DIAZEPINO-THIENO-QUINOXALINE COMPOUNDS AND THEIR USE IN THERAPY CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of and priority to United States Provisional Patent Application serial number 63/463,773, filed May 3, 2023; United States Provisional Patent Application serial number 63/435,008, filed December 23, 2022; and United States Provisional Patent Application serial number 63/401,377, filed August 26, 2022; the contents of each of which are hereby incorporated by reference in their entirety. FIELD OF THE INVENTION [0002] The invention provides diazepino-thieno-quinoxaline compounds, pharmaceutical compositions, their use for inhibiting mitogen-activated protein (MAP) kinase-activated protein kinase 2 (MAPKAPK2, MK2), and their use in the treatment of a disease or condition, such as an inflammatory disorder. BACKGROUND [0003] 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. Inflammatory disorders can be characterized according to whether they are acute or chronic. Common inflammatory disorders affecting a significant number of patients annually include inflammatory bowel disease, asthma, rheumatoid arthritis, ulcerative colitis, and Crohn's disease. [0004] Common treatments currently available for treating inflammatory disorders include nonsteroidal anti-inflammatory drugs (such as aspirin, ibuprofen, or naproxen), corticosteroids (such as prednisone), and various biologic drugs such as abatacept, adalimumab, certolizumab, etanercept, infliximab, golimumab, rituximab, and tocilizumab. Compounds having inhibitory activity towards mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2 or MK2) have also been reported in literature for use in treating certain inflammatory disorders. See, for example, U.S. Patent Application 2016/0075720 and international patent applications [0005] Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2 or MK2) has been reported in the literature to mediate multiple p38 MAPK-dependent cellular responses. See, for example, U.S. Patent Application 2016/0075720. MK2 has also been reported to be an important intracellular regulator of the production of cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and interferon gamma (IFN ^), each of which are involved in several acute and chronic inflammatory diseases. MK2 has also been implicated in heart failure, brain ischemic injury, regulation of stress resistance, and the production of TNF-α. See, e.g., Deak et al., EMBO.17:4426-4441 (1998); Shi et al., Biol. Chem.383:1519-1536 (2002); Staklatvala., Curr. Opin. Pharmacol.4:372-377 (2004); and Shiroto et al., J. Mol. Cardiol.38:93-97 (2005). [0006] While existing treatments for inflammatory disorders provide a medical benefit to patients, existing treatments are not effective for a significant percentage of patients and/or have undesirable adverse effects. Thus, new therapies are needed for treating inflammatory disorders. The present invention addresses the foregoing needs and provides other related advantages. SUMMARY [0007] The invention provides diazepino-thieno-quinoxaline compounds, pharmaceutical compositions, their use for inhibiting MK2, and their use in the treatment of a disease or condition, such as an inflammatory disorder. In particular, one aspect of the invention provides a collection of diazepino-thieno-quinoxaline 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 diazepino-thieno-quinoxaline 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 method of treating a disease or condition mediated by MK2 in a subject. The method comprises administering a therapeutically effective amount of a compound described herein, such as a compound of Formula I or I-A, to a subject in need thereof to treat the disease or condition, as further described in the detailed description. [0009] Another aspect of the invention provides a method of inhibiting the activity of a MK2. The method comprises contacting a MK2 with an effective amount of a compound described herein, such as a compound of Formula I or I-A, to inhibit the activity of said MK2, as further described in the detailed description. [0010] Another aspect of the invention provides a method of covalently modifying a MK2. The method comprises contacting a MK2 with an effective amount of a compound described herein, such as a compound of Formula I or I-A, to covalently modify the MK2, as further described in the detailed description. Another aspect of the invention provides a covalently modified MK2 formed by the foregoing method. DETAILED DESCRIPTION [0011] The invention provides diazepino-thieno-quinoxaline compounds, pharmaceutical compositions, their use for inhibiting MK2, and their use in the treatment of a disease or condition, such as an inflammatory 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 C ₃ -C ₆ 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 C _1-4 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 C _1-8 (or C _1-6 ) 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., –(CH ₂ ) _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 “-(C ₀ alkylene)-“ refers to a bond. Accordingly, the term “-(C _0-3 alkylene)-” encompasses a bond (i.e., C ₀ ) and a -(C _1-3 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” or “halo” 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 is 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] 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). [0029] 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 an 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. [0030] 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. [0031] 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. [0032] Each optional substituent on a substitutable carbon is a monovalent substituent independently selected from halogen; –(CH ₂ ) _0–4 R°; –(CH ₂ ) _0–4 OR°; -O(CH ₂ ) _0-4 R ^o , –O–(CH ₂ ) _{0– 4} C(O)OR°; –(CH ₂ ) _0–4 CH(OR°) ₂ ; –(CH ₂ ) _0–4 SR°; –(CH ₂ ) _0–4 Ph, which may be substituted with R°; –(CH ₂ ) _0–4 O(CH ₂ ) _0–1 Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH ₂ ) _0–4 O(CH ₂ ) _0–1 -pyridyl which may be substituted with R°; –NO ₂ ; – CN; –N ₃ ; -(CH ₂ ) _0–4 N(R°) ₂ ; –(CH ₂ ) _0–4 N(R°)C(O)R°; –N(R°)C(S)R°; –(CH ₂ ) _0–4 N(R°)C(O)NR° ₂ ; -N(R°)C(S)NR° ₂ ; –(CH ₂ ) _0–4 N(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°; –(CH ₂ ) _0–4 C(O)R°; –C(S)R°; –(CH ₂ ) _0–4 C(O)OR°; –(CH ₂ ) _0–4 C(O)SR°; -(CH ₂ ) _0–4 C(O)OSiR° ₃ ; –(CH ₂ ) _0–4 OC(O)R°; –OC(O)(CH ₂ ) _0–4 SR–, SC(S)SR°; –(CH ₂ ) _{0– 4} SC(O)R°; –(CH ₂ ) _0–4 C(O)NR° ₂ ; –C(S)NR° ₂ ; –C(S)SR°; –SC(S)SR°, -(CH ₂ ) _0–4 OC(O)NR° ₂ ; -C(O)N(OR°)R°; –C(O)C(O)R°; –C(O)CH ₂ C(O)R°; –C(NOR°)R°; -(CH ₂ ) _0–4 SSR°; –(CH ₂ ) _{0– 4} S(O) ₂ R°; –(CH ₂ ) _0–4 S(O) ₂ OR°; –(CH ₂ ) _0–4 OS(O) ₂ R°; –S(O) ₂ NR° ₂ ; –S(O)(NR°)R°; – S(O) ₂ N=C(NR° ₂ ) ₂ ; -(CH ₂ ) _0–4 S(O)R°; -N(R°)S(O) ₂ NR° ₂ ; –N(R°)S(O) ₂ R°; –N(OR°)R°; – C(NH)NR° ₂ ; –P(O) ₂ R°; -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 –(C _1–4 straight or branched alkylene)C(O)O–N(R°) ₂ . [0033] Each R° is independently hydrogen, C _1–6 aliphatic, –CH ₂ Ph, –O(CH ₂ ) _0–1 Ph, -CH ₂ -(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, –(CH ₂ ) _0–2 R ^● , –(haloR ^● ), –(CH ₂ ) _0–2 OH, –(CH ₂ ) _0–2 OR ^● , – (CH ₂ ) _0–2 CH(OR ^● ) ₂ ; -O(haloR ^● ), –CN, –N ₃ , –(CH ₂ ) _0–2 C(O)R ^● , –(CH ₂ ) _0–2 C(O)OH, –(CH ₂ ) _{0– 2} C(O)OR ^● , –(CH ₂ ) _0–2 SR ^● , –(CH ₂ ) _0–2 SH, –(CH ₂ ) _0–2 NH ₂ , –(CH ₂ ) _0–2 NHR ^● , –(CH ₂ ) _0–2 NR ^● 2, – NO ₂ , –SiR ^● ₃ , –OSiR ^● ₃ , -C(O)SR ^● _, –(C _1–4 straight or branched alkylene)C(O)OR ^● , or –SSR ^● . [0034] Each R ^● is independently selected from C _1–4 aliphatic, –CH ₂ Ph, –O(CH ₂ ) _0–1 Ph, 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) ₂ R ^* , =NR ^* , =NOR ^* , – O(C(R ^* ₂ )) _2–3 O–, or –S(C(R ^* ₂ )) _2–3 S–, or a divalent substituent bound to vicinal substitutable carbons of an “optionally substituted” group is –O(CR ^* ₂ ) _2–3 O–, 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. [0035] 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 ^● , –NH ₂ , –NHR ^● , –NR ^● 2, or –NO ₂ , wherein each R ^● is independently selected from C _1–4 aliphatic, –CH ₂ Ph, –O(CH ₂ ) _0–1 Ph, 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. [0036] 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)CH ₂ C(O)R ^† , -S(O) ₂ R ^† , -S(O) ₂ NR ^† 2, –C(S)NR ^† 2, – C(NH)NR ^† 2, or –N(R ^† )S(O) ₂ R ^† ; 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 ^● , –NH ₂ , –NHR ^● , –NR ^● ₂ , or –NO ₂ , wherein each R ^● is independently selected from C _1–4 aliphatic, –CH ₂ Ph, –O(CH ₂ ) _0–1 Ph, 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] 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. [0038] 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, 33, 201-217; 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. [0039] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1–4 alkyl) ₄ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate. [0040] 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 ¹³ C- or ¹⁴ C-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. [0041] 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. [0042] 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. [0043] 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. [0044] Unless specified otherwise, the term “about” refers to within ±10% of the stated value. The invention encompasses embodiments where the value is within ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1% of the stated value. [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 C ₁ -C ₁₂ alkyl, C ₁ -C ₁₀ alkyl, and C ₁ -C ₆ 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 “C ₃ -C ₆ 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 -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ CF ₃ , -CF ₂ CF ₃ , and the like. The term “haloalkylene” refers to a bivalent haloalkyl group. [0049] 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. [0050] 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 -OCH ₂ F, -OCHF ₂ , -OCF ₃ , -OCH ₂ CF ₃ , -OCF ₂ CF ₃ , and the like. The term “hydroxyalkoxyl” refers to an alkoxyl group that is substituted with at least one hydroxyl. Exemplary hydroxyalkoxyl groups include -OCH ₂ CH ₂ OH, -OCH ₂ C(H)(OH)CH ₂ CH ₂ OH, and the like. The term “halohydroxyalkoxyl” refers to an alkoxyl group that is substituted with at least one halo and at least one hydroxyl. Exemplary halohydroxyalkoxyl groups include - OCH ₂ C(H)(OH)-CH ₂ F, and the like. The term “alkoxylene” refers to a bivalent alkoxyl group. [0051] The term “oxo” is art-recognized and refers to a “=O” substituent. For example, a cyclopentane substituted with an oxo group is cyclopentanone. [0052] The symbol “ ” indicates a point of attachment. [0053] 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. [0054] 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 H ₂ O. [0055] As used herein, the terms “subject” and “patient” are used interchangeably 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, include humans. [0056] As used herein, the term “compound” refers to a quantity of molecules that is sufficient to be weighed, tested for its structural identity, and to have a demonstrable use (e.g., a quantity that can be shown to be active in an assay, an in vitro test, or in vivo test, or a quantity that can be administered to a patient and provide a therapeutic benefit). [0057] The term “IC ₅₀ ” 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. [0059] 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. [0060] 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. [0061] 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 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]. [0062] 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. [0063] As a general matter, compositions specifying a percentage are by weight unless otherwise specified. I. Diazepino-thieno-quinoxaline Compounds [0064] The invention provides diazepino-thieno-quinoxaline 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. [0065] One aspect of the invention provides a compound represented by Formula I: or a pharmaceutically acceptable salt thereof, wherein: R ¹ and R ³ are independently hydrogen, C _1-4 alkyl, or C _3-4 cycloalkyl; R ² is C _1-4 alkyl, C _1-4 hydroxyalkyl, -C(O)N(R ⁶ )(R ⁷ ), or hydrogen; or, alternatively, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 3-7 membered saturated carbocyclic ring or a 3-7 membered saturated heterocyclic ring containing 1 or 2 nitrogen atoms, wherein the carbocyclylic ring and the heterocyclylic ring are substituted with 1 or 2 occurrences of R ²⁰ ; R ⁴ is hydrogen, C _1-4 alkyl, or -C(O)N(R ⁶ )(R ⁷ ); or R ⁴ and R ³ are taken together to form oxo; , each of which is substituted with n occurrences of R ⁹ ; (ii) phenyl or 6- membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatoms are nitrogen atoms, where the phenyl and heteroaryl are substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; or (iii) 6-membered monocyclic, unsaturated oxo-heterocyclyl containing 1 or 2 nitrogen atoms, wherein the oxo-heterocyclyl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; R ⁶ and R ⁷ are independently hydrogen, C _1-6 alkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; or R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom; R ⁸ is hydrogen, C _1-4 alkyl, or -(C _2-4 alkylene)-(C _1-4 alkoxyl); R ⁹ is -(C _1-6 alkylene)-(C _1-6 alkoxyl), C _1-6 alkoxyl, -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, phosphorous, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ), -C(O)N(R ⁶ )(R ⁷ ), -C(O)N(R ⁶ )(R ¹³ ), -(C _0-6 alkylene)-S(O) ₂ R ¹⁸ , -(C _0-6 alkylene)-S(O)(=NR ¹⁵ )R ¹⁸ , -S(O) ₂ N(R ⁶ )(R ⁷ ), -(C _0-6 alkylene)-N(R ⁶ )C(O)R ¹⁴ , -(C _0-6 alkylene)- (N(R ¹⁵ )S(O)(N(R ^15A ))-R ¹⁸ ), halo, C _1-6 alkyl, C _1-6 haloalkyl, cyano, -(C _0-6 alkylene)- P(O)(R ⁶ )(R ⁷ ), -(C _0-6 alkylene)-(3-7 membered saturated monocyclic or bicyclic carbocyclyl), - (C _0-6 alkylene)-O-(3-7 membered saturated monocyclic or bicyclic carbocyclyl, wherein the carbocyclyl is substituted with m occurrences of R ¹² ), -(C _0-6 alkylene)-O-(C _1-6 haloalkyl), -(C _1-6 alkylene)-N(R ⁶ )(R ⁷ ), -(C _1-6 alkylene)-O-C(O)(R ¹⁹ ), -(C _1-6 alkylene)-(C _1-4 alkynyl), -(C _1-6 alkylene)-O-(C _1-4 alkynyl), or deuterium; or two R ⁹ groups on adjacent atoms are taken together with the atoms to which they are bonded to form a 5-7 membered heterocyclic ring containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclic ring is substituted with t instances of R ¹² ; R ¹⁰ is a group capable of forming a covalent bond to a sulfhydryl group; R ¹¹ is halo, hydroxyl, C _1-6 alkyl, C _1-6 haloalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), C _3-7 cycloalkyl, C _1-6 alkoxyl, or -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ); R ¹² represents independently for each occurrence halo, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _3-7 cycloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, -C(O)R ¹⁹ , - C(O)(OH), -O-(C _1-4 haloalkyl), -O-(C _1-4 halohydroxyalkoxyl), or oxo; or two R ¹² groups, taken together with the carbon atom to which they are attached, form a 3-7 membered saturated carbocyclic ring or a 3-7 membered saturated heterocyclic ring containing 1 heteroatom selected from nitrogen and oxygen, wherein the carbocyclic ring and the heterocyclic ring are substituted with 1 or 2 occurrences of R ²⁰ ; R ¹³ is a 4-7 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ ; R ¹⁴ represents independently for each occurrence hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; R ¹⁵ and R ^15A are independently hydrogen or C _1-4 alkyl; R ¹⁶ is hydrogen, C _1-4 alkyl, or hydroxyl; R ¹⁷ is hydrogen, C _1-4 alkyl, or -(C _2-4 alkylene)-(C _1-4 alkoxyl); R ¹⁸ is C _1-4 alkyl, -(C _1-6 alkylene)-C(O) ₂ OH, -(C _1-6 alkylene)-(C _1-6 alkoxyl), or C _3-6 cycloalkyl; R ¹⁹ represents independently for each occurrence C _1-6 alkyl,C _3-6 cycloalkyl, or -(C _1-6 alkylene)-(C _3-6 cycloalkyl); R ²⁰ is hydrogen, C _1-4 alkyl, -(C _0-4 alkylene)-(C _1-6 alkoxyl), -C(O)-(C _1-4 alkyl), or C _3-7 cycloalkyl; X is -N(R ¹⁷ )-, -O-, or -CH ₂ ; and m and p are independently 0, 1, or 2; n is 0, 1, 2, or 3; and t is 0, 1, 2, 3, 4, 5, or 6. [0066] 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). [0067] In certain embodiments, the compound is a compound of Formula I. [0068] As defined generally above, R ¹ and R ³ are independently hydrogen, C _1-4 alkyl, or C _3-4 cycloalkyl. In certain embodiments, R ¹ and R ³ are hydrogen. In certain embodiments, R ¹ is hydrogen. In certain embodiments, R ¹ is C _1-4 alkyl. In certain embodiments, R ¹ is C ₁ alkyl. In certain embodiments, R ¹ is C ₂ alkyl. In certain embodiments, R ¹ is C ₃ alkyl. In certain embodiments, R ¹ is C ₄ alkyl. In certain embodiments, R ¹ is C _3-4 cycloalkyl. In certain embodiments, R ¹ is C ₃ cycloalkyl. In certain embodiments, R ¹ is C ₄ cycloalkyl. In certain embodiments, R ³ is hydrogen. In certain embodiments, R ³ is C _1-4 alkyl. In certain embodiments, R ³ is C ₁ alkyl. In certain embodiments, R ³ is C ₂ alkyl. In certain embodiments, R ³ is C ₃ alkyl. In certain embodiments, R ³ is C ₄ alkyl. In certain embodiments, R ³ is C _3-4 cycloalkyl. In certain embodiments, R ³ is C ₃ cycloalkyl. In certain embodiments, R ³ is C ₄ cycloalkyl. In certain embodiments, R ¹ is selected from the groups depicted in the compounds in Table 1, below. In certain embodiments, R ³ is selected from the groups depicted in the compounds in Table 1, below. [0069] As defined generally above, R ² is C _1-4 alkyl, C _1-4 hydroxyalkyl, -C(O)N(R ⁶ )(R ⁷ ), or hydrogen; or, alternatively, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 3-7 membered saturated carbocyclic ring or a 3-7 membered saturated heterocyclic ring containing 1 or 2 nitrogen atoms, wherein the carbocyclic ring and the heterocyclic ring are substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ² is C _1-4 alkyl. In certain embodiments, R ² is -CH ₃ . In certain embodiments, R ² is C _1-4 hydroxyalkyl. In certain embodiments, R ² is -C(O)N(R ⁶ )(R ⁷ ). In certain embodiments, R ² is hydrogen. In certain embodiments, R ² is C ₂ alkyl. In certain embodiments, R ² is C ₃ alkyl. In certain embodiments, R ² is C ₄ alkyl. In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 3-7 membered saturated carbocyclic ring, wherein the carbocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 3 membered saturated carbocyclic ring, wherein the carbocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 4 membered saturated carbocyclic ring, wherein the carbocyclyic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 5 membered saturated carbocyclic ring, wherein the carbocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 6 membered saturated carbocyclic ring, wherein the carbocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 7 membered saturated carbocyclic ring, wherein the carbocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 3-7 membered saturated heterocyclic ring containing 1 or 2 nitrogen atoms, wherein the heterocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 3 membered saturated heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 4 membered saturated heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 5 membered satured heterocyclic ring containing 1 or 2 nitrogen atoms, wherein the heterocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 6 membered saturated heterocyclic ring containing 1 or 2 nitrogen atoms, wherein the heterocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 7 membered satured heterocyclic ring containing 1 or 2 nitrogen atoms, wherein the heterocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ² is selected from the groups depicted in the compounds in Table 1, below. [0070] As defined generally above, R ⁴ is hydrogen, C _1-4 alkyl, or -C(O)N(R ⁶ )(R ⁷ ); or R ⁴ and R ³ are taken together to form oxo. In certain embodiments, R ⁴ is hydrogen. In certain embodiments, R ⁴ is -C(O)N(R ⁶ )(R ⁷ ). In certain embodiments, R ⁴ and R ³ are taken together to form oxo. In certain embodiments, R ⁴ is C _1-4 alkyl. In certain embodiments, R ⁴ is selected from the groups depicted in the compounds in Table 1, below.

occurrences of R ⁹ ; (ii) phenyl or 6-membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatom(s) are nitrogen, and wherein the phenyl and heteroaryl are substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; or (iii) 6-membered monocyclic, unsaturated oxo-heterocyclyl containing 1 or 2 heteroatoms, wherein the heteroatoms are nitrogen, and the oxo-heterocyclyl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . occurrences of R ⁹ ; or (ii) phenyl or 6-membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatom(s) are nitrogen, and wherein the phenyl and heteroaryl are substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, , of which is substituted with n occurrences of R ⁹ ; (ii) phenyl or 6-membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatom(s) are nitrogen, and wherein the phenyl and heteroaryl are substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, , each of which is substituted with n occurrences of R ⁹ . In certain embodiments, substituted with n occurrences of R ⁹ . [0073] In certain embodiments, substituted with n occurrences of R ⁹ . [0074] In certain embodiments, , each of which is substituted with n occurrences of R ⁹ . In certain embodiments, substituted with n occurrences of R ⁹ . In certain embodiments, R ⁵ is phenyl or 6-membered heteroaryl containing 1 heteroatoms, wherein the heteroatoms are nitrogen atoms, wherein the phenyl and heteroaryl are substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is phenyl substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is a 6-membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatoms are nitrogen atoms, and the heteroaryl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is a pyridinyl substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is a 6-membered monocyclic, unsaturated oxo-heterocyclyl containing 1 or 2 heteroatoms, wherein the heteroatoms are nitrogen atoms, and the heterocyclyl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, , each of which is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is , each of which is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, . embodiments, , which substituted with n occurrences of R ⁹ . In certain embodiments, , which is substituted with n occurrences of R ⁹ . In certain embodiments, , which is substituted with n occurrences of R ⁹ . In certain embodiments, , which is substituted with n occurrences of R ⁹ . In certain embodiments, , which is substituted with n occurrences of R ⁹ . In certain embodiments, , which is substituted with n occurrences of R ⁹ . In certain embodiments, , which is substituted with n occurrences of R ⁹ . In certain embodiments, substituted with n occurrences of R ⁹ . In certain embodiments, substituted with n occurrences of R ⁹ . In certain embodiments, substituted with n occurrences of R ⁹ . In certain embodiments, R ⁵ is ted with n occurrences of R ⁹ . In certain embodiments, R ⁵ is substituted with n occurrences of R ⁹ . In certain embodiments, R ⁵ is substituted with n occurrences of R ⁹ . In certain embodiments, R ⁵ is substituted with n occurrences of R ⁹ . In certain embodiments, substituted with n occurrences of R ⁹ . In certain embodiments, R ⁵ is substituted with n occurrences of R ⁹ . In certain embodiments, substituted with n occurrences of R ⁹ . In certain embodiments, substituted with n occurrences of R ⁹ . In certain embodiments, substituted with n occurrences of R ⁹ . In certain embodiments, substituted with n occurrences of R ⁹ . In certain embodiments, R ⁵ is selected from the groups depicted in the compounds in Table 1, below. [0075] As defined generally above, R ⁶ and R ⁷ are independently hydrogen, C _1-6 alkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; or R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ are independently hydrogen or C _1-6 alkyl. In certain embodiments, R ⁶ is hydrogen. In certain embodiments, R ⁶ is C _1-6 alkyl. In certain embodiments, R ⁶ is -(C _1-6 alkylene)-(C _3-7 cycloalkyl), In certain embodiments, R ⁶ is C _3-7 cycloalkyl. In certain embodiments, R ⁷ is hydrogen. In certain embodiments, R ⁷ is C _1-6 alkyl. In certain embodiments, R ⁷ is -(C _1-6 alkylene)-(C _3-7 cycloalkyl), In certain embodiments, R ⁷ is C _3-7 cycloalkyl. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 4 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 5 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 6 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 7 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ is selected from the groups depicted in the compounds in Table 1, below. In certain embodiments, R ⁷ is selected from the groups depicted in the compounds in Table 1, below. [0076] As defined generally above, R ⁸ is hydrogen, C _1-4 alkyl, or –(C _2-4 alkylene)-(C _1-4 alkoxyl). In certain embodiments, R ⁸ is hydrogen. In certain embodiments, R ⁸ is C _1-4 alkyl. In certain embodiments, R ⁸ is C ₁ alkyl. In certain embodiments, R ⁸ is C ₂ alkyl. In certain embodiments, R ⁸ is C ₃ alkyl. In certain embodiments, R ⁸ is C ₄ alkyl. In certain embodiments, R ⁸ is –(C _2-4 alkylene)-(C _1-4 alkoxyl). In certain embodiments, R ⁸ is selected from the groups depicted in the compounds in Table 1, below. [0077] As defined generally above, R ⁹ is –(C _1-6 alkylene)-(C _1-6 alkoxyl), C _1-6 alkoxyl, -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, phosphorous, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ), -C(O)N(R ⁶ )(R ⁷ ), -C(O)N(R ⁶ )(R ¹³ ), -(C _0-6 alkylene)- S(O) ₂ R ¹⁸ , -(C _0-6 alkylene)-S(O)(=NR ¹⁵ )R ¹⁸ , -S(O) ₂ N(R ⁶ )(R ⁷ ), -(C _0-6 alkylene)-N(R ⁶ )C(O)R ¹⁴ , - (C _0-6 alkylene)-(N(R ¹⁵ )S(O)(N(R ^15A ))-R ¹⁸ ), halo, C _1-6 alkyl, C _1-6 haloalkyl, cyano, -(C _0-6 alkylene)-P(O)(R ⁶ )(R ⁷ ), -(C _0-6 alkylene)-(3-7 membered saturated monocyclic or bicyclic carbocyclyl), -(C _0-6 alkylene)-O-(3-7 membered saturated monocyclic or bicyclic carbocyclyl, wherein the carbocyclyl is substituted with m occurrences of R ¹² ), -(C _0-6 alkylene)-O-(C _1-6 haloalkyl), -(C _1-6 alkylene)-N(R ⁶ )(R ⁷ ), -(C _1-6 alkylene)-O-C(O)(R ¹⁹ ), -(C _1-6 alkylene)-(C _1-4 alkynyl), -(C _1-6 alkylene)-O-(C _1-4 alkynyl), or deuterium, or two R ⁹ groups on adjacent atoms are taken together with the atoms to which they are bonded to form a 5-7 membered heterocyclic ring containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclic ring is substituted with t instances of R ¹² . In certain embodiments, R ⁹ is –(C _1-6 alkylene)-(C _1-6 alkoxyl), C _1-6 alkoxyl, -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, phosphorous, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ), -C(O)N(R ⁶ )(R ⁷ ), -C(O)N(R ⁶ )(R ¹³ ), -(C _0-6 alkylene)-S(O) ₂ R ¹⁸ , -(C _0-6 alkylene)- S(O)(=NR ¹⁵ )R ¹⁸ , -S(O) ₂ N(R ⁶ )(R ⁷ ), -(C _0-6 alkylene)-N(R ⁶ )C(O)R ¹⁴ , -(C _0-6 alkylene)- (N(R ¹⁵ )S(O)(N(R ^15A ))-R ¹⁸ ), halo, C _1-6 haloalkyl, cyano, -(C _0-6 alkylene)-P(O)(R ⁶ )(R ⁷ ), -(C _0-6 alkylene)-(3-7 membered saturated monocyclic or bicyclic carbocyclyl), -(C _0-6 alkylene)-O-(3- 7 membered saturated monocyclic or bicyclic carbocyclyl, wherein the carbocyclyl is substituted with m occurrences of R ¹² ), -(C _0-6 alkylene)-O-(C _1-6 haloalkyl), -(C _1-6 alkylene)- N(R ⁶ )(R ⁷ ), -(C _1-6 alkylene)-O-C(O)(R ¹⁹ ), -(C _1-6 alkylene)-(C _1-4 alkynyl), -(C _1-6 alkylene)-O-(C ₁ - 4 alkynyl), or deuterium. [0078] In certain embodiments, R ⁹ is –(C _1-6 alkylene)-(C _1-6 alkoxyl). In certain embodiments, R ⁹ is –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is - C(O)N(R ⁶ )(R ⁷ ), -C(O)N(R ⁶ )(R ¹³ ), -(C _0-6 alkylene)-N(R ⁶ )C(O)(R ¹⁴ ), -(C _0-6 alkylene)- (N(R ¹⁵ )S(O)(N(C _1-4 alkyl))-C _1-4 alkyl), or –(C _0-6 alkylene)-(S(O)(NH)-(C _1-4 alkyl)). In certain embodiments, R ⁹ is C _1-6 alkoxyl. In certain embodiments, R ⁹ is -C(O)N(R ⁶ )(R ⁷ ). In certain embodiments, R ⁹ is -C(O)N(R ⁶ )(R ¹³ ). In certain embodiments, R ⁹ is -(C _0-6 alkylene)-S(O) ₂ R ¹⁸ . In certain embodiments, R ⁹ is -(C _0-6 alkylene)-S(O)(=NR ¹⁵ )R ¹⁸ . In certain embodiments, R ⁹ is - (C _0-6 alkylene)-S(O)(=NH)R ¹⁸ . In certain embodiments, R ⁹ is -S(O) ₂ N(R ⁶ )(R ⁷ ). In certain embodiments, R ⁹ is -(C _0-6 alkylene)-N(R ⁶ )C(O)R ¹⁴ . In certain embodiments, R ⁹ is -(C _0-6 alkylene)-(N(R ¹⁵ )S(O)(N(R ^15A ))-R ¹⁸ ). In certain embodiments, R ⁹ is -(C _0-6 alkylene)- (N(R ¹⁵ )S(O)(N(C _1-4 alkyl))-C _1-4 alkyl). In certain embodiments, R ⁹ is –(C _0-6 alkylene)- (S(O)(NH)-(C _1-4 alkyl)). In certain embodiments, R ⁹ is deuterium. In certain embodiments, R ⁹ is –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, phosphorous, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1 heteroatom selected from oxygen, nitrogen, phosphorous, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 2 heteroatoms selected from oxygen, nitrogen, phosphorous, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 3 heteroatoms selected from oxygen, nitrogen, phosphorous, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). [0079] In certain embodiments, R ⁹ is –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, phosphorous, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is –(C _1-3 alkylene)-(5-6 membered saturated monocyclic heterocyclyl containing 1 or 2 heteroatoms selected from oxygen, nitrogen, phosphorous, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is , each of which is substituted with 0, 1, 2, or 3 instances of R ¹² . In certain embodiments, R ⁹ is . [0080] In certain embodiments, R ⁹ is –(C _1-3 alkylene)-(7-10 membered saturated bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, phosphorous, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is –(C _1-3 alkylene)-(7-10 membered saturated spiro-bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, phosphorous, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is each of which is substituted with 0, 1, 2, or 3 instances of R ¹² . [0081] In certain embodiments, R ⁹ is halo. In certain embodiments, R ⁹ is C _1-6 alkyl. In certain embodiments, R ⁹ is C _1-6 haloalkyl. In certain embodiments, R ⁹ is cyano. In certain embodiments, R ⁹ is -(C _0-6 alkylene)-P(O)(R ⁶ )(R ⁷ ). In certain embodiments, R ⁹ is -(C _0-6 alkylene)-(3-7 membered saturated monocyclic or bicyclic carbocyclyl). In certain embodiments, R ⁹ is -(C _0-6 alkylene)-O-(3-7 membered saturated monocyclic or bicyclic carbocyclyl, wherein the carbocyclyl is substituted with m occurrences of R ¹² ). In certain embodiments, R ⁹ is -(C _0-6 alkylene)-O-(C _1-6 haloalkyl). In certain embodiments, R ⁹ is -(C _1-6 alkylene)-N(R ⁶ )(R ⁷ ). In certain embodiments, R ⁹ is -(C _1-6 alkylene)-O-C(O)(R ¹⁹ ). In certain embodiments, R ⁹ is -(C _1-6 alkylene)-(C _1-4 alkynyl). In certain embodiments, R ⁹ is -(C _1-6 alkylene)-O-(C _1-4 alkynyl). [0082] In certain embodiments, two R ⁹ groups on adjacent atoms are taken together with the atoms to which they are bonded to form a 5-7 membered heterocyclic ring containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclic ring is substituted with t instances of R ¹² . [0083] In certain embodiments, R ⁹ is selected from the groups depicted in the compounds in Table 1, below. [0084] As defined generally above, R ¹⁰ is a group capable of forming a covalent bond to a sulfhydryl group. In certain embodiments, R ¹⁰ is -N(H)C(O)(C _2-4 alkenyl). In certain embodiments, R ¹⁰ is -N(H)C(O)CH=CH ₂ . In certain embodiments, R ¹⁰ is selected from the groups depicted in the compounds in Table 1, below. [0085] As defined generally above, R ¹¹ is halo, hydroxyl, C _1-6 alkyl, C _1-6 haloalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), C _3-7 cycloalkyl, C _1-6 alkoxyl, or –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ represents independently for each occurrence halo, hydroxyl, C _1-6 alkyl, or C _1-6 haloalkyl. In certain embodiments, R ¹¹ represents independently for each occurrence halo, C _1-6 alkyl, or –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ is halo. In certain embodiments, R ¹¹ is hydroxyl. In certain embodiments, R ¹¹ is C _1-6 alkyl. In certain embodiments, R ¹¹ is C _1-6 haloalkyl. In certain embodiments, R ¹¹ is -(C _1-6 alkylene)- (C _3-7 cycloalkyl). In certain embodiments, R ¹¹ is C _3-7 cycloalkyl. In certain embodiments, R ¹¹ is C _1-6 alkoxyl. In certain embodiments, R ¹¹ is –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ is –(C _0-6 alkylene)-(4-10 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ is –(C _0-6 alkylene)-(4-10 membered saturated bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ is selected from the groups depicted in the compounds in Table 1, below. [0086] As defined generally above, R ¹² represents independently for each occurrence halo, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _3-7 cycloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, -C(O)R ¹⁹ , -C(O)(OH), -O-(C _1-4 haloalkyl), -O-(C _1-4 halohydroxyalkoxyl), or oxo; or two R ¹² groups, taken together with the carbon atom to which they are attached, form a 3-7 membered saturated carbocyclic ring or a 3-7 membered saturated heterocyclic ring containing 1 heteroatom selected from nitrogen and oxygen, wherein the carbocyclic ring and the heterocyclic ring are substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹² represents independently for each occurrence halo, C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, or oxo. In certain embodiments, R ¹² is halo. In certain embodiments, R ¹² is C _1-6 alkyl. In certain embodiments, R ¹² is C ₁ alkyl. In certain embodiments, R ¹² is C ₂ alkyl. In certain embodiments, R ¹² is C ₃ alkyl. In certain embodiments, R ¹² is C ₄ alkyl. In certain embodiments, R ¹² is C ₅ alkyl. In certain embodiments, R ¹² is C6 alkyl. In certain embodiments, R ¹² is C _1-6 haloalkyl. In certain embodiments, R ¹² is C _3-7 cycloalkyl. In certain embodiments, R ¹² is C _1-6 alkoxyl. In certain embodiments, R ¹² is C _1-6 haloalkoxyl. In certain embodiments, R ¹² is oxo. In certain embodiments, R ¹² is hydroxy. In certain embodiments, R ¹² is C _1-6 hydroxyalkyl. In certain embodiments, R ¹² is -C(O)R ¹⁹ . [0087] In certain embodiments, R ¹² represents independently for each occurrence halo, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _3-7 cycloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, -C(O)R ¹⁹ , or oxo. In certain embodiments, R ¹² represents independently for each occurrence halo, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _3-7 cycloalkyl, or - C(O)R ¹⁹ . In certain embodiments, R ¹² represents independently for each occurrence C _1-6 alkyl. In certain embodiments, R ¹² represents independently for each occurrence -C(O)(OH). In certain embodiments, R ¹² represents independently for each occurrence -O-(C _1-4 haloalkyl). In certain embodiments, R ¹² represents independently for each occurrence -O-(C _1-4 halohydroxyalkoxyl). In certain embodiments, R ¹² represents independently for each occurrence oxo. In certain embodiments, two R ¹² groups, taken together with the carbon atom to which they are attached, form a 3-7 membered saturated carbocyclic ring or a 3-7 membered saturated heterocyclic ring containing 1 heteroatom selected from nitrogen and oxygen, wherein the carbocyclic ring and the heterocyclic ring are substituted with 1 or 2 occurrences of R ²⁰ . [0088] In certain embodiments, R ¹² is selected from the groups depicted in the compounds in Table 1, below. [0089] As defined generally above, R ¹³ is a 4-7 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 4 membered saturated monocyclic heterocyclyl containing 1 oxygen heteroatom, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 4 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 5 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 6 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 7 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is selected from the groups depicted in the compounds in Table 1, below. [0090] As defined generally above, R ¹⁴ represents independently for each occurrence hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl. In certain embodiments, R ¹⁴ represents independently for each occurrence hydrogen, C _1-6 alkyl, or C _1-6 hydroxyalkyl. In certain embodiments, R ¹⁴ is hydrogen. In certain embodiments, R ¹⁴ is C _1-6 alkyl. In certain embodiments, R ¹⁴ is C _1-6 hydroxyalkyl. In certain embodiments, R ¹⁴ is - (C _1-6 alkylene)-(C _3-7 cycloalkyl). In certain embodiments, R ¹⁴ is C _3-7 cycloalkyl. In certain embodiments, R ¹⁴ is selected from the groups depicted in the compounds in Table 1, below. [0091] As defined generally above, R ¹⁵ and R ^15A are independently hydrogen or C _1-4 alkyl. In certain embodiments, R ¹⁵ and R ^15A are independently hydrogen. In certain embodiments, R ¹⁵ and R ^15A are independently C _1-4 alkyl. In certain embodiments, R ¹⁵ and R ^15A are each C ₁ alkyl. In certain embodiments, R ¹⁵ and R ^15A are each C ₂ alkyl. In certain embodiments, R ¹⁵ and R ^15A are independently C ₃ alkyl. In certain embodiments, R ¹⁵ and R ^15A are independently C ₄ alkyl. In certain embodiments, R ¹⁵ is selected from the groups depicted in the compounds in Table 1, below. [0092] As defined generally above, R ¹⁶ is hydrogen, C _1-4 alkyl, or hydroxyl. In certain embodiments, R ¹⁶ is hydrogen. In certain embodiments, R ¹⁶ is C _1-4 alkyl. In certain embodiments, R ¹⁶ is C ₁ alkyl. In certain embodiments, R ¹⁶ is C ₂ alkyl. In certain embodiments, R ¹⁶ is C ₃ alkyl. In certain embodiments, R ¹⁶ is C ₄ alkyl. In certain embodiments, R ¹⁶ is hydroxyl. In certain embodiments, R ¹⁶ is selected from the groups depicted in the compounds in Table 1, below. [0093] As defined generally above, R ¹⁷ is hydrogen, C _1-4 alkyl, or –(C _2-4 alkylene)-(C _1-4 alkoxyl). In certain embodiments, R ¹⁷ is hydrogen. In certain embodiments, R ¹⁷ is C _1-4 alkyl. In certain embodiments, R ¹⁷ is C ₁ alkyl. In certain embodiments, R ¹⁷ is C ₂ alkyl. In certain embodiments, R ¹⁷ is C ₃ alkyl. In certain embodiments, R ¹⁷ is C ₄ alkyl. In certain embodiments, R ¹⁷ is –(C _2-4 alkylene)-(C _1-4 alkoxyl). In certain embodiments, R ¹⁷ is selected from the groups depicted in the compounds in Table 1, below. [0094] As defined generally above, R ¹⁸ is C _1-4 alkyl, -(C _1-6 alkylene)-C(O) ₂ OH, -(C _1-6 alkylene)-(C _1-6 alkoxyl), or C _3-6 cycloalkyl. In certain embodiments, R ¹⁸ is C _1-4 alkyl. In certain embodiments, R ¹⁸ is C ₁ alkyl. In certain embodiments, R ¹⁸ is C ₂ alkyl. In certain embodiments, R ¹⁸ is C ₃ alkyl. In certain embodiments, R ¹⁸ is C ₄ alkyl. In certain embodiments, R ¹⁸ is C _3-6 cycloalkyl. In certain embodiments, R ¹⁸ is C ₃ cycloalkyl. In certain embodiments, R ¹⁸ is C ₄ cycloalkyl. In certain embodiments, R ¹⁸ is C ₅ cycloalkyl. In certain embodiments, R ¹⁸ is C ₆ cycloalkyl. In certain embodiments, R ¹⁸ is -(C _1-6 alkylene)-C(O) ₂ OH. In certain embodiments, R ¹⁸ is -(C _1-6 alkylene)-(C _1-6 alkoxyl). In certain embodiments, R ¹⁸ is selected from the groups depicted in the compounds in Table 1, below. [0095] As defined generally above, R ¹⁹ represents independently for each occurrence C _1-6 alkyl, C _3-6 cycloalkyl, or -(C _1-6 alkylene)-(C _3-6 cycloalkyl). In certain embodiments, R ¹⁹ is C _1-6 alkyl. In certain embodiments, R ¹⁹ is methyl. In certain embodiments, R ¹⁹ is ethyl. In certain embodiments, R ¹⁹ is C _3-6 cycloalkyl. In certain embodiments, R ¹⁹ is -(C _1-6 alkylene)-(C _3-6 cycloalkyl). In certain embodiments, R ¹⁹ is selected from the groups depicted in the compounds in Table 1, below. [0096] As defined generally above, R ²⁰ is hydrogen, C _1-4 alkyl, oxo, -(C _0-4 alkylene)-(C _1-6 alkoxyl), -C(O)-(C _1-4 alkyl), or C _3-7 cycloalkyl. In certain embodiments, R ²⁰ is hydrogen. In certain embodiments, R ²⁰ is C _1-4 alkyl. In certain embodiments, R ²⁰ is -CH ₃ . In certain embodiments, R ²⁰ is -CH ₂ CH _3. In certain embodiments, R ²⁰ is -CH ₂ CH ₂ CH ₃ . In certain embodiments, R ²⁰ is -CH(CH ₃ ) ₂ . In certain embodiments, R ²⁰ is -(C ₀ -4 alkylene)-(C _1-6 alkoxyl). In certain embodiments, R ²⁰ is (C _1-6 alkoxyl). In certain embodiments, R ²⁰ is -C(O)-(C _1-4 alkyl). In certain embodiments, R ²⁰ is -C(O)CH ₃ . In certain embodiments, In certain embodiments, R ²⁰ is -C(O)CH ₂ CH ₃ . In certain embodiments, R ²⁰ is C _3-7 cycloalkyl. In certain embodiments, R ²⁰ is cyclopropyl. In certain embodiments, R ²⁰ is cyclobutyl. In certain embodiments, R ²⁰ is cyclopentyl. In certain embodiments, R ²⁰ is cyclohexyl. In certain embodiments, R ²⁰ is cycloheptyl. In certain embodiments, R ²⁰ is selected from the groups depicted in the compounds in Table 1, below. [0097] As defined generally above, X is -N(R ¹⁷ )-, -O-, or -CH ₂ -. In certain embodiments, X is -N(R ¹⁷ )-. In certain embodiments, X is -O-. In certain embodiments, X is -CH ₂ -. In certain embodiments, X is selected from the groups depicted in the compounds in Table 1, below. [0098] As defined generally above, m and p are independently 0, 1, or 2. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, n, t, and p are independently 0, 1, or 2. [0099] As defined generally above, n is 0, 1, 2, or 3. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. [0100] As defined generally above, t is 0, 1, 2, 3, 4, or 6. In certain embodiments, t is 0. In certain embodiments, t is 1. In certain embodiments, t is 2. In certain embodiments, t is 3. In certain embodiments, t is 4. In certain embodiments, t is 5. In certain embodiments, t is 6. In certain embodiments, t is 1, 2, or 3. In certain embodiments, t is 2, 3, or 4. [0101] The description above describes multiple embodiments relating to compounds of Formula I. The patent application specifically contemplates all combinations of the embodiments. [0102] In certain embodiments, the compound of Formula I is further defined by Formula Ia: Ia or a pharmaceutically acceptable salt thereof. In certain embodiments, the definition of variable R ⁵ is one of the embodiments described above in connection with Formula I. [0103] In certain embodiments, the compound of Formula I is further defined by Formula Ib: Ib or a pharmaceutically acceptable salt thereof. In certain embodiments, the definition of variable R ⁵ is one of the embodiments described above in connection with Formula I. [0104] In certain embodiments, the compound of Formula I is further defined by Formula Ic, Id, or Ie: Ie or a pharmaceutically acceptable salt thereof. In certain embodiments, the definition of variables R ⁵ , R ⁶ , R ⁷ , and R ¹⁰ is one of the embodiments described above in connection with Formula I. [0105] In certain embodiments, the compound of Formula I is further defined by Formula If: If or a pharmaceutically acceptable salt thereof. In certain embodiments, the definition of variable R ⁵ is one of the embodiments described above in connection with Formula I. [0106] In certain embodiments, the compound of Formula I is further defined by Formula Ih: or a pharmaceutically acceptable salt thereof, wherein q is 0, 1, or 2. In certain embodiments, the definition of variables R ⁵ and R ²⁰ is one of the embodiments described above in connection with Formula I. [0107] In certain embodiments, the compound of Formula I is further defined by Formula Ii or Ij: Ii Ij or a pharmaceutically acceptable salt thereof, wherein q is 0, 1, or 2. In certain embodiments, the definition of variables R ⁵ and R ²⁰ is one of the embodiments described above in connection with Formula I. [0108] In certain embodiments, the compound of Formula I is further defined by Formula Ik or Il: or a pharmaceutically acceptable salt thereof, wherein q is 0, 1, or 2. In certain embodiments, the definition of variables R ⁵ and R ²⁰ is one of the embodiments described above in connection with Formula I. [0109] In certain embodiments, the compound of Formula I is further defined by one of Formulae Im, In, or Io: or a pharmaceutically acceptable salt thereof, wherein q is 0, 1, or 2. In certain embodiments, the definition of variables R ⁵ and R ²⁰ is one of the embodiments described above in connection with Formula I. [0110] In certain embodiments, the compound of Formula I is further defined by one of Formulae Ip, Iq, or Ir: or a pharmaceutically acceptable salt thereof, wherein q is 0, 1, or 2. In certain embodiments, the definition of variables R ⁵ and R ²⁰ is one of the embodiments described above in connection with Formula I. [0111] Another aspect of the invention provides a compound represented by Formula I-A: or a pharmaceutically acceptable salt thereof, wherein: R ¹ and R ³ are independently hydrogen, C _1-4 alkyl, or C _3-4 cycloalkyl; R ² is C _1-4 alkyl, C _1-4 hydroxyalkyl, -C(O)N(R ⁶ )(R ⁷ ), or hydrogen; or, alternatively, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 3-7 membered saturated carbocyclic ring or a 3-7 membered saturated heterocyclic ring containing 1 or 2 nitrogen atoms, wherein the carbocyclic ring and the heterocyclic ring are substituted with 1 or 2 occurrences of R ²⁰ ; R ⁴ is hydrogen, C _1-4 alkyl, or -C(O)N(R ⁶ )(R ⁷ ); or R ⁴ and R ³ are taken together to form oxo; of which is substituted with n occurrences of R ⁹ ; (ii) phenyl or 6-membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatoms are nitrogen atoms, where the phenyl and heteroaryl are substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; or (iii) 6- membered monocyclic, unsaturated oxo-heterocyclyl containing 1 or 2 heteroatoms, wherein the heteroatoms are nitrogen atom, and the heterocyclyl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; R ⁶ and R ⁷ are independently hydrogen, C _1-6 alkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; or R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom; R ⁸ , R ¹⁵ , and R ¹⁷ are independently hydrogen or C _1-4 alkyl; R ⁹ is –(C _1-6 alkylene)-(C _1-6 alkoxyl), C _1-6 alkoxyl, -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ), - C(O)N(R ⁶ )(R ⁷ ), -C(O)N(R ⁶ )(R ¹³ ), -(C _0-6 alkylene)-N(R ⁶ )C(O)(R ¹⁴ ), -(C _0-6 alkylene)- (N(R ¹⁵ )S(O)(N(C _1-4 alkyl))-C _1-4 alkyl), -(C _0-6 alkylene)-(S(O)(NH)-(C _1-4 alkyl)), or deuterium; R ¹⁰ is a group capable of forming a covalent bond to a sulfhydryl group; R ¹¹ is halo, hydroxyl, C _1-6 alkyl, C _1-6 haloalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), C _3-7 cycloalkyl, C _1-6 alkoxyl, or –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ); R ¹² represents independently for each occurrence halo, C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl, or C _1-6 alkoxyl; R ¹³ is a 4-7 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ ; R ¹⁴ represents independently for each occurrence hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; R ¹⁶ is hydrogen, C _1-4 alkyl, or hydroxyl; R ²⁰ is hydrogen, C _1-4 alkyl, oxo, -(C ₀ -4 alkylene)-(C _1-6 alkoxyl), -C(O)-(C _1-4 alkyl), or C _3-7 cycloalkyl; n and p are independently 0, 1, or 2; and t is 0, 1, 2, 3, 4, 5, or 6. [0112] 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). [0113] In certain embodiments, the compound is a compound of Formula I-A. [0114] As defined generally above, R ¹ and R ³ are independently hydrogen, C _1-4 alkyl, or C _3-4 cycloalkyl. In certain embodiments, R ¹ and R ³ are hydrogen. In certain embodiments, R ¹ is hydrogen. In certain embodiments, R ¹ is C _1-4 alkyl. In certain embodiments, R ¹ is C ₁ alkyl. In certain embodiments, R ¹ is C ₂ alkyl. In certain embodiments, R ¹ is C ₃ alkyl. In certain embodiments, R ¹ is C ₄ alkyl. In certain embodiments, R ¹ is C _3-4 cycloalkyl. In certain embodiments, R ¹ is C ₃ cycloalkyl. In certain embodiments, R ¹ is C ₄ cycloalkyl. In certain embodiments, R ³ is hydrogen. In certain embodiments, R ³ is C _1-4 alkyl. In certain embodiments, R ³ is C ₁ alkyl. In certain embodiments, R ³ is C ₂ alkyl. In certain embodiments, R ³ is C ₃ alkyl. In certain embodiments, R ³ is C ₄ alkyl. In certain embodiments, R ³ is C _3-4 cycloalkyl. In certain embodiments, R ³ is C ₃ cycloalkyl. In certain embodiments, R ³ is C ₄ cycloalkyl. In certain embodiments, R ¹ is selected from the groups depicted in the compounds in Table 1, below. In certain embodiments, R ³ is selected from the groups depicted in the compounds in Table 1, below. [0115] As defined generally above, R ² is C _1-4 alkyl, C _1-4 hydroxyalkyl, -C(O)N(R ⁶ )(R ⁷ ), or hydrogen; or, alternatively, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 3-7 membered saturated carbocyclic ring or a 3-7 membered satured heterocyclic ring containing 1 or 2 nitrogen atoms, wherein the carbocyclic ring and the heterocyclic ring are substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ² is C _1-4 alkyl. In certain embodiments, R ² is -CH ₃ . In certain embodiments, R ² is C _1-4 hydroxyalkyl. In certain embodiments, R ² is -C(O)N(R ⁶ )(R ⁷ ). In certain embodiments, R ² is hydrogen. In certain embodiments, R ² is C ₂ alkyl. In certain embodiments, R ² is C ₃ alkyl. In certain embodiments, R ² is C ₄ alkyl. In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 3-7 membered saturated carbocyclic ring, wherein the carbocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 3 membered saturated carbocyclic ring, wherein the carbocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 4 membered saturated carbocyclic ring, wherein the carbocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 5 membered saturated carbocyclic ring, wherein the carbocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 6 membered saturated carbocyclic ring, wherein the carbocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 7 membered saturated carbocyclic ring, wherein the carbocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 3-7 membered saturated heterocyclic ring containing 1 or 2 nitrogen atoms, wherein the heterocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 3 membered saturated heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 4 membered saturated heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 5 membered saturated heterocyclic ring containing 1 or 2 nitrogen atoms, wherein the heterocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 6 membered saturated heterocyclic ring containing 1 or 2 nitrogen atoms, wherein the heterocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 7 membered saturated heterocyclic ring containing 1 or 2 nitrogen atoms, wherein the heterocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ² is selected from the groups depicted in the compounds in Table 1, below. [0116] As defined generally above, R ⁴ is hydrogen, C _1-4 alkyl, or -C(O)N(R ⁶ )(R ⁷ ); or R ⁴ and R ³ are taken together to form oxo. In certain embodiments, R ⁴ is hydrogen. In certain embodiments, R ⁴ is -C(O)N(R ⁶ )(R ⁷ ). In certain embodiments, R ⁴ and R ³ are taken together to form oxo. In certain embodiments, R ⁴ is C _1-4 alkyl. In certain embodiments, R ⁴ is selected from the groups depicted in the compounds in Table 1, below. [0117] As defined generally above, , each of which is substituted with n occurrences of R ⁹ ; (ii) phenyl or 6-membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatom(s) are nitrogen, and wherein the phenyl and heteroaryl are substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; or (iii) 6-membered monocyclic, unsaturated oxo-heterocyclyl containing 1 or 2 heteroatoms, wherein the heteroatom(s) are nitrogen, and the oxo-heterocyclyl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is c , . embodiments, substituted with n occurrences of R ⁹ . In certain embodiments, , each of which is substituted with n occurrences of R ⁹ . [0118] In certain embodiments, R ⁹ is –(C _1-3 alkylene)-(5-6 membered saturated monocyclic heterocyclyl containing 1 or 2 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is each of which is substituted with 0, 1, 2, or 3 instances of R ¹² . In certain embodiments, R ⁹ is – (C _1-3 alkylene)-(7-10 membered saturated bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is –(C _1-3 alkylene)-(7-10 membered saturated spiro-bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, , each of which is substituted with 0, 1, 2, or 3 instances of R ¹² . [0119] In certain embodiments, R ⁵ is phenyl or 6-membered heteroaryl containing 1 or 2 heteroatom(s), wherein the heteroatom(s) are nitrogen atom, and the phenyl and heteroaryl are substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is phenyl substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is a 6-membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatoms are nitrogen atom, and the heteroaryl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is a pyridinyl substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is a 6-membered monocyclic, unsaturated oxo- heterocyclyl containing 1 or 2 nitrogen atoms, wherein the heterocyclyl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, , each of which is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, , each of which is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, , which substituted with n occurrences of R ⁹ . In certain embodiments, , which is substituted with n occurrences of R ⁹ . In certain embodiments, , which is substituted with n occurrences of R ⁹ . In certain embodiments, , which is substituted with n occurrences of R ⁹ . In certain embodiments, , which is substituted with n occurrences of R ⁹ . In certain embodiments, R ⁵ is selected from the groups depicted in the compounds in Table 1, below. [0120] As defined generally above, R ⁶ and R ⁷ are independently hydrogen, C _1-6 alkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; or R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ are independently hydrogen or C _1-6 alkyl. In certain embodiments, R ⁶ is hydrogen. In certain embodiments, R ⁶ is C _1-6 alkyl. In certain embodiments, R ⁶ is -(C _1-6 alkylene)-(C _3-7 cycloalkyl), In certain embodiments, R ⁶ is C _3-7 cycloalkyl. In certain embodiments, R ⁷ is hydrogen. In certain embodiments, R ⁷ is C _1-6 alkyl. In certain embodiments, R ⁷ is -(C _1-6 alkylene)-(C _3-7 cycloalkyl), In certain embodiments, R ⁷ is C _3-7 cycloalkyl. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 4 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 5 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 6 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 7 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ is selected from the groups depicted in the compounds in Table 1, below. In certain embodiments, R ⁷ is selected from the groups depicted in the compounds in Table 1, below. [0121] As defined generally above, R ⁸ , R ¹⁵ , and R ¹⁷ are independently hydrogen or C _1-4 alkyl. In certain embodiments, R ⁸ is hydrogen. In certain embodiments, R ⁸ is C _1-4 alkyl. In certain embodiments, R ⁸ is C ₁ alkyl. In certain embodiments, R ⁸ is C ₂ alkyl. In certain embodiments, R ⁸ is C ₃ alkyl. In certain embodiments, R ⁸ is C ₄ alkyl. In certain embodiments, R ¹⁵ is hydrogen. In certain embodiments, R ¹⁵ is C _1-4 alkyl. In certain embodiments, R ¹⁵ is C ₁ alkyl. In certain embodiments, R ¹⁵ is C ₂ alkyl. In certain embodiments, R ¹⁵ is C ₃ alkyl. In certain embodiments, R ¹⁵ is C ₄ alkyl. In certain embodiments, R ¹⁷ is hydrogen. In certain embodiments, R ¹⁷ is C _1-4 alkyl. In certain embodiments, R ¹⁷ is C ₁ alkyl. In certain embodiments, R ¹⁷ is C ₂ alkyl. In certain embodiments, R ¹⁷ is C ₃ alkyl. In certain embodiments, R ¹⁷ is C ₄ alkyl. In certain embodiments, R ⁸ is selected from the groups depicted in the compounds in Table 1, below. In certain embodiments, R ¹⁵ is selected from the groups depicted in the compounds in Table 1, below. In certain embodiments, R ¹⁷ is selected from the groups depicted in the compounds in Table 1, below. [0122] As defined generally above, R ⁹ is –(C _1-6 alkylene)-(C _1-6 alkoxyl), C _1-6 alkoxyl, -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ), -C(O)N(R ⁶ )(R ⁷ ), -C(O)N(R ⁶ )(R ¹³ ), -(C _0-6 alkylene)-N(R ⁶ )C(O)R ¹⁴ , - (C _0-6 alkylene)-(N(R ¹⁵ )S(O)(N(C _1-4 alkyl))-C _1-4 alkyl), -(C _0-6 alkylene)-(S(O)(NH)-(C _1-4 alkyl)), or deuterium. In certain embodiments, R ⁹ is –(C _1-6 alkylene)-(C _1-6 alkoxyl). In certain embodiments, R ⁹ is –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is - C(O)N(R ⁶ )(R ⁷ ), -C(O)N(R ⁶ )(R ¹³ ), -(C _0-6 alkylene)-N(R ⁶ )C(O)(R ¹⁴ ), -(C _0-6 alkylene)- (N(R ¹⁵ )S(O)(N(C _1-4 alkyl))-C _1-4 alkyl), or –(C _0-6 alkylene)-(S(O)(NH)-(C _1-4 alkyl)). In certain embodiments, R ⁹ is C _1-6 alkoxyl. In certain embodiments, R ⁹ is -C(O)N(R ⁶ )(R ⁷ ). In certain embodiments, R ⁹ is -C(O)N(R ⁶ )(R ¹³ ). In certain embodiments, R ⁹ is -(C _0-6 alkylene)- N(R ⁶ )C(O)R ¹⁴ . In certain embodiments, R ⁹ is -(C _0-6 alkylene)-(N(R ¹⁵ )S(O)(N(C _1-4 alkyl))-C _1-4 alkyl). In certain embodiments, R ⁹ is –(C _0-6 alkylene)-(S(O)(NH)-(C _1-4 alkyl)). In certain embodiments, R ⁹ is deuterium. In certain embodiments, R ⁹ is -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1 heteroatom selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 2 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). [0123] In certain embodiments, R ⁹ is –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is –(C _1-3 alkylene)-(5-6 membered saturated monocyclic heterocyclyl containing 1 or 2 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted or 3 instances of R ¹² . In certain embodiments, R ⁹ is , , [0124] In certain embodiments, R ⁹ is –(C _1-3 alkylene)-(7-10 membered saturated bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is – (C _1-3 alkylene)-(7-10 membered saturated spiro-bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is , , each of which is substituted with 0, 1, 2, or 3 instances of R ¹² . [0125] In certain embodiments, R ⁹ is selected from the groups depicted in the compounds in Table 1, below. [0126] As defined generally above, R ¹⁰ is a group capable of forming a covalent bond to a sulfhydryl group. In certain embodiments, R ¹⁰ is -N(H)C(O)(C _2-4 alkenyl). In certain embodiments, R ¹⁰ is -N(H)C(O)CH=CH ₂ . In certain embodiments, R ¹⁰ is selected from the groups depicted in the compounds in Table 1, below. [0127] As defined generally above, R ¹¹ is halo, hydroxyl, C _1-6 alkyl, C _1-6 haloalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), C _3-7 cycloalkyl, C _1-6 alkoxyl, or –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ represents independently for each occurrence halo, hydroxyl, C _1-6 alkyl, or C _1-6 haloalkyl. In certain embodiments, R ¹¹ represents independently for each occurrence halo, C _1-6 alkyl, or –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ is halo. In certain embodiments, R ¹¹ is hydroxyl. In certain embodiments, R ¹¹ is C _1-6 alkyl. In certain embodiments, R ¹¹ is C _1-6 haloalkyl. In certain embodiments, R ¹¹ is -(C _1-6 alkylene)- (C _3-7 cycloalkyl). In certain embodiments, R ¹¹ is C _3-7 cycloalkyl. In certain embodiments, R ¹¹ is C _1-6 alkoxyl. In certain embodiments, R ¹¹ is –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ is –(C _0-6 alkylene)-(4-10 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ is –(C _0-6 alkylene)-(4-10 membered saturated bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ is selected from the groups depicted in the compounds in Table 1, below. [0128] As defined generally above, R ¹² represents independently for each occurrence halo, C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl, or C _1-6 alkoxyl. In certain embodiments, R ¹² is halo. In certain embodiments, R ¹² is C _1-6 alkyl. In certain embodiments, R ¹² is C ₁ alkyl. In certain embodiments, R ¹² is C ₂ alkyl. In certain embodiments, R ¹² is C ₃ alkyl. In certain embodiments, R ¹² is C ₄ alkyl. In certain embodiments, R ¹² is C ₅ alkyl. In certain embodiments, R ¹² is C6 alkyl. In certain embodiments, R ¹² is C _1-6 haloalkyl. In certain embodiments, R ¹² is C _3-7 cycloalkyl. In certain embodiments, R ¹² is C _1-6 alkoxyl. In certain embodiments, R ¹² is selected from the groups depicted in the compounds in Table 1, below. [0129] As defined generally above, R ¹³ is a 4-7 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 4 membered saturated monocyclic heterocyclyl containing 1 oxygen heteroatom, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 4 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 5 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 6 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 7 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is selected from the groups depicted in the compounds in Table 1, below. [0130] As defined generally above, R ¹⁴ represents independently for each occurrence hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl. In certain embodiments, R ¹⁴ represents independently for each occurrence hydrogen, C _1-6 alkyl, or C _1-6 hydroxyalkyl. In certain embodiments, R ¹⁴ is hydrogen. In certain embodiments, R ¹⁴ is C _1-6 alkyl. In certain embodiments, R ¹⁴ is C _1-6 hydroxyalkyl. In certain embodiments, R ¹⁴ is - (C _1-6 alkylene)-(C _3-7 cycloalkyl). In certain embodiments, R ¹⁴ is C _3-7 cycloalkyl. In certain embodiments, R ¹⁴ is selected from the groups depicted in the compounds in Table 1, below. [0131] As defined generally above, R ¹⁶ is hydrogen, C _1-4 alkyl, or hydroxyl. In certain embodiments, R ¹⁶ is hydrogen. In certain embodiments, R ¹⁶ is C _1-4 alkyl. In certain embodiments, R ¹⁶ is C ₁ alkyl. In certain embodiments, R ¹⁶ is C ₂ alkyl. In certain embodiments, R ¹⁶ is C ₃ alkyl. In certain embodiments, R ¹⁶ is C ₄ alkyl. In certain embodiments, R ¹⁶ is hydroxyl. In certain embodiments, R ¹⁶ is selected from the groups depicted in the compounds in Table 1, below. [0132] As defined generally above, R ²⁰ is hydrogen, C _1-4 alkyl, oxo, -(C _0-4 alkylene)-(C _1-6 alkoxyl), -C(O)-(C _1-4 alkyl), or C _3-7 cycloalkyl. In certain embodiments, R ²⁰ is hydrogen. In certain embodiments, R ²⁰ is C _1-4 alkyl. In certain embodiments, R ²⁰ is -CH ₃ . In certain embodiments, R ²⁰ is -CH ₂ CH ₃ . In certain embodiments, R ²⁰ is -CH ₂ CH ₂ CH ₃ . In certain embodiments, R ²⁰ is -CH(CH ₃ ) ₂ . In certain embodiments, R ²⁰ is -(C _0-4 alkylene)-(C _1-6 alkoxyl). In certain embodiments, R ²⁰ is (C _1-6 alkoxyl). In certain embodiments, R ²⁰ is -C(O)-(C _1-4 alkyl). In certain embodiments, R ²⁰ is -C(O)CH ₃ . In certain embodiments, In certain embodiments, R ²⁰ is -C(O)CH ₂ CH ₃ . In certain embodiments, R ²⁰ is C _3-7 cycloalkyl. In certain embodiments, R ²⁰ is cyclopropyl. In certain embodiments, R ²⁰ is cyclobutyl. In certain embodiments, R ²⁰ is cyclopentyl. In certain embodiments, R ²⁰ is cyclohexyl. In certain embodiments, R ²⁰ is cycloheptyl. In certain embodiments, R ²⁰ is selected from the groups depicted in the compounds in Table 1, below. [0133] As defined generally above, n and p are independently 0, 1, or 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. [0134] As defined generally above, t is 0, 1, 2, 3, 4, 5, or 6. In certain embodiments, t is 0. In certain embodiments, t is 1. In certain embodiments, t is 2. In certain embodiments, t is 3. In certain embodiments, t is 4. In certain embodiments, t is 5. In certain embodiments, t is 6. In certain embodiments, t is 0, 1, or 2. In certain embodiments, t is 1, 2, or 3. In certain embodiments, n, t, and p are independently 0, 1, or 2. [0135] The description above describes multiple embodiments relating to compounds of Formula I-A. The patent application specifically contemplates all combinations of the embodiments. [0136] Another aspect of the invention provides a compound represented by Formula I-B: (I-B) or a pharmaceutically acceptable salt thereof, wherein: R ¹ and R ³ are independently hydrogen, C _1-4 alkyl, or C _3-4 cycloalkyl; R ² is C _1-4 alkyl, C _1-4 hydroxyalkyl, -C(O)N(R ⁶ )(R ⁷ ), or hydrogen; or, alternatively, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 3-7 membered saturated carbocyclic ring or a 3-7 membered saturated heterocyclic ring containing 1 or 2 nitrogen atoms, wherein the carbocyclic ring and the heterocyclic ring are substituted with 1 or 2 occurrences of R ²⁰ ; R ⁴ is hydrogen, C _1-4 alkyl, or -C(O)N(R ⁶ )(R ⁷ ); or R ⁴ and R ³ are taken together to form oxo; of which is substituted with n occurrences of R ⁹ ; (ii) phenyl or 6-membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatom(s) are nitrogen, where the phenyl and heteroaryl are substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; or (iii) 6- membered monocyclic, unsaturated oxo-heterocyclyl containing 1 or 2 heteroatoms, wherein the heteroatom(s) are nitrogen, and the oxo-heterocyclyl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; R ⁶ and R ⁷ are independently hydrogen, C _1-6 alkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; or R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom; R ⁸ , R ¹⁵ , and R ¹⁷ are independently hydrogen or C _1-4 alkyl; R ⁹ is -(C _1-6 alkylene)-(C _1-6 alkoxyl) or -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ); R ¹⁰ is a group capable of forming a covalent bond to a sulfhydryl group; R ¹¹ is halo, hydroxyl, C _1-6 alkyl, C _1-6 haloalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), C _3-7 cycloalkyl, C _1-6 alkoxyl, or –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ); R ¹² represents independently for each occurrence halo, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _3-7 cycloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, -C(O)R ¹⁹ , or oxo; R ¹³ is a 4-7 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ ; R ¹⁴ represents independently for each occurrence hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; R ¹⁶ is hydrogen, C _1-4 alkyl, or hydroxyl; R ¹⁹ represents independently for each occurrence C _1-6 alkyl, C _3-6 cycloalkyl, or -(C _1-6 alkylene)-(C _3-6 cycloalkyl); R ²⁰ is hydrogen, C _1-4 alkyl, oxo, -(C _0-4 alkylene)-(C _1-6 alkoxyl), -C(O)-(C _1-4 alkyl), or C _3-7 cycloalkyl; n and p are independently 0, 1, or 2; and t is 0, 1, 2, 3, 4, 5, or 6. [0137] 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). [0138] In certain embodiments, the compound is a compound of Formula I-B. [0139] As defined generally above, R ¹ and R ³ are independently hydrogen, C _1-4 alkyl, or C _3-4 cycloalkyl. In certain embodiments, R ¹ and R ³ are hydrogen. In certain embodiments, R ¹ is hydrogen. In certain embodiments, R ¹ is C _1-4 alkyl. In certain embodiments, R ¹ is C ₁ alkyl. In certain embodiments, R ¹ is C ₂ alkyl. In certain embodiments, R ¹ is C ₃ alkyl. In certain embodiments, R ¹ is C ₄ alkyl. In certain embodiments, R ¹ is C _3-4 cycloalkyl. In certain embodiments, R ¹ is C ₃ cycloalkyl. In certain embodiments, R ¹ is C ₄ cycloalkyl. In certain embodiments, R ³ is hydrogen. In certain embodiments, R ³ is C _1-4 alkyl. In certain embodiments, R ³ is C ₁ alkyl. In certain embodiments, R ³ is C ₂ alkyl. In certain embodiments, R ³ is C ₃ alkyl. In certain embodiments, R ³ is C ₄ alkyl. In certain embodiments, R ³ is C _3-4 cycloalkyl. In certain embodiments, R ³ is C ₃ cycloalkyl. In certain embodiments, R ³ is C ₄ cycloalkyl. In certain embodiments, R ¹ is selected from the groups depicted in the compounds in Table 1, below. In certain embodiments, R ³ is selected from the groups depicted in the compounds in Table 1, below. [0140] As defined generally above, R ² is C _1-4 alkyl, C _1-4 hydroxyalkyl, -C(O)N(R ⁶ )(R ⁷ ), or hydrogen; or, alternatively, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 3-7 membered saturated carbocyclic ring or a 3-7 membered saturated heterocyclic ring containing 1 or 2 nitrogen atoms, wherein the carbocyclic ring and the heterocyclic ring are substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ² is C _1-4 alkyl. In certain embodiments, R ² is -CH ₃ . In certain embodiments, R ² is C _1-4 hydroxyalkyl. In certain embodiments, R ² is -C(O)N(R ⁶ )(R ⁷ ). In certain embodiments, R ² is hydrogen. In certain embodiments, R ² is C ₂ alkyl. In certain embodiments, R ² is C ₃ alkyl. In certain embodiments, R ² is C ₄ alkyl. In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 3-7 membered saturated carbocyclic ring, wherein the carbocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 3 membered saturated carbocyclic ring, wherein the carbocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 4 membered saturated carbocyclic ring, wherein the carbocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 5 membered saturated carbocyclic ring, wherein the carbocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 6 membered saturated carbocyclic ring, wherein the carbocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 7 membered saturated carbocyclic ring, wherein the carbocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 3-7 membered saturated heterocyclic ring containing 1 or 2 nitrogen atoms, wherein the heterocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 3 membered saturated heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 4 membered saturated heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 5 saturated membered heterocyclic ring containing 1 or 2 nitrogen atoms, wherein the heterocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 6 saturated membered heterocyclic ring containing 1 or 2 nitrogen atoms, wherein the heterocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 7 saturated membered heterocyclic ring containing 1 or 2 nitrogen atoms, wherein the heterocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ² is selected from the groups depicted in the compounds in Table 1, below. [0141] As defined generally above, R ⁴ is hydrogen, C _1-4 alkyl, or -C(O)N(R ⁶ )(R ⁷ ); or R ⁴ and R ³ are taken together to form oxo. In certain embodiments, R ⁴ is hydrogen. In certain embodiments, R ⁴ is -C(O)N(R ⁶ )(R ⁷ ). In certain embodiments, R ⁴ and R ³ are taken together to form oxo. In certain embodiments, R ⁴ is C _1-4 alkyl. In certain embodiments, R ⁴ is selected from the groups depicted in the compounds in Table 1, below. , each of which is substituted with n occurrences of R ⁹ ; (ii) phenyl or 6-membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatom(s) are nitrogen, and wherein the phenyl and heteroaryl are substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; or (iii) 6-membered monocyclic, unsaturated oxo-heterocyclyl containing 1 or 2 heteroatoms, wherein the heteroatom(s) are nitrogen, and the oxo-heterocyclyl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is c , . embodiments, substituted with n occurrences of R ⁹ . In certain embodiments, , each of which is substituted with n occurrences of R ⁹ . [0143] In certain embodiments, R ⁵ is phenyl or 6-membered heteroaryl containing 1 or 2 heteroatom(s), wherein the heteroatom(s) are nitrogen atom, and the phenyl and heteroaryl are substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is phenyl substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is a 6-membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatoms are nitrogen atom, and the heteroaryl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is a pyridinyl substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is a 6-membered monocyclic, unsaturated oxo- heterocyclyl containing 1 or 2 nitrogen atoms, wherein the heterocyclyl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, , each of which is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, , each of which is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, , which substituted with n occurrences of R ⁹ . In certain embodiments, , which is substituted with n occurrences of R ⁹ . In certain embodiments, , which is substituted with n occurrences of R ⁹ . In certain embodiments, , which is substituted with n occurrences of R ⁹ . In certain embodiments, , which is substituted with n occurrences of R ⁹ . In certain embodiments, R ⁵ is selected from the groups depicted in the compounds in Table 1, below. [0144] As defined generally above, R ⁶ and R ⁷ are independently hydrogen, C _1-6 alkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; or R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ are independently hydrogen or C _1-6 alkyl. In certain embodiments, R ⁶ is hydrogen. In certain embodiments, R ⁶ is C _1-6 alkyl. In certain embodiments, R ⁶ is -(C _1-6 alkylene)-(C _3-7 cycloalkyl), In certain embodiments, R ⁶ is C _3-7 cycloalkyl. In certain embodiments, R ⁷ is hydrogen. In certain embodiments, R ⁷ is C _1-6 alkyl. In certain embodiments, R ⁷ is -(C _1-6 alkylene)-(C _3-7 cycloalkyl), In certain embodiments, R ⁷ is C _3-7 cycloalkyl. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 4 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 5 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 6 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 7 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ is selected from the groups depicted in the compounds in Table 1, below. In certain embodiments, R ⁷ is selected from the groups depicted in the compounds in Table 1, below. [0145] As defined generally above, R ⁸ , R ¹⁵ , and R ¹⁷ are independently hydrogen or C _1-4 alkyl. In certain embodiments, R ⁸ is hydrogen. In certain embodiments, R ⁸ is C _1-4 alkyl. In certain embodiments, R ⁸ is C ₁ alkyl. In certain embodiments, R ⁸ is C ₂ alkyl. In certain embodiments, R ⁸ is C ₃ alkyl. In certain embodiments, R ⁸ is C ₄ alkyl. In certain embodiments, R ¹⁵ is hydrogen. In certain embodiments, R ¹⁵ is C _1-4 alkyl. In certain embodiments, R ¹⁵ is C ₁ alkyl. In certain embodiments, R ¹⁵ is C ₂ alkyl. In certain embodiments, R ¹⁵ is C ₃ alkyl. In certain embodiments, R ¹⁵ is C ₄ alkyl. In certain embodiments, R ¹⁷ is hydrogen. In certain embodiments, R ¹⁷ is C _1-4 alkyl. In certain embodiments, R ¹⁷ is C ₁ alkyl. In certain embodiments, R ¹⁷ is C ₂ alkyl. In certain embodiments, R ¹⁷ is C ₃ alkyl. In certain embodiments, R ¹⁷ is C ₄ alkyl. In certain embodiments, R ⁸ is selected from the groups depicted in the compounds in Table 1, below. In certain embodiments, R ¹⁵ is selected from the groups depicted in the compounds in Table 1, below. In certain embodiments, R ¹⁷ is selected from the groups depicted in the compounds in Table 1, below. [0146] As defined generally above, R ⁹ is -(C _1-6 alkylene)-(C _1-6 alkoxyl) or -(C _0-6 alkylene)-(4- 10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1 heteroatom selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 2 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). [0147] In certain embodiments, R ⁹ is –(C _1-3 alkylene)-(5-6 membered saturated monocyclic heterocyclyl containing 1 or 2 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is , each of which is substituted with 0, 1, 2, or 3 instances of R ¹² . In certain embodiments, R ⁹ is . [0148] In certain embodiments, R ⁹ is –(C _1-3 alkylene)-(7-10 membered saturated bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is – (C _1-3 alkylene)-(7-10 membered saturated spiro-bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, , instances of R ¹² . [0149] In certain embodiments, R ⁹ is selected from the groups depicted in the compounds in Table 1, below. [0150] As defined generally above, R ¹⁰ is a group capable of forming a covalent bond to a sulfhydryl group. In certain embodiments, R ¹⁰ is -N(H)C(O)(C _2-4 alkenyl). In certain embodiments, R ¹⁰ is -N(H)C(O)CH=CH ₂ . In certain embodiments, R ¹⁰ is selected from the groups depicted in the compounds in Table 1, below. [0151] As defined generally above, R ¹¹ is halo, hydroxyl, C _1-6 alkyl, C _1-6 haloalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), C _3-7 cycloalkyl, C _1-6 alkoxyl, or –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ represents independently for each occurrence halo, hydroxyl, C _1-6 alkyl, or C _1-6 haloalkyl. In certain embodiments, R ¹¹ represents independently for each occurrence halo, C _1-6 alkyl, or –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ is halo. In certain embodiments, R ¹¹ is hydroxyl. In certain embodiments, R ¹¹ is C _1-6 alkyl. In certain embodiments, R ¹¹ is C _1-6 haloalkyl. In certain embodiments, R ¹¹ is -(C _1-6 alkylene)- (C _3-7 cycloalkyl). In certain embodiments, R ¹¹ is C _3-7 cycloalkyl. In certain embodiments, R ¹¹ is C _1-6 alkoxyl. In certain embodiments, R ¹¹ is –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ is –(C _0-6 alkylene)-(4-10 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ is –(C _0-6 alkylene)-(4-10 membered saturated bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ is selected from the groups depicted in the compounds in Table 1, below. [0152] As defined generally above, R ¹² represents independently for each occurrence halo, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _3-7 cycloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, -C(O)R ¹⁹ , or oxo. In certain embodiments, R ¹² represents independently for each occurrence halo, C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, or oxo. In certain embodiments, R ¹² is halo. In certain embodiments, R ¹² is C _1-6 alkyl. In certain embodiments, R ¹² is C ₁ alkyl. In certain embodiments, R ¹² is C ₂ alkyl. In certain embodiments, R ¹² is C ₃ alkyl. In certain embodiments, R ¹² is C ₄ alkyl. In certain embodiments, R ¹² is C ₅ alkyl. In certain embodiments, R ¹² is C ₆ alkyl. In certain embodiments, R ¹² is C _1-6 haloalkyl. In certain embodiments, R ¹² is C _3-7 cycloalkyl. In certain embodiments, R ¹² is C _1-6 alkoxyl. In certain embodiments, R ¹² is C _1-6 haloalkoxyl. In certain embodiments, R ¹² is oxo. In certain embodiments, R ¹² is hydroxy. In certain embodiments, R ¹² is C _1-6 hydroxyalkyl. In certain embodiments, R ¹² is -C(O)R ¹⁹ . [0153] In certain embodiments, R ¹² represents independently for each occurrence halo, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _3-7 cycloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, -C(O)R ¹⁹ , or oxo. In certain embodiments, R ¹² represents independently for each occurrence halo, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _3-7 cycloalkyl, or - C(O)R ¹⁹ . In certain embodiments, R ¹² represents independently for each occurrence C _1-6 alkyl. In certain embodiments, R ¹² is selected from the groups depicted in the compounds in Table 1, below. [0154] As defined generally above, R ¹³ is a 4-7 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 4 membered saturated monocyclic heterocyclyl containing 1 oxygen heteroatom, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 4 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 5 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 6 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 7 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is selected from the groups depicted in the compounds in Table 1, below. [0155] As defined generally above, R ¹⁴ represents independently for each occurrence hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl. In certain embodiments, R ¹⁴ represents independently for each occurrence hydrogen, C _1-6 alkyl, or C _1-6 hydroxyalkyl. In certain embodiments, R ¹⁴ is hydrogen. In certain embodiments, R ¹⁴ is C _1-6 alkyl. In certain embodiments, R ¹⁴ is C _1-6 hydroxyalkyl. In certain embodiments, R ¹⁴ is - (C _1-6 alkylene)-(C _3-7 cycloalkyl). In certain embodiments, R ¹⁴ is C _3-7 cycloalkyl. In certain embodiments, R ¹⁴ is selected from the groups depicted in the compounds in Table 1, below. [0156] As defined generally above, R ¹⁶ is hydrogen, C _1-4 alkyl, or hydroxyl. In certain embodiments, R ¹⁶ is hydrogen. In certain embodiments, R ¹⁶ is C _1-4 alkyl. In certain embodiments, R ¹⁶ is C ₁ alkyl. In certain embodiments, R ¹⁶ is C ₂ alkyl. In certain embodiments, R ¹⁶ is C ₃ alkyl. In certain embodiments, R ¹⁶ is C ₄ alkyl. In certain embodiments, R ¹⁶ is hydroxyl. In certain embodiments, R ¹⁶ is selected from the groups depicted in the compounds in Table 1, below. [0157] As defined generally above, R ¹⁹ represents independently for each occurrence C _1-6 alkyl, C _3-6 cycloalkyl, or -(C _1-6 alkylene)-(C _3-6 cycloalkyl). In certain embodiments, R ¹⁹ is C _1-6 alkyl. In certain embodiments, R ¹⁹ is methyl. In certain embodiments, R ¹⁹ is ethyl. In certain embodiments, R ¹⁹ is C _3-6 cycloalkyl. In certain embodiments, R ¹⁹ is -(C _1-6 alkylene)-(C _3-6 cycloalkyl). In certain embodiments, R ¹⁹ is selected from the groups depicted in the compounds in Table 1, below. [0158] As defined generally above, R ²⁰ is hydrogen, C _1-4 alkyl, oxo, -(C _0-4 alkylene)-(C _1-6 alkoxyl), -C(O)-(C _1-4 alkyl), or C _3-7 cycloalkyl. In certain embodiments, R ²⁰ is hydrogen. In certain embodiments, R ²⁰ is C _1-4 alkyl. In certain embodiments, R ²⁰ is -CH ₃ . In certain embodiments, R ²⁰ is -CH ₂ CH _3. In certain embodiments, R ²⁰ is -CH ₂ CH ₂ CH ₃ . In certain embodiments, R ²⁰ is -CH(CH ₃ ) ₂ . In certain embodiments, R ²⁰ is -(C _0-4 alkylene)-(C _1-6 alkoxyl). In certain embodiments, R ²⁰ is (C _1-6 alkoxyl). In certain embodiments, R ²⁰ is -C(O)-(C _1-4 alkyl). In certain embodiments, R ²⁰ is -C(O)CH ₃ . In certain embodiments, In certain embodiments, R ²⁰ is -C(O)CH ₂ CH ₃ . In certain embodiments, R ²⁰ is C _3-7 cycloalkyl. In certain embodiments, R ²⁰ is cyclopropyl. In certain embodiments, R ²⁰ is cyclobutyl. In certain embodiments, R ²⁰ is cyclopentyl. In certain embodiments, R ²⁰ is cyclohexyl. In certain embodiments, R ²⁰ is cycloheptyl. In certain embodiments, R ²⁰ is selected from the groups depicted in the compounds in Table 1, below. [0159] As defined generally above, n, and p are independently 0, 1, or 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, n, t, and p are independently 0, 1, or 2. [0160] As defined generally above, t is 0, 1, 2, 3, 4, 5, or 6. In certain embodiments, t is 0. In certain embodiments, t is 1. In certain embodiments, t is 2. In certain embodiments, t is 3. In certain embodiments, t is 4. In certain embodiments, t is 5. In certain embodiments, t is 1, 2, or 3. In certain embodiments, t is 2, 3 or 4. [0161] The description above describes multiple embodiments relating to compounds of Formula I-B. The patent application specifically contemplates all combinations of the embodiments. [0162] Another aspect of the invention provides a compound represented by Formula I-1: (I-1) or a pharmaceutically acceptable salt thereof, wherein: R ¹ and R ³ are independently hydrogen, C _1-4 alkyl, or C _3-4 cycloalkyl; R ² is C _1-4 alkyl, C _1-4 hydroxyalkyl, -C(O)N(R ⁶ )(R ⁷ ), or hydrogen; or, alternatively, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 3-7 membered saturated carbocyclic ring or a 3-7 membered saturated heterocyclic ring containing 1 or 2 nitrogen atoms, wherein the carbocyclic ring and the heterocyclic ring are substituted with 1 or 2 occurrences of R ²⁰ ; R ⁴ is hydrogen, C _1-4 alkyl, or -C(O)N(R ⁶ )(R ⁷ ); or R ⁴ and R ³ are taken together to form oxo; , , each of which is substituted with n occurrences of R ⁹ ; (ii) phenyl or 6-membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatoms are nitrogen atoms, where the phenyl and heteroaryl are substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; or (iii) 6-membered monocyclic, unsaturated oxo-heterocyclyl containing 1 or 2 nitrogen atoms, wherein the oxo-heterocyclyl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; R ⁶ and R ⁷ are independently hydrogen, C _1-6 alkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; or R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom; R ⁸ is hydrogen, C _1-4 alkyl, or -(C _2-4 alkylene)-(C _1-4 alkoxyl); R ⁹ is -(C _1-6 alkylene)-(C _1-6 alkoxyl), C _1-6 alkoxyl, -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ), - C(O)N(R ⁶ )(R ⁷ ), -C(O)N(R ⁶ )(R ¹³ ), -S(O) ₂ R ¹⁸ , -S(O)(=NH)R ¹⁸ , -S(O) ₂ N(R ⁶ )(R ⁷ ), -(C _0-6 alkylene)-N(R ⁶ )C(O)R ¹⁴ , -(C _0-6 alkylene)-(N(R ¹⁵ )S(O)(N(C _1-4 alkyl))-C _1-4 alkyl), -(C _0-6 alkylene)-(S(O)(NH)-(C _1-4 alkyl)), or deuterium; R ¹⁰ is a group capable of forming a covalent bond to a sulfhydryl group; R ¹¹ is halo, hydroxyl, C _1-6 alkyl, C _1-6 haloalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), C _3-7 cycloalkyl, C _1-6 alkoxyl, or -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ); R ¹² represents independently for each occurrence halo, C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, or oxo; R ¹³ is a 4-7 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ ; R ¹⁴ represents independently for each occurrence hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; R ¹⁵ is hydrogen or C _1-4 alkyl; R ¹⁶ is hydrogen, C _1-4 alkyl, or hydroxyl; R ¹⁷ is hydrogen, C _1-4 alkyl, or -(C _2-4 alkylene)-(C _1-4 alkoxyl); R ¹⁸ is C _1-4 alkyl or C _3-6 cycloalkyl; R ²⁰ is hydrogen, C _1-4 alkyl, -(C _0-4 alkylene)-(C _1-6 alkoxyl), -C(O)-(C _1-4 alkyl), or C _3-7 cycloalkyl; X is -N(R ¹⁷ )-, -O-, or -CH ₂ ; and n, t, and p are independently 0, 1, or 2. [0163] 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). [0164] In certain embodiments, the compound is a compound of Formula I-1. [0165] In certain embodiments, the definition of one or more variables of Formula I-1 is as set forth above in connection with Formula I. [0166] Another aspect of the invention provides a compound represented by Formula I-A-1: or a pharmaceutically acceptable salt thereof, wherein: R ¹ and R ³ are independently hydrogen, C _1-4 alkyl, or C _3-4 cycloalkyl; R ² is C _1-4 alkyl, C _1-4 hydroxyalkyl, -C(O)N(R ⁶ )(R ⁷ ), or hydrogen; or, alternatively, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 3-7 membered saturated carbocyclic ring or a 3-7 membered saturated heterocyclic ring containing 1 or 2 nitrogen atoms, wherein the carbocyclic ring and the heterocyclic ring are substituted with 1 or 2 occurrences of R ²⁰ ; R ⁴ is hydrogen, C _1-4 alkyl, or -C(O)N(R ⁶ )(R ⁷ ); or R ⁴ and R ³ are taken together to form oxo; of which is substituted with n occurrences of R ⁹ ; (ii) phenyl or 6-membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatoms are nitrogen atoms, where the phenyl and heteroaryl are substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; or (iii) 6- membered monocyclic, unsaturated oxo-heterocyclyl containing 1 or 2 heteroatoms, wherein the heteroatoms are nitrogen atom, and the heterocyclyl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; R ⁶ and R ⁷ are independently hydrogen, C _1-6 alkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; or R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom; R ⁸ , R ¹⁵ , and R ¹⁷ are independently hydrogen or C _1-4 alkyl; R ⁹ is –(C _1-6 alkylene)-(C _1-6 alkoxyl), C _1-6 alkoxyl, -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ), - C(O)N(R ⁶ )(R ⁷ ), -C(O)N(R ⁶ )(R ¹³ ), -(C _0-6 alkylene)-N(R ⁶ )C(O)(R ¹⁴ ), -(C _0-6 alkylene)- (N(R ¹⁵ )S(O)(N(C _1-4 alkyl))-C _1-4 alkyl), -(C _0-6 alkylene)-(S(O)(NH)-(C _1-4 alkyl)), or deuterium; R ¹⁰ is a group capable of forming a covalent bond to a sulfhydryl group; R ¹¹ is halo, hydroxyl, C _1-6 alkyl, C _1-6 haloalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), C _3-7 cycloalkyl, C _1-6 alkoxyl, or –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ); R ¹² represents independently for each occurrence halo, C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl, or C _1-6 alkoxyl; R ¹³ is a 4-7 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ ; R ¹⁴ represents independently for each occurrence hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; R ¹⁶ is hydrogen, C _1-4 alkyl, or hydroxyl; R ²⁰ is hydrogen, C _1-4 alkyl, -(C _0-4 alkylene)-(C _1-6 alkoxyl), -C(O)-(C _1-4 alkyl), or C _3-7 cycloalkyl; and n, t, and p are independently 0, 1, or 2. [0167] In certain embodiments, the definition of one or more variables of Formula I-A-1 is as set forth above in connection with Formula I-A. [0168] Another aspect of the invention provides a compound represented by Formula I-2: (I-2) or a pharmaceutically acceptable salt thereof, wherein: R ¹ and R ³ are independently hydrogen, C _1-4 alkyl, or C _3-4 cycloalkyl; R ² is C _1-4 alkyl, C _1-4 hydroxyalkyl, -C(O)N(R ⁶ )(R ⁷ ), or hydrogen; or, alternatively, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 3-7 membered saturated carbocyclic ring or a 3-7 membered saturated heterocyclic ring containing 1 or 2 nitrogen atoms, wherein the carbocyclylic ring and the heterocyclylic ring are substituted with 1 or 2 occurrences of R ²⁰ ; R ⁴ is hydrogen, C _1-4 alkyl, or -C(O)N(R ⁶ )(R ⁷ ); or R ⁴ and R ³ are taken together to form oxo; , , each of which is substituted with n occurrences of R ⁹ ; (ii) phenyl or 6-membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatoms are nitrogen atoms, where the phenyl and heteroaryl are substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; or (iii) 6-membered monocyclic, unsaturated oxo- heterocyclyl containing 1 or 2 nitrogen atoms, wherein the oxo-heterocyclyl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; R ⁶ and R ⁷ are independently hydrogen, C _1-6 alkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; or R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom; R ⁸ is hydrogen, C _1-4 alkyl, or -(C _2-4 alkylene)-(C _1-4 alkoxyl); R ⁹ is -(C _1-6 alkylene)-(C _1-6 alkoxyl), C _1-6 alkoxyl, -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, phosphorous, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ), -C(O)N(R ⁶ )(R ⁷ ), -C(O)N(R ⁶ )(R ¹³ ), -(C _0-6 alkylene)-S(O) ₂ R ¹⁸ , -(C _0-6 alkylene)-S(O)(=NR ¹⁵ )R ¹⁸ , -S(O) ₂ N(R ⁶ )(R ⁷ ), -(C _0-6 alkylene)-N(R ⁶ )C(O)R ¹⁴ , -(C _0-6 alkylene)- (N(R ¹⁵ )S(O)(N(R ^15A ))-R ¹⁸ ), halo, C _1-6 haloalkyl, cyano, -(C _0-6 alkylene)-P(O)(R ⁶ )(R ⁷ ), -(C _0-6 alkylene)-(3-7 membered saturated monocyclic or bicyclic carbocyclyl), -(C _0-6 alkylene)-O-(3- 7 membered saturated monocyclic or bicyclic carbocyclyl, wherein the carbocyclyl is substituted with m occurrences of R ¹² ), -(C _0-6 alkylene)-O-(C _1-6 haloalkyl), -(C _1-6 alkylene)- N(R ⁶ )(R ⁷ ), -(C _1-6 alkylene)-O-C(O)(R ¹⁹ ), -(C _1-6 alkylene)-(C _1-4 alkynyl), -(C _1-6 alkylene)-O-(C _{1- 4} alkynyl), or deuterium; R ¹⁰ is a group capable of forming a covalent bond to a sulfhydryl group; R ¹¹ is halo, hydroxyl, C _1-6 alkyl, C _1-6 haloalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), C _3-7 cycloalkyl, C _1-6 alkoxyl, or -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ); R ¹² represents independently for each occurrence halo, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _3-7 cycloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, -C(O)R ¹⁹ , - C(O)(OH), -O-(C _1-4 haloalkyl), -O-(C _1-4 halohydroxyalkoxyl), or oxo; or two R ¹² groups, taken together with the carbon atom to which they are attached, form a 3-7 membered saturated carbocyclic ring or a 3-7 membered saturated heterocyclic ring containing 1 heteroatom selected from nitrogen and oxygen, wherein the carbocyclic ring and the heterocyclic ring are substituted with 1 or 2 occurrences of R ²⁰ ; R ¹³ is a 4-7 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ ; R ¹⁴ represents independently for each occurrence hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; R ¹⁵ and R ^15A are independently hydrogen or C _1-4 alkyl; R ¹⁶ is hydrogen, C _1-4 alkyl, or hydroxyl; R ¹⁷ is hydrogen, C _1-4 alkyl, or -(C _2-4 alkylene)-(C _1-4 alkoxyl); R ¹⁸ is C _1-4 alkyl, -(C _1-6 alkylene)-C(O) ₂ OH, -(C _1-6 alkylene)-(C _1-6 alkoxyl), or C _3-6 cycloalkyl; R ¹⁹ represents independently for each occurrence C _1-6 alkyl, C _3-6 cycloalkyl, or -(C _1-6 alkylene)-(C _3-6 cycloalkyl); R ²⁰ is hydrogen, C _1-4 alkyl, -(C _0-4 alkylene)-(C _1-6 alkoxyl), -C(O)-(C _1-4 alkyl), or C _3-7 cycloalkyl; X is -N(R ¹⁷ )-, -O-, or -CH ₂ ; and m and p are independently 0, 1, or 2; n is 0, 1, 2, or 3; and t is 0, 1, 2, 3, 4, 5, or 6. [0169] The definitions of variables in Formula I-2 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). [0170] In certain embodiments, the compound is a compound of Formula I-2. [0171] As defined generally above, R ¹ and R ³ are independently hydrogen, C _1-4 alkyl, or C _3-4 cycloalkyl. In certain embodiments, R ¹ and R ³ are hydrogen. In certain embodiments, R ¹ is hydrogen. In certain embodiments, R ¹ is C _1-4 alkyl. In certain embodiments, R ¹ is C ₁ alkyl. In certain embodiments, R ¹ is C ₂ alkyl. In certain embodiments, R ¹ is C ₃ alkyl. In certain embodiments, R ¹ is C ₄ alkyl. In certain embodiments, R ¹ is C _3-4 cycloalkyl. In certain embodiments, R ¹ is C ₃ cycloalkyl. In certain embodiments, R ¹ is C ₄ cycloalkyl. In certain embodiments, R ³ is hydrogen. In certain embodiments, R ³ is C _1-4 alkyl. In certain embodiments, R ³ is C ₁ alkyl. In certain embodiments, R ³ is C ₂ alkyl. In certain embodiments, R ³ is C ₃ alkyl. In certain embodiments, R ³ is C ₄ alkyl. In certain embodiments, R ³ is C _3-4 cycloalkyl. In certain embodiments, R ³ is C ₃ cycloalkyl. In certain embodiments, R ³ is C ₄ cycloalkyl. In certain embodiments, R ¹ is selected from the groups depicted in the compounds in Table 1, below. In certain embodiments, R ³ is selected from the groups depicted in the compounds in Table 1, below. [0172] As defined generally above, R ² is C _1-4 alkyl, C _1-4 hydroxyalkyl, -C(O)N(R ⁶ )(R ⁷ ), or hydrogen; or, alternatively, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 3-7 membered saturated carbocyclic ring or a 3-7 membered saturated heterocyclic ring containing 1 or 2 nitrogen atoms, wherein the carbocyclic ring and the heterocyclic ring are substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ² is C _1-4 alkyl. In certain embodiments, R ² is -CH ₃ . In certain embodiments, R ² is C _1-4 hydroxyalkyl. In certain embodiments, R ² is -C(O)N(R ⁶ )(R ⁷ ). In certain embodiments, R ² is hydrogen. In certain embodiments, R ² is C ₂ alkyl. In certain embodiments, R ² is C ₃ alkyl. In certain embodiments, R ² is C ₄ alkyl. In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 3-7 membered saturated carbocyclic ring, wherein the carbocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 3 membered saturated carbocyclic ring, wherein the carbocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 4 membered saturated carbocyclic ring, wherein the carbocyclyic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 5 membered saturated carbocyclic ring, wherein the carbocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 6 membered saturated carbocyclic ring, wherein the carbocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 7 membered saturated carbocyclic ring, wherein the carbocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 3-7 membered saturated heterocyclic ring containing 1 or 2 nitrogen atoms, wherein the heterocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 3 membered saturated heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 4 membered saturated heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 5 membered satured heterocyclic ring containing 1 or 2 nitrogen atoms, wherein the heterocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 6 membered saturated heterocyclic ring containing 1 or 2 nitrogen atoms, wherein the heterocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 7 membered satured heterocyclic ring containing 1 or 2 nitrogen atoms, wherein the heterocyclic ring is substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ² is selected from the groups depicted in the compounds in Table 1, below. [0173] As defined generally above, R ⁴ is hydrogen, C _1-4 alkyl, or -C(O)N(R ⁶ )(R ⁷ ); or R ⁴ and R ³ are taken together to form oxo. In certain embodiments, R ⁴ is hydrogen. In certain embodiments, R ⁴ is -C(O)N(R ⁶ )(R ⁷ ). In certain embodiments, R ⁴ and R ³ are taken together to form oxo. In certain embodiments, R ⁴ is C _1-4 alkyl. In certain embodiments, R ⁴ is selected from the groups depicted in the compounds in Table 1, below. substituted with n occurrences of R ⁹ ; (ii) phenyl or 6-membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatom(s) are nitrogen, and wherein the phenyl and heteroaryl are substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; or (iii) 6-membered monocyclic, unsaturated oxo-heterocyclyl containing 1 or 2 heteroatoms, wherein the heteroatoms are nitrogen, and the oxo-heterocyclyl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ .

