SUMMARY [0004] In one aspect, the present disclosure provides compounds of Formula (I): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, wherein: R ¹ is -NH ₂ , -NHCH ₃ , -NHCH ₂ CH ₃ , -N(CH ₃ ) ₂ , or -N(CH ₂ CH ₃ ) ₂ ; R ² and R ³ are each independently H or optionally substituted C ₁ -C ₆ alkyl, optionally wherein R ² and R ³ are joined to form an optionally substituted carbocycle; R ⁴ is -OR ^a , wherein R ^a is H or optionally substituted C ₁ -C ₆ alkyl; R ⁵ is H, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^b , -NO ₂ , -CN, or -N(R ^c ) ₂ ; R ⁶ is H, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^b , -NO ₂ , -CN, or -N(R ^c ) ₂ ; each of X ¹ , X ² , X ³ , and X ⁴ is independently N, N ⁺ -O-, or CR ₇ , wherein each instance of R ⁷ is independently H, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^b , -NO ₂ , -CN, or -N(R ^c ) ₂ ; provided that at least one of X ¹ , X ² , X ³ , and X ⁴ is N or N ⁺ -O-; each of Y ¹ , Y ² , Y ³ , and Y ⁴ is independently N or CR ⁸ , wherein each instance of R ⁸ is independently H, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^b , -NO ₂ , -CN, or -N(R ^c ) ₂ ; each instance of R ^b is independently H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted acyl; and each instance of R ^c is independently H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted acyl. [0005] In another aspect, the present disclosure provides compounds of Formula (II): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, wherein: Ring A is aryl or heteroaryl; R ¹¹ is -NH ₂ , -NHCH ₃ , -NHCH ₂ CH ₃ , -N(CH ₃ ) ₂ , -N(CH ₂ CH ₃ ) ₂ , -NHCD ₃ , -NHCD ₂ CD ₃ , - N(CD ₃ ) ₂ , or -N(CD ₂ CD ₃ ) ₂ ; R ¹² and R ¹³ are each independently H, halogen, or optionally substituted C ₁ -C ₆ alkyl, optionally wherein R ¹² and R ¹³ are joined to form an optionally substituted carbocycle; R ¹⁴ is H, halogen, optionally substituted C ₁ -C ₆ alkyl, carbocyclyl, -OR ^a , -CN, or -N(R ^d ) ₂ , wherein R ^a is H or optionally substituted C ₁ -C ₆ alkyl; R ¹⁵ is H, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^b , -NO ₂ , -CN, or -N(R ^c ) ₂ ; each instance of R ¹⁶ is independently halogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^b , -NO ₂ , -CN, or -N(R ^c ) ₂ ; each of Y ⁵ , Y ⁶ , Y ⁷ , and Y ⁸ is independently N or CR ¹⁷ , wherein each instance of R ¹⁷ is independently H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^b , -NO ₂ , -CN, or -N(R ^c ) ₂ ; each instance of R ^b is independently H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted acyl; each instance of R ^c is independently H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted acyl; each instance of R ^d is independently H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted acyl; and n is 0, 1, 2, 3, or 4. [0006] In another aspect, the present disclosure provides compounds of Formula (III): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, wherein: R ²¹ is -NH ₂ , -NHCH ₃ , -NHCH ₂ CH ₃ , -N(CH ₃ ) ₂ , or -N(CH ₂ CH ₃ ) ₂ ; R ²² and R ²³ are each independently H or optionally substituted C ₁ -C ₆ alkyl, optionally wherein R ²² and R ²³ are joined to form an optionally substituted carbocycle; R ²⁴ is -OR ^a , wherein R ^a is H or optionally substituted C ₁ -C ₆ alkyl; R ²⁵ is H, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^b , -NO ₂ , -CN, or -N(R ^c ) ₂ ; each of X ⁵ , X ⁶ , X ⁷ , and X ⁸ is independently N, N ⁺ -O-, or CR ²⁶ , wherein each instance of R ²⁶ is independently H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^b , -NO ₂ , -CN, or -N(R ^c ) ₂ ; provided that at least one of X ⁵ , X ⁶ , X ⁷ , and X ⁸ is N or N ⁺ -O-; each of Y ⁹ , Y ¹⁰ , Y ¹¹ , and Y ¹² is independently N or CR ²⁷ , wherein each instance of R ²⁷ is independently H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^b , -NO ₂ , -CN, or -N(R ^c ) ₂ ; each instance of R ^b is independently H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted acyl; and each instance of R ^c is independently H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted acyl. [0007] In another aspect, the present disclosure provides pharmaceutical compositions comprising any of the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, and a pharmaceutically acceptable excipient. [0008] In another aspect, the present disclosure provides methods of inhibiting CDK11 in a biological sample or a subject, the method comprising contacting the biological sample with or administering to the subject an effective amount of any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein. [0009] In another aspect, the present disclosure provides methods of inducing apoptosis in a cell in a biological sample or a subject, the method comprising contacting the biological sample with or administering to the subject an effective amount of any of the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions disclosed herein. [0010] In another aspect, the present disclosure provides methods of treating a disease associated with overexpression and/or hyperactivation of CDK11 in a subject in need thereof, the method comprising administering a therapeutically effective amount of any of the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions disclosed herein, to the subject. [0011] In another aspect, the present disclosure provides methods of treating a disease associated with aberrant activity of CDK11 in a subject in need thereof, the method comprising administering a therapeutically effective amount of any of the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions disclosed herein, to the subject. [0012] In another aspect, the present disclosure provides methods of treating cancer in a subject in need thereof, the method comprising administering a therapeutically effective amount of any of the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions disclosed herein, to the subject. [0013] In another aspect, any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein, are for use in inhibiting CDK11 in a biological sample or a subject. [0014] In another aspect, any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein, are for use in inducing apoptosis in a cell in a biological sample or a subject. [0015] In another aspect, any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein, are for use in treating a disease associated with overexpression and/or hyperactivation of CDK11 in a subject in need thereof. [0016] In another aspect, any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein, are for use in treating a disease associated with aberrant activity of CDK11 in a subject in need thereof. [0017] In another aspect, any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein, are for use in treating cancer in a subject in need thereof. [0018] In another aspect, the present disclosure provides uses of any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein, in the manufacture of a medicament for treating a disease associated with overexpression and/or hyperactivation of CDK11 in a subject in need thereof. [0019] In another aspect, the present disclosure provides uses of any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein, in the manufacture of a medicament for treating a disease associated with aberrant activity of CDK11 in a subject in need thereof. [0020] In another aspect, the present disclosure provides uses of any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein, in the manufacture of a medicament for treating cancer in a subject in need thereof. [0021] In another aspect, the present disclosure provides kits comprising any of the compounds provided herein or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein, and instructions for using the compound, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or the pharmaceutical composition. [0022] The details of one or more embodiments of the present disclosure are set forth herein. Other features, objects, and advantages of the present disclosure will be apparent from the Detailed Description, Examples, and Claims. DEFINITIONS [0023] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 ^th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Michael B. Smith, March’s Advanced Organic Chemistry, 7 ^th Edition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3 ^rd Edition, Cambridge University Press, Cambridge, 1987. [0024] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers. [0025] In a formula, the bond is a single bond, the dashed line is a single bond or absent, and the bond or is a single or double bond. [0026] Unless otherwise provided, formulae and structures depicted herein include compounds that do not include isotopically enriched atoms, and also include compounds that include isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of ¹⁹ F with ¹⁸ F, or the replacement of a carbon by a ¹³ C- or ¹⁴ C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays. [0027] The term “isotopes” refers to variants of a particular chemical element such that, while all isotopes of a given element share the same number of protons in each atom of the element, those isotopes differ in the number of neutrons. The term “radioactivity” or “radioactive decay” refers to the process by which a nucleus of an unstable isotope (e.g., ¹⁸ F) loses energy by emitting particles or rays (e.g., alpha particles, beta particles, and gamma rays) of ionizing radiation. Such an unstable isotope or a material including the unstable isotope is referred to as “radioactive.” The Curie (Ci) is a non-SI (non-International System of Units) unit of radioactivity and is defined as 1 Ci = 3.7 × 10 ¹⁰ decays per second. The term “specific activity” refers to the unit radioactivity of a material (e.g., a compound of Formula (I), Formula (II), Formula (III), or a salt, tautomer, stereoisomer, or isotopically labeled derivative (e.g., ¹⁸ F labeled derivative) thereof). In certain embodiments, the term “specific activity” refers to the radioactivity of a material per micromole (µmol) of the material. [0028] When a range of values (“range”) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided. For example “ C _1-6 alkyl” encompasses, C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C _1-6 , C _1-5 , C _1-4 , C _1-3 , C _1–2 , C _2–6 , C _2–5 , C _2–4 , C _2–3 , C _3–6 , C _3–5 , C _3–4 , C _4–6 , C _4–5 , and C _5–6 alkyl. [0029] The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups. [0030] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C _1-20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C _1-12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C _1–10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C _1–9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C _1–8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C _1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C _1–6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C _1–5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C _1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C _1–3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C _1–2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C ₁ alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C _2-6 alkyl”). Examples of C _1-6 alkyl groups include methyl (C ₁ ), ethyl (C ₂ ), propyl (C ₃ ) (e.g., n-propyl, isopropyl), butyl (C ₄ ) (e.g., n-butyl, tert- butyl, sec-butyl, isobutyl), pentyl (C ₅ ) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2- butanyl, tert-amyl), and hexyl (C ₆ ) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C ₇ ), n-octyl (C ₈ ), n-dodecyl (C ₁₂ ), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C _1-12 alkyl (such as unsubstituted C _1-6 alkyl, e.g., −CH ₃ (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n- propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C _1–12 alkyl (such as substituted C _1-6 alkyl, e.g., –CH ₂ F, –CHF ₂ , –CF ₃ , –CH ₂ CH ₂ F, –CH ₂ CHF ₂ , – CH ₂ CF ₃ , or benzyl (Bn)). [0031] The term “haloalkyl” is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. “Perhaloalkyl” is a subset of haloalkyl, and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 20 carbon atoms (“C _1–20 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 10 carbon atoms (“C _1–10 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 9 carbon atoms (“C _1–9 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“C _1–8 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 7 carbon atoms (“C _1-7 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C _1-6 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 5 carbon atoms (“C _1–5 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C _1-4 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C _1–3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C _1–2 haloalkyl”). In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with fluoro to provide a “perfluoroalkyl” group. In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with chloro to provide a “perchloroalkyl” group. Examples of haloalkyl groups include –CHF ₂ , −CH ₂ F, −CF ₃ , −CH ₂ CF ₃ , −CF ₂ CF ₃ , −CF ₂ CF ₂ CF ₃ , −CCl ₃ , −CFCl ₂ , −CF ₂ Cl, and the like. [0032] The term “heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC _1–20 alkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC _1-12 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 11 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC _1–11 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC _1–10 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC _1–9 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC _1–8 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC _1–7 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC _1-6 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC _1–5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms within the parent chain (“heteroC _1-4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC _1–3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC _1–2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC ₁ alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC _2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC _1-12 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC _1–12 alkyl. [0033] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 1 to 20 carbon atoms (“C _1-20 alkenyl”). In some embodiments, an alkenyl group has 1 to 12 carbon atoms (“C _1–12 alkenyl”). In some embodiments, an alkenyl group has 1 to 11 carbon atoms (“C _1-11 alkenyl”). In some embodiments, an alkenyl group has 1 to 10 carbon atoms (“C _1–10 alkenyl”). In some embodiments, an alkenyl group has 1 to 9 carbon atoms (“C _1–9 alkenyl”). In some embodiments, an alkenyl group has 1 to 8 carbon atoms (“C _1–8 alkenyl”). In some embodiments, an alkenyl group has 1 to 7 carbon atoms (“C _1-7 alkenyl”). In some embodiments, an alkenyl group has 1 to 6 carbon atoms (“C _1–6 alkenyl”). In some embodiments, an alkenyl group has 1 to 5 carbon atoms (“C _1-5 alkenyl”). In some embodiments, an alkenyl group has 1 to 4 carbon atoms (“C _1-4 alkenyl”). In some embodiments, an alkenyl group has 1 to 3 carbon atoms (“C _1–3 alkenyl”). In some embodiments, an alkenyl group has 1 to 2 carbon atoms (“C _1–2 alkenyl”). In some embodiments, an alkenyl group has 1 carbon atom (“C ₁ alkenyl”). The one or more carbon- carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C _1-4 alkenyl groups include methylidenyl ( C ₁ ), ethenyl (C ₂ ), 1-propenyl (C ₃ ), 2- propenyl (C ₃ ), 1-butenyl (C ₄ ), 2-butenyl (C ₄ ), butadienyl (C ₄ ), and the like. Examples of C _1–6 alkenyl groups include the aforementioned C _2-4 alkenyl groups as well as pentenyl (C ₅ ), pentadienyl (C ₅ ), hexenyl (C ₆ ), and the like. Additional examples of alkenyl include heptenyl (C ₇ ), octenyl (C ₈ ), octatrienyl (C ₈ ), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C _1-20 alkenyl. In certain embodiments, the alkenyl group is a substituted C _1-20 alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., −CH=CHCH ₃ or may be in the (E)- or (Z)-configuration. [0034] The term “heteroalkenyl” refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC _1-20 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC _1-12 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 11 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC _1-11 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC _1–10 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC _1–9 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC _1–8 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC _1-7 alkenyl”). In some embodiments, a heteroalkenyl group has 1to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC _1–6 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC _1-5 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC _1-4 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC _1–3 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 2 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC _1-2 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC _1–6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC _1-20 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC _1–20 alkenyl. [0035] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C _1-20 alkynyl”). In some embodiments, an alkynyl group has 1 to 10 carbon atoms (“C _1–10 alkynyl”). In some embodiments, an alkynyl group has 1 to 9 carbon atoms (“C _1–9 alkynyl”). In some embodiments, an alkynyl group has 1 to 8 carbon atoms (“C _1–8 alkynyl”). In some embodiments, an alkynyl group has 1 to 7 carbon atoms (“C _1-7 alkynyl”). In some embodiments, an alkynyl group has 1 to 6 carbon atoms (“C _1-6 alkynyl”). In some embodiments, an alkynyl group has 1 to 5 carbon atoms (“C _1-5 alkynyl”). In some embodiments, an alkynyl group has 1 to 4 carbon atoms (“C _1-4 alkynyl”). In some embodiments, an alkynyl group has 1 to 3 carbon atoms (“C _1-3 alkynyl”). In some embodiments, an alkynyl group has 1 to 2 carbon atoms (“C _1-2 alkynyl”). In some embodiments, an alkynyl group has 1 carbon atom (“C ₁ alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C _1-4 alkynyl groups include, without limitation, methylidynyl (C ₁ ), ethynyl (C ₂ ), 1-propynyl (C ₃ ), 2-propynyl (C ₃ ), 1-butynyl (C ₄ ), 2-butynyl (C ₄ ), and the like. Examples of C _1-6 alkenyl groups include the aforementioned C _2-4 alkynyl groups as well as pentynyl (C ₅ ), hexynyl (C ₆ ), and the like. Additional examples of alkynyl include heptynyl (C ₇ ), octynyl (C ₈ ), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C _1-20 alkynyl. In certain embodiments, the alkynyl group is a substituted C _1-20 alkynyl. [0036] The term “heteroalkynyl” refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 1 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC _1–20 alkynyl”). In certain embodiments, a heteroalkynyl group refers to a group having from 1 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC _1–10 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC _1–9 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC _1–8 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC _1-7 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC _1–6 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC _1-5 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 4 carbon atoms, at least one triple bond, and 1or 2 heteroatoms within the parent chain (“heteroC _1-4 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC _1–3 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC _1–2 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC ₁ - ₆ alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC _1-20 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC _1-20 alkynyl. [0037] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C _3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 14 ring carbon atoms (“C _3-14 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 13 ring carbon atoms (“C _3-13 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 12 ring carbon atoms (“C _3-12 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 11 ring carbon atoms (“C _3-11 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C _3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C _3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C _3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C _3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C _4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C _5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C _5-10 carbocyclyl”). Exemplary C _3-6 carbocyclyl groups include cyclopropyl (C ₃ ), cyclopropenyl (C ₃ ), cyclobutyl (C ₄ ), cyclobutenyl (C ₄ ), cyclopentyl (C ₅ ), cyclopentenyl (C ₅ ), cyclohexyl (C ₆ ), cyclohexenyl (C ₆ ), cyclohexadienyl (C ₆ ), and the like. Exemplary C _3-8 carbocyclyl groups include the aforementioned C _3-6 carbocyclyl groups as well as cycloheptyl (C ₇ ), cycloheptenyl (C ₇ ), cycloheptadienyl (C ₇ ), cycloheptatrienyl (C ₇ ), cyclooctyl (C ₈ ), cyclooctenyl (C ₈ ), bicyclo[2.2.1]heptanyl (C ₇ ), bicyclo[2.2.2]octanyl (C ₈ ), and the like. Exemplary C _3-10 carbocyclyl groups include the aforementioned C _3-8 carbocyclyl groups as well as cyclononyl (C ₉ ), cyclononenyl (C ₉ ), cyclodecyl (C ₁₀ ), cyclodecenyl (C ₁₀ ), octahydro-1H- indenyl (C ₉ ), decahydronaphthalenyl (C ₁₀ ), spiro[4.5]decanyl (C ₁₀ ), and the like. Exemplary C _3-8 carbocyclyl groups include the aforementioned C _3-10 carbocyclyl groups as well as cycloundecyl (C ₁₁ ), spiro[5.5]undecanyl (C ₁₁ ), cyclododecyl (C ₁₂ ), cyclododecenyl (C ₁₂ ), cyclotridecane (C ₁₃ ), cyclotetradecane (C ₁₄ ), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C ₃ - 14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C _3-14 carbocyclyl. [0038] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C _3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C _3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C _3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C _3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C _4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C _5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C _5-10 cycloalkyl”). Examples of C _5-6 cycloalkyl groups include cyclopentyl (C ₅ ) and cyclohexyl (C ₅ ). Examples of C _3-6 cycloalkyl groups include the aforementioned C _5-6 cycloalkyl groups as well as cyclopropyl (C ₃ ) and cyclobutyl (C ₄ ). Examples of C _3-8 cycloalkyl groups include the aforementioned C _3-6 cycloalkyl groups as well as cycloheptyl (C ₇ ) and cyclooctyl (C ₈ ). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C _3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C _3- 14 _{cycloalkyl. In certain embodiments, the carbocyclyl includes 0, 1, or 2 C=C double bonds in} the carbocyclic ring system, as valency permits. [0039] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non- aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3–14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3–14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3–14 membered heterocyclyl. In certain embodiments, the heterocyclyl is substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits. [0040] In some embodiments, a heterocyclyl group is a 5–10 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–8 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–6 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”). In some embodiments, the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. [0041] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5- membered heterocyclyl groups containing 2 heteroatoms include dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2- b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3- dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H- pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2- b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like. [0042] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C _6-14 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C ₆ aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C ₁₀ aryl”; e.g., naphthyl such as 1–naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C ₁₄ aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is an unsubstituted C _6-14 aryl. In certain embodiments, the aryl group is a substituted C _6-14 aryl. [0043] “Aralkyl” is a subset of “alkyl” and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety. [0044] The term “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, e.g., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). In certain embodiments, the heteroaryl is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl is substituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. [0045] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl. [0046] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5- membered heteroaryl groups containing 3 heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6- bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl. [0047] “Heteroaralkyl” is a subset of “alkyl” and refers to an alkyl group substituted by a heteroaryl group, wherein the point of attachment is on the alkyl moiety. [0048] The term “unsaturated bond” refers to a double or triple bond. [0049] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond. [0050] The term “saturated” or “fully saturated” refers to a moiety that does not contain a double or triple bond, e.g., the moiety only contains single bonds. [0051] Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl. [0052] A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. “Optionally substituted” refers to a group which is substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The invention is not limited in any manner by the exemplary substituents described herein. [0053] Exemplary carbon atom substituents include halogen, −CN, −NO ₂ , −N ₃ , −SO ₂ H, −SO ₃ H, −OH, −OR ^aa , −ON(R ^bb ) ₂ , −N(R ^bb ) ₂ , −N(R ^bb ) ₃ ⁺ X ⁻ , −N(OR ^cc )R ^bb , −SH, −SR ^aa , −SSR ^cc , −C(=O)R ^aa , −CO ₂ H, −CHO, −C(OR ^cc ) ₂ , −CO ₂ R ^aa , −OC(=O)R ^aa , −OCO ₂ R ^aa , −C(=O)N(R ^bb ) ₂ , −OC(=O)N(R ^bb ) ₂ , −NR ^bb C(=O)R ^aa , −NR ^bb CO ₂ R ^aa , −NR ^bb C(=O)N(R ^bb ) ₂ , −C(=NR ^bb )R ^aa , −C(=NR ^bb )OR ^aa , −OC(=NR ^bb )R ^aa , −OC(=NR ^bb )OR ^aa , −C(=NR ^bb )N(R ^bb ) ₂ , −OC(=NR ^bb )N(R ^bb ) ₂ , −NR ^bb C(=NR ^bb )N(R ^bb ) ₂ , −C(=O)NR ^bb SO ₂ R ^aa , −NR ^bb SO ₂ R ^aa , −SO ₂ N(R ^bb ) ₂ , −SO ₂ R ^aa , −SO ₂ OR ^aa , −OSO ₂ R ^aa , −S(=O)R ^aa , −OS(=O)R ^aa , −Si(R ^aa ) ₃ , −OSi(R ^aa ) ₃ −C(=S)N(R ^bb ) ₂ , −C(=O)SR ^aa , −C(=S)SR ^aa , −SC(=S)SR ^aa , −SC(=O)SR ^aa , −OC(=O)SR ^aa , −SC(=O)OR ^aa , −SC(=O)R ^aa , −P(=O)(R ^aa ) ₂ , −P(=O)(OR ^cc ) ₂ , −OP(=O)(R ^aa ) ₂ , −OP(=O)(OR ^cc ) ₂ , −P(=O)(N(R ^bb ) ₂ ) ₂ , −OP(=O)(N(R ^bb ) ₂ ) ₂ , −NR ^bb P(=O)(R ^aa ) ₂ , −NR ^bb P(=O)(OR ^cc ) ₂ , −NR ^bb P(=O)(N(R ^bb ) ₂ ) ₂ , −P(R ^cc ) ₂ , −P(OR ^cc ) ₂ , −P(R ^cc ) ₃ ⁺ X ⁻ , −P(OR ^cc ) ₃ ⁺ X ⁻ , −P(R ^cc ) ₄ , −P(OR ^cc ) ₄ , −OP(R ^cc ) ₂ , −OP(R ^cc ) ₃ ⁺ X ⁻ , −OP(OR ^cc ) ₂ , −OP(OR ^cc ) ₃ ⁺ X ⁻ , −OP(R ^cc )4, −OP(OR ^cc )4, −B(R ^aa ) ₂ , −B(OR ^cc ) ₂ , −BR ^aa (OR ^cc ), C _1-20 alkyl, C _1-20 perhaloalkyl, C _1-20 alkenyl, C _1-20 alkynyl, heteroC _1-20 alkyl, heteroC _1-20 alkenyl, heteroC _1–20 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups; wherein X ⁻ is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(R ^bb ) ₂ , =NNR ^bb C(=O)R ^aa , =NNR ^bb C(=O)OR ^aa , =NNR ^bb S(=O) ₂ R ^aa , =NR ^bb , or =NOR ^cc ; wherein: each instance of R ^aa is, independently, selected from C _1–20 alkyl, C _1–20 perhaloalkyl, C _1-20 alkenyl, C _1-20 alkynyl, heteroC _1-20 alkyl, heteroC _1-20 alkenyl, heteroC ₁ - 2 ₀ alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl, or two R ^aa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups; each instance of R ^bb is, independently, selected from hydrogen, −OH, −OR ^aa , −N(R ^cc ) ₂ , −CN, −C(=O)R ^aa , −C(=O)N(R ^cc ) ₂ , −CO ₂ R ^aa , −SO ₂ R ^aa , −C(=NR ^cc )OR ^aa , −C(=NR ^cc )N(R ^cc ) ₂ , −SO ₂ N(R ^cc ) ₂ , −SO ₂ R ^cc , −SO ₂ OR ^cc , −SOR ^aa , −C(=S)N(R ^cc ) ₂ , −C(=O)SR ^cc , −C(=S)SR ^cc , −P(=O)(R ^aa ) ₂ , −P(=O)(OR ^cc ) ₂ , −P(=O)(N(R ^cc ) ₂ ) ₂ , C _1–20 alkyl, C _1-20 perhaloalkyl, C _1-20 alkenyl, C _1-20 alkynyl, heteroC _1-20 alkyl, heteroC _1-20 alkenyl, heteroC _1-20 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl, or two R ^bb groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups; each instance of R ^cc is, independently, selected from hydrogen, C _1–20 alkyl, C _1–20 perhaloalkyl, C _1-20 alkenyl, C _1-20 alkynyl, heteroC _1-20 alkyl, heteroC _1-20 alkenyl, heteroC _1-20 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl, or two R ^cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups; each instance of R ^dd is, independently, selected from halogen, −CN, −NO ₂ , −N ₃ , −SO ₂ H, −SO ₃ H, −OH, −OR ^ee , −ON(R ^ff ) ₂ , −N(R ^ff ) ₂ , −N(R ^ff ) ₃ ⁺ X ⁻ , −N(OR ^ee )R ^ff , −SH, −SR ^ee , −SSR ^ee , −C(=O)R ^ee , −CO ₂ H, −CO ₂ R ^ee , −OC(=O)R ^ee , −OCO ₂ R ^ee , −C(=O)N(R ^ff ) ₂ , −OC(=O)N(R ^ff ) ₂ , −NR ^ff C(=O)R ^ee , −NR ^ff CO ₂ R ^ee , −NR ^ff C(=O)N(R ^ff ) ₂ , −C(=NR ^ff )OR ^ee , −OC(=NR ^ff )R ^ee , −OC(=NR ^ff )OR ^ee , −C(=NR ^ff )N(R ^ff ) ₂ , −OC(=NR ^ff )N(R ^ff ) ₂ , −NR ^ff C(=NR ^ff )N(R ^ff ) ₂ , −NR ^ff SO ₂ R ^ee , −SO ₂ N(R ^ff ) ₂ , −SO ₂ R ^ee , −SO ₂ OR ^ee , −OSO ₂ R ^ee , −S(=O)R ^ee , −Si(R ^ee ) ₃ , −OSi(R ^ee ) ₃ , −C(=S)N(R ^ff ) ₂ , −C(=O)SR ^ee , −C(=S)SR ^ee , −SC(=S)SR ^ee , −P(=O)(OR ^ee ) ₂ , −P(=O)(R ^ee ) ₂ , −OP(=O)(R ^ee ) ₂ , −OP(=O)(OR ^ee ) ₂ , C _1–10 alkyl, C _1–10 perhaloalkyl, C _1–10 alkenyl, C _1–10 alkynyl, heteroC _1–10 alkyl, heteroC ₁ - ₁₀ alkenyl, heteroC _1–10 alkynyl, C _3-10 carbocyclyl, 3-10 membered heterocyclyl, C _6-10 aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups, or two geminal R ^dd substituents are joined to form =O or =S; wherein X ⁻ is a counterion; each instance of R ^ee is, independently, selected from C _1–10 alkyl, C _1–10 perhaloalkyl, C _1–10 alkenyl, C _1–10 alkynyl, heteroC _1–10 alkyl, heteroC _1–10 alkenyl, heteroC _1–10 alkynyl, C _3-10 carbocyclyl, C _6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups; each instance of R ^ff is, independently, selected from hydrogen, C _1–10 alkyl, C _1–10 perhaloalkyl, C _1–10 alkenyl, C _1–10 alkynyl, heteroC _1–10 alkyl, heteroC _1–10 alkenyl, heteroC _1–10 alkynyl, C _3-10 carbocyclyl, 3-10 membered heterocyclyl, C _6-10 aryl, and 5-10 membered heteroaryl, or two R ^ff groups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups; each instance of R ^gg is, independently, halogen, −CN, −NO ₂ , −N3, −SO ₂ H, −SO ₃ H, −OH, −OC _1-6 alkyl, −ON(C _1-6 alkyl) ₂ , −N(C _1-6 alkyl) ₂ , −N(C _1-6 alkyl) ₃ ⁺ X ⁻ , −NH(C _1–6 alkyl) ₂ ⁺ X ⁻ , −NH ₂ (C _1–6 alkyl) ⁺ X ⁻ , −NH ₃ ⁺ X ⁻ , −N(OC _1–6 alkyl)(C _1–6 alkyl), −N(OH)(C _1–6 alkyl), −NH(OH), −SH, −SC _1–6 alkyl, −SS(C _1–6 alkyl), −C(=O)(C _1–6 alkyl), −CO ₂ H, −CO ₂ (C _1-6 alkyl), −OC(=O)(C _1-6 alkyl), −OCO ₂ (C _1-6 alkyl), −C(=O)NH ₂ , −C(=O)N(C _1-6 alkyl) ₂ , −OC(=O)NH(C _1-6 alkyl), −NHC(=O)( C _1-6 alkyl), −N(C _1-6 alkyl)C(=O)( C _1–6 alkyl), −NHCO ₂ (C _1–6 alkyl), −NHC(=O)N(C _1–6 alkyl) ₂ , −NHC(=O)NH(C _1-6 alkyl), −NHC(=O)NH ₂ , −C(=NH)O(C _1-6 alkyl), −OC(=NH)(C _1-6 alkyl), −OC(=NH)OC _1-6 alkyl, −C(=NH)N(C _1-6 alkyl) ₂ , −C(=NH)NH(C _1-6 alkyl), −C(=NH)NH ₂ , −OC(=NH)N(C _1–6 alkyl) ₂ , −OC(NH)NH(C _1–6 alkyl), −OC(NH)NH ₂ , −NHC(NH)N(C _1-6 alkyl) ₂ , −NHC(=NH)NH ₂ , −NHSO ₂ (C _1-6 alkyl), −SO ₂ N(C _1-6 alkyl) ₂ , −SO ₂ NH(C _1-6 alkyl), −SO ₂ NH ₂ , −SO ₂ C _1-6 alkyl, −SO ₂ OC _1-6 alkyl, −OSO ₂ C _1-6 alkyl, −SOC _1–6 alkyl, −Si(C _1–6 alkyl) ₃ , −OSi(C _1–6 alkyl) ₃ −C(=S)N(C _1–6 alkyl) ₂ , C(=S)NH(C _1–6 alkyl), C(=S)NH ₂ , −C(=O)S(C _1–6 alkyl), −C(=S)SC _1–6 alkyl, −SC(=S)SC _1–6 alkyl, −P(=O)(OC _1-6 alkyl) ₂ , −P(=O)(C _1-6 alkyl) ₂ , −OP(=O)(C _1-6 alkyl) ₂ , −OP(=O)(OC _1-6 alkyl) ₂ , C _1–10 alkyl, C _1–10 perhaloalkyl, C _1–10 alkenyl, C _1–10 alkynyl, heteroC _1–10 alkyl, heteroC _1–10 alkenyl, heteroC _1–10 alkynyl, C _3-10 carbocyclyl, C _6-10 aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl; or two geminal R ^gg substituents can be joined to form =O or =S; and each X ⁻ is a counterion. [0054] In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C _1-6 alkyl, −OR ^aa , −SR ^aa , −N(R ^bb ) ₂ , –CN, –SCN, –NO ₂ , −C(=O)R ^aa , −CO ₂ R ^aa , −C(=O)N(R ^bb ) ₂ , −OC(=O)R ^aa , −OCO ₂ R ^aa , −OC(=O)N(R ^bb ) ₂ , −NR ^bb C(=O)R ^aa , −NR ^bb CO ₂ R ^aa , or −NR ^bb C(=O)N(R ^bb ) ₂ . In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C _1–10 alkyl, −OR ^aa , −SR ^aa , −N(R ^bb ) ₂ , –CN, –SCN, –NO ₂ , −C(=O)R ^aa , −CO ₂ R ^aa , −C(=O)N(R ^bb ) ₂ , −OC(=O)R ^aa , −OCO ₂ R ^aa , −OC(=O)N(R ^bb ) ₂ , −NR ^bb C(=O)R ^aa , −NR ^bb CO ₂ R ^aa , or −NR ^bb C(=O)N(R ^bb ) ₂ , wherein R ^aa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C _1–10 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each R ^bb is independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C _1–10 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C _1-6 alkyl, −OR ^aa , −SR ^aa , −N(R ^bb ) ₂ , –CN, –SCN, or –NO ₂ . In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen moieties) or unsubstituted C _1–10 alkyl, −OR ^aa , −SR ^aa , −N(R ^bb ) ₂ , –CN, –SCN, or –NO ₂ , wherein R ^aa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C _1–10 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each R ^bb is independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C _1–10 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). [0055] In certain embodiments, the molecular weight of a carbon atom substituent is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g/mol. In certain embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and/or silicon atoms. In certain embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and/or nitrogen atoms. In certain embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and/or iodine atoms. In certain embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, and/or chlorine atoms. [0056] The term “halo” or “halogen” refers to fluorine (fluoro, −F), chlorine (chloro, −Cl), bromine (bromo, −Br), or iodine (iodo, −I). [0057] The term “hydroxyl” or “hydroxy” refers to the group −OH. The term “substituted hydroxyl” or “substituted hydroxyl,” by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from −OR ^aa , −ON(R ^bb ) ₂ , −OC(=O)SR ^aa , −OC(=O)R ^aa , −OCO ₂ R ^aa , −OC(=O)N(R ^bb ) ₂ , −OC(=NR ^bb )R ^aa , −OC(=NR ^bb )OR ^aa , −OC(=NR ^bb )N(R ^bb ) ₂ , −OS(=O)R ^aa , −OSO ₂ R ^aa , −OSi(R ^aa ) ₃ , −OP(R ^cc ) ₂ , −OP(R ^cc ) ₃ ⁺ X ⁻ , −OP(OR ^cc ) ₂ , −OP(OR ^cc ) ₃ ⁺ X ⁻ , −OP(=O)(R ^aa ) ₂ , −OP(=O)(OR ^cc ) ₂ , and −OP(=O)(N(R ^bb )) ₂ , wherein X ⁻ , R ^aa , R ^bb , and R ^cc are as defined herein. [0058] The term “thiol” or “thio” refers to the group –SH. The term “substituted thiol” or “substituted thio,” by extension, refers to a thiol group wherein the sulfur atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from –SR ^aa , –S=SR ^cc , –SC(=S)SR ^aa , –SC(=S)OR ^aa , –SC(=S) N(R ^bb ) ₂ , –SC(=O)SR ^aa , –SC(=O)OR ^aa , –SC(=O)N(R ^bb ) ₂ , and –SC(=O)R ^aa , wherein R ^aa and R ^cc are as defined herein. [0059] The term “amino” refers to the group −NH ₂ . The term “substituted amino,” by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the “substituted amino” is a monosubstituted amino or a disubstituted amino group. [0060] The term “monosubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with one hydrogen and one group other than hydrogen, and includes groups selected from −NH(R ^bb ), −NHC(=O)R ^aa , −NHCO ₂ R ^aa , −NHC(=O)N(R ^bb ) ₂ , −NHC(=NR ^bb )N(R ^bb ) ₂ , −NHSO ₂ R ^aa , −NHP(=O)(OR ^cc ) ₂ , and −NHP(=O)(N(R ^bb ) ₂ ) ₂ , wherein R ^aa , R ^bb and R ^cc are as defined herein, and wherein R ^bb of the group −NH(R ^bb ) is not hydrogen. [0061] The term “disubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with two groups other than hydrogen, and includes groups selected from −N(R ^bb ) ₂ , −NR ^bb C(=O)R ^aa , −NR ^bb CO ₂ R ^aa , −NR ^bb C(=O)N(R ^bb ) ₂ , −NR ^bb C(=NR ^bb )N(R ^bb ) ₂ , −NR ^bb SO ₂ R ^aa , −NR ^bb P(=O)(OR ^cc ) ₂ , and −NR ^bb P(=O)(N(R ^bb ) ₂ ) ₂ , wherein R ^aa , R ^bb , and R ^cc are as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen. [0062] The term “trisubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from −N(R ^bb ) ₃ and −N(R ^bb ) ₃ ⁺ X ⁻ , wherein R ^bb and X ⁻ are as defined herein. [0063] The term “sulfonyl” refers to a group selected from –SO ₂ N(R ^bb ) ₂ , –SO ₂ R ^aa , and –SO ₂ OR ^aa , wherein R ^aa and R ^bb are as defined herein. [0064] The term “sulfinyl” refers to the group –S(=O)R ^aa , wherein R ^aa is as defined herein. [0065] The term “acyl” refers to a group having the general formula −C(=O)R ^X1 , −C(=O)OR ^X1 , −C(=O)−O−C(=O)R ^X1 , −C(=O)SR ^X1 , −C(=O)N(R ^X1 ) ₂ , −C(=S)R ^X1 , −C(=S)N(R ^X1 ) ₂ , and −C(=S)S(R ^X1 ), −C(=NR ^X1 )R ^X1 , −C(=NR ^X1 )OR ^X1 , −C(=NR ^X1 )SR ^X1 , and −C(=NR ^X1 )N(R ^X1 ) ₂ , wherein R ^X1 is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di- aliphaticamino, mono- or di- heteroaliphaticamino, mono- or di- alkylamino, mono- or di- heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two R ^X1 groups taken together form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehydes (−CHO), carboxylic acids (−CO ₂ H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted). [0066] The term “carbonyl” refers to a group wherein the carbon directly attached to the parent molecule is sp ² hybridized, and is substituted with an oxygen, nitrogen or sulfur atom, e.g., a group selected from ketones (–C(=O)R ^aa ), carboxylic acids (–CO ₂ H), aldehydes (–CHO), esters (–CO ₂ R ^aa , –C(=O)SR ^aa , –C(=S)SR ^aa ), amides (–C(=O)N(R ^bb ) ₂ , –C(=O)NR ^bb SO ₂ R ^aa , −C(=S)N(R ^bb ) ₂ ), and imines (–C(=NR ^bb )R ^aa , –C(=NR ^bb )OR ^aa ), –C(=NR ^bb )N(R ^bb ) ₂ ), wherein R ^aa and R ^bb are as defined herein. [0067] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, −OH, −OR ^aa , −N(R ^cc ) ₂ , −CN, −C(=O)R ^aa , −C(=O)N(R ^cc ) ₂ , −CO ₂ R ^aa , −SO ₂ R ^aa , −C(=NR ^bb )R ^aa , −C(=NR ^cc )OR ^aa , −C(=NR ^cc )N(R ^cc ) ₂ , −SO ₂ N(R ^cc ) ₂ , −SO ₂ R ^cc , −SO ₂ OR ^cc , −SOR ^aa , −C(=S)N(R ^cc ) ₂ , −C(=O)SR ^cc , −C(=S)SR ^cc , −P(=O)(OR ^cc ) ₂ , −P(=O)(R ^aa ) ₂ , −P(=O)(N(R ^cc ) ₂ ) ₂ , C _1-20 alkyl, C _1-20 perhaloalkyl, C _1-20 alkenyl, C _1-20 alkynyl, hetero C _1-20 alkyl, hetero C _1–20 alkenyl, hetero C _1–20 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl, or two R ^cc groups attached to an N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups, and wherein R ^aa , R ^bb , R ^cc and R ^dd are as defined above. [0068] In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C _1-6 alkyl, −C(=O)R ^aa , −CO ₂ R ^aa , −C(=O)N(R ^bb ) ₂ , or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C _1-10 alkyl, −C(=O)R ^aa , −CO ₂ R ^aa , −C(=O)N(R ^bb ) ₂ , or a nitrogen protecting group, wherein R ^aa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C _1–10 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each R ^bb is independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C _1-10 alkyl, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C _1-6 alkyl or a nitrogen protecting group. [0069] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include −OH, −OR ^aa , −N(R ^cc ) ₂ , −C(=O)R ^aa , −C(=O)N(R ^cc ) ₂ , −CO ₂ R ^aa , −SO ₂ R ^aa , −C(=NR ^cc )R ^aa , −C(=NR ^cc )OR ^aa , −C(=NR ^cc )N(R ^cc ) ₂ , −SO ₂ N(R ^cc ) ₂ , −SO ₂ R ^cc , −SO ₂ OR ^cc , −SOR ^aa , −C(=S)N(R ^cc ) ₂ , −C(=O)SR ^cc , −C(=S)SR ^cc , C _1–10 alkyl (e.g., aralkyl, heteroaralkyl), C _1-20 alkenyl, C _1-20 alkynyl, hetero C _1-20 alkyl, hetero C _1-20 alkenyl, hetero C _1-20 alkynyl, C _3-10 carbocyclyl, 3- 14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups, and wherein R ^aa , R ^bb , R ^cc and R ^dd are as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 ^rd edition, John Wiley & Sons, 1999, incorporated herein by reference. [0070] For example, in certain embodiments, at least one nitrogen protecting group is an amide group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., −C(=O)R ^aa ) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3- pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o- nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N’- dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o- nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o- phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o- nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o- (benzoyloxymethyl)benzamide. [0071] In certain embodiments, at least one nitrogen protecting group is a carbamate group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., −C(=O)OR ^aa ) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of methyl carbamate, ethyl carbamate, 9- fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7- dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10- tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2- phenylethyl carbamate (hZ), 1–(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2- haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2- trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di- t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and 4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1- adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p- methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p- chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2- methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p- (dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6- chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p- decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N- dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p’-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1- methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5- dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1- phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p- (phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate. [0072] In certain embodiments, at least one nitrogen protecting group is a sulfonamide group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., −S(=O) ₂ R ^aa ) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6- trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β- trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4′,8′- dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide. [0073] In certain embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of phenothiazinyl-(10)-acyl derivatives, N’-p-toluenesulfonylaminoacyl derivatives, N’-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3- diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3- dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N- allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1- isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N- di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N- [(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7- dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N’- oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p- methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N’,N’-dimethylaminomethylene)amine, N-p-nitrobenzylideneamine, N-salicylideneamine, N- 5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N- cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N- diphenylborinic acid derivatives, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N- copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys). In some embodiments, two instances of a nitrogen protecting group together with the nitrogen atoms to which the nitrogen protecting groups are attached are N,N’-isopropylidenediamine. [0074] In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts. [0075] In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C _1-10 alkyl, −C(=O)R ^aa , −CO ₂ R ^aa , −C(=O)N(R ^bb ) ₂ , or an oxygen protecting group. In certain embodiments, each oxygen atom substituents is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C _1-6 alkyl, −C(=O)R ^aa , −CO ₂ R ^aa , −C(=O)N(R ^bb ) ₂ , or an oxygen protecting group, wherein R ^aa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C _1–10 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each R ^bb is independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C _1–10 alkyl, or a nitrogen protecting group. In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C _1-6 alkyl or an oxygen protecting group. [0076] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygen protecting groups include −R ^aa , −N(R ^bb ) ₂ , −C(=O)SR ^aa , −C(=O)R ^aa , −CO ₂ R ^aa , −C(=O)N(R ^bb ) ₂ , −C(=NR ^bb )R ^aa , −C(=NR ^bb )OR ^aa , −C(=NR ^bb )N(R ^bb ) ₂ , −S(=O)R ^aa , −SO ₂ R ^aa , −Si(R ^aa ) ₃ , −P(R ^cc ) ₂ , −P(R ^cc ) ₃ ⁺ X ⁻ , −P(OR ^cc ) ₂ , −P(OR ^cc ) ₃ ⁺ X ⁻ , −P(=O)(R ^aa ) ₂ , −P(=O)(OR ^cc ) ₂ , and −P(=O)(N(R ^bb ) ₂ ) ₂ , wherein X ⁻ , R ^aa , R ^bb , and R ^cc are as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 ^rd edition, John Wiley & Sons, 1999, incorporated herein by reference. [0077] In certain embodiments, each oxygen protecting group, together with the oxygen atom to which the oxygen protecting group is attached, is selected from the group consisting of methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1- methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin- 4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a- octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl (PMB), 3,4- dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p- cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, 4,4′-dimethoxytrityl (4,4′- dimethoxytriphenylmethyl or DMT), α-naphthyldiphenylmethyl, p- methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p- methoxyphenyl)methyl, 4-(4’-bromophenacyloxyphenyl)diphenylmethyl, 4,4′,4″-tris(4,5- dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(levulinoyloxyphenyl)methyl, 4,4′,4″- tris(benzoyloxyphenyl)methyl, 4,4’-Dimethoxy-3"‘-[N-(imidazolylmethyl) ]trityl Ether (IDTr- OR), 4,4’-Dimethoxy-3"‘-[N-(imidazolylethyl)carbamoyl]trityl Ether (IETr-OR), 1,1-bis(4- methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10- oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t- butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4- (ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4- methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2- (triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p- methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p- nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate (MTMEC-OR), 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6- dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4- bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N’,N’- tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). [0078] In certain embodiments, at least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl. [0079] In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C _1–10 alkyl, −C(=O)R ^aa , −CO ₂ R ^aa , −C(=O)N(R ^bb ) ₂ , or a sulfur protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C _1–10 alkyl, −C(=O)R ^aa , −CO ₂ R ^aa , −C(=O)N(R ^bb ) ₂ , or a sulfur protecting group, wherein R ^aa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C _1-10 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each R ^bb is independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C _1–10 alkyl, or a nitrogen protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C _1-6 alkyl or a sulfur protecting group. [0080] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). In some embodiments, each sulfur protecting group is selected from the group consisting of −R ^aa , −N(R ^bb ) ₂ , −C(=O)SR ^aa , −C(=O)R ^aa , −CO ₂ R ^aa , −C(=O)N(R ^bb ) ₂ , −C(=NR ^bb )R ^aa , −C(=NR ^bb )OR ^aa , −C(=NR ^bb )N(R ^bb ) ₂ , −S(=O)R ^aa , −SO ₂ R ^aa , −Si(R ^aa ) ₃ , −P(R ^cc ) ₂ , −P(R ^cc ) ₃ ⁺ X ⁻ , −P(OR ^cc ) ₂ , −P(OR ^cc ) ₃ ⁺ X ⁻ , −P(=O)(R ^aa ) ₂ , −P(=O)(OR ^cc ) ₂ , and −P(=O)(N(R ^bb ) ₂ ) ₂ , wherein R ^aa , R ^bb , and R ^cc are as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 ^rd edition, John Wiley & Sons, 1999, incorporated herein by reference. [0081] In certain embodiments, the molecular weight of a substituent is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g/mol. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and/or silicon atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and/or nitrogen atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and/or iodine atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, and/or chlorine atoms. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond donors. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond acceptors. [0082] A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (e.g., including one formal negative charge). An anionic counterion may also be multivalent (e.g., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F ^– , Cl ^– , Br ^– , I ^– ), NO ₃ ^– , ClO ₄ ^– , OH ^– , H ₂ PO ₄ ^– , HCO ₃ ⁻ , HSO ₄ ^– , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p– toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5–sulfonate, ethan–1–sulfonic acid–2–sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF ₄ ⁻ , PF ₄ ^– , PF ₆ ^– , AsF ₆ ^– , SbF ₆ ^– , B[3,5-(CF ₃ ) ₂ C ₆ H ₃ ] ₄ ] ^– , B(C ₆ F ₅ ) ₄ ⁻ , BPh ₄ ^– , Al(OC(CF ₃ ) ₃ ) ₄ ^– , and carborane anions (e.g., CB ₁₁ H ₁₂ ^– or (HCB ₁₁ Me ₅ Br ₆ ) ^– ). Exemplary counterions which may be multivalent include CO ₃ ²⁻ , HPO ₄ ²⁻ , PO ₄ ³⁻ , B ₄ O ₇ ²⁻ , SO ₄ ²⁻ , S ₂ O ₃ ²⁻ , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes. [0083] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The invention is not limited in any manner by the above exemplary listing of substituents. [0084] The following definitions are more general terms used throughout the present application. [0085] As used herein, the term “salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts. Salts include ionic compounds that result from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge). Salts of the compounds of this invention include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, hippurate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. [0086] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N ⁺ (C _1-4 alkyl) ₄ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. [0087] The term “solvate” refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates. [0088] The term “stoichiometric solvate” refers to a solvate, which comprises a compound (e.g., a compound disclosed herein) and a solvent, wherein the solvent molecules are an integral part of the crystal lattice, in which they interact strongly with the compound and each other. The removal of the solvent molecules will cause instability of the crystal network, which subsequently collapses into an amorphous phase or recrystallizes as a new crystalline form with reduced solvent content. [0089] The term “non-stoichiometric solvate” refers to a solvate, which comprises a compound (e.g., a compound disclosed herein) and a solvent, wherein the solvent content may vary without major changes in the crystal structure. The amount of solvent in the crystal lattice only depends on the partial pressure of solvent in the surrounding atmosphere. In the fully solvated state, non- stoichiometric solvates may, but not necessarily have to, show an integer molar ratio of solvent to the compound. During drying of a non-stoichiometric solvate, a portion of the solvent may be removed without significantly disturbing the crystal network, and the resulting solvate can subsequently be resolvated to give the initial crystalline form. Unlike stoichiometric solvates, the desolvation and resolvation of non-stoichiometric solvates is not accompanied by a phase transition, and all solvation states represent the same crystal form. [0090] The term “hydrate” refers to a compound that is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R⋅x H ₂ O, wherein R is the compound, and x is a number greater than 0. A given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R⋅0.5 H ₂ O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R⋅2 H ₂ O) and hexahydrates (R⋅6 H ₂ O)). [0091] The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to- imine, and enamine-to-(a different enamine) tautomerizations. [0092] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. [0093] Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (−)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”. [0094] The term “crystalline” or “crystalline form” refers to a solid form substantially exhibiting three-dimensional order. In certain embodiments, a crystalline form of a solid is a solid form that is substantially not amorphous. In certain embodiments, the X-ray powder diffraction (XRPD) pattern of a crystalline form includes one or more sharply defined peaks. [0095] The term “amorphous” or “amorphous form” refers to a form of a solid (“solid form”), the form substantially lacking three-dimensional order. In certain embodiments, an amorphous form of a solid is a solid form that is substantially not crystalline. In certain embodiments, the X-ray powder diffraction (XRPD) pattern of an amorphous form includes a wide scattering band with a peak at 2θ of, e.g., between 20 and 70°, inclusive, using CuKα radiation. In certain embodiments, the XRPD pattern of an amorphous form further includes one or more peaks attributed to crystalline structures. In certain embodiments, the maximum intensity of any one of the one or more peaks attributed to crystalline structures observed at a 2θ of between 20 and 70°, inclusive, is not more than 300-fold, not more than 100-fold, not more than 30-fold, not more than 10-fold, or not more than 3-fold of the maximum intensity of the wide scattering band. In certain embodiments, the XRPD pattern of an amorphous form includes no peaks attributed to crystalline structures. [0096] The term “co-crystal” refers to a crystalline structure comprising at least two different components (e.g., a compound disclosed herein and an acid), wherein each of the components is independently an atom, ion, or molecule. In certain embodiments, none of the components is a solvent. In certain embodiments, at least one of the components is a solvent. A co-crystal of a compound disclosed herein and an acid is different from a salt formed from a compound disclosed herein and the acid. In the salt, a compound disclosed herein is complexed with the acid in a way that proton transfer (e.g., a complete proton transfer) from the acid to a compound disclosed herein easily occurs at room temperature. In the co-crystal, however, a compound disclosed herein is complexed with the acid in a way that proton transfer from the acid to a compound disclosed herein does not easily occur at room temperature. In certain embodiments, in the co-crystal, there is no proton transfer from the acid to a compound disclosed herein. In certain embodiments, in the co-crystal, there is partial proton transfer from the acid to a compound disclosed herein. Co-crystals may be useful to improve the properties (e.g., solubility, stability, and ease of formulation) of a compound disclosed herein. [0097] The term “polymorph” refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions. [0098] The term “prodrugs” refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgaard, H., Design of Prodrugs, pp.7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds described herein may be preferred. [0099] The terms “composition” and “formulation” are used interchangeably. [0100] A “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be a male or female at any stage of development. The non-human animal may be a transgenic animal or genetically engineered animal. The term “patient” refers to a human subject in need of treatment of a disease. [0101] The term “biological sample” refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise). Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample. [0102] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject. [0103] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence. [0104] The terms “condition,” “disease,” and “disorder” are used interchangeably. An “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, severeity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses. In certain embodiments, the desired dosage is delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage is delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations). [0105] In certain embodiments, an effective amount of a compound for administration one or more times a day to a 70 kg adult human comprises about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form. [0106] In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels sufficient to deliver from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect. [0107] It will be appreciated that dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult. [0108] A “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for inhibiting CDK11. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating cancer. In certain embodiments, cancer is melanoma or breast cancer. In certain embodiments, a therapeutically effective amount is an amount sufficient for inhibiting CDK11 to treat cancer. In certain embodiments, cancer is melanoma or breast cancer. [0109] A “prophylactically effective amount” of a compound described herein is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient for inhibiting CDK11. In certain embodiments, a prophylactically effective amount is an amount sufficient for treating cancer. In certain embodiments, cancer is melanoma or breast cancer. In certain embodiments, a prophylactically effective amount is an amount sufficient for inhibiting CDK11 to treat cancer. In certain embodiments, cancer is melanoma or breast cancer. [0110] The term “prevent,” “preventing,” or “prevention” refers to a prophylactic treatment of a subject who is not and was not with a disease but is at risk of developing the disease or who was with a disease, is not with the disease, but is at risk of regression of the disease. In certain embodiments, the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population. [0111] As used herein the term “inhibit” or “inhibition” in the context of enzymes, for example, a kinase such as CDK11, refers to a reduction in the activity of the enzyme. In some embodiments, the term refers to a reduction of the level of enzyme activity, e.g., CDK11 activity, to a level that is statistically significantly lower than an initial level, which may, for example, be a baseline level of enzyme activity. In some embodiments, the term refers to a reduction of the level of enzyme activity, e.g., CDK11 activity, to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of enzyme activity. [0112] A “proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). A proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis. Exemplary proliferative diseases include cancers (i.e., “malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases. [0113] The term “angiogenesis” refers to the physiological process through which new blood vessels form from pre-existing vessels. Angiogenesis is distinct from vasculogenesis, which is the de novo formation of endothelial cells from mesoderm cell precursors. The first vessels in a developing embryo form through vasculogenesis, after which angiogenesis is responsible for most blood vessel growth during normal or abnormal development. Angiogenesis is a vital process in growth and development, as well as in wound healing and in the formation of granulation tissue. However, angiogenesis is also a fundamental step in the transition of tumors from a benign state to a malignant one, leading to the use of angiogenesis inhibitors in the treatment of cancer. Angiogenesis may be chemically stimulated by angiogenic proteins, such as growth factors (e.g., VEGF). “Pathological angiogenesis” refers to abnormal (e.g., excessive or insufficient) angiogenesis that amounts to and/or is associated with a disease. [0114] The terms “neoplasm” and “tumor” are used herein interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue. A neoplasm or tumor may be “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis. A “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin. In addition, a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias. In some cases, certain “benign” tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor’s neoplastic cells, and these tumors are referred to as “pre-malignant neoplasms.” An exemplary pre-malignant neoplasm is a teratoma. In contrast, a “malignant neoplasm” is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites. The term “metastasis,” “metastatic,” or “metastasize” refers to the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue and is typically identifiable by the presence of a “secondary tumor” or “secondary cell mass” of the tissue type of the primary or original tumor and not of that of the organ or tissue in which the secondary (metastatic) tumor is located. For example, a prostate cancer that has migrated to bone is said to be metastasized prostate cancer and includes cancerous prostate cancer cells growing in bone tissue. [0115] The term “cancer” refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues. See e.g., Stedman’s Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990. Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett’s adenocarcinoma); Ewing’s sarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenström’s macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more leukemia/lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. Wilms’ tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g.,bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget’s disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget’s disease of the vulva). [0116] A “kinase” is a type of enzyme that transfers phosphate groups from high energy donor molecules, such as ATP, to specific substrates, referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases. One of the largest groups of kinases are protein kinases, which act on and modify the activity of specific proteins. Kinases are used extensively to transmit signals and control complex processes in cells. Various other kinases act on small molecules such as lipids, carbohydrates, amino acids, and nucleotides, either for signaling or to prime them for metabolic pathways. Kinases are often named after their substrates. More than 500 different protein kinases have been identified in humans. These exemplary human protein kinases include, but are not limited to, AAK1, ABL, ACK, ACTR2, ACTR2B, AKT1, AKT2, AKT3, ALK, ALK1, ALK2, ALK4, ALK7, AMPKa1, AMPKa2, ANKRD3, ANPa, ANPb, ARAF, ARAFps, ARG, AurA, AurAps1, AurAps2, AurB, AurBps1, AurC, AXL, BARK1, BARK2, BIKE, BLK, BMPR1A, BMPR1Aps1, BMPR1Aps2, BMPR1B, BMPR2, BMX, BRAF, BRAFps, BRK, BRSK1, BRSK2, BTK, BUB1, BUBR1, CaMK1a, CaMK1b, CaMK1d, CaMK1g, CaMK2a, CaMK2b, CaMK2d, CaMK2g, CaMK4, CaMKK1, CaMKK2, caMLCK, CASK, CCK4, CCRK, CDC2, CDC7, CDK10, CDK11, CDK2, CDK3, CDK4, CDK4ps, CDK5, CDK5ps, CDK6, CDK7, CDK7ps, CDK8, CDK8ps, CDK9, CDKL1, CDKL2, CDKL3, CDKL4, CDKL5, CGDps, CHED, CHK1, CHK2, CHK2ps1, CHK2ps2, CK1a, CK1a2, CK1aps1, CK1aps2, CK1aps3, CK1d, CK1e, CK1g1, CK1g2, CK1g2ps, CK1g3, CK2a1, CK2a1–rs, CK2a2, CLIK1, CLIK1L, CLK1, CLK2, CLK2ps, CLK3, CLK3ps, CLK4, COT, CRIK, CRK7, CSK, CTK, CYGD, CYGF, DAPK1, DAPK2, DAPK3, DCAMKL1, DCAMKL2, DCAMKL3, DDR1, DDR2, DLK, DMPK1, DMPK2, DRAK1, DRAK2, DYRK1A, DYRK1B, DYRK2, DYRK3, DYRK4, EGFR, EphA1, EphA10, EphA2, EphA3, EphA4, EphA5, EphA6, EphA7, EphA8, EphB1, EphB2, EphB3, EphB4, EphB6, Erk1, Erk2, Erk3, Erk3ps1, Erk3ps2, Erk3ps3, Erk3ps4, Erk4, Erk5, Erk7, FAK, FER, FERps, FES, FGFR1, FGFR2, FGFR3, FGFR4, FGR, FLT1, FLT1ps, FLT3, FLT4, FMS, FRK, Fused, FYN, GAK, GCK, GCN2, GCN22, GPRK4, GPRK5, GPRK6, GPRK6ps, GPRK7, GSK3A, GSK3B, Haspin, HCK, HER2/ErbB2, HER3/ErbB3, HER4/ErbB4, HH498, HIPK1, HIPK2, HIPK3, HIPK4, HPK1, HRI, HRIps, HSER, HUNK, ICK, IGF1R, IKKa, IKKb, IKKe, ILK, INSR, IRAK1, IRAK2, IRAK3, IRAK4, IRE1, IRE2, IRR, ITK, JAK1, JAK2, JAK3, JNK1, JNK2, JNK3, KDR, KHS1, KHS2, KIS, KIT, KSGCps, KSR1, KSR2, LATS1, LATS2, LCK, LIMK1, LIMK2, LIMK2ps, LKB1, LMR1, LMR2, LMR3, LOK, LRRK1, LRRK2, LTK, LYN, LZK, MAK, MAP2K1, MAP2K1ps, MAP2K2, MAP2K2ps, MAP2K3, MAP2K4, MAP2K5, MAP2K6, MAP2K7, MAP3K1, MAP3K2, MAP3K3, MAP3K4, MAP3K5, MAP3K6, MAP3K7, MAP3K8, MAPKAPK2, MAPKAPK3, MAPKAPK5, MAPKAPKps1, MARK1, MARK2, MARK3, MARK4, MARKps01, MARKps02, MARKps03, MARKps04, MARKps05, MARKps07, MARKps08, MARKps09, MARKps10, MARKps11, MARKps12, MARKps13, MARKps15, MARKps16, MARKps17, MARKps18, MARKps19, MARKps20, MARKps21, MARKps22, MARKps23, MARKps24, MARKps25, MARKps26, MARKps27, MARKps28, MARKps29, MARKps30, MAST1, MAST2, MAST3, MAST4, MASTL, MELK, MER, MET, MISR2, MLK1, MLK2, MLK3, MLK4, MLKL, MNK1, MNK1ps, MNK2, MOK, MOS, MPSK1, MPSK1ps, MRCKa, MRCKb, MRCKps, MSK1, MSK12, MSK2, MSK22, MSSK1, MST1, MST2, MST3, MST3ps, MST4, MUSK, MYO3A, MYO3B, MYT1, NDR1, NDR2, NEK1, NEK10, NEK11, NEK2, NEK2ps1, NEK2ps2, NEK2ps3, NEK3, NEK4, NEK4ps, NEK5, NEK6, NEK7, NEK8, NEK9, NIK, NIM1, NLK, NRBP1, NRBP2, NuaK1, NuaK2, Obscn, Obscn2, OSR1, p38a, p38b, p38d, p38g, p70S6K, p70S6Kb, p70S6Kps1, p70S6Kps2, PAK1, PAK2, PAK2ps, PAK3, PAK4, PAK5, PAK6, PASK, PBK, PCTAIRE1, PCTAIRE2, PCTAIRE3, PDGFRa, PDGFRb, PDK1, PEK, PFTAIRE1, PFTAIRE2, PHKg1, PHKg1ps1, PHKg1ps2, PHKg1ps3, PHKg2, PIK3R4, PIM1, PIM2, PIM3, PINK1, PITSLRE, PKACa, PKACb, PKACg, PKCa, PKCb, PKCd, PKCe, PKCg, PKCh, PKCi, PKCips, PKCt, PKCz, PKD1, PKD2, PKD3, PKG1, PKG2, PKN1, PKN2, PKN3, PKR, PLK1, PLK1ps1, PLK1ps2, PLK2, PLK3, PLK4, PRKX, PRKXps, PRKY, PRP4, PRP4ps, PRPK, PSKH1, PSKH1ps, PSKH2, PYK2, QIK, QSK, RAF1, RAF1ps, RET, RHOK, RIPK1, RIPK2, RIPK3, RNAseL, ROCK1, ROCK2, RON, ROR1, ROR2, ROS, RSK1, RSK12, RSK2, RSK22, RSK3, RSK32, RSK4, RSK42, RSKL1, RSKL2, RYK, RYKps, SAKps, SBK, SCYL1, SCYL2, SCYL2ps, SCYL3, SGK, SgK050ps, SgK069, SgK071, SgK085, SgK110, SgK196, SGK2, SgK223, SgK269, SgK288, SGK3, SgK307, SgK384ps, SgK396, SgK424, SgK493, SgK494, SgK495, SgK496, SIK(e.g., SIK1, SIK2), skMLCK, SLK, Slob, smMLCK, SNRK, SPEG, SPEG2, SRC, SRM, SRPK1, SRPK2, SRPK2ps, SSTK, STK33, STK33ps, STLK3, STLK5, STLK6, STLK6ps1, STLK6–rs, SuRTK106, SYK, TAK1, TAO1, TAO2, TAO3, TBCK, TBK1, TEC, TESK1, TESK2, TGFbR1, TGFbR2, TIE1, TIE2, TLK1, TLK1ps, TLK2, TLK2ps1, TLK2ps2, TNK1, Trad, Trb1, Trb2, Trb3, Trio, TRKA, TRKB, TRKC, TSSK1, TSSK2, TSSK3, TSSK4, TSSKps1, TSSKps2, TTBK1, TTBK2, TTK, TTN, TXK, TYK2, TYK22, TYRO3, TYRO3ps, ULK1, ULK2, ULK3, ULK4, VACAMKL, VRK1, VRK2, VRK3, VRK3ps, Wee1, Wee1B, Wee1Bps, Wee1ps1, Wee1ps2, Wnk1, Wnk2, Wnk3, Wnk4, YANK1, YANK2, YANK3, YES, YESps, YSK1, ZAK, ZAP70, ZC1/HGK, ZC2/TNIK, ZC3/MINK, and ZC4/NRK. DETAILED DESCRIPTION [0117] Kinases, such as CDK11, are implicated in a wide variety of diseases (e.g., proliferative diseases, such as cancer). Provided herein are compounds of Formula (I), Formula (II), and Formula (III), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, or prodrugs thereof. The provided compounds may be kinase inhibitors. In certain embodiments, the kinase is CDK11. Also provided herein are pharmaceutical compositions and kits including the provided compounds. Further provided are methods of using the provided compounds, pharmaceutical compositions, and kits for inhibiting CDK11 in a biological sample or a subject, inducing apoptosis in a cell in a biological sample or a subject, treating a disease associated with overexpression and/or hyperactivation of CDK11 in a subject, treating a disease associated with aberrant activity of CDK11 in a subject, and treating cancer in a subject. Compounds [0118] In one aspect, the present disclosure provides compounds of Formula (I): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, wherein: R ¹ is -NH ₂ , -NHCH ₃ , -NHCH ₂ CH ₃ , -N(CH ₃ ) ₂ , or -N(CH ₂ CH ₃ ) ₂ ; R ² and R ³ are each independently H or optionally substituted C ₁ -C ₆ alkyl, optionally wherein R ² and R ³ are joined to form an optionally substituted carbocycle; R ⁴ is -OR ^a , wherein R ^a is H or optionally substituted C ₁ -C ₆ alkyl; R ⁵ is H, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^b , -NO ₂ , -CN, or -N(R ^c ) ₂ ; R ⁶ is H, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^b , -NO ₂ , -CN, or -N(R ^c ) ₂ ; each of X ¹ , X ² , X ³ , and X ⁴ is independently N, N ⁺ -O-, or CR7, wherein each instance of R ⁷ is independently H, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^b , -NO ₂ , -CN, or -N(R ^c ) ₂ ; provided that at least one of X ¹ , X ² , X ³ , and X ⁴ is N or N ⁺ -O-; each of Y ¹ , Y ² , Y ³ , and Y ⁴ is independently N or CR ⁸ , wherein each instance of R ⁸ is independently H, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^b , -NO ₂ , -CN, or -N(R ^c ) ₂ ; each instance of R ^b is independently H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted acyl; and each instance of R ^c is independently H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted acyl. [0119] In some embodiments, one of X ¹ , X ² , X ³ , and X ⁴ is N, and the other three of X ¹ , X ² , X ³ , and X ⁴ are CR ⁷ . In certain embodiments, each of X ¹ , X ² , and X ³ is CR ⁷ , and X ⁴ is N. In some embodiments, at least one instance of R ⁷ is optionally substituted C _1-6 alkyl. In certain embodiments, the R ⁷ bound to X ¹ is optionally substituted C _1-6 alkyl. In certain embodiments, at least one instance of R ⁷ is methyl. In certain embodiments, at least one instance of R ⁷ is OH. In some embodiments, at least one of X ¹ , X ² , X ³ , and X ⁴ is CH. In some embodiments, at least two of X ¹ , X ² , X ³ , and X ⁴ are CH. In certain embodiments, three of X ¹ , X ² , X ³ , and X ⁴ are CH. [0120] In some embodiments, the compounds are of Formula (I-a): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof. [0121] In some embodiments, each of Y ¹ , Y ² , Y ³ , and Y ⁴ is CR ⁸ . In certain embodiments, each of Y ¹ , Y ² , Y ³ , and Y ⁴ is CH. [0122] In some embodiments, the compounds are of Formula (I-b): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof. [0123] In some embodiments, the compounds are of Formula (I-c): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof. [0124] In some embodiments, R ¹ is NH ₂ . In some embodiments, R ¹ is N(CH ₃ ) ₂ . In some embodiments, R ¹ is NHCH ₃ . [0125] In some embodiments, R ² is H. In some embodiments, R ³ is H. In certain embodiments, R ² and R ³ are both H. In some embodiments, R ² is C _1-6 alkyl. In some embodiments, R ³ is C _1-6 alkyl. In certain embodiments, one of R ² or R ³ is C _1-6 alkyl, and the other of R ² or R ³ is H. In some embodiments, R ² is CH ₃ . In some embodiments, R ³ is CH ₃ . In certain embodiments, one of R ² or R ³ is CH ₃ , and the other of R ² or R ³ is H. In certain embodiments, R ² and R ³ are joined together to form a cyclopropyl ring. [0126] In some embodiments, R ⁴ is OH, OCH ₃ , OCH ₂ CH ₃ , OCHF ₂ , OCF ₂ H, or OCF ₃ . In certain embodiments, R ⁴ is OH. In certain embodiments, R ⁴ is OCH ₃ . In certain embodiments, R ⁴ is CH ₂ F, CHF ₂ , or CF ₃ . [0127] In some embodiments, R ⁵ is H, halogen, or haloalkyl. In certain embodiments, R ⁵ is H. In certain embodiments, R ⁵ is F. In certain embodiments, R ⁵ is CH ₂ F, CHF ₂ , or CF ₃ . [0128] In some embodiments, R ⁶ is optionally substituted C _1-6 alkyl. In certain embodiments, R ⁶ is haloalkyl. In certain embodiments, R ⁶ is CH ₃ . In certain embodiments, R ⁶ is CH ₂ F. [0129] In some embodiments, a compound of Formula (I) is selected from the group consisting of:

