HETEROBIFUNCTIONAL COMPOUNDS AND METHODS OF TREATING DISEASE CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of and priority to United States Provisional Patent Application serial number 63/494,406, filed April 5, 2023, and United States Provisional Patent Application serial number 63/404,569, filed September 8, 2022; the contents of each of which are hereby incorporated by reference. FIELD OF THE INVENTION [0002] The invention provides heterobifunctional compounds, pharmaceutical compositions, and their use treating disease, such as cancer. BACKGROUND [0003] Cancer continues to be a significant health problem despite the substantial research efforts and scientific advances reported in the literature for treating this disease. Solid tumors, including prostate cancer, breast cancer, and lung cancer remain highly prevalent among the world population. The incidence of prostate cancer increases with age, and with increasing longevity of human subjects, there continues to be a corresponding rise in the number of patients suffering from prostate cancer. Breast cancer is one of the most common cancers among women and is a leading cause of death for women between ages 50-55. Lung cancer is a leading cause of death among cancer patients, where over 85% of lung cancers are non-small cell lung cancer (NSCLC). Many lung cancers are attributed to tobacco smoking. Current treatment options for these cancers are not effective for all patients and/or can have substantial adverse side effects. [0004] New therapies are needed to address this unmet need in cancer therapy. In particular, new therapies are needed that achieve an anti-cancer effect through a different mechanism than commonly available therapies. Exemplary mechanisms for common anti-cancer therapies include (a) alkylation of DNA which limits ability of the cell to reproduce, (b) topoisomerase inhibition, in which the therapeutic agent inhibits the activity of a topoisomerases thereby limiting separation of strands of DNA, and (c) mitotic inhibition, where the therapeutic agent reduces ability of the cell to divide. New therapies that achieve an anti-cancer effect through a different mechanism present an opportunity to treat cancers more effectively and/or to treat cancers that have become resistant to currently available medicines. [0005] The present invention addresses the foregoing needs and provides other related advantages. SUMMARY [0006] The invention provides heterobifunctional compounds, pharmaceutical compositions, and their use treating disease, such as cancer. In particular, one aspect of the invention provides a collection of heterobifunctional 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 heterobifunctional compounds are described in the detailed description. The compounds may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier. [0007] Another aspect of the invention provides a collection of heterobifunctional compounds, such as a compound represented by Formula II: or a pharmaceutically acceptable salt thereof, where the variables are as defined in the detailed description. Further description of additional collections of heterobifunctional 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 cancer. The method comprises administering to a patient in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I or II, to treat the cancer. [0009] Another aspect of the invention provides a method of causing death of a cancer cell. The method comprises contacting a cancer cell with an effective amount of a compound described herein, such as a compound of Formula I or II, to cause death of the cancer cell. DETAILED DESCRIPTION [0010] The invention provides heterobifunctional compounds, pharmaceutical compositions, and their use treating disease, such as cancer. 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. [0011] 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 [0012] 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. [0013] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “cycloaliphatic”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. [0014] 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: [0015] Exemplary bridged bicyclics include: . [0016] The term “lower alkyl” refers to a C1-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. [0017] The term “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms. [0018] 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)). [0019] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation. [0020] 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. [0021] 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. [0022] The term “-(C0 alkylene)-“ refers to a bond. Accordingly, the term “-(C0-3 alkylene)-” encompasses a bond (i.e., C0) and a -(C1-3 alkylene)- group. [0023] 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. [0024] The term “halogen” means F, Cl, Br, or I. [0025] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non– aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. The term “haloaryl” refers to an aryl group that is substituted with at least one halogen. Exemplary haloaryl groups include chlorophenyl (e.g., 3- chlorophenyl, 4-chlorophenyl), fluorophenyl, and the like. The term “phenylene” refers to a bivalent phenyl group. [0026] 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. The term “haloheteroaryl” refers to a heteroaryl group that is substituted with at least one halogen. Exemplary haloheteroaryl groups include chloropyridine, fluoropyridine, chloropyrazole, fluoropyrazole, and the like. The term “heteroarylene” refers to a bivalent heteroaryl group. Similarly, the terms “pyrazolylene”, “imidazolylene”, and “pyrrolylene”, respectively refer to bivalent pyrazolyl, imidazolyl, and pyrrolyl groups. Similarly, the terms “pyridazinylene,” “pyrimidinylene,” “pyrazinylene,” and “pyridinylene,” respectively refer to bivalent pyridazinyl, pyrimidinyl, pyrazinyl, and pyridinyl groups. [0027] 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). [0028] 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 “heterocyclylene” refers to a bivalent heterocyclyl group. The terms “piperidinylene,” “piperazinylene,” and “azetidinylene”, respectively refer to bivalent piperidinyl, piperazinyl, and azetidinyl groups. [0029] As used herein, the term “heterocycloalkyl” refers to a saturated heterocyclyl. The term “heterocycloalkylene” refers to a bivalent heterocycloalkyl group. [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–(CH ₂ ) _0– 4C(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– 1Ph 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; –N3; -(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– 4SC(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 ^ₒ 2) ₂ ; -(CH ₂ ) _0–4 S(O)R ^ₒ ; -N(R ^ₒ )S(O) ₂ NR ^ₒ 2; –N(R ^ₒ )S(O) ₂ R ^ₒ ; –N(OR ^ₒ )R ^ₒ ; – C(NH)NR ^ₒ 2; –P(O) ₂ R ^ₒ ; -P(O)R ^ₒ 2; -OP(O)R ^ₒ 2; –OP(O)(OR ^ₒ ) ₂ ; SiR ^ₒ 3; –(C _1–4 straight or branched alkylene)O–N(R ^ₒ ) ₂ ; or –(C _1–4 straight or branched alkylene)C(O)O–N(R ^ₒ ) ₂ . [0033] Each R ^ₒ is independently hydrogen, C1–6 aliphatic, –CH ₂ Ph, –O(CH ₂ ) _0– 1Ph, -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 ^ₒ , 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 ^ₒ selected from =O and =S; or each R ^ₒ 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, –N3, –(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 NH2, –(CH ₂ ) _0–2 NHR ^● , –(CH ₂ ) _0–2 NR ^● 2, – NO2, –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– 1Ph, or a 5– 6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ^● is unsubstituted or where preceded by halo is substituted only with one or more halogens; or wherein an optional substituent on a saturated carbon is a divalent substituent independently selected from =O, =S, =NNR ^* ₂ , =NNHC(O)R ^* , =NNHC(O)OR ^* , =NNHS(O) 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 C1–6 aliphatic, R ^* is optionally substituted with halogen, – R ^● , -(haloR ^● ), -OH, –OR ^● , –O(haloR ^● ), –CN, –C(O)OH, –C(O)OR ^● , –NH2, –NHR ^● , –NR ^● 2, or –NO2, wherein each R ^● is independently selected from C _1–4 aliphatic, –CH ₂ Ph, –O(CH ₂ ) _0– 1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ^● is unsubstituted or where preceded by halo is substituted only with one or more halogens. [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† , –C(S)NR ^† 2, – C(NH)NR ^† 2, or –N(R ^† )S(O) ₂ R ^† ; wherein each R ^† is independently hydrogen, C1–6 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 C1–6 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– 1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ^● is unsubstituted or where preceded by halo is substituted only with one or more halogens. [0037] 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) 33201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference. [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 a 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] The terms “a” and “an” as used herein mean “one or more” and include the plural unless the context is inappropriate. [0045] 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, C1-C10 alkyl, and C1-C6 alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1- butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3- methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc. [0046] The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as “C3-C6 cycloalkyl,” derived from a cycloalkane. Exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl. The term “cycloalkylene” refers to a bivalent cycloalkyl group. [0047] The term “haloalkyl” refers to an alkyl group that is substituted with at least one halogen. Exemplary haloalkyl groups include -CH ₂ F, -CHF2, -CF3, -CH ₂ CF3, -CF2CF3, and the like. The term “chloroalkyl” refers to an alkyl group that is substituted with at least one chloro. The term “bromoalkyl” refers to an alkyl group that is substituted with at least one bromo. The term “haloalkylene” refers to a bivalent haloalkyl group. [0048] The term “hydroxyalkyl” refers to an alkyl group that is substituted with at least one hydroxyl. Exemplary hydroxyalkyl groups include -CH ₂ CH ₂ OH, -C(H)(OH)CH3, -CH ₂ C(H)(OH)CH ₂ CH ₂ OH, and the like. [0049] The term “heteroalkyl” refers to an alkyl group in which one or more carbon atoms has been replaced by a heteroatom (e.g., N, O, or S). Exemplary heteroalkyl groups include -OCH ₃ , -CH ₂ OCH ₃ , -CH ₂ CH ₂ N(CH ₃ ) ₂ , and -CH ₂ CH ₂ OH. The heteroalkyl group may contain, for example, from 2-4, 2-6, or 2-8 atoms selected from the group consisting of carbon and a heteroatom (e.g., N, O, or S). The phrase 3-8 membered heteroalkyl refers to a heteroalkyl group having from 3 to 8 atoms selected from the group consisting of carbon and a heteroatom. The term “heteroalkylene” refers to a bivalent heteroalkyl group. [0050] The terms “alkenyl” and “alkynyl” are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively. The term “haloalkenyl” refers to an alkenyl group that is substituted with at least one halogen. The term “fluoroalkenyl” refers to an alkenyl group that is substituted with at least one fluoro. The term “nitroalkenyl” refers to an alkenyl group that is substituted with at least one nitro. [0051] The term “carbocyclylene” refers to a bivalent cycloaliphatic group. [0052] 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, -OCHF2, -OCF3, -OCH ₂ CF3, -OCF2CF3, and the like. [0053] The term “oxo” is art-recognized and refers to a “=O” substituent. For example, a cyclopentane susbsituted with an oxo group is cyclopentanone. [0054] The term “amino” is art-recognized and refers to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas: wherein R ⁵⁰ , R ⁵¹ , R ⁵² and R ⁵³ each independently represent a hydrogen, an alkyl, an alkenyl, -(CH ₂ )m-R ⁶¹ , or R ⁵⁰ and R ⁵¹ , taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R ⁶¹ represents an aryl, a 3-7 membered cycloalkyl, a 4-7 membered cycloalkenyl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; and m is zero or an integer in the range of 1 to 8. [0055] The term “amido” is art-recognized and refers to both unsubstituted and substituted amides, e.g., a moiety that may be represented by the general formulas: wherein R ⁵⁰ and R ⁵¹ each independently represent a hydrogen, an alkyl, an alkenyl, -(CH ₂ )m- R ⁶¹ , or R ⁵⁰ and R ⁵¹ , taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R ⁶¹ represents an aryl, a 3-7 membered cycloalkyl, a 4-7 membered cycloalkenyl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; and m is zero or an integer in the range of 1 to 8; and R ⁵² is an alkyl, an alkenyl, or -(CH ₂ )m-R ⁶¹ . [0056] The symbol “ ” indicates a point of attachment. [0057] 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. [0058] One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H2O. [0059] As used herein, the terms “subject” and “patient” are used interchangeable and refer to organisms to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably includes humans. [0060] The term “IC50” is art-recognized and refers to the concentration of a compound that is required to achieve 50% inhibition of the target. [0061] As used herein, the term “effective amount” refers to the amount of a compound sufficient to effect beneficial or desired results (e.g., a therapeutic, ameliorative, inhibitory or preventative result). An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. As used herein, the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof. [0062] 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. [0063] As used herein, the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil/water or water/oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see e.g., Martin, Remington’s Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA [1975]. [0064] For therapeutic use, salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. [0065] In addition, when a compound of the invention contains both a basic moiety (such as, but not limited to, a pyridine or imidazole) and an acidic moiety (such as, but not limited to, a carboxylic acid) zwitterions (“inner salts”) may be formed. Such acidic and basic salts used within the scope of the invention are pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts. Such salts of the compounds of the invention may be formed, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization. [0066] 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. [0067] As a general matter, compositions specifying a percentage are by weight unless otherwise specified. I. Heterobifunctional Compounds [0068] One aspect of the invention provides heterobifunctional 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. Without being bound by theory, the compounds can facilitate therapeutic effects by binding to both an androgen receptor and BRD4 (bromodomain-containing protein 4). Part A: Compound of Formula I [0069] One aspect of the invention provides a compound represented by Formula I: or a pharmaceutically acceptable salt thereof; wherein: R ¹ is phenyl substituted by cyano, halogen, and m occurrences of R ⁴ ; R ² and R ³ are independently hydrogen or C1-4 alkyl; R ⁴ is C _1-4 alkyl; R ⁵ represents independently for each occurrence C1-4 alkyl or halogen; A ¹ is a pyridazinylene, pyrimidinylene, pyrazinylene, pyridinylene, or phenylene, each of which is substituted with n occurrences of R ⁵ ; L is a linker; and A ² is one of the following: R ^1A is C1-4 alkyl or C3-4 cycloalkyl; R ^2A represents independently for each occurrence C1-4 alkyl or C3-4 cycloalkyl; R ^3A is phenyl substituted with 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, or C1-C4 haloalkyl; R ^4A is -(C1-6 alkylene)-C(O)N(R ^5A )(R ^6A ), -(C1-6 alkylene)-N(R ^5A )C(O)R ^7A , -(C1-6 alkylene)-CO2R ^7A , -(C1-6 alkylene)-OC(O)R ^7A , or -(C0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), -(C _1-6 alkylene)-cyano, C _1-6 alkyl, or hydrogen; or R ^4A and R ^10A taken together with the carbon atom to which they are attached form a C3-5 saturated carbocyclic ring; R ^5A and R ^6A are independently hydrogen, C _1-6 alkyl, or C _3-6 cycloalkyl; or R ^5A and R ^6A are taken together with the nitrogen atom to which they are attached to form a 3-7 membered ring containing 1 nitrogen atom; R ^7A is C1-6 alkyl, -(C1-6 alkylene)-(C3-6 cycloalkyl), or C3-6 cycloalkyl; R ^8A represents independently for each occurrence C _1-4 alkyl or -N(R ^9A ) ₂ ; R ^9A represents independently for each occurrence hydrogen or C1-4 alkyl; R ^10A is hydrogen or C _1-4 alkyl; and m, n, p, and q are independently 0, 1, or 2. [0070] 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). [0071] In certain embodiments, the compound is a compound of Formula I. [0072] As define generally above, R ¹ is phenyl substituted by cyano, halogen, and m occurrences of R ⁴ . In certain embodiments, R ¹ is phenyl substituted by cyano, halogen, and 0 occurrences of R ⁴ . In certain embodiments, R ¹ is phenyl substituted by cyano, halogen, and 1 occurrence of R ⁴ . In certain embodiments, R ¹ is phenyl substituted by cyano, halogen, and 2 occurrences of R ⁴ . In certain embodiments, R ¹ is phenyl substituted by cyano, Cl, and 0 occurrences of R ⁴ . In certain embodiments, R ¹ is . In certain embodiments, R ¹ is selected from the groups depicted in the compounds in Table 1 below. [0073] As defined generally above, R ² is hydrogen or C1-4 alkyl. In certain embodiments, R ² is hydrogen. In certain embodiments, R ² is C _1-4 alkyl. In certain embodiments, R ² is selected from the groups depicted in the compounds in Table 1 below. [0074] As defined generally above, R ³ is hydrogen or C1-4 alkyl. In certain embodiments, R ³ is hydrogen. In certain embodiments, R ³ is C _1-4 alkyl. In certain embodiments, R ³ is selected from the groups depicted in the compounds in Table 1 below. [0075] As defined generally above, A ¹ is a pyridazinylene, pyrimidinylene, pyrazinylene, pyridinylene, or phenylene, each of which is substituted with n occurrences of R ⁵ . In certain embodiments, A ¹ is pyridazinylene substituted with n occurrences of R ⁵ . In certain embodiments, A ¹ is . In certain embodiments, A ¹ is pyrimidinylene substituted with n occurrences of R ⁵ . In certain embodiments, A ¹ is , where ** is the point of attachment to L. In certain embodiments, A ¹ is , where ** is the point of attachment to L. In certain embodiments, A ¹ is pyrazinylene substituted with n occurrences of R ⁵ . In certain embodiments, A ¹ is . In certain embodiments, A ¹ is pyridinylene substituted with n occurrences of R ⁵ . In certain embodiments, A ¹ is , where ** is the point of attachment to L. In certain embodiments, A ¹ is phenylene substituted with n occurrences of R ⁵ . In certain embodiments, A ¹ is ¹ In certain embodiments, A is a pyridazinylene substituted with 0 occurrences of R ⁵ . In certain embodiments, A ¹ is a pyrimidinylene substituted with 0 occurrences of R ⁵ . In certain embodiments, A ¹ is a pyrazinylene substituted with 0 occurrences of R ⁵ . In certain embodiments, A ¹ is a pyridinylene, substituted with 0 occurrences of R ⁵ . In certain embodiments, A ¹ is a phenylene substituted with 0 occurrences of R ⁵ . In certain embodiments, A ¹ is selected from the groups depicted in the compounds in Table 1 below. [0076] As defined generally above, A ² is . In certain embodiments, A ² is . In certain embodiments, A ² is In certain embodiments, A ² is In certain embodiments, A ² is . In certain embodiments, A ² is . In certain embodiments, A ² i In certain embodiments, A ² is ^{. In} certain embodiments, A ² is or . In certain embodiments, A ² is [0077] In certain embodiments, A ² is . In certain embodiments, A ² is . In certain embodiments, A ² is certain embodiments, A ² is In c ² ertain embodiments, A is . In ce ² rtain embodiments, A is In certain embodiments, A ² is o . In certain embodiments, A ² is In certain embodiments, A ² is . In certain embodiments, A ² is , In certain embodime ² nts, A is In certain embodiments, A ² is , In certain embodiments, A ² is

[0078] In certain embodiments, A ² is selected from the groups depicted in the compounds in Table 1 below. [0079] As defined generally above, R ^1A is C _1-4 alkyl or C _3-4 cycloalkyl. In certain embodiments, R ^1A is C1-4 alkyl. In certain embodiments, is methyl. In certain embodiments, R ^1A is C _3-4 cycloalkyl. In certain embodiments, R ^1A is selected from the groups depicted in the compounds in Table 1 below. [0080] As defined generally above, R ^2A represents independently for each occurrence C1-4 alkyl or C _3-4 cycloalkyl. In certain embodiments, R ^2A is C _1-4 alkyl. In certain embodiments, R2A is methyl. In certain embodiments, R ^2A is C3-4 cycloalkyl. In certain embodiments, R ^2A is selected from the groups depicted in the compounds in Table 1 below. [0081] As defined generally above, R ^3A is phenyl substituted with 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, or C1-C4 haloalkyl. In certain embodiments, R3A is phenyl substituted with halo. In certain embodiments, R ^3A is phenyl substituted with 1 substituent selected from halo, C1-C4 alkyl, or C1-C4 haloalkyl. In certain embodiments, R ^3A is phenyl substituted with 2 substituents independently selected from halo, C ₁ -C ₄ alkyl, or C ₁ -C ₄ haloalkyl. In certain embodiments, R ^3A is phenyl substituted with 3 substituents independently selected from halo, C ₁ -C ₄ alkyl, or C ₁ -C ₄ haloalkyl. In certain embodiments, R ^3A is selected from the groups depicted in the compounds in Table 1 below. [0082] As defined generally above, R ^4A is -(C1-6 alkylene)-C(O)N(R ^5A )(R ^6A ), -(C1-6 alkylene)- N(R ^5A )C(O)R ^7A , -(C _1-6 alkylene)-CO ₂ R ^7A , -(C _1-6 alkylene)-OC(O)R ^7A , -(C _0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), -(C _1-6 alkylene)-cyano, C _1-6 alkyl, or hydrogen; or R ^4A and R ^10A taken together with the carbon atom to which they are attached form a C3-5 saturated carbocyclic ring. In certain embodiments, R ^4A is -(C _1-6 alkylene)-C(O)N(R ^5A )(R ^6A ), -(C _1-6 alkylene)- N(R ^5A )C(O)R ^7A , -(C1-6 alkylene)-CO2R ^7A , -(C1-6 alkylene)-OC(O)R ^7A , r -(C0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In certain embodiments, R ^4A is -(C1-6 alkylene)-C(O)N(R ^5A )(R ^6A ), -(C1-6 alkylene)-N(R ^5A )C(O)R ^7A , -(C1-6 alkylene)-CO2R ^7A , or -(C1-6 alkylene)-OC(O)R ^7A . In certain embodiments, R ^4A is hydrogen. In certain embodiments, R ^4A is -(C1-6 alkylene)-cyano. In certain embodiments, R ^4A is C1-6 alkyl. In certain embodiments, R ^4A is -(C1-6 alkylene)- C(O)N(R ^5A )(R ^6A ). In certain embodiments, R ^4A is -(C1-6 alkylene)-CO2R ^7A . In certain embodiments, R ^4A is -(C _1-6 alkylene)-N(R ^5A )C(O)R ^7A . In certain embodiments, R ^4A is -(C _1-6 alkylene)-OC(O)R ^7A . In certain embodiments, R ^4A is -(C0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In certain embodiments, R ^4A and R ^10A taken together with the carbon atom to which they are attached form a C _3-5 saturated carbocyclic ring. In certain embodiments, R ^4A is selected from the groups depicted in the compounds in Table 1 below. [0083] As defined generally above, R ^5A and R ^6A are independently hydrogen, C1-6 alkyl, or C3-6 cycloalkyl; or R ^5A and R ^6A are taken together with the nitrogen atom to which they are attached to form a 3-7 membered ring containing 1 nitrogen atom. In certain embodiments, R ^5A and R ^6A are independently hydrogen, C1-6 alkyl, or C3-6 cycloalkyl. In certain embodiments, R ^5A is hydrogen. In certain embodiments, R ^5A is C1-6 alkyl. In certain embodiments, R ^5A is C3-6 cycloalkyl. In certain embodiments, R ^6A is hydrogen. In certain embodiments, R ^6A is C1-6 alkyl. In certain embodiments, R ^6A is C3-6 cycloalkyl. In certain embodiments, R ^5A and R ^6A are taken together with the nitrogen atom to which they are attached to form a 3-7 membered ring containing 1 nitrogen atom. In certain embodiments, R ^5A and R ^6A are taken together with the nitrogen atom to which they are attached to form a 3-membered ring containing 1 nitrogen atom. In certain embodiments, R ^5A and R ^6A are taken together with the nitrogen atom to which they are attached to form a 4-membered ring containing 1 nitrogen atom. In certain embodiments, R ^5A and R ^6A are taken together with the nitrogen atom to which they are attached to form a 5-membered ring containing 1 nitrogen atom. In certain embodiments, R ^5A and R ^6A are taken together with the nitrogen atom to which they are attached to form a 6-membered ring containing 1 nitrogen atom. In certain embodiments, R ^5A and R ^6A are taken together with the nitrogen atom to which they are attached to form a 7-membered ring containing 1 nitrogen atom. In certain embodiments, R ^5A is selected from the groups depicted in the compounds in Table 1 below. In certain embodiments, R ^6A is selected from the groups depicted in the compounds in Table 1 below. [0084] As defined generally above, R ^7A is C1-6 alkyl, -(C1-6 alkylene)-(C3-6 cycloalkyl), or C3-6 cycloalkyl. In certain embodiments, R ^7A is C1-6 alkyl. In certain embodiments, R ^7A is -(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R ^7A is C3-6 cycloalkyl. In certain embodiments, R ^7A is selected from the groups depicted in the compounds in Table 1 below. [0085] As defined generally above, R ^8A represents independently for each occurrence C1-4 alkyl or -N(R ^9A ) ₂ . In certain embodiments, R ^8A represents independently for each occurrence C1-4 alkyl. In certain embodiments, R ^8A represents independently for each occurrence -N(R ^9A ) ₂ . In certain embodiments, R ^8A is C _1-4 alkyl. In certain embodiments, R ^8A is -N(R ^9A ) ₂ . In certain embodiments, R ^8A is -N(H)CH3. In certain embodiments, R ^8A is selected from the groups depicted in the compounds in Table 1 below. [0086] As defined generally above, R ^9A represents independently for each occurrence hydrogen or C1-4 alkyl. In certain embodiments, R ^9A represents independently for each occurrence C1-4 alkyl. In certain embodiments, R ^9A is hydrogen. In certain embodiments, R ^9A is C _1-4 alkyl. In certain embodiments, R ^9A represents independently for each occurrence hydrogen or methyl. In certain embodiments, R ^9A is selected from the groups depicted in the compounds in Table 1 below. [0087] As defined generally above, R ^10A is hydrogen or C1-4 alkyl. In certain embodiments, R ^10A is hydrogen. In certain embodiments, R ^10A is C _1-4 alkyl. In certain embodiments, R ^10A is methyl. In certain embodiments, R ^10A is selected from the groups depicted in the compounds in Table 1 below. [0088] As defined generally above, m, n, and p are independently 0, 1, or 2. In certain embodiments, p is 2. In certain embodiments, p is 1. In certain embodiments, p is 0. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, p is selected from the corresponding value in the groups depicted in the compounds in Table 1 below. In certain embodiments, m is selected from the corresponding value in the groups depicted in the compounds in Table 1 below. In certain embodiments, n is selected from the corresponding value in the groups depicted in the compounds in Table 1 below. [0089] In certain embodiments, the compound of Formula I is further defined by Formula Ia or Ib, or a pharmaceutically acceptable salt thereof: In certain embodiments, the definition of variables R ¹ , R ² , R ³ , A ¹ , and A ² is one of the embodiments described above in connection with Formula I. In certain embodiments, the compound is a compound of Formula Ia or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula Ib or a pharmaceutically acceptable salt thereof. [0090] In certain embodiments, the compound of Formula I is further defined by Formula 1c or a pharmaceutically acceptable salt thereof: In certain embodiments, the definition of variables A ¹ and A ² is one of the embodiments described above in connection with Formula I. [0091] In certain embodiments, the compound of Formula I is further defined by Formula 1d or a pharmaceutically acceptable salt thereof: In certain embodiments, the definition of variables A ¹ and A ² is one of the embodiments described above in connection with Formula I. [0092] The compounds may be further characterized according to, for example, the identity of L. Exemplary further embodiments for L are provided in Part C below. Part A-1: Compounds of Formula I-1 [0093] One aspect of the invention provides a compound represented by Formula I-1: (I-1) or a pharmaceutically acceptable salt thereof; wherein: R ¹ is phenyl substituted by cyano, halogen, and m occurrences of R ⁴ ; R ² and R ³ are independently hydrogen or C _1-4 alkyl; R ⁴ is C1-4 alkyl; R ⁵ represents independently for each occurrence C _1-4 alkyl or halogen; A ¹ is a pyridazinylene, pyrimidinylene, pyrazinylene, pyridinylene, or phenylene, each of which is substituted with n occurrences of R ⁵ ; L is a linker; and A ² is one of the following: R ^1A is C _1-4 alkyl or C _3-4 cycloalkyl; R ^2A represents independently for each occurrence C1-4 alkyl or C3-4 cycloalkyl; R ^3A is phenyl substituted with 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, or C1-C4 haloalkyl; R ^4A is -(C _1-6 alkylene)-C(O)N(R ^5A )(R ^6A ), -(C _1-6 alkylene)-N(R ^5A )C(O)R ^7A , -(C _1-6 alkylene)-CO2R ^7A , -(C1-6 alkylene)-OC(O)R ^7A , or -(C0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur); R ^5A and R ^6A are independently hydrogen, C _1-6 alkyl, or C _3-6 cycloalkyl; or R ^5A and R ^6A are taken together with the nitrogen atom to which they are attached to form a 3-7 membered ring containing 1 nitrogen atom; R ^7A is C1-6 alkyl, -(C1-6 alkylene)-(C3-6 cycloalkyl), or C3-6 cycloalkyl; and m, n, and p are independently 0, 1, or 2. [0094] 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). [0095] In certain embodiments, the compound is a compound of Formula I-1. [0096] As define generally above, R ¹ is phenyl substituted by cyano, halogen, and m occurrences of R ⁴ . In certain embodiments, R ¹ is phenyl substituted by cyano, halogen, and 0 occurrences of R ⁴ . In certain embodiments, R ¹ is phenyl substituted by cyano, halogen, and 1 occurrence of R ⁴ . In certain embodiments, R ¹ is phenyl substituted by cyano, halogen, and 2 occurrences of R ⁴ . In certain embodiments, R ¹ is phenyl substituted by cyano, Cl, and 0 occurrences of R ⁴ . In certain embodiments, R ¹ is . In certain embodiments, R ¹ is selected from the groups depicted in the compounds in Table 1 below. [0097] As defined generally above, R ² is hydrogen or C1-4 alkyl. In certain embodiments, R ² is hydrogen. In certain embodiments, R ² is C _1-4 alkyl. In certain embodiments, R ² is selected from the groups depicted in the compounds in Table 1 below. [0098] As defined generally above, R ³ is hydrogen or C1-4 alkyl. In certain embodiments, R ³ is hydrogen. In certain embodiments, R ³ is C _1-4 alkyl. In certain embodiments, R ³ is selected from the groups depicted in the compounds in Table 1 below. [0099] As defined generally above, A ¹ is a pyridazinylene, pyrimidinylene, pyrazinylene, pyridinylene, or phenylene, each of which is substituted with n occurrences of R ⁵ . In certain embodiments, A ¹ is pyridazinylene substituted with n occurrences of R ⁵ . In certain embodiments, A ¹ is . In certain embodiments, A ¹ is pyrimidinylene substituted with n occurrences of R ⁵ . In certain embodiments, A ¹ is where ** is the point of attachment to L. In certain embodiments, A ¹ is where ** is the point of attachment to L. In certain embodiments, A ¹ is pyrazinylene substituted with n occurrences of R ⁵ . In certain embodiments, A ¹ is . In certain embodiments, A ¹ is pyridinylene substituted with n occurrences of R ⁵ . In certain embodiments, A ¹ is , where ** is the point of attachment to L. In certain embodiments, A ¹ is phenylene substituted with n occurrences of R ⁵ . In certain embodiments, A ¹ is . In certain embodiments, A ¹ is a pyridazinylene substituted with 0 occurrences of R ⁵ . In certain embodiments, A ¹ is a pyrimidinylene substituted with 0 occurrences of R ⁵ . In certain embodiments, A ¹ is a pyrazinylene substituted with 0 occurrences of R ⁵ . In certain embodiments, A ¹ is a pyridinylene, substituted with 0 occurrences of R ⁵ . In certain embodiments, A ¹ is a phenylene substituted with 0 occurrences of R ⁵ . In certain embodiments, A ¹ is selected from the groups depicted in the compounds in Table 1 below. [0100] As defined generally above, [0101] In certain embodiments, certain embodiments, A ² is In certain embodiments, A ² is . In certain embodiments,

embodiments, A ² is selected from the groups depicted in the compounds in Table 1 below. [0102] As defined generally above, R ^1A is C1-4 alkyl or C3-4 cycloalkyl. In certain embodiments, R ^1A is C1-4 alkyl. In certain embodiments, is methyl. In certain embodiments, R ^1A is C3-4 cycloalkyl. In certain embodiments, R ^1A is selected from the groups depicted in the compounds in Table 1 below. [0103] As defined generally above, R ^2A represents independently for each occurrence C _1-4 alkyl or C cycloalkyl. In certain em ^2A 2A 3-4 bodiments, R is C1-4 alkyl. In certain embodiments, R is methyl. In certain embodiments, R ^2A is C _3-4 cycloalkyl. In certain embodiments, R ^2A is selected from the groups depicted in the compounds in Table 1 below. [0104] As defined generally above, R ^3A is phenyl substituted with 1, 2, or 3 substituents independently selected from halo, C ₁ -C ₄ alkyl, or C ₁ -C ₄ haloalkyl. In certain embodiments, R3A is phenyl substituted with halo. In certain embodiments, R ^3A is phenyl substituted with 1 substituent selected from halo, C ₁ -C ₄ alkyl, or C ₁ -C ₄ haloalkyl. In certain embodiments, R ^3A is phenyl substituted with 2 substituents independently selected from halo, C1-C4 alkyl, or C1-C4 haloalkyl. In certain embodiments, R ^3A is phenyl substituted with 3 substituents independently selected from halo, C1-C4 alkyl, or C1-C4 haloalkyl. In certain embodiments, R ^3A is selected from the groups depicted in the compounds in Table 1 below. [0105] As defined generally above, R ^4A is -(C _1-6 alkylene)-C(O)N(R ^5A )(R ^6A ), -(C _1-6 alkylene)- N(R ^5A )C(O)R ^7A , -(C1-6 alkylene)-CO2R ^7A , -(C1-6 alkylene)-OC(O)R ^7A , or -(C0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In certain embodiments, R ^4A is -(C1-6 alkylene)-C(O)N(R ^5A )(R ^6A ), -(C1-6 alkylene)-N(R ^5A )C(O)R ^7A , -(C1-6 alkylene)-CO2R ^7A , or -(C1-6 alkylene)-OC(O)R ^7A . In certain embodiments, R ^4A is -(C1-6 alkylene)-C(O)N(R ^5A )(R ^6A ). In certain embodiments, R ^4A is -(C1-6 alkylene)-CO2R ^7A . In certain embodiments, R ^4A is -(C1-6 alkylene)-N(R ^5A )C(O)R ^7A . In certain embodiments, R ^4A is -(C1-6 alkylene)-OC(O)R ^7A . In certain embodiments, R ^4A is -(C0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In certain embodiments, R ^4A is selected from the groups depicted in the compounds in Table 1 below. [0106] As defined generally above, R ^5A and R ^6A are independently hydrogen, C _1-6 alkyl, or C _3-6 cycloalkyl; or R ^5A and R ^6A are taken together with the nitrogen atom to which they are attached to form a 3-7 membered ring containing 1 nitrogen atom. In certain embodiments, R ^5A and R ^6A are independently hydrogen, C1-6 alkyl, or C3-6 cycloalkyl. In certain embodiments, R ^5A is hydrogen. In certain embodiments, R ^5A is C _1-6 alkyl. In certain embodiments, R ^5A is C _3-6 cycloalkyl. In certain embodiments, R ^6A is hydrogen. In certain embodiments, R ^6A is C1-6 alkyl. In certain embodiments, R ^6A is C3-6 cycloalkyl. In certain embodiments, R ^5A and R ^6A are taken together with the nitrogen atom to which they are attached to form a 3-7 membered ring containing 1 nitrogen atom. In certain embodiments, R ^5A and R ^6A are taken together with the nitrogen atom to which they are attached to form a 3-membered ring containing 1 nitrogen atom. In certain embodiments, R ^5A and R ^6A are taken together with the nitrogen atom to which they are attached to form a 4-membered ring containing 1 nitrogen atom. In certain embodiments, R ^5A and R ^6A are taken together with the nitrogen atom to which they are attached to form a 5-membered ring containing 1 nitrogen atom. In certain embodiments, R ^5A and R ^6A are taken together with the nitrogen atom to which they are attached to form a 6-membered ring containing 1 nitrogen atom. In certain embodiments, R ^5A and R ^6A are taken together with the nitrogen atom to which they are attached to form a 7-membered ring containing 1 nitrogen atom. In certain embodiments, R ^5A is selected from the groups depicted in the compounds in Table 1 below. In certain embodiments, R ^6A is selected from the groups depicted in the compounds in Table 1 below. [0107] As defined generally above, R ^7A is C _1-6 alkyl, -(C _1-6 alkylene)-(C _3-6 cycloalkyl), or C _3-6 cycloalkyl. In certain embodiments, R ^7A is C _1-6 alkyl. In certain embodiments, R ^7A is -(C _1-6 alkylene)-(C _3-6 cycloalkyl). In certain embodiments, R ^7A is C _3-6 cycloalkyl. In certain embodiments, R ^7A is selected from the groups depicted in the compounds in Table 1 below. [0108] As defined generally above, m, n, and p are independently 0, 1, or 2. In certain embodiments, p is 2. In certain embodiments, p is 1. In certain embodiments, p is 0. In certain embodiments, t is 2. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, p is selected from the corresponding value in the groups depicted in the compounds in Table 1 below. In certain embodiments, m is selected from the corresponding value in the groups depicted in the compounds in Table 1 below. In certain embodiments, n is selected from the corresponding value in the groups depicted in the compounds in Table 1 below. [0109] In certain embodiments, the compound of Formula I-1 is further defined by Formula Ia or Ib, or a pharmaceutically acceptable salt thereof: [0110] In certain embodiments, the definition of variables R ¹ , R ² , R ³ , A ¹ , and A ² is one of the embodiments described above in connection with Formula I-1. In certain embodiments, the compound is a compound of Formula Ia-1 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula Ib-1 or a pharmaceutically acceptable salt thereof. [0111] In certain embodiments, the compound of Formula I-1 is further defined by Formula 1c- 1 or a pharmaceutically acceptable salt thereof: [0112] In certain embodiments, the definition of variables A ¹ and A ² is one of the embodiments described above in connection with Formula I-1. [0113] In certain embodiments, the compound of Formula I-1 is further defined by Formula 1d-1 or a pharmaceutically acceptable salt thereof: [0114] In certain embodiments, the definition of variables A ¹ and A ² is one of the embodiments described above in connection with Formula I-1. [0115] The compounds may be further characterized according to, for example, the identity of L. Exemplary further embodiments for L are provided in Part C below. Part A-2: Compounds of Formula I* [0116] Another aspect of the invention provides a compound represented by Formula I*: or a pharmaceutically acceptable salt thereof; wherein: R ¹ is phenyl substituted by cyano, halogen, and m occurrences of R ⁴ ; R ² and R ³ are independently hydrogen or C1-4 alkyl; R ⁴ is C _1-4 alkyl; R ⁵ represents independently for each occurrence C1-4 alkyl or halogen; A ¹ is a pyridazinylene, pyrimidinylene, pyrazinylene, pyridinylene, or phenylene, each of which is substituted with n occurrences of R ⁵ ; L is a linker; and A ² is one of the following: R ^1A is C _1-4 alkyl or C _3-4 cycloalkyl; R ^2A represents independently for each occurrence C1-4 alkyl or C3-4 cycloalkyl; R ^4A is -(C _1-6 alkylene)-O-(C _1-6 alkyl), C _1-6 hydroxyalkyl, C _1-6 haloalkyl, -(C _1-6 alkylene)-C(O)N(R ^5A )(R ^6A ), -(C1-6 alkylene)-N(R ^5A )C(O)R ^7A , -(C1-6 alkylene)-CO2R ^7A , - (C _1-6 alkylene)-OC(O)R ^7A , -(C _0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), -(C1-6 alkylene)- cyano, C _1-6 alkyl, or hydrogen; or R ^4A and R ^10A taken together with the carbon atom to which they are attached form a C3-5 saturated carbocyclic ring; R ^5A and R ^6A are independently hydrogen, C1-6 alkyl, or C3-6 cycloalkyl; or R ^5A and R ^6A are taken together with the nitrogen atom to which they are attached to form a 3-7 membered ring containing 1 nitrogen atom; R ^7A is C1-6 alkyl, -(C1-6 alkylene)-(C3-6 cycloalkyl), or C3-6 cycloalkyl; R ^8A represents independently for each occurrence C1-4 alkyl or -N(R ^9A ) ₂ ; R ^9A represents independently for each occurrence hydrogen or C1-4 alkyl; R ^10A is hydrogen or C1-4 alkyl; R ^11A represents independently for each occurrence halogen; and m, n, p, and q are independently 0, 1, or 2. [0117] In certain embodiments, the compound is a compound of Formula Ic* or a pharmaceutically acceptable salt thereof: (1c*). [0118] In certain embodiments, the compound is a compound of Formula Id* or a pharmaceutically acceptable salt thereof: [0119] In certain embodiments, A ¹ is In certain embodiments, A ¹ is , where ** is the point of attachment to L. [0120] In certain embodiments, A ² is , wherein q is 1. [0121] In certain embodiments, R ^4A is -(C0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In certain embodiments, R ^4A is -(C1-6 alkylene)-O-(C1-6 alkyl), C1-6 hydroxyalkyl, or C1-6 haloalkyl. [0122] In certain embodiments, A ² is o . In certain embodiments, A ² is one of the following: . In certain embodiments, A ² is one of the following: [0123] In certain embodiments, A ² is certain embodiments, A ² is [0124] The compounds may be further characterized according to, for example, the identity of L. Exemplary further embodiments for L are provided in Part C below. Part A-3: Compounds of Formula Ie, If, and Ig and Other Compounds [0125] Another aspect of the invention provides a compound represented by Formula Ie, If, or Ig, or a pharmaceutically acceptable salt thereof:

Ig wherein L is one of the following: (i) a 7-11 membered spirocyclic or fused bicyclic saturated heterocyclic ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen; (ii) -(7-11 membered spirocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C2-4 alkynylene)-***, wherein *** is the point of attachment to the phenylene group in said formula; or (iii) -N(C1-4 alkyl)-(C1-6 alkylene)-(4-7 membered saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-***, wherein *** is the point of attachment to the phenylene group in said formula. [0126] In certain embodiments, the compound is represented by Formula Ih or a pharmaceutically acceptable salt thereof: [0127] In certain embodiments, the compound is represented by Formula Ii or a pharmaceutically acceptable salt thereof:

[0128] In certain embodiments, the compound is represented by Formula Ij or a pharmaceutically acceptable salt thereof: [0129] In certain embodiments, the compound is represented by Formula Ik or a pharmaceutically acceptable salt thereof: [0130] In certain embodiments, the compound is represented by Formula Il or a pharmaceutically acceptable salt thereof: [0131] In certain embodiments, L is a 7-11 membered spirocyclic or fused bicyclic saturated heterocyclic ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen. In certain embodiments, L is -(7-11 membered spirocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C2-4 alkynylene)-***, wherein *** is the point of attachment to the phenylene group in said formula. In certain embodiments, L is - N(C1-4 alkyl)-(C1-6 alkylene)-(4-7 membered saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-***, wherein *** is the point of attachment to the phenylene group in said formula. [0132] In certain embodiments, L is one of the following: wherein *** is the point of attachment to the phenylene group in said formula. [0133] Another aspect of the invention provides a compound represented by Formula Im, In, or Io, or a pharmaceutically acceptable salt thereof:

wherein L is one of the following: (i) a 7-11 membered spirocyclic or fused bicyclic saturated heterocyclic ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen; (ii) -(7-11 membered spirocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C2-4 alkynylene)-***, wherein *** is the point of attachment to the phenylene group in said formula; or (iii) -N(C1-4 alkyl)-(C1-6 alkylene)-(4-7 membered saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-***, wherein *** is the point of attachment to the phenylene group in said formula. [0134] In certain embodiments, the compound is represented by Formula Im or a pharmaceutically acceptable salt thereof: [0135] In certain embodiments, the compound is represented by Formula In or a pharmaceutically acceptable salt thereof: [0136] In certain embodiments, the compound is represented by Formula Io or a pharmaceutically acceptable salt thereof: [0137] In certain embodiments, the compound is represented by Formula Ip or a pharmaceutically acceptable salt thereof:

Ip. [0138] In certain embodiments, the compound is represented by Formula Iq or a pharmaceutically acceptable salt thereof: [0139] In certain embodiments, L is a 7-11 membered spirocyclic or fused bicyclic saturated heterocyclic ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen. In certain embodiments, L is -(7-11 membered spirocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C2-4 alkynylene)-***, wherein *** is the point of attachment to the phenylene group in said formula. In certain embodiments, L is - N(C1-4 alkyl)-(C1-6 alkylene)-(4-7 membered saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-***, wherein *** is the point of attachment to the phenylene group in said formula.

