HETEROBIFUNCTIONAL COMPOUNDS AND THEIR USE IN TREATING DISEASE CROSS-REFERENCE TO RELATED APPLICATION [0001] This application claims priority to U.S. provisional patent application No. 63/251,717, filed on October 4, 2021, the contents of which are hereby incorporated by reference in their entirety. FIELD OF THE INVENTION [0002] The invention provides heterobifunctional compounds, pharmaceutical compositions, and their use in 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 in 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 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 to treat the cancer. [0008] 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, to cause death of the cancer cell. DETAILED DESCRIPTION [0009] The invention provides heterobifunctional compounds, pharmaceutical compositions, and their use in 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. [00010] 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 [00011] 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. [00012] 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. [00013] 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: [00014] Exemplary bridged bicyclics include: . [00015] The term “lower alkyl” refers to a C _1-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. [00016] The term “lower haloalkyl” refers to a C _1-4 straight or branched alkyl group that is substituted with one or more halogen atoms. [00017] 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)). [00018] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation. [00019] 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. [00020] 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. [00021] The term “-(C0 alkylene)-“ refers to a bond. Accordingly, the term “-(C0-3 alkylene)-” encompasses a bond (i.e., C ₀ ) and a -(C _1-3 alkylene)- group. [00022] 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. [00023] The term “halogen” means F, Cl, Br, or I. [00024] 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. [00025] 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 pi 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 “pyridinylene” and “pyrimidinylene”, respectively refer to bivalent pyridinyl and pyrimidinyl groups. [00026] 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). [00027] 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. [00028] As used herein, the term “heterocycloakyl” refers to a saturated heterocyclyl. The term “heterocycloakyl” refers to a bivalent heterocycloakyl group. [00029] 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. [00030] 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. [00031] Each optional substituent on a substitutable carbon is a monovalent substituent independently selected from halogen; –(CH ₂ ) _0–4 R°; –(CH ₂ ) _0–4 OR°; -O(CH ₂ ) _0-4 R ^o , –O–(CH ₂ ) _0– 4C(O)OR°; –(CH2)0–4CH(OR°)2; –(CH2)0–4SR°; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH ₂ ) _0–4 O(CH ₂ ) _0–1 -pyridyl which may be substituted with R°; –NO ₂ ; – CN; –N3; -(CH2)0–4N(R°)2; –(CH2)0–4N(R°)C(O)R°; –N(R°)C(S)R°; –(CH2)0–4N(R°)C(O)NR°2; -N(R°)C(S)NR° ₂ ; –(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°; –(CH2)0–4C(O)R°; –C(S)R°; –(CH2)0–4C(O)OR°; –(CH2)0–4C(O)SR°; -(CH2)0–4C(O)OSiR°3; –(CH2)0–4OC(O)R°; –OC(O)(CH2)0–4SR–, SC(S)SR°; –(CH2)0– 4SC(O)R°; –(CH2)0–4C(O)NR°2; –C(S)NR°2; –C(S)SR°; –SC(S)SR°, -(CH2)0–4OC(O)NR°2; -C(O)N(OR°)R°; –C(O)C(O)R°; –C(O)CH ₂ C(O)R°; –C(NOR°)R°; -(CH ₂ ) _0–4 SSR°; –(CH ₂ ) _0– 4S(O)2R°; –(CH2)0–4S(O)2OR°; –(CH2)0–4OS(O)2R°; –S(O)2NR°2; –S(O)(NR°)R°; – S(O)2N=C(NR°2)2; -(CH2)0–4S(O)R°; -N(R°)S(O)2NR°2; –N(R°)S(O)2R°; –N(OR°)R°; – C(NH)NR° ₂ ; –P(O) ₂ R°; -P(O)R° ₂ ; -OP(O)R° ₂ ; –OP(O)(OR°) ₂ ; SiR° ₃ ; –(C _1–4 straight or branched alkylene)O–N(R°) ₂ ; or –(C _1–4 straight or branched alkylene)C(O)O–N(R°) ₂ . [00032] Each R° is independently hydrogen, C1–6 aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2-(5- 6 membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted by a divalent substituent on a saturated carbon atom of R° selected from =O and =S; or each R° is optionally substituted with a monovalent substituent independently selected from halogen, –(CH ₂ ) _0–2 R ^● , –(haloR ^● ), –(CH ₂ ) _0–2 OH, –(CH ₂ ) _0–2 OR ^º , – (CH2)0–2CH(OR ^● )2; -O(haloR ^● ), –CN, –N3, –(CH2)0–2C(O)R ^● , –(CH2)0–2C(O)OH, –(CH2)0– ₂ C(O)OR ^● , –(CH ₂ ) _0–2 SR ^● , –(CH ₂ ) _0–2 SH, –(CH ₂ ) _0–2 NH ₂ , –(CH ₂ ) _0–2 NHR ^● , –(CH ₂ ) _0–2 NR ^● ₂ , – NO2, –SiR ^● 3, –OSiR ^● 3, -C(O)SR ^● , –(C1–4 straight or branched alkylene)C(O)OR ^● , or –SSR ^● . [00033] Each R ^● is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ^● is unsubstituted or where preceded by halo is substituted only with one or more halogens; 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))2–3O–, or –S(C(R ^* 2))2–3S–, or a divalent substituent bound to vicinal substitutable carbons of an “optionally substituted” group is –O(CR ^* ₂ ) _2–3 O–, wherein each independent occurrence of R ^* is selected from hydrogen, C1–6 aliphatic or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00034] 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 –NO ₂ , wherein each R ^● is independently selected from C _1–4 aliphatic, –CH ₂ Ph, –O(CH ₂ ) _0–1 Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ^● is unsubstituted or where preceded by halo is substituted only with one or more halogens. [00035] An optional substituent on a substitutable nitrogen is independently –R ^† , –NR ^† 2, – C(O)R ^† , –C(O)OR ^† , –C(O)C(O)R ^† , –C(O)CH ₂ C(O)R ^† , -S(O) ₂ R ^† , -S(O) ₂ NR ^† ₂ , –C(S)NR ^† ₂ , – C(NH)NR ^† 2, or –N(R ^† )S(O)2R ^† ; 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 ^● , –NH2, –NHR ^● , –NR ^● 2, or –NO2, wherein each R ^● is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ^● is unsubstituted or where preceded by halo is substituted only with one or more halogens. [00036] 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. [00037] 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. [00038] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C1–4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate. [00039] 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. Additionally, unless otherwise stated, structures depicted herein are also meant to include 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. [00040] 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. [00041] 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. [00042] 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. [00043] The terms “a” and “an” as used herein mean “one or more” and include the plural unless the context is inappropriate. [00044] The term “alkyl” refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C1-C12 alkyl, C ₁ -C ₁₀ alkyl, and C ₁ -C ₆ alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1- butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl- 1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2- dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc. [00045] 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. [00046] The term “haloalkyl” refers to an alkyl group that is substituted with at least one halogen. Exemplary haloalkyl groups include -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, and the like. The term “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. [00047] The term “hydroxyalkyl” refers to an alkyl group that is substituted with at least one hydroxyl. Exemplary hydroxyalkyl groups include -CH2CH2OH, -C(H)(OH)CH3, -CH ₂ C(H)(OH)CH ₂ CH ₂ OH, and the like. [00048] 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. [00049] 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. [00050] The term “carbocyclylene” refers to a bivalent cycloaliphatic group. [00051] The terms “alkoxyl” or “alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. The term “haloalkoxyl” refers to an alkoxyl group that is substituted with at least one halogen. Exemplary haloalkoxyl groups include -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -OCF2CF3, and the like. [00052] The term “oxo” is art-recognized and refers to a “=O” substituent. For example, a cyclopentane susbsituted with an oxo group is cyclopentanone. [00053] 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 an p y p y rogen, 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. [00054] 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 in yl, 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 -(CH2)m-R ⁶¹ . [00055] The symbol “ ” indicates a point of attachment. [00056] 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. [00057] One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H ₂ O. [00058] 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. [00059] The term “IC50” is art-recognized and refers to the concentration of a compound that is required to achieve 50% inhibition of the target. [00060] 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. [00061] 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. [00062] 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]. [00063] 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. [00064] 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. [00065] 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. [00066] As a general matter, compositions specifying a percentage are by weight unless otherwise specified. I. Heterobifunctional Compounds [00067] 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. Part A: Compounds of Formula I [00068] One aspect of the invention provides a compound represented by Formula I: or a pharmaceutic R ¹ , R ² , R ³ , and R ⁴ are independently H, D, halo, or C ₁ - ₄ alkyl; R ⁵ is H or C1-4 alkyl; X is -C(O)- or -S(O) ₂ -; EPL is a moiety that binds to an effector protein selected from CDK1, CDK2, CDK9, mTOR, PLK1, BRD4, AURKA, AURKB, MEK, Src, c-KIT, KIF11, HSP90, tubulin, proteasome, topoisomerase, or HDAC; TPL is a moiety that binds to a target protein selected from KRAS, HER2, or EGFR; L ¹ is a bond, **-linker-O-, or **-linker-N(R ⁵ )-, where ** is a point of attachment to EPL; and L ² is a bond or a linker; wherein L ¹ is connected to a nitrogen or oxygen atom of EPL when L ¹ is a bond. [00069] 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). [00070] In certain embodiments, the compound is a compound of Formula I. [00071] As generally defined above, EPL is a moiety that binds to an effector protein selected from CDK1, CDK2, CDK9, mTOR, PLK1, BRD4, AURKA, AURKB, MEK, Src, c- KIT, KIF11, HSP90, Tubulin, Proteasome, Topoisomerase, or HDAC. In certain embodiments, the EPL is a moiety that binds to CDK1, CDK2, CDK9, mTOR, PLK1, or BRD4. In certain embodiments, the EPL is a moiety that binds to mTOR. In certain embodiments, the EPL is a moiety that binds to PLK1. In certain embodiments, the EPL is a moiety that binds to CDK1. In certain embodiments, the EPL is a moiety that binds to CDK2. In certain embodiments, the EPL is a moiety that binds to CDK9. In certain embodiments, the EPL is a moiety that binds to BRD4. In certain embodiments, the EPL is a moiety that binds to AURKA. In certain embodiments, the EPL is a moiety that binds to AURKB. In certain embodiments, the EPL is a moiety that binds to MEK. In certain embodiments, the EPL is a moiety that binds to Src. In certain embodiments, the EPL is a moiety that binds to c-KIT. In certain embodiments, the EPL is a moiety that binds to KIF11. In certain embodiments, the EPL is a moiety that binds to HSP90. In certain embodiments, the EPL is a moiety that binds to tubulin. In certain embodiments, the EPL is a moiety that binds to proteasome. In certain embodiments, the EPL is a moiety that binds to topoisomerase. In certain embodiments, the EPL is a moiety that binds to HDAC. In certain embodiments, the EPL is selected from those depicted in the compounds in any one of Tables 1, 2, 3, 4, 5, 6, or 7 below. In certain embodiments, the EPL is selected from those depicted in the compounds in any one of Tables 1-A, 2-A, 3-A, 4-A, or 5-A below. [00072] Further description of exemplary EPL moieties are described below: A. Moiety for CDK1 [00073] In certain embodiments, the EPL is a moiety that binds to Cyclin-Dependent Kinase 1 (CDK1). Exemplary compounds that bind to CDK1 are reported in the literature, including: ^• as described by Sivakumar, M., et al. in WO2007/148158; • , as described by Lucking, U., et al. in WO2005/037800; • , as described by D'Alessio, R., et al. in WO2004/104007; • as described by Guzi, T.J., et al. in WO2005/077954 ; as described by Wyatt, P.G., et al. in WO2005/012256; • as described by Brumby, T., et al. in WO2002/096888; • as described by Dumont, J.A., et al. in WO2000/044362; • , as described by Wang, S., et al. in WO2013/156780; • as described by Wang, Z., et al. in • as described by Wang, S., et al. in WO2009/118567; as described by Caligiuri, M., et al. in Chem Biol (London) [00074] In certain embodiments, the EPL is a radical of one of the above compounds, which is attached to L ¹ through a modifiable oxygen, nitrogen, or carbon atom. [00075] In certain embodiments, the EPL has the following formula: wherein: R ^1a and R ^2a each represent independently for each occurrence halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C3-C6 cycloalkyl, hydroxyl, C1-C6 alkoxy, or cyano; R ^3a represents independently for each occurrence C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, hydroxyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, or -(C1-C6 alkylene)-(C1-C6 alkoxy), m is 0, 1, or 2; and n and p each represent independently 0, 1, 2, or 3. [00076] In certain embodiments, the EPL has the following formula: wherein: R ^1a and R ^2a each represent independently for each occurrence halo, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, hydroxyl, C1-C6 alkoxy, or cyano; R ^3a represents independently for each occurrence C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, hydroxyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ hydroxyalkyl, or -(C ₁ -C ₆ alkylene)-(C ₁ -C ₆ alkoxy), m is 0, 1, or 2; and n and p each represent independently 0, 1, 2, or 3. [00077] In certain embodiments, the EPL has the following formula: wherein: R ^1a , R ^2a and R ^3a each represent independently for each occurrence halo, C1-C6 alkyl, C1-C6 haloalkyl, C ₃ -C ₆ cycloalkyl, hydroxyl, C ₁ -C ₆ alkoxy, or cyano; m and p each represent independently 0, 1, or 2; and n is 0, 1 or 2. [00078] In certain embodiments, the EPL is one of the following: . [00079] In certain embodiments, the EPL is one of the following: . B. Moiety for CDK2 [00080] In certain embodiments, the EPL is a moiety that binds to Cyclin-Dependent Kinase 2 (CDK2). Exemplary compounds that bind to CDK2 are reported in the literature, including: • • ; • • , as described bySheldrake, P.W., et al. in WO2008/122767 ; • as described by Guzi, T.J., et al. in WO2005/077954 ; • , as described by Wyatt, P.G., et al. in WO2005/012256; , as described by Brumby, T., et al. in WO2002/096888; • s described by Dumont, J.A., et al. in WO2000/044362; • as described by Hao, M., et al. in [00081] In certain embodiments, the EPL is a radical of one of the above compounds, which is attached to L ¹ through a modifiable oxygen, nitrogen, or carbon atom. [00082] In certain embodiments, the EPL has the following formula: wherein: R ^1a and R ^2a each represent independently for each occurrence halo, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, hydroxyl, C1-C6 alkoxy, or cyano; R ^3a represents independently for each occurrence C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, hydroxyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ hydroxyalkyl, or -(C ₁ -C ₆ alkylene)-(C ₁ -C ₆ alkoxy), m is 0, 1, or 2; and n and p each represent independently 0, 1, 2, or 3. [00083] In certain embodiments, the EPL has the following formula: wherein: R ^1a and R ^2a each represent independently for each occurrence halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, hydroxyl, C ₁ -C ₆ alkoxy, or cyano; R ^3a represents independently for each occurrence C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, hydroxyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ hydroxyalkyl, or -(C ₁ -C ₆ alkylene)-(C ₁ -C ₆ alkoxy), m is 0, 1, or 2; and n and p each represent independently 0, 1, 2, or 3. [00084] In certain embodiments, the EPL is one of the following: . C. Moiety for CDK9 [00085] In certain embodiments, the EPL is a moiety that binds to Cyclin-Dependent Kinase 9 (CDK9). Exemplary compounds that bind to CDK9 are reported in the literature, including: _• • • 54; • ; • , , ., . • • • described by Guzi, T.J., et al. in WO2005/077954 ; • • • • WO2017/044858; • ; • 1. [00086] In certain embodiments, the EPL is a radical of one of the above compounds, which is attached to L ¹ through a modifiable oxygen, nitrogen, or carbon atom. [00087] In certain embodiments, the EPL has the following formula: wherein: R ^1a and R ^2a each represent independently for each occurrence halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C3-C6 cycloalkyl, hydroxyl, C1-C6 alkoxy, or cyano; R ^3a represents independently for each occurrence C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, hydroxyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, or -(C1-C6 alkylene)-(C1-C6 alkoxy); m is 0, 1, or 2; and n and p each represent independently 0, 1, 2, or 3. [00088] In certain embodiments, the EPL has the following formula: wherein: R ^1a and R ^2a each represent independently for each occurrence halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C3-C6 cycloalkyl, hydroxyl, C1-C6 alkoxy, or cyano; R ^3a represents independently for each occurrence C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, hydroxyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ hydroxyalkyl, or -(C ₁ -C ₆ alkylene)-(C ₁ -C ₆ alkoxy); m is 0, 1, or 2; and n and p each represent independently 0, 1, 2, or 3. [00089] In certain embodiments, the EPL is one of the following: . [00090] In certain embodiments, the EPL has the following formula: wherein: R ^1a and R ^2a each represent independently for each occurrence C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₃ -C ₆ cycloalkyl; R ^3a represents independently for each occurrence C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, halogen, hydroxyl, or C ₁ -C ₆ alkoxy; m is 0, 1, or 2; and n and p each represent independently 0, 1, 2, or 3. [00091] In certain embodiments, the EPL is one of the following: . D. Moiety for mTOR [00092] In certain embodiments, the EPL is a moiety that binds to Mammalian Target of Rapamycin (mTOR). Exemplary moieties that bind mTOR are reported in the literature, including: • • aymon, H. et al., WO 2014/172424 and WO 2014/172425; • •

