WO2025072437A1 - Heteroaryl compounds and their use in treating medical conditions - Google Patents

Abstract

The invention provides heteroaryl compounds, pharmaceutical compositions, and their use in the treatment of a disease or condition, such as a proliferative disorder, inflammatory disorder, autoimmune disorder, or metabolic disorder.

Description

HETEROARYL COMPOUNDS AND THEIR USE IN TREATING MEDICAL CONDITIONS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of and priority to United States Provisional Patent Application serial number 63/585,430, filed September 26, 2023, the contents of which are hereby incorporated by reference in their entirety. FIELD OF THE INVENTION [0002] The invention provides heteroaryl compounds, pharmaceutical compositions, and their use in the treatment of a disease or condition, such as a proliferative disorder, inflammatory disorder, autoimmune disorder, or metabolic disorder. BACKGROUND [0003] Cancer continues to be a significant health problem despite the substantial research efforts and scientific advances reported in the literature for treating this disease. Solid tumors, including prostate cancer, breast cancer, and lung cancer remain highly prevalent among the world population. Current treatment options for these cancers are not effective for all patients and/or can have substantial adverse side effects. Moreover, new therapies that achieve an anti- cancer effect through a different mechanism present an opportunity to treat cancers more effectively and/or to treat cancers that have become resistant to currently available medicines. [0004] Inflammatory disorders impact a substantial number of patients and often involve situations where the patient’s biological response to a stimulus results in the immune system attacking the body’s own cells or tissues. This can lead to abnormal inflammation and result in chronic pain, redness, swelling, stiffness, and/or damage to normal tissues. Current treatment options for these inflammatory disorders are not effective for all patients and/or can have substantial adverse side effects. [0005] Nicotinamide adenine dinucleotide (NAD+) is a cofactor that plays an important role in many physiologically essential processes, such as metabolism, energy production, DNA repair, and signaling. Nicotinamide phosphoribosyltransferase (NAmPRTase or NAMPT) is essential for the biosynthesis of NAD+. In mammals, the rate-limiting step in NAD+ biosynthesis is the salvage of NAM and conversion to nicotinamide mononucleotide (NMN) catalyzed by NAMPT. Thus, inhibition of NAMPT leads to depletion of NAD+ and a decrease in diseased cell proliferation and even diseased cell death. As a result, NAMPT inhibitors are useful for treating a variety of cancers, metabolic disorders, or inflammatory disorders. [0006] The need exists for new therapeutic methods and compounds for treating diseases or conditions associated with NAMPT activity. The present invention addresses the foregoing needs and provides other related advantages. SUMMARY [0007] The invention provides heteroaryl compounds, pharmaceutical compositions, and their use in the treatment of a disease or condition, such as a proliferative disorder, inflammatory disorder, autoimmune disorder, or metabolic disorder. In particular, one aspect of the invention provides a collection of heteroaryl compounds, such as a compound represented by Formula I: or a pharmaceutically acceptable salt thereof, where the variables are as defined in the detailed description. Further description of additional collections of heteroaryl compounds are described in the detailed description. The compounds may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier. [0008] Another aspect of the invention provides a collection of heteroaryl compounds, such as a compound represented by Formula I-1: (I-1) or a pharmaceutically acceptable salt thereof, where the variables are as defined in the detailed description. Further description of additional collections of heteroaryl compounds are described in the detailed description. The compounds may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier. [0009] Another aspect of the invention provides a method of treating a disease or condition mediated by NAMPT. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, I-1, I-A, I-B, I-C, or I-D, to treat the disease or condition, as further described in the detailed description. [0010] Another aspect of the invention provides a method of inhibiting the activity of NAMPT. The method comprises contacting a NAMPT with an effective amount of a compound described herein, such as a compound of Formula I, I-1, I-A, I-B, I-C, or I-D, to inhibit the activity of said NAMPT, as further described in the detailed description. DETAILED DESCRIPTION [0011] The invention provides heteroaryl compounds, pharmaceutical compositions, and their use in the treatment of a disease or condition, such as a proliferative disorder, inflammatory disorder, autoimmune disorder, or metabolic disorder. The practice of the present invention employs, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology. Such techniques are explained in the literature, such as in “Comprehensive Organic Synthesis” (B.M. Trost & I. Fleming, eds., 1991-1992); “Handbook of experimental immunology” (D.M. Weir & C.C. Blackwell, eds.); “Current protocols in molecular biology” (F.M. Ausubel et al., eds., 1987, and periodic updates); and “Current protocols in immunology” (J.E. Coligan et al., eds., 1991), each of which is herein incorporated by reference in its entirety. [0012] Various aspects of the invention are set forth below in sections; however, aspects of the invention described in one particular section are not to be limited to any particular section. Further, when a variable is not accompanied by a definition, the previous definition of the variable controls. Definitions [0013] Compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence, the definition of “alkyl” applies to “alkyl” as well as the “alkyl” portions of “-O-alkyl” etc. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5^th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference. [0014] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “cycloaliphatic”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. [0015] As used herein, the term “bicyclic ring” or “bicyclic ring system” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term “heterobicyclic” is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include: [0016] Exemplary bridged bicyclics include:

. [0017] The term “lower alkyl” refers to a C1-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. [0018] The term “lower haloalkyl” refers to a C_1-4 straight or branched alkyl group that is substituted with one or more halogen atoms. [0019] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as in N-substituted pyrrolidinyl)). [0020] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation. [0021] As used herein, the term “bivalent C1-8 (or C1-6) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein. [0022] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., –(CH₂)_n–, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. [0023] The term “-(C₀ alkylene)-“ refers to a bond. Accordingly, the term “-(C_0-3 alkylene)-” encompasses a bond (i.e., C0) and a -(C1-3 alkylene)- group. [0024] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. [0025] The term “halogen” means F, Cl, Br, or I. [0026] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. The term “phenylene” refers to a multivalent phenyl group having the appropriate number of open valences to account for groups attached to it. For example, “phenylene” is a bivalent phenyl group when it has two groups attached to it (e.g., “phenylene” is a trivalent phenyl group when it has three groups attached to it (e.g. . The term “arylene” refers to a bivalent aryl group. [0027] The terms “heteroaryl” and “heteroar–,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ^ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where unless otherwise specified, the radical or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. A heteroaryl group may be mono– or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted. [0028] The term “heteroarylene” refers to a multivalent heteroaryl group having the appropriate number of open valences to account for groups attached to it. For example, “heteroarylene” is a bivalent heteroaryl group when it has two groups attached to it; “heteroarylene” is a trivalent heteroaryl group when it has three groups attached to it. [0029] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclic or 7–10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4–dihydro– 2H–pyrrolyl), NH (as in pyrrolidinyl), or ⁺NR (as in N–substituted pyrrolidinyl). [0030] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6- azaspiro[3.3]heptane, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono– or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted. The term “oxo-heterocyclyl” refers to a heterocyclyl substituted by one or more oxo group. The term “heterocyclylene” refers to a multivalent heterocyclyl group having the appropriate number of open valences to account for groups attached to it. For example, “heterocyclylene” is a bivalent heterocyclyl group when it has two groups attached to it; “heterocyclylene” is a trivalent heterocyclyl group when it has three groups attached to it. The term “oxo-heterocyclylene” refers to a multivalent oxo-heterocyclyl group having the appropriate number of open valences to account for groups attached to it. [0031] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined. [0032] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. [0033] Each optional substituent on a substitutable carbon is a monovalent substituent independently selected from halogen; –(CH₂)_0–4R ^; –(CH₂)_0–4OR ^; -O(CH₂)_0-4R^o, –O–(CH₂)_{0– 4}C(O)OR°; –(CH₂)_0–4CH(OR ^)₂; –(CH₂)_0–4SR ^; –(CH₂)_0–4Ph, which may be substituted with R°; –(CH₂)_0–4O(CH₂)_0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH₂)_0–4O(CH₂)_0–1-pyridyl which may be substituted with R°; –NO₂; –CN; – N3; -(CH2)0–4N(R ^)2; –(CH2)0–4N(R ^)C(O)R ^; –N(R ^)C(S)R ^; –(CH2)0–4N(R ^)C(O)NR ^2; -N(R ^)C(S)NR ^₂; –(CH₂)_0–4N(R ^)C(O)OR ^; –N(R ^)N(R ^)C(O)R ^; -N(R ^)N(R ^)C(O)NR ^₂; -N(R ^)N(R ^)C(O)OR ^; –(CH₂)_0–4C(O)R ^; –C(S)R ^; –(CH₂)_0–4C(O)OR ^; –(CH₂)_0–4C(O)SR ^; -(CH₂)_0–4C(O)OSiR ^₃; –(CH₂)_0–4OC(O)R ^; –OC(O)(CH₂)_0–4SR–, SC(S)SR°; –(CH₂)_0–4SC(O)R ^; –(CH₂)_0–4C(O)NR ^₂; –C(S)NR ^₂; –C(S)SR°; –SC(S)SR°, -(CH₂)_0–4OC(O)NR ^₂; -C(O)N(OR ^)R ^; –C(O)C(O)R ^; –C(O)CH₂C(O)R ^; –C(NOR ^)R ^; -(CH₂)_0–4SSR ^; –(CH₂)_{0– 4}S(O)₂R ^; –(CH₂)_0–4S(O)₂OR ^; –(CH₂)_0–4OS(O)₂R ^; –S(O)₂NR ^₂; –S(O)(NR ^)R ^; – S(O)₂N=C(NR ^₂)₂; -(CH₂)_0–4S(O)R ^; -N(R ^)S(O)₂NR ^₂; –N(R ^)S(O)₂R ^; –N(OR ^)R ^; – C(NH)NR ^₂; –P(O)₂R ^; -P(O)R ^₂; -OP(O)R ^₂; –OP(O)(OR ^)₂; SiR ^₃; –(C_1–4 straight or branched alkylene)O–N(R ^)2; or –(C1–4 straight or branched alkylene)C(O)O–N(R ^)2. [0034] Each R ^ is independently hydrogen, C1–6 aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2-(5-6 membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ^, taken together with their intervening atom(s), form a 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted by a divalent substituent on a saturated carbon atom of R ^ selected from =O and =S; or each R ^ is optionally substituted with a monovalent substituent independently selected from halogen, –(CH2)0–2R ^{^}, –(haloR ^{^}), –(CH2)0–2OH, –(CH2)0–2OR ^{^}, – (CH₂)_0–2CH(OR ^{^})₂; -O(haloR ^{^}), –CN, –N₃, –(CH₂)_0–2C(O)R ^{^}, –(CH₂)_0–2C(O)OH, –(CH₂)_{0– 2}C(O)OR ^{^}, –(CH₂)_0–2SR ^{^}, –(CH₂)_0–2SH, –(CH₂)_0–2NH₂, –(CH₂)_0–2NHR ^{^}, –(CH₂)_0–2NR ^{^} ₂, –NO₂, –SiR ^{^}3, –OSiR ^{^}3, -C(O)SR ^{^}, –(C1–4 straight or branched alkylene)C(O)OR ^{^}, or –SSR ^{^}. [0035] Each R ^{^} is independently selected from C_1–4 aliphatic, –CH₂Ph, –O(CH₂)_0–1Ph, or a 5– 6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ^{^} is unsubstituted or where preceded by halo is substituted only with one or more halogens; or wherein an optional substituent on a saturated carbon is a divalent substituent independently selected from =O, =S, =NNR^*2, =NNHC(O)R^*, =NNHC(O)OR^*, =NNHS(O)2R^*, =NR^*, =NOR^*, –O(C(R^*2))2–3O–, or – S(C(R^*2))2–3S–, or a divalent substituent bound to vicinal substitutable carbons of an “optionally substituted” group is –O(CR^* ₂)_2–3O–, wherein each independent occurrence of R^* is selected from hydrogen, C_1–6 aliphatic or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0036] When R^* is C1–6 aliphatic, R^* is optionally substituted with halogen, – R ^{^}, -(haloR ^{^}), -OH, –OR ^{^}, –O(haloR ^{^}), –CN, –C(O)OH, –C(O)OR ^{^}, –NH₂, –NHR ^{^}, –NR ^{^} ₂, or –NO2, wherein each R ^{^} is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ^{^} is unsubstituted or where preceded by halo is substituted only with one or more halogens. [0037] An optional substituent on a substitutable nitrogen is independently –R^†, –NR^†2, – C(O)R^†, –C(O)OR^†, –C(O)C(O)R^†, –C(O)CH₂C(O)R^†, -S(O)₂R^†, -S(O)₂NR^† ₂, –C(S)NR^† ₂, – C(NH)NR^† ₂, or –N(R^†)S(O)₂R^†; wherein each R^† is independently hydrogen, C_1–6 aliphatic, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, two independent occurrences of R^†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein when R^† is C_1–6 aliphatic, R^† is optionally substituted with halogen, –R ^{^}, -(haloR ^{^}), -OH, –OR ^{^}, – O(haloR ^{^}), –CN, –C(O)OH, –C(O)OR ^{^}, –NH2, –NHR ^{^}, –NR ^{^}2, or –NO2, wherein each R ^{^} is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ^{^} is unsubstituted or where preceded by halo is substituted only with one or more halogens. [0038] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. 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 used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like. [0039] Further, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference. [0040] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N⁺(C1–4alkyl)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, loweralkyl sulfonate and aryl sulfonate. [0041] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. The invention includes compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention. [0042] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Alternatively, a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis. Still further, where the molecule contains a basic functional group (such as amino) or an acidic functional group (such as carboxylic acid) diastereomeric salts are formed with an appropriate optically- active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure enantiomers. [0043] Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. Chiral center(s) in a compound of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. Further, to the extent a compound described herein may exist as an atropisomer (e.g., substituted biaryls), all forms of such atropisomer are considered part of this invention. [0044] Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. If a chemical compound is referred to using both a chemical structure and a chemical name, and an ambiguity exists between the structure and the name, the structure predominates. It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences. [0045] The terms “a” and “an” as used herein mean “one or more” and include the plural unless the context is inappropriate. [0046] The term “alkyl” refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C1-C12 alkyl, C₁-C₁₀ alkyl, and C₁-C₆ alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3- methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1- butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc. [0047] The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as “C3-C6 cycloalkyl,” derived from a cycloalkane. Exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl. The term “cycloalkylene” refers to a bivalent cycloalkyl group. [0048] The term “haloalkyl” refers to an alkyl group that is substituted with at least one halogen. Exemplary haloalkyl groups include -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, and the like. The term “haloalkylene” refers to a bivalent haloalkyl group. [0049] The term “hydroxyalkyl” refers to an alkyl group that is substituted with at least one hydroxyl. Exemplary hydroxyalkyl groups include -CH2CH2OH, -C(H)(OH)CH3, -CH2C(H)(OH)CH2CH2OH, and the like. [0050] The terms “alkenyl” and “alkynyl” are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively. [0051] The terms “alkoxyl” or “alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. The term “haloalkoxyl” refers to an alkoxyl group that is substituted with at least one halogen. Exemplary haloalkoxyl groups include -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -OCF2CF3, and the like. [0052] The term “oxo” is art-recognized and refers to a “=O” substituent. For example, a cyclopentane susbstituted with an oxo group is cyclopentanone. [0053] The symbol “ ” indicates a point of attachment. [0054] When any substituent or variable occurs more than one time in any constituent or the compound of the invention, its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise indicated. [0055] One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H2O. [0056] As used herein, the terms “subject” and “patient” are used interchangeable and refer to organisms to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably includes humans. [0057] The term “IC50” is art-recognized and refers to the concentration of a compound that is required to achieve 50% inhibition of the target. [0058] As used herein, the term “effective amount” refers to the amount of a compound sufficient to effect beneficial or desired results (e.g., a therapeutic, ameliorative, inhibitory or preventative result). An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. As used herein, the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof. [0059] As used herein, the term “pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo. [0060] As used herein, the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil/water or water/oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see e.g., Martin, Remington’s Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA [1975]. [0061] For therapeutic use, salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. [0062] In addition, when a compound of the invention contains both a basic moiety (such as, but not limited to, a pyridine or imidazole) and an acidic moiety (such as, but not limited to, a carboxylic acid) zwitterions (“inner salts”) may be formed. Such acidic and basic salts used within the scope of the invention are pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts. Such salts of the compounds of the invention may be formed, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization. [0063] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps. [0064] As a general matter, compositions specifying a percentage are by weight unless otherwise specified. I. Heteroaryl Compounds [0065] One aspect of the invention provides heteroaryl compounds. The compounds may be used in the pharmaceutical compositions and therapeutic methods described herein. Exemplary compounds are described in the following sections, along with exemplary procedures for making the compounds. [0066] One aspect of the invention provides a compound represented by Formula I: or a pharmaceutically acceptable salt thereof; wherein: A¹ is substituted with p occurrences of R², wherein B¹ is a 6-membered aryl ring or a 5-6 membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur; A² is a 4-8 membered saturated or partially unsaturated heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, a 5-8 membered saturated bicyclic carbocyclylene, or a covalent bond, wherein the heterocyclylene, monocyclic carbocyclylene, and bicyclic carbocyclylene are substituted with 0 or 1 occurrences of R³; A³ is phenylene substituted with 0 or 1 occurrences of R³; R^1A, R^1B, and R^1C each represent independently for each occurrence hydrogen or C1-4 alkyl; R² represents independently for each occurrence halo, C_1-4 haloalkyl, C_1-4 alkoxyl, C_1-4 alkyl, or C1-4 hydroxyalkyl; R³ represents independently for each occurrence halo or C_1-4 alkyl; Z is one of the following: a) -C(O)R⁴, -C(O)-(C1-4 alkylene)-R⁴, -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl), - C(O)-(C_1-4 alkylene)-N(R^1A)-S(O)₂-(C_1-4 alkyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)- R⁴, -C(O)-(C1-4 alkylene)-O-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]y- (C1-6 alkoxyl), -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R⁹), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or -C(O)-(C3-7 cycloalkyl substituted with one -N(R^1A)-S(O)2-(C1-6 alkyl) or -N(R^1A)-C(O)-(C1-6 alkyl)); b) -C(O)-N(R^1A)-(C_1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R^1A)(R^1B), -C(O)-N(R^1A)-(C_1-6 alkyl), -C(O)-N(R^1A)-(C_1-4 haloalkyl), -C(O)- N(R^1A)-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl), -C(O)-N(R^1B)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]x-(C1-6 alkoxyl), -C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), - C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1A)(R^1B), -C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-C(O)-O-(C1-6 alkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-6 hydroxyalkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1B)-S(O)₂-R⁶, -C(O)-N(R^1A)-(C_1-4 alkylene)- N(R^1B)-S(O)2-(C1-4 alkyl), -C(O)-N(R^1A)-(C0-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R^1A)-(C1-4 alkylene)-(C3-7 cycloalkyl), or -C(O)-N(R^1A)- S(O)₂-R⁷; c) -C(O)-C(O)-N(R^1A)-R⁵, -C(O)-C(O)-N(R^1A)(R^1B), -C(O)-C(O)-N(R^1A)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl),-C(O)-C(O)-N(R^1A)-S(O)2-(C1-6 alkyl), -C(O)- C(O)-N(R^1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-C(O)-R⁴, -C(O)-C(O)-OH, -C(O)-OH, -C(O)-O-(C_1-6 alkyl), -C(O)-O-(C_1-4 alkylene)-O-(C1-4 alkylene)-N(R^1A)(R^1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R^1A)(R^1B))-(C1-4 hydroxyalkyl), or -C(O)-O-(C1-4 alkylene)-(5- membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R⁹); d) -N(R^1A)-C(O)-C(O)-N(R^1B)-(C_1-6 hydroxyalkyl), -N(R^1A)-C(O)-C(O)-N(R^1B)(R^1C), - N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-4 alkylene)-N(R^1C)-C(O)-(C1-4 alkyl), or -N(R^1A)- C(O)-C(O)-N(R^1B)-(C1-6 alkylene)-N(R^1C)-S(O)2-(C1-4 alkyl); e) -N(R^1A)-C(O)-N(R^1B)-(C_1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R^1A)-C(O)-N(R^1B)(R^1C), -N(R^1A)-C(O)-N(R^1B)-(C1-4 haloalkyl), -N(R^1A)-C(O)- N(R^1B)-[(C1-4 alkylene)-O-]x-R⁶, -N(R^1A)-C(O)-N(R^1B)-(C1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -N(R^1A)-C(O)-(morpholinyl), or -N(R^1A)- C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH); f) -N(R^1A)-C(O)-(C_1-6 hydroxyalkyl), -N(R^1A)-C(O)-(C_1-4 alkylene)-N(R^1B)-C(O)-(C_1-4 alkyl), -N(R^1A)-C(O)-(C_1-4 alkylene)-N(R^1B)-S(O)₂-(C_1-4 alkyl), -N(R^1A)-C(O)-(C_1-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -N(R^1A)-C(O)-O-[(C1-4 alkylene)- O-]x-R⁶, -N(R^1A)-C(O)-O-(C1-4 alkylene)-(phenyl), or -N(R^1A)-S(O)2-R⁷; g) -S(O)₂-(C_1-6 hydroxyalkyl), -S(O)₂-(C_1-6 alkyl), -S(O)₂-(C_1-4 alkylene)-(C_1-6 alkoxyl), -S(O)2-(C1-4 alkylene)-C(O)-O-(C1-6 alkyl), -S(O)2-[(C1-4 alkylene)-O-]x-R⁵, -S(O)2- (C3-7 cycloalkyl), -S(O)2-N(R^1A)-(C1-6 hydroxyalkyl), -S(O)2-N(R^1A)(R^1B), -S(O)2- N(R^1A)-C(O)-(C_1-6 alkyl), -S(O)₂-N(R^1A)-C(O)-O-(C_1-6 alkyl), or -S(O)₂-N(R^1A)- C(O)-N(R^1B)(R^1C); h) -(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-N(R^1A)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-N(R^1A)-C(O)-(C_1-6 hydroxyalkyl), -(C_1-4 alkylene)-C(O)-OH, or -(C_1-4 alkylene)-C(O)-O-(C_1-6 alkyl); i) a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R^1A; or j) hydrogen; R⁴ is C1-6 hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, a 5-7 membered di-oxo- heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl; R⁵ is C1-6 alkyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), C1-6 alkoxyl, -(C1-6 alkylene)-N(R^1A)(R^1B), or -(C_1-6 alkylene)-N(R^1A)-C(O)-O-(C_1-6 alkyl); R⁶ is C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, or -(C1-4 alkylene)-(C1-4 alkoxyl); R⁷ is C1-4 alkyl, C1-4 alkoxyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), -(C0-4 alkylene)-N(R^1A)(R^1B), -(C_0-6 alkylene)-N(R^1B)-C(O)-(C_1-4 alkyl), or -N(R^1B)-C(O)-O-R⁸; R⁸ is C1-4 alkyl or -(C0-4 alkylene)-(phenyl); R⁹ is oxo, C1-4 alkyl, hydroxyl, or -C(O)-O-(C1-4 alkyl); m and n are independently 1 or 2; p is 0, 1, 2, 3, or 4; x is 1, 2, 3, 4, or 5; and y and z are independently 1, 2, or 3; provided that when B¹ is a 6-membered aryl ring substituted with 0 or 1 occurrences of R², then Z is not -C(O)R⁴ or -C(O)-(C1-4 alkylene)-R⁴. [0067] The definitions of variables in Formula I above encompass multiple chemical groups. The application contemplates embodiments where, for example, (i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, (ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and (iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii). [0068] In certain embodiments, the compound is a compound of Formula I. [0069] As defined generally above, A¹ is substituted with p occurrences of R², wherein B¹ is a 6-membered aryl ring or a 5-6 membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur. [0070] In certain embodiments, A¹ is substituted with p occurrences of R², wherein B¹ is a 6-membered aryl ring or a 6-membered heteroaryl ring containing 1 or 2 heteroatoms that are nitrogen. [0071] In certain embodiments, A¹ is substituted with p occurrences of R², wherein B¹ is a 6-membered aryl ring. In certain embodiments, A¹ is substituted with p occurrences of R², wherein B¹ is a 5-6 membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur. In certain embodiments, A¹ is substituted with p occurrences of R², wherein B¹ is a 5-membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur. In certain embodiments, A¹ is substituted with p occurrences of R², wherein B¹ is a 6- membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur. [0072] In certain embodiments, A¹ is substituted with p occurrences of R², wherein B¹ is a 6-membered aryl ring or a 6-membered heteroaryl ring containing 1 or 2 heteroatoms that are nitrogen. In certain embodiments, A¹ is substituted with p occurrences of R², wherein B¹ is a 6-membered aryl ring or . In certain embodiments, A¹ substituted with p occurrences of R², wherein B¹ is a 6-membered heteroaryl ring containing 1 or 2 heteroatoms that are nitrogen. In certain embodiments, A¹ is substituted with p occurrences of R², wherein B¹ is a 6-membered heteroaryl ring containing 2 heteroatoms that are nitrogen. [0073] In certain embodiments, A¹ is substituted with p occurrences of R², substituted with 1, 2 or 3 occurrences of R², or substituted with 2, 3, or 4 occurrences of R². In certain embodiments, A¹ is substituted with p occurrences of R², or substituted with 2, 3, or 4 occurrences of R². In certain embodiments, A¹ is substituted with p occurrences of R² or substituted with 1, 2 or 3 occurrences of R². [0074] In certain embodiments, A¹ is substituted with 1, 2 or 3 occurrences of R², substituted with 1, 2 or 3 occurrences of R², or substituted with 2, 3, or 4 occurrences of R². In certain embodiments, A¹ is substituted with 1, 2, or 3 occurrences of R², or substituted with 2, 3, or 4 occurrences of R². In certain embodiments, A¹ is substituted with 1, 2 or 3 occurrences of R², substituted with 1, 2 or 3 occurrences of R². [0075] In certain embodiments, A¹ is substituted with 0 or 1 occurrences of R², substituted with 1 or 2 occurrences of R², or substituted with 1 or 2 occurrences of R². In certain embodiments, A¹ is substituted with 0 or 1 occurrence of R², or substituted with 1 or 2. [0076] In certain embodiments, , each of which is substituted with p occurrences of R². [0077] In certain embodiments, A¹ is substituted with p occurrences of R². In certain embodiments, substituted with 2, 3, or 4 occurrences of R². In certain embodiments, substituted with 1 or 2 occurrences of R². In certain embodiments, A¹ is substituted with 2 occurrences of R². In certain embodiments, A¹ substituted with 3 occurrences of R². In certain embodiments, A¹ is substituted with 4 occurrences of R². [0078] In certain embodiments, A¹ is substituted with p occurrences of R². In certain embodiments, A¹ is substituted with 1, 2, or 3 occurrences of R². In certain embodiments, substituted with 0 or 1 occurrence of R². In certain embodiments, A¹ is substituted with p occurrences of R². In certain embodiments, substituted with p occurrences of R². [0079] In certain embodiments, A¹ is substituted with p occurrences of R². In certain embodiments, A¹ is substituted with 1, 2 or 3 occurrences of R². In certain embodiments, A¹ is substituted with 1 or 2 occurrences of R². In certain embodiments, A¹ is substituted with 1 occurrence of R². [0080] In certain embodiments, A¹ is In certain emb ¹ odiments, A is [0081] In certain embodiments, A¹ is In certain embodiments, certain embodiments, A¹ is , , . In certain emb ¹ odiments, A is In certain embodiments, A¹ is [0082] In certain embodiments, certain embodiments, A¹ is In certain embodiments, A^{1 1} is In certain embodiments, A In certain embodiments, A¹ is In certain embodiments, [0083] In certain embodiments, A¹ is In certain embodiments, A 25 , , , , , [0084] In certain embodiments, A¹ is In certain e ¹ mbodiments, A is [0085] In certain embodiments, A¹ is . In certain embodiments, certain embodiments, A¹ is . In certain embodiments, A¹ is In certain embodiments, A¹ is 26 [0086] In certain embodiments, A¹ is . In certain embodiments, A¹ is In cer ^{1 1} tain embodiments, A is In certain embodiments, A is In certain embodiments ^{1 1} , A is In certain embodiments, A is In certain embodiments, A¹ is In certain ¹ embodiments, A is In certain embodiments, A¹ is ¹ In certain embodiments, A . In certain embodiments, A¹ is . In c ¹ ertain embodiments, A is In certain ^{1 1} embodiments, A is In certain embodiments, A is selected from the groups depicted in the compounds in Table 1, below. [0087] As defined generally above, A² is a 4-8 membered saturated or partially unsaturated heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, a 5-8 membered saturated bicyclic carbocyclylene, or a covalent bond; wherein the heterocyclylene, monocyclic carbocyclylene, and bicyclic carbocyclylene are substituted with 0 or 1 occurrences of R³. [0088] In certain embodiments, A² is a 6-membered saturated or partially unsaturated heterocyclylene containing 1 heteroatom that is nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, a 5-8 membered saturated bicyclic carbocyclylene, or a covalent bond; wherein the heterocyclylene, monocyclic carbocyclylene, and bicyclic carbocyclylene are substituted with 0 or 1 occurrences of R³. [0089] In certain embodiments, A² is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, or a 5-8 membered saturated bridged bicyclic carbocyclylene, each of which is substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, or a 5-8 membered saturated bridged bicyclic carbocyclylene. [0090] In certain embodiments, A² is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, wherein the heterocyclylene is substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is a 6- membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, wherein the heterocyclylene is substituted with 1 occurrence of R³. In certain embodiments, A² is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen. [0091] In certain embodiments, A² is a 6-membered saturated or partially unsaturated monocyclic carbocyclylene substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is a 6-membered saturated or partially unsaturated monocyclic carbocyclylene substituted with 1 occurrence of R³. In certain embodiments, A² is a 6-membered saturated or partially unsaturated monocyclic carbocyclylene. [0092] In some embodiments, A² is a 4-8 membered saturated or partially unsaturated heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen, wherein the heterocyclylene is substituted with 0 or 1 occurrences of R³. [0093] In some embodiments, A² is a 5-8 membered saturated bicyclic carbocyclylene substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is a 5-8 membered saturated bridged bicyclic carbocyclylene substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is a 5-8 membered saturated bridged bicyclic carbocyclylene substituted with 1 occurrence of R³. In certain embodiments, A² is a 5-8 membered saturated bridged bicyclic carbocyclylene. [0094] In certain embodiments, A² is a 5-8 membered saturated bridged bicyclic carbocyclylene or a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen, each of which is substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is a 5-8 membered saturated bridged bicyclic carbocyclylene or a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen. [0095] In certain embodiments, A² is a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen, wherein the bridged bicyclic heterocyclylene is substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen, wherein the bridged bicyclic heterocyclylene is substituted with 1 occurrence of R³. In certain embodiments, A² is a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen. [0096] In some embodiments, A² is a 4-6 membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from oxygen and nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, a 5-8 membered saturated bridged bicyclic carbocyclylene, each of which is substituted with 0 or 1 occurrences of R³; or A² is a covalent bond. [0097] In certain embodiments, A² is a 6-membered saturated or partially unsaturated heterocyclylene containing 1 heteroatom that is nitrogen, wherein the heterocyclylene is substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is a 5-8 membered saturated bicyclic carbocyclylene, wherein the bicyclic carbocyclylene is substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is a covalent bond. [0098] In certain embodiments, , each of which is substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is one of the following: , wherein the nitrogen atom is attached to Z; wherein the saturated carbon is attached to Z; or wherein A² is substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is one of the following: , wherein the nitrogen atom is attached to Z; ) o wherein the saturated carbon is attached to Z; or . [0099] In certain embodiments, A² is each of which is substituted with 0 or 1 occurrences of R³, wherein the nitrogen atom of A² is attached to Z. In certain embodiments, A² is ² wherein the nitrogen atom of A is attached to Z. In certain embodiments, A² is wherein the saturated carbon is attached to Z, wherein A² is substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is wherein the saturated carbon is attached to Z. In certain embodiments, A² is , each of which is substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is [0100] In certain embodiments, A² is substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is substituted with 0 or 1 occurrences of R³, wherein the nitrogen atom of A² is attached to Z. In certain embodiments, A² is substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is substituted with 0 or 1 occurrences of R³, wherein the nitrogen atom of A² is attached to Z. In certain embodiments, A² is substituted with 0 or 1 occurrences of R³, wherein the saturated carbon of A² is attached to Z. [0101] In certain embodiments, A² is . In certain embodiments, A² is . In certain embodiments, A² is . In certain embodiments, A² is , wherein the nitrogen atom of A² is attached to Z. In certain embodiments, A² is In certain embodiments, A² is . In certain embodiments, A² is . In certain embodiments, A² is , wherein the nitrogen atom of A² is attached to Z. In certain embodiments, A² is , wherein the saturated carbon of A² is attached to Z. [0102] In certain embodiments, A² is substituted with 0 occurrences of R³. In certain embodiments, A² is selected from the groups depicted in the compounds in Table 1, below. [0103] As defined generally above, A³ is phenylene substituted with 0 or 1 occurrences of R³. In some embodiments, A³ is para-phenylene substituted with 0 or 1 occurrences of R³. In some embodiments, A³ is phenylene. In some embodiments, A³ is para-phenylene. In certain embodiments, A³ is . In some embodiments, A³ is selected from the groups depicted in the compounds in Table 1, below. [0104] As defined generally above, R^1A, R^1B, and R^1C each represent independently for each occurrence hydrogen or C1-4 alkyl. In certain embodiments, R^1A, R^1B, and R^1C are hydrogen. In certain embodiments, R^1A and R^1B are both hydrogen. In certain embodiments, R^1A and R^1B are both methyl. In certain embodiments, R^1A is hydrogen. In certain embodiments, at least one instance of R^1A is hydrogen. In certain embodiments, each R^1A is independently C1-4 alkyl. In certain embodiments, R^1B is hydrogen. In certain embodiments, at least one instance of R^1B is hydrogen. In certain embodiments, each R^1B is independently C_1-4 alkyl. In certain embodiments, R^1C is hydrogen. In certain embodiments, at least one instance of R^1C is hydrogen. In certain embodiments, each R^1C is independently C1-4 alkyl. In certain embodiments, R^1A is selected from the groups depicted in the compounds in Table 1, below. In certain embodiments, R^1B is selected from the groups depicted in the compounds in Table 1, below. In certain embodiments, R^1C is selected from the groups depicted in the compounds in Table 1, below. [0105] As defined generally above, R² represents independently for each occurrence halo, C1- ₄ haloalkyl, C_1-4 alkoxyl, C_1-4 alkyl, or C_1-4 hydroxyalkyl. In certain embodiments, R² represents independently for each occurrence fluoro, chloro, -CF3, -OCH3, -CH3, or -CH2OH. In certain embodiments, R² represents independently for each occurrence halo. In certain embodiments, each R² is independently fluoro or chloro. In certain embodiments, R² is fluoro. In certain embodiments, R² is chloro. In certain embodiments, R² is selected from the groups depicted in the compounds in Table 1, below. [0106] As defined generally above, R³ represents independently for each occurrence halo or C1-4 alkyl. In certain embodiments, R³ represents independently for each occurrence halo. In certain embodiments, R³ represents independently for each occurrence C_1-4 alkyl. In certain embodiments, R³ is fluoro. In certain embodiments, R³ is chloro. In certain embodiments, R³ is methyl. In certain embodiments, R³ is selected from the groups depicted in the compounds in Table 1, below. [0107] As defined generally above, Z is one of the following: a) -C(O)R⁴, -C(O)-(C1-4 alkylene)-R⁴, -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-S(O)₂-(C_1-4 alkyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)- R⁴, -C(O)-(C1-4 alkylene)-O-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]y- (C1-6 alkoxyl), -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R⁹), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C_1-4 alkyl and one -OH), or -C(O)-(C_3-7 cycloalkyl substituted with one -N(R^1A)-S(O)2-(C1-6 alkyl) or -N(R^1A)-C(O)-(C1-6 alkyl)); b) -C(O)-N(R^1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R^1A)(R^1B), -C(O)-N(R^1A)-(C_1-6 alkyl), -C(O)-N(R^1A)-(C_1-4 haloalkyl), -C(O)- N(R^1A)-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl), -C(O)-N(R^1B)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]x-(C1-6 alkoxyl), -C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), -C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1A)(R^1B), -C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-C(O)-O-(C1-6 alkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-6 hydroxyalkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1B)-S(O)₂-R⁶, -C(O)-N(R^1A)-(C_1-4 alkylene)- N(R^1B)-S(O)₂-(C_1-4 alkyl), -C(O)-N(R^1A)-(C_0-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R^1A)-(C1-4 alkylene)-(C3-7 cycloalkyl), or -C(O)-N(R^1A)- S(O)2-R⁷; c) -C(O)-C(O)-N(R^1A)-R⁵, -C(O)-C(O)-N(R^1A)(R^1B), -C(O)-C(O)-N(R^1A)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl),-C(O)-C(O)-N(R^1A)-S(O)2-(C1-6 alkyl), -C(O)- C(O)-N(R^1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-C(O)-R⁴, -C(O)-C(O)-OH, -C(O)-OH, -C(O)-O-(C_1-6 alkyl), -C(O)-O-(C_1-4 alkylene)-O-(C1-4 alkylene)-N(R^1A)(R^1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R^1A)(R^1B))-(C1-4 hydroxyalkyl), or -C(O)-O-(C1-4 alkylene)-(5- membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R⁹); d) -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl), -N(R^1A)-C(O)-C(O)-N(R^1B)(R^1C), -N(R^1A)-C(O)-C(O)-N(R^1B)-(C_1-4 alkylene)-N(R^1C)-C(O)-(C_1-4 alkyl), or -N(R^1A)- C(O)-C(O)-N(R^1B)-(C1-6 alkylene)-N(R^1C)-S(O)2-(C1-4 alkyl); e) -N(R^1A)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R^1A)-C(O)-N(R^1B)(R^1C), -N(R^1A)-C(O)-N(R^1B)-(C_1-4 haloalkyl), -N(R^1A)-C(O)- N(R^1B)-[(C1-4 alkylene)-O-]x-R⁶, -N(R^1A)-C(O)-N(R^1B)-(C1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -N(R^1A)-C(O)-(morpholinyl), or -N(R^1A)- C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C_1-4 alkyl and one -OH); f) -N(R^1A)-C(O)-(C1-6 hydroxyalkyl), -N(R^1A)-C(O)-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), -N(R^1A)-C(O)-(C1-4 alkylene)-N(R^1B)-S(O)2-(C1-4 alkyl), -N(R^1A)-C(O)-(C1-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -N(R^1A)-C(O)-O-[(C_1-4 alkylene)- O-]x-R⁶, -N(R^1A)-C(O)-O-(C1-4 alkylene)-(phenyl), or -N(R^1A)-S(O)2-R⁷; g) -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-(C1-6 alkyl), -S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl), -S(O)₂-(C_1-4 alkylene)-C(O)-O-(C_1-6 alkyl), -S(O)₂-[(C_1-4 alkylene)-O-]_x-R⁵, -S(O)₂- (C3-7 cycloalkyl), -S(O)2-N(R^1A)-(C1-6 hydroxyalkyl), -S(O)2-N(R^1A)(R^1B), -S(O)2- N(R^1A)-C(O)-(C1-6 alkyl), -S(O)2-N(R^1A)-C(O)-O-(C1-6 alkyl), or -S(O)2-N(R^1A)- C(O)-N(R^1B)(R^1C); h) -(C_1-6 hydroxyalkyl), -(C_1-4 alkylene)-C(O)-N(R^1A)-(C_1-6 hydroxyalkyl), -(C_1-4 alkylene)-N(R^1A)-C(O)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-OH, or -(C1-4 alkylene)-C(O)-O-(C1-6 alkyl); i) a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R^1A; or j) hydrogen; provided that when B¹ is a 6-membered aryl ring substituted with 0 or 1 occurrences of R², then Z is not -C(O)R⁴ or -C(O)-(C1-4 alkylene)-R⁴. [0108] In certain embodiments, Z is one of the following: a) -C(O)R⁴, -C(O)-(C1-4 alkylene)-R⁴, -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl), - C(O)-(C1-4 alkylene)-N(R^1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)- R⁴, -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_3-8 cycloalkyl substituted with z occurrence of R⁹), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or -C(O)-(C3-7 cycloalkyl substituted with one - N(R^1A)-S(O)₂-(C_1-6 alkyl) or -N(R^1A)-C(O)-(C_1-6 alkyl)); b) -C(O)-N(R^1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R^1A)(R^1B), -C(O)-N(R^1A)-(C1-6 alkyl), -C(O)-N(R^1A)-(C1-4 haloalkyl), -C(O)- N(R^1A)-(C_1-4 alkylene)-O-(C_1-6 hydroxyalkyl), -C(O)-N(R^1B)-(C_1-4 alkylene)-[O-(C_1-4 alkylene)-]_x-(C_1-6 alkoxyl), -C(O)-N(R^1A)-(C_1-4 alkylene)-N(R^1B)-C(O)-(C_1-4 alkyl), - C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1A)(R^1B), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-C(O)-O-(C1-6 alkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1B)-C(O)-(C_1-6 hydroxyalkyl), -C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-S(O)2-R⁶, -C(O)-N(R^1A)-(C1-4 alkylene)- N(R^1B)-S(O)2-(C1-4 alkyl), -C(O)-N(R^1A)-(C0-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R^1A)-(C_1-4 alkylene)-(C_3-7 cycloalkyl), or -C(O)-N(R^1A)- S(O)2-R⁷; c) -C(O)-C(O)-N(R^1A)-R⁵, -C(O)-C(O)-N(R^1A)(R^1B), -C(O)-C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1A)-C(O)-(C_1-4 alkyl),-C(O)-C(O)-N(R^1A)-S(O)₂-(C_1-6 alkyl), -C(O)- C(O)-N(R^1A)-(C_1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-C(O)-R⁴, -C(O)-C(O)-OH, -C(O)-O-(C1-4 alkylene)-O-(C1-4 alkylene)- N(R^1A)(R^1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R^1A)(R^1B))- (C_1-4 hydroxyalkyl), or -C(O)-O-(C_1-4 alkylene)-(5-membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R⁹); d) -N(R^1A)-C(O)-C(O)-N(R^1B)-(C_1-6 hydroxyalkyl), -N(R^1A)-C(O)-C(O)-N(R^1B)(R^1C), - N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-4 alkylene)-N(R^1C)-C(O)-(C1-4 alkyl), or -N(R^1A)- C(O)-C(O)-N(R^1B)-(C1-6 alkylene)-N(R^1C)-S(O)2-(C1-4 alkyl); e) -N(R^1A)-C(O)-N(R^1B)-(C_1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R^1A)-C(O)-N(R^1B)(R^1C), -N(R^1A)-C(O)-N(R^1B)-(C1-4 haloalkyl), -N(R^1A)-C(O)- N(R^1B)-[(C1-4 alkylene)-O-]x-R⁶, -N(R^1A)-C(O)-N(R^1B)-(C1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -N(R^1A)-C(O)-(morpholinyl), or -N(R^1A)- C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH); f) -N(R^1A)-C(O)-(C_1-4 alkylene)-N(R^1B)-C(O)-(C_1-4 alkyl), -N(R^1A)-C(O)-(C_1-4 alkylene)-N(R^1B)-S(O)2-(C1-4 alkyl), -N(R^1A)-C(O)-O-[(C1-4 alkylene)-O-]x-R⁶, or -N(R^1A)-S(O)2-R⁷; g) -S(O)₂-(C_1-6 hydroxyalkyl), -S(O)₂-(C_1-4 alkylene)-(C_1-6 alkoxyl), -S(O)₂-(C_1-4 alkylene)-C(O)-O-(C_1-6 alkyl), -S(O)₂-[(C_1-4 alkylene)-O-]_x-R⁵, -S(O)₂-N(R^1A)-(C_1-6 hydroxyalkyl), -S(O)2-N(R^1A)(R^1B), -S(O)2-N(R^1A)-C(O)-(C1-6 alkyl), -S(O)2-N(R^1A)- C(O)-O-(C1-6 alkyl), or -S(O)2-N(R^1A)-C(O)-N(R^1B)(R^1C); h) -(C_1-6 hydroxyalkyl), -(C_1-4 alkylene)-C(O)-N(R^1A)-(C_1-6 hydroxyalkyl), -(C_1-4 alkylene)-N(R^1A)-C(O)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-OH, or -(C1-4 alkylene)-C(O)-O-(C1-6 alkyl); or i) a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R^1A; provided that when B¹ is a 6-membered aryl ring substituted with 0 or 1 occurrences of R², or B¹ is substituted with 0 occurrences of R², then Z is not -C(O)R⁴ or -C(O)-(C1-4 alkylene)- R⁴. [0109] In certain embodiments, Z is one of the following: a) -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-S(O)2- (C_1-4 alkyl), -C(O)-(C_1-4 alkylene)-O-(C_1-4 alkyl), or -C(O)-(C_1-4 alkylene)-[O-(C_1-4 alkylene)-]y-(C1-6 alkoxyl); b) -C(O)-N(R^1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R^1A)(R^1B), -C(O)-N(R^1A)-(C_1-6 alkyl), -C(O)-N(R^1A)-(C_1-4 haloalkyl), -C(O)- N(R^1A)-(C_1-4 alkylene)-O-(C_1-6 hydroxyalkyl), -C(O)-N(R^1B)-(C_1-4 alkylene)-[O-(C_1-4 alkylene)-]x-(C1-6 alkoxyl), -C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1A)(R^1B), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1B)-C(O)-O-(C_1-6 alkyl), -C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-6 hydroxyalkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-S(O)2-R⁶, or -C(O)-N(R^1A)-(C1-4 alkylene)- N(R^1B)-S(O)₂-(C_1-4 alkyl); c) -C(O)-C(O)-N(R^1A)-R⁵, -C(O)-C(O)-N(R^1A)(R^1B), -C(O)-C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl),-C(O)-C(O)-N(R^1A)-S(O)2-(C1-6 alkyl), -C(O)- C(O)-OH, -C(O)-OH, -C(O)-O-(C_1-6 alkyl), -C(O)-O-(C_1-4 alkylene)-O-(C_1-4 alkylene)-N(R^1A)(R^1B), or -C(O)-O-(C_1-4 alkylene substituted with 1 occurrence of - N(R^1A)(R^1B))-(C1-4 hydroxyalkyl); d) -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl), -N(R^1A)-C(O)-C(O)-N(R^1B)(R^1C), -N(R^1A)-C(O)-C(O)-N(R^1B)-(C_1-4 alkylene)-N(R^1C)-C(O)-(C_1-4 alkyl), or -N(R^1A)- C(O)-C(O)-N(R^1B)-(C1-6 alkylene)-N(R^1C)-S(O)2-(C1-4 alkyl); e) -N(R^1A)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R^1A)-C(O)-N(R^1B)(R^1C), -N(R^1A)-C(O)-N(R^1B)-(C_1-4 haloalkyl), or -N(R^1A)-C(O)- N(R^1B)-[(C1-4 alkylene)-O-]x-R⁶; f) -N(R^1A)-C(O)-(C1-6 hydroxyalkyl), -N(R^1A)-C(O)-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), -N(R^1A)-C(O)-(C_1-4 alkylene)-N(R^1B)-S(O)₂-(C_1-4 alkyl), or -N(R^1A)-C(O)-O- [(C_1-4 alkylene)-O-]_x-R⁶; g) -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-(C1-6 alkyl), -S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl), -S(O)2-(C1-4 alkylene)-C(O)-O-(C1-6 alkyl), -S(O)2-[(C1-4 alkylene)-O-]x-R⁵, -S(O)2- N(R^1A)-(C_1-6 hydroxyalkyl), -S(O)₂-N(R^1A)(R^1B), -S(O)₂-N(R^1A)-C(O)-(C_1-6 alkyl), - S(O)2-N(R^1A)-C(O)-O-(C1-6 alkyl), or -S(O)2-N(R^1A)-C(O)-N(R^1B)(R^1C); h) -(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-N(R^1A)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-N(R^1A)-C(O)-(C_1-6 hydroxyalkyl), -(C_1-4 alkylene)-C(O)-OH, or -(C_1-4 alkylene)-C(O)-O-(C1-6 alkyl); or i) hydrogen. [0110] In certain embodiments, Z is one of the following: a) -C(O)-(C1-6 hydroxyalkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)- R⁴, -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_3-8 cycloalkyl substituted with z occurrence of R⁹), or -C(O)-(C3-7 cycloalkyl substituted with one -N(R^1A)-S(O)2-(C1-6 alkyl) or - N(R^1A)-C(O)-(C1-6 alkyl)); b) -C(O)-N(R^1A)-(C_1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R^1A)(R^1B), -C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), or -C(O)- N(R^1A)-(C1-4 alkylene)-N(R^1B)-S(O)2-(C1-4 alkyl); c) -C(O)-C(O)-N(R^1A)-(C_1-6 hydroxyalkyl), -C(O)-C(O)-N(R^1A)-(C_1-4 alkylene)-N(R^1A)- C(O)-(C_1-4 alkyl), -C(O)-C(O)-N(R^1A)-S(O)₂-(C_1-6 alkyl), or -C(O)-C(O)-(C_1-6 hydroxyalkyl); d) -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl), -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-4 alkylene)-N(R^1C)-C(O)-(C_1-4 alkyl), or -N(R^1A)-C(O)-C(O)-N(R^1B)-(C_1-6 alkylene)- N(R^1C)-S(O)2-(C1-4 alkyl); e) -N(R^1A)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo); f) -N(R^1A)-C(O)-(C_1-4 alkylene)-N(R^1B)-C(O)-(C_1-4 alkyl), -N(R^1A)-C(O)-(C_1-4 alkylene)-N(R^1B)-S(O)2-(C1-4 alkyl), or -N(R^1A)-S(O)2-R⁷; g) -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-N(R^1A)-(C1-6 hydroxyalkyl), -S(O)2-N(R^1A)-C(O)- (C_1-6 alkyl), or -S(O)₂-N(R^1A)-C(O)-O-(C_1-6 alkyl); or h) a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R^1A. In certain embodiments, Z is selected from the groups above, provided that when B¹ is a 6- membered aryl ring substituted with 0 or 1 occurrences of R², then Z is not -C(O)-(C_1-6 hydroxyalkyl). In certain embodiments, Z is selected from the groups above, provided that when B¹ is a 6-membered aryl ring substituted with 0 or 1 occurrences of R², or B¹ is substituted with 0 occurrences of R², then Z is not -C(O)-(C_1-6 hydroxyalkyl). [0111] In some embodiments, Z is -C(O)R⁴, -C(O)-(C_1-4 alkylene)-R⁴, -C(O)-OH, -C(O)-O- (C1-6 alkyl), -C(O)-N(R^1A)(R^1B), -C(O)-O-(C1-4 alkylene)-O-(C1-4 alkylene)-N(R^1A)(R^1B), -C(O)- O-(C1-4 alkylene substituted with 1 occurrence of -N(R^1A)(R^1B))-(C1-4 hydroxyalkyl), -S(O)2-(C1- ₆ alkyl), -S(O)₂-(C_3-7 cycloalkyl), -S(O)₂-N(R^1A)(R^1B), -S(O)₂-N(R^1A)-C(O)-(C_1-6 alkyl), -S(O)₂- N(R^1A)-C(O)-O-(C1-6 alkyl), -S(O)2-N(R^1A)-C(O)-N(R^1B)(R^1C), -S(O)2-[(C1-4 alkylene)-O-]x-R⁵, - N(R^1A)-C(O)-(C1-4 alkylene)-(5-6 membered saturated heterocyclyl containing 1 oxygen atom), - N(R^1A)-C(O)-O-(C_1-4 alkylene)-(phenyl), -N(R^1A)-C(O)-O-[(C_1-4 alkylene)-O-]_x-R⁶, -N(R^1A)- C(O)-N(R^1B)-[(C1-4 alkylene)-O-]x-R⁶, -C(O)-N(R^1A)-(C1-6 hydroxyalkyl), -C(O)-N(R^1A)-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)- N(R^1A)(R^1B), -N(R^1A)-C(O)-N(R^1B)-[(C_1-6 hydroxyalkyl), -C(O)-(C_1-4 alkylene)-[O-(C_1-4 alkylene)-]_y-(C_1-6 alkoxyl), -C(O)N(R^1B)-(C_1-4 alkylene)-[O-(C_1-4 alkylene)-]_y-(C_1-6 alkoxyl), - C(O)-C(O)-OH, -C(O)-C(O)-N(R^1A)(R^1B), -N(R^1A)-C(O)-(C1-6 hydroxyalkyl), -C(O)-C(O)- N(R^1A)-R⁵, -N(R^1A)-C(O)-C(O)-N(R^1B)(R^1C), -C(O)-N(R^1A)-S(O)2-R⁷, -N(R^1A)-S(O)2-R⁷, -C(O)- C(O)-N(R^1A)-S(O)₂-(C_1-6 alkyl), -S(O)₂-(C_1-4 alkylene)-(C_1-6 alkoxyl), -C(O)-C(O)-N(R^1A)-(C_1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-O-(C1-4 alkylene)-(5 membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R⁹), or hydrogen; provided that when B¹ is a 6- membered aryl ring substituted with 0 or 1 occurrences of R², then Z is not -C(O)R⁴ or -C(O)- (C1-4 alkylene)-R⁴. [0112] In some embodiments, Z is -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_3-7 cycloalkyl substituted with z occurrence of R⁹), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), -C(O)-(C3-7 cycloalkyl substituted with one -N(R^1A)-S(O)2-(C1-6 alkyl) or -N(R^1A)-C(O)-(C1-6 alkyl)), -C(O)-N(R^1A)-(C0-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R^1A)-(C_1-4 alkylene)-(C_3-7 cycloalkyl), -C(O)- C(O)-N(R^1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-O- (C1-4 alkylene)-(5-membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R⁹), -N(R^1A)-C(O)-N(R^1B)- (C1-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -N(R^1A)-C(O)-(C1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -N(R^1A)-C(O)-(morpholinyl), -N(R^1A)-C(O)- (azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C_1-4 alkyl and one - OH), -S(O)₂-(C_3-7 cycloalkyl), or a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R^1A. [0113] In some embodiments, Z is -C(O)R⁴, -C(O)-(C1-4 alkylene)-R⁴, -C(O)-(C1-4 alkylene)- N(R^1A)-C(O)-(C_1-4 alkyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-S(O)₂-(C_1-4 alkyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-R⁴, -C(O)-(C1-4 alkylene)-O-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]y-(C1-6 alkoxyl), -C(O)-N(R^1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-N(R^1A)(R^1B), -C(O)-N(R^1A)-(C_1-6 alkyl), -C(O)-N(R^1A)-(C_1-4 haloalkyl), -C(O)- N(R^1A)-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl), -C(O)-N(R^1B)-(C1-4 alkylene)-[O-(C1-4 alkylene)- ]x-(C1-6 alkoxyl), -C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1A)(R^1B), -C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]_x-(C_1-4 alkylene)- N(R^1B)-C(O)-O-(C_1-6 alkyl), -C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1B)-C(O)- (C1-6 hydroxyalkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-S(O)2-R⁶, -C(O)- N(R^1A)-(C1-4 alkylene)-N(R^1B)-S(O)2-(C1-4 alkyl), -C(O)-N(R^1A)-S(O)2-R⁷, -C(O)-C(O)- N(R^1A)(R^1B), -C(O)-C(O)-N(R^1A)-R⁵, -C(O)-C(O)-N(R^1A)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_1-4 alkyl),-C(O)-C(O)-N(R^1A)-S(O)2-(C1-6 alkyl), -C(O)-C(O)-R⁴, -C(O)-C(O)-OH, -C(O)-OH, - C(O)-O-(C1-6 alkyl), -C(O)-O-(C1-4 alkylene)-O-(C1-4 alkylene)-N(R^1A)(R^1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R^1A)(R^1B))-(C_1-4 hydroxyalkyl), -N(R^1A)-C(O)- C(O)-N(R^1B)-(C1-6 hydroxyalkyl), -N(R^1A)-C(O)-C(O)-N(R^1B)(R^1C), -N(R^1A)-C(O)-C(O)- N(R^1B)-(C1-4 alkylene)-N(R^1C)-C(O)-(C1-4 alkyl), -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-6 alkylene)- N(R^1C)-S(O)₂-(C_1-4 alkyl), -N(R^1A)-C(O)-N(R^1B)-(C_1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R^1A)-C(O)-N(R^1B)(R^1C), -N(R^1A)-C(O)-N(R^1B)-(C_1-4 haloalkyl), -N(R^1A)- C(O)-N(R^1B)-[(C1-4 alkylene)-O-]x-R⁶, -N(R^1A)-C(O)-O-[(C1-4 alkylene)-O-]x-R⁶, -N(R^1A)-C(O)- O-(C1-4 alkylene)-(phenyl), -N(R^1A)-C(O)-(C1-6 hydroxyalkyl), -N(R^1A)-C(O)-(C1-4 alkylene)- N(R^1B)-C(O)-(C_1-4 alkyl), -N(R^1A)-C(O)-(C_1-4 alkylene)-N(R^1B)-S(O)₂-(C_1-4 alkyl), -N(R^1A)- S(O)2-R⁷, -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-(C1-6 alkyl), -S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl), - S(O)2-(C1-4 alkylene)-C(O)-O-(C1-6 alkyl), -S(O)2-[(C1-4 alkylene)-O-]x-R⁵, -S(O)2-N(R^1A)-(C1-6 hydroxyalkyl), -S(O)₂-N(R^1A)(R^1B), -S(O)₂-N(R^1A)-C(O)-(C_1-6 alkyl), -S(O)₂-N(R^1A)-C(O)-O- (C1-6 alkyl), -S(O)2-N(R^1A)-C(O)-N(R^1B)(R^1C), -(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)- N(R^1A)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-N(R^1A)-C(O)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)- C(O)-OH, or -(C_1-4 alkylene)-C(O)-O-(C_1-6 alkyl); provided that when B¹ is a 6-membered aryl ring substituted with 0 or 1 occurrences of R², then Z is not -C(O)R⁴ or -C(O)-(C_1-4 alkylene)-R⁴. [0114] In some embodiments, Z is -C(O)R⁴, -C(O)-(C_1-4 alkylene)-R⁴, -C(O)-(C_1-4 alkylene)- N(R^1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-R⁴, -C(O)-(C1-4 alkylene)-O-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]_y-(C_1-6 alkoxyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_3-8 cycloalkyl substituted with z occurrence of R⁹), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or -C(O)-(C3-7 cycloalkyl substituted with one -N(R^1A)-S(O)2- (C_1-6 alkyl) or -N(R^1A)-C(O)-(C_1-6 alkyl)); provided that when B¹ is a 6-membered aryl ring substituted with 0 or 1 occurrences of R², then Z is not -C(O)R⁴ or -C(O)-(C1-4 alkylene)-R⁴. [0115] In some embodiments, Z is -C(O)R⁴, -C(O)-(C1-4 alkylene)-R⁴, -C(O)-(C1-4 alkylene)- N(R^1A)-C(O)-(C_1-4 alkyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-S(O)₂-(C_1-4 alkyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-R⁴, -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_3-8 cycloalkyl substituted with z occurrence of R⁹), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or -C(O)-(C3-7 cycloalkyl substituted with one -N(R^1A)-S(O)2- (C_1-6 alkyl) or -N(R^1A)-C(O)-(C_1-6 alkyl)); provided that when B¹ is a 6-membered aryl ring substituted with 0 or 1 occurrences of R², then Z is not -C(O)R⁴ or -C(O)-(C1-4 alkylene)-R⁴. [0116] In certain embodiments, Z is -C(O)-(C1-6 hydroxyalkyl), -C(O)-(C1-4 alkylene)- N(R^1A)-C(O)-(C_1-4 alkyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-S(O)₂-(C_1-4 alkyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-R⁴, -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R⁹), or -C(O)-(C3-7 cycloalkyl substituted with one -N(R^1A)-S(O)2-(C1-6 alkyl) or -N(R^1A)-C(O)-(C_1-6 alkyl)). In certain embodiments, Z is -C(O)-(C_1-6 hydroxyalkyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_1-4 alkyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-S(O)₂-(C_1-4 alkyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-R⁴, -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R⁹), or -C(O)-(C3-7 cycloalkyl substituted with one -N(R^1A)-S(O)2-(C1-6 alkyl) or -N(R^1A)-C(O)-(C_1-6 alkyl)); provided that when B¹ is a 6-membered aryl ring substituted with 0 or 1 occurrences of R², then Z is not -C(O)-(C1-6 hydroxyalkyl). [0117] In certain embodiments, Z is -C(O)R⁴ or -C(O)-(C1-4 alkylene)-R⁴. In certain embodiments, Z is -C(O)R⁴ or -C(O)-(C_1-4 alkylene)-R⁴; provided that B¹ is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R². [0118] In certain embodiments, Z is -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl), -C(O)- (C_1-4 alkylene)-N(R^1A)-S(O)₂-(C_1-4 alkyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-R⁴, -C(O)-(C_1-4 alkylene)-O-(C_1-4 alkyl), -C(O)-(C_1-4 alkylene)-[O-(C_1-4 alkylene)-]_y-(C_1-6 alkoxyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R⁹), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or - C(O)-(C_3-7 cycloalkyl substituted with one -N(R^1A)-S(O)₂-(C_1-6 alkyl) or -N(R^1A)-C(O)-(C_1-6 alkyl)). In certain embodiments, Z is -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl), -C(O)-(C1- 4 alkylene)-N(R^1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-R⁴, -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C_3-8 cycloalkyl substituted with z occurrence of R⁹), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or - C(O)-(C3-7 cycloalkyl substituted with one -N(R^1A)-S(O)2-(C1-6 alkyl) or -N(R^1A)-C(O)-(C1-6 alkyl)). [0119] In some embodiments, Z is -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_1-4 alkyl), -C(O)- (C1-4 alkylene)-N(R^1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-R⁴, -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R⁹), or -C(O)-(C3-7 cycloalkyl substituted with one -N(R^1A)-S(O)₂-(C_1-6 alkyl) or -N(R^1A)-C(O)-(C_1-6 alkyl)). In certain embodiments, Z is -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-S(O)2-(C1-4 alkyl), or -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-R⁴. In certain embodiments, Z is -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_1-4 alkyl) or -C(O)-(C_1-4 alkylene)- N(R^1A)-S(O)2-(C1-4 alkyl). In some embodiments, Z is -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-R⁴, - C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R⁹), or - C(O)-(C_3-7 cycloalkyl substituted with one -N(R^1A)-S(O)₂-(C_1-6 alkyl) or -N(R^1A)-C(O)-(C_1-6 alkyl)). In certain embodiments, Z is -C(O)-(C_1-4 alkylene)-O-(C_1-4 alkyl) or -C(O)-(C_1-4 alkylene)-[O-(C1-4 alkylene)-]y-(C1-6 alkoxyl). In certain embodiments, Z is -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R⁹), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C_1-4 alkyl and one -OH) or - C(O)-(C3-7 cycloalkyl substituted with one -N(R^1A)-S(O)2-(C1-6 alkyl) or -N(R^1A)-C(O)-(C1-6 alkyl)). [0120] In some embodiments, Z is -C(O)-N(R^1A)-(C_1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-N(R^1A)(R^1B), -C(O)-N(R^1A)-(C1-6 alkyl), -C(O)-N(R^1A)-(C1-4 haloalkyl), -C(O)-N(R^1A)-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl), -C(O)-N(R^1B)-(C1-4 alkylene)- [O-(C_1-4 alkylene)-]_x-(C_1-6 alkoxyl), -C(O)-N(R^1A)-(C_1-4 alkylene)-N(R^1B)-C(O)-(C_1-4 alkyl), - C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1A)(R^1B), -C(O)-N(R^1A)-[(C_1-4 alkylene)- O-]_x-(C_1-4 alkylene)-N(R^1B)-C(O)-O-(C_1-6 alkyl), -C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1B)-C(O)-(C1-6 hydroxyalkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)- N(R^1B)-S(O)2-R⁶, -C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1B)-S(O)2-(C1-4 alkyl), -C(O)-N(R^1A)-(C0-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R^1A)-(C_1-4 alkylene)-(C_3-7 cycloalkyl), or -C(O)-N(R^1A)-S(O)2-R⁷. [0121] In certain embodiments, Z is -C(O)-N(R^1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-N(R^1A)(R^1B), -C(O)-N(R^1A)-(C_1-6 alkyl), -C(O)-N(R^1A)-(C_1-4 haloalkyl), -C(O)-N(R^1A)-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl), -C(O)-N(R^1B)-(C1-4 alkylene)- [O-(C1-4 alkylene)-]x-(C1-6 alkoxyl), -C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), - C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1A)(R^1B), -C(O)-N(R^1A)-[(C_1-4 alkylene)- O-]_x-(C_1-4 alkylene)-N(R^1B)-C(O)-O-(C_1-6 alkyl), -C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1B)-C(O)-(C1-6 hydroxyalkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)- N(R^1B)-S(O)2-R⁶, -C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1B)-S(O)2-(C1-4 alkyl), -C(O)-N(R^1A)-(C0-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), or -C(O)-N(R^1A)-(C_1-4 alkylene)-(C_3-7 cycloalkyl). [0122] In certain embodiments, Z is -C(O)-N(R^1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-N(R^1A)(R^1B), -C(O)-N(R^1A)-(C_1-4 alkylene)-N(R^1B)-C(O)-(C_1-4 alkyl), or -C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1B)-S(O)2-(C1-4 alkyl). [0123] In certain embodiments, Z is -C(O)-N(R^1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-N(R^1A)(R^1B), -C(O)-N(R^1A)-(C_1-6 alkyl), or -C(O)-N(R^1A)-(C_1-4 haloalkyl). In certain embodiments, Z is -C(O)-N(R^1A)-(C_1-4 alkylene)-O-(C_1-6 hydroxyalkyl), - C(O)-N(R^1B)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]x-(C1-6 alkoxyl), -C(O)-N(R^1A)-(C1-4 alkylene)- N(R^1B)-C(O)-(C1-4 alkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1A)(R^1B), - C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1B)-C(O)-O-(C_1-6 alkyl), -C(O)-N(R^1A)- [(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-6 hydroxyalkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-S(O)2-R⁶, -C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1B)-S(O)2-(C1- ₄ alkyl), -C(O)-N(R^1A)-(C_0-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R^1A)- (C1-4 alkylene)-(C3-7 cycloalkyl), or -C(O)-N(R^1A)-S(O)2-R⁷. [0124] In some embodiments, Z is -C(O)-C(O)-N(R^1A)-R⁵, -C(O)-C(O)-N(R^1A)(R^1B), -C(O)- C(O)-N(R^1A)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_1-4 alkyl),-C(O)-C(O)-N(R^1A)-S(O)₂-(C_1-6 alkyl), - C(O)-C(O)-N(R^1A)-(C_1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), - C(O)-C(O)-R⁴, -C(O)-C(O)-OH, -C(O)-OH, -C(O)-O-(C1-6 alkyl), -C(O)-O-(C1-4 alkylene)-O- (C1-4 alkylene)-N(R^1A)(R^1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of - N(R^1A)(R^1B))-(C_1-4 hydroxyalkyl), or -C(O)-O-(C_1-4 alkylene)-(5-membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R⁹). [0125] In some embodiments, Z is -C(O)-C(O)-N(R^1A)-R⁵, -C(O)-C(O)-N(R^1A)(R^1B), -C(O)- C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl),-C(O)-C(O)-N(R^1A)-S(O)2-(C1-6 alkyl), - C(O)-C(O)-N(R^1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), - C(O)-C(O)-R⁴, -C(O)-C(O)-OH, -C(O)-O-(C_1-4 alkylene)-O-(C_1-4 alkylene)-N(R^1A)(R^1B), -C(O)- O-(C_1-4 alkylene substituted with 1 occurrence of -N(R^1A)(R^1B))-(C_1-4 hydroxyalkyl), or -C(O)- O-(C1-4 alkylene)-(5-membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R⁹). [0126] In certain embodiments, -C(O)-C(O)-N(R^1A)-(C_1-6 hydroxyalkyl), -C(O)-C(O)- N(R^1A)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl), -C(O)-C(O)-N(R^1A)-S(O)2-(C1-6 alkyl), or - C(O)-C(O)-(C1-6 hydroxyalkyl). [0127] In certain embodiments, Z is -C(O)-C(O)-N(R^1A)-R⁵, -C(O)-C(O)-N(R^1A)(R^1B), - C(O)-C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl),-C(O)-C(O)-N(R^1A)-S(O)2-(C1-6 alkyl), or -C(O)-C(O)-N(R^1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-C(O)-R⁴, or -C(O)-C(O)-OH. In certain embodiments, Z is -C(O)-C(O)-N(R^1A)- R⁵, -C(O)-C(O)-N(R^1A)(R^1B), -C(O)-C(O)-N(R^1A)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_1-4 alkyl),- C(O)-C(O)-N(R^1A)-S(O)2-(C1-6 alkyl), or -C(O)-C(O)-N(R^1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms). [0128] In certain embodiments, Z is -C(O)-C(O)-R⁴ or -C(O)-C(O)-OH. In certain embodiments, Z is -C(O)-OH or -C(O)-O-(C1-6 alkyl). In certain embodiments, Z is -C(O)-O- (C1-4 alkylene)-O-(C1-4 alkylene)-N(R^1A)(R^1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R^1A)(R^1B))-(C_1-4 hydroxyalkyl), or -C(O)-O-(C_1-4 alkylene)-(5-membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R⁹). [0129] In some embodiments, Z is -N(R^1A)-C(O)-C(O)-N(R^1B)-(C_1-6 hydroxyalkyl), -N(R^1A)- C(O)-C(O)-N(R^1B)(R^1C), -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-4 alkylene)-N(R^1C)-C(O)-(C1-4 alkyl), or -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-6 alkylene)-N(R^1C)-S(O)2-(C1-4 alkyl). In certain embodiments, Z is -N(R^1A)-C(O)-C(O)-N(R^1B)-(C_1-6 hydroxyalkyl), -N(R^1A)-C(O)-C(O)-N(R^1B)- (C1-4 alkylene)-N(R^1C)-C(O)-(C1-4 alkyl), or -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-6 alkylene)-N(R^1C)- S(O)2-(C1-4 alkyl). [0130] In some embodiments, Z is -N(R^1A)-C(O)-N(R^1B)-(C_1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R^1A)-C(O)-N(R^1B)(R^1C), -N(R^1A)-C(O)-N(R^1B)-(C1-4 haloalkyl), - N(R^1A)-C(O)-N(R^1B)-[(C1-4 alkylene)-O-]x-R⁶, -N(R^1A)-C(O)-N(R^1B)-(C1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -N(R^1A)-C(O)-(morpholinyl), or -N(R^1A)-C(O)- (azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C_1-4 alkyl and one - OH). [0131] In certain embodiments, Z is -N(R^1A)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R^1A)-C(O)-N(R^1B)(R^1C), -N(R^1A)-C(O)-N(R^1B)-(C_1-4 haloalkyl), or -N(R^1A)-C(O)-N(R^1B)-[(C1-4 alkylene)-O-]x-R⁶. In certain embodiments, Z is - N(R^1A)-C(O)-N(R^1B)-(C1-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -N(R^1A)-C(O)- (morpholinyl), or -N(R^1A)-C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH). [0132] In some embodiments, Z is -N(R^1A)-C(O)-(C1-6 hydroxyalkyl), -N(R^1A)-C(O)-(C1-4 alkylene)-N(R^1B)-C(O)-(C_1-4 alkyl), -N(R^1A)-C(O)-(C_1-4 alkylene)-N(R^1B)-S(O)₂-(C_1-4 alkyl), - N(R^1A)-C(O)-(C_1-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -N(R^1A)-C(O)-O-[(C_1-4 alkylene)-O-]x-R⁶, -N(R^1A)-C(O)-O-(C1-4 alkylene)-(phenyl), or -N(R^1A)-S(O)2-R⁷. [0133] In some embodiments, Z is -N(R^1A)-C(O)-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), - N(R^1A)-C(O)-(C_1-4 alkylene)-N(R^1B)-S(O)₂-(C_1-4 alkyl), -N(R^1A)-C(O)-O-[(C_1-4 alkylene)-O-]_x- R⁶, or -N(R^1A)-S(O)2-R⁷. In certain embodiments, Z is -N(R^1A)-C(O)-(C1-4 alkylene)-N(R^1B)- C(O)-(C1-4 alkyl), -N(R^1A)-C(O)-(C1-4 alkylene)-N(R^1B)-S(O)2-(C1-4 alkyl), or -N(R^1A)-S(O)2-R⁷. In certain embodiments, Z is -N(R^1A)-C(O)-(C_1-6 hydroxyalkyl), -N(R^1A)-C(O)-(C_1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), or -N(R^1A)-C(O)-O-(C1-4 alkylene)-(phenyl). [0134] In certain embodiments, Z is -N(R^1A)-C(O)-(C1-6 hydroxyalkyl), -N(R^1A)-C(O)-(C1-4 alkylene)-N(R^1B)-C(O)-(C_1-4 alkyl), -N(R^1A)-C(O)-(C_1-4 alkylene)-N(R^1B)-S(O)₂-(C_1-4 alkyl), or -N(R^1A)-C(O)-(C_1-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl). In some embodiments, Z is -N(R^1A)-C(O)-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), -N(R^1A)-C(O)-(C1-4 alkylene)- N(R^1B)-S(O)2-(C1-4 alkyl), or -N(R^1A)-C(O)-O-[(C1-4 alkylene)-O-]x-R⁶. In certain embodiments, Z is -N(R^1A)-C(O)-O-[(C_1-4 alkylene)-O-]_x-R⁶ or -N(R^1A)-C(O)-O-(C_1-4 alkylene)-(phenyl). [0135] In some embodiments, Z is -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-(C1-6 alkyl), -S(O)2-(C1- 4 alkylene)-(C1-6 alkoxyl), -S(O)2-(C1-4 alkylene)-C(O)-O-(C1-6 alkyl), -S(O)2-[(C1-4 alkylene)-O- ]_x-R⁵, -S(O)₂-(C_3-7 cycloalkyl), -S(O)₂-N(R^1A)-(C_1-6 hydroxyalkyl), -S(O)₂-N(R^1A)(R^1B), -S(O)₂- N(R^1A)-C(O)-(C1-6 alkyl), -S(O)2-N(R^1A)-C(O)-O-(C1-6 alkyl), or -S(O)2-N(R^1A)-C(O)- N(R^1B)(R^1C). In some embodiments, Z is -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-(C1-4 alkylene)-(C1- ₆ alkoxyl), -S(O)₂-(C_1-4 alkylene)-C(O)-O-(C_1-6 alkyl), -S(O)₂-[(C_1-4 alkylene)-O-]_x-R⁵, -S(O)₂- N(R^1A)-(C_1-6 hydroxyalkyl), -S(O)₂-N(R^1A)(R^1B), -S(O)₂-N(R^1A)-C(O)-(C_1-6 alkyl), -S(O)₂- N(R^1A)-C(O)-O-(C1-6 alkyl), or -S(O)2-N(R^1A)-C(O)-N(R^1B)(R^1C). In certain embodiments, Z is - S(O)2-(C1-6 alkyl) or -S(O)2-(C3-7 cycloalkyl). [0136] In certain embodiments, Z is -S(O)₂-(C_1-6 hydroxyalkyl), -S(O)₂-N(R^1A)-(C_1-6 hydroxyalkyl), -S(O)2-N(R^1A)-C(O)-(C1-6 alkyl), or -S(O)2-N(R^1A)-C(O)-O-(C1-6 alkyl). In certain embodiments, Z is -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-(C1-6 alkyl), -S(O)2-(C1-4 alkylene)- (C_1-6 alkoxyl), -S(O)₂-(C_1-4 alkylene)-C(O)-O-(C_1-6 alkyl), -S(O)₂-[(C_1-4 alkylene)-O-]_x-R⁵, or - S(O)2-(C3-7 cycloalkyl). In certain embodiments, Z is -S(O)2-N(R^1A)-(C1-6 hydroxyalkyl) or - S(O)2-N(R^1A)(R^1B). In certain embodiments, Z is -S(O)2-N(R^1A)-C(O)-(C1-6 alkyl), -S(O)2- N(R^1A)-C(O)-O-(C_1-6 alkyl), or -S(O)₂-N(R^1A)-C(O)-N(R^1B)(R^1C). [0137] In some embodiments, Z is -S(O)₂-[(C_1-4 alkylene)-O-]_x-R⁵, -S(O)₂-N(R^1A)-C(O)-(C_1-6 alkyl), or -S(O)2-N(R^1A)-C(O)-O-(C1-6 alkyl). In some embodiments, Z is -S(O)2-[(C1-4 alkylene)-O-]x-(C1-6 alkyl), -S(O)2-N(R^1A)-C(O)-(C1-6 alkyl), or -S(O)2-N(R^1A)-C(O)-O-(C1-6 alkyl). [0138] In some embodiments, Z is -(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-N(R^1A)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-N(R^1A)-C(O)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-OH, or - (C_1-4 alkylene)-C(O)-O-(C_1-6 alkyl). [0139] In some embodiments, Z is -C(O)R⁴, -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-R⁴, -C(O)- (C_1-4 alkylene)-N(R^1A)-C(O)-(C_3-8 cycloalkyl substituted with z occurrence of R⁹), -C(O)-(C_3-7 cycloalkyl substituted with one -N(R^1A)-S(O)₂-(C_1-6 alkyl) or -N(R^1A)-C(O)-(C_1-6 alkyl)), -C(O)- N(R^1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-C(O)-N(R^1A)-R⁵, - N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl), -N(R^1A)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R^1A)-C(O)-(C_1-6 hydroxyalkyl), -N(R^1A)-S(O)₂- R⁷, -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-[(C1-4 alkylene)-O-]x-R⁵, -S(O)2-N(R^1A)-C(O)-(C1-6 alkyl), -S(O)2-N(R^1A)-C(O)-O-(C1-6 alkyl), or a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R^1A; provided that when B¹ is a 6-membered aryl ring substituted with 0 or 1 occurrences of R², then Z is not -C(O)R⁴. In some embodiments, Z is -C(O)R⁴, -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C_1-4 alkyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-S(O)₂-(C_1-4 alkyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-R⁴, -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_3-8 cycloalkyl substituted with z occurrence of R⁹), -C(O)-(C3-7 cycloalkyl substituted with one -N(R^1A)-S(O)2-(C1-6 alkyl) or - N(R^1A)-C(O)-(C1-6 alkyl)), -C(O)-N(R^1A)-(C1-6 hydroxyalkyl), -C(O)-C(O)-N(R^1A)-(C1-6 hydroxyalkyl), -N(R^1A)-C(O)-C(O)-N(R^1B)-(C_1-6 hydroxyalkyl), -N(R^1A)-C(O)-N(R^1B)-(C_1-6 hydroxyalkyl), -N(R^1A)-C(O)-(C1-6 hydroxyalkyl), -S(O)2-[(C1-4 alkylene)-O-]x-(C1-6 alkyl), - S(O)2-[(C1-4 alkylene)-O-]x-S(O)2-N(R^1A)-C(O)-(C1-6 alkyl), or -S(O)2-N(R^1A)-C(O)-O-(C1-6 alkyl); provided that when B¹ is a 6-membered aryl ring substituted with 0 or 1 occurrences of R², then Z is not -C(O)R⁴. [0140] In some embodiments, Z is -C(O)R⁴, -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-S(O)₂-(C_1-4 alkyl), -C(O)-N(R^1A)-(C_1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-C(O)-N(R^1A)-R⁵, and -N(R^1A)-C(O)-C(O)-N(R^1B)-(C_1-6 hydroxyalkyl). In some embodiments, Z is -C(O)R⁴, -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-S(O)2-(C1-4 alkyl), -C(O)-N(R^1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-C(O)-N(R^1A)-R⁵, and -N(R^1A)-C(O)-C(O)- N(R^1B)-(C1-6 hydroxyalkyl); provided that when B¹ is a 6-membered aryl ring substituted with 0 or 1 occurrences of R², then Z is not -C(O)R⁴. [0141] In some embodiments, Z is -C(O)R⁴, -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-S(O)2-(C1-4 alkyl), -C(O)-N(R^1A)-(C1-6 hydroxyalkyl), -C(O)- C(O)-N(R^1A)-(C1-6 hydroxyalkyl), or -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl). In some embodiments, Z is -C(O)R⁴, -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_1-4 alkyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-S(O)₂-(C_1-4 alkyl), -C(O)-N(R^1A)-(C_1-6 hydroxyalkyl), -C(O)-C(O)-N(R^1A)-(C_{1- 6} hydroxyalkyl), or -N(R^1A)-C(O)-C(O)-N(R^1B)-(C_1-6 hydroxyalkyl); provided that when B¹ is a 6-membered aryl ring substituted with 0 or 1 occurrences of R², then Z is not -C(O)R⁴. [0142] In some embodiments, Z is -N(R^1A)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo) or -N(R^1A)-C(O)-(C_1-6 hydroxyalkyl). In some embodiments, Z is - N(R^1A)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl) or -N(R^1A)-C(O)-(C1-6 hydroxyalkyl). [0143] In certain embodiments, Z is -C(O)R⁴. In certain embodiments, Z is -C(O)R⁴, provided that B¹ is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R². In certain embodiments, Z is -C(O)-(C1-6 hydroxyalkyl). In certain embodiments, Z is -C(O)-(C1-6 hydroxyalkyl), provided that B¹ is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R². In certain embodiments, Z is -C(O)-(C_1-4 alkylene)-R⁴. In certain embodiments, Z is -C(O)-(C_1-4 alkylene)-R⁴, provided that B¹ is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R². [0144] In some embodiments, Z is -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl). In some embodiments, Z is -C(O)-(C_1-4 alkylene)-N(R^1A)-S(O)₂-(C_1-4 alkyl). In some embodiments, Z is - C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-R⁴. In some embodiments, Z is -C(O)-(C1-4 alkylene)-O-(C1-4 alkyl). In some embodiments, Z is -C(O)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]y-(C1-6 alkoxyl). In some embodiments, Z is -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_3-8 cycloalkyl substituted with z occurrence of R⁹). In some embodiments, Z is -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C3-8 cycloalkyl substituted with one -OH). In some embodiments, Z is -C(O)-(C1-4 alkylene)-N(R^1A)- C(O)-(C_5-8 bridged bicyclic cycloalkyl substituted with z occurrence of R⁹). In some embodiments, Z is -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH). In some embodiments, Z is -C(O)-(C3-7 cycloalkyl substituted with one -N(R^1A)-S(O)2-(C1-6 alkyl) or -N(R^1A)-C(O)-(C1-6 alkyl)). In some embodiments, Z is - C(O)-(C_3-7 cycloalkyl gem-substituted with one -N(R^1A)-S(O)₂-(C_1-6 alkyl) or -N(R^1A)-C(O)-(C_1- 6 alkyl)). [0145] In some embodiments, Z is -C(O)-N(R^1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo). In some embodiments, Z is -C(O)-N(R^1A)-(C_1-6 hydroxyalkyl). In some embodiments, Z is -C(O)-N(R^1A)-(C1-6 hydroxyalkyl substituted with 1 occurrence of halo). In some embodiments, Z is -C(O)-N(R^1A)(R^1B). In some embodiments, Z is -C(O)-N(R^1A)-(C1-6 alkyl). In some embodiments, Z is -C(O)-N(R^1A)-(C_1-4 haloalkyl). In some embodiments, Z is - C(O)-N(R^1A)-(C_1-4 alkylene)-O-(C_1-6 hydroxyalkyl). In some embodiments, Z is -C(O)-N(R^1B)- (C1-4 alkylene)-[O-(C1-4 alkylene)-]x-(C1-6 alkoxyl). In some embodiments, Z is -C(O)-N(R^1A)- (C1-4 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl). In some embodiments, Z is -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1A)(R^1B). In some embodiments, Z is -C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-C(O)-O-(C1-6 alkyl). In some embodiments, Z is -C(O)- N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-6 hydroxyalkyl). In some embodiments, Z is -C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1B)-S(O)₂-R⁶. In some embodiments, Z is -C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1B)-S(O)2-(C1-4 alkyl). In some embodiments, Z is -C(O)-N(R^1A)-(C0-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl). In some embodiments, Z is -C(O)-N(R^1A)-(C_1-4 alkylene)-(C_3-7 cycloalkyl). In some embodiments, Z is -C(O)-N(R^1A)-S(O)₂-R⁷. [0146] In some embodiments, Z is -C(O)-C(O)-N(R^1A)-R⁵. In some embodiments, Z is -C(O)- C(O)-N(R^1A)-(C1-6 hydroxyalkyl). In some embodiments, Z is -C(O)-C(O)-N(R^1A)(R^1B). In some embodiments, Z is -C(O)-C(O)-N(R^1A)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_1-4 alkyl). In some embodiments, Z is -C(O)-C(O)-N(R^1A)-S(O)2-(C1-6 alkyl). In some embodiments, Z is -C(O)- C(O)-N(R^1A)-(C1-4 alkylene)-(5-membered heteroaryl containing 1-4 nitrogen atoms). In some embodiments, Z is -C(O)-C(O)-R⁴. In some embodiments, Z is -C(O)-C(O)-OH. [0147] In some embodiments, Z is -C(O)-OH. In some embodiments, Z is -C(O)-O-(C1-6 alkyl). In some embodiments, Z is -C(O)-O-(C1-4 alkylene)-O-(C1-4 alkylene)-N(R^1A)(R^1B). In some embodiments, Z is -C(O)-O-(C_1-4 alkylene substituted with 1 occurrence of -N(R^1A)(R^1B))- (C_1-4 hydroxyalkyl). In some embodiments, Z is -C(O)-O-(C_1-4 alkylene)-(5-membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R⁹). [0148] In some embodiments, Z is -N(R^1A)-C(O)-C(O)-N(R^1B)-(C_1-6 hydroxyalkyl). In some embodiments, Z is -N(R^1A)-C(O)-C(O)-N(R^1B)(R^1C). In some embodiments, Z is -N(R^1A)-C(O)- C(O)-N(R^1B)-(C1-4 alkylene)-N(R^1C)-C(O)-(C1-4 alkyl). In some embodiments, Z is -N(R^1A)- C(O)-C(O)-N(R^1B)-(C_1-6 alkylene)-N(R^1C)-S(O)₂-(C_1-4 alkyl). [0149] In some embodiments, Z is -N(R^1A)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo). In some embodiments, Z is -N(R^1A)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl). In some embodiments, Z is -N(R^1A)-C(O)-N(R^1B)(R^1C). In some embodiments, Z is -N(R^1A)-C(O)-N(R^1B)-(C_1-4 haloalkyl). In some embodiments, Z is -N(R^1A)-C(O)-N(R^1B)-[(C_1- 4 alkylene)-O-]x-R⁶. In some embodiments, Z is -N(R^1A)-C(O)-N(R^1B)-(C1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl). In some embodiments, Z is -N(R^1A)-C(O)- (morpholinyl). In some embodiments, Z is-N(R^1A)-C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH). [0150] In some embodiments, Z is -N(R^1A)-C(O)-(C1-6 hydroxyalkyl). In some embodiments, Z is -N(R^1A)-C(O)-(C_1-4 alkylene)-N(R^1B)-C(O)-(C_1-4 alkyl). In some embodiments, Z is - N(R^1A)-C(O)-(C1-4 alkylene)-N(R^1B)-S(O)2-(C1-4 alkyl). In some embodiments, Z is -N(R^1A)- C(O)-O-[(C1-4 alkylene)-O-]x-R⁶. In some embodiments, Z is -N(R^1A)-C(O)-O-(C1-4 alkylene)- (phenyl). In some embodiments, Z is -N(R^1A)-C(O)-(C_1-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl). In some embodiments, Z is -N(R^1A)-S(O)₂-R⁷. In some embodiments, Z is - N(R^1A)-S(O)2-(C0-4 alkylene)-N(R^1A)(R^1B). In some embodiments, Z is -N(R^1A)-S(O)2-(C0-6 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl). In some embodiments, Z is -N(R^1A)-S(O)2-N(R^1B)-C(O)-O- R⁸. In some embodiments, Z is -N(R^1A)-S(O)₂-N(R^1B)-CO₂-(C_1-4 alkylene)-(phenyl). [0151] In some embodiments, Z is -S(O)2-(C1-6 hydroxyalkyl). In some embodiments, Z is - S(O)2-(C1-6 alkyl). In some embodiments, Z is -S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl). In some embodiments, Z is -S(O)₂-(C_1-4 alkylene)-C(O)-O-(C_1-6 alkyl). In some embodiments, Z is - S(O)2-[(C1-4 alkylene)-O-]x-R⁵. In some embodiments, Z is -S(O)2-[(C1-4 alkylene)-O-]x-(C1-6 alkyl). In some embodiments, Z is -S(O)2-(C3-7 cycloalkyl). In some embodiments, Z is -S(O)2- N(R^1A)-(C_1-6 hydroxyalkyl). In some embodiments, Z is -S(O)₂-N(R^1A)(R^1B). In some embodiments, Z is -S(O)₂-N(R^1A)-C(O)-(C_1-6 alkyl). In some embodiments, Z is -S(O)₂-N(R^1A)- C(O)-O-(C1-6 alkyl). In some embodiments, Z is -S(O)2-N(R^1A)-C(O)-N(R^1B)(R^1C). [0152] In some embodiments, Z is -(C1-6 hydroxyalkyl). In some embodiments, Z is -(C1-4 alkylene)-C(O)-N(R^1A)-(C_1-6 hydroxyalkyl). In some embodiments, Z is -(C_1-4 alkylene)-N(R^1A)- C(O)-(C1-6 hydroxyalkyl). In some embodiments, Z is -(C1-4 alkylene)-C(O)-OH. In some embodiments, Z is -(C1-4 alkylene)-C(O)-O-(C1-6 alkyl). [0153] In some embodiments, Z is a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R^1A. In some embodiments, Z is oxazolidinonyl or imidazolidinonyl substituted with one C_1-4 alkyl. In certain embodiments, Z is hydrogen. [0154] In certain embodiments, Z is [0155] In certain embodiments, Z is 51

[0156] In certain embodiments, Z is In certain embodiments, Z is 52

, , , , , provided that when B¹ is a 6-membered aryl ring substituted with 0 or 1 occurrences of R², then Z is not [0157] In certain embodiments, Z is ; provided that when B¹ is a 6-membered aryl ring 53 substituted with 0 or 1 occurrences of R², then Z is not . In certain embodiments, Z is ; provided that when B¹ is a 6- membered aryl ring substituted with 0 or 1 occurrences of R², then Z is not . [0158] In certain embodiments, provided that when ¹ B is a 6-membered aryl ring substituted with 0 or 1 occurrences of R², then Z is not . In certain embodiments, Z provided t ¹ hat when B is a 6-membered aryl ring substituted with 0 or 1 occurrences of R², then Z is not . In certain embodiments, Z is certain embodiments, Z is In certain embodiments, Z is [0159] In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is 55 In certain embodiments, [0160] In certain embodiments, Z is . In certain embodiments, , , In certain embodiments, Z is [0161] In certain embodiments, Z is . In certain embodiments, Z is , provided that B¹ is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R². In certain embodiments, certain embodiments, certain embodiments, Z is . In certain embodiments, 56 certain embodiments, In certain embodiments, provided that B¹ is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R². In certain embodiments, certain embodiments, certain embodiments, . In certain embodiments, certain embodiments, Z is . In certain embodiments, certain embodiments, Z is . In certain embodiments, . In certain embodiments, Z is . In certain embodiments, . In certain embodiments, In certain embodiments, In certain embodiments, . In certain embodiments, . In certain embodiments, . In certain embodiments, Z is In certain embodiments, Z is certain embodiments, certain embodiments, Z i In certain embodiments, Z is In certain embodiments, Z is . [0162] In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is 58

In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, certain embodiments, Z is . In certain embodiments, Z is certain embodiments, Z is . In certain embodiments, In certain embodiments, Z i . In certain embodiments, Z is certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is 63 In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is [0163] In certain embodiments above for variable Z that contain -C(O)R⁴, -C(O)-(C1-4 alkylene)-R⁴, and/or -C(O)-(C1-6 hydroxyalkyl); it is provided that when B¹ is a 6-membered aryl ring substituted with 0 or 1 occurrences of R², or B¹ is substituted with 0 occurrences of R², then Z is not -C(O)R⁴, -C(O)-(C1-6 hydroxyalkyl), or -C(O)-(C1-4 alkylene)-R⁴. [0164] In certain embodiments, Z is selected from the groups depicted in the compounds in Table 1, below. [0165] As defined generally above, R⁴ is C_1-6 hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, a 5-7 membered di-oxo-heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl. [0166] In some embodiments, R⁴ is a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, a 5-7 membered di-oxo- heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl. [0167] In certain embodiments, R⁴ is C1-6 hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is C_1-6 hydroxyalkyl. In certain embodiments, R⁴ is a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 3 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 4 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 5 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 3-7 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 3 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 4 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 5 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 6-membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 7 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 5-7 membered di-oxo-heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, and oxygen. In certain embodiments, R⁴ is selected from the groups depicted in the compounds in Table 1, below. [0168] As defined generally above, R⁵ is C1-6 alkyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), C1-6 alkoxyl, -(C1-6 alkylene)-N(R^1A)(R^1B), or -(C1-6 alkylene)-N(R^1A)-C(O)-O-(C1-6 alkyl). In some embodiments, R⁵ is C_1-6 alkyl, C_1-6 hydroxyalkyl, -(C_1-4 alkylene)-(C_1-4 alkoxyl), or C_1-6 alkoxyl. In certain embodiments, R⁵ is C_1-6 alkyl, C_1-6 hydroxyalkyl, or C_1-6 alkoxyl. In certain embodiments, R⁵ is C1-6 alkyl. In certain embodiments, R⁵ is -CH3. In certain embodiments, R⁵ is C1-6 hydroxyalkyl. In certain embodiments, R⁵ is C1-6 alkoxyl. In certain embodiments, R⁵ is -(C_1-4 alkylene)-(C_1-4 alkoxyl) or -(C_1-6 alkylene)-N(R^1A)(R^1B). In certain embodiments, R⁵ is -(C1-4 alkylene)-(C1-4 alkoxyl). In certain embodiments, R⁵ is -(C1-6 alkylene)-N(R^1A)(R^1B). In certain embodiments, R⁵ is -(C1-6 alkylene)-N(R^1A)-C(O)-O-(C1-6 alkyl). In certain embodiments, R⁵ is selected from the groups depicted in the compounds in Table 1, below. [0169] As defined generally above, R⁶ is C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, or -(C1- ₄ alkylene)-(C_1-4 alkoxyl). In certain embodiments, R⁶ is C_1-4 alkyl, C_1-4 hydroxyalkyl, or C_1-4 haloalkyl. In certain embodiments, R⁶ is C_1-4 alkyl. In certain embodiments, R⁶ is -CH₃. In certain embodiments, R⁶ is C1-4 hydroxyalkyl. In certain embodiments, R⁶ is C1-4 haloalkyl. In certain embodiments, R⁶ is -(C1-4 alkylene)-(C1-4 alkoxyl). In certain embodiments, R⁶ is selected from the groups depicted in the compounds in Table 1, below. [0170] As defined generally above, R⁷ is C1-4 alkyl, C1-4 alkoxyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), -(C0-4 alkylene)-N(R^1A)(R^1B), -(C0-6 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), or -N(R^1B)-C(O)-O-R⁸. In some embodiments, R⁷ is C_1-4 alkyl, C_1-4 alkoxyl or C_1-6 hydroxyalkyl. In some embodiments, R⁷ is -(C1-4 alkylene)-(C1-4 alkoxyl), -(C0-4 alkylene)- N(R^1A)(R^1B), -(C0-6 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), or -N(R^1B)-C(O)-O-R⁸. In some embodiments, R⁷ is -(C_0-4 alkylene)-N(R^1A)(R^1B), -(C_0-6 alkylene)-N(R^1B)-C(O)-(C_1-4 alkyl), or - N(R^1B)-C(O)-O-R⁸. In some embodiments, R⁷ is -N(R^1A)(R^1B), -N(R^1B)-C(O)-(C_1-4 alkyl), or - N(R^1B)-C(O)-O-R⁸. In some embodiments, R⁷ is -(C1-4 alkylene)-N(R^1A)(R^1B) or -(C1-6 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl). In some embodiments, R⁷ is C1-4 alkyl, C1-4 alkoxyl, -(C1-4 alkylene)-(C_1-4 alkoxyl), -(C_0-4 alkylene)-N(R^1A)(R^1B), or -N(R^1B)-C(O)-O-R⁸. In certain embodiments, R⁷ is C1-4 alkyl, C1-4 alkoxyl, -(C0-4 alkylene)-N(R^1A)(R^1B), or -N(R^1B)-C(O)-O-R⁸. [0171] In certain embodiments, R⁷ is C1-4 alkyl. In certain embodiments, R⁷ is -CH3. In certain embodiments, R⁷ is C_1-4 alkoxyl. In certain embodiments, R⁷ is C_1-6 hydroxyalkyl. In certain embodiments, R⁷ is -(C0-4 alkylene)-N(R^1A)(R^1B). In certain embodiments, R⁷ is - N(R^1A)(R^1B). In certain embodiments, R⁷ is -(C1-4 alkylene)-N(R^1A)(R^1B). In certain embodiments, R⁷ is -N(R^1B)-C(O)-O-R⁸. In certain embodiments, R⁷ is -(C_1-4 alkylene)-(C_1-4 alkoxyl). In certain embodiments, R⁷ is -(C_0-6 alkylene)-N(R^1B)-C(O)-(C_1-4 alkyl). In certain embodiments, R⁷ is -N(R^1B)-C(O)-(C1-4 alkyl). In certain embodiments, R⁷ is -(C1-6 alkylene)- N(R^1B)-C(O)-(C1-4 alkyl). In certain embodiments, R⁷ is selected from the groups depicted in the compounds in Table 1, below. [0172] As defined generally above, R⁸ is C1-4 alkyl or -(C0-4 alkylene)-(phenyl). In certain embodiments, R⁸ is C1-4 alkyl. In certain embodiments, R⁸ is -CH3. In certain embodiments, R⁸ is -(C_0-4 alkylene)-(phenyl). In certain embodiments, R⁸ is selected from the groups depicted in the compounds in Table 1, below. [0173] As defined generally above, R⁹ is oxo, C1-4 alkyl, hydroxyl, or -C(O)-O-(C1-4 alkyl). In certain embodiments, R⁹ is oxo. In certain embodiments, R⁹ is C_1-4 alkyl. In certain embodiments, R⁹ is -CH₃. In certain embodiments, R⁹ is hydroxyl. In certain embodiments, R⁹ is -C(O)-O-(C1-4 alkyl). In certain embodiments, R⁹ is selected from the groups depicted in the compounds in Table 1, below. [0174] As defined generally above, m and n are independently 1 or 2. In certain embodiments, m and n are 1. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, m is selected from the values represented in the compounds in Table 1, below. In certain embodiments, n is selected from the values represented in the compounds in Table 1, below. [0175] As defined generally above, p is 0, 1, 2, 3, or 4. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4. In certain embodiments, p is 0 or 1. In certain embodiments, p is 1 or 2. In certain embodiments p is 2 or 3. In certain embodiments p is 3 or 4. In certain embodiments p is 0, 1, or 2. In certain embodiments p is 1, 2, or 3. In certain embodiments, p is 2, 3, or 4. In certain embodiments p is 0, 1, 2, or 3. In certain embodiments p is 1, 2, 3, or 4. In certain embodiments, p is selected from the values represented in the compounds in Table 1, below. [0176] As defined generally above, x is 1, 2, 3, 4, or 5. In certain embodiments, x is 1. In certain embodiments, x is 2. In certain embodiments, x is 3. In certain embodiments, x is 4. In certain embodiments, x is 5. In certain embodiments, x is selected from the values represented in the compounds in Table 1, below. [0177] As defined generally above, y and z are independently 1, 2, or 3. In certain embodiments, y is 1. In certain embodiments, y is 2. In certain embodiments, y is 3. In certain embodiments, y is selected from the values represented in the compounds in Table 1, below. In certain embodiments, z is 1. In certain embodiments, z is 2. In certain embodiments, z is 3. In certain embodiments, z is selected from the values represented in the compounds in Table 1, below. [0178] The description above describes multiple embodiments relating to compounds of Formula I. The patent application specifically contemplates all combinations of the embodiments. [0179] Another aspect of the invention provides a compound represented by Formula I-B: or a pharmaceutically acceptable salt thereof; wherein: substituted with p occurrences of R², substituted with 1, 2 or 3 occurrences of R², or substituted with 2, 3, or 4 occurrences of R²; A² is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, or a 5-8 membered saturated bridged bicyclic carbocyclylene, wherein the heterocyclylene, monocyclic carbocyclylene, and bicyclic carbocyclylene are substituted with 0 or 1 occurrences of R³; R^1A, R^1B, and R^1C each represent independently for each occurrence hydrogen or C1-4 alkyl; R² represents independently for each occurrence halo, C1-4 haloalkyl, C1-4 alkoxyl, C1-4 alkyl, or C1-4 hydroxyalkyl; R³ is halo or C_1-4 alkyl; Z is one of the following: a) -C(O)R⁴, -C(O)-(C1-4 alkylene)-R⁴, -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl), - C(O)-(C1-4 alkylene)-N(R^1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)- R⁴, -C(O)-(C_1-4 alkylene)-O-(C_1-4 alkyl), -C(O)-(C_1-4 alkylene)-[O-(C_1-4 alkylene)-]_y- (C1-6 alkoxyl), -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R⁹), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C_1-4 alkyl and one -OH), or -C(O)-(C_3-7 cycloalkyl substituted with one -N(R^1A)-S(O)2-(C1-6 alkyl) or -N(R^1A)-C(O)-(C1-6 alkyl)); b) -C(O)-N(R^1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R^1A)(R^1B), -C(O)-N(R^1A)-(C_1-6 alkyl), -C(O)-N(R^1A)-(C_1-4 haloalkyl), -C(O)- N(R^1A)-(C_1-4 alkylene)-O-(C_1-6 hydroxyalkyl), -C(O)-N(R^1B)-(C_1-4 alkylene)-[O-(C_1-4 alkylene)-]x-(C1-6 alkoxyl), -C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), - C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1A)(R^1B), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1B)-C(O)-O-(C_1-6 alkyl), -C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-6 hydroxyalkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-S(O)2-R⁶, -C(O)-N(R^1A)-(C1-4 alkylene)- N(R^1B)-S(O)₂-(C_1-4 alkyl), -C(O)-N(R^1A)-(C_0-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R^1A)-(C1-4 alkylene)-(C3-7 cycloalkyl), or -C(O)-N(R^1A)- S(O)2-R⁷; c) -C(O)-C(O)-N(R^1A)-R⁵, -C(O)-C(O)-N(R^1A)(R^1B), -C(O)-C(O)-N(R^1A)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl),-C(O)-C(O)-N(R^1A)-S(O)2-(C1-6 alkyl), -C(O)- C(O)-N(R^1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-C(O)-R⁴, -C(O)-C(O)-OH, -C(O)-OH, -C(O)-O-(C_1-6 alkyl), -C(O)-O-(C_1-4 alkylene)-O-(C1-4 alkylene)-N(R^1A)(R^1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R^1A)(R^1B))-(C1-4 hydroxyalkyl), or -C(O)-O-(C1-4 alkylene)-(5- membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R⁹); d) -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl), -N(R^1A)-C(O)-C(O)-N(R^1B)(R^1C), - N(R^1A)-C(O)-C(O)-N(R^1B)-(C_1-4 alkylene)-N(R^1C)-C(O)-(C_1-4 alkyl), or -N(R^1A)- C(O)-C(O)-N(R^1B)-(C_1-6 alkylene)-N(R^1C)-S(O)₂-(C_1-4 alkyl); e) -N(R^1A)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R^1A)-C(O)-N(R^1B)(R^1C), -N(R^1A)-C(O)-N(R^1B)-(C1-4 haloalkyl), -N(R^1A)-C(O)- N(R^1B)-[(C_1-4 alkylene)-O-]_x-R⁶, -N(R^1A)-C(O)-N(R^1B)-(C_1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -N(R^1A)-C(O)-(morpholinyl), or -N(R^1A)- C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C_1-4 alkyl and one -OH); f) -N(R^1A)-C(O)-(C1-6 hydroxyalkyl), -N(R^1A)-C(O)-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), -N(R^1A)-C(O)-(C1-4 alkylene)-N(R^1B)-S(O)2-(C1-4 alkyl), -N(R^1A)-C(O)-(C1-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -N(R^1A)-C(O)-O-[(C_1-4 alkylene)- O-]_x-R⁶, -N(R^1A)-C(O)-O-(C_1-4 alkylene)-(phenyl), or -N(R^1A)-S(O)₂-R⁷; g) -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-(C1-6 alkyl), -S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl), -S(O)2-(C1-4 alkylene)-C(O)-O-(C1-6 alkyl), -S(O)2-[(C1-4 alkylene)-O-]x-R⁵, -S(O)2- (C_3-7 cycloalkyl), -S(O)₂-N(R^1A)-(C_1-6 hydroxyalkyl), -S(O)₂-N(R^1A)(R^1B), -S(O)₂- N(R^1A)-C(O)-(C1-6 alkyl), -S(O)2-N(R^1A)-C(O)-O-(C1-6 alkyl), or -S(O)2-N(R^1A)- C(O)-N(R^1B)(R^1C); h) -(C_1-6 hydroxyalkyl), -(C_1-4 alkylene)-C(O)-N(R^1A)-(C_1-6 hydroxyalkyl), -(C_1-4 alkylene)-N(R^1A)-C(O)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-OH, or -(C1-4 alkylene)-C(O)-O-(C1-6 alkyl); i) a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R^1A; or j) hydrogen; R⁴ is C1-6 hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, a 5-7 membered di-oxo- heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl; R⁵ is C_1-6 alkyl, C_1-6 hydroxyalkyl, -(C_1-4 alkylene)-(C_1-4 alkoxyl), C_1-6 alkoxyl, -(C_1-6 alkylene)-N(R^1A)(R^1B), or -(C_1-6 alkylene)-N(R^1A)-C(O)-O-(C_1-6 alkyl); R⁶ is C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, or -(C1-4 alkylene)-(C1-4 alkoxyl); R⁷ is C1-4 alkyl, C1-4 alkoxyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), -(C0-4 alkylene)-N(R^1A)(R^1B), -(C_0-6 alkylene)-N(R^1B)-C(O)-(C_1-4 alkyl), or -N(R^1B)-C(O)-O-R⁸; R⁸ is C1-4 alkyl or -(C0-4 alkylene)-(phenyl); R⁹ is oxo, C1-4 alkyl, hydroxyl, or -C(O)-O-(C1-4 alkyl); p is 0, 1, 2, 3, or 4; x is 1, 2, 3, 4, or 5; and y and z are independently 1, 2, or 3. [0180] The definitions of variables in Formula I-B above encompass multiple chemical groups. The application contemplates embodiments where, for example, (i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, (ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and (iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii). [0181] In certain embodiments, the compound is a compound of Formula I-B. [0182] As defined generally above, A¹ is substituted with p occurrences of R², substituted with 1, 2 or 3 occurrences of R², or substituted with 2, 3, or 4 occurrences of R². In certain embodiments, A¹ is substituted with p occurrences of R², or substituted with 2, 3, or 4 occurrences of R². In certain embodiments, A¹ is substituted with p occurrences of R² or substituted with 1, 2 or 3 occurrences of R². [0183] In certain embodiments, A¹ is substituted with 1, 2 or 3 occurrences of R², substituted with 1, 2 or 3 occurrences of R², or substituted with 2, 3, or 4 occurrences of R². In certain embodiments, A¹ is substituted with 1, 2, or 3 occurrences of R², or substituted with 2, 3, or 4 occurrences of R². In certain embodiments, A¹ substituted with 1, 2 or 3 occurrences of R², substituted with 1, 2 or 3 occurrences of R². [0184] In certain embodiments, A¹ is substituted with p occurrences of R². In certain embodiments, A¹ is substituted with 1, 2, or 3 occurrences of R². In certain embodiments, substituted with 0 or 1 occurrence of R². [0185] In certain embodiments, A¹ is substituted with 1, 2 or 3 occurrences of R². In certain embodiments, A¹ is substituted with 1 or 2 occurrences of R². In certain embodiments, A¹ is substituted with 1 occurrence of R². [0186] In certain embodiments, A¹ is substituted with 2, 3, or 4 occurrences of R². In certain embodiments, A¹ is ² substituted with 2 occurrences of R . In certain embodiments, A¹ is substituted with 3 occurrences of R². In certain embodiments, A is substituted with 4 occurrences of R². [0187] In certain embodiments, A¹ is In certain embodiments, A¹ is [0188] In certain embodiments, certain embodiments, . In certain embodiments, In certain embodiments, A¹ is [0189] In certain embodiments, . In certain embodiments, A¹ is In certain embodiments, A¹ is In certain embodiments, A¹ [0190] In certain embodiments, A¹ is In certain emb ¹ odiments, A is [0191] In certain embodiments, certain embodiments, certain embodiments, In certain embodiments, A¹ is . [0192] In certain embodiments, A¹ is . In certain embodiments, A¹ is In certain embodiments, A¹ is ¹ In certain embodiments, A is In certain embodiments, A¹ i ¹ s . In certain embodiments, A In certain embodiments, A¹ is . In certain embodiments, A¹ . [0193] As generally defined above, A² is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, or a 5-8 membered saturated bridged bicyclic carbocyclylene, wherein the heterocyclylene, monocyclic carbocyclylene, and bicyclic carbocyclylene are substituted with 0 or 1 occurrences of R³. [0194] In certain embodiments, A² is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, or a 5-8 membered saturated bridged bicyclic carbocyclylene. [0195] In certain embodiments, A² is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, wherein the heterocyclylene is substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is a 6- membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, wherein the heterocyclylene is substituted with 1 occurrence of R³. In certain embodiments, A² is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen. [0196] In certain embodiments, A² is a 6-membered saturated or partially unsaturated monocyclic carbocyclylene substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is a 6-membered saturated or partially unsaturated monocyclic carbocyclylene substituted with 1 occurrence of R³. In certain embodiments, A² is a 6-membered saturated or partially unsaturated monocyclic carbocyclylene. [0197] In certain embodiments, A² is a 5-8 membered saturated bridged bicyclic carbocyclylene substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is a 5-8 membered saturated bridged bicyclic carbocyclylene substituted with 1 occurrence of R³. In certain embodiments, A² is a 5-8 membered saturated bridged bicyclic carbocyclylene. [0198] In certain embodiments, , , each of which is substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is one of the following: , wherein the nitrogen atom is attached to Z; wherein the saturated carbon is attached to Z; or wherein A² is substituted with 0 or 1 occurrences of R³. [0199] In certain embodiments, A² is one of the following: , wherein the nitrogen atom is attached to Z; wherein the saturated carbon is attached to Z; or [0200] In certain embodiments, A² is , each of which is substituted with 0 or 1 occurrences of R³, wherein the nitrogen atom of A² is attached to Z. In certain embodiments, A² is , wherein the nitrogen atom of A² is attached to Z. In certain embodiments, A² is wherein the saturated carbon is attached to Z, wherein A² is substituted with 0 or 1 occurrences of R³. In certain embodiments, wherein the saturated carbon is attached to Z. In certain embodiments, A² is each of which is substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is . [0201] In certain embodiments, A² is substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is substituted with 0 or 1 occurrences of R³, wherein the nitrogen atom of A² is attached to Z. In certain embodiments, A² is substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is substituted with 0 or 1 occurrences of R³, wherein the saturated carbon of A² is attached to Z. [0202] In certain embodiments, A² is . In certain embodiments, A² is In certain embodiments, A² is . In certain embodiments, A² is , wherein the nitrogen atom of A² is attached to Z. In certain embodiments, A² is . In certain embodiments, A² is . In certain embodiments, A² is wherein the saturated carbon of A² is attached to Z. In certain embodiments, A² is substituted with 0 occurrences of R³. [0203] As generally defined above, R³ is halo or C_1-4 alkyl. In some embodiments, R³ is halo. In some embodiments, R³ is C1-4 alkyl. In some embodiments, R³ is methyl. [0204] In certain embodiments, the definition of each of variables R^1A, R^1B, R^1C, R², R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, p, x, y, z, and Z is one of the embodiments described above in connection with Formula I. [0205] The description above describes multiple embodiments relating to compounds of Formula I-B. The patent application specifically contemplates all combinations of the embodiments. [0206] Another aspect of the invention provides a compound represented by Formula I-C: or a pharmaceutically acceptable salt thereof; wherein: A¹ is substituted with p occurrences of R², wherein B¹ is a 6-membered aryl ring or a 6-membered heteroaryl ring containing 1 or 2 heteroatoms that are nitrogen; A² is a 5-8 membered saturated bridged bicyclic carbocyclylene or a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen, wherein the bicyclic carbocyclylene and heterocyclylene are substituted with 0 or 1 occurrences of R³; R^1A, R^1B, and R^1C each represent independently for each occurrence hydrogen or C_1-4 alkyl; R² represents independently for each occurrence halo, C1-4 haloalkyl, C1-4 alkoxyl, C1-4 alkyl, or C1-4 hydroxyalkyl; R³ is halo or C_1-4 alkyl; Z is one of the following: a) -C(O)R⁴, -C(O)-(C1-4 alkylene)-R⁴, -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl), - C(O)-(C_1-4 alkylene)-N(R^1A)-S(O)₂-(C_1-4 alkyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)- R⁴, -C(O)-(C1-4 alkylene)-O-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]y- (C1-6 alkoxyl), -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R⁹), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C_1-4 alkyl and one -OH), or -C(O)-(C_3-7 cycloalkyl substituted with one -N(R^1A)-S(O)2-(C1-6 alkyl) or -N(R^1A)-C(O)-(C1-6 alkyl)); b) -C(O)-N(R^1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R^1A)(R^1B), -C(O)-N(R^1A)-(C_1-6 alkyl), -C(O)-N(R^1A)-(C_1-4 haloalkyl), -C(O)- N(R^1A)-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl), -C(O)-N(R^1B)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]x-(C1-6 alkoxyl), -C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), - C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1A)(R^1B), -C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-C(O)-O-(C1-6 alkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-6 hydroxyalkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1B)-S(O)₂-R⁶, -C(O)-N(R^1A)-(C_1-4 alkylene)- N(R^1B)-S(O)₂-(C_1-4 alkyl), -C(O)-N(R^1A)-(C_0-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R^1A)-(C_1-4 alkylene)-(C_3-7 cycloalkyl), or -C(O)-N(R^1A)- S(O)2-R⁷; c) -C(O)-C(O)-N(R^1A)-R⁵, -C(O)-C(O)-N(R^1A)(R^1B), -C(O)-C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1A)-C(O)-(C_1-4 alkyl),-C(O)-C(O)-N(R^1A)-S(O)₂-(C_1-6 alkyl), -C(O)- C(O)-N(R^1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-C(O)-R⁴, -C(O)-C(O)-OH, -C(O)-OH, -C(O)-O-(C1-6 alkyl), -C(O)-O-(C1-4 alkylene)-O-(C_1-4 alkylene)-N(R^1A)(R^1B), -C(O)-O-(C_1-4 alkylene substituted with 1 occurrence of -N(R^1A)(R^1B))-(C1-4 hydroxyalkyl), or -C(O)-O-(C1-4 alkylene)-(5- membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R⁹); d) -N(R^1A)-C(O)-C(O)-N(R^1B)-(C_1-6 hydroxyalkyl), -N(R^1A)-C(O)-C(O)-N(R^1B)(R^1C), - N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-4 alkylene)-N(R^1C)-C(O)-(C1-4 alkyl), or -N(R^1A)- C(O)-C(O)-N(R^1B)-(C1-6 alkylene)-N(R^1C)-S(O)2-(C1-4 alkyl); e) -N(R^1A)-C(O)-N(R^1B)-(C_1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R^1A)-C(O)-N(R^1B)(R^1C), -N(R^1A)-C(O)-N(R^1B)-(C1-4 haloalkyl), -N(R^1A)-C(O)- N(R^1B)-[(C1-4 alkylene)-O-]x-R⁶, -N(R^1A)-C(O)-N(R^1B)-(C1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -N(R^1A)-C(O)-(morpholinyl), or -N(R^1A)- C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH); f) -N(R^1A)-C(O)-(C_1-6 hydroxyalkyl), -N(R^1A)-C(O)-(C_1-4 alkylene)-N(R^1B)-C(O)-(C_1-4 alkyl), -N(R^1A)-C(O)-(C_1-4 alkylene)-N(R^1B)-S(O)₂-(C_1-4 alkyl), -N(R^1A)-C(O)-(C_1-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -N(R^1A)-C(O)-O-[(C1-4 alkylene)- O-]x-R⁶, -N(R^1A)-C(O)-O-(C1-4 alkylene)-(phenyl), or -N(R^1A)-S(O)2-R⁷; g) -S(O)₂-(C_1-6 hydroxyalkyl), -S(O)₂-(C_1-6 alkyl), -S(O)₂-(C_1-4 alkylene)-(C_1-6 alkoxyl), -S(O)2-(C1-4 alkylene)-C(O)-O-(C1-6 alkyl), -S(O)2-[(C1-4 alkylene)-O-]x-R⁵, -S(O)2- (C3-7 cycloalkyl), -S(O)2-N(R^1A)-(C1-6 hydroxyalkyl), -S(O)2-N(R^1A)(R^1B), -S(O)2- N(R^1A)-C(O)-(C_1-6 alkyl), -S(O)₂-N(R^1A)-C(O)-O-(C_1-6 alkyl), or -S(O)₂-N(R^1A)- C(O)-N(R^1B)(R^1C); h) -(C_1-6 hydroxyalkyl), -(C_1-4 alkylene)-C(O)-N(R^1A)-(C_1-6 hydroxyalkyl), -(C_1-4 alkylene)-N(R^1A)-C(O)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-OH, or -(C1-4 alkylene)-C(O)-O-(C1-6 alkyl); i) a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R^1A; or j) hydrogen; R⁴ is C1-6 hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, a 5-7 membered di-oxo- heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl; R⁵ is C1-6 alkyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), C1-6 alkoxyl, -(C1-6 alkylene)-N(R^1A)(R^1B), or -(C_1-6 alkylene)-N(R^1A)-C(O)-O-(C_1-6 alkyl); R⁶ is C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, or -(C1-4 alkylene)-(C1-4 alkoxyl); R⁷ is C1-4 alkyl, C1-4 alkoxyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), -(C0-4 alkylene)-N(R^1A)(R^1B), -(C_0-6 alkylene)-N(R^1B)-C(O)-(C_1-4 alkyl), or -N(R^1B)-C(O)-O-R⁸; R⁸ is C1-4 alkyl or -(C0-4 alkylene)-(phenyl); R⁹ is oxo, C1-4 alkyl, hydroxyl, or -C(O)-O-(C1-4 alkyl); p is 0, 1, 2, 3, or 4; x is 1, 2, 3, 4, or 5; and y and z are independently 1, 2, or 3. [0207] The definitions of variables in Formula I-C above encompass multiple chemical groups. The application contemplates embodiments where, for example, (i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, (ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and (iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii). [0208] In certain embodiments, the compound is a compound of Formula I-C. [0209] As defined generally above, A¹ is substituted with p occurrences of R², wherein B¹ is a 6-membered aryl ring or a 6-membered heteroaryl ring containing 1 or 2 heteroatoms that are nitrogen. [0210] In certain embodiments, A¹ is substituted with p occurrences of R², wherein B¹ is a 6-membered aryl ring or . In certain embodiments, A¹ is substituted with p occurrences of R², wherein B¹ is a 6-membered heteroaryl ring containing 1 or 2 heteroatoms that are nitrogen. In certain embodiments, A¹ is substituted with p occurrences of R², wherein B¹ is a 6-membered heteroaryl ring containing 2 heteroatoms that are nitrogen. [0211] In certain embodiments, A¹ is substituted with p occurrences of R², substituted with 1, 2 or 3 occurrences of R², or substituted with 2, 3, or 4 occurrences of R². In certain embodiments, A¹ is substituted with p occurrences of R², or substituted with 2, 3, or 4 occurrences of R². In certain embodiments, A¹ is substituted with p occurrences of R² or substituted with 1, 2 or 3 occurrences of R². [0212] In certain embodiments, A¹ is substituted with 1, 2 or 3 occurrences of R², substituted with 1, 2 or 3 occurrences of R², or substituted with 2, 3, or 4 occurrences of R². In certain embodiments, A¹ is substituted with 1, 2, or 3 occurrences of R², or substituted with 2, 3, or 4 occurrences of R². In certain embodiments, A¹ is substituted with 1, 2 or 3 occurrences of R², substituted with 1, 2 or 3 occurrences of R². [0213] In certain embodiments, A¹ is substituted with 0 or 1 occurrences of R², substituted with 1 or 2 occurrences of R², or substituted with 1 or 2 occurrences of R². In certain embodiments, A¹ is substituted with 0 or 1 occurrence of R², or substituted with 1 or 2. [0214] In certain embodiments, A¹ is substituted with p occurrences of R². In certain embodiments, A¹ is or substituted with 2, 3, or 4 occurrences of R². In certain embodiments, substituted with 1 or 2 occurrences of R². In certain embodiments, A¹ is or substituted with 2 occurrences of R². In certain embodiments, A¹ is substituted with 3 occurrences of R². In certain embodiments, A¹ is substituted with 4 occurrences of R². [0215] In certain embodiments, A¹ is substituted with p occurrences of R². In certain embodiments, substituted with 1, 2, or 3 occurrences of R². In certain embodiments, A¹ is substituted with 0 or 1 occurrence of R². [0216] In certain embodiments, A¹ is substituted with p occurrences of R². In certain embodiments, A¹ is substituted with 1, 2 or 3 occurrences of R². In certain embodiments, A¹ is substituted with 1 or 2 occurrences of R². In certain embodiments, A¹ is substituted with 1 occurrence of R². [0217] In certain embodiments, A¹ is , , , I ¹ n certain embodiments, A is [0218] In certain embodiments, A¹ is In certain embodiments, certain embodiments, A¹ is , , or . In certain embodiments, A¹ is . In certain embodiments, A¹ is [0219] In certain embodiments, certain embodiments, A¹ is In certain embodiments, A¹ is I ¹ n certain embodiments, A In certain em ¹ bodiments, A is In certain embodiments, [0220] In certain embodiments, A¹ is [0221] In certain embodiments, A¹ is , In certain e ¹ mbodiments, A is [0222] In certain embodiments, A¹ is . In certain embodiments, A¹ is In certain embod ¹ iments, A is In certain e ¹ mbodiments, A is or In certain embodiments, A¹ is [0223] In certain embodiments, A¹ is . In certain embodiments, A¹ is . In certain embodiments, A¹ is . In certain embodiments, A¹ is . In certain embodiments, certain embodiments, A¹ is In certain embodiments, A¹ is In certain embodimen ¹ ts, A is In certain embodiments, A¹ is In certain em ¹ bodiments, A . In certain embodiments, A¹ is In cer ¹ tain embodiments, A is [0224] As defined generally above, A² is a 5-8 membered saturated bridged bicyclic carbocyclylene or a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen, wherein the bicyclic carbocyclylene and heterocyclylene are substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is a 5-8 membered saturated bridged bicyclic carbocyclylene or a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen. [0225] In certain embodiments, A² is a 5-8 membered saturated bridged bicyclic carbocyclylene substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is a 5-8 membered saturated bridged bicyclic carbocyclylene substituted with 1 occurrence of R³. In certain embodiments, A² is a 5-8 membered saturated bridged bicyclic carbocyclylene. [0226] In certain embodiments, A² is a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen, wherein the bridged bicyclic heterocyclylene is substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen, wherein the bridged bicyclic heterocyclylene is substituted with 1 occurrence of R³. In certain embodiments, A² is a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen. [0227] In certain embodiments, A² is each of which is substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is . In certain embodiments, A² is substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is substituted with 0 or 1 occurrences of R³, wherein the nitrogen atom of A² is attached to Z. In certain embodiments, A² is . In certain embodiments, A² is . In certain embodiments, A² is . In certain embodiments, A² is , wherein the nitrogen atom of A² is attached to Z. [0228] In certain embodiments, A² is substituted with 0 occurrences of R³. [0229] As defined generally above, R³ is halo or C_1-4 alkyl. In some embodiments, R³ is halo. In some embodiments, R³ is C_1-4 alkyl. In some embodiments, R³ is methyl. [0230] As defined generally above, Z is one of the following: a) -C(O)R⁴, -C(O)-(C1-4 alkylene)-R⁴, -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl), - C(O)-(C_1-4 alkylene)-N(R^1A)-S(O)₂-(C_1-4 alkyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)- R⁴, -C(O)-(C1-4 alkylene)-O-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]y- (C1-6 alkoxyl), -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R⁹), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C_1-4 alkyl and one -OH), or -C(O)-(C_3-7 cycloalkyl substituted with one -N(R^1A)-S(O)2-(C1-6 alkyl) or -N(R^1A)-C(O)-(C1-6 alkyl)); b) -C(O)-N(R^1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R^1A)(R^1B), -C(O)-N(R^1A)-(C_1-6 alkyl), -C(O)-N(R^1A)-(C_1-4 haloalkyl), -C(O)- N(R^1A)-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl), -C(O)-N(R^1B)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]x-(C1-6 alkoxyl), -C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), - C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1A)(R^1B), -C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-C(O)-O-(C1-6 alkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-6 hydroxyalkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1B)-S(O)₂-R⁶, -C(O)-N(R^1A)-(C_1-4 alkylene)- N(R^1B)-S(O)₂-(C_1-4 alkyl), -C(O)-N(R^1A)-(C_0-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R^1A)-(C1-4 alkylene)-(C3-7 cycloalkyl), or -C(O)-N(R^1A)- S(O)2-R⁷; c) -C(O)-C(O)-N(R^1A)-R⁵, -C(O)-C(O)-N(R^1A)(R^1B), -C(O)-C(O)-N(R^1A)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl),-C(O)-C(O)-N(R^1A)-S(O)2-(C1-6 alkyl), -C(O)- C(O)-N(R^1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-C(O)-R⁴, -C(O)-C(O)-OH, -C(O)-OH, -C(O)-O-(C_1-6 alkyl), -C(O)-O-(C_1-4 alkylene)-O-(C1-4 alkylene)-N(R^1A)(R^1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R^1A)(R^1B))-(C1-4 hydroxyalkyl), or -C(O)-O-(C1-4 alkylene)-(5- membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R⁹); d) -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl), -N(R^1A)-C(O)-C(O)-N(R^1B)(R^1C), - N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-4 alkylene)-N(R^1C)-C(O)-(C1-4 alkyl), or -N(R^1A)- C(O)-C(O)-N(R^1B)-(C_1-6 alkylene)-N(R^1C)-S(O)₂-(C_1-4 alkyl); e) -N(R^1A)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R^1A)-C(O)-N(R^1B)(R^1C), -N(R^1A)-C(O)-N(R^1B)-(C1-4 haloalkyl), -N(R^1A)-C(O)- N(R^1B)-[(C_1-4 alkylene)-O-]_x-R⁶, -N(R^1A)-C(O)-N(R^1B)-(C_1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -N(R^1A)-C(O)-(morpholinyl), or -N(R^1A)- C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C_1-4 alkyl and one -OH); f) -N(R^1A)-C(O)-(C_1-6 hydroxyalkyl), -N(R^1A)-C(O)-(C_1-4 alkylene)-N(R^1B)-C(O)-(C_1-4 alkyl), -N(R^1A)-C(O)-(C1-4 alkylene)-N(R^1B)-S(O)2-(C1-4 alkyl), -N(R^1A)-C(O)-(C1-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -N(R^1A)-C(O)-O-[(C1-4 alkylene)- O-]_x-R⁶, -N(R^1A)-C(O)-O-(C_1-4 alkylene)-(phenyl), or -N(R^1A)-S(O)₂-R⁷; g) -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-(C1-6 alkyl), -S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl), -S(O)2-(C1-4 alkylene)-C(O)-O-(C1-6 alkyl), -S(O)2-[(C1-4 alkylene)-O-]x-R⁵, -S(O)2- (C_3-7 cycloalkyl), -S(O)₂-N(R^1A)-(C_1-6 hydroxyalkyl), -S(O)₂-N(R^1A)(R^1B), -S(O)₂- N(R^1A)-C(O)-(C1-6 alkyl), -S(O)2-N(R^1A)-C(O)-O-(C1-6 alkyl), or -S(O)2-N(R^1A)- C(O)-N(R^1B)(R^1C); h) -(C_1-6 hydroxyalkyl), -(C_1-4 alkylene)-C(O)-N(R^1A)-(C_1-6 hydroxyalkyl), -(C_1-4 alkylene)-N(R^1A)-C(O)-(C_1-6 hydroxyalkyl), -(C_1-4 alkylene)-C(O)-OH, or -(C_1-4 alkylene)-C(O)-O-(C1-6 alkyl); i) a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R^1A; or j) hydrogen. [0231] In certain embodiments, Z is one of the following: a) -C(O)R⁴, -C(O)-(C1-4 alkylene)-R⁴, -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl), - C(O)-(C1-4 alkylene)-N(R^1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)- R⁴, -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_3-8 cycloalkyl substituted with z occurrence of R⁹), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or -C(O)-(C3-7 cycloalkyl substituted with one - N(R^1A)-S(O)2-(C1-6 alkyl) or -N(R^1A)-C(O)-(C1-6 alkyl)); b) -C(O)-N(R^1A)-(C_1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R^1A)(R^1B), -C(O)-N(R^1A)-(C1-6 alkyl), -C(O)-N(R^1A)-(C1-4 haloalkyl), -C(O)- N(R^1A)-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl), -C(O)-N(R^1B)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]_x-(C_1-6 alkoxyl), -C(O)-N(R^1A)-(C_1-4 alkylene)-N(R^1B)-C(O)-(C_1-4 alkyl), - C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1A)(R^1B), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-C(O)-O-(C1-6 alkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1B)-C(O)-(C_1-6 hydroxyalkyl), -C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-S(O)2-R⁶, -C(O)-N(R^1A)-(C1-4 alkylene)- N(R^1B)-S(O)2-(C1-4 alkyl), -C(O)-N(R^1A)-(C0-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R^1A)-(C_1-4 alkylene)-(C_3-7 cycloalkyl), or -C(O)-N(R^1A)- S(O)2-R⁷; c) -C(O)-C(O)-N(R^1A)-R⁵, -C(O)-C(O)-N(R^1A)(R^1B), -C(O)-C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1A)-C(O)-(C_1-4 alkyl),-C(O)-C(O)-N(R^1A)-S(O)₂-(C_1-6 alkyl), -C(O)- C(O)-N(R^1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-C(O)-R⁴, -C(O)-C(O)-OH, -C(O)-O-(C1-4 alkylene)-O-(C1-4 alkylene)- N(R^1A)(R^1B), -C(O)-O-(C_1-4 alkylene substituted with 1 occurrence of -N(R^1A)(R^1B))- (C_1-4 hydroxyalkyl), or -C(O)-O-(C_1-4 alkylene)-(5-membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R⁹); d) -N(R^1A)-C(O)-C(O)-N(R^1B)-(C_1-6 hydroxyalkyl), -N(R^1A)-C(O)-C(O)-N(R^1B)(R^1C), - N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-4 alkylene)-N(R^1C)-C(O)-(C1-4 alkyl), or -N(R^1A)- C(O)-C(O)-N(R^1B)-(C1-6 alkylene)-N(R^1C)-S(O)2-(C1-4 alkyl); e) -N(R^1A)-C(O)-N(R^1B)-(C_1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R^1A)-C(O)-N(R^1B)(R^1C), -N(R^1A)-C(O)-N(R^1B)-(C1-4 haloalkyl), -N(R^1A)-C(O)- N(R^1B)-[(C1-4 alkylene)-O-]x-R⁶, -N(R^1A)-C(O)-N(R^1B)-(C1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -N(R^1A)-C(O)-(morpholinyl), or -N(R^1A)- C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH); f) -N(R^1A)-C(O)-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), -N(R^1A)-C(O)-(C1-4 alkylene)-N(R^1B)-S(O)₂-(C_1-4 alkyl), -N(R^1A)-C(O)-O-[(C_1-4 alkylene)-O-]_x-R⁶, or - N(R^1A)-S(O)2-R⁷; g) -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl), -S(O)2-(C1-4 alkylene)-C(O)-O-(C_1-6 alkyl), -S(O)₂-[(C_1-4 alkylene)-O-]_x-R⁵, -S(O)₂-N(R^1A)-(C_1-6 hydroxyalkyl), -S(O)2-N(R^1A)(R^1B), -S(O)2-N(R^1A)-C(O)-(C1-6 alkyl), -S(O)2-N(R^1A)- C(O)-O-(C1-6 alkyl), or -S(O)2-N(R^1A)-C(O)-N(R^1B)(R^1C); h) -(C_1-6 hydroxyalkyl), -(C_1-4 alkylene)-C(O)-N(R^1A)-(C_1-6 hydroxyalkyl), -(C_1-4 alkylene)-N(R^1A)-C(O)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-OH, or -(C1-4 alkylene)-C(O)-O-(C1-6 alkyl); or i) a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R^1A. [0232] In certain embodiments, Z is one of the following: a) -C(O)-(C_1-6 hydroxyalkyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)- R⁴, -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R⁹), or -C(O)-(C_3-7 cycloalkyl substituted with one -N(R^1A)-S(O)₂-(C_1-6 alkyl) or - N(R^1A)-C(O)-(C_1-6 alkyl)); b) -C(O)-N(R^1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R^1A)(R^1B), -C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), or -C(O)- N(R^1A)-(C_1-4 alkylene)-N(R^1B)-S(O)₂-(C_1-4 alkyl); c) -C(O)-C(O)-N(R^1A)-(C1-6 hydroxyalkyl), -C(O)-C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1A)- C(O)-(C1-4 alkyl), -C(O)-C(O)-N(R^1A)-S(O)2-(C1-6 alkyl), or -C(O)-C(O)-(C1-6 hydroxyalkyl); d) -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl), -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-4 alkylene)-N(R^1C)-C(O)-(C1-4 alkyl), or -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-6 alkylene)- N(R^1C)-S(O)₂-(C_1-4 alkyl); e) -N(R^1A)-C(O)-N(R^1B)-(C_1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo); f) -N(R^1A)-C(O)-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), -N(R^1A)-C(O)-(C1-4 alkylene)-N(R^1B)-S(O)2-(C1-4 alkyl), or -N(R^1A)-S(O)2-R⁷; g) -S(O)₂-(C_1-6 hydroxyalkyl), -S(O)₂-N(R^1A)-(C_1-6 hydroxyalkyl), -S(O)₂-N(R^1A)-C(O)- (C1-6 alkyl), or -S(O)2-N(R^1A)-C(O)-O-(C1-6 alkyl); or h) a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R^1A. [0233] In certain embodiments, Z is -C(O)R⁴, -C(O)-(C_1-4 alkylene)-R⁴, -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-R⁴, -C(O)-(C1-4 alkylene)-O-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]_y-(C_1-6 alkoxyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_3-8 cycloalkyl substituted with z occurrence of R⁹), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or -C(O)-(C3-7 cycloalkyl substituted with one -N(R^1A)-S(O)2- (C_1-6 alkyl) or -N(R^1A)-C(O)-(C_1-6 alkyl)). [0234] In certain embodiments, Z is -C(O)R⁴, -C(O)-(C1-4 alkylene)-R⁴, -C(O)-(C1-4 alkylene)- N(R^1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-R⁴, -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_3-8 cycloalkyl substituted with z occurrence of R⁹), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or -C(O)-(C3-7 cycloalkyl substituted with one -N(R^1A)-S(O)2- (C1-6 alkyl) or -N(R^1A)-C(O)-(C1-6 alkyl)). [0235] In some embodiments, Z is -C(O)R⁴, -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-R⁴, -C(O)- (C1-4 alkylene)-N(R^1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R⁹), -C(O)-(C3-7 cycloalkyl substituted with one -N(R^1A)-S(O)₂-(C_1-6 alkyl) or -N(R^1A)-C(O)-(C_1-6 alkyl)), -C(O)- N(R^1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-C(O)-N(R^1A)-R⁵, - N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl), -N(R^1A)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R^1A)-C(O)-(C_1-6 hydroxyalkyl), -N(R^1A)-S(O)₂- R⁷, -S(O)₂-(C_1-6 hydroxyalkyl), -S(O)₂-[(C_1-4 alkylene)-O-]_x-R⁵, -S(O)₂-N(R^1A)-C(O)-(C_1-6 alkyl), -S(O)2-N(R^1A)-C(O)-O-(C1-6 alkyl), or a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R^1A. In some embodiments, Z is -C(O)R⁴, -C(O)-(C_1-4 alkylene)-N(R^1A)- C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)- N(R^1A)-C(O)-R⁴, -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R⁹), -C(O)-(C_3-7 cycloalkyl substituted with one -N(R^1A)-S(O)₂-(C_1-6 alkyl) or - N(R^1A)-C(O)-(C1-6 alkyl)), -C(O)-N(R^1A)-(C1-6 hydroxyalkyl), -C(O)-C(O)-N(R^1A)-(C1-6 hydroxyalkyl), -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl), -N(R^1A)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl), -N(R^1A)-C(O)-(C_1-6 hydroxyalkyl), -S(O)₂-[(C_1-4 alkylene)-O-]_x-(C_1-6 alkyl), - S(O)₂-[(C_1-4 alkylene)-O-]_x-S(O)₂-N(R^1A)-C(O)-(C_1-6 alkyl), or -S(O)₂-N(R^1A)-C(O)-O-(C_1-6 alkyl). [0236] In some embodiments, Z is -C(O)R⁴, -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-S(O)₂-(C_1-4 alkyl), -C(O)-N(R^1A)-(C_1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-C(O)-N(R^1A)-R⁵, and -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl). In some embodiments, Z is -C(O)R⁴, -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-S(O)₂-(C_1-4 alkyl), -C(O)-N(R^1A)-(C_1-6 hydroxyalkyl), - C(O)-C(O)-N(R^1A)-(C1-6 hydroxyalkyl), or -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl). [0237] In certain embodiments, the definition of variable Z is one of the embodiments described above in connection with Formula I. In certain embodiments, the definition of variable Z is one of the embodiments described below in connection with Formula I-D. [0238] In certain embodiments, the definition of each of variables R^1A, R^1B, R^1C, R², R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, p, x, y, and z is one of the embodiments described above in connection with Formula I. [0239] The description above describes multiple embodiments relating to compounds of Formula I-C. The patent application specifically contemplates all combinations of the embodiments. [0240] Another aspect of the invention provides a compound represented by Formula I-D: or a pharmaceutically acceptable salt thereof; wherein: A¹ is substituted with p occurrences of R², wherein B¹ is a 6-membered aryl ring or a 6-membered heteroaryl ring containing 1 or 2 heteroatoms that are nitrogen; A² is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, or a 5-8 membered saturated bridged bicyclic carbocyclylene, wherein the heterocyclylene, monocyclic carbocyclylene, and bicyclic carbocyclylene are substituted with 0 or 1 occurrences of R³; R^1A, R^1B, and R^1C each represent independently for each occurrence hydrogen or C_1-4 alkyl; R² represents independently for each occurrence halo, C1-4 haloalkyl, C1-4 alkoxyl, C1-4 alkyl, or C_1-4 hydroxyalkyl; R³ is halo or C1-4 alkyl; Z is one of the following: a) -C(O)R⁴, -C(O)-(C_1-4 alkylene)-R⁴, -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_1-4 alkyl), - C(O)-(C_1-4 alkylene)-N(R^1A)-S(O)₂-(C_1-4 alkyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)- R⁴, -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R⁹), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C_1-4 alkyl and one -OH), or -C(O)-(C_3-7 cycloalkyl substituted with one - N(R^1A)-S(O)2-(C1-6 alkyl) or -N(R^1A)-C(O)-(C1-6 alkyl)); b) -C(O)-N(R^1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R^1A)(R^1B), -C(O)-N(R^1A)-(C_1-6 alkyl), -C(O)-N(R^1A)-(C_1-4 haloalkyl), -C(O)- N(R^1A)-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl), -C(O)-N(R^1B)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]x-(C1-6 alkoxyl), -C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), - C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1A)(R^1B), -C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1B)-C(O)-O-(C_1-6 alkyl), -C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-6 hydroxyalkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-S(O)2-R⁶, -C(O)-N(R^1A)-(C1-4 alkylene)- N(R^1B)-S(O)₂-(C_1-4 alkyl), -C(O)-N(R^1A)-(C_0-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R^1A)-(C1-4 alkylene)-(C3-7 cycloalkyl), or -C(O)-N(R^1A)- S(O)2-R⁷; c) -C(O)-C(O)-N(R^1A)-R⁵, -C(O)-C(O)-N(R^1A)(R^1B), -C(O)-C(O)-N(R^1A)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl),-C(O)-C(O)-N(R^1A)-S(O)2-(C1-6 alkyl), -C(O)- C(O)-N(R^1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-C(O)-R⁴, -C(O)-C(O)-OH, -C(O)-O-(C_1-4 alkylene)-O-(C_1-4 alkylene)- N(R^1A)(R^1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R^1A)(R^1B))- (C1-4 hydroxyalkyl), or -C(O)-O-(C1-4 alkylene)-(5-membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R⁹); d) -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl), -N(R^1A)-C(O)-C(O)-N(R^1B)(R^1C), - N(R^1A)-C(O)-C(O)-N(R^1B)-(C_1-4 alkylene)-N(R^1C)-C(O)-(C_1-4 alkyl), or -N(R^1A)- C(O)-C(O)-N(R^1B)-(C1-6 alkylene)-N(R^1C)-S(O)2-(C1-4 alkyl); e) -N(R^1A)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R^1A)-C(O)-N(R^1B)(R^1C), -N(R^1A)-C(O)-N(R^1B)-(C_1-4 haloalkyl), -N(R^1A)-C(O)- N(R^1B)-[(C_1-4 alkylene)-O-]_x-R⁶, -N(R^1A)-C(O)-N(R^1B)-(C_1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -N(R^1A)-C(O)-(morpholinyl), or -N(R^1A)- C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C_1-4 alkyl and one -OH); f) -N(R^1A)-C(O)-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), -N(R^1A)-C(O)-(C1-4 alkylene)-N(R^1B)-S(O)2-(C1-4 alkyl), -N(R^1A)-C(O)-O-[(C1-4 alkylene)-O-]x-R⁶, or - N(R^1A)-S(O)₂-R⁷; g) -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl), -S(O)2-(C1-4 alkylene)-C(O)-O-(C1-6 alkyl), -S(O)2-[(C1-4 alkylene)-O-]x-R⁵, -S(O)2-N(R^1A)-(C1-6 hydroxyalkyl), -S(O)₂-N(R^1A)(R^1B), -S(O)₂-N(R^1A)-C(O)-(C_1-6 alkyl), -S(O)₂-N(R^1A)- C(O)-O-(C_1-6 alkyl), or -S(O)₂-N(R^1A)-C(O)-N(R^1B)(R^1C); h) -(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-N(R^1A)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-N(R^1A)-C(O)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-OH, or -(C1-4 alkylene)-C(O)-O-(C_1-6 alkyl); or i) a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R^1A; R⁴ is C_1-6 hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, a 5-7 membered di-oxo- heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl; R⁵ is C1-6 alkyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), C1-6 alkoxyl, -(C1-6 alkylene)-N(R^1A)(R^1B), or -(C_1-6 alkylene)-N(R^1A)-C(O)-O-(C_1-6 alkyl); R⁶ is C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, or -(C1-4 alkylene)-(C1-4 alkoxyl); R⁷ is C1-4 alkyl, C1-4 alkoxyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), -(C0-4 alkylene)-N(R^1A)(R^1B), -(C_0-6 alkylene)-N(R^1B)-C(O)-(C_1-4 alkyl), or -N(R^1B)-C(O)-O-R⁸; R⁸ is C1-4 alkyl or -(C0-4 alkylene)-(phenyl); R⁹ is oxo, C1-4 alkyl, hydroxyl, or -C(O)-O-(C1-4 alkyl); p is 0, 1, 2, 3, or 4; x is 1, 2, 3, 4, or 5; and z is 1, 2, or 3; provided that when B¹ is a 6-membered aryl ring substituted with 0 or 1 occurrences of R², or B¹ is substituted with 0 occurrences of R², then Z is no ⁴ t -C(O)R or -C(O)- (C1-4 alkylene)-R⁴. [0241] The definitions of variables in Formula I-D above encompass multiple chemical groups. The application contemplates embodiments where, for example, (i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, (ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and (iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii). [0242] In certain embodiments, the compound is a compound of Formula I-D. [0243] In certain embodiments, the definition of variable A¹ is one of the embodiments described above in connection with Formula I-C. [0244] In certain embodiments, the definition of each of variables A² and R³ is one of the embodiments described above in connection with Formula I-B. [0245] As generally defined above, Z is one of the following: a) -C(O)R⁴, -C(O)-(C1-4 alkylene)-R⁴, -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl), - C(O)-(C1-4 alkylene)-N(R^1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)- R⁴, -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_3-8 cycloalkyl substituted with z occurrence of R⁹), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or -C(O)-(C3-7 cycloalkyl substituted with one - N(R^1A)-S(O)₂-(C_1-6 alkyl) or -N(R^1A)-C(O)-(C_1-6 alkyl)); b) -C(O)-N(R^1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R^1A)(R^1B), -C(O)-N(R^1A)-(C1-6 alkyl), -C(O)-N(R^1A)-(C1-4 haloalkyl), -C(O)- N(R^1A)-(C_1-4 alkylene)-O-(C_1-6 hydroxyalkyl), -C(O)-N(R^1B)-(C_1-4 alkylene)-[O-(C_1-4 alkylene)-]_x-(C_1-6 alkoxyl), -C(O)-N(R^1A)-(C_1-4 alkylene)-N(R^1B)-C(O)-(C_1-4 alkyl), - C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1A)(R^1B), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-C(O)-O-(C1-6 alkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1B)-C(O)-(C_1-6 hydroxyalkyl), -C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-S(O)2-R⁶, -C(O)-N(R^1A)-(C1-4 alkylene)- N(R^1B)-S(O)2-(C1-4 alkyl), -C(O)-N(R^1A)-(C0-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R^1A)-(C_1-4 alkylene)-(C_3-7 cycloalkyl), or -C(O)-N(R^1A)- S(O)2-R⁷; c) -C(O)-C(O)-N(R^1A)-R⁵, -C(O)-C(O)-N(R^1A)(R^1B), -C(O)-C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1A)-C(O)-(C_1-4 alkyl),-C(O)-C(O)-N(R^1A)-S(O)₂-(C_1-6 alkyl), -C(O)- C(O)-N(R^1A)-(C_1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-C(O)-R⁴, -C(O)-C(O)-OH, -C(O)-O-(C1-4 alkylene)-O-(C1-4 alkylene)- N(R^1A)(R^1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R^1A)(R^1B))- (C_1-4 hydroxyalkyl), or -C(O)-O-(C_1-4 alkylene)-(5-membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R⁹); d) -N(R^1A)-C(O)-C(O)-N(R^1B)-(C_1-6 hydroxyalkyl), -N(R^1A)-C(O)-C(O)-N(R^1B)(R^1C), - N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-4 alkylene)-N(R^1C)-C(O)-(C1-4 alkyl), or -N(R^1A)- C(O)-C(O)-N(R^1B)-(C1-6 alkylene)-N(R^1C)-S(O)2-(C1-4 alkyl); e) -N(R^1A)-C(O)-N(R^1B)-(C_1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R^1A)-C(O)-N(R^1B)(R^1C), -N(R^1A)-C(O)-N(R^1B)-(C1-4 haloalkyl), -N(R^1A)-C(O)- N(R^1B)-[(C1-4 alkylene)-O-]x-R⁶, -N(R^1A)-C(O)-N(R^1B)-(C1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -N(R^1A)-C(O)-(morpholinyl), or -N(R^1A)- C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH); f) -N(R^1A)-C(O)-(C_1-4 alkylene)-N(R^1B)-C(O)-(C_1-4 alkyl), -N(R^1A)-C(O)-(C_1-4 alkylene)-N(R^1B)-S(O)2-(C1-4 alkyl), -N(R^1A)-C(O)-O-[(C1-4 alkylene)-O-]x-R⁶, or -N(R^1A)-S(O)2-R⁷; g) -S(O)₂-(C_1-6 hydroxyalkyl), -S(O)₂-(C_1-4 alkylene)-(C_1-6 alkoxyl), -S(O)₂-(C_1-4 alkylene)-C(O)-O-(C_1-6 alkyl), -S(O)₂-[(C_1-4 alkylene)-O-]_x-R⁵, -S(O)₂-N(R^1A)-(C_1-6 hydroxyalkyl), -S(O)2-N(R^1A)(R^1B), -S(O)2-N(R^1A)-C(O)-(C1-6 alkyl), -S(O)2-N(R^1A)- C(O)-O-(C1-6 alkyl), or -S(O)2-N(R^1A)-C(O)-N(R^1B)(R^1C); h) -(C_1-6 hydroxyalkyl), -(C_1-4 alkylene)-C(O)-N(R^1A)-(C_1-6 hydroxyalkyl), -(C_1-4 alkylene)-N(R^1A)-C(O)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-OH, or -(C1-4 alkylene)-C(O)-O-(C1-6 alkyl); or i) a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R^1A; provided that when B¹ is a 6-membered aryl ring substituted with 0 or 1 occurrences of R², or B¹ is substituted with 0 occurrences of R², then Z is not -C(O)R⁴ or -C(O)-(C1-4 alkylene)- R⁴. [0246] In certain embodiments, Z is one of the following: a) -C(O)-(C1-6 hydroxyalkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-S(O)₂-(C_1-4 alkyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)- R⁴, -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R⁹), or -C(O)-(C3-7 cycloalkyl substituted with one -N(R^1A)-S(O)2-(C1-6 alkyl) or - N(R^1A)-C(O)-(C_1-6 alkyl)); b) -C(O)-N(R^1A)-(C_1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R^1A)(R^1B), -C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), or -C(O)- N(R^1A)-(C1-4 alkylene)-N(R^1B)-S(O)2-(C1-4 alkyl); c) -C(O)-C(O)-N(R^1A)-(C_1-6 hydroxyalkyl), -C(O)-C(O)-N(R^1A)-(C_1-4 alkylene)-N(R^1A)- C(O)-(C1-4 alkyl), -C(O)-C(O)-N(R^1A)-S(O)2-(C1-6 alkyl), or -C(O)-C(O)-(C1-6 hydroxyalkyl); d) -N(R^1A)-C(O)-C(O)-N(R^1B)-(C_1-6 hydroxyalkyl), -N(R^1A)-C(O)-C(O)-N(R^1B)-(C_1-4 alkylene)-N(R^1C)-C(O)-(C1-4 alkyl), or -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-6 alkylene)- N(R^1C)-S(O)2-(C1-4 alkyl); e) -N(R^1A)-C(O)-N(R^1B)-(C_1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo); f) -N(R^1A)-C(O)-(C_1-4 alkylene)-N(R^1B)-C(O)-(C_1-4 alkyl), -N(R^1A)-C(O)-(C_1-4 alkylene)-N(R^1B)-S(O)2-(C1-4 alkyl), or -N(R^1A)-S(O)2-R⁷; g) -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-N(R^1A)-(C1-6 hydroxyalkyl), -S(O)2-N(R^1A)-C(O)- (C_1-6 alkyl), or -S(O)₂-N(R^1A)-C(O)-O-(C_1-6 alkyl); or h) a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R^1A; provided that when B¹ is a 6-membered aryl ring substituted with 0 or 1 occurrences of R², or B¹ is substituted with 0 occurrences of R², then Z is not -C(O)-(C_1-6 hydroxyalkyl). [0247] In some embodiments, Z is -C(O)R⁴, -C(O)-(C1-4 alkylene)-R⁴, -C(O)-(C1-4 alkylene)- N(R^1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-R⁴, -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_3-8 cycloalkyl substituted with z occurrence of R⁹), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or -C(O)-(C3-7 cycloalkyl substituted with one -N(R^1A)-S(O)2- (C_1-6 alkyl) or -N(R^1A)-C(O)-(C_1-6 alkyl)); provided that when B¹ is a 6-membered aryl ring substituted with 0 or 1 occurrences of R², or B¹ is substituted with 0 occurrences of R², then Z is not -C(O)R⁴ or -C(O)-(C1-4 alkylene)-R⁴. [0248] In certain embodiments, Z is -C(O)-(C_1-6 hydroxyalkyl), -C(O)-(C_1-4 alkylene)- N(R^1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-R⁴, -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R⁹), or -C(O)-(C_3-7 cycloalkyl substituted with one -N(R^1A)-S(O)₂-(C_1-6 alkyl) or -N(R^1A)-C(O)-(C1-6 alkyl)). In certain embodiments, Z is -C(O)-(C1-6 hydroxyalkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-R⁴, -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_3-8 cycloalkyl substituted with z occurrence of R⁹), or -C(O)-(C3-7 cycloalkyl substituted with one -N(R^1A)-S(O)2-(C1-6 alkyl) or -N(R^1A)-C(O)-(C1-6 alkyl)); provided that when B¹ is a 6-membered aryl ring substituted with 0 or 1 occurrences of R², or B¹ is substituted with 0 occurrences of R², then Z is not - C(O)-(C_1-6 hydroxyalkyl). [0249] In certain embodiments, Z is -C(O)R⁴ or -C(O)-(C1-4 alkylene)-R⁴. In certain embodiments, Z is -C(O)R⁴ or -C(O)-(C1-4 alkylene)-R⁴; provided that B¹ is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R², or substituted with 0 occurrences of R². [0250] In certain embodiments, Z is -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl), -C(O)- (C_1-4 alkylene)-N(R^1A)-S(O)₂-(C_1-4 alkyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-R⁴, -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_3-8 cycloalkyl substituted with z occurrence of R⁹), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or - C(O)-(C3-7 cycloalkyl substituted with one -N(R^1A)-S(O)2-(C1-6 alkyl) or -N(R^1A)-C(O)-(C1-6 alkyl)). [0251] In some embodiments, Z is -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl), -C(O)- (C1-4 alkylene)-N(R^1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-R⁴, -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C_3-8 cycloalkyl substituted with z occurrence of R⁹), or -C(O)-(C_3-7 cycloalkyl substituted with one -N(R^1A)-S(O)2-(C1-6 alkyl) or -N(R^1A)-C(O)-(C1-6 alkyl)). In certain embodiments, Z is -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-S(O)₂-(C_1-4 alkyl), or -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-R⁴. In certain embodiments, Z is -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_1-4 alkyl) or -C(O)-(C_1-4 alkylene)- N(R^1A)-S(O)2-(C1-4 alkyl). In some embodiments, Z is -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-R⁴, - C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R⁹), or - C(O)-(C_3-7 cycloalkyl substituted with one -N(R^1A)-S(O)₂-(C_1-6 alkyl) or -N(R^1A)-C(O)-(C_1-6 alkyl)). In certain embodiments, Z is -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R⁹), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C_1-4 alkyl and one -OH) or -C(O)-(C_3-7 cycloalkyl substituted with one -N(R^1A)-S(O)2-(C1-6 alkyl) or -N(R^1A)-C(O)-(C1-6 alkyl)). [0252] In some embodiments, Z is -C(O)-N(R^1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-N(R^1A)(R^1B), -C(O)-N(R^1A)-(C_1-6 alkyl), -C(O)-N(R^1A)-(C_1-4 haloalkyl), -C(O)-N(R^1A)-(C_1-4 alkylene)-O-(C_1-6 hydroxyalkyl), -C(O)-N(R^1B)-(C_1-4 alkylene)- [O-(C1-4 alkylene)-]x-(C1-6 alkoxyl), -C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), - C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1A)(R^1B), -C(O)-N(R^1A)-[(C1-4 alkylene)- O-]_x-(C_1-4 alkylene)-N(R^1B)-C(O)-O-(C_1-6 alkyl), -C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1B)-C(O)-(C1-6 hydroxyalkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)- N(R^1B)-S(O)2-R⁶, -C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1B)-S(O)2-(C1-4 alkyl), -C(O)-N(R^1A)-(C0-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R^1A)-(C_1-4 alkylene)-(C_3-7 cycloalkyl), or -C(O)-N(R^1A)-S(O)2-R⁷. [0253] In certain embodiments, Z is -C(O)-N(R^1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-N(R^1A)(R^1B), -C(O)-N(R^1A)-(C_1-6 alkyl), -C(O)-N(R^1A)-(C_1-4 haloalkyl), -C(O)-N(R^1A)-(C_1-4 alkylene)-O-(C_1-6 hydroxyalkyl), -C(O)-N(R^1B)-(C_1-4 alkylene)- [O-(C1-4 alkylene)-]x-(C1-6 alkoxyl), -C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), - C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1A)(R^1B), -C(O)-N(R^1A)-[(C1-4 alkylene)- O-]_x-(C_1-4 alkylene)-N(R^1B)-C(O)-O-(C_1-6 alkyl), -C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1B)-C(O)-(C1-6 hydroxyalkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)- N(R^1B)-S(O)2-R⁶, -C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1B)-S(O)2-(C1-4 alkyl), -C(O)-N(R^1A)-(C0-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), or -C(O)-N(R^1A)-(C_1-4 alkylene)-(C_3-7 cycloalkyl). [0254] In certain embodiments, Z is -C(O)-N(R^1A)-(C_1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-N(R^1A)(R^1B), -C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), or -C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1B)-S(O)2-(C1-4 alkyl). [0255] In certain embodiments, Z is -C(O)-N(R^1A)-(C_1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-N(R^1A)(R^1B), -C(O)-N(R^1A)-(C1-6 alkyl), or -C(O)-N(R^1A)-(C1-4 haloalkyl). In certain embodiments, Z is -C(O)-N(R^1A)-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl), - C(O)-N(R^1B)-(C_1-4 alkylene)-[O-(C_1-4 alkylene)-]_x-(C_1-6 alkoxyl), -C(O)-N(R^1A)-(C_1-4 alkylene)- N(R^1B)-C(O)-(C1-4 alkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1A)(R^1B), - C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-C(O)-O-(C1-6 alkyl), -C(O)-N(R^1A)- [(C_1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1B)-C(O)-(C_1-6 hydroxyalkyl), -C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1B)-S(O)₂-R⁶, -C(O)-N(R^1A)-(C_1-4 alkylene)-N(R^1B)-S(O)₂-(C_1- 4 alkyl), -C(O)-N(R^1A)-(C0-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R^1A)- (C1-4 alkylene)-(C3-7 cycloalkyl), or -C(O)-N(R^1A)-S(O)2-R⁷. [0256] In some embodiments, Z is -C(O)-C(O)-N(R^1A)-R⁵, -C(O)-C(O)-N(R^1A)(R^1B), -C(O)- C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl),-C(O)-C(O)-N(R^1A)-S(O)2-(C1-6 alkyl), - C(O)-C(O)-N(R^1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), - C(O)-C(O)-R⁴, -C(O)-C(O)-OH, -C(O)-O-(C_1-4 alkylene)-O-(C_1-4 alkylene)-N(R^1A)(R^1B), -C(O)- O-(C1-4 alkylene substituted with 1 occurrence of -N(R^1A)(R^1B))-(C1-4 hydroxyalkyl), or -C(O)- O-(C1-4 alkylene)-(5-membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R⁹). [0257] In certain embodiments, -C(O)-C(O)-N(R^1A)-(C_1-6 hydroxyalkyl), -C(O)-C(O)- N(R^1A)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl), -C(O)-C(O)-N(R^1A)-S(O)2-(C1-6 alkyl), or - C(O)-C(O)-(C1-6 hydroxyalkyl). [0258] In certain embodiments, Z is -C(O)-C(O)-N(R^1A)-R⁵, -C(O)-C(O)-N(R^1A)(R^1B), - C(O)-C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl),-C(O)-C(O)-N(R^1A)-S(O)2-(C1-6 alkyl), or -C(O)-C(O)-N(R^1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-C(O)-R⁴, or -C(O)-C(O)-OH. In certain embodiments, Z is -C(O)-C(O)-N(R^1A)- R⁵, -C(O)-C(O)-N(R^1A)(R^1B), -C(O)-C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl),- C(O)-C(O)-N(R^1A)-S(O)2-(C1-6 alkyl), or -C(O)-C(O)-N(R^1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms). [0259] In certain embodiments, Z is -C(O)-C(O)-R⁴ or -C(O)-C(O)-OH. In certain embodiments, Z is -C(O)-O-(C1-4 alkylene)-O-(C1-4 alkylene)-N(R^1A)(R^1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R^1A)(R^1B))-(C1-4 hydroxyalkyl), or -C(O)-O-(C1-4 alkylene)-(5-membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R⁹). [0260] In some embodiments, Z is -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl), -N(R^1A)- C(O)-C(O)-N(R^1B)(R^1C), -N(R^1A)-C(O)-C(O)-N(R^1B)-(C_1-4 alkylene)-N(R^1C)-C(O)-(C_1-4 alkyl), or -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-6 alkylene)-N(R^1C)-S(O)2-(C1-4 alkyl). In certain embodiments, Z is -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl), -N(R^1A)-C(O)-C(O)-N(R^1B)- (C_1-4 alkylene)-N(R^1C)-C(O)-(C_1-4 alkyl), or -N(R^1A)-C(O)-C(O)-N(R^1B)-(C_1-6 alkylene)-N(R^1C)- S(O)₂-(C_1-4 alkyl). [0261] In some embodiments, Z is -N(R^1A)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R^1A)-C(O)-N(R^1B)(R^1C), -N(R^1A)-C(O)-N(R^1B)-(C1-4 haloalkyl), - N(R^1A)-C(O)-N(R^1B)-[(C_1-4 alkylene)-O-]_x-R⁶, -N(R^1A)-C(O)-N(R^1B)-(C_1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -N(R^1A)-C(O)-(morpholinyl), or -N(R^1A)-C(O)- (azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one - OH). [0262] In certain embodiments, Z is -N(R^1A)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R^1A)-C(O)-N(R^1B)(R^1C), -N(R^1A)-C(O)-N(R^1B)-(C1-4 haloalkyl), or -N(R^1A)-C(O)-N(R^1B)-[(C_1-4 alkylene)-O-]_x-R⁶. In certain embodiments, Z is - N(R^1A)-C(O)-N(R^1B)-(C_1-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -N(R^1A)-C(O)- (morpholinyl), or -N(R^1A)-C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH). [0263] In some embodiments, Z is -N(R^1A)-C(O)-(C_1-4 alkylene)-N(R^1B)-C(O)-(C_1-4 alkyl), - N(R^1A)-C(O)-(C1-4 alkylene)-N(R^1B)-S(O)2-(C1-4 alkyl), -N(R^1A)-C(O)-O-[(C1-4 alkylene)-O-]x- R⁶, or -N(R^1A)-S(O)2-R⁷. In certain embodiments, Z is -N(R^1A)-C(O)-(C1-4 alkylene)-N(R^1B)- C(O)-(C_1-4 alkyl), -N(R^1A)-C(O)-(C_1-4 alkylene)-N(R^1B)-S(O)₂-(C_1-4 alkyl), or -N(R^1A)-S(O)₂-R⁷. In some embodiments, Z is -N(R^1A)-C(O)-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), -N(R^1A)- C(O)-(C1-4 alkylene)-N(R^1B)-S(O)2-(C1-4 alkyl), or -N(R^1A)-C(O)-O-[(C1-4 alkylene)-O-]x-R⁶. [0264] In some embodiments, Z is -S(O)₂-(C_1-6 hydroxyalkyl), -S(O)₂-(C_1-4 alkylene)-(C_1-6 alkoxyl), -S(O)2-(C1-4 alkylene)-C(O)-O-(C1-6 alkyl), -S(O)2-[(C1-4 alkylene)-O-]x-R⁵, -S(O)2- N(R^1A)-(C1-6 hydroxyalkyl), -S(O)2-N(R^1A)(R^1B), -S(O)2-N(R^1A)-C(O)-(C1-6 alkyl), -S(O)2- N(R^1A)-C(O)-O-(C_1-6 alkyl), or -S(O)₂-N(R^1A)-C(O)-N(R^1B)(R^1C). In certain embodiments, Z is - S(O)2-(C1-6 hydroxyalkyl), -S(O)2-N(R^1A)-(C1-6 hydroxyalkyl), -S(O)2-N(R^1A)-C(O)-(C1-6 alkyl), or -S(O)2-N(R^1A)-C(O)-O-(C1-6 alkyl). In certain embodiments, Z is -S(O)2-N(R^1A)-(C1-6 hydroxyalkyl) or -S(O)₂-N(R^1A)(R^1B). In certain embodiments, Z is -S(O)₂-N(R^1A)-C(O)-(C_1-6 alkyl), -S(O)2-N(R^1A)-C(O)-O-(C1-6 alkyl), or -S(O)2-N(R^1A)-C(O)-N(R^1B)(R^1C). In some embodiments, Z is -S(O)2-[(C1-4 alkylene)-O-]x-R⁵, -S(O)2-N(R^1A)-C(O)-(C1-6 alkyl), or -S(O)2- N(R^1A)-C(O)-O-(C_1-6 alkyl). In some embodiments, Z is -S(O)₂-[(C_1-4 alkylene)-O-]_x-(C_1-6 alkyl), -S(O)₂-N(R^1A)-C(O)-(C_1-6 alkyl), or -S(O)₂-N(R^1A)-C(O)-O-(C_1-6 alkyl). [0265] In some embodiments, Z is -(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-N(R^1A)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-N(R^1A)-C(O)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-OH, or - (C_1-4 alkylene)-C(O)-O-(C_1-6 alkyl). [0266] In some embodiments, Z is -C(O)R⁴, -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-S(O)2-(C1-4 alkyl), -C(O)-N(R^1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-C(O)-N(R^1A)-R⁵, and -N(R^1A)-C(O)-C(O)-N(R^1B)-(C_1-6 hydroxyalkyl). In some embodiments, Z is -C(O)R⁴, -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-S(O)2-(C1-4 alkyl), -C(O)-N(R^1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-C(O)-N(R^1A)-R⁵, and -N(R^1A)-C(O)-C(O)- N(R^1B)-(C_1-6 hydroxyalkyl); provided that when B¹ is a 6-membered aryl ring substituted with 0 or 1 occurrences of R², or B¹ is substituted with 0 occurrences of R², then Z is not - C(O)R⁴. [0267] In some embodiments, Z is -C(O)R⁴, -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-S(O)2-(C1-4 alkyl), -C(O)-N(R^1A)-(C1-6 hydroxyalkyl), -C(O)- C(O)-N(R^1A)-(C1-6 hydroxyalkyl), or -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl).In some embodiments, Z is -C(O)R⁴, -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_1-4 alkyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-S(O)2-(C1-4 alkyl), -C(O)-N(R^1A)-(C1-6 hydroxyalkyl), -C(O)-C(O)-N(R^1A)-(C1- 6 hydroxyalkyl), or -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl); provided that when B¹ is a 6-membered aryl ring substituted with 0 or 1 occurrences of R², or B¹ is substituted with 0 occurrences of R², then Z is not -C(O)R⁴. [0268] In certain embodiments, Z is -C(O)R⁴. In certain embodiments, Z is -C(O)R⁴, provided that B¹ is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R², or substituted with 0 occurrences of R². In certain embodiments, Z is -C(O)-(C_1-6 hydroxyalkyl). In certain embodiments, Z is -C(O)-(C1-6 hydroxyalkyl), provided that B¹ is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R², or substituted with 0 occurrences of R². In certain embodiments, Z is -C(O)-(C_1-4 alkylene)-R⁴. In certain embodiments, Z is -C(O)-(C1-4 alkylene)-R⁴, provided that B¹ is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R², or substituted with 0 occurrences of R². [0269] In some embodiments, Z is -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_1-4 alkyl). In some embodiments, Z is -C(O)-(C_1-4 alkylene)-N(R^1A)-S(O)₂-(C_1-4 alkyl). In some embodiments, Z is - C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-R⁴. In some embodiments, Z is -C(O)-(C1-4 alkylene)-N(R^1A)- C(O)-(C_3-8 cycloalkyl substituted with z occurrence of R⁹). In some embodiments, Z is -C(O)- (C_1-4 alkylene)-N(R^1A)-C(O)-(C_3-8 cycloalkyl substituted with one -OH). In some embodiments, Z is -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C5-8 bridged bicyclic cycloalkyl substituted with z occurrence of R⁹). In some embodiments, Z is -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C_1-4 alkyl and one -OH). In some embodiments, Z is -C(O)- (C3-7 cycloalkyl substituted with one -N(R^1A)-S(O)2-(C1-6 alkyl) or -N(R^1A)-C(O)-(C1-6 alkyl)). In some embodiments, Z is -C(O)-(C3-7 cycloalkyl gem-substituted with one -N(R^1A)-S(O)2-(C1-6 alkyl) or -N(R^1A)-C(O)-(C_1-6 alkyl)). [0270] In some embodiments, Z is -C(O)-N(R^1A)-(C_1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo). In some embodiments, Z is -C(O)-N(R^1A)-(C1-6 hydroxyalkyl). In some embodiments, Z is -C(O)-N(R^1A)-(C_1-6 hydroxyalkyl substituted with 1 occurrence of halo). In some embodiments, Z is -C(O)-N(R^1A)(R^1B). In some embodiments, Z is -C(O)-N(R^1A)-(C_1-6 alkyl). In some embodiments, Z is -C(O)-N(R^1A)-(C1-4 haloalkyl). In some embodiments, Z is - C(O)-N(R^1A)-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl). In some embodiments, Z is -C(O)-N(R^1B)- (C_1-4 alkylene)-[O-(C_1-4 alkylene)-]_x-(C_1-6 alkoxyl). In some embodiments, Z is -C(O)-N(R^1A)- (C1-4 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl). In some embodiments, Z is -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1A)(R^1B). In some embodiments, Z is -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1B)-C(O)-O-(C_1-6 alkyl). In some embodiments, Z is -C(O)- N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-6 hydroxyalkyl). In some embodiments, Z is -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-S(O)2-R⁶. In some embodiments, Z is -C(O)-N(R^1A)-(C_1-4 alkylene)-N(R^1B)-S(O)₂-(C_1-4 alkyl). In some embodiments, Z is -C(O)-N(R^1A)-(C_0-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl). In some embodiments, Z is -C(O)-N(R^1A)-(C1-4 alkylene)-(C3-7 cycloalkyl). In some embodiments, Z is -C(O)-N(R^1A)-S(O)2-R⁷. [0271] In some embodiments, Z is -C(O)-C(O)-N(R^1A)-R⁵. In some embodiments, Z is -C(O)- C(O)-N(R^1A)-(C1-6 hydroxyalkyl). In some embodiments, Z is -C(O)-C(O)-N(R^1A)(R^1B). In some embodiments, Z is -C(O)-C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl). In some embodiments, Z is -C(O)-C(O)-N(R^1A)-S(O)₂-(C_1-6 alkyl). In some embodiments, Z is -C(O)- C(O)-N(R^1A)-(C1-4 alkylene)-(5-membered heteroaryl containing 1-4 nitrogen atoms). In some embodiments, Z is -C(O)-C(O)-R⁴. In some embodiments, Z is -C(O)-C(O)-OH. [0272] In some embodiments, Z is -C(O)-O-(C_1-4 alkylene)-O-(C_1-4 alkylene)-N(R^1A)(R^1B). In some embodiments, Z is -C(O)-O-(C_1-4 alkylene substituted with 1 occurrence of -N(R^1A)(R^1B))- (C1-4 hydroxyalkyl). In some embodiments, Z is -C(O)-O-(C1-4 alkylene)-(5-membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R⁹). [0273] In some embodiments, Z is -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl). In some embodiments, Z is -N(R^1A)-C(O)-C(O)-N(R^1B)(R^1C). In some embodiments, Z is -N(R^1A)-C(O)- C(O)-N(R^1B)-(C_1-4 alkylene)-N(R^1C)-C(O)-(C_1-4 alkyl). In some embodiments, Z is -N(R^1A)- C(O)-C(O)-N(R^1B)-(C1-6 alkylene)-N(R^1C)-S(O)2-(C1-4 alkyl). [0274] In some embodiments, Z is -N(R^1A)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo). In some embodiments, Z is -N(R^1A)-C(O)-N(R^1B)-(C_1-6 hydroxyalkyl). In some embodiments, Z is -N(R^1A)-C(O)-N(R^1B)(R^1C). In some embodiments, Z is -N(R^1A)-C(O)-N(R^1B)-(C1-4 haloalkyl). In some embodiments, Z is -N(R^1A)-C(O)-N(R^1B)-[(C1- 4 alkylene)-O-]x-R⁶. In some embodiments, Z is -N(R^1A)-C(O)-N(R^1B)-(C1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl). In some embodiments, Z is -N(R^1A)-C(O)- (morpholinyl). In some embodiments, Z is-N(R^1A)-C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH). [0275] In some embodiments, Z is -N(R^1A)-C(O)-(C_1-4 alkylene)-N(R^1B)-C(O)-(C_1-4 alkyl). In some embodiments, Z is -N(R^1A)-C(O)-(C1-4 alkylene)-N(R^1B)-S(O)2-(C1-4 alkyl). In some embodiments, Z is -N(R^1A)-C(O)-O-[(C1-4 alkylene)-O-]x-R⁶. In some embodiments, Z is - N(R^1A)-S(O)₂-R⁷. In some embodiments, Z is -N(R^1A)-S(O)₂-(C_0-4 alkylene)-N(R^1A)(R^1B). In some embodiments, Z is -N(R^1A)-S(O)₂-(C_0-6 alkylene)-N(R^1B)-C(O)-(C_1-4 alkyl). In some embodiments, Z is -N(R^1A)-S(O)2-N(R^1B)-C(O)-O-R⁸. In some embodiments, Z is -N(R^1A)- S(O)2-N(R^1B)-CO2-(C1-4 alkylene)-(phenyl). [0276] In some embodiments, Z is -S(O)₂-(C_1-6 hydroxyalkyl). In some embodiments, Z is - S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl). In some embodiments, Z is -S(O)2-(C1-4 alkylene)-C(O)-O- (C1-6 alkyl). In some embodiments, Z is -S(O)2-[(C1-4 alkylene)-O-]x-R⁵. In some embodiments, Z is -S(O)₂-[(C_1-4 alkylene)-O-]_x-(C_1-6 alkyl). In some embodiments, Z is -S(O)₂-N(R^1A)-(C_1-6 hydroxyalkyl). In some embodiments, Z is -S(O)2-N(R^1A)(R^1B). In some embodiments, Z is - S(O)2-N(R^1A)-C(O)-(C1-6 alkyl). In some embodiments, Z is -S(O)2-N(R^1A)-C(O)-O-(C1-6 alkyl). In some embodiments, Z is -S(O)₂-N(R^1A)-C(O)-N(R^1B)(R^1C). [0277] In some embodiments, Z is -(C_1-6 hydroxyalkyl). In some embodiments, Z is -(C_1-4 alkylene)-C(O)-N(R^1A)-(C1-6 hydroxyalkyl). In some embodiments, Z is -(C1-4 alkylene)-N(R^1A)- C(O)-(C1-6 hydroxyalkyl). In some embodiments, Z is -(C1-4 alkylene)-C(O)-OH. In some embodiments, Z is -(C_1-4 alkylene)-C(O)-O-(C_1-6 alkyl). [0278] In some embodiments, Z is a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R^1A. In some embodiments, Z is oxazolidinonyl or imidazolidinonyl substituted with one C1-4 alkyl. [0279] In certain embodiments, Z is In certain embodiments, Z is 109 provided that if B¹ is a 6-membered aryl ring substituted with 0 or 1 occurrences of R², or substituted with 0 occurrences of R², then Z is not . [0280] In certain embodiments, Z is provided that if B¹ is a 6-membered aryl ring substituted with 0 or 1 occurrences of R², or substituted with 0 occurrences of R², then Z is not . [0281] In certain embodiments, provided ¹ that if B is a 6-membered aryl ring substituted with 0 or 1 occurrences of R², or substituted with 0 occurrences of R², then Z is not . In certain embodiments, provided that if B¹ is a 6-membered aryl ring substituted with 0 or 1 occurrences of R², or substituted with 0 occurrences of R², then Z is not . In certain embodiments, Z In certain embodiments, Z is In certain embodiments, Z is [0282] In certain embodiments, Z is In certain embodiments, Z is 111 , In certain embodiments, Z is . In certain embodiments, Z is [0283] In certain embodiments, Z is ; provided that if B¹ is a 6-membered aryl ring substituted with 0 or 1 occurrences of R², or substituted with 0 occurrences of R², then Z is not . [0284] In certain embodiments, Z is . In certain embodiments, Z is ; provided that B¹ is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R², or substituted with 0 occurrences of R². In certain embodiments, Z is certain embodiments, certain embodiments, embodiments, . In certain embodiments, . In certain embodiments, Z is ; provided that B¹ is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R², or substituted with 0 occurrences of R². In certain embodiments, certain embodiments, certain embodiments, . In certain embodiments, . In certain embodiments, Z is . In certain embodiments, . In certain embodiments, Z is . In certain embodiments, embodiments, Z is . In certain embodiments, Z is . In certain embodiments, In certain embodiments, Z is . In certain embodiments, 113 In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z In certain embodiments, [0285] In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z In certain embodiments, Z is , In certain embodiments, Z is [0286] As generally defined above, z is 1, 2 or 3. In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3. [0287] In certain embodiments, the definition of each of variables R^1A, R^1B, R^1C, R², R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, p, and x is one of the embodiments described above in connection with Formula I. [0288] The description above describes multiple embodiments relating to compounds of Formula I-D. The patent application specifically contemplates all combinations of the embodiments. [0289] Another aspect of the invention provides a compound represented by Formula I-1: (I-1) or a pharmaceutically acceptable salt thereof; wherein: A¹ is substituted with p occurrences of R², wherein B¹ is a 6-membered aryl ring or a 5-6 membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur; A² is a 6-membered saturated or partially unsaturated heterocyclylene containing 1 heteroatom selected from nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, a 5-8 membered saturated bicyclic carbocyclylene, or a covalent bond, wherein the heterocyclylene, monocyclic carbocyclylene, and bicyclic carbocyclylene are substituted with 0 or 1 occurrences of R³; R^1A, R^1B, and R^1C each represent independently for each occurrence hydrogen or C_1-4 alkyl; R² represents independently for each occurrence halo; R³ is halo or C_1-4 alkyl; Z is -C(O)R⁴, -C(O)-(C_1-4 alkylene)-R⁴, -C(O)-OH, -C(O)-O-(C_1-6 alkyl), -C(O)- N(R^1A)(R^1B), -C(O)-O-(C1-4 alkylene)-O-(C1-4 alkylene)-N(R^1A)(R^1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R^1A)(R^1B))-(C1-4 hydroxyalkyl), -S(O)2-(C1-6 alkyl), - S(O)₂-(C_3-7 cycloalkyl), -S(O)₂-N(R^1A)(R^1B), -S(O)₂-N(R^1A)-C(O)-(C_1-6 alkyl), -S(O)₂- N(R^1A)-C(O)-O-(C1-6 alkyl), -S(O)2-N(R^1A)-C(O)-N(R^1B)(R^1C), -S(O)2-[(C1-4 alkylene)-O-]x- R⁵, -N(R^1A)-C(O)-(C1-4 alkylene)-(5-6 membered saturated heterocyclyl containing 1 oxygen atom), -N(R^1A)-C(O)-O-(C_1-4 alkylene)-(phenyl), -N(R^1A)-C(O)-O-[(C_1-4 alkylene)-O-]_x-R⁶, - N(R^1A)-C(O)-N(R^1B)-[(C1-4 alkylene)-O-]x-R⁶, -C(O)-N(R^1A)-(C1-6 hydroxyalkyl), -C(O)- N(R^1A)-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1A)(R^1B), -N(R^1A)-C(O)-N(R^1B)-[(C_1-6 hydroxyalkyl), -C(O)-(C_1-4 alkylene)- [O-(C_1-4 alkylene)-]_y-(C_1-6 alkoxyl), -C(O)N(R^1B)-(C_1-4 alkylene)-[O-(C_1-4 alkylene)-]_y-(C_1-6 alkoxyl), -C(O)-C(O)-OH, -C(O)-C(O)-N(R^1A)(R^1B), -N(R^1A)-C(O)-(C1-6 hydroxyalkyl), - C(O)-C(O)-N(R^1A)-R⁵, -N(R^1A)-C(O)-C(O)-N(R^1B)(R^1C), -C(O)-N(R^1A)-S(O)2-R⁷, -N(R^1A)- S(O)₂-R⁷, -N(R^1A)-S(O)₂-N(R^1B)-CO₂-(C_1-4 alkylene)-phenyl, -C(O)-C(O)-N(R^1A)-S(O)₂-(C_1- 6 alkyl), -S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl), -C(O)-C(O)-N(R^1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-O-(C1-4 alkylene)-(5 membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R⁹), or hydrogen; R⁴ is C1-6 hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, a 5-7 membered di-oxo- heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl; R⁵ is C1-6 alkyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), or C1-6 alkoxyl; R⁶ is C1-4 alkyl, C1-4 hydroxyalkyl, or C1-4 haloalkyl; R⁷ is C_1-4 alkyl, C_1-4 alkoxyl, -(C_1-4 alkylene)-(C_1-4 alkoxyl), -(C_0-4 alkylene)- N(R^1A)(R^1B), or -N(R^1B)-C(O)-O-R⁸; R⁸ is C1-4 alkyl or -(C0-4 alkylene)-(phenyl); R⁹ is oxo, C1-4 alkyl, hydroxyl, or -C(O)-O-(C1-4 alkyl); m is 1 or 2; n is 1 or 2; p is 0, 1, 2, 3, or 4; x is 1, 2, 3, 4, or 5; and y and z are independently 1, 2, or 3; provided that when B¹ is a 6-membered aryl ring substituted with 0 or 1 occurrences of R², then Z is not -C(O)R⁴ or -C(O)-(C_1-4 alkylene)-R⁴. [0290] The definitions of variables in Formula I-1 above encompass multiple chemical groups. The application contemplates embodiments where, for example, (i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, (ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and (iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii). [0291] In certain embodiments, the compound is a compound of Formula I-1. [0292] As defined generally above, A¹ is substituted with p occurrences of R², wherein B¹ is a 6-membered aryl ring or a 5-6 membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur. In certain embodiments, A¹ is substituted with p occurrences of R², wherein B¹ is a 6-membered aryl ring. In certain embodiments, A¹ is substituted with p occurrences of R², wherein B¹ is a 5-6 membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur. In certain embodiments, A¹ is substituted with p occurrences of R², wherein B¹ is a 5-membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur. In certain embodiments, A¹ is substituted with p occurrences of R², wherein B¹ is a 6-membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur. [0293] In certain embodiments, , each of which is substituted by p occurrences of halo. In certain embodiments, A¹ substituted by p occurrences of halo. In certain embodiments, A¹ is substituted by p occurrences of halo. In certain embodiments, A¹ is substituted by p occurrences of halo. In certain embodiments, A¹ is substituted by p occurrences of halo. [0294] In certain embodiments, A¹ is In ¹ certain embodiments, A In certain embodiments, A¹ is In certain embodiments, A¹ In certain embodiments, A¹ is In certain embodiments, A¹ In certain embodiments, A¹ is In c ¹ ertain embodiments, A is In certain embodiments, A¹ is In certain embodiments, A¹ is . In certain embodiments, A¹ is In certai ¹ n e mbodiments, A In certain embodimen ^{1 1} ts, A is In certain embodiments, A is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below. [0295] As defined generally above, A² is a 6-membered saturated or partially unsaturated heterocyclylene containing 1 heteroatom selected from nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, a 5-8 membered saturated bicyclic carbocyclylene, or a covalent bond, wherein the heterocyclylene, monocyclic carbocyclylene, and bicyclic carbocyclylene are substituted with 0 or 1 occurrences of R³. In certain embodiments, , , each of which is substituted with 0 or 1 occurrences of R³, or a covalent bond, wherein ***is the point of attachment to Z. In certain embodiments, A² is a 6- membered saturated or partially unsaturated heterocyclylene containing 1 heteroatom selected from nitrogen, wherein the heterocyclylene is substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, wherein the monocyclic carbocyclylene is substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is a 5-8 membered saturated bicyclic carbocyclylene, wherein the bicyclic carbocyclylene is substituted with 0 or 1 occurrences of R³. In certain embodiments, A² is a covalent bond. In certain embodiments, A² is substituted with 0 or 1 occurrences of R³, wherein ***is the point of attachment to Z. In certain embodiments, A² is substituted with 0 or 1 occurrences of R³, wherein ***is the point of attachment to Z. In certain embodiments, A² is substituted with 0 or 1 occurrences of R³, wherein ***is the point of attachment to Z. In certain embodiments, A² is substituted with 0 or 1 occurrences of R³, wherein ***is the point of attachment to Z. In certain embodiments, A² is substituted with 0 or 1 occurrences of R³, wherein ***is the point of attachment to Z. In certain embodiments, A² is substituted with 0 or 1 occurrences of R³, wherein ***is the point of attachment to Z. In certain embodiments, A² is each of which is substituted with 0 or 1 occurrences of R³, wherein ***is the point of attachment to Z. In certain embodiments, A² is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below. [0296] As defined generally above, R^1A, R^1B, and R^1C each represent independently for each occurrence hydrogen or C1-4 alkyl. In certain embodiments, R^1A is hydrogen. In certain embodiments, R^1A is C1-4 alkyl. In certain embodiments, R^1B is hydrogen. In certain embodiments, R^1B is C_1-4 alkyl. In certain embodiments, R^1C is hydrogen. In certain embodiments, R^1C is C1-4 alkyl. In certain embodiments, R^1A and R^1B are both hydrogen. In certain embodiments, R^1A and R^1B are both methyl. In certain embodiments, R^1A is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below. [0297] As defined generally above, R² represents independently for each occurrence halo. In certain embodiments, R² is fluoro or chloro. In certain embodiments, R² is fluoro. In certain embodiments, R² is chloro. In certain embodiments, R² is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below. [0298] As defined generally above, R³ is halo or C1-4 alkyl. In certain embodiments, R³ is halo. In certain embodiments, R³ is C1-4 alkyl. In certain embodiments, R³ is fluoro. In certain embodiments, R³ is chloro. In certain embodiments, R³ is methyl. In certain embodiments, R³ is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below. [0299] As defined generally above, Z is -C(O)R⁴, -C(O)-(C1-4 alkylene)-R⁴, -C(O)-OH, - C(O)-O-(C_1-6 alkyl), -C(O)-N(R^1A)(R^1B), -C(O)-O-(C_1-4 alkylene)-O-(C_1-4 alkylene)- N(R^1A)(R^1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R^1A)(R^1B))-(C1-4 hydroxyalkyl), -S(O)2-(C1-6 alkyl), -S(O)2-(C3-7 cycloalkyl), -S(O)2-N(R^1A)(R^1B), -S(O)2-N(R^1A)- C(O)-(C_1-6 alkyl), -S(O)₂-N(R^1A)-C(O)-O-(C_1-6 alkyl), -S(O)₂-N(R^1A)-C(O)-N(R^1B)(R^1C), -S(O)₂- [(C_1-4 alkylene)-O-]_x-R⁵, -N(R^1A)-C(O)-(C_1-4 alkylene)-(5-6 membered saturated heterocyclyl containing 1 oxygen atom), -N(R^1A)-C(O)-O-(C1-4 alkylene)-(phenyl), -N(R^1A)-C(O)-O-[(C1-4 alkylene)-O-]x-R⁶, -N(R^1A)-C(O)-N(R^1B)-[(C1-4 alkylene)-O-]x-R⁶, -C(O)-N(R^1A)-(C1-6 hydroxyalkyl), -C(O)-N(R^1A)-(C_1-4 alkylene)-O-(C_1-6 hydroxyalkyl), -C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1A)(R^1B), -N(R^1A)-C(O)-N(R^1B)-[(C1-6 hydroxyalkyl), -C(O)- (C1-4 alkylene)-[O-(C1-4 alkylene)-]y-(C1-6 alkoxyl), -C(O)N(R^1B)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]_y-(C_1-6 alkoxyl), -C(O)-C(O)-OH, -C(O)-C(O)-N(R^1A)(R^1B), -N(R^1A)-C(O)-(C_1-6 hydroxyalkyl), -C(O)-C(O)-N(R^1A)-R⁵, -N(R^1A)-C(O)-C(O)-N(R^1B)(R^1C), -C(O)-N(R^1A)-S(O)2- R⁷, -N(R^1A)-S(O)2-R⁷, -N(R^1A)-S(O)2-N(R^1B)-CO2-(C1-4 alkylene)-phenyl, -C(O)-C(O)-N(R^1A)- S(O)₂-(C_1-6 alkyl), -S(O)₂-(C_1-4 alkylene)-(C_1-6 alkoxyl), -C(O)-C(O)-N(R^1A)-(C_1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-O-(C_1-4 alkylene)-(5 membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R⁹), or hydrogen. [0300] In certain embodiments, Z is hydrogen. In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is or In certain embodiments, Z is 122