[0140] In certain embodiments, L is one of the following: wherein *** is the point of attachment to the phenylene group in said formula. Part B: Compounds of Formula II [0141] Another aspect of the invention provides a compound represented by Formula II: or a pharmaceutically acceptable salt thereof; wherein: TPL is a group defined by Formula II-1 that is substituted by one occurrence of R ^II-1A , wherein Formula II-1 is represented by: or a pharmaceutically acceptable salt thereof; wherein: R ^II-1A is a bond to L; R ¹ is phenyl substituted by cyano, halogen, and m occurrences of R ⁴ ; R ² and R ³ are independently hydrogen or C1-4 alkyl; R ⁴ is C _1-4 alkyl; R ⁵ represents independently for each occurrence C1-4 alkyl or halogen; A ¹ is a pyridazinyl, pyrimidinyl, pyrazinyl, pyridinyl, or phenyl, each of which is substituted with n occurrences of R ⁵ ; L is a linker; EPL is a moiety that binds to BRD4; and m and n are independently 0, 1, or 2. [0142] 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). [0143] In certain embodiments, the compound is a compound of Formula II. [0144] As defined generally above, R ¹ is phenyl substituted by cyano, halogen, and m occurrences of R ⁴ . In certain embodiments, R ¹ is phenyl substituted by cyano, halogen, and 0 occurrences of R ⁴ . In certain embodiments, R ¹ is . In certain embodiments, R ¹ is phenyl substituted by cyano, halogen, and 1 occurrences of R ⁴ . In certain embodiments, R ¹ is phenyl substituted by cyano, halogen, and 2 occurrences of R ⁴ . In certain embodiments, R ¹ is phenyl substituted by cyano, Cl, and 0 occurrences of R ⁴ . In certain embodiments, R ¹ is selected from the groups depicted in the compounds in Table 1 below. [0145] As defined generally above, R ² and R ³ are independently hydrogen or C1-4 alkyl. In certain embodiments, R ² is hydrogen. In certain embodiments, R ³ is hydrogen. In certain embodiments, R ² is C1-4 alkyl. In certain embodiments, R ³ is C1-4 alkyl. In certain embodiments, R ² and R ³ are each independently selected from the groups depicted in the compounds in Table 1 below. In certain embodiments, R ² and R ³ are each independently selected from the groups depicted in the compounds in Table 1 below. [0146] As defined generally above, A ¹ is a pyridazinyl, pyrimidinyl, pyrazinyl, pyridinyl, or phenyl, each of which is substituted with n occurrences of R ⁵ . In certain embodiments, A ¹ is pyridazinyl substituted with n occurrences of R ⁵ . In certain embodiments, A ¹ is pyrimidinyl substituted with n occurrences of R ⁵ . In certain embodiments, A ¹ is pyrazinyl substituted with n occurrences of R ⁵ . In certain embodiments, A ¹ is pyridinyl substituted with n occurrences of R ⁵ . In In certain embodiments, A ¹ is phenyl substituted with n occurrences of R ⁵ . In certain embodiments, A ¹ is selected from the groups depicted in the compounds in Table 1 below. [0147] In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, m is selected from the corresponding value in the groups depicted in the compounds in Table 1 below. In certain embodiments, n is selected from the corresponding value in the groups depicted in the compounds in Table 1 below. [0148] In certain embodiments, the TPL is that is substituted by one occurrence of R ^II-1A . [0149] In certain embodiments, the TPL is that is substituted by one occurrence of R ^II-1A . In certain embodiments, the TPL is In certain embodiments, the TPL is [0150] In certain embodiments, the EPL is defined by Formula II-2 that is substituted by one occurrence of R ^II-2A , wherein Formula II-2 is represented by: wherein R ^II-2A is a bond to L; R ^1A is C1-4 alkyl or C3-4 cycloalkyl; R ^2A represents independently for each occurrence C1-4 alkyl or C3-4 cycloalkyl; R ^3A is phenyl substituted with 1, 2, or 3 substituents independently selected from halo, C ₁ -C ₄ alkyl, or C ₁ -C ₄ haloalkyl; R ^4A is -(C1-6 alkylene)-C(O)N(R ^5A )(R ^6A ), -(C1-6 alkylene)-N(R ^5A )C(O)R ^7A , -(C1-6 alkylene)-CO2R ^7A , -(C1-6 alkylene)-OC(O)R ^7A , or -(C0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur); R ^5A and R ^6A are independently hydrogen, C1-6 alkyl, or C3-6 cycloalkyl; or R ^5A and R ^6A are taken together with the nitrogen atom to which they are attached to form a 3-7 membered ring containing 1 nitrogen atom; R ^7A is C1-6 alkyl, -(C1-6 alkylene)-(C3-6 cycloalkyl), or C3-6 cycloalkyl; and p is 0, 1, or 2. [0151] In certain embodiments, the EPL is defined by Formula II-2 that is substituted by one occurrence of R ^II-2A , wherein Formula II-2 is represented by: wherein R ^II-2A is a bond to L; R ^1A is C _1-4 alkyl or C _3-4 cycloalkyl; R ^2A represents independently for each occurrence C1-4 alkyl or C3-4 cycloalkyl; R ^3A is phenyl substituted with 1, 2, or 3 substituents independently selected from halo, C ₁ -C ₄ alkyl, or C ₁ -C ₄ haloalkyl; R ^4A is -(C _1-6 alkylene)-C(O)N(R ^5A )(R ^6A ), -(C _1-6 alkylene)-N(R ^5A )C(O)R ^7A , -(C _1-6 alkylene)-CO2R ^7A , -(C1-6 alkylene)-OC(O)R ^7A , r -(C0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), - (C1-6 alkylene)-cyano, C1-6 alkyl, or hydrogen; or R ^4A and R ^10A taken together with the carbon atom to which they are attached form a C _3-5 saturated carbocyclic ring; R ^5A and R ^6A are independently hydrogen, C1-6 alkyl, or C3-6 cycloalkyl; or R ^5A and R ^6A are taken together with the nitrogen atom to which they are attached to form a 3-7 membered ring containing 1 nitrogen atom; R ^7A is C1-6 alkyl, -(C1-6 alkylene)-(C3-6 cycloalkyl), or C3-6 cycloalkyl; R ^8A is represents independently for each occurrence C1-4 alkyl or -N(R ^9A ) ₂ ; R ^9A represents independently for each occurrence hydrogen or C _1-4 alkyl; R ^10A is hydrogen or C _1-4 alkyl; and p and q are independently 0, 1, or 2. [0152] In certain embodiments, the EPL is , each of which is substituted by one occurrence of R ^II-2A , wherein R ^II-2A is a bond to L. [0153] In certain embodiments, the EPL is one of the following: R ^1A is C _1-4 alkyl or C _3-4 cycloalkyl; R ^2A represents independently for each occurrence C _1-4 alkyl or C _3-4 cycloalkyl; R ^3A is phenyl substituted with 1, 2, or 3 substituents independently selected from halo, C ₁ -C ₄ alkyl, or C ₁ -C ₄ haloalkyl; R ^4A is -(C1-6 alkylene)-C(O)N(R ^5A )(R ^6A ), -(C1-6 alkylene)-N(R ^5A )C(O)R ^7A , -(C1-6 alkylene)-CO2R ^7A , -(C1-6 alkylene)-OC(O)R ^7A , or -(C1-6 alkylene)-OC(O)R ^7A . R ^5A and R ^6A are independently hydrogen, C1-6 alkyl, or C3-6 cycloalkyl; or R ^5A and R ^6A are taken together with the nitrogen atom to which they are attached to form a 3-7 membered ring containing 1 nitrogen atom; R ^7A is C1-6 alkyl, -(C1-6 alkylene)-(C3-6 cycloalkyl), or C3-6 cycloalkyl; and p is 0, 1, or 2 [0154] In certain embodiments, the certain embodiments, the EPL is [0155] In certain embodiments, the EPL is . In certain embodiments, the EPL is . In certain embodiments, the EPL is . [0156] As defined generally above, R ^1A is C _1-4 alkyl or C _3-4 cycloalkyl. In certain embodiments, R ^1A is C1-4 alkyl. In certain embodiments, is methyl. In certain embodiments, R ^1A is C _3-4 cycloalkyl. In certain embodiments, R ^1A is selected from the groups depicted in the compounds in Table 1 below. [0157] As defined generally above, R ^2A represents independently for each occurrence C1-4 alkyl or C _3-4 cycloalkyl. In certain embodiments, R ^2A is C _1-4 alkyl. In certain embodiments, R2A is methyl. In certain embodiments, R ^2A is C3-4 cycloalkyl. In certain embodiments, R ^2A is selected from the groups depicted in the compounds in Table 1 below. [0158] As defined generally above, R ^3A is phenyl substituted with 1, 2, or 3 substituents independently selected from halo, C 3A 1-C4 alkyl, or C1-C4 haloalkyl. In certain embodiments, R is phenyl substituted with halo. In certain embodiments, R ^3A is phenyl substituted with 1 substituent selected from halo, C1-C4 alkyl, or C1-C4 haloalkyl. In certain embodiments, R ^3A is phenyl substituted with 2 substituents independently selected from halo, C ₁ -C ₄ alkyl, or C ₁ -C ₄ haloalkyl. In certain embodiments, R ^3A is phenyl substituted with 3 substituents independently selected from halo, C ₁ -C ₄ alkyl, or C ₁ -C ₄ haloalkyl. In certain embodiments, R ^3A is selected from the groups depicted in the compounds in Table 1 below. [0159] As defined generally above, R ^4A is -(C1-6 alkylene)-C(O)N(R ^5A )(R ^6A ), -(C1-6 alkylene)- N(R ^5A )C(O)R ^7A , -(C _1-6 alkylene)-CO ₂ R ^7A , -(C _1-6 alkylene)-OC(O)R ^7A , r -(C _0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), -(C _1-6 alkylene)-cyano, C _1-6 alkyl, or hydrogen; or R ^4A and R ^10A taken together with the carbon atom to which they are attached form a C3-5 saturated carbocyclic ring. In certain embodiments, R ^4A is -(C _1-6 alkylene)-C(O)N(R ^5A )(R ^6A ), -(C _1-6 alkylene)- N(R ^5A )C(O)R ^7A , -(C1-6 alkylene)-CO2R ^7A , -(C1-6 alkylene)-OC(O)R ^7A , or -(C0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In certain embodiments, R ^4A is -(C1-6 alkylene)-C(O)N(R ^5A )(R ^6A ), -(C1-6 alkylene)-N(R ^5A )C(O)R ^7A , -(C _1-6 alkylene)-CO ₂ R ^7A , or -(C _1-6 alkylene)-OC(O)R ^7A . In certain embodiments, R ^4A is -(C1-6 alkylene)-C(O)N(R ^5A )(R ^6A ). In certain embodiments, R ^4A is -(C1-6 alkylene)-CO2R ^7A . In certain embodiments, R ^4A is -(C1-6 alkylene)-N(R ^5A )C(O)R ^7A . In certain embodiments, R ^4A is -(C1-6 alkylene)-OC(O)R ^7A . In certain embodiments, R ^4A is -(C0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In certain embodiments, R ^4A is -(C1-6 alkylene)-cyano. In certain embodiments, R ^4A is C1-6 alkyl. In certain embodiments, R ^4A is hydrogen. In certain embodiments, R ^4A and R ^10A taken together with the carbon atom to which they are attached form a C3-5 saturated carbocyclic ring. In certain embodiments, R ^4A is selected from the groups depicted in the compounds in Table 1 below. [0160] As defined generally above, R ^5A and R ^6A are independently hydrogen, C1-6 alkyl, or C3-6 cycloalkyl; or R ^5A and R ^6A are taken together with the nitrogen atom to which they are attached to form a 3-7 membered ring containing 1 nitrogen atom. In certain embodiments, R ^5A and R ^6A are independently hydrogen, C _1-6 alkyl, or C _3-6 cycloalkyl. In certain embodiments, R ^5A is hydrogen. In certain embodiments, R ^5A is C1-6 alkyl. In certain embodiments, R ^5A is C3-6 cycloalkyl. In certain embodiments, R ^6A is hydrogen. In certain embodiments, R ^6A is C1-6 alkyl. In certain embodiments, R ^6A is C3-6 cycloalkyl. In certain embodiments, R ^5A and R ^6A are taken together with the nitrogen atom to which they are attached to form a 3-7 membered ring containing 1 nitrogen atom. In certain embodiments, R ^5A and R ^6A are taken together with the nitrogen atom to which they are attached to form a 3-membered ring containing 1 nitrogen atom. In certain embodiments, R ^5A and R ^6A are taken together with the nitrogen atom to which they are attached to form a 4-membered ring containing 1 nitrogen atom. In certain embodiments, R ^5A and R ^6A are taken together with the nitrogen atom to which they are attached to form a 5-membered ring containing 1 nitrogen atom. In certain embodiments, R ^5A and R ^6A are taken together with the nitrogen atom to which they are attached to form a 6-membered ring containing 1 nitrogen atom. In certain embodiments, R ^5A and R ^6A are taken together with the nitrogen atom to which they are attached to form a 7-membered ring containing 1 nitrogen atom. In certain embodiments, R ^5A is selected from the groups depicted in the compounds in Table 1 below. In certain embodiments, R ^6A is selected from the groups depicted in the compounds in Table 1 below. [0161] As defined generally above, R ^7A is C _1-6 alkyl, -(C _1-6 alkylene)-(C _3-6 cycloalkyl), or C _3-6 cycloalkyl. In certain embodiments, R ^7A is C _1-6 alkyl. In certain embodiments, R ^7A is -(C _1-6 alkylene)-(C _3-6 cycloalkyl). In certain embodiments, R ^7A is C _3-6 cycloalkyl. In certain embodiments, R ^7A is selected from the groups depicted in the compounds in Table 1 below. [0162] As defined generally above, R ^8A represents independently for each occurrence C1-4 alkyl or -N(R ^9A ) ₂ . In certain embodiments, R ^8A represents independently for each occurrence C1-4 alkyl. In certain embodiments, R ^8A represents independently for each occurrence -N(R ^9A ) ₂ . In certain embodiments, R ^8A is C1-4 alkyl. In certain embodiments, R ^8A is -N(R ^9A ) ₂ . In certain embodiments, R ^8A is -N(H)CH3. In certain embodiments, R ^8A is selected from the groups depicted in the compounds in Table 1 below. [0163] As defined generally above, R ^9A represents independently for each occurrence hydrogen or C _1-4 alkyl. In certain embodiments, R ^9A represents independently for each occurrence C _1-4 alkyl. In certain embodiments, R ^9A is hydrogen. In certain embodiments, R ^9A is C1-4 alkyl. In certain embodiments, R ^9A represents independently for each occurrence hydrogen or methyl. In certain embodiments, R ^9A is selected from the groups depicted in the compounds in Table 1 below. [0164] As defined generally above, R ^10A is hydrogen or C _1-4 alkyl. In certain embodiments, R ^10A is hydrogen. In certain embodiments, R ^10A is C1-4 alkyl. In certain embodiments, R ^10A is methyl. In certain embodiments, R ^10A is selected from the groups depicted in the compounds in Table 1 below.In certain embodiments, p is 2. In certain embodiments, p is 1. In certain embodiments, p is 0. In certain embodiments, t is 2. In certain embodiments, p is selected from the corresponding value in the groups depicted in the compounds in Table 1 below. [0165] In certain embodiments, q is 2. In certain embodiments, q is 1. In certain embodiments, q is 0. In certain embodiments, q is selected from the corresponding value in the groups depicted in the compounds in Table 1 below. [0166] In certain embodiments, the EPL is defined by variable A ² set forth above in connection with Formula I. In certain embodiments, the EPL is defined by one or more of the embodiments for variable A ² set forth in connection with Formula I. [0167] The compounds may be further characterized according to, for example, the identity of L. Exemplary further embodiments for L are provided in Part C below. Part C: Exemplary Further Description of Linker (L) Component of Compounds of Formula I and II [0168] Compounds of Formula I and II may be further characterized according to, for example, the identity of the linker (L) component. A variety of linkers are known to one of skill in the art and may be used in the heterobifunctional compounds described herein. For example, in certain embodiments, L comprises one or more optionally substituted groups selected from amino acids, polyether chains, aliphatic groups, and any combinations thereof. In certain embodiments, L consists of one or more optionally substituted groups selected from amino acids, polyether chains, aliphatic groups, and any combinations thereof. In certain embodiments, L consists of one or more groups selected from amino acids, polyether chains, aliphatic groups, and any combinations thereof. [0169] In some embodiments, L is symmetrical. In some embodiments, L is asymmetric. In certain embodiments, L is a bond. [0170] In certain embodiments, L is a covalent bond or a bivalent C _1-30 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein 1-15 methylene units of L are optionally and independently replaced by cyclopropylene, -N(H)-, -N(C _1-4 alkyl)-, -N(C _3-5 cycloalkyl)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O) ₂ -, -S(O) ₂ N(H)-, -S(O) ₂ N(C1-4 alkyl)-, -S(O) ₂ N(C _3-5 cycloalkyl)-, -N(H)C(O)-, -N(C _1-4 alkyl)C(O)-, -N(C _3-5 cycloalkyl)C(O)-, -C(O)N(H)-, -C(O)N(C1-4 alkyl)-, -C(O)N(C3-5 cycloalkyl)-, phenylene, an 8-10 membered bicyclic arylene, a 4-7 membered saturated or partially unsaturated carbocyclylene, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylene, a 3-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylene having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0171] In certain embodiments, L is a bivalent, saturated or unsaturated, straight or branched C _1-60 hydrocarbon chain, wherein 0-20 methylene units of the hydrocarbon are independently replaced with -O-, -S-, -N(R**)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O) ₂ -, -N(R**)S(O) ₂ -, - S(O) ₂ N(R**)-, -N(R**)C(O)-, -C(O)N(R**)-, -OC(O)N(R**)-, -N(R**)C(O)O-, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R** represents independently for each occurrence hydrogen, C1-6 alkyl, or C3-6 cycloalkyl. [0172] In certain embodiments, L is a bivalent, saturated or unsaturated, straight or branched C1-60 hydrocarbon chain, wherein 0-20 methylene units of the hydrocarbon are independently replaced with -O-, -S-, -N(H)-, -N(C _1-6 alkyl)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O) ₂ -, -N(H)S(O) ₂ - , -N(C1-6 alkyl)S(O) ₂ -, -S(O) ₂ N(H)-, -S(O) ₂ N(C1-6 alkyl)-, -N(H)C(O)-, -N(C1-6 alkyl)C(O)-, - C(O)N(H)-, -C(O)N(C _1-6 alkyl)-, -OC(O)N(H)-, -OC(O)N(C _1-6 alkyl)-, -N(H)C(O)O-, -N(C _1-6 alkyl)C(O)O-, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3- 10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0173] In certain embodiments, L is a bivalent, saturated, straight or branched C3-30 hydrocarbon chain, wherein 0-15 methylene units of the hydrocarbon are independently replaced with -O-, -N(H)-, -N(C1-6 alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C1-6 alkyl)C(O)- , -C(O)N(H)-, -C(O)N(C1-6 alkyl)-, 3-10 membered carbocyclyl, or 3-10 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0174] In certain embodiments, L is a bivalent, saturated, straight or branched C3-30 hydrocarbon chain, wherein 0-15 methylene units of the hydrocarbon are independently replaced with -O-, -N(H)-, -N(C1-6 alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C1-6 alkyl)C(O)- , -C(O)N(H)-, or -C(O)N(C _1-6 alkyl)-. [0175] In yet other embodiments, L comprises a polyethylene glycol chain ranging in size from about 1 to about 12 ethylene glycol units, from about 1 to about 10 ethylene glycol units, from about 2 to about 6 ethylene glycol units, from about 2 to about 5 ethylene glycol units, or from about 2 to about 4 ethylene glycol units. In yet other embodiments, L is a diradical of a polyethylene glycol chain ranging in size from about 1 to about 12 ethylene glycol units, from about 1 to about 10 ethylene glycol units, from about 2 to about 6 ethylene glycol units, from about 2 to about 5 ethylene glycol units, or from about 2 to about 4 ethylene glycol units. [0176] In certain embodiments, L is a heteroalkylene having from 4 to 30 atoms selected from carbon, oxygen, nitrogen, and sulfur. In certain embodiments, L is a heteroalkylene having from 4 to 20 atoms selected from carbon, oxygen, nitrogen, and sulfur. In certain embodiments, L is a heteroalkylene having from 4 to 10 atoms selected from carbon, oxygen, nitrogen, and sulfur. In certain embodiments, L is a heteroalkylene having from 4 to 30 atoms selected from carbon, oxygen, and nitrogen. In certain embodiments, L is a heteroalkylene having from 4 to 20 atoms selected from carbon, oxygen, and nitrogen. In certain embodiments, L is a heteroalkylene having from 4 to 10 atoms selected from carbon, oxygen, and nitrogen. In certain embodiments, L is a heteroalkylene having from 4 to 30 atoms selected from carbon and oxygen. In certain embodiments, L is a heteroalkylene having from 4 to 20 atoms selected from carbon and oxygen. In certain embodiments, L is a heteroalkylene having from 4 to 10 atoms selected from carbon and oxygen. [0177] In additional embodiments, the L is an optionally substituted (poly)ethyleneglycol having between 1 and about 100 ethylene glycol units, between about 1 and about 50 ethylene glycol units, between 1 and about 25 ethylene glycol units, between about 1 and about 10 ethylene glycol units, between 1 and about 8 ethylene glycol units, between 1 and about 6 ethylene glycol units, between 2 and about 4 ethylene glycol units, or optionally substituted alkyl groups interdispersed with optionally substituted, O, N, S, P or Si atoms. In certain embodiments, L is substituted with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocycle group. [0178] In certain embodiments, L is a bivalent, saturated or unsaturated, straight or branched C1-45 hydrocarbon chain, wherein 0-10 methylene units of the hydrocarbon are independently replaced with -O-, -S-, -N(R**)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O) ₂ -, -N(R**)S(O) ₂ -, - S(O) ₂ N(R**)-, -N(R**)C(O)-, -C(O)N(R**)-, -OC(O)N(R**)-, -N(R**)C(O)O-, optionally substituted carbocyclyl, or optionally substituted heterocyclyl, wherein R** represents independently for each occurrence hydrogen, C1-6 alkyl, or C3-6 cycloalkyl. [0179] In certain embodiments, L is a bivalent, saturated or unsaturated, straight or branched C _1-45 hydrocarbon chain, wherein 0-10 methylene units of the hydrocarbon are independently replaced with -O-, -S-, -N(R**)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O) ₂ -, -N(R**)S(O) ₂ -, - S(O) ₂ N(R**)-, -N(R**)C(O)-, -C(O)N(R**)-, -OC(O)N(R**)-, -N(R**)C(O)O-, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein R** represents independently for each occurrence hydrogen, C1-6 alkyl, or C3-6 cycloalkyl. [0180] In certain embodiments, L has the formula -N(R)-(optionally substituted 3-20 membered heteroalkylene) _p -CH ₂ -C(O)-, wherein R is hydrogen or optionally substituted C ₁ -C ₆ alkyl, and p is 0 or 1. [0181] In certain embodiments, L has the formula -N(R)-(3-20 membered heteroalkylene)p- CH ₂ -C(O)-; wherein the 3-20 membered heteroalkylene is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halogen, C1-C6 haloalkyl, C3-C6 cycloalkyl, hydroxyl, and cyano; R is hydrogen or optionally substituted C ₁ -C ₆ alkyl; and p is 0 or 1. [0182] In certain embodiments, L has the formula -N(R)-(3-20 membered heteroalkylene)p- CH ₂ -C(O)-; wherein the 3-20 membered heteroalkylene is optionally substituted with 1, 2, or 3 substituents independently selected from halogen and C1-C6 haloalkyl; R is hydrogen or C1-C6 alkyl; and p is 0 or 1. [0183] In certain embodiments, L is a bivalent, saturated or unsaturated, straight or branched C1-60 hydrocarbon chain, wherein 0-20 methylene units of the hydrocarbon are independently replaced with -O-, -S-, -N(H)-, -N(C _1-6 alkyl)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O) ₂ -, -N(H)S(O) ₂ - , -N(C1-6 alkyl)S(O) ₂ -, -S(O) ₂ N(H)-, -S(O) ₂ N(C1-6 alkyl)-, -N(H)C(O)-, -N(C1-6 alkyl)C(O)-, - C(O)N(H)-, -C(O)N(C _1-6 alkyl)-, -OC(O)N(H)-, -OC(O)N(C _1-6 alkyl)-, -N(H)C(O)O-, -N(C _1-6 alkyl)C(O)O-, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3- 10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0184] In certain embodiments, L is a bivalent, saturated, straight or branched C3-30 hydrocarbon chain, wherein 0-15 methylene units of the hydrocarbon are independently replaced with -O-, -N(H)-, -N(C1-6 alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C1-6 alkyl)C(O)- , -C(O)N(H)-, -C(O)N(C _1-6 alkyl)-, 3-10 membered carbocyclyl, or 3-10 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0185] In certain embodiments, L is a bivalent, saturated, straight or branched C _3-30 hydrocarbon chain, wherein 0-15 methylene units of the hydrocarbon are independently replaced with -O-, -N(H)-, -N(C _1-6 alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C _1-6 alkyl)C(O)- , -C(O)N(H)-, or -C(O)N(C1-6 alkyl)-. [0186] In certain embodiments, L is a bivalent, saturated or unsaturated, straight or branched C _5-40 hydrocarbon chain, wherein 1-20 methylene units of the hydrocarbon are independently replaced with -O-, -N(H)-, -N(C1-6 alkyl)-, -N(H)C(O)-, -N(C1-6 alkyl)C(O)-, -C(O)N(H)-, - C(O)N(C _1-6 alkyl)-, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0187] In certain embodiments, L is -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ )1-15-O-***, wherein *** is the point of attachment to A ² . [0188] In certain embodiments, L is -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ ) _1-5 -O-***, wherein *** is the point of attachment to A ² . [0189] In certain embodiments, L is -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ ) _6-10 -O-***, wherein *** is the point of attachment to A ² . [0190] In certain embodiments, L is -piperidinylene-(OCH ₂ CH ₂ )1-15-O-***, wherein *** is the point of attachment to A ² . [0191] In certain embodiments, L is , wherein *** is the point of attachment to A ² . In certain embodiments, L is , wherein *** is the point of attachment to A ² . In certain embodiments, L is , wherein *** is the point of attachment to A ² . [0192] In certain embodiments, L is -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ )1-15-N(H)C(O)-C1-10 alkylene-***, -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ )1-15-N(C1-4 alkyl)C(O)-C1-10 alkylene-***, -(3- 7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ )1-15-C(O)N(H)-C1-10 alkylene-***, or -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ ) _1- 15-C(O)N(C1-4 alkyl)-C1-10 alkylene-***, wherein *** is the point of attachment to A ² . [0193] In certain embodiments, L is -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ ) _1-10 -N(H)C(O)-C _1-5 alkylene- ***, -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ ) _1-10 -N(C _1-4 alkyl)C(O)-C _1-5 alkylene-***, -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)- (OCH ₂ CH ₂ ) _1-10 -C(O)N(H)-C _1-5 alkylene-***, or -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-OCH ₂ CH ₂ )1-10- C(O)N(C _1-4 alkyl)-C _1-5 alkylene-***, wherein *** is the point of attachment to A ² . [0194] In certain embodiments, L is -piperidinylene-(OCH ₂ CH ₂ ) _1-5 -N(H)C(O)-C _1-5 alkylene- ***, -piperidinylene-(OCH ₂ CH ₂ )1-5-N(C1-4 alkyl)C(O)-C1-5 alkylene-***, -piperidinylene- (OCH ₂ CH ₂ ) _1-5 -C(O)N(H)-C _1-5 alkylene-***, or -piperidinylene-(OCH ₂ CH ₂ ) _1-5 -C(O)N(C _1-4 alkyl)-C1-5 alkylene-***, wherein *** is the point of attachment to A ² . [0195] In certain embodiments, L is -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ ) _1-10 -***, -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)- (C _0-10 alkylene)-O-***, or -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-C1-10 alkylene, wherein *** is the point of attachment to A ² . [0196] In certain embodiments, L is -piperidinylene-(OCH ₂ CH ₂ )1-5-***, -piperidinylene-(C0-5 alkylene)-O-***, or -piperidinylene-(C1-5 alkylene)-***, wherein *** is the point of attachment to A ² . [0197] In certain embodiments, L is -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-X ¹ -***, wherein *** is the point of attachment to A ² , and X ¹ is (i) C1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, -N(H)-, or -N(C1-4 alkyl)-, (ii) a 3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen, or (iii) -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)- (C1-10 alkylene)-. [0198] In certain embodiments, L is -(piperidinylene)-X ¹ -***, wherein *** is the point of attachment to A ² , and X ¹ is (i) C _1-5 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, -N(H)-, or -N(C1-4 alkyl)-, (ii) a 3-4 membered monocyclic saturated heterocyclic ring containing 1 heteroatom selected from nitrogen, or (iii) -(3-4 membered monocyclic saturated heterocyclic ring containing 1 heteroatom selected from nitrogen)-(C1-5 alkylene)-. [0199] In certain embodiments, L is , wherein *** is the point of attachment to A ² , and X ¹ is (i) C _1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O- , -N(H)-, or -N(C1-4 alkyl)-, (ii) a 3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen, or (iii) -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C1-10 alkylene)-. [0200] In certain embodiments, L is -(piperazinylene)-X ¹ -***, wherein *** is the point of attachment to A ² , and X ¹ is (i) C1-5 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, (ii) a 3-4 membered monocyclic saturated heterocyclic ring containing 1 heteroatom selected from nitrogen, or (iii) -(3-4 membered monocyclic saturated heterocyclic ring containing 1 heteroatom selected from nitrogen)-(C _1-5 alkylene)-. [0201] In certain embodiments, L is , wherein *** is the point of attachment to A ² , and X ¹ is (i) C1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O- , (ii) a 3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen, or (iii) -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C1-10 alkylene)-. [0202] In certain embodiments, L is -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-X ² -(C1-10 alkylene)-***, wherein *** is the point of attachment to A ² , and X ² is -O-, -N(H)-, or -N(C _1-6 alkyl)-. In certain embodiments, L is -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-X ² -(C1-10 alkylene)-***, wherein *** is the point of attachment to A ² , and X ² is -O-. [0203] In certain embodiments, L is -(piperidinylene)-X ² -(C1-10 alkylene)-***, wherein *** is the point of attachment to A ² , and X ² is -O-, -N(H)-, or -N(C _1-6 alkyl)-. In certain embodiments, L is -(piperidinylene)-X ² -(C1-10 alkylene)-***, wherein *** is the point of attachment to A ² , and X ² is -O-. [0204] In certain embodiments, L is -(piperidinylene)-X ² -(a 3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-***, wherein *** is the point of attachment to A ² , and X ² is -O-, -N(H)-, or -N(C _1-6 alkyl)-. In certain embodiments, L is -(piperidinylene)-X ² -(a 3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-***, wherein *** is the point of attachment to A ² , and X ² is -O-. [0205] In certain embodiments, L is , wherein *** is the point of attachment to A ² , and X ² is -O-, -N(H)-, or -N(C1-6 alkyl)-. In certain embodiments, L i , wherein *** is the point of attachment to A ² , and X ² is - O-. [0206] In certain embodiments, L is , wherein *** is the point of attachment to A ² , and X ² is -O-, -N(H)-, or -N(C _1-6 alkyl)-. In certain embodiments, L is , wherein *** is the point of attachment to A ² , and X ² is -O-. [0207] In certain embodiments, L is -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-X ¹ -***, wherein *** is the point of attachment to A ² , and X ¹ is -(OCH ₂ CH ₂ ) _1-10 where 1 CH ₂ group is optionally replaced with - C(H)(C3-6 cycloalkyl)-. [0208] In certain embodiments, L is a 7-11 membered spirocyclic or fused bicyclic saturated heterocyclic ring containing 1, 2, or 3 heteroatoms selected from nitrogen and oxygen. In certain embodiments, L is a 7-8 membered spirocyclic or fused bicyclic saturated heterocyclic ring containing 2 heteroatoms selected from nitrogen. [0209] In certain embodiments, L is -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-X ³ -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-, wherein X ³ is C _1-10 alkylene, -O-, -N(H)-, -N(C1-4 alkyl)-, or a bond. [0210] In certain embodiments, L is -(piperidinylene)-(C1-5 alkylene)-(piperazinylene)-***, wherein *** is the point of attachment to A ² . [0211] In certain embodiments, L is -(piperazinylene)-(azetidinylene)-*** or (azetidinylene)- (piperazinylene)-***, wherein *** is the point of attachment to A ² . [0212] In certain embodiments, L is -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-X ³ -(C3-6 cycloalkylene)-O-***, -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-X ³ -(C3-6 cycloalkylene)-N(H)-***, or -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-X ³ -(C3-6 cycloalkylene)-N(C _1-4 alkyl)-***, wherein *** is the point of attachment to A ² , and X ³ is C _1-10 alkylene, -O-, -N(H)-, -N(C1-4 alkyl)-, or a bond. [0213] In certain embodiments, L is -(piperidinylene)-X ³ -(C _3-6 cycloalkylene)-O-***, - (piperidinylene)-X ³ -(C3-6 cycloalkylene)-N(H)-***, or -(piperidinylene)-X ³ -(C3-6 cycloalkylene)-***, wherein *** is the point of attachment to A ² , and X ³ is C _1-10 alkylene, -O-, -N(H)-, -N(C1-4 alkyl)-, or a bond. [0214] In certain embodiments, L has the formula –(C0-12 alkylene)-(optionally substituted 3-40 membered heteroalkylene)-(C _0-12 alkylene)-. [0215] In certain embodiments, L is wherein *** is the point of attachment to A ² . [0216] In certain embodiments, L is , wherein *** is the point of attachment to A ² . [0217] In certain embodiments, L is , wherein *** is the point of attachment to A ² . [0218] In certain embodiments, L is wherein *** is the point of attachment to A ² . [0219] In certain embodiments, L is -(8-12 membered spirocyclic heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C _3-4 cycloalkylene)-***, - (8-12 membered spirocyclic heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C _0-4 alkylene)-***, -(8-12 membered spirocyclic heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-C(O)-(C _1-4 alkylene)-***, -(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(3-5 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-***, -(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-O-***, -(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(C _0-4 alkylene)-***, -(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms )-(C0-4 alkylene)-O-***, -(8-12 membered spirocyclic heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-C(O))-***, -(8-12 membered spirocyclic heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen)-O-(C _0-6 alkylene)-***, -(8- 12 membered spirocyclic heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen)- (C _1-6 alkylene)-O-(C _0-6 alkylene)-***, -(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms )-C(O)N(H)-(C0-6 alkylene)-***, -(N(C1-6 alkyl)-(C0-6 alkylene)- C(O)N(H)-(C0-6 alkylene)-***, -(8-12 membered spirocyclic heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C2-4 alkynylene)-***, -(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(C1-6 alkyl)-(3-5 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-***, -(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-C(O)N(H)-(C0-6 alkylene)-N(H))-***, -(C(O)N(H)-(C0-6 alkylene)-(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms )-***, -(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-N(C1-6 alkyl)-(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-O-***, -C(O)-(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-C(O)-***, -(C0-6 alkylene)-(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-C(O)-***, -(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-C(O)-(C _0-6 alkylene)***, -C(O)-(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C1-6 alkylene)-***, -(C(O)N(H)-(C _1-6 alkylene)-C(O)N(H)-(C _0-6 alkylene)-***, or -(8-11 membered fused bicyclic heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C _1-4 alkylene)-***, wherein *** is the point of attachment to A ² . [0220] In certain embodiments, L is -N(C1-6 alkyl)-(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-C(O)-(C0-6 alkylene)- ***, -(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C0-4 alkylene)-O-***, -(C0-6 alkylene)-N(H)C(O)N(H)- (C0-6 alkylene)-***, -N(H)-(C0-6 alkylene)-(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C0-6 alkylene)-***, - (C0-6 alkylene)-C(O)-(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C0-6 alkylene)-***, -(C0-6 alkylene)-(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)- C(O)N(C1-6 alkyl)-(C0-6 alkylene)-***, -(C0-6 alkylene)-(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C0-6 alkylene)-N(C1-6 alkyl)-(3-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-***, -(4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen)-(C _0-6 alkylene)-O-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen)-O-***, -(4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen)-(C _0-6 alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen)-O-***, -(4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen)-(C _0-6 alkylene)- (5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen)-***, -(8-12 membered spirocyclic heterocyclyl substituted with 1 or 2 fluoro containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C1-4 alkylene)-***, -(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C0-4 alkylene)-(C3-6 cycloalkylene)-(C0-4 alkylene)-O-***, -(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C0-4 alkylene)-(C3-6 cycloalkylene)-(C0-4 alkylene)-***, -(C0-4 alkylene)-(8-12 membered spirocyclic heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-***, -(C0-4 alkylene)-(C3-6 cycloalkylene)-(C2-4 alkynylene)-***, -(C0-4 alkylene)-(8-10 membered fused bicyclic heterocyclyl substituted with 1 or two fluoro containing 1 or 2 heteroatoms selected from nitrogen)-(C0-4 alkylene)-***, -(8-12 membered spirocyclic heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-O-***, -(8-12 membered spirocyclic heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C _0-4 alkylene)-(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-***, -(C0-4 alkylene)-(4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen)-(phenylene substituted with trifluoromethyl)-(C0-4 alkylene)-N(H)-***, or is -(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-C(O)-(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C _0-6 alkylene)-***, -(C _3-6 cycloalkylene)-C(O)N(C _1-6 alkyl)(C0-6 alkylene)-***, -(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(phenylene substituted with 0 or 1 occurrence of methyl or halo)-(C0-6 alkylene)-***, -(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C _0-6 alkylene)-(5-6 membered saturated monocyclic oxo-substituted heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C _0-6 alkylene)-***, -(8-12 membered spirocyclic C _1-4 alkyl substituted heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C0-6 alkylene)-(O) _0-1 ***, -(C _2-4 alkynylene)-(8-12 membered spirocyclic heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C0-4 alkylene)-***, -(C0- ₄ alkylene)-(C _3-7 cycloalkylene)-(C _2-4 alkynylene)-***, -(C _1-4 alkylene)-(8-12 membered spirocyclic heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C _0-4 alkylene)-***, -(C _1-4 alkylene)-(5-7 membered saturated heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C0-4 alkylene)-***, -(C _0-4 alkylene)-(5-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(C2-4 alkenylene)-***, or -(C0-4 alkylene)-(6-8 membered saturated heterocyclyl substituted with 1 or 2 fluoro containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(C0-4 alkylene)-***, wherein *** is the point of attachment to A ² . Additional Exemplary Embodiments for L [0221] In certain embodiments, L is -N(H)-(C _2-9 alkylene)-O-(C _1-6 alkylene)-C(O)-***, -N(H)- (C10-20 alkylene)-O-(C1-6 alkylene)-C(O)-***, -N(H)-[(C2-4 alkylene)-O-]2-6-(C1-6 alkylene)- C(O)-***, -N(H)-[(C _2-4 alkylene)-O-] _7-15 -(C _1-6 alkylene)-C(O)-***, -N(H)-(C _1-6 alkylene)-C(O)- ***, -N(H)-(C7-15 alkylene)-C(O)-***, -N(H)-[(C2-4 alkylene)-O-]2-6-(C1-6 alkylene)-***, -N(H)- [(C _2-4 alkylene)-O-] _7-15 -(C _1-6 alkylene)-***, -N(H)-(C _2-9 alkylene)-O-(C _1-6 alkylene)-C(O)N(C _1-6 alkyl)-(C1-6 alkylene)-***, -N(H)-(C2-9 alkylene)-O-(C1-6 alkylene)-C(O)N(H)-(C1-6 alkylene)- ***, -N(H)-[(C _2-4 alkylene)-O-] _2-6 -(C _1-6 alkylene)-N(H)-(C _1-6 alkylene)-***, -N(H)-[(C _2-4 alkylene)-O-]7-15-(C1-6 alkylene)-N(H)-(C1-6 alkylene)-***, -N(H)-[(C2-4 alkylene)-O-]2-6-(C1-6 alkylene)-N(C _1-6 alkyl)-(C _1-6 alkylene)-***, or -N(H)-[(C _2-4 alkylene)-O-] _7-15 -(C _1-6 alkylene)- N(C1-6 alkyl)-(C1-6 alkylene)-***, where *** is a point of attachment to A ² . [0222] In certain embodiments, L is -N(H)-(C2-9 alkylene)-O-(C1-6 alkylene)-C(O)-***, -N(H)- (C _10-20 alkylene)-O-(C _1-6 alkylene)-C(O)-***, -N(H)-[CH ₂ CH ₂ -O-] _2-6 -(C _1-6 alkylene)-C(O)-***, -N(H)-[CH ₂ CH ₂ -O-]7-15-(C1-6 alkylene)-C(O)-***, -N(H)-(C1-6 alkylene)-C(O)-***, -N(H)-(C7- ₁₅ alkylene)-C(O)-***, -N(H)-[CH ₂ CH ₂ -O-] _2-6 -(C _1-6 alkylene)-***, -N(H)-[CH ₂ CH ₂ -O-] _7-15 -(C _1- 6 alkylene)-***, -N(H)-(C2-9 alkylene)-O-(C1-6 alkylene)-C(O)N(C1-6 alkyl)-(C1-6 alkylene)-***, -N(H)-(C _2-9 alkylene)-O-(C _1-6 alkylene)-C(O)N(H)-(C _1-6 alkylene)-***, -N(H)-[CH ₂ CH ₂ -O-] _2-6 - (C1-6 alkylene)-N(H)-(C1-6 alkylene)-***, -N(H)-[CH ₂ CH ₂ -O-]7-15-(C1-6 alkylene)-N(H)-(C1-6 alkylene)-***, -N(H)-[CH ₂ CH ₂ -O-] _2-6 -(C _1-6 alkylene)-N(C _1-6 alkyl)-(C _1-6 alkylene)-***, or - N(H)-[CH ₂ CH ₂ -O-]7-15-(C1-6 alkylene)-N(C1-6 alkyl)-(C1-6 alkylene)-***, where *** is a point of attachment to A ² . [0223] In certain embodiments, L is -N(H)-[(C _2-4 alkylene)-O-] _2-6 -(C _1-6 alkylene)-C(O)-***, - N(H)-[(C2-4 alkylene)-O-]7-15-(C1-6 alkylene)-C(O)-***, -N(H)-(C1-6 alkylene)-N(C1-6 alkyl)C(O)-(C _1-6 alkylene)***, -N(H)-(C _1-6 alkylene)-N(H)C(O)-(C _1-6 alkylene)***, -N(H)-(C _2-6 alkylene)-***, -N(H)-(C7-15 alkylene)-***, -N(C1-6 alkyl)-(C2-6 alkylene)-***, -N(C1-6 alkyl)- (C _7-15 alkylene)-***, -N(H)-[(C _2-4 alkylene)-O-] _2-6 -(C _1-6 alkylene)-***, -N(H)-[(C _2-4 alkylene)- O-]7-15-(C1-6 alkylene)-***, -N(H)-(C1-6 alkylene)-(3-6 membered heterocycloalkylene)-(C1-6 alkylene)-N(C _1-6 alkyl)-(C _1-6 alkylene)-***, -N(H)-(C _1-6 alkylene)-(3-6 membered heterocycloalkylene)-(C1-6 alkylene)-N(H)-(C1-6 alkylene)-***, -N(H)-(C2-6 alkylene)-N(H)-(C1- ₆ alkylene)-***, or -N(H)-(C _2-6 alkylene)-N(C _1-6 alkyl)-(C _1-6 alkylene)-***, where *** is a point of attachment to A ² . [0224] In certain embodiments, L is -N(H)-[CH ₂ CH ₂ -O-]2-6-(C1-6 alkylene)-C(O)-***, -N(H)- [CH ₂ CH ₂ -O-] _7-15 -(C _1-6 alkylene)-C(O)-***, -N(H)-(C _1-6 alkylene)-N(C _1-6 alkyl)C(O)-(C _1-6 alkylene)***, -N(H)-(C1-6 alkylene)-N(H)C(O)-(C1-6 alkylene)***, -N(H)-(C2-6 alkylene)-***, - N(H)-(C7-15 alkylene)-***, -N(C1-6 alkyl)-(C2-6 alkylene)-***, -N(C1-6 alkyl)-(C7-15 alkylene)- ***, -N(H)-[CH ₂ CH ₂ -O-]2-6-(C1-6 alkylene)-***, -N(H)-[CH ₂ CH ₂ -O-]7-15-(C1-6 alkylene)-***, - N(H)-(C1-6 alkylene)-(3-6 membered heterocycloalkylene)-(C1-6 alkylene)-N(C1-6 alkyl)-(C1-6 alkylene)-***, -N(H)-(C1-6 alkylene)-(3-6 membered heterocycloalkylene)-(C1-6 alkylene)- N(H)-(C1-6 alkylene)-***, -N(H)-(C2-6 alkylene)-N(H)-(C1-6 alkylene)-***, or -N(H)-(C2-6 alkylene)-N(C1-6 alkyl)-(C1-6 alkylene)-***, where *** is a point of attachment to A ² . [0225] In certain embodiments, L is -[(C2-4 alkylene)-O-]2-6-(C1-6 alkylene)-***, -[(C2-4 alkylene)-O-] _7-15 -(C _1-6 alkylene)-***, -[(C _2-4 alkylene)-O-] _2-6 -(C _1-6 alkylene)-N(C _1-6 alkyl)(C _1-6 alkylene)-***, -[(C2-4 alkylene)-O-]7-15-(C1-6 alkylene)-N(C1-6 alkyl)(C1-6 alkylene)-***, -[(C2-4 alkylene)-O-] _2-6 -(C _1-6 alkylene)-N(H)(C _1-6 alkylene)-***, -[(C _2-4 alkylene)-O-] _7-15 -(C _1-6 alkylene)-N(H)(C1-6 alkylene)-***, -(C1-9 alkylene)-C(O)N(H)-(C1-6 alkylene)-***, -(C1-9 alkylene)-N(H)C(O)-(C _1-6 alkylene)-***, -(C _1-9 alkylene)-C(O)N(H)-[(C _2-4 alkylene)-O-] _2-6 -(C _1- 6 alkylene)-***, -(C1-9 alkylene)-N(H)C(O)-[(C2-4 alkylene)-O-]2-6-(C1-6 alkylene)-***, -(C1-9 alkylene)-C(O)N(H)-[(C2-4 alkylene)-O-]7-15-(C1-6 alkylene)-***, -(C1-9 alkylene)-N(H)C(O)- [(C2-4 alkylene)-O-]7-15-(C1-6 alkylene)-***, -(C1-9 alkylene)-C(O)N(H)-[(C2-4 alkylene)-O-]2-6- (C1-6 alkylene)-N(C1-6 alkyl)-(C1-6 alkylene)-***, -(C1-9 alkylene)-N(H)C(O)-[(C2-4 alkylene)-O- ]2-6-(C1-6 alkylene)-N(C1-6 alkyl)-(C1-6 alkylene)-***, -(C1-9 alkylene)-C(O)N(H)-[(C2-4 alkylene)-O-]7-15-(C1-6 alkylene)-N(C1-6 alkyl)-(C1-6 alkylene)-***, or -(C1-9 alkylene)- N(H)C(O)-[(C2-4 alkylene)-O-]7-15-(C1-6 alkylene)-N(C1-6 alkyl)-(C1-6 alkylene)-***, where *** is a point of attachment to A ² . [0226] In certain embodiments, L is -[CH ₂ CH ₂ -O-] _2-6 -(C _1-6 alkylene)-***, -[CH ₂ CH ₂ -O-] _7-15 - (C1-6 alkylene)-***, -[CH ₂ CH ₂ -O-]2-6-(C1-6 alkylene)-N(C1-6 alkyl)(C1-6 alkylene)-***, - [CH ₂ CH ₂ -O-] _7-15 -(C _1-6 alkylene)-N(C _1-6 alkyl)(C _1-6 alkylene)-***, -[CH ₂ CH ₂ -O-] _2-6 -(C _1-6 alkylene)-N(H)(C1-6 alkylene)-***, -[CH ₂ CH ₂ -O-]7-15-(C1-6 alkylene)-N(H)(C1-6 alkylene)-***, - (C _1-9 alkylene)-C(O)N(H)-(C _1-6 alkylene)-***, -(C _1-9 alkylene)-N(H)C(O)-(C _1-6 alkylene)-***, - (C1-9 alkylene)-C(O)N(H)-[CH ₂ CH ₂ -O-]2-6-(C1-6 alkylene)-***, -(C1-9 alkylene)-N(H)C(O)- [CH ₂ CH ₂ -O-] _2-6 -(C _1-6 alkylene)-***, -(C _1-9 alkylene)-C(O)N(H)-[CH ₂ CH ₂ -O-] _7-15 -(C _1-6 alkylene)-***, -(C _1-9 alkylene)-N(H)C(O)-[CH ₂ CH ₂ -O-] _7-15 -(C _1-6 alkylene)-***, -(C _1-9 alkylene)-C(O)N(H)-[CH ₂ CH ₂ -O-] _2-6 -(C _1-6 alkylene)-N(C _1-6 alkyl)-(C _1-6 alkylene)-***, -(C _1-9 alkylene)-N(H)C(O)-[CH ₂ CH ₂ -O-] _2-6 -(C _1-6 alkylene)-N(C _1-6 alkyl)-(C _1-6 alkylene)-***, -(C _1-9 alkylene)-C(O)N(H)-[CH ₂ CH ₂ -O-] _7-15 -(C _1-6 alkylene)-N(C _1-6 alkyl)-(C _1-6 alkylene)-***, or -(C _{1- 9} alkylene)-N(H)C(O)-[(CH ₂ CH ₂ -O-] _7-15 -(C _1-6 alkylene)-N(C _1-6 alkyl)-(C _1-6 alkylene)-***, where *** is a point of attachment to A ² . [0227] In certain embodiments, L is -N(H)-[(C _2-4 alkylene)-O-] _2-6 -(C _1-6 alkylene)-N(H)-***, - N(H)-[(C2-4 alkylene)-O-]7-15-(C1-6 alkylene)-N(H)-***, -N(C1-6 alkyl)-[(C2-4 alkylene)-O-]2-6- (C1-6 alkylene)-N(H)-***, -N(C1-6 alkyl)-[(C2-4 alkylene)-O-]7-15-(C1-6 alkylene)-N(H)-***, - N(C1-6 alkyl)-[(C2-4 alkylene)-O-]2-6-(C1-6 alkylene)-N(C1-6 alkyl)-***, or -N(C1-6 alkyl)-[(C2-4 alkylene)-O-]7-15-(C1-6 alkylene)-N(C1-6 alkyl)-***, where *** is a point of attachment to A ² . [0228] In certain embodiments, L is -N(H)-[CH ₂ CH ₂ -O-]2-6-(C1-6 alkylene)-N(H)-***, -N(H)- [CH ₂ CH ₂ -O-] _7-15 -(C _1-6 alkylene)-N(H)-***, -N(C _1-6 alkyl)-[CH ₂ CH ₂ -O-] _2-6 -(C _1-6 alkylene)- N(H)-***, -N(C1-6 alkyl)-[CH ₂ CH ₂ -O-]7-15-(C1-6 alkylene)-N(H)-***, -N(C1-6 alkyl)-[CH ₂ CH ₂ - O-] _2-6 -(C _1-6 alkylene)-N(C _1-6 alkyl)-***, or -N(C _1-6 alkyl)-[CH ₂ CH ₂ -O-] _7-15 -(C _1-6 alkylene)- N(C1-6 alkyl)-***, where *** is a point of attachment to A ² . [0229] In some embodiments, L is one of the following:

; wherein a dashed bond indicates a point of attachment. [0230] In certain embodiments, L is -C(H)(R ¹⁰⁰ )-, -C(R ¹⁰⁰ ) ₂ -, O, -N(R ¹⁰¹ )-, -S(O) ₂ -, an optionally substituted C3-7 cycloalkylene, an optionally substituted C4-7 cycloalkenylene, or an optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R ¹⁰⁰ represents independently for each occurrence hydrogen, halogen, C _1-6 alkyl, or C _3-6 cycloalkyl, and R ¹⁰¹ is hydrogen, C _1-6 alkyl, or C _3-6 cycloalkyl. In certain embodiments, R ¹⁰⁰ represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R ¹⁰¹ is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. [0231] In certain embodiments, L is -CH ₂ -Y ²⁰ -, -C(H)(R ¹⁰⁰ )-Y ²⁰ -, -C(R ¹⁰⁰ ) ₂ -Y ²⁰ -, -O-Y ²⁰ -, - N(R ¹⁰¹ )-Y ²⁰ -, -S(O) ₂ -Y ²⁰ -, -C(O)-Y ²⁰ -, -(optionally substituted C3-7 cycloalkylene)-Y ²⁰ -, - (optionally substituted C _4-7 cycloalkenylene)-Y ²⁰ -, -(optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur)- Y ²⁰ -, -Y ²⁰ -CH ₂ -, -Y ²⁰ -C(H)(R ¹⁰⁰ )-, -Y ²⁰ -C(R ¹⁰⁰ ) ₂ -, -Y ²⁰ -O-, -Y ²⁰ -N(R ¹⁰¹ )-, -Y ²⁰ -S(O) ₂ -, -Y ²⁰ - C(O)-, -Y ²⁰ -(optionally substituted C3-7 cycloalkylene)-, -Y ²⁰ -(optionally substituted C4-7 cycloalkenylene)-, or -Y ²⁰ -(optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur)-; wherein R ¹⁰⁰ represents independently for each occurrence hydrogen, halogen, C1-6 alkyl, or C3-6 cycloalkyl, and R ¹⁰¹ is hydrogen, C1-6 alkyl, or C3-6 cycloalkyl. In certain embodiments, R ¹⁰⁰ represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R ¹⁰¹ is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. [0232] In certain embodiments, L is one of the following: [0233] wherein X ²⁰ , Y ²⁰ , and Z ²⁰ are independently -CH ₂ -, -C(H)(R ¹⁰⁰ )-, -C(R ¹⁰⁰ ) ₂ -, O, - N(R ¹⁰¹ )-, -S(O) ₂ -, -C(O)-, an optionally substituted C _3-7 cycloalkylene, or an optionally substituted C4-7 cycloalkenylene; wherein R ¹⁰⁰ represents independently for each occurrence hydrogen, halogen, C _1-6 alkyl, or C _3-6 cycloalkyl, and R ¹⁰¹ is hydrogen, C _1-6 alkyl, or C _3-6 cycloalkyl. In certain embodiments, R ¹⁰⁰ represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R ¹⁰¹ is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. [0234] In certain embodiments, L is one of the following: [0235] wherein X ²⁰ , Y ²⁰ , and Z ²⁰ are independently -C(R ¹⁰⁰ )- or -N-; wherein R ¹⁰⁰ represents independently for each occurrence hydrogen, halogen, C _1-6 alkyl, or C _3-6 cycloalkyl. In certain embodiments, R ¹⁰⁰ represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. [0236] In certain embodiments, L is -X ²⁰ -Y ²⁰ -Z ²⁰ -, wherein X ²⁰ , Y ²⁰ , and Z ²⁰ are independently -CH ₂ -, -C(H)(R ¹⁰⁰ )-, -C(R ¹⁰⁰ ) ₂ -, O, -N(R ¹⁰¹ )-, -S(O) ₂ -, -C(O)-, an optionally substituted C3-7 cycloalkylene, an optionally substituted C _4-7 cycloalkenylene, or optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R ¹⁰⁰ represents independently for each occurrence hydrogen, halogen, C _1-6 alkyl, or C3-6 cycloalkyl, and R ¹⁰¹ is hydrogen, C1-6 alkyl, or C3-6 cycloalkyl. In certain embodiments, R ¹⁰⁰ represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R ¹⁰¹ is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. [0237] In certain embodiments, L is -X ²⁰ =Y ²⁰ -Z ²¹ -, wherein X ²⁰ and Y ²⁰ are independently - C(R ¹⁰⁰ )- or -N-, and Z ²¹ is -CH ₂ -, -C(H)(R ¹⁰⁰ )-, -C(R ¹⁰⁰ ) ₂ -, O, -N(R ¹⁰¹ )-, -S(O) ₂ -, -C(O)-, an optionally substituted C _3-7 cycloalkylene, or an optionally substituted C _4-7 cycloalkenylene; wherein R ¹⁰⁰ represents independently for each occurrence hydrogen, halogen, C1-6 alkyl, or C3- ₆ cycloalkyl, and R ¹⁰¹ is hydrogen, C _1-6 alkyl, or C _3-6 cycloalkyl. In certain embodiments, R100 represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R ¹⁰¹ is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. [0238] In certain embodiments, L is -C≡C-Z ²⁰ -, wherein Z ²⁰ is -CH ₂ -, -C(H)(R ¹⁰⁰ )-, -C(R ¹⁰⁰ ) ₂ -, O, -N(R ¹⁰¹ )-, -S(O) ₂ -, -C(O)-, an optionally substituted C _3-7 cycloalkylene, or an optionally substituted C4-7 cycloalkenylene; wherein R ¹⁰⁰ represents independently for each occurrence hydrogen, halogen, C _1-6 alkyl, or C _3-6 cycloalkyl, and R ¹⁰¹ is hydrogen, C _1-6 alkyl, or C _3-6 cycloalkyl. In certain embodiments, R ¹⁰⁰ represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R ¹⁰¹ is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. [0239] In certain embodiments, L is one of the following:

[0240] wherein X ²⁰ , Y ²⁰ , and Z ²⁰ are independently -CH ₂ -, -C(H)(R ¹⁰⁰ )-, -C(R ¹⁰⁰ ) ₂ -, O, - N(R ¹⁰¹ )-, -S(O) ₂ -, -C(O)-, an optionally substituted C3-7 cycloalkylene, an optionally substituted C _4-7 cycloalkenylene, or optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R ¹⁰⁰ represents independently for each occurrence hydrogen, halogen, C _1-6 alkyl, or C _3-6 cycloalkyl, and R ¹⁰¹ is hydrogen, C1-6 alkyl, or C3-6 cycloalkyl. In certain embodiments, R ¹⁰⁰ represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R ¹⁰¹ is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. [0241] In certain embodiments, L is one of the following: [0242] wherein V ²⁰ , W ²⁰ , X ²⁰ , Y ²⁰ , and Z ²⁰ are independently -CH ₂ -, -C(H)(R ¹⁰⁰ )-, -C(R ¹⁰⁰ ) ₂ -, O, -N(R ¹⁰¹ )-, -S(O) ₂ -, -C(O)-, an optionally substituted C3-7 cycloalkylene, an optionally substituted C4-7 cycloalkenylene, or optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R ¹⁰⁰ represents independently for each occurrence hydrogen, halogen, C1-6 alkyl, or C3-6 cycloalkyl, and R ¹⁰¹ is hydrogen, C1-6 alkyl, or C3-6 cycloalkyl. In certain embodiments, R ¹⁰⁰ represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R ¹⁰¹ is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. [0243] In certain embodiments, L is one of the following: [0244] wherein W ²⁰ , X ²⁰ , Y ²⁰ , and Z ²⁰ are independently -C(R ¹⁰⁰ )- or -N-; wherein R ¹⁰⁰ represents independently for each occurrence hydrogen, halogen, C1-6 alkyl, or C3-6 cycloalkyl. In certain embodiments, R ¹⁰⁰ represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. [0245] In certain embodiments, L is one of the following: [0246] wherein W ²⁰ , X ²⁰ , Y ²⁰ , and Z ²⁰ are independently -C(R ¹⁰⁰ )- or -N-; wherein R ¹⁰⁰ represents independently for each occurrence hydrogen, halogen, C _1-6 alkyl, or C _3-6 cycloalkyl. In certain embodiments, R ¹⁰⁰ represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. [0247] In certain embodiments, L is one of the following: [0248] wherein U, V, W, X, Y, and Z are independently -CH ₂ -, -C(H)(R ¹⁰⁰ )-, -C(R ¹⁰⁰ ) ₂ -, O, - N(R ¹⁰¹ )-, -S(O) ₂ -, -C(O)-, an optionally substituted C3-7 cycloalkylene, an optionally substituted C4-7 cycloalkenylene, or optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R ¹⁰⁰ represents independently for each occurrence hydrogen, halogen, C1-6 alkyl, or C3-6 cycloalkyl; R ¹⁰¹ is hydrogen, C1-6 alkyl, or C3-6 cycloalkyl; and a dashed bond indicates a point of attachment. In certain embodiments, R ¹⁰⁰ represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R ¹⁰¹ is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. [0249] In certain embodiments, L is one of the following: [0250] wherein X, Y, and Z are independently -C(R ¹⁰⁰ )- or -N-; V and W are independently - CH ₂ -, -C(H)(R ¹⁰⁰ )-, -C(R ¹⁰⁰ ) ₂ -, O, -N(R ¹⁰¹ )-, -S(O) ₂ -, -C(O)-, an optionally substituted C3-7 cycloalkylene, an optionally substituted C _4-7 cycloalkenylene, or optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R ¹⁰⁰ represents independently for each occurrence hydrogen, halogen, C _1-6 alkyl, or C3-6 cycloalkyl; R ¹⁰¹ is hydrogen, C1-6 alkyl, or C3-6 cycloalkyl; and a dashed bond indicates a point of attachment. In certain embodiments, R ¹⁰⁰ represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R ¹⁰¹ is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. [0251] In certain embodiments, L is one of the following: [0252] wherein W, X, Y, and Z are independently -C(R ¹⁰⁰ )- or -N-; V is -CH ₂ -, -C(H)(R ¹⁰⁰ )-, - C(R ¹⁰⁰ ) ₂ -, O, -N(R ¹⁰¹ )-, -S(O) ₂ -, -C(O)-, an optionally substituted C3-7 cycloalkylene, an optionally substituted C4-7 cycloalkenylene, or optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R ¹⁰⁰ represents independently for each occurrence hydrogen, halogen, C1-6 alkyl, or C3- 6 cycloalkyl; R ¹⁰¹ is hydrogen, C1-6 alkyl, or C3-6 cycloalkyl; and a dashed bond indicates a point of attachment. In certain embodiments, R ¹⁰⁰ represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R ¹⁰¹ is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. [0253] In certain embodiments, L is one of the following:

[0254] wherein T, U, V, W, X, Y, and Z are independently -CH ₂ -, -C(H)(R ¹⁰⁰ )-, -C(R ¹⁰⁰ ) ₂ -, O, -N(R ¹⁰¹ )-, -S(O) ₂ -, -C(O)-, an optionally substituted C3-7 cycloalkylene, an optionally substituted C4-7 cycloalkenylene, or optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R ¹⁰⁰ represents independently for each occurrence hydrogen, halogen, C1-6 alkyl, or C3-6 cycloalkyl; R ¹⁰¹ is hydrogen, C1-6 alkyl, or C3-6 cycloalkyl; and a dashed bond indicates a point of attachment. In certain embodiments, R ¹⁰⁰ represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R ¹⁰¹ is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. [0255] In certain embodiments, L is one of the following: [0256] wherein W, X, Y, and Z are independently -C(R ¹⁰⁰ )- or -N-; U and V are independently -CH ₂ -, -C(H)(R ¹⁰⁰ )-, -C(R ¹⁰⁰ ) ₂ -, O, -N(R ¹⁰¹ )-, -S(O) ₂ -, -C(O)-, an optionally substituted C _3-7 cycloalkylene, an optionally substituted C4-7 cycloalkenylene, or optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; R ¹⁰⁰ represents independently for each occurrence hydrogen, halogen, C1-6 alkyl, or C _3-6 cycloalkyl; R ¹⁰¹ is hydrogen, C _1-6 alkyl, or C _3-6 cycloalkyl; and a dashed bond indicates a point of attachment. In certain embodiments, R ¹⁰⁰ represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R ¹⁰¹ is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. [0257] In certain embodiments, L is one of the following: [0258] wherein X, Y, and Z are independently -C(R ¹⁰⁰ )- or -N-; U, V, and W are independently -CH ₂ -, -C(H)(R ¹⁰⁰ )-, -C(R ¹⁰⁰ ) ₂ -, O, -N(R ¹⁰¹ )-, -S(O) ₂ -, -C(O)-, an optionally substituted C3-7 cycloalkylene, an optionally substituted C _4-7 cycloalkenylene, or optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R ¹⁰⁰ represents independently for each occurrence hydrogen, halogen, C _1-6 alkyl, or C3-6 cycloalkyl; R ¹⁰¹ is hydrogen, C1-6 alkyl, or C3-6 cycloalkyl; and a dashed bond indicates a point of attachment. In certain embodiments, R ¹⁰⁰ represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R ¹⁰¹ is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. [0259] In certain embodiments, L is one of the following:

[0260] variables m, n, o, p, and q are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0261] In certain embodiments, L is one of the following:

wherein any m or n are independently 0, 1, 2, 3, 4, 5, or 6; and any X is H or F.

[0262] In certain embodiments, L is one of the following:

wherein any m or n are independently 0, 1, 2, 3, 4, 5, or 6. [0263] In certain embodiments, L is one of the following:

[0264] wherein any m or n are independently 0, 1, 2, 3, 4, 5, or 6. [0265] In certain embodiments, L is one of the following:

[0266] In certain embodiments, L is one of the following:

[0267] In certain embodiments, L has the formula –(C0-12 alkylene)-(optionally substituted 3-40 membered heteroalkylene)-(C _0-12 alkylene)-. In certain embodiments, L is C _4-14 alkylene. In certain embodiments, L is -(CH ₂ )6-10-. [0268] In certain embodiments, L is -CH ₂ CH ₂ (OCH ₂ CH ₂ )-***, -CH ₂ CH ₂ (OCH ₂ CH ₂ ) ₂ -***, - CH ₂ CH ₂ (OCH ₂ CH ₂ ) ₃ -***, -CH ₂ CH ₂ (OCH ₂ CH ₂ ) ₄ -***, -CH ₂ CH ₂ (OCH ₂ CH ₂ ) ₅ -***, - CH ₂ CH ₂ (OCH ₂ CH ₂ )6-***, -CH ₂ CH ₂ (OCH ₂ CH ₂ )7-***, -CH ₂ CH ₂ (OCH ₂ CH ₂ )8-***, - CH ₂ CH ₂ (OCH ₂ CH ₂ ) ₉ -***, -CH ₂ CH ₂ (OCH ₂ CH ₂ ) ₁₀ -***, -CH ₂ CH ₂ (OCH ₂ CH ₂ ) ₁₁ -***, - CH ₂ CH ₂ (OCH ₂ CH ₂ )12-***, -CH ₂ CH ₂ (OCH ₂ CH ₂ )13-***, -CH ₂ CH ₂ (OCH ₂ CH ₂ )14-***, - CH ₂ CH ₂ (OCH ₂ CH ₂ ) ₁₅ -***, or -CH ₂ CH ₂ (OCH ₂ CH ₂ ) _16-20 -***, where *** is a point of attachment to A ² . [0269] In certain embodiments, L is -(C2-20 alkylene)-(OCH ₂ CH ₂ ) ₂ -4-(C0-4 alkylene)-***, -(C2-20 alkylene)-(OCH ₂ CH ₂ ) _5-7 -(C _0-4 alkylene)-***, -(C _2-20 alkylene)-(OCH ₂ CH ₂ ) _8-10 -(C _0-4 alkylene)- ***, -(C2-20 alkylene)-(OCH ₂ CH ₂ )11-13-(C0-4 alkylene)-***, -(C2-20 alkylene)-(OCH ₂ CH ₂ )14-16- (C _0-4 alkylene)-***, -(C _2-20 alkylene)-(OCH ₂ CH ₂ ) _17-20 -(C _0-4 alkylene)-***, -(C _1-20 alkylene)- (OCH ₂ CH ₂ )1-10-(C0-4 alkylene)-C(O)-***, or -(C1-20 alkylene)-(OCH ₂ CH ₂ )11-20-(C0-4 alkylene)- C(O)-***, where *** is a point of attachment to A ² . [0270] In certain embodiments, L is -O(CH ₂ CH ₂ O) ₂ -4-(C0-4 alkylene)-***, -O(CH ₂ CH ₂ O)5-7- (C0-4 alkylene)-***, -O(CH ₂ CH ₂ O)8-10-(C0-4 alkylene)-***, -O(CH ₂ CH ₂ O)11-13-(C0-4 alkylene)- ***, -O(CH ₂ CH ₂ O)14-16-(C0-4 alkylene)-***, -O(CH ₂ CH ₂ O)16-20-(C0-4 alkylene)-***, - O(CH ₂ CH ₂ O) ₂ -10-(C0-4 alkylene)C(O)-***, or -O(CH ₂ CH ₂ O)11-20-(C0-4 alkylene)C(O)-***, where *** is a point of attachment to A ² . [0271] In certain embodiments, L is -(C0-20 alkylene)-(OCH ₂ CH ₂ )1-10-(N(C1-4 alkyl))-***, -(C0- 2 ₀ alkylene)-(OCH ₂ CH ₂ ) _11-20 -(N(C _1-4 alkyl))-***, -(C _0-20 alkylene)-(CH ₂ CH ₂ O) _1-10 -(C _2-10 alkylene)-(N(C1-4 alkyl))-(C0-10 alkylene)-***, or -(C0-20 alkylene)-(CH ₂ CH ₂ O)11-20-(C2-10 alkylene)-(N(C _1-4 alkyl))-(C _0-10 alkylene)-***, where *** is a point of attachment to A ² . [0272] In certain embodiments, L is selected from those depicted in the compounds in Table 1, below. Exemplary Specific Compounds [0273] In certain embodiments, the compound is a compound in Table 1, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1. In certain embodiments, the compound is a compound selected from compounds I-1 through I-44 in Table 1. In certain embodiments, the compound is a compound selected from compounds I-1 through I-44 in Table 1, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound selected from compounds I-1 through I-199 in Table 1. In certain embodiments, the compound is a compound selected from compounds I-1 through I-199 in Table 1, or a pharmaceutically acceptable salt thereof. TABLE 1.