occurrences of R ⁹ ; (ii) phenyl or 6-membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatom(s) are nitrogen, and wherein the phenyl and heteroaryl are substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, , e , . [0176] In certain embodiments, substituted with n occurrences of R ⁹ . [0177] In certain embodiments, substituted with n occurrences of R ⁹ . In certain embodiments, R ⁵ is phenyl or 6-membered heteroaryl containing 1 heteroatoms, wherein the heteroatoms are nitrogen atoms, wherein the phenyl and heteroaryl are substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is phenyl substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is a 6-membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatoms are nitrogen atoms, and the heteroaryl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is a pyridinyl substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is a 6-membered monocyclic, unsaturated oxo-heterocyclyl containing 1 or 2 heteroatoms, wherein the heteroatoms are nitrogen atoms, and the heterocyclyl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, , each of which is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is , each of which is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, . certain embodiments, , which substituted with n occurrences of R ⁹ . In certain embodiments, , which is substituted with n occurrences of R ⁹ . In certain embodiments, , which is substituted with n occurrences of R ⁹ . In certain embodiments, , which is substituted with n occurrences of R ⁹ . In certain embodiments, , which is substituted with n occurrences of R ⁹ . In certain embodiments, , which is substituted with n occurrences of R ⁹ . In certain embodiments, , which is substituted with n occurrences of R ⁹ . In certain embodiments, substituted with n occurrences of R ⁹ . In certain embodiments, substituted with n occurrences of R ⁹ . In certain embodiments, R ⁵ is selected from the groups depicted in the compounds in Table 1, below. [0178] As defined generally above, R ⁶ and R ⁷ are independently hydrogen, C _1-6 alkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; or R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ are independently hydrogen or C _1-6 alkyl. In certain embodiments, R ⁶ is hydrogen. In certain embodiments, R ⁶ is C _1-6 alkyl. In certain embodiments, R ⁶ is -(C _1-6 alkylene)-(C _3-7 cycloalkyl), In certain embodiments, R ⁶ is C _3-7 cycloalkyl. In certain embodiments, R ⁷ is hydrogen. In certain embodiments, R ⁷ is C _1-6 alkyl. In certain embodiments, R ⁷ is -(C _1-6 alkylene)-(C _3-7 cycloalkyl), In certain embodiments, R ⁷ is C _3-7 cycloalkyl. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 4 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 5 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 6 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 7 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ is selected from the groups depicted in the compounds in Table 1, below. In certain embodiments, R ⁷ is selected from the groups depicted in the compounds in Table 1, below. [0179] As defined generally above, R ⁸ is hydrogen, C _1-4 alkyl, or –(C _2-4 alkylene)-(C _1-4 alkoxyl). In certain embodiments, R ⁸ is hydrogen. In certain embodiments, R ⁸ is C _1-4 alkyl. In certain embodiments, R ⁸ is C ₁ alkyl. In certain embodiments, R ⁸ is C ₂ alkyl. In certain embodiments, R ⁸ is C ₃ alkyl. In certain embodiments, R ⁸ is C ₄ alkyl. In certain embodiments, R ⁸ is –(C _2-4 alkylene)-(C _1-4 alkoxyl). In certain embodiments, R ⁸ is selected from the groups depicted in the compounds in Table 1, below. [0180] As defined generally above, R ⁹ is –(C _1-6 alkylene)-(C _1-6 alkoxyl), C _1-6 alkoxyl, -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, phosphorous, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ), -C(O)N(R ⁶ )(R ⁷ ), -C(O)N(R ⁶ )(R ¹³ ), -(C _0-6 alkylene)- S(O) ₂ R ¹⁸ , -(C _0-6 alkylene)-S(O)(=NR ¹⁵ )R ¹⁸ , -S(O) ₂ N(R ⁶ )(R ⁷ ), -(C _0-6 alkylene)-N(R ⁶ )C(O)R ¹⁴ , - (C _0-6 alkylene)-(N(R ¹⁵ )S(O)(N(R ^15A ))-R ¹⁸ ), halo, C _1-6 haloalkyl, cyano, -(C _0-6 alkylene)- P(O)(R ⁶ )(R ⁷ ), -(C _0-6 alkylene)-(3-7 membered saturated monocyclic or bicyclic carbocyclyl), - (C _0-6 alkylene)-O-(3-7 membered saturated monocyclic or bicyclic carbocyclyl, wherein the carbocyclyl is substituted with m occurrences of R ¹² ), -(C _0-6 alkylene)-O-(C _1-6 haloalkyl), -(C _1-6 alkylene)-N(R ⁶ )(R ⁷ ), -(C _1-6 alkylene)-O-C(O)(R ¹⁹ ), -(C _1-6 alkylene)-(C _1-4 alkynyl), -(C _1-6 alkylene)-O-(C _1-4 alkynyl), or deuterium. In certain embodiments, R ⁹ is –(C _1-6 alkylene)-(C _1-6 alkoxyl). In certain embodiments, R ⁹ is –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is -C(O)N(R ⁶ )(R ⁷ ), -C(O)N(R ⁶ )(R ¹³ ), -(C _0-6 alkylene)-N(R ⁶ )C(O)(R ¹⁴ ), -(C _0-6 alkylene)- (N(R ¹⁵ )S(O)(N(C _1-4 alkyl))-C _1-4 alkyl), or –(C _0-6 alkylene)-(S(O)(NH)-(C _1-4 alkyl)). In certain embodiments, R ⁹ is C _1-6 alkoxyl. In certain embodiments, R ⁹ is -C(O)N(R ⁶ )(R ⁷ ). In certain embodiments, R ⁹ is -C(O)N(R ⁶ )(R ¹³ ). In certain embodiments, R ⁹ is -(C _0-6 alkylene)-S(O) ₂ R ¹⁸ . In certain embodiments, R ⁹ is -(C _0-6 alkylene)-S(O)(=NR ¹⁵ )R ¹⁸ . In certain embodiments, R ⁹ is - (C _0-6 alkylene)-S(O)(=NH)R ¹⁸ . In certain embodiments, R ⁹ is -S(O) ₂ N(R ⁶ )(R ⁷ ). In certain embodiments, R ⁹ is -(C _0-6 alkylene)-N(R ⁶ )C(O)R ¹⁴ . In certain embodiments, R ⁹ is -(C _0-6 alkylene)-(N(R ¹⁵ )S(O)(N(R ^15A ))-R ¹⁸ ). In certain embodiments, R ⁹ is -(C _0-6 alkylene)- (N(R ¹⁵ )S(O)(N(C _1-4 alkyl))-C _1-4 alkyl). In certain embodiments, R ⁹ is –(C _0-6 alkylene)- (S(O)(NH)-(C _1-4 alkyl)). In certain embodiments, R ⁹ is deuterium. In certain embodiments, R ⁹ is –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, phosphorous, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1 heteroatom selected from oxygen, nitrogen, phosphorous, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 2 heteroatoms selected from oxygen, nitrogen, phosphorous, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 3 heteroatoms selected from oxygen, nitrogen, phosphorous, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). [0181] In certain embodiments, R ⁹ is –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, phosphorous, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is –(C _1-3 alkylene)-(5-6 membered saturated monocyclic heterocyclyl containing 1 or 2 heteroatoms selected from oxygen, nitrogen, phosphorous, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is , each of which is substituted with 0, 1, 2, or 3 instances of R ¹² . In certain embodiments, R ⁹ is . [0182] In certain embodiments, R ⁹ is –(C _1-3 alkylene)-(7-10 membered saturated bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, phosphorous, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is –(C _1-3 alkylene)-(7-10 membered saturated spiro-bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, phosphorous, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is each of which is substituted with 0, 1, 2, or 3 instances of R ¹² . [0183] In certain embodiments, R ⁹ is halo. In certain embodiments, R ⁹ is C _1-6 haloalkyl. In certain embodiments, R ⁹ is cyano. In certain embodiments, R ⁹ is -(C _0-6 alkylene)-P(O)(R ⁶ )(R ⁷ ). In certain embodiments, R ⁹ is -(C _0-6 alkylene)-(3-7 membered saturated monocyclic or bicyclic carbocyclyl). In certain embodiments, R ⁹ is -(C _0-6 alkylene)-O-(3-7 membered saturated monocyclic or bicyclic carbocyclyl, wherein the carbocyclyl is substituted with m occurrences of R ¹² ). In certain embodiments, R ⁹ is -(C _0-6 alkylene)-O-(C _1-6 haloalkyl). In certain embodiments, R ⁹ is -(C _1-6 alkylene)-N(R ⁶ )(R ⁷ ). In certain embodiments, R ⁹ is -(C _1-6 alkylene)- O-C(O)(R ¹⁹ ). In certain embodiments, R ⁹ is -(C _1-6 alkylene)-(C _1-4 alkynyl). In certain embodiments, R ⁹ is -(C _1-6 alkylene)-O-(C _1-4 alkynyl). [0184] In certain embodiments, R ⁹ is selected from the groups depicted in the compounds in Table 1, below. [0185] As defined generally above, R ¹⁰ is a group capable of forming a covalent bond to a sulfhydryl group. In certain embodiments, R ¹⁰ is -N(H)C(O)(C _2-4 alkenyl). In certain embodiments, R ¹⁰ is -N(H)C(O)CH=CH ₂ . In certain embodiments, R ¹⁰ is selected from the groups depicted in the compounds in Table 1, below. [0186] As defined generally above, R ¹¹ is halo, hydroxyl, C _1-6 alkyl, C _1-6 haloalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), C _3-7 cycloalkyl, C _1-6 alkoxyl, or –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ represents independently for each occurrence halo, hydroxyl, C _1-6 alkyl, or C _1-6 haloalkyl. In certain embodiments, R ¹¹ represents independently for each occurrence halo, C _1-6 alkyl, or –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ is halo. In certain embodiments, R ¹¹ is hydroxyl. In certain embodiments, R ¹¹ is C _1-6 alkyl. In certain embodiments, R ¹¹ is C _1-6 haloalkyl. In certain embodiments, R ¹¹ is -(C _1-6 alkylene)- (C _3-7 cycloalkyl). In certain embodiments, R ¹¹ is C _3-7 cycloalkyl. In certain embodiments, R ¹¹ is C _1-6 alkoxyl. In certain embodiments, R ¹¹ is –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ is –(C _0-6 alkylene)-(4-10 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ is –(C _0-6 alkylene)-(4-10 membered saturated bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ is selected from the groups depicted in the compounds in Table 1, below. [0187] As defined generally above, R ¹² represents independently for each occurrence halo, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _3-7 cycloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, -C(O)R ¹⁹ , -C(O)(OH), -O-(C _1-4 haloalkyl), -O-(C _1-4 halohydroxyalkoxyl), or oxo; or two R ¹² groups, taken together with the carbon atom to which they are attached, form a 3-7 membered saturated carbocyclic ring or a 3-7 membered saturated heterocyclic ring containing 1 heteroatom selected from nitrogen and oxygen, wherein the carbocyclic ring and the heterocyclic ring are substituted with 1 or 2 occurrences of R ²⁰ . In certain embodiments, R ¹² represents independently for each occurrence halo, C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, or oxo. In certain embodiments, R ¹² is halo. In certain embodiments, R ¹² is C _1-6 alkyl. In certain embodiments, R ¹² is C ₁ alkyl. In certain embodiments, R ¹² is C ₂ alkyl. In certain embodiments, R ¹² is C ₃ alkyl. In certain embodiments, R ¹² is C ₄ alkyl. In certain embodiments, R ¹² is C ₅ alkyl. In certain embodiments, R ¹² is C ₆ alkyl. In certain embodiments, R ¹² is C _1-6 haloalkyl. In certain embodiments, R ¹² is C _3-7 cycloalkyl. In certain embodiments, R ¹² is C _1-6 alkoxyl. In certain embodiments, R ¹² is C _1-6 haloalkoxyl. In certain embodiments, R ¹² is oxo. In certain embodiments, R ¹² is hydroxy. In certain embodiments, R ¹² is C _1-6 hydroxyalkyl. In certain embodiments, R ¹² is -C(O)R ¹⁹ . [0188] In certain embodiments, R ¹² represents independently for each occurrence halo, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _3-7 cycloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, -C(O)R ¹⁹ , or oxo. In certain embodiments, R ¹² represents independently for each occurrence halo, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _3-7 cycloalkyl, or - C(O)R ¹⁹ . In certain embodiments, R ¹² represents independently for each occurrence C _1-6 alkyl. In certain embodiments, R ¹² represents independently for each occurrence -C(O)(OH). In certain embodiments, R ¹² represents independently for each occurrence -O-(C _1-4 haloalkyl). In certain embodiments, R ¹² represents independently for each occurrence -O-(C _1-4 halohydroxyalkoxyl). In certain embodiments, R ¹² represents independently for each occurrence oxo. In certain embodiments, two R ¹² groups, taken together with the carbon atom to which they are attached, form a 3-7 membered saturated carbocyclic ring or a 3-7 membered saturated heterocyclic ring containing 1 heteroatom selected from nitrogen and oxygen, wherein the carbocyclic ring and the heterocyclic ring are substituted with 1 or 2 occurrences of R ²⁰ . [0189] In certain embodiments, R ¹² is selected from the groups depicted in the compounds in Table 1, below. [0190] As defined generally above, R ¹³ is a 4-7 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 4 membered saturated monocyclic heterocyclyl containing 1 oxygen heteroatom, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 4 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 5 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 6 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 7 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is selected from the groups depicted in the compounds in Table 1, below. [0191] As defined generally above, R ¹⁴ represents independently for each occurrence hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl. In certain embodiments, R ¹⁴ represents independently for each occurrence hydrogen, C _1-6 alkyl, or C _1-6 hydroxyalkyl. In certain embodiments, R ¹⁴ is hydrogen. In certain embodiments, R ¹⁴ is C _1-6 alkyl. In certain embodiments, R ¹⁴ is C _1-6 hydroxyalkyl. In certain embodiments, R ¹⁴ is - (C _1-6 alkylene)-(C _3-7 cycloalkyl). In certain embodiments, R ¹⁴ is C _3-7 cycloalkyl. In certain embodiments, R ¹⁴ is selected from the groups depicted in the compounds in Table 1, below. [0192] As defined generally above, R ¹⁵ and R ^15A are independently hydrogen or C _1-4 alkyl. In certain embodiments, R ¹⁵ and R ^15A are independently hydrogen. In certain embodiments, R ¹⁵ and R ^15A are independently C _1-4 alkyl. In certain embodiments, R ¹⁵ and R ^15A are each C ₁ alkyl. In certain embodiments, R ¹⁵ and R ^15A are each C ₂ alkyl. In certain embodiments, R ¹⁵ and R ^15A are independently C ₃ alkyl. In certain embodiments, R ¹⁵ and R ^15A are independently C ₄ alkyl. In certain embodiments, R ¹⁵ is selected from the groups depicted in the compounds in Table 1, below. [0193] As defined generally above, R ¹⁶ is hydrogen, C _1-4 alkyl, or hydroxyl. In certain embodiments, R ¹⁶ is hydrogen. In certain embodiments, R ¹⁶ is C _1-4 alkyl. In certain embodiments, R ¹⁶ is C ₁ alkyl. In certain embodiments, R ¹⁶ is C ₂ alkyl. In certain embodiments, R ¹⁶ is C ₃ alkyl. In certain embodiments, R ¹⁶ is C ₄ alkyl. In certain embodiments, R ¹⁶ is hydroxyl. In certain embodiments, R ¹⁶ is selected from the groups depicted in the compounds in Table 1, below. [0194] As defined generally above, R ¹⁷ is hydrogen, C _1-4 alkyl, or –(C _2-4 alkylene)-(C _1-4 alkoxyl). In certain embodiments, R ¹⁷ is hydrogen. In certain embodiments, R ¹⁷ is C _1-4 alkyl. In certain embodiments, R ¹⁷ is C ₁ alkyl. In certain embodiments, R ¹⁷ is C ₂ alkyl. In certain embodiments, R ¹⁷ is C ₃ alkyl. In certain embodiments, R ¹⁷ is C ₄ alkyl. In certain embodiments, R ¹⁷ is –(C _2-4 alkylene)-(C _1-4 alkoxyl). In certain embodiments, R ¹⁷ is selected from the groups depicted in the compounds in Table 1, below. [0195] As defined generally above, R ¹⁸ is C _1-4 alkyl, -(C _1-6 alkylene)-C(O) ₂ OH, -(C _1-6 alkylene)-(C _1-6 alkoxyl), or C _3-6 cycloalkyl. In certain embodiments, R ¹⁸ is C _1-4 alkyl. In certain embodiments, R ¹⁸ is C ₁ alkyl. In certain embodiments, R ¹⁸ is C ₂ alkyl. In certain embodiments, R ¹⁸ is C ₃ alkyl. In certain embodiments, R ¹⁸ is C ₄ alkyl. In certain embodiments, R ¹⁸ is C _3-6 cycloalkyl. In certain embodiments, R ¹⁸ is C ₃ cycloalkyl. In certain embodiments, R ¹⁸ is C ₄ cycloalkyl. In certain embodiments, R ¹⁸ is C ₅ cycloalkyl. In certain embodiments, R ¹⁸ is C6 cycloalkyl. In certain embodiments, R ¹⁸ is -(C _1-6 alkylene)-C(O) ₂ OH. In certain embodiments, R ¹⁸ is -(C _1-6 alkylene)-(C _1-6 alkoxyl). In certain embodiments, R ¹⁸ is selected from the groups depicted in the compounds in Table 1, below. [0196] As defined generally above, R ¹⁹ represents independently for each occurrence C _1-6 alkyl, C _3-6 cycloalkyl, or -(C _1-6 alkylene)-(C _3-6 cycloalkyl). In certain embodiments, R ¹⁹ is C _1-6 alkyl. In certain embodiments, R ¹⁹ is methyl. In certain embodiments, R ¹⁹ is ethyl. In certain embodiments, R ¹⁹ is C _3-6 cycloalkyl. In certain embodiments, R ¹⁹ is -(C _1-6 alkylene)-(C _3-6 cycloalkyl). In certain embodiments, R ¹⁹ is selected from the groups depicted in the compounds in Table 1, below. [0197] As defined generally above, R ²⁰ is hydrogen, C _1-4 alkyl, oxo, -(C _0-4 alkylene)-(C _1-6 alkoxyl), -C(O)-(C _1-4 alkyl), or C _3-7 cycloalkyl. In certain embodiments, R ²⁰ is hydrogen. In certain embodiments, R ²⁰ is C _1-4 alkyl. In certain embodiments, R ²⁰ is -CH ₃ . In certain embodiments, R ²⁰ is -CH ₂ CH ₃ . In certain embodiments, R ²⁰ is -CH ₂ CH ₂ CH ₃ . In certain embodiments, R ²⁰ is -CH(CH ₃ ) ₂ . In certain embodiments, R ²⁰ is -(C _0-4 alkylene)-(C _1-6 alkoxyl). In certain embodiments, R ²⁰ is (C _1-6 alkoxyl). In certain embodiments, R ²⁰ is -C(O)-(C _1-4 alkyl). In certain embodiments, R ²⁰ is -C(O)CH ₃ . In certain embodiments, In certain embodiments, R ²⁰ is -C(O)CH ₂ CH ₃ . In certain embodiments, R ²⁰ is C _3-7 cycloalkyl. In certain embodiments, R ²⁰ is cyclopropyl. In certain embodiments, R ²⁰ is cyclobutyl. In certain embodiments, R ²⁰ is cyclopentyl. In certain embodiments, R ²⁰ is cyclohexyl. In certain embodiments, R ²⁰ is cycloheptyl. In certain embodiments, R ²⁰ is selected from the groups depicted in the compounds in Table 1, below. [0198] As defined generally above, X is -N(R ¹⁷ )-, -O-, or -CH ₂ -. In certain embodiments, X is -N(R ¹⁷ )-. In certain embodiments, X is -O-. In certain embodiments, X is -CH ₂ -. In certain embodiments, X is selected from the groups depicted in the compounds in Table 1, below. [0199] As defined generally above, m and p are independently 0, 1, or 2. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, n, t, and p are independently 0, 1, or 2. [0200] As defined generally above, n is 0, 1, 2, or 3. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. [0201] As defined generally above, t is 0, 1, 2, 3, 4, or 6. In certain embodiments, t is 0. In certain embodiments, t is 1. In certain embodiments, t is 2. In certain embodiments, t is 3. In certain embodiments, t is 4. In certain embodiments, t is 5. In certain embodiments, t is 6. In certain embodiments, t is 1, 2, or 3. In certain embodiments, t is 2, 3, or 4. [0202] The description above describes multiple embodiments relating to compounds of Formula I-2. The patent application specifically contemplates all combinations of the embodiments. [0203] In certain embodiments, the compound of Formula I-2 is further defined by Formula I- 2a: or a pharmaceutically acceptable salt thereof. In certain embodiments, the definition of variable R ⁵ is one of the embodiments described above in connection with Formula I-2. [0204] In certain embodiments, the compound of Formula I-2 is further defined by Formula I- 2b: or a pharmaceutically acceptable salt thereof. In certain embodiments, the definition of variable R ⁵ is one of the embodiments described above in connection with Formula I-2. [0205] In certain embodiments, the compound of Formula I-2 is further defined by Formula I- 2c, Id, or Ie: I-2c I-2d I-2e or a pharmaceutically acceptable salt thereof. In certain embodiments, the definition of variables R ⁵ , R ⁶ , R ⁷ , and R ¹⁰ is one of the embodiments described above in connection with Formula I-2. [0206] In certain embodiments, the compound of Formula I-2 is further defined by Formula I- 2f: or a pharmaceutically acceptable salt thereof. In certain embodiments, the definition of variable R ⁵ is one of the embodiments described above in connection with Formula I-2. [0207] In certain embodiments, the compound of Formula I-2 is further defined by Formula I- 2h: I-2h or a pharmaceutically acceptable salt thereof, wherein q is 0, 1, or 2. In certain embodiments, the definition of variables R ⁵ and R ²⁰ is one of the embodiments described above in connection with Formula I-2. [0208] In certain embodiments, the compound of Formula I-2 is further defined by Formula I- 2i or Ij: or a pharmaceutically acceptable salt thereof, wherein q is 0, 1, or 2. In certain embodiments, the definition of variables R ⁵ and R ²⁰ is one of the embodiments described above in connection with Formula I-2. [0209] In certain embodiments, the compound of Formula I-2 is further defined by Formula I- 2k or Il: or a pharmaceutically acceptable salt thereof, wherein q is 0, 1, or 2. In certain embodiments, the definition of variables R ⁵ and R ²⁰ is one of the embodiments described above in connection with Formula I-2. [0210] In certain embodiments, the compound of Formula I-2 is further defined by one of Formulae Im, In, or Io: or a pharmaceutically acceptable salt thereof, wherein q is 0, 1, or 2. In certain embodiments, the definition of variables R ⁵ and R ²⁰ is one of the embodiments described above in connection with Formula I-2. [0211] In certain embodiments, the compound of Formula I-2 is further defined by one of Formulae I-2p, I-2q, or I-12r: or a pharmaceutically acceptable salt thereof, wherein q is 0, 1, or 2. In certain embodiments, the definition of variables R ⁵ and R ²⁰ is one of the embodiments described above in connection with Formula I-2. [0212] Another aspect of the invention provides a compound represented by Formula II: or a pharmaceutically acceptable salt thereof, wherein: R ¹ and R ³ are independently hydrogen, C _1-4 alkyl, or C _3-4 cycloalkyl; R ² is C _1-4 alkyl, C _1-4 hydroxyalkyl, -C(O)N(R ⁶ )(R ⁷ ), or hydrogen; R ⁴ is hydrogen, C _1-4 alkyl, or -C(O)N(R ⁶ )(R ⁷ ); or R ⁴ and R ³ are taken together to form oxo; , each of which is substituted with n occurrences of R ⁹ ; (ii) phenyl or 6-membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatoms are nitrogen atoms, where the phenyl and heteroaryl are substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; or (iii) 6-membered monocyclic, unsaturated oxo- heterocyclyl containing 1 or 2 nitrogen atoms, wherein the oxo-heterocyclyl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; R ⁶ and R ⁷ are independently hydrogen, C _1-6 alkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; or R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom; R ⁸ is hydrogen, C _1-4 alkyl, or -(C _2-4 alkylene)-(C _1-4 alkoxyl); R ⁹ is -(C _1-6 alkylene)-(C _1-6 alkoxyl), C _1-6 alkoxyl, -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ), - C(O)N(R ⁶ )(R ⁷ ), -C(O)N(R ⁶ )(R ¹³ ), -S(O) ₂ R ¹⁸ , -S(O)(=NH)R ¹⁸ , -S(O) ₂ N(R ⁶ )(R ⁷ ), -(C _0-6 alkylene)-N(R ⁶ )C(O)R ¹⁴ , -(C _0-6 alkylene)-(N(R ¹⁵ )S(O)(N(C _1-4 alkyl))-C _1-4 alkyl), -(C _0-6 alkylene)-(S(O)(NH)-(C _1-4 alkyl)), or deuterium; R ¹⁰ is a group capable of forming a covalent bond to a sulfhydryl group; R ¹¹ is halo, hydroxyl, C _1-6 alkyl, C _1-6 haloalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), C _3-7 cycloalkyl, C _1-6 alkoxyl, or -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ); R ¹² represents independently for each occurrence halo, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _3-7 cycloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, -C(O)R ¹⁹ , or oxo; R ¹³ is a 4-7 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ ; R ¹⁴ represents independently for each occurrence hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; R ¹⁵ is hydrogen or C _1-4 alkyl; R ¹⁶ is hydrogen, C _1-4 alkyl, or hydroxyl; R ¹⁷ is hydrogen, C _1-4 alkyl, or -(C _2-4 alkylene)-(C _1-4 alkoxyl); R ¹⁸ is C _1-4 alkyl or C _3-6 cycloalkyl; R ¹⁹ represents independently for each occurrence C _1-6 alkyl, C _3-6 cycloalkyl, or -(C _1-6 alkylene)-(C _3-6 cycloalkyl); X is -N(R ¹⁷ )-, -O-, or -CH ₂ ; and n, and p are independently 0, 1, or 2; and t is 0, 1, 2, 3, 4, 5, or 6. [0213] The definitions of variables in Formula II 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). [0214] In certain embodiments, the compound is a compound of Formula II. [0215] As defined generally above, R ¹ and R ³ are independently hydrogen, C _1-4 alkyl, or C _3-4 cycloalkyl. In certain embodiments, R ¹ and R ³ are hydrogen. In certain embodiments, R ¹ is hydrogen. In certain embodiments, R ¹ is C _1-4 alkyl. In certain embodiments, R ¹ is C ₁ alkyl. In certain embodiments, R ¹ is C ₂ alkyl. In certain embodiments, R ¹ is C ₃ alkyl. In certain embodiments, R ¹ is C ₄ alkyl. In certain embodiments, R ¹ is C _3-4 cycloalkyl. In certain embodiments, R ¹ is C ₃ cycloalkyl. In certain embodiments, R ¹ is C ₄ cycloalkyl. In certain embodiments, R ³ is hydrogen. In certain embodiments, R ³ is C _1-4 alkyl. In certain embodiments, R ³ is C ₁ alkyl. In certain embodiments, R ³ is C ₂ alkyl. In certain embodiments, R ³ is C ₃ alkyl. In certain embodiments, R ³ is C ₄ alkyl. In certain embodiments, R ³ is C _3-4 cycloalkyl. In certain embodiments, R ³ is C ₃ cycloalkyl. In certain embodiments, R ³ is C ₄ cycloalkyl. In certain embodiments, R ¹ is selected from the groups depicted in the compounds in Table 1, below. In certain embodiments, R ³ is selected from the groups depicted in the compounds in Table 1, below. [0216] As defined generally above, R ² is C _1-4 alkyl, C _1-4 hydroxyalkyl, -C(O)N(R ⁶ )(R ⁷ ), or hydrogen. In certain embodiments, R ² is C _1-4 alkyl. In certain embodiments, R ² is -CH ₃ . In certain embodiments, R ² is C _1-4 hydroxyalkyl. In certain embodiments, R ² is -C(O)N(R ⁶ )(R ⁷ ). In certain embodiments, R ² is hydrogen. In certain embodiments, R ² is C ₂ alkyl. In certain embodiments, R ² is C ₃ alkyl. In certain embodiments, R ² is C ₄ alkyl. In certain embodiments, R ² is selected from the groups depicted in the compounds in Table 1, below. [0217] As defined generally above, R ⁴ is hydrogen, C _1-4 alkyl, or -C(O)N(R ⁶ )(R ⁷ ); or R ⁴ and R ³ are taken together to form oxo. In certain embodiments, R ⁴ is hydrogen. In certain embodiments, R ⁴ is -C(O)N(R ⁶ )(R ⁷ ). In certain embodiments, R ⁴ and R ³ are taken together to form oxo. In certain embodiments, R ⁴ is C _1-4 alkyl. In certain embodiments, R ⁴ is selected from the groups depicted in the compounds in Table 1, below. substituted with n occurrences of R ⁹ ; (ii) phenyl or 6-membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatom(s) are nitrogen, and wherein the phenyl and heteroaryl are substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; or (iii) 6-membered monocyclic, unsaturated oxo-heterocyclyl containing 1 or 2 heteroatoms, wherein the heteroatoms are nitrogen, and the oxo-heterocyclyl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . occurrences of R ⁹ ; (ii) phenyl or 6-membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatom(s) are nitrogen, and wherein the phenyl and heteroaryl are substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, , e , . [0220] In certain embodiments, substituted with n occurrences of R ⁹ . [0221] In certain embodiments, substituted with n occurrences of R ⁹ . In certain embodiments, R ⁵ is phenyl or 6-membered heteroaryl containing 1 heteroatoms, wherein the heteroatoms are nitrogen atoms, wherein the phenyl and heteroaryl are substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is phenyl substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is a 6-membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatoms are nitrogen atoms, and the heteroaryl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is a pyridinyl substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is a 6-membered monocyclic, unsaturated oxo-heterocyclyl containing 1 or 2 heteroatoms, wherein the heteroatoms are nitrogen atoms, and the heterocyclyl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is , each of which is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is , each of which is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, . embodiments, , which substituted with n occurrences of R ⁹ . In certain embodiments, , which is substituted with n occurrences of R ⁹ . In certain embodiments, , which is substituted with n occurrences of R ⁹ . In certain embodiments, , which is substituted with n occurrences of R ⁹ . In certain embodiments, , which is substituted with n occurrences of R ⁹ . In certain embodiments, , which is substituted with n occurrences of R ⁹ . In certain embodiments, , which is substituted with n occurrences of R ⁹ . In certain embodiments, substituted with n occurrences of R ⁹ . In certain embodiments, substituted with n occurrences of R ⁹ . In certain embodiments, R ⁵ is selected from the groups depicted in the compounds in Table 1, below. [0222] As defined generally above, R ⁶ and R ⁷ are independently hydrogen, C _1-6 alkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; or R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ are independently hydrogen or C _1-6 alkyl. In certain embodiments, R ⁶ is hydrogen. In certain embodiments, R ⁶ is C _1-6 alkyl. In certain embodiments, R ⁶ is -(C _1-6 alkylene)-(C _3-7 cycloalkyl), In certain embodiments, R ⁶ is C _3-7 cycloalkyl. In certain embodiments, R ⁷ is hydrogen. In certain embodiments, R ⁷ is C _1-6 alkyl. In certain embodiments, R ⁷ is -(C _1-6 alkylene)-(C _3-7 cycloalkyl), In certain embodiments, R ⁷ is C _3-7 cycloalkyl. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 4 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 5 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 6 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 7 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ is selected from the groups depicted in the compounds in Table 1, below. In certain embodiments, R ⁷ is selected from the groups depicted in the compounds in Table 1, below. [0223] As defined generally above, R ⁸ is hydrogen, C _1-4 alkyl, or –(C _2-4 alkylene)-(C _1-4 alkoxyl). In certain embodiments, R ⁸ is hydrogen. In certain embodiments, R ⁸ is C _1-4 alkyl. In certain embodiments, R ⁸ is C ₁ alkyl. In certain embodiments, R ⁸ is C ₂ alkyl. In certain embodiments, R ⁸ is C ₃ alkyl. In certain embodiments, R ⁸ is C ₄ alkyl. In certain embodiments, R ⁸ is –(C _2-4 alkylene)-(C _1-4 alkoxyl). In certain embodiments, R ⁸ is selected from the groups depicted in the compounds in Table 1, below. [0224] As defined generally above, R ⁹ is –(C _1-6 alkylene)-(C _1-6 alkoxyl), C _1-6 alkoxyl, -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ), -C(O)N(R ⁶ )(R ⁷ ), -C(O)N(R ⁶ )(R ¹³ ), -S(O) ₂ R ¹⁸ , -S(O)(=NH)R ¹⁸ , - S(O) ₂ N(R ⁶ )(R ⁷ ), -(C _0-6 alkylene)-N(R ⁶ )C(O)R ¹⁴ , -(C _0-6 alkylene)-(N(R ¹⁵ )S(O)(N(C _1-4 alkyl))- C _1-4 alkyl), -(C _0-6 alkylene)-(S(O)(NH)-(C _1-4 alkyl)), or deuterium. In certain embodiments, R ⁹ is –(C _1-6 alkylene)-(C _1-6 alkoxyl). In certain embodiments, R ⁹ is –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is -C(O)N(R ⁶ )(R ⁷ ), -C(O)N(R ⁶ )(R ¹³ ), -(C _0-6 alkylene)-N(R ⁶ )C(O)(R ¹⁴ ), -(C _0-6 alkylene)-(N(R ¹⁵ )S(O)(N(C _1-4 alkyl))-C _1-4 alkyl), or –(C _0-6 alkylene)-(S(O)(NH)-(C _1-4 alkyl)). In certain embodiments, R ⁹ is C _1-6 alkoxyl. In certain embodiments, R ⁹ is -C(O)N(R ⁶ )(R ⁷ ). In certain embodiments, R ⁹ is -C(O)N(R ⁶ )(R ¹³ ). In certain embodiments, R ⁹ is -S(O) ₂ R ¹⁸ . In certain embodiments, R ⁹ is -S(O)(=NH)R ¹⁸ . In certain embodiments, R ⁹ is -S(O) ₂ N(R ⁶ )(R ⁷ ). In certain embodiments, R ⁹ is -(C _0-6 alkylene)- N(R ⁶ )C(O)R ¹⁴ . In certain embodiments, R ⁹ is -(C _0-6 alkylene)-(N(R ¹⁵ )S(O)(N(C _1-4 alkyl))-C _1-4 alkyl). In certain embodiments, R ⁹ is –(C _0-6 alkylene)-(S(O)(NH)-(C _1-4 alkyl)). In certain embodiments, R ⁹ is deuterium. In certain embodiments, R ⁹ is -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1 heteroatom selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 2 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). [0225] In certain embodiments, R ⁹ is –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is –(C _1-3 alkylene)-(5-6 membered saturated monocyclic heterocyclyl containing 1 or 2 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, [0226] In certain embodiments, R ⁹ is –(C _1-3 alkylene)-(7-10 membered saturated bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is – (C _1-3 alkylene)-(7-10 membered saturated spiro-bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is , , each of which is substituted with 0, 1, 2, or 3 instances of R ¹² . [0227] In certain embodiments, R ⁹ is selected from the groups depicted in the compounds in Table 1, below. [0228] As defined generally above, R ¹⁰ is a group capable of forming a covalent bond to a sulfhydryl group. In certain embodiments, R ¹⁰ is -N(H)C(O)(C _2-4 alkenyl). In certain embodiments, R ¹⁰ is -N(H)C(O)CH=CH ₂ . In certain embodiments, R ¹⁰ is selected from the groups depicted in the compounds in Table 1, below. [0229] As defined generally above, R ¹¹ is halo, hydroxyl, C _1-6 alkyl, C _1-6 haloalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), C _3-7 cycloalkyl, C _1-6 alkoxyl, or –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ represents independently for each occurrence halo, hydroxyl, C _1-6 alkyl, or C _1-6 haloalkyl. In certain embodiments, R ¹¹ represents independently for each occurrence halo, C _1-6 alkyl, or –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ is halo. In certain embodiments, R ¹¹ is hydroxyl. In certain embodiments, R ¹¹ is C _1-6 alkyl. In certain embodiments, R ¹¹ is C _1-6 haloalkyl. In certain embodiments, R ¹¹ is -(C _1-6 alkylene)- (C _3-7 cycloalkyl). In certain embodiments, R ¹¹ is C _3-7 cycloalkyl. In certain embodiments, R ¹¹ is C _1-6 alkoxyl. In certain embodiments, R ¹¹ is –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ is –(C _0-6 alkylene)-(4-10 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ is –(C _0-6 alkylene)-(4-10 membered saturated bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ is selected from the groups depicted in the compounds in Table 1, below. [0230] As defined generally above, R ¹² represents independently for each occurrence halo, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _3-7 cycloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, -C(O)R ¹⁹ , or oxo. In certain embodiments, R ¹² represents independently for each occurrence halo, C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, or oxo. In certain embodiments, R ¹² is halo. In certain embodiments, R ¹² is C _1-6 alkyl. In certain embodiments, R ¹² is C ₁ alkyl. In certain embodiments, R ¹² is C ₂ alkyl. In certain embodiments, R ¹² is C ₃ alkyl. In certain embodiments, R ¹² is C ₄ alkyl. In certain embodiments, R ¹² is C ₅ alkyl. In certain embodiments, R ¹² is C ₆ alkyl. In certain embodiments, R ¹² is C _1-6 haloalkyl. In certain embodiments, R ¹² is C _3-7 cycloalkyl. In certain embodiments, R ¹² is C _1-6 alkoxyl. In certain embodiments, R ¹² is C _1-6 haloalkoxyl. In certain embodiments, R ¹² is oxo. In certain embodiments, R ¹² is hydroxy. In certain embodiments, R ¹² is C _1-6 hydroxyalkyl. In certain embodiments, R ¹² is -C(O)R ¹⁹ . [0231] In certain embodiments, R ¹² represents independently for each occurrence halo, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _3-7 cycloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, -C(O)R ¹⁹ , or oxo. In certain embodiments, R ¹² represents independently for each occurrence halo, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _3-7 cycloalkyl, or - C(O)R ¹⁹ . In certain embodiments, R ¹² represents independently for each occurrence C _1-6 alkyl. [0232] In certain embodiments, R ¹² is selected from the groups depicted in the compounds in Table 1, below. [0233] As defined generally above, R ¹³ is a 4-7 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 4 membered saturated monocyclic heterocyclyl containing 1 oxygen heteroatom, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 4 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 5 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 6 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 7 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is selected from the groups depicted in the compounds in Table 1, below. [0234] As defined generally above, R ¹⁴ represents independently for each occurrence hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl. In certain embodiments, R ¹⁴ represents independently for each occurrence hydrogen, C _1-6 alkyl, or C _1-6 hydroxyalkyl. In certain embodiments, R ¹⁴ is hydrogen. In certain embodiments, R ¹⁴ is C _1-6 alkyl. In certain embodiments, R ¹⁴ is C _1-6 hydroxyalkyl. In certain embodiments, R ¹⁴ is - (C _1-6 alkylene)-(C _3-7 cycloalkyl). In certain embodiments, R ¹⁴ is C _3-7 cycloalkyl. In certain embodiments, R ¹⁴ is selected from the groups depicted in the compounds in Table 1, below. [0235] As defined generally above, R ¹⁵ is hydrogen or C _1-4 alkyl. In certain embodiments, R ¹⁵ is hydrogen. In certain embodiments, R ¹⁵ is C _1-4 alkyl. In certain embodiments, R ¹⁵ is C ₁ alkyl. In certain embodiments, R ¹⁵ is C ₂ alkyl. In certain embodiments, R ¹⁵ is C ₃ alkyl. In certain embodiments, R ¹⁵ is C ₄ alkyl. In certain embodiments, R ¹⁵ is selected from the groups depicted in the compounds in Table 1, below. [0236] As defined generally above, R ¹⁶ is hydrogen, C _1-4 alkyl, or hydroxyl. In certain embodiments, R ¹⁶ is hydrogen. In certain embodiments, R ¹⁶ is C _1-4 alkyl. In certain embodiments, R ¹⁶ is C ₁ alkyl. In certain embodiments, R ¹⁶ is C ₂ alkyl. In certain embodiments, R ¹⁶ is C ₃ alkyl. In certain embodiments, R ¹⁶ is C ₄ alkyl. In certain embodiments, R ¹⁶ is hydroxyl. In certain embodiments, R ¹⁶ is selected from the groups depicted in the compounds in Table 1, below. [0237] As defined generally above, R ¹⁷ is hydrogen, C _1-4 alkyl, or –(C _2-4 alkylene)-(C _1-4 alkoxyl). In certain embodiments, R ¹⁷ is hydrogen. In certain embodiments, R ¹⁷ is C _1-4 alkyl. In certain embodiments, R ¹⁷ is C ₁ alkyl. In certain embodiments, R ¹⁷ is C ₂ alkyl. In certain embodiments, R ¹⁷ is C ₃ alkyl. In certain embodiments, R ¹⁷ is C ₄ alkyl. In certain embodiments, R ¹⁷ is –(C _2-4 alkylene)-(C _1-4 alkoxyl). In certain embodiments, R ¹⁷ is selected from the groups depicted in the compounds in Table 1, below. [0238] As defined generally above, R ¹⁸ is C _1-4 alkyl or C _3-6 cycloalkyl. In certain embodiments, R ¹⁸ is C _1-4 alkyl. In certain embodiments, R ¹⁸ is C ₁ alkyl. In certain embodiments, R ¹⁸ is C ₂ alkyl. In certain embodiments, R ¹⁸ is C ₃ alkyl. In certain embodiments, R ¹⁸ is C ₄ alkyl. In certain embodiments, R ¹⁸ is C _3-6 cycloalkyl. In certain embodiments, R ¹⁸ is C ₃ cycloalkyl. In certain embodiments, R ¹⁸ is C ₄ cycloalkyl. In certain embodiments, R ¹⁸ is C ₅ cycloalkyl. In certain embodiments, R ¹⁸ is C ₆ cycloalkyl. In certain embodiments, R ¹⁸ is selected from the groups depicted in the compounds in Table 1, below. [0239] As defined generally above, R ¹⁹ represents independently for each occurrence C _1-6 alkyl, C _3-6 cycloalkyl, or -(C _1-6 alkylene)-(C _3-6 cycloalkyl). In certain embodiments, R ¹⁹ is C _1-6 alkyl. In certain embodiments, R ¹⁹ is methyl. In certain embodiments, R ¹⁹ is ethyl. In certain embodiments, R ¹⁹ is C _3-6 cycloalkyl. In certain embodiments, R ¹⁹ is -(C _1-6 alkylene)-(C _3-6 cycloalkyl). In certain embodiments, R ¹⁹ is selected from the groups depicted in the compounds in Table 1, below. [0240] As defined generally above, X is -N(R ¹⁷ )-, -O-, or -CH ₂ -. In certain embodiments, X is -N(R ¹⁷ )-. In certain embodiments, X is -O-. In certain embodiments, X is -CH ₂ -. In certain embodiments, X is selected from the groups depicted in the compounds in Table 1, below. [0241] As defined generally above, n, and p are independently 0, 1, or 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, n, t, and p are independently 0, 1, or 2. [0242] As defined generally above, t is 0, 1, 2, 3, 4, or 6. In certain embodiments, t is 0. In certain embodiments, t is 1. In certain embodiments, t is 2. In certain embodiments, t is 3. In certain embodiments, t is 4. In certain embodiments, t is 5. In certain embodiments, t is 6. In certain embodiments, t is 1, 2, or 3. In certain embodiments, t is 2, 3, or 4. [0243] The description above describes multiple embodiments relating to compounds of Formula II. The patent application specifically contemplates all combinations of the embodiments. [0244] In certain embodiments, the compound of Formula I is further defined by Formula IIa: IIa or a pharmaceutically acceptable salt thereof. In certain embodiments, the definition of variable R ⁵ is one of the embodiments described above in connection with Formula II. [0245] In certain embodiments, the compound of Formula II is further defined by Formula IIb: IIb or a pharmaceutically acceptable salt thereof. In certain embodiments, the definition of variable R ⁵ is one of the embodiments described above in connection with Formula II. [0246] In certain embodiments, the compound of Formula II is further defined by Formula IIc, IId, or IIe: IIe or a pharmaceutically acceptable salt thereof. In certain embodiments, the definition of variables R ⁵ , R ⁶ , R ⁷ , and R ¹⁰ is one of the embodiments described above in connection with Formula II. [0247] In certain embodiments, the compound of Formula II is further defined by Formula IIf: IIf or a pharmaceutically acceptable salt thereof. In certain embodiments, the definition of variable R ⁵ is one of the embodiments described above in connection with Formula II. [0248] Another aspect of the invention provides a compound represented by Formula II-A: or a pharmaceutically acceptable salt thereof, wherein: R ¹ and R ³ are independently hydrogen, C _1-4 alkyl, or C _3-4 cycloalkyl; R ² is C _1-4 alkyl, C _1-4 hydroxyalkyl, -C(O)N(R ⁶ )(R ⁷ ), or hydrogen; R ⁴ is hydrogen, C _1-4 alkyl, or -C(O)N(R ⁶ )(R ⁷ ); or R ⁴ and R ³ are taken together to form oxo; of which is substituted with n occurrences of R ⁹ ; (ii) phenyl or 6-membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatoms are nitrogen atoms, where the phenyl and heteroaryl are substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; or (iii) 6- membered monocyclic, unsaturated oxo-heterocyclyl containing 1 or 2 heteroatoms, wherein the heteroatoms are nitrogen atom, and the heterocyclyl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; R ⁶ and R ⁷ are independently hydrogen, C _1-6 alkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; or R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom; R ⁸ , R ¹⁵ , and R ¹⁷ are independently hydrogen or C _1-4 alkyl; R ⁹ is –(C _1-6 alkylene)-(C _1-6 alkoxyl), C _1-6 alkoxyl, -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ), - C(O)N(R ⁶ )(R ⁷ ), -C(O)N(R ⁶ )(R ¹³ ), -(C _0-6 alkylene)-N(R ⁶ )C(O)(R ¹⁴ ), -(C _0-6 alkylene)- (N(R ¹⁵ )S(O)(N(C _1-4 alkyl))-C _1-4 alkyl), -(C _0-6 alkylene)-(S(O)(NH)-(C _1-4 alkyl)), or deuterium; R ¹⁰ is a group capable of forming a covalent bond to a sulfhydryl group; R ¹¹ is halo, hydroxyl, C _1-6 alkyl, C _1-6 haloalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), C _3-7 cycloalkyl, C _1-6 alkoxyl, or –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ); R ¹² represents independently for each occurrence halo, C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl, or C _1-6 alkoxyl; R ¹³ is a 4-7 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ ; R ¹⁴ represents independently for each occurrence hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; R ¹⁶ is hydrogen, C _1-4 alkyl, or hydroxyl; n and p are independently 0, 1, or 2; and t is 0, 1, 2, 3, 4, 5, or 6. [0249] The definitions of variables in Formula II-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). [0250] In certain embodiments, the compound is a compound of Formula II-A. [0251] As defined generally above, R ¹ and R ³ are independently hydrogen, C _1-4 alkyl, or C _3-4 cycloalkyl. In certain embodiments, R ¹ and R ³ are hydrogen. In certain embodiments, R ¹ is hydrogen. In certain embodiments, R ¹ is C _1-4 alkyl. In certain embodiments, R ¹ is C ₁ alkyl. In certain embodiments, R ¹ is C ₂ alkyl. In certain embodiments, R ¹ is C ₃ alkyl. In certain embodiments, R ¹ is C ₄ alkyl. In certain embodiments, R ¹ is C _3-4 cycloalkyl. In certain embodiments, R ¹ is C ₃ cycloalkyl. In certain embodiments, R ¹ is C ₄ cycloalkyl. In certain embodiments, R ³ is hydrogen. In certain embodiments, R ³ is C _1-4 alkyl. In certain embodiments, R ³ is C ₁ alkyl. In certain embodiments, R ³ is C ₂ alkyl. In certain embodiments, R ³ is C ₃ alkyl. In certain embodiments, R ³ is C ₄ alkyl. In certain embodiments, R ³ is C _3-4 cycloalkyl. In certain embodiments, R ³ is C ₃ cycloalkyl. In certain embodiments, R ³ is C ₄ cycloalkyl. In certain embodiments, R ¹ is selected from the groups depicted in the compounds in Table 1, below. In certain embodiments, R ³ is selected from the groups depicted in the compounds in Table 1, below. [0252] As defined generally above, R ² is C _1-4 alkyl, C _1-4 hydroxyalkyl, -C(O)N(R ⁶ )(R ⁷ ), or hydrogen. In certain embodiments, R ² is C _1-4 alkyl. In certain embodiments, R ² is -CH ₃ . In certain embodiments, R ² is C _1-4 hydroxyalkyl. In certain embodiments, R ² is -C(O)N(R ⁶ )(R ⁷ ). In certain embodiments, R ² is hydrogen. In certain embodiments, R ² is C ₂ alkyl. In certain embodiments, R ² is C ₃ alkyl. In certain embodiments, R ² is C ₄ alkyl. In certain embodiments, R ² is selected from the groups depicted in the compounds in Table 1, below. [0253] As defined generally above, R ⁴ is hydrogen, C _1-4 alkyl, or -C(O)N(R ⁶ )(R ⁷ ); or R ⁴ and R ³ are taken together to form oxo. In certain embodiments, R ⁴ is hydrogen. In certain embodiments, R ⁴ is -C(O)N(R ⁶ )(R ⁷ ). In certain embodiments, R ⁴ and R ³ are taken together to form oxo. In certain embodiments, R ⁴ is C _1-4 alkyl. In certain embodiments, R ⁴ is selected from the groups depicted in the compounds in Table 1, below. , each of which is substituted with n occurrences of R ⁹ ; (ii) phenyl or 6-membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatom(s) are nitrogen, and wherein the phenyl and heteroaryl are substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; or (iii) 6-membered monocyclic, unsaturated oxo-heterocyclyl containing 1 or 2 heteroatoms, wherein the heteroatom(s) are nitrogen, and the oxo-heterocyclyl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is c , . embodiments, substituted with n occurrences of R ⁹ . In certain embodiments, , each of which is substituted with n occurrences of R ⁹ . [0255] In certain embodiments, R ⁹ is –(C _1-3 alkylene)-(5-6 membered saturated monocyclic heterocyclyl containing 1 or 2 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is , each of which is substituted with 0, 1, 2, or 3 instances of R ¹² . In certain embodiments, R ⁹ is – (C _1-3 alkylene)-(7-10 membered saturated bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is –(C _1-3 alkylene)-(7-10 membered saturated spiro-bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, , each of which is substituted with 0, 1, 2, or 3 instances of R ¹² . [0256] In certain embodiments, R ⁵ is phenyl or 6-membered heteroaryl containing 1 or 2 heteroatom(s), wherein the heteroatom(s) are nitrogen atom, and the phenyl and heteroaryl are substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is phenyl substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is a 6-membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatoms are nitrogen atom, and the heteroaryl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is a pyridinyl substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is a 6-membered monocyclic, unsaturated oxo- heterocyclyl containing 1 or 2 nitrogen atoms, wherein the heterocyclyl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, , each of which is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, , each of which is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, , which substituted with n occurrences of R ⁹ . In certain embodiments, , which is substituted with n occurrences of R ⁹ . In certain embodiments, , which is substituted with n occurrences of R ⁹ . In certain embodiments, , which is substituted with n occurrences of R ⁹ . In certain embodiments, , which is substituted with n occurrences of R ⁹ . In certain embodiments, R ⁵ is selected from the groups depicted in the compounds in Table 1, below. [0257] As defined generally above, R ⁶ and R ⁷ are independently hydrogen, C _1-6 alkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; or R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ are independently hydrogen or C _1-6 alkyl. In certain embodiments, R ⁶ is hydrogen. In certain embodiments, R ⁶ is C _1-6 alkyl. In certain embodiments, R ⁶ is -(C _1-6 alkylene)-(C _3-7 cycloalkyl), In certain embodiments, R ⁶ is C _3-7 cycloalkyl. In certain embodiments, R ⁷ is hydrogen. In certain embodiments, R ⁷ is C _1-6 alkyl. In certain embodiments, R ⁷ is -(C _1-6 alkylene)-(C _3-7 cycloalkyl), In certain embodiments, R ⁷ is C _3-7 cycloalkyl. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 4 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 5 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 6 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 7 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ is selected from the groups depicted in the compounds in Table 1, below. In certain embodiments, R ⁷ is selected from the groups depicted in the compounds in Table 1, below. [0258] As defined generally above, R ⁸ , R ¹⁵ , and R ¹⁷ are independently hydrogen or C _1-4 alkyl. In certain embodiments, R ⁸ is hydrogen. In certain embodiments, R ⁸ is C _1-4 alkyl. In certain embodiments, R ⁸ is C ₁ alkyl. In certain embodiments, R ⁸ is C ₂ alkyl. In certain embodiments, R ⁸ is C ₃ alkyl. In certain embodiments, R ⁸ is C ₄ alkyl. In certain embodiments, R ¹⁵ is hydrogen. In certain embodiments, R ¹⁵ is C _1-4 alkyl. In certain embodiments, R ¹⁵ is C ₁ alkyl. In certain embodiments, R ¹⁵ is C ₂ alkyl. In certain embodiments, R ¹⁵ is C ₃ alkyl. In certain embodiments, R ¹⁵ is C ₄ alkyl. In certain embodiments, R ¹⁷ is hydrogen. In certain embodiments, R ¹⁷ is C _1-4 alkyl. In certain embodiments, R ¹⁷ is C ₁ alkyl. In certain embodiments, R ¹⁷ is C ₂ alkyl. In certain embodiments, R ¹⁷ is C ₃ alkyl. In certain embodiments, R ¹⁷ is C ₄ alkyl. In certain embodiments, R ⁸ is selected from the groups depicted in the compounds in Table 1, below. In certain embodiments, R ¹⁵ is selected from the groups depicted in the compounds in Table 1, below. In certain embodiments, R ¹⁷ is selected from the groups depicted in the compounds in Table 1, below. [0259] As defined generally above, R ⁹ is –(C _1-6 alkylene)-(C _1-6 alkoxyl), C _1-6 alkoxyl, -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ), -C(O)N(R ⁶ )(R ⁷ ), -C(O)N(R ⁶ )(R ¹³ ), -(C _0-6 alkylene)-N(R ⁶ )C(O)R ¹⁴ , - (C _0-6 alkylene)-(N(R ¹⁵ )S(O)(N(C _1-4 alkyl))-C _1-4 alkyl), -(C _0-6 alkylene)-(S(O)(NH)-(C _1-4 alkyl)), or deuterium. In certain embodiments, R ⁹ is –(C _1-6 alkylene)-(C _1-6 alkoxyl). In certain embodiments, R ⁹ is –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is - C(O)N(R ⁶ )(R ⁷ ), -C(O)N(R ⁶ )(R ¹³ ), -(C _0-6 alkylene)-N(R ⁶ )C(O)(R ¹⁴ ), -(C _0-6 alkylene)- (N(R ¹⁵ )S(O)(N(C _1-4 alkyl))-C _1-4 alkyl), or –(C _0-6 alkylene)-(S(O)(NH)-(C _1-4 alkyl)). In certain embodiments, R ⁹ is C _1-6 alkoxyl. In certain embodiments, R ⁹ is -C(O)N(R ⁶ )(R ⁷ ). In certain embodiments, R ⁹ is -C(O)N(R ⁶ )(R ¹³ ). In certain embodiments, R ⁹ is -(C _0-6 alkylene)- N(R ⁶ )C(O)R ¹⁴ . In certain embodiments, R ⁹ is -(C _0-6 alkylene)-(N(R ¹⁵ )S(O)(N(C _1-4 alkyl))-C _1-4 alkyl). In certain embodiments, R ⁹ is –(C _0-6 alkylene)-(S(O)(NH)-(C _1-4 alkyl)). In certain embodiments, R ⁹ is deuterium. In certain embodiments, R ⁹ is -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1 heteroatom selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 2 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). [0260] In certain embodiments, R ⁹ is –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is –(C _1-3 alkylene)-(5-6 membered saturated monocyclic heterocyclyl containing 1 or 2 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, [0261] In certain embodiments, R ⁹ is –(C _1-3 alkylene)-(7-10 membered saturated bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is – (C _1-3 alkylene)-(7-10 membered saturated spiro-bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is , , each of which is substituted with 0, 1, 2, or 3 instances of R ¹² . [0262] In certain embodiments, R ⁹ is selected from the groups depicted in the compounds in Table 1, below. [0263] As defined generally above, R ¹⁰ is a group capable of forming a covalent bond to a sulfhydryl group. In certain embodiments, R ¹⁰ is -N(H)C(O)(C _2-4 alkenyl). In certain embodiments, R ¹⁰ is -N(H)C(O)CH=CH ₂ . In certain embodiments, R ¹⁰ is selected from the groups depicted in the compounds in Table 1, below. [0264] As defined generally above, R ¹¹ is halo, hydroxyl, C _1-6 alkyl, C _1-6 haloalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), C _3-7 cycloalkyl, C _1-6 alkoxyl, or –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ represents independently for each occurrence halo, hydroxyl, C _1-6 alkyl, or C _1-6 haloalkyl. In certain embodiments, R ¹¹ represents independently for each occurrence halo, C _1-6 alkyl, or –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ is halo. In certain embodiments, R ¹¹ is hydroxyl. In certain embodiments, R ¹¹ is C _1-6 alkyl. In certain embodiments, R ¹¹ is C _1-6 haloalkyl. In certain embodiments, R ¹¹ is -(C _1-6 alkylene)- (C _3-7 cycloalkyl). In certain embodiments, R ¹¹ is C _3-7 cycloalkyl. In certain embodiments, R ¹¹ is C _1-6 alkoxyl. In certain embodiments, R ¹¹ is –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ is –(C _0-6 alkylene)-(4-10 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ is –(C _0-6 alkylene)-(4-10 membered saturated bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ is selected from the groups depicted in the compounds in Table 1, below. [0265] As defined generally above, R ¹² represents independently for each occurrence halo, C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl, or C _1-6 alkoxyl. In certain embodiments, R ¹² is halo. In certain embodiments, R ¹² is C _1-6 alkyl. In certain embodiments, R ¹² is C ₁ alkyl. In certain embodiments, R ¹² is C ₂ alkyl. In certain embodiments, R ¹² is C ₃ alkyl. In certain embodiments, R ¹² is C ₄ alkyl. In certain embodiments, R ¹² is C ₅ alkyl. In certain embodiments, R ¹² is C6 alkyl. In certain embodiments, R ¹² is C _1-6 haloalkyl. In certain embodiments, R ¹² is C _3-7 cycloalkyl. In certain embodiments, R ¹² is C _1-6 alkoxyl. In certain embodiments, R ¹² is selected from the groups depicted in the compounds in Table 1, below. [0266] As defined generally above, R ¹³ is a 4-7 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 4 membered saturated monocyclic heterocyclyl containing 1 oxygen heteroatom, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 4 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 5 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 6 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 7 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is selected from the groups depicted in the compounds in Table 1, below. [0267] As defined generally above, R ¹⁴ represents independently for each occurrence hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl. In certain embodiments, R ¹⁴ represents independently for each occurrence hydrogen, C _1-6 alkyl, or C _1-6 hydroxyalkyl. In certain embodiments, R ¹⁴ is hydrogen. In certain embodiments, R ¹⁴ is C _1-6 alkyl. In certain embodiments, R ¹⁴ is C _1-6 hydroxyalkyl. In certain embodiments, R ¹⁴ is - (C _1-6 alkylene)-(C _3-7 cycloalkyl). In certain embodiments, R ¹⁴ is C _3-7 cycloalkyl. In certain embodiments, R ¹⁴ is selected from the groups depicted in the compounds in Table 1, below. [0268] As defined generally above, R ¹⁶ is hydrogen, C _1-4 alkyl, or hydroxyl. In certain embodiments, R ¹⁶ is hydrogen. In certain embodiments, R ¹⁶ is C _1-4 alkyl. In certain embodiments, R ¹⁶ is C ₁ alkyl. In certain embodiments, R ¹⁶ is C ₂ alkyl. In certain embodiments, R ¹⁶ is C ₃ alkyl. In certain embodiments, R ¹⁶ is C ₄ alkyl. In certain embodiments, R ¹⁶ is hydroxyl. In certain embodiments, R ¹⁶ is selected from the groups depicted in the compounds in Table 1, below. [0269] As defined generally above, n and p are independently 0, 1, or 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. [0270] As defined generally above, t is 0, 1, 2, 3, 4, 5, or 6. In certain embodiments, t is 0. In certain embodiments, t is 1. In certain embodiments, t is 2. In certain embodiments, t is 3. In certain embodiments, t is 4. In certain embodiments, t is 5. In certain embodiments, t is 6. In certain embodiments, t is 0, 1, or 2. In certain embodiments, t is 1, 2, or 3. In certain embodiments, n, t, and p are independently 0, 1, or 2. [0271] The description above describes multiple embodiments relating to compounds of Formula II-A. The patent application specifically contemplates all combinations of the embodiments. [0272] Another aspect of the invention provides a compound represented by Formula II-B: or a pharmaceutically acceptable salt thereof, wherein: R ¹ and R ³ are independently hydrogen, C _1-4 alkyl, or C _3-4 cycloalkyl; R ² is C _1-4 alkyl, C _1-4 hydroxyalkyl, -C(O)N(R ⁶ )(R ⁷ ), or hydrogen; R ⁴ is hydrogen, C _1-4 alkyl, or -C(O)N(R ⁶ )(R ⁷ ); or R ⁴ and R ³ are taken together to form oxo; of which is substituted with n occurrences of R ⁹ ; (ii) phenyl or 6-membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatom(s) are nitrogen, where the phenyl and heteroaryl are substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; or (iii) 6- membered monocyclic, unsaturated oxo-heterocyclyl containing 1 or 2 heteroatoms, wherein the heteroatom(s) are nitrogen, and the oxo-heterocyclyl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; R ⁶ and R ⁷ are independently hydrogen, C _1-6 alkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; or R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom; R ⁸ , R ¹⁵ , and R ¹⁷ are independently hydrogen or C _1-4 alkyl; R ⁹ is -(C _1-6 alkylene)-(C _1-6 alkoxyl) or -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ); R ¹⁰ is a group capable of forming a covalent bond to a sulfhydryl group; R ¹¹ is halo, hydroxyl, C _1-6 alkyl, C _1-6 haloalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), C _3-7 cycloalkyl, C _1-6 alkoxyl, or –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ); R ¹² represents independently for each occurrence halo, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _3-7 cycloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, -C(O)R ¹⁹ , or oxo; R ¹³ is a 4-7 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ ; R ¹⁴ represents independently for each occurrence hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; R ¹⁶ is hydrogen, C _1-4 alkyl, or hydroxyl; R ¹⁹ represents independently for each occurrence C _1-6 alkyl, C _3-6 cycloalkyl, or -(C _1-6 alkylene)-(C _3-6 cycloalkyl); n and p are independently 0, 1, or 2; and t is 0, 1, 2, 3, 4, 5, or 6. [0273] The definitions of variables in Formula II-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). [0274] In certain embodiments, the compound is a compound of Formula II-B. [0275] As defined generally above, R ¹ and R ³ are independently hydrogen, C _1-4 alkyl, or C _3-4 cycloalkyl. In certain embodiments, R ¹ and R ³ are hydrogen. In certain embodiments, R ¹ is hydrogen. In certain embodiments, R ¹ is C _1-4 alkyl. In certain embodiments, R ¹ is C ₁ alkyl. In certain embodiments, R ¹ is C ₂ alkyl. In certain embodiments, R ¹ is C ₃ alkyl. In certain embodiments, R ¹ is C ₄ alkyl. In certain embodiments, R ¹ is C _3-4 cycloalkyl. In certain embodiments, R ¹ is C ₃ cycloalkyl. In certain embodiments, R ¹ is C ₄ cycloalkyl. In certain embodiments, R ³ is hydrogen. In certain embodiments, R ³ is C _1-4 alkyl. In certain embodiments, R ³ is C ₁ alkyl. In certain embodiments, R ³ is C ₂ alkyl. In certain embodiments, R ³ is C ₃ alkyl. In certain embodiments, R ³ is C ₄ alkyl. In certain embodiments, R ³ is C _3-4 cycloalkyl. In certain embodiments, R ³ is C ₃ cycloalkyl. In certain embodiments, R ³ is C ₄ cycloalkyl. In certain embodiments, R ¹ is selected from the groups depicted in the compounds in Table 1, below. In certain embodiments, R ³ is selected from the groups depicted in the compounds in Table 1, below. [0276] As defined generally above, R ² is C _1-4 alkyl, C _1-4 hydroxyalkyl, -C(O)N(R ⁶ )(R ⁷ ), or hydrogen. In certain embodiments, R ² is C _1-4 alkyl. In certain embodiments, R ² is -CH ₃ . In certain embodiments, R ² is C _1-4 hydroxyalkyl. In certain embodiments, R ² is -C(O)N(R ⁶ )(R ⁷ ). In certain embodiments, R ² is hydrogen. In certain embodiments, R ² is C ₂ alkyl. In certain embodiments, R ² is C ₃ alkyl. In certain embodiments, R ² is C ₄ alkyl. In certain embodiments, R ² is selected from the groups depicted in the compounds in Table 1, below. [0277] As defined generally above, R ⁴ is hydrogen, C _1-4 alkyl, or -C(O)N(R ⁶ )(R ⁷ ); or R ⁴ and R ³ are taken together to form oxo. In certain embodiments, R ⁴ is hydrogen. In certain embodiments, R ⁴ is -C(O)N(R ⁶ )(R ⁷ ). In certain embodiments, R ⁴ and R ³ are taken together to form oxo. In certain embodiments, R ⁴ is C _1-4 alkyl. In certain embodiments, R ⁴ is selected from the groups depicted in the compounds in Table 1, below. [0278] As defined generally above, , each of which is substituted with n occurrences of R ⁹ ; (ii) phenyl or 6-membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatom(s) are nitrogen, and wherein the phenyl and heteroaryl are substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; or (iii) 6-membered monocyclic, unsaturated oxo-heterocyclyl containing 1 or 2 heteroatoms, wherein the heteroatom(s) are nitrogen, and the oxo-heterocyclyl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is c , . embodiments, substituted with n occurrences of R ⁹ . In certain embodiments, , each of which is substituted with n occurrences of R ⁹ . [0279] In certain embodiments, R ⁵ is phenyl or 6-membered heteroaryl containing 1 or 2 heteroatom(s), wherein the heteroatom(s) are nitrogen atom, and the phenyl and heteroaryl are substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is phenyl substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is a 6-membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatoms are nitrogen atom, and the heteroaryl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is a pyridinyl substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, R ⁵ is a 6-membered monocyclic, unsaturated oxo- heterocyclyl containing 1 or 2 nitrogen atoms, wherein the heterocyclyl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, , each of which is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, , each of which is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . In certain embodiments, , which substituted with n occurrences of R ⁹ . In certain embodiments, , which is substituted with n occurrences of R ⁹ . In certain embodiments, , which is substituted with n occurrences of R ⁹ . In certain embodiments, , which is substituted with n occurrences of R ⁹ . In certain embodiments, , which is substituted with n occurrences of R ⁹ . In certain embodiments, R ⁵ is selected from the groups depicted in the compounds in Table 1, below. [0280] As defined generally above, R ⁶ and R ⁷ are independently hydrogen, C _1-6 alkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; or R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ are independently hydrogen or C _1-6 alkyl. In certain embodiments, R ⁶ is hydrogen. In certain embodiments, R ⁶ is C _1-6 alkyl. In certain embodiments, R ⁶ is -(C _1-6 alkylene)-(C _3-7 cycloalkyl), In certain embodiments, R ⁶ is C _3-7 cycloalkyl. In certain embodiments, R ⁷ is hydrogen. In certain embodiments, R ⁷ is C _1-6 alkyl. In certain embodiments, R ⁷ is -(C _1-6 alkylene)-(C _3-7 cycloalkyl), In certain embodiments, R ⁷ is C _3-7 cycloalkyl. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 4 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 5 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 6 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 7 membered heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R ⁶ is selected from the groups depicted in the compounds in Table 1, below. In certain embodiments, R ⁷ is selected from the groups depicted in the compounds in Table 1, below. [0281] As defined generally above, R ⁸ , R ¹⁵ , and R ¹⁷ are independently hydrogen or C _1-4 alkyl. In certain embodiments, R ⁸ is hydrogen. In certain embodiments, R ⁸ is C _1-4 alkyl. In certain embodiments, R ⁸ is C ₁ alkyl. In certain embodiments, R ⁸ is C ₂ alkyl. In certain embodiments, R ⁸ is C ₃ alkyl. In certain embodiments, R ⁸ is C ₄ alkyl. In certain embodiments, R ¹⁵ is hydrogen. In certain embodiments, R ¹⁵ is C _1-4 alkyl. In certain embodiments, R ¹⁵ is C ₁ alkyl. In certain embodiments, R ¹⁵ is C ₂ alkyl. In certain embodiments, R ¹⁵ is C ₃ alkyl. In certain embodiments, R ¹⁵ is C ₄ alkyl. In certain embodiments, R ¹⁷ is hydrogen. In certain embodiments, R ¹⁷ is C _1-4 alkyl. In certain embodiments, R ¹⁷ is C ₁ alkyl. In certain embodiments, R ¹⁷ is C ₂ alkyl. In certain embodiments, R ¹⁷ is C ₃ alkyl. In certain embodiments, R ¹⁷ is C ₄ alkyl. In certain embodiments, R ⁸ is selected from the groups depicted in the compounds in Table 1, below. In certain embodiments, R ¹⁵ is selected from the groups depicted in the compounds in Table 1, below. In certain embodiments, R ¹⁷ is selected from the groups depicted in the compounds in Table 1, below. [0282] As defined generally above, R ⁹ is -(C _1-6 alkylene)-(C _1-6 alkoxyl) or -(C _0-6 alkylene)-(4- 10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1 heteroatom selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 2 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). [0283] In certain embodiments, R ⁹ is –(C _1-3 alkylene)-(5-6 membered saturated monocyclic heterocyclyl containing 1 or 2 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is , each of which is substituted with 0, 1, 2, or 3 instances of R ¹² . In certain embodiments, R ⁹ is . [0284] In certain embodiments, R ⁹ is –(C _1-3 alkylene)-(7-10 membered saturated bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is – (C _1-3 alkylene)-(7-10 membered saturated spiro-bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ⁹ is , , instances of R ¹² . [0285] In certain embodiments, R ⁹ is selected from the groups depicted in the compounds in Table 1, below. [0286] As defined generally above, R ¹⁰ is a group capable of forming a covalent bond to a sulfhydryl group. In certain embodiments, R ¹⁰ is -N(H)C(O)(C _2-4 alkenyl). In certain embodiments, R ¹⁰ is -N(H)C(O)CH=CH ₂ . In certain embodiments, R ¹⁰ is selected from the groups depicted in the compounds in Table 1, below. [0287] As defined generally above, R ¹¹ is halo, hydroxyl, C _1-6 alkyl, C _1-6 haloalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), C _3-7 cycloalkyl, C _1-6 alkoxyl, or –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ represents independently for each occurrence halo, hydroxyl, C _1-6 alkyl, or C _1-6 haloalkyl. In certain embodiments, R ¹¹ represents independently for each occurrence halo, C _1-6 alkyl, or –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ is halo. In certain embodiments, R ¹¹ is hydroxyl. In certain embodiments, R ¹¹ is C _1-6 alkyl. In certain embodiments, R ¹¹ is C _1-6 haloalkyl. In certain embodiments, R ¹¹ is -(C _1-6 alkylene)- (C _3-7 cycloalkyl). In certain embodiments, R ¹¹ is C _3-7 cycloalkyl. In certain embodiments, R ¹¹ is C _1-6 alkoxyl. In certain embodiments, R ¹¹ is –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ is –(C _0-6 alkylene)-(4-10 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ is –(C _0-6 alkylene)-(4-10 membered saturated bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). In certain embodiments, R ¹¹ is selected from the groups depicted in the compounds in Table 1, below. [0288] As defined generally above, R ¹² represents independently for each occurrence halo, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _3-7 cycloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, -C(O)R ¹⁹ , or oxo. In certain embodiments, R ¹² represents independently for each occurrence halo, C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, or oxo. In certain embodiments, R ¹² is halo. In certain embodiments, R ¹² is C _1-6 alkyl. In certain embodiments, R ¹² is C ₁ alkyl. In certain embodiments, R ¹² is C ₂ alkyl. In certain embodiments, R ¹² is C ₃ alkyl. In certain embodiments, R ¹² is C ₄ alkyl. In certain embodiments, R ¹² is C ₅ alkyl. In certain embodiments, R ¹² is C ₆ alkyl. In certain embodiments, R ¹² is C _1-6 haloalkyl. In certain embodiments, R ¹² is C _3-7 cycloalkyl. In certain embodiments, R ¹² is C _1-6 alkoxyl. In certain embodiments, R ¹² is C _1-6 haloalkoxyl. In certain embodiments, R ¹² is oxo. In certain embodiments, R ¹² is hydroxy. In certain embodiments, R ¹² is C _1-6 hydroxyalkyl. In certain embodiments, R ¹² is -C(O)R ¹⁹ . [0289] In certain embodiments, R ¹² represents independently for each occurrence halo, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _3-7 cycloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, -C(O)R ¹⁹ , or oxo. In certain embodiments, R ¹² represents independently for each occurrence halo, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _3-7 cycloalkyl, or - C(O)R ¹⁹ . In certain embodiments, R ¹² represents independently for each occurrence C _1-6 alkyl. In certain embodiments, R ¹² is selected from the groups depicted in the compounds in Table 1, below. [0290] As defined generally above, R ¹³ is a 4-7 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 4 membered saturated monocyclic heterocyclyl containing 1 oxygen heteroatom, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 4 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 5 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 6 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is a 7 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . In certain embodiments, R ¹³ is selected from the groups depicted in the compounds in Table 1, below. [0291] As defined generally above, R ¹⁴ represents independently for each occurrence hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl. In certain embodiments, R ¹⁴ represents independently for each occurrence hydrogen, C _1-6 alkyl, or C _1-6 hydroxyalkyl. In certain embodiments, R ¹⁴ is hydrogen. In certain embodiments, R ¹⁴ is C _1-6 alkyl. In certain embodiments, R ¹⁴ is C _1-6 hydroxyalkyl. In certain embodiments, R ¹⁴ is - (C _1-6 alkylene)-(C _3-7 cycloalkyl). In certain embodiments, R ¹⁴ is C _3-7 cycloalkyl. In certain embodiments, R ¹⁴ is selected from the groups depicted in the compounds in Table 1, below. [0292] As defined generally above, R ¹⁶ is hydrogen, C _1-4 alkyl, or hydroxyl. In certain embodiments, R ¹⁶ is hydrogen. In certain embodiments, R ¹⁶ is C _1-4 alkyl. In certain embodiments, R ¹⁶ is C ₁ alkyl. In certain embodiments, R ¹⁶ is C ₂ alkyl. In certain embodiments, R ¹⁶ is C ₃ alkyl. In certain embodiments, R ¹⁶ is C ₄ alkyl. In certain embodiments, R ¹⁶ is hydroxyl. In certain embodiments, R ¹⁶ is selected from the groups depicted in the compounds in Table 1, below. [0293] As defined generally above, R ¹⁹ represents independently for each occurrence C _1-6 alkyl, C _3-6 cycloalkyl, or -(C _1-6 alkylene)-(C _3-6 cycloalkyl). In certain embodiments, R ¹⁹ is C _1-6 alkyl. In certain embodiments, R ¹⁹ is methyl. In certain embodiments, R ¹⁹ is ethyl. In certain embodiments, R ¹⁹ is C _3-6 cycloalkyl. In certain embodiments, R ¹⁹ is -(C _1-6 alkylene)-(C _3-6 cycloalkyl). In certain embodiments, R ¹⁹ is selected from the groups depicted in the compounds in Table 1, below. [0294] As defined generally above, n, and p are independently 0, 1, or 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, n, t, and p are independently 0, 1, or 2. [0295] As defined generally above, t is 0, 1, 2, 3, 4, 5, or 6. In certain embodiments, t is 0. In certain embodiments, t is 1. In certain embodiments, t is 2. In certain embodiments, t is 3. In certain embodiments, t is 4. In certain embodiments, t is 5. In certain embodiments, t is 1, 2, or 3. In certain embodiments, t is 2, 3 or 4. [0296] The description above describes multiple embodiments relating to compounds of Formula II-B. The patent application specifically contemplates all combinations of the embodiments. [0297] One aspect of the invention provides a compound represented by Formula II-1: (II-1) or a pharmaceutically acceptable salt thereof, wherein: R ¹ and R ³ are independently hydrogen, C _1-4 alkyl, or C _3-4 cycloalkyl; R ² is C _1-4 alkyl, C _1-4 hydroxyalkyl, -C(O)N(R ⁶ )(R ⁷ ), or hydrogen; R ⁴ is hydrogen, C _1-4 alkyl, or -C(O)N(R ⁶ )(R ⁷ ); or R ⁴ and R ³ are taken together to form oxo; , each of which is substituted with n occurrences of R ⁹ ; (ii) phenyl or 6-membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatoms are nitrogen atoms, where the phenyl and heteroaryl are substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; or (iii) 6-membered monocyclic, unsaturated oxo-heterocyclyl containing 1 or 2 nitrogen atoms, wherein the oxo-heterocyclyl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; R ⁶ and R ⁷ are independently hydrogen, C _1-6 alkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; or R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom; R ⁸ is hydrogen, C _1-4 alkyl, or -(C _2-4 alkylene)-(C _1-4 alkoxyl); R ⁹ is -(C _1-6 alkylene)-(C _1-6 alkoxyl), C _1-6 alkoxyl, -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ), - C(O)N(R ⁶ )(R ⁷ ), -C(O)N(R ⁶ )(R ¹³ ), -S(O) ₂ R ¹⁸ , -S(O)(=NH)R ¹⁸ , -S(O) ₂ N(R ⁶ )(R ⁷ ), -(C _0-6 alkylene)-N(R ⁶ )C(O)R ¹⁴ , -(C _0-6 alkylene)-(N(R ¹⁵ )S(O)(N(C _1-4 alkyl))-C _1-4 alkyl), -(C _0-6 alkylene)-(S(O)(NH)-(C _1-4 alkyl)), or deuterium; R ¹⁰ is a group capable of forming a covalent bond to a sulfhydryl group; R ¹¹ is halo, hydroxyl, C _1-6 alkyl, C _1-6 haloalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), C _3-7 cycloalkyl, C _1-6 alkoxyl, or -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ); R ¹² represents independently for each occurrence halo, C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, or oxo; R ¹³ is a 4-7 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ ; R ¹⁴ represents independently for each occurrence hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; R ¹⁵ is hydrogen or C _1-4 alkyl; R ¹⁶ is hydrogen, C _1-4 alkyl, or hydroxyl; R ¹⁷ is hydrogen, C _1-4 alkyl, or -(C _2-4 alkylene)-(C _1-4 alkoxyl); R ¹⁸ is C _1-4 alkyl or C _3-6 cycloalkyl; X is -N(R ¹⁷ )-, -O-, or -CH ₂ ; and n, t, and p are independently 0, 1, or 2. [0298] The definitions of variables in Formula II-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). [0299] In certain embodiments, the compound is a compound of Formula II-1. [0300] In certain embodiments, the definition of one or more variables of Formula II-1 is as set forth above in connection with Formula II. [0301] Another aspect of the invention provides a compound represented by Formula II-A-1: (II-A-1) or a pharmaceutically acceptable salt thereof, wherein: R ¹ and R ³ are independently hydrogen, C _1-4 alkyl, or C _3-4 cycloalkyl; R ² is C _1-4 alkyl, C _1-4 hydroxyalkyl, -C(O)N(R ⁶ )(R ⁷ ), or hydrogen; R ⁴ is hydrogen, C _1-4 alkyl, or -C(O)N(R ⁶ )(R ⁷ ); or R ⁴ and R ³ are taken together to form oxo; of which is substituted with n occurrences of R ⁹ ; (ii) phenyl or 6-membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatoms are nitrogen atoms, where the phenyl and heteroaryl are substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; or (iii) 6- membered monocyclic, unsaturated oxo-heterocyclyl containing 1 or 2 heteroatoms, wherein the heteroatoms are nitrogen atom, and the heterocyclyl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; R ⁶ and R ⁷ are independently hydrogen, C _1-6 alkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; or R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom; R ⁸ , R ¹⁵ , and R ¹⁷ are independently hydrogen or C _1-4 alkyl; R ⁹ is –(C _1-6 alkylene)-(C _1-6 alkoxyl), C _1-6 alkoxyl, -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ), - C(O)N(R ⁶ )(R ⁷ ), -C(O)N(R ⁶ )(R ¹³ ), -(C _0-6 alkylene)-N(R ⁶ )C(O)(R ¹⁴ ), -(C _0-6 alkylene)- (N(R ¹⁵ )S(O)(N(C _1-4 alkyl))-C _1-4 alkyl), -(C _0-6 alkylene)-(S(O)(NH)-(C _1-4 alkyl)), or deuterium; R ¹⁰ is a group capable of forming a covalent bond to a sulfhydryl group; R ¹¹ is halo, hydroxyl, C _1-6 alkyl, C _1-6 haloalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), C _3-7 cycloalkyl, C _1-6 alkoxyl, or –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ); R ¹² represents independently for each occurrence halo, C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl, or C _1-6 alkoxyl; R ¹³ is a 4-7 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ ; R ¹⁴ represents independently for each occurrence hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; R ¹⁶ is hydrogen, C _1-4 alkyl, or hydroxyl; and n, t, and p are independently 0, 1, or 2. [0302] In certain embodiments, the definition of one or more variables of Formula II-A-1 is as set forth above in connection with Formula II-A. [0303] Another aspect of the invention provides a compound represented by Formula III: or a pharmaceutically acceptable salt thereof, wherein: R ¹ and R ³ are independently hydrogen, C _1-4 alkyl, or C _3-4 cycloalkyl; R ² is C _1-4 alkyl, C _1-4 hydroxyalkyl, -C(O)N(R ⁶ )(R ⁷ ), or hydrogen; or, alternatively, R ¹ and R ² , taken together with the carbon atom to which they are attached, form a 3-7 membered saturated carbocyclic ring or a 3-7 membered saturated heterocyclic ring containing 1 or 2 nitrogen atoms, wherein the carbocyclylic ring and the heterocyclylic ring are substituted with 1 or 2 occurrences of R ²⁰ ; R ⁴ is hydrogen, C _1-4 alkyl, or -C(O)N(R ⁶ )(R ⁷ ); or R ⁴ and R ³ are taken together to form occurrences of R ⁹ ; (ii) phenyl or 6-membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatoms are nitrogen atoms, where the phenyl and heteroaryl are substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; or (iii) 6-membered monocyclic, unsaturated oxo-heterocyclyl containing 1 or 2 nitrogen atoms, wherein the oxo-heterocyclyl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; R ⁶ and R ⁷ are independently hydrogen, C _1-6 alkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; or R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom; R ⁸ is hydrogen, C _1-4 alkyl, or -(C _2-4 alkylene)-(C _1-4 alkoxyl); R ⁹ is -(C _1-6 alkylene)-(C _1-6 alkoxyl), C _1-6 alkoxyl, -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, phosphorous, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ), -C(O)N(R ⁶ )(R ⁷ ), -C(O)N(R ⁶ )(R ¹³ ), -(C _0-6 alkylene)-S(O) ₂ R ¹⁸ , -(C _0-6 alkylene)-S(O)(=NR ¹⁵ )R ¹⁸ , -S(O) ₂ N(R ⁶ )(R ⁷ ), -(C _0-6 alkylene)-N(R ⁶ )C(O)R ¹⁴ , -(C _0-6 alkylene)- (N(R ¹⁵ )S(O)(N(R ^15A ))-R ¹⁸ ), halo, C _1-6 haloalkyl, cyano, -(C _0-6 alkylene)-P(O)(R ⁶ )(R ⁷ ), -(C _0-6 alkylene)-(3-7 membered saturated monocyclic or bicyclic carbocyclyl), -(C _0-6 alkylene)-O-(3- 7 membered saturated monocyclic or bicyclic carbocyclyl, wherein the carbocyclyl is substituted with m occurrences of R ¹² ), -(C _0-6 alkylene)-O-(C _1-6 haloalkyl), -(C _1-6 alkylene)- N(R ⁶ )(R ⁷ ), -(C _1-6 alkylene)-O-C(O)(R ¹⁹ ), -(C _1-6 alkylene)-(C _1-4 alkynyl), -(C _1-6 alkylene)-O-(C _1- 4 alkynyl), or deuterium; or two R ⁹ groups on adjacent atoms are taken together with the atoms to which they are bonded to form a 5-7 membered heterocyclic ring containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclic ring is substituted with t instances of R ¹² ; R ¹⁰ is a group capable of forming a covalent bond to a sulfhydryl group; R ¹¹ is halo, hydroxyl, C _1-6 alkyl, C _1-6 haloalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), C _3-7 cycloalkyl, C _1-6 alkoxyl, or -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ); R ¹² represents independently for each occurrence halo, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _3-7 cycloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, -C(O)R ¹⁹ , - C(O)(OH), -O-(C _1-4 haloalkyl), -O-(C _1-4 halohydroxyalkoxyl), or oxo; or two R ¹² groups, taken together with the carbon atom to which they are attached, form a 3-7 membered saturated carbocyclic ring or a 3-7 membered saturated heterocyclic ring containing 1 heteroatom selected from nitrogen and oxygen, wherein the carbocyclic ring and the heterocyclic ring are substituted with 1 or 2 occurrences of R ²⁰ ; R ¹³ is a 4-7 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ ; R ¹⁴ represents independently for each occurrence hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; R ¹⁵ and R ^15A are independently hydrogen or C _1-4 alkyl; R ¹⁶ is hydrogen, C _1-4 alkyl, or hydroxyl; R ¹⁷ is hydrogen, C _1-4 alkyl, or -(C _2-4 alkylene)-(C _1-4 alkoxyl); R ¹⁸ is C _1-4 alkyl, -(C _1-6 alkylene)-C(O) ₂ OH, -(C _1-6 alkylene)-(C _1-6 alkoxyl), or C _3-6 cycloalkyl; R ¹⁹ represents independently for each occurrence C _1-6 alkyl, C _3-6 cycloalkyl, or -(C _1-6 alkylene)-(C _3-6 cycloalkyl); R ²⁰ is hydrogen, C _1-4 alkyl, -(C _0-4 alkylene)-(C _1-6 alkoxyl), -C(O)-(C _1-4 alkyl), or C _3-7 cycloalkyl; X is -N(R ¹⁷ )-, -O-, or -CH ₂ ; Z ¹ is N or -C(H)-; and m and p are independently 0, 1, or 2; n is 0, 1, 2, or 3; and t is 0, 1, 2, 3, 4, 5, or 6. [0304] The definitions of variables in Formula III 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). [0305] In certain embodiments, Z ¹ is N. In certain embodiments, Z ¹ is -C(H)-. [0306] In certain embodiments, a variable set forth in Formula III is selected from one of the variable definitions set forth above for embodiments of Formula I. [0307] Another aspect of the invention provides a compound in Table 1 below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1. In certain embodiments, the compound is one of compounds I-1 to I-51 in Table 1 below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is one of compounds I-1 to I-51 in Table 1 below. In certain embodiments, the compound is one of compounds I-1 to I-88 in Table 1 below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is one of compounds I-1 to I-88 in Table 1 below. In certain embodiments, the compound is one of compounds I-1 to I-163 in Table 1 below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is one of compounds I-1 to I-163 in Table 1 below. TABLE 1.

