alkyl, — (C 1 -C6 alkylenyl)NRaRb, — (C1-C6 alkylenyl)NC(O)Ra, — (C1-C6 alkylenyl) C(O)NRa, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb, — (C1-C6 alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc,• Y 1-Y4 are independently selected from — N or — CR’, and R’ is H or halogen;• Ri, Rs, and R7 are each independently selected from:o — H, — C4-C10 heterocyclyl, — C(O)heterocyclyl, — N(Ra)heterocyclyl, — C(Ra)heterocyclyl, — O-heterocyclyl, — C(O)heteroaryl, — N(Ra)heteroaryl, — C(Ra)heteroaryl, — O- heteroaryl, wherein wherein any said 4-10 membered heterocycle is optionally substituted with one, two or three nitrogen or oxygen, oro an aryl, a sulfur-containing heteroaryl, an oxygen-containing heteroaryl, or a nitrogen-containing heteroaryl, each of which may be substituted with 1, 2, or 3 substituents independently selected from halogen, — CN, — (Ci-Ce alkylenyl)NRaRb, — ORa, — (Ci-Ce alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRb, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb— (Ci-Ce alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc, and — (Ci-Ce alkylenyl)RcRc, — CO heterocyclyl;• R2and R3 are each independently selected from — H, — C1-C4 alkyl, — Ci- C4 aminoalkyl, and — C1-C4 alkoxy-Ci-C4 alkyl, or alternatively, R2and R3 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl optionally substituted by a 4-8 membered heterocycloalkyl; wherein each occurrence of Raand Rbcan be independently — II, — Ci-Cg alkenyl, — Ci-Ce alkynyl, — Ci-Ce haloalkyl, — Rc, heterocyclyl, or — Ci-Ce alkyl, wherein the — Ci-Ce alkyl can be substituted with a substituent selected from — ORe, — NReRf, — C(O)ORe, — C(O)NReRf, — S(O)2Re, — S(O)2NReRf, and — Rc;-75- 45844530.1wherein each occurrence of Rcand Rccan be independently aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl, wherein each Rcgroup may be substituted with 1, 2, 3, 4, or 5 Rdgroups;wherein each occurrence of Rdcan be independently — Ci-Ce heteroaryl, — CO heteroaryl, wherein it can be optionally substituted with 1, 2, 3, 4, or 5 Regroups; — Ci-Ce alkyl, — C2-C6 alkenyl, — C2-C6 alkynyl, halogen, Ci-Ce haloalkyl, — CN, NO2, ORe, S(O)2NReRf, C(O)Re, C(O)NReRf, NReRf, N(Re)C(O)Rf, — (Ci-C6alkylenyl)-ORe, — (Ci-C6alkylenyl)-C(O)NReRf, — (Ci-C6alkylenyl)-NReRf, or — (Ci-C6alkylenyl)-N(Re)C(O)Rf; andwherein each occurrence of Reand Rfcan be independently — H, halogen, — CN, — Ci- Ce alkyl, — Ci-O, cycloalkyl, aryl, heteroaryl or — Ci-Ce haloalkyl; optionally wherein Ri can be any one of the following:-76- 45844530.1Paragraph 4. The compound of paragraph 2, wherein said compound has the following Formula IV:Formula IVor a pharmaceutically acceptable salt thereof, wherein all X, Y and R groups and subgroups (e.g., Y1-Y7, R1-R20, Ra-Rs, R’, etc.) are each independently selected from those identified and disclosed in Formula II, and / or Illa-b above.Paragraph 5. The compound of paragraph 4, wherein said compound has the following Formula Va, Vb, or Vc:Formula Va Formula Vb Formula Vc or a pharmaceutically acceptable salt thereof, wherein wherein all X, Y and R groups and subgroups (e.g., Yi-Yn, R1-R20, Ra-Rs, R’, etc.) are each independently selected from those identified and disclosed in Formula II, and / or Illa-b and / or IV above or as additionally indicated below:-77- 45844530.1• Y2, and Ys-Yn are independently selected from — N or — CR’, and R’ is H or halogen; and• Rn, R12, and R13 are independently selected from — H, halogen, — CN, — (Ci-C6alkylenyl)NRaRb, — ORa, — (Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRb, — C(O)NRaRb, — N(Ra)C(O)Rb, NRaRb’ — (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc, and — (Ci-Ce alkylenyl)RcRc, — CO heterocyclyl. Paragraph 6. The compound of paragraph 5, wherein said compound has the following Formula Via, VIb, or Vic:Formula Via Formula VIb Formula Vic or a pharmaceutically acceptable salt thereof, wherein all X, Y and R groups and subgroups (e.g., Y1-Y7, R1-R20, Ra-Rg, R’, etc.) are each independently selected from those identified and disclosed in Formula II, and / or Illa-b and / or IV and / or Va-c above.-78- 45844530.1Paragraph 7. The compound of paragraph 2, wherein said compound has the following Formula IX:Formula IXor a pharmaceutically acceptable salt thereof, wherein:• X is independently selected from — Ci-Ce alkyl, — (Ci-Ce alkylenyl)NRaRb,— (Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl) C(O)NRa, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb— (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc;n is selected from 1-3:• Y1-Y3 are independently selected from — N or — CR’, and R’ is H or halogen;• Ri and R2 are each independently selected from the group of — H, — C4- C10 heterocyclyl, - heteroaryl, — C(O)heterocyclyl, — N(Ra)heterocyclyl, — C(Ra)heterocyclyl, — O-heterocyclyl, — C(O)heteroaryl, — N(Ra)heteroaryl, — C(Ra)heteroaryl, — O-heteroaryl, wherein any said 4-10 membered heterocycle optionally contains one, two or three nitrogen or oxygen; wherein a aryl, a sulfur-containing heteroaryl, an oxygen-containing heteroaryl, or a nitrogen-containing heteroaryl, each of which may be substituted with 1, 2, or 3 substituents independently selected from halogen, -CN, -alkyl, — (Ci-C& alkylenyl)NRaRh, — ORa, — (Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRb, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb’ — (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc, and — (Ci-Ce alkylenyl)RcRc; — CO heterocyclyl;• R3 and R4 are each independently selected from the group of H and Ci- C4 alkyl, C1-C4 aminoalkyl and C1-C4 alkoxy-Ci-C4 alkyl, or alternatively R3-79- 45844530.1and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl optionally substituted by a 4-8 membered heterocycloalkyl;• R9 and Rio are each independently selected from the group of — C4-C10 heterocyclyl, — CO heterocyclyl, wherein any said 4-10 membered heterocycle optionally contains one, two or three nitrogen, wherein each occurrence of Raand Rbcan be independently — H, — Ci-Ce alkenyl, — Ci-Ce alkynyl, — Ci-Ce haloalkyl, — Rc, heterocyclyl, or — Ci-Ce alkyl, wherein the — Ci-Ce alkyl can be substituted with a substituent selected from — ORe, — NReRf, — C( )ORe, — C(O)NReRf, — S(O)2Re, — S(O)2NReRf, and — Rc, or R9and R10with the carbon atom to which they are attached form one or more aryl groups, heteroaryl groups, polyaryls groups, heterocyclyl groups, cycloalkyl groups, and / or cycloalkenyl groups, optionally substituted with one or more Ragroups; wherein each occurrence of Rcand Rccan be independently aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl, wherein each Rcgroup may be substituted with 1, 2, 3, 4, or 5 Rdgroups;wherein each occurrence of Rdcan be independently — Ci-Ce heteroaryl, — CO heteroaryl, wherein it can be optionally substituted with 1, 2, 3, 4, or 5 Regroups; — Ci-Ce alkyl, — C2-C6alkenyl, — C2-Ce alkynyl, halogen, Ci-Ce haloalkyl, — CN, — NO2, — ORC, — S(O)2NRcRf, — C(O)RC, — C(O)NRcRf, — NRcRf, — N(Rc)C(O)Rf, — (Ci-C6alkylenyl)-ORe, — (Ci-C6alkylenyl)-C(O)NReRf, — (Ci-C6alkylenyl)-NReRf, or — (Ci-C6alkylenyl)-N(Re)C(O)Rf; andwherein each occurrence of Reand Rfcan be independently — H, halogen, — CN, — Ci-Ce alkyl, — Ci-Ce cycloalkyl, aryl, heteroaryl or — Ci-Ce haloalkyl.-80- 45844530.1Paragraph 8. The compound of paragraph 2, wherein said compound has the following Formula X or Formula X’:Formula X Formula X’or a pharmaceutically acceptable salt thereof, wherein:• X is independently — Ci-Ce alkyl, — (Ci-Ce alkylenyl)NRaRb, — (Ci-Ce alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl) C(O)NRa, — C(O)NRaRb, — N(Ra)C(O)Rb, NRaRb— (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc, • Y 1-Y4 are independently, NR’ or — CR’, and R’ is H or halogen; Y5 and Y7 are independently, NR’ or — CR’, and R’ is H, — Ci-Ce alkyl, — Ci-Ce cycloalkyl• Z is independently -O-, -CO, -NH, -NRa- -CH2, — Ci-Ce alkyl, — C(O)NRaRb, — N(Ra)C(O)Rb• R2 and Rs is selected from the group of — H, — C4-C10 heterocyclyl, - heteroaryl, — C(O)heterocyclyl, — N(Ra)heterocyclyl, — C(Ra)heterocyclyl, — O-heterocyclyl, — C(O)heteroaryl, — N(Ra)heteroaryl, — C(Ra)heteroaryl, — O-heteroaryl, wherein any said 4-10 membered heterocycle optionally contains one, two or three nitrogen or oxygen; wherein aryl, heterocyclyl, a sulfur- containing heteroaryl, an oxygen-containing heteroaryl, or a nitrogencontaining heteroaryl, each of which may be substituted with 1, 2, or 3 substituents independently selected from halogen, heterocyclyl, alkyl, -CN, — (Ci-C6alkylenyl)NRaRb, — ORa, — (Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRb, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb’ — (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc, and — (Ci-Ce alkylenyl)RcRc; — CO heterocyclyl,• R3 and R4 are each independently selected from the group of H and Ci- C4 alkyl, C1-C4 aminoalkyl and C1-C4 alkoxy-Ci-C4 alkyl, or alternatively R3-81- 45844530.1and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl optionally substituted by a 4-8 membered heterocycloalkyl• R5 is selected from the group of — C4-C10 heterocyclyl, — CO heterocyclyl, wherein any said 4-10 membered heterocycle optionally contains one, two or three nitrogen;wherein each occurrence of Raand Rbcan be independently — H, — Ci-Ce alkenyl, — Ci-Ce alkynyl, — Ci-Ce haloalkyl, — Rc, heterocyclyl, or — Ci-Ce alkyl, wherein the — Ci-Ce alkyl can be substituted with a substituent selected from — ORe, — NReRf, — C(O)ORe, — C(O)NReRf, — S(O)2Re, — S(O)2NReRf, and — Rc;wherein each occurrence of Rcand Rccan be independently aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl, wherein each Rcgroup may be substituted with 1, 2, 3, 4, or 5 Rdgroups;wherein each occurrence of Rdcan be independently — Ci-Ce heteroaryl, — CO heteroaryl, wherein it can be optionally substituted with 1, 2, 3, 4, or 5 Regroups; — Ci-Ce alkyl, — C2-Ce alkenyl, — C2-Ce alkynyl, halogen, Ci-Ce haloalkyl, — CN, — NO2, — ORe, — S(O)2NReRf, — C(O)Re, — C(O)NReRf, — NReRf, — N(Re)C(O)Rf, — (Ci-Ce alkylenyl)-ORe, — (Ci-Ce alkylenyl)-C(O)NReRf, — (Ci-Ce alkylenyl)-NReRf, or — (Ci-C6alkylenyl)-N(Re)C(O)Rf;and wherein each occurrence of Reand Rfcan be independently — H, halogen, — CN, — Ci-Ce alkyl, — Ci-Ce cycloalkyl, aryl, heteroaryl or — Ci-Ce haloalkyl. optionally wherein R5 can be any one of the following:-82- 45844530.1Paragraph 9. The compound of any one of paragraphs 1 to 8, wherein said compound has a structure of any compounds found in Table 1.Paragraph 10. The compound of paragraph 7, wherein the compound isParagraph 11. The compound of paragraph 2, wherein said compound has the following Formula Vila, Vllb, or Vile:-83- 45844530.1or a pharmaceutically acceptable salt thereof, wherein all X, Y and R groups and subgroups (e.g., Y1-Y7, R1-R20, Ra-Rs, R’, etc.) are each independently selected from those identified and disclosed in Formula II, and / or Illa-b and / or IV and / or Va-c and / or Vile above.Paragraph 12. The compound of any one paragraphs 1-2, 7-8, or 11, wherein said compound has a structure of any compound found in Table 2.Paragraph 13. The compound of paragraph 1, wherein said compound has the following Formula Villa or Vlllb:Formula Villa Formula Vlllbor a pharmaceutically acceptable salt thereof, wherein all X, Y and R groups and subgroups (e.g., Y1-Y7, R1-R20, Ra-Rs, R’, etc.) are each independently selected from those identified and disclosed in Formula II, and / or Illa-b and / or IV and / or Va-c and / or Vile and / or Vllla-c above or as additionally indicated below:-84- 45844530.1Y2, and Y4-Y7 are independently selected from — N or — CR’, and R’ is H or halogen; andR15 is selected from — H, halogen, — CN. — (Ci-C6alkylenyl)NRaRb, — ORa, — (Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRb, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb’ — (Ci-Cg alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc, and — (Ci-Ce alkylenyl)RcRc, — CO heterocyclyl.Paragraph 14. The compound of paragraph 1, wherein said compound has the following Formula XI or Formula XF:or a pharmaceutically acceptable salt thereof, wherein:• X is independently — Ci-Ce alkyl, — (C1-C6 alkylenyl)NRaRb, — (Ci-CY alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl) C(O)NRa, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb— (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc;• Y1-Y4 are independently, N or — CR’, and R’ is H or halogen; Y5 and Y7 are independently, NR’ or — CR', and R’ is H, — Ci-Ce alkyl, — Ci-Ce cycloalkyl;• R4 is selected from the group of — H, — C4-C10 heterocyclyl, — CO heterocyclyl, wherein any said 4-10 membered heterocycle contains one, two or three nitrogen; wherein aryl, a sulfur-containing heteroaryl, an oxygencontaining heteroaryl, or a nitrogen-containing heteroaryl, each of which may be substituted with 1, 2, or 3 substituents independently selected from halogen,-85- 45844530.1-CN, — (Ci-C6alkylenyl)NRaRb, — 0Ra, — (Ci-C6alkylenyl)NC(O)Ra, — (Ci- C6alkylenyl)C(O)NRa, — N(Ra)S(O)2Rh, — S(O)2NRaRb, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb’ — (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc, and — (Ci-Ce alkylenyl)RcRc; — CO heterocyclyl;• R2and R3 are each independently selected from the group of H and Ci- C4 alkyl, C1-C4 aminoalkyl and C1-C4 alkoxy-Ci-C4 alkyl, or alternatively R2and R3 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl optionally substituted by a 4-8 membered heterocycloalkyl;• R4 is selected from the group of — C4-C10 heterocyclyl, — CO heterocyclyl, wherein any said 4-10 membered heterocyclyl contains one, two or three nitrogen;wherein each occurrence of Raand Rbcan be independently — H, — Ci-Ce alkenyl, — Ci-Ce alkynyl, — Ci-Ce haloalkyl, — Rc, heterocyclyl, or — Ci-Ce alkyl, wherein the — Ci-Ce alkyl can be substituted with a substituent selected from — ORe, — NReRf, — C(O)ORe, — C(O)NReRf, — S(O)2Re, — S(O)2NReRf, and — Rc;wherein each occurrence of Rcand Rccan be independently aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl, wherein each Rcgroup may be substituted with 1, 2, 3, 4, or 5 Rdgroups;wherein each occurrence of Rdcan be independently — Ci-Ce heteroaryl, — CO heteroaryl, wherein it can be optionally substituted with 1, 2, 3, 4, or 5 Regroups; — Ci-Ce alkyl, — C2-C6alkenyl, — C2-Ce alkynyl, halogen, Ci-Ce haloalkyl, — CN, — NO2, — ORe, — S(O)2NReRf, — C(O)Re, — C(O)NReRf, — NReRf, — N(Re)C(O)Rf, — (Ci-Ce alkylenyl)- ORe, — (Ci-Ce alkylenyl)-C(O)NReRf, — (Ci-Ce alkylenyl)-NReRf, or — (Ci-C6alkylenyl)-N(Re)C(O)Rf;and wherein each occurrence of Reand Rfcan be independently — H, halogen, — CN, — Ci-Ce alkyl, — Ci-Ce cycloalkyl, aryl, heteroaryl or — Ci-Ce haloalkyl. optionally, wherein R4 can be any one of the:-86- 45844530.1Paragraph 15. The compound of any one paragraphs 1-2, or 13-14, wherein said compound has a structure of any compounds found in Table 3.Paragraph 16. A pharmaceutical composition containing the compound of any one of paragraphs 1 to 15.Paragraph 17. A method of reducing viral load in a subject infected with SARS-CoV2 involving administering a pharmaceutical composition containing the compound of any one of paragraphs 1 to 15 to the subject.Paragraph 18. A method of treating or preventing a SARS-CoV2 infection in a subject involving administering a pharmaceutical composition containing the compound of any one of paragraphs 1 to 15 to the subject.Paragraph 19. Use of a pharmaceutical composition containing the compound of any one of paragraphs 1 to 15 to the subject to reduce viral load in a subject infected with SARS- CoV2.Paragraph 20. Use of a pharmaceutical composition containing the compound of any one of paragraphs 1 to 15 to treat a subject infected with SARS-CoV2.-87- 45844530.1EXAMPLESExample 1: Synthesis of (R)-5-(azetidin-3-ylamino)-N-(l-(isoquinolin-4-yl)ethyl)-2-methylbenzamide (SUN-052)

[0137] Step 1: To the mixture of 5-amino-2-methyl-benzoic acid (3.00 g, 19.9 mmol, 1.0 eq) and tert-butyl 3-oxoazetidine-l -carboxylate (10.2 g, 59.5 mmol, 3.0 eq) in MeOH (20 mL) was added AcOH (5.25 g, 87.3 mmol, 5 mL, 4.4 eq), after stirred at 50 °C for 2 h and cool down, NaBH₃CN (6.24 g, 99.2 mmol, 5.0 eq) was added to the above mixture. The reaction mixture was stirred at 20 °C for 3 h. LCMS showed the raw material was consumed up and desired mass ion in one peak. The mixture was filtered and the filter cake was dried under reduced pressure to give 5-[(l-tert-butoxycarbonylazetidin-3-yl) amino]-2-methyl-benzoic acid (5.10 g, 83.9% yield) as a white solid. 'H NMR (400 MHz, CDCh) 57.19 (d, 7= 2.4 Hz, 1H), 7.08 (d, 7= 8.4 Hz, 1H), 6.63 (dd, 7= 8.0, 2.4 Hz, 1H), 4.28-4.35 (m, 2H), 4.18-4.27 (m, 1H), 3.70-3.77 (m, 2H), 2.52 (s, 3H), 1.45 (s, 9H). LCMS: [M+Na]+329.1.

[0138] Step 2: To the mixture of 5-[(l-tert-butoxycarbonylazetidin-3-yl)amino]-2-methyl-benzoic acid (50 mg, 0.163 mmol, 1.0 eq) and (lR)-l-(4-isoquinolyl)ethanamine (31 mg, 0.180 mmol, l.l eq) in DMF (1 mL) was added HATU (71 mg, 0.186 mmol, 1.1 eq) and DMAP (44 mg, 0.359 mmol, 2.2 eq). The reaction mixture was stirred at 25 °C for 16 h. LCMS showed the raw material was consumed up and desired mass ion was detected. The mixture was diluted with water (~5 mL) and extracted with ethyl acetate (~4 mL x 3). The organic phase was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give crude product. The crude was purified by column chromatography (SiO2, 74 % ethyl acetate in petroleum ether) to give tert-butyl 3-[3-[[(lR)-l-(4-isoquinolyl)ethyl|carbamoyl|-4-methyl-anilino|azetidine-l -carboxylate (40 mg, 52.2% yield) as a colorless solid. 'H NMR (400 MHz, CDCh) 59.19 (s, 1H), 8.61 (s, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.84 (t, J = 7.6 Hz, 1H), 7.69 (t, J = 7.4 Hz, 1H), 7.00 (d, 7= 8.0 Hz, 1H), 6.48 (d, 7= 2.4 Hz, 1H), 6.42 (dd, 7= 8.4, 2.4 Hz, 1H), 6.19-6.25 (m, 1H),-88- 45844530.16.05-6.15 (m, 1H), 4.17-4.24 (m, 2H), 4.04-4.10 (m, 1H), 3.94-4.03 (m, 1H), 3.58-3.68 (m, 2H), 2.29 (s, 3H), 1.82 (d, 7= 6.8 Hz, 1H), 1.43 (s, 1H). LCMS: [M+H]+461.3.

[0139] Step 3: To the mixture of tert-butyl 3-[3-[[(lR)-l-(4-isoquinolyl)ethyl]carbamoyl]-4-methyl-anilino]azetidine-l -carboxylate (40 mg, 0.879 mmol, 1.0 eq) in DCM (0.5 mL) was added HCl / dioxane (1 M, 0.5 mL). Then the reaction mixture was stirred at 20 °C for 2 h. LCMS showed the raw material was consumed up. The reaction mixture was concentrated under reduced pressure to give crude product. The crude was dissolved in MeOH (1 mL) and purified by prep-HPLC (column: C18 150x30 mm; mobile phase: [Water (HCl)-MeCN]; gradient: 0%-37% B over 9 min). Most of solvent was removed under reduced pressure and the residue was lyophilized to give a yellow solid. The yellow solid dissolved in water (-2.5 mL) and lyophilized to give 5-(azetidin-3-ylamino)-N-[(lR)-l-(4-isoquinolyl)ethyl]-2-methyl-benzamide (3.40 mg, 8.26% yield, 99.15% purity, 3HC1) as a yellow solid.XH NMR (400 MHz, DMSO-Je) 9.80 (s, 1H), 9.15 (br s, 2H), 9.03 (d, J = 7.6 Hz, 1H), 8.61 (s, 1H), 8.56 (t, J = 8.4 Hz, 2H), 8.26 (t, J = 7.6 Hz, 1H), 8. O4 (t, 7= 7.2 Hz, 1H), 6.98 (d, 7 = 7.6 Hz, 1H), 6.52 (d, 7 = 2.0 Hz, 1H), 6.50 (s, 1H), 5.88-6.00 (m, 1H), 4.31-4.39 (m, 1H), 4.19-4.25 (m, 2H), 3.72-3.82 (m, 2H), 2.10 (s, 3H), 1.64 (d, 7= 6.8 Hz, 3H). LCMS:[M+H]+361.3Example 2: Synthesis of (R)-5-(azetidin-3-ylamino)-2-methyl-N-(l-(quinolin-4-yl)ethyl)benzamide (SUN-053):

[0140] Step 1: To a solution of 5-[(l-tert-butoxycarbonylazetidin-3-yl)amino]-2-methyl-benzoic acid (50 mg, 0.164 mmol, 1.0 eq) in DMF (1 mL) were added (lR)-l-(4-quinolyl)ethanamine (31 mg, 0.180 mmol, 1.1 eq), HATU (71 mg, 0.186 mmol, 1.14 eq) and DMAP (44 mg, 0.360 mmol, 2.2 eq), then the mixture was stirred at 10 °C for 12 h under N2. TLC (EtOAc: PE = 1: 1, UV) showed one new spot with larger polarity was detected. The mixture was diluted with H2O (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic phase was washed with sat. aq. NH.4Cl (5 mL), dried over anhydrous Na2SOi. filtered-89- 45844530.1and the filtrate was concentrated under reduced pressure to give a crude. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 82% Ethyl acetate / Petroleum ether gradient @ 30 mL / min) to give compound tertbutyl 3-[4-methyl-3-[[(lR)-l-(4-quinolyl)ethyl]carbamoyl]anilino]azetidine-l-carboxylate (45 mg, 58.2% yield) as a yellow oil. H NMR (400 MHz, CDCb) <58.91 (d, J= 4.8 Hz, 1H), 8.25 (d, 7= 8.4 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.78 (t, 7= 7.2 Hz, 1H), 7.66 (t, 7 = 7.2 Hz, 1H), 7.46 (d, 7 = 4.8 Hz, 1H), 7.02 (d, 7= 8.4 Hz, 1H), 6.52 (d, 7= 2.0 Hz, 1H), 6.47 (dd, 7 = 8.4 Hz, 2.4 Hz, 1H), 6.06-6.21 (m, 2H), 4.20-4.28 (m, 2H), 4.12-4.18 (m, 1H), 4.03 (br s, 1H), 3.64-3.72 (m, 2H), 2.30 (s, 3H), 1.76 (d, 7= 6.4 Hz, 3H), 1.45 (s, 9H). LCMS: [M+H]+461.1

[0141] Step 2: To a solution of tert-butyl 3-[4-methyl-3-[[(lR)-l-(4-quinolyl)ethyl]carbamoyl]anilino]azetidine-l -carboxylate (45 mg, 0.0977 mmol, 1.0 eq) in DCM (0.5 mL) was added HCl / dioxane (2 M, 1 mL), then the mixture was stirred at 15 °C for 2 h. ECMS showed main peak with desired MS was detected. The mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: Cl 8 150x30 mm; mobile phase: [Water (HCl)-MeCN]; gradient: 0%-28% B over 9 min). Most of solvent was removed under reduced pressure and the mixture was lyophilized to give compound 5-(azetidin-3-ylamino)-2-methyl-N-[(lR)-l-(4-quinolyl)ethyl]benzamide (19.2 mg, 41.5% yield, 99.2% purity, 3HC1) as a yellow solid. 'H NMR (400 MHz, DMSO-t / e) 3 9.58 (br s, 1H), 9.47 (br s, 1H), 9.37 (d, 7 = 5.6 Hz, 1H), 9.28 (d, 7 = 6.4 Hz, 1H), 8.74 (d, 7 = 8.4 Hz, 1H), 8.53 (d, 7 = 8.4 Hz, 1H), 8.21 (t, 7= 7.6 Hz, 1H), 8.00-8.12 (m, 2H), 7.00 (d, 7 = 8.4 Hz, 1H), 6.61 (s, 1H), 6.56 (d, 7 = 8.0 Hz, 1H), 5.96-6.08 (m, 1H), 4.36-4.55 (m, 1H), 4.16-4.28 (m, 2H), 3.75-3.88 (m, 2H), 2.12 (s, 3H), 1.61 (d, 7= 6.8 Hz, 3H). LCMS: [M+H]+361.3 Example 3: Synthesis of (R)-5-(azetidin-3-ylamino)-2-melhyl-N-(l-(quinolin-5-yl)ethyl)benzamide (SUN-054):

[0142] Step 1: To the mixture of 5-[(l-tert-butoxycarbonylazetidin-3-yl)amino]-2-methyl-benzoic acid (60 mg, 0.196 mmol, 1.0 eq) and (lR)-l-(5-quinolyl)ethanamine (37 mg,-90- 45844530.10.215 mmol, l.l eq) in DMF (1 mL) was added HATU (85 mg, 0.223 mmol, 1.1 eq) and DMAP (53 mg, 0.431 mmol, 2.2 eq). The reaction mixture was stirred at 25 °C for 16 h. LCMS showed the raw material was consumed up and desired mass ion was detected. The mixture was diluted with water (~5 mL) and extracted with ethyl acetate (-4 mL x 3). The organic phase was dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give crude product. The crude was purified by column chromatography (SiO2, 60% ethyl acetate in petroleum ether) to give tert-butyl 3-[4-methyl-3-[[(lR)-l-(5-quinolyl)ethyl]carbamoyl]anilino]azetidine-l-carboxylate (60 mg, 64.9% yield) as a white solid. 'H NMR (400 MHz, CHLOROFORM-tZ) <58.92-9.01 (m, 1H), 8.75 (d, J= 6.0 Hz, 1H), 8.14-8.21 (m, 1H), 7.71-7.80 (m, 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.51-7.59 (m, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.38-6.48 (m, 2H), 6.07-6.20 (m, 1H), 5.95 (d, J= 8.4 Hz, 1H), 4.18-4.27 (m, 2H), 4.08-4.17 (m, 1H), 3.60-3.72 (m, 2H), 2.26 (s, 3H), 1.80 (d, J= 6.8 Hz, 3H), 1.44 (s, 9H). LCMS: [M+H]+461.2

[0143] Step 2: To the mixture of tert-butyl 3-[4-methyL3-[[(lR)-l-(5-quinolyl)ethyl]carbamoyl]anilino]azetidine-l-carboxylate (60 mg, 0.130 mmol, 1.0 eq) in DCM (1.5 mL) was added HCl / dioxane (1 M, 1.5 mL). The reaction mixture was stirred at 20 °C for 3 h. LCMS showed the raw material was consumed up and desired mass ion in one peak. The reaction mixture was concentrated under reduced pressure to give crude product, which was dissolved in MeOH (1 mL) and purified by prep-HPLC (column: Cl 8 150x30 mm; mobile phase: [Water (HCl)-MeCN]; gradient: 0%-30% B over 9 min). Most of solvent was removed under reduced pressure and the residue was lyophilized to give 5-(azetidin-3-ylamino)-2-methyl-N-[(lR)-l-(5-quinolyl)ethyl]benzamide (14.7 mg, 23.9% yield, 99.52% purity, 3HC1) as a yellow solid. 'H NMR (400 MHz, DMSO-cfe) S 9.64 (br s, 2H), 9.58 (d, J = 8.8 Hz, 1H), 9.50 (br s, 1H), 9.36 (d, J = 5.2 Hz, 1H), 9.09 (d, J = 7.6 Hz, 1H), 8.44 (d, J = 8.4 Hz, 1H), 8.21 (t, J = 7.6 Hz, 2H), 8.03 (d, J = 7.2 Hz, 1H), 6.97 (br d, J = 8.8 Hz, 1H), 6.48-6.58 (m, 2H), 5.90-6.03 (m, 1H), 4.29-4.42 (m, 1H), 4.13-4.24 (m, 2H), 3.74-3.86 (m, 2H), 2.08 (s, 3H), 1.59 (d, J = 6.8 Hz, 3H). LCMS: [M+H]+361.3-91- 45844530.1Example 4: Synthesis of (R)-5-(azetidin-3-ylamino)-N-(l-(isoquinolin-5-yl)ethyl)-2-methylbenzamide (SUN-055):

[0144] Step 1: To a solution of 5-[(l-tert-butoxycarbonylazetidin-3-yl)amino]-2-methyl-benzoic acid (82 mg, 0.269 mmol, 1.0 eq) in DMF (2 mL) were added (lR)-l-(5-isoquinolyl)ethanamine (51 mg, 0.296 mmol, 1.1 eq), HATU (116 mg, 0.307 mmol, 1.14 eq) and DMAP (72 mg, 0.592 mmol, 2.2 eq), then the mixture was stirred at 10 °C for 12 h under N2. TLC (EtOAc: PE = 1: 1, UV) showed one new spot with larger polarity was detected. The mixture was diluted with H2O (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic phase was washed with sat. aq. NH4CI (5 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a crude. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaElash® Silica Flash Column, Eluent of 80% Ethyl acetate / Petroleum ether gradient @ 35 mL / min) to give compound tertbutyl 3-[3-[[(lR)-l-(5-isoquinolyl)ethyl]carbamoyl]-4-methyl-anilino]azetidine-l-carboxylate (70 mg, 56.4% yield) as a yellow oil.JH NMR (400 MHz, CDCI3) S 9.29 (s, 1H), 8.59 (d, J= 6.0 Hz, 1H), 8.07 (d, J= 6.0 Hz, 1H), 7.97 (d, J= 8.0 Hz, 1H), 7.80 (d, J= 6.8 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.48 (d, J = 2.4 Hz, 1H), 6.44 (dd, J = 8.4 Hz, 2.8 Hz, 1H), 5.96-6.10 (m, 2H), 4.18-4.26 (m, 2H), 4.10-4.15 (m, 1H), 3.62-3.69 (m, 2H), 2.28 (s, 3H), 1.78 (d, J = 6.4 Hz, 3H), 1.44 (s, 9H). LCMS: [M+H]+461.2