Synthetic Methods [0274] Methods for preparing compounds described herein are illustrated in the following synthetic Schemes. The Schemes are given 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. [0275] 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, such as described in, for example, “Protecting Groups in Organic Synthesis”, T. W. Greene and P. G. M. Wuts, 3 ^rd edition, John Wiley & Sons, 1999, the entire contents of which are hereby incorporated by reference. [0276] The synthetic route illustrated in Scheme 1 is a general method for preparing compounds of Formula F. Reaction of carboxylic acid A and amine B under amide coupling conditions provides amide C. Removal of the protection group (Pg) from compound C provides compound D. The Pg may be, for example, a Boc protecting group that can be removed by treating the compound with trifluoroacetic acid. Coupling of compound D with compound E (such as a nucleophilic aromatic substitution reaction when X is an amino group and the leaving group in compound E is chloro) provides the final compound of Formula F. SCHEME 1. [0277] The modular synthetic route illustrated in Scheme 1 can be readily modified to provide additional compounds by conducting functional group transformations on the intermediate and/or 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, 3rd Ed. (Richard C. Larock, ed., John Wiley & Sons, New York: 2018). Protecting group strategies may be deployed as appropriate to accommodate differing functional groups in the molecules used in the synthetic route. Protecting group chemistry and strategy is described in, for example, 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, 5th Ed., (Peter G. M. Wuts, John Wiley & Sons: 2014). II. Therapeutic Applications [0278] The heterobifunctional compounds described herein, such as a compound of Formula I, II, or other compounds in Section I, provide therapeutic benefits to patients suffering from cancer. Accordingly, one aspect of the invention provides a method of treating cancer. The method comprises administering to a patient in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, II, or other compound in Section I, to treat the cancer. In certain embodiments, the compound is a compound of Formula I. In certain embodiments, the particular compound of Formula I is a compound defined by one of the embodiments described above. Cancer [0279] In certain embodiments, the cancer is ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, stomach cancer, colon cancer, rectal cancer, skin cancer, sebaceous gland carcinoma, bile duct and gallbladder cancers, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, lymphoma, or leukemia. In certain embodiments, the cancer is prostate cancer. [0280] In certain embodiments, the cancer is squamous cell cancer, lung cancer including small cell lung cancer, non-small cell lung cancer, vulval cancer, thyroid cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, and head and neck cancer. In certain embodiments, the cancer is at least one selected from the group consisting of ALL, T-lineage Acute lymphoblastic Leukemia (T- ALL), T-lineage lymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cell Leukemia, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, Burkitts Lymphoma, B- cell ALL, Philadelphia chromosome positive ALL, Philadelphia chromosome positive CML, lymphoma, leukemia, multiple myeloma myeloproliferative diseases, large B cell lymphoma, or B cell Lymphoma. [0281] In certain embodiments, the cancer is a solid tumor or leukemia. In certain other embodiments, the cancer is colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, lung cancer, leukemia, bladder cancer, stomach cancer, cervical cancer, testicular cancer, skin cancer, rectal cancer, thyroid cancer, kidney cancer, uterus cancer, espophagus cancer, liver cancer, an acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, or retinoblastoma. In certain other embodiments, the cancer is small cell lung cancer, non-small cell lung cancer, melanoma, cancer of the central nervous system tissue, brain cancer, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, cutaneous T- Cell lymphoma, cutaneous B-Cell lymphoma, or diffuse large B-Cell lymphoma. In certain other embodiments, the cancer is breast cancer, colon cancer, small-cell lung cancer, non-small cell lung cancer, prostate cancer, renal cancer, ovarian cancer, leukemia, melanoma, or cancer of the central nervous system tissue. In certain other embodiments, the cancer is colon cancer, small-cell lung cancer, non-small cell lung cancer, renal cancer, ovarian cancer, renal cancer, or melanoma. [0282] In certain embodiments, the cancer is a fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms’ tumor, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, or hemangioblastoma. [0283] In certain embodiments, the cancer is a neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastase, glioblastoma multiforms, glioblastoma, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, rectal adeno carcinoma, Dukes C & D colorectal cancer, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi’s sarcoma, karotype acute myeloblastic leukemia, Hodgkin’s lymphoma, non- Hodgkin’s lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma, low grade follicular lymphoma, metastatic melanoma, localized melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma, scelroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressive, hormone refractory prostate cancer, resected high-risk soft tissue sarcoma, unrescectable hepatocellular carcinoma, Waidenstrom’s macroglobulinemia, smoldering myeloma, indolent myeloma, fallopian tube cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, castrate resistant prostate cancer, castrate resistant metastatic prostate cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, or leiomyoma. [0284] In certain embodiments, the cancer is bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, non- Hodgkins's lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocortical cancer, gall bladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers. [0285] In certain embodiments, the cancer is hepatocellular carcinoma, ovarian cancer, ovarian epithelial cancer, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical adenoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal/stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma, or brain cancer; neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST); Waldenstrom's macroglobulinemia; or medulloblastoma. [0286] In certain embodiments, the cancer is hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma. [0287] In certain embodiments, the cancer is a solid tumor, such as a sarcoma, carcinoma, or lymphoma. In certain embodiments, the cancer is kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or liver cancer; melanoma; breast cancer; colorectal carcinoma, or colorectal cancer; colon cancer; rectal cancer; anal cancer; lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical carcinoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal/stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma, or brain cancer; neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST); Waldenstrom's macroglobulinemia; or medulloblastoma. [0288] In certain embodiments, the cancer is renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, brain cancer, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma. [0289] In certain embodiments, the cancer is hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma. [0290] In certain embodiments, the cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer, or ovarian carcinoma. In some embodiments, the cancer is ovarian epithelial cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is uterine papillary serous carcinoma (UPSC). In some embodiments, the cancer is hepatocholangiocarcinoma. In some embodiments, the cancer is soft tissue and bone synovial sarcoma. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is anaplastic thyroid cancer. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer, or pancreatic ductal carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumors (MPNST). In some embodiments, the cancer is neurofibromatosis-1 associated MPNST. In some embodiments, the cancer is Waldenstrom's macroglobulinemia. In some embodiments, the cancer is medulloblastoma. Causing Death of Cancer Cell [0291] Another aspect of the invention provides a method of causing death of a cancer cell. The method comprises contacting a cancer cell with an effective amount of a compound described herein, such as a compound of Formula I or II, or other compounds in Section I, to cause death of the cancer cell. In certain embodiments, the particular compound of Formula I or II is a compound defined by one of the embodiments described above. [0292] In certain embodiments, the cancer cell is selected from ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, stomach cancer, colon cancer, rectal cancer, skin cancer, sebaceous gland carcinoma, bile duct and gallbladder cancers, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, lymphoma, or leukemia. In certain embodiments, the cancer cell is one or more of the cancers recited in the section above entitled “Cancer.” In certain embodiments, the cancer cell is a prostate cancer cell. Combination Therapies [0293] The compounds useful within the methods of the invention may be used in combination with one or more additional therapeutic agents useful for treating any disease contemplated herein. These additional therapeutic agents may comprise compounds that are commercially available or synthetically accessible to those skilled in the art. These additional therapeutic agents are known to treat, prevent, or reduce the symptoms, of a disease or disorder contemplated herein. [0294] Accordingly, in certain embodiments, the method further comprises administering to the subject an additional therapeutic agent that treats the disease contemplated herein. [0295] In certain embodiments, administering the compound of the invention to the subject allows for administering a lower dose of the additional therapeutic agent as compared to the dose of the additional therapeutic agent alone that is required to achieve similar results in treating the disease contemplated herein. For example, in certain embodiments, the compound of the invention enhances the therapeutic activity of the additional therapeutic compound, thereby allowing for a lower dose of the additional therapeutic compound to provide the same effect. [0296] A synergistic effect may be calculated, for example, using suitable methods such as, for example, the Sigmoid-Emax equation (Holford & Scheiner, 1981, Clin. Pharmacokinet.6:429- 453), the equation of Loewe additivity (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol.114:313-326) and the median-effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul.22:27-55). Each equation referred to above may be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination. The corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively. [0297] In certain embodiments, the compound of the invention and the therapeutic agent are co-administered to the subject. In other embodiments, the compound of the invention and the therapeutic agent are coformulated and co-administered to the subject. [0298] In certain embodiments, the compound is administered in combination with a second therapeutic agent having activity against cancer. In certain embodiments, the second therapeutic agent is mitomycin, tretinoin, ribomustin, gemcitabine, vincristine, etoposide, cladribine, mitobronitol, methotrexate, doxorubicin, carboquone, pentostatin, nitracrine, zinostatin, cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole, fotemustine, thymalfasin, sobuzoxane, nedaplatin, cytarabine, bicalutamide, vinorelbine, vesnarinone, aminoglutethimide, amsacrine, proglumide, elliptinium acetate, ketanserin, doxifluridine, etretinate, isotretinoin, streptozocin, nimustine, vindesine, flutamide, drogenil, butocin, carmofur, razoxane, sizofilan, carboplatin, mitolactol, tegafur, ifosfamide, prednimustine, picibanil, levamisole, teniposide, improsulfan, enocitabine, lisuride, oxymetholone, tamoxifen, progesterone, mepitiostane, epitiostanol, formestane, interferon-alpha, interferon-2 alpha, interferon-beta, interferon-gamma, colony stimulating factor-1, colony stimulating factor-2, denileukin diftitox, interleukin-2, and leutinizing hormone releasing factor. [0299] In certain embodiments, the second therapeutic agent is an mTOR inhibitor, which inhibits cell proliferation, angiogenesis and glucose uptake. Approved mTOR inhibitors useful in the present invention include everolimus (Afinitor®, Novartis); temsirolimus (Torisel®, Pfizer); and sirolimus (Rapamune®, Pfizer). [0300] In certain embodiments, the second therapeutic agent is a Poly ADP ribose polymerase (PARP) inhibitor. Approved PARP inhibitors useful in the present invention include olaparib (Lynparza®, AstraZeneca); rucaparib (Rubraca®, Clovis Oncology); and niraparib (Zejula®, Tesaro). Other PARP inhibitors being studied which may be used in the present invention include talazoparib (MDV3800/BMN 673/LT00673, Medivation/Pfizer/Biomarin); veliparib (ABT-888, AbbVie); and BGB-290 (BeiGene, Inc.). [0301] In certain embodiments, the second therapeutic agent is a phosphatidylinositol 3 kinase (PI3K) inhibitor. Approved PI3K inhibitors useful in the present invention include idelalisib (Zydelig®, Gilead). Other PI3K inhibitors being studied which may be used in the present invention include alpelisib (BYL719, Novartis); taselisib (GDC-0032, Genentech/Roche); pictilisib (GDC-0941, Genentech/Roche); copanlisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly RP5230, TG Therapeutics). [0302] In certain embodiments, the second therapeutic agent is a proteasome inhibitor. Approved proteasome inhibitors useful in the present invention include bortezomib (Velcade®, Takeda); carfilzomib (Kyprolis®, Amgen); and ixazomib (Ninlaro®, Takeda). [0303] In certain embodiments, the second therapeutic agent is a histone deacetylase (HDAC) inhibitor. Approved HDAC inhibitors useful in the present invention include vorinostat (Zolinza®, Merck); romidepsin (Istodax®, Celgene); panobinostat (Farydak®, Novartis); and belinostat (Beleodaq®, Spectrum Pharmaceuticals). Other HDAC inhibitors being studied which may be used in the present invention include entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide (Epidaza®, HBI-8000, Chipscreen Biosciences, China). [0304] In certain embodiments, the second therapeutic agent is a CDK inhibitor, such as a CDK 4/6 inhibitor. Approved CDK 4/6 inhibitors useful in the present invention include palbociclib (Ibrance®, Pfizer); and ribociclib (Kisqali®, Novartis). Other CDK 4/6 inhibitors being studied which may be used in the present invention include abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics). [0305] In certain embodiments, the second therapeutic agent is an indoleamine (2,3)- dioxygenase (IDO) inhibitor. IDO inhibitors being studied which may be used in the present invention include epacadostat (INCB024360, Incyte); indoximod (NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis); GDC-0919 (Genentech/Roche); PF- 06840003 (Pfizer); BMS:F001287 (Bristol-Myers Squibb); Phy906/KD108 (Phytoceutica); and an enzyme that breaks down kynurenine (Kynase, Kyn Therapeutics). [0306] In certain embodiments, the second therapeutic agent is a growth factor antagonist, such as an antagonist of platelet-derived growth factor (PDGF), or epidermal growth factor (EGF) or its receptor (EGFR). Approved PDGF antagonists which may be used in the present invention include olaratumab (Lartruvo®; Eli Lilly). Approved EGFR antagonists which may be used in the present invention include cetuximab (Erbitux®, Eli Lilly); necitumumab (Portrazza®, Eli Lilly), panitumumab (Vectibix®, Amgen); and osimertinib (targeting activated EGFR, Tagrisso®, AstraZeneca). [0307] In certain embodiments, the second therapeutic agent is an aromatase inhibitor. Approved aromatase inhibitors which may be used in the present invention include exemestane (Aromasin®, Pfizer); anastazole (Arimidex®, AstraZeneca) and letrozole (Femara®, Novartis). [0308] In certain embodiments, the second therapeutic agent is an antagonist of the hedgehog pathway. Approved hedgehog pathway inhibitors which may be used in the present invention include sonidegib (Odomzo®, Sun Pharmaceuticals); and vismodegib (Erivedge®, Genentech), both for treatment of basal cell carcinoma. [0309] In certain embodiments, the second therapeutic agent is a folic acid inhibitor. Approved folic acid inhibitors useful in the present invention include pemetrexed (Alimta®, Eli Lilly). [0310] In certain embodiments, the second therapeutic agent is a CC chemokine receptor 4 (CCR4) inhibitor. CCR4 inhibitors being studied that may be useful in the present invention include mogamulizumab (Poteligeo®, Kyowa Hakko Kirin, Japan). [0311] In certain embodiments, the second therapeutic agent is an isocitrate dehydrogenase (IDH) inhibitor. IDH inhibitors being studied which may be used in the present invention include AG120 (Celgene; NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010). [0312] In certain embodiments, the second therapeutic agent is an arginase inhibitor. Arginase inhibitors being studied which may be used in the present invention include AEB1102 (pegylated recombinant arginase, Aeglea Biotherapeutics), which is being studied in Phase 1 clinical trials for acute myeloid leukemia and myelodysplastic syndrome (NCT02732184) and solid tumors (NCT02561234); and CB-1158 (Calithera Biosciences). [0313] In certain embodiments, the second therapeutic agent is a glutaminase inhibitor. Glutaminase inhibitors being studied which may be used in the present invention include CB- 839 (Calithera Biosciences). [0314] In certain embodiments, the second therapeutic agent is an antibody that binds to tumor antigens, that is, proteins expressed on the cell surface of tumor cells. Approved antibodies that bind to tumor antigens which may be used in the present invention include rituximab (Rituxan®, Genentech/BiogenIdec); ofatumumab (anti-CD20, Arzerra®, GlaxoSmithKline); obinutuzumab (anti-CD20, Gazyva®, Genentech), ibritumomab (anti-CD20 and Yttrium-90, Zevalin®, Spectrum Pharmaceuticals); daratumumab (anti-CD38, Darzalex®, Janssen Biotech), dinutuximab (anti-glycolipid GD2, Unituxin®, United Therapeutics); trastuzumab (anti-HER2, Herceptin®, Genentech); ado-trastuzumab emtansine (anti-HER2, fused to emtansine, Kadcyla®, Genentech); and pertuzumab (anti-HER2, Perjeta®, Genentech); and brentuximab vedotin (anti-CD30-drug conjugate, Adcetris®, Seattle Genetics). [0315] In certain embodiments, the second therapeutic agent is a topoisomerase inhibitor. Approved topoisomerase inhibitors useful in the present invention include irinotecan (Onivyde®, Merrimack Pharmaceuticals); topotecan (Hycamtin®, GlaxoSmithKline). Topoisomerase inhibitors being studied which may be used in the present invention include pixantrone (Pixuvri®, CTI Biopharma). [0316] In certain embodiments, the second therapeutic agent is a nucleoside inhibitor, or other therapeutic that interfere with normal DNA synthesis, protein synthesis, cell replication, or will otherwise inhibit rapidly proliferating cells. Such nucleoside inhibitors or other therapeutics include trabectedin (guanidine alkylating agent, Yondelis®, Janssen Oncology), mechlorethamine (alkylating agent, Valchlor®, Aktelion Pharmaceuticals); vincristine (Oncovin®, Eli Lilly; Vincasar®, Teva Pharmaceuticals; Marqibo®, Talon Therapeutics); temozolomide (prodrug to alkylating agent 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC) Temodar®, Merck); cytarabine injection (ara-C, antimetabolic cytidine analog, Pfizer); lomustine (alkylating agent, CeeNU®, Bristol-Myers Squibb; Gleostine®, NextSource Biotechnology); azacitidine (pyrimidine nucleoside analog of cytidine, Vidaza®, Celgene); omacetaxine mepesuccinate (cephalotaxine ester) (protein synthesis inhibitor, Synribo®; Teva Pharmaceuticals); asparaginase Erwinia chrysanthemi (enzyme for depletion of asparagine, Elspar®, Lundbeck; Erwinaze®, EUSA Pharma); eribulin mesylate (microtubule inhibitor, tubulin-based antimitotic, Halaven®, Eisai); cabazitaxel (microtubule inhibitor, tubulin-based antimitotic, Jevtana®, Sanofi-Aventis); capacetrine (thymidylate synthase inhibitor, Xeloda®, Genentech); bendamustine (bifunctional mechlorethamine derivative, believed to form interstrand DNA cross-links, Treanda®, Cephalon/Teva); ixabepilone (semi-synthetic analog of epothilone B, microtubule inhibitor, tubulin-based antimitotic, Ixempra®, Bristol-Myers Squibb); nelarabine (prodrug of deoxyguanosine analog, nucleoside metabolic inhibitor, Arranon®, Novartis); clorafabine (prodrug of ribonucleotide reductase inhibitor, competitive inhibitor of deoxycytidine, Clolar®, Sanofi-Aventis); and trifluridine and tipiracil (thymidine- based nucleoside analog and thymidine phosphorylase inhibitor, Lonsurf®, Taiho Oncology). [0317] In certain embodiments, the second therapeutic agent is a platinum-based therapeutic, also referred to as platins. Platins cause cross-linking of DNA, such that they inhibit DNA repair and/or DNA synthesis, mostly in rapidly reproducing cells, such as cancer cells. Approved platinum-based therapeutics which may be used in the present invention include cisplatin (Platinol®, Bristol-Myers Squibb); carboplatin (Paraplatin®, Bristol-Myers Squibb; also, Teva; Pfizer); oxaliplatin (Eloxitin® Sanofi-Aventis); and nedaplatin (Aqupla®, Shionogi). Other platinum-based therapeutics which have undergone clinical testing and may be used in the present invention include picoplatin (Poniard Pharmaceuticals); and satraplatin (JM-216, Agennix). [0318] In certain embodiments, the second therapeutic agent is a taxane compound, which causes disruption of microtubules, which are essential for cell division. Approved taxane compounds which may be used in the present invention include paclitaxel (Taxol®, Bristol- Myers Squibb), docetaxel (Taxotere®, Sanofi-Aventis; Docefrez®, Sun Pharmaceutical), albumin-bound paclitaxel (Abraxane®; Abraxis/Celgene), and cabazitaxel (Jevtana®, Sanofi- Aventis). Other taxane compounds which have undergone clinical testing and may be used in the present invention include SID530 (SK Chemicals, Co.) (NCT00931008). [0319] In certain embodiments, the second therapeutic agent is an inhibitor of anti-apoptotic proteins, such as BCL-2. Approved anti-apoptotics which may be used in the present invention include venetoclax (Venclexta®, AbbVie/Genentech); and blinatumomab (Blincyto®, Amgen). Other therapeutic agents targeting apoptotic proteins which have undergone clinical testing and may be used in the present invention include navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740). [0320] In certain embodiments, the second therapeutic agent is a selective estrogen receptor modulator (SERM), which interferes with the synthesis or activity of estrogens. Approved SERMs useful in the present invention include raloxifene (Evista®, Eli Lilly). [0321] In certain embodiments, the second therapeutic agent is an inhibitor of interaction between the two primary p53 suppressor proteins, MDMX and MDM2. Inhibitors of p53 suppression proteins being studied which may be used in the present invention include ALRN- 6924 (Aileron), a stapled peptide that equipotently binds to and disrupts the interaction of MDMX and MDM2 with p53. ALRN-6924 is currently being evaluated in clinical trials for the treatment of AML, advanced myelodysplastic syndrome (MDS) and peripheral T-cell lymphoma (PTCL) (NCT02909972; NCT02264613). [0322] In certain embodiments, the second therapeutic agent is an inhibitor of transforming growth factor-beta (TGF-beta or TGFβ). Inhibitors of TGF-beta proteins being studied which may be used in the present invention include NIS793 (Novartis), an anti-TGF-beta antibody being tested in the clinic for treatment of various cancers, including breast, lung, hepatocellular, colorectal, pancreatic, prostate and renal cancer (NCT 02947165). In some embodiments, the inhibitor of TGF-beta proteins is fresolimumab (GC1008; Sanofi-Genzyme), which is being studied for melanoma (NCT00923169); renal cell carcinoma (NCT00356460); and non-small cell lung cancer (NCT02581787). Additionally, in some embodiments, the additional therapeutic agent is a TGF-beta trap, such as described in Connolly et al. (2012) Int'l J. Biological Sciences 8:964-978. One therapeutic compound currently in clinical trials for treatment of solid tumors is M7824 (Merck KgaA—formerly MSB0011459X), which is a bispecific, anti-PD-L1/TGFβ trap compound (NCT02699515); and (NCT02517398). M7824 is comprised of a fully human IgG1 antibody against PD-L1 fused to the extracellular domain of human TGF-beta receptor II, which functions as a TGFβ “trap.” [0323] In certain embodiments, the second therapeutic agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from sipuleucel-T (Provenge®, Dendreon/Valeant Pharmaceuticals), which has been approved for treatment of asymptomatic, or minimally symptomatic metastatic castrate-resistant (hormone-refractory) prostate cancer; and talimogene laherparepvec (Imlygic®, BioVex/Amgen, previously known as T-VEC), a genetically modified oncolytic viral therapy approved for treatment of unresectable cutaneous, subcutaneous and nodal lesions in melanoma. In some embodiments, the additional therapeutic agent is selected from an oncolytic viral therapy such as pexastimogene devacirepvec (PexaVec/JX-594, SillaJen/formerly Jennerex Biotherapeutics), a thymidine kinase- (TK-) deficient vaccinia virus engineered to express GM-CSF, for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); pelareorep (Reolysin®, Oncolytics Biotech), a variant of respiratory enteric orphan virus (reovirus) which does not replicate in cells that are not RAS-activated, in numerous cancers, including colorectal cancer (NCT01622543); prostate cancer (NCT01619813); head and neck squamous cell cancer (NCT01166542); pancreatic adenocarcinoma (NCT00998322); and non-small cell lung cancer (NSCLC) (NCT 00861627); enadenotucirev (NG-348, PsiOxus, formerly known as ColoAd1), an adenovirus engineered to express a full length CD80 and an antibody fragment specific for the T-cell receptor CD3 protein, in ovarian cancer (NCT02028117); metastatic or advanced epithelial tumors such as in colorectal cancer, bladder cancer, head and neck squamous cell carcinoma and salivary gland cancer (NCT02636036); ONCOS-102 (Targovax/formerly Oncos), an adenovirus engineered to express GM-CSF, in melanoma (NCT03003676); and peritoneal disease, colorectal cancer or ovarian cancer (NCT02963831); GL-ONC1 (GLV-1h68/GLV-1h153, Genelux GmbH), vaccinia viruses engineered to express beta-galactosidase (beta-gal)/beta-glucoronidase or beta- gal/human sodium iodide symporter (hNIS), respectively, were studied in peritoneal carcinomatosis (NCT01443260); fallopian tube cancer, ovarian cancer (NCT 02759588); or CG0070 (Cold Genesys), an adenovirus engineered to express GM-CSF, in bladder cancer (NCT02365818). [0324] In certain embodiments, the second therapeutic agent is an immune checkpoint inhibitor selected from a PD-1 antagonist, a PD-L1 antagonist, or a CTLA-4 antagonist. In some embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is administered in combination with nivolumab (anti-PD-1 antibody, Opdivo®, Bristol-Myers Squibb); pembrolizumab (anti-PD-1 antibody, Keytruda®, Merck); ipilimumab (anti-CTLA-4 antibody, Yervoy®, Bristol-Myers Squibb); durvalumab (anti-PD-L1 antibody, Imfinzi®, AstraZeneca); or atezolizumab (anti-PD-L1 antibody, Tecentriq®, Genentech). Other immune checkpoint inhibitors suitable for use in the present invention include REGN2810 (Regeneron), an anti-PD-1 antibody tested in patients with basal cell carcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cell carcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma (NCT03002376); pidilizumab (CureTech), also known as CT- 011, an antibody that binds to PD-1, in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; avelumab (Bavencio®, Pfizer/Merck KGaA), also known as MSB0010718C), a fully human IgG1 anti-PD-L1 antibody, in clinical trials for non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, renal cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer; and PDR001 (Novartis), an inhibitory antibody that binds to PD-1, in clinical trials for non-small cell lung cancer, melanoma, triple negative breast cancer and advanced or metastatic solid tumors. Tremelimumab (CP-675,206; Astrazeneca) is a fully human monoclonal antibody against CTLA-4 that has been in studied in clinical trials for a number of indications, including: mesothelioma, colorectal cancer, kidney cancer, breast cancer, lung cancer and non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell cancer, squamous cell cancer of the head and neck, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic cancer in the liver, liver cancer, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplastic thyroid cancer, urothelial cancer, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884 (Agenus) is an anti-CTLA4 antibody that is being studied in Phase 1 clinical trials for advanced solid tumors (NCT02694822). [0325] Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, Formula II, or other compounds in Section I) in the manufacture of a medicament. In certain embodiments, the medicament is for treating a disease described herein, such as cancer. [0326] Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, Formula II, or other compounds in Section I) for treating a medical disease, such a disease described herein (e.g., cancer). Evaluation of Cellular Growth Inhibition of HEK293 cells and HeLa cells [0327] Compounds can be evaluated for ability to inhibit the proliferation of HEK293 cells or HeLa cells according to the following procedure. HEK293 and HeLa cells are cultured in DMEM medium supplemented with 10% fetal bovine serum and 1% Penn/Strep. Cells are seeded in white 384-well plates at 500 cells/well in 25 ^L complete medium. Following seeding, plates are spun at 300 × g^for three minutes and cultured at 37 °C with 5% CO ₂ ^in a humidified tissue culture incubator. After 24 hours, compounds are titrated in 100% DMSO and diluted in complete cell culture medium. A 25 ^L aliquot of compound/media mixture is added to cells to bring total volume in well to 50 ^L. DMSO alone is used as a negative control. Plates are then spun at 300×g^for three minutes and stored at 37 °C with 5% CO2 for three days. On Day 0 and Day 3 of compound treatment, cell viability is quantified with CellTiter-Glo 2.0 reagent (Promega). After equilibrating microplates at room temperature for 30 minutes, 25 µL CellTiter-Glo 2.0 reagent is dispensed into each well to bring total volume to 75 ^L. Plates are mixed on shaker for 2 minutes at 500rpm, followed by a 10- minute incubation at room temperature. Following a quick spin, luminescence readings are measured with an EnVision Plate Reader. Data is normalized to DMSO treated Day 0 and Day 3 readings. A four-parameter non-linear regression curve fit is applied to dose-response data in GraphPad Prism data analysis software to determine the half maximal growth inhibitory concentration (GI ₅₀ ) for each compound. III. Pharmaceutical Compositions and Dosing Considerations [0328] 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) and a pharmaceutically acceptable carrier. [0329] 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. [0330] 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. [0331] 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. [0332] 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. [0333] 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. [0334] 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. [0335] 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. [0336] 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. [0337] In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, trouches and the like), the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non-ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. [0338] 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. [0339] 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. [0340] 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. [0341] 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. [0342] 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. [0343] 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. [0344] 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. [0345] 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. [0346] 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. [0347] 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. [0348] 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. [0349] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention. [0350] 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. [0351] 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. [0352] 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. [0353] 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. [0354] 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. [0355] 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. [0356] 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. [0357] 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. [0358] 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. [0359] 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. [0360] 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. [0361] 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. [0362] 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. [0363] 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. [0364] 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. [0365] 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. [0366] The invention further provides a unit dosage form (such as a tablet or capsule) comprising a heterobifunctional substituted phenylpyrimidinone or related compound described herein in a therapeutically effective amount for the treatment of a medical disorder described herein. IV. MEDICAL KITS [0367] Another aspect of this invention is a kit comprising (i) a compound described herein, such as a compound of Formula I, and (ii) instructions for use, such as treating cancer. V. E ^NUMERATED E ^MBODIMENTS [0368] Another aspect of the invention provides the following enumerated embodiments: Embodiment No.1. A compound represented by Formula I: or a pharmaceutically acceptable salt thereof; wherein: R ¹ is phenyl substituted by cyano, halogen, and m occurrences of R ⁴ ; R ² and R ³ are independently hydrogen or C _1-4 alkyl; R ⁴ is C1-4 alkyl; R ⁵ represents independently for each occurrence C1-4 alkyl or halogen; A ¹ is a pyridazinylene, pyrimidinylene, pyrazinylene, pyridinylene, or phenylene, each of which is substituted with n occurrences of R ⁵ ; L is a linker; and A ² is one of the following: R ^1A is C _1-4 alkyl or C _3-4 cycloalkyl; R ^2A represents independently for each occurrence C1-4 alkyl or C3-4 cycloalkyl; R ^3A is phenyl substituted with 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, or C1-C4 haloalkyl; R ^4A is -(C _1-6 alkylene)-C(O)N(R ^5A )(R ^6A ), -(C _1-6 alkylene)-N(R ^5A )C(O)R ^7A , -(C _1-6 alkylene)-CO2R ^7A , -(C1-6 alkylene)-OC(O)R ^7A , or -(C0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur); R ^5A and R ^6A are independently hydrogen, C _1-6 alkyl, or C _3-6 cycloalkyl; or R ^5A and R ^6A are taken together with the nitrogen atom to which they are attached to form a 3-7 membered ring containing 1 nitrogen atom; R ^7A is C1-6 alkyl, -(C1-6 alkylene)-(C3-6 cycloalkyl), or C3-6 cycloalkyl; and m, n, and p are independently 0, 1, or 2. Embodiment No.2. The compound of embodiment 1, wherein m is 0. Embodiment No.3. The compound of embodiment 1, wherein R ¹ is . Embodiment No.4. The compound of any one of embodiments 1-3, wherein R ² is hydrogen. Embodiment No.5. The compound of any one of embodiments 1-4, wherein R ³ is hydrogen. Embodiment No.6. The compound of any one of embodiments 1-5, wherein the compound is a compound of Formula I. Embodiment No.7. The compound of any one of embodiments 1-5, wherein the compound is a compound of Formula Ia or Ib, or a pharmaceutically acceptable salt thereof: (1a) (1b). Embodiment No.8. The compound of any one of embodiments 1-5, wherein the compound is a compound of Formula Ic or a pharmaceutically acceptable salt thereof: Embodiment No.9. The compound of any one of embodiments 1-5, wherein the compound is a compound of Formula Id or a pharmaceutically acceptable salt thereof: Embodiment No.10. The compound of any one of embodiments 1-9, wherein A ¹ is pyridazinylene substituted with n occurrences of R ⁵ . Embodiment No.11. The compound of any one of embodiments 1-9, wherein A ¹ is . Embodiment No.12. The compound of any one of embodiments 1-9, wherein A ¹ is pyrimidinylene substituted with n occurrences of R ⁵ . Embodiment No.13. The compound of any one of embodiments 1-9, wherein A ¹ is the point of attachment to L. Embodiment No.14. The compound of any one of embodiments 1-9, wherein A ¹ is the point of attachment to L. Embodiment No.15. The compound of any one of embodiments 1-9, wherein A ¹ is pyrazinylene substituted with n occurrences of R ⁵ . Embodiment No.16. The compound of any one of embodiments 1-9, wherein A ¹ is . Embodiment No.17. The compound of any one of embodiments 1-9, wherein A ¹ is pyridinylene substituted with n occurrences of R ⁵ . Embodiment No.18. The compound of any one of embodiments 1-9, wherein A ¹ is the point of attachment to L. Embodiment No.19. The compound of any one of embodiments 1-9, wherein A ¹ is phenylene substituted with n occurrences of R ⁵ . Embodiment No.20. The compound of any one of embodiments 1-9, wherein A ¹ is . Embodiment No.21. The compound of any one of embodiments 1-10, 12, 15, 17, or 19, wherein n is 0. Embodiment No.22. The compound of any one of embodiments 1-21, wherein A ² is . Embodiment No.23. The compound of any one of embodiments 1-22, wherein R ^3A is phenyl substituted with halo. Embodiment No.24. The compound of any one of embodiments 1-21, wherein A ² is . Embodiment No.25. The compound of any one of embodiments 1-21 or 24, wherein R ^4A is -(C1-6 alkylene)-C(O)N(R ^5A )(R ^6A ). Embodiment No.26. The compound of any one of embodiments 1-21 or 24, wherein R ^4A is -(C1-6 alkylene)-CO2R ^7A . Embodiment No.27. The compound of any one of embodiments 1-26, wherein R ^1A is C1-4 alkyl. Embodiment No.28. The compound of any one of embodiments 1-26, wherein R ^1A is methyl. Embodiment No.29. The compound of any one of embodiments 1-28, wherein R ^2A is C1-4 alkyl. Embodiment No.30. The compound of any one of embodiments 1-28, wherein R ^2A is methyl. Embodiment No.31. The compound of any one of embodiments 1-30, wherein p is 2. Embodiment No.32. The compound of any one of embodiments 1-21, wherein A ² is , Embodiment No.33. The compound of any one of embodiments 1-21, wherein A ² is . Embodiment No.34. The compound of any one of embodiments 1-21, wherein A ² is Embodiment No.35. The compound of any one of embodiments 1-34, wherein L is a bivalent, saturated or unsaturated, straight or branched C1-60 hydrocarbon chain, wherein 0-20 methylene units of the hydrocarbon are independently replaced with -O-, -S-, - N(H)-, -N(C1-6 alkyl)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O) ₂ -, -N(H)S(O) ₂ -, -N(C1-6 alkyl)S(O) ₂ -, -S(O) ₂ N(H)-, -S(O) ₂ N(C1-6 alkyl)-, -N(H)C(O)-, -N(C1-6 alkyl)C(O)-, - C(O)N(H)-, -C(O)N(C1-6 alkyl)-, -OC(O)N(H)-, -OC(O)N(C1-6 alkyl)-, -N(H)C(O)O- , -N(C1-6 alkyl)C(O)O-, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Embodiment No.36. The compound of any one of embodiments 1-34, wherein L is a bivalent, saturated, straight or branched C3-30 hydrocarbon chain, wherein 0-15 methylene units of the hydrocarbon are independently replaced with -O-, -N(H)-, -N(C _1- 6 alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C1-6 alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C1- 6 alkyl)-, 3-10 membered carbocyclyl, or 3-10 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Embodiment No.37. The compound of any one of embodiments 1-34, wherein L is a bivalent, saturated, straight or branched C3-30 hydrocarbon chain, wherein 0-15 methylene units of the hydrocarbon are independently replaced with -O-, -N(H)-, -N(C _1- 6 alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C1-6 alkyl)C(O)-, -C(O)N(H)-, or - C(O)N(C _1-6 alkyl)-. Embodiment No.38. The compound of any one of embodiments 1-34, wherein L is a bivalent, saturated or unsaturated, straight or branched C _5-40 hydrocarbon chain, wherein 1-20 methylene units of the hydrocarbon are independently replaced with -O-, -N(H)-, - N(C _1-6 alkyl)-, -N(H)C(O)-, -N(C _1-6 alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C _1-6 alkyl)-, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Embodiment No.39. The compound of any one of embodiments 1-34, wherein L is -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ ) _1-15 -O-***, wherein *** is the point of attachment to A ² . Embodiment No.40. The compound of any one of embodiments 1-34, wherein L is -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ ) _1-5 -O-***, wherein *** is the point of attachment to A ² . Embodiment No.41. The compound of any one of embodiments 1-34, wherein L is -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ ) _6-10 -O-***, wherein *** is the point of attachment to A ² . Embodiment No.42. The compound of any one of embodiments 1-34, wherein L is - piperidinylene-(OCH ₂ CH ₂ )1-15-O-***, wherein *** is the point of attachment to A ² . Embodiment No.43. The compound of any one of embodiments 1-34, wherein L is , wherein *** is the point of attachment to A ² . Embodiment No.44. The compound of any one of embodiments 1-34, wherein L is , wherein *** is the point of attachment to A ² . Embodiment No.45. The compound of any one of embodiments 1-34, wherein L is , wherein *** is the point of attachment to A ² . Embodiment No.46. The compound of any one of embodiments 1-34, wherein L is -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ )1-15-N(H)C(O)-C1-10 alkylene-***, -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ )1-15-N(C1-4 alkyl)C(O)-C1-10 alkylene-***, -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ )1-15-C(O)N(H)-C1-10 alkylene-***, or -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ )1-15-C(O)N(C1-4 alkyl)-C1-10 alkylene-***, wherein *** is the point of attachment to A ² . Embodiment No.47. The compound of any one of embodiments 1-34, wherein L is - piperidinylene-(OCH ₂ CH ₂ ) _1-5 -N(H)C(O)-C _1-5 alkylene-***, -piperidinylene- (OCH ₂ CH ₂ )1-5-N(C1-4 alkyl)C(O)-C1-5 alkylene-***, -piperidinylene-(OCH ₂ CH ₂ )1-5- C(O)N(H)-C _1-5 alkylene-***, or -piperidinylene-(OCH ₂ CH ₂ ) _1-5 -C(O)N(C _1-4 alkyl)-C _1-5 alkylene-***, wherein *** is the point of attachment to A ² . Embodiment No.48. The compound of any one of embodiments 1-34, wherein L is -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ ) _1-10 -***, -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C0-10 alkylene)- O-***, or -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-C1-10 alkylene, wherein *** is the point of attachment to A ² . Embodiment No.49. The compound of any one of embodiments 1-34, wherein L is - piperidinylene-(OCH ₂ CH ₂ )1-5-***, -piperidinylene-(C0-5 alkylene)-O-***, or - piperidinylene-(C1-5 alkylene)-***, wherein *** is the point of attachment to A ² . Embodiment No.50. The compound of any one of embodiments 1-34, wherein L is -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-X ¹ -***, wherein *** is the point of attachment to A ² , and X ¹ is (i) C1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, -N(H)-, or -N(C _1-4 alkyl)-, (ii) a 3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen, or (iii) -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C1-10 alkylene)-. Embodiment No.51. The compound of any one of embodiments 1-34, wherein L is - (piperidinylene)-X ¹ -***, wherein *** is the point of attachment to A ² , and X ¹ is (i) C1-5 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, -N(H)-, or - N(C1-4 alkyl)-, (ii) a 3-4 membered monocyclic saturated heterocyclic ring containing 1 heteroatom selected from nitrogen, or (iii) -(3-4 membered monocyclic saturated heterocyclic ring containing 1 heteroatom selected from nitrogen)-(C1-5 alkylene)-. Embodiment No.52. The compound of any one of embodiments 1-34, wherein L is , wherein *** is the point of attachment to A ² , and X ¹ is (i) C _1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, -N(H)-, or - N(C _1-4 alkyl)-, (ii) a 3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen, or (iii) -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _1-10 alkylene)- . Embodiment No.53. The compound of any one of embodiments 1-34, wherein L is - (piperazinylene)-X ¹ -***, wherein *** is the point of attachment to A ² , and X ¹ is (i) C1-5 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, (ii) a 3-4 membered monocyclic saturated heterocyclic ring containing 1 heteroatom selected from nitrogen, or (iii) -(3-4 membered monocyclic saturated heterocyclic ring containing 1 heteroatom selected from nitrogen)-(C1-5 alkylene)-. Embodiment No.54. The compound of any one of embodiments 1-34, wherein L is , wherein *** is the point of attachment to A ² , and X ¹ is (i) C1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, (ii) a 3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen, or (iii) -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C1-10 alkylene)-. Embodiment No.55. The compound of any one of embodiments 1-34, wherein L is -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-X ² -(C1-10 alkylene)-***, wherein *** is the point of attachment to A ² , and X ² is -O-, -N(H)-, or -N(C1-6 alkyl)-. Embodiment No.56. The compound of any one of embodiments 1-34, wherein L is - (piperidinylene)-X ² -(C1-10 alkylene)-***, wherein *** is the point of attachment to A ² , and X ² is -O-, -N(H)-, or -N(C _1-6 alkyl)-. Embodiment No.57. The compound of any one of embodiments 1-34, wherein L is - (piperidinylene)-X ² -(a 3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-***, wherein *** is the point of attachment to A ² , and X ² is -O-, -N(H)-, or -N(C _1-6 alkyl)-. Embodiment No.58. The compound of any one of embodiments 1-34, wherein L is , wherein *** is the point of attachment to A ² , and X ² is -O-, -N(H)-, or -N(C _1-6 alkyl)-. Embodiment No.59. The compound of any one of embodiments 1-34, wherein L is , wherein *** is the point of attachment to A ² , and X ² is -O-, -N(H)-, or -N(C _1-6 alkyl)-. Embodiment No.60. The compound of any one of embodiments 55-59, wherein X ² is -O-. Embodiment No.61. The compound of any one of embodiments 1-34, wherein L is -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-X ¹ -***, wherein *** is the point of attachment to A ² , and X ¹ is -(OCH ₂ CH ₂ )1-10 where 1 CH ₂ group is optionally replaced with -C(H)(C3-6 cycloalkyl)-. Embodiment No.62. The compound of any one of embodiments 1-34 wherein L is a 7-11 membered spirocyclic or fused bicyclic saturated heterocyclic ring containing 1, 2, or 3 heteroatoms selected from nitrogen and oxygen. Embodiment No.63. The compound of any one of embodiments 1-34, wherein L is a 7-8 membered spirocyclic or fused bicyclic saturated heterocyclic ring containing 2 heteroatoms selected from nitrogen. Embodiment No.64. The compound of any one of embodiments 1-34, wherein L is -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-X ³ -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-, wherein X ³ is C1-10 alkylene, - O-, -N(H)-, -N(C1-4 alkyl)-, or a bond. Embodiment No.65. The compound of any one of embodiments 1-34, wherein L is - (piperidinylene)-(C1-5 alkylene)-(piperazinylene)-***, wherein *** is the point of attachment to A ² . Embodiment No.66. The compound of any one of embodiments 1-34, wherein L is - (piperazinylene)-(azetidinylene)-*** or (azetidinylene)-(piperazinylene)-***, wherein *** is the point of attachment to A ² . Embodiment No.67. The compound of any one of embodiments 1-34, wherein L is -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-X ³ -(C _3-6 cycloalkylene)-O-***, -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-X ³ - (C _3-6 cycloalkylene)-N(H)-***, or -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-X ³ -(C3-6 cycloalkylene)- N(C _1-4 alkyl)-***, wherein *** is the point of attachment to A ² , and X ³ is C _1-10 alkylene, -O-, -N(H)-, -N(C1-4 alkyl)-, or a bond. Embodiment No.68. The compound of any one of embodiments 1-34, wherein L is - (piperidinylene)-X ³ -(C3-6 cycloalkylene)-O-***, -(piperidinylene)-X ³ -(C3-6 cycloalkylene)-N(H)-***, or -(piperidinylene)-X ³ -(C _3-6 cycloalkylene)-***, wherein *** is the point of attachment to A ² , and X ³ is C1-10 alkylene, -O-, -N(H)-, -N(C1-4 alkyl)-, or a bond. Embodiment No.69. The compound of any one of embodiments 1-34, wherein L has the formula –(C _0-12 alkylene)-(optionally substituted 3-40 membered heteroalkylene)-(C _0-12 alkylene)-. Embodiment No.70. The compound of any one of embodiments 1-34, wherein L is one of the following: wherein *** is the point of attachment to A ² . Embodiment No.71. The compound of any one of embodiments 1-34, wherein L is one of the following: wherein *** is the point of attachment to A ² . EXAMPLES [0369] The invention now being generally described, will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and is not intended to limit the invention. General Methods [0370] All reactions were carried out under an atmosphere of dry nitrogen or argon. Glassware was oven-dried prior to use. Unless otherwise indicated, common reagents or materials were obtained from commercial sources and used without further purification. N,N- Diisopropylethylamine (DIPEA) was obtained anhydrous by distillation over potassium hydroxide. Tetrahydrofuran (THF), dichloromethane (CH ₂ Cl2), and dimethylformamide (DMF) was dried by a PureSolv ^TM solvent drying system. PTLC refers to preparatory thin layer chromatographic separation. Abbreviations: HFIP (hexafluoroisopropanol), HEPES (4-(2- hydroxyethyl)-1-piperazineethanesulfonic acid. Flash column chromatography was performed using silica gel 60 (230-400 mesh). Analytical thin layer chromatography (TLC) was carried out on Merck silica gel plates with QF-254 indicator and visualized by UV or KMnO4. [0371] ¹ H and ¹³ C NMR spectra were recorded on an Agilent DD2500 (500 MHz ¹ H; 125 MHz ¹³ C) or Agilent DD ₂ 600 (600 MHz ¹ H; 150 MHz ¹³ C) or Agilent DD ₂ 400 (400 MHz ¹ H; 100 MHz ¹³ C) spectrometer at room temperature. Chemical shifts were reported in ppm relative to the residual CDCl ₃ (δ 7.26 ppm ¹ H; δ 77.0 ppm ¹³ C), CD ₃ OD (δ 3.31 ppm ¹ H; δ 49.00 ppm ¹³ C), or d6-DMSO (δ 2.50 ppm ¹ H; δ 39.52 ppm ¹³ C). NMR chemical shifts were expressed in ppm relative to internal solvent peaks, and coupling constants were measured in Hz. (bs = broad signal). In most cases, only peaks of the major rotamer are reported. [0372] Mass spectra were obtained using Agilent 1100 series LC/MSD spectrometers. Analytical HPLC analyses were carried out on 250 x 4.6 mm C-18 column using gradient conditions (10-100% B, flow rate = 1.0 mL/min, 20 min), or as as described in the LC-MS Method tables. [0373] Unless indicated otherwise, preparative HPLC was carried out on 250 x 21.2 mm C- 18 column using gradient conditions (10-100% B, flow rate = 10.0 mL/min, 20 min). The eluents used were: solvent A (H ₂ O with 0.1% TFA) and solvent B (CH ₃ CN with 0.1% TFA). Final products were typically purified via reversed-phase HPLC, PTLC, or flash column chromatography. [0374] The following abbreviations are used herein:ACN: acetonitrile; Bn: benzyl; Boc: tert-butoxycarbonyl; DCM: dichloromethane; DIEA: diisopropylethylamine; DMAP: 4- dimethylaminopyridine; DMF: dimethylformamide; DMSO: dimethylsulfoxide; EtOH: ethanol; EA or EtOAc: ethyl acetate; equiv. or eq.: molar equivalents; FA: formic acid; h: hour or hours; HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyri dinium 3- oxide hexafluorophosphate; HPLC: high-pressure liquid chromatography; JQ1: 2-[(9S)-7-(4- chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricy clo[8.3.0.0 ^2,6 ]trideca- 2(6),4,7,10,12-pentaen-9-yl]acetic acid; LCMS or LC-MS: liquid chromatography-mass spectrometry; MeOH: methanol; MS: mass spectrometry; NMP: N-methylpyrrolidone; NMR: nuclear magnetic resonance; PE: petroleum ether; rt: room temperature;TEA: triethylamine; TFA: trifluoroacetic acid; THF: tetrahydrofuran; and Tos or Ts: p-toluenesulfonyl. EXAMPLE 1 – Synthesis of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4-[2-[[2-[(9S) - 7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraza tricyclo[8.3.0.0 ^2,6 ]trideca- 2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]-1-piperidyl ]pyridazine-3-carboxamide (I-1) [0375] Step 1: Preparation of tert-butyl 4-[2-(1,3 -dioxoisoindolin-2-yl)ethoxy] piperidine-1-carboxylate. A solution of tert-butyl 4-[2-(p-tolylsulfonyloxy) ethoxy]piperidine-1-carboxylate (517 mg, 1.3 mmol, 1.2 equiv) and (1,3-dioxoisoindolin-2- yl)potassium (200 mg, 1.1 mmol, 1.0 equiv) in DMF (5 mL) was stirred at 50 ℃ for 12 hours. The mixture was partitioned between H2O (50 mL) and ethyl acetate (100 mL). The organic phase was separated, washed with H2O (2 x 50 mL), dried over Na2SO4, filtered, and concentrated to give tert-butyl 4-[2-(1,3 -dioxoisoindolin-2-yl)ethoxy]piperidine-1-carboxylate (400 mg, 98% yield) as a yellow solid. [0376] Step 2: Preparation of tert-butyl 4-(2-aminoethoxy) piperidine-1-carboxylate. To a solution of tert-butyl 4-[2-(1, 3-dioxoisoindolin-2-yl)ethoxy]piperidine-1-carboxylate (2.5 g, 6.7 mmol, 1.0 equiv) in ethanol (20 mL) was added NH ₂ NH ₂ .H ₂ O (5.9 g, 118 mmol, 17 equiv). The mixture was stirred at 70 ℃ for 12 hours. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm, 5 ^m; mobile phase: [water (NH4HCO3)-ACN]; B%: 12%-42%, 10 min) to give tert-butyl 4-(2-aminoethoxy) piperidine-1-carboxylate (800 mg, 49% yield) as a white oil. ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.47 (s, 9 H), 1.50 - 1.60 (m, 5 H), 1.76 - 1.92 (m, 2 H), 2.87 (t, J=5.20 Hz, 2 H), 3.06 - 3.13 (m, 2 H), 3.40 - 3.55 (m, 3 H), 3.69 - 3.85 (m, 2 H). [0377] Step 3: Preparation of tert-butyl 4-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13- trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9- yl]acetyl]amino]ethoxy]piperidine-1-carboxylate. To a solution of tert-butyl 4-(2- aminoethoxy)piperidine-1-carboxylate (100 mg, 409 ^mol, 1.0 equiv) and 2-[(9S)-7-(4- chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricy clo[8.3.0.0 ^2,6 ]trideca- 2(6),4,7,10,12-pentaen-9-yl]acetic acid (164 mg, 409 ^mol, 1.0 equiv) in DMF (3 mL) was added HATU (171 mg, 450 ^mol, 1.1 equiv) and diisopropylethylamine (211 mg, 1.64 mmol, 4.0 equiv). The mixture was stirred at 25 ℃ for 0.5 hour and purified by prep-HPLC (column: Waters Xbridge C18150 x 50 mm, 10 ^m; mobile phase: [water (NH4HCO3)-ACN]; B%: 40%-70%, 10 min) to give tert-butyl 4-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia- 1,8,11,12-tetrazatricyclo[8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9- yl]acetyl]amino]ethoxy]piperidine-1-carboxylate (150 mg, 58% yield) as a white solid. [0378] Step 4: Preparation of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia- 1,8,11,12-tetrazatricyclo[8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[2-(4- piperidyloxy)ethyl]acetamide. To a solution of tert-butyl 4-[2-[[2-[(9S)-7-(4-chlorophenyl)- 4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9- yl]acetyl]amino]ethoxy]piperidine-1-carboxylate (75 mg, 119 ^mol, 1.0 equiv) in DCM (4 mL) was added TFA (1.0 mL). The mixture was stirred at 25 ℃ for 0.5 hour. The residue was used for the next step directly. [0379] Step 5: Preparation of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4-[2-[[2- [(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12- tetrazatricyclo[8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]etho xy]-1- piperidyl]pyridazine-3-carboxamide (I-1). To a solution of 2-[(9S)-7-(4-chlorophenyl)- 4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]- N-[2-(4-piperidyloxy)ethyl] acetamide (75 mg, 116 ^mol, 1.0 equiv, TFA salt) and 6-chloro-N- [4-(3-chloro-4-cyano-phenoxy)cyclohexyl]pyridazine-3-carboxa mide (45 mg, 116 ^mol, 1.0 equiv) in NMP (2 mL) was added K ₂ CO ₃ (32 mg, 233 ^mol, 2.0 equiv). The mixture was stirred at 50 ℃ for 12 hours. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150 x 50mm, 3 ^m; mobile phase: [water (FA)-ACN]; B%: 50%-80%, 10 min) to give N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4-[2-[[2-[(9S) -7-(4-chlorophenyl)- 4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9- yl]acetyl]amino]ethoxy]-1-piperidyl]pyridazine-3-carboxamide (35 mg, 34% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d6): δ 1.44 - 1.56 (m, 4 H), 1.60 - 1.70 (m, 5 H), 1.87 - 1.96 (m, 4 H), 2.07 - 2.14 (m, 2 H), 3.18 - 3.32 (m, 7 H), 3.39 – 3.42 (m, 5 H), 3.52 ( t, J=5.69 Hz, 2 H), 3.63 - 3.66 (m, 1 H), 3.80 - 3.97 (m, 1 H), 4.02 - 4.19 (m, 2 H), 4.49 - 4.61 (m, 2 H), 7.12- 7.15 (m, 1 H), 7.33 - 7.49 (m, 6 H), 7.80 - 7.87 (m, 2 H), 8.27 (t, J=5.50 Hz, 1 H), 8.59 (d, J=8.0 Hz, 1 H). LC-MS: MS (ES ⁺ ): RT = 2.652 min, m/z = 441.1, 881.2; LC-MS Method 25.