and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, and prodrugs thereof. [0130] In certain embodiments, a compound of Formula (I) is selected from the group consisting of: and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, and prodrugs thereof. [0131] In another aspect, the present disclosure provides compounds of Formula (II): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, wherein: Ring A is aryl or heteroaryl; R ¹¹ is -NH ₂ , -NHCH ₃ , -NHCH ₂ CH ₃ , -N(CH ₃ ) ₂ , -N(CH ₂ CH ₃ ) ₂ , -NHCD ₃ , -NHCD ₂ CD ₃ , - N(CD ₃ ) ₂ , or -N(CD ₂ CD ₃ ) ₂ ; R ¹² and R ¹³ are each independently H, halogen, or optionally substituted C ₁ -C ₆ alkyl, optionally wherein R ¹² and R ¹³ are joined to form an optionally substituted carbocycle; R ¹⁴ is H, halogen, optionally substituted C ₁ -C ₆ alkyl, carbocyclyl, -OR ^a , -CN, or -N(R ^d ) ₂ , wherein R ^a is H or optionally substituted C ₁ -C ₆ alkyl; R ¹⁵ is H, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^b , -NO ₂ , -CN, or -N(R ^c ) ₂ ; each instance of R ¹⁶ is independently halogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^b , -NO ₂ , -CN, or -N(R ^c ) ₂ ; each of Y ⁵ , Y ⁶ , Y ⁷ , and Y ⁸ is independently N or CR ¹⁷ , wherein each instance of R ¹⁷ is independently H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^b , -NO ₂ , -CN, or -N(R ^c ) ₂ ; each instance of R ^b is independently H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted acyl; each instance of R ^c is independently H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted acyl; each instance of R ^d is independently H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted acyl; and n is 0, 1, 2, 3, or 4. [0132] In some embodiments, Ring A is thiophenyl or phenyl. In certain embodiments, Ring A is thiophenyl.

[0133] In some embodiments, the compounds are of Formula (II-a): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof. [0134] In some embodiments, each of Y ⁵ , Y ⁶ , Y ⁷ , and Y ⁸ is CR ¹⁷ . In certain embodiments, each of Y ⁵ , Y ⁶ , Y ⁷ , and Y ⁸ is CH. [0135] In some embodiments, the compounds are of Formula (II-b): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof. [0136] In some embodiments, the compounds are of Formula (II-c): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof. [0137] In some embodiments, R ¹¹ is NH ₂ . In some embodiments, R ¹¹ is N(CH ₃ ) ₂ . In some embodiments, R ¹¹ is NHCH ₃ . In some embodiments, R ¹¹ is -NHCD ₃ . In some embodiments, R ¹¹ is -NHCD ₂ CD ₃ . In some embodiments, R ¹¹ is -N(CD ₃ ) ₂ . In some embodiments, R ¹¹ is - N(CD ₂ CD ₃ ) ₂ . [0138] In some embodiments, R ¹² is H. In some embodiments, R ¹³ is H. In certain embodiments, R ¹² and R ¹³ are both H. In some embodiments, one of R ¹² or R ¹³ is optionally substituted C _1-6 alkyl, and the other of R ¹² or R ¹³ is H. In some embodiments, one of R ¹² or R ¹³ is C _1-6 alkyl substituted with at least one instance of halogen, and the other of R ¹² or R ¹³ is H. In some embodiments, one of R ¹² or R ¹³ is CH ₂ F, CHF ₂ , or CF ₃ , and the other of R ¹² or R ¹³ is H. In some embodiments, R ¹² is C _1-6 alkyl. In some embodiments, R ¹³ is C _1-6 alkyl. In certain embodiments, one of R ¹² or R ¹³ is C _1-6 alkyl, and the other of R ¹² or R ¹³ is H. In some embodiments, R ¹² is CH ₃ . In some embodiments, R ¹³ is CH ₃ . In certain embodiments, one of R ¹² or R ¹³ is CH ₃ , and the other of R ¹² or R ¹³ is H. In certain embodiments, R ¹² and R ¹³ are joined together to form a cyclopropyl or cyclobutyl ring. [0139] In some embodiments, R ¹⁴ is optionally substituted C ₁ -C ₆ alkyl. In some embodiments, R ¹⁴ is haloalkyl. In certain embodiments, R ¹⁴ is CH ₃ or CH ₂ CH ₃ . In certain embodiments, R ¹⁴ is CH ₂ F, CHF ₂ or CF ₃ . In certain embodiments, R ¹⁴ is -OR ^a . In certain embodiments, R ¹⁴ is OH, OCH ₃ , OCH ₂ CH ₃ , OCHF ₂ , OCF ₂ H, or OCF ₃ . In certain embodiments, R ¹⁴ is Cl. In certain embodiments, R ¹⁴ is cyclopropyl. [0140] In some embodiments, R ¹⁵ is H, halogen, optionally substituted C _1-6 alkyl, -NO ₂ , or - N(R ^c ) ₂ . In certain embodiments, R ¹⁵ is CH ₃ . In certain embodiments, R ¹⁵ is CH ₂ F, CHF ₂ , or CF ₃ . In certain embodiments, R ¹⁵ is Cl. In certain embodiments, R ¹⁵ is NH ₂ . In certain embodiments, R ¹⁵ is F. [0141] In some embodiments, R ¹⁶ is halogen, optionally substituted alkyl, optionally substituted heteroalkyl, or -OR ^b . In certain embodiments, R ¹⁶ is CH ₃ or CH ₂ CH ₃ . In certain embodiments, R ¹⁶ is C _1-6 haloalkyl. In certain embodiments, R ¹⁶ is CH ₂ F, CHF ₂ , or CF ₃ . In certain embodiments, R ¹⁶ is F. In certain embodiments, R ¹⁶ is OH or OCH ₃ . In certain embodiments, R ¹⁶ is C _1–10 heteroalkyl consisting of 1, 2, or 3 oxygens in the heteroalkyl chain. In certain embodiments, R ¹⁶ is C _1-10 heteroalkyl consisting of 1 or 2 oxygens in the heteroalkyl chain. In certain embodiments, R ¹⁶ is selected from the group consisting of [0142] In some embodiments, n is 0, 1, or 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. [0143] In some embodiments, a compound of Formula (II) is selected from the group consisting of:

and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, and prodrugs thereof. [0144] In certain embodiments, a compound of Formula (II) is selected from the group consisting of: and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, and prodrugs thereof. [0145] In another aspect, the present disclosure provides compounds of Formula (III): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, wherein: R ²¹ is -NH ₂ , -NHCH ₃ , -NHCH ₂ CH ₃ , -N(CH ₃ ) ₂ , or -N(CH ₂ CH ₃ ) ₂ ; R ²² and R ²³ are each independently H or optionally substituted C ₁ -C ₆ alkyl, optionally wherein R ²² and R ²³ are joined to form an optionally substituted carbocycle; R ²⁴ is -OR ^a , wherein R ^a is H or optionally substituted C ₁ -C ₆ alkyl; R ²⁵ is H, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^b , -NO ₂ , -CN, or -N(R ^c ) ₂ ; each of X ⁵ , X ⁶ , X ⁷ , and X ⁸ is independently N, N ⁺ -O-, or CR ²⁶ , wherein each instance of R ²⁶ is independently H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^b , -NO ₂ , -CN, or -N(R ^c ) ₂ ; provided that at least one of X ⁵ , X ⁶ , X ⁷ , and X ⁸ is N or N ⁺ -O-; each of Y ⁹ , Y ¹⁰ , Y ¹¹ , and Y ¹² is independently N or CR ²⁷ , wherein each instance of R ²⁷ is independently H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^b , -NO ₂ , -CN, or -N(R ^c ) ₂ ; each instance of R ^b is independently H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted acyl; and each instance of R ^c is independently H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted acyl. [0146] In some embodiments, one of X ⁵ , X ⁶ , X ⁷ , and X ⁸ are N, and the other three of X ⁵ , X ⁶ , X ⁷ , and X ⁸ are CR ²⁶ . In certain embodiments, each of X ⁵ , X ⁶ , and X ⁷ is CR ²⁶ , and X ⁸ is N. In some embodiments, at least one instance of R ²⁶ is optionally substituted C _1-6 alkyl. In certain embodiments, the R ²⁶ bound to X ⁵ is optionally substituted C _1-6 alkyl. In certain embodiments, at least one instance of R ²⁶ is methyl. In some embodiments, at least one of X ⁵ , X ⁶ , X ⁷ , and X ⁸ is CH. In some embodiments, at least two of X ⁵ , X ⁶ , X ⁷ , and X ⁸ are CH. In certain embodiments, three of X ⁵ , X ⁶ , X ⁷ , and X ⁸ are CH. [0147] In some embodiments, the compounds are of Formula (III-a): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof. [0148] In some embodiments, each of Y ⁹ , Y ¹⁰ , Y ¹¹ , and Y ¹² is CR ²⁷ . In certain embodiments, each of Y ⁹ , Y ¹⁰ , Y ¹¹ , and Y ¹² is CH. [0149] In some embodiments, the compounds are of Formula (III-b): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof. [0150] In some embodiments, the compounds are of Formula (III-c): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof. [0151] In certain embodiments, R ²¹ is NH ₂ . In certain embodiments, R ²¹ is N(CH ₃ ) ₂ . [0152] In some embodiments, R ²² is H. In some embodiments, R ²³ is H. In certain embodiments, R ²² and R ²³ are both H. In some embodiments, R ²² is C _1-6 alkyl. In some embodiments, R ²³ is C _1-6 alkyl. In certain embodiments, one of R ²² or R ²³ is C _1-6 alkyl, and the other of R ²² or R ²³ is H. In some embodiments, R ²² is CH ₃ . In some embodiments, R ²³ is CH ₃ . In certain embodiments, one of R ²² or R ²³ is CH ₃ , and the other of R ²² or R ²³ is H. In certain embodiments, R ²² and R ²³ are joined together to form a cyclopropyl ring. [0153] In some embodiments, R ²⁴ is OH, OCH ₃ , OCH ₂ CH ₃ , OCHF ₂ , OCF ₂ H, or OCF ₃ . In certain embodiments, R ²⁴ is OH. In certain embodiments, R ²⁴ is OCH ₃ . In certain embodiments, R ²⁴ is CH ₂ F, CHF ₂ , or CF ₃ . [0154] In some embodiments, R ²⁵ is optionally substituted C _1-6 alkyl. In certain embodiments, R ²⁵ is CH ₂ F, CHF ₂ , or CF ₃ . In certain embodiments, R ²⁵ is CH ₃ , CH ₂ F, or CH ₂ OH. [0155] In some embodiments, R ²⁶ is optionally substituted C _1-6 alkyl. In certain embodiments, R ²⁶ is CH ₃ . [0156] In some embodiments, a compound of Formula (III) is selected from the group consisting of:

and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, and prodrugs thereof. [0157] In some embodiments, a compound of Formula (III) is selected from the group consisting of: and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, and prodrugs thereof. [0158] In certain embodiments, the present disclosure provides compounds of Formula (I), or a pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure provides compounds of Formula (II), or a pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof. Pharmaceutical Compositions, Kits, and Administration [0159] In another aspect, the present disclosure provides pharmaceutical compositions comprising any of the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, and a pharmaceutically acceptable excipient. [0160] In certain embodiments, the compound described herein is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is an amount effective for treating a proliferative disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a proliferative disease in a subject in need thereof. In certain embodiments, the proliferative disease is cancer. In certain embodiments, the cancer is melanoma or breast cancer. In certain embodiments, the effective amount is an amount effective for reducing the risk of developing a disease in a subject in need thereof. In certain embodiments, a disease is a proliferative disease. In certain embodiments, the effective amount is an amount effective for inhibiting the activity (e.g., aberrant activity, such as increased activity) of a protein kinase in a subject or cell. In certain embodiments, a protein kinase is CDK11. In certain embodiments, the effective amount is an amount effective for inhibiting the activity of a protein kinase by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 98%. In certain embodiments, a protein kinase is CDK11. [0161] In certain embodiments, the subject is an animal. The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject described herein is a human. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs). In certain embodiments, the subject is a fish or reptile. [0162] In certain embodiments, the cell is present in vitro. In certain embodiments, the cell is present in vivo. [0163] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmaceutics. In general, such preparatory methods include bringing the compound described herein (i.e., the “active ingredient”) into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit. [0164] Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as one- half or one-third of such a dosage. [0165] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered. In some embodiments, the composition comprises between 0.1% and 100% (w/w) active ingredient. [0166] In some embodiments, pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. In some embodiments, excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and/or perfuming agents are present in the composition. [0167] In some embodiments, diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, and/or powdered sugar, and mixtures thereof. [0168] In some embodiments, exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, and/or quaternary ammonium compounds, and mixtures thereof. [0169] In some embodiments, exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween ^® 20), polyoxyethylene sorbitan (Tween ^® 60), polyoxyethylene sorbitan monooleate (Tween ^® 80), sorbitan monopalmitate (Span ^® 40), sorbitan monostearate (Span ^® 60), sorbitan tristearate (Span ^® 65), glyceryl monooleate, sorbitan monooleate (Span ^® 80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj ^® 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol ^® ), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor ^® ), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij ^® 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic ^® F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, and/or docusate sodium, and mixtures thereof. [0170] In some embodiments, exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum ^® ), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, and/or alcohol, and mixtures thereof. [0171] In some embodiments, exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In certain embodiments, the preservative is a chelating agent. [0172] In some embodiments, exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and/or sodium sulfite. [0173] In some embodiments, exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and/or tartaric acid and salts and hydrates thereof. In some embodiments, exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and/or thimerosal. [0174] In some embodiments, exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and/or sorbic acid. [0175] In some embodiments, exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and/or phenylethyl alcohol. [0176] In some embodiments, exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and/or phytic acid. [0177] In some embodiments, preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant ^® Plus, Phenonip ^® , methylparaben, Germall ^® 115, Germaben ^® II, Neolone ^® , Kathon ^® , and/or Euxyl ^® . [0178] In some embodiments, exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D- gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer’s solution, and/or ethyl alcohol, and mixtures thereof. [0179] In some embodiments, exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, and/or sodium lauryl sulfate, and mixtures thereof. [0180] In some embodiments, exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, and/or silicone oil, and mixtures thereof. [0181] In some embodiments, liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and/or elixirs. In some embodiments, the liquid dosage forms comprise inert diluents commonly used in the art. In certain embodiments, inert diluents include water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, and/or polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In some embodiments, the oral compositions include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein are mixed with solubilizing agents such as Cremophor ^® , alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof. [0182] In some embodiments, the compounds provided herein are provided in injectable preparations. In some embodiments, injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, are formulated according to the known art using suitable dispersing or wetting agents and suspending agents. In some embodiments, the sterile injectable preparation is a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. In certain embodiments, the vehicles and solvents employed are water, Ringer’s solution, U.S.P., and/or isotonic sodium chloride solution. In certain embodiments, sterile, fixed oils are employed as a solvent or suspending medium. In certain embodiments, any bland fixed oil is employed, including synthetic mono- or di-glycerides. In certain embodiments, fatty acids such as oleic acid are used in the preparation of injectables. [0183] In some embodiments, the injectable formulations are sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. [0184] In some embodiments, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. In some embodiments, this is accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. In some embodiments, the rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, depends upon crystal size and crystalline form. In some embodiments, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. [0185] In some embodiments, compositions comprising the compounds provided herein are formulated for rectal or vaginal administration. In some embodiments, compositions for rectal or vaginal administration are suppositories which can be prepared by mixing the conjugates described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient. [0186] In some embodiments, solid dosage forms for oral administration are capsules, tablets, pills, powders, and granules. In some embodiments, in such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In some embodiments, in the case of capsules, tablets, and pills, the dosage form includes a buffering agent. [0187] In some embodiments, solid compositions of a similar type are employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. In some embodiments, the solid dosage forms of tablets, dragees, capsules, pills, and granules are prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. In some embodiments, they comprise opacifying agents and are of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. In some embodiments, encapsulating compositions used include polymeric substances and/or waxes. In some embodiments, solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like. [0188] In some embodiments, the active ingredient is in a micro-encapsulated form with one or more excipients as noted above. In some embodiments, the solid dosage forms of tablets, dragees, capsules, pills, and granules is prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In some embodiments, the active ingredient are admixed with at least one inert diluent such as sucrose, lactose, or starch. In certain embodiments, such dosage forms comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In some embodiments, in the case of capsules, tablets and pills, the dosage forms comprise buffering agents. In some embodiments, the dosage forms optionally comprise opacifying agents and are of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating agents which can be used include polymeric substances and waxes. [0189] In some embodiments, dosage forms for topical and/or transdermal administration of a compound described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and/or patches. In some embodiments, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers. Additionally, the present disclosure contemplates the use of transdermal patches to deliver any of the compounds described herein, which often have the added advantage of providing controlled delivery of an active ingredient to the body. In some embodiments, such dosage forms are prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium. In certain embodiments, the rate is controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel. [0190] Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. In some embodiments, intradermal compositions are administered by devices which limit the effective penetration length of a needle into the skin. In some embodiments, conventional syringes are used in the classical mantoux method of intradermal administration. In some embodiments, jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are used. In some embodiments, ballistic powder/particle delivery devices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are used. [0191] In some embodiments, the present disclosure provides formulations comprising any of the compounds disclosed herein for topical administration. In some embodiments, formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions. In some embodiments, topically administrable formulations comprise from about 1% to about 10% (w/w) active ingredient. In some embodiments, the concentration of the active ingredient is as high as the solubility limit of the active ingredient in the solvent. In certain embodiments, formulations for topical administration further comprise one or more of the additional ingredients described herein. [0192] In some embodiments, a pharmaceutical composition described herein is prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity. In some embodiments, such a formulation comprises dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self-propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container. In certain embodiments, such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. In certain embodiments, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. In some embodiments, dry powder compositions include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form. [0193] In some embodiments, the compositions provided herein include low boiling propellants. Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure. In some embodiments, the propellant constitutes 50 to 99.9% (w/w) of the composition, and the active ingredient constitutes 0.1 to 20% (w/w) of the composition. In some embodiments, the propellant further comprises additional ingredients such as a liquid non- ionic and/or solid anionic surfactant and/or a solid diluent. In certain embodiments, the solid diluent has a particle size of the same order as particles comprising the active ingredient. [0194] In some embodiments, pharmaceutical compositions described herein formulated for pulmonary delivery provide the active ingredient in the form of droplets of a solution and/or suspension. In some embodiments, such formulations are prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and are conveniently administered using any nebulization and/or atomization device. In certain embodiments, such formulations further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate. In certain embodiments, the droplets provided by this route of administration have an average diameter in the range from about 0.1 to about 200 nanometers. [0195] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares. [0196] In some embodiments, formulations for nasal administration comprise from about as little as 0.1% (w/w) to as much as 100% (w/w) of the active ingredient, and optionally comprise one or more of the additional ingredients described herein. In some embodiments, a pharmaceutical composition described herein is prepared, packaged, and/or sold in a formulation for buccal administration. In certain embodiments, such formulations are in the form of tablets and/or lozenges made using conventional methods, and contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein. In certain embodiments, formulations for buccal administration comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient. In certain embodiments, such powdered, aerosolized, and/or aerosolized formulations, when dispersed, have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and optionally further comprise one or more of the additional ingredients described herein. [0197] In some embodiments, a pharmaceutical composition described herein is prepared, packaged, and/or sold in a formulation for ophthalmic administration. In some embodiments, such formulations are in the form of eye drops including, for example, a 0.1-1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. In some embodiments, such drops further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein. Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are also contemplated as being within the scope of this disclosure. [0198] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation. [0199] In some embodiments, compounds provided herein are formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts. [0200] In some embodiments, the compounds and compositions provided herein are administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). In certain embodiments, the compound or pharmaceutical composition described herein is suitable for topical administration to the eye of a subject. [0201] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. In some embodiments, an effective amount is included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a compound described herein. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell. In certain embodiments, a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 µg and 1 µg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein. [0202] Dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult. [0203] In some embodiments, a compound or composition, as described herein, is administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and/or prophylactically active agents). In certain embodiments, the compounds or compositions are administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof, and/or in inhibiting the activity of a protein kinase in a subject or cell), improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects. In certain embodiments, a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both. In some embodiments, the additional pharmaceutical agent achieves a desired effect for the same disorder. In some embodiments, the additional pharmaceutical agent achieves different effects. [0204] In some embodiments, the compound or composition is administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a disease (e.g., a proliferative disease). In some embodiments, each additional pharmaceutical agent is administered at a dose and/or on a time schedule determined for that pharmaceutical agent. In some embodiments, the additional pharmaceutical agents are administered together with each other and/or with the compound or composition described herein in a single dose or composition or administered separately in different doses or compositions. The particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually. [0205] The additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, anti-angiogenesis agents, steroidal or non-steroidal anti-inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti-allergic agents, contraceptive agents, pain- relieving agents, anesthetics, anti–coagulants, inhibitors of an enzyme, steroidal agents, steroidal or antihistamine, antigens, vaccines, antibodies, decongestant, sedatives, opioids, analgesics, anti–pyretics, hormones, and prostaglandins. In certain embodiments, the additional pharmaceutical agent is an anti-proliferative agent. In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent. In certain embodiments, the additional pharmaceutical agent is an anti-viral agent. In certain embodiments, the additional pharmaceutical agent is an binder or inhibitor of a protein kinase. In certain embodiments, the additional pharmaceutical agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acids, and other agents that promote differentiation. In certain embodiments, the compounds described herein or pharmaceutical compositions can be administered in combination with an anti-cancer therapy including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy. Additional pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved by the US Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells. [0206] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). In some embodiments, the kits provided comprise a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container). In some embodiments, provided kits optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form one unit dosage form. [0207] Thus, in one aspect, provided are kits including a first container comprising a compound or pharmaceutical composition described herein. In certain embodiments, the kits are useful for treating a disease (e.g., a proliferative disease) in a subject in need thereof. In certain embodiments, the kits are useful for preventing a disease (e.g., a proliferative disease) in a subject in need thereof. In certain embodiments, the kits are useful for reducing the risk of developing a disease (e.g., a proliferative disease) in a subject in need thereof. In certain embodiments, the kits are useful for inhibiting the activity (e.g., aberrant activity, such as increased activity) of a protein kinase (e.g., CDK11) in a subject or a cell. [0208] In certain embodiments, a kit described herein further includes instructions for using the kit. In some embodiments, a kit described herein also includes information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits and instructions provide for treating a disease (e.g., a proliferative disease) in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease (e.g., a proliferative disease) in a subject in need thereof. In certain embodiments, the kits and instructions provide for reducing the risk of developing a disease (e.g., a proliferative disease) in a subject in need thereof. In certain embodiments, the kits and instructions provide for inhibiting the activity (e.g., aberrant activity, such as increased activity) of a protein kinase (e.g., CDK11) in a subject or a cell. In some embodiments, a kit described herein includes one or more additional pharmaceutical agents described herein as a separate composition. Methods of Treatment and Uses [0209] In another aspect, the present disclosure provides methods of inhibiting CDK11 in a biological sample or a subject, the method comprising contacting the biological sample with or administering to the subject an effective amount of any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein. In some embodiments, the subject is a human. [0210] In another aspect, the present disclosure provides methods of inducing apoptosis in a cell in a biological sample or a subject, the method comprising contacting the biological sample with or administering to the subject an effective amount of any of the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions disclosed herein. In some embodiments, the subject is a human. [0211] In another aspect, the present disclosure provides methods of treating a disease associated with overexpression and/or hyperactivation of CDK11 in a subject in need thereof, the method comprising administering a therapeutically effective amount of any of the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions disclosed herein, to the subject. In some embodiments, the disease is a proliferative disease. In certain embodiments, the disease is cancer. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is melanoma. In some embodiments, the subject is a human. [0212] In another aspect, the present disclosure provides methods of treating a disease associated with aberrant activity of CDK11 in a subject in need thereof, the method comprising administering a therapeutically effective amount of any of the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions disclosed herein, to the subject. In some embodiments, the disease is a proliferative disease. In certain embodiments, the disease is cancer. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is melanoma. In some embodiments, the subject is a human. [0213] In another aspect, the present disclosure provides methods of treating cancer in a subject in need thereof, the method comprising administering a therapeutically effective amount of any of the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions disclosed herein, to the subject. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is melanoma. In some embodiments, the subject is a human. [0214] In another aspect, any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein, are for use in inhibiting CDK11 in a biological sample or a subject. In some embodiments, the subject is a human. [0215] In another aspect, any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein, are for use in inducing apoptosis in a cell in a biological sample or a subject. In some embodiments, the subject is a human. [0216] In another aspect, any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein, are for use in treating a disease associated with overexpression and/or hyperactivation of CDK11 in a subject in need thereof. In some embodiments, the disease is a proliferative disease. In certain embodiments, the disease is cancer. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is melanoma. In some embodiments, the subject is a human. [0217] In another aspect, any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein, are for use in treating a disease associated with aberrant activity of CDK11 in a subject in need thereof. In some embodiments, the disease is a proliferative disease. In certain embodiments, the disease is cancer. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is melanoma. In some embodiments, the subject is a human. [0218] In another aspect, any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein, are for use in treating cancer in a subject in need thereof. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is melanoma. In some embodiments, the subject is a human. [0219] In another aspect, the present disclosure provides uses of any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein, in the manufacture of a medicament for treating a disease associated with overexpression and/or hyperactivation of CDK11 in a subject in need thereof. In some embodiments, the disease is a proliferative disease. In certain embodiments, the disease is cancer. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is melanoma. In some embodiments, the subject is a human. [0220] In another aspect, the present disclosure provides uses of any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein, in the manufacture of a medicament for treating a disease associated with aberrant activity of CDK11 in a subject in need thereof. In some embodiments, the disease is a proliferative disease. In certain embodiments, the disease is cancer. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is melanoma. In some embodiments, the subject is a human. [0221] In another aspect, the present disclosure provides uses of any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein, in the manufacture of a medicament for treating cancer in a subject in need thereof. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is melanoma. In some embodiments, the subject is a human. [0222] In another aspect, the present disclosure provides kits comprising any of the compounds provided herein or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein, and instructions for using the compound, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or the pharmaceutical composition. EXAMPLES Example 1. Synthesis of Compounds General Methods and Materials [0223] The urea formation was performed using a Discovery Microwave Synthesizer. All reactions were monitored by TLC with 0.25 mm E. Merck precoated silica gel plates (60 F ₂ 54) and Waters liquid chromatography-mass spectroscopy (LCMS).LC-MS spectra were recorded on a Waters Acquity I class UPLC system using the following system [solvent A: acetonitrile, solvent B: 0.1% formic in water or solvent A: acetonitrile, solvent B: 0.1% ammonia in water or solvent A: acetonitrile, solvent B: 0.1% TFA in water. Formic acid and ammonia were used as HPLC grade. All the separations were performed at ambient temperatures. [0224] Reverse phase HPLC was performed on Waters HPLC system using following system [solvent A: acetonitrile, solvent B: 0.2% NH ₃ in water]. Ammonia was used as HPLC grade. All the separations were performed at ambient temperatures. For analytical RP-HPLC analysis [Interchim:Acquity BEH C ₁ 8 (2.1 x 100 mm, 1.7 um)], the flow rate was 0.4 ml.min ^-1 ; injection volume: 10 µL, detection wavelengths: 220 nm and 254 nm. The following gradient was used: 0.01 min 90 % B, over 8 min to 10 % B, 4 min 10 % B. [0225] Purification of reaction products was carried out by column chromatography using commercially available silica or flash chromatography using Combiflash Rf with Teledyne IscoRediSepRfHigh Performance Gold or SilicycleSiliaSep High Performance columns (40, 80, or 120 g). The purity of all final compounds was over 95% and was analysed with Waters LCMS system. [0226] ¹ H NMR spectra were recorded on Varion400 MHz spectrometers and are reported in ppm with the solvent resonance employed as the internal standard [CDCl ₃ at 7.26 ppm, DMSO- d6 at 2.50 ppm]. Peaks are reported as (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet or unresolved, br s = broad signal, coupling constant(s) in Hz, integration). [0227] Compounds of Formula (I), Formula (II), and Formula (III) may be prepared as follows: Formula (I):

Table of Abbreviations aq.: aqueous (Boc) ₂ O: Di-tert-butyl dicarbonate n-BuOH: n-butanol cHex: cyclohexane CV: column value d: doublet (NMR) d: days DBDMH: 1,3-dibromo-5,5-dimethylhydantoin dd: doublet of doublets DCM = Dichloromethane DIPEA: N,N-diethylisopropyl amine DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide DMP: Dess–Martin Periodinane EDC.HCl: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride equiv.: equivalents Et ₂ O: diethyl ether EtOAc: ethyl acetate g: gram h: hours H: proton HATU:1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b ]pyridinium 3-oxid hexafluorophosphate HCl: hydrochloric acid H ₂ O: water HOBt: 1-hydroxybenzotriazol Hz: Hertz IPA: iso-propanol J: scalar ¹ H- ¹ H coupling constant K ₂ CO ₃ : Potassium carbonate KOAc: Potassium acetate KOH: Potassium hydroxide L: Liter LC-MS: liquid chromatography – mass spectrometry m: multiplet ^M : molar mAU: milli absorption units Me: Methyl MeCN: Acetonitrile MeOH: Methanol mg: milli gram MHz: Mega Hertz min: minutes µw: microwave N2: Nitrogen NaH: Sodium hydride NaHCO ₃ : Sodium bicarbonate NaOH: Sodium hydroxide Na ₂ SO ₄ : Sodium sulfate NBS: N-bromo succinimide NCS: N-chloro succinimide NMR: Nuclear Magnetic Resonance PCC: Pyridinium chlorochromate PMB-Cl: para-methoxybenzyl chloride Pd (dppf)Cl2: [1,1’-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) Pd2dba3: Tris(dibenzylideneacetone)dipalladium(0) Pd118: [1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium (II) POCl3: Phosphorus (V) oxychloride quant.: quantitative R _f : retention factor (TLC) rt: room temperature s: singlet SiO ₂ : Silicon dioxide (silica) TCFH: Tetramethylchloroformamidinium hexafluorophosphate TFA: Trifluoro acetic acid THF: Tetrahydrofuran TLC: Thin layer chromatography XantPhos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

Scheme 1: Synthesis of I-1000, I-1001, and I-1002 Scheme 1a: Synthesis of key intermediate 7: Step-1: [0228] To a stirred solution of compound 1 (20 g, 0.099 mol) in DCM (200 mL) was added oxalyl chloride (37.42 g, 0.297 mol) then reaction mixture was stirred at RT for 4h. Reaction was monitored by TLC; after completion of reaction solvent was evaporated by reduced pressure and crude was used for next step without purification. The acid chloride was dissolved in DCM (200 mL) followed by the addition of compound 2 (8.4 g, 0.063 mol) and TEA (18.3 g, 0.18 mol) then reaction mixture was stirred at RT for 18h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with DCM (2x1L), organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound 3. Crude compound was purified by column chromatography using a silica gel (100: 200 mesh) and compound was eluted using 5% EtOAc in Hexane to afford compound 3 (25 g, Yield: 86.8%) as an off white solid. [0229] LCMS: m/z = 321.14 [M+2H] ⁺ , 89.84 % (1.36 min). [0230] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-2: [0231] To a stirred solution of compound 3 (25 g, 0.077 mol) in DCM was added NaH (3.14 g, 0.13 mol) at 0 ^o C followed by PMB-Cl (10.20 g, 0.06 mol) then reaction mixture was stirred at RT for 18h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with DCM (2x1L), organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude compound was purified by column chromatography using silica gel (100:200 mesh) and compound was eluted using 10% EtOAc in Hexane to afford compound 4 (28 g, Yield: 81.6%) as an off white solid. [0232] LCMS: m/z = 441.21 [M+2H] ⁺ , 12.67 % (1.55 min). [0233] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-3: [0234] To a stirred solution of compound 4 (1.5 g, 0.004 mmol) in DMA (15 mL) was added potassium acetate (1.2 g, 0.012 mol) followed by Pd(P ^t Bu3) ₂ catalyst (127 mg, 0.002 mmol) then reaction mixture was stirred at 150 ^o C for 4h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with ethyl acetate (2x200 mL), organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude compound was used for next step without purification. Crude compound was purified by column chromatography using silica gel (100:200 mesh) and compound was eluted using 10% EtOAc in Hexane to afford compound 5 (800 mg, Yield: 65%) as an off white solid. [0235] LCMS: m/z = 361.23 [M+H] ⁺ , 92.58 % (1.40 min). [0236] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-4: [0237] Trifluoro acetic acid (20 mL) was added to compound 5 (1.4 g, 0.003 mol) at 0 ^o C. The resulting reaction mixture allowed to room temperature and stirred at 100 °C for 16h. Completion of the reaction was monitored by TLC, after completion, the reaction mixture quenched with aq. NaHCO ₃ solution and extracted with EtOAc (2x200 mL). The organic washed with brine solution (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Crude compound was purified by column chromatography using silica gel (100:200 mesh) and compound was eluted using 10% EtOAc in Hexane to afford compound 6 (1.1 g, Yield: 42.8 %) as a pale brown solid. [0238] LCMS: m/z = 241.16 [M+H] ⁺ , 87.48% (1.07 min). [0239] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-5: [0240] To a stirred solution of compound 6 (1 g, 0.004 mol) in 2 mL (1:1) DCM-AcOH was added 1,3 dibromo,5,5 dimethyl hydantoin (356 mg, 0.001 mol) at 0 ^o C then reaction mixture was stirred at room temperature for 3h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with DCM (2x100 mL), organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude compound was purified by column chromatography using silica gel (100:200 mesh) and compound was eluted using 20% EtOAc in Hexane to afford compound 7 (900 mg, Yield: 68.1%) as an off white solid. [0241] LCMS: m/z = 320.96 [M+2H] ⁺ , 74.93 % (1.33 min). [0242] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Scheme 1b: Synthesis of Intermidiate-5: Step-1: [0243] To a solution mixture of compound 1 (30 g, 150.7 mmol) and p-Toluenesulfonylmethyl isocyanide (35.27 g, 180.9 mmol) in 1,2-Dimethoxy ethane (480.0 mL) was added a solution of potassium tert-butoxide (25.32 g, 226.1 mmol) in ^t BuOH (120.0 mL) at -15 ^o C. The reaction mixture was stirred at 0 ^o C for 3h and was quenched with water (100 mL) and extracted with hexane (2x200 mL). Combined organic layers were dried over Na ₂ SO ₄ and concentrated under vacuo to afford compound 2 (20 g, Crude). Crude was taken to next step without any further purification. Step-2: [0244] To a solution mixture of compound 2 (20 g, 95.2 mmol) in THF (100 mL) was added BH ₃ .DMS (10 M in DMS) (10.5 mL, 104.7 mmol) at reflux temperature. Reaction mixture was kept for 30 min at reflux, cooled to room temperature and pH adjusted to 2.0 with 6N HCl and neutralized with aq.6N NaOH, this solution was extracted with DCM (2x200 mL). Combined organic layer was dried over Na ₂ SO ₄ and concentrated under vacuo to afford compound 3 (20 g, crude). Crude was taken to next step without any further purification. [0245] LCMS: m/z = 216.02 [M+2H] ⁺ , 47.86% (1.06 min). [0246] Method: Column: Acquity BEH C ₁ 8 (2.1 x 50 mm, 1.7 μm), Mobile Phase: A-0.01% FA, in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90), Flow Rate: 0.4 mL/min. Step-3: [0247] To a solution mixture of compound 3 (20 g, 93.4 mmol) in DCM (200 mL) was added TEA (19.6 mL, 140.1 mmol) and followed by (Boc) ₂ O (25.7 mL, 112.0 mmol) at 0 ^o C. Reaction mixture was kept at room temperature for 2h and evaporated under vacuo. Crude compound was purified by column chromatography using silica gel (100:200 mesh) and compound was eluted using 5% EtOAc in Hexane to afford compound 4 (13 g, Yield: 44.3%) as an off white solid. [0248] LCMS: m/z = 260.02 [M-56 +2H] ⁺ , 66.90% (1.87 min). [0249] Method: Column: Acquity BEH C ₁ 8 (2.1 x 50 mm, 1.7 μm), Mobile Phase: A-0.01% FA, in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90), Flow Rate: 0.4 mL/min. Step-4: [0250] To a solution mixture of compound 4 (6.0 g, 19.10 mmol) in Dioxane (60 mL) was added Bis(pinacolato)diboron (5.82 g, 22.9 mmol), Pd(dppf)Cl2 (567.1 mg, 0.76 mmol) followed by KOAc (3.74 g, 38.2 mmol) at rt and degassed with N ₂ for 5 min at room temperature. Reaction mixture was kept for 15h at 90 ^o C. After completion, reaction mixture was cooled to rt and quenched with water (100 mL) and extracted with EtOAc (2x100 mL). Combined organic layers were washed with water and brine, concentrated under vacuo. Crude compound was purified by column chromatography using a silica gel (100:200 mesh) and compound was eluted using 5% EtOAc in hexane to afford compound 5 (5.8 g, Yield: 84.2%) as an off white solid. [0251] LCMS: m/z = 362.2 [M+H] ⁺ , 89.61% (1.97 min). [0252] Method: Column: Acquity BEH C ₁ 8 (2.1 x 50 mm, 1.7 μm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90), Flow Rate: 0.4 mL/min. [0253] ¹ H NMR [400 MHz, DMSO-d6]: 7.59 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 7.6 Hz, 2H), 6.85 (t, J = 5.6 Hz, 1H), 3.07-3.01 (m, 2H), 2.87-2.86 (m, 1H), 1.34-1.28 (m, 21H), 1.16-1.13 (m, 3H). Scheme 1c: Synthesis of I-1000, I-1001, and I-1002 Step-6: [0254] To a stirred solution of compound 7 (200 mg, 0.62 mol) in Dioxane (4 mL) solution was added compound 8 (272 mg, 0.75mol) followed by Cs2CO ₃ (306 mg, 0.0 mol). Reaction mixture was degassed for 15 minutes then Pd(dppf)Cl ₂ catalyst (23 mg, 0.003 mol) was added and again degassed for 10 minutes then reaction mixture was stirred at 85 ^o C for 15h. Reaction was monitored by LCMS. The reaction mixture was poured into water and extracted with DCM (2x20 mL), organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude compound was purified by column chromatography using silica gel (100: 200 mesh) and compound was eluted using 30% EtOAc in Hexane to afford compound 9 (112 mg, Yield: 37.8%) as an off white solid. [0255] LCMS: m/z = 474.08 [M+H] ⁺ , 14.16 % (1.92 min). [0256] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-7: Synthesis of I-1000 [0257] To a stirred solution of compound 9 (500 mg, 1.054 mol) in 1,4-dioxane (5 mL) was added 4M HCl in dioxane (5 mL) at 0 ^o C then reaction mixture was stirred at rt for 4h. Reaction was monitored by TLC; after completion, reaction mixture was diluted with water (5 mL) and washed with ethyl acetate (2x50 mL). Aqueous layer was quenched with aq. NaHCO ₃ and extracted with 10% MeOH in DCM (2x50 mL). Organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude was purified by reverse phase C-18 chromatography to afford I-1000 as a white solid (12 mg, Yield: 1.5%). [0258] LCMS: m/z: 374.24[M+H] ⁺ , 92.58% (1.36min). [0259] Method: Column: Acquity BEH C ₁ 8 (2.1 x 50 mm, 1.7 μm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90), Flow Rate: 0.4 mL/min. [0260] ¹ H NMR [400 MHz, DMSO-d ₆ ]: 8.66 (s, 1H), 7.33-7.30 (m, 3H), 7.15-7.12 (m, 4H), 3.69 (s, 1H), 2.78-2.71 (m, 3H), 1.28-1.26 (d, J = 6 Hz, 3H). Step-8: Synthesis of I-1001 [0261] To a stirred solution of compound I-1000 (500 mg,0.1.34 mmol) in DCM (50 mL) was added Boron tribromide (1 mL) at 0 ⁰ C, then reaction mixture was stirred at room temperature for 16h. Reaction was monitored by TLC; after completion, solvent was evaporated then reaction mixture was quenched in water and extracted with DCM (2x50 mL). Organic layer was concentrated and washed with pentane to afford compound I-1001 as white solid (108 mg, Yield: 22%). [0262] LCMS: m/z: 360.18[M+H] ⁺ , 97.36% (1.26 min). [0263] Method: Column: Acquity BEH C ₁ 8 (2.1 x 50 mm, 1.7 μm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90), Flow Rate: 0.4 mL/min. [0264] ¹ H NMR [400 MHz, DMSO-d6]: 8.63-8.61 (d, J = 5.6 Hz 1H), 8.31 (s 1H), 7.33 (m, 2H), 7.22-7.12 (m, 4H), 7.02 (s, 1H), 2.95-2.85 (m, 3H), 2.50-2.46 (s, 3H), 1.28-1.26 (d, J = 6 Hz 3H).