[0145] Step 2: To a solution of tert-butyl 3-[3- [[( lR)-l-(5-isoquinolyl)ethyl]carbamoyl]-4-methyl-anilino]azetidine-l -carboxylate (70 mg, 0.152 mmol, 1.0 eq) in DCM (0.5 mL) was added HCl / dioxane (2 M, 1.5 mL), then the mixture was stirred at 15 °C for 2 h. LCMS showed main peak with desired MS was detected. The mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: C18 150x30 mm; mobile phase: [Water (HCl)-MeCN]; gradient: 0%-28% B over 9 min). Most of solvent was removed under reduced pressure and the mixture was lyophilized to give compound 5-(azetidin-3-ylamino)-N-[(lR)-l-(5-isoquinolyl)ethyl]-2-methyl-benzamide (24.1 mg, 33.5% yield, 99.4% purity, 3HC1) as a yellow solid. 5.4 mg was for delivery. 18.7 mg was in hand.-92- 45844530.1m NMR (400 MHz, DMSO-de) 89.98 (s, 1H), 9.55 (br s, 1H), 9.45 (br s, 1H), 9.05 (d, J = 7.2 Hz, 1H), 8.80 (s, 2H), 8.51 (d, J = 8.0 Hz, 1H), 8.27 (d, J = 7.2 Hz, 1H), 8.07 (t, J = 7.6 Hz, 1H), 6.97 (d, 7= 8.0 Hz, 1H), 6.45-6.57 (m, 2H), 5.85-5.98 (m, 1H), 4.31-4.40 (m, 1H), 4.13-4.24 (m, 2H), 3.72-3.85 (m, 2H), 2.09 (s, 3H), 1.60 (d, J= 6.8 Hz, 3H). LCMS: [M+H]+361.3 Example 5: Synthesis of (R)-5-(azetidin-3-ylamino)-2-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)naphthalen-l-yl)ethyl)benzamide (SUN-058):

[0146] Step l: To a mixture of 5-[(l-tert-butoxycarbonylazetidin-3-yl)amino]-2-methyl-benzoic acid (120 mg, 0.392 mmol, 1.0 eq) and (lR)-l-(3-chloro-l-naphthyl)ethanamine (106 mg, 0.438 mmol, 1.1 eq, HC1) in DMF (2 mL) was added HATU (172 mg, 0.452 mmol, 1.2 eq), DMAP (106 mg, 0.868 mmol, 2.2 eq) under N2 and the mixture was stirred at 25 °C for 16 h. TLC (PE: EtOAc = 1: 1, UV) showed the starting material was consumed and new spots was observed. The mixture was diluted with water (6 mL), extracted with EtOAc (6 mL x 3). The combined organic phase was washed with brine (6 mL x 2), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a crude. The crude was purified by column chromatography (SiO2, Ethyl acetate in Petroleum ether = 0% to 50%, 12 g, 40 mL / min, UV) to give tert-butyl 3-[3-[[(lR)-l-(3-chloro-l-naphthyl)ethyl]carbamoyl]-4-methyl-anilino]azetidine-l -carboxylate (160 mg, 82.7% yield) as a white solid.1H NMR (400 MHz, DMSO-rfo) 88.86 (d, 7= 7.6 Hz, 1H), 8.22-8.27 (m, 1H), 7.94-8.00 (m, 2H), 7.59-7.66 (m, 2H), 7.57 (d, 7 = 2.0 Hz, 1H), 6.97 (d, 7 = 8.8 Hz, 1H), 6.41-6.50 (m, 2H), 6.25 (d, 7 = 6.0 Hz, 1H), 5.82-5.91 (m, 1H), 4.08-4.21 (m, 3H), 3.56-3.63 (m, 2H), 2.13 (s, 3H), 1.55 (d, 7 = 6.8 Hz, 3H), 1.39 (s, 9H). LCMS: [M+H-tBu]+438.1

[0147] Step 2: To a mixture of tert-butyl 3-[3-[[(lR)-l-(3-chloro-l-naphthyl)ethyl]carbamoyl]-4-methyl-anilino]azetidine-l-carboxylate (75 mg, 0.152 mmol, 1.0 eq) and l-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (63 mg, 0.304 mmol, 2.0 eq) in DMF (1.5 mL), H2O (0.3 mL) was added t-BuONa (29 mg, 0.304 mmol, 2.0 eq), XPhos-Pd-G3 (13 mg, 0.0152 mmol, 0.1 eq) under N2 and the mixture was stirred at 100 °C for 1.25 h. TLC (PE: EA = 1:1, UV) showed the starting material was consumed and new spots was observed. The mixture was diluted with H2O (6 mL) and extracted with EtOAC (6 mL x -93- 45844530.13). The combined organic phase was washed with water (6 mL), dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give a crude. The crude was purified by column chromatography (SiO2, Ethyl acetate in Petroleum ether = 0% to 80%, 4 g, 35 mL / min, UV) to give tert-butyl 3-[4-methyl-3-[[(lR)-l-[3-(l-methylpyrazol-3-yl)-l-naphthyl]ethyl]carbamoyl]anilino]azetidine-l -carboxylate (75 mg, 91.5% yield) as light yellow oil. H NMR (400 MHz, DMSO-rfe) <58.90 (d, J= 8.0 Hz, 1H), 8.17-8.23 (m, 2H), 8.14 (s, 1H), 7.96-8.00 (m, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.51-7.58 (m, 2H), 6.92-6.98 (m, 1H), 6.80 (d, J= 2.4 Hz, 1H), 6.43-6.49 (m, 2H), 6.17-6.25 (m, 1H), 5.89 (t, 7 = 7.2 Hz, 1H), 4.07-4.18 (m, 3H), 3.91 (s, 3H), 3.54-3.62 (m, 2H), 2.13 (s, 3H), 1.59 (d, 7 = 7.2 Hz, 3H), 1.38 (s, 9H). LCMS: [M+H]+540.3

[0148] Step 3: To a compound of tert-butyl 3-[4-methyl-3-[[(lR)-l-[3-(l-methylpyrazol-3-yl)-l-naphthyl]ethyl]carbamoyl]anilino]azetidine-l -carboxylate (75 mg, 0.139 mmol, 1.0 eq) in HCl / dioxane (2 M, 2.5 mL) under N2 and the mixture was stirred at 25 °C for 14 h. crude LCMS showed the starting material was consumed and desired mass ion was observed. The mixture was concentrated under reduced pressure to remove HCl / dioxane and give crude as a yellow solid. The mixture was diluted with MeOH (2.0 mL) and the solution was purified by prep-HPLC (column: C 18 150 x 30 mm; mobile phase: [Water (HC1) -MeCN]; gradient: 10% - 60% B over 9 min). Most of solvent was removed under reduced pressure and the mixture was lyophilized to give 5-(azetidin-3-ylamino)-2-methyl-N-[(lR)-l-[3-(l-methylpyrazol-3-yl)-l-naphthyl]ethyl]benzamide (30.7 mg, 43.1% yield, 100% purity, 2HC1) as a pink solid. H NMR (400 MHz, DMSO-rfc) d 9.26 (br s, 2H), 8.91 (d, 7 = 7.6 Hz, 1H), 8.17-8.22 (m, 2H), 8.13 (s, 1H), 7.95-8.01 (m, 1H), 7.79 (d, 7 = 2.4 Hz, 1H), 7.50-7.59 (m, 2H), 6.98 (d, 7= 8.0 Hz, 1H), 6.80 (d, 7 = 2.4 Hz, 1H), 6.48-6.53 (m, 2H), 5.83-5.93 (m, 1H), 4.30-4.37 (m, 1H), 4.15-4.23 (m, 2H), 3.91 (s, 3H), 3.73-3.81 (m, 2H), 2.13 (s, 3H), 1.59 (d, 7= 6.8 Hz, 3H). LCMS: [M+H]+440.1.-94- 45844530.1Example 6: Synthesis of (R)-5-(azetidin-3-ylamino)-N-(l-(3,5-bis(l-methyl-lH-pyrazol-3-yl)pheny 1 ) ethyl ) - 2-methy Ibenzami de ( SUN-067):

[0149] Stepl: To a mixture of 5-[(l-tert-butoxycarbonylazetidin-3-yl)amino]-2-methyl-benzoic acid (120 mg, 0.392 mmol, 1.0 eq) and (lR)-l-(3-chloro-l-naphthyl)ethanamine (106 mg, 0.438 mmol, 1.1 eq, HC1) in DMF (2 mL) was added HATU (172 mg, 0.452 mmol, 1.2 eq), DMAP (106 mg, 0.868 mmol, 2.2 eq) under N2 and the mixture was stirred at 25 °C for 16 h. TLC (PE: EtOAc = 1: 1, UV) showed the starting material was consumed and new spots was observed. The mixture was diluted with water (6 mL), extracted with EtOAc (6 mL x 3). The combined organic phase was washed with brine (6 mL x 2), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a crude. The crude was purified by column chromatography (SiO2, Ethyl acetate in Petroleum ether = 0% to 50%, 12 g, 40 mL / min, UV) to give tert-butyl 3-[3-[[(lR)-l-(3-chloro-l-naphthyl)ethyl]carbamoyl]-4-methyl-anilino]azetidine-l -carboxylate (160 mg, 82.7% yield) as a white solid.XH NMR (400 MHz, DMSO-de) ri 8.86 (d, J = 7.6 Hz, 1H), 8.22-8.27 (m, 1H), 7.94-8.00 (m, 2H), 7.59-7.66 (m, 2H), 7.57 (d, J = 2.0 Hz, 1H), 6.97 (d, J= 8.8 Hz, 1H), 6.41-6.50 (m, 2H), 6.25 (d, J= 6.0 Hz. 1H), 5.82-5.91 (m. 1H), 4.08-4.21 (m, 3H). 3.56-3.63 (m, 2H). 2.13 (s, 3H). 1.55 (d, J = 6.8 Hz, 3H), 1.39 (s, 9H). LCMS: [M+H-tBu]+438.1

[0150] Step 2: To a solution of tert-butyl 3-[3-[[(lR)-l-(3,5-dichlorophenyl)ethyl]carbamoyl]-4-methyl-anilino]azetidine-l-carboxylate (200 mg, 0.418 mmol, 1.0 eq) in DMF (4 mL) and H2O (0.8 mL) were added l-methyl-3-(4,4,5,5-tetramethyl--95- 45844530.1l,3,2-dioxaborolan-2-yl)pyrazole (261 mg, 1.25 mmol, 3.0 eq), t-BuONa (80 mg, 0.836 mmol, 2.0 eq) and XPhos Pd G3 (35 mg, 0.0418 mmol, 0.1 eq), then the brown mixture was stirred at 100 °C for 1 h under N2. TLC (PE: EtOAc = 0: 1, UV) showed the starting material was consumed and one new spot with larger polarity was detected. The combined mixture was diluted with H2O (15 mL) and extracted with EOAc (10 mL x 3). The combined organic phase was washed with sat. aq. NEUCl (10 mL x 2), dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give a crude. The residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® Silica Flash Column, Eluent of 40% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to give compound tert-butyl 3- [3 - [[( 1 R)-l-[3,5-bis(l-methylpyrazol-3-yl)phenyl]ethyl]carbamoyl]-4-methyl-anilino]azetidine-l-carboxylate (150 mg, 57.2% yield) as a white gum.XH NMR (400 MHz, DMSO-rfc) 38.71 (d, 7= 8.0 Hz, 1H), 8.03 (s, 1H), 7.71 (s, 4H), 6.96 (d, J= 8.4 Hz, 1H), 6.71 (d, J = 2.4 Hz, 2H), 6.42-6.49 (m, 2H), 6.20 (d, J = 5.6 Hz, 1H), 5.10-5.22 (m, 1H), 4.09-4.22 (m, 3H), 3.90 (s, 6H), 3.55-3.65 (m, 2H), 2.13 (s, 3H), 1.48 (d, J= 6.8 Hz, 3H), 1.38 (s, 9H).

[0151] Step 3: To a solution of tert-butyl 3-[3-[[(lR)-l-[3,5-bis(l-methylpyrazol-3-yl)phenyl]ethyl]carbamoyl]-4-methyl-anilino]azetidine-l-carboxylate (150 mg, 0.263 mmol, 1.0 eq) in DCM (2 mL) was added HCl / dioxane (2 M, 2 mL), then the mixture was stirred at 10 °C for 12 h. LCMS showed main peak with desired MS was detected. The mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: C18 150x30 mm: mobile phase: [Water (HCl)-MeCN]; gradient: 10%-50% B over 9 min). Most of solvent was removed under reduced pressure and the mixture was lyophilized to give compound 5-(azetidin-3-ylamino)-N-[(lR)-l-[3,5-bis(l-methylpyrazol-3-yl)phenyl]ethyl]-2-methyl-benzamide (99.3 mg, 69.5% yield, 100% purity, 2HC1) as a white solid.! H NMR (400 MHz, DMSO-de) 39.40-9.60 (m, 2H), 8.77 (d, J= 8.0 Hz, 1H), 8.61 (s, 2H), 8.06 (s, 1H), 7.70-7.82 (m, 4H), 7.00 (d, J = 8.8 Hz, 1H), 6.73 (d, J = 2.0 Hz, 2H), 6.50-6.60 (m, 2H), 5.09-5.22 (m, 1H), 4.30-4.42 (m, 1H), 4.14-4.24 (m, 2H), 3.90 (s, 6H), 3.76-3.86 (m, 2H), 2.13 (s, 3H), 1.48 (d, J= 7.2 Hz, 3H). LCMS: [M+H]+470.4.-96- 45844530.1Example 7: Synthesis of (R)-5-(cyclobutylamino)-2-methyl-N-(l-(7-(l-methyl-lH-pyrazol-3-yl)quinolin-5-yl)ethyl)benzamide (SUN-060):

[0152] Step 1: To a solution of 5,7-dichloroquinoline (300 mg, 1.51 mmol, 1.0 eq) in DMF (3 mL) and H2O (0.6 mL) were added l-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (315 mg, 1.51 mmol, 1.0 eq), Cs2CO3 (987 mg, 3.03 mmol, 2.0 eq) and XPhos Pd G3 (128 mg, 0.151 mmol, 0.1 eq), then the mixture was stirred at 100 °C for 1 h under N2. LCMS showed two peaks with desired MS was detected. The mixture was diluted with H2O (30 mL) and extracted with EOAc (20 mL x 3). The combined organic phase was concentrated under reduced pressure to give a crude. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 41% Ethyl acetate / Petroleum ether gradient @ 35 mL / min) to give 230 mg impure product, which was repurified by prep-HPLC (column: Boston Prime C18 150*30 mm*5 um; mobile phase: [water (ammonia hydroxide v / v)-ACN]; gradient: 30%-50% B over 11 min). Most of solvent was removed under reduced pressure and the mixture was respectively lyophilized to give byproduct 7-chloro-5-(l-methylpyrazol-3-yl)quinoline (110 mg, 29.8% yield) as a white solid and compound 5-chloro-7-(l-methylpyrazol-3-yl)quinoline (80 mg, 21.6% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) 5 8.99 (dd, J = 4.0, 1.2 Hz, 1H), 8.53 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H), 8.24 (s, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.60-7.70 (m, 1H), 7.03 (d, J = 2.4 Hz, 1H), 3.94 (s, 3H).

[0153] Step 2: To a solution of 5-chloro-7-(l-methylpyrazol-3-yl)quinoline (1.40 g, 5.74 mmol, 1.0 eq) in DMF (20 mL) were added tributyl(l -ethoxy vinyl) stannane (3.11 g, 8.62 mmol, 1.5 eq), Pd(PPh3)2C12 (806 mg, 1.15 mmol, 0.2 eq) and t-Bu3P (11.6 g, 5.74 mmol, 10% purity in toluene, 1.0 eq), then the mixture was stirred at 120 °C for 14 h under N2. TLC (PE: EtOAc = 3: 1, UV) showed the starting material was consumed and one new spot with-97- 45844530.1larger polarity was detected. The mixture was cooled to 10 °C. Then the mixture was added sat. aq. KF (80 mL). The solution was stirred at 10 °C for 30 min. The mixture was extracted with EtOAc (60 mL x 3). The combined organic phase was washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a crude compound 5-(l-ethoxyvinyl)-7-(l-methylpyrazol-3-yl)quinoline (1.70 g, crude) as a yellow oil.

[0154] Step 3: To a yellow solution of 5-(l -ethoxy vinyl)-7-(l -methylpyrazol-3-yl)quinoline (5.74 mmol, 1.0 eq) in THF (20 mL) was added 2N aq. HC1 (5.74 mmol, 10 mL), then the yellow mixture was stirred at 15 °C for 2 h under N2. TLC (PE: EtOAc = 2: 1, UV) showed the starting material was consumed and one new spot with larger polarity was detected. The mixture was diluted with H2O (60 mL). The aqueous solution was adjusted pH to 8~9. The mixture was extracted with EtOAc (50 mL x 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a crude. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column. Eluent of 53-60% Ethyl acetate / Petroleum ether gradient @ 45 mL / min) to give compound l-[7-(l-methylpyrazol-3-yl)-5-quinolyl]ethanone (910 mg, 61.7% yield for two steps) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) 5 8.90-8.97 (m, 2H), 8.62 (d, J = 1.6 Hz, 1H), 8.54 (s, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.55-7.61 (m, 1H), 7.06 (d, J = 2.0 Hz, 1H), 3.97 (s, 3H). 2.80 (s, 3H).

[0155] Step 4: To a solution of l-[7-(l-methylpyrazol-3-yl)-5-quinolyl]ethanone (910 mg, 3.62 mmol, 1.0 eq) in THF (20 mL) were added (S)-2-methylpropane-2-sulfinamide (1.32 g, 10.9 mmol, 3.0 eq) and Ti(OEt)4 (2.48 g, 10.9 mmol, 3.0 eq) at 15 °C, then the mixture was stirred at 70 °C for 5 h under N2. TLC (PE: EtOAc = 1: 1, UV) showed the starting material was consumed and one new spot with larger polarity was detected. The mixture was cooled to 15 °C. The reaction mixture was diluted with H2O (50 mL) and EtOAc (50 mL). The suspension was formed. The mixture was filtered. The filter cake was washed with EtOAc (20 mL). The filtrate was separated. The aqueous phase was extracted with EtOAc (40 mL x 2). The combined organic phase was washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a crude. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 92% Ethyl acetate / Petroleum ether gradient @ 45 mL / min) to give compound (NE, S)-2-methyl-N-[l-[7-(l-methylpyrazol-3-yl)-5-quinolyl]ethylidene]propane-2-sulfinamide (1.10 g, 85.7% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) 5 8.91--98- 45844530.18.97 (m, 1H), 8.61 (d, J = 8.8 Hz, 1H), 8.47 (s, 1H), 8.25 (s, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.52-7.58 (m, 1H), 7.03 (d, J = 2.0 Hz, 1H), 3.95 (s, 3H), 2.88 (s, 3H), 1.21 (s, 9H).

[0156] Step 5: To a solution of (NE, S)-2-methyl-N-[l-[7-(l-methylpyrazol-3-yl)-5-quinolyl]ethylidene]propane-2-sulfinamide (1.10 g, 3.10 mmol, 1.0 eq) in THF (15 ml.) was added L-selectride (1 M in THF, 4.65 mmol, 1.5 eq) at -70 °C, then the yellow solution was stirred at -70 °C for 2 h under N2. TLC (PE: EtOAc = 0: 1, UV) showed the starting material was consumed and one new spot with larger polarity was detected. The mixture was quenched slowly with sat. aq. NH4C1 (30 mL) at -10 °C-0 °C. The mixture was diluted with H2O (30 mL) and extracted with EtOAc (40 mL x 3). The combined organic phase was washed with 1% NaClO (50 mL x 2), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a crude. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 100% Ethyl acetate / Petroleum ether to 10% Methanol / Ethyl acetate gradient @ 45 ml. / min) to give compound (S)-2-methyl-N-[(lR)-l-[7-(l-methylpyrazol-3-yl)-5-quinolyl]ethyl]propane-2-sulfinamide (890 mg, 80.5% yield) as a yellow oil. 1H NMR (400 MHz. DMSO-d6) 5 8.86-8.90 (m, 1H), 8.63 (d,.1 = 8.8 Hz, 1H), 8.27 (s, 1H), 8.20 (d,.1 = 1.6 Hz, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.46-7.52 (m, 1H), 6.90 (d, J = 2.4 Hz, 1H), 5.60 (d,.1 = 5.6 Hz, 1H), 5.14-5.25 (m, 1H), 3.94 (s, 3H), 1.67 (d, J = 6.8 Hz, 3H), 1.10 (s, 9H); LCMS: [M+H]+ 357.2

[0157] Step 6: To a solution of 2,2-dimethyl-N-[(lR)-l-[7-(l-methylpyrazol-3-yl)-5-quinolyl]ethyl]propanamide (890 mg, 2.65 mmol, 1.0 eq) in DCM (10 mL) was added HCl / dioxane (2 M, 10 mL), then the yellow suspension was stirred at 15 °C for 12 h under N2. TLC (EtOAc: MeOH = 10: 1, UV) showed one new spot with larger polarity was detected. The mixture was filtered. The filter cake was dried under reduced pressure to give compound (1R)-l-[7-(l-methylpyrazol-3-yl)-5-quinolyl]ethanamine (760 mg, 88.3% yield, 2HC1) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) 5 9.43 (d, J = 8.8 Hz, 1H), 9.22-9.30 (m, 3H), 8.90 (s, 1H), 8.80 (s, 1H), 8.01-8.09 (m, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.23 (d, J = 2.0 Hz, 1H), 5.30-5.50 (m, 1H), 3.99 (s, 3H). 1.70 (d, J = 6.8 Hz, 3H).

[0158] Step 7: To a solution of (lR)-l-[7-(l-methylpyrazol-3-yl)-5-quinolyl]ethanamine (100 mg, 0.307 mmol, 1.1 eq, 2HC1) in DMF (4 mL) were added 5-[(l-tert-butoxycarbonylazetidin-3-yl)amino]-2-methyl-benzoic acid (86 mg, 0.279 mmol, 1.0 eq), HATU (121 mg, 0.319 mmol, 1.14 eq) and DMAP (75 mg, 0.615 mmol, 2.2 eq), then the solution was stirred at 15 °C for 14 h under N2. TLC (EtOAc: PE = 2: 1, UV) showed the starting material was consumed and two new spots were detected. The mixture was diluted-99- 45844530.1with H20 (15 mL) and extracted with EOAc (10 mL x 3). The combined organic phase was washed with sat. aq. NH4C1 (10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a crude. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 100% Ethyl acetate / Petroleum ether to 6% Methanol / Ethyl acetate gradient @ 35 mL / min) to give compound tert-butyl 3-[4-methyl-3-[[(lR)-l-[7-(l-methylpyrazol-3-yl)-5-quinolyl]ethyl]carbamoyl]anilino]azetidine-l -carboxylate (90 mg, 47.7% yield) as a yellow gum. LCMS: [M+H]+ 541.5

[0159] Step 8: To a solution of tert-butyl 3-[4-methyl-3-[[(lR)-l-[7-(l-methylpyrazol-3-yl)-5-quinolyl]ethyl]carbamoyl]anilino]azetidine-l-carboxylate (90 mg, 0.166 mmol, 1.0 eq) in DCM (1 mL) was added HCl / dioxane (2 M, 2 mL), then the mixture was stirred at 15 °C for 12 h under N2. LCMS showed main peak with desired MS was detected. The mixture was concentrated under reduced pressure to give a crude, which was purified by prep-HPLC (column: Boston Prime C18 150*30 mm*5 um; mobile phase: [Water (FA)-MeCN]; gradient: 0%-30% B over 9 min). Most of solvent was removed under reduced pressure and the mixture was lyophilized to give compound 5-(azetidin-3-ylamino)-2-methyl-N-[(lR)-l-[7-(l-methylpyrazol-3-yl)-5-quinolyl]ethyl]benzamide (35 mg, 47.7% yield, impure) as a white solid. Impure compound 5-(azetidin-3-ylamino)-2-methyl-N-[(lR)-l-[7-(l-methylpyrazol-3-yl)-5-quinolyl]ethyl]benzamide (35 mg) was send to SFC. The residue was purified by SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 um); mobile phase: [CO2-EtOH (0.1% NH3H2O)J; B%: 40%%, isocratic elution mode). The desired fraction (peak 2, Rt = 1.566) was concentrated under reduced pressure. Then MeCN (5 mL) and H2O (25 mL) were added, and the solvent was lyophilized to give compound 5-(azetidin-3-ylamino)-2-methyLN-[(lR)-l-[7-(l-methylpyrazol-3-yl)-5-quinolyl]ethyl]benzamide (14.4 mg, 41.1% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) 5 8.89-8.97 (m, 2H), 8.67 (d, J = 8.8 Hz, 1H), 8.67 (s, 1H), 8.65 (s, 1H), 7.81 (d,.1 = 2.0 Hz, 1H), 7.50-7.60 (m, 1H), 6.88-6.95 (m, 2H), 6.42-6.48 (m, 2H), 6.01-6.15 (m, 1H), 5.82-5.91 (m, 1H), 4.09-4.21 (m, 1H), 3.93 (s, 3H), 3.63-3.75 (m, 211), 3.48-3.61 (m, 211), 2.10 (s, 311), 1.59 (d,.1 = 6.8 Hz, 311); LCMS: [M+H]+ 441.1.-100- 45844530.1Example 8: Synthesis of (R)-5-(azetidin-3-ylamino)-N-(l-(3-(5- ((cyclopentylamino)methyl)thiophen-2-yl)-5-(l -methyl- lH-pyrazol-3-yl)phenyl)ethyl)-2- methylbenzamide (SUN-061):

[0160] Step 1: To a solution of tert-butyl 3-[3-[[(lR)-l-(3,5- dichlorophenyl)ethyl]carbamoyl]-4-methyl-anilino]azetidine-l-carboxylate (130 mg, 0.271 mmol, 1.0 eq) in DMF (2.5 mL) and H2O (0.5 mL) were added l-methyl-3-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (59 mg, 0.285 mmol, 1.05 eq), XPhos Pd G3 (23 mg, 0.0272 mmol, 0.1 eq) and CS2CO3 (177 mg, 0.543 mmol, 2.0 eq), then the mixture was stirred at 100 °C for 1 h under N2. TLC (PE: EtOAc = 0: 1, UV) showed new spots with larger polarity were detected. The mixture was diluted with H2O (12 mL) and extracted with EOAc (10 mL x 3). The combined organic phase was washed with sat. aq. NEUCl (10 mL x 2), dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give a crude, which was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 85% Ethyl acetate / Petroleum ether gradient @ 35 mL / min) to give compound tert-butyl 3-|3-LL(lR)-l-|3-chloro-5-(l-methylpyrazol-3- yl)phenyl]ethyl]carbamoyl]-4-methyl-anilino]azetidine-l-carboxylate (110 mg, 66.8% yield) as a yellow oil. LCMS: [M+H-Boc]+424.1

[0161] Preparation of (5-((cyclopentylamino)methyl)thiophen-2-yl)boronic acid-101- 45844530.1

[0162] To a solution of cyclopentanamine (819 mg, 9.62 mmol, 1.0 eq) in MeOH (10 mL) were added a solution of (5-formyl-2-thienyl)boronic acid (1.50 g, 9.62 mmol, 1.0 eq) in MeOH (10 mL) and a solution of NaBH₃CN (1.21 g, 19.2 mmol, 2.0 eq) in MeOH (3 mL), then the mixture was stirred at 10 °C for 12 h under N2. LCMS showed main peak with desired MS was detected. The mixture was diluted with H2O (120 mL) and extracted with EOAc (100 mL x 3). The combined organic phase was washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a crude. The 1 / 2 residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 95% Ethyl acetate / Petroleum ether gradient @ 45 mL / min) to give compound [5-[(cyclopentylamino)methyl]-2-thienyl]boronic acid (850 mg, 33.3% yield) as a yellow solid. Another 1 / 2 residue was purified by prep-HPLC (column: Boston Prime C18 150*30 mm*5 um; mobile phase: [water (ammonia hydroxide v / v)-ACN]; gradient: 0%-40% B over 11 min). Most of solvent was removed under reduced pressure and the mixture was lyophilized to give compound [5-[(cyclopentylamino)methyl]-2-thienyl]boronic acid (450 mg, 20.8% yield) as a white solid. 'H NMR (400 MHz, DMSO-rie) ri 7.32-7.52 (m, 1H), 6.92-7.10 (m, 1H), 3.85-3.97 (m, 2H), 3.00-3.15 (m, 1H), 1.55-1.82 (m, 4H), 1.30-1.51 (m, 4H). LCMS:[M+H]+226.1

[0163] Step 2: To a solution of tert-butyl 3-[3-[[(lR)-l-[3-chloro-5-(l-methylpyrazol-3-yl)phenyl]ethyl]carbamoyl]-4-methyl-anilino]azetidine-l-carboxylate (80 mg, 0.153 mmol, 1.0 eq) in DMF (2 mL) and H2O (0.4 mL) were added [5-[(cyclopentylamino)methyl]-2-thienyl]boronic acid (103 mg, 0.458 mmol, 3.0 eq), XPhos Pd G3 (13 mg, 0.0153 mmol, 0.1 eq) and CS2CO3 (99 mg, 0.305 mmol, 2.0 eq), then the mixture was stirred at 100 °C for 1 h under N2. TLC (EtOAc: MeOH = 20: 1, UV) showed one new spot with larger polarity was detected. The mixture was diluted with H2O (15 mL) and extracted with EOAc (10 mL x 3). The combined organic phase was washed with sat. aq. NILCl (10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a crude, which was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 20% Methanol / Ethyl acetate gradient @ 40 mL / min) to give compound tertbutyl 3-[3-[[(lR)-l-[3-[5-[(cyclopentylamino)methyl]-2-thienyl]-5-(l-methylpyrazol-3--102- 45844530.1yl)phenyl]ethyl]carbamoyl]-4-methyl-anilino]azetidine-l -carboxylate (80 mg, 41.9% yield) as a yellow oil. LCMS: [M+H]+669.4