EXAMPLE 2 – Synthesis of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4-[2-[2-[2-[[2 - [(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12- tetrazatricyclo[8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9- yl]acetyl]amino]ethoxy]ethoxy]ethoxy]-1-piperidyl]pyridazine -3-carboxamide (I-2) [0380] To a solution of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12 - tetrazatricyclo[8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[2-[2-[2-(4- piperidyloxy)ethoxy]ethoxy]ethyl]acetamide (71 mg, 97 ^mol, 1.0 equiv, TFA salt) in NMP (1 mL) was added K ₂ CO ₃ (40 mg, 292 ^mol, 3.0 equiv) and 6-chloro-N-[4-(3-chloro-4-cyano- phenoxy)cyclohexyl]pyridazine-3-carboxamide (42 mg, 107 ^mol, 1.1 equiv). The mixture was stirred at 50 ℃ for 6 hours and concentrated. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm, 5 ^m; mobile phase: [water(NH ₄ HCO ₃ )-ACN]; B%: 46%-76%, 9 min) to give N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4-[2-[2-[2-[[2 -[(9S)-7-(4- chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricy clo[8.3.0.0 ^2,6 ] trideca- 2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]ethoxy] ethoxy]-1-piperidyl] pyridazine-3- carboxamide (I-12) (37.8 mg, 39% yield,) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.46 (d, J = 8.0 Hz, 1 H), 8.14 (t, J = 5.6 Hz, 1 H), 7.8 (m, 2 H), 7.45 (q, J = 8.6 Hz, 4 H), 7.27- 7.38 (m, 2 H), 7.13 (m, 1 H), 4.48-4.59 (m, 2 H), 4.00-4.11 (m, 2 H), 3.80-3.92 (m, 1 H), 3.52- 3.72 (m, 9 H), 3.46-3.51 (m, 2 H), 3.35-3.44 (m, 2 H), 3.24-3.33 (m, 3 H), 3.18-3.21 (m, 1 H), 2.59 (s, 3 H), 2.40 (s, 3 H), 2.06-2.15 (m, 2 H), 1.91 (d, J = 3.0 Hz, 4 H), 1.44-1.72 (m, 9 H). LC-MS: MS (ES ⁺ ): RT = 2.922 min, m/z = 486.0, 971.2; LC-MS Method 10. EXAMPLE 3 – Synthesis of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4-[2-[2-[2-[2- [2-[[2-[7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12 - tetrazatricyclo[8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9- yl]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-1-piperi dyl]pyridazine-3- carboxamide (I-3) [0381] Step 1: Preparation of tert-butyl 4-[2-[2-[2-[2-[2-(1,3-dioxoisoindolin-2- yl)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxyla te. To a solution of tert- butyl 4-[2-[2-[2-[2-[2-(p-tolylsulfonyloxy)ethoxy]ethoxy]ethoxy]et hoxy]ethoxy]piperidine-1- carboxylate (6.10 g, 10.59 mmol, 1.0 equiv) in DMF (120 mL) was added (1,3- dioxoisoindolin-2-yl)potassium(1+) (3.92 g, 21.18 mmol, 2.0 equiv). The mixture was stirred at 50 ℃ for 12 hours. To the reaction mixture was added water (120 mL), and the mixture was extracted with EtOAc (100 mL). The combined organic phase was washed with brine (200 mL x 3), filtered, and concentrated in vacuuo. The residue was purified by column chromatography (SiO2, PE/EA = 5/1 to 0/1) to give tert-butyl 4-[2-[2-[2-[2-[2-(1,3-dioxoisoindolin-2- yl)ethoxy]ethoxy] ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate (4.83 g, 83% yield) as a yellow oil. [0382] Step 2: Preparation of tert-butyl 4-[2-[2-[2-[2-(2-aminoethoxy)ethoxy] ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate. To a solution of tert-butyl 4-[2-[2-[2-[2-[2- (1,3-dioxo-3a,7a-dihydroisoindol-2-yl)ethoxy]ethoxy]ethoxy] ethoxy]ethoxy]piperidine-1- carboxylate (1.0 g, 1.8 mmol, 1.0 equiv) in EtOH (30 mL) was added N ₂ H ₄ .H ₂ O (924 mg, 18 mmol, 98% purity, 10 eq). The mixture was stirred at 70 ℃ for 2 hours and concentrated. The residue was purified by prep-HPLC (column: Shim-pack C ₁₈ 150 x 25, 10 ^m; mobile phase: [water(FA)-ACN]; B%: 5%-35%,10 min) to give tert-butyl 4-[2-[2-[2-[2-(2- aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxy late (620 mg, 81% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.57-8.50 (m, 1H), 3.90-3.60 (m, 20H), 3.53-3.43 (m, 2H), 3.10- 3.07 (m, 2H), 2.99 (s, 2H), 1.92-1.82 (m, 2H), 1.53-1.48 (m, 1H), 1.46 (s, 9H). [0383] Step 3: Preparation of tert-butyl 4-[2-[2-[2-[2-[2-[[2-[(9S)-7-(4-chlorophenyl)- 4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen- 9-yl]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]piperid ine-1-carboxylate. To a solution of tert-butyl 4-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]pip eridine-1- carboxylate (100 mg, 237 ^mol, 1 equiv), 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia- 1,8,11,12-tetrazatricyclo[8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (95 mg, 237 ^mol, 1.0 equiv) in DMF (3 mL) was added DIEA (92 mg, 713 ^mol, 3.0 equiv) and HATU (135 mg, 356 ^mol, 1.5 equiv). The mixture was stirred at 20 ℃ for 0.5 hour and concentrated. The residue was purified by prep-HPLC(column: Waters Xbridge 150 x 25 mm, 5 ^m; mobile phase: [water(NH4HCO3)-ACN]; B%: 46%-76%, 8 min) to give tert-butyl 4-[2-[2-[2-[2-[2-[[2- [(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-t etrazatricyclo[8.3.0.0 ^2,6 ]trideca- 2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]ethoxy]ethox y]ethoxy]ethoxy]piperidine-1- carboxylate (120 mg, 62% yield). [0384] Step 4: Preparation of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia- 1,8,11,12-tetrazatricyclo[8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[2-[2-[2-[2-[2 -(4- piperidyloxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]acetamide. To a solution of tert-butyl 4-[2- [2-[2-[2-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3- thia-1,8,11,12- tetrazatricyclo[8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]etho xy] ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate (120 mg, 149 ^mol, 1.0 equiv) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at 25 ℃ for 0.5 hour and concentrated to give 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12 -tetrazatricyclo [8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[2-[2-[2-[2-[2 -(4- piperidyloxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]acetamide (100 mg, 95% yield). [0385] Step 5: Preparation of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4-[2-[2- [2-[2-[2-[[2-[7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8 ,11,12-tetrazatricyclo [8.3.0.0 ^2,6 ] trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]etho xy]ethoxy] ethoxy]ethoxy]-1-piperidyl]pyridazine-3-carboxamide (I-3). To a solution of 2-[7-(4- chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricy clo[8.3.0.0 ^2,6 ]trideca- 2(6),4,7,10,12-pentaen-9-yl]-N-[2-[2-[2-[2-[2-(4- piperidyloxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]acetamide (120 mg, 146 ^mol, 1.0 equiv) in NMP (2 mL) was added K2CO3 (202 mg, 1.47 mmol, 10 equiv) and 6-chloro-N-[4-(3-chloro-4- cyano-phenoxy)cyclohexyl]pyridazine-3-carboxamide (57 mg, 146 ^mol, 1.0 equiv). The mixture was stirred at 70 ℃ for 3 hours and concentrated. The residue was purified by prep- HPLC (column: Unisil 3-100 C18 Ultra 150 x 50 mm, 3 ^m; mobile phase: [water(FA)-ACN]; B%: 50%-80%,5min) to give N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4-[2-[2-[2-[2- [2-[[2-[7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12 -tetrazatricyclo[8.3.0.0 ^2,6 ]trideca- 2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy] ethoxy]ethoxy]ethoxy]ethoxy]-1- piperidyl]pyridazine-3-carboxamide (73 mg, 46% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.12- 8.06 (m, 1H), 7.93-7.85 (m, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.47-7.32 (m, 4H), 7.22-7.10 (m, 1H), 7.01 (d, J = 2.3 Hz, 1H), 6.86 (s, 1H), 4.79-4.68 (m, 1H), 4.40-4.26 (m, 1H), 4.09-4.01 (m, 3H), 3.99-3.85 (m, 1H), 3.83-3.72 (m, 2H), 3.71-3.65 (m, 17H), 3.60 (s, 2H), 3.56-3.45 (m, 4H), 2.75 (s, 2H), 2.44-2.41 (m, 3H), 2.26-2.07 (m, 6H), 2.04-1.88 (m, 3H), 1.85-1.78 (m, 2H), 1.68-1.60 (m, 2H), 1.55-1.47 (m, 2H). LC-MS: MS (ES ⁺ ): RT = 2.909 min, m/z = 530.1, 1059.3; LC-MS Method 10.

EXAMPLE 4 – Synthesis of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4-[2-[2-[2-[2- [2-[2-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thi a-1,8,11,12-tetrazatricyclo [8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino ]ethoxy]ethoxy]ethoxy] ethoxy]ethoxy]ethoxy]ethoxy]-1-piperidyl]pyridazine-3-carbox amide (I-4)

[0386] Step 1: Preparation of 2-[2-[2-[2-[2-[2-(2-benzyloxyethoxy)ethoxy]ethoxy] ethoxy] ethoxy]ethoxy]ethyl-4-methylbenzenesulfonate. To a solution of 2-[2-[2-[2-[2-[2-(2- benzyloxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol (19 g, 45.6 mmol, equiv) in DCM (150 mL) was added Et ₃ N (13.8 g, 137 mmol, 3 equiv), DMAP (557 mg, 4.56 mmol, 0.1 equiv), and TosCl (13 g, 68.4 mmol, 1.5 equiv) at 0 °C. The mixture was stirred at 20 °C for 12 hours. The mixture was partitioned in water (30 mL). The organic phase was separated, washed with ethyl acetate (3 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (SiO ₂ , PE/EA from 1/1 to 1/10) to give 2- [2-[2-[2-[2-[2-(2-benzyloxyethoxy)ethoxy]ethoxy]ethoxy] ethoxy]ethoxy]ethyl4- methylbenzenesulfonate (20.7 g, 79% yield) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.72 (d, J = 8.4 Hz, 2H), 7.29 - 7.18 (m, 7H), 4.49 (s, 2H), 4.10 - 4.06 (m, 2H), 3.64 - 3.50 (m, 26H), 2.37 (s, 3H). [0387] Step 2: Preparation of tert-butyl 4-[2-[2-[2-[2-[2-[2-(2-benzyloxyethoxy) ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carbo xylate. To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (3.77 g, 18.7 mmol, 1 equiv) in THF (100 mL) was added NaH (900 mg, 22.5 mmol, 60% purity, 1.2 equiv) at 0 ℃. The mixture was stirred at 20 ℃ for 0.5 hour, and 2-[2-[2-[2-[2-[2-(2-benzyloxyethoxy)ethoxy]ethoxy]ethoxy] ethoxy]ethoxy] ethyl 4-methylbenzenesulfonate (10.7 g, 18.7 mmol, 1 equiv) was added at 0 ℃. The mixture was stirred at 20 ℃ for 12 hours. The reaction mixture was poured into water (60 mL) and extracted with ethyl acetate (3 x 100 mL). The organic phase was dried over Na2SO4 and concentrated. The residue was purified by column chromatography (SiO2, PE/EA from 1/0 to 0/1) to give tert-butyl 4-[2-[2-[2-[2-[2-[2-(2-benzyloxyethoxy)ethoxy]ethoxy] ethoxy] ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate (9 g, 80% yield) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.34 (d, J = 4.4 Hz, 5H), 4.57 (s, 2H), 3.70 - 3.63 (m, 33H), 2.05 (s, 2H), 1.58 - 1.49 (m, 2H), 1.46 (s, 9H). [0388] Step 3: Preparation of tert-butyl 4-[2-[2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy] ethoxy]ethoxy]ethoxy] ethoxy]ethoxy]piperidine-1-carboxylate. To a solution of tert-butyl 4-[2-[2-[2-[2-[2-[2-(2-benzyloxyethoxy)ethoxy]ethoxy]ethoxy] ethoxy]ethoxy]ethoxy] piperidine-1-carboxylate (9 g, 15 mmol, 1 equiv) in MeOH (100 mL) was added Pd(OH) ₂ (1 g, 713 ^mol, 10% purity). The mixture was stirred under H2 (50 Psi) at 30 ℃ for 12 hours. The mixture was concentrated under reduced pressure to give tert-butyl 4-[2-[2-[2-[2-[2-[2-(2- hydroxyethoxy) ethoxy]ethoxy]ethoxy]ethoxy] ethoxy]ethoxy]piperidine-1-carboxylate (7.56 g, 99% yield) as a yellow oil. ¹ H NMR (400 MHz, CDCl3) δ 3.68 - 3.64 (m, 33H), 1.89 - 1.78 (m, 2H), 1.59 - 1.49 (m, 2H), 1.46 (s, 9H). [0389] Step 4: Preparation of tert-butyl4-[2-[2-[2-[2-[2-[2-[2-(p-tolylsulfonyloxy) ethoxy] ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carbo xylate. To a solution of tert-butyl 4-[2-[2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy] ethoxy]ethoxy] ethoxy] piperidine-1-carboxylate (500 mg, 981 ^mol, 1 equiv) in DCM (2 mL) was added TosCl (281 mg, 1.47 mmol, 1.5 equiv) at 0 ℃ and TEA (298 mg, 2.94 mmol, 3 equiv). The mixture was stirred at 20 ℃ for 12 hours and concentrated. The residue was purified by column chromatography (PE/EA from 10/1 to 1/2) to give tert-butyl4-[2-[2-[2-[2- [2-[2-[2-(p-tolylsulfonyloxy)ethoxy]ethoxy]ethoxy]ethoxy]eth oxy] ethoxy]ethoxy]piperidine- 1-carboxylate (650 mg, 100% yield) as a yellow oil. [0390] Step 5: Preparation of tert-butyl 4-[2-[2-[2-[2-[2-[2-[2-(1,3-dioxoisoindolin-2- yl)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]piperidi ne-1-carboxylate. To a solution of tert-butyl 4-[2-[2-[2-[2-[2-[2-[2-(p-tolylsulfonyloxy)ethoxy]ethoxy]eth oxy] ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate (1.5 g, 2.26 mmol, 1.2 equiv) in DMF (10 mL) was added (1,3-dioxoisoindolin-2-yl)potassium (349 mg, 1.88 mmol, 1 equiv). The mixture was stirred at 50 ℃ for 12 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The organic phase was dried over Na2SO4 and concentrated. The residue was purified by column chromatography (SiO ₂ , PE/EA from 1/0 to 0/1) to give tert-butyl 4-[2-[2-[2-[2-[2-[2-[2-(1,3-dioxoisoindolin-2-yl)ethoxy]etho xy] ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate (1 g, 87% yield) as a yellow oil. [0391] Step 6: Preparation of tert-butyl 4-[2-[2-[2-[2-[2-[2-(2-aminoethoxy)ethoxy] ethoxy]ethoxy]ethoxy]ethoxy]ethoxy] piperidine-1-carboxylate. To a solution of tert-butyl 4-[2-[2-[2-[2-[2-[2-[2-(1,3-dioxoisoindolin-2-yl)ethoxy]etho xy]ethoxy] ethoxy]ethoxy]ethoxy] ethoxy]piperidine-1-carboxylate (1.05 g, 1.64 mmol, 1 equiv) in EtOH (100 mL) was added NH2NH2 ^. H2O (1.36 g, 27.2 mmol, 16.5 equiv). The mixture was stirred at 80 ℃ for 12 hours and concentrated. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm, 5 ^m; mobile phase: [water(NH4HCO3)-ACN]; B%: 10%-40%, 10 min) to give tert-butyl 4-[2-[2-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy] ethoxy]ethoxy] ethoxy]ethoxy] piperidine- 1-carboxylate (400 mg, 48% yield) as a yellow oil. [0392] Step 7: Preparation of tert-butyl 4-[2-[2-[2-[2-[2-[2-[2-[[2-[(9S)-7-(4- chlorophenyl)-4,5,13-trimethyl -3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]ethoxy]ethox y]ethoxy]ethoxy] ethoxy]ethoxy]piperidine-1-carboxylate. To a solution of tert-butyl 4-[2-[2-[2-[2-[2-[2-(2- aminoethoxy)ethoxy] ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate (100 mg, 197 ^mol, 1 equiv) in DMF (2 mL) was added 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3- thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,1 0,12-pentaen-9-yl]acetic acid (79 mg, 153 ^mol, 7.79e-1 equiv, TFA salt), HATU (90 mg, 236 ^mol, 1.2 equiv), and DIEA (127 mg, 983 ^mol, 5 equiv). The mixture was stirred at 25 ℃ for 0.5 hour and concentrated. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm, 5 ^m; mobile phase: [water( NH4HCO3)-ACN]; B%: 49%-79%, 8 min) to give tert-butyl 4-[2-[2-[2-[2-[2-[2- [2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8, 11,12-tetrazatricyclo[8.3.0.02,6] trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]etho xy]ethoxy]ethoxy]ethoxy]ethoxy] ethoxy]piperidine-1-carboxylate (170 mg, 97% yield) as a yellow oil. [0393] Step 8: Preparation of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia- 1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-9-yl]-N-[2-[2-[2-[2-[2- [2-[2-(4-piperidyloxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]eth oxy]ethyl]acetamide. To a solution of tert-butyl 4-[2-[2-[2-[2-[2-[2-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-t rimethyl-3- thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,1 0,12-pentaen-9-yl]acetyl]amino] ethoxy] ethoxy] ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate (80 mg, 90 ^mol, 1 equiv) in DCM (1 mL) was added TFA (0.5 mL). The mixture was stirred at 25 ℃ for 0.5 hour and concentrated to give 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12 - tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9- yl]-N-[2-[2-[2-[2-[2-[2-[2-(4- piperidyloxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl ]acetamide (80 mg, 98% yield, TFA salt) as a yellow oil. [0394] Step 9: Preparation of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4-[2-[2- [2-[2-[2-[2-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl -3-thia-1,8,11,12-tetrazatricyclo [8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino ]ethoxy]ethoxy]ethoxy] ethoxy]ethoxy]ethoxy]ethoxy]-1-piperidyl]pyridazine-3-carbox amide (I-4). To a solution of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12 -tetrazatricyclo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-9-yl]-N-[2-[2-[2-[2-[2-[2-[2-(4-piper idyloxy)ethoxy]ethoxy]ethoxy] ethoxy]ethoxy]ethoxy]ethyl]acetamide (80 mg, 88 ^mol, 1 equiv, TFA salt) in NMP (1 mL) was added K2CO3 (122 mg, 884 ^mol, 10 equiv) and 6-chloro-N-[4-(3-chloro-4-cyano- phenoxy)cyclohexyl]pyridazine-3-carboxamide (35 mg, 88 ^mol, 1 equiv). The mixture was stirred at 70 ℃ for 12 hours and concentrated. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150 x 50 mm, 3 ^m; mobile phase: [water(FA)-ACN]; B%: 45%-75%, 10 min) to give N-[4-(3-chloro-4-cyano-phenoxy) cyclohexyl]-6-[4-[2-[2-[2-[2-[2- [2-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1 ,8,11,12-tetrazatricyclo [8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino ] ethoxy]ethoxy]ethoxy]ethoxy] ethoxy]ethoxy]ethoxy]-1-piperidyl]pyridazine-3-carboxamide (I-14) (29 mg, 26% yield) as a white solid. ¹ H NMR (400 MHz, METHANOL-d4) δ 7.90 (d, J = 9.6 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.51 - 7.40 (m, 4H), 7.30 (d, J = 9.6 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.06 (dd, J = 2.4, 8.8 Hz, 1H), 4.66 (dd, J = 5.2, 9.0 Hz, 1H), 4.56 - 4.49 (m, 1H), 4.10 (m, J = 3.6, 6.8, 13.2 Hz, 2H), 4.03 - 3.95 (m, 1H), 3.68 - 3.43 (m, 32H), 2.71 (s, 3H), 2.46 (s, 3H), 2.23 - 2.08 (m, 4H), 2.04 - 1.96 (m, 2H), 1.74 - 1.59 (m, 10H). LC-MS: MS (ES ⁺ ): RT = 2.928 min, m/z = 573.2, 1145.3; LC-MS Method 10. EXAMPLE 5 – Synthesis of Additional Compounds [0395] The following compounds were prepared using procedures analogous to those described above I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I- 20, I-21, I-22, I-23, I-24, I-25, I-26, I-27, I-28, I-29, I-30, I-31, I-32, I-33, I-34, I-35, I-36, I-37, I-38, I-39, I-40, I-41, I-42, I-43, and I-44. EXAMPLE 6 – Synthesis of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[1-[[1-[4-[(9S) - 9-[2-(ethylamino)-2-oxo-ethyl]-4,5,13-trimethyl-3-thia-1,8,1 1,12-tetrazatricyclo[8.3.0.02,6] trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]-4-piperidyl]meth yl]azetidin-3-yl]oxy- pyridazin e-3-carboxamide (I-72)

[0396] Step 1: Preparation of tert-butyl 3-[6-[[4-(3-chloro-4-cyano-phenoxy) cyclohexyl]carbamoyl]pyridazin-3-yl]oxyazetidine-1-carboxyla te. To a solution of tert- butyl 3-hydroxyazetidine-1-carboxylate (88 mg, 511 umol, 1.0 equiv, known compound from WO2021/127443, 2021, A1) in THF (2 mL) was added NaH (31 mg, 767 umol, 60% purity, 1.5 equiv) at 0 °C for 0.5 h, 6-chloro-N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]pyridazin e- 3-carboxamide (200 mg, 511 umol, 1.0 equiv) was added at 0 °C. The mixture was stirred at 20 °C for 12 h. [0397] Step 2: Preparation of 6-(azetidin-3-yloxy)-N-[4-(3-chloro-4-cyano-phenoxy) cyclohexyl]pyridazine-3-carboxamide. To the solution of tert-butyl 3-[6-[[4-(3-chloro-4- cyano-phenoxy)cyclohexyl]carbamoyl]pyridazin-3-yl]oxyazetidi ne-1-carboxylate (50 mg, 95 umol, 1.0 equiv) in DCM (2 mL) was added 2,6-LUTIDINE (313 mg, 2.9 mmol, 0.3 mL, 31 equiv) and TMSOTf (315 mg, 1.42 mmol, 256 uL, 15.0 equiv) at 0 °C, then the solution was stirred at 0 °C for 0.5 h. The solution was quenched with 0.05 mL H2O (25eq) at 0 °C, and the solution was used for next step directly. [0398] Step 3: Preparation of tert-butyl 2-[(9S)-7-[4-[4-(dimethoxymethyl)-1- piperidyl] phenyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8. 3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-9-yl]acetate. To a solution of tert-butyl 2-[(9S)-7-(4-chlorophenyl)- 4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9- yl]acetate (500 mg, 1.09 mmol, 1.0 equiv) and 4-(dimethoxymethyl)piperidine (261 mg, 1.64 mmol, 1.5 equiv) in dioxane (10 mL) was added Cs ₂ CO ₃ (1.07 g, 3.28 mmol, 3.0 equiv) and SPhos Pd G3 (85 mg, 109 umol, 0.1 equiv). The mixture was stirred at 90 °C for 12. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purification by prep-HPLC (column: Waters Xbridge C18150*50mm* 10um;mobile phase: [water( NH4HCO3)-ACN];B%: 48%-78%,10min) to give tert-butyl 2-[(9S)-7-[4-[4- (dimethoxymethyl)-1-piperidyl]phenyl]-4,5,13-trimethyl-3-thi a-1,8,11,12- tetrazatricyclo[8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]acetate (596 mg, 94% yield). [0399] Step 4: Preparation of 2-[(9S)-7-[4-(4-formyl-1-piperidyl)phenyl]-4,5,13- trimethyl -3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4, 7,10,12-pentaen-9- yl]acetic acid. The solution of tert-butyl 2-[(9S)-7-[4-[4-(dimethoxymethyl)-1- piperidyl]phenyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazat ricyclo[8.3.0.0 ^2,6 ]trideca- 2(6),4,7,10,12-pentaen-9-yl]acetate (60 mg, 103 umol, 1.0 equiv) in TFA (1 mL) and DCM (1 mL) was stirred at 25 °C for 1 h. The solution was concentrated under reduced pressure to give 2-[(9S)-7-[4-(4-formyl-1-piperidyl)phenyl]-4,5,13-trimethyl- 3-thia-1,8,11,12- tetrazatricyclo[8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (61 mg, crude, TFA salt) as brown oil. [0400] Step 5: Preparation of 2-[(9S)-7-[4-[4-[[3-[6-[[4-(3-chloro-4-cyano-phenoxy) cyclohexyl]carbamoyl]pyridazin-3-yl]oxyazetidin-1-yl]methyl] -1-piperidyl]phenyl]-4,5,13- trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]tridec a-2(6),4,7,10,12-pentaen-9- yl]acetic acid. To a solution of 2-[(9S)-7-[4-(4-formyl-1-piperidyl)phenyl]-4,5,13-trimethyl- 3- thia-1,8,11,12-tetrazatricyclo[8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (61 mg, 103 umol, 1.1 equiv, TFA salt) in DCM (4 mL) was added TEA (102 mg, 1.01 mmol, 10 equiv) and 6-(azetidin-3-yloxy)-N-[4-(3-chloro-4-cyano-phenoxy)cyclohex yl]pyridazine-3- carboxamide (53 mg, 98 umol, 1.0 equiv, TFA salt) and NaBH(OAc)3 (145 mg, 685 umol, 7.0 equiv) at 0 °C, then the solution was stirred at 20 °C for 0.5 h. The solution was concentrated and purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water( NH4HCO3)-ACN];B%: 20%-50%,8min) to give 2-[(9S)-7-[4-[4-[[3-[6-[[4-(3-chloro-4-cyano- phenoxy)cyclohexyl]carbamoyl]pyridazin-3-yl]oxyazetidin-1-yl ]methyl]-1-piperidyl]phenyl]- 4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9- yl]acetic acid (26 mg 30% yield) as a yellow solid. [0401] Step 6: Preparation of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[1-[[1-[4- [(9S)-9-[2-(ethylamino)-2-oxo-ethyl]-4,5,13-trimethyl-3-thia -1,8,11,12-tetrazatricyclo [8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]-4-pi peridyl]methyl]azetidin-3-yl] oxy-pyridazine-3-carboxamide. A solution of 2-[(9S)-7-[4-[4-[[3-[6-[[4-(3-chloro-4-cyano- phenoxy)cyclohexyl]carbamoyl]pyridazin-3-yl]oxyazetidin-1-yl ]methyl]-1-piperidyl]phenyl]- 4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9- yl]acetic acid (26 mg, 29 umol, 1.0 equiv) and ethanamine (4 mg, 88 umol, 3.0 equiv) and DIEA (15 mg, 115 umol, 3.9 equiv) and HATU (17 mg, 44 umol, 1.5 equiv) in DMF (0.5 mL) was stirred at 20 °C for 0.5 h. The solution was purified by prep-HPLC (column: Waters Xbridge C18150*50mm* 10um;mobile phase: [water( NH4HCO3)-ACN];B%: 50%- 80%,10min) to give N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[1-[[1-[4-[(9S) -9-[2- (ethylamino)-2-oxo-ethyl]-4,5,13-trimethyl-3-thia-1,8,11,12- tetrazatricyclo[8.3.0.0 ^2,6 ]trideca- 2(6),4,7,10,12-pentaen-7-yl]phenyl]-4-piperidyl]methyl]azeti din-3-yl]oxy-pyridazine-3- carboxamide (13 mg, 47% yield) as a white solid. ¹ H NMR (400 MHz, CDCl3): δ 8.24 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.35 (d, J = 8.8 Hz, 2H), 7.16 (d, J = 8.8 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.91-6.78 (m, 3H), 6.50 (s, 1H), 5.55-5.45 (m, 1H), 4.60-4.50 (m, 1H), 4.43-4.27 (m, 1H), 4.19-4.03 (m, 1H), 3.95-3.90 (m, 2H), 3.84-3.73 (m, 2H), 3.59-3.51 (m, 1H), 3.44-3.22 (m, 5H), 2.87-2.62 (m, 5H), 2.54-2.36 (m, 5H), 2.29- 2.14 (m, 4H), 1.85-1.80 (m, 2H), 1.77-1.69 (m, 5H), 1.56-1.44 (m, 3H), 1.38-1.25 (m, 2H), 1.19 (t, J = 7.2 Hz, 3H) LC-MS: MS (ES ⁺ ): RT = 1.473 min, m/z = 917.5 [M + H ⁺ ]; LCMS method: 25 EXAMPLE 7 – Synthesis of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4-[2-[4-[(9S)- 4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetr azatricyclo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-7-yl]phenyl]ethyl]-1-piperidyl]pyrida zine-3-carboxamide (I-74) [0402] Step 1: Preparation of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia- 1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-9-yl]acetic acid. To a solution of tert-butyl 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12 - tetrazatricyclo[8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]acetate (1.0 g, 2.1 mmol, 1.0 equiv) in DCM (10 mL) was added TFA (7.7 g, 67 mmol, 5.0 mL, 30 equiv). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was used for next step directly to give compound 2- [(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-t etrazatricyclo[8.3.0.0 ^2,6 ]trideca- 2(6),4,7,10,12-pentaen-9-yl]acetic acid (877 mg, 99% yield). [0403] Step 2: Preparation of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia- 1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-9-yl]acetamide. To a solution of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12 - tetrazatricyclo[8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (877 mg, 2.19 mmol, 1.0 equiv) and NH4Cl (351 mg, 6.56 mmol, 3.0 equiv) in DMF (8 mL) was added HATU (915 mg, 2.41 mmol, 1.1 equiv) and DIEA (848 mg, 6.56 mmol, 3.0 equiv). The mixture was stirred at 25 °C for 1 h. The mixture was filtered and concentrated. The residue was purified by prep- HPLC (column: Waters Xbridge C18150*50mm* 10um;mobile phase: [water( NH ₄ HCO ₃ )- ACN];B%: 24%-54%,10min) to give 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia- 1,8,11,12-tetrazatricyclo[8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide (740 mg, 84% yield). [0404] Step 3: Preparation of 2-[[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia- 1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-9-yl]methyl]oxazole. To a solution of 1,3-dioxol-2-one (103 mg, 1.20 mmol, 1.2 equiv) and 2-[(9S)-7-(4-chlorophenyl)- 4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9- yl]acetamide (400 mg, 1.00 mmol, 1.0 equiv) in PPA (4 mL). The mixture was stirred at 160 °C for 3 h. The mixture was quenched by addition H2O 50 mL at 0°C, and then diluted with EA 200 mL. The mixture was extracted with H2O (15 mL * 2). The combined organic layers were washed with H2O (10 mL * 3), drid over [Na2SO4], filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=2/1 to 0/1) to give compound 2-[[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,1 2- tetrazatricyclo [8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (260 mg, 61% yield). [0405] Step 4: Preparation of tert-butyl 4-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2- ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]tridec a-2(6),4,7,10,12-pentaen-7- yl]phenyl]ethynyl]piperidine-1-carboxylate. To a solution of 2-[[(9S)-7-(4-chlorophenyl)- 4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6 ]trideca-2(6),4,7,10,12-pentaen-9- yl]methyl]oxazole (400 mg, 943 umol, 1.0 equiv), tert-butyl 4-ethynylpiperidine-1-carboxylate (237 mg, 1.13 mmol, 1.2 equiv), Cs ₂ CO ₃ (614 mg, 1.89 mmol, 2.0 equiv) in DMF (4 mL), ACN (4 mL) was added [2-(2-aminophenyl)phenyl]palladium(1+);bis(1-adamantyl)-buty l- phosphane;methanesulfonate (69 mg, 94 umol, 0.1 equiv). The mixture was stirred at 90 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 5 g SepaFlash® Silica Flash Column, Eluent of 100% Ethyl acetate/Petroleum ethergradient @ 18 mL/min) to give the tert-butyl 4-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia- 1,8,11,12- tetrazatricyclo [8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]ethyn yl]piperidine-1- carboxylate (460 mg, 770 umol, 81% yield) as a yellow solid. [0406] Step 5: Preparation of tert-butyl 4-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2- ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]tridec a-2(6),4,7,10,12-pentaen-7- yl]phenyl]ethyl]piperidine-1-carboxylate. A mixture of tert-butyl 4-[2-[4-[(9S)-4,5,13- trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatric yclo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-7-yl]phenyl]ethynyl]piperidine-1-carb oxylate (410 mg, 687 umol, 1.0 equiv), Pd/C (200 mg, 687 umol, 10% purity, 1.0 equiv) in MeOH (5 mL) was degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 25 °C for 2 h under H ₂ atmosphere. The reaction mixture filtered and concentrated under reduced pressure to give a residue and used for next step directly. Compound tert-butyl 4-[2-[4-[(9S)-4,5,13-trimethyl-9- (oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0 2,6]trideca-2(6),4,7,10,12-pentaen- 7-yl]phenyl]ethyl]piperidine-1-carboxylate (305 mg, 507 umol, 73% yield) as a yellow solid. [0407] Step 6: Preparation of 2-[[(9S)-4,5,13-trimethyl-7-[4-[2-(4-piperidyl)ethyl] phenyl]-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-9-yl] methyl]oxazole. A mixture of tert-butyl 4-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)- 3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7 ,10,12-pentaen-7-yl]phenyl]ethyl] piperidine-1-carboxylate (280 mg, 466 umol, 1.0 equiv) in DCM (3 mL), TFA (1 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue and used for next step directly. Compound 2-[[(9S)-4,5,13-trimethyl-7-[4-[2-(4- piperidyl)ethyl] phenyl]-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca- 2(6),4,7,10,12- pentaen-9-yl]methyl] oxazole (286 mg, 465 umol, 99% yield, TFA) as a yellow oil.