Step-9: Synthesis of I-1002 [0265] To a stirred solution of compound I-1001 (100 mg, 0.278 mol) in methanol (10 mL) was added formaldehyde (16 mg, 0.533 mol) followed by sodium cyanoborohydride (36 mg, 0.573 mol) and catalytic amount of acetic acid (0.2 mL). Reaction was monitored by TLC; after completion of reaction, solvent was evaporated then reaction mixture was quenched in water and (10 mL) extracted with DCM (2x10 mL). Organic layer was concentrated and washed with pentane. Crude was purified by preparative HPLC to afford compound I-1002 as white solid (20 mg, Yield: 11.8%). [0266] LCMS: m/z: 387.19[M+H] ⁺ , 96.76% (1.34 min). [0267] Method: Column: Acquity BEH C ₁ 8 (2.1 x 50 mm, 1.7 μm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90), Flow Rate: 0.4 mL/min. [0268] ¹ H NMR [400 MHz, DMSO-d ₆ ]: 9.20 (s, 1H), 8.65-8.65(d, J = 3.2 Hz, 1H), 8.14 (s, 1H), 7.36-7.35 (d, J = 7.2 Hz, 2H), 7.21-7.05 (m, 5H), 3.10-3.05 (m, 1H), 2.70-2.69 (s, 3H), 2.46 (s, 3H), 2.36 (s, 3H), 1.289-1.235 (d, J = 5.4 Hz, 3H). Scheme 2: Synthesis of I-1003, I-1004, I-1005, I-1006, and I-1007

Step-1: [0269] To a stirred solution of compound 1 (20 g, 0.099 mol) in DCM (200 mL) was added oxalyl chloride (25.4 mL, 0.297 mol) followed by DMF (2 mL) at 0 °C. Then the reaction mixture allowed to stir at room temperature for 3h. Completion of the reaction was monitored by TLC; after completion of reaction, solvent was evaporated by reduced pressure under N ₂ atmosphere. The resulting crude dissolved in DCM (50 mL) and added to a solution of compound 2 (10.8 g, 0.079 mol) in DCM (150 mL) and TEA (41 mL, 0.297 mol) at 0 °C. The resulting mixture stirred at rt for 18h. Completion of the reaction was monitored by TLC; after completion, reaction mass diluted with DCM (1L) and washed with water (500 mL), brine solution (500 mL). Organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (20% EtOAc in hexane as an eluent) to afford compound 3 (26 g, Yield: 89%) as brown solid. [0270] LCMS: m/z: 321.26 [M+2] ⁺ , 95.27 % (1.40 min). [0271] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-2: [0272] To a stirred solution of compound 3 (25 g, 0.077 mol) in DMF (250 mL) was added NaH (60% , 9.3 g, 0.233 mol) at 0 °C and stirred for 30 min. PMB-Cl (15.7 mL, 0.116 mol) was added at same temperature. The resulting reaction mixture was allowed to stirred at room temperature for 3h. Completion of the reaction was monitored by TLC; after completion, reaction mass poured into ice cold water, obtained solid was filtered off and washed with water (200 mL). The solid was dissolved in ethyl acetate (500 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was triturated with ether and filtered to afford compound 4 (20 g, Yield: 58.8%) as pale brown solid. [0273] LCMS: m/z: 442.10 [M+H] ⁺ , 97.91 % (1.72 min). [0274] Method:Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10,1.5/90, 3/90), Flow Rate: 0.4 mL/min. Step-3: [0275] To a stirred solution of compound 4 (20 g, 0.045 mol) in DMA (200 mL) was added potassium acetate (17.6 g, 0.180 mol) and Pd(P ^t Bu3) ₂ (1.4 g, 0.002 mol) at room temperature. The resulting mixture degassed with nitrogen for 20 min and heated at 150 ^o C for 4h. Completion of the reaction was monitored by TLC; after completion, reaction mass poured into ice cold water, obtained solid was filtered off and washed with water (100 mL). The solid was re-dissolved in ethyl acetate (500 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was triturated with ether and filtered to afford compound 5 (10 g, Yield: 61%) as brown solid. [0276] LCMS: m/z: 241.16 [M+1] ⁺ , 79.90 % (1.20 min). [0277] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-4: Synthesis of I-1003 [0278] Compound 5 (10 g, 0.027 mol) was suspended in TFA (100 mL) in a sealed tube at room temperature. The resulting reaction mixture sitter at 100 °C for 16h. Completion of the reaction was monitored by TLC; after completion of the reaction solvent was evaporated under reduced pressure. The resulting residue was quenched with water, basified using sat NaHCO ₃ solution and extracted with 10% MeOH in DCM (500 mL). The organic layer washed with water (300 mL), brine (300 mL) and dried over Na ₂ SO ₄ and concentrated in vacuo. The crude compound was triturated with ether, filtered and dried to afford I-1003 (4 g, Yield: 59%) as brown solid. [0279] LCMS: m/z: 241.13 [M+H] ⁺ , 98.06 % (1.96 min). [0280] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) Flow Rate: 0.4 mL/min. [0281] ¹ H NMR [400 MHz, DMSO-d ₆ ]: 10.90 (s, 1H), 9.92 (s, 1H), 8.80 (d, J = 4.8 Hz, 1H), 8.12 (d, J = 5.2 Hz, 1H), 7.92 (d, J = 1.6 Hz, 1H), 7.05 (d, J = 1.6 Hz, 1H), 3.87 (s, 3H), 2.46 (s, 3H). Step-5: Synthesis of I-1004 [0282] To a stirred suspension of I-1003 (2.5 g, 10.416 mmol) in conc. H ₂ SO ₄ (25 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (2.9 g, 10.416 mmol) at 0 °C and stirred at same temperature for 2h. Completion of the reaction was monitored by LCMS; after completion reaction mass was poured into crushed ice, obtained solid was filtered off. The solid was re- dissolved in 10% MeOH in DCM (100 mL) dried over anhydrous Na ₂ SO _4, filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (40% EtOAc in hexane as eluent) to afford I-1004 (1.4 g, Yield: 42%) as brown solid. [0283] LCMS: m/z: 320.94 [M+2H] ⁺ , 91.80 % (2.22 min). [0284] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90), Flow Rate: 0.4 mL/min. [0285] ¹ H NMR [400 MHz, DMSO-d ₆ ]: 10.89 (s, 1H), 10.74 (s, 1H), 8.81 (d, J = 4.8 Hz, 1H), 8.17 (d, J = 4.8 Hz, 1H), 7.33 (s, 1H), 3.88 (s, 3H), 2.43 (s, 3H). Step-6: [0286] To a stirred solution of compound I-1004 (1.5 g, 4.716 mmol) in 1,4-dioxane (30 mL), water (3 mL), compound 6 (2.55 g, 7.075 mmol) and K ₂ CO ₃ (1.95 g, 14.148 mmol) were added in a sealed tube. The reaction mixture degassed with nitrogen for 10 minutes and added Pd-118 (154 mg, 0.235 mmol) again degassed for 10 min. Then the resulting reaction mixture was stirred at 85 ^o C for 15h. Completion of the reaction was monitored by TLC; after completion reaction mass quenched with ice cold water and extracted with ethyl acetate (2x200 mL). The organic layer was washed with brine solution (200 mL) dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (30% EtOAc in Hexane as an eluent) to afford compound 7 (280 mg, Yield: 54.6%) as a white solid. [0287] LCMS: m/z: 474.44 [M+H] ⁺ , 40 % (1.57 min). [0288] Method:Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90), Flow Rate: 0.4 mL/min. Step-7: Synthesis of I-1005 [0289] To a stirred solution of compound 7 (200 mg, 0.422 mmol) in 1,4-dioxane (2 mL) was added 4M HCl in dioxane (2 mL) at 0 ^o C then reaction mixture was stirred at rt for 4h. Reaction was monitored by TLC; after completion of reaction, reaction mixture poured into ice cold water and basified using sat NaHCO ₃ and extracted with 10% MeOH in DCM. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Crude compound was triturated with acetonitrile and filtered to afford I-1005 (80 mg, Yield: 50.9%) as a pale brown solid. [0290] LCMS: m/z: 374.24 [M+H] ⁺ , 97.82% (1.47 min). [0291] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) Flow Rate: 0.4 mL/min. [0292] ¹ H NMR [400 MHz, DMSO-d ₆ ]: 8.54 (d, J = 4.8 Hz, 1H), 8.36 (brs, 1H), 8.08 (t, J = 3.2 Hz, 2H), 7.38 (d, J = 8 Hz, 2H), 7.33 (s, 1H), 7.21 (d, J = 8 Hz, 2H), 3.70 (s, 3H), 2.93-2.85 (m, 3H), 2.56 (s, 2H), 1.32 (d, J = 6 Hz, 3H). Step-8: Synthesis of I-1006: [0293] Compound I-1005 (250 mg, 0.670 mmol) was suspended in 37% HBr in AcOH (2.5 mL) at rt. The resulting reaction mixture heated at 100 °C for 3h. Completion of the reaction was monitored by LCMS; after completion of reaction, excess HBr solution evaporated. The resulting crude was dissolved in water and washed with 10% MeOH in DCM (10 mL). The aqueous layer was purified by reverse phase combi flash column chromatography (0.1% aq formic acid and ACN as eluent and lyophilized) to afford I-1006 (30 mg, Yield: 12%) as off-white solid. [0294] LCMS: m/z: 360.18 [M+H] ⁺ , 96.66% (1.30 min). [0295] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90), Flow Rate: 0.4 mL/min. [0296] ¹ H NMR [400 MHz, DMSO-d ₆ ]: 8.52 (d, J = 5.2 Hz, 1H), 8.34 (s, 1H), 8.17 (s, 1H), 8.08 (d, J = 5.6 Hz, 1H), 7.39-7.36 (m, 2H), 7.22 (d, J = 8 Hz 2H), 7.07 (s, 1H), 2.95-2.88 (m, 3H), 2.45 (s, 3H), 1.32 (d, J = 6.4 Hz, 3H). Step-9: Synthesis of I-1007 [0297] To a stirred solution of I-1006 (25 mg, 0.069 mmol) in MeOH (3 mL) was added formaldehyde (12 mg, 0.139 mmol), sodium cyanoborohydride (9 mg, 0.139 mmol) and 2 drops of acetic acid. The reaction mixture stirred at room temperature for 15h. Completion of the reaction was monitored by LCMS; after completion, solvent was evaporated under reduced pressure. The residue was dissolved in DCM (5 mL) and washed with water (5 mL), brine solution (5 mL). The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Crude was purified by reverse phase combi flash column chromatography (0.1% aq formic acid and ACN as eluent and lyophilized) to afford I-1007 (4 mg, Yield: 14.8%) as off-white solid. [0298] LCMS: m/z: 388.23 [M+1] ⁺ , 95.12% (1.37 min). [0299] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90), Flow Rate: 0.4 mL/min. [0300] ¹ H NMR [400 MHz, DMSO-d ₆ ]: 10.77 (s, 1H), 10.25 (s, 1H), 8.52 (d, J = 6.8 Hz, 1H), 8.19 (d, J = 12 Hz, 1H), 8.08 (d, J = 5.2 Hz, 1H), 7.36-7.34 (m, 2H), 7.19-7.16 (m, 2H), 7.06 (s, 1H), 3.01 (q, J = 7.2 Hz, 1H), 2.44 (s, 3H), 2.20 (s, 6H), 1.25 (d, J = 6.8 Hz, 3H). Scheme 3: Synthesis of I-1008, I-1009, and I-1010 Step-1: [0301] To a stirred solution of compound 1 (25 g, 123.7 mol) in DCM (250 mL) was added EDC. HCL (23.7 g.123.7 mol) and compound 2 (23.7 g.0.173.2 mol) was added slowly. The resulting reaction mixture was allowed to stir at room temperature for 16h. Completion of the reaction was monitored by TLC and after completion, the reaction mass was diluted with DCM (1L) and washed with water (500 mL), brine solution (500 mL), and organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Crude compound was purified by column chromatography using silica gel (100: 200 mesh) and compound was eluted using 5% EtOAc in Hexane to afford compound 3. (18 g, Yield: 50%) as a pale brown solid. [0302] LCMS: m/z = 323.14 [M+2] ⁺ , 62.73% (1.23 min). [0303] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-2: [0304] To a stirred solution of compound 3 (28.6 g, 0.089 mol) in DMF (280 mL) was added NaH (60%, 13 g, 0.267 mol) at 0 ^o C and stirred for 20 min. PMB-Cl (18.1 mL, 0.133 mol) added at same temperature. The resulting reaction mixture allowed to stir at rt for 5h. Completion of the reaction was monitored by TLC and after completion of the reaction, the reaction mixture quenched with saturated aq. NH4Cl solution and extracted with EtOAc (2x1L). The organic layer washed with water (500 mL), brine solution (500 mL), dried over Na ₂ SO _4, filtered and concentrated in vacuo to afford crude compound as brown gum. Crude compound was purified by column chromatography using a silica gel (100: 200 mesh) and compound was eluted using 10% EtOAc in Hexane to afford compound 4 (24.1 g, Yield: 69%) as a pale brown solid. [0305] LCMS: m/z = 443.17 [M+2] ⁺ , 47.99% (1.55 min). [0306] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-3: [0307] To a stirred solution of compound 4 (16.1 g, 0.036 mol) in DMA (160 mL) KOAc was added (14.3 g, 0.146 mol) followed by Pd(P ^t Bu ₃ ) ₂ (1.1 g, 0.002 mol) at room temperature. The reaction mixture degassed with nitrogen for 20 min, then heated to 150 °C and stirred for 4h. Completion of the reaction was monitored by TLC, after completion, reaction mixture poured crushed into ice and filtered the solid. The solid was dissolved in 10% MeOH in DCM (1L), washed with brine solution (500 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was triturated with Ether, filtered and dried to afford pure compound 5 as off- white solid. (10.1 g, Yield: 77%) as a pale brown solid. [0308] LCMS: m/z = 361.23 [M+1] ⁺ , 92.58 % (1.40 min). [0309] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-4: [0310] Trifluoroacetic acid (120 mL) was added to the compound 5 (12 g, 0.050 mol) in a sealed tube at room temperature. The resulting mixture heated to 100°C and stirred for 16h. Completion of the reaction was monitored by TLC, LCMS which shows completion of the reaction. Crude compound was purified by column chromatography using a silica gel (100: 200 mesh) and compound was eluted using 20% EtOAc in Hexane to afford compound 6 (9 g, Yield: 50%) as an off white solid. [0311] LCMS: m/z = 241.16 [M+1] ⁺ , 45.68% (1.22 min). [0312] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-5: [0313] To a stirred solution of compound 6 (1 g, 0.004 mol) in H ₂ SO ₄ (10 mL) was added 1,3- dibromo-5,5-dimethylhydantoin (DBDMH) (1.1 g, 0.004 mol) at 0 °C. The resulting mixture was stirred at room temperature for 3h. Completion of the reaction was monitored by TLC and LCMS. After completion, reaction mass poured into crushed ice and extracted with EtOAc. The organic layer was washed with sat. NaHCO ₃ , water and brine solution and dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was triturated with ether, filtered and dried to afford compound 7 as brown solid. (500 mg, Yield: 40%) as an off white solid. [0314] LCMS: m/z = 320.96 [M+2H] ⁺ , 74.93 % (1.33 min). [0315] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-6: [0316] To a stirred solution of compound 7 (400 mg, 1.257 mmol) and compound 8 (683 mg, 1.886 mmol) in Dioxane (16 mL) and water (1 mL) was added K2CO ₃ (520 mg, 3.773 mmol), Pd-118 (40 mg, 0.062 mmol) at room temperature. The resulting reaction mixture degassed with nitrogen for 10 min. Then the reaction mixture heated to 150 °C and stirred for 30 min. Completion of the reaction was monitored by TLC and LCMS. Crude was washed with n- pentane and ether to afford compound 9 (280 mg, Yield: 50%) as a pale brown solid. [0317] LCMS: m/z = 474.08 [M+1] ⁺ , 14.16 % (1.92 min). [0318] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-7: Synthesis of I-1008 [0319] To a stirred solution of compound 9 (900 mg, 1.898 mmol) in 1,4-dioxane (10 mL) was added 4M HCl in dioxane (10 mL) at 0 ^o C then reaction mixture was stirred at rt for 2h. Reaction was monitored by TLC; after completion of reaction mixture was diluted with water and washed with ethyl acetate (2x300 L). Aqueous layer was quenched with aq. NaHCO ₃ and extracted with 10% MeOH in DCM (2x200 mL). Organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude compound was purified by column chromatography using silica gel (100: 200 mesh) and compound was eluted using 10% EtOAc in hexane to afford I-1008 (500 mg, Yield: 70%) as an off white solid. [0320] LCMS: m/z: 373.17[M+H] ⁺ , 93.11% (1.51 min). [0321] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90), Flow Rate: 0.4 mL/min. [0322] ¹ H NMR [400 MHz, DMSO-d6]: 8.53-8.51 (m, 1H), 8.39 (s, 1H),7.41 (m, 1H), 7.32 (s, 1H), 7.166 (d, J = 6 Hz, 2H), 7.00 (m, 2H), 33.63 (s, 3H), 2.92-2.85 (m, 3H), 2.67 (s, 3H), 1.30- 1.23 (m, 4H). Step-8: Synthesis of I-1009 [0323] To a stirred solution of compound I-1008 (100 mg, 0.268 mmol) was added HBr in AcOH (2 mL) at 0 ^o C then reaction mixture was stirred at 100 ⁰ C for 15h. Reaction was monitored by TLC. Reaction mixture was evaporated to afford crude compound was purified by column chromatography using a silica gel (100:200 mesh) and compound was eluted using 10% EtOAc in Hexane to afford compound I-1009 (20 mg, Yield: 20%) as an off white solid. [0324] LCMS: m/z: 359.16[M+H] ⁺ , 92.24 % (1.45min). [0325] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90), Flow Rate: 0.4 mL/min. [0326] ¹ H NMR [400 MHz, DMSO-d ₆ ]: 8.532 (m, 1H), 8.366 (s, 1H), 8.255 (m, 1H), 7.395 (m, 1H), 7.183 (d, J = 8 Hz, 2H), 7.084 (s, 1H), 7.021 (d, J = 8.4 Hz, 2H), 3.415 (s, 1H), 2.951-2.912 (t, J = 15.6 Hz, 3H), 2.553-2.453 (m, 3H), 1.301 (t, J = 3.2 Hz, 2H). Step-9: Synthesis of I-1010 [0327] To a stirred solution of compound I-1009 (30 mg, 0.083 mmol) in methanol (1 mL) was added formaldehyde (0.1 mL) followed by sodium cyanoborohydride (10 mg, 0.167 mmol) and catalytic amount of acetic acid (0.1 mL). Reaction was monitored by TLC; after completion of reaction solvent was evaporated, then reaction mixture was quenched in water and extracted with DCM (2x5 mL). Organic layer was concentrated and washed with pentane. Crude was purified by preparative HPLC to afford I-1010 (10 mg, Yield: 35%) as white solid. [0328] LCMS: m/z: 387.19[M+H] ⁺ , 94.42 % (1.46 min). [0329] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90), Flow Rate: 0.4 mL/min. [0330] ¹ H NMR [400 MHz, DMSO-d6]: 10.62 (s, 1H), 8.97 (s, 1H), 8.52 (m, 1H), 8.32 (m, 1H), 7.13 (m, 1H), 7.39-733 (m, 1H), 7.13 (d, J = 8 Hz, 2H), 7.07 (s, 1H), 6.95 (d, J = 8.1 Hz, 2H), 2.95-2.89 (m, 1H), 2.50-2.39 (s, 5H), 2.18 (s, 6H), 1.24 (d, J = 6.8 Hz, 2H).

Scheme 4: Synthesis of II-1001, II-1002, and II-1003 Step-1: [0331] To a stirred solution of compound 1 (10 g, 44.44 mmol) in DCM (100 mL) was added Oxalyl chloride (8.4 mL, 133.32 mmol) at 0 ⁰ C then reaction mixture was stirred at room temperature for 4h. Reaction was monitored by TLC; after completion of reaction solvent was evaporated by reduced pressure and crude was used for next step without purification. Acid chloride solution was dissolved in DCM (100 mL) was added compound 2 (4.9 g, 35.55 mmol) followed by TEA (9 mL, 88.88 mmol), then reaction mixture was stirred at rt for 16h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with DCM (2x500 mL), organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude compound was purified by column chromatography using silica gel (100: 200 mesh). Compound was eluted using 10% EtOAc in Hexane to afford compound 3 (7 g, Yield: 48%) as a white solid. [0332] LCMS: m/z: 329.01 [M+2] ⁺ , 98.46 % (1.47 min). [0333] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-2: [0334] To a stirred solution of compound 3 (6 g, 18.340 mol) in DCM (200 mL) was added DMAP (1.9 g, 9.170 mol) at 0 ^o C followed by (Boc) ₂ O (5.9 g, 27.570 mmol) then reaction mixture was stirred at room temperature for 18h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with DCM (2x500 mL). Organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude compound was purified by column chromatography using silica gel (100: 200 mesh) and compound was eluted using 10% EtOAc in Hexane to afford compound 4 (6 g, Yield: 77%) as a white solid. [0335] LCMS: m/z: 429.06 [M+2H] ⁺ , 97.08 % (1.76 min). [0336] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-3: [0337] To a stirred solution of compound 4 (3 g, 7.020 mmol) in DMA (30 mL) was added potassium acetate (2.75 g, 28.080 mmol) followed by Pd(P ^t Bu ₃ ) ₂ catalyst (215 mg, 0.421 mmol) then reaction mixture was stirred at 150 ^o C for 4h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with ethyl acetate (2x300 mL), organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound 5. Crude compound was purified by column chromatography using silica gel (100: 200 mesh) and compound was eluted using 20% EtOAc in Hexane to afford compound 5 (1 g, Yield: 58%) as a white solid. [0338] LCMS: m/z: 247.13 [M+H] ⁺ , 95.22 % (1.15 min). [0339] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-4: [0340] To a stirred solution of compound 5 (2 g, 8.33 mmol) in DCM was added NBS (1.76 g, 9.9 mmol) at 0 ^o C then reaction mixture was stirred at room temperature for 18h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with DCM (2x200 mL), organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude compound was washed with pentane and ether to afford compound 6 (1 g, Yield: 39%) as a white solid. [0341] LCMS: m/z: 326.98 [M+2H] ⁺ , 42.02 % (1.50 min). [0342] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-5: [0343] To a stirred solution of compound 6 (500 mg, 1.53 mmol) in Dioxane (20 mL) solution was added compound 7 (1.13g, 3.07 mmol) followed by NaHCO ₃ (385 mg, 4.59 mmol). Reaction mixture was degassed for 15 minutes, then Pd(dppf)Cl2 catalyst (112 mg, 0.053 mmol) was added and again degassed for 10 minutes. The reaction mixture was stirred at 85 ^o C for 15h. Reaction was monitored by LCMS. Reaction mixture was poured into ice cold water and extracted with ethyl acetate (2x100 mL). Organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude compound was purified by column chromatography using a silica gel (100: 200 mesh). Compound was eluted using 20% EtOAc in Hexane to afford pure compound 8 (60 mg, Yield: 8%) as a white solid. [0344] LCMS: m/z: 480.28 [M+1H] ⁺ , 24.36 % (1.72 min). [0345] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-6: Synthesis of II-1001 [0346] To a stirred solution of compound 8 (500 mg, 1.04 mmol) in 1,4-dioxane (5 mL) was added 4M HCl in dioxane (2.5 mL) at 0 ^o C then reaction mixture was stirred at rt for 15h. Reaction was monitored by TLC; after completion of reaction, reaction mixture was diluted with water and washed with ethyl acetate (2x100 mL). Aqueous Layer Was quenched with aq. NaHCO ₃ and extracted with 10% MeOH in DCM (2x100 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude compound was purified by column chromatography using silica gel (100: 200 mesh). Compound was eluted using 10% EtOAc in Hexane to afford II-1001 (10 mg, Yield: 17.2 %) as a white solid. [0347] LCMS: m/z: 380.20 [M+H] ⁺ , 96.20% (1.48 min). [0348] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90), Flow Rate: 0.4 mL/min. [0349] ¹ H NMR [400 MHz, DMSO-d6]: 7.767 (s, 1H), 7.2 (d, J = 12.8 Hz, 2H), 7.19 (d, J = 7.2 Hz, 2H), 3.78 (s, 2H), 2.67 (s, 3H), 1.29-1.23 (m, 4H), 1.29 (t, J = 6 Hz, 3H).

Step-7: Synthesis of II-1002: [0350] To a stirred solution of compound II-1001 (300 mg, 0.791 mmol) was added Hydrogen bromide (3 mL) at 0 ^o C then reaction mixture was stirred at 100 ⁰ C for 16h. Reaction was monitored by TLC. reaction mixture was poured into ice water. Water layer directly concentrated and purified by reverse-phase C-18 using acetonitrile/water (with 0.01% HCOOH) to afford II- 1002 (11 mg, Yield: 2.6 %) as a white solid. [0351] LCMS: m/z: 365.12[M+H] ⁺ , 98.52% (1.20 min). [0352] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90), Flow Rate: 0.4 mL/min. [0353] ¹ H NMR [400 MHz, DMSO-d ₆ ]: ¹ H NMR [400 MHz, DMSO-d ₆ ]: 8.32 (s, 1H), 7.7 (d, J = 9.2 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 5.91 (d, J = 5.91 Hz, 2H) ,2.95-2.90 (m, 3H), 2.60 (s, 3H), 1.30-1.279 (m, 3H). Step-8: Synthesis of II-1003 [0354] To a stirred solution of compound II-1002 (100 mg, 0.27 mmol) in methanol (5 mL) was formaldehyde (16.4 mg, 0.54 mmol) followed by sodium cyanoborohydride (34.2 mg, 0.547 mmol) and catalytic amount of acetic acid (one drop). Reaction was monitored by TLC; after completion of reaction, solvent was evaporated then reaction mixture was quenched in water and extracted with DCM (2x10 mL). Organic layer was concentrated and washed with pentane. Crude was purified using reverse phase C-18 using acetonitrile/water (0.01% FA) to afford II- 1003 (8 mg, Yield: 7.4%) as an off white solid. [0355] LCMS: m/z: 393.12 [M+H] ⁺ , 96.92% (1.49 min). [0356] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90), Flow Rate: 0.4 mL/min. [0357] ¹ H NMR [400 MHz, DMSO-d ₆ ]: ¹ H NMR [400 MHz, DMSO-d ₆ ]: 8.32 (s, 1H), 7.7 (d, J = 9.2 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 5.91 (d, J = 5.91 Hz, 2H) ,2.95-2.90 (m, 3H), 2.60 (s, 3H), 2.32 (s, 6H), 1.30-1.279 (m, 3H). Scheme 5: Synthesis of I-1012, I-1013, and I-1014

Step-1: [0358] To a stirred solution of compound 1 (20 g, 0.099 mol) in DCM (200 mL) was added Oxalyl chloride (25 mL, 0.297 mol) then reaction mixture was stirred at room temperature for 18h. Reaction was monitored by TLC; after completion of reaction solvent was evaporated by reduced pressure and crude was used for next step without purification. Acid chloride was dissolved in DCM (200 mL) was added compound 2 (10.9 g, 0.079 mmol) followed by TEA (27 mL, 0.099 mol) then reaction mixture was stirred at RT for 18h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with DCM (2x500 mL), organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude compound was purified by column chromatography using a silica gel (100: 200 mesh) and compound was eluted using 10% EtOAc in Hexane to afford compound 3 (14 g, Yield: 45%) as an off white solid. [0359] LCMS: m/z = 323.09 [M+2H] ⁺ , 80.29 % (1.32 min). [0360] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-2 [0361] To a stirred solution of compound 3 (10 g, 0.041 mol) in DMF (50 mL) was added NaH (2.9 g, 0.124 mol) at 0 ^o C followed by PMB-Cl (8.4 mL, 0.062 mol) then reaction mixture was stirred at room temperature for 5h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with DCM (2x500 mL), organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude compound was purified by column chromatography using silica gel (100: 200 mesh) compound was eluted using 10% EtOAc in hexane. Compound was eluted using 10% EtOAc in Hexane to afford compound 4 (8 g, Yield: 58%) as an off white solid. [0362] LCMS: m/z = 323.09 [M+2H] ⁺ , 80.29 % (1.32 min). [0363] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-3 [0364] To a stirred solution of compound 4 (20 g, 0.045 mol) in DMA (200 mL) was added potassium acetate (25 g, 0.181mol) followed by Pd(P ^t Bu ₃ ) ₂ , catalyst (1.39 g, 0.002 mol) then reaction mixture was stirred at 150 ^o C for 16h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with ethyl acetate (2x500 mL), organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude compound was purified by column chromatography using silica gel (100: 200 mesh) and compound was eluted using 10% EtOAc in Hexane to afford compound 5 (11 g, Yield: 68.75%) as an off white solid. [0365] LCMS: m/z = 241.10 [M+2] ⁺ , 17.51 % (1.26 min). [0366] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-4 [0367] To a stirred solution of compound 5 (23 g, 0.063 mol) in TFA stirred at 100 ^o C for 18h. Reaction was monitored by TLC; after completion of reaction mixture was diluted with ice water and quenched with aq. NaHCO ₃ and extracted with DCM (3x500 mL), organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude compound was purified by column chromatography using silica gel (100: 200 mesh) and compound was eluted using 10% EtOAc in Hexane to afford compound 6 (7 g, Yield: 46.6%) as an off white solid. [0368] LCMS: m/z: 240.09[M+H] ⁺ , 96.44 % (1.27min). [0369] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90), Flow Rate: 0.4 mL/min. Step-5 [0370] To a stirred solution of compound 6 (1 g, 0.004 mol) in DCM-AcOH (50 mL, 1:1) was added NBS (2.2 g, 0.124 mol) at 0 ^o C then reaction mixture was stirred at room temperature for 18h. Reaction was monitored by TLC. Reaction mixture was poured into ice cold water and extracted with DCM (2x200 mL), organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude was washed with n-pentane and ether to afford compound 7 (500 mg, Yield: 38%) as a pale brown solid. [0371] LCMS: m/z = 321.04 [M+2H] ⁺ , 34.72% (1.55 min). [0372] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 6: [0373] To a stirred solution of compound 7 (500 mg, 1.560 mmol) in Dioxane (5 mL) solution was added compound 8 (848 mg, 2.340 mmol) followed by K2CO ₃ (636 mg, 4.680 mmol). Reaction mixture was degassed for 15 minutes then Pd118 catalyst (101 mg, 0.156 mmol) was added and again degassed for 10 minutes then reaction mixture was stirred at 85 ^o C for 16h. After completion, the reaction mixture was poured into ice cold water and extracted with ethyl acetate (2x100 mL). Organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated to afford crude compound. Crude compound was purified by column chromatography using silica gel (100: 200 mesh) and compound was eluted using 20% EtOAc in Hexane to afford compound 9 (22 mg, Yield: 4.5%) as an off white solid. [0374] LCMS: m/z = 474.22 [M+1H] ⁺ , 22.90% (1.75 min). [0375] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 7: Synthesis of I-1012 [0376] To a stirred solution of compound 9 (500 mg, 1.04 mmol) in 1,4-dioxane (5 mL) was added 4N HCl in dioxane (2.5 mL) at 0 ^o C then reaction mixture was stirred at room temperature for 15h. Reaction was monitored by TLC; after completion of reaction, reaction mixture was diluted with water and washed with ethyl acetate (100 mL). Aqueous layer was quenched with aq. NaHCO ₃ and extracted with 10% MeOH in DCM (2x100 mL). Organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound I-1012 (80 mg, Yield: 20%) as a pale brown solid. [0377] LCMS: m/z: 473.45 [M+H] ⁺ , 95.13 % (2.86 min). [0378] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90), Flow Rate: 0.4 mL/min. [0379] ¹ H NMR [400 MHz, DMSO-d ₆ ]: 8.35 (s, 1H), 7.68 (d, J = 5.2 Hz, 1H), 7.36 (m, J = 7.2 Hz, 2H), 7.26-7.18 (m, 3H), 6.95-6.92 (m, 1H), 3.77 (s, 3H), 2.79-255 (m, 6H), 1.29-1.27 (m, 3H). Step 8: Synthesis of I-1013 [0380] To a stirred solution of compound I-1012 (100 mg, 0.268 mmol) was added Hydrogen bromide (0.2 mL) at 0 ^o C then reaction mixture was stirred at 100 ⁰ C for 16h. Reaction was monitored by TLC. After completion of reaction, solvent was evaporated then reaction mixture was quenched in water. Water layer was purified by reverse-phase C-18 column chromatography to afford compound I-1013 (6 mg, Yield: 8%) as a pale brown solid. [0381] LCMS: m/z: 359.16[M+H] ⁺ , 83.03% (1.85 min). [0382] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90), Flow Rate: 0.4 mL/min. [0383] ¹ H NMR [400 MHz, DMSO-d6]: 8.35 (s, 1H), 7.68 (d, J = 5.2 Hz, 1H), 7.36 (m, J = 7.2 Hz, 2H), 7.26-7.18 (m, 3H), 6.95-6.92 (m, 1H), 3.77 (s, 3H), 2.79-255 (m, 3H), 1.29-1.27 (m, 3H). Scheme 6: Synthesis of II-1004 and II-1005: Step 1: [0384] To a stirred solution of compound 1 (30 g, 0.194 mol) in DMF (300 mL) was added NBS (41.5 g, 0.233 mol) at 0 °C. The resulting mixture stirred at 60 ⁰ c for 16h. Completion of the reaction was monitored by TLC. After completion, reaction mass extracted with EtOAc (2x1L). Organic layer washed with sat. NaHCO ₃ (1L) _, water (1L) and brine (1L) solution. The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was triturated with ether, filtered and dried to afford to afford compound 2 as brown solid (34.9 g, Yield: 77.55%) as an off white solid. [0385] LCMS: m/z: 234.79 [M+2H] ⁺ , 90.21 % (1.07 min). [0386] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 2: [0387] To a stirred solution of compound 2 (34.9 g, 0.149 mol) in POCl3 (137 mL, 1.497 mol) at room temperature, then reaction mixture was stirred at 100 ^o C for 3h. Reaction was monitored by TLC; after completion of reaction mixture was diluted with ice water (500 mL) and quenched with aq NaHCO ₃ and extracted with DCM (2x500 mL). Organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound 3 which used for the next step without any purification. [0388] LCMS: m/z: 252.86 [M+2] ⁺ , 93.29 % (1.54 min). [0389] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 3: [0390] To a stirred solution of compound 3 (28 g, 0.111 mol) in MeOH (280 mL) was added Sodium methoxide (7.5 g,0.140 mol) at 0 °C. The resulting was mixture stirred at 80 ^o C for 2h. Completion of the reaction was monitored by TLC. After completion, reaction mass reaction mixture was evaporated under vacuum than extracted with EtOAc and water. Organic layer washed with brine solution. The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was triturated with ether, filtered and dried to afford compound 4 (20 g, Yield: 74.0%) as brown solid. [0391] LCMS: m/z: 247.21 [M+1] ⁺ , 88.32 % (1.62 min). [0392] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 4: [0393] To a stirred solution of compound 4 (2 g, 0.009 mol) and compound 5 (3.5 g, 0.009 mol) in Dioxane (20 mL) and water (2 mL) was added K2CO ₃ (3.3 g, 0.024 mol), Pd-118 (264 mg, 0.024 mmol) at room temperature. The resulting reaction mixture degassed with nitrogen for 10 min. Then the reaction mixture heated to 90 °C and stirred for 6h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with ethyl acetate (2x100 mL), organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound 6. Crude compound was purified by column chromatography using a silica gel (100: 200 mesh) compound was eluted using 20% EtOAc in Hexane to afford compound 6 (2 g, Yield: 66.0%) as a white solid. [0394] LCMS: m/z: 346.10 [M-BOC] ⁺ , 83.25 % (1.88 min). [0395] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90), Flow Rate: 0.4 mL/min. Step 5: [0396] To a stirred solution of compound 6 (4 g, 0.010 mol) in THF (20 mL) and water (6.8 ml) was added Iron Powder (5 g,0.050 mol) and NH ₄ Cl (6.7 g,0.107 mol) at room temperature. The resulting mixture stirred at 80 ^o C for 10 h. Completion of the reaction was monitored by TLC. After completion, reaction mass reaction mixture was filter and pass the celite and evaporated under vacuum than extracted with EtOAc and water. Organic layer washed with brine solution. The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was used for next step. (2 g, Yield: 50 %) as a white solid. [0397] LCMS: m/z: 372.24 [M+1] ⁺ , 79.48 % (1.53 min). [0398] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 6: [0399] To a stirred solution of compound 7 (2.6 g, 0.010 mol) in MeOH (30 mL) was added AcOH (2 mL) followed compound 8 (1.4 mL, 0.011 mol) at rt. The resulting reaction mixture allowed to stir at room temperature for 1h, then NaBH ₄ (785 mg, 0.021 mmol) was added slowly at 0 ^o C. The resulting reaction mixture allowed to stir at room temperature for 2h. Completion of the reaction was monitored by TLC, after completion, reaction mass directly evaporated under vacuo than extracted with DCM and water, washed with brine solution. Organic layer dried over Na ₂ SO _4, filtered and concentrated in vacuo. The crude compound was purified by silica gel (100- 200 mesh) column chromatography (5-7% ethyl acetate in hexane as eluent) to afford pure compound 9 obtained as a white solid and it was used for next step (2.3 g, Yield: 69.69%). [0400] LCMS: m/z: 492.58 [M+1H] ⁺ , 21.49 % (1.92 min). [0401] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 7: [0402] To a stirred solution of compound 9 (2.3 g, 0.004 mol) in DCM (25 mL) was added TEA (8 mL, 0.014 mmol) at rt. Compound 10 (1.1 g, 0.004 mmol) added at 0 ^o C. The resulting reaction mixture allowed to stir at room temperature for 3h. Completion of the reaction was monitored by TLC, after completion, reaction mass diluted with DCM (200 mL) and washed with water (100 mL), aqs NaHCO ₃ solution (100 mL) and brine solution (100 mL). Organic layer dried over Na ₂ SO ₄ , filtered and concentrate in vacuo. Crude compound was purified by column chromatography using a silica gel (100: 200 mesh) compound was eluted using 10% EtOAc in Hexane to afford compound 11 (1.5 g, Yield: 46%). [0403] LCMS: m/z: 706.09 [M+2] ⁺ , 25.16 % (1.89 min). [0404] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 8: [0405] To a stirred solution of compound 11 (2.2 g, 0.003 mol) in DMA (22 mL) was added KOAc (1.2 g, 0.012 mol), Pd(P ^t Bu ₃ ) ₂ (950 mg, 0.0001 mol) at room temperature. The reaction mixture degassed with nitrogen for 20 min, then heated at 150 °C and stirred for 4h. Completion of the reaction was monitored by TLC, after completion, reaction mixture poured crushed into ice and filtered the solid. The solid was dissolved in 10% MeOH in DCM (100 mL), washed with brine solution (100 mL), dried over Na ₂ SO _4, filtered and concentrated in vacuo. The crude compound was triturated with ether, filtered and dried to afford pure compound 12 as an off- white solid (400 mg, Yield: 25%). [0406] LCMS: m/z: 624.26 [M+1] ⁺ , 42.28% (1.32 min). [0407] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 9: [0408] Trifluoroacetic acid (3 mL) was added to the compound 12 (280 mg, 0.449 mmol) in a sealed tube at room temperature. The resulting mixture heated to 100 °C and stirred for 16h. Completion of the reaction was monitored by TLC, after completion, reaction mixture quenched in crushed ice and extracted with EtOAc. The organic layer washed with sat. NaHCO ₃ , water and brine solution. The organic layer dried over Na ₂ SO _4, filtered and concentrated in vacuo. Crude compound was purified by column chromatography using a silica gel (100: 200 mesh) compound was eluted using 20% EtOAc in Hexane to afford compound II-1010 (7.1 mg, Yield: 4.1%) as a white solid. [0409] LCMS: m/z: 404.15 [M+1] ⁺ , 96.79 % (1.57 min). [0410] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. [0411] ¹ H NMR [400 MHz, DMSO-d ₆ ]: 10.31 (s, 1H), 7.38 (t, J = 5.6 Hz, 2H), 7.24-7.11 (m, 4H), 6.68 (d, J = 8.4 Hz, 1H), 3.85 (s, 3H), 3.75 (s, 3H), 3.12-3.04 (m, 3H), 2.65 (s, 3H), 1.34 (d, J = 6 Hz, 3H). Step 10: [0412] To a stirred solution of compound II-1004 (300 mg, 1.074 mmol) in DCM (15 mL) was added Boron tribromide (30 ml, 10.746 mmol) at 0 ^o C then reaction mixture was heated to 100 °C and stirred for 3h. Reaction was monitored by TLC; after completion of reaction, solvent was evaporated then reaction mixture was quenched in water and extracted with DCM. Aqueous layer was purified by C-18 reverse phase column chromatography to afford II-1005 (5 mg, Yield: 1.8 %) as a white solid. [0413] LCMS: m/z: 376.41 [M+1] ⁺ , 94.58% (1.47 min). [0414] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) Flow Rate: 0.4 mL/min. [0415] ¹ H NMR [400 MHz, DMSO-d6]: 13.72 (s, 1H), 11.11 (s, 1H), 7.82 (s, 2H), 7.53-7.38 (m, 2H), 7.26-7.10 (m, 1H), 6.97-6.90 (m, 1H), 6.55-6.52 (m, 1H), 3.09 (t, J = 6 Hz, 3H), 1.33 (d, J = 5.6 Hz, 3H). Scheme 7: Synthesis of II-1006:

Step 1: [0416] To a stirred solution of compound 1 (20 g, 96.618 mmol) in DMF (200 mL) was added compound 2 (13.3 g, 96.61 mmol) followed by HATU (55.07 g, 144.92 mmol) and DIPEA (31.15 g, 241.54 mmol) then reaction mixture was stirred at room temperature for 18h. Reaction was monitored by TLC; after completion of reaction solvent was evaporated by reduced pressure and crude compound was purified by column chromatography using a silica gel (100: 200 mesh) and compound was eluted using 10% EtOAc in Hexane to afford compound 3 (18.5 g, Yield: 58.6%) as an off white solid. [0417] LCMS: m/z: 329.01 [M+2] ⁺ , 98.46 % (1.47 min). [0418] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 2: [0419] To a stirred solution of compound 3 (10 g, 30.581 mmol) in DMF (100 mL) was added 60% NaH (2.2 g, 91.74 mmol) at 0 ^o C and stirred for 20 min. MOM-Cl (3.69 g, 45.87 mmol) was added at 0 °C. The resulting reaction mixture allowed to stir at room temperature for 5h. Completion of the reaction was monitored by TLC, after completion, reaction mixture quenched with sat. NH ₄ Cl solution and extracted with EtOAc (2x500 mL). The organic washed with brine solution (500 mL), dried over Na ₂ SO _4, filtered and concentrated in vacuo. Crude compound was purified by column chromatography using silica gel (100: 200 mesh) and compound was eluted using 5% EtOAc in Hexane to afford compound 4. (4.1 g, Yield: 36.2%) as an off white solid. [0420] LCMS: m/z: 372.97 [M+2] ⁺ , 94.35 % (1.43 min). [0421] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 3: [0422] To a stirred solution of compound 4 (5 g, 13.51 mmol) in DMA (50 mL) was added KOAc (5.29 g, 54.05 mmol), Pd(t-Bu ₃ P) ₂ (414 mg, 0.81 mmol) at room temperature. The resulting reaction mixture degassed with nitrogen for 15 min. Then the reaction mixture heated to 150 °C and stirred for 4h. Completion of the reaction was monitored by TLC. After completion, reaction mass cooled to rt, quenched with cold water and extracted with EtOAc (2x500 mL). Organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Crude compound was purified by column chromatography using a silica gel (100: 200 mesh) and compound was eluted using 20% EtOAc in Hexane to afford compound 5. (1.8 g, Yield: 46.0%) as an off white solid. [0423] LCMS: m/z: 291.06 [M+1] ⁺ , 56.03 % (1.39 min). [0424] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 4: [0425] To a stirred solution of compound 5 (800 mg, 2.758 mmol) in THF (8 mL) was added LDA (5.5 mg, 5.517 mmol) at -78 ^o C and stirred for 30 min. Methyl iodide (583 mg, 4.137 mmol) added at -78 ^o C. The resulting reaction mixture allowed to stir at -78 ^o C for 2h. Completion of the reaction was monitored by TLC, after completion of reaction, reaction mixture quenched with water and extracted with EtOAc (2x300 mL). The organic washed brine solution, dried over Na ₂ SO _4, filtered and concentrated in vacuo. Crude compound was purified by column chromatography using a silica gel (100: 200 mesh) and compound was eluted using 10% EtOAc in Hexane to afford compound 6 (325 mg, Yield: 38.8%) as an off white solid. [0426] LCMS: m/z: 305.07 [M+1] ⁺ , 79.38 % (1.52 min). [0427] Method:Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 5: [0428] To a stirred solution of compound 6 (200 mg, 0.657 mmol) in H ₂ SO ₄ (2 mL) was added 1,3- dibromo5,5-dimethyl hydatoin (112 mg, 0.394 mmol) then reaction mixture was stirred at room temperature for 2h. Reaction was monitored by TLC; after completion of reaction, mixture was quenched in ice water and extracted with DCM. Organic layer was concentrated under reduced pressure; Crude compound was purified by column chromatography using a silica gel (100: 200 mesh) and compound was eluted using 20% EtOAc in Hexane to afford compound 7 (106 mg, Yield: 23.8%) as an off white solid. [0429] LCMS: m/z: 340.98 [M+2] ⁺ , 22.01 % (1.51 min). [0430] Method:Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 6: [0431] To a stirred solution of compound 7 (120 mg, 0.353 mmol) in Dioxane (1.2 mL) solution was added compound 8 (166 mg, 0.460 mmol) followed by sodium bicarbonate (88 mg, 1.059 mmol). Reaction mixture was degassed for 15 minutes then Pd(dppf)Cl ₂ catalyst (10 mg, 0.014 mmol) was added and again degassed for 10 minutes then reaction mixture was stirred at 85 ^o C for 15h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with ethyl acetate, organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude compound was purified by column chromatography using silica gel (100: 200 mesh) and compound was eluted using 10% EtOAc in Hexane to afford compound 9 (26 mg, Yield: 14.9%) as an off white solid. [0432] LCMS: m/z: 494.24 [M+1] ⁺ , 44.37 % (1.65 min). [0433] Method:Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 7: [0434] To a stirred solution of compound 9 (60 mg, 0.121 mmol) in 1,4-dioxane (1 mL) was added 4M HCl in dioxane (0.300 mL) at 0 ^o C then reaction mixture was stirred at rt for 2h. Reaction was monitored by TLC; after completion of reaction, reaction mixture was quenched with aq. NaHCO ₃ and extracted with ethyl acetate. Crude was purified by C-18 reverse phase column chromatography to afford II-1006 (3.7 mg, Yield: 7.7%) as a white solid. [0435] LCMS: m/z: 394.30 [M+1] ⁺ , 99.16 % (1.57 min). [0436] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) Flow Rate: 0.4 mL/min. [0437] ¹ H NMR [400 MHz, DMSO-d6]: 7.43 (d, J = 7.6 Hz, 2H), 7.29 (d, J = 7.6 Hz, 2H), 6.04 (s, 1H), 3.56 (s, 3H), 2.84-2.79 (m, 3H), 2.60 (s, 3H), 2.34 (s, 3H), 1.28 (d, J = 6.4 Hz, 3H). Scheme 8: Synthesis of Chiral boronic ester (R): Step 1: [0438] To a stirred solution of compound 1 (25 g, 0.185 mol) in DCM (250 mL) was added Trifluoracetic anhydride (42.7 mL, 0.203 mol) in DCM then reaction mixture was stirred at room temperature for 1h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with DCM (2x1L), organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude was used for next step without any purification. Step 2: [0439] To a stirred solution of compound 2 (25 g, 0.108 mol) in DCM (500 mL) was added Methane sulphonic acid (25 mL) followed by DBDMH (3.08 g, 0.108 mol) at 0 ^o C then reaction mixture was stirred at room temperature for 18h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with DCM (2x1L), organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude compound. The crude compound was purified by silica gel column chromatography (10% EtOAc in hexane as eluent) to afford 4 (30 g, Yield: 90%) as brown solid. [0440] LCMS: m/z: 310.11 [M+2H] ⁺ , 40.13 % (1.59 min). [0441] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 3: [0442] To a stirred solution of compound 4 (21 g, 0.68.3 mmol) in MeOH was added 2N NaOH (68 mL, 136.6 mmol), then reaction mixture was stirred at 40 ^o C for 14h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with DCM (2x1L), organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. The crude compound was purified by silica gel column chromatography (30% EtOAc in hexane as eluent to afford 5 (15 g, Yield: 87%) as brown solid. [0443] LCMS: m/z: 216.07 [M+2H] ⁺ , 39.51 % (0.85 min). [0444] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 4: [0445] To a stirred solution of compound 5 (40 g, 0.186 mol) in CHCl ₃ (1L), was added TEA (35 mL, 0.373 mol) at 0 ^o C followed by (Boc) ₂ O (55 mL, 0.279 mol) then reaction mixture was stirred at room temperature for 18h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with DCM (2x1L), organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. The crude compound was purified by silica gel column chromatography (12% EtOAc in hexane as eluent) to afford 6 (40 g, Yield: 69%) as brown solid. [0446] LCMS: m/z: 260.07 [M-BOC] ⁺ , 54.59 % (3.40 min). [0447] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90), Flow Rate: 0.4 mL/min. Step 5: [0448] To a stirred solution of compound 6 (15 g, 0.047 mol) in Dioxane (150 mL) was added Bis(pinacolato)diboron (18.2 g, 0.071 mol). Reaction mixture was degassed for 15 minutes then Pd(dppf)Cl2 catalyst (1.37 g, 0.001 mol) was added and again degassed for 10 minutes then reaction mixture was stirred at 90 ^o C for 15h. Reaction was monitored by TLC; after completion of reaction mixture was quenched in water and extracted with DCM (2x1L). The crude compound was purified by silica gel column chromatography (40% EtOAc in hexane as eluent) to afford 7 (11 g, Yield: 64%) as white solid. [0449] LCMS: m/z: 306.25 [M-BOC] ⁺ , 95.45 % (1.81 min). [0450] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90), Flow Rate: 0.4 mL/min. [0451] ¹ H NMR [400 MHz, DMSO-d ₆ ]: 7.59 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 7.6 Hz, 2H), 6.83 (s, 1H), 3.07-3.01 (m, 2H), 2.89-2.84 (m, 1H), 1.34 (s, 9H), 1.25 (s, 12H), 1.14 (d, J = 6.8 Hz, 3H). Scheme 9: Synthesis of I-1009 (R): Step-1: [0452] To a stirred solution of compound 1 (25 g, 123.7 mol) in DCM (250 mL) was added EDC.HCl (23.7 g.123.7 mol) and compound 2 (23.7 g.0.173.2 mol) was added slowly. The resulting reaction mixture allowed to stir at room temperature for 16h. Completion of the reaction was monitored by TLC, after completion, reaction mass diluted with DCM (1L) and washed with water (500 mL), brine solution (500 mL). Organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Crude compound was purified by column chromatography using a silica gel (100: 200 mesh) and compound was eluted using 5% EtOAc in Hexane to afford compound 3. (18 g, Yield: 50%) as a pale brown solid. [0453] LCMS: m/z = 323.14 [M+2] ⁺ , 62.73% (1.23 min). [0454] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-2: [0455] To a stirred solution of compound 3 (28.6 g, 0.089 mol) in DMF (280 mL) was added 60% NaH (13 g, 0.267 mol) at 0 ^o C and stirred for 20 min. PMB-Cl (18.1 mL, 0.133 mol) was added at same temperature. The resulting reaction mixture allowed to stir at room temperature for 5h. Completion of the reaction was monitored by TLC, after completion of the reaction, reaction mixture quenched with sat. NH ₄ Cl solution and extracted with EtOAc (2x1L). The organic layer washed with water (1L), brine solution (1L), dried over Na ₂ SO _4, filtered and concentrated in vacuo to afford crude compound as brown gum. Crude compound was purified by column chromatography using silica gel (100: 200 mesh) and compound was eluted using 10% EtOAc in Hexane to afford compound 4. (24.1 g, Yield: 69%) as a pale brown solid. [0456] LCMS: m/z = 443.17 [M+2] ⁺ , 47.99% (1.55 min). [0457] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-3: [0458] To a stirred solution of compound 4 (16.1 g, 0.036 mol) in DMA (160 mL) was added KOAc (14.3 g, 0.146 mol) followed by Pd(P ^t Bu ₃ ) ₂ (1.1 g, 0.002 mol) at room temperature. The reaction mixture degassed with nitrogen for 20 min, then heated to 150 °C and stirred for 4h. Completion of the reaction was monitored by TLC, after completion, reaction mixture poured crushed into ice and filtered the solid. The solid was dissolved in 10% MeOH in DCM (1L), washed with brine solution (1L), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was triturated with Ether, filtered and dried to afford pure compound 5 as off- white solid. (10.1 g, Yield: 77%) as a pale brown solid. [0459] LCMS: m/z = 361.23 [M+1] ⁺ , 92.58 % (1.40 min). [0460] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-4: [0461] Trifluoroacetic acid (120 mL) was added to the compound 5 (12 g, 0.050 mol) in a sealed tube at room temperature. The resulting mixture heated to 100 °C and stirred for 16h. Completion of the reaction was monitored by TLC, LCMS which shows completion of the reaction. Crude compound was purified by column chromatography using a silica gel (100: 200 mesh) and compound was eluted using 20% EtOAc in Hexane to afford compound 6. (9 g, Yield: 50%) as an off-white solid. [0462] LCMS: m/z = 241.16 [M+1] ⁺ , 45.68% (1.22 min). [0463] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-5: [0464] To a stirred solution of compound 6 (1 g, 0.004 mol) in H ₂ SO ₄ (10 mL) was added 1,3- dibromo-5,5-dimethylhydantoin (DBDMH) (1.1 g, 0.004 mol) at 0 °C. The resulting mixture stirred at room temperature for 3h. Completion of the reaction was monitored by TLC and LCMS. After completion, reaction mass poured into crushed ice and extracted with EtOAc (2x100 mL). Organic layer washed with sat. NaHCO ₃ , water and brine solution (100 mL). The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was triturated with ether, filtered and dried to afford compound 7 as brown solid. (500 mg, Yield: 40%) as an off-white solid. [0465] LCMS: m/z = 320.96 [M+2H] ⁺ , 74.93 % (1.33 min). [0466] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-6: [0467] To a stirred solution of compound 7 (1 g, 0.003 mol) and compound 8 (1.6 g, 0.004 mol) in Dioxane (20 ml) and water (1 ml) was added K ₂ CO ₃ (1.3 g, 0.009 mol), Pd-118 catalyst (102 mg, 0.001 mol) at room temperature. The resulting reaction mixture degassed with nitrogen for 10 min. Then the reaction mixture heated to 150 °C and stirred for 15h. Completion of the reaction was monitored by TLC and LCMS; which shows des-bromo product mass. crude was washed with n-pentane and ether to afford compound 9. (450 mg, Yield: 30.2%) as a pale brown solid. [0468] LCMS: m/z = 474.61 [M+1] ⁺ , 61.41 % (1.64 min). [0469] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-7: [0470] To a stirred solution of compound 9 (450 mg, 0.949 mol) in 1,4-dioxane (10 mL) was added 4M HCl in dioxane (10 mL) at 0 ^o C then reaction mixture was stirred at rt for 6h. Reaction was monitored by TLC; after completion of reaction mixture was diluted with water and washed with ethyl acetate. Aqueous Layer Was quenched with aq. NaHCO ₃ and extracted with 10% MeOH in DCM. Organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude compound was purified by column chromatography using silica gel (100: 200 mesh) and compound was eluted using 10% EtOAc in Hexane to afford compound 10 (120 mg, Yield: 33.8%) as an off white solid. [0471] LCMS: m/z: 374.26 [M+H] ⁺ , 87.47 % (0.89 min). [0472] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-8: [0473] To a stirred solution of compound 10 (120 mg, 0.320 mmol) was added Hydrogen bromide (0.2 mL) at 0 ^o C then reaction mixture was stirred at 100 ^o C for 15h. Reaction was monitored by TLC. Reaction mixture was evaporated to afford crude compound was purified by column chromatography using silica gel (100: 200 mesh) and compound was eluted using 10% EtOAc in Hexane to afford I-1009 (30 mg, Yield: 26.1%) as an off white solid. [0474] LCMS: m/z: 360.25 [M+H] ⁺ , 92.48 % (1.45 min). [0475] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) Flow Rate: 0.4 mL/min. [0476] ¹ H NMR [400 MHz, DMSO-d6]: 8.53-8.50 (m, 1H), 8.36 (s, 1H), 8.27-8.25 (m, 1H), 7.39-7.36 (m, 1H), 7.17 (d, J = 8 Hz, 2H), 7.08 (s, 1H), 7.01 (d, J = 8.4 Hz, 2H), 2.93 (t, J = 15.6 Hz, 3H), 2.47 (s, 3H).1.31 (t, J = 3.2 Hz, 3H). Scheme 10: Synthesis of II-1007 Step 1: [0477] To a stirred solution of compound 1 (30 g, 0.194 mol) in DMF (300 mL) was added NBS (41.5 g,0.233 mol) at 0 °C. The resulting mixture stirred at 60 ^o C for 16 h. Completion of the reaction was monitored by TLC. After completion, reaction mass extracted with EtOAc. Organic layer washed with sat. NaHCO _3, water and brine solution. The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was triturated with ether, filtered and dried to afford to afford compound 2 as brown solid (34.9 g, Yield: 77.6%) as an off white solid. [0478] LCMS: m/z: 234.79 [M+2H] ⁺ , 90.21 % (1.07 min). [0479] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 2: [0480] To a stirred solution of compound 2 (34.9 g, 0.149 mol) in POCl3 (137 ml, 1.497 mol) at rt then reaction mixture was stirred at 100 ^o C for 3h. Reaction was monitored by TLC; after completion of reaction mixture was diluted with ice water and quenched with aq. NaHCO ₃ and extracted with water and DCM. Organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Used for the next step without any purification. [0481] LCMS: m/z: 252.86 [M+2H] ⁺ , 93.29 % (1.54 min). [0482] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 3: [0483] To a stirred solution of compound 3 (28 g, 0.111 mol) in MeOH (280 mL) was added Sodium methoxide (7.5 g,0.140 mol) at 0 °C. The resulting mixture stirred at 80 ^o C for 3 h. Completion of the reaction was monitored by TLC. After completion, reaction mass reaction mixture was evaporated under vacuum than extracted with EtOAc and water. Organic layer washed with brine solution. The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was triturated with ether, filtered and dried to afford compound 4 (20 g, Yield: 74.0%) as brown solid. [0484] LCMS: m/z: 247.21 [M+1H] ⁺ , 88.32 % (1.62 min). [0485] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 4: [0486] To a stirred solution of compound 4 (2 g, 0.009 mol) and compound 5 (3.5 g, 0.009 mol) in Dioxane (20 mL) and water (2 ml) was added K ₂ CO ₃ (3.3 g, 0.024 mol), Pd-118 (264 mg, 0.024 mmol) at room temperature. The resulting reaction mixture degassed with nitrogen for 10 min. Then the reaction mixture heated to 80 °C and stirred for 16h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with ethyl acetate, organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound 6. Crude compound was purified by column chromatography using a silica gel (100: 200 mesh) compound was eluted using 20% EtOAc in Hexane to afford compound 6 (1.6 g, Yield: 54.6%) as a white solid. (2 g, Yield: 66.0%) as a white solid. [0487] LCMS: m/z: 346.10 [M-BOC] ⁺ , 83.25 % (1.88 min). [0488] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90), Flow Rate: 0.4 mL/min. Step 5: [0489] To a stirred solution of compound 6 (4 g, 0.010 mol) in THF (20 mL) and water (6.8 mL) was added Iron Powder (5 g, 0.050 mol) and NH4Cl (6.7 g, 0.107 mol) at. The resulting mixture stirred at 80 ⁰ C for 10h. Completion of the reaction was monitored by TLC. After completion, reaction mass reaction mixture was filter and pass the celite room temperature and evaporated under vacume than extracted with EtOAc (2x500 mL) and water (500 mL). Organic layer washed with brine solution. The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Crude compound was purified by column chromatography using silica gel (100: 200 mesh). Compound was eluted using 10% EtOAc in Hexane to afford compound 7 (2 g, Yield: 50 %) as a white solid. [0490] LCMS: m/z: 372.24 [M+1H] ⁺ , 79.48 % (1.53 min). [0491] Method: Column: Kinetex EVO C18 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 6: [0492] To a stirred solution of compound 7 (2.6 g, 0.010 mol) in MeOH (30 mL) was added AcOH (2 mL) followed compound 8 (1.4 mL, 0.011 mol) at room temperature. The resulting reaction mixture allowed to stir at room temperature for 1h followed by NaBH ₄ (785 mg, 0.021 mmol) was added slowly at 0 ^o C. The resulting reaction mixture allowed to stir at room temperature for 2h. Completion of the reaction was monitored by TLC, after completion, reaction mass directly evaporated under vacuo than extracted with DCM (300 mL) and water (300 mL), washed with brine solution (300 mL). Organic layer dried over Na ₂ SO _4, filtered and concentrated in vacuo. The crude compound was purified by silica gel (100-200 mesh) column chromatography (5-7% ethyl acetate in hexane as eluent) to afford pure compound 9 was used for next step. (2.3 g, Yield: 69.7%) as a white solid. Step 7: [0493] To a stirred solution of compound 9 (1.6 g, 0.008 mol) in DCM (40 mL) was added TEA (3.4 mL, 0.024 mmol) at room temperature. Compound 10 (4 g, 0.004 mmol) added at 0 ^o C. The resulting reaction mixture allowed to stir at room temperature for 3h. Completion of the reaction was monitored by TLC, after completion, reaction mass diluted with DCM and washed with aq. NaHCO ₃ solution and brine solution. Organic layer dried over Na ₂ SO ₄ , filtered and concentrate in vacuo. Crude compound was purified by column chromatography using a silica gel (100: 200 mesh) compound was eluted using 30% EtOAc in Hexane to afford compound 11 (1.2 g, Yield: 22%). [0494] LCMS: m/z: 682.1 [M+2H] ⁺ , 80.31 % (1.96 min). [0495] Method: Column: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A- 0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 8: [0496] To a stirred solution of compound 11 (1.6 g, 0.002 mol) in DMA (16 mL) was added KOAc (1.29 g, 0.009 mol), Pd(P ^t Bu ₃ ) ₂ (61 mg, 0.0001 mol) at room temperature. The reaction mixture degassed with nitrogen for 20 min, then heated to 150 °C and stirred for 4h. Completion of the reaction was monitored by TLC, after completion, reaction mixture poured crushed into ice and filtered the solid. The solid was dissolved in 10% MeOH in DCM, washed with brine solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was triturated with Ether, filtered and dried to afford pure compound as off-white solid. Crude compound was purified by column chromatography using a silica gel (100: 200 mesh) compound was eluted using 10% EtOAc in Hexane to afford compound 12 (80 mg, Yield: 5%). [0497] LCMS: m/z: 600.27 [M+1H] ⁺ , 92.03 % (1.99 min). [0498] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 9: [0499] To a stirred solution of compound 12 (100 mg,0.207 mmol) was added HBr in AcOH (2 mL) at 0 ^o C then reaction mixture was stirred at 100 ⁰ C room temperature for 8h. Reaction was monitored by TLC; after completion of reaction solvent was evaporated then reaction mixture was quenched in water and extracted with DCM. Aqueous layer was purified by C-18 reverse phase column chromatography to afford crude compound 13 (80 mg, Yield: 80 %) as a white solid. [0500] LCMS: m/z: 468.23 [M+1H] ⁺ , 81.83% (0.83 min). [0501] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 10: [0502] To a stirred solution of compound 13 (100 mg,0.273 mmol) was added POCl ₃ (2 ml) at 0 ^o C then reaction mixture was stirred at100 ^o C room temperature for 16h. Reaction was monitored by TLC; after completion of reaction solvent was evaporated then reaction mixture was quenched in water and extracted with DCM. Aqueous layer was purified by C-18 reverse phase column chromatography to afford crude compound II-1007 (4 mg, Yield: 4 %) as a yellow solid. [0503] LCMS: m/z: 384.17 [M+1H] ⁺ , 99.43% (1.81 min). [0504] Method: Column: Acquity BEH C ₁ 8 (2.1 x 50 mm, 1.7 μm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90), Flow Rate: 0.4 mL/min. [0505] ¹ H NMR [400 MHz, DMSO-d6]: ¹ H NMR [400 MHz, DMSO-d6]: 8.32 (s, 1H), 7.7 (d, J = 9.2 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 5.91 (d, J = 5.91 Hz, 2H), 2.95-2.90 (m, 3H), 2.60 (s, 3H), 1.30-1.279 (m, 3H).

Scheme 11: Synthesis of I-1011 Step 1: [0506] NaOMe (11.3 g, 210.172 mol) was added portion wise to a solution of compound 1 (25 g, 105.086 mol) dissolved in DMSO (250 mL) at room temperature under nitrogen atmosphere. The mixture was stirred for 16h and then poured into water and extracted with ethyl acetate (2x1000 mL). The organic phase was washed with water (1000 mL) and brine (1000 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Crude compound was purified by column chromatography using silica gel (100: 200 mesh) compound was eluted using 4% EtOAc in Hexane to afford compound 2 (12.8 g, Yield: 48.7%) as a brown solid. [0507] ¹ H NMR [400 MHz, DMSO-d6]: 8.01-7.98 (m, 1H), 7.39 (t, J = 8.4 Hz 1H), 3.95 (s, 3H). Step 2: [0508] To a stirred solution of compound 2 (12.8 g, 51.200 mmol) in Dioxane (128 ml) solution was added compound 2 (3.98 g, 66.560 mmol) followed by Cs2CO ₃ (50.06 g, 153.600 mmol). Reaction mixture was degassed for 15 minutes then Palladium catalyst (2.2 g, 3.072 mmol) was added and again degassed for 10 minutes then reaction mixture was stirred at 85 ^o C for 16 h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with ethyl acetate, organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude compound was purified by column chromatography using a silica gel (100: 200 mesh) compound was eluted using 5% EtOAc in Hexane to afford compound 3 (6.5 g, Yield: 68.6%) as a brown solid. [0509] ¹ H NMR [400 MHz, CDCl3]: 7.92-7.89 (m, 1H), 6.89 (t, J = 8.4 Hz, 1H), 3.97(s, 3H), 2.54 (d, J = 2.8 Hz, 3H). Step 3: [0510] To a solution mixture of compound 3 (10 g, 54.054 mmol) in THF-water (100 mL, 3:1 ratio) was added Fe (15.09 g, 270.2 mmol) followed by ammonium chloride (28.9 g, 540.12 mmol) at rt and continued at 60 ^o C for 2h. Reaction mixture was basified with sat. NaHCO ₃ solution and extracted with EtOAc. Total organic layers were dried over Na ₂ SO ₄ and concentrated under vacuo. to afford compound 4. Crude compound was used for next step without purification. (10 g, crude). [0511] LCMS: m/z = 156.06 [M+H] ⁺ , 17.41% (0.71 min). [0512] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 4: [0513] To a stirred solution of compound 4 (7.8 g, 38.613 mmol) in DCM (78 ml) was added compound 5 (5.98 g, 38.613 mmol) followed by EDC.HCl (14.8 g, 77.226 mmol) then reaction mixture was stirred at room temperature for 16h. Reaction was monitored by TLC; after completion of reaction solvent was evaporated by reduced pressure and Crude compound was purified by column chromatography using a silica gel (100: 200 mesh) compound was eluted using 10% EtOAc in Hexane to afford compound 6 (7 g, Yield: 53.5%) as a brown solid. [0514] LCMS: m/z = 341.08 [M+2H] ⁺ , 36.77% (1.30 min). [0515] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 5: [0516] To a stirred solution of compound 6 (7 g, 20.648 mmol) in DMF (70 mL) was added 60% NaH (1.4 g, 61.944 mmol) at 0 ^o C and stirred for 20 min. PMB-Cl (4.8 g, 30.973 mmol) added at 0 °C. The resulting reaction mixture allowed to stirred at room temperature for 3h. Completion of the reaction was monitored by TLC, after completion of reaction, reaction mixture quenched with sat. NH4Cl solution and extracted with EtOAc (2x500 mL). The organic washed brine solution, dried over Na ₂ SO _4, filtered and concentrated in vacuo. Crude compound was purified by column chromatography using a silica gel (100: 200 mesh) compound was eluted using 10% EtOAc in Hexane to afford compound 7 (5.6 g, Yield: 59.1%) as a brown solid. [0517] LCMS: m/z = 461.09 [M+2H] ⁺ , 54.59% (1.30 min). [0518] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 6: [0519] To a stirred solution of compound 7 (5 g, 10.893 mmol) in DMA (50 mL) was added KOAc (4.27 g, 43.572 mmol), Pd(P ^t Bu ₃ ) ₂ (333 mg, 0.653 mmol) at room temperature. The resulting reaction mixture degassed with nitrogen for 15 min. Then the reaction mixture heated to 150 °C and stirred for 16h. Completion of the reaction was monitored by TLC. After completion, reaction mass cooled to RT, quenched with cold water and extracted with EtOAc. Organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Crude compound was purified by column chromatography using silica gel (100: 200 mesh) compound was eluted using 10% EtOAc in Hexane to afford compound 8 (2.1 g, Yield: 51.1%) as a white solid. [0520] LCMS: m/z = 379.20 [M+1H] ⁺ , 65.44% (1.69 min). [0521] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 7: [0522] To a solution mixture of compound 8 (1.5 g, 3.968 mmol) in H ₂ SO ₄ (15 mL) was added 1,3-Dibromo-5,5-dimethyl hydantoin (1.1 g, 3.968 mmol) at 0 ^o C and continuous the reaction at 0 ^o C for 1h. Reaction was monitored by TLC; after completion of reaction, mixture was quenched in ice water and extracted with DCM. Organic layer was concentrated under reduced pressure; crude was washed with pentane and diethyl ether to afford compound 9 (1.2 g, Yield: 90.2%) as a brown solid. [0523] LCMS: m/z = 339.00 [M+2H] ⁺ , 79.84% (1.46 min). [0524] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min.

Step 8: [0525] To a stirred solution of compound 9 (1 g, 4.219 mmol) in Dioxane (10 mL) solution was added compound 10 (2.2 g, 6.329 mmol) followed by K2CO ₃ (1.7 g, 12.657 mmol). Reaction mixture was degassed for 15 minutes then Pd(dppf)Cl2 catalyst (164 mg, 0.253 mmol) was added and again degassed for 10 minutes then reaction mixture was stirred at 85 ^o C for 16h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with ethyl acetate (2x300 mL), organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude compound was purified by column chromatography using a silica gel (100: 200 mesh) compound was eluted using 20% EtOAc in Hexane to afford compound 8 (243 mg, Yield: 16.7%) as a white solid. [0526] LCMS: m/z = 492.31 [M+1H] ⁺ , 7.83% (1.76 min). [0527] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 9: [0528] To a stirred solution of compound 11 (486 mg, 0.989 mmol) in 1,4-dioxane (4.8 mL) was added dioxane/HCl (2.969 mL) at 0 ^o C then reaction mixture was stirred at room temperature for 2h. Reaction was monitored by TLC; after completion of reaction, reaction mixture was quenched with aq. NaHCO ₃ and extracted with ethyl acetate. Crude compound was purified by column chromatography using a silica gel (100: 200 mesh) compound was eluted using 40% EtOAc in Hexane to afford compound 12 (200 mg, Yield: 51.7%) as a white solid. [0529] LCMS: m/z = 392.21 [M+1H] ⁺ , 32.33% (0.96 min). [0530] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 10: [0531] To a stirred solution of compound 12 (150 mg, 0.383 mmol) in DCM (1.5 ml) was added boron tribromide (1.1 mL, 1.150 mmol) at 0 ⁰ C then reaction mixture was stirred at RT for 15h. Reaction was monitored by TLC; after completion of reaction solvent was evaporated then reaction mixture was quenched in water and extracted with DCM. Aqueous layer was purified by C-18 reverse phase column chromatography to afford I-1011. Prep purification is in progress.

Scheme 12: Synthesis of II-1001 (R) Step-1: [0532] To a stirred solution of compound 1 (20 g, 0.096 mmol) in DMF (250 mL) was added compound 2 (13.3 g, 0.096 mmol) followed by DIPEA (53 mL, 0.28 mmol) and HATU (54 g, 0.144 mmol) then reaction mixture was stirred at room temperature for 5h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with EtOAc (2x1L), organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude compound was purified by column chromatography using silica gel (100: 200 mesh) and compound was eluted using 20% EtOAc in Hexane to afford compound 3 (20 g, Yield: 64%) as an off white solid. [0533] LCMS: m/z = 335.20[M+2H] ⁺ , 93.03 % (1.68 min). [0534] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-2: [0535] To a stirred solution of compound 3 (10 g, 0.030 mol) in DMF (100 mL) was added NaH (2.2 g, 0.09 mol) at 0 ^o C followed by PMB-Cl (7 mL, 0.06 mol) then reaction mixture was stirred at for 3h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with EtoAc (2x500 mL), organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude compound was purified by column chromatography using silica gel (100:200 mesh) and compound was eluted using 10% EtOAc in Hexane to afford compound 4 (8 g, Yield: 59%) as an off-white solid. [0536] LCMS: m/z = 447.35 [M+2H] ⁺ , 80.52 room temperature % (1.65 min). [0537] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-3: [0538] To a stirred solution of compound 4 (15 g, 0.033 mmol) in DMA (150 mL) was added potassium acetate (13.1 g, 0.134 mol) followed by Pd (P ^t Bu ₃ ) ₂ catalyst (1.01 g, 0.002 mmol) then reaction mixture was stirred at 150 ^o C for 4h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with ethyl acetate (2x200 mL), organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude compound was used for next step without purification. Crude compound was purified by column chromatography using silica gel (100:200 mesh) and compound was eluted using 10% EtOAc in Hexane to afford compound 5 (3.5 g, Yield: 28.7 %) as an off-white solid. Step-4: [0539] Trifluoro acetic acid (50 mL) was added to compound 5 (11 g, 0.030 mol) at 0 ^o C. The resulting reaction mixture allowed to room temperature and stirred at 100 °C for 16h. Completion of the reaction was monitored by TLC, after completion, the reaction mixture quenched with aq. NaHCO ₃ solution and extracted with EtOAc (2x200 mL). The organic washed with brine solution (100 mL), dried over Na ₂ SO _4, filtered and concentrated in vacuo. Crude compound was purified by column chromatography using silica gel (100:200 mesh) and compound was eluted using 10% EtOAc in Hexane to afford compound 6 (1.1 g, Yield: 42.8 %) as an off-white solid. [0540] LCMS: m/z = 246.16 [M+H] ⁺ , 87.7% (1.15min). [0541] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min.

Step-5: [0542] To a stirred solution of compound 6 (1 g, 0.004 mol) in 2 mL (1:1) DCM was added NBS (863 mg, 0.004 mol) at 0 ^o C then reaction mixture was stirred at room temperature for 16h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with DCM (2x100 mL), organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude compound was purified by column chromatography using silica gel (100:200 mesh) and compound was eluted using 20% EtOAc in Hexane to afford compound 7 (500 mg, Yield: 38%) as an off white solid. [0543] LCMS: m/z = 325. [M+H] ⁺ , 66.37% (1.44min). [0544] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min.

Scheme 13: Synthesis of II-1008 Step-1: [0545] To a cold solution of compound 1 (3 g, 11.90 mmol) in THF (30 mL) was added 60% NaH (525 mg, 13.147 mmol) followed by diethylmalonate (2.2 mL, 13.147 mmol). After completion of addition the reaction mixture was stirred for 15 min and the solvent was evaporated under reduced pressure. The resulting residue was stirred at 110 °C for 1.5 h. The reaction mixture was brought to 0 °C and 6M aqueous H ₂ SO ₄ (17 mL) was added. The resulting suspension was stirred at 110 °C overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, reaction mass poured into cold water and basified with NaHCO ₃ . The resulting precipitate filtered and dissolved in EtOAc, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to afford compound 2 (1.5 g, 54.5%) as a reddish solid. [0546] LCMS: m/z: 232.98 [M+2H] ⁺ , 98.19% (1.61 min). [0547] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 ìm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90), Flow Rate: 0.4 mL/min. [0548] ¹ H NMR [400 MHz, CDCl3]: δ 8.44 (s, 1H), 2.80 (s, 3H), 2.72 (s, 3H). Step-2: [0549] To a stirred solution of compound 2 (2 g, 8.63 mmol) and compound 3 (4.7 g, 12.95 mmol) in Dioxane (20 ml) and water (2 ml) was added NaHCO ₃ (2.17 g, 25.89 mmol), Pd(dppf)Cl2 (315 mg, 0.43 mmol) at room temperature. The resulting reaction mixture degassed with nitrogen for 10 min. Then the reaction mixture stirred at 90 °C for 6h. The progress of the reaction was monitored by TLC, after completion of the reaction evaporated the solvent. The residue was dissolved in EtOAc and washed with water, brine solution. The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (15% EtOAc in Hexane as eluent) to afford compound 4 (2.5 g, 75%) as a yellow liquid. [0550] LCMS: m/z: 386.31 [M+1H] ⁺ , 97.7% (1.83 min). [0551] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 ìm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90), Flow Rate: 0.4 mL/min. [0552] ¹ H NMR [400 MHz, CDCl3]: δ 8.15 (s, 1H), 7.33-7.26 (m, 4H), 4.52 (brs, 1H), 3.43- 3.38 (m, 1H), 3.29-3.23 (m, 1H), 3.03-2.97 (m, 1H), 2.88 (s, 3H), 2.58 (s, 3H), 1.42 (s, 9H), 1.31 (d, J=6.8 Hz, 3H). Step-3: [0553] To a stirred solution of compound 4 (2.7 g, 7.01 mmol) in THF (30 mL) and water (4.5 mL) was added Iron Powder (1.9 g, 35.06 mmol) and NH4Cl (3.7 g, 70.12 mmol) The resulting mixture stirred at 80 °C for overnight. Progress of the reaction was monitored by TLC. After completion of the reaction, filtered the reaction mass through celite and washed with EtOAc, separated the two layers. Organic layer washed with brine solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (20% EtOAc in hexane as eluent) to afford compound 5 (1.6 g, 64.2%) as yellow liquid. [0554] LCMS: m/z: 356.76 [M+1H] ⁺ , 85.10% (1.04 min). [0555] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 ìm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90), Flow Rate: 0.4 mL/min.

Step-4: [0556] To a stirred solution of compound 5 (1.2 g, 3.38 mmol) in MeOH (10 mL) was added compound 6 (0.6 mL, 4.05 mmol) followed by cat AcOH (0.1 mL) at room temperature and stirred for 1h. The reaction mixture cooled to 0 °C and added NaBH ₄ (385 mg, 10.14 mmol) portion wise and continued the stirring at rt for 2h. The reaction progress was monitored by TLC, after completion of the reaction, reaction mass quenched with water and extracted with EtOAc. The organic layer washed with cold water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (20% EtOAc in Hexane as eluent) to afford compound 7 (700 mg, 43.7%) as a pale-yellow liquid. [0557] LCMS: m/z: 476.71 [M+1H] ⁺ , 95.05% (1.20 min). [0558] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 ìm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90), Flow Rate: 0.4 mL/min. Step-5: [0559] To a stirred solution of compound 8 (915 g, 4.42 mmol) in DCM (20 mL) was added oxalyl chloride (1.1 mL, 13.26 mmol as per acid) followed by cat DMF (0.2 mL) at 0 °C. Then the reaction mixture allowed to stir at room temperature for 3h. Completion of the reaction was monitored by TLC; after completion of reaction solvent was evaporated under reduced pressure at N2 atmosphere. The resulting crude dissolved in DCM (20 mL) and added to a solution of compound 7 (700 mg, 1.47 mmol) in DCM (30 mL) and TEA (3 mL, 22.10 mmol as per acid) at 0 °C. The resulting mixture stirred at rt for 3h. Completion of the reaction was monitored by TLC; after completion, reaction mass diluted with DCM and washed with water, brine solution. Organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by C-18 column chromatography (65% ACN in 0.1 FA as an eluent) to afford compound 9 (380 mg, 38.8%) as brown gum. [0560] LCMS: m/z: 666.50 [M+1H] ⁺ , 98.29% (1.73 min). [0561] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 ìm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90), Flow Rate: 0.4 mL/min. Step-6: [0562] To a solution of compound 9 (40 mg, 0.06 mmol) in DMA (10 mL) was added KOAc (30 mg, 0.30 mmol) and Pd(P ^t Bu3) ₂ (3 mg, 0.006 mmol) at room temperature. The reaction mixture degassed with nitrogen for 10 min. The reaction mixture stirred at 150 °C in microwave for 1.5h. Progress of the reaction was monitored by TLC, after completion of the reaction, reaction mass poured into ice-cold water and extracted with EtOAc. The organic layer washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude residue was purified by C-18 column chromatography (70% ACN in 0.1 FA as an eluent and lyophilized) to afford compound 10 (15 mg, 42.8%) as off-white solid. [0563] LCMS: m/z: 584.84 [M+1H] ⁺ , 82.48% (1.68 min). [0564] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 ìm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90), Flow Rate: 0.4 mL/min. Scheme 14: Synthesis of I-1016 and I-1017

Step-1: [0565] To a stirred solution of compound 1 (22 g, 194.6 mmol) in acetone (29 ml, 389.3 mmol) was added piperidine (1 ml) and acetic acid (22 ml) stirred at 90 ^o C for 24h. The progress of the reaction was monitored by TLC. After completion of starting material, the reaction mixture was cooled to rt and then concentrated under vacuum. The residue was diluted with 50 ml of water and extracted with ethyl acetate. The organic layer washed with brine solution, dried over Na ₂ SO _4, filtered, and concentrated in vacuo to afford crude compound. Crude was purified by column chromatography using a silica gel (100: 200 mesh), and compound was eluted using 3% EtOAc in Hexane as an eluent to afford compound 2 (20 g, 67%) as pale-yellow oil. [0566] LCMS: m/z = 176.23 [M+Na] ⁺ , 82.14 % (1.34 min). [0567] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-2: [0568] N, N-Dimethylformamide dimethyl acetal (19 ml, 143.79 mmol) was added dropwise to a stirred solution of compound 2 (20 g 130.71 mmol) in ethanol (200 ml). The resulting solution was stirred for 15 h at 80 ^o C. After completion of the reaction, the reaction mixture was cooled to rt and concentrated under vacuum. The residue was diluted with 50 ml of water and extracted with ethyl acetate (200 ml). The organic layer washed with brine solution, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo to afford crude compound. Crude was purified by column chromatography using a silica gel (100: 200 mesh), and compound was eluted using 5% EtOAc in Hexane as an eluent to afford compound 3 (22 g, 80.8%). [0569] LCMS: m/z = 231.16 [M+Na] ⁺ , 74.15 % (1.22 min). [0570] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-3: [0571] HBr (40% in acetic acid, 125 ml) was added dropwise to a 40 ^o C stirred solution of compound 3 (25 g, 120.19 mmol) in acetic acid (125 ml), and the resulting solution was stirred for 15h at 55 ^o C. The reaction mixture was cooled to rt and then poured into 10 ml of cold water. The pH value of the solution was adjusted to 9 with 2M aqueous sodium carbonate solution. Concentrated under vacuum. The resulting mixture was extracted with ethyl acetate (500 ml). The organic layer was washed with brine solution, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo to afford crude compound. Crude was purified by column chromatography using a silica gel (100: 200 mesh), and compound was eluted using 5% EtOAc in Hexane as an eluent to afford compound 4 (23 g, 78.7%) as a brown liquid. [0572] LCMS: m/z = 244.01 [M+1] ⁺ , 90.09 % (2.46 min). [0573] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) Flow Rate: 0.4 mL/min. Step-4: [0574] To a stirred solution of compound 4 (6 g, 24.69 mmol) in Dioxane:H ₂ O (60 ml 1:1) was added NaOH (3.95 g, 98.76 mmol) at 0 ^o C, and then the reaction mixture was stirred at 80 ^o C for 15 h. The mixture was allowed to cool to RT, diluted with H ₂ O, and washed with ethyl acetate (3 x 30 mL). The aqueous layer was acidified with concentrated hydrochloric acid to make pH=1 and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (25 mL), dried over Na ₂ SO ₄ , and filtered. The filtrate was concentrated in vacuo to afford the compound 5 (2.2 g, 41.5%) as a white solid. [0575] LCMS: m/z = 213.99 [M-1]-, 98.04 % (0.44 min). [0576] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min.

Step-5: [0577] Compound 5 (4 g, 18.604 mmol) in SOCl ₂ (40 ml) was stirred at 70 ^o C for 2 h. Completion of the reaction was monitored by TLC. After completion of reaction, solvent was evaporated under reduced pressure at N2 atmosphere. The resulting crude dissolved in DCM (20 ml) and added to a solution of compound 6 (2.3 g, 14.833 mmol) in DCM (20 ml) and TEA (10 ml, 74.418 mmol) at 0 °C. The resulting mixture stirred at rt for 4 h. Completion of the reaction was monitored by TLC. After completion, the reaction was diluted with DCM (200 ml) and washed with water and brine solution. The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The crude compound was purified using silica gel (100:200 mesh), and compound was eluted with 20% EtOAc in hexane to afford compound 7 as an off-white solid (4.3 g, 65.7%). [0578] LCMS: m/z = 353.07 [M+1] ⁺ , 98.09 % (1.34 min). [0579] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-6: [0580] To a stirred solution of compound 7 (4 g, 11.363 mmol) in DMF (40 mL) was added NaH (818 mg, 34.083 mmol) at 0 ^o C followed by MOM-Cl (1.36 g, 17.045 mmol), and then the reaction mixture was stirred at rt for 6 h. The reaction was monitored by TLC, and then the reaction mixture was poured into ice cold water and extracted with DCM (200 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. The crude compound was purified by column chromatography using a silica gel (100:200 mesh) using 20% EtOAc:Hexane as an eluent to afford compound 8 as a white solid (2.5 g, 55.5%). [0581] LCMS: m/z = 419.13 [M+Na] ⁺ , 75.19 % (1.44 min). [0582] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-7: [0583] To a stirred solution of compound 8 (2.0 g, 5.05 mmol) in DMA (20 ml), potassium acetate (2.47 g, 25.252 mmol) was added, followed by Pd(PtBu3) ₂ (258 mg, 0.252 mmol). The reaction mixture was then stirred at 150 °C for 16 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was poured into ice-cold water and extracted with ethyl acetate (200 ml x 3). The organic layers were dried over anhydrous Na ₂ SO ₄ and evaporated to afford the crude compound. The crude compound was purified by column chromatography using silica gel (100-200 mesh), and the compound was eluted using 10% EtOAc in hexane to yield compound 9 as an off-white solid (820 mg, 51.5% yield). [0584] LCMS: m/z = 317.25 [M+1] ⁺ , 96.44 % (1.65 min). [0585] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-8: [0586] To a stirred mixture of compound 9 (1.1 g, 3.481 mmol) in H ₂ SO ₄ (11 ml), 1,3-Dibromo- 5,5-dimethyl hydantoin (992 mg, 3.481 mmol) was added at 0°C, and the reaction was continued at 0 °C for 1 hour. The reaction progress was monitored by TLC. After the completion of the reaction, the mixture was quenched in ice water and extracted with DCM. The organic layer was concentrated under reduced pressure to yield crude compound 10 as a brown solid (800 mg, 66.1%). The crude product was used for the next step without purification. [0587] LCMS: m/z = 351.16 [M+1] ⁺ , 85.53 % (1.61 min). [0588] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-9: [0589] To a stirred solution of compound 10 (500 mg, 1.428 mmol) in 5 ml of dioxane, compound 11 (773 mg, 2.142 mmol) was added, followed by potassium carbonate (591 mg, 4.285 mmol). The reaction mixture was degassed for 15 minutes, and then Pd(dppf)Cl2 (63 mg, 0.085 mmol) was added. It was degassed again for 10 minutes, and the reaction mixture was stirred at 85°C for 1 hour under microwave irradiation. The reaction was monitored by TLC. After completion, the reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to obtain the crude compound. The crude product was purified by column chromatography using silica gel (100-200 mesh) to yield the off-white solid. [0590] LCMS: m/z = 506.71 [M+1] ⁺ , 54.01 % (1.61 min). [0591] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-10: [0592] To a stirred solution of crude compound 12 (300 mg, 0.594 mmol) in 1,4-dioxane (3 ml), dioxane/HCl (4 ml) was added at 0°C, and the reaction mixture was stirred at room temperature for 4 hours. The reaction was monitored by TLC and LCMS. After the completion of the reaction, the excess TFA was evaporated in vacuo. The residue was purified by preparative HPLC and lyophilized to yield I-1016 (5 mg, 2.08%) as a white solid. [0593] LCMS: m/z: 406.35 [M+1] ⁺ , 96.96% (1.82 min). [0594] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm). [0595] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN. [0596] (T/%B: 0.01/10, 0.5/10, 4/90, 7/90). [0597] Flow Rate: 0.4 mL/min. [0598] ¹ H NMR [400 MHz, DMSO-d6]: δ 8.39 (brs, 1H), 8.02 (d, J = 4.8 Hz, 1H), 7.20-7.16 (m, 3H), 7.04 (d, J = 6.4 Hz, 2H), 3.49 (s, 3H), 2.86-2.79 (m, 3H), 2.67 (s, 3H), 2.43 (s, 3H), 1.30 (d, J = 6Hz, 3H). Step-11: [0599] Compound 12 (150 mg, 0.29 mmol) was suspended in 40% HBr in water (3 mL) and stirred at 80 °C for 2 hours. The reaction progress was monitored by LCMS. After completion of the reaction, the excess HBr was evaporated to afford the crude compound. The residue was purified by preparative HPLC and lyophilized to yield I-1017 (15 mg, 12.9%) as a white solid. [0600] LCMS: m/z: 392.29 [M+1] ⁺ , 96.36% (1.71 min). [0601] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm). [0602] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN. [0603] (T/%B: 0.01/10, 0.5/10, 4/90, 7/90). [0604] Flow Rate: 0.4 mL/min. [0605] ¹ H NMR [400 MHz, DMSO-d ₆ ]: 7.97 (d, J = 4.4 Hz, 1H), 7.13 (d, J = 4.4 Hz, 3H), 6.96 (s, 2H), 2.79 (s, 3H), 2.73-2.69 (m, 3H), 2.42 (s, 3H), 1.26 (d, J = 6.4Hz, 3H). Scheme 15: Synthesis of II-1007

Step 1: [0606] To a stirred solution of compound 1 (30 g, 0.194 mol) in DMF (300 mL) was added NBS (41.5 g,0.233 mol) at 0 °C. The resulting mixture stirred at 60 ^o C for 16 h. Completion of the reaction was monitored by TLC. After completion, the reaction was extracted with EtOAc. The organic layer was washed with sat. NaHCO _3, water, and brine solution. The organic layer was then dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The crude compound was triturated with ether, filtered, and dried to afford to afford compound 2 as a brown solid (34.9 g, Yield: 77.6%) as an off white solid. [0607] LCMS: m/z: 234.79 [M+2H] ⁺ , 90.21 % (1.07 min). [0608] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 2: [0609] A solution of compound 2 (34.9 g, 0.149 mol) in POCl ₃ (137 ml, 1.497 mol) was stirred at rt, and then the reaction mixture was stirred at 100 ^o C for 3h. Reaction was monitored by TLC; after completion of the reaction, the mixture was diluted with ice water, quenched with aq. NaHCO ₃ , and extracted with water and DCM. The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound (used for the next step without any purification). [0610] LCMS: m/z: 252.86 [M+2H] ⁺ , 93.29 % (1.54 min). [0611] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 3: [0612] To a stirred solution of compound 3 (28 g, 0.111 mol) in MeOH (280 mL) was added sodium methoxide (7.5 g, 0.140 mol) at 0 °C. The resulting mixture stirred at 80 ^o C for 3 h. Completion of the reaction was monitored by TLC. After completion, the reaction mixture was evaporated under vacuum and then extracted with EtOAc and water. The organic layer was washed with brine solution. The organic layer was then dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The crude compound was triturated with ether, filtered, and dried to afford compound 4 (20 g, Yield: 74.0%) as brown solid. [0613] LCMS: m/z: 247.21 [M+1H] ⁺ , 88.32 % (1.62 min). [0614] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min.

Step 4: [0615] To a stirre d solution of compound 4 (2 g, 0.009 mol) and compound 5 (3.5 g, 0.009 mol) in Dioxane (20 mL) and water (2 ml) was added K2CO ₃ (3.3 g, 0.024 mol) and Pd-118 (264 mg, 0.024 mmol) at room temperature. The resulting reaction mixture was degassed with nitrogen for 10 min. Then the reaction mixture heated to 80 °C and stirred for 16 h. The reaction was monitored by TLC. The reaction mixture was then poured into ice cold water and extracted with ethyl acetate, and the organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound 6. Crude compound was purified by column chromatography using silica gel (100:200 mesh), and compound was eluted using 20% EtOAc in Hexane to afford compound 6 (2 g, Yield: 66.0%) as a white solid. [0616] LCMS: m/z: 346.10 [M-BOC] ⁺ , 83.25 % (1.88 min). [0617] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90), Flow Rate: 0.4 mL/min. Step 5: [0618] To a stirred solution of compound 6 (4 g, 0.010 mol) in THF (20 mL) and water (6.8 mL) was added Iron Powder (5 g, 0.050 mol) and NH4Cl (6.7 g, 0.107 mol). The resulting mixture stirred at 80 ⁰ C for 10h. Completion of the reaction was monitored by TLC. After completion, the reaction mixture was filter, passed through celite at room temperature, and evaporated under vacuum, then extracted with EtOAc (2x500 mL) and water (500 mL). The organic layer was washed with brine solution. Then the organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. Crude compound was purified by column chromatography using silica gel (100: 200 mesh). Compound was eluted using 10% EtOAc in Hexane to afford compound 7 (2 g, Yield: 50 %) as a white solid. [0619] LCMS: m/z: 372.24 [M+1H] ⁺ , 79.48 % (1.53 min). [0620] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 6: [0621] To a stirred solution of compound 7 (2.6 g, 0.010 mol) in MeOH (30 mL) was added AcOH (2 mL) followed by compound 8 (1.4 mL, 0.011 mol) at room temperature. The resulting reaction mixture was allowed to stir at room temperature for 1 h, then NaBH4 (785 mg, 0.021 mmol) was added slowly at 0 ^o C. The resulting reaction mixture was allowed to stir at room temperature for 2 h. Completion of the reaction was monitored by TLC, and after completion, the reaction was directly evaporated under vacuum than extracted with DCM (300 mL) and water (300 mL) and washed with brine solution (300 mL). The organic layer dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The crude compound was purified by silica gel (100-200 mesh) column chromatography (5-7% ethyl acetate in hexane as eluent) to afford pure compound 9 (2.3 g, Yield: 69.7%) as a white solid. Step 7: [0622] To a stirred solution of compound 9 (1.6 g, 0.008 mol) in DCM (40 mL) was added TEA (3.4 mL, 0.024 mmol) at room temperature. Compound 10 (4 g, 0.004 mmol) was added at 0 ^o C. The resulting reaction mixture was allowed to stir at room temperature for 3 h. Completion of the reaction was monitored by TLC, and after completion, the reaction was diluted with DCM and washed with aq. NaHCO ₃ solution and brine solution. The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. Crude compound was purified by column chromatography using silica gel (100:200 mesh), and compound was eluted using 30% EtOAc in Hexane to afford compound 11 (1.2 g, Yield: 22%). [0623] LCMS: m/z: 682.1 [M+2H] ⁺ , 80.31 % (1.96 min). [0624] Method: Column: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A- 0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 8: [0625] To a stirred solution of compound 11 (1.6 g, 0.002 mol) in DMA (16 mL) was added KOAc (1.29 g, 0.009 mol), Pd(P ^t Bu ₃ ) ₂ (61 mg, 0.0001 mol) at room temperature. The reaction mixture was degassed with nitrogen for 20 min, then heated to 150 °C and stirred for 4h. Completion of the reaction was monitored by TLC, and after completion, the reaction mixture was poured into crushed ice, and the solid was filtered. The solid was dissolved in 10% MeOH in DCM, washed with brine solution, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The crude compound was triturated with Ether, filtered, and dried to afford pure compound as an off- white solid. Crude compound was purified by column chromatography using silica gel (100:200 mesh), and compound was eluted using 10% EtOAc in Hexane to afford compound 12 (80 mg, Yield: 5%). [0626] LCMS: m/z: 600.27 [M+1H] ⁺ , 92.03 % (1.99 min). [0627] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in CAN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 9: [0628] To a stirred solution of compound 12 (100 mg,0.207 mmol) was added HBr in AcOH (2 mL) at 0 ^o C, and then the reaction mixture was stirred at 100 ⁰ C for 8h. The reaction was monitored by TLC; after completion of the reaction, solvent was evaporated, then the reaction mixture was quenched in water and extracted with DCM. The aqueous layer was purified by C- 18 reverse phase column chromatography to afford crude compound 13 (80 mg, Yield: 80 %) as a white solid. [0629] LCMS: m/z: 468.23 [M+1H] ⁺ , 81.83% (0.83 min). [0630] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min.

Step 10: [0631] To a stirred solution of compound 13 (100 mg,0.273 mmol) was added POCl ₃ (2 ml) at 0 ^o C, and then the reaction mixture was stirred at100 ^o C for 16h. The reaction was monitored by TLC; after completion of the reaction, solvent was evaporated, and then the reaction mixture was quenched in water and extracted with DCM. The aqueous layer was purified by C-18 reverse phase column chromatography to afford crude compound II-1007 (4 mg, Yield: 4 %) as a yellow solid. [0632] LCMS: m/z: 384.17 [M+1H] ⁺ , 99.43% (1.81 min). [0633] Method: Column: Acquity BEH C ₁ 8 (2.1 x 50 mm, 1.7 μm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90), Flow Rate: 0.4 mL/min. [0634] ¹ H NMR [400 MHz, DMSO-d ₆ ]: ¹ H NMR [400 MHz, DMSO-d ₆ ]: 8.32 (s, 1H), 7.7 (d, J = 9.2 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 5.91 (d, J = 5.91 Hz, 2H) ,2.95-2.90 (m, 3H), 2.60 (s, 3H), 1.30-1.279 (m, 3H).

Scheme 16: Synthesis of I-1011 Step 1: [0635] NaOMe (11.3 g, 210.172 mol) was added portion wise to a solution of compound 1 (25 g, 105.086 mol) dissolved in DMSO (250 mL) at room temperature under nitrogen atmosphere. The mixture was stirred for 16h and then poured into water and extracted with ethyl acetate (2x1000 mL). The organic phase was washed with water (1000 mL) and brine (1000 mL), dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure. Crude compound was purified by column chromatography using silica gel (100:200 mesh) compound was eluted using 4% EtOAc in Hexane to afford compound 2 (12.8 g, Yield: 48.7%) as a brown solid. [0636] ¹ H NMR [400 MHz, DMSO-d ₆ ]: 8.01-7.98 (m, 1H), 7.39 (t, J = 8.4 Hz 1H), 3.95 (s, 3H). Step 2: [0637] To a stirred solution of compound 2 (12.8 g, 51.200 mmol) in Dioxane (128 ml) solution was added compound 2 (3.98 g, 66.560 mmol) followed by Cs ₂ CO ₃ (50.06 g, 153.600 mmol). Reaction mixture was degassed for 15 minutes then Palladium catalyst (2.2 g, 3.072 mmol) was added and again degassed for 10 minutes then reaction mixture was stirred at 85 ^o C for 16 h. The reaction was monitored by TLC. The reaction mixture was thenpoured into ice cold water and extracted with ethyl acetate, and the organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude compound was purified by column chromatography using a silica gel (100:200 mesh), and compound was eluted using 5% EtOAc in Hexane to afford compound 3 (6.5 g, Yield: 68.6%) as a brown solid. [0638] ¹ H NMR [400 MHz, CDCl3]: 7.92-7.89 (m, 1H), 6.89 (t, J = 8.4 Hz, 1H), 3.97(s, 3H), 2.54 (d, J = 2.8 Hz, 3H). Step 3: [0639] To a solution mixture of compound 3 (10 g, 54.054 mmol) in THF-water (100 mL, 3:1 ratio) was added Fe (15.09 g, 270.2 mmol) followed by ammonium chloride (28.9 g, 540.12 mmol) at rt and continued at 60 ^o C for 2h. Reaction mixture was basified with sat. NaHCO ₃ solution and extracted with EtOAc. Total organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to afford compound 4. Crude compound was used for the next step without purification. (10 g, crude). [0640] LCMS: m/z = 156.06 [M+H] ⁺ , 17.41% (0.71 min). [0641] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 4: [0642] To a stirred solution of compound 4 (7.8 g, 38.613 mmol) in DCM (78 ml) was added compound 5 (5.98 g, 38.613 mmol) followed by EDC.HCl (14.8 g, 77.226 mmol), and then the reaction mixture was stirred at room temperature for 16h. The reaction was monitored by TLC; after completion of reaction, solvent was evaporated by reduced pressure and crude compound was purified by column chromatography using silica gel (100:200 mesh). Compound was eluted using 10% EtOAc in Hexane to afford compound 6 (7 g, Yield: 53.5%) as a brown solid. [0643] LCMS: m/z = 341.08 [M+2H] ⁺ , 36.77% (1.30 min). [0644] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 5: [0645] To a stirred solution of compound 6 (7 g, 20.648 mmol) in DMF (70 mL) was added 60% NaH (1.4 g, 61.944 mmol) at 0 ^o C and stirred for 20 min. PMB-Cl (4.8 g, 30.973 mmol) added at 0 °C. The resulting reaction mixture allowed to stir at room temperature for 3h. Completion of the reaction was monitored by TLC, and after completion of reaction, the reaction mixture was quenched with sat. NH4Cl solution and extracted with EtOAc (2x500 mL). The organic layer was washed with brine solution, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. Crude compound was purified by column chromatography using silica gel (100:200 mesh), and compound was eluted using 10% EtOAc in Hexane to afford compound 7 (5.6 g, Yield: 59.1%) as a brown solid. [0646] LCMS: m/z = 461.09 [M+2H] ⁺ , 54.59% (1.30 min). [0647] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 6: [0648] To a stirred solution of compound 7 (5 g, 10.893 mmol) in DMA (50 mL) was added KOAc (4.27 g, 43.572 mmol), Pd(P ^t Bu ₃ ) ₂ (333 mg, 0.653 mmol) at room temperature. The resulting reaction mixture degassed with nitrogen for 15 min. Then the reaction mixture was heated to 150 °C and stirred for 16h. Completion of the reaction was monitored by TLC. After completion, the reaction was cooled to RT, quenched with cold water, and extracted with EtOAc. The organic layer was then dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. Crude compound was purified by column chromatography using silica gel (100:200 mesh), and compound was eluted using 10% EtOAc in Hexane to afford compound 8 (2.1 g, Yield: 51.1%) as a white solid. [0649] LCMS: m/z = 379.20 [M+1H] ⁺ , 65.44% (1.69 min). [0650] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 7: [0651] To a solution mixture of compound 8 (1.5 g, 3.968 mmol) in H ₂ SO ₄ (15 mL) was added 1,3-Dibromo-5,5-dimethyl hydantoin (1.1 g, 3.968 mmol) at 0 ^o C, and the reaction was stirred at 0 ^o C for 1h. The reaction was monitored by TLC; after completion of the reaction, the mixture was quenched in ice water and extracted with DCM. The organic layer was concentrated under reduced pressure, and the crude was washed with pentane and diethyl ether to afford compound 9 (1.2 g, Yield: 90.2%) as a brown solid. [0652] LCMS: m/z = 339.00 [M+2H] ⁺ , 79.84% (1.46 min). [0653] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 8: [0654] To a stirred solution of compound 9 (1 g, 4.219 mmol) in Dioxane (10 mL) solution was added compound 10 (2.2 g, 6.329 mmol) followed by K2CO ₃ (1.7 g, 12.657 mmol). The reaction mixture was degassed for 15 minutes, and then Pd(dppf)Cl2 catalyst (164 mg, 0.253 mmol) was added and again degassed for 10 minutes. The reaction mixture was then stirred at 85 ^o C for 16h. The reaction was monitored by TLC. The reaction mixture was then poured into ice cold water and extracted with ethyl acetate (2x300 mL), and the organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude compound was purified by column chromatography using silica gel (100:200 mesh), and compound was eluted using 20% EtOAc in Hexane to afford compound 8 (243 mg, Yield: 16.7%) as a white solid. [0655] LCMS: m/z = 492.31 [M+1H] ⁺ , 7.83% (1.76 min). [0656] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 9: [0657] To a stirred solution of compound 11 (486 mg, 0.989 mmol) in 1,4-dioxane (4.8 mL) was added dioxane/HCl (2.969 mL) at 0 ^o C then reaction mixture was stirred at room temperature for 2h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with aq. NaHCO ₃ and extracted with ethyl acetate. Crude compound was purified by column chromatography using silica gel (100:200 mesh), and compound was eluted using 40% EtOAc in Hexane to afford compound 12 (200 mg, Yield: 51.7%) as a white solid. [0658] LCMS: m/z = 392.21 [M+1H] ⁺ , 32.33% (0.96 min). [0659] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min.