[0164] Step 3: To a solution of tert-butyl 3-[3-[[(lR)-l-[3-[5-[(cyclopentylamino)methyl]-2-thienyl]-5-(l-methylpyrazol-3-yl)phenyl]ethyl]carbamoyl]-4-methyl-anilino]azetidine-l -carboxylate (80 mg, 0.119 mmol, 1.0 eq) in DCM (1 mL) was added HCl / dioxane (2 M, 1.5 mL), then the mixture was stirred at 10 °C for 1 h 30 min. LCMS showed main peak with desired MS was detected. The mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: C18 150x30 mm; mobile phase: [Water (HCl)-MeCN]; gradient: 12%-52% B over 9 min). Most of solvent was removed under reduced pressure and the mixture was lyophilized to give compound 5-(azetidin-3-ylaniino)-N-[(lR)-l-[3-[5-[(cyclopentylamino)methyl]-2-thienyl]-5-(l-methylpyrazol-3-yl)phenyl]ethyl]-2-methyl-benzamide (20.7 mg, 24.8% yield, 97.38% purity, 3HC1) as a yellow solid. H NMR (400 MHz, DMSO-rfc) b 9.59-9.71 (m, 2H), 9.35-9.50 (m, 2H), 8.79 (d, J= 8.0 Hz, 1H), 7.90 (s, 1H), 7.78 (s, 2H), 7.58 (s, 1H), 7.53 (d, 7= 3.6 Hz, 1H), 7.42 (d, 7= 3.2 Hz, 1H), 6.95-7.02 (m, 1H), 6.76 (d, 7= 2.0 Hz, 1H), 6.48-6.57 (m, 2H), 5.11-5.21 (m, 1H), 4.32-4.41 (m, 3H), 4.15-4.25 (m, 2H), 3.91 (s, 3H), 3.75-3.85 (m, 2H), 3.40-3.53 (m, 1H), 2.13 (s, 3H), 1.92-2.02 (m, 2H), 1.68-1.80 (m, 4H), 1.44-1.56 (m, 5H). LCMS:[M+H]+569.5-103- 45844530.1Example 9: Synthesis of (R)-2-amino-A-(l-(3-(5-((cyclopentylamino)methyl)thiophen-2-yl)-5-(l-methyl-lH-pyrazol-3-yl)phenyl)ethyl)-5-methylisonicotinamide (SUN-062):

[0165] Step 1: To a mixture of 2-amino-5 -methyl -pyridine-4-carboxylic acid (80 mg, 0.526 mmol, 1.0 eq) and (lR)-l-(3,5-dichlorophenyl)ethanamine (120 mg, 0.530 mmol, 1.0 eq, HC1) in DMF (2.0 mL) was added HATU (200 mg, 0.526 mmol, 1.0 eq), DMAP (6.42 mg, 0.0526 mmol, 0.1 eq), TEA (160 mg, 1.58 mmol, 3.0 eq) under N2 and the mixture was stirred at 25 °C for 16 h. crude LCMS showed the starting material was consumed and desired mass ion was observed. The mixture was combined with ES27095-234, diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (10 mL x 3), dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give a crude. The crude was purified by column chromatography (SiO2, Ethyl acetate in Petroleum ether = 0% to 100%, 4 g, 30 mL / min, UV) to give 2-amino-N-[(lR)-l-(3,5-dichlorophenyl)ethyl]-5-methyl-pyridine-4-carboxamide (128 mg, 60.1% yield) as a white solid. 'H NMR (400 MHz, DMSO-rfo) d 8.87 (d, J = 8.0 Hz. 1H), 7.77 (s, 1H), 7.45-7.52 (m, 1H), 7.43 (d, J = 1.6 Hz, 2H), 6.37 (s, 1H), 5.87 (s, 2H), 5.03-5.11 (m, 1H), 2.01 (s, 3H), 1.39 (d, 7 = 7.2 Hz, 3H). LCMS: [M+H]+324.0

[0166] Step 2: To a mixture of 2-amino-N-[(lR)-l-(3,5-dichlorophenyl)ethyl]-5-methyl-pyridine-4-carboxamide (118 mg, 0.364 mmol, 1.0 eq) and l-methyl-3-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (76 mg, 0.365 mmol, 1.0 eq) in DMF (3.5 mL), H2O (0.7 mL) was added Cs2CO3(237 mg, 0.727 mmol, 2.0 eq), XPhos Pd G3 (31 mg, 0.0364 -104- 45844530.1mmol, 0.1 eq) under N2 and the mixture was stirred at 100 °C for 1 h. TLC (PE: EA = 0: 1, UV) showed the starting material was consumed and new spots was observed. The mixture was diluted with H2O (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic phase was washed with brine (15 mL x 3), dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give a crude. The crude was purified by column chromatography (S1O2. Ethyl acetate in Petroleum ether = 0% to 100% then Methanol in Ethyl acetate = 0% to 10%, 4 g, 30 mL / min, UV) to give 2-amino-N-[(lR)-l-[3-chloro-5-(l-methylpyrazol-3-yl)phenyl]ethyl]-5-methyl-pyridine-4-carboxamide (32 mg, 23.8% yield) as a white solid. 'H NMR (400 MHz, DMSO-rfe) <58.91 (d, J = 7.6 Hz, 1H), 7.72-7.81 (m, 3H), 7.65-7.70 (m, 1H), 7.33 (s, 1H), 6.76 (d, J = 2.0 Hz, 1H), 6.37 (s, 1H), 5.87 (s, 2H), 5.05-5.16 (m, 1H), 3.89 (s, 3H), 2.02 (s, 3H), 1.42 (d, 7= 6.8 Hz, 3H). LCMS: [M+H]+370.1

[0167] Step 3: To a mixture of 2-amino-N-[(lR)-l-[3-chloro-5-(l-methylpyrazol-3-yl)phenyl]ethyl]-5-methyl-pyridine-4-carboxamide (29 mg, 0.0784 mmol, 1.0 eq) and [5-[(cyclopentylamino)methyl]-2-thienyl]boronic acid (110 mg, 0.489 mmol, 6.2 eq) in DMF (1 mL), H2O (0.2 mL) was added CS2CO3 (77 mg, 0.236 mmol, 3.0 eq), XPhos Pd G3 (6.6 mg, 0.00784 mmol, 0.1 eq) under N2 and the mixture was stirred at 100 °C for 2 h. crude LCMS showed the starting material was consumed and desired mass ion was observed. The mixture was concentrated under reduced pressure to give crude as a brown solid. The crude was diluted with water (3 mL), extracted with EtOAc (3 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give crude as light brown oil (60 mg). The crude was diluted with MeOH (2.0 mL) and purified by prep-HPLC (column: Boston Prime Cl 8 150 * 30 mm * 5 um; mobile phase: [water (ammonia hydroxide v / v) - ACN]; gradient: 40% - 60% B over 11 min). Most of solvent was removed under reduced pressure and the mixture was lyophilized to give 2-amino-N-[(lR)-l-[3-[5-[(cyclopentylamino)methyl]-2-thienyl]-5-(l-methylpyrazol-3-yl)phenyl]ethyl]-5-methyl-pyridine-4-carboxamide (0.8 mg, 1.91% yield, 96.41% purity) as a white solid. And 2-amino-N-[(lR)-l-[3-[5-[(cyclopentylamino)methyl]-2-thienyl]-5-(l-methylpyrazol-3-yl)phenyl]ethyl]-5-methyl-pyridine-4-carboxamide (2.6 mg, 6.31% yield, 97.97% purity) as a light red solid. H NMR (500 MHz, DMSO-rfe) d 8.90 (d, J= 8.0 Hz, 1H), 7.86 (s, 1H), 7.73-7.79 (m, 2H), 7.71 (s, 1H), 7.53 (s, 1H), 7.37 (d, J = 3.5 Hz, 1H), 6.96 (d, J= 3.5 Hz, 1H), 6.75 (d, J = 2.0 Hz, 1H), 6.38 (s, 1H), 5.84 (s, 2H), 5.10-5.18 (m, 1H), 3.90 (s, 3H), 3.87 (s, 2H), 3.03-3.11 (m, 1H), 2.23 (br s, 1H), 2.04 (s, 3H), 1.68-1.76 (m, 2H), 1.59-1.68 (m, 2H), 1.43-1.50 (m, 5H), 1.30-1.38 (m, 2H). LCMS: [M+H]+515.2-105- 45844530.1Example 10: Synthesis of (R)-2-amino-5-methyl-iV-(l-(7-(l-methyl-lH-pyrazol-3-yl)quinolin-5-yl)ethyl)isonicotinamide (SUN-059):

[0168] Step 1: To a mixture of methyl 2-amino-5-bromo-pyridine-4-carboxylate (2.30 g, 9.95 mmol, 1.0 eq) and 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (9.04 g, 36.0 mmol, 3.6 eq) in DMSO (40 mL) was added dicyclohexyl- [2-(2,6-dimethoxyphenyl)phenyl]phosphane (818 mg, 1.99 mmol, 0.2 eq), K3PO4 (4.23 g, 19.9 mmol, 2.0 eq), Pd(OAc)2 (224 mg, 0.998 mmol, 0.1 eq) and the mixture was stirred at 80 °C for 16 h. crude LCMS showed the starting material was remained and desired mass ion was observed. The mixture was stirred at 100 °C for 3 h under N2. TLC (PE: EtOAc = 1:1, UV) showed the starting material was consumed and new spots was observed. The mixture was diluted with H2O (60 mL) and extracted with EtOAc (60 mL x 3). The combined organic phase was washed with brine (60 mL x 4), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a crude. The crude was purified by column chromatography (SiO2, Ethyl acetate in Petroleum ether = 0% to 80%, 20 g, 45 mL / min, UV) to give methyl 2-amino-5 -methyl -pyridine-4-carboxylate (1.32 g, 79.8% yield) as a yellow solid. 'H NMR (400 MHz, DMSO-tfc) 37.87 (s, 1H), 6.83 (s, 1H), 6.01 (s, 2H), 3.81 (s, 3H), 2.23 (s, 3H). LCMS: [M+H]+167.1

[0169] Step 2: To a compound of methyl 2-amino-5-methyl-pyridine-4-carboxylate (1.32 g, 7.94 mmol, 1.0 eq) in MeOH (20 mL), H2O (20 mL) was added NaOH (1 M, 7.95 mL) under N2 and the mixture was stirred at 60 °C for 1.25 h. TLC (PE: EA = 1:1, UV) showed the starting material was consumed and one new main spot was observed. The mixture was concentrated under reduced pressure to remove MeOH, then the mixture was extracted with EtOAc (20 mL x 3). The water layer was lyophilized under reduced pressure to give crude as a yellow solid. The crude was triturated with acetone (20 mL) at 25 °C for 1 h. The suspension was filtered, and the filter cake was dried under reduced pressure to give 2-amino-5-methyl-pyridine-4-carboxylic acid (890 mg, crude) as a yellow solid. 'H NMR (400 MHz, DMSO-rfc) 37.56 (s, 1H), 6.46 (s, 1H), 5.37 (s, 2H), 2.12 (s, 3H).

[0170] Step 3: To a mixture of (lR)-l-[7-(l-methylpyrazol-3-yl)-5-quinolyl]ethanamine (100 mg, 0.307 mmol, 1.2 eq, 2HC1) and 2-amino-5-methyl-pyridine-4-carboxylic acid (40 mg, -106- 45844530.10.263 mmol, 1.0 eq) in DMF (1.3 mL) was added HATU (115 mg, 0.302 mmol, 1.15 eq), DMAP (71 mg, 0.581 mmol, 2.2 eq) under N2 and the mixture was stirred at 25 °C for 16 h. TLC (DCM: MeOH = 10: 1, UV) showed the starting material was consumed and new spots was observed. The mixture was concentrated under reduced pressure to give a crude. The crude was purified by column chromatography (SiO2, Methanol in Dichloromethane = 0% to 10%, 4 g, 25 mL / min, UV) to give desired product (140 mg, impure). The impure product was diluted with MeOH (2.0 mL) and purified by prep-HPLC (column: Boston Prime Cl 8 150 * 30 mm * 5 um; mobile phase: [Water (NH3H2O - NH4HCO3) - MeCN]; gradient: 20% - 40% B over 11 min). Most of solvent was removed under reduced pressure and the mixture was lyophilized to give 2-amino-5-methyl-N-[(lR)-l-[7-(l-methylpyrazol-3-yl)-5-quinolyl]ethyl]pyridine-4-carboxamide (41.2 mg) as a crude solid. The compound was purification by SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 um); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%:40%, isocratic elution mode). Most of solvent was removed under reduced pressure and the residue was lyophilized to give product.1H NMR (400 MHz, DMSO-cfe) <5 9.12 (d, J = 8.0 Hz, 1H), 8.91 (d, J = 4.0 Hz, 1H), 8.64 (d, J = 8.4 Hz, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 7.81 (d, J = 2.0 Hz, 1H) 7.76 (s, 1 H), 7.50-7.60 (m, 1H), 6.91 (d, J = 2.0 Hz, 1H), 6.36 (s, 1H), 5.81-5.91 (m, 3H), 3.93 (s, 3H), 2.01 (s, 3H), 1.59 (d, J= 6.8 Hz, 3H). LCMS: [M+H]+387.1Example 11: Synthesis of ( / ?)-V-(l-(3-(5-((cyclopentylamino)methyl)thiophen-2-yl)-5-(l-methyl-lH-pyrazol-3-yl)phenyl)ethyl)-5-methyl-2-(4-methylpiperazin-l-yl)isonicotinamide (SUN-081):-107- 45844530.1

[0171] Step 1: To the mixture of methyl 2-chloro-5-methyl-pyridine-4-carboxylate (3.90 g, 21.0 mmol, 1.0 eq) and 1 -methylpiperazine (3.16 g, 31.5 mmol, 3.50 mL, 1.5 eq) in dioxane (60 mL) were added Pd(OAc)2 (472 mg, 2.10 mmol, 0.1 eq), RuPhos (1.96 g, 4.20 mmol, 0.2 eq) and CS2CO3 (20.5 g, 63.0 mmol, 3.0 eq). Then the reaction mixture was heated to 100 °C for 2 h under N2. LCMS showed the raw material was consumed up and desired mass ion was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give crude product, which was purified by column chromatograph (SiO2, 4% MeOH in DCM) to give methyl 5-methyl-2-(4-methylpiperazin-l-yl)pyridine-4-carboxylate (4.55 g, 82.6% yield) as a yellow oil.JH NMR (400 MHz, CHLOROFORM-^ 8.12 (s, 1H), 7.11 (s, 1H), 3.92 (s, 3H), 3.53-3.61 (m, 4H), 2.51-2.59 (m, 4H), 2.40 (s, 3H), 2.36 (s, 3H). LCMS: [M+H]+250.0

[0172] Step 2: Methyl 5-methyl-2-(4-methylpiperazin-l-yl)pyridine-4-carboxylate (4.55 g, 18.3 mmol, 1.0 eq) was dissolved in MeOH (40 mL). A solution of NaOH (766 mg, 19.2 mmol, 1.05 eq) in H2O (40 mL) was added to the above mixture. The reaction mixture was heated to 60 °C and stirred for 4 h. LCMS showed the raw material was consumed up and desired mass ion in one peak. The reaction mixture was acidified with HC1 (2 M) until pH~3 and concentrated under reduced pressure to give crude product, which was triturated with DCM (10 mL) at 20 °C for 30 min, then the mixture was filtered and the filter cake was dried under reduced pressure to give 5-methyl-2-(4-methylpiperazin-l-yl)pyridine-4-carboxylic acid (5.48 g, 86.7% yield, 2HC1) as a white solid. 1H NMR (400 MHz, D2O) <57.88 (d, J= 2.4 Hz, 1H), 7.26-7.37 (m, 1H), 4.29 (d, J = 14.4 Hz, 2H), 3.72 (d, J = 12.8 Hz, 2H), 3.56-3.68 (m, 2H), 3.26-3.38 (m, 2H), 2.99 (s, 3H), 2.22-2.30 (m, 3H). LCMS: [M+H]+236.0

[0173] Step 3: To the mixture of 5-methyl-2-(4-methylpiperazin-l-yl)pyridine-4-carboxylic acid (400 mg, 1.30 mmol, 1.0 eq, 2HC1) and (lR)-l-(3,5-dichlorophenyl)ethanamine (294 mg, 1.30 mmol, 1.0 eq, HC1) in DMF (4 mL) were added HATU (493 mg, 1.30 mmol, 1.0 eq), DMAP (15.9 mg, 0.130 mmol, 0.1 eq) and TEA (197 mg, 1.95 mmol, 1.5 eq). The resulting mixture was stirred at 20 °C for 16 h. TLC (DCM: MeOH = 10:1, UV) showed the reaction was consumed up and new spots were formed. The reaction mixture was diluted with water (10 mL), and extracted with DCM (8 mL x 5), the organic phase were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give crude product, which was purified by column chromatograph (SiO2, 11% MeOH in DCM) to give N-[(lR)-l-(3,5-dichlorophenyl)ethyl]-5-methyl-2-(4-methylpiperazin- 1 -yl)pyridine-4-carboxamide (520 mg, 91.5% yield) as a yellow solid.JH NMR (400 MHz, CHLOROFORM-^ / ) 57.96 (s, 1H), 7.31 (s, 1H), 7.27 (s, 2H), 6.84 (br s, 1H)-108- 45844530.16.61 (s, 1H), 5.08-5.21 (m, 1H), 3.59-3.79 (m, 4H). 3.00-3.11 (m, 4H), 2.73 (s, 3H), 2.15 (s, 3H), 1.56 (br d, J= 6.8 Hz, 3H). LCMS: [M+H]+409.1

[0174] Step 4: To the mixture of N-[(lR)-l-(3,5-dichlorophenyl)ethyl]-5-methyl-2-(4-methylpiperazin-l-yl)pyridine-4-carboxamide (520 mg, 1.28 mmol, 1.0 eq) and 1 -methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (279 mg, 1.34 mmol, 1.05 eq) in DMF (5 mL) were added XPhos Pd G3 (108 mg, 0.128 mmol, 0.1 eq), CS2CO3 (832 mg, 2.55 mmol, 2.0 eq) and H2O (1 mL). The reaction mixture was heated to 100 °C for 1 h. TLC (DCM: MeOH = 10:1, UV) showed the reactant was consumed up and new spots were formed. After the reaction was completed, the reaction mixture was cooled to 25 °C. To the reaction mixture was added water (-15 mL) and extracted with DCM (10 mL x 3), the organic phase were dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give crude product, which was purified by column chromatograph (SiO2, 7% MeOH in DCM) to give N-[(1R)-1 -[3-chloro-5-(l-methylpyrazol-3-yl)phenyl]ethyl]-5-methyl-2-(4-methylpiperazin-l-yl)pyridine-4-carboxamide (200 mg, 28.4% yield) as a yellow solid. 'H NMR (400 MHz, CHLOROFORM-7) 58.05 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.28 (s, 1H), 6.61 (s, 1H), 6.52-6.56 (m, 1H), 6.00 (d, J= 8.0 Hz, 1H), 5.26-5.39 (m, 1H), 3.96 (s, 3 H), 3.50-3.58 (m, 4H), 2.49-2.57 (m, 4H), 2.35 (s, 3 H), 2.24 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H). LCMS: [M+H]+453.3

[0175] Step 5: To the mixture of N-[(lR)-l-[3-chloro-5-(l-methylpyrazol-3-yl)phenyl]ethyl]-5-methyl-2-(4-methylpiperazin-l-yl)pyridine-4-carboxamide (60 mg, 0.132 mmol, 1.0 eq) and [5-[(cyclopentylamino)methyl]-2-thienyl]boronic acid (33 mg, 0.146 mmol, 1.1 eq) in DMF (1 mL) and H2O (0.2 mL), were added XPhos Pd G3 (11 mg, 0.013 mmol, 0.1 eq) and CS2CO3 (86 mg, 0.265 mmol, 2.0 eq). The reaction mixture was heated to 100 °C for 1 h under N2. LCMS showed the raw material was consumed up and desired mass ion was detected (62% purity, 220 nm). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give crude product, which was dissolved in MeOH (1 mL) and purified by prep-HPLC (column: C18 150x30 mm; mobile phase: [Water (HQ)-MeCN]; gradient: 5%-45% B over 9 min). Most of solvent was removed under reduced pressure and the residue was lyophilized to give N-[(lR)-l-[3-[5-[(cyclopentylamino)methyl]-2-thienyl]-5-(l-methylpyrazol-3-yl)phenyl]ethyl]-5-methyl-2-(4-methylpiperazin-l-yl)pyridine-4-carboxamide (16 mg, 17.9% yield, 99.24% purity, 2HC1) as a yellow gum. 'H NMR (400 MHz, DMSO-rfc) 5 11.47 (br s, 1H), 9.60 (d, J = 4.4 Hz, 2H), 9.31 (d, J = 7.6 Hz, 1H), 8.04 (s, 1H), 7.91 (s, 1H), 7.82 (s, 1H), 7.78 (d, J = 2.2 Hz, 1H), 7.63 (s, 1H), 7.56 (d, J = 3.6 Hz, 1H), 7.42 (d, 7= 3.6 Hz, 1H), 7.23 (s, 1H), 6.78 (d, J = 2.4 Hz, 1H), 5.14-5.25 (m, 1H),-109- 45844530.14.48 (d, J = 14.0 Hz, 2H), 4.32-4.40 (m, 2H), 3.91 (s, 3H), 3.44-3.57 (m, 5H), 3.07-3.21 (m, 2H), 2.79 (d, J = 3.2 Hz, 3H), 2.15 (s, 3H), 1.94-2.04 (m, 2H), 1.67-179 (m, 4H), 1.45-1.58 (m, 5H). LCMS: [M+H]+598.2Example 12: Synthesis of (R)-A-(l-(3-(5-((cyclopentylamino)methyl)thiophen-2-yl)-5-(l- methyl-lH-pyrazol-3-yl)phenyl)ethyl)-2-methyl-5-(4-methylpiperazin-l-yl)benzamide(SUN-082):

[0176] Step 1: To a solution of 2-methyl-5-(4-methylpiperazin-l-yl)benzoic acid (956 mg, 3.53 mmol, 1.0 eq, HCl) in DMF (15 mL) were added (lR)-l-(3,5- dichlorophenyl)ethanamine (800 mg, 3.53 mmol, 1.0 eq, HC1), HATU (1.61 g, 4.24 mmol, 1.2 eq), DMAP (43 mg, 0.353 mmol, 0.1 eq) and TEA (1.79 g, 17.6 mmol, 5.0 eq), then the mixture was stirred at 20 °C for 14 h under N2. TLC (DCM: MeOH = 20:1, UV) showed the starting material was consumed and one new spot with larger polarity was detected. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (80 mL x 3). The combined organic phase was washed with sat. aq. NH4CI (60 mL x 2), dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give a crude, which was purified by flash silica gel chromatography (1SCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 10% Methanol / Dichloromethane gradient @ 40 mL / min) to give compound N-[(1R)- l-(3,5-dichlorophenyl)ethyl]-2-methyl-5-(4-methylpiperazin-l-yl)benzamide (1.10 g, 76.6% yield) as a yellow oil. H NMR (400 MHz, CDCE) <57.28 (s, 1H), 7.19-7.23 (m, 1H), 7.10 (d, J= 8.8 Hz, 1H), 6.83-6.93 (m, 2H), 6.32 (d, J= 7.6 Hz, 1H), 5.12-5.25 (m, 1H), 3.23-3.30 (m, 4H), 2.82-2.88 (m, 4H), 2.56 (s, 3H), 2.29 (s, 3H), 1.56 (d, 7 = 7.2 Hz, 3H). LCMS: [M+H]+406.2

[0177] Step 2: To a solution of N-[(lR)-l-(3,5-dichlorophenyl)ethyl]-2-methyl-5-(4- methylpiperazin-l-yl)benzamide (600 mg, 1.48 mmol, 1.0 eq) in DMF (10 mL) and H2O (2 mL) were added l-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (307 mg, 1.48 mmol, 1.0 eq), XPhos Pd G3 (125 mg, 0.147 mmol, 0.1 eq) and CS2CO3 (962 mg, 2.95 mmol, 2.0 eq), then the mixture was stirred at 100 °C for 1 h under N2. TLC (DCM: MeOH =-110- 45844530.110: 1, UV) showed the starting material was consumed and two new spots with similar polarity were detected. The reaction mixture was diluted with H2O (60 mL) and extracted with EtOAc (50 mL x 3). The combined organic phase was washed with sat. aq. NH4CI (40 mL x 2), dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give a crude, which was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 10% Methanol / Dichloromethane gradient @ 40 mL / min) to give compound N-[(1R)-1 -[3-chloro-5-(l-methylpyrazol-3-yl)phenyl]ethyl]-2-methyl-5-(4-methylpiperazin-l-yl)benzamide (240 mg, 25.8% yield) as a yellow gum. LCMS: [M+H]+452.2

[0178] Step 3: To a solution of N-[(lR)-l-[3-chloro-5-(l-methylpyrazol-3-yl)phenyl]ethyl]-2-methyl-5-(4-methylpiperazin-l-yl)benzamide (120 mg, 0.265 mmol, 1.0 eq) in DMF (3 mL) and H2O (0.6 mL) were added [5-[(cyclopentylamino)methyl]-2-thienyl]boronic acid (66 mg, 0.292 mmol, 1.1 eq), XPhos Pd G3 (22 mg, 0.0265 mmol, 0.1 eq) and CS2CO3 (173 mg, 0.531 mmol, 2.0 eq), then the mixture was stirred at 100 °C for 1 h under N2. LCMS showed 55% with desired MS was detected. The mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: Boston Prime C18 150*30 mm*5 um; mobile phase: [Water (NIIdLO-NILIICOq-McCN]: gradient: 50%-70% B over 11 min). Most of solvent was removed under reduced pressure and the mixture was lyophilized to give compound N-[(lR)-l-[3-[5-[(cyclopentylamino)methyl]-2-thienyl]-5-(l-methylpyrazol-3-yl)phenyl]ethyl]-2-methyl-5-(4-methylpiperazin-l-yl)benzamide (38.3 mg, 24.1% yield, 99.66% purity) as a white solid.1H NMR (400 MHz, DMSO-rfo) <58.77 (d, J = 8.0 Hz, 1H), 7.86 (s, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.73 (s, 1H), 7.56 (s, 1H), 7.38 (d, J = 3.6 Hz, 1H), 7.07 (d, J= 8.4 Hz, 1H), 6.96 (d, J= 3.6 Hz, 1H), 6.91 (dd, J = 8.4, 2.4 Hz, 1H), 6.88 (d, J= 2.8 Hz, 1H), 6.76 (d, J= 2.4 Hz, 1H), 5.09-5.23 (m, 1H), 3.90 (s, 3H), 3.87 (s, 2H), 3.02-3.15 (m, 5H), 2.43 (t, J= 4.8 Hz, 4H), 2.22 (s, 3H), 2.19 (s, 3H), 1.68-1.78 (m, 2H), 1.58-1.67 (m, 2H), 1.40-1.52 (m, 5H), 1.29-1.39 (m, 2H). LCMS: [M+H]+597.3-111- 45844530.1Example 13: Synthesis of (R)-2-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(5-(pyrrolidin-1 -ylmethyl)thiophen-2-yl)phenyl)ethyl)-5 -(4- methylpi perazin- 1 -yl)benzamide (SUN-083):

[0179] Step 1: To a solution of N-[(lR)-l-[3-chloro-5-(l-methylpyrazol-3-yl)phenyl]ethyl]-2-methyl-5-(4-methylpiperazin-l-yl)benzamide (150 mg, 0.332 mmol, 1.0 eq) in DMF (3 mL) and H2O (0.6 mL) were added (5-formyl-2-thienyl)boronic acid (57 mg, 0.365 mmol, 1.1 eq), XPhos Pd G3 (28 mg, 0.0332 mmol, 0.1 eq) and CS2CO3 (216 mg, 0.664 mmol, 2.0 eq), then the mixture was stirred at 100 °C for 2 h under N2. LCMS showed main peak with desired MS was detected. The mixture was diluted with H2O (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic phase was washed with sat. aq. NH4CI (20 mL x 2), dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give a crude, which was purified by flash silica gel chromatography (ISCO®; 20 g SepaPlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate / Petroleum ether to 12% Methanol / Ethyl acetate gradient @ 40 mL / min) to give compound N-[(lR)-l-[3-(5-formyl-2-thienyl)-5-(l-methylpyrazol-3-yl)phenyl]ethyl]-2-methyl-5-(4-methylpiperazin-l-yl)benzamide (100 mg, impure) as a yellow oil. 'H NMR (400 MHz, CDCI3) S 9.82 (s, 1H), 7.77 (s, 1H), 7.68 (d, J = 4.0 Hz, 1H), 7.60-7.65 (m, 1H), 7.42 (d, J = 4.0 Hz, 1H), 7.34 (d, J = 2.0 Hz, 1H), 7.00-7.04 (m, 1H), 6.85-6.89 (m, 1H), 6.78-6.83 (m, 1H), 6.52 (d, J = 2.4 Hz, 1H), 6.07 (d, J = 8.0 Hz, 1H), 5.28-5.38 (m, 1H), 3.90 (s, 3H), 3.05-3.15 (m, 4H), 2.48-2.56 (m, 4H), 2.23-2.30 (m, 6H), 1.59 (d, J = 7.2 Hz, 3H). LCMS: [M+H]+528.1

[0180] Step 2: To a solution of N-[(lR)-l-[3-(5-formyl-2-thienyl)-5-(l-methylpyrazol-3-yl)phenyl]ethyl]-2-methyl-5-(4-methylpiperazin-l-yl)benzamide (100 mg, impure) in McOH (3 mL) were added pyrrolidine (20 mg, 0.284 mmol, 1.5 eq) and AcOH (11 mg, 0.189 mmol, 1.0 eq) at 25 °C, then the mixture was stirred at 50 °C for 12 h under N2. The yellow solution was cooled to 25 °C. NaBI I3CN (36 mg, 0.568 mmol, 3.0 eq) was added to the above solution, then the mixture was stirred at 50 °C for 2 h under N2. LCMS showed 57% with desired MS was detected. The mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: Boston Prime C18 150*30 mm*5 um;-112- 45844530.1mobile phase: [Water (NH3H2O-NH4HCO3)-MeCN]: gradient: 53%-73% B over 10 min). Most of solvent was removed under reduced pressure and the mixture was lyophilized to give compound 2-methyl-5-(4-methylpiperazin-l-yl)-N-[(lR)-l-[3-(l-methylpyrazol-3-yl)-5-[5-(pyrrolidin-l-ylmethyl)-2-thienyl]phenyl]ethyl]benzamide (29.8 mg, 26.6% yield, 98.68% purity) as a white solid.NMR (400 MHz, DMSO-t / s) 38.76 (d, J = 8.4 Hz, 1H), 7.87 (s, 1H), 7.71-7.78 (m, 2H), 7.56 (s, 1H), 7.38 (d, J = 3.2 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H). 6.96 (d, J = 3.6 Hz, 1H), 6.86-6.94 (m, 2H), 6.76 (d, J = 2.0 Hz, 1H), 5.10-5.20 (m, 1H), 3.90 (s, 3H), 3.79 (s, 2H), 3.11 (t, J = 4.4 Hz, 4H), 2.51-2.56 (m, 4H), 2.44 (t, J = 4.8 Hz, 4H), 2.22 (s, 3H), 2.18 (s, 3H), 1.66-1.75 (m, 4H), 1.48 (d, 7 = 7.2 Hz, 3H). LCMS: [M+H]+583.2 Example 14: Synthesis of (R)-5-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(5-(pyrrolidin-l-ylmethyl)thiophen-2-yl)phenyl)ethyl)-2-(4-methylpiperazin-l-yl)isonicotinamide (SUN-120):

[0181] Step 1: To the mixture of N-[(lR)-l-[3-chloro-5-(l-methylpyrazol-3-yl)phenyl]ethyl]-5-methyl-2-(4-methylpiperazin-l-yl)pyridine-4-carboxamide (140 mg, 0.309 mmol, 1.0 eq) and (5-fomiyl-2-thienyl)boronic acid (57.8 mg, 0.371 mmol, 1.2 eq) in DMF (2 mL) and H2O (0.4 mL), were added XPhos Pd G3 (26.2 mg, 0.031 mmol, 0.1 eq) and CS2CO3 (201 mg, 0.618 mmol, 2.0 eq). The reaction mixture was heated to 100 °C for 1 h under N2. TLC (DCM: MeOH = 10: 1, UV) showed the reactant was not consumed up and new spots were formed. To the reaction mixture was added water (~8 mL), and extracted with ethyl acetate (5 mL x 5), the organic phase were dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give crude product, which was purified by column chromatograph (SiO2, 12% MeOH in DCM) to give N-[(lR)-l-[3-(5-formyl-2-thienyl)-5-(l-methylpyrazol-3-yl)phenyl]ethyl]-5-methyl-2-(4-methylpiperazin-l-yl)pyridine-4-carboxamide (100 mg, 56.9% yield) as a yellow solid. LCMS: [M+H]+529.3.