, In certain embodiments, Z is In certain embodiments, Z is , In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is n certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, certain embodiments, . In certain embodiments, Z is certain embodiments, Z is . In certain embodiments, In certain embodiments, Z i . In certain embodiments, Z is . In certain embodiments, Z i . In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . ain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z i . In certain embodiments, Z is . In certain embodiments, . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is [0301] In certain embodiments, Z is -C(O)R⁴. In certain embodiments, Z is -C(O)-(C1-4 alkylene)-R⁴. In certain embodiments, Z is -C(O)-OH. In certain embodiments, Z is -C(O)-O- (C1-6 alkyl). In certain embodiments, Z is -C(O)-N(R^1A)(R^1B). In certain embodiments, Z is - C(O)-O-(C_1-4 alkylene)-O-(C_1-4 alkylene)-N(R^1A)(R^1B). In certain embodiments, Z is -C(O)-O- (C1-4 alkylene substituted with 1 occurrence of -N(R^1A)(R^1B))-(C1-4 hydroxyalkyl). In certain embodiments, Z is -S(O)2-(C1-6 alkyl). In certain embodiments, Z is -S(O)2-(C3-7 cycloalkyl). In certain embodiments, Z is -S(O)₂-N(R^1A)(R^1B). In certain embodiments, Z is -S(O)₂-N(R^1A)- C(O)-(C1-6 alkyl). In certain embodiments, Z is -S(O)2-N(R^1A)-C(O)-O-(C1-6 alkyl). In certain embodiments, Z is -S(O)2-N(R^1A)-C(O)-N(R^1B)(R^1C). In certain embodiments, Z is -S(O)2-[(C1-4 alkylene)-O-]_x-R⁵. In certain embodiments, Z is -N(R^1A)-C(O)-(C_1-4 alkylene)-(5-6 membered saturated heterocyclyl containing 1 oxygen atom). In certain embodiments, Z is -N(R^1A)-C(O)- O-(C1-4 alkylene)-(phenyl). In certain embodiments, Z is -N(R^1A)-C(O)-O-[(C1-4 alkylene)-O-]x- R⁶. In certain embodiments, Z is -N(R^1A)-C(O)-N(R^1B)-[(C_1-4 alkylene)-O-]_x-R⁶. In certain embodiments, Z is -C(O)-N(R^1A)-(C_1-6 hydroxyalkyl). In certain embodiments, Z is -C(O)- N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1A)(R^1B). In certain embodiments, Z is -N(R^1A)- C(O)-N(R^1B)-[(C1-6 hydroxyalkyl). In certain embodiments, Z is -C(O)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]_y-(C_1-6 alkoxyl). In certain embodiments, Z is -C(O)-C(O)-OH. In certain embodiments, Z is -C(O)-C(O)-N(R^1A)(R^1B). In certain embodiments, Z is -N(R^1A)-C(O)-(C1-6 hydroxyalkyl). In certain embodiments, Z is -C(O)-C(O)-N(R^1A)-R⁵. In certain embodiments, Z is -N(R^1A)-C(O)-C(O)-N(R^1B)(R^1C). In certain embodiments, Z is -C(O)-N(R^1A)-S(O)₂-R⁷. In certain embodiments, Z is -N(R^1A)-S(O)2-R⁷. In certain embodiments, Z is -C(O)-C(O)-N(R^1A)- S(O)2-(C1-6 alkyl), -S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl), -C(O)-C(O)-N(R^1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms). In certain embodiments, Z is -C(O)-O-(C_{1- 4} alkylene)-(5 membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R⁹). In certain embodiments, Z is hydrogen. [0302] In certain embodiments, Z is -C(O)-N(R^1A)-(C_1-4 alkylene)-O-(C_1-6 hydroxyalkyl). In certain embodiments, Z is -C(O)N(R^1B)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]y-(C1-6 alkoxyl). In certain embodiments, Z is -N(R^1A)-S(O)2-N(R^1B)-CO2-(C1-4 alkylene)-phenyl. [0303] In certain embodiments, Z is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below. [0304] As defined generally above, R⁴ is C1-6 hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, a 5-7 membered di-oxo-heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is C_1-6 hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is C_1-6 hydroxyalkyl. In certain embodiments, R⁴ is a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 3 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 4 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 5 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 3-7 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 3 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 4 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 5 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 6-membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 7 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 5-7 membered di-oxo-heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, and oxygen. In certain embodiments, R⁴ is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below. [0305] As defined generally above, R⁵ is C_1-6 alkyl, C_1-6 hydroxyalkyl, -(C_1-4 alkylene)-(C_1-4 alkoxyl), or C1-6 alkoxyl. In certain embodiments, R⁵ is C1-6 alkyl, C1-6 hydroxalkyl, or C1-6 alkoxyl. In certain embodiments, R⁵ is C1-6 alkyl. In certain embodiments, R⁵ is C1-6 hydroxalkyl. In certain embodiments, R⁵ is C_1-6 alkoxyl. In certain embodiments, R⁵ is -(C_1-4 alkylene)-(C1-4 alkoxyl). In certain embodiments, R⁵ is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below. [0306] As defined generally above, R⁶ is C_1-4 alkyl, C_1-4 hydroxyalkyl, or C_1-4 haloalkyl. In certain embodiments, R⁶ is C_1-4 alkyl. In certain embodiments, R⁶ is C_1-4 hydroxyalkyl. In certain embodiments, R⁶ is C1-4 haloalkyl. In certain embodiments, R⁶ is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below. [0307] As defined generally above, R⁷ is C_1-4 alkyl, C_1-4 alkoxyl, -(C_1-4 alkylene)-(C_1-4 alkoxyl), -(C0-4 alkylene)-N(R^1A)(R^1B), or -N(R^1B)-C(O)-O-R⁸. In certain embodiments, R⁷ is C1- 4 alkyl, C1-4 alkoxyl, -(C0-4 alkylene)-N(R^1A)(R^1B), or -N(R^1B)-C(O)-O-R⁸. In certain embodiments, R⁷ is C_1-4 alkyl. In certain embodiments, R⁷ is C_1-4 alkoxyl. In certain embodiments, R⁷ is -(C0-4 alkylene)-N(R^1A)(R^1B). In certain embodiments, R⁷ is -N(R^1B)-C(O)- O-R⁸. In certain embodiments, R⁷ is -(C1-4 alkylene)-(C1-4 alkoxyl). In certain embodiments, R⁷ is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below. [0308] As defined generally above, R⁸ is C_1-4 alkyl or -(C_0-4 alkylene)-(phenyl). In certain embodiments, R⁸ is C1-4 alkyl. In certain embodiments, R⁸ is -(C0-4 alkylene)-(phenyl). In certain embodiments, R⁸ is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below. [0309] As defined generally above, R⁹ is oxo, C1-4 alkyl, hydroxyl, or -C(O)-O-(C1-4 alkyl). In certain embodiments, R⁹ is oxo. In certain embodiments, R⁹ is C1-4 alkyl. In certain embodiments, R⁹ is hydroxyl. In certain embodiments, R⁹ is -C(O)-O-(C_1-4 alkyl). In certain embodiments, R⁹ is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below. [0310] As defined generally above, m is 1 or 2. In certain embodiments, m is 1. In certain embodiments, m is 2. [0311] As defined generally above, n is 1 or 2. In certain embodiments, n is 1. In certain embodiments, n is 2. [0312] As defined generally above, p is 0, 1, 2, 3, or 4. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4. In certain embodiments, p is selected from a corresponding value in the groups depicted in compounds I-1 through I-180 in Table 1, below. [0313] As defined generally above, x is 1, 2, 3, 4, or 5. In certain embodiments, x is 1. In certain embodiments, x is 2. In certain embodiments, x is 3. In certain embodiments, x is 4. In certain embodiments, x is 5. In certain embodiments, x is selected from a corresponding value in the groups depicted in compounds I-1 through I-180 in Table 1, below. [0314] As defined generally above, y and z are independently 1, 2, or 3. In certain embodiments, y is 1. In certain embodiments, y is selected from a corresponding value in the groups depicted in the compounds in Table 1, below. In certain embodiments, y is 2. In certain embodiments, y is 3. In certain embodiments, z is 1. In certain embodiments, z is 2. In certain embodiments, z is 3. In certain embodiments, z is selected from a corresponding value in the groups depicted in compounds I-1 through I-180 in Table 1, below. [0315] The description above describes multiple embodiments relating to compounds of Formula I-1. The patent application specifically contemplates all combinations of the embodiments. [0316] In certain embodiments, the compound of Formula I is further defined by Formula Ia: or a pharmaceutically acceptable salt thereof. In certain embodiments, the definition of variables A¹, A², R¹, and Z is one of the embodiments described above in connection with Formula I. In certain embodiments, the definition of variables A¹, A², R¹, and Z is one of the embodiments described above in connection with Formula I-1. [0317] In certain embodiments, the compound of Formula I is further defined by Formula Ib: or a pharmaceutically acceptable salt thereof, wherein: B¹ is a 6-membered aryl ring or a 5-6 membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur, wherein the aryl and heteroaryl are substituted with p occurrences of R². [0318] In certain embodiments, the definition of variables A², R¹, and Z is one of the embodiments described above in connection with Formula I. In certain embodiments, the definition of variables A², R¹, and Z is one of the embodiments described above in connection with Formula I-1. [0319] In certain embodiments, each of which is substituted by 0, 1, 2, 3, or 4 occurrences of halo. In certain embodiments, B¹ is [0320] The description above describes multiple embodiments relating to compounds of Formula Ib. The patent application specifically contemplates all combinations of the embodiments. [0321] In certain embodiments, the compound of Formula I is further defined by Formula Ic: or a pharmaceutically acceptable salt thereof, wherein: B¹ is a 6-membered aryl ring or a 5-6 membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur, wherein the aryl and heteroaryl are substituted with p occurrences of R². In certain embodiments, the definition of variables A², R¹, and Z is one of the embodiments described above in connection with Formula I. In certain embodiments, the definition of variables A², R¹, and Z is one of the embodiments described above in connection with Formula I-1. In certain embodiments, B¹ is each of which is substituted by 0, 1, 2, 3, or 4 occurrences of halo. In certain embodiments, B¹ is [0322] The description above describes multiple embodiments relating to compounds of Formula Ic. The patent application specifically contemplates all combinations of the embodiments. [0323] In certain embodiments, the compound of Formula I is further defined by Formula Id: or a pharmaceutically acceptable salt thereof, wherein X is -C(H)- or -N-. In certain embodiments, X is -C(H)-. In certain embodiments, X is -C(R²)-, and the aromatic ring of the isoindoline is substituted with 0, 1, 2, or 3 additional occurrences of R². In certain embodiments, X is -C(R²)-, and the aromatic ring of the isoindoline is not substituted with any additional occurrences of R². In certain embodiments, X is -C(R²)-, and the aromatic ring of the isoindoline is substituted with 1 additional occurrence of R². In certain embodiments, X is -C(R²)-, and the aromatic ring of the isoindoline is substituted with 2 additional occurrences of R². In certain embodiments, X is -N-. In certain embodiments, the definition of variables A², R², p, and Z is one of the embodiments described above in connection with Formula I. In certain embodiments, the definition of variables A², R², p, and Z is one of the embodiments described above in connection with Formula I-1. [0324] In certain embodiments, the compound of Formula I is further defined by Formula Ie: or a pharmaceutically acceptable salt thereof, wherein Y and Q each represent independently N or S. In certain embodiments, the definition of variables A² and Z is one of the embodiments described above in connection with Formula I. In certain embodiments, the definition of variables A² and Z is one of the embodiments described above in connection with Formula I-1. [0325] In certain embodiments, the compound of Formula I is further defined by Formula If, Ig, Ih, or Ii: or a pharmaceutically acceptable salt thereof. In certain embodiments, the definition of variables R², p, and Z is one of the embodiments described above in connection with Formula I. In certain embodiments, the definition of variables R², p, and Z is one of the embodiments described above in connection with Formula I-1. [0326] In certain embodiments, the compound of Formula I is further defined by Formulae Ij or Ik: or a pharmaceutically acceptable salt thereof. In certain embodiments, the definition of variables R², p, and Z is one of the embodiments described above in connection with Formula I. In certain embodiments, the definition of variables R², p, and Z is one of the embodiments described above in connection with Formula I-1. [0327] In certain embodiments, the compound of Formula I is further defined by Formula Il: or a pharmaceutically acceptable salt thereof. In certain embodiments, the definition of variable Z is one of the embodiments described above in connection with Formula I. In certain embodiments, the definition of variable Z is one of the embodiments described above in connection with Formula I-1. [0328] The description above describes multiple embodiments relating to compounds of Formula Il. The patent application specifically contemplates all combinations of the embodiments. [0329] Another aspect of the invention provides a compound represented by Formula I-A: (I-A) or a pharmaceutically acceptable salt thereof; wherein: A¹ is each of which is substituted by p occurrences of halo; A² is a covalent bond; or A² is each of which is substituted with 0 or 1 occurrences of R³, wherein ***is the point of attachment to Z; R^1A, R^1B, and R^1C represent independently for each occurrence hydrogen or C1-4 alkyl; R³ is halo or C_1-4 alkyl; Z is -C(O)R⁴, -C(O)-(C1-4 alkylene)-R⁴, -C(O)-OH, -C(O)-O-(C1-6 alkyl), -C(O)- N(R^1A)(R^1B), -C(O)-O-(C1-4 alkylene)-O-(C1-4 alkylene)-N(R^1A)(R^1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R^1A)(R^1B))-(C_1-4 hydroxyalkyl), -S(O)₂-(C_1-6 alkyl), - S(O)2-(C3-7 cycloalkyl), -S(O)2-N(R^1A)(R^1B), -S(O)2-N(R^1A)-C(O)-(C1-6 alkyl), -S(O)2- N(R^1A)-C(O)-O-(C1-6 alkyl), -S(O)2-N(R^1A)-C(O)-N(R^1B)(R^1C), -S(O)2-[(C1-4 alkylene)-O-]x- R⁵, -N(R^1A)-C(O)-(C_1-4 alkylene)-(5-6 membered saturated heterocyclyl containing 1 oxygen atom), -N(R^1A)-C(O)-O-(C1-4 alkylene)-(phenyl), -N(R^1A)-C(O)-O-[(C1-4 alkylene)-O-]x-R⁶, - N(R^1A)-C(O)-N(R^1B)-[(C1-4 alkylene)-O-]x-R⁶, -C(O)-N(R^1A)-(C1-6 hydroxyalkyl), -C(O)- N(R^1A)-[(C_1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1A)(R^1B), -N(R^1A)-C(O)-N(R^1B)-[(C_1-6 hydroxyalkyl), -C(O)-(C_1-4 alkylene)-[O-(C_1-4 alkylene)-]_y-(C_1-6 alkoxyl), -C(O)-C(O)-OH, - C(O)-C(O)-N(R^1A)(R^1B), -N(R^1A)-C(O)-(C1-6 hydroxyalkyl), -C(O)-C(O)-N(R^1A)-R⁵, - N(R^1A)-C(O)-C(O)-N(R^1B)(R^1C), -C(O)-N(R^1A)-S(O)2-R⁷, -N(R^1A)-S(O)2-R⁷, -C(O)-C(O)- N(R^1A)-S(O)₂-(C_1-6 alkyl), -S(O)₂-(C_1-4 alkylene)-(C_1-6 alkoxyl), -C(O)-C(O)-N(R^1A)-(C_1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-O-(C1-4 alkylene)- (5 membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom), or hydrogen, wherein the heterocyclyl is substituted with z occurrences of R⁹); R⁴ is C1-6 hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl; R⁵ is C1-6 alkyl, C1-6 hydroxalkyl or C1-6 alkoxyl; R⁶ is C1-4 alkyl, C1-4 hydroxyalkyl, or C1-4 haloalkyl; R⁷ is C_1-4 alkyl, C_1-4 alkoxyl, -(C_0-4 alkylene)-N(R^1A)(R^1B), or -N(R^1B)-C(O)-O-R⁸; R⁸ is C1-4 alkyl or -(C0-4 alkylene)-(phenyl); R⁹ is oxo, C1-4 alkyl, or -C(O)-O-(C1-4 alkyl); p is 0, 1, 2, 3, or 4; x is 1, 2, 3, 4, or 5; and y and z are independently 1, 2, or 3. [0330] The definitions of variables in Formula I-A above encompass multiple chemical groups. The application contemplates embodiments where, for example, (i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, (ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and (iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii). [0331] In certain embodiments, the compound is a compound of Formula I-A. [0332] As defined generally above, A¹ is , , , or , each of which is substituted by p occurrences of halo. In certain embodiments, A¹ is substituted by p occurrences of halo. In certain embodiments, A¹ is substituted by p occurrences of halo. In certain embodiments, A¹ is substituted by p occurrences of halo. In certain embodiments, A¹ is substituted by p occurrences of halo. In certain embodiments, A¹ is In certain 139 embodiments, A¹ is In certain embodiments, A¹ is In certain embodiments, A¹ is In certain embodiments, A¹ is In certain embodiments, A¹ is In certain embodiments, A¹ is In certain embodiments, A¹ is In certain embodiments, A¹ is In certain embodiments, In certain embodiments, certain embodiments, A¹ is . In certain embodiments, A¹ is certain embodiments, A¹ is selected from the groups depicted in the compounds in Table 1, below. [0333] As defined generally above, A² is a covalent bond; or , which is substituted with 0 or 1 occurrences of R³, wherein ***is the point of attachment to Z. In certain embodiments, A² is a covalent bond. In certain embodiments, A² is substituted with 0 or 1 occurrences of R³, wherein ***is the point of attachment to Z. In certain embodiments, A² is substituted with 0 or ³ 1 occurrences of R , wherein ***is the point of attachment to Z. In certain embodiments, A² is substituted with 0 or 1 occurrences of R³, wherein ***is the point of attachment to Z. In certain embodiments, A² is substituted with 0 or 1 occurrences of R³, wherein ***is the point of attachment to Z. In certain embodiments, A² is substituted with 0 or 1 occurrences of R³, wherein ***is the point of attachment to Z. In certain embodiments, A² is substituted with 0 or 1 occurrences of R³, wherein ***is the point of attachment to Z. In certain embodiments, A² is , each of which is substituted with 0 or 1 occurrences of R³, wherein ***is the point of attachment to Z. In certain embodiments, A² is selected from the groups depicted in the compounds in Table 1, below. [0334] As defined generally above, R^1A, R^1B, and R^1C each represent independently for each occurrence hydrogen or C_1-4 alkyl. In certain embodiments, R^1A is hydrogen. In certain embodiments, R^1A is C1-4 alkyl. In certain embodiments, R^1B is hydrogen. In certain embodiments, R^1B is C_1-4 alkyl. In certain embodiments, R^1C is hydrogen. In certain embodiments, R^1C is C_1-4 alkyl. In certain embodiments, R^1A and R^1B are both hydrogen. In certain embodiments, R^1A and R^1B are both methyl. In certain embodiments, R^1A is selected from the groups depicted in the compounds in Table 1, below. [0335] As defined generally above, R³ is halo or C_1-4 alkyl. In certain embodiments, R³ is halo. In certain embodiments, R³ is C_1-4 alkyl. In certain embodiments, R³ is fluoro. In certain embodiments, R³ is chloro. In certain embodiments, R³ is methyl. In certain embodiments, R³ is selected from the groups depicted in the compounds in Table 1, below. [0336] As defined generally above, Z is -C(O)R⁴, -C(O)-(C_1-4 alkylene)-R⁴, -C(O)-OH, -C(O)-O- (C1-6 alkyl), -C(O)-N(R^1A)(R^1B), -C(O)-O-(C1-4 alkylene)-O-(C1-4 alkylene)-N(R^1A)(R^1B), -C(O)- O-(C_1-4 alkylene substituted with 1 occurrence of -N(R^1A)(R^1B))-(C_1-4 hydroxyalkyl), -S(O)₂-(C_{1- 6} alkyl), -S(O)₂-(C_3-7 cycloalkyl), -S(O)₂-N(R^1A)(R^1B), -S(O)₂-N(R^1A)-C(O)-(C_1-6 alkyl), -S(O)₂- N(R^1A)-C(O)-O-(C1-6 alkyl), -S(O)2-N(R^1A)-C(O)-N(R^1B)(R^1C), -S(O)2-[(C1-4 alkylene)-O-]x-R⁵, - N(R^1A)-C(O)-(C1-4 alkylene)-(5-6 membered saturated heterocyclyl containing 1 oxygen atom), - N(R^1A)-C(O)-O-(C_1-4 alkylene)-(phenyl), -N(R^1A)-C(O)-O-[(C_1-4 alkylene)-O-]_x-R⁶, -N(R^1A)- C(O)-N(R^1B)-[(C1-4 alkylene)-O-]x-R⁶, -C(O)-N(R^1A)-(C1-6 hydroxyalkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1A)(R^1B), -N(R^1A)-C(O)-N(R^1B)-[(C_1-6 hydroxyalkyl), -C(O)- (C1-4 alkylene)-[O-(C1-4 alkylene)-]y-(C1-6 alkoxyl), -C(O)-C(O)-OH, -C(O)-C(O)-N(R^1A)(R^1B), - N(R^1A)-C(O)-(C1-6 hydroxyalkyl), -C(O)-C(O)-N(R^1A)-R⁵, -N(R^1A)-C(O)-C(O)-N(R^1B)(R^1C), - C(O)-N(R^1A)-S(O)₂-R⁷, -N(R^1A)-S(O)₂-R⁷, -C(O)-C(O)-N(R^1A)-S(O)₂-(C_1-6 alkyl), -S(O)₂-(C_1-4 alkylene)-(C1-6 alkoxyl), -C(O)-C(O)-N(R^1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-O-(C1-4 alkylene)-(5 membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom), or hydrogen, wherein the heterocyclyl is substituted with z occurrences of R⁹. In certain embodiments, Z is hydrogen. In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is or . In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is , , In certain embodiments, Z is , In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, certain embodiments, Z i . In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z i . In certain embodiments, Z is . In certain embodiments, Z i . In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is certain embodiments, Z is . In certain embodiments, Z is ain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, . In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is [0337] In certain embodiments, Z is -C(O)R⁴. In certain embodiments, Z is -C(O)-(C1-4 alkylene)-R⁴. In certain embodiments, Z is -C(O)-OH. In certain embodiments, Z is -C(O)-O- (C1-6 alkyl). In certain embodiments, Z is -C(O)-N(R^1A)(R^1B). In certain embodiments, Z is - C(O)-O-(C_1-4 alkylene)-O-(C_1-4 alkylene)-N(R^1A)(R^1B). In certain embodiments, Z is -C(O)-O- (C1-4 alkylene substituted with 1 occurrence of -N(R^1A)(R^1B))-(C1-4 hydroxyalkyl). In certain embodiments, Z is -S(O)2-(C1-6 alkyl). In certain embodiments, Z is -S(O)2-(C3-7 cycloalkyl). In certain embodiments, Z is -S(O)₂-N(R^1A)(R^1B). In certain embodiments, Z is -S(O)₂-N(R^1A)- C(O)-(C1-6 alkyl). In certain embodiments, Z is -S(O)2-N(R^1A)-C(O)-O-(C1-6 alkyl). In certain embodiments, Z is -S(O)2-N(R^1A)-C(O)-N(R^1B)(R^1C). In certain embodiments, Z is -S(O)2-[(C1-4 alkylene)-O-]_x-R⁵. In certain embodiments, Z is -N(R^1A)-C(O)-(C_1-4 alkylene)-(5-6 membered saturated heterocyclyl containing 1 oxygen atom). In certain embodiments, Z is -N(R^1A)-C(O)- O-(C1-4 alkylene)-(phenyl). In certain embodiments, Z is -N(R^1A)-C(O)-O-[(C1-4 alkylene)-O-]x- R⁶. In certain embodiments, Z is -N(R^1A)-C(O)-N(R^1B)-[(C_1-4 alkylene)-O-]_x-R⁶. In certain embodiments, Z is -C(O)-N(R^1A)-(C_1-6 hydroxyalkyl). In certain embodiments, Z is -C(O)- N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1A)(R^1B). In certain embodiments, Z is -N(R^1A)- C(O)-N(R^1B)-[(C1-6 hydroxyalkyl). In certain embodiments, Z is -C(O)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]_y-(C_1-6 alkoxyl). In certain embodiments, Z is -C(O)-C(O)-OH. In certain embodiments, Z is -C(O)-C(O)-N(R^1A)(R^1B). In certain embodiments, Z is -N(R^1A)-C(O)-(C1-6 hydroxyalkyl). In certain embodiments, Z is -C(O)-C(O)-N(R^1A)-R⁵. In certain embodiments, Z is -N(R^1A)-C(O)-C(O)-N(R^1B)(R^1C). In certain embodiments, Z is -C(O)-N(R^1A)-S(O)₂-R⁷. In certain embodiments, Z is -N(R^1A)-S(O)2-R⁷. In certain embodiments, Z is -C(O)-C(O)-N(R^1A)- S(O)2-(C1-6 alkyl), -S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl), -C(O)-C(O)-N(R^1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms). In certain embodiments, Z is -C(O)-O-(C_{1- 4} alkylene)-(5 membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R⁹). In certain embodiments, Z is hydrogen. In certain embodiments, Z is selected from the groups depicted in the compounds in Table 1, below. [0338] As defined generally above, R⁴ is C1-6 hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is C1-6 hydroxyalkyl. In certain embodiments, R⁴ is a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 3 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 4 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 5 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 3-7 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 3 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 4 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 5 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 6-membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is a 7 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R⁴ is selected from the groups depicted in the compounds in Table 1, below. [0339] As defined generally above, R⁵ is C_1-6 alkyl, C_1-6 hydroxalkyl, or C_1-6 alkoxyl. In certain embodiments, R⁵ is C1-6 alkyl. In certain embodiments, R⁵ is C1-6 hydroxalkyl. In certain embodiments, R⁵ is C1-6 alkoxyl. In certain embodiments, R⁵ is selected from the groups depicted in the compounds in Table 1, below. [0340] As defined generally above, R⁶ is C1-4 alkyl, C1-4 hydroxyalkyl, or C1-4 haloalkyl. In certain embodiments, R⁶ is C1-4 alkyl. In certain embodiments, R⁶ is C1-4 hydroxyalkyl. In certain embodiments, R⁶ is C_1-4 haloalkyl. In certain embodiments, R⁶ is selected from the groups depicted in the compounds in Table 1, below. [0341] As defined generally above, R⁷ is C_1-4 alkyl, C_1-4 alkoxyl, -(C_0-4 alkylene)- N(R^1A)(R^1B), or -N(R^1B)-C(O)-O-R⁸. In certain embodiments, R⁷ is C1-4 alkyl. In certain embodiments, R⁷ is C1-4 alkoxyl. In certain embodiments, R⁷ is -(C0-4 alkylene)-N(R^1A)(R^1B). In certain embodiments, R⁷ is -N(R^1B)-C(O)-O-R⁸. In certain embodiments, R⁷ is selected from the groups depicted in the compounds in Table 1, below. [0342] As defined generally above, R⁸ is C1-4 alkyl or -(C0-4 alkylene)-(phenyl). In certain embodiments, R⁸ is C_1-4 alkyl. In certain embodiments, R⁸ is -(C_0-4 alkylene)-(phenyl). In certain embodiments, R⁸ is selected from the groups depicted in the compounds in Table 1, below. [0343] As defined generally above, R⁹ is oxo, C_1-4 alkyl, or -C(O)-O-(C_1-4 alkyl). In certain embodiments, R⁹ is oxo. In certain embodiments, R⁹ is C_1-4 alkyl. In certain embodiments, R⁹ is -C(O)-O-(C1-4 alkyl). In certain embodiments, R⁹ is selected from the groups depicted in the compounds in Table 1, below. [0344] As defined generally above, p is 0, 1, 2, 3, or 4. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4. In certain embodiments, p is selected from a corresponding value in the groups depicted in the compounds in Table 1, below. [0345] As defined generally above, x is 1, 2, 3, 4, or 5. In certain embodiments, x is 1. In certain embodiments, x is 2. In certain embodiments, x is 3. In certain embodiments, x is 4. In certain embodiments, x is 5. In certain embodiments, x is selected from a corresponding value in the groups depicted in the compounds in Table 1, below. [0346] As defined generally above, y and z are independently 1, 2, or 3. In certain embodiments, y is 1. In certain embodiments, y is 2. In certain embodiments, y is 3. In certain embodiments, y is selected from a corresponding value in the groups depicted in the compounds in Table 1, below. In certain embodiments, z is 1. In certain embodiments, z is 2. In certain embodiments, z is 3. In certain embodiments, z is selected from a corresponding value in the groups depicted in the compounds in Table 1, below. [0347] The description above describes multiple embodiments relating to compounds of Formula I-A. The patent application specifically contemplates all combinations of the embodiments. [0348] The definitions of variables in Formula I-A above encompass multiple chemical groups. The application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii). Exemplary Specific Compounds [0349] In certain embodiments, the compound is a compound in Table 1 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1. In certain embodiments, the compound is a compound selected from I-1 through I- 180 in Table 1, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound selected from I-1 through I-180 in Table 1. TABLE 1. Exemplary Compounds

198

[0350] In certain embodiments, the compound is a compound in Table 1, or a pharmaceutically acceptable salt thereof, wherein the compound has at least one activity of “A” or “B” in one of the biochemical assays in Table 3. In certain embodiments, the compound is a compound in Table 1, or a pharmaceutically acceptable salt thereof, wherein the compound has at least one activity of “A” in one of the biochemical assays in Table 3. In certain embodiments, the compound is a compound in Table 1, or a pharmaceutically acceptable salt thereof, wherein the compound has at least one activity of “A” or “B” in one of the cell-based assays in Table 3. In certain embodiments, the compound is a compound in Table 1, or a pharmaceutically acceptable salt thereof, wherein the compound has at least one activity of “A” in one of the cell- based assays in Table 3. [0351] In certain embodiments, the compound is a compound in Table 1, wherein the compound has at least one activity of “A” or “B” in one of the biochemical assays in Table 3. In certain embodiments, the compound is a compound in Table 1, wherein the compound has at least one activity of “A” in one of the biochemical assays in Table 3. In certain embodiments, the compound is a compound in Table 1, wherein the compound has at least one activity of “A” or “B” in one of the cell-based assays in Table 3. In certain embodiments, the compound is a compound in Table 1, wherein the compound has at least one activity of “A” in one of the cell- based assays in Table 3. [0352] In certain embodiments, the compound is a compound in Table 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula I-B. In certain embodiments, the compound is a compound in Table 1, wherein the compound is a compound of Formula I-B. In certain embodiments, the compound is a compound in Table 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula I- C. In certain embodiments, the compound is a compound in Table 1, wherein the compound is a compound of Formula I-C. In certain embodiments, the compound is a compound in Table 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula I- D. In certain embodiments, the compound is a compound in Table 1, wherein the compound is a compound of Formula I-D. [0353] In certain embodiments, the compound is a compound in the table below, or a pharmaceutically acceptable salt thereof: 216

. [0354] In certain embodiments, the compound is a compound in the table above. In certain embodiments, the compound is a compound in the table above, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula I-B. In certain embodiments, the compound is a compound in the table above, wherein the compound is a compound of Formula I-B. In certain embodiments, the compound is a compound in the table above, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula I-C. In certain embodiments, the compound is a compound in the table above, wherein the compound is a compound of Formula I-C. In certain embodiments, the compound is a compound in the table above, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula I-D. In certain embodiments, the compound is a compound in the table above, wherein the compound is a compound of Formula I-D. [0355] In certain embodiments, the compound is one of the following: Synthetic Methods [0356] Methods for preparing compounds described herein are illustrated in the following synthetic Scheme. The Scheme is given for the purpose of illustrating the invention, and not intended to limit the scope or spirit of the invention. Starting materials shown in the Scheme can be obtained from commercial sources or can be prepared based on procedures described in the literature. [0357] Scheme 1 illustrates a general method for preparing heteroaryl compounds F. Amine A is coupled with a protected piperidine or other suitable reagent (e.g., a cyclohexane, bicyclo[2.2.2.]octane, dihydropyridine, etc.) using, for example, a Suzuki or Stille coupling to afford compound B. Compound B is reacted with an acyl chloride to form carbamate C. Carbamate C is then reacted with an optionally substituted isoindoline or other heteroaryl compound (e.g., a pyrrolo-pyridine, pyrrolo-pyrazine, a pyrolo-thiazole, etc.) to form protected isoindoline compound D. Deprotection of compound D affords the free amine compound E, which is then reacted with a carboxylic acid to form heteroaryl compound F. Depending on the type of Z group and A² ring present in Formula I, I-1, I-A, I-B, I-C, or I-D above, other conventional methodologies may be employed for the conversion of compound E into heteroaryl F in place of the amine-carboxylic acid coupling step. SCHEME 1. [0358] In the Scheme, it is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated (for example, use of protecting groups or alternative reactions). Protecting group chemistry and strategy is well known in the art, for example, as described in detail in “Protecting Groups in Organic Synthesis”, T. W. Greene and P. G. M. Wuts, 3^rd edition, John Wiley & Sons, 1999, the entire contents of which are hereby incorporated by reference. The modular synthetic route illustrated in Scheme 1 can also be readily modified by one of skill in the art to provide additional compounds by conducting functional group transformations on the intermediate and final compounds. Such functional group transformations are well known in the art, as described in, for example, “Comprehensive Organic Synthesis” (B.M. Trost & I. Fleming, eds., 1991-1992). II. Therapeutic Applications [0359] The heteroaryl compounds described herein, such as a compound of Formula I, I-1, I-A, I-B, I-C, or I-D, or other compounds in Section I, provide therapeutic benefits to subjects suffering a disease or condition mediated by NAMPT. Description of exemplary therapeutic applications are provided herein below. [0360] One aspect of the invention provides a method of treating a disease or condition mediated by NAMPT. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, I-1, I-A, I-B, I-C, or I-D, to treat the disease or condition. [0361] Another aspect of the invention provides a method of treating a disease or condition described herein. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, I-1, I-A, I-B, I-C, or I-D, to treat the disease or condition. [0362] Another aspect of the invention provides a method of inhibiting the activity of NAMPT. The method comprises contacting a NAMPT with an effective amount of a compound described herein, such as a compound of Formula I, I-1, I-A, I-B, I-C, or I-D, to inhibit the activity of said NAMPT. [0363] In certain embodiments, the disease or condition is selected from a proliferative disorder (e.g., cancer, neoplasia), inflammatory disorder (e.g., chronic inflammatory disorder, acute inflammatory disorder, auto-inflammatory disorder), autoimmune disorder, fibrotic disorder, metabolic disorder, cardiovascular disorder, cerebrovascular disorder, and myeloid cell-driven hyper-inflammatory response in a COVID-19 infection. [0364] In certain embodiments, the disease or condition mediated by NAMPT is a NAPRT- negative cancer. In certain embodiments, the disease or condition mediated by NAMPT is psoriasis, dermatitis, vitiligo, ichthyosis, alopecia areata, epidermolysis bullosa, hidradenitis suppurativa, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, or kidney disease. In certain embodiments, the disease or condition mediated by NAMPT is inflammatory bowel disease. [0365] In certain embodiments, the heteroaryl compounds described herein, such as a compound of Formula I, I-1, I-A, I-B, I-C, or I-D, or other compounds in Section I, provide therapeutic benefits to subjects suffering from cancer (e.g., pancreatic cancer, melanoma, glioma, lung cancer, colon cancer, rectal cancer, breast cancer, cervical cancer, prostate cancer, gastric cancer, skin cancer, liver cancer, bile duct cancer, nervous system cancer, lymphoma, leukemia), intestinal or inflammatory bowel disease, diseases of overactive T-cells, psoriasis, neurodegenerative diseases, acute kidney disease, inflammation, stroke, acute infarct, inflammatory bowel disease, acute lung injury, rheumatoid arthritis, nephropathy, fibrosis, or sepsis. [0366] Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, I-1, I-A, I-B, I-C, or I-D or other compounds in Section I) in the manufacture of a medicament. In certain embodiments, the medicament is for treating a disease or condition described herein, such as a proliferative disorder, inflammatory disorder, or metabolic disorder. [0367] Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, I-1, I-A, I-B, I-C, or I-D or other compounds in Section I) for treating a disease or condition, such as a disease or condition described herein. [0368] In certain embodiments, the subject is a human. In certain embodiments, the subject is an adult human. In certain embodiments, the subject is a pediatric human. In certain embodiments, the subject is a geriatric human. Exemplary Diseases or Conditions [0369] Exemplary diseases and disorders include but are not limited to those described herein. In certain embodiments, the disease or condition is a proliferative disorder (e.g., cancer, neoplasia), an inflammatory disorder (e.g., chronic inflammatory disorder, acute inflammatory disorder, auto-inflammatory disorder), an autoimmune disorder, a fibrotic disorder, a metabolic disorder, a cardiovascular disorder, a cerebrovascular disorder, or a myeloid cell-driven hyper- inflammatory response in COVID-19 infections. In certain embodiments, the proliferative disease is cancer. In certain embodiments, the proliferative disease is pancreatic cancer, melanoma, glioma, lung cancer, colon cancer, rectal cancer, breast cancer, cervical cancer, prostate cancer, gastric cancer, skin cancer, liver cancer, bile duct cancer, nervous system cancer, lymphoma, leukemia, or a combination thereof. In certain embodiments, the disease or condition is an inflammatory disorder (e.g., intestinal or inflammatory bowel disease, diseases of overactive T-cells, psoriasis, neurodegenerative diseases, acute kidney disease, inflammation, stroke, acute infarct, inflammatory bowel disease, acute lung injury, rheumatoid arthritis, nephropathy, fibrosis, or sepsis. In certain embodiments, the disease or condition is a NAPRT- negative cancer. In certain embodiments, the disease or condition is psoriasis, dermatitis, vitiligo, ichthyosis, alopecia areata, epidermolysis bullosa, hidradenitis suppurativa, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, or kidney disease. In certain embodiments, the disease or condition is inflammatory bowel disease. [0370] Exemplary proliferative diseases include but are not limited to those described herein. In certain embodiments, the proliferative disease or condition to be treated or prevented using the compounds described herein is cancer. [0371] Additional 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, triple negative breast cancer (TNBC)); 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)); 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 neuroendocrine 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; vulvar cancer (e.g., Paget's disease of the vulva); Burkitt lymphoma; primary intraocular lymphoma; classic Hodgkin lymphoma; biphenotypic acute leukemia; T cell lymphoma; nasal-type T cell lymphoma; enteropathy-type T-cell lymphoma; subcutaneous panniculitis-like T-cell lymphoma; blastic NK- cell lymphoma; T-cell prolymphocytic leukemia, and NK-cell leukemia. [0372] In certain embodiments, the cancer is a hematological malignancy. Exemplary hematological malignancies include but are not limited to leukemia, such as acute lymphoblastic 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), chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)), acute non-lymphocytic leukemia (ANLL), acute promyelocytic leukemia (APL), and acute myelomonocytic leukemia (AMMoL); 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 (DLBCL, e.g., activated B-cell (ABC) DLBCL (ABC-DLBCL))), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt’s lymphoma, Waldenstrom’s macroglobulinemia (WM, lymphoplasmacytic lymphoma), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, central nervous system (CNS) lymphoma (e.g., primary CNS lymphoma and secondary 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); lymphoma of an immune privileged site (e.g., cerebral lymphoma, ocular lymphoma, lymphoma of the placenta, lymphoma of the fetus, testicular lymphoma); a mixture of one or more leukemia/lymphoma as described above; myelodysplasia; multiple myeloma (MM); heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease), polycythemia vera, Wilm’s tumor, and Ewing’s sarcoma. [0373] In certain embodiments, said disease or condition is a cancer. In certain embodiments, said disease or condition is an angiogenesis disorder. In certain embodiments, said disease or condition is a multiple myeloma. In certain embodiments, said disease or condition is a leukemia (e.g., acute lymphocytic leukemia, acute and chronic myelogenous leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, chronic myelomonocytic leukemia, or promyelocytic leukemia). [0374] In certain embodiments, the cancer is a solid tumor, leukemia, or lymphoma. In certain embodiments, the cancer is ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, stomach cancer, colon cancer, rectal cancer, skin cancer, sebaceous gland carcinoma, bile duct and gallbladder cancers, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, or thyroid cancer. [0375] In certain embodiments, said disease or condition is a lymphoma (e.g., B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, diffuse large B cell lymphoma, hairy cell lymphoma, Burkitt’s lymphoma, mast cell tumors, Hodgkin's disease or non-Hodgkin’s disease). In certain embodiments, said disease or condition is myelodysplastic syndrome. In certain embodiments, said disease or condition is fibrosarcoma. In certain embodiments, said disease or condition is rhabdomyosarcoma. In certain embodiments, said disease or condition is astrocytoma. In certain embodiments, said disease or condition is neuroblastoma. In certain embodiments, said disease or condition is glioma and schwannomas. In certain embodiments, said disease or condition is melanoma. In certain embodiments, said disease or condition is seminoma. In certain embodiments, said disease or condition is teratocarcinoma. In certain embodiments, said disease or condition is osteosarcoma. In certain embodiments, said disease or condition is xenoderma pigmentosum. In certain embodiments, said disease or condition is keratoctanthoma. In certain embodiments, said disease or condition is thyroid follicular cancer. In certain embodiments, said disease or condition is Kaposi's sarcoma. In certain embodiments, said disease or condition is melanoma. In certain embodiments, said disease or condition is teratoma. In certain embodiments, said disease or condition is rhabdomyosarcoma. In certain embodiments, said disease or condition is a metastatic and bone disorder. In certain embodiments, said disease or condition is cancer of the bone. In certain embodiments, said disease or condition is cancer of the mouth/pharynx. In certain embodiments, said disease or condition is cancer of the esophagus. In certain embodiments, said disease or condition is cancer of the larynx. In certain embodiments, said disease or condition is cancer of the stomach. In certain embodiments, said disease or condition is cancer of the intestine. In certain embodiments, said disease or condition is cancer of the colon. In certain embodiments, said disease or condition is cancer of the rectum. In certain embodiments, said disease or condition is cancer of the lung (e.g., non-small cell lung cancer or small cell lung cancer). In certain embodiments, said disease or condition is cancer of the liver. In certain embodiments, said disease or condition is cancer of the pancreas. In certain embodiments, said disease or condition is cancer of the nerve. In certain embodiments, said disease or condition is cancer of the brain (e.g., glioma or glioblastoma multiforme). In certain embodiments, said disease or condition is cancer of the head and neck. In certain embodiments, said disease or condition is cancer of the throat. In certain embodiments, said disease or condition is cancer of the ovary. In certain embodiments, said disease or condition is cancer of the uterus. In certain embodiments, said disease or condition is cancer of the prostate. In certain embodiments, said disease or condition is cancer of the testis. In certain embodiments, said disease or condition is cancer of the bladder. In certain embodiments, said disease or condition is cancer of the kidney. In certain embodiments, said disease or condition is cancer of the breast. In certain embodiments, said disease or condition is cancer of the gall bladder. In certain embodiments, said disease or condition is cancer of the cervix. In certain embodiments, said disease or condition is cancer of the thyroid. In certain embodiments, said disease or condition is cancer of the prostate. In certain embodiments, said disease or condition is cancer of the skin (e.g., skin squamous cell carcinoma). In certain embodiments, said disease or condition is a solid tumor. In certain embodiments, said disease or condition is gastric cancer. In certain embodiments, said disease or condition is hepatocellular carcinoma. In certain embodiments, said disease or condition is a peripheral nerve sheath tumor. In certain embodiments, said disease or condition is pulmonary arterial hypertension. [0376] In certain embodiments, the disease is a cancer associated with a viral infection. In certain embodiments, the disease is a cancer resulting from infection with an oncovirus. In certain embodiments, the oncovirus is hepatitis A, hepatitis B, hepatitis C, human T- lymphotropic virus (HTLV), human papillomavirus (HPV), Kaposi's sarcoma-associated herpesvirus (HHV-8), Merkel cell polyomavirus, or Epstein-Barr virus (EBV). In certain embodiments, the disease is human T-lymphotropic virus. In certain embodiments, the disease is Kaposi’s sarcoma-associated herpesvirus. In certain embodiments, the disease is Epstein-Barr virus. Leukemias and lymphomas which may be associated with an oncoviral include: for HTLV, adult T-cell leukemia; for HHV-8, Castleman's disease and primary effusion lymphoma; and for EBV, Burkitt's lymphoma, Hodgkin’s lymphoma, and post-transplant lymphoproliferative disease. [0377] In certain embodiments, said disease or condition is an inflammatory disorder or allergic disorder. In certain embodiments, said disease or condition is an inflammatory disorder, such as autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, auto- inflammatory disorders, fibrotic disorders, metabolic disorders, neoplasias, cardiovascular or cerebrovascular disorders, and myeloid cell-driven hyper-inflammatory response in COVID-19 infections. In certain embodiments, said disease or condition is an allergic disorder, such as asthma and allergic rhinitis. [0378] In certain embodiments, said disease or condition is a disease or disorder of tissues and systemic disease [e.g., systemic lupus erythematosus (SLE); immune thrombocytopenic purpura (ITP); autoimmune hemolytic anemia (AHA); autoimmune neutropenia (AIN); Evans syndrome; proliferative and hyperproliferative diseases, such as cancer, atherosclerosis, rheumatoid arthritis, psoriasis, idiopathic pulmonary fibrosis, scleroderma, cirrhosis of the liver; and Acquired Immunodeficiency Syndrome (AIDS)]. In certain embodiments, said disease or condition is an immunologically-mediated disease, such as allograft rejection (e.g., rejection of transplanted organs or tissues). In certain embodiments, said disease or condition is a tissue injury (e.g., associated with organ transplant or revascularization procedures). In certain embodiments, said disease or condition is a disease or disorder of the respiratory tract (e.g., asthma). In certain embodiments, said disease or condition is allergic rhinitis. In certain embodiments, said disease or condition is a disease or disorder of the bone and joints (e.g., arthritis, rheumatoid arthritis). In certain embodiments, said disease or condition is a disease or disorder of the skin. In certain embodiments, said disease or condition is a disease or disorder of the gastrointestinal tract. [0379] Exemplary diseases of the respiratory tract include but are not limited to those described herein. In certain embodiments, said disease or condition is a reversible obstructive airways disease, such as asthma (e.g., bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, and dust asthma). In certain embodiments, said disease or condition is chronic or inveterate asthma (e.g., late asthma airways hyper-responsiveness). In certain embodiments, said disease or condition is bronchitis. In certain embodiments, said disease or condition is a condition characterized by an inflammation of the nasal mucus membrane. In certain embodiments, said disease or condition is acute rhinitis. In certain embodiments, said disease or condition is allergic rhinitis. In certain embodiments, said disease or condition is atrophic rhinitis. In certain embodiments, said disease or condition is chronic rhinitis (e.g., rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca, and rhinitis medicamentosa). In certain embodiments, said disease or condition is membranous rhinitis (e.g., croupous rhinitis, fibrinous rhinitis, pseudomembranous rhinitis, and scrofoulous rhinitis). In certain embodiments, said disease or condition is seasonal rhinitis [e.g., rhinitis nervosa (hay fever), vasomotor rhinitis, sarcoidosis, farmer's lung, and related diseases, such as fibroid lung and idiopathic interstitial pneumonia]. [0380] Exemplary diseases of the bone and joints include but are not limited to those described herein. In certain embodiments, said disease or condition includes pannus formation. In certain embodiments, said disease or condition does not include pannus formation. In certain embodiments, said disease or condition is rheumatoid arthritis. In certain embodiments, said disease or condition is seronegative spondyloarthropathis (e.g., ankylosing spondylitis, psoriatic arthritis, and Reiter's disease). In certain embodiments, said disease or condition is Behcet's disease. In certain embodiments, said disease or condition is Sjogren's syndrome. In certain embodiments, said disease or condition is systemic sclerosis. [0381] Exemplary diseases and disorders of the skin include but are not limited to those described herein. In certain embodiments, said disease or condition is psoriasis. In certain embodiments, said disease or condition is systemic sclerosis. In certain embodiments, said disease or condition is dermatitis. In certain embodiments, said disease or condition is atopical dermatitis. In certain embodiments, said disease or condition is contact dermatitis. In certain embodiments, said disease or condition is eczematous dermatitis. In certain embodiments, said disease or condition is seborrhoetic dermatitis. In certain embodiments, said disease or condition is Lichen planus. In certain embodiments, said disease or condition is Pemphigus. In certain embodiments, said disease or condition is bullous Pemphigus. In certain embodiments, said disease or condition is epidermolysis bullosa. In certain embodiments, said disease or condition is urticaria. In certain embodiments, said disease or condition is angiodermas. In certain embodiments, said disease or condition is vasculitides. In certain embodiments, said disease or condition is erythemas. In certain embodiments, said disease or condition is cutaneous eosinophilias. In certain embodiments, said disease or condition is uveitis. In certain embodiments, said disease or condition is alopecia. In certain embodiments, said disease or condition is areata. In certain embodiments, said disease or condition is alopecia areata. In certain embodiments, said disease or condition is vernal conjunctivitis. [0382] Exemplary diseases and disorders of the gastrointestinal tract include but are not limited to those described herein. In certain embodiments, said disease or condition is Coeliac disease. In certain embodiments, said disease or condition is proctitis. In certain embodiments, said disease or condition is eosinophilic gastro-enteritis. In certain embodiments, said disease or condition is mastocytosis. In certain embodiments, said disease or condition is pancreatitis. In certain embodiments, said disease or condition is Crohn's disease. In certain embodiments, said disease or condition is ulcerative colitis. In certain embodiments, said disease or condition is a food-related allergy having effects remote from the gut (e.g., migraine, rhinitis, and eczema). [0383] Exemplary diseases and disorders of other tissues and systemic disease include but are not limited to those described herein. In certain embodiments, said disease or condition is multiple sclerosis. In certain embodiments, said disease or condition is atherosclerosis. In certain embodiments, said disease or condition is acquired immunodeficiency syndrome (AIDS). In certain embodiments, said disease or condition is lupus. In certain embodiments, said disease or condition is lupus erythematosus. In certain embodiments, said disease or condition is systemic lupus erythematosus. In certain embodiments, said disease or condition is Hashimoto's thyroiditis. In certain embodiments, said disease or condition is myasthenia gravis. In certain embodiments, said disease or condition is type I diabetes. In certain embodiments, said disease or condition is nephrotic syndrome. In certain embodiments, said disease or condition is eosinophilia fasciitis. In certain embodiments, said disease or condition is hyper IgE syndrome. In certain embodiments, said disease or condition is lepromatous leprosy. In certain embodiments, said disease or condition is sezary syndrome. In certain embodiments, said disease or condition is idiopathic thrombocytopenia purpura. In certain embodiments, said disease or condition is restenosis following angioplasty. In certain embodiments, said disease or condition is a tumor (e.g., leukemia, lymphomas). In certain embodiments, said disease or condition is atherosclerosis. [0384] Exemplary allograft rejections include but are not limited to those described herein. In certain embodiments, said disease or condition is acute chronic allograft rejection (e.g., following transplantation of kidney, heart, liver, lung, bone marrow, skin, or cornea). In certain embodiments, said disease or condition is chronic allograft rejection (e.g., following transplantation of kidney, heart, liver, lung, bone marrow, skin, or cornea). In certain embodiments, said disease or condition is chronic graft-versus-host disease. [0385] In certain embodiments, said disease or condition is an acute inflammatory disorder. In certain embodiments, said disease or condition is an auto-inflammatory disorder. In certain embodiments, said disease or condition is a fibrotic disorder. In certain embodiments, said disease or condition is a metabolic disorder. In certain embodiments, said disease or condition is a neoplasia. In certain embodiments, said disease or condition is a cardiovascular or cerebrovascular disorder. In certain embodiments, said disease or condition is a myeloid cell- driven hyper-inflammatory response in COVID-19 infections. [0386] In certain embodiments, said disease or condition is an autoimmune disorder. In certain embodiments, said disease or condition is a chronic inflammatory disorder. In certain embodiments, said disease or condition is an acute inflammatory disorder. In certain embodiments, said disease or condition is an auto-inflammatory disorder. In certain embodiments, said disease or condition is a combination of one, two, or all three of a chronic inflammatory disorder, an acute inflammatory disorder, and an auto-inflammatory disorder. [0387] Exemplary autoimmune and/or inflammatory and/or auto-inflammatory disorders include but are not limited to those described herein. In certain embodiments, said disease or condition is an inflammatory bowel disease (e.g., ulcerative colitis or Crohn’s disease). In certain embodiments, said disease or condition is multiple sclerosis. In certain embodiments, said disease or condition is psoriasis. In certain embodiments, said disease or condition is arthritis. In certain embodiments, said disease or condition is rheumatoid arthritis. In certain embodiments, said disease or condition is osteoarthritis. In certain embodiments, said disease or condition is juvenile arthritis. In certain embodiments, said disease or condition is psoriatic arthritis. In certain embodiments, said disease or condition is reactive arthritis. In certain embodiments, said disease or condition is ankylosing spondylitis. In certain embodiments, said disease or condition is cryopyrin-associated periodic syndromes. In certain embodiments, said disease or condition is Muckle-Wells syndrome. In certain embodiments, said disease or condition is familial cold auto-inflammatory syndrome. In certain embodiments, said disease or condition is neonatal-onset multisystem inflammatory disease. In certain embodiments, said disease or condition is TNF receptor-associated periodic syndrome. In certain embodiments, said disease or condition is acute and chronic pancreatitis. In certain embodiments, said disease or condition is atherosclerosis. In certain embodiments, said disease or condition is gout. In certain embodiments, said disease or condition is a fibrotic disorder (e.g., hepatic fibrosis or idiopathic pulmonary fibrosis). In certain embodiments, said disease or condition is nephropathy. In certain embodiments, said disease or condition is sarcoidosis. In certain embodiments, said disease or condition is scleroderma. In certain embodiments, said disease or condition is anaphylaxis. In certain embodiments, said disease or condition is diabetes (e.g., diabetes mellitus type 1 or diabetes mellitus type 2). In certain embodiments, said disease or condition is diabetic retinopathy. In certain embodiments, said disease or condition is Still's disease. In certain embodiments, said disease or condition is vasculitis. In certain embodiments, said disease or condition is sarcoidosis. In certain embodiments, said disease or condition is pulmonary inflammation. In certain embodiments, said disease or condition is respiratory failure. In certain embodiments, said disease or condition is acute respiratory distress syndrome. In certain embodiments, said disease or condition is chronic eosinophilic pneumonia. In certain embodiments, said disease or condition is wet and dry age-related macular degeneration. In certain embodiments, said disease or condition is autoimmune hemolytic syndromes. In certain embodiments, said disease or condition is autoimmune and inflammatory hepatitis. In certain embodiments, said disease or condition is autoimmune neuropathy. In certain embodiments, said disease or condition is autoimmune ovarian failure. In certain embodiments, said disease or condition is autoimmune orchitis. In certain embodiments, said disease or condition is autoimmune thrombocytopenia. In certain embodiments, said disease or condition is silicone implant-associated autoimmune disease. In certain embodiments, said disease or condition is Sjogren's syndrome. In certain embodiments, said disease or condition is familial Mediterranean fever. In certain embodiments, said disease or condition is systemic lupus erythematosus. In certain embodiments, said disease or condition is vasculitis syndromes (e.g., temporal, Takayasu’s and giant cell arteritis, Behcet’s disease or Wegener's granulomatosis). In certain embodiments, said disease or condition is vitiligo. In certain embodiments, said disease or condition is ichthyosis. In certain embodiments, said disease or condition is secondary hematologic manifestation of autoimmune diseases (e.g., anemias). In certain embodiments, said disease or condition is drug-induced autoimmunity. In certain embodiments, said disease or condition is Hashimoto’s thyroiditis. In certain embodiments, said disease or condition is hypophysitis. In certain embodiments, said disease or condition is idiopathic thrombocytic pupura. In certain embodiments, said disease or condition is metal-induced autoimmunity. In certain embodiments, said disease or condition is myasthenia gravis. In certain embodiments, said disease or condition is pemphigus. In certain embodiments, said disease or condition is autoimmune deafness (e.g., Meniere's disease). In certain embodiments, said disease or condition is Goodpasture's syndrome. In certain embodiments, said disease or condition is Graves’ disease. In certain embodiments, said disease or condition is an HW-related autoimmune syndromes. In certain embodiments, said disease or condition is Guillain-Barre disease. In certain embodiments, said disease or condition is Addison’s disease. In certain embodiments, said disease or condition is anti-phospholipid syndrome. In certain embodiments, said disease or condition is asthma. In certain embodiments, said disease or condition is atopic dermatitis. In certain embodiments, said disease or condition is Celiac disease. In certain embodiments, said disease or condition is Cushing’s syndrome. In certain embodiments, said disease or condition is dermatomyositis. In certain embodiments, said disease or condition is idiopathic adrenal atrophy. In certain embodiments, said disease or condition is idiopathic thrombocytopenia. In certain embodiments, said disease or condition is Kawasaki syndrome. In certain embodiments, said disease or condition is Lambert-Eaton Syndrome. In certain embodiments, said disease or condition is pernicious anemia. In certain embodiments, said disease or condition is pollinosis. In certain embodiments, said disease or condition is polyarteritis nodosa. In certain embodiments, said disease or condition is primary biliary cirrhosis. In certain embodiments, said disease or condition is primary sclerosing cholangitis. In certain embodiments, said disease or condition is Raynaud’s disease. In certain embodiments, said disease or condition is Raynaud’s phenomenon. In certain embodiments, said disease or condition is Reiter’s Syndrome. In certain embodiments, said disease or condition is relapsing polychondritis. In certain embodiments, said disease or condition is Schmidt’s syndrome. In certain embodiments, said disease or condition is thyrotoxidosis. In certain embodiments, said disease or condition is sepsis. In certain embodiments, said disease or condition is septic shock. In certain embodiments, said disease or condition is endotoxic shock. In certain embodiments, said disease or condition is exotoxin-induced toxic shock. In certain embodiments, said disease or condition is gram negative sepsis. In certain embodiments, said disease or condition is toxic shock syndrome. In certain embodiments, said disease or condition is glomerulonephritis. In certain embodiments, said disease or condition is peritonitis. In certain embodiments, said disease or condition is interstitial cystitis. In certain embodiments, said disease or condition is hyperoxia-induced inflammations. In certain embodiments, said disease or condition is chronic obstructive pulmonary disease (COPD). In certain embodiments, said disease or condition is emphysema. In certain embodiments, said disease or condition is nasal inflammation. In certain embodiments, said disease or condition is vasculitis. In certain embodiments, said disease or condition is graft vs. host reaction (e.g., graft vs. host disease). In certain embodiments, said disease or condition is allograft rejections (e.g., acute allograft rejection or chronic allograft rejection). In certain embodiments, said disease or condition is early transplantation rejection (e.g., acute allograft rejection). In certain embodiments, said disease or condition is reperfusion injury. In certain embodiments, said disease or condition is pain (e.g., acute pain, chronic pain, neuropathic pain, or fibromyalgia). In certain embodiments, said disease or condition is a chronic infection. In certain embodiments, said disease or condition is meningitis. In certain embodiments, said disease or condition is encephalitis. In certain embodiments, said disease or condition is myocarditis. In certain embodiments, said disease or condition is gingivitis. In certain embodiments, said disease or condition is post-surgical trauma. In certain embodiments, said disease or condition is tissue injury. In certain embodiments, said disease or condition is traumatic brain injury. In certain embodiments, said disease or condition is enterocolitis. In certain embodiments, said disease or condition is sinusitis. In certain embodiments, said disease or condition is uveitis. In certain embodiments, said disease or condition is ocular inflammation. In certain embodiments, said disease or condition is optic neuritis. In certain embodiments, said disease or condition is gastric ulcers. In certain embodiments, said disease or condition is esophagitis. In certain embodiments, said disease or condition is peritonitis. In certain embodiments, said disease or condition is periodontitis. In certain embodiments, said disease or condition is dermatomyositis. In certain embodiments, said disease or condition is gastritis. In certain embodiments, said disease or condition is myositis. In certain embodiments, said disease or condition is polymyalgia. In certain embodiments, said disease or condition is pneumonia. In certain embodiments, said disease or condition is bronchitis. In certain embodiments, the disease or condition is endometriosis. In certain embodiments, the disease or condition is necrotizing vasculitis. In certain embodiments, the disease or condition is lymphadenitis. In certain embodiments, the disease or condition is peri-arteritis nodosa. In certain embodiments, the disease or condition is anti-phospholipid antibody syndrome. In certain embodiments, the disease or condition is pemphigus vulgaris. In certain embodiments, the disease or condition is Lyme disease. In certain embodiments, the disease or condition is cardiomyopathy. In certain embodiments, the disease or condition is rheumatic fever. In certain embodiments, the disease or condition is a blistering disorder. In certain embodiments, the disease or condition is an antibody-mediated vasculitis syndrome. In certain embodiments, the disease or condition is an immune-complex vasculitide. In certain embodiments, the disease or condition is oedema. In certain embodiments, the disease or condition is embolism. In certain embodiments, the disease or condition is fibrosis. In certain embodiments, the disease or condition is silicosis. In certain embodiments, the disease or condition is BENTA disease. In certain embodiments, the disease or condition is berylliosis. [0388] Exemplary fibrotic disorders include but are not limited to those described herein. In certain embodiments, said disease or condition is systemic sclerosis/scleroderma. In certain embodiments, said disease or condition is lupus nephritis. In certain embodiments, said disease or condition is connective tissue disease. In certain embodiments, said disease or condition is wound healing. In certain embodiments, said disease or condition is surgical scarring. In certain embodiments, said disease or condition is spinal cord injury. In certain embodiments, said disease or condition is CNS scarring. In certain embodiments, said disease or condition is acute lung injury. In certain embodiments, said disease or condition is pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis or cystic fibrosis). In certain embodiments, said disease or condition is chronic obstructive pulmonary disease. In certain embodiments, said disease or condition is adult respiratory distress syndrome. In certain embodiments, said disease or condition is acute lung injury. In certain embodiments, said disease or condition is drug- induced lung injury. In certain embodiments, said disease or condition is glomerulonephritis. In certain embodiments, said disease or condition is kidney disease. In certain embodiments, said disease or condition is chronic kidney disease (e.g., diabetic nephropathy). In certain embodiments, said disease or condition is hypertension-induced nephropathy. In certain embodiments, said disease or condition is alimentary track or gastrointestinal fibrosis. In certain embodiments, said disease or condition is renal fibrosis. In certain embodiments, said disease or condition is hepatic or biliary fibrosis. In certain embodiments, said disease or condition is liver fibrosis (e.g., nonalcoholic steatohepatitis, hepatitis C, or hepatocellular carcinoma). In certain embodiments, said disease or condition is cirrhosis (e.g., primary biliary cirrhosis or cirrhosis due to fatty liver disease, such as alcoholic and nonalcoholic steatosis). In certain embodiments, said disease or condition is radiation-induced fibrosis (e.g., head and neck, gastrointestinal or pulmonary). In certain embodiments, said disease or condition is primary sclerosing cholangitis. In certain embodiments, said disease or condition is restenosis. In certain embodiments, said disease or condition is cardiac fibrosis (e.g., endomyocardial fibrosis or atrial fibrosis). In certain embodiments, said disease or condition is ophthalmic scarring. In certain embodiments, said disease or condition is fibrosclerosis. In certain embodiments, said disease or condition is a fibrotic cancer. In certain embodiments, said disease or condition is fibroids. In certain embodiments, said disease or condition is fibroma. In certain embodiments, said disease or condition is a fibroadenoma. In certain embodiments, said disease or condition is a fibrosarcoma. In certain embodiments, said disease or condition is transplant arteriopathy. In certain embodiments, said disease or condition is keloid. In certain embodiments, said disease or condition is mediastinal fibrosis. In certain embodiments, said disease or condition is myelofibrosis. In certain embodiments, said disease or condition is retroperitoneal fibrosis. In certain embodiments, said disease or condition is progressive massive fibrosis. In certain embodiments, said disease or condition is nephrogenic systemic fibrosis. [0389] Exemplary metabolic disorders include but are not limited to those described herein. In certain embodiments, said disease or condition is obesity. In certain embodiments, said disease or condition is steroid-resistance. In certain embodiments, said disease or condition is glucose intolerance. In certain embodiments, said disease or condition is metabolic syndrome. [0390] Exemplary cardiovascular or cerebrovascular disorders include but are not limited to those described herein. In certain embodiments, said disease or condition is atherosclerosis. In certain embodiments, said disease or condition is restenosis of an atherosclerotic coronary artery. In certain embodiments, said disease or condition is acute coronary syndrome. In certain embodiments, said disease or condition is myocardial infarction. In certain embodiments, said disease or condition is cardiac-allograft vasculopathy. In certain embodiments, said disease or condition is stroke. In certain embodiments, said disease or condition is a central nervous system disorder with an inflammatory or apoptotic component. In certain embodiments, said disease or condition is Alzheimer's disease. In certain embodiments, said disease or condition is Parkinson's disease. In certain embodiments, said disease or condition is Huntington’s disease. In certain embodiments, said disease or condition is amyotrophic lateral sclerosis. In certain embodiments, said disease or condition is spinal cord injury. In certain embodiments, said disease or condition is neuronal ischemia. In certain embodiments, said disease or condition is peripheral neuropathy. [0391] In certain embodiments, said disease or condition is a disease or disorder associated with a coronavirus (e.g., SARS-CoV-2). In certain embodiments, said coronavirus is SARS-CoV-2. In certain embodiments, the disease or disorder associated with SARS-CoV-2 is COVID-19. [0392] In certain embodiments, the disease or condition is a rheumatic disease. In certain embodiments, the disease or condition is an inflammatory arthropathy. In certain embodiments, the disease or condition is rheumatoid arthritis, juvenile arthritis, Still's disease, juvenile rheumatoid arthritis, systemic onset rheumatoid arthritis, pauciarticular rheumatoid arthritis, pauciarticular juvenile rheumatoid arthritis, polyarticular rheumatoid arthritis, enteropathic arthritis, juvenile Reiter's Syndrome, ankylosing spondylitis, juvenile ankylosing spondylitis, SEA Syndrome, reactive arthritis (reactive arthropathy), psoriatic arthropathy, juvenile enteropathic arthritis, polymyalgia rheumatica, enteropathic spondylitis, juvenile Idiopathic Arthritis (JIA), juvenile psoriatic arthritis, juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, giant cell arteritis, secondary osteoarthritis from an inflammatory disease. [0393] In certain embodiments, the disease or condition is a connective tissue disease. In certain embodiments, the disease or condition is lupus, systemic lupus erythematosus, juvenile systemic lupus erythematosus, nephritis, Sjögren's syndrome, scleroderma (systemic sclerosis), Raynaud's phenomenon, juvenile scleroderma, polymyositis, dermatomyositis, polymyositis- dermatomyositis, polymyalgia rheumatica, a mixed connective tissue disease, sarcoidosis, fibromyalgia, vasculitis microscopic polyangiitis, vasculitis, eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss Syndrome), granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis), polyarteritis nodosa, Henoch-Schönlein purpura, idiopathic thrombocytopenic thrombotic purpura, juvenile vasculitis, polyarteritis nodossa (also known as panarteritis nodosa, periarteritis nodosa Kussmaul disease, Kussmaul-Maier disease or PAN), serum sickness, myasthenia gravis, Takayasu's arteritis, Behçet’s syndrome, Kawasaki’s disease (mucocutaneous lymph node syndrome), Buerger’s disease (thromboangiitis obliterans), Vogt–Koyanagi–Harada syndrome, Addison’s disease, Hashimoto’s thyroiditis, primary biliary sclerosis, autoimmune hepatitis, chronic aggressive hepatitis, nonalcoholic hepatic steatosis, sclerosing cholangitis, membranous glomerulopathy, polymyositis, myositis, atherosclerosis, autoimmune hemolytic anemia, autoimmune orchitis, Goodpasture's disease, [0394] In certain embodiments, the disease or condition is a neurodegenerative disease or neuroinflammatory disease. In certain embodiments, the disease or condition is multiple sclerosis, amyotropic lateral sclerosis, Guillain-Barre disease, autoimmune encephalomyelitis, Alzheimer's disease, major depressive disorder, traumatic brain injury, epilepsy, Parkinson’s disease, or bipolar disorder. [0395] In certain embodiments, the disease or condition is an inflammatory bowel disease (IBD). In certain embodiments, the disease or condition is Crohn's disease, ulcerative colitis, Celiac Sprue, Celiac disease, proctitis, eosinophilic gastroenteritis, autoimmune atrophic gastritis of pernicious anemia, or mastocytosis. [0396] In certain embodiments, the disease or condition is a skin autoimmune disorder. In certain embodiments, the disease or condition is psoriasis. In certain embodiments, the disease or condition is eczema. In certain embodiments, the disease or condition is plaque psoriasis, Guttate psoriasis, psoriatic epidermal hyperplasia, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, atopic dermatitis, eczema dermatitis, dermatitis, rosacea, pruritus, alopecia areata, vitiligo, epidermal hyperplasia, juvenile dermatomyositis, dermatomyositis, or hidradenitis suppurativa. In certain embodiments, said disease or condition is hidradenitis suppurativa. [0397] In certain embodiments, the disease or condition is an organ or cell transplant rejection. In certain embodiments, the disease or condition is graft-versus-host disease. In certain embodiments, the disease or condition is chronic graft-versus-host disease, acute graft-versus- host disease, or organ or cell transplant rejection such as bone marrow, cartilage, cornea, heart, intervertebral disc, islet, kidney, limb, liver, lung, muscle, myoblast, nerve, pancreas, skin, small intestine, or trachea, or xeno transplantation. [0398] In certain embodiments, the disease or condition is an autoimmune disease of the eye. In certain embodiments, the disease or condition is Graves' disease, noninfectious uveitis, dry eye syndrome, sympathetic ophthalmia, Cogan's syndrome, keratoconjunctivitis, vernal conjunctivitis, uveitis (e.g., uveitis associated with Behcet's disease and lens-induced uveitis), keratitis, herpetic keratitis, conical keratitis, corneal epithelial dystrophy, keratoleukoma, ocular premphigus, Mooren's ulcer, scleritis, keratoconjunctivitis sicca (dry eye), phlyctenule, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmitis, allergic conjunctivitis, or ocular neovascularization [0399] In certain embodiments, the disease or condition is an ocular manifestation of an autoimmune disease. [0400] In certain embodiments, the disease or condition is a respiratory disease. In certain embodiments, the disease or condition is asthma, chronic obstructive pulmonary disease, or acute respiratory disease. [0401] In certain embodiments, the disease or condition is diabetes. In certain embodiments, the disease or condition is Type I diabetes mellitus, Type II diabetes mellitus, or juvenile onset diabetes. [0402] In certain embodiments, the disease or condition is thyroid cancer, duodenal, neuroendocrine carcinoma (NEC), uterine cancer, small cell lung cancer (SCLC), hepatocellular carcinoma, mesothelioma, breast cancer, sarcoma, ovarian cancer, renal cell carcinoma, rectal cancer, head and neck cancer, prostate cancer, pancreatic cancer, melanoma, colorectal cancer, cervix cancer, non-small cell lung cancer (NSCLC), cholangiocarcinoma, or endometrial cancer. [0403] In certain embodiments, the disease or condition is an autoimmune disease or atherosclerosis. [0404] In certain embodiments, the disease or condition is ovarian cancer, breast cancer, uterine cancer, colon cancer, cervical cancer, lung cancer, prostate cancer, skin cancer, bladder cancer, pancreatic cancer, leukemia, lymphoma, Hodgkin’s disease, viral infections, Human Immunodeficiency Virus, hepatitis virus, herpes virus, herpes simplex, inflammatory disorders, irritable bowel syndrome, inflammatory bowel disease, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, osteoarthritis, osteoporosis, dermatitis, atopic dermatitis, psoriasis, systemic lupus erythematosus, multiple Sclerosis, psoriatic arthritis, ankylosing spondylitis, graft-versus-host disease, Alzheimer's disease, cerebrovascular accident, atherosclerosis, diabetes, glomerulonephritis, metabolic Syndrome, non-Small cell lung cancer, Small cell lung cancer, multiple myeloma, leukemias, lymphomas, squamous cell cancers, kidney cancer, urethral and bladder cancers, cancers of head and neck, cancers of the brain and central nervous system (CNS). [0405] In certain embodiments, the disease or condition is cancer, an autoimmune disease, viral disease, fungal disease, neurological/neurodegenerative disorder, arthritis, inflammation, anti-proliferative (e.g., ocular retinopathy), neuronal, alopecia and cardiovascular disease. In certain embodiments, the disease or condition is a carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, including Small cell lung cancer, non-small cell lung cancer, head and neck, esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma, and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and pro myelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and Schwannomas; and other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, Xeroderma pigmentosum, keratocanthoma, thyroid follicular cancer and Kaposi's sarcoma. [0406] Without being bound by theory, there are multiple instances where decreasing NAD levels through NAMPT inhibition or in general have been associated with positive outcome in treating disease. For example, it has previously been shown that activated T-cells require increased NAD levels, and are more sensitive to NAMPTi than quiescent cells (Bruzzone et al. (2009) in PLoS ONE 4(11): e7897). Therefore NAMPT inhibitors show promise in immunosuppression of auto-immune disease, decreasing hyperactivation of the immune system in IBD (Gerner et al. in Gut 2018; 67:1813-1823), Psoriasis (Arroyo et al. in Int. J. Mol. Sci.2023, 24(9), 7992), vitiligo (Becatti et al. in J Cell Mol Med. (2014) vol.18(3): 514–529) and alopecia among others (Mercurio et al. in Int. J. Mol. Sci.2021, 22(13), 6860; Martínez- Morcillo et al. (2021) in PLoS Biol 19(11): e3001455). [0407] NAMPT expression has also been positively correlated with markers of inflammation, and NAMPTi decreases the expression of these same inflammation markers (Gerner et al. in Gut 2018; 67:1813-1823). Multiple mouse models of lung injury have demonstrated a significant benefit to treatment with NAMPT inhibitors (Geng-Chin Wu et al. in Respiratory Research 2017;18(1):71; Moreno-Vinasco et al. in Am J Respir Cell Mol Biol.2014 Aug; 51(2): 223–228). NAMPT is also found to be upregulated in COPD and negatively correlated with lung function (Huang Y, Niu Y, Wang X, Li X, He Y and Liu X (2024) in Identification of novel biomarkers related to neutrophilic inflammation in COPD. Front. Immunol.). [0408] NAMPT knockdown has been shown to reduce atherosclerosis by promoting cholesterol efflux and macrophage RCT through the PPARa-LXRa-ABCA1/G1 pathway both in vitro and in vivo (Li et al. in Scientific Reports volume 6, Article number: 26746 (2016)). [0409] In graft-versus-host disease (GVHD), NAMPT is highly expressed in both serum and T-cells. NAMPT inhibition strongly attenuates symptoms of GVHD in in vivo models and depletes NAD levels in activated T-cells (Gerner RR et al. in Leukemia 2020; 34(7):1885-1897). In rheumatoid arthritis, miR-23b is associated with RA where it is downregulated. It has been demonstrated to target NAMPT so NAMPT inhibitors are understood to provide a benefit in treating rheumatoid arthritis (Lv, R., Yu, J. & Sun, Q. in Future Oncol. (Lond. Engl.) 16(10), 541–458; and Liu, X. et al. in Gene 712(143911), 143911). Medical Uses [0410] Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, I-1, I-A, I-B, I-C, or I-D, or other compounds in Section I) in the manufacture of a medicament. In certain embodiments, the medicament is for treating a disorder described herein, such as cancer. [0411] Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, I-1, I-A, I-B, I-C, or I-D, or other compounds in Section I) for treating a medical disorder, such as a medical disorder described herein, such as cancer. [0412] Compounds described herein may also be used as a component in an antibody-drug conjugate. For example, compounds described herein may be conjugated to an antibody to form an antibody-drug conjugate. The antibody-drug conjugate may be used to treat disorder and conditions described herein. III. Combination Therapy [0413] Another aspect of the invention provides for combination therapy. Heteroaryl compounds described herein (e.g., a compound of Formula I, I-1, I-A, I-B, I-C, or I-D or other compounds in Section I) or their pharmaceutically acceptable salts may be used in combination with additional therapeutic agents to treat diseases or conditions, such as an inflammatory disorder. [0414] Accordingly, in some embodiments, the present invention provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method includes co-administering one additional therapeutic agent. In some embodiments, the method includes co-administering two additional therapeutic agents. [0415] One or more other therapeutic agents may be administered separately from a compound or composition of the invention, as part of a multiple dosage regimen. Alternatively, one or more other therapeutic agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as a multiple dosage regime, one or more other therapeutic agent and a compound or composition of the invention may be administered simultaneously, sequentially or within a period of time from one another. [0416] In certain embodiments, the compounds of the disclosure can be administered with one or more of an additional therapeutic agent, sequentially or concurrently, either by the same route or by different routes of administration. When administered sequentially, the time between administrations is selected to benefit, among others, the therapeutic efficacy and/or safety of the combination treatment. In certain embodiments, the compound of the disclosure can be administered first followed by a second therapeutic agent, or alternatively, the second therapeutic agent administered first followed by the compound of the disclosure. In certain embodiments, the compound of the disclosure can be administered for the same duration as the second therapeutic agent, or alternatively, for a longer or shorter duration as the second therapeutic compound. [0417] When administered concurrently, the compounds of the disclosure can be administered separately at the same time as the additional therapeutic agent, by the same or different routes, or administered in a single composition by the same route. In certain embodiments, the compound of the disclosure is prepared as a first pharmaceutical composition, and the additional therapeutic agent prepared as a second pharmaceutical composition, where the first pharmaceutical composition and the additional pharmaceutical composition are administered simultaneously, sequentially, or separately. In certain embodiments, the amount and frequency of administration of the additional therapeutic agent can used standard dosages and standard administration frequencies used for the particular therapeutic agent. See, e.g., Physicians’ Desk Reference, 70th Ed., PDR Network, 2015; incorporated herein by reference. [0418] In certain embodiments, the additional therapeutic agent is a leukotriene inhibitor, non- steroidal anti-inflammatory drug (NSAID), steroid, tyrosine kinase inhibitor, receptor kinase inhibitor, modulator of nuclear receptor family of transcription factor, HSP90 inhibitor, adenosine receptor (A₂A) agonist, disease modifying antirheumatic drugs (DMARDS), phosphodiesterase (PDE) inhibitor, neutrophil elastase inhibitor, modulator of Axl kinase, an anti-cancer agent, anti-allergic agent, anti-nausea agent (or anti-emetic), pain reliever, cytoprotective agent, anticoagulant, antiplatelet agent and dual antiplatelet therapy, angiotensin- converting enzyme (ACE) inhibitor, angiotensin II receptor blocker, angiotensin receptor- neprilysin inhibitor, beta blocker, combined alpha- and beta-blocker, calcium channel blocker, cholesterol-lowering medication (e.g., statins, nicotinic acids, cholesterol absorption inhibitors, combination statin and cholesterol absorption inhibitors), digitalis preparation, diuretic, vasodilator, antiarrhythmic agent (e.g., Class Ia, Class Ib, Class Ic, Class II, Class III, Class IV, Class V), or a combination thereof. In certain embodiments, the additional therapeutic agent is an anti-cancer agent, an analgesic, an anti-inflammatory agent, or a combination thereof. [0419] In certain embodiments, the additional therapeutic agent is a leukotriene inhibitor. Examples of leukotriene inhibitors considered for use in combination therapies of the invention include but are not limited to montelukast, zafirlukast, pranlukast, zileuton, or combinations thereof. [0420] In certain embodiments, the additional therapeutic agent is a NSAID. Examples of NSAIDs considered for use in combination therapies of the invention include but are not limited to acetylsalicylic acid, diflunisal, salsalate, ibuprofen, dexibuprofen, naioxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, nabumetone, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, phenylbutazone, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, celecoxib, or combinations thereof. [0421] In certain embodiments, the additional therapeutic agent is a steroid. Examples of steroids considered for use in combination therapies of the invention include but are not limited to prednisone, prednisolone, methylprednisone, triacmcinolone, betamethasone, dexamethasone, and prodrugs thereof. [0422] In certain embodiments, the additional therapeutic agent is a tyrosine kinase inhibitor. Examples of tyrosine kinase inhibitors considered for use in combination therapies of the invention include but are not limited to inhibitors of the following kinases, including, among others: JAK, Syk, JNK/SAPK, MAPK, PI-3K, and/or Ripk2. In certain embodiments, the tyrosine kinase inhibitor is ruxolitinib, tofacitinib, oclactinib, filgotinib, ganotinib, lestaurtinib, momelotinib, pacritinib, upadacitinib, peficitinib, fedratinib, bentamapimod, D-JNKI-1 (XG-102, AM-111), ponatinib, WEHI-345, OD36, GSK583, idelalisib, copanlisib, taselisib, duvelisib, alpelisib, umbralisib, dactolisib, CUDC-907, entospletinib, fostamatinib, or combinations thereof. [0423] In certain embodiments, the additional therapeutic agent is a receptor kinase inhibitor, including among others, an inhibitor of EGFR or HER2. Examples of receptor kinase inhibitors considered for use in combination therapies of the invention include but are not limited to gefitinib, erlotinib, neratinib, lapatinib, cetuximab, panitumumab, vandetanib, necitumumab, osimertinib, trastuzumab, neratinib, lapatinib, pertuzumab, or combinations thereof. [0424] In certain embodiments, the additional therapeutic agent is a modulator of nuclear receptor family of transcription factors, including, among others, an inhibitor of PPAR, RXR, FXR, or LXR. In certain embodiments, the inhibitor is pioglitazone, bexarotene, obeticholic acid, ursodeoxycholic acid, fexaramine, hypocholamide, or combinations thereof. [0425] In certain embodiments, the additional therapeutic agent is an HSP90 inhibitor. Examples of HSP90 inhibitors considered for use in combination therapies of the invention include but are not limited to ganetespib, 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010, or combinations thereof. [0426] In certain embodiments, the additional therapeutic agent is an adenosine receptor 2A (A2A) agonist. Examples of adenosine receptor agonists considered for use in combination therapies of the invention include but are not limited to those disclosed in U.S. Pat. No. 9,067,963, which is incorporated herein by reference. In certain embodiments, the adenosine receptor agonist is LNC-3050, LNC-3015, LNC-3047, LNC-3052, or combinations thereof. [0427] In certain embodiments, the additional therapeutic agent is selected from disease modifying antirheumatic drugs (DMARDS). Examples of DMARDS considered for use in combination therapies of the invention include but are not limited to tocilizumab, certolizumab, etanercept, adalimumab, anakinra, abatacept, infliximab, rituximab, golimumab, uteskinumab, or combinations thereof. [0428] In certain embodiments, the additional therapeutic agent is a phosphodiesterase (PDE) inhibitor. Examples of phosphodiesterase inhibitor considered for use in combination therapies of the invention include but are not limited to apremilast, crisaborole, piclimilast, drotaverine, ibudulast, roflumilast, sildenafil, tadalafil, vardenafil, or combinations thereof. [0429] In certain embodiments, the additional therapeutic agent is a neutrophil elastase inhibitor. Examples of neutrophil elastase inhibitors considered for use in combination therapies of the invention include but are not limited to sivelestat. [0430] In certain embodiments, the additional therapeutic agent is a modulator of Axl kinase. Examples of modulators of Axl kinase considered for use in combination therapies of the invention include but are not limited to bemcentinib (BGB324 or R428), TP-0903, LY2801653, amuvatinib (MP-470), bosutinib (SKI-606), MGCD 265, ASP2215, cabozantinib (XL184), foretinib (GSK1363089/XL880), and SGI-7079. In certain embodiments, the modulator of Axl kinase is a monoclonal antibody targeting AXL (e.g., YW327.6S2) or an AXL decoy receptor (e.g., GL2I.T), or glesatinib, merestinib, or a dual Flt3-Axl inhibitor such as gilteritinib. [0431] In certain embodiments, the additional therapeutic agent is an anti-cancer agent or chemo-therapeutic agent. Examples of anti-cancer agents considered for use in combination therapies of the invention include but are not limited erlotinib, bortezomib, fulvestrant, sunitib, imatinib mesylate, letrozole, finasunate, platins such as oxaliplatin, carboplatin, and cisplatin, finasunate, fluorouracil, rapamycin, leucovorin, lapatinib, lonafamib, sorafenib, gefitinib, camptothecin, topotecan, bryostatin, adezelesin, anthracyclin, carzelesin, bizelesin, dolastatin, auristatins, duocarmycin, eleutherobin, taxols such as paclitaxel or docetaxel, cyclophosphamide, doxorubicin, vincristine, prednisone or prednisolone, other alkylating agents such as mechlorethamine, chlorambucil, and ifosfamide, antimetabolites such as azathioprine or mercaptopurine, other microtubule inhibitors (vinca alkaloids like vincristine, vinblastine, vinorelbine, and vindesine, as well as taxanes), podophyllotoxins (etoposide, teniposide, etoposide phosphate, and epipodophyllotoxins), topoisomerase inhibitors, other cytotoxins such as actinomycin, daunorubicin, valrubicin, idarubicin, edrecolomab, epirubicin, bleomycin, plicamycin, mitomycin, as well as other anticancer antibodies (cetuximab, bevacizumab, ibritumomab, abagovomab, adecatumumab, afutuzumab, alacizumab, alemtuzumab, anatumomab, apolizumab, bavituximab, belimumab, bivatuzumab mertansine, blinatumomab, brentuximab vedotin, cantuzumab mertansine, catumazomab, cetuximab, citatuzumab bogatox, cixutumumab, clivatuzumab tetraxetan, conatumumab, dacetuzumab, daclizumab, detumomab, ecromeximab, edrecolomab, elotuzumab, epratuzumab, ertumaxomab, etaracizumab, farletuzumab, figitumumab, fresolimumab, galiximab, gembatumumab vedotin, gemtuzumab, ibritumomab tiuxetan, inotuzumab ozogamicin, intetumumab, ipilimumab, iratumumab, labetuzumab, lexatumumab, lintuzumab, lucatumumab, lumilisimab, mapatumumab, matuzumab, milatuzumab, mitumomab, nacolomab tafenatox, naptumomab estafenatox, necitumumab, nimotuzumab, ofatumumab, olaratumab, oportuzumab monatox, oregovomab, panitumumab, pemtumomab, pertuzumab, pintumomab, pritumumab, ramucirumab, rilotumumab, robatumumab, rituximab, sibrotuzumab, tacatuzumab tetraxetan, taplitumomab paptox, tenatumomab, ticilimumab, tigatuzumab, tositumomab or ¹³¹I-tositumomab, trastuzumab, tremelimumab, tuocotuzumab celmoleukin, veltuzumab, visilizumab, volocixumab, votumumab, zalutumumab, zanolimumab, IGN-101, MDX-010, ABX-EGR, EMD72000, ior-t1, MDX-220, MRA, H-11 scFv, huJ591, TriGem, TriAb, R3, MT-201, G-250, ACA-125, Onyvax- 105, CD:-960,Cea-Vac, BrevaRex AR54, IMC-1C11, GlioMab-H, ING-1, anti-LCG MAbs, MT- 103, KSB-303, Therex, KW2871, anti-HMI.24, Anti-PTHrP, 2C4 antibody, SGN-30, TRAIL-RI MAb, Prostate Cancer antibody, H22xKi-r, ABX-Mai, Imuteran, Monopharm-C), and antibody- drug conjugates comprising any of the above agents (especially auristatins MMAE and MMAF, maytansinoids like DM-1, calicheamycins, or various cytotoxins). [0432] In certain embodiments, the additional therapeutic agent is selected from anastrozole (ARIMIDEX®), bicalutamide (CASODEX®), bleomycin sulfate (BLENOXANE®), busulfan (MYLERAN®), busulfan injection (BUSULFEX®), capecitabine (XELODA®), N4- pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (PARAPLATIN®), carmustine (BiCNU®), chlorambucil (LEUKERAN®), cisplatin (PLATINOL®), cladribine (LEUSTATIN®), cyclophosphamide (CYTOXAN® or NEOSAR®), cytarabine, cytosine arabinoside (CYTOSAR-U®), cytarabine liposome injection (DEPOCYT®), dacarbazine (DTIC-Dome®), dactinomycin (actinomycin D, COSMEGAN®), daunorubicin hydrochloride (CERUBIDINE®), daunorubicin citrate liposome injection (DAUNOXOME®), dexamethasone, docetaxel (TAXOTERE®), doxorubicin hydrochloride (ADRIAMYCIN®, RUBEX®), etoposide (VEPESID®), fludarabine phosphate (FLUDARA®), 5-fluorouracil (ADRUCIL®, EFUDEX®), flutamide (EULEXIN®), tezacitibine, gemcitabine (difluorodeoxycitidine), hydroxyurea (HYDREA®), idarubicin (IDAMYCIN®), ifosfamide (IFEX®), irinotecan (CAMPTOSAR®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (ALKERAN®), 6-mercaptopurine (PURINETHOL®), methotrexate (FOLEX®), mitoxantrone (NOVANTRONE®), gemtuzumab ozogamicin (MYLOTARGTM), paclitaxel (TAXOL®), nab- paclitaxel (ABRAXANE®), phoenix (Yttrium90/MX-DTPA), pentostatin, polifeprosan 20 with carmustine implant (GLIADEL®), tamoxifen citrate (NOLVADEX®), teniposide (VUMON®), 6-thioguanine, thiotepa, tirapazamine (TIRAZONE®), topotecan hydrochloride for injection (HYCAMPTIN®), vinblastine (VELBAN®), vincristine (ONCOVIN®), and vinorelbine (NAVELBINE®). [0433] In certain embodiments, the additional therapeutic agent is capable of inhibiting BRAF, MEK, CDK4/6, SHP-2, HDAC, EGFR, MET, mTOR, PI3K or AKT, or a combination thereof. In a particular embodiment, the compounds of the present invention are combined with another therapeutic agent selected from vemurafinib, debrafinib, LGX818, trametinib, MEK162, LEE011, PD-0332991, panobinostat, verinostat, romidepsin, cetuximab, gefitinib, erlotinib, lapatinib, panitumumab, vandetanib, INC280, everolimus, simolimus, BMK120, BYL719 or CLR457, or a combination thereof. [0434] In certain embodiments, the additional therapeutic agent is selected based on the disease or condition that is being treated. For example, in the treatment of melanoma, the additional therapeutic agent is selected from aldesleukin (e.g., PROLEUKIN®), dabrafenib (e.g., TAFINLAR®), dacarbazine, recombinant interferon alfa-2b (e.g., INTRON® A), ipilimumab, trametinib (e.g., MEKINIST®), peginterferon alfa-2b (e.g., PEGINTRON®, SYLATRONTM), vemurafenib (e.g., ZELBORAF®)), and ipilimumab (e.g., YERVOY®). [0435] For the treatment of ovarian cancer, the additional therapeutic agent is selected from doxorubicin hydrochloride (Adriamycin®), carboplatin (PARAPLATIN®), cyclophosphamide (CYTOXAN®, NEOSAR®), cisplatin (PLATINOL®, PLATINOL-AQ®), doxorubicin hydrochloride liposome (DOXIL®, DOX-SL®, EVACET®, LIPODOX®), gemcitabine hydrochloride (GEMZAR®), topotecan hydrochloride (HYCAMTIN®), and paclitaxel (TAXOL®). [0436] For the treatment of thyroid cancer, the additional therapeutic agent is selected from doxorubicin hydrochloride (Adriamycin®), cabozantinib-S-malate (COMETRIQ®), and vandetanib (CAPRELSA®). [0437] For the treatment of colon cancer, the additional therapeutic agent is selected from fluorouracil (e.g., ADRUCIL®, EFUDEX®, FLUOROPLEX®), bevacizumab (AVASTIN®), irinotecan hydrochloride (CAMPTOSTAR®), capecitabine (XELODA®), cetuximab (ERBITUX®), oxaliplatin (ELOXATIN®), leucovorin calcium (WELLCOVORIN®), regorafenib (STIVARGA®), panitumumab (VECTIBIX®), and ziv-aflibercept (ZALTRAP®). [0438] For the treatment of lung cancer, the additional therapeutic agent is selected from methotrexate, methotrexate LPF (e.g., FOLEX®, FOLEX PFS®, Abitrexate®, MEXATE®, MEXATE-AQ®), paclitaxel (TAXOL®), paclitaxel albumin-stabilized nanoparticle formulation (ABRAXANE®), afatinib dimaleate (GILOTRIF®), pemetrexed disodium (ALIMTA®), bevacizumab (AVASTIN®), carboplatin (PARAPLATIN®), cisplatin (PLATINOL®, PLATINOL-AQ®), crizotinib (XALKORI®), erlotinib hydrochloride (TARCEVA®), gefitinib (IRESSA®), and gemcitabine hydrochloride (GEMZAR®). [0439] For the treatment of pancreatic cancer, the additional therapeutic agent may be selected from fluorouracil (ADRUCIL®), EFUDEX®, FLUOROPLEX®), erlotinib hydrochloride (TARCEVA®), gemcitabine hydrochloride (GEMZAR®), and mitomycin or mitomycin C (MITOZYTREXTM, MUTAMYCIN®). [0440] For the treatment of cervical cancer, the additional therapeutic agent is selected from bleomycin (BLENOXANE®), cisplatin (PLATINOL®, PLATINOL-AQ®) and topotecan hydrochloride (HYCAMTIN®). [0441] For the treatment of head and neck cancer, the additional therapeutic agent is selected from methotrexate, methotrexate LPF (e.g., FOLEX®, FOLEX PFS®, Abitrexate®, MEXATE®, MEXATE-AQ®), fluorouracil (ADRUCIL®, EFUDEX®, FLUOROPLEX®), bleomycin (BLENOXANE®), cetuximab (ERBITUX®), cisplatin (PLATINOL®, PLATINOL- AQ®) and docetaxel (TAXOTERE®). [0442] For the treatment of leukemia, including chronic myelomonocytic leukemia (CMML), the additional therapeutic agent is selected from bosutinib (BOSULIF®), cyclophosphamide (CYTOXAN®, NEOSAR®), cytarabine (CYTOSAR-U®, TARABINE PFS®), dasatinib (SPRYCEL®), imatinib mesylate (GLEEVEC®), ponatinib (ICLUSIG®), nilotinib (TASIGNA®) and omacetaxine mepesuccinate (SYNRIBO®). [0443] In certain embodiments, the additional therapeutic agent is a PARP inhibitor, a dihydrofolate reductase inhibitor (e.g., pemetrexed), or a BCL-2 inhibitor (e.g., ventoclax). [0444] In certain embodiments, the additional therapeutic agent is Temozolomide, Venetoclax, Niraparib, 5-Fluoruracil, Paclitaxel, Gemcitabine, Olaparib, Pemetrexed, Bortezomib, Etoposide, TRAIL, Ibrutinib, Vorinostat, FX-11, Rituxumab, Cisplatin, Indoximod, or a pharmaceutically acceptable salt thereof. In certain embodiments, the additional therapeutic agent is anti-PD1 agent, such as an anti-PD1 antibody. [0445] In certain embodiments, the additional therapeutic agent is a DNA interactive agent (such as cisplatin or doxorubicin)); a taxane (e.g. taxotere, taxol); a topoisomerase II inhibitor (such as etoposide); a topoisomerase I inhibitor (such as irinotecan (or CPT-11), camptostar, or topotecan); a tubulin interacting agent (such as paclitaxel, docetaxel or the epothilones); a hormonal agent (such as tamoxifen); a thymidilate synthase inhibitor (such as 5-fluorouracil or 5-FU); an anti-metabolite (such as methoxtrexate); an alkylating agent (such as temozolomide, cyclophosphamide); a farnesyl protein transferase inhibitor (such as, SARASARTM.(4-2-4- (11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5- 6cyclohepta 1.2-bipyridin-11-yl--1- piperidinyl-2-oxoethyl-1-piperidine-carboxamide, or SCH 66336), tipifarnib (Zarnestra® or R115777 from Janssen Pharmaceuticals), L778,123 (a farnesyl protein transferase inhibitor from Merck & Company), BMS 214662 (a farnesyl protein transferase inhibitor from Bristol-Myers Squibb Pharmaceuticals, Princeton, N.J.); signal transduction inhibitors (such as, IressaR, TarcevaR (EGFR kinase inhibitors), antibodies to EGFR (e.g., C225), GLEEVECR (C-ablkinase inhibitor from Novartis Pharmaceuticals); an interferon such as, for example, Intron® (from Merck & Company), Peg-Intron® (from Merck & Company); a hormonal therapy combination; or an aromatase combination; ara C, adriamycin, cytoxan, and gemcitabine. Other anti-cancer (also known as anti-neoplastic) agents include but are not limited to Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, BuSulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, FloXuri dine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin, oxaliplatin (ELOXATINR), Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mito mycin-C. L-Asparaginase, Teniposide 17C-Ethinylestradiol. Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestro lacetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levami, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade®, Zevalin, Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa, Altre tamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane, Ifosfomide, Rituximab, C225, and Campath, 5-fluorouracil and leucovorin, with or without a 5-HT, receptor inhibitor (e.g., dolansetron, granisetron, ondansetron). [0446] In certain embodiments, the additional therapeutic agent is an inhibitor of DNA Polymerase Theta (PolO) activity such as molecules described in WO 2023/233295 and WO 2024/121290. [0447] In certain embodiments, the additional therapeutic agent is a Pol Theta inhibitor and a PARP inhibitor. [0448] In some instances, patients may experience allergic reactions to the compounds of the present invention and/or other anti-cancer agent(s) during or after administration. Therefore, anti-allergic agents may be administered to minimize the risk of an allergic reaction. Suitable anti-allergic agents include corticosteroids, such as dexamethasone (e.g., DECADRON®), beclomethasone (e.g., BECLOVENT®), hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate; e.g., ALA-CORT®, hydrocortisone phosphate, Solu-CORTEF®, HYDROCORT Acetate® and LANACORT®), prednisolone (e.g., DELTA-Cortel®, ORAPRED®, PEDIAPRED® and PRELONE®), prednisone (e.g., DELTASONE®, LIQUID RED®, METICORTEN® and ORASONE®), methylprednisolone (also known as 6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate; e.g., DURALONE®, MEDRALONE®, MEDROL®, M- PREDNISOL® and SOLU-MEDROL®); antihistamines, such as diphenhydramine (e.g., BENADRYL®), hydroxyzine, and cyproheptadine; and bronchodilators, such as the beta- adrenergic receptor agonists, albuterol (e.g., PROVENTIL®), and terbutaline (BRETHINE®). [0449] In other instances, patients may experience nausea during and after administration of the compound of the present invention and/or other anti-cancer agent(s). Therefore, anti-emetics may be administered in preventing nausea (upper stomach) and vomiting. Suitable anti-emetics include aprepitant (EMEND®), ondansetron (ZOFRAN®), granisetron HCl (KYTRIL®), lorazepam (ATIVAN®. dexamethasone (DECADRON®), prochlorperazine (COMPAZINE®), casopitant (REZONIC® and Zunrisa®), and combinations thereof. [0450] In yet other instances, medication to alleviate the pain experienced during the treatment period is prescribed to make the patient more comfortable. Common over-the-counter analgesics, such TYLENOL®, are often used. Opioid analgesic drugs such as hydrocodone/paracetamol or hydrocodone/acetaminophen (e.g., VICODIN®), morphine (e.g., ASTRAMORPH® or AVINZA®), oxycodone (e.g., OXYCONTIN® or PERCOCET®), oxymorphone hydrochloride (OPANA®), and fentanyl (e.g., DURAGESIC®) are also useful for moderate or severe pain. [0451] Furthermore, cytoprotective agents (such as neuroprotectants, free-radical scavengers, cardioprotectors, anthracycline extravasation neutralizers, nutrients and the like) may be used as an adjunct therapy to protect normal cells from treatment toxicity and to limit organ toxicities. Suitable cytoprotective agents include amifostine (ETHYOL®), glutamine, dimesna (TAVOCEPT®), mesna (MESNEX®), dexrazoxane (ZINECARD® or TOTECT®), xaliproden (XAPRILA®), and leucovorin (also known as calcium leucovorin, citrovorum factor and folinic acid). [0452] In certain embodiments, the second therapeutic agent is an anticoagulant. Examples of anticoagulants considered for use in combination therapies of the invention include but are not limited to apixaban, dabigatran, edoxaban, heparin, rivaroxaban, warfarin, or combinations thereof. [0453] In certain embodiments, the second therapeutic agent is an antiplatelet agent and dual antiplatelet therapy. Examples of antiplatelet agents and dual antiplatelet therapy considered for use in combination therapies of the invention include but are not limited to aspirin, clopidogrel, dipyridamole, prasugrel, ticagrelor, or combinations thereof. [0454] In certain embodiments, the second therapeutic agent is an angiotensin-converting enzyme (ACE) inhibitor. Examples of angiotensin-converting enzyme (ACE) inhibitors considered for use in combination therapies of the invention include but are not limited to benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, or combinations thereof. [0455] In certain embodiments, the second therapeutic agent is an angiotensin II receptor blocker. Examples of angiotensin II receptor blockers considered for use in combination therapies of the invention include but are not limited to azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, or combinations thereof. [0456] In certain embodiments, the second therapeutic agent is an angiotensin receptor- neprilysin inhibitor. Examples of angiotensin receptor-neprilysin inhibitors considered for use in combination therapies of the invention include but are not limited to sacubitril/valsartan. [0457] In certain embodiments, the second therapeutic agent is a beta blocker. Examples of beta blockers considered for use in combination therapies of the invention include but are not limited to acebutolol, atenolol, betaxolol, bisoprolol/hydrochlorothiazide, bisoprolol, metoprolol, nadolol, propranolol, sotalol, or combinations thereof. [0458] In certain embodiments, the second therapeutic agent is a combined alpha- and beta- blocker. Examples of combined alpha- and beta-blockers considered for use in combination therapies of the invention include but are not limited to carvedilol, labetalol hydrochloride, or combinations thereof. [0459] In certain embodiments, the second therapeutic agent is a calcium channel blocker. Examples of calcium channel blockers considered for use in combination therapies of the invention include but are not limited to amlodipine, diltiazem, felodipine, nifedipine, nimodipine, nisoldipine, verapamil, or combinations thereof. [0460] In certain embodiments, the second therapeutic agent is a cholesterol-lowering medication. Examples of cholesterol-lowering medications considered for use in combination therapies of the invention include but are not limited to statins (e.g., atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), nicotinic acids (e.g., niacin), cholesterol absorption inhibitors (e.g., ezetimibe), combination statin and cholesterol absorption inhibitors (e.g., ezetimibe/simvastatin), or combinations thereof. [0461] In certain embodiments, the second therapeutic agent is a digitalis preparation. Examples of digitalis preparations considered for use in combination therapies of the invention include but are not limited to digoxin. [0462] In certain embodiments, the second therapeutic agent is a diuretic. Examples of diuretics considered for use in combination therapies of the invention include but are not limited to acetazolamide, amiloride, bumetanide, chlorothiazide, chlorthalidone, furosemide, hydro- chlorothiazide, indapamide, metalozone, spironolactone, torsemide, or combinations thereof. [0463] In certain embodiments, the second therapeutic agent is a vasodilator. Examples of vasodilators considered for use in combination therapies of the invention include but are not limited to isosorbide dinitrate, isosorbide mononitrate, hydralazine, nitroglycerin, minoxidil, or combinations thereof. [0464] In certain embodiments, the second therapeutic agent is an antiarrhythmic agent. Examples of antiarrhythmic agent considered for use in combination therapies of the invention include but are not limited to Class Ia antiarrhythmic agents (e.g., quinidine, ajmaline, procain amide, dispyramide, sparteine), Class Ib antiarrhythmic agents (e.g., lidocaine, phenytoin, mexiletine, tocainide), Class Ic antiarrhythmic agents (e.g., encainide, flecainide, propafenone, moricizine), Class II antiarrhythmic agents (e.g., carvedilol, propranolol, esmolol, timolol, metoprolol, atenolol, bisoprolol, nebivolol), Class III antiarrhythmic agents (e.g., amiodarone, sotalol, ibutilide, dofetilide, dronedarone, E-4031, vernakalant), Class IV antiarrhythmic agents (e.g., verapamil, diltiazem; Class V, such as adenosine, digoxin, magnesium sulfate), or combinations thereof. [0465] In certain embodiments, the second therapeutic agent is an agent used to treat a metabolic disorder. Examples of metabolic disorder agents considered for use in combination therapies of the invention include but are not limited to statins (e.g., atorvastatin, simvastatin, rosuvastatin), cholesterol absorption inhibitors (e.g., ezetimibe), insulin-sensitizing agents (e.g., rosiglitazone, metformin), GLP-1 receptor agonists (e.g., exenatide), DPP-4 inhibitors (e.g., sitagliptin), thiazolidinediones (e.g., pioglitazone), or combinations thereof. [0466] In yet another aspect, a compound of the present invention may be used in combination with known therapeutic processes, for example, with the administration of hormones or in radiation therapy. In certain instances, a compound of the present invention may be used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy. [0467] The doses and dosage regimen of the active ingredients used in the combination therapy may be determined by an attending clinician. In certain embodiments, the compound described herein (e.g., a compound of Formula I, I-1, I-A, I-B, I-C, or I-D or other compounds in Section I) and the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy for treating the disease or condition. In other embodiments, the compound described herein (e.g., a compound of Formula I, I-1, I-A, I-B, I-C, or I-D or other compounds in Section I) and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating the disease or condition. In certain embodiments, the compound described herein (e.g., a compound of Formula I, I-1, I-A, I-B, I-C, or I-D or other compounds in Section I) and the additional therapeutic agent(s) are present in the same composition, which is suitable for oral administration. [0468] In certain embodiments, the compound described herein (e.g., a compound of Formula I, I-1, I-A, I-B, I-C, or I-D or other compounds in Section I) and the additional therapeutic agent(s) may act additively or synergistically. A synergistic combination may allow the use of lower dosages of one or more agents and/or less frequent administration of one or more agents of a combination therapy. A lower dosage or less frequent administration of one or more agents may lower toxicity of the therapy without reducing the efficacy of the therapy. IV. Pharmaceutical Compositions and Dosing Considerations [0469] As indicated above, the invention provides pharmaceutical compositions, which comprise a therapeutically-effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents. The pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally. In certain embodiments, the invention provides a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula I, I-1, I-A, I-B, I-C, or I-D, or other compounds in Section I) and a pharmaceutically acceptable carrier. [0470] The phrase “therapeutically effective amount” as used herein means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment. [0471] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. [0472] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions. [0473] Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. [0474] Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent. [0475] In certain embodiments, a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention. In certain embodiments, an aforementioned formulation renders orally bioavailable a compound of the present invention. [0476] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product. [0477] Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste. [0478] In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, trouches and the like), the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non-ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. [0479] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. [0480] The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients. [0481] Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. [0482] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents. [0483] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. [0484] Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound. [0485] Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate. [0486] Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required. [0487] The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. [0488] Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. [0489] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel. [0490] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention. [0491] Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents. [0492] Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. [0493] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin. [0494] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. [0495] Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue. [0496] When the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier. [0497] The preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred. [0498] The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. [0499] The phrases “systemic administration,” “administered systemically,” “peripheral administration” and “administered peripherally” as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient’s system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration. [0500] These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually. [0501] Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art. [0502] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. [0503] The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. [0504] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. [0505] In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Preferably, the compounds are administered at about 0.01 mg/kg to about 200 mg/kg, more preferably at about 0.1 mg/kg to about 100 mg/kg, even more preferably at about 0.5 mg/kg to about 50 mg/kg. When the compounds described herein are co-administered with another agent (e.g., as sensitizing agents), the effective amount may be less than when the agent is used alone. [0506] If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day. [0507] The invention further provides a unit dosage form (such as a tablet or capsule) comprising a heteroaryl substituted phenylpyrimidinone or related compound described herein in a therapeutically effective amount for the treatment of a medical disorder described herein. V. MEDICAL KITS [0508] Another aspect of this invention is a kit comprising a therapeutically effective amount of a compound described herein (e.g., a compound of Formula I, I-1, I-A, I-B, I-C, or I-D or other compounds in Section I), a pharmaceutically acceptable carrier, vehicle or diluent, and optionally at least one additional therapeutic agent listed above. In certain embodiments, the kit further comprises instructions, such as instructions for treating a disease described herein. VI. ENUMERATED EMBODIMENTS [0509] The following exemplary embodiments are provided: [0510] Embodiment 1. A compound represented by Formula I: or a pharmaceutically acceptable salt thereof; wherein: A¹ is substituted with p occurrences of R², wherein B¹ is a 6-membered aryl ring or a 5-6 membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur; A² is a 6-membered saturated or partially unsaturated heterocyclylene containing 1 heteroatom selected from nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, a 5-8 membered saturated bicyclic carbocyclylene, or a covalent bond, wherein the heterocyclylene, monocyclic carbocyclylene, and bicyclic carbocyclylene are substituted with 0 or 1 occurrences of R³; R^1A, R^1B, and R^1C each represent independently for each occurrence hydrogen or C1-4 alkyl; R² represents independently for each occurrence halo; R³ is halo or C1-4 alkyl; Z is -C(O)R⁴, -C(O)-(C1-4 alkylene)-R⁴, -C(O)-OH, -C(O)-O-(C1-6 alkyl), -C(O)- N(R^1A)(R^1B), -C(O)-O-(C_1-4 alkylene)-O-(C_1-4 alkylene)-N(R^1A)(R^1B), -C(O)-O-(C_1-4 alkylene substituted with 1 occurrence of -N(R^1A)(R^1B))-(C1-4 hydroxyalkyl), -S(O)2-(C1-6 alkyl), - S(O)2-(C3-7 cycloalkyl), -S(O)2-N(R^1A)(R^1B), -S(O)2-N(R^1A)-C(O)-(C1-6 alkyl), -S(O)2- N(R^1A)-C(O)-O-(C_1-6 alkyl), -S(O)₂-N(R^1A)-C(O)-N(R^1B)(R^1C), -S(O)₂-[(C_1-4 alkylene)-O-]_x- R⁵, -N(R^1A)-C(O)-(C1-4 alkylene)-(5-6 membered saturated heterocyclyl containing 1 oxygen atom), -N(R^1A)-C(O)-O-(C1-4 alkylene)-(phenyl), -N(R^1A)-C(O)-O-[(C1-4 alkylene)-O-]x-R⁶, - N(R^1A)-C(O)-N(R^1B)-[(C_1-4 alkylene)-O-]_x-R⁶, -C(O)-N(R^1A)-(C_1-6 hydroxyalkyl), -C(O)- N(R^1A)-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1A)(R^1B), -N(R^1A)-C(O)-N(R^1B)-[(C1-6 hydroxyalkyl), -C(O)-(C1-4 alkylene)- [O-(C_1-4 alkylene)-]_y-(C_1-6 alkoxyl), -C(O)N(R^1B)-(C_1-4 alkylene)-[O-(C_1-4 alkylene)-]_y-(C_1-6 alkoxyl), -C(O)-C(O)-OH, -C(O)-C(O)-N(R^1A)(R^1B), -N(R^1A)-C(O)-(C1-6 hydroxyalkyl), - C(O)-C(O)-N(R^1A)-R⁵, -N(R^1A)-C(O)-C(O)-N(R^1B)(R^1C), -C(O)-N(R^1A)-S(O)2-R⁷, -N(R^1A)- S(O)₂-R⁷, -N(R^1A)-S(O)₂-N(R^1B)-CO₂-(C_1-4 alkylene)-phenyl, -C(O)-C(O)-N(R^1A)-S(O)₂-(C_1- 6 alkyl), -S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl), -C(O)-C(O)-N(R^1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-O-(C1-4 alkylene)-(5 membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R⁹), or hydrogen; R⁴ is C1-6 hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, a 5-7 membered di-oxo- heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl; R⁵ is C_1-6 alkyl, C_1-6 hydroxyalkyl, -(C_1-4 alkylene)-(C_1-4 alkoxyl), or C_1-6 alkoxyl; R⁶ is C1-4 alkyl, C1-4 hydroxyalkyl, or C1-4 haloalkyl; R⁷ is C1-4 alkyl, C1-4 alkoxyl, -(C1-4 alkylene)-(C1-4 alkoxyl), -(C0-4 alkylene)- N(R^1A)(R^1B), or -N(R^1B)-C(O)-O-R⁸; R⁸ is C_1-4 alkyl or -(C_0-4 alkylene)-(phenyl); R⁹ is oxo, C1-4 alkyl, hydroxyl, or -C(O)-O-(C1-4 alkyl); m is 1 or 2; n is 1 or 2; p is 0, 1, 2, 3, or 4; x is 1, 2, 3, 4, or 5; and y and z are independently 1, 2, or 3; provided that when B¹ is a 6-membered aryl ring substituted with 0 or 1 occurrences of R², then Z is not -C(O)R⁴ or -C(O)-(C1-4 alkylene)-R⁴. [0511] Embodiment 2. The compound of embodiment 1, wherein the compound is a compound of Formula I. [0512] Embodiment 3. The compound of embodiment 1 or 2, wherein R^1A is hydrogen. [0513] Embodiment 4. The compound of any one of embodiments 1-3, wherein R² is fluoro or chloro. [0514] Embodiment 5. The compound of any one of embodiments 1-3, wherein R² is fluoro. [0515] Embodiment 6. The compound of any one of embodiments 1-5, wherein A¹ is each of which is substituted by p occurrences of halo. [0516] Embodiment 7. The compound of any one of embodiments 1-5, wherein A¹ is , , [0517] Embodiment 8. The compound of any one of embodiments 1-5, wherein A¹ is [0518] Embodiment 9. The compound of any one of embodiments 1-5, wherein A¹ is 267 [0519] Embodiment 10. The compound of any one of embodiments 1-9, wherein A² is , , , , , , each of which is substituted with 0 or 1 occurrences of R³, or a covalent bond, wherein ***is the point of attachment to Z. [0520] Embodiment 11. The compound of embodiment 1, wherein the compound is a compound of Formula Ia: or a pharmaceutically acceptable salt thereof. [0521] Embodiment 12. The compound of embodiment 1, wherein the compound is a compound of Formula Ib: or a pharmaceutically acceptable salt thereof, wherein: B¹ is a 6-membered aryl ring or a 5-6 membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur, wherein the aryl and heteroaryl are substituted with p occurrences of R². [0522] Embodiment 13. The compound of embodiment 1, wherein the compound is a compound of Formula Ic: or a pharmaceutically acceptable salt thereof, wherein: B¹ is a 6-membered aryl ring or a 5-6 membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur, wherein the aryl and heteroaryl are substituted with p occurrences of R². [0523] Embodiment 14. The compound of embodiment 12 or 13, wherein [0524] Embodiment 15. The compound of embodiment 12 or 13, wherein , [0525] Embodiment 16. The compound of embodiment 1, wherein the compound is a compound of Formula Id: or a pharmaceutically acceptable salt thereof, wherein X is -C(H)- or -N-. [0526] Embodiment 17. The compound of embodiment 1, wherein the compound is a compound of Formula Ie: or a pharmaceutically acceptable salt thereof, wherein Y and Q each represent independently N or S. [0527] Embodiment 18. The compound of any one of embodiments 1-17, wherein A² is , each of which is substituted with 0 or 1 occurrences of R³, wherein ***is the point of attachment to Z. [0528] Embodiment 19. The compound of embodiment 1, wherein the compound is a compound of Formula If, Ig, Ih, or Ii, or a pharmaceutically acceptable salt thereof: [0529] Embodiment 20. The compound of embodiment 1, wherein the compound is a compound of Formula Ij or Ik: (Ij) (Ik) or a pharmaceutically acceptable salt thereof. [0530] Embodiment 21. The compound of embodiment 1, wherein the compound is a compound of Formula Il: or a pharmaceutically acceptable salt thereof. [0531] Embodiment 22. The compound of embodiment 1, wherein the compound is a compound of Formula I-A: or a pharmaceutically acceptable salt thereof; wherein: each of which is substituted by p occurrences of halo; A² is a covalent bond; , each of which is substituted with 0 or 1 occurrences of R³, wherein ***is the point of attachment to Z; R^1A, R^1B, and R^1C represent independently for each occurrence hydrogen or C1-4 alkyl; R³ is halo or C_1-4 alkyl; Z is -C(O)R⁴, -C(O)-(C1-4 alkylene)-R⁴, -C(O)-OH, -C(O)-O-(C1-6 alkyl), -C(O)- N(R^1A)(R^1B), -C(O)-O-(C1-4 alkylene)-O-(C1-4 alkylene)-N(R^1A)(R^1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R^1A)(R^1B))-(C_1-4 hydroxyalkyl), -S(O)₂-(C_1-6 alkyl), - S(O)₂-(C_3-7 cycloalkyl), -S(O)₂-N(R^1A)(R^1B), -S(O)₂-N(R^1A)-C(O)-(C_1-6 alkyl), -S(O)₂- N(R^1A)-C(O)-O-(C1-6 alkyl), -S(O)2-N(R^1A)-C(O)-N(R^1B)(R^1C), -S(O)2-[(C1-4 alkylene)-O-]x- R⁵, -N(R^1A)-C(O)-(C1-4 alkylene)-(5-6 membered saturated heterocyclyl containing 1 oxygen atom), -N(R^1A)-C(O)-O-(C_1-4 alkylene)-(phenyl), -N(R^1A)-C(O)-O-[(C_1-4 alkylene)-O-]_x-R⁶, - N(R^1A)-C(O)-N(R^1B)-[(C1-4 alkylene)-O-]x-R⁶, -C(O)-N(R^1A)-(C1-6 hydroxyalkyl), -C(O)- N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1A)(R^1B), -N(R^1A)-C(O)-N(R^1B)-[(C1-6 hydroxyalkyl), -C(O)-(C_1-4 alkylene)-[O-(C_1-4 alkylene)-]_y-(C_1-6 alkoxyl), -C(O)-C(O)-OH, - C(O)-C(O)-N(R^1A)(R^1B), -N(R^1A)-C(O)-(C1-6 hydroxyalkyl), -C(O)-C(O)-N(R^1A)-R⁵, - N(R^1A)-C(O)-C(O)-N(R^1B)(R^1C), -C(O)-N(R^1A)-S(O)2-R⁷, -N(R^1A)-S(O)2-R⁷, -C(O)-C(O)- N(R^1A)-S(O)₂-(C_1-6 alkyl), -S(O)₂-(C_1-4 alkylene)-(C_1-6 alkoxyl), -C(O)-C(O)-N(R^1A)-(C_1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-O-(C_1-4 alkylene)- (5 membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom), or hydrogen, wherein the heterocyclyl is substituted with z occurrences of R⁹); R⁴ is C_1-6 hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl; R⁵ is C1-6 alkyl, C1-6 hydroxalkyl or C1-6 alkoxyl; R⁶ is C1-4 alkyl, C1-4 hydroxyalkyl, or C1-4 haloalkyl; R⁷ is C_1-4 alkyl, C_1-4 alkoxyl, -(C_0-4 alkylene)-N(R^1A)(R^1B), or -N(R^1B)-C(O)-O-R⁸; R⁸ is C1-4 alkyl or -(C0-4 alkylene)-(phenyl); R⁹ is oxo, C_1-4 alkyl, or -C(O)-O-(C_1-4 alkyl); p is 0, 1, 2, 3, or 4; x is 1, 2, 3, 4, or 5; and y and z are independently 1, 2, or 3 provided that when B¹ is a 6-membered aryl ring substituted with 0 or 1 occurrences of R², then Z is not -C(O)R⁴ or -C(O)-(C1-4 alkylene)-R⁴. [0532] Embodiment 23. The compound of embodiment 22, wherein the compound is a compound of Formula I-A. [0533] Embodiment 24. The compound of embodiment 22 or 23, wherein A¹ is . [0534] Embodiment 25. The compound of embodiment 22 or 23, wherein A¹ is [0535] Embodiment 26. The compound of any one of embodiments 1-25, wherein A² is each of which is substituted with 0 or 1 occurrences of R³, wherein ***is the point of attachment to Z. [0536] Embodiment 27. The compound of any one of embodiments 1-26, wherein is hydrogen. [0537] Embodiment 28. The compound of any one of embodiments 1-26, wherein Z is , [0538] Embodiment 29. The compound of any one of embodiments 1-26, wherein Z is , , , [0539] Embodiment 30. The compound of any one of embodiments 1-26, wherein Z is . [0540] Embodiment 31. The compound of any one of embodiments 1-26, wherein Z is [0541] Embodiment 32. The compound of any one of embodiments 1-26, wherein Z is ,