[0308] The compounds may be further characterized according to selectivity of the compound towards MK2. In order words, the compounds may be characterized by preferrenctial activity at MK2 relative to other protein targets. In certain embodiments, the compounds have significantly more potent binding to MK2 relative to another protein target, such as a protein target selected from a tyrosine kinase protein, a serine threonine kinase-enzyme, a casein kinase 1 (CK1) protein, an AGC kinase, or a Ca2+/calmodulin-dependent protein kinase class of enzyme (CMGC). In certain embodiments, the compounds have significantly more potent binding to MK2 relative to a tyrosine kinase protein. In certain embodiments, the compounds have significantly more potent binding to MK2 relative to a serine threonine kinase-enzyme. In certain embodiments, the compounds have significantly more potent binding to MK2 relative to a casein kinase 1 (CK1) protein. In certain embodiments, the compounds have significantly more potent binding to MK2 relative to an AGC kinase. In certain embodiments, the compounds have significantly more potent binding to MK2 relative to a Ca2+/calmodulin- dependent protein kinase class of enzyme (CMGC). [0309] The selectivity of the compound may be further characterized according to the magnitude of the more potent binding of the compound to MK2 compared to another protein target. For example, in certain embodiments, the compound has at least 2 fold more potent binding to MK2 compared to another protein target. In certain embodiments, the compound has at least 5 fold more potent binding to MK2 compared to another protein target. In certain embodiments, the compound has at least 10, 20, 30, 40, 50 or 100 fold more potent binding to MK2 compared to another protein target. [0310] Binding affinity of compounds described herein to MK2 and/or other proteins can be determined using assay procedures known in the art and/or described in publications. For example, a Eurofins assay can be used to quantitatively measure interactions between a test compound and more than 489 kinase proteins and disease relevant mutant variants. In the Eurofins assay, ligands for target proteins to be interegated around bound to a solid support. Then the solid-support bound ligands are exposed to a mixture of test compound and a protein kinase. Test compounds that bind to a protein kinase prevent binding of the protein kinase to the solid-support bound ligands. The amount of protein kinase bound to ligand-bound-to-solid support is measured, and used to determine whether the test compound bound the protein kinase. [0311] Preferrential binding of the compound to MK2 may reduce the occurrence of undesired affects that may be caused by the compound binding to a target other than MK2. For example, such preferential binding of the compound to MK2 may reduce the occurrence of adverse side effects when the compound is used a medicine in patients. [0312] Methods for preparing compounds described herein are illustrated in the following synthetic schemes. The schemes are provided for the purpose of illustrating the invention, and are not intended to limit the scope or spirit of the invention. Starting materials shown in the schemes can be obtained from commercial sources or can be prepared based on procedures described in the literature. Additional strategies for preparing starting materials and other compounds are described in, for example, WO 2016/044463 A1, the entirety of which is hereby incorporated by reference. [0313] In the schemes, 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, 3 ^rd Edition, T. W. Greene and P. G. M. Wuts, John Wiley & Sons, 1999 and Greene’s Protective Groups in Organic Synthesis, 5 ^th Ed., (Peter G. M. Wuts, John Wiley & Sons: 2014), the entire contents of both of which are hereby incorporated by reference. [0314] The synthetic route illustrated in Scheme 1 is a general method for preparing diazepino-thieno-quinoxaline compounds. In Scheme 1, Ar represents an optionally substituted aryl or heteroaryl ring and LG represents a leaving group suitable for nucleophilic aromatic substitution. SCHEME 1. [0315] The modular synthetic routes illustrated in Scheme 1 can also be readily modified by one of skill in the art to provide additional diazepino-thieno-quinoxalines and related 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); Organic Synthesis, 3 ^rd Ed. (Michael B. Smith, Wavefunction, Inc., Irvine: 2010); Modern Methods of Organic Synthesis, 4 ^th Ed. (William Carruthers and Iain Coldham, Cambridge University Press, Cambridge: 2004); March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 8 ^th Ed., (Michael B. Smith, John Wiley & Sons, New York: 2020); and Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3 ^rd Ed. (Richard C. Larock, ed., John Wiley & Sons, New York: 2018). II. Therapeutic Applications of Diazepino-thieno-quinoxaline Compounds [0316] The diazepino-thieno-quinoxaline compounds described herein, such as a compound of Formula I, I-A, I-B, II, II-A, II-B, or other compounds in Section I, provide therapeutic benefits to subjects suffering from inflammatory disorders (e.g., 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) and other diseases or conditions. [0317] Accordingly, one aspect of the invention provides a method for treating a disease or condition mediated by MK2. The method comprises administering a therapeutically effective amount of a compound described herein, such as a compound of Formula I, I-A, I-B, II, II-A, II-B, or other compounds in Section I, to a subject in need thereof to treat the disease or condition. In certain embodiments, the compound is a compound of Formula I, I-AI-B, II, II- A, II-B, or other compounds in Section 1, defined by one of the embodiments described above. Further description of exemplary diseases or conditions mediated by MK2 is provided herein below. [0318] Another aspect of the invention provides a method of inhibiting the activity of a MK2. The method comprises contacting a MK2 with an effective amount of a diazepino-thieno- quinoxaline compound or related compound described herein, such as a compound of Formula I, I-A, I-B, II, II-A, II-B, or other compounds in Section I, to inhibit the activity of said MK2. In certain embodiments, the compound is a compound of Formula I, I-A, I-B, II, II-A, II-B, or other compounds in Section I, defined by one of the embodiments described above. [0319] Another aspect of the invention provides a method of covalently modifying a MK2. The method comprises contacting a MK2 with an effective amount of a compound described herein, such as a compound of Formula I, I-A, I-B, II, II-A, II-B, or other compounds in Section I, to covalently modify the MK2. In certain embodiments, the compound is a compound of Formula I, I-A, I-B, II, II-A, II-B, or other compounds in Section I, defined by one of the embodiments described above. In certain embodiments, the MK2 is in a subject and the method comprises administered to the subject an effective amount of a compound described herein, such as a compound of Formula I, I-A, I-B, II, II-A, II-B, or other compounds in Section I. In certain embodiments, the subject is suffering from a treating a disease or condition mediated by MK2. [0320] Another aspect of the invention provides a covalently modified MK2 formed by the foregoing method. In certain embodiments, the MK2 is in a subject and the method comprises administered to the subject an effective amount of a compound described herein, such as a compound of Formula I, I-A, I-B, II, II-A, II-B, or other compounds in Section I. Exemplary Diseases or Conditions Mediated by MK2 [0321] In one embodiment, the disease or condition mediated by MK2 is an inflammatory disorder, such as an autoimmune disorder, chronic inflammatory disorder, acute inflammatory disorder, auto-inflammatory disorder, fibrotic disorder, metabolic disorder, neoplasia, cardiovascular or cerebrovascular disorder, or myeloid cell-driven hyper-inflammatory response in COVID-19 infection. [0322] In one embodiment, the disease or condition mediated by MK2 is ankylosing spondylitis, rheumatoid arthritis, 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, psoriatic arthritis, hidradenitis suppurativa, cryopyrin-associated periodic syndromes, or juvenile idiopathic arthritis. In one embodiment, the disease or condition mediated by MK2 is ankylosing spondylitis, rheumatoid arthritis, psoriasis, 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, or asthma. In one embodiment, the disease or condition mediated by MK2 is rheumatoid arthritis, ankylosing spondylitis, plaque psoriasis, psoriatic arthritis, ulcerative colitis, Crohn’s disease, hidradenitis suppurativa, cryopyrin-associated periodic syndromes, or juvenile idiopathic arthritis. In one embodiment, the disease or condition mediated by MK2 is cancer. In one embodiment, the disease or condition mediated by MK2 is a cancer selected from pancreatic cancer, colorectal cancer, multiple myeloma, lung cancer, gastric cancer, breast cancer, nasopharyngeal cancer, skin cancer, bladder cancer, prostate cancer, head and neck cancer, or glioblastoma. In one embodiment, the disease or condition mediated by MK2 is pancreatic cancer. [0323] In certain embodiments, said disease or condition mediated by MK2 is an acute inflammatory disorder. In certain embodiments, said disease or condition mediated by MK2 is an auto-inflammatory disorder. In certain embodiments, said disease or condition mediated by MK2 is a fibrotic disorder. In certain embodiments, said disease or condition mediated by MK2 is a metabolic disorder. In certain embodiments, said disease or condition mediated by MK2 is a neoplasia. In certain embodiments, said disease or condition mediated by MK2 is a cardiovascular or cerebrovascular disorder. In certain embodiments, said disease or condition mediated by MK2 is a myeloid cell-driven hyper-inflammatory response in COVID-19 infections. [0324] In certain embodiments, said disease or condition mediated by MK2 is an autoimmune disorder. In certain embodiments, said disease or condition mediated by MK2 is a chronic inflammatory disorder. In certain embodiments, said disease or condition mediated by MK2 is an acute inflammatory disorder. In certain embodiments, said disease or condition mediated by MK2 is an auto-inflammatory disorder. In certain embodiments, said disease or condition mediated by MK2 is a combination of one, two, or all three of a chronic inflammatory disorder, an acute inflammatory disorder, and an auto-inflammatory disorder. [0325] In certain embodiments, said disease or condition mediated by MK2 is an inflammatory bowel disease (e.g., ulcerative colitis or Crohn’s disease). In certain embodiments, said disease or condition mediated by MK2 is multiple sclerosis. In certain embodiments, said disease or condition mediated by MK2 is psoriasis. In certain embodiments, said disease or condition mediated by MK2 is arthritis. In certain embodiments, said disease or condition mediated by MK2 is rheumatoid arthritis. In certain embodiments, said disease or condition mediated by MK2 is osteoarthritis. In certain embodiments, said disease or condition mediated by MK2 is juvenile arthritis. In certain embodiments, said disease or condition mediated by MK2 is psoriatic arthritis. In certain embodiments, said disease or condition mediated by MK2 is reactive arthritis. In certain embodiments, said disease or condition mediated by MK2 is ankylosing spondylitis. In certain embodiments, said disease or condition mediated by MK2 is cryopyrin-associated periodic syndromes. In certain embodiments, said disease or condition mediated by MK2 is Muckle-Wells syndrome. In certain embodiments, said disease or condition mediated by MK2 is familial cold auto-inflammatory syndrome. In certain embodiments, said disease or condition mediated by MK2 is neonatal-onset multisystem inflammatory disease. In certain embodiments, said disease or condition mediated by MK2 is TNF receptor-associated periodic syndrome. In certain embodiments, said disease or condition mediated by MK2 is acute and chronic pancreatitis. In certain embodiments, said disease or condition mediated by MK2 is atherosclerosis. In certain embodiments, said disease or condition mediated by MK2 is gout. In certain embodiments, said disease or condition mediated by MK2 is a fibrotic disorder (e.g., hepatic fibrosis or idiopathic pulmonary fibrosis). In certain embodiments, said disease or condition mediated by MK2 is nephropathy. In certain embodiments, said disease or condition mediated by MK2 is sarcoidosis. In certain embodiments, said disease or condition mediated by MK2 is scleroderma. In certain embodiments, said disease or condition mediated by MK2 is anaphylaxis. In certain embodiments, said disease or condition mediated by MK2 is diabetes (e.g., diabetes mellitus type 1 or diabetes mellitus type 2). In certain embodiments, said disease or condition mediated by MK2 is diabetic retinopathy. In certain embodiments, said disease or condition mediated by MK2 is Still’s disease. In certain embodiments, said disease or condition mediated by MK2 is vasculitis. In certain embodiments, said disease or condition mediated by MK2 is sarcoidosis. In certain embodiments, said disease or condition mediated by MK2 is pulmonary inflammation. In certain embodiments, said disease or condition mediated by MK2 is acute respiratory distress syndrome. In certain embodiments, said disease or condition mediated by MK2 is wet and dry age-related macular degeneration. In certain embodiments, said disease or condition mediated by MK2 is autoimmune hemolytic syndromes. In certain embodiments, said disease or condition mediated by MK2 is autoimmune and inflammatory hepatitis. In certain embodiments, said disease or condition mediated by MK2 is autoimmune neuropathy. In certain embodiments, said disease or condition mediated by MK2 is autoimmune ovarian failure. In certain embodiments, said disease or condition mediated by MK2 is autoimmune orchitis. In certain embodiments, said disease or condition mediated by MK2 is autoimmune thrombocytopenia. In certain embodiments, said disease or condition mediated by MK2 is silicone implant-associated autoimmune disease. In certain embodiments, said disease or condition mediated by MK2 is Sjogren’s syndrome. In certain embodiments, said disease or condition mediated by MK2 is familial Mediterranean fever. In certain embodiments, said disease or condition mediated by MK2 is systemic lupus erythematosus. In certain embodiments, said disease or condition mediated by MK2 is vasculitis syndromes (e.g., t. emporal, Takayasu’s and giant cell arteritis, Behcet’s disease or Wegener’s granulomatosis). In certain embodiments, said disease or condition mediated by MK2 is vitiligo. In certain embodiments, said disease or condition mediated by MK2 is secondary hematologic manifestation of autoimmune diseases (e.g., anemias). In certain embodiments, said disease or condition mediated by MK2 is drug-induced autoimmunity. In certain embodiments, said disease or condition mediated by MK2 is Hashimoto’s thyroiditis. In certain embodiments, said disease or condition mediated by MK2 is hypophysitis. In certain embodiments, said disease or condition mediated by MK2 is idiopathic thrombocytic pupura. In certain embodiments, said disease or condition mediated by MK2 is metal-induced autoimmunity. In certain embodiments, said disease or condition mediated by MK2 is myasthenia gravis. In certain embodiments, said disease or condition mediated by MK2 is pemphigus. In certain embodiments, said disease or condition mediated by MK2 is autoimmune deafness (e.g., Meniere’s disease). In certain embodiments, said disease or condition mediated by MK2 is Goodpasture’s syndrome. In certain embodiments, said disease or condition mediated by MK2 is Graves’ disease. In certain embodiments, said disease or condition mediated by MK2 is an HW-related autoimmune syndromes. In certain embodiments, said disease or condition mediated by MK2 is Gullain-Barre disease. In certain embodiments, said disease or condition mediated by MK2 is Addison’s disease. In certain embodiments, said disease or condition mediated by MK2 is anti-phospholipid syndrome. In certain embodiments, said disease or condition mediated by MK2 is asthma. In certain embodiments, said disease or condition mediated by MK2 is atopic dermatitis. In certain embodiments, said disease or condition mediated by MK2 is Celiac disease. In certain embodiments, said disease or condition mediated by MK2 is Cushing’s syndrome. In certain embodiments, said disease or condition mediated by MK2 is dermatomyositis. In certain embodiments, said disease or condition mediated by MK2 is idiopathic adrenal atrophy. In certain embodiments, said disease or condition mediated by MK2 is idiopathic thrombocytopenia. In certain embodiments, said disease or condition mediated by MK2 is Kawasaki syndrome. In certain embodiments, said disease or condition mediated by MK2 is Lambert-Eaton Syndrome. In certain embodiments, said disease or condition mediated by MK2 is pernicious anemia. In certain embodiments, said disease or condition mediated by MK2 is pollinosis. In certain embodiments, said disease or condition mediated by MK2 is polyarteritis nodosa. In certain embodiments, said disease or condition mediated by MK2 is primary biliary cirrhosis. In certain embodiments, said disease or condition mediated by MK2 is primary sclerosing cholangitis. In certain embodiments, said disease or condition mediated by MK2 is Raynaud’s disease. In certain embodiments, said disease or condition mediated by MK2 is Raynaud’s phenomenon. In certain embodiments, said disease or condition mediated by MK2 is Reiter’s Syndrome. In certain embodiments, said disease or condition mediated by MK2 is relapsing polychondritis. In certain embodiments, said disease or condition mediated by MK2 is Schmidt’s syndrome. In certain embodiments, said disease or condition mediated by MK2 is thyrotoxidosis. In certain embodiments, said disease or condition mediated by MK2 is sepsis. In certain embodiments, said disease or condition mediated by MK2 is septic shock. In certain embodiments, said disease or condition mediated by MK2 is endotoxic shock. In certain embodiments, said disease or condition mediated by MK2 is exotoxin-induced toxic shock. In certain embodiments, said disease or condition mediated by MK2 is gram negative sepsis. In certain embodiments, said disease or condition mediated by MK2 is toxic shock syndrome. In certain embodiments, said disease or condition mediated by MK2 is glomerulonephritis. In certain embodiments, said disease or condition mediated by MK2 is peritonitis. In certain embodiments, said disease or condition mediated by MK2 is interstitial cystitis. In certain embodiments, said disease or condition mediated by MK2 is hyperoxia-induced inflammations. In certain embodiments, said disease or condition mediated by MK2 is chronic obstructive pulmonary disease (COPD). In certain embodiments, said disease or condition mediated by MK2 is vasculitis. In certain embodiments, said disease or condition mediated by MK2 is graft vs. host reaction (e.g., graft vs. host disease). In certain embodiments, said disease or condition mediated by MK2 is allograft rejections (e.g., acute allograft rejection or chronic allograft rejection). In certain embodiments, said disease or condition mediated by MK2 is early transplantation rejection (e.g., acute allograft rejection). In certain embodiments, said disease or condition mediated by MK2 is reperfusion injury. In certain embodiments, said disease or condition mediated by MK2 is pain (e.g., acute pain, chronic pain, neuropathic pain, or fibromyalgia). In certain embodiments, said disease or condition mediated by MK2 is a chronic infection. In certain embodiments, said disease or condition mediated by MK2 is meningitis. In certain embodiments, said disease or condition mediated by MK2 is encephalitis. In certain embodiments, said disease or condition mediated by MK2 is myocarditis. In certain embodiments, said disease or condition mediated by MK2 is gingivitis. In certain embodiments, said disease or condition mediated by MK2 is post-surgical trauma. In certain embodiments, said disease or condition mediated by MK2 is tissue injury. In certain embodiments, said disease or condition mediated by MK2 is traumatic brain injury. In certain embodiments, said disease or condition mediated by MK2 is enterocolitis. In certain embodiments, said disease or condition mediated by MK2 is sinusitis. In certain embodiments, said disease or condition mediated by MK2 is uveitis. In certain embodiments, said disease or condition mediated by MK2 is ocular inflammation. In certain embodiments, said disease or condition mediated by MK2 is optic neuritis. In certain embodiments, said disease or condition mediated by MK2 is gastric ulcers. In certain embodiments, said disease or condition mediated by MK2 is esophagitis. In certain embodiments, said disease or condition mediated by MK2 is peritonitis. In certain embodiments, said disease or condition mediated by MK2 is periodontitis. In certain embodiments, said disease or condition mediated by MK2 is dermatomyositis. In certain embodiments, said disease or condition mediated by MK2 is gastritis. In certain embodiments, said disease or condition mediated by MK2 is myositis. In certain embodiments, said disease or condition mediated by MK2 is polymyalgia. In certain embodiments, said disease or condition mediated by MK2 is pneumonia. In certain embodiments, said disease or condition mediated by MK2 is bronchitis. [0326] In certain embodiments, the disorder or condition mediated by MK2 is a fibrotic disorder. In certain embodiments, said disease or condition mediated by MK2 is systemic sclerosis/scleroderma. In certain embodiments, said disease or condition mediated by MK2 is lupus nephritis. In certain embodiments, said disease or condition mediated by MK2 is connective tissue disease. In certain embodiments, said disease or condition mediated by MK2 is wound healing. In certain embodiments, said disease or condition mediated by MK2 is surgical scarring. In certain embodiments, said disease or condition mediated by MK2 is spinal cord injury. In certain embodiments, said disease or condition mediated by MK2 is CNS scarring. In certain embodiments, said disease or condition mediated by MK2 is acute lung injury. In certain embodiments, said disease or condition mediated by MK2 is pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis or cystic fibrosis). In certain embodiments, said disease or condition mediated by MK2 is chronic obstructive pulmonary disease. In certain embodiments, said disease or condition mediated by MK2 is adult respiratory distress syndrome. In certain embodiments, said disease or condition mediated by MK2 is acute lung injury. In certain embodiments, said disease or condition mediated by MK2 is drug- induced lung injury. In certain embodiments, said disease or condition mediated by MK2 is glomerulonephritis. In certain embodiments, said disease or condition mediated by MK2 is chronic kidney disease (e.g., diabetic nephropathy). In certain embodiments, said disease or condition mediated by MK2 is hypertension-induced nephropathy. In certain embodiments, said disease or condition mediated by MK2 is alimentary track or gastrointestinal fibrosis. In certain embodiments, said disease or condition mediated by MK2 is renal fibrosis. In certain embodiments, said disease or condition mediated by MK2 is hepatic or biliary fibrosis. In certain embodiments, said disease or condition mediated by MK2 is liver fibrosis (e.g., nonalcoholic steatohepatitis, hepatitis C, or hepatocellular carcinoma). In certain embodiments, said disease or condition mediated by MK2 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 mediated by MK2 is radiation-induced fibrosis (e.g., head and neck, gastrointestinal or pulmonary). In certain embodiments, said disease or condition mediated by MK2 is primary sclerosing cholangitis. In certain embodiments, said disease or condition mediated by MK2 is restenosis. In certain embodiments, said disease or condition mediated by MK2 is cardiac fibrosis (e.g., endomyocardial fibrosis or atrial fibrosis). In certain embodiments, said disease or condition mediated by MK2 is opthalmic scarring. In certain embodiments, said disease or condition mediated by MK2 is fibrosclerosis. In certain embodiments, said disease or condition mediated by MK2 is a fibrotic cancer. In certain embodiments, said disease or condition mediated by MK2 is fibroids. In certain embodiments, said disease or condition mediated by MK2 is fibroma. In certain embodiments, said disease or condition mediated by MK2 is a fibroadenoma. In certain embodiments, said disease or condition mediated by MK2 is a fibrosarcoma. In certain embodiments, said disease or condition mediated by MK2 is transplant arteriopathy. In certain embodiments, said disease or condition mediated by MK2 is keloid. In certain embodiments, said disease or condition mediated by MK2 is mediastinal fibrosis. In certain embodiments, said disease or condition mediated by MK2 is myelofibrosis. In certain embodiments, said disease or condition mediated by MK2 is retroperitoneal fibrosis. In certain embodiments, said disease or condition mediated by MK2 is progressive massive fibrosis. In certain embodiments, said disease or condition mediated by MK2 is nephrogenic systemic fibrosis. [0327] In certain embodiments, said disease or condition mediated by MK2 is a metabolic disorders. In certain embodiments, said disease or condition mediated by MK2 is obesity. In certain embodiments, said disease or condition mediated by MK2 is steroid-resistance. In certain embodiments, said disease or condition mediated by MK2 is glucose intolerance. In certain embodiments, said disease or condition mediated by MK2 is metabolic syndrome. [0328] In certain embodiments, said disease or condition mediated by MK2 is a neoplasia. In certain embodiments, said disease or condition mediated by MK2 is a cancer. In certain embodiments, said disease or condition mediated by MK2 is an angiogenesis disorder. In certain embodiments, said disease or condition mediated by MK2 is a multiple myeloma. In certain embodiments, said disease or condition mediated by MK2 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). [0329] In certain embodiments, said disease or condition mediated by MK2 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 mediated by MK2 is myelodysplastic syndrome. In certain embodiments, said disease or condition mediated by MK2 is fibrosarcoma. In certain embodiments, said disease or condition mediated by MK2 is rhabdomyosarcoma. In certain embodiments, said disease or condition mediated by MK2 is astrocytoma. In certain embodiments, said disease or condition mediated by MK2 is neuroblastoma. In certain embodiments, said disease or condition mediated by MK2 is glioma and schwannomas. In certain embodiments, said disease or condition mediated by MK2 is melanoma. In certain embodiments, said disease or condition mediated by MK2 is seminoma. In certain embodiments, said disease or condition mediated by MK2 is teratocarcinoma. In certain embodiments, said disease or condition mediated by MK2 is osteosarcoma. In certain embodiments, said disease or condition mediated by MK2 is xenoderma pigmentosum. In certain embodiments, said disease or condition mediated by MK2 is keratoctanthoma. In certain embodiments, said disease or condition mediated by MK2 is thyroid follicular cancer. In certain embodiments, said disease or condition mediated by MK2 is Kaposi’s sarcoma. In certain embodiments, said disease or condition mediated by MK2 is melanoma. In certain embodiments, said disease or condition mediated by MK2 is teratoma. In certain embodiments, said disease or condition mediated by MK2 is rhabdomyosarcoma. In certain embodiments, said disease or condition mediated by MK2 is a metastatic and bone disorder. In certain embodiments, said disease or condition mediated by MK2 is cancer of the bone. In certain embodiments, said disease or condition mediated by MK2 is cancer of the mouth/pharynx. In certain embodiments, said disease or condition mediated by MK2 is cancer of the esophagus. In certain embodiments, said disease or condition mediated by MK2 is cancer of the larynx. In certain embodiments, said disease or condition mediated by MK2 is cancer of the stomach. In certain embodiments, said disease or condition mediated by MK2 is cancer of the intestine. In certain embodiments, said disease or condition mediated by MK2 is cancer of the colon. In certain embodiments, said disease or condition mediated by MK2 is cancer of the rectum. In certain embodiments, said disease or condition mediated by MK2 is cancer of the lung (e.g., non-small cell lung cancer or small cell lung cancer). In certain embodiments, said disease or condition mediated by MK2 is cancer of the liver. In certain embodiments, said disease or condition mediated by MK2 is cancer of the pancreas. In certain embodiments, said disease or condition mediated by MK2 is cancer of the nerve. In certain embodiments, said disease or condition mediated by MK2 is cancer of the brain (e.g., glioma or glioblastoma multiforme). In certain embodiments, said disease or condition mediated by MK2 is cancer of the head and neck. In certain embodiments, said disease or condition mediated by MK2 is cancer of the throat. In certain embodiments, said disease or condition mediated by MK2 is cancer of the ovary. In certain embodiments, said disease or condition mediated by MK2 is cancer of the uterus. In certain embodiments, said disease or condition mediated by MK2 is cancer of the prostate. In certain embodiments, said disease or condition mediated by MK2 is cancer of the testis. In certain embodiments, said disease or condition mediated by MK2 is cancer of the bladder. In certain embodiments, said disease or condition mediated by MK2 is cancer of the kidney. In certain embodiments, said disease or condition mediated by MK2 is cancer of the breast. In certain embodiments, said disease or condition mediated by MK2 is cancer of the gall bladder. In certain embodiments, said disease or condition mediated by MK2 is cancer of the cervix. In certain embodiments, said disease or condition mediated by MK2 is cancer of the thyroid. In certain embodiments, said disease or condition mediated by MK2 is cancer of the prostate. In certain embodiments, said disease or condition mediated by MK2 is cancer of the skin (e.g., skin squamous cell carcinoma). In certain embodiments, said disease or condition mediated by MK2 is a solid tumor. In certain embodiments, said disease or condition mediated by MK2 is gastric cancer. In certain embodiments, said disease or condition mediated by MK2 is hepatocellular carcinoma. In certain embodiments, said disease or condition mediated by MK2 is a peripheral nerve sheath tumor. In certain embodiments, said disease or condition mediated by MK2 is pulmonary arterial hypertension. [0330] In certain embodiments, said disease or condition mediated by MK2 is a cardiovascular or cerebrovascular disorder. In certain embodiments, said disease or condition mediated by MK2 is atherosclerosis. In certain embodiments, said disease or condition mediated by MK2 is restenosis of an atherosclerotic coronary artery. In certain embodiments, said disease or condition mediated by MK2 is acute coronary syndrome. In certain embodiments, said disease or condition mediated by MK2 is myocardial infarction. In certain embodiments, said disease or condition mediated by MK2 is cardiac-allograft vasculopathy. In certain embodiments, said disease or condition mediated by MK2 is stroke. In certain embodiments, said disease or condition mediated by MK2 is a central nervous system disorder with an inflammatory or apoptotic component. In certain embodiments, said disease or condition mediated by MK2 is Alzheimer’s disease. In certain embodiments, said disease or condition mediated by MK2 is Parkinson’s disease. In certain embodiments, said disease or condition mediated by MK2 is Huntington’s disease. In certain embodiments, said disease or condition mediated by MK2 is amyotrophic lateral sclerosis. In certain embodiments, said disease or condition mediated by MK2 is spinal cord injury. In certain embodiments, said disease or condition mediated by MK2 is neuronal ischemia. In certain embodiments, said disease or condition mediated by MK2 is peripheral neuropathy. [0331] In certain embodiments, said disease or condition mediated by MK2 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. [0332] In certain embodiments, the disease or condition mediated by MK2 is a rheumatic disease. In certain embodiments, the disease or condition mediated by MK2 is an inflammatory arthropathy. In certain embodiments, the disease or condition mediated by MK2 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. [0333] In certain embodiments, the disease or condition mediated by MK2 is a connective tissue disease. In certain embodiments, the disease or condition mediated by MK2 is lupus, systemic lupus erythematosus, juvenile systemic lupus erythematosus, nephritis, Sjögren’s syndrome, scleroderma (systemic sclerosis), Raynaud’s phenomenonjuvenile 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, [0334] In certain embodiments, the disease or condition mediated by MK2 is a neurodegenerative disease or neuroinflammatory disease. In certain embodiments, the disease or condition mediated by MK2 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. [0335] In certain embodiments, the disease or condition mediated by MK2 is an inflammatory bowel disease. In certain embodiments, the disease or condition mediated by MK2 is Crohn’s disease, ulcerative colitis, Celiac Sprue, Celiac disease, proctitis, eosinophilic gastroenteritis, autoimmune atrophic gastritis of pernicious anemia, or mastocytosis. [0336] In certain embodiments, the disease or condition mediated by MK2 is a skin autoimmune disorder. In certain embodiments, the disease or condition mediated by MK2 is psoriasis. In certain embodiments, the disease or condition mediated by MK2 is plaque psoriasis, Guttate psoriasis, psoriatic epidermal hyperplasia, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, atopic dermatitis, eczema dermatitis, dermatitis, pruritus, epidermal hyperplasia, juvenile dermatomyositis, dermatomyositis, or hidradenitis suppurativa. [0337] In certain embodiments, the disease or condition mediated by MK2 is an autoimmune disease of the eye. In certain embodiments, the disease or condition mediated by MK2 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 [0338] In certain embodiments, the disease or condition mediated by MK2 is an ocular manifestation of an autoimmune disease. [0339] In certain embodiments, the disease or condition mediated by MK2 is a respiratory disease. In certain embodiments, the disease or condition mediated by MK2 is asthma, chronic obstructive pulmonary disease, or acute respiratory disease. [0340] In certain embodiments, the disease or condition mediated by MK2 is diabetes. In certain embodiments, the disease or condition mediated by MK2 is Type I diabetes mellitus, Type II diabetes mellitus, or juvenile onset diabetes [0341] 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. [0342] Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, I-A, I-B, II, II-A, II-B, 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 an inflammatory disorder. [0343] Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, I-A, I-B, II, II-A, II-B, or other compounds in Section I) for treating a disease or condition, such as a disease or condition described herein (e.g., an inflammatory disorder). III. Combination Therapy [0344] Another aspect of the invention provides for combination therapy. Diazepino-thieno- quinoxaline compounds described herein (e.g., a compound of Formula I, I-A, I-B, II, II-A, II- B, 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. [0345] 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. [0346] 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. [0347] In certain embodiments, the compounds of the disclosure can be administered with one or more of a second 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. [0348] When administered concurrently, the compounds of the disclosure can be administered separately at the same time as the second 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 second therapeutic agent prepared as a second pharmaceutical composition, where the first pharmaceutical composition and the second pharmaceutical composition are administered simultaneously, sequentially, or separately. In certain embodiments, the amount and frequency of administration of the second therapeutic agent can used standard dosages and standard administration frequencies used for the particular therapeutic agent. See, e.g., Physicians’ Desk Reference, 70 ^th Ed., PDR Network, 2015; incorporated herein by reference. [0349] 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, 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. [0350] In certain embodiments, the second therapeutic agent is a leukotriene inhibitor. Exemplary leukotriene inhibitors are montelukast, zafirlukast, pranlukast, zileuton, or combinations thereof. [0351] In certain embodiments, the second therapeutic agent is a an NSAID. Exemplary NSAIDs are 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. [0352] In certain embodiments, the second therapeutic agent is a steroid. Exemplary steroids are prednisone, prednisolone, methylprednisone, triacmcinolone, betamethasone, dexamethasone, and prodrugs thereof. [0353] In certain embodiments, the second therapeutic agent is a tyrosine kinase inhibitor. Exemplary tyrosine kinase inhibitors are 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. [0354] In certain embodiments, the second therapeutic agent is a receptor kinase inhibitor, including among others, an inhibitor of EGFR or HER2. Exemplary receptor kinase inhibitors are gefitinib, erlotinib, neratinib, lapatinib, cetuximab, panitumumab, vandetanib, necitumumab, osimertinib, trastuzumab, neratinib, lapatinib, pertuzumab, or combinations thereof. [0355] In certain embodiments, the second 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. [0356] In certain embodiments, the second therapeutic agent is an HSP90 inhibitor. Exemplary HSP90 inhibitors are ganetespib, 17-AAG (17-allylaminogeldanamycin, NSC ₃ 30507), 17- DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF ₂ 024, CNF1010, or combinations thereof. [0357] In certain embodiments, the second therapeutic agent is an adenosine receptor 2A (A ₂ A) agonist. Exemplary adenosine receptor agonists are 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. [0358] In certain embodiments, the second therapeutic agent is selected from disease modifying antirheumatic drugs (DMARDS). Exemplary DMARDS are tocilizumab, certolizumab, etanercept, adalimumab, anakinra, abatacept, infliximab, rituximab, golimumab, uteskinumab, or combinations thereof. [0359] In certain embodiments, the second therapeutic agent is a phosphodiesterase (PDE) inhibitor. Exemplary phosphodiesterase inhibitors are apremilast, crisaborole, piclimilast, drotaverine, ibudulast, roflumilast, sildenafil, tadalafil, vardenafil, or combinations thereof. [0360] In certain embodiments, the second 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. [0361] In certain embodiments, the second therapeutic agent is a modulator of Axl kinase. Exemplary modulators of Axl kinase are 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. [0362] 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 ¹³¹ I-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-1C ₁ 1, GlioMab-H, ING-1, anti-LCG Mabs, MT-103, KSB-303, Therex, KW2871, anti-HMI.24, Anti- PTHrP, 2C ₄ antibody, SGN-30, TRAIL-RI Mab, Prostate Cancer antibody, H ₂ 2xKi-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). [0363] 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®). [0364] 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. [0365] 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®). [0366] 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®). [0367] For the treatment of thyroid cancer, the additional therapeutic agent is selected from doxorubicin hydrochloride (Adriamycin®), cabozantinib-S-malate (COMETRIQ®), and vandetanib (CAPRELSA®). [0368] 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®). [0369] 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®). [0370] For the treatment of pancreatic cancer, the other therapeutic agent may be selected from fluorouracil (ADRUCIL®), EFUDEX®, FLUOROPLEX®), erlotinib hydrochloride (TARCEVA®), gemcitabine hydrochloride (GEMZAR®), and mitomycin or mitomycin C (MITOZYTREXTM, MUTAMYCIN®). [0371] For the treatment of cervical cancer, the additional therapeutic agent is selected from bleomycin (BLENOXANE®), cisplatin (PLATINOL®, PLATINOL-AQ®) and topotecan hydrochloride (HYCAMTIN®). [0372] 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®). [0373] 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®). [0374] 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®). [0375] 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. [0376] 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. [0377] 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). [0378] 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. [0379] 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-A, I-B, II, II-A, II-B, 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-A, I-B, II, II- A, II-B, 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-A, I-B, II, II-A, II-B, or other compounds in Section I) and the additional therapeutic agent(s) are present in the same composition, which is suitable for oral administration. [0380] In certain embodiments, the compound described herein (e.g., a compound of Formula I or I-A, 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. [0381] 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-A, I-B, II, II-A, II-B, 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. IV. Pharmaceutical Compositions and Dosing Considerations [0382] 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 or I-A) and a pharmaceutically acceptable carrier. [0383] 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. [0384] 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. [0385] 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. 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. [0386] 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. [0387] 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. [0388] 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. [0389] 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. [0390] In solid dosage forms of the invention for oral administration (e.g., 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. [0391] 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. [0392] 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. [0393] 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. [0394] 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. [0395] 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. [0396] 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. [0397] 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. [0398] 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. [0399] 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. [0400] 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. [0401] 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. [0402] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention. [0403] 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. [0404] 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. [0405] 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. [0406] 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. [0407] 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. [0408] 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. [0409] 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. [0410] 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. [0411] 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. [0412] 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. [0413] 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. [0414] 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. [0415] 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. [0416] 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. [0417] 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. [0418] 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. [0419] The invention further provides a unit dosage form (such as a tablet or capsule) comprising a diazepino-thieno-quinoxaline compound or related compound described herein in a therapeutically effective amount for the treatment of a disease or condition described herein. V. Medical Kits [0420] Another aspect of the invention provides a medical kit comprising, for example, (i) a compound described herein, and (ii) instructions for use according to a method described herein. VI. Enumerated Embodiments [0421] The following exemplary embodiments are provided, the numbering of which is not to be construed as designating levels of importance: [0422] Embodiment 1 provides a compound of formula (II): or a pharmaceutically acceptable salt thereof, wherein: R ¹ and R ³ are independently hydrogen, C _1-4 alkyl, or C _3-4 cycloalkyl; R ² is C _1-4 alkyl, C _1-4 hydroxyalkyl, -C(O)N(R ⁶ )(R ⁷ ), or hydrogen; R ⁴ is hydrogen, C _1-4 alkyl, or -C(O)N(R ⁶ )(R ⁷ ); or R ⁴ and R ³ are taken together to form oxo; occurrences of R ⁹ ; (ii) phenyl or 6-membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatom(s) are nitrogen, where the phenyl and heteroaryl are substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; or (iii) 6-membered monocyclic, unsaturated oxo- heterocyclyl containing 1 or 2 heteroatoms, wherein the heteroatom(s) are nitrogen, and the oxo-heterocyclyl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; R ⁶ and R ⁷ are independently hydrogen, C _1-6 alkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; or R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom; R ⁸ is hydrogen, C _1-4 alkyl, or –(C _2-4 alkylene)-(C _1-4 alkoxyl); R ⁹ is –(C _1-6 alkylene)-(C _1-6 alkoxyl), C _1-6 alkoxyl, -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ), - C(O)N(R ⁶ )(R ⁷ ), -C(O)N(R ⁶ )(R ¹³ ), -S(O) ₂ R ¹⁸ , -S(O)(=NH)R ¹⁸ , -S(O) ₂ N(R ⁶ )(R ⁷ ), -(C _0-6 alkylene)-N(R ⁶ )C(O)R ¹⁴ , -(C _0-6 alkylene)-(N(R ¹⁵ )S(O)(N(C _1-4 alkyl))-C _1-4 alkyl), -(C _0-6 alkylene)-(S(O)(NH)-(C _1-4 alkyl)), or deuterium; R ¹⁰ is a group capable of forming a covalent bond to a sulfhydryl group; R ¹¹ is halo, hydroxyl, C _1-6 alkyl, C _1-6 haloalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), C _3-7 cycloalkyl, C _1-6 alkoxyl, or –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ); R ¹² represents independently for each occurrence halo, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _3-7 cycloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, -C(O)R ¹⁹ , or oxo; R ¹³ is a 4-7 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ ; R ¹⁴ represents independently for each occurrence hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; R ¹⁵ is hydrogen or C _1-4 alkyl; R ¹⁶ is hydrogen, C _1-4 alkyl, or hydroxyl; R ¹⁷ is hydrogen, C _1-4 alkyl, or –(C _2-4 alkylene)-(C _1-4 alkoxyl); R ¹⁸ is C _1-4 alkyl or C _3-6 cycloalkyl; R ¹⁹ represents independently for each occurrence C _1-6 alkyl, C _3-6 cycloalkyl, or -(C _1-6 alkylene)-(C _3-6 cycloalkyl); X is -N(R ¹⁷ )-, -O-, or -CH ₂ -; n, and p are independently 0, 1, or 2; and t is 0, 1, 2, 3, 4, 5, or 6. [0423] Embodiment 2 provides the compound of Embodiment 1, wherein the compound is a compound of Formula II. [0424] Embodiment 3 provides the compound of Embodiment 1 or 2, wherein X is -N(R ¹⁷ )-. [0425] Embodiment 4 provides the compound of Embodiment 1 or 2, wherein X is -O-. [0426] Embodiment 5 provides the compound of Embodiment 1 or 2, wherein X is -CH ₂ -. [0427] Embodiment 6 provides the compound of Embodiment 1, wherein the compound is a compound of formula IIa: or a pharmaceutically acceptable salt thereof. [0428] Embodiment 7 provides the compound of Embodiment 1, wherein the compound is a compound of formula IIb: or a pharmaceutically acceptable salt thereof. [0429] Embodiment 8 provides the compound of Embodiment 1, wherein the compound is a compound of formula IIc, IId, or IIe: IIe or a pharmaceutically acceptable salt thereof. [0430] Embodiment 9 provides the compound of Embodiment 1, wherein the compound is a compound of formula IIf: IIf or a pharmaceutically acceptable salt thereof. [0431] Embodiment 10 provides the compound of Embodiment 1, wherein the compound is a compound of Formula II-A: (II-A) or a pharmaceutically acceptable salt thereof, wherein: R ¹ and R ³ are independently hydrogen, C _1-4 alkyl, or C _3-4 cycloalkyl; R ² is C _1-4 alkyl, C _1-4 hydroxyalkyl, -C(O)N(R ⁶ )(R ⁷ ), or hydrogen; R ⁴ is hydrogen, C _1-4 alkyl, or -C(O)N(R ⁶ )(R ⁷ ); or R ⁴ and R ³ are taken together to form oxo; of which is substituted with n occurrences of R ⁹ ; (ii) phenyl or 6-membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatom(s) are nitrogen, where the phenyl and heteroaryl are substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; or (iii) 6- membered monocyclic, unsaturated oxo-heterocyclyl containing 1 or 2 heteroatoms, wherein the heteroatom(s) are nitrogen, and the oxo-heterocyclyl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; R ⁶ and R ⁷ are independently hydrogen, C _1-6 alkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; or R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom; R ⁸ , R ¹⁵ , and R ¹⁷ are independently hydrogen or C _1-4 alkyl; R ⁹ is –(C _1-6 alkylene)-(C _1-6 alkoxyl), C _1-6 alkoxyl, -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ), - C(O)N(R ⁶ )(R ⁷ ), -C(O)N(R ⁶ )(R ¹³ ), -(C _0-6 alkylene)-N(R ⁶ )C(O)(R ¹⁴ ), -(C _0-6 alkylene)- (N(R ¹⁵ )S(O)(N(C _1-4 alkyl))-C _1-4 alkyl), -(C _0-6 alkylene)-(S(O)(NH)-(C _1-4 alkyl)), or deuterium; R ¹⁰ is a group capable of forming a covalent bond to a sulfhydryl group; R ¹¹ is halo, hydroxyl, C _1-6 alkyl, C _1-6 haloalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), C _3-7 cycloalkyl, C _1-6 alkoxyl, or –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ); R ¹² represents independently for each occurrence halo, C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl, or C _1-6 alkoxyl; R ¹³ is a 4-7 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ ; R ¹⁴ represents independently for each occurrence hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; R ¹⁶ is hydrogen, C _1-4 alkyl, or hydroxyl; n and p are independently 0, 1, or 2; and t is 0, 1, 2, 3, 4, 5, or 6. [0432] Embodiment 11 provides the compound of Embodiment 10, wherein the compound is a compound of Formula II-A. [0433] Embodiment 12 provides the compound of Embodiment 1, wherein the compound is a compound of Formula II-B: or a pharmaceutically acceptable salt thereof, wherein: R ¹ and R ³ are independently hydrogen, C _1-4 alkyl, or C _3-4 cycloalkyl; R ² is C _1-4 alkyl, C _1-4 hydroxyalkyl, -C(O)N(R ⁶ )(R ⁷ ), or hydrogen; R ⁴ is hydrogen, C _1-4 alkyl, or -C(O)N(R ⁶ )(R ⁷ ); or R ⁴ and R ³ are taken together to form oxo; , each of which is substituted with n occurrences of R ⁹ ; (ii) phenyl or 6-membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatom(s) are nitrogen, where the phenyl and heteroaryl are substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; or (iii) 6- membered monocyclic, unsaturated oxo-heterocyclyl containing 1 or 2 heteroatoms, wherein the heteroatom(s) are nitrogen, and the oxo-heterocyclyl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ ; R ⁶ and R ⁷ are independently hydrogen, C _1-6 alkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; or R ⁶ and R ⁷ when bonded to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom; R ⁸ , R ¹⁵ , and R ¹⁷ are independently hydrogen or C _1-4 alkyl; R ⁹ is -(C _1-6 alkylene)-(C _1-6 alkoxyl) or -(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ); R ¹⁰ is a group capable of forming a covalent bond to a sulfhydryl group; R ¹¹ is halo, hydroxyl, C _1-6 alkyl, C _1-6 haloalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), C _3-7 cycloalkyl, C _1-6 alkoxyl, or –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ); R ¹² represents independently for each occurrence halo, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _3-7 cycloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, -C(O)R ¹⁹ , or oxo; R ¹³ is a 4-7 membered saturated monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹⁶ ; R ¹⁴ represents independently for each occurrence hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, -(C _1-6 alkylene)-(C _3-7 cycloalkyl), or C _3-7 cycloalkyl; R ¹⁶ is hydrogen, C _1-4 alkyl, or hydroxyl; R ¹⁹ represents independently for each occurrence C _1-6 alkyl, C _3-6 cycloalkyl, or -(C _1-6 alkylene)-(C _3-6 cycloalkyl); n and p are independently 0, 1, or 2; and t is 0, 1, 2, 3, 4, 5, or 6. [0434] Embodiment 13 provides the compound of Embodiment 12, wherein the compound is a compound of Formula II-B. [0435] Embodiment 14 provides the compound of any one of Embodiments 1-3 or 10-13, wherein R ¹⁷ is hydrogen. [0436] Embodiment 15 provides the compound of any one of Embodiments 1-5 or 10-14, wherein R ¹ and R ³ are hydrogen. [0437] Embodiment 16 provides the compound of any one of Embodiments 1-5 or 10-15, wherein R ² is C _1-4 alkyl. [0438] Embodiment 17 provides the compound of any one of Embodiments 1-5 or 10-15, wherein R ² is -CH ₃ . [0439] Embodiment 18 provides the compound of any one of Embodiments 1-5 or 10-15, wherein R ² is C _1-4 hydroxyalkyl. [0440] Embodiment 19 provides the compound of any one of Embodiments 1-5 or 10-15, wherein R ² is -C(O)N(R ⁶ )(R ⁷ ). [0441] Embodiment 20 provides the compound of any one of Embodiments 1-5 or 10-15, wherein R ² is hydrogen. [0442] Embodiment 21 provides the compound of any one of Embodiments 1-5 or 10-20, wherein R ⁴ is hydrogen. [0443] Embodiment 22 provides the compound of any one of Embodiments 1-5 or 10-20, wherein R ⁴ is -C(O)N(R ⁶ )(R ⁷ ). [0444] Embodiment 23 provides the compound of any one of Embodiments 1-5 or 10-22, wherein R ⁴ and R ³ are taken together to form oxo. [0445] Embodiment 24 provides the compound of any one of Embodiments 1-23, wherein R ⁵ is , each of which is substituted with n occurrences of R ⁹ . [0446] Embodiment 25 provides the compound of any one of Embodiments 1-23, wherein R ⁵ is substituted with n occurrences of R ⁹ . [0447] Embodiment 26 provides the compound of any one of Embodiments 1-23, wherein R ⁵ is substituted with n occurrences of R ⁹ . [0448] Embodiment 27 provides the compound of any one of Embodiments 1-23, wherein R ⁵ is , each of which is substituted with n occurrences of R ⁹ . [0449] Embodiment 28 provides the compound of any one of Embodiments 1-27, wherein n is 1. [0450] Embodiment 29 provides the compound of any one of Embodiments 1-28, wherein R ⁹ is –(C _1-6 alkylene)-(C _1-6 alkoxyl). [0451] Embodiment 30 provides the compound of any one of Embodiments 1-28, wherein R ⁹ is –(C _0-6 alkylene)-(4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). [0452] Embodiment 31 provides the compound of any one of Embodiments 1-28, wherein R ⁹ is –(C _1-3 alkylene)-(5-6 membered saturated monocyclic heterocyclyl containing 1 or 2 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). [0453] Embodiment 32 provides the compound of any one of Embodiments 1-28, wherein R ⁹ is , each of which is substituted with 0, 1, 2, or 3 instances of R ¹² . [0454] Embodiment 33 provides the compound of any one of Embodiments 1-28, wherein R ⁹ is . [0455] Embodiment 34 provides the compound of any one of Embodiments 1-28, wherein R ⁹ is –(C _1-3 alkylene)-(7-10 membered saturated bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). [0456] Embodiment 35 provides the compound of any one of Embodiments 1-28, wherein R ⁹ is –(C _1-3 alkylene)-(7-10 membered saturated spiro-bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). [0457] Embodiment 36 provides the compound of any one of Embodiments 1-28, wherein R ⁹ is , each of which is substituted with 0, 1, 2, or 3 instances of R ¹² . [0458] Embodiment 37 provides the compound of any one of Embodiments 1-28, 30, 31, 34, or 35, wherein t is 1, 2 or 3. [0459] Embodiment 38 provides the compound of any one of Embodiments 1-31, wherein R ¹² represents independently for each occurrence halo, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _3-7 cycloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, -C(O)R ¹⁹ , or oxo. [0460] Embodiment 39 provides the compound of any one of Embodiments 1-32 or 34-37, wherein R ¹² represents independently for each occurrence halo, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _3-7 cycloalkyl, or -C(O)R ¹⁹ . [0461] Embodiment 40 provides the compound of any one of Embodiments 1-32 or 34-37, wherein R ¹² represents independently for each occurrence C _1-6 alkyl. [0462] Embodiment 41 provides the compound of any one of Embodiments 1-28, wherein R ⁹ is -C(O)N(R ⁶ )(R ⁷ ), -C(O)N(R ⁶ )(R ¹³ ), -(C _0-6 alkylene)-N(R ⁶ )C(O)(R ¹⁴ ), -(C _0-6 alkylene)- (N(R ¹⁵ )S(O)(N(C _1-4 alkyl))-C _1-4 alkyl), or –(C _0-6 alkylene)-(S(O)(NH)-(C _1-4 alkyl)). [0463] Embodiment 42 provides the compound of any one of Embodiments 1-23, wherein R ⁵ is phenyl or 6-membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatom(s) are nitrogen, where the phenyl and heteroaryl are substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . [0464] Embodiment 43 provides the compound of any one of Embodiments 1-23, wherein R ⁵ is phenyl substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . [0465] Embodiment 44 provides the compound of any one of Embodiments 1-23, wherein R ⁵ is a 6-membered heteroaryl containing 1 or 2 heteroatoms, wherein the heteroatom(s) are nitrogen, where the heteroaryl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . [0466] Embodiment 45 provides the compound of any one of Embodiments 1-23, wherein R ⁵ is a pyridinyl substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . [0467] Embodiment 46 provides the compound of any one of Embodiments 1-23, wherein R ⁵ is a 6-membered monocyclic, unsaturated oxo-heterocyclyl containing 1 or 2 heteroatoms, wherein the heteroatom(s) are nitrogen, and the oxo-heterocyclyl is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . [0468] Embodiment 47 provides the compound of any one of Embodiments 1-23, wherein R ⁵ is , each of which is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . [0469] Embodiment 48 provides the compound of any one of Embodiments 1-23, wherein R ⁵ is , each of which is substituted with 1 occurrence of R ¹⁰ and p occurrences of R ¹¹ . [0470] Embodiment 49 provides the compound of any one of Embodiments 1-23 or 42-48, wherein R ¹⁰ is -N(H)C(O)(C _2-4 alkenyl). [0471] Embodiment 50 provides the compound of any one of Embodiments 1-23 or 42-48, wherein R ¹⁰ is -N(H)C(O)CH=CH ₂ . [0472] Embodiment 51 provides the compound of any one of Embodiments 1-23 or 42-50, wherein p is 1. [0473] Embodiment 52 provides the compound of any one of Embodiments 1-23 or 42-50, wherein p is 2. [0474] Embodiment 53 provides the compound of any one of Embodiments 1-23 or 48-52, wherein R ¹¹ represents independently for each occurrence halo, hydroxyl, C _1-6 alkyl, or C _1-6 haloalkyl. [0475] Embodiment 54 provides the compound of any one of Embodiments 1-23 or 48-52, wherein R ¹¹ represents independently for each occurrence halo, C _1-6 alkyl, or –(C _0-6 alkylene)- (4-10 membered saturated monocyclic or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with t instances of R ¹² ). [0476] Embodiment 55 provides the compound of any one of Embodiments 1-23 or 41-54, wherein R ⁶ and R ⁷ are independently hydrogen or C _1-6 alkyl. [0477] Embodiment 56 provides the compound of any one of Embodiments 1-23 or 41-54, wherein R ¹⁴ represents independently for each occurrence hydrogen, C _1-6 alkyl, or C _1-6 hydroxyalkyl. [0478] Embodiment 57 provides the compound of any one of Embodiments 1-23 or 41-56, wherein R ¹³ is a 4 membered saturated monocyclic heterocyclyl containing 1 heteroatom selected from oxygen, wherein the heterocyclyl is substituted with t instances of R ¹⁶ . [0479] Embodiment 58 provides the compound of any one of Embodiments 1-28, 30, 31, 34, or 35, or 42-57, wherein t is 1. [0480] Embodiment 59 provides the compound of any one of Embodiments 1-23, wherein R ⁵ is . [0481] Embodiment 60 provides a compound in Table 1 herein, or a pharmaceutically acceptable salt thereof. [0482] Embodiment 61 provides a pharmaceutical composition comprising a compound of any one of Embodiments 1-60 and a pharmaceutically acceptable carrier. [0483] Embodiment 62 provides a method for treating a disease or condition mediated by MK2, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of Embodiments 1-60 to treat the disease or condition. [0484] Embodiment 63 provides the method of Embodiment 62, wherein said disease or condition mediated by MK2 is an inflammatory disorder. [0485] Embodiment 64 provides the method of Embodiment 62, wherein said disease or condition mediated by MK2 is ankylosing spondylitis, rheumatoid arthritis, 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, psoriatic arthritis, hidradenitis suppurativa, cryopyrin- associated periodic syndromes, or juvenile idiopathic arthritis. [0486] Embodiment 65 provides the method of Embodiment 62, wherein said disease or condition mediated by MK2 is ankylosing spondylitis, rheumatoid arthritis, psoriasis, 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, or asthma. [0487] Embodiment 66 provides the method of Embodiment 62, wherein said disease or condition mediated by MK2 is rheumatoid arthritis, ankylosing spondylitis, plaque psoriasis, psoriatic arthritis, ulcerative colitis, Crohn’s disease, hidradenitis suppurativa, cryopyrin- associated periodic syndromes, or juvenile idiopathic arthritis. [0488] Embodiment 67 provides the method of Embodiment 62, wherein said disease or condition mediated by MK2 is cancer. [0489] Embodiment 68 provides the method of Embodiment 62, wherein said disease or condition mediated by MK2 is a cancer selected from pancreatic cancer, colorectal cancer, multiple myeloma, lung cancer, gastric cancer, breast cancer, nasopharyngeal cancer, skin cancer, bladder cancer, prostate cancer, head and neck cancer, or glioblastoma. [0490] Embodiment 69 provides the method of Embodiment 62, wherein said disease or condition mediated by MK2 is pancreatic cancer. [0491] Embodiment 70 provides the method of any one of Embodiments 62-69, wherein the subject is a human. [0492] Embodiment 71 provides a method of inhibiting the activity of a MK2, comprising contacting a MK2 with an effective amount of a compound of any one of Embodiments 1-60 to inhibit the activity of said MK2. [0493] Embodiment 72 provides a method of covalently modifying a MK2, comprising contacting a MK2 with an effective amount of a compound of any one of Embodiments 1-60 to covalently modify the MK2. [0494] Embodiment 73 provides a covalently modified MK2 formed by the method of Embodiment 72. EXAMPLES [0495] The invention now being generally described, will be moret readily understood by reference to the following examples, which are included merely for purposes of illustrating certain aspects and embodiments of the present invention, and are not intended to limit the invention. EXAMPLE 1 – Synthesis of (R)-3-((2-Chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-10- methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’:4,5 ]thieno[3,2-f]quinoxaline-8-one (I-1) [0496] Step 1: Preparation of 2-Chloro-6-nitroquinoxaline. A mixture of 6-nitroquinoxalin- 2-ol (3 g, 15.7 mmol) in phosphoroyl trichloride (30 mL, 15.7 mmol) was stirred for 18 hours at 70 °C Then, the phosphoroyl trichloride was removed in vacuo. The resulting residue was dissolved in dichloromethane (200 mL), washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuuo to give 2-chloro-6-nitroquinoxaline (2.6 g, 12.4 mmol) as a yellow solid. LCMS: Rt: 1.92 min; no mass. [0497] Step 2: Preparation of 2-Methoxy-6-nitroquinoxaline. A mixture of 2-chloro-6- nitroquinoxaline (1 g, 4.77 mmol), methoxysodium (1.03 g, 1.2 eq., 5.73 mmol) in methanol (20 mL, 494 mmol) was stirred for 3 hours at room temperature. Then, the solvent was removed in vacuo. The resulting residue was suspendered in water (50 mL) and stirred for 0.5 hours. The resulting solid was collected by filtration and dried in vacuo to give 2-methoxy-6- nitroquinoxaline (940 mg, 4.58 mmol) as a grey solid. LCMS: Rt: 1.99 min; [M+H] ⁺ = 206.1. [0498] Step 3: Preparation of 2-Methoxyquinoxalin-6-amine. A mixture of 2-methoxy-6- nitroquinoxaline (840 mg, 4.09 mmol) and palladium (10% on active carbone, 434 mg, 0.1 eq., 409 µmol) in dioxane (10 mL) was stirred for 3 hours at room temperature under hydrogen. Then, the reaction mixture was filtered through CELITE ^® diatomaceous earth. The filtrate was concentrated to give 2-methoxyquinoxalin-6-amine (600 mg, crude) as a black solid. LCMS: Rt: 1.81 min; [M+H] ⁺ = 176.2. [0499] Step 4: Preparation of 5-Bromo-2-methoxyquinoxalin-6-amine. A solution of 2- methoxyquinoxalin-6-amine (0.6 g, 3.42 mmol) and 1-bromopyrrolidine-2,5-dione (610 mg, 3.42 mmol) in N,N-dimethylformamide (5 mL) was stirred for 2 hours at room temperature. The solvent was removed, and the resulting residue was purified by flash chromatography (dichloromethane/methanol = 99/1) to give 5-bromo-2-methoxyquinoxalin-6-amine (410 mg, 1.44 mmol) as a yellow solid. LCMS: Rt: 1.80min; [M+H] ⁺ = 254.1. [0500] Step 5: Preparation of 6-Amino-2-methoxyquinoxaline-5-carbonitrile. A mixture of 5-bromo-2-methoxyquinoxalin-6-amine (0.3 g, 1.18 mmol), zinc cyanide (139 mg, 1.18 mmol), iodocopper (67.5 mg, 0.3 eq., 354 µmol), and tetrakis(triphenylphosphine)palladium (137 mg, 0.1 eq., 118 µmol) in dimethylformamide (30 mL, 387 mmol) was stirred for 16 hours at 125 °C. After cooling the reaction mixture to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL), washed with water and brine, and concentrated in vacuo. The resulting residue was purified by flash chromatography (dichloromethane/methanol = 97/3) to give 6-amino-2-methoxyquinoxaline-5-carbonitrile (120 mg, crude) as a yellow solid. LCMS: Rt: 1.71 min; [M+H] ⁺ = 201.1. [0501] Step 6: Preparation of 6-Bromo-2-methoxyquinoxaline-5-carbonitrile. A mixture of 6-amino-2-methoxyquinoxaline-5-carbonitrile (50 mg, 250 µmol) and tert-butyl nitrate (44.6 mg, 1.5 eq., 375 µmol) in acetonitrile (4 mL, 76.6 mmol) was stirred for 1 hour at 0 °C, then dibromocopper (83.7 mg, 1.5 eq., 375 µmol) was added. Next, the reaction solution was stirred for 5 hours at 50 °C. Then, the reaction solution was quenched with brine and extracted with ethyl acetate (60 mL x 2). The organic phase was concentrated in vacuo to give 6-bromo-2- methoxyquinoxaline-5-carbonitrile (60 mg, 198 µmol) as a yellow solid. LCMS: Rt: 1.88 min; [M+H] ⁺ = 264.0. [0502] Step 7: Preparation of Methyl 9-amino-3-methoxythieno[3,2-f]quinoxaline-8- carboxylate. A mixture of 6-bromo-2-methoxyquinoxaline-5-carbonitrile (60 mg, 227 µmol), methyl 2-sulfanylacetate (36.2 mg, 1.5 eq., 341 µmol), and sodium methanolate (24.5 mg, 2 eq., 454 µmol) in methanol (3.64 mL, 89.8 mmol) was stirred for 4 hours at 90 °C. Then, the solvent was removed from the reaction mixture. The resulting residue was dissolved in ethyl acetate (50 mL), washed with water and brine, dried over sodium sulfate, and concentrated in vacuo to give methyl 9-amino-3-methoxythieno[3,2-f]quinoxaline-8-carboxylate (70 mg, 0.242 mmol) as a yellow solid. The crude product was used directly in the next step. LCMS: Rt = 2.20 min, [M+H] ⁺ =290.1. [0503] Step 8: Preparation of Methyl (R)-9-((2-((tert-butoxycarbonyl)amino)propyl) amino)-3-methoxythieno[3,2-f]quinoxaline-8-carboxylate. A mixture of methyl 9-amino-3- methoxythieno[3,2-f]quinoxaline-8-carboxylate (70 mg, 195 µmol), tert-butyl (4R)-4-methyl- 2,2-dioxo-1,2λ⁶,3-oxathiazolidine-3-carboxylate (69.5 mg, 1.5 eq., 293 µmol), and sodium hydride (7.03 mg, 0.9 eq., 176 µmol) in N,N-dimethylformamide (3mL) was stirred for 4 hours at room temperature. Then, the reaction solution was quenched with saturated aqueous ammonium chloride and the resulting mixture was purified by Prep-HPLC to give methyl (R)- 9-((2-((tert-butoxycarbonyl)amino)propyl)amino)-3-methoxythi eno[3,2-f]quinoxaline-8- carboxylate (70 mg, 0.157 mmol) as a yellow solid. LCMS: Rt = 2.247 min, [M+H] ⁺ =447.0. [0504] Step 9: Preparation of Methyl (R)-9-((2-aminopropyl)amino)-3-hydroxythieno[3,2- f]quinoxaline-8-carboxylate. A mixture of methyl 9-{[(2R)-2-{[(tert-butoxy)carbonyl] amino}propyl]amino}-3-methoxythieno[3,2-f]quinoxaline-8-carb oxylate (70 mg, 157 µmol) in hydrochloric acid (4M in methanol, 3mL) was stirred for 4 hours at room temperature. Then, the reaction mixture was concentrated to give methyl (R)-9-((2-aminopropyl)amino)-3- hydroxythieno[3,2-f]quinoxaline-8-carboxylate as a brown oil. The crude product was used directly in the next step. LCMS: Rt = 1.359 min, [M+H] ⁺ =333.0. [0505] Step 10: Preparation of (R)-3-Hydroxy-10-methyl-9,10,11,12-tetrahydro-8H- [1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one. A mixture of methyl 9-{[(2R)-2- aminopropyl]amino}-3-hydroxythieno[3,2-f]quinoxaline-8-carbo xylate (65 mg, 196 µmol) and sodium methanolate (31.7 mg, 3 eq., 587 µmol) in methanol (5 mL) was stirred at 80 °C for 20 hours. After cooling the reaction mixture to room temperature, the reaction mixture was filtered. The filtrate was concentrated to give (R)-3-hydroxy-10-methyl-9,10,11,12-tetrahydro- 8H-[1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-8-on e (50 mg, 166 µmol) as a black oil. The crude product was used directly in the next step. LCMS: Rt=1.65min, [M+H ₂ O+H] ⁺ =319.0. [0506] Step 11: Preparation of (R)-3-((2-Chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-10- methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’:4,5 ]thieno[3,2-f]quinoxalin-8-one. A mixture of (R)-3-hydroxy-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazep ino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (50 mg, 166 µmol), 2,4-dichloro-5-(ethoxymethyl) pyrimidine (68.9 mg, 2 eq., 333 µmol) and dipotassium carbonate in dimethylformamide (4 mL, 51.7 mmol) was stirred for 24 hours at room temperature. Then, the reaction mixture was filtered, and the filtrate was purified by Prep-HPLC to give (R)-3-((2-chloro-5- (ethoxymethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetra hydro-8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one formate (12.8 mg, 0.027 mmol) as a yellow solid. LCMS: Rt: 1.77 min; [M+H] ⁺ = 471.0; 100% purity at 214 nm. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.10 (s, 1H), 8.80 (s, 1H), 8.77 (s, 1H), 8.36 (s, 1H), 8.34 (s, 1H), 8.01 (d, J = 4.4 Hz, 1H), 7.96 (d, J = 8.9 Hz, 1H), 4.69 (s, 2H), 3.63 (dd, J = 14.0, 7.0 Hz, 5H), 1.24 – 1.18 (m, 6H). EXAMPLE 2 – Synthesis of (R)-3-((2-chloro-5-(morpholinomethyl)pyrimidin-4-yl)oxy)- 10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’: 4,5]thieno[3,2-f]quinoxalin-8- one (I-2) [0507] Step 1. Preparation of 2,4-dichloro-5-(iodomethyl)pyrimidine. A mixture of 2,4- dichloro-5-(chloromethyl)pyrimidine (0.5 g, 2.53 mmol) and sodium iodide (456 mg, 1.2 eq., 3.0 mmol) in acetone (5 mL) was stirred at 60 °C for 2 hours. Then, the reaction mixture was filtered, and the filtrate was concentrated under vacuum to give 2,4-dichloro-5- (iodomethyl)pyrimidine (0.7 g, 2.28 mmol) as a brown solid. [M+H] ⁺ = 289, rt = 1.80 min. [0508] Step 2. Preparation of 4-((2,4-dichloropyrimidin-5-yl)methyl)morpholine. A mixture of 2,4-dichloro-5-(iodomethyl)pyrimidine (450 mg, 1.56 mmol), morpholine (136 mg, 1.56 mmol), and potassium carbonate (323 mg, 1.5 eq., 2.34 mmol) in acetonitrile (15 mL) was stirred at room temperature for 4 hours. Then, the reaction mixture was filtered, and the filtrate was concentrated to dryness and purified via silica gel chromatography eluting with ethyl acetate and petroleum ether. Pure fractions from the chromatography were combined and concentrated to afford 180 mg (0.61 mmol) of 4-((2,4-dichloropyrimidin-5- yl)methyl)morpholine as a yellow oil. [M+H] ⁺ 248, rt = 1.06 min. [0509] Step 3. Preparation of (R)-3-((2-chloro-5-(morpholinomethyl)pyrimidin-4-yl)oxy)- 10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’: 4,5]thieno[3,2-f]quinoxalin-8- one. A mixture of 4-((2,4-dichloropyrimidin-5-yl)methyl)morpholine (62 mg, 1.5 eq., 0.25 mmol), (R)-3-hydroxy-10-methyl-9,10,11,12-tetrahydro-8H- [1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (50 mg, 0.166 mmol), and potassium carbonate (46 mg, 2 eq., 0.33 mmol) in DMSO (3 mL) was stirred at room temperature for 24 hours. Then, the reaction mixture was filtered, and the filtrate was purified via RP-HPLC to afford the title compound (13 mg, 0.024 mmol) as a yellow solid. [M+H] ⁺ = 512, rt = 1.50 min. ¹ H NMR (400MHz, DMSO-d6) δ 9.08 (s, 1H), 8.79 (d, J = 10.6Hz, 2H), 8.34 (d, J = 8.8Hz, 1H), 8.11 – 7.84 (m, 2H), 3.69 (s, 4H), 3.58 (d, J = 15.0Hz, 6H), 2.48 – 2.36 (m, 4H), 1.22 (d, J = 6.3Hz, 3H). EXAMPLE 3 – Synthesis of (R)-3-((2-chloro-5-((3,3-dimethyl-2-oxopyrrolidin-1- yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydr o-8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (I-56) [0510] The title compound was prepared using the following procedures. [0511] Step 1. Preparation of 1-((2,4-dichloropyrimidin-5-yl)methyl)-3,3-dimethyl- pyrrolidin-2-one. To the mixture of 2,4-dichloro-5-(iodomethyl)pyrimidine (0.1 g, 1 eq, 346 µmol) in tetrahydrofuran (4 mL) was added 3,3-dimethylpyrrolidin-2-one (39.2 mg, 1 eq, 346 µmol) and potassium 2-methylpropan-2-olate (77.7 mg, 2 eq, 692 µmol) at 0 °C. The mixture was stirred at 0 °C for 2 hours. LCMS analysis of the reaction mixture showed the starting material was consumed and the desired peak was detected. Two additional vials were set up as described above. All three reaction mixtures were combined and diluted with water (20 mL) then extracted with ethyl acetate (3 × 15 mL). The organic phase was combined, washed with brine (5 mL) and dried over by sodium sulfonate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by prep-TLC (petroleum ether/ethyl acetate = 1/1, R _f = 0.5) to give 64 mg (17.09%) of 1-((2,4- dichloropyrimidin-5-yl)methyl)-3,3-dimethylpyrrolidin-2-one as a yellow oil. LCMS (ESI ⁺ ): Rt = 1.422 min, m/z 274.1 (M+H)+. [0512] Step 2. Preparation of (R)-3-((2-chloro-5-((3,3-dimethyl-2-oxopyrrolidin-1- yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydr o-8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one . To the mixture of 1-((2,4-dichloropyrimidin-5- yl)methyl)-3,3-dimethylpyrrolidin-2-one (60 mg, 1 eq, 153 µmol) in dimethyl sulfoxide (5.25 mL) was added (R)-3-hydroxy-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazep ino[5’,6’:4,5] thieno[3,2-f]quinoxalin-8-one (23 mg, 76.6 µmol, 0.5 eq) and cesium carbonate (99.8 mg, 2 eq, 306 µmol) at 25 °.C The resulting mixture was stirred at 25 °C for 3.5 hours. LCMS analysis of the reaction mixture showed the material peak was consumed and the desired peak was detected. The reaction mixture was filtered to give the residue, which was purified by prep- HPLC to give 17.5 mg (20.62%) of (R)-3-((2-chloro-5-((3,3-dimethyl-2-oxopyrrolidin-1- yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydr o-8H-[1,4]diazepino[5’,6’:4,5] thieno[3,2-f]quinoxalin-8-one as a yellow solid. LCMS (ESI+): Rt = 1.664 min, m/z = 538.1 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d6) 9.07 (s, 1H), 8.83 – 8.76 (m, 1H), 8.64 (s, 1H), 8.34 (d, J = 8.9 Hz, 1H), 8.00 (br d, J = 4.1 Hz, 1H), 7.93 (d, J = 9.0 Hz, 1H), 4.57 (s, 2H), 3.68 (br dd, J = 3.6, 6.3 Hz, 1H), 3.60 (br s, 2H), 3.37 (br s, 2H), 1.84 (t, J = 6.8 Hz, 2H), 1.22 (d, J = 6.6 Hz, 3H), 1.02 (s, 6H). EXAMPLE 4 – Synthesis of (15R)-5-({2-chloro-5-[(2,2- dimethylpyrrolidin-1-yl)methyl] pyrimidin-4-yl}oxy)-15-methyl-11-thia-3,6,14,17-tetraazatetr acyclo [8.8.0.0²,⁷.0¹²,¹⁸] octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (I-57) [0513] The title compound was prepared using the following procedures. [0514] Step 1. Preparation of 2,4-dichloro-5-[(2,2- dimethylpyrrolidin-1-yl)methyl] pyrimidine. To a solution of 2,2-dimethylpyrrolidine (0.1 g, 1eq, 743 µmol) in acetonitrile (1 mL) at 0 °C was added potassium 2-methylpropan-2-olate (1.11 mL, 1.5 eq, 1 M in THF). After stirring the reaction mixture at 0 °C for 10 min, 2,4-dichloro-5-(iodomethyl)pyrimidine (258 mg, 1.2 eq, 892 µmol) was added to the reaction mixture. Then, the reaction mixture was stirred at 0 °C for 1 hour. LCMS analysis of the reaction mixture showed the starting material was consumed and the desired product was detected. Two additional vials were set up as described above. All three reaction mixtures were combined, and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by prep-HPLC to obtain 240 mg (41.3%) of 2,4-dichloro-5-[(2,2- dimethylpyrrolidin-1-yl)methyl]pyrimidine as a white solid. LCMS: Rt = 0.810 min, m/z = 259.9 (M+H) ⁺ . [0515] Step 2. Preparation of (15R)-5-({2-chloro-5-[(2,2- dimethylpyrrolidin-1-yl)methyl] pyrimidin-4-yl}oxy)-15-methyl-11-thia-3,6,14,17-tetraazatetr acyclo [8.8.0.0²,⁷.0¹²,¹⁸] octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one. To a solution of 2,4-dichloro-5-[(2,2- dimethylpyrrolidin-1-yl)methyl]pyrimidine (20 mg, 1.5 eq, 76.9 µmol) in dimethyl sulfoxide (0.5 mL) at room temperature was added (15R)-5-hydroxy-15-methyl-11-thia-3,6,14,17- tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)- hexaen-13-one (15.4 mg, 1 eq, 51.3 µmol) and dipotassium carbonate (14.2 mg, 2 eq, 103 µmol). Then, the reaction mixture was stirred at 45 °C for 2 hours. Two additional vials were set up as described above. All three reaction mixtures were combined and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by prep-HPLC to obtained 16 mg (29.34%) of (15R)-5-({2-chloro-5-[(2,2- dimethylpyrrolidin-1-yl)methyl]pyrimidin-4-yl}oxy)- 15-methyl-11-thia-3,6,14,17-tetraazatetracyclo[8.8.0.0²,⁷ .0¹²,¹⁸]octadeca- 1(10),2(7),3,5,8,12(18)-hexaen-13-one as a yellow solid. LCMS: Rt = 2.087 min, m/z = 524.2 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.80 (t, J = 3.8 Hz, 1H), 8.72 (s, 1H), 8.33 (d, J = 8.9 Hz, 1H), 8.00 (d, J = 4.4 Hz, 1H), 7.94 (d, J = 8.9 Hz, 1H), 3.71 (s, 2H), 3.67 (td, J = 3.5, 6.8 Hz, 1H), 3.60 (br s, 2H), 2.71 (t, J = 7.0 Hz, 2H), 1.72 – 1.63 (m, 2H), 1.63 – 1.55 (m, 2H), 1.22 (d, J = 6.6 Hz, 3H), 1.06 (s, 6H). EXAMPLE 5 – Synthesis of (15R)-5-{[2-chloro-5 –({4-oxo-5-azaspiro[2.4]heptan-5- yl}methyl)pyrimidin-4-yl] oxy}-15-methyl-11-thia-3,6,14, 17-tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)- hexaen-13-one (I-54) [0516] The title compound was prepared using the following procedures. [0517] Step 1. Preparation of 5-[(2,4-dichloropyrimidin-5-yl)methyl]-5-azaspiro[2.4] heptan-4-one. To a solution of 5-azaspiro[2.4]heptan-4-one (10 mg, 90 µmol) in tetrahydrofuran (1 mL) at 0 °C was added potassium 2-methylpropan-2-ol (20.4 mg, 2 eq, 180 µmol) and 2,4-dichloro-5-(iodomethyl)pyrimidine (26 mg, 1 eq, 90 µmol). The resulting mixture was stirred at 0 °C for 1 hour. LCMS analysis of the reaction mixture showed the starting material was consumed completely and the desired product was detected. Four additional vials were set up as described above. All the five reaction mixtures were combined. The reaction mixture was quenched with water (10 mL), extracted with ethyl acetate (3 × 10 mL), the organic was washed with brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (eluted with petroleum ether / ethyl acetate=2/3, R _f =0.4) to give 26 mg (21.2%) of 5-[(2,4-dichloropyrimidin-5-yl)methyl]-5-azaspiro[2.4]heptan -4-one as a yellow solid. LCMS: Rt = 0.374 min, m/z =272.2(M+H) ⁺ . [0518] Step 2. Preparation of (15R)-5-{[2-chloro-5 –({4-oxo-5-azaspiro[2.4]heptan-5- yl}methyl)pyrimidin-4-yl] oxy}-15-methyl-11-thia-3,6,14, 17-tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)- hexaen-13-one. To a solution of 5-[(2,4- dichloropyrimidin-5-yl)methyl]-5-azaspiro[2.4]heptan-4-one (20 mg, 73.5 µmol) in dimethyl sulfoxide (1.5 mL) at room temperature was added dipotassium carbonate (20.3 mg, 2 eq, 147 µmol) and (15R)-5-hydroxy-15-methyl-11-thia-3,6,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸] octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (21 mg, 0.95 eq, 69.8 µmol). The resulting mixture was stirred at 60 °C for 1 hour. LCMS analysis of the reaction mixture showed the starting material was consumed completely and the desired product was detected. The reaction mixture was filtered, and the filtrate was purified by prep-HPLC to give 16.3 mg (41.3%) of (15R)-5-{[2-chloro-5 –({4-oxo-5-azaspiro[2.4]heptan-5-yl}methyl)pyrimidin-4-yl] oxy}-15- methyl-11-thia-3,6,14, 17-tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(1 0),2(7),3,5, 8,12(18)- hexaen-13-one as a yellow solid. LCMS: Rt =1.722 min, m/z = 536.3 (M+H) ⁺ . ¹ H NMR (400 MHz, CD3OD) δ 9.10 (br s, 1H), 8.90 (s, 1H), 8.68 (s, 1H), 8.15 (d, J = 9.0 Hz, 1H), 7.85 (d, J = 9.0 Hz, 1H), 4.71 (s, 2H), 3.87 – 3.78 (m, 1H), 3.75 – 3.64 (m, 2H), 3.63 – 3.56 (m, 2H), 2.10 (t, J = 7.4 Hz, 2H), 1.36 (d, J = 6.8 Hz, 3H), 0.92 – 0.84 (m, 2H), 0.70 – 0.61 (m, 2H). EXAMPLE 6 – Synthesis of (R)-3-((2-chloro-5-((2-oxopyrrolidin-1-yl)methyl)pyrimidin-4 - yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5� ��,6’:4,5]thieno[3,2- f]quinoxalin-8-one (I-81) [0519] The title compound was prepared using the following procedures. [0520] Step 1. Preparation of 1-((2,4-dichloropyrimidin-5-yl)methyl)pyrrolidin-2-one. To a solution of 2,4-dichloro-5-(iodomethyl)pyrimidine (0.3 g, 1 eq, 1.04 mmol) in tetrahydrofuran (3 mL) was added pyrrolidin-2-one (88.4 mg, 1 eq, 1.04 mmol) and sodium hydride (62.3 mg, 1.5 eq, 1.56 mmol, 60% w/w) at 0 °C. The resulting mixture was stirred at 0 °C for 1 hour. LCMS showed that the starting material peak was consumed, and the desired peak was detected. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phase was washed with brine (1 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (eluted with petroleum ether/ethyl acetate = 3/1, R _f = 0.6) to give 80 mg (33.84%) of 1-((2,4- dichloropyrimidin-5-yl)methyl)pyrrolidin-2-one as a yellow solid. LCMS (ESI ⁺ ): Rt = 0.526 min, m/z 287.1 (M+H) ⁺ . [0521] Step 2. Preparation of (R)-3-((2-chloro-5-((2-oxopyrrolidin-1-yl)methyl)pyrimidin- 4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[ 5’,6’:4,5]thieno[3,2-f] quinoxalin-8-one. To a solution of 1-((2,4-dichloropyrimidin-5-yl)methyl)pyrrolidin-2-one (50 mg, 1 eq, 203 µmol) in dimethyl sulfoxide (1 mL) was added (R)-3-hydroxy-10-methyl- 9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno [3,2-f]quinoxalin-8-one (61 mg, 1 eq, 203 µmol) and potassium carbonate (56 mg, 2 eq, 406 µmol) at 25 °C. The resulting mixture was stirred at 60 °C for 1 hour. LCMS showed the starting material peak was consumed, and the desired peak was detected. After cooling to 20 °C, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phase was washed with brine (20 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep HPLC to give 22 mg (21.2%) of (R)-3-((2-chloro-5-((2-oxopyrrolidin-1-yl)methyl) pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4] diazepino[5’,6’:4,5] thieno[3,2- f]quinoxalin-8-one as an orange solid. LCMS (ESI ⁺ ): Rt = 1.486 min, m/z = 510.1 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.05 (s, 1H), 8.77 (t, J = 3.8 Hz, 1H), 8.63 (s, 1H), 8.31 (d, J = 9.0 Hz, 1H), 7.97 (d, J = 4.4 Hz, 1H), 7.91 (d, J = 9.0 Hz, 1H), 4.54 (s, 2H), 3.67 – 3.61 (m, 1H), 3.57 (br s, 2H), 3.41 (t, J = 7.0 Hz, 2H), 2.25 – 2.18 (m, 2H), 1.97 – 1.89 (m, 2H), 1.18 (d, J = 6.8 Hz, 3H). EXAMPLE 7 – Synthesis of (R)-4-((2-chloro-4-((10-methyl-8-oxo-9,10,11,12- tetrahydro- 8H-[1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-3-yl )oxy)pyrimidin-5-yl)methyl) morpholin-3-one (I-80) [0522] The title compound was prepared using the following procedures. [0523] Step 1. Preparation of 4-((2,4-dichloropyrimidin-5-yl)methyl)morpholin-3-one. To a solution of 2,4-dichloro-5-(iodomethyl)pyrimidine (10 mg, 1 eq, 34.6 µmol) in acetonitrile (0.3 mL) was added morpholin-3-one (3.5 mg, 1 eq, 34.6 µmol) and potassium 2- methylpropan-2-olate (11.7 mg, 3 eq, 104 µmol) at 25 °C. The reaction mixture was stirred at 25 °C for 1 hour. TLC (petroleum ether/ethyl acetate = 1/1, R _f = 0.4) showed the starting material was consumed completely and the desired product was formed. Twenty additional vials were set up as described above. All twenty-one reaction mixtures were combined, diluted with water (126 mL), and extracted with ethyl acetate (3 × 42 mL). The organic phase was combined and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (petroleum ether/ethyl acetate = 1/1, R _f = 0.4) to give 40 mg (21%) of 4-((2,4- dichloropyrimidin-5-yl)methyl)morpholin-3-one as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) 8.66 (s, 1H), 4.60 (s, 2H), 4.13 (s, 2H), 3.90 – 3.83 (m, 2H), 3.44 – 3.38 (m, 2H). [0524] Step 2. Preparation of (R)-4-((2-chloro-4-((10-methyl-8-oxo-9,10,11,12- tetrahydro- 8H-[1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-3-yl )oxy)pyrimidin-5-yl)methyl) morpholin-3-one. To a solution of 4-((2,4-dichloropyrimidin-5-yl)methyl)morpholin-3-one (5 mg, 3 eq, 19.1 µmol) in dimethyl sulfoxide (0.2 mL) was added (R)-3-hydroxy-10-methyl- 9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno [3,2-f]quinoxalin-8-one (1.91 mg, 1 eq, 6.36 µmol) and ethylbis(propan-2-yl)amine (2.47 mg, 3 eq, 19.1 µmol) at 25 °C. The reaction mixture was heated to 60 °C and stirred at 60 °C for 3 hours. LCMS showed 8% of the starting material remained and the desired mass was detected. Seven additional vials were set up as described above. After cooling to room temperature, all eight reaction mixtures were combined and filtered. The filtrate was purified by prep-HPLC to give 7.1 mg (26%) of (R)-4- ((2-chloro-4-((10-methyl-8-oxo-9,10,11,12- tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno[3,2- f]quinoxalin-3-yl)oxy)pyrimidin-5-yl)methyl)morpholin-3-one as a yellow solid. LCMS (ESI+): Rt = 1.440 min, m/z 526.0 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.09 (s, 1H), 8.80 (br s, 1H), 8.68 (s, 1H), 8.34 (d, J = 8.9 Hz, 1H), 8.00 (br d, J = 4.0 Hz, 1H), 7.95 (d, J = 8.9 Hz, 1H), 4.72 (s, 2H), 4.10 (s, 2H), 3.89 (t, J = 5.0 Hz, 2H), 3.68 (br d, J = 2.5 Hz, 1H), 3.60 (br s, 2H), 3.53 (t, J = 5.0 Hz, 2H), 1.22 (d, J = 6.6 Hz, 3H). EXAMPLE 8 – Synthesis of (10R)-3-((2-chloro-5-((3-methyl-2- oxopyrrolidin-1- yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydr o-8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (I-79) [0525] The title compound was prepared using the following procedures. [0526] Step 1. Preparation of 1-((2,4-dichloropyrimidin-5-yl) methyl)-3-methylpyrrolidin- 2-one. To a solution of 3-methylpyrrolidin-2-one (50 mg, 504 µmol) in tetrahydrofuran (2.5 mL) at 0 °C was added potassium 2-methylpropan-2-ol (114 mg, 2 eq, 1.01 mmol) and 2,4- dichloro-5-(iodomethyl)pyrimidine (175 mg, 1.2 eq, 605 µmol). The resulting mixture was stirred at 0 °C for 1 hour. LCMS analysis showed the starting material was consumed completely and the desired product was detected. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (eluted with petroleum ether/ethyl acetate=2/3, R _f =0.23) to give 25 mg (19%) of 1-((2,4-dichloropyrimidin- 5-yl) methyl)-3-methylpyrrolidin-2-one as a yellow solid. LCMS: Rt= 0.464 min, m/z = 260.1 (M+H) ⁺ . [0527] Step 2. Preparation of (10R)-3-((2-chloro-5-((3-methyl-2- oxopyrrolidin-1- yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydr o-8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one. To a solution of 1-((2,4-dichloropyrimidin-5- yl)methyl)-3-methylpyrrolidin-2-one (25 mg, 96.1 µmol) in dimethyl sulfoxide (1 mL) at room temperature was added dipotassium carbonate (26.6 mg, 2 eq, 192 µmol) and (R)-3-hydroxy- 10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (23.1 mg, 0.8 eq, 76.9 µmol). The resulting mixture was stirred at 25 °C for 12 hours. LCMS showed the starting material remained and the desired product was detected. The reaction mixture was filtered, and the filtrate was purified by prep-HPLC to give 13.6 mg (27%) of (10R)-3-((2-chloro-5-((3-methyl-2- oxopyrrolidin-1-yl)methyl)pyrimidin-4-yl)oxy)-10-methyl- 9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno [3,2-f]quinoxalin-8-one as a yellow solid. LCMS: Rt= 2.376 min, m/z = 524.1 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.09 (s, 1H), 8.80 (br s, 1H), 8.65 (s, 1H), 8.35 (d, J = 8.9 Hz, 1H), 8.00 (br d, J = 4.3 Hz, 1H), 7.94 (d, J = 8.9 Hz, 1H), 4.59 (d, J = 3.1 Hz, 2H), 3.69 (br dd, J = 3.2, 6.4 Hz, 1H), 3.61 (br s, 2H), 3.38 (dd, J = 4.6, 8.6 Hz, 2H), 2.47 – 2.38 (m, 1H), 2.27 – 2.15 (m, 1H), 1.66 – 1.51 (m, 1H), 1.23 (d, J = 6.6 Hz, 3H), 1.04 (d, J = 7.1 Hz, 3H). EXAMPLE 9 – Synthesis of (10R)-3-((2-chloro-5-((4-methyl-2- oxopyrrolidin-1- yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydr o-8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (I-78) [0528] The title compound was prepared using the following procedures. [0529] Step 1. Preparation of 1-((2,4-dichloropyrimidin-5-yl) methyl)-4-methylpyrrolidin- 2-one. To a solution of 4-methylpyrrolidin-2-one (50 mg, 504 µmol) in tetrahydrofuran (2.5 mL) at 0 °C was added potassium 2-methylpropan-2-ol (114 mg, 2 eq, 1.01 mmol) and 2,4- dichloro-5-(iodomethyl)pyrimidine (175 mg, 1.2 eq, 605 µmol). The resulting mixture was stirred at 0 °C for 1 hour. LCMS showed the starting material was consumed completely and the desired product was detected. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (eluted with petroleum ether/ethyl acetate=2/3, R _f = 0.3) to give 20 mg (15.2%) of 1-((2,4-dichloropyrimidin-5-yl) methyl)-4-methylpyrrolidin-2-one as a yellow solid. LCMS: Rt= 0.466 min, m/z = 260.0 (M+H) ⁺ . [0530] Step 2. Preparation of (10R)-3-((2-chloro-5-((4-methyl-2- oxopyrrolidin-1- yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydr o-8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one. To a solution of 1-((2,4-dichloropyrimidin-5- yl)methyl)-4-methylpyrrolidin-2-one (20 mg, 76.9 µmol) in dimethyl sulfoxide (1 mL) at 25 °C was added dipotassium carbonate (21.3 mg, 2 eq, 154 µmol) and (R)-3-hydroxy-10-methyl- 9,10,11,12-tetrahydro-8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (18.5 mg, 0.8 eq, 61.5 µmol). The resulting mixture was stirred at 25 °C for 12 hours. LCMS showed the starting material remained and the desired product was detected. The reaction mixture was filtered, and the filtrate was purified by prep-HPLC to give 11 mg (27.3%) of (10R)-3-((2- chloro-5-((4-methyl-2- oxopyrrolidin-1-yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10 ,11,12- tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quin oxalin-8-one as a yellow solid. LCMS: Rt= 2.383 min, m/z = 524.1 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.08 (s, 1H), 8.80 (br s, 1H), 8.67 (s, 1H), 8.34 (d, J = 8.9 Hz, 1H), 8.00 (d, J = 4.4 Hz, 1H), 7.94 (d, J = 8.9 Hz, 1H), 4.57 (s, 2H), 3.68 (dt, J = 3.3, 6.9 Hz, 1H), 3.63 – 3.52 (m, 3H), 3.02 (dd, J = 5.7, 9.2 Hz, 1H), 2.46 – 2.36 (m, 2H), 1.99 – 1.85 (m, 1H), 1.22 (d, J = 6.7 Hz, 3H), 1.05 (d, J = 6.3 Hz, 3H). EXAMPLE 10 – Synthesis of (R)-3-((2-chloro-5- ((2-oxopiperidin-1-yl)methyl)pyrimidin- 4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[ 5’,6’:4,5]thieno[3,2- f]quinoxalin-8-one (I-77) [0531] The title compound was prepared using the following procedures. [0532] Step 1. Preparation of 1-((2,4-dichloropyrimidin-5-yl)methyl)piperidin-2-one. To a solution of 2,4-dichloro-5-(iodomethyl)pyrimidine (0.1 g, 1 eq, 346 µmol) in acetonitrile (2 mL) was added piperidin-2-one (34.3 mg, 1 eq, 346 µmol) and potassium tert-butoxide (77.7 mg, 2 eq, 692 µmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. TLC (ethyl acetate, R _f = 0.45) showed the starting material was consumed and the desired spot was formed. The reaction mixture was diluted with water (4 mL) and extracted with ethyl acetate (3 × 2 mL). The organic phase was washed with brine (3 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (eluted with ethyl acetate, R _f = 0.45) to give 20 mg (22.1%) of 1-((2,4-dichloropyrimidin-5-yl)methyl)piperidin-2-one as a white solid. LCMS: Rt = 0.715 min, m/z = 260.0 (M+H) ⁺ . [0533] Step 2. Preparation of (R)-3-((2-chloro-5- ((2-oxopiperidin-1-yl)methyl)pyrimidin- 4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[ 5’,6’:4,5]thieno[3,2- f]quinoxalin-8-one. To a solution of 1-((2,4-dichloropyrimidin-5-yl)methyl)piperidin-2-one (17.3 mg, 1 eq, 66.6 µmol,) in dimethyl sulfoxide (1 mL) was added (R)-3-hydroxy-10-methyl- 9,10,11,12 -tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno[3,2-f]qui noxalin-8-one (20 mg, 1 eq, 66.6 µmol) and potassium carbonate (18.4 mg, 2 eq, 133 µmol) at 25 °C. The resulting mixture was heated to 60 °C and stirred at 60 °C for 1 hour. LCMS showed the starting material was consumed and the desired peak was detected. After cooling to 20 °C, the reaction mixtures were combined, diluted with water (2 mL), and extracted with ethyl acetate (3 × 1 mL). The organic phase was washed with brine (1 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by HPLC to give 6.5 mg (18.63%) of (R)-3-((2-chloro-5- ((2- oxopiperidin-1-yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10, 11,12-tetrahydro-8H- [1,4]diazepino[5’,6’:4,5] thieno[3,2-f]quinoxalin-8-one as a white solid. LCMS (ESI+): Rt = 0.419 min, m/z 524.2 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.10 (s, 1H), 8.83 – 8.78 (m, 1H), 8.60 (s, 1H), 8.35 (d, J = 8.9 Hz, 1H), 8.00 (br d, J = 3.5 Hz, 1H), 7.96 (d, J = 8.9 Hz, 1H), 4.66 (s, 2H), 3.70 – 3.65 (m, 1H), 3.60 (br s, 2H), 3.43 (br t, J = 5.8 Hz, 2H), 2.29 (t, J = 6.3 Hz, 2H), 1.81 – 1.71 (m, 4H), 1.22 (d, J = 6.8 Hz, 3H). EXAMPLE 11 – Synthesis of (R)-3-((2-chloro-4- ((10-methyl-8-oxo-9,10,11,12-tetrahydro- 8H-[1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-3-yl )oxy)pyrimidin-5-yl)methyl) oxazolidin-2-one ( [0534] The title compound was prepared using the following procedures. [0535] Step 1. Preparation of 3-((2,4-dichloropyrimidin-5-yl) methyl)oxazolidin-2-one. To a solution of 2,4-dichloro-5-(iodomethyl)pyrimidine (0.1 g, 1 eq, 346 µmol) in tetrahydrofuran (2 mL) was added oxazolidin-2-one (30.1 mg, 1 eq, 346 µmol) and potassium tert-butoxide (77.7 mg, 2 eq, 692 µmol) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 hour. LCMS showed the starting material remained and the desired Ms was detected. The mixture was diluted with water (6 mL) and extracted with ethyl acetate (3 × 5 mL). The organic phase was combined and washed with brine (10 mL), then dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrate under reduced pressure to give a residue. The residue was purified by prep-TLC (eluted with ethyl acetate, R _f = 0.7) to afford 40 mg (46.59%) of 3-((2,4-dichloropyrimidin-5-yl) methyl)oxazolidin-2-one as a yellow solid. LCMS (ESI+): Rt = 0.323 min, m/z 289.1 (M+H) ⁺ . [0536] Step 2. Preparation of (R)-3-((2-chloro-4- ((10-methyl-8-oxo-9,10,11,12-tetrahydro- 8H-[1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-3-yl )oxy)pyrimidin-5-yl)methyl) oxazolidin-2-one. To a solution of 3-((2,4-dichloropyrimidin-5-yl)methyl)oxazolidin-2-one (42 mg, 1 eq, 165 µmol) in dimethyl sulfoxide (0.5 mL) was added (R)-3-hydroxy-10-methyl- 9,10,11,12- tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quin oxalin-8-one (50 mg, 1 eq, 165 µmol) and potassium carbonate (46 mg, 2 eq, 330 µmol) at 25 °C. The reaction mixture was heated to 60 °C and stirred at 60 °C for 1 hour. LCMS showed the starting material was consumed completely and the desired product was detected. After cooling to 20 °C, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 5 mL). The organic phase was combined, washed with brine (5 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to afford 16.7 mg (19.59%) of (R)-3- ((2-chloro-4- ((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5� ��,6’:4,5]thieno[3,2- f]quinoxalin-3-yl)oxy)pyrimidin-5-yl)methyl)oxazolidin-2-one as an orange solid. LCMS (ESI+): Rt = 1.464 min, m/z 512.1 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.10 (s, 1H), 8.83 – 8.75 (m, 2H), 8.35 (d, J = 9.0 Hz, 1H), 8.05 – 7.99 (m, 1H), 7.96 (d, J = 8.8 Hz, 1H), 4.58 (s, 2H), 4.31 (br t, J = 8.0 Hz, 2H), 3.66 (br t, J = 7.9 Hz, 3H), 3.60 (br s, 2H), 1.22 (br d, J = 6.8 Hz, 3H). EXAMPLE 12 – Synthesis of (R)-6-((2-chloro-4-((10-methyl-8-oxo-9,10,11,12-tetrahydro- 8H-[1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-3-yl )oxy)pyrimidin-5-yl)methyl)-2- oxa-6-azaspiro[3.4]octan-7-one (I-75) [0537] The title compound was prepared using the following procedures. [0538] Step 1. Preparation of 6-((2,4-dichloropyrimidin-5-yl)methyl)-2-oxa-6- azaspiro[3.4]octan-7-one. To a solution of 2-oxa-6-azaspiro[3.4]octan-7-one (0.1 g, 1 eq, 787 µmol) in tetrahydrofuran (2 mL) was added potassium 2-methylpropan-2-olate (177 mg, 2 eq, 1.57 mmol) and 2,4-dichloro-5-(iodomethyl)pyrimidine (227 mg, 1 eq, 787 µmol) at 0 °C. The mixture was stirred for 1 hour. LCMS showed the starting material was consumed and the desired peak was detected. The mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 × 2 mL). The combined organic phase was washed with brine (2 mL) and dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (eluted with ethyl acetate, R _f = 0.3) to give 60 mg (26.48%) of 6-((2,4-dichloropyrimidin-5-yl)methyl)-2-oxa-6- azaspiro[3.4]octan-7-one as a yellow solid. LCMS (ESI+): Rt = 1.012 min, m/z 288.1 (M+H) ⁺ . [0539] Step 2. Preparation of (R)-6-((2-chloro-4-((10-methyl-8-oxo-9,10,11,12-tetrahydro- 8H-[1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-3-yl )oxy)pyrimidin-5-yl)methyl)-2- oxa-6-azaspiro[3.4]octan-7-one. To a solution of (R)-3-hydroxy-10-methyl-9,10,11,12- tetrahydro-8H-[1,4]diazepino[5’,6’:4,5] thieno[3,2-f]quinoxalin-8-one (10 mg, 1 eq, 33.3 µmol) in dimethyl sulfoxide (2.5 mL) was added cesium carbonate (32.5 mg, 3 eq, 99.9 µmol) and 6- ((2,4-dichloropyrimidin-5-yl) methyl)-2-oxa-6-azaspiro[3.4]octan-7-one (28.8 mg, 3 eq, 99.9 µmol) at 25 °C. The mixture was heated to 60 °C and stirred at 60 °C for 1 hour. LCMS showed the starting material was consumed and the desired peak was detected. Three additional vials were set up as described above. After cooling to room temperature, all four reaction mixtures were combined and diluted with water (5 mL) then extracted with ethyl acetate (3 × 3 mL). The combined mixture was filtered, and the filtrate was purified by prep- HPLC to give 22.7 mg (50.11%) of (R)-6-((2-chloro-4-((10-methyl-8-oxo-9,10,11,12- tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quin oxalin-3-yl)oxy)pyrimidin-5- yl)methyl)-2-oxa-6-azaspiro[3.4]octan-7-one as a yellow solid. LCMS (ESI+): Rt = 1.410 min, m/z 552.1 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.08 (s, 1H), 8.80 (t, J = 4.0 Hz, 1H), 8.66 (s, 1H), 8.35 (d, J = 8.8 Hz, 1H), 8.01 (d, J = 4.4 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 4.56-4.52 (m, 6H), 3.75 (s, 2H), 3.70-3.65(m, 1H), 3.60 (s, 2H), 2.68 (s, 2H), 1.21 (d, J = 6.4 Hz, 3H). EXAMPLE 13 – Synthesis of (15R)-5-[(2-chloro-5-{[3-(hydroxymethyl)-2-oxopyrrolidin- 1-yl]methyl}pyrimidin-4-yl)oxy]-15-methyl-11-thia-3,6,14,17- tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2,4,6,8,12(18)-hex aen-13-one (I-74) [0540] The title compound was prepared using the following procedures. [0541] Step 1. Preparation of 3-{[(tert-butyldimethylsilyl) oxy] methyl} pyrrolidin-2-one. To a solution of 3-(hydroxymethyl)pyrrolidin-2-one (0.1 g, 869 µmol) in dichloromethane (2 mL) at 0 °C was added 1H-imidazole (88.7 mg, 1.5 eq, 1.3 mmol) and tert-butyl (chloro) dimethylsilane (170 mg, 1.3 eq, 1.13 mmol). Then, the reaction mixture was stirred at 25 °C for 2 hours. LCMS showed the starting material was consumed and the desired product mass was detected. One additional vial was set up as described above. Both reaction mixtures were combined and concentrated under vacuum to give a crude product, which was purified by prep- TLC (eluted with ethyl acetate, R _f = 0.35) to give 70 mg (2.05%) of 3-{[(tert- butyldimethylsilyl) oxy] methyl} pyrrolidin-2-one as a white solid. LCMS: Rt = 0.959 min, m/z = 230.2 (M+H) ⁺ . [0542] Step 2. Preparation of 3-{[(tert-butyldimethylsilyl)oxy]methyl}-1-[(2,4-dichloro- pyrimidin-5-yl)methyl] pyrrolidin-2-one. To a solution of 3-{[(tert-butyldimethyl- silyl)oxy]methyl}pyrrolidin-2-one (0.2 g, 872 µmol) in tetrahydrofuran (0.5 mL) at 0 °C was added 2-methylpropan-2-olate potassium (196 mg, 2 eq, 1.74 mmol) and 2,4-dichloro-5- (iodomethyl)pyrimidine (315 mg, 1.3 eq, 1.09 mmol). The reaction mixture was stirred at 0 °C for 1 hour. LCMS showed the starting material was consumed and the desired product was detected. The reaction mixture was filtered, and the filtrate was purified by prep-TLC (eluted with ethyl acetate, R _f = 0.4) to obtain 45 mg (13.22%) of 3-{[(tert-butyldimethylsilyl)oxy] methyl}-1-[(2,4-dichloropyrimidin-5-yl)methyl] pyrrolidin-2-one as a white solid. LCMS: Rt = 0.927, m/z = 389.9 (M+H) ⁺ . [0543] Step 3. Preparation of (15R)-5-({5-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}-2- oxopyrrolidin-1-yl)methyl]-2-chloropyrimidin-4-yl}oxy)-15-me thyl-11-thia-3,6,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10), 2,4,6,8,12(18)-hexaen-13-one. To a solution of 3-{[(tert-butyldimethylsilyl)oxy]methyl}-1-[(2,4-dichloropyr imidin-5-yl) methyl] pyrrolidin-2-one (50 mg, 128 µmol) in dimethyl sulfoxide (1 mL) at 25 °C was added (15R)-5- hydroxy-15-methyl-11-thia-3,6,14,17-tetraazatetracyclo[8.8.0 .0²,⁷.0¹²,¹⁸]octadeca- 1(10),2(7),3,5,8,12(18)-hexaen-13-one (30.8 mg, 0.8 eq, 102 µmol) and dipotassium carbonate (35.4 mg, 2 eq, 256 µmol). Then, the reaction mixture was stirred at 60 °C for 1 hour. LCMS showed the starting material was consumed and the desired product was detected. The reaction mixture was purified directly by prep-TLC (eluted with ethyl acetate, R _f = 0.35) to give 30 mg (35.80%) of (15R)-5-({5-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}-2- oxopyrrolidin-1- yl)methyl]-2-chloropyrimidin-4-yl}oxy)-15-methyl-11-thia-3,6 ,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸] octadeca-1(10),2,4,6,8,12(18)-hexaen-13-one as a yellow solid. LCMS: Rt = 0.576 min, m/z = 654.3 (M+H) ⁺ . [0544] Step 4. Preparation of (15R)-5-[(2-chloro-5-{[3-(hydroxymethyl) -2-oxopyrrolidin- 1-yl]methyl}pyrimidin-4-yl)oxy]-15-methyl-11-thia-3,6,14,17- tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2,4,6,8,12(18)-hex aen-13-one. (15R)-5-({5-[(3-{[(tert- Butyldimethylsilyl)oxy]methyl}-2-oxopyrrolidin-1-yl)methyl]- 2-chloropyrimidin-4-yl}oxy)- 15-methyl-11-thia-3,6,14,17-tetraazatetracyclo[8.8.0.0²,⁷ .0¹²,¹⁸]octadeca-1(10),2,4,6,8,12(18)- hexaen-13-one (20 mg, 30.6 µmol) was added to a mixture of dichloromethane (0.50 mL) and trifluoroacetic acid (0.50 mL) at room temperature. The mixture was stirred at 25 °C for 0.5 hour. LCMS showed the starting material was consumed and the desired product was detected. One additional vial was set up as described above. Both reaction mixtures were combined and purified by prep-HPLC to give 3 mg (9.72%) (15R)-5-[(2-chloro-5-{[3-(hydroxymethyl) -2- oxopyrrolidin-1-yl]methyl}pyrimidin-4-yl)oxy]-15-methyl-11-t hia-3,6,14,17-tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2,4,6,8,12(18)-hex aen-13-one as a yellow solid. LCMS: Rt = 2.128 min, m/z = 540.2 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.03 (br s, 1H), 8.79 (s, 1H), 8.56 (s, 1H), 8.10 (d, J = 9.0 Hz, 1H), 7.91 (d, J = 9.0 Hz, 1H), 6.65 (br s, 1H), 4.91 (dd, J = 3.4, 15.4 Hz, 1H), 4.48 (dd, J = 3.4, 15.4 Hz, 1H), 4.04 (dd, J = 3.3, 11.0 Hz, 1H), 3.93 – 3.83 (m, 1H), 3.82 – 3.70 (m, 2H), 3.62 (ddd, J = 3.3, 6.3, 13.6 Hz, 1H), 3.48 (dd, J = 5.6, 8.7 Hz, 2H), 2.77 – 2.66 (m, 1H), 2.31 – 2.20 (m, 1H), 2.09 – 1.99 (m, 1H), 1.43 (d, J = 6.9 Hz, 3H). EXAMPLE 14 – Synthesis of (10R)-3-((2-chloro-5-((4-hydroxy-2- oxopyrrolidin-1- yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydr o-8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (I-73) [0545] The title compound was prepared using the following procedures. [0546] Step 1. Preparation of 4-((tert-butyldimethylsilyl) oxy) pyrrolidin-2-one. To a solution of 4-hydroxypyrrolidin-2-one (0.5 g, 1 eq, 4.95 mmol) and imidazole (1.01 g, 3 eq, 14.8 mmol) in dichloromethane (10 mL) at 0 °C was added tert-butylchlorodimethylsilane (1.12 g, 1.5 eq, 7.42 mmol). The reaction mixture was stirred at 25 °C for 14 hours. LCMS showed the starting material was consumed and the desired product was detected. The reaction mixture was filtered, and the filtrate was diluted with water (10 mL) and extracted with dichloromethane (4 mL × 3). The combined organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford the crude product, which was purified via silica gel chromatography eluting with 50% ethyl acetate in petroleum. Pure fractions were combined and concentrated to afford 0.78g (72.9%) of 4-((tert-butyldimethylsilyl) oxy) pyrrolidin-2-one as a white solid. LCMS: Rt = 0.836 min, m/z = 216.2 (M+H) ⁺ . [0547] Step 2. Preparation of 4-(((tert-butyldimethylsilyl) oxy) methyl-1-((2, 4- dichloropyrimidin-5-yl) methyl) pyrrolidin-2-one. To a solution of 4-((tert-butyl- dimethylsilyl)oxy)-1-((2,4-dichloropyrimidin-5-yl)methyl) pyrrolidin-2-one(20 mg, 1 eq, 92.9 µmol) and 2,4-dichloro-5-(iodomethyl)pyrimidine (26.8 mg, 1 eq 92.9 µmol) in tetrahydrofuran (1 mL) at 0 °C was added potassium 2-methylpropan-2-olate (20.8 mg, 2 eq, 186 µmol). The reaction mixture was stirred at 0 °C for 1 hour. LCMS showed the starting material was consumed and the desired product was detected. The reaction mixture was washed with aqueous ammonium chloride (3 × 1 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford the crude product, which was purified via silica gel chromatography eluting with 50% ethyl acetate in petroleum. Pure fractions were combined and concentrated to afford 12.5 mg (35.8%) of 4-(((tert- butyldimethylsilyl) oxy) methyl-1-((2, 4-dichloropyrimidin-5-yl) methyl) pyrrolidin-2-one as a brown solid. LCMS: Rt = 0.560 min, m/z = 376.2 (M+H) ⁺ . [0548] Step 3. Preparation of (10R)-3-((5-((4-((tert-butyldimethylsilyl)oxy)-2- oxopyrrolidin-1-yl)methyl)-2-chloropyrimidin-4-yl)oxy)-10-me thyl-9,10,11,12- tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno[3,2-f] quinoxalin-8-one. To a solution of 4- (((tert-butyldimethylsilyl)oxy) methyl)-1-((2,4-dichloropyrimidin-5-yl) methyl) pyrrolidin-2- one (20 mg, 1.1 eq, 53.1 µmol) and (R)-3-hydroxy-10-methyl-9,10,11, 12-tetrahydro-8H- [1,4]diazepino[5’,6’:4,5]thieno[3,2-f] quinoxalin-8-one (14.5 mg, 1 eq, 48.3 µmol) in (methylsulfinyl) methane (1 mL, 14 mmol) at 25 °C was added cesium carbonate (23.6 mg, 1.5 eq., 72.5 µmol). The reaction was stirred at 25 °C for 3 hours. LCMS showed the starting material was consumed and the desired product was detected. The reaction mixture was poured into water (5 mL), and extracted with ethyl acetate (3 × 2 mL). The organic phase was combined, washed with brine (3 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford crude 25 mg (80.9%) of (10R)-3-((5- ((4-((tert-butyldimethylsilyl)oxy)-2-oxopyrrolidin-1-yl)meth yl)-2-chloropyrimidin-4-yl)oxy)- 10-methyl-9,10,11,12- tetrahydro -8H-[1,4]diazepino[5’,6’:4,5]thieno[3,2-f] quinoxalin-8-one as a yellow solid, which was used directly in the next step. LCMS: Rt = 0.549 min, m/z = 640.3 (M+H) ⁺ . [0549] Step 4. Preparation of (10R)-3-((2-chloro-5-((4-hydroxy-2- oxopyrrolidin-1- yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydr o-8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one. To a solution of (10R)-3-((5-((4-((tert- butyldimethylsilyl)oxy)-2-oxopyrrolidin-1-yl) methyl)-2-chloropyrimidin-4-yl)oxy)-10-methyl- 9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno [3,2-f]quinoxalin-8-one (20 mg, 1 eq, 31.2 µmol) in acetonitrile (0.4 mL, 7.66 mmol) and formic acid (0.1 mL, 2.63 mmol) at 25 °C was added potassium hydrogen fluoride (14.6 mg, 6 eq, 187 µmol). The reaction mixture was stirred 3 hours at 25 °C. LCMS showed the starting material was consumed and the desired product was detected. The reaction mixture was purified by prep-HPLC to afford 3.5 mg (21.3%) (10R)-3-((2-chloro-5-((4-hydroxy-2- oxopyrrolidin-1-yl)methyl)pyrimidin-4-yl)oxy)- 10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’: 4,5]thieno[3,2-f]quinoxalin-8-one as a white solid. LCMS: Rt = 0.327 min, m/z = 526.2 (M+H) ⁺ . ¹ H NMR (400 MHz, CD3OD) δ 8.94 (s, 1H), 8.66 (s, 1H), 8.20 (d, J = 9.0 Hz, 1H), 7.91 (d, J = 9.0 Hz, 1H), 4.78 – 4.62 (m, 3H), 4.49 – 4.43 (m, 1H), 3.86 – 3.78 (m, 2H), 3.71 – 3.66 (m, 2H), 3.42 (dd, J = 1.4, 10.6 Hz, 1H), 2.72 (dd, J = 6.3, 17.3 Hz, 1H), 2.29 (dd, J = 1.6, 17.1 Hz, 1H), 1.35 (d, J = 6.8 Hz, 3H). EXAMPLE 15 – Synthesis of (15R)-5-[(2-chloro-5-{[2-(hydroxymethyl)-5-oxopyrrolidin- 1-yl]methyl}pyrimidin-4-yl)oxy]-15-methyl-11-thia-3,6,14,17- tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2,4,6,8,12(18)-hex aen-13-one (I-72)