[0182] Step 2: To the mixture of N-[(lR)-l-[3-(5-formyl-2-thienyl)-5-(l-methylpyrazol-3-yl)phenyl]ethyl]-5-methyl-2-(4-methylpiperazin-l-yl)pyridine-4- -113- 45844530.1carboxamide (50 mg, 0.095 mmol, 1.0 eq) and pyrrolidine (10 mg, 0.142 mmol, 1.5 eq) in MeOH (1 mL) was added AcOH (6 mg, 0.095 mmol, 1.0 eq), then the mixture was heated to 50 °C for 16 h. After the reaction mixture was cooled to 25 °C, NaBI hCN (18 mg, 0.284 mmol, 3.0 eq) was added to the above reaction mixture, then the resulting mixture was heated to 50 °C for 2 h. LCMS showed the raw material was consumed up and desired mass ion was detected (87% purity, 220 nm). The reaction mixture was concentrated under reduced pressure to give crude product, which was dissolved in MeOH (1 mL) and purified by prep-HPLC. (column: Boston Prime C18 150*30 mm*5 um; mobile phase: [Water (NH3H2O-NH4HCOj)-MeCN]; gradient: 45%-65% B over 11 min). Most of solvent was removed under reduced pressure and the residue was lyophilized to give 5-methyl-2-(4-methylpiperazin- 1 -yl)-N-[(lR)-l-[3-(l-methylpyrazol-3-yl)-5-[5-(pyrrolidin-l-ylmethyl)-2-thienyl]phenyl]ethyl]pyridine-4-carboxamide (7.5 mg, 12.9% yield, 95.12% purity) as a white solid. 'H NMR (400 MHz, DMSO-&) 38.93 (d, J = 8.0 Hz, 1H), 7.99 (s, 1H), 7.87 (s, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.73 (s, 1H), 7.55 (s, 1H), 7.38 (d, J = 3.6 Hz, 1H), 6.97 (d, J = 3.6 Hz. 1H), 6.77 (d, J = 2.0 Hz, 1H), 6.74 (s, 1H), 5.10-5.20 (m, 1H), 3.90 (s, 3H), 3.78 (s. 2H), 3.42-3.49 (m, 4H), 2.51-2.54 (m, 4H), 2.34-2.43 (m, 4H), 2.21 (s, 3H), 2.10 (s, 3H), 1.71 (br s, 4H), 1.48 (d, J = 7.2 Hz, 3H). LCMS: [M+H]+584.2.Example 15: Synthesis of (R)-2-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)-5-(4-methylpiperazin-l-yl)benzamide (SUN-084):

[0183] To a solution of N-[(lR)-l-[3-chloro-5-(l-methylpyrazol-3-yl)phenyl]ethyl]-2-methyl-5-(4-methylpiperazin-l-yl)benzamide (120 mg, 0.265 mmol, 1.0 eq) in DMF (3 mL) and H2O (0.6 mL) were added 2-thienylboronic acid (37 mg, 0.292 mmol, 1.1 eq), XPhos Pd G3 (22 mg, 0.0265 mmol, 0.1 eq) and CS2CO3 (173 mg, 0.531 mmol, 2.0 eq), then the mixture was stirred at 100 °C for 1 h under N2. LCMS showed 57% with desired MS was detected. The mixture was concentrated under reduced pressure to give a residue, which was purified by prep- -114- 45844530.1HPLC (column: Boston Prime Cl 8 150*30 mm* 5 um; mobile phase: [Water (NH3H2O-NH4HCO3)-MeCN]; gradient: 45%-65% B over 11 min). Most of solvent was removed under reduced pressure and the mixture was lyophilized to give compound 2-methyl-5-(4-methylpiperazin-l-yl)-N-[(lR)-l-[3-(l-methylpyrazol-3-yl)-5-(2-thienyl)phenyl]ethyl]benzamide (36.3 mg, 27.3% yield, 99.90% purity) as a white solid.NMR (400 MHz, DMSO-rfo) d' 8.78 (d, 7= 8.4 Hz, 1H), 7.91 (s, 1H), 7.74-7.81 (m, 2H), 7.54-7.63 (m, 3H), 7.14-7.21 (m, 1H), 7.07 (d, J= 8.0 Hz, 1H), 6.86-6.95 (m, 2H), 6.77 (d, J= 2.0 Hz, 1H), 5.10-5.23 (m, 1H), 3.91 (s, 3H), 3.11 (t, 7 = 4.8 Hz, 4H), 2.44 (t, 7= 5.2 Hz, 4H), 2.22 (s, 3H), 2.19 (s, 3H), 1.49 (d, 7 = 7.2 Hz, 3H). LCMS: [M+H]+500.1.Example 16: Synthesis of (R)-5-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(5-(pyrrolidin-l-ylmethyl)thiophen-2-yl)phenyl)ethyl)-2-(4-methylpiperazin-l-yl)isonicotinamide (SUN-120):

[0184] Step 1: To the mixture of N-[(lR)-l-[3-chloro-5-(l-methylpyrazol-3-yl)phenyl]ethyl]-5-methyl-2-(4-methylpiperazin-l-yl)pyridine-4-carboxamide (140 mg, 0.309 mmol, 1.0 eq) and (5-formyl-2-thienyl)boronic acid (57.8 mg, 0.371 mmol, 1.2 eq) in DMF (2 mL) and H2O (0.4 mL), were added XPhos Pd G3 (26.2 mg, 0.031 mmol, 0.1 eq) and CS2CO3 (201 mg, 0.618 mmol, 2.0 eq). The reaction mixture was heated to 100 °C for 1 h under N2. TLC (DCM: MeOH = 10: 1, UV) showed the reactant was not consumed up and new spots were formed. To the reaction mixture was added water (~8 mL), and extracted with ethyl acetate (5 mL x 5), the organic phase were dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give crude product, which was purified by column chromatograph (SiO2, 12% MeOH in DCM) to give N-[(lR)-l-[3-(5-formyl-2-thienyl)-5-(l-methylpyrazol-3-yl)phenyl]ethyl]-5-methyl-2-(4-methylpiperazin-l-yl)pyridine-4-carboxamide (100 mg, 56.9% yield) as a yellow solid. LCMS: [M+H]+529.3.

[0185] Step 2: To the mixture of N-[(lR)-l-[3-(5-formyl-2-thienyl)-5-(l-methylpyrazol-3-yl)phenyl]ethyl]-5-methyl-2-(4-methylpiperazin-l-yl)pyridine-4-carboxamide (50 mg, 0.095 -115- 45844530.1mmol, 1.0 eq) and pyrrolidine (10 mg, 0.142 mmol, 1.5 eq) in MeOH ( 1 mL) was added AcOH (6 mg, 0.095 mmol, 1.0 eq), then the mixture was heated to 50 °C for 16 h. After the reaction mixture was cooled to 25 °C, NaBHiCN (18 mg, 0.284 mmol, 3.0 eq) was added to the above reaction mixture, then the resulting mixture was heated to 50 °C for 2 h. LCMS showed the raw material was consumed up and desired mass ion was detected (87% purity, 220 nm). The reaction mixture was concentrated under reduced pressure to give crude product, which was dissolved in MeOH (1 mL) and purified by prep-HPLC. (column: Boston Prime Cl 8 150*30 mm*5 um; mobile phase: [Water (NH3H2O-NH4HCO3)-MeCN]; gradient: 45%-65% B over 11 min). Most of solvent was removed under reduced pressure and the residue was lyophilized to give 5-methyl-2-(4-methylpiperazin-l-yl)-N-[(lR)-l-[3-(l-methylpyrazol-3-yl)-5-[5-(pyrrolidin-l-ylmethyl)-2-thienyl]phenyl]ethyl]pyridine-4-carboxamide (7.5 mg, 12.9% yield, 95.12% purity) as a white solid. 'H NMR (400 MHz, DMSO-dfe) 38.93 (d, J = 8.0 Hz, 1H), 7.99 (s, 1H), 7.87 (s, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.73 (s, 1H), 7.55 (s, 1H), 7.38 (d, J = 3.6 Hz, 1H), 6.97 (d, J = 3.6 Hz, 1H), 6.77 (d, J = 2.0 Hz, 1H), 6.74 (s, 1H), 5.10-5.20 (m, 1H), 3.90 (s, 3H), 3.78 (s, 2H), 3.42-3.49 (m, 4H). 2.51-2.54 (m, 4H), 2.34-2.43 (m, 4H), 2.21 (s, 3H), 2.10 (s, 3H), 1.71 (br s, 4H), 1.48 (d, J = 7.2 Hz, 3H). LCMS: [M+H]+584.2.Example 17: Synthesis of (R)-A-(l-(3-(5-((cyclopentylamino)methyl)thiophen-2-yl)-5-(l-methyl-lH-pyrazol-4-yl)phenyl)ethyl)-2-methyl-5-(4-methylpiperazin-l-yl)benzamide(SUN-130):

[0186] Step 1: To a solution of l-(3,5-dibromophenyl)ethanone (4.00 g, 14.4 mmol, 1.0 eq) in toluene (75 mL), EtOH (30 mL) and H2O (15 mL) were added l-methyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyrazole (2.69 g, 12.9 mmol, 0.9 eq), Pd(PPh3)4 (831 mg, 0.719 mmol, 0.05 eq) and Na2COs (3.05 g, 28.8 mmol, 2.0 eq), then the mixture was stirred at 90 °C for 12 h under N2. TLC (PE: EtOAc = 3: 1, UV) showed the starting material was consumed and one -116- 45844530.1new spot with larger polarity was detected. The reaction mixture was cooled to 25 °C. The reaction mixture was diluted with H2O (160 mL) and extracted with EtOAc (120 mL x 3). The combined organic phase was washed with brine (60 mL x 2), dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give a crude. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 60% Ethyl acetate / Petroleum ether gradient @ 50 mL / min) to give compound l-[3-bromo-5-(l-methylpyrazol-4-yl)phenyl]ethanone (2.76 g, 59.1% yield) as a pale yellow solid. 'H NMR (400 MHz, DMSO-ifc) 38.35 (s, 1H), 8.07 (s, 1H), 7.99-8.05 (m, 2H), 7.81-7.85 (m, 1H), 3.87 (s, 3H), 2.62 (s, 3H).

[0187] Step 2: To a solution of l-[3-bromo-5-(l-methylpyrazol-4-yl)phenyl]ethanone (2.76 g, 9.89 mmol, 1.0 eq) in THF (80 mL) were added (S)-2-niethylpropane-2-sulfinamide (3.60 g, 29.7 mmol, 3.0 eq) and Ti(OEt)4 (6.77 g, 29.7 mmol, 3.0 eq) at 25 °C, then the yellow solution was stirred at 70 °C for 14 h under N2. TEC (PE: EtOAc = 2: 1, UV) showed the starting material was consumed and one new spot with larger polarity was detected. The mixture was cooled to 25 °C. The reaction mixture was diluted with H2O (120 mL) and EtOAc (100 mL). The mixture was filtered. The mixture was separated. The aqueous phase was extracted with EtOAc (80 mL x 2). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a crude. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 65-80% Ethyl acetate / Petroleum ether gradient @ 50 mL / min) to give compound (NE, S)-N-ll-[3-bromo-5-(l-methylpyrazol-4-yl)phenylJethylideneJ-2-methyl-propane-2-sulfinamide (3.45 g, 91.3% yield) as a yellow oil.1H NMR (400 MHz, CDCl₃) 37.82 (s, 1H), 7.77 (s, 1H), 7.73 (s, 1H), 7.67 (s, 1H), 7.64 (s, 1H), 3.93 (s, 3H), 2.73 (s, 3H), 1.30 (s, 9H).

[0188] Step 3: To a solution of (NE, S)-N-[l-[3-bromo-5-(l-methylpyrazol-4-yl)phenyl]ethylidene]-2-methyl-propane-2-sulfinamide (3.45 g, 9.02 mmol, 1.0 eq) in THF (50 mL) was added L-selectride ( 1 Min THF, 13.5 mmol, 1.5 eq) at -70 °C, then the yellow solution was stirred at -70 °C for 2 h and 25 °C for 12 h under N2. TLC (PE: EtOAc = 0: 1, UV) showed the starting material was consumed and one new spot with larger polarity was detected. The mixture was quenched slowly with sat. aq. NH4CI (50 mL) at -10 °C-0 °C and stirred at 0 °C for 15 min under N2. The mixture was diluted with H2O (60 mL) and extracted with EtOAc (80 mL x 2). The combined organic phase was washed with 1% NaClO (50 mL x 2), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a crude. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash®-117- 45844530.1Silica Flash Column, Eluent of 100% Ethyl acetate / Petroleum ether to 10% Methanol / Ethyl acetate gradient @ 50 mL / min) to give compound (S)-N-[(lR)-l-[3-bromo-5-(l-methylpyrazol-4-yl)phenyl]ethyl]-2-methyl-propane-2-sulfinamide (3.10 g, 89.4% yield) as a yellow oil. H NMR (400 MHz, CDCl3) <57.70 (s, 1H), 7.59 (s, 1H), 7.47 (d, J = 1.6 Hz, 1H), 7.32 (s, 1H), 7.28 (t, J= 1.6 Hz, 1H), 4.47-4.57 (m, 1H), 3.91 (s, 3H), 1.50 (d, J= 6.8 Hz, 3H), 1.19 (s, 9H).

[0189] Step 4: To a solution of (S)-N-[(lR)-l-[3-bromo-5-(l-methylpyrazol-4-yl)phenyl]ethyl]-2-methyl-propane-2-sulfinamide (3.10 g, 8.07 mmol, 1.0 eq) in DCM (30 mL) was added HCl / dioxane (2 M, 15 mL), then the white suspension was stirred at 25 °C for 14 h under N2. TLC (DCM: MeOH = 10: 1, UV) showed the starting material was consumed and one new spot with larger polarity was detected. The mixture was filtered. The filter cake was dried under reduced pressure to give 2.25 g impure product. The residue was diluted with pure water (30 mL) and CH3CN (5 mL). The mixture was lyophilized to give compound (lR)-l-[3-bromo-5-(l-methylpyrazol-4-yl)phenyl]ethanamine (2.20 g, 76.3% yield, 98.7% purity, 2HC1) as a yellow solid.NMR (400 MHz, DMSO-rf<s) 38.83 (br s, 3H), 8.27 (s, 1H), 7.99 (s, 1H), 7.96 (s, 1H), 7.77 (s, 1H), 7.57 (s, 1H), 4.26-4.45 (m, 1H), 3.86 (s, 3H), 1.54 (d, J = 6.8 Hz, 3H); LCMS: [M-NH2]+263.0.

[0190] Step 5: To a solution of (lR)-l-|3-bromo-5-(l-methylpyrazol-4-yl)phenyl|ethanamine (200 mg, 0.566 mmol, 1.0 eq, 2HC1) in DMF (5 mL) were added 2-methyl-5-(4-methylpiperazin-l-yl)benzoic acid (153 mg, 0.566 mmol, 1.0 eq, HC1), HATU (258 mg, 0.679 mmol, 1.2 eq), DMAP (7 mg, 0.0566 mmol, 0.1 eq) and TEA (344 mg, 3.40 mmol, 6.0 eq), then the mixture was stirred at 25 °C for 14 h under N2. TLC (DCM: MeOH = 10: 1, UV) showed the starting material was consumed and one new spot with larger polarity was detected. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic phase was washed with sat. aq. NH4CI (15 mL x 2), dried over anhydrous Na2SO4. filtered and the filtrate was concentrated under reduced pressure to give a crude. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 15% Methanol / Dichloromethane gradient @ 40 mL / min) to give compound N-[(lR)-l-[3-bromo-5-(l-methylpyrazol-4-yl)phenyl]ethyl]-2-methyl-5-(4-methylpiperazin- 1 -yl)benzamide (200 mg, 71.1% yield) as a yellow oil. LCMS: [M+H]+498.0.

[0191] Step 6: To a solution of N-[(lR)-l-[3-bromo-5-(l-methylpyrazol-4-yl)phenyl]ethyl]-2-methyl-5-(4-methylpiperazin-l-yl)benzamide (180 mg, 0.363 mmol, 1.0 eq) in DMF (3 mL)-118- 45844530.1and H2O (0.6 mL) were added (5-formyl-2-thienyl)boronic acid (113 mg, 0.725 mmol, 2.0 eq), Pd(dppf)C12 (27 mg, 0.0363 mmol, 0.1 eq) and CS2CO3 (236 mg, 0.725 mmol, 2.0 eq), then the brown suspension was stirred at 100 °C for 3 h under N2. LCMS showed 71% with desired MS was detected. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (25 mLx 3). The combined organic phase was washed with sat. aq. NH4CI (15 mLx 2), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a crude. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate / Petroleum ether to 20% Methanol / Dichloromethane gradient @ 40 mL / min) to give compound N-[(lR)-l-[3-(5-formyl-2-thienyl)-5-(l-methylpyrazol-4-yl)phenyl]ethyl]-2-methyl-5-(4-methylpiperazin-l-yl)benzamide (125 mg, 58.8% yield) as a yellow oil. LCMS: [M+H]+528.2.

[0192] Step 7: To a solution of N-[(lR)-l-[3-(5-formyl-2-thienyl)-5-(l-methylpyrazol-4-yl)phenyl]ethyl]-2-methyl-5-(4-methylpiperazin-l -yl)benzamide (125 mg, 0.237 mmol, 1.0 eq) in MeOH (3 mL) were added cyclopentanamine (30 mg, 0.355 mmol, 1.5 eq) and AcOH (14 mg, 0.237 mmol, 1.0 eq) at 25 °C, then the mixture was stirred at 50 °C for 12 h under N2. The mixture was cooled to 25 °C. NaBFLCN (45 mg, 0.711 mmol, 3.0 eq) was added to the above mixture, then the brown solution was further stirred at 50°C for 2 h under N2. LCMS showed main peak with desired MS was detected. The mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: Boston Prime Cl 8 150*30 mm*5 um; mobile phase: [Water (NHOLO-NILIICOq-MeCNI gradient: 48%-68% B over 10 min). Most of solvent was removed under reduced pressure and the mixture was lyophilized to give compound A-[(lR)-l-[3-[5-[(cyclopentylamino)methyl]-2-thienyl]-5-(l-methylpyrazol-4-yl)phenyl]ethyl]-2-methyl-5-(4-methylpiperazin-l-yl)benzamide (40.3 mg, 28.2% yield, 99.06% purity) as a pink solid.NMR (400 MHz, DMSO- e) <58.73 (d, J = 8.4 Hz, 1H), 8.22 (s, 1H), 7.92 (s, 1H). 7.68 (s, 1H), 7.50 (s, 1H), 7.46 (s, 1H), 7.40 (d, J= 3.6 Hz, 1H), 7.07 (d, J= 8.4 Hz, 1H), 7.00 (d, J= 3.6 Hz, 1H), 6.92 (dd, J= 8.4, 2.4 Hz, 1H), 6.87 (d, J= 2.4 Hz, 1H), 5.06-5.19 (m, 1H), 3.92 (s, 2H), 3.88 (s, 3H), 3.06-3.15 (m, 5H), 2.44 (t, J = 4.8 Hz, 411), 2.22 (s, 311), 2.19 (s, 311), 1.70-1.83 (m, 211), 1.58-1.69 (m, 211), 1.43-1.51 (m, 5H), 1.31-1.42 (m, 2H); LCMS: [M+H]+597.2.-119- 45844530.1Example 18: Synthesis of 2-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)cyclopropyl)-5-(4-methylpiperazin-l-yl)benzamide (SC1-284).

[0193] Step 1: To a solution of 3,5-dibromobenzonitrile (2.5 g, 9.58 mmol, 1 eq.) in diethyl ether (40 mL) was added tetraisopropoxytitanium (2.99 g, 3.20 mL, 1.1 eq., 10.54 mmol) with stirring at -78 °C, followed by dropwise addition of ethylmagnesium bromide (2.81 g, 2.2 eq., 7.03 mL, 3 M in Et20, 21.08 mmol). The reaction was stirred at -78 °C for 0.5 h and slowly brought to room temperature. To the reaction mixture was added BF3. OEt2 (5.667 g, 5.059 mL, 2 eq., 48% wt, 19.16 mmol) and stirred for 0.5 h. The reaction progress was monitored by TLC and on completion the reaction mixture was slowly added to satd. NaHCCh (25 mL) and extracted with EtOAc (3 x 25 mL). The combined organic layer was washed with water and dried over sodium sulfate. Purification by silica gel chromatography (SiO2 column, 40 g, 5 - 80% EtOAc / Hex)) afforded l-(3,5-dibromophenyl)cyclopropan-l-amine (0.9 g, 30 %) as pale yellow liquid.

[0194] Step 2: To a solution of l-(3,5-dibromophenyl)cyclopropan-l -amine (0.88 g, 3.02 mmol, 1 eq.) in THF (10 mL) and water (2.5 mL) was added sodium bicarbonate (3.30 g, 39.3 mmol, 13 eq.,) and B0C2C) (1.98 g,, 9.07 mmol, 2.08 mL, 3 eq.). The reaction mixture was stirred for 16 h at 25 °C. On completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layer was dried over sodium sulfate and evaporated to give crude mixture. Purification by silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 5 - 15% EtOAc in Hexane gradient-120- 45844530.1@ 80 mL / min) afforded tert-butyl (l-(3,5-dibromophenyl)cyclopropyl)carbamate (0.85 g, 72 %) as white solid.

[0195] Step 3: To a solution of tert-butyl ( l-(3,5-dibromophenyl)cyclopropyl)carbamate (0.47 g, 1.20 mmol, 1 eq.) in 1,4-Dioxane (4.0 ml.) and Water (1.33 ml.) was added 1-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.25 g, 1.20 mmol, 1.0 eq.) and cesium carbonate (0.78 g, 2.40 mmol. 2 eq.). The reaction mixture was purged with Ar followed by addition of PdCh(dppf)-CH2Cl adduct (98.1 mg, 0.120 mmol, 0.1 eq.). The reaction mixture was stirred at 80 °C for 12 h. The reaction was monitored by LCMS. On completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layer was dried over sodium sulfate and evaporated to give a crude mixture. Purification by silica gel chromatography (ISCO®: 40 g SepaFlash® Silica Flash Column, Eluent of 5 - 30% EtOAc in Hexane gradient @ 40 mL / min) afforded tert-butyl (l-(3-bromo-5-(l -methyl- lH-pyrazol-3-yl)phenyl)cyclopropyl)carbamate (0.18g, 35 %, 92% Purity) as pale yellow liquid.

[0196] Step 4: To a solution of tert-butyl (l-(3-chloro-5-(l-methyl-lH-pyrazol-3-yl)phenyl)cyclopropyl)carbamate (0.25 g,, 0.68 mmol, 95% wt, 1 eq.) in 1,4-Dioxane (3.0 mL) and water (1.0 mL) was added thiophen-2-ylboronic acid (0.26 g, 2.03 mmol, 3 eq.) and cesium carbonate (0.44 g, 1.35 mmol, 2 eq.) at room temperature. The reaction mixture was purged with Ar for 15 min followed by addition of XPhos Pd G2 (106 mg, 0.14 mmol, 0.2 eq.). The reaction mixture was stirred at 90 °C for 20 h. The reaction progress was monitored by LCMS. On completion the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layer was dried over sodium sulfate and evaporated to give crude mixture. Purification by silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 5 - 40% EtOAc in Hexane gradient @ 40 mL / min) afforded tert-butyl (l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)cyclopropyl)carbamate (0.190 g, 70.9 %) as yellow semi-solid.

[0197] Step 5: To a solution of tert-butyl (l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)cyclopropyl)carbamate (0.19 g, 0.480 mmol, 1 eq.) in 1,4-Dioxane (5.0 mL) was added a solution of hydrogen chloride (1.20 mL, 4.80 mmol, 4 M in dioxane, 10 eq.,) at 0 °C. The reaction mixture was stirred at room temperature for 12 h. Reaction progress was monitored by TLC (MeOH: DCM = 1:9, UV). On completion reaction mixture was evaporated to dryness and triturated with Et2O to give white solid l-(3-(l -methyl- lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)cyclopropan-l -amine hydrochloride (150 mg, 94.1 %).-121- 45844530.1

[0198] Step 6: To a solution of l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)cyclopropan- 1 -amine hydrochloride (0.030 g, 0.090 mmol, 1 eq.) in DMF (3.0 mL) was added 2-methyl-5-(4-methylpiperazin-l-yl)benzoic acid hydrochloride (29 mg, 1.2 eq., 0.11 mmol), HATU (52 mg, 0.14 mmol, 1.5 eq.)and DIPEA (0.11 mL, 0.63 mmol, 7 eq.) at room temperature. The reaction mixture was stirred at room temperature for 12 h. The reaction was monitored by LCMS. On completion the reaction mixture was purified by HPLC (column: C18 50x30 mm; mobile phase: [Water (Formic acid )- Acetonitrile]; flow rate = 10 mL / min, gradient: 5%-50% B over 13 min) to give 2-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)cyclopropyl)-5-(4-methylpiperazin-l-yl)benzamide (8 mg, 20 %) as white solid.JH NMR (400 MHz, acetonitrile-d₃) 57.88 (t, J = 1.5 Hz, 1H), 7.63 (t, J = 1.6 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.51 (brs, 1H), 7.48 (t, 7= 1.7 Hz, 1H), 7.47 (dd, 7= 3.6, 1.1 Hz, 1H), 7.41 (dd, J= 5.1, 1.0 Hz, 1H), 7.15 - 7.08 (m, 2H), 6.98 (d, J = 2.6 Hz, 1H), 6.91 (dd, J = 8.4, 2.7 Hz, 1H), 6.67 (d, J = 2.3 Hz, 1H), 3.90 (s, 3H) 3.26 - 3.21 (m, 4H), 2.70 - 2.66 (m, 4H), 2.38 (s, 3H), 2.28 (s, 3H), 1.41 - 1.38 (m, 4H). LCMS: [M+H]+512.25.Example 19: Synthesis of N-(l-(3-(5-chlorothiophen-2-yl)-5-(l-methyl-lH-pyrazol-3-yl)phenyl)cyclopropyl)-2-methyl-5-(4-methylpiperazin- 1 -yl)benzamide (SC1-298)

[0199] Step 1: To a solution of tert-butyl (l-(3-bromo-5-(l-methyl-lH-pyrazol-3-yl)phenyl)cyclopropyl)carbamate (0.17 g, 0.42 mmol, 1 eq.) in 1,4-Dioxane (3.0 mL) and Water (1.0 mL) was added PdCl₂(dppf)-CH₂Cl₂ adduct (34.6 mg, 0.042 mmol, 0.1 eq) and cesium carbonate (0.28 g, 2 eq, 0.85 mmol) at room temperature. The reaction mixture was purged with Ar for 15 min. The reaction mixture was stirred at 80 °C for 12 h. On completion as checked by LCMS, the reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 5 mL). The organic layer was washed with water and dried over sodium sulfate. Purification by silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 5 - 80% EtOAc in Hexane gradient @ 13 mL / min) afforded tert-butyl (l-(3-(5-chlorothiophen-2-yl)-5-(l -methyl- lH-pyrazol-3-yl)phenyl)cyclopropyl)carbamate (80 mg, 44 %) as off-white solid.-122- 45844530.1

[0200] Step 2: To a solution tert-butyl (l-(3-(5-chlorothiophen-2-yl)-5-(l-methyl-lH-pyrazol-3-yl)phenyl)cyclopropyl)carbamate (0.095 g, 0.22 mmol, 1 eq.) in 1,4- Dioxane (0.8 mL) was added a solution of HC1 (0.83 mL, 4 M in dioxane, 3.3 mmol, 15 eq.) in dioxane at 0 °C. The reaction mixture was stirred at room temperature for 12 h. The reaction was monitored by TLC (MeOH: DCM = 1:9, UV) and solvent was evaporated on completion. The crude mixture was triturated with cold Et20 to give l-(3-(5-chlorothiophen-2-yl)-5-(l-methyl-lH-pyrazol-3-yl)phenyl)cyclopropan-l -amine (0.042 g, 58 %) as white solid.

[0201] Step 3: To a solution of l-(3-(5-chlorothiophen-2-yl)-5-(l-methyl-lH-pyrazol-3-yl)phenyl)cyclopropan-l -amine (0.04 g, 0.13 mmol, 1 eq.) in DMF (2 mL) was added 2-methyl-5-(4-methylpiperazin-l-yl)benzoic acid (42 mg, 0.18 mmol, 1.4 eq.), DIPEA (0.13 mL, 0.76 mmol, 6 eq.) and HATU (73 mg, 0.19 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred at room temperature for 12 h. The reaction was monitored by LCMS. On completion the reaction mixture was purified by HPLC (column: Cl 8 50x30 mm; mobile phase: [Water (Formic acid )- Acetonitrile]; flow rate = 15 mL / min, gradient: 35%-95% B over 10 min) to give N-(l-(3-(5-chlorothiophen-2-yl)-5-(l-methyl-lH-pyrazol-3-yl)phenyl)cyclopropyl)-2-methyl-5-(4-methylpiperazin-l-yl)benzamide (0.023 g, 33 %) as white solid. 'll NMR (400 MHz, CDCl₃) 57.78 - 7.76 (m, 1H), 7.65 - 7.62 (m, 1H), 7.48 -7.46 (m, 1H), 7.39 (d, 7 = 2.1 Hz, 1H), 7.13 (d, 7= 3.9 Hz, 1H), 7.10 (d, 7 = 8.4 Hz, 1H), 6.94 (d, 7 = 2.4 Hz, 1H), 6.90 - 6.87 (m, 2H), 6.55 (d, 7 = 2.2 Hz, 1H), 6.44 (s, 1H), 3.96 (s, 3H), 3.27 - 3.21 (m, 4H). 2.74 - 2.67 (m, 4H), 2.42 (s, 3H), 2.34 (s, 3H), 1.51 - 1.39 (m, 4H).LCMS: [M+H]+546.21.Example 20: Synthesis of 5-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)cyclopropyl)-2-(4-methylpiperazin- 1 -yl)isonicotinamide (SC1-258)

[0202] To a solution of 5-methyl-2-(4-methylpiperazin-l-yl)isonicotinic acid (19 mg, 0.072 mmol, 89% wt, 1.2 eq.) in DMF (0.5 mL) was added l-(3-(l-methyl-lH-pyrazol-3-yl)- -123- 45844530.15-(thiophen-2-yl)phenyl)cyclopropan-l-aminium chloride (0.020 g, 0.06 mmol, 1 eq.), HATU (34 mg, 0.09 mmol, 1.5 eq.)and DIPEA (0.06 mL, 0.36 mmol, 6 eq.) at room temperature. The reaction mixture was stirred at room temperature for 12 h. The reaction was monitored by LCMS. On completion the reaction mixture was purified by HPLC (column: Cl 8 50x30 mm; mobile phase: [Water (Formic acid )-Acetonitrile]; flow rate = 15 mL / min gradient: 5%-45% B over 8 min) to give 5-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)cyclopropyl)-2-(4-methylpiperazin-l-yl)isonicotinamide (10 mg, 32 %) as white solid. 'll NMR (400 MHz, CDCl3) 5 8.02 (s, 1H), 7.86 (s, 1H), 7.68 (s, 1H), 7.56 (t, J = 1.6 Hz, 1H), 7.38 (d, 7 = 2.2 Hz, 1H), 7.36 (dd, 7 = 3.5, 0.8 Hz, 1H), 7.27 (dd, 7= 5.1, 0.7 Hz, 1H), 7.07 (dd, 7 = 5.0, 3.7 Hz, 1H), 6.71 (brs, 1H). 6.62 (s, 1H), 6.55 (d, 7 = 2.2 Hz, 1H), 3.94 (s, 3H), 3.72 - 3.66 (m, 4H), 2.90 - 2.80 (m, 4H), 2.53 (s, 3H), 2.24 (s, 3H), 1.49 - 1.37 (m, 4H). LCMS: [M+H]+513.25.Example 21: Synthesis of N-(l-(3-(5-fluorothiophen-2-yl)-5-(l-methyl-lH-pyrazol-3-yl)phenyl)cyclopropyl)-5-methyl-2-(4-methylpiperazin-l-yl)isoni cotinamide (SC1-283)

[0203] Step 1: Procedure same as Step 1 in synthesis of 2-methyl-N-(l-(3-(l-methyl-1 H-pyrazol-3 -y l)-5 -(thiophen-2-yl)phenyl)cyclopropy l)-5 -(4-methy Ipiperazin- 1 -vDbenzamide. Intermediate l-(3-bromo-5-chlorophenyl)cyclopropan-l-amine synthesized from 3-bromo-5-chlorobenzonitrile (CAS no. 304854-55-5)

[0204] Step 2: Procedure same as Step 2 in synthesis of 2-methyl-N-(l-(3-(l-methyl-1 H-pyrazol-3 -y 1) -5 -(thiophen-2-yl)phenyl)cyclopropyl)-5 -(4-methy Ipiperazin- 1 -yl)benzamide (SC1-284). Intermediate tert-butyl (l-(3-bromo-5--124- 45844530.1chlorophenyl)cyclopropyl)carbamate synthesized from l-(3-bromo-5-chlorophenyl)cyclopropan- 1 -amine.