[0408] Step 7: Preparation of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4-[2-[4- [(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,1 2-tetrazatricyclo[8.3.0.02,6] trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]ethyl]-1-piperidy l]pyridazine-3-carboxamide. A mixture of 2-[[(9S)-4,5,13-trimethyl-7-[4-[2-(4-piperidyl)ethyl]phenyl] -3-thia-1,8,11,12- tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9- yl]methyl]oxazole (143 mg, 285 umol, 1.0 equiv), 6-chloro-N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]pyridazin e-3- carboxamide (89 mg, 228 umol, 0.8 equiv), K2CO3 (118 mg, 856 umol, 3.0 equiv) in DMF (1.5 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 60 °C for 2 h under N2 atmosphere. The reaction mixture was filtered. The residue was purified by prep- HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)- ACN];B%: 63%-93%,8min) to give the N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4-[2- [4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,1 1,12-tetrazatricyclo [8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]ethyl ]-1-piperidyl]pyridazine-3- carboxamide (86 mg, 87umol, 30% yield, 98% purity, TFA) as a yellow solid. ¹ H NMR: (400 MHz, MeOD) δ = 8.44 (s, 1H), 7.92 - 7.84 (m, 2H), 7.69 (d, J = 8.8 Hz, 1H), 7.32 - 7.22 (m, 5H), 7.20 (d, J = 2.4 Hz, 1H), 7.13 (s, 1H), 7.08 - 7.01 (m, 1H), 4.79 - 4.74 (m, 3H), 4.59 (s, 2H), 4.49 (d, J = 12.8 Hz, 3H), 4.00 - 3.95 (m, 2H), 3.05 - 2.94 (m, 2H), 2.75 - 2.72 (m, 1H), 2.71 (s, 3H), 2.45 (s, 3H), 2.25 - 2.16 (m, 2H), 2.13 - 2.05 (m, 2H), 1.93 - 1.84 (m, 2H), 1.67 (s, 3H), 1.64 (s, 2H), 1.61 (s, 2H), 1.34 - 1.19 (m, 3H). LC-MS: MS (ES+): RT = 2.850 min, m/z = 855.6 [M + H ⁺ ]; LCMS method: 25. EXAMPLE 8 – Synthesis of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[2-[[4-[(9S)- 4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetr azatricyclo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-7-yl]phenyl]methyl]-2,7-diazaspiro[3. 5]nonan-7-yl]pyridazine-3- carboxamide (I-109)

[0409] Step 1: Preparation of (7-tert-butoxycarbonyl-2,7-diazaspiro[3.5]nonan-2- yl)methyl-trifluoro-boron;potassium hydride. To a solution of tert-butyl 2,7-diazaspiro[3.5] nonane-7-carboxylate;hydrochloride (1.0 g, 3.8mmol, 1.1 equiv) in THF (6 mL) was added potassium;bromomethyl(trifluoro)boranuide (728 mg, 3.6 mmol, 1.0 equiv). The mixture is stirred for 3 h at 80° C. After concentrated, the residue was suspended in ACN (21 mL) and combined with K ₂ CO ₃ (501 mg, 3.6 mmol, 10 equiv). The mixture was stirred at 25°C for 12h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was used for next step without further purification. Compound (7-tert- butoxycarbonyl-2,7-diazaspiro[3.5]nonan-2-yl)methyl-trifluor o-boron;potassium hydride (1 g, 3.2 mmol, 88% yield) was obtained as a white foam. [0410] Step 2: Preparation of tert-butyl 2-[[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2- ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]tridec a-2(6),4,7,10,12-pentaen-7- yl]phenyl]methyl]-2,7-diazaspiro[3.5]nonane-7-carboxylate. To a solution of 2-[[(9S)-7-(4- chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricy clo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (400 mg, 943.6 umol, 1.0 equiv),(7-tert- butoxycarbonyl-2,7-diazaspiro[3.5]nonan-2-yl)methyl-trifluor o-boron;potassium hydride (490 mg, 1.4 mmol, 1.5 equiv) in THF (6 mL) and H ₂ O (3 mL) was added Pd(OAc) ₂ (11 mg, 47.2 umol, 0.05 equiv) and XPhos (45 mg, 94.4 umol, 0.1 equiv), Cs2CO3 (922 mg, 2.8 mmol, 3.0 equiv). The mixture was stirred at 90 °C for 12 h. The residue was diluted with 30 mL water and extracted with EA (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue .The residue was purified by prep-HPLC(column: Waters Xbridge C18150*50mm* 10um;mobile phase: [water( NH4HCO3)-ACN];B%: 39%-69%,10min). Compound tert-butyl 2-[[4-[(9S)-4,5,13-trimethyl-9- (oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0 2,6]trideca-2(6),4,7,10,12-pentaen- 7-yl]phenyl]methyl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (225 mg, 358.4 umol, 38% yield) was obtained as a white solid. [0411] Step 3: Preparation of 2-[[(9S)-7-[4-(2,7-diazaspiro[3.5]nonan-2-ylmethyl) phenyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8. 3.0.02,6]trideca-2(6),4,7,10,12- pentaen-9-yl]methyl]oxazole. To a solution of tert-butyl 2-[[4-[(9S)-4,5,13-trimethyl-9- (oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0 2,6]trideca-2(6),4,7,10,12-pentaen- 7-yl]phenyl]methyl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (225 mg, 358 umol, 1.0 equiv) in DCM (1 mL) was added TFA (0.5 mL). The reaction mixture was concentrated under reduced pressure to give a compound 2-[[(9S)-7-[4-(2,7-diazaspiro[3.5]nonan-2-ylmethyl)phenyl]- 4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6 ]trideca-2(6),4,7,10,12-pentaen-9- yl]methyl] oxazole (225 mg, 358 umol, 99% yield, TFA salt) as a colorless oil. [0412] Step 4: Preparation of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[2-[[4- [(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,1 2-tetrazatricyclo[8.3.0.02,6] trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]methyl]-2,7-diaza spiro[3.5]nonan-7-yl] pyridazine-3-carboxamide. The solution of tert-butyl 2-[(9S)-7-[4-[4-(dimethoxymethyl)-1- piperidyl]phenyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazat ricyclo[8.3.0.0 ^2,6 ]trideca- 2(6),4,7,10,12-pentaen-9-yl]acetate (60 mg, 103 umol, 1.0 equiv) in TFA (1 mL) and DCM (1 mL) was stirred at 25 °C for 1 h. The solution was concentrated under reduced pressure to give 2-[(9S)-7-[4-(4-formyl-1-piperidyl)phenyl]-4,5,13-trimethyl- 3-thia-1,8,11,12-tetrazatricyclo [8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (61 mg, crude, TFA salt) as brown oil. To a solution of 2-[[(9S)-7-[4-(2,7-diazaspiro[3.5]nonan-2-ylmethyl)phenyl]-4 ,5,13- trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]tridec a-2(6),4,7,10,12-pentaen-9- yl]methyl]oxazole (140 mg, 265 umol, 1.0 equiv), 6-chloro-N-[4-(3-chloro-4-cyano- phenoxy)cyclohexyl] pyridazine-3-carboxamide (104 mg, 265 umol, 1.0 equiv) in NMP (1.5 mL) was added K2CO3 (110 mg, 796 umol, 3.0 equiv). The mixture was stirred at 50 °C for 12 h. After filtered, the filtrate was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10um;mobile phase: [water(FA)-ACN];B%: 24%-54%,10min) to afford N-[4-(3- chloro-4-cyano-phenoxy)cyclohexyl]-6-[2-[[4-[(9S)-4,5,13-tri methyl-9-(oxazol-2-ylmethyl)-3- thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,1 0,12-pentaen-7-yl]phenyl]methyl]- 2,7-diazaspiro[3.5]nonan-7-yl]pyridazine-3-carboxamide (129 mg, 143 umol, 54% yield, 98% purity) as a yellow solid. ¹ H NMR (400 MHz, CD3OD) 7.86 - 7.92 (m, 2 H) 7.65 - 7.71 (m, 1 H) 7.42 - 7.48 (m, 4 H) 7.26 - 7.33 (m, 1 H) 7.17 - 7.22 (m, 1 H) 7.10 - 7.15 (m, 1 H) 7.01 - 7.07 (m, 1 H) 4.75 - 4.81 (m, 1 H) 4.45 - 4.56 (m, 1 H) 4.10 - 4.18 (m, 2 H) 3.90 - 4.06 (m, 3 H) 3.57 - 3.79 (m, 8 H) 2.66 - 2.75 (m, 3 H) 2.43 - 2.47 (m, 3 H) 2.15 - 2.24 (m, 2 H) 2.04 - 2.14 (m, 2 H) 1.88 - 1.95 (m, 4 H) 1.57 - 1.70 (m, 7 H). LC-MS: MS (ES ⁺ ): RT = 2.070 min, m/z = 882.4 [M+H ⁺ ]; LCMS method: 10. EXAMPLE 9 – Synthesis of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[2-[4-[(9S)- 4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetr azatricyclo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-7-yl]phenyl]-2,7-diazaspiro[3.5]nonan -7-yl]pyridazine-3- carboxamide (I-132) [0413] Step 1: Preparation of tert-butyl 2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2- ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]tridec a-2(6),4,7,10,12-pentaen-7- yl]phenyl]-2,7-diazaspiro[3.5]nonane-7-carboxylate. To a solution of 2-[[(9S)-7-(4-chloro- phenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8. 3.0.02,6]trideca-2(6),4,7,10,12- pentaen-9-yl]methyl]oxazole (210 mg, 495 umol, 1.0 equiv) and tert-butyl 2,7-diazaspiro[3.5] nonane-7-carboxylate;hydrochloride (195 mg, 743 umol, 1.5 equiv) in dioxane (5 mL) was added SPhos Pd G ₃ (77.3 mg, 99.1 umol, 0.2 equiv) and Cs ₂ CO ₃ (484 mg, 1.49 mmol, 3.0 equiv). The mixture was stirred at 90 °C for 12 h. The residue was diluted with H2O (50 mL) and extracted with EA (20 mL x 3). The organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to afford crude product. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 42%-72%,10min) to afford tert-butyl 2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia- 1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-7-yl]phenyl]-2,7-diazaspiro [3.5]nonane-7-carboxylate (270 mg, 440 umol, 89% yield) as a yellow oil . [0414] Step 2: Preparation of 2-[[(9S)-7-[4-(2,7-diazaspiro[3.5]nonan-2-yl)phenyl]- 4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6 ]trideca-2(6),4,7,10,12-pentaen- 9-yl]methyl]oxazole. To a solution of tert-butyl 2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2- ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]tridec a-2(6),4,7,10,12-pentaen-7- yl]phenyl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (110 mg, 179 umol, 1.0 equiv) in DCM (2 mL) was added TFA (1 mL) .The mixture was stirred at 25 °C for 0.5 h .The reaction mixture was concentrated to afford 2-[[(9S)-7-[4-(2,7-diazaspiro[3.5]nonan-2-yl)phenyl]-4,5,13- trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]tridec a-2(6),4,7,10,12-pentaen-9- yl]methyl] oxazole (113 mg, crude, TFA salt) as a yellow oil and it was used into the next step without further purification. Step 3: Preparationof N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[2-[4-[(9S)-4,5 ,13- trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatric yclo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-7-yl]phenyl]-2,7-diazaspiro[3.5]nonan -7-yl]pyridazine-3- carboxamide. To a solution of 2-[[(9S)-7-[4-(2,7-diazaspiro[3.5]nonan-2-yl)phenyl]-4,5,13- trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]tridec a-2(6),4,7,10,12-pentaen-9- yl]methyl]oxazole (164 mg, 261 umol, 1.0 equiv, TFA salt) and 6-chloro-N-[4-(3-chloro-4- cyano-phenoxy)cyclohexyl]pyridazine-3-carboxamide (112 mg, 287 umol, 1.1 equiv) in NMP (2 mL) was added K2CO3 (108 mg, 784 umol, 3.0 equiv). The mixture was stirred at 50 °C for 12 h. After filtered, the filtrate was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10um;mobile phase: [water(FA)-ACN];B%: 54%-74%,10min) to afford N-[4-(3- chloro-4-cyano-phenoxy)cyclohexyl]-6-[2-[4-[(9S)-4,5,13-trim ethyl-9-(oxazol-2-ylmethyl)-3- thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,1 0,12-pentaen-7-yl]phenyl]-2,7- diazaspiro[3.5]nonan-7-yl]pyridazine-3-carboxamide (70 mg, 77 umol, 30% yield, 96% purity) as a yellow solid. ¹ H NMR (400 MHz, CD3OD) δ 7.94 - 7.89 (m, 2H), 7.69 (d, J = 8.8 Hz, 1H), 7.34 (br t, J = 9.2 Hz, 3H), 7.20 (d, J = 2.3 Hz, 1H), 7.15 (s, 1H), 7.07 - 7.02 (m, 1H), 6.52 - 6.46 (m, 2H), 4.95 - 4.88 (m, 2H), 4.05 - 3.95 (m, 3H), 3.88 - 3.77 (m, 8H), 2.73 (s, 3H), 2.49 (s, 3H), 2.25 - 2.17 (m, 2H), 2.11 (br d, J = 3.8 Hz, 2H), 1.96 (br d, J = 4.0 Hz, 4H), 1.82 - 1.76 (m, 3H), 1.69 - 1.59 (m, 4H). LC-MS: MS (ES ⁺ ): RT = 2.243 min, m/z = 868.4 [M+H ⁺ ]; LCMS method: 10. EXAMPLE 10 – Synthesis of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[2-[4-[(9E)- 4,5,13-trimethyl-9-(oxazol-2-ylmethylene)-3-thia-1,8,11,12-t etrazatricyclo[8.3.0.02,6] trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5] nonan-7-yl]pyridazine-3- carboxamide (I-135) [0415] Step 1: Preparation of tert-butyl 2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2- ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]tridec a-2(6),4,7,10,12-pentaen-7- yl]phenoxy]-7-azaspiro[3.5]nonane-7-carboxylate. To a solution of 2-[[(9S)-7-(4- chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricy clo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (300 mg, 707 umol, 1.0 equiv), tert-butyl 2- hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (853 mg, 3.54 mmol, 5.0 equiv) in dioxane (5 mL) was added tBuXPhos Pd G3 (112 mg, 141 umol, 0.2 equiv) and Cs ₂ CO ₃ (1.1 g, 3.5 mmol, 5.0 equiv). The mixture was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 2 h under N ₂ atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 2 g SepaFlash® Silica Flash Column, Eluent of 0~3% Methanol/Dichloromethanegradient @ 18 mL/min) to give the tert-butyl 2-[4-[(9S)-4,5,13- trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatric yclo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonane-7 -carboxylate (210 mg, 333 umol, 47% yield) as a yellow solid. [0416] Step 2: Preparation of tert-butyl 2-[4-[(9Z)-4,5,13-trimethyl-9-(oxazol-2- ylmethylene)-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]tri deca-2(6),4,7,10,12-pentaen-7- yl]phenoxy]-7-azaspiro[3.5]nonane-7-carboxylate. A mixture of tert-butyl 2-[4-[(9S)-4,5,13- trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatric yclo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonane-7 -carboxylate (200 mg, 318 μmol, 1.0 equiv), Pd(OAc) ₂ (22 mg, 96 μmol, 0.3 equiv), K ₂ CO ₃ (66 mg, 477 μmol, 1.5 equiv) and dcpp (83 mg, 191 μmol, 0.6 equiv) in DMSO (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 120 °C for 12 h under N ₂ atmosphere. The reaction mixture filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:69%-99% B over 10 min) to give the tert-butyl 2-[4-[(9Z)-4,5,13- trimethyl-9-(oxazol-2-ylmethylene)-3-thia-1,8,11,12-tetrazat ricyclo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonane-7 -carboxylate (60 mg, 96 μmol, 30% yield) as a yellow solid. [0417] Step 3: Preparation of 2-[(E)-[7-[4-(7-azaspiro[3.5]nonan-2-yloxy)phenyl]- 4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6 ]trideca-2(6),4,7,10,12-pentaen- 9-ylidene]methyl]oxazole. A mixture of tert-butyl 2-[4-[(9E)-4,5,13-trimethyl-9-(oxazol-2- ylmethylene)-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]tri deca-2(6),4,7,10,12-pentaen-7- yl]phenoxy]-7-azaspiro[3.5]nonane-7-carboxylate (50 mg, 80 μmol, 1.0 equiv) in DCM (3 mL) and TFA (1 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 25 °C for 2 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give the 2-[(E)-[7-[4-(7-azaspiro[3.5]nonan-2-yloxy)phenyl]-4,5,13-tr imethyl-3- thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,1 0,12-pentaen-9- ylidene]methyl]oxazole (51 mg, 80 μmol, 100% yield, TFA) as a colorless oil. Step 4: Preparation of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[2-[4-[(9E)-4,5 ,13- trimethyl-9-(oxazol-2-ylmethylene)-3-thia-1,8,11,12-tetrazat ricyclo [8.3.0.02,6] trideca- 2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonan-7- yl]pyridazine-3- carboxamide. A mixture of 2-[(E)-[7-[4-(7-azaspiro[3.5]nonan-2-yloxy)phenyl]-4,5,13- trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]tridec a-2(6),4,7,10,12-pentaen-9- ylidene]methyl]oxazole (70 mg, 110mol, 1.0quiv, TFA), 6-chloro-N-[4-(3-chloro-4-cyano- phenoxy)cyclohexyl]pyridazine-3-carboxamide (47 mg, 120 μmol, 1.1 equiv), K2CO3 (151 mg, 1 mmol, 10.0 equiv) in NMP (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 12 h under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water( NH4HCO3)- ACN];gradient:54%-84% B over 10 min) to give the N-[4-(3-chloro-4-cyano- phenoxy)cyclohexyl]-6-[2-[4-[(9E)-4,5,13-trimethyl-9-(oxazol -2-ylmethylene)-3-thia- 1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-7-yl]phenoxy]-7- azaspiro[3.5]nonan-7-yl]pyridazine-3-carboxamide (37 mg, 39 μmol, 36% yield) as a yellow solid. ¹ H NMR: (400 MHz, MeOD) δ = 8.07 (s, 1H), 7.89 (d, J = 9.6 Hz, 1H), 7.79 - 7.71 (m, 2H), 7.69 (d, J = 8.8 Hz, 1H), 7.39 - 7.33 (m, 1H), 7.30 (d, J = 9.6 Hz, 1H), 7.22 - 7.17 (m, 1H), 7.08 - 7.02 (m, 1H), 6.99 - 6.93 (m, 2H), 6.44 (s, 1H), 4.58 (s, 1H), 4.55 - 4.46 (m, 1H), 4.02 - 3.91 (m, 1H), 3.82 - 3.77 (m, 2H), 3.75 - 3.69 (m, 2H), 2.77 (s, 3H), 2.63 - 2.54 (m, 2H), 2.41 (s, 3H), 2.25 - 2.16 (m, 2H), 2.15 - 2.07 (m, 2H), 2.07 - 1.98 (m, 3H), 1.83 - 1.74 (m, 4H), 1.72 (s, 3H), 1.68 - 1.61 (m, 4H). LC-MS: MS (ES ⁺ ): RT = 2.689 min, m/z = 881.4 [M +H ⁺ ]; LCMS method: 25 EXAMPLE 11 – Synthesis of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4-[3-[4-[(9S)- 4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetr azatricyclo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-7-yl]phenyl]prop-2-ynyl]-1-piperidyl] pyridazine-3-carboxamide (I- 136)

[0418] Step 1: Preparation of tert-butyl 4-prop-2-ynylpiperidine-1-carboxylate. To A mixture of tert-butyl 4-(2-oxoethyl) piperidine-1-carboxylate (5 g, 22.0 mmol, 1.0 equiv), 1- diazo-1- dimethoxyphosphoryl-propan-2-one (5.5 g, 28.6 mmol, 1.3 equiv), K2CO3 (6.1 g, 43.9 mmol, 2.0 equiv), in MeOH (50 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20 °C for 12 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=100/1 to 10/1) to give tert-butyl 4-prop- 2-ynylpiperidine-1-carboxylate (4.4 g, 90 % yield). [0419] Step 2: Preparation of crude tert-butyl 4-[3-[4-[(9S)-4,5,13-trimethyl-9- (oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0 2,6]trideca-2(6),4,7,10,12- pentaen-7-yl]phenyl]prop-2-ynyl]piperidine-1-carboxylate. A mixture of tert-butyl 4-prop- 2-ynylpiperidine-1-carboxylate (869 mg, 3.9 mmol, 3.0 equiv),2-[[(9S)-7-(4-chlorophenyl)- 4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6 ]trideca-2(6),4,7,10,12-pentaen-9- yl]methyl]oxazole (550 mg, 1.3 mmol, 1.0 equiv), Cs ₂ CO ₃ (845.5 mg, 2.6 mmol, 2.0 equiv),[2- (2-aminophenyl)phenyl]-methylsulfonyloxy-palladium;2-(2-dicy clohexylphosphanylphenyl)- N,N-dimethyl-aniline (99mg, 129 μmol, 0.1 equiv) in ACN (15 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 12 h under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2,DCM:MEOD to 10/1) to give tert- butyl 4-[3-[4-[(9S)-4,5,13-trimethyl-9- (oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo [8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]prop- 2-ynyl]piperidine-1-carboxylate (460 mg, 58 % yield). [0420] Step 3: Preparationof crude 2-[[(9S)-4,5,13-trimethyl-7-[4-[3-(4-piperidyl)prop- 1-ynyl]phenyl]-3-thia- 1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen- 9-yl]methyl]oxazole. To To a solution of tert-butyl 4-[3-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2- ylmethyl) -3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4, 7,10,12-pentaen-7- yl]phenyl]prop-2-ynyl]piperidine-1-carboxylate (460 mg, 753 μmol, 1.0 equiv) in DCM (5 mL) was added TFA (85 mg, 753 μmol, 55 μL, 1.0 equiv). The mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered and the filter was concentrated. The product was used directly for next step. [0421] Step 4: Preparation of crude N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4- [3-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1, 8,11,12- tetrazatricyclo[8.3.0.02,6] trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]prop-2-ynyl]-1- piperidyl]pyridazine-3-carboxamide. To a solution of 2-[[(9S)-4,5,13-trimethyl-7-[4-[3-(4- piperidyl)prop-1-ynyl]phenyl]-3-thia- 1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (200 mg, 390 μmol, 1.0 equiv),6-chloro-N-[4-(3- chloro-4-cyano-phenoxy)cyclohexyl]pyridazine-3-carboxamide (153 mg, 391 μmol, 1.0 equiv) in NMP (3 mL) was slowly charged with DIEA (101 mg, 783 μmol, 136 μL, 2.0 equiv). The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was filtered and the filter was concentrated. The residue was purified by prep-TLC (SiO2, DCM: MeOH = 10:1). The product was used directly for next step. [0422] Step 5: Preparation of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4-[3-[4- [(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,1 2-tetrazatricyclo[8.3.0.02,6] trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]prop-2-ynyl]-1-pi peridyl]pyridazine-3- carboxamide. To The residue was purified by prep-SFC (EW30421-752-P1A1) (column: DAICEL CHIRALPAK AS(250mm*30mm,10um);mobile phase: [CO2-ACN/MeOH(0.1% NH ₃ H ₂ O)];B%:65%, isocratic elution mode) to give N-[4-(3-chloro-4-cyano-phenoxy) cyclohexyl]-6-[4-[3-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-yl methyl)-3-thia-1,8,11,12- tetrazatricyclo[8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]prop-2-yny l]-1- piperidyl]pyridazine-3-carboxamide (83 mg, 23 % yield)(Rt=2.538 min). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.99 (d, J = 9.2 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.64 (s, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.38 - 7.31 (m, 4H), 7.05 (s, 1H), 7.03 - 6.96 (m, 2H), 6.86 (s, 1H), 4.74 (t, J = 7.2 Hz, 1H), 4.56 (s, 2H), 4.38 - 4.28 (m, 1H), 4.18 - 4.07 (m, 2H), 4.07 - 4.02 (m, 1H), 3.07 (s, 2H), 2.69 (s, 3H), 2.47 - 2.43 (m, 2H), 2.41 (s, 3H), 2.19 (s, 4H), 2.02 (s, 2H), 1.99 - 1.90 (m, 1H), 1.71 (s, 2H), 1.65 - 1.63 (m, 2H), 1.54 - 1.38 (m, 5H). LC-MS: MS (ES ⁺ ): RT = 2.472 min, m/z = 865.4 [M + H ⁺ ]; LCMS method: 25 EXAMPLE 12 – Synthesis of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4-[(9S)- 4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetr azatricyclo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-7-yl]phenoxy]pyridazine-3-carboxamide (I-141) [0423] Step 1: Preparation of 4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia- 1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-7-yl]phenol. To A mixture of 2-[[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,1 2- tetrazatricyclo[8.3.0.02,6] trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (5.8 g, 13.7 mmol, 1.0 equiv), BrettPhos Pd G3 (1.2 g, 1.4 mmol, 0.1 equiv), KOH (3.8 g, 68.4 mmol, 5.0 equiv) in dioxane (58 mL) and H2O (11.6 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 3 h under N ₂ atmosphere. The reaction mixture was partitioned between Ethyl acetate (2000 mL) and water (500 mL). The organic phase was separated, washed with brine (500 mL x 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Dichloromethane : Methanol=40/1) to give the 4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)- 3-thia-1,8,11,12-tetrazatricyclo [8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenol (3.5 g, 8.6 mmol, 63% yield) as a yellow solid. [0424] Step 2: Preparation of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4-[(9S)- 4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetr azatricyclo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-7-yl]phenoxy]pyridazine-3-carboxamide . To a solution of 6-chloro- N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]pyridazine-3-carbo xamide (96 mg, 247 μmol, 1.0 equiv) in NMP (2 mL) was added K2CO3 (102 mg, 740 μmol, 3.0 equiv) and 4-[(9S)-4,5,13- trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatric yclo[8.3.0.02,6]trideca-2(6),4,7, 10,12-pentaen-7-yl]phenol (100 mg, 247 μmol, 1.0 equiv). The mixture was stirred at 50 °C for 12 h. The mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 * 25 mm * 5 um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 46%-76% B over 10 min) to give N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4- [(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,1 2- tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7- yl]phenoxy]pyridazine-3- carboxamide (95 mg, 51% yield, 99% purity) as a white solid. ¹ H NMR (400 MHz, CDCl3): δ 8.33 (d, J = 9.2 Hz, 1H), 7.92-7.83 (m, 1H), 7.65 (s, 1H), 7.55 (m, J = 8.8, 13.6 Hz, 3H), 7.33 (d, J = 9.2 Hz, 1H), 7.22 (d, J = 8.8 Hz, 2H), 7.06 (s, 1H), 7.00 (d, J = 2.4 Hz, 1H), 6.86 (m, J = 2.4, 8.8 Hz, 1H), 4.78 (t, J = 7.2 Hz, 1H), 4.37-4.27 (m, 1H), 4.17-4.03 (m, 3H), 2.70 (s, 3H), 2.43 (s, 3H), 2.24-2.14 (m, 4H), 1.78 (s, 3H), 1.73-1.66 (m, 2H), 1.52-1.43 (m, 2H). LC-MS: MS (ES ⁺ ): RT = 2.592 min, m/z = 760.2 [M + H ⁺ ]; LCMS method: 10. EXAMPLE 13 – Synthesis of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[2-[[4-[(9S)- 4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetr azatricyclo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-7-yl]phenyl]methylene]-6-azaspiro[3.5 ]nonan-6-yl]pyridazine-3- carboxamide (I-142)

[0425] Step 1: Preparation of tert-butyl 2-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)methylene]-6-azaspiro[3.5]nonane-6- carboxylate. To the solution of TMP (2.2 g, 16 mmol, 2.7 mL, 2.0 equiv) in THF (12 mL) was added n-BuLi (2.5 M, 6.4 mL, 2.0 equiv) at -30 °C, then the solution was stirred at -30 °C for 0.5 h. The solution of 4,4,5,5-tetramethyl-2- [(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]-1,3,2-dioxaborol ane (3.2 g, 12 mmol, 1.5 equiv) in THF (4 mL) was added to the solution at -70 °C. The mixture was stirred at -70 °C for 0.5 h. tert-butyl 2-oxo-6-azaspiro[3.5]nonane-6- carboxylate (1.9 g, 8.0 mmol, 1.0 equiv) in THF (4 mL) was added to the mixtue at -70 °C, the mixture was stirred at -70 °C for 2 h. Then stirred at 25 °C for 12 h and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 20/1 to 10/1) to give tert-butyl 2- [(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-6-a zaspiro[3.5]nonane-6- carboxylate (1.7 g, 59% yield) as colorless oil. [0426] Step 2: Preparation of crude tert-butyl 2-[[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2- ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]tridec a-2(6),4,7,10,12-pentaen-7- yl]phenyl]methylene]-6-azaspiro[3.5]nonane-6-carboxylate. A mixture of 2-[[(9S)-7-(4- chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricy clo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (600 mg, 1.4 mmol, 1.0 equiv), tert-butyl 2- [(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-6-a zaspiro[3.5]nonane-6-carboxylate (1 g, 2.8 mmol, 2.0 equiv), SPhos Pd G3 (110 mg, 142 μmol, 0.1 equiv) and Cs2CO3 (461 mg, 1.4 mmol, 1.0 equiv) in DMF (10 mL) was degassed and purged with N ₂ for 3 times. The mixture was stirred at 90 °C for 12 h under N2 atmosphere and concentrated. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 0/1) to give tert- butyl 2-[[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1, 8,11,12- tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7, 10,12-pentaen-7-yl]phenyl]methylene]-6- azaspiro[3.5]nonane-6-carboxylate (700 mg, 79% yield) as a yellow oil. [0427] Step 3: Preparation of crude 2-[[(9S)-7-[4-(6-azaspiro[3.5]nonan-2-ylidene- methyl)phenyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatric yclo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole. To a solution of tert-butyl 2-[[4-[(9S)-4,5,13- trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatric yclo[8.3.0.02,6]trideca-2(6),4, 7,10,12-pentaen-7-yl]phenyl]methylene]-6-azaspiro[3.5]nonane -6-carboxylate (700 mg, 1 mmol, 1.0 equiv) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to get the residue. The resiude was diltured with 10 mL DCM and adjusted the pH to 7~8 with saturated NaHCO3 aqueous, then extracted with DCM(20 mL * 3), the combined organic layer was concentrated under reduced pressure to give a crude product. [0428] Step 4: Preparation of crude N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[2- [[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8, 11,12-tetrazatricyclo[8.3.0.02,6] trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]methylene]-6-azas piro[3.5]nonan-6-yl] pyridazine-3-carboxamide. To a solution of 2-[[(9S)-7-[4-(6-azaspiro[3.5]nonan-2- ylidenemethyl)phenyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetr azatricyclo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (330 mg, 629 μmol, 1.0 equiv) in NMP (4.5 mL) was added DIEA (162 mg, 1.26 mmol, 219 μL, 2.0 equiv) and 6-chloro-N-[4-(3-chloro-4- cyano-phenoxy)cyclohexyl]pyridazine-3-carboxamide (246 mg, 629 μmol, 1.0 equiv). The mixture was stirred at 50 °C for 12 h. The solution was diluted with water (5 mL) and extracted with Ethyl acetate (20 mL*3). The combined organic layer was concentrated under reduced pressure to get the residue. The residue was purified by prep-TLC(SiO ₂ , Ethyl acetate: MeOH = 10:1) to give crude N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[2-[[4-[(9S)-4, 5,13- trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatric yclo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-7-yl]phenyl] methylene]-6-azaspiro[3.5]nonan-6-yl]pyridazine-3- carboxamide (190 mg, 34% yield) as a yellow solid. [0429] Step 5: Preparation of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[2-[[4- [(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,1 2-tetrazatricyclo[8.3.0.02,6] trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]methylene]-6-azas piro[3.5]nonan-6- yl]pyridazine-3-carboxamide. N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[2-[[4-[4,5,13- trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatric yclo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-7-yl]phenyl]methylene]-6-azaspiro[3.5 ]nonan-6-yl]pyridazine-3- carboxamide (190 mg, 216 μmol, 1.0 equiv) was purified by SFC (column: DAICEL CHIRALPAK AS(250mm*30mm,10um); mobile phase: [CO2-ACN/MeOH(0.1% NH3H2O)];B%:50%, isocratic elution mode) to give N-[4-(3-chloro-4-cyano-phenoxy) cyclohexyl]-6-[2-[[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylme thyl)-3-thia-1,8,11,12- tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7- yl]phenyl]methylene]-6- azaspiro[3.5]nonan-6-yl]pyridazine-3-carboxamide (81 mg, 42% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.99-7.91 (m, 1H), 7.89-7.80 (m, 1H), 7.63 (s, 1H), 7.60-7.51 (m, 1H), 7.37-7.29 (m, 2H), 7.19-7.10 (m, 2H), 7.08-6.94 (m, 3H), 6.90-6.82 (m, 1H), 6.26-6.18 (m, 1H), 4.80-4.65 (m, 1H), 4.40-4.26 (m, 1H), 4.17-3.98 (m, 3H), 3.86-3.73 (m, 2H), 3.71- 3.59 (m, 2H), 2.88-2.54 (m, 7H), 2.46-2.33 (m, 3H), 2.26-2.09 (m, 4H), 1.86-1.78 (m, 2H), 1.71-1.62 (m, 6H), 1.53-1.37 (m, 2H). LC-MS: MS (ES ⁺ ): RT = 2.566 min, m/z = 879.4 [M + H ⁺ ]; LCMS Method: 25. EXAMPLE 14 – Synthesis of Additional Compounds [0430] The following compounds were synthesized using procedures analogous to those described above: I-45, I-46, I-47, I-48, I-49, I-50, I-51, I-52, I-53, I-54, I-55, I-56, I-57, I-58, I- 59, I-60, I-61, I-62, I-63, I-64, I-65, I-66, I-67, I-68, I-69, I-70, I-71, I-73, I-75, I-76, I-77, I-78, I-79, I-80, I-81, I-82, I-83, I-84, I-85, I-86, I-87, I-88, I-89, I-90, I-91, I-92, I-93, I-94, I-95, I- 96, I-97, I-98, I-101, I-102, I-103, I-104, I-105, I-106, I-107, I-108, I-110, I-111, I-112, I-113, I-114, I-115, I-116, I-117, I-118, I-119, I-120, I-121, I-122, I-123, I-124, I-125, I-126, I-127, I- 128, I-129, I-130, I-131, I-133, I-134, I-137, I-138, I-139, I-140, and I-143. EXAMPLE 15 – Compound Characterization [0431] Exemplary compounds were characterized by LCMS. The characterization data is outlined in Table 2 below. TABLE 2. EXAMPLE 16 – Synthesis of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[8-[4-[(9S)- 4,5,9,13-tetramethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0. 02,6]trideca-2(6),4,7,10,12- pentaen-7-yl]phenyl]-2-azaspiro[4.4]nonan-2-yl]pyridazine-3- carboxamide (I-821) [0432] Step 1: Preparation of tert-butyl 8-(4-chlorophenyl)-2-azaspiro[4.4]non-7-ene- 2-carboxylate. A mixture of tert-butyl 8-(trifluoromethylsulfonyloxy)-2-azaspiro[4.4]non-7- ene-2-carboxylate (2.0 g, 5.4 mmol, 1.0 equiv), (4-chlorophenyl)boronic acid (1.1 g, 7.0 mmol, 1.3 equiv), Pd(PPh3) ₂ Cl2 (378 mg, 539 μmol, 0.1 equiv), NaHCO3 (905 mg, 10.8 mmol, 419 μL, 2.0 equiv) in THF (20 mL) and H2O (6 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 65 °C for 12 h under N2 atmosphere. The reaction mixture was partitioned between Ethyl acetate 100 mL and H2O 200 mL (100 mL x 2). The organic phase was separated, washed with brine 100 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 10/1 to 5/1) to give the tert-butyl 8-(4-chlorophenyl)-2- azaspiro [4.4]non-7-ene-2-carboxylate (2.5 g, 5.2 mmol, 96% yield) as a yellow solid. [0433] Step 2: Preparation of tert-butyl 8-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)phenyl]-2-azaspiro[4.4]non-7-ene-2-carboxylate. A mixture of tert-butyl 8-(4- chlorophenyl)-2-azaspiro[4.4]non-7-ene-2-carboxylate (2.5 g, 7.4 mmol, 1.0 equiv), BPD (2.8 g, 11.1 mmol, 1.5 equiv), KOAc (2.2 g, 22.1 mmol, 3.0 equiv), XPhos (527 mg, 1.1 mmol, 0.15 equiv) and Pd2(dba)3 (337 mg, 368 μmol, 0.05 equiv) in dioxane (25 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 70 °C for 12 h under N ₂ atmosphere. The reaction mixture was partitioned between ethyl acetate 100 mL and H2O 200 mL (100 mL x 2). The resulting organic phase was separated, washed with brine 100 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge C18150*50mm* 10um;mobile phase: [water( NH4HCO3)-ACN];gradient:70%-100% B over 10 min) to give the tert-butyl 8-[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-azasp iro[4.4]non-7-ene-2-carboxylate (2.0 g, 4.7 mmol, 64% yield) as a yellow solid. [0434] Step 3: Preparation of tert-butyl 8-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)phenyl]-2-azaspiro[4.4]nonane-2-carboxylate. To a solution of tert-butyl 8-[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-azaspiro[4.4]n on-7-ene-2-carboxylate (1.5 g, 3.5 mmol, 1.0 equiv) in MeOH (15 mL) was added Pd/C (1.5 g, 14.1 mmol, 10% purity, 4.0 equiv). The mixture was stirred at 50 °C for 12 h under H2 (50 psi). The reaction mixture was filtered and concentrated under reduced pressure to give the tert-butyl 8-[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-azaspiro[4.4]n onane-2-carboxylate (1.4 g, 3.4 mmol, 96% yield) as a white oil. [0435] Step 4: Preparation of tert-butyl 8-[4-[(9S)-4,5,9,13-tetramethyl-3-thia- 1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-7-yl]phenyl]-2- azaspiro[4.4] nonane-2-carboxylate. A mixture of tert-butyl 8-[4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]-2-azaspiro[4.4]nonane-2-carboxylat e (1.0 g, 2.3 mmol, 1.0 equiv), (9S)-7-chloro-4,5,9,13-tetramethyl-3-thia-1,8,11,12-tetrazat ricyclo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaene (985 mg, 3.5 mmol, 1.5 equiv), Pd(dppf)Cl2 (171 mg, 234 μmol, 0.1 equiv), Cs ₂ CO ₃ (2.3 g, 7.0 mmol, 3.0 equiv) in THF (10 mL) and H ₂ O (4 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 50 °C for 3 h under N2 atmosphere. The reaction mixture was partitioned between Ethyl acetate 100 mL and H ₂ O 200 mL (100 mL x 2). The organic phase was separated, washed with brine 100 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol = 50/1 to 20/1) to give the tert-butyl 8-[4-[(9S)-4,5,9,13-tetramethyl-3-thia-1,8,11,12-tetrazatric yclo[8.3.0.02,6] trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]-2-azaspiro[4.4]n onane-2-carboxylate (340 mg, 586 μmol, 25% yield) as a white solid. [0436] Step 5: Preparation of tert-butyl 8-[4-[(9S)-4,5,9,13-tetramethyl-3-thia- 1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-7-yl]phenyl]-2- azaspiro[4.4] nonane-2-carboxylate. The residue was purified by SFC (P1 = 80 mg, Rt = 1.085 min) (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [CO ₂ - ACN/MeOH(0.1% NH3H2O)];B%:50%, isocratic elution mode) to give the tert-butyl 8-[4- [(9S)-4,5,9,13-tetramethyl-3-thia-1,8,11,12-tetrazatricyclo[ 8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-7-yl]phenyl]-2-azaspiro[4.4]nonane-2-carboxylate (80 mg, 144 μmol, 23% yield) as a yellow solid. [0437] Step 6: Preparation of (9S)-7-[4-(2-azaspiro[4.4]nonan-8-yl)phenyl]-4,5,9,13- tetramethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trid eca-2(6),4,7,10,12-pentaene. To a solution of tert-butyl 8-[4-[(9S)-4,5,9,13-tetramethyl-3-thia-1,8,11,12-tetrazatric yclo [8.3.0.02,6] trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]-2-azaspiro[4.4]n onane-2-carboxylate (80 mg, 147 μmol, 1.0 equiv) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give the (9S)-7-[4-(2-azaspiro[4.4]nonan-8-yl)phenyl]-4,5,9,13-tetram ethyl-3-thia-1,8,11,12- tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaene (65 mg, 147 μmol, 100% yield) as a yellow oil. [0438] Step 7: Preparation of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[8-[4- [(9S)-4,5,9,13-tetramethyl-3-thia-1,8,11,12-tetrazatricyclo[ 8.3.0.02,6]trideca-2(6),4,7, 10,12-pentaen-7-yl]phenyl]-2-azaspiro[4.4]nonan-2-yl]pyridaz ine-3-carboxamide (I-821). A mixture of (9S)-7-[4-(2-azaspiro[4.4]nonan-8-yl)phenyl]-4,5,9,13-tetram ethyl-3-thia- 1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaene (92 mg, 206 μmol, 1.0 equiv), 6-chloro-N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]pyridazin e-3-carboxamide (97 mg, 248 μmol, 1.2 equiv), DIEA (53 mg, 413 μmol, 72 μL, 2.0 equiv) in NMP (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 70 °C for 12 h under N ₂ atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:63%-83% B over 10 min) to give the N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[8-[4-[(9S)-4,5 ,9,13-tetramethyl-3- thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,1 0,12-pentaen-7-yl]phenyl]-2- azaspiro[4.4]nonan-2-yl]pyridazine-3-carboxamide (88 mg, 107 μmol, 52% yield) as a yellow solid. ¹ H NMR: (400 MHz, DMSO-d6) δ = 8.50 (d, J = 8.4 Hz, 1H), 7.89 - 7.78 (m, 2H), 7.40 - 7.29 (m, 5H), 7.18 - 7.07 (m, 1H), 6.99 - 6.88 (m, 1H), 4.59 - 4.47 (m, 1H), 4.26 - 4.13 (m, 1H), 3.91 - 3.74 (m, 2H), 2.59 (s, 3H), 2.39 (s, 3H), 2.19 - 2.05 (m, 5H), 2.02 - 1.97 (m, 2H), 1.95 - 1.81 (m, 7H), 1.78 - 1.67 (m, 4H), 1.66 - 1.48 (m, 8H). LC-MS: MS (ES ⁺ ): RT = 2.038 min, m/z = 800.5 [M + H ⁺ ], LCMS Method: 25. EXAMPLE 17 – Synthesis of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[8-[4-[(9S)- 4,5,9,13-tetramethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0. 02,6]trideca-2(6),4,7,10,12- pentaen-7-yl]phenyl]-2-azaspiro[4.4]nonan-2-yl]pyridazine-3- carboxamide (I-822) I-822 [0439] Step 1: Preparation of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[8-[4- [(9S)-4,5,9,13-tetramethyl-3-thia-1,8,11,12-tetrazatricyclo[ 8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-7-yl]phenyl]-2-azaspiro[4.4]nonan-2-y l]pyridazine-3-carboxamide. To A mixture of (9S)-7-[4-(2-azaspiro[4.4]nonan-8-yl)phenyl]-4,5,9,13-tetram ethyl-3-thia- 1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaene (34 mg, 76 μmol, 1.0 equiv), 6-chloro-N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]pyridazin e-3-carboxamide (36 mg, 92 μmol, 1.2 equiv), DIEA (20 mg, 153 μmol, 27 μL, 2.0 equiv) in NMP (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 70 °C for 12 h under N ₂ atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:63%-83% B over 10 min) to give the N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[8-[4-[(9S)-4,5 ,9,13-tetramethyl-3- thia-1,8,11,12-tetrazatricyclo [8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]-2- azaspiro[4.4]nonan-2-yl]pyridazine-3-carboxamide (9 mg, 10 μmol, 14% yield) as a yellow solid. ¹ H NMR: (400 MHz, DMSO-d6) δ = 8.54 - 8.48 (m, 1H), 7.88 - 7.81 (m, 2H), 7.39 - 7.31 (m, 5H), 7.16 - 7.10 (m, 1H), 6.99 - 6.93 (m, 1H), 4.60 - 4.49 (m, 1H), 4.25 - 4.18 (m, 1H), 3.90 - 3.80 (m, 2H), 2.59 (s, 3H), 2.40 (s, 3H), 2.14 - 2.00 (m, 7H), 1.95 - 1.84 (m, 7H), 1.79 - 1.73 (m, 2H), 1.70 - 1.48 (m, 10H). LC-MS: MS (ES ⁺ ): RT = 2.033 min, m/z = 800.5 [M + H ⁺ ], LCMS Method: 25. EXAMPLE 18 – Synthesis of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[8-[4-[(9S)- 4,5,9,13-tetramethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0. 02,6]trideca-2(6),4,7,10,12- pentaen-7-yl]phenyl]-2-azaspiro[4.4]nonan-2-yl]pyridazine-3- carboxamide (I-823) I-823 [0440] Step 1: Preparation of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[8-[4- [(9S)-4,5,9,13-tetramethyl-3-thia-1,8,11,12-tetrazatricyclo[ 8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-7-yl]phenyl]-2-azaspiro[4.4]nonan-2-y l]pyridazine-3-carboxamide. A mixture of (9S)-7-[4-(2-azaspiro[4.4]nonan-8-yl)phenyl]-4,5,9,13-tetram ethyl-3-thia- 1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaene (96 mg, 215 μmol, 1.0 equiv), 6-chloro-N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]pyridazin e-3-carboxamide (101 mg, 259 μmol, 1.2 equiv), DIEA (56 mg, 431 μmol, 75 μL, 2.0 equiv) in NMP (2 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 70 °C for 12 h under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:63%-83% B over 10 min) to give the N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[8-[4-[(9S)-4,5 ,9,13-tetramethyl-3- thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,1 0,12-pentaen-7-yl]phenyl]-2- azaspiro[4.4]nonan-2-yl]pyridazine-3-carboxamide (75 mg, 91 μmol, 42% yield) as a yellow solid. ¹ H NMR: (400 MHz, DMSO-d6) δ = 8.50 (d, J = 8.0 Hz, 1H), 7.87 - 7.79 (m, 2H), 7.39 - 7.30 (m, 5H), 7.17 - 7.10 (m, 1H), 6.94 (d, J = 9.6 Hz, 1H), 4.60 - 4.48 (m, 1H), 4.26 - 4.16 (m, 1H), 3.91 - 3.70 (m, 2H), 2.59 (s, 3H), 2.39 (s, 3H), 2.20 - 2.06 (m, 5H), 2.03 - 1.97 (m, 2H), 1.95 - 1.83 (m, 7H), 1.77 - 1.66 (m, 4H), 1.66 - 1.48 (m, 8H). LC-MS: MS (ES ⁺ ): RT = 2.035 min, m/z = 800.5 [M + H ⁺ ], LCMS Method: 25. EXAMPLE 19 – Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(8-(4- ((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][ 1,2,4]triazolo[4,3-a][1,4] diazepin-4-yl)phenyl)-2-azaspiro[4.5]decan-2-yl)pyridazine-3 -carboxamide (I-824) [0441] Step 1: Preparation of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia- 1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-9-yl]acetic acid. To a solution of tert-butyl 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12 - tetrazatricyclo [8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]acetate (1.0 g, 2.1 mmol, 1.0 equiv) in DCM (10 mL) was added TFA (7.7 g, 67 mmol, 5.0 mL, 30 equiv). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was used for next step directly to give compound 2- [(9S)-7-(4-chloro phenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8. 3.0.0 ^2,6 ]trideca- 2(6),4,7,10,12-pentaen-9-yl]acetic acid (877 mg, 99% yield). [0442] Step 2: Preparation of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia- 1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-9-yl]acetamide. To a solution of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12 -tetrazatricyclo [8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (877 mg, 2.19 mmol, 1.0 equiv) and NH4Cl (351 mg, 6.56 mmol, 3.0 equiv) in DMF (8 mL) was added HATU (915 mg, 2.41 mmol, 1.1 equiv) and DIEA (848 mg, 6.56 mmol, 3.0 equiv). The mixture was stirred at 25 °C for 1 h. The mixture was filtered and concentrated. The residue was purified by prep-HPLC (column: Waters Xbridge C18150*50mm* 10um;mobile phase: [water( NH4HCO3)-ACN];B%: 24%- 54%,10min) to give 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12 - tetrazatricyclo [8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide (740 mg, 84% yield). [0443] Step 3: Preparation of 2-[[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia- 1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-9-yl]methyl]oxazole. To a solution of 1,3-dioxol-2-one (103 mg, 1.20 mmol, 1.2 equiv) and 2-[(9S)-7-(4-chlorophenyl)- 4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9- yl]acetamide (400 mg, 1.00 mmol, 1.0 equiv) in PPA (4 mL). The mixture was stirred at 160 °C for 3 h. The mixture was quenched by addition H ₂ O 50 mL at 0°C, and then diluted with EA 200 mL. The mixture was extracted with H2O (15 mL * 2). The combined organic layers were washed with H ₂ O (10 mL * 3), dried over [Na ₂ SO ₄ ], filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=2/1 to 0/1) to give compound 2-[[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,1 2- tetrazatricyclo [8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (260 mg, 61% yield). [0444] Step 4: Preparation of tert-butyl 8-hydroxy-2-azaspiro[4.5]decane-2- carboxylate. To a solution of tert-butyl 8-oxo-2-azaspiro[4.5]decane-2-carboxylate (2 g, 7.8 mmol, 1 equiv) in DCM (20 mL) was added NaBH ₄ (400 mg, 10 mmol, 1.3 equiv).The mixture was stirred at 20 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. After filtration, the filtrate was concentrated to afford crude product tert-butyl 8-hydroxy-2-azaspiro[4.5]decane-2-carboxylate. [0445] Step 5: Preparation of tert-butyl 8-iodo-2-azaspiro[4.5]decane-2-carboxylate. To a solution of tert-butyl 8-hydroxy-2-azaspiro[4.5]decane-2-carboxylate (2 g, 7.8 mmol, 1 equiv) in DCM (20 mL) was added PPh ₃ (2.8 g, 10 mmol, 1.4 equiv) and imidazole (1.6 g, 23 mmol, 3 equiv) and I2 (2.9 g, 11 mmol, 2 mL, 1.5 equiv) .The mixture was stirred at 40 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Then purified by prep-TLC (SiO2, EA: PE = 5: 1) to afford compound tert-butyl 8- iodo-2-azaspiro[4.5]decane-2-carboxylate (2 g, 69 % yield) as a white oil. [0446] Step 6: Preparation of (2-tert-butoxycarbonyl-2-azaspiro[4.5]decan-8-yl)-iodo- zinc. To a stirring solution of Zn (830 mg, 12 mmol, 5.8 equiv) in DMAC (2 mL) was added TMSCl (88 mg, 810 μmol, 102 μL, 0.37 equiv) and 1,2-dibromoethane (152 mg, 810 μmol, 61 μL, 0.37 equiv) in DMAC (1 mL) at 40 °C. After stirring for 30 min, tert-butyl 8- iodo-2-azaspiro[4.5]decane-2-carboxylate (800 mg, 2 mmol, 1 equiv) was added. The mixture was stirred at 40 °C for another 1 h, after filtration, the filtrate was concentrated to afford crude product (2-tert-butoxycarbonyl-2-azaspiro[4.5]decan-8-yl)-iodo-zinc. [0447] Step 7: Preparation of tert-butyl (S)-8-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)- 6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)phe nyl)-2-azaspiro[4.5]decane-2- carboxylate. To a solution of (2-tert-butoxycarbonyl-2-azaspiro[4.5]decan-8-yl)-iodo-zinc (3.50 g, 8 mmol, 3.5 equiv), 2-[[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,1 2- tetrazatricyclo[8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (984 mg, 2 mmol, 1 equiv) in THF (10 mL) was added dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl] phosphane;methanesulfonate;(2-phenylanilino)palladium(1+) (362 mg, 464 μmol, 0.2 equiv). The mixture was stirred at 70 °C for 3 h. The reaction mixture was partitioned between EA 20 mL. The organic phase was separated, washed with H ₂ O 5 mL (5 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex luna C18150 * 25 mm* 10 um; mobile phase: [water (FA)- ACN]; gradient: 63 %-93 % B over 10 min) to give tert-butyl (S)-8-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3, 2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-4-yl)phenyl)-2-azaspiro[4.5]decane-2-carboxy late (1 g, 68.70% yield). [0448] Step 8: Preparation of tert-butyl (S)-8-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)- 6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)phe nyl)-2-azaspiro[4.5]decane-2- carboxylate. The compound tert-butyl (S)-8-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H- thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)phenyl )-2-azaspiro[4.5]decane-2- carboxylate was by SFC. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by SFC (column: DAICEL CHIRALPAK IK (250 mm* 30 mm, 10 um); mobile phase: [CO2- ACN/ EtOH (0.1 % NH3H2O)]; B %:55 %, isocratic elution mode) and was purified by SFC (column: DAICEL CHIRALPAK AD (250 mm* 30 mm, 10 um); mobile phase: [CO2 –CAN/ i-PrOH (0.1 % NH3H2O)]; B %: 60 %, isocratic elution mode) to give compound tert-butyl (S)-8-(4-(2,3,9-trimethyl-6-(oxazol-2- ylmethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepi n-4-yl)phenyl)-2-azaspiro [4.5]decane-2-carboxylate (400 mg, 36 % yield). [0449] Step 9: Preparation of (S)-2-((4-(4-(2-azaspiro[4.5]decan-8-yl)phenyl)-2,3,9- trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepi n-6-yl)methyl)oxazole. To a solution of tert-butyl (S)-8-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3, 2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)phenyl)-2-azaspir o[4.5]decane-2-carboxylate (180 mg, 287 μmol, 1 equiv) in DCM (2 mL) was added TFA (98 mg, 861 μmol, 63 μL, 3 equiv). The mixture was stirred at 25 °C for 0.5 h . The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude compound (S)-2-((4-(4-(2- azaspiro[4.5]decan-8-yl)phenyl)-2,3,9-trimethyl-6H-thieno[3, 2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-6-yl)methyl) oxazole (150 mg) was used into the next step without further purification. [0450] Step 10: Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6- (8-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3 ,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-4-yl)phenyl)-2-azaspiro[4.5]decan-2-yl)pyrid azine-3-carboxamide (I-824). To a solution of 6-chloro-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)py ridazine-3- carboxamide (46 mg, 119 μmol, 1.05 equiv), (S)-2-((4-(4-(2-azaspiro[4.5]decan-8-yl)phenyl)- 2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]d iazepin-6-yl)methyl)oxazole (60 mg, 113 μmol, 1 equiv) in NMP (1 mL) was added DIEA (44 mg, 341 μmol, 59 μL, 3 equiv). The mixture was stirred at 70 °C for 12 h . The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex luna C18150* 25 mm* 10 um; mobile phase: [water (FA)- ACN]; gradient: 62 %-92 % B over 10 min) to give compound N-((1r,4r)-4-(3-chloro- 4-cyano phenoxy)cyclohexyl)-6-(8-(4-((S)-2,3,9-trimethyl-6-(oxazol-2 -ylmethyl)-6H- thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)phenyl )-2-azaspiro[4.5]decan-2- yl)pyridazine-3-carboxamide (40 mg, 40 % yield). ¹ H NMR: (400 MHz, METHANOL-d ₄ ) δ ppm 1.68 - 1.62 (m, 9 H) 1.91 - 1.80 (m, 4 H) 1.97 (m, 2 H) 2.15 - 2.07 (m, 2 H) 2.21 (m, 2 H) 2.47 (s, 3 H) 2.73 (s, 3 H) 3.33 (m, 4 H) 3.58 - 3.69 (m, 3 H) 4.08 – 3.94 (m, 3 H) 4.57 - 4.48 (m, 1 H) 4.79 (m, 1 H) 7.16 - 7.03 (m, 3 H) 7.21 (d, J=2.36 Hz, 1 H) 7.32 (m, , 4 H) 7.70 (d, J=8.72Hz, 1 H) 7.98 - 7.90 (m, 2 H). QC-LCMS: MS (ES ⁺ ): RT =2.281 min, m/z =881.6 [M+H ⁺ ], LCMS Method: 25. EXAMPLE 20 – Synthesis of 6-[(3aR,6aS)-2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2- ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]tridec a-2(6),4,7,10,12-pentaen-7- yl]phenyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl] -N-[4-(3-chloro-4-cyano- phenoxy)cyclohexyl]pyridazine-3-carboxamide (I-825)