[0550] The title compound was prepared using the following procedures. [0551] Step 1. Preparation of 5-{[(tert-butyldimethylsilyl)oxy]methyl}pyrrolidin-2-one. To a solution of 5-(hydroxymethyl)pyrrolidin-2-one (112 mg, 973 µmol) in dichloromethane (1.12 mL) at 0 °C was added 1H-imidazole (99.3 mg, 1.5 eq, 1.46 mmol) and tert-butyl(chloro) dimethylsilane (191 mg, 1.3 eq., 1.26 mmol). Then, the reaction mixture was stirred at 25 °C for 12 hours. LCMS showed the starting material was consumed and the desired product was detected. Three additional vials were set up as described above. All four reaction mixtures were combined and filtered. The filtrate was concentrated under reduced pressure to give crude product, which was purified by silica gel chromatography eluting with ethyl acetate. Pure fractions were combined and concentrated to afford 750 mg (46.2%) of 5-{[(tert-butyl- dimethylsilyl)oxy]methyl}pyrrolidin-2-one as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.96 (br s, 1H), 3.76 (br s, 1H), 3.63 (dd, J = 3.9, 10.0 Hz, 1H), 3.45 (dd, J = 7.7, 10.0 Hz, 1H), 2.45 – 2.28 (m, 2H), 2.24 – 2.11 (m, 1H), 1.81 – 1.69 (m, 1H), 0.97 – 0.80 (m, 9H), 0.06 (s, 6H). [0552] Step 2. Preparation of 5-{[(tert-butyldimethylsilyl)oxy]methyl}-1-[(2,4-dichloro- pyrimidin-5-yl)methyl]pyrrolidin-2-one. To a solution of 5-{[(tert-butyldimethylsilyl) oxy]methyl}pyrrolidin-2-one (108 mg, 424 µmol) in tetrahydrofuran (1.2 mL) at 0 °C was added 2,4-dichloro-5-(iodomethyl)pyrimidine (122 mg, 424 µmol) and potassium 2- methylpropan-2-ol (95.9 mg, 2 eq, 847 µmol). Then, the reaction mixture was stirred at 0 °C for 1 hour. LCMS showed the starting material was consumed and the desired product was detected. Five additional vials were set up as described above. All six reaction mixtures were combined and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (eluted with petroleum ether/ethyl acetate=3/2) to afford 110 mg (8.8%) of 5-{[(tert-butyldimethylsilyl)oxy]methyl}-1-[(2,4-dichloropyr imidin-5- yl)methyl]pyrrolidin-2-one as a yellow oil. [0553] Step 3. Preparation of (15R)-5-({5-[(2-{[(tert-butyldimethylsilyl)oxy]methyl}-5- oxopyrrolidin-1-yl)methyl]-2-chloropyrimidin-4-yl}oxy)-15-me thyl-11-thia-3,6,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10), 2,4,6,8,12(18)-hexaen-13-one. To a solution of 5-{[(tert-butyldimethylsilyl)oxy]methyl}-1-[(2,4-dichloropyr imidin-5-yl)me-thyl]pyrrolidin- 2-one (16.2 mg, 41.6 µmol) in dimethyl sulfoxide (0.5 mL) at room temperature was added dipotassium carbonate (11.5 mg, 2 eq, 83.2 µmol) and (15R)-5-hydroxy-15-methyl-11-thia- 3,6,14,17-tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octad eca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (10 mg, 0.8 eq, 33.3 µmol). Then, the reaction mixture was stirred at 60 °C for 1 hour. LCMS showed the starting material was consumed and the desired product mass was detected. One additional vial was set up as described above. Both reaction mixtures were combined and quenched with water (10 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 30 mg (49.5%) of (15R)- 5-({5-[(2-{[(tert-butyldimethylsilyl)oxy]methyl}-5-oxopyrrol idin-1-yl)methyl]-2- chloropyrimidin-4-yl}oxy)-15-methyl-11-thia-3,6,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10), 2,4,6,8,12(18)-hexaen-13-one as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.80 (br s, 1H), 8.65 (s, 1H), 8.35 (d, J = 8.9 Hz, 1H), 8.00 (br d, J = 4.4 Hz, 1H), 7.93 (d, J = 8.9 Hz, 1H), 4.75 (d, J = 16.3 Hz, 1H), 4.46 (d, J = 16.3 Hz, 1H), 3.84 – 3.75 (m, 2H), 3.69 – 3.58 (m, 4H), 2.23 (br dd, J = 4.3, 10.0 Hz, 1H), 2.20 – 2.09 (m, 2H), 1.84 – 1.76 (m, 1H), 1.23 (s, 3H), 0.82 (s, 9H), 0.01 (d, J = 5.4 Hz, 6H). [0554] Step 4. Preparation of (15R)-5-[(2-chloro-5-{[2-(hydroxymethyl)-5-oxopyrrolidin- 1-yl]methyl}pyrimidin-4-yl)oxy]-15-methyl-11-thia-3,6,14,17- tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2,4,6,8,12(18)-hex aen-13-one. To a solution of (15R)-5-({5- [(2-{[(tert-butyldimethylsilyl)oxy]methyl}-5-oxopyrrolidin-1 -yl) methyl]-2-chloropyrimidin-4- yl}oxy)-15-methyl-11-thia-3,6,14,17-tetraazatetracyclo[8.8.0 .0²,⁷.0¹²,¹⁸]octadeca- 1(10),2,4,6,8,12 (18)-hexaen-13-one (15 mg, 20.6 µmol) in acetonitrile (0.45 mL) at 25 °C was added formic acid (0.3 mL) and potassium hydrogen fluoride (30 mg, 25 eq, 508 µmol). Then, the reaction mixture was stirred at 25 °C for 1 hour. LCMS showed the starting material was consumed and the desired product was detected. The reaction mixture was filtered, and the filtrate was purified directly by prep-HPLC to give 4.3 mg (37.8%) (15R)-5-[(2-chloro-5-{[2- (hydroxymethyl)-5-oxopyrrolidin-1-yl]methyl}pyrimidin-4-yl)o xy]-15-methyl-11-thia- 3,6,14,17-tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2,4,6,8,12(18)-hex aen-13-one as an orange solid. LCMS (ESI+): Rt = 0.513 min, m/z 540.2 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.94 (s, 1H), 8.67 (s, 1H), 8.20 (d, J = 8.9 Hz, 1H), 7.91 (d, J = 9.0 Hz, 1H), 4.97 (d, J = 15.9 Hz, 1H), 4.56 (d, J = 15.8 Hz, 1H), 3.89 – 3.79 (m, 3H), 3.72 – 3.67 (m, 2H), 3.65 – 3.59 (m, 1H), 2.56 – 2.46 (m, 1H), 2.36 – 2.27 (m, 1H), 2.24 – 2.13 (m, 1H), 2.01 – 1.91 (m, 1H), 1.36 (d, J = 6.8 Hz, 3H). EXAMPLE 16 – Synthesis of (R)-3-((2-chloro-5- ((1,1-dioxido-3-oxothiomorpholino) methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8 H-[1,4]diazepino[5’,6’:4,5] thieno[3,2-f]quinoxalin-8-one (I-71) [0555] The title compound was prepared using the following procedures. [0556] Step 1. Preparation of 4-((2,4-dichloropyrimidin-5-yl) methyl)thiomorpholin-3- one. To a solution of thiomorpholin-3-one (100 mg, 1 eq, 854 µmol) in tetrahydrofuran (2 mL) was added 2,4-dichloro-5-(iodomethyl)pyrimidine (246 mg, 1 eq, 854 µmol) and potassium tert-butoxide (191.6 mg, , 2 eq, 1.708 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour. LCMS showed the starting material peak was consumed and the desired peak was detected. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 5 mL). The organic phase was combined, washed with brine (20 mL), and then dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (eluted with petroleum ether/ethyl acetate = 1/3, R _f = 0.4) to afford 60 mg (25.27%) of 4-((2,4- dichloropyrimidin-5-yl) methyl)thiomorpholin-3-one as a yellow solid. LCMS (ESI+): Rt = 0.672 min, m/z 278.1 (M+H) ⁺ . [0557] Step 2. Preparation of 4-((2,4-dichloropyrimidin-5-yl)methyl)thiomorpholin-3-one 1,1-dioxide. To a solution of 4-((2,4-dichloropyrimidin-5-yl)methyl)thiomorpholin-3-one (60 mg, 1 eq, 216 µmol) in dichloromethane (1.2 mL) was added 3-chlorobenzene-1-carboperoxoic acid (92 mg, 2.1 eq, 453 µmol, 85% purity) at 25 °C. The reaction mixture was stirred at 25 °C for 1 hour. LCMS showed the starting material peak was consumed, and the desired peak was detected. The reaction mixture was quenched with an aqueous solution of sodium sulfite (5 mL) and extracted with ethyl acetate (3 × 5 mL). The organic phase was combined, washed with brine (10 mL), and then dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (eluted with petroleum ether/ethyl acetate = 1/1 R _f = 0.4) to afford 30 mg (44.84%) of 4-((2,4-dichloropyrimidin-5-yl)methyl)thiomorpholin-3-one 1,1-dioxide as a yellow solid. LCMS (ESI+): Rt = 0.442 min, m/z 310.0 (M+H) ⁺ . [0558] Step 3. Preparation of (R)-3-((2-chloro-5- ((1,1-dioxido-3-oxothiomorpholino) methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8 H-[1,4]diazepino[5’,6’:4,5] thieno[3,2-f]quinoxalin-8-one. To a solution of 4-((2,4-dichloropyrimidin-5- yl)methyl)thiomorpholin-3-one 1,1-dioxide (30 mg, 1.5 eq, 96.7 µmol) in dimethyl sulfoxide (1 mL) was added (R)-3-hydroxy- 10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’: 4,5] thieno[3,2-f]quinoxalin-8-one (20 mg, 1 eq, 66.6 µmol) and potassium carbonate (18.4 mg, 2 eq, 133 µmol) at 25 °.C The reaction mixture was heated to 60 °C and stirred at 60 °C for 1 hour. LCMS showed the starting material peak was consumed and the desired peak was detected. After cooling to 20 °C, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to afford 20 mg (52.32%) of (R)-3-((2-chloro-5- ((1,1-dioxido-3-oxothiomorpholino)methyl)pyrimidin-4- yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5� ��,6’:4,5]thieno[3,2-f]quinoxalin- 8-one as an orange solid. LCMS: Rt = 0.550 min, m/z = 574.1 (M+H) ⁺ . ¹ H NMR (400 MHz, CD3CN) 9.07 – 8.97 (m, 1H), 8.87 (s, 1H), 8.59 (s, 1H), 8.18 (d, J = 9.0 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.00 – 6.84 (m, 1H), 4.78 (s, 2H), 4.07 (s, 2H), 3.95 (dd, J = 5.2, 6.7 Hz, 2H), 3.81 (br d, J = 5.3 Hz, 1H), 3.72 – 3.60 (m, 2H), 3.53 – 3.40 (m, 2H), 1.32 (d, J = 6.8 Hz, 3H). EXAMPLE 17 – Synthesis of (R)-3-((2-chloro-5-((3-oxo-2,8-diazaspiro[4.5]decan-2- yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydr o-8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (I-70) [0559] The title compound was prepared using the following procedures. [0560] Step 1. Preparation of tert-butyl 2-((2,4-dichloropyrimidin-5-yl)methyl)-3-oxo-2,8- diazaspiro[4.5]decane- 8-carboxylate. To a solution of tert-butyl 3-oxo-2,8- diazaspiro[4.5]decane-8-carboxylate (70.4 mg, 1 eq, 277 µmol) in tetrahydrofuran (1 mL) was added 2,4-dichloro-5-(iodomethyl)pyrimidine (80 mg, 1 eq, 277 µmol) and potassium tert- butoxide (62.1 mg, 2 eq, 554 µmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour. LCMS showed the material peak was consumed and the desired peak was detected. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (eluted with ethyl acetate, R _f = 0.4) to afford 24 mg (14.33%) of tert- butyl 2-((2,4-dichloropyrimidin-5-yl)methyl)-3-oxo-2,8-diazaspiro[ 4.5]decane- 8-carboxylate as a yellow solid. LCMS (ESI+): Rt = 0.706 min, m/z 359.1 (M-55) ⁺ /400.0 (M-55+41) ⁺ . [0561] Step 2. Preparation of tert-butyl (R)-2-((2-chloro-4-((10-methyl-8-oxo-9,10,11,12- tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quin oxalin-3-yl)oxy)pyrimidin-5- yl)methyl)-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate. To a solution of tert-butyl 2- ((2,4-dichloropyrimidin-5-yl)methyl) -3-oxo-2,8-diazaspiro[4.5] decane-8-carboxylate (50 mg, 1.8 eq, 120 µmol) in dimethyl sulfoxide (0.5 mL) was added (R)-3-hydroxy-10-methyl- 9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno [3,2-f]quinoxalin-8-one (20 mg, 1 eq, 66.6 µmol) and cesium carbonate (43.4 mg, 2 eq, 133 µmol) at 25 °.C The reaction mixture was stirred at 25 °C for 1 hour. LCMS showed the starting material peak was consumed and the desired peak was detected. The reaction mixture was quenched with water (3 mL) and extracted with ethyl acetate (3 × 3 mL). The combined organic phase was washed with brine (6 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to afford 40 mg (crude) of tert-butyl (R)-2-((2-chloro-4- ((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5� ��,6’:4,5]thieno[3,2-f]quinoxalin- 3-yl)oxy)pyrimidin-5-yl)methyl)-3-oxo-2,8-diazaspiro[4.5]dec ane-8-carboxylate as an orange solid. LCMS (ESI+): t _R = 0.744 min, m/z 623.4 (M-55+H) ⁺ /679.6(M+H) ⁺ . [0562] Step 3. Preparation of (R)-3-((2-chloro-5-((3-oxo-2,8-diazaspiro[4.5]decan-2- yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydr o-8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one. To a solution of tert-butyl (R)-2-((2-chloro-4-((10- methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6� ��:4,5]thieno[3,2-f]quinoxalin-3- yl)oxy)pyrimidin-5-yl)methyl)-3-oxo-2,8-diazaspiro[4.5]decan e-8-carboxylate (40 mg, 1 eq, 58.9 µmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.1 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 1 hour. LCMS showed the starting material peak was consumed and the desired peak was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to afford 11 mg (26.95%) of (R)-3-((2-chloro-5-((3-oxo-2,8-diazaspiro[4.5]decan-2-yl)met hyl)pyrimidin-4- yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5� ��,6’:4,5]thieno[3,2-f]quinoxalin- 8-one as an orange solid. LCMS (ESI+): Rt = 0.328 min, m/z 579.1 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ CN) 8.91 (br s, 1H), 8.84 (s, 1H), 8.58 (s, 1H), 8.16 (d, J = 9.0 Hz, 1H), 7.90 – 7.84 (m, 1H), 7.78 – 7.60 (m, 1H), 7.57 – 7.37 (m, 1H), 6.51 (br d, J = 4.0 Hz, 1H), 4.58 (s, 2H), 3.83 – 3.74 (m, 1H), 3.72 – 3.57 (m, 2H), 3.36 (s, 2H), 3.14 (br d, J = 3.0 Hz, 4H), 2.30 (s, 2H), 1.91 – 1.78 (m, 4H), 1.30 (d, J = 6.9 Hz, 3H).

EXAMPLE 18 – Synthesis of (R)-3-((2-chloro-5-((5-oxo-2,6-diazaspiro[3.4]octan-6- yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydr o-8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (I-69) [0563] The title compound was prepared using the following procedures. [0564] Step 1. Preparation of tert-butyl 6-((2,4-dichloropyrimidin-5-yl)methyl)-5-oxo-2,6- diazaspiro[3.4]octane-2-carboxylate. To a solution of tert-butyl 5-oxo-2,6-diazaspiro[3.4] octane-2-carboxylate (50 mg, 1 eq, 221 µmol) in tetrahydrofuran (2 mL) was added 2,4- dichloro-5-(iodomethyl)pyrimidine (63.8 mg, 1 eq, 221 µmol) and potassium 2-methylpropan- 2-olate (49.6 mg, 2 eq, 442 µmol) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 hour. LCMS showed the starting material was consumed and the desired Ms was detected. One additional vial was set up as described above. Both reaction mixtures were combined, diluted with water (12 mL), and extracted with ethyl acetate (3 × 4 mL). The combined organic phase was washed with brine (12 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (eluted with ethyl acetate, R _f = 0.4) to give 75 mg (43.82%) of tert-butyl 6-((2,4- dichloropyrimidin-5-yl)methyl)-5-oxo-2,6-diazaspiro[3.4]octa ne-2-carboxylate as a yellow solid. LCMS: Rt = 1.664 min, m/z 331.0 (M-55+H) ⁺ /287.1 (M-100+H) ⁺ . [0565] Step 2. Preparation of tert-butyl (R)-6-((2-chloro-4-((10-methyl-8-oxo-9,10,11,12- tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quin oxalin-3-yl)oxy)pyrimidin-5- yl)methyl)-5-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate. To a solution of (R)-3-hydroxy- 10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (10 mg, 1 eq, 33.3 µmol) in dimethyl sulfoxide (1 mL) was added tert-butyl 6-((2,4-dichloro- pyrimidin-5-yl)methyl)-5-oxo-2,6-diazaspiro[3.4]octane -2-carboxylate (25.8 mg, 2 eq, 66.6 µmol) and cesium carbonate (21.7 mg, 2 eq, 66.6 µmol) at 25 °.C The reaction mixture was heated to 50 °C and stirred at 50 °C for 1 hour. LCMS showed the starting material was consumed and the desired Ms was detected. Two additional vials were set up as described above. After cooling to room temperature, all three reaction mixtures were combined, diluted with water (3 mL), and extracted with ethyl acetate (3 × 1 mL). The organic phase was combined, washed with brine (60 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to afford 40 mg (55.35%) of tert-butyl (R)-6-((2-chloro-4-((10-methyl-8-oxo-9,10,11,12- tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quin oxalin-3-yl)oxy)pyrimidin-5- yl)methyl)-5-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate as an orange solid. LCMS (ESI+): Rt = 1.773 min, m/z 551.1(M+H) ⁺ /595.1(M+41+H) ⁺ /651.2 (M+H) ⁺ . [0566] Step 3. (R)-3-((2-chloro-5-((5-oxo-2,6-diazaspiro[3.4]octan-6-yl)met hyl)pyrimidin- 4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[ 5’,6’:4,5]thieno[3,2-f] quinoxalin-8-one. To a solution of tert-butyl (R)-6-((2-chloro-4-((10-methyl-8-oxo-9,10,11,12- tetrahydro-8H–[1,4]diazepino[5’,6’:4,5]thieno[3,2-f]qu inoxalin-3-yl)oxy)pyrimidin-5- yl)methyl)-5-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate (10 mg, 1 eq, 15.4 µmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.1 mL) at 25 °C. The reaction mixture was heated to 40 °C and stirred at 40 °C for 1 hour. LCMS showed the starting material was consumed and the desired Ms was detected. Three additional vials were set up as described above. After cooling to room temperature, all four reaction mixtures were combined and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC to afford 28 mg (81.78%) of (R)-3-((2-chloro-5-((5-oxo-2,6-diazaspiro[3.4]octan-6- yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydr o-8H-[1,4]diazepino[5’,6’:4,5] thieno[3,2-f]quinoxalin-8-one as an orange solid. LCMS (ESI+): Rt= 1.257 min, m/z 276.5(1/2M+H) ⁺ /551.1 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.09 (s, 1H), 8.90 (br s, 1H), 8.79 (br s, 2H), 8.72 (s, 1H), 8.35 (d, J = 8.9 Hz, 1H), 8.00 (br d, J = 4.3 Hz, 1H), 7.94 (d, J = 8.9 Hz, 1H), 4.63 (s, 2H), 4.06 – 4.01 (m, 2H), 3.92 – 3.85 (m, 2H), 3.72 – 3.65 (m, 1H), 3.60 (br s, 2H), 3.37 (t, J = 6.8 Hz, 2H), 2.40 (t, J = 6.8 Hz, 2H), 1.22 (d, J = 6.6 Hz, 3H). EXAMPLE 19 – Synthesis of (R)-3-((5-((2-acetyl-5-oxo-2,6-diazaspiro [3.4]octan-6- yl)methyl)-2-chloropyrimidin-4-yl)oxy)-10-methyl-9,10,11,12- tetrahydro-8H-[1,4] diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (I-68) [0567] The title compound was prepared using the following procedures. [0568] To a solution of (R)-3-((2-chloro-5-((5-oxo-2,6-diazaspiro[3.4]octan-6-yl)met hyl) pyrimidin- 4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2- f]quinoxalin-8-one (15 mg, 1 eq, 27.2 µmol) in tetrahydrofuran (0.5 mL) was added triethylamine (5.51 mg, 2 eq, 54.4 µmol) and acetyl chloride (2.14 mg, 1 eq, 27.2 µmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour. LCMS showed the starting material was consumed and the desired Ms was detected. One additional vial was set up as described above. Both reaction mixtures were combined, diluted with water (3 mL), and extracted with ethyl acetate (3 × 1 mL). The organic phase was combined, washed with brine (3 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give 3.8 mg (11.77%) of (R)-3-((5-((2- acetyl-5-oxo-2,6-diazaspiro [3.4]octan-6-yl)methyl)-2-chloropyrimidin-4-yl)oxy)-10-methy l- 9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno [3,2-f]quinoxalin-8-one as an orange solid. LCMS (ESI+): Rt = 1.415 min, m/z 593.0 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.08 (s, 1H), 8.80 (br s, 1H), 8.71 (s, 1H), 8.35 (d, J = 8.9 Hz, 1H), 7.99 (br d, J = 4.1 Hz, 1H), 7.94 (d, J = 9.0 Hz, 1H), 4.62 (s, 2H), 4.13 – 4.07 (m, 1H), 3.95 (d, J = 8.1 Hz, 1H), 3.87 (d, J = 9.4 Hz, 1H), 3.70 (br d, J = 9.4 Hz, 2H), 3.60 (br s, 2H), 3.37 (br s, 2H), 2.33 – 2.29 (m, 2H), 1.71 (d, J = 1.0 Hz, 3H), 1.22 (d, J = 6.8 Hz, 3H).