[0205] Step 3: To a solution of tert-butyl (l-(3-bromo-5-chlorophenyl)cyclopropyl)carbamate (0.070 g, 0.20 mmol, 1.8 eq.) in 1,4-Dioxane (1.2 mL) and Water (0.3 mL) was added 2-(5-fluorothiophen-2-yl)-4, 4,5, 5 -tetramethyl- 1,3,2-dioxaborolane (26 mg, 0.11 mmol, 1 eq.) and sodium carbonate (24 mg, 2 eq., 0.23 mmol) at room temperature. The reaction mixture was purged with Ar for 15 min followed by addition of PdCl2(dppf)-CH2Cl2adduct (19 mg, 0.023 mmol, 0.2 eq.). The reaction mixture was stirred at 80°C for 24 h. On completion of reaction as checked by LCMS. Reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2 x 5 mL). The organic layer was washed with brine (5 mL), dried over sodium sulphate and evaporated. Purification by silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 5 - 20% EtOAc in Hexane gradient @ 13 mL / min) afforded tert-butyl (l-(3-chloro-5-(5-fluorothiophen-2-yl)phenyl)cyclopropyl)carbamate (12 mg, 29 %) as colorless oil.

[0206] Step 4: To a solution of tert-butyl (l-(3-chloro-5-(5-fluorothiophen-2-yl)phenyl)cyclopropyl)carbamate (0.012 g, 0.033 mmol, 1 eq.) in 1,4-Dioxane (0.4 mL) and Water (0.13 mL) was added l-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (10 mg, 0.05 mmol, 1.5 eq.) and tripotassium phosphate (14 mg, 0.065 mmol, 2 eq.) at room temperature. The reaction mixture was purged with Ar for 15 min followed by addition of XPhos Pd G2 (5.1 mg, 0.007 mmol, 0.2 eq.). The reaction mixture was stirred at 80 °C for 12 h. The reaction was monitored by LCMS. Reaction mixture was diluted with EtOAc (5 mL) and washed with water (2 x 5 mL). The organic layer was washed with brine (5 mL). The organic layer was evaporated to give crude mixture tert-butyl (l-(3-(5-fluorothiophen-2-yl)-5-(1 -methyl- lH-pyrazol-3-yl)phenyl)cyclopropyl)carbamate (20 mg) which was used directly in the next step.

[0207] Step 5: Procedure same as Step 5 in synthesis of 2-methyl-N-(l-(3-(l-methyl-1 H-pyrazol-3 -y l)-5 -(thiophen-2-yl)phenyl)cyclopropy l)-5 -(4-methy Ipiperazin- 1 -yl)benzamide. Intermediate l-(3-(5-fluorothiophen-2-yl)-5-(l -methyl- lH-pyrazol-3-yl)phenyl)cyclopropan-l -amine hydrochloride (15 mg) synthesized from tert-butyl (l-(3-(5-fluorothiophen-2-yl)-5-(l -methyl- 1 H-pyrazol-3 -yl)phenyl)cyclopropyl)carbamate

[0208] Step 6: To a solution of 5-methyl-2-(4-methylpiperazin-l-yl)isonicotinic acid (14 mg, 0.057 mmol, 1.2 eq.) in DMF (1.0 mL) was added 1-(3-(5-fluorothiophen-2-yl)-5-(1-methyl-1H-pyrazol-3-yl)phenyl)cyclopropan-1-amine (0.015 g, 0.048 mmol, 1 eq.), HATU (27-125- 45844530.1mg, 0.072 mmol, 1.5 eq.), DMAP (8.8 mg, 0.072 mmol, 1.5 eq.) and DIPEA (0.05 mL, 0.29 mmol, 6 eq.) and stirred at room temperature. The reaction was monitored by LCMS. On completion of reaction mixture was diluted with EtOAc (5 mL) and washed with water (2 x 5 mL). The organic layer was washed with brine (5 mL), dried over sodium sulphate and evaporated to give a crude mixture. The crude mixture was purified by HPLC (column: Cl 8 50x30 mm; mobile phase: [Water (Formic acid )- Acetonitrile]; flow rate = 15 mL / min gradient: 15% - 95% B over 26 min) to give N-(l-(3-(5-fluorothiophen-2-yl)-5-(l -methyl- 1H-pyrazol- 3-yl)phenyl)cyclopropyl)-5-methyl-2-(4-methylpiperazin-l-yl)isonicotinamide (5 mg, 20 %) as white solid.NMR (400 MHz, Acetonitrile-d₃ ) δ 8.03 (s, 1H), 7.77 (t, J = 1.5 Hz, 1H), 7.65 (t, / = 1.5 Hz, 1H), 7.62 (brs, 1H), 7.53 (d, J = 2.2 Hz, 1H), 7.34 (t, J= 1.6 Hz, 1H), 7.11 (t, J = 3.8 Hz, 1H), 6.75 (s, 1H), 6.66 (d, J = 2.3 Hz, 1H), 6.60 (dd, J = 4.1, 2.1 Hz, 1H), 3.90 (s, 3H), 3.63 (s, 4H), 2.73 (s, 4H), 2.44 (s, 3H), 2.21 (s, 3H), 1.39 (s, 4H). LCMS: [M+H]+531.24.Example 22: Synthesis of N-(l-(3-(5-fluorothiophen-2-yl)-5-(l-methyl-lH-pyrazol-3-yl)phenyl)cyclopropyl)-2-methyl-5-(4-methylpiperazin-l-yl)benzamide (SC2-009)

[0209] Step 1: To a solution of l-(3-bromo-5-chlorophenyl)cyclopropan-l-amine (0.30 g, 1.22 mmol, 1 eq.) in DMF (2 mL) was added 2-methyl-5-(4-methylpiperazin-l-yl)benzoic acid (0.34 g,, 1.46 mmol, 1.2 eq.), HATU (0.7 gg, 1.83 mmol, 1.5 eq.) and DIPEA (0.85 mL, 4.87 mmol, 4 eq.) at 25 °C. The reaction mixture was stirred for 12 h at 25 °C. The reaction was monitored by LCMS. The reaction mixture was diluted with cold water (10 mL) and extracted with EtOAc (3 xlO mL). The organic layer was dried over sodium sulfate and evaporated to give crude mixture. Purification by silica gel chromatography (ISCO®; 24 g SepaFlash® Silica Flash Column, Eluent of 1 - 20% MeOH in DCM gradient @ 40 mL / min 1 - 20% MeOH / DCM, 24g column) afforded N-(l-(3-bromo-5-chlorophenyl)cyclopropyl)-2-methyl-5-(4-methylpiperazin-l-yl)benzamide (462 mg, 82.0 %) as off-white solid.-126- 45844530.1

[0210] Step 2: Procedure same as Step 3 in synthesis of N-(l-(3-(5-fluorothiophen-2-yl)-5-(l-methyl-lH-pyrazol-3-yl)phenyl)cyclopropyl)-5-methyl-2-(4-methylpiperazin-l-yl)isonicotinamide(SCl-283). Intermediate N-(l-(3-chloro-5-(5-fluorothiophen-2-yl)phenyl)cyclopropyl)-2-methyl-5-(4-methylpiperazin-l-yl)benzamide (41 mg, 39.0%) synthesized from N-(l-(3-bromo-5-chlorophenyl)cyclopropyl)-2-methyl-5-(4-methylpiperazin-l-yl)benzamide (100 mg).

[0211] Step 3: Procedure same as Step 4 in synthesis of N-(l-(3-(5-fluorothiophen-2-yl)-5-(l-methyl-lH-pyrazol-3-yl)phenyl)cyclopropyl)-5-methyl-2-(4-methylpiperazin-l-yl)isonicotinamide (SC1-283). Product N-(l-(3-(5-fluorothiophen-2-yl)-5-(l-methyl-lH-pyrazol-3-yl)phenyl)cyclopropyl)-2-methyl-5-(4-methylpiperazin-l-yl)benzamide (20 mg, 46%) from N-(l-(3-chloro-5-(5-fluorothiophen-2-yl)phenyl)cyclopropyl)-2-methyl-5-(4-methylpiperazin-l-yl)benzamide (40 mg). N-(l-(3-(5-fluorothiophen-2-yl)-5-(l-methyl-lH-pyrazol-3-yl)phenyl)cyclopropyl)-2-methyl-5-(4-methylpiperazin-l -yl)benzamideXH NMR (400 MHz, Acetonitrile-d3) 5 7.79 - 7.76 (m, 1H), 7.65 - 7.63 (m, 1H), 7.53 (d, J = 2.2 Hz, 1H), 7.46 (brs, 1H), 7.37 - 7.34 (m, 1H), 7.13 - 7.08 (m. 2H), 6.98 - 6.95 (m, 1H), 6.91 (dd, J = 8.4, 2.7 Hz, 1H), 6.66 (d, J= 2.2 Hz, 1H). 6.60 (dd. J = 4.0, 2.1 Hz, 1H). 3.90 (s, 3H), 3.22 - 3.16 (m, 4H), 2.61 - 2.54 (m, 4H), 2.31 (s, 3H), 2.28 (s, 3H), 1.39 (s, 4H). LCMS: [M+H]+530.24.Example 23: Synthesis of 2-methyl-A-(l-(2-(l-methyl-lH-pyrazol-3-yl)-6-(thiophen-2-yl)pyridin-4-yl)cyclopropyl)-5-(4-methylpiperazin-l-yl)benzamide (ID-5-4):

[0212] Step 1: To a solution of 2-bromo-6-chloro-4-methylpyridine (1030.0 mg, 5 mmol) in THF (30 mL) under N2was added LDA (5.0 mL, 2 M, 10 mmol) at -78 °C. The reaction mixture was stirred at -78 °C under N2 for 30 min, followed by the addition of dimethyl-127- 45844530.1carbonate (1270 mg, 14.1 mmol) at 0 °C. The reaction mixture was stirred at 0 °C under N2 for 1 h, then quenched with sat. NH4C1 at 0 °C. The reaction mixture was partitioned between ethyl acetate and H₂O (200 / 50 mL), the organic layer was separated, and the aqueous layer was re-extracted with ethyl acetate (50 mL). The combined organic layer was washed with brine, dried with anhydrous Na2SO4, and evaporated in vacuo. The residue was purified by silica gel chromatography using a combiflash (20 g silica gel column, PE: EA= 1: 0 to 0: 1) to afford methyl 2-(2-bromo-6-chloropyridin-4-yl)acetate (792 mg, 60%) as a yellow oil. LCMS m / z calc, for C8H7BrClNO2+ [M+H]+.

[0213] Step 2: To a solution of methyl 2-(2-bromo-6-chloropyridin-4-yl)acetate (792 mg, 3 mmol) in DMF (20.0 mL) were added 1,2-dibromoethane (845 mg, 4.5 mmol), Cs2CO3 (1952 mg, 6 mmol), tetra-n-butylammonium fluoride (3.3mL, 1 M, 3.3 mmol), and NaOH (240 mg, 6 mmol) at 20 °C. The reaction mixture was stirred at 20 °C for 15 h. LCMS showed a mass peak of the desired product. The reaction mixture was then partitioned between ethyl acetate and H2O (250 / 1 OOmL). The organic layer was separated, and the aqueous layer was reextracted with ethyl acetate (150 mL). The combined organic layer was washed with brine, dried with anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue was then purified by silica gel chromatography using a combiflash (30 g silica gel column, PE: EA= 1: 0 to 0: 1) to afford methyl l-(2-chloroquinolin-4-yl)cyclopropane-l -carboxylate (691.2 mg, 80%) as a yellow solid. LCMS m / z calc, for C₁₀H₉ClBrNO₂⁺ [M+H]+

[0214] Step 3: To a solution of methyl l-(2-bromo-6-chloropyridin-4-yl)cyclopropane-1 -carboxylate (690.0 mg, 2.4 mmol) in 1,4-dioxane (20.0 mL) under N2 were added sat. aq. Na₂CO₃ (4.0 mL), Pd(dppf)C12 (85mg, 0.1 mmol), and l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-lH-pyrazole (500 mg, 2.4 mmol) at 20 °C. The reaction mixture was stirred at 100 °C under N2 for 15 h. LCMS showed a mass peak of the desired product. The reaction mixture was then filtered, and the filtrate was concentrated in vacuo and purified by silica gel chromatography using combiflash (20 g silica gel column, PE: EA= 1: 0 to 0: 1) to afford methyl l-(2-chloro-6-(l-methyl-lH-pyrazol-3-yl)pyridin-4-yl)cyclopropane-l-carboxylate (558.2 mg, 80%) as a yellow oil. LCMS m / z calc, for C14H14C1N3O2+ [M+H]+

[0215] Step 4: To a solution of methyl l-(2-chloro-6-(l -methyl- lH-pyrazol-3-yl)pyridin-4-yl)cyclopropane-l -carboxylate (580 mg, 2 mmol) in 1,4-dioxane (20.0 mL) under N2 were added sat. aq. Na2CO3 (4.0 mL), X-phos Pd-G2 (85mg, 0.1 mmol), and thiophen-2-ylboronic acid (500 mg, 4 mmol) at 20 °C. The reaction mixture was stirred at 100 °C under N2 for 15 h. LCMS showed a mass peak of the desired product. The reaction mixture was then-128- 45844530.1filtered, and the filtrate was concentrated in vacuo and purified by silica gel chromatography using combiflash (20 g silica gel column, PE: EA= 1: 0 to 0: 1) to afford methyl l-(2-(l-methyl-lH-pyrazol-3-yl)-6-(thiophen-2-yl)pyridin-4-yl)cyclopropane-l -carboxylate (540. mg, 80%) as a yellow oil. LCMS m / z calc, for C18H17N3O2S+ [M+H]+ 339.4 found 339.5

[0216] Step 5: To a solution of Preparation of methyl l-(2-(l-methyl-lH-pyrazol-3-yl)-6-(thiophen-2-yl)pyridin-4-yl)cyclopropane-l -carboxylate (339 mg, 1 mmol) in MeOH (60mL) was added 10% aq. NaOH (1.5mL) at 20 °C. The reaction mixture was stirred at 20 °C for 15 h. LCMS showed a mass peak of the desired product. The reaction mixture was then acidified with IN HC1 to pH = 1 at 0 °C and partitioned between ethyl acetate and H2O (250 / 50 mL). The organic layer was separated, and the aqueous layer was re-extracted with ethyl acetate (150 mL). The combined organic layer was washed with brine, dried with anhydrous Na2SO4, and evaporated in vacuo to afford l-(2-(l -methyl- lH-pyrazol-3-y l)-6-(thiophen-2-yl)pyridin-4-yl)cyclopropane-l -carboxylic acid (324 mg, 100%) as a yellow solid. LCMS m / z calc, for C17H15N3O2S+ [M+H]+ 325.3.0, found 325.4.

[0217] Step 6: To a solution of l-(2-(l-methyl-lH-pyrazol-3-yl)-6-(thiophen-2-yl)pyridin-4-yl)cyclopropane-l -carboxylic acid (339.0 mg, 1 mmol) in toluene (6.0 mL) under N2, was added diphenylphosphoryl azide (306 mg, 1.1 mmol) and TEA (202 mg, 2.2 mmol) at 20 °C. The reaction mixture was stirred at 90 °C under N2 for 2 h, then evaporated in vacuo to afford a crude. The crude was dissolved in 1,4- dioxane (40mL), followed by adding aq. NaOH (10%, 2 mL) at 20 °C under N2. The reaction mixture was stirred at 90 °C for 15 h. LCMS showed a mass peak of the desired product. The reaction mixture was then partitioned between ethyl acetate and H2O (25 / 15 mL). The organic layer was separated, and the aqueous layer was re-extracted with ethyl acetate (50 mL). The combined organic layer was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in 30 mL MeOH, then 10 mL 1 N HC1 was added to the solution at 20 °C. The reaction mixture was stirred at 20 °C for 1 h, then partitioned between ethyl acetate and H2O (250 / 150 mL). The organic layer was discarded, and the aqueous layer was basified with NH3. H2O to pH = 9 at 0 °C, followed by extraction with DCM (20 mL). The organic layer was washed with brine, dried with anhydrous Na2SO4 and concentrated in vacuo to afford 1-(2-(1-methyl-1H-pyrazol-3-yl)-6-(thiophen-2-yl)pyridin-4-yl)cyclopropan-l-amine (180 mg, 60%) as a white solid. LCMS m / z calc, for C16H16N4S+ [M+H]+

[0218] Step 7: To a solution of 2-methyl-5-(4-methylpiperazin-l-yl)benzoic acid (25 mg, 0.11 mmol) in DMF (1 mL) was added TEA (30 mg, 0.3 mmol), HATU (54 mg, 0.14-129- 45844530.1mmol) followed by addition of l-(2-(l -methyl- lH-pyrazol-3-y l)-6-(thiophen-2-yl)pyridin-4-yl)cyclopropan- 1 -amine (30 mg, 0.1 mmol) at room temperature. The reaction mixture was stirred at 25 °C for 12 hour. The reaction progress was monitored by LCMS. On completion the reaction mixture was purified by HPLC to afforded 2-methyl-N-(l-(2-(l-methyl-lH-pyrazol-3-yl)-6-(thiophen-2-yl)pyridin-4-yl)cyclopropyl)-5-(4-methylpiperazin-l-yl)benzamide (25 mg, 53 %) as white solid. ¹H NMR (400 MHz, CDCl3) 6 8.02 (s, 1H), 7.86 (s, 1H), 7.68 (s, 1H), 7.56 (t, J = 1.6 Hz, 1H), 7.38 (d, J = 2.2 Hz, 1H), 7.36 (dd, J = 3.5, 0.8 Hz, 1H), 7.27 (dd, J = 5.1, 0.7 Hz, 1H), 7.07 (dd, J = 5.0, 3.7 Hz, 1H), 6.71 (brs, 1H), 6.62 (s, 1H), 6.55 (d, J = 2.2 Hz, 1H), 3.94 (s, 3H), 3.72 - 3.66 (m, 4H), 2.90 - 2.80 (m, 4H), 2.53 (s, 3H), 2.24 (s, 3H), 1.49 - 1.37 (m, 4H). LCMS: [M+H]+513.25.Example 24: Synthesis of 5-chloro-2-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)cyclopropyl)benzamide (SC1-285)

[0219] To a solution of l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)cyclopropan-l -amine hydrochloride (49 mg, 0.15 mmol, 1 eq.) in DMF (3.0 mL) was added 5-chloro-2-methylbenzoic acid (0.025 g, 0.15 mmol, 1.0 eq.), DIPEA (0.13 mL, 0.73 mmol, 5 eq.)and HATU (84 mg, 0.22 mmol, 1.5 eq.) at room temperature. The reaction mixture was stirred at room temperature for 12 h. The reaction was monitored by LCMS. On completion the reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layer was dried over sodium sulfate and evaporated to give crude mixture. Purification by silica gel chromatography ( ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 5 - 100% EtOAc in Hexane gradient @ 13 mL / min) afforded 5-chloro-2-methyl-N-(l-(3-(l -methyl- lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)cyclopropyl)benzamide (0.03 g, 50 %) as white solid. ¹H NMR (400 MHz, CDCb) δ 7.86 (s, 1H), 7.69 (s, 1H), 7.51 (s, 1H), 7.40 - 7.33 (m, 3H), 7.30 - 7.23 (m, 2H), 7.16-7.10 (m, 1H), 7.09 - 7.04 (m, 1H), 6.60 -6.40 (m, 2H). 3.95 (s, 3H), 2.38 (s, 3H), 1.52 - 1.36 (m, 4H). LCMS: [M+H]+448.13-130- 45844530.1Example 25: Synthesis of 2-chloro-5-methyl-N-(l-(3-(l -methyl- lH-pyrazol-3-yl)-5- (thiophen-2-yl)phenyl)cyclopropyl)isonicotinamide (SC1-257)To a solution of l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)cyclopropan-l-aminium chloride (0.020 g, 0.060 mmol, 1 eq.) in DMF (0.5 mL) was added DIPEA (42 pF. 0.24 mmol, 4 eq.), HATU (34 mg, 0.090 mmol, 1.5 eq.) and 2-chloro-5-methylisonicotinic acid (11 mg, 0.066 mmol, 1.1 eq.). The reaction mixture was stirred at room temperature for 3 h. Reaction mixture was diluted with EtOAc (5 mL) and washed with water (2 x 5 mL). The organic layer was washed with brine (5 mL). Purification by silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 5 - 60% EtOAc in Hexane gradient @ 13 mL / min)) afforded 2-chloro-5-methyl-N-(l-(3-(l -methyl- lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)cyclopropyl)isonicotinamide (7.7 mg, 28 %) as white solid, ’ll NMR (400 MHz CDCh) 5 8.23 (s, 1H), 7.86 (s, 1H), 7.73 (s, 1H), 7.60 - 7.35 (m, 3H), 7.25 - 7.00 (m, 2H), 6.70 -6.45 (m, 2H). 3.96 (s, 3H), 2.34 (s, 3H), 1.55 -1.35 (m, 4H). LCMS: [M+H]+449.12. Example 26: Synthesis of 5-amino-2-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5- (thiophen-2-yl)phenyl)cyclopropyl)benzamide (SC1-300)Step 1: To a solution of 5-amino-2-methylbenzoic acid (3.00 g, 19.85 mmol, 1 eq.) in 1,4-Dioxane (20 mL) and Water (20 mL) was added sodium hydroxide (aq.19.85 mL, 1 M, 19.85 mmol, 1 eq.) andBoc2O (4.8 g, 21.83 mmol, 1.1 eq.) at room temperature. The reaction mixture was stirred for 10 h at room temperature. The reaction was monitored by TLC (MeOH: DCM = 5:95, UV) and on completion neutralized by 1 M HC1. The white precipitate was filtered to-131- 45844530.1afford 5-((tert-butoxycarbonyl)amino)-2-methylbenzoic acid (3.0 g, 60 %) and used directly in the next step.

[0220] Step 2: To a solution of 5-((tert-butoxycarbonyl)amino)-2-methylbenzoic acid (49 mg, 0.20 mmol, 1.3 eq.,) in DMF (2 ml,) was added l-(3-(l -methyl- lH-pyrazol-3-yl)-5- (thiophen-2-yl)phenyl)cyclopropan-l -amine hydrochloride (0.05 g, 0.15 mmol, 1 eq.), HATU (86 mg, 0.23 mmol. 1.5 eq.) and DIPEA (0.16 mL, 0.90 mmol, 6 eq.) at room temperature. The reaction mixture was stirred for 12 h at room temperature. The reaction was monitored by LCMS. Reaction mixture was diluted with EtOAc (5 mL) and washed with water (2 x 5 mL). The organic layer was washed with brine (5 mL). The combined organic layer was evaporated to give a crude mixture. Purification by silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 5 - 100% EtOAc in Hexane gradient @ 13 niL / min) afforded tert-butyl (4-methyl-3-((l-(3-(l -methyl- lH-pyrazol-3-yl)-5-(thiophen-2- yl)phenyl)cyclopropyl)carbamoyl)phenyl)carbamate (75 mg, 94 %) as white solid.

[0221] Step 3: To a solution of tert-butyl (4-methyl-3-((l-(3-(l-methyl-lH-pyrazol-3- yl)-5-(thiophen-2-yl)phenyl)cyclopropyl)carbamoyl)phenyl)carbamate (0.075 g, 0.14 mmol, 1 eq.) in 1,4-Dioxane (2 mL) was added a solution of HC1 (0.20 mL, 4 M, 0.80 mmol, 5.6 eq.) in dioxane at 0 °C. The reaction mixture was stirred for 12 h at room temperature. The reaction was monitored by LCMS. On completion the solvent was evaporated to dryness and triturated with cold Et20 to give 5-amino-2-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2- yl)phenyl)cyclopropyl)benzamide (20 mg, 33 %) as white solid.JH NMR (400 MHz, Methanol-cfi) 57.93 (s, 1H), 7.75 - 7.65 (m, 3H), 7.50 - 7.35 (m, 5H), 7.14 - 7.12 (m, 1H), 6.74 (d, J = 2.2 Hz, 1H), 3.99 (s, 3H), 2.43 (s. 3H), 1.50 - 1.36 (m, 4H). LCMS: [M+H]+429.18. Synthesis of intermediate: (R)-l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl) ethan-1 -amine.-132- 45844530.1

[0222] Step 1: To a solution of (R)-l-(3,5-dichlorophenyl)ethan-l-amine (1.00 g, 5.26 mmol, 1 eq.) in THF (10 mL) and Water (5 mL) was added sodium bicarbonate (4.42 g, 52.61 mmol, 10 eq.) andBoc2O (1.50 g„ 6.84 mmol, 1.3 eq.) atO °C. The reaction mixture was stirred for 12 h at room temperature. The reaction progress was monitored by TLC (EtOAc: Hexane = 5:95, UV). On completion the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The organic layer was combined, dried over sodium sulfate and evaporated to give a crude mixture. Purification by silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 5 - 20% EtOAc in Elexane gradient @ 60 mL / min) afforded tert-butyl (R)-(l-(3,5-dichlorophenyl)ethyl)carbamate (1.4 g, 92 %).

[0223] Step 2: To a solution of tert-butyl (R)-(l-(3,5-dichlorophcnyl)cthyl)carbamatc (1.2 g, 4.1 mmol, 1 eq.) in DMF (7 mL) and water (1.4 mL) was added thiophen-2-ylboronic acid (0.53 g, 4.1 mmol, 1 eq.) and cesium carbonate (2.7 g, 8.3 mmol, 2 eq.) at room temperature. The reaction mixture was purged with Ar for 15 min followed by addition of XPhos Pd G3 (0.35 g, 0.41 mmol, 0.1 eq.). The reaction mixture was stirred at 100 °C for 1 h. The reaction progress was monitored by LCMS. On completion the reaction mixture was diluted with EtOAc (20 mL) and washed with water (2 x 20 mL). The organic layer was washed with brine (20 mL), dried over sodium sulphate and evaporated. Purification by silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 5 - 30% EtOAc in Hexane gradient @ 60 mL / min) afforded tert-butyl (R)-(l-(3-chloro-5-(thiophen-2-yl)phenyl)ethyl)carbamate (0.80 g, 57 %) as colorless liquid.

[0224] Step 3: To a solution of tert-butyl (R)-(l-(3-chloro-5-(thiophen-2-yl)phenyl)ethyl)carbamate (1.23 g, 3.64 mmol, 1 eq.) in 1,4-Dioxane (5 mL) and Water (1.7 mL) was added l-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.98 g, 4.73 mmol, 1.3 eq.) and cesium carbonate (2.4 g, 7.28 mmol, 2 eq.) at room temperature. The reaction mixture was purged with Ar for 15 min followed by addition of XPhos Pd G2 (0.28 g mg, 0.35 mmol, 0.1 eq.). The reaction mixture was stirred at 90 °C for 1 h. The reaction progress was monitored by LCMS. On completion the reaction mixture was diluted with EtOAc (20 mL) and washed with water (2 x 20 mL). The organic layer was washed with brine (20 mL), dried over sodium sulphate and evaporated. Purification by silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 5 - 100% EtOAc in Hexane gradient @ 60 mL / min) afforded tert-butyl (R)-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)carbamate (0.91 g, 65.5 %) as colourless liquid.-133- 45844530.1

[0225] Step 4: To a solution of tert-butyl (R)-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)carbamate (0.870 g, 2.27 mmol, 1 eq.) in Dioxane (30 mL)and was added a solution of HC1 (2.84 mL, 4 M, 11.3 mmol, 5 eq.) in dioxane at room temperature. The reaction mixture was stirred at room temperature for 12 h. On completion, the reaction solvent was evaporated and triturated with cold Et20 to give (R)-l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethan-l-amine (0.6 g mg, 93.3 %) as white solid. Example 27: Synthesis of (R)-5-(4-(dimethylamino)piperidin-l-yl)-2-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)benzamide (SC2- 040)

[0226] Step 1: To a solution of l,l,l-trifluoro-N-phenyl-N-((trifhioromethyl)sulfonyl) methanesulfonamide (10.7 g,, 30.1 mmol, 1 eq.) in DCM (100 mL) was added methyl 5-hydroxy-2-methylbenzoate (5.0 g, 30.1 mmol, 1 eq.), triethylamine (6.1 g, 8.4 mL, 60.2 mmol., 2 eq.) and DMAP (1.84 g, 15.0 mmol, 0.5 eq.). The reaction mixture was stirred at room temperature for 6 h. On completion the organic layer was washed with water (3 x 100 mL). The organic layer was dried and evaporated to dryness to give crude mixture. Purification by silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Fluent of 5 - 80% EtOAc in Hexane gradient @ 60 mL / min) afforded methyl 2-methyL5- (((trifluoromethyl)sulfonyl)oxy)benzoate (7.3 g, 81 %) as colorless liquid.

[0227] Step 2: To a solution of methyl 2-methyl-5- (((trifluoroniethyl)sulfonyl)oxy)benzoate (0.30 g, 1.01 mmol, 1 eq.) in 1,4-Dioxane (5 mL) was added N, N-dimethylpiperidin-4-amine (0.16 g, 1.21 mmol, 1.2 eq.) and cesium carbonate (0.98 g, 3.02 mmol, 3 eq.) at room temperature. The reaction mixture was purged with Ar gas for 15 min followed by addition of RuPhos Pd G3 (84.1 mg, 0.101 mmol, 0.1 eq.). The reaction mixture was stirred for 6 h at 100 °C. On completion the reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 5 mL). The organic layer was combined, dried over sodium sulfate and evaporated to give crude mixture. Purification by silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 5 - 100% EtOAc-134- 45844530.1in Hexane gradient @ 25 mL / min) afforded methyl 5-(4-(dimethylamino)piperidin-l-yl)-2-methylbenzoate (0.197 g, 70.9 %) as pale yellow oil.