, as described in Yu, C. et al., US2014/038991; escribed in Conejo-Garcia, J.R. et al., WO 2017/062426; , as described in Rageot, D. et al., US2019/284178; • as described in Pei, Z. et al., WO 2011/058025; • s described in Li, X. et al., WO 2013/016999; • ; • WO 2010/151601; • . [00093] In certain embodiments, the EPL is a radical of one of the above compounds, which is attached to L ¹ through a modifiable oxygen, nitrogen, or carbon atom. [00094] In certain embodiments, the EPL has the following formula: wherein: R ^1a and each R ^2a represent independently for each occurrence halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C3-C6 cycloalkyl, hydroxyl, C1-C6 alkoxy, or cyano; R ^3a is hydrogen, C ₁ -C ₆ alkyl, or C ₃ -C ₆ cycloalkyl; X is O, S, or N(R ^3a ); and m is 0, 1, 2, or 3. [00095] In certain embodiments, the EPL has the following formula: wherein: R ^1a and R ^2a each represent independently for each occurrence halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C3-C6 cycloalkyl; R ^3a and R ^4a each represent independently for each occurrence halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C3-C6 cycloalkyl, hydroxyl, C1-C6 alkoxy, or cyano; m, n, and q each represent independently 0, 1, 2, or 3; and p is 0, 1, or 2. [00096] In certain embodiments, the EPL is one of the following: . E. Moiety for PLK1 [00097] In certain embodiments, the EPL is a moiety that binds to Polo Like Kinase 1 (PLK1). Exemplary compounds that bind to PLK1 are reported in the literature, including: • • ; • • ; • • • , , ., . Chem Lett 2017, 27(5): 1311; • described by Bharathan, I.T., et al. in WO2010/065134. [00098] In certain embodiments, the EPL is a radical of one of the above compounds, which is attached to L ¹ through a modifiable oxygen, nitrogen, or carbon atom. [00099] In certain embodiments, the EPL has the following formula: wherein: R ^1a and R ^2a each represent independently C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or hydrogen; R ^3a is C3-C6 cycloalkyl, C1-C6 alkyl, C1-C6 haloalkyl, or hydrogen; R ^4a represents independently for each occurrence halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, hydroxyl, C1-C6 alkoxy, or cyano; and m is 0, 1, 2, or 3. [000100] In certain embodiments, the certain embodiments, the [000101] In certain embodiments, the EPL has the following formula: wherein: R ^1a and R ^2a each represent independently for each occurrence C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or hydrogen; R ^3a is C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or hydrogen; R ^4a represents independently for each occurrence halo, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, hydroxyl, C ₁ -C ₆ alkoxy, or cyano; A ¹ is a 3-7 membered saturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclyl is optionally substituted with 1 or 2 occurrences of R ^4a ; and m is 0, 1, 2, or 3. [000102] In certain embodiments, the EPL has the following formula: wherein: R ^1a and R ^2a each represent independently for each occurrence C1-C6 alkyl, C1-C6 haloalkyl, or hydrogen; R ^3a is C3-C6 cycloalkyl, C1-C6 alkyl, C1-C6 haloalkyl, or hydrogen; R ^4a represents independently for each occurrence halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, hydroxyl, C1-C6 alkoxy, or cyano; A ¹ is a 3-7 membered saturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclyl is optionally substituted with 1 or 2 occurrences of R ^4a ; and m is 0, 1, 2, or 3. [000103] In certain embodiments, the EPL is one of the following: . F. Moiety for BRD4 [000104] In certain embodiments, the EPL is a moiety that binds to bromodomain-containing protein 4 (BRD4). Exemplary compounds that bind to BRD4 are reported in the literature, including: • ; • • ; • described by Chen, L., et al. in ACS Med Chem Lett 2015, vol.6(7), page 764; • • Bioorg Med Chem Lett 2018, vol.28(21), page 3483; • • hem Lett 2017, vol.8(8), page 847; • ; • • • , vol.61(10), page 4317; • ; • • • i • Chem Biol 2014, vol.9(5), page 1160; • ; • • vol.152, page 542; • , • 2018, vol.9(3), page 262; • described by Kharenko, O.A., et al. in J Med Chem 2018, vol.61(18), page 8202. [000105] In certain embodiments, the EPL is a radical of one of the above compounds, which is attached to L ¹ through a modifiable oxygen, nitrogen, or carbon atom. [000106] In certain embodiments, the EPL has the following formula: wherein: R ^1a is phenyl, C3-C8 cycloalkyl, or 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1- C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, hydroxyl, C1-C6 alkoxy, or cyano; R ^2a and each R ^3a represent independently for each occurrence halo, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, hydroxyl, C1-C6 alkoxy, or cyano; m is 0, 1, or 2; and n is 0, 1, 2, 3, or 4. [000107] In certain embodiments, the G. Moiety for AURKA [000108] In certain embodiments, the EPL is a moiety that binds to Aurora Kinase A (AURKA). Exemplary compounds that bind to AURKA are reported in the literature, including: • ; • • 5800; • described by Lucking, U., et al. in WO2005/037800; • • 9; • • • • • • ; • hem Lett 2006, 16(22): 5778. [000109] In certain embodiments, the EPL is a radical of one of the above compounds, which is attached to L ¹ through a modifiable oxygen, nitrogen, or carbon atom. [000110] In certain embodiments, the EPL has the following formula: wherein: R ^1a is 4-7 membered, saturated heterocyclylene containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R ^2a is a 5-6membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the heteroaryl is optionally substituted with 1 or 2 substituents independently selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C3- C6 cycloalkyl, hydroxyl, C1-C6 alkoxy, or cyano; R ^3a represents independently for each occurrence H or C1-C6 alkyl; and R ^4a is phenyl or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from -N(R ^3a )C(O)-(C3-C6 cycloalkyl), - N(R ^3a )C(O)-(C ₁ -C ₆ alkyl), halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, hydroxyl, C1-C6 alkoxy, or cyano. [000111] In certain embodiments, the EPL has the following formula: wherein: R ^1a is phenyl or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C3-C6 cycloalkyl, hydroxyl, C1-C6 alkoxy, or cyano. R ^2a is –(phenylene)- (4-7 membered, saturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein the heterocyclyl is optionally substituted with 1 or 2 substituents independently selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, hydroxyl, C1-C6 alkoxy, or cyano; and R ^3a represents independently for each occurrence H or C ₁ -C ₆ alkyl. [000112] In certain embodiments, the EPL is one of the following: . H. Moiety for AURKB [000113] In certain embodiments, the EPL is a moiety that binds to Aurora Kinase B (AURKB). Exemplary compounds that bind to AURKB are reported in the literature, including: • • • ; • • • WO2004/058781; • described by Berdini, V., et al. in WO2006/070195; • • • • • • [000114] In certain embodiments, the EPL is a radical of one of the above compounds, which is attached to L ¹ through a modifiable oxygen, nitrogen, or carbon atom. [000115] In certain embodiments, the EPL has the following formula: wherein: R ^1a is a 4-10 membered heteroalkylene; R ^2a , R ^3a , and R ^5a are independently H or C1-C6 alkyl; and R ^4a is phenyl or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, hydroxyl, C1-C6 alkoxy, or cyano. [000116] In certain embodiments, the EPL is one of the following: . I. Moiety for MEK [000117] In certain embodiments, the EPL is a moiety that binds to and inhibits Mitogen- activated protein kinase kinase (MEK). Exemplary compounds that bind to and inhibit MEK are reported in the literature, including: • l 13(4), page 823; • , • • 69(17), page 6839; • , as described in Aoki, T. et al., ACS Med Chem Lett 2014, vol 5(4), page 309; • [000118] In certain embodiments, the EPL is a radical of one of the above compounds, which is attached to L ¹ through a modifiable oxygen, nitrogen, or carbon atom. [000119] In certain embodiments, the EPL is a moiety that binds to and inhibits MEK1. In certain embodiments, the EPL is a moiety that binds to and inhibits MEK2. In certain embodiments, the EPL is a moiety that binds to and inhibits both MEK1 and MEK2. [000120] In certain embodiments, the EPL has the formula: wherein: R ^1a is phenyl or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, hydroxyl, C1-C6 alkoxy, or cyano; and R ^2a is –(C2-6 alkylene optionally substituted by one hydroxyl). [000121] In certain embodiments, the EPL is one of the following: . J. Moiety for Src [000122] In certain embodiments, the EPL is a moiety that binds to and inhibits proto- oncogene tyrosine-protein kinase (Src). Exemplary compounds that bind to and inhibit Src are reported in the literature, including: • Med Chem 2006, 49(19): 5671. • , as described in Verones, V. et al., in Eur J Med Chem 2010, 45(12): 5678. • , • • • • Chem Lett 2003, 13(21): 3797. • , • Chem 2015, 58(9): 3957. • , • • , , . ., C Int Conf Mol Targets Cancer Ther · 2011-11-12 / 2011-11-16 · San Francisco, United States · Abst A239,Mol Cancer Ther 2011, 10(Suppl.1). • : 8 • • • 21(7): 1724. • described in Zhang, C. et al., in J Med Chem 2015, 58(9): 3957. • Assoc Cancer Res (AACR) 2008, 49, Abst 4869. • : • • • 2004, 2(8), Abst 406. • • • described in Fabian, C. et al., in 108th Annu Meet Am Assoc Cancer Res (AACR) · 2017-04-01 / 2017-04-05 · Washington, D.C., United States · Abst 1207,Cancer Res 2017, 77(13). • described in Britten, C. et al., in Eur J Cancer Suppl 2008, 6(12), Abst 390. [000123] In certain embodiments, the EPL is a radical of one of the above compounds, which is attached to L ¹ through a modifiable oxygen, nitrogen, or carbon atom. [000124] In certain embodiments, the EPL is one of the following: . K. Moiety for c-KIT [000125] In certain embodiments, the EPL is a moiety that binds to c-KIT. Exemplary compounds that bind to c-KIT are reported in the literature, including: • described by Mahadevan, D. et al., in Oncogene 2007, vol 26(27), page. • • al., in Bioorg. Med. Chem.2017, vol 25(12), page 3195. • described by Yao, G. et al., in CN106749223. ^• • • • • WO2011053938. • • • . ^• • , , .. ., [000126] In certain embodiments, the EPL is a radical of one of the above compounds, which is attached to L ¹ through a modifiable oxygen, nitrogen, or carbon atom. [000127] In certain embodiments, the EPL is a radical of dasatinib, imatinib mesylate (STI571), sunitinib, regorafenib (BAY 73-4506), pazopanib HCl (GW786034 HCl), dovitinib (TKI-258), masitinib (AB1010), tivozanib (AV-951), motesanib diphosphate (AMG-706), amuvatinib (MP-470), levatinib (E7080), osi-930, Ki8751, telatinib, pozopanib, dovitinib (TKI- 258), ripretinib (DCC-2618), sunitinib, Ki20227, avapritinib (BLU-285), AZD3229, AZD2932, regorafenib monohydrate, dovitinib (TKI258), pexidartinib (PLX3397), PDGFR inhibitor 1, or sitravatinib (MGCD516). [000128] In certain embodiments, the EPL is one of the following: . L. Moiety for KIF11 [000129] In certain embodiments, the EPL is a moiety that binds to Kinesin Family Member 11 (KIF11). Exemplary compounds that bind to KIF11 are reported in the literature, including: • • 70701 ; • escribed by Wood, K.W., et al. in WO2007/067752 ; • described by Liu, J., et al. in WO2009/002808; • described by Liu, J., et al. in WO2013/141264 [000130] In certain embodiments, the EPL is a radical of one of the above compounds, which is attached to L ¹ through a modifiable oxygen, nitrogen, or carbon atom. [000131] In certain embodiments, the EPL has the following formula: wherein: R ^1a and R ^2a each represent independently for each occurrence halo, C1-C6 alkyl, C1-C6 haloalkyl, C ₃ -C ₆ cycloalkyl, hydroxyl, C ₁ -C ₆ alkoxy, or cyano; R ^3a is H, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl; and m and n each represent independently 0, 1, 2, or 3. [000132] In certain embodiments, the EPL has the following formula: wherein: R ^1a and R ^2a each represent independently for each occurrence halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C3-C6 cycloalkyl, hydroxyl, C1-C6 alkoxy, or cyano; R ^3a and R ^4a each represent independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₃ -C ₆ cycloalkyl; and m and n each represent independently 0, 1, 2, or 3. [000133] In certain embodiments, the EPL has the following formula: wherein: R ^1a and R ^2a each represent independently for each occurrence halo, C1-C6 alkyl, C1-C6 haloalkyl, C ₃ -C ₆ cycloalkyl, hydroxyl, C ₁ -C ₆ alkoxy, or cyano; R ^3a is H, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl; and m and n each represent independently 0, 1, 2, or 3. [000134] In certain embodiments, the EPL is one of the following: [000135] In certain embodiments, the EPL is: . [000136] In certain embodiments, the EPL is one of the following: . M. Moiety for HSP90 [000137] In certain embodiments, the EPL is a moiety that binds to HSP90. Exemplary compounds that bind to HSP90 are reported in the literature, including: • • • ; • • • 06/091963; • described by Giannini, G., et al. in WO2012/084602. [000138] In certain embodiments, the EPL is a radical of one of the above compounds, which is attached to L ¹ through a modifiable oxygen, nitrogen, or carbon atom. [000139] In certain embodiments, the EPL is one of the following: . N. Moiety for Tubulin [000140] In certain embodiments, the EPL is a moiety that binds to tubulin. Exemplary compounds that bind to tubulin are reported in the literature, including: • described by Hangauer, D.G., et al. in WO2006/071960; • • ; • , , . ., . • ; • • 81; • • ; • • [000141] In certain embodiments, the EPL is a radical of one of the above compounds, which is attached to L ¹ through a modifiable oxygen, nitrogen, or carbon atom. [000142] In certain embodiments, the EPL is one of the following: . [000143] In certain embodiments, the EPL is one of the following: . [000144] In certain embodiments, the EPL is one of the following: wherein: R ^1a is phenyl, C ₃ -C ₆ cycloalkyl, or 5-6 membered heteroaryl containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur; wherein the phenyl, cycloalkyl, and heteroaryl are substituted with 0, 1, 2, or 3 groups independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, halogen, hydroxyl, C ₁ -C ₆ alkoxy, or -C(O)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the heteroaryl is substituted with 0, 1, 2, or 3 groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C ₃ -C ₆ cycloalkyl, halogen, hydroxyl, or C ₁ -C ₆ alkoxy); R ^2a each represent independently for each occurrence C1-C6 alkyl, C1-C6 haloalkyl, or C3- C ₆ cycloalkyl; R ^3a represents independently for each occurrence C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, halogen, hydroxyl, or C ₁ -C ₆ alkoxy; R ^4a is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; n and p are independently 0, 1, or 2. [000145] In certain embodiments, R ^1a is phenyl substituted with 0, 1, 2, or 3 groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or halogen. In certain embodiments, R ^2a is C ₁ -C ₆ alkyl. In certain embodiments, R ^3a is C ₁ -C ₆ alkyl. In certain embodiments, R ^4a is hydrogen. [000146] In certain embodiments, the EPL is one of the following: . O. Moiety for Proteasome [000147] In certain embodiments, the EPL is a moiety that binds to and/or inhibits the proteasome. Exemplary compounds that bind to and/or inhibit the proteasome are reported in the literature, including: • • ; • 731; • • ; • • , as described by Olhava, E.J., et al. in WO2009/020448; • , as described by Qin, Y., et al. in WO2019/228299. [000148] In certain embodiments, the EPL is a radical of one of the above compounds, which is attached to L ¹ through a modifiable oxygen, nitrogen, or carbon atom. [000149] In certain embodiments, the EPL is one of the following: l . P. Moiety for Topoisomerase [000150] In certain embodiments, the EPL is a moiety that binds to topoisomerase. [000151] In certain embodiments, the EPL is a moiety that binds to DNA Topoisomerase I (TOP1). Exemplary compounds that bind to TOP1 are reported in the literature, including: • ; • • • • ; • • • , • [000152] In certain embodiments, the EPL is a radical of one of the above compounds, which is attached to L ¹ through a modifiable oxygen, nitrogen, or carbon atom. [000153] In certain embodiments, the EPL is is a moiety that bind to topoisomerase I (TOP1). [000154] In certain embodiments, the EPL is one of the following: . [000155] In certain embodiments, the EPL is the following: . Q. Moiety for HDAC [000156] In certain embodiments, the EPL is a moiety that binds to Histone Deacetylase (HDAC). Exemplary compounds that bind to HDAC are reported in the literature, including: • • ; • • • ; • • • • . [000157] In certain embodiments, the EPL is a radical of one of the above compounds, which is attached to L ¹ through a modifiable oxygen, nitrogen, or carbon atom.