EXAMPLE 20 – Synthesis of (10R)-3-((2-chloro-5-((3-hydroxy-2-oxopyrrolidin-1- yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydr o-8H-[1,4] diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (I-67) [0569] The title compound was prepared using the following procedures. [0570] Step 1. Preparation of 3-((tert-butyldimethylsilyl)oxy) pyrrolidin-2-one. To a solution of 3-hydroxypyrrolidin-2-one (0.5 g, 4.95 mmol) in dichloromethane (5 mL) at 0 °C was added 1H-imidazole (505 mg, 1.5 eq, 7.42 mmol) and tert-butyl(chloro) dimethylsilane (969 mg, 1.3 eq, 6.43 mmol). The resulting mixture was stirred at 25 °C for 16 hours. LCMS showed the starting material was consumed and the desired product mass was detected. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (20 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified via silica gel chromatography eluting with ethyl acetate to afford 0.8 g (75.1%) of 3-((tert-butyldimethylsilyl)oxy) pyrrolidin-2-one as a white solid. LCMS: Rt = 0.555 min, m/z = 216.2 (M+H) ⁺ . [0571] Step 2. Preparation of 3-((tert-butyldimethylsilyl)oxy)-1-((2,4-dichloropyrimidin-5 - yl)methyl) pyrrolidin-2-one. To a solution of 3-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-one (0.2 g, 929 µmol) in tetrahydrofuran (4 mL) at 0 °C was added potassium 2-methylpropan-2-ol (210 mg, 2 eq, 1.86 mmol) and 2,4-dichloro-5-(iodomethyl)pyrimidine (268 mg, 929 µmol). The resulting mixture was stirred at 0 °C for 1 hour. LCMS showed the starting material was consumed completely and the desired product was detected. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (eluted with petroleum ether/ethyl acetate=3/2, R _f =0.55) to give 75 mg (21.4%) of 3-((tert-butyldimethylsilyl)oxy)-1-((2,4-dichloropyrimidin-5 -yl)methyl) pyrrolidin-2-one as a colorless oil. LCMS: Rt = 0.676 min, m/z = 376.1 (M+H) ⁺ . [0572] Step 3. Preparation of (10R)-3-((5-((3-((tert-butyldimethylsilyl)oxy)-2- oxopyrrolidin -1-yl)methyl)-2-chloropyrimidin-4-yl)oxy)-10-methyl-9,10,11, 12- tetrahydro-8H-[1,4] diazepino[5’,6’:4,5]thieo[3,2-f]quinoxalin-8-one. To a solution of 3- ((tert-butyl-dimethylsilyl)oxy)-1-((2,4-dichloropyrimidin-5- yl)methyl) pyrrolidin-2-one (50 mg, 133 µmol) in dimethyl sulfoxide (1 mL) at 25 °C was added dipotassium carbonate (36.7 mg, 2 eq, 266 µmol) and (R)-3-hydroxy-10-methyl- 9,10,11,12-tetrahydro-8H- [1,4]diazepino[5’,6’:4,5]thieno [3,2-f]quinoxalin-8-one (31.9 mg, 0.8 eq, 106 µmol). The resulting mixture was heated to 60 °C and stirred at 60 °C for 1 hour. LCMS showed the starting material was consumed and the desired product was detected. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phase was washed with brine (3 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (eluted with ethyl acetate, R _f =0.5) to give 0.1 g (57.84%, contained DMSO) of (10R)-3-((5-((3-((tert-butyldimethylsilyl)oxy)-2-oxopyrrolid in -1-yl)methyl)-2- chloropyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H - [1,4]diazepino[5’,6’:4,5]thieo[3,2-f]quinoxalin-8-one as a yellow oil, which was used directly in the next step without further purification. LCMS: Rt= 0.558 min, m/z = 640.3 (M+H) ⁺ . [0573] Step 4. Preparation of (10R)-3-((2-chloro-5-((3-hydroxy-2-oxopyrrolidin-1- yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydr o-8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one. To a solution of potassium hydrogen fluoride (54.5 mg, 30 eq, 922 µmol) in formic acid (0.1 mL) and acetonitrile (0.5 mL) at room temperature was added (10R)-3-((5-((3-((tert-butyldimethylsilyl)oxy) -2-oxopyrrolidin-1-yl)methyl)-2- chloropyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H -[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (40 mg, 30.7 µmol). The resulting mixture was heated to 35 °C and stirred at 35 °C for 3 hours. LCMS showed the starting material was consumed completely and the desired product was detected. The reaction mixture was filtered, and the filtrate was purified by prep-HPLC to give 2 mg (12.3%) of (10R)-3-((2-chloro-5-((3-hydroxy- 2-oxopyrrolidin-1-yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9, 10,11,12-tetrahydro-8H- [1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one as a yellow solid. LCMS: Rt= 1.304 min, m/z = 526.1 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.08 (s, 1H), 8.80 (br s, 1H), 8.65 (s, 1H), 8.35 (d, J = 8.9 Hz, 1H), 8.03 – 7.90 (m, 2H), 4.59 (q, J = 15.8 Hz, 2H), 4.15 (t, J = 8.2 Hz, 1H), 3.74 – 3.55 (m, 4H), 3.54 – 3.48 (m, 1H), 2.32 – 2.24 (m, 1H), 1.80 – 1.74 (m, 1H), 1.22 (br d, J = 6.6 Hz, 3H). EXAMPLE 21 – Synthesis of (10R)-3-((2-chloro-5-((4-hydroxy-2-oxopyrrolidin-1-yl) methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8 H-[1,4]diazepino[5’,6’:4,5] thieno[3,2-f]quinoxalin-8-one (I-66) [0574] The title compound was prepared using the following procedures. [0575] Step 1. Preparation of 4-(((tert-butyldimethylsilyl) oxy) methyl) pyrrolidin-2-one. To a solution of 4-(hydroxymethyl)pyrrolidin-2-one (120 mg, 1 eq, 1.04 mmol) and imidazole (213 mg, 3 eq, 3.13 mmol) in dichloromethane (5 mL) at 0 °C was added tert-butylchloro- dimethylsilane (236 mg, 1.5 eq, 1.56 mmol). The reaction mixture was stirred at 25 °C for 14 hours. LCMS showed the starting material was consumed and the desired product was detected. The reaction mixture was filtered, and the filtrate was diluted with water (10 mL) and extracted with dichloromethane (4 mL × 3). The combined organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford the crude product, which was purified via silica gel chromatography eluting with 50% ethyl acetate in petroleum. Pure fractions were combined and concentrated to afford 630 mg (87.9%) of 4-(((tert-butyldimethylsilyl) oxy) methyl) pyrrolidin-2-one as a white solid. LCMS: Rt = 0.570 min, m/z = 459.4 (2M+H) ⁺ . [0576] Step 2. Preparation of 4-(((tert-butyldimethylsilyl)oxy)methyl)-1-((2,4- dichloropyrimidin-5-yl)methyl)pyrrolidin-2-one. To a solution 4-(((tert-butyldimethylsilyl) oxy)methyl)pyrrolidin-2-one (300 mg, 1 eq, 1.31 mmol) and 2,4-dichloro-5-(iodomethyl) pyrimidine (378 mg, 1 eq, 1.31 mmol) in tetrahydrofuran (8 mL) at 0 °C was added potassium 2-methylpropan-2-olate (294 mg, 2 eq, 2.62 mmol). The reaction mixture was stirred at 0 °C for 1 hour. LCMS showed the starting material was consumed and the desired product was detected. The reaction mixture was washed with aqueous ammonium chloride (3 × 5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford the crude product, which was purified via silica gel chromatography eluting with 50% ethyl acetate in petroleum. Pure fractions were combined and concentrated to afford 92 mg (18%) of 4-(((tert-butyldimethylsilyl)oxy)methyl)-1-((2,4-dichloropyr imidin-5- yl)methyl) pyrrolidin-2-one as a yellow oil. LCMS: Rt = 0.678 min, m/z = 390.2 (M+H) ⁺ . [0577] Step 3. Preparation of (10R)-3-((5-((4-(((tert-butyldimethylsilyl)oxy) methyl) -2- oxopyrrolidin-1-yl)methyl)-2-chloropyrimidin-4-yl) oxy)-10-methyl-9,10,11,12- tetrahydro-8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one. To a solution of 4- (((tert-butyldimethylsilyl)oxy) methyl)-1-((2,4-dichloropyrimidin-5-yl) methyl)pyrrolidin-2- one (20 mg, 1 eq., 5.12 mmol) and (R)-3-hydroxy-10-methyl -9,10,11,12-tetrahydro-8H- [1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (14.6 mg, 0.95 eq, 48.7 mmol) in dimethyl sulfoxide (0.5 mL) at room temperature was added cesium carbonate (25 mg, 1.5 eq, 76.8 µmol). The reaction was stirred at 25 °C for 3 hours. LCMS showed the starting material was consumed and the desired product was detected. The reaction mixture was poured into water (2 mL) and extracted with ethyl acetate (1 mL × 3). The organic phase was combined, washed with brine (1 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford 26 mg (81%) of crude (10R)-3-((5-((4-(((tert- butyldimethylsilyl)oxy) methyl) -2-oxopyrrolidin-1-yl) methyl)-2-chloropyrimidin-4-yl) oxy)- 10- methyl-9,10,11,12- tetrahydro-8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one as a yellow solid, which was used directly in the next step. LCMS: Rt = 0.541 min, m/z = 654.3 (M+H) ⁺ . [0578] Step 4. Preparation of (10R)-3-((2-chloro-5-((4-hydroxy-2-oxopyrrolidin-1- yl)methyl)pyrimidin-4-yl)oxy)-10-metyl-9,10,11,12-tetrahydro -8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one. To a solution of (10R)-3-((5-((4-(((tert-butyl- dimethylsilyl)oxy) methyl)-2-oxopyrrolidin -1-yl) methyl)-2-chloropyrimidin-4-yl)oxy)- 10- methyl -9,10,11,12-tetrahydro-8H-[1,4] diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (60 mg, 91.7 µmol) in acetonitrile (1 mL, 19.1 mmol) and formic acid (0.2 mL, 5.26 mmol) at room temperature was added potassium difluorohydrogen (43 mg, 6 eq, 550 µmol). The reaction mixture was stirred at 25 °C for 3 hours. LCMS showed the starting material was consumed and the desired product was detected. The reaction mixture was filtered, and the filtrate was purified by prep-HPLC to give 5 mg (10.3%) of (10R)-3-((2-chloro-5-((4-hydroxy- 2-oxopyrrolidin-1-yl)methyl)pyrimidin-4-yl)oxy)-10-metyl-9,1 0,11,12-tetrahydro-8H- [1,4]diazepino[5’,6’:4,5] thieno[3,2-f]quinoxalin-8-one as a white solid. LCMS: Rt = 1.449 min, m/z = 540.1 (M+H) ⁺ . ¹ H NMR (400 MHz, CD3OD) δ 8.94 (s, 1H), 8.68 (s, 1H), 8.18 (d, J = 9.0 Hz, 1H), 7.90 (d, J = 8.9 Hz, 1H), 4.76 – 4.59 (m, 2H), 3.87 – 3.79 (m, 1H), 3.75 – 3.63 (m, 3H), 3.57 (t, J = 5.8 Hz, 2H), 3.41 (dd, J = 4.9, 9.9 Hz, 1H), 2.70 – 2.38 (m, 2H), 2.25 (dd, J = 5.3, 16.6 Hz, 1H), 1.36 (d, J = 6.9 Hz, 3H). EXAMPLE 22 – Synthesis of (R)-3-((5-((2-acetyl- 7-oxo-2,6-diazaspiro[3.4]octan-6-yl) methyl)-2-chloropyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tet rahydro-8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (I-65) [0579] The title compound was prepared using the following procedures. [0580] Step 1. Preparation of (R)-3-((5-((2-acetyl- 7-oxo-2,6-diazaspiro[3.4]octan-6-yl) methyl)-2-chloropyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tet rahydro-8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one. To a solution of (R)-3-((2-chloro-5-((7-oxo-2,6- diazaspiro[3.4]octan-6-yl)methyl)pyrimidin -4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H- [1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (6 mg, 1 eq, 10.9 µmol) in dichloromethane (0.5 mL) was added triethylamine (3.31 mg, 3 eq, 32.7 µmol) at 0 °C. After warming to 25 °C, the reaction mixture was stirred at 25 °C for 1 hour. LCMS showed the starting material was consumed and 78% of the desired Ms was detected. One additional vial was set up as described above. Both reaction mixtures were combined, diluted with water (10 mL), and extracted with ethyl acetate (3 × 7 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give 6.5 mg (50.33%) of (R)-3-((5-((2-acetyl- 7-oxo-2,6-diazaspiro[3.4]octan-6-yl)methyl)- 2-chloropyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro- 8H-[1,4]diazepino[5’,6’:4,5] thieno[3,2-f]quinoxalin-8-one as a yellow solid. LCMS (ESI+): Rt = 0.371 min, m/z 593.2 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.09 (s, 1H), 8.80 (t, J = 3.8 Hz, 1H), 8.67 (s, 1H), 8.35 (d, J = 9.0 Hz, 1H), 8.01 (d, J = 4.2 Hz, 1H), 7.95 (d, J = 9.0 Hz, 1H), 4.58 (s, 2H), 4.13 – 4.05 (m, 2H), 3.87 – 3.78 (m, 2H), 3.71 – 3.64 (m, 3H), 3.60 (br s, 2H), 2.62 (s, 2H), 1.72 (s, 3H), 1.22 (d, J = 6.6 Hz, 3H). EXAMPLE 23 – Synthesis of (R)-3-((2-chloro-5-((7-oxo-2,6-diazaspiro[3.4]octan- 6- yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydr o-8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (I-64) [0581] The title compound was prepared using the following procedures. [0582] Step 1. Preparation of tert-butyl 6-((2,4-dichloropyrimidin-5-yl)methyl)-7-oxo-2,6- diazaspiro[3.4]octane-2-carboxylate. To a solution of tert-butyl 7-oxo-2,6-diazaspiro[3.4] octane-2-carboxylate (78.3 mg, 1 eq, 346 µmol) in tetrahydrofuran (1 mL) was added 2,4- dichloro-5-(iodomethyl)pyrimidine (100 mg, 1 eq, 346 µmol) and potassium tert-butoxide (77.7 mg, 2 eq, 692 µmol) at 0 °C. The mixture was stirred for 1 hour. LCMS showed the starting material was consumed and the desired peak was detected. Four additional vials were set up as described above. All five reaction mixtures were diluted with water (15 mL) and extracted with ethyl acetate (3 × 8 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (eluted with ethyl acetate = 1, R _f = 0.45) to give 60 mg (44.76%) of tert-butyl 6-((2,4-dichloropyrimidin-5- yl)methyl)-7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate as a yellow solid. (400 MHz, CD ₃ OD) 8.57 (s, 1H), 4.57 (s, 2H), 3.97 – 3.86 (m, 4H), 3.64 (s, 2H), 2.73 (s, 2H), 2.01 (s, 1H), 1.43 (s, 9H). [0583] Step 2. Preparation of tert-butyl (R)-6-((2-chloro-4-((10-methyl -8-oxo-9,10,11,12- tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quin oxalin-3-yl)oxy)pyrimidin-5- yl)methyl)-7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate. To a solution of tert-butyl 6- ((2,4-dichloropyrimidin-5-yl)methyl)-7-oxo-2,6-diazaspiro [3.4]octane-2-carboxylate (19.3 mg, 1.5 eq, 49.9 µmol) in dimethyl sulfoxide (1 mL) was added (R)-3-hydroxy-10-methyl- 9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno [3,2-f]quinoxalin-8-one (10 mg, 1 eq, 33.3 µmol) and cesium carbonate (21.7 mg, 2 eq, 66.6 µmol) at 25 °C. The reaction mixture was heated to 50 °C and stirred for 1 hour. LCMS showed the starting material was consumed and the desired peak was detected. One additional vial was set up as described above. Two reaction mixtures were combined, diluted with water (5 mL), and extracted with ethyl acetate (3 × 5 mL). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 60 mg (crude) of tert-butyl (R)-6-((2-chloro-4-((10-methyl -8-oxo-9,10,11,12-tetrahydro- 8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-3-yl)oxy)pyrimidin-5- yl)methyl)-7-oxo- 2,6-diazaspiro [3.4]octane-2-carboxylate as a yellow solid. LCMS: Rt = 0.450 min, m/z = 651.3 (M+H) ⁺ . [0584] Step 3. Preparation of (R)-3-((2-chloro-5-((7-oxo-2,6-diazaspiro[3.4]octan- 6- yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydr o-8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one. To a solution of tert-butyl (R)-6-((2-chloro-4-((10- methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6� ��:4,5]thieno[3,2-f]quinoxalin-3- yl)oxy)pyrimidin-5-yl)methyl)-7-oxo-2,6-diazaspiro[3.4]octan e-2-carboxylate (55 mg, crude) in dichloromethane (1 mL) was added trifluoroacetic acid (0.1 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 1 hour. LCMS showed the starting material was consumed and the desired peak was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give 10 mg (19.8%) of (R)-3-((2- chloro-5-((7-oxo-2,6-diazaspiro[3.4]octan- 6-yl)methyl)pyrimidin-4-yl)oxy)-10-methyl- 9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno [3,2-f]quinoxalin-8-one as an orange solid. LCMS: Rt = 0.523 min, m/z = 551.3 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.09 (s, 1H), 8.80 (t, J = 3.7 Hz, 1H), 8.66 (s, 1H), 8.35 (d, J = 8.8 Hz, 1H), 8.01 (d, J = 4.2 Hz, 1H), 7.94 (d, J = 9.0 Hz, 1H), 4.56 (s, 2H), 3.87 – 3.80 (m, 4H), 3.71 – 3.63 (m, 3H), 3.60 (br s, 2H), 2.62 – 2.58 (m, 2H), 1.36 – 1.34 (m, 9H), 1.22 (d, J = 6.8 Hz, 3H). EXAMPLE 24 – Synthesis of (R)-3-((5-((8-acetyl-3-oxo-2,8-diazaspiro[4.5]decan-2-yl) methyl)-2-chloropyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tet rahydro-8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (I-63) [0585] The title compound was prepared using the following procedures. [0586] To a solution of (R)-3-((2-chloro-5-((3-oxo-2,8-diazaspiro[4.5]decan-2-yl)met hyl) pyrimidin -4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2- f]quinoxalin-8-one (10 mg, 1 eq, 17.3 µmol) in dichloromethane (0.5 mL) was added triethylamine (5.15 mg, 2 eq, 34.5 µmol) and acetyl chloride (1.36 mg, 1 eq, 17.3 µmol) at 25 °C. The mixture was stirred at 25 °C for 1 hour. LCMS showed the starting material peak was consumed and the desired peak was detected. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give 2 mg (6.25%) of (R)-3-((5-((8-acetyl-3-oxo-2,8-diazaspiro[4.5]decan-2-yl)met hyl)-2- chloropyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H - [1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one as an orange solid. LCMS (ESI+): Rt = 0.400 min, m/z 621.2 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.08 (s, 1H), 8.80 (br s, 1H), 8.69 (s, 1H), 8.35 (d, J = 8.9 Hz, 1H), 8.00 (d, J = 4.4 Hz, 1H), 7.94 (d, J = 9.0 Hz, 1H), 4.58 (s, 2H), 3.72 – 3.64 (m, 1H), 3.60 (br s, 2H), 3.50 (br d, J = 5.6 Hz, 2H), 3.30 (s, 4H), 2.26 (s, 2H), 1.97 (s, 3H), 1.57 (br t, J = 5.4 Hz, 2H), 1.48 (br t, J = 5.6 Hz, 2H), 1.22 (d, J = 6.6 Hz, 3H). EXAMPLE 25 – Synthesis of (R)-3-((2-chloro-5-((8-methyl-3-oxo-2,8-diazaspiro [4.5]decan-2-yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11 ,12-tetrahydro-8H- [1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (I-62) [0587] The title compound was prepared using the following procedures. [0588] To a solution of (R)-3-((2-chloro-5-((3-oxo-2,8-diazaspiro[4.5]decan-2-yl)met hyl) pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4] diazepino[5’,6’:4,5] thieno[3,2- f]quinoxalin-8-one (10 mg, 1 eq, 17.3 µmol, 50% purity) in methanol (0.5 mL) was added formaldehyde (1.4 mg, 1 eq, 17.3 µmol, 37% in water) and sodium cyanoborohydride (2.17 mg, 2 eq, 34.5 µmol) at 25 ℃. The resulting mixture was stirred at 25 ℃ for 1 hour. LCMS showed the starting material peak was consumed and the desired peak was detected. Three additional vials were set up as described above. All four reaction mixtures were filtered, and the filtrate was concentrated under reduced perssure to give a residue. The residue was purified by prep-HPLC to give 4.20 mg (8.60%) of (R)-3-((2-chloro-5-((8-methyl-3-oxo-2,8-diazaspiro [4.5]decan-2-yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11 ,12-tetrahydro-8H- [1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one as an orange solid. LCMS (ESI+): Rt = 0.336 min, m/z 593.5 (M+H) ⁺ . ¹ H NMR (400 MHz, D ₂ O) 8.66 (d, J = 6.9 Hz, 1H), 8.49 (d, J = 9.9 Hz, 1H), 7.60 (br dd, J = 5.0, 7.9 Hz, 1H), 7.32 – 7.19 (m, 1H), 4.74 – 4.72 (m, 2H), 3.64 (s, 2H), 3.51 (s, 4H), 3.36 (br d, J = 6.5 Hz, 1H), 3.14 (br d, J = 1.5 Hz, 2H), 2.89 (d, J = 10.9 Hz, 3H), 2.67 – 2.46 (m, 2H), 2.15 – 1.87 (m, 4H), 1.27 (br d, J = 6.9 Hz, 3H). EXAMPLE 26 – Synthesis of (R)-3-((2-chloro-5-((4-methyl-3-oxopiperazin-1-yl)methyl) pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4] diazepino[5’,6’:4,5] thieno[3,2-f]quinolin-8-one (I-61) [0589] The title compound was prepared using the following procedures. [0590] Step 1. Preparation of 4-((2,4-dichloropyrimidin-5-yl) methyl)-1-methylpiperazin- 2-one. To a solution of 2,4-dichloro-5-(iodomethyl)pyrimidine (50 mg, 1 eq, 173 µmol) in acetonitrile (0.5 mL) was added 1-methylpiperazin-2-one (19.8 mg, 1 eq, 173 µmol) and potassium carbonate (47.8 mg, 2 eq, 346 µmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. TLC (eluted with ethyl acetate, R _f = 0.45) showed the starting material was consumed and the desired spot was formed. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 5 mL). The organic phase was washed with brine (3 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (eluted with ethyl acetate, R _f = 0.45) to give 20 mg (42%) of 4-((2,4-dichloropyrimidin-5-yl) methyl)-1-methylpiperazin-2-one as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) 8.80 (s, 1H), 3.81 (s, 2H), 3.45 (t, J = 5.4 Hz, 2H), 3.35 (s, 2H), 3.00 (s, 3H), 2.89 (t, J = 5.4 Hz, 2H). [0591] Step 2. Preparation of (R)-3-((2-chloro-5-((4-methyl-3-oxopiperazin-1- yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydr o-8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinolin-8-one. To a solution of (15R)-5-hydroxy-15-methyl-11-thia- 3,6,14,17-tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)- hexaen-13-one (10 mg, 1 eq, 33.3 µmol) in dimethyl sulfoxide (0.6 mL) was added 4-[(2,4-dichloropyrimidin- 5-yl)methyl]-1- methylpiperazin-2-one (18.3 mg, 2 eq, 66.6 µmol) and potassium carbonate (9.2 mg, 2 eq, 66.6 µmol) at 25 °C. The reaction mixture was heated to 60 °C and stirred at 60 °C for 1 hour. LCMS showed the starting material was consumed and the desired peak was detected. One additional vial was set up as described above. After cooling to 20 °C, both reaction mixtures were combined, diluted with water (10 mL), and extracted with ethyl acetate (3 × 5 mL). The organic phase was washed with brine (5 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give 28 mg (78.03%) of (R)-3-((2-chloro-5-((4-methyl-3-oxopiperazin-1-yl)methyl)pyr imidin-4-yl)oxy)-10-methyl- 9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno [3,2-f]quinolin-8-one as an orange solid. LCMS (ESI+): Rt = 0.367 min, m/z 539.2 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.09 (s, 1H), 8.81 (s, 2H), 8.35 (d, J = 8.9 Hz, 1H), 8.00 (br d, J = 3.9 Hz, 1H), 7.95 (d, J = 8.9 Hz, 1H), 4.09 – 3.87 (m, 2H), 3.70 – 3.66 (m, 1H), 3.60 (br s, 2H), 3.36 – 3.31 (m, 5H), 3.07 – 2.93 (m, 2H), 2.85 – 2.77 (m, 3H), 1.22 (br d, J = 6.6 Hz, 3H). EXAMPLE 27 – Synthesis of (15R)-5-({2-chloro-5-[(3-oxopiperazin-1-yl)methyl] pyrimidin-4-yl}oxy)-15-methyl-11-thia-3,6,14,17-tetraazatetr acyclo[8.8.0.0²,⁷.0¹²,¹⁸] octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (I-60) [0592] The title compound was prepared using the following procedures. [0593] Step 1. Preparation of 4-[(2,4-dichloropyrimidin-5-yl)methyl] piperazin – 2-one. To a solution of piperazin-2-one (250 mg, 2.5 mmol) in dimethyl sulfoxide (2 mL) at room temperature was added dipotassium carbonate (690 mg, 2 eq, 4.99 mmol) and 2,4-dichloro-5- (iodomethyl) pyrimidine (577 mg, 0.8 eq, 2 mmol). The reaction mixture was stirred at 25 ℃ for 2 hours. TLC (eluted with ethyl acetate/methanol = 20/1, R _f = 0.2) showed the staring material was consumed completely and the desired product was formed. Three additional vials were set up as described above. All four reaction mixtures were combined and filtered. The filtrate was purified by prep-HPLC to give 0.6 g (22.09%) of 4-[(2,4-dichloropyrimidin-5- yl)methyl] piperazin-2-one as a yellow solid. LCMS: Rt = 1.471 min, 50.93% purity, m/z = 261.1 (M+H) ⁺ . [0594] Step 2. Preparation of (15R)-5-({2-chloro-5-[(3-oxopiperazin-1-yl)methyl] pyrimidin-4-yl}oxy)-15-methyl-11-thia-3,6,14,17-tetraazatetr acyclo[8.8.0.0²,⁷.0¹²,¹⁸] octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one. To a solution of (15R)-5-hydroxy-15- methyl-11-thia-3,6,14,17-tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)- hexaen-13-one (40 mg, 0.8 eq, 133 µmol) in dimethyl sulfoxide (0.5 mL) at room temperature was added dipotassium carbonate (46 mg, 2 eq, 333 µmol) and 4-[(2,4-dichloropyrimidin-5- yl)methyl] piperazin-2-one (86.9 mg, 2 eq, 333 µmol). The reaction mixture was heated to 70 °C and stirred at 70 °C for 2 hours. LCMS showed the starting material remained and the desired product was detected. The reaction mixture was filtered, and the filtrate was purified by prep-HPLC to give 45 mg (51.49%) of (15R)-5-({2-chloro-5-[(3-oxopiperazin-1- yl)methyl]pyrimidin-4-yl}oxy)-15-methyl-11-thia-3,6,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10), 2(7),3,5,8,12(18)-hexaen-13-one as a yellow solid. LCMS: Rt = 1.471 min, m/z = 525.2 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.08 (s, 1H), 8.84 – 8.73 (m, 2H), 8.34 (d, J = 8.9 Hz, 1H), 7.99 (br d, J = 4.5 Hz, 1H), 7.95 (d, J = 8.9 Hz, 1H), 7.77 (br s, 1H), 3.78 (s, 2H), 3.71 – 3.64 (m, 1H), 3.60 (br s, 2H), 3.17 (br s, 2H), 3.10 (s, 2H), 2.70 (br t, J = 5.2 Hz, 2H), 1.22 (d, J = 6.6 Hz, 3H). EXAMPLE 28 – Synthesis of (15R)-5-({2-chloro-5-[(2-oxopiperazin-1-yl)methyl] pyrimidin-4-yl}oxy)-15-methyl-11-thia-3,6,14,17-tetraazatetr acyclo[8.8.0.0²,⁷.0¹²,¹⁸] octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (I-59) [0595] The title compound was prepared using the following procedures. [0596] Step 1. Preparation of tert-butyl 4-[(2,4-dichloropyrimidin-5-yl)methyl]-3- oxopiperazine-1-carboxylate. To a solution of 2,4-dichloro-5-(iodomethyl)pyrimidine (0.5 g, 1.73 mmol) and tert-butyl 3-oxopiperazine-1-carboxylate (347 mg, 1 eq, 1.73 mmol) in tetrahydrofuran (20 mL, 246 mmol) was added 2-methylpropan-2-olate (154 mg, 1.2 eq, 2.08 mmol) at room temperature. Then, the mixture was stirred at 25 °C for 2 hours. LCMS showed the starting material was consumed and the desired product was detected. Then, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography eluting with 25% ethyl acetate in petroleum ether to afford 215 mg (34.4%) of tert-butyl 4-[(2,4-dichloropyrimidin-5-yl)methyl]- 3-oxopiperazine-1-carboxylate as a colorless oil. LCMS: Rt = 0.474 min, m/z = 304.9 (M- tBu+H) ⁺ . [0597] Step 2. Preparation of (15R)-5-({2-chloro-5-[(2-oxopiperazin-1- yl)methyl]pyrimidin-4-yl}oxy)-15-methyl-11-thia-3,6,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10), 2(7),3,5,8,12(18)-hexaen-13-one. To a solution of tert-butyl 4-[(2-chloro-4-{[(15R)-15-methyl-13-oxo-11-thia-3,6,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10), 2(7), 3,5,8,12(18)-hexaen-5- yl]oxy}pyrimidin-5-yl)methyl]-3-oxopiperazine-1-carboxylate (190 mg, 304 µmol) in dichloromethane (10 mL, 156 mmol) was added trifluoroacetic acid (1 mL). The mixture was stirred at 25 °C for 1 hour. LCMS indicated the starting material was consumed and the desired product was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC. Pure fractions were combined and lyophilized to afford 130 mg (61.9%) of (15R)-5-({2-chloro-5-[(2-oxopiperazin-1-yl)methyl] pyrimidin-4-yl}oxy)-15-methyl-11-thia-3,6,14,17-tetraazatetr acyclo[8.8.0.0²,⁷.0¹²,¹⁸] octadeca- 1(10),2(7),3,5,8,12(18)-hexaen-13-one (TFA salt) as an orange solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.22 (br s, 2H), 9.11 (s, 1H), 8.81 (br s, 1H), 8.70 (s, 1H), 8.37 (d, J = 8.9 Hz, 1H), 8.04 (br d, J = 4.3 Hz, 1H), 7.96 (d, J = 9.0 Hz, 1H), 4.77 (s, 2H), 3.87 (s, 2H), 3.76 – 3.64 (m, 3H), 3.60 (br s, 2H), 3.51 – 3.51 (m, 1H), 3.51 – 3.48 (m, 2H), 1.22 (d, J = 6.6 Hz, 3H). EXAMPLE 29 – Synthesis of (15R)-5-({2-chloro-5-[(4-methyl-2-oxopiperazin-1-yl) methyl]pyrimidin-4-yl}oxy)-15-methyl-11-thia-3,6,14,17-tetra azatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸] octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (I-55) [0598] The title compound was prepared using the following procedures. [0599] To a solution of (15R)-5-({2-chloro-5-[(2-oxopiperazin-1-yl)methyl]pyrimidin- 4- yl}oxy) -15-methyl-11-thia-3,6,14,17-tetraazatetracyclo[8.8.0.0²,� �.0¹²,¹⁸]octadeca- 1(10),2(7),3,5,8,12(18)-hexaen-13-one (0.1 g, 1 eq, 190 µmol) in methanol (5 mL) at room temperature was added formaldehyde (0.5 mL, 30% aqueous solution) and acetic acid (0.1 mL, 9.2 eq, 1.75 mmol). The reaction mixture was stirred at 25 °C for 0.5 hour. Then, to the reaction mixture was added cyanoboranuide sodium (23.9 mg, 2 eq, 381 µmol) at 25 °C. The mixture was stirred at 25 °C for 1 hour. LCMS showed the starting material was consumed completely and the desired product was detected. The reaction mixture was purified by prep- HPLC to afford 37 mg (35.7%) (15R)-5-({2-chloro-5- [(4-methyl-2-oxopiperazin-1- yl)methyl]pyrimidin-4-yl}oxy)-15-methyl-11-thia-3,6,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10), 2(7),3,5,8,12(18)-hexaen-13-one as an orange solid. LCMS: Rt = 0.446 min, m/z = 539.1 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.98 – 8.95 (m, 1H), 8.72 – 8.70 (m, 1H), 8.19 (d, J = 8.9 Hz, 1H), 7.92 – 7.88 (m, 1H), 4.85 – 4.83 (m, 2H), 3.95 (s, 2H), 3.93 – 3.88 (m, 2H), 3.86 – 3.79 (m, 1H), 3.74 – 3.66 (m, 2H), 3.60 (br t, J = 5.3 Hz, 2H), 2.97 (s, 3H), 1.36 (d, J = 6.8 Hz, 3H). EXAMPLE 30 – Synthesis of (15R)-5-[(2-chloro-5-{[(3R)-3-methyl-2- oxopyrrolidin-1-yl] methyl}pyrimidin-4-yl)oxy]-15-methyl-11-thia-3,6,14,17-tetra azatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)- hexaen-13-one (I-53) and (15R)-5-[(2- chloro-5-{[(3S)-3-methyl-2-oxopyrrolidin-1-yl]methyl}pyrimid in-4-yl)oxy]-15- methyl-11- thia-3,6,14,17-tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸] octadeca-1(10),2(7),3,5,8,12(18)-hexaen- [0600] The title compound was prepared using the following procedures. [0601] (15R)-5-({2-chloro-5-[(3-methyl-2-oxopyrrolidin-1-yl)methyl] pyrimidin-4-yl}oxy)-15- methyl-11-thia-3,6,14,17-tetraazatetracyclo[8.8.0.0²,⁷.0� �²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)- hexaen-13-one (0.1 g, 191 µmol) was separated by SFC and further purified by prep-HPLC to furnish 28.6 mg (28.6%) of (15R)-5-[(2-chloro-5-{[(3R)-3-methyl-2- oxopyrrolidin-1-yl] methyl}pyrimidin-4-yl)oxy]-15-methyl-11-thia-3,6,14,17-tetra azatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸] octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (I-53) as a yellow solid and 28.2 mg (28.2%) of (15R)-5-[(2-chloro-5-{[(3S)-3-methyl-2-oxopyrrolidin-1-yl]me thyl} pyrimidin-4-yl)oxy]-15- methyl-11-thia-3,6,14,17-tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)- hexaen-13-one (I-52) as a yellow solid. (I-53): ¹ H NMR (400 MHz, DMSO-d ₆ ,) δ 9.08 (s, 1H), 8.80 (br t, J = 3.8 Hz, 1H), 8.65 (s, 1H), 8.35 (d, J = 8.9 Hz, 1H), 8.00 (br d, J = 4.3 Hz, 1H), 7.94 (d, J = 8.9 Hz, 1H), 4.66 – 4.51 (m, 2H), 3.77 – 3.54 (m, 3H), 3.39 – 3.34 (m, 2H), 2.43 – 2.38 (m, 1H), 2.26 – 2.15 (m, 1H), 1.58 (qd, J = 8.7, 12.2 Hz, 1H), 1.22 (d, J = 6.6 Hz, 3H), 1.03 (d, J = 7.1 Hz, 3H). (I-52): ¹ H NMR (400 MHz, DMSO-d ₆ + D2O) δ 9.01 (s, 1H), 8.86 (br s, 1H), 8.61 (s, 1H), 8.29 (d, J = 9.0 Hz, 1H), 7.91 (d, J = 9.0 Hz, 1H), 4.67 – 4.43 (m, 2H), 3.72 – 3.51 (m, 3H), 3.34 (dd, J = 5.6, 8.1 Hz, 2H), 2.42 – 2.34 (m, 1H), 2.18 (dt, J = 5.6, 12.9 Hz, 1H), 1.53 (qd, J = 8.6, 12.3 Hz, 1H), 1.19 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 7.1 Hz, 3H). EXAMPLE 31 – Synthesis of (R)-3-((2-chloro-5-(((R)-4- methyl-2-oxopyrrolidin-1- yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydr o-8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (I-82) and (R)-3-((2-chloro-5-(((S)-4-methyl-2- oxopyrrolidin-1-yl)methyl)pyrimidin-4-yl) oxy)-10-methyl-9,10,11,12-tetrahydro-8H- [1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (I-83) [0602] The title compound was prepared using the following procedures. [0603] (10R)-3-((2-Chloro-5-((4-methyl-2-oxopyrrolidin-1-yl)methyl) pyrimidin-4-yl)oxy)-10- methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’:4,5 ]thieno[3,2-f]quinoxalin-8-one (0.15 g, 286 µmol) was separated by SFC to obtain 38.4 mg (25.6%) of (R)-3-((2-chloro-5-(((R)-4- methyl-2-oxopyrrolidin-1-yl)methyl)pyrimidin-4-yl)oxy)-10-me thyl-9,10,11,12-tetrahydro-8H- [1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (I-82) as a yellow solid and 50.5 mg (33.6%) of (R)-3-((2-chloro-5-(((S)-4-methyl-2-oxopyrrolidin-1-yl)methy l)pyrimidin-4-yl) oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’, 6’:4,5]thieno[3,2-f]quinoxalin-8- one (I-83) as a yellow solid. I-82: LCMS: Rt = 2.365 min, 98.3% purity, m/z = 524.2 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.08 (s, 1H), 8.85 – 8.76 (m, 1H), 8.67 (s, 1H), 8.35 (d, J = 9.0 Hz, 1H), 8.00 (br d, J = 4.3 Hz, 1H), 7.94 (d, J = 8.9 Hz, 1H), 4.57 (s, 2H), 3.74 – 3.50 (m, 4H), 3.03 (dd, J = 5.9, 9.1 Hz, 1H), 2.45 – 2.38 (m, 2H), 1.97 – 1.87 (m, 1H), 1.22 (d, J = 6.6 Hz, 3H), 1.05 (d, J = 6.3 Hz, 3H). I-83: LCMS: Rt = 2.361 min, 95.8% purity, m/z = 524.2 (M+H)+. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.08 (s, 1H), 8.80 (br s, 1H), 8.67 (s, 1H), 8.34 (d, J = 8.9 Hz, 1H), 8.00 (br d, J = 4.1 Hz, 1H), 7.94 (d, J = 8.9 Hz, 1H), 4.57 (s, 2H), 3.73 – 3.51 (m, 4H), 3.02 (dd, J = 5.8, 9.1 Hz, 1H), 2.46 – 2.37 (m, 2H), 1.97 – 1.86 (m, 1H), 1.22 (br d, J = 6.6 Hz, 3H), 1.05 (d, J = 6.3 Hz, 3H). EXAMPLE 32 – Synthesis of 4-((2-chloro-4-((10,10-dimethyl-8-oxo-9,10,11,12-tetrahydro- 8H-[1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-3-yl )oxy)pyrimidin-5-yl)methyl) morpholin-3-one (I-89) [0604] The title compound was prepared using the following procedures. [0605] Step 1. Preparation of methyl 3-[2-(tert butoxycarbonylamino)-2-methyl-propyl- amino]-11-methoxy-5-thia-10,13- diazatricyclo[7.4.0.0²,⁶]trideca-1(9),2(6),3,7,10,12- hexaene-4-carboxylate. To a solution of methyl 3-bromo-11-methoxy-5-thia-10,13- diazatricyclo[7.4.0.0²,⁶] trideca-1(9),2(6),3,7,10,12-hexaene-4-carboxylate(0.1 g, 1 eq, 283 µmol) in 1,4-dioxane (2 mL) was added 2-amino-1,1-dimethylethylamino-tert-butylformylate (53.3 mg, 1 eq, 283 µmol) and cesium carbonate (184 mg, 2 eq, 566 µmol). The mixture was degassed and purged with nitrogen 3 times at 20 °C. Then, to the reaction mixture was added 2-biphenylid-2’-amine-2,2’-bis(diphenylphosphino)-1,1’ -binaphthyl-methanesulfonicacid- palladium (28.1 mg, 0.1 eq, 28.3 µmol) at 20 °C under a nitrogen atmosphere. The resulting mixture was heated to 90 °C and stirred at 90 °C for 2 hours. LCMS showed the starting material was consumed and the desired peak was detected. TLC (petroleum ether/ethyl acetate = 3/1, R _f = 0.6) showed the starting material was consumed and the desired spot was formed. Ten additional vials were set up as described above. After cooling to 20 °C, all eleven reaction mixtures were combined, diluted with water (50 mL), and extracted with ethyl acetate (3 × 20 mL). The organic phase was washed with brine (20 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatogrpahy to give 820 mg (57%) of methyl 3-[2-(tert butoxycarbonylamino)-2-methylpropylamino]-11-methoxy-5-thia- 10,13-diazatricyclo[7.4.0.0²,⁶] trideca-1(9),2(6),3,7,10,12-hexaene-4-carboxylate as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.01 (br t, J = 4.5 Hz, 1H), 8.67 (s, 1H), 8.19 (d, J = 8.9 Hz, 1H), 7.90 (d, J = 8.9 Hz, 1H), 6.59 (br s, 1H), 4.09 (s, 3H), 3.80 (s, 3H), 3.72 (br d, J = 4.8 Hz, 2H), 1.24 (s, 6H), 1.11 (s, 9H). [0606] Step 2. Preparation of of methyl 9-((2-amino-2-methylpropyl)amino)-3-methoxy- thieno[3,2-f]quinoxaline- 8-carboxylate. To a solution of methyl 9-((2-((tert-butoxy- carbonyl)amino)-2-methylpropyl)amino)-3-methoxythieno[3,2-f] quinoxaline-8-carboxylate (0.4 g, 1 eq, 869 µmol) in dichloromethane (4 mL) was added trifluoroacetic acid (0.4 mL) at 20 °C. The reaction mixture was stirred at 20 °C for 2 hours. LCMS showed the starting material was consumed and the desired peak was detected. One additional vial was set up as described above. Both reaction mixtures were combined and concentrated under reduced pressure to give 600 mg (crude) of methyl 9-((2-amino-2-methylpropyl)amino)-3- methoxythieno [3,2-f]quinoxaline- 8-carboxylate as a yellow solid. LCMS (ESI+): Rt = 0.415 min, m/z 361.2 (M+H) ⁺ . [0607] Step 3. Preparation of 3-methoxy-10,10-dimethyl-9,10,11,12-tetrahydro-8H- [1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one. To a solution of methyl 3-(2-amino- 2-methylpropylamino)-11-methoxy-5-thia-10,13- diazatricyclo[7.4.0.0²,⁶]trideca-1(9),2(6),3,7, 10,12-hexaene-4-carboxylate (67.4 mg, 1 eq, 375 µmol) in methanol (1.06 mL) was added sodium methoxide (67.4 mg, 3 eq, 375 µmol) at 20 °C under N2 atmosphere. The reaction mixture was heated to 60 °C and stirred at 60 °C for 3 hours. LCMS showed the starting material was consumed and the desired peak was detected. One additional vial was set up as described above. After cooling to 20 °C, both reaction mixtures were combined and concentrated under reduced pressure to give a residue. The residue was diluted with water (1 mL) and filtered. The filter cake was dried under reduced pressure to give 70 mg (85.3%) of 3- methoxy-10,10-dimethyl-9,10,11,12-tetrahydro-8H-[1,4]diazepi no[5’,6’:4,5]thieno[3,2- f]quinoxalin-8-one as a yellow solid. LCMS (ESI+): Rt = 0.666 min, m/z 461.4 (M+H) ⁺ . [0608] Step 4. Preparation of 3-hydroxy-10,10-dimethyl-9,10,11,12-tetrahydro-8H- [1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one. A solution of 5-methoxy-15,15- dimethyl-11-thia-3,6,14,17-tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)- hexaen-13-one (35 mg, 1 eq, 107 µmol) in an acetic acid solution of hydrobromic acid (0.1 mL, 33%) was stirred at 60 °C for 2 hours. LCMS showed the starting material was consumed and the desired peak was detected. One additional vial was set up as described above. After cooling to 25 °C, both reaction mixtures were combined and concentrated under reduced pressure to give 60 mg (67%) of 3-hydroxy-10,10-dimethyl-9,10,11,12-tetrahydro-8H- [1,4]diazepino[5’,6’:4,5] thieno[3,2-f]quinoxalin-8-one as a red solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 13.16 – 12.41 (m, 1H), 8.69 – 8.49 (m, 1H), 8.25 (s, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.80 (br s, 1H), 7.40 (d, J = 8.8 Hz, 1H), 3.36 (s, 2H), 1.22 (s, 6H). [0609] Step 5. Preparation of 4-((2-chloro-4-((10,10-dimethyl-8-oxo-9,10,11,12- tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quin oxalin-3-yl)oxy)pyrimidin-5- yl)methyl) morpholin-3-one. To a solution of 5-hydroxy-15,15-dimethyl-11-thia-3,6,14,17- tetra-azatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10) ,2(7),3,5,8,12(18)-hexaen-13-one (14 mg, 1 eq, 44.5 µmol) in dimethyl sulfoxide (0.35 mL) was added 4-[(2,4-dichloro-5- pyrimidinyl)methyl]-3-morpholinone (11.7 mg, 1 eq, 44.5 µmol) and cesium carbonate (29 mg, 2 eq, 89.1 µmol) at 20 °C. The reaction mixture was heated to 60 °C and stirred at 60 °C for 1 hour. LCMS showed the starting material was consumed and the desired peak was detected. One additional vial was set up as described above. After cooling to 20 °,C both reaction mixtures were combined and filtered. The filtrate was purified by prep-HPLC to give 18 mg (37.5%) of 4-((2-chloro-4-((10,10-dimethyl-8-oxo-9,10,11,12-tetrahydro- 8H- [1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-3-yl)ox y)pyrimidin-5-yl)methyl)morpholin-3- one as an orange solid. LCMS (ESI+): Rt = 1.546 min, m/z 540.3 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.11 (s, 1H), 8.85 (br s, 1H), 8.68 (s, 1H), 8.35 (d, J = 8.9 Hz, 1H), 7.96 (d, J = 8.9 Hz, 1H), 7.91 (s, 1H), 4.72 (s, 2H), 4.11 (s, 2H), 3.89 (br t, J = 4.9 Hz, 2H), 3.53 (br t, J = 4.8 Hz, 2H), 3.46 (br s, 2H), 1.26 (s, 6H). EXAMPLE 33 – Synthesis of 3-((2-chloro-5-((4-methyl-2-oxopyrrolidin-1-yl)methyl) pyrimidin-4-yl)oxy)-10,10-dimethyl-9,10,11,12-tetrahydro-8H- [1,4]diazepino[5’,6’:4,5] thieno[3,2-f]quinoxalin-8-one (I-90) . [0610] The title compound was prepared using the following procedures. [0611] To a solution of 5-hydroxy-15,15-dimethyl-11-thia-3,6,14,17-tetraazatetracycl o [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)- hexaen-13-one (14 mg, 1 eq, 44.5 µmol) in dimethyl sulfoxide (0.28 mL) was added 1-[(2,4-dichloro-5-pyrimidinyl)methyl] -4-methyl-2- pyrrolidinone (11.6 mg, 1 eq, 44.5 µmol) and cesium carbonate (29 mg, 2 eq, 89.1 µmol) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hours. LCMS showed the starting material was consumed and the desired peak was detected. One additional vial was set up as described above. Both reaction mixtures were combined and filtered. The filtrate was purified by prep- HPLC to afford 4 mg (8.3%) of 3-((2-chloro-5-((4-methyl-2-oxopyrrolidin-1-yl)methyl) pyrimidin-4-yl)oxy)-10,10-dimethyl-9,10,11,12-tetrahydro-8H- [1,4]diazepino [5’,6’:4,5] thieno[3,2-f]quinoxalin-8-one as an orange solid. LCMS (ESI+): Rt = 1.674 min, m/z 538.4 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.09 (s, 1H), 8.85 (br s, 1H), 8.67 (s, 1H), 8.35 (d, J = 8.9 Hz, 1H), 7.95 (d, J = 9.0 Hz, 1H), 7.91 (s, 1H), 4.57 (s, 2H), 3.56 (br t, J = 7.9 Hz, 1H), 3.46 (br d, J = 2.5 Hz, 2H), 3.03 (dd, J = 5.7, 9.3 Hz, 1H), 2.44 – 2.38 (m, 2H), 1.97 – 1.87 (m, 1H), 1.26 (s, 6H), 1.05 (d, J = 6.0 Hz, 3H). EXAMPLE 34 – Synthesis of (R)-3-((2-chloro-5-(oxetan-3-yl)pyrimidin-4-yl)oxy)- 10- methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’:4,5 ]thieno[3,2-f]quinoxalin-8-one (I- 98) [0612] The title compound was prepared using the following procedures. [0613] Step 1. Preparation of 2,4-dichloro-5-(oxetan-3-yl)pyrimidine. To a solution of 5- bromo-2,4-dichloropyrimidine (0.5 g, 1 eq, 2.19 mmol) in methoxymethane (5 mL) at 25 °C was added 3-iodooxetane (404 mg, 1 eq, 2.19 mmol), (Ir(dF(CF ₃ )ppy) ₂ (dtbbpy))PF6 (2.46 mg, 0.001 eq, 2.19 µmol), 1,2-dimethoxyethane; dichloronickel (2.41 mg, 0.005 eq, 11 µmol), sodium carbonate (465 mg, 2 eq, 4.39 mmol), 4,4’-di-tert-butyl-2,2’-bipyridine (2.94 mg, 0.005 eq, 11 µmol) and 1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)trisilane (546 mg, 1 eq, 2.19 mmol). The mixture was stirred at 25 °C for 12 hours under argon at 34 w blue LED. LCMS showed the starting material was consumed and the desired peak was detected. The mixture was quenched to water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phase was combined and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (petroleum ether/ethyl acetate = 1/1, R _f = 0.5) to afford 125 mg (27.78%) 2,4-dichloro-5-(oxetan-3-yl)pyrimidine as a colorless oil. LCMS: Rt = 0.522 min, m/z = 205.1 _(M+H) ^+. [0614] Step 2. Preparation of (R)-3-((2-chloro-5-(oxetan-3-yl)pyrimidin-4-yl)oxy)- 10- methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’:4,5 ]thieno[3,2-f]quinoxalin-8-one. To a solution of 2,4-dichloro-5-(oxetan-3-yl)pyrimidine (35 mg, 1 eq, 171 µmol) in dimethyl sulfoxide (1 mL) was added (R)-3-hydroxy-10-methyl-9,10,11,12-tetrahydro- 8H- [1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (51.3 mg, 1 eq, 171 µmol) and potassium carbonate (47.2 mg, 2 eq, 341 µmol) at 25 °C. The mixture was heated to 60 °C and stirred at 60 °C for 1hr. LCMS showed the starting material peak was consumed and the desired peak was detected. The reaction mixture was quenched by water (3 mL) and extracted with ethyl acetate (3 × 3 mL). The organic phase was washed with brine (5 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduce pressure to give a residue. The residue was purified by prep-HPLC to afford 65 mg (81.21%) of (R)-3-((2-chloro-5-(oxetan-3-yl)pyrimidin-4-yl)oxy)- 10-methyl-9,10,11,12- tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno [3,2-f]quinoxalin-8-one as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 8.36 (d, J = 8.9 Hz, 1H), 8.02 – 7.94 (m, 1H), 5.01 – 4.94 (m, 1H), 4.60 (quin, J = 7.8 Hz, 1H), 1.23 (d, J = 6.6 Hz, 1H). EXAMPLE 35 – Synthesis of (R)-3-((2-chloro-6-(methoxymethyl)pyrimidin-4-yl)oxy)-10- methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’:4,5 ]thieno[3,2-f]quinoxalin-8-one (I- 99) [0615] The title compound was prepared using the following procedures. [0616] Step 1. Preparation of 6-(methoxymethyl)pyrimidine-2,4-diol. A solution of 6- (chloromethyl)pyrimidine-2,4-diol (1 g, 1 eq, 6.23 mmol) in sodium methanol (3 mL, 30% methanol solution) was stirred at 70 °C for 2 hours. LCMS showed the starting material peak was consumed and the desired peak was detected. The reaction mixture was filtered, and the filter cake was washed with methanol (50 mL). The filter cake was collected and dried under reduced pressure to afford 500 mg crude of 6-(methoxymethyl)pyrimidine-2,4-diol (0.5 g, 3.2 mmol) as a white solid. LCMS (ESI+) Rt = 0.132 min, m/z 157.2/198.2 (M+H) ⁺ /(M+42) ⁺ . [0617] Step 2. Preparation of 2,4-dichloro-5-(methoxymethyl)pyrimidine. A suspension of 5-(methoxymethyl)-1,2,3,4-tetrahydropyrimidine-2,4-dione (0.5 g, 1 eq, 3.2 mmol) in phosphoroyl trichloride (5 mL) at 25 °C was heated to 120 °C and stirred at 120 °C for 12 hours. LCMS showed the starting material peak was consumed and the desired peak was detected. The reaction mixture was concentrated under reduced pressure to give a residue.The residue was purified by prep-TLC (eluted with petroleum ether/ethyl acetate = 2/1, R _f = 0.4) to afford 0.2 g (32.26%) of 2,4-dichloro-5-(methoxymethyl)pyrimidine as a yellow solid. LCMS (ESI+): Rt = 0.639 min, m/z 193.1 (M+H) ⁺ [0618] Step 3. Preparation of (R)-3-((2-chloro-6-(methoxymethyl)pyrimidin-4-yl)oxy)-10- methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’:4,5 ]thieno[3,2-f]quinoxalin-8-one. To a solution of 2,4-dichloro-6-(methoxymethyl)pyrimidine (50 mg, 1 eq, 259 µmol) in dimethyl sulfoxide (3 mL) was added with (R)-3-hydroxy-10-methyl-9,10,11,12-tetrahydro- 8H-[1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-8-on e (77.8 mg, 1 eq, 259 µmol) and potassium carbonate (71.6 mg, 2 eq, 518 µmol) at 25 °C. The reaction mixture was heated to 60 °C and stirred at 60 °C for 0.5 hour. TLC (eluted with petroleum ether/acetate ethyl = 3/1, R _f = 0.35) showed the starting material was consumed completely and the desired product was formed. After cooling to 25 °C, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to afford 7.5 mg of (R)-3-((2-chloro-6-(methoxymethyl)pyrimidin-4-yl)oxy)-10-met hyl- 9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno [3,2-f]quinoxalin-8-one as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 8.84 – 8.78 (m, 1H), 8.35 (d, J = 9.0 Hz, 1H), 8.04 – 7.91 (m, 1H), 3.71 – 3.56 (m, 1H), 1.22 (d, J = 6.6 Hz, 1H). EXAMPLE 36 – Synthesis of (R)-3-((2-chloro-5-(piperidin-1- ylmethyl)pyrimidin-4- yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5� ��,6’:4,5]thieno[3,2- f]quinoxalin-8-one (I-100) [0619] The title compound was prepared using the following procedures. [0620] Step 1. Preparation of 2, 4-dichloro-5-(piperidin-1-ylmethyl) pyrimidine. To a solution of 2,4-dichloro-5-(iodomethyl)pyrimidine (0.3 g, 1 eq, 1.04 mmol) in acetonitrile (3 mL) at 0 °C was added dipotassium carbonate (287 mg, 2 eq, 2.08 mmol) and piperidine (62 mg, 0.7 eq, 0.73 mmol). The reaction mixture was stirred at 0 °C for 0.5 hour. TLC (eluted with petroleum ether/acetate ethyl =1/1, R _f = 0.4) showed the starting material was consumed completely and the desired product was formed. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (eluted with petroleum ether/acetate ethyl =1/1, R _f = 0.5) to afford 100 mg (28%) of 2, 4-dichloro-5-(piperidin-1-ylmethyl) pyrimidine as a yellow oil, which was used directly in the next step. LCMS: Rt = 0.935 min, m/z = 246.1 (M+H) ⁺ . [0621] Step 2. Preparation of (R)-3-((2-chloro-5-(piperidin-1- ylmethyl)pyrimidin-4- yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5� ��,6’:4,5]thieno[3,2- f]quinoxalin-8-one. To a solution of (R)-3-hydroxy-10-methyl-9,10,11,12-tetrahydro-8H- [1,4]diazepino[5’,6’:4,5] thieno[3,2-f]quinoxalin-8-one (122 mg, 1 eq, 406 µmol) in dimethylsulfoxide (2 mL) at room temperature was added 2,4-dichloro-5- (iodomethyl)pyrimidine (122 mg, 1 eq, 406 µmol) and cesium carbonate (265 mg, 2 eq, 813 µmol) under a nitrogen atmosphere. The resulting mixture was heated to 45 °C and stirred at 45 °C for 1 hour under a nitrogen atmosphere. LCMS showed the starting material was consumed completely and the desired product was formed. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to afford 17.6 mg (8%) of (R)-3-((2-chloro-5-(piperidin-1- ylmethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro -8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one as a yellow solid. LCMS: Rt = 2.037 min, m/z = 510.3 (M+H) ⁺ . ¹ H NMR (400 MHz, D ₂ O) δ 8.90 – 8.81 (m, 1H), 8.56 (s, 1H), 7.55 (br d, J = 8.8 Hz, 1H), 7.25 (br d, J = 8.5 Hz, 1H), 4.63 – 4.56 (m, 2H), 3.76 – 3.65 (m, 3H), 3.52 – 3.45 (m, 1H), 3.44 – 3.32 (m, 1H), 3.22 (br t, J = 12.3 Hz, 2H), 2.11 – 1.96 (m, 2H), 1.93 – 1.72 (m, 3H), 1.62 – 1.46 (m, 1H), 1.25 (br d, J = 6.8 Hz, 3H). EXAMPLE 37 – Synthesis of (R)-3-((2-chloro-5-((4-(2-fluoroethyl)piperazin-1-yl)methyl) pyrimidin -4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5’,6’:4,5] thieno[3,2-f]quinoxalin-8-one (I-101) [0622] The title compound was prepared using the following procedures. [0623] Step 1. Preparation of 2, 4-dichloro-5-((4-(2-fluoroethyl) piperazin-1-yl)methyl) pyrimidine. To a solution of 2,4-dichloro-5-(iodomethyl)pyrimidine (50 mg, 1 eq, 173 µmol) in acetonitrile (1 mL) at 0 °C was added dipotassium carbonate (48 mg, 2 eq, 346 µmol) and 1-(2- fluoroethyl) piperazine hydrochloride (14.6 mg, 0.5 eq, 86 µmol). The reaction mixture was stirred at 0 °C for 0.5 hour. TLC (eluted with petroleum ether/acetate ethyl =1/1, R _f = 0.2) showed the starting material was consumed completely and the desired product was formed. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent to give a residue. The residue was purified by prep-TLC (eluted with petroleum ether/acetate ethyl =1/1, R _f = 0.2) to afford 3 mg (5%) of 2, 4-dichloro-5-((4-(2- fluoroethyl) piperazin-1-yl)methyl)pyrimidine as a yellow oil. 1H NMR (400 MHz, CDCl ₃ ) δ 8.63 (s, 1H), 4.65 (t, J = 4.8 Hz, 1H), 4.53 (t, J = 4.8 Hz, 1H), 3.60 (s, 2H), 2.78 (t, J = 4.8 Hz, 1H), 2.71 (t, J = 4.8 Hz, 1H), 2.60 (br s, 8H). [0624] Step 2. Preparation of (R)-3-((2-chloro-5-((4-(2-fluoroethyl)piperazin-1- yl)methyl)pyrimidin -4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one. To a solution of (R)-3-hydroxy-10-methyl-9,10,11,12- tetrahydro-8H-[1,4]diazepino[5’,6’:4,5] thieno[3,2-f]quinoxalin-8-one (8.8 mg, 1 eq, 31 µmol) in dimethylsulfoxide (0.5 mL) at room temperature was added 2,4-dichloro-5-((4-(2- fluoroethyl) piperazin-1-yl)methyl)pyrimidine (9 mg, 1 eq, 31 µmol) and dipotassium carbonate (8.5 mg, 2 eq, 61 µmol) under a nitrogen atmosphere. The resulting mixture was heated to 45 °C and stirred at 45 °C for 1 hour under a nitrogen atmosphere. LCMS analysis showed the starting material was consumed completely and the desired product was formed. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to afford 4.5 mg (26%) of (R)-3-((2- chloro-5-((4-(2-fluoroethyl) piperazin-1-yl)methyl)pyrimidin -4-yl)oxy)-10-methyl-9,10,11,12- tetrahydro-8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.68 (br s, 1H), 9.10 – 9.05 (m, 1H), 8.79 (br s, 2H), 8.36 (d, J = 8.9 Hz, 1H), 8.01 (br d, J = 4.4 Hz, 1H), 7.95 (d, J = 8.9 Hz, 1H), 4.97 – 4.70 (m, 2H), 3.81 (br s, 2H), 3.73 – 3.48 (m, 9H), 3.24 – 3.02 (m, 4H), 1.22 (d, J = 6.8 Hz, 3H). EXAMPLE 38 – Synthesis of (R)-3-((2-chloro-5-((1,1-dioxidothiomorpholino) methyl) pyrimidin -4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5’,6’:4,5]thieno [3,2-f]quinoxalin-8-one (I-102) [0625] The title compound was prepared using the following procedures. [0626] Step 1. Preparation of 4-((2, 4-dichloropyrimidin-5- yl) methyl)thiomorpholine 1, 1-dioxide. To a solution of 2,4-dichloro-5-(iodomethyl)pyrimidine (50 mg, 1 eq, 173 µmol) in acetonitrile (1 mL) at 0 °C was added thiomorpholine 1,1-dioxide (23.4 mg, 1 eq, 173 µmol) and dipotassium carbonate (47.8 mg, 2 eq, 346 µmol). The reaction mixture was stirred at 0 °C for 0.5 hour. LCMS showed the starting material was consumed and the desired product was detected. One additional vial was set up as described above. Both reaction mixtures were combined. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (eluted with petroleum ether/ethyl acetate=3/1) to obtain 63 mg (61.4%) crude of 4-((2, 4-dichloropyrimidin-5- yl) methyl)thiomorpholine 1, 1-dioxide as a yellow solid, which was used directly in the next step. LCMS: Rt = 0.725 min, m/z =296.21(M+H) ⁺ [0627] Step 2. Preparation of (R)-3-((2-chloro-5-((1,1-dioxidothiomorpholino)methyl) pyrimidin -4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5’,6’:4,5] thieno[3,2-f]quinoxalin-8-one. To a solution of 4-((2,4-dichloropyrimidin-5-yl)methyl) thiomorpholine 1,1-dioxide (30 mg, 1 eq, 101 µmol) in dimethylsulfoxide (1 mL) at 0 °C was added 5-hydroxy-11-thia-3,6,14,17 -tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10) ,2(7), 3,5,8,12(18)-hexaen-13-one (29 mg, 1 eq, 101 µmol). The reaction mixture was stirred at 0 °C for 0.5 hour. TLC (eluted with petroleum ether/ethyl acetate=3/1, R _f = 0.56) showed the starting material was consumed and the desired product was formed. One additional vial was set up as described above. Both reaction mixtures were combined and filtered and the filtrate was purified by prep-HPLC to obtain 43.8 mg (38.6%) of (R)-3-((2-chloro-5-((1,1- dioxidothiomorpholino) methyl)pyrimidin -4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H- [1,4]diazepino[5’,6’:4,5] thieno[3,2-f]quinoxalin-8-one as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.04 (s, 1H), 8.86 – 8.81 (m, 1H), 8.80 (s, 1H), 8.31 (d, J = 8.9 Hz, 1H), 7.93 (d, J = 9.0 Hz, 1H), 3.88 (s, 2H), 3.71 – 3.63 (m, 2H), 3.59 – 3.56 (m, 1H), 3.13 (br d, J = 5.1 Hz, 4H), 3.07 – 2.96 (m, 4H), 1.20 (d, J = 6.6 Hz, 3H). EXAMPLE 39 – Synthesis of (15R)-5-[(2-chloro-5-{[4-(2-fluoroethoxy)piperidin-1-yl] methyl}pyrimidin-4-yl)oxy]-15-methyl-11-thia-3,6,14,17-tetra azatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸] octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (I-103) [0628] The title compound was prepared using the following procedures. [0629] Step 1. Preparation of 2, 4-dichloro-5-{[4- (2-fluoroethoxy)piperidin-1-yl]methyl} pyrimidine. To a solution of 2,4-dichloro-5-(iodomethyl)pyrimidine (50 mg, 1 eq, 173 µmol) in acetonitrile (1 mL) at 0 °C was added 4-(2-fluoroethoxy)piperidine hydrochloride (22.6 mg, 0.5 eq, 86.5 µmol) and dipotassium carbonate (47.8 mg, 2 eq, 346 µmol). The mixture was stirred at 0 °C for 0.5 hour. LCMS indicated the starting material was consumed and the desired product was detected. The reaction mixture was filtered, and the filtrate was directly purified by prep-TLC (eluting with petroleum ether/ethyl acetate = 3/1) to afford 10 mg (18.8%) of 2, 4-dichloro-5-{[4- (2-fluoroethoxy)piperidin-1-yl]methyl}pyrimidine as a colorless oil. LCMS: Rt= 0.849 min, m/z = 308.1 (M+H) ⁺ [0630] Step 2. Preparation of (15R)-5-[(2-chloro-5-{[4-(2-fluoroethoxy)piperidin-1-yl] methyl}pyrimidin-4-yl)oxy]-15-methyl-11-thia-3,6,14,17-tetra azatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸] octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one. To a solution of 2,4-dichloro-5-{[4-(2- fluoroethoxy)piperidin-1-yl]methyl}pyrimidine (80 mg, 1 eq, 260 µmol) in dimethyl sulfoxide (4 mL) at room temperature was added (15R)-5-hydroxy-15-methyl -11-thia-3,6,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca- 1(10),2(7),3,5,8,12(18)-hexaen -13-one (78 mg, 1 eq, 260 µmol) and dipotassium carbonate (71.8 mg, 2 eq, 519 µmol). Then, the mixture was stirred at 60 °C for 0.5 hour. LCMS analysis showed the starting material was consumed completely and the desired product was detected. The mixture was filtered, and the filtrate was directly purified by prep-HPLC to afford 37 mg (20.7%) (15R)-5-[(2-chloro-5-{[4-(2- fluoroethoxy) piperidin-1-yl]methyl}pyrimidin-4-yl)oxy]-15-methyl-11-thia- 3,6,14,17- tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)- hexaen-13-one as an orange solid. LCMS: Rt = 1.203 min, m/z = 572.1 (M+H) ⁺ . EXAMPLE 40 – Synthesis of (R)-3-((2-chloro-5-((methylsulfonyl)methyl)pyrimidin-4- yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5� ��,6’:4,5]thieno[3,2- f]quinoxalin-8-one (I-104) [0631] The title compound was prepared using the following procedures. [0632] Step 1. Preparation of 2,4-dichloro-5-((methylsulfonyl)methyl) pyrimidine. To a solution of 2,4-dichloro-5-(iodomethyl)pyrimidine (0.1 g, 1 eq, 346 µmol) in dichloromethane (3 mL) and dimethyl sulfoxide (0.6 mL) was added sodium methanesulfinate (35.3 mg, 1 eq, 346 µmol) at 25 °.C The reaction mixture was heated to 50 °C and stirred for 3 hours. LCMS showed the starting material was consumed and the desired peak was detected. After cooling to 25 °C, the reaction mixture was concentrated under reduced pressure to remove dichloromethane and give 0.6 mL of a solution of 2,4-dichloro-5-((methylsulfonyl)methyl) pyrimidine, which was used directly in the next step. LCMS (ESI+): Rt = 0.482, m/z 241.1 (M+H) ⁺ 282 (M+42) ⁺ . [0633] Step 2. Preparation of (R)-3-((2-chloro-5-((methylsulfonyl)methyl)pyrimidin-4- yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5� ��,6’:4,5]thieno[3,2-f] quinoxalin-8-one. To a solution of 2,4-dichloro-5-((methylsulfonyl)methyl)pyrimidine (crude) in dimethyl sulfoxide (1 mL) was added (R)-3-hydroxy-10-methyl-9,10,11,12-tetrahydro-8H- [1,4] diazepino[5’,6’:4,5]thieno[3,2-f] quinoxalin-8-one (49.8 mg, 0.8 eq, 166 µmol) and potassium carbonate (57.3 mg, 2 eq, 415 µmol) at 25 °C. The reaction mixture was heated to 60 °C and stirred for 2 hours. LCMS showed the starting material was consumed and the desired peak was detected. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to afford 6.2 mg (5.92%) of (R)-3-((2-chloro-5-((methylsulfonyl)methyl)pyrimidin-4-yl)ox y)-10-methyl- 9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno [3,2-f]quinoxalin-8-one as a brown solid. LCMS (ESI+): Rt = 0.594, m/z 505.0 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO) 9.05 (s, 1H), 8.82 (s, 1H), 8.79 (t, J = 3.8 Hz, 1H), 8.36 (d, J = 8.8 Hz, 1H), 8.01 (br d, J = 4.6 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 4.79 (s, 2H), 3.67 (br dd, J = 3.4, 6.9 Hz, 1H), 3.60 (br s, 2H), 3.20 (s, 3H), 1.21 (d, J = 6.6 Hz, 3H). EXAMPLE 41 – Synthesis of (R)-3-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl) (methyl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diaze pino[5’,6’:4,5]thieno[3,2- f]quinoxalin-8-one (I-105) [0634] The title compound was prepared using the following procedures. [0635] Step 1. Preparation of 2-chloro-5-(ethoxymethyl)-N-methylpyrimidin-4-amine. To a solution of 2,4-dichloro-5-(ethoxymethyl)pyrimidine (0.2 g, 1 eq, 966 µmol) in dimethyl- formamide (2 mL) was added methanaminium chloride (65.2 mg, 1 eq, 966 µmol) and dipotassium carbonate (0.4 g, 3 eq, 2.9 mmol) at 25 °C under nitrogen. The mixture was stirred at 25 °C for 18 hours. LCMS showed the material was consumed completely and a major peak with the desired Ms was detected. Nine additional vials were set up as described above. All ten reactions mixture were combined and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (eluted with petroleum ether/ethyl acetate = 1/0 to 2/1) to give 1.07 g (55.13%) of 2-chloro-5- (ethoxymethyl)-N-methylpyrimidin-4-amine as a white solid. LCMS (ESI+): Rt = 0.702 min, m/z 202.1 (M+H) ⁺ . [0636] Step 2. Preparation of (R)-3-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl) (methyl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diaze pino[5’,6’:4,5]thieno[3,2- f]quinoxalin-8-one. To a solution of 2-chloro-5-(ethoxymethyl)-N-methylpyrimidin-4-amine (6.33 mg, 1 eq, 31.4 µmol) and (R)-3-chloro-10-methyl-9,10,11,12-tetrahydro-8H- [1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (10 mg, 1 eq 31.4 µmol) in 1,4-dioxane (1 mL) was added cesium carbonate (20.4 mg, 2 eq, 62.7 µmol) and methanesulfonato(2-di-t- butylphosphino-2,4,6-tri-i-propyl-1,1-biphenyl)(2-amino-1,1- biphenyl-2-yl)palladium(II) (2.49 mg, 0.1 eq, 3.14 µmol) at 25 °C under nitrogen. The mixture was heated to 90 °C and stirred at 90 °C for 12 hours. LCMS showed the material was consumed completely and a major peak with the desired Ms was detected. Four additional vials were set up as described above. After cooling to 25 °C, all five reaction mixtures were combined, diluted with water (20 mL), and extracted with ethyl acetate (3 × 10 mL). The organic layers were combined, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral condition) to give 8.1 mg (10.67%) of (R)-3-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)(methyl)amin o)-10-methyl-9,10,11,12- tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quin oxalin-8-one as a yellow solid. LCMS (ESI+): Rt = 1.764 min, m/z 484.1 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.05 (s, 1H), 9.02 – 8.96 (m, 1H), 8.39 (d, J = 9.0 Hz, 1H), 8.05 – 8.00 (m, 2H), 6.98 – 6.93 (m, 1H), 4.52 – 4.42 (m, 1H), 4.35 (s, 2H), 4.05 (d, J = 6.1 Hz, 1H), 3.57 – 3.45 (m, 3H), 2.87 (d, J = 4.6 Hz, 3H), 1.36 (d, J = 6.8 Hz, 3H), 1.16 (t, J = 7.0 Hz, 3H).

EXAMPLE 42 – Synthesis of (15R)-5-[(2-chloro-5-{[3-(2-fluoroethoxy) azetidin-1-yl] methyl}pyrimidin-4-yl)oxy]-15-methyl-11-thia-3,6,14,17-tetra azatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸] octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (I-106) [0637] The title compound was prepared using the following procedures. [0638] Step 1. Preparation of tert-butyl-3-(2-fluoroethoxy) azetidine-1-carboxylate. To a solution of tert-butyl-3-hydroxyazetidine-1-carboxylate (0.5 g, 1.0 eq., 2.89 mmol) in dimethylformamide (5 mL) was added sodium hydride (127 mg, 3.18 mmol, 60% dispersion in mineral oil) at 25 °C. After stirring at 25 °C for 0.5 hour, ethanol-2-fluoro-1-(4-methyl- benzenesulfonate) (693 mg, 3.18 mmol) was added to the mixture, and the mixture was stirred at 25 °C for another 1 hour. TLC (eluted with petroleum ether/acetate ethyl =1/1, R _f = 0.55, stained with ninhydrin) showed the starting material was consumed and the desired product was formed. Three additional vials were set up as described above. All four reaction mixtures were combined and quenched with water (50 mL) and extracted with acetate ethyl (20 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified via silica gel chromatography eluting with 25-50% ethyl acetate in petroleum. Pure fractions were combined and concentrated to afford 2 g (79%) of tert-butyl-3- (2-fluoroethoxy) azetidine-1-carboxylate as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.67 – 4.58 (m, 1H), 4.54 – 4.47 (m, 1H), 4.34 – 4.25 (m, 1H), 4.09 (dd, J = 6.7, 9.4 Hz, 2H), 3.87 (dd, J = 4.3, 9.5 Hz, 2H), 3.73 – 3.66 (m, 1H), 3.65 – 3.58 (m, 1H), 1.44 (s, 9H) [0639] Step 2. Preparation of 3-(2-fluoroethoxy) azetidine. Methanol (2 mL, 49.4 mmol) was cooled to 0 °C and acetyl chloride (0.6 mL) was added dropwise keeping the temperature under 5 °.C After stirring for 10 minutes, tert-butyl-3-(2-fluoroethoxy) azetidine-1-carboxylate (0.2 g, 912 µmol) was added to the mixture, and the mixture was stirred at 25 °C for 1 hour. TLC (eluted with petroleum ether/ethyl acetate =1/1, R _f = 0.01, stained with ninhydrin) showed the starting material was consumed completely and the desired product spot was formed. The reaction mixture was concentrated under reduced pressure to give 90 mg (HCl salt 74.53%) of 3-(2-fluoroethoxy) azetidine as a colorless oil. ¹ H NMR (400 MHz, D2O-d2) δ ppm 4.65 – 4.61 (m, 1H), 4.58 – 4.49 (m, 2H), 4.30 (br dd, J = 6.7, 12.0 Hz, 2H), 4.03 (br dd, J = 5.1, 11.9 Hz, 2H), 3.80 – 3.75 (m, 1H), 3.72 – 3.67 (m, 1H), 3.29 (s, 2H). [0640] Step 3. Preparation of 2,4-dichloro-5-{[3-(2-fluoroethoxy)azetidin-1- yl]methyl}pyrimidine. To a solution of 3-(2-fluoroethoxy)azetidine (41.2 mg, 346 µmol) in acetonitrile (2 mL) was added 2,4-dichloro-5-(iodomethyl)pyrimidine (0.1 g, 346 µmol) and dipotassium carbonate (95.7 mg, 2 eq., 692 µmol) at 0 °C. Then, the reaction mixture was stirred at 0 °C for 0.5 hour. LCMS showed 19% of the starting material remained and 29% of the desired product mass was detected. One additional vial was set up as described above. Both reaction mixtures were combined and purified with prep-TLC (eluted with petroleum ether/ethyl acetate=1/1) to obtain 2,4-dichloro-5-{[3-(2-fluoroethoxy)azetidin-1-yl]methyl}- pyrimidine 30 mg (27.85%) of 2,4-dichloro-5-{[3-(2-fluoroethoxy)azetidin-1-yl]methyl}- pyrimidine as a yellow oil, which was used directly in the next step without further purification. LCMS: Rt = 0.494 min, m/z = 280.0 (M+H) ⁺ . [0641] Step 4. Preparation of (15R)-5-[(2-chloro-5-{[3-(2-fluoroethoxy) azetidin-1- yl]methyl}pyrimidin-4-yl)oxy]-15-methyl-11-thia-3,6,14,17-te traazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)- hexaen-13-one. To a solution of 2,4- dichloro-5-{[3-(2-fluoroethoxy)azetidin-1-yl]methyl}pyrimidi ne (30 mg, 1 eq., 107 µmol) in dimethyl sulfoxide (1.5 mL) was added (15R)-5-hydroxy-15-methyl-11-thia-3,6,14,17-tetra- azatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7), 3,5,8,12(18)-hexaen-13-one (32.2 mg, 1 eq., 107 µmol) and dipotassium carbonate (29.6 mg, 2 eq., 214 µmol) at 25 °.C Then, the reaction mixture was stirred at 60 °C for 1 hour. LCMS showed the starting material remained and the desired product was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified with prep-HPLC to obtain (15R)-5-[(2-chloro-5- {[3-(2-fluoroethoxy) azetidin-1-yl]methyl}pyrimidin-4-yl)oxy]-15-methyl-11-thia-3 ,6,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10), 2(7),3,5,8,12(18)-hexaen-13-one (3.5 mg, 6.43 µmol, 6.01%) as a yellow solid. LCMS: Rt = 1.843 min, m/z = 544.3 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.81 – 8.75 (m, 1H), 8.71 (s, 1H), 8.29 (s, 1H), 8.21 (d, J = 8.9 Hz, 1H), 7.94 – 7.86 (m, 2H), 5.41 (s, 2H), 4.60 – 4.48 (m, 3H), 4.48 – 4.42 (m, 2H), 4.15 (br d, J = 6.1 Hz, 2H), 3.70 – 3.62 (m, 2H), 3.62 – 3.55 (m, 3H), 1.20 (d, J = 6.6 Hz, 3H). EXAMPLE 43 – Synthesis of (R)-3-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-9,10- dimethyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’:4 ,5]thieno[3,2-f]quinoxalin-8-one (I-107) I ^-107 [0642] The title compound was prepared using the following procedures. [0643] Step 1. Preparation of (R)-9-((2-((tert-butoxycarbonyl)amino)propyl)amino)-3- methoxythieno[3,2-f]quinoxaline-8-carboxylate. To a solution of methyl 9-amino-3- methoxythieno[3,2-f]quinoxaline-8-carboxylate (0.2 g, 1 eq, 691 µmol) in dry dimethylformamide (10 mL) was added sodium hydride (332 mg, 12 eq, 8.3 mmol, 60% purity) at 0 °C under nitrogen. The reaction mixture was stirred at 0 °C for 10 minutes under nitrogen and tert-butyl (4R)-4-methyl-2,2-dioxo-1,2λ⁶,3-oxathiazolidine-3-carboxy late (164 mg, 1 eq, 691 µmol) was added at 0 °C under nitrogen. The reaction mixture was stirred at 0 °C for 10 minutes under nitrogen. TLC (petroleum ether/ethyl acetate = 4/1, R _f = 0.25) showed the starting material was consumed and the desired spot was formed. Nine additional vials were set up as described above. All ten reaction mixtures were combined, slowly quenched with water (80 mL) at 0 °C, diluted with water (400 mL), and extracted with dichloromethane (3 × 240 mL). The organic phase was combined, washed with brine (400 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 1.8 g (53%) of methyl (R)-9-((2-((tert-butoxycarbonyl)amino)propyl)amino)-3-methox ythieno[3,2- f]quinoxaline-8-carboxylate as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.21 – 9.01 (m, 1H), 8.62 – 8.57 (m, 1H), 8.20 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 9.0 Hz, 1H), 6.87 – 6.73 (m, 1H), 4.07 (s, 3H), 3.84 – 3.65 (m, 5H), 3.44 – 3.34 (m, 1H), 1.17 (s, 9H), 1.05 (d, J = 6.4 Hz, 3H). [0644] Step 2. Preparation of (R)-9-((2-((tert-butoxycarbonyl)(methyl)amino) propyl)amino)-3-methoxythieno[3,2-f]quinoxaline-8-carboxylat e. To a solution of methyl (R)-9-((2-((tert-butoxycarbonyl)amino)propyl)amino)-3-methox ythieno[3,2-f]quinoxaline-8- carboxylate (0.1 g, 1 eq, 224 µmol) in dimethylformamide (1 mL) was added sodium hydride (16.1 mg, 2.4 eq, 537 µmol, 60% purity) at 0 °C. The mixture was stirred at 0 °C for 10 minutes under nitrogen and iodomethane (31.8 mg, 1 eq, 224 µmol) was added at 0 °C under nitrogen. The reaction mixture was warmed to 25 °C and stirred at 25 °C for 1 hour under nitrogen. TLC (petroleum ether/ethyl acetate = 4/1, R _f = 0.25) showed the starting material was consumed and the desired spot was formed. Four additional vials were set up as described above. All five reaction mixtures were combined, slowly quenched by the addition of water (20 mL) at 0 °C, and extracted with dichloromethane (3 × 30 mL). The organic phase was combined, washed with brine (60 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 380 mg (58%) of methyl (R)-9-((2-((tert- butoxycarbonyl)(methyl) amino)propyl)amino)-3-methoxythieno[3,2-f]quinoxaline-8- carboxylate as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.16 – 8.91 (m, 1H), 8.64 – 8.44 (m, 1H), 8.16 (br d, J = 8.9 Hz, 1H), 7.85 (br d, J = 8.8 Hz, 1H), 4.35 – 3.90 (m, 5H), 3.81 (s, 3H), 3.57 – 3.37 (m, 1H), 2.64 (br s, 3H), 1.09 – 0.94 (m, 12H). [0645] Step 3. Preparation of methyl (R)-3-hydroxy-9-((2-(methylamino)propyl) amino)thieno[3,2-f]quinoxaline-8-carboxylate. A solution of methyl (R)-9-((2-((tert- butoxycarbonyl)(methyl)amino)propyl)amino)-3-methoxythieno[3 ,2-f]quinoxaline-8- carboxylate (495 mg, 1 eq, 1.07 mmol) in co-solvents hydrochloric acid (12 M, 5 mL) and methyl alcohol (5 mL) was heated to 80 °C and stirred at 80 °C for 4 hours. TLC (ethyl acetate/methyl alcohol = 1/3, R _f = 0.72) showed the starting material was consumed and the desired spot was formed. After cooling to 20 °C, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in water (10 mL), basified to pH = 9 with a saturated aqueous solution of sodium bicarbonate, and extracted with ethyl acetate (3 × 5 mL). The organic phase was combined, washed with brine (10 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 290 mg (77%) of methyl (R)-3-hydroxy-9-((2-(methylamino)propyl)amino)thieno[3,2-f]q uinoxaline-8- carboxylate as a yellow solid, which was used directly in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) 8.93 – 8.78 (m, 1H), 8.29 – 8.15 (m, 1H), 8.04 – 7.95 (m, 1H), 7.48 – 7.42 (m, 1H), 3.80 – 3.73 (m, 3H), 3.51 – 3.36 (m, 2H), 2.65 (d, J = 1.5 Hz, 1H), 2.34 – 2.29 (m, 3H), 1.06 – 0.99 (m, 3H). [0646] Step 4. Preparation of (R)-3-hydroxy-9,10-dimethyl-9,10,11,12-tetrahydro-8H- [1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one. To a solution of methyl (R)-3- hydroxy-9-((2-(methylamino)propyl)amino)thieno[3,2-f]quinoxa line-8-carboxylate (290 mg, 1 eq, 837 µmol) in methanol (20 mL) was added sodium methoxide (90.5 mg, 2 eq, 1.67 mmol) at 25 °C. The reaction mixture was heated to 80 °C and stirred at 80 °C for 12 hours. TLC (dichloromethane/methanol = 10/1, R _f = 0.35) showed the starting material was consumed completely and the desired spot was formed. After cooling to 20 °C, the reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by trituration with ethyl acetate/water = 10/1 (66 mL) at 25 °C for 30 minutes to obtain 0.2 g (76%) of (R)-3-hydroxy-9,10-dimethyl-9,10,11,12-tetrahydro-8H- [1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one as a yellow solid, which was used directly in the next step without further purification. [0647] Step 5. Preparation of (R)-3-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-9,10- dimethyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’:4 ,5]thieno[3,2-f]quinoxalin-8-one. To a solution of (R)-3-hydroxy-9,10-dimethyl-9,10,11,12-tetrahydro-8H-[1,4]di azepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (10 mg, 1 eq, 31.8 µmol) in dimethyl sulfoxide (0.5 mL) was added 2,4-dichloro-5-(ethoxymethyl)pyrimidine (6.59 mg, 1 eq, 31.8 µmol) and N- ethyl-N-isopropylpropan-2-amine (8.22 mg, 2 eq, 63.6 µmol) at 25 °C. The mixture was heated to 60 °C and stirred at 60 °C for 1 hour. After cooling to 25 °,C the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral condition) to afford 6 mg (5%) of (R)-3-((2-chloro-5- (ethoxymethyl) pyrimidin-4-yl)oxy)-9,10-dimethyl-9,10,11,12-tetrahydro-8H- [1,4]diazepino[5’,6’:4,5]thieno [3,2-f]quinoxalin-8-one as a yellow solid. EXAMPLE 44 – Synthesis of (R)-3-((2-chloro-5- ((methylamino)methyl)pyrimidin-4- yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5� ��,6’:4,5]thieno[3,2- f]quinoxalin-8-one (I-108) [0648] The title compound was prepared using the following procedures. [0649] Step 1. Preparation of tert-butyl ((2,4-dichloropyrimidin-5-yl)methyl)(methyl) carbamate. To a solution of 2,4-dichloro-5-(iodomethyl)pyrimidine (0.1 g, 1 eq, 346 µmol) in tetrahydrofuran (1 mL) at 25 °C was added tert-butyl methylcarbamate (45.4 mg, 1 eq, 346 µmol) and sodium hydride (16.6 mg, , 2 eq, 692 µmol, 60% purity) at 0 °C. The mixture was stirred at 0 °C for 1 hour. LCMS showed the starting material peak was consumed and the desired peak was detected. Three additional vials were set up as described above. All four reaction mixtures were combined and quenched with water (30 mL). The mixture was extracted with ethyl acetate (3 × 15 mL). The organic phase was combined and washed with brine (10 mL) and then dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (eluted with petroleum ether/ethyl acetate = 3/1, R _f = 0.65) to afford 130 mg (32.14%) tert-butyl ((2,4-dichloropyrimidin-5-yl)methyl)(methyl)carbamate as a yellow oil. LCMS (ESI+): Rt = 0.785 min, m/z 333.2 (M+42) ⁺ . [0650] Step 2. Preparation of tert-butyl (R)-((2-chloro-4-((10-methyl-8-oxo-9,10,11,12 - tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quin oxalin-3-yl)oxy)pyrimidin-5- yl)methyl)(methyl)carbamate. To a solution of tert-butyl ((2,4-dichloropyrimidin-5- yl)methyl)(methyl)carbamate (60 mg, 205 µmol, 1 eq.) in dimethyl sulfoxide (1 mL) was added (R)-3-hydroxy-10-methyl- 9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno [3,2- f]quinoxalin-8-one (61.7 mg, 205 µmol, 1 eq.) and potassium carbonate (56.8 mg, 411 µmol, 2 eq.) at 25 °C. The mixture was heated to 60 °C and stirred for 1 hour. LCMS showed the starting material peak was consumed and the desired peak was detected. After cooling to room temperature, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 × 1 mL). The organic phase was combined and washed with brine (3 mL) and then dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to afford 50 mg crude of tert-butyl (R)-((2-chloro-4-((10- methyl-8-oxo-9,10,11,12 -tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno[3,2-f]qui noxalin-3- yl)oxy)pyrimidin-5-yl)methyl)(methyl)carbamate as an orange solid, which was used directly in the next step without further purification. LCMS (ESI+): Rt = 0.765 min, m/z 556.2 (M+H) ⁺ . [0651] Step 3. Preparation of (R)-3-((2-chloro-5- ((methylamino)methyl)pyrimidin-4- yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5� ��,6’:4,5]thieno[3,2- f]quinoxalin-8-one. To a solution of tert-butyl (R)-((2-chloro-4-((10-methyl-8-oxo-9,10,11,12- tetrahydro-8H-[1,4] diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-3-yl)oxy)pyr imidin-5- yl)methyl)(methyl)carbamate (25 mg, 1 eq, 45 µmol) in dichloromethane (2 Ml) was added trifluoroacetic acid (0.2 Ml) at 25 °.C The mixture was stirred at 25 °C for 1 hour. LCMS showed the starting material peak was consumed and the desired peak was detected. One additional vial was set up as described above. Both reaction mixtures were combined and the pH was adjusted to about 7 with triethylamine. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to afford 8.5 mg (10.36%) of (R)-3-((2-chloro-5- ((methylamino)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,1 2- tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quin oxalin-8-one as an orange solid. LCMS (ESI+): Rt = 1.178 min, m/z 456.1 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8.88 – 8.83 (m, 1H), 8.69 (s, 1H), 8.06 – 7.90 (m, 2H), 7.85 – 7.81 (m, 1H), 7.64 (d, J = 8.9 Hz, 1H), 4.69 (br s, 2H), 3.67 – 3.62 (m, 1H), 3.55 (br s, 2H), 3.28 (br s, 3H), 1.20 (d, J = 6.5 Hz, 3H).