[0542] Embodiment 33. The compound of any one of embodiments 1-26, wherein Z is , , , [0543] Embodiment 34. The compound of any one of embodiments 1-26, wherein Z is , , [0544] Embodiment 35. The compound of any one of embodiments 1-26, wherein Z is [0545] Embodiment 36. The compound of any one of embodiments 1-26, wherein Z is . [0546] Embodiment 37. The compound of any one of embodiments 1-26, wherein Z is [0547] Embodiment 38. A compound in Table 1 herein, or a pharmaceutically acceptable salt thereof. [0548] Embodiment 39. A pharmaceutical composition comprising a compound of any one of embodiments 1-38 and a pharmaceutically acceptable carrier. [0549] Embodiment 40. A method for treating a disease or condition mediated by NAMPT, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of embodiments 1-38 to treat the disease or condition. [0550] Embodiment 41. The method of embodiment 40, wherein said disease or condition mediated by NAMPT is a proliferative disorder. [0551] Embodiment 42. The method of embodiment 40, wherein said disease or condition mediated by NAMPT is an inflammatory disorder. [0552] Embodiment 43. The method of embodiment 40, wherein said disease or condition mediated by NAMPT is a metabolic disorder. [0553] Embodiment 44. The method of embodiment 40, wherein said disease or condition mediated by NAMPT is selected from cancer, neoplasia, chronic inflammatory disorder, acute inflammatory disorder, auto-inflammatory disorder, metabolic disorder, and a combination thereof. [0554] Embodiment 45. The method of embodiment 40, wherein said disease or condition mediated by NAMPT is cancer. [0555] Embodiment 46. The method of embodiment 45, wherein the cancer is pancreatic cancer, melanoma, glioma, lung cancer, colon cancer, rectal cancer, breast cancer, cervical cancer, prostate cancer, gastric cancer, skin cancer, liver cancer, bile duct cancer, nervous system cancer, a lymphoma, leukemia, ovarian cancer, uterine cancer, endometrial cancer, testicular cancer, brain cancer, oral cancer, esophageal cancer, head and neck cancer, stomach cancer, sebaceous gland carcinoma, gallbladder cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, urothelial cancer, colorectal cancer, or glioblastoma multiforme. [0556] Embodiment 47. The method of any one of embodiments 44-46, wherein the cancer is a NAPRT-negative cancer. [0557] Embodiment 48. The method of embodiment 40, wherein said disease or condition mediated by NAMPT is allergic rhinitis, nasal inflammation, asthma, chronic obstructive pulmonary disease (COPD), bronchitis, emphysema, chronic eosinophilic pneumonia, adult respiratory distress syndrome, sinusitis, allergic conjunctivitis, idiopathic pulmonary fibrosis, atopic dermatitis, asthma, allergic rhinitis, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, multiple sclerosis, endometriosis, eczema, psoriasis, rosacea, or lupus erythematosus. [0558] Embodiment 49. The method of embodiment 40, wherein said disease or condition mediated by NAMPT is multiple sclerosis, ankylosing spondylitis, arthritis, osteoarthritis, juvenile arthritis, reactive arthritis, rheumatoid arthritis, psoriatic arthritis, acquired immunodeficiency syndrome (AIDS), Coeliac disease, psoriasis, chronic graft-versus-host disease, acute graft-versus- host disease, Crohn’s disease, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, Celiac Sprue, idiopathic thrombocytopenic thrombotic purpura, myasthenia gravis, Sjogren’s syndrome, scleroderma, ulcerative colitis, asthma, uveitis, rosacea, dermatitis, alopecia areata, vitiligo, arthritis, Type 1 diabetes, lupus erythematosus, systemic lupus erythematosus, Hashimoto’s thyroiditis, myasthenia gravis, nephrotic syndrome, eosinophilia fasciitis, hyper IgE syndrome, lepromatous leprosy, sezary syndrome, idiopathic thrombocytopenia purpura, restenosis following angioplasty, a tumor, or atherosclerosis. [0559] Embodiment 50. The method of embodiment 40, wherein said disease or condition mediated by NAMPT is psoriasis, dermatitis, vitiligo, ichthyosis, alopecia areata, epidermolysis bullosa, hidradenitis suppurativa, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, or kidney disease. [0560] Embodiment 51. The method of embodiment 40, wherein said disease or condition mediated by NAMPT is inflammatory bowel disease (IBD). [0561] Embodiment 52. The method of any one of embodiments 40-51, wherein the subject is a human. [0562] Embodiment 53. A method of inhibiting the activity of NAMPT, comprising contacting a NAMPT with an effective amount of a compound of any one of embodiments 1-38 to inhibit the activity of said NAMPT. EXAMPLES [0563] The invention now being generally described, will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and is not intended to limit the invention. GENERAL PROCEDURE A: PREPARATION OF PHENYL CARBAMATES: [0564] To a stirred solution of amine (1 equiv) and DIPEA (2.5 equiv) in THF (concentration of amine in THF = ~0.18 M) was added phenyl chloroformate (1.2 equiv) at 0 °C. After the addition, the reaction mixture was stirred at 0 °C for 30 min and rt for 2 h. The reaction mixture was poured into ice cold water. The precipitate was filtered and dried. GENERAL PROCEDURE B: PREPARATION OF UREAS FROM PHENYL CARBAMATES: [0565] Amine (1.1 equiv) was added to a solution of phenyl carbamate (1.0 equiv) and DIPEA (5 equiv) in THF (concentration of phenyl carbamate in THF = ~0.13 M) at ambient temperature. The reaction mixture was stirred at 70 ^oC for 16 h. The volatiles were concentrated, and the reaction mixture was poured in ice cold water, stirred for 10 min, and the precipitate was filtered. GENERAL PROCEDURE C: DEPROTECTION OF BOC GROUP: [0566] To a stirred solution of Boc-protected compound (1 equiv) in DCM (concentration of Boc-protected compound in DCM = ~0.11 M) was added HCl (7.0 equiv, 4.0 N in 1,4-dioxane) at 0 ^oC, then the reaction mixture was stirred at rt for 2 h. The volatiles were evaporated under reduced pressure, then the reaction mixture was treated with saturated aqueous NaHCO₃, and the precipitate was filtered. GENERAL PROCEDURE D: ACID-AMINE COUPLING: [0567] To a stirred solution of amine (1 equiv) in DMF (concentration of amine in DMF = ~0.1 M) was added an acid (2 equiv), EDCI (2 equiv), HOBt (2 equiv) and triethylamine (5 equiv) and stirred at rt for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with ice cold water and the precipitate was filtered and washed with water, and dried to give the crude compound. The residue was triturated with EtOAc. LCMS METHODS USED IN THE PREPARATION OF CHEMICAL COMPOUNDS [0568] Method A: X-Bridge BEH C-18 (3x50 mmx2.5mm); mobile phase: A; 0.025% formic acid in H2O; B; ACN; injection volume: 2 µL; flow rate: 1.2 mL/min; column temperature: 50 ^oC; gradient: 2% B to 98% B in 2.2 min, hold until 3 min, at 3.2 min B conc. is 2% until up to 4 min. [0569] Method B: X-select CSH 18 (3x50 mmx2.5mm); mobile phase: A; 0.025% formic acid in H2O; B; ACN; injection volume: 2 µL; flow rate: 1.2 mL/min; column temperature: 50 ^oC; gradient: 0% B to 98% B in 2 min, hold until 3 min, at 3.2 min B conc. is 0 % until up to 4 min. [0570] Method C: X-select CSH 18 (3x50 mmx2.5mm); mobile phase: A; 0.05% formic acid in H2O: ACN (95:5); B: 0.05% formic acid in ACN; injection volume: 2 µL; flow rate: 1.2 mL/min; column temperature: 50 ^oC; gradient: 0% B to 98% B in 2 min, hold until 3 min, at 3.2 min B conc. is 0 % until up to 4 min. [0571] Method D: X-select CSH C18 (3x50 mmx2.5µm); mobile phase: A: 2mM in ammonium bicarbonate; B: ACN; injection volume:2 µL; flow rate:1.2 mL/min; column temperature: 50 ^oC; gradient: 0% B to 98% B in 2 min, hold until 3 min, at 3.2 min B conc. is 0 % until up to 4 min. [0572] Method E: X-Select CSH-C18 (3.0x50mm, 2.5µm); mobile phase: A: 2.5mM; NH₄HCO₃ in water; mobile phase: B: ACN; injection volume: 2 µL; (gradient) T/B%:0.0/2, 0.3/2, 2.0/98, 2.8/98, 3.0/2, 3.7/2; flow rate: 1 ml/min; column temp.: 40 °C. [0573] Method F: CORTECS UPLC C18 (3x30) mm, 1.6µm; flow rate: 0.85 mL/min; mobile phase A: 0.05% formic acid in water; mobile phase B: 0.05% formic acid in ACN; injection volume: 2 µL; column temp.: 45 °C; gradient program (time/%B): 0.0/3, 0.1/3, 1.4/97, 2.0/97, 2.05/3, 2.5/3. [0574] Method G: X-select CSH 18 (3x50 mmx2.5mm); mobile phase: A: 0.05% TFA in H2O; B: 0.05% TFA in ACN; injection volume: 2µL; flow rate: 1mL/min; column temperature: 40 ^oC; gradient (time/%B): 0.0/2, 0.3/2, 2/98, 2.8/98, 3.0/2, 3.7/2. [0575] Method H: X-Select CSH-C18 (3.0x50mm, 2.5µm); mobile phase: A: 2.5mM NH₄HCO₃ in water + 5% ACN; mobile phase: B: 100% ACN; injection volume: 2 µL; gradient: time/B%: 0.0/2, 0.3/2, 2.0/98, 2.8/98, 3.0/2, 3.7/2; flow rate: 1 ml/min; column Temp.: 40 °C. [0576] Method I: X-Select CSH C18, (50mm*3.0mm, 2.5µm); mobile phase A: 0.05% formic acid in water; mobile phase B: 0.05% formic acid in acetonitrile; flow rate: 1.0mL/min; column temperature: 40 °C; gradient (time/B%): 0.01/2, 0.3/2, 2.0/98, 2.8/98, 3.0/2, 3.7/2. EXAMPLE 1A – SYNTHESIS OF 4-FLUORO-N-(4-(1-(2-HYDROXY-2-METHYL- PROPANOYL)PIPERIDIN-4-YL)PHENYL)ISOINDOLINE-2-CARBOXAMIDE (I-137) [0577] Step 1: Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (1-3): A mixture of compound 1-1 (25 g, 145.3 mmol), compound 1-2 (49.43 g, 159.9 mmol), and Cs₂CO₃ (95.2 g, 290.7 mmol) in 1,4-dioxane: H₂O (1:1, 250 mL) was degassed with argon for 5 min. X-Phos (7.07 g, 14.5 mmol) and Pd₂(dba)₃ (6.86 g, 7.26 mmol) were added to the reaction mixture at room temperature. The reaction mixture was stirred for 15 min while degassing with argon. The reaction mixture was stirred at 90 ^oC for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with ethyl acetate. The organic layer was mixed with water and extracted with ethyl acetate. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a sticky crude residue, which was triturated with n- heptane, and the precipitated solid was filtered and dried under reduced pressure to afford the title compound 1-3 (25.00 g, 91.11 mmol, 62.69% yield) as a cream colored solid. [0578] Step 2: Synthesis of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (1-4): To a stirred solution of compound 1-3 (15.0 g, 54.71 mmol) in methanol (150 mL) was added 10% palladium on carbon (50% wet, 5.82 g) and the reaction mixture was stirred at room temperature for 16 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with ethyl acetate. The combined organic layers were concentrated under reduced pressure to afford the title crude compound 1-4 (11.5 g, 41.6 mmol, 76.10% yield) as an off white solid. The crude compound was used in the next step without further purification. [0579] Step 3: Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)piperidine-1- carboxylate (1-6): To a stirred solution of compound 1-4 (25.00 g, 90.45 mmol) in DCM (250 mL) was added pyridine (14.69 mL, 180.9 mmol) and DMAP (1.12 g, 9.04 mmol) and the reaction mixture was stirred at room temperature, followed by addition of compound 1-5 (15.58 g, 99.49 mmol) at 0 ^oC. The reaction mixture was then the reaction mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether and the precipitated solids were filtered and dried under reduced pressure to afford the title compound 1-6 (20.5 g, 51.7 mmol, 57.20% yield) as an off white solid. [0580] Step 4: Synthesis of tert-butyl 4-(4-(4-fluoroisoindoline-2- carboxamido)phenyl)piperidine-1-carboxylate (1-8): To a stirred solution of compound 1-6 (28.00 g, 70.62 mmol) and compound 1-7 (14.71 g, 84.74 mmol) in DMF (140 mL) at room temperature was added DIPEA (61.7 mL, 353.1 mmol) and then the reaction mixture was stirred at 90 ^oC for 4 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ice cold water, the precipitated solid was filtered, washed with n-heptane (2 x 60 mL), and dried under reduced pressure to afford the title compound 1-8 (15.00 g, 34.13 mmol, 48.33% yield) as an off-white solid. [0581] Step 5: Synthesis of 4-fluoro-N-(4-(piperidin-4-yl)phenyl)isoindoline-2- carboxamide (1-9): To a stirred solution of compound 1-8 (15.00 g, 34.13 mmol) in 1,4-dioxane (75 mL) was added 4 M HCl in 1,4-dioxane (85.32 mL, 341.3 mmol) at 0 ^oC and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (70 mL) and the filtered solid compound was dried under reduced pressure to afford the desired compound 1-9 (11.00 g, 32.41 mmol, 94.96% yield) as an off-white solid. [0582] Step 6: Synthesis of 4-fluoro-N-(4-(1-(2-hydroxy-2-methylpropanoyl)piperidin-4- yl)phenyl)isoindoline-2-carboxamide (I-137): To stirred solution of compound 1-9 (22.00 g, 64.82 mmol), 2-hydroxy-2-methylpropanoic acid 1-10 (10.12 g, 97.23 mmol) in DMF (20 mL) were added DIPEA (56.6 mL, 324.1 mmol), followed by HATU (50.82 g, 129.6 mmol) at 0 ^oC. The resulting mixture was stirred at room temperature for 16 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was poured into ice-cold water and a gummy solid precipitated out. The solid was collected by filtration and dissolved in 10% MeOH-DCM. The resulting mixture was filtered to remove undissolved solids, and the filtrate was concentrated and a gummy solid was obtained. This gummy solid was washed by MeOH and the solid material was collected by filtration. This solid material was dissolved in 10% MeOH- DCM at 60 ^oC. This mixture was left at rt. After a few hours, solids precipitated out, which were collected by filtration. This solid material was dried to afford the title compound 4-fluoro-N-(4-(1- (2-hydroxy-2-methylpropanoyl)piperidin-4-yl)phenyl)isoindoline-2-carboxamide (I-137, 11.10 g, 26.09 mmol, 40.25% yield) as an off white solid. HPLC: Rt 7.728 min, purity: 98.79%; method: HPLC_X-Bridge; column: X-Bridge C18 (4.6*150) mm x 5 ^m, mobile phase: A – 5 mm ammonium bicarbonate in water B – acetonitrile, injection volume: 5.0µL, flow rate: 1.0 mL/minute, gradient: time(min)/ B Conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. LCMS : 426.2 (M+H), Rt 2.051 min, 99.31%; method details: column: X-Select CSH C18 (3.0*50mm, 2.5 ^m), mobile phase A: 2.5Mm, ammonium bicarbonate in H₂O+ 5% ACN, mobile phase B: 100% CAN, gradient %B: 0/2, 0.3/2, 2.0/98, 2.8/98, 3.0/2,3.7/2, flow rate: 1.0 ml/min, column oven temp: 40 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (s, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.37 (dd, J = 5.3, 7.9 Hz, 1H), 7.21 (d, J = 7.4 Hz, 1H), 7.16 – 7.10 (m, 3H), 5.36 (s, 1H), 5.03 – 4.52 (m, 6H), 3.01-2.62 (m, 3H), 1.86 – 1.71 (m, 2H), 1.61 – 1.45 (m, 2H), 1.34 (s, 6H). EXAMPLE 1B - SYNTHESIS OF 4-FLUORO-N-(4-(1-(2-HYDROXY-2-METHYL- PROPANOYL)PIPERIDIN-4-YL)PHENYL)ISOINDOLINE-2-CARBOXAMIDE (I-137) [0583] Step 1: Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylatecarbamate (1-3): A mixture of compound 1-1 (10.0 g, 58.13 mmol), compound 1-2 (21.57 g, 69.76 mmol), and Cs2CO3 (37.78 g, 116.26 mmol) in 1,2-Dioxane: H2O (70:30, 100 mL) was degassed with argon for 5 minutes. X-Phos (1.2 g, 2.47 mmol) and Pd₂(dba)₃ (1,06 g, 1.16 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred for 15 min while degassing with argon, and then the reaction mixture was heated to 100 ^oC and stirred for 18 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with ethyl acetate. The organic layer was mixed with water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluting with 30% EtOAc in heptane) to afford the title compound 1-3 (8.0 g, 29.19 mmol, 50.82% yield) as a yellow solid. [0584] Step 2: Synthesis of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (1-4): To a stirred solution of compound 1-3 (5.0 g, 18.22 mmol) in ethanol (50 mL) was added 10% palladium on carbon (0.73 g) and the reaction mixture was stirred at room temperature for 16 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with ethyl acetate. The combined organic layers were concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluting with 35% EtOAc in heptane) to afford the title compound 1-4 (4.7 g, 17.00 mmol, 93.43% yield) as an off white solid. [0585] Step 3: Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)piperidine- 1-carboxylate (1-6): To a stirred solution of compound 1-4 (4.3 g, 16 mmol) in DCM (50 mL) was added pyridine (2.5 mL, 31 mmol) and DMAP (0.19 g, 1.6 mmol) and the reaction mixture was stirred at room temperature and then compound 1-5 (2.3 mL, 19 mmol) was added at 0 ^oC and then the reaction mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the title crude compound 1-6 (6.9 g, crude) as an off white solid. The crude compound was used in the next step with further purification. [0586] Step 4: Synthesis of tert-butyl 4-(4-(4-fluoroisoindoline-2-carboxamido)phenyl) piperidine-1-carboxylate (1-8): To a stirred solution of compound 1-6 (6.9 g, 17 mmol) and compound 1-7 (3.10 g, 19 mmol) in DMF (30 mL) at room temperature was added DIPEA (15 mL, 87 mmol) and then the reaction mixture was stirred at 80 ^oC for 3 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by Combi Flash chromatography (eluting with 40-50 % EtOAc in heptane) to afford the title compound 1-8 (3.8 g, 8.65 mmol, 49.35% yield) as an off-white solid. [0587] Step 5: Synthesis of 4-fluoro-N-(4-(piperidin-4-yl)phenyl)isoindoline-2- carboxamide (1-9): To a stirred solution of compound 1-8 (3.8 g, 8.6 mmol) in 1,4-dioxane (10 mL) was added 4 M HCl in 1,4-dioxane (22 mL, 86 mmol) at 0 ^oC and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (10 mL) and then with n-pentane (5 mLx2), and then the solid compound was filtered and dried under reduced pressure to afford the desired compound 1-9 (2.9 g, 8.5 mmol, 99% yield) as an off- white solid. [0588] Step 6: Synthesis of 4-fluoro-N-(4-(1-(2-hydroxy-2-methylpropanoyl)piperidin-4- yl)phenyl)isoindoline-2-carboxamide (I-137): To stirred solution of compound 1-9 (1.5 g, 4.4 mmol), 2-hydroxy-2-methylpropanoic acid 1-10 (0.55 g, 5.3 mmol), and HATU (2.6 g, 6.6 mmol) in DMF (20 mL) was added N,N-diisopropylethylamine (2.3 mL, 13 mmol) at 0 ℃ and the reaction mixture was stirred at room temperature for 16 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with cold water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by Combi Flash chromatography (eluting with 35 to 50 % EtOAc in hexane) to afford the title compound 4-fluoro-N-(4-(1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl)phenyl)isoindoline-2- carboxamide (I-137, 395 mg, 0.928 mmol, 21% yield) as an off white solid. HPLC: Rt 7.772min, purity: 98.78%; Method: column: X-Bridge C18 (4.6*150) mm x 5 ^m; mobile phase: A - 5 mM ammonium bicarbonate in water; B - acetonitrile injection volume: 5.0µL, flow rate: 1.0 mL/minute gradient: time (min)/ B Conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. LCMS: 426.06 (M+H), Rt 1.26 min & 1.84min, 98.96%. Method F. ¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (s, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.37 (dt, J = 5.4, 7.8 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 7.13 (d, J = 8.6 Hz, 3H), 5.36 (s, 1H), 4.87 - 4.74 (m, 5H), 4.72 - 4.47 (m, 1H), 2.76 - 2.66 (m, 1H), 1.82 - 1.71 (m, 2H), 1.58 - 1.46 (m, 2H), 1.34 (s, 6H), 1.29 - 1.23 (m, 2H). 286 EXAMPLE 2 - SYNTHESIS OF TERT-BUTYL (N-((1R,4R)-4-(4-(4- FLUOROISOINDOLINE-2-CARBOXAMIDO)PHENYL)CYCLOHEXANE-1- CARBONYL)SULFAMOYL)CARBAMATE (I-67) AND 4-FLUORO-N-(4-((1R,4R)-4- (SULFAMOYL-CARBAMOYL)CYCLOHEXYL)PHENYL)ISOINDOLINE-2- CARBOXAMIDE (I-53) [0589] Step 1: Synthesis of (1r,4r)-4-phenylcyclohexane-1-carboxylic acid (2-2): To a stirred solution of compound 2-1 (10.0 g, 41.89 mmol) in MeOH (50 mL) were added triethylamine (6.7 mL) and 10% palladium on carbon (50% wet, 3.3 g) at rt. The reaction mixture was stirred at 50 ^oC for 18 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The combined organic layers were concentrated under reduced pressure to afford the title crude compound 2-2 (8.0 g, 39.16 mmol, 93.47% yield) as a white solid. The crude compound was used in the next step without further purification. LC-MS: MS calcd. for chemical formula C₁₃H₁₆O₂: 204.27; Found: 203.14 [M-H]-; Method F. [0590] Step 2: Synthesis of (1r,4r)-4-(4-nitrophenyl)cyclohexane-1-carboxylic acid (2-3): To a mixture of compound 2-2 (2.0 g, 9.79 mmol) and potassium nitrate (0.29 g, 2.94 mmol) was added sulphuric acid (20 mL, 45.6 mmol) dropwise at 0 ^oC. The reaction mixture was stirred for 30 min. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and the precipitated solid was collected by filtration and dried under reduced pressure to afford the title crude compound 2-3 (1.7 g, 6.8 mmol, 70% yield) as a white solid. The crude compound was used in the next step without further purification. LC-MS: MS calcd. for chemical formula: C13H15NO4: 249.27; Found: 248.5 [M-H]-; Method F. [0591] Step 3: Synthesis of tert-butyl (1r,4r)-4-(4-nitrophenyl)cyclohexane-1-carboxylate (2-4): To a stirred solution of compound 2-3 (1.0 g, 4.01 mmol) in t-BuOH (10 mL) was added Boc-anhydride (1.57 g, 7.12 mmol) followed by DMAP (0.15 g, 1.20 mmol) at 0 ^oC. The mixture was then the reaction mixture was stirred at 80 ^oC for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with cold water and extracted with EtOAc. The combined organic layers were washed with water, followed by brine, and then dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography on a 4 g silica gel cartridge (eluting with 2 to 4% MeOH in DCM) to afford the title compound 2-4 (0.4 g, 1.31 mmol, 32.65% yield) as an off white solid. LC-MS: MS calcd. for chemical formula: C17H23NO4: 305.37; Found: 304.16 [M-H]-; Method F. [0592] Step 4: Synthesis of tert-butyl (1r,4r)-4-(4-aminophenyl)cyclohexane-1- carboxylate (2-5): To a stirred solution of compound 2-4 (0.5 g, 1.64 mmol) in ethanol (20 mL) was added 10% palladium on carbon (50% wet, 0.15 g 1.41 mmol) and the reaction mixture was stirred at rt for 16 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The combined organic layers were concentrated under reduced pressure to afford the crude compound 2-5 (0.35 g, 1.271 mmol, 77.63% yield) as a pale red solid. LC-MS: MS calcd. for chemical formula: C₁₇H₂₅NO₂: 275.39; Found: 275.94 [M+H]⁺; Method F. [0593] Step 5: Synthesis of tert-butyl (1r,4r)-4-(4-((phenoxycarbonyl)amino) phenyl) cyclohexane-1-carboxylate (2-7): To a stirred solution of compound 2-5 (0.25 g, 0.908 mmol) in DCM (10 mL) were added pyridine (0.15 mL, 1.816 mmol) followed by phenyl chloroformate 2- 6 (0.17 g, 1.09 mmol) at 0 ^oC and then the reaction mixture was stirred at rt for 1 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were concentrated under reduced pressure to afford the crude compound 2-7 (0.2 g, 0.506 mmol, 55.71% yield) as a pale- yellow solid. The crude compound was used in the next step without further purification. LC-MS: MS calcd. for chemical formula: C24H29NO4: 395.5; Found: 396.01 [M+H]⁺ ; Method F. [0594] Step 6: Synthesis of tert-butyl (1r,4r)-4-(4-(4-fluoroisoindoline-2-carboxamido) phenyl)cyclohexane-1-carboxylate (2-9): To a stirred solution of compound 2-7 (0.3 g, 0.849 mmol) and compound 2-8 (0.14 g, 1.02 mmol) in DMF (5 mL) was added DIPEA (0.45 mL, 2.55 mmol) at rt and then the reaction mixture was stirred at 80 ^oC for 1 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the title crude compound 2- 9 (0.25 g, 0.57 mmol, 67.16% yield) as an off-white solid. The crude compound was used in the next step without further purification. LC-MS: MS calcd. for chemical formula: C26H31FN2O3: 438.54; Found: 439.3 [M+H]⁺; Method F. [0595] Step 7: Synthesis of (1r,4r)-4-(4-(4-fluoroisoindoline-2-carboxamido)phenyl) cyclohexane-1-carboxylic acid (2-10): To the stirred solution of compound 2-9 (0.15 g, 0.342 mmol) in DCM (5 mL), was added trifluoroacetic acid (TFA) (1 mL) at 0 ^oC. The reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the reaction was directly concentrated under reduced pressure to afford the crude compound 2-10 (0.125 g, 0.33 mmol, 95.56% yield) as a light brown solid. The crude compound was used in the next step without further purification. LC-MS: MS calcd. for chemical formula: C22H23FN2O3: 382.44; Found: 383.3 [M+H]⁺; Method F. [0596] Step 8: Synthesis of tert-butyl (N-((1r,4r)-4-(4-(4-fluoroisoindoline-2- carboxamido)phenyl)cyclohexane-1-carbonyl)sulfamoyl)carbamate (I-67): To a stirred solution of compound 2-10 (0.15 g, 0.392 mmol) in DMF (2 mL) at 0 ^oC were added DIPEA (0.35 mL, 1.96 mmol) and HATU (0.226 g, 0.588 mmol). After 5 min, compound 2-11 (0.092 g, 0.470 mmol) was added and the reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by CombiFlash (Nexgen- 300) chromatography using a 4 g silica gel cartridge and 2-5% MeOH in DCM as the eluent to afford the title compound (0.030 g, 0.053 mmol, 16% yield) as an off white solid. LC-MS: MS calcd. for chemical formula C₂₇H₃₃FN₄O₆S: 560.64; Found: 561.08 [M+H]⁺; Method F. [0597] Step 9: Synthesis of 4-fluoro-N-(4-((1r,4r)-4-(sulfamoylcarbamoyl) cyclohexyl) phenyl)isoindoline-2-carboxamide (I-53): To a stirred solution of compound I-67 (0.025 g, 0.045 mmol) in DCM (1 mL), was added 4 M HCl in 1,4-dioxane (2 mL) at 0 ^oC and the reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then sequentially triturated with diethyl ether (2 mL) and then with n-pentane (2 mL x 2). After each trituration, the solid compound was collected by filtration and dried under reduced pressure. The crude compound was then purified by prep-HPLC to afford the title compound 4-fluoro-N-(4-((1r,4r)-4-(sulfamoyl carbamoyl)cyclohexyl)phenyl)isoindoline-2-carboxamide (I-53, 9 mg, 0.019 mmol, 43.83% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d₆) δ 11.33 (s, 1H), 8.33 (s, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.38 (dt, J = 5.3, 7.8 Hz, 1H), 7.27 (s, 2H), 7.21 (d, J = 7.6 Hz, 1H), 7.16 - 7.08 (m, 3H), 4.80 (d, J = 9.2 Hz, 4H), 2.46 - 2.39 (m, 1H), 2.27 (t, J = 11.3 Hz, 1H), 1.86 (t, J = 12.4 Hz, 4H), 1.56 - 1.36 (m, 4H). LCMS: ret. time : 1.30 min, 98.16%, LC-MS: MS calcd. for chemical formula: C₂₂H₂₅FN₄O₄S: 460.52; Found: 461.01 [M+H]⁺; Method F. HPLC: Rt 6.650 min, 96.51%; column: X-Select CSH C18 (4.6x150) mm x 5 ^m; mobile phase A: 0.1% TFA in water & B: ACN; flow rate: 1.2 mL/min; column oven temp.: 30 °C; gradient: time (min)/ B conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. Prep-HPLC purification method: column: X-select 18(250*30MM*5U); mobile phase A: 0.1% FA in water; mobile phase B: ACN; flow rate: 25 mL/min; gradient (time/%B) 0/15, 3/15, 10/35, 20/48, 25/53, 35/60, 40/68, 45/75, 55/85, 60/98. EXAMPLE 3 - SYNTHESIS OF 2-(4-(4-(5-FLUOROISOINDOLINE-2- CARBOXAMIDO) PHENYL)PIPERIDIN-1-YL)-2-OXOACETIC ACID (I-52) [0598] Step 1: Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (3-3): A mixture of compound 3-1 (2.00 g, 11.6 mmol), compound 3-2 (4.31 g, 14.0 mmol), and Cs2CO3 (11.4 g, 34.9 mmol) in 1,4-dioxane:H2O (1:1) (20 mL) was degassed with argon for 5 min. X-Phos (0.56 g, 1.16 mmol) and Pd2(dba)3 (0.55 g, 0.581 mmol) were added to the reaction mixture at rt. The reaction mixture was stirred for 15 min while degassing with argon, and then the reaction mixture was stirred to 100 ^oC for 16 h. After completion of the reaction (monitored by TLC), the reaction was concentrated under vacuum to obtain the crude. The crude was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by CombiFlash (Nexgen-300) chromatography using a 24 g silica gel cartridge and 35-45% EtOAc in n-heptane as the eluent to afford the title compound 3-3 (2.0 g, 7.28 mmol, 62.7% yield) as an off white solid. LC-MS: MS calcd. for chemical formula: C16H22N2O2: 274.36; found: 275.3 [M+H]⁺; Method E. [0599] Step 2: Synthesis of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (3-4): To a stirred solution of compound 3-3 (2.00 g, 7.29 mmol) in ethanol (20 mL) was added 10% palladium on carbon (50% wet, 0.155 g) and the reaction mixture was stirred at rt for 16 h under a hydrogen atmosphere at 50 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The organic layer was concentrated under reduced pressure to afford the title crude compound 3-4 (1.6 g, 5.8 mmol, 79% yield) as an off white solid. LC-MS: MS calcd. for chemical formula: C₁₆H₂₄N₂O₂: 276.38; found: 221.3 [(M–Isobutene)+H]⁺; Method E. [0600] Step 3: Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)piperidine- 1-carboxylate (3-6): To a stirred solution of compound 3-4 (0.8 g, 2.89 mmol) in DCM (10 mL) at 0 ^oC were added pyridine (0.46 mL, 0.72 mmol) and compound 3-5 (0.54 g, 3.473 mmol) followed by DMAP (0.035 g, 0.289 mmol). The resulting mixture was stirred at rt for 16 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether and n-pentane, and the filtered the solid was dried under reduced pressure to afford the title compound 3-6 (1.0 g, 2.52 mmol, 87.14%yield) as an off white solid. LC-MS: MS calcd. for chemical formula: C₂₃H₂₈N₂O₄: 396.49; found: 341.2 [(M–Isobutene)+H]⁺; Method E. [0601] Step 4: Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) piperidine-1-carboxylate (3-8): To a stirred solution of compound 3-6 (1.12 g, 2.82 mmol) in DMF (4 mL) were added compound 3-7 (0.465 g, 3.39 mmol) and DIPEA (4.93 mL, 28.2 mmol) at rt. The resulting mixture was heated to 80 ^oC for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and the precipitated solids were filtered, washed with diethyl ether and n-pentane, and dried under reduced pressure to afford the title compound 3-8 (0.85 g, 1.934 mmol, 68.5% yield) as a brown solid. LCMS: MS calcd. for chemical formula: C₂₅H₃₀FN₃O₃: 439.53; found: 383.96 [(M-Isobutene)+H]⁺; Method G. [0602] Step 5: Synthesis of 5-fluoro-N-(4-(piperidin-4-yl)phenyl)isoindoline-2- carboxamide hydrochloride (3-9): To a stirred solution of compound 3-8 (1.8 g, 4.1 mmol) in 1,4-dioxane (20 mL) was added 4 M HCl in 1,4-dioxane (10 mL, 41 mmol) dropwise at 0 ^oC. The resulting mixture was stirred at rt for 8 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated sequentially with diethyl ether (10 mL) and then with pentane (5 mL x 2). The solids were filtered and dried under reduced pressure to afford the desired compound 3-9 (1.5 g, 4.0 mmol, 97% yield) as a pale brown solid. The resulting crude HCl salt was used in the next step without further purification. LC-MS: MS calcd. for chemical formula: C20H22FN3O: 339.41; found: 340.00 [M+H]⁺; Method F. [0603] Step 6: Synthesis of methyl 2-(4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) piperidin-1-yl)-2-oxoacetate (3-11): To a stirred solution of compound 3-9 (0.5 g, 1.33 mmol) in DCM (10 mL) was added triethylamine (0.560 mL, 4.00 mmol) at 0 ˚C, followed by dropwise addition of methyl 2-chloro-2-oxoacetate 3-10 (0.196 g, 1.60 mmol), and the reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by CombiFlash chromatography using a 4 g silica gel cartridge and 60-70% EtOAc in n-heptane as the eluent to afford the title compound 3-11 (0.18 g, 0.423 mmol, 31.73% yield) as a brown solid. LC-MS: MS calcd. for chemical formula: C₂₃H₂₄FN₃O₄: 425.46; found: 426.05 [M+H]⁺; Method F. [0604] Step 7: Synthesis of 2-(4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)piperidin- 1-yl)-2-oxoacetic acid (I-52): To a stirred solution of compound 3-11 (0.18 g, 0.423 mmol) in THF: MeOH: H₂O (1:1:1, 3 ml) was added LiOH (0.016 g, 0.635 mmol) at 0 ^oC and the resulting mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the MeOH and THF were evaporated under reduced pressure. The crude residue was diluted with H2O and acidified with 1.0 N HCl to pH~3 to 5 and extracted with EtOAc. The organic layer was concentrated, and the crude residue was purified by prep-HPLC to afford the title compound 2-(4- (4-(5-fluoroisoindoline-2-carboxamido)phenyl)piperidin-1-yl)-2-oxoacetic acid (I-52, 7 mg, 0.017 mmol, 4.02% yield) as a pale brown solid.¹H NMR (400 MHz, DMSO-d₆) δ 8.29 (s, 1H), 7.46 (d, J = 7.8 Hz, 2H), 7.40 - 7.34 (m, 1H), 7.22 (d, J = 8.5 Hz, 1H), 7.11 d, J = 7.9 Hz, 3H), 4.73 (d, J = 11.5 Hz, 4H), 4.42 - 4.32 (m, 1H), 3.85 - 3.71 (m, 1H), 3.11 - 2.98 (m, 1H), 2.74 - 2.60 (m, 2H), 1.83 - 1.69 (m, 2H), 1.59 - 1.35 (m, 2H); LC-MS: ret. time : 1.11 min, 96.02%; MS calcd. for chemical formula: C22H22FN3O4 : 411.43; found: 411.95 [M+H]⁺; Method F. HPLC: ret. time: 7.077 min, purity: 98.41%, column: X-Select CSH C18 (4.6x150)mm x 5 ^m; mobile phase A: 0.1% TFA in water; B: ACN; flow rate: 1.2 mL/min; column oven temp.: 30 °C; gradient: time (min)/ B conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. Prep-HPLC purification method: preparative column: X-select; mobile phase A: 0.1% FA; mobile phase B: ACN; flow rate 25 ml/min; gradient (time/%B) 0/5, 3/5, 10/15, 15/30, 20/40, 25/50, 35/70, 45/90, 50/98. EXAMPLE 4 - SYNTHESIS OF 4,6-DIFLUORO-N-(4-(1-(3-HYDROXY-3-METHYL- BUTANOYL)PIPERIDIN-4-YL)PHENYL)ISOINDOLINE-2-CARBOXAMIDE (I-51) [0605] Step 1: Synthesis of tert-butyl 4-(4-nitrophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (4-3): A mixture of compound 4-1 (5.0 g, 24.75 mmol), compound 4-2 (9.47 g, 29.70 mmol), and Cs2CO3 (24.2 g, 74.26 mmol) in 1,4-dioxane:H2O (50:50, 100 mL) was degassed with argon for 5 min. Pd₂(dba)₃ (1.168 g, 1.24 mmol) and X-Phos (1.17 g, 2.47 mmol) were added to the reaction mixture at rt. The reaction mixture was stirred for 15 min while degassing with argon, and then the reaction mixture was stirred to 90 ^oC for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The organic layer was mixed with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by CombiFlash (Nexgen-300) chromatography using a 40 g silica gel cartridge and using 30-40% EtOAc in n-heptane as the eluent to afford the title compound 4-3 (6.0 g, 19.72 mmol, 79.66%yield) as a pale-yellow solid. LC-MS: MS calcd. for chemical formula: C₁₆H₂₀N₂O₄: 304.35; found: 249.12 [(M–Isobutene)+H]⁺; Method F. [0606] Step 2: Synthesis of 4-(4-nitrophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (4-4): To a stirred solution of compound 4-3 (1.5 g, 4.9 mmol) in 1,4-dioxane (10 mL) was added HCl in 1,4-dioxane (5 mL, 20 mmol) at 0 ^oC. The reaction mixture was then the reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated sequentially with diethyl ether (10 mL) and then with n-pentane (5 mL x 2). The filtered the solid compound was dried under reduced pressure to afford compound 4-4 (1.0 g, 4.89 mmol, 94% yield) as an off white solid. The resulting crude HCl salt was used in the next step without further purification. LC-MS : MS calcd. For chemical formula: C11H12N2O2: 204.23; found: 205.4 [M+H]⁺; Method F. [0607] Step 3: Synthesis of 3-hydroxy-3-methyl-1-(4-(4-nitrophenyl)-3,6-dihydropyridin- 1(2H)-yl)butan-1-one (4-6): To a stirred solution of compound 4-4 (1.0 g, 4.89 mmol) in DMF (20 mL) were added compound 4-5 (0.69 g, 5.87 mmol), EDC.HCl (1.4 g, 7.34 mmol), HOBt (1.01 g, 7.34 mmol) and DIPEA (2.57 mL, 14.69 mmol) at rt, and the reaction mixture was then the reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by CombiFlash (Nexgen-300) chromatography using a 24 g silica gel cartridge and 30-40% EtOAc in n-heptane as the eluent to afford the title compound 4-6 (1.0 g, 3.28 mmol, 63.76% yield) as a yellow liquid. LC-MS: MS calcd. for chemical formula: C₁₆H₂₀N₂O₄: 304.35; found: 305.2 [M+H]⁺; Method F: column: CORTECS UPLC C18 (3x30) mm, 1.6um; flow rate: 0.85 mL/min; mobile phase A: 0.05% formic acid in water; mobile phase B: 0.05% formic acid in ACN; injection volume: 2 µL; column temp.: 45 °C; gradient program %time/B: 0.0/3, 0.1/3, 1.4/97, 2.0/97, 2.05/3, 2.5/3. [0608] Step 4: Synthesis of 1-(4-(4-aminophenyl)piperidin-1-yl)-3-hydroxy-3-methyl butan-1-one (4-7): To a stirred solution of compound 4-6 (1.0 g, 3.28 mmol) in MeOH (30 mL) was added 10% palladium on carbon (50% wet, 0.36 g) and the reaction mixture was stirred at rt for 16 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The combined organic layers were concentrated under reduced pressure to afford the title compound 4-7 (0.83 g, 3.00 mmol, 81.33% yield) as a yellow liquid. LC-MS : MS calcd. For chemical formula: C₁₆H₂₄N₂O₄: 276.38; found: 276.95 [M+H]⁺; Method F. [0609] Step 5: Synthesis of phenyl (4-(1-(3-hydroxy-3-methylbutanoyl)piperidin-4- yl)phenyl)carbamate (4-9): To a stirred solution of compound 4-7 (0.83 g, 3.00 mmol) in DCM (20 mL) were added pyridine (0.74 mL, 9.01 mmol) and compound 4-8 (0.57 g, 3.60 mmol) at 0 ^oC and then the reaction mixture was stirred at rt for 2 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (Nexgen-300) chromatography using a 12 g silica gel cartridge and 3-5% MeOH in DCM as the eluent to afford the title compound 4-9 (0.8 g, 1.917 mmol, 63.83% yield) as a white solid. LC-MS: MS calcd. for chemical formula: C₂₃H₂₈N₂O₄: 396.49; found: 397.03 [M+H]⁺; Method F. [0610] Step 6: Synthesis of 4,6-difluoro-N-(4-(1-(3-hydroxy-3-methylbutanoyl)piperidin- 4-yl)phenyl)isoindoline-2-carboxamide (I-51): To a stirred solution of compound 4-9 (0.2 g, 0.504 mmol) in DMF (5 mL) were added compound 4-10 (0.094 g, 0.605 mmol) and DIPEA (0.264 mL, 1.51 mmol) at rt and the resulting mixture was stirred at 60 ^oC for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ice cold water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by CombiFlash (Nexgen-300) chromatography using a 4 g silica gel cartridge and 1-3% MeOH in DCM as the eluent to afford compound I-51 (125 mg, 0.263 mmol, 52.24% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.36 (s, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.22 - 7.10 (m, 4H), 4.93 (s, 1H), 4.77 (s, 4H), 4.60 (d, J = 12.8 Hz, 1H), 4.10 (d, J = 12.5 Hz, 1H), 3.08 (t, J = 12.1 Hz, 1H), 2.76 - 2.66 (m, 1H), 2.64 - 2.55 (m, 1H), 2.48 (s, 2H), 1.78 (d, J = 12.1 Hz, 2H), 1.53 (dq, J = 3.7, 12.5 Hz, 1H), 1.44 - 1.34 (m, 1H), 1.18 (s, 6H). LC-MS: ret. time: 1.36 min, 95.64%; MS calcd. for chemical formula C₂₅H₂₉F₂N₃O₃: 457.52; Found: 458.07 [M+H]⁺; Method F. HPLC: ret. time: 7.610 min, purity 96.44%; column: X-Select CSH C18 (4.6x150) mm x 5 ^m; mobile phase A: 0.1% TFA in water, B: ACN;, flow rate: 1.2 mL/min; column oven temp.:30 °C; gradient: time (min)/ B% conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. EXAMPLE 5 - SYNTHESIS OF (1R,4R)-4-(4-(4,6-DIFLUOROISOINDOLINE-2- CARBOXAMIDO)PHENYL)CYCLOHEXANE-1-CARBOXYLIC ACID (I-50) [0611] Step 1: Synthesis of (1r,4r)-4-phenylcyclohexane-1-carboxylic acid (5-2): To a stirred solution of compound 5-1 (10.0 g, 41.89 mmol) in methanol (50 mL) were added triethylamine (6.7 mL) and 10% palladium on carbon (50% wet, 3.3 g, 31 mmol) at rt. The reaction mixture was stirred at 50 ^oC for 18 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The combined organic layers were concentrated under reduced pressure to afford the title crude compound 5-2 (8.0 g, 39.16 mmol, 93.47% yield) as a white solid. The crude compound was used in the next step without further purification. LC-MS: MS calcd. for chemical formula C13H16O2: 204.27; Found: 203.14 [M+H]⁺; Method E. [0612] Step 2: Synthesis of (1r,4r)-4-(4-nitrophenyl)cyclohexane-1-carboxylic acid (5-3): To a mixture of compound 5-2 (2.0 g, 9.79 mmol) and potassium nitrate (0.29 g, 2.94 mmol) was added sulphuric acid (20 mL, 45.6 mmol) dropwise at 0 ^oC. The reaction mixture was stirred for 30 min. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and the precipitated solid were filtered and dried under reduced pressure to afford the title crude compound 5-3 (1.7 g, 6.8 mmol, 70% yield) as a white solid. The crude compound was used in the next step without further purification. LC-MS: MS calcd. For chemical formula: C13H15NO4: 249.27; Found: 248.5 [M+H]⁺; Method E. [0613] Step 3: Synthesis of tert-butyl (1r,4r)-4-(4-nitrophenyl)cyclohexane-1-carboxylate (5-4): To a stirred solution of compound 5-3 (1.0 g, 4.01 mmol) in t-BuOH (10 mL) were added Boc-anhydride (1.57 g, 7.12 mmol), followed by DMAP (0.15 g, 1.20 mmol) at 0 ^oC. The reaction mixture was then the reaction mixture was stirred at 80 ^oC for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with cold water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by CombiFlash (Nexgen-300) chromatography using a 12 g silica gel cartridge and 2-4% MeOH in DCM as the eluent to afford the title compound 5-4 (0.4 g, 1.31 mmol, 32.65% yield) as an off white solid. LC-MS: MS calcd. For chemical formula: C17H23NO4: 305.37; Found: 304.16 [M+H]⁺; Method E. [0614] Step 4: Synthesis of tert-butyl (1r,4r)-4-(4-aminophenyl)cyclohexane-1- carboxylate (5-5): To a stirred solution of compound 5-4 (0.5 g, 1.64 mmol) in ethanol (20 mL) was added 10% palladium on carbon (50% wet, 0.15 g 1.41 mmol) and the reaction mixture was stirred at rt for 16 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The combined organic layers were concentrated under reduced pressure to afford the crude compound 5-5 (0.35 g, 1.271 mmol, 77.63% yield) as a pale red solid. LC-MS: MS calcd. for chemical formula: C17H25NO2: 275.39; Found: 275.94 [M+H]^+; Method F. [0615] Step 5: Synthesis of tert-butyl (1r,4r)-4-(4-((phenoxycarbonyl) amino) phenyl) cyclohexane-1-carboxylate (5-7): To a stirred solution of compound 5-5 (0.35 g, 1.271 mmol) in DCM (5 mL) were added pyridine (0.21 mL, 2.54 mmol) followed by phenyl chloroformate 5-6 (0.24 g, 1.52 mmol) at 0 ^oC. The reaction mixture was then the reaction mixture was stirred at rt for 16 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure to afford the title crude compound 5-7 (0.25 g, 0.632 mmol, 49.74% yield) as a yellow solid. The crude compound was used in the next step without further purification. LC-MS: MS calcd. for chemical formula: C₂₄H₂₉NO₄: 395.5; Found: 396.02 [M+H]⁺; Method F. [0616] Step 6: Synthesis of tert-butyl (1r,4r)-4-(4-(4,6-difluoroisoindoline-2- carboxamido)phenyl)cyclohexane-1-carboxylate (5-9): To a stirred solution of compound 5-7 (0.4 g, 1.01 mmol) and compound 5-8 (0.188 g, 1.21 mmol) in DMF (10 mL) was added DIPEA (0.9 mL, 5.06 mmol) at rt. The reaction mixture was then the reaction mixture was stirred at 80 ^oC for 1 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the title crude compound 5-9 (0.2 g, 0.438 mmol, 43.32% yield) as an off-white solid. The crude compound was used in the next step without further purification. LC-MS: MS calcd. for chemical formula: C26H30F2N2O3: 456.5; Found: 457.3 [M+H]⁺; Method F. [0617] Step 7: Synthesis of (1r,4r)-4-(4-(4,6-difluoroisoindoline-2-carboxamido)phenyl) cyclohexane-1-carboxylic acid (I-50): To the stirred solution of compound 5-9 (0.2 g, 0.438 mmol) in DCM (10 mL), was added trifluoroacetic acid (TFA) (1 mL) at 0 ^oC. The reaction mixture was then the reaction mixture was stirred at rt for 2 h. after completion of the reaction (monitored by TLC), The organic layer was mixed with water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude residue was purified by prep-HPLC to afford (1r,4r)-4-(4-(4,6- difluoroisoindoline-2-carboxamido)phenyl)cyclohexane-1-carboxylic acid (I-50, 30 mg, 0.074 mmol, 17.10% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d₆) δ 12.03 (s, 1H), 8.34 (s, 1H), 7.44 (d, J = 8.6 Hz, 2H), 7.23 - 7.08 (m, 4H), 4.77 (s, 4H), 2.45 - 2.39 (m, 1H), 2.29 - 2.13 (m, 1H), 1.98 (d, J = 7.8 Hz, 2H), 1.81 (d, J = 7.6 Hz, 2H), 1.48 - 1.40 (m, 4H). LCMS: ret. time : 1.40 min, 98.23%, MS calcd. for chemical formula: C₂₂H₂₂F₂N₂O₃: 400.4; Found: 400.98 [M+H]⁺; Method F. HPLC: Rt 5.942 min, 99.93%; column : X-Select CSH C18 (4.6*150) mm x 5 ^m; mobile phase: A - 0.1% TFA in water B – ACN; flow rate: 1.2 mL/min; column oven temp.: 30 °C; gradient: time (min)/ B conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. Prep-HPLC purification method: No. of injections 7 (5.5 mg /inj) column: iCellulose 5 (30 x 250*4.6mm, 5u); mobile phase A: n-Hexane; mobile phase B: IPA; eluent A: 50% & B: 50%; total flow rate (mL/min): 38 min; detection: 245 nm. EXAMPLE 6 - SYNTHESIS OF 4,6-DIFLUORO-N-(4-(4-(2-HYDROXY-2- METHYLPROPANAMIDO)CYCLOHEXYL)PHENYL)ISOINDOLINE-2- CARBOXAMIDE FIRST-ELUTING ISOMER (I-142) AND SECOND-ELUTING [0618] Step 1: Synthesis of tert-butyl (4'-nitro-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4- yl)carbamate (6-3): A mixture of compound of compound 6-1 (5.0 g, 24.75 mmol), compound 6- 2 (9.60 g 29.70 mmol) and Cs2CO3 (24.2 g, 74.26 mmol) in 1,4-dioxane:H2O (50:50, 100 mL) was degassed with argon for 5 min. X-Phos (1.2 g, 2.47) and Pd₂(dba)₃ (1.16 g, 1.24 mmol) were added to the reaction mixture at rt. The reaction mixture was stirred for 15 min while degassing with argon, and then the reaction mixture was heated to 90 ^oC and stirred for 16 h. After completion of the reaction (monitored by TLC), the solvent was evaporated under vacuum to obtain the crude. The crude was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by CombiFlash (Nexgen-300) chromatography using a 24 g silica gel cartridge and 50 - 60% EtOAc in heptane as the eluent to afford the title compound 6-3 (5.8 g, 18 mmol, 74% yield) as a pale-yellow solid. LC-MS: MS calcd. For chemical formula C17H22N2O4: 318.4; Found: 262.85 [(M-isobutene) + H)]⁺; Method F. [0619] Step 2: Synthesis of 4'-nitro-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-amine (6-4): To a stirred solution of compound 6-3 (5.8 g, 18 mmol) in 1,4-dioxane (10 mL) was added 4 M HCl in 1,4-dioxane (45 mL, 180 mmol) slowly at 0 ^oC and then the reaction mixture was stirred at rt for 6 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (10 mL) and then with n- pentane (5 mL x 2). The collected solid compound was dried under reduced pressure to afford the desired compound 6-4 (4.5 g, 18 mmol, 97% yield) as an off white solid. The resulting crude HCl salt was used in the next step without further purification. LC-MS: MS calcd. for chemical formula C12H14N2O2: 218.26 Found: 219.16 [M+H]⁺; Method F. [0620] Step 3: Synthesis of 2-hydroxy-2-methyl-N-(4’-nitro-2,3,4,5-tetrahydro-[1,1’- biphenyl]-4-yl)propenamide (6-6): To a stirred solution of compound 6-4 (5.0 g, 15 mmol) and compound 6-5 (1.9 g, 18 mmol) in DMF (10 mL) were added EDC.HCl (4.5 g, 23 mmol) and HOBt (3.2 g, 23 mmol), followed by DIPEA (8.0 mL, 46 mmol) at 0 ^oC and then the reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with cold water and the precipitated solid was filtered and washed with diethyl ether and n-pentane. The solid was then dried under reduced pressure to afford the title compound 6-6 (4.10 g, 13.5 mmol, 88% yield) as a pale brown solid. LC-MS : MS calcd. For chemical formula: C16H20N2O4, 304.3; Found: 304.94 [M+H]⁺; Method F. [0621] Step 4: Synthesis of N-(4-(4-aminophenyl)cyclohexyl)-2-hydroxy-2- methylpropanamide (6-7): To a stirred solution of compound 6-6 (4.0 g, 13 mmol) in ethanol (40 mL) was added 10% Pd/C (50% wet, 0.14 g) and the reaction mixture was stirred at rt for 16 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with ethanol. The combined organic layers were concentrated under reduced pressure to afford the title compound 6-7 (3.30 g, 11.9 mmol, 91%yield) as an off white solid. LC-MS: MS calcd. for chemical formula C16H24N2O2: 276.4; Found: 276.92 [M+H]⁺; Method F. [0622] Step 5: Synthesis of phenyl (4-(4-(2-hydroxy-2-methylpropanamido)cyclohexyl) phenyl)carbamate (6-9): To a stirred solution of compound 6-7 (3.10 g, 11.2 mmol) in DCM (2 mL) was added pyridine (1.82 mL, 22.4 mmol) at rt. Compound 6-8 (1.9 mL, 13.5 mmol) was then added at 0 ^oC and the resulting reaction mixture was stirred at rt for 2 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether and n-pentane, filtered, and dried under reduced pressure to afford the title compound 6-9 (3.5 g, 8.8 mmol, 79% yield) as a pale-yellow solid. LC-MS: MS calcd. For chemical formula C23H28N2O4: 396.5; Found: 397.05 [M+H]⁺; Method F. [0623] Step 6: Synthesis of 4,6-difluoro-N-(4-(4-(2-hydroxy-2-methylpropanamido) cyclohexyl)phenyl)isoindoline-2-carboxamide (I-49): To a stirred solution of compound 6-9 (0.1 g, 0.25 mmol) in DMF (5 mL) were added compound 6-10 (0.047 g, 0.30 mmol) and DIPEA (0.22 mL, 1.26 mmol) at rt and the reaction mixture was stirred at 70 ^oC for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ice cold water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by CombiFlash (Nexgen-300) chromatography using a 40 g silica gel cartridge abd 60 - 70% EtOAc in n-heptane as the eluent to afford the title compound 4,6-difluoro-N-(4-(4-(2-hydroxy-2- methylpropanamido)cyclohexyl)phenyl)isoindoline-2-carboxamide (I-49) (30 mg, 0.065 mmol, 26.00% yield) as a pale brown solid.¹H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 7.3 Hz, 1H), 7.45 (dd, J = 8.6, 10.5 Hz, 2H), 7.33 (d, J = 8.5 Hz, 1H), 7.22 - 7.07 (m, 4H), 5.55 - 5.31 (m, 1H), 4.77 (s, 4H), 3.93 - 3.55 (m, 1H), 2.45 - 2.37 (m, 1H), 1.86 - 1.73 (m, 3H), 1.68 - 1.58 (m, 3H), 1.54 - 1.35 (m, 2H), 1.25 (d, J = 10.4 Hz, 6H). LCMS: ret. time: 1.93 min & 1.95 min, 27.49% & 72.42%; MS calcd. for chemical formula C₂₅H₂₉F₂N₃O₃: 457.5; Found: 458.32 [M+H]⁺; Method G. HPLC: ret. time: 7.528 min & 7.620 min, purity 53.31% & 45.49%; column : X-Select CSH C18 (4.6*150) mm x 5 ^m mobile phase: A - 0.1% TFA in water B – ACN, flow rate: 1.2. mL/minute, column oven temp.:30 °C, gradient: time (min)/ B Conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. [0624] Step 7: Chiral Prep-HPLC purification to afford First-Eluting Isomer (I-142) and Second-Eluting Isomer (I-143): Chiral prep-HPLC purification method: No. of injections 19 (8 mg /Inj), column: Chiral pack IG (30 x 250*4.6 mm, 5u), mobile phase A: MeOH mobile phase B: ACN, eluent A: 10% & B: 90%. total flow rate (mL/min): 48 min. [0625] Data for First-Eluting Isomer (I-142, 18.80 mg, white solid): ¹H NMR (400 MHz, DMSO-d₆) δ 8.33 (s, 1H), 7.44 (d, J = 8.6 Hz, 2H), 7.32 (d, J = 8.4 Hz, 1H), 7.23 - 7.10 (m, 4H), 5.41 - 5.30 (m, 1H), 4.77 (s, 4H), 3.64 - 3.53 (m, 1H), 2.46 - 2.38 (m, 1H), 1.86 - 1.76 (m, 4H), 1.57 - 1.35 (m, 4H), 1.24 (s, 6H). LCMS: ret. time : 1.38 min, 99.58%; MS calcd. for chemical formula C₂₅H₂₉F₂N₃O₃: 457.5; Found: 458.16 [M+H]⁺; Method F. HPLC: ret. time: 7.537 min, purity: 99.75% column: X-Select CSH C18 (4.6x150) mm x 5 ^m; mobile phase A: 0.1% TFA in water B: ACN, flow rate: 1.2 mL/min; column oven temp.: 30°C, gradient: time (min)/ B conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. Chiral HPLC: ret. time: 6.132 min, purity: 99.31%, column: CHIRALPAK- IG ((250 x 4.6mm, 5 ^m), mobile phase A: MeOH: ACN (10:90) A: 100% flow: 1.0 mL/min. [0626] Data for Second-Eluting Isomer (I-143, 13.10 mg, off white solid): ¹H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.33 (br d, J = 7.4 Hz, 1H), 7.22 - 7.12 (m, 4H), 5.51 (s, 1H), 4.78 (s, 4H), 3.92 - 3.87 (m, 1H), 1.80 - 1.74 (m, 2H),2.56- 2.52 (m, 1H), 1.68 - 1.56 (m, 6H), 1.27 (s, 6H). LCMS: ret. time: 2.478 min, 99.19%; MS calcd. for chemical formula C25H29F2N3O3: 457.5; Found: 458.4 [M+H]⁺; Method G. HPLC: ret. time: 7.674 min, purity: 95.02%, column: X-Select CSH C18 (4.6*150) mm x 5 ^m; mobile phase: A - 0.1% TFA in water B – ACN; flow rate: 1.2 mL/min; column oven temp.: 30 °C; gradient: %time (min)/ B conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. Chiral HPLC: ret. time: 8.388 min, purity: 96.34%; column: CHIRALPAK- IG (250 x 4.6mm, 5ìm); mobile phase A: MeOH: ACN (10:90); A: 100 % flow: 1.0 mL/min. EXAMPLE 7 - SYNTHESIS OF N-(4-(1-((N,N-DIMETHYLSULFAMOYL) CARBAMOYL)-1,2,3,6-TETRAHYDROPYRIDIN-4-YL)PHENYL)-5-FLUORO- ISOINDOLINE-2-CARBOXAMIDE (I-48) [0627] Step 1: Synthesis of (4-(dimethylamino)pyridin-1-ium-1-carbonyl)(N,N- dimethylsulfamoyl)amide (7-9): To a stirred solution of compound 7-1a (0.5 g, 4.027 mmol) in ACN (5 mL) were added compound 7-2b (0.98 g, 8.054 mmol) and diphenyl carbonate (0.96 g, 4.429 mmol) at 0 ^oC. The mixture was then the reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the solid was filtered and washed with MTBE and dried under reduced pressure (50 ^oC) to afford compound 7-9 (0.3 g, 1.101 mmol, 27.35% 304 yield) as an off white solid. The resulting crude salt was used in the next step without further purification. LC-MS: MS calcd. for chemical formula C10H16N4O3S: 272.32; Found: 228.88 [(M – NMe2)+H]⁺; Method F. [0628] Step 2: Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (7-3): A mixture of compound of compound 7-1 (5.00 g, 29.06 mmol), compound 7- 2 (10.19 g, 31.97 mmol), and K3PO4 (20.15 g, 93.012 mmol) in 1,2-DME:H2O (10:1,110 mL) was degassed with argon for 5 minutes. Pd(dppf)Cl₂.DCM (1.21 g, 1.45 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred for 15 minutes while degassing with argon, and then the reaction mixture was heated to 90 ^oC and stirred for 16 h. After completion of the reaction (monitored by TLC), the solvent was evaporated under vacuum to obtain the crude mixture. The crude mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by combiFlash (Nexgen- 300) chromatography using a 24 g silica gel cartridge and 20 - 35% EtOAc in n-heptane as the eluent to afford the title compound 7-3 (4.0 g, 14.58 mmol, 50.15% yield) as an off white solid. LC-MS: MS calcd. for chemical formula C16H22N2O2, 274.36; Found: 275.18 [M+H]⁺; Method F. [0629] Step 3: Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (7-5): To a stirred solution of compound 7-3 (2.0 g, 7.28 mmol) in DCM (20 mL) were added pyridine (1.17 mL, 14.58 mmol) and compound 7-4 (1.37 g, 8.74 mmol), followed by DMAP (0.089 g, 0.73) at 0 ^oC and then the reaction mixture was stirred at rt for 16 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether and n-pentane, and the solids were dried under reduced pressure to afford the title compound 7-5 (2.35 g, 5.96 mmol, 81.7% yield) as an off white solid. LC-MS: MS calcd. for chemical formula C23H26N2O4: 394.47; Found: 339.2. [(M-Isobutene) + H]⁺. Method F. [0630] Step 4: Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)- 3,6-dihydropyridine-1(2H)-carboxylate (7-7): To a stirred solution of compound 7-5 (2.35 g, 5.96 mmol) in DMF (4 mL) were added compound 7-6 (0.89 g, 6.55 mmol) and DIPEA (5.20 mL, 29.8 mmol) at rt and the reaction mixture was stirred at 80 ^oC for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and the precipitated solids were filtered and washed with diethylether and n-pentane and dried under reduced pressure to afford the title compound 7-7 (2.4 g, 5.5 mmol, 92%yield) as a light brown solid. LC-MS: MS calcd. for chemical formula C₂₅H₂₈FN₃O₃: 437.5; Found: 438.08 [M+H]⁺; Method F. [0631] Step 5: Synthesis of 5-fluoro-N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl) isoindoline-2-carboxamide hydrochloride (7-8): To a stirred solution of compound 7-7 (2.4 g, 5.5 mmol) in DCM (20 mL) was added 4 M HCl in 1,4-dioxane (20 mL) dropwise at 0 ^oC and then the reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (10 mL) and then with n-pentane (5 mL x 2). The filtered solid compound was then dried under reduced pressure to afford the desired compound 7-8 (1.6 g, 4.54 mmol, 83% yield) as a brown solid. The resulting crude HCl salt was used in the next step without further purification. LC-MS: MS calcd. for chemical formula C₂₀H₂₀FN₃O: 337.4; Found: 337.95 [M+H]⁺; Method F. [0632] Step 6: Synthesis of N-(4-(1-((N,N-dimethylsulfamoyl)carbamoyl)-1,2,3,6- tetrahydropyridin-4-yl)phenyl)-5-fluoroisoindoline-2-carboxamide (I-48): To a stirred solution of compound 7-8 (0.3 g, 0.80 mmol) in CAN (10 mL), were added DIPEA (0.155 mL, 0.88 mmol), followed by compound 7-9 (0.22 g, 0.80 mmol) at 0 ^oC. The reaction mixture was then the reaction mixture was stirred at 50 ^oC for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by prep-HPLC purification to afford desired the compound N-(4-(1-((N,N-dimethylsulfamoyl)carbamoyl)-1,2,3,6-tetrahydropyridin-4- yl)phenyl)-5-fluoroisoindoline-2-carboxamide (I-48, 10 mg, 0.020 mmol, 2.56% yield) as a pale yellow solid.¹H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.53 (d, J = 8.8 Hz, 2H), 7.39 (dd, J = 5.1, 8.3 Hz, 1H), 7.33 (d, J = 8.8 Hz, 2H), 7.23 (dd, J = 2.1, 8.9 Hz, 1H), 7.17 - 7.09 (m, 1H), 6.71 - 6.55 (m, 1H), 6.08 (s, 1H), 4.74 (d, J = 11.5 Hz, 4H), 3.99 (d, J = 2.3 Hz, 2H), 3.54 (t, J = 5.2 Hz, 2H), 2.36 - 2.31 (m, 2H), 1.90 (s, 6H). LC-MS: ret. time: 1.912 min; 95.76%; MS calcd. for chemical formula C23H26FN5O4S: 487.55; Found: 488.2 [M+H]⁺; Method E. HPLC: ret. time: 7.021 min, purity: 95.02%, column: X-Select CSH C18 (4.6*150) mm x 5 ^m; mobile phase: A - 5 Mm; ammonium acetate in water B – ACN; flow rate: 1.0 mL/min; column oven temp.: 30 °C; gradient: time (min)/ B conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. Prep-HPLC purification method: preparative column: X select C18 mobile phase A: 10 mM ammonium acetate in water; mobile phase B: 100 % ACN; flow rate: 25 ml/min; gradient 0/2, 5/2, 10/6, 30/25. EXAMPLE 8 - SYNTHESIS OF 5-FLUORO-N-(4-(1-((2-(2-(2-(2-HYDROXY- ETHOXY)ETHOXY)ETHOXY)ETHYL)SULFONYL)PIPERIDIN-4-YL)PHENYL) ISOINDOLINE-2-CARBOXAMIDE (I-47) [0633] Step 1: Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (8-3): A mixture of compound of compound 8-1 (5.00 g, 29.06 mmol), compound 8- 2 (10.19 g, 31.97 mmol), and K3PO4 (20.15 g, 93.012 mmol) in 1,2-DME:H2O (10:1, 110 mL) was degassed with argon for 5 min. Pd(dppf)Cl2.DCM (1.21 g, 1.45 mmol) was added to the reaction mixture at rt. The reaction mixture was stirred for 15 min while degassing with argon, and then the reaction mixture was stirred at 90 ^oC for 16 h. After completion of the reaction (monitored by TLC), the volatiles were evaporated under vacuum to obtain the crude. The crude was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by CombiFlash (Nexgen-300) chromatography using a 24 g silica gel cartridge and 20 - 35% EtOAc in n-heptane as the eluent to afford the title compound 8-3 (4.0 g, 14.58 mmol, 50.15% yield) as an off white solid. LC-MS: MS calcd. for chemical formula: C₁₆H₂₂N₂O₂: 274.36; found: 275.3 [M+H]⁺; Method F. [0634] Step 2: Synthesis of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (8-4): To a stirred solution of compound 8-3 (5.0 g, 18.22 mmol) in methanol (20 mL) was added 10% palladium on carbon (50% wet, 2.5 g) and the reaction mixture was stirred at rt for 16 h under a hydrogen atmosphere at 50 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The organic layers were concentrated under reduced pressure to afford the title crude compound 8-4 (5.0 g, 18.09 mmol, 99.28% yield) as an off white solid. LC-MS: MS calcd. for chemical formula: C16H24N2O2: 276.38; found: 277.34 [M+H]⁺; Method F. [0635] Step 3: Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)piperidine- 1-carboxylate (8-6): To a stirred solution of compound 8-4 (5.0 g, 18.09 mmol) in DCM (20 mL) were added pyridine (2.90 mL, 36.18 mmol) and compound 8-5 (3.39 g, 21.71 mmol), followed by DMAP (0.232 g, 1.80 mmol)) at 0 ^oC and then the reaction mixture was stirred at rt for 16 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether and n-pentane, and the solids were dried under reduced pressure to afford the title compound 8-6 (7.0 g, 17.65 mmol, 97.59%yield) as an off white solid. LC-MS: MS calcd. for chemical formula: C23H28N2O4: 396.49; found: 341.2 [(M- Isobutene) + H]⁺; Method F. [0636] Step 4: Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) piperidine-1-carboxylate (8-8): To a stirred solution of compound 8-6 (3.5 g, 8.8 mmol) in DMF (30 mL), were added compound 8-7 (1.7 g, 9.7 mmol) and DIPEA (7.23 mL, 44 mmol) at rt and then the reaction mixture was stirred at 90 ℃ for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with EtOAc. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude mixture was triturated with diethyl ether and n-pentane, filtered, and dried under reduced pressure to afford the title compound 8-8 (2.7 g, 6.1 mmol, 70% yield) as a brown solid. LCMS: MS calcd. for chemical formula: C25H30FN3O3: 439.53; found: 383.96 [(M- Isobutene) + H]⁺; Method F. [0637] Step 5: Synthesis of 5-fluoro-N-(4-(piperidin-4-yl)phenyl)isoindoline-2- carboxamide hydrochloride (8-9): To a stirred solution of compound 8-8 (1.8 g, 4.1 mmol) in DCM (20 mL) was added 4 M HCl in 1,4-dioxane (10 mL, 41 mmol) drop-wise at 0 ^oC and then the reaction mixtue was stirred at rt for 1 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (10 mL) and then with pentane (5 mL x 2). The filtered the solid compound was dried under reduced pressure to afford the desired compound 8-9 (1.5 g, 4.0 mmol, 97% yield) as a pale brown solid. The resulting crude HCl salt was used in the next step without further purification. LC-MS: MS calcd. for chemical formula: C₂₀H₂₂FN₃O: 339.41; found: 340.00 [M+H]⁺; Method E. [0638] Step 6: Synthesis of 5-fluoro-N-(4-(1-(vinylsulfonyl)piperidin-4-yl)phenyl) isoindoline-2-carboxamide (8-11): To a stirred solution of compound 8-9 (0.1 g, 0.295 mmol) in DCM (5 mL), were added DBU (0.23 g, 1.47 mmol) and DMAP (0.004 g, 0.029 mmol) at 0 ^oC. After 10 min, 2-chloroethane-1-sulfonyl chloride 8-10 (0.11 g, 0.67 mmol) was added and the reaction mixture was stirred at rt for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was directly concentrated under reduced pressure to afford the desired compound 8-11 (0.10 g, 0.23 mmol, crude) as an orange solid. The crude compound was used in the next step without further purification. LC-MS: MS calcd. for chemical formula: C22H24FN3O3S: 429.51; found: 429.97 [M+H]⁺; Method F. [0639] Step 7: Synthesis of 5-fluoro-N-(4-(1-((2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy) ethyl)sulfonyl)piperidin-4-yl)phenyl)isoindoline-2-carboxamide (I-47): To a stirred solution of sodium hydride (0.019 g, 0.47 mmol) in DMF (5 mL), was added 2,2'-(ethane-1,2- diylbis(oxy))bis(ethan-1-ol) 8-12 (0.042 g, 0.28 mmol). After 10 min, compound 8-11 (0.1 g, 0.233 mmol) was added at rt. The reaction was stirred at rt for 16 h and then the reaction mixture was stirred at 60 ^oC for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by prep HPLC to afford 5-fluoro-N-(4-(1-((2-(2-(2-(2-hydroxy ethoxy)ethoxy)ethoxy)ethyl)sulfonyl)piperidin-4-yl)phenyl)isoindoline-2-carboxamide (I-47, 12 mg, 0.0207 mmol, 8.89% yield) as a white solid.¹H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.38 (dd, J = 5.3, 8.4 Hz, 1H), 7.23 (dd, J = 2.3, 9.3 Hz, 1H), 7.16 - 7.12 (m, 3H), 4.73 (d, J = 11.7 Hz, 4H), 4.56 (t, J = 5.4 Hz, 1H), 3.79 - 3.73 (m, 2H), 3.68 (d, J = 11.7 Hz, 2H), 3.56 (s, 4H), 3.54 - 3.52 (m, 4H), 3.49 - 3.46 (m, 2H), 3.43 - 3.39 (m, 2H), 3.36 - 3.33 (m, 2H), 2.95 - 2.88 (m, 2H), 2.60 - 2.55 (m, 1H), 1.85 - 1.79 (m, 2H), 1.66 - 1.58 (m, 2H). LC- MS : ret. Time : 1.996 min, 98.95%; MS calcd. For chemical formula: C28H38FN3O7S: 579.7; found: 580.4 [M+H]⁺; Method E. HPLC: ret. time: 7.254 min, 99.71%; column: X-Select CSH C18 (4.6x150) mm x 5 ^m; mobile phase: A - 0.1% Formic acid in water: ACN (95:05) B – ACN; flow rate: 1.0 mL/min; gradient: time (min)/ B conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. Prep-HPLC purification method: preparative column: x-select, mobile phase A: 0.1% FA mobile phase B: ACN; flow rate 25 ml/min; gradient (time/%B) 0/5, 3/5, 10/15, 15/30, 20/40, 25/50, 35/70, 45/90, 50/98. EXAMPLE 9 - SYNTHESIS OF 4,6-DIFLUORO-N-(4-((1R,4R)-4-((3-HYDROXY-2,2- DIMETHYLPROPYL)CARBAMOYL)CYCLOHEXYL)PHENYL)ISOINDOLINE-2- CARBOXAMIDE (I-46) [0640] Step 1: Synthesis of (1r,4r)-4-phenylcyclohexane-1-carboxylic acid (9-2): To a stirred solution of compound 9-1 (10.0 g, 41.89 mmol) in methanol (50 mL) were added Triethylamine (6.7 mL) and 10% palladium on carbon (50% wet,3.3 g) at rt. The reaction mixture was stirred at 50 ^oC for 18 h under hydrogen gas AT 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The combined organic layers were concentrated under reduced pressure to afford the title crude compound 9-2 (8.0 g, 39.16 mmol, 93.47% yield) as a white solid. The crude compound was used in the next step without further purification. LC-MS: MS calcd. for chemical formula C₁₃H₁₆O₂: 204.27; Found: 203.14 [M+H]⁺; Method E. [0641] Step 2: Synthesis of (1r,4r)-4-(4-nitrophenyl)cyclohexane-1-carboxylic acid (9-3): To a mixture of compound 9-2 (2.0 g, 9.79 mmol) and potassium nitrate (0.29 g, 2.94 mmol) was added sulphuric acid (20 mL, 45.6 mmol) dropwise at 0 ^oC. The reaction mixture was stirred for 30 min. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and the precipitated solid was filtered and dried under reduced pressure to afford the title crude compound 9-3 (1.7 g, 6.8 mmol, 70% yield) as a white solid. The crude compound was used in the next step without further purification. LC-MS : MS calcd. For chemical formula: C13H15NO4: 249.27; Found: 248.5 [M+H]⁺; Method E. [0642] Step 3: Synthesis of tert-butyl (1r,4r)-4-(4-nitrophenyl)cyclohexane-1-carboxylate (9-4): To a stirred solution of compound 9-3 (5.0 g, 20.06 mmol) in t-butyl alcohol (40 mL) was added Boc-anhydride (21.89 g, 100.3 mmol), followed by DMAP (0.742 g, 6.017 mmol) at 0 ^oC and then the reaction mixture was stirred at 80 ^oC for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with cold water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to afford the title compound 9-4 (2.3 g, 7.5 mmol, 38% yield) as an off white solid. The crude compound was used in the next step without further purification. LC-MS: MS calcd. for chemical formula: C₁₇H₂₃NO₄: 305.37; Found: 304.20 [M+H]⁺; Method E. [0643] Step 4: Synthesis of tert-butyl (1r,4r)-4-(4-aminophenyl)cyclohexane-1- carboxylate (9-5): To a stirred solution of compound 9-4 (0.5 g, 1.64 mmol) in ethanol (20 mL) was added 10% palladium on carbon (50% wet, 0.15 g) and the reaction mixture was stirred at rt for 16 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The combined organic layers were concentrated under reduced pressure to afford the crude compound 9-5 (0.35 g, 1.271 mmol, 77.63% yield) as a pale red solid. LC-MS : MS calcd. For chemical formula: C17H25NO2: 275.39; Found: 276.23 [M+H]⁺; Method E. [0644] Step 5: Synthesis of tert-butyl (1r,4r)-4-(4-((phenoxycarbonyl)amino) phenyl) cyclohexane-1-carboxylate (9-7): To a stirred solution of compound 9-5 (0.35 g, 1.271 mmol) in DCM (5 mL) was added pyridine (0.21 mL, 2.54 mmol), followed by phenyl chloroformate 9-6 (0.24 g, 1.52 mmol) at 0 ^oC, and then the reaction mixture was stirred at rt for 16 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure to afford the title crude compound 9-7 (0.25 g, 0.632 mmol, 49.74% yield) as a yellow solid. The crude compound was used in the next step without further purification. LC-MS: MS calcd. for chemical formula: C₂₄H₂₉NO₄: 395.5; Found: 396.02 [M+H]⁺; Method F. [0645] Step 6: Synthesis of tert-butyl (1r,4r)-4-(4-(4,6-difluoroisoindoline-2- carboxamido)phenyl)cyclohexane-1-carboxylate (9-9): To a stirred solution of compound 9-7 (0.5 g, 1.26 mmol) and compound 9-8 (0.235 g, 1.52 mmol) in DMF (5 mL) was added DIPEA (1.12 mL, 6.32 mmol) and the mixture was stirred at 80 ^oC for 1 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to afford the title crude compound 9- 9 (0.4 g, 0.876 mmol, 69.31% yield) as an off-white solid. The crude compound was used in the next step without further purification. LC-MS : MS calcd. For chemical formula: C26H30F2N2O3: 456.5; Found: 457.09 [M+H]⁺; Method F. [0646] Step 7: Synthesis of (1r,4r)-4-(4-(4,6-difluoroisoindoline-2-carboxamido)phenyl) cyclohexane-1-carboxylic acid (9-10): To the stirred solution of compound 9-9 (0.4 g, 0.876 mmol) in DCM (10 mL), was added trifluoroacetic acid (3 mL) at 0 ^oC. The reaction mixture stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (10 mL) and then with pentane (5 mL x 2). The filtered the solid compound was dried under reduced pressure to afford the desired compound 9-10 (0.3 g, 0.749 mmol, 85.51% yield) as a brown solid. LC-MS : MS calcd. For chemical formula: C₂₂H₂₂F₂N₂O₃: 400.4; Found: 401.02 [M+H]⁺; Method F. [0647] Step 8: Synthesis of 4,6-difluoro-N-(4-((1r,4r)-4-((3-hydroxy-2,2-dimethylpropyl) carbamoyl)cyclohexyl)phenyl)isoindoline-2-carboxamide (I-46): To a stirred solution of the compound 9-10 (0.2 g, 0.499 mmol) in DMF (5 mL) were added DIPEA (0.44 mL, 2.498 mmol) and HATU (0.288 g, 0.749 mmol) at 0 ^oC. After for 5 min, compound 9-11 (0.062 g.0.5994 mmol) was added to the above reaction mixture and the reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by CombiFlash (Nexgen-300) chromatography using a 4 g silica gel cartridge and 1- 3% MeOH in DCM as the eluent to afford of the title compound 4,6-difluoro-N-(4-((1r,4r)-4-((3-hydroxy-2,2- dimethylpropyl)carbamoyl)cyclohexyl)phenyl)isoindoline-2-carboxamide (I-46, 40 mg, 0.082 mmol, 16.49% Yield) as an off white solid.¹H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.76 (t, J = 6.3 Hz, 1H), 7.44 (d, J = 8.5 Hz, 2H), 7.22 - 7.09 (m, 4H), 4.77 (s, 4H), 4.51 (t, J = 6.1 Hz, 1H), 3.04 (d, J = 6.1 Hz, 2H), 2.92 (d, J = 6.3 Hz, 2H), 2.47 - 2.38 (m, 1H), 2.28 - 2.18 (m, 1H), 1.82 (d, J = 10.4 Hz, 4H), 1.60 - 1.35 (m, 4H), 0.76 (s, 6H). LCMS : ret. Time : 1.44 min, 96.67%, LC-MS: MS calcd. For chemical formula: C₂₇H₃₃F₂N₃O₃: 485.6; Found: 486.22 [M+H]⁺; Method F. HPLC: ret. time: 8.078 min, 95.02%; ; column : X-Select CSH C18 (4.6x150) mm x 5 ^m; mobile phase: A - 0.1% TFA in water B – ACN, flow rate: 1.2 mL/min; column oven temp.: 30 °C; gradient: %time (min)/ B conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. EXAMPLE 10 - SYNTHESIS OF 3-FLUORO-N-(4-(1-(3-HYDROXY-3-METHYL- BUTANOYL)PIPERIDIN-4-YL)PHENYL)-5,7-DIHYDRO-6H-PYRROLO[3,4- B]PYRIDINE-6-CARBOXAMIDE (I-45)

[0648] Step 1: Synthesis of tert-butyl 4-(4-nitrophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (10-3): A mixture of compound 10-1 (5.0 g, 24.75 mmol), compound 10-2 (9.47 g, 29.70 mmol), and Cs2CO3 (24.2 g, 74.26 mmol) in 1,4-dioxane:H2O (50:50, 100 mL) was degassed with argon for 5 min. Pd2(dba)3 (1.168 g, 1.24 mmol) and X-Phos (1.17 g, 2.47 mmol), was added to the reaction mixture at rt. The reaction mixture was stirred for 15 min while degassing with argon, and then the reaction mixture was heated to 90 ^oC and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The organic layer was mixed with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by CombiFlash (Nexgen-300) chromatography using a 40 g silica gel cartridge and using 30-40% EtOAc in n-heptane as the eluent to afford the title compound 10-3 (6.0 g, 19.72 mmol, 79.66%yield) as a pale-yellow solid. LC-MS: MS calcd. for chemical formula: C16H20N2O4: 304.35; found: 249.12 [(M–Isobutene)+H]⁺; Method F. [0649] Step 2: Synthesis of 4-(4-nitrophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (10-4): To a stirred solution of compound 10-3 (1.5 g, 4.9 mmol) in 1,4-dioxane (10 mL) was added HCl in 1,4-dioxane (5 mL, 20 mmol) at 0 ^oC and then the mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (10 mL) and then with n-pentane (5 mL x 2). The filtered the solid compound was dried under reduced pressure to afford compound 10-4 (1.0 g, 4.89 mmol, 94% yield) as an off white solid. The resulting crude HCl salt was used in the next step without further purification. LC-MS: MS calcd. for chemical formula: C11H12N2O2: 204.23; found: 205.4 [M+H]⁺; Method F. [0650] Step 3: Synthesis of 3-hydroxy-3-methyl-1-(4-(4-nitrophenyl)-3,6-dihydropyridin- 1(2H)-yl)butan-1-one (10-6): To a stirred solution of compound 10-4 (1.0 g, 4.89 mmol) in DMF (20 mL) were added compound 10-5 (0.69 g, 5.87 mmol), EDC.HCl (1.4 g, 7.34 mmol), HOBt (1.01 g, 7.34 mmol) and DIPEA (2.57 mL, 14.69 mmol) at rt and the reaction mixture was stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by CombiFlash (Nexgen-300) chromatography using a 24 g silica gel cartridge and 30- 40% EtOAc in n-heptane as the eluent to afford the title compound 10-6 (1.0 g, 3.28 mmol, 63.76% yield) as a yellow liquid. LC-MS : MS calcd. For chemical formula: C₁₆H₂₀N₂O₄: 304.35; found: 305.2 [M+H]⁺; Method F. [0651] Step 4: Synthesis of 1-(4-(4-aminophenyl)piperidin-1-yl)-3-hydroxy-3- methylbutan-1-one (10-7): To a stirred solution of compound 10-6 (1.0 g, 3.28 mmol) in MeOH (30 mL) was added 10% palladium on carbon (50% wet, 0.36 g) and the reaction mixture was stirred at rt for 16 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The combined organic layers were concentrated under reduced pressure to afford the title compound 10-7 (0.83 g, 3.00 mmol, 81.33% yield) as a yellow liquid. LC-MS: MS calcd. for chemical formula: C16H24N2O4: 276.38; found: 276.95 [M+H]⁺; Method F. [0652] Step 5: Synthesis of phenyl (4-(1-(3-hydroxy-3-methylbutanoyl)piperidin-4- yl)phenyl)carbamate (10-9): To a stirred solution of compound 10-7 (0.83 g, 3.00 mmol) in DCM (20 mL) were added pyridine (0.74 mL, 9.01 mmol) and compound 10-8 (0.57 g, 3.60 mmol) at 0 ^oC and then the reaction mixture was stirred at rt for 2 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (Nexgen-300) using a 12 g silica gel cartridge and 3-5% MeOH in DCM as the eluent to afford the title compound 10-9 (0.8 g, 1.917 mmol, 63.83% yield) as a white solid. LC-MS: MS calcd. for chemical formula: C23H28N2O4: 396.49; found: 397.03 [M+H]⁺; Method F. [0653] Step 6: Synthesis of 3-fluoro-N-(4-(1-(3-hydroxy-3-methylbutanoyl)piperidin-4- yl)phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide (I-45): To a stirred solution of compound 10-9 (0.2 g, 0.50 mmol) in DMF (1 mL) were added 3-fluoro-6,7-dihydro-5H- pyrrolo[3,4-b]pyridine (compound 10-10, 0.084 g, 0.60 mmol) and DIPEA (0.26 mL, 1.51 mmol) dropwise at rt. The reaction mixture was then the reaction mixture was stirred at 60 ˚C for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by CombiFlash (Nexgen-300) chromatography using a 4 g silica gel cartridge and 3% MeOH in DCM as the eluent to afford the title compound 3-fluoro-N-(4-(1-(3-hydroxy-3-methylbutanoyl) piperidin-4-yl)phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide (I-45, 148 mg, 0.325 mmol, 66% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 1.3 Hz, 1H), 8.35 (s, 1H), 7.79 (dd, J = 2.6, 9.0 Hz, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.13 (d, J = 8.6 Hz, 2H), 4.92 (s, 1H), 4.77 (s, 2H), 4.72 (s, 2H), 4.60 (d, J = 13.0 Hz, 1H), 4.10 (d, J = 13.1 Hz, 1H), 3.08 (t, J = 12.0 Hz, 1H), 2.76 – 2.67 (m, 1H), 2.64 – 2.56 (m, 1H), 2.48 – 2.42 (m, 2H), 1.78 (d, J = 12.1 Hz, 2H), 1.60 – 1.49 (m, 1H), 1.46 – 1.33 (m, 1H), 1.19 (s, 6H). LCMS: ret. time : 1.18 min, 98.27%; MS calcd. For Chemical Formula; C₂₄H₂₉FN₄O₃ : 440.52; found : 441.10 [M+H]⁺; Method F. HPLC: ret. time : 6.962 min, purity : 96.95%; column: X-Select CSH C18 (4.6x150) mm x 5 ^m; mobile phase: A – 0.1% TFA in water B – ACN; flow rate: 1.2 ml/min; column oven temp.: 30 °C; gradient: time (min)/ B conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. EXAMPLE 11 – SYNTHESIS OF TERT-BUTYL ((4-(4-(5-FLUOROISOINDOLINE-2- CARBOXAMIDO)PHENYL)PIPERIDIN-1-YL)SULFONYL)CARBAMATE (I-44)

[0654] Step 1: Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (11-3): A mixture of compound of compound 11-1 (5.00 g, 29.06 mmol), compound 11-2 (10.19 g, 31.97 mmol) and K3PO4 (20.15 g, 93.012 mmol) in 1,2-DME:H2O (10:1, 110 mL) was degassed with argon for 5 min. Pd(dppf)Cl₂.DCM (1.21 g, 1.45 mmol) was added to the reaction mixture at rt. The reaction mixture was stirred for 15 min while degassing with argon, and then the reaction mixture was heated to 90 ^oC and stirred for 16 h. After completion of the reaction (monitored by TLC), the volatiles were evaporated under vacuum to obtain the crude. The crude was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by CombiFlash (Nexgen-300) chromatography using a 24 g silica gel cartridge by using 20 - 35% EtOAc in n-heptane as the eluent to afford the title compound 11-3 (4.0 g, 14.58 mmol, 50.15% yield) as an off white solid. LC-MS: MS calcd. for chemical formula: C16H22N2O2: 274.36; found: 275.3 [M+H]⁺; Method F. [0655] Step 2: Synthesis of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (11-4): To a stirred solution of compound 11-3 (5.0 g, 18.22 mmol) in methanol (20 mL) was added 10% palladium on carbon (50% wet, 2.5 g) and the reaction mixture was stirred at rt for 16 h under a hydrogen atmosphere at 50 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The organic layer was concentrated under reduced pressure to afford the title crude compound 11-4 (5.0 g, 18.09 mmol, 99.28% yield) as an off white solid. LC-MS: MS calcd. for chemical formula: C₁₆H₂₄N₂O₂: 276.38; found: 277.34 [M+H]⁺; Method E. [0656] Step 3: Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)piperidine- 1-carboxylate (11-6): To a stirred solution of compound 11-4 (5.0 g, 18.09 mmol) in DCM (2 mL) were added pyridine (2.90 mL, 36.18 mmol) at rt. Then, compound 11-5 (3.39 g, 21.71 mmol) and DMAP (0.232 g, 1.80 mmol)) were added at 0 ^oC, followed by stirring at rt for 16 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether and n-pentane. The filtered solids were dried under reduced pressure to afford the title compound 11-6 (7.0 g, 17.65 mmol, 97.59%yield) as an off white solid. LC-MS : MS calcd. For chemical formula: C₂₃H₂₈N₂O₄: 396.49; found: 341.2 [(M-Isobutene) + H]⁺; Method E. [0657] Step 4: Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) piperidine-1-carboxylate (11-8): To a stirred solution of compound 11-6 (1.12 g, 2.82 mmol) in DMF (30 mL) were added compound 11-7 (0.46 g, 3.39 mmol) and DIPEA (4.93 mL, 28.2 mmol) at rt. The reaction mixture was then heated at 80 ^oC for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was triturated with diethyl ether and n-pentane, filtered, and dried under reduced pressure to afford the title compound 11-8 (0.85 g, 1.93 mmol, 68.5% yield) as a brown solid. LCMS: MS calcd. for chemical formula: C₂₅H₃₀FN₃O₃: 439.53; found: 383.96 [(M- Isobutene) + H]⁺; Method G. [0658] Step 5: Synthesis of 5-fluoro-N-(4-(piperidin-4-yl)phenyl)isoindoline-2- carboxamide hydrochloride (11-9): To a stirred solution of compound 11-8 (1.8 g, 4.1 mmol) in DCM (20 mL) was added 4 M HCl in 1,4-dioxane (10 mL, 41 mmol) dropwise at 0 ^oC and then the reaction mixture was stirred at rt for 1 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (10 mL) and then with n-pentane (5 mL x 2), filtered, and the solid compound was dried under reduced pressure to afford compound 11-9 (1.5 g, 4.0 mmol, 97% yield) as a pale brown solid. The resulting crude HCl salt was used in the next step without further purification. LC-MS: MS calcd. for chemical formula: C₂₀H₂₂FN₃O: 339.41; found: 340.00 [M+H]⁺; Method F. [0659] Step 6: Synthesis of tert-butyl ((4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) piperidin-1-yl)sulfonyl)carbamate (I-44): To a stirred solution of compound 11-9 (0.4 g, 1.17 mmol) in DCM (10 mL) were added compound 18-9 (0.36 g, 1.17 mmol) and DIPEA (0.31 mL, 1.76 mmol) at rt and then the reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography using a 4 g silica gel cartridge and eluting with 1-2% MeOH in DCM to afford the title compound tert-butyl ((4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) piperidin-1- yl)sulfonyl)carbamate (I-44, 40 mg, 0.077 mmol, 22.52% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d₆) δ 10.93 (s, 1H), 8.29 (s, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.38 (dd, J = 5.3, 8.2 Hz, 1H), 7.22 (d, J = 9.1 Hz, 1H), 7.16 - 7.10 (m, 3H), 4.73 (d, J = 11.9 Hz, 4H), 3.75 (d, J = 12.0 Hz, 2H), 2.96 - 2.87 (m, 2H), 2.64 - 2.55 (m, 1H), 1.82 (d, J = 11.6 Hz, 2H), 1.60 (dq, J = 3.7, 12.3 Hz, 2H), 1.45 (s, 9H). LCMS: ret. time: 2.015 min, 95.91%; MS calcd. for chemical formula: C25H31FN4O5S, 518.60; found: 517.2 [M+H]⁺; Method E. HPLC: Ret time: 7.649 min, 95.16%; Method: X-Bridge C18 (4.6*150) mm x 5 ^m; mobile phase: A - 5mM ammonium bicarbonate in water; B – ACN; flow rate: 1.0. mL/min; gradient: time (min)/ B conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. EXAMPLE 12 - SYNTHESIS OF 4,6-DIFLUORO-N-(4-(1-(3-HYDROXY-2,2- DIMETHYLPROPANOYL)PIPERIDIN-4-YL)PHENYL)ISOINDOLINE-2- CARBOXAMIDE (I-34)

[0660] Step 1: Synthesis of tert-butyl 4-(4-nitrophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (12-3): A mixture of compound 12-1 (5.0 g, 24.75 mmol), compound 12-2 (9.47 g 29.03 mmol), and Cs₂CO₃ (24.2 g, 74.26 mmol) in 1,4-dioxane:H₂O (50:50, 100 mL) was degassed with argon for 5 min. X-Phos (1.2 g, 2.47) and Pd2(dba)3 (1.16 g, 1.24 mmol) were added to the reaction mixture at rt. The reaction mixture was stirred for 15 min while degassing with argon, and then the reaction mixture was stirred to 90 ^oC and stirred for 16 h. After completion of the reaction (monitored by TLC), the volatiles were evaporated under vacuum to obtain the crude. The crude was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by CombiFlash (Nexgen-300) chromatography using a 24 g silica gel cartridge and 20-30% EtOAc in n-heptane as the eluent to afford the title compound 12-3 (6.0 g, 19.72 mmol, 79.66%) as an off white solid. LC-MS: MS calcd. for chemical formula: C₁₆H₂₀N₂O₄: 304.35; found: 249.12 [(M – Isobutene) + H]⁺; Method F. [0661] Step 2: Synthesis of 4-(4-nitrophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (12-4): To a stirred solution of compound 12-3 (0.6 g, 1.97 mmol) in 1,4-dioxane (10 mL) was added 4 M HCl in 1,4-dioxane (3 mL, 12 mmol) dropwise at 0 ^oC and then the reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (5 mL) and then with pentane (4 mL x 2), filtered, and the solid compound was dried under reduced pressure to afford the desired compound 12-4 (0.4 g, 1.919 mmol, 97.35% yield) as an off white solid. The resulting crude HCl salt was used in the next step without further purification. LC-MS: MS calcd. for chemical formula: C11H12N2O2: 204.23; found: 205.4 [M+H]⁺; Method E. [0662] Step 3: Synthesis of 3-hydroxy-2,2-dimethyl-1-(4-(4-nitrophenyl)-3,6-dihydro pyridin-1(2H)-yl)propan-1-one (12-6): To a stirred solution of compound 12-4 (0.4 g, 1.95 mmol) and compound 12-5 (0.31 g, 2.35 mmol) in DMF (5 mL) were added EDC.HCl (0.44, 2.35 mmol) and HOBt (0.40 g, 2.35 mmol), followed by DIPEA (1.03 mL, 5.87 mmol) at 0 ^oC. The reaction mixture was then the reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with cold water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by CombiFlash (Nexgen-300) chromatography using a 12 g silica gel cartridge and 70% EtOAc in heptane as the eluent to afford the title compound 12-6 (0.5 g, 1.57 mmol, 80.17% yield) as a yellow liquid. LC- MS: MS calcd. for chemical formula: C16H20N2O4: 304.35; found: 304.95 [M+H]⁺; Method F. [0663] Step 4: Synthesis of 1-(4-(4-aminophenyl)piperidin-1-yl)-3-hydroxy-2,2-dimethyl propan-1-one (12-7): To a stirred solution of compound 12-6 (0.5 g, 1.57 mmol) in MeOH (8 mL) was added 10% Pd/C (50% wet, 0.3 g) and the reaction mixture was stirred at rt for 16 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with MeOH. The combined organic layers were concentrated under reduced pressure to afford the titled crude compound 12-7 (0.35 g, 1.07 mmol, 68.31% yield) as a yellow liquid. LC-MS: MS calcd. for chemical formula: C₁₆H₂₄N₂O₄: 276.38; found: 276.97 [M+H]⁺; Method F. [0664] Step 5: Synthesis of phenyl (4-(1-(3-hydroxy-2,2-dimethylpropanoyl)piperidin-4- yl)phenyl)carbamate (12-9): To a stirred solution of compound 12-7 (0.3 g, 1.03 mmol) in DCM (10 mL) were added pyridine (0.25 mL, 3.09 mmol), followed by compound 12-8 (0.196 g, 1.24 mmol) at 0 ^oC and then the reaction mixture was stirred at rt for 2 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by CombiFlash (Nexgen-300) chromatography using a 12 g silica gel cartridge and 50-65% EtOAc in n-heptane as the eluent to afford the title compound 12-9 (0.35 g, 0.85 mmol, 82.53% yield) as an off white solid. LC-MS: MS calcd. for chemical formula: C₂₃H₂₈N₂O₄: 396.49; found: 397.07 [M+H]⁺; Method F. [0665] Step 6: Synthesis of 4,6-difluoro-N-(4-(1-(3-hydroxy-2,2-dimethylpropanoyl) piperidin-4-yl)phenyl)isoindoline-2-carboxamide (I-34): To a stirred solution of compound 12- 9 (0.2 g, 0.504 mmol) in DMF (5 mL) were added compound 12-10 (0.094 g, 0.605 mmol) and DIPEA (0.264 mL, 1.51 mmol) at rt. The reaction was then the reaction mixture was stirred at 60 ^oC for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ice cold water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by CombiFlash (Nexgen-300) chromatography using a 4 g silica gel cartridge and 60-80% EtOAc in heptane as the eluent to afford 4,6-difluoro-N-(4-(1-(3-hydroxy-2,2-dimethylpropanoyl) piperidin-4-yl)phenyl)isoindoline-2-carboxamide (I-34, 110 mg, 0.223 mmol, 44.20% yield) as an off white solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.22 – 7.09 (m, 4H), 4.77 (s, 4H), 4.50 (t, J = 5.9 Hz, 1H), 4.45 – 4.37 (m, 2H), 3.43 (d, J = 6.0 Hz, 2H), 2.91 – 2.79 (m, 2H), 2.76 – 2.68 (m, 1H), 1.78 (d, J = 11.1 Hz, 2H), 1.54 – 1.39 (m, 2H), 1.18 (s, 6H). LC-MS: ret. time: 2.115 min, 99.35%; MS calcd. For Chemical Formula: C25H29F2N3O3: 457.52; found: 458.4 [M+H]⁺; Method G. HPLC: ret. time: 7.691min, purity 97.40%; column: X-Select CSH C18 (4.6x150) mm x 5 ^m; mobile phase: A – 0.1% TFA in water B – ACN; flow rate: 1.2 mL/min; column oven temp.: 30 °C; gradient: time (min)/ B conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. EXAMPLE 13 – SYNTHESIS OF 5-FLUORO-N-(4-(1-(2-((2-HYDROXY-2-METHYL- PROPYL)AMINO)-2-OXOACETYL)PIPERIDIN-4-YL)PHENYL) ISOINDOLINE-2- CARBOXAMIDE (I-33)

[0666] Step 1: Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (13-3): A mixture of compound of compound 13-1 (5.00 g, 29.06 mmol), compound 13-2 (10.19 g, 31.97 mmol) and K3PO4 (20.15 g, 93.012 mmol) in 1,2-DME:H2O (10:1, 110 mL) was degassed with argon for 5 minutes. Pd(dppf)Cl₂.DCM (1.21 g, 1.45 mmol) was added to the reaction mixture at rt. The reaction mixture was stirred for 15 minutes while degassing with argon, and then the reaction mixture was heated to 90 ^oC and stirred for 16 h. After completion of the reaction (monitored by TLC), the volatiles were evaporated under vacuum to obtain the crude. The crude was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by CombiFlash (Nexgen-300) chromatography using a 24 g silica gel cartridge and 20 - 35% EtOAc in heptane as the eluent to afford the title compound 13-3 (4.0 g, 14.58 mmol, 50.15% yield) as an off white solid. LC-MS: MS calcd. for chemical formula: C16H22N2O2: 274.36; found: 275.3 [M+H]⁺; Method F. [0667] Step 2: Synthesis of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (13-4): To a stirred solution of compound 13-3 (5.0 g, 18.22 mmol) in methanol (20 mL) was added 10% palladium on carbon (50% wet, 2.5 g) and the reaction mixture was stirred at rt for 16 h under a hydrogen atmosphere at 50 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The organic layer was concentrated under reduced pressure to afford the title crude compound 13-4 (5.0 g, 18.09 mmol, 99.28% yield) as an off white solid. LC-MS: MS calcd. for chemical formula: C16H24N2O2: 276.38; found: 277.34 [M+H]⁺; Method F. [0668] Step 3: Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)piperidine- 1-carboxylate (13-6): To a stirred solution of compound 13-4 (5.0 g, 18.09 mmol) in DCM (2 mL) were added pyridine (2.90 mL, 36.18 mmol) at rt, and compound 13-5 (3.39 g, 21.71 mmol) and DMAP (0.232 g, 1.80 mmol)) were added at 0 ^oC, and then the reaction mixture was stirred at rt for 16 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether and n-pentane. The solids were filtered and dried under reduced pressure to afford the title compound 13-6 (7.0 g, 17.65 mmol, 97.59%yield) as an off white solid. LC-MS: MS calcd. for chemical formula: C23H28N2O4: 396.49; found: 341.2 [(M-Isobutene)+H]⁺; Method E. [0669] Step 4: Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) piperidine-1-carboxylate (13-8): To a stirred solution of compound 13-6 (2.0 g, 5.04 mmol) in DMF (20 mL) were added compound 13-7 (0.96 g, 5.54 mmol) and DIPEA (4.35 mL, 25.22 mmol) at rt and then the reaction mixture was heated to 90 ^oC for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was triturated with diethyl ether, filtered and dried under reduced pressure to afford the title compound 13-8 (1.7 g, 3.90 mmol, 77% yield) as a brown solid. LCMS: MS calcd. for chemical formula: C25H30FN3O3: 439.53; found: 440.05 [M+H]⁺; Method F. [0670] Step 5: Synthesis of 5-fluoro-N-(4-(piperidin-4-yl)phenyl)isoindoline-2- carboxamide hydrochloride (13-9): To a stirred solution of compound 13-8 (1.7 g, 3.9 mmol) in 1,4-dioxane (10 mL) was added 4 M HCl in 1,4-dioxane (14.62 mL, 58.5 mmol) slowly at 0 ^oC and then the reaction mixture was stirred at rt for 1 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (8 mL) and then with n-pentane (4 mL x 2), the solids filtered and dried under reduced pressure to afford the desired compound 13-9 (0.8 g, 2.35 mmol, 61% yield) as a brown solid. The resulting crude HCl salt was used in the next step without further purification. LC-MS: MS calcd. for chemical formula: C20H22FN3O: 339.41; found: 340.6 [M+H]⁺; Method F. [0671] Step 6: Synthesis of ethyl 2-(4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) piperidin-1-yl)-2-oxoacetate (13-11): To a stirred solution of compound 13-9 (1.0 g, 2.66 mmol) in DCM (20 mL) was added DIPEA (1.40 mL, 8.00 mmol) at 0 ℃, followed by ethyl 2-chloro-2- oxo-acetate 13-10 (0.364 g, 2.66 mmol) dropwise and the reaction mixture was then the reaction mixture was stirred to rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by CombiFlash (Nexgen-300) chromatography using a 40 g silica gel cartridge and 60-80% EtOAc in heptane as the eluent to afford the title compound 13-11 (0.33 g, 0.75 mmol, 28.15% yield) as a pale brown gummy liquid. LC-MS: MS calcd. for chemical formula: C24H26FN3O4: 439.49; found: 440.09 [M+H]⁺; Method F. [0672] Step 7: Synthesis of 2-(4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)piperidin- 1-yl)-2-oxoacetic acid (13-12): To a stirred solution of compound 13-11 (0.32 g, 0.728 mmol) in 1,4-dioxane (4.6 ml) was added a 1 M NaOH solution (4.6 mL) and the resulting reaction mixture was stirred at rt for 5 h. After completion of the reaction (monitored by TLC), the volatiles were evaporated under reduced pressure. The crude residue was acidified with 1.0 N HCl to pH 4-5, and the precipitated solid was filtered, washed with water, and dried under reduced pressure to afford the title compound 13-12 (0.19 g, 0.4618 mmol, 63.43% yield) as an off white solid. LC-MS: MS calcd. for chemical formula: C₂₂H₂₂FN₃O₄: 411.43; found: 412.03 [M+H]⁺; Method F. [0673] Step 8: Synthesis of 5-fluoro-N-(4-(1-(2-((2-hydroxy-2-methylpropyl)amino)-2- oxoacetyl)piperidin-4-yl)phenyl)isoindoline-2-carboxamide (I-33): To the stirred solution of compound 13-12 (0.1 g, 0.2431 mmol) in DCM (2 mL) at rt was added DIPEA (0.13 mL, 0.729 mmol) and 50% T3P in EtOAc (2 equiv., 0.486 mmol). Then, 1-amino-2-methyl-propan-2-ol 13- 13 (0.1 g, 1.12 mmol) was added and the reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with DCM. The combined organic layers were with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by Prep- HPLC to afford the title compound 5-fluoro-N-(4-(1-(2-((2-hydroxy-2-methylpropyl)amino)-2- oxoacetyl)piperidin-4-yl)phenyl)isoindoline-2-carboxamide (I-33, 20 mg, 0.041 mmol, 17.05% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d₆) δ 8.52 - 8.46 (m, 1H), 8.29 (s, 1H), 7.47 (d, J = 8.5 Hz, 2H), 7.38 (dd, J = 5.2, 8.3 Hz, 1H), 7.23 (dd, J = 2.1, 9.1 Hz, 1H), 7.16 - 7.10 (m, 3H), 4.73 (d, J = 11.6 Hz, 4H), 4.47 (s, 1H), 4.41 (d, J = 12.8 Hz, 1H), 3.86 (d, J = 13.0 Hz, 1H), 3.19 - 3.05 (m, 4H), 2.80 - 2.68 (m, 2H), 1.85 - 1.73 (m, 2H), 1.69 - 1.45 (m, 2H), 1.08 (s, 6H). HPLC: ret. time: 6.779 min, purity: 99.77%, column: X-Select CSH C18 (4.6*150) mm x 5 ^m mobile phase: A - 0.1% TFA in water B – ACN, flow rate: 1.2. mL/minute, column oven temp.: 30 °C, gradient: time (min)/ B conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. LCMS: 99.73%; ret. time: 1.27 min, MS calcd. for chemical formula C₂₆H₃₁FN₄O₄: 482.56; Found: 483.15 [M+H]⁺; Method F. Prep-HPLC purification method: preparative column: x-select C18 (250x30mm, 5µ), mobile phase A: 0.1% FA in water mobile phase B: ACN, flow rate: 25, gradient (time/%B) 0/5, 3/5, 20/50, 33/70, 45/88, 60/98. EXAMPLE 14 - SYNTHESIS OF 4,6-DIFLUORO-N-(4-((1R,4R)-4-(METHYL- CARBAMOYL)CYCLOHEXYL)PHENYL)ISOINDOLINE-2-CARBOXAMIDE (I-32) [0674] Step 1: Synthesis of (1r,4r)-4-phenylcyclohexane-1-carboxylic acid (14-2): To a stirred solution of compound 14-1 (10.0 g, 41.89 mmol) in methanol (50 mL) were added triethylamine (6.7 mL) and 10% palladium on carbon (50% wet, 3.3 g) at rt. The reaction mixture was stirred at 50 ^oC for 18 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The combined organic layers were concentrated under reduced pressure to afford the title crude compound 14-2 (8.0 g, 39.16 mmol, 93.47% yield) as a white solid. The crude compound was used in the next step without further purification. LC-MS: MS calcd. for chemical formula C₁₃H₁₆O₂: 204.27; Found: 203.14 [M+H]⁺; Method E. [0675] Step 2: Synthesis of (1r,4r)-4-(4-nitrophenyl)cyclohexane-1-carboxylic acid (14-3): To a mixture of compound 14-2 (4.0 g, 19.58 mmol) and potassium nitrite (0.59 g, 5.874 mmol) was added sulphuric acid (40 mL, 91.2 mmol) dropwise at 0 ^oC. The reaction mixture was stirred at 0 ^oC for 30 min. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and the precipitated solid was filtered off and dried under reduced pressure to afford the title crude compound 14-3 (2.1 g, 8.4 mmol, 43% yield) as a white solid. The crude compound was used in the next step without further purification. LC-MS: MS calcd. for chemical formula: C13H15NO4: 249.27; Found: 248.12 [M+H]⁺; Method E. [0676] Step 3: Synthesis of tert-butyl (1r,4r)-4-(4-nitrophenyl)cyclohexane-1-carboxylate (14-4): To a stirred solution of compound 14-3 (5 g, 20.06 mmol) in t-butyl alcohol (40 mL) was added Boc-anhydride (21.89 g, 100.3 mmol), followed by DMAP (0.742 g, 6.017 mmol) at 0 ^oC and then the reaction mixture was stirred at 80 ^oC for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with cold water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to afford the title compound 14-4 (2.3 g, 7.5 mmol, 38% yield) as an off white solid. The crude compound was used in the next step without further purification. LC-MS: MS calcd. for chemical formula: C₁₇H₂₃NO₄: 305.37; Found: 304.20 [M+H]⁺; Method F. [0677] Step 4: Synthesis of tert-butyl (1r,4r)-4-(4-aminophenyl)cyclohexane-1- carboxylate (14-5): To a stirred solution of compound 14-4 (2.3 g, 7.5 mmol) in ethanol (25 mL) was added 10% palladium on carbon (50% wet, 0.5 g) and the reaction mixture was stirred at rt for 16 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The combined organic layers were concentrated under reduced pressure to afford the crude compound 14-5 (1.6 g, 5.80 mmol, 76% yield) as a pale red solid. The crude compound was used in the next step without further purification. LC-MS: MS calcd. for chemical formula: C17H25NO2: 275.39; Found: 276.15 [M+H]⁺ Method F. [0678] Step 5: Synthesis of tert-butyl (1r,4r)-4-(4-((phenoxycarbonyl) amino)phenyl) cyclohexane-1-carboxylate (14-7): To a stirred solution of compound 14-5 (1.5 g, 5.4 mmol) in DCM (15 mL) at 0 ^oC were added pyridine (0.88 mL, 11 mmol), followed by phenyl chloroformate 14-6 (1.0 g, 6.5 mmol). The reaction mixture was then the reaction mixture was stirred at rt for 16 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure to afford the title crude compound 14-7 (1.1 g, 2.8 mmol, 51% yield) as a yellow solid. The crude compound was used in the next step without further purification. LC-MS: MS calcd. for chemical formula: C24H29NO4: 395.5; Found: 396.49 [M+H]⁺; Method F. [0679] Step 6: Synthesis of tert-butyl (1r,4r)-4-(4-(4,6-difluoroisoindoline-2-carbox amido)phenyl)cyclohexane-1-carboxylate (14-9): To a stirred solution of compound 14-7 (0.5 g, 1.26 mmol) and compound 14-8 (0.235 g, 1.52 mmol) in DMF (5 mL) was added DIPEA (1.12 mL, 6.32 mmol) at rt and then the reaction mixture was stirred at 80 ^oC for 1 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to afford the title crude compound 14-9 (0.4 g, 0.876 mmol, 69.31% yield) as an off-white solid. The crude compound was used in the next step without further purification. LC-MS: MS calcd. for chemical formula: C26H30F2N2O3: 456.5; Found: 457.09 [M+H]⁺; Method F. [0680] Step 7: Synthesis of (1r,4r)-4-(4-(4,6-difluoroisoindoline-2-carboxamido)phenyl) cyclohexane-1-carboxylic acid (14-10): To the stirred solution of compound 14-9 (0.4 g, 0.876 mmol) in DCM (10 mL), was added trifluoroacetic acid (3 mL) at 0 ^oC. The reaction mixture was then the reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (10 mL) and then with n-pentane (5 mL x 2), filtered, and the solid compound was dried under reduced pressure to afford the desired compound 14-10 (0.3 g, 0.749 mmol, 85.51% Yield) as a brown solid. LC-MS: MS calcd. for chemical formula: C₂₂H₂₂F₂N₂O₃: 400.4; Found: 401.02 [M+H]⁺; Method F. [0681] Step 8: Synthesis of 4,6-difluoro-N-(4-((1r,4r)-4-(methylcarbamoyl)cyclohexyl) phenyl)isoindoline-2-carboxamide (I-32): To the stirred solution of the compound 14-10 (0.2 g, 0.499 mmol) in the DMF (5 mL) was added DIPEA (0.44 mL, 2.49 mmol) and HATU (0.28 g, 0.749 mmol) at 0 ^oC. After 5 min, methylamine 14-11 (0.019 g, 0.599 mmol) was added. The reaction mixture stirred at rt for 16 h. After completion of the reaction (monitored by TLC), The organic layer was mixed with water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by CombiFlash (Nexgen-300) chromatography using a 4 g silica gel cartridge and 2-4% MeOH in DCM as the eluent to afford the title compound 4,6-difluoro-N- (4-((1r,4r)-4-(methylcarbamoyl)cyclohexyl)phenyl)isoindoline-2-carboxamide (I-32, 30 mg, 0.072 mmol, 47.10% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 7.69 - 7.62 (m, 1H), 7.44 (d, J = 8.5 Hz, 2H), 7.22 - 7.14 (m, 2H), 7.11 (d, J = 8.5 Hz, 2H), 4.77 (s, 4H), 2.56 (d, J = 4.5 Hz, 3H), 2.42 (t, J = 11.6 Hz, 1H), 2.18 - 2.04. LCMS: ret. time: 1.36 min, 98.46%, MS calcd. for chemical formula: C23H25F2N3O2: 413.4; Found: 414.09 [M+H]⁺; Method F. HPLC: ret. time: 7.454 min, 98.01%; column : X-Select CSH C18 (4.6x150) mm x 5 ^m; mobile phase: A - 0.1% TFA in water B –ACN; flow rate: 1.2 mL/min; column oven temp.: 30 °C; gradient: %time (min)/ B Conc. : 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. EXAMPLE 15 - SYNTHESIS OF 4,6-DIFLUORO-N-(4-((1R,4R)-4-((2-HYDROXY-2- METHYLPROPYL)CARBAMOYL)CYCLOHEXYL)PHENYL)ISOINDOLINE-2- CARBOXAMIDE (I-31)

[0682] Step 1: Synthesis of (1r,4r)-4-phenylcyclohexane-1-carboxylic acid (15-2): To a stirred solution of compound 15-1 (10.0 g, 41.89 mmol) in methanol (50 mL) were added triethylamine (6.7 mL) and 10% palladium on carbon (50% wet, 3.3 g) at rt. The reaction mixture was stirred at 50 ^oC for 18 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The combined organic layers were concentrated under reduced pressure to afford the title crude compound 15-2 (8.0 g, 39.16 mmol, 93.47% yield) as a white solid. The crude compound was used in the next step without further purification. LC-MS: MS calcd. for chemical formula C13H16O2: 204.27; Found: 203.14 [M+H]⁺; Method E. [0683] Step 2: Synthesis of (1r,4r)-4-(4-nitrophenyl)cyclohexane-1-carboxylic acid (15-3): To a mixture of compound 15-2 (4 g, 19.58 mmol) and potassium nitrite (0.59 g, 5.874 mmol), was added sulphuric acid (40 mL, 91.2 mmol) dropwise at 0 ^oC. The reaction mixture was stirred at 0 ^oC for 30 min. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and the precipitated solid was filtered off and dried under reduced pressure to afford the title crude compound 15-3 (2.1 g, 8.4 mmol, 43% yield) as a white solid. The crude compound was used in the next step without further purification. LC-MS: MS calcd. for chemical formula: C₁₃H₁₅NO₄: 249.27; Found: 248.12 [M+H]⁺; Method E. [0684] Step 3: Synthesis of tert-butyl (1r,4r)-4-(4-nitrophenyl)cyclohexane-1-carboxylate (15-4): To a stirred solution of compound 15-3 (5.0 g, 20.06 mmol) in t-butyl alcohol (40 mL) was added di-tert-butyl decarbonate (21.89 g, 100.3 mmol), followed by DMAP (0.742 g, 6.017 mmol) at 0 ^oC. Then, the reaction mixture was stirred at 80 ^oC for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to afford the title compound 15-4 (2.3 g, 7.5 mmol, 38% yield) as an off white solid. The crude compound was used in the next step without further purification. LC-MS: MS calcd. for chemical formula: C₁₇H₂₃NO₄: 305.37; Found: 304.20 [M+H]⁺; Method E. [0685] Step 4: Synthesis of tert-butyl (1r,4r)-4-(4-aminophenyl)cyclohexane-1- carboxylate (15-5): To a stirred solution of compound 15-4 (2.3 g, 7.5 mmol) in ethanol (25 mL) was added 10% palladium on carbon (50% wet, 0.5 g) and the reaction mixture was stirred at rt for 16 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The combined organic layers were concentrated under reduced pressure to afford the crude compound 15-5 (1.6 g, 5.80 mmol, 76% yield) as a pale red solid. The crude compound was used in the next step without further purification. LC-MS: MS calcd. for chemical formula: C17H25NO2: 275.39; Found: 276.15 [M+H]⁺; Method F. [0686] Step 5: Synthesis of tert-butyl (1r,4r)-4-(4-((phenoxycarbonyl)amino) phenyl) cyclohexane-1-carboxylate (15-7): To a stirred solution of compound 15-5 (1.5 g, 5.4 mmol) in DCM (15 mL) at 0 ℃ was added pyridine (0.88 mL, 11 mmol), followed by phenyl chloroformate 15-6 (1.0 g, 6.5 mmol). The reaction was then the reaction mixture was stirred at rt for 16 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure to afford the title crude compound 15-7 (1.1 g, 2.8 mmol, 51% yield) as a yellow solid. The crude compound was used in the next step without further purification. LC-MS: MS calcd. for chemical formula: C24H29NO4: 395.5; Found: 396.49 [M+H]⁺; Method F. [0687] Step 6: Synthesis of tert-butyl (1r,4r)-4-(4-(4,6-difluoroisoindoline-2-carbox amido)phenyl)cyclohexane-1-carboxylate (15-9): To a stirred solution of compound 15-7 (0.5 g, 1.26 mmol) and compound 15-8 (0.235 g, 1.52 mmol) in DMF (5 mL) at rt was added DIPEA (1.12 mL, 6.32 mmol), and then the reaction mixture was stirred at 80 ^oC for 1 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the title crude compound 15-9 (0.4 g, 0.876 mmol, 69.31% yield) as an off-white solid. The crude compound was used in the next step without further purification. LC-MS: MS calcd. for chemical formula: C26H30F2N2O3: 456.5; Found: 457.09 [M+H]⁺; Method G. [0688] Step 7: Synthesis of (1r,4r)-4-(4-(4,6-difluoroisoindoline-2-carboxamido) phenyl)cyclohexane-1-carboxylic acid (15-10): To the stirred solution of compound 15-9 (0.4 g, 0.876 mmol) in DCM (10 mL), was added trifluoroacetic acid (3 mL) at 0 ^oC. The reaction mixture was then the reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (10 mL) and then with n-pentane (5 mL x 2). The filtered the solid compound was then dried under reduced pressure to afford the desired compound 15-10 (0.3 g, 0.749 mmol, 85.51% yield) as a brown solid. LC-MS: MS calcd. for chemical formula: C22H22F2N2O3: 400.4; Found: 401.02 [M+H]⁺; Method F. [0689] Step 8: Synthesis of 4,6-difluoro-N-(4-((1r,4r)-4-((2-hydroxy-2-methylpropyl) carbamoyl)cyclohexyl)phenyl)isoindoline-2-carboxamide (I-31): To a stirred solution of compound 15-10 (0.1 g, 0.249 mmol) in the DMF (5 mL), was added DIPEA (0.22 mL, 1.25 mmol) and HATU (0.14 g, 0.374 mmol) at 0 ^oC. After 5 min, 1-amino-2-methylpropan-2-ol 15- 11 (0.027 g 0.299 mmol) was added. The reaction mixture was then the reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), The organic layer was mixed with water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by CombiFlash (Nexgen-300) chromatography using a 4 g silica gel cartridge and 2-4% MeOH in DCM as the eluent to afford the title compound 4,6-difluoro-N-(4-((1r,4r)-4- ((2-hydroxy-2-methylpropyl)carbamoyl)cyclohexyl)phenyl)isoindoline-2-carboxamide (I-31, 55.5 mg, 0.118 mmol, 14.52% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 7.58 (t, J = 6.0 Hz, 1H), 7.44 (d, J = 8.6 Hz, 2H), 7.22 - 7.14 (m, 2H), 7.11 (d, J = 8.5 Hz, 2H), 4.77 (s, 4H), 4.43 (s, 1H), 3.02 (d, J = 6.0 Hz, 2H), 2.48 - 2.37 (m, 1H), 2.30 - 2.30 (m, 1H), 1.82 (d, J = 11.6 Hz, 4H), 1.58 - 1.33 (m, 4H), 1.04 (s, 6H). LC-MS: ret. time: 1.37 min, 95.03%; MS calcd. for chemical formula: C₂₂H₂₂F₂N₂O₃: 471.5; Found: 472.15 [M+H]⁺; Method F. HPLC: ret. time: 7.098 min, 96.12%; column: X-Select CSH C18, 5.0 µm; 150 X 4.6 mm, mobile phase A: 0.1% FA in (water:ACN)(95:5)V/V; mobile phase B: ACN; column temperature: 30 °C; flow rate: 1.0 ml/min; gradient: 0/5, 1/5, 8/100, 12/100, 14/5, 18/5; diluent: ACN: water. EXAMPLE 16 - SYNTHESIS OF 4,6-DIFLUORO-N-(4-((1R,4R)-4-((2-(2-HYDROXY- ETHOXY)ETHYL)CARBAMOYL)CYCLOHEXYL)PHENYL)ISOINDOLINE-2- CARBOXAMIDE (I-30) [0690] Step 1: Synthesis of (1r,4r)-4-phenylcyclohexane-1-carboxylic acid (16-2): To a stirred solution of compound 16-1 (10.0 g, 41.89 mmol) in methanol (50 mL) were added triethylamine (6.7 mL) and 10% palladium on carbon (50% wet, 3.3 g) at rt. The reaction mixture was then the reaction mixture was stirred at 50 ^oC for 18 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The combined organic layers were concentrated under reduced pressure to afford the title crude compound 16-2 (8.0 g, 39.16 mmol, 93.47% yield) as a white solid. The crude compound was used in the next step without further purification. LC- MS: MS calcd. for chemical formula C₁₃H₁₆O₂: 204.27; Found: 203.14 [M+H]⁺; Method E. [0691] Step 2: Synthesis of (1r,4r)-4-(4-nitrophenyl)cyclohexane-1-carboxylic acid (16-3): A mixture of compound 16-2 (4 g, 19.58 mmol) and potassium nitrite (0.59 g, 5.874 mmol) was added sulphuric acid (40 mL, 91.2 mmol) dropwise at 0 ^oC. The reaction mixture was stirred at 0 ^oC for 30 min. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and the precipitated solid was filtered off and dried under reduced pressure to afford the title crude compound 16-3 (2.1 g, 8.4 mmol, 43% yield) as a white solid. The crude compound was used in the next step without further purification. LC-MS: MS calcd. for chemical formula: C13H15NO4: 249.27; Found: 248.12 [M+H]⁺; Method E. [0692] Step 3: Synthesis of tert-butyl (1r,4r)-4-(4-nitrophenyl)cyclohexane-1-carboxylate (16-4): To a stirred solution of compound 16-3 (5.0 g, 20.06 mmol) in t-butyl alcohol (40 mL) was added di-terrt-butyl dicarbonate (21.89 g, 100.3 mmol), followed by DMAP (0.742 g, 6.017 mmol) at 0 ^oC and then the reaction mixture was stirred at 80 ^oC for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to afford the title compound 16-4 (2.3 g, 7.5 mmol, 38% yield) as an off white solid. The crude compound was used in the next step without further purification. LC-MS: MS calcd. for chemical formula: C₁₇H₂₃NO₄: 305.37; Found: 304.20 [M+H]⁺; Method E. [0693] Step 4: Synthesis of tert-butyl (1r,4r)-4-(4-aminophenyl)cyclohexane-1- carboxylate (16-5): To a stirred solution of compound 16-4 (2.3 g, 7.5 mmol) in ethanol (25 mL) was added 10% palladium on carbon (50% wet, 0.5 g) and the reaction mixture was stirred at rt for 16 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The combined organic layers were concentrated under reduced pressure to afford the crude compound 16-5 (1.6 g, 5.80 mmol, 76% yield) as a pale red solid. The crude compound was used in the next step without further purification. LC-MS: MS calcd. for chemical formula: C17H25NO2: 275.39; Found: 276.15 [M+H]⁺; Method F. [0694] Step 5: Synthesis of tert-butyl (1r,4r)-4-(4-((phenoxycarbonyl)amino)phenyl) cyclohexane-1-carboxylate (16-7): To a stirred solution of compound 16-5 (1.5 g, 5.4 mmol) in DCM (15 mL) was added pyridine (0.88 mL, 11 mmol), followed by phenyl chloroformate 16-6 (1.0 g, 6.5 mmol) at 0 ^oC and the reaction mixture was then the reaction mixture was stirred at rt for 16 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure to afford the title crude compound 16-7 (1.1 g, 2.8 mmol, 51% yield) as a yellow solid. The crude compound was used in the next step without further purification. LC-MS: MS calcd. for chemical formula: C24H29NO4: 395.5; Found: 396.49 [M+H]⁺; Method F. [0695] Step 6: Synthesis of tert-butyl (1r,4r)-4-(4-(4,6-difluoroisoindoline-2- carboxamido)phenyl)cyclohexane-1-carboxylate (16-9): To a stirred solution of compound 16- 7 (0.5 g, 1.26 mmol), and compound 16-8 (0.235 g, 1.52 mmol) in DMF (5 mL) was added DIPEA (1.12 mL, 6.32 mmol) at rt and then the reaction mixture was stirred at 80 ^oC for 1 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the title crude compound 16-9 (0.4 g, 0.876 mmol, 69.31% yield) as an off-white solid. The crude compound was used in the next step without further purification. LC-MS: MS calcd. for chemical formula: C26H30F2N2O3: 456.5; Found: 457.09 [M+H]⁺; Method G. [0696] Step 7: Synthesis of (1r,4r)-4-(4-(4,6-difluoroisoindoline-2-carboxamido)phenyl) cyclohexane-1-carboxylic acid (16-10): To the stirred solution of compound 16-9 (0.4 g, 0.876 mmol) in DCM (10 mL) was added trifluoroacetic acid (3 mL) at 0 ^oC. The reaction mixture stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (10 mL) and then with n-pentane (5 mL x 2), and then the solid compound was filtered and dried under reduced pressure to afford the desired compound 16-10 (0.3 g, 0.749 mmol, 85.51% yield) as a brown solid. LC- MS: MS calcd. for chemical formula: C₂₂H₂₂F₂N₂O₃: 400.4; Found: 401.02 [M+H]⁺; Method F. [0697] Step 8: Synthesis of 4,6-difluoro-N-(4-((1s,4s)-4-((2-(2-hydroxyethoxy)ethyl) carbamoyl)cyclohexyl)phenyl)isoindoline-2-carboxamide (I-30): To the stirred solution of the compound 16-10 (0.1 g, 0.249 mmol) in the DMF (2 mL), were added DIPEA (0.22 mL, 1.25 mmol) and HATU (0.15 g, 0.374 mmol) at 0 ^oC. After 5 min, 2-(2-aminoethoxy)ethan-1-ol 16-11 (0.032 g 0.299 mmol) was added. The reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction was diluted with ice cold water, and the precipitated solids were filtered. The crude compound was washed with n-pentane and diethyl ether and dried under reduced pressure to afford the title compound 4,6-difluoro-N-(4-((1s,4s)-4- ((2-(2-hydroxyethoxy)ethyl)carbamoyl)cyclohexyl)phenyl)isoindoline-2-carboxamide (I-30, 57 mg, 0.113 mmol, 45.41% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 7.76 (t, J = 5.6 Hz, 1H), 7.44 (d, J = 8.5 Hz, 2H), 7.24 - 7.13 (m, 2H), 7.11 (d, J = 8.5 Hz, 2H), 4.77 (s, 4H), 4.56 (t, J = 5.5 Hz, 1H), 3.53 - 3.47 (m, 2H), 3.44 - 3.38 (m, 4H), 3.20 (q, J = 6.0 Hz, 2H), 2.47 - 2.39 (m, 1H), 2.21 - 2.11 (m, 1H), 1.85 - 1.76 (m, 4H), 1.55 - 1.34 (m, 4H). LC-MS: ret. time : 1.34 min, 95.41%, MS calcd. for chemical formula: C₂₆H₃₁F₂N₃O₄: 487.55; Found: 488.15 [M + H]. Method F. HPLC: ret. time: 6.781 min, 97.09%; column: X-Select CSH C18, 5.0 µm; 150 X 4.6 mm; mobile phase A: 0.1% FA in (water:ACN)(95:5)V/V; mobile phase B: ACN; column temperature: 30 °C; flow rate: 1.0 ml/min; gradient: 0/5, 1/5, 8/100, 12/100, 14/5, 18/5; diluent: ACN: water. EXAMPLE 17 - SYNTHESIS OF 2-(4-(4-(5-FLUOROISOINDOLINE-2- CARBOXAMIDO)PHENYL)-3,6-DIHYDROPYRIDIN-1(2H)-YL)-2-OXOACETIC ACID (I-27) AND 5-FLUORO-N-(4-(1-(2-((2-HYDROXY-2-METHYL-PROPYL)AMINO)-2- OXOACETYL)-1,2,3,6-TETRAHYDROPYRIDIN-4-YL) PHENYL)ISOINDOLINE-2- CARBOXAMIDE (I-29)