[0228] Step 3: To a solution of methyl 5-(4-(dimethylamino)piperidin-l-yl)-2-methylbenzoate (0.190 g, 0.69 mmol, 1 eq.) in THF (2 mL), MeOH (1 mL) and Water (0.5 ml.) was added LiOIMFO (0.09 g, 2.06 mmol, 3 eq.). The reaction was stirred at room temperature for 12 h. On completion of reaction as checked by TLC (MeOH / DCM=l:9. UV), the reaction mixture was evaporated and diluted with water (5 mL). 1 N HC1 was added to the reaction mixture followed by addition of EtOAc (5 mL). The organic layer was separated, dried using sodium sulfate and evaporated to give crude product. Purification by silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 1 - 15% MeOH in DCM gradient @ 13 mL / min; 1% triethyl amine additive) afforded 5-(4-(dimethylamino)piperidin-l-yl)-2-methylbenzoic acid (0.16 g, 89%).

[0229] Step 4: To a solution of 5-(4-(dimethylamino)piperidin-l-yl)-2-methylbenzoic acid (28 mg, 0.11 mmol, 1.2 eq.) in DMF (1 mL) was added DIPEA (78 pL, 0.45 mmol, 4 eq.), HATH (54 mg, 0.14 mmol, 1.6 eq.) followed by addition of (R)-l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethan-l-amine hydrochloride (0.03 g, 95% wt, 0.089 mmol, 1 eq.) at room temperature. The reaction mixture was stirred at 25 °C for 12 h. The reaction progress was monitored by LCMS. On completion the reaction mixture was purified by HPLC (column: C1850x30 mm; mobile phase: [Water (Formic acid )-Methanol]; flow rate = 15 mL / min, gradient: 5%-58% B over 8 min) to give (R)-5-(4-(dimethylamino)piperidin-l-yl)-2-methyl- / V-(l-(3-( 1 -methyl- lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)benzamide (25 mg, 53 %) as white solid. ’ll NMR (400 MHz, MeOH-dr ) 8 7.98 (s, 1H), 7.74 (s, 1H), 7.67 - 7.62 (m, 2H), 7.49 (d, J = 3.2 Hz, 1H), 7.41 (d, J = 4.9 Hz, 1H), 7.14 - 7.11 (m, 2H), 6.99-6.95 (m, 2H), 6.70 (d, J = 2.1 Hz, 1H), 5.27 (q, J = 6.9 Hz, 1H), 3.96 (s, 3H), 3.78 (d, 7 = 12.3 Hz, 2H), 2.89 (t, J = 11.3 Hz, 1H), 2.72 (t, 7= 12.2 Hz, 2H), 2.64 (s, 6H), 2.27 (s, 3H), 2.04 (d, 7 = 11.4 Hz, 2H), 1.71 (q, 7 = 11.0 Hz, 2H), 1.60 (d, J = 7.0 Hz, 3H). LCMS: [M+H]+528.28-135- 45844530.1Example 28: Synthesis of (R)-2-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)-5-(2,6-diazaspiro[3.3]heptan-2-yl)benzamide (SC2- 055)

[0230] StepProcedure same as Step 2 in synthesis of (R)-5-(4- (dimethylamino)piperidin-l-yl)-2-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)benzamide (SC2-040). Starting material tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (587 mg) afforded tert-butyl 6-(3-(methoxycarbonyl)-4-methylphenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (157 mg, 45%)

[0231] Step 2: Procedure same as Step 3 in synthesis of (R)-5-(4-(dimethylamino)piperidin-l-yl)-2-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)benzamide (SC2-040). Starting material tert-butyl 6-(3-(methoxycarbonyl)-4-methylphenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (157 mg) afforded crude mixture of 5-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-2-methylbenzoic acid. Crude used directly in next step.

[0232] Step 3: Procedure same as Step 4 in synthesis of (R)-5-(4-(dimethylamino)piperidin-l-yl)-2-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)benzamide (SC2-040). Crude starting material 5-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-2-methylbenzoic acid afforded tert-butyl (R)-6-(4-methyl-3-((l-(3-(1 -methyl- lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)carbamoyl)phenyl)-2, 6-diazaspiro[3.3]heptane-2-carboxylate (30 mg, 42%)

[0233] Step 4: To a solution of tert-butyl (R)-6-(4-methyl-3-((l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)carbamoyl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (0.03 g, 0.040 mmol, 1 eq., 95% wt) in DCM (1 mb) was added TEA (45 mg, 0.031 mL,, 0.40 mmol, 10 eq.) at room temperature. The reaction mixture was stirred at room temperature for 12 h. The reaction progress was monitored by LCMS. On completion the reaction mixture was purified by HPLC (column: C18 50x30 mm; mobile phase: [Water (Formic acid )-Acetonitrile]; flow rate = 15 ml / min gradient: 20%-60% B over 12 min) to give (R)-2-methyl-N-(l-(3-(l -methyl- lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)-5-(2, 6- -136- 45844530.1diazaspiro[3.3]heptan-2-yl)benzamide (5 mg, 30 %) as white solid.XH NMR (400 MHz, CDCh) 57.98 (brs, 1H), 7.91 (s, 1H), 7.73 (s, 1H), 7.53 (s, 1H), 7.42 - 7.36 (m, 2H), 7.31 -7.28 (m, 1H), 7.11 - 7.07 (m, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.58 (s, 1H), 6.46 (s, 1H), 6.41 (d, J= 8.3 Hz, 1H), 6.01 (d, J= 7.6 Hz, 1H), 5.40 - 5.36 (m, 1H), 4.33 (s, 2H), 4.22 (s, 2H), 3.98 - 3.40 (m. 6H), 2.31 (s, 4H),1.65 (d, J = 6.8 Hz, 3H). LCMS: [M+H]+498.23.Example 29: Synthesis of (R)-5-(3-(dimethylamino)azetidin-l-yl)-2-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)benzamide (SC2 - 072)

[0234] Step 1: Procedure same as Step 2 in synthesis of (R)-5-(4-(dimcthylamino)pipcridin-l -yl)-2-mcthyl-N-(l-(3-(l -methyl- lH-pyrazol-3-yl)-5-(thiophcn-2-yl)phenyl)ethyl)benzamide (SC2-040). Starting material N, N-dimethylazetidin-3-amine dihydrochloride (192 mg) afforded methyl 5-(3-(dimethylamino)azetidin-l-yl)-2-methylbenzoate (140 mg, 56%).

[0235] Step 2: Procedure same as Step 3 in synthesis of SC2-040. Starting material methyl 5-(3-(dimethylamino)azetidin-l-yl)-2-methylbenzoate (140 mg) afforded 5-(3-(dimcthylamino)azctidin-l-yl)-2-mcthylbenzoic acid (80 mg, 60%)

[0236] Step 3: Procedure same as Step 4 in synthesis of (R)-5-(4-(dimethylamino)piperidin- 1 -yl)-2-methyl-N-(l -(3-(l -methyl- lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)benzamide (SC2-040). Reaction between (R)-l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethan-l -amine hydrochloride (20 mg) and 5-(3-(dimethylamino)azetidin-l-yl)-2-methylbenzoic acid (18 mg) afforded the final product (R)-5-(3-(dimcthylamino)azctidin-l-yl)-2-mcthyl-N-(l-(3-(l-mcthyl-lH-pyrazol-3-yl)-5-(thiophcn-2-yl)phenyl)ethyl)benzamide (8 mg, 30%). ’ll NMR (400 MHz, CDCh) 57.93 (s, 1H), 7.73 (s, 1H), 7.55 (s, 1H). 7.40 (s, 2H), 7.29 (d, J = 4.0 Hz, 1H), 7.09 (s, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.59 (s, 1H), 6.44 (s, 1H), 6.39 (d, J = 7.4 Hz, 1H), 6.09 (d, J = 6.9 Hz, 1H), 5.40 - 5.32-137- 45844530.1(m, 1H), 3.97 (s, 3H), 3.92 (s, 2H), 3.63 (d, J = 5.2 Hz, 2H), 3.34 (s, 1H), 2.31 (s, 3H), 2.28 (s, 6H), 1.66 (d, J= 6.3 Hz, 3H). LCMS: [M+H]+500.25.Example 30: Synthesis of (R)-2-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)-5-(2,7-diazaspiro[3.5]nonan-7-yl)benzamide (SC2 - 087)

[0237] Step 1: Procedure same as Step 2 in synthesis of (R)-5-(4-(dimethylamino)piperidin-l-yl)-2-methyl-N-(l-(3-(l -methyl- lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)benzamide (SC2-040). Reaction between methyl 2-methyl-5-(((trifluoromethyl)sulfonyl)oxy)benzoate (300 mg) and tert-butyl 2,7-diazaspiro[3.5]nonane- 2-carboxylate (273 mg) afforded the intermediate tert-butyl 2-(3-(methoxycarbonyl)-4-methylphenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (269 mg, 71.4%)

[0238] Step 2: Procedure same as Step 3 in synthesis of (R)-5-(4-(dimethylamino)piperidin-l-yl)-2-methyl-N-(l-(3-(l -methyl- lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)benzamide (SC2-040) except solvent used was THF / Water (2:1). Starting material tert-butyl 2-(3-(methoxycarbonyl)-4-methylphenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (269 mg) afforded 5-(7-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-methylbenzoic acid (150 mg, 58%) as crude mixture. Crude was used directly in the next step.

[0239] Step 3: Procedure same as Step 4 in synthesis of (R)-5-(4-(dimethylamino)piperidin-l-yl)-2-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)benzamide (SC2-040). Reaction between l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethan-l -amine hydrochloride (50 mg) and 5-(7-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-methylbenzoic acid (62 mg) afforded tert-butyl (R)-2-(4-methyl-3-((l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)carbamoyl)phenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (90 mg, 92%).

[0240] Step 4: Procedure same as Step 4 in synthesis of (R)-2-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)-5-(2,6-diazaspiro[3.3]heptan-2-yl)benzamide (SC2-055). Starting material tert-butyl (R)-7-(4-methyl-3-((l-(3-(l -methyl- 1H- -138- 45844530.1pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)carbamoyl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (80 mg) afforded crude mixture containing desired product. Purification by preparative HPLC (column: C18 50x30 mm; mobile phase: [Water (Formic acid )-Acetonitrile]; flow rate = 20 ml / min gradient: 5%-55% B over 12 min) afforded (R)-2-methyl-N-(l-(3-(l -methyl- lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)-5-(2, 7-diazaspiro[3.5]nonan-7-yl)benzamide (10 mg, 15%).rH NMR (400 MHz, MeOH-d4) 5 8.54 (s, 1H), 7.97 (s, 1H), 7.73 (s, 1H), 7.67 - 7.63 (m, 2H), 7.48 (d, J = 3.5 Hz, 1H), 7.41 (d, J = 5.1 Hz, 1H), 7.15 - 7.09 (m, 2H), 7.00 - 6.93 (m, 2H), 6.69 (d, 7 = 2.2 Hz, 1H), 5.27 (q, 7 = 7.0 Hz, 1H), 3.96 (s, 3H), 3.83 (s, 4H), 3.13 - 3.02 (m, 4H), 2.26 (s, 3H), 1.98 - 1.93 (m, 4H), 1.59 (d, 7= 7.1 Hz, 3H). LCMS: [M+H]+526.27.Example 31: Synthesis of (R)-2-niethyl-N-(l-(3-(l -methyl- lH-pyrazol-3-yl)-5-(thiophen-2- yl)phenyl)ethyl)-5-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)benzamide (SC2 - 090).

[0241] To a solution of (R)-2-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)-5-(2,7-diazaspiro[3.5]nonan-7-yl)benzamide (0.047 g, 0.089 mmol, 1 eq.) in MeOH (0.2 mL) was added formaldehyde (40 pL, 0.54 mmol, 6 eq., 37% wt) and TFA (1 drop). The reaction mixture was stirred at 25 °C for 0.5 h. To the reaction mixture was added sodium triacetoxyborohydride (0.11 g, 0.54 mmol, 6 eq.) portion-wise. The reaction mixture was stirred for 0.5 h at 25 °C. On completion of reaction, solvent was evaporated, followed by addition of satd. NallC i (2 mL). The organic components were extracted with EtOAc (3 x 3 mL). The combined organic layer was dried and evaporated to give a crude mixture. Purification by preparative HPLC (column: C18 50x30 mm; mobile phase: [Water (Formic acid )- Acetonitrile]; flow rate = 15 ml / min gradient: 20%-45% B over 10 min) afforded (R)-2-methyl-N-(l-(3-(l -methyl- lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)-5-(2-methyl-2, 7-diazaspiro[3.5]nonan-7-yl)benzamide (15 mg, 31 %).JH NMR (400 MHz, MeOH-d4) 57.95-139- 45844530.1(s, 1H), 7.71 (s, 1H), 7.63 - 7.60 (m, 2H), 7.46 (d, J = 3.5 Hz, 1H), 7.39 (d, J = 5.0 Hz, 1H), 7.15 - 7.05 (m, 2H), 6.96 - 6.90 (m, 2H), 6.67 (d, J= 2.1 Hz), 5.24 (q, J = 6.9 Hz, 1H), 3.94 (s, 3H), 3.65 (s, 4H), 3.10 - 3.04 (m, 4H), 2.71 (s, 3H), 2.24 (s, 3H), 1.94- 1.86 (m, 4H), 1.57 (d, J = 7.0 Hz, 3H). LCMS: [M+H]+540.28Example 32: Synthesis of (R)-2-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)-5-(2-(oxetan-3-yl)-2,7-diazaspiro[3.5]nonan-7-yl)benzamide formate (SC2 -142)

[0242] Step 1: To a solution of tcrt-butyl 7-(3-(mcthoxycarbonyl)-4-mcthylphcnyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (0.441 g, 1.18 mmol, 1 eq.) in DCM (3 niL) was added TFA (0.3 mL, 3.53 mmol, 3 eq.) at 0 °C. The reaction mixture was stirred for 12 h at room temperature. The reaction progress was monitored by LCMS. On completion, the reaction solvent was evaporated and crude compound methyl 2-methyl-5-(2,7-diazaspiro[3.5]nonan-7-yl)benzoate was used directly in next step.

[0243] Step 2: Procedure similar to synthesis of (R)-2-mcthyl-N-(l-(3-(l-mcthyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)-5-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)benzamide (SC2-090) except DCE used as solvent instead of MeOH. Reaction between methyl 2-methyl-5-(2,7-diazaspiro[3.5]nonan-7-yl)benzoate (170 mg) and oxetan-3-one (58 mg) afforded crude product methyl 2-methyl-5-(2-(oxetan-3-yl)-2,7-diazaspiro[3.5]nonan-7-yl)benzoate.

[0244] Step 3: Procedure same as step 3 in synthesis of (R)-5-(4-(dimethylamino)piperidin-l-yl)-2-methyl-N-(l-(3-(l -methyl- lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)benzamide (SC2-040). Starting material methyl 2-methyl-5-(2-(oxetan-3-yl)-2,7-diazaspiro[3.5]nonan-7-yl)benzoate (44 mg) afforded crude intermediate 2-methyl-5-(2-(oxetan-3-yl)-2,7-diazaspiro[3.5]nonan-7-yl)benzoic acid (35 mg).-140- 45844530.1

[0245] Step 4: Procedure same as Step 4 in synthesis of (R)-5-(4-(dimethylamino)piperidin-l-yl)-2-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)benzamide (SC2-040). Reaction between l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethan-l -amine hydrochloride (30 mg) and 2-methyl-5-(2-(oxetan-3-yl)-2,7-diazaspiro[3.5]nonan-7-yl)benzoic acid (35 mg) afforded crude mixture. Purification by preparative HPLC (column: C18 50x30 mm; mobile phase: [Water (Formic acid )-Acetonitrile]; flow rate = 10 ml / min gradient: 20%-28% B over 6.5 min followed by isocratic hold for 3.5 min) afforded (R)-2-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)-5-(2-(oxetan-3-yl)-2,7-diazaspiro[3.5]nonan-7-yl)benzamide formate. 'H NMR (400 MHz, MeOH-dr) 57.95 (s, 1H), 7.71 (s, 1H), 7.63 (s, 2H), 7.46 (d. J = 3.5 Hz, 1H), 7.40 (d, 7= 5.1 Hz, 1H), 7.13 - 7.05 (m, 2H), 6.96 - 6.94 (m, 2H), 6.67 (d, 7 = 2.0 Hz, 1H), 5.24 (q, 7 = 7.1 Hz, 1H), 4.72 (t, 7= 6.8 Hz, 2H), 4.51 - 4.44 (m, 2H), 3.94 (s, 3H), 3.84 (t, 7 = 5.7 Hz, 1H), 3.16 (s, 4H), 3.09 - 3.03 (m, 4H), 2.24 (s, 3H), 1.91 - 1.84 (m, 4H), 1.57 (d, 7 = 7.1 Hz, 3H). LCMS: [M+H]+582.29.Example 33: Synthesis of 2-methyl-N-((R)-l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)-5-(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)benzamide (SC2 - 091)

[0246] Step 1: Procedure same as Step 2 in synthesis of (R)-5-(4- (dimethylamino)piperidin-l -yl)-2-methyl-N-(l-(3-(l -methyl- lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)benzamide (SC2-040). Reaction of tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (239 mg) and methyl 2-methyl-5-(((trifluoromethyl)sulfonyl)oxy)benzoate (300 mg) afforded tert-butyl 3-(3-(methoxycarbonyl)-4-methylphenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (300 mg, 86%)-141- 45844530.1

[0247] Step 2: Procedure same as Step 1 in synthesis of (R)-2-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)-5-(2-(oxetan-3-yl)-2,7-diazaspiro[3.5]nonan-7-yl)benzamide formate (SC2-142). Starting material tert-butyl 3-(3-(methoxycarbonyl)-4-methylphenyl)-3,6-diazabicyclo[3.1.1 ]heptane-6-carboxylate (150 mg) afforded methyl 5-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-methylbenzoate (96 mg, 90%).

[0248] Step 3: Procedure same as Step 2 in synthesis of (R)-2-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)-5-(2-(oxetan-3-yl)-2,7-diazaspiro[3.5]nonan-7-yl)benzamide formate (SC2-142). Reaction between methyl 5-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-methylbenzoate (80 mg) and formaldehyde (119 mg, 0.14 mL, 37% Wt) afforded methyl 2-methyl-5-(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)benzoate (40 mg, 50%)

[0249] Step 4: Procedure same as Step 3 in synthesis of (R)-2-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)-5-(2-(oxetan-3-yl)-2,7-diazaspiro[3.5]nonan-7-yl)benzamide formate (SC2-142). Starting material methyl 2-methyl-5-(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)benzoate (100 mg) afforded 2-methyl-5-(6-mcthyl-3,6-diazabicyclo[3.1.1]hcptan-3-yl)benzoic acid (75 mg, 79%).

[0250] Step 5: Procedure same as Step 4 in synthesis of (R)-2-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)-5-(2-(oxetan-3-yl)-2,7-diazaspiro[3.5]nonan-7-yl)benzamide formate (SC2-142). Reaction between l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethan-l -amine hydrochloride (17 mg) and 2-methyl-5-(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)benzoic acid (16 mg) afforded crude product. Purification by preparative HPLC (column: C18 50x30 mm; mobile phase: [Water (Formic acid ) -Acetonitrile]; flow rate = 15 ml / min gradient: 5%-55% B over 7 min) afforded 2-methyl-N-((R)-l-(3-(l -methyl- 1 H-pyrazol-3-yl)-5-(thiophen-2-yl)pheny l)ethyl)-5-(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)benzamide (3 mg, 10 %).XH NMR (400 MHz, MeOH-cU) 57.97 (s, 1H), 7.74 (s, 1H), 7.66 (s, 1H), 7.63 (d, J = 1.3 Hz, 1H), 7.47 (d, J= 3.3 Hz, 1H), 7.40 (d, J= 5.0 Hz. 1H), 7.15 (d, J = 8.3 Hz, 1H). 7.13 - 7.08 (m, 1H), 6.82 - 6.76 (m, 2H), 6.69 (d, J = 1.5 Hz, 1H), 5.28 (q, J = 6.8 Hz, 1H), 4.35 - 4.20 (m, 2H), 3.95 (s, 3H), 3.90 - 3.65 (m, 4H), 3.42 - 2.79 (m, 2H), 2.42 (s, 2H), 2.28 (s, 3H), 2.10 - 1.89 (m, 1H), 1.60 (d, J= 7.0 Hz, 3H). LCMS: [M+H]+512.25-142- 45844530.1Example 34: Synthesis of 5-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-methyl-N-((R)-l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)benzamide (SC2-133)

[0251] Step 1: To a suspension of 5-(6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-methylbenzoic acid (25 mg, 0.075 mmol, 1.2 eq.) in DMF (0.1 mL) was added DIPEA (16 pL, 0.094 mmol, 1.5 eq.) and HATU (36 mg, 0.094 mmol, 1.5 eq.). The reaction mixture was stirred for 10 min at rt. To the reaction mixture was added a solution of 1 -(3-( 1 -methyl- lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethan- 1 -amine hydrochloride (0.02 g, 0.063 mmol, 1 eq.) and DIPEA (0.016 mL, 0.094 mmol, 1.5 eq.) in DMF (0.1 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. On completion the reaction solvent was evaporated and triturated with Et20 to give white solid teit-butyl 3-(4-methyl-3-(((R)-l-(3-(l-methyl-lILpyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)carbamoyl)phenyl)-3,6-diazabicyclo[3.1.1 ]heptane-6-carboxylate (19 mg, 51 %).

[0252] Step 2: Procedure same as that of Step 4 in synthesis of (R)-2-methyl-N-(l-(3-(1 -methyl- lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)-5-(2,7-diazaspiro[3.5]nonan-7-yl)benzamide (SC2-087). Starting material tert-butyl 3-(4-methyL3-(((R)-l-(3-(l -methyl- 1H-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)carbamoyl)phenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (19 mg) afforded crude product which was purified by prep HPLC (column: C18 50x30 mm; mobile phase: [Water (Formic acid )-Acetonitrile]; flow rate = 18 ml / min gradient: 5%-40% B over 8 min) to yield 5-(3,6-diazabicyclo[3.1.1 ]heptan-3-yl)-2-methyl-N-((R)-l-(3-(l -methyl- lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)benzamide (5 mg, 30%).JH NMR (400 MHz, MeOH-d4) 57.98 (s, 1H). 7.75 (s, 1H), 7.67 (s, 1H), 7.64 (d, J = 1.8 Hz, 1H), 7.48 (d, J = 3.0 Hz, 1H), 7.41 (d, J = 4.9 Hz, 1H), 7.16 (d, 7= 8.4 Hz, 1H), 7.14-7.10 (m, 1H), 6.82 (d, J = 8.5 Hz, 1H), 6.79 (s, 1H), 6.70 (d, 7= 2.0 Hz, 1H), 5.30 (q, 7 = 6.8 Hz, 1H), 4.48 (s, 2H), 3.88 - 3.69 (m, 4H), 3.31-143- 45844530.1(s, 4H), 3.02 (s, 1H), 2.29 (s, 3H), 1.97 (d, J = 9.9 Hz, 1H), 1.61 (d, J = 7.0 Hz, 3H). LCMS:[M+H]+498.23.Example 35: Synthesis of (R)-2-methyl-N-(l-(3-(l-methyl-lILpyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)-5-(( 1 -methylpiperidin-4-yl)oxy)benzamide (SC2-144)

[0253] Step 1: To a solution of methyl 5-hydroxy-2-methylbenzoate (0.30 g, 1.81 mmol, 1 eq.) in THF (4 mL)was added tert-butyl 4-hydroxypiperidine-l -carboxylate (0.4 g, 1.99 mmol, 1.1 eq.), triphenylphosphine (0.57 g, 2.17 mmol, 1.2 eq.) and DIAD (0.46 mL, 2.35 mmol, 1.3 eq.) at 0 °C. The reaction mixture was stirred at room temperature for 12 h. The reaction progress was monitored by TLC (EtOAc: Hexane = 1:9, UV). On reaction completion, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layer was dried over sodium sulfate and evaporated to give a crude mixture. Purification by silica gel chromatography (ISCO®: 40 g SepaFlash® Silica Flash Column, Eluent of 5 - 60% EtOAc in Hexane gradient @ 60 mL / min ) afforded tert-butyl 4-(3-(methoxycarbonyl)-4-methylphenoxy)piperidine-l -carboxylate (307 mg, 48.7 %).

[0254] Step 2: Procedure same as Step 1 in synthesis of (R)-2-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)-5-(2-(oxetan-3-yl)-2,7-diazaspiro[3.5]nonan-7-yl)benzamide formate (SC2-142). Starting material tert-butyl 4-(3-(methoxycarbonyl)-4-methylphenoxy)piperidine-l -carboxylate (300 mg) afforded crude product methyl 2-methyl-5-(piperidin-4-yloxy)benzoate (150 mg).

[0255] Step 3: Procedure same as that for the synthesis of (R)-2-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)-5-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)benzamide (SC2-090). Reaction of methyl 2-methyl-5-(piperidin-4-yloxy)benzoate (150 mg) with formaldehyde (293 mg, 269 pL, 37% Wt) afforded methyl 2-methyl-5-((l-methylpiperidin-4-yl)oxy)benzoate (101 mg, 63%) as colourless oil.-144- 45844530.1

[0256] Step 4: Procedure same as Step 3 in synthesis of (R)-2-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)-5-(2-(oxetan-3-yl)-2,7-diazaspiro[3.5]nonan-7-yl)benzamide formate (SC2-142). Starting material methyl 2-methyl-5-((l-methylpiperidin-4-yl)oxy)benzoate (101 mg) afforded crude product 2-methyl-5-((l-methylpiperidin-4-yl)oxy)benzoic acid (80 mg).

[0257] Step 5: Procedure same as Step 4 in synthesis of (R)-2-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)-5-(2-(oxetan-3-yl)-2,7-diazaspiro[3.5]nonan-7-yl)benzamide formate (SC2-142). Reaction between l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethan-l-amine hydrochloride (20 mg) and 2-methyl-5-((l-methylpiperidin-4-yl)oxy)benzoic acid (19 mg) afforded crude product. Purification by preparative HPLC (column: C18 50x30 mm; mobile phase: [Water (Formic acid ) -Acetonitrile]; flow rate = 15 ml / min gradient: 50%-95% B over 5 min) (R)-2-methyl-N-(l-(3-(l -methyl- lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)-5-((l-methylpiperidin-4-yl)oxy)benzamide formate (8 mg, 20%).JH NMR (400 MHz, CDCI3) 8 8.46 (s, 1H), 7.92 (s, 1H), 7.73 (s, 1H), 7.53 (s, 1H), 7.40 (d, 7= 1.5 Hz, 1H), 7.38 (d, J = 3.5 Hz, 1H), 7.30 (d, J = 5.0 Hz, 1H), 7.13 - 7.03 (m, 2H), 6.90 (d, J = 2.2 Hz, 1H), 6.82 (dd, J = 8.4, 2.3 Hz, 1H), 6.58 (d, J = 1.6 Hz, 1H), 6.03 (d, J = 8.0 Hz, 1H), 5.38 (p, J = 6.8 Hz, 1H), 4.51 (s, 1H), 3.96 (s, 3H), 3.31 - 2.98 (m, 4H), 2.61 (s, 3H), 2.36 (s, 3H), 2.23 - 2.21 (m, 2H), 2.1 - 1.9 (m, 2H), 1.66 (d, J= 6.8 Hz, 3H). LCMS: [M+H]+515.25Example 36: Synthesis of (R)-2-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)-5-(4-(oxetan-3-yl)piperazin-l-yl)benzamide (ID-5-71):

[0258] Stepl: To a solution of l,l,l-trifhioro-N-phenyl-N-((trifhioromethyl)sulfonyl) methanesulfonamide (10.7 g, 1 Eq, 30.1 mmol) in DCM (100 mL) was added methyl 5-hydroxy-2-methylbenzoate (5.00 g, 1 Eq, 30.1 mmol), triethylamine (6.09 g. 8.39 mL, 2 Eq, 60.2 mmol)and DMAP (1.84 g, 0.5 Eq, 15.0 mmol). The reaction mixture was stirred at room temperature for 6 h. On completion the organic layer was washed with water (3 x 100 mL). The organic layer was dried and evaporated to dryness to give crude mixture. Purification by-145- 45844530.1silica gel chromatography (5 - 80% EtOAc / Hex, 40 g column) afforded methyl 2-methyl-5-(((trifhioromethyl)sulfonyl)oxy)benzoate (7.3 g, 24 mmol, 81 %) as colorless liquid.

[0259] Step 2: To a solution of methyl 2-methyl-5- (((trifluoromethyl)sulfonyl)oxy)benzoate (0.300 g, 1 Eq, 1.01 mmol) in 1,4-Dioxane (5 nd.) was added tert-butyl piperazine- 1 -carboxylate (186 mg, 1.2 Eq, 1.21 mmol) and cesium carbonate (983 mg, 3 Eq, 3.02 mmol) at room tmperature. The reaction mixture was purged with Ar gas for 15 min followed by addition of RuPhos Pd G3 (84.1 mg, 0.1 eq, 0.101 mmol). The reaction mixture was stirred for 6 h at 100 °C. On completion the reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 5 mL). The organic layer was combined, dried over sodium sulfate and evaporated to give crude mixture. Purification by silica gel chromatography (5 - 100% EtOAc / Hex, 12 g column) afforded tert-butyl 4-(3-(methoxycarbonyl)-4-methylphenyl)piperazine-l -carboxylate (267 mg, 80 %) as pale yellow oil.

[0260] Step 3: To a solution of tert-butyl 4-(3-(methoxycarbonyl)-4-methylphenyl)piperazine-l -carboxylate (267mg, 0.8mmol) in 1,4-Dioxane was added 1 ml of 4M HC1 at 0°C and stir at room temp for 16 hr. After the completion of reaction the solvent was concentrated and obtained methyl 2-methyl-5-(piperazin-l-yl)benzoate (250 mg, 100 %) off white solid:

[0261] Step 4: To a solution of methyl 2-methyl-5 -(piperazin- l-yl)benzoate 250 mg in MeOH 10 ml was added formaldehyde 37% (0.4 ml 8 mmol) and 0.5 ml HO Ac was added stir for 30 min at 50°C and then sodium cyanoborohydride (158 mg 2.4 mmol) was added and stir for 16 hr. Then the reaction mixture was washed with IN HC1 and extracted with DCM.. The organic layer was dried and evaporated to dryness to give crude mixture. Purification by silica gel chromatography (0 -10% DCM) afforded methyl 2-methyl-5-(4-(oxetan-3-yl)piperazin-l-yl)benzoate 150 mg 51 %) as off white solid.