I-825 [0451] Step 1: Preparation of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia- 1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-9-yl]acetic acid. To a solution of tert-butyl 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12 - tetrazatricyclo[8.3.0.0 ^2,6 ] trideca-2(6),4,7,10,12-pentaen-9-yl]acetate (1.0 g, 2.1 mmol, 1.0 equiv) in DCM (10 mL) was added TFA (7.7 g, 67 mmol, 5.0 mL, 30 equiv). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was used for next step directly to give compound 2- [(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-t etrazatricyclo[8.3.0.0 ^2,6 ]trideca- 2(6),4,7,10,12-pentaen-9-yl]acetic acid (877 mg, 99% yield). [0452] Step 2: Preparation of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia- 1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-9-yl]acetamide. To a solution of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12 -tetrazatricyclo [8.3.0.0 ^2,6 ] trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (877 mg, 2.19 mmol, 1.0 equiv) and NH ₄ Cl (351 mg, 6.56 mmol, 3.0 equiv) in DMF (8 mL) was added HATU (915 mg, 2.41 mmol, 1.1 equiv) and DIEA (848 mg, 6.56 mmol, 3.0 equiv). The mixture was stirred at 25 °C for 1 h. The mixture was filtered and concentrated. The residue was purified by prep-HPLC (column: Waters Xbridge C18150*50mm* 10um;mobile phase: [water( NH4HCO3)-ACN];B%: 24%- 54%,10min) to give 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12 - tetrazatricyclo [8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide (740 mg, 84% yield). [0453] Step 3: Preparation of 2-[[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia- 1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-9-yl]methyl]oxazole. To a solution of 1,3-dioxol-2-one (103 mg, 1.20 mmol, 1.2 equiv) and 2-[(9S)-7-(4-chlorophenyl)- 4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9- yl]acetamide (400 mg, 1.00 mmol, 1.0 equiv) in PPA (4 mL). The mixture was stirred at 160 °C for 3 h. The mixture was quenched by addition H2O 50 mL at 0°C, and then diluted with EA 200 mL. The mixture was extracted with H2O (15 mL * 2). The combined organic layers were washed with H2O (10 mL * 3), dried over [Na2SO4], filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=2/1 to 0/1) to give compound 2-[[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,1 2- tetrazatricyclo [8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (260 mg, 61% yield). [0454] Step 4: Preparation of 2-[[(9S)-4,5,13-trimethyl-7-[4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]-3-thia-1,8,11,12-tetrazatricyclo[8 .3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole. A mixture of 2-[[(9S)-7-(4-chlorophenyl)- 4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6 ]trideca-2(6),4,7,10,12-pentaen-9- yl]methyl]oxazole (3.0 g, 7.0 mmol, 1.0 equiv), BPD (5.4 g, 21.2 mmol, 3.0 equiv), dichloropalladium; tricyclohexylphosphane (1.0 g, 1.4 mmol, 0.2 equiv) and KOAc (1.5 g, 15.6 mmol, 2.2 equiv) in THF (60 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 70 °C for 12 h under N2 atmosphere. The reaction mixture was poured into 100 mL of EtOAc. The crude mixture was filtered through a pad of celatom ^® and was poured onto H2O 100 ml. The organic phase was separated, washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (Silicon dioxide, Dichloromethane : Methanol = 20:1) to give the 2-[[(9S)-4,5,13-trimethyl-7-[4-(4,4,5,5-tetramethyl-1,3,2-di oxaborolan-2- yl)phenyl]-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]tride ca-2(6),4,7,10,12-pentaen-9- yl]methyl]oxazole (1.2 g, 2.3 mmol, 33 % yield) as a brown oil. [0455] Step 5: Preparation of [4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia- 1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-7-yl]phenyl]boronic acid. To a solution of 2-[[(9S)-4,5,13-trimethyl-7-[4-(4,4,5,5-tetramethyl-1,3,2-di oxaborolan- 2-yl)phenyl]-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]tri deca-2(6),4,7,10,12-pentaen-9- yl]methyl]oxazole (1 g, 1.94 mmol, 1.0 equiv) in Acetone (12 mL) and H ₂ O (12 mL) was added NH ₄ OAc (748 mg, 9.70 mmol, 5.0 equiv) and NaIO ₄ (2.07 g, 9.70 mmol, 5.0 equiv). The mixture was stirred at 25 °C for 12h. The reaction mixture was quenched by Na ₂ SO ₃ (30 ml) at 0 °C. To the reaction mixture was added water (50 mL) and the mixture was extracted with EtOAc (50 mL). The combined organic phase was washed with brine (50 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated to give [4-[(9S)-4,5,13-trimethyl-9-(oxazol-2- ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]tridec a-2(6),4,7,10,12-pentaen-7- yl]phenyl]boronic acid (500 mg, 59% yield) as a yellow solid. [0456] Step 6: Preparation of tert-butyl (3aR,6aS)-2-[4-[(9S)-4,5,13-trimethyl-9- (oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0 2,6]trideca-2(6),4,7,10,12- pentaen-7-yl]phenyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]py rrole-5-carboxylate. To a solution of [4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,1 1,12-tetrazatricyclo [8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]boronic acid (300 mg, 692 μmol, 1 equiv) in DCM (8 mL) was added TEA (350 mg, 3.46 mmol, 5 equiv), Cu(OAc) ₂ (252 mg, 1.38 mmol, 2 eq), tert-butyl (3aR,6aS)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5 - carboxylate (441 mg, 2.08 mmol, 3 equiv) and 4A MS. The mixture was stirred at 20 °C for 12 h. The residue was purified by prep-TLC (SiO ₂ , DCM: MeOH = 10:1) to give tert-butyl (3aR,6aS)-2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)- 3-thia-1,8,11,12- tetrazatricyclo[8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]-1,3,3a,4, 6,6a- hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (270 mg, 65 % yield) as a white solid. [0457] Step 7: Preparation of 2-[[(9S)-7-[4-[(3aR,6aS)-2,3,3a,4,6,6a-hexahydro-1H- pyrrolo[3,4-c]pyrrol-5-yl]phenyl]-4,5,13-trimethyl-3-thia-1, 8,11,12-tetrazatricyclo [8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazo le. To a solution of tert-butyl (3aR,6aS)-2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)- 3-thia-1,8,11,12-tetrazatricyclo [8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]-1,3,3a,4, 6,6a-hexahydropyrrolo[3,4- c]pyrrole-5-carboxylate (100 mg, 167 μmol, 1 equiv) in DCM (2 mL) was added TFA (1mL). The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was filtered and concentrated under reduced pressure to give crude product 2-[[(9S)-7-[4-[(3aR,6aS)-2,3,3a,4,6,6a- hexahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl]phenyl]-4,5,13-trimet hyl-3-thia-1,8,11,12- tetrazatricyclo [8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (166 mg) as a yellow oil. [0458] Step 8: Preparation of 6-[(3aR,6aS)-2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2- ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]tridec a-2(6),4,7,10,12-pentaen-7- yl]phenyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl] -N-[4-(3-chloro-4-cyano- phenoxy)cyclohexyl]pyridazine-3-carboxamide (I-825). To a solution of 2-[[(9S)-7-[4- [(3aR,6aS)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5 -yl]phenyl]-4,5,13-trimethyl-3- thia-1,8,11,12-tetrazatricyclo[8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (83 mg, 166 μmol, 1 equiv) in NMP (1 mL) was added DIEA (64 mg, 498 μmol, 3 equiv) and 6- chloro-N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]pyridazine- 3-carboxamide (72 mg, 183 μmol, 1.1 equiv). The mixture was stirred at 70 °C for 12 h. The residue was purified by prep- HPLC (column: Waters xbridge 150*25mm 10um; mobile phase: [water( NH4HCO3) - ACN]; gradient: 52 % - 72 % B over 8 min) to give 6-[(3aR,6aS)-2-[4-[(9S)-4,5,13-trimethyl-9- (oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0 ^2,6 ]trideca-2(6),4,7,10,12-pentaen- 7-yl] phenyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-N- [4-(3-chloro-4-cyano- phenoxy) cyclohexyl]pyridazine-3-carboxamide (36 mg, 24 % yield) as a white solid. ¹ HNMR (400 MHz, CDCl3) δ ppm 8.01 (d, J=9.36 Hz, 1 H), 7.88 (d, J=8.00 Hz, 1 H), 7.62 (s, 1 H), 7.56 (d, J=8.76 Hz, 1 H), 7.31 (d, J=8.24 Hz, 2 H), 7.00 - 7.04 (m, 2 H), 6.84 - 6.87 (m, 1 H), 6.72 (d, J=9.36 Hz, 1 H), 6.47 (d, J=8.88 Hz, 2 H), 4.65 - 4.71 (m, 1 H), 4.29 - 4.38 (m, 1 H), 3.89 - 4.14 (m, 5 H), 3.55 - 3.73 (m, 4 H), 3.22 - 3.37 (m, 4 H), 2.61 - 2.69 (m, 3 H), 2.41 (s, 3 H), 2.12 - 2.22 (m, 4 H), 1.75 (s, 4 H), 1.42 - 1.53 (m, 3 H). LC-MS: MS (ES ⁺ ): RT = 2.082 min, m/z = 854.4 [M + H ⁺ ]; LCMS Method: 10. EXAMPLE 21 – Synthesis of 6-[(3aS,6aR)-3a,6a-dimethyl-2-[4-[(9S)-4,5,13-trimethyl-9- (oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0 2,6]trideca-2(6),4,7,10,12- pentaen-7-yl]phenyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrol- 5-yl]-N-[4-(3-chloro-4-cyano- phenoxy)cyclohexyl]pyridazine-3-carboxamide (I-826) [0459] Step 1: Preparation of tert-butyl (3aS,6aR)-3a,6a-dimethyl-2-[4-[(9S)-4,5,13- trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatric yclo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-7-yl]phenyl]-1,3,4,6-tetrahydropyrrol o[3,4-c]pyrrole-5- carboxylate. To a solution of [4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia- 1,8,11,12-tetrazatricyclo [8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]boron ic acid (300 mg, 692 μmol, 1 equiv) and tert-butyl (3aS,6aR)-3a,6a-dimethyl-2,3,4,6-tetrahydro-1H- pyrrolo[3,4-c]pyrrole-5-carboxylate (230 mg, 956 μmol, 1.3 equiv) and TEA (350 mg, 3 mmol, 481 μL, 5 equiv) and Cu(OAc) ₂ (251 mg, 1.38 mmol, 2 equiv) in DCM (6 mL) was added O ₂ (692.38 μmol, 1 eq) and 4A MS (692 μmol, 1 equiv). The mixture was stirred at 25 °C for 12 h. The residue was purified by prep-HPLC (column: Waters Xbridge C18150*50mm* 10um;mobile phase: [water( NH4HCO3)-ACN]; gradient:47%-77% B over 10 min) to afford compound tert-butyl (3aS,6aR)-3a,6a-dimethyl-2-[4-[(9S)-4,5,13-trimethyl-9-(oxaz ol-2- ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]tridec a-2(6),4,7,10,12-pentaen-7- yl]phenyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxy late (120 mg, 27 % yield) as a yellow solid. [0460] Step 2: Preparation of 2-[[(9S)-7-[4-[(3aR,6aS)-3a,6a-dimethyl-2,3,4,6- tetrahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl]phenyl]-4,5,13-trime thyl-3-thia-1,8,11,12- tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9- yl]methyl]oxazole. To a solution of tert-butyl (3aS,6aR)-3a,6a-dimethyl-2-[4-[(9S)-4,5,13-trimethyl-9-(oxaz ol-2- ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]tridec a-2(6),4,7,10,12-pentaen-7- yl]phenyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxy late (100 mg, 159 μmol, 1 equiv) in DCM (3 mL) was added TFA (18 mg, 159 μmol, 11 μL, 1 equiv).The mixture was stirred at 25 °C for 30 min. After filtration, the filtrate was concentrated to afford crude product 2-[[(9S)-7-[4-[(3aR,6aS)-3a,6a-dimethyl-2,3,4,6-tetrahydro-1 H-pyrrolo[3,4-c]pyrrol-5- yl]phenyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo [8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-9-yl]methyl]oxazole. [0461] Step 3: Preparation of 6-[(3aS,6aR)-3a,6a-dimethyl-2-[4-[(9S)-4,5,13-trimethyl- 9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo[8.3.0 .02,6]trideca-2(6),4,7,10,12- pentaen-7-yl]phenyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrol- 5-yl]-N-[4-(3-chloro-4-cyano- phenoxy)cyclohexyl]pyridazine-3-carboxamide (I-826). To a solution of 2-[[(9S)-7-[4- [(3aR,6aS)-3a,6a-dimethyl-2,3,4,6-tetrahydro-1H-pyrrolo[3,4- c]pyrrol-5-yl]phenyl]-4,5,13- trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]tridec a-2(6),4,7,10,12-pentaen-9- yl]methyl]oxazole (40 mg, 75 μmol, 1 equiv) and 6-chloro-N-[4-(3-chloro-4-cyano-phenoxy) cyclohexyl]pyridazine-3-carboxamide (31 mg, 79 μmol, 1.05 equiv) in NMP (1 mL) was added DIEA (29 mg, 227 μmol, 39 μL, 3 equiv).The mixture was stirred at 70 °C for 12 h. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water( NH4HCO3)-ACN];gradient:48%-68% B over 10 min) to afford compound 6- [(3aS,6aR)-3a,6a-dimethyl-2-[4-[(9S)-4,5,13-trimethyl-9-(oxa zol-2-ylmethyl)-3-thia-1,8,11,12- tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7- yl]phenyl]-1,3,4,6- tetrahydropyrrolo [3,4-c]pyrrol-5-yl]-N-[4-(3-chloro-4-cyano-phenoxy)cyclohexy l]pyridazine- 3-carboxamide (11 mg, 15 % yield) as a yellow solid. ¹ H NMR (METHANOL-d4, 400 MHz) δ 8.0-7.9 (m, 2H), 7.7 (d, 1H, J=8.8 Hz), 7.3-7.2 (m, 3H), 7.1 (s, 1H), 7.0 (d, 1H, J=2.4, 8.8 Hz), 7.0 (d, 1H, J=9.6 Hz), 6.5 (d, 2H, J=9.2 Hz), 4.7 (d, 1H, J=6.5, 8.0 Hz), 4.6-4.5 (m, 2H), 4.0-3.9 (m, 3H), 3.9-3.7 (m, 2H), 3.7-3.6 (m, 2H), 3.5 (d, 2H, J=10.4 Hz), 3.4 (d, 2H, J=10 Hz), 2.7 (s, 3H), 2.4 (s, 3H), 2.2 (s, 2H), 2.1 (d, 2H, J=4.0 Hz), 1.7 (s, 3H), 1.7-1.6 (m, 3H), 1.3 (s, 5H), 1.2-1.2 (m, 1H). LC-MS: MS (ES+): RT = 1.842 min, m/z =882.6 [M]; LCMS Method: 10. EXAMPLE 22 – Synthesis of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[9-[4-[(9S)- 4,5,9,13-tetramethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0. 02,6]trideca-2(6),4,7,10,12- pentaen-7-yl]phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-2-yl]pyr idazine-3-carboxamide (I- 827)