[0698] Step 1: Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylatecarbamate (17-3): A mixture of compound 17-1 (10.0 g, 58.13 mmol), compound 17-2 (20.38 g, 63.94 mmol), and K3PO4 (37.77 g, 174.40 mmol) in 1,2-DME: H2O (70:30) (60 mL) was degassed with argon for 5 min. Pd(dppf)Cl2.DCM (2.42 g, 2.90 mmol) was added to the reaction mixture at rt. The reaction mixture was stirred for 15 min while degassing with argon, and then the reaction mixture was stirred at 90 ^oC for 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The organic layer was mixed with water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by CombiFlash (Nexgen-300) chromatography using a 40 g silica gel cartridge and 10 - 15% EtOAc in heptane as the eluent to afford the title compound 17-3 (14.0 g, 51.02 mmol, 87.77% yield) as a yellow solid. LC-MS: MS calcd. for chemical formula C16H22N2O2: 274.36; Found: 274.95 [M+H]⁺; Method F. [0699] Step 2: Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (17-5): To a solution of compound 17-3 (5.0 g, 18.22 mmol) in DCM (100 mL) was added pyridine (2.92 mL, 36.44 mmol) and DMAP (0.22 g, 1.82 mmol) and the reaction mixture was stirred at rt. Then compound 17-4 (3.42 g, 21.87 mmol) was added at 0 ^oC and then the reaction mixture was stirred at rt for 2 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The obtained solid was washed with diethyl ether and n-pentane and dried under reduced pressure to afford the title compound 17-5 (6.0 g, 15.21 mmol, 83.47% yield) as an off white solid. LC-MS: MS calcd. for chemical formula C23H26N2O42: 394.47; Found: 294.90 [(M-Boc) +H]⁺; Method F. [0700] Step 3: Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)- 3,6-dihydropyridine-1(2H)-carboxylate (17-7): To a stirred solution of compound 17-5 (3.0 g, 7.60 mmol) and compound 17-6 (1.25 g, 9.12 mmol) in DMF (30 mL) at rt was added DIPEA (13.28 mL, 76.05 mmol), and then the reaction mixture was stirred at 80 ^oC for 3 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The obtained solid was washed with diethyl ether and n-pentane and dried under reduced pressure to afford the title compound 17- 7 (2.5 g, 5.7 mmol, 75% yield) as a brown solid. LC-MS: MS calcd. for chemical formula C₂₅H₂₈FN₃O₃: 437.5; Found: 438.2 [M+H]⁺; Method F. [0701] Step 4: Synthesis of 5-fluoro-N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl) isoindoline-2-carboxamide, hydro chlorine (17-8): To a stirred solution of compound 17-7 (2.5 g, 5.7 mmol) in 1,4-dioxane (10 mL) was added 4 M HCl in 1,4-dioxane (14 mL, 57 mmol) at 0 ^oC and the reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (8 mL) and then with n-pentane (4 mL x 2), and then the solid compound was filtered and dried under reduced pressure to afford the desired compound 17-8 (2.0 g, 5.350 mmol, 99% yield) as an off-white solid. The resulting crude HCl salt was used in the next step without further purification. LC-MS: MS calcd. for chemical formula C20H20FN3O: 337.4; Found: 338.16 [M+H]⁺; Method F. [0702] Step 5: Synthesis of ethyl 2-(4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)-3,6- dihydropyridin-1(2H)-yl)-2-oxoacetate (17-10): To stirred solution of compound 17-8 (1.0 g, 2.68 mmol), in DMF (20 mL), was added DIPEA (1.41 mL, 8.04 mmol), followed by ethyl 2- chloro-2-oxoacetate 17-9 (0.366 g, 2.68 mmol) at 0 ^oC and the reaction mixture was stirred at rt for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The crude was purified by CombiFlash (Nexgen-300) chromatography using a 24 g silica gel cartridge and 5 - 10% MeOH in DCM as the eluent to afford the title compound 17-10 (0.32 g, 0.731 mmol, 27.27%yield) as a pale brown solid. LC- MS: MS calcd. for chemical formula C24H24FN3O4: 437.5; Found: 438.06 [M+H]⁺; Method F. [0703] Step 6: Synthesis of 2-(4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)-3,6- dihydropyridin-1(2H)-yl)-2-oxoacetic acid (I-27): To a stirred solution of compound 17-10 (0.32 g, 0.731 mmol) in 1,4-dioxane (4.6 mL) was added a 1 N NaOH solution (4.6 mL) at room temperature and the reaction mixture was stirred at room temperature for 5 h. After completion of the reaction (monitored by TLC), the reaction mixture was acidified with 1 N HCl solution to pH~4-5, the solid that formed was filtered, washed with water, and dried under reduced pressure to afford title the compound 2-(4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)-3,6- dihydropyridin-1(2H)-yl)-2-oxoacetic acid (I-27, 0.19 g, 0.46 mmol, 63.45% yield) as an off- white solid. LC-MS: MS calcd. for chemical formula C₂₂H₂₀FN₃O₄, 409.42; Found, 409.97 [M+H]⁺; Method F. [0704] Step 7: Synthesis of 5-fluoro-N-(4-(1-(2-((2-hydroxy-2-methylpropyl)amino)-2- oxoacetyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide (I-29): To a stirred solution of compound I-27 (0.1 g, 0.244 mmol) in DCM (2 mL) was added DIPEA (0.13 mL0.733 mmol) and 50% T3P in EtOAc (0.32 g 0.488 mmol) at rt. After 15 min, 1-amino-2- methyl-propan-2-ol 17-12 (0.1 g, 1.23 mmol) was added to the above reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice water, extracted with DCM, and concentrated under reduced pressure. The crude compound was purified by Prep-HPLC to afford compound 5-fluoro-N-(4-(1-(2-((2-hydroxy-2-methylpropyl)amino)-2-oxoacetyl)- 1,2,3,6-tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide (I-29, 20 mg, 0.041 mmol, 17.04% yield) as an off-white solid.¹H NMR (400 MHz, DMSO-d6) δ 8.57 - 8.43 (m, 1H), 8.41 - 8.19 (m, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.41 - 7.33 (m, 3H), 7.23 (dd, J = 2.1, 9.0 Hz, 1H), 7.17 - 7.11 (m, 1H), 6.14 - 6.08 (m, 1H), 4.74 (d, J = 11.6 Hz, 4H), 4.50 - 4.46 (m, 1H), 4.19 - 4.10 (m, 2H), 3.71 (t, J = 5.8 Hz, 1H), 3.66 (t, J = 5.6 Hz, 1H), 3.15 - 3.09 (m, 2H), 2.56 - 2.53 (s, 2H), 1.13 - 1.06 (m, 6H). LCMS: ret. time: 1.29 min, 97.82%; MS calcd. for chemical formula, C26H29FN4O4, 480.54; found: 481.09 [M+H]⁺; Method F. HPLC: Rt 6.890 min, purity: 95.90%; column: X-Select CSH C18 (4.6*150) mm x 5 ^m mobile phase: A - 0.1% TFA in water B – acetonitrile, injection volume: 5.0µL, flow rate: 1.2 mL/minute, column oven temp.: 30°C, gradient: time(min)/ B Conc. : 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5.; Prep-HPLC purification method: preparative column: x-select C-18 (250x30mm, 5µ) mobile phase A: 0.1% FA in water mobile phase B: ACN, flow rate 20 mL/min, gradient (time/%B) 0/10, 2/10, 10/25, 25/45, 30/80, 35/98. EXAMPLE 18 - SYNTHESIS OF N-(4-(1-(N-ACETYLSULFAMOYL)-1,2,3,6- TETRAHYDROPYRIDIN-4-YL)PHENYL)-5-FLUOROISOINDOLINE-2- CARBOXAMIDE (I-28) [0705] Step 1: Synthesis of tert-butyl ((4-(dimethyl-l4-azaneylidene)pyridin-1(4H)- yl)sulfonyl)carbamate (18-9): To a stirred solution of 2-methylpropan-2-ol (18-1a) (0.5 g, 6.746 mmol) in DCM (5 mL) were added chlorosulfonyl isocyanate (18-2b) (0.9547 g, 6.746 mmol) and compound (18-3c) (1.648 g, 13.49 mmol) at 0 ^oC. The mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), heptane was added to the reaction mixture. The obtained precipitated was filtered, washed with n-heptane, and dried under reduced pressure to afford the compound 18-9 (2.0 g, 6.59 mmol, 97.72% yield) as a white solid. LC-MS: MS calcd. for chemical formula C₁₂H₂₁N₃O₄S: 303.4; Found: 303.90 [M + 1]; Method F. [0706] Step 2: Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylatecarbamate (18-3): A mixture of compound 18-1 (10.0 g, 58.13 mmol), compound 18-2 (20.38 g, 63.94 mmol), and K₃PO₄ (37.77 g, 174.40 mmol) in 1,2-DME: H₂O (70:30) (60 mL) was degassed with argon for 5 min. Pd(dppf)Cl2.DCM (2.42 g, 2.90 mmol) was added to the reaction mixture at rt. The reaction mixture was stirred for 15 min while degassing with argon, and then the reaction mixture was stirred at 90 ^oC for 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The organic layer was mixed with water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by CombiFlash (Nexgen-300) chromatography using a 40 g silica gel cartridge and 10 – 15% EtOAc in n-heptane as the eluent to afford the title compound 18-3 (14.0 g, 51.02 mmol, 87.77% yield) as a yellow solid. LC-MS: MS calcd. for chemical formula C₁₆H₂₂N₂O₂: 274.36; Found: 274.95 [M+H]⁺; Method F. [0707] Step 3: Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (18-5): To a stirred solution of compound 18-3 (5.0 g, 18.22 mmol) in DCM (20 mL) were added pyridine (2.92 mL, 36.44 mmol) and DMAP (0.22 g, 1.82 mmol), followed by compound 18-4 (3.42 g, 21.87 mmol) at 0 ^oC. Then the reaction mixture was stirred at rt for 2 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The obtained solid was washed with diethyl ether and n-pentane and dried under reduced pressure to afford the title compound 18-5 (6.0 g, 15.21 mmol, 83.47% yield) as an off white solid. LC-MS: MS calcd. for chemical formula C₂₃H₂₆N₂O₄₂: 394.47; Found: 294.90 [(M-Boc)+H]⁺; Method F. [0708] Step 4: Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)- 3,6-dihydropyridine-1(2H)-carboxylate (18-7): To a stirred solution of compound 18-5 (3.0 g, 7.60 mmol) and compound 18-6 (1.25 g, 9.12 mmol) in DMF (30 mL) at rt was added DIPEA (13.28 mL, 76.05 mmol), then the reaction mixture was stirred at 80 ^oC for 3 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The obtained solid was washed with diethyl ether and n-pentane and dried under reduced pressure to afford the title compound 18- 7 (2.5 g, 5.7 mmol, 75% yield) as a brown solid. LC-MS: MS calcd. for chemical formula C₂₅H₂₈FN₃O₃: 437.5; Found: 438.2 [M+H]⁺; Method F. [0709] Step 5: Synthesis of 5-fluoro-N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl) isoindoline-2-carboxamide hydro chlorine (18-8): To a stirred solution of compound 18-7 (2.5 g, 5.7 mmol) in 1,4-dioxane (10 mL) was added 4 M HCl in 1,4-dioxane (14 mL, 57 mmol) at 0 ^oC and the reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (8 mL) and then with n-pentane (4 mL x 2), and then the solid compound was filtered and dried under reduced pressure to afford the desired compound 18-8 (2.0 g, 5.350 mmol, 99%yield) as an off-white solid. The resulting crude HCl salt was used in the next step without further purification. LC-MS: MS calcd. for chemical formula C20H20FN3O: 337.4; Found: 338.16 [M+H]⁺; Method F. [0710] Step 6: Synthesis of tert-butyl ((4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)- 3,6-dihydropyridin-1(2H)-yl)sulfonyl)carbamate (18-10): To a stirred solution of compound 18-8 (0.3 g, 0.889 mmol) in DCM (8 mL) were added compound 18-9 (0.26 g, 0.889 mmol) and DIPEA (0.23 mL, 1.334 mmol) at rt and then the reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by (Nexgen- 300) chromatography using a 4 g silica gel cartridge and 1-2% MeOH in DCM as the eluent to afford the title compound 18-10 (0.2 g, 0.38 mmol, 43.54% yield)) as an off white solid. LC-MS: MS calcd. for chemical formula C₂₅H₂₉FN₄O₅S: 516.59; Found: 517.4 [M+H]⁺; Method E. [0711] Step 7: Synthesis of 5-fluoro-N-(4-(1-sulfamoyl-1,2,3,6-tetrahydropyridin-4- yl)phenyl)isoindoline-2-carboxamide (18-11): To a stirred solution of compound 18-10 (0.2 g, 0.38 mmol) in 1,4-dioxane (10 mL) was added 4 M HCl in 1,4-dioxane (1.99 mL, 7.98 mmol) at 0 ^oC and the reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (4 mL) and then with n-pentane (3 mL x 2), and then the solid compound was filtered and dried under reduced pressure to afford the desired compound 18-11 (0.15 g, 0.360 mmol, 93.03% yield) as a brown solid. LC-MS: MS calcd. for chemical formula C₂₀H₂₁FN₄O₃S: 416.50; Found: 416.97 [M+H]⁺; Method F. [0712] Step 8: Synthesis of N-(4-(1-(N-acetylsulfamoyl)-1,2,3,6-tetrahydropyridin-4- yl)phenyl)-5-fluoroisoindoline-2-carboxamide (I-28): To a stirred solution of compound 18-11 (0.12 g.0.288 mmol) in DCM (6 mL) was added triethylamine (0.121 mL, 0.864 mmol) and acetic anhydride (0.0412 mL, 0.432 mmol) at 0 ^oC. The reaction mixture was allowed to stir at rt for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by prep-HPLC to afford the title compound N-(4-(1-(N-acetylsulfamoyl)-1,2,3,6- tetrahydropyridin-4-yl)phenyl)-5-fluoroisoindoline-2-carboxamide (I-28, 13 mg, 0.028 mmol, 9.86% yield) as an off-white solid.¹H NMR (400 MHz, DMSO-d6) δ 11.53 (s, 1H), 8.40 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.42 - 7.31 (m, 3H), 7.25 - 7.21 (m, 1H), 7.17 - 7.10 (m, 1H), 6.08 (s, 1H), 4.74 (d, J = 11.5 Hz, 4H), 3.92 (d, J = 2.1 Hz, 2H), 3.44 (t, J = 5.6 Hz, 2H), 2.54 (s, 2H), 1.95 (s, 3H). LC-MS: ret. time: 1.39 min. 97.82%; MS calcd. for chemical formula C22H23FN4O4S: 458.51; Found: 459.00 [M+H]⁺; Method F. HPLC: Rt 7.144 min, purity: 97.54%; column: X- Select CSH C18, 5.0 µm; 150 X 4.6 mm mobile phase A: 0.1% FA in (Water:ACN)(95:5)V/V; mobile phase B: ACN; column temperature: 30 °C; flow rate: 1.0 ml/ min; gradient: 0/5, 1/5, 8/100, 12/100, 14/5, 18/5, diluent: ACN : water. Prep-HPLC purification method: preparative column: x- select C18(250*30mm,5µ), mobile phase A: 0.1% FA in water, mobile phase B: ACN, flow rate 25 mL/min, gradient (time/%B) 0/15, 3/15, 10/40, 15/50, 20/55, 25/60, 30/65, 35/70, 50/98. EXAMPLE 19 – SYNTHESIS OF N-(4-((1R,4R)-4-((2-(2-(DIMETHYLAMINO)ETHOXY) ETHYL)CARBAMOYL)CYCLOHEXYL)PHENYL)ISOINDOLINE-2-CARBOXAMIDE FIRST-ELUTING ISOMER (I-132)

[0713] Step 1: Synthesis of (1r,4r)-4-phenylcyclohexane-1-carboxylic acid (21-2): To a stirred solution of compound 21-1 (10.0 g, 44.89 mmol) in methanol (50 mL) were added triethylamine (6.7 mL) and 10% palladium on carbon (3.5 g, 33.66 mmol) at room temperature. The reaction mixture was stirred at 50 ^oC for 18 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with ethyl acetate. The combined organic layers were concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluting with 30% EtOAc in heptane) to afford the title compound 21-2 (8.2 g, 40.14 mmol, 96.47% yield) as a white solid. [0714] Step 2: Synthesis of (1r,4r)-4-(4-nitrophenyl)cyclohexane-1-carboxylic acid (21-3): A mixture of compound 21-2 (4.0 g, 19.58 mmol) in nitrobenzene (10 mL), were added sulfuric acid (2.07 ml, 39.16 mmol) and nitric acid (1.63 mL, 39.16 mmol) dropwise at 0 ^oC. The reaction mixture was stirred for 1 hour. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with DCM. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluting with 50% EtOAc in heptane) to afford the title compound 21-3 (2.0 g, 8.03 mmol, 81% yield) as a white solid. [0715] Step 3: Synthesis of (1r,4r)-N-(2-(2-(dimethylamino)ethoxy)ethyl)-4-(4- nitrophenyl)cyclohexane-1-carboxamide (21-5): To A stirred solution of compound 21-3 (2.0 g, 8.03 mmol), 2-(2-aminoethoxy)-N,N-dimethylethan-1-amine 21-4 (2.0 g, 9.62 mmol) and HATU (4.55 g, 12.04 mmol) in DMF (10 mL) was added diisopropylethylamine (2.8 mL, 16.06 mmol) at 0 ^oC and the reaction mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with cold water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by Combi Flash chromatography (eluting with 2 to 4% MeOH in DCM) to afford the title compound 21-5 (2.0 g, 5.50 mmol, 68% yield) as a white solid. [0716] Step 4: Synthesis of (1r,4r)-4-(4-aminophenyl)-N-(2-(2-(dimethylamino) ethoxy)ethyl)cyclohexane-1-carboxamide (21-6): To a stirred solution of compound 21-5 (2 g, 5.50 mmol) in ethanol (20 mL) was added 10% palladium on carbon (0.44 g, 4.12 mmol) and the reaction mixture was stirred at room temperature for 16 hours under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with ethyl acetate. The combined organic layers were concentrated under reduced pressure to afford the crude compound 21-6 (1.6 g, 4.79 mmol, 87% yield) as an off white solid. [0717] Step 5: Synthesis of phenyl (4-((1r,4r)-4-((2-(2-(dimethylamino)ethoxy) ethyl)carbamoyl)cyclohexyl)phenyl)carbamate (21-8): To a stirred solution of compound 21-6 (1.6 g, 4.79 mmol) in DCM (20 mL) at 0 ^oC were added pyridine (1.16 mL, 14.39 mmol) followed by phenyl chloroformate 21-7 (0.89 g, 5.74 mmol) and then the reaction mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure. The crude compound was purified by Combi Flash chromatography (eluting with 25% EtOAc in heptane) to afford the title compound 21-8 (1.8 g, 3.96 mmol, 82% yield) as an off-white solid. [0718] Step 6: Synthesis of N-(4-((1r,4r)-4-((2-(2-(dimethylamino)ethoxy)ethyl) carbamoyl)cyclohexyl)phenyl)isoindoline-2-carboxamide (I-132): To a stirred solution of compound 21-8 (1.0 g, 2.20 mmol) and compound 21-9 (0.32 g, 2.64 mmol) in DMF (10 mL) at room temperature was added diisopropylethylamine (0.42 mL, 4.40 mmol) and then the reaction mixture was stirred at 80 ^oC for 3 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by Prep-HPLC to afford the title compound N-(4-((1r,4r)-4-((2-(2-(dimethylamino)ethoxy)ethyl) carbamoyl) cyclohexyl) phenyl)isoindoline-2-carboxamide (I-132, 165 mg, 0.344 mmol, 15% yield) as an off- white solid. HPLC: Rt 5.942 min, 99.93%; column: X-Select CSH C18 (4.6*150) mm x 5 ^m mobile phase: A - 0.1% TFA in water B - acetonitrile flow rate: 1.2. mL/minute column oven temp.: 30°C gradient: time(min)/ B Conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/55 LCMS: (M+H), Rt 1.13 min, 99.08%, Method F.¹H NMR (400 MHz, DMSO-d₆) δ 8.24 (s, 1H), 7.79 (t, J = 5.6 Hz, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.38 - 7.34 (m, 2H), 7.33 - 7.28 (m, 2H), 7.11 (d, J = 8.5 Hz, 2H), 4.75 (s, 4H), 3.46 (t, J = 6.0 Hz, 2H), 3.39 (t, J = 5.9 Hz, 2H), 3.18 (q, J = 5.8 Hz, 2H), 2.46 - 2.36 (m, 3H), 2.20 - 2.10 (m, 7H), 1.86 - 1.75 (m, 4H), 1.56 - 1.34 (m, 4H). Compound I- 132 elutes before Compound I-133 during HPLC analysis. EXAMPLE 20 - SYNTHESIS OF N-(4-(4-(SULFAMOYLAMINO)CYCLOHEXYL) PHENYL)ISOINDOLINE-2-CARBOXAMIDE (I-129) AND TERT-BUTYL (N-(4-(4- (ISOINDOLINE-2-CARBOXAMIDO)PHENYL)CYCLOHEXYL) SULFAMOYL)CARBAMATE (I-128)

[0719] Step 1: Synthesis of tert-butyl (4'-amino-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4- yl)carbamate (22-3): A stirred mixture of compound 22-1 (5.06 g, 29.2 mmol), compound 22-2 (9.4 g, 29.2 mmol), and Cs₂CO₃ (19 g, 58.4 mmol) in 1,4-dioxane:H₂O (50:50, 100 mL) was degassed with argon for 5 minutes. X-Phos (1.4 g, 2.92 mmol) and Pd(dppf)Cl₂DCM (0.47 g, 0.058 mmol) were added to the reaction mixture at room temperature. The reaction mixture was stirred for 15 minutes while degassing with nitrogen, and then the reaction mixture was heated to 90 ^oC and stirred for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with ethyl acetate. The organic layer was mixed with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluting with 10-15% EtOAc in heptane) to afford the title compound 22-3 (6.0 g, 20.83 mmol, 71% yield) as an off-white solid. [0720] Step 2: Synthesis of tert-butyl (4-(4-aminophenyl)cyclohexyl)carbamate (22-4): To a stirred solution of compound 22-3 (6.2 g, 20.15 mmol) in ethanol (20 mL) was added 10% palladium on carbon ( 2.28 g, 201.5 mmol ) and the reaction mixture was stirred at room temperature for 16 h under hydrogen gas at 50 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with ethyl acetate. The combined organic layers were concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluting with 10-20% EtOAc in heptane) to afford the title compound 22-4 (4.82 g, 16.62mmol, 89% yield) as an off-white solid. [0721] Step 3: Synthesis of tert-butyl (4-(4-((phenoxycarbonyl)amino) phenyl) cyclohexyl)carbamate (22-6): To a stirred solution of compound 22-4 (2.15 g, 8.6 mmol) in DCM (30 mL) was added pyridine (1.4 mL, 17.2 mmol) and DMAP (0.10 g, 0.86 mmol) and were stirred at room temperature before compound 22-5 (1.3 mL, 10.3 mmol) was added at 0 ^oC. The reaction mixture was then stirred at room temperature for 6 hours under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluting with 10-20% EtOAc in heptane) to afford the title compound 22-6 (2.5 g, 6.09 mmol, 84% yield) as an off-white solid. [0722] Step 4: Synthesis of tert-butyl (4-(4-(isoindoline-2-carboxamido)phenyl) cyclohexyl)carbamate (22-8): To a stirred solution of compound 22-6 (4.7 g, 11.4 mmol) and compound 22-7 (2.0 g, 12.6 mmol) in DMF (40 mL) at room temperature was added DIPEA (3.8 mL, 34.2 mmol) and then the reaction mixture was stirred at 80 ^oC for 4 hours under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by Combi Flash chromatography (eluting with 15-40 % EtOAc in heptane) to afford the title compound 22-8 (4.0 g, 9.19 mmol, 80% yield) as an off-white solid. [0723] Step 5: Synthesis of N-(4-(4-aminocyclohexyl)phenyl)isoindoline-2-carboxamide hydrochloride (22-9): To a stirred solution of compound 22-8 (4.0 g, 9.19 mmol) in 1,4-dioxane (40 mL) was added 4 M HCl in 1,4-dioxane (23 mL, 91.9 mmol) at 0 ^oC and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (20 mL) and then with pentane (10 mLx2), and then the solid compound was filtered and dried under reduced pressure to afford the desired compound 22-9 (3.0 g, 8.95 mmol, 83% yield) as an off-white solid. [0724] Step 6: Synthesis of N-(4-(4-(sulfamoylamino)cyclohexyl)phenyl)isoindoline-2- carboxamide (I-129): A stirred solution of compound 22-9 (0.05 g, 0.23 mmol) and sulfamide (0.2 g, 1.7 mmol) in 1,4-dioxane (5 mL) at room temperature was heated to 120 ^oC and stirred for 8 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with 10% MeOH in DCM. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by Prep-HPLC to afford the title compound N-(4-(4-(sulfamoylamino)cyclohexyl)phenyl)isoindoline-2-carboxamide (I-129, 20 mg, 0.048 mmol, 11% yield) as an off-white solid. HPLC: Rt 96.07 min, 96.07%, Method:- formic_C&D_PORT.lcm, column: X-Select CSH C18 (4.6*150) mm x 5 ^m mobile phase: A - 0.1% Formic acid in water : acetonitrile(95:05) B - acetonitrile flow rate: 1.0. mL/minute gradient: time(min)/ B Conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. LCMS: 415.26 (M+H) Rt 2.08 min, 95.64%, method details: column: Bakerbond Q2100 C181.8um; 2.1x50mm; mobile phase A :0.05% FA in water; mobile phase B : 0.05% FA in ACN; flow rate: 0.6 mL/min; oven temperature: 40 °C; gradient program (time/B%): 0/5; 0.2/5; 2.3/98; 3.3/98; 3.8/5; 4.5/5; ¹H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.44 (d, J = 8.6 Hz, 2H), 7.38 - 7.34 (m, 2H), 7.33 - 7.29 (m, 2H), 7.17 (d, J = 8.6 Hz, 2H), 6.64 (d, J = 6.8 Hz, 1H), 6.45 (s, 2H), 4.75 (s, 4H), 3.55 - 3.49 (m, 1H), 2.44 - 2.39 (m, 1H), 1.91 - 1.76 (m, 4H), 1.61 - 1.47 (m, 4H). [0725] Step 7: Synthesis of tert-butyl (N-(4-(4-(isoindoline-2-carboxamido)phenyl) cyclohexyl)sulfamoyl)carbamate (I-128): To a stirred solution of compound I-129 (0.085 g, 0.205 mmol) in DCM (5 mL) was added triethylamine (0.031 g, 0.307 mmol) and Boc-anhydride (0.054 g, 0.246 mmol) at room temperature and stirred at room temperature for 5 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were concentrated under reduced pressure. The crude compound was purified by Combi Flash chromatography (eluting with 35% EtOAc in heptane) to afford the title compound tert-butyl (N-(4-(4-(isoindoline-2- carboxamido)phenyl)cyclohexyl)sulfamoyl)carbamate (I-128, 15 mg, 0.029 mmol, 14% yield) as a white solid. Data for I-128: mixture of diastereoisomers: HPLC: Rt 7.957 min & 8.069 min, (purity: 20.12% & 75.62%), column: X-Bridge C18 (4.6*150) mm 5.0 µm mobile phase: A - 5 mM ammonium acetate in water; B – acetonitrile; injection volume: 5.0 µL; flow rate: 1.0 mL/minute. LCMS: 515.35 & 515.35 (M+H), Rt 2.36 min & 2.40 min, (purity: 17.58% & 79.44%), column: Bakerbond Q2100 C181.8um; 2.1x50mm mobile phase A: 0.05% FA in water; mobile phase B: 0.05% FA in CAN; flow rate: 0.6 ml; oven temperature: 40 °C; gradient program (time/B%): 0/5; 0.2/5; 2.3/98; 3.3/98; 3.8/5; 4.5/5.¹H NMR (400 MHz, DMSO-d₆) δ 10.77 (s, 1H), 8.24 (s, 1H), 7.75 -7.73 (m, 1H), 7.44 (d, J = 8.6 Hz, 2H), 7.38 - 7.36 (m, 2H), 7.35 - 7.29 (m, 2H), 7.17 (d, J = 8.6 Hz, 2H), 4.75 (s, 4H), 3.55 - 3.49 (m, 1H), 2.44 - 2.39 (m, 1H), 1.91 - 1.75 (m, 4H), 1.62 - 1.55 (m, 2H), 1.53 - 1.47 (m, 2H), 1.47 (s, 9H). EXAMPLE 21 - SYNTHESIS OF TERT-BUTYL ((4-(4-(5-FLUOROISOINDOLINE-2- CARBOXAMIDO)PHENYL)-3,6-DIHYDROPYRIDIN-1(2H)-YL)SULFONYL) CARBAMATE (I-108) [0726] Step 1: Synthesis of tert-butyl ((4-(dimethyl-l4-azaneylidene)pyridin-1(4H)- yl)sulfonyl)carbamate (23-9): To a stirred solution of 2-methylpropan-2-ol (23-1a) (0.5 g, 6.746 mmol) in DCM (5 mL) was added chlorosulfonyl isocyanate (23-2b) (0.95 g, 6.746 mmol) and N,N-dimethylpyridin-4-amine (1.648 g, 13.49 mmol) at 0 ^oC. The mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was filtered and the solid was washed with heptane twice to afford compound 23-9 (1.8 g, 90% yield) as an off-white solid. [0727] Step 2: Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (23-3): A mixture of compound 23-1 (10.0 g, 58.13 mmol), compound 23-2 (21.57 g, 69.75 mmol), and Cs₂CO₃ (40.3 g, 186.02 mmol) in 1,2-DME:H₂O (10:1, 110 mL) was degassed with argon for 5 minutes. Pd2(dppf)Cl2 (2.238 g, 2.90 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred for 15 minutes while degassing with argon, and then the reaction mixture was heated to 90 ^oC and stirred for 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with ethyl acetate. The organic layer was mixed with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluting with 35% EtOAc in heptane) to afford the title compound 23-3 (9.0 g, 32.80 mmol, 56.42% yield) as an off white solid. [0728] Step 3: Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (23-5): To a stirred solution of compound 23-3 (6.0 g, 22 mmol) in DCM (100 mL) was added pyridine (3.6 mL, 44 mmol) and DMAP (0.27 g, 2.2 mmol) at room temperature and then compound 23-4 (3.3 mL, 26 mmol) was added at 0 ^oC. Then the reaction mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure) to give the crude compound 23-5 (8.60 g, 22 mmol, 100% yield) as an off white solid. [0729] Step 4: Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (23-7): To a stirred solution of compound 23-5 (2.35 g, 5.96 mmol) and compound 23-6 (0.89 g, 6.55 mmol) in DMF (25 mL) at room temperature was added DIPEA (5.20 mL, 29.8 mmol) and then the reaction mixture was stirred at room temperature for 4 hours under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether and n-pentane, filtered and dried under reduced pressure to afford the title compound 23-7 (2.4 g, 5.5 mmol, 92% yield) as a pale-yellow solid. [0730] Step 5: Synthesis of 5-fluoro-N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl) isoindoline-2-carboxamide hydrochloride (23-8): To a stirred solution of compound 23-7 (2.4 g, 5.5 mmol) in 1,4-dioxane (20 mL) was added 4 M HCl in 1,4-dioxane (20.62 mL, 82.5 mmol) at 0 ^oC and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (10 mL) and then with pentane (5 mLx2), and then the solid compound was filtered and dried under reduced pressure to afford the desired compound 23-8 (1.60 g, 4.54 mmol, 83% yield) as a brown solid. [0731] Step 6: Synthesis of tert-butyl ((4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)- 3,6-dihydropyridin-1(2H)-yl)sulfonyl)carbamate (I-108): To a stirred solution of compound 23-8 (0.5 g, 1.482 mmol) and compound 23-9 (0.45 g, 1.482 mmol) in DCM (10 mL) were added DIPEA (0.39 mL, 2.223 mmol) and HATU (0.16 g, 0.40 mmol) at room temperature and then the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with cold water and extracted with DCM. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluting with 35% EtOAc in heptane) to afford of the title compound tert-butyl ((4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)-3,6-dihydropyridin- 1(2H)-yl)sulfonyl)carbamate (I-108, 25 mg, 0.048 mmol, 3.27% yield) as an off white solid. HPLC: Rt 7.384 min, purity: 95.30%; FA Xselect 18 min HPLC50DC), column: X-BRIDGE BEH PEP C18 (150X4.6) 3.5 ^m mobile phase A: 0.05% TFA in water mobile phase B: 0.05 % TFA in acetonitrile column temperature: 40°C flow rate: 1.0 ml/ min gradient: 0/05, 2/05, 8/95, 12/95, 15/0517.50/0518/05 diluent: ACN: water (80:20). LCMS: 517.34 (M+H), Rt 2.09 min, 95.10%; Method G.¹H NMR (400 MHz, DMSO-d₆) δ11.03 (s, 1H), 8.41 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.39 (dd, J = 5.1, 8.4 Hz, 1H), 7.34 (d, J = 8.6 Hz, 2H), 7.23 (dd, J = 2.0, 9.0 Hz, 1H), 7.17 - 7.10 (m, 1H), 6.10 (s, 1H), 4.74 (d, J = 11.4 Hz, 4H), 3.94 (d, J = 1.9 Hz, 2H), 3.46 (t, J = 5.6 Hz, 2H), 2.57 - 2.53 (m, 2H), 1.38 (s, 9H).

EXAMPLE 22 - SYNTHESIS OF 5-FLUORO-N-(4-(1-((2-(2-(2-METHOXYETHOXY) ETHOXY)ETHYL)SULFONYL)PIPERIDIN-4-YL)PHENYL)ISOINDOLINE-2- CARBOXAMIDE (I-93) [0732] Step 1: Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (24-3): A mixture of compound of compound 24-1 (2.00 g, 11.6 mmol), compound 24-2 (4.31 g, 14.0 mmol) and Cs₂CO₃ (11.4 g, 34.9 mmol) in 1,4-dioxane:H₂O (1:1, 20 mL) was degassed with argon for 5 minutes. X-Phos (0.56 g, 1.16 mmol) and Pd2(dba)3 (0.55 g, 0.581 mmol) were added to the reaction mixture at room temperature. The reaction mixture was stirred for 15 minutes while degassing with argon, and then the reaction mixture was heated to 100 ^oC and stirred for 16 h. After completion of the reaction (monitored by TLC), the volatiles were evaporated under vacuum to obtain the crude. The crude was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by Combi flash chromatography using 45% EtOAc in heptane as the eluent to afford the title compound 24- 3 (2.0 g, 7.28 mmol, 62.7% yield) as an off white solid. [0733] Step 2: Synthesis of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (24-4): To a stirred solution of compound 24-3 (2.50 g, 9.1 mmol) in ethanol (20 mL) was added 10% palladium on carbon (0.5 g, 4.69 mmol) and the reaction mixture was stirred at room temperature for 16 h under a hydrogen atmosphere at 50 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with ethyl acetate. The organic layer was concentrated under reduced pressure to afford the title crude compound 24-4 (2.4 g, 8.68 mmol, 95% yield) as a pale yellow solid. [0734] Step 3: Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)piperidine- 1-carboxylate (24-6): To a stirred solution of compound 24-4 (2.40 g, 8.68 mmol) in DCM (30 mL) was added pyridine (1.4 mL, 17.4 mmol) at room temperature, and compound 24-5 (1.27 mL, 10.4 mmol) and DMAP (0.010 g, 0.086 mmol) were added at 0 ^oC, and then the reaction mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether and n-pentane, and the solids were filtered and dried under reduced pressure to afford the title compound 24-6 (3.1 g, 7.8 mmol, 90% yield) as a pale yellow solid. [0735] Step 4: Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) piperidine-1-carboxylate (24-8): To a stirred solution of compound 24-6 (3.1 g, 7.8 mmol) in DMF (30 mL) were added compound 24-7 (1.3 g, 9.4 mmol) and DIPEA (5.5 mL, 31 mmol) at room temperature and then the reaction mixture was stirred at 80 ^oC for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ice cold water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude compound was purified by Combi Flash chromatography (eluting with 2 to 5% MeOH in DCM) to afford the title compound 24-8 (3.0 g, 6.8 mmol, 87% yield) as a pale brown solid. [0736] Step 5: Synthesis of 5-fluoro-N-(4-(piperidin-4-yl)phenyl)isoindoline-2- carboxamide hydrochloride (24-9): To a stirred solution of compound 24-8 (4.0 g, 9.1 mmol) in DCM (40 mL) was added 4 M HCl in 1,4-dioxane (22.75 mL, 91 mmol) slowly at 0 ^oC and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (10 mL) and then with pentane (5 mLx2), and then the solid compound was filtered and dried under reduced pressure to afford the desired compound 24-9 (2.8 g, 8.2 mmol, 91% yield) as a pale yellow solid. [0737] Step 6: Synthesis of 5-fluoro-N-(4-(1-(vinylsulfonyl)piperidin-4-yl)phenyl) isoindoline-2-carboxamide (24-11): To a stirred solution of compound 24-9 (0.2 g, 0.562 mmol) in DCM (4 mL) was added triethylamine (0.23 mL, 1.68 mmol), followed by compound 24-10 (0.107 g, 0.844 mmol) drop wise at 0 ˚C and the reaction mixture was stirred to room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was directly evaporated under reduced pressure to afford the crude compound 24-11 (0.245 g, 0.549 mmol, 97.70% yield) as an orange solid. The crude compound was used in the next step without purification. [0738] Step 7: Synthesis of 5-fluoro-N-(4-(1-((2-(2-(2-methoxyethoxy)ethoxy)ethyl) sulfonyl)piperidin-4-yl)phenyl)isoindoline-2-carboxamide (I-93): To the stirred solution sodium hydride (0.018 g, 0.698 mmol) in THF (4 mL) was added 2-(2-methoxyethoxy)ethan-1-ol 24-12 (0.067 g, 0.558 mmol) at 0 ˚C and the reaction mixture was stirred for 30 min, and then compound 24-11 (0.2 g, 0.465 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction (monitored by TLC), the volatiles were evaporated under vacuum to obtain the crude. The crude was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by Prep HPLC purification to afford the desired compound 5-fluoro-N-(4-(1-((2-(2-(2- methoxyethoxy)ethoxy)ethyl)sulfonyl)piperidin-4-yl)phenyl)isoindoline-2-carboxamide (I-93, 18 mg, 0.032 mmol, 7.03% yield) as an off white solid. HPLC: Rt 7.747 min, purity: 99.89%, column: X-Select CSH C18 (4.6*150) mm x 5 ^m mobile phase: A - 0.1% formic acid in water : acetonitrile(95:05) B - acetonitrile flow rate: 1.0. mL/minute gradient: time(min)/ B Conc. : 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. LCMS: 550 (M+H), Rt 1.40 min, 99.88%; method details: column: CORTECS UPLC C18 (3*30)mm, 1.6um flow rate: 0.85 mL/min; mobile phase A: 0.05% TFA in water mobile phase B: 0.05% TFA in acetonitrile column temp.: 45°C; gradient program time/B: 0.0/3, 0.1/3,1.4/97, 2.0/97, 2.05/3,2.5/3.¹H NMR (400 MHz, DMSO-d₆) δ 8.29 (s, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.38 (dd, J = 5.3, 8.4 Hz, 1H), 7.23 (dd, J = 2.3, 9.0 Hz, 1H), 7.16 - 7.10 (m, 3H), 4.73 (d, J = 11.4 Hz, 4H), 3.75 (t, J = 6.1 Hz, 2H), 3.68 (br d, J = 11.8 Hz, 2H), 3.57 - 3.51 (m, 6H), 3.46 - 3.41 (m, 2H), 3.35 - 3.33 (m, 2H), 3.23 (s, 3H), 2.96 - 2.85 (m, 3H), 2.59 (d, J = 4.1 Hz, 1H), 1.86 - 1.79 (m, 2H), 1.66 - 1.57 (m, 2H). EXAMPLE 23 - SYNTHESIS OF N-(4-(1-((2,5,8,11-TETRAOXATRIDECAN-13- YL)SULFONYL)PIPERIDIN-4-YL)PHENYL)-5-FLUOROISOINDOLINE-2- CARBOXAMIDE (I-88) [0739] Step 1: Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (25-3): A mixture of compound of compound 25-1 (5.00 g, 29.06 mmol), compound 25-2 (10.19 g, 31.97 mmol) and K₃PO₄ (20.15 g, 93.012 mmol) in 1,2-DME:H₂O (10:1, 110 mL) was degassed with argon for 5 minutes. Pd2(dppf)Cl2.DCM (1.21 g, 1.45 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred for 15 minutes while degassing with argon, and then the reaction mixture was heated to 90 ^oC and stirred for 16 hours. After completion of the reaction (monitored by TLC), the volatiles were evaporated under vacuum to obtain the crude product. The crude product was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by Combi flash chromatography using 35% EtOAc in heptane as the eluent to afford the title compound 25-3 (4.0 g, 14.58 mmol, 50.15% yield) as an off white solid. [0740] Step 2: Synthesis of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (25-4): To a stirred solution of compound 25-3 (5.0 g, 18.22 mmol) in methanol (20 mL) was added 10% palladium on carbon (2.5 g) and the reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere at 50 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with ethyl acetate. The organic layer was concentrated under reduced pressure to afford the title crude compound 25-4 (5.0 g, 18.09 mmol, 99.28% yield) as an off white solid. [0741] Step 3: Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)piperidine- 1-carboxylate (25-6): To a stirred solution of compound 25-4 (5.0 g, 18.09 mmol) in DCM (2 mL) were added pyridine (2.90 mL, 36.18 mmol) at room temperature, and compound 25-5 (3.39 g, 21.71 mmol) and DMAP (0.232 g, 1.80 mmol)) were added at 0 ^oC. The reaction mixture was then stirred at room temperature for 16 hours under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether and n-pentane. The filtered solids were dried under reduced pressure to afford the title compound 25-6 (7.0 g, 17.65 mmol, 97.59% yield) as an off white solid. [0742] Step 4: Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) piperidine-1-carboxylate (25-8): To a stirred solution of compound 25-6 (3.50 g, 8.8 mmol) in DMF (30 mL) were added compound 25-7 (1.7 g, 9.7 mmol) and DIPEA (7.43 mL, 44 mmol) at room temperature and then the reaction mixture was heated to 90^oC for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was triturated with diethyl ether and n-pentane, filtered, and dried under reduced pressure to afford the title compound 25-8 (2.7 g, 6.14 mmol, 70% yield) as a brown solid. [0743] Step 5: Synthesis of 5-fluoro-N-(4-(piperidin-4-yl)phenyl)isoindoline-2- carboxamide hydrochloride (25-9): To a stirred solution of compound 25-8 (1.8 g, 4.1 mmol) in 1,4-dioxane (20 mL) was added 4 M HCl in 1,4-dioxane (10 mL, 41 mmol) slowly at 0 ^oC and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (8 mL) and then with pentane (4 mL x 2), and then the solid compound was filtered and dried under reduced pressure to afford the desired compound 25-9 (1.5 g, 4.0 mmol 97% yield) as a pale brown solid. [0744] Step 6: Synthesis of 5-fluoro-N-(4-(1-(vinylsulfonyl)piperidin-4-yl)phenyl) isoindoline-2-carboxamide (25-11): To a stirred solution of compound 25-9 (0.4 g, 1.125 mmol) in DCM (20 mL) was added DBU (4.71 g, 31 mmol) at 0 ˚C, followed by compound 25-10 (0.214 g, 1.68 mmol) dropwise and the reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction (monitored by TLC), the reaction mixture was directly evaporated under reduced pressure. The crude compound was purified by CombiFlash column chromatography using 15% MeOH in DCM as an eluent to afford title of compound 25-11 (0.49 g, 1.100 mmol, 97.70% yield) as a brown solid. [0745] Step 7: Synthesis of N-(4-(1-((2,5,8,11-tetraoxatridecan-13-yl)sulfonyl)piperidin-4- yl)phenyl)-5-fluoroisoindoline-2-carboxamide (I-88): To a stirred solution of NaH (60%) (0.0490 g, 1.013 mmol) in THF (15 mL) were added 2-(2-(2-methoxyethoxy)ethoxy)ethan-1-ol 25-12 (0.133 g, 0.810 mmol) followed by compound 25-11 (0.29 g, 0.675 mmol) at room temperature and then the reaction mixture was stirred at room temperature at for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by Prep HPLC purification to afford the desired compound N-(4-(1-((2,5,8,11-tetraoxatridecan-13- yl)sulfonyl)piperidin-4-yl)phenyl)-5-fluoroisoindoline-2-carboxamide (I-88, 25 mg, 0.042 mmol, 6.24% yield) as an off white solid. HPLC: Rt 6.892 min, purity: 95.80%, column: X-Select CSH C18 (4.6*150) mm x 5 ^m mobile phase: A - 0.1% TFA in water B - acetonitrile flow rate: 1.2. mL/minute column oven temp.: 30°C gradient: time(min)/ B Conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. LCMS: 594.14 (M+H), Rt 1.37 min, 95.36%; method details: column: CORTECS UPLC C18 (3*30) mm, 1.6 um; flow rate: 0.85 mL/min. Mobile phase A: 0.05% FA in water; mobile phase B: 0.05% FA in acetonitrile column temp.: 45°C; gradient program time/B: 0.0/3, 0.1/3, 1.4/97, 2.0/97, 2.05/3, 2.5/3.¹H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.38 (dd, J = 5.3, 8.3 Hz, 1H), 7.23 (dd, J = 2.1, 9.2 Hz, 1H), 7.16 - 7.11 (m, 3H), 5.30 (s, 1H), 4.73 (d, J = 11.7 Hz, 4H), 3.75 (t, J = 6.1 Hz, 2H), 3.71 - 3.64 (m, 2H), 3.58 - 3.54 (m, 4H), 3.54 - 3.49 (m, 6H), 3.44 - 3.40 (m, 2H), 3.38 - 3.34 (m, 2H), 3.23 (s, 3H), 2.95 - 2.87 (m, 2H), 2.60 - 2.54 (m, 1H), 1.87 - 1.78 (m, 2H), 1.66 - 1.54 (m, 2H). EXAMPLE 24 - SYNTHESIS OF N-(4-(1-(2-(DIMETHYLAMINO)-2-OXOACETYL) PIPERIDIN-4-YL)PHENYL)-5-FLUOROISOINDOLINE-2-CARBOXAMIDE (I-85) [0746] Step 1: Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (26-3): A mixture of compound of compound 26-1 (2.00 g, 11.6 mmol), compound 26-2 (4.31 g, 14.0 mmol), and Cs₂CO₃ (11.4 g, 34.9 mmol) in 1,4-dioxane:H₂O (1:1, 20 mL) was degassed with argon for 5 minutes. X-Phos (0.56 g, 1.16 mmol) and Pd2(dba)3 (0.55 g, 0.581 mmol) were added to the reaction mixture at room temperature. The reaction mixture was stirred for 15 minutes while degassing with argon, and then the reaction mixture was heated to 100 ^oC and stirred for 16 hours. After completion of the reaction (monitored by TLC), the volatiles were evaporated under vacuum to obtain the crude. The crude was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by Combi flash chromatography using 45% EtOAc in heptane as the eluent to afford the title compound 26- 3 (2.0 g, 7.28 mmol, 62.7% yield) as an off white solid. [0747] Step 2: Synthesis of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (26-4): To a stirred solution of compound 26-3 (2.00 g, 7.29 mmol) in ethanol (20 mL) was added 10% palladium on carbon (0.155 g, 1.46 mmol) and the reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere at 50 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with ethyl acetate. The organic layer was concentrated under reduced pressure to afford the title crude compound 26-4 (0.20 g, 5.8 mmol, 79% yield) as an off white solid. [0748] Step 3: Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)piperidine- 1-carboxylate (26-6): To a stirred solution of compound 26-4 (0.8 g, 2.89 mmol) in DCM (2 mL) were added pyridine (0.46 mL, 0.72 mmol) at room temperature and compound 26-5 (0.54 g, 3.473 mmol). DMAP (0.035 g, 0.289 mmol) was added at 0 ^oC, then the reaction mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether and n-pentane, and the solids were filtered and dried under reduced pressure to afford the title compound 26-6 (1.0 g, 2.52 mmol, 87.14% yield) as an off white solid. [0749] Step 4: Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) piperidine-1-carboxylate (26-8): To a stirred solution of compound 26-6 (1.12 g, 2.82 mmol) in DMF (4 mL) were added compound 26-7 (0.465 g, 3.39 mmol) and DIPEA (4.93 mL, 28.2 mmol) at room temperature and heated at 80 ^oC for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water, and the precipitated solids were filtered and washed with diethyl ether and n-pentane and dried under reduced pressure to afford the title compound 26-8 (0.85 g, 1.934 mmol, 68.5% yield) as a brown solid. [0750] Step 5: Synthesis of 5-fluoro-N-(4-(piperidin-4-yl)phenyl)isoindoline-2- carboxamide hydrochloride (26-9): To a stirred solution of compound 26-8 (0.85 g, 1.934 mmol) in 1,4-dioxane (10 mL) was added 4 M HCl in 1,4-dioxane (9.52 mL, 38 mmol) slowly at 0 ^oC and the reaction mixture was stirred at room temperature for 8 hours. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (10 mL) and then with pentane (5 mL x 2), and then the solid compound was filtered and dried under reduced pressure to afford the desired compound 26-9 (0.72 g, 0.336 mmol, 99% yield) as a brown solid. [0751] Step 6: Synthesis of N-(4-(1-(2-(dimethylamino)-2-oxoacetyl)piperidin-4-yl) phenyl)-5-fluoroisoindoline-2-carboxamide (I-85): To the stirred solution of 26-9 (0.08 g, 0.212 mmol) in DMF (1 mL) were added 2-(dimethylamino)-2-oxoacetic acid 26-10 (0.037 g, 0.698 mmol), HATU (0.1251 g, 0.3192 mmol) and DIPEA (0.11 mL, 0.63 mmol) at 0 ˚ C and the reaction mixture was stirred for 8 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water, and the precipitated solids were filtered and washed with diethyl ether and n-pentane and dried under reduced pressure to afford the title compound N- (4-(1-(2-(dimethylamino)-2-oxoacetyl)piperidin-4-yl)phenyl)-5-fluoroisoindoline-2-carboxamide (I-85, 45 mg, 0.102 mmol, 48.22% yield) as a pale brown solid. HPLC: Rt 7.448 min, purity: 95.43%, column: X-Bridge C18 (4.6*150) mm x 5 ^m mobile phase: A - 5 mM ammonium bicarbonate in water B - acetonitrile injection volume: 5.0µL, flow rate: 1.0 mL/minute. LCMS: 439.08 (M+H), Rt 1.26 min, 97.42%; method details: column : CORTECS UPLC C18 (3*30) mm, 1.6um flow rate: 0.85 mL/min. Mobile phase A: 0.05% FA in water; mobile phase B: 0.05% FA in acetonitrile; column temp.: 45°C; gradient program time/B: 0.0/3, 0.1/3, 1.4/97, 2.0/97, 2.05/3, 2.5/3.¹H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.47 (d, J = 8.7 Hz, 2H), 7.38 (dd, J = 5.2, 8.4 Hz, 1H), 7.22 (dd, J = 2.1, 9.0 Hz, 1H), 7.16 - 7.10 (m, 3H), 4.73 (br d, J = 11.5 Hz, 4H), 4.48 - 4.38 (m, 1H), 3.53 (br d, J = 13.4 Hz, 1H), 3.20 (dt, J = 2.4, 12.9 Hz, 1H), 2.93 (s, 3H), 2.88 (s, 3H), 2.77 (dq, J = 2.7, 12.9 Hz, 2H), 1.83 (br t, J = 11.2 Hz, 2H), 1.58 - 1.43 (m, 2H). EXAMPLE 25 - SYNTHESIS OF 4,6-DIFLUORO-N-(4-(1-(2-HYDROXY-2-METHYL- PROPANOYL)-1,2,3,6-TETRAHYDROPYRIDIN-4-YL)PHENYL) ISOINDOLINE-2- CARBOXAMIDE (I-75)

[0752] Step 1: Synthesis of tert-butyl 4-(4-nitrophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (27-3): A mixture of compound of compound 27-1 (2.0 g, 9.90 mmol), compound 27-2 (3.67 g, 11.88 mmol), and Cs2CO3 (6.48 g, 19.80 mmol) in 1,2-DME:H2O (10:1, 110 mL) was degassed with argon for 5 minutes. X-Phos (0.48 g, 0.99 mmol) and Pd2(dba)3 (0.47 g, 0.49 mmol) were added to the reaction mixture at room temperature. The reaction mixture was stirred for 15 minutes while degassing with argon, and then the reaction mixture was heated to 90 ^oC and stirred for 16 hours. After completion of the reaction (monitored by TLC), the volatiles were evaporated under vacuum to obtain the crude. The crude was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by Combi flash chromatography using 50-60% EtOAc in heptane as the eluent to afford the title compound 27-3 (2.2 g, 7.2 mmol, 73% yield) as a pale-yellow solid. [0753] Step 2: Synthesis of 4-(4-nitrophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (27-4): To a stirred solution of compound 27-3 (2.2 g, 7.2 mmol) in 1,4-dioxane (20 mL) was added 4 M HCl in 1,4-dioxane (18 mL, 72 mmol) slowly at 0 ^oC and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (8 mL) and then with n-pentane (4 mL x 2), and then the solid compound was filtered and dried under reduced pressure to afford the desired compound 27-4 (1.8 g, 7.5 mmol 100% yield) as an off white solid. [0754] Step 3: Synthesis of 2-hydroxy-2-methyl-1-(4-(4-nitrophenyl)piperidin-1- yl)propan-1-one (27-6): To a stirred solution of compound 27-4 (2.0 g, 8.31 mmol) in DMF (20 mL) were added compound 27-5 (1.03 g, 9.97 mmol) and DIPEA (4.35 mL, 24.92 mmol) at room temperature and the reaction mixture was stirred for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was triturated with diethyl ether and n-pentane, filtered, and dried under reduced pressure to afford the title compound 27-6 (2.0 g, 6.88 mmol, 82.91% yield) as an off white solid. [0755] Step 4: Synthesis of 1-(4-(4-aminophenyl)piperidin-1-yl)-2-hydroxy-2- methylpropan-1-one (27-7): To a stirred solution of compound 27-6 (1.0 g, 3.44 mmol) in DMF (10 mL) was added 4,4'-bipyridine (0.026 g, 0.17 mmol). Then added BBA (B₂OH₄, 1.55 g, 17.2 mmol) was slowly added portion wise at 0 ˚C and the reaction mixture was stirred at rt for 1 hour. The reaction mixture was quenched with ice water, the solid formed was filtered, dried under vacuum and washed with n-pentane and diethyl ether twice or thrice and dried under vacuum to afford compound 27-7 (0.63 g, 2.42 mmol, 70.26% yield) as a pale brown solid. [0756] Step 5: Synthesis of phenyl (4-(1-(2-hydroxy-2-methylpropanoyl)-1,2,3,6- tetrahydropyridin-4-yl)phenyl)carbamate (27-9): To a stirred solution of compound 27-7 (0.62 g, 2.38 mmol) in DCM (13 mL) was added pyridine (0.38 mL, 4.74 mmol) at room temperature. Compound 27-8 (0.45 g, 2.858 mmol) and DMAP (0.029 g, 0.238 mmol) were added at 0 ^oC then the reaction mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether and n-pentane. The solids were filtered and dried under reduced pressure to afford the title compound 27-9 (0.63 g, 1.656 mmol, 69.53% yield) as a pale brown solid. [0757] Step 6: Synthesis of 4,6-difluoro-N-(4-(1-(2-hydroxy-2-methylpropanoyl)-1,2,3,6- tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide (I-75): To a stirred solution of compound 27-9 (0.07 g, 0.184 mmol) in DMF (1 mL) were added compound 27-10 (0.034 g, 0.221 mmol) and DIPEA (0.16 mL, 0.92 mmol) at room temperature and heated at 80 ^oC for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was triturated with diethyl ether and n-pentane, filtered and dried under reduced pressure to afford the title compound 4,6-difluoro-N-(4-(1-(2-hydroxy-2-methylpropanoyl)-1,2,3,6- tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide (I-75, 52 mg, 0.117 mmol, 64.01% yield) as a pale-yellow solid. HPLC: Rt 7.523 min, 95.06%, column: X-Select CSH C18 (4.6*150) mm x 5 ^m mobile phase: A - 0.1% TFA in water B - acetonitrile flow rate: 1.2 mL/minute; column oven temp.: 30°C gradient: time(min)/ B Conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/55. LCMS: 442.07 (M+H), Rt 1.34 min, 95.34%; method details: column: CORTECS UPLC C18 (3*30) mm, 1.6 um flow rate: 0.85 mL/min. mobile phase A: 0.05% FA in water; mobile phase B: 0.05% FA in acetonitrile; column temp.: 45°C; gradient program time/B: 0.0/3, 0.1/3,1.4/97, 2.0/97, 2.05/3, 2.5/3.¹H NMR (400 MHz, DMSO-d₆) δ 8.46 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H), 7.22 - 7.12 (m, 2H), 6.13 (s, 1H), 5.43 (s, 1H), 4.79 (s, 4H), 4.60 - 3.51 (m, 4H), 2.47 - 2.38 (m, 2H), 1.34 (s, 6H). EXAMPLE 26 - SYNTHESIS OF N-(4-(1-(2-HYDROXY-2-METHYLPROPANOYL) PIPERIDIN-4-YL)PHENYL)-5,7-DIHYDRO-6H-PYRROLO[3,4-B]PYRAZINE-6- CARBOXAMIDE (I-68) [0758] Step 1: Synthesis of tert-butyl 4-(4-nitrophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (28-3): A mixture of compound of compound 28-1 (2.0 g, 9.90 mmol), compound 28-2 (3.67 g, 11.88 mmol) and Cs₂CO₃ (6.48 g, 19.80 mmol) in 1,2-DME:H₂O (10:1, 110 mL) was degassed with argon for 5 minutes. X-Phos (0.48 g, 0.99 mmol) and Pd2(dba)3 (0.47 g, 0.49 mmol) were added to the reaction mixture at room temperature. The reaction mixture was stirred for 15 minutes while degassing with argon, and then the reaction mixture was heated to 90 ^oC and stirred for 16 hours. After completion of the reaction (monitored by TLC), the volatiles were evaporated under vacuum to obtain the crude. The crude was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by Combi flash chromatography using 50-60% EtOAc in heptane as the eluent to afford the title compound 28-3 (2.2 g, 7.2 mmol, 73% yield) as a pale-yellow solid. [0759] Step 2: Synthesis of 4-(4-nitrophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (28-4): To a stirred solution of compound 28-3 (2.2 g, 7.2 mmol) in 1,4-dioxane (20 mL) was added 4 M HCl in 1,4-dioxane (18 mL, 72 mmol) slowly at 0 ^oC and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (8 mL) and then with n-pentane (4 mL x 2), and then the solid compound was filtered and dried under reduced pressure to afford the desired compound 28-4 (1.8 g, 7.5 mmol 100% yield) as an off white solid. [0760] Step 3: Synthesis of 2-hydroxy-2-methyl-1-(4-(4-nitrophenyl)piperidin-1- yl)propan-1-one (28-6): To a stirred solution of compound 28-4 (2.0 g, 8.31 mmol) in DMF (20 mL) were added compound 28-5 (1.03 g, 9.97 mmol) and DIPEA (4.35 mL, 24.92 mmol) at room temperature and stirred for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was triturated with diethyl ether and n-pentane, filtered, and dried under reduced pressure to afford the title compound 28-6 (2.0 g, 6.88 mmol, 82.91%yield) as an off white solid. [0761] Step 4: Synthesis of 1-(4-(4-aminophenyl)piperidin-1-yl)-2-hydroxy-2-methyl propan-1-one (28-7): To a stirred solution of compound 28-6 (1.0 g, 3.44 mmol) in ethanol (10 mL) was added 10% palladium on carbon (0.5 g, 4.696 mmol) and the reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere at 50 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with ethyl acetate. The organic layer was concentrated under reduced pressure to afford the title crude compound 28-7 (0.52 g, 1.98 mmol, 57.53% yield) as an off white solid. [0762] Step 5: Synthesis of phenyl (4-(1-(2-hydroxy-2-methylpropanoyl)piperidin-4- yl)phenyl)carbamate (28-9): To a stirred solution of compound 28-7 (0.52 g, 1.98 mmol) in DCM (5 mL) was added pyridine (0.32 mL, 3.96 mmol) at room temperature and compound 28-8 (0.37 g, 2.37 mmol) and DMAP (0.024 g, 0.198 mmol)) were added at 0 ^oC, and then the reaction mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether and n-pentane. The solids were filtered and then dried under reduced pressure to afford the title compound 28-9 (0.51 g, 1.33 mmol, 67.30% yield) as an off white solid. [0763] Step 6: Synthesis of N-(4-(1-(2-hydroxy-2-methylpropanoyl)piperidin-4- yl)phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyrazine-6-carboxamide (I-68): To a stirred solution of compound 28-9 (0.1 g, 0.26 mmol) in DMF (1 mL) were added compound 28-10 (0.049 g, 0.312 mmol) and DIPEA (0.46 mL, 2.61 mmol) at room temperature and heated at 80 ^oC for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was triturated with diethyl ether and n-pentane, filtered, and dried under reduced pressure to afford the title compound N-(4-(1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl)phenyl)-5,7- dihydro-6H-pyrrolo[3,4-b]pyrazine-6-carboxamide (I-68, 30 mg, 0.073 mmol, 28.01% yield) as a pale brown solid. HPLC: Rt 5.846 min, 99.81%; column: X-Select CSH C18 (4.6*150) mm x 5 ^m mobile phase: A - 0.1% TFA in water B - acetonitrile flow rate: 1.2 mL/minute column oven temp.: 30°C gradient: time(min)/ B Conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. LCMS: 410.06 (M+H), Rt 1.00 min, 99.58%; method details: column: CORTECS UPLC C18 (3*30) mm, 1.6um flow rate: 0.85 mL/min. mobile phase A: 0.05% FA in water; mobile phase B: 0.05% FA in acetonitrile; column temp.: 45°C; gradient program time/B: 0.0/3, 0.1/3,1.4/97, 2.0/97, 2.05/3,2.5/3.¹H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 2H), 8.40 (s, 1H), 7.49 (d, J = 8.6 Hz, 2H), 7.14 (d, J = 8.5 Hz, 2H), 5.36 (s, 1H), 4.96 - 4.86 (m, 1H), 4.81 (s, 4H), 4.76 - 4.67 (m, 1H), 3.05 - 2.82 (m, 1H), 2.77 - 2.65 (m, 2H), 1.82 - 1.74 (m, 2H), 1.60 - 1.42 (m, 2H), 1.34 (s, 6H). EXAMPLE 27 - SYNTHESIS OF 5-FLUORO-N-(4-(1-(2-(2-(2-METHOXYETHOXY) ETHOXY)-2-METHYLPROPANOYL)-1,2,3,6-TETRAHYDROPYRIDIN-4-YL) PHENYL)ISOINDOLINE-2-CARBOXAMIDE (I-138) [0764] Step 1: Synthesis of 2-(2-(2-methoxyethoxy)ethoxy)-2-methylpropanoic acid (29-9): To a stirred solution of compound 29-1a (0.1 g, 0.59 mmol) in toluene (2 mL) were added compound 29-2b (2.87 g, 2.39 mmol) and DIPEA (0.21 mL, 1.19 mmol) at room temperature and heated at 40 ^oC for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the crude compound 29-9 (0.1 g, 0.48 mmol, 80.97% yield) as an off white semi-solid. [0765] Step 2: Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (29-3): A mixture of compound 29-1 (10.0 g, 58.13 mmol), compound 29-2 (21.57 g, 69.75 mmol) and Cs₂CO₃ (40.3 g, 186.02 mmol) in 1,2-DME:H₂O (10:1, 110 mL) was degassed with argon for 5 minutes. Pd2(dppf)Cl2.DCM complex (2.238 g, 2.90 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred for 15 minutes while degassing with argon, and then the reaction mixture was heated to 90 ^oC and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with ethyl acetate. The organic layer was mixed with water and the aqueous layer was then extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluting with 35% EtOAc in heptane) to afford the title compound 29-3 (9.0 g, 32.80 mmol, 56.42% yield) as an off white solid. [0766] Step 3: Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)-3,6-dihydro pyridine-1(2H)-carboxylate (29-5): To a stirred solution of compound 29-3 (6.0 g, 22 mmol) in DCM (100 mL) was added pyridine (3.6 mL, 44 mmol) and DMAP (0.27 g, 2.2 mmol) and stirred at room temperature. Compound 29-4 (3.3 mL, 26 mmol) was then added at 0 ^oC and then the reaction mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give the crude compound 29-5 (8.60 g, 22 mmol, 100% yield) as an off white solid. [0767] Step 4: Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)- 3,6-dihydropyridine-1(2H)-carboxylate (29-7): To a stirred solution of compound 29-5 (8.60 g, 22.0 mmol) and compound 29-6 (3.8 g, 22.0 mmol) in DMF (40 mL) at room temperature was added DIPEA (19 mL, 14.0 mmol) and then the reaction mixture was stirred at 80 ^oC for 3 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by Combi Flash chromatography (eluting with 40-50% EtOAc in Heptane) to afford the title compound 29-7 (8.40 g, 19.00 mmol, 88% yield) as an off-white solid. [0768] Step 5: Synthesis of 5-fluoro-N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl) isoindoline-2-carboxamide hydrochloride (29-8): To a stirred solution of compound 29-7 (8.40 g, 19.00 mmol) in 1,4-dioxane (40 mL) was added 4 M HCl in 1,4-dioxane (48 mL, 190 mmol) at 0 ^oC and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (20 mL) and then with pentane (10 mLx2), and then the solid compound was filtered and dried under reduced pressure to afford the desired compound 29-8 (6.0 g, 17.80 mmol, 93% yield) as an off white solid. [0769] Step 6: Synthesis of 5-fluoro-N-(4-(1-(2-(2-(2-methoxyethoxy)ethoxy)-2-methyl propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide (I-138): To a stirred solution of 2-(2-(2-methoxyethoxy)ethoxy)-2-methylpropanoic acid 29-9 (0.066 g, 0.321 mmol) in DMF (3 mL) were added N,N-diisopropylethylamine (1.86 mL, 10.7 mmol) and HATU (0.16 g, 0.40 mmol) at 0 ^oC and the reaction mixture was stirred at room temperature for 30 min. Then compound 29-8 (0.1 g, 0.267 mmol) was added at 0 ℃ and the reaction mixture was stirred at room temperature for 16 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with cold water and extracted with DCM. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by Prep-HPLC to afford the title compound 5-fluoro-N-(4-(1-(2-(2-(2-methoxyethoxy)ethoxy)-2-methylpropanoyl)- 1,2,3,6-tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide (I-138, 9.0 mg, 0.017 mmol, 6.40% yield) as a pale yellow solid. HPLC: Rt 7.796 min, purity: 95.06%, column: X-Select CSH C18 (4.6*150) mm x 5 ^m mobile phase: A - 0.1% TFA in water B - acetonitrile flow rate: 1.2 mL/minute column oven temp.: 30°C gradient: time(min)/ B Conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. LCMS: 526.1 (M+H), Rt 2.13 min, 93.36%; method details: column: X- Select CSH C18, (50mm*3.0mm,2.5µ) mobile phase A: 0.05% formic Acid in water; mobile phase B: 0.05% formic acid in acetonitrile; flow rate: 1.0mL/min; column temperature: 40°C gradient program (B%): 0.0/2, 0.3/2,2.0/98, 2.8/98, 3.0/2, 3.7/2.¹H NMR (400 MHz, DMSO-d6) δ8.39 (s, 1H), 7.55 (d, J = 8.6 Hz, 2H), 7.41 - 7.33 (m, 3H), 7.26 - 7.20 (m, 1H), 7.17 - 7.11 (m, 1H), 6.13 (s, 1H), 4.74 (d, J = 11.5 Hz, 4H), 4.58 (s, 1H), 4.15 - 4.02 (m, 2H), 3.74 - 3.67 (m, 1H), 3.56 - 3.40 (m, 9H), 3.23 (s, 3H), 2.47 - 2.41 (m, 1H), 1.36 (s, 6H). EXAMPLE 28 - SYNTHESIS OF 5-FLUORO-N-(4-(1-(2-(2-(2-METHOXY-ETHOXY) ETHOXY)-2-METHYLPROPANOYL)PIPERIDIN-4-YL)PHENYL) ISOINDOLINE-2- CARBOXAMIDE (I-139) Step 1: Synthesis of 2-(2-(2-methoxyethoxy)ethoxy)-2-methylpropanoic acid (30-10): To a stirred solution of compound 30-1a (0.15 g, 0.89 mmol) in 1,4-dioxane (3 mL) were added compound 30-2b (0.43 g, 3.59 mmol) and DIPEA (0.31 mL, 1.79 mmol) at room temperature and then the reaction mixture was heated at 60 ^oC for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to afford the crude compound 30-10 (0.12 g, 0.581 mmol, 64.779% yield) as a colorless liquid. Step 2: Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (30-3): A mixture of compound of compound 30-1 (5.00 g, 29.06 mmol), compound 30-2 (10.19 g, 31.97 mmol), and K3PO4 (20.15 g, 93.012 mmol) in 1,2-DME:H2O (10:1, 110 mL) was degassed with argon for 5 minutes. Pd₂(dppf)Cl₂.DCM (1.21 g, 1.45 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred for 15 min while degassing with argon, and then the reaction mixture was heated to 90 ^oC and stirred for 16 h. After completion of the reaction (monitored by TLC), the volatiles were evaporated under vacuum to obtain the crude. The crude was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by Combi flash chromatography using 35% EtOAc in heptane as the eluent to afford the title compound 30-3 (4.0 g, 14.58 mmol, 50.15% yield) as an off white solid. [0770] Step 3: Synthesis of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (30-4): To a stirred solution of compound 30-3 (5.0 g, 18.22 mmol) in methanol (20 mL) was added 10% palladium on carbon (2.5 g) and the reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere at 50 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with ethyl acetate. The organic layer was concentrated under reduced pressure to afford the title crude compound 30-4 (5.0 g, 18.09 mmol, 99.28% yield) as an off white solid. [0771] Step 4: Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)piperidine- 1-carboxylate (30-6): To a stirred solution of compound 30-4 (5.0 g, 18.09 mmol) in DCM (2 mL) was added pyridine (2.90 mL, 36.18 mmol) at room temperature and then compound 30-5 (3.39 g, 21.71 mmol) and DMAP (0.232 g, 1.80 mmol) were added at 0 ^oC and then the reaction mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether and n-pentane and the solids were filtered and dried under reduced pressure to afford the title compound 30-6 (7.0 g, 17.65 mmol, 97.59% yield) as an off white solid. [0772] Step 5: Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) piperidine-1-carboxylate (30-8): To a stirred solution of compound 30-6 (3.50 g, 8.8 mmol) in DMF (30 mL) were added compound 30-7 (1.7 g, 9.7 mmol) and DIPEA (7.43 mL, 44 mmol) at room temperature and heated at 90 ^oC for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was triturated with diethylether and n-pentane, filtered and dried under reduced pressure to afford the title compound 30-8 (2.7 g, 6.14 mmol, 70% yield) as a brown solid. [0773] Step 6: Synthesis of 5-fluoro-N-(4-(piperidin-4-yl)phenyl)isoindoline-2- carboxamide hydrochloride (30-9): To a stirred solution of compound 30-8 (2.7 g, 6.14 mmol) in 1,4-dioxane (20 mL) was added 4 M HCl in 1,4-dioxane (15 mL, 61.4 mmol) slowly at 0 ^oC and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (10 mL) and then with pentane (5 mL x 2), and then the solid compound was filtered and dried under reduced pressure to afford the desired compound 30-9 (2.10 g, 6.19 mmol, 100% yield) as a brown solid. [0774] Step 7: Synthesis of 5-fluoro-N-(4-(1-(2-(2-(2-methoxyethoxy)ethoxy)-2-methyl propanoyl)piperidin-4-yl)phenyl)isoindoline-2-carboxamide (I-139): To the stirred solution of 2-(2-(2-methoxyethoxy)ethoxy)-2-methylpropanoic acid (30-10, 0.065 g, 1.33 mmol) in DMF (3 mL) was added HATU (0.154 g, 0.399 mmol), DIPEA (0.23 mL, 0.63 mmol) and compound 30- 9 (0.10 g, 0.266 mmol) at 0 ˚C and stirred for 8 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by Prep HPLC to afford the title compound 5-fluoro-N-(4-(1-(2-(2-(2-methoxyethoxy)ethoxy)-2-methylpropanoyl) piperidin-4-yl)phenyl)isoindoline-2-carboxamide (I-139, 13 mg, 0.024 mmol, 9.26% yield) as a pale yellow solid. HPLC: Rt 4.392 min, purity: 96.58%, column: Bakerbond Q2100 C18, 1.8 µm, 100 x 2.1 mm mobile phase A: 0.05% FA in water; mobile phase B: 0.05% FA in acetonitrile; column temperature: 40°C; flow rate: 0.6 ml/ min gradient: 0/5, 1/5, 5/95, 8.5/95, 8.8/5, 11/5. diluent: ACN: water. LCMS: 528.18 (M+H), Rt 1.38 min, 97.68%; Method F.¹H NMR (400 MHz, DMSO-d₆) δ 8.29 (s, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.38 (dd, J = 5.3, 8.3 Hz, 1H), 7.23 (dd, J = 2.0, 9.2 Hz, 1H), 7.17 - 7.10 (m, 3H), 4.90 - 4.83 (m, 1H), 4.73 (d, J = 11.6 Hz, 4H), 4.61 - 4.51 (m, 1H), 3.56 - 3.49 (m, 3H), 3.44 - 3.39 (m, 3H), 3.21 (s, 3H), 3.13 - 3.04 (m, 1H), 2.76 - 2.63 (m, 2H), 1.84 - 1.75 (m, 2H), 1.57 - 1.44 (m, 2H), 1.36 (s, 6H). EXAMPLE 29 - SYNTHESIS OF 4,7-DIFLUORO-N-(4-(1-(2-HYDROXY-2-METHYL- PROPANOYL)PIPERIDIN-4-YL)PHENYL)ISOINDOLINE-2-CARBOXAMIDE (I-65) [0775] To a stirred solution of 4,7-difluoro-N-(4-(1-(2-hydroxy-2-methylpropanoyl)-1,2,3,6- tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide (0.025 g, 0.056 mmol) in THF (2 mL), was added 10% palladium on carbon (0.072 g, 0.067 mmol) and the reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere at 50 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with ethyl acetate. The organic layer was concentrated under reduced pressure. The crude compound was purified by prep-HPLC to afford 4,7-difluoro-N-(4-(1-(2-hydroxy-2- methylpropanoyl)piperidin-4-yl)phenyl)isoindoline-2-carboxamide (I-65, 8.0 mg, 0.018 mmol, 31.86% yield) as an off white solid. HPLC: Rt 7.581min, 97.74%, column: X-Select CSH C18 (4.6*150) mm x 5 ^m mobile phase: A - 0.1% TFA in water B - acetonitrile flow rate: 1.2. mL/minute column oven temp.: 30 °C gradient: time(min)/ B Conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5, 18.0/5. LCMS: 444.00 (M+H); Method F.¹H NMR (400 MHz, DMSO- d₆) δ 8.40 (s, 1H), 7.48 (d, J = 8.6 Hz, 2H), 7.22 (t, J = 6.0 Hz, 2H), 7.13 (d, J = 8.6 Hz, 2H), 5.36 (s, 1H), 4.83 (s, 4H), 3.26 - 3.20 (m, 2H), 3.05 - 2.83 (m, 2H), 2.75 - 2.69 (m, 1H), 1.83 - 1.72 (m, 2H), 1.59 - 1.46 (m, 2H), 1.33 (s, 6H). EXAMPLE 30 - SYNTHESIS OF 5-FLUORO-N-(4-(1-((2-(2-HYDROXYETHOXY) ETHYL)SULFONYL)PIPERIDIN-4-YL)PHENYL)ISOINDOLINE-2-CARBOXAMIDE

[0776] Step 1: Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (32-3): A mixture of compound of compound 32-1 (5.00 g, 29.06 mmol), compound 32-2 (10.19 g, 31.97 mmol) and K3PO4 (20.15 g, 93.012 mmol) in 1,2-DME:H2O (10:1, 110 mL) was degassed with argon for 5 minutes. Pd2(dppf)Cl2.DCM (1.21 g, 1.45 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred for 15 min while degassing with argon, and then the reaction mixture was heated to 90 ^oC and stirred for 16 h. After completion of the reaction (monitored by TLC), the volatiles were evaporated under vacuum to obtain the crude. The crude was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by CombiFlash chromatography using 35% EtOAc in heptane as the eluent to afford the title compound 32-3 (4.0 g, 14.58 mmol, 50.15% yield) as an off white solid. [0777] Step 2: Synthesis of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (32-4): To a stirred solution of compound 32-3 (5.0 g, 18.22 mmol) in methanol (20 mL) was added 10% palladium on carbon (2.5 g) and the reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere at 50 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with ethyl acetate. The organic layer was concentrated under reduced pressure to afford the title crude compound 32-4 (5.0 g, 18.09 mmol, 99.28% yield) as an off white solid. [0778] Step 3: Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)piperidine- 1-carboxylate (32-6): To a stirred solution of compound 32-4 (5.0 g, 18.09 mmol) in DCM (2 mL) was added pyridine (2.90 mL, 36.18 mmol) at room temperature and compound 32-5 (3.39 g, 21.71 mmol) and DMAP (0.232 g, 1.80 mmol) were added at 0 ^oC, and then the reaction mixture was stirred at room temperature for 16 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether and n-pentane and the solids were filtered and dried under reduced pressure to afford the title compound 32-6 (7.0 g, 17.65 mmol, 97.59% yield) as an off white solid. [0779] Step 4: Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido) phenyl)piperidine-1-carboxylate (32-8): To a stirred solution of compound 32-6 (3.50 g, 8.8 mmol) in DMF (30 mL) were added compound 32-7 (1.7 g, 9.7 mmol) and DIPEA (7.43 mL, 44 mmol) at room temperature and heated at 90 ^oC for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was triturated with diethyl ether and n-pentane, filtered and dried under reduced pressure to afford the title compound 32-8 (2.7 g, 6.14 mmol, 70% yield) as a brown solid. [0780] Step 5: Synthesis of 5-fluoro-N-(4-(piperidin-4-yl)phenyl)isoindoline-2- carboxamide hydrochloride (32-9): To a stirred solution of compound 32-8 (2.7 g, 6.14 mmol) in 1,4-dioxane (20 mL) was added 4 M HCl in 1,4-dioxane (15 mL, 61.4 mmol) slowly at 0 ^oC and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (10 mL) and then with pentane (5 mL X 2), and then the solid compound was filtered and dried under reduced pressure to afford the desired compound 32-9 (2.10 g, 6.19 mmol, 100% yield) as a brown solid. [0781] Step 6: Synthesis of 5-fluoro-N-(4-(1-(vinylsulfonyl)piperidin-4-yl)phenyl) isoindoline-2-carboxamide (32-11): To the stirred solution of compound 32-9 (2.1 g, 6.2 mmol) in DCM (20 mL) was added DBU (4.71 g, 31 mmol) at 0 ˚C, followed by compound 32-10 (0.85 g, 6.8 mmol) drop wise and the reaction mixture was stirred to room temperature for 3 hours. After completion of the reaction (monitored by TLC), the reaction mixture was directly evaporated under reduced pressure. The crude compound was purified by CombiFlash column chromatography using 15% MeOH in DCM as an eluent to afford title of compound 32-11 (0.4 g, 0.931 mmol, 15% yield) as a brown gummy mass. [0782] Step 7: Synthesis of 5-fluoro-N-(4-(1-((2-(2-hydroxyethoxy)ethyl)sulfonyl) piperidin-4-yl)phenyl)isoindoline-2-carboxamide (I-55): To the stirred solution of NaH (60%) (0.014 g, 0.349 mmol) in THF (5 mL) were added ethane-1,2-diol 32-12 (0.017 g, 0.279 mmol) followed by compound 32-11 (0.01 g, 0.232 mmol) at room temperature and then the reaction mixture was stirred at room temperature at for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by Prep HPLC purification to afford the desired compound 5-fluoro-N-(4-(1-((2-(2-hydroxyethoxy)ethyl)sulfonyl)piperidin-4-yl) phenyl)isoindoline-2-carboxamide (I-55, 4.10 mg, 0.008 mmol, 3.6% yield) as a white solid. HPLC: Rt 6.331 min, purity: 98.41%, column: X-Select CSH C18 (4.6*150) mm x 5 ^m; mobile phase: A - 0.1% TFA in water; B – acetonitrile; flow rate: 1.2 mL/minute; column oven temp.: 30 °C; gradient: time(min)/ B conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. LCMS: 492.10 (M+H), Rt 1.27 min, 98.93%; Method F.¹H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.47 (d, J = 8.5 Hz, 2H), 7.38 (dd, J = 5.4, 8.6 Hz, 1H), 7.25 - 7.20 (m, 1H), 7.16 - 7.11 (m, 3H), 4.73 (d, J = 12.4 Hz, 4H), 4.62 (t, J = 5.3 Hz, 1H), 3.76 (t, J = 6.1 Hz, 2H), 3.71 - 3.64 (m, 2H), 3.56 - 3.51 (m, 2H), 3.49 - 3.45 (m, 2H), 3.36 - 3.33 (m, 2H), 2.95 - 2.87 (m, 2H), 2.62 - 2.57 (m, 1H), 1.88 - 1.77 (m, 2H), 1.64 - 1.56 (m, 2H). EXAMPLE 31 - SYNTHESIS OF 5-FLUORO-N-(4-(1-((2-(2-(2-HYDROXYETHOXY) ETHOXY)ETHYL)SULFONYL)PIPERIDIN-4-YL)PHENYL)ISOINDOLINE-2- CARBOXAMIDE (I

[0783] Step 1: Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (33-3): A mixture of compound of compound 33-1 (5.0 g, 29.06 mmol), compound 33-2 (10.19 g, 31.97 mmol) and K₃PO₄ (20.15 g, 93.012 mmol) in 1,2-DME:H₂O (10:1, 110 mL) was degassed with argon for 5 minutes. Pd2(dppf)Cl2.DCM (1.21 g, 1.45 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred for 15 min while degassing with argon, and then the reaction mixture was heated to 90 ^oC and stirred for 16 h. After completion of the reaction (monitored by TLC), the volatiles were evaporated under vacuum to obtain the crude. The crude was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by Combi flash chromatography using 35% EtOAc in heptane as the eluent to afford the title compound 33-3 (4.0 g, 14.58 mmol, 50.15% yield) as an off white solid. [0784] Step 2: Synthesis of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (33-4): To a stirred solution of compound 33-3 (5.0 g, 18.22 mmol) in methanol (20 mL) was added 10% palladium on carbon (2.5 g) and the reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere at 50 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with ethyl acetate. The organic layer was concentrated under reduced pressure to afford the title crude compound 33-4 (5.0 g, 18.09 mmol, 99.28% yield) as an off white solid. [0785] Step 3: Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)piperidine- 1-carboxylate (33-6): To a stirred solution of compound 33-4 (5.0 g, 18.09 mmol) in DCM (2 mL) was added pyridine (2.90 mL, 36.18 mmol) at room temperature and compound 33-5 (3.39 g, 21.71 mmol) and DMAP (0.232 g, 1.80 mmol) were added at 0 ^oC, and then the reaction mixture was stirred at room temperature for 16 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether and n-pentane and the solids were filtered and dried under reduced pressure to afford the title compound 33-6 (7.0 g, 17.65 mmol, 97.59% yield) as an off white solid. [0786] Step 4: Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido) phenyl)piperidine-1-carboxylate (33-8): To a stirred solution of compound 33-6 (3.50 g, 8.8 mmol) in DMF (30 mL) were added compound 33-7 (1.7 g, 9.7 mmol) and DIPEA (7.43 mL, 44 mmol) at room temperature and heated at 90 ^oC for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was triturated with diethylether and n-pentane, filtered and dried under reduced pressure to afford the title compound 33-8 (2.7 g, 6.14 mmol, 70% yield) as a brown solid. [0787] Step 5: Synthesis of 5-fluoro-N-(4-(piperidin-4-yl)phenyl)isoindoline-2- carboxamide hydrochloride (33-9): To a stirred solution of compound 33-8 (2.7 g, 6.14 mmol) in 1,4-dioxane (20 mL) was added 4 M HCl in 1,4-dioxane (15 mL, 61.4 mmol) slowly at 0 ^oC and the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (10 mL) and then with pentane (5 mL x 2), and then the solid compound was filtered and dried under reduced pressure to afford the desired compound 33-9 (2.10 g, 6.19 mmol, 100% yield) as a brown solid. [0788] Step 6: Synthesis of 5-fluoro-N-(4-(1-(vinylsulfonyl)piperidin-4-yl)phenyl) isoindoline-2-carboxamide (33-11): To the stirred solution of compound 33-9 (2.1 g, 6.2 mmol) in DCM (20 mL) was added DBU (4.71 g, 31 mmol) at 0 ˚C, followed by compound 33-10 (0.85 g, 6.8 mmol) and the reaction mixture was stirred to room temperature for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was directly evaporated under reduced pressure. The crude compound was purified by CombiFlash column chromatography using 15% MeOH in DCM as an eluent to afford title of compound 33-11 (0.4 g, 0.931 mmol, 15% yield) as a brown gummy mass. [0789] Step 7: Synthesis of 5-fluoro-N-(4-(1-((2-(2-(2-hydroxyethoxy)ethoxy) ethyl) sulfonyl)piperidin-4-yl)phenyl)isoindoline-2-carboxamide (I-54): To the stirred solution of NaH (60%) (0.018 g, 0.46 mmol) in THF (5 mL) were added ethane-2,2'-oxybis(ethan-1-ol) 33- 12 (0.029 g, 0.279 mmol) followed by compound 33-11 (0.01 g, 0.232 mmol) at room temperature and then reaction mixture was stirred at room temperature at for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was dilute with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by CombiFlash column chromatography using 15% MeOH in DCM as an eluent to afford the title of compound 5-fluoro- N-(4-(1-((2-(2-(2-hydroxyethoxy)ethoxy)ethyl)sulfonyl)piperidin-4-yl)phenyl)isoindoline-2- carboxamide (I-54, 4.0 mg, 0.0074 mmol, 3.21% yield) as a white solid. HPLC: Rt 6.332 min, purity: 95.38%, column: X-Select CSH C18 (4.6*150) mm x 5 ^m; mobile phase: A - 0.1% TFA in water B - acetonitrile flow rate: 1.2. mL/minute; column oven temp.: 30 °C gradient: time(min)/ B conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. LCMS: 536.0 (M+H), Rt 1.27 min, 98.30%; Method F.¹H NMR (400 MHz, DMSO-d₆) δ 8.29 (s, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.38 (dd, J = 5.1, 8.6 Hz, 1H), 7.23 (dd, J = 2.1, 9.1 Hz, 1H), 7.17 - 7.10 (m, 3H), 6.50 (s, 1H), 4.73 (d, J = 11.6 Hz, 4H), 4.57 (t, J = 5.4 Hz, 1H), 3.75 (t, J = 6.1 Hz, 2H), 3.71 - 3.65 (m, 2H), 3.58 - 3.54 (m, 3H), 3.50 (q, J = 4.9 Hz, 2H), 3.46 - 3.42 (m, 2H), 3.36 - 3.33 (m, 2H), 2.96 - 2.87 (m, 2H), 2.61 - 2.55 (m, 1H), 1.86 - 1.79 (m, 2H), 1.67 - 1.55 (m, 2H). 379 EXAMPLE 32 - SYNTHESIS OF (1R,4R)-4-(4-(4,6-DIFLUOROISOINDOLINE-2- CARBOXAMIDO)PHENYL)CYCLOHEXANE-1-CARBOXYLIC ACID (I-50) [0790] Step 1: Synthesis of (1r,4r)-4-phenylcyclohexane-1-carboxylic acid (37-2): To a stirred solution of compound 37-1 (10.0 g, 41.89 mmol) in methanol (50 mL) was added triethylamine (6.7 mL) and 10% palladium on carbon (50% wet, 3.3 g, 31 mmol) at rt. The reaction mixture was stirred at 50 ^oC for 18 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The combined organic layers were concentrated under reduced pressure to afford the title crude compound 37-2 (8.0 g, 39.16 mmol, 93.47% yield) as a white solid. The crude compound was used in the next step without further purification. LC-MS: MS calcd. for chemical formula C13H16O2: 204.27; Found: 203.14 [M+H]⁺; Method E: X-Select CSH- C18 (3.0x50mm, 2.5µm); mobile phase: A: 2.5mM NH₄HCO₃ in water; mobile phase: B: ACN; injection volume: 2 µL; (gradient) T/B%:0.0/2, 0.3/2, 2.0/98, 2.8/98, 3.0/2, 3.7/2; flow rate: 1 ml/min; column temp.: 40 °C. [0791] Step 2: Synthesis of (1r,4r)-4-(4-nitrophenyl)cyclohexane-1-carboxylic acid (37-3): A mixture of compound 37-2 (2.0 g, 9.79 mmol) and potassium nitrate (0.29 g, 2.94 mmol), was added sulphuric acid (20 mL, 45.6 mmol) dropwise at 0 ^oC. The reaction mixture was stirred for 30 min. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and the precipitated solid was filtered and dried under reduced pressure to afford the title crude compound 37-3 (1.7 g, 6.8 mmol, 70% yield) as a white solid. The crude compound was used in the next step without further purification. LC-MS: MS calcd. for chemical formula: C13H15NO4: 249.27; Found: 248.5 [M+H]⁺; Method E. [0792] Step 3: Synthesis of tert-butyl (1r,4r)-4-(4-nitrophenyl)cyclohexane-1-carboxylate (37-4): To a stirred solution of compound 37-3 (1.0 g, 4.01 mmol), in t-BuOH (10 mL) was added Boc-anhydride (1.57 g, 7.12 mmol) followed by DMAP (0.15 g, 1.20 mmol) at 0 ^oC and the reaction mixture was stirred at 80 ^oC for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with cold water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by CombiFlash (Nexgen-300) chromatography using a 12 g silica gel cartridge and 2-4% MeOH in DCM as the eluent to afford the title compound 37-4 (0.4 g, 1.31 mmol, 32.65% yield) as an off white solid. LC-MS: MS calcd. for chemical formula: C17H23NO4: 305.37; Found: 304.16 [M+H]⁺; Method E. [0793] Step 4: Synthesis of tert-butyl (1r,4r)-4-(4-aminophenyl)cyclohexane-1- carboxylate (37-5): To a stirred solution of compound 37-4 (0.5 g, 1.64 mmol) in ethanol (20 mL) was added 10% palladium on carbon (50% wet, 0.15 g 1.41 mmol) and the reaction mixture was stirred at rt for 16 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The combined organic layers were concentrated under reduced pressure to afford the crude compound 37-5 (0.35 g, 1.271 mmol, 77.63% yield) as a pale red solid. LC-MS: MS calcd. for chemical formula: C17H25NO2: 275.39; Found: 275.94 [M+H]⁺; Method F. [0794] Step 5: Synthesis of tert-butyl (1r,4r)-4-(4-((phenoxycarbonyl)amino) phenyl) cyclohexane-1-carboxylate (37-7): To a stirred solution of compound 37-5 (0.35 g, 1.271 mmol) in DCM (5 mL) was added pyridine (0.21 mL, 2.54 mmol) followed by phenyl chloroformate 37- 6 (0.24 g, 1.52 mmol) at 0 ^oC and then the reaction mixture was stirred at rt for 16 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure to afford the title crude compound 37-7 (0.25 g, 0.632 mmol, 49.74% yield) as a yellow solid. The crude compound was used in the next step without further purification. LC- MS : MS calcd. For chemical formula: C₂₄H₂₉NO₄: 395.5; Found: 396.02 [M+H]⁺; Method F. [0795] Step 6: Synthesis of tert-butyl (1r,4r)-4-(4-(4,6-difluoroisoindoline-2- carboxamido)phenyl)cyclohexane-1-carboxylate (37-9): To a stirred solution of compound 37- 7 (0.4 g, 1.01 mmol) and compound 37-8 (0.188 g, 1.21 mmol) in DMF (10 mL) was added DIPEA (0.9 mL, 5.06 mmol) at rt and then the reaction mixture was stirred at 80 ^oC for 1 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to afford the title crude compound 37-9 (0.2 g, 0.438 mmol, 43.32% yield) as an off-white solid. The crude compound was used in the next step without further purification. LC-MS: MS calcd. for chemical formula: C₂₆H₃₀F₂N₂O₃: 456.5; Found: 457.3 [M+H]⁺; Method F. [0796] Step 7: Synthesis of (1r,4r)-4-(4-(4,6-difluoroisoindoline-2-carboxamido)phenyl) cyclohexane-1-carboxylic acid (I-50): To the stirred solution of compound 37-9 (0.2 g, 0.438 mmol) in DCM (10 mL), was added trifluoroacetic acid (TFA) (1 mL) at 0 ^oC. The reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the organic layer was mixed with water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude residue was purified by prep-HPLC to afford the title compound (1r,4r)-4-(4-(4,6- difluoroisoindoline-2-carboxamido)phenyl)cyclohexane-1-carboxylic acid (I-50, 30 mg, 0.074 mmol, 17.10% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d6) δ 12.03 (s, 1H), 8.34 (s, 1H), 7.44 (d, J = 8.6 Hz, 2H), 7.23 - 7.08 (m, 4H), 4.77 (s, 4H), 2.45 - 2.39 (m, 1H), 2.29 - 2.13 (m, 1H), 1.98 (d, J = 7.8 Hz, 2H), 1.81 (d, J = 7.6 Hz, 2H), 1.48 - 1.40 (m, 4H). LCMS: ret. time : 1.40 min, 98.23%, MS calcd. for chemical formula: C22H22F2N2O3: 400.4; Found: 400.98 [M+H]⁺; Method F. HPLC: Rt 5.942 min, 99.93%; column: X-Select CSH C18 (4.6*150) mm x 5 ^m; mobile phase: A - 0.1% TFA in water B – ACN; flow rate: 1.2 mL/min; column oven temp.: 30 °C; gradient: time (min)/ B conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. Prep-HPLC purification method: no. of injections 7 (5.5 mg /inj) column: iCellulose 5 (30 x 250*4.6mm, 5u); mobile phase A: n-hexane; mobile phase B: IPA; eluent A: 50% & B: 50%; total flow rate (mL/min): 38 min; detection: 245 nm. EXAMPLE 33 – SYNTHESIS OF TERT-BUTYL 4-(4-(3-FLUORO-6,7-DIHYDRO-5H- PYRROLO[3,4-B]PYRIDINE-6-CARBOXAMIDO)PHENYL)PIPERIDINE-1- CARBOXYLATE (I-56) AND 3-FLUORO-N-(4-(1-(2-HYDROXY-2- METHYLPROPANOYL)PIPERIDIN-4-YL)PHENYL)-5,7-DIHYDRO-6H- PYRROLO[3,4-B]PYRIDINE-6-CARBOXAMIDE (I-95) [0797] Step 1: Preparation of tert-butyl 4-(4-((phenoxycarbonyl)amino) phenyl) piperidine-1-carboxylate (52-2): 52-2 was prepared according to General Procedure A using 52- 1 (10.0 g, 36.23 mmol) to yield 13 g of 52-2 (90% yield) as a white solid.¹H NMR (300 MHz, DMSO-d6) δ 10.15 (s, 1H), 7.59-7.34 (m, 4H), 7.33-7.07 (m, 5H), 4.07 (m, 2H), 3.01-2.56 (m, 4H), 1.73-1.68 (m, 2H), 1.51-1.47 (m, 1H), 1.43 (s, 9H). LC-MS: [M+H]⁺ = 397.20. Column: X Bridge C18 4.6*50mm*3.5um; Mobile Phase- A: 10 mm ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. [0798] Step 2: Preparation of tert-butyl 4-(4-(3-fluoro-6,7-dihydro-5H-pyrrolo[3,4- b]pyridine-6-carboxamido) phenyl)piperidine-1-carboxylate (I-56): I-56 was prepared according to General Procedure B using 52-3 (584 mg, 2.77 mmol) and 52-2 (1.0 g, 2.52 mmol) to yield 1.0 g of tert-butyl 4-(4-(3-fluoro-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-6-carboxamido) phenyl)piperidine-1-carboxylate (I-56, 90% yield) as a white solid.¹H NMR (300 MHz, DMSO- d₆) δ 8.48 (s, 1H), 8.37 (s, 1H), 7.79 (d, J = 7.5 Hz, 1H), 7.47 (d, J = 8.2 Hz, 2H), 7.13 (d, J = 8.1 Hz, 2H), 4.75 (d, J = 14.5 Hz, 4H), 3.92-3.85 (m, 3H), 3.01-2.52 (m, 4H), 1.75-1.71 (m, 2H), 1.42 (s, 9H). LCMS: 441.2 (M+H), purity: 98.87% by AUC, rt: 4.87, UV: 260 nm. Column: X Bridge C184.6*50mm*3.5um; mobile phase- A: 10 mM ammonium acetate B: 100% ACN; gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. [0799] Step 3: Preparation of 3-fluoro-N-(4-(piperidin-4-yl)phenyl)-5,7-dihydro-6H- pyrrolo[3,4-b]pyridine-6-carboxamide (52-5): 52-5 was prepared according to General Procedure C using I-56 (1.0 g, 2.27 mmol) to yield 680 mg of 52-5 (88% yield) as a white solid. ¹H NMR (300 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.35 (s, 1H), 7.80 (dd, J = 9.0, 2.6 Hz, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.11 (d, J = 8.5 Hz, 2H), 4.75 (d, J = 14.0 Hz, 4H), 3.11-2.98 (m, 3H), 2.61- 2.55 (m, 3H), 1.75-1.34 (m, 4H). LC-MS: [M+H]⁺ = 341.1. Column: X Bridge C18 4.6*50mm*3.5um; mobile phase- A: 10 mM ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. [0800] Step 4: Preparation of 3-fluoro-N-(4-(1-(2-hydroxy-2-methylpropanoyl)piperidin- 4-yl)phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide (I-95): I-95 was prepared according to General Procedure D using 52-5 (600 mg, 1.76 mmol) and 52-6 (366 mg, 3.52 mmol) to yield 410 mg of 3-fluoro-N-(4-(1-(2-hydroxy-2-methylpropanoyl)piperidin-4- yl)phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide (I-95, 55% yield) as an off- white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.37 (s, 1H), 7.80 (dd, J = 9.0, 2.7 Hz, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.13 (d, J = 8.6 Hz, 2H), 5.40 (s, 1H), 4.75 (d, J = 13.8 Hz, 5H), 2.88-2.56 (m, 3H), 1.73-1.68 (m, 5H), 1.33 (s, 6H). LCMS: 427.37 (M+H), purity: 97.21% by AUC, rt: 4.43, UV: 254 nm. LCMS method: Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mm Ammonium Acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; Flow rate: 0.6mL/min. HPLC: Purity- 97.25% by AUC, RT- 7.42, UV- 240 nm. HPLC method: Column: X Bridge C184.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH3CN; Flow rate: 1.2 mL/min; Diluent: Methanol (100%). EXAMPLE 34 – SYNTHESIS OF 3-FLUORO-N-(4-(1-(2-HYDROXY-2-METHYL- PROPANOYL)-1,2,3,6-TETRAHYDROPYRIDIN-4-YL)PHENYL)-5,7-DIHYDRO-6H- PYRROLO[3,4-B]PYRIDINE-6-CARBOXAMIDE (I-103) [0801] Step 1: Preparation of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (53-3): To a stirred solution of 53-2 (10.0 g, 58.14 mmol) and 53-1 (26.96 g, 87.2 mmol) in DMF (150 mL) was added sodium carbonate (12.3 g, 116.2 mmol, 2.0 M aqueous solution) and the reaction mixture was purged with argon for 10 min. Then Pd(TPP)₄ (3.3 g, 2.9 mmol) was added, and the reaction mixture was purged for 5 min. The reaction mixture was stirred at 90 °C for 6 h. After completion of the reaction, the reaction mixture was cooled to rt, diluted with ice cold water (500 mL) and extracted with ethyl acetate (3x250 mL). The combined organic layer was washed with a brine solution (2x100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product. The product was purified by combi-flash chromatography (eluent: 0-30% ethyl acetate in hexanes) to afford 8.0 g of 53-3 (50% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 7.11 (d, J = 9.0 Hz, 2H), 6.52 (d, J = 8.8 Hz, 2H), 5.88 (brs, 1H), 5.08 (brs, 2H), 3.91-3.96 (m, 2H), 3.53-3.44 (m, 2H), 2.34-2.39 (m, 2H), 1.42 (s, 9H). LC-MS: [M+H]⁺ = 275.2. Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mM ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. [0802] Step 2: Preparation of tert-butyl4-(4-((phenoxycarbonyl)amino)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (53-4): 53-4 was prepared using General Procedure A and tert-butyl 4-(4-aminophenyl)-3,6-dihydro pyridine-1(2H)-carboxylate (53-3) (4.8 g, 17.52 mmol). The product was obtained after filtration, which afforded 6.0 g of 53-4 (87% yield) as a white solid.¹H NMR (300 MHz, DMSO-d6) δ 10.27 (s, 1H), 7.54-7.08 (m, 9H), 6.11 (s, 1H), 3.99 (s, 2H), 3.70-3.40 (m, 2H), 2.44 (s, 2H), 1.42 (s, 9H). LC-MS: [M+H]⁺ = 395.20. Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mM ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. [0803] Step 3: Preparation of tert-butyl 4-(4-(3-fluoro-6,7-dihydro-5H-pyrrolo[3,4- b]pyridine-6-carboxamido) phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (53-6): 53-6 was prepared using General Procedure B and tert-butyl 4-(4-((phenoxycarbonyl) amino)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (53-4) (1.0 g, 2.53 mmol). The product was obtained after solid filtration, which afforded 900 mg of 53-6 (81% yield) as a white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.47 (d, J = 5.9 Hz, 2H), 7.80 (dd, J = 9.0, 2.4 Hz, 1H), 7.56 (d, J = 8.7 Hz, 2H), 7.40-7.28 (m, 2H), 6.08 (s, 1H), 4.76 (d, J = 13.1 Hz, 4H), 3.98 (s, 2H), 3.59-3.53 (m, 2H), 2.48- 2.42 (m, 2H), 1.43 (s, 9H). LC-MS: [M+H]⁺ = 439.20. Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mM ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. [0804] Step 4: Preparation of 3-fluoro-N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-5,7- dihydro-6H-pyrrolo[3,4-b] pyridine-6-carboxamide (53-7): 53-7 was prepared using General Procedure C and tert-butyl 4-(4-(3-fluoro-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-6- carboxamido)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (53-6) (900 mg, 2.05 mmol). 600 mg of 53-7 (86% yield) was obtained as a white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.45 (d, J = 14.9 Hz, 2H), 7.80 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 6.13 (s, 1H), 4.76 (d, J = 13.5 Hz, 4H), 3.23-2.58 (m, 4H), 2.34-2.3 (m, 2H). LC-MS: [M+H]⁺ = 339.20 [0805] Step 5: Preparation of 3-fluoro-N-(4-(1-(2-hydroxy-2-methylpropanoyl)-1,2,3,6- tetrahydropyridin-4-yl) phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide (I- 103): I-103 was prepared using General Procedure D and 3-fluoro-N-(4-(1,2,3,6- tetrahydropyridin-4-yl)phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide (53-7) (600 mg, 1.77 mmol). The product was obtained after filtration, which afforded 420 mg of 3- fluoro-N-(4-(1-(2-hydroxy-2-methylpropanoyl)-1,2,3,6-tetrahydropyridin-4-yl) phenyl)-5,7- dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide (I-103, 56% yield) as a white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.47 (d, J = 6.4 Hz, 2H), 7.80 (d, J = 6.8 Hz, 1H), 7.56 (d, J = 8.6 Hz, 2H), 7.37 (d, J = 8.7 Hz, 2H), 6.14 (s, 1H), 5.45 (s, 1H), 4.76 (d, J = 13.1 Hz, 4H), 4.6-3.5 (m, 4H), 2.53-2.49 (m, 2H), 1.34 (s, 6H). LCMS: 425.1 (M+H), purity- 96.13% by AUC, rt- 3.40, UV- 260 nm. Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mm ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. HPLC: purity- 95.81% by AUC, rt- 11.26, UV- 272 nm. Column: X Bridge C184.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH3CN; flow rate: 1.2 mL/min; Diluent: Methanol (100%). EXAMPLE 35 – SYNTHESIS OF 3-FLUORO-N-(4-(1-(METHYLSULFONYL)-1,2,3,6- TETRAHYDROPYRIDIN-4-YL)PHENYL)-5,7-DIHYDRO-6H-PYRROLO[3,4-B] PYRIDINE-6-CARBOXAMIDE (I-94) [0806] A stirred solution of 53-7 (100 mg, 0.34 mmol) in DCM (5.0 mL) was added DIPEA (0.23 mL, 1.36 mmol), followed by methane sulfonyl chloride (0.04 mL, 0.51 mmol) at 0 ^oC dropwise. The reaction mixture was stirred at rt for 16 h, then the reaction mixture was diluted with ice cold water and stirred for 10 min. The precipitate was filtered and washed with water and then dried under vacuum to afford 70 mg of 3-fluoro-N-(4-(1-(methylsulfonyl)-1,2,3,6- tetrahydropyridin-4-yl)phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide (I-94, 50% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.48 (s, 2H), 7.88-7.73 (m, 1H), 7.57 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 8.7 Hz, 2H), 6.14 (s, 1H), 4.77 (d, J = 12.7 Hz, 4H), 3.85 (s, 2H), 3.47-3.34 (m, 2H), 2.95-2.87 (m, 3H), 2.58-2.53 (m, 2H). LCMS: 417.1 (M+H), purity- 96.67% by AUC, rt- 4.085, UV-270 nm. Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mM ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. HPLC: purity- 96.72% by AUC, rt- 37.82 & 38.06, UV- 270 nm. Column: X Bridge C18 4.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH3CN; flow rate: 1.2 mL/min; Diluent: Methanol (100%). EXAMPLE 36 – SYNTHESIS OF TERT-BUTYL 4-(4-(4,6-DIFLUOROISOINDOLINE-2- CARBOXAMIDO)PHENYL)PIPERIDINE-1-CARBOXYLATE (I-58), 4,6-DIFLUORO- N-(4-(PIPERIDIN-4-YL)PHENYL)ISOINDOLINE-2-CARBOXAMIDE (I-57) AND 4,6- DIFLUORO-N-(4-(1-(2-HYDROXY-2-METHYLPROPANOYL) PIPERIDIN-4- YL)PHENYL)ISOINDOLINE-2-CARBOXAMIDE (I-60) [0807] Step 1: Preparation of tert-butyl 4-(4-(4,6-difluoroisoindoline-2- carboxamido)phenyl) piperidine-1-carboxylate (I-58): I-58 was prepared according to General Procedure B using tert-butyl 4-(4-((phenoxycarbonyl)amino) phenyl)piperidine-1-carboxylate (720 mg, 1.82 mmol). 630 mg of tert-butyl 4-(4-(4,6-difluoroisoindoline-2-carboxamido)phenyl) piperidine-1-carboxylate (I-58, 76% yield) was obtained as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.38 (s, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.32-7.04 (m, 2H), 6.84-6.62 (m, 1H), 4.77 (s, 4H), 4.21-3.93 (m, 2H), 2.65 (m, 4H), 1.80-1.45 (m, 3H), 1.42 (s, 9H). LCMS: 458.1 (M+H), purity- 96.45% by AUC, rt- 5.429, UV-260 nm. Column: X Bridge C184.6* 50mm* 3.5um; Mobile Phase- A: 10 mM ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. [0808] Step 2: Preparation of 4,6-difluoro-N-(4-(piperidin-4-yl)phenyl)isoindoline-2- carboxamide hydrochloride (I-57): I-57 was prepared according to General Procedure C using tert-butyl 4-(4-(4,6-difluoroisoindoline-2-carboxamido)phenyl) piperidine-1-carboxylate (I-58, 630 mg, 1.38 mmol).480 mg of I-57 (90% yield) was obtained as a white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.73 (d, J = 8.6 Hz, 2H), 8.45 (s, 1H), 7.51 (d, J = 8.6 Hz, 2H), 7.32-6.99 (m, 4H), 4.78 (s, 4H), 3.33 (s, 2H), 3.01-2.95 (m, 2H), 2.80-2.73 (m, 1H), 1.89-1.81 (m, 4H). LC-MS: [M+H]⁺ = 358.20. Column: X Bridge C18 4.6*50mm*3.5um; Mobile Phase- A: 10 mM ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. [0809] Step 3: Preparation of 4,6-difluoro-N-(4-(1-(2-hydroxy-2-methylpropanoyl) piperidin-4-yl)phenyl) isoindoline-2-carboxamide (I-60): I-60 was prepared according to General Procedure D using 4,6-difluoro-N-(4-(piperidin-4-yl)phenyl)isoindoline-2-carboxamide hydrochloride (I-57, 70 mg, 0.178 mmol). 55 mg of 4,6-difluoro-N-(4-(1-(2-hydroxy-2- methylpropanoyl)piperidin-4-yl)phenyl) isoindoline-2-carboxamide (I-60, 64% yield) was obtained as a white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.27-7.05 (m, 4H), 5.40 (s, 1H), 4.77 (s, 4H), 3.12-2.56 (m, 4H), 1.71-1.61 (m, 5H), 1.33 (s, 6H). LCMS: 444.3 (M+H), purity- 95.6% by AUC, rt- 5.12, UV-260 nm. LCMS method: Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mM Ammonium Acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; Flow rate: 0.6mL/min. HPLC: purity- 95.51% by AUC, rt- 9.04, UV- 240 nm. HPLC method: Column: X Bridge C184.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH₃CN; Flow rate: 1.2 mL/min; Diluent: Methanol (100%). EXAMPLE 37 – SYNTHESIS OF 4,6-DIFLUORO-N-(4-(1-(3-HYDROXY-OXETANE-3- CARBONYL)PIPERIDIN-4-YL)PHENYL)ISOINDOLINE -2-CARBOXAMIDE (I-40) [0810] I-40 was prepared according to General Procedure D using 4,6-difluoro-N-(4- (piperidin-4-yl)phenyl)isoindoline-2-carboxamide hydrochloride (55-4) (70 mg, 0.178 mmol).65 mg of 4,6-difluoro-N-(4-(1-(3-hydroxyoxetane-3-carbonyl)piperidin-4-yl)phenyl)isoindoline -2- carboxamide (I-40, 83% yield) was obtained as a white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.19 (m, 4H), 6.77 (s, 1H), 4.94 (d, J = 6.7 Hz, 1H), 4.84 (t, J = 8.5 Hz, 1H), 4.77 (s, 4H), 4.52-4.46 (m, 2H), 3.60-3.56 (m, 1H), 3.3-2.60 (m, 2H), 2.73-2.66 (m, 2H), 1.91-1.37 (m, 4H). LCMS: 458.38 (M+H), purity- 95.73 by AUC, rt- 4.90, UV-260 nm. Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mM ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. HPLC: purity- 93.31% by AUC, rt- 8.41, UV- 240 nm. Column: X Bridge C18 4.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH₃CN; flow rate: 1.2 mL/min; Diluent: Methanol (100%). EXAMPLE 38 – SYNTHESIS OF 4,6-DIFLUORO-N-(4-(1-(METHYLSULFONYL) PIPERIDIN-4-YL)PHENYL)ISOINDOLINE-2-CARBOXAMIDE (I-39) [0811] A stirred solution of 55-4 (70 mg, 0.17 mmol) in DMF (2.0 mL) was added triethyl amine (0.24 mL, 1.78 mmol), followed by methane sulfonyl chloride (0.03 mL, 0.35 mmol) at 0 ^oC dropwise. The reaction mixture was stirred at rt for 2 h, then the reaction mixture diluted with ice cold water, stirred for 10 min, and then the precipitate was filtered and dried to obtain 55 mg of 4,6-difluoro-N-(4-(1-(methylsulfonyl)piperidin-4-yl)phenyl)isoindoline-2-carboxamide (I-39, 74% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.48 (d, J = 8.6 Hz, 2H), 7.19 (m, 4H), 4.87 (s, 4H), 3.67 (m, 2H), 2.87 (s, 3H), 2.78-2.70 (m, 3H), 1.9-1.2 (m, 4H). LCMS: 436.1 (M+H), purity- 91.537% by AUC, rt- 4.69, UV-260 nm. Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mm ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. HPLC: purity- 90.62% by AUC, rt- 9.36, UV- 240 nm. Column: X Bridge C184.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH3CN; flow rate: 1.2 mL/min; Diluent: Methanol (100%). EXAMPLE 39 – SYNTHESIS OF (S)-(2-OXOOXAZOLIDIN-4-YL)METHYL 4-(4-(4,6- DIFLUOROISOINDOLINE-2-CARBOXAMIDO)PHENYL)PIPERIDINE-1- CARBOXYLATE (I-35) [0812] Step 1: Preparation of N-(4-(1-(1H-imidazole-1-carbonyl)piperidin-4-yl)phenyl)- 4,6-difluoroisoindoline-2-carboxamide (58-5): To a stirred solution of 55-4 (100 mg, 0.254 mmol) in ACN (2.0 mL) was added DIPEA (0.11 mL, 0.636 mmol) and CDI (103 mg, 0.636 mmol) at rt and the reaction mixture was stirred at rt for 3 h. After complete consumption of the starting material, the reaction mixture was cooled to 0 ^oC and the precipitate was filtered and dried to afford 90 mg of 58-5 (78% yield) as a white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.06 (s, 1H), 7.57-7.44 (m, 3H), 7.29-7.11 (m, 4H), 7.09-7.00 (m, 1H), 4.78 (s, 4H), 4.01 (d, J = 12.5 Hz, 2H), 3.16 (t, J = 11.8 Hz, 2H), 2.85-2.67 (m, 1H), 1.76-1.71 (m, 4H). [0813] Step 2: Preparation of (S)-(2-oxooxazolidin-4-yl)methyl 4-(4-(4,6-difluoro isoindoline-2-carboxamido) phenyl)piperidine-1-carboxylate (I-35): To a stirred solution of 58-6 in THF (2.0 mL) was added NaH (12 mg, 0.465 mmol) at rt and the reaction mixture was stirred for 10 min, followed by the addition of 58-5 (70 mg, 0.155 mmol). The reaction mixture was then stirred at rt for 3 h. After complete consumption of the starting material, the reaction mixture was quenched with a saturated aqueous solution of NH₄Cl, and then the precipitate was filtered and dried to obtain 25 mg of (S)-(2-oxooxazolidin-4-yl)methyl 4-(4-(4,6- difluoroisoindoline-2-carboxamido) phenyl)piperidine-1-carboxylate (I-35, 32% yield) as an off- white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.37 (s, 1H), 7.86 (s, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.17 (dt, J = 15.8, 9.1 Hz, 4H), 4.77 (s, 4H), 4.38 (t, J = 8.4 Hz, 1H), 4.08-4.06 (m, 6H), 2.73-2.69 (m, 3H), 1.68-1.60 (m, 4H). LCMS: 501.37 (M+H), purity- 94.24% by AUC, rt- 4.98, UV-220 nm. Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mM ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. HPLC: purity- 96.73% by AUC, rt- 8.65, UV- 245 nm. Column: X Bridge C184.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH3CN; flow rate: 1.2 mL/min; Diluent: Methanol (100%).