EXAMPLE 45 – Synthesis of (15R)-5-[(2-chloro-5-methanesulfonylpyrimidin-4- yl)oxy]- 15-methyl-11-thia-3,6,14,17-tetraazatetracyclo[8.8.0.0²,⁷ .0¹²,¹⁸]octadeca- 1(10),2(7),3,5,8,12(18)-hexaen-13-one (I-109) [0652] The title compound was prepared using the following procedures. [0653] Step 1. Preparation of 2,4-dichloro-5-methanesulfonylpyrimidine. To a solution of 2,4-dichloro-5-(methylsulfanyl)pyrimidine (0.1 g, 1 eq, 513 µmol) in dichloromethane (5 mL) was added 3-chlorobenzene-1-carboperoxoic acid (312 mg, 3 eq, 1.54 mmol, 85% purity) at 0 °C. The reaction mixture was allowed to warm to 25 °C and stirred at 25 °C for 12 hours. LCMS showed the starting material peak was consumed and the desired Ms was detected. Four additional vials were set up as described above. All five reaction mixtures were combined, quenched with saturated Na ₂ SO ₃ solution (10 mL), and extracted with ethyl acetate (3 × 5 mL). The organic phase was combined and washed with brine (10 mL), dried over anhydrous sodium sulfate, and filtered . The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to afford 110 mg (18.6%) of 2,4-dichloro-5- methanesulfonylpyrimidine as a white solid. LCMS: Rt = 0.570 min, m/z 227.0 (M+H) ⁺ . [0654] Step 2. Preparation of (15R)-5-[(2-chloro-5-methanesulfonylpyrimidin-4-yl)oxy]- 15-methyl-11-thia-3,6,14,17-tetraazatetracyclo[8.8.0.0²,⁷ .0¹²,¹⁸]octadeca- 1(10),2(7),3,5,8,12(18)-hexaen-13-one. To a solution of (15R)-5-hydroxy-15-methyl-11-thia- 3,6,14,17-tetra-azatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octa deca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (5 mg, 1 eq, 16.6 µmol) in dimethyl sulfoxide (0.3 mL) was added 2,4-dichloro-5- methanesulfonylpyrimidine (3.78 mg, 1 eq, 16.6 µmol) and ethylbis(propan-2-yl)amine (4.3 mg, 2 eq, 33.3 µmol) at 25 °.C The reaction mixture was stirred at 25 °C for 1 hour. LCMS showed the starting material peak was consumed and the desired peak was detected. Four additional vials were set up as described above. After cooling to 25 °,C all five reaction mixtures were combined and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to afford 6 mg (14.68%) of (15R)-5- [(2-chloro-5-methanesulfonylpyrimidin-4- yl)oxy]-15-methyl-11-thia-3,6,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10), 2(7), 3,5,8,12(18)-hexaen-13-one as an orange solid. LCMS: Rt = 0.622 min, m/z 491.1 (M+H) ⁺ 554.1(M+42 +23) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.18 (s, 1H), 9.14 – 9.07 (m, 1H), 8.80 (br s, 1H), 8.39 (d, J = 9.0 Hz, 1H), 8.04 – 7.98 (m, 2H), 3.71 – 3.65 (m, 1H), 3.61 (br s, 2H), 3.56 (s, 3H), 1.22 (br d, J = 6.6 Hz, 3H). EXAMPLE 46 – Synthesis of 2-chloro-4-{[(15R)-15-methyl-13-oxo-11-thia-3,6,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10), 2(7),3,5,8,12(18)-hexaen-5-yl]oxy} pyrimidine-5-carboxamide (I-110) [0655] The title compound was prepared using the following procedures. [0656] To a solution of (15R)-5-hydroxy-15-methyl-11-thia-3,6,14,17-tetraazatetracyc lo[8.8.0. 0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)-hexaen- 13-one (5 mg, 1 eq, 16.6 µmol) in dimethyl sulfoxide (0.5 mL) was added 2,4-dichloropyrimidine-5-carboxamide (3.2 mg, 1 eq, 16.6 µmol) and potassium carbonate (4.6 mg, 2 eq, 33.3 µmol) at 25 °C. The reaction mixture was heated to 60 °C and stirred at 60 °C for 0.5 hour. LCMS showed the starting material peak was consumed and the desired peak was detected. Nine additional vials were set up as described above. After cooling to 20 °C, all ten reaction mixtures were combined and filtered. The filtrate was purified by prep-HPLC to afford 6 mg (7.91%) of 2-chloro-4-{[(15R)-15-methyl- 13-oxo-11-thia-3,6,14,17-tetraazatetracyclo[8.8.0.0²,⁷.0� �²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)- hexaen-5-yl]oxy}pyrimidine-5-carboxamide as an orange solid. LCMS: Rt = 1.292 min, m/z 456.0 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 13.15 (br dd, J = 1.7, 4.6 Hz, 1H), 9.89 (s, 1H), 8.90 (br d, J = 3.1 Hz, 1H), 8.63 (s, 1H), 8.21 (d, J = 8.9 Hz, 1H), 7.95 – 7.83 (m, 2H), 3.68 – 3.64 (m, 1H), 3.59 (br s, 2H), 1.21 (d, J = 6.6 Hz, 3H). EXAMPLE 47 – Synthesis of (R)-3-((2-chloro-5-(pyrrolidine-1-carbonyl)pyrimidin-4- yl)oxy)-10-methyl- 9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno [3,2-f] quinoxalin-8-one (I-111) [0657] The title compound was prepared using the following procedures. [0658] Step 1. Preparation of (2,4-dichloropyrimidin-5-yl)(pyrrolidin-1-yl)methanone. To 2,4-dichloropyrimidine-5-carboxylic acid (350 mg, 1 eq, 1.81 mmol) was added thionyl chloride (3.5 mL) at 25 °C. The reaction mixture was heated to 80 °C and then stirred at 80 °C for 3 hours. TLC (quenched by methanol)(eluted with petroleum ether/ethyl acetate = 3/1, R _f = 0.5) showed the starting material was consumed and the desired spot was detected. Two additional vials were set up as described above. After cooling to 20, all three mixtures were combined and concentrated under reduced pressure to give a residue, which was used directly in the next step. To the residue in tetrahydrofuran (40 mL) was added pyrrolidine (135 mg, 1 eq, 1.89 mmol) in tetrahydrofuran (8 mL) dropwise. Next, triethylamine (383 mg, 2 eq, 3.78 mmol) was added to the mixture at -78 °C. The mixture was stirred at -78 °C for 1 hour. LCMS showed the starting material was consumed and the desired peak was detected. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (eluted with ethyl acetate, R _f = 0.75) to afford 110 mg (23.63%) (2,4- dichloropyrimidin-5-yl)(pyrrolidin-1-yl)methanone as a white solid. LCMS (ESI+): Rt = 0.602 min, m/z 246.3 (M+H) ⁺ . [0659] Step 2. Preparation of (R)-3-((2-chloro-5-(pyrrolidine-1-carbonyl)pyrimidin-4- yl)oxy)-10-methyl- 9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno [3,2-f] quinoxalin-8-one. To a mixture of (2,4-dichloropyrimidin-5-yl)(pyrrolidin-1-yl)methanone (10 mg, 1 eq, 40.6 µmol) in dimethyl sulfoxide (0.5 mL) was added (R)-3-hydroxy-10-methy l- 9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno [3,2-f]quinoxalin-8-one (12.2 mg, 1 eq, 40.6 µmol) and potassium carbonate (11.2 mg, , 2 eq, 81.3 µmol) at 25 °C. The reaction mixture was heated to 40 °C and stirred for 1 hour. LCMS showed the material peak was consumed and the desired peak was detected. Six additional vials were set up as described above. After cooling to 25 °C, all seven reaction mixtures were combined and filtered to obtain a clarified solution, which was purified by prep-HPLC (neutral condition) to afford 27 mg (18.67%) of (R)-3-((2-chloro-5-(pyrrolidine-1-carbonyl)pyrimidin-4-yl)ox y)-10-methyl- 9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno [3,2-f]quinoxalin-8-one as a yellow solid. LCMS (ESI+): Rt = 0.662 min, m/z = 510.4 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.13 (s, 1H), 8.92 (s, 1H), 8.82 (s, 1H), 8.79 (s, 1H), 8.37 – 8.35 (m, 1H), 8.35 – 8.32 (m, 1H), 8.03 – 7.99 (m, 1H), 7.97 (d, J = 3.3 Hz, 1H), 7.94 (s, 1H), 3.72 – 3.64 (m, 1H), 3.62 – 3.58 (m, 2H), 3.55 (s, 1H), 3.52 – 3.46 (m, 1H), 3.39 (t, J = 6.5 Hz, 1H), 3.29 – 3.26 (m, 1H), 1.90 – 1.82 (m, 4H), 1.22 (br d, J = 7.0 Hz, 3H). EXAMPLE 48 – Synthesis of (15R)-5-[(2-chloro-5-{[4-(2,3-difluoropropoxy)piperidin-1- yl]methyl}pyrimidin-4-yl)oxy]-15-methyl-11-thia3,6,14,17-tet raazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸] octadeca1 (10),2(7),3,5,8,12(18)-hexaen-13-one (I-112) , s TEA.3HF, TEA Nonafluorobutanesulfonyl fluoride , MeCN, 0~20 °C, 2 hrs [0660] The title compound was prepared using the following procedures. [0661] ^{Step 1. Preparation of} tert-butyl 4-(prop-2-en-1-yloxy) piperidine-1-carboxylate ^. To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (10 g, 1 eq, 49.7 mmol) in tetrahydrofuran (150 mL) at 0 °C was added sodium hydride (5.96 g, 3 eq, 149 mmol, 60% dispersion in mineral oil). To the mixture was added 3-bromoprop-1-ene (12 g, 2eq, 99.4 mmol) dropwise over 1 hour at 0 °.C The resulting mixture was stirred at 25 °C for an additional 16 hours. TLC (eluted with petroleum ether/ethyl acetate= 3/1, R _f = 0.35) showed the starting material was consumed and the desired product was formed. The reaction mixture was quenched with water (500 mL) and extracted with ethyl acetate (3 × 500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, and filtered ^. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography eluting with 0-10% ethyl acetate in petroleum ether. Pure fractions were combined and concentrated to afford 10 g (83.4%) of tert-butyl 4- (prop-2-en-1-yloxy) piperidine-1-carboxylate as a yellow oil. 1H NMR (400 MHz, CDCl ₃ ) δ 5.93 (tdd, J = 5.4, 10.6, 17.2 Hz, 1H), 5.35 – 5.25 (m, 1H), 5.18 (dd, J = 1.5, 10.4 Hz, 1H), 4.05 – 3.98 (m, 2H), 3.83 – 3.73 (m, 2H), 3.51 (tt, J = 3.9, 8.1 Hz, 1H), 3.08 (ddd, J = 3.4, 9.5, 13.3 Hz, 2H), 1.89 – 1.80 (m, 2H), 1.58 – 1.51 (m, 2H), 1.46 (s, 9H). [0662] Step 2. Preparation of tert-butyl 4-[(oxiran-2-yl) methoxy] piperidine-1- carboxylate. To a solution of tert-butyl 4-(prop-2-en-1-yloxy) piperidine-1-carboxylate (0.1 g, 1 eq, 414 µmol) in chloroform (1.5 mL) at 25 °C was added 3-chlorobenzene-1-carboperoxoic acid (143 mg, 2 eq, 829 µmol). Then, the reaction mixture was stirred at 60 °C for 12 hours. TLC (eluted with petroleum ether/ethyl acetate = 2/1, R _f =0.3, stain with ninhydrin) showed the starting material remained, and the desired product was formed. Nineteen additional vials were set up as described above. All twenty mixtures were combined and diluted with aqueous sodium bicarbonate (50 mL) and extracted with dichloromethane (3 × 30 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography eluting with 0-25% ethyl acetate in petroleum ether. Pure fractions were combined and concentrated to afford 1 g (46.8%) of tert-butyl 4-[(oxiran-2- yl) methoxy] piperidine-1-carboxylate as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.81 – 3.74 (m, 3H), 3.58 – 3.50 (m, 1H), 3.45 (dd, J = 5.8, 11.5 Hz, 1H), 3.18 – 3.05 (m, 3H), 2.82 (t, J = 4.6 Hz, 1H), 2.63 (dd, J = 2.7, 5.1 Hz, 1H), 1.85 (br dd, J = 3.0, 9.5 Hz, 2H), 1.54 – 1.50 (m, 2H), 1.46 (s, 9H). [0663] Step 3. Preparation of tert-butyl 4-(3-fluoro-2-hydroxypropoxy) piperidine-1- carboxylate. To a solution of tert-butyl 4-[(oxiran-2-yl)methoxy]piperidine-1-carboxylate (120 mg, 466 µmol) in 2,2’-(ethane-1,2-diylbis(oxy))bis(ethan-1-ol) (2.4 mL) at 25 °C was added potassium hydrogen fluoride (82.7 mg, 3 eq, 1.4 mmol). Then, the reaction mixture was stirred at 130 °C for 5 hours. TLC (eluted with petroleum ether/ethyl acetate = 1/1, R _f =0.3, ninhydrin) showed the starting material remained and the desired product was formed. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (3 × 3 mL). The combined organic phase was washed with brine (5 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure _{to give a residue. The residue was purified} by silica gel chromatography eluting with 25-35% ethyl acetate in petroleum ether. Pure fractions were combined and concentrated to afford 28 mg _(21.6%) of tert-butyl 4-(3-fluoro-2-hydroxypropoxy) piperidine-1-carboxylate as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.58 (s, 1H), 4.47 – 4.36 (m, 1H), 4.01 (quind, J = 5.1, 18.0 Hz, 1H), 3.80 – 3.68 (m, 2H), 3.63 – 3.47 (m, 3H), 3.12 (ddd, J = 3.5, 9.2, 13.2 Hz, 2H), 1.88 – 1.80 (m, 2H), 1.55 – 1.50 (m, 2H), 1.50 – 1.43 (m, 9H). [0664] Step 4. Preparation of tert-butyl 4-(2, 3-difluoropropoxy) piperidine-1-carboxylate. To a solution of tert-butyl 4- (3-fluoro-2-hydroxypropoxy) piperidine-1-carboxylate (830 mg, 1 eq, 2.99 mmol) in acetonitrile (16.6 mL) at 0 °C was added 2-[bis(2-hydroxyethyl) amino]ethan-1-ol (2.01 g, 4.5 eq, 13.5 mmol)，triethylamine trihydrofluoride (1.21 g, 2.5 eq, 7.48 mmol) and nonafluorobutane-1-sulfonyl fluoride (1.81 g, 2 eq, 5.99 mmol). The reaction mixture was stirred at 0 °C for 1 hour and then at 20 ° C for 1 hour. TLC (eluted with petroleum ether/acetate ethyl =2/1, R _f = 0.5) showed the starting material was consumed and the desired product was formed. The reaction mixture was quenched with water (20 mL) and extracted with acetate ethyl (3 × 10 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography eluting with 10-25% ethyl acetate in petroleum ether. Pure fractions were combined and concentrated to afford 460 mg (55.03%) of tert-butyl 4-(2, 3-difluoropropoxy) piperidine-1-carboxylate as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.01 – 4.77 (m, 1H), 4.76 – 4.45 (m, 2H), 3.74 – 3.66 (m, 1H), 3.65 – 3.55 (m, 3H), 3.50 (tt, J = 3.8, 8.1 Hz, 1H), 3.02 (br t, J = 9.9 Hz, 2H), 1.84 – 1.71 (m, 2H), 1.39 (s, 9H), 1.36 – 1.27 (m, 2H). [0665] Step 5. Preparation of 4-(2,3-difluoropropoxy)piperidine. tert-Butyl 4-(2,3- difluoropropoxy)piperidine-1-carboxylate (0.2 g, 1 eq, 716 µmol) was added to a mixture of dichloromethane (1 mL) and trifluoroacetic acid (0.2 mL) at room temperature. The resulting mixture was stirred at 25 °C for 0.5 hour. TLC (eluted with petroleum ether/acetate ethyl = 2/1, R _f = 0.2) showed the starting material was consumed and the desired product was formed. The reaction mixture was concentrated under reduced pressure to give128 mg (99.75%) of crude 4- (2,3-difluoropropoxy) piperidine as a yellow oil, which was used directly in the next step without further purification. ¹ H NMR (400 MHz, D ₂ O) δ 5.03 – 4.81 (m, 1H), 4.73 – 4.49 (m, 2H), 3.88 – 3.81 (m, 1H), 3.79 – 3.70 (m, 2H), 3.35 – 3.23 (m, 2H), 3.06 (ddd, J = 3.3, 8.6, 12.5 Hz, 2H), 2.06 (br d, J = 10.8 Hz, 2H), 1.84 – 1.73 (m, 2H). [0666] Step 6. Preparation of 2,4-dichloro-5-{[4-(2,3-difluoropropoxy)piperidin-1-yl] methyl}pyrimidine. To a solution of 4-(2,3-difluoropropoxy)piperidine (128 mg, 1 eq.714 µmol) in acetonitrile (2 mL) at room temperature was added dipotassium carbonate (296 mg, 3 eq, 2.14 mmol) and 2,4-dichloro-5-(iodomethyl)pyrimidine (206 mg, 1 eq, 714 µmol). The reaction mixture was stirred at 0 °C for 0.5 hour. TLC (eluted with petroleum ether/acetate ethyl = 2/1, R _f = 0.5) showed the starting material was consumed and the desired product was formed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (eluted with petroleum ether/ethyl acetate=2/1) to give 0.1 g (41.1%) 2, 4- dichloro-5-{[4-(2,3-difluoropropoxy)piperidin-1-yl] methyl}pyrimidine as a colorless oil, which was used directly in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.73 (s, 1H), 4.97 – 4.75 (m, 1H), 4.74 – 4.46 (m, 2H), 3.72 – 3.60 (m, 2H), 3.55 (s, 2H), 3.41 – 3.35 (m, 1H), 2.72 – 2.62 (m, 2H), 2.21 (br t, J = 9.2 Hz, 2H), 1.82 (br d, J = 9.8 Hz, 2H), 1.47 (q, J = 8.9 Hz, 2H). [0667] Step 7. Preparation of (15R)-5-[(2-chloro-5-{[4-(2,3-difluoropropoxy)piperidin-1- yl]methyl}pyrimidin-4-yl)oxy]-15-methyl-11-thia3,6,14,17- tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸] octadeca1 (10),2(7),3,5,8,12(18)-hexaen-13-one. To a solution of (15R)-5- hydroxy-15-methyl-11-thia-3,6,14,17-tetraazatetracyclo[8.8.0 .0²,⁷.0¹², ¹⁸]octadeca- 1(10),2(7),3,5,8,12(18)-hexaen-13-one (20 mg, 1 eq, 66.6 µmol) in dimethyl sulfoxide (1 mL) at 25 °C was added dipotassium carbonate (18.4 mg, 2 eq, 133 µmol) and 2,4-dichloro-5-{[4- (2,3-difluoropropoxy)piperidin-1-yl]methyl}pyrimidine (22.7 mg, 1 eq, 66.6 µmol). Then, the reaction mixture was stirred at 25 °C for 0.5 hour under a nitrogen atmosphere. LCMS showed the starting material was consumed and the desired product was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC to give 9 mg ( 22.3% ) of (15R)-5-[(2-chloro-5-{[4-(2,3-difluoropropoxy)piperidin-1- yl]methyl}pyrimidin-4-yl)oxy]-15-methyl-11-thia3,6,14,17- tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸] octadeca1 (10),2(7),3,5,8,12(18)-hexaen-13-one as a yellow solid. LCMS: Rt=0.554 min, m/z = 604.2 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.07 (s, 1H), 8.89 (s, 1H), 8.34 (d, J = 8.8 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H), 4.60 (br s, 5H), 3.74 – 3.70 (m, 2H), 3.58 (br d, J = 8.4 Hz, 3H), 3.51 – 3.13 (m, 4H), 2.30 – 2.13 (m, 1H), 2.11 – 1.97 (m, 1H), 1.96 – 1.78 (m, 1H), 1.72 – 1.47 (m, 1H), 1.20 (d, J = 6.7 Hz, 3H). EXAMPLE 49 – Synthesis of (R)-3-((2-chloro-5-((1,1-dioxidoisothiazolidin-2- yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydr o-8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (I-113) [0668] The title compound was prepared using the following procedures. [0669] Step 1. Preparation of 2-((2,4-dichloropyrimidin-5-yl)methyl)isothiazolidine 1,1- dioxide. To a solution of 2,4-dichloro-5-(iodomethyl)pyrimidine (20 mg, 1 eq, 69.2 µmol) in dimethylformamide (4 mL) was added dipotassium carbonate (19.1 mg, 2 eq, 138 µmol) at 25 °C. Then, isothiazolidine 1,1-dioxide (8.39 mg, 1 eq, 69.2 µmol) was added to the reaction mixture at -60 °C dropwise. The mixture was stirred at -60 °C for 1 hour, Then, the mixture was warmed to 0 °C and stirred at 0 °C for 1 hour. Nine additional vials were set up as described above. All ten reaction mixtures were combined, diluted with water (100 mL), and extracted with ethyl acetate (3 × 50 mL). The organics phase was combined, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (petroleum ether/ethyl acetate = 1/1, R _f = 0.4) to afford 30 mg (15%) of 2-((2,4-dichloropyrimidin-5-yl)methyl)isothiazolidine 1,1-dioxide as a white solid. LCMS: Rt = 0.373 min, m/z =282.1 (M+H) ⁺ . [0670] Step 2. Preparation of (R)-3-((2-chloro-5-((1,1-dioxidoisothiazolidin-2-yl) methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8 H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one . To a solution of 2-((2,4-dichloropyrimidin-5- yl)methyl)isothiazolidine 1,1-dioxide (10 mg, 1 eq, 35.4 µmol) in dimethyl sulfoxide (2.5 mL) was added (R)-3-hydroxy-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazep ino[5’,6’:4,5] thieno[3,2-f]quinoxalin-8-one (10.6 mg, 1 eq, 35.4 µmol) and dicesium carbonate (23.1 mg, 2 eq, 70.9 µmol) at 25 °C. The mixture was heated to 60 °C and stirred at 60 °C for 1 hour. After cooling to 25 °C, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 5 mL). The organic phase was combined, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (formic acid conditions) to afford 8.2 mg (17%) of (R)-3-((2- chloro-5-((1,1-dioxidoisothiazolidin-2-yl)methyl)pyrimidin-4 -yl)oxy)-10-methyl-9,10,11,12- tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quin oxalin-8-one as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.06 (s, 1H), 8.84 – 8.75 (m, 2H), 8.35 (d, J = 8.8 Hz, 1H), 8.01 (d, J = 4.4 Hz, 1H), 7.96 (d, J = 9.0 Hz, 1H), 4.36 (s, 2H), 3.71 – 3.64 (m, 1H), 3.60 (br s, 2H), 3.38 – 3.34 (m, 2H), 3.30 – 3.26 (m, 2H), 2.31 – 2.24 (m, 2H), 1.22 (d, J = 6.6 Hz, 3H). EXAMPLE 50 – Synthesis of (R)-3-((2-chloro-5-((cyclopropylsulfonyl)methyl) pyrimidin- 4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[ 5’,6’:4,5]thieno[3,2-f] quinoxalin-8-one (I-114) [0671] The title compound was prepared using the following procedures. [0672] Step 1. Preparation of 2,4-dichloro-5-((cyclopropylsulfonyl)methyl)pyrimidine. To a solution of 2,4-dichloro-5-(iodomethyl)pyrimidine (113 mg, 1 eq, 390 µmol) in dichloromethane (2.5 mL) and dimethyl sulfoxide (0.5 mL) was added sodium cyclopropane- sulfinate (50 mg, 1 eq, 390 µmol) at 25 °C. The reaction mixture was heated to 50 °C and stirred at 50 °C for 0.5 hour. LCMS showed the starting material was consumed and the desired peak was detected. One additional vial was set up as described above. After cooling to 25 °C, both reaction mixtures were combined. The mixture was concentrated under reduced pressure to afford 1 mL of a black solution of 2,4-dichloro-5 –((cyclopropylsulfonyl)methyl) pyrimidine, which was used directly in the next step. LCMS (ESI+): Rt = 0.541 min, m/z 266.8 (M+H) ⁺ . [0673] Step 2. Preparation of (R)-3-((2-chloro-5-((cyclopropylsulfonyl)methyl) pyrimidin- 4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[ 5’,6’:4,5]thieno[3,2-f] quinoxalin-8-one. To a solution of 2,4-dichloro-5-((cyclopropylsulfonyl)methyl)pyrimidine (crude) in dimethyl sulfoxide (3 mL) was added (R)-3-hydroxy-10-methyl-9,10,11,12- tetrahydro-8H-[1,4] diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (56.2 mg, 0.5 eq, 187 µmol) and potassium carbonate (103 mg, 2 eq, 749 µmol) at 25 °C. The reaction mixture was heated to 60 °C and stirred at 60 °C for 1 hour. LCMS showed the starting material was consumed completely and the desired product was detected. The reaction mixture was filtered, and the filtrate was purified by prep-HPLC to afford 6 mg (1.51%) of (R)-3-((2-chloro-5- ((cyclopropylsulfonyl)methyl) pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H- [1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one as a yellow solid. LCMS (ESI+): Rt = 0.680 min, m/z 531.1 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.12 – 8.91 (m, 1H), 8.85 – 8.62 (m, 2H), 8.40 – 8.19 (m, 1H), 8.05 – 7.75 (m, 2H), 4.91 – 4.64 (m, 2H), 3.64 – 3.60 (m, 1H), 3.57 – 3.53 (m, 2H), 2.94 – 2.88 (m, 1H), 1.20 – 1.14 (m, 3H), 1.08 – 0.94 (m, 4H). EXAMPLE 51 – Synthesis of (15R)-5-[(2-chloro-5-{[4-(3-fluoro-2-hydroxypropoxy) piperidin-1-yl]methyl} pyrimidin-4-yl)oxy]-15-methyl-11-thia-3,6,14,17-tetra- azatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7), 3,5,8,12(18)-hexaen-13-one (I-115) [0674] The title compound was prepared using the following procedures. [0675] Step 1. Preparation of 1-fluoro-3-(piperidin-4-yloxy)propan-2-ol. To a solution of tert-butyl 4-(3-fluoro-2-hydroxypropoxy)piperidine-1-carboxylate (0.1 g, 1 eq, 361 µmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.1 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hours. LCMS showed the starting material was consumed and the desired Ms was detected. Two additional vials were set up as described above. All three reaction mixtures were combined and concentrated under reduced pressure to give 0.2 g of crude 1-fluoro-3-(piperidin-4-yloxy)propan-2-ol as a colorless oil, which was used directly in the next step without further purification. LCMS (ESI+): Rt = 2.574 min, m/z 178.1 (M+H) ⁺ . [0676] Step 2. Preparation of 1-({1-[(2,4-dichloropyrimidin-5-yl)methyl]piperidin-4- yl}oxy)-3-fluoropropan-2-ol. To a solution of 1-fluoro-3-(piperidin-4-yloxy)propan-2-ol (0.1 g, 1 eq, 564 µmol) in acetonitrile (2 mL) was added potassium carbonate (156 mg, 2 eq, 1.13 mmol) and 2,4-dichloro-5-(iodomethyl)pyrimidine (196 mg, 1.2 eq, 677 µmol) at 25 °.C The mixture was stirred at 25 °C for 12 hours. LCMS showed the starting material was consumed and the desired Ms was detected. One additional vial was set up as described above. Both reaction mixtures were combined, diluted with water (12 mL), and extracted with ethyl acetate (3 × 4 mL). The combined organic phase was washed with brine (12 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (eluted with ethyl acetate, R _f = 0.4) to give 70 mg (18.34%) of 1-({1-[(2,4-dichloropyrimidin-5-yl)methyl]piperidin-4-yl}oxy )-3-fluoropropan-2- ol as a yellow oil. LCMS (ESI+): Rt = 0.762 min, m/z 338.1 (M+H) ⁺ . [0677] Step 3. Preparation of (15R)-5-[(2-chloro-5-{[4-(3-fluoro-2-hydroxypropoxy) piperidin-1-yl]methyl}pyrimidin-4-yl)oxy]-15-methyl-11-thia- 3,6,14,17-tetra- azatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7), 3,5,8,12(18)-hexaen-13-one. To a solution of (15R)-5-hydroxy-15-methyl-11-thia-3,6,14,17-tetraazatetracyc lo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca- 1(10),2(7),3,5,8,12(18)-hexaen-13-one (5 mg, 1 eq, 16.6 µmol) in dimethyl sulfoxide (0.5 mL) was added 1-({1-[(2,4-dichloropyrimidin-5-yl)methyl]piperidin -4-yl}oxy)-3-fluoropropan-2-ol (11.3 mg, 2 eq, 33.3 µmol) and cesium carbonate (10.8 mg, 2 eq, 33.3 µmol) at 25 °C. The reaction mixture was heated to 50 °C and stirred at 50 °C for 1 hour. LCMS showed the starting material was consumed and the desired Ms was detected. Five additional vials were set up as described above. After cooling to 25 °C, all six reaction mixtures were combined and filtered. The filtrate was purified by prep-HPLC to give 7 mg (11.64%) of (15R)-5-[(2-chloro- 5-{[4-(3-fluoro-2-hydroxypropoxy)piperidin-1-yl]methyl} pyrimidin-4-yl)oxy]-15-methyl-11- thia-3,6,14,17-tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸] octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13- one as an orange solid. LCMS (ESI+): Rt = 1.237 min, m/z 602.1 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.06 (s, 1H), 8.79 (br t, J = 3.9 Hz, 1H), 8.74 (s, 1H), 8.37 – 8.29 (m, 1H), 8.13 (s, 1H), 8.05 – 7.97 (m, 1H), 7.96 – 7.89 (m, 1H), 5.10 (br d, J = 3.8 Hz, 1H), 4.46 – 4.22 (m, 2H), 3.67 (s, 4H), 3.60 (br s, 2H), 3.37 (br s, 2H), 2.82 – 2.66 (m, 2H), 2.24 (br t, J = 9.3 Hz, 2H), 1.81 (br d, J = 10.1 Hz, 2H), 1.50 – 1.37 (m, 2H), 1.22 (d, J = 6.6 Hz, 3H). EXAMPLE 52 – Synthesis of (R)-3-((2-chloro-5-(((2-methoxyethyl)sulfonyl)methyl) pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4] diazepino[5’,6’:4,5] thieno[3,2-f]quinoxalin-8-one (I-116) [0678] The title compound was prepared using the following procedures. [0679] Step 1. Preparation of sodium 2-methoxyethane-1-sulfinate. To a solution of 2- methoxyethane-1-sulfonyl chloride (0.3 g, 1 eq, 1.89 mmol) in water (3 mL) was added sodium sodium sulfonate (477 mg, 2 eq, 3.78 mmol) at 25 °C. The mixture was stirred at 25 °C for 2 hours. TLC showed (eluted with petroleum ether/ethyl acetate = 1/1, R _f = 0.05) starting material was consumed and one new spot was detected. Four additional vials were set up as described above. All five reaction mixtures were combined and lyophilized to afford 2.5 g of crude sodium 2-methoxyethane-1-sulfinate as a product, which was used directly in the next step. [0680] Step 2. Preparation of 2,4-dichloro-5-(((2- methoxyethyl)sulfonyl)methyl)pyrimidine. To a solution of sodium 2-methoxyethane-1- sulfinate (625 mg, 2 eq, 1.28 mmol) in acetonitrile (8 mL) was added 2,4-dichloro-5- (iodomethyl)pyrimidine (185 mg, 1 eq, 642 µmol) at 25 °C. Then, the reaction mixture was stirred at 80 °C for 6 hours. LCMS showed the material peak was consumed and the desired peak was detected. Three additional vials were set up as described above. After cooling to 25 °C, all four reaction mixtures were combined and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (eluted with petroleum ether/ethyl acetate = 0/1 to 1/1) to afford 75 mg (36.9%) of 2,4-dichloro-5-(((2- methoxyethyl)sulfonyl)methyl)pyrimidine as a colorless oil. LCMS (ESI+): Rt = 0.537 min, m/z 285.0 (M+H) ⁺ . [0681] Step 3. Preparation of (R)-3-((2-chloro-5-(((2-methoxyethyl)sulfonyl)methyl) pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4] diazepino[5’,6’:4,5] thieno[3,2-f]quinoxalin-8-one. To a solution of 2,4-dichloro-5-(((2-methoxyethyl)sulfonyl) methyl)pyrimidine (20 mg, 1 eq, 70.1 µmol) and (R)-3-hydroxy-10-methyl-9,10,11,12- tetrahydro-8H-[1,4]diazepino[5’,6’:4,5] thieno[3,2-f]quinoxalin-8-one (21.1 mg, 1 eq, 70.1 µmol) in dimethyl sulfoxide (2 mL) was added potassium carbonate (29.1 mg, 3 eq, 210 µmol) at 25 °C. The reaction mixture was heated to 50 °C and stirred at 50 °C for 0.5 hour. LCMS showed starting material remained and 12% of the desired Ms was detected. One additional vial was set up as described above. Both reaction mixture were combined and quenched with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to afford 8 mg (10.39%) of (R)-3-((2-chloro-5-(((2-methoxyethyl)sulfonyl)methyl)pyrimid in-4- yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5� ��,6’:4,5]thieno[3,2-f]quinoxalin- 8-one as a yellow solid. LCMS (ESI+): Rt = 0.419 min, m/z 549.1 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.13 (s, 1H), 9.02 (s, 1H), 8.80 (s, 1H), 8.70 (s, 1H), 8.36 (d, J = 9.0 Hz, 1H), 8.33 (s, 1H), 8.02 (br d, J = 4.2 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.94 (s, 1H), 4.78 (s, 2H), 4.70 (s, 1H), 3.81 – 3.73 (m, 2H), 3.67 (br dd, J = 3.1, 6.6 Hz, 1H), 3.65 – 3.61 (m, 2H), 3.61 – 3.55 (m, 2H), 3.32 (br s, 1H), 3.26 (s, 3H), 1.21 (d, J = 6.6 Hz, 3H). EXAMPLE 53 – Synthesis of (10R) -3- ((2-chloro-5-(1-(methylsulfonyl)ethyl)pyrimidin-4- yl) oxy)-10-methyl-9, 10,11,12- tetrahydro-8H-[1,4]diazepio [5’,6’:4,5] thieno[3,2-f] quinoxalin -8-one (I-117) [0682] The title compound was prepared using the following procedures. [0683] Step 1. Preparation of 2,4-dichloro-5-(1-methanesulfonylethyl)pyrimidine. To a solution of 2,4-dichloro-5-(methanesulfonylmethyl)pyrimidine (0.1 g, 1 eq, 415 µmol) in dimethylformamide (4 mL) at 0 °C was added sodium 2-methylpropan-2-olate (39.9 mg, 1 eq, 415 µmol) and iodomethane (58.9 mg, 1 eq, 415 µmol) under nitrogen. The reaction mixture was stirred at 0 °C for 6 hours under nitrogen. LCMS showed the starting material was consumed and the desired product was detected. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic phase was washed with brine (5 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by prep-TLC (eluted with petroleum ether/ethyl acetate = 3/1) to obtain 39.9 mg (24.1%) of 2,4-dichloro-5-(1- methanesulfonylethyl)pyrimidine as a yellow solid. LCMS: Rt = 1.766 min, m/z = 254.9 (M+H) ⁺ . [0684] Step 2. Preparation of (10R) -3- ((2-chloro-5-(1-(methylsulfonyl)ethyl)pyrimidin-4- yl) oxy)-10-methyl-9, 10,11,12- tetrahydro-8H-[1,4]diazepio [5’,6’:4,5] thieno[3,2-f] quinoxalin -8-one. To a solution of 2,4-dichloro-5-(1-methanesulfonylethyl)pyrimidine (20 mg, 1.2 eq, 78.4 µmol) in dimethyl sulfoxide (2 mL) at 25 °C was added dipotassium carbonate (21.7 mg, 2 eq, 157 µmol) and (15R)-5-hydroxy-15-methyl-11-thia-3,6,14,17-tetraazatetracyc lo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)- hexaen-13-one (18.8 mg, 1 eq, 62.7 µmol). Then, the reaction mixture was heated to 60 °C and stirred at 60 °C for 1 hour. LCMS showed the starting material was consumed and the desired product mass was detected. The reaction mixture was filtered, and the filtrate was purified by prep-HPLC directly to obtain 15 mg (34.8%) of (10R) -3- ((2-chloro-5-(1-(methylsulfonyl)ethyl)pyrimidin-4-yl) oxy)-10-methyl-9, 10,11,12- tetrahydro-8H-[1,4]diazepio [5’,6’:4,5] thieno[3,2-f] quinoxalin -8-one as a yellow solid. LCMS: Rt = 0.386 min, m/z = 519.2 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (s, 1H), 8.91 (s, 1H), 8.79 (br s, 1H), 8.36 (d, J = 8.9 Hz, 1H), 8.01 – 7.94 (m, 2H), 5.02 (d, J = 7.4 Hz, 1H), 3.67 (br s, 1H), 3.60 (br s, 2H), 3.16 (s, 3H), 1.80 (d, J = 7.1 Hz, 3H), 1.22 (br d, J = 6.3 Hz, 3H). EXAMPLE 54 – Synthesis of 3-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-11- methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’:4,5 ]thieno[3,2-f]quinoxalin-8-one (I- 118) [0685] The title compound was prepared using the following procedures. [0686] Step 1. Preparation of methyl 9-((1-((tert-butoxycarbonyl)amino)propan-2- yl)amino)-3-methoxythieno[3,2-f]quinoxaline-8-carboxylate. To a solution of methyl 9- bromo-3-methoxythieno[3,2-f]quinoxaline-8-carboxylate (50 mg, 1 eq, 142 µmol) in 1, 4- dioxane (0.5 mL) was added tert-butyl (2-aminopropyl)carbamate (24.7 mg, 1 eq, 142 µmol), dicesium carbonate (92.3 mg, 2 eq, 283 µmol), and chloro[(S)-(-)-2,2-Bis(diphenylphosphino)- 1,1-binaphthyl](2-amino-1,1-biphenyl-2-yl) palladium (III) (14 mg, 0.1 eq, 14.2 µmol) at 20 °C under nitrogen. The reaction mixture was heated to 90 °C and stirred at 90 °C for 12 hours. TLC (petroleum ether/ethyl acetate = 3/1, R _f = 0.4) showed the starting material was consumed and the desired spot was formed. Nine additional vials were set up as described above. After cooling to 20 °C, all ten reaction mixtures were combined, diluted with water (20 mL), and extracted with ethyl acetate (3 × 10 mL). The organic phase was combined, washed with brine (20 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (formic acid conditions) to give 150 mg (23%) of methyl 9-((1-((tert-butoxycarbonyl)amino)propan-2-yl)amino)-3- methoxythieno[3,2-f]quinoxaline-8-carboxylate as a yellow solid. LCMS (ESI+): Rt = 2.424 min, m/z 447.1 (M+H)+. [0687] Step 2. Preparation of methyl 9-((1-aminopropan-2-yl)amino)-3- methoxythieno[3,2-f]quinoxaline-8-carboxylate. To a solution of methyl 9-((1-((tert- butoxycarbonyl) amino)propan-2-yl)amino)-3-methoxythieno[3,2-f]quinoxaline-8 -carboxylate (37.5 mg, 1 eq, 75.7 µmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (50 µL) at 25 °C. The mixture was stirred at 25 °C for 2 hours. TLC (petroleum ether/ethyl acetate = 1/1, R _f = 0.4) showed the starting material was consumed and the desired spot was formed. Three additional vials were set up as described above. All four reaction mixtures were combined and concentrated under reduced pressure to give 130 mg (78%) of methyl 9-((1- aminopropan-2-yl)amino)-3-methoxythieno[3,2-f]quinoxaline-8- carboxylate as a yellow solid, which was used directly in the next step without purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) 8.70 (s, 1H), 8.67 – 8.58 (m, 1H), 8.26 (d, J = 8.8 Hz, 1H), 7.99 – 7.89 (m, 3H), 4.62 – 4.45 (m, 1H), 4.09 (s, 3H), 3.85 (s, 3H), 3.15 – 3.00 (m, 2H), 1.24 (br d, J = 6.4 Hz, 3H). [0688] Step 3. Preparation of 3-methoxy-11-methyl-9,10,11,12-tetrahydro-8H- [1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one. To a solution of methyl 9-((1- aminopropan-2-yl)amino)-3-methoxythieno[3,2-f]quinoxaline-8- carboxylate (32.5 mg, 1 eq, 93.8 µmol) in methanol (650 µL) was added sodium methoxide (50.7 mg, 10 eq, 938 µmol) at 25 °C. The mixture was heated to 80 °C and stirred at 80 °C for 2 hours. TLC (ethyl acetate, R _f = 0.3) showed the starting material was consumed and the desired spot was formed. Three additional vials were set up as described above. After cooling to 25 °,C all four reaction mixtures were combined and concentrated under reduced pressure to give a residue. The residue was triturated with water (5 mL) at 25 °C for 10 minutes to give 60 mg (50%) of 3- methoxy-11-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5� ��,6’:4,5]thieno[3,2- f]quinoxalin-8-one as a yellow solid, which was used directly in the next step without purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) 8.90 (br s, 1H), 8.67 (s, 1H), 8.18 (d, J = 8.9 Hz, 1H), 7.95 – 7.80 (m, 2H), 4.10 – 4.04 (m, 3H), 3.86 (br d, J = 2.6 Hz, 1H), 3.17 (d, J = 4.9 Hz, 2H), 1.32 (br d, J = 6.3 Hz, 3H). [0689] Step 4. Preparation of 3-hydroxy-11-methyl-9,10,11,12-tetrahydro-8H-[1,4] diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one. To a solution of 3-methoxy-11-methyl- 9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno [3,2-f]quinoxalin-8-one (30 mg, 1 eq, 95.4 µmol) in acetonitrile (0.5 mL) was added sodium iodide (28.6 mg, 2 eq, 191 µmol) and chlorotrimethylsilane (20.7 mg, 2 eq, 191 µmol) at 20 °C. The reaction mixture was heated to 65 °C and stirred at 65 °C for 2 hours. TLC (ethyl acetate, R _f = 0.2) showed the starting material was consumed and the desired spot was formed. One additional vial was set up as described above. After cooling to 20 °C, both reaction mixtures were combined and concentrated under reduced pressure to give a residue. The residue was triturated with water (2 mL) at 25 °C for 10 minutes and filtered. The filter cake was dried under reduced pressure to give 40 mg (69%) of 3-hydroxy-11-methyl-9,10,11,12-tetrahydro-8H- [1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one as a yellow solid, which was used directly in the next step without purification. [0690] Step 5. Preparation of 3-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-11- methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’:4,5 ]thieno[3,2-f]quinoxalin-8-one. To a solution of 3-hydroxy-11-methyl-9,10,11,12-tetrahydro-8H- [1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (40 mg, 1 eq, 133 µmol) in dimethyl sulfoxide (286 µL) was added 2,4-dichloro-5-(ethoxymethyl)pyrimidine (13.8 mg, 0.5 eq, 66.6 µmol) and dipotassium carbonate (36.8 mg, 2 eq, 266 µmol) at 20 °.C The reaction mixture was heated to 60 °C and stirred at 60 °C for 1 hour. LCMS showed all of the starting material was consumed and the desired product was detected. After cooling to 20 °C, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 × 2 mL). The organic phase was combined, washed with brine (5 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (formic acid conditions) to give 21.5 mg (34%) of 3-((2-chloro-5- (ethoxymethyl)pyrimidin-4-yl)oxy)-11-methyl-9,10,11,12-tetra hydro-8H- [1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) 8.98 (br s, 1H), 8.77 (s, 1H), 8.69 (s, 1H), 8.09 (d, J = 8.9 Hz, 1H), 7.90 (d, J = 8.9 Hz, 1H), 6.30 (br s, 1H), 4.74 (s, 2H), 3.97 (br dd, J = 5.5, 6.8 Hz, 1H), 3.71 (q, J = 7.0 Hz, 2H), 3.59 – 3.45 (m, 2H), 1.51 (d, J = 6.6 Hz, 3H), 1.32 (t, J = 7.0 Hz, 3H). EXAMPLE 55 – Synthesis of (R)-3-((2-chloro-5-(dimethylphosphoryl)pyrimidin-4- yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5� ��,6’:4,5]thieno[3,2- f]quinoxalin-8-one (I-92) [0691] The title compound was prepared using the following procedures. [0692] Step 1. Preparation of (2,4-dimethoxypyrimidin-5-yl)dimethylphosphine oxide. To a solution of 5-iodo-2,4-dimethoxypyrimidine (2 g, 1 eq, 7.5 mmol) in 1,4-dioxane (20 mL) was added dimethylphosphine (1.17 g, 2 eq, 15.0 mmol), potassium acetate (1.48 g, 2 eq, 15 mmol), [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]dipheny lphosphane (435 mg, 0.1 eq, 0.752 mmol), and palladium diacetate (169 mg, 0.1 eq, 0.752 mmol) at 20 °C under argon. The reaction mixture was heated to 100 °C and stirred at 100 °C for 2 hours under argon. LCMS showed the starting material was consumed completely and the desired product was detected. Seven additional vials were set up as described above. After cooling to 20 °C, all eight reaction mixtures were combined and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (eluted with ethyl acetate/methanol = 1/0 to 4/1) to afford 12 g (98.4%) of (2,4- dimethoxypyrimidin-5-yl)dimethylphosphine oxide as a yellow oil. LCMS (ESI+): Rt = 0.583, m/z 217.1 (M+H) ⁺ . [0693] Step 2. Preparation of (2,4-dihydroxypyrimidin-5-yl)dimethylphosphine oxide. To a solution of (2,4-dimethoxypyrimidin-5-yl)dimethylphosphine oxide (2 g, 1 eq, 9.3 mmol) in dichloromethane (80 mL) was added iodotrimethylsilane (2.7 mL, 2 eq, 18.6 mmol) at 20 °.C The mixture was stirred at 20 °C for 0.5 hour. LCMS showed the starting material was consumed completely and a major peak with desired mass was detected. Five addition vials were set up as described above. All six reaction mixtures were combined and concentrated under reduced pressure to give a residue. The residue was purified by trituration with ethyl acetate (2 × 50 mL) at 20 °C for 30 minutes to afford 8.1 g (68.9%) of (2,4- dihydroxypyrimidin-5-yl)dimethylphosphine oxide as a brown solid. LCMS (ESI+): Rt =0.176 min, m/z 189.0 (M+H) ⁺ . [0694] Step 3. Preparation of (2,4-dichloropyrimidin-5-yl)dimethylphosphine oxide. A solution of (2,4-dihydroxypyrimidin-5-yl)dimethylphosphine oxide (0.4 g, 1 eq, 2.1 mmol) in phosphoryl trichloride (4 mL) was heated to 140 °C and stirred at 140 °C for 1 hour under nitrogen. LCMS showed starting material was consumed completely and a major peak with desired mass was detected. Nine additional vials were set up as described above. After cooling to 25 °C, all ten reaction mixtures were combined and concentrated under reduced pressure to give a residue. The residue was dissolve in dichloromethane (3 mL), basified with saturated ammonium chloride (10 mL), and extracted with dichloromethane (3 × 5 mL). The organic phase was combined, washed with brine (2 × 25 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford 3.2 g (53.5%) of (2,4- dichloropyrimidin-5-yl)dimethylphosphine oxide as a brown oil, which was used directly in the next step without purification. LCMS (ESI+): Rt = 0.147 min, m/z 225.1 (M+H) ⁺ . [0695] Step 4. Preparation of (R)-3-((2-chloro-5-(dimethylphosphoryl)pyrimidin-4- yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5� ��,6’:4,5]thieno[3,2- f]quinoxalin-8-one. To a solution of (2,4-dichloropyrimidin-5-yl)dimethylphosphine oxide (5 mg, 1 eq, 0.02 mmol) in dimethyl sulfoxide (0.05 mL) was added (R)-3-hydroxy-10-methyl- 9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno [3,2-f]quinoxalin-8-one (6.67 mg, 2.5 eq, 0.05 mmol) and dipotassium acetate (6.2 g, 2 eq 0.04 mmol) at 25 °C. The reaction mixture was heated to 60 °C and stirred at 60 °C for 1 hour. TLC (petroleum ether/acetate ethyl = 3/1, R _f = 0.4) showed the starting material was consumed completely and the desired product was formed. Nine additional vials were set up as described above. After cooling to 25 °C, all ten reaction mixtures were combined and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give 8 mg (7.4%) of (R)-3-((2-chloro-5- (dimethylphosphoryl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12 -tetrahydro-8H- [1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.15 (s, 1H), 8.95 (d, J = 7.0 Hz, 1H), 8.81 (br s, 1H), 8.38 (d, J = 8.9 Hz, 1H), 8.05 – 7.95 (m, 2H), 3.69 (br d, J = 2.6 Hz, 1H), 3.61 (br s, 2H), 2.00 – 1.82 (m, 6H), 1.22 (d, J = 6.6 Hz, 3H). EXAMPLE 56 – Synthesis of (10R)-3-((2-chloro-5-((2,2-dioxido-2-thia-5-azabicyclo[2.2.1 ] heptan-5-yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12- tetrahydro-8H- [1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (I-119) [0696] The title compound was prepared using the following procedures. [0697] Step 1. Preparation of 5-((2,4-dichloropyrimidin-5-yl)methyl)-2-thia-5- azabicyclo[2.2.1]heptane 2,2-dioxide. To a mixture of 2-thia-5-azabicyclo[2.2.1]heptane 2,2- dioxide hydrochloride (50 mg, 1 eq, 272 µmol, 1 eq) in acetonitrile (4 mL) was added 2,4- dichloro-5-(iodomethyl)pyrimidine (78.7 mg, 1 eq, 272 µmol) and potassium carbonate (75.3 mg, 2 eq, 545 µmol) at 0 °C The reaction mixture was stirred at 0 °C for 3 hours. LCMS showed the material peak was consumed and the desired peak was detected. Three additional vials were set up as described above. All four reaction mixtures were combined and filtered to obtain a clarified solution, which was purified by prep-TLC (ethyl acetate, R _f = 0.7) to afford 150 mg (44.69%) of 5-((2,4-dichloropyrimidin-5-yl)methyl)-2-thia-5-azabicyclo[2 .2.1]heptane 2,2-dioxide as a white solid. LCMS (ESI+): Rt = 0.583 min, m/z 308.0 (M+H) ⁺ . [0698] Step 2. Preparation of (10R)-3-((2-chloro-5-((2,2-dioxido-2-thia-5-azabicyclo[2.2.1 ] heptan-5-yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12- tetrahydro-8H-[1,4] diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one. To a mixture of 5-((2,4- dichloropyrimidin-5-yl)methyl)-2-thia-5-azabicyclo[2.2.1]hep tane 2,2-dioxide (10 mg, 1 eq, 32.4 µmol) in dimethyl sulfoxide (1 mL) was added (R)-3-hydroxy-10-methyl-9,10,11,12- tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quin oxalin-8-one (4.87 mg, 0.5 eq, 16.2 µmol) and potassium carbonate (8.97 mg, 2 eq, 64.9 µmol) at 25 °C. The reaction mixture was heated to 60 °C and stirred at 60 °C for 0.5 hour. LCMS showed the material peak was consumed and the desired peak was detected. Two additional vials were set up as described above. After cooling to 25 °C, all three reaction mixtures were combined and filtered to give the clarified solution, which was purified by prep-HPLC to afford 10.7 mg (23.06%) of (10R)- 3-((2-chloro-5-((2,2-dioxido-2-thia-5-azabicyclo[2.2.1] heptan-5-yl)methyl)pyrimidin-4- yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5� ��,6’:4,5]thieno[3,2-f]quinoxalin- 8-one as a yellow solid. LCMS (ESI+): Rt = 0.636 min, m/z 572.2 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.08 (s, 1H), 8.84 – 8.77 (m, 2H), 8.34 (d, J = 9.0 Hz, 1H), 8.02 – 7.98 (m, 1H), 7.95 (d, J = 9.0 Hz, 1H), 4.00 (s, 2H), 3.90 – 3.84 (m, 1H), 3.81 – 3.76 (m, 1H), 3.71 – 3.65 (m, 1H), 3.60 (br s, 2H), 3.42 – 3.39 (m, 1H), 3.23 (br d, J = 11.2 Hz, 1H), 3.17 – 3.11 (m, 1H), 3.04 (br dd, J = 3.7, 12.7 Hz, 1H), 2.38 – 2.31 (m, 2H), 1.22 (d, J = 6.6 Hz, 3H). EXAMPLE 57 – Synthesis of (15R)-5-({2-chloro-6-[(morpholin-4-yl)methyl]pyrimidin-4- yl}oxy) -15-methyl-11-thia-3,6,14,17-tetraazatetracyclo[8.8.0.0²,� �.0¹²,¹⁸]octadeca- 1(10),2(7),3,5,8,12(18)-hexaen-13-one (I-120) [0699] The title compound was prepared using the following procedures. [0700] Step 1. Preparation of 2, 4-dichloro-6- (chloromethyl) pyrimidine. To a solution of 6-(hydroxymethyl)pyrimidine-2,4-diol (5 g, 1 eq, 35.2 mmol) at 0 °C in toluene (12.5 mL) was added phosphoroyl trichloride (7 mL, 2 eq, 70.4 mmol) and ethylbis(propan-2-yl)amine (19 mL, 3 eq, 106 mmol). The reaction mixture was heated to 120 °C and stirred at 120 °C for 16 hours. TLC (eluted with petroleum ether/acetate ethyl = 3/1, R _f = 0.4) showed the starting material remained and the desired product was formed. The reaction mixture was quenched slowly with saturated sodium bicarbonate solution and extracted with ethyl acetate (3 × 20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure to afford 6.3 g (90.6%) of 2, 4-dichloro-6- (chloromethyl) pyrimidine as a brown solid. The crude product was used directly in the next step without purification. LCMS: Rt=0.434 min, m/z = 197.1 (M+H) ⁺ . [0701] Step 2. Preparation of 2, 4-dichloro-6-(iodomethyl) pyrimidine. To a solution of 2, 4-dichloro-6-(chloromethyl) pyrimidine (6.3 g, 1 eq, 31.9 mmol) in acetone (31.5 mL) at room temperature was added sodium iodide (4.83 g, 1 eq, 32.2 mmol). The reaction mixture was stirred at 25 °C for 20 minutes, then heated to 60 °C and stirred at 60 °C for 20 minutes. TLC (eluted with petroleum ether / acetate ethyl = 3/1, R _f = 0.6) showed the starting material was consumed completely and the desired product was formed. The reaction mixture was filtered, and the filter cake was washed with acetone (100 mL). The filtrate was concentrated under reduced pressure to give a crude oil, which was purified via silical gel chromatography eluting with 5-15% ethyl acetate in petroleum ether. Pure fractions were combined and concentrated to afford 4.6 g (49.9%) of 2, 4-dichloro-6-(iodomethyl) pyrimidine as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.36 (s, 1H), 4.35 (s, 2H). [0702] Step 3. Preparation of 4-[(2,6-dichloropyrimidin-4-yl)methyl]morpholine. To a solution of morpholine (40 mg, 1 eq, 459 µmol) in acetonitrile (2 mL) at 25 °C was added ethylbis (propan-2-yl)amine (59.3 mg, 1 eq, 459 µmol) and 2,4-dichloro-6-(iodomethyl) pyrimidine (199 mg, 1.5 eq, 689 µmol). The reaction mixture was stirred at 25 °C for 0.5 hour. TLC (eluted with petroleum ether / acetate ethyl = 1/1, R _f = 0.4) showed the starting material was consumed and the desired product was formed. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC to afford 60 mg (52.6%) of 4-[(2,6-dichloropyrimidin-4-yl)methyl]morpholine as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.87 (s, 1H), 4.25 (br s, 4H), 3.04 (br s, 6H). [0703] Step 4. Preparation of (15R)-5-({2-chloro-6-[(morpholin-4-yl)methyl]pyrimidin-4- yl}oxy)-15-methyl-11-thia-3,6,14,17-tetraazatetracyclo[8.8.0 .0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7), 3,5,8,12(18)-hexaen-13-one. To a solution of (15R)-5-hydroxyl-15-methyl-11-thia-3, 6, 14, 17- tetraazatetracyclo [8.8.0.0², ⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-o ne (20 mg, 0.8 eq, 66.6 µmol) in acetonitrile (2 mL) at 25 °C was added dipotassium carbonate (23 mg, 2 eq, 166 µmol) and 4-[(2,6-dichloropyrimidin-4-yl)methyl]morpholine (31 mg, 1.5 eq, 125 µmol). The reaction mixture was stirred at 60 °C for 1 hour. LCMS showed that starting material remained and the desired product was detected. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to afford 9.8 mg (23%) of (15R)-5-({2-chloro-6-[(morpholin-4-yl)methyl] pyrimidin-4-yl}oxy) -15-methyl-11-thia-3,6,14,17-tetraazatetracyclo[8.8.0.0²,� �.0¹²,¹⁸] octadeca- 1(10),2(7),3,5,8,12(18)-hexaen-13-one as a yellow solid. LCMS: Rt = 0.456 min, m/z = 512.2 (M+H) ⁺ . EXAMPLE 58 – Synthesis of (R)-3-((2-chloro-6-((methylsulfonyl) methyl)pyrimidin-4- yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5� ��,6’:4,5]thieno[3,2- f]quinoxalin-8-one (I-121) I-121 [0704] The title compound was prepared using the following procedures. [0705] Step 1. Preparation of 2,4-dichloro-6-(methanesulfonylmethyl)pyrimidine. To a solution of 2,4-dichloro-6-(iodomethyl)pyrimidine (0.5 g, 1.73 mmol) in dimethyl sulfoxide (5 mL) and dichloromethane (5 mL) at 25 °C was added sodium methyl sulfinate (178 mg, 1.73 mmol). Then, the resulting mixture was stirred at 60 °C for 3 hours under a nitrogen atmosphere. LCMS showed the starting material was consumed and the desired product was detected. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (5 mL) and filtered. The filtrate was concentrated under reduced pressure to give 230 mg (55.1%) of 2,4-dichloro-6-(methanesulfonylmethyl)pyrimidine as a yellow solid. LCMS: Rt= 0.307 min, m/z = 241.0（M+H) ⁺ . [0706] Step 2. Preparation of (R)-3-((2-chloro-6-((methylsulfonyl) methyl)pyrimidin-4- yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5� ��,6’:4,5]thieno[3,2-f] quinoxalin-8-one. To a solution of 2,4-dichloro-6-((methylsulfonyl)methyl)pyrimidine (44.1 mg, 2 eq, 183 µmol) in dimethyl sulfoxide (2 mL) at room temperature was added dipotassium carbonate (25.3 mg, 2 eq, 183 µmol) and (R)-3-hydroxy-10-methyl-9,10,11,12-tetrahydro-8H- [1,4]diazepino[5’,6’:4,5]thieno[3,2-f] quinoxalin-8-one (22 mg, 0.8 eq, 73.3 µmol). The resulting mixture was heated to 60 °C and stirred at 60 °C for 3 hours. LCMS showed the starting material was consumed and the desired product was detected. The reaction mixture was filtered, and the filtrate was purified by prep-HPLC to give 2.9 mg (6.27%) of (R)-3-((2- chloro-6-((methylsulfonyl) methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8 H- [1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one as a yellow solid. LCMS: Rt= 1.585 min, m/z = 505.0 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.12 (s, 1H), 8.80 (br s, 1H), 8.35 (d, J = 8.9 Hz, 1H), 8.00 (br d, J = 4.1 Hz, 1H), 7.95 (d, J = 8.9 Hz, 1H), 7.62 (s, 1H), 4.81 (s, 2H), 3.66 (br s, 3H), 3.16 (s, 3H), 1.22 (d, J = 6.6 Hz, 3H). EXAMPLE 59 – Synthesis of (10R)-3-((2-chloro-5-((2-methyl-1,1-dioxidothiomorpholino) methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8 H-[1,4]diazepino[5’,6’:4,5] thieno[3,2-f]quinoxalin-8-one (I-122) [0707] The title compound was prepared using the following procedures. [0708] Step 1. Preparation of 4-((2,4-dichloropyrimidin-5-yl)methyl)-2- methylthiomorpholine 1,1-dioxide. To a solution of 2-methylthiomorpholine 1,1-dioxide (6 mg, 1 eq, 10.9 µmol) in acetonitrile (1 mL) was added 2,4-dichloro-5-(iodomethyl)pyrimidine (31.1 mg, 1 eq, 108 µmol) and N-ethyl-N-isopropylpropan-2-amine (27.8 mg, 2 eq, 215 µmol) at 0 °C. The reaction mixture was stirred for 1 hour. LCMS showed the starting material was consumed and the desired peak was detected. Four additional vials were set up as described above. All five reaction mixtures were combined, diluted with water (15 mL), and extracted with ethyl acetate (3 × 8 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (eluted with petroleum ether/ethyl acetate = 1/1, R _f = 0.6) to give 50 mg (29.93%) of 4-((2,4-dichloropyrimidin-5- yl)methyl)-2-methylthiomorpholine 1,1-dioxide as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) 8.62 (s, 1H), 3.75 (s, 2H), 3.27 – 3.03 (m, 5H), 3.02 – 2.95 (m, 1H), 2.78 (dd, J = 10.3, 12.3 Hz, 1H), 1.35 (d, J = 7.0 Hz, 3H). [0709] Step 2. Preparation of (10R)-3-((2-chloro-5-((2-methyl-1,1-dioxidothiomorpholino) methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8 H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one. To a solution of 4-((2,4-dichloropyrimidin-5- yl)methyl)-2-methylthiomorpholine 1,1-dioxide (25 mg, 1 eq, 80.6 µmol) in dimethyl sulfoxide (1.5 mL) was added (R)-3-hydroxy-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazep ino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (12.1 mg, 0.5 eq, 40.3 µmol) and cesium carbonate (27.8 mg, 2 eq, 215 µmol) at 60 °C. The mixture was stirred for 1 hour. LCMS showed the starting material was consumed and the desired peak was detected. One additional vial was set up as described above. After cooling to 25 °C, both reaction mixtures were combined, diluted with water (5 mL), and extracted with ethyl acetate (3 × 5 mL). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC to afford 19 mg (20.36%) of (10R)-3-((2-chloro-5-((2-methyl-1,1- dioxidothiomorpholino) methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8 H- [1,4]diazepino[5’,6’:4,5] thieno[3,2-f]quinoxalin-8-one as a yellow solid. LCMS (ESI+): Rt = 0.424 min, m/z = 574.1 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.04 (s, 1H), 8.80 (s, 1H), 8.79 – 8.75 (m, 1H), 8.31 (d, J = 9.0 Hz, 1H), 7.97 (d, J = 4.6 Hz, 1H), 7.91 (d, J = 9.0 Hz, 1H), 3.85 (d, J = 2.0 Hz, 2H), 3.69 – 3.61 (m, 1H), 3.61 – 3.52 (m, 2H), 3.26 – 3.06 (m, 5H), 2.91 – 2.78 (m, 1H), 2.61 – 2.53 (m, 1H), 1.18 (d, J = 6.8 Hz, 3H), 1.12 (d, J = 6.8 Hz, 3H). EXAMPLE 60 – Synthesis of (R)-3-((2-chloro-5-((4-methyl-4-oxido-1,4-azaphosphinan-1- yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydr o-8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (I-93) [0710] The title compound was prepared using the following procedures. [0711] Step 1. Preparation of 1-((2,4-dichloropyrimidin-5-yl)methyl)-4-methyl -1,4- azaphosphinane 4-oxide. To a solution of 4-methyl-1,4-azaphosphinane 4-oxide (10 mg, 1 eq, 75.1 µmol) and 2,4-dichloro-5-(iodomethyl)pyrimidine (23.9 mg, 1.1 eq, 82.6 µmol) in acetonitrile (1.5 mL) was added potassium carbonate (31.1 mg, 3 eq, 225 µmol) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 hour. TLC (eluted with ethyl acetate/methanol = 4/1, R _f = 0.3) showed the starting material was consumed and the desired spot was formed. Three additional vials were set up as described above. All four reaction mixtures were combined and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (eluted with ethyl acetate/methanol = 4/1, R _f = 0.3) to afford 32 mg (32.59%) of 1-((2,4-dichloropyrimidin-5-yl)methyl)-4-methyl -1,4-azaphosphinane 4-oxide as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) 8.77 – 8.53 (m, 1H), 3.82 – 3.61 (m, 2H), 3.14 – 2.96 (m, 2H), 2.92 – 2.72 (m, 2H), 2.15 – 2.05 (m, 2H), 1.98 – 1.80 (m, 2H), 1.58 (br d, J = 12.9 Hz, 3H). [0712] Step 2. Preparation of (R)-3-((2-chloro-5-((4-methyl-4-oxido-1,4-azaphosphinan-1- yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydr o-8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one. To a solution of (R)-3-hydroxy-10-methyl- 9,10,11,12-tetrahydro-8H-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (10.3 mg, 0.5 eq, 34.4 µmol) and 1-((2,4-dichloropyrimidin-5-yl)methyl)-4-methyl-1,4-azaphosp hinane 4- oxide (22.5 mg, 68.8 µmol, 1 eq.) in dimethyl sulfoxide (0.2 mL) was added potassium carbonate (19 mg, 2 eq, 138 µmol) at 25 °C. The reaction mixture was heated to 60 °C and stirred at 60 °C for 1 hour. LCMS showed the material peak was consumed and the desired peak was detected. One additional vial was set up as described above. After cooling to 25 °C, both reaction mixtures were combined, poured into water (10 mL), and extracted with ethyl acetate (3 × 10 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to afford 10 mg (12.81%) of (R)-3-((2- chloro-5-((4-methyl-4-oxido-1,4-azaphosphinan-1-yl)methyl)py rimidin-4-yl)oxy)-10-methyl- 9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno [3,2-f]quinoxalin-8-one as a yellow solid. LCMS (ESI+): Rt = 1.202 min, m/z 558.3 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.07 (s, 1H), 8.83 – 8.76 (m, 2H), 8.34 (d, J = 8.8 Hz, 1H), 8.01 (br d, J = 4.6 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H), 3.85 – 3.78 (m, 2H), 3.70 – 3.65 (m, 1H), 3.63 – 3.57 (m, 2H), 3.02 – 2.90 (m, 2H), 2.78 – 2.68 (m, 2H), 1.88 – 1.78 (m, 4H), 1.42 (d, J = 12.9 Hz, 3H), 1.22 (d, J = 6.8 Hz, 3H). EXAMPLE 61 – Synthesis of (R)-3-((2-chloro-5-(piperazin-1-ylmethyl) pyrimidin-4- yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5� ��,6’:4,5]thieno[3,2- f]quinoxalin-8-one [0713] The title compound was prepared using the following procedures. [0714] Step 1. Preparation of tert-butyl 4-[(2,4-dichloropyrimidin-5-yl) methyl]piperazine- 1-carboxylate. To a solution of tert-butyl piperazine-1-carboxylate (0.1 g, 1 eq, 537 µmol) in tetrahydrofuran (1 mL) at room temperature was added 2,4-dichloro-5-(iodomethyl)pyrimidine (155 mg, 1 eq, 537 µmol) and potassium tert-butoxide (120 mg, 2 eq, 1.07 mmol). The reaction mixture was stirred at 25 °C for 2 hours. LCMS analysis showed the starting material was consumed completely and the desired product was formed. Four additional vials were set up as described above. All five reaction mixtures were combined and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (petroleum ether/acetate ethyl = 10/1 R _f = 0.32) to afford 130 mg (12.5%) tert-butyl4-[(2,4- dichloropyrimidin-5-yl) methyl]piperazine-1-carboxylate as a yellow oil. LCMS: Rt = 0.576 min, m/z = 347.1 (M+H) ⁺ . [0715] Step 2. Preparation of tert-butyl (R)-4-((2-chloro-4-((10-methyl-8-oxo-9,10,11,12- tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quin oxalin-3-yl)oxy)pyrimidin-5- yl)methyl)piperazine-1-carboxylate. To a solution of tert-butyl 4-[(2,4-dichloropyrimidin-5- yl)methyl]piperazine-1-carboxylate (23 mg, 1 eq, 66.2 µmol) in dimethyl sulfoxide (0.5 mL) at room temperature was added (R)-3-hydroxy-10-methyl-9,10,11,12-tetrahydro-8H- [1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one (15.9 mg, 0.8 eq, 53 µmol) and dipotassium carbonate (18.3 mg, 2 eq, 132 µmol). The reaction mixture was heated to 60 °C and stirred at 60 °C for 1 hour. LCMS showed the starting material was consumed completely and the desired product was detected. Four additional vials were set up as described above. All five reaction mixtures were combined and filtered. The filtrate was purified by prep-HPLC to afford 120 mg (55.7%) tert-butyl(R)-4-((2-chloro-4-((10-methyl-8-oxo-9,10,11,12- tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quin oxalin-3-yl)oxy)pyrimidin-5- yl)methyl)piperazine-1-carboxylate as an orange solid. LCMS: Rt = 0.515 min, m/z = 611.3 (M+H) ⁺ . [0716] Step 3. Preparation of (R)-3-((2-chloro-5-(piperazin-1-ylmethyl) pyrimidin-4- yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5� ��,6’:4,5]thieno[3,2- f]quinoxalin-8-one. To a solution of tert-butyl 4-[(2-chloro-4-{[(15R)-15-methyl-13-oxo-11- thia-3,6,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10), 2(7),3,5,8,12(18)-hexaen-5- yl]oxy}pyrimidin-5-yl)methyl]piperazine-1-carboxylate (12 mg, 1 eq, 19.6 µmol) in dichloromethane (0.5 mL) at room temperature was added trifluoroacetic acid (0.1 mL). The reaction mixture was stirred at 25 °C for 1 hour. LCMS analysis showed the starting material was consumed completely and the desired product was formed. The reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC to afford 7 mg (57.0%) (R)-3-((2-chloro-5-(piperazin-1-ylmethyl) pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12- tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quin oxalin-8-one as an orange solid. LCMS: Rt = 1.307 min, m/z = 511.1 (M+H) ⁺ . ¹ H NMR (400 MHz, CD3OD) δ 8.94 (s, 1H), 8.74 (s, 1H), 8.21 (d, J = 8.9 Hz, 1H), 7.90 (d, J = 9.0 Hz, 1H), 3.90 – 3.79 (m, 3H), 3.74 – 3.67 (m, 2H), 3.27 – 3.22 (m, 4H), 2.91 – 2.78 (m, 4H), 1.36 (d, J = 6.8 Hz, 3H). EXAMPLE 62 – Synthesis of (R)-3-((2-chloro-5-(morpholinomethyl) pyrimidin-4-yl)oxy)- 10-methyl-9,10,11,12-tetrahydro-8H-azepino[4’,3’:4,5]thi eno[3,2-f]quinoxalin-8-one (I- [0717] The title compound was prepared using the following procedures. [0718] Step 1. Preparation of tert-butyl N-[(2R,3E)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)but-3-en-2-yl]carbamate. To a solution of tert-butyl N-[(2R)-but-3-yn-2- yl]carbamate (2 g, 1 eq, 11.8 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,3,2-dioxaborolane (3.54 g, 1.2 eq, 13.9 mmol) in 1,4-dioxane (17.8 mL) at room temperature were added methanol (1.26 mL), triphenylphosphane (310 mg, 1.18 mmol, 0.1 eq), and sodium tert-butoxide (114 mg, 0.1 eq, 1.18 mmol) in portions under a nitrogen atmosphere. To the mixture was added copper (2 ⁺ ) ditrifluoromethanesulfonate (214 mg, 0.05 eq, 591 µmol) in portions at 0 °.C The resulting mixture was stirred at 25 °C for 12 hours. LCMS analysis showed the starting material was consumed completely and the desired product was detected. The reaction mixture was diluted with water (20 mL) and ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (15 mL), dried over Na ₂ SO ₄ , and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified via silica gel column chromatography eluting with 0%-10% ethyl acetate in petroleum ether to afford 1.16 g (23.1%) of tert-butyl N-[(2R,3E)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)but-3- en-2-yl]carbamate as a white oil. LCMS: Rt= 0.521 min, m/z = 242.2 (M-56+H)+. [0719] Step 2. Preparation of methyl 9-[(1E,3R)-3-{[(tert-butoxy)carbonyl]amino}but-1- en-1-yl]-3-methoxythieno[3,2-f]quinoxaline-8-carboxylate. To a solution of tert-butyl N- [(2R,3E)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but- 3- en-2-yl]carbamate (610 mg, 1.2 eq, 2.05 mmol) in tetrahydrofuran (10.2 mL) and water (2.03 mL) at room temperature was added methyl 9-bromo-3-methoxythieno[3,2-f]quinoxaline-8-carboxylate (604 mg, 1 eq, 1.71 mmol), disodium carbonate (544 mg, 3 eq, 5.13 mmol), and [1,1-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (250 mg, 0.2 eq, 342 µmol) under a nitrogen atmosphere. The reaction mixture was heated to 80 °C and stirred at 80 °C for 3 hours. LCMS analysis showed the starting material was consumed completely and the desired product was detected. One additional vial was set up as desired above. Both reaction mixture were diluted with water (20 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organics were dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified via silica gel chromatography eluting with 0-10% ethyl acetate in heptane to afford 750 mg (46.17%) of methyl 9-[(1E,3R)-3-{[(tert- butoxy)carbonyl]amino} but-1-en-1-yl]-3-methoxythieno[3,2-f]quinoxaline-8-carboxyla te as a white solid. LCMS: Rt = 0.986 min, m/z = 443.9 (M+H)+. [0720] Step 3. Preparation of methyl 9-[(3R)-3-{[(tert-butoxy)carbonyl]amino}butyl]-3- methoxythieno[3,2-f] quinoxaline-8 -carboxylate. To a solution of methyl 9-[(1E,3R)-3- {[(tert-butoxy)carbonyl]amino}but-1-en-1-yl]-3- methoxythieno[3,2-f]quinoxaline-8- carboxylate (250 mg, 1 eq, 564 µmol) in tetrahydrofuran (41.7 mL) at room temperature was added Pd/C (20 mg, 10%) under a hydrogen balloon and the resulting mixture was stirred at 25 °C for 1 hour. LCMS analysis showed the starting material was consumed completely and the desired product was detected. Two additional vials were set up as desired above. All three reaction mixture were combined and filtered. The filtrate was concentrated under reduced pressure to give a residue as a yellow oil, which was purified via silica gel chromatography eluting with 0-10% ethyl acetate in petroleum ether to afford 475 mg (51.07%) of methyl 9- [(3R)-3-{[(tert-butoxy)carbonyl]amino}butyl]-3-methoxythieno [3,2-f] quinoxaline-8 - carboxylate as a yellow oil. LCMS: Rt = 0.691 min, m/z = 446.2 (M+H) ⁺ . [0721] Step 4. Preparation of methyl 9-[(3R)-3-aminobutyl]-3-methoxythieno [3,2- f]quinoxaline-8-carboxylate. To methyl-9-[(3R)-3-{[(tert-butoxy)carbonyl]amino}butyl]-3- methoxythieno[3,2-f]quinoxaline-8-carboxylate (215 mg, 1 eq, 11.2 µmol) was added hydrogen chloride in ethyl acetate (40 mL, 4 N) at room temperature, and the resulting mixture was stirred at 25 °C for 1 hour. LCMS analysis showed the starting material was consumed completely and the desired product was detected. Two additional vials were set up as described above. All three reaction mixture were combined and filtered. The filtrate was concentrated under reduced pressure to obtain 380 mg (75%) of crude methyl 9-[(3R)-3-aminobutyl]-3- methoxythieno [3,2-f]quinoxaline-8-carboxylate as a yellow solid, which was used directly in the next step without further purification. LCMS: Rt = 0.401 min, m/z = 346.2 (M+H)+. [0722] Step 5. Preparation of (15R)-5-methoxy-15-methyl-11-thia-3,6,14-triazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1,3,5,7,9,12(18)-hexaen- 13-one. To a solution of methyl 9-[(3R)-3- aminobutyl]-3-methoxythieno[3,2-f]quinoxaline-8- carboxylate (120 mg, 1 eq, 347 µmol) in methanol (1 mL) at room temperature was added methoxysodium (188 mg, 3 eq, 1.04 mmol). The reaction mixture was heated to 80 °C and stirred at 80 °C for 3 hours. LCMS analysis showed the starting material was consumed completely and the desired product was detected. Two additional vials were set up as described above. All three reaction mixture were concentrated under reduced pressure to give 180 mg (49.6%) of (15R)-5-methoxy-15-methyl- 11-thia-3,6,14-triazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]oc tadeca-1,3,5,7,9,12(18)-hexaen-13-one as a brown solid, which was used directly in the next step without further purification. LCMS: Rt = 0.622 min, m/z = 314.1 (M+H) ⁺ . [0723] Step 6. Preparation of (R)-3-hydroxy-10-methyl-9,10,11,12-tetrahydro-8H- azepino[4’,3’:4,5]thieno[3,2-f]quinoxalin-8-one. (15R)-5-Methoxy-15-methyl-11-thia-3,6,14- triazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1,3,5,7, 9,12(18)-hexaen-13-one (50 mg, 1 eq, 160 µmol) was added to hydrogen bromide (2 mL, 33% in acetic acid) at room temperature. The reaction mixture was heated to 80 °C and stirred at 80 °C for 1 hour. LCMS analysis showed the starting material was consumed completely and the desired product was detected. One additional vial was set up as described above. Both reaction mixture were combined and concentrated under reduced pressure to give 140 mg curde of (R)-3-hydroxy-10-methyl- 9,10,11,12-tetrahydro-8H-azepino[4’,3’:4,5]thieno[3,2-f] quinoxalin-8-one as a yellow solid, which was used directly in the next step without further purification. LCMS: Rt = 0.315 min, m/z = 300.1 (M+H)+. [0724] Step 7. Preparation of (R)-3-((2-chloro-5-(morpholinomethyl) pyrimidin-4-yl)oxy)- 10-methyl-9,10,11,12-tetrahydro-8H-azepino[4’,3’:4,5]thi eno[3,2-f]quinoxalin-8-one. To a solution of (R)-3-hydroxy-10-methyl-9,10,11,12-tetrahydro-8H-azepino[4� �,3’:4,5] thieno [3,2- f]quinoxalin-8-one (50 mg, 167 µmol, 1 eq) in dimethyl sulfoxide (12.5 mL) at room temperature was added 4-[(2,4-dichloropyrimidin-5-yl)methyl]morpholine (41.4 mg, 1 eq, 167 µmol) and dipotassium carbonate (46.2 mg, 2 eq, 334 µmol). The mixture reaction was heated to 60 °C and stirred at 60 °C for 1 hour. LCMS analysis showed the starting material was consumed and the desired product was detected. The reaction mixture was filtered, and the filtrate was purified by prep-HPLC to afford 10.5 mg (11.7%) of (R)-3-((2-chloro-5- (morpholinomethyl) pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H- azepino[4’,3’:4,5] thieno[3,2-f]quinoxalin-8-one as a white solid. LCMS: Rt = 0.479 min, m/z = 511.1 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.11 (s, 1H), 8.77 (s, 1H), 8.44 (d, J = 8.9 Hz, 1H), 8.36 (br d, J = 3.3 Hz, 1H), 7.95 (d, J = 8.9 Hz, 1H), 7.65 (d, J = 8.9 Hz, 1H), 3.99 – 3.89 (m, 1H), 3.89 – 3.71 (m, 2H), 3.71 – 3.60 (m, 3H), 3.60 – 3.51 (m, 4H), 3.44 (br s, 3H), 2.27 – 2.18 (m, 1H), 2.12 – 2.02 (m, 1H), 1.26 (d, J = 6.8 Hz, 3H). EXAMPLE 63 – Synthesis of (R)-3-((2-chloro-5-(((R)-2-methylmorpholino)methyl) pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4] diazepino[5’,6’:4,5]thieno [3,2-f]quinoxalin-8-one (I-125) [0725] The title compound was prepared using the following procedures. [0726] Step 1. Preparation of (2R)-4-[(2,4-dichloropyrimidin-5-yl)methyl]-2- methylmorpholine. To a solution of 2,4-dichloro-5-(iodomethyl)pyrimidine (571 mg, 2 eq, 1.98 mmol) in tetrahydrofuran (5 mL) at 0 °C was added ethylbis(propan-2-yl)amine (290 mg, 2.24 mmol, 2.3 eq) in acetonitrile (2 mL) and (2R)-2-methylmorpholine. The reaction mixture was stirred at 0° C for 1 hour. TLC (eluted with petroleum ether/acetate ethyl =3/1, R _f = 0.45) showed the starting material was consumed completely and the desired product was formed. The reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (3 × 5 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (eluted with petroleum ether/acetate ethyl =3/1, R _f =0.45) to afford 63 mg (24.3%) of (2R)-4-[(2,4-dichloropyrimidin-5-yl)methyl]-2-methylmorpholi ne as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.76 (s, 1H), 3.76 – 3.69 (m, 1H), 3.58 – 3.43 (m, 4H), 2.75 – 2.61 (m, 2H), 2.15 (dt, J = 3.2, 11.3 Hz, 1H), 1.84 (t, J = 10.4 Hz, 1H), 1.03 (d, J = 6.3 Hz, 3H). [0727] Step 2. Preparation of (R)-3-((2-chloro-5-(((R)-2-methylmorpholino)methyl) pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4] diazepino[5’,6’:4,5] thieno[3,2-f]quinoxalin-8-one. To a solution of (2R)-4-[(2,4-dichloropyrimidin-5-yl)methyl]- 2-methylmorpholine (40 mg, 1 eq, 153 µmol) in dimethyl sulfoxide (4 mL) at room temperature was added (R)-3-hydroxy-10-methyl-9,10,11,12-tetrahydro-8H- [1,4]diazepino[5’,6’:4,5] thieno[3,2-f]quinoxalin-8-one (36.7 mg, 0.8 eq, 122 µmol) and dipotassium carbonate (42.2 mg, 2 eq, 305 µmol). The reaction mixture was heated to 60 °C and stirred at 60 °C for 1 hour. LCMS analysis showed the starting material was consumed completely and the desired product was detected. The reaction mixture was filtered, and the filtrate was purified by prep-HPLC to afford 30.1 mg (35.8%) of (R)-3-((2-chloro-5-(((R)-2- methylmorpholino)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,1 1,12-tetrahydro-8H- [1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin-8-one as a yellow solid. LCMS: Rt = 0.318 min, m/z = 526.3 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.96 (s, 1H), 8.84 (s, 1H), 8.21 (d, J = 9.0 Hz, 1H), 7.91 (d, J = 8.9 Hz, 1H), 4.61 (br s, 2H), 4.15 (dd, J = 3.3, 12.9 Hz, 1H), 3.91 – 3.79 (m, 3H), 3.74 – 3.54 (m, 5H), 3.02 (br t, J = 11.2 Hz, 1H), 1.36 (d, J = 6.9 Hz, 3H), 1.28 (d, J = 6.4 Hz, 3H).