Step 10: [0660] To a stirred solution of compound 12 (150 mg, 0.383 mmol) in DCM (1.5 ml) was added boron tribromide (1.1 mL, 1.150 mmol) at 0 ⁰ C, and then the reaction mixture was stirred at RT for 15h. The reaction was monitored by TLC; after completion of the reaction, solvent was evaporated, and then the reaction mixture was quenched in water and extracted with DCM. The aqueous layer was purified by C-18 reverse phase column chromatography to afford I-1011. Scheme 17: Synthesis of II-1001(R) Step-1: [0661] To a stirred solution of compound 1 (20 g, 0.096 mmol) in DMF (250 mL) was added compound 2 (13.3 g, 0.096 mmol) followed by DIPEA (53 mL, 0.28 mmol) and HATU (54 g, 0.144 mmol), and then the reaction mixture was stirred at room temperature for 5h. The reaction was monitored by TLC; the reaction mixture was poured into ice cold water and extracted with EtOAc (2x1L), and the organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude compound was purified by column chromatography using silica gel (100:200 mesh), and compound was eluted using 20% EtOAc in Hexane to afford compound 3 (20 g, Yield: 64%) as an off white solid. [0662] LCMS: m/z = 335.20[M+2H] ⁺ , 93.03 % (1.68 min). [0663] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-2: [0664] To a stirred solution of compound 3 (10 g, 0.030 mol) in DMF (100 mL) was added NaH (2.2 g, 0.09 mol) at 0 ^o C followed by PMB-Cl (7 mL, 0.06 mol), and then the reaction mixture was stirred at rt for 3h. The reaction was monitored by TLC. The reaction mixture was then poured into ice cold water and extracted with EtOAc (2x500 mL), and the organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude compound was purified by column chromatography using silica gel (100:200 mesh), and compound was eluted using 10% EtOAc in Hexane to afford compound 4 (8 g, Yield: 59%) as an off white solid. [0665] LCMS: m/z = 447.35 [M+2H] ⁺ , 80.52 room temperature % (1.65 min). [0666] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-3: [0667] To a stirred solution of compound 4 (15 g, 0.033 mmol) in DMA (150 mL) was added potassium acetate (13.1 g, 0.134 mol) followed by Pd (P ^t Bu ₃ ) ₂ catalyst (1.01 g, 0.002 mmol), and then the reaction mixture was stirred at 150 ^o C for 4h. The reaction was monitored by TLC; the reaction mixture was then poured into ice cold water and extracted with ethyl acetate (2x 200 mL), and the organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude compound was used for the next step without purification. Crude compound was purified by column chromatography using silica gel (100:200 mesh), and compound was eluted using 10% EtOAc in Hexane to afford compound 5 (3.5 g, Yield: 28.7 %) as an off-white solid. Step-4: [0668] Trifluoro acetic acid (50 mL) was added to compound 5 (11 g, 0.030 mol) at 0 ^o C. The resulting reaction mixture was allowed to warm to room temperature and stirred at 100 °C for 16h. Completion of the reaction was monitored by TLC, and after completion, the reaction mixture was quenched with aq. NaHCO ₃ solution and extracted with EtOAc (2x200 mL). The organic layer was washed with brine solution (100 mL), dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. Crude compound was purified by column chromatography using silica gel (100:200 mesh), and compound was eluted using 10% EtOAc in Hexane to afford compound 6 (1.1 g, Yield: 42.8 %) as an off-white solid. [0669] LCMS: m/z = 246.16 [M+H] ⁺ , 87.7% (1.15min). [0670] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-5: [0671] To a stirred solution of compound 6 (1 g, 0.004 mol) in 2 mL (1:1) DCM was added NBS (863 mg, 0.004 mol) at 0 ^o C, and then the reaction mixture was stirred at room temperature for 16h. The reaction was monitored by TLC; the reaction mixture was then poured into ice cold water and extracted with DCM (2x100 mL), and the organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude compound was purified by column chromatography using silica gel (100:200 mesh), and compound was eluted using 20% EtOAc in Hexane to afford compound 7 (500 mg, Yield: 38%) as an off white solid. [0672] LCMS: m/z = 325. [M+H] ⁺ , 66.37% (1.44 min). [0673] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min.

Scheme 18: Synthesis of II-1008 Step-1: [0674] To a cold solution of compound 1 (3 g, 11.90 mmol) in THF (30 mL) was added 60% NaH (525 mg, 13.147 mmol) followed by diethylmalonate (2.2 mL, 13.147 mmol). After addition, the reaction mixture was stirred for 15 min, and the solvent was evaporated under reduced pressure. The resulting residue was stirred at 110 °C for 1.5 h. The reaction mixture was brought to 0 °C and 6M aqueous H ₂ SO ₄ (17 mL) was added. The resulting suspension was stirred at 110 °C overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was poured into cold water and basified with NaHCO _3. The resulting precipitate was filtered and dissolved in EtOAc, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo to afford compound 2 (1.5 g, 54.5%) as a reddish solid. [0675] LCMS: m/z: 232.98 [M+2H] ⁺ , 98.19% (1.61 min). [0676] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 ìm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90), Flow Rate: 0.4 mL/min. [0677] ¹ H NMR [400 MHz, CDCl3]: δ 8.44 (s, 1H), 2.80 (s, 3H), 2.72 (s, 3H). Step-2: [0678] To a stirred solution of compound 2 (2 g, 8.63 mmol) and compound 3 (4.7 g, 12.95 mmol) in Dioxane (20 ml) and water (2 ml) was added NaHCO ₃ (2.17 g, 25.89 mmol) and Pd(dppf)Cl ₂ (315 mg, 0.43 mmol) at room temperature. The resulting reaction mixture was degassed with nitrogen for 10 min. Then the reaction mixture was stirred at 90 °C for 6h. The progress of the reaction was monitored by TLC, and after completion of the reaction, the solvent was evaporated. The residue was dissolved in EtOAc and washed with water and brine solution. The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (15% EtOAc in Hexane as eluent) to afford compound 4 (2.5 g, 75%) as a yellow liquid. [0679] LCMS: m/z: 386.31 [M+1H] ⁺ , 97.7% (1.83 min). [0680] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 ìm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90), Flow Rate: 0.4 mL/min. [0681] ¹ H NMR [400 MHz, CDCl3]: δ 8.15 (s, 1H), 7.33-7.26 (m, 4H), 4.52 (brs, 1H), 3.43- 3.38 (m, 1H), 3.29-3.23 (m, 1H), 3.03-2.97 (m, 1H), 2.88 (s, 3H), 2.58 (s, 3H), 1.42 (s, 9H), 1.31 (d, J=6.8 Hz, 3H). Step-3: [0682] To a stirred solution of compound 4 (2.7 g, 7.01 mmol) in THF (30 mL) and water (4.5 mL) was added Iron Powder (1.9 g, 35.06 mmol) and NH ₄ Cl (3.7 g, 70.12 mmol). The resulting mixture was stirred at 80 °C overnight. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was filtered through celite and washed with EtOAc, and the two layers were separated. The organic layer was washed with brine solution, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (20% EtOAc in hexane as eluent) to afford compound 5 (1.6 g, 64.2%) as a yellow liquid. [0683] LCMS: m/z: 356.76 [M+1H] ⁺ , 85.10% (1.04 min). [0684] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 ìm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90), Flow Rate: 0.4 mL/min. Step-4: [0685] To a stirred solution of compound 5 (1.2 g, 3.38 mmol) in MeOH (10 mL) was added compound 6 (0.6 mL, 4.05 mmol) followed by cat AcOH (0.1 mL) at room temperature, and the reaction was stirred for 1h. The reaction mixture was cooled to 0 °C, and NaBH4 (385 mg, 10.14 mmol) was added portion wise. Stirring was continued at rt for 2h. The reaction progress was monitored by TLC, and after completion of the reaction, the reaction was quenched with water and extracted with EtOAc. The organic layer was washed with cold water and brine, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (20% EtOAc in Hexane as eluent) to afford compound 7 (700 mg, 43.7%) as a pale-yellow liquid. [0686] LCMS: m/z: 476.71 [M+1H] ⁺ , 95.05% (1.20 min). [0687] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 ìm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90), Flow Rate: 0.4 mL/min. Step-5: [0688] To a stirred solution of compound 8 (915 g, 4.42 mmol) in DCM (20 mL) was added oxalyl chloride (1.1 mL, 13.26 mmol as per acid) followed by cat DMF (0.2 mL) at 0 °C. Then the reaction mixture allowed to stir at room temperature for 3h. Completion of the reaction was monitored by TLC; after completion of the reaction, solvent was evaporated under reduced pressure at N ₂ atmosphere. The resulting crude was dissolved in DCM (20 mL) and added to a solution of compound 7 (700 mg, 1.47 mmol) in DCM (30 mL) and TEA (3 mL, 22.10 mmol as per acid) at 0 °C. The resulting mixture was stirred at rt for 3h. Completion of the reaction was monitored by TLC; after completion, the reaction was diluted with DCM and washed with water and brine solution. The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The crude compound was purified by C-18 column chromatography (65% ACN in 0.1 FA as an eluent) to afford compound 9 (380 mg, 38.8%) as a brown gum. [0689] LCMS: m/z: 666.50 [M+1H] ⁺ , 98.29% (1.73 min). [0690] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 ìm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90), Flow Rate: 0.4 mL/min. Step-6: [0691] To a solution of compound 9 (40 mg, 0.06 mmol) in DMA (10 mL) was added KOAc (30 mg, 0.30 mmol) and Pd(P ^t Bu ₃ ) ₂ (3 mg, 0.006 mmol) at room temperature. The reaction mixture was degassed with nitrogen for 10 min. The reaction mixture stirred at 150 °C in microwave for 1.5h. Progress of the reaction was monitored by TLC, and after completion of the reaction, the reaction was poured into ice-cold water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The crude residue was purified by C-18 column chromatography (70% ACN in 0.1% FA as an eluent and lyophilized) to afford compound 10 (15 mg, 42.8%) as off-white solid. [0692] LCMS: m/z: 584.84 [M+1H] ⁺ , 82.48% (1.68 min). [0693] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 ìm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90), Flow Rate: 0.4 mL/min.

Scheme 19: Synthesis of I-1001 and I-1002 Step-1: [0694] To a stirred solution of 20 g of compound 1 (99.50 mmol) in 100 mL of DCM, oxalyl chloride (18.2 mL, 144 mmol) was added, and the reaction mixture was stirred at room temperature for 4 hours. The reaction progress was monitored by TLC. After the completion of the reaction, the solvent was evaporated under reduced pressure, and the crude product was used for the next step without further purification. To a stirred solution of a derivative of compound 1 (20 g, 90 mmol) in 50 mL of DCM, compound 2 (8.4 g, 60 mmol) was added, followed by TEA (18.3 g, 180 mmol) at 0°C. The resulting reaction mixture was stirred at room temperature for 15 hours, and the progress of the reaction was monitored by TLC. After completion, the reaction mixture was poured into ice-cold water and extracted with DCM. The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to yield crude compound 3 (15 g, 47.1% yield) as a brown liquid, which was used for the next step without further purification. Step-2: [0695] To a stirred solution of compound 3 (14 g, 40 mmol) in DMF (140 ml), NaH (3.14 g, 130 mmol) was added at 0°C, followed by PMB-Cl (10.20 g, 60 mmol). The reaction mixture was stirred at room temperature for 18 hours, and the progress of the reaction was monitored by TLC. After completion, the reaction mixture was poured into ice-cold water and extracted with DCM. The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to yield the crude compound. The crude compound was further purified by column chromatography using silica gel (100-200 mesh) with 10% EtOAc in hexane as the eluent, resulting in compound 4 (9 g, 46.7% yield) as an off-white solid. [0696] LCMS: m/z: 441.52 [M+H] ⁺ , 75.12% (5.97 min). [0697] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 ìm) [0698] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, [0699] (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0700] Flow Rate: 0.4 mL/min. Step-3: [0701] To a stirred solution of compound 4 (1.5 g, 3.40 mmol) in DMA (15 mL), potassium acetate (1.2 g, 12.3 mmol) was added, followed by a palladium catalyst (127 mg, 0.014 mmol). The reaction mixture was stirred at 150°C for 4h. The reaction progress was monitored by TLC. After completion, the reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to yield crude compound 5 (600 mg, 49.1% yield) as a yellowish gummy. The crude compound was used for the next step without further purification. [0702] LCMS: m/z: 361.23 [M+H] ⁺ , 75.12% (5.97 min), [0703] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 ìm), [0704] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, [0705] (T/%B: 0.01/10, 0.5/10, 5/40, 10/90) [0706] Flow Rate: 0.4 mL/min. Step-4: [0707] Compound 5 (500 mg, 1.38 mmol) in a 50 mL round-bottom flask was treated with 5 mL of TFA at 0°C. The resulting reaction mixture was stirred at 100°C for 4 hours, and the reaction progress was monitored by TLC. After the completion of the reaction, TFA was evaporated under reduced pressure, and the mixture was then made basic by adding saturated sodium bicarbonate. The mixture was extracted with ethyl acetate (50 mL x 3). The organic layer was dried over Na ₂ SO ₄ , and the solvent was evaporated to afford crude compound 6 (250 mg, 75% yield). The crude compound was used as is for the next step without any further purification. [0708] LCMS: m/z: 241 [M+H] ⁺ , 50.62% (1.13min), [0709] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 ìm) [0710] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, [0711] (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0712] Flow Rate: 0.4 mL/min. Step-5: [0713] A solution of compound 6 (200 mg, 0.83 mmol) in 2 mL of a 1:1 mixture of dichloromethane (DCM) and acetic acid (AcOH) was stirred at 0°C, and N-bromosuccinimide (NBS) (177 mg, 1.00 mmol) was added. The reaction mixture was then stirred at room temperature for 18 hours with TLC used for reaction monitoring. Upon completion, the reaction mixture was quenched by pouring it into ice-cold water and subsequently extracted with DCM. The organic layer was desiccated over anhydrous sodium sulfate (Na ₂ SO ₄ ) and evaporated to yield crude compound 7 (240 mg, 90% yield). The crude compound was employed without further purification in the subsequent step. [0714] LCMS: m/z: 320.84 [M+2] ⁺ , 74.73% (1.31 min), [0715] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 ìm) [0716] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, [0717] (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0718] Flow Rate: 0.4 mL/min. Step-6: [0719] To a stirred solution of compound 7 (200 mg, 0.62 mmol) in Dioxane (4 ml) solution was added compound 8 (272mg, 0.75 mmol) followed by CS ₂ CO ₃ (613 mg, 1.886 mmol). Reaction mixture was degassed for 15 minutes then Pd (dppf)Cl2, (23 mg, 0.003 mmol) was added and again degassed for 10 minutes then reaction mixture was stirred at 150 ^o C for 1 h under microwave conditions. Reaction was monitored by LCMS. LCMS showed 20 % of product reaction mixture was poured into water and extracted with DCM, organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound 9 (100 mg, 33.6%). Crude compound was used for next step without purification. [0720] LCMS: m/z: 474.40[M+H] ⁺ , 27.20% (1.57min), [0721] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 ìm) [0722] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, [0723] (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0724] Flow Rate: 0.4 mL/min. Step-7: [0725] To a stirred solution of compound 9 (500 mg, 1.05 mmol) in 1,4-dioxane (5 ml) was added 4M HCl in dioxane (5 ml) at 0 ^o C then reaction mixture was stirred at rt for 2 h. Reaction was monitored by TLC; after completion of reaction, reaction mixture was concentrated under reduced pressure and diluted with cold water. Aqueous Layer Was quenched with aq. NaHCO ₃ and extracted with 10% MeOH in DCM. Organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound 10 (250 mg, 63.4% yield). The crude compound was used as such for the next step without any purification. [0726] LCMS: m/z: 374.24[M+H] ⁺ , 92.58% (1.36min), [0727] Column: Acquity BEH C ₁ 8 (2.1 x 50 mm, 1.7 μm), [0728] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, [0729] (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) [0730] Flow Rate: 0.4 mL/min. [0731] ¹ H NMR [400 MHz, DMSO-d ₆ ]: 8.66 (s, 1H), 7.33-7.30 (m, 3H), 7.15-7.12 (m, 4H), 3.69 (s, 1H), 2.78-2.71 (m, 3H), 1.28-1.26 (d, J = 6 Hz, 3H) Step-8: [0732] To a stirred solution of compound 10 (500 mg, 1.34 mmol) in DCM (1 mL), boron tribromide (1 mL) was added at 0°C. The reaction mixture was then stirred at room temperature overnight. Reaction progress was monitored by TLC. Upon completion of the reaction, the solvent was evaporated, and the reaction mixture was quenched in water. It was then extracted with DCM. The organic layer was concentrated and washed with pentane to yield compound I- 1001 (108 mg, yield: 22.4%) as a white solid. [0733] LCMS: m/z: 360.18[M+H] ⁺ , 97.36% (1.26 min), [0734] Column: Acquity BEH C ₁ 8 (2.1 x 50 mm, 1.7 μm), [0735] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, [0736] (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) [0737] Flow Rate: 0.4 mL/min. [0738] ¹ H NMR [400 MHz, DMSO-d6]: 8.63- (dd, J = 1.2 Hz, 1H), 8.31 (s 1H), 7.33-7.30 (m, 2H), 7.22-7.12 (m, 3H), 7.02 (s, 1H), 2.95-2.89 (m, 3H), 2.43 (s, 3H), 1.28 (d, J = 6.0 Hz, 3H). Step-9: [0739] To a stirred solution of I-1001 (700 mg, 1.94 mmol) in methanol (10 mL), formaldehyde (116 mg, 3.88 mmol), followed by sodium cyanoborohydride (244 mg, 0.388 mmol) and a catalytic amount of acetic acid (0.1 mL), were added. The reaction was monitored by TLC. After the completion of the reaction, the solvent was evaporated, and the reaction mixture was quenched in water and then extracted with DCM. The organic layer was concentrated and washed with pentane. The crude product was purified by preparative HPLC to yield I-1002 (90 mg, 11.9%) as a white solid. [0740] LCMS: m/z: 388.19[M+H] ⁺ , 96.76% (1.34 min), [0741] Column: Acquity BEH C ₁ 8 (2.1 x 50 mm, 1.7 μm), [0742] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, [0743] (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) [0744] Flow Rate: 0.4 mL/min. [0745] ¹ H NMR [400 MHz, DMSO-d6]: 9.20 (s, 1H), 8.65-8.65(d, J = 3.2 Hz, 1H), 8.14 (s, 1H), 7.36-7.35 (d, J = 7.2 Hz 3H), 7.21-7.05 (m, 2H), 3.10-3.05 (m, 3H), 2.70-2.69 (s, 3H), 2.46 (s, 3H), 2.36 (s, 3H), 1.28 (d, J = 5.4 Hz, 3H). Scheme 20: Synthesis of II-1011, II-1008 and II-1023

Step-1: [0746] To a cold solution of compound 1 (3 g, 11.90 mmol) in THF (30 mL) was added 60% NaH (525 mg, 13.147 mmol) followed by diethylmalonate (2.2 mL, 13.147 mmol). After completion of addition stirred the reaction mixture for 15 min and evaporated the solvent under reduced pressure. The resulting residue was stirred at 110 °C for 1.5 h. Then again reaction mixture to 0 °C and added 6M aqueous H ₂ SO ₄ (17 mL). The resulting suspension was stirred at 110 °C for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, reaction mass poured into cold water and basified with NaHCO _3. The resulting precipitate filtered and dissolved in EtOAc, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to afford compound 2 (1.5 g, yield: 54.5%) as a reddish solid. [0747] ¹ H NMR [400 MHz, CDCl3]: δ 8.44 (s, 1H), 2.80 (s, 3H), 2.72 (s, 3H). [0748] LCMS: m/z: 232.98 [M+2] ⁺ , 98.19% (1.61 min), [0749] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 ìm) [0750] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0751] Flow Rate: 0.4 mL/min. Step-2: [0752] To a stirred solution of compound 2 (2 g, 8.63 mmol) and compound 3 (4.7 g, 12.95 mmol) in Dioxane (20 ml) and water (2 ml) was added NaHCO ₃ (2.17 g, 25.89 mmol), Pd(dppf)Cl2 (315 mg, 0.43 mmol) at room temperature. The resulting reaction mixture degassed with nitrogen for 10 min. Then the reaction mixture stirred at 90 °C for 6 h. The progress of the reaction was monitored by TLC, after completion of the reaction evaporated the solvent. The residue was dissolved in EtOAc and washed with water, brine solution. The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (15% EtOAc in Hexane as eluent) to afford compound 4 (2.5 g, yield: 75%) as a yellow liquid. [0753] ¹ H NMR [400 MHz, CDCl3]: δ 8.15 (s, 1H), 7.33-7.26 (m, 4H), 4.52 (brs, 1H), 3.43- 3.38 (m, 1H), 3.29-3.23 (m, 1H), 3.03-2.97 (m, 1H), 2.88 (s, 3H), 2.58 (s, 3H), 1.42 (s, 9H), 1.31 (d, J=6.8 Hz, 3H). [0754] LCMS: m/z: 386.31 [M+1] ⁺ , 97.7% (1.83 min), [0755] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 ìm) [0756] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, [0757] (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0758] Flow Rate: 0.4 mL/min. Step-3: [0759] To a stirred solution of compound 4 (2.7 g, 7.01 mmol) in THF (30 mL) and water (4.5 ml) were added Iron Powder (1.9 g, 35.06 mmol), NH ₄ Cl (3.7 g, 70.12 mmol) at room temperature. The resulting mixture stirred at 70 °C for overnight. Progress of the reaction was monitored by TLC. After completion of the reaction, filtered the reaction mass through celite and washed with EtOAc, separated the two layers. Organic layer washed with brine solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (20% EtOAc in hexane as eluent) to afford compound 5 (1.6 g, yield: 64.2%) as yellow liquid. [0760] LCMS: m/z: 356.76 [M+1] ⁺ , 85.10% (1.04 min), [0761] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 ìm) [0762] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0763] Flow Rate: 0.4 mL/min.

Step-4: [0764] To a stirred solution of compound 5 (1.2 g, 3.38 mmol) in MeOH (10 mL) was added compound 6 (0.6 mL, 4.05 mmol) followed by cat AcOH (0.1 mL) at room temperature and continued te stirring for 1h. The reaction mixture cooled to 0 °C and added NaBH4 (385 mg, 10.14 mmol) portion wise. The resulting reaction mixture stirred at room temperature for 2 h. The reaction progress was monitored by TLC, after completion of the reaction, reaction mass quenched with water and extracted with EtOAc. The organic layer washed with cold water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (20% EtOAc in Hexane as eluent) to afford compound 7 (700 mg, 43.7%) as a pale-yellow liquid. [0765] LCMS: m/z: 476.71 [M+1] ⁺ , 95.05% (1.20 min), [0766] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 ìm) [0767] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0768] Flow Rate: 0.4 mL/min.

Step-5: [0769] To a solution of compound 7 (700 mg, 1.47 mmol), triethylamine (3 mL, 22.10 mmol) in DCM (30 mL) was added freshly prepared compound 8 (915 g, 4.42 mmol) in DCM (10 ml) drop wise at 0 °C. The resulting mixture stirred at room temperature for 3 h. The reaction progress was monitored by TLC, after completion, the reaction mass diluted with DCM (100 ml) and washed with water, brine solution. The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by C-18 column chromatography (65% ACN in 0.1 FA as an eluent and extracted) to afford compound 9 (380 mg, 38.8%) as brown gum. [0770] LCMS: m/z: 666.50 [M+1] ⁺ , 98.29% (1.73 min), [0771] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 ìm) [0772] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0773] Flow Rate: 0.4 mL/min. Step-6: [0774] To a solution of compound 9 (40 mg, 0.06 mmol) in DMA (10 mL) was added KOAc (30 mg, 0.30 mmol) and Pd(tBu ₃ P) ₂ (3 mg, 0.006 mmol) at rt. The reaction mixture degassed with nitrogen for 10 min. The reaction mixture stirred at 150 °C in microwave for 4 h. Progress of the reaction was monitored by TLC, after completion of the reaction, reaction mass poured into ice- cold water and extracted with EtOAc. The organic layer washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude residue was purified by RP C-18 column chromatography (70% ACN in 0.1 FA as an eluent and lyophilized) to afford compound 10 (15 mg, 42.8%) as off-white solid. [0775] LCMS: m/z: 584.84 [M+1] ⁺ , 82.48% (1.68 min), [0776] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 ìm), [0777] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) [0778] Flow Rate: 0.4 mL/min. Step-7: [0779] Trifluoroacetic acid (2 mL) was added to the compound 10 (200 mg, 0.343 mmol) in a seal tube at room temperature. The resulting mixture stir at 100 °C for 4 h. Completion of the reaction was monitored by TLC and LCMS, after completion, reaction mixture was directly evaporated under reduced pressure. The residue was diluted with water and washed with DCM. The aqueous layer concentrated in vacuo and resulting residue was purified by RP C-18 column (30% ACN in 0.1% FA as an eluent and lyophilized) to afford II-1008 (17 mg, 13.7%) as white solid. [0780] ¹ H NMR [400 MHz, DMSO-d6]: δ 7.81 (d, J=5.6 Hz, 1H), 7.50 (dd, J=5.6 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 5.80 (d, J=5.2 Hz, 1H), 3.16-3.00 (m, 3H), 2.76 (s, 3H), 2.20 (s, 3H), 1.35 (d, J = 6 Hz, 3H). [0781] LCMS: m/z: 364.22 [M+1] ⁺ , 98.55% (1.27 min), [0782] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm) [0783] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/2, 0.5/2, 2/90, 3/90) [0784] Flow Rate: 0.4 mL/min. Step-8: [0785] To a stirred solution of II-1008 (50 mg, 0.137 mmol) 35% HCHO (0.1 mL) in methanol (3 mL) was added two drops of acetic acid followed by sodium cyanoborohydride (25 mg, 0.413 mmol) at room temperature. The reaction mixture stirred for 5 h at room temperature. The progress of the reaction was monitored by LCMS; after completion of reaction solvent was evaporated in vacuo. The residue was diluted with water and extracted with 10% MeOH in DCM. The organic layer washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by reverse phase C-18 column (30% ACN in 0.1% FA as eluent and lyophilized) to afford II-1011 (3 mg, 5.5%) as a white solid. [0786] ¹ H NMR [400 MHz, DMSO-d6]: δ 11.23 (bs, 1H), 7.87 (d, J=4 Hz, 1H), 7.45 (d, J=5.2 Hz, 2H), 7.20 (d, J=7.6 Hz, 2H), 5.72 (d, J=5.6 Hz, 1H), 3.09-2.95 (m, 1H), 2.76 (s, 3H), 2.47- 2.37 (m, 2H), 2.21 (s, 6H), 2.16 (s, 3H), 1.30 (d, J=6.4 Hz, 3H). [0787] LCMS: m/z: 392.38 [M+1] ⁺ , 99.07% (2.02 min), [0788] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm), [0789] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/1, 1/1, 4/90, 6/90) [0790] Flow Rate: 0.4 mL/min. Step-9: [0791] To a solution of compound 10 (60 mg, 0.103 mmol) in DMF (2 mL) was added 60% NaH (15 mg, 0.308 mmol) at 0 °C and continued the stirring for 20 min. Then added methyl iodide (0.2 mL) and stirred at room temperature for 16 h. The progress of the reaction was monitored by LCMS, after completion, the reaction mass quenched with cold water and extracted with EtOAc (50 ml). The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to get crude compound 11 (60 mg, 98%) as brown gum. The crude compound used as such for next step without any purification. [0792] LCMS: m/z: 598.42 [M+1] ⁺ , 67.01% (1.83 min), [0793] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [0794] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0795] Flow Rate: 0.4 mL/min. Step-10: [0796] Trifluoroacetic acid (2 mL) was added to the compound 11 (200 mg, 0.343 mmol) in a seal tube at room temperature. The resulting mixture stir at 100 °C for 4 h. Completion of the reaction was monitored by TLC and LCMS, after completion, reaction mixture was directly evaporated. The residue was diluted with water and washed with DCM. The aqueous layer concentrated in vacuo and resulting residue was purified by RP C-18 column (30% ACN in 0.1% FA as eluent and lyophilized) to afford II-1023 (17 mg, 13.7%) as white solid. [0797] ¹ H NMR [400 MHz, DMSO-d6]: δ 7.87 (d, J=5.2 Hz, 1H), 7.49 (d, J=7.6 Hz, 2H), 7.23 (d, J = 7.6 Hz, 2H), 5.75 (d, J=5.6 Hz, 1H), 3.03-2.97 (m, 1H), 2.76-2.67 (m, 5H), 2.33 (s, 3H), 2.19 (s, 3H), 1.31 (d, J = 7.2 Hz, 3H). [0798] LCMS: m/z: 378.32 [M+1] ⁺ , 93.89% (3.84 min), [0799] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [0800] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/1, 3/1, 5/90, 6/90), [0801] Flow Rate: 0.4 mL/min. Scheme 21: Synthesis of II-1017, II-1020, II-1021, and II-1022 Step-1: [0802] To a stirred solution of compound 1 (10 g, 59 mmol) in DMF (100 mL) was added NBS (11.5 g, 65 mmol) portion wise at room temperature. After completion of addition, the reaction mixture stirred for 1h at same temperature. Progress of the reaction was monitored by TLC, after completion, reaction mass poured into ice cold water and extracted with EtOAc (3x250 ml). The combined organic layers were washed with sat. NaHCO _3, water and brine solution. The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was triturated with ether, filtered and dried to afford compound 2 (10 g, yield: 68.4%) as brown solid. [0803] ¹ H NMR [400 MHz, CDCl3]: δ 8.46 (s, 1H), 4.01 (s, 3H). [0804] LCMS: m/z: 248.04 [M+1] ⁺ , 98.18% (1.44 min), [0805] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm), [0806] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0807] Flow Rate: 0.4 mL/min. Step-2: [0808] Compound 2 (10 g, 40 mmol) was added portion wise to pyridine HF (40 mL) at 0 °C and stirred for 10 min. Then added NaNO ₂ (3 g, 44 mmol) portion wise to the reaction mixture at same temperature. The resulting reaction mixture stirred at room temperature for 2 h. Progress of the reaction was monitored by TLC, after completion, the reaction mass poured into ice cold water and extracted with EtOAc (2 x 250 ml). The organic layer washed with sat NaHCO ₃ (300 mL), brine solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to afford compound 3 (9 g, yield: 90%) as pale-yellow solid. [0809] ¹ H NMR [400 MHz, CDCl3]: δ 8.67 (d, J=8 Hz, 1H), 4.12 (s, 3H). [0810] LCMS: m/z: 248.89 [M-1] ⁺ , 95.05% (1.51 min), [0811] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [0812] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0813] Flow Rate: 0.4 mL/min. Step-3: [0814] To a stirred solution of compound 3 (1 g, 3.984 mmol) in conc. HCl (15 ml) was added Iron Powder (2.2 g, 39.84 mmol) at room temperature. The resulting mixture heat to reflux for overnight. Progress of the reaction was monitored by TLC, after completion, the reaction mass cooled to room temperature and filtered through celite pad. The filtrate was basified with 20% NaOH solution and extracted with DCM. The organic layer washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to afford compound 4 (750 mg, yield: 85%) as brown solid. The crude compound was used for next step without further purification. [0815] LCMS: m/z: 222.96 [M+1] ⁺ , 33.08% (1.31 min), [0816] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [0817] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0818] Flow Rate: 0.4 mL/min. Step-4: [0819] To a stirred solution of compound 4 (5 g, 0.021 mol) and compound 5 (9.3 g, 0.026 mol) in Dioxane (50 ml) and water (5 ml) was added K2CO ₃ (5.45 g, 0.065 mol), Pd-118 (791 mg, 0.001 mol) at room temperature. The resulting reaction mixture degassed with nitrogen for 20 min. Then the reaction mixture stirred at 85 °C for 16 h. The progress of the reaction was monitored by TLC, after completion, the reaction mass cooled to room temperature and filtered through celite pad, washed with EtOAc (250 ml). The filtrate was washed with water, brine solution. The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (15% EtOAc in Hexane as eluent) to afford compound 6 (2.4 g, yield: 53%) as a yellow liquid. [0820] LCMS: m/z: 386.30 [M+1] ⁺ , 67.8% (1.99 min), [0821] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [0822] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0823] Flow Rate: 0.4 mL/min. Step-5: [0824] To a stirred solution of compound 6 (1.9 g, 5.066 mmol) in MeOH (20 mL) was added compound 7 (0.8 mL, 6.079 mmol), cat. AcOH (0.5 mL) at room temperature and continued the stirring for 1 h. Then reaction mixture cool to 0 °C and added NaBH4 (385 mg, 10.132 mmol) portion wise. The resulting mixture stirred at room temperature for 3 h. The reaction progress was monitored by TLC, after completion, the reaction mixture quenched with cold water and extracted with EtOAc (2 x 100 ml). The organic layer washed with brine solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by column chromatography (30% EtOAc in hexane as an eluent) to afford pure compound 8 (1.8 g, yield: 72%) as yellow solid. [0825] LCMS: m/z: 496.37 [M+1] +, 84.47% (1.95 min), [0826] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm) [0827] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0828] Flow Rate: 0.4 mL/min. Step-6: [0829] To a stirred solution of compound 8 (1.9 g, 3.838 mmol), triethylamine (2.67 ml, 19.190 mmol) in DCM (15 ml) was added a solution of freshly prepared compound 9 (1.2 g, 5.757 mmol) in DCM (5 ml) drop wise at 0 °C. The resulting mixture allowed to stir at room temperature for 3 h. The reaction progress was monitored by TLC, after completion, the reaction mass diluted with DCM (50 ml) and washed with water, brine solution. The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by reverse phase C-18 column (70 % ACN in0.1% FA as eluent) to afford compound 10 (1.8 g, yield: 68.7%) as yellow semi-solid. [0830] LCMS: m/z: 630.09 [M-56] ⁺ , 95.14% (1.98 min), [0831] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm) [0832] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, [0833] (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0834] Flow Rate: 0.4 mL/min. Step-7: [0835] To a solution of compound 10 (1.2 g, 1.756 mmol) in DMA (15 mL) was added KOAc (688 mg, 7.024 mmol) and Pd(tBu ₃ P) ₂ (54 mg, 0.105 mmol) at room temperature. The reaction mixture degassed with nitrogen for 15 min and stirred at 150 °C in a microwave for 2 h. Progress of the reaction was monitored by LCMS, after completion, the reaction mass poured into ice-cold water and extracted with EtOAc (100 ml). The organic layer washed with water, brine solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude residue was purified by reverse phase C-18 column chromatography (70% ACN in 0.1% FA as an eluent and extracted) to afford compound 11 (350 mg, yield: 33.3%) as pale-yellow gum. [0836] LCMS: m/z: 604.37 [M+1] ⁺ , 85.45% (1.97 min), [0837] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm) [0838] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0839] Flow Rate: 0.4 mL/min. Step-8: [0840] Trifluoroacetic acid (1 mL) was added to compound 11 (60 mg, 0.099 mmol) in a sealed tube at room temperature. The resulting mixture stirred at 100 °C for 4 h. The progress of the reaction was monitored by LCMS, after completion, the reaction mass was directly evaporated in vacuo. The resulting residue was purified by reverse phase C-18 column (20% ACN in 0.1% FA as eluent and lyophilized) to afford II-1017 (3 mg, yield: 7.8%) as an off-white solid. [0841] ¹ H NMR [400 MHz, DMSO-d6]: δ 7.87(d, J=5.2 Hz, 1H), 7.40 (d, J=7.2 Hz, 2H), 7.24 (d, J=7.6 Hz, 2H), 5.85 (d, J=5.2 Hz, 1H), 3.82 (s, 3H), 2.89-2.80 (m, 3H), 1.32 (d, J=7.6 Hz, 3H). [0842] LCMS: m/z: 384.24 [M+1] ⁺ , 96.29% (1.51 min), [0843] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm), [0844] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) [0845] Flow Rate: 0.4 mL/min. Step-9: [0846] To a stirred solution of II-1017 (200 mg, 0.331 mmol) in DCE (6 mL) was added BBr3 in DCM (6 mL) at 0 °C. The resulting mixture allow to stir at room temperature for overnight. Progress of the reaction was monitored by LCMS, after completion, reaction mixture was quenched with cold water and extracted with DCM. The aqueous layer was evaporated under reduced pressure. The resulting residue was purified by reverse phase C-18 column (25% ACN in 0.1% FA as eluent and lyophilized) to afford II-1021 (8 mg, 6.5%) as an off-white solid. [0847] ¹ H NMR [400 MHz, DMSO-d6]: δ 7.84 (d, J=5.6 Hz, 1H), 7.42 (d, J=8.4 Hz, 2H), 7.24 (d, J=7.6 Hz, 2H), 5.95 (d, J=5.6 Hz, 1H), 3.04-2.94 (m, 3H), 1.33 (d, J=5.6 Hz, 3H). [0848] LCMS: m/z: 370.22 [M+1] ⁺ , 96.95% (0.85 min), [0849] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [0850] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0851] Flow Rate: 0.4 mL/min. Step-10: [0852] To a stirred solution of II-1021 (80 mg, 0.216 mmol) 35% HCHO (0.3 mL) in methanol (3 mL) was added acetic acid (0.05 mL) followed by sodium cyanoborohydride (68 mg, 1.084 mmol) at room temperature. The resulting reaction mixture stirred at room temperature for 5 h. The progress of the reaction was monitored by LCMS; after completion, reaction mass quenched with water and extracted with 10% MeOH in DCM. The organic layer washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude residue was purified by reverse phase C-18 column (30% ACN in 0.1% FA as eluent and lyophilized) to afford II-1022 (20 mg, 23%) as pale-yellow solid. [0853] ¹ H NMR [400 MHz, DMSO-d6]: δ 11.89 (bs, 1H), 7.83 (d, J=5.6 Hz, 1H), 7.39 (d, J=8 Hz, 2H), 7.20 (d, J=8 Hz, 2H), 5.87 (d, J=5.6 Hz, 1H), 3.05-2.99 (m, 1H), 2.54-2.40 (m, 2H), 2.20 (s, 6H), 1.27 (d, J=7.2 Hz, 3H). [0854] LCMS: m/z: 398.20 [M+1] ⁺ , 98.99% (1.31 min), [0855] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm), [0856] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90), [0857] Flow Rate: 0.4 mL/min. Step-11: [0858] To a stirred solution of II-1017 (70 mg, 0.182 mmol) 35% HCHO (0.1 mL) in methanol (2 mL) was added acetic acid (0.1 mL) followed by sodium cyanoborohydride (57 mg, 0.911 mmol) at room temperature. The resulting reaction mixture stirred at room temperature for 5 h. The progress of the reaction was monitored by LCMS, after completion, the reaction mass quenched with water and extracted with 10% MeOH in DCM (50 ml). The organic layer washed with brine solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude residue was purified by reverse phase C-18 column (25% ACN in 0.1% FA as eluent and lyophilized) to afford II-1020 (2.5 mg, 3%) as a white solid. [0859] ¹ H NMR [400 MHz, DMSO-d6]: δ 11.95 (bs, 1H), 7.84 (d, J=5.6 Hz, 1H), 7.40 (d, J=8 Hz, 2H), 7.21 (d, J=8 Hz, 2H), 5.80 (d, J=5.6 Hz, 1H), 3.78 (s, 3H), 3.05-2.99 (m, 3H), 2.50-2.37 (m, 2H), 2.18 (s, 6H), 1.28 (d, J=7.2 Hz, 3H). [0860] LCMS: m/z: 412.26 [M+1] ⁺ , 97.95% (1.71 min), [0861] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm), [0862] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) [0863] Flow Rate: 0.4 mL/min. Scheme 22: Synthesis of II-1021(R) Step-1: [0864] To a stirred solution of compound 1 (1.2 g, 5.429 mmol) and compound 2 (2.35 g, 6.515 mmol) in Dioxane (12 ml) and water (2 ml) was added K ₂ CO ₃ (2.2 g, 16.287 mmol), Pd-118 (353 mg, 0.543 mmol) at room temperature. The resulting reaction mixture degassed with nitrogen for 20 min. Then the reaction mixture stirred at 85 °C for 16 h. The progress of the reaction was monitored by TLC, after completion, the reaction mass cooled to room temperature and filtered through celite pad, washed with EtOAc (250 ml). The filtrate was washed with water, brine solution. The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (20% EtOAc in Hexane as eluent) to afford compound 3 (1.5 g, yield: 59%) as a yellow liquid. [0865] LCMS: m/z: 375.92 [M+1] ⁺ , 89.56% (1.62 min), [0866] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [0867] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0868] Flow Rate: 0.4 mL/min. Step-2: [0869] To a stirred solution of compound 3 (1.5 g, 4.001 mmol) in MeOH (20 mL) was added compound 4 (0.82 mL, 6.002 mmol), cat AcOH (0.5 mL) at room temperature and continued the stirring for 1 h. Then reaction mixture cool to 0 °C and added NaBH4 (456 mg, 12.001 mmol) portion wise. The resulting mixture stirred at room temperature for 3 h. The reaction progress was monitored by TLC, after completion, the reaction mixture quenched with cold water and extracted with EtOAc (2 x 100 ml). The organic layer washed with brine solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by column chromatography (30% EtOAc in hexane as an eluent) to afford pure compound 5 (1.8 g, yield: 91.3%) as yellow solid. [0870] LCMS: m/z: 496.30 [M+1] +, 90.50% (1.86 min), [0871] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [0872] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, [0873] (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0874] Flow Rate: 0.4 mL/min. Step-3: [0875] To a solution of compound 5 (1.6 g, 3.232 mmol), triethylamine (2.3 ml, 16.160 mmol) in DCM (20 ml) was added a solution of freshly prepared compound 6 (1.1 g, 5.757 mmol) in DCM (10 ml) drop wise at 0 °C. The resulting mixture allowed to stir at room temperature for 1 h. The reaction progress was monitored by TLC, after completion, the reaction mass diluted with DCM (50 ml) and washed with water, brine solution. The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by reverse phase C-18 column (25 % ACN in0.1% FA as eluent and extracted) to afford compound 7 (1.6 g, yield: 80%) as yellow semi-solid. [0876] LCMS: m/z: 630.09 [M-56] ⁺ , 95.14% (1.98 min), [0877] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm) [0878] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0879] Flow Rate: 0.4 mL/min. Step-4: [0880] To a solution of compound 7 (500 mg, 0.796 mmol) in DMA (10 mL) was added KOAc (312 mg, 3.184 mmol) and Pd(tBu3P) ₂ (25 mg, 0.047 mmol) at room temperature. The reaction mixture degassed with nitrogen for 15 min and stirred at 150 °C in a microwave for 2 h. The progress of the reaction was monitored by LCMS, after completion, the reaction mass poured into ice-cold water and extracted with EtOAc (2 x 100 ml). The organic layers washed with water, brine solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude residue was purified by reverse phase C-18 column chromatography (75% ACN in 0.1% FA as an eluent and extracted) to afford compound 8 (250 mg, yield: 56.5%) as pale-yellow gum. [0881] LCMS: m/z: 604.12 [M+1] ⁺ , 38.57% (1.97 min), [0882] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [0883] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0884] Flow Rate: 0.4 mL/min. Step-5: [0885] To a stirred solution of compound 8 (250 mg, 0.414 mmol) in DCE (5 mL) was added BBr3 in DCM (5 mL) at 0 °C. The resulting mixture allow to stir at room temperature for overnight. The progress of the reaction was monitored by LCMS, after completion, the reaction mixture was quenched with cold water and DCM (50 ml), separated the two layers. The aqueous layer was evaporated under reduced pressure. The resulting residue was purified by reverse phase C-18 column (15% ACN in 0.1% FA as eluent and lyophilized) to afford II-1021(R) (20 mg, 13%) as a white solid. [0886] ¹ H NMR [400 MHz, DMSO-d6]: δ 7.84 (d, J=5.6 Hz, 1H), 7.41 (d, J=8 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H), 5.94 (d, J=5.2 Hz, 1H), 2.98-2.87 (m, 3H), 1.32 (d, J=6.4 Hz, 3H). [0887] LCMS: m/z: 370.22 [M+1] ⁺ , 97.84% (1.35 min), [0888] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm), [0889] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) [0890] Flow Rate: 0.4 mL/min. Scheme 23: Synthesis of II-1028 Step-1: [0891] To a stirred solution of compound 1 (2 g, 8.63 mmol) and compound 2 (4.7 g, 12.95 mmol) in Dioxane (20 ml) and water (2 ml) was added NaHCO ₃ (2.17 g, 25.89 mmol), Pd(dppf)Cl ₂ (315 mg, 0.43 mmol) at room temperature. The resulting reaction mixture degassed with nitrogen for 10 min. Then the reaction mixture stirred at 90 °C for 6 h. The progress of the reaction was monitored by TLC, after completion of the reaction evaporated the solvent. The residue was dissolved in EtOAc and washed with water, brine solution. The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (15% EtOAc in Hexane as eluent) to afford compound 3 (2.5 g, yield: 75%) as a yellow liquid. [0892] ¹ H NMR [400 MHz, CDCl3]: δ 8.15 (s, 1H), 7.33-7.26 (m, 4H), 4.52 (brs, 1H), 3.43- 3.38 (m, 1H), 3.29-3.23 (m, 1H), 3.03-2.97 (m, 1H), 2.88 (s, 3H), 2.58 (s, 3H), 1.42 (s, 9H), 1.31 (d, J=6.8 Hz, 3H). [0893] LCMS: m/z: 386.31 [M+1] ⁺ , 97.7% (1.83 min), [0894] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 ìm) [0895] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0896] Flow Rate: 0.4 mL/min. Step-2: [0897] To a stirred solution of compound 3 (2.7 g, 7.01 mmol) in THF (30 mL) and water (4.5 ml) were added Iron Powder (1.9 g, 35.06 mmol), NH ₄ Cl (3.7 g, 70.12 mmol) at room temperature. The resulting mixture stirred at 80 °C for 16h. Progress of the reaction was monitored by TLC. After completion of the reaction, filtered the reaction mass through celite and washed with EtOAc, separated the two layers. Organic layer washed with brine solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (20% EtOAc in hexane as eluent) to afford compound 4 (1.6 g, yield: 64.2%) as yellow liquid. [0898] LCMS: m/z: 356.76 [M+1] ⁺ , 85.10% (1.04 min), [0899] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 ìm) [0900] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0901] Flow Rate: 0.4 mL/min. Step-3: [0902] To a stirred solution of compound 4 (1.2 g, 3.38 mmol) in MeOH (10 mL) was added compound 5 (0.6 mL, 4.05 mmol) followed by cat AcOH (0.1 mL) at room temperature and continued the stirring for 1h. The reaction mixture cooled to 0 °C and added NaBH4 (385 mg, 10.14 mmol) portion wise and stirred for 2 h at room temperature. The reaction progress was monitored by TLC, after completion of the reaction, the reaction mass quenched with water and extracted with EtOAc (2 x 50 ml). The organic layer washed with cold water, brine solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (20% EtOAc in Hexane as eluent) to afford compound 6 (700 mg, 43.7%) as a pale-yellow liquid. [0903] LCMS: m/z: 476.71 [M+1] ⁺ , 95.05% (1.20 min), [0904] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 ìm) [0905] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0906] Flow Rate: 0.4 mL/min. Step-4: [0907] To a solution of compound 6 (700 mg, 1.47 mmol), triethylamine (3 mL, 22.10 mmol) in DCM (20 mL) was added freshly prepared compound 7 (915 g, 4.42 mmol) in DCM (10 ml) drop wise at 0 °C. The resulting mixture stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC, after completion, the reaction mass diluted with DCM (50 ml) and washed with water, brine solution. The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by C-18 column chromatography (65% ACN in 0.1 FA as an eluent and extracted) to afford compound 8 (380 mg, 38.8%) as brown gummy. [0908] LCMS: m/z: 678.23 [M+1] ⁺ , 65.50% (1.73 min), [0909] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 ìm) [0910] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90), [0911] Flow Rate: 0.4 mL/min. Step-5: [0912] To a solution of compound 8 (40 mg, 0.06 mmol) in DMA (10 mL) was added KOAc (30 mg, 0.30 mmol) and Pd(tBu ₃ P) ₂ (3 mg, 0.006 mmol) at rt. The reaction mixture degassed with nitrogen for 10 min. The reaction mixture stirred at 150 °C in microwave for 1.5h. Progress of the reaction was monitored by TLC, after completion of the reaction, reaction mass poured into ice-cold water and extracted with EtOAc. The organic layer washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude residue was purified by RP C-18 column chromatography (70% ACN in 0.1 FA as an eluent and extracted) to afford compound 9 (15 mg, 42.8%) as off-white solid. [0913] LCMS: m/z: 598.60 [M+1] ⁺ , 56.96% (1.71 min), [0914] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [0915] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0916] Flow Rate: 0.4 mL/min. Step-6: [0917] Trifluoroacetic acid (2 mL) was added to the compound 9 (60 mg, 0.151 mmol) in a sealed tube at room temperature. The resulting reaction mixture stirred at 100 °C for 4 h. The progress of the reaction was monitored by LCMS, after completion, the reaction mass was directly evaporated under reduced pressure. The residue was purified by Prep HPLC and lyophilized to afford II-1028 (6 mg, 15.8%) as white solid. [0918] ¹ H NMR [400 MHz, DMSO-d6]: δ 7.44-7.42 (m, 2H), 7.21-7.18 (m, 2H), 5.24 (s, 1H), 2.85-2.79 (m, 3H), 2.74 (s, 3H), 2.28 (s, 3H), 2.21 (s, 3H), 1.31 (d, J=6 Hz, 3H). [0919] LCMS: m/z: 378.29 [M+1] ⁺ , 99.51% (2.11 min), [0920] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm) [0921] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/2, 0.5/2, 2/90, and 3/90), [0922] Flow Rate: 0.4 mL/min. Scheme 24: Synthesis of II-1029 and II-1032 Step-1: [0923] A solution of compound-1 (1 g, 4.504 mmol) in THF (5 ml) was added to 1M BH ₃ :THF complex (20 ml) at room temperature. The resulting mixture stirred at room temperature for overnight and 70 °C for 4 h. The reaction progress was monitored by TLC, after completion, the reaction mass poured into ice cold water and acidified with dil HCl (pH~1). Then basified using aq NaOH solution (pH~10) and extracted with EtOAc (2 x 50 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to get crude compound 2 (1 g, yield: 99%). The crude compound was used as such for next step without any purification. Step-2: [0924] To a stirred solution of compound 2 (1 g, 4.424 mmol) in DCM (10 mL) was added TEA (1.8 mL, 13.274 mmol) followed by (Boc) ₂ O (1.5 mL, 6.636 mmol) at 0 °C. The resulting mixture stirred at room temperature for overnight. The progress of the reaction was monitored by TLC, after completion, the reaction mass diluted with DCM (50 ml) and washed with water, brine solution. The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting crude was purified by silica gel column chromatography (5% EtOAc in Hexane as eluent) to afford compound 3 (900 mg, yield: 64%) as a white solid. [0925] ¹ H NMR [400 MHz, CDCl3]: δ 7.41 (d, J=8 Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 4.51 (bs, 1H), 3.29 (d, J=5.6 Hz, 2H), 1.39 (s, 9H), 0.82 (d, J=16.4 Hz, 4H). [0926] LCMS: m/z: 272.06 [M+2] +, 95.88% (1.77 min), [0927] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm) [0928] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0929] Flow Rate: 0.4 mL/min.

Step-3: [0930] To a stirred solution of compound 3 (900 mg, 2.846 mmol), B2Pin2 (1 g, 4.269 mmol) in Dioxane (10 mL) was added KOAc (557 mg, 0.5.693 mmol), Pd(dppf)Cl2 (83 mg, 0.113 mmol) at room temperature. The reaction mixture degassed with nitrogen for 15 min and stirred at 90°C for overnight. The progress of the reaction was monitored by TLC, after completion, the reaction mass filtered through celite and washed with EtOAc (100 ml). the organic layer washed with water, brine solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (4% EtOAc in hexane as eluent) to afford compound 4 (820 mg, yield: 82%) as white solid. [0931] ¹ H NMR [400 MHz, CDCl3]: δ 7.75 (d, J=8.4 Hz, 2H), 7.30 (d, J=8 Hz, 2H), 4.52 (bs, 1H), 3.33 (d, J=5.2 Hz, 2H), 1.42 (s, 9H), 1.33 (s, 12H), 0.88 (d, J=4.8 Hz, 4H). [0932] LCMS: m/z: 318.29 [M-56] ⁺ , 98.18% (1.86 min), [0933] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm) [0934] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, [0935] (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0936] Flow Rate: 0.4 mL/min.