EXAMPLE 40 – SYNTHESIS OF 4-FLUORO-N-(4-(1-(2-((2-HYDROXY-2-METHYL- PROPYL)AMINO)-2-OXOACETYL)PIPERIDIN-4-YL)PHENYL) ISOINDOLINE-2- CARBOXAMIDE (I-11) [0814] Step 1: Preparation of tert-butyl 4-(4-(4-fluoroisoindoline-2 carboxamido) phenyl)piperidine-1-carboxylate (59-3): 59-3 was prepared according to General Procedure B using tert-butyl 4-(4-((phenoxycarbonyl) amino)phenyl)piperidine-1-carboxylate (59-1) (750 mg, 1.89 mmol).510 mg of 59-3 (46% yield) was obtained as a white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.35 (s, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.38 (td, J = 7.9, 5.4 Hz, 1H), 7.26-7.06 (m, 4H), 4.80 (d, J = 5.9 Hz, 4H), 4.06 (d, J = 12.1 Hz, 2H), 2.95-2.52 (m, 3H), 1.85-1.47 (m, 3H), 1.41 (s, 10H). LC-MS: [M+H]⁺ = 440.2. Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mM ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. [0815] Step 2: Preparation of 4-fluoro-N-(4-(piperidin-4-yl)phenyl)isoindoline-2- carboxamide hydrochloride (59-4): 59-4 was prepared according to General Procedure C using tert-butyl 4-(4-(4-fluoroisoindoline -2-carboxamido)phenyl)piperidine-1-carboxylate (59-3) (150 mg, 0.34 mmol).120 mg of 59-4 (91% yield) was obtained as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.82 (d, J = 37.8 Hz, 2H), 8.44 (s, 1H), 7.52 (d, J = 8.6 Hz, 2H), 7.47-7.28 (m, 1H), 7.28-7.06 (m, 4H), 4.81 (d, J = 6.3 Hz, 4H), 3.55-3.15 (m, 2H), 3.09-2.62 (m, 3H), 2.05-1.60 (m, 4H). LC-MS: [M+H]⁺ = 340.2. Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mM ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. [0816] Step 3: Preparation of methyl 2-(4-(4-(4-fluoroisoindoline-2-carboxamido)phenyl) piperidin-1-yl)-2-oxoacetate (59-6): To a stirred solution of 59-4 (100 mg, 0.29 mmol) in DMF (2.0 mL) was added DIPEA (5.0 eq) and 59-5 (1.5 eq) at 0 ^oC, then the reaction mixture was stirred at rt for 16 h. After complete consumption of the starting material, the reaction mixture was diluted with ice cold water, stirred for 30 min, and the precipitate was filtered and dried to obtain 100 mg of 59-6 (81% yield) as an off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.42-7.31 (m, 1H), 7.27-7.05 (m, 4H), 4.80 (d, J = 5.9 Hz, 4H), 4.39-4.35 (m, 1H), 3.83 (s, 3H), 3.63-3.59 (m, 1H), 3.26-3.21 (m, 1H), 2.84-2.79 (m, 2H), 1.86-1.82 (m, 2H), 1.63-1.37 (m, 2H). LC-MS: [M+H]⁺ = 426.2. Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mm ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. [0817] Step 4: Preparation of 4-fluoro-N-(4-(1-(2-((2-hydroxy-2-methylpropyl)amino)-2- oxoacetyl)piperidin-4-yl)phenyl)isoindoline-2-carboxamide (I-11): A stirred solution of 59-6 (100 mg, 0.235 mmol) in MeOH (4.0 mL) was added triethyl amine (0.5 mL) and 59-7 (3.0 eq) at rt, then the reaction mixture heated to 80 ^oC for 16 h. The volatiles were concentrated under reduced pressure and the resulting residue was dissolved in ethyl acetate and washed with water and brine. The organic phase was isolated, dried with sodium sulfate, filtered, and concentrated in vacuo to afford the crude product. The crude product was purified by prep HPLC purification, which afforded 22 mg of 4-fluoro-N-(4-(1-(2-((2-hydroxy-2-methylpropyl)amino)-2-oxoacetyl) piperidin-4-yl)phenyl)isoindoline-2-carboxamide (I-11, 20% yield) as a light brown solid. ¹H NMR (300 MHz, DMSO-d6) δ 8.52 (t, J = 6.2 Hz, 1H), 8.36 (s, 1H), 7.49 (d, J = 8.5 Hz, 2H), 7.38 (dd, J = 12.9, 7.9 Hz, 1H), 7.28-7.03 (m, 4H), 4.80 (d, J = 6.0 Hz, 4H), 4.60-4.28 (m, 3H), 3.85 (d, J = 12.2 Hz, 2H), 3.15-3.09 (m, 1H), 2.76 (d, J = 12.4 Hz, 2H), 1.93-1.37 (m, 4H), 1.08 (s, 6H). LCMS: 483.36 (M+H), purity- 94.19% by AUC, rt- 4.67, UV-240 nm. Column: X Bridge C18 4.6*50mm*3.5um; Mobile Phase- A: 10 mm ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. HPLC: purity- 92.67% by AUC, rt- 8.31, UV- 240 nm. Column: X Bridge C184.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH₃CN; flow rate: 1.2 mL/min; Diluent: Methanol (100%). EXAMPLE 41 – SYNTHESIS OF 5-FLUORO-N-(4-(4-(METHYLCARBAMOYL) BICYCLO[2.2.2]OCTAN-1-YL)PHENYL)ISOINDOLINE-2-CARBOXAMIDE (I-64), 4- (4-(5-FLUOROISOINDOLINE-2-CARBOXAMIDO)PHENYL)BICYCLO[2.2.2] OCTANE-1-CARBOXYLIC ACID (I-384) AND METHYL 4-(4-(5-FLUORO ISOINDOLINE-2-CARBOXAMIDO)PHENYL) BICYCLO[2.2.2]OCTANE-1- [0818] Step 1: Preparation of methyl 4-bromobicyclo[2.2.2]octane-1-carboxylate (60-2): To a stirred solution of 60-1 (10.0 g, 47.16 mmol) in dibromomethane (300 mL) was added mercury oxide (10.18 g, 47.16 mmol) under a nitrogen atmosphere. Bromine (3.13 mL, 61.32) in dibromomethane (10 mL) was added slowly at 80 ^oC and maintained for 3 h. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, the reaction mixture was cooled to rt and then filtered through a pad of celite. The filtrate was concentrated under reduced pressure to obtain the crude product. The residue was purified by column chromatography (eluting with 5% EtOAc-Hexanes) which afforded 8.0 g of 60-2 (69% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 3.57 (d, J = 5.7 Hz, 3H), 2.30-2.11 (m, 6H), 2.04-1.81 (m, 6H). [0819] Step 2: Preparation of methyl 4-(4-acetamidophenyl)bicyclo[2.2.2]octane-1- carboxylate (60-4): To a stirred solution of 60-2 (5.8 g, 23.5 mmol) and 60-3 (3.2 g, 23.5 mmol) in 1,2-dichloroethane (230 mL) was added aluminum chloride (14.0 g, 105.7 mmol) in portions at 0 ^oC. Then the reaction mixture was stirred at rt for 16 h. After completion of the starting material, the reaction mixture was slowly poured into ice cold water. The aqueous layer was extracted with DCM (2x50 mL). The combined organic extracts were washed with water, brine, dried over sodium sulphate, filtered, and concentrated under reduced pressure to obtain the crude. The product was purified by column chromatography (eluting with 25% EtOAc-Hexanes), which afforded 3.5 g of 60-4 (49% yield) as a pale-yellow solid.¹H NMR (300 MHz, DMSO-d₆) δ 9.85 (s, 1H), 7.55-7.39 (m, 2H), 7.28-7.11 (m, 2H), 3.34 (s, 3H), 2.01 (d, J = 3.7 Hz, 3H), 1.83-1.75 (m, 12H). LC-MS: [M+H]⁺ = 302.2. Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mM ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. [0820] Step 3: Preparation of methyl 4-(4-aminophenyl)bicyclo[2.2.2]octane-1- carboxylate (60-5): A stirred solution of 60-4 (3.5 g, 11.6 mmol) in MeOH (75 mL) was added thionyl chloride (1.52 mL, 11.6 mmol) dropwise at rt, then the reaction mixture was heated to 70 ^oC for 8 h. After completion of the reaction, the reaction mixture was cooled to rt and the volatiles were removed under reduced pressure. The reaction mixture was diluted with water, basified with saturated aqueous NaHCO₃ and extracted with EtOAc (2x50 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. The product was purified by column chromatography (eluting with 15% EtOAc- Hexanes), which afforded 1.5 g of 60-5 (42%) as a pale-yellow solid.¹H NMR (300 MHz, DMSO- d₆) δ 6.98 (dd, J = 17.0, 8.2 Hz, 2H), 6.61-6.48 (m, 2H), 4.88 (s, 2H), 3.39 (s, 3H), 1.99-1.64 (m, 12H). LC-MS: [M+H]⁺ = 260.2. [0821] Step 4: Preparation of methyl 4-(4-((phenoxycarbonyl) amino)phenyl) bicyclo[2.2.2]octane-1-carboxylate (60-6): 60-6 was prepared according to General Procedure A using methyl 4-(4-aminophenyl)bicyclo [2.2.2]octane-1-carboxylate (60-5) (1.5 g, 5.0 mmol).1.8 g of 60-6 (69% yield) was obtained as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 10.12 (s, 1H), 7.55-7.34 (m, 4H), 7.33-7.10 (m, 5H), 3.33 (s, 3H), 1.99-1.64 (d, 12H). LC-MS: [M+H]⁺ = 380.2. Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mm ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. [0822] Step 5: Preparation of methyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) bicyclo[2.2.2]octane-1-carboxylate (I-231): I-231 was prepared according to General Procedure B using methyl 4-(4-((phenoxycarbonyl)amino) phenyl) bicyclo[2.2.2]octane-1-carboxylate (60- 6) (1.8 g, 4.74 mmol). 1.0 g of I-231 (50% yield) was obtained as an off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.54-7.33 (m, 3H), 7.33-7.05 (m, 4H), 4.73 (d, J = 8.2 Hz, 4H), 3.60 (s, 3H), 1.99-1.64 (m, 12H). LC-MS: [M+H]⁺ = 423.2. Column: X Bridge C18 4.6*50mm*3.5um; Mobile Phase- A: 10 mM ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. [0823] Step 6: Preparation of 4-(4-(5-fluoro-2,3-dihydro-1H-indene-2-carboxamido) phenyl)bicyclo[2.2.2]octane-1-carboxylic acid (I-384): To a stirred solution of I-231 (1.0 g, 2.36 mmol) in a mixture of THF: MeOH: H2O (30 mL; 1:1:1) was added lithium hydroxide monohydrate (0.59 g, 14.18 mmol) at rt and stirred for 24 h. After completion of the reaction, the volatiles were removed under reduced pressure and the reaction mixture was acidified with 1.0N HCl. The precipitate was filtered and dried to obtain 820 mg of I-384 (85% yield) as an off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ 12.03 (s, 1H), 8.28 (s, 1H), 7.56-7.29 (m, 3H), 7.29-6.98 (m, 4H), 4.72 (d, J = 8.1 Hz, 4H), 1.78 (s, 12H). LC-MS: [M+H]⁺ = 409.2. Column: X Bridge C18 4.6*50mm*3.5um; Mobile Phase- A: 10 mm ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. [0824] Step 7: Preparation of 5-fluoro-N-(4-(4-(methylcarbamoyl)bicyclo[2.2.2]octan-1- yl)phenyl)isoindoline-2-carboxamide (I-64): To a stirred solution of I-384 (100 mg, 0.24 mmol) in DMF (2.0 mL) was added DIPEA (79 mg, 0.61 mmol), HATU (139.6 mg, 0.36 mmol) and methylamine (0.2 mL, 0.36 mmol, 7% in THF) at 0 ^oC and then the reaction mixture was stirred at rt for 48 h. The reaction mixture was poured into ice cold water and the precipitate was filtered and dried to obtain 70 mg of 5-fluoro-N-(4-(4-(methylcarbamoyl)bicyclo[2.2.2]octan-1- yl)phenyl)isoindoline-2-carboxamide (I-64, 67% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.29 (s, 1H), 7.53-7.30 (m, 4H), 7.18 (dt, J = 18.2, 8.2 Hz, 4H), 4.72 (d, J = 8.0 Hz, 4H), 2.64-2.52 (m, 3H), 1.75 (s, 12H). LCMS: 422.2 (M+H), purity- 98.85% by AUC, rt- 4.44, UV-260 nm. Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mm ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. HPLC: purity- 98.4% by AUC, rt- 8.79, UV- 245 nm. Column: X Bridge C18 4.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH₃CN; flow rate: 1.2 mL/min; Diluent: Methanol (100%). EXAMPLE 42 – SYNTHESIS OF 5-FLUORO-N-(4-(4-(MORPHOLINE-4-CARBONYL) BICYCLO[2.2.2]OCTAN-1-YL)PHENYL) ISOINDOLINE -2-CARBOXAMIDE (I-63) [0825] To a stirred solution of 60-9 (100 mg, 0.24 mmol) in DMF (2.0 mL) was added DIPEA (79 mg, 0.61 mmol), HATU (139.6 mg, 0.36 mmol) and morpholine (25 mg, 0.29 mmol) at 0 ^oC, and then the reaction mixture was stirred at rt for 16 h. The reaction mixture was poured into ice cold water and the precipitate was filtered and dried to obtain 70 mg of 5-fluoro-N-(4-(4- (morpholine-4-carbonyl)bicyclo[2.2.2]octan-1-yl)phenyl) isoindoline -2-carboxamide (I-63, 59% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.28 (s, 1H), 7.66-7.29 (m, 3H), 7.28-7.03 (m, 4H), 4.72 (d, J = 8.1 Hz, 4H), 3.61-3.51 (m, 8H), 1.89-1.77 (m, 12H). LCMS: 478.2 (M+H), purity- 97.85% by AUC, rt- 4.65, UV-210 nm. Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mm ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. HPLC: purity- 96.07% by AUC, rt- 9.29, UV- 240 nm. Column: X Bridge C184.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH3CN; flow rate: 1.2 mL/min; Diluent: Methanol (100%). EXAMPLE 43 - PREPARATION OF 5-FLUORO-N-(4-(4-((2-HYDROXY-2-METHYL- PROPYL)CARBAMOYL)BICYCLO[2.2.2]OCTAN-1-YL) PHENYL)ISOINDOLINE-2- CARBOXAMIDE (I-59) [0826] To a stirred solution of 60-9 (100 mg, 0.24 mmol) in DMF (2.0 mL) was added DIPEA (79 mg, 0.61 mmol), HATU (139.6 mg, 0.36 mmol) and 62-10 (32 mg, 0.36 mmol) at 0 ^oC, and then the reaction mixture was stirred at rt for 16 h. The reaction mixture was poured into ice cold water and the precipitate was filtered and dried to obtain 70 mg of 5-fluoro-N-(4-(4-((2-hydroxy- 2-methylpropyl)carbamoyl)bicyclo[2.2.2]octan-1-yl) phenyl)isoindoline-2-carboxamide (I-59, 59% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.56-7.30 (m, 3H), 7.21-7.13 (m, 5H), 4.73 (d, J = 8.0 Hz, 4H), 4.55 (s, 1H), 3.05 (d, J = 5.9 Hz, 2H), 1.78 (s, 12H), 1.02 (s, 6H). LCMS: 480.2 (M+H), purity- 98.16% by AUC, rt- 4.43, UV-260 nm. Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mm ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. HPLC: purity- 97.78% by AUC, rt- 8.81, UV- 245 nm. Column: X Bridge C184.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH3CN; flow rate: 1.2 mL/min; Diluent: Methanol (100%). EXAMPLE 44 – SYNTHESIS OF 5-FLUORO-N-(4-(4-(2-HYDROXY-2-METHYL- PROPANAMIDO)BICYCLO[2.2.2]OCTAN-1-YL)PHENYL)ISOINDOLINE-2- CARBOXAMIDE (I-43) [0827] Step 1: Preparation of tert-butyl (4-(4-(5-fluoroisoindoline-2-carboxamido) phenyl)bicyclo[2.2.2]octan-1-yl) carbamate (63-9): To a stirred solution of 63-8 (400 mg, 0.99 mmol) in THF (40 mL) was added sodium azide (223 mg, 3.43 mmol), zinc triflate (11.73 mg, 0.032 mmol), and TBAB (47 mg, 0.147 mmol) at rt. Then (Boc)2O (235 mg, 1.078 mmol) was added at 40 ^oC and maintained for 16 h. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, the reaction mixture was cooled to rt and diluted with EtOAc (50 mL), washed with saturated aqueous NaHCO3 (25 mL), and the organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by column chromatography (eluting with 15% EtOAc-hexanes), which afforded 90 mg of 63-9 (25% yield).¹H NMR (300 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.40 (dd, J = 19.7, 7.0 Hz, 2H), 7.18 (dt, J = 18.6, 7.6 Hz, 4H), 6.84 (s, 1H), 5.45 (s, 1H), 4.73 (d, J = 8.1 Hz, 4H), 2.03 – 1.64 (m, 12H), 1.21 (s, 9H). LC-MS: [M+H]⁺ = 480.20. [0828] Step 2: Preparation of N-(4-(4-aminobicyclo[2.2.2]octan-1-yl)phenyl)-5- fluoroisoindoline-2-carboxamide (63-10): 63-10 was prepared according to General Procedure C using tert-butyl (4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)bicyclo[2.2.2]octan-1- yl)carbamate (63-9) (120 mg, 0.25 mmol).100 mg of 63-10 (96% yield) was obtained as a white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.31 (s, 1H), 7.98 (s, 3H), 7.52-7.30 (m, 3H), 7.18 (dt, J = 18.0, 7.4 Hz, 4H), 4.73 (d, J = 8.1 Hz, 4H), 1.84 (d, J = 10.2 Hz, 12H). LC-MS: [M+H]⁺ = 380.20. Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mm ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. [0829] Step 3: Preparation of 5-fluoro-N-(4-(4-(2-hydroxy-2-methylpropanamido) bicyclo[2.2.2]octan-1-yl)phenyl) isoindoline-2-carboxamide (I-43): I-43 was prepared according to General Procedure D using N-(4-(4-aminobicyclo [2.2.2]octan-1-yl)phenyl)-5- fluoroisoindoline-2-carboxamide (50 mg, 0.13 mmol). 8 mg of 5-fluoro-N-(4-(4-(2-hydroxy-2- methylpropanamido)bicyclo[2.2.2]octan-1-yl)phenyl)isoindoline-2-carboxamide (I-43, 16% yield) was obtained as a white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.27 (s, 1H), 7.45-7.38 (m, 3H), 7.23-7.16 (m, 4H), 6.84 (s, 1H), 5.45 (s, 1H), 4.73 (d, J = 8.1 Hz, 4H), 2.01-1.73 (m, 12H), 1.21 (s, 6H). LCMS: 466.2 (M+H), purity- 97.01% by AUC, rt- 4.65, UV-260 nm. Column: X Bridge C18 4.6*50mm*3.5um; Mobile Phase- A: 10 mm ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. HPLC: purity- 91.06% by AUC, rt- 9.08, UV- 245 nm. Column: X Bridge C184.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH3CN; flow rate: 1.2 mL/min; Diluent: Methanol (100%). EXAMPLE 45 - PREPARATION OF 5-FLUORO-N-(4-(4-((2-METHOXYETHYL) SULFONAMIDO)BICYCLO[2.2.2]OCTAN-1-YL)PHENYL) ISOINDOLINE-2- CARBOXAMIDE (I-42) [0830] A stirred solution of 63-10 (50 mg, 0.13 mmol) in DMF (5.0 mL) was added triethylamine (0.18 mL, 1.31 mmol) and DMAP (0.16 mg, 0.001 mmol) and followed by 64-12 (0.02 mL, 0.197 mmol) at 0 ^oC. The reaction mixture was stirred at rt for 16 h, then the reaction mixture was diluted with ice cold water and extracted with EtOAc (50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain the crude product. The residue was purified by column chromatography (eluting with 3% MeOH-DCM), which afforded 8 mg of 5-fluoro-N-(4-(4-((2-methoxyethyl)sulfonamido)bicyclo[2.2.2]octan-1-yl)phenyl) isoindoline-2-carboxamide (I-42, 12% yield) as an off-white solid.¹H NMR (300 MHz, DMSO- d6) δ 8.28 (s, 1H), 7.51-7.31 (m, 3H), 7.28-7.06 (m, 4H), 6.93 (s, 1H), 4.72 (d, J = 8.2 Hz, 4H), 3.67 (t, J = 6.6 Hz, 2H), 3.25 (d, J = 10.1 Hz, 5H), 1.85 (d, J = 8.4 Hz, 12H). LCMS: 502.36 (M+H), purity- 97.55% by AUC, rt- 5.32, UV-245 nm. Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mm ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. HPLC: purity- 96.20% by AUC, rt- 15.74, UV- 245 nm. Column: X Bridge C18 4.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH3CN; flow rate: 1.2 mL/min; Diluent: Methanol (100%). EXAMPLE 46 – SYNTHESIS OF 5-FLUORO-N-(4-(4-((2-METHOXYETHYL) SULFONAMIDO)BICYCLO[2.2.2]OCTAN-1-YL)PHENYL) ISOINDOLINE-2- CARBOXAMIDE (I-36) [0831] A solution of 63-8 (50 mg, 0.122 mmol) in THF (7 mL) was added triethylamine (0.02 mg, 0.183 mmol) and diphenylphoporyl azide (0.03 mL, 0.147 mmol) at rt and was then stirred at rt for 16 h. After complete consumption of the starting material, the reaction mixture was diluted with ice cold water (15 mL), extracted with toluene (2x10 mL), and the combined organic extracts were dried over Na₂SO₄. Half of the volume was removed through concentration under reduced pressure, and 65-13 (8.5 mg, 0.122 mmol) was added at rt. The reaction mixture was stirred at reflux for 16 h. After complete consumption of the starting material, the reaction mixture was diluted with cold water and extracted with EtOAc (2x25 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain the crude product. The residue was purified by column chromatography (eluting with 70% EtOAc-Hexanes) which afforded 15 mg of 5-fluoro-N-(4-(4-((2-methoxyethyl)sulfonamido)bicyclo[2.2.2]octan-1- yl)phenyl) isoindoline-2-carboxamide (I-36, 25% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.40 (dd, J = 17.2, 6.9 Hz, 3H), 7.17 (dt, J = 19.3, 9.5 Hz, 4H), 5.84- 5.58 (m, 2H), 4.72 (d, J = 8.3 Hz, 4H), 4.44 (s, 1H), 2.88 (d, J = 5.7 Hz, 2H), 1.83 (d, J = 4.6 Hz, 12H), 1.02 (s, 6H). LCMS: 495.45 (M+H), purity- 97.17% by AUC, rt- 4.97, UV-220 nm. LCMS Method: Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mm Ammonium Acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; Flow rate: 0.6mL/min. HPLC: purity- 98.78% by AUC, rt- 8.76, UV- 245 nm. HPLC method: Column: X Bridge C18 4.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH3CN; Flow rate: 1.2 mL/min; Diluent: Methanol (100%). EXAMPLE 47 – SYNTHESIS OF TERT-BUTYL 4-(4-(4,7-DIFLUOROISOINDOLINE-2- CARBOXAMIDO)PHENYL)-3,6-DIHYDROPYRIDINE-1(2H)-CARBOXYLATE (I-102) [0832] Step 1: Preparation of 2,3-bis(bromomethyl)-1,4-difluorobenzene (66-2): To a stirred solution of 66-1 (5.0 g, 35.21 mmol) in CCl₄ (150 mL) was added NBS (18.8 g, 3.0 eq) and AIBN (519 mg, 3.17 mmol) at rt, and then the reaction mixture was heated to reflux for 8 h. After complete consumption of the starting material, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The product was purified by column chromatography (eluting with 1% EtOAc/hexanes) to afford 5.2 g of 66-2 (50% yield) as a colourless syrup.¹H NMR (300 MHz, DMSO-d6) δ 7.41-7.30 (m, 2H), 4.79 (t, J = 1.2 Hz, 4H). LC-MS: [M+H]⁺ = 298.99, 300.99. Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mm ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. [0833] Step 2: Preparation of 4,7-difluoro-2-(4-methoxybenzyl)isoindoline (66-3): To a stirred solution of 66-2 (3.9 g, 13.08 mmol) in EtOH (400 mL) was added DIPEA (9.3 mL, 52.34 mmol) and 4-methoxy benzylamine (2.15 g, 15.70 mmol) at rt, and then the reaction mixture was heated to 40 ^oC for 16 h. After complete consumption of the starting material, the reaction mixture was cooled to rt and the volatiles were removed under reduced pressure. The reaction mixture was diluted with water and extracted with EtOAc, and the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (eluting with 2% EtOAc/Hexanes) which afforded 2.2 g of 66-3 (61% yield) as pale brown solid.¹H NMR (300 MHz, DMSO-d6) δ 7.28 (d, J = 8.7 Hz, 2H), 7.08 (t, J = 6.0 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 3.90 (s, 4H), 3.80 (s, 2H), 3.74 (s, 3H). LC- MS: [M+H]⁺ = 276.2. Column: X Bridge C18 4.6*50mm*3.5um; Mobile Phase- A: 10 mm ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. [0834] Step 3: Preparation of 4,7-difluoroisoindoline (66-4): A stirred solution of 66-3 (2.2 g, 8.0 mmol) in dichloroethane (40 mL) was added molecular sieves (2.0 g) and chloroethylchloroformate (2.63 mL, 24.0 mmol) slowly under a nitrogen atmosphere at rt. The resulting reaction mixture was heated to 90 ^oC for 5 h. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, the reaction mixture was cooled to rt and methanol (40 mL) was added, and then the mixture was heated to reflux for 30 min. After completion of reaction, the volatiles were removed under reduced pressure. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (2x30 mL). The aqueous layer was basified to pH ~9 using a 10% sodium hydroxide solution and extracted with EtOAc (2x50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford 970 mg of 66-4 (78% yield) as pale brown solid.¹H NMR (300 MHz, DMSO-d₆) δ 7.07 (t, J = 5.9 Hz, 2H), 4.12 (s, 4H). LC-MS: [M+H]⁺ = 156.1. Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mm ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. [0835] Step 4: Preparation of tert-butyl 4-(4-(4,7-difluoroisoindoline-2- carboxamido)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (I-102): I-102 was prepared according to General Procedure B using tert-butyl 4-(4-((phenoxycarbonyl) amino)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (66-4) (2.46 g, 6.26 mmol). After completion of reaction, the reaction mixture was cooled to rt, diluted with ice-cold water (100 mL) and extracted with ethyl acetate (3x50 mL). The combined organic layer was washed with a brine solution (2x50 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford the crude product. The crude product was triturated with MTBE to afford 850 mg of tert-butyl 4-(4-(4,7- difluoroisoindoline-2-carboxamido)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (I-102, 30% yield) as an off white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.57 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 8.8 Hz, 2H), 7.23 (t, J = 6.1 Hz, 2H), 6.09 (br s, 1H), 4.85 (s, 4H), 3.99 (br s, 2H), 3.53 (t, J = 5.6 Hz, 2H), 2.49-2.39 (m, 2H), 1.43 (s, 9H). LCMS: 456.2 (M+H), purity- 99.24% by AUC, rt- 6.18, UV-265 nm. Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mm ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. HPLC: purity- 89.99% by AUC, rt- 40.37, UV- 254 nm. Column: X Bridge C184.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH3CN; flow rate: 1.2 mL/min; Diluent: Methanol (100%). EXAMPLE 48 – SYNTHESIS OF 4,7-DIFLUORO-N-(4-(1-(2-HYDROXY-2- METHYLPROPANOYL)-1,2,3,6-TETRAHYDROPYRIDIN-4-YL)PHENYL) ISOINDOLINE-2-CARBOXAMIDE (I-105) [0836] Step 1: Preparation of 4,7-difluoro-N-(4-(1,2,3,6-tetrahydropyridin-4- yl)phenyl)isoindoline-2-carboxamide hydrochloride (67-7): 67-7 was prepared according to General Procedure C using tert-butyl 4-(4-(4,7-difluoroisoindoline-2-carboxamido)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (I-102) 850 mg, 1.87 mmol). The product was obtained after trituration with Et₂O (30 mL).600 mg of 67-7 (90% yield) was obtained as a white solid.¹H NMR (300 MHz, DMSO-d6) δ 9.11 (br s, 2H), 8.60 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 7.24 (t, J = 6.1 Hz, 2H), 6.14 (br s, 1H), 4.86 (s, 4H), 3.73 (br s, 2H), 3.32 (br d, J = 0.9 Hz, 2H), 2.67 (br s, 2H). LC-MS: [M+H]⁺ = 365.2. [0837] Step 2: Preparation of 4,7-difluoro-N-(4-(1-(2-hydroxy-2-methylpropanoyl)- 1,2,3,6-tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide (I-105): I-105 was prepared according to General Procedure D using 4,7-difluoro-N-(4-(1,2,3,6-tetrahydropyridin-4- yl)phenyl)isoindoline-2-carboxamide hydrochloride (67-7, 120 mg, 0.33 mmol). 60 mg of 4,7- difluoro-N-(4-(1-(2-hydroxy-2-methylpropanoyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl) isoindoline-2-carboxamide (I-105, 40% yield) was obtained as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.51 (s, 1H), 7.57 (d, J = 8.8 Hz, 2H), 7.37 (d, J = 8.7 Hz, 2H), 7.23 (t, J = 6.1 Hz, 2H), 6.14 (br s, 1H), 5.46 (s, 1H), 4.85 (s, 4H), 4.69-3.55 (m, 4H), 2.50-2.45 (m, 2H), 1.34 (s, 6H). LCMS: 442.2 (M+H), purity- 95.08% by AUC, rt- 4.55, UV-270 nm. Column: X Bridge C18 4.6*50mm*3.5um; Mobile Phase- A: 10 mm ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. HPLC: purity- 93.67% by AUC, rt- 40.23, UV- 270 nm. Column: X Bridge C184.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH₃CN; flow rate: 1.2 mL/min; Diluent: Methanol (100%). EXAMPLE 49 – SYNTHESIS OF TERT-BUTYL 4-(4-(6,7-DIHYDRO-5H-PYRROLO [3,4-B]PYRAZINE-6-CARBOXAMIDO)PHENYL)-3,6-DIHYDRO-PYRIDINE-1(2H)- CARBOXYLATE (I-82) [0838] Step 1: Preparation of 2,3-bis(bromomethyl)pyrazine (68-2): To a stirred solution of 68-1 (15.0 g, 138 mmol) in CCl₄ (338 mL) was added NBS (74 g, 416 mmol) and AIBN (4.52 g, 27.6 mmol) at rt, and then the reaction was heated to reflux for 16 h. After complete consumption of the starting material, the reaction mixture was filtered, and filtrate was concentrated under reduced pressure to obtain the crude product. The product was purified by column chromatography (eluting with 5% EtOAc/hexanes) which afforded 7.5 g of 68-2 as pale brown semisolid.¹HNMR (300 MHz, DMSO-d6) δ 8.63 (s, 2H), 4.87 (s, 4H). LC-MS: [M+H]⁺ = 264.99, 266.99. [0839] Step 2: Preparation of 6-trityl-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (68-3): To a stirred solution of 68-2 (7.0 g, 26.4 mmol) and trityl amine (4.10 g, 15.8 mmol) in DMF (84 mL) was added DIPEA (10.23 g, 79.2 mmol) at rt, and then the reaction mixture was heated to 60 ^oC for 3 h. After complete consumption of the starting material, the reaction mixture was diluted with ice cold water (100 mL) and extracted with ethyl acetate (3x50 mL). The combined organic layer was washed with a brine solution (2x50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product. The product was purified by column chromatography (eluting with 10% EtOAc/hexanes) which afforded 2.1 g of 68-3 (22% yield) as a pale-yellow solid.¹H NMR (300 MHz, DMSO-d6) δ 8.29 (s, 2H), 7.55-7.09 (m, 15 H), 3.99 (s, 4H). LC-MS: [M+H]⁺ = 364.20. [0840] Step 3: Preparation of 6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (68-4): To a stirred solution of 68-3 (410 mg, 1.13 mmol) in a mixture of CHCl3:MeOH (20 mL; 1:1) was added trifluoro acetic acid (20 mL) at 0 ^oC and then the reaction mixture was stirred at rt for 30 minutes. After complete consumption of the starting material, the volatiles were removed under reduced pressure.68-4 (120 mg) was obtained as a TFA salt and was used in the next step without further purification.¹HNMR (300 MHz, DMSO-d6) δ 8.62 (s, 2H), 4.64 (s, 4H). [0841] Step 4: Preparation of tert-butyl 4-(4-(6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine-6- carboxamido)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (I-82): I-82 was prepared according to General Procedure B using tert-butyl 4-(4-((phenoxycarbonyl) amino)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (66-4) (260 mg, 0.66 mmol).160 mg of tert-butyl 4-(4-(6,7- dihydro-5H-pyrrolo[3,4-b]pyrazine-6-carboxamido)phenyl)-3,6-dihydropyridine-1(2H)- carboxylate (I-82, 57% yield) was obtained as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 2H), 8.51 (s, 1H), 7.57 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 8.7 Hz, 2H), 6.09 (s, 1H), 4.82 (s, 4H), 4.02-3.97 (m, 2H), 3.53 (t, J = 5.7 Hz, 2H), 2.49-2.41 (m, 2H), 1.43 (s, 9H). LCMS: 422.1 (M+H), purity- 95.53% by AUC, rt- 4.62, UV-280 nm. Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mm ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. HPLC: purity- 90.19% by AUC, rt- 40.51, UV- 254 nm. Column: X Bridge C18 4.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH3CN; flow rate: 1.2 mL/min; Diluent: Methanol (100%). EXAMPLE 50 – SYNTHESIS OF N-(4-(1-(2-HYDROXY-2-METHYLPROPANOYL)- 1,2,3,6-TETRAHYDROPYRIDIN-4-YL)PHENYL)-5,7-DIHYDRO-6H-PYRROLO[3,4- B]PYRAZINE-6-CARBOXAMIDE (I-107) [0842] Step 1: Preparation of N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-5,7-dihydro- 6H-pyrrolo[3,4-b]pyrazine-6-carboxamide hydrochloride (69-7): 69-7 was prepared according to General Procedure C using tert-butyl 4-(4-(6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine-6- carboxamido)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (I-82) (150 mg, 0.35 mmol). The product was obtained after trituration with Et2O (30 mL).114 mg of 69-7 (81% yield) was obtained as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 9.16 (s, 2H), 8.62 (s, 1H), 8.56 (s, 2H), 7.63 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 8.8 Hz, 2H), 6.14 (s, 1H), 4.84 (s, 4H), 3.75-3.71 (m, 2H), 3.32-3.28 (m, 2H), 2.70-2.66 (m, 2H). LC-MS: [M+H]⁺ = 358.20. [0843] Step 2: Preparation of N-(4-(1-(2-hydroxy-2-methylpropanoyl)-1,2,3,6- tetrahydropyridin-4-yl)phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyrazine-6-carboxamide (I- 107): I-107 was prepared according to General Procedure D using N-(4-(1,2,3,6- tetrahydropyridin-4-yl)phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyrazine-6-carboxamide hydrochloride (69-7) (85 mg, 0.26 mmol). The product was obtained after solid filtration, which afforded 56 mg of N-(4-(1-(2-hydroxy-2-methylpropanoyl)-1,2,3,6-tetrahydropyridin-4- yl)phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyrazine-6-carboxamide (I-107, 52% yield) as an off- white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.55 (s, 2H), 8.51 (s, 1H), 7.58 (d, J = 8.7 Hz, 2H), 7.38 (d, J = 8.7 Hz, 2H), 6.15 (s, 1H), 5.46 (s, 1H), 4.83 (s, 4H), 4.12-4.08 (m, 4H), 2.49-2.33 (m, 2H), 1.30 (d, J = 28.1 Hz, 6H). LCMS: 408.2 (M+H), purity- 99.4% by AUC, rt- 3.61, UV-270 nm. Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mm ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. HPLC: purity- 95.66% by AUC, rt- 37.36, UV- 230 nm. Column: X Bridge C184.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH3CN; flow rate: 1.2 mL/min; Diluent: Methanol (100%). EXAMPLE 51 – SYNTHESIS OF N-(4-(1-(2-CYCLOPENTYLACETYL)-1,2,3,6- TETRAHYDROPYRIDIN-4-YL)PHENYL)-4,6-DIHYDRO-5H-PYRROLO[3,4- D]THIAZOLE-5-CARBOXAMIDE (I-62) [0844] Step 1: Preparation of tert-butyl 4-(4-(5,6-dihydro-4H-pyrrolo[3,4-d]thiazole-5- carboxamido)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (70-3): 70-3 was prepared according to General Procedure B using tert-butyl 4-(4-((phenoxycarbonyl) amino)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (70-1, 500 mg, 1.27 mmol).300 mg of 70-3 (44% yield) was obtained as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 9.12 (s, 1H), 8.45 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 8.7 Hz, 2H), 6.09 (s, 1H), 4.83-4.60 (m, 4H), 4.11-3.89 (m, 2H), 3.16-3.10 (m, 2H), 2.47-2.43 (m, 2H), 1.43 (s, 9H). LC-MS: [M+H]⁺ = 427.2. [0845] Step 2: Preparation of N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-4,6-dihydro- 5H-pyrrolo[3,4-d]thiazole-5-carboxamide hydrochloride (70-4): 70-4 was prepared according to General Procedure C using tert-butyl 4-(4-(5,6-dihydro-4H-pyrrolo[3,4-d]thiazole-5- carboxamido)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (70-3) (300 mg, 27 mmol). The product was obtained after the volatiles were removed, which afforded 200 mg (crude) of 70-4 as a pale-yellow solid.¹H NMR (300 MHz, DMSO-d6) δ 9.12 (s, 2H), 8.52 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H), 7.48-7.33 (m, 2H), 6.14 (s, 1H), 4.89-4.62 (m, 4H), 3.78-3.72 (m, 2H), 3.32-3.28 (m, 2H), 2.74-2.68 (m, 2H). LC-MS: [M+H]⁺ = 327.1. [0846] Step 3: Preparation of N-(4-(1-(2-cyclopentylacetyl)-1,2,3,6-tetrahydropyridin-4- yl)phenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxamide (I-62): I-62 was prepared according to General Procedure D using N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-4,6- dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxamide hydrochloride (70-4, 75 mg, 0.22 mmol). 35 mg of N-(4-(1-(2-cyclopentylacetyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-4,6-dihydro-5H- pyrrolo[3,4-d]thiazole-5-carboxamide (I-62, 69% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 9.12 (s, 1H), 8.43 (s, 1H), 7.55 (d, J = 8.7 Hz, 2H), 7.37 (dd, J = 8.8, 2.6 Hz, 2H), 6.12 (s, 1H), 4.73 (d, J = 21.1 Hz, 4H), 4.12 (d, J = 14.4 Hz, 2H), 3.77-3.55 (m, 2H), 2.4-2.0 (m, 4H), 1.9-1.0 (m, 9H). LCMS: 437.2 (M+H), purity- 99.07% by AUC, rt- 4.52, UV-250 nm. Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mm ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. HPLC: purity- 96.82% by AUC, rt- 8.99, UV- 270 nm. Column: X Bridge C18 4.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH₃CN; flow rate: 1.2 mL/min; Diluent: Methanol (100%). EXAMPLE 52 – SYNTHESIS OF N-(4-(1-(2-HYDROXY-2-METHYLPROPANOYL)- 1,2,3,6-TETRAHYDROPYRIDIN-4-YL)PHENYL)-4,6-DIHYDRO-5H-PYRROLO[3,4- D]THIAZOLE-5-CARBOXAMIDE (I-61) [0847] N-(4-(1-(2-hydroxy-2-methylpropanoyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-4,6- dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxamide (I-61) was prepared according to General Procedure D using N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-4,6-dihydro-5H-pyrrolo[3,4- d]thiazole-5-carboxamide hydrochloride (70-4) (75 mg, 0.22 mmol). 35 mg of N-(4-(1-(2- hydroxy-2-methylpropanoyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-4,6-dihydro-5H- pyrrolo[3,4-d]thiazole-5-carboxamide (I-61, 67% yield) was obtained as a white solid. ¹H NMR (300 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.43 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.37 (d, J = 8.7 Hz, 2H), 6.14 (s, 1H), 5.47 (s, 1H), 4.73 (m, J = 20.8 Hz, 4H), 4.4-3.9 (m, 4H), 2.55-2.47 (m, 2H), 1.26 (s, 6H). LCMS: 413.1 (M+H), purity- 99.05% by AUC, rt- 3.77, UV-260 nm. Column: X Bridge C18 4.6*50mm*3.5um; Mobile Phase- A: 10 mm ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. HPLC: purity- 96.46% by AUC, rt- 7.07, UV- 270 nm. Column: X Bridge C184.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH₃CN; flow rate: 1.2 mL/min; Diluent: Methanol (100%). EXAMPLE 53 – SYNTHESIS OF 5-FLUORO-N-(4-(1-(4-HYDROXY-1,1-DIOXIDO- TETRAHYDRO-2H-THIOPYRAN-4-CARBONYL)-1,2,3,6-TETRAHYDROPYRIDIN-4- YL)PHENYL)ISOINDOLINE-2-CARBOXAMIDE (I-140) [0848] Step 1: Preparation of tert-butyl 4-(4-(5-fluoroisoindoline-2- carboxamido)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (72-3): 72-3 was prepared according to General Procedure B using tert-butyl 4-(4-((phenoxycarbonyl) amino)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (72-1, 2.0 g, 5.0 mmol) 1.2 g of 72-3 (54% yield) as a white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.46-7.28 (m, 3H), 7.27-7.05 (m, 2H), 6.07 (s, 1H), 4.74 (d, J = 8.0 Hz, 4H), 3.99-3.96 (m, 2H), 3.68-3.44 (m, 2H), 2.46-2.42 (m, 2H), 1.42 (s, 9H). LC-MS: [M+H]⁺ = 438.20. [0849] Step 2: Preparation of 5-fluoro-N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl) isoindoline-2-carboxamide hydrochloride (72-4): 72-4 was prepared according to General Procedure C using tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (72-3, 1.2 g, 2.74 mmol). 1.0 g of 72-4 (98% yield) was obtained as a pale-yellow solid.¹H NMR (300 MHz, DMSO-d6) δ 9.11 (s, 2H), 8.45 (d, J = 24.7 Hz, 1H), 7.57 (dd, J = 18.1, 8.8 Hz, 2H), 7.43-7.32 (m, 3H), 7.26-7.01 (m, 2H), 6.12 (s, 1H), 4.75 (d, J = 7.6 Hz, 4H), 3.73-3.64 (m, 2H), 3.31-3.27 (m, 2H), 2.72-2.66 (m, 2H). LC-MS: [M+H]⁺ = 337.2. [0850] Step 3: Preparation of 5-fluoro-N-(4-(1-(4-hydroxy-1,1-dioxidotetrahydro-2H- thiopyran-4-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide (I- 140): I-140 was prepared according to General Procedure D using 5-fluoro-N-(4-(1,2,3,6- tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide hydrochloride (72-4, 75 mg, 0.2 mmol). 80 mg of 5-fluoro-N-(4-(1-(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-carbonyl)-1,2,3,6- tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide (I-140) (77% yield) as a white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.38 (dd, J = 13.2, 7.0 Hz, 3H), 7.17 (ddd, J = 17.9, 9.9, 4.6 Hz, 2H), 6.14 (d, J = 5.3 Hz, 2H), 4.74 (d, J = 8.0 Hz, 4H), 4.24- 3.49 (m, 5H), 3.25-3.05 (m, 4H), 2.43-2.00 (m, 5H). LCMS: 514.2 (M+H), purity- 98.51% by AUC, rt- 4.28, UV-270 nm. Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mm ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. HPLC: purity- 95.22% by AUC, rt- 39.15, UV- 254 nm. Column: X Bridge C18 4.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH3CN; flow rate: 1.2 mL/min; Diluent: Methanol (100%). EXAMPLE 54 – SYNTHESIS OF N-(4-(1-(1,1-DIOXIDOTETRAHYDRO-2H- THIOPYRAN-4-CARBONYL)-1,2,3,6-TETRAHYDROPYRIDIN-4-YL)PHENYL)-5- FLUOROISOINDOLINE-2-CARBOXAMIDE (I-141) [0851] I-141 was prepared according to General Procedure D using 5-fluoro-N-(4-(1,2,3,6- tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide hydrochloride (72-4) (75 mg, 0.2 mmol). 80 mg of N-(4-(1-(1,1-dioxidotetrahydro-2H-thiopyran-4-carbonyl)-1,2,3,6- tetrahydropyridin-4-yl)phenyl)-5-fluoroisoindoline-2-carboxamide (I-141) (80% yield) as an off white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.48-7.32 (m, 3H), 7.28-7.06 (m, 2H), 6.12 (s, 1H), 4.75 (d, J = 7.9 Hz, 4H), 4.32-3.97 (m, 2H), 3.83-3.56 (m, 2H), 3.25-3.0 (m, 5H), 2.51-2.49 (m, 2H), 2.10-1.95 (m, 4H). LCMS: 498.1 (M+H), purity- 99.32% by AUC, rt- 4.34, UV-270 nm. Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mm ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. HPLC: purity- 92.57% by AUC, rt- 38.93, UV- 245 nm. Column: X Bridge C184.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH3CN; flow rate: 1.2 mL/min; Diluent: Methanol (100%). EXAMPLE 55 – SYNTHESIS OF 3-FLUORO-N-(4-(2-HYDROXY-2-METHYL- PROPANAMIDO)PHENYL)-5,7-DIHYDRO-6H-PYRROLO[3,4-B]PYRIDINE-6- CARBOXAMIDE (I-38) [0852] Step 1: Preparation phenyl (4-nitrophenyl)carbamate (74-2): To a stirred mixture of 74-1 (1.0 g, 7.246 mmol) in EtOAc (10 mL), THF (2 mL), and water (2 mL) was added Na₂CO₃ (460 mg, 4.34 mmol) and phenyl chloroformate (1.2 g, 8.11 mmol) dropwise at 0 ^oC. The mixture was stirred at rt for 16 h. After complete consumption of the starting material, the volatiles were removed under reduced pressure and the resulting mixture was diluted with cold water (100 mL) and the precipitate was filtered and washed with water and then dried under vacuum to afford 1.4 g of 74-2 (76% yield) as a white solid.¹H NMR (300 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.32-8.16 (m, 2H), 7.84-7.67 (m, 2H), 7.47 (dd, J = 10.9, 4.7 Hz, 2H), 7.36-7.21 (m, 3H). [0853] Step 2: Preparation of 3-fluoro-N-(4-nitrophenyl)-5,7-dihydro-6H-pyrrolo[3,4- b]pyridine-6-carboxamide (74-4): 74-4 was prepared according to General Procedure B using phenyl (4-nitrophenyl)carbamate (74-2) (300 mg, 1.42 mmol).380 mg of 74-4 (90% yield) was obtained as a white solid.¹H NMR (300 MHz, DMSO-d₆) δ 9.11 (s, 1H), 8.49 (s, 1H), 8.17 (t, J = 11.5 Hz, 2H), 7.94-7.73 (m, 3H), 4.81 (d, J = 10.7 Hz, 4H). LC-MS: [M+H]⁺ = 303.1. [0854] Step 3: Preparation of N-(4-aminophenyl)-3-fluoro-5,7-dihydro-6H-pyrrolo[3,4- b]pyridine-6-carboxamide (74-5): A solution of 74-4 (380 mg, 1.25 mmol) in EtOH (6 mL) was added Pd-C (50 mg, 10%) at rt, and then the reaction mixture was stirred under a hydrogen atmosphere for 4 h. After complete consumption of the starting material, the reaction mixture was filtered through a pad of celite and washed with EtOH. The combined filtrate was concentrated under reduced pressure to afford 310 mg of 74-5 (91% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.47 (s, 1H), 8.03 (s, 1H), 7.90-7.68 (m, 1H), 7.14 (t, J = 11.7 Hz, 2H), 6.50 (d, J = 8.6 Hz, 2H), 4.92 (s, 2H), 4.70 (d, J = 16.1 Hz, 4H). LC-MS: [M+H]⁺ = 273.20. [0855] Step 4: Preparation of 3-fluoro-N-(4-(2-hydroxy-2-methylpropanamido)phenyl)- 5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide (I-38): I-38 was prepared according to General Procedure D using N-(4-aminophenyl)-3-fluoro-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine- 6-carboxamide (74-5, 80 mg, 0.294 mmol). 22 mg of 3-fluoro-N-(4-(2-hydroxy-2- methylpropanamido)phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide (I-38, 21% yield) was obtained as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.48 (s, 1H), 8.38 (s, 1H), 7.82 (s, 1H), 7.69-7.38 (m, 4H), 5.70 (s, 1H), 4.75 (d, J = 13.0 Hz, 4H), 1.35 (s, 6H). LCMS: 359.0 (M+H), purity- 96.32% by AUC, rt- 3.56, UV-260 nm. Column: X Bridge C18 4.6*50mm*3.5um; Mobile Phase- A: 10 mm ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. HPLC: purity- 98.03% by AUC, rt- 6.35, UV- 270 nm. Column: X Bridge C184.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH₃CN; flow rate: 1.2 mL/min; Diluent: Methanol (100%). EXAMPLE 56 – SYNTHESIS OF 3-FLUORO-N-(4-(3-HYDROXY-3- METHYLBUTANAMIDO)PHENYL)-5,7-DIHYDRO-6H-PYRROLO[3,4-B]PYRIDINE- 6-CARBOXAMIDE (I-37) [0856] I-37 was prepared according to General Procedure D using N-(4-aminophenyl)-3- fluoro-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide (74-5) (70 mg, 0.257 mmol).26 mg of 3-fluoro-N-(4-(3-hydroxy-3-methylbutanamido)phenyl)-5,7-dihydro-6H-pyrrolo[3,4- b]pyridine-6-carboxamide (I-37, 27% yield) was obtained as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.73 (s, 1H), 8.48 (s, 1H), 8.38 (s, 1H), 7.80 (dd, J = 8.9, 2.4 Hz, 1H), 7.46 (d, J = 4.4 Hz, 4H), 4.75 (d, J = 10.9 Hz, 5H), 2.40 (s, 2H), 1.23 (s, 6H). LCMS: 373.34 (M+H), purity- 92.67% by AUC, rt- 3.92, UV-260 nm. Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mm ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. HPLC: purity- 92.65% by AUC, rt- 6.42, UV- 265 nm. Column: X Bridge C184.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH3CN; flow rate: 1.2 mL/min; Diluent: Methanol (100%). EXAMPLE 57 – SYNTHESIS OF 4,5,6,7-TETRAFLUORO-N-(4-(1-(2-HYDROXY-2- METHYLPROPANOYL)PIPERIDIN-4-YL)PHENYL)ISOINDOLINE-2- CARBOXAMIDE (I-41) [0857] Step 1: Preparation of 4,5,6,7-tetrafluoroisoindoline hydrochloride (76-2): To a stirred solution of 76-1 (1.0 g, 4.5 mmol) in THF (10 mL) was added BF₃Et₂O (3.5 mL, 27.3 mmol) at rt and the reaction was stirred for 30 min. Then BH₃THF (54.7 mL, 54.7 mmol) was added dropwise at rt and the reaction mixture was slowly heated to 60 ^oC for 16 h. After completion of the reaction, the reaction mixture was cooled to rt and quenched with MeOH (1.5 mL, dropwise) until the bubbling ceased. Then 2.0 N HCl in water (8 mL) was added and the mixture was again heated to 80 ^oC for 3 h. Then the reaction mixture was cooled to rt and washed with Et2O (2x25 mL). The aqueous layer was brought to pH 14 with 6.0 N NaOH and extracted with EtOAc (3x50 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford the crude product. The residue was dissolved in DCM and HCl (1.0 mL, 4.0M in 1,4-Dioxane) was added at rt and the reaction mixture was stirred for 30 min. The volatiles were removed to afford 300 mg of 76-2 as an HCl salt (30% yield) that was an off white solid.¹H NMR (300 MHz, DMSO-d₆) δ 10.51 (s, 2H), 4.69 (s, 4H). LC-MS: [M+H]⁺ = 192.1. [0858] Step 2: Preparation of 4,5,6,7-tetrafluoro-N-(4-(1-(2-hydroxy-2- methylpropanoyl)piperidin-4-yl)phenyl) isoindoline-2-carboxamide (I-41): I-41 was prepared according to General Procedure B using phenyl (4-(1-(2-hydroxy-2-methylpropanoyl)piperidin-4- yl)phenyl)carbamate (76-2, 100 mg, 0.26 mmol). After completion of reaction, the volatiles were removed under reduced pressure and the reaction mixture was diluted with cold water (25 mL) and extracted with EtOAc (2x20 mL). The combined organic extracts were washed with brine (2x100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product. The product was purified by prep HPLC, which afforded 10 mg of 4,5,6,7-tetrafluoro-N- (4-(1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl)phenyl) isoindoline-2-carboxamide (I-41, 8% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.14 (d, J = 8.6 Hz, 2H), 5.38 (s, 1H), 4.79-4.72 (m, 6H), 2.75-2.69 (m, 3H), 1.80-1.75 (m, 2H), 1.55-1.49 (m, 2H), 1.33 (s, 6H). LCMS: 480.1 (M+H), purity- 99.5% by AUC, rt- 4.84, UV-240 nm. Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mm ammonium acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; flow rate: 0.6 mL/min. HPLC: purity- 99.81% by AUC, rt- 9.59, UV- 245 nm. Column: X Bridge C18 4.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH3CN; flow rate: 1.2 mL/min; Diluent: Methanol (100%). EXAMPLE 58 – SYNTHESIS OF 5-FLUORO-N-(4-(3-((2-HYDROXY-2-METHYL- PROPYL)CARBAMOYL)BICYCLO[1.1.1]PENTAN-1-YL)PHENYL)ISOINDOLINE-2- CARBOXAMIDE (I-16) [0859] Step 1: Preparation of 3-(4-nitrophenyl)bicyclo[1.1.1]pentane-1-carboxylic acid (77-2): To a stirred solution of 77-1 (2.0 g, 10.63 mmol) in trifluoro acetic acid (10 mL) was added fuming nitric acid (0.49 mL, 11.70 mmol) dropwise at 0 °C, then the reaction mixture was stirred at 0 ℃ for 4 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with cold water (25 mL) and stirred at 15 °C for 1 h. The obtained solid was filtered and dried under vacuum. The crude compound was triturated with Et₂O-pentane to afford 77-2 (1.0 g, 40%) as an off white solid.¹H NMR (300 MHz, CDCl₃) δ 8.19 (d, J = 8.7 Hz, 2H), 7.37 (d, J = 8.7 Hz, 2H), 2.43 (s, 6H). LC-MS: [M+H]⁺ = 234.2. [0860] Step 2: Preparation of methyl 3-(4-nitrophenyl)bicyclo[1.1.1]pentane-1- carboxylate (77-3): To a stirred solution of 77-2 (1.0 g, 4.29 mmol) in methanol (20 mL) was added thionyl chloride (1 mL) at 0 ℃ and the solution was heated to 60 ℃ for 5 hours. Then the reaction mixture was allowed to warm to rt and the volatiles were removed under reduced pressure. The concentrated mixture was quenched with sat. aqueous NaHCO₃ and extracted with EtOAc. The combined organic extracts were washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain 1.0 g of 77-3 (94%) as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.20 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 8.8 Hz, 2H), 3.64 (s, 3H), 2.35 (s, 6H). LC-MS: [M+H]⁺ = 248.1. [0861] Step 3: Preparation of methyl 3-(4-aminophenyl)bicyclo[1.1.1]pentane-1- carboxylate (77-4): To a stirred solution of 77-3 (1.0 g, 4.0 mmol) in DMF (10 mL) was added 4,4’-bipyridine (31.5 mg, 0.2 mmol) and hypodiboric acid (1.45 g, 16.1 mmol) at 0 ℃ and stirred for 10 min. The reaction mixture was diluted with ice cold water and extracted with EtOAc (2x25 mL), the combined organic extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain 77-4 (800 mg, 90%) as a pale-yellow semi solid.¹H NMR (300 MHz, DMSO-d6) δ 6.87 (d, J = 8.3 Hz, 2H), 6.49 (d, J = 8.4 Hz, 2H), 4.99 (s, 2H), 3.64 (s, 3H), 2.15 (s, 6H). LC-MS: [M+H]⁺ = 218.20. [0862] Step 4: Preparation of methyl 3-(4-((phenoxycarbonyl)amino) phenyl) bicyclo[1.1.1] pentane-1-carboxylate (77-5): 77-5 was prepared according to General Procedure A using methyl 3-(4-aminophenyl) bicyclo[1.1.1]pentane-1-carboxylate (77-4) (260 mg, 1.19 mmol). The product was obtained after filtration, which afforded 300 mg of 77-5 (74% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 10.20 (s, 1H), 7.53-7.35 (m, 4H), 7.29-7.14 (m, 5H), 3.63 (s, 3H), 2.24 (s, 6H). LC-MS: [M+H]⁺ = 338.20. [0863] Step 5: Preparation of methyl 3-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) bicyclo[1.1.1]pentane-1-carboxylate (77-7): 77-7 was prepared according to General Procedure B using methyl 3-(4-((phenoxycarbonyl) amino)phenyl)bicyclo[1.1.1]pentane-1-carboxylate (77- 5) (300 mg, 0.89 mmol). The product was obtained after filtration, which afforded 290 mg of 77- 7 (85% yield) as a white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.36 (s, 1H), 7.51 (d, J = 8.5 Hz, 2H), 7.38 (dd, J = 8.4, 5.2 Hz, 2H), 7.29-7.16 (m, 1H), 7.13 (d, J = 8.5 Hz, 2H), 4.73 (d, J = 7.8 Hz, 4H), 3.63 (s, 3H), 2.23 (s, 6H). LC-MS: [M+H]⁺ = 381.20. [0864] Step 6: Preparation of 3-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) bicyclo[1.1.1] pentane-1-carboxylic acid (77-8): LiOHH₂O (105 mg, 4.56 mmol) was added to a stirred solution of 77-7 (290 mg, 0.76 mmol) in THF, methanol and water (2:2:1, 25 mL) at rt and stirred for 16 h. The reaction was diluted with EtOAc (2x15 mL) and quenched using 1M HCl. The layers were separated, the organic layer was washed with brine, dried with Na₂SO₄ and concentrated under reduced pressure to yield 230 mg of 77-8 (82% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 12.38 (s, 1H), 8.36 (s, 1H), 7.50 (d, J = 8.5 Hz, 2H), 7.38 (dd, J = 8.3, 5.2 Hz, 1H), 7.19 (dd, J = 20.2, 9.0 Hz, 2H), 7.12 (d, J = 8.5 Hz, 2H), 4.73 (d, J = 8.3 Hz, 4H), 2.18 (s, 6H). LC-MS: [M+H]⁺ = 367.20. [0865] Step 7: Preparation of 5-fluoro-N-(4-(3-((2-hydroxy-2-methylpropyl)carbamoyl) bicyclo[1.1.1]pentan-1-yl)phenyl)isoindoline-2-carboxamide (I-16): I-16 was prepared according to General Procedure D using 3-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) bicyclo[1.1.1]pentane-1-carboxylic acid (77-8) (100 mg, 0.27 mmol). The product was obtained after filtration, which afforded 80 mg of 5-fluoro-N-(4-(3-((2-hydroxy-2-methylpropyl) carbamoyl)bicyclo[1.1.1]pentan-1-yl)phenyl)isoindoline-2-carboxamide (I-16, 67% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.50 (d, J = 8.5 Hz, 3H), 7.38 (dd, J = 8.2, 5.4 Hz, 1H), 7.28-7.16 (m, 2H), 7.11 (d, J = 8.4 Hz, 2H), 4.73 (d, J = 8.0 Hz, 4H), 4.49 (s, 1H), 3.05 (d, J = 6.1 Hz, 2H), 2.17 (d, J = 9.1 Hz, 6H), 1.04 (s, 6H). LCMS: 438.38 (M+H), purity: 97.33% by AUC, RT: 4.72, UV: 220 nm. HPLC: purity: 97.38% by AUC, RT: 8.32, UV: 250 nm. EXAMPLE 59 - SYNTHESIS OF BENZYL (3-(4-(5-FLUOROISOINDOLINE-2- CARBOXAMIDO)PHENYL)BICYCLO[1.1.1]PENTAN-1-YL)CARBAMATE (I-15) AND 5-FLUORO-N-(4-(3-(2-HYDROXY-2-METHYL-PROPANAMIDO)BICYCLO [1.1.1]PENTAN-1-YL)PHENYL)ISOINDOLINE-2-CARBOXAMIDE (I-166) [0866] Step 1: Preparation of benzyl (3-(4-nitrophenyl)bicyclo[1.1.1]pentan-1- yl)carbamate (78-2): To a stirred solution of 78-1 (500 mg, 2.14 mmol) in toluene (10 mL) and THF (2 mL) was added triethyl amine (0.59 mL, 4.29 mmol) and diphenyl phosphoryl azide (0.59 mL, 2.57 mmol) at ambient temperature and the reaction mixture was stirred at rt for 2 h. Then, benzyl alcohol (0.75 mL, 7.31 mmol) was added and the reaction mixture was stirred at 100 ℃ for 16 h. The reaction mixture was cooled to rt, diluted with cold water (25 mL), extracted with EtOAc (2x25 mL), and the combined organic extracts were washed with sat aq. NaHCO3 (25 mL). The organic layer was separated, dried, and concentrated to obtain a residue. The product was purified by column chromatography (18-20% EtOAc/heptane) to provide 77-2 (400 mg, 55%) as an off white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.16 (t, J = 8.8 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 7.45-7.29 (m, 5H), 5.02 (s, 2H), 4.5-4.48 (m, 1H), 2.28 (s, 6H). LC-MS: [M+H]⁺ = 339.20. [0867] Step 2: Preparation of benzyl (3-(4-aminophenyl)bicyclo[1.1.1]pentan-1- yl)carbamate (78-3): To a stirred solution of 78-2 (300 mg, 1.21 mmol) in DMF (5 mL) was added 4,4’-bipyridine (9.4 mg, 0.06 mmol) and hypodiboric acid (433 mg, 4.85 mmol) at 0 ℃ and the reaction mixture was stirred for 10 min. The reaction mixture was diluted with ice cold water and extracted with EtOAc (2x25 mL), the combined organic extracts were washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure to afford 260 mg of 78-3 (83% yield) as pale-yellow semi solid.¹H NMR (300 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.41- 7.25 (m, 5H), 6.85 (d, J = 8.3 Hz, 2H), 6.47 (d, J = 8.3 Hz, 2H), 5.0-4.93 (m, 4H), 2.03 (d, J = 24.4 Hz, 6H). LC-MS: [M+H]⁺ = 309.20. [0868] Step 3: Preparation of benzyl (3-(4-((phenoxycarbonyl)amino)phenyl)bicyclo [1.1.1]pentan-1-yl)carbamate (78-4): 78-4 was prepared according to General Procedure A using benzyl (3-(4-aminophenyl)bicyclo[1.1.1]pentan-1-yl)carbamate (78-3) (260 mg, 1.19 mmol). The product was obtained after filtration, which afforded 300 mg of 78-4 (59% yield) as a white solid. ¹H NMR (300 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.03 (s, 1H), 7.52-7.07 (m, 13H), 6.76 (t, J = 7.4 Hz, 1H), 5.01 (s, 2H), 2.16 (s, 6H). LC-MS: [M+H]⁺ = 429.20. [0869] Step 4: Preparation of benzyl (3-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) bicyclo[1.1.1]pentan-1-yl) carbamate (I-15): I-15 was prepared according to General Procedure B using benzyl (3-(4-((phenoxycarbonyl)amino)phenyl)bicyclo[1.1.1]pentan-1-yl)carbamate (78- 4) (300 mg, 0.89 mmol). The product was obtained after filtration, which afforded 290 mg of benzyl (3-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)bicyclo [1.1.1]pentan-1-yl) carbamate (I-15, 69% yield) as a white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.02 (s, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.42-7.29 (m, 6H), 7.27-7.00 (m, 4H), 5.02 (s, 2H), 4.73 (d, J = 8.1 Hz, 4H), 2.16 (s, 6H). LCMS: 472.36 (M+H), purity: 97.61% by AUC, RT: 5.75, UV: 210 nm. HPLC: purity: 98.05% by AUC, rt: 10.60, UV: 250 nm. [0870] Step 5: Preparation of N-(4-(3-aminobicyclo[1.1.1]pentan-1-yl)phenyl)-5- fluoroisoindoline-2-carboxamide hydrobromide (78-7): To a stirred solution of I-15 (150 mg, 0.32 mmol) in AcOH (3.5 mL) was added HBr (1.3 mL, 33% in AcOH) slowly at 0 ℃ under a nitrogen atmosphere, and then the reaction mixture was stirred at rt for 16 h. After complete consumption of starting material, the volatiles were removed under reduced pressure to afford the crude compound. The crude compound was triturated with MTBE to give 120 mg of 78-7 (90%) as pale brown solid.¹H NMR (300 MHz, DMSO-d6) δ 8.59 (s, 3H), 8.39 (s, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.39 (dd, J = 8.4, 5.3 Hz, 1H), 7.28-7.04 (m, 4H), 4.73 (d, J = 8.0 Hz, 4H), 2.23 (s, 6H). LC-MS: [M+H]⁺ = 338.20. [0871] Step 6: Preparation of 5-fluoro-N-(4-(3-(2-hydroxy-2-methylpropanamido) bicyclo[1.1.1]pentan-1-yl) phenyl)isoindoline-2-carboxamide (I-166): I-166 was prepared according to General Procedure D using N-(4-(3-aminobicyclo[1.1.1]pentan-1-yl)phenyl)-5- fluoroisoindoline-2-carboxamide hydrobromide (78-7) (120 mg, 0.28 mmol). The product was obtained after filtration, which afforded 60 mg of 5-fluoro-N-(4-(3-(2-hydroxy-2- methylpropanamido)bicyclo[1.1.1]pentan-1-yl)phenyl)isoindoline-2-carboxamide (I-166, 56% yield) as a white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.34 (s, 1H), 8.13 (s, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.38 (dd, J = 8.3, 5.2 Hz, 1H), 7.25-7.05 (m, 4H), 5.33 (s, 1H), 4.73 (d, J = 8.2 Hz, 4H), 2.32-2.10 (m, 6H), 1.24 (s, 6H). LCMS: 424.4 (M+H), purity: 97.22% by AUC, RT: 4.83, UV: 210 nm. HPLC: purity: 95.15% by AUC, RT: 8.67, UV: 252 nm. EXAMPLE 60 – SYNTHESIS OF 4,5,6-TRIFLUORO-N-(4-(1-(2-HYDROXY-2- METHYLPROPANOYL)PIPERIDIN-4-YL)PHENYL)ISOINDOLINE-2- CARBOXAMIDE (I-14) [0872] Step 1: Preparation of methyl 3,4,5-trifluorobenzoate (79-2): To a stirred solution of 79-1 (10.0 g, 56 mmol) in methanol (100 mL) was added thionyl chloride (10.14 mL, 56 mmol) at 0 ℃ and the solution was heated to 70 ℃ for 5 hours. Then the reaction mixture was allowed to warm to rt and the volatiles were removed under reduced pressure. The residue was quenched with a sat. aq. NaHCO₃ solution (50 mL) and extracted with EtOAc (2x50 mL). The combined organic extracts were washed with water, brine, dried over anhydrous Na2SO4 and concentrated in vacuo to afford 8.0 g of 79-2 (74%) as a colorless oil.¹H NMR (300 MHz, DMSO-d6) δ 7.71-7.66 (m, 2H), 3.93 (s, 3H). LC-MS: [M+H]⁺ = 191.1. [0873] Step 2: Preparation of 2,3,4-trifluoro-6-(methoxycarbonyl)benzoic acid (79-3): To a dry 2-necked round bottom flask was added a solution of diisopropylamine (9.2 mL, 65.8 mmol) in THF (40 mL). The flask was cooled to -78 ℃ and a solution of n-BuLi (16 mL, 52.6 mmol, 2.5M in n-hexanes) was added dropwise. Then the reaction mixture was stirred at 0 ℃ to 20 ℃ for 30 min. A solution of 79-2 (5.0 g, 26.3 mmol) in THF (10 mL) was added dropwise at -78 ℃ and the mixture was stirred for 1.5 h and then was allowed to warm to 20 ℃. CO₂ gas was bubbled through the reaction mixture, and the mixture was stirred at 20 ℃ for 2 h. A sodium hydroxide solution (50 mL, 1.0N in H2O) was added and the resulting mixture was extracted with t-butyl methyl ether (2x20 mL). The aqueous layer was acidified with 6.0N HCl to pH 1 and extracted with EtOAc (3x40 mL). The combined organic extracts were dried over Na₂SO₄ and concentrated to give 78-3 (3.8 g crude) as a white solid. The crude product was used for the next step directly. ¹H NMR (300 MHz, DMSO-d6) δ 14.12 (s, 1H), 7.95-7.72 (m, 1H), 3.96 (s, 3H). LC-MS: [M+H]⁺ = 235.2. [0874] Step 3: Preparation of 3,4,5-trifluorophthalic acid (79-4): Sodium hydroxide (1.94 g, 48.72 mmol) was added to a solution of 79-3 (3.8 g crude, 16.24 mmol) in methanol and water (6:1, 70 mL), and then the reaction mixture was heated to 70 ℃ for 2 h. The reaction was diluted with EtOAc (2x50 mL) and quenched using 6.0N HCl. The layers were separated, the organic layer was washed with brine, dried with Na2SO4 and concentrated under reduced pressure to afford 79-4 (2.3 g crude) as a white solid.¹H NMR (300 MHz, DMSO-d6) δ 13.84 (brs, 2H), 7.82-7.78 (m, 1H). LC-MS: [M+H]⁺ = 221.1. [0875] Step 4: Preparation of 4,5,6-trifluoroisoindoline-1,3-dione (79-5): A solution of 79- 4 (2.3 g, crude) in acetic anhydride (10 mL) was stirred at 120 °C for 3 hours. To the above mixture was added ammonia acetate (7.24 g) at 25 °C. The resulting mixture was stirred at 120 °C for 16 h. The reaction mixture was cooled to rt, quenched with ice cold water (30 mL), and diluted with EtOAc (2x50 mL). The combined organic extracts were dried with Na2SO4 and concentrated under reduced pressure to afford the crude. The crude was purified by flash column chromatography using silica gel (eluting with ethyl acetate in petroleum ether from 0 to 20%) to give 370 mg of 79-5 as a white solid.¹H NMR (300 MHz, DMSO) δ 11.74 (s, 1H), 8.03-7.76 (m, 1H). LC-MS: [M+H]⁺ = 202.2. [0876] Step 5: Preparation of 4,5,6-trifluoroisoindoline (79-6): To a stirred solution of 79-5 (370 mg, 1.83 mmol) in THF (4 mL) was added BF₃Et₂O (1.35 mL, 10.99 mmol) at rt and then the reaction mixture was stirred for 30 min. BH3THF (22 mL, 21.97 mmol) was then added dropwise at rt and the reaction mixture was slowly heated to 60 ℃ for 16 h. After completion of the reaction, the reaction mixture was cooled to rt and quenched with MeOH (2 mL, dropwise) until the bubbling ceased. Then 3.0N HCl (5 mL) was added and the mixture was again heated to 80 ℃ for 2 h. Then the reaction mixture was cooled to rt and washed with Et2O (2x25 mL). The aqueous layer was brought to pH 14 with a 6.0N NaOH solution and extracted with EtOAc (3x50 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford 250 mg of crude 79-6. The crude was dissolved in 1,4-dioxane (3.0 mL) and HCl (1.0 mL, 4.0M in 1,4-dioxane) was added at 0 ℃, stirred for 30 min, and then the volatiles were removed under reduced pressure and the crude was triturated with MTBE to afford 210 mg of 79-6 (66% yield) as a light pink solid.¹H NMR (300 MHz, DMSO-d6) δ 10.10 (brs, 2H), 7.54- 7.35 (m, 1H), 4.57 (d, J = 29.5 Hz, 4H). LC-MS: [M+H]⁺ = 174.1. [0877] Step 6: Preparation of tert-butyl 4-(4-(4,5,6-trifluoroisoindoline-2- carboxamido)phenyl)piperidine-1-carboxylate (79-8): 79-8 was prepared according to General Procedure B using tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)piperidine-1-carboxylate (79- 7, 150 mg, 0.38 mmol). The product was obtained after filtration, which afforded 170 mg of 79-8 as a white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.39 (s, 1H), 7.42 (dd, J = 17.8, 8.5 Hz, 3H), 7.13 (d, J = 8.5 Hz, 2H), 4.79 (d, J = 26.1 Hz, 4H), 4.06 (d, J = 12.0 Hz, 2H), 2.82-2.77 (m, 2H), 2.74-2.6 (m, 1H), 2.6-2.4 (m, 2H), 1.75-1.71 (m, 2H), 1.45 (s, 9H). LC-MS: [M+H]⁺ = 476.30. [0878] Step 7: Preparation of 4,5,6-trifluoro-N-(4-(piperidin-4-yl)phenyl)isoindoline-2- carboxamide hydrochloride (79-9): 79-9 was prepared according to General Procedure C using tert-butyl 4-(4-(4,5,6-trifluoroisoindoline-2-carboxamido)phenyl)piperidine-1-carboxylate (79-8) (170 mg, 0.35 mmol). The obtained solid was filtered and dried to obtain 120 mg of 79-9 (89% yield) as a white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.8-8.74 (m, 2H), 8.47 (s, 1H), 7.50 (d, J = 8.6 Hz, 2H), 7.45-7.34 (m, 1H), 7.12 (d, J = 8.6 Hz, 2H), 4.80 (d, J = 26.9 Hz, 4H), 3.36-3.32 (m, 2H), 3.02-2.94 (m, 2H), 2.78-2.72 (m, 1H), 1.92-1.77 (m, 4H). LC-MS: [M+H]⁺ = 376.30. [0879] Step 8: Preparation of 4,5,6-trifluoro-N-(4-(1-(2-hydroxy-2-methylpropanoyl) piperidin-4-yl)phenyl) isoindoline-2-carboxamide (I-14): I-14 was prepared according to General Procedure D using 4,5,6-trifluoro-N-(4-(piperidin-4-yl)phenyl)isoindoline-2- carboxamide (79-9) (100 mg, 0.211 mmol). The product was obtained after filtration, which afforded 75 mg of 4,5,6-trifluoro-N-(4-(1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl)phenyl) isoindoline-2-carboxamide (I-14, 61% yield) as an off-white solid.¹H NMR (300 MHz, DMSO- d₆) δ 8.39 (s, 1H), 7.43 (dd, J = 20.8, 7.8 Hz, 3H), 7.13 (d, J = 8.5 Hz, 2H), 5.38 (s, 1H), 4.79 (d, J = 26.3 Hz, 6H), 2.79-2.74 (m, 3H), 1.79-1.75 (m, 2H), 1.51 (s, 2H), 1.33 (s, 6H). LCMS: 462.32 (M+H), purity: 96.27% by AUC, RT: 5.20, UV: 220 nm HPLC: purity: 96.10% by AUC, RT: 9.42, UV: 240 nm. EXAMPLE 61 - SYNTHESIS OF 3-FLUORO-N-(4-(2-(TETRAHYDRO-2H-PYRAN-4- YL)ACETAMIDO)PHENYL)-5,7-DIHYDRO-6H-PYRROLO[3,4-B]PYRIDINE-6- CARBOXAMIDE (I-145) [0880] Compound I-145 was prepared according to General Procedure D using N-(4- aminophenyl)-3-fluoro-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide (80-1) (100 mg, 0.36 mmol). The product was obtained after filtration, which afforded 30 mg of 3-fluoro-N-(4-(2- (tetrahydro-2H-pyran-4-yl)acetamido)phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6- carboxamide (I-145, 21% yield) as a white solid.¹H NMR (300 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.47 (s, 1H), 8.36 (s, 1H), 7.80 (d, J = 9.0 Hz, 1H), 7.46 (s, 4H), 4.74 (d, J = 13.8 Hz, 4H), 3.83 (d, J = 8.4 Hz, 2H), 3.29-3.19 (m, 2H), 2.37-2.15 (m, 2H), 1.98 (s, 1H), 1.61-1.56 (m, 2H), 1.24 (m, 2H). LCMS: 399.33 (M+H), purity: 98.34% by AUC, RT: 4.03, UV:260 nm HPLC: purity: 97.83% by AUC, RT: 3.01, UV: 270 nm. EXAMPLE 62 – SYNTHESIS OF 3-FLUORO-N-(4-(2-(TETRAHYDROFURAN-3- YL)ACETAMIDO)PHENYL)-5,7-DIHYDRO-6H-PYRROLO[3,4-B]PYRIDINE-6- CARBOXAMIDE (I-13) [0881] Compound I-13 was prepared according to General Procedure D using N-(4- aminophenyl)-3-fluoro-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide (80-1) (100 mg, 0.36 mmol). The product was obtained after filtration, which afforded 30 mg of 3-fluoro-N-(4-(2- (tetrahydrofuran-3-yl)acetamido)phenyl)-5,7-dihydro-6H-pyrrolo [3,4-b]pyridine-6-carboxamide (I-13, 21% yield) as a white solid.¹H NMR (300 MHz, DMSO-d6) δ 9.81 (s, 1H), 8.48 (s, 1H), 8.36 (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.46 (s, 4H), 4.74 (d, J = 13.7 Hz, 4H), 3.89-3.51 (m, 3H), 3.32 (m, 1H), 2.5-2.41 (m, 1H), 2.38 (d, J = 6.6 Hz, 2H), 2.00 (s, 1H), 1.56 (d, J = 7.1 Hz, 1H). LCMS: 385.34 (M+H), purity: 97.42% by AUC, RT: 3.95, UV: 260 nm. HPLC: purity: 96.23% by AUC, RT: 6.60, UV: 270 nm. EXAMPLE 63 – SYNTHESIS OF 3-FLUORO-N-(4-(3-HYDROXY-2,2-DIMETHYL- PROPANAMIDO)PHENYL)-5,7-DIHYDRO-6H-PYRROLO[3,4-B]PYRIDINE-6- CARBOXAMIDE (I-12) [0882] Compound I-12 was prepared according to General Procedure D using N-(4- aminophenyl)-3-fluoro-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide (80-1) (100 mg, 0.36 mmol). The product was obtained after filtration, which afforded 18 mg of 3-fluoro-N-(4-(3- hydroxy-2,2-dimethylpropanamido)phenyl)-5,7-dihydro-6H-pyrrolo [3,4-b]pyridine-6- carboxamide (I-12, 13% yield) as a white solid.¹H NMR (300 MHz, DMSO-d₆) δ 9.15 (s, 1H), 8.48 (s, 1H), 8.37 (s, 1H), 7.80 (d, J = 7.0 Hz, 1H), 7.58-7.32 (m, 4H), 5.11 (s, 1H), 4.75 (d, J = 13.6 Hz, 4H), 3.49 (s, 2H), 1.13 (s, 6H). LCMS: 373.1 (M+H), purity: 99.19% by AUC, RT: 3.519, UV:260 nm. HPLC: purity: 98.25% by AUC, RT: 6.52, UV: 270 nm. EXAMPLE 64 – SYNTHESIS OF 3-FLUORO-N-(4-(1-(1-HYDROXYCYCLOBUTANE-1- CARBONYL)PIPERIDIN-4-YL)PHENYL)-5,7-DIHYDRO-6H-PYRROLO[3,4-B] PYRIDINE-6-CARBOXAMIDE (I-10) [0883] To a stirred solution of 81-1 (100 mg, 0.29 mmol) in DMF (5 mL) was added 81-3 (57 mg, 0.29 mmol), EDCI (230 mg, 1.1 mmol), HOBt (179 mg, 1.1 mmol) and triethylamine (0.2 mL, 1.45 mmol) at rt. The reaction mixture was then stirred at rt for 16 h. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, the reaction mixture was diluted with ice cold water and the precipitate was filtered and washed with water. The solids were dried to give the crude compound. The crude compound was triturated with hexanes (25 mL) to afford 32 mg of 3-fluoro-N-(4-(1-(1-hydroxycyclobutane-1- carbonyl)piperidin-4-yl)phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide (I-10, 25% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.48 (s, 1H), 8.35 (s, 1H), 7.79 (d, J = 6.6 Hz, 1H), 7.47 (d, J = 8.5 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H), 5.90 (s, 1H), 4.75 (d, J = 14.4 Hz, 4H), 4.53-4.50 (m, 1H), 4.22-4.16 (m, 1H), 2.99 (t, J = 12.2 Hz, 1H), 2.84-2.56 (m, 4H), 2.20-1.92 (m, 2H), 1.78-1.68 (m, 3H), 1.65-1.34 (m, 3H). LCMS: 439.39 (M+H), purity: 99.30% by AUC, RT: 4.43, UV: 220 nm. HPLC: purity: 98.33% by AUC, RT: 7.57, UV: 240 nm. EXAMPLE 65 – SYNTHESIS OF 3-FLUORO-N-(4-(1-(3-HYDROXYOXETANE-3- CARBONYL)PIPERIDIN-4-YL)PHENYL)-5,7-DIHYDRO-6H-PYRROLO[3,4- B]PYRIDINE-6-CARBOXAMIDE (I-9) [0884] Compound I-9 was prepared according to General Procedure D using 3-fluoro-N-(4- (piperidin-4-yl)phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide (81-1) (100 mg, 0.29 mmol). The product was obtained after filtration, which afforded 30 mg of 3-fluoro-N-(4- (1-(3-hydroxyoxetane-3-carbonyl)piperidin-4-yl)phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine- 6-carboxamide (I-9, 24% yield) as a white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.48 (s, 1H), 8.36 (s, 1H), 7.80 (d, J = 9.0 Hz, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 6.75 (s, 1H), 4.94 (d, J = 6.7 Hz, 1H), 4.85 (d, J = 6.8 Hz, 1H), 4.75 (d, J = 14.4 Hz, 4H), 4.49 (dd, J = 6.7, 2.9 Hz, 2H), 3.61-3.55 (m, 1H), 3.07-3.03 (m, 1H), 2.66 (m, 3H), 1.75-1.71 (m, 2H), 1.54- 1.51 (m, 2H). LCMS: 441.30 (M+H), purity: 95.82% by AUC, RT: 4.13, UV: 220 nm. HPLC: purity: 92.19% by AUC, RT: 6.95, UV: 240 nm. EXAMPLE 66 – SYNTHESIS OF N-(4-(1-(CYCLOPROPYLSULFONYL)PIPERIDIN-4- YL)PHENYL)-3-FLUORO-5,7-DIHYDRO-6H-PYRROLO[3,4-B]PYRIDINE-6- CARBOXAMIDE (I-8) [0885] To a stirred solution of 81-1 (70 mg, 0.20 mmol) in DMF (5.0 mL) was added triethyl amine (0.3 mL, 2.0 mmol), followed by 81-6 (42 mg, 0.30 mmol) at 0 ℃ dropwise. The reaction mixture was stirred at rt for 24 h, and then the reaction mixture was diluted with ice cold water and stirred for an additional 10 min. The precipitate was filtered and dried to afford 18 mg of N- (4-(1-(cyclopropylsulfonyl)piperidin-4-yl)phenyl)-3-fluoro-5,7-dihydro-6H-pyrrolo[3,4- b]pyridine-6-carboxamide (I-8, 20% yield) as an off-white solid.¹H NMR (300 MHz, DMSO- d6) δ 8.48 (s, 1H), 8.37 (s, 1H), 7.80 (d, J = 9.1 Hz, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.5 Hz, 2H), 4.75 (d, J = 14.1 Hz, 4H), 3.73-3.69 (m, 2H), 2.93 (t, J = 11.4 Hz, 2H), 2.70-2.53 (m, 2H), 1.87-1.83 (m, 2H), 1.66-1.62 (m, 2H), 1.10-0.82 (m, 4H). LCMS: 445.1 (M+H), purity: 99.16% by AUC, RT: 4.27, UV:250 nm. HPLC: purity: 98.79% by AUC, RT: 6.21, UV: 240 nm. EXAMPLE 67 – SYNTHESIS OF 3-FLUORO-N-(4-(1-((2-METHOXYETHYL) SULFONYL)PIPERIDIN-4-YL)PHENYL)-5,7-DIHYDRO-6H-PYRROLO[3,4- B]PYRIDINE-6-CARBOXAMIDE (I-164) [0886] To a stirred solution of 81-1 (70 mg, 0.20 mmol) in DMF (5.0 mL) was added triethylamine (0.3 mL, 2.0 mmol) and 81-2 (0.037 mL, 0.30 mmol) at 0 ℃ dropwise. The reaction mixture was stirred at rt for 16 h and the reaction mixture was poured into ice cold water, stirred for 10 min, and the precipitate was filtered and dried to obtain the crude product. The residue was purified by prep HPLC purification, which afforded 23 mg of 3-fluoro-N-(4-(1-((2- methoxyethyl)sulfonyl)piperidin-4-yl)phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6- carboxamide (I-164, 25% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.48 (s, 1H), 8.37 (s, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 8.6 Hz, 2H), 4.75 (d, J = 14.1 Hz, 4H), 3.69-3.65 (m, 3H), 3.41-3.21 (m, 6H), 2.91-2.85 (m, 2H), 1.85-1.81 (m, 3H), 1.65-1.59 (m, 2H). LCMS: 463.33 (M+H), purity: 96.0% by AUC, RT: 4.68, UV:240 nm. EXAMPLE 68 – SYNTHESIS OF 3-FLUORO-N-(4-(1-(1-HYDROXYCYCLOPROPANE- 1-CARBONYL)PIPERIDIN-4-YL)PHENYL)-5,7-DIHYDRO-6H-PYRROLO[3,4- B]PYRIDINE-6-CARBOXAMIDE (I-163) [0887] I-163 was prepared according to General Procedure D using 3-fluoro-N-(4-(piperidin- 4-yl)phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide (81-1) (100 mg, 0.29 mmol). The product was obtained after filtration, which afforded 20 mg of 3-fluoro-N-(4-(1-(1- hydroxycyclopropane-1-carbonyl)piperidin-4-yl)phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine- 6-carboxamide (I-163, 16% yield) as a white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.48 (s, 1H), 8.36 (s, 1H), 7.79 (dd, J = 8.9, 2.5 Hz, 1H), 7.47 (d, J = 8.5 Hz, 2H), 7.12 (t, J = 9.4 Hz, 2H), 6.30 (s, 1H), 4.75 (d, J = 14.1 Hz, 4H), 4.53 (s, 2H), 2.88-2.69 (m, 4H), 1.79 (d, J = 11.7 Hz, 2H), 1.47- 1.39 (m, 2H), 1.25-1.21 (m, 1H), 1.05-0.83 (m, 2H). LCMS: 425.38 (M+H), purity: 93.05% by AUC, RT: 4.27, UV:240 nm. HPLC: purity: 90.35% by AUC, RT: 7.32, UV: 240 nm. EXAMPLE 69 – SYNTHESIS OF 4,6-DIFLUORO-N-(4-(2-HYDROXY-2- METHYLPROPANAMIDO)PHENYL)ISOINDOLINE-2-CARBOXAMIDE (I-165) [0888] Step 1: Preparation of 4,6-difluoro-N-(4-nitrophenyl)isoindoline-2-carboxamide (82-3): 82-3 was prepared according to General Procedure B using phenyl (4- nitrophenyl)carbamate (82-1, 300 mg, 1.93 mmol). The product was obtained after filtration, which afforded 250 mg of 82-3 (40% yield) as a white solid.¹H NMR (300 MHz, DMSO-d₆) δ 9.12 (s, 1H), 8.19 (d, J = 9.2 Hz, 2H), 7.86 (d, J = 9.3 Hz, 2H), 7.30-7.11 (m, 2H), 4.84 (s, 4H). LC-MS: [M+H]⁺ = 320.1. [0889] Step 2: Preparation of N-(4-aminophenyl)-4,6-difluoroisoindoline-2-carboxamide (82-4): To a solution of 82-3 (250 mg, 0.78 mmol) in DMF (3 mL) was added hypoboric acid (278 mg, 3.13 mmol) and 4,4’-bipyridine (6.1 mg, 0.04 mmol) at 0 ℃, and then the reaction mixture was stirred at rt for 20 min. After complete consumption of the starting material, the reaction mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product (82-4, 170 mg). The crude product was used in the next step without further purification.¹H NMR (300 MHz, DMSO-d₆) δ 7.53-7.36 (m, 1H), 7.26-7.04 (m, 4H), 6.48 (d, J = 8.6 Hz, 2H), 4.88-4.64 (m, 6H). LC-MS: [M+H]⁺ = 290.3. [0890] Step 3: Preparation of 4,6-difluoro-N-(4-(2-hydroxy-2-methylpropanamido) phenyl)isoindoline-2-carboxamide (I-165): I-165 was prepared according to General Procedure D using N-(4-aminophenyl)-4,6-difluoroisoindoline-2-carboxamide (82-4) (100 mg, 0.34 mmol). The product was obtained after filtration, which afforded 32 mg of 4,6-difluoro-N-(4-(2-hydroxy- 2-methylpropanamido)phenyl)isoindoline-2-carboxamide (I-165, 24% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 9.41 (s, 1H), 8.38 (s, 1H), 7.60 (d, J = 8.9 Hz, 2H), 7.46 (d, J = 8.9 Hz, 2H), 7.19 (dd, J = 14.4, 9.0 Hz, 2H), 5.69 (s, 1H), 4.78 (s, 4H), 1.34 (s, 6H). LCMS: 376.27 (M+H), purity: 96.79% by AUC, RT: 4.73, UV:260 nm. HPLC: purity: 97.09% by AUC, RT: 7.16, UV: 260 nm. EXAMPLE 70 – SYNTHESIS OF 4-FLUORO-N-(4-(1-(2-((2-HYDROXY-2-METHYL- PROPYL)AMINO)-2-OXOACETYL)-1,2,3,6-TETRAHYDROPYRIDIN-4-YL)PHENYL) ISOINDOLINE-2-CARBOXAMIDE (I-162) [0891] Step 1: Preparation of tert-butyl 4-(4-(4-fluoroisoindoline-2- carboxamido)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (83-3): 83-3 was prepared according to General Procedure B using tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (83-1) (300 mg, 1.73 mmol). The product was obtained after filtration, which afforded 480 mg of 83-3 (63% yield) as a white solid. ¹H NMR (300 MHz, DMSO-d6) δ 8.45 (s, 1H), 7.56 (d, J = 8.7 Hz, 2H), 7.38 (dd, J = 16.2, 8.2 Hz, 3H), 7.25-7.05 (m, 2H), 6.08 (s, 1H), 4.82 (d, J = 6.8 Hz, 4H), 3.98 (s, 2H), 3.53 (t, J = 5.6 Hz, 2H), 2.44 (s, 2H), 1.43 (s, 9H). LC-MS: [M+H]⁺ = 438.3. [0892] Step 2: Preparation of 4-fluoro-N-(4-(1,2,3,6-tetrahydropyridin-4- yl)phenyl)isoindoline-2-carboxamide hydrochloride (83-4): 83-4 was prepared according to General Procedure C using tert-butyl 4-(4-(4-fluoroisoindoline-2-carboxamido)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (83-3) (400 mg, 0.91 mmol). The product was obtained after filtration, which afforded 200 mg of 83-4 (59% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.56 (d, J = 8.7 Hz, 2H), 7.37 (dd, J = 17.6, 8.3 Hz, 3H), 7.28-7.07 (m, 2H), 6.13 (s, 1H), 4.82 (d, J = 6.5 Hz, 4H), 3.95-3.07 (m, 4H), 3.02 (s, 2H), 2.41 (s, 2H). LC-MS: [M+H]⁺ = 338.2. [0893] Step 3: Preparation of methyl 2-(4-(4-(4-fluoroisoindoline-2-carboxamido) phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoacetate (83-6): To a stirred solution of 83-4 (100 mg, 0.37 mmol) in DMF (5.0 mL) was added diisopropyl ethyl amine (10.0 eq) and 83-5 (1.5 eq) at 0 ℃. Then the reaction mixture was stirred at rt for 16 h. After complete consumption of the starting material, the reaction mixture was diluted with ice cold water, stirred for 30 min, and the precipitate was filtered and dried to obtain 140 mg of 83-6 (90% yield) as an off-white solid.¹H NMR (300 MHz, DMSO) δ 8.47 (s, 1H), 7.58 (d, J = 8.7 Hz, 2H), 7.38 (t, J = 10.2 Hz, 3H), 7.27- 7.06 (m, 2H), 6.10 (d, J = 15.6 Hz, 1H), 4.82 (d, J = 6.7 Hz, 4H), 4.12-4.08 (m, 2H), 3.85 (s, 3H), 3.74-3.71 (m, 2H), 3.60-3.56 (m, 2H). LC-MS: [M+H]⁺ = 424.2. [0894] Step 4: Preparation of 4-fluoro-N-(4-(1-(2-((2-hydroxy-2-methylpropyl)amino)-2- oxoacetyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide (I-162): To a stirred solution of 83-6 (140 mg, 0.33 mmol) in MeOH (3.0 mL) was added triethyl amine (1.0 mL) and 83-7 (1.0 eq) at rt, and then the reaction mixture was heated to 60 ℃ for 16 h. The volatiles were removed under reduced pressure and the resultant residue was dissolved in ethyl acetate and washed with water and brine. The organic phase was isolated, dried with sodium sulfate, filtered, and concentrated in vacuo to afford the crude product. The crude product was purified by prep HPLC purification, which afforded 25 mg of 4-fluoro-N-(4-(1-(2-((2-hydroxy-2- methylpropyl)amino)-2-oxoacetyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)isoindoline-2- carboxamide (I-162, 16% yield) as an off white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.63-8.42 (m, 2H), 7.58 (d, J = 8.7 Hz, 2H), 7.38 (dd, J = 12.3, 9.1 Hz, 3H), 7.28-7.05 (m, 2H), 6.12 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 6.8 Hz, 4H), 4.51 (s, 1H), 4.19-4-13 (m, 2H), 3.80-3.51 (m, 2H), 3.12 (t, J = 6.2 Hz, 2H), 2.53 (d, J = 9.0 Hz, 2H), 1.09 (d, J = 4.6 Hz, 6H). LCMS: 481.1 (M+H), purity: 99.84% by AUC, RT: 4.21, UV:260 nm. HPLC: purity: 98.35% by AUC, RT: 15.41, UV: 270 nm. EXAMPLE 71 – SYNTHESIS OF N-(4-(1-(2-HYDROXY-2-METHYLPROPANOYL) PIPERIDIN-4-YL)PHENYL)-4,6-DIHYDRO-5H-PYRROLO[3,4-D]THIAZOLE-5- CARBOXAMIDE (I-161) [0895] Step 1: Preparation of tert-butyl 4-(4-(5,6-dihydro-4H-pyrrolo[3,4-d]thiazole-5- carboxamido)phenyl) piperidine-1-carboxylate (84-3): 84-3 was prepared according to General Procedure B using tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)piperidine-1-carboxylate (84- 1, 611 mg, 1.54 mmol). The product was obtained after filtration, which afforded 400 mg of 84-3 (60% yield) as an off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.31 (s, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H), 4.84-4.55 (m, 4H), 4.08-4.04 (m, 2H), 2.93-2.53 (m, 4H), 1.70 (t, J = 19.5 Hz, 2H), 1.55-1.31 (m, 10H). LC-MS: [M+H]⁺ = 429.2. [0896] Step 2: Preparation of N-(4-(piperidin-4-yl)phenyl)-4,6-dihydro-5H-pyrrolo[3,4- d]thiazole-5-carboxamide hydrochloride (84-4): 84-4 was prepared according to General Procedure C using tert-butyl 4-(4-(5,6-dihydro-4H-pyrrolo[3,4-d]thiazole-5-carboxamido)phenyl) piperidine-1-carboxylate (84-3, 400 mg, 0.93 mmol). The product was obtained after the volatiles were removed, which afforded 250 mg (crude) of 84-4 as an off-white solid.¹H NMR (300 MHz, DMSO) δ 9.11 (s, 1H), 8.31 (s, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.2 Hz, 2H), 4.71 (d, J = 22.1 Hz, 4H), 4.08 (s, 2H), 3.95-2.95 (m, 4H), 1.68 (s, 2H), 1.58-1.37 (m, 2H), 1.26 (m, 1H). LC-MS: [M+H]⁺ = 329.2. [0897] Step 3: Preparation of N-(4-(1-(2-hydroxy-2-methylpropanoyl)piperidin-4- yl)phenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxamide (I-161): I-161 was prepared according to General Procedure D using N-(4-(piperidin-4-yl)phenyl)-4,6-dihydro-5H- pyrrolo[3,4-d]thiazole-5-carboxamide hydrochloride (84-4) (100 mg, 0.23 mmol). The product was obtained after filtration, which afforded 70 mg of N-(4-(1-(2-hydroxy-2- methylpropanoyl)piperidin-4-yl)phenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxamide (I-161, 73% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.32 (s, 1H), 7.46 (d, J = 8.2 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 5.38 (s, 1H), 4.71 (d, J = 21.6 Hz, 6H), 2.84-2.80 (m, 3H), 1.8-1.75 (m, 2H), 1.51 (s, 2H), 1.33 (s, 6H). LCMS: 415.34 (M+H), purity: 99.43% by AUC, RT: 4.17, UV: 220 nm. HPLC: purity: 98.74% by AUC, RT: 6.77, UV: 230 nm. EXAMPLE 72 – SYNTHESIS OF 5-FLUORO-N-(4-(4-((2-HYDROXYETHYL) CARBAMOYL)BICYCLO[2.2.2]OCTAN-1-YL)PHENYL)ISOINDOLINE-2- CARBOXAMIDE (I-160) [0898] Compound I-160 was prepared according to General Procedure D using 4-(4-(5- fluoroisoindoline-2-carboxamido)phenyl)bicyclo[2.2.2]octane-1-carboxylic acid (85-8) (100 mg, 0.24 mmol). The product was obtained after filtration, which afforded 82 mg of 5-fluoro-N-(4-(4- ((2-hydroxyethyl)carbamoyl)bicyclo[2.2.2]octan-1-yl)phenyl)isoindoline-2-carboxamide (I-160, 76% yield) as a white solid.¹H NMR (300 MHz, DMSO) δ 8.27 (s, 1H), 7.30-7.26 (m, 8H), 4.72 (d, J = 8.2 Hz, 4H), 4.62 (t, J = 5.5 Hz, 1H), 3.47-3.31 (m, 2H), 3.11 (q, J = 6.1 Hz, 2H), 1.75 (s, 12H). LCMS: 452.37 (M+H), purity: 99.05% by AUC, RT: 4.73, UV:245 nm. HPLC: purity: 97.31% by AUC, RT: 8.42, UV: 240 nm. EXAMPLE 73 - SYNTHESIS OF 4,6-DIFLUORO-N-(4-((1S,4S)-4-((METHYL- SULFONYL)CARBAMOYL)CYCLOHEXYL)PHENYL)ISOINDOLINE-2- CARBOXAMIDE (I-26)

[0899] Step 1: Synthesis of (1r,4r)-4-phenylcyclohexane-1-carboxylic acid (86-2): To a stirred solution of compound 86-1 (10.0 g, 41.89 mmol) in methanol (50 mL) were added triethylamine (6.7 mL) and 10% palladium on carbon (50% wet, 3.3 g) at rt. The reaction mixture was stirred at 50 ℃ for 18 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The combined organic layers were concentrated under reduced pressure to afford the title crude compound 86-2 (8.0 g, 39.16 mmol, 93.47% yield) as a white solid. The crude compound was used in the next step without further purification. LC-MS: ret. time: 1.43 min, MS calcd. for chemical formula C13H16O2: 204.27; found: 203.14 [M-H]-. Method E. [0900] Step 2: Synthesis of (1r,4r)-4-(4-nitrophenyl)cyclohexane-1-carboxylic acid (86-3): To a mixture of compound 86-2 (4 g, 19.58 mmol) and potassium nitrite (0.59 g, 5.874 mmol) was added sulfuric acid (40 mL, 91.2 mmol) dropwise at 0 ℃. The reaction mixture was stirred at 0 ℃ for 30 min. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and the precipitated solid was filtered and dried under reduced pressure to afford the title crude compound 86-3 (2.1 g, 8.4 mmol, 43% yield) as a white solid. The crude compound was used in the next step without further purification. LC-MS: ret. time: 1.24 min, MS calcd. for chemical formula: C₁₃H₁₅NO₄: 249.27; found: 248.12 [M+H]⁺. Method H. [0901] Step 3: Synthesis of tert-butyl (1r,4r)-4-(4-nitrophenyl)cyclohexane-1-carboxylate (86-4): To a stirred solution of compound 86-3 (5.0 g, 20.06 mmol) in t-butyl alcohol (40 mL) was added di-tert-butyl dicarbonate (21.89 g, 100.3 mmol) followed by DMAP (0.742 g, 6.017 mmol) at 0 ℃ and stirred at 80 ℃ for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water followed by brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to afford the title compound 86-4 (2.3 g, 7.5 mmol, 38% yield) as an off white solid. The crude compound was used in the next step without further purification. LC-MS: ret. time: 1.78 min, MS calcd. for chemical formula: C17H23NO4: 305.37; found: 203.83 [M-H]-. Method F. [0902] Step 4: Synthesis of tert-butyl (1r,4r)-4-(4-aminophenyl)cyclohexane-1- carboxylate (86-5): To a stirred solution of compound 86-4 (2.3 g, 7.5 mmol) in ethanol (25 mL) was added 10% palladium on carbon (50% wet, 0.5 g) and stirred at rt for 16 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The combined organic layers were concentrated under reduced pressure to afford the crude compound 86-5 (1.6 g, 5.80 mmol, 76% yield) as a pale red solid. The crude compound was used in the next step without further purification. LC-MS: ret. time: 1.25 min, MS calcd. for chemical formula: C17H25NO2: 275.39; found: 276.15 [M+H]⁺. Method F. [0903] Step 5: Synthesis of tert-butyl (1r,4r)-4-(4-((phenoxycarbonyl)amino) phenyl)cyclohexane-1-carboxylate (86-7): To a stirred solution of compound 86-5 (1.5 g, 5.4 mmol) in DCM (15 mL) was added pyridine (0.88 mL, 11 mmol), followed by phenyl chloroformate 86-6 (1.0 g, 6.5 mmol) at 0 ℃. The reaction mixture was then stirred at rt for 16 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure to afford the title crude compound 86-7 (1.1 g, 2.8 mmol, 51% yield) as a yellow solid. The crude compound was used in the next step without further purification. LC-MS: ret. time: 2.41 min, MS calcd. for chemical formula: C24H29NO4: 395.5; found: 396.49 [M+H]⁺ Method F. [0904] Step 6: Synthesis of tert-butyl (1r,4r)-4-(4-(4,6-difluoroisoindoline-2- carboxamido) phenyl)cyclohexane-1-carboxylate (86-9): To the stirred solution of compound 86-7 (0.5 g, 1.26 mmol) and compound 86-8 (0.235 g, 1.52 mmol) in DMF (5 mL) was added DIPEA (1.12 mL, 6.32 mmol) at rt and then the reaction was stirred at 80 ℃ for 1 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to afford the title crude compound 86-9 (0.4 g, 0.876 mmol, 69.31% yield) as an off-white solid. The crude compound was used in the next step without further purification. LC-MS: ret. time: 1.26 min, MS calcd. for chemical formula: C26H30F2N2O3: 456.5; found: 457.09 [M+H]⁺. Method G. [0905] Step 7: Synthesis of (1r,4r)-4-(4-(4,6-difluoroisoindoline-2-carboxamido)phenyl) cyclohexane-1-carboxylic acid (86-10): To a stirred solution of compound 86-9 (0.4 g, 0.876 mmol) in DCM (10 mL), was added trifluoroacetic acid (TFA) (3 mL) at 0 ℃ and the reaction mixture stirred at rt for 2 h. After completion of the reaction (monitored by TLC), volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (10 mL) and then with n-pentane (5 mL x 2), and the solids were filtered and dried under reduced pressure to afford the title crude compound 86-10 (0.3 g, 0.749 mmol, 85.51% yield) as a brown solid. LC- MS: ret. time: 1.41 min, MS calcd. for chemical formula: C₂₂H₂₂F₂N₂O₃: 400.4; found: 401.02 [M+H]⁺. Method F. [0906] Step 8: Synthesis of 4,6-difluoro-N-(4-((1s,4s)-4-((methylsulfonyl)carbamoyl) cyclohexyl) phenyl)isoindoline-2-carboxamide (I-26): To a stirred solution of the compound 86- 10 (0.1 g, 0.249 mmol) in the DMF (2 mL) was added DIPEA (0.22 mL, 1.25 mmol) and HATU (0.15 g, 0.374 mmol) at 0 ℃. After 5 min, methane sulfonamide 86-11 (0.028 g 0.299 mmol) was added and the reaction mixture stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction was diluted with ice cold water and the precipitated solid was filtered. The crude compound was purified by CombiFlash (Nexgen-300) chromatography using a 4 g silica gel cartridge, and using 2-4% MeOH in DCM as the eluent to afford the title crude compound 4,6- difluoro-N-(4-((1s,4s)-4-((methylsulfonyl)carbamoyl)cyclohexyl)phenyl) isoindoline-2- carboxamide (I-26, 10 mg, 0.020 mmol, 8.38% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d6) δ: 11.66 (s, 1H), 8.34 (s, 1H), 7.45 (d, J = 8.6 Hz, 2H), 7.22 - 7.14 (m, 2H), 7.11 (d, J = 8.6 Hz, 2H), 4.77 (s, 4H), 3.22 (s, 3H), 2.47 - 2.40 (m, 1H), 2.36 - 2.27 (m, 1H), 1.92 (br d, J = 10.6 Hz, 2H), 1.87 - 1.80 (m, 2H), 1.54 - 1.33 (m, 4H). LC-MS: ret. time: 1.41 min, 99.60%, MS calcd. for chemical formula: C₂₃H₂₅F₂N₃O₄S: 477.52; found: 478.03 [M+H]⁺. Method F. HPLC: Rt 7.771 min, 96.14%; column: X-Select CSH C18 (4.6*150) mm 5 um; mobile phase: A - 0.1% TFA in water; B – acetonitrile, injection volume: 5.0 µL; flow rate: 1.2 mL/minute; column oven temp.: 30 °C; gradient program: time(min)/ B conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. EXAMPLE 74 - SYNTHESIS OF 5-FLUORO-N-(4-(1-(2-((3-HYDROXY-3-METHYL- BUTYL)AMINO)-2-OXOACETYL)-1,2,3,6-TETRAHYDROPYRIDIN-4-YL)PHENYL) ISOINDOLINE-2-CARBOXAMIDE (I-25) [0907] Step 1: Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate carbamate (87-3): A mixture of compound 87-1 (10.0 g, 58.13 mmol), compound 87-2 (20.38 g, 63.94 mmol), and K₃PO₄ (37.77 g, 174.40 mmol) in 1,2-DME: H₂O (70:30, 60 mL) was degassed with argon for 5 min. Pd(dppf)Cl2.DCM (2.42 g, 2.90 mmol), was added to the above mixture at rt. The reaction mixture was stirred for 15 min while degassing with argon, and then the reaction mixture was stirred at 90 ℃ for 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered and washed with EtOAc. The organic layer was diluted with water and extracted with EtOAc. The combined organic layers were washed with water followed by brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by Combi flash (Nexgen-300) chromatography using a 40 g silica gel cartridge, and by using 10 - 15% EtOAc in n-heptane as the eluent to afford the title compound 87-3 (14.0 g, 51.02 mmol, 87.77% yield) as a yellow solid. LC-MS: ret. time: 2.188 min, MS calcd. for chemical formula C16H22N2O2: 274.36; found: 274.95 [M+H]⁺. Method F. [0908] Step 2: Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (87-5): To a stirred solution of compound 87-3 (5.0 g, 18.22 mmol) in DCM (50 mL) was added pyridine (2.92 mL, 36.44 mmol) and DMAP (0.22 g, 1.82 mmol), followed by compound 87-4 (3.42 g, 21.87 mmol) at 0 ℃. Then the reaction mixture was stirred at rt for 2 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The obtained solid was washed with diethyl ether and n-pentane and dried under reduced pressure to afford the title compound 87-5 (6.0 g, 15.21 mmol, 83.47% yield) as an off white solid. LC-MS: ret. time: 1.69 min, MS calcd. for chemical formula C23H26N2O42: 394.47; found: 294.90 [(M-Boc) +H]⁺. Method F. [0909] Step 3: Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)- 3,6-dihydropyridine-1(2H)-carboxylate (87-7): To a stirred solution of compound 87-5 (3.0 g, 7.60 mmol) and compound 87-6 (1.25 g, 9.12 mmol) in DMF (30 mL) was added DIPEA (13.28 mL, 76.05 mmol) at rt and then the reaction mixture was stirred at 80 ℃ for 3 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The obtained solid was washed with diethyl ether and n-pentane and dried under reduced pressure to afford the title compound 87- 7 (2.5 g, 5.7 mmol, 75% yield) as a brown solid. LC-MS: ret. time: 2.11 min, MS calcd. for chemical formula C25H28FN3O3: 437.5; found: 438.2 [M+H]⁺. Method F. [0910] Step 4: Synthesis of 5-fluoro-N-(4-(1,2,3,6-tetrahydropyridin-4- yl)phenyl)isoindoline-2-carboxamide, hydro chlorine (87-8): To a stirred solution of compound 87-7 (2.5 g, 5.7 mmol) in 1,4-dioxane (10 mL) was added 4M HCl in 1,4-dioxane (14 mL, 57 mmol) dropwise at 0 ℃ and then the reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (8 mL) and then with n-pentane (4 mL x 2), and the filtered the solid compound was dried under reduced pressure to afford the desired compound 87-8 (2.0 g, 5.350 mmol, 99% yield) as an off-white solid. The resulting crude HCl salt was used in the next step without further purification. LC-MS: ret. time: 0.97 min, MS calcd. for chemical formula C20H20FN3O: 337.4; found: 338.16 [M+H]⁺. Method F. [0911] Step 5: Synthesis of ethyl 2-(4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)-3,6- dihydropyridin-1(2H)-yl)-2-oxoacetate (87-10): To stirred solution of compound 87-8 (0.8 g, 2.14 mmol) in DMF (16 mL) was added DIPEA (1.12 mL, 6.44 mmol), followed by ethyl 2- chloro-2-oxoacetate 87-9 (0.35 g, 2.574 mmol) at 0 ℃ and the reaction mixture was stirred at rt for 5 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The crude was purified by Combi flash (Nexgen-300) chromatography using a 24 g silica gel cartridge, and by using 90-100% EtOAc in heptane as the eluent to afford the title compound 87-10 (0.6 g, 1.371 mmol, 63.93%yield) as a pale brown solid. LC-MS: ret. time: 0.89 min, MS calcd. for chemical formula C₂₄H₂₄FN₃O₄: 437.5; found: 438.1 [M+H]⁺. Method F. [0912] Step 6: Synthesis of 5-fluoro-N-(4-(1-(2-((3-hydroxy-3-methylbutyl)amino)-2- oxoacetyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide (I-25): To a stirred solution of compound 87-10 (0.32 g, 0.73 mmol) in MeOH (13 mL) was added triethylamine (1.6 mL, 0.11 mmol) and 50% T3P in EtOAc (0.32 g 0.488 mmol) at rt. After 15 min, 1-amino-2-methyl-propan-2-ol 87-11 (0.1 g, 1.23 mmol) was added to the above reaction mixture at rt. The reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure and diluted with water, and extracted with 10% MeOH in DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by prep-HPLC to afford 5-fluoro-N-(4-(1-(2-((3-hydroxy-3- methylbutyl)amino)-2-oxoacetyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)isoindoline-2- carboxamide (I-25, 128 mg, 0.258 mmol, 35.38% yield) as an off-white solid.¹H NMR (400 MHz, DMSO-d6) δ 8.63 - 8.57 (m, 1H), 8.40 (s, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.41 - 7.33 (m, 3H), 7.23 (dd, J = 2.3, 9.1 Hz, 1H), 7.14 (t, J = 8.5 Hz, 1H), 6.14 - 6.09 (m, 1H), 4.74 (d, J = 11.6 Hz, 4H), 4.31 (d, J = 2.0 Hz, 1H), 4.18 - 4.09 (m, 2H), 3.72 - 3.62 (m, 2H), 3.27 - 3.16 (m, 2H), 2.53 - 2.52 (m, 2H), 1.60 - 1.54 (m, 2H), 1.13 - 1.09 (m, 6H). LCMS: ret. time: 1.22 min, 97.45%; MS calcd. for chemical formula, C27H31FN4O4, 494.57; found: 495.21 [M+H]⁺. Method F. HPLC: ret. time: 6.930 min, purity: 99.44%; column: X-Select CSH C18 (4.6*150) mm 5um; mobile phase: A - 0.1% TFA in water; B – ACN; injection volume: 5.0µL; flow rate: 1.2 mL/min; column oven temp.: 30 °C; gradient program: time(min)/ B conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. prep-HPLC purification method: preparative column: X-BRIDGE C18 (30*250)mm, 5µ, mobile phase -A: 0.1% TFA in water, mobile phase-B: 100% ACN, flow rate: 25ml/min, gradient (Time/%B): 0/15, 3/15, 8/40, 20/40, 30/45, 31/10. Solvents used for dilution: ACN +DMSO +FA. EXAMPLE 75 - SYNTHESIS OF 5-FLUORO-N-(4-(1-(2-((3-HYDROXY-3-METHYL- BUTYL)AMINO)-2-OXOACETYL)PIPERIDIN-4-YL)PHENYL) ISOINDOLINE-2- CARBOXAMIDE (I-24) [0913] Step 1: Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (88-3): A mixture of compound of compound 88-1 (5.00 g, 29.06 mmol), compound 88-2 (9.46 g, 29.70 mmol) and Cs₂CO₃ (24.2 g, 74.25 mmol) in 1,2-DME:H₂O (1:1, 100 mL) was 438 degassed with argon for 5 min. X-Phos (1.2 g, 2.47 mmol) and Pd₂dba₃ (1.16 g, 1.23 mmol) was added to the above mixture at room temperature. The reaction mixture was stirred for 15 min while degassing with argon, and then the reaction mixture was stirred at 90 ℃ for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum to afford the crude. The crude was diluted with water and extracted with EtOAc. The combined organic layers were washed with water followed by brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether and n-pentane, and the solids were filtered and dried under reduced pressure to afford the title compound 88-3 (6 g, 19.72 mmol, 79.66% yield) as an off white solid. LC-MS: ret. time: 1.63 min, MS calcd. for chemical formula C₁₆H₂₂N₂O_2; 274.36; found: 249.2 [(M-Isobutene)+H]⁺. Method G. [0914] Step 2: Synthesis of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (88-4): To a stirred solution of compound 88-3 (6.0 g, 19.72 mmol) in methanol (35 mL) was added 10% palladium on carbon (50% wet, 2.5 g) and the reaction mixture was stirred at room temperature for 16 h under a hydrogen atmosphere at 100 psi pressure in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The organic layer was concentrated under reduced pressure to afford the title crude compound 88-4 (5.40 g, 19.5 mmol, 99.10% yield) as an off white solid. LC-MS : ret. time: 1.17 min, MS calcd. for chemical formula: C₁₆H₂₄N₂O₂: 276.38; found: 221.21 [(M-Isobutene)+H]⁺. Method F. [0915] Step 3: Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)piperidine- 1-carboxylate (88-6): To a stirred solution of compound 88-4 (2.5 g, 9.0 mmol) in DCM (25 mL) was added pyridine (1.45 mL, 16.10 mmol) at room temperature followed by compound 88-5 (1.7 g, 11 mmol) and DMAP (0.11 g, 0.90 mmol)) at 0 ℃, and then the reaction mixture was stirred at room temperature for 8 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water followed by brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether and n-pentane, and the solids were filtered and dried under reduced pressure to afford the title compound 88-6 (2.1 g, 5.3 mmol, 59%yield) as an off white solid. LC-MS: ret. time: 1.66 min, MS calcd. for chemical formula: C₂₃H₂₈N₂O₄: 396.49; found: 340.95 [(M-Isobutene) + H]⁺. Method F. [0916] Step 4: Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) piperidine-1-carboxylate (88-8): To a stirred solution of compound 88-6 (2.1 g, 5.3 mmol) in DMF (25 mL) were added compound 88-7 (0.70 g, 6.4 mmol) and DIPEA (9.64 mL, 53 mmol) at room temperature and then the reaction mixture was stirred at 80 ℃ for 8 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with EtOAc. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was triturated with diethyl ether, filtered and dried under reduced pressure to afford the title compound 88-8 (1.8 g, 4.1 mmol, 77%yield) as a brown solid. LCMS: ret. time: 1.61 min, MS calcd. for chemical formula: C₂₅H₃₀FN₃O₃: 439.53; found: 438.33 [M-H]-. Method F. [0917] Step 5: Synthesis of 5-fluoro-N-(4-(piperidin-4-yl)phenyl)isoindoline-2- carboxamide hydrochloride (88-9): To a stirred solution of compound 88-8 (1.8 g, 4.1 mmol) in 1,4-dioxane (20 mL) was added 4M HCl in 1,4-dioxane (1041 mmol) slowly at 0 ℃ and stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (8 mL) and then with pentane (4 mL x 2), the solids were filtered and dried under reduced pressure to afford the desired compound 88-9 (1.5 g, 4.0 mmol, 97% yield) as a pale brown solid. The resulting crude HCl salt was used in the next step without further purification. LC-MS: ret. time: 1.06 min, MS calcd. for chemical formula: C20H22FN3O: 339.41; found: 340.02 [M+H]⁺. Method F. [0918] Step 6: Synthesis of ethyl 2-(4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) piperidin-1-yl)-2-oxoacetate (88-11): To a stirred solution of compound 88-9 (1.0 g, 2.66 mmol) in DCM (20 mL) was added DIPEA (1.40 mL, 8.00 mmol) at 0 ℃, followed by ethyl 2-chloro-2- oxoacetate 88-10 (0.364 g, 2.66 mmol) dropwise and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by Combi flash chromatography using 80-95% EtOAc in heptane as the eluent to afford the title compound 88-11 (0.4 g, 0.91 mmol, 34.12% yield) as a pale brown gummy liquid. LC-MS: ret. time: 1.38 min, MS calcd. for chemical formula: C₂₄H₂₆FN₃O₄: 439.49; found: 440.31 [M+H]⁺. Method F. [0919] Step 7: Synthesis of 2-(4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) piperidin-1-yl)-2-oxoacetic acid (88-12): To a stirred solution of compound 88-11 (0.4 g, 0.728 mmol) in 1,4-dioxane (5.8 ml) was added a 1M NaOH solution (5.8 mL) and then the reaction mixture was stirred at room temperature for 5 h. After completion of the reaction (monitored by TLC), the volatiles were evaporated under reduced pressure. The crude residue was acidified with 1.0 N HCl to pH-4-5, and the precipitated solids were washed with water and dried under reduced pressure to afford the title compound 88-12 (0.22 g, 0.534 mmol, 58.76% yield) as a pale brown solid. LC-MS: ret. time: 1.13 min, MS calcd. for chemical formula: C₂₂H₂₂FN₃O₄: 411.43; found: 412.03 [M+H]⁺. Method F. [0920] Step 8: Synthesis of 5-fluoro-N-(4-(1-(2-((3-hydroxy-3-methylbutyl)amino)-2- oxoacetyl) piperidin-4-yl)phenyl)isoindoline-2-carboxamide (I-24): To a stirred solution of compound 88-12 (0.1 g, 0.243 mmol) in DCM (2 mL) were added DIPEA (0.126 mL, 0.729 mmol) and 50% T3P in EtOAc (0.309 g, 0.486 mmol). Then 4-amino-2-methyl-butan-2-ol 88-13 (0.30 g, 2.93 mmol) was added to the and reaction mixture and it was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by prep- HPLC to afford 5-fluoro-N-(4-(1-(2-((3-hydroxy-3-methylbutyl) amino)-2-oxoacetyl)piperidin-4- yl)phenyl)isoindoline-2-carboxamide (I-24, 15 mg, 0.0302 mmol, 12.50% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d₆) δ 8.55 (t, J = 5.5 Hz, 1H), 8.30 (s, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.38 (dd, J = 5.2, 8.3 Hz, 1H), 7.23 (dd, J = 2.3, 9.1 Hz, 1H), 7.17 - 7.09 (m, 3H), 4.73 (d, J = 11.8 Hz, 4H), 4.44 - 4.36 (m, 1H), 3.89 - 3.79 (m, 1H), 3.24 - 3.10 (m, 3H), 2.78 - 2.69 (m, 2H), 1.85 - 1.76 (m, 2H), 1.60 - 1.44 (m, 4H), 1.10 (s, 6H). LC-MS: ret. time: 1.919 min, 97.90%; MS calcd. for chemical formula: C₂₇H₃₃FN₄O₄: 496.57; found: 497.2 [M+H]⁺. Method D. HPLC: Rt 6.868 min, purity: 98.51%, method: HPLC_X-Bridge, column: X-Select CSH C18 (4.6*150) mm 5um; mobile phase: A - 0.1% TFA in water; B – acetonitrile, injection volume: 5.0µL, flow rate: 1.2 mL/minute; column oven temp.: 30 °C, gradient program: time(min)/ B conc. : 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/55. prep-HPLC purification method: preparative column: YMC C- 18, mobile phase A: 0.1% TFA in H2O; mobile phase B: ACN, flow rate: 25ml/min, gradient (time/%B): 0/30, 3/30, 10/40, 20/50, 25/50, 40/98. Solvents used for dilution: ACN + water. EXAMPLE 76 - SYNTHESIS OF 5-FLUORO-N-(4-(1-(2-((2-METHOXYETHYL) AMINO)-2-OXOACETYL)-1,2,3,6-TETRAHYDROPYRIDIN-4-YL)PHENYL) ISOINDOLINE-2-CARBOXAMIDE (I-23) [0921] Step 1: Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate carbamate (89-3): A mixture of compound 89-1 (10.0 g, 58.13 mmol), compound 89-2 (20.38 g, 63.94 mmol), and K3PO4 (37.77 g, 174.40 mmol) in 1,2-DME: H2O (70:30, 60 mL) was degassed with argon for 5 min. Pd(dppf)Cl₂.DCM (2.42 g, 2.90 mmol), was added to the above mixture at rt. The reaction mixture was stirred for 15 min while degassing with argon, and then the reaction mixture was stirred at 90 ℃ for 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered and washed with EtOAc. The organic layer was diluted with water and extracted with EtOAc. The combined organic layers were washed with water followed by brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by Combi flash (Nexgen-300) chromatography using a 40 g silica gel cartridge, and by using 10 - 15% EtOAc in n-heptane as the eluent to afford the title compound 89-3 (14.0 g, 51.02 mmol, 87.77% yield) as a yellow solid. LC-MS: ret. time: 2.188 min, MS calcd. for chemical formula C16H22N2O2: 274.36; found: 274.95 [M+H]⁺. Method F. [0922] Step 2: Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (89-5): To a stirred solution of compound 89-3 (5.0 g, 18.22 mmol) in DCM (50 mL) were added pyridine (2.92 mL, 36.44 mmol) and DMAP (0.22 g, 1.82 mmol) followed by compound 89-4 (3.42 g, 21.87 mmol) at 0 ℃ and then the reaction mixture was stirred at rt for 2 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The solid was then washed with diethyl ether and n-pentane and dried under reduced pressure to afford the title compound 89-5 (6.0 g, 15.21 mmol, 83.47% yield) as an off white solid. LC-MS: ret. time: 1.69 min, MS calcd. for chemical formula C23H26N2O42: 394.47; found: 294.90 [(M-Boc) +H]⁺. Method F. [0923] Step 3: Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)- 3,6-dihydropyridine-1(2H)-carboxylate (89-7): To the stirred solution of compound 89-5 (3.0 g, 7.60 mmol) and compound 89-6 (1.25 g, 9.12 mmol) in DMF (30 mL) was added DIPEA (13.28 mL, 76.05 mmol) at rt and then the reaction mixture was stirred at 80 ℃ for 3 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The obtained solid was washed with diethyl ether and n-pentane and dried under reduced pressure to afford the title compound 89- 7 (2.5 g, 5.7 mmol, 75% yield) as a brown solid. LC-MS: ret. time: 2.11 min, MS calcd. for chemical formula C25H28FN3O3: 437.5; found: 438.2 [M+H]⁺. Method F. [0924] Step 4: Synthesis of 5-fluoro-N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl) isoindoline-2-carboxamide, hydro chlorine (89-8): To a stirred solution of compound 89-7 (2.5 g, 5.7 mmol) in 1,4-dioxane (10 mL) was added 4M HCl in 1,4-dioxane (14 mL, 57 mmol) dropwise at 0 ℃ and then the reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (8 mL) and then with n-pentane (4 mL x 2), and the solids were filtered and dried under reduced pressure to afford the desired compound 89-8 (2.0 g, 5.350 mmol, 99% yield) as an off-white solid. The resulting crude HCl salt was used in the next step without further purification. LC-MS: ret. time: 0.97 min, MS calcd. for chemical formula C₂₀H₂₀FN₃O: 337.4; found: 338.16 [M+H]⁺. Method F. [0925] Step 5: Synthesis of ethyl 2-(4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)-3,6- dihydropyridin-1(2H)-yl)-2-oxoacetate (89-10): To stirred solution of compound 89-8 (1.0 g, 2.68 mmol), in DMF (20 mL), was added DIPEA (1.41 mL, 8.04 mmol), followed by ethyl 2- chloro-2-oxoacetate 89-9 (0.366 g, 2.68 mmol) at 0 ℃ and then the reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The crude compound was triturated with diethyl ether and n-pentane, the solids were filtered and dried under reduced pressure to afford the title compound 89-10 (0.34 g, 0.77 mmol, 28.98% yield) as a pale brown solid. LC-MS: ret. time: 1.47 min, MS calcd. for chemical formula: C₂₄H₂₄FN₃O₄: 437.46; found: 438.03 [M+H]⁺. Method F. [0926] Step 6: Synthesis of 2-(4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)-3,6- dihydropyridin-1(2H)-yl)-2-oxoacetic acid (89-11): To a stirred solution of compound 89-10 (0.34 g, 0.777 mmol) in 1,4-dioxane (5 mL), was added an 1N NaOH solution (5.0 mL) at room temperature and the reaction mixture was stirred at room temperature for 5 h. After completion of the reaction (monitored by TLC), the reaction mixture was acidified with 1N HCl solution to pH ~ 4-5, the solid that formed was filtered and washed with water and dried under reduced pressure to afford title the compound 89-11 (0.21 g, 0.513 mmol, 66.00% yield) as an off-white solid. LC- MS: ret. time: 1.20 min, MS calcd. for chemical formula: C₂₂H₂₀FN₃O: 409.41; found: 409.97 [M+H]⁺. Method F. [0927] Step 7: Synthesis of 5-fluoro-N-(4-(1-(2-((2-methoxyethyl)amino)-2-oxoacetyl)- 1,2,3,6-tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide (I-23): To a stirred solution of compound 89-11 (0.1 g, 0.244 mmol) in DCM (2 mL) at rt, was added DIPEA (0.13 mL, 0.733 mmol) and 50% T₃P in EtOAc (0.32 g 0.488 mmol) at 0 ℃. After 15 min, 4-amino-2-methylbutan- 2-ol 89-12 (0.12 g, 1.59 mmol) was added to the above reaction mixture at room temperature. The reaction mixture was stirred to room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water, extracted with DCM, and concentrated under reduced pressure. The crude compound was purified by prep-HPLC to afford 5-fluoro-N-(4-(1-(2-((2-methoxyethyl)amino)-2-oxoacetyl)-1,2,3,6-tetrahydropyridin-4- yl)phenyl)isoindoline-2-carboxamide (I-23, 30 mg, 0.064 mmol, 26.33% yield) as an off-white solid.¹H NMR (400 MHz, DMSO-d6) δ 8.76 - 8.67 (m, 1H), 8.41 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.42 - 7.33 (m, 3H), 7.26 - 7.20 (m, 1H), 7.18 - 7.11 (m, 1H), 6.15 - 6.07 (m, 1H), 4.74 (d, J = 11.6 Hz, 4H), 4.18 - 4.08 (m, 2H), 3.73 - 3.62 (m, 2H), 3.41 (q, J = 5.5 Hz, 2H), 3.34 (s, 1H), 3.27 - 3.25 (m, 3H) 3.29 (s, 1H), 2.57 - 2.52 (m, 2H). LC-MS: ret. time: 1.951 min, 96.70%; MS calcd. for chemical formula: C₂₅H₂₇FN₄O₄: 466.51; found: 467.2 [M+H]⁺. Method G. HPLC: ret. time: 7.057 min, purity: 96.50%, method: HPLC_X-Bridge column: X-Select CSH C18 (4.6*150) mm 5u, mobile phase: A - 0.1% TFA in water; B – acetonitrile, injection volume: 5.0µL, flow rate: 1.2 mL/minute, column oven temp.: 30 °C, gradient program: time(min)/ B conc.: 0.01/5, 1.0/5, 8. EXAMPLE 77 - SYNTHESIS OF 5-FLUORO-N-(4-(1-(2-((2-METHOXYETHYL) AMINO)-2-OXOACETYL)PIPERIDIN-4-YL)PHENYL)ISOINDOLINE-2- CARBOXAMIDE (I-22) [0928] Step 1: Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (90-3): A mixture of compound of compound 90-1 (5.00 g, 29.06 mmol), compound 90-2 (9.46 g, 29.70 mmol), and Cs2CO3 (24.2 g, 74.25 mmol) in 1,4-dioxane:H2O (1:1, 100 mL) was degassed with argon for 5 min. X-Phos (1.2 g, 2.47 mmol) and Pd2dba3 (1.16 g, 1.23 mmol) was added to the above mixture at room temperature. The reaction mixture was stirred for 15 min while degassing with argon, and then the reaction mixture was heated to 90 ℃ and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum to afford the crude. The crude was diluted with water and extracted with EtOAc. The combined organic layers were washed with water followed by brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether and n-pentane and the solids were filtered and dried under reduced pressure to afford the title compound 90-3 (6 g, 19.72 mmol, 79.66% yield) as an off white solid. LC-MS: ret. time: 1.63 min, MS calcd. for chemical formula C₁₆H₂₂N₂O_2; 274.36; found: 249.2 [(M-Isobutene)+H]⁺. Method G. [0929] Step 2: Synthesis of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (90-4): To a stirred solution of compound 90-3 (6.0 g, 19.72 mmol) in methanol (35 mL) was added 10% palladium on carbon (50% wet) (2.5 g) and stirred at room temperature for 16 h under a hydrogen atmosphere at 100 psi pressure in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The organic layer was concentrated under reduced pressure to afford the title crude compound 90-4 (5.40 g, 19.5 mmol, 99.10% yield) as an off white solid. LC-MS: ret. time: 1.17 min, MS calcd. for chemical formula: C₁₆H₂₄N₂O₂: 276.38; found: 221.21 [(M-Isobutene)+H]⁺. Method F. [0930] Step 3: Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)piperidine- 1-carboxylate (90-6): To a stirred solution of compound 90-4 (2.5 g, 9.0 mmol) in DCM (25 mL) were added pyridine (1.45 mL, 16.10 mmol) at room temperature, followed by compound 90-5 (1.7 g, 11 mmol) and DMAP (0.11 g, 0.90 mmol)) at 0 ℃, and then the reaction mixture was stirred at room temperature for 8 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether and n-pentane, and the solids were filtered and dried under reduced pressure to afford the title compound 90-6 (2.1 g, 5.3 mmol, 59%yield) as an off white solid. LC-MS: ret. time: 1.66 min, MS calcd. for chemical formula: C₂₃H₂₈N₂O₄: 396.49; found: 340.95 [(M-Isobutene) + H]⁺. Method F. [0931] Step 4: Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) piperidine-1-carboxylate (90-8): To a stirred solution of compound 90-6 (2.1 g, 5.3 mmol) in DMF (25 mL) were added compound 90-7 (0.70 g, 6.4 mmol) and DIPEA (9.64 mL, 53 mmol) at room temperature and then the reaction mixture was heated to 80 ℃ for 8 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with EtOAc. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was triturated with diethyl ether and filtered and dried under reduced pressure to afford the title compound 90-8 (1.8 g, 4.1 mmol, 77%yield) as a brown solid. LCMS: ret. time: 1.61 min, MS calcd. for chemical formula: C₂₅H₃₀FN₃O₃: 439.53; found: 438.33 [M-H]-. Method F. [0932] Step 5: Synthesis of 5-fluoro-N-(4-(piperidin-4-yl)phenyl)isoindoline-2- carboxamide hydrochloride (90-9): To a stirred solution of compound 90-8 (1.8 g, 4.1 mmol) in 1,4-dioxane (20 mL) was added 4M HCl in 1,4-dioxane (10 41 mmol) slowly at 0 ℃ and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (8 mL) and then with pentane (4 mL x 2), and the solids were filtered and dried under reduced pressure to afford the desired compound 90-9 (1.5 g, 4.0 mmol, 97% yield) as a pale brown solid. The resulting crude HCl salt was used in the next step without further purification. LC-MS: ret. time: 1.06 min, MS calcd. for chemical formula: C20H22FN3O: 339.41; found: 340.02 [M+H]⁺. Method F. [0933] Step 6: Synthesis of ethyl 2-(4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) piperidin-1-yl)-2-oxoacetate (90-11): To a stirred solution of compound 90-9 (1.0 g, 2.66 mmol) in DCM (20 mL) was added DIPEA (1.40 mL, 8.00 mmol) at 0 ℃, followed by ethyl 2-chloro-2- oxoacetate 90-10 (0.364 g, 2.66 mmol) dropwise and the reaction mixture was stirred to room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by Combi flash chromatography using 80-95% EtOAc in heptane as the eluent to afford the title compound 90-11 (0.4 g, 0.91 mmol, 34.12% yield) as a pale brown gummy liquid. LC-MS: ret. time: 1.38 min, MS calcd. for chemical formula: C₂₄H₂₆FN₃O₄: 439.49; found: 440.31 [M+H]⁺. Method F. [0934] Step 7: Synthesis of 2-(4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) piperidin-1-yl)-2-oxoacetic acid (90-12): To a stirred solution of compound 90-11 (0.4 g, 0.728 mmol) in 1,4-dioxane (5.8 ml) was added a 1M NaOH solution (5.8 mL) and the reaction mixture was stirred room temperature for 5 h. After completion of the reaction (monitored by TLC), MeOH and THF were removed under reduced pressure. The crude residue was acidified with 1.0 N HCl to pH-4-5, and the precipitated solids were washed with water, and dried under reduced pressure to afford the title compound 90-12 (0.22 g, 0.534 mmol, 58.76% yield) as a pale brown solid. LC- MS: ret. time: 1.13 min, MS calcd. for chemical formula: C₂₂H₂₂FN₃O₄: 411.43; found: 412.03 [M+H]⁺. Method F. [0935] Step 8: Synthesis of 5-fluoro-N-(4-(1-(2-((2-methoxyethyl)amino)-2- oxoacetyl)piperidin-4-yl)phenyl)isoindoline-2-carboxamide (I-22): To a stirred solution of compound 90-12 (0.1 g, 0.243 mmol) in DCM (2 mL), were added DIPEA (0.126 mL, 0.729 mmol) and 50% T₃P in EtOAc (0.309 g, 0.486 mmol). Then 2-methoxyethan-1-amine 90-13 (0.22 g, 2.93 mmol) was added to the reaction mixture and it was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by prep- HPLC to afford the title compound 5-fluoro-N-(4-(1-(2-((2-methoxyethyl) amino)-2- oxoacetyl)piperidin-4-yl)phenyl)isoindoline-2-carboxamide (I-22, 15 mg, 0.0302 mmol, 13.17% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d₆) δ 8.69 (t, J = 5.6 Hz, 1H), 8.29 (s, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.38 (dd, J = 5.1, 8.4 Hz, 1H), 7.23 (dd, J = 2.3, 9.1 Hz, 1H), 7.16 - 7.10 (m, 3H), 4.73 (d, J = 11.6 Hz, 4H), 4.45 - 4.36 (m, 1H), 3.84 (d, J = 13.4 Hz, 1H), 3.41 - 3.36 (m, 2H), 3.29 - 3.25 (m, 2H), 3.25 (s, 3H), 3.19 - 3.10 (m, 1H), 2.79 - 2.70 (m, 2H), 1.86 - 1.72 (m, 2H), 1.66 - 1.56 (m, 1H), 1.55 - 1.44 (m, 1H). LC-MS: ret. time: 1.932 min, 99.65%; MS calcd. for chemical formula: C₂₅H₂₉FN₄O₄: 468.52; found: 469.2 [M+H]⁺. Method G. HPLC: ret. time: 6.948 min, purity: 99.86%, column: X-Select CSH C18 (4.6*150) mm 5um; mobile phase: A - 0.1% TFA in water; B – acetonitrile, flow rate: 1.2 mL/minute, column oven temp.: 30°C, gradient program: time (min)/ B Conc. : 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. EXAMPLE 78 - SYNTHESIS OF 5-FLUORO-N-(4-(1-SULFAMOYLPIPERIDIN-4- YL)PHENYL)ISOINDOLINE-2-CARBOXAMIDE (I-21) [0936] To a stirred solution of compound I-44 (0.3 g, 0.578 mmol) in DCM (2.5 mL) was added 4M HCl in 1,4-dioxane (3 mL) slowly at 0 ℃ and the reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (5 mL) and then with n-pentane (3 mL X 2) and the filtered the solids were dried under reduced pressure to afford the desired compound 5-fluoro-N-(4-(1-sulfamoylpiperidin-4-yl)phenyl)isoindoline-2-carboxamide (I-21, 230 mg, 0.549 mmol, 95.0% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d6) δ: 8.29 (s, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.43 - 7.34 (m, 1H), 7.22 (dd, J = 2.0, 9.1 Hz, 1H), 7.17 - 7.10 (m, 3H), 6.73 (s, 2H), 4.73 (d, J = 11.6 Hz, 4H), 3.62 - 3.53 (m, 2H), 2.66 - 2.56 (m, 2H), 2.48 - 2.44 (m, 1H), 1.84 (d, J = 11.5 Hz, 2H), 1.76 - 1.55 (m, 2H). LC-MS: ret. time: 1.31 min, 95.48%, MS calcd. for chemical formula: C₂₀H₂₃FN₄O₃S: 418.49; found: 419.00 [M+H]⁺. Method F. HPLC: Rt 7.201 min, 99.71%; method: HPLC_X-Bridge Column: X-Select CSH C18 (4.6*150) mm 5u, mobile phase: A - 0.1% TFA in water; B – acetonitrile, injection volume: 5.0µL, flow rate: 1.2 mL/minute, column oven temp.: 30 °C, gradient program: time(min)/ B conc. : 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. EXAMPLE 79 - SYNTHESIS OF 5-FLUORO-N-(4-(1-SULFAMOYL-1,2,3,6- TETRAHYDROPYRIDIN-4-YL)PHENYL)ISOINDOLINE-2-CARBOXAMIDE (I-20)

[0937] Step 1: Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (91-3): A mixture of compound of compound 91-1 (10 g, 58.13 mmol), compound 91-2 (20.38 g, 63.94 mmol) and K₃PO₄ (37.77 g, 174.40 mmol) in 1.2-DME:H₂O (3:2, 60 mL) was degassed with argon for 5 minutes. Pd(dppf)Cl2.DCM (2.42 g, 2.906 mmol) was added to the above mixture at room temperature. The reaction mixture was stirred for 15 minutes while degassing with argon, and then the reaction mixture was stirred at 100 ℃ for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum to afford the crude. The crude was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by Combi flash chromatography using 45% EtOAc in heptane as the eluent to afford the title compound 91-3 (14 g, 51.02 mmol, 87.77% yield) as a pale-yellow solid. LC-MS: ret. time: 2.188 min, MS calcd. for chemical formula: C₁₆H₂₂N₂O₂: 274.36; found: 274.95 [M+H]⁺. Method F. [0938] Step 2: Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (91-5): To a stirred solution of compound 91-3 (1.5 g, 5.5 mmol) in DCM (15 mL) was added pyridine (0.89 mL, 11 mmol), followed by compound 91-4 (1.0 g, 6.6 mmol) and DMAP (0.067 g, 0.73) at 0 ℃ then the reaction mixture was stirred at room temperature for 16 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether and n-pentane and the filtered solids were dried under reduced pressure to afford the title compound 91-5 (2.1 g, 5.3 mmol, 97%yield) as a pale-yellow solid. LC-MS: ret. time: 2.37 min, MS calcd. for chemical formula C₂₃H₂₆N₂O₄: 394.47; found: 339.2 [(M-Isobutene) +H]⁺. Method H. [0939] Step 3: Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)- 3,6-dihydropyridine-1(2H)-carboxylate (91-7): To a stirred solution of compound 91-5 (2.1 g, 5.3 mmol) in DMF (20 mL), was added compound 91-6 (0.80 g, 5.9 mmol) and DIPEA (4.6 mL, 27 mmol) at room temperature and then the reaction mixture was stirred at 80 ℃ for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water, and the precipitated solids were filtered and washed with diethyl ether and n-pentane and dried under reduced pressure to afford the title compound 91-7 (2.1 g, 4.8 mmol, 90% yield) as a light brown solid. LC-MS: ret. time: 2.352 min, MS calcd. for chemical formula: C₂₅H₂₈FN₃O₃: 437.5; found: 438.2 [M+H]⁺. Method F. [0940] Step 4: Synthesis of 5-fluoro-N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl) isoindoline-2-carboxamide hydrochloride (91-8): To a stirred solution of compound 91-7 (2.10 g, 4.80 mmol) in DCM (20 mL) was added 4M HCl in 1,4-dioxane (20 mL) slowly at 0 ℃ and then the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (10 mL) and then with n-pentane (5 mL X 2), and the filtered the solids were dried under reduced pressure to afford the desired compound 91-8 (1.5 g, 4.5 mmol, 93% yield) as a brown solid. The resulting crude HCl salt was used in the next step without further purification. LC-MS: ret. time: 1.01 min, MS calcd. for chemical formula C₂₀H₂₀FN₃O: 337.4; found: 338.39 [M+H]⁺. Method F. [0941] Step 5: Synthesis of tert-butyl ((4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)- 3,6-dihydropyridin-1(2H)-yl)sulfonyl)carbamate (91-11): To a stirred solution of compound 91-8 (1.5 g, 4.4 mmol) in DCM (15 mL) was added DIPEA (2.3 mL, 13 mmol) and compound 18- 9 (2.0 g, 6.7 mmol) at 0 ℃ and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water followed by brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by Combi flash chromatography using 2-5% MeOH in DCM as the eluent to afford the title compound 91-11 (0.7 g, 1.355 mmol, 30% yield) as an off white solid. LC-MS: ret. time: 1.58 min, MS calcd. for chemical formula: C₂₅H₂₉FN₄O₅S: 516.58; found: 517.38 [M+H]⁺. Method H. [0942] Step 6: Synthesis of 5-fluoro-N-(4-(1-sulfamoyl-1,2,3,6-tetrahydropyridin-4- yl)phenyl)isoindoline-2-carboxamide (I-20): To a stirred solution of compound 91-11 (0.25 g, 0.483 mmol) in DCM (2.5 mL) was added 4M HCl in 1,4-dioxane (2.5 mL, 10 mmol) slowly at 0 ℃ and stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (5 mL) and then with n-pentane (4 mL X 2), and the filtered the solids were dried under reduced pressure to afford the desired compound 5-fluoro-N-(4-(1-sulfamoyl-1,2,3,6- tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide (I-20, 150 mg, 0.36 mmol, 74.42% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d6) δ: 8.40 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.41 - 7.34 (m, 3H), 7.23 (dd, J = 2.2, 9.1 Hz, 1H), 7.19 - 7.10 (m, 1H), 6.83 (s, 2H), 6.15 – 6.10 (m, 1H), 4.75 (d, J = 11.6 Hz, 4H), 3.68 (d, J = 2.9 Hz, 2H), 3.23 - 3.17 (m, 2H), 2.60 - 2.54 (m, 2H). LC-MS: ret. time: 4.368 min, 96.69%; MS calcd. for chemical formula: C₂₀H₂₁FN₄O₃S: 416.47; found: 417.2 [M+H]⁺. Method G. HPLC: 7.216 min, purity: 95.18%, column: X-Select CSH C18 (4.6*150) mm 5um; mobile phase: A - 0.1% TFA in water; B – acetonitrile, injection volume: 5.0µL, flow rate: 1.2 mL/minute, column oven temp.: 30 °C, gradient program: time(min)/ B conc. : 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. EXAMPLE 80 - SYNTHESIS OF METHYL ((4-(4-(5-FLUOROISOINDOLINE-2- CARBOXAMIDO)PHENYL)-3,6-DIHYDROPYRIDIN-1(2H)-YL)SULFONYL) CARBAMATE (I-19)

[0943] Step 1: Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (92-3): A mixture of compound 92-1 (25 g, 145.3 mmol), compound 92-2 (49.43 g, 159.9 mmol), and Cs₂CO₃ (95.2 g, 290.7 mmol) in 1,4-dioxane: H₂O (1:1) (250 mL) was degassed with argon for 5 min. X-phos (0.707 g, 14.53 mmol) and Pd2(dba)3 (6.86 g, 7.26 mmol), was added to the above mixture at rt. The reaction mixture was stirred for 15 min while degassing with argon, and then the reaction mixture was stirred at 90 ℃ for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The organic layer was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The obtained sticky crude residue was triturated with n- heptane, and the precipitated solids were filtered and dried under reduced pressure to afford the title compound 92-3 (27.00 g, 98.40 mmol, 67.70% yield) as a solid. LC-MS: ret. time: 2.172 min, MS calcd. for chemical formula C₁₆H₂₂N₂O₂, 274.36; found: 275.4 [M+H]⁺. Method G. [0944] Step 2: Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (92-5): To a stirred solution of compound 92-3 (10 g, 36.44 mmol) in DCM (100 mL) was added pyridine (8.67 mL, 109.3 mmol) followed by phenyl chloroformate 92-4 (6.92g, 43.73 mmol) at 0 ℃ and then the reaction mixture was stirred at rt for 2 hours under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by combiFlash (Nexgen-300) chromatography using a 40 g silica gel cartridge, and by using 0-3% MeOH in DCM as the eluent to afford compound 92-5 (12.0 g, 24.64 mmol, 67.61% yield) as a white solid. LC-MS: ret. time: 1.70 min, MS calcd. for chemical formula C23H26N2O4: 394.47; found: 338.93 [(M-Isobutene)+H]⁺. Method F. [0945] Step 3: Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)- 3,6-dihydropyridine-1(2H)-carboxylate (92-7): To a stirred solution of compound 92-5 (10 g, 25.35 mmol), and compound 92-6 (3.824 g, 27.88 mmol) in DMF (100 mL) was added DIPEA (13.3 mL, 76.05 mmol) at rt. The reaction mixture stirred at 60 ℃ for 2 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by combiFlash (Nexgen-300) chromatography using a 40 g silica gel cartridge, and by using 60- 70% EtOAc in n-heptane as the eluent to afford the title compound 92-7 (10 g, 19.66 mmol, 77.55% yield) as an off white solid. LC-MS: ret. time: 1.64 min, MS calcd. for chemical formula C₂₅H₂₈FN₃O₃: 437.52; found: 438.12 [M+H]⁺. Method F. [0946] Step 4: Synthesis of 5-fluoro-N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl) isoindoline-2-carboxamide hydrochloride (92-8): To a stirred solution of compound 92-7 (10 g, 22.86 mmol) in DCM (150 mL) was added 4M HCl in 1,4-dioxane (75 mL, 297.18 mmol) at 0 ℃ and stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (20 mL) and then with n-pentane (10 mL x 2), and the filtered the solids were dried under reduced pressure to afford the desired compound 92-8 (10 g, crude) as a grey solid. The resulting crude HCl salt was used in the next step without further purification. LC-MS: ret. time: 1.05 min, MS calcd. for chemical formula C20H20FN3O: 337.4; found: 338.9 [M+H]⁺. Method F. [0947] Step 5: Synthesis of tert-butyl ((4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)- 3,6-dihydropyridin-1(2H)-yl)sulfonyl)carbamate (92-10): To a stirred solution of compound 92-8 (4.0 g, 11.86 mmol), compound 18-9 (4.32 g, 14.23 mmol) in DCM (40 mL) was added DIPEA (6.21 mL, 35.57 mmol) at rt and then the reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with cold water and extracted with DCM. The combined organic layers were washed with water followed by brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was triturated with DCM and n-heptane, and the filtered solids were dried under reduced pressure to afford of the title compound 92-10 (5.0 g, 9.68 mmol, 81.64% yield) as a grey solid. LC-MS: ret. time: 1.877 min, MS calcd. for chemical formula C25H29FN4O5S: 516.59; found: 517.10 [M+H]⁺. Method H. [0948] Step 6: Synthesis of 5-fluoro-N-(4-(1-sulfamoyl-1,2,3,6-tetrahydropyridin-4- yl)phenyl)isoindoline-2-carboxamide (92-11): To a stirred solution of compound 92-10 (5.0 g, 9.68 mmol) in DCM (50 mL) was added 4M HCl in 1,4-dioxane (36 mL, 145.2 mmol) slowly at 0 ℃ and the reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (10 mL) and then with n-pentane (5 mL X 2), and the filtered the solids were dried under reduced pressure to afford the desired compound 92-11 (3.6 g, 7.7 mmol, 79% yield) as a grey solid. LC-MS: ret. time: 1.26 min, MS calcd. for chemical formula: C20H21FN4O3S: 416.47; found: 417.23[M+H]⁺. Method F. [0949] Step 7: Synthesis of methyl ((4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)-3,6- dihydropyridin-1(2H)-yl)sulfonyl)carbamate (I-19): To a stirred solution of compound 92-12 (0.15 g, 0.361 mmol) in DCM (5 mL) was added triethylamine (0.17 g, 1.083 mmol) at 0 ℃. After 10 min, methyl chloroformate 92-13 (0.041 g, 0.432 mmol) and DMAP (2 mg) were added at 0 ℃ and the reaction mixture stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by prep-HPLC to afford the title compound methyl ((4- (4-(5-fluoroisoindoline-2-carboxamido)phenyl)-3,6-dihydropyridin-1(2H)-yl)sulfonyl)carbamate (I-19, 10 mg, 0.021 mmol, 5.85% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (s, 1H), 8.16 (s, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.41 - 7.31 (m, 3H), 7.23 (d, J = 9.0 Hz, 1H), 7.17 - 7.11 (m, 1H), 6.08 (s, 1H), 4.74 (d, J = 11.5 Hz, 4H), 3.71 (s, 2H), 3.44 - 3.37 (m, 3H), 3.26 - 3.21 (m, 3H), 2.46 - 2.40 (m, 2H). LC-MS: ret. time: 1.49 min, 97.98%, MS calcd. for chemical formula: C22H23FN4O5S: 474.5; found: 475.04 [M+H]⁺. Method F. HPLC: ret. time: 7.611 min, purity: 97.79%, method: HPLC_X-Bridge column: X-Select CSH C18 (4.6*150) mm 5um; mobile phase: A - 0.1% TFA in water; B – acetonitrile, injection volume: 5.0µL, flow rate: 1.2 mL/min, column oven temp.: 30 °C, gradient program: time(min)/ B conc. : 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. Prep HPLC purification method: preparative column: X-BRIDGE (250x30mm); 5µm, mobile phase A: 0.1% TFA in H2O, mobile phase B: ACN, flow rate: 25mL, gradient (time/%B): 0/30, 3/30, 8/50, 25/50. Solvents used for dilution: ACN+THF+water. EXAMPLE 81 - SYNTHESIS OF 5-FLUORO-N-(4-(1-(N-PIVALOYLSULFAMOYL)- 1,2,3,6-TETRAHYDROPYRIDIN-4-YL)PHENYL)ISOINDOLINE-2-CARBOXAMIDE (I- 177) [0950] Step 1: Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (93-3): A mixture of compound 93-1 (25 g, 145.3 mmol), compound 93-2 (49.43 g, 159.9 mmol), Cs₂CO₃ (95.2 g, 290.7 mmol) in 1,4-dioxane: H₂O (1:1) (250 mL) was degassed with argon for 5 min. X-Phos (0.707 g, 14.53 mmol) and Pd₂(dba)₃ (6.86 g, 7.26 mmol), was added to the above mixture at rt. The reaction mixture was stirred for 15 min while degassing with argon, and then the reaction mixture was stirred at 90 ℃ for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The organic layer was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water followed by brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The obtained sticky crude residue was triturated with n- heptane, and the precipitated solids were filtered and dried under reduced pressure to afford the title compound 93-3 (27.00 g, 98.40 mmol, 67.70% yield) as a solid. LC-MS: ret. time: 2.172 min, MS calcd. for chemical formula C16H22N2O2, 274.36; found: 275.4 [M+H]⁺. Method G. [0951] Step 2: Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (93-5): To a stirred solution of compound 93-3 (10 g, 36.44 mmol) in DCM (100 mL) was added pyridine (8.67 mL, 109.3 mmol), followed by phenyl chloroformate 93-4 (6.92g, 43.73 mmol) at 0 ℃, and then the reaction mixture was stirred at rt for 2 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by combiFlash (Nexgen-300) chromatography using a 40 g silica gel cartridge, and by using 0-3% MeOH in DCM as the eluent to afford compound 93-5 (12.0 g, 24.64 mmol, 67.61% yield) as a white solid. LC-MS: ret. time: 1.70 min, MS calcd. for chemical formula C23H26N2O4: 394.47; found: 338.93 [(M-Isobutene)+H]⁺. Method F. [0952] Step 3: Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)- 3,6-dihydropyridine-1(2H)-carboxylate (93-7): To a stirred solution of compound 93-5 (10 g, 25.35 mmol) and compound 93-6 (3.824 g, 27.88 mmol) in DMF (100 mL) was added DIPEA (13.3 mL, 76.05 mmol) at rt. The reaction mixture stirred at 60 ℃ for 2 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by combiFlash (Nexgen-300) chromatography using a 40 g silica gel cartridge, and by using 60- 70% EtOAc in n-heptane as the eluent to afford the title compound 93-7 (10 g, 19.66 mmol, 77.55% yield) as an off white solid. LC-MS: ret. time: 1.64 min, MS calcd. for chemical formula C₂₅H₂₈FN₃O₃: 437.52; found: 438.12 [M+H]⁺. Method F. [0953] Step 4: Synthesis of 5-fluoro-N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl) isoindoline-2-carboxamide hydrochloride (93-8): To a stirred solution of compound 93-7 (10 g, 22.86 mmol) in DCM (150 mL) was added 4M HCl in 1,4-dioxane (75 mL, 297.18 mmol) at 0 ℃ and the reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (20 mL) and then with n-pentane (10 mL x 2), and the filtered the solids were dried under reduced pressure to afford the desired compound 93-8 (10 g, crude) as a grey solid. The resulting crude HCl salt was used in the next step without further purification. LC-MS: ret. time: 1.05 min, MS calcd. for chemical formula C20H20FN3O: 337.4; found: 338.9 [M+H]⁺. Method F. [0954] Step 5: Synthesis of tert-butyl ((4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)- 3,6-dihydropyridin-1(2H)-yl)sulfonyl)carbamate (93-10): To a stirred solution of compound 93-8 (4.0 g, 11.86 mmol), compound 18-9 (4.32 g, 14.23 mmol) in DCM (40 mL) was added DIPEA (6.21 mL, 35.57 mmol) at rt and then the reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with cold water and extracted with DCM. The combined organic layers were washed with water followed by brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was triturated with DCM and n-heptane, and the filtered the solid was dried under reduced pressure to afford of the title compound 93-10 (5.0 g, 9.68 mmol, 81.64% yield) as a grey solid. LC-MS: ret. time: 1.877 min, MS calcd. for chemical formula: C25H29FN4O5S: 516.59; found: 517.10 [M+H]⁺. Method H. [0955] Step 6: Synthesis of 5-fluoro-N-(4-(1-sulfamoyl-1,2,3,6-tetrahydropyridin-4- yl)phenyl)isoindoline-2-carboxamide (93-11): To a stirred solution of compound 93-10 (5.0 g, 9.68 mmol) in DCM (50 mL) was added 4M HCl in 1,4-dioxane (36 mL, 145.2 mmol) slowly at 0 ℃ and the reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (10 mL) and then with n-pentane (5 mL x 2), and the filtered the solids were dried under reduced pressure to afford the desired compound 93-11 (3.6 g, 7.7 mmol, 79% yield) as a grey solid. LC-MS: ret. time: 1.26 min, MS calcd. for chemical formula : C₂₀H₂₁FN₄O₃S: 416.47; found: 417.23[M+H]⁺. Method F. [0956] Step 7: Synthesis of 5-fluoro-N-(4-(1-(N-pivaloylsulfamoyl)-1,2,3,6-tetrahydro pyridin-4-yl)phenyl)isoindoline-2-carboxamide (I-177): To a stirred solution of compound 93- 12 (0.1 g, 0.24 mmol) in DCM (3 mL) were added triethylamine (0.1 mL, 0.72 mmol) and pivalic anhydride 93-13 (0.0453 g, 0.24 mmol) at 0 ℃. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by combiFlash (Nexgen-300) chromatography using a 4 g silica gel cartridge, and using 1-2% MeOH in DCM as the eluent to afford the title compound 5-fluoro-N- (4-(1-(N-pivaloylsulfamoyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide (I-177, 60 mg, 0.119 mmol, 49.68% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.40 (s, 1H), 7.59 - 7.51 (m, J = 8.9 Hz, 2H), 7.39 (dd, J = 5.1, 8.4 Hz, 1H), 7.33 (d, J = 8.8 Hz, 2H), 7.23 (dd, J = 2.2, 9.1 Hz, 1H), 7.17 - 7.09 (m, 1H), 6.08 (s, 1H), 4.74 (d, J = 11.5 Hz, 4H), 3.99 - 3.89 (m, 2H), 3.47 (t, J = 5.7 Hz, 2H), 2.56 - 2.52 (m, 2H), 1.12 (s, 9H). LC-MS: ret. time: 1.58 min, 96.87%, MS calcd. for chemical formula: C25H29FN4O4S: 500.59; found: 501.09 [M+H]⁺. Method F. HPLC: ret. time: 7.216 min, purity: 95.18%, column: X-Select CSH C18 (4.6*150) mm 5um; mobile phase: A - 0.1% TFA in water; B – acetonitrile, injection volume: 5.0µL, flow rate: 1.2 mL/minute, column oven temp.: 30 °C, gradient program: time(min)/ B conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. EXAMPLE 82 - SYNTHESIS OF 5-FLUORO-N-(4-(1-(N-PROPIONYLSULFAMOYL)- 1,2,3,6-TETRAHYDROPYRIDIN-4-YL)PHENYL)ISOINDOLINE-2-CARBOXAMIDE (I- 176) 459