[000158] In certain embodiments, the EPL is one of the following: . [000159] In certain embodiments, the EPL is selected from those depicted in the compounds in Tables 1-7 below. In certain embodiments, the EPL is selected from those depicted in the compounds in Tables 1-A, 2-A, 3-A, 4-A, or 5-A below. [000160] As defined generally above, the TPL is a moiety that binds to a target protein selected from KRAS, HER2, or EGFR. In certain embodiments, TPL is a moiety that binds to KRAS. In certain embodiments, TPL is a moiety that binds to HER2. In certain embodiments, TPL is a moiety that binds to EGFR. [000161] In certain embodiments, TPL is selected from those depicted in the compounds in any one of Tables 1, 2, 3, 4, 5, 6, or 7 below. In certain embodiments, TPL is selected from those depicted in the compounds in any one of Tables 1-A, 2-A, 3-A, 4-A, or 5-A below. Exemplary further embodiments for TPL are provided in Part B below. [000162] As defined generally above, L ¹ is a bond, **-linker-O-, or **-linker-N(R ⁵ )-, where ** is a point of attachment to EPL, and L ¹ is connected to a nitrogen or oxygen atom of EPL when L ¹ is a bond. In certain embodiments, L ¹ is a bond. In certain embodiments, L ¹ is **- linker-O-. In certain embodiments, L ¹ is **-linker-N(R ⁵ )-, where ** is a point of attachment to EPL. In certain embodiments, L ¹ is selected from those depicted in the compounds in any one of Tables 1, 2, 3, 4, 5, 6, or 7 below. In certain embodiments, L ¹ is selected from those depicted in the compounds in any one of Tables 1-A, 2-A, 3-A, 4-A, or 5-A below. [000163] As defined generally above, L ² is a bond or a linker. In certain embodiments, L ² is a bond. In certain embodiments, L ² is a linker. In certain embodiments, L ² is selected from those depicted in the compounds in any one of Tables 1, 2, 3, 4, 5, 6, or 7 below. In certain embodiments, L ² is selected from those depicted in the compounds in any one of Tables 1-A, 2- A, 3-A, 4-A, or 5-A below. [000164] In certain embodiments, the linker 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(H)-, -N(C1-6 alkyl)-, -OC(O)-, -C(O)O-, -S(O)-, - S(O) ₂ -, -N(H)S(O) ₂ -, -N(C _1-6 alkyl)S(O) ₂ -, -S(O) ₂ N(H)-, -S(O) ₂ N(C _1-6 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(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. [000165] In certain embodiments, the linker has the formula –(C0-12 alkylene)-(optionally substituted 3-40 membered heteroalkylene)-(C0-12 alkylene)-. In certain embodiments, the linker is C4-14 alkylene. Exemplary More Specific Embodiments [000166] In certain embodiments, the compound is represented by Formula I-A: (I-A) or a pharmaceutically acceptable salt thereof; wherein: R ¹ and R ² each represent independently for each occurrence halo, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, hydroxyl, C1-C6 alkoxy, or cyano; R ³ represents independently for each occurrence C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, hydroxyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, or -(C1-C6 alkylene)-(C1-C6 alkoxy); TPL is a moiety that binds to a target protein selected from KRAS, HER2, or EGFR; m is 0, 1, or 2; n and p each represent independently 0, 1, 2, or 3; and L ² is a bond or a linker. [000167] The definitions of variables in Formula I-A above encompass multiple chemical groups. The application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii). [000168] In certain embodiments, the compound is a compound of Formula I-A. [000169] As defined generally above, R ¹ and R ² each represent independently for each occurrence halo, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, hydroxyl, C1-C6 alkoxy, or cyano. In certain embodiments, R ¹ and R ² each represent independently for each occurrence halo or C1-C6 alkyl. In certain embodiments, R ¹ and R ² each represent independently for each occurrence C ₁ -C ₆ alkyl. In certain embodiments, R ¹ and R ² are ethyl. In certain embodiments, R ¹ is C1-C6 alkyl. In certain embodiments, R ¹ is ethyl. [000170] As defined generally above, R ³ represents independently for each occurrence C1-C6 alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, hydroxyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ hydroxyalkyl, or -(C ₁ - C6 alkylene)-(C1-C6 alkoxy). In certain embodiments, R ³ represents independently for each occurrence C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or C ₁ -C ₆ hydroxyalkyl. In certain embodiments, R ³ is C1-C6 hydroxyalkyl. In certain embodiments, R ³ is C2-C3 hydroxyalkyl. [000171] As defined generally above, m is 0, 1, or 2. In certain embodiments, m is 1. In certain embodiments, m is 0. [000172] As defined generally above, n and p each represent independently 0, 1, 2, or 3. In certain embodiments, n and p each represent independently 0 or 1. In certain embodiments, n is 0 or 1. In certain embodiments, n is 0. In certain embodiments, p is 0 or 1. In certain embodiments, p is 1. [000173] As defined generally above, the TPL is a moiety that binds to a target protein selected from KRAS, HER2, or EGFR. In certain embodiments, TPL is a moiety that binds to KRAS. In certain embodiments, TPL is a moiety that binds to HER2. In certain embodiments, TPL is a moiety that binds to EGFR. In certain embodiments, TPL is selected from those depicted in the compounds in any one of Tables 1, 2, 3, 4, 5, 6, or 7 below. In certain embodiments, TPL is selected from those depicted in the compounds in any one of Tables 1-A, 2-A, 3-A, 4-A, or 5-A below. [000174] As defined generally above, L ² is a bond or a linker. In certain embodiments, L ² is a bond. In certain embodiments, L ² is a linker. [000175] In certain embodiments, the compound is represented by Formula I-B: (I-B) or a pharmaceutically acceptable salt thereof; wherein: R ¹ and R ² each represent independently for each occurrence halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C3-C6 cycloalkyl, hydroxyl, C1-C6 alkoxy, or cyano; R ³ represents independently for each occurrence C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, hydroxyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, or -(C1-C6 alkylene)-(C1-C6 alkoxy); m is 0, 1, or 2; and n and p each represent independently 0, 1, 2, or 3. TPL is a moiety that binds to a target protein selected from KRAS, HER2, or EGFR; and L ² is a bond or a linker. [000176] The definitions of variables in Formula I-B above encompass multiple chemical groups. The application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii). [000177] In certain embodiments, the compound is a compound of Formula I-B. [000178] As defined generally above, R ¹ and R ² each represent independently for each occurrence halo, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, hydroxyl, C1-C6 alkoxy, or cyano. In certain embodiments, R ¹ and R ² each represent independently for each occurrence halo or C1-C6 alkyl. In certain embodiments, R ¹ and R ² each represent independently for each occurrence C ₁ -C ₆ alkyl. In certain embodiments, R ¹ and R ² are ethyl. In certain embodiments, R ¹ is C1-C6 alkyl. In certain embodiments, R ¹ is ethyl. [000179] As defined generally above, R ³ represents independently for each occurrence C1-C6 alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, hydroxyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ hydroxyalkyl, or -(C ₁ - C6 alkylene)-(C1-C6 alkoxy). In certain embodiments, R ³ represents independently for each occurrence C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or C ₁ -C ₆ hydroxyalkyl. In certain embodiments, R ³ is C1-C6 hydroxyalkyl. In certain embodiments, R ³ is C2-C3 hydroxyalkyl. [000180] As defined generally above, m is 0, 1, or 2. In certain embodiments, m is 1. In certain embodiments, m is 0. [000181] As defined generally above, n and p each represent independently 0, 1, 2, or 3. In certain embodiments, n and p each represent independently 0 or 1. In certain embodiments, n is 0 or 1. In certain embodiments, n is 0. In certain embodiments, p is 0 or 1. In certain embodiments, p is 1. [000182] As defined generally above, the TPL is a moiety that binds to a target protein selected from KRAS, HER2, or EGFR. In certain embodiments, TPL is a moiety that binds to KRAS. In certain embodiments, TPL is a moiety that binds to HER2. In certain embodiments, TPL is a moiety that binds to EGFR. In certain embodiments, TPL is selected from those depicted in the compounds in any one of Tables 1, 2, 3, 4, 5, 6, or 7 below. In certain embodiments, TPL is selected from those depicted in the compounds in any one of Tables 1-A, 2-A, 3-A, 4-A, or 5-A below. [000183] As defined generally above, L ² is a bond or a linker. In certain embodiments, L ² is a bond. In certain embodiments, L ² is a linker. Part B: Exemplary Further Description of TPL Component of Compounds of Formula I, I-A, and I-B [000184] Compounds of Formula I, I-A, and I-B may be further characterized according to, for example, the identity of the TPL component. As generally described above, the TPL is a moiety that binds to a target protein selected from KRAS, HER2, or EGFR. In certain embodiments, TPL is a moiety that binds KRAS. In certain embodiments, TPL is a moiety that binds HER2. In certain embodiments, TPL is a moiety that binds EGFR. [000185] Exemplary moieties for the TPL component are described in more detail below. Moiety for HER2 [000186] In certain embodiments, the TPL is a moiety that binds human epidermal growth factor receptor 2 (HER2). Compounds that inhibit and/or bind to HER2 are reported in the literature, which include: • • • • • , as described in Wissner, A. et al., WO 2005/034955; • • • • • , , . ., 2012/122865. [000187] In certain embodiments, the TPL is a radical of one of the above compounds, which is attached to L ² through a modifiable oxygen, nitrogen, or carbon atom. [000188] In certain embodiments, the TPL is one of the following: wherein: R ^1A is -C(O)(NR ^5A )-(phenyl optionally substituted with 1, 2, 3, or 5 substituents independently selected from halo, hydroxyl, C _1-4 alkyl, C _1-4 alkoxyl, and -(C _1-4 alkylene- C(O)N(R ^5A )(R ^6A )); R ^2A is hydrogen, halo, hydroxyl, C _1-4 alkyl, C _1-4 alkoxyl, or -N(R ^5A )(R ^6A ); and R ^5A and R ^6A each represent independently for each occurrence hydrogen, C1-4 alkyl, C3-7 cycloalkyl, or -(C _1-4 alkylene)-C ₃ - ₇ cycloalkyl; or an occurrence of R ^5A and R ^6A attached to same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring. [000189] In certain embodiments, the TPL is one of the following: . [000190] In certain embodiments, the TPL is one of the following: wherein: R ^1A is -C(O)(NR ^5A )-(phenyl optionally substituted with 1, 2, 3, or 5 substituents independently selected from halo, hydroxyl, C _1-4 alkyl, C _1-4 alkoxyl, and -(C _1-4 alkylene- C(O)N(R ⁵ )(R ⁶ )); R ^2A is hydrogen, halo, hydroxyl, C _1-4 alkyl, C _1-4 alkoxyl, or -N(R ^5A )(R ^6A ); and R ^5A and R ^6A each represent independently for each occurrence hydrogen, C _1-4 alkyl, C ₃ - ₇ cycloalkyl, or -(C1-4 alkylene)-C3-7 cycloalkyl; or an occurrence of R ^5A and R ^6A attached to same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring. [000191] In certain embodiments, the . Moiety for EGFR [000192] In certain embodiments, the TPL is a moiety that binds to or inhibits epidermal growth factor receptor (EGFR). Exemplary compounds that bind to and/or inhibit EGFR are reported in the literature, such as Osimertinib and mavelertinib. A radical of such compounds reported in the literature that bind EGFR are amenable for use in the present invention. [000193] Exemplary compounds that inhibit or bind to EGFR that are reported in the literature include: • • 27960; • described in Bingaman, D.P. et al., WO 2014/152661; • ; • • , , . . ., ; • • , g, . ., ; • ; • , , . . ., ; • • 2016/060443; • described in Zhang, D. et al., WO 2014/187319; • • 2005/059678; • , as described in Lee, K. et al., WO 2012/064706. • . • • • [000194] In certain embodiments, the TPL is a radical of one of the above compounds, which is attached to L ² through a modifiable oxygen, nitrogen, or carbon atom. [000195] In certain embodiments, the TPL is one of the following: wherein: R ^1A is hydrogen, halo, hydroxyl, C1-4 alkyl, C1-4 alkoxyl, or N(R ^5A )(R ^6A ); and R ^2A is -(5-12 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein said heteroaryl is optionally substituted with 1, 2, 3, or 5 substituents independently selected from halo, hydroxyl, C _1-4 alkyl, and C _1-4 alkoxyl)-(5-12 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein said heteroaryl is optionally substituted with 1, 2, 3, or 5 substituents independently selected from halo, hydroxyl, C1-4 alkyl, and C1- 4 alkoxyl); and R ^5A and R ^6A each represent independently for each occurrence hydrogen, C1-4 alkyl, C3-7 cycloalkyl, or -(C1-4 alkylene)-C3-7 cycloalkyl; or an occurrence of R ^5A and R ^6A attached to same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring. [000196] In certain embodiments, the TPL is one of the following: wherein: R ^1A is C _1-4 alkyl; R ^2A is hydrogen or C1-4 alkyl; R ^3A is halo; and R ^4A is C2-6 alkenyl. [000197] In certain embodiments, the TPL is one of the following: wherein: R ^1A is C1-4 alkyl; R ^2A and R ^6A are independently hydrogen or C1-4 alkyl; R ^3A is halo; R ^5A is C1-6 alkyl or C3-6 cycloalkyl; and X ^1A is C _1-5 alkylene. [000198] In certain embodiments, the TPL is one of the following: wherein: R ^1A and R ^4A each represent independently for each occurrence hydrogen, halo, hydroxyl, C1-4 alkyl, C1-4 alkoxyl, or C3-6 cycloalkyl; R ^2A represents independently for each occurrence hydrogen or C1-4 alkyl; R ^3A is a 3-7 membered saturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with 0, 1, 2, or 3 substituents independently selected from halo, hydroxyl, C _1-4 alkyl, C1-4 alkoxyl, or C3-6 cycloalkyl; R ^5A is C _1-6 hydroxyalkyl or C _1-6 alkyl; R ^6A is C1-6 alkyl or or C3-6 cycloalkyl; R ^7A is C _1-6 alkylene)-N(R ^2A ) ₂ ; n and m are independently 1 or 2. [000199] In certain embodiments, the wherein R ^1A and R ^4A each represent independently for each occurrence hydrogen, halo, hydroxyl, C _1-4 alkyl, C1-4 alkoxyl, or C3-6 cycloalkyl; R ^2A represents independently for each occurrence hydrogen or C _1-4 alkyl; R ^3A is a 3-7 membered saturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with 0, 1, 2, or 3 substituents independently selected from halo, hydroxyl, C _1-4 alkyl, C1-4 alkoxyl, or C3-6 cycloalkyl; R ^5A is C1-6 hydroxyalkyl or C1-6 alkyl; and n and m are independently 1 or 2. [000200] In certain embodiments, the R ^3A is piperazinyl substituted with 0, 1, 2, or 3 substituents independently selected from halo and C1-4 alkyl. [000201] In certain embodiments, the TPL is one of the following: . [000202] In certain embodiments, the TPL is one of the following:

[000203] In certain embodiments, the TPL is one of the following:

[000204] In certain embodiments, the TPL is one of the following: . [000205] In certain embodiments, the TPL is one of the following:

, [000206] In certain embodiments, the , . Moiety for KRAS [000207] In certain embodiments, the TPL is a moiety that binds to KRas. Exemplary compounds that bind to KRas are reported in the literature, such as MRTX849 and AMG510. A radical of such compounds reported in the literature that bind KRas are amenable for use in the present invention. [000208] In certain embodiments, the TPL is one of the following: wherein: R ^1A represents independently for each occurrence hydrogen, halo, hydroxyl, C1-4 alkyl, or C _1-4 alkoxyl; R ^1B is C6-12 aryl or 6-12 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen, or sulfur, wherein the aryl and heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, hydroxyl, C1-4 alkyl, or C1-4 alkoxyl; R ^1C is -(C _1-6 alkylene)-3-7 membered saturated mono-cyclic or bicylic heterocyclyl containing 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur; R ^1D is -(C1-6 alkylene)-CN; R ^1E is C _6-12 aryl or 6-12 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen, or sulfur, wherein the aryl and heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, hydroxyl, C1-4 alkyl, or C1-4 alkoxyl; and R ^1F is C1-6 alkyl. [000209] In certain embodiments, the TPL is one of the following: : R ^1A represents independently for each occurrence hydrogen, halo, hydroxyl, C1-4 alkyl, or C _1-4 alkoxyl; R ^1B is C6-12 aryl optionally substituted by 1, 2, or 3 substituents independently selected from halo, hydroxyl, C _1-4 alkyl, or C _1-4 alkoxyl; R ^1C represents independently for each occurrence hydrogen, halo, or C1-4 alkyl; R ^1D represents independently for each occurrence (C1-6 alkylene)-CN; R ^1E is C _1-6 alkylene; and R ^1F is 3-6 membered saturated, monocyclic heterocyclylene containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. [000210] In certain embodiments, the TPL is the following: . [000211] In certain embodiments, the TPL is the following: . [000212] In certain embodiments, TPL is one of the following: [000213] In certain embodiments, TPL is one of the following: [000214] In certain embodiments, the TPL is one of the following: . [000215] In certain embodiments, the TPL is one of the following: [000216] In certain embodiments, the TPL is one of the following:

[000217] In certain embodiments, the TPL is a radical wherein X is hydrogen, halo, C1-6 alkyl, amino or C1-6 alkoxy; and the TPL is attached to L ² through a modifiable oxygen, nitrogen, or carbon atom.