[0262] Step 5: To a solution of methyl 2-methyl-5-(4-(oxetan-3-yl)piperazin-l-yl)benzoate (150.0 mg, 1 mmol) in THF 6 ml and MeOH (2mL) was added 10% aq. NaOH (1.5mL) at 20 °C. The reaction mixture was stirred at 20 °C for 15 h. LCMS showed a mass peak of the desired product. The reaction mixture was then acidified with IN HC1 to pH = 1 at 0 °C. The crude was purified over prep HPLC to afford 2-methyl-5-(4-(oxetan-3-yl)piperazin-l-yl)benzoic acid as 101 mg 78%) off white

[0263] Step 6: To a solution of methyl 2-methyl-5-(4-(oxetan-3-yl)piperazin-l-yl)benzoate (31 mg, 0.11 mmol) in DMF (1 mL) was added TEA (50 mg, 0.5 mmol), HATU -146- 45844530.1(54 mg, 0.14 mmol) followed by addition of (R)-l-(3-(l -methyl- lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethan- 1 -amine hydrochloride (30 mg, 0.1 mol) at room temperature. The reaction mixture was stirred at 25 °C for 12 hours. The reaction progress was monitored by LCMS. On completion the reaction mixture was purified by HPLC to afforded ((R)-2-methyl-N-(l-(3-(l-methyl-lH-pyrazol-3-yl)-5-(thiophen-2-yl)phenyl)ethyl)-5-(4-(oxetan-3-yl)piperazin-l-yl)benzamide (25 mg, 53 %) as white solid.XH NMR (400 MHz, METHANOL-D4) 67.95 (s, 1H), 7.71 (s, 1H), 7.66 - 7.58 (m, 3H), 7.46 (d, 7= 3.5 Hz, 1H), 7.38 (d, J = 5.0 Hz, 1H), 7.13 - 7.06 (m, 2H), 6.94 (d, J = 7.5 Hz, 2H), 6.67 (d, J = 2.4 Hz, 1H), 5.25 (d, J = 7.2 Hz, 1H), 4.70 (t, J = 6.6 Hz, 2H), 4.61 (d, J = 6.0 Hz, 2H), 3.93 (d, J = 2.9 Hz, 3H), 3.52 (t, J = 6.4 Hz, 1H), 3.18 (t, J= 5.1 Hz, 4H). 2.47 (t, J = 4.9 Hz. 4H), 2.24 (s, 3H), 1.58 (d, J = 7.1 Hz, 3H). Example 37: Synthesis of (R)-2-methyl-N-(l-(3-(methyl(l-methyl-lH-pyrazol-4-yl)amino)- 5-(thiophen-2-yl)phenyl)ethyl)-5-(4-methylpiperazin-l-yl)benzamide (MR-1-060):

[0264] To a solution of 2-methyl-5-(4-methylpiperazin-l-yl)benzoic acid (63 mg, 0.269 mmol, 1.0 eq) in DMF (2 mL) were added (R)-A-(3-(l-aminoethyl)-5-(thiophen-2-yl)phenyl)-A,l-dimethyl-lH-pyrazol-4-amine (92.5 mg, 0.296 mmol, 1.1 eq), HATU (116 mg, 0.307 mmol, 1.14 eq) and DMAP (72 mg, 0.592 mmol, 2.2 eq), then the mixture was stirred at 10 °C for 12 h under N2. TLC (EtOAc: PE = 1: 1, UV) showed one new spot with larger polarity was detected. The mixture was diluted with H2O (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic phase was washed with sat. aq. NH4CI (5 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a crude. The residue was purified by prep-HPLC (column: C18 150x30 mm; mobile phase: [Water (Formic acid)-Methanol]; gradient: 0%-28% B over 9 min). Most of solvent was removed under reduced pressure and the mixture was lyophilized to give compound (R)-2-methyl-N-(l-(3-(methyl(l-methyl-lH-pyrazol-4-yl)amino)-5-(thiophen-2-yl)phenyl)ethyl)-5-(4-methylpiperazin-l-yl)benzamide (45.9 mg, 32.3% yield, 99.4% purity) as off-white solid.XH NMR (400 MHz, CDCI3) 57.44 (s, 1H), 7.38 (s, 1H), 7.27 - 7.18 (m, 3H), 7.12 (d, J = 8.0 Hz, 1H), 7.08 - 6.94 (m, 5H), 6.83 (s, 1H), 5.14 (d, J = 6.9 Hz, 1H), 3.86 (s, 3H), 3.62 - 3.54 (m,-147- 45844530.14H), 3.23 (s, 4H), 2.85 (s, 3H), 2.31 (d, J = 5.3 Hz, 6H), 1.53 (d, J = 6.9 Hz, 3H). LCMS:[M+H]+529.73.Example 38: ( / ?)-2-methyl-N-(l-(3-((l-methyl-lH-pyrazol-4-yl)oxy)-5-(thiophen-2-yl)phenyl)ethyl)-5-(4-methylpiperazin-l-yl)benzamide (MR-1-061):

[0265] To a solution of 2-methyl-5-(4-methylpiperazin-l-yl)benzoic acid (63 mg, 0.269 mmol, 1.0 eq) in DMF (2 mF) were added (7?)-l-(3-((l-methyl-lH-pyrazol-4-yl)oxy)-5-(thiophen-2-yl)phenyl)ethan-l -amine (88.62 mg, 0.296 mmol, 1.1 eq), HATU (116 mg, 0.307 mmol, 1.14 eq) and DMAP (72 mg, 0.592 mmol, 2.2 eq), then the mixture was stirred at 10 °C for 12 h under N2. TLC (EtOAc: PE = 1: 1, UV) showed one new spot with larger polarity was detected. The mixture was diluted with H2O (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic phase was washed with sat. aq. NH4CI (5 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a crude. The residue was purified by prep-HPLC (column: C18 150x30 mm; mobile phase: [Water (Formic acid)-MethanolJ; gradient: 0%-28% B over 9 min). Most of solvent was removed under reduced pressure and the mixture was lyophilized to give compound ( / ?)-2-methyLN-(l-(3-(methyl(l-methyl-lH-pyrazol-4-yl)amino)-5-(thiophen-2-yl)phenyl)ethyl)-5-(4-methylpiperazin-l-yl)benzamide (47.6 mg, 34.3% yield, 99.4% purity) as off-white solid.1H NMR (400 MHz, CDCI3): 57.31 (s, 1H), 7.30 - 7.23 (m, 4H), 7.14 (q, J = 2.8 Hz, 1H), 7.1O -7.01 (m, 2H), 6.93 (t, J = 2.0 Hz, 1H), 6.87 (d, J = 2.6 Hz, 1H), 6.85 - 6.78 (m, 1H), 6.21 (d, J = 8.0 Hz, 1H), 5.29 - 5.17 (m, 1H), 3.37 - 3.30 (m, 4H), 3.15 (s, 1H), 3.01 - 2.94 (m, 4H), 2.62 (s, 311), 2.29 (s, 311), 1.56 (d, J= 7.0 Hz, 311). LCMS: [M+II]+516.68.-148- 45844530.1Example 39: (7?)-2-methyl-N-(l-(3-((l -methyl- lH-pyrazol-4-yl)oxy)-5-(thi ophen- 2-yl)phenyl) ethyl)-5-(4-methylpiperazin-l-yl)benzamide (MR-1-081):

[0266] To a solution of 2-methyl-5-(4-methylpiperazin-l-yl)benzoic acid (63 mg, 0.269 mmol, 1.0 eq) in DMF (2 mL) were added ( / ?)-l-(3-((l-methyl-lH-pyrazol-4-yl)methyl)-5-(thiophen-2-yl)phenyl)ethan-l -amine (88.84 mg, 0.296 mmol, 1.1 eq), HATU (116 mg, 0.307 mmol, 1.14 eq) and DMAP (72 mg, 0.592 mmol, 2.2 eq), then the mixture was stirred at 10 °C for 12 h under N2. TLC (EtOAc: PE = 1: 1, UV) showed one new spot with larger polarity was detected. The mixture was diluted with H2O (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic phase was washed with sat. aq. NH4CI (5 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a crude. The residue was purified by prep-IIPLC (column: C18 150x30 mm; mobile phase: [Water (Formic acid)-Methanol]; gradient: 0%-28% B over 9 min). Most of solvent was removed under reduced pressure and the mixture was lyophilized to give compound (7?)-2-methyl-7V-( 1 -(3-((l -methyl-1 H-pyrazol-4-yl)methyl)-5-(thiophen-2-yl)phenyl)ethyl)-5-(4-methylpiperazin-l -yl)benzamide (52.9 mg, 38.3% yield, 99.4% purity) as off-white solid.JH NMR (400 MHz, CDCl₃): 58.16 (s, 1H), 7.37 (s, 1H), 7.24 - 7.15 (m, 3H), 7.05 (d, J = 3.0 Hz, 2H), 7.01 - 6.91 (m, 2H), 6.77 (d, J = 2.7 Hz, 1H), 6.74- 6.67 (m, 1H). 6.43 (d, 7= 7.9 Hz, 1H), 5.17 (t, J = 7.2 Hz, 1H), 3.75 - 3.69 (m, 5H), 3.23 (t, J= 5.1 Hz, 4H), 3.08 - 3.02 (m, 4H), 2.62 (s, 3H), 2.19 (s, 3H), 1.50 (d,. / = 6.9 Hz, 3H). LCMS: [M+H]+514.71.-149- 45844530.1Example 40: Synthesis of ( / ?)-W(l-(3-(3,6-dihydro-2H-pyran-4-yl)-5-(l-methyl-l.f7-pyrazol- 3-yl)phenyl)ethyl)-2-methyl-5-(4-methylpiperazin-l-yl)benzamide (MR-1-062):

[0267] To a solution of A-[(l / ?)-l-[3-chloro-5-(l-methylpyrazol-3-yl)phenyl]ethyl]-2-methyl-5-(4-methylpiperazin-l-yl)benzamide (120 mg, 0.265 mmol, 1.0 eq) in DMF (3 mL) and H2O (0.6 mL) were added (3,6-dihydro-2H-pyran-4-yl)boronic acid (37.3 mg, 0.292 mmol, 1.1 eq), XPhos Pd G3 (22 mg, 0.0265 mmol, 0.1 eq) and CS2CO3 (173 mg, 0.531 mmol, 2.0 eq), then the mixture was stirred at 100 °C for 1 h under N2. LCMS showed 57% with desired MS was detected. The mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: Boston Prime Cl 8 150*30 mm*5 um; mobile phase: [Water (NH3H2O-NH4HCO3)-MeCN]; gradient: 45%-65% B over 11 min). Most of solvent was removed under reduced pressure and the mixture was lyophilized to give compound (7?)-A-(l-(3-(3,6-dihydro-2H-pyran-4-yl)-5-(l -methyl- lH-pyrazol-3-yl)phenyl)ethyl)-2-methyl-5-(4-methylpiperazin-l-yl)benzamide (42.7 mg, 32.3% yield, 99.90% purity) as a white solid. 'H NMR (400 MHz, CDCh): 87.70 (d, J = 4.3 Hz, 2H), 7.40 - 7.35 (m, 1H), 7.32 (s, 1H), 7.07 (d, J = 8.2 Hz, 1H), 6.90 (s, 1H), 6.84 (d, J = 8.2 Hz, 1H), 6.53 (s, 1H), 6.21 - 6.15 (m, 1H), 6.08 (d, J = 8.1 Hz, 1H), 5.34 (p, J = 7.0 Hz, 1H), 4.31 (q, J = 2.8 Hz, 2H), 3.93 (d, J = 6.7 Hz, 5H), 3.24 (s, 4H), 2.74 (s, 3H), 2.55 (tt, J = 5.5, 2.4 Hz, 2H), 2.46 (s, 3H), 2.31 (s, 3H), 1.62 (d, J = 6.9 Hz, 3H). LCMS: [M+H]+500.67.-150- 45844530.1Example 41: Synthesis of 5-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-A-((R)-l-(3-(3,6-dihydro-2H-pyran-4-yl)-5-(l -methyl- 177-pyrazol-3-yl)phenyl)ethyl)-2-methylbenzamide (MR-1-115):

[0268] Step 1: To a solution of 2-methyl-5-(4-methylpiperazin-l-yl)benzoic acid (956 mg, 3.53 mmol, 1.0 eq, HC1) in DMF (15 mL) were added (R)-l-(3,5-dichlorophenyl)ethan-l-amine (670 mg, 3.53 mmol, 1.0 eq), HATU (1.61 g, 4.24 mmol, 1.2 eq), DMAP (43 mg, 0.353 mmol, 0.1 eq) and TEA (1.79 g, 17.6 mmol, 5.0 eq), then the mixture was stirred at 20 °C for 14 h under N2. TLC (DCM: MeOH = 20:1, UV) showed the starting material was consumed and one new spot with larger polarity was detected. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (80 mL x 3). The combined organic phase was washed with sat. aq. NH4Q (60 mL x 2), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a crude, which was purified by flash silica gel chromatography (ISCO®; 20 g SepaHash® Silica Flash Column, Eluent of 10% Methanol / Dichloromethane gradient @ 40 mL / min) to give compound tert-butyl 3-(3-(((R)-l-(3,5-dichlorophenyl)ethyl)carbamoyl)-4-methylphenyl)-3,6-diazabicyclo|3.1.1Jheptane-6-carboxylate (1.364 g, 76.6% yield) as a yellow oil. LCMS: [M+H]+504.18.

[0269] Step 2: To a solution of tert-butyl 3-(3-(((R)-l-(3,5-dichlorophenyl)ethyl)carbamoyl)-4-methylphenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (1.835 g, 1 eq, 3.641 mmol) in 1,4-Dioxane (5.0 mL) and Water (1.67 mL) was added l-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (984.7 mg, 4.733 mmol) and cesium carbonate (2.372 g, 7.281 mmol) at room temperature. The reaction mixture was purged with Ar for 15 min followed by addition of XPhos Pd G2 (286.1 mg, 0.364mmol). The reaction mixture was stirred at 90 °C for 1 hour. The reaction progress was monitored by LCMS. On completion the reaction mixture was diluted with EtOAc (20 mL) and washed with water (2 x 20 mL). The organic layer was washed with brine (20 mL), dried over sodium sulphate and evaporated. Purification by silica gel chromatography (5 - 100% EtOAc / Hex, 40g column) afforded tert-butyl 3-(3-(((R)-l-(3-chloro-5-(l-methyl-lH-pyrazoL 3-yl)phenyl)ethyl)carbamoyl)-4-methylphenyl)-3,6-diazabicyclo[3.1.1] heptane-6-carboxylate (1.312 g, 65.5 %) as off-white solid. LCMS: [M+H]+551.12.-151- 45844530.1

[0270] Step 3: To a solution of 3-(3-((( / ?)-l-(3-chloro-5-(l -methyl- lH-pyrazol-3-yl)phenyl)ethyl) carbamoyl)-4-methylphenyl)-3,6-diazabicyclo[3.1.1] heptane-6-carboxylate (145.8 mg, 0.265 mmol, 1.0 eq) in DMF (3 mL) and H2O (0.6 mL) were added (3,6-dihydro-2H-pyran-4-yl)boronic acid (37.3 mg, 0.292 mmol, 1.1 eq), XPhos Pd G3 (22 mg, 0.0265 mmol, 0.1 eq) and CS2CO3 (173 mg, 0.531 mmol, 2.0 eq), then the mixture was stirred at 100 °C for 1 h under N2. LCMS showed 57% with desired MS was detected. The mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: Boston Prime C18 150*30 mm*5 um; mobile phase: [Water (NH3H2O-NH4HCO3)-MeCN]; gradient: 45%-65% B over 11 min). Most of solvent was removed under reduced pressure and the mixture was lyophilized to give compound tert-butyl 3-(3-((( / ?)-l-(3-(3,6-dihydro-2H-pyran-4-yl)-5-(l-methyl-lH-pyrazol-3-yl)phenyl) ethyl)carbamoyl)-4-methylphenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (57.5 mg, 36.3% yield, 99.90% purity) as a white solid. LCMS: [M+H]+598.34.

[0271] Step 4: To a solution of 3-(3-((( / ?)-l-(3-(3,6-dihydro-277-pyran-4-yl)-5-(l-methyl-lH-pyrazol-3-yl)phenyl) ethyl)carbamoyl)-4-methylphenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (54.3 mg, 0.091 mmol) in Dioxane (10 mL)and was added a solution of HC1 (16.56 mg, 0.114 mL, 4 molar, 0.452 mmol) in dioxane at r.t. The reaction mixture was sli rred at room temperature for 12 h. On completion, the reaction solvent was evaporated. Added water to residue and adjusted pH = 7 by aqNaHCO3 and extracted to give 5-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-A-(( / ?)-l-(3-(3,6-dihydro-277-pyran-4-yl)-5-(l-methyl-l / / -pyrazol-3-yl)phenyl)ethyl)-2-methylbenzamide (43.6 mg, 96.3 %) as white solid.LCMS: [M+H]+498.29-152- 45844530.1Example 42: Synthesis of A-((R)-l-(3-(3,6-dihydro-277-pyran-4-yl)-5-(l-methyl-lH-pyrazol- 3-yl)phenyl)ethyl)-2-methyl-5-(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)benzamide

[0272] To a solution of 5-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-A-((R)-l-(3-(3,6-dihydro-2H-pyran-4-yl)-5-(l-methyl-l / 7-pyrazol-3-yl)phenyl)ethyl)-2-methylbenzamide (0.044 g, 89 pmol) in MeOH (0.2 mb) was added formaldehyde (44 mg, 40 pL, 37% Wt, 6 Eq, 0.54 mmol) and AcOH (1.0 mg) (two drops). The reaction mixture was stirred at 25 °C for 0.5 h. To the reaction mixture was added sodium triacetoxyborohydride (0.11 g, 6 eq., 0.54 mmol) portion-wise. The reaction mixture was stirred for 0.5 hour at 25 °C. On completion of reaction, solvent was evaporated, followed by addition of satd. NaHCOs (2 mL). The organic components were extracted with EtOAc (3 x 3 mL). The combined organic layer was dried and evaporated to give a crude mixture. Purification by preparative HPLC (column: C18 50x30 mm; mobile phase: [Water (Formic acid )- Acetonitrile]; flow rate = 15 ml / min gradient: 20%-45% B over 10 min) afforded A-((7?)-l-(3-(3,6-dihydro-2H-pyran-4-yl)-5-(l-methyl-lH-pyrazol-3-yl)phenyl)ethyl)-2-methyl-5-(6-methyl-3,6-diazabicyclo [3.1.1]heptan-3-yl)benzamide (14 mg, 31 %). ’ll NMR (400 MHz, CDCl3) 5 7.70 (d, J = 6.2 Hz, 2H), 7.41 -7.32 (m, 2H), 7.14 (d, J = 8.5 Hz, 1H), 6.72 (d, J = 2.7 Hz, 1H), 6.70 - 6.63 (m, 1H), 6.54 (d, J = 2.2 Hz, 1H), 6.19 (s, 1H), 6.09 (d, J = 8.2 Hz, 1H), 5.42 - 5.30 (m, 1H), 4.47 (d, J = 5.9 Hz, 2H), 4.38 - 4.25 (m, 2H), 3.93 (d, 7 = 5.0 Hz, 6H), 3.76 (d, J = 12.5 Hz, 2H), 3.67 (d, 7 = 12.6 Hz, 2H), 3.36 - 3.32 (m, 1H), 2.59 - 2.52 (m, 2H), 2.47 (s, 3H), 2.35 - 2.26 (m, 3H), 1.90 (d, 7= 9.9 Hz, 1H), 1.64 (d, J = 6.9 Hz, 3H). LCMS: [M+H]+512.30.-153- 45844530.1Example 43: Synthesis of ( / ?)- -(l-(3-(3,6-dihydro-2H-pyran-4-yl)-5-(thiophen-2-yl)phenyl)ethyl)-2-methyl-5-(4-methylpiperazin-l-yl)benzamide (MR-1-122):

[0273] To a solution of ( / ?)-A-(l-(3-chloro-5-(thiophen-2-yl)phenyl)ethyl)-2-methyl-5-(4-methylpiperazin- 1 -yl)benzamide (120 mg, 0.265 mmol, 1.0 eq) in DMF (3 mL) and H2O (0.6 mL) were added (3,6-dihydro-2H-pyran-4-yl)boronic acid (37.3 mg, 0.292 mmol, 1.1 eq), XPhos Pd G3 (22 mg, 0.0265 mmol, 0.1 eq) and CS2CO3 (173 mg, 0.531 mmol, 2.0 eq), then the mixture was stirred al 100 °C for 1 h under N2. LCMS showed 57% with desired MS was detected. The mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPEC (column: Boston Prime Cl 8 150*30 mm*5 um; mobile phase: [Water (NH3H2O-NH4HCO3)-MeCN]; gradient: 45%-65% B over 11 min). Most of solvent was removed under reduced pressure and the mixture was lyophilized to give compound (R)-N-(l-(3-(3,6-dihydro-2H-pyran-4-yl)-5-(thiophen-2-yl)phenyl)ethyl)-2-methyl-5-(4-methylpiperazin- 1 -yl)benzamide (42.7 mg, 32.3% yield, 99.90% purity) as a white solid. H NMR (400 MHz, CDCI3): 57.50 (d,.1 = 1.6 Hz, 2H), 7.36 - 7.26 (m, 3H), 7.13 - 7.04 (m, 2H), 6.92 - 6.88 (m, 1H), 6.88 - 6.81 (m, 1H), 6.22 - 6.14 (m, 2H), 5.38 - 5.27 (m, 1H), 4.32 (q, J = 2.9 Hz, 2H), 3.93 (t, J = 5.4 Hz, 2H), 3.49 - 3.42 (m, 4H), 3.14 (t, J = 4.8 Hz, 4H), 2.72 (s, 3H), 2.58 - 2.50 (m, 2H), 2.32 (s, 3H), 1.62 (d, J = 6.9 Hz, 3H). LCMS: |M+H|+502.25.-154- 45844530.1Example 44: Synthesis of ( / ?)-A-(l-(3-(3,6-dihydro-27Lpyran-4-yl)-5-(l-methyl-17Lpyrazol- 3-yl)phenyl)ethyl)-2-methyl-5-((l-methylpiperidin-4-yl)oxy)benzamide (MR-1-131):

[0274] Step 1: To a solution of 2-methyl-5-((l-methylpiperidin-4-yl)oxy)benzoic acid (880 mg, 3.53 mmol) in DMF (15 mL) were added (7?)-l-(3,5-dichlorophenyl)ethan-l-amine (670 mg, 3.53 mmol, 1.0 eq), HATU (1.61 g, 4.24 mmol, 1.2 eq), DMAP (43 mg, 0.353 mmol, 0.1 eq) and TEA (1.79 g, 17.6 mmol, 5.0 eq), then the mixture was stirred at 20 °C for 14 h under N2. TLC (DCM: MeOH = 20:1, UV) showed the starting material was consumed and one new spot with larger polarity was detected. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (80 mL x 3). The combined organic phase was washed with sat. aq. NH4CI (60 mL x 2), dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give a crude, which was purified by flash silica gel chromatography (ISCO®: 20 g SepaHash® Silica Flash Column, Eluent of 10% Methanol / Dichloromethane gradient @ 40 mL / min) to give compound ( / ?)-A-(l-(3,5- dichlorophenyl)ethyl)-2-methyl-5-((l-methylpiperidin-4-yl)oxy)benzamide (1.14 g, 76.6% yield) as off-white solid. LCMS: [M+H]+421.15

[0275] Step 2: To a solution of (7?)-A-(l-(3,5-dichlorophenyl)ethyl)-2-methyL5-((l- methylpiperidin-4-yl)oxy)benzamide (1.534 g, 1 eq, 3.641 mmol) in 1,4-Dioxane (5.0 mL) and Water (1.67 mL) was added l-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (984.7 mg, 4.733 mmol) and cesium carbonate (2.372 g, 7.281 mmol) at room temperature. The reaction mixture was purged with Ar for 15 min followed by addition of XPhos Pd G2 (286.1 mg, 364.1 pmol). The reaction mixture was stirred at 90 °C for 1 hour. The reaction progress was monitored by LCMS. On completion the reaction mixture was diluted with EtOAc (20 mL) and washed with water (2 x 20 mL). The organic layer was washed with brine (20 ml,), dried over sodium sulphate and evaporated. Purification by silica gel chromatography (5 - 100% EtOAc / Hex, 40g column) afforded

[0276] (7?)-A-(l-(3-chloro-5-(l -methyl- lH-pyrazol-3-yl)phenyl)ethyl)-2-methyL5-((l - methylpiperidin-4-yl)oxy)benzamide (1.114 g, 65.5 %) as off-white solid. LCMS: [M+H]+467.22.-155- 45844530.1

[0277] Step 3: To a solution of (7?)- -(l-(3-chloro-5-(l-methyl-lH-pyrazol-3-yl)phenyl)ethyl)-2-methyl-5-((l-methylpiperidin-4-yl)oxy)benzamide (123.8 mg, 0.265 mmol, 1.0 eq) in DMF (3 mL) and H2O (0.6 mL) were added (3,6-dihydro-2H-pyran-4-yl)boronic acid (37.3 mg, 0.292 mmol, 1.1 eq), XPhos Pd G3 (22 mg, 0.0265 mmol, 0.1 eq) and CS2CO3 (173 mg, 0.531 mmol, 2.0 eq), then the mixture was stirred at 100 °C for 1 h under N2. LCMS showed 57% with desired MS was detected. The mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: Boston Prime C18 150*30 mm*5 um; mobile phase: [Water (NH3H2O-NH4HCO3)-MeCN]; gradient: 45%-65% B over 11 min). Most of solvent was removed under reduced pressure and the mixture was lyophilized to give compound (R)-A-(l-(3-(3,6-dihydro-27 / -pyran-4-yl)-5-(l-methyl-lH-pyrazol-3-yl)phenyl)ethyl)-2-methyl-5-((l -methylpiperidin-4-yl)oxy)benzamide (49.5 mg, 36.3% yield, 99.90% purity) as a white solid.JH NMR (400 MHz, CDCI3) 88.30 (s, 1H), 7.72 - 7.66 (m, 2H), 7.41 - 7.36 (m, 1H), 7.32 (s, 1H), 7.13 - 7.07 (m, 1H), 6.92 - 6.86 (m, 1H), 6.84 - 6.76 (m, 1H), 6.53 (d, J = 2.2 Hz, 1H), 6.20 - 6.14 (m, 2H), 5.39 - 5.25 (m, 1H), 4.56 (s, 1H), 4.34 - 4.28 (m, 2H), 3.96 - 3.88 (m, 5H), 3.22 (s, 2H), 3.13 - 3.05 (m, 2H), 2.71 (s, 3H), 2.59 - 2.51 (m, 2H), 2.34 - 2.24 (m, 4H), 2.11 - 2.02 (m, 2H), 1.62 (d, J = 6.8 Hz, 3H).LCMS: [M+H]+515.30.Example 45: Synthesis of ( / ?)-7V-(l-(3,5-bis(3,6-dihydro-2H-pyran-4-yl)phenyl)ethyl)-2-methyl-5-(4-methylpiperazin-l-yl)benzamide (MR-1-155):

[0278] To a solution of (R)-N-(l-(3,5-dichlorophenyl)elhyl)-2-melhyl-5-(4-melhylpiperazin-l-yljbenzamide (55 mg, 0.135 mmol, 1.0 eq) in Dioxane (2 mL) and H2O (0.5 mL) were added 3,6-Dihydro-2H-pyran-4-boronic acid pinacol ester (85 mg, 0.406 mmol, 3 eq), XPhos Pd G2 (32 mg, 0.0135 mmol, 0.1 eq) and CS2CO3 (132 mg, 0.406mmol, 3.0 eq), then the mixture was stirred at 90 °C for 1 h under N2. LCMS showed 57% with desired MS was detected. The -156- 45844530.1mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: Boston Prime C18 150*30 mm*5 um; mobile phase: [Water (NH3H2O-NH4HCO3)-MeCN]; gradient: 45%-65% B over 11 min). Most of solvent was removed under reduced pressure and the mixture was lyophilized to give compound (R)-N-( 1 -(3,5-bis(3,6-dihydro-2H-pyran-4-yl)phenyl)ethyl)-2-niethyl-5-(4-methylpiperazin-l-yl)benzamide (55.5 mg, 82.0% yield. 99.90% purity) as a white solid. LCMS: [M+H]+502.31.Example 46: Biological Assay to Test Inhibition Potency and Affinity

[0279] The compounds of the present disclosure were then tested for their inhibition potency and affinity for PLpro from SARS-CoV-2. SARS-CoV-2 PLpro expression and purification was as described: pETlla vector containing SARS-CoV-2 PLpro protein (pplab aa 1564-1878) with N-terminal, TEV-cleavable His-tag was transformed into BL21(DE3) cells and maintained in media containing 100 ug / mL carbenicillin. Protein expression was induced using an auto-induction protocol modified from Studier et al.46 Briefly, 1 mL day cultures were used to inoculate a 2L flask of 500 mL of Super LB containing 100 ug / mL carbenicillin. Cells were grown for 24h at 25°C and then harvested by centrifugation. All steps of SARS-CoV2 PLpro purification were performed at 4°C. Protein yield at each step was monitored by Bradford assay using BSA as a standard. Frozen cells pellets were lysed by sonication in Buffer A (50 mM HEPES, pH 8, 0.5 M NaCl) containing 10 ug / mL lysozyme. The lysate was clarified by centrifugation and loaded onto a 2-mL HiTrap Talon crude column equilibrated with Buffer A. Bound His6-PLpro was eluted with a linear gradient of 0-150 mM imidazole in Buffer A, and fractions containing His6-PLpro were pooled and exchanged into cleavage buffer (20 mM Tris-HCl pH 8.5, 5 mM DTT, 0.5 mM EDTA, 5% glycerol). A 1:100 molar ratio of TEV protease to PLpro was incubated at 4°C overnight to cleave the His6-tag. To remove the tag and TEV protease, the reaction was loaded onto a UNO-Q column equilibrated with 20 mM Tris HC1, pH 8.5, 3 mM DTT. Cleaved PLpro eluted first in a gradient from 0-150 mM NaCl over 20 column volumes. Fractions containing cleaved PLpro were pooled and concentrated to 12 mg / mL, frozen in liquid nitrogen, and stored at -80 °C.

[0280] The PLpro primary assay using PLpro as prepared above was conducted as described below and provided the data described in Table 4 in the column: “PLpro enzyme inhibition IC50 (pM) (60 min)”. The PLpro primary assay, which measures protease activity with the short peptide substrate Z-RLRGG-AMC (SEQ ID NO. 4) (Bachem), was performed in black, flat-bottom 384-well plates containing a final reaction volume of 50 pL. The assays were assembled at room temperature as follows: 40 pL of 50 nM PLpro in Buffer B (50 mM -157- 45844530.1HEPES, pH 7.5, 0.1 mg / mL BSA, 0.01% Triton-X 100, and 5 mM DTT) was dispensed into wells containing 0.1-1 yL of inhibitor in DMSO or appropriate controls. The enzyme was incubated with inhibitor for 10 min prior to substrate addition. Reactions were initiated with 10 pL of 62.5 pM RLRGG-AMC (SEQ ID NO. 4) in Buffer B. Plates were shaken vigorously for 30 s, and fluorescence from the release of AMC from peptide was monitored continuously for 15 min on a Tecan Infinite M200 Pro plate reader (Xexcitation=360 nm; Xemission=460 nm). Slopes from the linear portions of each progress curve were recorded and normalized to platebased controls. Positive control wells, representing 100% inhibition, included 10 pM GRL0617; negative control wells, representing 0% inhibition, included vehicle.

[0281] The selectivity of the most potent inhibitors was tested against the human deubiquitinating enzymes USP7 and USP14 (Boston Biochem). Assay conditions were similar to the PLpro primary assay, with the following substitutions: USP7 assays contained 4 nM USP7 and 0.5 uM Ub-AMC (Boston Biochem); USP14 assays contained 1.7 uM USP14, 4 uM Ub-AMC, and the addition of 5% glycerol to Buffer B. PLpro activity with ISG15-AMC and Ub-AMC were assayed in a manner similar to the PLpro primary assay. PLpro and substrate concentrations were modified as follows: 80 nM PLpro was assayed with 0.5 uM Ub-AMC, and 4 nM PLpro was assayed with 0.5 uM ISG15-AMC.