[0957] Step 1: Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (94-3): A mixture of compound 94-1 (25 g, 145.3 mmol), compound 94-2 (49.43 g, 159.9 mmol) and Cs2CO3 (95.2 g, 290.7 mmol) in 1,4-dioxane: H2O (1:1) (250 mL) was degassed with argon for 5 min. X-Phos (0.707 g, 14.53 mmol) and Pd2(dba)3 (6.86 g, 7.26 mmol), were added to the above mixture at rt. The reaction mixture was stirred for 15 min while degassing with argon, and then the reaction mixture was stirred at 90 ℃ for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The organic layer was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water followed by brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The obtained sticky crude residue was triturated n-heptane, and the precipitated solid was filtered and dried under reduced pressure to afford the title compound 94-3 (27.00 g, 98.40 mmol, 67.70% yield) as a solid. LC-MS: ret. time: 2.172 min, MS calcd. for chemical formula C16H22N2O2, 274.36; found: 275.4 [M+H]⁺. Method G. [0958] Step 2: Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (94-5): To a stirred solution of compound 94-3 (10 g, 36.44 mmol) in DCM (100 mL) was added pyridine (8.67 mL, 109.3 mmol) followed by phenyl chloroformate 94-4 (6.92g, 43.73 mmol) at 0 ℃ and the reaction mixture was stirred at rt for 2 hours under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by combiFlash (Nexgen-300) chromatography using a 40 g silica gel cartridge, and by using 0-3% MeOH in DCM as the eluent to afford compound 94-5 (12.0 g, 24.64 mmol, 67.61% yield) as a white solid. LC-MS: ret. time: 1.70 min, MS calcd. for chemical formula C23H26N2O4: 394.47; found: 338.93 [(M-Isobutene)+H]⁺. Method F. [0959] Step 3: Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)- 3,6-dihydropyridine-1(2H)-carboxylate (94-7): To a stirred solution of compound 94-5 (10 g, 25.35 mmol) and compound 94-6 (3.824 g, 27.88 mmol) in DMF (100 mL) was added DIPEA (13.3 mL, 76.05 mmol) at rt. The reaction mixture stirred at 60 ℃ for 2 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by combiFlash (Nexgen-300) chromatography using a 40 g silica gel cartridge, and by using 60- 70% EtOAc in n-heptane as the eluent to afford the title compound 94-7 (10 g, 19.66 mmol, 77.55% yield) as an off white solid. LC-MS: ret. time: 1.64 min, MS calcd. for chemical formula C25H28FN3O3: 437.52; found: 438.12 [M+H]⁺. Method F. [0960] Step 4: Synthesis of 5-fluoro-N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl) isoindoline-2-carboxamide hydrochloride (94-8): To a stirred solution of compound 94-7 (10 g, 22.86 mmol) in DCM (150 mL) was added 4M HCl in 1,4-dioxane (75 mL, 297.18 mmol) at 0 ℃ and the reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (20 mL) and then with n-pentane (10 mL x 2), and the filtered the solids were dried under reduced pressure to afford the desired compound 94-8 (10 g, crude) as a grey solid. The resulting crude HCl salt was used in the next step without further purification. LC-MS: ret. time: 1.05 min, MS calcd. for chemical formula C20H20FN3O: 337.4; found: 338.9 [M+H]⁺. Method F. [0961] Step 5: Synthesis of tert-butyl ((4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)- 3,6-dihydropyridin-1(2H)-yl)sulfonyl)carbamate (94-10): To a stirred solution of compound 94-8 (4.0 g, 11.86 mmol) and compound 18-9 (4.32 g, 14.23 mmol) in DCM (40 mL) was added DIPEA (6.21 mL, 35.57 mmol) at rt and then stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with cold water and extracted with DCM. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was triturated with DCM, n-heptane, filtered and dried under reduced pressure to afford of the title compound 94-10 (5.0 g, 9.68 mmol, 81.64% yield) as a grey solid. LC-MS: ret. time: 1.877 min, MS calcd. for chemical formula C₂₅H₂₉FN₄O₅S: 516.59; found: 517.10 [M+H]⁺. Method H. [0962] Step 6: Synthesis of 5-fluoro-N-(4-(1-sulfamoyl-1,2,3,6-tetrahydropyridin-4- yl)phenyl) isoindoline-2-carboxamide (94-11): To a stirred solution of compound 94-10 (5.0 g, 9.68 mmol) in DCM (50 mL) was added 4M HCl in 1,4-dioxane (36 mL, 145.2 mmol) slowly at 0 ℃ and then the reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (10 mL) and then with n-pentane (5 mL X 2), and the filtered the solids were dried under reduced pressure to afford the desired compound 94-11 (3.6 g, 7.7 mmol, 79% yield) as a grey solid. LC-MS: ret. time: 1.26 min, MS calcd. for chemical formula : C20H21FN4O3S: 416.47; found: 417.23[M+H]⁺. Method F. [0963] Step 7: Synthesis of 5-fluoro-N-(4-(1-(N-propionylsulfamoyl)-1,2,3,6-tetrahydro pyridin-4-yl)phenyl)isoindoline-2-carboxamide (I-176): To a stirred solution of compound 94- 11 (0.15 g, 0.361 mmol) in DCM (5 mL) was added DBU (0.17 mL, 1.083 mmol) at 0 ℃. After 10 min, propionic anhydride 94-13 (0.047 g, 0.361 mmol) was added dropwise at 0 ℃ and the reaction mixture was stirred at rt for 30 min. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by prep-HPLC to afford the title compound 5-fluoro-N- (4-(1-(N-propionylsulfamoyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl) isoindoline-2-carboxamide (I-176, 10 mg, 0.021 mmol, 49.68% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.58 - 11.30 (m, 1H), 8.40 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.39 (dd, J = 5.2, 8.4 Hz, 1H), 7.34 (d, J = 8.8 Hz, 2H), 7.23 (dd, J = 2.1, 8.9 Hz, 1H), 7.17 - 7.10 (m, 1H), 6.08 (s, 1H), 4.74 (d, J = 11.6 Hz, 4H), 3.95 - 3.88 (m, 2H), 3.43 (t, J = 5.7 Hz, 2H), 2.55 - 2.52 (m, 2H), 2.22 (q, J = 7.5 Hz, 2H), 0.96 (t, J = 7.5 Hz, 3H). LCMS: 473.07 (M+H), Rt 1.48 min, 98.81%; Method F. HPLC: ret. time: 7.637 min, purity: 98.85%, column: X-Select CSH C18 (4.6*150) mm 5um; mobile phase: A - 0.1% TFA in water; B – acetonitrile, injection volume: 5.0µL, flow rate: 1.2 mL/minute, column oven temp.: 30 °C, gradient program: time(min)/ B conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. Prep HPLC purification method: preparative column: X-bridge (250*30mm); 5µm, mobile phase A: 0.1% FA in H₂O, mobile phase B: 100% ACN, flow rate: 25mL, gradient (time/%B): 0/30, 3/30,20/60, 30/70, 40/80, 60/98, Solvents used for dilution: DMSO+THF+ACN. EXAMPLE 83 - SYNTHESIS OF TERT-BUTYL ((4-(4-(5-FLUOROISOINDOLINE-2- CARBOXAMIDO)PHENYL)-3,6-DIHYDROPYRIDIN-1(2H)-YL)SULFONYL) (METHYL)CARBAMATE (I-18) [0964] Step 1: Synthesis of tert-butyl 4-(4-nitrophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (95-3): A mixture of compound 95-1 (5.00 g, 24.8 mmol), compound 95-2 (10.40 g, 32.2 mmol), and Cs2CO3 (24.3 g, 74.3 mmol) in 1,4-dioxane: H2O (1:1) (100 mL) was degassed with argon for 5 min. X-Phos (1.20 g, 2.48 mmol) and Pd2(dba)3 (1.14 g, 1.24 mmol), were added to above mixture at rt. The reaction mixture was stirred for 15 min while degassing with argon, and then the reaction mixture was heated at 100 ℃ for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The organic layer was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by CombiFlash (Nexgen-300) chromatography using a 24 g silica gel cartridge, and by using 50-60% EtOAc in n-heptane as the eluent to afford the title compound 95-3 (5.0 g, 16.43 mmol, 66.40% yield) as a pale-yellow solid. LC-MS: ret. time: 1.73 min, MS calcd. for chemical formula C₁₆H₂₀N₂O_4; 304.34; found: 248.82 [(M-Isobutene)+H]⁺. Method F. [0965] Step 2: Synthesis of 4-(4-nitrophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (95-4): To a stirred solution of compound 95-3 (5.0 g, 16.43 mmol) in 14-dioxane (20 mL) was added 4M HCl in 1,4-dioxane (20 mL, 80 mmol) dropwise at 0 ℃ and then the reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (20 mL) and then with n-pentane (10 mLx2), and the filtered the solids were dried under reduced pressure to afford the desired compound 95-4 (3.9 g, 16 mmol, 99% yield) as an off-white solid. The resulting crude HCl salt was used in the next step without further purification. LC-MS: ret. time: 0.89 min, MS calcd. for chemical formula C₁₁H₁₂N₂O_2; 204.23; found: 204.79 [(M-Isobutene)+H]⁺. Method F. [0966] Step 3: Synthesis of tert-butyl ((4-(4-nitrophenyl)-3,6-dihydropyridin-1(2H)- yl)sulfonyl) carbamate (95-6): To a stirred solution of compound 95-4 (2.0 g, 9.79 mmol) in DCM (25 mL), were added compound 18-9 (4.43 g, 14.69 mmol) and DIPEA (5.13 mL, 29.38 mmol) and the reaction mixture was then stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by CombiFlash (Nexgen-300) chromatography using a 24 g silica gel cartridge, and by using 60-70% EtOAc in n-heptane as the eluent to afford the title compound 95-6 (0.55 g, 1.4 mmol, 15% yield) as a colorless gummy solid. LC-MS: ret. time: 1.52 min, MS calcd. for chemical formula C₁₆H₂₁N₃O_6; 383.42; found: 327.88 [(M-Isobutene)+H]⁺. Method F. [0967] Step 4: Synthesis of tert-butyl methyl((4-(4-nitrophenyl)-3,6-dihydropyridin- 1(2H)-yl)sulfonyl)carbamate (95-7): To a stirred solution of compound 95-6 (0.4 g, 1.043 mmol) in ACN (6 mL) was added potassium carbonate (0.216 g, 1.56 mmol) and dimethyl sulfate (0.159 g, 1.25 mmol) at rt, and the reaction mixture was stirred rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by Combi Flash chromatography eluting with 50-60% of EtOAc in n-heptane to afford the title compound 95-7 (0.34 g, 0.855 mmol, 82.01%yield), was a pale-yellow solid. LC-MS: ret. time: 1.68 min, MS calcd. for chemical formula, C₁₇H₂₃N₃O₆S; 397.45; found: 341.92 [(M-Isobutene)+H]⁺. Method F. [0968] Step 5: Synthesis of tert-butyl ((4-(4-aminophenyl)-3,6-dihydropyridin-1(2H)- yl)sulfonyl) (methyl)carbamate (95-8): To a stirred solution of compound 95-7 (0.3 g, 0.754 mmol) in DMF (5 mL) was added 4,4'-bipyridine (0.012 g, 0.075 mmol) and BBA (B2(OH)4), (0.43 g, 4.53 mmol) at 0 ℃ and the reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc, the organic layers were concentrated to give the crude, the crude was washed with diethyl ether, and the filtered the solids were dried under reduced pressure to afford compound 95-8 (0.25 g, 0.680 mmol, 90.11%yield) is a pale-yellow gummy solid. LC-MS: ret. time: 1.38 min, MS calcd. for chemical formula, C₁₇H₂₅N₃O₄S; 367.46; found: 367.96 [M+H]⁺. Method F. [0969] Step 6: Synthesis of tert-butyl methyl((4-(4-((phenoxycarbonyl)amino)phenyl)-3,6- dihydropyridin-1(2H)-yl)sulfonyl)carbamate (95-10): To a stirred solution of compound 95-8 (0.25 g, 0.680 mmol) in DCM (6 mL) was added pyridine (0.11 mL, 1.36 mmol) and DMAP (0.010 g, 0.087 mmol) at rt and then compound 95-9 (0.13 g, 0.816 mmol) was added at 0 ℃ and then the reaction mixture was stirred at rt for 16 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether, n-pentane, and the filtered the solids were dried under reduced pressure to afford compound 95-10 (0.3 g, 0.615 mmol, 90.44% yield) as a pale-yellow solid. The crude compound was used for the next step without further purification. LC-MS: ret. time: 1.727 min, MS calcd. for chemical formula, C₂₄H₂₉N₃O₆S; 487.57; found: 431.99 [(M-Isobutene)+H]⁺. Method F. [0970] Step 7: Synthesis of tert-butyl ((4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)- 3,6-dihydropyridin-1(2H)-yl)sulfonyl)(methyl)carbamate (I-18): To a stirred solution of compound 95-10 (0.15 g, 0.307 mmol) and compound 95-11 (0.050 g, 0.369 mmol) in DMF (5 mL) were added DIPEA (0.27 mL, 1.538 mmol) and then the reaction mixture was stirred at rt for 16 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by CombiFlash (Nexgen-300) chromatography using a 4 g silica gel cartridge, and using 2-5% MeOH in DCM as the eluent to afford the title compound tert-butyl ((4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)-3,6- dihydropyridin-1(2H)-yl)sulfonyl)(methyl)carbamate (I-18, 22 mg, 0.041 mmol, 13.48% yield) as a pale brown solid.¹H NMR (400 MHz, DMSO-d6) δ: 8.39 (s, 1H), 7.55 (br d, J = 7.8 Hz, 2H), 7.41 - 7.30 (m, 3H), 7.25 - 7.08 (m, 2H), 6.09 (s, 1H), 4.73 (d, J = 11.7 Hz, 4H), 3.96 (s, 2H), 3.52 – 3.47 (m, 2H), 3.18 (s, 3H), 2.65 - 2.53 (m, 2H), 1.42 (s, 9H). LC-MS: ret. time: 2.365 min, 95.17%; MS calcd. for chemical formula, C₂₆H₃₁FN₄O₅S; 530.61; found: 531.2 [M+H]⁺. Method G. HPLC: ret. time: 8.822 min, 95.07%; column: X-Select CSH C18 (4.6*150) mm 5um; mobile phase: A - 0.1% TFA in water; B – acetonitrile, injection volume: 5.0µL, flow rate: 1.2 mL/minute, column oven temp.: 30 °C, gradient program: time(min)/ B conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. EXAMPLE 84 - SYNTHESIS OF 5-FLUORO-N-(4-(1-SULFAMOYLPIPERIDIN-4- YL)PHENYL)ISOINDOLINE-2-CARBOXAMIDE (I-17) [0971] Step 1: Synthesis of 5-fluoro-N-(4-(1-sulfamoylpiperidin-4-yl)phenyl)isoindoline- 2-carboxamide (96-1):To a stirred solution of compound I-44 (0.3 g, 0.578 mmol) in DCM (10 mL) was added 4M HCl in 1,4-dioxane (5 mL) slowly at 0 ℃ and then the reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (5 mL) and then with n-pentane (3 mL X 2), and the filtered the solids were dried under reduced pressure to afford the desired compound 96-1 (0.22 g, 0.525 mmol, 90% yield) as a grey solid. The resulting crude HCl salt was used in the next step without further purification. LC-MS: ret. time: 1.32 min, MS Calcd. for chemical formula: C₂₀H₂₃FN₄O₃S: 418.49; found: 418.96 [M+H]⁺. Method F. [0972] Step 2: Synthesis of methyl ((4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) piperidin-1-yl)sulfonyl)carbamate (I-17): To a stirred solution of compound 96-1 (0.1 g, 0.238 mmol) in DCM (10 ml) was added triethylamine (0.1 mL, 0.717 mmol) and methyl chloroformate 96-2 (0.027 g, 0.286 mmol) at 0 ℃. The reaction mixture stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers washed with brine, dried with anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by prep-HPLC to afford the title compound methyl ((4-(4-(5-fluoroisoindoline-2-carboxamido) phenyl)piperidin-1- yl)sulfonyl)carbamate (I-17, 90 mg, 0.188 mmol, 79.05% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d₆) δ 11.31 (s, 1H), 8.29 (s, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.44 - 7.33 (m, 1H), 7.22 (dd, J = 2.1, 9.1 Hz, 1H), 7.13 (d, J = 8.6 Hz, 3H), 4.73 (d, J = 11.8 Hz, 4H), 3.80 - 3.70 (m, 2H), 3.67 (s, 3H), 3.00 - 2.87 (m, 2H), 2.62 - 2.54 (m, 1H), 1.89 - 1.78 (m, 2H), 1.70 - 1.53 (m, 2H). LC-MS: ret. time: 2.080 min, 95.38%; MS Calcd. for chemical formula: C22H25FN4O5S: 476.52; found: 477.2 [M+H]⁺. Method G. HPLC: ret. time: 7.909 min, 95.44%, column: X-Select CSH C18 (4.6*150) mm 5um; mobile phase: A - 0.1% formic acid in water: acetonitrile (95:05); B - acetonitrile flow rate: 1.0. mL/minute gradient program: time (min)/ B Conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. EXAMPLE 85 - SYNTHESIS OF N-(4-(1-(N-ACETYLSULFAMOYL)PIPERIDIN-4- YL)PHENYL)-5-FLUOROISOINDOLINE-2-CARBOXAMIDE (I-7) [0973] To a stirred solution of compound I-21 (0.2 g, 0.477 mmol) in DCM (3 mL) was added triethylamine (0.2 mL, 1.43 mmol) and acetic anhydride (0.060 g, 0.57 mmol) at 0 ℃. The reaction mixture was then stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by CombiFlash (Nexgen-300) chromatography using a 4 g silica gel cartridge, and using 1-1.5% methanol in DCM as the eluent to afford the compound N-(4-(1-(N- acetylsulfamoyl)piperidin-4-yl)phenyl)-5-fluoroisoindoline-2-carboxamide (I-7, 35 mg, 0.076 mmol, 15.90% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.29 (s, 1H), 7.47 (d, J = 8.5 Hz, 2H), 7.38 (dd, J = 5.3, 8.4 Hz, 1H), 7.22 (dd, J = 1.9, 9.1 Hz, 1H), 7.16 - 7.09 (m, 3H), 4.73 (d, J = 11.6 Hz, 4H), 3.73 (d, J = 12.4 Hz, 2H), 2.96 - 2.87 (m, 2H), 2.61 - 2.53 (m, 1H), 1.99 (s, 3H), 1.82 (d, J = 11.4 Hz, 2H), 1.60 (dq, J = 3.9, 12.4 Hz, 2H). LC-MS: ret. time: 1.43 min, 96.73%; MS Calcd. for chemical formula: C₂₂H₂₅FN₄O₄S, 518.60; found: 461.06 [M+H]⁺. Method F. HPLC: ret. time: 7.333 min, 99.29%; column: X-Select CSH C18 (4.6*150) mm 5um; mobile phase: A - 0.1% TFA in water; B – acetonitrile; injection volume: 5.0µL, flow rate: 1.2 mL/minute; column oven temp.: 30°C, gradient program: time(min)/ B conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. EXAMPLE 86 - SYNTHESIS OF ETHYL ((4-(4-(5-FLUOROISOINDOLINE-2- CARBOXAMIDO)PHENYL)-3,6-DIHYDROPYRIDIN-1(2H)-YL)SULFONYL) CARBAMATE (I-6) [0974] Step 1: Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (97-3): A mixture of compound 97-1 (25 g, 145.3 mmol) and compound 97-2 (43 g, 159.9 mmol), and Cs2CO3 (95.2 g, 290.7 mmol) in 1,4-dioxane: H2O (1:1) (250 mL) was degassed with argon for 5 min. X-Phos (0.707 g, 14.53 mmol) and Pd₂(dba)₃ (6.86 g, 7.26 mmol), was added to the above mixture at rt. The reaction mixture was stirred for 15 min while degassing with argon, and then the reaction mixture was stirred at 90 ℃ for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The organic layer was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The obtained sticky crude residue was triturated with n- heptane, and the precipitated solid was filtered and dried under reduced pressure to afford the title compound 97-3 (27.00 g, 98.40 mmol, 67.70% yield) as a solid. LC-MS: ret. time: 2.172 min, MS calcd. for chemical formula C16H22N2O2, 274.36; found: 275.4 [M+H]⁺. Method G. [0975] Step 2: Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (97-5): To a stirred solution of compound 97-3 (10 g, 36.44 mmol) in DCM (100 mL) was added pyridine (8.67 mL, 109.3 mmol) followed by phenyl chloroformate 97-4 (6.92g, 43.73 mmol) at 0 ℃ and then the reaction mixture was stirred at rt for 2 hours under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by CombiFlash (Nexgen-300) chromatography using a 40 g silica gel cartridge, and by using 0-3% MeOH in DCM as the eluent to afford compound 97-5 (12.0 g, 24.64 mmol, 67.61% yield) as a white solid. LC-MS: ret. time: 1.70 min, MS calcd. for chemical formula C₂₃H₂₆N₂O₄: 394.47; found: 338.93 [(M-Isobutene)+H]⁺. Method F. [0976] Step 3: Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)- 3,6-dihydropyridine-1(2H)-carboxylate (97-7): To a stirred solution of compound 97-5 (10 g, 25.35 mmol), and compound 97-6 (3.824 g, 27.88 mmol) in DMF (100 mL) was added DIPEA (13.3 mL, 76.05 mmol) at rt. The reaction mixture stirred at 60 ℃ for 2 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by CombiFlash (Nexgen-300) chromatography using a 40 g silica gel cartridge, and by using 60- 70% EtOAc in n-heptane as the eluent to afford the title compound 97-7 (10 g, 19.66 mmol, 77.55% yield) as an off white solid. LC-MS: ret. time: 1.64 min, MS calcd. for chemical formula C₂₅H₂₈FN₃O₃: 437.52; found: 438.12 [M+H]⁺. Method F. [0977] Step 4: Synthesis of 5-fluoro-N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl) isoindoline-2-carboxamide hydrochloride (97-8): To a stirred solution of compound 97-7 (10 g, 22.86 mmol) in DCM (150 mL) was added 4M HCl in 1,4-dioxane (75 mL, 297.18 mmol) at 0 ℃ and then the reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (20 mL) and then with n-pentane (10 mL x 2), and the filtered the solids were dried under reduced pressure to afford the desired compound 97-8 (10 g, crude) as a grey solid. The resulting crude HCl salt was used in the next step without further purification. LC-MS: ret. time: 1.05 min, MS calcd. for chemical formula C20H20FN3O: 337.4; found: 338.9 [M+H]⁺. Method F. [0978] Step 5: Synthesis of tert-butyl ((4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)- 3,6-dihydropyridin-1(2H)-yl)sulfonyl)carbamate (97-10): To a stirred solution of compound 97-8 (4.0 g, 11.86 mmol) and compound 18-9 (4.32 g, 14.23 mmol) in DCM (40 mL) was added DIPEA (6.21 mL, 35.57 mmol) at room temperature and then the reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with cold water and extracted with DCM. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was triturated with DCM and n-heptane, and the solids were filtered and dried under reduced pressure to afford of the title compound 97-10 (5.0 g, 9.68 mmol, 81.64% yield) as a grey solid. LC-MS: ret. time: 1.877 min, MS calcd. for chemical formula C25H29FN4O5S: 516.59; found: 517.10 [M+H]⁺. Method H. [0979] Step 6: Synthesis of 5-fluoro-N-(4-(1-sulfamoyl-1,2,3,6-tetrahydropyridin-4- yl)phenyl) isoindoline-2-carboxamide (97-11): To a stirred solution of compound 97-10 (5.0 g, 9.68 mmol) in DCM (50 mL) was added 4M HCl in 1,4-dioxane (36 mL, 145.2 mmol) slowly at 0 ℃ and then the reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (10 mL) and then with n-pentane (5 mL x 2), and the filtered the solids were dried under reduced pressure to afford the desired compound 97-11 (3.6 g, 7.7 mmol, 79% yield) as a grey solid. LC-MS: ret. time: 1.26 min, MS calcd. for chemical formula : C20H21FN4O3S: 416.47; found: 417.23[M+H]⁺. Method F. [0980] Step 7: Synthesis of ethyl ((4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)-3,6- dihydropyridin-1(2H)-yl)sulfonyl)carbamate (I-6): To a stirred solution of 97-11 (0.15 g, 0.36 mmol) in DCM (5 mL) was added triethylamine (TEA) (0.151 mL, 1.08 mmol) and ethyl chloroformate 97-12 (0.044 g, 0.396 mmol) at 0 ℃. The reaction mixture stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by CombiFlash (Nexgen-300) chromatography using a 4 g silica gel cartridge and using 0-1.5% Methanol in DCM as the eluent to afford the compound ethyl ((4-(4-(5-fluoroisoindoline-2- carboxamido)phenyl)-3,6-dihydropyridin-1(2H)-yl)sulfonyl)carbamate (I-6, 14.5 mg, 0.029 mmol, 8.24% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 8.40 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.41 - 7.32 (m, 3H), 7.23 (dd, J = 2.2, 9.1 Hz, 1H), 7.17 - 7.10 (m, 1H), 6.11 - 6.06 (m, 1H), 4.74 (d, J = 11.6 Hz, 4H), 4.08 (q, J = 7.1 Hz, 2H), 3.94 (d, J = 2.6 Hz, 2H), 3.47 (t, J = 5.7 Hz, 2H), 2.58 – 2.52 (m, 2H), 1.17 (t, J = 7.1 Hz, 3H). LC-MS: ret. time: 1.59 min, 96.33%, MS calcd. for chemical formula: C₂₃H₂₅FN₄O₅S: 488.53; found: 489.08 [M+H]⁺. Method F. HPLC: ret. time: 7.841 min; purity: 95.50%; column: X-Select CSH C18 (4.6x150) mm 5u; mobile phase: A - 0.1% TFA in water, B – acetonitrile, injection volume: 5.0 µL, flow rate: 1.2 mL/min; column oven temp.: 30 °C, gradient program: Time(min)/ %B Conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. EXAMPLE 87 - SYNTHESIS OF ISOPROPYL ((4-(4-(5-FLUOROISOINDOLINE-2- CARBOXAMIDO)PHENYL)-3,6-DIHYDROPYRIDIN-1(2H)-YL)SULFONYL) CARBAMATE (I-5) [0981] To a stirred solution of compound 97-11 (0.15 g, 0.36 mmol) in DCM (5 mL) was added triethylamine (0.151 mL, 1.08 mmol) and isopropyl carbonochloridate 98-1 (0.048 g, 0.396 mmol) at 0 ℃. The reaction mixture stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by CombiFlash (Nexgen-300) chromatography using a 4 g silica gel cartridge, and using 0-2% methanol in DCM as the eluent to afford the compound isopropyl ((4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)-3,6-dihydropyridin-1(2H)-yl)sulfonyl) carbamate (I-5, 9.80 mg, 0.019 mmol, 5.10% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d₆) δ 11.24 (s, 1H), 8.40 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.39 (dd, J = 5.2, 8.3 Hz, 1H), 7.34 (d, J = 8.8 Hz, 2H), 7.23 (dd, J = 2.0, 9.1 Hz, 1H), 7.17 - 7.11 (m, 1H), 6.10 (s, 1H), 4.85 - 4.78 (m, 1H), 4.74 (d, J = 11.8 Hz, 4H), 3.94 (d, J = 2.1 Hz, 2H), 3.47 (t, J = 5.6 Hz, 2H), 2.58 – 2.52 (m, 2H),, 1.18 (d, J = 6.3 Hz, 6H). LC-MS: ret. time: 1.64 min, 97.82%, MS calcd. for chemical formula: C₂₄H₂₇FN₄O₅S S: 502.56; found: 503.06 [M+H]⁺. Method F. HPLC: ret. time: 8.307min 95.90%, Method: Column: X-Select CSH C18 (4.6*150) mm 5um; mobile phase: A - 0.1% formic acid in water: acetonitrile (95:05); B – acetonitrile; flow rate: 1.0 mL/min; gradient program: time(min)/% B Conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. EXAMPLE 88 - SYNTHESIS OF 5-FLUORO-N-(4-(1-(N-ISOBUTYRYLSULFAMOYL)- 1,2,3,6-TETRAHYDROPYRIDIN-4-YL)PHENYL)ISOINDOLINE-2-CARBOXAMIDE (I- 4) [0982] To a stirred solution of compound 97-11 (0.2 g, 0.481 mmol) in DCM (5 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.222 g, 1.444 mmol) and the reaction mixture was stirred for 10 min at rt.2-methylpropanoyl 2-methylpropanoate 99-1 (0.076 g, 0.481 mmol) was added to the above mixture. The reaction mixture stirred at rt for 30 min. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by CombiFlash (Nexgen-300) chromatography using a 4 g silica gel cartridge, and using 0-1% methanol in DCM as the eluent to afford the compound 5-fluoro-N-(4-(1-(N-isobutyrylsulfamoyl)-1,2,3,6-tetrahydropyridin-4- yl)phenyl)isoindoline-2-carboxamide (I-4, 60 mg, 0.124 mmol, 25.67% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d₆) δ 11.44 (s, 1H), 8.40 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.39 (dd, J = 5.3, 8.4 Hz, 1H), 7.33 (d, J = 8.8 Hz, 2H), 7.23 (dd, J = 2.1, 9.1 Hz, 1H), 7.18 - 7.11 (m, 1H), 6.11 - 6.05 (m, 1H), 4.74 (d, J = 11.6 Hz, 4H), 3.96 - 3.91 (m, 2H), 3.45 (t, J = 5.7 Hz, 2H), 2.59 – 2.53 (m, 2H), 1.01 (d, J = 6.9 Hz, 6H). LC-MS: ret. time: 2.151 min 99.62%, MS calcd. for chemical formula: C24H27FN4O4S: 486.56; found: 487.2 [M+H]⁺. Method G. HPLC: ret. time: 7.859 min 95.06%, Column: X-Select CSH C18 (4.6*150) mm 5u, mobile phase: A - 0.1% TFA in water; B – acetonitrile; injection volume: 5.0µL, flow rate: 1.2 mL/min, column oven temp.: 30 °C, gradient program: time(min)/ B conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. EXAMPLE 89 - SYNTHESIS OF TERT-BUTYL ((4-(4-(6,7-DIHYDRO-5H-PYRROLO [3,4-B]PYRIDINE-6-CARBOXAMIDO)PHENYL)PIPERIDIN-1-YL)SULFONYL) CARBAMATE (I-3) [0983] Step 1: Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (100-3): A mixture of compound of compound 100-1 (25.00 g, 145.3 mmol) and compound 100-2 (49.43 g, 159.9 mmol), and cesium carbonate (95.2 g, 290.7 mmol) in 1,4- dioxane:H₂O (50:50) (100 mL) was degassed with argon for 5 min. X-Phos (7.070 g, 14.53 mmol) and Pd2(dba)3 (6.86 g, 7.267 mmol) were added to the above mixture at rt. The reaction mixture was stirred for 15 min while degassing with argon, and then the reaction mixture was heated to 90 ℃ and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with ethyl acetate twice. The organic layers were diluted with water. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude sticky compound was washed with n-heptane, and dried under reduced pressure to afford the title compound 100-3 (25 g, 91.11 mmol, 62.69% yield) as a solid (off white solid). LC-MS: ret. time: 2.17 min, MS calcd. for chemical formula C16H22N2O2, 274.36; found: 274.95 [M+H]⁺. Method F. [0984] Step 2: Synthesis of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (100-4): To a stirred solution of compound 100-3 (10.0 g, 36.4 mmol) in methanol (100 mL) was added 10% palladium on carbon (50% wet) (3.88 g) and then the reaction mixture was stirred at rt for 16 h under hydrogen atmosphere at 50 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The organic layer was concentrated under reduced pressure to afford the title crude compound 100-4 (8.5 g, 31 mmol, 84% yield) as a pale brown solid. LC-MS: ret. time: 1.85 min, MS calcd. for chemical formula: C₁₆H₂₄N₂O₂: 276.38; found: 275.27 [M-H]-. Method H. [0985] Step 3: Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)piperidine- 1-carboxylate (100-6): To a stirred solution of compound 100-4 (8.5 g, 31 mmol) in DCM (85 mL) was added pyridine (5.0 mL, 62 mmol), compound 100-5 (4.7 g, 37 mmol) followed by DMAP (0.38 g, 3.1 mmol) at 0 ℃ and then the reaction mixture was stirred at rt for 16 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether and n-pentane, the solids were filtered and dried under reduced pressure to afford the title compound 100-6 (10.0 g, 25.22 mmol, 82% yield) as a pale-yellow solid. LC-MS: ret. time: 2.48 min, MS calcd. for chemical formula: C₂₃H₂₈N₂O₄: 396.49; found: 341.1 [(M-Isobutene)+H]⁺. Method H. [0986] Step 4: Synthesis of tert-butyl 4-(4-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-6- carboxamido) phenyl)piperidine-1-carboxylate (100-8): To a stirred solution of compound 100- 6 (0.5 g, 1.261 mmol) in DMF (8 mL) were added compound 100-7 (0.26 g, 1.513 mmol) and DIPEA (1.10 mL, 6.305 mmol) at rt and then the reaction mixture was heated to 70 ℃ for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether and n-pentane, and the filtered the solids were dried under reduced pressure to afford the title compound 100-8 (0.4 g, 0.94 mmol, 75.08% yield) as a brown solid. LCMS: ret. time: 1.24 min, MS calcd. for chemical formula: C₂₄H₃₀N₄O₃: 422.53; found: 423.12 [M+H]⁺. Method F. [0987] Step 5: Synthesis of N-(4-(piperidin-4-yl)phenyl)-5,7-dihydro-6H-pyrrolo[3,4- b]pyridine-6-carboxamide hydrochloride (100-9): To a stirred solution of compound 100-8 (0.40 g, 0.99 mmol) in DCM (6 mL) was added 4M HCl in 1,4-dioxane (2.497 mL, 9.9 mmol) dropwise at 0 ℃ and then the reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (5 mL) and then with n-pentane (3 mL x 2), and the filtered the solids were dried under reduced pressure to afford the desired compound 100-9 (0.34 g, 0.902 mmol, 90.31% yield) as a pale brown solid. The resulting crude HCl salt was used in the next step without further purification. LC-MS: ret. time: 0.94 min, MS calcd. for chemical formula: C19H22N4O: 322.41; found: 323.01 [M+H]⁺. Method F. [0988] Step 6: Synthesis of tert-butyl ((4-(4-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-6- carboxamido)phenyl)piperidin-1-yl)sulfonyl)carbamate (I-3): To a stirred solution of compound 100-9 (0.3 g, 0.93 mmol) in DCM (5 mL) were added compound 18-9 (0.339 g, 1.117 mmol) and DIPEA (0.76 mL, 4.4 mmol) at rt and then the reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (using 4 g cartridge silica gel and eluting with 70-80% EtOAc in heptane) to afford the title compound tert-butyl ((4-(4-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-6- carboxamido)phenyl)piperidin-1-yl)sulfonyl)carbamate (I-3, 40 mg, 0.079 mmol, 8.57% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.49 - 8.45 (m, 1H), 8.33 (s, 1H), 7.80 (d, J = 7.3 Hz, 1H), 7.48 (d, J = 8.6 Hz, 2H), 7.36 - 7.29 (m, 1H), 7.13 (d, J = 8.6 Hz, 2H), 4.76 (d, J = 6.1 Hz, 4H), 3.78 - 3.70 (m, 2H), 2.96 - 2.87 (m, 2H), 2.63 - 2.55 (m, 1H), 1.86 - 1.79 (m, 2H), 1.61 (dq, J = 3.9, 12.5 Hz, 2H), 1.45 (s, 9H). LCMS: ret. time: 1.42 min, 97.81%; MS calcd. for chemical formula: C₂₄H₃₁N₅O₅S, 501.60; found: 502.64 [M+H]⁺. Method F. HPLC: Rt 6.284 min, 97.85%; column: X-Select CSH C18 (4.6*150) mm 5um; mobile phase: A - 0.1% TFA in water; B – acetonitrile; injection volume: 5.0µL, flow rate: 1.2 mL/minute, column oven temp.: 30 °C, gradient program: time(min)/ B conc. : 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. EXAMPLE 90 - SYNTHESIS OF ISOPROPYL ((4-(4-(5-FLUOROISOINDOLINE-2- CARBOXAMIDO)PHENYL)PIPERIDIN-1-YL)SULFONYL)CARBAMATE (I-2) [0989] To a stirred solution of I-21 (0.1 g, 0.238 mmol) in DCM (3 mL) was added triethylamine (0.1 mL, 0.716 mmol) and isopropyl carbonochloridate 101-1 (0.049 g, 0.262 mmol) at 0 ℃. The reaction mixture stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by CombiFlash (Nexgen-300) chromatography using a 4 g silica gel cartridge, and using 1-1.5% methanol in DCM as the eluent to afford the compound isopropyl ((4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)piperidin-1-yl)sulfonyl)carbamate (I-2, 44 mg, 0.086 mmol, 36.10% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.29 (s, 1H), 7.47 (d, J = 8.5 Hz, 2H), 7.38 (dd, J = 5.2, 8.3 Hz, 1H), 7.22 (dd, J = 2.0, 9.0 Hz, 1H), 7.16 - 7.10 (m, 3H), 4.93 - 4.81 (m, 1H), 4.73 (d, J = 11.6 Hz, 4H), 3.75 (d, J = 12.4 Hz, 2H), 2.99 - 2.88 (m, 2H), 2.64 - 2.54 (m, 1H), 1.87 - 1.78 (m, 2H), 1.61 (dq, J = 4.0, 12.5 Hz, 2H), 1.24 (d, J = 6.3 Hz, 6H). LC-MS: ret. time: 1.61 min, 97.58%, chemical formula: C24H29FN4O5S: 504.57; found: 505.16 [M+H]⁺. Method F. HPLC: ret. time: 8.318 min; 98.85%; Column: X-Select CSH C18 (4.6*150) mm 5u; mobile phase: A - 0.1% Formic acid in water: acetonitrile (95:05) B – acetonitrile; flow rate: 1.0 mL/min; gradient program: Time (min)/ B Conc.: .01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. EXAMPLE 91 - SYNTHESIS OF 5-FLUORO-N-(4-(1-(N-(METHYLCARBAMOYL) SULFAMOYL)-1,2,3,6-TETRAHYDROPYRIDIN-4-YL)PHENYL)ISOINDOLINE-2- CARBOXAMIDE (I-175) [0990] To a stirred solution of compound 97-11 (0.15 g, 0.36 mmol) in DCM (5 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.155 g, 0.99 mmol) followed by methylcarbamic chloride 102-1 (0.032 g, 0.396 mmol) at 0 ℃. The reaction mixture stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by prep-HPLC to afford the compound 5-fluoro-N-(4-(1-(N-(methylcarbamoyl)sulfamoyl)-1,2,3,6-tetrahydropyridin-4- yl)phenyl)isoindoline-2-carboxamide (I-175, 10 mg, 0.021 mmol, 6.0% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H) 8.41 (s, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.42 - 7.31 (m, 3H), 7.23 (d, J = 8.4 Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 6.26 (s, 1H), 6.13 - 6.07 (m, 1H), 4.75 (d, J = 11.4 Hz, 4H), 3.95 - 3.65 (m, 2H), 3.45 - 3.37 (m, 2H), 3.23 - 3.17 (m, 2H), 2.58 (d, J = 4.3 Hz, 3H), 2.55 - 2.53 (m, 2H). LC-MS: ret. time: 1.55 min, 95.84%, MS calcd. for chemical formula: C22H24FN5O4S: 473.52; found: 474.04 [M+H]⁺ . Method F. HPLC: ret. time: 7.364 min; purity: 96.49%; method: Column: X-Select CSH C18 (4.6*150) mm 5u, mobile phase: A - 0.1% formic acid in water: acetonitrile (95:05); B - acetonitrile flow rate: 1.0 mL/min, gradient program: time(min)/ B conc. : 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. prep-HPLC purification method: COLUMN X-bridge C 18 (30x250mm), mobile phase A: 0.1% FA in water, mobile phase B: ACN, flow rate: 25 ml/min; gradient (time/%B) 0/20, 3/20, 10/45, 15/50, 25/60, 35/70, 50/85, 60/98. EXAMPLE 92 - SYNTHESIS OF N-(4-(1-(N-(DIMETHYLCARBAMOYL) SULFAMOYL)-1,2,3,6-TETRAHYDROPYRIDIN-4-YL)PHENYL)-5-FLUORO- ISOINDOLINE-2-CARBOXAMIDE (I-174) [0991] To a stirred solution of compound 97-11 (0.2 g, 0.44 mmol) in DCM (5 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.210 g, 1.32 mmol) followed by and dimethylcarbamic chloride 103-1 (0.032 g, 0.396 mmol) at 0 ℃. The reaction mixture stirred at rt for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by prep- HPLC to afford the compound N-(4-(1-(N-(dimethylcarbamoyl)sulfamoyl)-1,2,3,6- tetrahydropyridin-4-yl)phenyl)-5-fluoroisoindoline-2-carboxamide (I-174, 12 mg, 0.024 mmol, 5.57% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d₆) δ: 10.16 (s, 1H), 8.41 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.41 - 7.32 (m, 3H), 7.23 (d, J = 7.1 Hz, 1H), 7.14 (t, J = 9.0 Hz, 1H), 6.09 (s, 1H), 4.75 (d, J = 11.6 Hz, 4H), 3.93 (s, 2H), 3.47 - 3.41 (m, 2H), 2.83 (s, 6H), 2.57 – 2.53 (m, 2H). LC-MS: ret. time: 1.54 min, 95.84%, MS calcd. for chemical formula: C₂₃H₂₆FN₅O₄S: 487.55; found: 488.07 [M+H]⁺ . Method F. HPLC: ret. time: 7.119 min; purity: 95.04%; method: Column: X-Select CSH C18, 5.0 µm, 150 X 4.6 mm mobile phase A: 0.1% FA in (water:ACN) (95:5)V/V mobile phase B: acetonitrile; Column Temperature: 30 °C, flow rate: 1.0 ml/min; gradient: 0/5, 1/5, 8/100, 12/100, 14/5, 18/5; Diluent: ACN: water. prep-HPLC purification method: COLUMN: X-bridge C 18 (30x250mm), mobile phase A: 0.1% TFA in H2O, mobile phase B: ACN, flow rate: 25 ml/min; Instrument ID: PREP-15; gradient (time/%B) 0/20, 3/20, 10/40, 20/45, 30/60. EXAMPLE 93 - SYNTHESIS OF 3-FLUORO-N-(4-(1-SULFAMOYL-1,2,3,6- TETRAHYDROPYRIDIN-4-YL)PHENYL)-5,7-DIHYDRO-6H-PYRROLO[3,4- B]PYRIDINE-6-CARBOXAMIDE (I-167) AND TERT-BUTYL ((4-(4-(3-FLUORO-6,7- DIHYDRO-5H-PYRROLO[3,4-B]PYRIDINE-6-CARBOXAMIDO)PHENYL)-3,6- DIHYDROPYRIDIN-1(2H)-YL)SULFONYL) CARBAMATE (I-173) [0992] Step 1: Synthesis of tert-butyl 4-(4-nitrophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (104-3): A mixture of compound of compound 104-1 (5.00 g, 24.8 mmol), compound 104-2 (10.4 g, 32.2 mmol) and Cs₂CO₃ (24.3 g, 74.3 mmol) in 1,4-dioxane:water (50:50) (100 mL) was degassed with argon for 5 min. X-Phos (1.20 g, 2.48 mmol) and Pd₂(dba)₃ (1.14 g, 1.24 mmol) were added to the above mixture at rt . The reaction mixture was stirred for 15 min while degassing with argon, and then the reaction mixture was stirred at 90 ℃ for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum to afford the crude. The crude was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by CombiFlash (Nexgen-300) chromatography using a 24 g silica gel cartridge and 50-60% EtOAc in heptane as the eluent to afford the title compound 104-3 (5.0 g, 16.43 mmol, 66% yield) as a pale-yellow solid. LC-MS: ret. time: 1.73 min, MS calcd. for chemical formula C16H20N2O4; 304.35; found: 248.82 [(M-Isobutene)+H]⁺. Method F. [0993] Step 2: Synthesis of 4-(4-nitrophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (104-4): To a stirred solution of compound 104-3 (5.0 g, 16.43 mmol) in 1,4-dioxane (20 mL) was added 4M HCl in 1,4-dioxane (41 mL, 164.3 mmol) slowly at 0 ℃ and then the reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (8 mL) and then with n-pentane (4 mL X 2), and the filtered the solids were dried under reduced pressure to afford the desired compound 104-4 (3.60 g , 15 mmol 91% yield) as an off white solid. The resulting crude HCl salt was used in the next step without further purification. LC-MS: ret. time: 0.90 min, MS calcd. for chemical formula C11H12N2O2: 204.23; found: 204.79 [M+H]⁺. Method F. [0994] Step 3: Synthesis of tert-butyl ((4-(4-nitrophenyl)-3,6-dihydropyridin-1(2H)- yl)sulfonyl)carbamate (104-6): To a stirred solution of compound 104-4 (1.7 g, 8.3 mmol) in DCM (20 mL) were added DIPEA ((5.8 mL, 33 mmol), compound 18-9 (3.0 g, 10 mmol) at 0 ℃ then the reaction mixture was stirred at rt for 16 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether and n-pentane, and the solids were filtered and dried under reduced pressure to afford the title compound 104-6 (1.0 g, 2.60 mmol, 31% yield) as a pale-yellow solid. LC-MS: ret. time: 1.59 min, MS calcd. for chemical formula: C16H21N3O6S: 383.42; found: 339.94 [(M- Isobutene)+H]⁺. Method F. [0995] Step 4: Synthesis of tert-butyl ((4-(4-aminophenyl)-3,6-dihydropyridin-1(2H)- yl)sulfonyl)carbamate (104-7): To a stirred solution of compound 104-6 (0.2 g, 0.5 mmol) in DMF (3 mL) was added 4,4'-bipyridine (0.008 g, 0.05 mmol). Then BBA (B₂OH₄) (0.3 g, 3 mmol) was added portion wise at 0 ℃ and the reaction mixture was stirred at rt for 2 h. The reaction mixture was quenched with ice cold water, and the solid formed was filtered, dried under vacuum and washed with n-pentane and diethyl ether twice or trice and dried under vacuum to afford compound 104-7 (0.12 g, 0.33 mmol, 70% yield) as a pale yellow semi-solid. LC-MS: ret. time: 1.24 min, MS calcd. for chemical formula: C₁₆H₂₃N₃O₄S: 353.4; found: 353.97 [M+H]⁺. Method F. [0996] Step 5: tert-butyl ((4-(4-((phenoxycarbonyl)amino)phenyl)-3,6-dihydropyridin- 1(2H)-yl)sulfonyl)carbamate (104-9): To a stirred solution of compound 104-7 (0.5 g, 1.415 mmol) in DCM (13 mL) was added pyridine (0.23 mL, 2.830 mmol) at rt and compound 104-8 (0.214 mL, 1.698 mmol) was added at 0 ℃ and then the reaction mixture was stirred at rt for 16 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether and n-pentane, and the solids were filtered and dried under reduced pressure to afford the title compound 104-9 (0.57 g 1.204 mmol, 85.08%yield) as a pale yellow solid. LC-MS: ret. time: 2.263 min, MS calcd. for chemical formula: C23H27N3O6S4: 473.5; found: 374.2 [(M-Boc)+H]⁺. Method G. [0997] Step 6: Synthesis of 3-fluoro-N-(4-(1-sulfamoyl-1,2,3,6-tetrahydropyridin-4- yl)phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide (I-167): To a stirred solution of compound 104-9 (0.3 g 0.633 mmol) in DMF (5 mL) were added compound 104-10 (0.10 g, 0.76 mmol) and DIPEA (0.55 mL, 3.17 mmol) and reaction was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with EtOAc. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by prep-HPLC to afford the title compound 3-fluoro-N-(4-(1-sulfamoyl- 1,2,3,6-tetrahydropyridin-4-yl)phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide (I- 167, 15 mg, 0.117 mmol, 64.01% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 7.0 Hz, 2H), 7.85 - 7.75 (m, 1H), 7.61 - 7.52 (m, J = 8.7 Hz, 2H), 7.41 - 7.33 (m, J = 8.7 Hz, 2H), 6.84 (s, 2H), 6.13 (s, 1H), 4.77 (d, J = 18.1 Hz, 4H), 3.68 (s, 2H), 3.27 - 3.12 (m, 2H), 2.60 - 2.54 (m, 2H). LC-MS: ret. time: 1.42 min, 98.13%: ret. time: min, MS calcd. for chemical formula C₁₉H₂₀FN₅O₃S: 417.46; found: 418.00 [M+H]⁺. Method F. HPLC: ret. time: 7.198 min, 97.80% Method: X-Select CSH C18 (4.6x150) mm 5um; mobile phase: A - 5 Mm; Ammonium Acetate in water; B – acetonitrile; flow rate: 1.0 mL/minute column oven temp.: 30 °C, gradient program: Time (min)/ B Conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. Prep-HPLC purification method: COLUMN: X-SELECT C-18 (30x250mm); mobile phase A: 10mM ammonium bicarbonate in water, mobile phase B: 100% ACN, flow rate: 25 ml/min; gradient time (min)(%B): 0/25, 0/20, 3/20, 10/25, 30/65. [0998] Step 7: Synthesis of tert-butyl ((4-(4-(3-fluoro-6,7-dihydro-5H-pyrrolo[3,4- b]pyridine-6-carboxamido)phenyl)-3,6-dihydropyridin-1(2H)-yl)sulfonyl)carbamate (I- 173): To a stirred solution of compound I-167 (5.5 mg, 0.013 mmol) in DCM (0.5 mL) was added triethylamine (0.0028 mL, 0.020 mmol) at 0 ℃. Then was boc-anhydride (0.0037 mL, 0.016 mmol) was added. The mixture was stirred for rt for 16 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was triturated with n-pentane and diethyl ether, and the solids were filtered to afford the title compound tert-butyl ((4-(4-(3-fluoro-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-6-carboxamido)phenyl)-3,6- dihydropyridin-1(2H)-yl)sulfonyl)carbamate (I-173, 5 mg, 0.0096 mmol, 73% yield) as an off- white solid.¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (d, J = 6.8 Hz, 2H), 7.92 - 7.68 (m, 2H), 7.57 (d, J = 8.8 Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H), 6.84 (s, 2H), 6.13 (s, 1H), 4.77 (d, J = 18.4 Hz, 4H), 3.68 (s, 2H), 3.20 (t, J = 5.6 Hz, 2H),), 2.59 – 2.254 (m, 2H), 1.24 (s, 9H). LC-MS: ret. time: 3.893 min, 95.83%: MS calcd. for chemical formula C₂₄H₂₈FN₅O₅S: 517.58; found: 518.2 [M+H]⁺. Method H. HPLC: ret. time: 6.716 min, 95.01%; column: X-Bridge C18 (4.6x150) mm 5u; mobile phase: A - 5 mM ammonium bicarbonate in water, B – acetonitrile; injection volume: 5.0µL, flow rate: 1.0 mL/minute; gradient program: time(min)/ B conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. EXAMPLE 94 - SYNTHESIS OF TERT-BUTYL ((4-(4-(6,7-DIHYDRO-5H-PYRROLO [3,4-B]PYRIDINE-6-CARBOXAMIDO)PHENYL)PIPERIDIN-1-YL)SULFONYL) CARBAMATE (I-172) [0999] Step 1: Synthesis of tert-butyl 4-(4-(2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2- carboxamido) phenyl)piperidine-1-carboxylate (105-8): To a stirred solution of compound 100- 6 (0.5 g, 1.261 mmol) in DMF (8 mL) was added compound 105-7 (0.26 g, 1.513 mmol) and DIPEA (1.10 mL, 6.305 mmol) at rt and the reaction mixture was stirred at 70 ℃ for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether and n-pentane, and the solids were filtered and dried under reduced pressure to afford the title compound 105-8 (0.4 g, 0.94 mmol, 75.08% yield) as a brown solid. LCMS: ret. time: 1.24 min, MS calcd. for chemical formula: C₂₄H₃₀N₄O₃: 422.53; found: 423.12 [M+H]⁺. Method F. [1000] Step 2: N-(4-(piperidin-4-yl)phenyl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2- carboxamide hydrochloride (105-9): To a stirred solution of compound 105-8 (0.4 g, 0.946 mmol) in 1,4-dioxane (8 mL) was added 4M HCl in 1,4-dioxane (2.4 mL, 9.46 mmol) dropwise at 0 ℃ and then the reaction mixture was stirred at rt for 8 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (5 mL) and then with n-pentane (3 mL x 2), and the filtered solids were dried under reduced pressure to afford the desired compound 105-9 (0.32 g, 0.89 mmol, 94.18% yield) as a brown solid. The resulting crude HCl salt was used in the next step without further purification. LC-MS: ret. time: 0.38 min, MS calcd. for chemical formula: C₁₉H₂₂N₄O: 322.41; found: 323.01 [M+H]⁺. Method F. [1001] Step 3 Synthesis of tert-butyl ((4-(4-(2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2- carboxamido)phenyl)piperidin-1-yl)sulfonyl)carbamate (I-172): To a stirred solution of compound 105-9 (0.3 g, 0.93 mmol) in DCM (5 mL) were added compound 18-9 (0.34 g, 1.117 mmol), and DIPEA (0.65 mL, 3.72 mmol) at rt and then the reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by Combi Flash chromatography (using a 4 g silica gel cartridge and eluting with 2-3% MeOH in DCM) to afford the title compound tert-butyl ((4-(4-(2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2- carboxamido)phenyl)piperidin-1-yl)sulfonyl)carbamate (I-172, 60 mg, 0.119 mmol, 12.85% Yield)) as an off white solid.¹H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.60 (s, 1H), 8.50 (d, J = 4.9 Hz, 1H), 8.35 (s, 1H), 7.50 - 7.41 (m, 3H), 7.13 (d, J = 8.7 Hz, 2H), 4.79 (d, J = 6.8 Hz, 4H), 3.74 (d, J = 12.6 Hz, 2H), 2.90 (t, J = 11.6 Hz, 2H), 2.65 - 2.54 (m, 1H), 1.81 (d, J = 11.0 Hz, 2H), 1.70 - 1.52 (m, 2H), 1.44 (s, 9H). LCMS: ret. time: 1.724 min, 99.02%; MS calcd. for chemical formula: C24H31N5O5S, 501.60; found: 502.1 [M+H]⁺. Method H. HPLC: Rt 6.234 min, 97.58%; Method: HPLC_X-Bridge, column: X-Select CSH C18 (4.6*150) mm 5um; mobile phase: A - 0.1% TFA in water; B – acetonitrile, injection volume: 5.0µL, flow rate: 1.2 mL/minute, column oven temp.: 30 °C, gradient program: time(min)/ B conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. Prep-HPLC purification method: column: X-select C-18 (30x250mm); mobile phase A: 10 mM; ammonium bicarbonate in water, mobile phase B: 100% ACN; flow rate: 25 ml/min: gradient (time/%B): 0/20, 3/20, 10/25, 20/35, 26/35, 30/98. EXAMPLE 95 - SYNTHESIS OF TERT-BUTYL ((4-(4-(6,7-DIHYDRO-5H- PYRROLO[3,4-B]PYRIDINE-6-CARBOXAMIDO)PHENYL)-3,6-DIHYDROPYRIDIN- 1(2H)-YL)SULFONYL)CARBAMATE (I-171) [1002] Step 1: Synthesis of tert-butyl 4-(4-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-6- carboxamido) phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (106-7): To a stirred solution of compound 97-5 (0.5 g, 1.261 mmol) in DMF (8 mL) were added compound 106-6 (0.19 g, 1.521 mmol) and DIPEA (1.11 mL, 6.34 mmol) at rt and then the reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by Combi Flash chromatography (using a 12 g silica gel cartridge and eluting with 2 to 5% MeOH in DCM to afford the title compound 106-7 (0.42 g, 0.99 mmol, 78.81% yield) as a pale brown solid. LC-MS: ret. time: 1.57 min, MS calcd. for chemical formula: C₂₄H₂₈N₄O₃: 420.51; found: 421.44 [M+H]⁺. Method F. [1003] Step 2: N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-5,7-dihydro-6H-pyrrolo[3,4- b]pyridine-6-carboxamide hydrochloride (106-8): To a stirred solution of compound 106-7 (0.42 g, 0.99 mmol) in DCM (8 mL) was added 4M HCl in 1,4-dioxane (2.5 mL, 10 mmol) dropwise at 0 ℃ and then the reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (5 mL) and then with n-pentane (3 mL x 2), and the filtered the solids were dried under reduced pressure to afford the desired compound 106-8 (0.31 g, 0.96 mmol, 90.31% yield) as a pale brown solid. The resulting crude HCl salt was used in the next step without further purification. LC-MS: ret. time: 1.01 min, MS calcd. for chemical formula: C₁₉H₂₀N₄O: 320.4; found: 320.99 [M+H]⁺. Method F. [1004] Step 3: Synthesis of tert-butyl ((4-(4-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-6- carboxamido)phenyl)-3,6-dihydropyridin-1(2H)-yl)sulfonyl)carbamate (I-171): To a stirred solution of compound 106-8 (0.3 g, 0.93 mmol) in DCM (10 mL) were added compound 18-9 (0.34 g, 1.121 mmol) and DIPEA (0.66 mL, 3.8 mmol) at rt and then the reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by prep-HPLC to afford the title compound tert-butyl ((4-(4-(6,7-dihydro- 5H-pyrrolo[3,4-b]pyridine-6-carboxamido)phenyl)-3,6-dihydropyridin-1(2H)-yl)sulfonyl) carbamate (I-171, 9 mg, 0.018 mmol, 1.924% yield)) as an off white solid.¹H NMR (400 MHz, DMSO-d6) δ 11.06 - 10.97 (m, 1H), 8.48 (d, J = 4.1 Hz, 1H), 8.44 (s, 1H), 7.80 (d, J = 7.3 Hz, 1H), 7.57 (d, J = 8.8 Hz, 2H), 7.38 - 7.31 (m, 3H), 6.11 (s, 1H), 4.78 (d, J = 5.0 Hz, 4H), 3.91 (s, 2H), 3.44 (s, 2H), 2.56 - 2.52 (m, 2H), 1.38 (s, 9H). LCMS: ret. time: 1.38 min, 99.36%; MS calcd. for chemical formula: C24H29N5O5S, 499.59; found: 500.37 [M+H]⁺. Method H. HPLC: Rt 6.061 min, 97.28%; Method: HPLC_X-Bridge; column: X-Bridge C18 (4.6*150) mm 5um; mobile phase: A - 5 mM ammonium bicarbonate in water, B – acetonitrile, injection volume: 5.0µL, column oven temp.: 50°C, flow rate: 1.0 mL/min, gradient program: time(min)/ B conc. : 0.01/5, 1.0/5, 7.0/100, 12.0/100, 14.0/5, 18.0/5. Prep-HPLC purification method: column: X-select C-18 (30x250mm) mobile phase A: 10 mM ammonium bicarbonate in water, mobile phase B: ACN; flow rate: 25 ml/min; gradient (time/%B): 0/20, 3/20, 10/25, 25/35, 30/98. EXAMPLE 96 - SYNTHESIS OF ETHYL ((4-(4-(5-FLUOROISOINDOLINE-2- CARBOXAMIDO)PHENYL)PIPERIDIN-1-YL)SULFONYL)CARBAMATE (I-170) [1005] To a stirred solution of compound I-21 (0.15 g, 0.36 mmol) in DCM (5 mL) was added triethylamine (0.15 mL, 1.075 mmol) and ethyl carbonochloridate 107-1 (0.044 g, 0.39 mmol) at 0 ℃. The reaction mixture was stirred at rt for 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by CombiFlash (Nexgen-300) chromatography using a 4 g silica gel cartridge, and using 0-1.5% MeOH in DCM as the eluent to afford the compound ethyl ((4-(4- (5-fluoroisoindoline-2-carboxamido)phenyl)piperidin-1-yl)sulfonyl)carbamate (I-170, 20 mg, 0.039 mmol, 11.15% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d₆) δ 11.25 (s, 1H), 8.30 (s, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.42 - 7.33 (m, 1H), 7.23 (dd, J = 2.1, 9.1 Hz, 1H), 7.16 - 7.10 (m, 3H), 4.73 (d, J = 11.6 Hz, 4H), 4.16 - 4.06 (m, 2H), 3.74 (d, J = 12.5 Hz, 2H), 2.98 - 2.87 (m, 2H), 2.62 - 2.54 (m, 1H), 1.82 (d, J = 11.0 Hz, 2H), 1.69 - 1.53 (m, 1H), 1.60 (dd, J = 3.7, 12.5 Hz, 1H), 1.22 (t, J = 7.1 Hz, 3H). LC-MS: ret. time: 1.68 min, 96.21%, MS calcd. for chemical formula: C23H27FN4O5S: 490.55; found: 491.09 [M+H]^+. Method F. HPLC: ret. time: 7.828 min; purity: 98.12%; method: Column: X-Select CSH C18 (4.6*150) mm 5u, mobile phase: A - 0.1% formic acid in water: acetonitrile(95:05); B – acetonitrile; flow rate: 1.0 mL/min, gradient program: time(min)/ B conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. EXAMPLE 97 - SYNTHESIS OF 5-FLUORO-N-(4-(1-(N-PIVALOYLSULFAMOYL) PIPERIDIN-4-YL)PHENYL)ISOINDOLINE-2-CARBOXAMIDE (I-169) [1006] To a stirred solution of compound I-21 (0.10 g, 0.24 mmol) in DMSO (5 mL) were added NaH (60%) (0.019 g, 0.477 mmol) followed by pivalic anhydride 108-1 (0.044 g, 0.39 mmol) at 0 ℃. The reaction mixture stirred at rt for 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by CombiFlash (Nexgen-300) chromatography using a 4 g silica gel cartridge, and using 0-1.5% MeOH in DCM as the eluent to afford the compound 5-fluoro-N-(4-(1-(N-pivaloylsulfamoyl)piperidin-4-yl)phenyl) isoindoline-2- carboxamide (I-169, 20 mg, 0.039 mmol, 11.15% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d₆) δ 11.01 (s, 1H), 8.30 (s, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.38 (t, J = 6.5 Hz, 1H), 7.22 (d, J = 9.1 Hz, 1H), 7.14 - 7.09 (m, 3H), 4.73 (d, J = 11.6 Hz, 4H), 3.77 (d, J = 12.4 Hz, 2H), 2.89 (t, J = 11.8 Hz, 2H), 2.62 - 2.55 (m, 1H), 1.81 (d, J = 11.0 Hz, 2H), 1.70 - 1.48 (m, 2H), 1.16 (s, 9H). LC-MS: ret. time: 1.71 min, 99.39%, MS calcd. for chemical formula: C₂₅H₃₁FN₄O₄S: 490.55; found: 503.11 [M+H]⁺. Method F. HPLC: ret. time: 8.099 min; purity: 99.87%; method: Column: X-Select CSH C18 (4.6*150) mm 5u, mobile phase: A - 0.1% formic acid in water: acetonitrile (95:05); B - acetonitrile; flow rate: 1.0 mL/min, gradient program: time(min)/ B conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. Prep-HPLC purification method: column: X-select (30x250mm) 5µm, mobile phase A 0.1% FA in water mobile phase B: ACN; flow rate: 25 ml/min; gradient (time/%B): 0/20, 3/20, 10/35, 30/55, 40/65, 60/98. EXAMPLE 98 - SYNTHESIS OF 5-FLUORO-N-(4-(1-(N-PROPIONYLSULFAMOYL) PIPERIDIN-4-YL)PHENYL)ISOINDOLINE-2-CARBOXAMIDE (I-168) [1007] To a stirred solution of sodium hydride (60% in mineral oil, 0.030 g, 0.72 mmol) in DMSO (5 mL) at 0 ℃ was added propionic anhydride 109-1 (0.052 g, 0.39 mmol and stirred for 10 min. Then compound I-21 (0.15 g, 0.35 mmol) was added. The reaction mixture stirred at rt for 6 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by prep- HPLC to afford the compound 5-fluoro-N-(4-(1-(N-propionylsulfamoyl)piperidin-4- yl)phenyl)isoindoline-2-carboxamide (I-168, 26 mg, 0.054 mmol, 15.28% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d6) δ: 11.44 (s, 1H), 8.30 (s, 1H), 7.46 (d, J = 8.7 Hz, 2H), 7.38 (dd, J = 5.2, 8.4 Hz, 1H), 7.23 (dd, J = 2.1, 8.9 Hz, 1H), 7.14 - 7.10 (m, 3H), 4.73 (d, J = 15.0 Hz, 4H), 3.73 (d, J = 12.4 Hz, 2H), 2.89 (t, J = 11.6 Hz, 2H), 2.61 - 2.53 (m, 1H), 2.25 (q, J = 7.5 Hz, 2H), 1.81 (d, J = 11.3 Hz, 2H), 1.60 (dq, J = 3.7, 12.6 Hz, 2H), 1.01 (t, J = 7.5 Hz, 3H). LC-MS: ret. time: 1.65 min, 98.66%, MS calcd. for chemical formula: C23H27FN4O4S: 474.55; found: 475.04 [M+H]⁺; Method F. HPLC: ret. time: 7.590 min; 99.45%; column: X-Select CSH C18 (4.6*150) mm 5um; mobile phase: A - 0.1% TFA in water; B – acetonitrile; flow rate: 1.2 mL/min; column oven temp.: 30 °C; gradient program: time(min)/ B conc. : 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. Prep-HPLC purification method: column: ATLANTIS (250*20mm); 5µm; mobile phase A: 0.1% FA in water; mobile phase B: ACN, flow rate: 25 ml/min; Instrument ID PREP- 09: gradient (time/%B) 0/20, 3/20, 10/40, 35/98. EXAMPLE 99 - SYNTHESIS OF N-(4-(1-(N-CARBAMOYLSULFAMOYL)-1,2,3,6- TETRAHYDROPYRIDIN-4-YL)PHENYL)-5-FLUOROISOINDOLINE-2- CARBOXAMIDE (I-159) [1008] To a stirred solution of compound 97-11 (0.2 g, 0.44 mmol) in DCM (5 mL) was added chlorosulfonyl isocyanate (0.026 g, 1.801 mmol) at 0 ℃. The reaction mixture stirred at rt for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by prep- HPLC to afford the compound N-(4-(1-(N-carbamoylsulfamoyl)-1,2,3,6-tetrahydropyridin-4- yl)phenyl)-5-fluoroisoindoline-2-carboxamide (I-159, 25 mg, 0.053 mmol, 14.96% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d6) δ 7.47 (d, J = 8.5 Hz, 2H), 7.35 (dd, J = 5.3, 8.4 Hz, 1H), 7.24 - 7.18 (m, 3H), 7.14 - 7.09 (m, 1H), 6.86 (s, 2H), 6.73 (s, 2H), 6.22 (s, 1H), 4.65 (d, J = 15.6 Hz, 4H), 3.69 (d, J = 2.9 Hz, 2H), 3.24 - 3.16 (m, 2H), 2.59 (s, 2H), 2.54 - 2.52 (m, 1H). LC-MS: ret. time: 1.824 min, 99.93%, MS calcd. for chemical formula: C21H22FN5O4S: 459.5; found: 460.4 [M+H]⁺. Method G. HPLC: ret. time: 6.523 min; purity: 99.10%; method: column: X-Select CSH C18 (4.6*150) mm 5um; mobile phase: A - 0.1% TFA in water; B – acetonitrile, flow rate: 1.2 mL/min, column oven temp.: 30°C gradient program: time(min)/ B conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. Prep-HPLC purification method: column: X-select C- 18(250*30mm);5µm mobile phase A 0.1% FA in water, mobile phase B ACN, flow rate: 25 ml/min, gradient (time/%B): 0/20, 3/20, 10/35, 15/45, 25/50, 30/98, solvents used for dilution: ACN+water. EXAMPLE 100 - SYNTHESIS OF TERT-BUTYL ((4-(4-(4-FLUOROISOINDOLINE-2- CARBOXAMIDO)PHENYL)-3,6-DIHYDROPYRIDIN-1(2H)-YL)SULFONYL) CARBAMATE (I-158) [1009] To the stirred solution of compound 83-4 (0.1 g, 0.29 mmol) in DCM (10 mL) was added DIPEA (0.154 mL, 0.889 mmol), followed by compound 18-9 (0.11 g, 0.35 mmol) at 0 ℃ and the reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by CombiFlash (Nexgen-300) chromatography using a 12 g silica gel cartridge and using 2-4% MeOH in DCM as the eluent to afford the compound tert-butyl ((4-(4-(4-fluoroisoindoline-2-carboxamido) phenyl)-3,6- dihydropyridin-1(2H)-yl)sulfonyl)carbamate (I-158, 15 mg, 0.029 mmol, 9.80% yield) as off white solid.¹H NMR (500 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.46 (s, 1H), 7.57 (d, J = 8.9 Hz, 2H), 7.39 - 7.33 (m, 3H), 7.22 (d, J = 7.6 Hz, 1H), 7.15 (t, J = 8.9 Hz, 1H), 6.12 - 6.08 (m, 1H), 4.82 (br d, J = 13.4 Hz, 4H), 3.93 (br s, 2H), 3.49 - 3.42 (m, 2H), 2.60 - 2.55 (m, 2H), 1.38 (s, 9H). LCMS: ret. time: 2.11 min, 95.73%, chemical formula: C₂₅H₃₁FN₄O₅S: 518.60; found: 419.00 [M+H]⁺. Method F. HPLC: ret. time: 8.141 min, 97.18%; method: column: X-Select CSH-C18- 50X3.0mm, 2.5u; mobile phase: A-0.05%FA in water, B: 0.05% FA in ACN gradient: time/%B: 0.0/2,0.3/2,2.0/98,2.8/98,3.0/2,3.7/2 flow rate: 1.0 mL/min, column oven: 40 °C. EXAMPLE 101 - SYNTHESIS OF TERT-BUTYL ((4-(4-(4-FLUOROISOINDOLINE-2- CARBOXAMIDO)PHENYL)PIPERIDIN-1-YL)SULFONYL)CARBAMATE (I-157) [1010] Step 1: Synthesis of tert-butyl 4-(4-(4-fluoroisoindoline-2-carboxamido)phenyl) piperidine-1-carboxylate (110-8): To a stirred solution of compound 100-6 (28.00 g, 70.62 mmol) and compound 110-7 (14.71 g, 84.74 mmol) in DMF (140 mL) at rt was added DIPEA (61.7 mL, 353.1 mmol) and then the reaction mixture was stirred at 90 ℃ for 4 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ice cold water, and the precipitated solid was filtered. The obtained solid was washed with n- heptane (2 x 60 mL), and dried under reduced pressure to afford the title compound 110-8 (15.00 g, 34.13 mmol, 48.33% yield) as an off-white solid. LCMS: ret. time: 1.65 min, MS calcd. for chemical formula: C25H30FN3O3: 439.53; found: 440.05 [M+H]⁺. Method H. [1011] Step 2: Synthesis of 4-fluoro-N-(4-(piperidin-4-yl)phenyl)isoindoline-2- carboxamide (110-9): To a stirred solution of compound 110-8 (1.0 g, 2.27 mmol) in 1,4-dioxane (5 mL) was added 4M HCl in 1,4-dioxane (10 mL, 40 mmol) dropwise at 0 ℃ and then the reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (10 mL) and then with n-pentane (5 mL x 2), and the filtered the solids were dried under reduced pressure to afford the desired compound 110-9 (0.7 g, 2.062 mmol, 90.65% yield) as an off white solid. The resulting crude HCl salt was used in the next step without further purification. LC-MS: ret. time: 1.35 min, MS calcd. for chemical formula: C₂₀H₂₂FN₃O: 339.41; found: 339.98 [M+H]⁺. Method F. [1012] Step 3: Synthesis of tert-butyl ((4-(4-(4-fluoroisoindoline-2-carboxamido)phenyl) piperidin-1-yl)sulfonyl)carbamate (I-157): To a stirred solution of compound 110-9 (0.70 g, 2.1 mmol) in DCM (10 mL) were added compound 18-9 (0.75 g, 2.5 mmol) and DIPEA (1.4 mL, 8.2 mmol) at 0 ℃ and then the reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by Combi Flash chromatography (using a 4 g silica gel cartridge and eluting with 2-4% MeOH in DCM) to afford the title compound tert-butyl ((4-(4-(4-fluoroisoindoline-2-carboxamido)phenyl)piperidin-1- yl)sulfonyl)carbamate (I-157, 0.48 g, 0.925 mmol, 45% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.35 (s, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.43 - 7.32 (m, 1H), 7.21 (d, J = 7.5 Hz, 1H), 7.18 - 7.08 (m, 3H), 4.80 (d, J = 8.9 Hz, 4H), 3.75 (d, J = 12.5 Hz, 2H), 2.99 - 2.84 (m, 2H), 2.62 - 2.52 (m, 1H), 1.82 (d, J = 11.1 Hz, 2H), 1.61 (dq, J = 3.9, 12.5 Hz, 2H), 1.45 (s, 9H). LCMS: ret. time: 1.92 min, 99.47%, MS calcd. chemical formula: C25H31FN4O5S: 518.60; found: 519.15 [M+H]⁺. Method F. HPLC: ret. time: 8.367 min, 98.88%; method: column: X-Select CSH C18 (4.6x150) mm 5um; mobile phase: A - 0.1% formic acid in water: acetonitrile (95:05) B - acetonitrile; flow rate: 1.0 mL/min; gradient program: Time (min)/ B Conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. EXAMPLE 102 - SYNTHESIS OF TERT-BUTYL ((4-(4-(2,3-DIHYDRO-1H- PYRROLO[3,4-C]PYRIDINE-2-CARBOXAMIDO)PHENYL)-3,6-DIHYDROPYRIDIN- 1(2H)-YL)SULFONYL)CARBAMATE (I-156) [1013] Step 1: Synthesis of tert-butyl 4-(4-(2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2- carboxamido)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (111-7): To a stirred solution of compound 97-5 (0.5 g, 1.261 mmol) in DMF (8 mL) were added compound 111-6 (0.19 g, 1.521 mmol) and DIPEA (1.11 mL, 6.34 mmol) at rt and the reaction mixture was stirred at 80 ℃ for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether and n-pentane, and the filtered the solids were dried under reduced pressure to afford the title compound 111-7 (0.39 g, 0.92 mmol, 73.18% yield) as a brown solid. LCMS: ret. time: 1.34 min, MS calcd. for chemical formula: C₂₄H₂₈N₄O₃: 420.51; found: 421.52 [M+H]⁺. Method F. [1014] Step 2: N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1,3-dihydro-2H-pyrrolo[3,4- c]pyridine-2-carboxamide (111-8): To a stirred solution of compound 111-7 (0.39 g, 0.92 mmol) in 1,4-dioxane (5 mL) was added 4M HCl in 1,4-dioxane (2.5 mL, 10 mmol) dropwise at 0 ℃ and then the reaction mixture was stirred at rt for 8 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (5 mL) and then with n-pentane (3 mL x 2), and the filtered the solids were dried under reduced pressure to afford the desired compound 111-8 (0.30 g, 0.84 mmol, 90.66% yield) as a brown solid. The resulting crude HCl salt was used in the next step without further purification. LC-MS: ret. time: 0.36 min, MS calcd. for chemical formula: C₁₉H₂₀N₄O: 320.4; found: 320.99 [M+H]⁺. Method F. [1015] Step 3: Synthesis of tert-butyl ((4-(4-(2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2- carboxamido)phenyl)-3,6-dihydropyridin-1(2H)-yl)sulfonyl)carbamate (I-156): To a stirred solution of compound 111-8 (0.2 g, 0.62 mmol) in DCM (5 mL) was added compound 18-9 (0.227 g, 0.74 mmol) and DIPEA (0.66 mL, 1.87 mmol) at rt and then the reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by prep-HPLC to afford the title compound tert-butyl ((4-(4-(2,3-dihydro-1H-pyrrolo[3,4- c]pyridine-2-carboxamido)phenyl)-3,6-dihydropyridin-1(2H)-yl)sulfonyl)carbamate (I-156, 15 mg, 0.030 mmol, 4.81% yield)) as a pale-yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 11.05 - 10.94 (m, 1H), 8.61 (s, 1H), 8.50 (d, J = 5.0 Hz, 1H), 8.46 (s, 1H), 7.60 - 7.50 (m, J = 8.9 Hz, 2H), 7.43 (d, J = 5.0 Hz, 1H), 7.39 - 7.31 (m, J = 8.8 Hz, 2H), 6.10 (s, 1H), 4.80 (d, J = 6.6 Hz, 4H), 3.89 (s, 2H), 3.40 (d, J = 7.1 Hz, 4H),1.37 (s, 9H). LCMS: ret. time: 1.697 min, 98.48%, chemical formula: C₂₄H₂₉N₅O₅S: 499.59; found: 500.3 [M+H]⁺. Method H. Prep-HPLC purification method: column: X-select (250x30mm);5µm, mobile phase A: 0.1% FA in water; mobile phase B: ACN, flow rate: 25 ml/min; gradient (time/%B): 0/30, 3/30, 5/55, 20/60, 30/80, 35/98. Solvents used for dilution: ACN+water +DMSO+THF. EXAMPLE 103 - SYNTHESIS OF N-(4-(1-(N-CARBAMOYLSULFAMOYL)PIPERIDIN- 4-YL)PHENYL)-5-FLUOROISOINDOLINE-2-CARBOXAMIDE (I-155) [1016] To a stirred solution of compound I-21 (0.15 g, 0.358 mmol) in acetonitrile (3 mL) was added carbonylsulfamyl chloride (0.077 g, 0.537 mmol) at 0 ℃ and the reaction mixture was stirred for 20 min. The reaction mixture was then stirred at rt for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by prep-HPLC to afford the compound N-(4-(1-(N-carbamoylsulfamoyl)piperidin-4-yl)phenyl)-5-fluoroisoindoline-2- carboxamide (I-155, 25 mg, 0.054 mmol, 15.11% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d6) δ 7.35 (dd, J = 5.2, 8.2 Hz, 1H), 7.29 (d, J = 8.5 Hz, 2H), 7.22 - 7.16 (m, 3H), 7.15 - 7.06 (m, 1H), 6.75 (s, 2H), 6.73 - 6.59 (m, 2H), 4.65 (br d, J = 15.9 Hz, 4H), 3.62 - 3.53 (m, 2H), 2.65 - 2.56 (m, 3H), 1.92 - 1.79 (m, 2H), 1.78 - 1.59 (m, 2H). LCMS: ret. time: 1.20 min, 98.93%, chemical formula: C21H24FN5O4S: 461.51; found: 462.06 [M+H]⁺. Method G. HLPC: ret time: 6.337 min, 98.52%; method: column: X-select CSH C18,(150 mm X 4.6 mm)5.0µm mobile phase A: 0.1% FA in (water:ACN)(95:5); mobile phase B: acetonitrile; column temperature: 30 °C; flow rate: 1.0 mL/ min; gradient: 0/5, 1/5, 8/100, 12/100, 14/5, 18/5. Prep-HPLC purification method: column X-SELECT C18 (250X30mm);5µm mobile phase A 0.1% FA in water, mobile phase B: 100% ACN flow rate: 25 ml/min, Instrument ID: PREP-15, gradient (time/%B) 0/15, 2/15, 10/45, 15/55, 20/60, 20.1/100. Solvents used for dilution: ACN+water+THF. EXAMPLE 104 - SYNTHESIS OF 5-FLUORO-N-(4-(1-(N-(METHYLCARBAMOYL) SULFAMOYL)PIPERIDIN-4-YL)PHENYL)ISOINDOLINE-2-CARBOXAMIDE (I-154) [1017] To a stirred solution of compound I-21 (0.15 g, 0.354 mmol) in DMSO (2 mL) was added sodium hydride (60%, 0.018 g, 0.65 mmol) at 0 ℃. Then after 20 min, methylcarbamic chloride 112-1 (0.035 g, 0.354 mmol) was added at 0 ℃. The reaction mixture stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by prep-HPLC to afford the compound 5-fluoro-N-(4-(1-(N-(methylcarbamoyl)sulfamoyl) piperidin-4-yl)phenyl)isoindoline-2-carboxamide (I-154, 42 mg, 0.088 mmol, 26.79% yield) as an off white solid.¹H NMR (500 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.46 (d, J = 8.7 Hz, 2H), 7.38 (dd, J = 5.2, 8.4 Hz, 1H), 7.23 (dd, J = 2.1, 9.1 Hz, 1H), 7.19 - 7.07 (m, 3H), 6.98 (s, 1H), 6.18 (s, 1H), 4.73 d, J = 15.0 Hz, 4H), 3.66 - 3.64 (m, 2H), 2.79 (t, J = 12.0 Hz, 2H), 2.58 (d, J = 4.6 Hz, 3H),1.78 (d, J = 11.6 Hz, 2H), 1.60 (q, J = 12.5 Hz, 2H). LCMS: ret. time: 1.765 min, 99.51%, chemical formula: C₂₂H₂₆FN₅O₄S: 475.54; found: 476.2 [M+H]⁺. Method H. HPLC: ret. time: 6.759 min, 97.04%; method: HPLC_X-Bridge column: X-Bridge C18 (4.6*150) mm 5um; mobile phase: A - 5 mM ammonium bicarbonate in water; B – acetonitrile; injection volume: 5.0µL, flow rate: 1.0 mL/minute gradient program: time(min)/ B conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. Prep-HPLC purification method: column: X-bridge (250x30mm); 5µm; mobile phase A: 10 mM ammonium bicarbonate in water, mobile phase B: ACN, flow rate: 22 ml/min, gradient (time/%B): 0/15, 2/15, 10/20, 15/35, 20/45, 25/45, 25.1/100. Solvents used for dilution: ACN+THF+water. EXAMPLE 105 - SYNTHESIS OF N-(4-(1-(N-(DIMETHYLCARBAMOYL) SULFAMOYL)PIPERIDIN-4-YL)PHENYL)-5-FLUOROISOINDOLINE-2- CARBOXAMIDE (I-153) [1018] A stirred solution of compound I-21 (0.15 g, 0.354 mmol) in DMSO (3 mL) was added NaH (60%, 0.026 g, 0.65 mmol), at 0 ℃. Then after 20 min dimethylcarbamic chloride 113-1 (0.053 g, 0.49 mmol) was added at 0 ℃. The reaction mixture stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by prep- HPLC to afford the compound N-(4-(1-(N-(dimethylcarbamoyl)sulfamoyl)piperidin-4-yl) phenyl)-5-fluoroisoindoline-2-carboxamide (I-153, 30 mg, 0.061 mmol, 18.58% yield) as an off white solid.¹H NMR (500 MHz, DMSO-d₆) δ 10.18 - 9.75 (m, 1H), 8.29 (s, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.38 (dd, J = 5.2, 8.4 Hz, 1H), 7.22 (br d, J = 8.9 Hz, 1H), 7.18 - 7.09 (m, 3H), 4.73 (br d, J = 11.9 Hz, 4H), 3.73 - 3.65 (m, 2H), 2.94 - 2.87 - 2.84 (s, 6H), 2.63 - 2.54 (m, 2H), 2.45 - 2.40 (m, 1H), 1.85 - 1.75 (m, 2H), 1.66 - 1.54 (m, 2H). LC-MS: ret. time: 1.66 min, 97.11%; chemical formula: C₂₂H₂₆FN₅O₄S: 475.54; found: 477.02 [M+H]⁺. Method G. HPLC: ret. time: 6.695 min, 95.09%; method: HPLC_X-Bridge column: X-Bridge C18 (4.6*150) mm 5um; mobile phase: A - 5 mM ammonium bicarbonate in water; B – acetonitrile; injection volume: 5.0µL, flow rate: 1.0 mL/minute gradient program: time(min)/ B conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. Prep-HPLC purification method: column X-BRIDGE C18 (250x30mm); 5µm, mobile phase A: 10 mM ammonium bicarbonate in water, mobile phase B ACN, flow rate: 22ml/min, gradient (time/%B) 0/20, 3/20, 10/30, 25/35. Solvents used for dilution: ACN+THF+DMSO. EXAMPLE 106 - SYNTHESIS OF 5-FLUORO-N-(4-(1-(N-ISOBUTYRYLSULFAMOYL) PIPERIDIN-4-YL)PHENYL)ISOINDOLINE-2-CARBOXAMIDE (I-152) [1019] To a stirred solution of compound I-21 (0.10 g, 0.239 mmol) in DMSO (2 mL) was added NaH (60%, 0.020 g, 0.477 mmol), followed by isobutyric anhydride 114-1 (0.038 g, 0.239 mmol) at 0 ℃. The reaction mixture stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by prep-HPLC to afford the compound 5-fluoro-N-(4-(1-(N-isobutyrylsulfamoyl)piperidin-4-yl)phenyl)isoindoline-2- carboxamide (I-152, 25 mg, 0.051 mmol, 21% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.30 (s, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.38 (t, J = 6.4 Hz, 1H), 7.23 (dd, J = 1.9, 9.1 Hz, 1H), 7.14 - 7.09 (m, 3H), 4.73 (d, J = 11.8 Hz, 4H), 3.75 (d, J = 12.5 Hz, 2H), 2.95 - 2.82 (m, 2H), 2.62 - 2.54 (m, 2H), 1.81 (d, J = 11.5 Hz, 2H), 1.71 - 1.49 (m, 2H), 1.05 (d, J = 6.9 Hz, 6H). LC-MS: ret. time: 2.13 min, 96.41%; chemical formula: C23H28FN5O4S: 489.58; found: 489.2 [M+H]⁺. Method G. HLPC: ret time: 7.658 min, 98.15%; method: column: X-select CSH C18, (150 mm X 4.6 mm)5.0µm mobile phase A: 0.1% FA in (water:ACN)(95:5); mobile phase B: acetonitrile; column temperature: 30 °C; flow rate: 1.0 mL/ min; gradient: 0/5, 1/5, 8/100, 12/100, 14/5, 18/5. diluent: ACN: water. Prep-HPLC purification method: column: X-bridge (250x30mm); 5µm; mobile phase A: 10 mM ammonium bicarbonate in water, mobile phase B: ACN, flow rate: 25 ml/min, gradient (time/%B): 0/20, 3/20, 10/40, 35/98. Solvents used for dilution: ACN+DMSO+THF. EXAMPLE 107 - SYNTHESIS OF 4-FLUORO-N-(4-(1-SULFAMOYLPIPERIDIN-4- YL)PHENYL)ISOINDOLINE-2-CARBOXAMIDE (I-178) AND 4-FLUORO-N-(4-(1- SULFAMOYLPIPERIDIN-4-YL)PHENYL) ISOINDOLINE-2-CARBOXAMIDE (I-151) [1020] Step 1: Synthesis of tert-butyl ((4-(4-(4-fluoroisoindoline-2-carboxamido)phenyl) piperidin-1-yl)sulfonyl)carbamate (115-1): To a stirred solution of compound 110-9 (0.70 g, 2.1 mmol) in DCM (10 mL) were added compound 18-9 (0.75 g, 2.5 mmol) and DIPEA (1.4 mL, 8.2 mmol) at 0 ℃ and then the reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by Combi Flash chromatography (using a 4 g silica gel cartridge and eluting with 2-4% MeOH in DCM) to afford the title compound 115-1 (0.48 g, 0.925 mmol, 45% yield) as an off white solid. LCMS: ret. time: 1.92 min, MS calcd. chemical formula: C25H31FN4O5S: 518.60; found: 519.15 [M+H]⁺. Method F. [1021] Step 2: Synthesis of 4-fluoro-N-(4-(1-sulfamoylpiperidin-4-yl)phenyl)isoindoline- 2-carboxamide (I-178): To a stirred solution of compound 115-1 (0.45 g, 0.0.86 mmol) in DCM (5 mL) was added 4M HCl in 1,4-dioxane (2.2 mL, 8.677 mmol) slowly at 0 ℃ and then the reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (5 mL) and then with n-pentane (3 mL x 2), and the filtered the solids were dried under reduced pressure. The crude compound was triturated with diethyl ether, and the precipitated solid was filtered and dried under reduced pressure to afford the desired compound 4-fluoro-N-(4-(1- sulfamoylpiperidin-4-yl)phenyl)isoindoline-2-carboxamide (I-178, 320 mg, 0.7646 mmol, 88.12% yield) as an off white solid. [1022] Step 3: Synthesis of 4-fluoro-N-(4-(1-(N-pivaloylsulfamoyl)piperidin-4- yl)phenyl)isoindoline-2-carboxamide (I-151): To a stirred solution of sodium hydride (60% in oil, 43 mg, 1.075 mmol) in DMSO (4 mL) was added compound I-178 (0.15 g, 0.358 mmol) and the reaction mixture was stirred for 5 min at rt. Compound 115-2 (0.26 g, 1.434 mmol) was added to the reaction mixture and then the reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ice cold water, and the precipitated solid was filtered and dried under reduced pressure to afford the compound 4-fluoro- N-(4-(1-(N-pivaloylsulfamoyl)piperidin-4-yl)phenyl)isoindoline-2-carboxamide (I-151, 80 mg, 0.159 mmol, 44.41% yield) as off white solid.¹H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.35 (s, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.43 - 7.31 (m, 1H), 7.21 (d, J = 7.5 Hz, 1H), 7.12 (d, J = 8.5 Hz, 3H), 4.80 (d, J = 9.0 Hz, 4H), 3.77 (d, J = 12.3 Hz, 2H), 2.90 (t, J = 11.8 Hz, 2H), 2.62 - 2.52 (m, 1H), 1.81 (d, J = 11.4 Hz, 2H), 1.70 - 1.48 (m, 2H), 1.16 (s, 9H). LCMS: ret. time: 1.89 min, 95.12%; MS calcd. for chemical formula: C25H31FN4O4S, 502.6; found: 503.11 [M+H]⁺. Method F. HPLC: ret. time: 96.46 min, 96.46%; column: X-Select CSH C18 (4.6*150) mm 5um; mobile phase: A - 0.1% TFA in water; B – acetonitrile; injection volume: 5.0µL, flow rate: 1.2 mL/minute; column oven temp.: 30°C; gradient program: time(min)/ B conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. EXAMPLE 108 - SYNTHESIS OF N-(4-(1-(2-HYDROXY-2-METHYLPROPANOYL) PIPERIDIN-4-YL)PHENYL)-4,6-DIHYDRO-5H-THIENO[2,3-C]PYRROLE-5- CARBOXAMIDE (I-150) [1023] Step 1: Synthesis of thiophene-2,3-diyldimethanol (116-2b): To a stirred solution of compound 116-1a (5.0 g, 35.7 mmol) in EtOH (50 mL) was added NaBH4 (2.70 g, 71.3 mmol) at 0 ℃. The reaction mixture was then stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with a sodium bicarbonate solution and concentrated under pressure. The obtained crude residue was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to afford the title compound (116-2b, 3.5 g, 24 mmol, 68% yield) as a yellow oil.¹H NMR (400 MHz, DMSO-d6) δ 7.29 (d, J = 5.0 Hz, 1H), 6.97 (d, J = 5.3 Hz, 1H), 5.34 (t, J = 5.6 Hz, 1H), 4.96 (t, J = 5.6 Hz, 1H), 4.61 (d, J = 5.5 Hz, 2H), 4.41 (d, J = 5.5 Hz, 2H). [1024] Step 2: Synthesis of 2,3-bis(chloromethyl)thiophene (116-3c): To a stirred solution of compound 116-2b (3.5 g, 24 mmol) in DCM (30 mL) was added SOCl2 (3.3 mL, 85 mmol) at 0 ℃. The reaction mixture was stirred to rt for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with a sodium bicarbonate solution and concentrated under pressure. The obtained crude residue was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the title compound (116-3c, 2.8 g, 15 mmol, 64% yield) as a brown oil.¹H NMR (400 MHz, DMSO-d6) δ 7.09 (d, J = 7.5 Hz, 1H), 7.56 (d, J = 7.5 Hz, 1H), 5.09 (s, 2H), 4.82 s, 2H). [1025] Step 3: Synthesis of 5-((4-nitrophenyl)sulfonyl)-5,6-dihydro-4H-thieno[2,3- c]pyrrole (116-5e): To a stirred solution of compound 116-3c (2.8 g, 15 mmol) in DMF (30 mL) was added K2CO3 (8.6 g, 62 mmol) and compound 116-4d (3.1 g, 15 mmol) at 0 ℃. The reaction mixture was then stirred at 60 ℃ for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ice cold water and the precipitated solids were filtered and dried under reduced pressure to afford the title compound (116-5e, 2.0 g, 6.443 mmol, 42% yield) as a brown solid. LC-MS: ret. time : 1.47 min, MS calcd. for chemical formula: C12H10N2O4S2: 310.34; found: 310.79 [M+H]⁺. Method F. [1026] Step 4: Synthesis of 5,6-dihydro-4H-thieno[2,3-c]pyrrole (116-10): To a stirred suspension of compound 116-5e (1 g, 3.22 mmol) in ACN (15 mL) was added Cs2CO3 (3.14 g, 9.66 mmol), followed by compound 116-6f (1.6 g, 9.66 mmol) and the reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ACN and filtered through a celite pad. The organic fraction was concentrated under reduced pressure and then acidified with 4N HCl and washed with diethyl ether. The aqueous layer was concentrated under reduced pressure to afford the title compound 116-10 (0.301 g, 2.4043 mmol, 74.63% yield) as a brown solid. LC-MS: ret. time: 0.34 min, MS calcd. for chemical formula: C6H7NS: 125.19; found: 126.0 [M+H]⁺. Method F. [1027] Step 5: Synthesis of tert-butyl 4-(4-nitrophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (116-3): A mixture of compound 116-1 (5.0 g, 24.75 mmol), compound 116-2 (9.47 g, 29.70 mmol), and Cs2CO3 (24.2 g, 74.26 mmol) in 1,4-dioxane:H2O (50:50, 100 mL) was degassed with argon for 5 min. Pd2(dba)3 (1.168 g, 1.24 mmol) and X-Phos (1.17 g, 2.47 mmol) were added to the above mixture at rt. The reaction mixture was stirred for 15 min while degassing with argon, and then the reaction mixture was stirred at 90 ℃ for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The organic layer was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by CombiFlash (Nexgen-300) chromatography using a 40 g silica gel cartridge and 30-40% EtOAc in n-heptane as the eluent to afford the title compound 116-3 (6.0 g, 19.72 mmol, 79.66%yield) as a pale-yellow solid. LC-MS: ret. time: 1.61 min, MS calcd. for chemical formula: C16H20N2O4: 304.35; found: 249.12 [(M–Isobutene)+H]⁺. Method F. [1028] Step 6: Synthesis of 4-(4-nitrophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (116-4): To a stirred solution of compound 116-3 (3.0 g, 9.85 mmol) in 1,4-dioxane (20 mL) was added HCl in 1,4-dioxane (30 mL) at 0 ℃ and then the reaction mixture was stirred at rt for 1 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (10 mL) and then with n-pentane (5 mL x 2), and the filtered the solids were dried under reduced pressure to afford the desired compound 116-4 (2.0 g, 9.79 mmol, 99.34% yield) as an off white solid. The resulting crude HCl salt was used in the next step without further purification. LC-MS: ret. time: 0.79 min, MS calcd. for chemical formula: C₁₁H₁₂N₂O₂: 204.23; found: 205.83 [M+H]⁺. Method F. [1029] Step 7: Synthesis of 2-hydroxy-2-methyl-1-(4-(4-nitrophenyl)-3,6-dihydropyridin- 1(2H)-yl)propan-1-one (116-6): To a stirred solution of compound 116-4 (1.3 g, 6.37 mmol) in DMF (10 mL) were added compound 116-5 (0.87 g, 8.28 mmol), HATU (3.74 g, 9.55 mmol), and DIPEA (4.45 mL, 25.5 mmol) at rt and the reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ice cold water and the precipitated solid was filtered and washed with diethyl ether and concentrated under reduced pressure to afford the title compound 116-6 (1.0 g, 3.44 mmol, 54.10% yield) as an off white solid. LC-MS: ret. time: 1.67 min, MS calcd. for chemical formula: C15H18N2O4: 290.32; found: 290.91 [M+H]⁺. Method F. [1030] Step 8: Synthesis of 1-(4-(4-aminophenyl)piperidin-1-yl)-2-hydroxy-2-methyl propan-1-one (116-7): To a stirred solution of compound 116-6 (1.0 g, 3.28 mmol) in MeOH (30 mL) was added 10% palladium on carbon (50% wet, 0.36 g) and then the reaction mixture was stirred at rt for 16 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The combined organic layers were concentrated under reduced pressure to afford the title compound 116-7 (0.59 g, 2.248 mmol, 65.27 % yield) as a pale brown solid. LC-MS: ret. time: 1.19 min, MS calcd. for chemical formula: C₁₅H₂₂N₂O₄: 262.35; found: 262.93 [M+H]⁺. Method F. [1031] Step 9: Synthesis of phenyl (4-(1-(2-hydroxy-2-methylpropanoyl)piperidin-4- yl)phenyl)carbamate (116-9): To a stirred solution of compound 116-7 (0.1 g, 0.381 mmol) in DCM (3 mL) were added pyridine (0.062 mL, 0.762 mmol), compound 116-8 (0.072 g, 0.45 mmol), and DMAP (0.005 g 0.038 mmol) at 0 ℃ and then the reaction mixture was stirred at rt for 2 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the title compound 116-9 (0.13 g, 0.34 mmol, 89.21% yield) as a brown solid. LC-MS: ret. time: 2.02 min, MS calcd. for chemical formula: C₂₂H₂₆N₂O₄: 382.46; found: 383.24 [M+H]⁺. Method G. [1032] Step 10: Synthesis of N-(4-(1-(2-hydroxy-2-methylpropanoyl)piperidin-4- yl)phenyl)-4,6-dihydro-5H-thieno[2,3-c]pyrrole-5-carboxamide (I-150): To a stirred solution of compound 116-9 (0.13 g, 0.34 mmol) in DMF (1 mL) were added compound 116-10 (0.063 g, 0.51 mmol) and DIPEA (0.29 mL, 1.700 mmol) slowly at rt and the reaction mixture was stirred at 80 ℃ for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by CombiFlash (Nexgen-300) chromatography using a 4 g silica gel cartridge, and using 15.25% EtOAc in heptane as the eluent to afford the title compound N-(4-(1-(2-hydroxy-2- methylpropanoyl)piperidin-4-yl)phenyl)-4,6-dihydro-5H-thieno[2,3-c]pyrrole-5-carboxamide (I- 150, 11 mg, 0.026 mmol, 7.85% yield) as an off-white solid.¹H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.54 (d, J = 4.9 Hz, 1H), 7.48 - 7.42 (m, J = 8.5 Hz, 2H), 7.18 - 7.05 (m, 2H), 7.00 (d, J = 5.0 Hz, 1H), 5.37 (s, 1H), 4.71 (s, 2H), 4.59 (s, 2H), 3.43 - 3.35 (m, 1H), 3.30 - 3.20 (m, 1H), 2.79 - 2.59 (m, 2H), 2.57 - 2.53 (m, 1H), 1.77 (d, J = 11.0 Hz, 2H), 1.60 - 1.42 (m, 2H), 1.33 (s, 6H). LCMS: ret. time: 1.86 min, 95.90%; MS calcd. for chemical formula C22H27N3O3S : 413.54; found: 414.2 [M+H]⁺. Method G. HPLC: ret. time: 7.026 min, purity: 96.12%; column: X-Select CSH C18 (4.6*150) mm 5um; mobile phase: A - 0.1% TFA in water; B - acetonitrile injection volume: 5.0µL, flow rate: 1.2 mL/minute; column oven temp.: 30°C; gradient program: time(min)/ B conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. EXAMPLE 109 - SYNTHESIS OF N-(4-(1-(2-(((2H-TETRAZOL-5-YL)METHYL) AMINO)-2-OXOACETYL)PIPERIDIN-4-YL)PHENYL)-5-FLUOROISOINDOLINE-2- CARBOXAMIDE (I-149) [1033] Step 1: Synthesis of ethyl 2-(4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) piperidin-1-yl)-2-oxoacetate (117-11): To a stirred solution of compound 88-9 (1.0 g, 2.66 mmol) in DCM (20 mL) was added DIPEA (1.40 mL, 8.00 mmol) at 0 ℃, followed by the slow addition of ethyl 2-chloro-2-oxoacetate 117-10 (0.364 g, 2.66 mmol) and the reaction mixture was then stirred to room temperature for 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was purified by Combi flash chromatography using 90-100% EtOAc in heptane as the eluent to afford the title compound 117-11 (0.4 g, 0.91 mmol, 34.12% yield) as a pale brown gummy liquid. LC-MS: ret. time: 2.140 min, MS calcd. for chemical formula: C₂₄H₂₆FN₃O₄: 439.49; found: 440.4 [M+H]⁺. Method F. [1034] Step 2: Synthesis of 2-(4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) piperidin-1-yl)-2-oxoacetic acid (117-12): To a stirred solution of compound 117-11 (0.38 g, 0.864 mmol) in 1,4-dioxane (4.6 ml) was added a 1M NaOH solution (4.6 mL) and the reaction mixture was stirred at room temperature for 5 h. After completion of the reaction (monitored by TLC), the volatiles were evaporated under reduced pressure. The crude residue was acidified with 1.0 N HCl to pH ~ 4-5, and the precipitated solid was washed with water and dried under reduced pressure to afford the title compound 117-12 (0.19 g, 0.461 mmol, 53.42% yield) as a pale brown solid. LC-MS: ret. time: 2.20 min, MS calcd. for chemical formula: C₂₂H₂₂FN₃O₄: 411.43; found: 412.1 [M+H]⁺. Method F. [1035] Step 3: Synthesis of N-(4-(1-(2-(((2H-tetrazol-5-yl)methyl)amino)-2-oxoacetyl) piperidin-4-yl)phenyl)-5-fluoroisoindoline-2-carboxamide (I-149): To the stirred solution of compound 117-12 (0.1 g, 0.243 mmol) in DMF (1 mL) were added DIPEA (0.210 mL, 1.215 mmol) and 50% T₃P in EtOAc (0.77 g1.215 mmol). Then (2H-tetrazol-5-yl)methanamine 117-13 (0.25 g, 2.53 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by prep- HPLC to afford the title compound N-(4-(1-(2-(((2H-tetrazol-5-yl)methyl)amino)-2- oxoacetyl)piperidin-4-yl)phenyl)-5-fluoroisoindoline-2-carboxamide (I-149, 65 mg, 0.132 mmol, 54.30% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.11- 9.07 (m, 1H), 8.29 (s, 1H), 7.42 - 7.38 (m, 1H), 7.37 - 7.33 (m, 1H), 7.21 - 7.16 (m, 1H), 7.14 - 7.08 (m, 1H), 4.70 (d, J = 12.2 Hz, 4H), 4.54 (s, 1H), 4.41 - 4.37 (m, 1H), 3.97 - 3.94 (m, 1H), 3.16 - 3.10 (m, 1H), 2.75 (t, J = 11.7 Hz, 2H), 1.84 - 1.70 (m, 1H), 1.64 - 1.52 (m, 1H), 1.50 - 1.41 (m, 1H). LC-MS: ret. time: 1.17 min, 98.41%; MS calcd. for chemical formula: C₂₄H₂₅FN₈O₃: 492.52; found: 492.52 [M+H]⁺. Method F. HPLC: ret. time: 6.394 min, purity: 98.19%, column: X-Bridge C18 (4.6*150) mm 5um; mobile phase: A - 5 mM ammonium bicarbonate in water, B – acetonitrile, injection volume: 5.0µL, flow rate: 1.0 mL/min, gradient program: time(min)/ B conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. Prep-HPLC purification method: column: X- Select CSH (250*25mm);5µm, mobile phase: A 10 mM ammonium bicarbonate in water, mobile phase B: ACN flow rate: 25ml/min, gradient (time/%B): 0/20, 3/20, 8/40, 15/40, 20/98, 35/98. Solvents used for dilution: ACN+water+THF. EXAMPLE 110 - SYNTHESIS OF TERT-BUTYL N-[[4-[4-[(3-FLUORO-5,7- DIHYDROPYRROLO[3,4-B]PYRIDINE-6-CARBONYL)AMINO]PHENYL]-1- PIPERIDYL]SULFONYL]CARBAMATE (I-148) [1036] Step 1: Synthesis of tert-butyl 4-(4-(3-fluoro-6,7-dihydro-5H-pyrrolo[3,4- b]pyridine-6-carboxamido)phenyl)piperidine-1-carboxylate (118-8): To a stirred solution of compound 100-6 (0.5 g, 1.261 mmol) in DMF (8 mL) were added compound 118-7 (0.26 g, 1.513 mmol) and DIPEA (1.09 mL, 6.305 mmol) at rt and the reaction mixture was stirred at 70 ℃ for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by Combi Flash chromatography (using a 12 g silica gel cartridge and eluting with 70-80% EtOAc in heptane to afford the title compound 118-8 (0.44 g, 0.99 mmol, 79.21% yield) as a pale-yellow solid. LCMS: ret. time: 2.00 min, MS calcd. for chemical formula: C₂₄H₂₉FN₄O₃: 440.51; found: 385.06 [(M- Isobutene) + H]⁺. Method F. [1037] Step 2: Synthesis of 3-fluoro-N-(4-(piperidin-4-yl)phenyl)-5,7-dihydro-6H- pyrrolo[3,4-b]pyridine-6-carboxamide hydrochloride (118-9): To a stirred solution of compound 118-8 (0.44 g, 0.99 mmol) in DCM (6 mL) was added 4M HCl in 1,4-dioxane (2.497 mL, 9.9 mmol) dropwise at 0 ℃ and then the reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (5 mL) and then with n-pentane (3 mL x 2), and the filtered the solids were dried under reduced pressure to afford the desired compound 118-9 (0.34 g, 0.902 mmol, 90.31% yield) as a pale brown solid. The resulting crude HCl salt was used in the next step without further purification. LC-MS: ret. time: 0.86 min MS calcd. for chemical formula: C20H21FN4O: 340.40; found: 341.03 [M+H]⁺. Method F. [1038] Step 3: Synthesis of tert-butyl N-[[4-[4-[(3-fluoro-5,7-dihydropyrrolo[3,4- b]pyridine-6-carbonyl)amino]phenyl]-1-piperidyl]sulfonyl]carbamate (I-148): To a stirred solution of compound 118-9 (0.2 g, 0.59 mmol) in DCM (5 mL) were added compound 18-9 (0.21 g, 0.705 mmol) and DIPEA (0.51 mL, 2.93 mmol) at rt and then the reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by Combi Flash chromatography (using a 4 g silica gel cartridge and eluting with 2-3% MeOH in DCM) to afford the title compound tert-butyl N-[[4-[4-[(3-fluoro-5,7- dihydropyrrolo[3,4-b]pyridine-6-carbonyl)amino]phenyl]-1-piperidyl]sulfonyl]carbamate (I-148, 84 mg, 0.161 mmol, 27.52% yield) as a pale brown solid.¹H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.47 (s, 1H), 8.35 (s, 1H), 7.79 (dd, J = 1.8, 9.2 Hz, 1H), 7.47 (d, 8.2 Hz 2H), 7.13 (d, J = 8.4 Hz, 2H), 4.75 (d, J = 19.6 Hz, 4H), 3.77 - 3.72 (m, 2H), 2.91 (t, J = 11.7 Hz, 2H), 2.59 (m, 1H), 1.82 (d, J = 12.1 Hz, 2H), 1.66 - 1.58 (m, 2H), 1.45 (s, 9H). LCMS: ret. time: 1.90 min, 98.33%; MS calcd. for chemical formula: C₂₄H₃₀FN₅O₅S, 519.59; found: 520.20 [M+H]⁺. Method F. HPLC: Rt 7.443 min, 97.33%; column: X-select CSH C18,(150 mm X 4.6 mm) 5.0µm; mobile phase A: 0.1% FA in water:acetonitrile (95:5); mobile phase B: acetonitrile; column temperature: 30 °C, flow rate: 1.0 mL/min, gradient: 0/5, 1/5, 8/100, 12/100, 14/5, 18/5; diluent: ACN: water. EXAMPLE 111 - SYNTHESIS OF N-(4-(1-((N,N-DIMETHYLSULFAMOYL) CARBAMOYL)-1,2,3,6-TETRAHYDROPYRIDIN-4-YL)PHENYL)-5- FLUOROISOINDOLINE-2-CARBOXAMIDE (I-147) [1039] Step 1: Synthesis of 4-fluoro-N-(4-(1-sulfamoyl-1,2,3,6-tetrahydropyridin-4- yl)phenyl)isoindoline-2-carboxamide (119-1): To a stirred solution of compound I-158 (0.17 g, 0.3291 mmol) in DCM (5 mL) was added 4M HCl in dioxane (2 mL, 8 mmol) dropwise at 0 ℃ and then the reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (10 mL) and then with n-pentane (5 mL x 2), and the filtered the solids were dried under reduced pressure to afford the desired compound 119-1 (0.12 g, 0.288 mmol, 87.55% yield) as a brown solid. The resulting crude HCl salt was used in the next step without further purification. LC-MS: ret. time: 1.76 min, MS calcd. for chemical formula: C20H21FN4O3: 416.47; found: 417.03 [M+H]⁺. Method F. [1040] Step 2: 4-fluoro-N-(4-(1-(N-pivaloylsulfamoyl)-1,2,3,6-tetrahydropyridin-4- yl)phenyl)isoindoline-2-carboxamide (I-147): To a stirred solution of sodium hydride (60% in oil, 0.013 g, 0.336 mmol) in DMSO (4 mL) was added compound 119-1 (0.07 g, 0.168 mmol) and the reaction mixture was stirred for 5 min at rt. Compound 119-2 (0.038 g, 0.201 mmol) was added to the reaction mixture and then the reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ice cold water, and the precipitated solid was filtered and dried under reduced pressure to afford the compound 4-fluoro- N-(4-(1-(N-pivaloylsulfamoyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide (I-147, 18 mg, 0.035 mmol, 21.39% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.45 (s, 1H), 7.56 (d, J = 8.9 Hz, 2H), 7.41 - 7.30 (m, 3H), 7.22 (d, J = 7.5 Hz, 1H), 7.14 (t, J = 8.7 Hz, 1H), 6.09 (s, 1H), 4.82 (d, J = 10.0 Hz, 4H), 3.98 – 3.92 (m, 2H), 3.58 - 3.34 (m, 2H), 2.61 - 2.55 (m, 2H), 1.11 (s, 9H). LC-MS: ret. time: 2.21 min; 95.36%; MS calcd. for chemical formula: C25H29FN4O4S: 500.59; found: 501.4 [M+H]⁺. Method G. HPLC: ret. time: 8.198 min, purity: 96.09%, column: X-Select CSH C18 (4.6*150) mm 5um; mobile phase: A - 0.1% TFA in water; B - acetonitrile; flow rate: 1.2 mL/min, column oven temp.:30°C gradient program: time(min)/ B conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. EXAMPLE 112 - SYNTHESIS OF 5-FLUORO-N-(4-(1-(2-(METHYLSULFONAMIDO)-2- OXOACETYL)PIPERIDIN-4-YL)PHENYL)ISOINDOLINE-2-CARBOXAMIDE (I-146) [1041] To the stirred solution of compound 117-12 (0.1 g, 0.243 mmol) in DMF (1 mL) were added DIPEA (0.126 mL, 0.729 mmol) and HATU (0.143 g0.36 mmol). Then, methane sulfonamide 120-1 (0.2 g, 2.10 mmol) was added and the reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by prep-HPLC to afford the title compound 5-fluoro-N-(4-(1-(2-(methylsulfonamido)-2- oxoacetyl)piperidin-4-yl)phenyl)isoindoline-2-carboxamide (I-146, 35 mg, 0.071 mmol, 29.48% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.45 (d, J = 8.3 Hz, 2H), 7.37 (dd, J = 5.1, 8.1 Hz, 1H), 7.21 (d, J = 7.3 Hz, 1H), 7.17 - 7.05 (m, 4H), 4.72 (d, J = 11.2 Hz, 4H), 4.34 (d, J = 12.7 Hz, 1H), 3.78 (d, J = 12.7 Hz, 1H), 3.03 (t, J = 11.7 Hz, 1H), 2.81 (s, 3H), 2.73 - 2.55 (m, 2H), 1.81 - 174 (m, 2H), 1.59 - 1.32 (m, 2H). LC-MS: ret. time: 1.68 min, 99.43%; MS calcd. for chemical formula: C23H25FN4O5S: 488.53; found: 489.08 [M+H]⁺. Method F. HPLC: Rt 7.214 min, purity: 99.33%, column: X-Select CSH C18 (4.6*150) mm 5um, mobile phase: A - 0.1% TFA in water, B – acetonitrile, flow rate: 1.2 mL/min, column oven temp.: 30 °C, gradient program: time(min)/ B conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. Prep-HPLC purification method: column: X-SELECT C18 (250*30mm);5µm, mobile phase A: 10 mM ammonium bicarbonate in H2O, mobile phase B: 100% ACN, flow rate: 25 ml/min, gradient (time/%B): 0/20, 2/20, 10/35, 15/45, 20/55, 30/70, 30.1/100. Solvents used for dilution: ACN+water+THF. [1042] Example 113-127: All reactions were performed under an atmosphere of nitrogen. All LCMS analyses were performed using Waters 2695 Liquid Chromatography (LC) system with 2996 PDA & Waters Micro mass ZQ ESCi Multimode Ionization. The MS was operated with an electro-spray ionization source (ESI) in both positive & negative ion mode. All the HPLC analyses were performed using Waters, Model: e2695. The following LCMS method was used: Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mm Ammonium Acetate B: 100% ACN; Gradient (time/%B) 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; Flow rate: 0.6mL/min. The following HPLC method was used: Column: X Bridge C184.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH₃CN; Flow rate: 1.2 mL/min; Diluent: Methanol (100%). EXAMPLE 113 – SYNTHESIS OF 5-FLUORO-N-(4-(4-((2-HYDROXY-2- METHYLPROPYL)CARBAMOYL)BICYCLO[2.2.2]OCTAN-1-YL)PHENYL) ISOINDOLINE-2-CARBOXAMIDE (I-59) [1043] Preparation of Ag (Phen)2OTf: To silver triflate (25.0 g, 0.097 mol) in MeOH (900 mL) was added 1,10-phenonthroline (35.15 g, 0.194 mol) in 125 mL of MeOH at RT and the temperature was maintained at RT for 16 h. The obtained solid was filtered and dried under reduced pressure to give 55.0 g of Ag (Phen)₂OTf (60% yield) as a white solid. ¹H NMR (300 MHz, DMSO-d6) δ 9.20 (d, 4H), 8.8 (d, 4H), 8.2 (s, 1H), 8.0 (pq, 4H). [1044] Step 1: Preparation of methyl 4-bromobicyclo [2.2.2] octane-1-carboxylate (2): To a stirred solution of 1 (125 g, 0.587 mol) in 1,2-dichloroethane (1.25 L) was added dibromo isocyanuricacid (135.6 g, 0.47 mol), and Ag (Phen)2OTf (8.91 g, 14.67 mmol, 2.5 mol%) at RT, then the mixture was heated to 80^oC for 16 h. The reaction mixture was cooled to RT and diluted with DCM (1.0 L), and the reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure to obtain the solid. The solid was taken into n-heptane (1.5 L) and stirred at RT for 4 h, filtered and the filtrate was concentrated under reduced pressure to obtain 125 g of 2 (86% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 3.57 (d, J = 5.7 Hz, 3H), 2.30-2.11 (m, 6H), 2.04-1.81 (m, 6H). [1045] Step 2: Preparation of methyl 4-(4-acetamidophenyl) bicyclo [2.2.2] octane-1- carboxylate (4): To a stirred solution of 2 (120.0 g, 0.48 mol) and 3 (66.3 g, 0.48 mol) in 1,2- dichloroethane (3.6 L) was added aluminium chloride (191 g, 1.44 mol) portion wise at 0^oC and the mixture was then stirred at RT for 16 h. After completion, the reaction mixture was slowly poured in ice cold water. The aqueous layer was extracted with DCM (2x2.0 L). The combined organic extracts were washed with water, brine, dried over sodium sulphate, filtered, and concentrated under reduced pressure to obtain the crude. The product was purified by column chromatography (eluting with 25% EtOAc-Hexanes) and followed by trituration with MTBE afforded 61 g of 4 (41% yield) as a pale-yellow solid.¹H NMR (300 MHz, DMSO-d6) δ 9.85 (s, 1H), 7.55-7.39 (m, 2H), 7.28-7.11 (m, 2H), 3.34 (s, 3H), 2.01 (d, J = 3.7 Hz, 3H), 1.83-1.75 (m, 12H). LC-MS: [M+H] ⁺ = 302.2. [1046] Step 3: Preparation of methyl 4-(4-aminophenyl) bicyclo [2.2.2] octane-1- carboxylate (5): A stirred solution of 4 (61.0 g, 0.2 mol) in MeOH (1.2 L) was added thionyl chloride (15.3 mL, 0.2 mol) dropwise at RT and then the reaction mixture was heated to 80^oC for 12 h. After completion, the reaction mixture was cooled to RT and the volatiles were removed under reduced pressure. The reaction mixture was diluted with water, basified with a sat. solution of NaHCO3 and extracted with EtOAc (2x1.0 L). The combined organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to obtain the product, which was further triturated with n-Heptane to give 47.2 g of 5 (90%) as an off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ 6.98 (dd, J = 17.0, 8.2 Hz, 2H), 6.61-6.48 (m, 2H), 4.88 (s, 2H), 3.39 (s, 3H), 1.99-1.64 (m, 12H). LC-MS: [M+H] ⁺ = 260.2. [1047] Step 4: Preparation of methyl 4-(4-((phenoxycarbonyl)amino) phenyl) bicyclo [2.2.2] octane-1-carboxylate (6): To a stirred solution of 5 (47.2 g, 0.182 mol) and DIPEA (96.5 mL, 0.546 mol) in THF (470 mL) was added phenyl chloroformate (33.95 g, 0.218 mol) slowly at 0°C. After addition, the reaction mixture was stirred at 0°C for 30 min and at RT for 4 h. The reaction mixture was poured into ice-cold water and the precipitate was filtered and dried to obtain the product which upon further trituration with n-heptane to give 61.5 g of 6 (89% yield) as a white solid.¹H NMR (300 MHz, DMSO-d6) δ 10.12 (s, 1H), 7.55-7.34 (m, 4H), 7.33-7.10 (m, 5H), 3.33 (s, 3H), 1.99-1.64 (d, 12H). LC-MS: [M+H] ⁺ = 380.2. [1048] Step 5: Preparation of methyl 4-(4-(5-fluoroisoindoline-2-carboxamido) phenyl) bicyclo [2.2.2] octane-1-carboxylate (8): 7 (42.1 g, 0.243 mol) was added to a solution of 6 (61.5 g, 0.162 mol) and triethylamine (126.7 mL, 0.726 mol) in THF (1.2 L) at ambient temperature. The reaction mixture was stirred at 65^oC for 16 h. After completion of the reaction, the reaction mixture was poured into ice cold water, stirred for 3 h, and the precipitate was filtered and washed with MTBE (500 mL) to afford 61 g of 8 (89% yield) as a white solid.¹H NMR (300 MHz, DMSO- d6) δ 8.29 (s, 1H), 7.54-7.33 (m, 3H), 7.33-7.05 (m, 4H), 4.73 (d, J = 8.2 Hz, 4H), 3.60 (s, 3H), 1.99-1.64 (m, 12H). LC-MS: [M+H] ⁺ = 423.2. [1049] Step 6: Preparation of 4-(4-(5-fluoro-2,3-dihydro-1H-indene-2-carboxamido) phenyl) bicyclo [2.2.2] octane-1-carboxylic acid (9): To a stirred solution of 8 (61 g, 0.144 mol) in a mixture of THF: MeOH: H₂O (1.2 L, 1:1:1) was added lithium hydroxide (17.26 g, 0.432 mol) at RT and the mixture was stirred at 50^oC for 16 h. After completion of the reaction, the reaction mixture was diluted with ice-cold water, acidified with 1.0 N HCl and the precipitate was filtered and dried to obtain 57.2 g of 9 (97% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 12.03 (s, 1H), 8.28 (s, 1H), 7.56-7.29 (m, 3H), 7.29-6.98 (m, 4H), 4.72 (d, J = 8.1 Hz, 4H), 1.78 (s, 12H). LC-MS: [M+H] ⁺ = 409.2. [1050] Step 7: Preparation of 5-fluoro-N-(4-(4-((2-hydroxy-2-methylpropyl) carbamoyl) bicyclo [2.2.2] octan-1-yl) phenyl) isoindoline-2-carboxamide: To a stirred solution of 9 (40 g, 98 mmol) in DMF (800 mL) was added K2CO3 (67.62 g, 490 mmol), EDCI (56.15 g, 294 mmol), HOBt (44.98 g, 294 mmol) and 10 (13 g, 147 mmol) at 0^oC. The reaction mixture was stirred at RT for 16 h. The reaction mixture was poured into ice-cold water, the precipitate was filtered and dried to obtain the crude product. The product was taken in EtOH (1.0 L) and heated to 70^oC for 16 h, then filtered to obtain 34 g of I-59 (70% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.56-7.30 (m, 3H), 7.21-7.13 (m, 5H), 4.73 (d, J = 8.0 Hz, 4H), 4.55 (s, 1H), 3.05 (d, J = 5.9 Hz, 2H), 1.78 (s, 12H), 1.02 (s, 6H). LCMS: 480.2 (M+H), Purity- 99.52% by AUC, RT- 13.80, UV-245 nm. LCMS Method: Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mm Ammonium Acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; Flow rate: 0.6mL/min. HPLC: Purity- 99.57% by AUC, RT- 14.18, UV- 245 nm. HPLC method: Column: X Bridge C184.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH3CN; Flow rate: 1.2 mL/min; Diluent: Methanol (100%). EXAMPLE 114 - SYNTHESIS OF 5-FLUORO-N-(4-(4-((3-HYDROXY-3- METHYLBUTYL)SULFONYL)BICYCLO[2.2.2]OCTAN-1-YL)PHENYL) ISOINDOLINE-2-CARBOXAMIDE (I-320) [1051] Step 1: Preparation of 1,3-dioxoisoindolin-2-yl 4-(4-(5-fluoroisoindoline-2- carboxamido) phenyl) bicyclo [2.2.2] octane-1-carboxylate (3): To a stirred solution of 1 (1.5 g, 3.67 mmol) in a mixture of DCM: DMF (15 mL, 2:1) were added DMAP (89.7 mg, 0.73 mmol) and 2-hydroxyisoindoline-1,3-dione (719 mg, 4.41 mmol) at 0^oC and the mixture was stirred for 15 min. Then diisopropyl carbodiimide (694.9 mg, 5.51 mmol) was slowly added at 0^oC and stirred at RT for 16 h. The reaction mixture was monitored by TLC and after completion of the reaction, the reaction mixture was poured into ice-cold water. The precipitate was filtered and dried to obtain 1.3 g of 3 (64% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.07- 7.90 (m, 4H), 7.51-7.33 (m, 3H), 7.27-7.09 (m, 4H), 4.74 (s, 2H), 4.72 (s, 2H), 2.10-1.99 (m, 6H), 1.92-1.82 (m, 6H). [1052] Step 2: Preparation of ethyl 3-((4-(4-(5-fluoroisoindoline-2-carboxamido) phenyl) bicyclo [2.2.2] octan-1-yl) sulfonyl) propanoate (5): To a stirred solution of 3 (1.5 g, 2.71 mmol) in DMF (15 mL) was added sodium dithionite (707 mg, 4.06 mmol), lithium acetate (179 mg, 2.71 mmol), triethylamine hydrochloride (935 mg, 6.77 mmol) and ethyl acrylate (823 mg, 8.23 mmol) at RT under N₂ atmosphere. The mixture was stirred at 60^oC for 6 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice-cold water (50 mL) and diluted with Ethyl acetate (2x25 mL), the combined organic extracts were washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure to afford the crude product. The product was purified by column chromatography (eluent- 0-50% ethyl acetate in hexanes) to afford 352 mg of 5 (25% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.34-8.27 (m, 1H), 7.46 (d, J = 8.8 Hz, 2H), 7.42-7.35 (m, 1H), 7.26-7.09 (m, 4H), 4.74 (s, 4H), 3.3 (q, J = 6.8 Hz, 2H), 4.1 (q, J = 7.2 Hz, 2H), 2.72 (t, J = 6.8 Hz, 2H), 2.01-1.81 (m, 12H), 1.20 (t, J = 7.1 Hz, 3H). [1053] Step 3: Preparation of 5-fluoro-N-(4-(4-((3-hydroxy-3-methylbutyl) sulfonyl) bicyclo [2.2.2] octan-1-yl) phenyl) isoindoline-2-carboxamide: To a stirred solution of 5 (350 mg, 0.66 mmol) in THF (7 mL) was added methyl magnesium iodide (660 mg, 3.96 mmol, 3.0M in Et2O) at 0°C and stirred for 1 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with saturated NH₄Cl and diluted with ethyl acetate (2x25 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. The product was purified by column chromatography (eluent-0-50% ethyl acetate in hexanes) which afforded 122.0 mg of I-320 (35% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.30 (s, 1H), 7.46 (d, J = 8.7 Hz, 2H), 7.42-7.35 (m, 1H), 7.26-7.09 (m, 4H), 4.74-4.71 (d, J = 8.0Hz, 4H), 4.47 (s, 1H), 3.07-2.95 (m, 2H), 2.02-1.82 (m, 12H), 1.79-1.71 (m, 2H), 1.13 (s, 6H). LCMS: 515.29 (M+H), Purity- 95.80% by AUC, RT- 5.08, UV-240 nm. HPLC: Purity- 93.45% by AUC, RT- 14.27, UV- 240 nm. EXAMPLE 115 – SYNTHESIS OF 3-FLUORO-N-(4-(4-((2-HYDROXY-2- METHYLPROPYL)CARBAMOYL)BICYCLO[2.2.2]OCTAN-1-YL)PHENYL)-5,7- DIHYDRO-6H-PYRROLO[3,4-B]PYRIDINE-6-CARBOXAMIDE (I-429) [1054] Step 1: Preparation of methyl 4-(4-(3-fluoro-6,7-dihydro-5H-pyrrolo[3,4-b] pyridine-6-carboxamido) phenyl) bicyclo [2.2.2] octane-1-carboxylate (3): To 1 (250 mg, 0.659 mmol) in THF (10 mL) was added 2 (167 mg, 0.791 mmol) and DIPEA (1.3 mL, 9.88 mmol) at ambient temperature. The reaction mixture was stirred at 60^oC for 16 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was cooled to RT and the volatiles were concentrated under reduced pressure. The residue was stirred in a mixture of MTBE (10 mL) and water (10 mL) for 2 h, and the precipitate was filtered and dried to obtain 200 mg of 3 (74% yield) as a white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.50- 8.46 (m, 1H), 8.34 (s, 1H), 7.83-7.76 (m, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.6 Hz, 2H), 4.77 (s, 2H), 4.72 (s, 2H), 3.59 (s, 3H), 1.88-1.72 (m, 12H). [1055] Step 2: Preparation of 4-(4-(3-fluoro-6,7-dihydro-5H-pyrrolo[3,4-b] pyridine-6- carboxamido) phenyl) bicyclo [2.2.2] octane-1-carboxylic acid (4): To a stirred solution of 3 (200 mg, 0.47 mmol) in a mixture of THF: MeOH: H2O (24 mL, 5:5:1) was added lithium hydroxide (102.1 mg, 4.25 mmol) at 0°C and the reaction mixture was stirred at RT for 48 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with ice-cold water and acidified (to pH ~2) using 2.0N HCl. The precipitate was filtered and dried to obtain 190 mg of 4 (98% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 12.03 (s, 1H), 8.49-8.46 (m, 1H), 8.34 (s, 1H), 7.79 (dd, J = 2.3, 9.1 Hz, 1H), 7.45 (d, J = 8.7 Hz, 2H), 7.21 (d, J = 8.7 Hz, 2H), 4.77 (s, 2H), 4.72 (s, 2H), 1.85-1.70 (m, 12H). [1056] Step 3: Preparation of 3-fluoro-N-(4-(4-((2-hydroxy-2-methylpropyl) carbamoyl) bicyclo [2.2.2] octan-1-yl) phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b] pyridine-6-carboxamide: To a stirred solution of 4 (100 mg, 0.24 mmol) in DMF (3 mL) was added triethyl amine (370 mg, 3.66 mmol), EDCI (210 mg, 1.10 mmol), HOBt (168 mg, 1.10 mmol) and 5 (28 mg, 0.317 mmol) at RT, then the reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was poured into ice- cold water (20 mL) and stirred for 2h. The precipitate was filtered and dried to obtain 82 mg of I- 429 (70% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.49-8.46 (m, 1H), 8.34 (s, 1H), 7.79 (dd, J = 2.6, 8.9 Hz, 1H), 7.45 (d, J = 8.7 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H), 7.11 (t, J = 5.9 Hz, 1H), 4.77 (s, 2H), 4.72 (s, 2H), 4.54 (s, 1H), 3.04 (d, J = 6.0 Hz, 2H), 1.82-1.74 (m, 12H), 1.02 (s, 6H). LCMS: 481.48 (M+H), Purity- 99.89% by AUC, RT- 4.42, UV-240 nm. LCMS Method: Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mm Ammonium Acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; Flow rate: 0.6mL/min. HPLC: Purity- 97.69% by AUC, RT- 24.29, UV- 240 nm. HPLC Method: Column: X Bridge C18 4.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH3CN; Flow rate: 1.2 mL/min; Diluent: Methanol (100%). EXAMPLE 116 – SYNTHESIS OF 4,6-DIFLUORO-N-(4-(1-((2-HYDROXY-2- METHYLPROPYL)SULFONYL)PIPERIDIN-4-YL)PHENYL)ISOINDOLINE-2- CARBOXAMIDE (I-392) [1057] Step 1: Preparation of 1-(benzylthio)-2-methylpropan-2-ol (9): To a stirred solution of 8 (10.0 g, 80.64 mmol) in a mixture of MeOH: water (20 mL 2:1) was added NaOH (6.4 g, 161.2 mmol) and phenyl methanethiol (10.4 g, 96.7 mmol) at 0°C under N2 atmosphere, then the reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (2x100 mL), the combined organic extracts were dried over Na2SO4, and concentrated under reduced pressure to afford the 12 g of 9 (94% yield) as a colourless liquid.¹H NMR (300 MHz, DMSO-d6) δ 7.33-7.29 (m, 4H), 7.28-7.19 (m, 1H), 4.47 (s, 1H), 3.75 (s, 2H), 2.45 (s, 2H), 1.12 (s, 6H). [1058] Step 2: Preparation of benzyl(2-(benzyloxy)-2-methylpropyl) sulfane (10): To a stirred solution of 9 (15.0 g, 76.5 mmol) in THF (150 mL) was added potassium tert-butoxide (17.1 g, 153 mmol) at RT. The mixture was stirred at 50°C for 30 min, then the reaction mixture was cooled to RT. Benzyl bromide (15.7 g, 91.83 mmol) was added at RT and the mixture was stirred for 16 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (150 mL) and extracted with EtOAc (2x150 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. The product was purified by column chromatography (eluent- 0-20% ethyl acetate in hexanes) to afford 13.0 g of 10 (59% yield) as a pale-yellow liquid. ¹H NMR (300 MHz, DMSO-d6) δ 7.38-7.19 (m, 10H), 4.36 (s, 2H), 3.76 (s, 2H), 2.67 (s, 2H), 1.24 (s, 6H). [1059] Step 3: Preparation of 2-(benzyloxy)-2-methylpropane-1-sulfonyl chloride (6): To a stirred solution of 10 (3.0 g, 10.49 mmol) in AcOH and water (50 mL 2:1) was added NCS (5.6 g, 41.96 mmol) at 0°C under N2 atmosphere and the mixture was stirred for 1 h. The reaction mixture was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc (2x30 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. The product was purified by column chromatography (eluent-0-20% ethyl acetate in hexanes) which afforded 2.0 g of 6 (74% yield) as a pale-yellow liquid.¹H NMR (300 MHz, DMSO-d6) δ 7.39-7.22 (m, 5H), 4.76 (s, 2H), 4.52 (s, 2H), 1.44 (s, 6H). [1060] Step 4: Preparation of tert-butyl 4-(4-((phenoxycarbonyl) amino) phenyl) piperidine-1-carboxylate (2): To a stirred solution of 1 (19.0 g, 68.76 mmol) and DIPEA (56.29 mL, 343.82 mmol) in THF (400 mL) was added phenyl chloroformate (13.22 g, 103.14 mmol) at 0 °C and the mixture was stirred for 30 min. The mixture was then warmed to RT and stirred for 2 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was poured into ice-cold water and the precipitate was filtered and dried to obtain 17 g of 2 (62% yield) as a white solid.¹H NMR (300 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.53-7.37 (m, 6H), 7.31-7.19 (m, 3H), 6.11 (s, 1H), 4.02- 3.96 (m, 2H), 3.53 (t, J = 5.6 Hz, 2H), 2.52-2.49 (m, 2H), 2.48-2.40 (m, 2H), 1.53 (s, 9H). [1061] Step 5: Preparation of tert-butyl 4-(4-(4,6-difluoroisoindoline-2-carboxamido) phenyl) piperidine-1-carboxylate (4): To a stirred solution of 2 (1.0 g, 2.52 mmol) and triethylamine (4.25 mL, 30.3 mmol) in THF (20 mL) was added 3 (0.469 g, 3.03 mmol) at ambient temperature, then the reaction mixture was stirred at 70^oC for 16 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was poured into ice- cold water and stirred for 10 min. The precipitate was filtered and dried to obtain 1.1 g of 4 (95% yield) as a white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.37 (s, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.25-7.09 (m, 4H), 4.77 (s, 4H), 4.14-3.96 (m, 2H), 2.89-2.74 (m, 2H), 2.66-2.54 (m, 1H), 1.78- 1.67 (m, 2H), 1.52-1.36 (m, 11H). LCMS: 458.1 (M+H), Purity- 99.97% by AUC, RT- 6.05, UV- 260 nm. [1062] Step 6: Preparation of 4,6-difluoro-N-(4-(piperidin-4-yl) phenyl) isoindoline-2- carboxamide (5): To a stirred solution of 4 (1.2 g, 2.62 mmol) in DCM (20 mL) was added HCl (5.0 mL; 4.0N in 1,4-dioxane) at 0^oC, and then the mixture was stirred at RT for 16 h. The reaction was monitored by TLC and LCMS and after completion of the reaction, the volatiles were removed under reduced pressure, then the reaction mixture was basified with NaHCO3, and the precipitate was filtered and dried to obtain 750 mg of 5 (80% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.37 (s, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.25-7.13 (m, 2H), 7.10 (d, J = 8.5 Hz, 2H), 4.77 (s, 4H), 3.10-2.99 (m, 2H), 2.67-2.55 (m, 3H), 1.75-1.64 (m, 2H), 1.59-1.41 (m, 2H). LC- MS: [M+H] ⁺ = 358.20 (M+H), Purity- 99.95% by AUC, RT- 4.40, UV-260 nm. [1063] Step 7: Preparation of N-(4-(1-((2-(benzyloxy)-2-methylpropyl) sulfonyl) piperidin-4-yl) phenyl)-4,6-difluoroisoindoline-2-carboxamide (7): To a stirred solution of 5 (350 mg, 0.92 mmol) in DMF (8 mL) was added triethyl amine (561 mg, 5.52 mmol), and 6 (318.6 mg, 1.38 mmol) at RT under N₂ atmosphere. Then the reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice-cold water, and extracted with 10% MeOH-DCM, the combined organic extracts were dried over Na2SO4, and concentrated under reduced pressure to afford the crude product. The product was purified by column chromatography (eluent-0-2% MeOH in DCM) which afforded 320 mg of 7 (59% yield) as an off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.41-7.22 (m, 5H), 7.21-7.14 (m, 2H), 7.11 (d, J = 8.6 Hz, 2H), 4.77 (s, 4H), 4.49 (s, 2H), 3.72-3.62 (m, 2H), 3.34 (s, 2H), 2.90-2.78 (m, 2H), 2.45-2.31 (m, 1H), 1.83-1.71 (m, 2H), 1.67-1.49 (m, 2H), 1.43 (s, 6H). [1064] Step 8: Preparation of 4,6-difluoro-N-(4-(1-((2-hydroxy-2-methylpropyl) sulfonyl) piperidin-4-yl) phenyl) isoindoline-2-carboxamide: To a stirred solution of 7 (200 mg, 0.343 mmol) in a mixture of THF: MeOH (10 mL) was added Pd/C (20 mg, 50% wet) at RT under H₂ (200 Psi) in a steel bomb, then the reaction mixture was stirred at 80^oC for 16 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a celite pad and washed with 50% MeOH-THF and the filtrate was concentrated under reduced pressure to afford the crude product. The product was purified by column chromatography (eluent-0-5% MeOH in DCM) which afforded 40 mg of I-392 (25% yield) as a white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.39 (s, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.25-7.11 (m, 4H), 4.83 (s, 1H), 4.77 (s, 4H), 3.73-3.62 (m, 2H), 3.10 (s, 2H), 2.93-2.79 (m, 2H), 2.65-2.54 (m, 1H), 1.90-1.78 (m, 2H), 1.70-1.52 (m, 2H), 1.31 (s, 6H). LC-MS: [M+H] ⁺ = 494.3120 (M+H), Purity- 96.69% by AUC, RT- 5.25, UV-260 nm. HPLC: Purity- 96.21% by AUC, RT- 14.71, UV- 240 nm. EXAMPLE 117 – SYNTHESIS OF N1-(4-(4-(3-FLUORO-6,7-DIHYDRO-5H- PYRROLO[3,4-B] PYRIDINE-6-CARBOXAMIDO) PHENYL) BICYCLO [2.2.2] OCTAN-1-YL)-N2-(2-HYDROXY-2-METHYLPROPYL) OXALAMIDE (I-389)

[1065] Step 1: Preparation of methyl 4-(4-((tert-butoxy carbonyl) amino) phenyl) bicyclo [2.2.2] octane-1-carboxylate (2): To a stirred solution of 1 (540 mg, 2.08 mmol) in a mixture of 1,4-dioxane: water (40 mL 1:1) was added NaHCO3 (870 mg, 10.60 mmol), followed by Boc- anhydride (1.36 g, 6.24 mmol) at 0°C under N₂ atmosphere. The reaction mixture was stirred at RT for 4 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2x20 mL), the combined organic layer was dried over Na₂SO₄ and concentrated under reduced pressure to afford the 740 mg of 2 (98.93% yield) as a brown solid.¹H NMR (300 MHz, DMSO-d₆) δ 9.21 (s, 1H), 7.33 (d, J = 8.7 Hz, 2H), 7.18 (d, J = 8.8 Hz, 2H), 3.59 (s, 3H), 1.86-1.68 (m, 12H), 1.46 (s, 9H). [1066] Step 2: Preparation of 4-(4-((tert-butoxy carbonyl) amino) phenyl) bicyclo [2.2.2] octane-1-carboxylic acid (3): To a stirred solution of 2 (7.0 g, 19.49 mmol) in a mixture of THF: MeOH: H2O (375 mL, 2:2:1) was added sodium hydroxide powder (7.01 g, 175.48 mmol) over 20 minutes at 0°C and the reaction mixture was stirred at RT for 24 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the volatiles were concentrated under reduced pressure, and then the reaction mixture was diluted with ice-cold water, acidified (to pH ~2) with sodium bisulphate, and the precipitate was filtered and dissolved in 30% MeOH- EtOAc (300 mL). The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure to obtain 6.5 g of 3 (97.01% yield) as a brown solid.¹H NMR (300 MHz, DMSO-d6) δ 11.2 (s, 1H), 9.20 (s, 1H), 7.33 (d, J = 8.8 Hz, 2H), 7.17 (d, J = 8.8 Hz, 2H), 1.81-1.69 (m, 12H), 1.46 (s, 9H). [1067] Step 3: Preparation of tert-butyl (4-(4-(((benzyloxy)carbonyl) amino) bicyclo [2.2.2] octan-1-yl) phenyl) carbamate (4): To a stirred solution of 3 (3.0 g, 8.69 mmol) in a mixture of THF: toluene (100 mL 2:1) was added molecular sieves (3.0 g), triethylamine (3.51 g, 34.78 mmol), and DPPA (5.73 g, 20.86 mmol) at RT, and the reaction mixture was stirred at RT for 4 h in sealed tube. The reaction mixture was monitored by TLC. After completion of the reaction, benzyl alcohol (1.87 g, 17.39 mmol) was added at RT and the reaction mixture was stirred at 100°C for 16 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3X100 mL). The combined organic extracts were dried over Na₂SO₄ and concentrated under reduced pressure to afford the crude product. The product was purified by column chromatography (eluent-0-30% ethyl acetate in hexanes) which afforded 2.5 g of 4 (64.1 % yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 9.19 (s, 1H), 7.39-7.28 (m, 7H), 7.17 (d, J = 8.8 Hz, 2H), 6.99 (s, 1H), 4.96 (s, 2H), 1.91-1.73 (m, 12H), 1.45 (s, 9H). [1068] Step 4: Preparation of benzyl (4-(4-aminophenyl) bicyclo [2.2.2] octan-1-yl) carbamate (5): To a stirred solution of 4 (3.2 g, 7.11 mmol) in DCM (100 mL) was added TFA (12.16 g, 106.65 mmol) at 0°C under N₂ atmosphere. Then the reaction mixture was stirred at 50°C for 30 min and then the reaction mixture was stirred at RT for 2 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was basified to (pH ~8-9) with sat NaHCO₃ solution (30 mL). The reaction mixture was extracted with DCM (2x50 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. The crude product was directly used in the next step without further purification to afford 2.0 g of 5 (80.64 %) as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.40-7.26 (m, 5H), 6.94 (d, J = 8.6 Hz, 2H), 6.46 (d, J = 8.6 Hz, 2H), 5.02-4.70 (m, 3H), 1.89-1.68 (m, 12H). LC-MS: [M+H] ⁺ = 351.36 (M+H), Purity- 90.03% by AUC, RT- 5.50, UV-260 nm. [1069] Step 5: Preparation of benzyl (4-(4-((phenoxycarbonyl)amino) phenyl) bicyclo [2.2.2] octan-1-yl) carbamate (6): To a stirred solution of 5 (19.0 g, 68.76 mmol) and DIPEA (56.29 mL, 343.82 mmol) in THF (400 mL) was added phenyl chloroformate (13.22 g, 103.14 mmol) at 0 °C, and then the mixture was stirred at RT for 2 h. After completion of the reaction, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3x350 mL), and the combined organic extracts were dried over Na2SO4, and concentrated under reduced pressure to afford 17 g of 6 (92.30% yield) as a white solid.¹H NMR (300 MHz, DMSO-d₆) δ 10.11 (s, 1H), 7.49-7.29 (m, 9H), 7.29-7.10 (m, 5H), 7.00 (s, 1H), 4.96 (s, 2H), 1.93-1.75 (m, 12H). [1070] Step 6: Preparation of benzyl (4-(4-(3-fluoro-6,7-dihydro-5H-pyrrolo[3,4-b] pyridine-6-carboxamido) phenyl) bicyclo [2.2.2] octan-1-yl) carbamate (8): To a stirred solution of 6 (520 mg, 1.106 mmol) and triethylamine (1.68 g, 16.59 mmol) in THF (20 mL) was added 7 (280 mg, 1.32 mmol) at ambient temperature. The reaction mixture was stirred at 70^oC for 16 h. The reaction was monitored by TLC and LCMS and after completion of the reaction, the reaction mixture was poured into ice-cold water and stirred for 10 min. The precipitate was filtered and dried to obtain 470 mg of 8 (82.74% yield) as an off-white solid.¹H NMR (300 MHz, DMSO- d6) δ 8.47 (d, J = 1.3 Hz, 1H), 8.33 (s, 1H), 7.79 (dd, J = 2.7, 8.9 Hz, 1H), 7.46-7.41 (m, J = 8.8 Hz, 2H), 7.40-7.31 (m, 5H), 7.20 (d, J = 8.8 Hz, 2H), 7.00 (s, 1H), 4.97 (s, 2H), 4.77 (s, 2H), 4.72 (s, 2H), 1.91-1.78 (m, 12H). [1071] Step 7: Preparation of N-(4-(4-amino bicyclo [2.2.2] octan-1-yl) phenyl)-3-fluoro- 5,7-dihydro-6H-pyrrolo [3,4-b] pyridine-6-carboxamide (9): A stirred solution of 8 (170 mg, 0.330 mmol) in acetic acid (2.0 mL) was added HBr (6.0 mL, 33% in acetic acid) at 0^oC, and then the mixture was stirred at RT for 24 h. The reaction was monitored by TLC and LCMS and after completion of the reaction, the volatiles were removed under reduced pressure. The resultant mixture was triturated with MTBE (3X20 mL), and the precipitate was filtered and dried to obtain 200 mg of 9 (98% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.48 (d, J = 1.3 Hz, 1H), 8.36 (s, 1H), 7.87-7.74 (m, 3H), 7.46 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H), 4.77 (s, 2H), 4.72 (s, 2H), 1.92-1.76 (m, 12H). [1072] Step 8: Preparation of methyl 2-((4-(4-(3-fluoro-6,7-dihydro-5H-pyrrolo[3,4-b] pyridine-6-carboxamido) phenyl) bicyclo [2.2.2] octan-1-yl) amino)-2-oxoacetate (11): To a stirred solution of 9 (200 mg, 0.43 mmol) in DMF (5 mL) was added DIPEA (280 mg, 2.15 mmol), and 10 (132 mg, 1.07 mmol) at 0°C under N2 atmosphere. The reaction mixture was stirred at RT for 16 h. Then another two lots of DIPEA (140 mg, 1.07 mmol), and 10 (53.0 mg, 0.43 mmol) were added at 0°C, and the mixture was again stirred at RT for 32 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was poured into ice-cold water and stirred for 10 min. The precipitate was filtered and dried to obtain 135 mg of 11 (66.83% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.48 (d, J = 1.3 Hz, 1H), 8.34 (s, 1H), 8.17 (s, 1H), 7.79 (dd, J = 2.5, 9.0 Hz, 1H), 7.44 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H), 4.77 (s, 2H), 4.72 (s, 2H), 3.74 (s, 3H), 2.03-1.76 (m, 12H). [1073] Step 9: Preparation of N1-(4-(4-(3-fluoro-6,7-dihydro-5H-pyrrolo[3,4-b] pyridine- 6-carboxamido) phenyl) bicyclo [2.2.2] octan-1-yl)-N2-(2-hydroxy-2-methylpropyl) oxalamide: To a stirred solution of 11 (120 mg, 0.26 mmol) in methanol (6 mL) was added triethylamine (260 mg, 2.6 mmol) and 12 (132 mg, 1.04 mmol) at RT in a sealed tube. Then the reaction mixture was stirred at 60°C for 16 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was cooled to RT and then the volatiles were removed under reduced pressure. The residue was diluted with water (20 mL) and MTBE (20 mL) and stirred for 2 h. The precipitate was filtered and dried to obtain 75 mg of I-389 (55% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.49-8.46 (m, 1H), 8.34 (s, 1H), 8.25 (t, J = 6.3 Hz, 1H), 7.83 (s, 1H), 7.79 (dd, J = 2.5, 9.0 Hz, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 8.7 Hz, 2H), 4.77 (s, 2H), 4.72 (s, 2H), 4.65 (s, 1H), 3.11 (d, J = 6.3 Hz, 2H), 2.06- 1.94 (m, 6H), 1.90-1.80 (m, 6H), 1.06 (s, 6H). LCMS: 524.30 (M+H), Purity- 96.33% by AUC, RT- 4.63, UV-240 nm. LCMS method: Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mm Ammonium Acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; Flow rate: 0.6mL/min. HPLC: Purity- 95.99% by AUC, RT- 17.64, UV- 270 nm. HPLC method: Column: X Bridge C18 4.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH₃CN; Flow rate: 1.2 mL/min; Diluent: Methanol (100%). EXAMPLE 118 – SYNTHESIS OF N1-(4-(4-(5-FLUOROISOINDOLINE-2- CARBOXAMIDO)PHENYL)BICYCLO[2.2.2]OCTAN-1-YL)-N2-(2-HYDROXY-2- METHYLPROPYL)OXALAMIDE (I-358) [1074] Step 1: Preparation of benzyl (4-(4-(5-fluoroisoindoline-2-carboxamido) phenyl) bicyclo [2.2.2] octan-1-yl) carbamate (3): To a stirred solution of 1 (2.0 g, 4.25 mmol) and triethylamine (1.68 g, 63.82 mmol) in THF (40 mL) was added 2 (1.1 g, 6.38 mmol) at ambient temperature. Then the reaction mixture was stirred at 55^oC for 16 h. The reaction was monitored by TLC and LCMS and after completion of the reaction, the reaction mixture was poured into ice- cold water and stirred for 10 min. The precipitate was washed with MTBE, filtered, and dried to obtain 1.93 g of 3 (88% yield) as an Off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.27 (s, 1H), 7.46-7.27 (m, 8H), 7.26-7.09 (m, 4H), 7.00 (s, 1H), 4.97 (s, 2H), 4.73 (s, 2H), 4.71 (s, 2H), 1.93-1.74 (m, 12H). LC-MS: [M+H] ⁺ = 440.2. [1075] Step 2: Preparation of N-(4-(4-aminobicyclo[2.2.2]octan-1-yl)phenyl)-5- fluoroisoindoline-2-carboxamide hydrobromide (4): A stirred solution of 3 (1.93 g, 3.762 mmol) in a mixture of THF: ethanol (60 mL, 1:1) was added Pd/C (570 mg 50% wet) at RT under H2 atmosphere. Then the reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a celite pad and the celite was washed with 50% MeOH in DCM (200 mL). The filtrate was concentrated under reduced pressure to afford 1.3 g of 4 (91% yield) as a white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.32-8.20 (m, 1H), 7.46-7.35 (m, 3H), 7.26-7.08 (m, 4H), 4.73 (s, 2H), 4.71 (s, 2H), 1.87-1.72 (m, 6H), 1.59-1.47 (m, 6H). [1076] Step 3: Preparation of methyl 2-((4-(4-(5-fluoroisoindoline-2-carboxamido) phenyl)bicyclo[2.2.2]octan-1-yl) amino)-2-oxoacetate (6): To a stirred solution of 4 (1.0 g, 2.638 mmol) in DMF (14 mL) was added DIPEA (680 mg, 5.277 mmol), and 5 (386 mg, 3.166 mmol) at 0°C under N2 atmosphere. Then the reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with ice-cold water (25 mL) and extracted with EtOAc (3x25 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. The product was purified by column chromatography (eluent-0-40% ethyl acetate in hexanes) to afford 600 mg of 6 (49% yield) as an off-white solid.¹H NMR (300 MHz, DMSO- d6) δ 8.28 (s, 1H), 8.17 (s, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.41-7.35 (m, 1H), 7.26-7.09 (m, 4H), 4.74 (s, 2H), 4.71 (s, 2H), 3.74 (s, 3H), 2.02-1.77 (m, 12H). [1077] Step 4: Preparation of N1-(4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) bicyclo[2.2.2]octan-1-yl)-N2-(2-hydroxy-2-methylpropyl) oxalamide: To a stirred solution of 6 (300 mg, 0.645 mmol) in methanol (30 mL) was added TEA (975 mg, 9.687 mmol), and 7 (287 mg, 3.229 mmol) at RT in a sealed tube. Then the reaction mixture was stirred at 55°C for 16 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was cooled to RT, and then the volatiles were removed under reduced pressure. The residue was diluted with water and MTBE stirred for 2 h. The precipitate was filtered and dried to obtain 280 mg of I-358 (83% yield) as an off-white solid.¹H NMR (300 MHz, DMSO- d₆) δ 8.30-8.20 (m, 2H), 7.84 (s, 1H), 7.47-7.35 (m, 3H), 7.26-7.09 (m, 4H), 4.74 (s, 2H), 4.71 (s, 2H), 4.66 (s, 1H), 3.10 (d, J = 6.3 Hz, 2H), 2.07-1.93 (m, 6H), 1.90-1.79 (m, 6H), 1.06 (s, 6H). LCMS: 523.37 (M+H), Purity- 98.79% by AUC, RT- 5.25, UV-245 nm. HPLC: Purity- 92.47% by AUC, RT- 14.56, UV- 250 nm. EXAMPLE 119 – SYNTHESIS OF 5-FLUORO-N-(4-(4-(3-(3-HYDROXY-3- METHYLBUTYL)UREIDO)BICYCLO[2.2.2]OCTAN-1-YL)PHENYL) ISOINDOLINE- 2-CARBOXAMIDE (I-236) [1078] Step 1: Preparation of phenyl (4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) bicyclo[2.2.2]octan-1-yl) carbamate (2): To a stirred solution of 1 (500 mg, 1.32 mmol) and DIPEA (0.55 mL, 3.3 mmol) in THF (10 mL) was added phenyl chloroformate (247.8 mg, 1.58 mmol) at 0 °C, then the mixture was stirred at RT for 2 h. The reaction was monitored by TLC and LCMS and after completion of the reaction, the reaction mixture was diluted with water (25 mL) and extracted with EtOAc (3x25 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford the crude. The crude product was triturated with n- pentane to afford 470 mg of 2 (71.42 %) as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.28 (s, 1H), 7.55 (s, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.41-7.33 (m, 3H), 7.26-7.05 (m, 7H), 4.74 (s, 2H), 4.71 (s, 2H), 1.99-1.79 (m, 12H). [1079] Step 2: Preparation of 5-fluoro-N-(4-(4-(3-(3-hydroxy-3-methylbutyl)ureido) bicyclo[2.2.2]octan-1-yl)phenyl)isoindoline-2-carboxamide: To a stirred solution of 2 (100 mg, 0.2 mmol) and triethylamine (202 mg, 2.0 mmol) in THF (3 mL) was added 3 (41 mg, 0.4 mmol) at ambient temperature. After addition, the reaction mixture was stirred at 70^oC for 16 h. The reaction was monitored by TLC and LCMS and after completion of the reaction, the reaction mixture was poured into ice-cold water and stirred for 10 min. The precipitate was filtered and dried to obtain the crude. The crude was purified by Prep TLC (eluent-0-5% MeOH-DCM) to afford 15 mg of I-236 (14% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.42 (d, J = 8.8 Hz, 2H), 7.40-7.35 (m, 1H), 7.26-7.09 (m, 4H), 5.58-5.52 (m, 2H), 4.73 (s, 2H), 4.71 (s, 2H), 4.27 (s, 1H), 3.06-2.94 (m, 2H), 1.90-1.75 (m, 12H), 1.49-1.39 (m, 2H), 1.07 (s, 6H). LCMS: 509.34 (M+H), Purity- 93.48% by AUC, RT- 5.03, UV-245 nm. HPLC: Purity- 91.37% by AUC, RT- 14.14, UV- 245 nm. EXAMPLE 120 – SYNTHESIS OF 5-FLUORO-N-(4-(4-(2-HYDROXY-N,2- DIMETHYLPROPANAMIDO)BICYCLO[2.2.2]OCTAN-1-YL)PHENYL) ISOINDOLINE-2-CARBOXAMIDE (I-234) [1080] Step 1: Preparation of 5-fluoro-N-(4-(4-formamidobicyclo [2.2.2] octan-1-yl) phenyl) isoindoline-2-carboxamide (2): To a stirred solution of acetic acid (0.33 mL) was added acetic anhydride (0.69 mL) at 0^oC in a sealed tube and then the reaction mixture was heated to 60^oC for 2 h. Then the reaction mixture was cooled to RT, 1 (1.0 g, 0.26 mmol) in THF (10 mL) was added to the reaction mixture and it was heated to 60^oC for 4 h. After complete consumption of the starting material, the reaction mixture was cooled to RT, diluted with water (25 mL), extracted with 10% MeOH-DCM (2x25 mL), and the combined organic layer was dried with Na2SO4 and filtered and concentrated under reduced pressure to obtain the crude. The product was purified by column chromatography and eluted with 5% MeOH-DCM to afford 1.0 g of 2 (93% yield) as off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.66 (d, J = 1.9 Hz, 1H), 7.48-7.34 (m, 3H), 7.26-7.09 (m, 4H), 4.73 (s, 2H), 4.71 (s, 2H), 1.97- 1.75 (m, 12H). LCMS: 408.27 (M+H), Purity- 80.21% by AUC, RT- 4.97, UV-245 nm. [1081] Step 2: Preparation of 5-fluoro-N-(4-(4-(methylamino) bicyclo [2.2.2] octan-1-yl) phenyl) isoindoline-2-carboxamide (3): To a stirred solution of 2 (1.0 g, 2.45 mmol) in THF (10 mL) was added BH3DMS (200 mg, 2.7 mmol) at 0^oC, and then the reaction mixture was heated to 80^oC for 2 h. After complete consumption of the starting material, the reaction mixture was quenched with MeOH, acidified to pH 2-3 using 2.0N HCl. The reaction mixture was refluxed for 2 h, cooled to RT, the volatiles were removed under reduced pressure. The resultant mixture was diluted with water and basified to pH ~10 using a 6.0N NaOH solution, and the obtained solid was extracted with 30% IPA-DCM. The combined organic extracts were washed with water, dried over Na₂SO₄, filtered and concentrated to obtain the crude. The product was purified by column chromatography and eluted with 10% MeOH-DCM to afford 500 mg of 3 (52% yield) as an off white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.44 (s, 1H), 7.43-7.38 (m, 2H), 7.25- 7.13 (m, J = 8.9 Hz, 4H), 4.73 (s, 2H), 4.71 (s, 2H), 2.15 (s, 3H), 1.88-1.69 (m, 6H), 1.62-1.46 (m, 6H). LCMS: 394.30 (M+H), Purity- 97.95% by AUC, RT- 4.60, UV-245 nm. [1082] Step 3: Preparation of methyl 2-((4-(4-(5-fluoroisoindoline-2-carboxamido) phenyl) bicyclo [2.2.2] octan-1-yl) (methyl)amino)-2-oxoacetate (5): To a stirred solution of 3 (250 mg, 0.63 mmol) in THF (5.0 mL) was added KO^tBu (214 mg, 1.9 mmol) at RT and the mixture was stirred for 30 minutes. 4 (93 mg, 0.76 mmol) was added at 0^oC, and the reaction mixture was stirred at RT for 16 h. After complete consumption of the starting material, the reaction mixture was diluted with ice water (30 mL) and extracted with EtOAc (2x25 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated under reduced pressure to obtain 170 mg of crude. The crude was used in the next step without further purification.¹H NMR (300 MHz, DMSO-d₆) δ 8.29 (s, 1H), 7.50-7.33 (m, 3H), 7.20 (m, J = 8.7 Hz, 4H), 4.74 (s, 2H), 4.71 (s, 2H), 3.78 (s, 3H), 2.82 (s, 3H), 2.23-2.01 (m, 6H), 1.95-1.78 (m, 6H). LCMS: 480.26 (M+H), Purity- 74.15% by AUC, RT- 5.55, UV-245 nm. [1083] Step 4: Preparation of 5-fluoro-N-(4-(4-(2-hydroxy-N,2-dimethylpropanamido) bicyclo [2.2.2] octan-1-yl) phenyl) isoindoline-2-carboxamide: To a stirred solution of 5 (170 mg, crude) in THF (5.0 mL) was added MeMgI (294 mg, 1.77 mmol, 3.0M in Et2O) at 0^oC and then the reaction mixture was stirred at RT for 2 h. After complete consumption of the starting material, the reaction mixture was quenched with a sat NH₄Cl solution and extracted with EtOAc (2x10 mL). The combined organic extracts were dried with Na₂SO₄, filtered and concentrated to give the crude. The product was purified by column chromatography and eluted with EtOAc to obtain 25 mg of I-234 as an off white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.47- 7.35 (m, 3H), 7.26-7.10 (m, 4H), 5.26 (s, 1H), 4.73 (s, 2H), 4.71 (s, 2H), 3.10 (s, 3H), 2.14-2.02 (m, 6H), 1.88-1.79 (m, 6H), 1.29 (s, 6H). LCMS: 480.33 (M+H), Purity- 98.86% by AUC, RT- 5.47, UV-245 nm. HPLC: Purity- 96.46% by AUC, RT- 15.32, UV- 245 nm. EXAMPLE 121 – SYNTHESIS OF N-(4-(4-(2-ACETAMIDO-2-METHYL PROPANAMIDO)BICYCLO[2.2.2]OCTAN-1-YL)PHENYL)-5-FLUORO ISOINDOLINE-2-CARBOXAMIDE (I-233) [1084] To a stirred solution of 1 (100 mg, 0.26 mmol) in DMF (2 mL) was added triethyl amine (166 mg, 1.30 mmol), EDCI (150 mg, 0.78 mmol), HOBt (120 mg, 0.78 mmol) and 2 (45 mg, 0.31 mmol) at 0^oC. The reaction mixture was stirred at RT for 16 h. The reaction mixture was poured into ice-cold water and the precipitate was filtered and dried to obtain the crude product. The product was taken in MTBE (3 mL) and heated to 70^oC for 16 h and then filtered to obtain 20 mg of I-233 (15% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.28 (s, 1H), 7.72 (s, 1H), 7.43 (d, J = 8.7 Hz, 2H), 7.41-7.35 (m, 1H), 7.26-7.09 (m, 4H), 6.68 (s, 1H), 4.73 (s, 2H), 4.71 (s, 2H), 1.93-1.73 (m, 15H), 1.30 (s, 6H). LCMS: 507.37 (M+H), Purity- 98.78 % by AUC, RT- 4.98, UV-245 nm. HPLC: Purity- 98.12% by AUC, RT- 14.01, UV- 245 nm. EXAMPLE 122 – SYNTHESIS OF 5-FLUORO-N-(4-(4-((2-HYDROXY-2-METHYL PROPYL)SULFONAMIDO)BICYCLO[2.2.2]OCTAN-1-YL)PHENYL) ISOINDOLINE-2- CARBOXAMIDE (I-200) [1085] Step 1: Preparation of N-(4-(4-((2-(benzyloxy)-2-methylpropyl) sulfonamido) bicyclo [2.2.2] octan-1-yl) phenyl)-5-fluoroisoindoline-2-carboxamide (3): To a stirred solution of 1 (350 mg, 0.92 mmol) in THF (5 mL) was added potassium tert-butoxide (561 mg, 5.52 mmol) and the reaction mixture was stirred at RT for 30 min.2 (318.6 mg, 1.38 mmol) was added at RT under N2 atmosphere and then the reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with water and extracted with 10% MeOH-DCM (2x50 mL) and the combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. The product was purified by column chromatography (eluent-0-5% MeOH in DCM) which afforded 45 mg of 3 (26.62% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.28 (s, 1H), 7.46-7.29 (m, 7H), 7.29-7.09 (m, 5H), 6.78 (s, 1H), 4.73 (s, 2H), 4.71 (s, 2H), 4.46 (s, 2H), 3.32 (s, 2H), 1.93-1.75 (m, 12H), 1.42 (s, 6H). [1086] Step 2: Preparation of 5-fluoro-N-(4-(4-((2-hydroxy-2-methylpropyl) sulfonamido) bicyclo [2.2.2] octan-1-yl) phenyl) isoindoline-2-carboxamide: To a stirred solution of 3 (1.93 g, 3.762 mmol) in a mixture of THF: ethanol (2.0 mL 1:1) was added Pd/C (10 mg 50% wet) at RT under H2 atmosphere. Then the reaction mixture was stirred at RT for 2 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a celite pad and washed with 10% MeOH-DCM (200 mL), and the filtrate was concentrated under reduced pressure to afford the 15 mg of I-200 (44% yield) as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.29 (s, 1H), 7.47-7.35 (m, 3H), 7.26-7.09 (m, 4H), 6.83 (s, 1H), 4.77-4.68 (m, 5H), 3.16 (s, 2H), 1.95-1.77 (m, 12H), 1.29 (s, 6H). LCMS: 516.34 (M+H), Purity- 93.77 % by AUC, RT- 5.30, UV-245 nm. HPLC: Purity- 95.26% by AUC, RT- 14.81, UV- 245 nm. EXAMPLE 123 – SYNTHESIS OF 4,5,6-TRIFLUORO-N-(4-(3-((2-HYDROXY-2- METHYLPROPYL)CARBAMOYL)BICYCLO[1.1.1]PENTAN-1-YL)PHENYL) ISOINDOLINE-2-CARBOXAMIDE (I-385)

[1087] Step 1: Preparation of 3-(4-nitrophenyl) bicyclo [1.1.1] pentane-1-carboxylic acid (2): To a stirred solution of 1 (2.5 g, 13.297 mmol) in trifluoro acetic acid (12.5 mL) was added fuming nitric acid (0.61 mL, 14.62 mmol) dropwise at 0°C and then the mixture was stirred at 0^oC for 4 h. The progress of the reaction was monitored by TLC and after completion of the reaction, the reaction mixture was quenched with ice-cold water (30 mL) and stirred at 15 °C for 1 h. The solid was filtered and dried under vacuum. The crude compound was triturated with Et₂O-pentane to afford 2 (30.42% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 12.52 (s, 1H), 8.19 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H), 2.30 (s, 6H). [1088] Step 2: Preparation of methyl 3-(4-nitrophenyl) bicyclo [1.1.1] pentane-1- carboxylate (3): To a stirred solution of 2 (450 mg, 1.931 mmol) in methanol (20 mL) was added thionyl chloride (0.3 mL) at 0^oC, and then the reaction mixture was heated to 60^oC for 3 hours. After complete consumption of the starting material, the reaction mixture was allowed to warm to RT and the volatiles were concentrated under reduced pressure. The residue was quenched with a sat NaHCO3 solution and extracted with EtOAc (3x100 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to obtain 470 mg of 3 (98.53%) as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.20 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 8.9 Hz, 2H), 3.65 (s, 3H), 2.35 (s, 6H). [1089] Step 3: Preparation of methyl 3-(4-aminophenyl) bicyclo [1.1.1] pentane-1- carboxylate (4): A stirred solution of 3 (470 mg, 1.9 mmol) in DMF (8 mL) was added 4,4’- bipyridine (14.84 mg, 0.095 mmol) and hypodiboric acid (682 mg, 7.6 mmol) at 0^oC and the mixture was stirred for 10 min. The reaction mixture was diluted with ice-cold water and extracted with EtOAc (2x25 mL). The combined organic extracts were washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure to obtain 4 (380 mg, 92.23%) as off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ 6.87 (d, J = 8.4 Hz, 2H), 6.49 (d, J = 8.4 Hz, 2H), 4.99 (s, 2H), 3.61 (s, 3H), 2.15 (s, 6H). [1090] Step 4: Preparation of methyl 3-(4-((phenoxycarbonyl)amino) phenyl) bicyclo [1.1.1] pentane-1-carboxylate (5): To a stirred solution of 4 (380 mg, 1.751 mmol) and DIPEA (0.71 mL, 4.377 mmol) in THF (15 mL) was added phenyl chloroformate (329 mg, 2.101 mmol) at 0 °C and then the mixture was stirred at RT for 2 h. The reaction was monitored by TLC and LCMS, after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3x50 mL). The combined organic extracts were dried over Na2SO4, and concentrated under reduced pressure to obtain the crude compound which was triturated with n- Pentane (80 mL) to afford 470 mg of 5 (82% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 10.21 (s, 1H), 7.48-7.38 (m, 4H), 7.30-7.15 (m, 5H), 3.63 (s, 3H), 2.24 (s, 6H). [1091] Step 5: Preparation of methyl 3-(4-(4,5,6-trifluoroisoindoline-2-carboxamido) phenyl) bicyclo [1.1.1] pentane-1-carboxylate (7): To a stirred solution of 5 (290 mg, 0.86 mmol) and triethylamine (1.30 g, 12.9 mmol) in THF (25 mL) was added 6 (177 mg, 1.11 mmol) at RT. The reaction mixture was stirred at 60^o C for 16 h. The reaction was monitored by TLC and LCMS and after completion of reaction, the reaction mixture was poured into ice cold water (20 mL) and stirred for 10 min. The precipitate was washed with MTBE and filtered and dried to obtain 230 mg of 7 (88% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ = 8.46 (s, 1H), 7.50 (d, J = 8.6 Hz, 2H), 7.44-7.37 (m, 1H), 7.13 (d, J = 8.6 Hz, 2H), 4.83 (s, 2H), 4.74 (s, 2H), 3.63 (s, 3H), 2.23 (s, 6H). [1092] Step 6: Preparation of 3-(4-(4,5,6-trifluoroisoindoline-2-carboxamido) phenyl) bicyclo [1.1.1] pentane-1-carboxylic acid (8): LiOHH₂O (64.6 mg, 2.69 mmol) was added to a stirred solution of 7 (280 mg, 0.67 mmol) in THF, methanol and water (1:1:1, 18 mL) at RT and the mixture was stirred for 16 h. After completion of the reaction, the volatiles were removed under reduced pressure, the mixture was acidified (pH ~2-3) with 1.0N HCl and the precipitate was filtered and dried to obtain 250 mg of 8 (92% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 12.49 (s, 1H), 8.45 (s, 1H), 7.49 (d, J = 8.5 Hz, 2H), 7.44-7.36 (m, 1H), 7.12 (d, J = 8.5 Hz, 2H), 4.83 (s, 2H), 4.74 (s, 2H), 2.18 (s, 6H). [1093] Step 7: Preparation of 4,5,6-trifluoro-N-(4-(3-((2-hydroxy-2-methylpropyl) carbamoyl) bicyclo [1.1.1] pentan-1-yl) phenyl) isoindoline-2-carboxamide: To a stirred solution of 8 (110 mg, 0.273 mmol) in DMF (4 mL) was added triethylamine (0.3 mL, 2.18 mmol), EDCI (235 mg, 1.23 mmol), HOBt (188 mg, 1.23 mmol) and 9 (29.2 mg, 0.33 mmol) at 0^oC. The reaction mixture was stirred at RT for 16 h. The reaction was monitored by TLC and LCMS and after completion of the reaction, the reaction mixture was poured into ice-cold water (25 mL) and stirred at RT for 3 h. The precipitate was filtered and dried to obtain 70 mg of I-385 (54% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.45 (s, 1H), 7.55-7.46 (m, 3H), 7.45-7.37 (m, 1H), 7.12 (d, J = 8.6 Hz, 2H), 4.84 (s, 2H), 4.75 (s, 3H), 3.05 (d, J = 6.1 Hz, 2H), 2.15 (s, 6H), 1.04 (s, 6H). LCMS: 474.28 (M+H), Purity- 98.46 % by AUC, RT- 4.95, UV-240 nm. HPLC: Purity- 96.66% by AUC, RT- 18.71, UV- 220 nm. EXAMPLE 124 – SYNTHESIS OF 5-FLUORO-N-(4-(4-((1-HYDROXY-2-METHYL PROPAN-2-YL)CARBAMOYL)BICYCLO[2.2.2]OCTAN-1-YL)PHENYL) ISOINDOLINE-2-CARBOXAMIDE (I-382) [1094] To a stirred solution of I-384 (100 mg, 0.24 mmol) in DMF (5.0 mL) was added 1 (26 mg, 0.29 mmol), followed by the addition of DIPEA (0.3 mL, 1.96 mmol) and HATU (335 mg, 0.88 mmol) at 0 ^oC. The reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was poured into ice-cold water and the precipitate was filtered, washed with water, and dried to obtain the crude product. The crude compound was triturated using ethanol to afford 60 mg of I-382 (51% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.44 (d, J = 8.7 Hz, 2H), 7.42-7.35 (m, 1H), 7.26-7.09 (m, 4H), 6.37 (s, 1H), 4.98 (t, J = 5.8 Hz, 1H), 4.74 (s, 2H), 4.71 (s, 2H), 3.32 (s, 2H), 1.75 (s, 12H), 1.18 (s, 6H). LCMS: 480.33 (M+H), Purity- 97.29 % by AUC, RT- 5.20, UV-250 nm. HPLC: Purity- 94.09% by AUC, RT- 12.78, UV- 245 nm.