Step-4: [0937] To a stirred solution of compound 4 (161 mg, 0.432 mmol) and compound 5 (100 mg, 0.432 mmol) in Dioxane (2 ml) and water (0.5 ml) was added NaHCO ₃ (109 mg, 1.298 mmol), Pd(dppf)Cl2 (19 mg, 0.025 mmol) at room temperature. The resulting reaction mixture degassed with nitrogen for 10 min and stirred at 90 °C for 16h. The progress of the reaction was monitored by TLC, after completion, the reaction mass diluted with EtOAc (50 ml), filtered through celite pad. The filtrate was washed with brine solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (15% EtOAc in Hexane as eluent) to afford compound 6 (100 g, yield: 67%) as a yellow liquid. [0938] LCMS: m/z: 398.27 [M+1] ⁺ , 57.68% (1.78 min), [0939] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [0940] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0941] Flow Rate: 0.4 mL/min. Step-5: [0942] To a stirred suspension of compound 6 (200 mg, 0.503 mmol) in THF (6 mL) and water (2 ml) was added NH ₄ Cl (269 mg, 5.037 mmol) followed by Iron Powder (140 mg, 2.518 mmol) at room temperature. The resulting mixture heated to 80 °C and stirred for overnight. The progress of the reaction was monitored by TLC, after completion, the reaction mass diluted with EtOAc (50 ml), filtered through celite pad. The filtrate was washed with water, brine solution. The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to get compound 7 (150 mg, yield: 85%) as yellow syrup. The crude compound used as such for next step without any purification. [0943] LCMS: m/z: 368.68 [M+1] ⁺ , 82.41% (1.04 min), [0944] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [0945] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0946] Flow Rate: 0.4 mL/min. Step-6: [0947] To a stirred solution of compound 7 (1.4 g, 3.814 mmol) in MeOH (15 mL) was added compound 8 (0.7 mL, 5.722 mmol) followed by AcOH (0.5 mL) at room temperature and continued the stirring for 1 h. Then reaction mixture cooled to 0 °C and added NaBH4 (434 mg, 11.444 mmol) portion wise. The reaction mixture allowed to stir at room temperature for 3 h. The progress of the reaction was monitored by TLC, after completion, the reaction mass quenched with cold water and extracted with DCM (2 x 50 ml). The combined organic layers were washed with brine solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (30% EtOAc in Hexane as eluent) to afford compound 9 (450 mg, yield: 25%) as a pale-yellow liquid. [0948] LCMS: m/z: 488.40 [M+1] ⁺ , 26.66% (1.21 min), [0949] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm) [0950] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0951] Flow Rate: 0.4 mL/min. Step-7: [0952] To a stirred solution of compound-9 (150 mg, 0.308 mmol) and TEA (0.1 mL, 0.924 mmol) in DCM (5 mL) was added a solution of freshly prepared compound 10 (103 mg, 0.462 mmol) in DCM (2 mL) at 0 °C. The resulting mixture allowed to stir at room temperature for 1 h. The progress of the reaction was monitored by TLC, after completion, the reaction mass diluted with DCM (50 ml) and washed with water, brine solution. The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by reverse phase C-18 column (65% ACN in 0.1% FA as eluent and extracted) to afford compound-11 (100 mg, yield: 48%) as pale yellow gum. [0953] LCMS: m/z: 678.14 [M+1] ⁺ , 99.52% (1.82 min), [0954] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [0955] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0956] Flow Rate: 0.4 mL/min.

Step-8: [0957] To a stirred solution of compound 11 (500 mg, 0.739 mmol) in DMA (5 mL) was added KOAc (289 mg, 2.958 mmol) and Pd(tBu ₃ P) ₂ (23 mg, 0.044 mmol) at room temperature. The reaction mixture degassed with nitrogen for 10 min and stirred at 150 °C in a microwave for 1 h. the progress of the reaction was monitored by TLC, after completion, the reaction mass poured into ice-cold water and extracted with EtOAc (2 x 100 ml). The combined organic layers were washed with cold water, brine solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude residue was purified by reverse phase C-18 column chromatography (70% ACN in 0.1% FA as an eluent and extracted) to afford compound 12 (210 mg, yield: 47%) as off-white solid. [0958] LCMS: m/z: 596.44 [M+1] ⁺ , 96.86% (1.75 min), [0959] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm) [0960] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0961] Flow Rate: 0.4 mL/min. Step-9: [0962] Trifluoroacetic acid (2 mL) was added to the compound 12 (100 mg, 0.167 mmol) room temperature. The resulting mixture stirred at 100 °C for 4 h. The progress of the reaction was monitored by LCMS, after completion, evaporated the solvent under reduced pressure. The resulting residue was purified by reverse phase C-18 column (10% ACN in 0.1% FA as eluent and lyophilized) to afford II-1029 (15 mg, 23.8%) as a white solid. [0963] ¹ H NMR [400 MHz, DMSO-d6]: δ 11.42 (bs, 1H), 7.88 (bs, 3H), 7.83 (d, J=5.6 Hz, 1H), 7.57 (d, J=8 Hz, 2H), 7.28 (d, J=8.4 Hz, 2H), 5.91 (d, J=5.6 Hz, 1H), 3.25 (d, J=5.6 Hz, 2H), 2.81 (s, 3H), 2.24 (s, 3H), 1.15-1.06 (m, 4H). [0964] LCMS: m/z: 376.29 [M+1] ⁺ , 99.60% (0.84 min), [0965] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm) [0966] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0967] Flow Rate: 0.4 mL/min. Step-10: [0968] To a solution of compound 12 (120 mg, 0.201 mmol) in DMF (3 mL) was added 60% NaH (28 mg, 0.604 mmol) at 0 °C. The resulting mixture stirred for 20 min and added methyl iodide (0.1 mL, 1.610 mmol). The reaction mixture allow to stir at room temperature for 3 h. Progress of the reaction was monitored by TLC and LCMS; after completion, reaction mass quenched with cold water and extracted with EtOAc. The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to get crude compound-13 (100 mg, 81.9%) as brown gum. The crude compound used as such for next step without any purification. Step-11:

[0969] Trifluoroacetic acid (1.5 mL) was added to the compound-13 (110 mg, 0.164 mmol) at room temperature. The resulting mixture stirred at 100 °C for 4 h. Completion of the reaction was monitored by LCMS; after completion, evaporated the solvent under reduced pressure. The resulting residue was purified by reverse phase C-18 column (5% ACN in 0.1% FA as eluent and lyophilized) to afford compound as off-white solid. Resulting solid was treated with basic resin in methanol at rt for 1 h and filtered. The filtrated was evaporated and lyophilized to afford II- 1032 (5 mg, 15.6%) as an off-white solid. [0970] ¹ H NMR [400 MHz, DMSO-d6]: δ 7.47-7.45 (m, 3H), 7.14 (d, J=8 Hz, 2H), 5.75 (d, J=6 Hz, 1H), 2.78 (s, 2H), 2.71 (s, 3H), 2.33 (s, 3H), 2.16 (s, 3H), 0.91-0.83 (m, 4H). [0971] LCMS: m/z: 390.19 [M+1] ⁺ , 98.34% (1.30 min), [0972] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm), [0973] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, [0974] (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) [0975] Flow Rate: 0.4 mL/min. Scheme 25: Synthesis of III-1000 Step-1: [0976] To a stirred solution of compound 1 (30 g, 0.194 mol) in DMF (300 mL) was added NBS (41.5 g, 0.233 mol) at 0°C. The resulting mixture stirred at 80 °C for 16 h. Progress of the reaction was monitored by TLC. After completion, the reaction mass poured into crushed ice. Resulting solid was filtered and washed with water. The resulting solid was dissolved in 10% methanol in dichloromethane, brine solution. The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to afford compound 2 (28 g, yield: 61.8%) as a brown solid. [0977] LCMS: m/z: 233.02 [M+2] ⁺ , 97.98 % (1.05 min), [0978] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [0979] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0980] Flow Rate: 0.4 mL/min. Step-2: [0981] POCl3 (80 ml) was added to the compound 2 (20 g, 0.086 mol) at room temperature. The resulting reaction mixture was refluxed for 7 h. Progress of the reaction was monitored by TLC, after completion, excess POCl ₃ evaporated under reduced pressure. The residue was diluted with ice cold water and basified using solid NaHCO ₃ upto pH~9 and extracted with EtOAc. The organic layer washed with brine solution, dried anhydrous Na ₂ SO ₄ , filtered and concentrated to afford compound 3 (20 g, yield: 93%) as brown solid. [0982] ¹ H NMR [400 MHz, DMSO-d ₆ ]: 8.55 (s, 1H), 2.82 (s, 3H). Step-3: [0983] To a stirred solution of compound 3 (12 g, 0.047 mol) in MeOH (120 mL) was added Sodium methoxide (3.2 g, 0.060 mol) portion wise at 0 °C. The resulting mixture allow to stir at 80 °C for 3 h. Progress of the reaction was monitored by TLC, after completion, evaporated the solvent under reduced pressure. The resulting residue diluted with water and extracted with EtOAc. The organic layer washed with brine solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was triturated with ether, filtered and dried to afford compound 4 (5.5 g, yield: 46.6%) as brown solid. [0984] LCMS: m/z: 247.06 [M+2] ⁺ , 93.92% (1.58 min), [0985] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [0986] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0987] Flow Rate: 0.4 mL/min. Step-4: [0988] To a stirred solution of 4 (5 g, 0.020 mol) and compound 5 (8.7 g, 0.024 mol) in Dioxane (50 mL) and water (5 mL) was added NaHCO ₃ (5.1 g, 0.060 mol), Pd(dppf)Cl ₂ (740 mg, 0.001 mol) at room temperature. The resulting reaction mixture degassed with nitrogen for 20 min and stirred at 90°C for 16h. Progress of the reaction was monitored by TLC, after completion, the reaction mass filtered through celite pad and washed with EtOAc. The filtrate was washed with water, brine solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (20% E.A in Hexane as eluent) to afford compound 6 (6 g, yield: 71.4%) as yellow liquid. [0989] LCMS: m/z: 402.35 [M+1] ⁺ , 85.16% (1.95 min), [0990] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [0991] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0992] Flow Rate: 0.4 mL/min. Step-5: [0993] To a stirred suspension of compound 6 (2 g, 4.987 mmol) in THF (30 mL) and water (10 ml) was added NH4Cl (1.33 g, 24.937 mmol) followed by Iron Powder (6.97 g, 24.937 mmol) at room temperature. The resulting mixture allow to stir at 80 °C for 16h. The progress of the reaction was monitored by TLC, after completion, the reaction mass filtered through celite pad and washed with EtOAc (150 ml). The filtrate was washed with water, brine solution. The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to get compound 7 (1.8 g, 97.2%). The crude compound used as such for next step without any purification. Step-6: [0994] To a stirred suspension of 7 (1.8 g, 4.851 mmol) in MeOH (20 mL) was added compound 8 (0.99 g, 7.277 mmol), cat AcOH (0.1 mL) at room temperature and continued the stirring for 1 h. Then reaction mixture cool to 0 °C and added NaBH4 (210 mg, 5.513 mmol) portion wise. The resulting mixture allowed to room temperature and stirred for 3 h. The progress of the reaction was monitored by TLC, after completion, the reaction mixture quenched with cold water and extracted with DCM (2 x 100 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuum. Resulting residue was purified by silica gel (100-200) column chromatography (30% EtOAc in hexane) to afford compound 9 (1.3 g, 54.6%) as yellow syrup. Step-7: [0995] To a stirred solution of 9 (2.5 g, 5.091 mmol) and compound 10 (1.23 g, 6.109 mmol) in DCM (25 mL) was added EDCI (1.46 g, 7.637 mmol) at room temperature and continued the stirring for overnight. The reaction progress was monitored by TLC, after completion, the reaction mass diluted with DCM and washed with water, brine solution. The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by RP-C ₁ 8 column (60% ACN in 0.1% FA as eluent and extracted) to afford compound 11 (550 mg, yield: 12.7%) as yellow syrup. [0996] LCMS: m/z: 677.30 [M+2] ⁺ , 95.06% (1.84 min), [0997] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [0998] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [0999] Flow Rate: 0.4 mL/min. Step-8: [1000] To a solution of 11 (500 mg, 0.742 mmol) in DMA (5 mL) was added KOAc (291 mg, 2.967 mmol) and Pd(tBu ₃ P) ₂ (38 mg, 0.074 mmol) at room temperature. The reaction mixture degassed with nitrogen for 15 min and stirred at 150 °C in a microwave for 2 h. Progress of the reaction was monitored by TLC, after completion, the reaction mass poured into ice-cold water and extracted with EtOAc. The organic layer washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude residue was purified by reverse phase C-18 column chromatography (70% ACN in 0.1% FA as an eluent and extracted) to afford compound 12 (250 mg, yield: 56.8%) as yellow solid. [1001] LCMS: m/z: 595.58 [M+1] ⁺ , 99.87% (1.98min), [1002] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [1003] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, [1004] (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1005] Flow Rate: 0.4 mL/min. Step-9: [1006] Trifluoroacetic acid (1mL) was added to the compound 12 (100 mg, 0.168 mmol) at room temperature. The resulting mixture stirred at 100 °C for 3 h. Progress of the reaction was monitored by LCMS, after completion, the reaction mixture was evaporated in vacuo. The resulting residue was purified by reverse phase C-18 column (25% ACN in 0.1% FA as eluent and lyophilized) to afford compound III-1003 (15 mg, yield: 24.7%) as a white solid. [1007] ¹ H NMR [400 MHz, DMSO-d6]: δ 8.58 (d, J=8 Hz, 1H), 8.34 (d, J=4.4 Hz, 1H), 7.53 (d, J=8 Hz, 1H), 7.23 (d, J=7. Hz, 2H), 7.08 (d, J=7.2 Hz, 2H), 3.77 (s, 3H), 2.96-2.94 (m, 3H), 2.72 (s, 3H), 1.33 ((d, J=4.8 Hz, 3H), 0.91-0.83 (m, 4H). [1008] LCMS: m/z: 375.27 [M+1] +, 96.06% (1.58 min), [1009] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm), [1010] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) [1011] Flow Rate: 0.4 mL/min. Step-10: [1012] To a stirred solution of III-1003 (30 mg, 0.080 mmol) 35% HCHO (0.2 mL) in methanol (1 mL) was added acetic acid (0.05 mL) followed by sodium cyanoborohydride (16 mg, 0.240 mmol) at room temperature. The resulting reaction mixture stirred at room temperature for overnight. The progress of the reaction was monitored by LCMS, after completion, the reaction mass quenched with water and extracted with 10% MeOH in DCM. The organic layer washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude residue was purified by reverse phase C-18 column (25% ACN in 0.1% FA as eluent and lyophilized) to afford compound III-1000 (25 mg, yield: 78%) as a white solid. [1013] ¹ H NMR [400 MHz, DMSO-d6]: δ 11.03 (s, 1H) 8.56 (dd, J=6.4 Hz, 1H), 8.32 (dd, J=2.4 Hz, 1H), 7.54-7.51 (m, 1H), 7.18 (d, J=8 Hz, 2H), 7.01 (d, J=7.6 Hz, 2H), 3.78 (s, 3H), 2.95-2.91 (m, 1H), 2.72 (s, 3H), 2.40 (d, J=7.2 Hz, 2H), 2.18 (s, 6H), 1.25 ((d, J=6.8 Hz, 3H). [1014] LCMS: m/z: 403.35 [M+1] ⁺ , 95.18% (1.64 min), [1015] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm), [1016] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) [1017] Flow Rate: 0.4 mL/min. Step-1: [1018] To a stirred solution of compound 1 (20 g, 97 mmol) in DMF (250 mL), compound 2 (13.3 g, 97 mmol) was added, followed by DIPEA (53 mL, 289 mmol) and HATU (54 g, 144 mmol). The reaction mixture was then stirred at room temperature for 5 hours. The reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was poured into ice-cold water and extracted with EtOAc (2x 500 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford the crude compound. The crude compound was purified by silica gel column chromatography (100:200 mesh) using 20% EtOAc in hexane as an eluent, to yield compound 3 (20 g, Yield: 64%) as an off-white solid. [1019] LCMS: m/z = 327.20[M+2] +, 98.46% (1.68 min). [1020] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-2: [1021] To a stirred solution of compound 3 (10 g, 30.5 mmol) in DMF (100 mL), NaH (2.2 g, 91.7 mmol) was added at 0°C, followed by PMB-Cl (7 mL, 61 mmol). The reaction mixture was stirred for 3 hours. The reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was poured into ice-cold water and extracted with EtOAc (2x 500 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to yield the crude compound. The crude compound was purified by silica gel column chromatography (100:200 mesh) using 10% EtOAc in hexane as an eluent, resulting in the formation of compound 4 (8 g, Yield: 59%) as an off-white solid. [1022] LCMS: m/z = 447.35 [M+2H] ⁺ , 80.52 % (1.65 min). [1023] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-3: [1024] To a stirred solution of compound 4 (15 g, 33 mmol) in DMA (150 mL), potassium acetate (13.1 g, 134 mmol) was added, followed by Pd (PtBu3) ₂ catalyst (1.01 g, 2.0 mmol). The reaction mixture was stirred at 150°C for 4 hours. The reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was poured into ice-cold water and extracted with ethyl acetate (2x 200 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to yield the crude compound. The crude compound was used for the next step without purification. The crude compound was then purified by silica gel column chromatography (100:200 mesh) using 10% EtOAc in hexane as an eluent, resulting in the formation of compound 5 (3.5 g, Yield: 28.7%) as an off-white solid. [1025] LCMS: m/z = 366.18 [M+1H] ⁺ , 98.41% (1.65 min). [1026] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min Step-4: [1027] Trifluoroacetic acid (50 mL) was added to compound 5 (11 g, 30 mmol) at 0°C. The resulting reaction mixture was allowed to reach room temperature and was stirred at 100°C for 16 hours. The completion of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with an aqueous NaHCO ₃ solution and extracted with EtOAc (2x 200 mL). The organic phase was washed with a brine solution (100 mL), dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The crude compound was then purified by silica gel column chromatography (100:200 mesh), and the compound was eluted using 40% EtOAc in hexane to yield compound 6 (1.1 g, Yield: 42.8%) as an off-white solid. [1028] LCMS: m/z = 246.16 [M+H] ⁺ , 95.22 % (1.15min). [1029] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-5: [1030] To a stirred solution of compound 6 (1 g, 4.06 mmol) in 2 mL of a 1:1 mixture of DCM was added NBS (863 mg, 4.06 mmol) at 0°C. The reaction mixture was then stirred at room temperature for 16 hours. The reaction was monitored by TLC. After completion, the reaction mixture was poured into ice-cold water and extracted with DCM (2x 100 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to yield the crude compound. The crude compound was purified by silica gel column chromatography (100:200 mesh) using 20% EtOAc in hexane, resulting in the formation of compound 7 (500 mg, Yield: 38%) as an off-white solid. [1031] LCMS: m/z = 325. [M+2] ⁺ , 42.02% (1.5min). [1032] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min Step-6: [1033] To a stirred solution of compound 7 (500 mg, 1.53 mmol) in dioxane (20 mL), compound 8 (1.13 g, 3.07 mmol) was added, followed by NaHCO ₃ (385 mg, 4.59 mmol). The reaction mixture was degassed for 15 minutes, and then Pd(dppf)Cl2 catalyst (112 mg, 0.053 mmol) was added, followed by another 10-minute degassing. The reaction mixture was stirred at 85°C for 15 hours. The reaction progress was monitored by LCMS. After completion, the reaction mixture was poured into ice-cold water and extracted with ethyl acetate (2x100 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to yield the crude compound. The crude compound was purified by column chromatography using silica gel (100:200 mesh). The compound was eluted using 20% EtOAc in hexane to afford pure compound 9 (60 mg, Yield: 8%) as a white solid. [1034] LCMS: m/z: 480.28 [M+1H] ⁺ , 24.36 % (1.72 min). [1035] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-7: [1036] To a stirred solution of compound 9 (500 mg, 1.04 mmol) in 1,4-dioxane (5 mL), 4M HCl in dioxane (2.5 mL) was added at 0°C. The reaction mixture was then stirred at room temperature for 15 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and washed with ethyl acetate (2x100 mL). The aqueous layer was quenched with aqueous NaHCO ₃ and extracted with 10% MeOH in DCM (2x100 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to yield the crude compound. The crude compound was purified by column chromatography using silica gel (100:200 mesh). The compound was eluted using 10% EtOAc in hexane to afford compound 10 (100 mg, Yield: 35%) as a white solid [1037] LCMS: m/z: 380.20 [M+H] ⁺ , 96.20% (1.48 min). [1038] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90), Flow Rate: 0.4 mL/min. [1039] ¹ H NMR [400 MHz, DMSO-d ₆ ]: 7.767 (s, 1H), 7.2 (d, J = 12.8 Hz, 2H), 7.19 (d, J = 7.2 Hz, 2H), 3.78 (s, 2H), 2.67 (s, 3H), 1.29-1.23 (m, 4H), 1.29 (t, J = 6 Hz, 3H).

Step-8: [1040] To a stirred solution of compound 10 (100 mg, 0.263 mmol) in methanol (2 mL), 35% HCHO (0.1 mL) was added, followed by two drops of acetic acid, and then sodium cyanoborohydride (35 mg, 0.527 mmol) at room temperature. The reaction mixture was stirred for 5 hours at room temperature. The progress of the reaction was monitored by LCMS. After completion of the reaction, the solvent was evaporated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The crude compound was purified by reverse- phase C-18 column chromatography (25% ACN in 0.1 FA as the eluent) and lyophilized to afford II-1014 (10 mg, 9%) as a white solid. [1041] LCMS: m/z: 408.24 [M+1]+, 98.18 % (1.81min), [1042] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm), [1043] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) [1044] Flow Rate: 0.4 mL/min. [1045] ¹ H NMR [400 MHz, DMSO-d6]: δ 7.79 (d, J = -5.60 Hz, 1H), 7.43 (d, J = -11.20 Hz, 2H), 7.21 (d, J = -7.60 Hz, 2H), 5.82 (d, J = -4.80 Hz, 1H), 3.80 (d, J = Hz, 3H), 2.74 (s, 3H), 1.31-1.29 (m, 3H).

Scheme 26: Synthesis of II-1018 and II-1015 Step-1: [1046] To a stirred solution of compound 2 (10 g, 46.94 mmol) was added SOCl ₂ (20.8 mL, 289 mmol) at 0 ⁰ C under nitrogen atmosphere. The reaction mixture was stirred at rt for 2h, after completion of reaction, the reaction mixture was concentrated and dried under high vacuum to obtain the intermediate acid chloride. The acid chloride was dissolved in CH ₂ CI ₂ (200 mL) followed by the addition of Et3N (25.42 mL, 177 mmol), compound 1 (9.6 g, 62.2 mmol) and the reaction were stirred at room temperature for 4h. The reaction mixture was concentrated. Crude compound was purified by silica gel column chromatography (100: 200 mesh) using 10% EtOAc in Hexane as an eluent afford compound 3 (10 g, Yield: 42 %) as an off white solid. [1047] LCMS: m/z: 335.20 [M+2] ⁺ , 65.43 % (1.41 min), [1048] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [1049] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, [1050] (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1051] Flow Rate: 0.4 mL/min. Step-2: [1052] To a stirred solution of compound 3 (6 g, 17.92 mol) in DMF (60 mL) was added NaH (1.2 g, 53.25 mol) at 0 ^o C followed by MOM-Cl (3 mL,26.20 mol) then reaction mixture was stirred at for 3h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with EtoAc (2x500 mL), organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude compound was purified by silica gel column chromatography (100: 200 mesh) using 10% EtOAc in Hexane as an eluent afford compound 4 (6.3 g, Yield: 78%) as an off white solid. [1053] Step-3: [1054] To a stirred solution of compound 4 (7 g, 0.018 mmol) in DMA (70 mL) was added potassium acetate (5.2 g, 0.56 mol) followed by Pd (P ^t Bu3) ₂ catalyst (943 mg, 5.4 mmol) then reaction mixture was stirred at 150 ^o C for 4h. The reaction progress was monitored by TLC, after completion, the reaction mixture was poured into ice cold water and extracted with ethyl acetate (2x200 mL), organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. The crude compound was purified by silica gel column chromatography (100: 200 mesh) using 10% EtOAc in Hexane as an eluent afford compound 5 (3 g, Yield: 45 %) as an off- white solid. [1055] LCMS: m/z = 298.34 [M+1] ⁺ , 86.63% (1.69min). [1056] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [1057] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, [1058] (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1059] Flow Rate: 0.4 mL/min. Step-4: [1060] To a stirred solution of compound 5 (1 g, 3.5 mol) in DCM: AcOH 20 mL (1:1) was added NBS (863 mg, 4.0 mol) at 0 ^o C then reaction mixture was stirred at room temperature for 16h. The reaction progress was monitored by TLC, after completion of reaction, The reaction mixture was poured into ice cold water and extracted with DCM (2x100 mL), organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude compound was purified by silica gel column chromatography (100:200 mesh) and compound was eluted using 20% EtOAc in Hexane to afford compound 6 (500 mg, Yield: 38%) as an off white solid. [1061] LCMS: m/z = 333.07 [M+2] ⁺ , 39.53% (1.65min). [1062] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [1063] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, [1064] (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1065] Flow Rate: 0.4 mL/min. Step-5: [1066] To a stirred solution of compound 6 (500 mg, 1.53 mmol) in Dioxane: H ₂ O (20 mL, 9:1) solution was added compound 7 (1.13 g, 3.07 mmol) followed by NaHCO ₃ (385 mg, 4.59 mmol). The reaction mixture was degassed for 15 minutes, then Pd(dppf)Cl ₂ catalyst (112 mg, 5.3 mmol) was added and again degassed for 10 minutes. The reaction mixture was stirred at 85 ^o C for 15h. Reaction was monitored by LCMS. Upon completion, the reaction mixture was poured into ice cold water and extracted with ethyl acetate (2x100 mL). Organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude compound was purified by column chromatography using a silica gel (100: 200 mesh). Compound was eluted using 20% EtOAc in Hexane to afford pure compound 8 (60 mg, Yield: 8%) as a white solid. [1067] LCMS: m/z = 487.56 [M+1] ⁺ , 10.54% (1.89 min). [1068] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [1069] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, [1070] (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1071] Flow Rate: 0.4 mL/min. Step-6: [1072] To a stirred solution of compound 8 (30 mg, 0.608 mmol) in 1,4-dioxane (3 mL) was added 4M HCl in dioxane (1.5 mL) at 0 ^o C then reaction mixture was stirred at rt for 2h. Reaction was monitored by TLC; after completion of reaction, reaction mixture was quenched with aq. NaHCO ₃ and extracted with ethyl acetate. Crude was purified by C-18 reverse phase column chromatography to afford II-1018 (1 mg, Yield: 4 %) as a white solid. [1073] LCMS: m/z: 387.47 [M+1]+, 98.23% (1.86 min), [1074] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm), [1075] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, [1076] (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) [1077] Flow Rate: 0.4 mL/min. [1078] Step-7: [1079] To a stirred solution of compound 8 (200 mg, 0.405 mmol) was added Hydrogen bromide (1 mL) at 0 ^o C then reaction mixture was stirred at 100 ^o C for 2h. Reaction was monitored by TLC. Reaction mixture was evaporated to afford crude compound was purified by Prep HPLC to afford II-1015 (3 mg, Yield: 1.96%) as an off white solid. [1080] LCMS: m/z: 373.31 [M+1]+, 98.06% (1.59min), [1081] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm), [1082] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, [1083] (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) [1084] Flow Rate: 0.4 mL/min. [1085] ¹ H NMR [400 MHz, DMSO-d ₆ ]: 7.28-7.25 (m, 3H), 7.15-7.01 (m, 4H), 2.91-2.85 (m, 3H), 2.73(s, 3H), 1.59 (s, 3H), 1.23 (m, 3H).

Scheme 27: Synthesis of I-1015 and I-1018 Step 1: [1086] NaOMe (11.3 g, 210 mol) was added portion wise to a solution of compound 1 (25 g, 105 mol) dissolved in DMSO (250 mL) at room temperature under nitrogen atmosphere. The mixture was stirred for 16h and then poured into water and extracted with ethyl acetate (2x1000 mL). The organic phase was washed with water (1000 mL) and brine (1000 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography using silica gel (100: 200 mesh) compound was eluted using 4% EtOAc in Hexane to afford compound 2 (12.8 g, Yield: 48.7%) as a brown solid. [1087] ¹ H NMR [400 MHz, DMSO-d6]: 8.01-7.98 (m, 1H), 7.39 (t, J = 8.4 Hz 1H), 3.95 (s, 3H). Step 2: [1088] To a stirred solution of compound 2 (12.8 g, 51.2 mmol) in Dioxane (128 ml) solution was added methyl boronic acid (3.98 g, 66.5 mmol) followed by Cs ₂ CO ₃ (50.0 g, 153 mmol). Reaction mixture was degassed for 15 minutes then Pd(dppf)Cl2 (2.2 g, 3.072 mmol) was added and again degassed for 10 minutes then reaction mixture was stirred at 85 ^o C for 16 h. The reaction progress was monitored by TLC, reaction mixture was poured into ice cold water and extracted with ethyl acetate, organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. The crude compound was purified by column chromatography silica gel (100: 200 mesh) using 5% EtOAc in Hexane to afford compound 3 (6.5 g, Yield: 68 %) as a brown solid. [1089] ¹ H NMR [400 MHz, CDCl3]: 7.92-7.89 (m, 1H), 6.89 (t, J = 8.4 Hz, 1H), 3.97(s, 3H), 2.54 (d, J = 2.8 Hz, 3H). Step 3: [1090] To a solution mixture of compound 3 (10 g, 54.05 mmol) in THF-water (100 mL, 3:1 ratio) was added Fe (15.09 g, 270.2 mmol) followed by ammonium chloride (28.9 g, 540.12 mmol) at rt and continued at 60 ^o C for 2h. Reaction mixture was basified with sat. NaHCO ₃ solution and extracted with EtOAc. Total organic layers were dried over Na ₂ SO ₄ and concentrated under vacuo to afford compound 4. Crude compound was used for next step without purification. (10 g, crude). [1091] LCMS: m/z = 156.06 [M+H] ⁺ , 17 % (0.71 min). [1092] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 4: [1093] To a stirred solution of compound 4 (7.8 g, 38.613 mmol) in DCM (78 ml) was added compound 5 (5.98 g, 38.613 mmol) followed by EDC.HCl (14.8 g, 77.2 mmol) then reaction mixture was stirred at room temperature for 16h. The reaction was monitored by TLC, after completion of reaction solvent was evaporated by reduced pressure and crude compound was purified by column chromatography using a silica gel (100: 200 mesh) compound was eluted using 10% EtOAc in hexane to afford compound 6 (7 g, Yield: 53 %) as a brown solid. [1094] LCMS: m/z = 341.08 [M+2H] ⁺ , 36 % (1.30 min). [1095] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 5: [1096] To a stirred solution of compound 6 (7 g, 20.648 mmol) in DMF (70 mL) was added 60% NaH (1.4 g, 61.9 mmol) at 0 ^o C and stirred for 20 min. PMB-Cl (4.8 g, 30.9 mmol) added at 0 °C. The resulting reaction mixture allowed to stirred at room temperature for 3h. Completion of the reaction was monitored by TLC, after completion of reaction, reaction mixture quenched with sat. NH4Cl solution and extracted with EtOAc (2x500 mL). The organic washed brine solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by column chromatography using a silica gel (100: 200 mesh) compound was eluted using 10% EtOAc in hexane to afford compound 7 (5.6 g, Yield: 59 %) as a brown solid. [1097] LCMS: m/z = 461.09 [M+2H] ⁺ , 54 % (1.30 min). [1098] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min Step 6: [1099] To a stirred solution of compound 7 (5 g, 10.893 mmol) in DMA (50 mL) was added KOAc (4.27 g, 43.57 mmol), Pd(P ^t Bu3) ₂ (333 mg, 0.653 mmol) at room temperature. The resulting reaction mixture degassed with nitrogen for 15 min. Then the reaction mixture heated to 150 °C and stirred for 16h. The completion of the reaction was monitored by TLC. After completion, reaction mass cooled to RT, quenched with cold water and extracted with EtOAc (200 ml). The separated organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Crude compound was purified by column chromatography using silica gel (100: 200 mesh) compound was eluted using 10% EtOAc in Hexane to afford compound 8 (2.1 g, Yield: 51 %) as a white solid. [1100] LCMS: m/z = 379.20 [M+1H] ⁺ , 65 % (1.69 min). [1101] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 7: [1102] To a solution mixture of compound 8 (1.5 g, 3.96 mmol) in H ₂ SO ₄ (15 mL) was added 1,3-Dibromo-5,5-dimethyl hydantoin (1.1 g, 3.96 mmol) at 0 ^o C and continuous the reaction at 0 ^o C for 1h. The reaction progress was monitored by TLC, after completion of reaction, mixture was quenched in ice water and extracted with DCM. The organic layer was concentrated under reduced pressure. The crude was triturated with pentane and diethyl ether to afford compound 9 (1.2 g, Yield: 90 %) as a brown solid. [1103] LCMS: m/z = 339.00 [M+2H] ⁺ , 79 % (1.46 min). [1104] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step 8: [1105] To a stirred solution of compound 9 (1 g, 4.219 mmol) in Dioxane (10 mL) solution was added compound 10 (2.2 g, 6.329 mmol) followed by K ₂ CO ₃ (1.7 g, 12.657 mmol). Reaction mixture was degassed for 15 minutes then Pd(dppf)Cl2 catalyst (164 mg, 0.253 mmol) was added and again degassed for 10 minutes then reaction mixture was stirred at 85 ^o C for 16h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with ethyl acetate (2x300 mL), organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. Crude compound was purified by column chromatography using a silica gel (100: 200 mesh) compound was eluted using 20% EtOAc in Hexane to afford compound 11 (243 mg, Yield: 16 %) as a white solid. [1106] LCMS: m/z = 492.31 [M+1H] ⁺ , 8 % (1.76 min). [1107] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-9: [1108] To a stirred solution of compound 11 (100 mg, 0.203 mmol) in 1,4-dioxane (1 mL) was added dioxane/HCl (0.610 mL) at 0 ^o C then reaction mixture was stirred at room temperature for 8h. Reaction was monitored by TLC; after completion of reaction, reaction mixture was quenched with aq. NaHCO ₃ and extracted with ethyl acetate. Crude compound was purified by C-18 reverse phase column chromatography to afford compound I-1015 (2.5 mg, Yield: 3.1%) as a white solid. [1109] LCMS: m/z = 392.33 [M+1] ⁺ , 98.10 % (1.69 min). [1110] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) Flow Rate: 0.4 mL/min. [1111] ¹ H NMR [400 MHz, DMSO-d ₆ ]: δ 8.53-8.51 (m, 1H), 8.32-8.25 (m, 1H), 7.42-7.37 (m, 1H), 7.21-7.19 (m, 2H), 7.07-7.03 (m, 2H), 3.51 (d, J = 2.4 Hz, 3H), 2.83-2.75 (m, 3H), 2.49 (s, 3H), 1.29-1.23 (m, 3H). Step-10: [1112] To a stirred solution of compound-9 (150 mg, 0.445 mmol) and compound-10A (200 mg, 0.534 mmol) in Dioxane:H ₂ O (2.2 ml, 2:0.2) was added K ₂ CO ₃ (123 mg, 0.890 mmol), Pd(OAc)2 (40 mg, 0.044 mmol) and xanthphos (51.4 mg, 0.089 mmol) at room temperature. The resulting reaction mixture degassed with nitrogen for 10 min. The reaction mixture heated to 90°C in a microwave and stirred for 2 h. progress of the reaction was monitored by LCMS; after completion, reaction mass diluted with EtOAc and filtered through celite. The filtrate washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was triturated with Ether and dried to get crude compound (11A) as brown solid. [1113] LCMS: m/z = 406.37 [M-Boc] ⁺ , 16.36 % (1.88 min). [1114] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min.

Step-11: [1115] To a stirred solution of compound 11A (120 mg, 0.237 mmol) in 1,4-dioxane (2 mL) was added dioxane/HCl (1 mL) at 0 ^o C then reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC, after completion of reaction, the reaction mixture was quenched with aq. NaHCO ₃ and extracted with ethyl acetate. Crude compound was purified by prep HPLC and lyophilized to afford compound I-1018 (1.6 mg, Yield: 1.66%) as a white solid. [1116] LCMS: m/z = 406.50 [M+1] ⁺ , 95.62 % (1.69 min). [1117] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) Flow Rate: 0.4 mL/min. [1118] ¹ H NMR [400 MHz, DMSO-d ₆ ]: δ 8.53-8.51 (m, 1H), 8.32-8.25 (m, 1H), 7.42-7.37 (m, 1H), 7.23 (d, J = 7.2 Hz, 2H), 7.02 (d, J = 10 Hz, 2H), 3.51 (s, 3H), 3.05-2.91 (m, 3H), 2.46 (s, 3H), 1.31 (d, J = 6.8 Hz, 3H). Scheme 28: Synthetic scheme for key intermediate (5): Synthetic scheme: I-1016 and I-1017: Step-1: [1119] To a stirred solution of compound 1 (22 g, 194.6 mmol) in acetone (29 ml, 389.3 mmol) was added piperidine (1 ml) and acetic acid (22 ml) stirred at 90 ^o C for 24h. The progress of the reaction was monitored by TLC, after completion of starting material the reaction mixture was cooled to rt and then concentrated under vaccum. The residue was diluted with 50 ml of water and extracted with ethyl acetate. The organic layer washed with brine solution, dried over Na ₂ SO _4, filtered and concentrated in vacuo to afford crude compound. Crude was purified by column chromatography using a silica gel (100: 200 mesh) and compound was eluted using 3% EtOAc in Hexane as an eluent to afford compound 2 (20 g, 67%) as pale-yellow oil. [1120] LCMS: m/z = 176.23 [M+Na] ⁺ , 82.14 % (1.34 min) [1121] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-2: [1122] N, N-Dimethylformamide dimethyl acetal (19 ml, 143.79 mmol) was added dropwise to a stirred solution of compound 2 (20 g 130.71 mmol) in ethanol (200 ml). The resulting solution was stirred for 15h at 80 ^o C. After completion of the reaction the reaction mixture was cooled to rt and concentrated under vacuum. The residue was diluted with 50 ml of water and extracted with ethyl acetate (200 ml). The organic layer washed with brine solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to afford crude compound. Crude was purified by column chromatography using a silica gel (100: 200 mesh) and compound was eluted using 5% EtOAc in Hexane as an eluent to afford compound 3 (22 g, 80.8%). [1123] LCMS: m/z = 231.16 [M+Na] ⁺ , 74.15 % (1.22 min), [1124] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-3: [1125] HBr (40% in acetic acid, 125 ml) was added dropwise to a 40 ^o C stirred solution of compound 3 (25 g, 120.19 mmol) in acetic acid (125 ml), and the resulting solution was stirred for 15h at 55 ^o C. The reaction mixture was cooled to rt and then poured into 10 ml of cold water. The pH value of the solution was adjusted to 9 with 2M aqueous sodium carbonate solution. Concentrated under vacuum. The resulting mixture was extracted with ethyl acetate (500 ml). The organic layer washed with brine solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to afford crude compound. Crude was purified by column chromatography using a silica gel (100: 200 mesh) and compound was eluted using 5% EtOAc in Hexane as an eluent to afford compound 4 (23 g, 78.7%) as a brown liquid. [1126] LCMS: m/z = 244.01 [M+1] ⁺ , 90.09 % (2.46 min), [1127] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) Flow Rate: 0.4 mL/min. Step-4: [1128] To a stirred solution of compound 4 (6 g, 24.69 mmol) in Dioxane: H ₂ O (60 ml 1:1) was added NaOH (3.95 g, 98.76 mmol) at 0 ^o C then reaction mixture was stirred at 80 ^o C for 15 h. The mixture was allowed to cool to RT, diluted with H ₂ O, washed with ethyl acetate (3 x 30 mL). The aqueous layer was acidified with concentrated hydrochloric acid to make pH=1, and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (25 mL), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo to afford the compound 5 (2.2 g, 41.5%) as a white solid. [1129] LCMS: m/z = 213.99 [M-1]-, 98.04 % (0.44 min), [1130] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-5: [1131] Compound 5 (4 g, 18.604 mmol) in SOCl2 (40 ml) was stirred at 70 ^o C for 2h. Completion of the reaction was monitored by TLC, after completion of reaction solvent was evaporated under reduced pressure at N ₂ atmosphere. The resulting crude dissolved in DCM (20 ml) and added to a solution of compound 6 (2.3 g, 14.833 mmol) in DCM (20 ml) and TEA (10 ml, 74.418 mmol) at 0 °C. The resulting mixture stirred at rt for 4h. Completion of the reaction was monitored by TLC, after completion, reaction mass diluted with DCM (200 ml) and washed with water, brine solution. Organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by using a silica gel (100: 200 mesh) compound was eluted with 20% EtOAc in hexane to afford compound 7 as an off-white solid (4.3 g, 65.7%). [1132] LCMS: m/z = 353.07 [M+1] ⁺ , 98.09 % (1.34 min), [1133] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-6: [1134] To a stirred solution of compound 7 (4 g, 11.363 mmol) in DMF (40 mL) was added NaH (818 mg, 34.083 mmol) at 0 ^o C followed by MOM-Cl (1.36 g, 17.045 mmol) then reaction mixture was stirred at rt for 6 h. Reaction was monitored by TLC, the reaction mixture was poured into ice cold water and extracted with DCM (200 ml), organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude compound. The Crude compound was purified by column chromatography using a silica gel (100: 200 mesh) using 20% EtOAc: Hexane as an eluent to afford compound 8 as a white solid (2.5 g, 55.5%). [1135] LCMS: m/z = 419.13 [M+Na] ⁺ , 75.19 % (1.44 min), [1136] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-7: [1137] To a stirred solution of compound 8 (2.0 g, 5.05 mmol) in DMA (20 ml), potassium acetate (2.47 g, 25.252 mmol) was added, followed by Pd(PtBu3)2 (258 mg, 0.252 mmol). The reaction mixture was then stirred at 150°C for 16 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was poured into ice-cold water and extracted with ethyl acetate (200 ml X 3). The organic layers were dried over anhydrous Na ₂ SO ₄ and evaporated to afford the crude compound. The crude compound was purified by column chromatography using silica gel (100-200 mesh), and the compound was eluted using 10% EtOAc in hexane to yield compound 9 as an off-white solid (820 mg, 51.5% yield) [1138] LCMS: m/z = 317.25 [M+1] ⁺ , 96.44 % (1.65 min), [1139] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-8: [1140] To a stirred mixture of compound 9 (1.1 g, 3.481 mmol) in H ₂ SO ₄ (11 ml), 1,3- Dibromo-5,5-dimethyl hydantoin (992 mg, 3.481 mmol) was added at 0°C, and the reaction was continued at 0°C for 1 hour. The reaction progress was monitored by TLC. After the completion of the reaction, the mixture was quenched in ice water and extracted with DCM. The organic layer was concentrated under reduced pressure to yield crude compound 10 as a brown solid (800 mg, 66.1%). The crude product was used for the next step without purification. [1141] LCMS: m/z = 351.16 [M+1] ⁺ , 85.53 % (1.61 min) [1142] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-9: [1143] To a stirred solution of compound 10 (500 mg, 1.428 mmol) in 5 ml of dioxane, compound 11 (773 mg, 2.142 mmol) was added, followed by potassium carbonate (591 mg, 4.285 mmol). The reaction mixture was degassed for 15 minutes, and then Pd(dppf)Cl2 (63 mg, 0.085 mmol) was added. It was degassed again for 10 minutes, and the reaction mixture was stirred at 85°C for 1 hour under microwave irradiation. The reaction was monitored by TLC. After completion, the reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to obtain the crude compound. The crude product was purified by column chromatography using silica gel (100-200 mesh) to yield the off-white solid [1144] LCMS: m/z = 506.71 [M+1] ⁺ , 54.01 % (1.61 min) [1145] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-10: [1146] To a stirred solution of crude compound 12 (300 mg, 0.594 mmol) in 1,4-dioxane (3 ml), dioxane/HCl (4 ml) was added at 0°C, and the reaction mixture was stirred at room temperature for 4 hours. The reaction was monitored by TLC and LCMS. After the completion of the reaction, the excess TFA was evaporated in vacuo. The residue was purified by preparative HPLC and lyophilized to yield I-1016 (5 mg, 2.08%) as a white solid. [1147] LCMS: m/z: 406.35 [M+1] ⁺ , 96.96% (1.82 min) [1148] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm), [1149] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) [1150] Flow Rate: 0.4 mL/min. [1151] ¹ H NMR [400 MHz, DMSO-d ₆ ]: δ 8.39 (brs, 1H), 8.02 (d, J = 4.8 Hz, 1H), 7.20-7.16 (m, 3H), 7.04 (d, J = 6.4 Hz, 2H), 3.49 (s, 3H), 2.86-2.79 (m, 3H), 2.67 (s, 3H), 2.43 (s, 3H), 1.30 (d, J = 6Hz, 3H). Step-11: [1152] Compound 12 (150 mg, 0.29 mmol) was suspended in 40% HBr in water (3 mL) and stirred at 80 °C for 2 hours. The reaction progress was monitored by LCMS. After the completion of the reaction, the excess HBr was evaporated to afford the crude compound. The residue was purified by preparative HPLC and lyophilized to yield I-1017 (15 mg, 12.9%) as a white solid. [1153] LCMS: m/z: 392.29 [M+1] ⁺ , 96.36% (1.71 min), [1154] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm), [1155] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) [1156] Flow Rate: 0.4 mL/min. [1157] ¹ H NMR [400 MHz, DMSO-d6]: 7.97 (d, J = 4.4 Hz, 1H), 7.13 (d, J = 4.4 Hz, 3H), 6.96 (s, 2H), 2.79 (s, 3H), 2.73-2.69 (m, 3H), 2.42 (s, 3H), 1.26 (d, J = 6.4Hz, 3H).

Scheme 29: Synthesis of II-1016 Step-1: [1158] To a stirred solution of compound 1 (20 g, 96 mmol) in DMF (250 mL), compound 2 (13.3 g, 96 mmol) was added, followed by DIPEA (53 mL, 289 mmol) and HATU (54 g, 144 mmol). The reaction mixture was stirred at room temperature for 5 hours. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was poured into ice-cold water and extracted with EtOAc (2x 500 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and then evaporated to yield crude compound. The crude compound was further purified by silica gel column chromatography (100:200 mesh) using a 20% EtOAc in Hexane eluent, resulting in the isolation of compound 3 (20 g) with a yield of 64% as an off-white solid. [1159] LCMS: m/z = 327.20[M+2] ⁺ , 98.46% (1.68 min). [1160] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-2: [1161] To a stirred solution of compound 3 (10 g, 30.5 mmol) in DMF (100 mL), NaH (2.2 g, 91.7 mmol) was added at 0°C, followed by PMB-Cl (7 mL, 61 mmol). The reaction mixture was stirred for 3 hours and monitored by TLC. After the reaction was complete, the mixture was poured into ice-cold water and extracted with EtOAc (2x500 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and then evaporated to yield the crude compound. Subsequently, the crude compound was purified by silica gel column chromatography (100:200 mesh) using a 10% EtOAc in Hexane eluent, resulting in the isolation of compound 4 (8 g) with a yield of 59% as an off-white solid. [1162] LCMS: m/z = 447.35 [M+2H] ⁺ , 80.52 % (1.65 min). [1163] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-3: [1164] To a stirred solution of compound 4 (15 g, 33.55 mmol) in DMA (150 mL), potassium acetate (13.1 g, 134 mmol) was added, followed by Pd (PtBu3) ₂ catalyst (1.01 g, 2.0 mmol). The reaction mixture was stirred at 150°C for 4 hours and monitored by TLC. After the reaction was complete, the mixture was poured into ice-cold water and extracted with ethyl acetate (2x200 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and then evaporated to yield the crude compound. The crude compound was used for the next step without purification. Subsequently, the crude compound was purified by silica gel column chromatography (100:200 mesh) using a 10% EtOAc in Hexane eluent, resulting in the isolation of compound 5 (3.5 g) with a yield of 28.7% as an off-white solid. [1165] LCMS: m/z = 366.18 [M+1H] ⁺ , 98.41% (1.65 min). [1166] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min Step-4: [1167] Trifluoroacetic acid (50 mL) was added to compound 6 (11 g, 30.0 mmol) at 0°C. The resulting reaction mixture was allowed to come to room temperature and stirred at 100°C for 16 hours. The completion of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with an aqueous NaHCO ₃ solution and then extracted with EtOAc (2x200 mL). The organic phase was washed with a brine solution (100 mL), dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The crude compound was further purified by silica gel column chromatography (100:200 mesh), and the compound was eluted using 40% EtOAc in Hexane to yield compound 7 (1.1 g) with a yield of 42.8% as an off-white solid. [1168] LCMS: m/z = 246.16 [M+H] ⁺ , 95.22 % (1.15min). [1169] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-5:

[1170] To a stirred solution of compound 6 (1 g, 4.0 mmol) in 2 mL of a 1:1 mixture of DCM was added NBS (863 mg, 4.0 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hours and monitored by TLC. After the reaction was complete, the mixture was poured into ice-cold water and extracted with DCM (2x100 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and then evaporated to yield the crude compound. Subsequently, the crude compound was purified by silica gel column chromatography (100:200 mesh) using 20% EtOAc in Hexane as an eluent, resulting in the isolation of compound 7 (500 mg) with a yield of 38% as an off-white solid. [1171] LCMS: m/z = 325. [M+2] ⁺ , 42.02% (1.5min). [1172] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min Step-6: [1173] To a stirred solution of compound 7 (500 mg, 1.50 mmol) in 1,4-dioxane (30 mL), 1 mL of water, compound 8 (597 mg, 1.65 mmol), and sodium bicarbonate (636 mg, 4.6 mmol) were added in a sealed tube. The reaction mixture was degassed with nitrogen for 10 minutes, and then Pd-118 (100 mg, 4.6 mmol) was added. The mixture was degassed again for 10 minutes. The resulting reaction mixture was stirred at 85°C for 15 hours. The completion of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (2x100 mL). The organic layer was washed with a brine solution (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated in vacuo. The crude compound was purified by silica gel column chromatography using a 30% EtOAc in Hexane eluent, resulting in the isolation of compound 9 (200 mg) with a yield of 26% as a brown solid. [1174] LCMS: m/z = 494.39 [M+1] ⁺ , 47.86% (1.84 min). [1175] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [1176] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1177] Flow Rate: 0.4 mL/min. Step-7: [1178] To a stirred solution of compound 8 (300 mg, 0.682 mmol) in 1,4-dioxane (5 mL), dioxane/HCl (2.5 mL) was added at 0°C. The reaction mixture was stirred at room temperature for 2 hours and monitored by TLC. After the completion of the reaction, the reaction mixture was diluted with water (10 mL) and washed with ethyl acetate (50 mL x 2). The aqueous layer was quenched with aqueous NaHCO ₃ and extracted with a 10% MeOH in DCM solution (50 mL x 2). The organic layer was dried over anhydrous Na ₂ SO ₄ and then evaporated to yield the crude compound. Subsequently, the crude compound was purified using a reverse-phase C-18 column with acetonitrile/water (with 0.01% HCOOH) as the eluent, resulting in the isolation of compound II-1019 (22 mg) with a yield of 6.2% as an off-white solid. [1179] LCMS: m/z: 393.50 [M+1] ⁺ , 95.95% (1.72 min), [1180] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm), [1181] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) [1182] Flow Rate: 0.4 mL/min. [1183] ¹ H NMR [400 MHz, DMSO-d6]: 7.767 (s, 1H), 7.2 (d, J = 12.8 Hz, 2H), 7.19 (d, J = 7.2 Hz, 2H), 3.78 (s, 3H), 3.32 (s, 3H), 2.74 (s, 3H), 2.68 (s, 3H),1.39(m,3H). Step-8: [1184] To a stirred solution of II-1019 (200 mg, 0.405 mmol) in 5 mL of DCM, 0.2 mL of BBr3 was added. The reaction was allowed to stir at room temperature for 15 hours, and the progress of the reaction was monitored by TLC and LCMS. Upon completion of the reaction, the reaction mixture was cooled and quenched with cold water. The reaction mixture was then extracted with 50 mL of DCM to remove organic impurities. The aqueous layer was concentrated and purified using reverse-phase C-18 column chromatography with acetonitrile/water (containing 0.01% HCOOH) as the eluent. This resulted in the isolation of compound II-1016 (6 mg) with a yield of 5.20% as a white solid. [1185] LCMS: m/z: 380.14 [M+1] ⁺ , 95.14% (1.34 min), [1186] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm), [1187] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) [1188] Flow Rate: 0.4 mL/min. [1189] ¹ H NMR [400 MHz, DMSO-d ₆ ]: 7.767 (s, 1H), 7.2 (d, J = 12.8 Hz, 2H), 7.19 (d, J = 7.2 Hz, 2H),5.93(m, 1H), 3.32 (s, 3H), 2.74 (s, 3H), 2.68 (s, 3H),1.39(m, 3H). Synthesis of II-1016(R): Step-6: [1190] To a stirred solution of compound 7 (250 mg, 0.7 mmol) in 1,4-dioxane (30 mL), 1 mL of water, compound 8 (300 mg, 8.2 mmol), and sodium bicarbonate (313 mg, 2.3 mmol) were added in a sealed tube. The reaction mixture was degassed with nitrogen for 10 minutes, and then Pd-118 (50 mg, 2.3 mmol) was added. The mixture was degassed again for 10 minutes. The resulting reaction mixture was stirred at 85°C for 15 hours. The completion of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (2x100 mL). The organic layer was washed with a brine solution (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated in vacuo. The crude compound was purified by silica gel column chromatography using a 30% EtOAc in Hexane eluent, resulting in the isolation of compound 9 (100 mg) with a yield of 26% as a brown solid. Step-7: [1191] To a stirred solution of compound 9 (50 mg, 0.101 mmol) in HBr (48% in aqueous solution) (2 mL) was heated at 80°C for 3 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by preparative HPLC and then lyophilized to yield II-1016(R) (5 mg, 13%) as an off-white solid. [1192] ¹ H NMR [400 MHz, DMSO-d ₆ ]: 7.767 (s, 1H), 7.2 (d, J = 12.8 Hz, 2H), 7.19 (d, J = 7.2 Hz, 2H),5.93(m, 1H), 3.32 (s, 3H), 2.74 (s, 3H), 2.68 (s, 3H),1.39(m, 3H). Synthesis of II-1033/II-1027(R)/II-1033(R)/II-1038(R)/II-1040(R)/II-1039( R)/II-1037(R)/II- 1016(R): Scheme 30: Synthesis of Intermidiate-8: Step-1: [1193] To a stirred solution of compound 1 (10 g, 0.0653 mol) in DCM:AcOH (20:1, 105 ml), NBS (13.9 g, 0.0784 mol) was added at 0°C. The reaction mixture was stirred at room temperature (RT) for 2 hours. The reaction was monitored by TLC. After the completion of the reaction, the mixture was poured into ice-cold water and extracted with a 10% methanol in DCM solution (200 ml X 3). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to yield (2) as a yellow solid (13.0 g, 86% yield). The crude compound was used as is for the next step without any purification. [1194] LCMS: m/z = 232.05 [M+1] ⁺ , 78.0% (1.30 min), [1195] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.1% FA in water; B- ACN, (T/%B: 0.01/10, 0.5/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-2: [1196] To a stirred solution of compound 2 (12.6 g, 0.054 mol) in DCM (126 ml), TEA (12.6 mL) was added, followed by Boc anhydride (31 ml, 0.135 mol) and DMAP (2.65 g, 0.022 mol). The reaction mixture was stirred at room temperature for 1 hour. The reaction progress was monitored by TLC. After the completion of the reaction, the mixture was poured into ice-cold water and extracted with DCM (300 ml × 3). The separated organic layers were dried over anhydrous Na ₂ SO ₄ and then evaporated to yield crude compound 3 as a pale brown oil (13.0 g, 55.3% yield). The crude compound was used for the next step without any purification. [1197] LCMS: m/z = 275.96 [M-156] ⁺ , 55.76% (1.72 min), [1198] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.1% FA in water; B- ACN, (T/%B: 0.01/10, 0.5/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-3: [1199] To a stirred solution of compound 3 (13 g, 30.16 mmol) in THF:Water (3:1) (130 ml), Fe (16.9 g, 301.62 mmol) was added, followed by NH4Cl (16.3 g, 301.62 mmol). The reaction mixture was stirred at 60°C for 6 hours. Reaction progress was monitored by TLC. After the completion of the reaction, the reaction mixture was diluted with water (200 ml) and extracted with DCM (200 ml × 2). The separated organic layers were dried over anhydrous Na ₂ SO ₄ and then evaporated to yield the crude compound. The crude product was purified by silica gel (100- 200 mesh) column chromatography using a 30% ethyl acetate:hexane eluent, resulting in compound 4 as a brown liquid (9.0 g, 75% yield). [1200] LCMS: m/z = 402.16 [M+1] ⁺ , 64.49% (1.46 min), [1201] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.1% FA in water; B- ACN, (T/%B: 0.01/10, 0.5/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-4: [1202] To a stirred solution of compound 4 (5 g, 12.4 mmol) in DCM:AcOH (25:1, 52 ml), NBS (2.66 g, 14.9 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The reaction progress was monitored by TLC. After completion, the reaction mixture was poured into ice-cold water (100 ml) and extracted with DCM (100 ml × 3). The organic layer was dried over anhydrous Na ₂ SO ₄ and then evaporated to yield the crude compound. The crude product was purified by silica gel (100-200 mesh) column chromatography using a 20% ethyl acetate:hexane eluent, resulting in compound 5 as a brown solid (2.0 g, 33.6% yield). [1203] LCMS: m/z = 480.10 [M+1] ⁺ , 70.73% (1.59 min), [1204] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.1% FA in water; B- ACN, (T/%B: 0.01/10, 0.5/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min.