[000218] In certain embodiments, the , wherein R = H, Me, Et, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHR', OH, or NH ₂ ; and R' is alkyl, alkenyl, amido, amino, aminoalky, or alkoxy. In certain embodiments, the ,

[000219] In certain embodiments, the (e.g., alkyl); and R’ is H or a linker (e.g., alkyl). [000220] In certain embodiments, the . [ wherein X is NH, NR ^a , CH2, CHR ^a , or C(R ^a )2; and R ^a is alkyl, alkenyl, amido, amino, aminoalky, or alkoxy. [000222] In certain embodiments, the wherein X is NH, NR ^a , CH2, CHR ^a , or C(R ^a )2; R ^a is alkyl, alkenyl, amido, amino, aminoalky, or alkoxy; and R' is H, Me, or Et. In certain embodiments, the , [ certain embodiments, the TPL is one of the following: wherein: R ^1A and R ^4A each represent independently for each occurrence hydrogen, halo, hydroxyl, C _1-4 alkyl, C _1-4 alkoxyl, or C _3-6 cycloalkyl; R ^2A represents independently for each occurrence hydrogen or C1-4 alkyl; R ^3A is a 3-7 membered saturated heterocyclylene containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the heterocyclylene is substituted with 0, 1, 2, or 3 substituents independently selected from halo and C _1-4 alkyl; R ^5A is hydrogen, halo, hydroxyl, or C1-4 alkyl; R ^6A is C _1-6 alkyl or C _3-6 cycloalkyl; R ^7A is C1-6 alkylene)-N(R ^8A )2; R ^8A is hydrogen, C1-6 alkyl, or C3-6 cycloalkyl; n and m are independently 1 or 2. [000224] In certain embodiments, the TPL is one of the following: wherein: R ^1A represents independently for each occurrence hydrogen, halo, hydroxyl, C _1-4 alkyl, C _1-4 alkoxyl, or C _3-6 cycloalkyl; R ^6A is C _1-6 alkyl or C _3-6 cycloalkyl; and n and m are independently 1 or 2. [000225] In certain embodiments, the TPL is one of the following: wherein: R ^1A and R ^4A each represent independently for each occurrence hydrogen, halo, hydroxyl, C1-4 alkyl, C1-4 alkoxyl, or C3-6 cycloalkyl; R ^2A represents independently for each occurrence hydrogen or C _1-4 alkyl; R ^3A is a 3-7 membered saturated heterocyclylene containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the heterocyclylene is substituted with 0, 1, 2, or 3 substituents independently selected from halo and C1-4 alkyl; R ^5A is hydrogen, halo, hydroxyl, or C _1-4 alkyl; R ^6A is C1-6 alkyl or C3-6 cycloalkyl; R ^7A is C _1-6 alkylene)-N(R ^8A ) ₂ ; R ^8A is hydrogen, C1-6 alkyl, or C3-6 cycloalkyl; n and m are independently 1 or 2. [000226] In certain embodiments, the TPL is one of the following: wherein: R ^1A and R ^4A each represent independently for each occurrence hydrogen, halo, hydroxyl, C1-4 alkyl, C1-4 alkoxyl, or C3-6 cycloalkyl; R ^3A is a 3-7 membered saturated heterocyclylene containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the heterocyclylene is substituted with 0, 1, 2, or 3 substituents independently selected from halo and C _1-4 alkyl; R ^5A is hydrogen, halo, hydroxyl, or C1-4 alkyl; R ^8A is hydrogen, C1-6 alkyl, or C3-6 cycloalkyl; and n and m are independently 1 or 2. [000227] In certain embodiments, the wherein R ^1A and R ^4A each represent independently for each occurrence hydrogen, halo, hydroxyl, C1-4 alkyl, C _1-4 alkoxyl, or C _3-6 cycloalkyl; R ^5A is hydrogen, halo, hydroxyl, or C _1-4 alkyl; R ^6A is C _1-6 alkyl or C3-6 cycloalkyl; R ^8A is hydrogen, C1-6 alkyl, or C3-6 cycloalkyl; n and m are independently 1 or 2. [000228] In certain embodiments, the TPL is one of the following: . [000229] In certain embodiments, the TPL is a moiety that binds to a mutated Kirsten rat sarcoma 2 viral oncogene homolog. Compounds that bind mutated Kirsten rat sarcoma 2 viral oncogene homolog are reported in the literature, which include: • • , , . ., 2016/161361; • • , as esc e ea e, . e a., e em e 2018, vol.9(6), page 557. • • • • 539. [000230] In certain embodiments, the TPL is a radical of one of the above compounds, which is attached to L ² through a modifiable oxygen, nitrogen, or carbon atom. Additional Features [000231] Compounds of Formula I, I-A, and I-B may be further characterized according to the molecular weight of the TPL. In certain embodiments, the TPL has a molecular weight of less than 1500 Da, 1200 Da, 1000 Da, 800 Da, 600 Da, 400 Da, 300 Da, 200 Da, 150 Da, or 100 Da. Compounds of Formula I may be further characterized according to the molecular weight of the EPL. In certain embodiments, the EPL has a molecular weight of less than 1500 Da, 1200 Da, 1000 Da, 800 Da, 600 Da, 400 Da, 300 Da, 200 Da, 150 Da, or 100 Da. [000232] In certain embodiments, the TPL is selected from those depicted in the compounds in Tables 1-7 below. In certain embodiments, the TPL is selected from those depicted in the compounds in Tables 1-A, 2-A, 3-A, 4-A, or 5-A below. Part C: Exemplary Further Description of Linker Component of Compounds of Formula I, I-A, and I-B [000233] Compounds of Formula I, I-A, and I-B may be further characterized according to, for example, the identity of the linker 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. [000234] In some embodiments, the linker is symmetrical. In some embodiments, the linker is asymmetric. [000235] In certain embodiments, the linker is a bivalent C1-30 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(C1-4 alkyl)-, -N(C3-5 cycloalkyl)-, -O-, - C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O) ₂ -, -S(O) ₂ N(H)-, -S(O) ₂ N(C _1-4 alkyl)-, -S(O) ₂ N(C _3- 5 cycloalkyl)-, -N(H)C(O)-, -N(C1-4 alkyl)C(O)-, -N(C3-5 cycloalkyl)C(O)-, -C(O)N(H)-, - C(O)N(C _1-4 alkyl)-, -C(O)N(C _3-5 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. [000236] In certain embodiments, the linker 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, C _1-6 alkyl, or C _3-6 cycloalkyl. [000237] In certain embodiments, the linker 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)2N(H)-, -S(O)2N(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(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. [000238] In yet other embodiments, the linker 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. [000239] In certain embodiments, the linker 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, the linker is a heteroalkylene having from 4 to 10 atoms selected from carbon, oxygen, nitrogen, and sulfur. In certain embodiments, the linker is a heteroalkylene having from 4 to 30 atoms selected from carbon, oxygen, and nitrogen. In certain embodiments, the linker is a heteroalkylene having from 4 to 20 atoms selected from carbon, oxygen, and nitrogen. In certain embodiments, the linker is a heteroalkylene having from 4 to 10 atoms selected from carbon, oxygen, and nitrogen. In certain embodiments, the linker is a heteroalkylene having from 4 to 30 atoms selected from carbon and oxygen. In certain embodiments, the linker is a heteroalkylene having from 4 to 20 atoms selected from carbon and oxygen. In certain embodiments, the linker is a heteroalkylene having from 4 to 10 atoms selected from carbon and oxygen. [000240] In additional embodiments, the linker 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, the linker is substituted with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocycle group. [000241] In certain embodiments, the linker 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)2N(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. [000242] In certain embodiments, the linker 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)2N(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, C _1-6 alkyl, or C3-6 cycloalkyl. [000243] In certain embodiments, the linker 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 - C6 alkyl, and p is 0 or 1. [000244] In certain embodiments, the linker 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 C1-C6 alkyl; and p is 0 or 1. [000245] In certain embodiments, the linker has the formula -N(R)-(3-20 membered heteroalkylene)p-CH2-C(O)-; wherein the 3-20 membered heteroalkylene is optionally substituted with 1, 2, or 3 substituents independently selected from halogen and C ₁ -C ₆ haloalkyl; R is hydrogen or C1-C6 alkyl; and p is 0 or 1. [000246] In some embodiments, the linker is one of the following:

; wherein a dashed bond indicates a point of attachment. [000247] In certain embodiments, the linker has the formula –(C0-12 alkylene)-(optionally substituted 3-40 membered heteroalkylene)-(C0-12 alkylene)-. In certain embodiments, the linker is C _4-14 alkylene. In certain embodiments, the linker is -(CH ₂ ) _6-10 -. [000248] In certain embodiments, the linker is selected from those depicted in the compounds in Tables 1-7 below. In certain embodiments, the linker is selected from those depicted in the compounds in Tables 1-A, 2-A, 3-A, 4-A, or 5-A below. Exemplary More Specific Embodiments [000249] In certain embodiments, the portion of Formula I is one of the following (thereby providing compounds that bind to Kras):

of the following (thereby providing compounds that bind to EGFR):

. [000251] In certain embodiments, the portion of Formula I is one of the following (thereby providing compounds that bind to HER2): . Exemplary Specific Compounds [000252] 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 in Table 1-A, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1-A. Table 1. Compounds that Bind CDK

Table 1-A. Additional Compounds that Bind CDK

[000253] In certain embodiments, the compound is a compound in Table 2, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 2. In certain embodiments, the compound is a compound in Table 2-A, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 2-A. Table 2. Compounds that Bind PLK1

Table 2-A. Additional Compound that Binds PLK1 [000254] In certain embodiments, the compound is a compound in Table 3, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 3. In certain embodiments, the compound is a compound in Table 3-A, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 3-A. Table 3. Compounds that Bind KIF11

[000255] In certain embodiments, the compound is a compound in Table 4, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 4. In certain embodiments, the compound is a compound in Table 4-A, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 4-A. Table 4. Compounds that Bind Topoisomerase Table 4-A. Additional Compound that Binds Topoisomerase [000256] In certain embodiments, the compound is a compound in Table 5, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 5. In certain embodiments, the compound is a compound in Table 5-A, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 5-A. Table 5. Compounds that Bind Tubulin

Table 5-A. Additional Compounds that Bind Tubulin

[000257] In certain embodiments, the compound is a compound in Table 6, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 6. Table 6. Additional Compounds

[000258] In certain embodiments, the compound is a compound in Table 7, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 7. Table 7. Additional Sulfone and Sulfonamide Compounds

[000259] In certain embodiments, the compound is a compound in any one of Tables 1-7, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in any one of Tables 1-7. In certain embodiments, the compound is a compound in any one of Tables 1-A, 2-A, 3-A, 4-A, or 5-A, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in any one of Tables 1-A, 2-A, 3-A, 4-A, or 5-A. Synthetic Methods [000260] 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. [000261] In the Schemes, it is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated (for example, use of protecting groups or alternative reactions). Protecting group chemistry and strategy is well known in the art, for example, as described in detail in “Protecting Groups in Organic Synthesis”, 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. [000262] The synthetic route illustrated in Scheme 1 is a general method for preparing heterobifunctional compounds D’. Reacting compound A’ (a precursor of EPL, for example, a discrete compound that is an effector protein ligand) with 3-bromo-2-(bromomethyl)propanoic acid affords intermediate B’. Reacting intermediate B’ with compound C’ (a precursor of TPL) under amide-coupling conditions affords heterobifunctional compound D’. It is understood by one skilled in the art of organic synthesis that protecting group strategies may be employed as necessary. SCHEME 1. II. Therapeutic Applications [000263] The heterobifunctional compounds described herein, such as a compound of Formula I, 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, or other compounds in Section I, to treat the cancer. In certain embodiments, the particular compound of Formula I is a compound defined by one of the embodiments described above. Cancer [000264] 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. [000265] 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. [000266] 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. [000267] 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. [000268] 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, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, or leiomyoma. [000269] 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. [000270] 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. [000271] 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. [000272] 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. [000273] 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. [000274] 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. [000275] 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 [000276] 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 other compounds in Section I, to cause death of the cancer cell. In certain embodiments, the particular compound of Formula I is a compound defined by one of the embodiments described above. [000277] 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.” Combination Therapies [000278] 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. [000279] Accordingly, in certain embodiments, the method further comprises administering to the subject an additional therapeutic agent that treats the disease contemplated herein. [000280] 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. [000281] A synergistic effect may be calculated, for example, using suitable methods such as, for example, the Sigmoid-E _max 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. [000282] 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. [000283] 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. [000284] 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). [000285] 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.). [000286] 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). [000287] 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). [000288] 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). [000289] 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). [000290] 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). [000291] 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). [000292] 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). [000293] 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. [000294] 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). [000295] 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). [000296] 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). [000297] 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). [000298] 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). [000299] 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). [000300] 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). [000301] 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). [000302] 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). [000303] 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). [000304] 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). [000305] 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). [000306] 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). [000307] 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.” [000308] 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). [000309] 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). [000310] Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I 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. [000311] Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I or other compounds in Section I) for treating a medical disease, such a disease described herein (e.g., cancer). III. Pharmaceutical Compositions and Dosing Considerations [000312] 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. [000313] 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. [000314] 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. [000315] 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. [000316] 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. [000317] 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. [000318] 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. [000319] 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. [000320] 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. [000321] 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. [000322] 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. [000323] 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. [000324] 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. [000325] 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. [000326] 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. [000327] 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. [000328] 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. [000329] 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. [000330] 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. [000331] 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. [000332] 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. [000333] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention. [000334] 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. [000335] 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. [000336] 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. [000337] 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. [000338] 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. [000339] 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. [000340] 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. [000341] 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. [000342] 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. [000343] 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. [000344] 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. [000345] 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. [000346] 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. [000347] 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. [000348] 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. [000349] 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. [000350] The invention further provides a unit dosage form (such as a tablet or capsule) comprising a heterobifunctional compound described herein in a therapeutically effective amount for the treatment of a medical disorder described herein. IV. MEDICAL KITS [000351] 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. EXAMPLES [000352] 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 [000353] 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 Cl ₂ ), and dimethylformamide (DMF) was dried by a PureSolvTM 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. ¹ H and ¹³ C NMR spectra were recorded on an Agilent DD2500 (500 MHz ¹ H; 125 MHz ¹³ C) or Agilent DD2600 (600 MHz ¹ H; 150 MHz ¹³ C) or Agilent DD2400 (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. 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. 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. The abbreviation “TFA” refers to trifluoroacetic acid.