EXAMPLE 125 – SYNTHESIS OF 4,5,6-TRIFLUORO-N-(4-(1-(2-HYDROXY-2- METHYLPROPANOYL)-1,2,3,6-TETRAHYDROPYRIDIN-4-YL)PHENYL) ISOINDOLINE-2-CARBOXAMIDE (I-355) [1095] Step 1: Preparation of 2,3,4-trifluoro-6-(methoxycarbonyl) benzoic acid (10): To stirred solution of DIPA (37 mL, 262 mmol) in THF (200 mL) was added 2.5 M of n-BuLi in hexane (84 mL, 210 mmol) dropwise at -78 ^o C under N2, and the mixture stirred for 1 h at -78 ^o C, and then slowly brought to 0-5 ^o C and stirred for 1 h. The mixture was then cooled to -78 ^o C and a solution of 9 (20 g, 105 mmol) in THF (50 mL) was added and the mixture was stirred at - 78 ^oC for 2 h. Then the reaction mixture was stirred at RT for 12 h. The reaction was monitored by TLC and LCMS and after completion of the reaction, the reaction mixture was poured into ice cold water and the organic phase was concentred under reduced pressure and washed with MTBE. The aqueous layer was acidified to pH=2-3 by using 3N HCl and extracted with 10% MeOH in DCM (2 x 250 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain 8 g of 10 (32.52 %) as a brown colour solid. ¹H NMR (300 MHz, DMSO-d₆) δ 13.92 (s, 1H), 7.86-7.78 (m, 1H), 3.84 (s, 3H). [1096] Step 2: Preparation of 3,4,5-trifluorophthalic acid (11): LiOHH₂O (3.0 g, 128 mmol) was added to a stirred solution of 10 (10 g, 42.7 mmol) in THF and water (3:1, 200 mL) at 0^oC and stirred at RT for 16 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, the volatiles were removed under reduced pressure, the reaction mixture was acidified with 3.0N HCl and extracted with 10% IPA-DCM (2x100 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain 15 g of 11 (Crude) as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 13.73 (s, 1H), 7.86-7.72 (m, 1H). [1097] Step 3: Preparation of 4,5,6-trifluoroisobenzofuran-1,3-dione (12): In a sealed tube, a solution of 11 (15 g, 68.18 mmol) in AC2O (15 mL) was stirred at 100 ^oC for 5 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was cooled to RT, poured into ice-cold water and extracted with DCM (3 x 100 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain 10 g of 12 (Crude) as an off-white solid. The obtained compound was used for the next step without further purification. [1098] Step 4: Preparation of 4,5,6-trifluoroisoindoline-1,3-dione (13): In a sealed tube, a solution of 12 (10 g, 49.50 mmol) in NH4OAc (38.11 g, 495 mmol) was stirred at 120 ^oC for 16 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was cooled to RT and poured into ice-cold water and the solid was filtered and washed with water and dried to afford the crude product. The product was purified by combi-flash chromatography (eluent-0-50% ethyl acetate in hexanes), which afforded 3.5 g of 13 (35% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 11.75 (s, 1H), 7.97-7.90 (m, 1H). [1099] Step 5: Preparation of 4,5,6-trifluoroisoindoline (14): To a stirred solution of 13 (3.0 g, 14.85 mmol) in THF (20 mL) was added BF3-Et2O (11 mL, 89.10 mmol), and the mixture was stirred for 30 min at RT. Then BH₃-THF (2.3 g, 178.21 mmol) was added at RT and the mixture was heated to 50^oC for 16 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was cooled to 0^oC and quenched with MeOH and by addition of 3N HCl, and then the reaction mixture was heated to 70 ^oC for 2 h. The reaction mixture was basified to pH ~ 10-11 by using a 10% NaOH solution and extracted with a 5% MeOH-DCM solution (2 x 100 mL). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain 2 g of 14 (80%) as an off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ 10.10 (s, 2H), 7.50-7.38 (m, 1H), 4.62 (s, 2H), 4.52 (s, 2H). [1100] Step 6: Preparation of 4,5,6-trifluoroisoindoline hydrochloride (5): To a stirred solution of 14 (1.0 g, 5.74 mmol) in diethyl ether (15 mL) was added HCl (2.0 mL; 4.0N in 1,4- dioxane) at 10 ^oC, and then the mixture was stirred at RT for 2 h. The reaction was monitored by TLC and LCMS and after completion of the reaction, the obtained solid was filtered and washed with n-Hexane and dried under reduced pressure to obtain 850 mg of 5 (70%) as an off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ 10.31 (s, 2H), 7.49-7.39 (m, J = 7.2, 8.4 Hz, 1H), 4.66-4.57 (m, 2H), 4.52 (s, 2H). [1101] Step 7: Preparation of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (3): To a stirred solution of 2 (10.0 g, 58.14 mmol) and 1 (26.96 g, 87.2 mmol) in DMF (150 mL) was added sodium carbonate (12.3 g, 116.2 mmol, 2.0M aqueous solution), and the reaction mixture was purged with argon for 10 min, and then added Pd(TPP)₄ (3.3 g, 2.9 mmol) was added and the mixture was again purged with argon for 5 min. The reaction mixture was stirred at 90°C for 6 h. The reaction was monitored by TLC and LCMS and after completion of the reaction, the reaction mixture was cooled to RT and diluted with ice-cold water (500 mL) and extracted with ethyl acetate (3x250 mL). The combined organic layer was washed with a brine solution (2x300 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the crude product. The product was purified by combi-flash chromatography (eluent-0-30% ethyl acetate in hexanes) which afforded 8.0 g of 3 (50% yield) as an off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ 7.11 (d, J = 9.0 Hz, 2H), 6.52 (d, J = 8.8 Hz, 2H), 5.88 (s, 1H), 5.08 (s, 2H), 3.91-3.96 (m, 2H), 3.53-3.44 (m, 2H), 2.34-2.39 (m, 2H), 1.42 (s, 9H). LC-MS: [M+H] ⁺ = 275.2. [1102] Step 8: Preparation of tert-butyl 4-(4-((phenoxycarbonyl)amino) phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (4): To a stirred solution of 3 (47.2 g, 0.18 mol) and DIPEA (96.5 mL, 0.54 mol) in THF (470 mL) was added phenyl chloroformate (33.95 g, 0.218 mol) slowly at 0°C. After addition, the reaction mixture was stirred at 0°C for 30 min and at RT for 4 h. The reaction was monitored by TLC and LCMS and after completion of the reaction, the reaction mixture was poured into ice cold water and the precipitate was filtered and dried to obtain the product, which upon further trituration with n-heptane gave 61.5 g of 4 (89% yield) as a white solid.¹H NMR (300 MHz, DMSO-d6) δ 10.27 (s, 1H), 7.54-7.08 (m, 9H), 6.11 (s, 1H), 3.99 (s, 2H), 3.70-3.40 (m, 2H), 2.44 (s, 2H), 1.42 (s, 9H). LC-MS: [M+H] ⁺ = 395.20. [1103] Step 9: Preparation of tert-butyl 4-(4-(4,5,6-trifluoroisoindoline-2-carboxamido) phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (6): 5 (300 mg, 0.243 mmol) was added to a solution of 4 (507 mg, 1.28 mmol) and triethylamine (3.0 mL, 21.3 mmol) in THF (15 mL) at ambient temperature. The reaction mixture was stirred at 65^oC for 16 h. The reaction was monitored by TLC and LCMS and after completion of the reaction, the reaction mixture was poured in ice-cold water, stirred for 3 h, and the precipitate was filtered and washed with MTBE (50 mL) to afford 320 mg of 6 (49% yield) as a white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.49 (s, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.45-7.31 (m, 3H), 6.08 (s, 1H), 4.85 (s, 2H), 4.76 (s, 2H), 4.02- 3.95 (m, 2H), 3.52 (t, J = 5.6 Hz, 2H), 2.48-2.39 (m, 2H), 1.42 (s, 9H). [1104] Step 10: Preparation of 4,5,6-trifluoro-N-(4-(1,2,3,6-tetrahydropyridin-4-yl) phenyl) isoindoline-2-carboxamide (7): To a stirred solution of 6 (0.32 g, 0.676 mmol) in DCM (5 mL) was added HCl (3.2 mL; 4.0N in 1,4-dioxane) at 0^oC, and then the mixture was stirred at RT for 16 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, the volatiles were concentrated under reduced pressure to obtain 180 mg of 7 (71%) as an off- white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.79 (s, 2H), 8.57 (s, 1H), 7.58 (d, J = 8.8 Hz, 2H), 7.45-7.37 (m, 3H), 6.15-6.10 (m, 1H), 4.86 (s, 2H), 4.76 (s, 2H), 3.73-3.67 (m, 2H), 3.30-3.24 (m, 2H), 2.68-2.59 (m, 2H). LC-MS: [M+H] ⁺ = 373.1. [1105] Step 11: Preparation of 4,5,6-trifluoro-N-(4-(1-(2-hydroxy-2-methylpropanoyl)- 1,2,3,6-tetrahydropyridin-4-yl) phenyl) isoindoline-2-carboxamide): To a stirred solution of 7 (0.1 g, 0.26 mmol) in DMF (2.0 mL) was added EDCI.HCl (256 mg, 1.33 mmol) and HOBt (203 mg, 1.33 mmol). TEA (0.6 mL, 3.9 mmol) was added, followed by addition of 8 (138 mg, 1.33 mmol) at RT. The reaction mixture was stirred at RT for 16 h. After completion of the reaction, the reaction mixture was poured into ice-cold water and the precipitate was filtered and dried to obtain 21 mg of I-355 (17%) as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.49 (s, 1H), 7.54 (d, J = 8.5 Hz, 2H), 7.45-7.33 (m, 3H), 6.17-6.10 (m, 1H), 5.45 (s, 1H), 4.73 (d, J = 7.5, 4H), 4.76 (s, 2H), 4.39-3.79 (m, 4H), 1.33 (s, 6H). LCMS: 460.17 (M+H), Purity- 99.79% by AUC, RT- 5.18, UV-270 nm. HPLC: Purity- 96.43% by AUC, RT- 14.11, UV- 260 nm. EXAMPLE 126 – SYNTHESIS OF N-(4-(4-((2-HYDROXY-2-METHYLPROPYL) CARBAMOYL)BICYCLO[2.2.2]OCTAN-1-YL)PHENYL)ISOINDOLINE-2- [1106] Step 1: Preparation of methyl 4-(4-(isoindoline-2-carboxamido) phenyl) bicyclo [2.2.2] octane-1-carboxylate (3): 2 (1.1 g, 2.86 mmol) was added to a solution of 1 (0.5 g, 3.17 mmol) and DIPEA (3.22 g, 31.7 mmol) in THF (10 mL) at ambient temperature. The reaction mixture was stirred at 65^oC for 16 h. The reaction was monitored by TLC and LCMS and after completion of the reaction, the reaction mixture was poured in ice-cold water, stirred for 3 h, and the precipitate was filtered and washed with MTBE (15 mL) to afford 460 mg of 3 (36% yield) as a white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.45 (d, J = 8.7 Hz, 2H), 7.39-7.26 (m, 4H), 7.20 (d, J = 8.7 Hz, 2H), 4.74 (s, 4H), 3.59 (s, 3H), 1.88-1.70 (m, 12H). LCMS: 405.24 (M+H), Purity- 100% by AUC, RT- 5.83, UV-245 nm. [1107] Step 2: Preparation of 4-(4-(isoindoline-2-carboxamido) phenyl) bicyclo [2.2.2] octane-1-carboxylic acid (4): To a stirred solution of 3 (460 mg, 1.13 mmol) in a mixture of THF: MeOH: H₂O (10 mL, 1:1:1) was added lithium hydroxide (247 mg, 5.65 mmol) at RT and the mixture was stirred at 55^oC for 16 h. The reaction was monitored by TLC and LCMS and after completion of the reaction, the reaction mixture was diluted with ice-cold water, acidified with 1.0N HCl, and the precipitate was filtered and dried to obtain 420 mg of 4 (95% yield) as an off- white solid.¹H NMR (300 MHz, DMSO-d6) δ 12.04 (s, 1H), 8.27 (s, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.39-7.28 (m, 4H), 7.20 (d, J = 8.7 Hz, 2H), 4.75 (s, 4H), 1.85-1.70 (m, 12H). LCMS: 391.26 (M+H), Purity- 99.06% by AUC, RT- 4.45, UV-245 nm. [1108] Step 3: Preparation of N-(4-(4-((2-hydroxy-2-methylpropyl) carbamoyl) bicyclo [2.2.2] octan-1-yl) phenyl) isoindoline-2-carboxamide: To a stirred solution of 9 (420 mg, 1.0 mmol) in DMF (5 mL) was added triethyl amine (680 mg, 5.0 mmol), EDCI (570 mg, 3.0 mmol), HOBt (460 mg, 3.0 mmol) and 5 (133.5 mg, 1.5 mmol) at 0^oC and then the reaction mixture was stirred at RT for 16 h. The reaction was monitored by TLC and LCMS and after completion of the reaction, the reaction mixture was poured into ice-cold water and the precipitate was filtered and dried to obtain the crude product. The product was taken into EtOH (10 mL) and heated to 70^oC for 16 h and then filtered to obtain 375 mg of I-249 (75% yield) as an off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.39-7.28 (m, 4H), 7.20 (d, J = 8.7 Hz, 2H), 7.12 (t, J = 6.0 Hz, 1H), 4.75 (s, 4H), 4.55 (s, 1H), 3.04 (d, J = 6.1 Hz, 2H), 1.85-1.70 (m, 12H), 1.02 (s, 6H). LCMS: 462.55 (M+H), Purity- 99.59% by AUC, RT- 13.80, UV-245 nm. HPLC: Purity- 99.61% by AUC, RT- 13.90, UV- 245 nm. EXAMPLE 127 – SYNTHESIS OF TERT-BUTYL (N-(4-(4-(5-FLUORO ISOINDOLINE- 2-CARBOXAMIDO)PHENYL)BICYCLO[2.2.2]OCTAN-1-YL) SULFAMOYL) CARBAMATE (I-357) [1109] Step 1: Preparation of tert-butyl (chlorosulfonyl) carbamate (2): To a stirred solution of 3 (600 mg, 4.255 mmol) in DCM (6 mL) was added molecular sieves (1.2 g), and tert- BuOH (0.44 mL, 20.86 mmol) at 0^oC. The reaction mixture was stirred at RT for 1 h. After 1 h, the reaction mixture was used for the next step without workup. [1110] Step 2: Preparation tert-butyl (N-(4-(4-(5-fluoroisoindoline-2-carboxamido) phenyl) bicyclo [2.2.2] octan-1-yl) sulfamoyl) carbamate: To a stirred solution of 1 (211 mg, 0.55 mmol) in THF (15 mL) was added KO^tBu (3.1 mL, 4.95 mmol, 1.6M in THF) at 0^oC and the mixture was stirred for 1 h, and then 2 (600 mg, 2.79 mmol) was added at 0^oC and the resulting reaction mixture was stirred at RT for 2 h. The reaction was monitored by TLC and LCMS and after completion of the reaction, the reaction mixture was quenched with water and stirred for 1 h. The precipitate was filtered and dried to obtain the crude. The crude material was purified by prep HPLC purification and afforded 30 mg of I-357 (9% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.27 (s, 1H), 7.46-7.34 (m, 4H), 7.25-7.09 (m, 4H), 4.73 (s, 2H), 4.71 (s, 2H), 1.91-1.75 (m, 12H), 1.44 (s, 9H). LCMS: 559.19 (M+H), Purity- 95.33% by AUC, RT- 5.53, UV-250 nm. HPLC: Purity- 94.77% by AUC, RT- 14.77, UV- 220 nm. EXAMPLE 128 – SYNTHESIS OF 3-FLUORO-N-(4-(1-(2-(4-HYDROXYBICYCLO [2.2.2]OCTANE-1-CARBOXAMIDO)-2-METHYLPROPANOYL)-1,2,3,6-TETRA HYDROPYRIDIN-4-YL)PHENYL)-5,7-DIHYDRO-6H-PYRROLO[3,4-B]PYRIDINE-6- CARBOXAMIDE (I-483) AND 3-FLUORO-N-(4-(1-(2-(4-HYDROXYBICYCLO [2.2.2] OCTANE-1-CARBOXAMIDO)-2-METHYLPROPANOYL)PIPERIDIN-4-YL)PHENYL)- 5,7-DIHYDRO-6H-PYRROLO[3,4-B]PYRIDINE-6-CARBOXAMIDE (I-479) [1111] Step 1: Preparation of tert-butyl (1-(4-(4-(3-fluoro-6,7-dihydro-5H-pyrrolo[3,4-b] pyridine-6-carboxamido) phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-methyl-1-oxopropan-2-yl) carbamate (2): To a stirred solution of 7 (3.6 g, 10.65 mmol) in DMF (36.0 mL) was added DIPEA (9.08 mL, 53.25 mmol), HATU (5.7 g, 15.97 mmol) and 1 (2.16 g, 10.65 mmol) at RT, then the reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC and LCMS. After consumption of the starting material, the reaction mixture was poured in ice-cold water, stirred for 15 min, the precipitate was filtered, washed with water and dried to obtain 5.3 g of 2 (94%) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.52-8.41 (m, 2H), 7.79 (dd, J = 2.5, 9.0 Hz, 1H), 7.61-7.48 (m, J = 8.7 Hz, 2H), 7.43-7.30 (m, 3H), 6.10 (s, 1H), 4.78 (s, 2H), 4.74 (s, 2H), 4.26-4.03 (m, 2H), 3.90-3.66 (m, 2H), 2.46-2.34 (m, 2H), 1.33 (s, 12H), 1.25 (s, 3H). LCMS: 524.07 (M+H). [1112] Step 2: Preparation of 3-fluoro-N-(4-(1-(2-methyl-2-((2,2,2-trifluoroacetyl)-l4- azaneyl)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl) phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b] pyridine-6-carboxamide (3): To a stirred solution of 2 (5.3 g, 10.09 mmol) in DCM (100 mL) was added trifluoroacetic acid (7.77 mL, 100.9 mmol) over 10 min at 0°C under N2 atmosphere, then the reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC and LCMS. After consumption of the starting material, the reaction mixture was concentrated under reduced pressure to afford the crude product. The crude product was triturated with MTBE (50 mL) which afforded 2.8 g of 3 (51%) as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.51-8.46 (m, 2H), 8.17 (bs, 3H), 7.80 (dd, J = 2.6, 9.0 Hz, 1H), 7.63-7.53 (m, J = 8.8 Hz, 2H), 7.37 (d, J = 8.7 Hz, 2H), 6.14 (s, 1H), 4.78 (s, 2H), 4.74 (s, 2H), 4.22 (s, 2H), 3.79 (t, J = 5.3 Hz, 2H), 2.57-2.51 (m, 2H), 1.59 (s, 6H). LCMS: 424.08 (M+H). [1113] Step 3: Preparation of 3-fluoro-N-(4-(1-(2-(4-hydroxybicyclo[2.2.2]octane-1- carboxamido)-2-methylpropanoyl)-1,2,3,6-tetrahydropyridin-4-yl) phenyl)-5,7-dihydro-6H- pyrrolo[3,4-b] pyridine-6-carboxamide (I-483): To a stirred solution of 3 (100 mg, 0.18 mmol) in DMF (4.0 mL) was added DIPEA (0.33 mL, 1.8 mmol), HATU (139 mg, 0.36 mmol) and 4 (46.6 mg, 0.27 mmol) at RT, then the reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC and LCMS. After consumption of the starting material, the reaction mixture was poured into ice-cold water, stirred for 15 min, and then the precipitate was filtered, washed with water and dried to obtain the crude. The crude was triturated with EtOAc (15 mL) to afford 30 mg of I-483 (27%) as a light green colour solid.¹H NMR (300 MHz, DMSO-d6) δ 8.50-8.43 (m, 2H), 7.80 (dd, J = 2.5, 8.9 Hz, 1H), 7.58-7.52 (m, J = 8.7 Hz, 2H), 7.46 (s, 1H), 7.38-7.30 (m, 2H), 6.06 (s, 1H), 4.78 (s, 2H), 4.74 (s, 2H), 4.28 (s, 1H), 4.19-3.96 (m, 2H), 3.73- 3.60 (m, 2H), 2.36 (s, 2H), 1.85-1.66 (m, 6H), 1.52-1.45 (m, 6H), 1.31 (s, 6H). LC-MS: [M+H] ⁺ = 576.20 (M+H). [1114] Step 4: Preparation of 3-fluoro-N-(4-(1-(2-(4-hydroxybicyclo[2.2.2]octane-1- carboxamido)-2-methyl propanoyl) piperidin-4-yl) phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b] pyridine-6-carboxamide (I-479): To a stirred solution of I-483 (125 mg, 0.217 mmol) in a mixture of THF: ethanol (14.0 mL, 1:1) was added Pd/C (35 mg, 50% wet) and AcOH (5 mg) at RT under H₂ atmosphere, then the reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a celite pad and washed with 10% MeOH-DCM (50 mL), the filtrate was concentrated under reduced pressure to afford the crude. The crude was triturated with EtOAc (20 mL) to afford 60 mg of I-479 (48% yield) as an Off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.48 (s, 1H), 8.36 (s, 1H), 7.80 (dd, J = 2.6, 9.1 Hz, 1H), 7.51-7.38 (m, 3H), 7.08 (d, J = 8.5 Hz, 2H), 4.77 (s, 2H), 4.72 (s, 2H), 4.53-4.37 (m, 2H), 4.28 (s, 1H), 2.76-2.53 (m, 3H), 1.80-1.65 (m, 8H), 1.52-1.45 (m, 6H), 1.41-1.29 (m, 8H). LC-MS: [M+H] ⁺ = 578.22 (M+H), Purity- 98.73% by AUC, RT- 4.22, UV-260 nm. LCMS Method: Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mm Ammonium Acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; Flow rate: 0.6mL/min. HPLC: Purity- 95.38% by AUC, RT- 11.87, UV- 240 nm. HPLC Method: Column: X Bridge C184.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH3CN; Flow rate: 1.2 mL/min; Diluent: Methanol (100%). EXAMPLE 129 – SYNTHESIS OF 5-FLUORO-N-(4-(1-(2-METHYL-2-(TETRAHYDRO- 2H-PYRAN-4-CARBOXAMIDO)PROPANOYL)PIPERIDIN-4-YL)PHENYL) ISOINDOLINE-2-CARBOXAMIDE (I-480) [1115] Step 1: Preparation of tert-butyl (1-(4-(4-(5-fluoroisoindoline-2-carboxamido) phenyl) piperidin-1-yl)-2-methyl-1-oxopropan-2-yl) carbamate (2): To a stirred solution of 5 (600 mg, 1.76 mmol) in DMF (12 mL) was added DIPEA (1.56 mL, 8.82 mmol), HATU (1.0 g, 2.64 mmol) and 1 (429.8 mg, 2.11 mmol) at RT, then the reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was poured in ice-cold water and stirred at RT for 2 h. The obtained precipitate was filtered and dried to obtain 600 mg of 2 (64%) as a pale brown solid.¹H NMR (300 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.49-7.33 (m, 4H), 7.26-7.19 (m, 1H), 7.17-7.02 (m, 3H), 4.74 (s, 2H), 4.71 (s, 2H), 4.55 (d, J = 12.5 Hz, 2H), 2.80-2.58 (m, 3H), 1.73 (d, J = 11.6 Hz, 2H), 1.47-1.29 (m, 17H). LCMS: 525.15 (M+H). [1116] Step 2: Preparation of 5-fluoro-N-(4-(1-(2-methyl-2-((2,2,2-trifluoroacetyl)-l4- azaneyl) propanoyl) piperidin-4-yl) phenyl) isoindoline-2-carboxamide (3): To a stirred solution of 2 (600 mg, 1.14 mmol) in DCM (50 mL) was added TFA (0.46 mL, 5.7 mmol) over 10 min at 0°C under N2 atmosphere, then the reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford the crude product. To the crude product was added toluene, followed by concentration under reduced pressure. The product was then triturated with MTBE (20 mL) to afford 590 mg of 3 (98%) as a pale brown solid.¹H NMR (300 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.15 (s, 3H), 7.48 (d, J = 8.5 Hz, 2H), 7.43-7.33 (m, 1H), 7.22 (dd, J = 2.2, 9.1 Hz, 1H), 7.19-7.09 (m, 3H), 4.74 (s, 2H), 4.71 (s, 2H), 4.44-4.00 (m, 2H), 3.10- 2.90 (m, 2H), 2.84-2.72 (m, 1H), 1.93-1.76 (m, 2H), 1.61-1.36 (m, 8H). [1117] Step 3: Preparation of 5-fluoro-N-(4-(1-(2-methyl-2-(tetrahydro-2H-pyran-4- carboxamido) propanoyl) piperidin-4-yl) phenyl) isoindoline-2-carboxamide (I-480): To a stirred solution of 3 (590 mg, 1.09 mmol) in DMF (5 mL) was added DIPEA (0.89 mL, 5.45 mmol), HATU (623.9 mg, 1.64 mmol) and 4 (427.3 mg, 3.28 mmol) at RT, then the reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was poured in ice-cold water and stirred at RT for 2 h. The obtained precipitate was filtered and dried to obtain 70 mg of I-480 (11%) as a pale brown solid.¹H NMR (300 MHz, DMSO-d6) δ 8.30 (s, 1H), 8.09 (s, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.42- 7.34 (m, 1H), 7.22 (d, J = 9.4 Hz, 1H), 7.18-7.05 (m, 3H), 4.74 (s, 2H), 4.71 (s, 2H), 4.48 (d, J = 10.5 Hz, 2H), 3.91-3.79 (m, 2H), 3.30-3.22 (m, 2H), 2.76-2.60 (m, 3H), 2.41-2.34 (m, 1H), 1.71 (d, J = 12.1 Hz, 2H), 1.57 (d, J = 2.6 Hz, 4H), 1.43-1.31 (m, 8H). LC-MS: [M+H] ⁺ = 537.15. EXAMPLE 130 – SYNTHESIS OF 7-FLUORO-N-(4-(1-(2-HYDROXY-2- METHYLPROPANOYL)-1,2,3,6-TETRAHYDROPYRIDIN-4-YL)PHENYL)-1,3- DIHYDRO-2H-PYRROLO[3,4-C]PYRIDINE-2-CARBOXAMIDE (I-290) [1118] Step 1: Preparation of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (3): A mixture of compound 1 (10 g, 56.38 mmol), compound 2 (20 g, 64.68 mmol), and K₃PO₄ (40 g, 180.4 mmol) in 1,2-DME: H₂O (10:2) (120 mL) was degassed with argon for 5 min. Pd(dppf)Cl₂.DCM (2.32 g, 2.8 mmol) was added to the above mixture at RT. The reaction mixture was stirred for 15 min. while degassing with argon, and then the reaction mixture was stirred at 90 ^oC and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a Celite pad and washed with EtOAc. The organic layer was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water followed by brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by CombiFlash (Nexgen-300) chromatography (40 g cartridge silica gel) using 25-35% EtOAc in n-heptane as an eluent to afford the title compound 3 (7.5 g, 27 mmol, 48% yield) as a white solid. LC-MS: Ret. Time: 1.11 min, MS calcd. for Chemical Formula: C16H22N2O2, 274.36; Found: 275.45 [M+H]⁺. X-select CSH 18 (3x50 mmx2.5mm); Mobile phase: A: 0.05% TFA in H2O; B: 0.05% TFA in ACN; Injection volume: 2µL; Flow rate: 1mL/min; column temperature: 40 ^oC; Gradient program: 0% B, %Time/B: 0.0/2, 0.3/2, 2/98, 2.8/98, 3.0/2, 3.7/2. [1119] Step 2: Preparation of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (5): To a stirred solution of compound 3 (0.45 g, 1.64 mmol) in DCM (5 mL) were added pyridine (0.26 mL, 3.28 mmol), DMAP (0.020 g, 0.16 mmol) and compound 4 (0.285 g, 1.80 mmol) at 0 ^oC, and then the mixture was stirred at RT for 2 h under nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The crude compound was triturated with diethyl ether, filtered and dried under reduced pressure to afford the title compound 5 (0.65 g, 1.25 mmol, 76.36% yield) as a grey solid. LC-MS: Ret. Time: 1.40 min, MS calcd. for Chemical Formula: C₂₃H₂₆N₂O₄: 394.47; Found: 339.40 [(M-Isobutene)+H]⁺. X-select CSH 18 (3x50 mmx2.5mm); Mobile phase: A: 0.05% TFA in H2O; B: 0.05% TFA in ACN; Injection volume: 2µL; Flow rate: 1 mL/min; column temperature: 40 ^oC; Gradient program: 0% B, %Time/B: 0.0/2, 0.3/2, 2/98, 2.8/98, 3.0/2, 3.7/2. [1120] Step 3: Preparation of tert-butyl 4-(4-(7-fluoro-2,3-dihydro-1H-pyrrolo[3,4- c]pyridine-2-carboxamido)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (7): To a stirred solution of compound 5 (0.413 g, 1.04 mmol) and compound 6 (0.1 g, 0.723 mmol) in DMF (6 mL) was added DIPEA (0.632 mL, 3.62 mmol) at 0 ^oC then the mixture was stirred at 80 ^oC for 6 h under nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water followed by brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by CombiFlash (Nexgen-300) chromatography (12 g cartridge silica gel) using 1.5-2% MeOH in DCM as an eluent to afford the title compound 7 (0.17 g, 0.38 mmol, 37.03% yield) as a pale brown solid. [1121] Step 4: Preparation of 7-fluoro-N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1,3- dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide hydrochloride (8): To a stirred solution of compound 7 (0.15 g, 0.325 mmol) in 1,4-dioxane (4 mL) was added 4M HCl in 1,4-dioxane (2 mL, 8 mmol) at 0 ^oC and stirred at RT for 2 h. After completion of the reaction (monitored by TLC), volatiles were removed under reduced pressure. The residue was then stirred in diethyl ether (5 mL) and then with pentane (3 mL x 2), filtered, and the solid compound was dried under reduced pressure to afford desired compound 8 (0.120 g, 0.27 mmol, 83.49% yield) as a pale yellow solid. The resulting crude obtained was used in the next step without further purification as an HCl salt. LC-MS: Ret. Time: 0.89 min, MS calcd. for Chemical Formula: C19H19FN4O: 338.39; Found: 339.40 [M+H]⁺. X-select CSH 18 (3x50 mmx2.5mm); Mobile phase: A: 0.05% TFA in H₂O; B: 0.05% TFA in ACN; Injection volume: 2µL; Flow rate: 1mL/min; column temperature: 40 ^oC; Gradient program: 0% B, %Time/B: 0.0/2, 0.3/2, 2/98, 2.8/98, 3.0/2, 3.7/2. [1122] Step 5: Preparation of 7-fluoro-N-(4-(1-(2-hydroxy-2-methylpropanoyl)-1,2,3,6- tetrahydropyridin-4-yl)phenyl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide (I- 290): To a stirred solution of compound 8 (0.055 g, 0.147 mmol) and DIPEA (0.13 mL, 0.744 mmol) in DMF (2 mL) were added HATU (0.083 g, 0.22 mmol) and compound 9 (0.015 g, 0.147 mmol) at 0 ^oC, and then the mixture was stirred at RT for 16 h under nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ice cold water and extracted with EtOAc. The combined organic layers were washed with a brine solution, and then dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a sticky crude compound. The crude compound was purified by prep-HPLC purification to afford the title compound (I-290, 10.2 mg, 0.024 mmol, 16% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d6) δ: 8.55 - 8.48 (m, 3H), 7.55 (d, J = 8.8 Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H), 6.17 - 6.10 (m, 1H), 5.44 (s, 1H), 4.89 (d, J = 12.4 Hz, 4H), 4.19 - 3.95 (m, 2H), 2.57 - 2.53 (m, 2H), 2.48 - 2.45 (m, 2H), 1.34 (s, 6H). LC-MS: Ret time: 1.03 min, 99.37%; MS calcd. for Chemical Formula C23H25FN4O3: 424.47; Found: 425.54 [M+H]⁺. Column: CORTECS UPLC C18 (3x30) mm, 1.6um; Flow rate: 0.85 mL/min; Mobile Phase A: 0.05% formic acid in Water; Mobile Phase B: 0.05% formic acid in ACN; Injection volume: 2 µL; Column Temp.: 45 °C; Gradient Program %Time/B: 0.0/3, 0.1/3, 1.4/97, 2.0/97, 2.05/3, 2.5/3. HPLC: Ret time: 7.453 min, 98.43%; Method: Column: X-Select CSH C18 (4.6*150) mm 5u Mobile Phase: A - 0.1% TFA in water B – Acetonitrile, Inj Volume; 5.0µL, Flow Rate: 1.2 mL/minute Column Oven Temp.:30°C Gradient program: Time (min)/ B Conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. Prep-HPLC purification method: Column Name: X-BRIDGE C1830*250 mm, Mobile Phase A: 0.1% Formic Acid in Water, Mobile Phase B: Acetonitrile, Flow rate: 25 mL/min, Loading (mg/injection): 3, Gradient (Time/%B): 0/5,5,5/5,30/40,35/45,36/98, Sample Diluent: ACN+water+THF. [1123] Step 6: Preparation of 3-bromo-4-(dimethoxymethyl)-5-fluoropyridine (2b): To a stirred solution of 3-bromo-5-fluoro-pyridine-4-carbaldehyde (1a) (5 g, 24.51 mmol) in MeOH (40 mL) were added trimethyl orthoformate (11 mL, 98.04 mmol) and PTSA (0.43 g, 2.45 mmol) at 0 ^oC. The reaction was stirred at 80°C for 3 h. Progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was directly concentrated and then poured into water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to afford compound (2b) (5 g, 19.91 mmol, 81.22% yield) as a pale yellow oil. LC-MS: Ret. Time: 1.18 min, MS calcd. for Chemical Formula: C8H9BrFNO2: 250.07; found: 250.23 & 252.22 [M+H]⁺ (Br-pattern). X-select CSH 18 (3x50 mmx2.5mm); Mobile phase: A: 0.05% TFA in H₂O; B: 0.05% TFA in ACN; Injection volume: 2µL; Flow rate: 1 mL/min; column temperature: 40 ^oC; Gradient program: 0% B, %Time/B: 0.0/2, 0.3/2, 2/98, 2.8/98, 3.0/2, 3.7/2. [1124] Step 7: Preparation of 4-(dimethoxymethyl)-5-fluoronicotinaldehyde (4d): To a stirred solution of compound (2b) (4 g, 15.99 mmol) in dry THF (80 mL) was added dropwise a solution of butyl lithium (2.5 mol/L) in hexane (7.0 mL, 17.596 mmol) at -78°C under argon atmosphere, and the reaction was stirred at the same temperature for 1 h (dark brown colour observed). To this was added dropwise N,N-dimethylformamide (3c) (12 mL, 159.96 mmol) at - 78°C, and then the mixture was stirred at the same temperature for an additional 1 h under argon atmosphere. Progress of the reaction was monitored by TLC. The reaction mixture was quenched by an ice cold aqueous saturated NH₄Cl solution (150 mL) and extracted with EtOAc (100 mL X 3). The combined organics were washed with brine (150 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give compound (4d) (3.1 g, 16 mmol, 97% yield) as a brown viscous oil.¹H NMR (400 MHz, CHLOROFORM-d) δ: 10.58 - 10.57 (m, 1H), 8.85 (s, 1H), 8.58 (d, J = 1.3 Hz, 1H), 5.64 (s, 1H), 3.45 (s, 6H). [1125] Step 8: Preparation of 5-fluoropyridine-3,4-dicarbaldehyde (5e): To a single necked 25 mL RBF was added compound (4d) (1.5 g, 7.5 mmol), followed by dropwise addition of a solution of HBr in acetic acid (20 mL, 110 mmol, 33%) at 0°C. The mixture was stirred at RT for 15 min. After completion of the reaction (monitored by TLC), the reaction mixture was directly concentrated under reduced pressure to give a sticky crude, which was co-evaporated with toluene and dried over under rotoevaporation to give compound (5e) (1.1 g, 7.18 mmol, 95% yield) as a brown sticky liquid. LC-MS: Ret. Time: 0.72 min, MS calcd. for Chemical Formula: C₇H₄FNO₂: 153.11; found: 153.9 [M+H]⁺. Column: X-Select CSH C18, (50mm*3.0mm,2.5µ), Mobile Phase A: 0.05% Formic Acid in Water, Mobile Phase B: 0.05% Formic Acid in Acetonitrile, Flow rate: 1.0mL/min., Column temperature: 40 °C, Gradient Program (B%) :0.01/2, 0.3/2, 2.0/98, 2.8/98, 3.0/2,3.7/2. [1126] Step 9: Preparation of (5-fluoropyridine-3,4-diyl)dimethanol (6f): To a stirred solution of compound (5e) (1.1 g, 7.18 mmol) in MeOH (70 mL) was added portion-wise NaBH₄ (1.3 g, 34 mmol) at 0 °C, then the mixture was stirred at RT for 16 h. After completion of the reaction (monitored by TLC), The reaction mass was quenched with ice-cold water (4 mL) and concentrated under reduced pressure to give the semi solid crude compound, which was diluted in MeOH (100 mL), filtered (NaBH₄ salt separated out), and the filtrate was concentrated under vacuum to give crude compound (6f) (1.1 g, 7.00 mmol, 97.51% yield) as a brown solid. LC-MS: Ret. Time: 0.33 min, MS calcd. for Chemical Formula: C7H8FNO2: 157.14; found: 158.0 [M+H]⁺. Column: X-Select CSH C18, (50mm*3.0mm, 2.5µ), Mobile Phase A: 0.05% Formic Acid in Water, Mobile Phase B: 0.05% Formic Acid in Acetonitrile, Flow rate: 1.0 mL/min., Column temperature: 40 °C, Gradient Program (B%): 0.01/2, 0.3/2, 2.0/98, 2.8/98, 3.0/2,3.7/2. [1127] Step 10: Preparation of 3,4-bis(chloromethyl)-5-fluoropyridine (7g): To a stirred solution of compound (6f) (1 g, 6.36 mmol) in DCM (16 mL) was added drop-wise SOCl₂ (7.00 mL, 95.45 mmol) at 0°C. Then the mixture was stirred at 45°C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was directly concentrated under reduced pressure to remove excess of thionyl chloride. Then to this was added slowly an ice-cold saturated NaHCO3 solution (50 mL; pH~8) and then the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give compound (7g) (0.6 g, 3.12 mmol, 49.00% yield) as a brown sticky mass. LC- MS: Ret. Time: 1.24 min, MS calcd. for Chemical Formula: C7H6Cl2FN: 194.03; found: 194.13 [M+H]⁺. X-select CSH 18 (3x50 mmx2.5mm); Mobile phase: A: 0.05% TFA in H2O; B: 0.05% TFA in ACN; Injection volume: 2µL; Flow rate: 1mL/min; column temperature: 40 ^oC; Gradient program: 0% B, %Time/B: 0.0/2, 0.3/2, 2/98, 2.8/98, 3.0/2, 3.7/2. [1128] Step 11: Preparation of (2,4-dimethoxybenzyl)-7-fluoro-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine (9i): To a stirred solution of compound (7g) (0.6 g, 3.09 mmol) in DCM (40 mL) was added compound (8h) (0.336 g, 2.01 mmol) followed by drop-wise addition of DIPEA (0.65 mL, 3.7 mmol) at 0 ^oC and the mixture was stirred at RT for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was directly concentrated under reduced pressure. The crude compound was purified by CombiFlash (Nexgen-300) chromatography (12 g cartridge silica gel) using 18-25% EtOAc in n-heptane as an eluent to afford compound (9i) (0.3 g, 1.04 mmol, 33.51% yield) as a brown sticky mass. LC-MS: Ret. Time: 1.462 min, MS calcd. for Chemical Formula: C16H17FN2O2: 288.32; found: 288.9 [M+H]⁺. Column: X-Select CSH C18, (50mm*3.0mm,2.5µ), Mobile Phase A: 0.05% Formic Acid in Water, Mobile Phase B: 0.05% Formic Acid in Acetonitrile, Flow rate: 1.0mL/min., Column temperature: 40 °C, Gradient Program (B%) :0.01/2, 0.3/2, 2.0/98, 2.8/98, 3.0/2,3.7/2. [1129] Step 12: Preparation of 7-fluoro-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine (6): A Teflon-lined screw cap sealed tube was charged with compound (9i) (0.22 g, 0.763 mmol). To this was added slowly TFA (13 mL) at 0°C, then the mixture was stirred at 90 °C for 16 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was directly concentrated under reduced pressure to give a brown sticky crude. To the crude was added EtOAc (4 mL) and 4 M HCl in 1,4-dioxane (3 mL) at 0°C, and then the mixture was stirred at RT for 30 min. The precipitated solid was filtered out and washed with EtOAc (4 mL), then dried under vacuum to give compound 6 (0.1 g, 0.723 mmol, 94.8% yield) as a brown solid (100 mg salt form). LC-MS: Ret. Time: (0.199 min, MS calcd. for Chemical Formula: C₇H₇FN₂: 138.15; found: 139.18 [M+H]⁺. Column: CORTECS UPLC C18 (3x30) mm, 1.6um; Flow rate: 0.85 mL/min; Mobile Phase A: 0.05% formic acid in Water; Mobile Phase B: 0.05% formic acid in ACN; Injection volume: 2 µL; Column Temp.: 45 °C; Gradient Program %Time/B: 0.0/3, 0.1/3, 1.4/97, 2.0/97, 2.05/3, 2.5/3. EXAMPLE 131 - SYNTHESIS OF ADDITIONAL COMPOUNDS [1130] General: All reactions were performed under an atmosphere of nitrogen. Nuclear magnetic resonance (NMR) spectra were obtained using a Bruker 300 MHz spectrometer in the indicated solvents. Splitting patterns are indicated as follows: s, singlet; d, doublet; t, triplet; m, multiplet; and brs, broad singlet. All LCMS analyses were performed using Waters 2695 Liquid Chromatography (LC) system with 2996 PDA & Waters Micro mass ZQ ESCi Multimode Ionization. The MS was operated with an electro-spray ionization source (ESI) in both positive & negative ion mode. All the HPLC analyses were performed using Waters, Model: e2695. [1131] The following LCMS method was used: Column: X Bridge C18 4.6*50mm*3.5um; Mobile Phase- A: 10 mm Ammonium Acetate B: 100% ACN; Gradient (time/%B): 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; Flow rate: 0.6mL/min. [1132] The following HPLC method was used: Column: X Bridge C184.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH₃CN; Flow rate: 1.2 mL/min; Diluent: Methanol (100%). [1133] The following general procedures were used: [1134] General Procedure-A: Preparation of Phenyl Carbamates: To a stirred solution of amine compound (1.0 eq) in THF was added DIPEA (2.5 eq), and phenyl chloroformate (1.2 eq) at 0 °C. After addition, the reaction mixture was stirred at 0 °C for 30 min and RT for 2 h. The reaction mixture was poured into ice-cold water and the precipitate was filtered and dried to provide the desired carbamate. [1135] General Procedure-B: Preparation of Ureas from Phenyl Carbamates: Substituted isoindoline (1.1 eq) was added to a solution of phenyl carbamate (1.0 eq) and DIPEA (5.0 eq) in THF at ambient temperature. The reaction mixture was stirred at 70^oC for 16 h. The volatiles were removed, and the reaction mixture was poured into ice-cold water and stirred for 10 min. The precipitate was filtered and dried to obtain the desired urea. [1136] General Procedure-C: Deprotection of Boc Group: To a stirred solution of Boc- intermediate (1.0 eq) in DCM was added HCl (5.0 eq, 4.0N in 1,4-dioxane) at 0^oC, then the mixture was stirred at RT for 2 h. The volatiles were removed under reduced pressure, and then the reaction mixture was basified with NaHCO3, and the precipitate was filtered and dried to provide the amine compound. [1137] General Procedure-D: Final Acid-Amine coupling: A stirred solution of amine derivative (1.0 eq) in DMF was added acid derivative (2.0 eq), EDCI (2.0 eq), HOBt (2.0 eq), and triethylamine (5.0 eq) at RT and the mixture was stirred at RT for 16 h. After complete consumption of the starting material, the reaction mixture was diluted with ice-cold water, the precipitate was filtered, washed with water and dried to obtain the desired amide. [1138] General Procedure-E: Hydrolysis of Ester Group: To a stirred solution of ester compound (1.0 eq) in a mixture of THF: MeOH: H₂O (2:1:1) was added lithium hydroxide (5.0 eq) at RT and the mixture was stirred for 16 h. After completion of the reaction, the reaction mixture was diluted with ice-cold water and acidified to pH~2-3 with 1.0N HCl. The precipitate was filtered and dried to provide the desired acid compound. [1139] General Procedure-F: Preparation of Oxoacetates: To a stirred solution of amine compound (1 eq.) in DMF was added DIPEA (2 eq.) and methyl 2-chloro-2-oxoacetate (1.1 eq.) at RT and the mixture was stirred for 6 h. The reaction was monitored by TLC. After complete consumption of the starting material, the reaction was diluted with water and extracted with EtOAc. The separated organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain crude. The crude was purified by flash chromatography to provide to desired oxo acetate. [1140] General Procedure G: Preparation of Unsymmetrical Oxalamides: To a stirred solution of oxoacetate compound (1 eq.) in MeOH was added TEA (10 eq.) and amine compound (1.5 eq.). The reaction was heated to 70-80 ^oC for 16 h. The reaction was monitored by TLC. After complete consumption of the starting material, the volatiles were removed under reduced pressure to obtain the crude residue, which was diluted with water and stirred for 10 min. The obtained solid was filtered and dried to obtain the crude product. The product was purified by flash chromatography to provide the desired compound. [1141] Synthetic Intermediates: The following intermediates were used in the chemical syntheses below. These intermediates were prepared according to the indicated example number. Part A - Preparation of N-(4-(4-((2-hydroxy-2-methylpropyl)carbamoyl)bicyclo[2.2.2] octan-1-yl)phenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxamide (I-428) [1142] Step 1: Preparation of methyl 4-(4-(5,6-dihydro-4H-pyrrolo [3,4-d] thiazole-5- carboxamido) phenyl) bicyclo [2.2.2] octane-1-carboxylate (2): 2 was prepared according to general procedure B, using G-Int-6 (200 mg, 0.659 mmol). The product was obtained after solid filtration, which afforded 200 mg of 2 (92% yield) as an off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.30 (s, 1H), 7.44 (d, J = 8.7 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H), 4.74 (d, J = 2.1 Hz, 2H), 4.68 (d, J = 3.5 Hz, 2H), 3.59 (s, 3H), 1.86 - 1.74 (m, 12H). LC-MS: [M+H] ⁺ = 412.1. [1143] Step 2: Preparation of 4-(4-(5,6-dihydro-4H-pyrrolo [3,4-d] thiazole-5- carboxamido) phenyl) bicyclo [2.2.2] octane-1-carboxylic acid (3): 3 was prepared according to general procedure E, using 2 (200 mg, 0.48 mmol). The product was obtained after solid filtration, which afforded 190 mg of 3 (98% yield) as an off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ 12.03 (s, 1H), 9.11 (s, 1H), 8.30 (s, 1H), 7.43 (d, J = 8.7 Hz, 2H), 7.21 (d, J = 8.7 Hz, 2H), 4.75 (s, 2H), 4.68 (s, 2H), 1.78 (s, 12H). LC-MS: [M+H] ⁺ = 398.15. [1144] Step 3: Preparation of N-(4-(4-((2-hydroxy-2-methylpropyl)carbamoyl) bicyclo[2.2.2] octan-1-yl)phenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxamide: I- 428 was prepared according to general procedure D using 3 (200 mg, 0.50 mmol). The product was obtained after solid filtration, which afforded 175 mg (74% yield) of I-428 as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.30 (s, 1H), 7.44 (d, J = 8.7 Hz, 2H), 7.22 (d, J = 8.8 Hz, 2H), 7.11 (t, J = 6.1 Hz, 1H), 4.79 - 4.65 (m, 4H), 4.54 (s, 1H), 3.05 (d, J = 6.1 Hz, 2H), 1.78 (s, 12H), 1.02 (s, 6H). LCMS: 469.39 (M+H), Purity- 94.43% by AUC, RT- 4.23, UV- 245 nm. HPLC: Purity- 94.35% by AUC, RT- 7.44, UV- 245 nm. Part B - Preparation of N-(4-(4-((2-hydroxy-2-methylpropyl)carbamoyl)bicyclo[2.2.2] octan-1-yl)phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide (I-427) [1145] Step 1: Preparation of methyl 4-(4-(6,7-dihydro-5H-pyrrolo [3,4-b] pyridine-6- carboxamido) phenyl) bicyclo [2.2.2] octane-1-carboxylate (2): 2 was prepared according to general procedure B, using G-Int-6 (250 mg, 0.66 mmol). The product was obtained after solid filtration, which afforded 180 mg (67% yield) of 2 as an off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ 8.47 (d, J = 4.6 Hz, 1H), 8.32 (s, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.32 (dd, J = 4.9, 7.6 Hz, 1H), 7.21 (d, J = 8.7 Hz, 2H), 4.76 (d, J = 3.5 Hz, 4H), 3.60 (s, 3H), 1.87 - 1.70 (m, 12H). LC-MS: [M+H] ⁺ = 406.13. [1146] Step 2: Preparation of 4-(4-(6,7-dihydro-5H-pyrrolo [3,4-b] pyridine-6- carboxamido) phenyl) bicyclo [2.2.2] octane-1-carboxylic acid (3): 3 was prepared according to general procedure E using 2 (0.21 g, 0.52 mmol). The product was obtained after solid filtration, which afforded 200 mg of 3 as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 12.02 (s, 1H), 8.47 (d, J = 4.2 Hz, 1H), 8.32 (s, 1H), 7.80 (d, J = 7.5 Hz, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.37 - 7.29 (m, 1H), 7.21 (d, J = 8.7 Hz, 2H), 4.76 (d, J = 3.2 Hz, 4H), 1.78 (s, 12H)LC-MS: [M+H] ⁺ = 392.15. [1147] Step 3: Preparation of N-(4-(4-((2-hydroxy-2-methylpropyl)carbamoyl)bicyclo [2.2.2]octan-1-yl)phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide: I-427 was prepared according to general procedure D using 3 (200 mg, 0.51 mmol). The product was obtained after solid filtration, which afforded 170 mg (72% yield) of I-427 as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.48 (d, J = 4.6 Hz, 1H), 8.32 (s, 1H), 7.80 (d, J = 7.2 Hz, 1H), 7.46 (d, J = 8.8 Hz, 2H), 7.37 - 7.28 (m, 1H), 7.22 (d, J = 8.3 Hz, 2H), 7.11 (t, J = 5.7 Hz, 1H), 4.75 (s, 4H), 4.54 (s, 1H), 3.05 (d, J = 5.9 Hz, 2H), 1.78 (s, 12H), 1.02 (s, 6H). LCMS: 463.2 (M+H), Purity- 95.66% by AUC, RT- 3.75, UV-245 nm. HPLC: Purity- 95.44% by AUC, RT- 7.33, UV- 245 nm. Part C - Preparation of 5-fluoro-N-(2-fluoro-4-(4-((2-hydroxy-2-methylpropyl) carbamoyl) bicyclo[2.2.2]octan-1-yl)phenyl)isoindoline-2-carboxamide (I-232) & Methyl 4-(3-fluoro-4- (5-fluoroisoindoline-2-carboxamido)phenyl)bicyclo[2.2.2]octane-1-carboxylate (I-230) [1148] Step 1: Preparation of methyl 4-(3-fluoro-4-(5-fluoroisoindoline-2-carboxamido) phenyl) bicyclo [2.2.2] octane-1-carboxylate: To a stirred solution of I-231 (500 mg, 1.23 mmol) in nitromethane: water (10 mL, 1:1) was added Selectflour (653 mg, 1.84 mmol) at 0^oC, and then the reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC and LCMS. After complete consumption of the starting material, the reaction mixture was quenched with water and extracted with EtOAc (2x30 mL). The combined organic extracts were dried with Na2SO4, filtered and concentrated to give the crude. The product was purified by column chromatography and eluted with EtOAc to obtain 170 mg of I-230 as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ = 8.04 (s, 1H), 7.50 - 7.34 (m, 2H), 7.23 (dd, J = 2.2, 9.2 Hz, 1H), 7.19 - 7.04 (m, 3H), 4.74 (s, 2H), 4.70 (s, 2H), 3.59 (s, 3H), 1.80 (s, 14H). LC-MS: [M+H] ⁺ = 441.27 (M+H), Purity- 99.08% by AUC, RT- 6.03, UV-260 nm. HPLC: Purity- 94.79% by AUC, RT- 16.57, UV- 240 nm. [1149] Step 2: Preparation of 4-(3-fluoro-4-(5-fluoroisoindoline-2-carboxamido) phenyl) bicyclo [2.2.2] octane-1-carboxylic acid (1): 1 was prepared according to general procedure E, using I-230 (150 mg, 0.34 mmol). The product was obtained after solid filtration, which afforded 50 mg of 1 as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 12.04 (s, 1H), 8.04 (s, 1H), 7.48-7.34 (m, 2H), 7.25-7.08 (m, 4H), 4.74 (s, 1H), 4.71 (s, 2H), 1.79 (s, 12H). LC-MS: [M+H] ⁺ = 427.23 (M+H), Purity- 98.67% by AUC, RT- 4.68, UV-260 nm. [1150] Step 3: Preparation of 5-fluoro-N-(2-fluoro-4-(4-((2-hydroxy-2-methylpropyl) carbamoyl) bicyclo [2.2.2] octan-1-yl) phenyl) isoindoline-2-carboxamide: I-232 was prepared according to general procedure D using 1 (45 mg, 0.105 mmol). The product was obtained after solid filtration, which was afforded 25 mg (48% yield) of I-232 as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.04 (s, 1H), 7.50-7.34 (m, 2H), 7.23 (dd, J = 2.3, 9.0 Hz, 1H), 7.19-7.05 (m, 4H), 4.74 (s, 2H), 4.72-4.68 (m, 2H), 4.54 (s, 1H), 3.04 (d, J = 6.0 Hz, 2H), 1.78 (s, 12H), 1.02 (s, 6H). LC-MS: [M+H] ⁺ = 498.34 (M+H), Purity- 99.14% by AUC, RT- 5.08, UV-260 nm. HPLC: Purity- 92.46% by AUC, RT- 14.29, UV- 240 nm. Part D - Preparation of methyl 4-(4-(isoindoline-2-carboxamido)phenyl) bicyclo[2.2.2] octane-1-carboxylate (I-229), methyl 4-(3-fluoro-4-(isoindoline-2-carboxamido)phenyl) bicyclo[2.2.2]octane-1-carboxylate (I-209), & N-(2-fluoro-4-(4-((2-hydroxy-2-methylpropyl) carbamoyl)bicyclo[2.2.2]octan-1-yl)phenyl)isoindoline-2-carboxamide (I-201) [1151] Step 1: Preparation of methyl 4-(4-(isoindoline-2-carboxamido) phenyl) bicyclo [2.2.2] octane-1-carboxylate: I-229 was prepared according to general procedure B, using G-Int- 6 (3.5 g, 9.23 mmol). The product was obtained after solid filtration, which afforded 2.8 g of I- 229 (75% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.27 (s, 1H), 7.49-7.42 (m, 2H), 7.38-7.28 (m, 4H), 7.25-7.14 (m, 2H), 4.75 (s, 4H), 3.59 (s, 3H), 1.88-1.71 (m, 12H). LC- MS: [M+H] ⁺ = 405.24 (M+H), Purity- 99.99% by AUC, RT- 5.90, UV-260 nm. [1152] Step 2: Preparation of methyl 4-(3-fluoro-4-(isoindoline-2-carboxamido) phenyl) bicyclo [2.2.2] octane-1-carboxylate: To a stirred solution of I-229 (1.5 g, 3.74 mmol) in nitromethane: water (30 mL, 1:1) was added to Selectflour (3.97 g, 11.22 mmol) at 0^oC, and then the reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC and LCMS. After complete consumption of the starting material, the reaction mixture was quenched with water and extracted with EtOAc (2x30 mL). The combined organic extracts were dried with Na2SO4, filtered and concentrated to give the crude. The product was triturated with MTBE (30 mL) to obtain 1.0 g of I-209 as off white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.02 (s, 1H), 7.46 (t, J = 8.6 Hz, 1H), 7.39-7.27 (m, 4H), 7.19-7.04 (m, 2H), 4.75 (s, 4H), 3.60 (s, 3H), 1.86- 1.76 (m, 12H). LC-MS: [M+H] ⁺ = 423.26 (M+H), Purity- 98.60% by AUC, RT- 6.03, UV-260 nm. HPLC: Purity- 96.74% by AUC, RT- 16.88, UV- 240 nm. [1153] Step 3: Preparation of 4-(3-fluoro-4-(isoindoline-2-carboxamido) phenyl) bicyclo [2.2.2] octane-1-carboxylic acid (2): 2 was prepared according to general procedure E using I- 209 (80 mg, 0.18 mmol). The product was obtained after solid filtration, which afforded 60 mg of 2 (78% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 12.10 (s, 1H), 8.01 (s, 1H), 7.46 (t, J = 8.5 Hz, 1H), 7.39 - 7.28 (m, 5H), 7.18 - 7.07 (m, 2H), 4.75 (s, 4H), 1.78 (s, 12H). LC- MS: [M+H] ⁺ = 409.28 (M+H), Purity- 99.68% by AUC, RT- 4.60, UV-260 nm. [1154] Step 4: Preparation of N-(2-fluoro-4-(4-((2-hydroxy-2-methyl propyl) carbamoyl) bicyclo [2.2.2] octan-1-yl) phenyl) isoindoline-2-carboxamide: I-201 was prepared according to general procedure D using 2 (50 mg, 0.105 mmol). The product was obtained after solid filtration, which afforded 10 mg (17% yield) of I-201 as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.46 (t, J = 8.3 Hz, 1H), 7.40-7.26 (m, 4H), 7.18-7.05 (m, 3H), 4.75 (s, 4H), 4.54 (s, 1H), 3.04 (d, J = 5.8 Hz, 2H), 1.88-1.64 (m, 12H), 1.02 (s, 6H). LC-MS: [M+H] ⁺ = 480.33 (M+H), Purity- 98.67 % by AUC, RT- 5.03, UV-260 nm. HPLC: Purity- 95.45% by AUC, RT- 14.31, UV- 240 nm. Part E - Compounds Prepared Using General Procedure D [1155] The following final compounds were prepared by coupling the indicated carboxylic acid and amine intermediates using general procedure D above.

Part F - Preparation of 5-fluoro-N-(4-(4-(3-(2-fluoroethyl)ureido)bicyclo[2.2.2]octan-1- yl)phenyl)isoindoline-2-carboxamide (I-318) [1156] I-318 was prepared according to general procedure B, using 1 (130 mg, 0.26 mmol). The product was purified by column chromatography (eluent-0-2% MeOH in DCM) which afforded 30 mg of I-318 (24% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.27 (s, 1H), 7.46-7.34 (m, 3H), 7.26-7.08 (m, 4H), 5.89 (t, J = 5.7 Hz, 1H), 5.70 (s, 1H), 4.73 (s, 2H), 4.71 (s, 2H), 4.44 (t, J = 5.0 Hz, 1H), 4.28 (t, J = 5.0 Hz, 1H), 3.31-3.15 (m, 2H), 1.95-1.73 (m, 12H). LCMS: 469.24 (M+H), Purity- 94.45% by AUC, RT- 5.13, UV-245 nm. HPLC: Purity- 90.30% by AUC, RT- 14.43, UV- 250 nm. [1157] The following final compounds were prepared by coupling the indicated carbamate and amine intermediates using the above procedure.

Part G - Preparation of 3-fluoro-N-(4-(4-(3-(3-hydroxy-3-methylbutyl)ureido)bicyclo [2.2.2]octan-1-yl)phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide (I-185) [1158] Step 1: Preparation of phenyl (4-(4-(3-fluoro-6,7-dihydro-5H-pyrrolo [3,4-b] pyridine-6-carboxamido) phenyl) bicyclo [2.2.2] octan-1-yl) carbamate (1): To a stirred solution of K-Int-9 (115 mg, 0.303 mmol) in THF (5 mL) was added DIPEA (0.13 mL, 0.758 mml) and phenyl chlorochromate (0.047 mL) at RT 0 ^oC. The reaction was stirred at RT for 3 h. The reaction was monitored by TLC. After the complete consumption of the starting material, the reaction was diluted with EtOAc and washed with water. The separated organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude. The crude was triturated with n-pentane to afford 140 mg (92% yield) of 1 as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.34 (s, 1H), 7.79 (dd, J = 2.6, 8.9 Hz, 1H), 7.54 (s, 1H), 7.44 (d, J = 8.7 Hz, 2H), 7.41 - 7.32 (m, 2H), 7.25 - 7.15 (m, 3H), 7.13 - 7.05 (m, 2H), 4.77 (s, 2H), 4.72 (s, 2H), 1.97 - 1.89 (m, 6H), 1.88 - 1.81 (m, 6H). LCMS: 501.24 (M+H), Purity- 94.48% by AUC, RT- 5.53, UV-245 nm. [1159] Step 2: Preparation of 3-fluoro-N-(4-(4-(3-(3-hydroxy-3-methylbutyl) ureido) bicyclo [2.2.2] octan-1-yl) phenyl)-5,7-dihydro-6H-pyrrolo [3,4-b] pyridine-6-carboxamide: A sealed tube containing a mixture of 1 (140 mg, 0.279 mmol), 2 (172 mg, 1.67 mmol) and TEA (0.58 mL, 4.18 mmol) in THF (2 mL) was heated 65 ^oC for 24 h. The reaction was monitored by TLC. After complete consumption of the starting material, the reaction was cooled to RT and the volatiles were removed under reduced pressure to obtain the crude. The crude was purified by flash chromatography and eluted with 0-5% MeOH in DCM to afford 40 mg (44% yield) of I-185 as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.33 (s, 1H), 7.79 (dd, J = 2.4, 9.0 Hz, 1H), 7.43 (d, J = 8.7 Hz, 2H), 7.20 (d, J = 8.8 Hz, 2H), 5.54 (s, 2H), 4.77 (s, 2H), 4.72 (s, 2H), 4.25 (s, 1H), 3.05 - 2.95 (m, 2H), 1.82 (d, J = 4.2 Hz, 12H), 1.47 - 1.37 (m, 2H), 1.08 (s, 6H). LCMS: 510.40 (M+H), Purity- 99.53% by AUC, RT- 4.52, UV-245 nm. HPLC: Purity- 99.45% by AUC, RT- 2.10, UV- 245 nm. Part H - Preparation of 4,5,6-trifluoro-N-(4-(4-(3-(2-hydroxy-2-methylpropyl)ureido) bicyclo[2.2.2]octan-1-yl)phenyl)isoindoline-2-carboxamide (I-319), 4,5,6-trifluoro-N-(4-(4- (3-(2-fluoroethyl)ureido)bicyclo[2.2.2]octan-1-yl)phenyl)isoindoline-2-carboxamide (I-283), & 4,5,6-trifluoro-N-(4-(4-(3-((tetrahydro-2H-pyran-4-yl)methyl)ureido)bicyclo[2.2.2]octan- 1-yl)phenyl)isoindoline-2-carboxamide (I-282)

[1160] Step 1: Preparation of benzyl (4-(4-(4,5,6-trifluoroisoindoline-2-carboxamido) phenyl) bicyclo [2.2.2] octan-1-yl) carbamate (2): 2 was prepared according to general procedure B using K-Int-6 (2.0 g, 4.25 mmol). The product was obtained after solid filtration, which afforded 1.7 g (74% yield) of 2 as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.45 - 7.27 (m, 8H), 7.19 (d, J = 8.7 Hz, 2H), 7.01 (s, 1H), 4.96 (s, 2H), 4.82 (s, 2H), 4.74 (s, 2H), 1.92 - 1.75 (m, 12H). LCMS: 550.59 (M+H). [1161] Step 2: Preparation of N-(4-(4-aminobicyclo [2.2.2] octan-1-yl) phenyl)-4,5,6- trifluoroisoindoline-2-carboxamide (3): To a stirred solution of 2 (1.93 g, 3.762 mmol) in a methanol (50 mL) was added Pd/C (850 mg 50% wet) at RT under H₂ atmosphere. The reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a celite pad, the pad was washed with 10% MeOH in DCM (200 mL), and the filtrate was concentrated under reduced pressure. The resulting precipitate was washed with MTBE, filtered, and dried to obtain the 1.2 g of 3 (93% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.45 - 7.32 (m, 3H), 7.19 (d, J = 8.7 Hz, 2H), 4.82 (s, 2H), 4.74 (s, 2H), 1.84 - 1.49 (m, 12H). LCMS: 416.46 (M+H). [1162] Step 3: Preparation of phenyl (4-(4-(4,5,6-trifluoroisoindoline-2-carboxamido) phenyl) bicyclo [2.2.2] octan-1-yl) carbamate (4): 4 was prepared according to general procedure A using 3 (1.5 g, 3.62 mmol). The product was obtained after solid filtration, which afforded 1.5 g (77% yield) of 4 as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.38 (s, 1H), 7.55 (s, 1H), 7.47 - 7.32 (m, 5H), 7.25 - 7.15 (m, 3H), 7.07 (d, J = 7.6 Hz, 2H), 4.83 (s, 2H), 4.74 (s, 2H), 2.02 - 1.74 (m, 12H). LCMS: 536.57 (M+H). [1163] Step 4: Preparation of 4,5,6-trifluoro-N-(4-(4-(3-(2-hydroxy-2-methyl propyl) ureido) bicyclo [2.2.2] octan-1-yl) phenyl) isoindoline-2-carboxamide: I-319 was prepared according to general procedure B, using 4 (100 mg, 0.2 mmol). The product was obtained after solid filtration, which afforded 30 mg (30% yield) of I-319 as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.46-7.36 (m, 3H), 7.23-7.14 (m, 2H), 5.79 (s, 1H), 5.69 (t, J = 5.7 Hz, 1H), 4.83 (s, 2H), 4.78-4.69 (m, 2H), 4.45 (s, 1H), 2.88 (d, J = 5.8 Hz, 2H), 1.82 ( d, J = 4.9 Hz, 12H), 1.02 (s, 6H). LCMS: 531.35 (M+H), Purity- 92.76% by AUC, RT- 5.20, UV-245 nm. HPLC: Purity- 92.78% by AUC, RT- 14.55, UV- 250 nm. [1164] Step 5: Preparation of 4,5,6-trifluoro-N-(4-(4-(3-(2-fluoroethyl) ureido) bicyclo [2.2.2] octan-1-yl) phenyl) isoindoline-2-carboxamide: I-283 was prepared according to general procedure B using 4 (100 mg, 0.2 mmol). The product was obtained after solid filtration, which afforded 40 mg (42% yield) of I-283 as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.47 - 7.36 (m, 3H), 7.19 (d, J = 8.8 Hz, 2H), 5.90 (t, J = 5.8 Hz, 1H), 5.71 (s, 1H), 4.83 (s, 2H), 4.74 (s, 2H), 4.44 (t, J = 5.0 Hz, 1H), 4.28 (t, J = 5.0 Hz, 1H), 3.32 - 3.15 (m, 2H), 1.96 - 1.72 (m, 12H). LCMS: 505.27 (M+H), Purity- 98.06% by AUC, RT- 5.35, UV-245 nm. HPLC: Purity- 93.93% by AUC, RT- 15.18, UV- 250 nm. [1165] Step 6: Preparation of 4,5,6-trifluoro-N-(4-(4-(3-((tetrahydro-2H-pyran-4-yl) methyl) ureido) bicyclo [2.2.2] octan-1-yl) phenyl) isoindoline-2-carboxamide: I-282 was prepared according to general procedure B using 4 (100 mg, 0.2 mmol). The product was obtained after solid filtration, which afforded 35 mg (34% yield) of I-282 as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.37 (s, 1H), 7.45-7.37 (m, 3H), 7.19 (d, J = 8.8 Hz, 2H), 5.82-5.42 (m, 2H), 4.83 (s, 2H), 4.74 (s, 2H), 3.95-3.82 (m, 2H), 3.31-3.18 (m, 2H), 2.83 (d, J = 6.0 Hz, 2H), 1.90-1.73 (m, 12H), 1.55-1.44 (m, 3H), 1.20-1.02 (m, 2H). LCMS: 557.43 (M+H), Purity- 98.87% by AUC, RT- 5.38, UV-245 nm. HPLC: Purity- 94.99% by AUC, RT- 15.06, UV- 250 nm.

Part - Preparation of 3-fluoro-N-(4-(1-((2-hydroxy-2-methylpropyl)sulfonyl)piperidin-4- yl)phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide (I-391) [1166] Step 1: Preparation of N-(4-(1-((2-(benzyloxy)-2-methylpropyl) sulfonyl) piperidin-4-yl) phenyl)-3-fluoro-5,7-dihydro-6H-pyrrolo[3,4-b] pyridine-6-carboxamide (1): To a stirred solution of B-Int-5 (100 mg, 0.29 mmol) in DMF (5 mL) was added triethyl amine (0.08 mL, 0.58 mmol), and R-Int-6 (126 mg, 0.35 mmol) at RT under N2 atmosphere. The reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice-cold water, and extracted with 10% MeOH-DCM, the combined organic extracts were dried over Na2SO4, and concentrated under reduced pressure to afford the crude product. The product was purified by column chromatography (eluent-0-2% MeOH in DCM) which afforded 70 mg of 1 (42% yield) as an off- white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.37 (s, 1H), 7.79 (dd, J = 2.8, 9.0 Hz, 1H), 7.48-7.48 (m, 1H), 7.41-7.24 (m, 5H), 7.11 (d, J = 8.6 Hz, 2H), 4.77 (s, 2H), 4.73 (s, 2H), 4.49 (s, 2H), 3.67 (d, J = 11.9 Hz, 2H), 3.35-3.34 (m, 2H), 2.90-2.79 (m, 2H), 2.47-2.31 (m, 1H), 1.86-1.71 (m, 2H), 1.66-1.52 (m, 2H), 1.43 (s, 6H). LCMS: 567.69 (M+H). [1167] Step 2: Preparation of 3-fluoro-N-(4-(1-((2-hydroxy-2-methylpropyl) sulfonyl) piperidin-4-yl) phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b] pyridine-6-carboxamide: To a stirred solution of 1 (70 mg, 0.12 mmol) in a mixture of THF: MeOH (5 mL 1:1) was added Pd/C (20 mg 50% wet) at RT under H2 (150 Psi) in a steel bomb. The reaction mixture was stirred at 80^oC for 4 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a celite pad and the pad washed with 50% MeOH-THF, and the filtrate was concentrated under reduced pressure to afford the crude product. The product was purified by column chromatography (eluent-0-5% MeOH in DCM) which afforded 20 mg of I- 391 (34% yield) as a white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.37 (s, 1H), 7.79 (dd, J = 2.7, 8.9 Hz, 1H), 7.48 (d, J = 8.6 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 4.82 (s, 1H), 4.77 (s, 2H), 4.73 (s, 2H), 3.72-3.63 (m, 2H), 3.10 (s, 2H), 2.92-2.80 (m, 2H), 2.59-2.53 (m, 1H), 1.89- 1.78 (m, 2H), 1.70-1.53 (m, 2H), 1.31 (s, 6H). LC-MS: [M+H] ⁺ = 477.18 (M+H), Purity- 93.07% by AUC, RT- 4.53, UV-260 nm. HPLC: Purity- 91.41% by AUC, RT- 9.77, UV- 240 nm. Part J - Preparation of 3-fluoro-N-(4-(1-((2-hydroxy-2-methylpropyl)sulfonyl)-1,2,3,6- tetrahydropyridin-4-yl)phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide (I- 321) [1168] Step 1: Preparation of N-(4-(1-((2-(benzyloxy)-2-methylpropyl) sulfonyl)-1,2,3, 6- tetrahydropyridin-4-yl) phenyl)-3-fluoro-5,7-dihydro-6H-pyrrolo[3,4-b] pyridine-6- carboxamide (1): To a stirred solution of A-Int-7 (350 mg, 0.93 mmol) in DMF (5 mL) was added triethyl amine (0.39 mL, 2.80 mmol), and R-Int-6 (367 mg, 1.40 mmol) at RT under N2 atmosphere. The reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice- cold water, extracted with 10% MeOH-DCM, and the combined organic extracts were dried over Na₂SO₄ and concentrated under reduced pressure to afford the crude product. The product was purified by column chromatography (eluent-0-2% MeOH in DCM), which afforded 100 mg of 1 (19% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.48 (s, 2H), 7.85-7.76 (m, 1H), 7.57 (d, J = 8.8 Hz, 2H), 7.40-7.22 (m, 7H), 6.10 (s, 1H), 4.79 (s, 2H), 4.74 (s, 2H), 4.49 (s, 2H), 3.92-3.82 (m, 2H), 3.44-3.36 (m, 4H), 2.58-2.53 (m, 2H), 1.44 (s, 6H). LC-MS: [M+H] ⁺ = 565.68 (M+H). [1169] Step 2: Preparation of 3-fluoro-N-(4-(1-((2-hydroxy-2-methylpropyl) sulfonyl)- 1,2,3,6-tetrahydropyridin-4-yl) phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b] pyridine-6- carboxamide: To a stirred solution of 1 (30 mg, 0.05 mmol) in ACN (3 mL) was added TMS-I (21 mg 0.106 mmol) at 0°C under N2, then the reaction mixture was stirred at below 20^oC for 2 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with methanol and a sodium thiosulfate solution and extracted with 10% MeOH-DCM. The combined organic extracts were dried over Na2SO4, and concentrated under reduced pressure to afford the crude product. The product was purified by column chromatography (eluent-0-2% MeOH in DCM) which afforded 15 mg of I-321 (60% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.48 (s, 2H), 7.80 (dd, J = 2.6, 9.0 Hz, 1H), 7.57 (d, J = 8.8 Hz, 2H), 7.37 (d, J = 8.7 Hz, 2H), 6.13 (s, 1H), 4.84 (s, 1H), 4.79 (s, 2H), 4.74 (s, 2H), 3.92-3.86 (m, 2H), 3.40 (t, J = 4.8 Hz, 2H), 3.16 (s, 2H), 2.60-2.52 (m, 2H), 1.31 (s, 6H). LC-MS: [M+H] ⁺ = 475.21 (M+H), Purity- 98.94% by AUC, RT- 4.53, UV-260 nm. HPLC: Purity- 97.28% by AUC, RT- 13.07, UV- 240 nm. Part K - Preparation of 4,6-difluoro-N-(4-(1-((2-hydroxy-2-methylpropyl)sulfonyl)-1,2,3,6- tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide (I-213) [1170] Step 1: Preparation of tert-butyl 4-(4-(4,6-difluoroisoindoline-2-carboxamido) phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (2): 2 was prepared according to general procedure B using A-Int-4 (1.0 g, 2.53 mmol). The product was obtained after solid filtration, which afforded 1.0 g of 2 (87% yield) as a white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.47 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.7 Hz, 2H), 7.25-7.12 (m, 2H), 6.08 (s, 1H), 4.78 (s, 5H), 3.98 (s, 3H), 3.52 (t, J = 5.5 Hz, 3H), 2.44 (s, 2H), 1.42 (s, 9H). LC-MS: 456.27 [M+H] ⁺, Purity- 99.98% by AUC, RT- 6.15, UV-260 nm. [1171] Step 2: Preparation of 4,6-difluoro-N-(4-(1,2,3,6-tetrahydropyridin-4-yl) phenyl) isoindoline-2-carboxamide (3): 3 was prepared according to general procedure C, using 2 (1.0 g, 2.19 mmol). The product was obtained after basification with NaHCO3 and the precipitate was filtered and dried to obtain 700 mg of 3 (89% yield) as a white solid.¹H NMR (300 MHz, DMSO- d6) δ 9.00-8.90 (m, 2H), 8.55 (s, 1H), 7.60 (d, J = 8.9 Hz, 2H), 7.40 (d, J = 8.7 Hz, 2H), 7.25-7.14 (m, 2H), 6.16 (s, 1H), 4.79 (s, 4H), 3.78-3.70 (m, J = 1.7 Hz, 2H), 3.35-3.27 (m, 2H), 2.69-2.61 (m, 2H). LC-MS: 356.24 [M+H] ⁺, Purity- 99.57% by AUC, RT- 4.48, UV-260 nm. [1172] Step 3: Preparation of N-(4-(1-((2-(benzyloxy)-2-methylpropyl) sulfonyl)-1,2,3,6- tetrahydropyridin-4-yl) phenyl)-4,6-difluoroisoindoline-2-carboxamide (4): To a stirred solution of 3 (100 mg, 0.28 mmol) in DMF (4 mL) was added triethyl amine (85.5 mg, 0.84 mmol), and R-Int-6 (110.7 mg, 0.42 mmol) at RT under N2 atmosphere. The reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice-cold water, and extracted with 10% MeOH- DCM. The combined organic extracts were dried over Na₂SO₄ and concentrated under reduced pressure to afford the crude product. The product was purified by column chromatography (eluent- 0-2% MeOH in DCM) which afforded 80 mg of 4 (49% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.49 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.39-7.28 (m, 7H), 7.28-7.13 (m, 4H), 6.10 (s, 1H), 4.79 (s, 4H), 4.48 (s, 2H), 3.89 (s, 2H), 3.43-3.37 (m, 3H), 2.58-2.52 (m, 2H), 1.44 (s, 6H). LC-MS: 582.2 [M+H] ⁺, Purity- 94.12% by AUC, RT- 5.35, UV-260 nm. [1173] Step 4: Preparation of 4,6-difluoro-N-(4-(1-((2-hydroxy-2-methylpropyl) sulfonyl)-1,2,3,6-tetrahydropyridin-4-yl) phenyl) isoindoline-2-carboxamide: To a stirred solution of 4 (80 mg, 0.13 mmol) in ACN (5 mL) was added TMS-I (55 mg 0.27 mmol) at 0°C under N_2, then the reaction mixture was stirred at below 20^oC for 2 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with methanol and a sodium thiosulfate solution and extracted with 10% MeOH-DCM. The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. The product was purified by column chromatography (eluent-0-2% MeOH in DCM) which afforded 30 mg of I-213 (74% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.50 (s, 1H), 7.56 (d, J = 8.9 Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H), 7.26-7.14 (m, 2H), 6.13 (s, 1H), 4.84 (s, 1H), 4.82-4.76 (m, 4H), 3.88 (d, J = 2.6 Hz, 2H), 3.43-3.36 (m, 2H), 3.16 (s, 2H), 2.59-2.51 (m, 2H), 1.31 (s, 6H). LC-MS: [M+H] ⁺ = 492.20 (M+H), Purity- 96.41% by AUC, RT- 5.28, UV-260 nm. HPLC: Purity- 94.80% by AUC, RT- 14.86, UV- 240 nm. Part L - Preparation of N-(4-(4-((2-hydroxy-2-methylpropyl)sulfonamido)bicyclo[2.2.2] octan-1-yl)phenyl)isoindoline-2-carboxamide (I-184) [1174] Step 1: Preparation of benzyl (4-(4-(isoindoline-2-carboxamido) phenyl) bicyclo [2.2.2] octan-1-yl) carbamate (2): 3 was prepared according to general procedure B, using K- Int-6 (700 mg, 1.48 mmol). The product was obtained after solid filtration, which afforded 500 mg of 2 (68% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.47- 7.41 (m, J = 8.7 Hz, 2H), 7.38-7.28 (m, 9H), 7.19 (d, J = 8.7 Hz, 2H), 7.00 (s, 1H), 4.97 (s, 2H), 4.74 (s, 4H), 1.89-1.78 (m, 12H). LC-MS: [M+H] ⁺ = 496.33 (M+H), Purity- 93.90% by AUC, RT- 6.05, UV-260 nm. [1175] Step 2: Preparation of N-(4-(4-aminobicyclo [2.2.2] octan-1-yl) phenyl) isoindoline- 2-carboxamide hydrobromide (3): To a stirred solution of 2 (700 mg, 1.41 mmol) in acetic acid (21 mL) was added HBr (21 mL, 33% in acetic acid) at 0^oC, then the mixture was stirred at RT for 16 h. The reaction was monitored by TLC and after completion of the reaction, it was diluted with EtOAc (50 mL) and stirred at RT for 1 h. The precipitate was filtered, dried, and triturated with MTBE (20 mL) to obtain 600 mg of 3 (96% yield) as an off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.94 (s, 3H), 7.50-7.43 (m, J = 8.7 Hz, 2H), 7.39-7.27 (m, 4H), 7.20 (d, J = 8.7 Hz, 2H), 4.75 (s, 8H), 1.90-1.78 (m, 12H). LC-MS: [M+H] ⁺ = 362.48 (M+H), Purity- 98.13% by AUC, RT 4.43, UV-260 nm. [1176] Step 3: Preparation of N-(4-(4-((2-(benzyloxy)-2-methylpropyl) sulfonamido) bicyclo [2.2.2] octan-1-yl) phenyl) isoindoline-2-carboxamide (4): To a stirred solution of 3 (600 mg, 1.66 mmol) in THF (20 mL) was added NaH (398 mg, 16.6 mmol) and the reaction mixture was stirred at RT for 30 min. R-Int-6 (1.3 g, 4.98 mmol) was added at 0°C under N2 atmosphere and then the reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with water and the precipitate was filtered and triturated with MTBE (20 mL), and then filtered and dried to obtain the crude product. The product was purified by column chromatography (eluent-0-2% MeOH in DCM), which afforded 80 mg of 4 (10% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.26 (s, 1H), 7.44 (d, J = 8.7 Hz, 2H), 7.38 - 7.25 (m, 9H), 7.17 (d, J = 8.8 Hz, 2H), 6.77 (s, 1H), 4.74 (s, 4H), 4.46 (s, 2H), 3.32 (s, 2H), 1.90 - 1.75 (m, 12H), 1.42 (s, 6H). LC-MS: [M+H] ⁺ = 588.62 M+H), Purity- 95.08% by AUC, RT- 6.13, UV-260 nm. [1177] Step 4: Preparation of N-(4-(4-((2-hydroxy-2-methylpropyl) sulfonamido) bicyclo [2.2.2] octan-1-yl) phenyl) isoindoline-2-carboxamide: To a stirred solution of 4 (80 mg, 0.13 mmol) in a mixture of THF: methanol (6.0 mL, 1:2) was added Pd/C (50 mg 50% wet) at RT under H2 atmosphere. Then the reaction mixture was stirred at RT for 4 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a celite pad and the pad was washed with 10% MeOH-DCM (200 mL). The filtrate was concentrated under reduced pressure to afford crude, and the crude was triturated with MTBE (10 mL) to afford 40 mg of I-184 (44% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.26 (s, 1H), 7.44 (d, J = 8.8 Hz, 2H), 7.38-7.27 (m, 4H), 7.18 (d, J = 8.8 Hz, 2H), 6.83 (s, 1H), 4.74 (s, 5H), 3.16 (s, 2H), 1.96-1.75 (m, 12H), 1.29 (s, 6H). LC-MS: [M+H] ⁺ = 498.42 (M+H), Purity- 98.38% by AUC, RT- 3.17, UV-260 nm. HPLC: Purity- 97.30% by AUC, RT- 14.72, UV- 240 nm. Part M - Preparation of benzyl (4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) bicyclo[2.2.2]octan-1-yl)carbamate (I-381) & N-(4-(4-((2-acetamido-2-methylpropyl) sulfonamido)bicyclo[2.2.2]octan-1-yl)phenyl)-5-fluoroisoindoline-2-carboxamide (I-183)

[1178] Step 1: Preparation of benzyl (1-hydroxy-2-methylpropan-2-yl) carbamate (8): To a stirred solution of 7 (2.0 g, 22.47 mmol) in DCM (35 mL) was added a sat. NaHCO3 solution (35 mL), followed by benzyl chloroformate (4.6 g, 26.96 mmol) at 0°C. The reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water, and extracted with DCM (2x50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The product was purified by column chromatography (eluent- 10-20% EtOAc in Hexane), which afforded 2.5 g of 8 (50% yield) as a colourless liquid.¹H NMR (300 MHz, DMSO-d6) δ 7.37-7.30 (m, 5H), 5.06-4.98 (m, 1H), 4.96-4.93 (m, 2H), 2.67 (s, 2H), 1.38 (s, 6H). [1179] Step 2: Preparation of S-(2-(((benzyloxy) carbonyl) amino)-2-methylpropyl) ethanethioate (9): To a stirred solution of TPP (1.5 g, 5.83 mmol) in THF (35 mL) at -78°C was added DIAD dropwise (1.15 g, 5.83 mmol), and the reaction mixture was stirred at -78°C for 30 min.8 (1.0 g, 4.48 mmol) was added, followed by thioacetic acid (443 mg, 5.83 mmol) at -78°C under N2 atmosphere. Then the reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with water and extracted with EtOAc (2x100 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude product. The product was purified by column chromatography (eluent-10-20% EtOAc in hexane), which afforded 510 mg of 9 (40% yield) as a pale-yellow liquid.¹H NMR (300 MHz, CDCl₃) δ 7.38- 7.30 (m, 3H), 5.05 (s, 1H), 4.89 (s, 1H), 3.30 (s, 2H), 2.35 (s, 3H), 1.35 (s, 6H). [1180] Step 3: Preparation of benzyl (1-(chlorosulfonyl)-2-methylpropan-2-yl) carbamate (4): To a stirred solution of NCS (141 mg, 1.063 mmol) in ACN (1.5 mL) was added HCl (0.05 mL, 2.0M in H₂O) and the reaction mixture was stirred at 0°C for 30 min. A solution of 9 (100 mg, 0.35 mmol) was added at 0°C, then the reaction mixture was stirred at 0°C for 30 min. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice-cold water and extracted with EtOAc (2x100 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude product.92 mg (crude) of 4 as a pale-yellow liquid was obtained.¹H NMR (300 MHz, DMSO-d6) δ 7.38-7.29 (m, 5H), 6.74 (s, 1H), 4.96 (s, 2H), 4.72 (t, J = 6.0 Hz, 1H), 3.35 (t, J = 2.9 Hz, 2H), 1.16 (s, 6H). [1181] Step 4: Preparation of benzyl (4-(4-(5-fluoroisoindoline-2-carboxamido) phenyl) bicyclo [2.2.2] octan-1-yl) carbamate: I-381 was prepared according to general procedure B using 1 (2.0 g, 4.25 mmol). The product was obtained after solid filtration, which afforded 1.93 g of I-381 (88% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.27 (s, 1H), 7.46- 7.27 (m, 8H), 7.26-7.09 (m, 4H), 7.00 (s, 1H), 4.97 (s, 2H), 4.73 (s, 2H), 4.71 (s, 2H), 1.93-1.74 (m, 12H). LC-MS: [M+H] ⁺ = 440.2. [1182] Step 5: Preparation of N-(4-(4-aminobicyclo [2.2.2] octan-1-yl) phenyl)-5- fluoroisoindoline-2-carboxamide hydrobromide (3): To a stirred solution of I-381 (1.93 g, 3.762 mmol) in a mixture of THF: ethanol (60 mL, 1:1) was added Pd/C (570 mg, 50% wet) at RT under H2 atmosphere. The reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a celite pad and the pad was washed with 50% MeOH in DCM (200 mL). The filtrate was concentrated under reduced pressure to afford the 1.3 g of 3 (91% yield) as a white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.32-8.20 (m, 1H), 7.46-7.35 (m, 3H), 7.26-7.08 (m, 4H), 4.73 (s, 2H), 4.71 (s, 2H), 1.87-1.72 (m, 6H), 1.59-1.47 (m, 6H). [1183] Step 6: Preparation of benzyl (1-(N-(4-(4-(5-fluoroisoindoline-2-carboxamido) phenyl) bicyclo [2.2.2] octan-1-yl) sulfamoyl)-2-methylpropan-2-yl) carbamate (5): To a stirred solution of 3 (150 mg, 0.395 mmol) in THF (2 mL) was added NaH (28.4 mg, 1.18 mmol) and the reaction mixture was stirred at RT for 30 min.4 (241 mg, 0.79 mmol) was added at 0°C under N2 atmosphere. The reaction mixture was stirred at RT for 2 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with water (20 mL) and extracted with EtOAc (2x50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The product was purified by column chromatography (eluent-0-50% EtOAc in hexane) which afforded 140 mg of 5 (55% yield) as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.28 (s, 1H), 7.46-7.32 (m, 8H), 7.25-7.09 (m, 6H), 6.91 (s, 1H), 5.00 (s, 2H), 4.73 (s, 2H), 4.71 (s, 2H), 3.46 (s, 2H), 1.90-1.73 (m, 13H), 1.40 (s, 6H). LC-MS: [M+H] ⁺ = 649.60 (M+H), Purity- 99.03% by AUC, RT- 5.88, UV-260 nm. [1184] Step 7: Preparation of N-(4-(4-((2-amino-2-methylpropyl) sulfonamido) bicyclo [2.2.2] octan-1-yl) phenyl)-5-fluoroisoindoline-2-carboxamide (6): To a stirred solution of 5 (125 mg, 0.19 mmol) in a mixture of THF: ethanol (8.0 mL, 1:1) was added Pd/C (50 mg 50% wet) at RT under H₂ atmosphere. Then the reaction mixture was stirred at RT for 2 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a celite pad and the pad was washed with 10% MeOH-DCM (30 mL). The filtrate was concentrated under reduced pressure to afford crude and the crude was triturated with MTBE (10 mL) to afford 97 mg of 6 (97% yield) as an off-white solid. LC-MS: [M+H] ⁺ = 515.42 (M+H), Purity- 85.10% by AUC, RT- 4.92, UV-260 nm. [1185] Step 8: Preparation of N-(4-(4-((2-acetamido-2-methylpropyl) sulfonamido) bicyclo [2.2.2] octan-1-yl) phenyl)-5-fluoroisoindoline-2-carboxamide: To a stirred solution of 6 (110 mg, 0.214 mmol) in DCM (5 mL) was added DIPEA (0.06 mL, 0.321 mmol), followed by Ac2O (26.19 mg, 0.256 mmol) at 0°C under N2 atmosphere. The reaction mixture was stirred at RT for 2 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice-cold water and extracted with DCM (2x50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The product was purified by column chromatography (eluent-40-70% EtOAc in hexane) which afforded 15 mg of I-183 (10% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.63 (s, 1H), 7.46-7.35 (m, 3H), 7.26-7.15 (m, 4H), 7.15-7.09 (m, 1H), 4.73 (s, 2H), 4.71 (s, 2H), 3.53 (s, 2H), 1.88-1.79 (m, 12H), 1.76 (s, 3H), 1.39 (s, 6H). LC-MS: [M+H] ⁺ = 557.57 (M+H), Purity- 95.13% by AUC, RT- 5.12, UV-260 nm. HPLC: Purity- 94.18% by AUC, RT- 14.61, UV- 240 nm.

Part N - Preparation of N-(4-(1-(2-((2-hydroxy-2-methylpropyl)amino)-2-oxoacetyl) piperidin-4-yl)phenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxamide (I-388) [1186] Step 1: Preparation of methyl 2-(4-(4-(5,6-dihydro-4H-pyrrolo [3,4-d] thiazole-5- carboxamido) phenyl) piperidin-1-yl)-2-oxoacetate: To a stirred solution of E-Int-3 (200 mg, 0.607 mmol) in DMF was added DIPEA (0.2 ml, 1.214 mmol) and 1 (0.06 mL) at RT and the mixture was stirred for 6 h. The reaction was monitored by TLC. After the complete consumption of the starting material, the reaction was diluted with water and extracted with EtOAc. The separated organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain crude. The crude was purified by flash chromatography and eluted with 30-50% of EtOAc in hexane to obtain 100 mg (40% yield) of 2 as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.11 (s, 1H), 8.33 (s, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 8.6 Hz, 2H), 4.74 (d, J = 2.9 Hz, 2H), 4.68 (d, J = 3.6 Hz, 2H), 4.41 - 4.32 (m, 1H), 3.83 (s, 3H), 3.64 - 3.55 (m, 1H), 3.30 - 3.20 (m, 1H), 2.90 - 2.71 (m, 3H), 1.89 - 1.78 (m, J = 11.5 Hz, 2H), 1.61 - 1.40 (m, 2H). LC-MS: [M+H] ⁺ = 414.13. [1187] Step 2: Preparation of N-(4-(1-(2-((2-hydroxy-2-methylpropyl)amino)-2- oxoacetyl)piperidin-4-yl)phenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxamide: To a stirred solution of 2 (180 mg, 0.434 mmol) in MeOH (5 mL) was added TEA (0.62 mL, 4.34 mmol) and 3 (58 mg, 0.652 mmol). The reaction was heated to 70-80 ^oC for 16 h. The reaction was monitored by TLC. After complete consumption of the starting material, the volatiles were removed under reduced pressure to obtain the crude residue, which was diluted with water and stirred for 10 min. The obtained solid was filtered and dried to obtain the crude product. The product was purified by flash chromatography and eluted with 0-5% MeOH in DCM to afford 18 mg (9% yield) of I-388 as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.51 (t, J = 6.1 Hz, 1H), 8.33 (s, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 8.5 Hz, 2H), 4.74 (d, J = 2.8 Hz, 2H), 4.68 (d, J = 3.5 Hz, 2H), 4.49 (s, 1H), 4.45-4.34 (m, 1H), 3.85 (d, J = 13.4 Hz, 1H), 3.22- 3.06 (m, 3H), 2.82-2.69 (m, 2H), 1.86-1.72 (m, 2H), 1.70-1.44 (m, 2H), 1.08 (s, 6H). LCMS: 472.22 (M+H), Purity- 99.20% by AUC, RT- 3.92, UV-245 nm. HPLC: Purity- 94.55% by AUC, RT- 16.32, UV- 240 nm. Part O - Preparation of N1-(4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)bicyclo [2.2.2]octan-1-yl)-N2,N2-dimethyloxalamide (I-359) [1188] I-359 was prepared according to general procedure G using L-Int-6 (70 mg, 0.15 mmol). The product was obtained after solid filtration, which afforded 35 mg (49% yield) of I-359 as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.16 (s, 1H), 7.48-7.34 (m, 3H), 7.26-7.09 (m, 4H), 4.74 (s, 2H), 4.71 (s, 2H), 2.92 (s, 3H), 2.82 (s, 3H), 2.00-1.78 (m, 12H). LCMS: 479.32 (M+H), Purity- 99.69% by AUC, RT- 5.02, UV-245 nm. HPLC: Purity- 97.90% by AUC, RT- 14.18, UV- 260 nm. Part P - Preparation of 3-fluoro-N-(4-(1-(2-((2-hydroxy-2-methylpropyl)amino)-2- oxoacetyl)piperidin-4-yl)phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide (I- 408) [1189] Step 1: Preparation of methyl 2-(4-(4-(3-fluoro-6,7-dihydro-5H-pyrrolo [3,4-b] pyridine-6-carboxamido) phenyl) piperidin-1-yl)-2-oxoacetate (2): 2 was prepared according to general procedure F using B-Int-5 (200 mg, 0.588 mmol). The product was obtained after solid filtration, which afforded 180 mg (60% yield) of 2 as an off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ 8.49-8.47 (m, 1H), 8.34 (s, 1H), 8.17 (s, 1H), 7.79 (dd, J = 2.8, 9.1 Hz, 1H), 7.44 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.7 Hz, 2H), 4.76 (s, 2H), 4.72 (s, 2H), 3.74 (s, 3H), 2.01-1.92 (m, 6H), 1.87-1.79 (m, 6H). LC-MS: [M+H] ⁺ = 427.14. [1190] Step 2: Preparation of 3-fluoro-N-(4-(1-(2-((2-hydroxy-2-methylpropyl) amino)-2- oxoacetyl) piperidin-4-yl) phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b] pyridine-6-carboxamide: I-408 was prepared according to general procedure G using 2 (140 mg, 0.328 mmol). The product was obtained after solid filtration, which afforded 15 mg (12% yield) of I-408 as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.55-8.46 (m, 2H), 8.37 (s, 1H), 7.79 (dd, J = 2.6, 8.9 Hz, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 8.5 Hz, 2H), 4.77 (s, 2H), 4.73 (s, 2H), 4.49 (s, 1H), 4.45-4.35 (m, 1H), 3.90-3.80 (m, 1H), 3.22-3.07 (m, 3H), 2.82-2.68 (m, 2H), 1.87-1.71 (m, 2H), 1.70-1.44 (m, 2H), 1.08 (s, 6H). LCMS: 484.28 (M+H), Purity- 97.88% by AUC, RT- 4.15, UV- 245 nm. HPLC: Purity- 95.07% by AUC, RT- 16.42, UV- 230 nm. Part Q - Preparation of N1-(3-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) bicyclo[1.1.1] pentan-1-yl)-N2-(2-hydroxy-2-methylpropyl)oxalamide (I-407) [1191] Step 1: Preparation of methyl 2-((3-(4-(5-fluoroisoindoline-2- carboxamido)phenyl)bicyclo[1.1.1]pentan-1-yl)amino)-2-oxoacetate (2): 2 was prepared according to general procedure F, using O-Int-7 (190 mg, 0.45 mmol). The product was obtained after solid filtration, which afforded 150 mg (78% yield) of 2 as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.35 (s, 1H), 7.49 (d, J = 8.6 Hz, 2H), 7.38 (dd, J = 5.3, 8.5 Hz, 1H), 7.23 (dd, J = 2.3, 9.3 Hz, 1H), 7.18 - 7.08 (m, 3H), 4.74 (s, 2H), 4.72 (s, 2H), 3.79 - 3.75 (m, 3H), 2.26 (s, 6H) LC-MS: [M+H] ⁺ = 424.15. [1192] Step 2: Preparation of N1-(3-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) bicyclo[1.1.1]pentan-1-yl)-N2-(2-hydroxy-2-methylpropyl)oxalamide: I-407 was prepared according to general procedure G, using 2 (100 mg, 0.236 mmol). The product was obtained after solid filtration, which afforded 49 mg (42% yield) of I-407 as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 9.41 (s, 1H), 8.35 (s, 1H), 8.22 (t, J = 6.3 Hz, 1H), 7.49 (d, J = 8.5 Hz, 2H), 7.43-7.34 (m, 1H), 7.23 (dd, J = 2.0, 9.2 Hz, 1H), 7.18-7.07 (m, 3H), 4.74 (s, 2H), 4.72 (s, 2H), 4.66 (s, 1H), 3.12 (d, J = 6.3 Hz, 2H), 2.27 (s, 6H), 1.06 (s, 6H). LCMS: 481.34 (M+H), Purity- 95.73% by AUC, RT- 4.97, UV-245 nm. HPLC: Purity- 95.75% by AUC, RT- 19.37, UV- 250 nm. Part R - Preparation of 4,5,6-trifluoro-N-(4-(1-(2-((2-hydroxy-2-methylpropyl)amino)-2- oxoacetyl)piperidin-4-yl)phenyl)isoindoline-2-carboxamide (I-387) [1193] Step 1: Preparation methyl 2-oxo-2-(4-(4-(4,5,6-trifluoroisoindoline-2- carboxamido)phenyl)piperidin-1-yl)acetate (2): 2 was prepared according to general procedure F using F-Int-9 (300 mg, 0.79 mmol). The product was obtained after solid filtration, which afforded 200 mg (59% yield) of 2 as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.51-7.37 (m, 3H), 7.14 (d, J = 8.4 Hz, 2H), 4.83 (s, 2H), 4.75 (s, 2H), 4.37 (br d, J = 12.8 Hz, 1H), 3.83 (s, 3H), 3.60 (d, J = 13.5 Hz, 1H), 3.30-3.17 (m, 1H), 2.91-2.71 (m, 2H), 1.84 (d, J = 12.7 Hz, 2H), 1.60-1.44 (m, 2H). LC-MS: [M+H] ⁺ = 462.15. [1194] Step 2: Preparation of 4,5,6-trifluoro-N-(4-(1-(2-((2-hydroxy-2- methylpropyl)amino)-2-oxoacetyl)piperidin-4-yl)phenyl)isoindoline-2-carboxamide: I-387 was prepared according to general procedure G using 3 (182 mg, 0.48 mmol). The product was obtained after solid filtration, which afforded 180 mg (83% yield) of I-387 as an off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ 8.51 (t, J = 6.0 Hz, 1H), 8.42-8.38 (m, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.45-7.36 (m, 1H), 7.14 (d, J = 8.5 Hz, 2H), 4.83 (s, 2H), 4.75 (s, 2H), 4.49 (s, 1H), 4.40 (d, J = 12.1 Hz, 1H), 3.93-3.75 (m, 1H), 3.20-3.03 (m, 3H), 2.83-2.58 (m, 2H), 1.86-1.71 (m, 2H), 1.69-1.41 (m, 2H), 1.08 (s, 6H). LCMS: 519.26 (M+H), Purity- 99.89% by AUC, RT- 4.92, UV- 245 nm. HPLC: Purity- 96.65% by AUC, RT- 12.66, UV- 230 nm. Part S - Preparation of 4,5,6-trifluoro-N-(4-(1-(2-((2-hydroxy-2-methylpropyl)amino)-2- oxoacetyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide (I-386) & tert- butyl 4-(4-(4,5,6-trifluoroisoindoline-2-carboxamido)phenyl)-3,6-dihydropyridine-1 - carboxylate (I-352) [1195] Step 1: Preparation of tert-butyl 4-(4-(4,5,6-trifluoroisoindoline-2-carboxamido) phenyl)-3,6-dihydropyridine-1(2H)-carboxylate: I-352 was prepared according to general procedure B using 1 (507 mg, 1.28 mmol). The product was obtained after solid filtration, which afforded 320 mg of I-352 (49% yield) as a white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.49 (s, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.45-7.31 (m, 3H), 6.08 (s, 1H), 4.85 (s, 2H), 4.76 (s, 2H), 4.02-3.95 (m, 2H), 3.52 (t, J = 5.6 Hz, 2H), 2.48-2.39 (m, 2H), 1.42 (s, 9H). [1196] Step 2: Preparation of 4,5,6-trifluoro-N-(4-(1,2,3,6-tetrahydropyridin-4-yl) phenyl) isoindoline-2-carboxamide (3): 3 was prepared according to general procedure C, using I-352 (320 mg, 0.67 mmol). The product was obtained after solid filtration, which afforded 180 mg of 3 (71% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.79 (s, 2H), 8.57 (s, 1H), 7.58 (d, J = 8.8 Hz, 2H), 7.45-7.37 (m, 3H), 6.15-6.10 (m, 1H), 4.86 (s, 2H), 4.76 (s, 2H), 3.73-3.67 (m, 2H), 3.30-3.24 (m, 2H), 2.68-2.59 (m, 2H). LC-MS: [M+H] ⁺ = 373.1. [1197] Step 3: Preparation of methyl 2-oxo-2-(4-(4-(4,5,6-trifluoroisoindoline-2- carboxamido)phenyl)-3,6-dihydropyridin-1(2H)-yl)acetate (5): 5 was prepared according to general procedure F using 3 (200 mg, 0.536 mmol). The product was obtained after solid filtration, which afforded 152 mg (61% yield) of 5 as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.56 (d, J = 8.7 Hz, 2H), 7.40-7.32 (m, 3H), 6.14-6.04 (m, 1H), 4.85 (s, 2H), 4.76 (s, 2H), 4.14 (d, J = 2.8 Hz, 2H), 3.85 (s, 3H), 3.73 (t, J = 5.8 Hz, 1H), 3.57 (t, J = 5.7 Hz, 1H), 2.57 - 2.52 (m, 2H). LC-MS: [M+H] ⁺ = 460.15. [1198] Step 4: Preparation of 4,5,6-trifluoro-N-(4-(1-(2-((2-hydroxy-2-methylpropyl) amino)-2-oxoacetyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide: I- 386 was prepared according to general procedure G using 5 (150 mg, 0.326 mmol). The product was obtained after solid filtration, which afforded 42 mg (25% yield) of I-386 as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.57-8.45 (m, 2H), 7.55 (d, J = 8.8 Hz, 2H), 7.45-7.32 (m, 3H), 6.16- 6.06 (m, 1H), 4.85 (s, 2H), 4.76 (s, 2H), 4.52-4.48 (m, 1H), 4.20-4.08 (m, 2H), 3.74- 3.61 (m, 2H), 3.17-3.07 (m, 2H), 2.57-2.52 (m, 2H), 1.09 (s, 3H), 1.08 (s, 3H). LCMS: 517.24 (M+H), Purity- 98.98% by AUC, RT- 4.97, UV-245 nm. HPLC: Purity- 94.03% by AUC, RT- 12.86, UV- 210 nm. Part T - Preparation of N-(4-(1-(2-(1,1-dioxidothiomorpholino)-2-oxoacetyl)-1,2,3,6- tetrahydropyridin-4-yl)phenyl)-5-fluoroisoindoline-2-carboxamide (I-410) [1199] Step 1: Preparation of methyl 2-(4-(4-(5-fluoroisoindoline-2- carboxamido)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoacetate (2): 2 was prepared according to general procedure F using C-Int-4 (900 mg, 2.39 mmol). The product was obtained after solid filtration, which afforded 700 mg (64% yield) of 2 as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.56 (d, J = 8.6 Hz, 2H), 7.40-7.32 (m, 3H), 7.23 (d, J = 9.1 Hz, 1H), 7.18-7.11 (m, 1H), 6.14-6.04 (m, 1H), 4.76 (s, 2H), 4.73 (s, 2H), 4.18-4.02 (m, 2H), 3.88 (s, 3H), 3.73 (t, J = 5.9 Hz, 1H), 3.61-3.53 (m, 1H), 2.59-2.52 (m, 2H). LCMS: 424.27 (M+H), Purity- 92.79% by AUC, RT- 5.18, UV-245 nm. [1200] Step 2: Preparation of 2-(4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)-3,6- dihydropyridin-1(2H)-yl)-2-oxoacetic acid (3): 3 was prepared according to general procedure E using 2 (1.0 g, 2.36 mmol). The product was obtained after solid filtration, which afforded 650 mg of 3 (67% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 14.45-13.91 (m, 1H), 8.43 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.41-7.32 (m, 3H), 7.23 (dd, J = 2.0, 9.1 Hz, 1H), 7.18-7.11 (m, 1H), 6.15-6.07 (m, 1H), 4.76 (s, 2H), 4.73 (s, 2H), 4.17-4.02 (m, 2H), 3.70 (t, J = 5.8 Hz, 1H), 3.64-3.52 (m, 1H), 2.59-2.53 (m, 2H). LCMS: 410.16 (M+H), Purity- 92.15% by AUC, RT- 4.12, UV-245 nm. [1201] Step 3: Preparation of N-(4-(1-(2-(1,1-dioxidothiomorpholino)-2-oxoacetyl)- 1,2,3,6-tetrahydropyridin-4-yl) phenyl)-5-fluoroisoindoline-2-carboxamide: I-410 was prepared according to general procedure D using 3 (800 mg, 1.95 mmol). The product was purified by column chromatography (eluent-3-6% MeOH in DCM), which upon trituration with n-heptane gave 250 mg of I-410 (24% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.43 (s, 1H), 7.57 (d, J = 8.8 Hz, 2H), 7.43-7.32 (m, 3H), 7.24 (dd, J = 2.2, 9.1 Hz, 1H), 7.19-7.10 (m, 1H), 6.16-6.04 (m, 1H), 4.76 (s, 2H), 4.73 (s, 2H), 4.20-4.03 (m, 2H), 4.00-3.89 (m, 2H), 3.80- 3.67 (m, 3H), 3.59 (t, J = 5.7 Hz, 1H), 3.33-3.27 (m, 2H), 3.24-3.13 (m, 2H), 2.58-2.52 (m, 2H). LCMS: 527.26 (M+H), Purity- 99.57% by AUC, RT- 4.83, UV-245 nm. HPLC: Purity- 96.05% by AUC, RT- 13.77, UV- 240 nm. Part U - Preparation of N-(4-(1-(2-(1,1-dioxidothiomorpholino)-2-oxoacetyl)piperidin-4- yl)phenyl)-5-fluoroisoindoline-2-carboxamide (I-409) [1202] Step 1: Preparation of methyl 2-(4-(4-(5-fluoroisoindoline-2-carboxamido) phenyl)piperidin-1-yl)-2-oxoacetate (2): 2 was prepared according to general procedure F, using D-Int-4 (350 mg, 0.815 mmol). The product was obtained after solid filtration, which afforded 180 mg (61% yield) of 2 as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 1H NMR (300 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.47 (d, J = 8.5 Hz, 3H), 7.38 (dd, J = 5.3, 8.3 Hz, 1H), 7.23 (dd, J = 2.0, 8.9 Hz, 1H), 7.19-7.08 (m, 3H), 4.75 (s, 2H), 4.71 (s, 2H), 4.40-4.28 (m, 1H), 3.82 (s, 3H), 3.66-3.54 (m, 1H), 3.32-3.21 (m, 1H), 2.91-2.75 (m, 2H), 1.90-1.78 (m, 2H), 1.61-1.41 (m, 2H). LC-MS: [M+H] ⁺ = 426.16. [1203] Step 2: Preparation of 2-(4-(4-(5-fluoroisoindoline-2-carboxamido) phenyl) piperidin-1-yl)-2-oxoacetic acid (4): 4 was prepared according to general procedure E, using 2 (1.3 g, 3.05 mmol). The product was obtained after solid filtration, which afforded 1.0 g of 4 (83%) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.43 - 7.34 (m, 1H), 7.22 (dd, J = 2.1, 9.1 Hz, 1H), 7.12 (d, J = 8.5 Hz, 3H), 4.74 (s, 2H), 4.36 (d, J = 12.7 Hz, 1H), 3.67 (m, J = 13.0 Hz, 1H), 3.32 - 3.10 (m, 1H), 2.75 (t, J = 11.7 Hz, 2H), 1.86 - 1.76 (m, 2H), 1.58 - 1.37 (m, 2H). LCMS: 412.43 (M+H). [1204] Step 3: Preparation N-(4-(1-(2-(1,1-dioxidothiomorpholino)-2-oxoacetyl) piperidin-4-yl) phenyl)-5-fluoroisoindoline-2-carboxamide: I-409 was prepared according to general procedure D using 4 (1.0 g, 2.43 mmol). The product was purified by column chromatography (eluent-0-5% MeOH in DCM), which upon further trituration with n-heptane gave 300 mg of I-409 (23% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.31 (s, 1H), 7.48 (d, J = 8.6 Hz, 2H), 7.39 (dd, J = 5.1, 8.3 Hz, 1H), 7.23 (dd, J = 2.2, 9.2 Hz, 1H), 7.18-7.09 (m, 3H), 4.74 (s, 2H), 4.72 (s, 2H), 4.42 (d, J = 12.9 Hz, 1H), 4.07-3.93 (m, 1H), 3.92- 3.81 (m, 1H), 3.79-3.61 (m, 3H), 3.32-3.30 (m, 3H), 3.26-3.14 (m, 2H), 2.89-2.70 (m, 2H), 1.93- 1.76 (m, 2H), 1.62-1.40 (m, 2H). LCMS: 529.21 (M+H), Purity- 97.22 % by AUC, RT- 4.82, UV- 245 nm. HPLC: Purity- 94.62% by AUC, RT- 13.71, UV- 240 nm. Part V - Preparation of N-(4-(1-(2-((2-acetamido-2-methylpropyl)amino)-2-oxoacetyl) piperidin-4-yl)phenyl)-5-fluoroisoindoline-2-carboxamide (I-212) [1205] Step 1: Preparation of benzyl (2-amino-2-methylpropyl) carbamate (3): To a stirred solution of 2 (0.5 g, 5.681 mmol) in toluene (10 mL) was added CbzCl (0.83 mL, 50% solution in toluene) at -5 ^oC and the mixture was stirred for 20 min, and then the mixture was stirred at RT for 2 h. The reaction was monitored by TLC. After complete consumption of the starting material, the reaction volatiles were removed under reduced pressure to obtain the crude product. The obtained solid was triturated with DCM and the solid was filtered. The filtrate was concentrated under reduced pressure to obtain 300 mg (25% yield) of 3 as a colourless oil.¹H NMR (300 MHz, DMSO-d6) δ 7.36 (s, 1H), 7.36-7.33 (m, 5H), 5.02 (s, 2H), 2.89 (d, J = 6.2 Hz, 2H), 1.91-1.67 (m, 2H), 0.94 (s, 6H). [1206] Step 2: Preparation of benzyl (2-acetamido-2-methylpropyl)carbamate (4): To a stirred solution of 3 (200 mg, 0.90 mmol) in DCM (4 mL) was added TEA (0.64 mL, 4.50 mmol). The reaction was cooled to 0 ^oC and Ac₂O (181 mg, 1.80 mmol) was added. The reaction was stirred for 2 h at RT and monitored by TLC. After complete consumption of the starting material, the reaction was diluted with DCM and the mixture was washed with water. The separated organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to provide 250 mg (84% yield) of 4 as colourless oil. ¹H NMR (300 MHz, DMSO-d₆) δ 7.40-7.25 (m, 6H), 5.16 (s, 1H), 5.02 (s, 2H), 3.22 (d, J = 6.3 Hz, 2H), 1.74 (s, 3H), 1.15 (s, 6H). [1207] Step 3: Preparation of N-(1-amino-2-methylpropan-2-yl) acetamide (1): To a stirred solution of 4 (600 mg, 2.56 mmol) in EtOH (15 mL) was added 10% Pd/C (300 mg). The reaction was stirred under hydrogen balloon pressure for 2 h at RT. The reaction was monitored by TLC. After complete consumption of the starting material, the reaction was filtered through a celite pad, and the filtrate was concentrated under pressure to obtain the crude. The crude was purified by flash chromatography (neutral alumina) and eluted with 0-5% MeOH in DCM to afford 100 mg (38% yield) of 1 as a colourless oil.¹H NMR (300 MHz, DMSO-d6) δ 7.68 (s, 1H), 2.92 (d, J = 6.1 Hz, 2H), 1.83 (s, 3H), 1.78-1.57 (m, 2H), 0.93 (s, 6H). [1208] Step 4: Preparation of N-(4-(1-(2-((2-acetamido-2-methylpropyl)amino)-2- oxoacetyl)piperidin-4-yl)phenyl)-5-fluoroisoindoline-2-carboxamide: I-212 was prepared according to general procedure D using P-Int-4 (80 mg, 0.193 mmol). The product was obtained after solid filtration, which afforded 17 mg (31% yield) of I-212 as an off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.21 (s, 1H), 7.92 (t, J = 6.1 Hz, 1H), 7.47 (d, J = 8.5 Hz, 2H), 7.38 (dd, J = 5.2, 8.3 Hz, 1H), 7.23 (d, J = 9.0 Hz, 1H), 7.18-7.09 (m, 3H), 4.74 (s, 2H), 4.71 (s, 2H), 4.37 (d, J = 12.7 Hz, 1H), 3.83 (d, J = 12.5 Hz, 1H), 3.27 (t, J = 5.5 Hz, 2H), 3.13 (t, J = 11.9 Hz, 1H), 2.82-2.63 (m, 2H), 1.84 (s, 3H), 1.82-1.73 (m, 2H), 1.68-1.40 (m, 2H), 1.33-1.21 (m, 6H). LCMS: 524.30 (M+H), Purity- 98.86% by AUC, RT- 4.76, UV-245 nm. HPLC: Purity- 97.46% by AUC, RT- 14.81, UV- 240 nm. Part W - Preparation of N-(4-(1-(2-((2-acetamido-2-methylpropyl)amino)-2-oxoacetyl)- 1,2,3,6-tetrahydropyridin-4-yl)phenyl)-5-fluoroisoindoline-2-carboxamide (I-211) [1209] I-211 was prepared as above according to general procedure D using Q-Int-3 (100 mg, 0.943 mmol). The product was obtained after solid filtration, which afforded 22 mg (38.0% yield) of I-211 as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.27-8.21 (m, 1H), 7.92 (t, J = 6.3 Hz, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.43-7.32 (m, 3H), 7.23 (dd, J = 2.2, 9.0 Hz, 1H), 7.19-7.09 (m, 1H), 6.16-6.05 (m, 1H), 4.76 (s, 2H), 4.73 (s, 2H), 4.15 (s, 1H), 4.09 (s, 1H), 3.71-3.59 (m, 2H), 3.32-3.24 (m, 2H), 2.58-2.41 (m, 2H), 1.88 (s, 3H), 1.30-1.22 (m, 6H). LCMS: 522.31 (M+H), Purity- 96.52% by AUC, RT- 4.78, UV-245 nm. HPLC: Purity- 94.16% by AUC, RT- 13.00, UV- 210 nm. Part X - Preparation of 3-fluoro-N-(4-(4-((2-methoxyethyl)sulfonamido)bicyclo[2.2.2] octan-1-yl)phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide (I-190) & N1-(4- (4-(3-fluoro-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-6-carboxamido) phenyl)bicyclo[2.2.2] octan-1-yl)-N2,N2-dimethyloxalamide (I-186) [1210] Step 1: Preparation of N1-(4-(4-(3-fluoro-6,7-dihydro-5H-pyrrolo[3,4-b] pyridine- 6-carboxamido) phenyl) bicyclo [2.2.2] octan-1-yl)-N2, N2-dimethyloxalamide: To a stirred solution of K-Int-9 (50 mg, 0.131 mmol) in DMF (2 mL) was added 1 (18.4 mg, 0.157 mmol) followed by the addition of DIPEA (0.1 mL, 0.657 mmol), HATU (99.9 mg, 0.263 mmol) and DMAP (3.2 mg, 0.026 mmol) at 0^oC. The reaction mixture was stirred at RT for 24 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was poured into ice-cold water and stirred at RT for 30 min. The precipitate was filtered and washed with water (15 mL) and dried to obtain the crude product. The product was purified by column chromatography (eluent-0-5% methanol in DCM) which afforded 15 mg of I-186 (24% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.48 (s, 1H), 8.35 (s, 1H), 8.17 (s, 1H), 7.79 (dd, J = 2.6, 9.0 Hz, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.7 Hz, 2H), 4.77 (s, 2H), 4.72 (s, 2H), 2.92 (s, 3H), 2.82 (s, 3H), 2.00 - 1.90 (m, 6H), 1.84 (d, J = 8.6 Hz, 6H). LC-MS: [M+H] ⁺ = 480.33 (M+H), Purity- 98.02% by AUC, RT- 4.52, UV-260 nm. HPLC: Purity- 99.22% by AUC, RT- 2.10, UV- 240 nm. [1211] Step 2: Preparation of 3-fluoro-N-(4-(4-((2-methoxyethyl) sulfonamido) bicyclo [2.2.2] octan-1-yl) phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b] pyridine-6-carboxamide: To a stirred solution of K-Int-9 (100 mg, 0.263 mmol) in DMF (5 mL) was added Cs₂CO₃ (255 mg, 0.789) and 2 (62.3 mg, 0.394 mmol) at RT, then the reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC. After completion of the reaction, the reaction mixture was poured into ice-cold water and stirred at RT for 30 min. The precipitate was filtered and washed with EtOAc (10 mL) to afford 42 mg of I-190 (32% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.47 (d, J = 1.4 Hz, 1H), 8.34 (s, 1H), 7.82 - 7.76 (m, 1H), 7.47 - 7.41 (m, 2H), 7.23 - 7.16 (m, 2H), 6.93 (s, 1H), 4.76 (s, 2H), 4.72 (s, 2H), 3.66 (t, J = 6.6 Hz, 2H), 3.28 - 3.22 (m, 5H), 1.92 - 1.76 (m, 12H). LC-MS: [M+H] ⁺ = 503.26 (M+H), Purity- 96.04% by AUC, RT- 4.80, UV-260 nm. HPLC: Purity- 91.12% by AUC, RT- 13.65, UV- 240 nm.

Part Y - Preparation of ethyl 3-((4-(4-(3-fluoro-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-6- carboxamido)phenyl)bicyclo[2.2.2]octan-1-yl)sulfonyl)propanoate (I-181) & 3-fluoro-N-(4- (4-((3-hydroxy-3-methylbutyl)sulfonyl)bicyclo[2.2.2]octan-1-yl)phenyl)-5,7-dihydro-6H- pyrrolo[3,4-b]pyridine-6-carboxamide (I-464) [1212] Step 1: Preparation of 1,3-dioxoisoindolin-2-yl 4-(4-(3-fluoro-6,7-dihydro-5H- pyrrolo[3,4-b] pyridine-6-carboxamido) phenyl) bicyclo [2.2.2] octane-1-carboxylate (2): To a stirred solution of H-Int-4 (1.0 g, 2.44 mmol) in a mixture of DCM: DMF (30 mL, 2:1) was added DMAP (146 mg, 1.22 mmol) and 1 (597 mg, 3.66 mmol) at 0^oC and the mixture was stirred for 15 min. Then Di-isopropyl carbodiimide (616 mg, 4.88 mmol) was added slowly at 0^oC and the mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC, after completion of the reaction, the reaction mixture was poured into ice-cold water and stirred for 2 h at RT, the precipitate was filtered and dried to obtain 920 mg of 2 (68% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.38 (s, 1H), 8.04-7.92 (m, 5H), 7.80 (dd, J = 2.7, 9.1 Hz, 2H), 7.54-7.43 (m, J = 8.8 Hz, 2H), 7.29-7.21 (m, J = 8.8 Hz, 2H), 4.78 (s, 2H), 4.73 (s, 2H), 2.12-1.97 (m, 6H), 1.95-1.80 (m, 6H). LCMS: 555.06 (M+H), Purity- 67.66 % by AUC, RT- 5.73, UV-240 nm. [1213] Step 2: Preparation of ethyl 3-((4-(4-(3-fluoro-6,7-dihydro-5H-pyrrolo [3,4-b] pyridine-6-carboxamido) phenyl) bicyclo [2.2.2] octan-1-yl) sulfonyl) propanoate: To a stirred solution of 2 (1.1 g, 1.98 mmol) in DMF (10 mL) was added sodium dithionite (518 mg, 2.97 mmol), lithium acetate (179 mg, 1.98 mmol), triethylamine hydrochloride (680 mg, 4.96 mmol) and 3 (595 mg, 5.95 mmol) at RT under N₂ atmosphere. The mixture was then stirred at 60^oC for 16 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice-cold water (100 mL) and diluted with ethyl acetate (2x25 mL), the combined organic extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. The product was purified by column chromatography (eluent-0-50% ethyl acetate in hexanes) which afforded 170 mg of I-181 (16% yield) as an off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.38 (s, 1H), 7.80 (dd, J = 2.7, 9.1 Hz, 1H), 7.51-7.44 (m, J = 8.6 Hz, 2H), 7.27-7.18 (m, J = 8.8 Hz, 2H), 4.78 (s, 2H), 4.73 (s, 2H), 4.11 (q, J = 7.2 Hz, 2H), 3.33-3.25 (m, 2H), 2.73 (t, J = 7.2 Hz, 2H), 2.03- 1.81 (m, 12H), 1.21 (t, J = 7.1 Hz, 3H). LCMS: 530.04 (M+H), Purity- 97.12% by AUC, RT- 5.02, UV-240 nm. LCMS Method: Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mm Ammonium Acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; Flow rate: 0.6mL/min. HPLC: Purity- 90.50% by AUC, RT- 14.02, UV- 240 nm. HPLC method: Column: X Bridge C184.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH₃CN; Flow rate: 1.2 mL/min; Diluent: Methanol (100%). [1214] Step 3: Preparation of 3-fluoro-N-(4-(4-((3-hydroxy-3-methylbutyl) sulfonyl) bicyclo [2.2.2] octan-1-yl) phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b] pyridine-6-carboxamide: To a stirred solution of I-181 (110 mg, 0.207 mmol) in THF (3 mL) was added methyl magnesium iodide (207 mg, 1.24 mmol, 3.0M in Et2O) at 0°C and the mixture was stirred for 1 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with saturated NH₄Cl and diluted with ethyl acetate (2x25 mL), the combined organic extracts were washed with brine, dried over Na₂SO_4, and concentrated under reduced pressure to afford the crude product. The product was purified by column chromatography (eluent- 0-5% MeOH in DCM) which afforded 18.0 mg of I-464 (17% yield) as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.49 (s, 1H), 8.38 (s, 1H), 7.80 (t, J = 1.0 Hz, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H), 4.78 (s, 2H), 4.73 (s, 2H), 4.49 (s, 1H), 3.05-2.97 (m, 2H), 2.02- 1.83 (m, 12H), 1.80-1.71 (m, 2H), 1.14 (s, 6H). LCMS: 516.08 (M+H), Purity- 98.80% by AUC, RT- 4.70, UV-240 nm. LCMS Method: Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mm Ammonium Acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; Flow rate: 0.6mL/min. HPLC: Purity- 98.55% by AUC, RT- 13.26, UV- 240 nm. HPLC method: Column: X Bridge C18 4.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH₃CN; Flow rate: 1.2 mL/min; Diluent: Methanol (100%). Part Z - Preparation of 5-fluoro-N-(4-(4-(2-hydroxypropan-2-yl)bicyclo[2.2.2]octan-1- yl)phenyl)isoindoline-2-carboxamide (I-356) [1215] To a stirred solution of I-231 (50 mg, 0.11 mmol) in a THF (5 mL) was added MeMgI (117 mg 0.70 mmol, 3.0M in Et2O) at 0°C under N2, then the reaction mixture was stirred at 35- 40^oC for 16 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc, the combined organic extracts were dried over Na2SO4, and concentrated under reduced pressure to afford the crude product. The product was purified by column chromatography (eluent- 0-40% EtOAc in hexane) which afforded 37 mg of I-356 (74% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.26 (s, 1H), 7.46-7.34 (m, 3H), 7.26-7.09 (m, 4H), 4.73 (s, 2H), 4.71 (s, 2H), 3.86 (s, 1H), 1.82-1.64 (m, 6H), 1.61-1.47 (m, 6H), 1.01 (s, 6H). LCMS: 423.26 (M+H), Purity- 93.76% by AUC, RT- 5.62, UV-245 nm. HPLC: Purity- 91.62% by AUC, RT- 15.08, UV- 250 nm. Part AA - Preparation of 5-fluoro-N-(4-(4-(3-(2-hydroxy-2-methylpropyl)-1- methylureido)bicyclo[2.2.2]octan-1-yl)phenyl)isoindoline-2-carboxamide (I-235) [1216] Step 1: Preparation of ethyl ((4-(4-(5-fluoro isoindoline-2-carboxamido) phenyl) bicyclo [2.2.2] octan-1-yl) (methyl) carbamoyl) glycinate (2): To a stirred solution of N-Int-3 (350 mg, 0.89 mmol) in THF (5.0 mL) was added NaH (42.7 mg, 1.78 mmol) at RT and the mixture was stirred for 30 minutes, then 1 (172 mg, 1.33 mmol) was added at 0^oC, and the reaction mixture was stirred at RT for 2 h. The reaction mixture was monitored by TLC and LCMS. After complete consumption of the starting material, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2x50 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 250 mg of 2 (54% yield) as an off- white solid. The crude was used in the next step without purification. ¹H NMR (300 MHz, DMSO- d6) δ 8.28 (s, 1H), 7.46-7.38 (m, 3H), 7.25-7.12 (m, 4H), 6.65-6.59 (m, 1H), 4.73 (s, 2H), 4.71 (s, 2H), 4.12-4.02 (m, 2H), 3.65 (d, J = 5.9 Hz, 2H), 2.76 (s, 3H), 2.06-1.99 (m, 6H), 1.83-1.76 (m, 6H), 1.21-1.16 (m, 3H). LC-MS: [M+H] ⁺ = 523.36 (M+H), Purity- 82.27% by AUC, RT- 5.48, UV-260 nm. [1217] Step 2: Preparation of 5-fluoro-N-(4-(4-(3-(2-hydroxy-2-methylpropyl)-1- methylureido) bicyclo [2.2.2] octan-1-yl) phenyl) isoindoline-2-carboxamide: To a stirred solution of 2 (160 mg, 0.30 mmol) in THF (5.0 mL) was added MeMgI (508 mg, 0.30 mmol, 3.0M in Et2O) at 0^oC, then the reaction mixture was stirred at RT for 2 h. The reaction mixture was monitored by TLC and LCMS. After complete consumption of the starting material, the reaction mixture was quenched with a sat NH₄Cl solution and extracted with EtOAc (2x30 mL). The combined organic extracts were dried with Na2SO4, filtered, and concentrated to give the crude. The product was purified by column chromatography and eluted with EtOAc to afford 20 mg of I-235 as off white solid. ¹H NMR (300 MHz, Methanol-d₄) δ 7.39-7.31 (m, 3H), 7.29-7.23 (m, 2H), 7.13-7.01 (m, 2H), 4.80 (s, 2H), 4.77 (s, 2H), 4.63 (s, 2H), 2.92-2.88 (m, 3H), 2.21-2.12 (m, 6H), 1.98-1.87 (m, 6H), 1.17 (s, 6H). LC-MS: [M+H] ⁺ = 509.36 (M+H), Purity- 98.15% by AUC, RT- 5.18, UV-260 nm HPLC: Purity- 90.79% by AUC, RT- 14.58, UV- 240 nm. Part AB - Preparation of 4,6-difluoro-N-(4-(3-((2-hydroxy-2-methylpropyl)carbamoyl) bicyclo[1.1.1]pentan-1-yl)phenyl)isoindoline-2-carboxamide (I-405) [1218] Step 1: Preparation of methyl 3-(4-(4,6-difluoroisoindoline-2- carboxamido)phenyl)bicyclo[1.1.1]pentane-1-carboxylate (2): 2 was prepared according to general procedure B, using J-Int-5 (119 mg, 0.77 mmol). The product was obtained after solid filtration, which afforded 185 mg of 2 (78% yield) as an off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.51 (d, J = 8.5 Hz, 2H), 7.24-7.10 (m, 4H), 4.77 (s, 4H), 3.63 (s, 3H), 2.23 (s, 6H). LC-MS: [M+H]⁺ = 399.14. [1219] Step 2: Preparation of 3-(4-(4,6-difluoroisoindoline-2-carboxamido) phenyl) bicyclo [1.1.1] pentane-1-carboxylic acid (3): 3 was prepared according to general procedure E, using 2 (185 mg, 0.46 mmol). The product was obtained after solid filtration, which afforded 180 mg of 3 as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 12.11 (s, 1H), 8.43 (s, 1H), 7.50 (d, J = 8.6 Hz, 2H), 7.24 - 7.09 (m, 4H), 4.77 (s, 4H), 2.18 (s, 6H). LC-MS: [M+H]⁺ = 385.17. [1220] Step 3: Preparation of 4,6-difluoro-N-(4-(3-((2-hydroxy-2-methylpropyl) carbamoyl)bicyclo[1.1.1]pentan-1-yl)phenyl)isoindoline-2-carboxamide: I-405 was prepared according to general procedure D using 3 (182 mg, 0.48 mmol). The product was obtained after solid filtration, which afforded 180 mg (83% yield) of I-405 as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.54-7.47 (m, 3H), 7.24-7.08 (m, 4H), 4.78 (s, 4H), 4.50 (s, 1H), 3.05 (d, J = 6.1 Hz, 2H), 2.15 (s, 6H), 1.04 (s, 6H). LCMS: 456.27 (M+H), Purity- 99.89% by AUC, RT- 4.88, UV-220 nm. HPLC: Purity- 98.92% by AUC, RT- 18.75, UV- 230 nm. Part AC - Preparation of tert-butyl 4-(4-(3-bromo-6,7-dihydro-5H-pyrrolo[3,4-b] pyridine- 6-carboxamido)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (I-350) [1221] I-350 was prepared according to general procedure B, using A-Int-4 (1.0 g, 2.53 mmol). The product was obtained after solid filtration, which afforded 650 mg of I-350 (51% yield) as a white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.60 (d, J = 2.2 Hz, 1H), 8.47 (s, 1H), 8.11 (d, J = 2.0 Hz, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.7 Hz, 2H), 6.08 (s, 1H), 4.77 (s, 2H), 4.73 (s, 2H), 3.98 (s, 2H), 3.53 (t, J = 5.6 Hz, 2H), 2.47-2.40 (m, 2H), 1.43 (s, 9H). LCMS: 501.0 (M+H), Purity- 99.73% by AUC, RT- 5.10, UV-245 nm. HPLC: Purity- 97.99% by AUC, RT- 16.50, UV- 250 nm. Part AD - Preparation of 3-fluoro-N-(4-(4-((2-methyl-2-(methylsulfonamido) propyl)carbamoyl)bicyclo[2.2.2]octan-1-yl)phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine- 6-carboxamide (I-191) [1222] Step 1: Preparation of benzyl (2-amino-2-methylpropyl) carbamate (3): To a stirred solution of 2 (1.0 g, 11.36 mmol) in toluene (20 mL) was added Benzyl chloroformate (1.48 g, 8.52 mmol) at 0^oC and then the reaction mixture was stirred at RT for 5 h. The reaction mixture was monitored by TLC and LCMS and after complete consumption of the starting material, the reaction mixture was poured into ice-cold water and extracted with EtOAc (2x100 mL). The combined organic extracts were dried with Na2SO4, filtered, and concentrated to give the crude. The product was purified by column chromatography (eluent-0-50% EtOAc in hexane) which afforded 200 mg of 3 (8.0% yield) as a colourless liquid.¹H NMR (300 MHz, DMSO-d6) δ 7.38- 7.28 (m, 5H), 7.20 (t, J = 5.9 Hz, 1H), 5.02 (s, 2H), 2.88 (d, J = 6.2 Hz, 2H), 1.36 (s, 2H), 0.93 (s, 6H). [1223] Step 2: Preparation of benzyl (2-methyl-2-(methylsulfonamido) propyl) carbamate (4): To a stirred solution of 3 (500 mg, 2.25 mmol) in DCM (20 mL) was added TEA (0.62 mL, 4.50 mmol), and methane sulfonic anhydride (590 mg, 3.37 mmol) at 0^oC and then the reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC and LCMS and after complete consumption of the starting material, the reaction mixture was poured into ice-cold water and extracted with DCM (2x100 mL). The combined organic extracts were dried with Na₂SO₄, filtered, and concentrated to obtain 170 mg of 4 (825.92% yield) as a colourless liquid. ¹H NMR (300 MHz, DMSO-d6) δ = 7.42-7.21 (m, 5H), 6.78 (s, 1H), 5.03 (s, 2H), 3.13 (d, J = 6.3 Hz, 2H), 2.94 (s, 3H), 1.19 (s, 6H). LC-MS: [M+H] ⁺ = 301.18 (M+H), Purity- 92.99% by AUC, RT- 4.68, UV-260 nm. [1224] Step 3: Preparation of N-(1-amino-2-methylpropan-2-yl) methanesulfonamide (1): To a stirred solution of 4 (170 mg, 0.566 mmol) in a mixture of THF: MeOH: Ethanol (15 mL) was added Pd/C (20 mg 50% wet) at RT under H₂, and then the reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a celite pad and the pad was washed with 10% MeOH- DCM and the filtrate was concentrated under reduced pressure to afford 60 mg of 1 (64% yield) as a white solid.¹H NMR (300 MHz, DMSO-d₆) δ 7.28-7.13 (m, 1H), 5.43-4.22 (m, 2H), 2.96 (s, 3H), 2.61 (s, 2H), 1.22 (s, 6H). [1225] Step 4: Preparation of 3-fluoro-N-(4-(4-((2-methyl-2-(methylsulfonamido) propyl) carbamoyl) bicyclo [2.2.2] octan-1-yl) phenyl)-5,7-dihydro-6H-pyrrolo [3,4-b] pyridine-6- carboxamide: I-191 was prepared according to general procedure D, using H-Int-4 (182 mg, 0.48 mmol). The product was obtained after solid filtration, which afforded 22 mg (32% yield) of I-191 as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.48 (s, 1H), 8.34 (s, 1H), 7.79 (dd, J = 2.6, 9.1 Hz, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.36 (t, J = 6.2 Hz, 1H), 7.22 (d, J = 8.8 Hz, 2H), 6.92 (s, 1H), 4.77 (s, 2H), 4.72 (s, 2H), 3.18 (d, J = 6.2 Hz, 2H), 2.95 (s, 3H), 1.78 (s, 12H), 1.20 (s, 6H). LC-MS: [M+H] ⁺ = 486.56 (M+H), Purity- 99.59% by AUC, RT- 5.02, UV-260 nm. HPLC: Purity- 98.12% by AUC, RT- 12.56, UV- 240 nm. Part AE - Preparation of 5-fluoro-N-(4-(4-(N-(2-hydroxy-2-methylpropyl)sulfamoyl) bicyclo[2.2.2]octan-1-yl)phenyl)isoindoline-2-carboxamide (I-210) [1226] To a stirred solution of I-351 (100 mg, 0.18 mmol) in DMSO was added NaOMe (9.9 mg, 0.18 mmol) at RT. The reaction was stirred at RT for 10 min, and then NCS (49 mg, 0.37 mmol), triethylamine (0.075 mL, 0.54 mmol), and 1 (13.7 mg, 0.37 mmol) were added at RT and the mixture was stirred for 16 h. The reaction was diluted with water and extracted with 10% MeOH-DCM (2x100 ml). The combined organic extract was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude solid. The product was purified by flash chromatography and eluted with 50-100% EtOAc-DCM to afford 15 mg (15% yield) of I-210 as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.3 (s, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.38 (dd, J = 5.2, 8.2 Hz, 1H), 7.26 - 7.10 (m, 4H), 6.78 (t, J = 6.1 Hz, 1H), 4.74 (s, 2H), 4.71 (s, 2H), 4.37 (s, 1H), 2.92 (d, J = 6.2 Hz, 2H), 1.97 - 1.74 (m, 12H), 1.08 (s, 6H). LCMS: 516.23 (M+H), Purity- 98.18% by AUC, RT- 5.12, UV-245 nm. HPLC: Purity- 95.37% by AUC, RT- 14.37, UV- 245 nm. Part AF - Preparation of 5-fluoro-N-(4-(3-((2-hydroxy-2-methylpropanamido) methyl)bicyclo[1.1.1]pentan-1-yl)phenyl)isoindoline-2-carboxamide (I-430) [1227] Step 1: Preparation of 5-fluoro-N-(4-(3-(hydroxymethyl) bicyclo [1.1.1] pentan-1- yl) phenyl) isoindoline-2-carboxamide (1): To a stirred solution of J-Int-7 (330 mg, 0.866 mmol) in dry THF (20 mL) was added LiBH4 (2.59 mL 0.27 mmol, 2.0M in THF) at 0°C under N2, and then the reaction mixture was stirred RT for 16 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with a saturated NH4Cl solution at 0°C, and extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to afford the 280 mg of 1 (92% yield) as an off- white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.32 (s, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.38 (dd, J = 5.2, 8.4 Hz, 1H), 7.23 (dd, J = 1.7, 8.9 Hz, 1H), 7.18 - 7.04 (m, 3H), 4.74 (s, 2H), 4.72 (s, 2H), 4.51 (t, J = 5.5 Hz, 1H), 3.45 (d, J = 5.5 Hz, 3H), 1.84 (s, 6H). LCMS: 353.41 (M+H). [1228] Steps 2 and 3: Preparation of N-(4-(3-(aminomethyl) bicyclo [1.1.1] pentan-1-yl) phenyl)-5-fluoroisoindoline-2-carboxamide hydrochloride (2): To a stirred solution of 1 (200 mg, 0.56 mmol) in a dry THF (5 mL) was added triethyl amine (0.31 mL 2.27 mmol), pyridine (179 mg, 2.27 mmol) and methane sulfonyl chloride (233 mg, 2.04 mmol) at 0°C under N₂. Then the reaction mixture was stirred at RT for 2 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with water and extracted with EtOAc. The combined organic extracts were dried over Na2SO4, and concentrated under reduced pressure to afford the crude, which was dissolved in DMF (5 mL) and NaN₃ (184 mg, 2.84 mmol) was added under N2. Then the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice-cold water and extracted with EtOAc. The combined organic extracts were dried over Na2SO4, concentrated under reduced pressure to afford the crude, and the crude was triturated with MTBE to afford 200 mg of 2 (91% yield) as a pale brown solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.34 (s, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.38 (dd, J = 5.0, 8.1 Hz, 1H), 7.23 (dd, J = 1.6, 9.1 Hz, 1H), 7.18 - 7.05 (m, 4H), 4.74 (s, 2H), 4.72 (s, 2H), 3.44 (s, 2H), 1.98 (s, 6H). LCMS: 378.42 (M+H). [1229] Step 4: Preparation of N-(4-(3-(aminomethyl) bicyclo [1.1.1] pentan-1-yl) phenyl)- 5-fluoroisoindoline-2-carboxamide hydrochloride (3): To a stirred solution of 2 (200 mg, 0.53 mmol) in ethanol (15 mL) was added 10% Pd/C (60 mg 50% wet) at RT under H2, then the reaction mixture was stirred at RT for 2 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a celite pad and washed with 50% MeOH-THF, and the filtrate was concentrated under reduced pressure to afford the crude product. The crude was dissolved in 1,4-dioxane (3 mL) and HCl (2.0 mL; 4.0N in 1,4-dioxane) was added at 0^oC. The reaction was stirred at RT for 16 h. The reaction was monitored by TLC and LCMS and after completion of the reaction, the volatiles were removed under reduced pressure, and the residue was triturated with MTBE and pentane to afford 100 mg of 3 (54% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.36 (s, 1H), 7.98 - 7.84 (m, 3H), 7.50 (d, J = 8.4 Hz, 2H), 7.46 - 7.31 (m, 1H), 7.22 (d, J = 8.7 Hz, 1H), 7.19 - 7.05 (m, 3H), 4.75 (s, 2H), 4.71 (s, 2H), 2.99 (q, J = 5.6 Hz, 2H), 2.00 - 1.97 (m, 6H). LCMS: 388.15 (M+H). [1230] Step 5: Preparation of 5-fluoro-N-(4-(3-((2-hydroxy-2-methylpropanamido) methyl) bicyclo [1.1.1] pentan-1-yl) phenyl) isoindoline-2-carboxamide: I-430 was prepared according to general procedure D using 3 (100 mg, 0.28 mmol). The product was obtained after solid filtration, which afforded 65 mg (52% yield) of I-430 as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.33 (s, 1H), 7.60 (t, J = 6.1 Hz, 1H), 7.47 (d, J = 8.5 Hz, 2H), 7.43-7.33 (m, 1H), 7.26-7.12 (m, 2H), 7.12-7.04 (m, 2H), 5.35 (s, 1H), 4.74 (s, 2H), 4.71 (s, 2H), 3.23 (d, J = 6.2 Hz, 2H), 1.83 (s, 6H), 1.26 (s, 6H). LCMS: 438.38 (M+H), Purity- 92.63% by AUC, RT- 4.92, UV-245 nm. HPLC: Purity- 89.78% by AUC, RT- 8.88, UV- 240 nm. Part AG - Preparation of 5-fluoro-N-(4-(3-(2-hydroxy-2-methylpropanoyl)-3- azabicyclo[3.2.1]octan-8-yl)phenyl)isoindoline-2-carboxamide (I-363) [1231] Step 1: Preparation of tert-butyl (4-(3-benzyl-8-hydroxy-3-azabicyclo [3.2.1] octan-8-yl) phenyl) carbamate (3): To a stirred solution of 1 (5.0 g, 18.45 mmol) in THF (Dry) (100 mL) was added n-BuLi (2.5 M in Hexane) (40 mL, 92.25 mmol) at -78^oC, and the mixture was stirred at -78°C for 1 h, then 2 (3.98 g, 18.45 mmol) was added at -78^oC. The reaction mixture was stirred at -78°C for 2 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with a saturated NH4Cl solution and diluted with ethyl acetate (2x200 mL), the combined organic extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. The product was purified by column chromatography (eluent-0-50% ethyl acetate in hexanes), which afforded 1.5 g of 3 (20% yield) as an off-white solid.¹H NMR (300 MHz, CDCl₃) δ 7.46-7.28 (m, 8H), 7.26 (s, 1H), 6.50 (s, 1H), 3.62 (s, 2H), 2.88 (d, J = 9.2 Hz, 2H), 2.65 (s, 2H), 2.53-2.27 (m, 2H), 2.42 (s, 1H), 1.87-1.72 (m, 2H), 1.57-1.46 (m, 10H), 1.45-1.36 (m, 2H). LCMS: 409.54 (M+H). [1232] Step 2: Preparation of 4-(3-benzyl-3-azabicyclo [3.2.1] octan-8-yl) aniline (4): To a stirred solution of 3 (1.5 g, 3.67 mmol) in a mixture of 1,2-dichloro ethane (80 mL) were added TFA (1.4 mL, 18.38 mmol) at 0^oC and the mixture was stirred for 15 min. Triethyl silane (1.74 mL, 11.02 mmol) was added slowly at 0^oC and the mixture was stirred at RT for 2 h. The reaction mixture was monitored by TLC and after completion of the reaction, the reaction mixture was quenched with water and extracted with EtOAc, dried over Na2SO4 and concentrated under reduced pressure to afford 700 mg of 4 (65.42% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 7.63 (d, J = 8.6 Hz, 2H), 7.37 - 7.15 (m, 9H), 3.23 (s, 2H), 2.93 (s, 1H), 2.66 (s, 2H), 2.40 - 2.23 (m, 4H), 1.93 - 1.77 (m, 4H). LCMS: 293.43 (M+H). [1233] Step 3: Preparation of phenyl (4-(3-benzyl-3-azabicyclo [3.2.1] octan-8-yl) phenyl) carbamate (5): 5 was prepared according to general procedure A, using 4 (280 mg, 0.95 mmol). The product was obtained after solid filtration, which afforded 390 mg (98% yield) of 5 as an off- white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.51 (s, 1H), 7.49 - 7.08 (m, 13H), 3.95 (s, 1H), 3.24 (s, 1H), 3.08 - 2.84 (m, 2H), 2.68 - 2.56 (m, 1H), 2.40 - 2.19 (m, 1H), 2.02 - 1.68 (m, 3H), 1.35 - 1.04 (m, 4H). LCMS: 413.22 (M+H). [1234] Step 4: Preparation of N-(4-(3-benzyl-3-azabicyclo [3.2.1] octan-8-yl) phenyl)-5- fluoroisoindoline-2-carboxamide (7): 7 was prepared according to general procedure B, using 5 (390 mg, 0.94 mmol). The product was obtained after solid filtration, which afforded 200 mg (46% yield) of 7 as a white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.49 (d, J = 8.6 Hz, 2H), 7.39 (dd, J = 5.2, 8.4 Hz, 1H), 7.29- 7.14 (m, 9H), 4.76 (s, 2H), 4.73 (s, 2H), 3.24 (s, 2H), 2.93-2.86 (m, 1H), 2.64 (s, 2H), 2.40-2.27 (m, 4H), 1.89-1.75 (m, 4H). LCMS: 465.58 (M+H). [1235] Step 5: Preparation of N-(4-(3-azabicyclo [3.2.1] octan-8-yl) phenyl)-5- fluoroisoindoline-2-carboxamide (8): To a stirred solution of 7 (200 mg, 0.343 mmol) in MeOH (5 mL) was added Pd/C (50 mg 50% wet) at RT under H2, then the reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a celite pad and the pad was washed with 10% MeOH-DCM, and the filtrate was concentrated under reduced pressure to afford the crude product. The product was triturated with MTBE and pentane to afford 150 mg of 8 (93.75% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.51 (d, J = 8.5 Hz, 2H), 7.44 - 7.32 (m, 1H), 7.28 - 7.12 (m, 4H), 4.75 (s, 2H), 4.73 (s, 2H), 4.16 - 4.06 (m, 1H), 3.44 - 3.37 (m, 2H), 3.16 (d, J = 4.8 Hz, 1H), 2.94 (d, J = 3.8 Hz, 1H), 2.90 - 2.81 (m, 2H), 2.33 - 2.23 (m, 2H), 1.83 - 1.76 (m, 3H). LCMS: 366.45 (M+H). [1236] Step 6: Preparation of 5-fluoro-N-(4-(3-(2-hydroxy-2-methylpropanoyl)-3- azabicyclo [3.2.1] octan-8-yl) phenyl) isoindoline-2-carboxamide: I-363 was prepared according to general procedure D using 8 (100 mg, 0.26 mmol). The product was obtained after solid filtration, which afforded 105 mg (56% yield) of I-363 as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.34 (s, 1H), 7.53 (d, J = 8.6 Hz, 2H), 7.43-7.35 (m, 1H), 7.29-7.20 (m, 3H), 7.19-7.10 (m, 1H), 5.24 (s, 1H), 4.75 (s, 2H), 4.72 (s, 2H), 4.51-4.32 (m, 1H), 4.04-3.83 (m, 1H), 3.29-3.07 (m, 1H), 2.93 (s, 1H), 2.85-2.65 (m, 3H), 1.88-1.72 (m, 3H), 1.60-1.44 (m, 1H), 1.39- 1.11 (m, 6H). LCMS: 452.35 (M+H), Purity- 95.60% by AUC, RT- 5.13, UV-245 nm. HPLC: Purity- 93.53% by AUC, RT- 14.49, UV- 240 nm. EXAMPLE 132 – SYNTHESIS OF 4-FLUORO-N-(4-(1-(2-METHYL-2-(METHYL SULFONAMIDO)PROPANOYL) PIPERIDIN-4-YL)PHENYL) ISOINDOLINE-2- CARBOXAMIDE (I-239) [1237] Step 1: Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (3): A mixture of compound 1 (25 g, 145.3 mmol), compound 2 (49.43 g, 159.9 mmol), Cs2CO3 (95.2 g, 290.7 mmol) in 1,4-dioxane: H2O (1:1) (250 mL) was degassed with argon for 5 min. X-phos (0.707 g, 14.53 mmol) and Pd2(dba)3 (6.86 g, 7.26 mmol) was added to the above mixture at RT. The reaction mixture was stirred for 15 min. while degassing with argon, and then the reaction mixture was heated to 90 ^oC and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through celite and washed with EtOAc. The organic layer was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water followed by brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. A sticky crude residue was obtained and triturated with n- heptane, and the precipitated solid was filtered and dried under reduced pressure to afford the title compound 3 (27.00 g, 98.40 mmol, 67.70% yield) as a cream solid. LC-MS (Method G): Ret. Time: 2.172 min, MS calcd. for Chemical Formula C16H22N2O2, 274.36; Found: 275.4 [M+H]⁺. [1238] Step 2: Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (5): To a stirred solution of compound 3 (2.0 g, 7.28 mmol) in DCM (20 mL) were added pyridine (1.75 mL, 21.87 mmol) and compound 4 (1.37 g, 8.74 mmol) at 0 ^oC and the mixture was stirred at RT for 2 h under nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water followed by brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether and n-pentane, and the filtered solid was dried under reduced pressure to afford the title compound 5 (2.5 g, 6.3 mmol, 75% yield) as an grey solid. LC-MS (Method F): Ret. Time: 2.126 min, MS calcd. for Chemical Formula: C23H26N2O4: 394.47; Found: 338.97 [(M- Isobutene) + H]⁺. [1239] Step 3: Synthesis of tert-butyl 4-(4-(4-fluoroisoindoline-2-carboxamido) phenyl)- 3,6-dihydro pyridine-1(2H)-carboxylate (7): To a stirred solution of compound 5 (2.5 g, 6.3 mmol) in DMF (25 mL) were added compound 6 (1.1 g, 6.3 mmol) and DIPEA (5.5 mL, 32 mmol) at RT and the mixture was stirred at 80 ^oC for 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water, and the precipitated solid was filtered and washed with diethyl ether and n-pentane and dried under reduced pressure to afford the title compound 7 (2.30 g, 5.3 mmol, 83%yield) as a pale grey solid. LC-MS (Method H): Ret. Time: 2.19 min, MS calcd. for Chemical Formula: C25H28FN3O3: 437.5; Found: 438.18 [M+H]⁺. [1240] Step 4: Synthesis of tert-butyl 4-(4-(4-fluoroisoindoline-2-carboxamido )phenyl) piperidine-1-carboxylate (8): To a stirred solution of compound 7 (0.2 g, 0.457 mmol) in THF (10 mL) was added 10% Pd/C (50% wet) (0.1 g) and stirred at RT for 16 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through celite and washed with EtOAc. The organic layer was concentrated under reduced pressure to afford the title crude compound 8 (0.18 g, 0.409 mmol, 89.59% yield) as a light white solid. LC-MS (Method H): Ret. Time: 2.429 min, MS calcd. for Chemical Formula: C25H30FN3O3: 439.53; Found: 440.0 [M+H]⁺. [1241] Step 5: Synthesis of 4-fluoro-N-(4-(piperidin-4-yl)phenyl)isoindoline-2- carboxamide hydrochloride (9): To a stirred solution of compound 8 (0.18 g, 0.41 mmol) in DCM (2 mL) was added 4M HCl in 1,4-dioxane (2 mL) slowly dropwise at 0 ^oC and the mixture was stirred at RT for 2 h. After completion of the reaction (monitored by TLC), volatiles were removed under reduced pressure. The residue was then stirred in diethyl ether (12 mL) and then with n-pentane (8 mL X 2), filtered and the solid compound was dried under reduced pressure to afford the desired compound 9 (0.135 g, 0.39 mmol, 97.12% yield) as a pale brown solid. The resulting crude obtained was used in the next step without further purification as an HCl salt. LC- MS (Method F): Ret. Time: 0.96 min, MS calcd. for Chemical Formula: C₂₀H₂₂FN₃O: 339.41; Found: 340.30 [M+H]⁺. [1242] Step 6: Synthesis of tert-butyl (1-(4-(4-(4-fluoroisoindoline-2-carboxamido) phenyl)piperidin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate (11): To a stirred solution of compound 9 (0.13 g, 0.38 mmol) in DMF (3 mL) were added compound 10 (0.117 g, 0.574 mmol), DIPEA (0.31 mL, 1.76 mmol) and HATU (0.30 g, 0.766 mmol) at RT and then the mixture was stirred at RT for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ice cold water, the precipitated solid was filtered, and concentrated under reduced pressure to afford the title compound 11 (0.175 g, 0.33 mmol, 87.09% yield) as an off white solid. LC-MS (Method F): Ret. Time: 1.32 min, MS calcd. for Chemical Formula: C₂₉H₃₇FN₄O₄: 524.64; Found: 525.44 [M+H]⁺. [1243] Step 7: Synthesis of N-(4-(1-(2-amino-2-methylpropanoyl)piperidin-4-yl)phenyl)- 4-fluoroiso indoline-2-carboxamide hydrochloride (12): To a stirred solution of compound 11 (0.175 g, 0.33 mmol) in DCM (2 mL) was added 4M HCl in 1,4-dioxane (2 mL) slowly dropwise at 0 ^oC and stirred at RT for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then stirred in diethyl ether (12 mL) and then with n-pentane (8 mL X 2), filtered and the solid compound was dried under reduced pressure to afford the desired compound 12 (0.135 g, 0.318 mmol, 95.33% yield) as a pale brown solid. The resulting crude obtained was used in the next step without further purification as an HCl salt. LC-MS (Method F): Ret. Time: 1.015 min, MS calcd. for Chemical Formula: C₂₄H₂₉FN₄O₂: 424.52; Found: 425.39 [M+H]⁺. [1244] Step 8: Synthesis of 4-fluoro-N-(4-(1-(2-methyl-2-(methylsulfonamido) propanoyl) piperidin-4-yl)phenyl)isoindoline-2-carboxamide (I-239): To a stirred solution of compound 12 (80 mg, 0.188 mmol) in DCM (4 ml) was added triethylamine (0.08 mL, 0.56 mmol) and Ms-Cl (22 mg, 0.188 mmol) at 0 ^oC. The reaction mixture was stirred at RT for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water followed by brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by CombiFlash (Nexgen-300) chromatography (4 g cartridge silica gel) using 3% MeOH in DCM as the eluent to afford the desired compound I-239 (14 mg, 0.03 mmol, 25.47% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d₆) δ: 8.35 (s, 1H), 7.57 (s, 1H), 7.48 (d, J = 8.6 Hz, 2H), 7.42 - 7.34 (m, 1H), 7.22 (d, J = 7.5 Hz, 1H), 7.17 - 7.09 (m, 3H), 4.81 (d, J = 8.6 Hz, 4H), 4.69 - 4.58 (m, 2H), 2.98 (s, 3H), 2.91 - 2.64 (m, 2H), 1.74 (d, J = 11.1 Hz, 2H), 1.67 - 1.52 (m, 3H), 1.46 (s, 6H). LC-MS (Method G): Ret time: 2.15 min, 97.68%; MS calcd. for Chemical Formula C₂₅H₃₁FN₄O₄S: 502.61; Found: 503.55 [M+H]⁺. HPLC: Ret time: 7.034 min, 97.84%; Method: column: X-Select CSH C18 (4.6*150) mm 5u Mobile Phase: A - 0.1% TFA in water, B – Acetonitrile, Inj Volume; 5.0µL, Flow Rate: 1.2 mL/minute, Column Oven Temp.:30°C, Gradient program: Time(min)/ B Conc. : 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. EXAMPLE 133 – SYNTHESIS OF N1-((1R,4R)-4-(4-(4-FLUOROISOINDOLINE-2- CARBOXAMIDO)PHENYL)CYCLOHEXYL)-N2-(2-HYDROXY-2- METHYLPROPYL)OXALAMIDE (I-265)