EXAMPLE 64 – Synthesis of 3-[(2-chloro-4-{[(15R)-15-methyl-13-oxo-11-thia-3,6,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10), 2(7),3,5,8,12(18)-hexaen-5- yl]oxy}pyrimidin-5-yl)methanesulfonyl]propanoic acid (I-94) [0728] The title compound was prepared using the following procedures. [0729] Step 1. Preparation of methyl 3-[(2,4-dichloropyrimidin-5-yl)methanesulfonyl] propanoate. To a solution of 2,4-dichloro-5-(iodomethyl)pyrimidine (0.5 g, 1 eq, 1.73 mmol) in dimethyl sulfoxide (5 mL) was added methyl 3-[(sodiooxy)sulfinyl] propanoate (332 mg, 1.1 eq, 1.9 mmol) at 20 °C. The reaction mixture was heated to 55 °C and stirred for 3 hours. TLC (eluted with petroleum ether/ethyl acetate = 1/1, R _f = 0.6) showed the starting material was consumed and the desired spot was formed. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 15 mL). The organic phase was washed with brine (3 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (petroleum ether/ethyl acetate = 1/1, R _f = 0.6) to give 450 mg (83%) of methyl 3-[(2,4- dichloropyrimidin-5-yl)methanesulfonyl]propanoate as a yellow solid. LCMS (ESI+): Rt = 1.251 min, m/z 313.2 (M+H) ⁺ . [0730] Step 2. Preparation of methyl 3-[(2-chloro-4- {[(15R)-15-methyl-13-oxo-11-thia- 3,6,14,17-tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octad eca-1(10),2(7),3,5,8,12(18)-hexaen-5- yl]oxy}pyrimidin-5-yl)methanesulfonyl]propanoate. To a solution of (15R)-5-hydroxy-15- methyl-11-thia-3,6,14,17-tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)- hexaen-13-one (50 mg, 1 eq, 166 µmol) in dimethyl sulfoxide (2 mL) was added methyl 3- [(2,4-dichloropyrimidin-5-yl)methanesulfonyl] propanoate (156 mg, 3 eq, 499 µmol) and potassium carbonate (138 mg, 6 eq, 999 µmol) at 25 °.C The reaction mixture was heated to 60 °C and stirred at 60 °C for 1 hour. LCMS showed the starting material was consumed and the desired peak was detected. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to afford 36.5 mg (38%) of methyl 3-[(2-chloro-4- {[(15R)-15-methyl-13-oxo-11-thia-3,6,14,17- tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)- hexaen-5- yl]oxy}pyrimidin-5-yl) methanesulfonyl]propanoate as a yellow solid. LCMS (ESI+): Rt = 1.593 min, m/z 577.2 (M+H) ⁺ . [0731] Step 3. Preparation of 3-[(2-chloro-4-{[(15R)-15-methyl-13-oxo-11-thia-3,6,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10), 2(7),3,5,8,12(18)-hexaen-5-yl]oxy} pyrimidin-5-yl)methanesulfonyl]propanoic acid. To a solution of methyl 3-[(2-chloro-4- {[(15R)-15-methyl-13-oxo-11-thia- 3,14,17-triazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca- 1(10),2(7),3,5,8,12(18)-hexaen-5-yl]oxy}pyrimidin-5-yl)metha nesulfonyl]propanoate (25 mg, 1 eq, 43.4 µmol) in chloroform (3 mL) was added trimethylstannane hydroxide (23.7 mg, 3 eq, 130 µmol) at 25 °.C The reaction mixture was heated to 80 °C and stirred at 80 °C for 5 hours. LCMS showed the starting material was consumed and the desired peak was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give 9 mg (36.83%) of 3-[(2-chloro-4-{[(15R)-15-methyl-13-oxo-11- thia-3,6,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10), 2(7),3,5,8,12(18)-hexaen-5- yl]oxy}pyrimidin-5-yl)methanesulfonyl]propanoic acid as a yellow solid. LCMS (ESI+): Rt = 1.424 min, m/z 563.2 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.05 (s, 1H), 8.83 (s, 1H), 8.81 – 8.77 (m, 1H), 8.36 (d, J = 8.8 Hz, 1H), 8.02 (br d, J = 4.4 Hz, 1H), 7.99 – 7.95 (m, 1H), 4.86 (s, 2H), 3.73 – 3.63 (m, 1H), 3.59 (br d, J = 4.8 Hz, 2H), 3.58 – 3.52 (m, 2H), 2.78 (t, J = 7.5 Hz, 2H), 1.21 (d, J = 6.6 Hz, 3H). EXAMPLE 65 – Synthesis of (R)-3-((2-chloro-5-(((S)-2- methylmorpholino)methyl) pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4] diazepino[5’,6’:4,5]thieno [3,2-f]quinoxalin-8-one (I-126) I-126 [0732] The title compound was prepared using the following procedures. [0733] Step 1. Preparation of (S)-4-((2,4-dichloropyrimidin-5-yl)methyl)-2- methylmorpholine. To a solution of (2S)-2-methylmorpholine (0.1 g, 1 eq, 989 µmol) in tetrahydrofuran (0.2 mL) at 0 °C was added 2,4-dichloro-5-(iodomethyl)pyrimidine (114 mg, 0.8 eq, 395 µmol) and ethylbis(propan-2-yl)amine (145 mg, 2.3 eq, 1.12 mmol) in acetonitrile (0.8 mL). The resulting mixture was stirred at 0 °C for 1 hour. LCMS analysis showed the starting material was consumed completely and the desired product was detected. Four additional vials were set up as decribed above. All five reaction mixtures were quenched with water (5 mL) and extracted with ethyl acetate (3 × 5 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by prep-TLC (eluted with petroleum ether/acetate ethyl =3/1, R _f = 0.35) to afford 513 mg (27.7%) of (S)-4-((2,4- dichloropyrimidin-5-yl)methyl)-2- methylmorpholine as a yellow oil. LCMS: Rt = 0.205 min, m/z = 262.2 (M+H)+. [0734] Step 2. Preparation of (R)-3-((2-chloro-5-(((S)-2-methylmorpholino)methyl) pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4] diazepino[5’,6’:4,5] thieno[3,2-f]quinoxalin-8-one. To a solution of (S)-4-((2,4-dichloropyrimidin-5-yl)methyl)-2- methylmorpholine (30 mg, 1 eq, 114 µmol) in dimethyl sulfoxide (2 mL) at room temperature was added (R)-3-hydroxy-10-methyl-9,10,11, 12-tetrahydro-8H-[1,4]diazepino[5’,6’:4,5] thieno[3,2-f]quinoxalin-8-one (27.5 mg, 0.8 eq, 91.6 µmol) and dipotassium carbonate (31.6 mg, 229 µmol, 2 eq). The reaction mixture was heated to 60 °C and stirred at 60 °C for 1 hour. LCMS analysis showed the starting material was consumed completely and the desired product was detected. One additional vial was set up as described above. Both reaction mixtures were combined and filtered. The filtrate was purified by prep-HPLC to afford 44.3 mg (35.1%) of (R)-3-((2-chloro-5-(((S)-2- methylmorpholino)methyl)pyrimidin-4-yl)oxy)-10-methyl- 9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno [3,2-f]quinoxalin-8-one as a yellow solid. LCMS: Rt = 0.320 min, m/z = 526.2 (M+H) ⁺ . ¹ H NMR (400 MHz, CD3OD) δ 8.96 (s, 1H), 8.85 (s, 1H), 8.81 (s, 1H), 8.21 (d, J = 8.9 Hz, 1H), 7.91 (d, J = 9.0 Hz, 1H), 4.62 (br s, 2H), 4.15 (dd, J = 3.2, 12.8 Hz, 1H), 3.93 – 3.77 (m, 3H), 3.76 – 3.52 (m, 5H), 3.03 (br t, J = 11.5 Hz, 1H), 1.39 – 1.39 (m, 1H), 1.36 (d, J = 6.8 Hz, 3H), 1.28 (d, J = 6.3 Hz, 3H). EXAMPLE 66 – Synthesis of (R)-3-((2-chloro-5-((4-methylpiperazin-1-yl)methyl) pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4] diazepino[5’,6’:4,5] thieno[3,2-f]quinoxalin-8-one (I-127) [0735] The title compound was prepared using the following procedures. [0736] To a solution of (R)-3-((2-chloro-5-(piperazin-1-ylmethyl)pyrimidin-4-yl)oxy) -10- methyl- 9,10,11,12-tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno [3,2-f]quinoxalin-8-one (20 mg, 1 eq, 39.1 µmol) in methanol (2 mL) at room temperature was added formaldehyde (50 µL, 37% in water) and acetic acid (50 µL). The reaction mixture was stirred at 25 °C for 0.5 hour. Then, to the reaction mixture was added cyanoboranuide sodium (3.34 µL, 1.6 eq, 63.7 µmol) at room temperature. The reaction mixture was stirred at 25 °C for 1 hour. LCMS analysis showed the starting material was consumed and the desired product was detected. The reaction mixture was filtered, and the filtrate was purified by prep-HPLC to afford 11 mg (53.5%) (R)- 3-((2-chloro-5-((4-methylpiperazin-1-yl)methyl) pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12- tetrahydro-8H-[1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quin oxalin-8-one as a brown solid. LCMS: Rt = 0.468 min, m/z = 525.3 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.94 (s, 1H), 8.74 (s, 1H), 8.22 (d, J = 8.9 Hz, 1H), 7.90 (d, J = 9.0 Hz, 1H), 3.89 (s, 2H), 3.83 (br s, 1H), 3.72 – 3.67 (m, 2H), 3.56 – 3.49 (m, 2H), 3.24 – 3.14 (m, 4H), 2.91 (s, 3H), 2.63 – 2.53 (m, 2H), 1.36 (d, J = 6.9 Hz, 3H). EXAMPLE 67 – Synthesis of (10R)-3-((2-chloro-5-((S-methylsulfonimidoyl)methyl) pyrimidin -4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5’,6’:4,5] thieno[3,2-f]quinoxalin-8-one (I-128) [0737] The title compound was prepared using the following procedures. [0738] Step 1. Preparation of 5-(chloromethyl) pyrimidine-2,4-diol. To a solution of 5- (hydroxymethyl)pyrimidine-2,4-diol (5 g, 1 eq, 35.2 mmol) in 1,4-dioxane (50 mL) at room temperature was added thionyl chloride (20 mL, 7.8 eq, 275 mmol). The reaction mixture was heated to 105 °C and stirred at 105 °C for 4 hours. TLC (eluted with methylene chloride/methanol =4/1, R _f = 0.5) showed the starting material was consumed completely and the desired product was formed. One additional vial was set up as described above. Both reaction mixtures were combined and dried under high vacuum to give 10.8 g (86.0%) of 5- (chloromethyl) pyrimidine-2,4-diol as a white solid, which was used directly in the next step. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.27 (br s, 1H), 11.03 (br d, J = 4.5 Hz, 1H), 7.74 (d, J = 6.0 Hz, 1H), 4.41 (s, 2H). [0739] Step 2. Preparation of 5-[(methylsulfanyl)methyl]pyrimidine-2,4-diol. To a solution of 5-(chloromethyl)pyrimidine-2,4-diol (10.8 g, 1 eq, 67.3 mmol) in dimethylformamide (108 mL) at room temperature was added (methylsulfanyl)sodium (11 g, 2.3 eq, 157 mmol). The reaction mixture was stirred at 25 °C for 12 hours. LCMS analysis showed the starting material was consumed completely and the desired product was formed. The reaction mixtures was diluted with ethyl acetate (100 mL) and filtered. The filter cake was dissolved in water and acidified to pH 5 with HCl (1N). The suspension was filtered, and the filtrate cake was dried under high vacuum to give 7 g (30.6%) 5-[(methylsulfanyl)methyl]pyrimidine -2,4-diol as a white solid, which was used directly in the next step. LCMS: Rt = 0.222 min, m/z = 173.1 (M+H) ⁺ . [0740] Step 3. Preparation of 2,4-dichloro-5-[(methylsulfanyl)methyl]pyrimidine.5- [(Methylsulfanyl)methyl]pyrimidine-2,4-diol (5 g, 1 eq, 29 mmol) was added to phosphoroyl trichloride (50 mL, 8.7 eq, 251 mmol) at room temperature. The resulting mixture was stirred at 115 °C for 3 hours under a nitrogen atmosphere. LCMS analysis showed the starting material was consumed completely and the desired product was detected. The reaction mixture was quenched with water (100 mL), extracted with dichloromethane (3 × 20 mL), dried over Na ₂ SO ₄ , and filtered. The filtrate was concentrated under reduced pressure. _{The residue was purified via} silica gel chromatography eluting with 10-20% ethyl acetate in petroleum ether. Pure fractions were combined and concentrated to afford 1.78 g (14.7%) of 2,4-dichloro-5- [(methylsulfanyl)methyl]pyrimidine as a white solid. LCMS:Rt=1.623 min, m/z=208.9 (M+H) ⁺ . [0741] Step 4. Preparation of N-{[(2,4-dichloropyrimidin-5-yl)methyl](methyl)-λ⁴- sulfanylidene}-4-methylbenzene-1-sulfonamide. To a solution of 2,4-dichloro-5- [(methylsulfanyl)methyl]pyrimidine (1 g, 1 eq, 4.78 mmol) in acetone (50 mL) at room temperature was added chloro(4-methylbenzenesulfonyl)azanide sodium (1.74 g, 1.6 eq, 7.65 mmol) and copper chloride (96.5 mg, 0.15 eq, 717 µmol). The reaction mixture was stirred at 70 °C for 7 hours. LCMS showed the starting material was consumed and the desired product was detected. The reaction mixture was filtered and washed with acetone (100 mL). The filter cake was collected to obtaine 1.45 g (80.1%) of N-{[(2,4-dichloropyrimidin-5- yl)methyl](methyl)-λ⁴-sulfanylidene}-4-methylbenzene-1-su lfonamide as a green solid. LCMS: Rt=0.408 min, m/z=377.8 (M+H) ⁺ . [0742] Step 5. Preparation of [(2,4-dichloropyrimidin-5-yl)methyl](methyl)[(4- methylbenzenesulfonyl)imino]-λ⁶-sulfanone. To a solution of sodium periodate (542 mg, 2 eq, 2.54 mmol) in water (5 mL) at room temperature was added dichloromethane (0.1 L) followed by trichlororutheniumtris(ylium) (52.6 mg, 0.2 eq, 254 µmol). To the dark-brown mixture was added N-{[(2,4-dichloropyrimidin-5-yl)methyl](methyl) -λ⁴-sulfanylidene}-4- methylbenzene-1-sulfonamide (480 mg, 1 eq, 1.27 mmol). The reaction mixture was stirred at 25 °C for 3 hours. TLC (eluted with petroleum ether/ethyl acetate= 1/2, R _f =0.5) showed the starting material was consumed and the desired product was formed. The reaction mixture was extracted with dichloromethane (3 × 60 mL). The combined organic phase was filtered and washed with acetone (2 × 80 mL). The filtrate was concentrated under reduced pressure to obtain 320 mg (64%) of [(2, 4-dichloropyrimidin-5-yl)methyl](methyl)[(4- methylbenzenesulfonyl)imino]-λ⁶-sulfanone as a white solid. LCMS: Rt=0.539 min, m/z=393.9(M+H) ⁺ . [0743] Step 6. Preparation of [(2,4-dichloropyrimidin-5-yl)methyl](imino) methyl-λ⁶- sulfanone. To [(2,4-dichloropyrimidin-5-yl)methyl](methyl)[(4-methylbenzen esulfonyl) imino]-λ⁶-sulfanone (0.1 g, 1 eq, 254 µmol) was added sulfuric acid (1.5 mL), and the resulting mixture was stirred at 25 °C for 2 hours. LCMS showed the starting material was consumed and the desired product was detected. The reaction mixture was then poured into ice water. The solution was neutralized with NaHCO3. The aqueous layer was extracted with dichloromethane (3 × 30 mL), dried over MgSO ₄ , and filtered. The filtrate was concentrated under reduced pressure to give 30 mg (49.3) of [(2,4-dichloropyrimidin -5-yl)methyl](imino) methyl-λ⁶-sulfanone as a yellow solid. LCMS: Rt = 0.213 min, m/z = 240.0(M+H) ⁺ . [0744] Step 7. Preparation of (10R)-3-((2-chloro-5-((S-methylsulfonimidoyl)methyl) pyrimidin -4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5',6':4,5] thieno[3,2-f]quinoxalin-8-one. To a solution of (R)-3-hydroxy-10-methyl-9,10,11,12- tetrahydro-8H-[1,4]diazepino[5',6':4,5] thieno[3,2-f]quinoxalin-8-one (10 mg, 0.8 eq, 33.3 µmol) in dimethyl sulfoxide (1 mL) at room temperature was added dipotassium carbonate (11.5 mg, 2 eq, 83.2 µmol) and [(2,4-dichloropyrimidin-5- yl)methyl](imino)methyl-λ⁶- sulfanone (15 mg, 1.5 eq, 62.4 µmol). The reaction mixture was stirred at 40 °C for 2 hours. LCMS showed the starting material was consumed and the desired product was detected. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to afford 8.2 mg (38.7%) of (10R)-3-((2- chloro-5-((S-methylsulfonimidoyl)methyl)pyrimidin -4-yl)oxy)-10-methyl-9,10,11,12- tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinoxal in-8-one as a yellow solid. LCMS: Rt = 1.405 min, m/z = 503.9 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.06 (s, 1H), 8.83 (s, 1H), 8.79 (br s, 1H), 8.36 (d, J = 8.8 Hz, 1H), 8.00 (br d, J = 4.4 Hz, 1H), 7.97 (d, J = 8.9 Hz, 1H), 4.92 - 4.77 (m, 2H), 3.68 (br dd, J = 3.8, 6.9 Hz, 1H), 3.60 (br s, 2H), 3.24 (s, 3H), 1.22 (d, J = 6.6 Hz, 3H). EXAMPLE 68 – Synthesis of (15R)-5-({2-chloro-5-[(dimethylphosphoryl) methyl]pyrimidin -4-yl}oxy)-15-methyl-11-thia-3,6,14,17-tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)- hexaen-13-one (I-129) [0745] The title compound was prepared using the following procedures. [0746] Step 1. Preparation of 2,4-dichloro-5-[(dimethylphosphoryl)methyl]pyrimidine. To a solution of (methylphosphonoyl)methane (270 mg, 1 eq, 3.46 mmol) in tetrahydrofuran (40 mL) was added lithium(1 ⁺ ) bis(trimethylsilyl)azanide (869 mg, 1.5 eq., 5.19 mmol) and 2,4- dichloro-5-(iodomethyl)pyrimidine (1 g, 1 eq, 3.46 mmol) at 0 °C under N ₂ . The resulting mixture was stirred at 0 °C for 1 hour under N2. One additional vial was set up as described above. The reaction mixture was combined, diluted with ethyl acetate (50 mL), and extracted with water (3 × 50 mL). The aqueous phase was filtered, and the filtrate was lyophilizaed to give a residue. The residue was purified by prep-HPLC to give 2,4-dichloro-5- [(dimethylphosphoryl)methyl] pyrimidine (66 mg, 2 eq., 276 µmol) as a brown solid. LCMS (ESI+): Rt = 0.273 min, m/z 239.1 (M+H) ⁺ . [0747] Step 2. Preparation of (15R)-5-({2-chloro-5-[(dimethylphosphoryl)methyl] pyrimidin -4-yl}oxy)-15-methyl-11-thia-3,6,14,17-tetraazatetracyclo[8. 8.0.0²,⁷.0¹²,¹⁸] octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one. To a solution of 2,4-dichloro-5- [(dimethylphosphoryl) methyl]pyrimidine (50 mg, 2 eq, 209 µmol) in dimethyl sulfoxide (3.75 mL) was added (15R)-5-hydroxy-15-methyl-11-thia-3,6,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10), 2(7), 3,5,8,12(18)-hexaen-13-one (31.4 mg, 1 eq, 105 µmol) and dipotassium carbonate (28.9 mg, 2 eq., 209 µmol) at 25 °C. After heating to 60 °C, the resulting mixture was stirred at 60 °C for 1 hour. LCMS showed the starting material peak was consumed and the desired peak was detected. Two additional vials were set up as described above. The reaction mixtures were combined and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give 3.5 mg (2.22%) of to give (15R)-5-({2-chloro-5- [(dimethylphosphoryl)methyl]pyrimidin -4-yl}oxy)-15-methyl-11-thia-3,6,14,17-tetraaza- tetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5 ,8,12(18)-hexaen-13-one as an orange solid. LCMS (ESI+): Rt = 0.354 min, m/z 503.2 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 8.94 (br s, 1H), 8.78 (s, 1H), 8.65 (d, J = 2.1 Hz, 1H), 8.11 (d, J = 8.9 Hz, 1H), 7.90 (d, J = 8.9 Hz, 1H), 5.92 (br s, 1H), 3.90 - 3.73 (m, 2H), 3.63 (br dd, J = 3.3, 6.3 Hz, 1H), 3.36 (d, J = 13.5 Hz, 2H), 1.69 (d, J = 12.6 Hz, 6H), 1.41 (d, J = 6.8 Hz, 3H). EXAMPLE 69 – Synthesis of (R)-3-((2-chloro-5-methoxypyrimidin-4-yl)oxy)-10-methyl- 9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2 -f]quinoxalin-8-one (I-130) [0748] The title compound was prepared using the following procedures. [0749] To a solution of (R)-3-hydroxy-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazep ino [5',6':4,5]thieno[3,2-f]quinoxalin-8-one (22.4 mg, 0.5 eq, 74.5 µmol) in dimethyl sulfoxide (1 mL) at room temperature was added dipotassium carbonate (41.2 mg, 2 eq, 298 µmol) and 2,4- dichloro-5- methoxypyrimidine (40 mg, 1.5 eq, 223 µmol). The reaction mixture was heated to 60 °C and stirred at 60 °C for 1 hour. LCMS showed the starting material was consumed and the desired product was detected. One additional vial was set up as described above. Both reaction mixtures were combined and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to afford 28.1 mg (28.31%) of (R)-3-((2-chloro-5-methoxypyrimidin-4-yl)oxy)-10-methyl-9,10 ,11,12-tetrahydro-8H- [1,4]diazepino [5',6':4,5]thieno[3,2-f]quinoxalin-8-one as a yellow solid. LCMS: Rt=2.379 min, m/z=443.1 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.09 (s, 1H), 8.83 - 8.76 (m, 1H), 8.67 - 8.59 (m, 1H), 8.32 (d, J = 8.9 Hz, 1H), 7.99 (br d, J = 4.4 Hz, 1H), 7.91 (d, J = 8.9 Hz, 1H), 4.00 (s, 3H), 3.71 - 3.65 (m, 1H), 3.60 (br s, 2H), 1.21 (d, J = 6.7 Hz, 3H). EXAMPLE 70 – Synthesis of (R)-3-((2-chloro-5-methoxypyrimidin-4-yl)oxy)-10-methyl- 9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2 -f]quinoxalin-8-one (I-131) [0750] The title compound was prepared using the following procedures. [0751] Step 1. Preparation of 1-[(2,4-dichloropyrimidin-5-yl)methyl]-3-(trifluoromethyl) pyrrolidin-3-ol. To a solution of 3-(trifluoromethyl)pyrrolidin-3-ol (0.1 g, 1 eq, 523 µmol) in acetonitrile (1 mL) at 0 °C was added potassium tert-butoxide in tetrahydrofuran (0.785 mL, 1.5 eq, 1 M). After stirring at 0 °C for 10 minutes, 2,4-dichloro-5-(iodomethyl)pyrimidine (181 mg, 1.2 eq, 628 µmol) was added to the mixture. Then, the reaction mixture was stirred at 0 °C for 1 hour. TLC (eluted with petroleum ether/ethyl acetate=1/1, R _f = 0.6) showed the starting material was consumed and the desired spot was formed. Two additional vials were set up as described above. All three reaction mixtures were combined and filtered. The filtrate was purified directly with prep-TLC (eluted with petroleum ether/ethyl acetate=1/1) to obtain 50 mg (15.11%) of 1-[(2,4-dichloropyrimidin-5-yl)methyl]-3-(trifluoromethyl)py rrolidin-3-ol as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.65 (s, 1H), 3.80 (d, J = 3.2 Hz, 2H), 3.08 - 2.95 (m, 2H), 2.79 (br d, J = 10.3 Hz, 1H), 2.75 - 2.67 (m, 1H), 2.38 (ddd, J = 6.5, 7.7, 13.9 Hz, 1H), 2.28 (s, 1H), 1.97 (td, J = 6.5, 13.4 Hz, 1H). [0752] Step 2. Preparation of (R)-3-((2-chloro-5-methoxypyrimidin-4-yl)oxy)-10-methyl- 9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2 -f]quinoxalin-8-one. To a solution of (R)-3-((2-chloro-5-methoxypyrimidin-4-yl)oxy)-10-methyl-9,10 ,11,12- tetrahydro- 8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinoxalin-8-one (39.6 mg, 1 eq, 132 µmol) in dimethyl sulfoxide (1 mL) at room temperature was added dipotassium carbonate (36.4 mg, 2 eq, 264 µmol) and 1-[(2,4-dichloropyrimidin-5-yl)methyl]-3-(trifluoromethyl)py rrolidin-3-ol (50 mg, 1.2 eq., 158 µmol). Then, the reaction mixture was stirred at 45 °C for 2 hours. LCMS showed that starting material remained and the desired product was detected. The reaction mixture was filtered, and the filtrate was purified directly with prep-HPLC to obtain 10 mg (12.3%) of (R)-3-((2-chloro-5-methoxypyrimidin-4-yl)oxy)-10-methyl-9,10 ,11,12-tetrahydro- 8H-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinoxalin-8-one as a yellow solid. LCMS: Rt = 1.837, 1.892 min, m/z = 580.2 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.07 (s, 1H), 8.80 (br t, J = 3.8 Hz, 1H), 8.77 (s, 1H), 8.34 (d, J = 8.9 Hz, 1H), 8.00 (br d, J = 4.3 Hz, 1H), 7.95 (d, J = 8.9 Hz, 1H), 6.24 (s, 1H), 3.85 (br d, J = 2.6 Hz, 2H), 3.67 (td, J = 3.5, 6.6 Hz, 1H), 3.60 (br s, 2H), 2.97 (br d, J = 10.4 Hz, 1H), 2.92 - 2.84 (m, 1H), 2.77 - 2.69 (m, 2H), 2.18 - 2.06 (m, 1H), 1.88 (td, J = 6.4, 13.1 Hz, 1H), 1.31 - 1.14 (m, 3H). EXAMPLE 71 – Synthesis of 2-chloro-4-{[(15R)-15-methyl-13-oxo-11-thia-3,6,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10), 2(7),3,5,8,12(18)-hexaen-5- yl]oxy}pyrimidin-5-yl)methyl acetate (I-132) [0753] The title compound was prepared using the following procedures. [0754] Step 1. Preparation of (2,4-dichloropyrimidin-5-yl)methyl acetate. To a solution of 2,4-dichloro-5-(iodomethyl)pyrimidine (50 mg, 1 eq, 173 µmol) in acetone (2 mL) was added potassium acetate (17 mg, 1 eq, 173 µmol) at 20 °C. The reaction mixture was stirred at 20 °C for 1 hour. TLC (eluted with petroleum ether/ethyl acetate = 3/1, R _f = 0.6) showed starting material was consumed and the desired spot was formed. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 5 mL). The organic phase was washed with brine (3 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (eluted with petroleum ether/ethyl acetate=3/1, R _f = 0.6) to give 20 mg (45.6%) of (2,4-dichloropyrimidin-5-yl)methyl acetate as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) 8.55 (s, 1H), 5.11 (s, 2H), 2.09 (s, 3H). [0755] Step 2. Preparation of 2-chloro-4-{[(15R)-15-methyl-13-oxo-11-thia-3,6,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10), 2(7),3,5,8,12(18)-hexaen-5-yl]oxy} pyrimidin-5-yl)methyl acetate. To a solution of (2,4-dichloropyrimidin-5-yl)methyl acetate (20 mg, 1.5 eq, 90.5 µmol) in dimethyl sulfoxide (0.9 mL) was added (15R)-5-hydroxy-15- methyl-11-thia-3,6,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10), 2(7),3,5,8,12(18)- hexaen-13-one (18.1 mg, 1 eq, 60.3 µmol) and cesium carbonate (39.3 mg, 2 eq, 121 µmol) at 25 °C. The reaction mixture was heated to 60 °C and stirred at 60 °C for 1 hour. LCMS showed the starting material was consumed and the desired peak was detected. One additional vial was set up as described above. After cooling to 20 °C, both reaction mixtures were combined, diluted with water (10 mL), and extracted with ethyl acetate (3 × 5 mL). The organic phase was washed with brine (5 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give 1.5 mg (5.13%) of 2-chloro-4-{[(15R)-15- methyl-13-oxo-11-thia-3,6,14,17-tetraazatetracyclo[8.8.0.0² ,⁷.0¹²,¹⁸]octadeca- 1(10),2(7),3,5,8,12(18)-hexaen-5-yl]oxy}pyrimidin-5-yl)methy l acetate as a yellow solid. LCMS (ESI+): Rt = 1.688 min, m/z 485.0 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 8.96 - 8.90 (m, 1H), 8.76 (s, 1H), 8.65 (s, 1H), 8.13 - 8.07 (m, 1H), 7.90 (br d, J = 8.9 Hz, 1H), 5.88 (br s, 1H), 5.33 (s, 2H), 3.87 - 3.73 (m, 2H), 3.65 - 3.56 (m, 1H), 2.17 (s, 3H), 1.40 (br d, J = 6.6 Hz, 3H). EXAMPLE 72 – Synthesis of (R)-3-((2-chloro-5-((3,3- difluoropyrrolidin-1-yl)methyl) pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4] diazepino[5',6':4,5] thieno[3,2-f]quinoxalin-8-one (I-133) [0756] The title compound was prepared using the following procedures. [0757] Step 1. Preparation of 2,4-dichloro-5-[(3,3-difluoropyrrolidin-1-yl)methyl] pyrimidine. To a solution of 3,3-difluoropyrrolidine hydrochloride (70 mg, 1 eq, 488 µmol) in acetonitrile (2.5 mL) at 0 °C was added dipotassium carbonate (80.9 mg, 1.2 eq, 585 µmol) and 2,4-dichloro-5-(iodomethyl)pyrimidine (141 mg, 1 eq, 488 µmol). The reaction mixture was stirred at 0 °C for 1 hour. TLC (eluted with petroleum ether/ethyl acetate =2/1, R _f = 0.6) showed the starting material was consumed and the desired product was formed. One additional vial was set up as described above. Both reaction mixtures were combined and filtered. The filtrate was purified by prep-TLC (PE/EA =3/1, R _f = 0.5) to afford 45 mg (14.63%) of 2,4-dichloro-5-[(3,3-difluoropyrrolidin-1-yl)methyl]pyrimidi ne as a colorless oil. LCMS: Rt = 0.438 min, m/z = 268.0 (M+H) ⁺ . [0758] Step 2. Preparation of (R)-3-((2-chloro-5-((3,3- difluoropyrrolidin-1-yl)methyl) pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4] diazepino[5',6':4,5] thieno[3,2-f]quinoxalin-8-one. To a solution of 2,4-dichloro-5-[(3,3-difluoropyrrolidin-1- yl)methyl]pyrimidine (45 mg, 1 eq, 143 µmol) in dimethyl sulfoxide (7.65 mL) at room temperature was added dipotassium carbonate (39.4 mg, 2 eq, 285 µmol) and (R)-3-hydroxy- 10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5', 6':4,5]thieno[3,2-f]quinoxalin-8-one (34.3 mg, 0.8 eq., 114 µmol). The reaction mixture was heated to 70 °C and stirred at 70 °C for 1 hour. LCMS analysis showed the starting material was consumed and the desired product was formed. The reaction mixture was filtered, and the filtrate was purified by prep-HPLC to afford 40 mg (48.5%) (R)-3-((2-chloro-5-((3,3- difluoropyrrolidin-1-yl)methyl)pyrimidin-4- yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5' ,6':4,5]thieno[3,2-f]quinoxalin-8- one as an orange solid. LCMS: Rt = 1.866 min, m/z = 532.2 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.08 (s, 1H), 8.82 - 8.78 (m, 1H), 8.77 (s, 1H), 8.34 (d, J = 9.0 Hz, 1H), 8.00 (br d, J = 4.1 Hz, 1H), 7.95 (d, J = 8.9 Hz, 1H), 3.86 (s, 2H), 3.72 - 3.63 (m, 1H), 3.60 (br s, 2H), 3.10 - 2.99 (m, 2H), 2.85 (t, J = 6.9 Hz, 2H), 2.35 - 2.19 (m, 2H), 1.25 - 1.19 (m, 3H). EXAMPLE 73 – Synthesis of (15R)-5-{[2-chloro-5-(trifluoromethyl)pyrimidin-4- yl]oxy}- 15-methyl-11-thia-3,6,14,17-tetraazatetracyclo[8.8.0.0²,⁷ .0¹²,¹⁸]octadeca-1(10),2(7), 3,5,8,12(18)-hexaen-13-one (I-134) [0759] The title compound was prepared using the following procedures. [0760] To a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (36.1 mg, 1 eq, 166 µmol) in dimethyl sulfoxide (3 mL) was added (15R)-5-hydroxy-15-methyl-11-thia-3,6,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10), 2(7),3,5,8,12(18)-hexaen-13-one (15 mg, 0.3 eq, 49.9 µmol) and cesium carbonate (32.5 mg, 0.6 eq, 99.9 µmol) at 25 °C. Then, the reaction mixture was stirred at 25 °C for 0.5 hour. LCMS showed the starting material was consumed and the desired peak was detected. The mixture was filtered to give a residue. The residue was purified by prep-HPLC to afford 12 mg (15.04%) of (15R)-5-{[2-chloro-5-(trifluoromethyl) pyrimidin-4- yl]oxy}-15-methyl-11-thia-3,6,14,17-tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca- 1(10),2(7),3,5,8,12(18)-hexaen-13-one as a yellow solid. LCMS (ESI+): Rt = 1.963 min, m/z 481.0 (M+H) ⁺ . EXAMPLE 74 – Synthesis of 1-(2-chloro-4-{[(15R)-15-methyl-13-oxo-11-thia-3,6,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10), 2(7),3,5,8,12(18)-hexaen-5-yl]oxy} pyrimidin-5-yl)ethyl acetate (I-135) [0761] The title compound was prepared using the following procedures. [0762] Step 1. Preparation of 1-(2,4-dichloropyrimidin-5-yl)ethyl acetate. To a solution of 1-(2,4-dichloropyrimidin-5-yl)ethan-1-ol (280 mg, 1 eq, 1.45 mmol) in tetrahydrofuran (15 mL) was added triethylamine (294 mg, 2 eq, 2.9 mmol) and acetyl chloride (1.71 g, 15 eq, 21.8 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 4 hours. LCMS showed the starting material peak was consumed and the desired peak was detected. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 15 mL). The organic phase was washed with brine (10 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (eluted with petroleum ether/ethyl acetate = 3/1, R _f = 0.5) to give 190 mg (47.92%) of 1-(2,4-dichloropyrimidin-5-yl)ethyl acetate as a light-yellow oil. LCMS (ESI+): Rt = 1.537 min, m/z 235.3 (M+H) ⁺ . [0763] Step 2. Preparation of 1-(2-chloro-4-{[(15R)-15-methyl-13-oxo-11-thia-3,6,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10), 2(7),3,5,8,12(18)-hexaen-5-yl]oxy} pyrimidin-5-yl)ethyl acetate. To a solution of 1-(2,4-dichloropyrimidin-5-yl)ethyl acetate (91 mg, 2 eq, 333 µmol) in dimethyl sulfoxide (3 mL) was added (15R)-5-hydroxy-15-methyl-11- thia-3,6,14,17-tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸] octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13- one (50 mg, 1 eq, 166 µmol) and cesium carbonate (108 mg, 2 eq, 333 µmol) at 20 °.C The mixture was heated to 60 °C and stirred at 60 °C for 4 hours. LCMS showed the starting material peak was consumed and the desired peak was detected. After cooling to room temperature, the reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic phase was washed with brine (5 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give 12 mg (14.39%) of 1-(2-chloro-4- {[(15R)-15-methyl-13-oxo-11-thia-3,6,14,17-tetraazatetracycl o[8.8.0.0²,⁷.0¹²,¹⁸]octadeca- 1(10),2(7),3,5,8,12(18)-hexaen-5-yl]oxy}pyrimidin-5-yl)ethyl acetate as an orange solid. LCMS (ESI+): Rt = 0.485 min, m/z 499.2 (M+H) ⁺ . ¹ H NMR (400 MHz, CHLOROFORM-d) 1.41 (d, J=6.75 Hz, 3 H) 1.58 (s, 2 H) 1.73 (d, J=6.63 Hz, 3 H) 2.16 (s, 3 H) 3.57 - 3.65 (m, 1 H) 3.75 - 3.89 (m, 2 H) 6.00 (br s, 1 H) 6.26 (q, J=6.59 Hz, 1 H) 7.91 (d, J=8.88 Hz, 1 H) 8.10 (d, J=9.01 Hz, 1 H) 8.65 (s, 1 H) 8.75 (s, 1 H) 8.95 (br s, 1 H). EXAMPLE 75 – Synthesis of 3'-((2-chloro-5-((4-methyl-2-oxopyrrolidin-1-yl)methyl) pyrimidin-4-yl)oxy)-11',12'-dihydrospiro[cyclopropane-1,10'- [1,4]diazepino [5',6':4,5] thieno[3,2-f]quinoxalin]-8'(9'H)-one (I-157) [0764] The title compound was prepared using the following procedures. [0765] To a solution of 3’-hydroxy-11’,12’-dihydrospiro[cyclopropane-1,10’-[ 1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin]-8’(9’H)-one (40 mg, 1 eq, 128 µmol) in dimethyl sulfoxide (0.5 mL) was added cesium carbonate (83.4 mg, 2 eq, 256 µmol) and 1-((2,4- dichloropyrimidin-5-yl)methyl)-4-methylpyrrolidin-2-one (33.3 mg, 1 eq, 128 µmol) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hours. LCMS showed the starting material peak was consumed and the desired peak was detected. The mixture was filtered, and the filtrate was purified by prep-HPLC to afford 17.4 mg (25.35%) of 3'-((2-chloro-5-((4-methyl-2- oxopyrrolidin-1-yl)methyl)pyrimidin-4-yl)oxy)-11',12'-dihydr ospiro[cyclopropane-1,10'- [1,4]diazepino[5',6':4,5]thieno[3,2-f]quinoxalin]-8'(9'H)-on e as an orange solid. LCMS (ESI+): Rt = 1.715 min, m/z 536.2 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.07 (s, 1H), 8.95 - 8.83 (m, 1H), 8.67 (s, 1H), 8.36 (d, J = 8.9 Hz, 1H), 8.25 (s, 1H), 7.95 (d, J = 8.9 Hz, 1H), 4.56 (s, 2H), 3.59 (br d, J = 3.1 Hz, 2H), 3.56 (br d, J = 1.3 Hz, 1H), 3.02 (dd, J = 5.8, 9.1 Hz, 1H), 2.45 - 2.38 (m, 2H), 1.98 - 1.85 (m, 1H), 1.05 (d, J = 6.1 Hz, 3H), 0.96 (br s, 2H), 0.87 (br s, 2H).

EXAMPLE 76 – Synthesis of 4-((2-chloro-4-((8'-oxo-8',9',11',12'-tetrahydrospiro [cyclopropane-1,10'-[1,4]diazepino[5',6':4,5]thieno[3,2-f]qu inoxalin]-3'-yl)oxy)pyrimidin- 5-yl)methyl)morpholin-3-one (I-158) [0766] The title compound was prepared using the following procedures. [0767] Step 1. Preparation of tert-butyl (1-(hydroxymethyl)cyclopropyl)carbamate. To a mixture of (1-aminocyclopropyl) methanol hydrochloride (1 g, 1 eq, 8.09 mmol) in dichloromethane (10 mL) was added triethylamine (2.05 g, 2.5 eq, 20.2 mmol), N,N- dimethylpyridin-4-amine (98.9 mg, 0.1 eq, 809 µmol), and di-tert-butyl dicarbonate (2.12 g, 1.2 eq, 9.71 mmol) at 20 °C. The mixture was stirred at 20 °C for 3 hours. TLC (petroleum ether/ethyl acetate =1/1, R _f = 0.5) showed the starting material spot was consumed and a new spot was formed. Seven additional vials were set up as described above. All eight reaction mixtures were poured into water (100 mL) and extracted with ethyl acetate (3 × 50 mL). The organic phase was washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate =1/1, R _f = 0.5) to afford 4.14 g (34.16%) of tert- butyl (1-(hydroxymethyl)cyclopropyl)carbamate as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) 7.03 (s, 1H), 4.55 (t, J = 5.6 Hz, 1H), 3.36 (d, J = 6.0 Hz, 2H), 1.35 (s, 9H), 0.62-0.59 (m, 2H), 0.52-0.49 (m, 2H). [0768] Step 2. Preparation of tert-butyl (1-((1,3-dioxoisoindolin-2-yl)methyl)cyclopropyl) carbamate. To a solution of tert-butyl (1-(hydroxymethyl)cyclopropyl)carbamate (4 g, 1 eq, 21.4 mmol) in tetrahydrofuran (40 mL) was added 1,3-isoindolinedione (3.14 g, 1 eq, 21.4 mmol), (E)-ethoxycarbonylazoethylformylate (7.44 g, 2 eq, 42.7 mmol), and triphenylphosphine (11.2 g, 2 eq, 42.7 mmol) at 25 °.C The resulting mixture was stirred at 25 °C for 12 hours. LCMS showed the starting material peak was consumed and the desired peak was detected. To the mixture was added ethyl acetate (40 mL), and the mixture was filtered. The filter cake was washed with ethyl acetate (30 mL) and dried under reduced pressure to afford 3 g (44.39%) of tert-butyl (1-((1,3-dioxoisoindolin-2-yl)methyl)cyclopropyl)carbamate as a white solid. LCMS (ESI+): Rt = 0.483 min, m/z 217.0 (M-100) ⁺ . [0769] Step 3. Preparation of tert-butyl (1-(aminomethyl)cyclopropyl)carbamate. To a solution of tert-butyl (1-((1,3-dioxoisoindolin-2-yl)methyl)cyclopropyl)carbamate (3 g, 1 eq, 9.48 mmol) in methanol (30 mL) was added hydrazine hydrate (15 mL, 80%) at 20 °C. The resulting mixture was stirred at 75 °C for 2 hours. LCMS showed the starting material peak was consumed and the desired peak was detected. After cooling to 25 °C, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (eluted with dichloromethane/methanol = 100/1 to 15/1) to afford 1 g (56.62%) of tert-butyl (1- (aminomethyl)cyclopropyl)carbamate as a white solid. LCMS (ESI+): Rt = 0.747 min, m/z 187.4 (M+H) ⁺ . [0770] Step 4. Preparation of methyl 9-(((1-((tert-butoxycarbonyl)amino)cyclopropyl) methyl)amino)-3-methoxythieno[3,2 -f]quinoxaline-8-carboxylate. To a solution of tert- butyl (1-(aminomethyl)cyclopropyl)carbamate (0.1 g, 1 eq, 537 µmol) in 1,4-dioxane (1.5 mL) was added methyl 9-bromo-3-methoxythieno[3,2-f]quinoxaline -8-carboxylate (379 mg, 1 eq, 1.07 mmol), cesium carbonate (350 mg, 2 eq, 1.07 mmol), and 2-biphenylid-2'-amine-2,2'- bis(diphenylphosphino)-1,1'-binaphthyl-methanesulfonicacid-p alladium (53.3 mg, 0.1 eq, 53.7 µmol) at 20 °C under a N ₂ atmosphere. The resulting mixture was heated to 90 °C and stirred at 90 °C for 2 hours. LCMS showed the starting material peak was consumed and the desired peak was detected. Four additional vials were set up as described above. All five reaction mixtures were poured into water (20 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phase was washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 100/1 to 3/1, R _f = 0.5) to afford 400 mg (32.5%) of methyl 9-(((1-((tert-butoxycarbonyl)amino)cyclopropyl)methyl)amino) -3- methoxythieno[3,2 -f]quinoxaline-8-carboxylate as a yellow solid. LCMS (ESI+): Rt = 0.634 min, m/z 459.1 (M+H) ⁺ . [0771] Step 5. Preparation of methyl 9-(((1-aminocyclopropyl)methyl)amino)-3- methoxythieno[3,2-f]quinoxaline-8-carboxylate. To a suspension of methyl 9-(((1-((tert- butoxycarbonyl)amino)cyclopropyl)methyl)amino)-3-methoxythie no[3,2-f]quinoxaline-8- carboxylate (0.1 g, 1 eq, 218 µmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.1 mL) at 20 °C. The reaction mixture was stirred at 20 °C for 1 hour. LCMS showed the starting material peak was consumed and the desired peak was detected. The mixture was concentrated under reduced pressure to give 0.1 g of crude methyl 9-(((1-aminocyclopropyl) methyl)amino)-3-methoxythieno[3,2-f]quinoxaline-8-carboxylat e as a red-brown oil. LCMS (ESI+): Rt = 0.390 min, m/z 359.0 (M+H) ⁺ . [0772] Step 6. Preparation of 3'-methoxy-11',12'-dihydrospiro[cyclopropane-1,10'- [1,4]diazepino[5',6':4,5]thieno[3,2-f]quinoxalin]-8'(9'H)-on e. Methyl 9-(((1-amino- cyclopropyl) methyl) amino)-3-methoxythieno [3, 2-f] quinoxaline-8-carboxylate (120 mg, 1 eq, 335 µmol) was suspended in a methanol solution of sodium methoxide (2 mL, 30%) at 20 °C. The resulting mixture was heated to 80 °C and stirred at 80 °C for 3 hours. LCMS showed the starting material peak was consumed, and the desired peak was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with water (5 mL) at 20 °C. The mixture was filtered, and the filter cake was dried under reduced pressure to afford 0.1 g of crude 3'-methoxy-11',12'-dihydrospiro[cyclopropane-1,10'- [1,4]diazepino[5',6':4,5]thieno[3,2-f]quinoxalin]-8'(9'H)-on e as a yellow solid. LCMS (ESI+): Rt = 0.452 min, m/z 326.9 (M+H) ⁺ . [0773] Step 7. Preparation of 3'-hydroxy-11',12'-dihydrospiro [cyclopropane-1,10'- [1,4]diazepino[5',6':4,5]thieno[3,2-f]quinoxalin]-8'(9'H)-on e. A solution of 3'-methoxy- 11',12'-dihydrospiro[cyclopropane-1,10'-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinoxalin]- 8'(9'H)-one (0.1 g, 1 eq, 306 µmol) in an acetic acid solution of hydrogen bromide (2 mL, 33%) at 20 °C was prepared. The reaction mixture was heated to 60 °C and stirred at 60 °C for 2 hours. LCMS showed the starting material peak was consumed, and the desired peak was detected. The mixture was filtered, and the filter cake was washed with dichloromethane (20 mL) to afford 88 mg (91.95%) of 3’-hydroxy-11’,12’-dihydrospiro [cyclopropane-1,10’- [1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin]-8’(9 ’H)-one as a brick-red solid. LCMS (ESI+): Rt = 0.303 min, m/z 313.1 (M+H) ⁺ . [0774] Step 8. Preparation of 4-((2-chloro-4-((8'-oxo-8',9',11',12'-tetrahydrospiro [cyclopropane-1,10'-[1,4]diazepino[5',6':4,5]thieno[3,2-f]qu inoxalin]-3'-yl)oxy)pyrimidin- 5-yl)methyl)morpholin-3-one. To a solution of 3'-hydroxy-11',12'-dihydrospiro[cyclopropane- 1,10'-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinoxalin]-8'(9'H)-one (40 mg, 1 eq, 128 µmol) in dimethyl sulfoxide (0.5 mL) was added cesium carbonate (83.4 mg, 2 eq, 256 µmol) and 4- ((2,4-dichloropyrimidin-5-yl)methyl)morpholin-3-one (33.6 mg, 1 eq, 128 µmol) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hours. LCMS showed the starting material peak was consumed and the desired peak was detected. The mixture was filtered, and the filtrate was purified by prep-HPLC to afford 36.9 mg (53.56%) of 4-((2-chloro-4-((8'-oxo-8',9',11',12'- tetrahydrospiro[cyclopropane-1,10'-[1,4]diazepino[5',6':4,5] thieno[3,2-f]quinoxalin]-3'- yl)oxy)pyrimidin-5-yl)methyl)morpholin-3-one as an orange solid. LCMS (ESI+): Rt = 1.593 min, m/z 538.2 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.09 (s, 1H), 8.90 (br s, 1H), 8.68 (s, 1H), 8.36 (d, J = 8.9 Hz, 1H), 8.26 (s, 1H), 7.97 (d, J = 9.0 Hz, 1H), 4.72 (s, 2H), 4.10 (s, 2H), 3.89 (br t, J = 4.8 Hz, 2H), 3.59 (br d, J = 2.1 Hz, 2H), 3.53 (br t, J = 4.9 Hz, 2H), 0.96 (br s, 2H), 0.87 (br s, 2H). EXAMPLE 77 – Synthesis of 3’-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-1- methyl-11’,12’- dihydrospiro[pyrrolidine-3,10’-[1,4]diazepino[5’,6’:4, 5]thieno[3,2- f]quinoxalin]-8’(9’H)-one (I-159)

[0775] The title compound was prepared using the following procedures. [0776] Step 1. Preparation of tert-butyl 3-amino-3-(nitromethyl) pyrrolidine-1- carboxylate. To a stirred solution of nitromethane (435 µL, 1.5 eq, 8.1 mmol) in a mixture of ammonia in methanol (8N, 10 mL) at 25 °C was added tert-butyl 3-oxopyrrolidine-1- carboxylate (1 g, 1 eq, 5.4 mmol). The reaction mixture was stirred at 25 °C for 18 hours. LCMS showed the starting material was consumed and the desired product was detected. Four additional vials were set up as described above. All five reaction mixtures were combined and concentrated under reduced pressure to afford 5.8 g (61.3%) of tert-butyl 3-amino-3- (nitromethyl) pyrrolidine-1-carboxylate as brown oil, which was used directly in the next step without purification. LCMS: Rt = 0.366 min, m/z = 244.1 (M-H) ⁺ . [0777] Step 2. Preparation of tert-butyl 3-{[(benzyloxy)carbonyl] amino}-3- (nitromethyl)pyrrolidine-1-carboxylate. To a stirred solution of tert-butyl 3-amino-3- (nitromethyl)pyrrolidine-1-carboxylate (5.8 g, 1 eq, 16.6 mmol) in dichloromethane (30 mL) at room temperature was added a solution of dipotassium carbonate (4.58 g, 2 eq, 33.1 mmol) in water (30 mL). The reaction mixture was cooled to 0 °C, and benzyl carbonochloridate (2.56 mL, 1.1 eq, 18.2 mmol) was added dropwise. The reaction mixture was stirred at 25 °C for 17 hours. LCMS showed the starting material was consumed and the desired product was detected. The reaction mixture were separated, and the aqueous phase was extracted with dichloromethane (50 mL × 3). The organic layers were combined and washed with brine (30 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was purified via silica gel chromatography eluting with 16-30% ethyl acetate in petroleum ether. Pure fractions were combined and concentrated to afford 3 g (47.8%) of tert-butyl 3-{[(benzyloxy)carbonyl] amino}-3-(nitromethyl)pyrrolidine- 1-carboxylate as a colorless oil. LCMS: Rt = 0.511 min, m/z = 378.2 (M-H) ⁺ . [0778] Step 3. Preparation of tert-butyl 3-(aminomethyl)- 3-(((benzyloxy) carbonyl) amino)pyrrolidine-1-carboxylate. To a stirred solution of tert-butyl 3-(((benzyloxy) carbonyl)amino)-3-(nitromethyl) pyrrolidine-1-carboxylate (2.3 g, 1 eq, 6.06 mmol) in methanol (25 mL) at 0 °C was added nickel(2+) hexahydrate dichloride (1.44 g, 1 eq, 6.06 mmol) followed by sodium borohydride (1.15 g, 5 eq, 30.3 mmol) portion-wise to avoid strong H ₂ evolution. The reaction mixture was stirred at 25 °C for 2 hours. LCMS showed the starting material was consumed and the desired product was detected. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (20 mL). The mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was diluted with water (50 mL) and extracted with dichloromethane (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude residue was purified via silica gel chromatography eluting with 16-20% methane in dichloromethane. Pure fractions were combined and concentrated to afford 1.1 g (51.9%) of tert-butyl 3-(aminomethyl)- 3-(((benzyloxy) carbonyl) amino)pyrrolidine-1-carboxylate as a colorless oil. LCMS: Rt = 2.607 min, m/z = 350.1 (M+H)+. [0779] Step 4. Preparation of methyl 9-(((3-(((benzyloxy) carbonyl)amino)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl)methyl)amino)-3-methoxythieno [3,2-f]quinoxaline-8- carboxylate. To a solution of tert-butyl 3-(aminomethyl)-3-(benzyloxycarbonylamino)-1- pyrrolidine carboxylate(130 mg, 1 eq, 372 µmol) in 1,4-dioxane (4 mL) at room temperature was added methyl 3-bromo-11-methoxy-5-thia-10,13-diazatricyclo[7.4.0.0²,⁶] trideca- 1(13),2(6), 3,7,9,11-hexaene-4-carboxylate (131 mg, 1 eq, 372 µmol), dicaesium(1+) carbonate (242 mg, 2 eq, 744 µmol), and rac-BINAP-Pd-G3 (73.8 mg, 0.2 eq, 74.4 µmol) under N ₂ . The reaction mixture was heated to 90 °C and stirred at 90 °C for 12 hours under N ₂ . LCMS showed the starting material was consumed and the desired product was detected. Four additional vials were set up as described above. All five reaction mixtures were combined and filtered through a Celite pad, and the filtrate was concentrated to give the crude product, which was purified via silica gel chromatography eluting with 10-30% ethyl acetate in petroleum ether. Pure fractions were combined and concentrated to afford 400 mg (34.6%) of methyl 9- (((3-(((benzyloxy) carbonyl)amino)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methy l)amino)-3- methoxythieno[3,2-f]quinoxaline-8-carboxylate as a yellow solid. LCMS: Rt =1.058 min, m/z = 622.4 (M+H)+. [0780] Step 5. Preparation of methyl 9-(((3-amino-1 -(tert-butoxycarbonyl) pyrrolidin-3- yl)methyl)amino)-3-methoxythieno[3,2-f]quinoxaline-8-carboxy late. To a solution of methyl 9-(((3-(((benzyloxy)carbonyl)amino)-1-(tert-butoxycarbonyl) pyrrolidin-3- yl)methyl)amino)-3-methoxythieno[3,2-f]quinoxaline-8-carboxy late (54 mg, 1 eq, 86.9 µmol) in propan-2-ol (2 mL) at room temperature was added ammonium formate (54.8 mg, 10 eq, 869 µmol) and Pd (10% in active carbon, 171 mg, 161 µmol). The reaction mixture was heated to 80 °C and stirred at 80 °C for 4 hours. TLC (eluted with petroleum ether/ ethyl acetate = 1/1, R _f = 0.3) showed the desired product was detected. Nine additional reaction mixtures were set up as described above. All ten reaction mixtures were combined, and the suspension was filtered through a Celite pad. The filter cake was washed with methane (15 mL × 2). The filtrate was concentrated under reduced pressure to give 450 mg (74.3%) of methyl 9-(((3- amino-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methyl)amino)-3 -methoxythieno[3,2- f]quinoxaline-8-carboxylate as a yellow solid. [0781] Step 6. Preparation of tert-butyl 3'-methoxy-8'-oxo-8',9',11',12' -tetrahydro- spiro[pyrrolidine-3,10'-[1,4]diazepino[5',6':4,5]thieno[3,2- f]quinoxaline]-1-carboxylate. To a solution of methyl 9-(((3-amino-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methyl)a mino) -3- methoxythieno[3,2-f]quinoxaline-8-carboxylate (90 mg, 1 eq, 129 µmol) in methanol (1 mL) at room temperature was added sodium methoxide (14 mg, 2 eq, 258 µmol). The reaction mixture was heated to 80 °C and stirred at 80 °C for 2 hours. LCMS showed the starting material was consumed and the desired product was detected. Four additional reaction vials were set up as described above. All five reaction mixtures were combined, and the precipitate was filtered and dried under high vacuum to give 0.2 g (67.9%) of tert-butyl 3'-methoxy-8'-oxo-8',9',11',12' - tetrahydrospiro[pyrrolidine-3,10'-[1,4]diazepino[5',6':4,5]t hieno[3,2-f]quinoxaline]-1- carboxylate as a yellow solid. LCMS: Rt = 0.506 min, m/z = 456.2 (M+H) ⁺ . [0782] Step 7. Preparation of 3'-methoxy-11',12'-dihydrospiro[pyrrolidine-3,10'- [1,4]diazepino[5',6':4,5]thieno[3,2-f]quinoxalin]-8'(9'H)-on e. To a solution of tert-butyl 3'- methoxy-8'-oxo-8',9',11',12'-tetrahydrospiro[pyrrolidine-3,1 0'-[1,4]diazepino[5',6':4,5] thieno[3,2-f]quinoxaline]-1-carboxylate (475 mg, 1 eq, 2.36 mmol) was added a mixture of trifluoroacetic acid (30 µL) in dichloromethane (150 µL) at room temperature. The reaction mixture was stirred at 20 °C for 2 hours. LCMS showed the starting material was consumed and the desired product was detected. The reaction mixture was concentrated under reduced pressure to afford 150 mg (89%) of 3'-methoxy-11',12'-dihydrospiro[pyrrolidine -3,10'- [1,4]diazepino[5',6':4,5]thieno[3,2-f]quinoxalin]-8'(9'H)-on e as a yellow solid, which was used directly in the next step without purification. LCMS: Rt = 0.376 min, m/z = 356.1 (M+H) ⁺ . [0783] Step 8. Preparation of 3'-methoxy-1-methyl-11',12'-dihydrospiro[pyrrolidine- 3,10'-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinoxalin]-8'(9 'H)-one. To a solution of 3'- methoxy-11',12'-dihydrospiro[pyrrolidine-3,10'-[1,4]diazepin o[5',6':4,5]thieno[3,2-f] quinoxalin]-8'(9'H)-one (150 mg, 1 eq, 422 µmol) in methanol (2 mL) at room temperature was added formaldehyde (19 mg, 1.5 eq, 633 µmol) and acetic acid (1.27 mg, 0.05 eq, 21.1 µmol). The reaction mixture was stirred at 25 °C for 30 minutes. Next, sodium boranidcarbonitrile (50.5 mg, 2 eq, 844 µmol) was added to the reaction mixture. The reaction mixture was stirred at 25 °C for 1 hour. LCMS showed the starting material was consumed and the desired product was detected. The reaction mixture was filtered, and the filter cake was washed with methanol (5 mL) and dried under high vacuum to give 0.1 g (64.1%) of 3'-methoxy-1-methyl-11',12'- dihydrospiro[pyrrolidine-3,10'-[1,4]diazepino[5',6':4,5]thie no[3,2-f]quinoxalin]-8'(9'H)-one as a yellow solid, which was used directly in the next step without purificaiton. LCMS: Rt = 0.423 min, m/z = 370.2 (M+H) ⁺ . [0784] Step 9. Preparation of 3'-hydroxy-1-methyl-11',12'-dihydrospiro[pyrrolidine-3,10'- [1,4]diazepino[5',6':4,5]thieno[3,2-f]quinoxalin]-8'(9'H)-on e. A solution of 3'-methoxy-1- methyl-11',12'-dihydrospiro[pyrrolidine-3,10'-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinoxalin]- 8'(9'H)-one (0.1 g, 1 eq, 271 µmol) in hydrogen bromide (33% in acetic acid, 1 mL) was heated to 90 °C for 1 hour. LCMS showed the starting material was consumed and the desired product was detected. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with dichloromethane(5 mL) and dried under high vacuum to give 0.1 g (83.1%) of 3'-hydroxy-1-methyl-11',12'-dihydrospiro[pyrrolidine-3,10'-[ 1,4]diazepino[5',6':4,5] thieno[3,2-f]quinoxalin]-8'(9'H)-one as a red solid, which was used directly in the next step without purificaiton. LCMS: Rt = 0.350 min, m/z = 356.1 (M+H) ⁺ . Step 10. Preparation of 3'-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-1-methyl- 11',12'-dihydrospiro[pyrrolidine-3,10'-[1,4]diazepino[5',6': 4,5]thieno[3,2-f]quinoxalin]- 8'(9'H)-one. To a solution of 3'-hydroxy-1-methyl-11',12'-dihydrospiro[pyrrolidine-3,10'- [1,4]diazepino [5',6':4,5]thieno[3,2-f]quinoxalin]-8'(9'H)-one (80 mg, 1 eq, 180 µmol) in dimethyl sulfoxide (1 mL) at room temperature was added 2,4-dichloro-5- (ethoxymethyl)pyrimidine (41 mg, 1.1 eq, 198 µmol) and dipotassium carbonate (49.8 mg, 2 eq, 360 µmol). The reaction mixture was heated to 40 °C and stirred at 40 °C for 1 hour. LCMS showed the starting material was consumed and the desired product was detected. The reaction mixture was purified by prep-HPLC directly to give 2 mg (2.11%) of 3'-((2-chloro-5- (ethoxymethyl)pyrimidin-4-yl)oxy)-1-methyl-11',12'- dihydrospiro[pyrrolidine-3,10'- [1,4]diazepino[5',6':4,5]thieno[3,2-f]quinoxalin]-8'(9'H)-on e tas a yellow solid. LCMS: Rt = 1.844 min & 1.872 min, m/z = 526.3 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.11 (s, 1H), 9.01 - 8.94 (m, 1H), 8.78 (s, 1H), 8.36 (d, J = 9.0 Hz, 1H), 8.15 (s, 1H), 7.98 (d, J = 9.0 Hz, 1H), 4.70 (s, 2H), 3.64 (br d, J = 7.0 Hz, 4H), 2.67 - 2.54 (m, 3H), 2.47 (br s, 1H), 2.25 (s, 3H), 2.02 - 1.89 (m, 2H), 1.21 (t, J = 7.0 Hz, 3H). EXAMPLE 78 – Synthesis of 3'-((2-chloro-5-(ethoxymethyl) pyrimidin-4-yl) oxy)-1- methyl-11',12'-dihydrospiro[piperidine- 4,10'-[1,4]diazepino[5',6':4,5] thieno[3,2- f]quinoxalin]-8'(9'H)-one (I-162)

[0785] Step 1. Preparation of tert-butyl 4-amino-4-(nitromethyl)piperidine-1-carboxylate. To a stirred solution of nitromethane (1.75 mL, 1.3 eq, 32.6 mmol) in a mixture of ammonia in methanol (8N, 50 mL) at room temperature was added tert-butyl 4-oxopiperidine-1-carboxylate (5 g, 1 eq, 25.1 mmol). The reaction mixture was stirred at 25 °C for 17 hours. LCMS showed the starting material was consumed and the desired product was detected. The reaction mixture was concentrated under reduced pressure. The mixture was quenched with water (100 mL) and extracted with dichloromethane (100 mL × 3). The organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 5 g (76.8%) of tert-butyl 4-amino-4-(nitromethyl)piperidine-1- carboxylate, which was used directly in the next step without purification. LCMS: Rt= 0.392 min, m/z = 245.1 (M-t-Bu+MeCN) ⁺ . [0786] Step 2. Preparation of tert-butyl 4-(((benzyloxy)carbonyl)amino)-4-(nitromethyl) piperidine -1- carboxylate. To a stirred solution of tert-butyl 4-amino-4-(nitromethyl) piperidine-1-carboxylate (5 g, 1 eq, 19.3 mmol) in dichloromethane (25 mL) was added a solution of dipotassium carbonate (5.33 g, 2 eq, 38.6 mmol) in water (25 mL). The reaction mixture was cooled to 0 °C and benzyl carbonochloridate (2.99 mL, 1.1 eq, 21.2 mmol) was added. The reaction mixture was stirred at 25 °C for 17 hours. LCMS showed the starting material was consumed completely and the desired product was detected. The reaction mixture was diluted with water (80 mL) and extracted with dichloromethane (50 mL × 3). The organic layers were combined, washed with brine (50 mL), dried over Na ₂ SO ₄ , and filtered. The filtrate was concentrated under reduced pressure to give 8.8 g (56.8%) of tert-butyl 4- (((benzyloxy) carbonyl)amino)-4-(nitromethyl)piperidine -1- carboxylate, which was used directly in the next step without purification. LCMS: Rt= 0.531 min, m/z = 294.2 (M-Boc+H) ⁺ . [0787] Step 3. Preparation of tert-butyl 4-(aminomethyl)-4-(((benzyloxy)carbonyl)amino) piperidine-1-carboxylate. To a solution of tert-butyl 4-(((benzyloxy)carbonyl)amino)-4- (nitromethyl)piperidine-1- carboxylate (8.8 g, 1 eq, 11 mmol) in methanol (43.9 mL) at 0 °C was added slowly nickel(2+) hexahydrate dichloride (1.44 g, 1 eq, 11 mmol) and sodium borohydride (2.07 g, 5 eq, 54.8 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at 25 °C for 2 hours. LCMS showed the starting material was consumed completely and the desired product was detected. The reaction mixture was quenched with saturated sodium bicarbonate solution (30 mL). The mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with dichloromethane (3×100 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was triturated with ethyl acetate (10 mL) and filtered. The filter cake was dried under reduced pressure to obtain 1.3 g (32.6%) of tert-butyl 4-(aminomethyl)-4-(((benzyloxy)carbonyl)amino)piperidine-1-c arboxylate as a white solid. LCMS: Rt= 0.374 min, m/z = 364.4 (M+H) ⁺ . [0788] Step 4. Preparation of methyl 9- (((4-(((benzyloxy)carbonyl)amino)-1-(tert- butoxycarbonyl)piperidin-4-yl)methyl) amino)-3-methoxythieno[3,2-f]quinoxaline-8- carboxylate. To a solution of tert-butyl 4-(aminomethyl)-4-(((benzyloxy)carbonyl)amino) piperidine- 1-carboxylate (296 mg, 1 eq, 814 µmol) in 1,4-dioxane (4 mL) at room temperature was added methyl 9-bromo-3-methoxythieno[3,2-f]quinoxaline-8-carboxylate (244 mg, 0.85 eq, 692 µmol), dicaesium carbonate (531 mg, 2 eq, 1.63 mmol), and rac-BINAP-Pd-G3 (162 mg, 0.2 eq, 163 µmol) under N ₂ . The resulting mixture was stirred at 90 °C for 12 hours under a nitrogen atmosphere. LCMS analysis showed the starting material was consumed completely and the desired product was formed. After cooling to room temperature, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined mixtures were washed with brine (20 mL), dried over Na ₂ SO ₄ , and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was purified via silica gel chromatography eluting with 10-20% ethyl acetate in petroleum ether to give 0.2 g (38.63%) of methyl 9-(((4-(((benzyloxy)carbonyl)amino)-1-(tert-butoxycarbonyl)p iperidin-4-yl)methyl) amino)-3-methoxythieno[3,2-f]quinoxaline-8-carboxylate as a yellow solid. LCMS: Rt= 2.535 min, m/z = 636.3 (M+H) ⁺ . [0789] Step 5. Preparation of methyl 9-(((4-amino-1-(tert-butoxycarbonyl)piperidin-4- yl)methyl)amino)-3-methoxythieno[3,2-f]quinoxaline -8-carboxylate. To a solution of methyl 9-(((4-(((benzyloxy)carbonyl)amino)-1-(tert-butoxycarbonyl)p iperidin-4- yl)methyl)amino)-3-methoxythieno[3,2-f]quinoxaline-8-carboxy late (820 mg, 1 eq 1.29 mmol) in propan-2-ol (20 mL) was added ammonium formate (488 mg, 6 eq 7.74 mmol) and palladium (820 mg, 0.59 eq 771 µmol). The reaction mixture was stirred at 80 °C for 6 hours under nitrogen. LCMS showed the starting material was consumed completely and the desired product was formed. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent to give 480 mg (38.63%) of methyl 9-(((4-amino-1- (tert-butoxycarbonyl)piperidin-4-yl)methyl)amino)-3-methoxyt hieno[3,2-f]quinoxaline -8- carboxylate, which was used directly in the next step without purification. LCMS: Rt= 0.458 min, m/z = 502.3 (M+H)+. [0790] Step 6. Preparation of tert-butyl 3’-methoxy-8’-oxo-8’,9’,11’,12’-tetrahydrospiro [piperidine-4,10’-[1,4]diazepino[5’,6’:4,5]thieno[3,2- f] quinoxaline]-1-carboxylate. To a solution of methyl 9-(((4-amino-1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)am ino)-3- methoxythieno[3,2-f]quinoxaline-8-carboxylate (158 mg, 1 eq 315 µmol) in methanol (10 mL) at room temperature was added sodium methoxide (51.1 mg, 3eq, 945 µmol). The reaction mixture was stirred at 80 °C for 4 hours under nitrogen. LCMS showed the starting material was consumed completely and the desired product was formed. The reaction mixture was filtered, and the filter cake was dried under high vacuum to give 60 mg (40.57%) of tert-butyl 3’-methoxy-8’-oxo-8’,9’,11’,12’-tetrahydrospiro[ piperidine-4,10’-[1,4]diazepino[5’,6’:4,5] thieno[3,2-f] quinoxaline]-1-carboxylate as a yellow solid. LCMS: Rt= 0.523 min, m/z = 470.2 (M+H) ⁺ . [0791] Step 7. Preparation of 3’-methoxy-11’,12’-dihydrospiro[piperidine-4,10’- [1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin]-8’(9 ’H)-one. tert-Butyl 3’-methoxy-8’-oxo- 8’,9’,11’,12’-tetrahydrospiro[piperidine-4,10’-[1, 4]diazepino[5’,6’: 4,5]thieno[3,2-f] quinoxaline]-1-carboxylate (60 mg, 1 eq, 128 µmol) was added to a mixture of trifluoroacetic acid (1 mL) in dichloromethane (2 mL) at room temperature. The reaction mixture was stirred at 20 °C for 2 hours under nitrogen. LCMS showed the starting material was consumed completely and the desired product was detected. The reaction mixture was concentrated under reduced pressure to give 60 mg (95.32%) of 3’-methoxy-11’,12’-dihydrospiro[piperidine-4,10’- [1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin]-8’(9 ’H)-one as a yellow solid, which was used directly in the next step without purification. LCMS: Rt= 0.334 min, m/z = 370.2 (M+H) ⁺ . [0792] Step 8. Preparation of 3’-methoxy-1-methyl-11’,12’-dihydrospiro[piperidine-4, 10’- [1,4]diazepino[5’,6’:4,5]thieno[3,2 -f]quinoxalin] -8’(9’H)-one. To a solution of 3’-methoxy- 11’,12’-dihydrospiro[piperidine-4,10’-[1,4]diazepino[5 ’,6’:4,5] thieno[3,2-f]quinoxalin]- 8’(9’H)-one (60 mg, 1 eq 162 µmol) in methanol (4 mL) at room temperature was added formaldehyde (1 mL) and acetic acid (0.5 mL). The reaction mixture was stirred at 25 °C for 1 hour. To the reaction mixture was added sodium boranuidcarbonitrile (20.4 mg, 2 eq 325 µmol), and the mixture was stirred at 25 °C for 1.5 hours under a nitrogen atmosphere. LCMS showed the starting material was consumed completely and the desired product was formed. The reaction mixture was filtered under reduced pressure to give 47 mg (75.4%) of 3’-methoxy -1- methyl-11’,12’-dihydrospiro [piperidine-4,10’-[1,4]diazepino[5’,6’:4,5]thieno[3,2 - f]quinoxalin] -8’(9’H)-one as a yellow solid, which was used directly in the next step without purification. LCMS: Rt= 0.331 min, m/z = 384.2 (M+H) ⁺ . [0793] Step 9. Preparation of 3’-hydroxy-1-methyl-11’,12’- dihydrospiro[piperidine-4,10’- [1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin]-8’(9 ’H)-one. To a solution of 3’-methoxy- 1-methyl-11’,12’-dihydrospiro[piperidine-4,10’-[1,4]di azepino [5’,6’:4,5]thieno[3,2- f]quinoxalin]-8’(9’H)-one (23 mg, 1 eq 60 µmol) was added hydrobromic acid (33% in acetic acid, 1 mL). The reaction mixture was stirred at 80 °C for 2 hours. LCMS showed the starting material was consumed completely and the desired product was formed. The reaction mixture was filtered, and the filter cake was washed with dichloromethane (20 mL) to give 20 mg (90.26%) of 3’-hydroxy-1-methyl-11’,12’- dihydrospiro[piperidine-4,10’- [1,4]diazepino[5’,6’:4,5]thieno[3,2-f]quinoxalin]-8’(9 ’H)-one as a yellow solid, which was used directly in the next step without purification. LCMS: Rt= 0.073 min, m/z = 370.2 (M+H) ⁺ . [0794] Step 10. Preparation of 3’-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl) oxy)-1- methyl-11’,12’-dihydrospiro[piperidine-4,10’-[1,4]diaz epino[5’,6’:4,5] thieno[3,2- f]quinoxalin]-8’(9’H)-one. To a solution of 3’-hydroxy-1-methyl-11’,12’-dihydrospiro [piperidine-4,10’-[1,4]diazepino [5’,6’:4,5]thieno[3,2-f]quinoxalin]-8’(9’H)-one (0.1 g, 1 eq, 271 µmol) in dimethyl sulfoxide (3.43 mL) at 0 °C was added 2,4-dichloro-5-(ethoxymethyl) pyrimidine (56 mg, 1 eq 271 µmol) and dipotassium carbonate (112 mg, 3 eq 812 µmol). The reaction mixture was stirred at 40 °C for 2 hours. LCMS showed the starting material was consumed completely and the desired product was formed. One additional vial was set up as described above. Both reaction mixtures were combined and purified by prep-HPLC to give a residue, which was further purified by SFC separation to give 5.4 mg (1.7%) of 3’-((2-chloro- 5-(ethoxymethyl) pyrimidin-4-yl) oxy)-1-methyl-11’,12’-dihydrospiro[piperidine- 4,10’- [1,4]diazepino[5’,6’:4,5] thieno[3,2-f]quinoxalin]-8’(9’H)-one as a yellow solid. LCMS: Rt= 1.232 min, m/z = 540.4 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.09 (s, 1H), 8.83 (br t, J = 4.1 Hz, 1H), 8.77 (s, 1H), 8.35 (d, J = 8.9 Hz, 1H), 7.96 (d, J = 8.9 Hz, 1H), 7.76 – 7.71 (m, 1H), 4.69 (s, 2H), 3.77 – 3.48 (m, 4H), 2.43 (br s, 2H), 2.36 (br d, J = 3.5 Hz, 2H), 2.19 (s, 3H), 1.73 – 1.62 (m, 4H), 1.20 (t, J = 7.0 Hz, 3H). EXAMPLE 79 – Synthesis of Additional Compounds [0795] The compounds in Table 2 were prepared using procedures analogous to those described herein above. TABLE 2.