[0462] Step 1: Preparation of tert-butyl 3-[[(2-chloroacetyl)amino]methyl]-3-hydroxy- pyrrolidine-1-carboxylate. To a solution of K ₂ CO ₃ (1.60 g, 11.6 mmol, 2.0 equiv) in H ₂ O (8 mL)was added tert-butyl 3-(aminomethyl)-3-hydroxy-pyrrolidine-1-carboxylate (1.25 g, 5.78 mmol, 1.0 equiv) in EtOAc (8 mL)at 0 °C, then added 2-chloroacetyl chloride (816 mg, 7.22 mmol, 575 μL, 1.3 equiv) slowly, the mixture was stirred at 25°C for 12h. The reaction mixture was quenched by addition H2O 10 mL at 0 °C, and then diluted with Ethyl acetate 50 mL and extracted with Ethyl acetate 150 mL (50 mL x 3). The combined organic layers were washed with H2O 60 mL (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/1 to 1/1) to give compound tert-butyl 3-[[(2-chloroacetyl) amino]methyl]-3-hydroxy-pyrrolidine-1-carboxylate (1.60 g, 5.47 mmol, 94 % yield) as a colorless oil. [0463] Step 2: Preparation of tert-butyl 8-oxo-6-oxa-2,9-diazaspiro[4.5]decane-2- carboxylate. To a solution of tert-butyl 3-[[(2-chloroacetyl)amino]methyl]-3-hydroxy- pyrrolidine-1-carboxylate (1.6 g, 5.5 mmol, 1.0 equiv) in IPA (15 mL) was added t-BuOK (1 M, 55 mL, 10 equiv). The mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by addition of H2O (20 mL) at 0 °C, and then diluted with Ethyl acetate (50 mL) and extracted with Ethyl acetate (20 mL x 3). The combined organic layers were washed with H2O (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=3/1 to 1/2) to give tert-butyl 8-oxo-6-oxa-2,9-diazaspiro[4.5]decane-2- carboxylate (1.3 g, 5.1 mmol, 93% yield) as a white solid. [0464] Step 3: Preparation of tert-butyl 6-oxa-2,9-diazaspiro[4.5]decane-2-carboxylate. To a solution of tert-butyl 8-oxo-6-oxa-2,9-diazaspiro[4.5]decane-2-carboxylate (600 mg, 2.34 mmol, 1.0 equiv) in THF (6 mL) was added BH3.THF (1 M, 9.36 mL, 4.0 equiv) at 0 °C. The mixture was stirred at 55 °C for 2 h. The reaction mixture was quenched slowly by addition of MeOH (10 mL) dropwise at 0°C. The reaction mixture was concentrated under reduced pressure to remove THF, and then MeOH (10 mL) and N,N,N',N'-tetramethylethane-1,2- diamine (1.09 g, 9.36 mmol, 1.41 mL, 4.0 equiv)was added. The mixture was stirred at 70 °C for 6 h. Then the reaction mixture was concentrated under reduced pressure to give crude compound tert-butyl 6-oxa-2,9-diazaspiro[4.5]decane-2-carboxylate (567 mg, 2.34 mmol) as a colorless oil. [0465] Step 4: Preparation of O9-benzyl O2-tert-butyl 6-oxa-2,9- diazaspiro[4.5]decane-2,9-dicarboxylate. To a solution of tert-butyl 6-oxa-2,9- diazaspiro[4.5]decane-2-carboxylate (567 mg, 2.34 mmol, 1.0 equiv) in DCM (5 mL) was added TEA (710 mg, 7.02 mmol, 977 μL, 3.0 equiv) and benzyl carbonochloridate (479 mg, 2.81 mmol, 401μL, 1.2 equiv). The mixture was stirred at 25 °C for 8 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep- TLC (Petroleum ether: Ethyl acetate =3:1) to give compound O9-benzyl O2-tert-butyl 6-oxa- 2,9-diazaspiro[4.5]decane-2,9-dicarboxylate (500 mg, 1.33 mmol, 57% yield) as a colorless oil. [0466] Step 5: Preparation of tert-butyl 6-oxa-2,9-diazaspiro[4.5]decane-2-carboxylate. To a solution of O9-benzyl O2-tert-butyl 6-oxa-2,9-diazaspiro[4.5]decane-2,9-dicarboxylate (500 mg, 1.33 mmol, 1.0 equiv) in THF (5 mL) was added Pd/C (500 mg, 470 μmol, 10% purit) and Pd(OH) ₂ (300 mg, 213.62 μmol, 10% purity) under N ₂ atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 psi) at 25 °C for 8 h. The reaction mixture was filtered, and the filter was concentrated. Then the reaction mixture was concentrated under reduced pressure to give crude compound tert-butyl 6-oxa-2,9- diazaspiro[4.5]decane-2-carboxylate (300 mg, 1.24 mmol) as a colorless oil. [0467] Step 6: Preparation of tert-butyl 9-[4-[(9S)-4,5,9,13-tetramethyl-3-thia- 1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-7-yl]phenyl]-6-oxa-2,9- diazaspiro[4.5]decane-2-carboxylate. To a solution of tert-butyl 6-oxa-2,9-diazaspiro[4.5] decane-2-carboxylate (299 mg, 1.24 mmol, 1.1 equiv) in dioxane (3 mL) was added (9S)-7-(4- chlorophenyl)-4,5,9,13-tetramethyl-3-thia-1,8,11,12-tetrazat ricyclo[8.3.0.02,6] trideca-2(6), 4,7,10,12-pentaene (420 mg, 1.18 mmol, 1.0 equiv), SPhos Pd G3 (91.8 mg, 118 μmol, 0.1 equiv) and Cs2CO3 (767 mg, 2.35 mmol, 2.0 equiv). The mixture was stirred at 90 °C for 3 hr. The reaction mixture was filtered, and the filter was concentrated. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)- ACN];gradient:24%-54% B over 10 min) to give compound tert-butyl 9-[4-[(9S)-4,5,9,13- tetramethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trid eca-2(6),4,7,10,12-pentaen-7- yl]phenyl]-6-oxa-2,9-diazaspiro[4.5]decane-2-carboxylate (300 mg, 533 μmol, 45 % yield) as a yellow solid. [0468] Step 7: Preparation of tert-butyl 9-[4-[(9S)-4,5,9,13-tetramethyl-3-thia-1,8,11, 12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen -7-yl]phenyl]-6-oxa-2,9- diazaspiro[4.5]decane-2-carboxylate. Tert-butyl 9-[4-[(9S)-4,5,9,13-tetramethyl-3-thia- 1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-7-yl]phenyl]-6-oxa-2,9- diazaspiro[4.5]decane-2-carboxylate was purified by prep-SFC (column: DAICEL CHIRALCEL OX (250mm*30mm,10um);mobile phase: [CO2-ACN/EtOH(0.1% NH3H2O)];B%:50%, isocratic elution mode) to afford tert-butyl 9-[4-[(9S)-4,5,9,13- tetramethyl-3-thia-1,8,11,12-tetrazatricyclo [8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7- yl]phenyl]-6-oxa-2,9-diazaspiro[4.5] decane-2-carboxylate (205 mg, 364 μmol, 41 % yield) and tert-butyl 9-[4-[(9S)-4,5,9,13-tetramethyl-3-thia-1,8,11,12-tetrazatric yclo [8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]-6-ox a-2,9-diazaspiro[4.5]decane-2- carboxylate (270 mg, 480 μmol, 54 % yield) as yellow solid. [0469] Step 8: Preparation of 9-[4-[(9S)-4,5,9,13-tetramethyl-3-thia-1,8,11,12- tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7- yl]phenyl]-6-oxa-2,9- diazaspiro[4.5]decane. To a solution of tert-butyl 9-[4-[(9S)-4,5,9,13-tetramethyl-3-thia- 1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-7-yl]phenyl]-6-oxa-2,9- diazaspiro[4.5]decane-2-carboxylate (200 mg, 355 μmol, 1.0 equiv) in DCM (1 mL) was added TFA (0.5 mL) .The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated and basified with sat. NaHCO ₃ at 0°C. The mixture were extracted with DCM/MeOH (10:1, 50 mL x 2), dried over Na ₂ SO ₄ , filtered and concentrated to give compound 9-[4-[(9S)-4,5,9,13- tetramethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trid eca-2(6),4,7,10,12-pentaen-7- yl]phenyl]-6-oxa-2,9-diazaspiro[4.5]decane (160 mg, 346 μmol) as a white solid. [0470] Step 9: Preparation of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[9-[4- [(9S)-4,5,9,13-tetramethyl-3-thia-1,8,11,12-tetrazatricyclo[ 8.3.0.02,6]trideca-2(6),4,7, 10,12-pentaen-7-yl]phenyl]-6-oxa-2,9-diazaspiro[4.5]decan-2- yl]pyridazine-3- carboxamide (I-827). To a solution of 9-[4-[(9S)-4,5,9,13-tetramethyl-3-thia-1,8,11,12- tetrazatricyclo [8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]-6-ox a-2,9- diazaspiro[4.5]decane (80.0 mg, 173 μmol, 1.0 equiv) in NMP (0.5 mL) was added DIEA (67.1 mg, 519 μmol, 90.4 μL, 3.0 equiv) and 6-chloro-N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl] pyridazine-3-carboxamide (81.2 mg, 208 μmol, 1.2 equiv). The mixture was stirred at 65 °C for 12 h. The reaction mixture was diluted with H2O (5 mL). After filtered, the filter cake was triturated with THF (0.5 mL) at 25 ^o C for 1 h to afford compound N-[4-(3-chloro-4-cyano- phenoxy)cyclohexyl]-6-[9-[4-[(9S)-4,5,9,13-tetramethyl-3-thi a-1,8,11,12-tetrazatricyclo [8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]-6-ox a-2,9-diazaspiro[4.5]decan-2- yl]pyridazine-3-carboxamide (46.4 mg, 56.8 μmol, 33% yield) as a white solid. ¹ H NMR (400 MHz, DMSO- d6) 8.64 - 8.47 (m, 1H), 7.89 - 7.77 (m, 2H), 7.43 - 7.28 (m, 3H), 7.19 - 7.09 (m, 1H), 7.02 - 6.92 (m, 3H), 4.60 - 4.48 (m, 1H), 4.20 - 4.11 (m, 1H), 3.95 - 3.69 (m, 6H), 3.64 - 3.55 (m, 2H), 2.70 - 2.65 (m, 1H), 2.40 - 2.37 (m, 2H), 2.35 - 2.31 (m, 1H), 2.29 - 2.22 (m, 2H), 2.20 - 2.06 (m, 4H), 1.95 - 1.82 (m, 6H), 1.73 - 1.46 (m, 9H). LC-MS: MS (ES ⁺ ): RT = 2.051 min, m/z = 817.2 [M + H ⁺ ]; LCMS Method: 10. EXAMPLE 23 – Synthesis of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[6-[2-[3- fluoro-4-[4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8, 11,12-tetrazatricyclo [8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]ethyn yl]-2-azaspiro[3.3]heptan-2- yl]pyridazine-3-carboxamide (I-828) [0471] Step 1: Preparation of 3-(4-chloro-2-fluoro-phenyl)-3-oxo-propanenitrile. To a solution of acetonitrile (9.3 g, 225.3 mmol, 11.9 mL, 1.7 equiv) in THF (200 mL) was stirred at -78°C under N ₂ protection. Then the n-BuLi (2.5 M, 106.0 mL, 2.0 equiv) was added to the mixture and stirred for 0.5 h. Then the methyl 4-chloro-2-fluoro-benzoate (25.0 g, 132.5 mmol, 1.0 equiv) in THF (20 mL) was dropwised and the mixture was stirred for 1.5 h under N ₂ protection. The reaction mixture was quenched with saturated aqueous NH4Cl (200 ml) solution at 0 °C. And the resulting mixture was extracted with ethyl acetate (100 mL x 4). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was triturated with Petroleum ether/Ethyl acetate = 20/1 at 25 ^o C for 30 min to give compound 3-(4-chloro-2-fluoro-phenyl)-3-oxo-propanenitrile (23.0 g, 116.4 mmol, 87.80% yield) as a yellow solid. [0472] Step 2: Preparation of (2-amino-4,5-dimethyl-3-thienyl)-(4-chloro-2-fluoro- phenyl)methanone. To a solution of 3-(4-chloro-2-fluoro-phenyl)-3-oxo-propanenitrile (23.0 g, 116.4 mmol, 1.0 equiv) and butan-2-one (8.4 g, 116.4 mmol, 10.4 mL, 1.0 equiv) in EtOH (200 mL) was added TEA (23.6 g, 232.8 mmol, 32.4 mL, 2.0 equiv) and S (4.4 g, 138.5 mmol, 1.2 equiv). The mixture was stirred at 50 °C for 12 h. To the reaction mixture was added water (500 mL) and the mixture was extracted with ethyl acetate (500 mL x 3). The combined organic phase was washed with brine (500 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=35/1 to 30/1) to give compound (2-amino-4,5-dimethyl-3-thienyl)-(4- chloro-2-fluoro-phenyl)methanone (10.0 g, 35.2 mmol, 30% yield) as a yellow oil. [0473] Step 3: Preparation of tert-butyl (3S)-4-[[3-(4-chloro-2-fluoro-benzoyl)-4,5- dimethyl-2-thienyl]amino]-3-(9H-fluoren-9-ylmethoxycarbonyla mino)-4-oxo-butanoate. To a solution of (2-amino-4,5-dimethyl-3-thienyl)-(4-chloro-2-fluoro-phenyl)m ethanone (8.8 g, 31.0 mmol, 1.0 equiv) and (2S)-4-tert-butoxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4 - oxo-butanoic acid (19.1 g, 46.5 mmol, 1.5 equiv) in EtOAc (40 mL) was added Py (9.8 g, 124.0 mmol, 10.0 mL, 4.0 equiv) and T ₄ P (44.7 g, 62.0 mmol, 50% purity, 2.0 equiv). The mixture was stirred at 25 °C for 12 h. The reaction mixture was added water (300 mL) and the mixture was extracted with ethyl acetate (80 mL x 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=8/1 to 6/1) to give the tert-butyl (3S)-4-[[3-(4-chloro-2-fluoro-benzoyl)-4,5-dimethyl-2-thieny l]amino]-3- (9H-fluoren-9-ylmethoxycarbonylamino)-4-oxo-butanoate (15.5 g, 22.9 mmol, 73% yield) was obtained as a yellow oil. [0474] Step 4: Preparation of tert-butyl (3S)-3-amino-4-[[3-(4-chloro-2-fluoro- benzoyl)-4,5-dimethyl-2-thienyl]amino]-4-oxo-butanoate. To a solution of tert-butyl (3S)-4- [[3-(4-chloro-2-fluoro-benzoyl)-4,5-dimethyl-2-thienyl]amino ]-3-(9H-fluoren-9-ylmethoxy- carbonylamino)-4-oxo-butanoate (14.0 g, 20.7 mmol, 1.0 equiv) in DCM (280 mL) was added Piperidine (5.3 g, 62.0 mmol, 6.1 mL, 3.0 equiv). The mixture was stirred at 25 °C for 2 h. To the reaction mixture was added water (300 mL) and the mixture was extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with brine (350 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/1 to 8/1) to give the compound tert-butyl (3S)-3-amino-4-[[3-(4-chloro-2-fluoro-benzoyl)-4,5-dimethyl- 2- thienyl]amino]-4-oxo-butanoate (9.4 g, 20.7 mmol, 99 % yield) as a yellow oil. [0475] Step 5: Preparation of tert-butyl 2-[(3S)-5-(4-chloro-2-fluoro-phenyl)-6,7- dimethyl-2-oxo-1,3-dihydrothieno[2,3-e][1,4]diazepin-3-yl]ac etate. To a solution of tert- butyl (3S)-3-amino-4-[[3-(4-chloro-2-fluoro-benzoyl)-4,5-dimethyl- 2-thienyl]amino]-4-oxo- butanoate (9.4 g, 20.6 mmol, 1.0 equiv) in EtOH (90 mL) was added AcOH (31.5 g, 524.0 mmol, 30.0 mL, 25.4 equiv). The mixture was stirred at 90 °C for 3 h. The reaction mixture was added water (100 mL) and the mixture was extracted with ethyl acetate (150 mL x 3). The combined organic phase was washed with brine (150 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=8/1 to 6/1) to give the tert-butyl 2-[(3S)-5-(4-chloro-2-fluoro- phenyl)-6,7-dimethyl-2-oxo-1,3-dihydrothieno[2,3-e][1,4]diaz epin-3-yl]acetate (8.9 g, 20.4 mmol, 98% yield) as a yellow oil. [0476] Step 6: Preparation of tert-butyl 2-[(9S)-7-(4-chloro-2-fluoro-phenyl)-4,5,13- trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]tridec a-2(6),4,7,10,12-pentaen-9- yl]acetate. The t-BuOK (1.0 M, 22.4 mL, 1.1 equiv) was added to tert-butyl 2-[(3S)-5-(4- chloro-2-fluoro-phenyl)-6,7-dimethyl-2-oxo-1,3-dihydrothieno [2,3-e][1,4]diazepin-3-yl]acetate (8.9 g, 20.4 mmol, 1.0 equiv) in THF (90 mL) at -78 °C, and stirred at 25 °C for 30 min. The reaction mixture was cooled to -78 °C. [ Chloro(phenoxy)phosphoryl]oxybenzene (6.6 g, 24.4 mmol, 5.1 mL, 1.2 equiv) was added to reaction mixture. The resulting mixture was warmed to 25 °C over 45 min. Then the acetohydrazide (2.3 g, 30.6 mmol, 1.5 equiv) was added to reaction mixture. The reaction mixture was stirred at 25°C, n-BuOH (90 mL) was added to reaction mixture and heated to 90 °C for 1h. The reaction mixture was quenched with saturated aqueous NH4Cl (100 ml) solution at 0 °C dropwise. And the resulting mixture was extracted with ethyl acetate (100 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=8/1 to 6/1) to give the tert-butyl 2-[(9S)- 7-(4-chloro-2-fluoro-phenyl)-4,5,13-trimethyl-3-thia-1,8,11, 12- tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9- yl]acetate (8.9 g, 18.74 mmol, 91% yield) as a yellow oil. [0477] Step 7: Preparation of 2-[(9S)-7-(4-chloro-2-fluoro-phenyl)-4,5,13-trimethyl-3- thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,1 0,12-pentaen-9-yl]acetic acid. To a solution of tert-butyl 2-[(9S)-7-(4-chloro-2-fluoro-phenyl)-4,5,13-trimethyl-3-thia -1,8,11,12- tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9- yl]acetate (8.9 g, 18.7 mmol, 1.0 equiv) in DCM (40 mL) was added TFA (20.0 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was used for next step directly. Compound 2-[(9S)-7-(4-chloro-2-fluoro-phenyl)- 4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6 ]trideca-2(6),4,7,10,12-pentaen-9- yl]acetic acid (7.8 g, 18.6 mmol) was obtained as a yellow oil. [0478] Step 8: Preparation of 2-[(9S)-7-(4-chloro-2-fluoro-phenyl)-4,5,13-trimethyl-3- thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,1 0,12-pentaen-9-yl]-N-(2,2- dimethoxyethyl)acetamide. To a solution of 2-[(9S)-7-(4-chloro-2-fluoro-phenyl)-4,5,13- trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]tridec a-2(6),4,7,10,12-pentaen-9-yl]acetic acid (7.8 g, 18.6 mmol, 1.0 equiv) and 2,2-dimethoxyethanamine (5.8 g, 55.8 mmol, 6.09 mL, 3.0 equiv) in DMF (70 mL) was added HATU (7.8 g, 20.5 mmol, 1.1 equiv) and DIEA (7.2 g, 55.8 mmol, 9.73 mL, 3.0 equiv). The mixture was stirred at 25 °C for 0.5 h. To the reaction mixture was added water (20 mL) and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , DCM/MeOH=40/1 to 20/1) to give 2-[(9S)-7-(4-chloro-2-fluoro- phenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8. 3.0.02,6]trideca-2(6),4,7,10,12- pentaen-9-yl]-N-(2,2-dimethoxyethyl) acetamide (6.3 g, 12.5 mmol, 66% yield) as a yellow oil. [0479] Step 9: Preparation of 2-[[(9S)-7-(4-chloro-2-fluoro-phenyl)-4,5,13-trimethyl-3- thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,1 0,12-pentaen-9- yl]methyl]oxazole. To a solution of 2-[(9S)-7-(4-chloro-2-fluoro-phenyl)-4,5,13-trimethyl-3- thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,1 0,12-pentaen-9-yl]-N-(2,2- dimethoxyethyl)acetamide (2.0 g, 3.9 mmol, 1.0 equiv) in BLAH;methanesulfonic acid (20 mL) .The mixture was stirred at 100 °C for 12 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (200 ml) solution at 0 °C dropwise. And the resulting mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , DCM: MeOH =30/1 to 20/1), The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250*70mm,10 um); mobile phase: [water (FA)-ACN]; gradient:40%-70% B over 20 min). To give the 2-[[(9S)-7-(4-chloro-2-fluoro-phenyl)-4,5,13- trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]tridec a-2(6),4,7,10,12-pentaen-9- yl]methyl]oxazole (3.0 g, 6.79 mmol, 57% yield) was obtained as a white solid. [0480] Step 10: Preparation of tert-butyl 6-[2-[3-fluoro-4-[4,5,13-trimethyl-9-(oxazol-2- ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]tridec a-2(6),4,7,10,12-pentaen-7- yl]phenyl]ethynyl]-2-azaspiro[3.3]heptane-2-carboxylate. A mixture of tert-butyl 6- ethynyl-2-azaspiro[3.3]heptane-2-carboxylate (500 mg, 2.3 mmol, 2.5 equiv), 2-[[(9S)-7-(4- chloro-2-fluoro-phenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-te trazatricyclo[8.3.0.02,6]trideca- 2(6),4,7, 10,12-pentaen-9-yl]methyl]oxazole (400 mg, 905 μmol, 1.0 equiv), [2-(2- aminophenyl) phenyl]-methylsulfonyloxy-palladium;2-(2-dicyclohexylphospha nylphenyl)- N,N-dimethyl-aniline (69 mg, 90 μmol, 0.1 equiv), Cs2CO3 (589 mg, 1.8 mmol, 2.0 equiv) in MeCN (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 2 h under N2 atmosphere. To the reaction mixture was added water (20 mL) and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*40mm* 15um; mobile phase: [water (FA)-ACN]; gradient:55%-85% B over 15 min). The residue was purified by prep-SFC(column: DAICEL CHIRALPAK AS(250mm*30mm,10um);mobile phase: [CO ₂ - MeOH];B%:50%, isocratic elution mode) to give the tert-butyl 6-[2-[3-fluoro-4-[4,5,13- trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatric yclo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-7-yl]phenyl] ethynyl]-2-azaspiro[3.3]heptane-2-carboxylate (140 mg, 223.38 μmol, 24.68% yield) was obtained as a yellow oil. And tert-butyl 6-[2-[3-fluoro-4- [4,5,13-trimethyl-9-(oxazol-2-ylmethyl) -3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-7-yl]phenyl]ethynyl]-2-azaspiro[3.3]h eptane-2-carboxylate (140 mg, 223.38 μmol, 24.68% yield) was obtained as a yellow oil. [0481] Step 11: Preparation of 2-[[7-[4-[2-(2-azaspiro[3.3]heptan-6-yl)ethynyl]-2- fluoro-phenyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatric yclo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole. To a solution of tert-butyl 6-[2-[3-fluoro-4- [4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tet razatricyclo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-7-yl]phenyl]ethynyl]-2-azaspiro[3.3]h eptane-2-carboxylate (140 mg, 223 μmol, 1.0 equiv) in DCM (3 mL) was added TFA (1.0 mL) .The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (10 ml) solution at 0 °C dropwise. And the resulting mixture was extracted with ethyl acetate (10 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was used for next step directly. Compound 2-[[7-[4-[2-(2- azaspiro[3.3]heptan-6-yl)ethynyl]-2-fluoro-phenyl]-4,5,13-tr imethyl-3-thia-1,8,11,12- tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9- yl]methyl]oxazole (120 mg, crude) was obtained as a yellow oil. [0482] Step 12: Preparation of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[6-[2-[3- fluoro-4-[4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8, 11,12-tetrazatricyclo [8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]ethyn yl]-2-azaspiro[3.3]heptan-2- yl]pyridazine-3-carboxamide (I-828). To a solution of 2-[[7-[4-[2-(2-azaspiro[3.3]heptan-6- yl)ethynyl]-2-fluoro-phenyl]-4,5,13-trimethyl-3-thia-1,8,11, 12- tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9- yl]methyl]oxazole (60 mg, 113 μmol, 1.0 equiv) and 6-chloro-N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]pyridazin e-3- carboxamide (44 mg, 113 μmol, 1.0 equiv) in NMP (1 mL) was added DIEA (29 mg, 227 μmol, 39 μL, 2.0 equiv)The mixture was stirred at 70 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um; mobile phase: [water (FA)- ACN]; gradient:57%-87% B over 10 min). Compound N-[4-(3-chloro-4-cyano- phenoxy)cyclohexyl]-6-[6-[2-[3-fluoro-4-[4,5,13-trimethyl-9- (oxazol-2-ylmethyl)-3-thia- 1,8,11,12-tetrazatricyclo [8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl] phenyl]ethynyl]-2- azaspiro[3.3]heptan-2-yl]pyridazine-3-carboxamide (35 mg, 39 μmol, 34% yield, 98.46% purity) was obtained as a white solid. ¹ H NMR: (400 MHz, DMSO-d6) δ = 8.57-5.50 (m, 1H), 8.03-7.86 (m, 1H), 7.86 - 7.80 (m, H), 7.38 - 7.30 (m, 4H), 7.29-7.20 (m, 2H), 6.85 - 6.82 (m, 1H), 4.76 - 4.73 (m, 1H), 4.56 - 4.53 (m, 2H), 4.18 - 4.12 (m, 4H), 3.88 - 3.82 (m, 4H), 2.67- 2.64 (m, 6H), 2.62-2.59 (m, 4H), 2.41 -2.38 (m, 2H), 2.11 - 1.91 (m, 2H), 1.63 - 1.60 (m, 4H), 1.60 - 1.58 (m, 2H). LC-MS: MS (ES ⁺ ): RT = 2.599 min, m/z = 881.2 [M + H ⁺ ], LCMS Method: 10. EXAMPLE 24 – Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-2- (methyl((1-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thie no[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-4-yl)phenyl)piperidin-3-yl)methyl)amino)pyri midine-5-carboxamide (I- 797) [0483] Step 1: Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-2- (methyl((1-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thie no[3,2-f][1,2,4]triazolo[4,3- a][1,4] diazepin-4-yl)phenyl)piperidin-3-yl)methyl)amino)pyrimidine- 5-carboxamide. Under protection of N2, to a solution of 2-((4-(4-bromophenyl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)methyl)oxazole (280.2 mg, 0.600 mmol, 1.00 eq) and tert-butyl methyl(piperidin-3-ylmethyl)carbamate (0.900 mmol, 1.50 eq) in Dioxane (3.0 mL) was added Cs ₂ CO ₃ (585.0 mg, 1.800 mmol, 3.00 eq), and Sphos Pd G3 (26.25 mg, 0.030 mmol, 0.050 eq). The mixture was stirred at 100 °C for 16 hrs. Spot checked by LCMS. The solution was concentrated by Speedvac. The residue was extracted with H ₂ O (3 mL x 1) and EtOAc (3 mL x 3). The organic layers were concentrated by Speedvac and purified by prep- HPLC to give tert-butyl methyl((1-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thien o[3,2- f][1,2,4]triazolo [4,3-a][1,4]diazepin-4-yl)phenyl)piperidin-3-yl)methyl)carba mate. [0484] Step 2: Synthesis of N-methyl-1-(1-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)- 6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)phe nyl)piperidin-3- yl)methanamine:To a solution of tert-butyl methyl((1-(4-(2,3,9-trimethyl-6-(oxazol-2- ylmethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepi n-4-yl)phenyl)piperidin-3- yl)methyl)carbamate in DCM (2.0 mL) was added HCl-Dioxane (2.0 mL). The mixture was shaken at 30 ^o C for 2 hrs. Spot checked by LCMS. The solution was concentrated by Speedvac. The residue N-methyl-1-(1-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-t hieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)phenyl) piperidin-3-yl)methanamine (crude) was used for the next step without further purification. [0485] Step 3: Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-2- (methyl((1-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thie no[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-4-yl)phenyl)piperidin-3-yl)methyl)amino)pyri midine-5-carboxamide: Under protection of N ₂ , to a solution of N-methyl-1-(1-(4-(2,3,9-trimethyl-6-(oxazol-2- ylmethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepi n-4-yl)phenyl)piperidin-3- yl)methanamine (0.080 mmol, 1.00 eq) and 2-chloro-N-((1r,4r)-4-(3-chloro-4- cyanophenoxy)cyclohexyl)pyrimidine-5-carboxamide (0.080 mmol, 1.00 eq) in Dioxane (1.0 mL) was added Cs ₂ CO ₃ (156.0 mg, 0.48 mmol, 6.00 eq), BrettPhos Pd G3 (3.6 mg, 0.004 mmol, 0.05 eq). The mixture was stirred at 80 °C for 16 hrs. Spot checked by LCMS. The solution was concentrated by Speedvac. The residue was extracted with H ₂ O (3 mL x 1) and EtOAc (3 mL x 3). The organic layers were concentrated by Speedvac and purified by prep- HPLC to give the title compound (7.92 mg, 0.009 mmol, 2% yield). LC-MS: MS (ES ⁺ ): RT = 2.42 min, m/z = 873.2 [M + H ⁺ ]; LCMS Method: 25. EXAMPLE 25 – Synthesis of Additional Compounds [0486] The following compounds were synthesized using procedures analogous to those described above: compounds I-200 to I-820. EXAMPLE 26 – Compound Characterization [0487] Exemplary compounds were characterized by LCMS. The characterization data is outlined in Table 2A below. TABLE 2A.

EXAMPLE 27– Assay for Binding Affinity to Androgen Receptor [0488] Exemplary compounds were tested for ability to bind to the androgen receptor. Experimental procedures and results are provided below. Part I – Experimental Procedure [0489] Fractions of cell cytosol (106 cell/point) were incubated for 24 hr at 4 °C with 1 nM [ ³ H]methyltrienolone in the absence or presence of the test compound in a buffer containing 25 mM Hepes-Tris (pH 7.4), 1 mM EDTA, 10 mM Na ₂ MoO ₄ , 2 mM DTT, 5 μM triamcinolone acetonide, and 10% glycerol. Nonspecific binding was determined in the presence of 1 μM testosterone. Following incubation, the samples were filtered rapidly under vacuum through glass fiber filters (GF/B, Packard) presoaked with 0.3% PEI and rinsed several times with ice- cold 50 mM Tris-HCl using a 96-sample cell harvester (Unifilter, Packard). The filters were dried then counted for radioactivity in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard). The results are expressed as a percent inhibition of the control radioligand specific binding. The standard reference compound is testosterone, which is tested in each experiment at several concentrations to obtain a competition curve from which its IC50 is calculated. Part II – Results [0490] Results showing ability of exemplary compounds to bind to the androgen receptor are provided in Table 3 below. The symbol “++++” indicates a Kd less than 0.05 ^M. The symbol “+++” indicates an Kd in the range of 0.05 ^M to 0.5 ^M. The symbol “++” indicates a Kd in the range of greater than 0.5 ^M to 2.5 ^M. The symbol “+” indicates a Kd greater than 2.5 ^M. TABLE 3. EXAMPLE 28 – Assay for Binding Affinity to BRD4-BD1 [0491] Exemplary compounds were tested for ability to bind to BRD4-BD1. Experimental procedures and results are provided below. Part I – Experimental Procedure [0492] Compounds were tested using a bromoKdELECT assay. T7 phage strains displaying bromodomains were grown in parallel in 24-well blocks in an E. coli host derived from the BL21 strain. E. coli were grown to log-phase and infected with T7 phage from a frozen stock (multiplicity of infection = 0.4) and incubated with shaking at 32 °C until lysis (90-150 minutes). The lysates were centrifuged (5,000 x g) and filtered (0.2μm) to remove cell debris. Streptavidin-coated magnetic beads were treated with biotinylated small molecule or acetylated peptide ligands for 30 minutes at room temperature to generate affinity resins for bromodomain assays. The liganded beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce nonspecific phage binding. Binding reactions were assembled by combining bromodomains, liganded affinity beads, and test compounds in 1x binding buffer (17% SeaBlock, 0.33x PBS, 0.04% Tween 20, 0.02% BSA, 0.004% Sodium azide, 7.4 mM DTT). Test compounds were prepared as 1000X stocks in 100% DMSO. Kds were determined using an 11-point 3-fold compound dilution series with one DMSO control point. All compounds for Kd measurements are distributed by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds were then diluted directly into the assays such that the final concentration of DMSO was 0.09%. All reactions performed in polypropylene 384-well plates. Each was a final volume of 0.02 ml. The assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (1x PBS, 0.05% Tween 20). The beads were then resuspended in elution buffer (1x PBS, 0.05% Tween 20, 2 μM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The bromodomain concentration in the eluates was measured by qPCR. Part II – Results [0493] Results showing ability of exemplary compounds to bind to BRD4-BD1 are provided in Table 4 below. The symbol “++++” indicates a Kd less than 0.05 ^M. The symbol “+++” indicates a Kd in the range of 0.05 ^M to 0.5 ^M. The symbol “++” indicates a Kd in the range of greater than 0.5 ^M to 2.5 ^M. The symbol “+” indicates a Kd greater than 2.5 ^M. TABLE 4. EXAMPLE 29 – Assay for Binding Affinity to BRD4-BD2 [0494] Exemplary compounds were tested for ability to bind to BRD4-BD2. Experimental procedures and results are provided below. Part I – Experimental Procedure [0495] Compounds were tested using a bromoKdELECT assay. T7 phage strains displaying bromodomains were grown in parallel in 24-well blocks in an E. coli host derived from the BL21 strain. E. coli were grown to log-phase and infected with T7 phage from a frozen stock (multiplicity of infection = 0.4) and incubated with shaking at 32 °C until lysis (90-150 minutes). The lysates were centrifuged (5,000 x g) and filtered (0.2μm) to remove cell debris. Streptavidin-coated magnetic beads were treated with biotinylated small molecule or acetylated peptide ligands for 30 minutes at room temperature to generate affinity resins for bromodomain assays. The liganded beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce nonspecific phage binding. Binding reactions were assembled by combining bromodomains, liganded affinity beads, and test compounds in 1x binding buffer (17% SeaBlock, 0.33x PBS, 0.04% Tween 20, 0.02% BSA, 0.004% Sodium azide, 7.4 mM DTT). Test compounds were prepared as 1000X stocks in 100% DMSO. Kds were determined using an 11-point 3-fold compound dilution series with one DMSO control point. All compounds for Kd measurements are distributed by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds were then diluted directly into the assays such that the final concentration of DMSO was 0.09%. All reactions performed in polypropylene 384-well plates. Each was a final volume of 0.02 ml. The assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (1x PBS, 0.05% Tween 20). The beads were then resuspended in elution buffer (1x PBS, 0.05% Tween 20, 2 μM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The bromodomain concentration in the eluates was measured by qPCR. Part II – Results [0496] Results showing ability of exemplary compounds to bind to BRD4-BD2 are provided in Table 5 below. The symbol “++++” indicates a Kd less than 0.05 ^M. The symbol “+++” indicates a Kd in the range of 0.05 ^M to 0.5 ^M. The symbol “++” indicates a Kd in the range of greater than 0.5 ^M to 2.5 ^M. The symbol “+” indicates a Kd greater than 2.5 ^M. TABLE 5. EXAMPLE 30 – Cellular Growth Inhibition Assay Using T-Rex 293 Cells [0497] Exemplary compounds were tested for ability to inhibit the proliferation of the following types of cells: (i) a T-Rex 293 cell line having increased expression of androgen receptor protein due to exposure to doxycycline and (ii) a T-Rex 293 cell line lacking increased expression of androgen receptor protein. Experimental procedures and results are provided below. Part I – Experimental Procedure [0498] The following types of cells were prepared for this experiment: (i) a T-Rex 293 cell line having increased expression of androgen receptor protein due to exposure to doxycycline and (ii) a T-Rex 293 cell line lacking increased expression of androgen receptor protein. Ability of the test compounds to inhibit proliferation of the foregoing cell types was evaluated according to the procedures set forth below. [0499] The doxycycline-inducible androgen receptor protein expressing cell line was established using the following protocol: T-Rex 293 cells were purchased from Invitrogen (Cat#R71007) and transfected using Lipofectamine 2000 with the wild-type androgen receptor protein sequence cloned into the pcDNA4/TO vector. Transfected cells were selected using 400 µg/mL Zeocin (Invitrogen Cat#R25001). Following selection, single clones were raised and maintained in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w/w Tetracycline-free fetal bovine serum (FBS) and 250 µg/mL Zeocin. Clones were analyzed for expression of androgen receptor protein in the presence and absence of 10 ng/mL doxycycline (Sigma Cat#D9891), and a single doxycycline-inducible clone (hereinafter “SC3”) was selected for use in downstream assays. [0500] The SC3 cells were seeded on poly-D-lysine coated, black clear-bottom 384- well plates at 2500/well, in 25 ^L Phenol Red Free Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w/w charcoal-dextran treated fetal bovine serum (FBS) and 1% w/w pen-strep, with or without 10 ng/mL doxycycline. Pen-Strep is a commercially available mixture of penicillin G and streptomycin, which is used in mammalian cell culture media to prevent bacterial contamination. Phenol Red Free Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w/w charcoal-dextran treated fetal bovine serum (FBS) and 1% w/w pen-strep, with or without 10 ng/mL doxycycline is herein referred to as Treatment Medium. Following seeding of cells in the plates, the plates were spun at 300 × g^for 30 seconds, then equilibrated to room temperature for 30 minutes, and then deposited^in a humidified tissue culture incubator maintained at 37 °C with 5% CO2. [0501] At 24 hours after seeding of the cells, dilutions of test compound were prepared in DMSO and dissolved in Treatment Medium, to achieve a final DMSO concentration of 0.5% w/w, thereby providing the Test Compound Solution. A 25 ^L aliquot of the Test Compound Solution was added to cells in the well plates. An equal volume of a solution containing DMSO and Treatment Medium was used as a negative control. Following treatment of cells with Test Compound Solution or said equal volume of a solution containing DMSO and Treatment Medium, the plates were spun at 300 × g for 30 seconds, and then left in an incubator for 72 hours. [0502] At the end of the treatment duration, cell viability was quantified with CellTiter-Glo 2.0 reagent (Promega Cat#G9243). For this purpose, plates were equilibrated to room temperature for 30 minutes, and then 25 µL of CellTiter-Glo 2.0 reagent was added to cells in the plate wells. Plates were then agitated on a shaker for two minutes at 500 rpm and subsequently incubated at room temperature for 10 minutes. Following incubation, the plates were spun at 3000 x g for 30 seconds, then sealed with an optical adhesive cover, and luminescence readings were measured with an EnVision Plate Reader. [0503] Data was normalized using zero luminescence for baseline. A four-parameter non- linear regression curve fit was applied to dose-response data in GraphPad Prism data analysis software to determine the half-maximal growth inhibitory concentration (GI50) for each test compound. Part II – Results [0504] The half-maximal growth inhibitory concentration (GI50) results are provided in Tables 6 and 7 below for exemplary compounds. Table 6 provides results from the experiment analyzing ability of test compounds to inhibit proliferation of the T-Rex 293 cell line SC3 cells having increased expression of androgen receptor protein due to exposure to doxycycline. The symbol “++++” indicates a GI50 less than 0.5 qM. The symbol “+++” indicates an GI50 in the range of 0.5 qM to 1.5 qM. The symbol “++” indicates a GI50 in the range of greater than 1.5 qM to 3 qM. The symbol “+” indicates a GI ₅₀ greater than 3 qM. TABLE 6. [0505] Table 7 provides results from the experiment analyzing ability of test compounds to inhibit proliferation of the T-Rex 293 cell line SC3 cells lacking increased expression of androgen receptor protein since such cells were not exposed to doxycycline. The symbol “++++” indicates a GI50 less than 0.5 qM. The symbol “+++” indicates an GI50 in the range of 0.5 qM to 1.5 qM. The symbol “++” indicates a GI ₅₀ in the range of greater than 1.5 qM to 3 qM. The symbol “+” indicates a GI ₅₀ greater than 3 qM. TABLE 7.

EXAMPLE 31 – Cellular Growth Inhibition Assay for VCaP Cells [0506] Exemplary compounds were tested for ability to inhibit the proliferation of VCaP cells. VCap cells are a commercially available human prostate cancer cell line. Experimental procedures and results are provided below. Part I – Experimental Procedure [0507] VCaP cells were purchased from American Type Cell Culture (ATCC Cat#CRL2876) and then seeded on poly-D-lysine coated, black clear-bottom 384-well plates at 5000/well in 25 qL Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w/w Fetal bovine serum (FBS) and 1% w/w Pen-Strep. Pen-Strep is a commercially available mixture of penicillin G and streptomycin, which is used in mammalian cell culture media to prevent bacterial contamination. Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w/w fetal bovine serum (FBS) and 1% w/w Pen-Strep is herein referred to as FYMI[TMU[ AMLQ\T( ;VSSV^QUO ZMMLQUO VN KMSSZ QU [PM WSI[MZ& [PM WSI[MZ ^MYM ZW\U I[ -** f OkNVY -* ZMKVULZ& [PMU MX\QSQJYI[ML [V YVVT [MTWMYI[\YM NVY -* TQU\[MZ& IUL [PMU LMWVZQ[MLkQU I humidified tissue culture incubator maintained at 37 °C with 5% CO2. [0508] At 24 hours after seeding of the cells, dilutions of test compound were prepared in DMSO and dissolved in Treatment Medium, to achieve a final DMSO concentration of 0.5% w/w, thereby providing the Test Compound Solution. A 25 qL aliquot of the Test Compound Solution was added to cells in the well plates. An equal volume of a solution containing DMSO and Treatment Medium was used as a negative control. Following treatment of cells with Test Compound Solution or said equal volume of a solution containing DMSO and Treatment Medium, the plates were spun at 300 × g for 30 seconds, and then left in an incubator for 72 hours. [0509] At the end of the treatment duration, cell viability was quantified with CellTiter-Glo 2.0 reagent (Promega Cat#G9243). For this purpose, plates were equilibrated to room temperature for 30 minutes, and then 25 µL of CellTiter-Glo 2.0 reagent was added to cells in the plate wells. Plates were then agitated on a shaker for two minutes at 500 rpm and subsequently incubated at room temperature for 10 minutes. Following incubation, the plates were spun at 3000 x g for 30 seconds, then sealed with an optical adhesive cover, and luminescence readings were measured with an EnVision Plate Reader. [0510] Data was normalized using zero luminescence for baseline. A four-parameter non- linear regression curve fit was applied to dose-response data in GraphPad Prism data analysis software to determine the half-maximal growth inhibitory concentration (GI50) for each test compound. Part II – Results [0511] The half-maximal growth inhibitory concentration (GI50) results are provided in Table 8 below for exemplary compounds. The symbol “++++” indicates a GI ₅₀ less than 0.5 qM. The symbol “+++” indicates an GI50 in the range of 0.5 qM to 1.5 qM. The symbol “++” indicates a GI ₅₀ in the range of greater than 1.5 qM to 3 qM. The symbol “+” indicates a GI ₅₀ greater than 3 qM. TABLE 8.

EXAMPLE 32 – Cellular Growth Inhibition Assay Using T-Rex 293 Cells [0512] Exemplary compounds were tested for ability to inhibit the proliferation of the following types of cells: (i) a T-Rex 293 cell line having increased expression of progesterone receptor isoform B protein due to exposure of doxycycline and (ii) a T-Rex 293 cell line lacking increased expression of progesterone receptor isoform B protein. Experimental procedures and results are provided below. Part I – Experimental Procedure [0513] The following types of cells were prepared for this experiment: (i) a T-Rex 293 cell line having increased expression of progesterone receptor isoform B protein due to exposure to doxycycline and (ii) a T-Rex 293 cell line lacking increased expression of progesterone receptor isoform B protein. Ability of the test compounds to inhibit proliferation of the foregoing cell types was evaluated according to the procedures set forth below. [0514] The doxycycline-inducible progesterone receptor isoform B protein expressing cell line was established using the following protocol: T-Rex 293 cells were purchased from Invitrogen (Cat#R71007) and transfected using Lipofectamine 2000 with the wild-type progesterone receptor B protein sequence cloned into the pcDNA4/TO vector. Transfected cells were selected using 400 µg/mL Zeocin (Invitrogen Cat#R25001). Following selection, single clones were raised and maintained in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w/w Tetracycline-free fetal bovine serum (FBS) and 250 µg/mL Zeocin. Clones were analyzed for expression of progesterone receptor isoform B protein in the presence and absence of 10 ng/mL doxycycline (Sigma Cat#D9891), and a single doxycycline- inducible clone (hereinafter “SC”) was selected for use in downstream assays. [0515] The SC cells were seeded on poly-D-lysine coated, black clear-bottom 384- well plates at 2500/well, in 25 qL Phenol Red Free Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w/w charcoal-dextran treated fetal bovine serum (FBS) and 1% w/w pen-strep, with or without 10 ng/mL doxycycline. Pen-Strep is a commercially available mixture of penicillin G and streptomycin, which is used in mammalian cell culture media to prevent bacterial contamination. Phenol Red Free Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w/w charcoal-dextran treated fetal bovine serum (FBS) and 1% w/w pen-strep, with or without 10 ng/mL doxycycline is herein referred to as Treatment AMLQ\T( ;VSSV^QUO ZMMLQUO VN KMSSZ QU [PM WSI[MZ& [PM WSI[MZ ^MYM ZW\U I[ -** f OkNVY -* ZMKVULZ& [PMU MX\QSQJYI[ML [V YVVT [MTWMYI[\YM NVY -* TQU\[MZ& IUL [PMU LMWVZQ[MLkQU I humidified tissue culture incubator maintained at 37 °C with 5% CO2. [0516] At 24 hours after seeding of the cells, dilutions of test compound were prepared in DMSO and dissolved in Treatment Medium, to achieve a final DMSO concentration of 0.5% w/w, thereby providing the Test Compound Solution. A 25 qL aliquot of the Test Compound Solution was added to cells in the well plates. An equal volume of a solution containing DMSO and Treatment Medium was used as a negative control. Following treatment of cells with Test Compound Solution or said equal volume of a solution containing DMSO and Treatment Medium, the plates were spun at 300 × g for 30 seconds, and then left in an incubator for 72 hours. [0517] At the end of the treatment duration, cell viability was quantified with CellTiter-Glo 2.0 reagent (Promega Cat#G9243). For this purpose, plates were equilibrated to room temperature for 30 minutes, and then 25 µL of CellTiter-Glo 2.0 reagent was added to cells in the plate wells. Plates were then agitated on a shaker for two minutes at 500 rpm and subsequently incubated at room temperature for 10 minutes. Following incubation, the plates were spun at 3000 x g for 30 seconds, then sealed with an optical adhesive cover, and luminescence readings were measured with an EnVision Plate Reader (Perkin Elmer). [0518] Data was normalized using zero luminescence for baseline. A four-parameter non- linear regression curve fit was applied to dose-response data in GraphPad Prism data analysis software to determine the half-maximal growth inhibitory concentration (GI50) for each test compound. Part II – Results [0519] The half-maximal growth inhibitory concentration (GI ₅₀ ) results are provided in Tables 9 and 10 below for exemplary compounds. Table 9 provides results from the experiment analyzing ability of test compounds to inhibit proliferation of the T-Rex 293 cell line SC cells having increased expression of progesterone receptor isoform B protein due to exposure to doxycycline. The symbol “++++” indicates a GI ₅₀ less than 0.5 qM. The symbol “+++” indicates an GI ₅₀ in the range of 0.5 qM to 1.5 qM. The symbol “++” indicates a GI ₅₀ in the range of greater than 1.5 qM to 3 qM. The symbol “+” indicates a GI50 greater than 3 qM. TABLE 9. Attorney Docket No.401507-013WO (203477) [0520] Table 10 provides results from the experiment analyzing ability of test compounds to inhibit proliferation of the T-Rex 293 cell line SC cells lacking increased expression of progesterone receptor isoform B protein since such cells were not exposed to doxycycline. The symbol “++++” indicates a GI50 less than 0.5 qM. The symbol “+++” indicates an GI50 in the range of 0.5 qM to 1.5 qM. The symbol “++” indicates a GI ₅₀ in the range of greater than 1.5 qM to 3 qM. The symbol “+” indicates a GI ₅₀ greater than 3 qM. TABLE 10. EXAMPLE 33 – Cellular Growth Inhibition Assay for T47D Cells [0521] Exemplary compounds were tested for ability to inhibit the proliferation of T47D cells. T47D cells are a commercially available human breast cancer cell line. Experimental procedures and results are provided below. Part I – Experimental Procedure [0522] T47D cells were purchased from American Type Cell Culture (ATCC Cat# HTB- 133) and then seeded on poly-D-lysine coated, black clear-bottom 384-well plates at 3000/well in 25 qL Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w/w Fetal bovine serum (FBS), 0.2 units/mL recombinant human insulin (Gibco Cat# 12585014), and 1% w/w Pen-Strep. Pen-Strep is a commercially available mixture of penicillin G and streptomycin, which is used in mammalian cell culture media to prevent bacterial contamination. Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w/w fetal bovine serum (FBS), 0.2 units/mL recombinant human insulin, and 1% w/w Pen-Strep is herein referred to as Treatment Medium. Following seeding of cells in the plates, the plates ^MYM ZW\U I[ -** f OkNVY -* ZMKVULZ& [PMU MX\QSQJYI[ML [V YVVT [MTWMYI[\YM NVY -* TQU\[MZ& IUL [PMU LMWVZQ[MLkQU I P\TQLQNQML [QZZ\M K\S[\YM QUK\JI[VY TIQU[IQUML I[ -1 b8 ^Q[P /" 8C2. [0523] At 24 hours after seeding of the cells, dilutions of test compound were prepared in DMSO and dissolved in Treatment Medium, to achieve a final DMSO concentration of 0.5% w/w, thereby providing the Test Compound Solution. A 25 qL aliquot of the Test Compound Solution was added to cells in the well plates. An equal volume of a solution containing DMSO and Treatment Medium was used as a negative control. Following treatment of cells with Test Compound Solution or said equal volume of a solution containing DMSO and Treatment Medium, the plates were spun at 300 × g for 30 seconds, and then left in an incubator for 72 hours. [0524] At the end of the treatment duration, cell viability was quantified with CellTiter-Glo 2.0 reagent (Promega Cat#G9243). For this purpose, plates were equilibrated to room temperature for 30 minutes, and then 25 µL of CellTiter-Glo 2.0 reagent was added to cells in the plate wells. Plates were then agitated on a shaker for two minutes at 500 rpm and subsequently incubated at room temperature for 10 minutes. Following incubation, the plates were spun at 3000 x g for 30 seconds, then sealed with an optical adhesive cover, and luminescence readings were measured with an EnVision Plate Reader (Perkin Elmer). [0525] Data was normalized using zero luminescence for baseline. A four-parameter non- linear regression curve fit was applied to dose-response data in GraphPad Prism data analysis software to determine the half-maximal growth inhibitory concentration (GI50) for each test compound. Part II – Results [0526] The half-maximal growth inhibitory concentration (GI ₅₀ ) results are provided in Table 11 below for exemplary compounds. The symbol “++++” indicates a GI50 less than 0.5 qM. The symbol “+++” indicates an GI ₅₀ in the range of 0.5 qM to 1.5 qM. The symbol “++” indicates a GI50 in the range of greater than 1.5 qM to 3 qM. The symbol “+” indicates a GI50 greater than 3 qM. TABLE 11.

34 – Assay for Binding Affinity to Progesterone Receptor [0527] Exemplary compounds were tested for ability to bind to the progesterone receptor. Experimental procedures and results are provided below. Part I – Experimental Procedure [0528] Compounds were tested using the PR Human Progesterone NHR Binding (Agonist Radioligand) Assay, Cerep at Eurofins Discovery using a modified version of the protocol from Sarup et al. (Cancer Res 1988;48:5071-5078). Briefly, cytosolic fractions of T47D cells were incubated with 0.5 nM [ ³ H]progesterone for 1 hour at 4°C in the absence or presence of the test KVTWV\UL( BVUZWMKQNQK JQULQUO ^IZ LM[MYTQUML QU [PM WYMZMUKM VN + jA WYVTMOMZ[VUM( Reactions were subjected to scintillation counting. Results are expressed as a percent inhibition of the control radioligand specific binding. Part II – Results [0529] Results showing ability of exemplary compounds to bind to the progesterone receptor are provided in Table 12 below. The symbol “++++” indicates a Kd less than 0.05 qM. The symbol “+++” indicates an Kd in the range of 0.05 qM to 0.5 qM. The symbol “++” indicates a Kd in the range of greater than 0.5 qM to 2.5 qM. The symbol “+” indicates a Kd greater than 2.5 qM. TABLE 12. 35 – FP Assay for Binding Affinity to Progesterone Receptor [0530] Exemplary compounds were tested for ability to bind to the progesterone receptor ligand binding domain (LBD). Experimental procedures and results are provided below. Part I – Experimental Procedure [0531] Compounds were tested using the PolarScreen™ Progesterone Receptor Competitor Assay Kit (Life Technologies Cat# A15905 or a15906), as per the manufacturer’s instructions. Briefly, GST-tagged PR LBD, Fluormone tracer, and compound were mixed and incubated for 2 hours at room temperature in the dark. Following incubation, the plates were spun at 3000 x g for 30 seconds, then sealed with an optical adhesive cover, and fluorescence polarization was measured using appropriate excitation and emission filters with an EnVision Plate Reader (Perkin Elmer). Compound concentration vs. mP value were plotted in Prism (GraphPad). A four-parameter non-linear regression curve fit was applied to dose-response data to determine the half-maximal inhibitory concentration (IC50) for each test compound. Part II – Results [0532] The half-maximal inhibitory concentration (IC ₅₀ ) results are provided in Table 13 below for exemplary compounds. The symbol “++++” indicates a IC50 less than 0.05 qM. The symbol “+++” indicates an IC ₅₀ in the range of 0.05 qM to 0.5 qM. The symbol “++” indicates a IC50 in the range of greater than 0.5 qM to 2.5 qM. The symbol “+” indicates a IC50 greater than 2.5 qM. TABLE 13. INCORPORATION BY REFERENCE [0533] The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes. EQUIVALENTS [0534] 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.