Step-5: [1205] To a stirred solution of compound 5 (1.0 g, 2.08 mmol) in Dioxane:H ₂ O (9:1, 10 mL), compound 6 (970 mg, 0.52 mmol) was added, followed by K2CO ₃ (864 mg, 6.26 mmol) at room temperature. The reaction mixture was degassed for 15 minutes, and then Pd-118 (136 mg, 0.208 mmol) was added. It was degassed again for 10 minutes, and the reaction mixture was stirred at 70°C for 5 hours. The reaction progress was monitored by TLC. After the completion of the reaction, the reaction mixture was filtered through celite. The celite bed was washed with ethyl acetate (100 ml × 2). The filtrate was diluted with water (50 ml) and extracted with ethyl acetate (50 ml × 4). The separated organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield the crude compound 7. The crude product was purified by silica gel (100-200 mesh) column chromatography using a 30% ethyl acetate:hexane eluent, resulting in compound 7 as a yellow liquid (600 mg, 53.5% yield). [1206] LCMS: m/z = 542.29 [M+1] ⁺ , 75.3% (1.61 min), [1207] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.1% FA in water; B- ACN, (T/%B: 0.01/10, 0.5/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-6: [1208] To a stirred solution of compound 7 (2.2 g, 4.06 mmol) in Methanol: H ₂ O (3:1, 4 mL), lithium hydroxide (683 mg, 16.2 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After the completion of the reaction, the solvent was evaporated under reduced pressure, and the reaction mixture was diluted with 10% methanol in DCM, followed by decanting. The decanted organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to yield compound 8 as a pale brown solid (1.4 g, 84.3% yield). The crude compound was used as-is for the next step without any further purification. [1209] LCMS: m/z = 410.12 [M+1] ⁺ , 79.0% (1.31 min), [1210] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.1% FA in water; B- ACN, (T/%B: 0.01/10, 0.5/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Racemate Borate: Scheme 31: Synthesis of Intermidiate-5: Step-1: [1211] To a solution mixture of compound 1 (30 g, 150.7 mmol) and p-Toluenesulfonylmethyl isocyanide (35.27 g, 180.9 mmol) in 1,2-Dimethoxy ethane (480.0 mL) was added a solution of potassium tert-butoxide (25.32 g, 226.1 mmol) in ^t BuOH (120.0 mL) at -15 ^o C. The reaction mixture was stirred at 0 ^o C for 3h and was quenched with water (100 mL) and extracted with hexane (2x200 mL). Combined organic layers were dried over Na ₂ SO ₄ and concentrated under vacuo to afford compound 2 (20 g, Crude). Crude was taken to next step without any further purification. Step-2: [1212] To a solution mixture of compound 2 (20 g, 95.2 mmol) in THF (100 mL), BH ₃ .DMS (10 M in DMS) (10.5 mL, 104.7 mmol) was added at reflux temperature. The reaction mixture was kept at reflux for 30 minutes, then cooled to room temperature. The pH was adjusted to 2.0 with 6N HCl and neutralized with aqueous 6N NaOH. This solution was extracted with DCM (2 × 200 mL). The combined organic layer was dried over Na ₂ SO ₄ and concentrated under vacuum to yield compound 3 (20 g, crude). The crude product was used in the next step without any further purification. [1213] LCMS: m/z = 216.02 [M+2H] ⁺ , 47.86% (1.06 min). [1214] Method: Column: Acquity BEH C ₁ 8 (2.1 x 50 mm, 1.7 μm), Mobile Phase: A-0.01% FA, in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90), Flow Rate: 0.4 mL/min. Step-3: [1215] To a solution mixture of compound 3 (20 g, 93.4 mmol) in DCM (200 mL), TEA (19.6 mL, 140.1 mmol) was added, followed by (Boc) ₂ O (25.7 mL, 112.0 mmol) at 0°C. The reaction mixture was kept at room temperature for 2 hours and then evaporated under vacuum. The crude compound was purified by column chromatography using silica gel (100-200 mesh), eluting the compound with 5% EtOAc in hexane to yield compound 4 (13 g, yield: 44.3%) as an off-white solid. [1216] LCMS: m/z = 260.02 [M-56 +2H] ⁺ , 66.90% (1.87 min). [1217] Method: Column: Acquity BEH C ₁ 8 (2.1 x 50 mm, 1.7 μm), Mobile Phase: A-0.01% FA, in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90), Flow Rate: 0.4 mL/min. Step-4: [1218] To a solution mixture of compound 4 (6.0 g, 19.1 mmol) in Dioxane (60 mL), Bis(pinacolato)diboron (5.82 g, 22.9 mmol), Pd(dppf)Cl2 (567.1 mg, 0.76 mmol), and KOAc (3.74 g, 38.2 mmol) were added at room temperature. The reaction mixture was degassed with N2 for 5 minutes, then kept at 90°C for 15 hours. After completion, the reaction mixture was cooled to room temperature, quenched with water (100 mL), and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with water and brine, and then concentrated under vacuum. The crude compound was purified by column chromatography using silica gel (100-200 mesh), eluting the compound with 5% EtOAc in hexane to yield compound 5 (5.8 g, yield: 84.2%) as an off-white solid. [1219] LCMS: m/z = 362.2 [M+H] ⁺ , 89.61% (1.97 min). [1220] Method: Column: Acquity BEH C ₁ 8 (2.1 x 50 mm, 1.7 μm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90), Flow Rate: 0.4 mL/min. [1221] ¹ H NMR [400 MHz, DMSO-d6]: 7.59 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 7.6 Hz, 2H), 6.85 (t, J = 5.6 Hz, 1H), 3.07-3.01 (m, 2H), 2.87-2.86 (m, 1H), 1.34-1.28 (m, 21H), 1.16-1.13 (m, 3H). Chiral Borate: Scheme 32: Synthesis of Intermidiate-5: Step-1 & 2: [1222] To a stirred solution of Trifluoroacetic anhydride (30 mL) in DCM (250 mL), compound 1 (25 g, 0.185 mol) was added portion-wise at 0°C. The resulting reaction mixture was allowed to stir at room temperature for 1 hour. The reaction mixture was then cooled to 0°C, and methane sulfonic acid (30 mL, 1.2 vol) was added, followed by DBDMH (30 g, 108 mol) added portion- wise over 10 minutes. The resulting mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC. After completion, the reaction mass was slowly quenched with cold water and extracted with DCM (500 ml). The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The resulting crude product was used as-is for the next step without any further purification. Step-3: [1223] To a stirred solution of compound 4 (45 g, 0.145 mol) in MeOH (225 mL, 5 vol) was added 2N aq NaOH (225 mL, 5 vol) at 0 °C. The resulting reaction mixture allow to stir at rt for 4 h. Progress of the reaction was monitored by TLC; after completion, Evaporated the solvent under reduced pressure. The resulting residue was diluted with water and extracted with DCM. The organic layer washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude compound used as such for next without any purification. Step-4: [1224] To a stirred solution of compound 5 (29 g, 0.135 mol) in DCM (290 mL, 10 vol), TEA (54 mL, 0.405 mol, 3 eq) was added, followed by (Boc) ₂ O (46 mL, 0.203 mol, 1.5 eq) at 0 °C. The resulting reaction mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was completed, it was diluted with DCM and washed with water and a brine solution. The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The resulting residue was purified by silica gel (100-200 mesh) column chromatography (4% E.A. in Hexane as the eluent) to afford the pure compound as a white solid. [1225] LCMS: m/z = 258.07 [M-56] ⁺ , 87% (1.74min). [1226] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-5: [1227] To a stirred suspension of compound 6 (30 g, 0.095 mol) and B2Pin2 (36 g, 0.143 mol) in Dioxane (300 ml, 10 vol), KOAc (27 g, 0.285 mol) was added at room temperature. The resulting mixture was degassed with nitrogen for 15 minutes, and Pd(dppf)Cl2 (3.4 g, 0.0047 mol) was added. The reaction mixture was degassed again for 10 minutes and stirred at 90°C overnight. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mass was cooled to room temperature and filtered through celite. The filtrate was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel (100-200 mesh) column chromatography using 5% ethyl acetate in hexane as the eluent to afford the pure compound as an off-white semi-solid. [1228] LCMS: m/z = 306.24 [M-56] ⁺ , 77.62% (1.87min). [1229] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Chiral N-Methyl Borate: Scheme 33: Synthesis of Intermidiate-8: Step-1: [1230] To a stirred solution of compound 6 (29 g, 0.092 mol) in DMF (290 mL, 10 vol), 60% sodium hydride (11 g, 0.458 mol) was added portion-wise over 10 minutes at 0°C. After 20 minutes, MeI was added (17.7 mL, 0.277 mol) at 0°C. The resulting reaction mixture was stirred at room temperature for 4 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, it was diluted with ice-cold water and extracted with ethyl acetate (500 ml × 2). The organic layer was then washed with a brine solution. The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo to afford the crude compound 2 (30 g, 99%). The crude was used as-is for the next step without any purification. [1231] LCMS: m/z: 274.16 [M+2] ⁺ , 74.41 % (1.98 min) [1232] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-2: [1233] To a stirred suspension of compound 8 (30 g, 0.0914 mol) and B2Pin2 (34 g, 0.137 mol) in dioxane (300 mL, 10 vol), KOAc (26 g, 0.247 mol) was added at room temperature. The resulting mixture was degassed with nitrogen for 15 minutes, and then Pd(dppf)Cl2 (3.3 g, 0.0046 mol, 0.05 eq) was added. The reaction mixture was degassed again for 10 minutes and stirred at 90°C for 15 hours. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mass was cooled to room temperature and filtered through celite. The filtrate was subsequently diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel (100-200 mesh) column chromatography using 5% ethyl acetate in hexane as the eluent, yielding pure compound 9 as a yellow-colored gum (15.0 g, 43.6% yield). [1234] LCMS: m/z: 376.42 [M+1] ⁺ , 81.77 % (2.22 min), [1235] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Scheme 34: Synthesis of II-1033: Step-1: [1236] To a stirred solution of compound 8 (40 mg, 0.097 mmol) in Dioxane:H ₂ O (1 mL) was added compound-5 (38.8 mg, 0.107 mmol) and NaHCO ₃ (26.4 mg, 0.27 mmol) Reaction mixture was degassed for 10 minutes then Pd-118 (7 mg, 0.009 mmol) was added and again degassed for 10 minutes then reaction mixture was stirred at 90 ^o C for 15 h. Reaction was monitored by TLC; After completion of reaction, reaction mixture was filtered and filtrate was evaporated to afford the crude compound. The crude was purified by reverse phase combi flash chromatography to afford compound 9 as an off-white solid (10 mg, 22.2% yield). [1237] LCMS: m/z = 465.34 [M+1] ⁺ , 99.4% (1.25 min), [1238] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.1% FA in water; B- ACN, (T/%B: 0.01/10, 0.5/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-2: [1239] To a stirred solution of Compound 9 (10 mg, 0.021 mmol) in DCM (0.2 ml), TFA (0.2 ml) was added at 0°C. The resulting reaction mixture was stirred at room temperature for 6 hours. The reaction progress was monitored by TLC and LCMS. After the reaction was complete, the excess TFA was evaporated in vacuo. The residue was purified by preparative HPLC and then lyophilized, yielding II-1033 as a white solid (1.5 mg, 19.2% yield). [1240] LCMS: m/z = 365.23 [M+1] ⁺ , 99.37 % (2.02min) [1241] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.1% NH ₃ in water; B- ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) Flow Rate: 0.4 mL/min. [1242] ¹ H NMR [400 MHz, DMSO-d6]: 7.76 (d, J = 5.2 Hz, 1H), 7.45 (t, J = 6.4 Hz, 2H), 7.22 (t, J = 6.4 Hz, 2H), 5.82 (d, J = 5.2 Hz, 1H), 4.92 (s, 2H), 2.83-2.78 (m, 1H), 2.79-2.77 (m, 2H), 2.61 (s, 3H), 1.30 (d, J = 6.8 Hz, 3H). Scheme 35: Synthesis of II-1033(R): Step-1: [1243] To a stirred solution of compound 8 (250 mg, 0.611 mmol) in Dioxane:H ₂ O (2.5 mL, 8:2), compound 7 (331 mg, 0.916 mmol), and potassium carbonate (253 mg, 1.833 mmol) were added. The reaction mixture was degassed for 15 minutes. Then, Pd-118 (39 mg, 0.061 mmol) was added, and the mixture was degassed again for 10 minutes. The reaction mixture was stirred at 90°C for 15 hours. The reaction progress was monitored by TLC. After completion of the reaction, the mixture was filtered, and the filtrate was evaporated to yield the crude compound. The crude product was purified by reverse-phase combi-flash chromatography, resulting in the isolation of compound 9 as a pale yellow solid (80 mg, 28.2% yield). [1244] LCMS: m/z = 465.92 [M+1] ⁺ , 87.9 % (1.26 min), [1245] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.1% FA in water; B- ACN, (T/%B: 0.01/10, 0.5/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-2: [1246] To a stirred solution of compound 9 (80 mg, 0.172 mmol) in DCM (0.8 mL), TFA (0.4 mL) was added at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS, After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to yield the crude compound. The crude product was then purified by preparative HPLC and subsequently lyophilized, resulting in the isolation of II-1033(R) as a white solid (22 mg, 35% yield). [1247] LCMS: m/z = 364.97 [M+1] ⁺ , 96.44% (1.95 min) [1248] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.1% NH ₃ in water; B- ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) Flow Rate: 0.4 mL/min. [1249] ¹ H NMR [400 MHz, DMSO-d ₆ ]: 7.77 (d, J = 5.6 Hz, 1H), 7.45 (t, J = 6.0 Hz, 2H), 7.22 (t, J = 6.0 Hz, 2H), 5.82 (d, J = 5.6 Hz, 1H), 4.89 (s, 2H), 2.85-2.80 (m, 3H), 2.62 (s, 3H), 1.30 (d, J = 6.4 Hz, 3H). Scheme 36: Synthesis of II-1027(R): Step-1: [1250] To a stirred solution of compound 9 (40 mg, 0.086 mmol) in Conc. HCl (0.8 ml) was added NaNO ₂ (6.5 mg, 0.095 mmol) followed by CuCl (9.4 mg, 0.095 mmol) at 0 ^o C. The resulting mixture was stirred at 80 ^o C for 2h. Reaction was monitored by LCMS. LCMS showed 50% of desired product mass. After completion of reaction evaporated HCl under reduced pressure to afford the crude compound. Crude was purified by Preparative HPLC to afford II-1027(R) as white solid (5 mg, 15.1% yield). [1251] LCMS: m/z = 384.20 [M+1] ⁺ , 98.85% (1.63 min) [1252] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.73m) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10,4/90, 7/90) Flow Rate: 0.4 mL/min. [1253] ¹ H NMR [400 MHz, DMSO-d ₆ ]: 7.87 (d, J = 5.2 Hz, 1H), 7.48 (d, J = 7.6 Hz, 2H), 7.24 (d, J = 7.6 Hz, 2H), 6.86 (bs, 3H), 5.75 (d, J = 5.2 Hz, 1H), 2.93-2.90 (m, 3H), 2.77 (s, H), 1.33 (d, J = 6.0 Hz, 3H). Scheme 37: Synthesis of II-1038(R):

Step-1: [1254] To a stirred solution of compound 9 (40 mg, 0.086 mmol) in 47% HBr in water (1.2 mL), NaNO ₂ (13.1 mg, 0.189 mmol) was added, followed by CuBr (27 mg, 0.189 mmol) at 0°C. The resulting mixture was stirred at 80°C for 2 hours. The reaction was monitored by LCMS, which indicated a 61.5% yield of the desired product. After the completion of the reaction, HBr was evaporated under reduced pressure to yield the crude compound. The crude product was then purified by preparative HPLC, resulting in the isolation of II-1038(R) as a white solid (4 mg, 10.8% yield). [1255] LCMS: m/z = 428.11 [M+1] ⁺ , 99.50% (1.69 min) [1256] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.73m) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10,4/90, 7/90) Flow Rate: 0.4 mL/min. [1257] ¹ H NMR [400 MHz, DMSO-d ₆ ]: 8.34 (bs, 1H), 7.86 (d, J = 5.6 Hz, 1H), 7.48 (d, J = 7.7 Hz, 2H), 7.26 (d, J = 7.6 Hz, 2H), 5.71 (d, J = 5.6 Hz, 1H), 2.95-2.87 (m, 3H), 2.77 (s, H), 1.34 (d, J = 6.4 Hz, 3H).

Scheme 38: Synthesis of II-1040(R): Step-1: [1258] To a stirred solution of compound 8 (120 mg, 0.293 mmol) in Dioxane:H ₂ O (2.4 mL), compound 3 (165 mg, 0.440 mmol), and potassium carbonate (121 mg, 0.880 mmol) were added. The reaction mixture was degassed for 15 minutes. Then, Pd-118 (19 mg, 0.029 mmol) was introduced, and the mixture was degassed again for 10 minutes. The reaction mixture was stirred at 90°C for 15 hours. The reaction progress was monitored by TLC. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was evaporated to yield the crude compound. The crude product was purified by reverse-phase combi-flash chromatography using acetonitrile with 0.1% formic acid as the eluent, resulting in the isolation of compound 10 as a pale brown solid (100 mg, 71.4% yield) [1259] LCMS: m/z = 479.37 [M+1] ⁺ , 97.0 % (1.41 min) [1260] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.1% FA in water; B- ACN, (T/%B: 0.01/10, 0.5/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-2: [1261] To a stirred solution of compound 10 (90 mg, 0.188 mmol) in DCM (1.8 mL), TFA (0.9 mL) was added at 0°C. The resulting mixture was stirred at room temperature for 3 hours. The reaction was monitored by LCMS. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to yield the crude compound. The crude product was then purified by preparative HPLC, resulting in the isolation of II-1040(R) as an off-white solid (20 mg, 28.1% yield) [1262] LCMS: m/z = 379.29 [M+1] ⁺ , 96.3% (3.05 min) [1263] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.1% NH ₃ in water; B- ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 6/90) Flow Rate: 0.4 mL/min. [1264] ¹ H NMR [400 MHz, DMSO-d6]: 7.76 (d, J = 5.2 Hz, 1H), 7.46 (t, J = 6.4 Hz, 2H), 7.21 (t, J = 6.4 Hz, 2H), 5.81 (d, J = 5.2 Hz, 1H), 4.90 (s, 2H), 3.00-2.97 (m, 1H), 2.76-2.71 (m, 2H), 2.62 (s, 3H), 1.31 (d, J = 7.2 Hz, 3H). Scheme 39: Synthesis of II-1037(R) and II-1016(R): Step-1: [1265] To a stirred solution of compound 10 (120 mg, 0.251 mmol) in concentrated HCl (2.4 mL), NaNO ₂ (26 mg, 0.376 mmol) was added at 0°C. After 15 minutes, CuCl (37 mg, 0.376 mmol) was introduced. The resulting mixture was stirred at 80°C for 2 hours. The reaction was monitored by LCMS, which showed 46% of II-1037(R) and 40% of II-1016(R) as the desired product masses. After the completion of the reaction, HCl was evaporated under reduced pressure to yield the crude compound. The crude product was then purified by preparative HPLC, resulting in the isolation of II-1037(R) as an off-white solid (20 mg, 40% yield) and II-1016(R) as a pale yellow solid (20 mg, 43% yield). [1266] II-1037(R) Analytical Data: [1267] LCMS: m/z = 398.21 [M+1] ⁺ , 99.6% (2.42 min), [1268] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm) Mobile Phase: A-0.1% NH ₃ in water; B- ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) Flow Rate: 0.4 mL/min. [1269] ¹ H NMR [400 MHz, DMSO-d6]: 7.83 (d, J = 5.2 Hz, 1H), 7.46 (d, J = 7.6 Hz, 2H), 7.25 (d, J = 7.6 Hz, 2H), 5.71 (d, J = 5.2 Hz, 1H), 3.02-2.97 (m, 1H), 2.76-2.70 (m, 2H), 2.33 (s, 3H), 1.32 (d, J = 6.8 Hz, 3H). [1270] II-1016(R) Analytical Data: [1271] LCMS: m/z = 380.24 [M+1] ⁺ , 99.17% (1.25 min [1272] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) Flow Rate: 0.4 mL/min. [1273] ¹ H NMR [400 MHz, DMSO-d ₆ ]: 7.80 (d, J = 5.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 5.92 (d, J = 5.6 Hz, 1H), 3.00-2.97 (m, 1H), 2.79-2.70 (m, 2H), 2.64 (s, 3H), 2.36 (s, 3H), 1.31 (d, J = 6.8 Hz, 3H). Scheme 40: Synthesis of II-1039(R) & II-1016(R): Step-1: [1274] To a stirred solution of compound 10 (80 mg, 0.167 mmol) in 47% aqueous HBr (2.4 ml) was added NaNO ₂ (23 mg, 0.334 mmol) at 0 ^o C, after 15 mins CuBr (48 mg, 0.334 mmol) was added. The resulting mixture was stirred at 80 ^o C for 2h. Reaction was monitored by LCMS. After completion of reaction, the excess HBr was evaporated under reduced pressure to afford the crude compound. The crude was purified by preparative HPLC and lyophilized to afford II-1039 (R) as off-white solid (7 mg, 9.5% yield). [1275] LCMS: m/z = 442.14 [M+1] ⁺ , 98.4% (1.52 min) [1276] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) Flow Rate: 0.4 mL/min. [1277] ¹ H NMR [400 MHz, DMSO-d6]: 7.75 (d, J = 5.6 Hz, 1H), 7.44 (d, J = 7.2 Hz, 2H), 7.22 (d, J = 7.2 Hz, 2H), 5.65 (d, J = 5.6 Hz, 1H), 3.00-2.96 (m, 1H), 2.75-2.69 (m, 5H), 2.58 (s, 3H), 1.31 (d, J = 6.8 Hz, 3H). Scheme 41: Synthesis of Key intermediate 11: Step-1: [1278] To a stirred solution of compound 1 (50 g, 0.324 mol) in DMF (500 mL) was added NBS (69.3 g, 0.389 mol) at 0°C. The resulting mixture stirred at 90°C for 16 h. Progress of reaction was monitored by TLC, after completion, the reaction mass was poured into ice cold water, obtained solid was filtered off. The solid compound was dissolved in 10% MeOH in DCM (2 Lit), washed with water (1L), brine solution (0.5 L). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to afford compound 2 (46 g, yield: 60%) as a brown solid. [1279] LCMS: m/z: 233.02 [M+2] ⁺ , 97.98 % (1.05 min), [1280] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [1281] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, [1282] (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1283] Flow Rate: 0.4 mL/min. Step-2: [1284] POCl ₃ (184 mL, 4 vol) was added to compound 2 (46 g, 0.197 mol) at room temperature. The resulting reaction mixture was stirred at 100 ^o C for 5 h. Progress of the reaction was monitored by TLC, after completion, excess POCl3 was evaporated under reduced pressure. The resulting residue was diluted with ice cold water (1000 mL). The solid was filtered through the whatmann filter paper. The obtained solid was dried under reduced pressure to afford compound 3 (48 g, yield: 97%) as brown solid. [1285] ¹ H NMR [400 MHz, DMSO-d6]: 8.55 (s, 1H), 2.82 (s, 3H). Step-3: [1286] To a cold suspension of 60% NaH (10 g, 0.210 mol) in THF (480 mL) was added Diethyl malonate (34 mL, 0.210 mol) at 0 °C and continued the stirring for 15 min. Then added compound 3 (48 g, 0.191 mol) portion at same temperature and stirred for another 15 min. Then evaporated the total solvent under reduced pressure, resulting residue was stirred at 110 °C for 1.5 h. The reaction mixture cooled to 0 °C and added 6M aqueous H ₂ SO ₄ (240 mL). The resulting suspension was stirred at 110 °C for overnight. The progress of the reaction was monitored by TLC; after completion, reaction mass poured into cold water and basified with NaHCO ₃ and extracted with Ethyl acetate. The organic layer washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to afford compound 4 (34 g, yield: 77%) as a reddish solid. [1287] ¹ H NMR [400 MHz, CDCl3]: 8.44 (s, 1H), 2.80 (s, 3H), 2.72 (s, 3H). [1288] LCMS: m/z: 232.98 [M+2] ⁺ , 98.19 % (1.61 min), [1289] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 ìm) [1290] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, [1291] (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1292] Flow Rate: 0.4 mL/min. Step-4: [1293] To a stirred solution of compound 4 (10 g, 0.043 mol) in DMSO (100 mL) was added CuI (1.63 g, 0.0.0086 mol), L-Proline (1.98 g, 0.017 mol) followed by K2CO ₃ (8.9 g, 0.064 mol) in a seal tube at rt. The resulting reaction mixture degassed with N ₂ for 15 min and added aq ammonia (10 mL, 1 vol). The seal tube was fitted with cap and stirred at 100 °C for 7 h. After completion, reaction mass quenched with cold water and filtered through celite. The filtrate was extracted with EtOAc and washed with cold water, brine solution. The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting crude was purified by silica gel (100- 200) column chromatography (25% E.A in hexane as eluent) to afford compound 5 (3.3 g, yield: 45.8%) as a brown solid. [1294] LCMS: m/z: 168.06 [M+1] ⁺ , 97.13 % (0.93 min), [1295] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [1296] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, [1297] (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1298] Flow Rate: 0.4 mL/min. Step-5: [1299] To a stirred solution of compound 5 (7 g, 42 mmol) and compound 6 (8.67 g, 42 mmol) in MeCN (140 mL) was added TCFH (23.5 g, 84 mmol) followed by NMI (17 mL, 209 mmol) at 0 °C. The resulting mixture stirred at 80 °C for 5 h. Progress of the reaction was monitored by TLC; after completion, reaction mass quenched with cold water and extracted with EtAOc. Organic layer washed with brine solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting crude was triturated with Ether and filtered, dried under reduced pressure to afford compound 7 (8 g, yield: 53.6%) as a pale-yellow solid. [1300] ¹ H NMR [400 MHz, DMSO-d ₆ ]: 10.10 (s, 1H), 8.68 (s, 1H), 7.95 (d, J = 5.2 Hz, 1H), 7.29 (d, J = 5.6 Hz, 1H), 2.73 (s, 3H), 2.60 (s, 3H). [1301] LCMS: m/z: 356.07 [M+2] ⁺ , 92.65 % (1.5 min), [1302] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [1303] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, [1304] (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1305] Flow Rate: 0.4 mL/min. Step-6:

[1306] To a stirred solution of compound 7 (10 g, 0.028 mol) and 4-methoxybenzyl chloride (6.5 mL, 0.047 mol) in MeCN (200 mL) was added DBU (8.1 mL, 0.056 mol) at rt. The resulting mixture stirred for 4 h at 80 °C. After completion, reaction mass quenched with cold water and extracted with EtOAc (200 ml x 2). The combined organic layer washed with brine solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude residue was purified by silica gel (100-200 mesh) column chromatography (25% EtOAc in hexane as eluent). The resulting solid was triturated with Ether, pentane and dried to afford compound 8 (9 g, yield: 67.3%) as a pale-yellow solid. [1307] LCMS: m/z: 476.29 [M+2] ⁺ , 96.25 % (1.64 min), [1308] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [1309] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, [1310] (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1311] Flow Rate: 0.4 mL/min. Step-7: [1312] To a stirred solution of compound 8 (3 g, 6.289 mmol) in DMA (30 mL) was added KOAc (2.46 g, 25.157 mmol) at room temperature. The resulting mixture degassed with nitrogen for 15 min. Then added Pd(tBu ₃ P) ₂ (194 mg, 0.377 mmol) and again degassed for another 10 min. The resulting mixture stirred at 150 °C for overnight. Completion of the reaction was monitored by LCMS; after completion, reaction mass poured into ice cold water and extracted with ethyl acetate. Organic layer washed with brine solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to get compound 9 (2.3 g, yield: 90.7%) as brown gum. The crude material used as such for next step without any purification. [1313] LCMS: m/z: 396.23 [M+1] ⁺ , 50.99 % (3.21 min), [1314] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [1315] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, [1316] (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1317] Flow Rate: 0.4 mL/min. Step-8: [1318] To a stirred suspension of compound 9 (9 g, 0.022 mol) in THF (135 mL) and water (25 mL) was added NH ₄ Cl (12.1 g, 0.226 mol) followed by Iron powder (12.6 g, 0.226 mol) at room temperature. The resulting mixture stirred at 80 °C for overnight. Progress of the reaction was monitored by TLC; after completion, reaction mass diluted with ethyl acetate and filtered through celite. The filtrate was washed with brine solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to get compound 10 (7 g, yield: 84.6%) as brown gum. The crude material used as such for next step without any purification. [1319] LCMS: m/z: 34.92 [M+1] ⁺ , 34.92 % (0.89 min), [1320] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [1321] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, [1322] (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1323] Flow Rate: 0.4 mL/min. Step-9: [1324] To a stirred suspension of CuBr (2.74 g, 19.178 mmol) in MeCN (30 mL) was added tert- butylnitrite (2.3 mL, 19.178 mmol) at 0 °C. The resulting mixture stirred at same temperature for 20 min. Then added a solution of compound 10 (3.5 g, 9.589 mmol) dissolved in MeCN (20 mL) at 0 °C. The reaction mixture allowed to stir at room temperature for 2 h. After completion, reaction mass quenched with water and filtered through celite, washed with ethyl acetate. The filtrate was extracted with ethyl acetate and washed with brine solution. The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by silica gel (100-200 mesh) column chromatography (20% E.A in hexane as eluent) to afford compound 11 (800 mg, yield: 19.5%) as a pale-yellow solid. [1325] LCMS: m/z: 429.15 [M+2] ⁺ , 83.42 % (1.72 min), [1326] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [1327] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, [1328] (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1329] Flow Rate: 0.4 mL/min. Scheme 42: Synthesis of II-1023(R) Step-1: [1330] To a stirred suspension of compound 11 (2 g, 4.662 mmol) and compound 12 (2.62 g, 6.993 mmol) in dioxane (60 ml), water (4 mL) was added NaHCO ₃ (1.2 g, 13.986 mmol) at room temperature. The resulting reaction mixture degassed with nitrogen for 20 min. Then added Pd(dppf)Cl2 (205 mg, 0.279 mmol) and again degassed for 5 min. The reaction mixture stirred at 90 °C for overnight. After completion, reaction mass filtered through celite, washed with ethyl acetate. The filtrate was washed with water, brine solution. The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by reverse phase C-18 column chromatography (65% CAN in 0.1% FA as eluent and extracted) to afford compound 13 (1.2 g, yield: 43.1%) as an off-white solid. [1331] LCMS: m/z: 598.46 [M+1] ⁺ , 99.24 % (1.88 min), [1332] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [1333] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, [1334] (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1335] Flow Rate: 0.4 mL/min.

Step-2: [1336] Trifluoroacetic acid (30 mL) was added to compound 3 (3 g, 5.025 mmol) at room temperature. The resulting mixture stirred at 100 °C for 3 h. After completion, evaporated the excess TFA reduced pressure. The resulting residue was diluted with water and dichloromethane, separated the two layers. The aqueous layer basified with saturated NaHCO ₃ upto pH~9 and extracted with 10% MeOH in DCM. The organic layer washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting solid was sonication in MeCN, filtered and washed with cold MeCN. The resulting solid was dried under reduced pressure to afford compound (II-1023(R)) (1.02 g, yield: 53.9%) as a white solid. [1337] ¹ H NMR [400 MHz, DMSO-d ₆ ]: 7.80 (d, J = 6 Hz, 1H), 7.43 (d, J = 7.6 Hz, 2H), 7.20 (d, J = 7.6 Hz, 2H), 6.5 (brs, 2H), 5.74 (d, J = 5.2 Hz, 1H), 3.00-2.98 (m, 1H), 2.75 (s, 3H), 2.73- 2.68 (m, 2H), 2.32 (s, 3H), 2.20 (s, 3H), 1.31 (d, J = 6.8 Hz, 3H). [1338] LCMS: m/z: 378.34 [M+2] ⁺ , 97.16 % (18.94 min), [1339] Column: Kinetix: C ₁ 8100 A (150 x 4.6 mm, 2.60m), [1340] Mobile Phase: A-0.1% NH ₃ in Water; B-ACN, [1341] (T/B%: 0.01/10,1/10, 15/40, 20/45, 25/90, 30/90), [1342] Flow Rate: 0.8 mL/min.

Scheme 43: Synthesis of II-1046(R) Step-1: [1343] To a stirred suspension of compound 11 (300 mg, 0.699 mmol) and compound 12 (302 mg, 0.839 mmol) in dioxane (5 mL), water (0.3 mL) was added K ₂ CO ₃ (289 mg, 2.097 mmol) at room temperature. The resulting reaction mixture degassed with nitrogen for 15 min. Then added Pd-118 (14 mg, 0.020 mmol), again degassed for 5 min. The reaction mixture stirred at 90 °C for 5 h. After completion of reaction, reaction mass filtered through celite, washed with ethyl acetate. The filtrate was washed with water, brine solution. The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by reverse phase C-18 column chromatography (65% CAN in 0.1% FA as eluent and extracted) to afford compound 13 (210 mg, yield: 51.5%) as an off-white semi solid. [1344] LCMS: m/z: 584.64 [M+1] ⁺ , 97.00 % (1.79 min), [1345] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [1346] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, [1347] (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1348] Flow Rate: 0.4 mL/min. Step-2: [1349] To a stirred solution of compound 13 (120 mg, 0.205 mmol) in DMF (3 mL) was added NaH (24 mg, 0.617 mmol) at 0 °C and continued the stirring for 20 min before being addition of CD ₃ I (90 mg, 0.617 mmol). The resulting mixture stirred at room temperature for overnight. Reaction was monitored by LCMS; after completion of reaction, reaction mass quenched with cold water and extracted with ethyl acetate. Organic layer washed with brine solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude residue was purified by reverse phase C- 18 column chromatography (55% ACN in 0.1% FA as eluent and extracted) to afford compound 14 (60 mg, yield: 48.7%) as pale-yellow gummy. [1350] LCMS: m/z: 601.55 [M+1] ⁺ , 78.08 % (1.88 min), [1351] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [1352] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, [1353] (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1354] Flow Rate: 0.4 mL/min.

Step-3: [1355] Trifluoroacetic acid (1.5 mL) was added to the compound 14 (60 mg, 0.10 mmol) at room temperature. The resulting mixture stirred at 100 °C for 3 h. After completion of reaction, evaporated the excess TFA reduced pressure. The resulting residue was purified by prep HPLC and lyophilized to afford compound II-1046(R) (16 mg, yield: 21.5%) as a white solid. [1356] ¹ H NMR [400 MHz, DMSO-d ₆ ]: 7.85 (d, J = 5.6 Hz, 1H), 7.44 (d, J = 8 Hz, 2H), 7.20 (d, J = 8 Hz, 2H), 5.74 (d, J = 5.2 Hz, 1H), 3.02-2.97 (m, 1H), 2.76 (s, 3H), 2.74-2.67 (m, 2H), 2.20 (s, 3H), 1.31 (d, J = 6.8 Hz, 3H). [1357] LCMS: m/z: 381.45 [M+1] ⁺ , 98.82 % (3.18 min), [1358] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [1359] Mobile Phase: A-0.1% NH ₃ in water; B- ACN, [1360] (T/%B: 0.01/2, 1/2, 5/90, 6/90), [1361] Flow Rate: 0.4 mL/min. Scheme 44: Synthesis of II-1036 Step-1: [1362] To a solution mixture of compound 1 (500 mg, 1.666 mmol) and B ₂ Pin ₂ (634 mg, 2.499 mmol) in Dioxane (10 ml) was added KOAc (490 mg, 4.999 mmol), Pd(dppf)Cl2 (73 mg, 0.999 mmol) and dppf (55 mg, 0.999 mmol) at rt. The resulting mixture degassed with N2 for 15 min and stirred at 90 ^o C for 16h. After completion of reaction, reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was washed with water and brine solution, dried over Na ₂ SO ₄ , filtered and concentrated under vacuo. Resulting crude was purified by silica gel (100-200) column chromatography (5% EtOAc in hexane as eluent) to afford compound 2 (400 mg, yield: 69.2%) as an off white semi solid. [1363] LCMS: m/z = 292 [M-tBu] ⁺ , 34.08% (1.87 min). [1364] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [1365] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, [1366] (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1367] Flow Rate: 0.4 mL/min. Step-2: [1368] To a stirred suspension of compound 2 (49 mg, 0.139 mmol) and compound 11 (50 mg, 0.116 mmol) in dioxane: water (3.3 ml, 10:1) was added NaHCO ₃ (29 mg, 0.348 mmol), Pd(dppf)Cl2 (205 mg, 0.279 mmol) at room temperature. The resulting reaction mixture degassed with nitrogen for 10 min. The reaction mixture stirred at 90 °C for 6 h. After completion of reaction, reaction mass filtered through celite, washed with ethyl acetate. The filtrate was washed with water, brine solution. The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by reverse phase C-18 column chromatography (65% MeCN in 0.1% FA as an eluent and extracted) to afford compound 3 (40 mg, yield: 60.6%) as pale brown gum. [1369] LCMS: m/z: 570.39 [M+1] ⁺ , 71.27 % (1.78 min), [1370] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [1371] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, [1372] (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1373] Flow Rate: 0.4 mL/min. Step-3: [1374] Trifluoroacetic acid (2 mL) was added to compound 3 (90 mg, 0.157 mmol) at room temperature. The resulting mixture stirred at 100 °C for 3 h. After completion of reaction, evaporated the excess TFA under reduced pressure. The resulting residue was purified by reverse phase C-18 column chromatography (15% ACN in 0.1% FA as eluent and lyophilized) to afford compound II-1036 (23 mg, yield: 41.8%) as a white solid. [1375] ¹ H NMR [400 MHz, DMSO-d ₆ ]: 7.83 (d, J = 5.2 Hz, 1H), 7.50 (d, J = 8 Hz, 2H), 7.28 (d, J = 8 Hz, 2H), 5.86 (d, J = 5.6 Hz, 1H), 3.15 (t, J = 7.2 Hz, 2H), 3.01 (t, J = 8.8 Hz, 2H), 2.83 (s, 3H), 2.47 (s, 3H). [1376] LCMS: m/z: 350.25 [M+1] ⁺ , 95.77 % (1.13 min), [1377] Column: Kinetix: C ₁ 8100 A (150 x 4.6 mm, 2.60m), [1378] Mobile Phase: A-0.1% NH ₃ in Water; B-ACN, [1379] (T/B%: 0.01/10,1/10, 15/40, 20/45, 25/90, 30/90), [1380] Flow Rate: 0.8 mL/min. Scheme 45: Synthesis of II-1030 Step-1: [1381] To a solution mixture of compound 1 (5 g, 25 mmol) and p-Toluene sulfonylmethyl isocyanide (5.8 g, 30.0 mmol) in 1,2-Dimethoxy ethane (50 ml) was added a solution of potassium tert-butoxide (4.5 g, 37.0 mmol) in t-BuOH (20 mL) at -15oC. The reaction mixture was stirred at 0oC for 2 h and was quenched with water (100 ml) and extracted with hexane (2x50 ml). Combined organic layers were dried over Na ₂ SO ₄ and concentrated under vacuo to afford compound 2 (5 g, 94.8%). Crude was taken to next step without any further purification. Step-2: [1382] To a solution mixture of compound 2 (5 g, 23.8 mmol) in THF (50 mL) was added BH ₃ .DMS (10 M in DMS) (5 mL) at reflux temperature. Reaction mixture was continuous for 30 min at reflux, cooled to rt and pH adjusted to 2 with 6N HCl and neutralize with 6N NaOH, this solution was extracted with DCM (2x50 ml). Combined organic layer was dried over Na ₂ SO ₄ and concentrated under vacuo to afford compound 3 (5 g, 97.8%). Crude was used as such for next step without any further purification. Step-3: [1383] To a solution mixture of compound 3 (5 g, 20 mmol) in DCM (50 ml) was added TEA (4 mL, 60 mmol) and followed by (Boc) ₂ O (5.6 mL, 20 mmol) at 0oC. Reaction mixture was continuous for 2h at rt and evaporated under vacuo. Crude compound was purified by column chromatography silica gel (100: 200 mesh) using 5% EtOAc in Hexane as an eluent to afford compound 4 (2.1 g, Yield-29%) as an off white solid. Step-4: [1384] To a stirred solution of compound 4 (300 mg, 0.955 mmol) in Dioxane (3 ml) was added Bis(pinacolato)diboron (291 mg, 1.14 mmol) and potassium Acetate (280 mg, 2.857 mmol) Reaction mixture was degassed for 15 minutes then Pd(dppf)Cl2 (70 mg, 0.095 mmol) was added and again degassed for 10 minutes then reaction mixture was stirred at 90oC for 15 h. The reaction was monitored by TLC and LCMS, After completion of reaction, The filtrate was diluted with water and extracted with 10% methanol in DCM (100 ml). The organic layer was concentrated to afford the crude compound 5 (Crude, 260 mg, 97.3% of yield) as brown gummy liquid. Crude was used as such for next step without any purification. [1385] LCMS: m/z = 281.17 [M+1]+, 13.0% % (0.81 min) [1386] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-5:

[1387] To a stirred solution of compound 11 (200 mg, 0.466 mmol) and compound 5 (220 mg, 0.606 mmol) in Dioxane (4 ml) and water (0.4 ml) was added NaHCO ₃ (117 mg, 1.398 mmol) in a seal tube at room temperature. The resulting mixture degassed with nitrogen for 10 min. Then added Pd(dppf)Cl ₂ (8.5 mg, 0.011 mmol) and again degassed for 5 min. Then the reaction mixture stirred at 90 °C for 16 h. The progress of the reaction was monitored by TLC, after completion, the reaction mass was filtered through celite pad, washed with EtOAc. The filtrate was washed with water, brine solution. The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by reverse phase C-18 column chromatography (50% ACN in 0.1% FA as eluent and extracted) to afford compound 6 (100 mg, yield: 29.5%) as a yellow gum. [1388] LCMS: m/z: 585.35 [M+1] ⁺ , 40.62% (3.03 min), [1389] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [1390] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1391] Flow Rate: 0.4 mL/min. Step-2:

[1392] Trifluoroacetic acid (2 mL) was added to the compound 6 (100 mg, 0.170 mmol) at room temperature. The resulting reaction mixture stirred at 100 °C for 4 h. The reaction progress was monitored by LCMS, after completion of reaction, evaporated the excess solvent under reduced pressure. The resulting residue was purified by Prep HPLC and lyophilized to afford compound II-1030 (12 mg, yield: 19.3%) as a white solid. [1393] 1H NMR [400 MHz, DMSO-d6]: 8.42 (s, 1H), 7.89 (t, J = 5.2 Hz, 1H), 7.72 (dd, J = 1.6 Hz, 1H), 7.48 (d, J = 6.8 Hz, 1H), 5.76 (t, J = 4 Hz, 1H), 3.04-2.96 (m, 2H), 2.86-2.81 (m, 1H), 2.77 (s, 3H), 2.20 (s, 3H), 1.33 (d, J = 6.8 Hz, 3H). [1394] LCMS: m/z: 365.25 [M+1] ⁺ , 99.21% (2.01 min), [1395] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm), [1396] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/2, 1/2, 5/90, 6/90) [1397] Flow Rate: 0.4 mL/min. Scheme 46: Synthesis of II-1031(R) & 1047(R):

Step-1: [1398] To a stirred solution of compound 11 (200 mg, 0.465 mmol) CHCl3 (2 ml) was added mCPBA (88 mg, 0.511 mmol) at 0 ^° C under nitrogen atmosphere. The reaction mixture was stirred at 70 °C for 4 h. After completion of reaction, the reaction mixture was diluted with DCM (50 ml) and washed with water. The organic layer washed with NaHCO ₃ (50 ml), brine solution. The organic layer dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was triturated with ether and dried to afford compound 12 (200 mg, yield: 96%) as an off-white solid. Step-2: [1399] To a stirred solution of compound 12 (200 mg, 0.448 mmol) in Ac ₂ O (2 ml) at room temperature. The resulting mixture stirred at 100 °C for 3 h. The progress of the reaction was monitored by TLC, after completion, the reaction mass diluted with DCM and purified by silica gel (100-200) column chromatography (50% ethyl acetate in hexane as an eluent) to afford compound 13 (150 mg, yield: 68.8%) as an off-white solid. [1400] LCMS: m/z: 487 [M+1] ⁺ , 93.67% (1.56 min), [1401] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [1402] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1403] Flow Rate: 0.4 mL/min. Step-3: [1404] To a stirred solution of compound 13 (150 mg, 0.308 mmol) and compound 14 (111 mg, 0.308 mmol) in dioxane (2 ml) and water (0.2 ml) was added K2CO ₃ (127 mg, 0.924 mmol) and Pd-118 (10 mg, 0.015 mmol) at room temperature. The resulting reaction mixture was degassed with nitrogen for 10 minutes and stirred at 90°C overnight. The progress of the reaction was monitored by TLC. After completion, the reaction mass was diluted with EtOAc (100 ml) and filtered through a celite pad. The filtrate was washed with a brine solution, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (15% EtOAc in hexane as an eluent) to afford compound 15 (120 mg, 60%) as a yellow liquid. [1405] LCMS: m/z: 642.54 [M+1] ⁺ , 80.49% (1.86 min), [1406] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [1407] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1408] Flow Rate: 0.4 mL/min. Step-4: [1409] To a stirred solution of compound 15 (100 mg, 0.156 mmol) in MeOH (1 ml), K2CO ₃ (22 mg, 0.156 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was filtered and washed with DCM The crude The filtrate was concentrated under reduced pressure to get compound 16 (80 mg, yield: 86%) as pale yellow solid. The solid compound used as such for next step without any purification. [1410] LCMS: m/z: 600.42 [M+1] ⁺ , 48.47% (1.78 min), [1411] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [1412] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1413] Flow Rate: 0.4 mL/min. Step-5:

[1414] Trifluoroacetic acid (1 mL) was added to compound 16 (70 mg, 0.109 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 3 hours. The completion of the reaction was monitored by LCMS. After completion, the solvent was evaporated under reduced pressure. The resulting residue was purified by reverse-phase HPLC column chromatography (10% ACN in 0.1% FA as the eluent and lyophilizes) to afford II-1031(R) (30 mg, 73%) as a white solid. [1415] LCMS: m/z: 380.27 [M+1] ⁺ , 96.74% (1.22min), [1416] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm), [1417] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) [1418] Flow Rate: 0.4 mL/min. [1419] ¹ H NMR [400 MHz, DMSO-d ₆ ]: 7.81 (d, J = 5.2 Hz, 1H), 7.43 (d, J = 7.2 Hz, 2H), 7.23 (d, J = 7.2 Hz, 2H), 5.77 (d, J = 5.6 Hz, 1H), 5.01 (s, 2H) 2.85-2.76 (m, 3H), 2.23 (s, 3H), 1.31 (d, J = 8 Hz, 3H). Step-6: [1420] To a stirred solution of compound 13 (200 mg, 0.416 mmol) and compound 17 (146 mg, 0.410 mmol) in Dioxane (2 ml) and water (0.2 ml) was added K2CO ₃ (170 mg, 1.232 mmol), Pd- 118 (16 mg, 0.024 mmol) at room temperature. The resulting reaction mixture degassed with nitrogen for 10 min and stirred at 90 °C for overnight. Progress of the reaction was monitored by TLC; after completion, the reaction mass diluted with EtOAc (100 ml) and filtered through celite pad. The filtrate was washed with brine solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by silica gel (100-200) column chromatography (15% EtOAc in Hexane as eluent) to afford compound 18 (120 mg, yield: 47%) as a yellow liquid. [1421] LCMS: m/z: 655.80 [M+1] ⁺ , 32.98% (1.96 min), [1422] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [1423] Mobile Phase: A-0.01% FA in water; B-0.01% [1424] FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1425] Flow Rate: 0.4 mL/min. Step-7: [1426] To a stirred solution of compound 18 (120 mg, 0.183 mmol) in MeOH (2 ml), K2CO ₃ (25 mg, 0.183 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 3 h. After completion, the reaction mixture was concentrated under reduced pressure. The crude product was diluted with DCM and filtered through celite. The celite was washed with DCM (10 ml). The filtrate was concentrated under reduced pressure to get compound 19 (30 mg, yield: 26%) as an off-white solid. The crude compound used as such for next step. [1427] LCMS: m/z: 613, 77. [M+1] ⁺ , 32.98% (1.96 min), [1428] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [1429] Mobile Phase: A-0.01% FA in water; B-0.01%FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, and 3/90) [1430] Flow Rate: 0.4 mL/min. Step-8: [1431] Trifluoroacetic acid (1 mL) was added to compound 19 (60 mg, 0.097 mmol) at room temperature. The resulting mixture was stirred at 100°C for 4 hours. The completion of the reaction was monitored by LCMS. After completion, the solvent was evaporated under reduced pressure. The resulting residue was purified by reverse-phase C-18 column chromatography (10% ACN in 0.1% FA as the eluent) and then lyophilized, yielding II-1047(R) (26%) as a white solid. [1432] ¹ H NMR [400 MHz, DMSO-d ₆ ]: 7.84 (d, J = 5.6 Hz, 1H), 7.46 (d, J = 7.6 Hz, 2H), 7.23 (d, J = 8 Hz, 2H), 5.77 (d, J = 5.2 Hz, 1H), 5.01 (s, 2H) 3.02-3.00 (m, 1H), 2.76-2.67 (m, 2H), 2.34 (s, 3H), 2.23 (s, 3H), 1.32 (d, J = 6.8 Hz, 3H). [1433] LCMS: m/z: 394.38 [M+1] ⁺ , 96.98% (2.26 min), [1434] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm), [1435] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) [1436] Flow Rate: 0.4 mL/min. Scheme 47: Synthesis of II-1034(P1) and II-1034(P2) Step-1: [1437] To a stirred solution of compound 1 (5 g, 21.4 mmol) in THF (100 mL), a solution of 2M NaHMDS (35 mL) in THF was added at -78°C over a period of 10 minutes. The reaction mixture was stirred for 1 hour at the same temperature. After 1 hour, a solution of MeI (2 mL, 10.3 mmol) in THF (100 mL) was added dropwise over a period of 5 minutes. The reaction mixture was then stirred for 16 hours at room temperature. The progress of the reaction was monitored by TLC and LCMS analysis. After the completion of the reaction, the reaction mixture was quenched with 1N HCl. Ice-cold water (100 mL) was added, and the mixture was extracted with ethyl acetate (3 x 100 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to yield compound 2 (8 g, 96.15%) as a pale brown liquid. The crude compound was used for the next step without purification. [1438] ¹ H NMR [400 MHz, DMSO-d ₆ ]: 12.51 (bs, 1H), 7.69 (t, J = 7.6 Hz, 1H), 7.32 (d, J = 10.4 Hz, 1H,), 7.11 (d, J = 8.0 Hz, 1H), 3.77 (q, J = 7.8 Hz, 1H), 1.37 (d, J = 6.8 Hz, 3H) Step-2: [1439] To a stirred solution of compound 2 (1 g, 4.06 mmol, 1.0 eq.) in MeOH (10 mL), Thionyl chloride (5 mL) was added at 0°C. The reaction mixture was then stirred for 4 hours at room temperature. The progress of the reaction was monitored by TLC analysis. After the completion of the reaction, the reaction mass was evaporated under vacuum in the presence of an argon atmosphere. Ice-cold water (100 mL) was added, and the mixture was extracted with ethyl acetate (3 x 100 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to yield compound 3 (1 g, 99.00%) as a pale brown liquid. The crude compound was used for the next step without purification. [1440] ¹ H NMR [400 MHz, DMSO-d6]: 7.69 (d, J = 8.0 Hz, 1H), 7.35 (dd, J = 2.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 3.89 (q, J = 6.8 Hz, 1H), 3.63(s, 3H), 1.41 (d, J = 6.8 Hz, 3H) Step-3: [1441] To a stirred solution of compound 3 (1.2 g, 4.63 mmol) in DCM (25 mL), DIABAL-H (1 M) (14 mL, 13.9 mmol) was added at -78°C. The reaction mixture was then stirred for 1 hour at - 78°C. The progress of the reaction was monitored by TLC and LCMS analysis. After the completion of the reaction, the reaction mixture was quenched by adding MeOH, followed by ammonium chloride solution at 0°C, resulting in the formation of a precipitate. This was filtered through a celite bed, washed with a 10% MeOH: DCM solution (100 mL x 2). Ice-cold water (100 mL) was added, and the mixture was extracted with a 10% MeOH: DCM solution (3 x 100 mL). The separated organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to yield compound 4 (1 g, 93.45%) as a pale-yellow liquid. The crude compound was used for the next step without purification. [1442] ¹ H NMR [400 MHz, DMSO-d ₆ ]: 7.69 (d, J = 8.0 Hz, 1H), 7.35 (dd, J = 2.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 4.70 (t, J = 10.4 Hz, 1H), 3.50-3.43(m, 2H), 2.84 (q, J=20.4 Hz , 1H), 1.41 (d, J = 6.8 Hz, 3H) Step-4: [1443] To a stirred solution of compound 4 (3 g, 12.98 mmol) in DCM (40 mL), DMP (5.5 g, 12.98 mmol) was slowly and portion-wise added at 0°C. The reaction mixture was then stirred for 30 minutes at 0°C. The progress of the reaction was monitored by TLC analysis. After the completion of the reaction, the reaction mixture was filtered through a celite bed, washed with DCM, and ice-cold water (100 mL) was added. The mixture was then extracted with DCM (3 x 100 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to yield compound 5 (3 g, 95.20%) as a pale yellow liquid. The crude compound was used for the next step without purification. [1444] ¹ H NMR [400 MHz, DMSO-d ₆ ]: 9.59 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.35 (dd, J = 2.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 3.80 (q, J = 7.2 Hz, 1H), 1.41 (d, J = 6.8 Hz, 3H) Step-5: [1445] To a stirred solution of compound 5 (3 g, 2.17 mmol) in THF (30 mL) was combined with R-Sulfinamide (1.8 g, 10.86 mmol) and Ti(OEt)4 (5.4 mL, 10.86 mmol) at 0°C. The reaction mixture was then stirred for 2 hours at 70°C. The progress of the reaction was monitored by TLC and LCMS analysis. After the completion of the reaction, the reaction mixture was quenched with ice-cold water, resulting in the formation of a precipitate. This was filtered through a celite bed, washed with ethyl acetate (100 ml X 3). Ice-cold water (100 mL) was added, and the mixture was extracted with ethyl acetate (3 x 100 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford the crude compound (3 g). The crude compound was purified by normal phase column chromatography using silica gel (100-200 mesh), and the compound was eluted using 10% EtOAc in hexane to yield compound 6 (650 mg, 14.97%) as a pale yellow liquid. [1446] LCMS: m/z = 334.11 [M+1] ⁺ , 97.92 % (1.71 min) [1447] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) Flow Rate: 0.4 mL/min. Step-6: [1448] To a stirred solution of compound 6 (0.650 g, 1.951 mmol) in MeOH (20 mL), NaBH4 (37 mg, 0.975 mmol) was added at 0°C. The reaction mixture was then stirred for 4 hours at room temperature. The progress of the reaction was monitored by TLC and LCMS analysis. After the completion of the reaction, the reaction mass was evaporated under reduced vacuum. Ice-cold water (100 mL) was added, and the mixture was extracted with ethyl acetate (3 x 100 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to yield compound 7 & 7A (500 mg, 76.56%) as a pale yellow liquid. The crude compound was used for the next step without purification. [1449] LCMS of 7 and 7A: m/z = 336.1 [M+1] ⁺ , 40.14 % (5.68 min) 7 & m/z = 336.13 [M+1] ⁺ , 42.42 % (5.77min) [1450] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 5/40, 10/90) Flow Rate: 0.4 mL/min. Step-7: [1451] To a stirred solution of compound 7 & 7A (300 mg, 0.892 mmol) in 1,4-Dioxane (6 mL) under an argon atmosphere, potassium acetate (263 mg, 2.676 mmol), and B2Pin2 (451 mg, 1.785 mmol) were added. The reaction mixture was degassed for 5 minutes. Pd-118 (60 mg, 0.089 mmol) was then added, and the reaction mixture was degassed again for 5 minutes. The reaction mixture was stirred for 16 hours at 100°C. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was filtered through a celite bed. Ice-cold water (150 ml) was added, and the mixture was extracted with ethyl acetate (3 x 150 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford compound 8 & 8A (320 mg, 93.56%) as a pale brown liquid. The crude compound was used for the next step. Step-8: [1452] To a stirred solution of compound 11 (200 mg, 0.46 mmol) in 1,4-Dioxane (4 mL) and H ₂ O (1 mL) under an argon atmosphere, potassium carbonate (192 mg, 1.3953 mmol), and compound 8 & 8A (890 mg, 2.32 mmol) were added. The reaction mixture was degassed for 5 minutes. Pd-118 (15 mg, 0.023 mmol) was then added, and the reaction mixture was degassed again for 5 minutes. The reaction mixture was stirred for 3 hours at 100°C. The progress of the reaction was monitored by TLC and LCMS analysis. After the completion of the reaction, the reaction mass was quenched with ice-cold water. It was filtered through a celite bed, washed with ethyl acetate. Ice-cold water (150 mL) was added, and the mixture was extracted with ethyl acetate (3 x 150 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford the crude compound (0.450 g). The crude compound was purified by preparative purification, followed by lyophilization, yielding compound 10 & 10A (120 mg, 42.64%) (10 Peak 1 = 60 mg, 10A Peak 2 = 60 mg) as an off-white solid [1453] LCMS: m/z = 606.56 [M+1] ⁺ , 95.97 % (3.01 min) Peak 1 & m/z = 606.59 [M+1] ⁺ , 98.25 % (3.08 min) Peak 2 [1454] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) Flow Rate: 0.4 mL/min. Step-9: [1455] To a stirred solution of compound 9 (60 mg, 0.09917 mmol) in DCM (2 mL) under an argon atmosphere, TFA (1 mL) was added at 0°C. The reaction mixture was stirred for 16 hours at room temperature. The progress of the reaction was monitored by LCMS analysis. After the completion of the reaction, the reaction mass was evaporated under reduced pressure. Ice-cold water (20 mL) was added, followed by basification with a saturated sodium bicarbonate solution, and the mixture was extracted with a 10% MeOH:DCM solution (3 x 50 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford the crude compound (100 mg) as an off-white solid. The crude material was purified by preparative purification, followed by lyophilization, yielding compound II-1034(P1) (18 mg, 48.64%) as an off-white solid. [1456] LCMS: m/z = 382.27 [M+1] ⁺ , 99.15 % (2.05 min). [1457] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/2, 1/2, 5/90, 6/90), Flow Rate: 0.4 mL/min [1458] Prep Method: Column: Xtimate C ₁ 8 (150 x 21.2mm, 52m), Mobile Phase: A-0.1% FA in water; B-100% ACN, (T/%B: 0/5, 5/5, 20/35) Flow Rate: 17 ml/min. [1459] ¹ H NMR [400 MHz, DMSO-d ₆ ]: 8.34 (bs, 1H), 7.92 (dd, J = 3.2 Hz, 1H), 7.39-7.31 (m, 3H), 6.00 (t, J = 5.6 Hz, 1H), 2.99-2.91 (m, 3H), 2.77 (s, 3H), 2.32 (s, 3H), 1.34 (d, J = 5.2 Hz, 3H). Step-9:

[1460] To a stirred solution of compound 9A (60 mg, 0.09917 mmol) in DCM (2 mL) under an argon atmosphere, TFA (1 mL) was added at 0°C. The reaction mixture was stirred for 16 hours at room temperature. The progress of the reaction was monitored by LCMS analysis. After the completion of the reaction, the reaction mass was evaporated under reduced pressure. Ice-cold water (20 mL) was added, followed by basification with a saturated sodium bicarbonate solution, and the mixture was extracted with a 10% MeOH: DCM solution (3 x 50 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford the crude compound (100 mg) as an off-white solid. The crude material was purified by preparative purification, followed by lyophilization, yielding compound II-1034(P2) (2 mg, 18.76%) as an off-white solid. [1461] LCMS: m/z = 382.26 [M+1] ⁺ , 97.23 % (1.16 min). [1462] Method: Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm), Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) Flow Rate: 0.4 mL/min. Prep Method: Column: ZodiaC C ₁ 8 (150 x 21.2m, 5 µm), Mobile Phase: A-0.2% NH ₃ in water; B-100% ACN, (T/%B: 0/15, 2/15, 20/50) Flow Rate: 17 ml/min. [1463] ¹ H NMR [400 MHz, CD3OD]: 7.76 (d, J = 5.6 Hz, 1H), 7.34-7.26 (m, 3H), 6.17 (d, J = 5.6 Hz, 1H), 3.04-2.97 (m, 3H), 2.83 (s, 3H), 2.30 (s, 3H), 1.41 (d, J = 6.4 Hz, 3H). Synthesis of II-1012/II-1024/II-1013/II-1025: Scheme 48: Synthesis of key intermediate 9 (Bromo): Step-1: [1464] To a stirred solution of compound 1 (30 g, 194 mmol) in DMF (300 mL) was added N- bromo succinimide (41.5 g, 233 mmol) at 0°C. The resulting mixture stirred at 80°C for overnight. After completion, reaction mass poured into crushed ice, resulting solid was filtered and washed with water. The solid was dissolved in 10% methanol in dichloromethane and washed with brine solution. The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to afford compound 2 (28 g, yield: 61.8%) as a brown solid. Step-2: [1465] POCl ₃ (80 ml, 4 vol) was added to compound 2 (20 g, 86 mmol) at room temperature. The resulting reaction mixture was refluxed for 7 h. Completion of the reaction was monitored by TLC; after completion, excess POCl3 was evaporated under reduced pressure. The residue was diluted with ice cold water and basified using solid NaHCO ₃ up to pH~9 and extracted with ethyl acetate (300 mL X 2). Combined organic layer washed with brine solution, dried anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to afford compound 3 (20 g, yield: 93%) as brown solid. Step-3: [1466] To a stirred solution of compound 3 (12 g, 47 mmol) in Methanol (120 mL) was added sodium methoxide (3.2 g, 60 mmol) portion wise at 0°C. The resulting mixture allow to stir at 80 °C for 3 h. Completion of the reaction was monitored by TLC, after completion of reaction, evaporated the solvent under reduced pressure. The resulting residue diluted with water and extracted with ethyl acetate (200 ml X 2). The combined organic layer washed with brine solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting crude was triturated with ether, filtered and dried to afford compound 4 (5.5 g, yield: 46.6%) as brown solid. Step-4: [1467] To a stirred solution of compound 4 (5 g, 20 mmol) and compound 5 (8.7 g, 24 mmol) in Dioxane (50 mL) and water (5 mL) was added NaHCO ₃ (5.1 g, 60 mmol) at room temperature. The resulting mixture degassed with nitrogen for 15 min and added Pd(dppf)Cl2 (740 mg, 1 mmol), again degassed for 5 min. The reaction mixture stirred for overnight at 85°C. After completion of reaction, reaction mass filtered through celite and washed with ethyl acetate. The filtrate was washed with water, brine solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (20% E.A in Hexane as eluent) to afford compound 6 (6 g, yield: 71.4%) as yellow liquid. Step-5: [1468] Aqueous HBr (30 mL) was added to compound 6 (6 g, 14 mmol) at room temperature. The resulting mixture refluxed for overnight. Reaction was monitored by TLC; after completion, reaction mass quenched with ice cold water and basified using sodium hydroxide and extracted with 10% MeOH in DCM. The organic layer washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to afford compound 7 (2 g, yield: 48%) as brown liquid. The crude compound was used as such for next step. [1469] LCMS: m/z: 288.18 [M+1] ⁺ , 99.09% (0.83 min), [1470] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm) [1471] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1472] Flow Rate: 0.4 mL/min. Step-6:

[1473] To a stirred suspension of compound 7 (2 g, 6.968 mmol) in MeCN (30 mL) was added POBr3 (3.98 g, 13.937 mmol) at room temperature in a seal tube. The resulting mixture stirred at 100 °C for overnight. The reaction was monitored by TLC, after completion, reaction mass diluted with water and basified using sat NaHCO ₃ , extracted with 10% MeOH in DCM (100 ml). The organic layer washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to afford compound 8 (1.4 g, yield: 57.3%) as brown semi solid. The crude compound used as such for next step without any purification. [1474] LCMS: m/z: 350.17 [M+1] ⁺ , 92.09% (0.99 min), [1475] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm) [1476] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1477] Flow Rate: 0.4 mL/min.

Step-7: [1478] To a stirred mixture of compound 8 (2 g, 5.698 mmol) and triethyl amine (2.3 mL, 17.09 mmol) in DCM (20 mL) was added DMAP (69 mg, 0.569 mmol) followed by (Boc) ₂ O (1.9 mL, 8.54 mmol) at 0 °C. The resulting mixture stirred at room temperature for 4 h. Completion of the reaction was monitored by TLC; after completion, reaction mass diluted with DCM and washed with water, brine solution. The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (10% EtOAc in Hexane as eluent) to afford compound 9 (1.2 g, yield: 48%) as a brown liquid. [1479] LCMS: m/z: 452.04 [M+1] ⁺ , 97.62% (1.81 min), [1480] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm) [1481] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1482] Flow Rate: 0.4 mL/min.

Scheme 49: Synthesis of II-1013 and II-1024 Step-1: [1483] To a stirred mixture of compound 9 (500 mg, 1.10 mmol) and Ethyl boronic acid (246 mg, 3.32 mmol) in toluene (10 ml) and water (1 ml) was added K ₂ CO ₃ (306 mg, 2.21 mmol) at room temperature. The resulting mixture degassed with nitrogen for 15 min and added Pd(OAc) ₂ (25 mg, 0.110 mmol), PCy3 (62.1 mg, 0.221 mmol) again degassed for 5 min. The resulting reaction mixture degassed with nitrogen for 15 min, stirred the reaction mixture at 90 °C for 5 h. The Progress of the reaction was monitored by TLC, after completion, reaction mass filtered through celite pad, washed with ethyl acetate. The filtrate was washed with water, brine solution dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (8% EtOAC in Hexane as an eluent) to afford compound 10 (400 mg, yield: 90.49%) as brown liquid. [1484] LCMS: m/z: 400.36 [M+1] ⁺ , 98.25% (1.87 min), [1485] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm) [1486] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1487] Flow Rate: 0.4 mL/min. Step-2: [1488] To a stirred suspension of compound 10 (800 mg, 2.005 mmol) in THF (10 mL) and water (1.5 ml) was added NH ₄ Cl (1 g, 20.050 mmol) followed by Iron Powder (0.56 g, 10.025 mmol) at room temperature. The resulting mixture stirred at 70 °C for overnight. The progress of the reaction was monitored by TLC, after completion, reaction mass filtered through celite and washed with ethyl acetate. The filtrate was washed with water, brine solution dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (35% EtOAc in hexane as eluent) to afford compound 11 (680 mg, yield: 92%) as yellow liquid. [1489] LCMS: m/z: 370.35 [M+1] ⁺ , 38.25% (1.16 min), [1490] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm) [1491] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, [1492] (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1493] Flow Rate: 0.4 mL/min. Step-3: [1494] To a stirred solution of compound 11 (680 mg, 1.837 mmol) in MeOH (7 mL) was added compound 12 (0.2 mL, 2.203 mmol), cat. AcOH (0.05 mL) at room temperature and stirred for 1 h. Then reaction mixture cool to 0 °C and added NaBH4 (210 mg, 5.513 mmol) portion wise. The resulting mixture allowed to room temperature and stirred for 3 h. Completion of the reaction was monitored by TLC, after completion, reaction mixture quenched with cold water and extracted with DCM (200 ml). The organic layer washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacu0. Resulting residue was purified by silica gel column chromatography 30% EtOAc in hexane as an eluent to afford compound 13 (275 mg, yield: 30%) as yellow syrup. [1495] LCMS: m/z: 490.46 [M+1] +, 88.46% (1.24 min), [1496] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm) [1497] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1498] Flow Rate: 0.4 mL/min. Step-4: [1499] To a stirred solution of compound 13 (280 mg, 0.573 mmol) and TEA (0.2 mL, 1.721 mmol) in DCM (10 mL) was added a solution of freshly prepared compound 14 (178 mg, 0.860 mmol) in DCM (2 mL) at 0 °C. The resulting mixture allowed to room temperature and stirred for 3 h. Completion of the reaction was monitored by TLC; after completion of reaction, reaction mass diluted with DCM (100 ml X 3) and washed with water, brine solution. The separated organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by reverse phase C-18 column chromatography using 70% ACN in 0.1% FA as an eluent and extracted in EtOAc to afford compound 15 (150 mg, yield: 38%) as yellow semi- solid. [1500] LCMS: m/z: 678.30 [M-56] ⁺ , 76.05% (1.86 min), [1501] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm) [1502] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1503] Flow Rate: 0.4 mL/min. Step-5: [1504] To a solution of compound 15 (150 mg, 0.221 mmol) in DMA (3 mL) was added KOAc (87 mg, 0.884 mmol) and Pd(tBu3P) ₂ (14 mg, 0.022 mmol) at room temperature. The reaction mixture degassed with nitrogen for 10 min. The resulting mixture stirred at 150 °C in a microwave for 2 h. Reaction was monitored by TLC and LCMS; after completion of reaction, reaction mass poured into ice-cold water and extracted with ethyl acetate (100 ml X 2). The organic layer washed with water, brine solution and dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude residue was purified by reverse phase C-18 column chromatography (75% ACN in 0.1% FA as an eluent and extracted with EtOAc) to afford compound 16 (70 mg, yield: 53%) as pale-yellow gum. [1505] LCMS: m/z: 598.37 [M+1] ⁺ , 96.0% (1.82 min), [1506] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm) [1507] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1508] Flow Rate: 0.4 mL/min. Step-6: [1509] Trifluoroacetic acid (5 mL) was added to the compound 16 (70 mg, 0.117 mmol) at room temperature. The resulting mixture stirred at 100 °C for 3 h. completion of the reaction was monitored by LCMS; after completion of reaction, excess TFA was evaporated in vacuo. The resulting residue was purified by reverse phase C-18 column (15% ACN in 0.1% FA as eluent and lyophilized) to afford II-1013 (6 mg, yield: 13%) as a white solid. [1510] ¹ H NMR [400 MHz, DMSO-d6]: 11.34 (brs, 1H), 8.01 (brs, 2H), 7.81 (d, J = 5.2 Hz, 1H), 7.51 (t, J = 7.2 Hz, 2H), 7.25 (d, J = 4 Hz, 1H), 5.74 (d, J = 5.6 Hz, 1H), 3.21-3.08 (m, 4H), 2.89 (s, 3H), 1.38 (d, J = 5.6 Hz, 3H), 1.16 (t, J = 3.6 Hz, 3H). [1511] LCMS: m/z: 378.30 [M+1] +, 97.38% (1.20 min), [1512] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm), [1513] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) [1514] Flow Rate: 0.4 mL/min.

Step-7: [1515] To a stirred mixture of II-1013 (80 mg, 0.212 mmol) and 35% HCHO (0.1 mL) in methanol (2 mL) was added acetic acid (0.05 mL) followed by sodium cyanoborohydride (43 mg, 0.636 mmol) at room temperature. The resulting reaction mixture stirred for 16 h at rt. Completion of the reaction was monitored by LCMS, after completion of reaction, the reaction mass quenched with water and extracted with 10% MeOH in DCM. The organic layer washed with brine solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude residue was purified by reverse phase C-18 column chromatography (25% ACN in 0.1% FA as an eluent and lyophilized) to afford II-1024 (3 mg, yield: 3.48%) as a white solid. [1516] ¹ H NMR [400 MHz, DMSO-d6]: 9.25 (brs, 1H), 8.39 (brs, 1H), 7.43 (t, J = 4.4 Hz, 3H), 7.30 (d, J = 1.6 Hz, 1H), 7.23 (s, 2H), 5.90 (d, J = 4.8 Hz, 1H), 3.30-3.25 (m, 1H), 3.03-2.98 (m, 1H), 2.94-2.89 (m, 1H), 2.53 (s, 3H), 1.47 (d, J = 6.8 Hz, 3H), 1.15 (t, J = 6.8 Hz, 3H). [1517] LCMS: m/z: 405.90 [M+1] ⁺ , 98.65% (0.87 min), [1518] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm) [1519] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1520] Flow Rate: 0.4 mL/min.

Scheme 50: Synthesis of II-1012 and II-1025 Step-1: [1521] To a stirred solution of compound 9 (300 mg, 0.665 mmol) and cyclopropyl boronic acid (171 mg, 1.995 mmol) in toluene (3 ml) and water (0.4 ml) was added K2CO ₃ (183 mg, 1.330 mmol), Pd(OAc) ₂ (15 mg, 0.066 mmol) followed by PCy ₃ (37 mg, 0.133 mmol) at room temperature. The resulting reaction mixture degassed with nitrogen for 20 min and stirred at 90 °C for 1 h in a microwave. Progress of the reaction was monitored by TLC; after completion of reaction, reaction mass diluted with EtOAc, filtered through celite pad. The filtrate was washed with water, brine solution dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (10% EtOAc in Hexane as eluent) to afford compound 10 (170 mg, yield: 62%) as yellow syrup. [1522] LCMS: m/z: 412.37 [M+1] ⁺ , 99.72% (2.00 min), [1523] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm) [1524] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1525] Flow Rate: 0.4 mL/min. Step-2: [1526] To a stirred suspension of compound 10 (160 mg, 0.438 mmol) in THF (3 mL) and water (0.5 ml) was added NH ₄ Cl (234 mg, 4.379 mmol) followed by Iron Powder (244 mg, 4.379 mmol) at room temperature. The resulting mixture allow to stir at 80 °C for overnight. Completion of the reaction was monitored by TLC; after completion of reaction, reaction mass filtered through celite and washed with EtOAc. The filtrate was washed with water, brine solution. The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to get compound 11 (160 mg, yield: 95.8%) as a yellow gum. [1527] LCMS: m/z: 382.37 [M+1] ⁺ , 52.88% (1.10 min), [1528] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm) [1529] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1530] Flow Rate: 0.4 mL/min. Step-3: [1531] To a stirred solution of compound 11 (160 mg, 0.417 mmol) in MeOH (3 mL) was added compound 12 (68 mg, 0.501 mmol), cat AcOH (0.05 mL) at room temperature and continued the stirring for 1 h. Then reaction mixture cool to 0 °C and added NaBH ₄ (32 mg, 0.835 mmol) portion wise. The resulting mixture allowed to room temperature and stirred for 3 h. After completion of reaction, reaction mixture quenched with cold water and extracted with DCM. The organic layer washed with brine solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Resulting residue was purified by silica gel column chromatography (30% EtOAc in hexane as eluent) to afford compound 13 (100 mg, yield: 47.6%) as pale-yellow semi solid. [1532] LCMS: m/z: 502.46 [M+1] +, 99.11% (1.30 min), [1533] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm) [1534] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1535] Flow Rate: 0.4 mL/min. Step-4: [1536] To a stirred solution of 13 (100 mg, 0.199 mmol) and TEA (0.14 mL, 0.199 mmol) in DCM (3 mL) was added a solution of freshly prepared compound 14 (41 mg, 0.199 mmol) in DCM (2 mL) at 0 °C. The resulting mixture allowed to stir at room temperature for 3 h. After completion of reaction, the reaction mass diluted with DCM (50 ml) and washed with water, brine solution. Organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by RP-C ₁ 8 column (70% ACN in 0.1% FA as eluent and extracted) to afford 15 (80 mg, yield: 66%) as an off-white solid. [1537] LCMS: m/z: 690.37 [M-56] ⁺ , 50.73% (2.11 min), [1538] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm) [1539] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1540] Flow Rate: 0.4 mL/min. Step-5: [1541] To a solution of compound 15 (150 mg, 0.217 mmol) in DMA (2 mL) was added KOAc (85 mg, 0.869 mmol) and Pd(tBu3P) ₂ (11 mg, 0.021 mmol) at room temperature. The reaction mixture degassed with nitrogen for 10 min and stirred at 150 °C in a microwave for 2 h. Progress of the reaction was monitored by TLC and LCMS, after completion, the reaction mass poured into ice-cold water and extracted with EtOAc (2 X 50 ml). The combined organic layer washed with water, brine solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude residue was purified by reverse phase C-18 column chromatography (70% ACN in 0.1% FA as an eluent and extracted) to afford 16 (50 mg, yield: 37%) as colourless semi solid. [1542] LCMS: m/z: 610.30 [M+1] ⁺ , 95.84% (2.06 min), [1543] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm) [1544] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1545] Flow Rate: 0.4 mL/min. Step-6: [1546] Trifluoroacetic acid (1 mL) was added to compound 16 (30 mg, 0.0.049 mmol) at room temperature. The resulting mixture stirred at 100 °C for 3 h. The reaction progress was monitored by LCMS, after completion, evaporated the excess solvent under reduced pressure. The resulting residue was purified by reverse phase C-18 column (10% ACN in 0.1% FA as eluent and lyophilized) to afford II-1012 (3.5 mg, yield: 18%) as a white solid. [1547] ¹ H NMR [400 MHz, DMSO-d6]: 7.80 (d, J = 5.2 Hz, 1H), 7.47 (d, J = 7.6 Hz, 2H), 7.30 (d, J = 7.2 Hz, 2H), 5.76 (d, J = 4.8 Hz, 1H), 2.99 (m, 3H), 2.71 (s, 3H), 1.65 (m, 1H), 1.34 (bs, 3H), 0.93 (bs, 2H), 0.71 (d, J = 5.2 Hz, 2H). [1548] LCMS: m/z: 390.23 [M+1] +, 97.87% (0.95 min), [1549] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm) [1550] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1551] Flow Rate: 0.4 mL/min. Step-7: [1552] To a solution of compound 16 (90 mg, 0.147 mmol) in DMF (2 mL) was added 60% NaH (21 mg, 0.442 mmol) at 0 °C and stirred for 20 min and added methyl iodide (0.2 mL, 0.442 mmol). The reaction mixture was allowed to stir at room temperature for 4 h. The progress of the reaction was monitored by LCMS, after completion, the reaction mass quenched with cold water and extracted with EtOAc. Organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Resulting crude was purified by reverse phase C-18 combi flash column (65% ACN in 0.1% FA as eluent and extracted) to afford compound 17 (30 mg, yield: 49%) as colourless semi solid. [1553] LCMS: m/z: 624.38 [M+1] ⁺ , 95.07% (2.20 min), [1554] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm) [1555] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1556] Flow Rate: 0.4 mL/min.

Step-9: [1557] Trifluoroacetic acid (1 mL) was added to compound 17 (30 mg, 0.048 mmol) at room temperature. The resulting mixture stirred at 100 °C for 3 h. Completion of the reaction was monitored by LCMS, after completion of reaction, evaporated the excess solvent under reduced pressure. The resulting residue was purified by reverse phase C-18 column (15% ACN in 0.1% FA as eluent and lyophilized) to afford II-1025 (6 mg, 31.5%) as an off-white solid. [1558] ¹ H NMR [400 MHz, DMSO-d6]: 7.80 (d, J = 5.6 Hz, 1H), 7.48 (d, J = 7.6 Hz, 2H), 7.29 (d, J = 8 Hz, 2H), 5.74 (d, J = 5.2 Hz, 1H), 3.20 (m, 1H), 2.91 (m, 2H), 2.71 (s, 3H), 2.43 (s, 3H), 1.66 (m, 1H), 1.34 (d, J = 6.4 Hz, 3H), 0.93 (bs, 2H), 0.73 (m, 2H). [1559] LCMS: m/z: 403.88 [M+1] ⁺ , 99.65% (1.64 min), [1560] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 μm), [1561] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) [1562] Flow Rate: 0.4 mL/min.

Scheme 51: Synthesis of II-1035(R) and II-1044(R): Step-1: [1563] To a cold solution of compound 1 (3 g, 11.90 mmol) in THF (30 mL) was added 60% NaH (525 mg, 13.147 mmol) followed by diethylmalonate (2.2 mL, 13.147 mmol). After completion of addition stirred the reaction mixture for 15 min and evaporated the solvent under reduced pressure. The resulting residue was stirred at 110 °C for 1.5 h. Then again reaction mixture to 0 °C and added 6M aqueous H ₂ SO ₄ (17 mL). The resulting suspension was stirred at 110 °C for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, reaction mass poured into cold water and basified with NaHCO ₃ . The resulting precipitate filtered and dissolved in EtOAc, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to afford compound 2 (1.5 g, 54.5%) as a reddish solid. [1564] ¹ H NMR [400 MHz, CDCl3]: δ 8.44 (s, 1H), 2.80 (s, 3H), 2.72 (s, 3H). [1565] LCMS: m/z: 232.98 [M+2] ⁺ , 98.19% (1.61 min), [1566] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 ìm) [1567] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1568] Flow Rate: 0.4 mL/min. Step-2: [1569] To a stirred solution of compound 2 (2 g, 8.63 mmol) and compound 3 (4.7 g, 12.95 mmol) in Dioxane (20 ml) and water (2 ml) was added NaHCO ₃ (2.17 g, 25.89 mmol), Pd(dppf)Cl2 (315 mg, 0.43 mmol) at room temperature. The resulting reaction mixture degassed with nitrogen for 10 min. Then the reaction mixture stirred at 90 °C for 5 h. The progress of the reaction was monitored by TLC, after completion of the reaction evaporated the solvent. The residue was dissolved in EtOAc and washed with water, brine solution. The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (15% EtOAc in Hexane as eluent) to afford compound 4 (2.5 g, 75%) as a yellow liquid. [1570] ¹ H NMR [400 MHz, CDCl3]: δ 8.15 (s, 1H), 7.33-7.26 (m, 4H), 4.52 (brs, 1H), 3.43- 3.38 (m, 1H), 3.29-3.23 (m, 1H), 3.03-2.97 (m, 1H), 2.88 (s, 3H), 2.58 (s, 3H), 1.42 (s, 9H), 1.31 (d, J=6.8 Hz, 3H). [1571] LCMS: m/z: 386.31 [M+1] ⁺ , 97.7% (1.83 min), [1572] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 ìm) [1573] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1574] Flow Rate: 0.4 mL/min. Step-3: [1575] To a stirred solution of compound-4 (2.7 g, 7.01 mmol) in THF (30 mL) and water (4.5 ml) was added Iron Powder (1.9 g, 35.06 mmol) and NH ₄ Cl (3.7 g, 70.12 mmol) The resulting mixture stirred at 70 °C for overnight. Progress of the reaction was monitored by TLC. After completion of the reaction, filtered the reaction mass through celite and washed with EtOAc, separated the two layers. Organic layer washed with brine solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (20% EtOAc in hexane as eluent) to afford compound 5 (1.6 g, 64.2%) as yellow liquid. [1576] LCMS: m/z: 356.76 [M+1] ⁺ , 85.10% (1.04 min), [1577] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 ìm) [1578] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1579] Flow Rate: 0.4 mL/min. Step-4: [1580] To a stirred solution of compound 5 (1.2 g, 3.38 mmol) in MeOH (10 mL) was added compound 6 (0.6 mL, 4.05 mmol) followed by cat AcOH (0.1 mL) at rt and stirred for 1h. The reaction mixture cooled to 0 °C and added NaBH ₄ (385 mg, 10.14 mmol) portion wise and continued the stirring at rt for 2 h. The reaction progress was monitored by TLC, after completion of the reaction, reaction mass quenched with water and extracted with EtOAc. The organic layer washed with cold water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (20% EtOAc in Hexane as eluent) to afford compound 7 (700 mg, 43.7%) as a pale-yellow liquid. [1581] LCMS: m/z: 476.71 [M+1] ⁺ , 95.05% (1.20 min), [1582] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 ìm) [1583] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1584] Flow Rate: 0.4 mL/min. Step-5: [1585] To a stirred solution of compound 7 (250 mg, 0.525 mmol) and TEA (0.2 mL) in DCM (5 ml) was added freshly prepared compound 8 (121 mg, 0.525 mmol) at 0 °C. The resulting reaction mixture stirred at room temperature for 3 h. Completion of the reaction was monitored by TLC, after completion of reaction, the reaction mass diluted with DCM (50 ml) and washed with water, brine solution. The organic layer dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting crude was purified by reverse phase C-18 column chromatography (75% ACN in 0.1% FA as eluent and extracted) to afford compound 9 (200 mg, 55%) as brown gum. [1586] LCMS: m/z: 688.46 [M+1] ⁺ , 66% (1.67 min), [1587] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [1588] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1589] Flow Rate: 0.4 mL/min. Step-6: [1590] To a stirred solution of compound 9 (150 mg, 0.218 mmol) in DMA (2 mL) was added KOAc (85 mg, 0.872 mmol) and Pd(tBu ₃ P) ₂ (9 mg, 0.017 mmol) at room temperature. The reaction mixture degassed with nitrogen for 10 min and stirred at 150 °C for 16 h. Progress of the reaction was monitored by TLC, after completion of reaction, the reaction mass poured into ice- cold water and extracted with EtOAc. The organic layer washed with water, brine solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude residue was purified by reverse phase C-18 column chromatography (70% ACN in 0.1% FA as eluent and extracted) to afford compound 10 (58 mg, 44%) as a white solid. [1591] LCMS: m/z: 608.46 [M+1] ⁺ , 75.84% (3.43 min), [1592] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [1593] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.5/10,4/90, 7/90) [1594] Flow Rate: 0.4 mL/min. Step-7: [1595] To a stirred solution of compound 10 (60 mg, 0.155 mmol) in Dichloromethane (3mL) was added HBr (48% in aq) (1 ml) at 0 °C. The resulting mixture stirred at room temperature for overnight. The reaction progress was monitored by LCMS, after completion of reaction, the reaction mass was evaporated under reduced pressure. The residue was diluted with water and washed with DCM. The aqueous layer concentrated in vacuo and resulting residue was purified by reverse phase C-18 column chromatography (10% ACN in 0.1% FA as eluent and lyophilized) to afford II-1035(R) (14 mg, 24.13%) as white solid. [1596] ¹ H NMR [400 MHz, DMSO-d6]: 14.32 (brs, 2H), 7.40 (t, J = 6.8 Hz, 2H), 7.20-7.19 (m, 2H), 7.09 (t, J = 8.4 Hz, 1H), 6.85 (d, J = 8 Hz, 1H), 6.38 (d, J = 9.6 Hz, 1H), 5.97 (bs, 2H),2.87- 2.80 (m, 2H), 2.73 (s, 3H), 2.17 (s, 3H), 1.30 (d, J = 5.6 Hz, 3H). [1597] LCMS: m/z: 373.97 [M+1] ⁺ , 98.20% (2.61 min), [1598] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm), [1599] Mobile Phase: A-0.10% NH ₃ in water; B-ACN, (T/%B: 0.01/10, 0.5/10, 4/90, 7/90) [1600] Flow Rate: 0.4 mL/min. Step-8: [1601] To a stirred solution of compound 10 (130 mg, 0.214 mmol) in DMF (3 mL) was added NaH (31 mg, 0.642 mmol) at 0 °C and continued the stirring for 20 min. Then added Iodomethane (0.3 ml) and continued the stirring for overnight at room temperature. The reaction progress was monitored by LCMS, after completion, the reaction mass quenched with cold water and extracted with ethyl acetate. Organic layer washed with brine solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude residue was purified by reverse phase C-18 column chromatography (50% ACN in 0.1% FA as eluent and extracted) to afford compound 11 (80 mg, yield: 60.15%) as pale yellow gum. [1602] LCMS: m/z: 622.90 [M+1] ⁺ , 58% (1.73 min), [1603] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [1604] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1605] Flow Rate: 0.4 mL/min. Step-9: [1606] Aqueous HBr (2 mL) was added to compound-11 (80 mg, 0.199 mmol) at room temperature in a seal tube. The resulting mixture stirred at 100 °C for 3h. The reaction progress was monitored by LCMS, after completion of reaction, the reaction mass was evaporated under reduced pressure. The residue was diluted with water and washed with DCM. The aqueous layer concentrated under reduced pressure. The resulting residue was purified by preparative HPLC and lyophilized) to afford II-1042(R) (25 mg, yield: 32.4%) as a white solid. [1607] ¹ H NMR [400 MHz, DMSO-d6]: 14.04 (brs, 1H), 7.41 (d, J = 5.6 Hz, 2H), 7.18 (d, J = 7.2 Hz, 2H), 7.10 (t, J = 8 Hz, 1H), 6.88 (d, J = 8 Hz, 1H), 6.38 (d, J = 8 Hz, 1H), 3.02-2.97(m, 1H), 2.79-2.67 (m, 5H), 2.33 (s, 3H), 2.17 (s, 3H), 1.30 (d, J = 6.8 Hz, 3H). [1608] LCMS: m/z: 388.37 [M+1] ⁺ , 99.51% (0.84 min), [1609] Column: Kinetex EVO C ₁ 8 (2.1 x 50 mm, 1.7 µm) [1610] Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN, (T/%B: 0.01/10, 0.2/10, 1.5/90, 3/90) [1611] Flow Rate: 0.4 mL/min. Example 2. In Vitro CDK11B Inhibition Assay [1612] Compounds were assessed for their ability to inhibit CDK11B in vitro in a radiometric protein kinase assay ( ³³ PanQinase ^TM Activity Assay). All kinase assays were performed in 96- well ScintiPlates ^TM from PerkinElmer (Boston, MA, USA) in a 50 ml reaction volume. The reaction cocktail was pipetted in four steps in the following order: 1) 25 μl of assay buffer (standard buffer/[g- ³³ P]-ATP); 2) 10 μl of ATP solution (in H ₂ O); 3) 5 μl of test compound (in 10 % DMSO); and 4) 10 μl of enzyme/substrate mixture. [1613] The assay for the protein kinase contained 70 mM HEPES-NaOH pH 7.5, 3 mM MgCl ₂ , 3 mM MnCl2, 3 μM Na-orthovanadate, 1.2 mM DTT, 50 µg/ml PEG20000, ATP (corresponding to the apparent ATP-Km of the kinase: 0.1µM), [g- ³³ P]-ATP (approx.9 x 10 ⁰⁵ cpm per well), 200ng protein kinase, and substrate (SUPT5754-837, 2µg). [1614] The reaction cocktails were incubated at 30°C for 60 minutes. The reaction was stopped with 50 ml of 2 % (v/v) H ₃ PO ₄ , and plates were aspirated and washed two times with 200 ml 0.9 % (w/v) NaCl. Incorporation of ³³ P _i was determined with a microplate scintillation counter (Microbeta, Wallac). [1615] IC ₅ 0 values are represented as either “A” (less than 50 nM), “B” (50 nM to 500 nM), and “C” (greater than 500 nM). Example 3. In Vitro Functional CDK11 Assay [1616] Inhibition of CDK11 function by the compounds disclosed herein is assessed by monitoring the phosphorylation of the C-terminal domain of RNAPII at Ser2 (as described in Gajdušková, P. et al. Nat. Struct. Mol. Biol.27, 500–510 (2020)). RNAPII phosphorylation is monitored using SDS-PAGE gel electrophoresis and immunoblotting with specific antibodies that recognize the phosphorylation versions of the C-terminal domain of RNAPII. The compounds of the present disclosure are expected to inhibit CDK11 function in vitro. Example 4. Cellular CDK11 Selectivity Assay [1617] Compound selectivity for CDK11 is assessed by comparing the viability of compound- treated cancer cells that express wild-type CDK11 or that express the CDK11B ^G579S resistance mutation (as described in Lin, A. et al. Sci. Transl. Med.11, eaaw8412 (2019)). Relevant cancers may include those that over-express or under-express CDK11 or its activating partner Cyclin L (Loyer, P. et al. J. Biol. Chem.283, 7721–7732 (2008)). For example, relevant cancers include, but are not limited to, melanoma (e.g., A375 cells), ovarian carcinoma (e.g., A2780 cells), colon cancer (e.g., DLD1 cells), breast cancer (e.g., MDA-MB-231 cells), lung carcinoma (e.g., A549 cells), and colorectal cancer (e.g., HCT116 cells), as well as any of the other cancers provided herein. A culture of approximately 1,000 A375, A2780, DLD1, MDA-MB-231, A549, or HCT116 cells that express either CDK11B-WT or CDK11B ^G579S are plated in each well of a 96-well plate. Twenty-four hours after plating, the cells are treated with the test compound, starting at a top concentration of 10 µM and then decreasing by 3-fold serial dilutions. Seventy- two hours after addition of the compound, the surviving cells are quantified and used to assess both the potency of the compound and its selectivity for CDK11. The compounds of the present disclosure are expected to display selectivity for the inhibition of CDK11 over CDK11B ^G579S . Compound selectivity for inhibition of CDK11 over other cyclin-dependent kinases (e.g., CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK12, CDK13, CDK14, CDK15, CDK16, CDK17, CDK18, CDK19, and/or CDK20) is also assessed, and it is expected that selectivity of the compounds of the present disclosure for inhibition of CDK11 over CDK11B ^G579S correlates with selectivity for inhibition of CDK11 over CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK12, CDK13, CDK14, CDK15, CDK16, CDK17, CDK18, CDK19, and/or CDK20. Example 5. In Vivo Animal Testing [1618] The compounds described herein are tested for their ability to inhibit growth of human cells derived from various cancer types, including bladder (e.g., TCP-1020 cells), breast (e.g., MDA-MB-231 cells), melanoma (e.g., A375 cells), ovarian (e.g., A2780 cells), pancreas (e.g., PC-1 cells or Capan-2 cells), prostate (e.g., LNCaP, PC ₃ , or DU145 cells), glioblastoma (e.g., LN229, SNB19, U87, or U251 cells), leukemia (e.g., TCP-1020 cells), lymphoma (e.g., TCP- 1015 cells), colorectal (e.g., HCT116 cells), kidney (e.g., Caki-1 cells), or lung (e.g., A549 cells) cancer. Human tumor cells are transplanted, either under the skin or into the organ type in which the tumor originated, into immunocompromised mice (athymic nude mice, severely compromised immunodeficient (SCID) mice, or other immunocompromised mice) that do not reject human cells. Test mice are treated with test compound in vehicle at varying doses of the test compound, while control mice are treated with a vehicle control. Dosing is performed daily, and the test compound or vehicle is delivered either orally or by intraperitoneal injection. The compounds of the present disclosure are expected to cause inhibition of tumor growth as compared to control. Example 6. In Vitro CDK9 Inhibition Assay and CDK9/CDK11 Selectivity [1619] Compounds were assessed for their ability to inhibit CDK9 in vitro in a radiometric protein kinase assay ( ³³ PanQinase ^TM Activity Assay). CDK9 inhibition data was compared to CDK11 data (provided above) to assess CDK9/CDK11 selectivity. All kinase assays were performed in 96-well ScintiPlates ^TM from PerkinElmer (Boston, MA, USA) in a 50 ml reaction volume. The reaction cocktail was pipetted in four steps in the following order: 1) 25 μl of assay buffer (standard buffer/[g- ³³ P]-ATP); 2) 10 μl of ATP solution (in H ₂ O); 3) 5 μl of test compound (in 10 % DMSO); and 4) 10 μl of enzyme/substrate mixture. [1620] The assay for the protein kinase contained 70 mM HEPES-NaOH pH 7.5, 3 mM MgCl2, 3 mM MnCl2, 3 μM Na-orthovanadate, 1.2 mM DTT, 50 µg/ml PEG20000, ATP (variable concentrations, corresponding to the apparent ATP-K _m of the respective kinase, see table below), [g- ³³ P]-ATP (approx.1 x 10 ⁰⁶ cpm per well), protein kinase (variable amounts, see table below), and substrate (variable amounts, see table below). [1621] The following amounts of enzyme and substrate were used per well: [1622] The reaction cocktails were incubated at 30°C for 60 minutes. The reaction was stopped with 50 ml of 2 % (v/v) H ₃ PO ₄ , and plates were aspirated and washed two times with 200 ml0.9 % (w/v) NaCl. Incorporation of ³³ Pi was determined with a microplate scintillation counter (Microbeta, Wallac). [1623] CDK9 IC ₅₀ values are represented as either “A” (less than 50 nM), “B” (50 nM to 500 nM), and “C” (greater than 500 nM). Example 7. Solubility and Pharmacokinetics of Select Compounds [1624] The solubility and pharmacokinetic (PK) properties of select compounds were assessed. It was found that several compounds exhibit unexpectedly high solubility (in PBS, pH 7.4), typically ranging at the upper measurable range of the kinetic solubility assay (approximately 300 µM). Solubility was significantly improved as compared to the prior-developed compound OTS-964 (structure provided below; Yang, Y. et al. PBK/TOPK Inhibitor OTS964 Resistance is Mediated by ABCB1-Dependent Transport Function in Cancer: In Vitro and In Vivo Study. Mol. Cancer 21:40 (2022)), which was determined to have a solubility of 0.3 µM in PBS, pH 7.4. [1625] Compared to the prior-developed compound OTS-964, significantly increased concentration of free drug in plasma (area under the curve, AUC) was also observed for several compounds. Typically, 10-100-fold increased concentration of unbound drug as compared to OTS-964 after p.o. (oral) administration in mice was observed at the same dose of compound while maintaining biochemical and cellular potency (values are provided in the table below). [1626] For PK testing, mice were maintained in a controlled environment of the experimental animal room with a temperature of 19-25 °C, relative humidity of 30-70%, a light/dark cycle of ~12 hours, and 15-20 fresh air changes per hour. Mice were housed individually with enrichment throughout the experiment period in clean, sterilized polycarbonate rodent cages (Dimension; L 23.5 X B 16.0 X H 12.5 cubic centimeter) covered with stainless steel grid top mesh having provision for water bottles and feed. Autoclaved clean corn cob was used as a bedding material. The bedding material were analyzed for microbial and contaminant analysis as per routine analysis procedures of test facility. Mice were fed ad libitum with autoclaved pellet feed. Drinking water processed by reverse osmosis followed by autoclaving was provided ad libitum to all mice via water bottles. Mice were acclimatized for 3 days prior to initiation of experiment. [1627] To prepare compounds for administration, compounds were weighed into a 15 mL vial and dissolved in a mixture of solvents (e.g., 10% DMSO, 40% PEG300 or PEG400, 5% Tween- 80 or Cremophor, and 45% saline; or 10% HPBCD, 45% dextrose, and 45% water). The solutions were stirred until clear. For oral dosing, the selected mice were fasted for 4 to 6 hours, and feed was offered 2 hours post-dose. Mice used for intravenous dosing were not fasted. A 10 mg/kg dose was used for oral administration, and a 1 mg/ kg, 5 mg/kg, or 50 mg/kg dose was used for intravenous administration. In the oral route of administration, dose formulation was administered to mice by oral gavage using a 1 mL disposable syringe attached to 20 gauge oral gavage needle based on body weight. In intravenous route of administration, dose formulation was administered to mice by using 1 mL disposable syringe attached to 26G size needle. Blood was collected from all mice at different time points through retro orbital sinus in micro centrifuge tubes with EDTA as anticoagulant. For each mouse, approximately 200 µL of blood sample was collected. Blood was centrifuged at 4000 rpm for 10 minutes at 4 °C (± 2 °C) to obtain plasma. Plasma was separated with the help of micropipette and collected in pre-labeled vials. All samples were stored in deep freezer at -80º C until they are processed for extraction and analysis using LC-MS/MS.

REFERENCES 1. Malumbres, M. Cyclin-dependent kinases. Genome Biol.15, 122 (2014). 2. Asghar, U., Witkiewicz, A. K., Turner, N. C. & Knudsen, E. S. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat. Rev. Drug Discov.14, 130–146 (2015). 3. Nur Husna, S. M., Tan, H.-T. T., Mohamud, R., Dyhl-Polk, A. & Wong, K. K. Inhibitors targeting CDK4/6, PARP and PI3K in breast cancer: a review. Ther. Adv. Med. Oncol.10, 1758835918808509 (2018). 4. Loyer, P. & Trembley, J. H. Roles of CDK/Cyclin complexes in transcription and pre- mRNA splicing: Cyclins L and CDK11 at the cross-roads of cell cycle and regulation of gene expression. Semin. Cell Dev. Biol. (2020) doi:10.1016/j.semcdb.2020.04.016. 5. Hu, D., Mayeda, A., Trembley, J. H., Lahti, J. M. & Kidd, V. J. CDK11 complexes promote pre-mRNA splicing. J. Biol. Chem.278, 8623–8629 (2003). 6. Li, T., Inoue, A., Lahti, J. M. & Kidd, V. J. Failure To Proliferate and Mitotic Arrest of CDK11p110/p58-Null Mutant Mice at the Blastocyst Stage of Embryonic Cell Development. Mol. Cell. Biol.24, 3188–3197 (2004). 7. Hu, D., Valentine, M., Kidd, V. J. & Lahti, J. M. CDK11(p58) is required for the maintenance of sister chromatid cohesion. J. Cell Sci.120, 2424–2434 (2007). 8. Trembley, J. H. et al. PITSLRE p110 Protein Kinases Associate with Transcription Complexes and Affect Their Activity. J. Biol. Chem.277, 2589–2596 (2002). 9. Gajdušková, P. et al. CDK11 is required for transcription of replication-dependent histone genes. Nat. Struct. Mol. Biol.27, 500–510 (2020). 10. Dickinson, L. A., Edgar, A. J., Ehley, J. & Gottesfeld, J. M. Cyclin L Is an RS Domain Protein Involved in Pre-mRNA Splicing. J. Biol. Chem.277, 25465–25473 (2002). 11. Zhou, Y. et al. Cyclin-dependent kinase 11 p110 (CDK11 p110 ) is crucial for human breast cancer cell proliferation and growth. Sci. Rep.5, 10433 (2015). 12. Ahmed, R. L. et al. CDK11 Loss Induces Cell Cycle Dysfunction and Death of BRAF and NRAS Melanoma Cells. Pharmaceuticals 12, 50 (2019). 13. Zhou, Y., Shen, J. K., Hornicek, F. J., Kan, Q. & Duan, Z. The emerging roles and therapeutic potential of cyclin-dependent kinase 11 (CDK11) in human cancer. Oncotarget 7, 40846–40859 (2016). 14. Lin, A. et al. Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials. Sci. Transl. Med.11, eaaw8412 (2019). 15. Loyer, P. et al. Characterization of Cyclin L1 and L2 Interactions with CDK11 and Splicing Factors: Influence Of Cyclin L Isoforms On Splice Site Selection. J. Biol. Chem.283, 7721–7732 (2008). 16. Miura, G. Mistaken Identity. Nat. Chem. Biol.15(11):1029 (2019). 17. Yang, Y. et al. PBK/TOPK Inhibitor OTS964 Resistance is Mediated by ABCB1- Dependent Transport Function in Cancer: In Vitro and In Vivo Study. Mol. Cancer 21:40 (2022). 18. Yang, Y. et al. OTS964, a TOPK Inhibitor, Is Susceptible to ABCG2-Mediated Drug Resistance Front. Pharmacol.12:620874 (2021). EQUIVALENTS AND SCOPE [1628] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process. [1629] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub–range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. [1630] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art. [1631] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.