EXAMPLE 1 - Synthesis of Compound I-1 [000354] Compound 1, starting material in the above reaction scheme, is a known compound reported in J. Med. Chem., 2020, 63, 6679 – 6693. 1.1 Preparation of compound I-1 [000355] To a solution of 6-fluoro-7-(2-fluoro-6-hydroxy-phenyl)-1-(2-isopropyl-4-meth yl-3- pyridyl)-4-[(2S)-2-methylpiperazin-1-yl]pyrido[2,3-d]pyrimid in-2-one (38 mg, 61 µmol, 1.0 equiv, TFA salt) and 2-[[5-[[[3-ethyl-5-[(2S)-2-(2-hydroxyethyl)-1-piperidyl]pyra zolo[1,5- a]pyrimidin-7-yl]amino]methyl]-2-oxo-1-pyridyl]methyl]prop-2 -enoic acid (29 mg, 61 µmol, 1.0 equiv) in DMF (1.0 mL) was added DIEA (40 mg, 306 µmol, 5.0 equiv), HOBt (17 mg, 122 µmol, 2.0 equiv) and EDCI (24 mg, 122 µmol, 2.0 equiv). The mixture was stirred at 25 °C for 16 h and then concentrated. The resulting residue was purified by prep-HPLC (column: Phenomenex Synergi Max-RP C18150*21.2mm*4µm; mobile phase: [water(TFA)-ACN]; B%: 29%-49%, 7min) and prep-HPLC (column: Waters Xbridge 150*25mm* 5µm; mobile phase: [water( NH ₄ HCO ₃ )-ACN]; B%: 38%-68%, 8min) to give 4-[(2S)-4-[2-[[5-[[[3-ethyl-5- [(2S)-2-(2-hydroxyethyl)-1-piperidyl]pyrazolo[1,5-a]pyrimidi n-7-yl]amino]methyl]-2-oxo-1- pyridyl]methyl]prop-2-enoyl]-2-methyl-piperazin-1-yl]-6-fluo ro-7-(2-fluoro-6-hydroxy- phenyl)-1-(2-isopropyl-4-methyl-3-pyridyl)pyrido[2,3-d]pyrim idin-2-one (3.7 mg, 6 % yield) as a yellow solid. ¹ H NMR: (400 MHz, MeOD): δ 8.43 - 8.35 (m, 1H), 8.24 - 8.02 (m, 1H), 7.80 - 7.68 (m, 2H), 7.28 - 7.17 (m, 2H), 6.69 - 6.52 (m, 3H), 5.70 - 5.59 (m, 1H), 5.52 - 5.40 (m, 2H), 5.27 - 4.95 (m, 4H), 4.78 - 4.52 (m, 1H), 4.47 - 4.35 (m, 2H), 4.34 - 4.12 (m, 2H), 3.65 - 3.39 (m, 3H), 3.23 - 2.65 (m, 3H), 2.64 - 2.35 (m, 2H), 2.18 - 2.05 (m, 1H), 2.03 - 1.89 (m, 3H), 1.82 - 1.63 (m, 6H), 1.60 - 1.35 (m, 1H), 1.34 - 1.05 (m, 10H), 1.04 - 0.79 (m, 4H). LC-MS: MS (ES+): RT = 1.707 min, m/z = 969.4 [M + H+], LC-MS METHOD 25.

EXAMPLE 2 - Synthesis of Compound I-2 [000356] Compound 2 is described in, for example, J. Med. Chem., 2020, 63, 6679 – 6693. 2.1 Preparation of compound I-2 [000357] To a solution of 2-[[5-[[[3-ethyl-5-[(2S)-2-(2-hydroxyethyl)-1- piperidyl]pyrazolo[1,5-a]pyrimidin-7-yl]amino]methyl]-2-oxo- 1-pyridyl]methyl]prop-2-enoic acid (40 mg, 83 µmol, 1.0 equiv) and 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1- methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]p yrimidin-4-yl]piperazin-2- yl]acetonitrile (44 mg, 83 µmol, 1.0 equiv) in DMF (1 mL) was added HATU (32 mg, 83 µmol, 1.0 equiv) and DIEA (54 mg, 416 µmol, 5.0 equiv). The mixture was stirred at 25 °C for 1 h and purified by prep-HPLC (column: YMC Triart 30*150mm*7µm; mobile phase: [water(HCl)-ACN]; B%: 40%-60%, 9min) to give 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)- 1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d ]pyrimidin-4-yl]-1-[2-[[5-[[[3- ethyl-5-[(2S)-2-(2-hydroxyethyl)-1-piperidyl]pyrazolo[1,5-a] pyrimidin-7-yl]amino]methyl]-2- oxo-1-pyridyl]methyl]prop-2-enoyl]piperazin-2-yl]acetonitril e (5 mg, 6% yield) as a white solid. ¹ 7.75 (m, 1H), 7.69-7.67 (m, 1H), 7.53-7.51 (m, 2H), 7.49-7.38 (m, 3H), 7.31-7.30 (m, 2H), 6.62-6.58 (m, 1H), 5.65-5.62 (m, 1H), 5.35-5.33 (m, 1H), 4.58-4.35 (m, 6H), 4.34-4.33 (m, 2H), 4.33-4.28 (m, 4H), 3.58-3.48 (m, 4H), 3.18- 3.13 (m, 10H), 2.58-2.57 (m, 4H), 2.49-2.47 (m, 4H) 2.47-2.19 (m, 6H), 1.75-1.74 (m, 2H), 1.74-1.73 (m, 8H), 1.73-1.68 (m, 2H), 1.17-1.14 (m, 3H), 0.90-0.88 (m, 3H). LC-MS: MS (ES+): RT = 1.915 min, m/z = 994.5 [M + H+], LC-MS METHOD 25. EXAMPLE 3 - Synthesis of (S)-5-(((3-ethyl-5-(2-(2-hydroxyethyl)piperidin-1- yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)pyridin-2-ol 3.1 Preparation of compound 2 [000358] To a solution of BnOH (3.0 g, 28 mmol, 1.3 equiv) in THF (60 mL) was added NaH (1.3 g, 32 mmol, 60% purity, 1.5 equiv) at 0 °C. The mixture was stirred at 25 °C for 0.5 h and 6-chloropyridine-3-carbonitrile (3 g, 22 mmol, 1.0 equiv) was added. The mixture was stirred at 25 °C for 0.5 h and poured into ethyl acetate (200 mL). The mixture was stirred for 0.2 h and filtered. The filtrate was concentrated to give 6-benzyloxypyridine-3-carbonitrile (4 g, 88% yield) as a yellow solid. LC-MS: MS (ES+): RT = 0.852 min, m/z = 211.1 [M + H+]. 3.2 Preparation of compound 3 [000359] To a mixture of 6-benzyloxypyridine-3-carbonitrile (4.0 g, 19 mmol, 1.0 equiv), NiCl ₂ •6H ₂ O (904 mg, 3.81 mmol, 0.2 equiv) and Boc ₂ O (8.3 g, 38 mmol, 2.0 equiv) in MeOH (60 mL) was added NaBH4 (1.83 g, 48 mmol, 2.5 equiv) in small portions at 0 °C. The mixture was stirred at 0 °C for 1 h and concentrated. The residue was poured into ethyl acetate (200 mL), washed with water (200 mL), brine (200 mL), dried over by Na2SO4, filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 1:0 to 10:1) to give tert-butyl N-[(6-benzyloxy-3- pyridyl)methyl]carbamate (4.2 g, 70% yield) as a yellow solid. ¹ H NMR: (400 MHz, CDCl ₃ ): δ 8.08 (d, J = 2.4 Hz, 1H) 7.57 (d, J = 7.2 Hz, 1H), 7.43-7.51 (m, 2H), 7.29-7.43 (m, 4H), 6.80 (d, J = 8.4 Hz, 1H), 5.38 (s, 2H), 4.26 (d, J = 5.2 Hz, 2H), 1.47 (s, 9H). LC-MS: MS (ES+): RT = 0.879 min, m/z = 315.1 [M +H+]. 3.3 Preparation of compound 4 [000360] To a solution of tert-butyl N-[(6-benzyloxy-3-pyridyl)methyl]carbamate (11 g, 35 mmol, 1.0 equiv) in DCM (70 mL) was added TFA (30.8 g, 270 mmol, 7.7 equiv). The mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated to give crude (6-benzyloxy-3- pyridyl)methanamine (11.4 g, 34.73 mmol, crude, TFA salt) as a yellow oil. 3.4 Preparation of compound 5 [000361] To a solution of (6-benzyloxy-3-pyridyl)methanamine (11.5 g, 35 mmol, 1.5 equiv, TFA salt) and 5,7-dichloro-3-ethyl-pyrazolo[1,5-a]pyrimidine (5.0 g, 23 mmol, 1.0 equiv) in MeCN (100 mL) was added NaHCO3 (5.9 g, 70 mmol, 3.0 equiv) and DIEA (3.0 g, 23 mmol, 1.0 equiv). The mixture was stirred at 80 °C for 12 h. The mixture was filtered and concentrated. The residue was purified by column: Kromasil Eternity XT 250*80mm*10µm; mobile phase: [water(10mM NH ₄ HCO ₃ )-ACN]; B%: 60%-90%, 20 min to give N-[(6- benzyloxy-3-pyridyl)methyl]-5-chloro-3-ethyl-pyrazolo[1,5-a] pyrimidin-7-amine (8.2 g, 89% yield) as a brown solid. LC-MS: MS (ES+): RT = 1.040 min, m/z = 394.1 [M + H+]. 3.5 Preparation of compound 6 [000362] To a solution of N-[(6-benzyloxy-3-pyridyl)methyl]-5-chloro-3-ethyl-pyrazolo[ 1,5- a]pyrimidin-7-amine (2.0 g, 5 mmol, 1.0 equiv) and 2-[(2S)-2-piperidyl]ethanol (984 mg, 7.6 mmol, 1.5 equiv) in NMP (2 mL) was added KF (1.48 g, 25 mmol, 5.0 equiv). The mixture was heated to 140 °C and stirred under N2 for 12 h. The solution was poured into ethyl acetate (200 mL), washed with water (100 mL), brine (100 mL), dried over by Na2SO4. The combined organic layer was concentrated and the residue was purified by silica gel chromatography (Petroleum ether : Ethyl acetate = 20:1 to 1:1) to give 2-[(2S)-1-[7-[(6-benzyloxy-3- pyridyl)methylamino]-3-ethyl-pyrazolo[1,5-a]pyrimidin-5-yl]- 2-piperidyl]ethanol (0.8 g, 32% yield) as a yellow oil. LC-MS: MS (ES+): RT = 0.818 min, m/z = 487.2 [M +H+]. 3.6 Preparation of 5-[[[3-ethyl-5-[(2S)-2-(2-hydroxyethyl)-1-piperidyl]pyrazolo [1,5- a]pyrimidin-7-yl]amino]methyl]pyridin-2-ol [000363] To a solution of 2-[(2S)-1-[7-[(6-benzyloxy-3-pyridyl)methylamino]-3-ethyl- pyrazolo[1,5-a]pyrimidin-5-yl]-2-piperidyl]ethanol (580 mg, 1.2 mmol, 1.0 equiv) in DCM (10 mL) was added BCl3 (1 M, 10 mL, 1.0 equiv) at 0 °C. The mixture was stirred at 25 °C for 1 h and quenched with saturated sodium bicarbonate (30 mL) and ammonium hydroxide (3 mL) at 0 °C. The mixture was stirred at 25 °C for 1 h and extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica column chromatography on silica gel ( Dichloromethane : Methanol from 50/1 to 5/1) to give 5-[[[3-ethyl-5-[(2S)-2-(2-hydroxyethyl)- 1-piperidyl]pyrazolo[1,5-a]pyrimidin-7-yl]amino]methyl]pyrid in-2-ol (375 mg, 78% yield) as an off-white solid. ¹ H NMR: (400 MHz, DMSO-d ₆ ): δ 11.43 (s, 1H), 7.71 (t, J = 6.4 Hz, 1H), 7.64 (s, 1H), 7.53 (dd, J = 2.4, 9.6 Hz, 1H), 7.46 (d, J = 2.4 Hz, 1H), 6.30 (d, J = 9.6 Hz, 1H), 5.59 (s, 1H), 4.72 (t, J = 5.4 Hz, 1H), 4.61 (s, 1H), 4.34-4.19 (m, 3H), 3.43-3.35 (m, 2H), 2.84 (t, J = 12.4 Hz, 1H), 2.49-2.44 (m, 2H), 1.89-1.76 (m, 1H), 1.70-1.54 (m, 6H), 1.43-1.30 (m, 1H), 1.17 (t, J = 7.6 Hz, 3H). LC-MS: MS (ES+): RT = 2.213 min, m/z = 397.2 [M + H+]; LC- MS METHOD 01. EXAMPLE 4 - Synthesis of (2S)-5-(2,5-difluorophenyl)-2-[3-[(4-hydroxy-2- pyridyl)amino]propyl]-N-methoxy-N-methyl-2-phenyl-1,3,4-thia diazole-3-carboxamide 4.1 Preparation of compound 2 [000364] To a mixture of pyrrolidin-2-one (2 g, 23 mmol, 1 equiv) and 2-bromo-4-methoxy- pyridine (5.7 g, 30 mmol, 1.3 equiv) in dioxane (60 mL) was added CuI (90 mg, 470 µmol, 0.02 equiv), K2CO3 (6.5 g, 47 mmol, 2 equiv) and N,N'-dimethylethane-1,2-diamine (207 mg, 2 mmol, 0.1 equiv). The mixture was stirred at 110 °C for 12 h under N ₂ . Then, the mixture was concentrated and the resulting residue was purified by column (Petroleum ether: Ethyl acetate = 10:1 to 3:1) to give 1-(4-methoxy-2-pyridyl) pyrrolidin-2-one (2.6 g, 58 % yield) as colorless oil. ¹ NMR: (400 MHz, CDCl3): δ 8.07 (d, 1H, J = 6.0 Hz), 7.98 (d, 1H, J = 2.4 Hz), 6.54 (dd, 2H, J = 6.0 Hz, J = 2.4 Hz), 4.05 - 4.02 (m, 2H), 3.80 (s, 3H), 2.61 - 2.57 (m, 2H), 2.09 - 2.01 (m, 2H). 4.2 Preparation of compound 3 [000365] To a mixture of 1-(4-methoxy-2-pyridyl) pyrrolidin-2-one (2 g, 10 mmol, 1 equiv) in THF (30 mL) was added dropwise PhMgBr (3 M, 4 mL, 1.2 equiv) at 0 °C. The mixture was stirred at 0 °C for 1h under N2. Then, the mixture was quenched with water (100 mL) and extracted with EtOAc (3 x 60 mL). The combined organic layer was concentrated under reduced pressure to give 4-[(4-methoxy-2-pyridyl) amino]-1-phenyl-butan-1-one (2.8 g, 99 % yield) as a white solid. LC-MS: MS (ES+): RT = 0.757 min, m/z =271.2 [M + H+]. 4.3 Preparation of compound 4 [000366] To a solution of 4-[(4-methoxy-2-pyridyl) amino]-1-phenyl-butan-1-one (3.2 g, 12 mmol, 1 equiv) in THF (20 mL) was added Boc ₂ O (4.0 g, 18 mmol, 1.5 equiv) and Et ₃ N (2 g, 24 mmol, 3 mL, 2 equiv). The mixture was stirred at 25 °C for 12 h. The resulting residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=15/1 to 6/1) to give tert-butyl N-(4-methoxy-2-pyridyl)-N-(4-oxo-4-phenyl-butyl) carbamate (2.9 g, 66 % yield) as a white solid. ¹ H NMR: (400 MHz, CDCl ₃ ): δ 5.88 (d, 1H, J = 5.6 Hz), 7.95 - 7.93 (m, 2H), 7.57 - 7.53 (m, 1H), 7.49 - 7.40 (m, 2H), 7.19 (d, 1H, J = 2.0 Hz), 6.56 (dd, 1H, J = 5.6 Hz, J = 2.0 Hz), 4.16 - 4.05 (m, 2H), 3.84 (s, 3H), 3.05 - 3.02 (m, 2H), 2.11 - 2.04 (m, 2H), 1.51 (s, 9H). 4.4 Preparation of compound 6 [000367] To a solution of tert-butyl N-(4-methoxy-2-pyridyl)-N-(4-oxo-4-phenyl- butyl)carbamate (0.8 g, 2 mmol, 1 equiv) and 2,5-difluorobenzenecarbothiohydrazide (0.5 g, 3 mmol, 1 equiv) in EtOH (10 mL) was added AcOH (130 mg, 2 mmol, 1 equiv). The mixture was stirred at 80 °C for 12 h and concentrated. The resulting residue was purified by prep- HPLC (column: Waters Xbridge C18150*50mm* 10 µm; mobile phase: [water (NH4HCO3)- ACN]; B%: 54%-84%, 11 min) to give tert-butyl N-[3-[5-(2,5-difluorophenyl)-2-phenyl-3H- 1,3,4-thiadiazol-2-yl]propyl]-N-(4-methoxy-2-pyridyl)carbama te (0.4 g, 34 % yield) as a white solid. LC-MS: MS (ES+): RT = 0.881 min, m/z =540.2 [M + H+]. 4.5 Preparation of compound 7 [000368] To a solution of tert-butyl N-[3-[5-(2,5-difluorophenyl)-2-phenyl-3H-1,3,4- thiadiazol-2-yl]propyl]-N-(4-methoxy-2-pyridyl)carbamate (0.4 g, 703 µmol, 1 equiv) and N- methoxy-N-methyl-carbamoyl chloride (96 mg, 773 µmol, 1.1 equiv) in DCM (3 mL) was added Py (167 mg, 2 mmol, 170 µL, 3 equiv). The mixture was stirred at 25 °C for 2 h. The mixture was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate = 2:1) to give tert- butyl N-[3-[5-(2, 5-difluorophenyl)-3-[methoxy (methyl) carbamoyl]-2-phenyl-1,3,4- thiadiazol-2-yl]propyl]-N-(4-methoxy-2-pyridyl)carbamate (0.3 g, 68 % yield) as a white solid. LC-MS: MS (ES+): RT = 1.01 min, m/z = 628.7 [M + H+]. 4.6 Preparation of (2S)-5-(2,5-difluorophenyl)-2-[3-[(4-hydroxy-2- pyridyl)amino]propyl]-N-methoxy-N-methyl-2-phenyl-1,3,4-thia diazole-3-carboxamide [000369] To a solution of tert-butyl N-[3-[5-(2,5-difluorophenyl)-3- [methoxy(methyl)carbamoyl]-2-phenyl-1,3,4-thiadiazol-2-yl]pr opyl]-N-(4-methoxy-2- pyridyl)carbamate (120 mg, 191 µmol, 1 equiv) in DCM (5 mL) was added BBr3 (958 mg, 4 mmol, 20 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 h and purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5µm; mobile phase: [water (NH4HCO3)-ACN]; B%: 54%-84%, 9 min) to give (2S)-5-(2,5-difluorophenyl)-2-[3-[(4-hydroxy-2- pyridyl)amino]propyl]-N-methoxy-N-methyl-2-phenyl-1,3,4-thia diazole-3-carboxamide (18 mg, 18 % yield) as a pink solid. NMR: (400 MHz, CD3OD): δ 7.77 - 7.71 (m, 2H), 7.56 - 7.54 (m, 2H), 7.43 - 7.37 (m, 2H), 7.33 - 7.24 (m, 3H), 6.27 (dd, 1H, J = 6.0 Hz, J = 2.0 Hz), 6.11 (d, 1H, J = 2.4 Hz), 3.83 (s, 3H), 3.45 - 3.40 (m, 2H), 3.18 - 3.12 (m, 4H), 2.63 - 2.55 (m, 1H), 1.80 - 1.75 (m, 1H). LC-MS: MS (ES+): RT = 1.91 min, m/z =514.2 [M + H+]; LC-MS METHOD 25. EXAMPLE 5 – Synthesis of Additional Compounds [000370] The follow compounds were prepared using procedures analogous to those described above.