EXAMPLE 80 – Synthesis of (R)-3-((2-chloro-5-((prop-2-yn-1-yloxy)methyl)pyrimidin-4- yl)oxy)-10- methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thi eno[3,2- f]quinoxalin-8-one (I-149) [0796] Step 1.2,4-dichloro-5-[(prop-2- yn-1-yloxy)methyl] pyrimidine. To a solution of prop-2-yn-1-ol (97 mg, 1 eq, 1.73 mmol) in tetrahydrofuran (5 mL) at -70 °C was added potassium tert-butoxide (291 mg, 1.5 eq, 2.6 mmol) and 2,4-dichloro-5-(iodomethyl)pyrimidine (0.5 g, 1 eq, 1.73 mmol). The reaction mixture was stirred at -70 °C for 0.5 hr. LCMS showed the starting material was consumed and desired product was detected. Three additional vials were set up as described above. All the four reaction mixtures were combined and quenched by 15 mL water and extracted by ethyl acetate (3 × 10 mL). The organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by Prep-HPLC to obtained 40 mg (2.66%) 2,4-dichloro-5-[(prop-2- yn-1-yloxy)methyl] pyrimidine as colourless oil. LCMS: Rt = 6.571 min, m/z = 217.0 (M+H) ⁺ . [0797] Step 2. (R)-3-((2-chloro-5-((prop-2-yn-1-yloxy)methyl)pyrimidin-4-yl )oxy)-10- methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thi eno[3,2-f]quinoxalin-8-one. To a solution of 2,4-dichloro-5-[(prop-2-yn-1-yloxy)methyl]pyrimidine (50 mg, 1 eq, 230 µmol) in dimethyl sulfoxide (1.25 mL) at rt was added (R)-3-hydroxy-10-methyl-9,10,11, 12- tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinoxal in-8-one (55.3 mg, 0.8 eq, 184 µmol) and dipotassium carbonate (63.7 mg, 2 eq, 461 µmol). The reaction was heated to 60 °C and stirred at 60 °C for 1 hr. LCMS showed the starting material was consumed and desired product was detected. The reaction was purified directly by prep-HPLC to give 54 mg (48.74%) of (R)-3-((2-chloro-5-((prop-2-yn-1-yloxy)methyl)pyrimidin-4-yl )oxy)-10- methyl- 9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2 -f]quinoxalin-8-one as a yellow solid. LCMS: Rt = 1.732, m/z = 481.0 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.10 (s, 1H), 8.81 (br d, J = 4.0 Hz, 1H), 8.78 - 8.78 (m, 1H), 8.77 (s, 1H), 8.35 (d, J = 8.9 Hz, 1H), 8.00 (br d, J = 4.4 Hz, 1H), 7.97 (d, J = 8.9 Hz, 1H), 4.77 (s, 2H), 4.36 (d, J = 2.4 Hz, 2H), 3.71 - 3.66 (m, 1H), 3.61 (br s, 2H), 3.55 (t, J = 2.3 Hz, 1H), 1.22 (d, J = 6.7 Hz, 3H). Example 81 - Synthesis of (15R)-5-({2-chloro-6-methyl-5-[(morpholin-4-yl)methyl] pyrimidin-4-yl}oxy)-15-methyl-11-thia-3,6,14,17-tetraazatetr acyclo [8.8.0.0²,⁷.0¹²,¹⁸] octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (I-150) and (15R)-5-({4-chloro-6-methyl-5- [(morpholin-4-yl)methyl]pyrimidin-2-yl}oxy)-15-methyl-11-thi a-3,6,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10), 2(7),3,5,8,12(18)-hexaen-13-one (I-151). [0798] Step 1.5-(hydroxymethyl)-6-methylpyrimidine-2, 4-diol. A solution of 6- methylpyrimidine-2, 4-diol (5 g, 1 eq, 39.6 mmol) in sodium hydroxide (45 mL, 1.25 mol/L) was stirred at 15 °C for 10 min. To the above mixture was added formaldehyde (50 mL) was added dropwise. The reaction mixture was stirred at 25 °C for 3 hrs. The suspension was filtered and the filter cake was washed with ethanol (50 mL), then the filter cake was dried under reduced pressure to give residue. The residue was triturated by ethanol (100 mL) and filtered. The filter cake was dried under reduced pressure to afford 8.8 g crude of 5- (hydroxymethyl)-6-methylpyrimidine-2, 4-diol was used into the next step without further purification. ¹ H NMR (400 MHz, D2O) 4.39 (s, 2H), 2.16 (s, 3H). [0799] Step 2.2, 4-dichloro-5-(chloromethyl)-6-methylpyrimidine. A solution of 5- (hydroxymethyl)-6-methylpyrimidine-2, 4-diol (8 g crude) in phosphoroyl trichloride (80 mL) was stirred at 100 °C for 2 hrs. TLC (eluted with petroleum ether/ethyl acetate =1/1, R _f =0.63) showed starting material was consumed and a new spot was formed. The reaction mixture was concentrated under reduced pressure to give residue which was quenched by water (80 mL). The solution was extracted with ethyl acetate (2 × 40 mL). Then aqueous phase was basified by sodium hydroxide (1 N) and extracted with ethyl acetate (3 × 30 mL). The organic phase was combined and washed with sodium bicarbonate (80 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure to give residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate=100/1 to 1/1) to afford 4 g (36.92%) of 2, 4-dichloro-5-(chloromethyl)-6- methylpyrimidine was obtained as a white solid. LCMS (ESI+): Rt = 1.770 min, m/z 211.1 (M+H) ⁺ . [0800] Step 3.2, 4-dichloro-5-(iodomethyl)-6-methylpyrimidine. To a solution of 2,4- dichloro-5-(chloromethyl)-6-methylpyrimidine (1 g, 1 eq, 4.73 mmol) in acetone (10 mL) was added sodium iodide (709 mg, 1 eq, 4.73 mmol) at 25 °C. The mixture was stirred at 25 °C for 25 mins. LCMS showed starting material was consumed and desired peak was detected. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to afford 1.5 g crude of 2, 4-dichloro-5-(iodomethyl)-6-methylpyrimidine was used into the next step without further purification. LCMS (ESI+): Rt = 0.542 min, m/z 302.9 (M+H) ⁺ . [0801] Step 4.4-[(2, 4-dichloro-6-methylpyrimidin-5-yl) methyl] morpholine. To a solution of 2,4-dichloro-5-(iodomethyl)-6-methylpyrimidine (1.5 g, 1 eq, 4.95 mmol) in acetonitrile (15 mL) was added morpholine hydrochloride (345 mg, 0.8 eq., 3.96 mmol) and potassium carbonate (1.37 g, 2 eq, 9.9 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hr. LCMS showed starting material was consumed and desired peak was detected. TLC (eluted with petroleum ether/ethyl acetate =1/1, R _f =0.53) showed starting material was consumed and a new spot was formed. The reaction mixtures were combined and diluted with water (15 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic phase was washed with brine (50 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure to give residue. The residue was purified by column on chromatography (eluted with petroleum ether/ethyl acetate=100/1 to 1/1) to give 0.6 g (46.22%) of 4-[(2, 4-dichloro-6-methylpyrimidin-5-yl) methyl] morpholine was obtained as a white solid. LCMS (ESI+): Rt = 0.252 min, m/z 262.1 (M+H) ⁺ . [0802] Step 5. (15R)-5-({2-chloro-6-methyl-5-[(morpholin-4-yl)methyl]pyrimi din-4- yl}oxy)-15-methyl-11-thia-3,6,14,17-tetraazatetracyclo[8.8.0 .0²,⁷.0¹²,¹⁸]octadeca- 1(10),2(7),3,5, 8,12(18)-hexaen-13-one and (15R)-5-({4-chloro-6-methyl-5-[(morpholin-4- yl)methyl] pyrimidin-2-yl}oxy)-15-methyl-11-thia-3,6,14,17-tetraazatetr acyclo [8.8.0.0²,⁷.0¹²,¹⁸] octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one. To a solution of 4-[(2,4- dichloro-6-methylpyrimidin-5-yl)methyl] morpholine (69.8 mg, 1 eq, 266 µmol) in dimethyl sulfoxide (4 mL) was added (15R)-5-hydroxy-15-methyl-11-thia- 3,6,14,17-tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)- hexaen-13-one (80 mg, 1 eq, 266 µmol) and potassium carbonate (73.6 mg, 2 eq, 533 µmol). The mixture was stirred at 60 °C for 1 hr. LCMS showed the starting material was consumed and two desired peaks were detected. The reaction mixtures were combined and diluted with water (10 mL) extracted with ethyl acetate (3 × 15 mL). The organic phase was washed with brine (20 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure to give residue. The residue was purified by HPLC (neutral condition) to give 8 mg (5.71%) of (15R)-5-({2-chloro-6-methyl-5-[(morpholin-4-yl)methyl]pyrimi din-4-yl}oxy)-15- methyl-11-thia-3,6,14,17-tetraazatetracyclo[8.8.0.0²,⁷.0� �²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)- hexaen-13-one as a orange solid. LCMS (ESI+): Rt = 0.308 min, 0.346 min, m/z 526.1(M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 9.02 - 8.84 (m, 1H), 8.76 - 8.63 (m, 1H), 8.08 (br d, J = 8.1 Hz, 1H), 7.93 - 7.79 (m, 1H), 5.97 (br s, 1H), 3.90 - 3.81 (m, 1H), 3.81 - 3.72 (m, 2H), 3.69 (br s, 4H), 3.62 (br d, J = 1.8 Hz, 2H), 2.71 (br s, 3H), 2.58 (br s, 4H), 1.41 (br d, J = 5.5 Hz, 3H)and 2 mg (1.43%) of (15R)-5-({4-chloro-6-methyl-5-[(morpholin-4-yl)methyl]pyrimi din-2- yl}oxy)-15-methyl-11-thia-3,6,14,17-tetraazatetracyclo[8.8.0 .0²,⁷.0¹²,¹⁸]octadeca- 1(10),2(7),3,5,8,12(18)-hexaen-13-one as orange solid. LCMS (ESI+): Rt = 2.754 min, m/z 526.1 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 8.90 (br s, 1H), 8.65 (s, 1H), 7.99 (d, J = 8.9 Hz, 1H), 7.81 (d, J = 8.9 Hz, 1H), 5.87 (br s, 1H), 3.77 (br dd, J = 6.1, 9.9 Hz, 1H), 3.69 (br dd, J = 4.6, 13.4 Hz, 1H), 3.61 (br s, 4H), 3.57 (s, 2H), 3.54 - 3.49 (m, 1H), 2.55 (s, 3H), 2.45 (br s, 4H), 1.33 (br d, J = 6.6 Hz, 3H). Example 82 - Synthesis of (R)-3-((2-chloro-5-morpholinopyrimidin-4-yl)oxy)-10-methyl- 9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2 -f]quinoxalin-8-one (I-152). [0803] To a solution of 4-(2,4-dichloropyrimidin-5-yl)morpholine (24.6 mg, 1.05 eq, 105 µmol) and (R)-3–hydroxy-10-methyl-9,10,11,12-tetrahydro-8H- [1,4]diazepino[5',6':4,5]thieno[3,2-f]quinoxalin-8-one (30 mg, 1 eq, 99.9 µmol) in dimethyl sulfoxide (0.5 mL) at rt was added cesium carbonate (65.1 mg, 2 eq, 0.2 mmol). The reaction mixture was heated up to 60 °C and stirred at 60 °C for 1 hr. LCMS showed the starting material was consumed, desired product was detected. The reaction mixture filter and the filtrate was purified by prep-HPLC to afford 3.5 mg (7.4%) (R)-3-((2-chloro-5- morpholinopyrimidin-4-yl)oxy)-10-methyl- 9,10,11,12-tetrahydro-8H- [1,4]diazepino[5',6':4,5]thieno[3,2-f]quinoxalin-8-one as an orange solid. LCMS: Rt = 0.436 min, m/z = 498.1 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.12 (s, 1H), 8.83 - 8.77 (m, 1H), 8.41 (s, 1H), 8.35 (d, J = 8.9 Hz, 1H), 8.01 (br d, J = 4.5 Hz, 1H), 7.96 (d, J = 8.9 Hz, 1H), 3.78 - 3.71 (m, 4H), 3.68 (br dd, J = 3.6, 6.2 Hz, 1H), 3.61 (br s, 2H), 3.30 - 3.23 (m, 4H), 1.22 (d, J = 6.6 Hz, 3H). Example 83 - Synthesis of 4-[(2-chloro-4-{[(15R)-15-methyl-13- oxo-11-thia-3,6,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10), 2(7),3,5,8,12(18)-hexaen-5- yl]oxy}pyrimidin-5-yl)methyl]-3-methyl-1λ⁶-thiomorpholine -1,1-dione (I-154) [0804] Step 1.4-[(2,4-dichloropyrimidin-5-yl)methyl]-3- methylthiomorpholine. To a solution of 2,4-dichloro-5-(iodomethyl)pyrimidine (123 mg, 1 eq, 427 µmol) in tetrahydrofuran (2 mL) was potassium 2-methylpropan-2-olate (95.7 mg, 2 eq, 853 µmol) and 3-methyl- thiomorpholine (50 mg, 1 eq, 427 µmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hr. One additional vial was set up as described above. All two reaction mixtures were combined, diluted with water (12 mL) and extracted with ethyl acetate (3 × 4 mL). The organic phase was combined, washed with brine (12 mL) and dried over sodium sulfate. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by prep-TLC (eluted with petroleum ether/ethyl acetate = 3/1, R _f = 0.4) to give 40 mg (10.11%) of 4-[(2,4-dichloropyrimidin-5-yl)methyl]-3- methylthiomorpholine as a yellow solid. LCMS (ESI+): Rt = 0.830 min, m/z 278.2 (M+H) ⁺ . [0805] Step 2.4-[(2,4-dichloropyrimidin-5-yl) methyl]-3-methyl-1λ⁶-thiomorpholine-1,1- dione. To a solution of 4-[(2,4-dichloropyrimidin-5-yl)methyl]-3-methylthiomorpholin e (30 mg, 1 eq, 64.7 µmol) in ethyl acetate (0.5 mL) and water (0.5 mL) was added Oxone (54.4 mg, 5 eq, 324 µmol) at 20 °C. The reaction mixture was stirred at 25 °C for 12 hrs. One additional vial was set up as described above. All two reaction mixtures were combined, quenched by saturated sodium sulfite solution (3 mL), extracted with ethyl acetate (3 × 2 mL). The organic phase was combined, washed with brine (3 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purity by prep-TLC (eluted with petroleum ether/ethyl acetate = 1/1, R _f = 0.45) to give 10 mg (17.33%) 4-[(2,4- dichloropyrimidin-5-yl) methyl]-3-methyl-1λ⁶-thiomorpholine-1,1-dione as colorless oil. LCMS: Rt = 1.331 min, m/z = 310.0 (M+H) ⁺ . [0806] Step 3.4-[(2-chloro-4-{[(15R)-15-methyl-13- oxo-11-thia-3,6,14,17-tetraaza- tetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5 ,8,12(18)-hexaen-5-yl]oxy}pyrimidin-5- yl)methyl]-3-methyl-1λ⁶-thiomorpholine-1,1-dione. To a solution of (15R)-5-hydroxy-15- methyl-11-thia-3,6,14,17-tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)- hexaen-13-one (5 mg, 1 eq, 16.6 µmol) in dimethyl sulfoxide (0.5 mL) was added 4-[(2,4- dichloropyrimidin-5-yl) methyl]-3-methyl-1λ⁶-thiomorpholine-1,1-dione (10 mg, 1.9 eq, 32.2 µmol), cesium carbonate (10.8 mg, 2 eq, 33.3 µmol) at 20 °C. The reaction mixture was heated to 60 °C and stirred at 60 °C for 1 hr. After cooling to 20 °C, the mixture was filtered and the filtrate was purified by prep-HPLC to give 0.3 mg (1.85%) of 4-[(2-chloro-4-{[(15R)-15- methyl-13- oxo-11-thia-3,6,14,17-tetraazatetracyclo[8.8.0.0²,⁷.0¹² ,¹⁸]octadeca- 1(10),2(7),3,5,8,12(18)-hexaen-5-yl]oxy}pyrimidin-5-yl)methy l]-3-methyl-1λ⁶-thiomorpholine- 1,1-dione as orange solid. LCMS (ESI+): Rt = 1.591 min, m/z 574.1 (M+H) ⁺ . ¹ H NMR (400 MHz, CD3CN) 8.91 (br s, 1H), 8.83 (s, 1H), 8.74 (s, 1H), 8.17 (d, J = 9.0 Hz, 1H), 7.88 (d, J = 9.0 Hz, 1H), 6.42 (br d, J = 3.6 Hz, 1H), 4.05 (d, J = 15.5 Hz, 1H), 3.84 - 3.73 (m, 2H), 3.71 - 3.56 (m, 2H), 3.42 - 3.27 (m, 2H), 3.22 - 2.88 (m, 5H), 1.31 (t, J = 6.1 Hz, 6H). Example 84 - Synthesis of (15R)-15-methyl-5-{[5-(trifluoromethyl)pyrimidin-4-yl]oxy}-1 1- thia-3,6,14,17-tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸] octadeca-1(10),2(7),3,5,8,12(18)-hexaen- 13-one (I-155). [0807] To a solution of (15R)-5-{[2-chloro-5-(trifluoromethyl) pyrimidin-4-yl] oxy}-15- methyl-11-thia-3,6,14,17-tetraazatetracyclo[8.8.0.0²,⁷.0� �²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)- hexaen-13-one (1 mg, 1 eq, 2.08 µmol) in tetrahydrofuran (1 mL) was added palladium (221 µg, 0.1 eq, 0.208 µmol) in tetrahydrofuran (1 mL) and at 25 °C under H ₂ (15 Psi) atmosphere. The mixture was stirred at 25 °C for 8 hrs. Three additional vials were set up as described above. All four mixture was combined, filtered and the filtrate was purified by prep-HPLC to give 3.5 mg (94.25%) of (15R)-15-methyl-5-{[5-(trifluoromethyl)pyrimidin-4-yl]oxy}-1 1-thia- 3,6,14,17-tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octad eca-1(10),2(7),3,5,8,12(18)-hexaen-13-one as yellow solid. LCMS (ESI+): Rt = 1.811 min, m/z 447.0 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 9.28 (s, 1H), 9.15 (s, 1H), 9.04 (s, 1H), 8.79 (br t, J = 3.9 Hz, 1H), 8.36 (d, J = 8.9 Hz, 1H), 8.00 (br d, J = 4.5 Hz, 1H), 7.99 (s, 1H), 3.67 (td, J = 3.5, 6.6 Hz, 1H), 3.60 (br s, 2H), 1.22 (d, J = 6.6 Hz, 3H). Example 85 - Synthesis of (R)-3-((2-chloro-6-cyclopropylpyrimidin-4-yl)oxy)-10-methyl- 9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2 -f]quinoxalin-8-one (I-156). [0808] To a solution of 2,4-dichloro-6-cyclopropylpyrimidine (19.8 mg, 1.05 eq, 105 µmol) and (R)- 3–hydroxy-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepin o[5',6':4,5]thieno[3,2- f]quinoxalin-8-one (30 mg, 1 eq, 99.9 µmol) in dimethyl sulfoxide (0.5 mL) at rt was added cesium carbonate (58.7 mg, 2 eq, 0.2 mmol). The reaction was stirred at 60 °C for 1 hr. The reaction mixture was filtered and the filtrate was purified by prep-HPLC to afford 7.8 mg (17%) (R)-3-((2-chloro-6-cyclopropylpyrimidin-4-yl)oxy)-10-methyl- 9,10,11,12-tetrahydro- 8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinoxalin-8-one as an orange solid. LCMS: Rt = 0.640 min, m/z = 453.1 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.06 (s, 1H), 8.81 (br t, J = 3.6 Hz, 1H), 8.34 (d, J = 8.9 Hz, 1H), 8.00 (br d, J = 4.3 Hz, 1H), 7.95 (d, J = 8.9 Hz, 1H), 7.46 (s, 1H), 3.73 - 3.64 (m, 1H), 3.64 - 3.55 (m, 2H), 2.27 - 2.21 (m, 1H), 1.22 (d, J = 6.6 Hz, 3H), 1.20 - 1.15 (m, 2H), 1.13 - 1.07 (m, 2H). Example 86 - Synthesis of (R)-3-((4-ethoxy-2-(methylsulfonyl)pyrimidin-5-yl)methoxy)- 10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5] thieno[3,2-f]quinoxalin-8-one (I-145). [0809] Step 1.5-(chloromethyl)-4-ethoxy-2-(methylthio)pyrimidine. To a solution of (4- chloro-2-(methylthio)pyrimidin-5-yl)methanol (1 g, 1 eq, 5.25 mmol) in dichloromethane (20 mL) was added N-ethyl-N-isopropylpropan-2-amine (6.78 g, 10 eq, 52.5 mmol) and methanesulfonyl chloride (6.01 g, 10 eq, 52.5 mmol) at 0 °C dropwise. The mixture was stirred at 0 °C for 15 mins, then added ethanol (20 mL). The mixture was warmed to 25 °C and stirred at 25 °C for 12 hrs. LCMS showed the starting material was consumed completely and desired product was detected. One additional vial was set up as described above. All two reaction mixtures were combined, quenched by addition water (10 mL) at 0 °C slowly and extracted with dichloromethane (3 × 15 mL). The organic layers were combined, washed with brine (30 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC to obtain 1 g (43%) of 5- (chloromethyl)-4-ethoxy-2-(methylthio)pyrimidine as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 8.43 (s, 1H), 4.63 (s, 2H), 4.46 (q, J = 7.0 Hz, 2H), 2.50 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H). [0810] Step 2.5-(chloromethyl)-4-ethoxy-2-(methylsulfonyl)pyrimidine. To a solution of 5- (chloromethyl)-4-ethoxy-2-(methylthio)pyrimidine (0.1 g, 1 eq, 457 µmol) in dichloromethane (1 mL) was added 3-chlorobenzene-1-carboperoxoic acid (237 mg, 3 eq, 1.37 mmol) at 0 °C dropwise. The reaction mixture was stirred at 0 °C for 5 mins. Then the mixture was warmed to 25 °C and stirred at 25 °C for 1 hr. Three additional vials were set up as described above. All four reaction mixtures were combined, quenched by addition water (5 mL) at 0 °C slowly and extracted with dichloromethane (3 × 7 mL). The organic layers were combined, washed with brine (10 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give residue, which was purified by prep-HPLC to obtain 105 mg (22%) of 5-(chloromethyl)-4-ethoxy-2-(methylsulfonyl)pyrimidine as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 8.86 (s, 1H), 4.76 (s, 2H), 4.58 (q, J = 7.0 Hz, 2H), 3.41 (s, 3H), 1.40 (t, J = 7.0 Hz, 3H). [0811] Step 3. (R)-3-((4-ethoxy-2-(methylsulfonyl)pyrimidin-5-yl)methoxy)-1 0-methyl- 9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2 -f]quinoxalin-8-one. To a solution of 5-(chloromethyl)-4-ethoxy-2-(methylsulfonyl)pyrimidine (8.3 mg, 1 eq, 33.1 µmol) in dimethylformamide (1.66 mL) was added (R)-3-hydroxy-10-methyl-9,10,11,12-tetrahydro- 8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinoxalin-8-one (9.94 mg, 1 eq, 33.1 µmol) and dipotassium carbonate (9.15 mg, 2 eq, 66.2 µmol) at 25 °C. The mixture was heated to 60 °C and stirred at 60 °C for 30 mins. LCMS showed the starting reactant was consumed completely and desired product was detected. Two additional vials were set up as described above. After cooling to 25 °C, all three reaction mixtures were combined and filtered. The filtrate was concentrated under reduced pressure to give residue, which was purified by prep-HPLC (neutral condition) to obtain 7 mg (14%) of (R)-3-((4-ethoxy-2-(methylsulfonyl)pyrimidin-5- yl)methoxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepin o[5',6':4,5]thieno[3,2- f]quinoxalin-8-one as a yellow solid. LCMS: Rt = 2.520 min, 100% purity, m/z = 515.0 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 8.93 (br s, 1H), 8.79 (s, 1H), 8.52 (s, 1H), 8.02 (d, J = 8.9 Hz, 1H), 7.83 (d, J = 8.9 Hz, 1H), 5.95 (br s, 1H), 5.63 (s, 2H), 4.68 (q, J = 7.1 Hz, 2H), 3.88 - 3.79 (m, 1H), 3.75 (dd, J = 4.8, 13.4 Hz, 1H), 3.58 (ddd, J = 3.4, 6.4, 13.4 Hz, 1H), 3.35 (s, 3H), 1.49 (t, J = 7.1 Hz, 3H), 1.39 (d, J = 6.8 Hz, 3H). Example 87 - Synthesis of (R)-3-((2-chloro-5-((4-(2-fluoroethoxy)piperidin-1-yl)methyl ) pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4] diazepino[5',6':4,5]thieno [3,2-f]quinolin-8-one (I-143) [0812] Step 1. tert-butyl 4-(2-fluoroethoxy)piperidine-1-carboxylate. A solution of tert- butyl 4-hydroxypiperidine-1-carboxylate (2.5 g, 1.0 eq., 12.4 mmol) in tetrahydrofuran (20 mL) was added sodium hydride (447 mg, 1.5 eq., 18.6 mmol) at 0°C slowly and stirred at 0°C for 30 min.1-bromo-2-fluoroethane (3.15 g, 2 eq., 24.8 mmol) was added and stirred at 0°C to room temperature for 16 hours. The mixture was poured into ice water (50 mL) and extracted with ethyl acetate (30 mL x 2). The organic layers were washed with water (20 mL x 2), dried with sodium sulfate, filtered, concentrated. The residue was purified with column chromatography use acetone (0~50%) in petroleum ether to give tert-butyl 4-(2-fluoroethoxy)piperidine-1- carboxylate (1.1 g, 4.45 mmol) as a light oil. LC-MS: Rt: 1.20 min, [M-56+H] ⁺ = 192.2. [0813] Step 2.4-(2-fluoroethoxy)piperidine. A solution of tert-butyl 4-(2- fluoroethoxy)piperidine-1-carboxylate (0.1 g, 1 eq., 404 µmol) in hydrochloric acid (4M in dioxane, 4 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give 4-(2-fluoroethoxy)piperidine (60 mg, 408 µmol) as a white solid. The crude material was carried into the next reaction without further purification. LC-MS: Rt: 0.34 min, [M+H] ⁺ = 148.4. [0814] Step 3.2,4-dichloro-5-((4-(2-fluoroethoxy)piperidin-1-yl)methyl)p yrimidine. To a solution of 4-(2-fluoroethoxy)piperidine (60 mg, 1 eq., 408 µmol) in acetonitrile (3 mL) was added 2,4-dichloro-5-(iodomethyl)pyrimidine (236 mg, 2 eq., 815 µmol) and dipotassium carbonate (169 mg, 3 eq., 1.22 mmol) at 0°C. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified with column chromatography using ethyl acetate (0~30%) in petroleum ether to give 2,4-dichloro-5-{[4-(2- fluoroethoxy)piperidin-1-yl]methyl}pyrimidine (30 mg, 97.3 µmol) as yellow oil. LC-MS: Rt: 1.75 min, [M+H] ⁺ = 309.1. [0815] Step 4. (R)-3-((2-chloro-5-((4-(2-fluoroethoxy)piperidin-1-yl)methyl )pyrimidin-4- yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5' ,6':4,5]thieno[3,2-f]quinolin- 8-one. To a solution of 2,4-dichloro-5-{[4-(2-fluoroethoxy)piperidin-1-yl]methyl}pyr imidine (30 mg, 1 eq., 97.3 µmol) in N,N-dimethylformamide (2 mL) was added (R)-3-hydroxy-10- methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thi eno[3,2-f]quinolin-8-one (29.1 mg, 1 eq., 97.3 µmol) and dipotassium carbonate (40.4 mg, 3 eq., 292 µmol) at room temperature. After stirring at room temperature for 16 hours, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (20 mL * 2). The organic layers were washed with water (20 mL * 2), dried with sodium sulfate, filtered and concentrated. The residue was purified with prep-HPLC (Column: Xbridge 21.2*250mm C18, 10 um, Mobile Phase A: water(10 mmol/L ammonium bicarbonate) B: acetonitrile) to give (R)-3-((2-chloro-5- ((4-(2-fluoroethoxy) piperidin-1-yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11, 12- tetrahydro-8H-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinolin-8-one (6.1 mg, 10.7 µmol) as yellow solid. LC-MS: Rt: 1.53 min, [M+H] ⁺ = 571.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.35 (d, J = 9.2 Hz, 1H), 8.70 (s, 1H), 8.16 (dd, J = 16.3, 6.6 Hz, 2H), 7.84 (d, J = 8.9 Hz, 1H), 7.60 (d, J = 9.0 Hz, 1H), 7.16 (s, 1H), 4.67 – 4.38 (m, 2H), 3.73 – 3.44 (m, 7H), 2.76 (s, 3H), 2.38 – 2.20 (m, 2H), 1.84 (s, 2H), 1.48 (d, J = 9.6 Hz, 2H), 1.19 (d, J = 6.7 Hz, 3H). Example 88 - Synthesis of (R)-3-((2-chloro-5-((2-fluoroethoxy)methyl)pyrimidin-4-yl)ox y)- 10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5] thieno[3,2-f]quinolin-8-one (I-142) [0816] Step 1.2,4-dichloro-5-(iodomethyl)pyrimidine. A mixture of 2,4-dichloro-5- (chloromethyl)pyrimidine (0.5 g, 1.0 eq., 2.53 mmol) and iodosodium (456 mg, 1.2 eq., 3.04 mmol) in acetone (5 mL) was stirred for 2 hs at 60 oC. The reaction mixture was filtered. The filtrate was concentrated in vacuum to give 2,4-dichloro-5-(iodomethyl)pyrimidine (0.7 g, 72% yield) as brown solid. The crude material was carried into the next reaction without further purification. LCMS: Rt: 1.80 min; [M+H] ⁺ =288.8. [0817] Step 2.2,4-dichloro-5-((2-fluoroethoxy)methyl)pyrimidine. A solution of 2- fluoroethan-1-ol (30 mg, 1 eq., 468 µmol) in tetrahydrofuran (1.5 mL) was added sodium hydride (8.43 mg, 1.5 eq., 351 µmol) at 0°C and stirred at 0°C for 30 min.2,4-dichloro-5- (iodomethyl)pyrimidine (135 mg, 2 eq., 468 µmol) was added into the mixture and stirred at room temperature for 2 hours. The mixture was poured into ice water, extracted with ethyl acetate (30 mL * 2). The organic layers were washed with water (20 mL * 2), dried with sodium sulfate, filtered and concentrated. The residue was purified with column chromatography use acetone (0~50%) in petroleum ether to give 2,4-dichloro-5-[(2- fluoroethoxy)methyl]pyrimidine (80 mg, 355 µmol) as a yellow solid. LC-MS: Rt: 1.64 min, [M+H] ⁺ = 225.7. [0818] Step 3. (R)-3-((2-chloro-5-((2-fluoroethoxy)methyl)pyrimidin-4-yl)ox y)-10-methyl- 9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2 -f]quinolin-8-one. To a solution of 2,4-dichloro-5-[(2-fluoroethoxy)methyl]pyrimidine (80 mg, 1 eq., 355 µmol) in dimethylformamide (3 mL) was added (R)-3-hydroxy-10-methyl-9,10,11,12-tetrahydro- 8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one (R)-3-hydroxy-10-methyl-9,10,11,12- tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin -8-one (106 mg, 1 eq., 355 µmol) and dipotassium carbonate (246 mg, 5 eq., 1.78 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 2). The organic layers were washed with water (20 mL x2), dried with sodium sulfate, filtered and concentrated. The residue was purified with prep- HPLC (Column: Xbridge 21.2*250mm C18, 10 um, Mobile Phase A: water (10 mmol/L ammonium bicarbonate) B: acetonitrile) to give (R)-3-((2-chloro-5-((2- fluoroethoxy)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12 -tetrahydro-8H- [1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one (11 mg, 22.5 µmol) as yellow solid. LC- MS: Rt: 1.48 min, [M+H] ⁺ = 488.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.37 (d, J = 9.1 Hz, 1H), 8.74 (s, 1H), 8.17 (dd, J = 20.7, 6.6 Hz, 2H), 7.87 (d, J = 8.9 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.17 (s, 1H), 4.76 (s, 2H), 4.70 – 4.55 (m, 2H), 3.90 – 3.78 (m, 2H), 3.62 (d, J = 5.4 Hz, 1H), 3.47 (s, 2H), 1.19 (d, J = 6.7 Hz, 3H). Example 89 - Synthesis of (R)-3-((2-chloropyrimidin-4-yl)(2-methoxyethyl)amino)-10- methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thi eno[3,2-f]quinoxalin-8-one (I- 147) [0819] Step 1. (R)-3-chloro-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepi no[5',6':4,5] thieno[3,2-f]quinoxalin-8-one. To a solution of (R)-3-hydroxy-10-methyl-9,10,11,12- tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinoxal in-8-one (125 mg, 416 µmol) in toluene (1 mL, 8.45 mmol) was added phosphoroyl trichloride (1 mL, 666 µmol) at 20 °C. The reaction mixture was heated to 80 °C and stirred at 80 °C for 1 hr. TLC (petroleum ether/ethyl acetate = 0/1, R _f = 0.3) showed the starting material was consumed and desired spot was formed. Seven additional vials were set up as described above. After cooling to 20 °C, all eight reaction mixtures were combined and concentrated under reduced pressure to give a residue, which was purified by trituration with ethyl acetate (50 mL) at 25 °C for 30 mins. The mixture was filtered and the filter cake was dried under reduced pressure to give 0.8 g (70%) of (R)-3-chloro-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepi no[5',6':4,5]thieno[3,2- f]quinoxalin-8-one as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.03 (s, 1H), 8.75 - 8.62 (m, 1H), 8.36 (d, J = 8.9 Hz, 1H), 8.06 - 7.93 (m, 2H), 3.67 (br dd, J = 3.3, 7.0 Hz, 1H), 3.61 - 3.56 (m, 2H), 1.20 (d, J = 6.6 Hz, 3H). ^[0820] Step 2. (R)-3-((2-methoxyethyl)(2-methoxypyrimidin-4-yl)amino)-10-me thyl- 9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2 -f]quinoxalin-8-one. ^{To a} solution of (R)-3-chloro-10-methyl-9,10,11,12-tetrahydro-8H- [1,4]diazepino[5',6':4,5]thieno[3,2-f]quinoxalin-8-one (0.1 g, 314 µmol) in 2-methylbutan-2-ol (2 mL) was added 2-methoxy-N-(2-methoxyethyl)pyrimidin-4-amine (172 mg, 3 eq, 941 µmol), dicaesium carbonate (204 mg, 2 eq, 627 µmol) and (2-dicyclohexylphosphino-2′,6′- diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl) ]palladium(II)methanesulfonate (26.7 mg, 0.1 eq, 31.4 µmol) at 20 °C. The reaction mixture was heated to 90 °C and stirred at 90 °C for 12 hrs. TLC (ethyl acetate, R _f = 0.5) showed the starting material was consumed and desired spot was formed. The mixture was diluted with water (6 mL) and extracted with ethyl acetate (3 × 2 mL). The combined organic layer was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (neutral condition) to give 20 mg (13%) of (R)-3-((2-methoxyethyl)(2-methoxypyrimidin-4-yl)amino)-10-me thyl-9,10,11,12-tetrahydro- 8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinoxalin-8-one as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.11 (s, 1H), 8.85 (t, J = 3.8 Hz, 1H), 8.30 - 8.20 (m, 2H), 7.94 (d, J = 4.4 Hz, 1H), 7.90 (d, J = 8.9 Hz, 1H), 6.90 (d, J = 5.9 Hz, 1H), 4.43 (t, J = 5.6 Hz, 2H), 3.83 (s, 3H), 3.70 (t, J = 5.7 Hz, 2H), 3.68 - 3.63 (m, 1H), 3.58 (br s, 2H), 3.18 (s, 3H), 1.21 (d, J = 6.8 Hz, 3H). [0821] Step 3. (R)-3-((2-chloropyrimidin-4-yl)(2-methoxyethyl)amino)-10-met hyl- 9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2 -f]quinoxalin-8-one. To a solution of (R)-3-((2-methoxyethyl)(2-methoxypyrimidin-4-yl)amino)-10-me thyl-9,10,11,12- tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinoxal in-8-one (2 mg, 4.3 µmol) in toluene (0.1 mL, 845 µmol) was added phosphoroyl trichloride (0.1 mL) and diisopropylethylamine (1.67 mg, 3 eq, 12.9 µmol) at 20 °C. The reaction mixture was heated to 80 °C and stirred at 80 °C for 1 hr. LCMS showed starting material was consumed and desired product was detected. Nine additional vials were set up as described above. After cooling to 20 °C, all ten reaction mixtures were combined, diluted with water (6 mL) and extracted with ethyl acetate (2 × 3 mL). The organic phase was combined, washed with brine (5 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (neutral condition) to give 0.5 mg (2%) of (R)-3- ((2-chloropyrimidin-4-yl)(2-methoxyethyl)amino)-10-methyl-9, 10,11,12-tetrahydro-8H- [1,4]diazepino[5',6':4,5]thieno [3,2-f]quinoxalin-8-one as brown solid. LCMS (ESI+): Rt = 2.550 min, 100% purity, m/z 470.1 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.12 (s, 1H), 8.88 - 8.80 (m, 1H), 8.35 (d, J = 6.0 Hz, 1H), 8.26 (d, J = 9.0 Hz, 1H), 7.96 (br d, J = 3.9 Hz, 1H), 7.92 (d, J = 8.9 Hz, 1H), 7.25 (d, J = 6.0 Hz, 1H), 4.42 (br t, J = 5.3 Hz, 2H), 3.69 (br t, J = 5.4 Hz, 3H), 3.60 (br s, 2H), 3.16 (s, 3H), 1.21 (br d, J = 6.5 Hz, 3H). Example 90 - Synthesis of 3-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-9,10,11,12- tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinoxal in-8-one (I-146) [0822] Step 1. Methyl 9-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-3-methoxy- thieno[3,2-f]quinoxaline-8-carboxylate. A solution of methyl 9-amino-3-methoxythieno[3,2- f]quinoxaline-8-carboxylate (60 mg, 207 µmol) and tert-butyl N-(2-oxoethyl)carbamate (66 mg, 2 eq, 415 µmol) in dichloromethane (3 mL, 46.9 mmol) was stirred at 25 °C for 1 hr. Then triethylsilane (99.4 µL, 3 eq, 622 µmol) and hydrogen trifluoroacetate (46.2 µL, 3 eq, 622 µmol) was added to the reaction mixture at 25 °C. The mixture was heated to 40 °C and stirred at 40 °C for 12 hrs. TLC (ethyl acetate, R _f = 0) showed about 60% of starting material was remained and desired spot was formed. Nine additional vials were set up as described above. After cooling to 25 °C, all ten reaction mixtures were combined, diluted with water (50 mL), acidified to pH = 3 with hydrochloric acid (2 M) and extracted with dichloromethane (3 × 20 mL). The aqueous phase was combined, basified to pH = 8 with solution of sodium hydroxide (2 M) and extracted with dichloromethane (3 × 20 mL). The organic phase was combined, washed with brine (50 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC to give 30 mg (3%) of methyl 9-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-3- methoxythieno[3,2-f]quinoxaline-8-carboxylate as yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.49 - 8.42 (m, 2H), 7.87 (q, J = 9.0 Hz, 2H), 4.13 (s, 3H), 3.94 - 3.89 (m, 5H), 3.50 (br s, 2H). [0823] Step 2. Methyl 9-((2-aminoethyl)amino)-3-hydroxythieno[3,2-f]quinoxaline-8- carboxylate. A solution of methyl 9-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-3- methoxythieno[3,2-f]quinoxaline-8-carboxylate (10 mg, 30.1 µmol) in co-solvents hydrogen chloride (12 M, 0.2 mL) and methanol (0.2 mL, 4.94 mmol) was heated to 80 °C and stirred at 80 °C for 2 hrs. LCMS showed starting material was consumed and desired product was detected. Four additional vials were set up as described above. After cooling to 20 °C, all five reaction mixtures were combined and concentrated under reduced pressure to give 30 mg crude of methyl 9-((2-aminoethyl)amino)-3-hydroxythieno[3,2-f]quinoxaline-8- carboxylate as yellow solid, which was used for the next step without further purification. LCMS (ESI+): tR = 0.443 min, m/z 319.0 (M+H) ⁺ . [0824] Step 2.3-hydroxy-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4, 5]thieno[3,2- f]quinoxalin-8-one. To a solution of methyl 9-((2-aminoethyl)amino)-3-hydroxythieno[3,2- f]quinoxaline-8-carboxylate (10 mg, 31.4 µmol) in methanol (1 mL, 24.7 mmol) was added sodium methanolate (3.39 mg, 2 eq, 62.8 µmol) at 20 °C. The mixture was heated to 80 °C and stirred at 80 °C for 2 hrs. LCMS showed starting material was consumed and desired product was detected. Two additional vials were set up as described above. After cooling to 20 °C, all three reaction mixtures were combined, quenched with water (5 mL) and extracted with ethyl acetate (3 × 2 mL). The organic phase was combined, washed with brine (5 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 24 mg crude of 3-hydroxy-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5] thieno[3,2-f]quinoxalin- 8-one as yellow solid, which was used for next step without further purification. LCMS (ESI+): Rt = 0.406 min, m/z 286.9 (M+H) ⁺ . [0825] Step 3.3-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-9,10,11,1 2-tetrahydro- 8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinoxalin-8-one. To a solution of 3-hydroxy- 9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2 -f]quinoxalin-8-one (8 mg, 27.9 µmol) and 2,4-dichloro-5-(ethoxymethyl)pyrimidine (5.79 mg, 27.9 µmol) in dimethyl sulfoxide (0.5 mL, 6.99 mmol) was added dicaesium carbonate (9.1 mg, 27.9 µmol) at 25 °C. The mixture was heated to 60 °C and stirred at 60 °C for 1 hr. LCMS showed staring material was consumed and desired product was detected. After cooling to 20 °C, the reaction mixture was filtered and the filtrate was purified by prep-HPLC to give 5 mg (13%) of 3-((2-chloro-5- (ethoxymethyl)pyrimidin-4-yl)oxy)-9,10,11,12-tetrahydro-8H- [1,4]diazepino[5',6':4,5]thieno[3,2-f]quinoxalin-8-one as red solid. LCMS (ESI+):Rt = 0.683 min, m/z 457.1 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ = 9.08 (s, 1H), 8.84 (br t, J = 3.8 Hz, 1H), 8.77 (s, 1H), 8.34 (d, J = 8.9 Hz, 1H), 8.02 - 7.92 (m, 2H), 4.69 (s, 2H), 3.73 (br d, J = 2.6 Hz, 2H), 3.66 - 3.60 (m, 2H), 3.46 (br s, 2H), 1.24 - 1.17 (m, 3H). Example 91 - Synthesis of (R)-3-((2-chloro-5-(methoxymethyl)pyrimidin-4-yl)oxy)-10- methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thi eno[3,2-f]quinoxalin-8-one (I- 144) [0826] To a solution of 2,4-dichloro-5-(methoxymethyl)pyrimidine (6.43 mg, 33.3 µmol) in dimethyl sulfoxide (1 mL, 14 mmol) was added (R)-3-hydroxy-10-methyl-9,10,11,12- tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinoxal in-8-one (10 mg, 33.3 µmol) and cesium carbonate (32.5 mg, 3 eq, 99.9 µmol) at 25 °C, the reaction mixture was heated to 60 °C and stirred at 60 °C for 1 hr. LCMS showed starting material was consumed and desired Ms was detected. Four additional vials were set up as described above. After cooling to 25 °C, all five reaction mixtures were combined and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (formic acid condition) to give 12 mg (15.59%) of (R)-3-((2-chloro-5-(methoxymethyl)pyrimidin-4-yl)oxy)-10-met hyl- 9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2 -f]quinoxalin-8-one as yellow solid. LCMS (ESI+): m/z 457.0 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.10 (s, 1H), 8.80 (t, J = 3.9 Hz, 1H), 8.77 (s, 1H), 8.35 (d, J = 9.0 Hz, 1H), 8.01 (d, J = 4.4 Hz, 1H), 7.96 (d, J = 9.0 Hz, 1H), 4.65 (s, 2H), 3.71 - 3.64 (m, 1H), 3.60 (br s, 2H), 3.43 (s, 3H), 1.22 (d, J = 6.6 Hz, 3H). Example 92 - Synthesis of 2-chloro-4-{[(15R)-15-methyl-13-oxo-11-thia-3,6,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10), 2,4,6,8,12(18)-hexaen-5- yl]oxy}pyrimidine-5-carbonitrile (I-140) [0827] To a solution of (15R)-5-hydroxy-15-methyl-11-thia-3,6,14,17-tetraazatetracyc lo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)- hexaen-13-one (50 mg, 166 µmol) in dimethylformamide (5 mL, 64.6 mmol) and dimethyl sulfoxide (5 mL, 69.9 mmol) was added 2,4-dichloropyrimidine-5-carbonitrile (57.9 mg, 2 eq, 333 µmol) and caesium carbonate (81.4 mg, 1.5 eq, 250 µmol) at -20 °C. The mixture was stirred at -20 °C for 1 hr. LCMS showed starting material was consumed and desired Ms was detected. Two additional vials were set up as described above. All three reaction mixtures were combined, diluted with water (50 mL) and extracted with ethyl acetate (3 × 30 mL). The organic phase was combined, washed with brine (50 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (trifluoroacetic acid condition) to give 8 mg (3.66%) of 2-chloro-4-{[(15R)-15-methyl-13-oxo-11-thia-3,6,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10), 2,4,6,8,12(18)-hexaen-5-yl]oxy}pyrimidine- 5-carbonitrile as orange solid. LCMS (ESI+): m/z 438.0 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.37 (s, 1H), 9.16 (s, 1H), 8.80 (br s, 1H), 8.39 (d, J = 9.0 Hz, 1H), 8.06 - 7.96 (m, 2H), 3.71 - 3.65 (m, 1H), 3.61 (br s, 2H), 1.22 (d, J = 6.6 Hz, 3H). Example 93 - Synthesis of (15R)-5-({2-chloro-5-[(3,3-difluoroazetidin-1-yl)methyl] pyrimidin-4-yl}oxy)-15-methyl-11-thia-3,6,14,17-tetraazatetr acyclo[8.8.0.0²,⁷.0¹²,¹⁸] octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (I-139) [0828] Step 1.2,4-dichloro-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrimidi ne. To a solution of 2,4-dichloro-5-(iodomethyl)pyrimidine (0.1 g, 1 eq., 346 µmol) in acetonitrile (1 mL) was added 3,3-difluoroazetidine (16.1 mg, 0.5 eq., 173 µmol) and dipotassium carbonate (95.7 mg, 2 eq., 692 µmol) and the mixture was stirred at 0 °C for 1 hr. LCMS showed starting material peak was consumed and the desired peak was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give residue, which was purified by pre- TLC (eluted with petroleum ehter/ethyl acetate = 3/1, R _f = 0.4) to afford 25 mg (28.43%) of 2,4-dichloro-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrimidine as white solid. LCMS (ESI+): Rt = 0.600 min, m/z 254.1 (M+H) ⁺ . [0829] Step 2. (15R)-5-({2-chloro-5-[(3,3-difluoroazetidin-1-yl)methyl]pyri midin-4- yl}oxy)-15-methyl-11-thia-3,6,14,17-tetraazatetracyclo[8.8.0 .0²,⁷.0¹²,¹⁸]octadeca- 1(10),2(7),3,5,8, 12(18)-hexaen-13-one. To a solution of 2,4-dichloro-5-[(3,3-difluoroazetidin- 1-yl)methyl] pyrimidine (25 mg, 1 eq., 98 µmol) in dimethyl sulfoxide (0.5 mL) was added (15R)-5-hydroxy-15-methyl-11-thia-3,6,14,17-tetraazatetracyc lo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca- 1(10),2(7),3,5,8,12(18)-hexaen-13-one (29.5 mg, 1 eq., 98 µmol) and dipotassium carbonate (27.1 mg, 2 eq., 196 µmol) and the mixture was stirred at 60 °C for 30 min. LCMS showed starting material peak was consumed and the desired peak was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give residue, which was purified by prep-HPLC to afford 11.5 mg (22.51%) of (15R)-5-({2-chloro-5-[(3,3- difluoroazetidin-1-yl)methyl]pyrimidin-4-yl}oxy)-15-methyl-1 1-thia-3,6,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10), 2(7),3, 5,8,12(18)-hexaen-13-one as yellow solid. LCMS (ESI+): Rt = 1.518 min, m/z 518.0 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.05 (s, 1H), 8.77 (t, J = 3.8 Hz, 1H), 8.70 (s, 1H), 8.31 (d, J = 9.0 Hz, 1H), 7.97 (d, J = 4.4 Hz, 1H), 7.92 (d, J = 9.0 Hz, 1H), 3.92 (s, 2H), 3.83 - 3.72 (m, 4H), 3.68 - 3.60 (m, 1H), 3.60 - 3.54 (m, 2H), 1.18 (d, J = 6.8 Hz, 3H). Example 94 - Synthesis of (R)-3-((2-chloropyrimidin-4-yl)oxy)-10-methyl-9,10,11,12- tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinoxal in-8-one (I-138) [0830] To a solution of (R)-3-hydroxy-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazep ino [5',6':4,5]thieno[3,2-f]quinoxalin-8-one (70 mg, 1 eq, 233 µmol) in dimethyl sulfoxide (5.6 mL) was added 2,4-dichloropyrimidine (34.7 mg, 233 µmol) and cesium carbonate (152 mg, 2 eq, 466 µmol) at 25 °C. The reaction mixture was heated to 60 °C and stirred at 60 °C for 3 hrs LCMS analysis showed the starting material was consumed completely and desired product was detected. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by prep- HPLC to afford 12 mg (12.47%) of (R)-3-((2-chloropyrimidin-4-yl)oxy)-10-methyl-9,10,11,12- tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinoxal in-8-one as a yellow solid. LCMS (ESI+): m/z 413.0 (M+H) +.1H NMR (400 MHz, DMSO-d6) δ ppm 9.09 (s, 1H), 8.81 (br d, J = 5.3 Hz, 2H), 8.34 (d, J = 8.8 Hz, 1H), 8.05 - 7.90 (m, 2H), 7.57 (d, J = 5.5 Hz, 1H), 3.71 - 3.64 (m, 1H), 3.64 - 3.56 (m, 2H), 1.21 (br d, J = 6.6 Hz, 3H). Example 95 - Synthesis of (15R)-5-{[2-chloro-5-(ethoxymethyl)pyrimidin-4-yl]amino}-15- methyl-11-thia-3,6,14,17-tetraazatetracyclo[8.8.0.0²,⁷.0� �²,¹⁸]octadeca-1(10),2(7),3,5,8, 12(18)-hexaen-13-one (I-137) [0831] Step 1.2-chloro-5-(ethoxymethyl)pyrimidin-4-amine. A solution of 2,4-dichloro-5- (ethoxymethyl)pyrimidine (3 g, 14.5 mmol) in ammonia/methanol (30 mL, 7 M) was stirred at 25 ℃ for 3 hrs. LC-MS showed starting material was consumed completely and desired Ms was detected. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (neutral condition: column: Welch Xtimate C18250*100 mm#10 um; liquid phase: [A-water (10 mM ammonium bicarbonate); B-acetonitrile] B%: 5%- 30%, 20 min]) to give 1.36 g (49.43%) of 2-chloro-5-(ethoxymethyl)pyrimidin-4-amine as white solid. LCMS: tR = 0.618 min, m/z = 188.1 (M+H) ⁺ . [0832] Step 2. (15R)-5-{[2-chloro-5-(ethoxymethyl)pyrimidin-4-yl]amino}-15- methyl-11- thia-3,6,14,17-tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸] octadeca-1(10),2(7),3,5,8,12(18)-hexaen- 13-one. To a solution of 2-chloro-5-(ethoxymethyl)pyrimidin-4-amine (80 mg, 426 µmol), (15R)-5-chloro-15-methyl-11-thia-3,6,14,17-tetraazatetracycl o[8.8.0.0²,⁷.0¹²,¹⁸]octadeca- 1(10),2(7), 3,5,8,12(18)-hexaen-13-one (136 mg, 426 µmol) and dicaesium(1+) carbonate (278 mg, 2 eq, 853 µmol) in 1,4-dioxane (8 mL, 93.8 mmol) was added [5-(diphenylphosphanyl)- 9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (24.7 mg, 0.1 eq, 42.6 µmol) and tris(1,5- diphenylpenta-1,4-dien-3-one) dipalladium (39 mg, 0.1 eq, 42.6 µmol) at 25 °C under nitrogen. The mixture was heated to 100 °C and stirred at 100 °C for 12 hrs under nitrogen. LC-MS showed starting material was consumed completely and desired Ms was detected. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (neutral condition) to give 13 mg (6.49%) of (15R)-5-{[2-chloro-5-(ethoxymethyl) pyrimidin-4-yl]amino}-15-methyl-11-thia-3,6,14,17-tetraazate tracyclo [8.8.0.0²,⁷.0¹²,¹⁸] octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one as yellow solid. LCMS: t _R = 1.933 min, m/z = 470.1 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.04 - 9.94 (m, 1H), 9.66 (s, 1H), 8.92 - 8.82 (m, 1H), 8.39 (s, 1H), 8.23 (d, J = 9.0 Hz, 1H), 7.95 (d, J = 4.6 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 4.68 (s, 2H), 3.72 - 3.63 (m, 1H), 3.60 (q, J = 7.0 Hz, 4H), 1.24 - 1.19 (m, 6H). Example 96 - Synthesis of (R)-3-((2-chloro-5-fluoropyrimidin-4-yl)oxy)-10-methyl- 9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2 -f]quinoxalin-8-one (I-136) [0833] To a solution of 2,4-dichloro-5-fluoropyrimidine (11.1 mg, 66.6 µmol) and (15R)-5- hydroxy-15-methyl-11-thia-3,6,14,17-tetraazatetracyclo[8.8.0 .0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3, 5,8,12(18)-hexaen-13-one (20 mg, 66.6 µmol) in dimethylformamide (2 mL, 25.8 mmol) was added dipotassium carbonate (27.6 mg, 3 eq, 0.2 mmol) at 25 °C, the mixture was heated to 60 °C and stirred at 60 °C for 3 hrs. LCMS showed starting material was consumed and desired Ms was detected. Two additional vials were set up as described above. After cooling to 25 °C, all three reaction mixtures were combined and filtered, the filtrate was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC to give 50 mg (58%) of (R)-3-((2-chloro-5-fluoropyrimidin-4-yl)oxy)-10-methyl-9,10, 11,12-tetrahydro-8H- [1,4]diazepino [5',6':4,5]thieno[3,2-f]quinoxalin-8-one as red solid. LCMS (ESI+): m/z 431.0 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.16 (s, 1H), 9.01 (d, J = 2.3 Hz, 1H), 8.79 (t, J = 3.9 Hz, 1H), 8.36 (d, J = 8.9 Hz, 1H), 8.00 (br d, J = 4.3 Hz, 1H), 7.95 (d, J = 9.0 Hz, 1H), 5.75 (s, 1H), 3.71 - 3.65 (m, 1H), 3.61 (br s, 2H), 1.22 (d, J = 6.6 Hz, 3H). Example 97 - Synthesis of 3-[(4-{(R)-15-methyl-13-oxo-11-thia-3,6,14,17-tetraaza- tetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca- 1(10),2(7),3,5,8,12(18)-hexaen-5-yloxy}-2-chloro-5- pyrimidinyl)methoxy]bicyclo[1.1.1]pentane-1-carboxylic acid (I-97) [0834] Step 1. methyl 3-[(2,4-dichloro-5-pyrimidinyl)methoxy]bicycle [1.1.1]pentane-1- carboxylate. To a solution of 2,4-dichloro-5-(iodomethyl)pyrimidine (50 mg, 1 eq., 173 µmol) in tetrahydrofuran (2 mL) was added methyl 3-hydroxybicyclo[1.1.1]pentane-1-carboxylate (24.6 mg, 1 eq., 173 µmol) and potassium 2-methylpropan-2-ol (49 mg, 2.5 eq., 433 µmol) at - 60 °C. Then the reaction mixture was stirred at -60 °C for 1 hr. LCMS showed starting material was consumed and desired Ms was detected. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 × 5 mL). The organic phase was washed with brine (15 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to give residue, which was purified by prep-TLC (eluted with petroleum ether/ethyl acetate = 3/1, R _f = 0.5) to give 20 mg (38.16%) of methyl 3-[(2,4-dichloro-5-pyrimidinyl)methoxy]bicycle [1.1.1]pentane-1-carboxylate as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) 8.65 (s, 1H), 4.59 (s, 2H), 3.72 (s, 3H), 2.28 (s, 6H). [0835] Step 2. Methyl 3-[(4-{(R)-15-methyl-13-oxo-11-thia-3,6,14,17-tetraazatetrac yclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)- hexaen-5-yloxy}-2-chloro-5-pyrimidinyl) methoxy]bicyclo[1.1.1]pentane-1-carboxylate. To a solution of methyl 3-[(2,4-dichloro-5- pyrimidinyl)methoxy]bicyclo[1.1.1]pentane- 1-carboxylate (5 mg, 1 eq., 16.5 µmol) and (R)-5- hydroxy-15-methyl-11-thia-3,6,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca- 1(10),2(7),3,5,8,12(18)-hexaen-13-one (4.95 mg, 1 eq., 16.5 µmol) in dimethyl sulfoxide (0.2 mL) was added dipotassium carbonate (4.56 mg, 2 eq., 33 µmol) at 25 °C. The reaction mixture was heated to 60 °C and stirred at 60 °C for 2 hrs. LCMS showed starting material was consumed and the desired Ms was detected. One additional vial was set up as described above. After cooling to 20 °C, two reaction mixtures were combined, poured into water (2 mL) and then extracted by ethyl acetate (3 × 2 mL). The organic layers were combined and washed with brine (6 mL), dried over by anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue, which was used for next step without purification. [0836] Step 3.3-[(4-{(R)-15-methyl-13-oxo-11-thia-3,6,14,17-tetraazatetr acyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca- 1(10),2(7),3,5,8,12(18)-hexaen-5-yloxy}-2-chloro-5- pyrimidinyl)methoxy]bicyclo[1.1.1]pentane-1-carboxylic acid. To a solution of methyl 3- [(4-{(R)-15-methyl-13-oxo-11-thia-3,6,14,17-tetraazatetracyc lo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca- 1(10),2(7),3,5,8,12(18)-hexaen-5-yloxy}-2-chloro-5-pyrimidin yl) methoxy]bicyclo[1.1.1] pentane-1-carboxylate (14.5 mg, 1 eq., 25.6 µmol) in chloroform (1 mL) was added trimethytin hydroxide (69.4 mg, 15 eq., 384 µmol) at 25 °C. The reaction mixture was heated to 80 °C and stirred at 80 °C for 6 hrs. LCMS showed starting material was consumed, desired Ms was detected. One additional vial was set up as described above. After cooling to 20 °C, two reaction mixtures were combined and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC to afford 5 mg (17.68%) of 3-[(4-{(R)-15-methyl-13-oxo- 11-thia-3,6,14,17-tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹� ��]octadeca- 1(10),2(7),3,5,8,12(18)-hexaen- 5-yloxy}-2-chloro-5-pyrimidinyl)methoxy]bicyclo [1.1.1]pentane-1-carboxylic acid as white solid. LCMS (ESI+): Rt = 1.639 min, m/z 553.3 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 9.00 (br s, 1H), 8.77 (s, 1H), 8.69 (s, 1H), 8.10 (d, J = 9.0 Hz, 1H), 7.95 - 7.88 (m, 1H), 7.36 (br d, J = 2.0 Hz, 1H), 4.77 (s, 2H), 3.91 - 3.81 (m, 1H), 3.77 (br dd, J = 4.5, 13.1 Hz, 1H), 3.67 - 3.53 (m, 1H), 2.33 (br s, 6H), 1.42 (br d, J = 6.8 Hz, 3H). Example 98 - Synthesis of (1s,3s)-3-[(4-{(R)-15-methyl-13-oxo-11-thia-3,6,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10), 2(7),3,5,8,12(18)-hexaen-5-yloxy}-2- chloro-5-pyrimidinyl)methoxy]-1-methylcyclobutanecarboxylic acid (I-96) [0837] Step 1. Methyl (1s, 3s)-3-[(2, 4-dichloro-5-pyrimidinyl) methoxy]-1- methylcyclobutanecarboxylate and methyl (1r, 3r)-3-[(2,4-dichloro-5-pyrimidinyl) methoxy]-1-methylcyclobutanecarboxylate. To a solution of 2,4-dichloro-5-(iodomethyl) pyrimidine (0.2 g, 1eq., 692 µmol) in tetrahydrofuran (2 mL) was added methyl 3-hydroxy-1- methylcyclobutanecarboxylate (99.8 mg, 1 eq., 692 µmol) and potassium 2-methylpropan-2-ol (157 mg, 2 eq., 1.38 mmol) at -60 °C and stirred at -60 °C for 1 hr. LCMS showed starting material was consumed and desired Ms was detected. Six additional vials were set up as described above. After warming to room temperature, seven reaction mixtures were combined, diluted with water (40 mL) and extracted with ethyl acetate (3 × 15 mL). The organic phase was combined, washed with brine (40 mL) and dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure to give residue, which was purified by prep-HPLC to give 200 mg (12.62%) of methyl (1s, 3s)-3-[(2, 4-dichloro-5- pyrimidinyl) methoxy]-1-methylcyclobutanecarboxylate as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) 8.65 (s, 1H), 4.46 (s, 2H), 4.23 - 4.14 (m, 1H), 3.72 (s, 3H), 2.58 - 2.45 (m, 2H), 2.33 - 2.23 (m, 2H), 1.41 (s, 3H). [0838] And 210 mg (13.25%) of methyl (1r, 3r)-3-[(2,4-dichloro-5-pyrimidinyl)methoxy]-1- methylcyclobutanecarboxylate as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) 8.65 (s, 1H), 4.47 (s, 2H), 4.25 - 4.17 (m, 1H), 3.73 (s, 3H), 2.87 - 2.76 (m, 2H), 2.03 - 1.92 (m, 2H), 1.45 (s, 3H). [0839] Step 2. methyl(1s,3s)-3-[(4-{(R)-15-methyl-13-oxo-11-thia-3,6,14,17- tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)- hexaen-5-yloxy}-2- chloro-5-pyrimidinyl)methoxy]-1-methylcyclobutanecarboxylate . To a solution of (15R)-5- hydroxy-15-methyl-11-thia-3,6,14,17-tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca- 1(10),2(7),3,5,8,12(18)-hexaen-13-one (30 mg, 1 eq., 99.9 µmol) and methyl (1s,3s)-3-[(2,4- dichloro-5-pyrimidinyl)methoxy]-1-methylcyclobutanecarboxyla te (32 mg, 1.1 eq., 105 µmol) in dimethyl sulfoxide (1 mL) was added potassium carbonate (27.6 mg, 2 eq., 0.2 mmol) at 20 °C. The reaction mixture was heated to 60 °C and stirred at 60 °C for 2 hrs. LCMS showed starting material was consumed and the desired Ms was detected. One additional vial were set up as described above. After cooling to 20 °C, all two reaction mixtures were combined, diluted with water (6 mL), extracted with ethyl acetate (3 × 2 mL). The organic phase was combined, washed with brine (6 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 50 mg (35.19%) methyl(1s,3s)-3-[(4-{(R)-15- methyl-13-oxo-11-thia-3,6,14,17-tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca- 1(10),2(7),3,5,8,12(18)-hexaen-5-yloxy}-2-chloro-5-pyrimidin yl)methoxy]-1- methylcyclobutanecarboxylate as orange solid. LCMS (ESI+): Rt = 1.971 min, m/z 569.3 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.08 (s, 1H), 8.83 - 8.74 (m, 2H), 8.35 (d, J = 9.0 Hz, 1H), 8.00 (br d, J = 4.4 Hz, 1H), 7.95 (d, J = 8.9 Hz, 1H), 4.60 (s, 2H), 4.33 - 4.24 (m, 1H), 3.71 - 3.65 (m, 1H), 3.65 - 3.55 (m, 5H), 2.36 - 2.29 (m, 2H), 2.25 - 2.18 (m, 2H), 1.32 (s, 3H), 1.22 (d, J = 6.6 Hz, 3H). [0840] Step 3. (1s,3s)-3-[(4-{(R)-15-methyl-13-oxo-11-thia-3,6,14,17-tetraa zatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)- hexaen-5-yloxy}-2-chloro-5-pyrimidinyl) methoxy]-1-methylcyclobutanecarboxylic acid. To a solution of methyl (1s,3s)-3-[(4-{(R)- 15-methyl-13-oxo-11-thia-3,6,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10), 2(7),3, 5,8,12(18)-hexaen-5-yloxy}-2-chloro-5-pyrimidinyl)methoxy]-1 -methylcyclo- butanecarboxylate (50 mg, 1eq., 87.9 µmol) in trichloromethane (2 mL) was added trimethylstannanol (79.4 mg, 5 eq., 439 µmol) at 20 °C. The reaction mixture was heated to 80 °C and stirred at 80 °C for 12 hrs. LCMS showed starting material was consumed and desired Ms was detected. After cooling to 20 °C, the mixture was filtered and the filtrate was concentrated under reduced pressure to give residue, which was purified by prep-HPLC to give 34 mg (69.72%) of (1s,3s)-3-[(4-{(R)-15-methyl-13-oxo-11-thia-3,6,14,17-tetraa zatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3, 5,8,12(18)-hexaen-5-yloxy}-2-chloro-5-pyrimidinyl) methoxy]-1-methyl-cyclobutanecarboxylic acid as orange solid. LCMS (ESI+): Rt = 1.669 min, m/z 555.1 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 12.28 (br s, 1H), 9.09 (s, 1H), 8.80 (br t, J = 3.9 Hz, 1H), 8.78 (s, 1H), 8.35 (d, J = 8.9 Hz, 1H), 8.01 (d, J = 4.4 Hz, 1H), 7.96 (d, J = 8.9 Hz, 1H), 4.60 (s, 2H), 4.31 - 4.22 (m, 1H), 3.72 - 3.64 (m, 1H), 3.63 - 3.55 (m, 2H), 2.35 - 2.28 (m, 2H), 2.21 - 2.14 (m, 2H), 1.30 (s, 3H), 1.22 (d, J = 6.6 Hz, 3H). Example 99 - Synthesis of (1r,3r)-3-[(4-{(R)-15-methyl-13-oxo-11-thia-3,6,14,17- tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)- hexaen-5-yloxy}-2- chloro-5-pyrimidinyl)methoxy]-1-methylcyclobutanecarboxylic acid (I-95) [0841] Step 1. Methyl(1r,3r)-3-[(4-{(R)-15-methyl-13-oxo-11-thia-3,6,14,17- tetraaza- tetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)- hexaen-5-yloxy}-2-chloro-5- pyrimidinyl)methoxy]-1-methylcyclobutanecarboxylate. To a solution of (15R)-5-hydroxy- 15-methyl-11-thia-3,6,14,17-tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5, 8,12(18)-hexaen-13-one (30 mg, 1 eq., 99.9 µmol) and methyl (1r,3r)-3-[(2,4-dichloro-5- pyrimidinyl) methoxy]-1-methylcyclobutanecarboxylate (32 mg, 1 eq., 105 µmol) in dimethyl sulfoxide (0.5 mL) was added dipotassium carbonate (27.6 mg, 2 eq., 0.2 mmol) at 20 °C. The reaction mixture was heated to 60 °C and stirred at 60 °C for 2 hrs. LCMS showed starting material was consumed and desired Ms was detected. One additional vial were set up as described above. After cooling to 20 °C, two reaction mixtures were combined, diluted with water (6 mL) and extracted with ethyl acetate (3 × 2 mL). The organic phase was combined, washed with brine (6 mL) anddried over sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford 50 mg (35.19%) of methyl(1r,3r)-3- [(4-{(R)-15-methyl-13-oxo-11-thia-3,6,14,17-tetraazatetracyc lo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca- 1(10),2(7),3,5,8,12(18)-hexaen-5-yloxy}-2-chloro-5-pyrimidin yl)methoxy]-1- methylcyclobutanecarboxylate as orange solid. LCMS (ESI+): Rt = 2.019 min, m/z 569.4 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.08 (s, 1H), 8.79 (s, 2H), 8.34 (d, J = 9.0 Hz, 1H), 8.00 (br d, J = 4.4 Hz, 1H), 7.95 (d, J = 8.9 Hz, 1H), 4.60 (s, 2H), 4.22 - 4.13 (m, 1H), 3.73 - 3.65 (m, 1H), 3.65 - 3.53 (m, 5H), 2.74 - 2.66 (m, 2H), 1.98 - 1.89 (m, 2H), 1.35 (s, 3H), 1.22 (d, J = 6.8 Hz, 3H). [0842] Step 2. (1r,3r)-3-[(4-{(R)-15-methyl-13-oxo-11-thia-3,6,14,17-tetraa zatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)- hexaen-5-yloxy}-2-chloro-5-pyrimidinyl) methoxy]-1-methylcyclobutanecarboxylic acid. To a solution of methyl (1r,3r)-3-[(4-{(R)- 15-methyl-13-oxo-11-thia-3,6,14,17 -tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10) ,2(7),3,5, 8,12(18)-hexaen-5-yloxy}-2-chloro-5-pyrimidinyl)methoxy]-1-m ethylcyclobutanecarboxylate (50 mg, 1 eq., 87.9 µmol) in trichloromethane (1.67 mL) was added trimethylstannanol (79.4 mg, 5 eq., 439 µmol) at 20 °C. The reaction mixture was heated to 80 °C and stirred at 80 °C for 12 hrs. LCMS showed starting material was consumed and desired Ms was detected. After cooling to 20 °C, the mixture was filtered and the filtrate was purified by prep-HPLC to afford 24 mg (49.21%) of (1r,3r)-3-[(4-{(R)-15-methyl-13-oxo-11-thia-3,6,14,17-tetraa zatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)- hexaen-5-yloxy}-2-chloro-5-pyrimidinyl) methoxy]-1-methylcyclobutanecarboxylic acid as orange solid. LCMS (ESI+): Rt = 1.694 min, m/z 555.1 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 12.33 (br s, 1H), 9.09 (s, 1H), 8.83 - 8.77 (m, 2H), 8.35 (d, J = 8.9 Hz, 1H), 8.01 (br d, J = 4.1 Hz, 1H), 7.96 (d, J = 8.9 Hz, 1H), 4.60 (s, 2H), 4.23 - 4.12 (m, 1H), 3.71 - 3.64 (m, 1H), 3.60 (br s, 2H), 2.72 - 2.64 (m, 2H), 1.94 - 1.84 (m, 2H), 1.32 (s, 3H), 1.22 (d, J = 6.6 Hz, 3H). Example 100 - Synthesis of 5-(5-{[(S)-4-(difluoromethyl)-2-oxo-1,3-oxazolidin-3- yl]methyl} -2-chloro-4-pyrimidinyloxy)-15,15-dimethyl-11-thia-3,6,14,17 - tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)- hexaen-13-one (I-91) [0843] Step 1.3-[(2,4-dichloro-5-pyrimidinyl) methyl]-4-(difluoromethyl)-1,3-oxazolidin- 2-one. To a solution of 4-(difluoromethyl)-1,3-oxazolidin-2-one (50 mg, 1 eq, 365 µmol) in tetrahydrofuran (1 mL) at 0 °C was added potassium tert-butoxide (81.9 mg, 2 eq, 729 µmol) and 2,4-dichloro-5-(iodomethyl)pyrimidine (126 mg, 1.2 eq, 438 µmol). The reaction mixture was stirred at 0 °C for 0.5 hr. LCMS showed the starting material was consumed completely and desired product was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent to give a residue, which was purified via silica gel chromatography eluting with 10-30% ethyl acetate in petroleum ether. Pure fractions were combined and concentrated to afford 60 mg (55.1%) of 3-[(2,4-dichloro-5-pyrimidinyl) methyl]-4-(difluoromethyl)-1,3-oxazolidin-2-one as a yellow solid. LCMS: Rt= 0.372 min, m/z =298.0(M+H) ⁺ . [0844] Step 2.5-(5-{[(S)-4-(difluoromethyl)-2-oxo-1,3-oxazolidin-3-yl]me thyl} -2-chloro-4- pyrimidinyloxy)-15,15-dimethyl-11-thia-3,6,14,17-tetraazatet racyclo[8.8.0.0²,⁷.0¹²,¹⁸] octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one. To a solution of 5-hydroxy-15,15-dimethyl- 11-thia-3,6,14,17-tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹� ��]octadeca-1(10),2(7),3,5,8,12(18)-hexaen- 13-one (42.2 mg, 1 eq, 134 µmol) in dimethyl sulfoxide (1 mL) at 25 °C was added potassium carbonate (37.1 mg, 2 eq, 268 µmol) and (S)-3-[(2,4-dichloro-5-pyrimidinyl)methyl]-4- (difluoromethyl)-1,3-oxazolidin-2- one (40 mg, 1 eq, 134 µmol). The reaction mixture was stirred at 40 °C for 2 hrs. LCMS showed the starting material was consumed and desired product was detected. One additional vials was set up as described above. Both reaction mixtures were combined and filtered, the filtrate was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC to afford 9.8 mg (12.6%) of 5-(5-{[(S)-4- (difluoromethyl)-2-oxo-1,3-oxazolidin-3-yl]methyl} -2-chloro-4-pyrimidinyloxy)-15,15- dimethyl-11-thia-3,6,14,17-tetraazatetracyclo[8.8.0.0²,⁷. 0¹²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)- hexaen-13-one as a yellow solid. LCMS: R _t = 2.416 min, m/z = 576.1 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.10 (s, 1H), 8.86 (t, J = 4.0 Hz, 1H), 8.76 (s, 1H), 8.37 (d, J = 8.9 Hz, 1H), 7.97 (d, J = 8.9 Hz, 1H), 7.91 (s, 1H), 6.59 - 6.20 (m, 1H), 4.83 (d, J = 16.3 Hz, 1H), 4.59 (d, J = 16.3 Hz, 1H), 4.52 - 4.40 (m, 2H), 4.38 - 4.30 (m, 1H), 3.47 (br d, J = 3.5 Hz, 2H), 1.27 (s, 6H).

Example 101 - Synthesis of (R)-5-{2-chloro-5-[(3-hydroxy-3-methyl-2-oxo-1-pyrrolidinyl) methyl]-4-pyrimidinyloxy}-15-methyl-11-thia-3,6,14,17-tetraa zatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)- hexaen-13-one (I-84) H OMe NH ₂ OH-HCl, NaOH, formaldehyde H ₂ , Pd/C O MeOH, water, 35-70 °C, 2 hrs EtOH, 25 °C, 12 hrs [0845] Step 1. Methyl 5-methyl-1, 2-oxazolidine-5-carboxylate. To a solution of hydrogen hydroxylamine chloride (20 g, 1 eq., 288 mmol) and sodium hydroxide (11.5 g, 1 eq., 288 mmol) in methanol (20 mL) and water (40 mL) were added dropwise formaldehyde 37%w/w (23.4 g, 1 eq., 288 mmol) at a sufficiently slow rate that the temperature did not exceed 35 °C. Subsequently, methyl 2-methylprop-2-enoate (28.8 g, 1 eq., 288 mmol) were added on completion of addition. The mixture was heated to 70 °C and stirred at 70 °C for 12 hrs. TLC (eluted with dichloromethane/methanol = 10/1, R _f = 0.6) showed starting material spot was consumed and the desired spot was detected. The reaction solution was extracted with dichloromethane (3 × 50 mL). The combined organic phase was washed with brine (100 mL) then dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure to give residue. The residue was purified by column on silica gel (eluted with petroleum ether/ethyl acetate = 2/3 to 1/1) to afford 9.7 g (19.72%) of methyl 5-methyl-1, 2-oxazolidine-5-carboxylate as orange oil. ¹ H NMR (400 MHz, CDCl ₃ ) 3.74 (br s, 3 H) 3.24 - 3.35 (m, 1 H) 3.16 (td, J = 11.26, 8.2 Hz, 1 H) 2.49 (td, J = 12.63, 8.2 Hz, 1 H) 2.11 (m, 1 H) 1.52 (s, 3 H). [0846] Step 2.3-hydroxy-3-methylpyrrolidin-2-one. To a suspension of palladium on carbon (3 g, 10%) in ethanol (30 mL) was added methyl 5-methyltetrahydro-5-isoxazolecarboxylate (3 g, 1 eq., 20.7 mmol) at 20 °C under H ₂ atmosphere (15 psi). LCMS showed starting material peak was consumed and the desired peak was detected. The mixture was filtered and the filtrate was concentrated under reduced pressure to give residue. The residue was triturated by acetonitrile (50 mL) and the mixture was filtered. The filter cake was washed with acetonitrile (10 mL) twice and dried under reduced pressure to afford 1 g (42.03%) of 3-hydroxy-3- methylpyrrolidin-2-one as off-white solid. LCMS (ESI+): Rt = 0.069 min, m/z 116.2 (M+H) ⁺ . [0847] Step 3.1-[(2,4-dichloro-5-pyrimidinyl)methyl]-3-hydroxy-3-methyl- 2- pyrrolidinone. To a solution of 3-hydroxy-3-methyl-2-pyrrolidinone (0.2 g, 1 eq., 1.74 mmol) in dimethylformamide (3 mL) was added potassium 2-methyl-2-propanolate (390 mg, 2 eq., 3.47 mmol) and 2,4-dichloro-5-(iodomethyl)pyrimidine (502 mg, 1 eq., 1.74 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 hrs. LCMS showed starting material peak was consumed and the desired peak was detected. One additional view was set up as described above. Two reaction mixtures were poured into water (20 mL) and was extracted with ethyl acetate (3 × 10 mL). The organic phase was combined, washed with brine (30 mL) and dried over Na ₂ SO ₄ . The mixture was filtered and the filtrate was concentrated under reduced pressure to give residue. The residue was purified by prep-TLC (eluted with ethyl acetate, R _f = 0.6) to afford 18 mg (3.75%) 1-[(2,4-dichloro-5-pyrimidinyl)methyl]-3-hydroxy-3-methyl-2- pyrrolidinone as yellow oil. LCMS (ESI+): Rt = 0.984 min, m/z 276.3 (M+H) ⁺ . [0848] Step 4. (R)-5-{2-chloro-5-[(3-hydroxy-3-methyl-2-oxo-1-pyrrolidinyl) methyl]-4- pyrimidinyloxy}-15-methyl-11-thia-3,6,14,17-tetraazatetracyc lo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca- 1(10),2(7),3,5,8,12(18)-hexaen-13-one. To a solution of 1-[(2,4-dichloro-5- pyrimidinyl)methyl]-3-hydroxy-3-methyl-2-pyrrolidinone (18 mg, 1.5 eq., 65.2 µmol) in dimethyl sulfoxide (0.5 mL) was added (R)-5-hydroxy-15-methyl-11-thia-3,6,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸] octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (13.1 mg, 1 eq., 43.5 µmol) and dipotassium carbonate (12 mg, 2 eq., 86.9 µmol) at 20 °C. Then resulting mixture was heated to 60 °C and stirred at 60 °C for 2 hrs. LCMS showed starting material peak was consumed and the desired peak was detected. The mixture was filtered and the filtrate was concentrated under reduced pressure to give residue. The residue was purified by prep-HPLC to afford 3 mg (12.78%) (R)-5-{2-chloro-5-[(3-hydroxy-3-methyl-2-oxo-1- pyrrolidinyl)methyl]-4-pyrimidinyloxy}-15-methyl-11-thia-3,6 ,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10), 2(7),3,5,8,12(18)-hexaen-13-one as orange solid. LCMS (ESI+): Rt = 1.425 min, m/z 540.1 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.07 (s, 1H), 8.80 (br t, J = 3.9 Hz, 1H), 8.63 (s, 1H), 8.35 (d, J = 8.9 Hz, 1H), 8.00 (br d, J = 4.5 Hz, 1H), 7.95 (d, J = 8.9 Hz, 1H), 5.37 (s, 1H), 4.65 - 4.53 (m, 2H), 3.72 - 3.64 (m, 1H), 3.60 (br s, 2H), 3.45 - 3.38 (m, 1H), 3.30 - 3.25 (m, 1H), 1.98 (t, J = 6.5 Hz, 2H), 1.24 - 1.18 (m, 6H). Example 102 - Synthesis of (R)-5-(2-chloro-5-fluoro-4-pyrimidinylamino)-15-methyl-11- thia-3,6,14,17-tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸] octadeca-1,3,5,7,9,12(18)-hexaen-13-one (I-165) [0849] To a solution of (R)-5-bromo-15-methyl-11-thia-3,6,14,17 tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1,3,5,7,9,12(18)-hexaen- 13-one (10 mg, 1 eq., 27.5 µmol) in 1,4- dioxane (1 mL) was added 2-chloro-5-fluoro-4-pyrimidinylamine (4.87 mg, 1.2 eq., 33 µmol), sodium 2-methyl-2-propanolate (7.94 mg, 3 eq., 82.6 µmol) and methanesulfonato[9,9- dimethyl-4,5-bis(diphenylphosphino)xanthene](2-methylamino-1 ,1-biphenyl-2-yl)palladium(II) (2.65 mg, 0.1 eq, 2.75 µmol) at 25 °C, after dagessed and purged nitrogen for 3 times. The reaction mixture was heated to 90 °C and stirred at 90 °C for 1 hr. LCMS showed starting material was consumed and the desired Ms was detected. Nine additional views were set up as discribe above. After cooling to room temperature, all ten mixtures were combined and quenched by water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phase was combined, washed with brine (50 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC to afford 50 mg (41.57%) of (R)-5-(2-chloro-5-fluoro-4- pyrimidinylamino)-15-methyl-11-thia-3,6,14,17-tetraazatetrac yclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca- 1,3,5,7,9,12(18)-hexaen-13-one as yellow solid. LCMS (ESI+): Rt = 1.797 min, m/z 430.1 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 11.39 - 11.17 (m, 1H), 9.55 (s, 1H), 8.86 (br t, J = 3.7 Hz, 1H), 8.53 (d, J = 3.1 Hz, 1H), 8.23 (d, J = 8.9 Hz, 1H), 7.93 (br d, J = 4.3 Hz, 1H), 7.87 (d, J = 8.9 Hz, 1H), 3.71 - 3.64 (m, 1H), 3.60 (br s, 2H), 1.21 (d, J = 6.6 Hz, 3H).

Example 103 - Synthesis of 5'-[2-chloro-5-(ethoxymethyl)-4-pyrimidinyloxy]spiro [azetidine-3,15'-[11]thia[3,6,14,17]tetraazatetracyclo [8.8.0.0 ² , ⁷ .0 ¹² , ¹⁸ ]octadeca [1(10),2(7),3,5,8,12(18)]hexaen]-13'-one and 5'-[2-chloro-5-(ethoxymethyl)-4- pyrimidinyloxy]-1-methylspiro[azetidi- ne-3,15'-[11]thia[3,6,14,17] tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca[1(10),2(7),3,5,8,12 (18)]hexaen]-13'-one (I-161) [0850] Step 1. tert-butyl 3-hydroxy-3-(nitromethyl)azetidine-1-carboxylate. To a solution of tert-butyl 3-oxoazetidine-1-carboxylate (1 g, 1 eq, 5.84 mmol) in ethanol (5 mL) at rt was added nitromethane (1.19 mL, 3.8 eq., 22.2 mmol) and triethylamine (162 µL, 0.2 eq, 1.17 mmol). Then the reaction mixture was stirred at 25 °C for 12 hrs. TLC (eluted with petroleum ether/ethyl acetate=3/1, R _f = 0.4) showed the starting material was consumed and desired spot was formed. Four additional reaction vials were set up as described above. All five reaction mixtures were combined and concentrated under reduced pressure to give 7 g (92.8%) of tert- butyl 3-hydroxy-3-(nitromethyl)azetidine-1-carboxylate as a white solid, which was used directly for the next step, without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.44 (s, 1H), 4.86 (s, 2H), 4.04 (br d, J = 8.4 Hz, 2H), 3.74 (br d, J = 9.0 Hz, 2H), 1.38 (s, 9H). [0851] Step 2. tert-butyl 3-(nitromethylidene)azetidine-1-carboxylate. To a stirred solution of tert-butyl 3-hydroxy-3-(nitromethyl)azetidine-1-carboxylate (3.5 g, 1 eq, 13.1 mmol) in dry dichloromethane (35 mL) at -78 °C was added dropwise N,N-diethyl(trifluorothio)amine (2.39 mL, 1.2 eq, 18.1 mmol) under nitrogen atmosphere. Then cooling bath was removed, and the reaction mixture was stirred at -78 °C for 3 hrs under nitrogen atmosphere. LCMS showed the starting material was consumed and the desired product mass was detected. One additional vial was set up as described above. The reaction mixture was cooled to 0 °C, both reaction mixtures were combined and quenched slowly with saturated aqueous solution of sodium bicarbonate (50 mL). The aqueous layer was extracted with dichloromethane (30 mL × 3), washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain 6 g (83.6%) of tert-butyl 3- (nitromethylidene)azetidine-1-carboxylate as yellow oil, which was engaged in the next step, without further purification. LCMS: Rt= 0.450 min, m/z = 213.0 (M-H)-. [0852] Step 3. tert-butyl 3-amino-3-(nitromethyl)azetidine-1- carboxylate. The intermediate of tert-butyl 3-(nitromethylidene) azetidine-1-carboxylate (2 g, 0.95 eq, 9.34 mmol) was dissolved in a solution of ammonia (2.8 mL, 7 N) in methanol, and the reaction mixture was stirred at 25 °C for 2 hrs. LCMS showed the starting material was consumed and the desired product mass was detected. Two additional vials were set up as described above. All three reaction mixtures were combined and concentrated under reduced pressure to obtain 6.4 g (84.7%) of tert-butyl 3-amino-3-(nitromethyl)azetidine-1- carboxylate as an orange solid, which was used directly for the next step, without further purification. LCMS: Rt= 0.343 min, m/z = 272.1 (M+41) ⁺ . [0853] Step 4. tert-butyl 3-{[(benzyloxy)carbonyl]amino}-3-(nitromethyl)azetidine-1- carboxylate. To a stirred solution of tert-butyl 3-amino-3-(nitromethyl)azetidine-1- carboxylate (1.6 g, 1 eq, 6.92 mmol) in dichloromethane (16 mL) at 20 °C was added a solution of sodium hydrogen carbonate (1.16 g, 2 eq, 13.8 mmol) in water (16 mL). The reaction mixture was cooled to 0 °C, benzyl carbonochloridate (974 µL, 1 eq, 6.92 mmol) was added dropwise. Then the reaction mixture was stirred at 20 °C for 17 hrs. LCMS showed the starting material was consumed and the desired product mass was detected. Three additional vials were set up as described above. All four reaction mixtures were combined and the two phases were separated. The aqueous layer was extracted with dichloromethane (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to afford 6 g (47.4%) of tert-butyl 3-{[(benzyloxy)carbonyl]amino}-3-(nitromethyl)azetidine-1-ca rboxylate as a yellow solid, which was engaged in the next step, without further purification. LCMS: Rt= 0.499 min, m/z = 364.2 (M-H)-. [0854] Step 5. tert-butyl 3-(aminomethyl)-3-{[(benzyloxy)carbonyl]amino}azetidine-1- carboxylate. To a solution of tert-butyl 3-{[(benzyloxy)carbonyl]amino}-3-(nitromethyl) azetidine-1- carboxylate (1.5 g, 1 eq, 4.11 mmol) in methanol (22.5 mL) at 0 °C was added dichloronickel hexahydrate (976 mg, 1 eq, 4.11 mmol) and sodium borohydride (777 mg, 5 eq, 20.5 mmol) in portions under nitrogen atmosphere. Then the reaction mixture was stirred at 25 °C for 1 hr. LCMS showed the starting material was consumed and the desired product mass was detected. Three additional vials were set up as described above. All four reaction mixtures were combined and quenched by saturated aqueous solution of sodium bicarbonate. The mixture was filtered through a pad of Celite, the filtrate was concentrated under reduced pressure to give a residue, which was diluted with water and extracted with dichloromethane (50 mL × 3), the combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel on column eluted with 5-10% methanol in dichloromethane. Pure fractions were combined and concentrated to afford 1.5 g (27.2%) of tert-butyl 3-(aminomethyl)-3-{[(benzyloxy)carbonyl]amino}azetidine-1-ca rboxylate as a white solid. LCMS: Rt= 0.432 min, m/z = 671.4 (2M+H) ⁺ . [0855] Step 6. tert-butyl 3-{[(benzyloxy)carbonyl] amino}-3-({[3-methoxy-8-(methoxy- carbonyl)thieno[3,2-f]quinoxalin-9-yl]amino}methyl)azetidine -1-carboxylate. To a solution of tert-butyl 3-(aminomethyl)-3-{[(benzyloxy)carbonyl]amino}azetidine-1-ca rboxylate (0.3 g, 1 eq, 894 µmol) in 1,4-dioxane (5 mL) at 20 °C was added methyl 9-bromo-3- methoxythieno[3,2-f]quinoxaline-8-carboxylate (527 mg, 1 eq, 894 µmol), methanesulfonato [2,2-bis(diphenyl-phosphino)-1,1-binaphthyl](2-amino-1,1-bip henyl-2-yl)palladium (178 mg, 0.2 eq, 179 µmol) and dicaesium carbonate (583 mg, 2 eq, 1.79 mmol) under nitrogen atmosphere. Then the reaction mixture was stirred at 90 °C for 12 hrs under nitrogen atmosphere. LCMS showed the starting material was consumed and the desired product mass was detected. Four additional vials were set up as described above. After cooling to room temperature, all five reaction mixtures were combined and filtered through a celite pad, the filtrate was concentrated to give a residue, which was purified by silica gel chromatography eluting with 10-30% ethyl acetate in petroleum ether. Pour fractions were combined and concentrated to afford 0.5 g (18.4%) of tert-butyl 3-{[(benzyloxy)carbonyl] amino}-3-({[3- methoxy-8-(methoxycarbonyl)thieno[3,2-f]quinoxalin-9-yl]amin o}methyl)azetidine-1- carboxylate as a yellow solid. LCMS: Rt =0.645 min, m/z = 608.3 (M+H) ⁺ . [0856] Step 7. tert-butyl 3-amino-3-({[3-methoxy-8-(methoxycarbonyl) thieno[3,2- f]quinoxalin-9-yl]amino}methyl) azetidine-1-carboxylate. To a stirred solution of tert-butyl 3-{[(benzyloxy)carbonyl]amino}-3-({[3-methoxy-8- (methoxycarbonyl)thieno[3,2- f]quinoxalin-9-yl]amino}methyl)azetidine-1-carboxylate (0.2 g, 329 µmol) in isopropanol (5 mL) at 20 °C were added palladium on carbon (10% wt, 35 mg, 0.1 eq, 32.9 µmol) and ammonium formate (125 mg, 6 eq, 1.97 mmol). Then the reaction mixture was stirred at 80 °C for 4 hrs. LCMS showed the starting material was consumed and the desired product mass was detected. One additional vial was set up as described above. After cooling to room temperature, all two reaction mixtures were combined and filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give 260 mg (66.7%) of tert-butyl 3- amino-3-({[3-methoxy-8-(methoxy-carbonyl)thieno[3,2-f]quinox alin-9- yl]amino}methyl)azetidine-1-carboxylate as a yellow solid, which was used directly for the next step, without further purification. LCMS: Rt =0.536 min, m/z = 474.2 (M+H) ⁺ . [0857] Step 8. tert-butyl 5'-methoxy-13'-oxospiro[azetidine-3,15'-[11]thia[3,6,14,17] tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca[1(10), 2(7),3,5,8,12(18)]hexaene]-1-carboxylate. To a solution of methyl 3-{[(3-amino-1-tert-butoxycarbonyl-3-azetidinyl)methyl]amino }-11- methoxy-5-thia-10,13-diazatricyclo[7.4.0.0²,⁶]trideca-1(9 ),2(6),3,7,10,12-hexaene-4-carboxy- late (130 mg, 1 eq, 275 µmol) in methanol (5 mL) at 20 °C was added sodium methoxide (44.5 mg, 3 eq, 824 µmol). Then the reaction mixture was heated up to 80 °C and stirred at 80 °C for 2 hrs. LCMS showed the starting material was consumed and the desired product mass was detected. One additional vial was set up as described above. After cooling to room temperature, both reaction mixtures were combined and concentrated under reduced pressure to give a crude product, which was triturated with methanol (5 mL). The resulting solid was filtered through a funnel, rinsed with methanol, and dried under reduced pressure to give 140 mg (57.7%) tert-butyl 5'-methoxy-13'-oxospiro[azetidine-3,15'-[11]thia[3,6,14,17] tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca[1(10),2(7),3,5,8,12(18)] hexaene]-1-carboxylate as a yellow solid. LCMS: Rt =0.628 min, m/z = 442.2 (M+H) ⁺ . [0858] Step 9.5'-hydroxyspiro[azetidine-3,15'-[11]thia[3,6,14,17]tetraaz atetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca[1(10),2(7),3,5,8,12(18)] hexaen]-13'-one. A mixture solution of tert- butyl 5'-methoxy-13'-oxospiro[azetidine-3,15'-[11]thia[3,6,14,17]t etraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca[1(10),2(7),3,5,8,12(18)] hexaene]-1-carboxylate (0.1 g, 226 µmol) and hydrogen bromide in acetic acid (0.1 mL) was stirred at 40 °C for 5 hrs. LCMS showed the starting material was consumed and desired product mass was detected. The suspension was diluted with dichloromethane (1 mL) and filtered, the filter cake was collected and dried over under reduced pressure to obtain the crude product 80 mg (86.3%) of-5'- hydroxyspiro[azetidine-3,15'- [11]thia[3,6,14,17]tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹ ⁸]octadeca[1(10),2(7),3,5,8,12(18)] hexaen]- 13'-one as a brown solid, which was used directly for the next step, without further purification. LCMS: Rt = 0.210 min, m/z = 328.2 (M+H) ⁺ . [0859] Step 10. tert-butyl 5'-hydroxy-13'-oxospiro [azetidine-3,15'-[11]thia[3,6,14,17] tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca[1(10), 2(7),3,5,8,12(18)]hexaene]-1-carboxylate. To a solution of 5'-hydroxyspiro[azetidine-3,15'-[11]thia[3,6,14,17]tetraazat etracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca[1(10),2(7),3,5,8,12(18)] hexaen]-13'-one (70 mg, 1 eq, 214 µmol) in dichloromethane (1 mL) at 20 °C were added triethylamine (14.8 µL, 0.5 eq, 107 µmol) and tert-butoxy-tert-butoxycarbonylformylate (98.3 µL, 2 eq, 428 µmol). Then the reaction mixture was stirred at 20 °C for 2 hrs. LCMS showed the starting material was consumed and the desired product mass was detected. The suspension was filtered and the filter cake was washed with dichloromethane (1 mL × 3), then the solid was collected and dried over under reduced pressure to obtain 85 mg (83.6%) of tert-butyl 5'-hydroxy-13'-oxospiro [azetidine-3,15'-[11]thia [3,6,14,17]tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octa deca[1(10),2(7),3,5,8,12(18)]hexaene]-1- carboxylate as a brown solid, which was used directly for the next step, without further purification. LCMS: Rt = 0.379 min, m/z = 426.2 (M-H) ⁺ . [0860] Step 11. tert-butyl5'-[2-chloro-5-(ethoxymethyl)-4-pyrimidinyloxy]-13 '- oxospiro[azetidine-3,15'-[11]thia[3,6,14,17]tetraazatetracyc lo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca [1(10),2(7),3,5,8,12(18)]hexaene]-1-carboxylate. To a solution of tert-butyl 5'-hydroxy-13'- oxospiro[azetidine-3,15'-[11]thia[3,6,14,17] tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca [1(10),2(7),3,5,8,12(18)]hexaene]-1-carboxylate (85 mg, 1 eq, 199 µmol) in dimethyl sulfoxide (1 mL) at 20 °C were added dipotassium carbonate (55 mg, 2 eq., 398 µmol) and 2,4-dichloro- 5-(ethoxymethyl)pyrimidine (41.2 mg, 1 eq, 199 µmol). Then the reaction mixture was stirred at 50 °C for 3 hrs. LCMS showed the starting material remained and the desired product mass was detected. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (5 mL × 3), the combined organic phase was washed brine (10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give 0.1 g (67.2%) of tert-butyl5'-[2-chloro-5-(ethoxymethyl)-4-pyrimidinyloxy]-13 '- oxospiro[azetidine-3,15'-[11]thia[3,6,14,17]tetraazatetracyc lo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca [1(10),2(7),3,5,8,12(18)]hexaene]-1-carboxylate as a yellow oil, which was used directly for the next step, without further purification. LCMS: Rt= 0.662 min, m/z = 598.2 (M+H) ⁺ . [0861] Step 12.5'-[2-chloro-5-(ethoxymethyl)-4-pyrimidinyloxy]spiro[azet idine-3,15'- [11]thia[3,6,14,17]tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹ ⁸] octadeca[1(10),2(7),3,5,8,12(18)] hexaen]-13'-one. To a solution of tert-butyl5'-[2-chloro-5-(ethoxymethyl)-4-pyrimidinyloxy]- 13'-oxospiro [azetidine-3,15'-[11]thia[3,6,14,17]tetraazatetracyclo[8.8.0 .0²,⁷.0¹²,¹⁸]octadeca [1(10),2(7),3,5, 8,12(18)]hexaene]-1-carboxylate (0.1 g, 1 eq, 167 µmol) in dichloromethane (3 mL) at 20 °C was added trifluoroacetic acid (1 mL). Then the reaction mixture was stirred at 20 °C for 2 hrs. LCMS showed the starting material was consumed and the desired product mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified with prep-HPLC to obtain 17.4 mg (20.6%) of 5'-[2-chloro-5- (ethoxymethyl)-4-pyrimidinyloxy]spiro[azetidine-3,15'-[11]th ia[3,6,14,17]tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca[1(10),2(7),3,5,8,12(18)] hexaen]-13'-one as a yellow solid. LCMS: Rt = 0.368 min, m/z = 498.2 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.15 (s, 1H), 8.98 (br t, J = 3.9 Hz, 2H), 8.87 (s, 1H), 8.79 (s, 1H), 8.39 (d, J = 8.9 Hz, 1H), 8.01 (d, J = 9.0 Hz, 1H), 4.70 (s, 2H), 4.17 (br d, J = 6.6 Hz, 2H), 4.03 (br d, J = 10.8 Hz, 2H), 3.93 (br s, 2H), 3.64 (q, J = 7.0 Hz, 2H), 1.20 (t, J = 7.0 Hz, 3H). [0862] Step 13.5'-[2-chloro-5-(ethoxymethyl)-4-pyrimidinyloxy]-1-methyls piro[azetidi- ne-3,15'-[11]thia[3,6,14,17]tetraazatetracyclo[8.8.0.0²,⁷ .0¹²,¹⁸] octadeca[1(10),2(7),3,5,8,12 (18)]hexaen]-13'-one. To a solution of 5'-[2-chloro-5-(ethoxymethyl)-4-pyrimidinyloxy] spiro[azetidine-3,15'-[11] thia[3,6,14,17]tetraazatetracyclo [8.8.0.0 ² , ⁷ .0 ¹² , ¹⁸ ]octadeca [1(10),2(7),3,5,8,12(18)]hexaen]- 13'-one (0.1 g, 1 eq, 201 µmol) in methanol (2 mL) at 20 °C were added formaldehyde (81.5 mg, 5 eq., 1 mmol) and acetic acid (1.21 mg, 0.1 eq., 20.1 µmol). After stirring at 20 °C for 30 min, sodium boranidcarbonitrile (25.2 mg, 2 eq., 402 µmol) was added to the reaction mixture, and then stirred at 20 °C for another 1 hr. LCMS showed the starting material was consumed and the desired product mass was detected. One additional vial was set up as described above. All the two reaction mixtures were combined and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC to obtain 0.1 g (48.63%) 5'-[2-chloro-5-(ethoxymethyl)-4-pyrimidinyloxy]-1- methylspiro[azetidine-3,15'-[11]thia[3,6,14,17]tetraazatetra cyclo[8.8.0.0²,⁷.0¹²,¹⁸] octadeca[1(10),2(7),3,5,8,12(18)]hexaen]-13'-one as a yellow solid. 10.4 mg of the product was delivered for batch 1. Then the rest 89.6 mg of the product was further purification by prep-HPLC for the to obtain 27.6 mg (21.5%) of 5'-[2-chloro-5-(ethoxymethyl)-4- pyrimidinyloxy]-1-methylspiro[azetidi- ne-3,15'-[11]thia [3,6,14,17]tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca[1(10),2(7),3,5,8,12 (18)]hexaen]-13'-one as a yellow solid. LCMS: Rt = 1.298 min, m/z = 512.1 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.11 (s, 1H), 8.98 (br t, J = 4.3 Hz, 1H), 8.77 (s, 1H), 8.49 (s, 1H), 8.35 (d, J = 8.9 Hz, 1H), 8.14 (s, 1H), 7.97 (d, J = 8.9 Hz, 1H), 4.70 (s, 2H), 3.84 (br d, J = 2.8 Hz, 2H), 3.64 (q, J = 7.0 Hz, 2H), 3.44 (br d, J = 3.3 Hz, 2H), 3.18 - 3.06 (m, 2H), 2.33 (s, 3H), 1.20 (t, J = 7.0 Hz, 3H). Example 104 - Synthesis of (R)-5-(2-chloro-4-pyridyloxy)-15-methyl -11-thia-3,6,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1,3,5, 7,9,12(18)-hexaen-13-one (I-168) [0863] To a solution of 2-chloro-4-pyridinol (17.8 mg, 1 eq, 138 µmol) in dimethylformamide (2 mL) was added (R)-5-bromo-15-methyl-11-thia-3,6,14,17-tetraazatetracyclo[8 .8.0.0²,⁷.0¹²,¹⁸] octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (50 mg, 1 eq, 138 µmol), copper(1+) (875 µg, 0.1 eq, 13.8 µmol), dicaesium carbonate (89.7 mg, 2 eq, 275 µmol) and 1,2-bis(methylamino) ethane (1.21 mg, 0.1 eq, 13.8 µmol) under nitrogen. The reaction mixture was stirred at 80 °C for 12 hrs under nitrogen. LCMS showed the starting material was consumed and desired product was detected. The reaction mixture was filtered and the filtrate was purified directly by prep-HPLC to obtain 10.5 mg (18.5%) (R)-5-(2-chloro-4-pyridyloxy)-15-methyl -11-thia- 3,6,14,17-tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octad eca-1,3,5,7,9,12(18)-hexaen-13-one as yellow solid. LCMS: Rt = 1.613 min, m/z = 412.1 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.97 (s, 1H), 8.81 (t, J = 3.6 Hz, 1H), 8.50 (d, J = 5.6 Hz, 1H), 8.26 (d, J = 9.0 Hz, 1H), 8.01 - 7.95 (m, 1H), 7.83 (d, J = 8.9 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.49 (dd, J = 2.0, 5.6 Hz, 1H), 3.74 - 3.64 (m, 1H), 3.64 - 3.54 (m, 2H), 1.21 (d, J = 6.6 Hz, 3H). Example 105 - Synthesis of (R)-5-(6-chloro-2-pyridyloxy)-15-methyl-11-thia-3,6,14,17- tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1,3,5, 7,9,12(18)-hexaen-13-one (I-169) [0864] To a solution of 6-chloro-2-pyridinol (21.4 mg, 1.2 eq, 165 µmol) in dimethylformamide (2 mL) at rt was added (R)-5-bromo-15-methyl-11-thia-3,6,14,17- tetraazatetracyclo[8.8.0.0², ⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-o ne (50 mg, 1 eq, 138 µmol), copper(1+) (875 µg, 0.1 eq, 13.8 µmol), dicaesium carbonate (89.7 mg, 2 eq, 275 µmol) and 1,2-bis(methylamino)ethane (1.21 mg, 0.1 eq, 13.8 µmol) under nitrogen. The reaction mixture was stirred at 80 °C for 12 hrs under nitrogen. LCMS analysis showed the starting material was consumed completely and desired product was detected. The reaction mixture was filtered and the filtrate was purified directly by prep-HPLC to obtain 23.2 mg (40.9%) (R)-5-(6-chloro-2-pyridyloxy)-15-methyl-11-thia-3,6,14,17-te traazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1,3,5,7,9,12(18)-hexaen- 13-one as yellow solid. LCMS: R _t = 1.645 min, m/z = 412.1 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.99 (s, 1H), 8.81 (t, J = 3.7 Hz, 1H), 8.27 (d, J = 8.9 Hz, 1H), 8.15 (s, 1H), 8.08 (t, J = 7.9 Hz, 1H), 7.98 (br d, J = 4.3 Hz, 1H), 7.84 (d, J = 9.0 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 3.73 - 3.65 (m, 1H), 3.64 - 3.56 (m, 2H), 1.22 (d, J = 6.6 Hz, 3H). Example 106 - Synthesis of 5-[(2-chloro-4-pyrimidinyl)methoxy]-15-methyl-11-thia- 3,6,14,17-tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octad eca-1,3,5,7,9,12(18)-hexaen-13-one (I-167) [0865] To a solution of 2-chloro-4-(chloromethyl)pyrimidine (50 mg, 307 µmol) and (R)-5- hydroxy-15-methyl-11-thia-3,6,14,17-tetraazatetracyclo[8.8.0 .0²,⁷.0¹²,¹⁸]octadeca- 1,3,5,7,9,12(18)-hexaen-13-one (92.1 mg, 307 µmol) in dimethylformamide (5 mL) was added dipotassium carbonate (212 mg, 5 eq, 307 µmol) at 20 °C. The mixture was heated to 70 °C and stirred at 70 °C for 2 hrs. LCMS showed the starting material was consumed and desired Ms was detected. One vial was set up as described above. After cooling to 20 °C, all two reaction mixtures were combined and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (neutral condition: column: Phenomenex Luna C18100*30 mm*3 um; mobile phase: [A: H ₂ O (0.2% FA); B: acetonitrile]; B%: 25.00% - 60.00%, 8.00 min) to obtain (R)-5-[(2-chloro-4-pyrimidinyl)methoxy]-15- methyl-11-thia-3,6,14,17-tetraazatetracyclo[8.8.0.0²,⁷.0� �²,¹⁸]octadeca-1,3,5,7,9,12(18)-hexaen- 13-one (11.6 mg, 27.2 µmol) as brown solid. LCMS (ESI+): Rt1 = 1.341 min, m/z = 427.1 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.82 - 8.76 (m, 2H), 8.18 (d, J = 8.9 Hz, 1H), 7.93 (br d, J = 4.4 Hz, 1H), 7.81 - 7.72 (m, 2H), 5.68 (s, 2H), 3.69 - 3.63 (m, 1H), 3.58 (br s, 2H), 1.20 (d, J = 6.6 Hz, 3H). Example 107 - Synthesis of (R)-5-(6-chloro-4-pyrimidinyloxy)-15-methyl-11-thia- 3,6,14,17-tetraazatetracyclo[8.8.0.0²,⁷.0¹²,¹⁸]octad eca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (I-170) [0866] To a solution of (R)-5-hydroxy-15-methyl-11-thia-3,6,14,17-tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)- hexaen-13-one (20.2 mg, 67.1 µmol) in dimethyl sulfoxide (0.2 mL) was added 4,6-dichloropyrimidine (10 mg, 67.1 µmol) and dipotassium carbonate (18.6 mg, 2 eq, 134 µmol) at 20 °C. The mixture was heated to 60 °C and stirred at 60 °C for 2 hrs. Nine additional vials were set up as described above. After cooling to 25 °C, all ten reaction mixture were combined and purified by prep-HPLC (neutral condition) to give (R)-5-(6-chloro-4-pyrimidinyloxy)-15-methyl-11-thia-3,6,14,1 7- tetraazatetracyclo [8.8.0.0²,⁷.0¹²,¹⁸]octadeca-1(10),2(7),3,5,8,12(18)- hexaen-13-one (88.7 mg, 215 µmol, 29.1%) as yellow solid. LCMS (ESI+): m/z 413.1 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.05 (s, 1H), 8.80 (t, J = 3.9 Hz, 1H), 8.76 (d, J = 0.8 Hz, 1H), 8.32 (d, J = 9.0 Hz, 1H), 7.99 (d, J = 4.4 Hz, 1H), 7.93 (d, J = 8.9 Hz, 1H), 7.80 (d, J = 0.8 Hz, 1H), 3.73 - 3.53 (m, 3H), 1.21 (d, J = 6.6 Hz, 3H). EXAMPLE 108 – Analysis of Biological Activity [0867] Exemplary assays for evaluating the biological activity of compounds described herein are described below. MK2 Biochemical Assay [0868] An ADP-Glo™ Kinase Assay can be used to monitor MK2 kinase activity by measuring effects on MK2 phosphorylation of a peptide substrate, HSP27tide (RRLNRQLSVA-amide). The kinase reaction is conducted in a 384-well, low-flange, white, flat-bottomed polystyrene nonbinding surface plate. MK2 is diluted to 0.625 nM in the BSA-containing assay buffer (40 mM Tris pH 7.5, 20 mM MgCl ₂ , 0.125 mg/ml BSA, 0.5 mM TCEP) and 6 μL is added to each well. Subsequently, test compounds dissolved in the DMSO or the DMSO alone (as control) are diluted to 5% DMSO in BSA-free assay buffer (40 mM Tris pH 7.5, 20 mM MgCl ₂ , 0.5 mM TCEP) and a 3 μL aliquot is added to each well. The plate is incubated at room temperature for 1 hour. The reaction is initiated by adding 3 μL of 50 ^M ATP and 3 μL of 1 mg/mL substrate. The plate is incubated on the shaker at room temperature for 1 hour at 300 rpm. The reaction is terminated, and the remaining ATP depleted by adding 15 μL of ADP-Glo™ Reagent to each well. The plate is incubated for 40 minutes at room temperature. Lastly, 30 μL of the Kinase Detection Reagent is added to each well, and the plate is incubated for another 30 minutes at room temperature. The luminescence of each well is measured by EnVision® (PerkinElmer). [0869] The above procedure was performed for the compounds in Table 3, for which the results are provided. The symbol “+++” indicates a IC ₅₀ less than 5 nM. The symbol “++” indicates an IC ₅₀ in the range of 5 nM to 100 nM. The symbol “+” indicates a IC ₅₀ greater than 100 nM. TABLE 3. HeLa Cell HSP27 S78 Phosphorylation Assay [0870] Phospho HSP27 ELISA and total HSP27 ELISA may be performed with PathScan® Phospho-HSP27 (Ser78) Sandwich ELISA Kit (Cell Signaling: 7290) and PathScan® Total HSP27 Sandwich ELISA Kit (Cell Signaling: 7295), respectively. HeLa cells (ATCC: CCL-2) are cultured in DMEM with 10% heat-inactivated fetal calf serum and 100 U/mL Penicillin- Streptomycin at 37 °C and 5% CO ₂ . A day before the assay, HeLa cells are plated at 0.25x10 ⁵ /well in a 96-well plate. On the following day, the cells are incubated with test compounds in the culture media at 37 °C (100 μL/well). After 1 hour incubation, the cells are treated with IL-1b (10 ng/mL) for 20 minutes at 37 °C (200 μl/well). After incubation, cells are washed with PBS 1x and lysed with 200 μL of lysis buffer (from ELISA kit) containing phosphatase inhibitor cocktail to each well, and incubated on ice for 5 minutes. Subsequently, cell lysates are centrifuged for 10 min (x3,000 g) at 4 °C. The supernatant samples are assayed by ELISA for the presence of 378hosphor HSP27 S78 and total HSP27. PBMCs (Peripheral Blood Mononuclear Cells) TNF- ^ Release Assay [0871] TNF-α ELISA may be performed with Human TNF alpha ELISA Kit (Abcam: ab181421). PBMCs are cultured in RPMI 1640 Medium with 10% heat-inactivated fetal calf serum and 100 U/mL Penicillin-Streptomycin at 37 °C and 5% CO ₂ . PBMCs are plated at 1x10 ⁵ /well in a 96-well plate and incubated with test compounds in the culture media at 37 ℃ (100 μl/well). After 1 hour incubation, the cells are treated with lipopolysaccharide (LPS, 100 ng/ml) for 4 hours at 37 °C (200 μL/well). After incubation, the supernatant samples are assayed by the ELISA for the presence of TNF-α. [0872] The above procedure was performed using exemplary compounds; results are provided in Table 4. The symbol “+++” indicates a IC ₅₀ less than 20 nM. The symbol “++” indicates an IC ₅₀ in the range of 20 nM to 100 nM. The symbol “+” indicates a IC ₅₀ greater than 100 nM. TABLE 4.

INCORPORATION BY REFERENCE [0873] The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes. EQUIVALENTS [0874] 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.