[1245] Step 1: Synthesis of tert-butyl (4'-nitro-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4- yl)carbamate (3): A mixture of compound 1 (5.0 g, 24.75 mmol), compound 2 (10.0 g, 30.94 mmol), and Cs2CO3 (24.19 g, 74.27 mmol) in 1,4-dioxane:H2O (1:1) (100 mL) was degassed with argon for 5 minutes. Pd2(dba)3 (1.16 g, 1.24 mmol) and X-phos (1.20 g, 2.47 mmol) was added to the above mixture at RT. The reaction mixture was stirred for 15 minutes while degassing with argon, and then the reaction mixture was heated to 90 ^oC and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The organic layer was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was triturated with n-heptane and filtered and dried under reduced pressure to afford the title compound 3 (5.0 g, 15.70 mmol, 63.44% yield) as an off white solid. The crude compound was used in the next step without further purification.¹H NMR (400 MHz, DMSO-d6) δ: 8.17 (d, J = 9.0 Hz, 2H), 7.68 (d, J = 9.0 Hz, 2H), 6.87 (d, J = 7.1 Hz, 1H), 6.39 - 6.30 (m, 1H), 3.60 - 3.52 (m, 1H), 2.57 - 2.53 (m, 1H), 2.47 - 2.41 (m, 1H), 2.17 - 2.07 (m, 1H), 1.97 - 1.89 (m, 1H), 1.62 - 1.53 (m, 1H), 1.40 (s, 9H), 1.39 - 1.36 (m, 1H). [1246] Step 2: Synthesis of tert-butyl (4-(4-aminophenyl)cyclohexyl)carbamate (4): To a stirred solution of compound 3 (5.0 g, 15.70 mmol) in MeOH (50 mL) was added 10% palladium on carbon (50% wet) (2.50 g) and the mixture was stirred at RT for 16 h under hydrogen gas at 150 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The combined organic layers were concentrated under reduced pressure to give a gummy mass. The crude residue was triturated with diethyl ether, filtered and dried to give two isomers: the trans-isomer 4 (2.7 g, off white solid) and another in the mother liquor (filtrate) cis-isomer (2.0 g, as an orange solid). The trans-isomer was used in next step. Data for trans-isomer: (2.7 g, off white solid): LC MS (Method I): Ret. Time: 1.85 min, 97.01%; MS calcd. for Chemical Formula C₁₇H₂₆N₂O₂: 290.41; Found: 235.0 [M- Isobutene+H]⁺.¹H NMR (400 MHz, DMSO-d6) δ: 6.86 (d, J = 8.3 Hz, 2H), 6.72 (br d, J = 8.1 Hz, 1H), 6.47 (d, J = 8.4 Hz, 2H), 4.78 (s, 2H), 3.30 - 3.18 (m, 1H), 2.27 - 2.18 (m, 1H), 1.83 (br d, J = 10.6 Hz, 2H), 1.71 (br d, J = 12.5 Hz, 2H), 1.44 - 1.32 (m, 11H), 1.30 - 1.19 (m, 2H). Data for Cis-isomer (2.0 g, orange solid): ¹H NMR (400 MHz, DMSO-d6) δ: 6.93 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 1H), 6.49 - 6.45 (m, 2H), 4.80 - 4.73 (m, 2H), 3.70 - 3.64 (m, 1H), 2.35 - 2.21 (m, 1H), 1.86 - 1.63 (m, 4H), 1.58 - 1.43 (m, 3H), 1.40 (s, 10H). [1247] Step 3: Synthesis of phenyl (4-((1r,4r)-4-((tert-butoxycarbonyl)amino) cyclohexyl) phenyl) carbamate (6): To a stirred solution of compound 4 (2.70 g, 9.3 mmol) in DCM (20 mL) was added pyridine (1.5 mL, 419 mmol) and compound 5 (1.7 g, 11 mmol) at 0 ^oC then stirred at RT for 2 h under nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether, n-pentane, filtered and dried under reduced pressure to afford the title compound 6 (2.6 g, 6.3 mmol, 64% yield) as an off white solid. The crude compound was used in the next step without further purification. LC-MS (Method I): Ret. Time: 2.53 min, MS calcd. for Chemical Formula C₂₄H₃₀N₂O₄: 410.51; Found: 355.0 [(M- isobutene)+H]⁺. [1248] Step 4: Synthesis of tert-butyl ((1r,4r)-4-(4-(4-fluoroisoindoline-2-carboxamido) phenyl) cyclohexyl)carbamate (8): To a stirred solution of compound 6 (0.7 g, 1.70 mmol) and compound 7 (0.343 g, 1.87 mmol) in DMF (10 mL) was added DIPEA (1.49 mL, 8.526 mmol) at RT and then stirred at 80 ^oC for 4 h under nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ice cold water and the precipitated solid was filtered and washed with diethyl ether and n-pentane and dried under reduced pressure to afford the title compound 8 (0.60 g, 1.323 mmol, 77.57% yield) as an off-white solid. LC-MS (Method I): Ret. Time: 2.49 min, MS calcd. for Chemical Formula C26H32FN3O3: 453.56; Found: 354.0 [M-Boc)+H]⁺. [1249] Step 5: Synthesis of N-(4-((1r,4r)-4-aminocyclohexyl)phenyl)-4-fluoroisoindoline- 2-carboxamide hydrochloride (9): To a stirred solution of compound 8 (0.7 g, 1.54 mmol) in DCM (10 mL) was added 4M HCl in 1,4-dioxane (5 mL) at 0 ^oC and the mixture was stirred at RT for 2 h. After completion of the reaction (monitored by TLC), volatiles were removed under reduced pressure. The residue was then stirred in diethyl ether (10 mL) and then with pentane (5 mL x 2), and filtered and the solid compound was dried under reduced pressure to afford the desired compound 9 (0.5 g, 1.415 mmol, 91.68% yield) as an off white solid. The resulting crude obtained was used in the next step without further purification as an HCl salt. LC-MS (Method I): Ret. Time: 1.711 min, MS calcd. for Chemical Formula C21H24FN3O: 353.44; Found: 354.3 [M+H]⁺. [1250] Step 6: Synthesis of ethyl 2-(((1r,4r)-4-(4-(4-fluoroisoindoline-2-carboxamido) phenyl)cyclohexyl)amino)-2-oxoacetate (11): To the stirred solution of compound 9 (0.2 g, 0.565 mmol) in DCM (20 mL) was added triethylamine (0.24 mL, 1.69 mmol) at 0 ˚C, followed by ethyl 2-chloro-2-oxoacetate 10 (0.086 g, 0.622 mmol) slowly drop wise and the reaction mixture was stirred to RT for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with DCM. The combined organic layers were with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford crude compound 11 (0.15 g, 0.33 mmol, 58.45% yield) as an off white solid. The crude compound was used in the next step without further purification. LC-MS (Method I): Ret. Time: 2.24 min, MS calcd. for Chemical Formula: C25H28FN3O4: 453.51; found: 454.1 [M+H]⁺. [1251] Step 7: Synthesis of N1-((1r,4r)-4-(4-(4-fluoroisoindoline-2-carboxamido)phenyl) cyclohexyl)-N2-(2-hydroxy-2-methylpropyl)oxalamide (I-265): To a stirred solution of compound 11 (0.15 g, 0.33 mmol) in MeOH (5 mL) were added triethylamine (0.14 mL, 0.99 mmol) and 1-amino-2-methylpropan-2-ol 12 (0.093 g, 0.99 mmol) and the reaction mixture was stirred at 65⁰C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered and washed with MeOH to give a solid compound that was dried under reduced pressure to afford the title compound (100 mg, 0.20 mmol, 60.88% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d₆) δ: 8.66 (d, J = 8.6 Hz, 1H), 8.32 (s, 1H), 8.28 - 8.20 (m, 1H), 7.45 (d, J = 8.3 Hz, 2H), 7.41 - 7.34 (m, 1H), 7.22 (d, J = 7.4 Hz, 1H), 7.14 (d, J = 7.9 Hz, 3H), 4.80 (d, J = 9.1 Hz, 4H), 4.66 (s, 1H), 3.74 - 3.64 (m, 1H), 3.13 (d, J = 6.0 Hz, 2H), 2.44 -2.39 (s, 1H), 1.81 (d, J = 7.0 Hz, 4H), 1.62 - 1.47 (m, 4H), 1.07 (s, 6H). LCMS (Method I): Ret. Time: 2.15 min, 99.84%; MS calcd. Formula: C27H33FN4O4: 496.58; Found: 497.2 [M+H]⁺. Chiral HPLC: Ret. Time: 5.539 min, 100.00%; Method: column: Mobile Phase A: n-Hexane, 633574 Mobile Phase B: EtOH: MeOH (1:1), Column Name: Chiralpak. IC (250X4.6mm, 5µm), A B: 20:80. HPLC: Ret. Time: 7.455 min, 98.86%; Method: column: X-Select CSH C18 (4.6*150) mm 5u, Mobile Phase: A - 0.1% TFA in water, B – Acetonitrile, Inj Volume; 5.0µL, Flow Rate: 1.2 mL/min, Column Oven Temp.:30 °C, Gradient program: Time (min)/ B Conc. : 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. EXAMPLE 134 – SYNTHESIS OF N1-((1R,4R)-4-(4-(3-FLUORO-6,7-DIHYDRO-5H- PYRROLO[3,4-B]PYRIDINE-6-CARBOXAMIDO)PHENYL)CYCLOHEXYL)-N2-(2- HYDROXY-2-METHYLPROPYL)OXALAMIDE (I-204) [1252] Step 1: Synthesis of tert-butyl (4'-nitro-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4- yl)carbamate (3): A mixture of compound 1 (5 g, 24.75 mmol), compound 2 (10 g, 30.94 mmol), and Cs2CO3 (24 g, 73.65 mmol) in 1,4-dioxane:H2O (1:1) (100 mL) was degassed with argon for 5 minutes. Pd2(dba)3 (1.3 g, 1.4 mmol) and X-phos (1.2 g, 2.5 mmol) was added to the above mixture at RT. The reaction mixture was stirred for 15 minutes while degassing with argon, and then the reaction mixture was heated to 90 ^oC and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The organic layer was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude was triturated with n-heptane, filtered and dried under reduced pressure to afford the title compound 3 (4.2 g, 13 mmol, 53% yield) as an off white solid. The crude compound was used in the next step without further purification. LC-MS (Method I): Ret. Time : 2.30 min, MS calcd. for Chemical Formula C17H22N2O4: 318.37; Found: 262.9 [(M-Isobutene)+H]⁺. [1253] Step 2: Synthesis of tert-butyl (4-(4-aminophenyl)cyclohexyl)carbamate (4): To a stirred solution of compound 3 (4.2 g, 13 mmol) in MeOH (40 mL) was added 10% palladium on carbon (50% wet) (2.0 g) and the mixture was stirred at RT for 16 h under hydrogen gas at 150 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The combined organic layers were concentrated under reduced pressure to give a gummy mass. The crude residue was triturated with diethyl ether, the precipitated solid was filtered and dried under reduced pressure to give compound 4 (Trans-isomer, 1.0 g, off white solid) and the other isomer that was found in the mother liquor (filtrate) was concentrated to give the cis-isomer (3.0 g, as a solid). The trans isomer was used for the next step. LC-MS (Method I): Ret. Time: 1.98 min, MS calcd. for Chemical Formula C₁₇H₂₆N₂O₂: 290.41; Found: 235.0 [M-Isobutene+H]⁺. [1254] Step 3: Synthesis of phenyl (4-((1r,4r)-4-((tert-butoxycarbonyl)amino) cyclohexyl) phenyl)carbamate (6): To a stirred solution of compound 4 (1.0 g, 3.44 mmol) in DCM (30 mL) was added pyridine (0.56 mL, 6.88 mmol) and compound 5 (0.647 g, 4.13 mmol) at 0 ^oC then the mixture was stirred at RT for 2 h under nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether, filtered and dried under reduced pressure to give compound 6 (1.2 g, 2.9 mmol, 85% yield) as an off white solid. LC-MS (Method I): Ret. Time: 2.28 min, MS calcd. for Chemical Formula C24H30N2O4: 410.51; Found: 354.9 [(M-isobutene)+H]⁺. [1255] Step 4: Synthesis of tert-butyl ((1r,4r)-4-(4-(3-fluoro-6,7-dihydro-5H-pyrrolo [3,4- b]pyridine-6-carboxamido)phenyl)cyclohexyl)carbamate (8): To a stirred solution of compound 6 (0.55 g, 1.34 mmol) and compound 7 (0.292 g, 1.608 mmol) in DMF (10 mL) was added DIPEA (1.17 mL, 6.69 mmol) at RT and then the mixture was refluxed at 80 ^oC for 3-4 h under nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to afford the title compound 8 (0.55 g, 1.21 mmol, 90.32% yield) as an off white solid. LC-MS (Method I): Ret. Time: 1.32 min, MS calcd. for Chemical Formula C25H31FN4O3: 454.55; Found: 455.61 [M+H]⁺. [1256] Step 5: Synthesis of N-(4-((1r,4r)-4-aminocyclohexyl)phenyl)-3-fluoro-5,7- dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide hydrochloride (9): To a stirred solution of compound 8 (0.55 g, 1.21 mmol) in DCM (10 mL) was added 4 M HCl in 1,4-dioxane (5 mL) at 0 ^oC and the mixture was stirred at RT for 2-3 h. After completion of the reaction (monitored by TLC), volatiles were removed under reduced pressure. The residue was then stirred in diethyl ether (10 mL) and then with pentane (5 mL x 2), filtered and the solid compound was dried under reduced pressure to afford the desired compound 9 (0.45 g, crude) as an off white solid. The resulting crude obtained was used in the next step without further purification as an HCl salt. LC- MS (Method I): Ret. Time: 1.28 min, MS calcd. for Chemical Formula C20H23FN4O: 354.4; Found: 355.1 [M+H]⁺. [1257] Step 6: Synthesis of ethyl 2-(((1r,4r)-4-(4-(3-fluoro-6,7-dihydro-5H-pyrrolo[3,4- b]pyridine-6-carboxamido)phenyl)cyclohexyl)amino)-2-oxoacetate (11): To a stirred solution of compound 9 (0.35 g, 0.98 mmol) in DCM (10 mL) was added NaH (60%) (00.158 g, 3.95 mmol) at 0 ˚C, followed by ethyl 2-chloro-2-oxoacetate 10 (0.165 g, 1.185 mmol) slowly drop wise and the reaction mixture was stirred to RT for 3-4 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by CombiFlash (Nexgen- 300) chromatography (12 g cartridge silica gel) using 100% EtOAc in n-heptane as an eluent to afford the title crude compound 11 (0.2 g, 0.44 mmol, 44.56% yield) as an off white solid. LC-MS (Method I): Ret. Time: 1.78 min, MS calcd. for Chemical Formula: C₂₅H₃₁FN₄O₃: 455.1; found: 455.3 [M+H]⁺. [1258] Step 7: Synthesis of N1-((1r,4r)-4-(4-(3-fluoro-6,7-dihydro-5H-pyrrolo[3,4-b] pyridine-6-carboxamido)phenyl)cyclohexyl)-N2-(2-hydroxy-2-methylpropyl)oxalamide (I- 204): To a stirred solution of compound 11 (0.2 g, 0.44 mmol) in MeOH (5 mL) were added 1- amino-2-methylpropan-2-ol 12 (0.124 g, 1.32 mmol) and triethylamine (0.185 mL, 1.32 mmol) and the reaction mixture was stirred at 60-70 ^oC for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled and the precipitated solid was filtered, washed with MeOH and dried under reduced pressure to afford the title compound (87 mg, 0.174 mmol, 39.73% yield) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ: 8.68 - 8.63 (m, 1H), 8.48 (d, J = 1.1 Hz, 1H), 8.33 (s, 1H), 8.24 (t, J = 6.4 Hz, 1H), 7.80 (dd, J = 2.5, 9.0 Hz, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 4.78 (s, 2H), 4.73 (s, 2H), 4.66 (s, 1H), 3.78 - 3.65 (m, 1H), 3.13 (d, J = 6.3 Hz, 2H), 2.43 - 2.38 (m, 1H), 1.81 (d, J = 8.3 Hz, 4H), 1.61 - 1.48 (m, 4H), 1.07 (s, 6H). LCMS (Method F): Ret. Time: 1.08 min, 96.44%; MS calcd. Formula: C₂₆H₃₂FN₅O₄: 497.57; Found: 498.58 [M+H]+. HPLC: Ret. Time: 6.876 min, 98.10%; Method: column: X-Select C18 (4.6x150)mm 5.0µm, Mobile Phase A: 0.1% FA in (ACN:H2O) (5:95)V/V, Mobile Phase B: Acetonitrile (100%), Column Temperature: 30 °C, Flow Rate: 1.0 mL/min, Gradient: 0.00/5, 1.00/5, 8.00/100, 12.00/100, 16.00/5, 18.00/5 Diluent: ACN : Water (80:20). Prep-HPLC purification method: column Name : X-SELECT, Mobile Phase A: 0.1% Formic Acid in Water, Mobile Phase B: Acetonitrile, Flow rate : 22 ml/min, Loading(mg/injection): 20, Gradient(Time/%B): 0/10, 3/10, 8/35, 20/50, Sample Diluent: ACN+WATER+THF+DMSO. EXAMPLE 135 – SYNTHESIS OF N1-((1R,4R)-4-(4-(4-FLUOROISOINDOLINE-2- CARBOXAMIDO)PHENYL)CYCLOHEXYL)-N2-(2-HYDROXY-2-METHYLPROPYL) OXALAMIDE (I-264) [1259] Step 1: Synthesis of tert-butyl (4'-nitro-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4- yl)carbamate (3): A mixture of compound 1 (5.0 g, 24.75 mmol), compound 2 (10.0 g, 30.94 mmol), and Cs2CO3 (24.19 g, 74.27 mmol) in 1,4-dioxane:H2O (1:1) (100 mL) was degassed with argon for 5 minutes. Pd₂(dba)₃ (1.16 g, 1.24 mmolX-phos (1.20 g, 2.47 mmol) was added to the above mixture at RT. The reaction mixture was stirred for 15 minutes while degassing with argon, and then the reaction mixture was heated to 90 ^oC and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The organic layer was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was triturated with n-heptane, filtered and dried under reduced pressure to afford the title compound 3 (5.0 g, 15.70 mmol, 63.44% yield) as an off white solid. The crude compound was used in the next step without further purification.¹H NMR (400 MHz, DMSO-d6) δ: 8.17 (d, J = 9.0 Hz, 2H), 7.68 (d, J = 9.0 Hz, 2H), 6.87 (d, J = 7.1 Hz, 1H), 6.39 - 6.30 (m, 1H), 3.60 - 3.52 (m, 1H), 2.57 - 2.53 (m, 1H), 2.47 - 2.41 (m, 1H), 2.17 - 2.07 (m, 1H), 1.97 - 1.89 (m, 1H), 1.62 - 1.53 (m, 1H), 1.40 (s, 9H), 1.39 - 1.36 (m, 1H). [1260] Step 2: Synthesis of tert-butyl (4-(4-aminophenyl)cyclohexyl)carbamate (4): To a stirred solution of compound 3 (5.0 g, 15.70 mmol) in MeOH (50 mL) was added 10% palladium on carbon (50% wet) (2.50 g) and stirred at RT for 16 h under hydrogen gas at 150 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The combined organic layers were concentrated under reduced pressure to give a gummy mass. The crude residue was triturated with diethyl ether, filtered and dried to give two isomers. One was the trans-isomer 4 (2.7 g, off white solid) and the cis isomer (2.0 g, as an orange solid) was in the mother liquor (filtrate). The cis-isomer was used in the next step. Data for trans isomer (2.7g, off white solid): LC-MS (Method I): Ret. Time: 1.85 min, 97.01%; MS calcd. for Chemical Formula C17H26N2O2: 290.41; Found: 235.0 [M- Isobutene+H]⁺.¹H NMR (400 MHz, DMSO-d6) δ: 6.86 (d, J = 8.3 Hz, 2H), 6.72 (br d, J = 8.1 Hz, 1H), 6.47 (d, J = 8.4 Hz, 2H), 4.78 (s, 2H), 3.30 - 3.18 (m, 1H), 2.27 - 2.18 (m, 1H), 1.83 (br d, J = 10.6 Hz, 2H), 1.71 (br d, J = 12.5 Hz, 2H), 1.44 - 1.32 (m, 11H), 1.30 - 1.19 (m, 2H). Data for cis-isomer (2.0 g, orange solid): ¹H NMR (400 MHz, DMSO-d6) δ: 6.93 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 1H), 6.49 - 6.45 (m, 2H), 4.80 - 4.73 (m, 2H), 3.70 - 3.64 (m, 1H), 2.35 - 2.21 (m, 1H), 1.86 - 1.63 (m, 4H), 1.58 - 1.43 (m, 3H), 1.40 (s, 10H). [1261] Step 3: Synthesis of phenyl (4-((1s,4s)-4-((tert-butoxycarbonyl)amino)cyclohexyl) phenyl)carbamate (6): To a stirred solution of compound 4 (2 g, 6.88 mmol) in DCM (10 mL) was added pyridine (1.12 mL, 413.77 mmol) and compound 5 (1.294 g, 5.3 mmol) at 0 ^oC, then the mixture was stirred at RT for 2 h under nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether, n-pentane, filtered and dried under reduced pressure to afford the title compound 6 (1.8 g, 4.4 mmol, 68% yield) as an off white solid. The crude compound was used in the next step without further purification. LC- MS (Method I): Ret. Time: 2.55 min, MS calcd. for Chemical Formula C₂₄H₃₀N₂O₄: 410.51; Found: 311.0 [(M-Boc)+H]⁺. [1262] Step 4: Synthesis of tert-butyl ((1s,4s)-4-(4-(4-fluoroisoindoline-2- carboxamido)phenyl) cyclohexyl)carbamate (8): To a stirred solution of compound 6 (1.8 g, 4.4 mmol) and compound 7 (0.72 g, 5.3 mmol) in DMF (10 mL) was added DIPEA (3.8 mL, 22 mmol) at RT and then the mixture was stirred at 80 ^oC for 4 h under nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ice cold water and the precipitated solid was filtered and washed with diethyl ether and n-pentane and dried under reduced pressure to afford the title compound 8 (1.4 g, 3.1 mmol, 70% yield) as an off-white solid. LC-MS (Method I): Ret. Time: 2.49 min, MS calcd. for Chemical Formula C26H32FN3O3: 453.56; Found: 398.0 [M-Isobutene)+H]⁺. [1263] Step 5: Synthesis of N-(4-((1s,4s)-4-aminocyclohexyl)phenyl)-4-fluoro isoindoline- 2-carboxamide hydrochloride (9): To a stirred solution of compound 8 (1.4 g, 3.1 mmol) in DCM (10 mL) was added 4M HCl in 1,4-dioxane (5 mL) at 0 ^oC and the mixture was stirred at RT for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then stirred in diethyl ether (10 mL) and then with pentane (5 mL x 2), and the filtered solid compound was dried under reduced pressure to afford the desired compound 9 (1.0 g, 2.83 mmol, crude) as an off white solid. The resulting crude obtained was used in the next step without further purification as an HCl salt. LC-MS (Method I): Ret. Time: 1.692 min, MS calcd. for Chemical Formula C21H24FN3O: 353.44; Found: 354.2 [M+H]⁺. [1264] Step 6: Synthesis of ethyl 2-(((1s,4s)-4-(4-(4-fluoroisoindoline-2-carboxamido) phenyl)cyclohexyl)amino)-2-oxoacetate (11): To the stirred solution of compound 9 (0.2 g, 0.565 mmol) in DCM (10 mL) was added triethylamine (0.24 mL, 1.69 mmol) at 0 ˚C, followed by ethyl 2-chloro-2-oxoacetate 10 (0.086 g, 0.622 mmol) drop wise and the reaction mixture was stirred to 0 ^oC for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by CombiFlash (Nexgen-300) chromatography (4 g cartridge silica gel) using 100% EtOAc in n-heptane as an eluent to afford the crude compound 11 (0.16 g, 0.35 mmol, 62.34% yield) as an off white solid. LC-MS (Method I): Ret. Time: 2.27 min, MS calcd. for Chemical Formula: C25H28FN3O4: 453.51; found: 454.1 [M+H]⁺. [1265] Step 7: Synthesis of N1-((1s,4s)-4-(4-(4-fluoroisoindoline-2-carboxamido) phenyl) cyclohexyl)-N2-(2-hydroxy-2-methylpropyl)oxalamide (I-264): To a stirred solution of compound 11 (0.15 g, 0.33 mmol) in MeOH (5 mL) were added triethylamine (0.14 mL, 0.99 mmol) and 1-amino-2-methylpropan-2-ol 12 (0.093 g, 0.99 mmol) and the reaction mixture was stirred at 65⁰C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered and washed with MeOH to give the solid compound, which was dried under reduced pressure to afford the title compound (35 mg, 0.070 mmol, 21.31% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d₆) δ: 8.39 (d, J = 7.6 Hz, 1H), 8.34 (s, 1H), 8.28 (t, J = 6.1 Hz, 1H), 7.47 (d, J = 8.5 Hz, 2H), 7.42 - 7.35 (m, 1H), 7.23 - 7.12 (m, 4H), 4.81 (d, J = 8.9 Hz, 4H), 4.66 (s, 1H), 4.02 - 3.97 (m, 1H), 3.14 (d, J = 6.4 Hz, 2H), 2.58 – 2.55 (m, 1H), 1.88 - 1.61 (m, 8H), 1.08 (s, 6H). LCMS (Method I): Ret. Time: 2.15 min, 99.84%; MS calcd. Formula: C₂₇H₃₃FN₄O₄: 496.58; Found: 497.3 [M+H]⁺. Chiral HPLC: Ret. Time: 7.029 min, 99.38%; Method: column: Mobile Phase A: n-Hexane, 633574 Mobile Phase B: EtOH: MeOH (1:1), Column Name: Chiralpak. IC (250X4.6mm, 5µm), A B: 20:80. HPLC: Ret. Time: 7.814 min, 95.06%; Method: column: X-Select C18 (4.6x150)mm 5.0µm, Mobile Phase A: 0.1% FA in (ACN:H₂O) (5:95)V/V, Mobile Phase B: Acetonitrile (100%) Column Temperature: 30 °C, Flow Rate: 1.0 mL/min Gradient: 0.00/5, 1.00/5, 8.00/100, 12.00/100, 16.00/5, 18.00/5 Diluent: ACN: Water (80:20). EXAMPLE 136 - SYNTHESIS OF N-(4-(1-(1-ACETAMIDOCYCLOPENTANE-1- CARBONYL)PIPERIDIN-4-YL)PHENYL)-3-FLUORO-5,7-DIHYDRO-6H- PYRROLO[3,4-B]PYRIDINE-6-CARBOXAMIDE (I-237) [1266] Step 1: Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (3): A mixture of compound 1 (10 g, 56.38 mmol), compound 2 (20 g, 64.68 mmol), and K₃PO₄ (40 g, 184.7 mmol) in 1,2-DME: H₂O (10:2) (120 mL) was degassed with argon for 5 min. Pd(dppf)Cl2.DCM (2.3 g, 2.8 mmol) was added to the above mixture at RT. The reaction mixture was stirred for 15 min. while degassing with argon, and then the reaction mixture was stirred at 90 ^oC for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The organic layer was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water followed by brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by Combi-Flash chromatography (eluting with 25-35% EtOAc in heptane) to afford the title compound 3 (11 g, 40.08 mmol, 69% yield) as a white solid. LC-MS (Method F): Ret. Time: 1.20 min, MS calcd. for Chemical Formula C₁₆H₂₂N₂O₂, 274.36; Found: 275.41 [M+H]⁺. [1267] Step 2: Synthesis of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (4): To a stirred solution of compound 3 (5.50 g, 20.04 mmol) in methanol (50 mL) was added 10% palladium on carbon (50% wet) (2.77 g) and the mixture was stirred at RT for 16 h under hydrogen atmosphere at 150 psi pressure in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The organic layer was concentrated under reduced pressure to afford the title crude compound 4 (5.5 g, 20 mmol, 99% yield) as a pale brown solid. LC-MS (Method G): Ret. Time: 1.06 min, MS calcd. for Chemical Formula: C₁₆H₂₄N₂O₂: 276.38; found: 221.35 [(M-Isobutene)+H]⁺. [1268] Step 3: Synthesis of tert-butyl 4-(4-((phenoxycarbonyl) amino)phenyl) piperidine- 1-carboxylate (6): To a stirred solution of compound 4 (5.5 g, 20 mmol) in DCM (10 mL) were added pyridine (3.20 mL, 40 mmol) and DMAP (0.25 g, 2.0 mmol) followed by compound 5 (3.5 g, 22 mmol) at 0 ^oC, then the mixture was stirred at RT for 2 h under nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water followed by brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether and n-pentane, and the filtered solid was dried under reduced pressure to afford the title compound 6 (6.0 g, 15 mmol, 62% yield) as an off white solid. The crude compound was used in the next step without further purification. LC-MS (Method I): Ret. Time: 3.016 min, MS calcd. for Chemical Formula: C₂₃H₂₈N₂O₄: 396.49; found: 340.9 [(M-Isobutene) + H]⁺. [1269] Step 4: Synthesis of tert-butyl 4-(4-(3-fluoro-6,7-dihydro-5H-pyrrolo[3,4- b]pyridine-6-carboxamido)phenyl)piperidine-1-carboxylate (8): To a stirred solution of compound 6 (2 g, 5.04 mmol) in DMF (10 mL) were added compound 7 (0.789 g, 4.53 mmol) and DIPEA (5.13 mL, 30.24 mmol) at RT and the mixture was stirred at 80 ^oC for 6 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water followed by brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether and n-pentane, and the filtered solid was dried under reduced pressure to afford the title compound 8 (1.5 g, 3.40 mmol, 80% yield) as pale brown solid. LCMS (Method F): Ret. Time: 1.32 min, MS calcd. for Chemical Formula: C₂₄H₂₉FN₄O₃: 440.51; found: 441.41 [M+H]⁺. [1270] Step 5: Synthesis of 3-fluoro-N-(4-(piperidin-4-yl)phenyl)-5,7-dihydro-6H- pyrrolo[3,4-b]pyridine-6-carboxamide hydrochloride (9): To a stirred solution of compound 8 (1.5 g, 3.40 mmol) in DCM (30 mL) was added 4M HCl in 1,4-dioxane (7 mL) drop-wise at 0 ^oC and the mixture was stirred at RT for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then stirred in diethyl ether (15 mL) and then with n-pentane (10 mL x 2), and the filtered solid compound was dried under reduced pressure to afford the desired compound 9 (1.3 g, crude) as a brown solid. The resulting crude obtained was used in the next step without further purification as an HCl salt. LC-MS (Method F): Ret. Time: 0.80 min, MS calcd. for Chemical Formula: C₂₀H₂₁FN₄O: 340.40; found: 341.32 [M+H]⁺. [1271] Step 6: Synthesis of tert-butyl (1-(4-(4-(3-fluoro-6,7-dihydro-5H-pyrrolo[3,4- b]pyridine-6-carboxamido)phenyl)piperidine-1-carbonyl)cyclopentyl)carbamate (11): A mixture of 1-((tert-butoxycarbonyl)amino)cyclopentane-1-carboxylic acid 10 (0.252 g, 1.102 mmol) in DMF (3 mL) were added DIPEA (0.63 mL, 3.672 mmol), EDC.HCl (0.43 g, 2.203 mmol), and HOBt (0.2 g, 1.47 mmol) and the mixture stirred at RT for 20 min. and a solution of compound 9 (0.25 g, 0.734 mmol) was added. The reaction mixture stirred at RT for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ice cold water. The precipitated solid was filtered, washed with water, and dried under reduced pressure to afford the crude compound 11 (0.275 g, 0.49 mmol, 67.88% yield) as a pale brown solid. The crude compound was used in the next step without further purification. LC-MS (Method G): Ret. Time: 2.247 min, MS calcd. for Chemical Formula: C30H38FN5O4: 551.66; Found: 552.67 [M+H]⁺. [1272] Step 7: Synthesis of N-(4-(1-(1-aminocyclopentane-1-carbonyl)piperidin-4- yl)phenyl)-3-fluoro-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide hydrochloride (12): To a stirred solution of compound 11 (0.275 g, 0.49 mmol) in DCM (3 mL) was added 4 M HCl in dioxane (3 mL) drop-wise at 0 ^oC and stirred at RT for 3 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure and then triturated with diethyl ether (5 mL), washed with n-pentane (3 x 2 mL ), filtered and dried under vacuum to give the desired compound 12 (0.22 g, crude) as a pale brown solid. The resulting crude obtained was used in the next step without further purification as a HCl salt. LCMS (Method G): Ret. Time: 1.88 min, MS calcd. for Chemical Formula: C25H30FN5O2: 451.55; Found: 452.64 [M+H]⁺. [1273] Step 8: Synthesis of N-(4-(1-(1-acetamidocyclopentane-1-carbonyl)piperidin-4- yl)phenyl)-3-fluoro-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide (I-237): To a stirred solution of compound 12 (0.06 g, 0.22 mmol) in DCM (3 mL) was added TEA (0.06 mL, 0.398 mmol) and acetic anhydride (0.015 g, 0.146 mmol) drop-wise at 0 °C. The reaction mixture was stirred at RT for 5 h. After completion of the reaction (monitored by TLC), the reaction mixture was directly filtered, washed with diethyl ether and dried under vacuum to give the crude. The obtained crude compound was triturated with 20% MeOH + diethyl ether, filtered and dried under vacuum to afford title of the compound (17 mg, 0.034 mmol, 25.92% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d₆) δ: 8.49 - 8.46 (m, 1H), 8.35 (s, 1H), 8.21 (s, 1H), 7.79 (dd, J = 2.6, 8.9 Hz, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H), 4.77 (s, 2H), 4.72 (s, 2H), 4.51 - 4.24 (m, 2H), 3.07 - 2.83 (m, 1H), 2.75 - 2.69 (m, 1H), 2.59 (d, J = 2.1 Hz, 1H), 2.26 - 2.12 (m, 2H), 1.87 - 1.79 (m, 5H), 1.73 (d, J = 11.9 Hz, 2H), 1.64 - 1.53 (m, 4H), 1.43 - 1.30 (m, 2H). LC-MS (Method G): Ret time: 1.95 min, 96.93%; MS calcd. for Chemical Formula C27H32FN5O3: 493.58; Found: 494.59 [M+H]⁺. HPLC: Ret time: 6.274 min, 97.40%; Method: column: X-Select CSH C18 (4.6 x 150mm, 5 ^m) Mobile Phase: A - 0.1% TFA in water, B – Acetonitrile, Inj Volume; 5.0µL, Flow Rate: 1.2 mL/minute Column Oven Temp.: 30 °C, Gradient program: Time(min)/ B Conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. EXAMPLE 137 – SYNTHESIS OF 5-FLUORO-N-(4-(4-(3-METHYL-2-OXOIMIDA ZOLIDIN-1-YL) BICYCLO [2.2.2] OCTAN-1-YL) PHENYL) ISOINDOLINE-2- CARBOXAMIDE (I-482) [1274] Step 1: Preparation of tert-butyl (2-((4-(4-(5-fluoroisoindoline-2- carboxamido)phenyl)bicyclo[2.2.2]octan-1-yl)amino)ethyl)(methyl)carbamate (2): To a stirred solution of 1A (500 mg, 1.31 mmol) in 1,2-DCE (5 mL) was added 1 (272 mg, 1.58 mol) and sodium triacetoxyborohydride (416 mg, 1.96 mmol) at RT and maintained at RT for 16 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with water (50 mL) and extracted with 10% MeOH in DCM (2x50 mL). The combined organic layer was dried over Na₂SO₄ and concentrated under reduced pressure to afford the crude product. The crude product was triturated with MTBE to obtain 500 mg of 2 (71% yield) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.47-7.35 (m, 3H), 7.25-7.13 (m, 5H), 4.73 (s, 2H), 4.71 (s, 2H), 3.21-3.12 (m, 2H), 2.79 (s, 3H), 2.62 (t, J = 6.8 Hz, 2H), 1.85-1.76 (m, 6H), 1.63-1.51 (m, 6H), 1.39 (s, 9H). LCMS = 538.1 (M+H). Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mm Ammonium Acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; Flow rate: 0.6mL/min. [1275] Step 2: Preparation of 5-fluoro-N-(4-(4-((2-(methylamino) ethyl) amino) bicyclo [2.2.2] octan-1-yl) phenyl) isoindoline-2-carboxamide (3): To a stirred solution of 2 (400 mg, 0.750 mmol) in DCM (10 mL) was added TFA (5 mL), at 0°C under N2 atmosphere, then the reaction mixture was stirred at RT for 2 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was basified to (pH ~8-9) with a sat NaHCO3 solution (30 mL). The reaction mixture was extracted with DCM (2x50 mL). The combined organic layer was dried over Na₂SO₄, and concentrated under reduced pressure to afford 300 mg of 3 as an off-white solid. The obtained compound was used for the next without purification. LCMS: 537.37 (M+H), Purity- 89.04% by AUC, RT- 4.60, UV-240 nm. Column: X Bridge C18 4.6*50mm*3.5um; Mobile Phase- A: 10 mm Ammonium Acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; Flow rate: 0.6mL/min. [1276] Step 3: Preparation of 5-fluoro-N-(4-(4-(3-methyl-2-oxoimidazolidin-1-yl) bicyclo [2.2.2] octan-1-yl) phenyl) isoindoline-2-carboxamide (I-482): To a stirred solution of 3 (50 mg, 0.11 mmol) in THF (2 mL) was added DBU (26.1 mg, 0.172 mmol), and CDI (22 mg, 0.13 mmol) at RT under N2 atmosphere, then the reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with water (50 mL), extracted with 10% MeOH-DCM (2x50 mL), and the combined organic extracts were dried over Na₂SO₄, and concentrated under reduced pressure to afford the crude product. The product was purified by column chromatography (eluent-0-10% MeOH in DCM) which afforded 10 mg of I-482 (19% yield) as an off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.46-7.36 (m, 3H), 7.25-7.13 (m, 4H), 4.73 (s, 2H), 4.71 (s, 2H), 3.25- 3.21 (m, 2H), 3.12 (d, J = 7.2 Hz, 2H), 2.58 (s, 3H), 1.99-1.80 (m, 12H). LC-MS: [M+H] ⁺ = 463.29 (M+H), Purity- 99.76% by AUC, RT- 5.47, UV-245 nm. LCMS method: Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mm Ammonium Acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; Flow rate: 0.6mL/min. HPLC: Purity- 90.72% by AUC, RT- 15.28, UV- 245 nm: HPLC method: Column: X Bridge C18 4.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH₃CN; Flow rate: 1.2 mL/min; Diluent: Methanol (100%). EXAMPLE 138 – SYNTHESIS OF 5-FLUORO-N-(4-(4-(2-OXOOXAZOLIDIN-3-YL) BICYCLO [2.2.2] OCTAN-1-YL) PHENYL) ISOINDOLINE-2-CARBOXAMIDE (I-481) [1277] To a stirred solution of 2 (100 mg, 0.263 mmol) in THF (5 mL) was added DIPEA (0.14 mL, 0.79 mmol) and 1 (56 mg, 0.395 mmol) at 0°C. The reaction mixture was stirred at RT for 3 h, then KO^tBu (115 mg, 1.03 mmol) was added at RT and the mixture was stirred for 48 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with water (25 mL), and stirred for 1 h and the obtained solid was filtered, which was purified by flash chromatography (eluent-1-5 % MeOH-DCM) to afford 50 mg (38% yield) of I-481 as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.29 (s, 1H), 7.44 (d, J = 8.7 Hz, 3H), 7.20 (d, J = 8.6 Hz, 4H), 4.74 (s, 2H), 4.71 (s, 2H), 4.15 (t, J = 7.8 Hz, 2H), 3.57 (t, J = 7.8 Hz, 2H), 2.03-1.83 (m, 12H). LC-MS: [M+H] ⁺ = 450.26 (M+H), Purity- 98.61% by AUC, RT- 5.35, UV-245 nm. LCMS method: Column: X Bridge C184.6*50mm*3.5um; Mobile Phase- A: 10 mm Ammonium Acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; Flow rate: 0.6mL/min. HPLC: Purity- 96.97% by AUC, RT- 15.00, UV- 245 nm. HPLC method: Column: X Bridge C18 4.6*250mm*5.0 um; Mobile Phase: Solvent A: 10 mM ammonium acetate in water, Solvent B: CH₃CN; Flow rate: 1.2 mL/min; Diluent: Methanol (100%). EXAMPLE 139 – SYNTHESIS OF N-(4-(1-(2-ACETAMIDO-2-METHYLPROPANOYL)- 1,2,3,6-TETRAHYDROPYRIDIN-4-YL)PHENYL)-5-FLUOROISOINDOLINE-2- CARBOXAMIDE (I-296) [1278] Step 1: Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (3): A mixture of compound 1 (25 g, 145.3 mmol), compound 2 (49.43 g, 159.9 mmol), and Cs₂CO₃ (95.2 g, 290.7 mmol) in 1,4-dioxane: H₂O (1:1) (250 mL) was degassed with argon for 5 min. X-phos (0.707 g, 14.53 mmol) and Pd2(dba)3 (6.86 g, 7.26 mmol) was added to the above mixture at RT. The reaction mixture was stirred for 15 min. while degassing with argon, and then the reaction mixture was stirred at 90 ^oC for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The organic layer was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water followed by brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. A sticky crude residue was obtained, and it was triturated n- heptane, and the precipitated solid was filtered and dried under reduced pressure to afford the title 614 compound 3 (27.00 g, 98.40 mmol, 67.70% yield) as a cream solid. LC-MS (Method F): Ret. Time: 2.17 min, MS calcd. for Chemical Formula C16H22N2O2, 274.36; Found: 274.95 [M+H]⁺. [1279] Step 2: Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)-3,6-dihydro pyridine-1(2H)-carboxylate (5): To a stirred solution of compound 3 (3.0 g, 10.93 mmol) in DCM (50 mL) was added pyridine (1.78 mL, 21.87 mmol) and DMAP (0.136 g, 1.09 mmol) and the mixture was stirred at RT. Then compound 4 (1.88 g, 12.03 mmol) was added at 0^oC. The mixture was then stirred at RT for 2 h under nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The obtained solid was washed with diethyl ether and n-pentane and dried under reduced pressure to afford the title compound 5 (4.2 g, 11 mmol, 97% yield) as a brown solid. LC-MS (Method G): Ret. Time: 1.65 min, MS calcd. for Chemical formula: C23H26N2O4: 394.46; Found: 338.97 [(M-Isobutene)+H]⁺. [1280] Step 3: Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)- 3,6-dihydropyridine-1(2H)-carboxylate (7): To a stirred solution of compound 5 (3.0 g, 7.344 mmol) and compound 6 (1.11 g, 8.078 mmol) in DMF (30 mL) at RT was added DIPEA (6.41 mL, 36.72 mmol), and the mixture was then stirred at 80 ^oC for 4 h under nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by CombiFlash (Nexgen-300) chromatography (12 g cartridge of silica gel) using 50% EtOAc in n-heptane as the eluent to afford the title compound 7 (2.8 g, 6.2 mmol, 84% yield) as a pale brown solid. LC-MS (Method I): Ret. Time: 2.46 min, MS calcd. for Chemical formula: C25H28FN3O3: 437.51; Found: 438.3 [M+H]⁺. [1281] Step 4: Synthesis of 5-fluoro-N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl) isoindoline-2-carboxamide (8): To a stirred solution of compound 7 (0.5 g, 1.143 mmol) in 1,4- dioxane (5 mL) was added 4M HCl in 1,4-dioxane (3 mL) at 0 ^oC and the mixture was stirred at RT for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then stirred in diethyl ether (10 mL) and then with n-pentane (5 mLx2). The filtered solid compound was dried under reduced pressure to afford the desired compound 8 (0.414 g, 1.108 mmol, 96.91% yield) as a pale brown solid. The resulting crude obtained was used in the next step without further purification as an HCl salt. LC-MS (Method G): Ret. Time: 1.88 min, MS calcd. for Chemical formula: C20H20FN3O: 337.39; Found: 337.9 [M +H]⁺. [1282] Step 5: Synthesis of tert-butyl (1-(4-(4-(5-fluoroisoindoline-2-carboxamido) phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-methyl-1-oxopropan-2-yl)carbamate (10): To a stirred solution of compound 9 (0.141 g, 0.695 mmol) and DIPEA (0.47 mL, 2.67 mmol) in DMF (2 mL) were added HATU (0.411 g, 1.07 mmol) and compound 8 (0.2 g, 0.535 mmol) at 0 ^oC. The mixture was then stirred at RT for 16 h under nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ice cold water and the precipitated solid was filtered and washed with diethyl ether and dried under reduced pressure to afford the title compound 10 (0.25 g, 0.478 mmol, 89.41% yield) as a pale brown solid. LC-MS (Method F): Ret. Time: 1.29 min, MS calcd. for Chemical Formula: C29H35FN4O4: 522.62; Found: 523.63 [M+H]⁺. [1283] Step 6: Synthesis of N-(4-(1-(2-amino-2-methylpropanoyl)-1,2,3,6-tetrahydro pyridin-4-yl)phenyl)-5-fluoroisoindoline-2-carboxamide (11): To a stirred solution of compound 10 (0.25 g, 0.47 mmol) in DCM (3 mL) was added 4M HCl in 1,4-dioxane (3 mL) at 0 ^oC and the mixture was stirred at RT for 3 h. After completion of the reaction (monitored by TLC), volatiles were removed under reduced pressure. The residue was then stirred in diethyl ether (5 mL) and then with pentane (3 mL x 2). The mixture was filtered and the solid compound was dried under reduced pressure to afford compound 11 (0.2 g, crude) as a pale brown solid. The resulting crude was used in the next step without further purification as an HCl salt. LC-MS (Method F): Ret. Time: 1.035 min, MS calcd. for Chemical Formula: C₂₄H₂₇FN₄O₂: 422.50; Found: 423.35 [M+H]⁺. [1284] Step 7: Synthesis of N-(4-(1-(2-acetamido-2-methylpropanoyl)-1,2,3,6-tetrahydro pyridin-4-yl)phenyl)-5-fluoroisoindoline-2-carboxamide (I-296): To a stirred solution of compound 11 (0.2 g, 0.47 mmol) in DCM (3 mL) was added triethylamine (0.2 mL, 1.42 mmol) and acetic anhydride (0.064 g, 0.615 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered and washed/triturated with DCM. The filtered solid compound was dried under reduced pressure to afford the title compound (102.00 mg, 0.101 mmol, 32.88% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d₆) δ: 8.40 (s, 1H), 8.23 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.42 - 7.33 (m, 3H), 7.23 (dd, J = 1.9, 9.1 Hz, 1H), 7.17 - 7.11 (m, 1H), 6.08 (s, 1H), 4.74 (d, J = 11.6 Hz, 4H), 4.24 - 4.02 (m, 2H), 3.74 (s, 2H), 2.43 - 2.35 (m, 2H), 1.83 (s, 3H), 1.35 (s, 6H). LCMS (Method F): Ret. Time: 1.12 min, 99.49%; MS calcd. for Chemical Formula: C26H29FN4O3: 464.54; Found: 465.59 [M+H]+. HPLC: Ret. Time: 7.551 min, 97.54%; Method: column: X-Select C18 (4.6x150) mm 5.0 µm, Mobile Phase A: 0.1% FA in (ACN:H₂O) (5:95) v/v; Mobile Phase B: Acetonitrile (100%); Column Temperature: 30 °C; Flow Rate: 1.0 mL/min; Gradient (time/% B): 0.00/5, 1.00/5, 8.00/100, 12.00/100, 16.00/5, 18.00/5; Diluent: ACN: water (80:20). EXAMPLE 140 - SYNTHESIS OF 3-FLUORO-N-(4-(1-(2-METHYL-2-(TETRAHYDRO- 2H-PYRAN-4-CARBOXAMIDO)PROPANOYL)-1,2,3,6-TETRAHYDROPYRIDIN-4-YL) PHENYL)-5,7-DIHYDRO-6H-PYRROLO[3,4-B]PYRIDINE-6-CARBOXAMIDE (I-261) AND 3-FLUORO-N-(4-(1-(2-METHYL-2-(TETRAHYDRO-2H-PYRAN-4- CARBOXAMIDO)PROPANOYL)PIPERIDIN-4-YL)PHENYL)-5,7-DIHYDRO-6H- PYRROLO[3,4-B]PYRIDINE-6-CARBOXAMIDE (I-260) 617

[1285] Step 1: Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (3): A mixture of compound 1 (10 g, 56.38 mmol), compound 2 (20.05 g, 64.84 mmol), and K3PO4 (39.08 g, 180.44 mmol) in 1,2-DME: H2O (10:2) (120 mL) was degassed with argon for 5 min. Pd(dppf)Cl2.DCM (2.34 g, 2.81 mmol) was added to the above mixture at RT. The reaction mixture was stirred for 15 min. while degassing with argon, and then the reaction mixture was stirred at 90 ^oC for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The organic layer was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water followed by brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by CombiFlash (Nexgen-300) chromatography (40 g silica gel cartridge) using 25-35% EtOAc in n-heptane as an eluent to afford the title compound 3 (11 g, 40 mmol, 69% yield) as a brown solid. LC-MS (Method F): Ret. Time: 1.22 min, MS calcd. for Chemical Formula: C16H22N2O2, 274.36; Found: 275.41 [M+H]⁺. [1286] Step 2: Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (5): To a stirred solution of compound 3 (5.50 g, 20.0 mmol) in DCM (100 mL) were added pyridine (3.3 mL, 40.1 mmol), compound 4 (3.49 g, 22.0 mmol) and DMAP (0.247 g, 2.00 mmol) at 0 ^oC. The mixture was then stirred at 0 ^oC for 2 h under nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether, filtered and dried under reduced pressure to afford the title compound 5 (6.0 g, 15.20 mmol, 74.8% yield) as a pale brown solid. LC-MS (Method G): Ret. Time: 1.65 min, MS calcd. for Chemical Formula: C23H26N2O4: 394.47; Found: 339.40 [(M- Isobutene)+H]⁺. [1287] Step 3: Synthesis of tert-butyl 4-(4-(3-fluoro-6,7-dihydro-5H-pyrrolo[3,4- b]pyridine-6-carboxamido)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (7): To a stirred solution of compound 5 (4.0 g, 10.14 mmol) in DMF (150 mL) were added DIPEA (10.6 mL, 60.84 mmol) and compound 6 (1.59 g, 9.12 mmol) at 0 ^oC, and then the mixture was stirred at 80 ^oC for 6 h under nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ice cold water. The precipitated solid was filtered and dried under reduced pressure. The crude compound was triturated with diethyl ether, filtered, and then dried under reduced pressure to afford the title compound 7 (5.5 g, crude) as a pale brown solid. LC-MS (Method G): Ret. Time: 1.466 min, MS calcd. for Chemical Formula C24H27FN4O3: 438.50; Found: 439.56 [M+H]⁺. [1288] Step 4: Synthesis of 3-fluoro-N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-5,7- dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide hydrochloride (8): To a stirred solution of compound 7 (5.0 g, 9.37 mmol) in DCM (40 mL) was added 4M HCl in 1,4-dioxane (40 mL) at 0 ^oC and the mixture was stirred at RT for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then stirred in diethyl ether (5 mL) and then with pentane (5 mL x 2). The filtered solid compound was dried under reduced pressure to afford desired compound 8 (3.5 g, 10.34 mmol, 99% yield) as a pale brown solid. The resulting crude compound was used in the next step without further purification as an HCl salt. LC-MS (Method F): Ret. Time: 0.86 min, MS calcd. for Chemical Formula: C19H19FN4O: 338.39; Found: 339.48 [M+H]⁺. [1289] Step 5: Synthesis of tert-butyl (1-(4-(4-(3-fluoro-6,7-dihydro-5H-pyrrolo[3,4- b]pyridine-6-carboxamido)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-methyl-1-oxopropan-2- yl)carbamate (10): To a stirred solution of compound 8 (1.5 g, 4.43 mmol) in DMF (15 mL) were added DIPEA (3.00 mL, 17.72 mmol), compound 9 (0.90 g, 4.43 mmol), and HATU (2.52 g, 6.645 mmol) at 0 ^oC. The mixture was then stirred at RT for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ice cold water. The precipitated solid was filtered and then dried under reduced pressure. The crude compound was triturated with diethyl ether, filtered and then dried under reduced pressure to afford the title compound 10 (1.2 g, 2.29 mmol, 48%yield) as a pale brown solid. The crude compound was used in the next step without further purification. LC-MS (Method F): Ret. Time: 1.154 min, & 1.171 min, MS calcd. for Chemical Formula: C₂₈H₃₄FN₅O₄: 524.53 & 523.61; Found: 524.49 [M+H]⁺. [1290] Step 6: Synthesis of N-(4-(1-(2-amino-2-methylpropanoyl)-1,2,3,6- tetrahydropyridin-4-yl)phenyl)-3-fluoro-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6- carboxamide 2,2,2-trifluoroacetate (11): To compound 10 (1.2 g, 2.29 mmol) in DCM (10 mL) was added 2,2,2-trifluoroacetic acid (3.5 mL) dropwise at 0 ^oC and the mixture was stirred at RT for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then stirred in diethyl ether (15 mL), followed by pentane (10 mL x 2). The filtered the solid compound was dried under reduced pressure to afford the desired compound 11 (1.1 g, crude) as a pale brown solid. The resulting crude was used in the next step without further purification as a TFA salt. LC-MS (Method F): Ret. Time: 0.876 min, MS calcd. for Chemical Formula: C₂₃H₂₆FN₅O₂: 423.49; Found: 424.44 [M+H]⁺. [1291] Step 7: Synthesis of 3-fluoro-N-(4-(1-(2-methyl-2-(tetrahydro-2H-pyran-4- carboxamido)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-5,7-dihydro-6H-pyrrolo [3,4-b]pyridine-6-carboxamide (I-261): To a stirred solution of compound 11 (0.25 g, 0.46 mmol) in DCM (12 mL) was added DIPEA (0.48 mL, 2.72 mmol) and the mixture was stirred for 20 min. Compound 12 (0.025 g, 0.165 mmol) was then added at 0 °C. Then the reaction mixture was stirred at RT for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with cold water and extracted with 5% MeOH in DCM. The combined organic layers were washed brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether, filtered and dried under reduced pressure. The obtained crude was triturated with diethyl ether, filtered and dried under reduced pressure to afford compound I-261 (0.15 g, 0.28 mmol, 60.61% yield) as a pale brown solid. LCMS (Method F): Ret. Time: 1.015 min, MS calcd. Formula: C29H34FN5O4: 535.62; Found: 536.42 M+H]⁺. [1292] Step 8: Synthesis of 3-fluoro-N-(4-(1-(2-methyl-2-(tetrahydro-2H-pyran-4- carboxamido)propanoyl)piperidin-4-yl)phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6- carboxamide (I-260): To a stirred solution of compound I-261 (0.15 g, 0.28 mmol) in NMP (1 mL), MeOH (7 mL), and 1,2-DCE (3 ml) was added 10% Pd/C (50% wet) (0.101 g) and the mixture was stirred at RT for 16 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad, which was washed with 10% MeOH in 1,2-DCE (20 mL). The filtrate was concentrated under reduced pressure to give brown solid. The crude residue was dissolved in DMSO (2 mL) and stirred at 50 °C for 1 h and then cooled to RT. The precipitated solid was filtered and washed with hot EtOH (1 mL) and dried under vacuum to afford compound I-260 (45 mg, 0.083 mmol, 51.67% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d6) δ: 8.48 (s, 1H), 8.36 (s, 1H), 8.08 (s, 1H), 7.80 (dd, J = 2.3, 8.9 Hz, 1H), 7.47 (d, J = 8.5 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H), 4.75 (d, J = 19.6 Hz, 4H), 4.54 - 4.45 (m, 2H), 3.92 - 3.78 (m, 2H), 3.31 - 3.23 (m, 2H), 2.77 - 2.61 (m, 3H), 2.41 - 2.35 (m, 1H), 1.72 (d, J = 11.4 Hz, 2H), 1.61 – 1.57 (m, 4H), 1.44 - 1.36 (m, 2H), 1.35 (s, 6H). LC-MS (Method F): Ret time: 1.00 min, 97.88%; MS calcd. for Chemical Formula C29H36FN5O4: 537.64; Found: 538.50 [M+H]⁺. HPLC: Ret time: 6.099 min, 98.73%; Method: Column: X-Select CSH C18 (4.6*150) mm 5u Mobile Phase: A - 0.1% Formic acid in water: Acetonitrile (95:05), B- Acetonitrile, Flow Rate: 1.0 mL/min, Gradient program: Time (min)/ B Conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. EXAMPLE 141 - SYNTHESIS OF 7-FLUORO-N-(4-(1-(2-HYDROXY-2- METHYLPROPANOYL)PIPERIDIN-4-YL)PHENYL)-1,3-DIHYDRO-2H-PYRROLO [3,4-C]PYRIDINE-2-CARBOXAMIDE (I-285)

[1293] Step 1: Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (3): A mixture of compound 1 (10 g, 56.38 mmol), compound 2 (20 g, 64.68 mmol), and K3PO4 (40 g, 184.7 mmol) in 1,2-DME: H2O (10:2) (120 mL) was degassed with argon for 5 min. Pd(dppf)Cl2.DCM (2.3 g, 2.8 mmol) was added to the above mixture at RT. The reaction mixture was stirred for 15 min while degassing with argon, and then the reaction mixture was stirred at 90 ^oC for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad, which was then washed with EtOAc. The collected organics were mixed with water, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by CombiFlash (Nexgen-300) chromatography (12 g silica gel cartridge) using 20-35% EtOAc in n-heptane as an eluent to afford the title compound 3 (11 g, 40.09 mmol, 69% yield) as a brown solid. LC-MS (Method F): Ret. Time: 1.29 min, MS calcd. for Chemical Formula C16H22N2O2, 274.36; Found: 275.41 [M+H]⁺. [1294] Step 2: Synthesis of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (4): To a stirred solution of compound 3 (5.50 g, 20.04 mmol) in MeoH (50 mL) was added 10% palladium on carbon (50% wet) (2.77 g) and the mixture was stirred at RT for 16 h under hydrogen atmosphere at 150 psi pressure in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad, which was washed with EtOAc. The organics were concentrated under reduced pressure to afford the title compound 4 (5.5 g, 20 mmol, 99% yield) as an off white solid. LC-MS (Method G): Ret. Time: 1.119 min, MS calcd. for Chemical Formula: C16H24N2O2: 276.38; found: 221.44 [(M-Isobutene)+H]⁺. [1295] Step 3: Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)piperidine- 1-carboxylate (6): To a stirred solution of compound 4 (5.5 g, 20 mmol) in DCM (40 mL) were added pyridine (3.2 mL, 40 mmol), compound 5 (3.5 g, 22 mmol), and DMAP (0.25 g, 2.0 mmol) at 0 ^oC. The mixture was then stirred at RT for 2 h under nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether and n-pentane. The filtered solids were dried under reduced pressure to afford the title compound 6 (5.0 g, 12.61 mmol, 87.14%yield) as a pale brown solid. The crude compound was used in the next step without further purification. LC-MS (Method I): Ret. Time: 3.01 min, MS calcd. for Chemical Formula: C23H28N2O4: 396.49; found: 340.9 [(M-Isobutene) + H]⁺. [1296] Step 4: Synthesis of tert-butyl 4-(4-(7-fluoro-2,3-dihydro-1H-pyrrolo[3,4- c]pyridine-2-carboxamido)phenyl)piperidine-1-carboxylate (8): To a stirred solution of compound 7 (0.15 g, 1.08 mmol) and compound 6 (0.38 g, 0.97 mmol) in DMF (5 mL) was added and DIPEA (1.09 mL, 6.48 mmol) at RT and the mixture was stirred at 80 ^oC for 6 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water. The precipitated solid was filleted and washed with water (5 mL), and then dried under vacuum to give a crude brown solid. The crude compound was purified by CombiFlash (Nexgen- 300) chromatography (12 g silica gel cartridge) using 1.5-2.5% MeOH in DCM as an eluent to afford the title compound 8 (0.15 g, 0.34 mmol, 38.60% yield) as a pale brown solid. LCMS (Method F): Ret. Time: 1.31 min, MS calcd. for Chemical Formula: C24H29FN4O3: 440.51; found: 385.2 [(M-Isobutene)+H]-. [1297] Step 5: Synthesis of 7-fluoro-N-(4-(piperidin-4-yl)phenyl)-1,3-dihydro-2H- pyrrolo[3,4-c]pyridine-2-carboxamide hydrochloride (9): To a stirred solution of compound 8 (0.15 g, 0.34 mmol) in DCM (2 mL) was added 4M HCl in 1,4-dioxane (2.5 mL) dropwise at 0 ^oC and the mixture was stirred at RT for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then stirred in diethyl ether (5 mL) and then with n-pentane (3 mL x 2), and the filtered solid compound was dried under reduced pressure to afford the desired compound 9 (0.12 g, 0.319 mmol, 81.57% yield) as an off white solid. The resulting crude was used in the next step without further purification as an HCl salt. LC-MS (Method G): Ret. Time: 1.64 min, MS calcd. for Chemical Formula: C19H21FN4O: 340.40; found: 341.48 [M+H]⁺. [1298] Step 6: Synthesis of 7-fluoro-N-(4-(1-(2-hydroxy-2-methylpropanoyl)piperidin-4- yl)phenyl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide (I-285): To a stirred solution of compound 9 (0.11 g, 0.266 mmol) and compound 10 (0.028 g, 0.266 mmol) in DMF (4 mL) were added DIPEA (0.23 mL, 1.33 mmol) and HATU (0.152 g, 0.399 mmol) at 0 ^oC, and then stirred at RT for 16 h under nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ice cold water and extracted with EtOAc. The combined organic layers were washed with a brine solution, dried over with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a sticky crude compound. The crude compound purified by prep-HPLC purification to afford the title compound (48 mg, 0.11 mmol, 58.02% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d6) δ: 8.51 - 8.48 (m, 2H), 8.42 (s, 1H), 7.50 - 7.46 (m, J = 8.6 Hz, 2H), 7.16 - 7.12 (m, J = 8.6 Hz, 2H), 5.38 (s, 1H), 4.91 – 4.52 (m, 6H), 2.80 - 2.65 (m, 1H), 2.54 -2.52 (m, 2H), 1.78 (d, J = 11.1 Hz, 2H), 1.58 - 1.43 (m, 2H), 1.34 (s, 6H). LC-MS (Method G): Ret time: 1.91 min, 98.70%; MS calcd. for Chemical Formula C₂₃H₂₇FN₄O₃: 426.49; Found: 427.54 [M+H]⁺. HPLC: Ret time: 5.827 min, 99.36%; Method: column: X-Select CSH C18 (4.6*150) mm 5u Mobile Phase: A - 0.1% TFA in water B – Acetonitrile, Inj Volume; 5.0µL, Flow Rate: 1.2 mL/min, column Oven Temp.: 30 °C, Gradient program: Time (min)/ B Conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5. [1299] Step 7: Synthesis of 3-bromo-4-(dimethoxymethyl)-5-fluoropyridine (2b): To a stirred solution of 3-bromo-5-fluoro-pyridine-4-carbaldehyde (1a) (5 g, 24.51 mmol) in MeOH (40 mL) were added trimethyl orthoformate (11 mL, 98.04 mmol) and PTSA (0.43 g, 2.45 mmol) at 0 ^oC. The reaction was stirred at 80°C for 3 h. Progress of the reaction was monitored by TLC. After completion of the reaction, it was directly concentrated and then poured into water and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to afford compound (2b) (5 g, 19.91 mmol, 81.22% yield) as a pale-yellow oil. LC-MS (Method G): Ret. Time: 1.18 min, MS calcd. for Chemical Formula: C8H9BrFNO2: 250.07; found: 250.23 & 252.22 [M+H]⁺ (Br-pattern). [1300] Step 8: Synthesis of 4-(dimethoxymethyl)-5-fluoronicotinaldehyde (4d): To a stirred solution of compound (2b) (4.0 g, 15.99 mmol) in dry THF (80 mL) was added dropwise a solution of butyl lithium (2.5 mol/L) in hexane (7.0 mL, 17.596 mmol) at -78°C under an argon atmosphere. The reaction was stirred at the same temperature for 1 h (dark brown colour observed). N,N-dimethylformamide (3c) (12 mL, 159.96 mmol) was then added dropwise at -78°C. The mixture was stirred at the same temperature for an additional 1 hour under argon atmosphere. Progress of the reaction was monitored by TLC. The reaction mixture was quenched with an ice cold aqueous, saturated NH4Cl solution (150 mL). The mixture was extracted with EtOAc (100 mL x 3). The combined organics were washed with brine (150 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give compound (4d) (3.1 g, 16 mmol, 97% yield) as a brown viscous oil.¹H NMR (400 MHz, CHLOROFORM-d) δ: 10.58 - 10.57 (m, 1H), 8.85 (s, 1H), 8.58 (d, J = 1.3 Hz, 1H), 5.64 (s, 1H), 3.45 (s, 6H). [1301] Step 9: Synthesis of 5-fluoropyridine-3,4-dicarbaldehyde (5e): To a single necked 25 mL RBF was added compound (4d) (1.5 g, 7.5 mmol). A solution of HBr in acetic acid (20 mL, 110 mmol, 33%) was added dropwise at 0°C, and then the mixture was stirred at RT for 15 min. After completion of the reaction (monitored by TLC), the reaction mixture was directly concentrated under reduced pressure to give a sticky crude compound, which was co-evaporated with toluene and dried by rotary evaporation to give compound (5e) (1.5 g, crude) as a brown sticky liquid. LC-MS (Method G): Ret. Time: 0.234 min, MS calcd. for Chemical Formula: C7H4FNO2: 153.11; found: 172.22 [(M-H2O)+H]⁺. [1302] Step 10: Synthesis of (5-fluoropyridine-3,4-diyl)dimethanol (6f): To a stirred solution of compound (5e) (1.5 g, 9.8 mmol) in MeOH (70 mL) was added NaBH₄ (1.3 g, 34 mmol) portion wise at 0 °C, and then the mixture was stirred at RT for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice-cold water and extracted with 15% MeOH in DCM (150 mL x 5). The combined organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give compound (6f) (1.5 g, 9.55 mmol, 55% yield) as a brown gummy mass. LC-MS (Method G): Ret. Time: 0.182 min, MS calcd. for Chemical Formula: C7H8FNO2: 157.14; found: 158.33 [M+H]⁺. [1303] Step 11: Synthesis of 3,4-bis(chloromethyl)-5-fluoropyridine (7g): To a stirred solution of compound (6f) (1.50 g, 9.5 mmol) in DCM (15 mL) was added SOCl2 (11.00 mL, 140 mmol) dropwise at 0°C, then the mixture was stirred at 45°C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was directly concentrated under reduced pressure to remove excess of thionyl chloride. To the resulting mixture was then slowly added an ice cold saturated NaHCO₃ solution (70 mL; pH~8), and the mixture was then extracted with EtOAc. The combined organic layers were washed with brine, dried over with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a brown sticky mass. The obtained crude compound was purified by CombiFlash (Nexgen-300) chromatography (12 g silica gel cartridge) using 15-18% EtOAc in n-heptane as an eluent to afford compound (7g) (0.47 g, 2.42 mmol, 24% yield) as an off white solid. LC-MS (Method G): Ret. Time: 1.24 min, MS calcd. for Chemical Formula: C₇H₆C_l2FN: 194.03; found: 194.13 [M+H]⁺. [1304] Step 12: Synthesis of (2,4-dimethoxybenzyl)-7-fluoro-2,3-dihydro-1H-pyrrolo[3,4- c]pyridine (9i): To a stirred solution of compound (7g) (0.47 g, 2.42 mmol) in DCM (30 mL) were added compound (8h) (0.81 g, 4.84 mmol) and DIPEA (0.51 mL, 2.91 mmol) at 0 ^oC and the mixture was stirred at RT for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was directly concentrated under reduced pressure. The crude compound was purified by CombiFlash (Nexgen-300) chromatography (12 g silica gel cartridge) using 18-25% EtOAc in n-heptane as an eluent to afford compound (9i) (0.43 g, 1.49 mmol, 27.71% yield) as a brown sticky mass. LC-MS (Method G): Ret. Time: 0.96 min, MS calcd. for Chemical Formula: C16H17FN2O2: 288.32; found: 289.33 [M+H]⁺. [1305] Step 13: Synthesis of 7-fluoro-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine (7): To a teflon-lined screw cap sealed tube was added compound (9i) (0.3 g, 1.04 mmol). TFA (20 mL) was slowly added at 0°C, and then the mixture was stirred at 90 °C for 16 h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was directly concentrated under reduced pressure to give a brown sticky crude compound. To the crude compound was added EtOAc (4 mL) and 4 M HCl in 1,4-dioxane (3 mL) at 0°C. The mixture was stirred at RT for 30 min, and the precipitated solid was filtered and washed with EtOAc (4 mL), and then dried under vacuum to give compound 7 (0.16 g, 1.15 mmol, 94.8% yield) as a brown solid (100 mg, salt form). LC-MS (Method F): Ret. Time: 0.199 min, MS calcd. for Chemical Formula: C7H7FN2: 138.15; found: 139.18 [M+H]⁺. EXAMPLE 142 - SYNTHESIS OF 3-FLUORO-N-(4-(1-(2-METHYL-2- (METHYLSULFONAMIDO)PROPANOYL)PIPERIDIN-4-YL)PHENYL)-5,7- DIHYDRO-6H-PYRROLO[3,4-B]PYRIDINE-6-CARBOXAMIDE (I-362) [1306] To a stirred solution of amine 1 (1 equiv, prepared as described in Example 33) in DMF (~0.1 M) was added carboxylic acid 2 (2 equiv), EDCI (2 equiv), HOBt (2 equiv) and triethylamine (5 equiv). The mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ice cold water. The resulting precipitate was filtered, washed with water, and dried. The solid was triturated with EtOAc to afford 3-fluoro-N-(4-(1-(2-methyl-2-(methylsulfonamido) propanoyl)piperidin-4-yl)phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide (I-362, 20% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 8.48 (s, 1H), 8.37 (s, 1H), 7.79 (dd, J = 2.6, 9.1 Hz, 1H), 7.58 (s, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.11 (d, J = 8.6 Hz, 2H), 4.77 (s, 2H), 4.73 (s, 2H), 4.68-4.57 (m, 2H), 2.97 (s, 3H), 2.89-2.57 (m, 3H), 1.80-1.51 (m, 4H), 1.45 (s, 6H). LC/MS: m/z = 504.1 [M+H]⁺; 96.72% pure by AUC; tR = 4.83, UV 250 nm. LC/MS Method: Column: X Bridge C18 (4.6 x 50mm, 3.5 ^m); Mobile Phase- A: 10 mm Ammonium Acetate B: 100% ACN; Gradient 0.0/10, 0.5/10, 4.0/90, 8.0/90, 8.1/10, 10.0/10; Flow rate: 0.6mL/min. EXAMPLE 143 - SYNTHESIS OF N-(4-(1-(2-ACETAMIDO-2-METHYLPROPANOYL) PIPERIDIN-4-YL)PHENYL)-3-FLUORO-5,7-DIHYDRO-6H-PYRROLO[3,4-B] PYRIDINE-6-CARBOXAMIDE (I-390) [1307] To a stirred solution of amine 1 (1 equiv, prepared as described in Example 33) in DMF (~0.1 M) was added carboxylic acid 2 (2 equiv), EDCI (2 equiv), HOBt (2 equiv), and triethylamine (5 equiv). The mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ice cold water. The resulting precipitate was filtered, washed with water, and dried. The solid was triturated with EtOAc to afford N-(4-(1-(2-acetamido-2- methylpropanoyl)piperidin-4-yl)phenyl)-3-fluoro-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6- carboxamide (I-390, 29% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 8.48 (s, 1H), 8.36 (s, 1H), 8.18 (s, 1H), 7.79 (dd, J = 2.6, 9.0 Hz, 1H), 7.47 (d, J = 8.5 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2H), 4.77 (s, 2H), 4.72 (s, 2H), 4.53-4.42 (m, 2H), 2.75-2.60 (m, 2H), 1.82 (s, 3H), 1.78-1.69 (m, 3H), 1.48- 1.28 (m, 8H). LC/MS: m/z = 468.2 [M+H]⁺; 98.41% pure by AUC, UV 250 nm. EXAMPLE 144 – SYNTHESIS OF N-(4-(1-(1-ACETAMIDOCYCLOPENTANE-1- CARBONYL)-1,2,3,6-TETRAHYDROPYRIDIN-4-YL)PHENYL)-3-FLUORO-5,7- DIHYDRO-6H-PYRROLO[3,4-B]PYRIDINE-6-CARBOXAMIDE (I-247) [1308] Step 1: Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (3): A mixture of compound 1 (10 g, 56.38 mmol), compound 2 (20.05 g, 64.84 mmol), and K₃PO₄ (39.08 g, 180.44 mmol) in 1,2-DME: H₂O (10:2) (120 mL) was degassed with argon for 5 min. Pd(dppf)Cl₂.DCM (2.34 g, 2.81 mmol) was added to the above mixture at RT. The reaction mixture was stirred for 15 min. while degassing with argon, and then the reaction mixture was stirred at 90 ^oC for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad, which was washed with EtOAc. The organic layer was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by CombiFlash (Nexgen-300) chromatography (40 g silica gel cartridge) using 25-35% EtOAc in n-heptane as an eluent to afford the title compound 3 (11 g, 40 mmol, 69% yield) as a brown solid. LC-MS (Method F): Ret. Time: 1.22 min, MS calcd. for Chemical Formula: C₁₆H₂₂N₂O₂, 274.36; Found: 275.41 [M+H]⁺. [1309] Step 2: Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (5): To a stirred solution of compound 3 (5.50 g, 20.0 mmol) in DCM (100 mL) were added pyridine (3.3 mL, 40.1 mmol), compound 4 (3.49 g, 22.0 mmol), and DMAP (0.247 g, 2.00 mmol) at 0 ^oC then the mixture was stirred at 0 ^oC for 2 h under nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether, filtered and dried under reduced pressure to afford the title compound 5 (6.0 g, 15.20 mmol, 74.8% yield) as a pale brown solid. LC-MS (Method G): Ret. Time: 1.65 min, MS calcd. for Chemical Formula: C₂₃H₂₆N₂O₄: 394.47; Found: 339.40 [(M-Isobutene)+H]⁺. [1310] Step 3: Synthesis of tert-butyl 4-(4-(3-fluoro-6,7-dihydro-5H-pyrrolo[3,4- b]pyridine-6-carboxamido)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (7): To a stirred solution of compound 5 (4.0 g, 10.14 mmol) in DMF (150 mL) were added DIPEA (10.6 mL, 60.84 mmol) and compound 6 (1.59 g, 9.12 mmol) at 0 ^oC, and then the mixture was stirred at 80 ^oC for 6 h under nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ice cold water, and the precipitated solid was filtered and dried under reduced pressure. The crude compound was triturated with diethyl ether, filtered and dried under reduced pressure to afford the title compound 7 (5.5 g, crude) as a pale brown solid. LC-MS (Method G): Ret. Time: 1.466 min, MS calcd. for Chemical Formula C24H27FN4O3: 438.50; Found: 439.56 [M+H]⁺. [1311] Step 4: Synthesis of 3-fluoro-N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-5,7- dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide hydrochloride (8): To a stirred solution of compound 7 (5.0 g, 9.37 mmol) in DCM (40 mL) was added 4M HCl in 1,4-dioxane (40 mL) at 0 ^oC and the mixture was stirred at RT for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then stirred in diethyl ether (5 mL) and then with pentane (5 mL x 2), and then the filtered solid compound was dried under reduced pressure to afford the desired compound 8 (3.5 g, 10.34 mmol, 99% yield) as a pale brown solid. The resulting crude obtained was used in the next step without further purification as an HCl salt. LC-MS (Method F): Ret. Time: 0.86 min, MS calcd. for Chemical Formula: C19H19FN4O: 338.39; Found: 339.48 [M+H]⁺. [1312] Step 5: Synthesis of tert-butyl (1-(4-(4-(3-fluoro-6,7-dihydro-5H-pyrrolo[3,4- b]pyridine-6-carboxamido)phenyl)-1,2,3,6-tetrahydropyridine-1-carbonyl)cyclopentyl) carbamate (10): To a stirred solution of compound 9 (0.254 g g, 1.108 mmol) in DMF (3 mL) were added DIPEA (0.63 mL, 3.694 mmol), EDC.HCl (0.43 g, 2.22 mmol), and HOBt (0.202 g, 1.48 mmol) at RT and the mixture was stirred for 30 min. Compound 8 (0.25 g, 0.738 mmol) was added and the mixture was stirred at RT for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ice cold water, and the precipitated solid was filtered and dried under reduced pressure. The crude compound was triturated with diethyl ether, filtered and dried under reduced pressure to afford the title compound 10 (0.275 g, 0.50 mmol, 67% yield) as a pale yellow solid. The crude compound was used in the next step without further purification. LC-MS (Method F): Ret. Time: 1.223 min, MS calcd. for Chemical Formula: C₃₀H₃₆FN₅O₄: 549.65; Found: 550.43 [M+H]⁺. [1313] Step 6: Synthesis of N-(4-(1-(1-aminocyclopentane-1-carbonyl)-1,2,3,6-tetra hydropyridin-4-yl)phenyl)-3-fluoro-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide hydrochloride (11): To a stirred solution of compound 10 (0.275 g, 0.50 mmol) in DCM (3 mL) was added 4M HCl in 1,4-dioxane (3 mL) dropwise at 0 ^oC and the mixture was stirred at RT for 3 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure, and then the resulting compound was triturated with diethyl ether (5 mL), washed with n-pentane (2 x 4 mL), filtered and dried under vacuum to afford the desired compound 11 (0.22 g, crude) as an off white solid. The resulting crude obtained was used in the next step without further purification as an HCl salt. LC-MS (Method F): Ret. Time: 0.92 min, MS calcd. for Chemical Formula: C25H28FN5O2: 449.53; Found: 450.45 [M+H]⁺. [1314] Step 7: Synthesis of N-(4-(1-(1-acetamidocyclopentane-1-carbonyl)-1,2,3,6- tetrahydropyridin-4-yl)phenyl)-3-fluoro-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6- carboxamide (I-247): To a stirred solution of compound 11 (0.22 g, 0.489 mmol) in DCM (5 mL) was added triethylamine (0.2 mL, 1.47 mmol) followed by acetic anhydride (0.054 g, 0.538 mmol) at 0 ^oC. The reaction mixture was stirred at RT for 16 h. After completion of the reaction (monitored by TLC), the solids were filtered and dried under vacuum to give the crude compound (185 mg). The crude compound (50 mg) was recrystallized with DMF and MeOH to afford title the compound (9.63 mg, 0.019 mmol) as an off white solid.¹H NMR (400 MHz, DMSO-d₆) δ: 8.50 - 8.45 (m, 2H), 8.28 (s, 1H), 7.80 (dd, J = 2.4, 8.9 Hz, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 8.8 Hz, 2H), 6.10 (s, 1H), 4.77 (d, J = 18.1 Hz, 4H), 4.14 - 4.00 (m, 2H), 3.70 – 3.65 (m, 2H), 2.39 (s, 2H), 2.25 - 2.13 (m, 2H), 1.89 - 1.78 (m, 5H), 1.65 - 1.52 (m, 4H). LC-MS (Method F): Ret time: 1.03 min, 97.77%; MS calcd. for Chemical Formula C₂₇H₃₀FN₅O₃: 491.57; Found: 492.49 [M+H]⁺. HPLC: Ret time: 6.368 min, 97.34%; Method: column: X-select CSH C18,150 mm X 4.6 mm X5.0µm, Mobile Phase A: 0.1% FA in (Water: ACN)(95:5)V/V, Mobile Phase B: Acetonitrile, Column Temperature: 30 °C, Flow Rate: 1.0 mL/min, Gradient: 0/5, 1/5, 8/100, 12/100, 14/5, 18/5; Diluent: (ACN: Water) (80:20) V/V. EXAMPLE 145 - SYNTHESIS OF (S)-4,5,6-TRIFLUORO-N-(4-(1-((2-FLUORO-3- HYDROXY-3-METHYLBUTYL)CARBAMOYL)-1,2,3,6-TETRAHYDROPYRIDIN-4- YL)PHENYL)ISOINDOLINE-2-CARBOXAMIDE (I-195)

[1315] Step 1: Synthesis of ethyl (2R)-2-(dibenzylamino)-3-hydroxy-propanoate (2b): To a mixture of compound (1a) (5 g, 37.55 mmol) in DMF (50 ml) were added BnBr (16.55g, 93.87 mmol), K2CO3 (10.48 g, 75.10mmol) and KI (3.11g, 18.77 mmol ) at 0 ^oC. The mixture was then stirred at RT for 16 hrs. After completion of the reaction (monitored by TLC), the reaction mixture was washed with ice cold water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by CombiFlash (Nexgen-300) chromatography (40 g silica gel cartridge) using 10-20% EtOAc in n-heptane as an eluent to afford the title compound (2b) (8 g, 23.21 mmol, 61.80% yield) as a colorless liquid. LC-MS (Method F): Ret. Time: 1.43 min, MS calcd. for Chemical Formula: C19H23NO3, 313.4; Found: 314.94 [M+H]⁺. [1316] Step 2: Synthesis of ethyl (2S)-3-(dibenzylamino)-2-fluoro-propanoate (3c): To a stirred solution of compound (2b) (8.0 g, 25.53 mmol) in THF (80 mL) was added DAST (4.36 mL, 31.40 mmol) at 0 ^oC and then the mixture was stirred at RT for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with a saturated sodium bicarbonate solution, diluted with water and extracted with EtOAc. The combined organic layers were dried with anhydrous sodium sulphate and concentrated under reduced pressure. The crude compound was purified by CombiFlash (Nexgen-300) chromatography (80 g cartridge, silica gel) using 10% EtOAc in n-heptane as an eluent to afford the title compound (3c) (8.0 g, 2.52 mmol, 79.49% yield) as an colorless liquid. LC-MS (Method F): Ret. Time: 1.55 min, MS calcd. for Chemical Formula: C₁₉H₂₂FNO₂: 315.4; Found: 316.85 [M+H]⁺. [1317] Step 3: Synthesis of (3S)-4-(dibenzylamino)-3-fluoro-2-methyl-butan-2-ol (4d): To a stirred solution of compound (3c) (4.0 g, 12.68 mmol) in THF (40 mL) was added CH3MgBr (3M in THF) (9.7 mL, 29.17 mmol) at 0 ^oC, and then the mixture was stirred at RT for 4 h under nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with a saturated ammonium chloride solution, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water followed by brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by CombiFlash (Nexgen-300) chromatography (24 g cartridge, silica gel) using 30% EtOAc in n- heptane as an eluent to afford the title compound (4d) (2.0 g, 4.31 mmol, 66% yield) as a colorless liquid. LC-MS (Method F): Ret. Time: 0.94 min, MS calcd. for Chemical Formula C₁₉H₂₄FNO: 301.4; Found: 302.92 [M+H]⁺. [1318] Step 4: Synthesis of (3S)-4-amino-3-fluoro-2-methyl-butan-2-ol (Int-9): To a degassed solution of (R)- 3-(dibenzylamino)-2-fluoropropan-l-ol (4d) (1.0 g, 3.32 mmol ) in ethanol (20 mL) were added 10% Pd/C (0.070 g, 0.663 mmol) and Pd(OH)2 (94 mg, 0.663 mmol) and the reaction mixture was hydrogenated in an autoclave at 600^oC at 140 psi for 14 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to RT, and filtered through a celite pad and the filtrate was concentrated under reduced pressure to afford the title compound Int-9 (330 mg, 2.885 mmol, 86.97% yield) as a colorless liquid. LCMS (Method F): Ret. Time: 0.36 min, MS calcd. for Chemical Formula: C5H12FNO: 121.15; Found: 122.28 [M+H]⁺. [1319] Step 5: Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (3): A mixture of compound 1 (5 g, 24.752 mmol), compound 2 (6,21 g, 29.703 mmol), and K₃PO₄ (19.4 g, 86.634 mmol) in 1,2-DME: H₂O (10:2) (35 mL) was degassed with argon for 5 min. Pd(dppf)Cl2.DCM (1.03 g, 1.237 mmol) was added to the above mixture at RT. The reaction mixture was stirred for 15 min while degassing with argon, and then the reaction mixture was stirred at 90 ^oC for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and the pad was washed with EtOAc. The organic layer was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by CombiFlash (Nexgen-300) chromatography (40 g cartridge, silica gel) using 25-35% EtOAc in n-heptane as an eluent to afford the title compound 8 (6.5 g, 21 mmol, 86% yield) as a brown solid. LC-MS (Method F): Ret. Time: 1.22 min, MS calcd. for Chemical Formula: C16H22N2O2, 274.36; Found: 275.41 [M+H]⁺. [1320] Step 6: Synthesis of tert-butyl 4-[4-(phenoxycarbonylamino)phenyl]-3,6-dihydro- 2H-pyridine-1-carboxylate (5): To a stirred solution of compound 3 (3.5 g, 13 mmol) in DCM (30 mL) were added pyridine (3.1 mL, 38 mmol) and compound 4 (1.9 ml, 15 mmol) at 0 ^oC, and then the mixture was stirred at RT for 2 h under nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water followed by brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether, filtered and dried under reduced pressure to afford the title compound 5 (4.0 g, 8.619 mmol, 68% yield) as a pale brown solid. LC-MS (Method F): Ret. Time: 1.65 min, MS calcd. for Chemical Formula: C23H26N2O4: 394.47; Found: 294.8 [(M-Boc)+H]⁺. [1321] Step 7: Synthesis of tert-butyl 4-[4-[(4,5,6-trifluoroisoindoline-2-carbonyl)amino] phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (7): To a stirred solution of compound 5 (0.5 g, 1.267 mmol) in DMF (5 mL) were added DIPEA (0.66 ml, 3.802 mmol) and compound 6 (0.219 g, 1.267 mmol) at 0 ^oC, and then the mixture was stirred at 80 ^oC for 6 h under nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ice cold water and the precipitated solid was filtered and dried under reduced pressure. The crude compound was triturated with diethyl ether, filtered and dried under reduced pressure to afford the title compound 7 (0.48 g, crude) as a pale brown solid. LC-MS (Method F): Ret. Time: 1.52 min, MS calcd. for Chemical Formula C25H26F3N3O3: 473.5; Found: 474.59 [M+H]⁺. [1322] Step 8: Synthesis of 4,5,6-trifluoro-N-[4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl] isoindoline-2-carboxamide (8): To a stirred solution of compound 7 (0.48 g, 1.014 mmol) in DCM (10 mL) was added 4M HCl in 1,4-dioxane (4 mL) at 0 ^oC and then the mixture was stirred at RT for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then stirred in diethyl ether (5 mL) and then with pentane (5 mL x 2), and the filtered solid compound was dried under reduced pressure to afford the desired compound 8 (0.31 g, 0.606 mmol, 59.78% yield) as a pale brown solid. The resulting crude obtained was used in the next step without further purification as an HCl salt. LC-MS (Method F): Ret. Time: 1.02 min, MS calcd. for Chemical Formula: C20H18F3N3O: 373.4; Found: 374.94 [M+H]⁺. [1323] Step 9: Synthesis of (S)-4,5,6-trifluoro-N-(4-(1-((2-fluoro-3-hydroxy-3-methyl butyl)carbamoyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide (I-195): To a stirred solution of compound 8 (0.15 g, 0.4017 mmol) in THF (4 mL) were added TEA (0.169 mL, 1.20 mmol) and triphosgene (0.135 g, 0.44 mmol) at 0 ^oC. The resulting mixture was stirred at RT for 2 h. Then compound Int-9 (0.058 g, 0.48 mmol) and TEA (0.1 ml) were added and the resulting mixture was stirred at RT for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried with anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound, which was purified by prep-HPLC purification to afford the title compound (10 mg, 0.019 mmol, 4.78% yield) as an off white solid.¹H NMR (400 MHz, DMSO-d₆) δ: 8.52 - 8.44 (m, 2H), 7.55 (d, J = 8.8 Hz, 2H), 7.45 - 7.39 (m, 1H), 7.37 (d, J = 8.6 Hz, 2H), 6.69 - 6.66 (m, 1H), 6.11 (s, 1H), 4.86 (s, 2H), 4.77 (s, 2H), 4.73 (s, 1H), 4.32 - 4.15 (m, 1H), 3.98 (d, J = 2.5 Hz, 2H), 3.53 (t, J = 5.8 Hz, 2H), 3.17 – 3.13 (m, 1H), 2.45 - 2.40 (m, 2H), 1.12 (d, J = 3.5 Hz, 6H). LCMS (Method G): Ret. Time: 2.35 min, 95.05%; MS calcd. for Chemical Formula: C26H28F4N4O3: 520.5; Found: 512.64 [M+H]⁺. HPLC: Ret. Time: 6.52 min, 95.06%; Column: X- select CSH C18,150 mm X 4.6 mm X5.0µm Mobile Phase A: 0.1% TFA in Water, Mobile Phase B: Acetonitrile, Column Temperature: 30 °C, Flow Rate: 1.2 mL/min, Gradient: 0/5, 1/5, 8/100, 12/100, 14/5, 18/5 Diluent: (ACN:Water) (80:20)V/V. Prep-HPLC purification method: column: YMC AQ ODS (250*20)mm,5µm, Mobile Phase A: 0.1% FA in water, Mobile Phase B: 100% ACN Flow rate: 17 ml/min, Gradient (Time/%B): 0/5,3/5,10/45,20/55,40/75,70/100. EXAMPLE 146 – SYNTHESIS OF ADDITIONAL COMPOUNDS [1324] The compounds in Table 2 were prepared by analogy to the methods described above. TABLE 2. Compound Characterization Data EXAMPLE 147 – BIOCHEMICAL AND CELL-BASED BIOLOGICAL ASSAYS [1325] Exemplary compounds were evaluated for biological activity in the assays described herein below. Part I - Biochemical Assay No.1 [1326] Experimental Procedure for Biochemical Assay No.1: Human recombinant enzyme (Uniprot P43490) was expressed with an N-terminal histidine tag (synthetic construct synthesized by ATUM) in E. coli BL21(DE3) using the procedure described by Burgos ES [Biochemistry 2008, 47(42), 11086; PMID: 18823127]. The enzyme was purified using nickel capture resin (IMAC procedure, same reference).The discontinuous enzymatic assay leverages chemical derivatization of the nicotinamide mononucleotide (NMN) enzyme product with 2- acetylbenzofuran (2-ABF) following a three-step procedure. [1327] Step A: The enzymatic reactions (background, positive, negative controls, and NMN calibration standards; total volume 35 uL) were incubated in a 96-well plate (VWR # 89049-178) for 2 h at 25 ℃ (25 mM TRIS, 100 mM NaCl, 5 mM MgCl2, 5% glycerol, at pH 8.0; with 10 nM human NAMPT, 6 microM NAM, 40 microM PRPP, 2.5 mM ATP and 1 mM mercapto- ethanol). Inhibitor concentrations ranged from 0.625 and 625 nM (four-point dose-response) with a final DMSO concentration of 1% v/v. After 2 h, reactions were quenched (2 uL 250 mM EDTA; magnesium capture) before derivatization [Putt KS and Hergenrother PJ Anal Biochem 2004, 326(1), 78; PMID: 14769338]. [1328] Step B: 28 uL of an ice-cold 2-ABF solution (12.5 mM in 1:1 DMSO/Ethanol) was added to react with NMN enzymatic product [Moriya T et al. Chem Commun 2012, 49(98), 11500; PMID: 24177803]. The reaction was temperature controlled (10 ℃) and the reaction was completed within 20 minutes. [1329] Step C: 60 uL of an ice-cold formic acid solution (80% v/v) was added and the reaction was incubated for 20 minutes at 10 ℃. A fluorescent signal developed. Samples (60 uL; electronic multichannel pipette) were transferred to a 384-well plate (Greiner # 781207) for reading and analysis (Ex/Em 430/475 nm). The derivatized product is fluorescent, and the read- out signal is proportional to the NMN levels. There is no reaction with nicotinamide (NAM) enzyme substrate. The fluorescence was corrected for background signal (human enzyme without NAM and without inhibitor) and normalized to vehicle-treated wells (human enzyme with substrates and without inhibitor). Part II - Biochemical Assay No.2 [1330] Experimental Procedure for Biochemical Assay No.2: Human recombinant enzyme (Uniprot P43490) was expressed with an N-terminal histidine tag (synthetic construct synthesized by ATUM) in E. coli BL21(DE3) using the procedure described by Burgos ES [Biochemistry 2008, 47(42), 11086; PMID: 18823127]. The enzyme was purified using nickel capture resin (IMAC procedure, same reference). [1331] With a commercial kit (BPS Bioscience #71276-1), the two-step enzyme-coupled assay converts NMN into NAD⁺ (the reactions consumes ATP and is catalyzed by nicotinamide nucleotide adenylyltransferase, NMNAT). The intermediate is further converted into fluorescent NADH by alcohol dehydrogenase (ADH) in the presence of ethanol and semi-carbazide [Burgos ES and Schramm VL Biochemistry 2008, 47(42), 11086; PMID: 18823127]. The procedure follows the manufacturer’s recommendations with a few modifications (human N-terminal histidine-tagged NAMPT was used at a final concentration of 10 nM, ATP concentration was increased to 2.5 mM, and MgCl2 was added to a final concentration of 5 mM). Inhibitor concentrations ranged from 0.625 to 625 nM (four-point dose-response), and the final DMSO concentration was 1% v/v. The reactions (background, positive, negative controls, and NADH calibration standards, total volume = 100 uL) were monitored continuously for 2.5 h. Slopes were established (RFU/h), corrected for background signal (enzyme without NAM and without inhibitor), and normalized to vehicle-treated wells (human enzyme with substrates and without inhibitor). Part III - Cell-Based Assay No.1 [1332] Experimental Procedure for Cell-Based Assay No.1: 96-well plates (VWR #10861-666) were seeded with U2OS cells (ATCC #HTB-96; 3000 cells per well, 100 uL media). DMEM (Gibco #12430-054) with 10% FBS (ATCC #30-2020) was used for culture. Cells were exposed to the inhibitors for 96 h (dose-response: either 0.125–1250 nM or 0.012– 125 nM; final DMSO concentration is 1%). After four days at 37 ℃ under 5% CO2 atmosphere, CellTiter 96 AQueous One Solution (Promega #G3581; 25 uL per well) was added to cells and media only wells (background signal). After 2 h incubation at 37 ℃, the signal was stabilized by the addition of an SDS solution (10% w/v; 25 uL) and the absorbance was measured at 490 nm. The signal was corrected for background signal and normalized to vehicle-treated wells (DMSO 1%). Part IV - Cell-Based Assay No.2 [1333] Experimental Procedure for Cell-Based Assay No.2: 96-well plates (VWR #10861- 666) were seeded with HCT116 cells (ATCC # CCL-247; 3000 cells per well, 100 uL media). DMEM (Gibco #12430-054) with 10% FBS (ATCC #30-2020) was used for culture. Cells were exposed to the inhibitors for 96 h (dose-response: either 0.125–1250 nM or 0.012–125 nM; final DMSO concentration is 1%). After four days at 37 ℃ under 5% CO₂ atmosphere, CellTiter 96 AQueous One Solution (Promega #G3581; 25 uL per well) was added to cells and media only wells (background signal). After 1 h incubation at 37 ℃, the signal was stabilized by the addition of an SDS solution (10% w/v; 25 uL) and absorbance was measured at 490 nm. The signal was corrected for background signal and normalized to vehicle-treated wells (DMSO 1%). Part V - Cell-Based Assay No.3 [1334] Experimental Procedure for Cell-Based Assay No.3: 96-well plates (VWR #10861- 666) were seeded with HCT116 cells (ATCC # CCL-247; 3000 cells per well, 100 uL medium). DMEM (Gibco #12430-054) with 10% FBS (ATCC #30-2020) was used for culture. Cells were exposed to the inhibitors for 96h (dose-response either 0.125–1250 nM or 0.012–125 nM; final DMSO concentration of 1%). After four days at 37 Celsius under 5% CO2 atmosphere, cell confluency was measured using IncuCyte instrument (Sartorius). The signal was normalized to vehicle-treated wells (DMSO 1%). Part VI - Results [1335] The results of biochemical assay #1, biochemical assay #2, cell-based assay #1, cell- based assay #2, and cell-based assay #3 are reported in the table below. For each assay, compounds with an EC₅₀ less than or equal to 5 nM are designated as “A”. Compounds with an EC₅₀ greater than 5 nM and less than or equal to 10 nM are designated as “B”. Compounds with an EC50 greater than 10 nM and less than or equal to 25 nM are designated as “C”. [1336] For the biochemical assays, compounds with an EC₅₀ greater than 25 nM are designated as “D”. For the cell-based assays, compounds with an EC50 greater than 25 nM and less than or equal to 500 nM are designated as “D”. For the cell-based assays, compounds with an EC50 greater than 500 nM are designated as “E”. TABLE 3. Biochemical and Cellular EC50 Data

EXAMPLE 148 – PHARMACOKINETIC ANALYSIS – SYSTEMIC VS. OCULAR [1337] Exemplary compounds were administered to mice, and then the mice were evaluated to determine the amount of compound in blood plasma (as a measure of systemic level of compound) and the amount of compound in the mice eyes. Without wishing to be bound by theory, it is desirable for the compound to have minimal accumulation in ocular tissue in order to minimize potential adverse side effects that can result from accumulation of a NAMPT inhibitor compound in ocular tissue. [1338] In this regard, one feature reported in the literature for certain NAMPT inhibitor compounds is retinal and cardiac toxicity. See, for example, Velma, G. R., et al. J. Med. Chem., 2024, Vol.67, No.8, p.5999-6026, and Tang, H., et al. Eur. J. Med. Chem., 2023, Vol.258, 115607. Compound B shown in Table 4 below has been reported to cause retinal damage in larval zebrafish. See, for example, Cassar, S., et al. Toxicological Sciences, 2017, Vol.161, 300–309. [1339] Experimental procedures used to evaluate the pharmacokinetics of exemplary compounds in mice is described below. Part I - Procedure [1340] Male C57BL/6 mice aged 6-12 weeks in a fed state (3 mice per group) were administered compound formulations by oral gavage a single time at the doses indicated in Table 5, below. Formulations were prepared at a concentration of 1 mg/mL in a solution containing DMSO (3% v/v) and water (97% v/v, containing 20% w/v captisol). Blood samples were collected in K2EDTA tubes via saphenous vein at 0.05, 0.25, 0.5, 1, 2, 6, 12, and 24 hours following compound administration. Plasma was then isolated by centrifugation of blood at 10,000 rpm and 4 ^oC for 10 minutes, and the plasma was stored at -70 ^oC until being analyzed. Whole eyes were resected at 24 hours. The whole eyes were homogenized in PBS (2:1 PBS:eye), and the homogenate was subjected to protein precipitation. To plasma or clarified eye homogenate was added an internal standard prepared in acetonitrile (Cetirizine 50 ng/mL), and the samples were vortexed, centrifuged, and analyzed using LC-MS/MS. Mass spectrometer: Xevo TQ-XS; UPLC: Waters; Column: Kinetex XB-C18, 100 A, 50 x 2.1 mm, 1.7 um; mobile phase A: 0.1% formic acid in acetonitrile; mobile phase B: 0.1% formic acid in water; column temperature: 45 ^oC; flow rate: 0.7 mL/min; gradient (time (min)/% A): 0.0/10%, 0.4/10%, 1.1/95%, 1.3/95%, 1.6/10%, 1.8/10%. Plasma of untreated mice was spiked with compound standards to prepare a calibration curve. [1341] Compounds Tested: Certain compounds tested in this assay are depicted in Tables 4- A, 4-B, 4-C, and 4-D, below. Table 4-A. Table 4-B.

Table 4-C. Table 4-D. Part II - Results [1342] Results of the pharmacokinetic assays described in Part I are presented in Tables 5-A, 5-B, 5-C, and 5-D, below, where the systemic area under the curve (AUC) was determined from 0-24 hours, and the concentration in the eye was determined at 24 hours. Results in Tables 5-A, 5-B, 5-C, and 5-D demonstrate that many of the compounds from Table 1 had higher ratios of AUC versus concentration in the eye than Compound A or Compound B. This demonstrates a performance benefit for these compounds from Table 1 compared to Compound A and Compound B. Table 5-A. Table 5-B.

Table 5-C. Table 5-D.

EXAMPLE 149 – RAT TOXICITY STUDIES [1343] Exemplary compounds were tested in rats to analyze for evidence of toxicity. Described herein below are procedures and results evaluating compounds I-95 and I-137 in rats. Part I - Procedures [1344] Female Sprague-Dawley rats (5 per group) were acclimatized for at least three days prior to the dose administration in cages with up to three rats per cage. Dose formulations were prepared fresh every day prior to dose administration at concentrations of 0.01, 0.03, 0.1, 0.3, and 0.5 mg/mL. Compound I-95 was dosed at 0.3, 1.0, 3.0, and 10.0 mg/kg. Compound I-137 was dosed at 0.1, 0.3, 1.0, and 3.0 mg/kg. For 7-day continuous dosing studies, formulations were administered once daily by oral gavage for a period of 7 consecutive days. For 14-day intermittent dosing studies, formulations were administered on days 1, 2, 3, 8, 9 and 10 by oral gavage. Part II - Results [1345] For compound I-95, no treatment-related histopathological findings were observed in the eyes or heart, in both continuous- and intermittent-dosing studies, at all doses tested. In both studies, animals appeared normal with no observable toxicities up to 3.0 mg/kg. At the 10.0 mg/kg dose in the continuous dosing study, two animals were found dead and three were moribund and sacrificed (on days 4 and 6 of the study). At the 10.0 mg/kg dose in the intermittent-dosing study, one animal was found dead on day 12 of the study. [1346] For compound I-137, no treatment-related histopathological findings were observed in the eyes or heart in the intermittent-dosing study, at all doses tested. In the continuous-dosing study, no treatment-related histopathological findings were observed in the heart at all doses tested, and treatment-related histopathological findings were only observed in the eyes at the highest dose (3.0 mg/kg), where 3 animals were observed to have retinal atrophy. [1347] In both studies, animals appeared normal with no observable toxicities up to 1.0 mg/kg. At the 3.0 mg/kg dose in the continuous-dosing study, multiple animals were found dead and/or moribund and sacrificed on day 7. At the 3.0 mg/kg dose in the intermittent-dosing study, no treatment-related mortalities were observed, but decrease in body weight and percent body weight gain were observed from day 8 to day 11. INCORPORATION BY REFERENCE [1348] The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes. EQUIVALENTS [1349] The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

Claims: 1. A compound represented by Formula I: or a pharmaceutically acceptable salt thereof; wherein: substituted with p occurrences of R², wherein B¹ is a 6-membered aryl ring or a 5-6 membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur; A² is a 4-8 membered saturated or partially unsaturated heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, a 5-8 membered saturated bicyclic carbocyclylene, or a covalent bond, wherein the heterocyclylene, monocyclic carbocyclylene, and bicyclic carbocyclylene are substituted with 0 or 1 occurrences of R³; A³ is phenylene substituted with 0 or 1 occurrences of R³; R^1A, R^1B, and R^1C each represent independently for each occurrence hydrogen or C1-4 alkyl; R² represents independently for each occurrence halo, C_1-4 haloalkyl, C_1-4 alkoxyl, C_1-4 alkyl, or C_1-4 hydroxyalkyl; R³ represents independently for each occurrence halo or C1-4 alkyl; Z is one of the following: a) -C(O)R⁴, -C(O)-(C_1-4 alkylene)-R⁴, -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)- R⁴, -C(O)-(C_1-4 alkylene)-O-(C_1-4 alkyl), -C(O)-(C_1-4 alkylene)-[O-(C_1-4 alkylene)-]_y- (C_1-6 alkoxyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_3-8 cycloalkyl substituted with z occurrence of R⁹), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C_1-4 alkyl and one -OH), or -C(O)-(C_3-7 cycloalkyl substituted with one -N(R^1A)-S(O)2-(C1-6 alkyl) or -N(R^1A)-C(O)-(C1-6 alkyl)); b) -C(O)-N(R^1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R^1A)(R^1B), -C(O)-N(R^1A)-(C_1-6 alkyl), -C(O)-N(R^1A)-(C_1-4 haloalkyl), -C(O)- N(R^1A)-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl), -C(O)-N(R^1B)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]x-(C1-6 alkoxyl), -C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), -C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1A)(R^1B), -C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-C(O)-O-(C1-6 alkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-6 hydroxyalkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1B)-S(O)₂-R⁶, -C(O)-N(R^1A)-(C_1-4 alkylene)- N(R^1B)-S(O)₂-(C_1-4 alkyl), -C(O)-N(R^1A)-(C_0-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R^1A)-(C1-4 alkylene)-(C3-7 cycloalkyl), or -C(O)-N(R^1A)- S(O)2-R⁷; c) -C(O)-C(O)-N(R^1A)-R⁵, -C(O)-C(O)-N(R^1A)(R^1B), -C(O)-C(O)-N(R^1A)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl),-C(O)-C(O)-N(R^1A)-S(O)2-(C1-6 alkyl), -C(O)- C(O)-N(R^1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-C(O)-R⁴, -C(O)-C(O)-OH, -C(O)-OH, -C(O)-O-(C_1-6 alkyl), -C(O)-O-(C_1-4 alkylene)-O-(C1-4 alkylene)-N(R^1A)(R^1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R^1A)(R^1B))-(C1-4 hydroxyalkyl), or -C(O)-O-(C1-4 alkylene)-(5- membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R⁹); d) -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl), -N(R^1A)-C(O)-C(O)-N(R^1B)(R^1C), -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-4 alkylene)-N(R^1C)-C(O)-(C1-4 alkyl), or -N(R^1A)- C(O)-C(O)-N(R^1B)-(C_1-6 alkylene)-N(R^1C)-S(O)₂-(C_1-4 alkyl); e) -N(R^1A)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R^1A)-C(O)-N(R^1B)(R^1C), -N(R^1A)-C(O)-N(R^1B)-(C1-4 haloalkyl), -N(R^1A)-C(O)- N(R^1B)-[(C_1-4 alkylene)-O-]_x-R⁶, -N(R^1A)-C(O)-N(R^1B)-(C_1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -N(R^1A)-C(O)-(morpholinyl), or -N(R^1A)- C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C_1-4 alkyl and one -OH); f) -N(R^1A)-C(O)-(C_1-6 hydroxyalkyl), -N(R^1A)-C(O)-(C_1-4 alkylene)-N(R^1B)-C(O)-(C_1-4 alkyl), -N(R^1A)-C(O)-(C1-4 alkylene)-N(R^1B)-S(O)2-(C1-4 alkyl), -N(R^1A)-C(O)-(C1-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -N(R^1A)-C(O)-O-[(C1-4 alkylene)- O-]_x-R⁶, -N(R^1A)-C(O)-O-(C_1-4 alkylene)-(phenyl), or -N(R^1A)-S(O)₂-R⁷; g) -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-(C1-6 alkyl), -S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl), -S(O)2-(C1-4 alkylene)-C(O)-O-(C1-6 alkyl), -S(O)2-[(C1-4 alkylene)-O-]x-R⁵, -S(O)2- (C_3-7 cycloalkyl), -S(O)₂-N(R^1A)-(C_1-6 hydroxyalkyl), -S(O)₂-N(R^1A)(R^1B), -S(O)₂- N(R^1A)-C(O)-(C1-6 alkyl), -S(O)2-N(R^1A)-C(O)-O-(C1-6 alkyl), or -S(O)2-N(R^1A)- C(O)-N(R^1B)(R^1C); h) -(C_1-6 hydroxyalkyl), -(C_1-4 alkylene)-C(O)-N(R^1A)-(C_1-6 hydroxyalkyl), -(C_1-4 alkylene)-N(R^1A)-C(O)-(C_1-6 hydroxyalkyl), -(C_1-4 alkylene)-C(O)-OH, or -(C_1-4 alkylene)-C(O)-O-(C1-6 alkyl); i) a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R^1A; or j) hydrogen; R⁴ is C_1-6 hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, a 5-7 membered di-oxo- heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl; R⁵ is C1-6 alkyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), C1-6 alkoxyl, -(C1-6 alkylene)-N(R^1A)(R^1B), or -(C1-6 alkylene)-N(R^1A)-C(O)-O-(C1-6 alkyl); R⁶ is C_1-4 alkyl, C_1-4 hydroxyalkyl, C_1-4 haloalkyl, or -(C_1-4 alkylene)-(C_1-4 alkoxyl); R⁷ is C1-4 alkyl, C1-4 alkoxyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), -(C0-4 alkylene)-N(R^1A)(R^1B), -(C0-6 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), or -N(R^1B)-C(O)-O-R⁸; R⁸ is C_1-4 alkyl or -(C_0-4 alkylene)-(phenyl); R⁹ is oxo, C1-4 alkyl, hydroxyl, or -C(O)-O-(C1-4 alkyl); m and n are independently 1 or 2; p is 0, 1, 2, 3, or 4; x is 1, 2, 3, 4, or 5; and y and z are independently 1, 2, or 3; provided that when B¹ is a 6-membered aryl ring substituted with 0 or 1 occurrences of R², then Z is not -C(O)R⁴ or -C(O)-(C1-4 alkylene)-R⁴.

2. The compound of claim 1, wherein A¹ is substituted with p occurrences of R², wherein B¹ is a 6-membered aryl ring or a 6-membered heteroaryl ring containing 1 or 2 heteroatoms that are nitrogen.

3. The compound of claim 1 or 2, wherein m and n are 1.

4. The compound of any one of claims 1-3, wherein A² is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, a 6- membered saturated or partially unsaturated monocyclic carbocyclylene, or a 5-8 membered saturated bridged bicyclic carbocyclylene, each of which is substituted with 0 or 1 occurrences of R³.

5. The compound of any one of claims 1-4, wherein A³ is para-phenylene substituted with 0 or 1 occurrences of R³.

6. The compound of any one of claims 1-5, wherein the compound is a compound of Formula I.

7. The compound of any one of claims 1-5, wherein the compound is represented by Formula I- B: (I-B) or a pharmaceutically acceptable salt thereof; wherein: A¹ is substituted with p occurrences of R², substituted with 1, 2 or 3 occurrences of R², or substituted with 2, 3, or 4 occurrences of R²; A² is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, or a 5-8 membered saturated bridged bicyclic carbocyclylene, each of which is substituted with 0 or 1 occurrences of R³; R^1A, R^1B, and R^1C each represent independently for each occurrence hydrogen or C_1-4 alkyl; R² represents independently for each occurrence halo, C1-4 haloalkyl, C1-4 alkoxyl, C1-4 alkyl, or C_1-4 hydroxyalkyl; R³ is halo or C1-4 alkyl; Z is one of the following: a) -C(O)R⁴, -C(O)-(C_1-4 alkylene)-R⁴, -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_1-4 alkyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-S(O)₂-(C_1-4 alkyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)- R⁴, -C(O)-(C1-4 alkylene)-O-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]y- (C_1-6 alkoxyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_3-8 cycloalkyl substituted with z occurrence of R⁹), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or -C(O)-(C3-7 cycloalkyl substituted with one -N(R^1A)-S(O)2-(C1-6 alkyl) or -N(R^1A)-C(O)-(C1-6 alkyl)); b) -C(O)-N(R^1A)-(C_1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R^1A)(R^1B), -C(O)-N(R^1A)-(C1-6 alkyl), -C(O)-N(R^1A)-(C1-4 haloalkyl), -C(O)- N(R^1A)-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl), -C(O)-N(R^1B)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]_x-(C_1-6 alkoxyl), -C(O)-N(R^1A)-(C_1-4 alkylene)-N(R^1B)-C(O)-(C_1-4 alkyl), -C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1A)(R^1B), -C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-C(O)-O-(C1-6 alkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1B)-C(O)-(C_1-6 hydroxyalkyl), -C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1B)-S(O)₂-R⁶, -C(O)-N(R^1A)-(C_1-4 alkylene)- N(R^1B)-S(O)₂-(C_1-4 alkyl), -C(O)-N(R^1A)-(C_0-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R^1A)-(C1-4 alkylene)-(C3-7 cycloalkyl), or -C(O)-N(R^1A)- S(O)2-R⁷; c) -C(O)-C(O)-N(R^1A)-R⁵, -C(O)-C(O)-N(R^1A)(R^1B), -C(O)-C(O)-N(R^1A)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl),-C(O)-C(O)-N(R^1A)-S(O)2-(C1-6 alkyl), -C(O)- C(O)-N(R^1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-C(O)-R⁴, -C(O)-C(O)-OH, -C(O)-OH, -C(O)-O-(C_1-6 alkyl), -C(O)-O-(C_1-4 alkylene)-O-(C1-4 alkylene)-N(R^1A)(R^1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R^1A)(R^1B))-(C1-4 hydroxyalkyl), or -C(O)-O-(C1-4 alkylene)-(5- membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R⁹); d) -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl), -N(R^1A)-C(O)-C(O)-N(R^1B)(R^1C), -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-4 alkylene)-N(R^1C)-C(O)-(C1-4 alkyl), or -N(R^1A)- C(O)-C(O)-N(R^1B)-(C_1-6 alkylene)-N(R^1C)-S(O)₂-(C_1-4 alkyl); e) -N(R^1A)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R^1A)-C(O)-N(R^1B)(R^1C), -N(R^1A)-C(O)-N(R^1B)-(C1-4 haloalkyl), -N(R^1A)-C(O)- N(R^1B)-[(C_1-4 alkylene)-O-]_x-R⁶, -N(R^1A)-C(O)-N(R^1B)-(C_1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -N(R^1A)-C(O)-(morpholinyl), or -N(R^1A)- C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C_1-4 alkyl and one -OH); f) -N(R^1A)-C(O)-(C_1-6 hydroxyalkyl), -N(R^1A)-C(O)-(C_1-4 alkylene)-N(R^1B)-C(O)-(C_1-4 alkyl), -N(R^1A)-C(O)-(C1-4 alkylene)-N(R^1B)-S(O)2-(C1-4 alkyl), -N(R^1A)-C(O)-(C1-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -N(R^1A)-C(O)-O-[(C1-4 alkylene)- O-]_x-R⁶, -N(R^1A)-C(O)-O-(C_1-4 alkylene)-(phenyl), or -N(R^1A)-S(O)₂-R⁷; g) -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-(C1-6 alkyl), -S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl), -S(O)2-(C1-4 alkylene)-C(O)-O-(C1-6 alkyl), -S(O)2-[(C1-4 alkylene)-O-]x-R⁵, -S(O)2- (C_3-7 cycloalkyl), -S(O)₂-N(R^1A)-(C_1-6 hydroxyalkyl), -S(O)₂-N(R^1A)(R^1B), -S(O)₂- N(R^1A)-C(O)-(C1-6 alkyl), -S(O)2-N(R^1A)-C(O)-O-(C1-6 alkyl), or -S(O)2-N(R^1A)- C(O)-N(R^1B)(R^1C); h) -(C_1-6 hydroxyalkyl), -(C_1-4 alkylene)-C(O)-N(R^1A)-(C_1-6 hydroxyalkyl), -(C_1-4 alkylene)-N(R^1A)-C(O)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-OH, or -(C1-4 alkylene)-C(O)-O-(C1-6 alkyl); i) a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R^1A; or j) hydrogen; R⁴ is C1-6 hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, a 5-7 membered di-oxo- heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl; R⁵ is C1-6 alkyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), C1-6 alkoxyl, -(C1-6 alkylene)-N(R^1A)(R^1B), or -(C_1-6 alkylene)-N(R^1A)-C(O)-O-(C_1-6 alkyl); R⁶ is C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, or -(C1-4 alkylene)-(C1-4 alkoxyl); R⁷ is C1-4 alkyl, C1-4 alkoxyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), -(C0-4 alkylene)-N(R^1A)(R^1B), -(C_0-6 alkylene)-N(R^1B)-C(O)-(C_1-4 alkyl), or -N(R^1B)-C(O)-O-R⁸; R⁸ is C1-4 alkyl or -(C0-4 alkylene)-(phenyl); R⁹ is oxo, C1-4 alkyl, hydroxyl, or -C(O)-O-(C1-4 alkyl); p is 0, 1, 2, 3, or 4; x is 1, 2, 3, 4, or 5; and y and z are independently 1, 2, or 3.

8. The compound of claim 7, wherein the compound is a compound of Formula I-B.

9. The compound of any one of claims 1-8, wherein A² is each of which is substituted with 0 or 1 occurrences of R³, wherein the nitrogen atom of A² is attached to Z.

10. The compound of any one of claims 1-8, wherein A² is wherein the saturated carbon is attached to Z, wherein A² is substituted with 0 or 1 occurrences of R³.

11. The compound of any one of claims 1-8, wherein A² is substituted with 0 or 1 occurrences of R³.

12. The compound of any one of claims 1-8, wherein A² is substituted with 0 or 1 occurrences of R³.

13. A compound represented by Formula I-C: or a pharmaceutically acceptable salt thereof; wherein: A¹ is substituted with p occurrences of R², wherein B¹ is a 6-membered aryl ring or a 6-membered heteroaryl ring containing 1 or 2 heteroatoms that are nitrogen; A² is a 5-8 membered saturated bridged bicyclic carbocyclylene or a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen, each of which is substituted with 0 or 1 occurrences of R³; R^1A, R^1B, and R^1C each represent independently for each occurrence hydrogen or C1-4 alkyl; R² represents independently for each occurrence halo, C1-4 haloalkyl, C1-4 alkoxyl, C1-4 alkyl, or C1-4 hydroxyalkyl; R³ is halo or C_1-4 alkyl; Z is one of the following: a) -C(O)R⁴, -C(O)-(C1-4 alkylene)-R⁴, -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)- R⁴, -C(O)-(C_1-4 alkylene)-O-(C_1-4 alkyl), -C(O)-(C_1-4 alkylene)-[O-(C_1-4 alkylene)-]_y- (C1-6 alkoxyl), -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R⁹), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C_1-4 alkyl and one -OH), or -C(O)-(C_3-7 cycloalkyl substituted with one -N(R^1A)-S(O)2-(C1-6 alkyl) or -N(R^1A)-C(O)-(C1-6 alkyl)); b) -C(O)-N(R^1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R^1A)(R^1B), -C(O)-N(R^1A)-(C_1-6 alkyl), -C(O)-N(R^1A)-(C_1-4 haloalkyl), -C(O)- N(R^1A)-(C_1-4 alkylene)-O-(C_1-6 hydroxyalkyl), -C(O)-N(R^1B)-(C_1-4 alkylene)-[O-(C_1-4 alkylene)-]x-(C1-6 alkoxyl), -C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1A)(R^1B), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1B)-C(O)-O-(C_1-6 alkyl), -C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-6 hydroxyalkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-S(O)2-R⁶, -C(O)-N(R^1A)-(C1-4 alkylene)- N(R^1B)-S(O)₂-(C_1-4 alkyl), -C(O)-N(R^1A)-(C_0-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R^1A)-(C1-4 alkylene)-(C3-7 cycloalkyl), or -C(O)-N(R^1A)- S(O)2-R⁷; c) -C(O)-C(O)-N(R^1A)-R⁵, -C(O)-C(O)-N(R^1A)(R^1B), -C(O)-C(O)-N(R^1A)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_1-4 alkyl),-C(O)-C(O)-N(R^1A)-S(O)₂-(C_1-6 alkyl), -C(O)- C(O)-N(R^1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-C(O)-R⁴, -C(O)-C(O)-OH, -C(O)-OH, -C(O)-O-(C1-6 alkyl), -C(O)-O-(C1-4 alkylene)-O-(C_1-4 alkylene)-N(R^1A)(R^1B), -C(O)-O-(C_1-4 alkylene substituted with 1 occurrence of -N(R^1A)(R^1B))-(C1-4 hydroxyalkyl), or -C(O)-O-(C1-4 alkylene)-(5- membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R⁹); d) -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl), -N(R^1A)-C(O)-C(O)-N(R^1B)(R^1C), -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-4 alkylene)-N(R^1C)-C(O)-(C1-4 alkyl), or -N(R^1A)- C(O)-C(O)-N(R^1B)-(C_1-6 alkylene)-N(R^1C)-S(O)₂-(C_1-4 alkyl); e) -N(R^1A)-C(O)-N(R^1B)-(C_1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R^1A)-C(O)-N(R^1B)(R^1C), -N(R^1A)-C(O)-N(R^1B)-(C1-4 haloalkyl), -N(R^1A)-C(O)- N(R^1B)-[(C1-4 alkylene)-O-]x-R⁶, -N(R^1A)-C(O)-N(R^1B)-(C1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -N(R^1A)-C(O)-(morpholinyl), or -N(R^1A)- C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH); f) -N(R^1A)-C(O)-(C_1-6 hydroxyalkyl), -N(R^1A)-C(O)-(C_1-4 alkylene)-N(R^1B)-C(O)-(C_1-4 alkyl), -N(R^1A)-C(O)-(C1-4 alkylene)-N(R^1B)-S(O)2-(C1-4 alkyl), -N(R^1A)-C(O)-(C1-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -N(R^1A)-C(O)-O-[(C1-4 alkylene)- O-]_x-R⁶, -N(R^1A)-C(O)-O-(C_1-4 alkylene)-(phenyl), or -N(R^1A)-S(O)₂-R⁷; g) -S(O)₂-(C_1-6 hydroxyalkyl), -S(O)₂-(C_1-6 alkyl), -S(O)₂-(C_1-4 alkylene)-(C_1-6 alkoxyl), -S(O)2-(C1-4 alkylene)-C(O)-O-(C1-6 alkyl), -S(O)2-[(C1-4 alkylene)-O-]x-R⁵, -S(O)2- (C3-7 cycloalkyl), -S(O)2-N(R^1A)-(C1-6 hydroxyalkyl), -S(O)2-N(R^1A)(R^1B), -S(O)2- N(R^1A)-C(O)-(C_1-6 alkyl), -S(O)₂-N(R^1A)-C(O)-O-(C_1-6 alkyl), or -S(O)₂-N(R^1A)- C(O)-N(R^1B)(R^1C); h) -(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-N(R^1A)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-N(R^1A)-C(O)-(C_1-6 hydroxyalkyl), -(C_1-4 alkylene)-C(O)-OH, or -(C_1-4 alkylene)-C(O)-O-(C1-6 alkyl); i) a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R^1A; or j) hydrogen; R⁴ is C1-6 hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, a 5-7 membered di-oxo- heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl; R⁵ is C1-6 alkyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), C1-6 alkoxyl, -(C1-6 alkylene)-N(R^1A)(R^1B), or -(C1-6 alkylene)-N(R^1A)-C(O)-O-(C1-6 alkyl); R⁶ is C_1-4 alkyl, C_1-4 hydroxyalkyl, C_1-4 haloalkyl, or -(C_1-4 alkylene)-(C_1-4 alkoxyl); R⁷ is C1-4 alkyl, C1-4 alkoxyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), -(C0-4 alkylene)-N(R^1A)(R^1B), -(C0-6 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), or -N(R^1B)-C(O)-O-R⁸; R⁸ is C_1-4 alkyl or -(C_0-4 alkylene)-(phenyl); R⁹ is oxo, C1-4 alkyl, hydroxyl, or -C(O)-O-(C1-4 alkyl); p is 0, 1, 2, 3, or 4; x is 1, 2, 3, 4, or 5; and y and z are independently 1, 2, or 3.

14. The compound of claim 13, wherein the compound is a compound of Formula I-C.

15. The compound of claim 13 or 14, wherein A² is substituted with 0 or 1 occurrences of R³.

16. The compound of any one of claims 1-5, wherein the compound is represented by Formula I- (I-D) or a pharmaceutically acceptable salt thereof; wherein: A¹ is substituted with p occurrences of R², wherein B¹ is a 6-membered aryl ring or a 6-membered heteroaryl ring containing 1 or 2 heteroatoms that are nitrogen; A² is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, or a 5-8 membered saturated bridged bicyclic carbocyclylene, wherein the heterocyclylene, monocyclic carbocyclylene, and bicyclic carbocyclylene are substituted with 0 or 1 occurrences of R³; R^1A, R^1B, and R^1C each represent independently for each occurrence hydrogen or C_1-4 alkyl; R² represents independently for each occurrence halo, C1-4 haloalkyl, C1-4 alkoxyl, C1-4 alkyl, or C_1-4 hydroxyalkyl; R³ is halo or C1-4 alkyl; Z is one of the following: a) -C(O)R⁴, -C(O)-(C_1-4 alkylene)-R⁴, -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)- R⁴, -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R⁹), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C_1-4 alkyl and one -OH), or -C(O)-(C_3-7 cycloalkyl substituted with one - N(R^1A)-S(O)2-(C1-6 alkyl) or -N(R^1A)-C(O)-(C1-6 alkyl)); b) -C(O)-N(R^1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R^1A)(R^1B), -C(O)-N(R^1A)-(C_1-6 alkyl), -C(O)-N(R^1A)-(C_1-4 haloalkyl), -C(O)- N(R^1A)-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl), -C(O)-N(R^1B)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]x-(C1-6 alkoxyl), -C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), -C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1A)(R^1B), -C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-C(O)-O-(C1-6 alkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-6 hydroxyalkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1B)-S(O)₂-R⁶, -C(O)-N(R^1A)-(C_1-4 alkylene)- N(R^1B)-S(O)₂-(C_1-4 alkyl), -C(O)-N(R^1A)-(C_0-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R^1A)-(C1-4 alkylene)-(C3-7 cycloalkyl), or -C(O)-N(R^1A)- S(O)2-R⁷; c) -C(O)-C(O)-N(R^1A)-R⁵, -C(O)-C(O)-N(R^1A)(R^1B), -C(O)-C(O)-N(R^1A)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl),-C(O)-C(O)-N(R^1A)-S(O)2-(C1-6 alkyl), -C(O)- C(O)-N(R^1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-C(O)-R⁴, -C(O)-C(O)-OH, -C(O)-O-(C_1-4 alkylene)-O-(C_1-4 alkylene)- N(R^1A)(R^1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R^1A)(R^1B))- (C1-4 hydroxyalkyl), or -C(O)-O-(C1-4 alkylene)-(5-membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R⁹); d) -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl), -N(R^1A)-C(O)-C(O)-N(R^1B)(R^1C), -N(R^1A)-C(O)-C(O)-N(R^1B)-(C_1-4 alkylene)-N(R^1C)-C(O)-(C_1-4 alkyl), or -N(R^1A)- C(O)-C(O)-N(R^1B)-(C1-6 alkylene)-N(R^1C)-S(O)2-(C1-4 alkyl); e) -N(R^1A)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R^1A)-C(O)-N(R^1B)(R^1C), -N(R^1A)-C(O)-N(R^1B)-(C_1-4 haloalkyl), -N(R^1A)-C(O)- N(R^1B)-[(C1-4 alkylene)-O-]x-R⁶, -N(R^1A)-C(O)-N(R^1B)-(C1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -N(R^1A)-C(O)-(morpholinyl), or -N(R^1A)- C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C_1-4 alkyl and one -OH); f) -N(R^1A)-C(O)-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), -N(R^1A)-C(O)-(C1-4 alkylene)-N(R^1B)-S(O)2-(C1-4 alkyl), -N(R^1A)-C(O)-O-[(C1-4 alkylene)-O-]x-R⁶, or -N(R^1A)-S(O)₂-R⁷; g) -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl), -S(O)2-(C1-4 alkylene)-C(O)-O-(C1-6 alkyl), -S(O)2-[(C1-4 alkylene)-O-]x-R⁵, -S(O)2-N(R^1A)-(C1-6 hydroxyalkyl), -S(O)₂-N(R^1A)(R^1B), -S(O)₂-N(R^1A)-C(O)-(C_1-6 alkyl), -S(O)₂-N(R^1A)- C(O)-O-(C1-6 alkyl), or -S(O)2-N(R^1A)-C(O)-N(R^1B)(R^1C); h) -(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-N(R^1A)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-N(R^1A)-C(O)-(C_1-6 hydroxyalkyl), -(C_1-4 alkylene)-C(O)-OH, or -(C_1-4 alkylene)-C(O)-O-(C_1-6 alkyl); or i) a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R^1A; R⁴ is C_1-6 hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, a 5-7 membered di-oxo- heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl; R⁵ is C_1-6 alkyl, C_1-6 hydroxyalkyl, -(C_1-4 alkylene)-(C_1-4 alkoxyl), C_1-6 alkoxyl, -(C_1-6 alkylene)-N(R^1A)(R^1B), or -(C1-6 alkylene)-N(R^1A)-C(O)-O-(C1-6 alkyl); R⁶ is C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, or -(C1-4 alkylene)-(C1-4 alkoxyl); R⁷ is C_1-4 alkyl, C_1-4 alkoxyl, C_1-6 hydroxyalkyl, -(C_1-4 alkylene)-(C_1-4 alkoxyl), -(C_0-4 alkylene)-N(R^1A)(R^1B), -(C0-6 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), or -N(R^1B)-C(O)-O-R⁸; R⁸ is C1-4 alkyl or -(C0-4 alkylene)-(phenyl); R⁹ is oxo, C_1-4 alkyl, hydroxyl, or -C(O)-O-(C_1-4 alkyl); p is 0, 1, 2, 3, or 4; x is 1, 2, 3, 4, or 5; and z is 1, 2, or 3; provided that when B¹ is a 6-membered aryl ring substituted with 0 or 1 occurrences of R², or B¹ is substituted with 0 occurrences of R², then Z is not -C(O)R⁴ or -C(O)- (C1-4 alkylene)-R⁴.

17. The compound of claim 16, wherein the compound is a compound of Formula I-D.

18. The compound of claim 16 or 17, wherein A² is each of which is substituted with 0 or 1 occurrences of R³, wherein the nitrogen atom of A² is attached to Z.

19. The compound of claim 16 or 17, wherein A² is wherein the saturated carbon is attached to Z, wherein A² is substituted with 0 or 1 occurrences of R³.

20. The compound of claim 16 or 17, wherein A² is substituted with 0 or 1 occurrences of R³.

21. The compound of claim 16 or 17, wherein A² is substituted with 0 or 1 occurrences of R³.

22. The compound of any one of claims 1-6 or 13-21, wherein A¹ is substituted with p occurrences of R².

23. The compound of any one of claims 1-6 or 13-21, wherein .

24. The compound of any one of claims 1-21, wherein A¹ is substituted with 2, 3, or 4 occurrences of R².

25. The compound of any one of claims 1-21, wherein .

26. The compound of any one of claims 1-21, wherein A¹ is substituted with 1, 2 or 3 occurrences of R².

27. The compound of any one of claims 1-21, wherein

28. The compound of any one of claims 1-21, wherein A¹ substituted with p occurrences of R².

29. The compound of any one of claims 1-21, wherein A¹ is .

30. The compound of any one of claims 1-22 or 28, wherein p is 1, 2, or 3.

31. The compound of any one of claims 1-30, wherein R² represents independently for each occurrence halo.

32. The compound of any one of claims 1-30, wherein R² is fluoro.

33. The compound of any one of claims 1-6 or 13-21, wherein .

34. The compound of any one of claims 1-21, wherein .

35. The compound of any one of claims 1-21, wherein

36. The compound of any one of claims 1-21, wherein A¹ is .

37. The compound of any one of claims 1-36, wherein A² is substituted with 0 occurrences of R³.

38. The compound of any one of claims 1-37, wherein Z is one of the following: a) -C(O)-(C1-6 hydroxyalkyl), -C(O)-(C1-4 alkylene)-N(R^1A)-C(O)-(C1-4 alkyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-S(O)₂-(C_1-4 alkyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)- R⁴, -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_3-8 cycloalkyl substituted with z occurrence of R⁹), or -C(O)-(C_3-7 cycloalkyl substituted with one -N(R^1A)-S(O)₂-(C_1-6 alkyl) or -N(R^1A)-C(O)-(C1-6 alkyl)); b) -C(O)-N(R^1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R^1A)(R^1B), -C(O)-N(R^1A)-(C_1-4 alkylene)-N(R^1B)-C(O)-(C_1-4 alkyl), or -C(O)- N(R^1A)-(C1-4 alkylene)-N(R^1B)-S(O)2-(C1-4 alkyl); c) -C(O)-C(O)-N(R^1A)-(C1-6 hydroxyalkyl), -C(O)-C(O)-N(R^1A)-(C1-4 alkylene)-N(R^1A)- C(O)-(C_1-4 alkyl), -C(O)-C(O)-N(R^1A)-S(O)₂-(C_1-6 alkyl), or -C(O)-C(O)-(C_1-6 hydroxyalkyl); d) -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl), -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-4 alkylene)-N(R^1C)-C(O)-(C_1-4 alkyl), or -N(R^1A)-C(O)-C(O)-N(R^1B)-(C_1-6 alkylene)- N(R^1C)-S(O)₂-(C_1-4 alkyl); e) -N(R^1A)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo); f) -N(R^1A)-C(O)-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), -N(R^1A)-C(O)-(C1-4 alkylene)-N(R^1B)-S(O)₂-(C_1-4 alkyl), or -N(R^1A)-S(O)₂-R⁷; g) -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-N(R^1A)-(C1-6 hydroxyalkyl), -S(O)2-N(R^1A)-C(O)- (C1-6 alkyl), or -S(O)2-N(R^1A)-C(O)-O-(C1-6 alkyl); or h) a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R^1A.

39. The compound of any one of claims 1-37, wherein Z is -C(O)R⁴ or -C(O)-(C1-4 alkylene)-R⁴.

40. The compound of any one of claims 1-37, wherein Z is -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)- (C_1-4 alkyl), -C(O)-(C_1-4 alkylene)-N(R^1A)-S(O)₂-(C_1-4 alkyl), or -C(O)-(C_1-4 alkylene)- N(R^1A)-C(O)-R⁴.

41. The compound of any one of claims 1-40, wherein R⁴ is C1-6 hydroxyalkyl.

42. The compound of any one of claims 1-37, wherein Z is -C(O)-(C_1-4 alkylene)-N(R^1A)-C(O)- (C3-8 cycloalkyl substituted with z occurrence of R⁹), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or -C(O)-(C3-7 cycloalkyl substituted with one -N(R^1A)-S(O)₂-(C_1-6 alkyl) or -N(R^1A)-C(O)-(C_1-6 alkyl)).

43. The compound of any one of claims 1-37, wherein Z is -C(O)-N(R^1A)-(C_1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-N(R^1A)(R^1B), -C(O)-N(R^1A)-(C1-6 alkyl), or -C(O)-N(R^1A)-(C1-4 haloalkyl).

44. The compound of any one of claims 1-37, wherein Z is -C(O)-N(R^1A)-(C_1-4 alkylene)-O-(C_1-6 hydroxyalkyl), -C(O)-N(R^1B)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]x-(C1-6 alkoxyl), -C(O)- N(R^1A)-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-4 alkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1A)(R^1B), -C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1B)-C(O)-O- (C1-6 alkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-C(O)-(C1-6 hydroxyalkyl), -C(O)-N(R^1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R^1B)-S(O)2-R⁶, -C(O)- N(R^1A)-(C_1-4 alkylene)-N(R^1B)-S(O)₂-(C_1-4 alkyl), -C(O)-N(R^1A)-(C_0-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R^1A)-(C_1-4 alkylene)-(C_3-7 cycloalkyl), or -C(O)-N(R^1A)-S(O)2-R⁷.

45. The compound of any one of claims 1-37, wherein Z is -C(O)-C(O)-N(R^1A)-R⁵, -C(O)-C(O)- N(R^1A)(R^1B), -C(O)-C(O)-N(R^1A)-(C_1-4 alkylene)-N(R^1A)-C(O)-(C_1-4 alkyl),-C(O)-C(O)- N(R^1A)-S(O)2-(C1-6 alkyl), -C(O)-C(O)-N(R^1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-C(O)-R⁴, or -C(O)-C(O)-OH.

46. The compound of any one of claims 1-37, wherein Z is -C(O)-C(O)-N(R^1A)-(C_1-6 hydroxyalkyl).

47. The compound of any one of claims 1-37, wherein Z is -C(O)-O-(C1-4 alkylene)-O-(C1-4 alkylene)-N(R^1A)(R^1B), -C(O)-O-(C_1-4 alkylene substituted with 1 occurrence of -N(R^1A)(R^1B))-(C_1-4 hydroxyalkyl), or -C(O)-O-(C_1-4 alkylene)-(5-membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R⁹).

48. The compound of any one of claims 1-37, wherein Z is -N(R^1A)-C(O)-C(O)-N(R^1B)-(C_1-6 hydroxyalkyl), -N(R^1A)-C(O)-C(O)-N(R^1B)(R^1C), -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-4 alkylene)-N(R^1C)-C(O)-(C1-4 alkyl), or -N(R^1A)-C(O)-C(O)-N(R^1B)-(C1-6 alkylene)-N(R^1C)- S(O)₂-(C_1-4 alkyl).

49. The compound of any one of claims 1-37, wherein Z is -N(R^1A)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R^1A)-C(O)-N(R^1B)(R^1C), -N(R^1A)-C(O)-N(R^1B)-(C_1-4 haloalkyl), -N(R^1A)-C(O)-N(R^1B)-[(C_1-4 alkylene)-O-]_x-R⁶, -N(R^1A)-C(O)-N(R^1B)-(C1-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -N(R^1A)- C(O)-(morpholinyl), or -N(R^1A)-C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C_1-4 alkyl and one -OH).

50. The compound of any one of claims 1-37, wherein Z is -N(R^1A)-C(O)-N(R^1B)-(C1-6 hydroxyalkyl).

51. The compound of any one of claims 1-37, wherein Z is -N(R^1A)-C(O)-(C_1-4 alkylene)- N(R^1B)-C(O)-(C1-4 alkyl), -N(R^1A)-C(O)-(C1-4 alkylene)-N(R^1B)-S(O)2-(C1-4 alkyl), or -N(R^1A)-C(O)-O-[(C1-4 alkylene)-O-]x-R⁶.

52. The compound of any one of claims 1-37, wherein Z is -N(R^1A)-S(O)₂-R⁷.

53. The compound of any one of claims 1-37, wherein Z is -S(O)₂-(C_1-6 hydroxyalkyl), -S(O)₂- (C1-4 alkylene)-(C1-6 alkoxyl), -S(O)2-(C1-4 alkylene)-C(O)-O-(C1-6 alkyl), -S(O)2-[(C1-4 alkylene)-O-]x-R⁵, -S(O)2-N(R^1A)-(C1-6 hydroxyalkyl), -S(O)2-N(R^1A)(R^1B), -S(O)2-N(R^1A)- C(O)-(C_1-6 alkyl), -S(O)₂-N(R^1A)-C(O)-O-(C_1-6 alkyl), or -S(O)₂-N(R^1A)-C(O)-N(R^1B)(R^1C).

54. The compound of any one of claims 1-37, wherein Z is -(C1-6 hydroxyalkyl), -(C1-4 alkylene)- C(O)-N(R^1A)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-N(R^1A)-C(O)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-OH, or -(C_1-4 alkylene)-C(O)-O-(C_1-6 alkyl).

55. The compound of any one of claims 1-37, wherein Z is a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R^1A.

56. The compound of any one of claims 1-37, wherein Z is -S(O)₂-(C_1-6 hydroxyalkyl).

57. The compound of any one of claims 1-37, wherein ,

58. The compound of any one of claims 1-37, wherein Z is .

59. The compound of any one of claims 1-37, wherein

60. The compound of any one of claims 1-37, wherein .

61. The compound of any one of claims 1-37, wherein .

62. The compound of any one of claims 1-55, wherein R^1A, R^1B, and R^1C are hydrogen.

63. A compound represented by Formula I-1: or a pharmaceutically acceptable salt thereof; wherein: A¹ is substituted with p occurrences of R², wherein B¹ is a 6-membered aryl ring or a 5-6 membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur; A² is a 6-membered saturated or partially unsaturated heterocyclylene containing 1 heteroatom selected from nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, a 5-8 membered saturated bicyclic carbocyclylene, or a covalent bond, wherein the heterocyclylene, monocyclic carbocyclylene, and bicyclic carbocyclylene are substituted with 0 or 1 occurrences of R³; R^1A, R^1B, and R^1C each represent independently for each occurrence hydrogen or C1-4 alkyl; R² represents independently for each occurrence halo; R³ is halo or C1-4 alkyl; Z is -C(O)R⁴, -C(O)-(C1-4 alkylene)-R⁴, -C(O)-OH, -C(O)-O-(C1-6 alkyl), -C(O)- N(R^1A)(R^1B), -C(O)-O-(C_1-4 alkylene)-O-(C_1-4 alkylene)-N(R^1A)(R^1B), -C(O)-O-(C_1-4 alkylene substituted with 1 occurrence of -N(R^1A)(R^1B))-(C1-4 hydroxyalkyl), -S(O)2-(C1-6 alkyl), -S(O)2-(C3-7 cycloalkyl), -S(O)2-N(R^1A)(R^1B), -S(O)2-N(R^1A)-C(O)-(C1-6 alkyl), -S(O)2- N(R^1A)-C(O)-O-(C_1-6 alkyl), -S(O)₂-N(R^1A)-C(O)-N(R^1B)(R^1C), -S(O)₂-[(C_1-4 alkylene)-O-]_x- R⁵, -N(R^1A)-C(O)-(C_1-4 alkylene)-(5-6 membered saturated heterocyclyl containing 1 oxygen atom), -N(R^1A)-C(O)-O-(C1-4 alkylene)-(phenyl), -N(R^1A)-C(O)-O-[(C1-4 alkylene)-O-]x-R⁶, -N(R^1A)-C(O)-N(R^1B)-[(C1-4 alkylene)-O-]x-R⁶, -C(O)-N(R^1A)-(C1-6 hydroxyalkyl), -C(O)- N(R^1A)-(C_1-4 alkylene)-O-(C_1-6 hydroxyalkyl), -C(O)-N(R^1A)-[(C_1-4 alkylene)-O-]_x-(C_1-4 alkylene)-N(R^1A)(R^1B), -N(R^1A)-C(O)-N(R^1B)-[(C_1-6 hydroxyalkyl), -C(O)-(C_1-4 alkylene)- [O-(C1-4 alkylene)-]y-(C1-6 alkoxyl), -C(O)N(R^1B)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]y-(C1-6 alkoxyl), -C(O)-C(O)-OH, -C(O)-C(O)-N(R^1A)(R^1B), -N(R^1A)-C(O)-(C1-6 hydroxyalkyl), -C(O)-C(O)-N(R^1A)-R⁵, -N(R^1A)-C(O)-C(O)-N(R^1B)(R^1C), -C(O)-N(R^1A)-S(O)₂-R⁷, -N(R^1A)- S(O)2-R⁷, -N(R^1A)-S(O)2-N(R^1B)-CO2-(C1-4 alkylene)-phenyl, -C(O)-C(O)-N(R^1A)-S(O)2-(C1- 6 alkyl), -S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl), -C(O)-C(O)-N(R^1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-O-(C_1-4 alkylene)-(5 membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R⁹), or hydrogen; R⁴ is C_1-6 hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, a 5-7 membered di-oxo- heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl; R⁵ is C1-6 alkyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), or C1-6 alkoxyl; R⁶ is C1-4 alkyl, C1-4 hydroxyalkyl, or C1-4 haloalkyl; R⁷ is C_1-4 alkyl, C_1-4 alkoxyl, -(C_1-4 alkylene)-(C_1-4 alkoxyl), -(C_0-4 alkylene)- N(R^1A)(R^1B), or -N(R^1B)-C(O)-O-R⁸; R⁸ is C1-4 alkyl or -(C0-4 alkylene)-(phenyl); R⁹ is oxo, C_1-4 alkyl, hydroxyl, or -C(O)-O-(C_1-4 alkyl); m is 1 or 2; n is 1 or 2; p is 0, 1, 2, 3, or 4; x is 1, 2, 3, 4, or 5; and y and z are independently 1, 2, or 3; provided that when B¹ is a 6-membered aryl ring substituted with 0 or 1 occurrences of R², then Z is not -C(O)R⁴ or -C(O)-(C_1-4 alkylene)-R⁴.

64. The compound of claim 63, wherein the compound is a compound of Formula I-1.

65. The compound of claim 63 or 64, wherein A¹ is .

66. The compound of claim 63 or 64, wherein A¹ is .

67. The compound of any one of claims 63-66, wherein A² is , each of which is substituted with 0 or 1 occurrences of R³, or a covalent bond, wherein *** is the point of attachment to Z.

68. The compound of claim 63, wherein the compound is a compound of Formula Id: or a pharmaceutically acceptable salt thereof, wherein X is -C(H)- or -N-.

69. The compound of any one of claims 63-68, wherein , each of which is substituted with 0 or 1 occurrences of R³, wherein ***is the point of attachment to Z.

70. The compound of any one of claims 63-69, wherein Z is , .

71. The compound of any one of claims 63-69, wherein Z is .

72. A compound in Table 1 herein, or a pharmaceutically acceptable salt thereof.

73. The compound of claim 72, wherein the compound is a compound in the table below, or a pharmaceutically acceptable salt thereof:

713

.

74. A pharmaceutical composition comprising a compound of any one of claims 1-73 and a pharmaceutically acceptable carrier.

75. A method for treating a disease or condition mediated by NAMPT, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-73 to treat the disease or condition.

76. The method of claim 75, wherein said disease or condition mediated by NAMPT is a proliferative disorder.

77. The method of claim 75, wherein said disease or condition mediated by NAMPT is an inflammatory disorder.

78. The method of claim 75, wherein said disease or condition mediated by NAMPT is a metabolic disorder.

79. The method of claim 75, wherein said disease or condition mediated by NAMPT is selected from cancer, neoplasia, chronic inflammatory disorder, acute inflammatory disorder, auto- inflammatory disorder, metabolic disorder, and a combination thereof.

80. The method of claim 75, wherein said disease or condition mediated by NAMPT is cancer.

81. The method of claim 80, wherein the cancer is pancreatic cancer, melanoma, glioma, lung cancer, colon cancer, rectal cancer, breast cancer, cervical cancer, prostate cancer, gastric cancer, skin cancer, liver cancer, bile duct cancer, nervous system cancer, a lymphoma, leukemia, ovarian cancer, uterine cancer, endometrial cancer, testicular cancer, brain cancer, oral cancer, esophageal cancer, head and neck cancer, stomach cancer, sebaceous gland carcinoma, gallbladder cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, urothelial cancer, colorectal cancer, or glioblastoma multiforme.

82. The method of claim 80, wherein the cancer is thyroid cancer, duodenal, neuroendocrine carcinoma (NEC), uterine cancer, small cell lung cancer (SCLC), hepatocellular carcinoma, mesothelioma, breast cancer, sarcoma, ovarian cancer, renal cell carcinoma, rectal cancer, head and neck cancer, prostate cancer, pancreatic cancer, melanoma, colorectal cancer, cervix cancer, non-small cell lung cancer (NSCLC), cholangiocarcinoma, or endometrial cancer.

83. The method of any one of claims 79-82, wherein the cancer is a NAPRT-negative cancer.

84. The method of claim 75, wherein said disease or condition mediated by NAMPT is allergic rhinitis, nasal inflammation, asthma, chronic obstructive pulmonary disease (COPD), bronchitis, emphysema, chronic eosinophilic pneumonia, adult respiratory distress syndrome, sinusitis, allergic conjunctivitis, idiopathic pulmonary fibrosis, atopic dermatitis, asthma, allergic rhinitis, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, multiple sclerosis, endometriosis, eczema, psoriasis, rosacea, or lupus erythematosus.

85. The method of claim 75, wherein said disease or condition mediated by NAMPT is multiple sclerosis, ankylosing spondylitis, arthritis, osteoarthritis, juvenile arthritis, reactive arthritis, rheumatoid arthritis, psoriatic arthritis, acquired immunodeficiency syndrome (AIDS), Coeliac disease, psoriasis, chronic graft-versus-host disease, acute graft-versus-host disease, Crohn’s disease, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, Celiac Sprue, idiopathic thrombocytopenic thrombotic purpura, myasthenia gravis, Sjogren’s syndrome, scleroderma, ulcerative colitis, asthma, uveitis, rosacea, dermatitis, alopecia areata, vitiligo, arthritis, Type 1 diabetes, lupus erythematosus, systemic lupus erythematosus, Hashimoto’s thyroiditis, myasthenia gravis, nephrotic syndrome, eosinophilia fasciitis, hyper IgE syndrome, lepromatous leprosy, sezary syndrome, idiopathic thrombocytopenia purpura, restenosis following angioplasty, a tumor, or atherosclerosis.

86. The method of claim 75, wherein said disease or condition mediated by NAMPT is psoriasis, dermatitis, vitiligo, ichthyosis, alopecia areata, epidermolysis bullosa, hidradenitis suppurativa, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, or kidney disease.

87. The method of claim 75, wherein said disease or condition mediated by NAMPT is inflammatory bowel disease (IBD).

88. The method of claim 75, wherein said disease or condition mediated by NAMPT is an autoimmune disease or atherosclerosis.

89. The method of any one of claims 75-88, wherein the subject is a human.

90. A method of inhibiting the activity of NAMPT, comprising contacting a NAMPT with an effective amount of a compound of any one of claims 1-73 to inhibit the activity of said NAMPT.