EXAMPLE 6 – Synthesis of Synthetic Intermediate Compounds [000371] The following compounds were prepared, and then used as synthetic intermediate compounds in the preparation of additional compounds. Compound A: (S)-5-(2,5-difluorophenyl)-2-(3-isocyanatopropyl)-N-methoxy- N-methyl-2- phenyl-1,3,4-thiadiazole-3(2H)-carboxamide [000372] Step 1. To a solution of tert-butyl N-[3-[(2S)-5-(2,5-difluorophenyl)-3- [methoxy(methyl)carbamoyl]-2-phenyl-1,3,4-thiadiazol-2-yl]pr opyl]carbamate (800 mg, 1.54 mmol, 1.0 eq, described in WO 2006/44825) in DCM (10 mL) was added TFA (3 mL). The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to afford (2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-methoxy-N-me thyl-2- phenyl-1,3,4-thiadiazole-3-carboxamide (700 mg, crude, TFA salt) as a yellow oil. [000373] Step 2. To a solution of 2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-methoxy-N- methyl-2-phenyl-1,3,4-thiadiazole-3-carboxamide (100 mg, 187 µmol, 1.0 eq, TFA salt) and Na ₂ CO ₃ (628 mg, 5.93 mmol, 31.7 eq) in DCM (3 mL) and H ₂ O (2 mL) was added triphosgene (0.589 g, 1.98 mmol, 10.6 eq), and then it was stirred for 2 h at 25 °C. The reaction mixture was poured into 20 mL water and then it was extracted with DCM (2 x 20 mL). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated to afford crude product.5- (2,5-difluorophenyl)-2-(3-isocyanatopropyl)-N-methoxy-N-meth yl-2-phenyl-1,3,4-thiadiazole- 3-carboxamide (83 mg, 186 µmol, 99% yield) was obtained as a yellow oil and used for the next step directly. Compound B: 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrol idin-2- yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1 -(2-(hydroxymethyl) acryloyl)piperazin-2-yl)acetonitrile [000374] Step 1. To a solution of 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile ( 2.39 g, 3.70 mmol, 1.0 eq, TFA salt; US2019/144444, 2019, A1), and 2- (((triisopropylsilyl)oxy)methyl)acrylic acid (1.43 g, 5.55 mmol, 1.5 eq; Bioorg. Med. Chem. Lett., 2015, 25, 5504) in DMF (20 mL) was added DIEA (1.43 g, 11.10 mmol, 1.93 mL, 3.0 eq) and T3P (2.77 g, 5.55 mmol, 3.24 mL, 1.5 eq). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was diluted with 100 mL H ₂ O and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give compound 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrol idin-2- yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1 -(2- (((triisopropylsilyl)oxy)methyl) acryloyl)piperazin-2-yl)acetonitrile (5.72 g, crude) as a brown oil and used for the next step directly. [000375] Step 2. To a solution of 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-yl)-1-(2- (((triisopropylsilyl)oxy)methyl)acryloyl)piperazin-2-yl)acet onitrile (5.70 g, 7.38 mmol, 1.0 eq) in DCM (40 mL) was added TFA (5 mL). The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with 100 mL NaHCO ₃ and extracted with DCM/MeOH (10:1, 50 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate= 0/1 to dichloromethane: methanol =5/1) to afford compound B (2.17 g, 3.5 mmol, 47 % yield) as a brown solid. ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 7.92 (d, J = 7.7 Hz, 1H), 7.74 (d, J = 3.2, 7.9 Hz, 1H), 7.61 - 7.49 (m, 2H), 7.47 - 7.40 (m, 1H), 7.38 - 7.30 (m, 1H), 5.43 (s, 1H), 5.32 - 4.89 (m, 2H), 4.26-4.37 (m, J = 5.5, 11.0 Hz, 1H), 4.22 - 4.08 (m, 4H), 3.95 (d, J = 13.7 Hz, 1H), 3.88 - 3.64 (m, 2H), 3.62 - 3.36 (m, 2H), 3.26 - 3.01 (m, 6H), 3.00 - 2.58 (m, 4H), 2.52 (s, 1H), 2.38 (s, 3H), 1.96 (s, 1H), 1.80 - 1.58 (m, 3H). Compound C: N-((3R,4R)-4-fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-y l)amino)-9- methyl-9H-purin-2-yl)pyrrolidin-3-yl)-2-(hydroxymethyl)acryl amide [000376] Step 1. To a solution of tert-butyl ((3R,4R)-4-fluoro-1-(6-((3-methoxy-1-methyl-1H- pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidin-3-yl)c arbamate (300 mg, 650 µmol, 1.0 eq) in DCM (1 mL) was added TFA (0.5 mL). The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give 2-((3R,4R)-3-amino-4- fluoropyrrolidin-1-yl)-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl )-9-methyl-9H-purin-6-amine (300 mg, 631 µmol, TFA salt) was used into the next step without further purification as a yellow gum. [000377] Step 2. To a solution of 2-((3R,4R)-3-amino-4-fluoropyrrolidin-1-yl)-N-(3-methoxy- 1-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-amine (300 mg, 631 µmol, 1.0 eq, TFA salt) and 2-(((triisopropylsilyl)oxy)methyl)acrylic acid (244 mg, 946 µmol, 1.5 eq) in DMF (3 mL) was added DIEA (244 mg, 1.89 mmol, 329 uL, 3.0 eq), EDCI (181 mg, 946 µmol, 1.5 eq) and HOBt (127 mg, 946 µmol, 1.5 eq). The mixture was stirred at 20 °C for 1 h. Then KF (366 mg, 6.31 mmol, 147 uL, 10 eq) and MeOH (3 mL) was added to the mixture. The mixture was stirred at 20 °C for 11 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge C18150 x 50mm, 10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 12%-42%,10min) to give N-((3R,4R)-4-fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-y l)amino)-9-methyl-9H- purin-2-yl)pyrrolidin-3-yl)-2-(hydroxymethyl)acrylamide (220 mg, 493 µmol, 78% yield) as a white solid. Compound D: (R)-2-(((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrah ydropteridin-2- yl)(2-methoxy-4-((1-methylpiperidin-4-yl)carbamoyl)phenyl)am ino)methyl)acrylic acid [000378] Step 1. To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-benzoic acid (0.5 g, 1.18 mmol, 1 eq; WO2017/24317, 2017, A2), 1- methylpiperidin-4-amine (134.19 mg, 1.18 mmol, 1 eq) in DMF (4 mL) was added DIEA (455.64 mg, 3.53 mmol, 614.07 uL, 3 eq) and EDCI (337.92 mg, 1.76 mmol, 1.5 eq), HOBt (238.18 mg, 1.76 mmol, 1.5 eq). The mixture was stirred at 25 °C for 0.5 h. The residue was purified by prep- HPLC (column: Waters Xbridge C18, 150 x 50mm, 10um; mobile phase: [water( NH4HCO3)- ACN]; B%: 32%-62%,11min) to give compound 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl]amino]-3-methoxy-N-(1-methyl-4-piperidy l)benzamide (0.48 g, 78 % yield) was obtained as a white solid. [000379] Step 2. To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-N-(1-methyl-4-piperidyl)benzamide (250 mg, 479 µmol, 1.0 eq), methyl 2-(bromomethyl)prop-2-enoate (172 mg, 958 µmol, 2.0 eq) in DMF (1 mL) was added K ₂ CO ₃ (265 mg, 1.92 mmol, 4.0 eq). The mixture was stirred at 50 °C for 12 h. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 x 50mm, 10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 31%-61%,11min) to give compound methyl 2-[[N-[(7R)-8- cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]-2-metho xy-4-[(1-methyl-4- piperidyl)carbamoyl]anilino]methyl]prop-2-enoate (0.2 g, 67 % yield) as a white solid. [000380] Step 3. To a solution of methyl 2-[[N-[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]-2-methoxy-4-[(1-methyl-4-piperidyl)carbamoyl] anilino]methyl]prop-2-enoate (0.2 g, 322.71 µmol, 1 eq) in THF (2 mL), H2O (2 mL) was added LiOH.H2O (54.17 mg, 1.29 mmol, 4 eq). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was adjusted to pH = 6 by HCl (1M). The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25mm, 5um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 18%-48%, 7min) to give compound 2-[[N-[(7R)- 8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]-2-met hoxy-4-[(1-methyl-4- piperidyl)carbamoyl]anilino]methyl]prop-2-enoic acid (170 mg, 86 % yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.54 (s, 1 H), 7.40 (s, 1 H), 7.12 - 7.23 (m, 2 H), 6.10 (s, 1 H), 5.57 (s, 1 H), 4.71 (s, 2 H), 4.11 (m, 2 H), 3.97 (s, 1 H), 3.75 (s, 3 H), 3.61 - 3.69 (m, 1 H), 3.25 (s, 6 H), 2.41 - 2.55 (m, 5 H), 1.54 - 2.04 (m, 11 H), 1.28 - 1.44 (m, 4 H), 0.72 - 0.82 (m, 3 H).