[0282] Secondary analysis of PLpro interaction is performed by analysis of binding affinity using Surface Plasmon Resonance (SPR). The His-tagged SARS-CoV-2 PLpro enzyme is initially prepared in phosphate buffer and diluted to 50 pg / mL with 10 mM sodium acetate (pH 5.5) and immobilized on a CM5 sensor chip by standard amine-coupling with running buffer PBSP (10 mM phosphate, pH 7.4, 2.7 mM KC1, 137 mM NaCl, 0.05 % Tween-20). The CM5 sensor chip surface is first activated by l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC)ZN-hydroxy succinimide (NHS) mixture using a Biacore 8K instrument (Cytiva). SARS-CoV-2 PLpro enzyme is immobilized to flow channels 1 through 4 followed by ethanolamine blocking on the unoccupied surface area, and immobilization levels for all four channels were similar at -12,000 RU. Each flow channel has its own reference channel, and blank immobilization using EDC / NHS and ethanolamine is done for all reference channels. Compound solutions with a series of increasing concentrations (0.049 - 30 pM at 2.5-fold dilution) are applied to all active and reference channels in SPR binding buffer (10 mM HEPES, pH 7.4, 150 mM NaCl, and 0.05% Tween- 20, 0.5 mM TCEP, and 2% DMSO) at a 30 pL / min flow rate at 25 °C. The data were double referenced with a reference channel and zero concentration (2% DMSO) responses, and reference subtracted sensorgrams are fitted with 1 to 1 Langmuir kinetic model using a Biacore Insight evaluation software,-158- 45844530.1producing two rate constants k3and kd). The equilibrium dissociation constants K ) are determined from two rate constants (XD = fa / fc). For steady-state affinity fittings, response units at each concentration are measured during the equilibration phase, and the KD values determined by fitting the data to a single rectangular hyperbolic curve equation, where y is the response, ymax is the maximum response and x is the compound concentration._ ymax'x” KD+X

[0283] The data in Table 4 demonstrates the potency for inhibition of PLpro after a 60 min incubation, which generally correlates with the binding affinity (KD) of the test compounds for PLpro from SARS-CoV-2. Early inhibitory enzymatic activity of PLpro after 6 minutes and % inhibition at 25 nM (60 min) for the representative compounds are shown in FIG. 22.

[0284] Table 4. Biological Assays for Representative Compounds of the Present Disclosure-159- 45844530.1Example 47: Cellular data and activity of Plpro inhibitors

[0285] As shown in FIG. 1, the activity of SARS-CoV-2 in A549 ace2 / TMPDRSS2 cells when treated with PLpro inhibitors in vitro was tested. Cells were infected with SARS-CoV-2 (strain WAI) with a MOI=0.01 in the presence of compound at lOpM and 1 pM and the positive control. Vehicle treatment serves as a negative control with Nirmatrielvir as the positive control. The infected cells were dosed and incubated for 48 hours at 37 C at 5% CO2 and cell material was harvested using TRIzol and purelink mini kit for RNA extraction and VILO-160- 45844530.1reagent was using for RT. RT-qPCR was done using Taqman fast for gene N1 and HPRTlc using a QuantS tudio3. Reduction of viral titer log change for representative PLpro compounds at lOpM and I pM are shown in FIG. 22. Additional data regarding the Plpro inhibitors can be found in FIG. 2 - FIG.22.

[0286] Cytochrome P450 Inhibition Profiles (FIG. 2A - 2T): As shown in FIG. 2F-2. T and 2P-2T, the inhibitory potential of SUN-084 against major human Cytochrome P450 (CYP) isoforms was evaluated to assess the risk of clinical drug-drug interactions (DDI). The enzymes tested included CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4. Dose-response curves were generated. FIG. 2A-2E and 2K-2O provide the corresponding dose-response curves for standard isoform-specific inhibitors (e.g., furafylline for 1A2, sulfaphenazole for 2C9, and ketoconazole for 3A4) as positive controls. The results indicate that SUN-084 possesses a favorable safety profile with negligible inhibition across the CYP spectrum at therapeutic concentrations.

[0287] Pharmacokinetic and Tissue Distribution Analysis (FIG. 3-7 and FIG. 15-21): The pharmacokinetic (PK) properties of SUN-084 were characterized in multiple species. In C57BU / 6I mice (FIG. 3, 4, 15, and 16), plasma concentration vs. time profiles following a 10 mg / kg oral (PO) dose demonstrated rapid absorption and robust systemic exposure. In SD rats (FIG. 5-7 and 17-20), absolute bioavailability was determined by comparing 1 mg / kg IV administration with 10 mg / kg PO administration. Crucially, as shown in FIG. 21, the tissue distribution of SUN-084 was evaluated in C57BL / 6J mice following a BID dosing regimen for 1.5 days. The data revealed strong lung enrichment, with an accumulation of over 50-fold in lung tissue relative to plasma. This high lung-to-plasma ratio is critical for the effective treatment of respiratory pathogens such as SARS-CoV-2.

[0288] In Vivo Efficacy and Metabolic Stability (FIG. 8-14): The antiviral efficacy of SUN-084 was demonstrated in a mouse model of infection. As shown in FIG. 8, treatment with SUN-084 resulted in a dose-dependent reduction in viral titers at 50, 100, and 150 mg / kg. Notably, the viral load reduction achieved by SUN-084 was superior to that of Nirmatrelvir at equivalent dosing intervals.

[0289] Metabolic stability was assessed in human liver microsomes (HLM) and hepatocytes. As shown in FIG. 9 and 10, SUN-084 remained stable in the presence of NADPH and UDPGA, indicating minimal susceptibility to oxidative and glucuronidation pathways. FIG. 11 confirms high metabolic stability in human hepatocytes (1 pM). Protein binding assays in mouse, rat, and human plasma (FIG. 12-14) showed consistent binding characteristics across -161- 45844530.1species, supporting the translation of effective doses from animal models to clinical application.Biological Assay Summary (FIG. 22A - 22E): Additional enzymatic and viral titer data for a library of representative PLpro compounds (including SUN-052 through MR- 1-155) are summarized in FIG. 22A-22E. These compounds were screened for their ability to inhibit the PLpro enzyme and reduce viral replication in vitro. This comprehensive SAR data set, in conjunction with the reduction of viral titer log change data shown across the figures, highlights the superior potency and pharmacological profile of the compounds described herein, with SUN-084 serving as a lead representative of the class.

[0290] From the foregoing, it will be appreciated that specific embodiments of the invention have been described herein for purposes of illustration, but that various modifications may be made without deviating from the scope of the invention. Accordingly, the invention is not limited except as by the appended claims.-162- 45844530.1

Claims

1. CLAIMSWe claim:

1. A compound of Formula la or lb:Formula la Formula lbor a pharmaceutically acceptable salt thereof, wherein:• Ar is selected from aryl, heteroaryl, heterocyclyl, cycloalkyl, and cycloalkenyl, wherein the Ar (i.e., aryl, heleroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl) can be substituted with 1, 2, 3, 4, or 5 Rdgroups;• X is independently selected from — H, — CH3, — Ci-Ce alkyl, — (Ci-Ce alkylenyl)NRaRb, — (Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb— (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalky lenyl)Rc;• Y 1-Y3 are independently — N or — CR', and R’ is H or halogen;• Ri is independently selected from — H, — NFL, — CH3, — Ci-Ce alkyl, — heterocyclyl, — (Ci-C6alkylenyl)NRaRb, — ORa, — (Ci-C6alkyIenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRb, — C(O)NRaRh, — N(Ra)C(O)Rb, — NRaRb, — (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc, — (Ci-C6alkylenyl)RcRc’, and — Ci-Ce alkyl, — C4-C10 heterocyclyl, — CO heterocyclyl, aryl, a sulfur-containing heteroaryl, an oxygen-containing heteroaryl, or a nitrogen-containing heteroaryl, wherein any said 4-10 membered heterocyclyl optionally contains one, two or three nitrogen, and wherein each aryl, heterocyclyl, or heteroaryl (e.g., — C4-C10 heterocyclyl, — CO heterocyclyl, aryl, sulfur-containing heteroaryl, oxygen-containing heteroaryl, or nitrogen-containing heteroaryl) may be substituted with 1, 2, or 3-163- 45844530.1substituents independently selected from halogen, — CN, — (Ci-Ce alkylenyl)NRaRb, — ORa, — (Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRb, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb, — (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc, — (Ci-Ce alkylenyl)RcRc, heterocyclyl, or — CO heterocyclyl;• R2and R3 are each independently selected from the group consisting of — H and — Cl- C4 alkyl, — C1-C4 aminoalkyl and — C1-C4 alkoxy-Cl-C4 alkyl, or alternatively R2and R3 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl optionally substituted by a 4-8 membered heterocycloalkyl;wherein each occurrence of Rdcan be independently selected from the following:• — II, — C4-C10 heterocyclyl, — heteroaryl, — C(O)heterocyclyl, — N(Ra)heterocyclyl, — C(Ra)heterocyclyl, — O-heterocyclyl, — C(O)heteroaryl, — N(Ra)heteroaryl, — C(Ra)heteroaryl, — O-heteroaryl, wherein any said 4-10 membered heterocyclyl optionally contains one, two or three nitrogen or oxygen; wherein aryl, a sulfur- containing heteroaryl, an oxygen-containing heteroaryl, or a nitrogen-containing heteroaryl, each of which may be substituted with 1, 2, or 3 substituents independently selected from halogen, — CN, — (Ci-C6alkylenyl)NRaRb, — ORa, — (Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRb, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb, — (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc, — (Ci-Ce alkylenyl)RcRc, — CO heterocyclyl; or• — Ci-Ce heteroaryl, — CO heteroaryl, wherein it can be optionally substituted with 1, 2, 3, 4, or 5 Regroups; — Ci-Ce alkyl, — C2-Ce alkenyl, — C2-Ce alkynyl, halogen, Ci- Ce haloalkyl, — CN, — NO2, — ORe, — S(O)2NReRf, — C(O)Re, — C(O)NReRf, — NReRf, — N(Re)C(O)Rf, — (Ci-C6alkylenyl)-ORe, — (Ci-C6alkylenyl)-C(O)NReRf, — (Ci-C6alkylenyl)-NReRf, or — (Ci-C6alkylenyl)-N(Re)C(O)Rf;wherein each occurrence of Raand Rbcan be independently selected from the following:• — H, — Ci-Ce alkenyl, — Ci-Ce alkynyl, — Ci-Ce haloalkyl, — Rc, heterocyclyl, or — Ci-Ce alkyl, wherein the — Ci-Ce alkyl can be substituted with a substituent selected from ORe, NReRf, C(O)ORe, C(O)NReRf, — S(O)2Re, — S(O)2NReRf, and — Rc;wherein each occurrence of Rcand Rccan be independently selected from the following:• aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl, wherein each Rcgroup may be substituted with 1, 2, 3, 4, or 5 Rdgroups; and-164- 45844530.1wherein each occurrence of Reand Rfcan be independently selected from the following:• — H, halogen, — CN, — Ci-CY alkyl, — Ci-Ce cycloalkyl, aryl, heteroaryl or — Ci-CY haloalkyloptionally, wherein Ri is any one of the following:

2. The compound of claim 1, wherein said compound has the following Formula II:Formula IIor a pharmaceutically acceptable salt thereof, wherein all X, Y and R groups and subgroups (e.g., Y1-Y7, R1-R20. Ra-Rs, R’, etc.) are each independently selected from those disclosed in Formula I above or as additionally indicated below:Yi-Ye are independently — N or — CR’, and R’ is H or halogen;-165- 45844530.1R4, RS, Re, R7, and Rs can each be independently selected from — H, — C4- C10 heterocyclyl, — heteroaryl, — C(O)heterocyclyl, — N(Ra)heterocyclyl, — C(Ra)heterocyclyl, — O-heterocyclyl, — C(O)heteroaryl, — N(Ra)heteroaryl, — C(Ra)heteroaryl, — O-heteroaryl, aryl, a sulfur- containing heteroaryl, an oxygen-containing heteroaryl, or a nitrogencontaining heteroaryl, wherein any said 4-10 membered heterocycle is optionally substituted with one, two or three nitrogen or oxygen, and wherein each aryl, heterocyclyl, or heteroaryl (e.g., — C4-C10 heterocyclyl, — C(O)heterocyclyl, aryl, sulfur-containing heteroaryl, oxygen-containing heteroaryl, or nitrogen-containing heteroaryl) may be substituted with 1, 2, or 3 substituents independently selected from halogen, — CN, — (Ci-Ce alkylenyl)NRaRb, — ORa, — (Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRb, — C(O)NRaRb, — N(Ra)C(O)Rb. — NRaRb, — (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc, — (Ci-Ce alkylenyl)RcRc, — CO heterocyclyl;alternatively:o R7 and Rs together with the carbon atom to which they are attached form a C3-C6 cycloalkyl, a C3-C6 heterocycl, a C3-C6 aryl, or a C3- Ce heteroaryl, each of which may be optionally substituted with 1, 2, or 3 substituents independently selected from halogen, — CN, — (Ci-C6alkylenyl)NRaRb, — ORa, — (Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRb, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb, — (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc, — (Ci-Ce alkylenyl)RcRc, — CO heterocyclyl;o R4 and R5 together with the carbon atom to which they arc attached form a C3-C6 cycloalkyl, a C -C6 heterocycl, a C3-C6 aryl, or a C3- (, heteroaryl, each of which may be optionally substituted with 1, 2, or 3 substituents independently selected from halogen, — CN, — (Ci-C6alkylenyl)NRaRb, — ORa, — (Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRb, — C(O)NRaRb. — N(Ra)C(O)Rb. — NRaRb, — (Ci-C6alkylenyl)Rc, —-166- 45844530.1(C1-C3 cycloalkylenyl)Rc, — (Ci-Ce alkylenyl)RcRc, — CO heterocyclyl.

3. The compound of claim 2, wherein said compound has the following Formula Illa or Illb:or a pharmaceutically acceptable salt thereof, wherein:X is independently selected from — C1-C6 alkyl, — (C1-C6 alkylenyl)NRaRb,— (C1-C6 alkylenyl)NC(O)Ra, — (C1-C6 alkylenyl) C(O)NRa, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb, — (C1-C6 alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc,Y1-Y4 are independently selected from — N or — CR’, and R’ is H or halogen;Ri, R5, and R7 are each independently selected from:o — H, — C4-C10 heterocyclyl — heteroaryl, — C(O)heterocyclyl, — N(Ra)heterocyclyl, — C(Ra)heterocyclyl, — O-heterocyclyl, — C(O)heteroaryl, — N(Ra)heteroaryl, — C(Ra)heteroaryl, — O- heteroaryl, wherein wherein any said 4-10 membered heterocycle is optionally substituted with one, two or three nitrogen or oxygen, or-167- 45844530.1o an aryl, a sulfur-containing heteroaryl, an oxygen-containing heteroaryl, or a nitrogen-containing heteroaryl, each of which may be substituted with 1, 2, or 3 substituents independently selected from halogen, — CN, — (Ci-C6alkylenyl)NRaRb, — ORa, — (Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRb, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb’ — (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc, and — (Ci-Ce alkylenyl)RcRc, — CO heterocyclyl;• R2and R3 are each independently selected from — H, — C1-C4 alkyl, — Ci- C4 aminoalkyl, and — C1-C4 alkoxy-Ci-C4 alkyl, or alternatively, R2and R3 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl optionally substituted by a 4-8 membered heterocycloalkyl; wherein each occurrence of Raand Rbcan be independently — H, — Ci-Ce alkenyl, — Ci-Ce alkynyl, — Ci-Ce haloalkyl, — Rc, heterocyclyl, or — Ci-Ce alkyl, wherein the — Ci-Ce alkyl can be substituted with a substituent selected from — ORe, — NReRf, — C(O)ORe, — C(O)NReRf, — S(O)2Re, — S(O)2NReRf, and — Rc;wherein each occurrence of Rcand Rccan be independently aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl, wherein each Rcgroup may be substituted with 1, 2, 3, 4, or 5 Rdgroups;wherein each occurrence of Rdcan be independently — Ci-Ce heteroaryl, — CO heteroaryl, wherein it can be optionally substituted with 1, 2, 3, 4, or 5 Regroups; — Ci-Ce alkyl, — C2-Ce alkenyl, — C2-Ce alkynyl, halogen, Ci-Ce haloalkyl, — CN, — NO2, — ORe, — S(O)2NReRf, — C(O)Re, — C(O)NReRf, — NReRf, — N(Re)C(O)Rf, — (Ci-C6alkylenyl)-ORe, — (Ci-C6alkylenyl)-C(O)NReRf, — (Ci-C6alkylenyl)-NReRf, or— (Ci-C6alkylenyl)-N(Re)C(O)Rf; andwherein each occurrence of Rcand R1can be independently — H, halogen, — CN, — Ci- Ce alkyl, — Ci-Ce cycloalkyl, aryl, heteroaryl or — Ci-Ce haloalkyl; optionally, Ri is any one of the following:-168- 45844530.

14. The compound of claim 2, wherein said compound has the following Formula IV:or a pharmaceutically acceptable salt thereof, wherein all X, Y and R groups and subgroups (e.g., Y1-Y7, R1-R20, Ra-Rs, R', etc.) are each independently selected from those identified and disclosed in Formula II, and / or Illa-b above.

5. The compound of claim 4, wherein said compound has the following Formula Va, Vb, or Vc:-169- 45844530.1Formula Va Formula Vb Formula Vc or a pharmaceutically acceptable salt thereof, wherein wherein all X, Y and R groups and subgroups (e.g., Yi-Yn, R1-R20, Ra-Rs, R’, etc.) are each independently selected from those identified and disclosed in Formula II, and / or Illa-b and / or IV above or as additionally indicated below:Y2, and Ys-Yn are independently selected from — N or — CR’, and R' is II or halogen; andRn, R12, and R13 are independently selected from — H, halogen, — CN, — (Ci-C6alkylenyl)NRaRb, — ORa, — (Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRb, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb’ — (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc, and — (Ci-Ce alkylenyl)RcRc, — CO heterocyclyl.-170- 45844530.

16. The compound of claim 5, wherein said compound has the following Formula Via, Vlb, or Vic:Formula Via Formula VIb Formula Vic or a pharmaceutically acceptable salt thereof, wherein all X, Y and R groups and subgroups (e.g., Y1-Y7, R1-R20, Ra-R8, R’, etc.) are each independently selected from those identified and disclosed in Formula II, and / or Illa-b and / or IV and / or Va-c above.

7. The compound of claim 2, wherein said compound has the following Formula IX:Formula IXor a pharmaceutically acceptable salt thereof, wherein:• X is independently selected from — Ci-Ce alkyl, — (Ci-Ce alkylenyl)NRaRb,— (Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl) C(O)NRa, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb’ — (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc;n is selected from 1-3;-171- 45844530.1• Y1-Y3 are independently selected from — NR’ or — CR’, and R’ is H or halogen;• Ri and R2 are each independently selected from the group of — H, — C4- C10 heterocyclyl, - heteroaryl — heteroaryl, — C(O)heterocyclyl, — N(Ra)heterocyclyl, — C(Ra)heterocyclyl, — O-heterocyclyl, — C(O)heteroaryl, — N(Ra)heteroaryl, — C(Ra)heteroaryl, — O-heteroaryl, wherein any said 4-10 membered heterocycle optionally contains one, two or three nitrogen or oxygen; wherein a aryl, a sulfur-containing heteroaryl, an oxygen-containing heteroaryl, or a nitrogen-containing heteroaryl, each of which may be substituted with 1, 2, or 3 substituents independently selected from halogen, -CN, -alkyl, — (Ci-Ce alkylenyl)NRaRb, — ORa, — (Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl)C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRb, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb’ — (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc, and — (C1-C6 alkylenyl)RcRc; — CO heterocyclyl,• R3 and R4 are each independently selected from the group consisting of H and C1-C4 alkyl, C1-C4 aminoalkyl and C1-C4 alkoxy-Ci-C4 alkyl, or alternatively R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl optionally substituted by a 4-8 membered heterocycloalkyl• R9 and Rio are each independently selected from the group of — C4-C10 heterocyclyl, — CO heterocyclyl, wherein any said 4-10 membered heterocycle optionally contains one, two or three nitrogen, wherein each occurrence of Raand Rbcan be independently — H, — Ci-Ce alkenyl, — Ci-Ce alkynyl, — Ci-Ce haloalkyl, — Rc, heterocyclyl, or — Ci-Ce alkyl, wherein the — Ci-Ce alkyl can be substituted with a substituent selected from — ORe, — NReRf, — C(O)ORe, — C(O)NReRf, — S(O)2Re, — S(O)2NReRf, and — Rc, or R9and Rio with the carbon atom to which they are attached form one or more aryl groups, heteroaryl groups, polyaryls groups, heterocyclyl groups, cycloalkyl groups, and / or cycloalkenyl groups, optionally substituted with one or more Ragroups;• wherein each occurrence of Raand Rbis independently — H, — Ci-Ce alkenyl, — Ci-Ce alkynyl, — Ci-Ce haloalkyl, — Rc, heterocyclyl, or — Ci-C& alkyl, wherein the — Ci-Ce alkyl can be substituted with a substituent selected-172- 45844530.1from — ORe, — NReRf, — C(O)ORe, — C(O)NReRf, — S(O)2Re, — S(O)2NReRf, and — Rc;wherein each occurrence of Rcand Rcis independently aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl, wherein each Rcgroup may be substituted with 1, 2, 3, 4, or 5 Rdgroups;wherein each occurrence of Rdcan be independently — Ci-Ce heteroaryl, — CO heteroaryl, wherein it can be optionally substituted with 1, 2, 3, 4, or 5 Regroups; — Ci-C6alkyl, — C2-Ce alkenyl, — C2-Ce alkynyl, halogen, Ci-Ce haloalkyl, — CN, — NO2, — ORe, — S(O)2NReRf, — C(O)Re, — C(O)NReRf, — NReRf, — N(Re)C(O)Rf, — (Ci-C6alkylenyl)-ORe, — (Ci-C6alkylenyl)-C(O)NReRf, — (Ci-C6alkylenyl)-NReRf, or — (Ci-C6alkylenyl)-N(Re)C(O)Rf; andwherein each occurrence of Reand Rfis independently — H, halogen, — CN, — Ci-Ce alkyl, — Ci-Ce cycloalkyl, aryl, heteroaryl or — Ci-Ce haloalkyl.

8. 1'he compound of claim 2, wherein said compound has the following Formula X or Formula X’:Formula X Formula X’or a pharmaceutically acceptable salt thereof, wherein:• X is independently — Ci-Ce alkyl, — (Ci-Cs alkylenyl)NRaRb, — (Ci-Ce alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl) C(O)NRa, C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb— (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc;• Y1-Y4 are independently, N or — CR’, and R’ is H or halogen; Y5-Y7 are independently, N or — CR’, and R’ is selected from H, — Ci-Ce alkyl,, — Ci-Ce cycloalkyl;-173- 45844530.1• Z is independently -0-, -CO, -NH, -NRa- -CH2, — Ci-Ce alkyl, — C(O)NRaRb, — N(Ra)C(O)Rb;• R2 and Rs is selected from the group of — H, — C4-C10 heterocyclyl, - heteroaryl, — heteroaryl, — C(O)heterocyclyl, — N(Ra)heterocyclyl, — C(Ra)heterocyclyl, — O-heterocyclyl, — C(O)heteroaryl, — N(Ra)heteroaryl, — C(Ra)heteroaryl, — O-heteroaryl, wherein any said 4-10 membered heterocycle optionally contains one, two or three nitrogen or oxygen; wherein aryl, heterocyclyl, a sulfur-containing heteroaryl, an oxygen-containing heteroaryl, or a nitrogen-containing heteroaryl, each of which may be substituted with 1, 2, or 3 substituents independently selected from halogen, heterocyclyl, alkyl, -CN, — (Ci-C6alkylenyl)NRaRb, — ORa. — (Ci-C6alkylenyl)NC(O)Ra, — (Ci-C6alkylenyl) C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRb, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb- — (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc, and — (Ci-Ce alkylenyl)RcRc; — CO heterocyclyl;• R3 and R4 are each independently selected from the group consisting of H and C1-C4 alkyl, C1-C4 aminoalkyl and C1-C4 alkoxy-Ci-C4 alkyl, or alternatively R3and R4together with the carbon atom to which they are attached form a C3-C5 cycloalkyl optionally substituted by a 4-8 membered heterocycloalkyl;• R5 is selected from the group of — C4-C10 heterocyclyl, — CO heterocyclyl, wherein any said 4-10 membered heterocycle optionally contains one, two or three nitrogen;wherein each occurrence of Raand Rbcan be independently — H, — Ci-Ce alkenyl, — Ci-Ce alkynyl, — Ci-Ce haloalkyl, — Rc, heterocyclyl, or — Ci-Ce alkyl, wherein the — Ci-Ce alkyl can be substituted with a substituent selected from — ORe, — NReRf, — C(O)ORe, — C(O)NReRf, — S(O)2Re, — S(O)2NReRf, and — Rc;wherein each occurrence of Rcand Rccan be independently aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkcnyl, wherein each Rcgroup may be substituted with 1, 2, 3, 4, or 5 Rdgroups;wherein each occurrence of Rdcan be independently — Ci-Ce heteroaryl, — CO heteroaryl, wherein it can be optionally substituted with 1, 2, 3, 4, or 5 Regroups; — Ci-Ce alkyl, — C2-C6 alkenyl, — C2-C6 alkynyl, halogen, C1-C6 haloalkyl, — CN, —-174- 45844530.1N02, — 0Re, — S(O)2NReRf, — C(O)Re, — C(O)NReRf, — NReRf, — N(Re)C(O)Rf, — (Ci-Ce alkylenyl)-ORe, — (Ci-Ce alkylenyl)-C(O)NReRf, — (Ci-Ce alkylenyl)-NReRf, or — (Ci-C6alkylenyl)-N(Re)C(O)Rf;and wherein each occurrence of Reand Rfcan be independently — H, halogen, — CN, — Ci-Ce alkyl, — Ci-Ce cycloalkyl, aryl, heteroaryl or — Ci-Cr, haloalkyl; optionally, wherein Rs is any one of the following:

9. The compound of claim 1, wherein said compound has a structure of any compounds found in Table 1.-175- 45844530.

111. The compound of claim 2, wherein said compound has the following Formula Vila, Vllb, or Vile:or a pharmaceutically acceptable salt thereof, wherein all X, Y and R groups and subgroups (e.g., Y1-Y7, R1-R20, Ra-Rs, R’, etc.) are each independently selected from those identified and disclosed in Formula II, and / or Illa-b and / or IV and / or Va-c and / or Vile above.-176- 45844530.

112. The compound of claim 1, wherein said compound has a structure of any compounds found in Table 2.

13. The compound of claim 1, wherein said compound has the following Formula Villa orVIIIb:Formula Villa Formula Vlllbor a pharmaceutically acceptable salt thereof, wherein all X, Y and R groups and subgroups (e.g., Y1-Y7, R1-R20, Ra-Rg, R’, etc.) are each independently selected from those identified and disclosed in Formula II, and / or Illa-b and / or IV and / or Va-c and / or Vile and / or Vllla-c above or as additionally indicated below:Y2, and Y4-Y7 are independently selected from — N or — CR’, and R’ is H or halogen; andR15 is selected from — H, halogen, — CN, — (Ci-Ce alkylenyl)NRaRb, — ORa, — (Ci-C6alkylcnyl)NC(O)Ra, — (Ci-C6alkylcnyl)C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRb, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb’ — (Ci-Ce alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc, and — (Ci-Ce alkylenyl)RcRc, — CO heterocyclyl.

14. The compound of claim 1, wherein said compound has the following Formula XI or Formula XT:-177- 45844530.1or a pharmaceutically acceptable salt thereof, wherein:• X is independently — Ci-C& alkyl, — (Ci-Cg alkylenyl)NRaRb, — (Ci-Ce alkylenyl)NC(O)Ra, -(Ci-Ce alkylenyl) C(O)NRa, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb’ — (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc;• Y1-Y4 are independently, N or — CR’, and R’ is H or halogen;• Y5-Y7 are independently, NR’ or — CR’, and R’ is selected from H, — Ci-Ce alkyl,, — Ci-Ce cycloalkyl;• R4 is selected from the group of — H, — C4-C10 heterocyclyl, — CO heterocyclyl, wherein any said 4-10 membered heterocycle contains one, two or three nitrogen; wherein aryl, a sulfur-containing heteroaryl, an oxygencontaining heteroaryl, or a nitrogen-containing heteroaryl, each of which may be substituted with 1, 2, or 3 substituents independently selected from halogen, -CN, — (Ci-C6alkylenyl)NRaRb, — ORa, — (Ci-C6alkylenyl)NC(O)Ra, — (Ci- Ce alkylenyl)C(O)NRa, — N(Ra)S(O)2Rb, — S(O)2NRaRb, — C(O)NRaRb, — N(Ra)C(O)Rb, — NRaRb— (Ci-C6alkylenyl)Rc, — (C1-C3 cycloalkylenyl)Rc, and — (Ci-Ce alkylenyl)RcRc; — CO heterocyclyl;• R2and R3 are each independently selected from the group consisting of H and C1-C4 alkyl, C1-C4 aminoalkyl and C1-C4 alkoxy-Ci-Cr alkyl, or alternatively R2and R3 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl optionally substituted by a 4-8 membered heterocycloalkyl;wherein each occurrence of Raand Rbcan be independently — H, — Ci-Ce alkenyl, — Ci-Ce alkynyl, — Ci-Ce haloalkyl, — Rc, heterocyclyl, or — Ci-Ce alkyl,-178- 45844530.1wherein the — Ci-Ce alkyl can be substituted with a substituent selected from — ORe, — NReRf, — C(O)ORe, — C(O)NReRf, — S(O)2Re, — S(O)2NReRf, and — Rc;wherein each occurrence of Rcand Rccan be independently aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl, wherein each Rcgroup may be substituted with 1, 2, 3, 4, or 5 Rdgroups;wherein each occurrence of Rdcan be independently — Ci-Ce heteroaryl, — CO heteroaryl, wherein it can be optionally substituted with 1, 2, 3, 4, or 5 Regroups; — Ci-C6alkyl, — C2-Ce alkenyl, — C2-Ce alkynyl, halogen, Ci-Ce haloalkyl, — CN, — NO2, — ORe, — S(O)2NReRf, — C(O)Re, — C(O)NReRf, — NReRf, — N(Re)C(O)Rf, — (Ci-C6alkylenyl)- ORe, — (Ci-C6alkylenyl)-C(O)NReRf, — (Ci-C6alkylenyl)-NReRf, or — (Ci-C6alkylenyl)-N(Re)C(O)Rf;and wherein each occurrence of Reand Rfcan be independently — H, halogen, — CN, — Ci-Ce alkyl, — Ci-Ce cycloalkyl, aryl, heteroaryl or — Ci-Ce haloalkyl; optionally, wherein R4 is any one of the following:

15. The compound of claim 1, wherein said compound has a structure of any compounds found in Table 3.

16. A pharmaceutical composition comprising the compound of claims 1.-179- 45844530.

117. A method of reducing viral load in a subject infected with SARS-CoV2 comprising administering a pharmaceutical composition comprising the compound of claim 1 to the subject.

18. A method of treating or preventing a S ARS-CoV2 infection in a subject comprising administering a pharmaceutical composition comprising the compound of claim 1 to the subject.

19. Use of a pharmaceutical composition comprising the compound of claim 1 to the subject to reduce viral load in a subject infected with SARS-CoV2.

20. Use of a pharmaceutical composition comprising the compound of claim 1 to treat a subject infected with SARS-CoV2.-180- 45844530.1

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