Compound E: 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrol idin-2- yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pi perazin-2-yl)acetonitrile [000381] Compound E was prepared as described in Euro. J. Med. Chem. (2022) vol. 230, pg 1140. Compound F: (S)-2-((5-(((3-ethyl-5-(2-(2-hydroxyethyl)piperidin-1-yl)pyr azolo[1,5- a]pyrimidin-7-yl)amino)methyl)-2-oxopyridin-1(2H)-yl)methyl) acrylic acid [000382] Step 1. To a solution of BnOH (3.0 g, 28 mmol, 1.3 equiv) in THF (60 mL) was added NaH (1.3 g, 32 mmol, 60% purity, 1.5 equiv) at 0 °C. The mixture was stirred at 25 °C for 0.5 h and 6-chloropyridine-3-carbonitrile (3 g, 22 mmol, 1.0 equiv) was added. The mixture was stirred at 25 °C for 0.5 h and poured into ethyl acetate (200 mL). The mixture was stirred for 0.2 h and filtered. The filtrate was concentrated to give 6-benzyloxypyridine-3-carbonitrile (4 g, 88% yield) as a yellow solid. [000383] Step 2. To a mixture of 6-benzyloxypyridine-3-carbonitrile (4.0 g, 19 mmol, 1.0 equiv), NiCl ₂ •6H ₂ O (904 mg, 3.81 mmol, 0.2 equiv) and Boc ₂ O (8.3 g, 38 mmol, 2.0 equiv) in MeOH (60 mL) was added NaBH4 (1.83 g, 48 mmol, 2.5 equiv) in small portions at 0 °C. The mixture was stirred at 0 °C for 1 h and concentrated. The residue was poured into ethyl acetate (200 mL), washed with water (200 mL), brine (200 mL), dried over by Na2SO4, filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 1:0 to 10:1) to give tert-butyl N-[(6-benzyloxy-3-pyridyl)methyl]carbamate (4.2 g, 70% yield) as a yellow solid. ¹ H NMR: (400 MHz, CDCl ₃ ): δ 8.08 (d, J = 2.4 Hz, 1H) 7.57 (d, J = 7.2 Hz, 1H), 7.43-7.51 (m, 2H), 7.29-7.43 (m, 4H), 6.80 (d, J = 8.4 Hz, 1H), 5.38 (s, 2H), 4.26 (d, J = 5.2 Hz, 2H), 1.47 (s, 9H). [000384] Step 3. To a solution of tert-butyl N-[(6-benzyloxy-3-pyridyl)methyl]carbamate (11 g, 35 mmol, 1.0 equiv) in DCM (70 mL) was added TFA (30.8 g, 270 mmol, 7.7 equiv). The mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated to give crude (6-benzyloxy-3- pyridyl)methanamine (11.4 g, 34.73 mmol, crude, TFA salt) as a yellow oil. [000385] Step 4. To a solution of (6-benzyloxy-3-pyridyl)methanamine (11.5 g, 35 mmol, 1.5 equiv, TFA salt) and 5,7-dichloro-3-ethyl-pyrazolo[1,5-a]pyrimidine (5.0 g, 23 mmol, 1.0 equiv) in MeCN (100 mL) was added NaHCO ₃ (5.9 g, 70 mmol, 3.0 equiv) and DIEA (3.0 g, 23 mmol, 1.0 equiv). The mixture was stirred at 80 °C for 12 h. The mixture was filtered and concentrated. The residue was purified by column: Kromasil Eternity XT 250 x 80mm, 10µm; mobile phase: [water(10mM NH ₄ HCO ₃ )-ACN]; B%: 60%-90%, 20 min to give N-[(6-benzyloxy-3- pyridyl)methyl]-5-chloro-3-ethyl-pyrazolo[1,5-a]pyrimidin-7- amine (8.2 g, 89% yield) as a brown solid. [000386] Step 5. To a solution of N-[(6-benzyloxy-3-pyridyl)methyl]-5-chloro-3-ethyl- pyrazolo[1,5-a]pyrimidin-7-amine (2.0 g, 5 mmol, 1.0 equiv) and 2-[(2S)-2-piperidyl]ethanol (984 mg, 7.6 mmol, 1.5 equiv) in NMP (2 mL) was added KF (1.48 g, 25 mmol, 5.0 equiv). The mixture was heated to 140 °C and stirred under N2 for 12 h. The solution was poured into ethyl acetate (200 mL), washed with water (100 mL), brine (100 mL), dried over by Na2SO4. The combined organic layer was concentrated and the residue was purified by silica gel chromatography (Petroleum ether : Ethyl acetate = 20:1 to 1:1) to give 2-[(2S)-1-[7-[(6- benzyloxy-3-pyridyl)methylamino]-3-ethyl-pyrazolo[1,5-a]pyri midin-5-yl]-2-piperidyl]ethanol (0.8 g, 32% yield) as a yellow oil. [000387] Step 6. To a solution of 2-[(2S)-1-[7-[(6-benzyloxy-3-pyridyl)methylamino]-3-ethyl- pyrazolo[1,5-a]pyrimidin-5-yl]-2-piperidyl]ethanol (580 mg, 1.2 mmol, 1.0 equiv) in DCM (10 mL) was added BCl ₃ (1 M, 10 mL, 1.0 equiv) at 0 °C. The mixture was stirred at 25 °C for 1 h and quenched with saturated sodium bicarbonate (30 mL) and ammonium hydroxide (3 mL) at 0 °C. The mixture was stirred at 25 °C for 1 h and extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica column chromatography on silica gel (Dichloromethane : Methanol from 50/1 to 5/1) to give 5-[[[3-ethyl-5-[(2S)-2-(2-hydroxyethyl)- 1-piperidyl]pyrazolo[1,5-a]pyrimidin-7-yl]amino]methyl]pyrid in-2-ol (375 mg, 78% yield) as an off-white solid. ¹ H NMR: (400 MHz, DMSO-d6): δ 11.43 (s, 1H), 7.71 (t, J = 6.4 Hz, 1H), 7.64 (s, 1H), 7.53 (dd, J = 2.4, 9.6 Hz, 1H), 7.46 (d, J = 2.4 Hz, 1H), 6.30 (d, J = 9.6 Hz, 1H), 5.59 (s, 1H), 4.72 (t, J = 5.4 Hz, 1H), 4.61 (s, 1H), 4.34-4.19 (m, 3H), 3.43-3.35 (m, 2H), 2.84 (t, J = 12.4 Hz, 1H), 2.49-2.44 (m, 2H), 1.89-1.76 (m, 1H), 1.70-1.54 (m, 6H), 1.43-1.30 (m, 1H), 1.17 (t, J = 7.6 Hz, 3H). [000388] Step 7. To a solution of 5-[[[3-ethyl-5-[(2S)-2-(2-hydroxyethyl)-1- piperidyl]pyrazolo[1,5-a]pyrimidin-7-yl]amino]methyl]pyridin -2-ol (50 mg, 0.13 mmol, 1 equiv) and K ₂ CO ₃ (52 mg, 0.38 mmol, 3 equiv) in DMF (1 mL) was added a solution of 3-bromo- 2-(bromomethyl)propanoic acid (46 mg, 0.19 mmol, 1.5 equiv) in DMF (0.5 mL) dropwise at 45 °C. The mixture was stirred at 45 °C for 12 h and concentrated. The resulting residue was purified by prep-HPLC (column: YMC Triart 30 x 150mm, 7 µm; mobile phase: [water(HCl)-ACN]; B%: 26%-46%, 9 min) to give 2-[[5-[[[3-ethyl-5-[(2S)-2-(2-hydroxyethyl)-1-piperidyl]pyra zolo[1,5- a]pyrimidin-7-yl]amino]methyl]-2-oxo-1-pyridyl]methyl]prop-2 -enoic acid (10 mg, 16% yield) as a yellow solid. Preparation G: 2-(azetidin-3-yl)-5-(3-hydroxynaphthalen-1-yl)-1-methyl-1,2- dihydro-3H- indazol-3-one (Compound G) [000389] Compound G was prepared as described in WO 2018/68017. Compound H: 2-[[(2Z,5Z)-2-benzylidene-5-[(5-tert-butyl-1H-imidazol-4-yl) methylene]- 3,6-dioxo-piperazin-1-yl]methyl]prop-2-enoic acid [000390] Step 1. To a solution of (3Z,6Z)-3-benzylidene-6-[(5-tert-butyl-1H-imidazol-4- yl)methylene]piperazine-2,5-dione (250 mg, 743 µmol, 1.0 eq) and Cs2CO3 (484 mg, 1.49 mmol, 2.0 eq) in DMF (6 mL) was added solution of tert-butyl 2-(bromomethyl)prop-2-enoate (181 mg, 818 µmol, 1.1 eq) in DMF (1 mL) dropwise at 20 °C. The resulting mixture was stirred at 20 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated to afford crude product. The residue was purified by prep-HPLC (column: Phenomenex C1875 x 30mm, 3um; mobile phase: [water(FA)-ACN]; B%: 52%-82%,7min). Compound tert-butyl 2- [[(2Z,5Z)-5-benzylidene-2-[(5-tert-butyl-1H-imidazol-4-yl)me thylene]-3,6-dioxo-piperazin-1- yl]methyl]prop-2-enoate (150 mg, 312 µmol, 42% yield) was obtained as a white solid. ¹ H NMR: (CDCl ₃ , 400 MHz) 7.57 (s, 1H), 7.40 - 7.30 (m, 3H), 7.30 - 7.28 (m, 2H), 7.11 - 7.08 (m, 1H), 6.13 - 6.04 (m, 1H), 5.11 - 4.97 (m, 1H), 4.54 - 4.42 (m, 2H), 1.48 - 1.44 (m, 9H), 1.40 - 1.36 (m, 9H). [000391] Step 2. To a solution of tert-butyl 2-[[(2Z,5Z)-5-benzylidene-2-[(5-tert-butyl-1H- imidazol-4-yl)methylene]-3,6-dioxo-piperazin-1-yl]methyl]pro p-2-enoate (150 mg, 315 µmol, 1.0 eq) in DCM (6 mL) was added TFA (3 mL). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was filtered and the filtrate was concentrated to afford crude product. The crude product 2-[[(2Z,5Z)-2-benzylidene-5-[(5-tert-butyl-1H-imidazol-4-yl) methylene]-3,6-dioxo- piperazin-1-yl]methyl]prop-2-enoic acid (132 mg, crude, TFA salt) as a yellow oil and it was used into the next step without further purification. Compound I: 2-((3R,4R)-3-amino-4-fluoropyrrolidin-1-yl)-N-(3-methoxy-1-m ethyl-1H- pyrazol-4-yl)-9-methyl-9H-purin-6-amine [000392] Step 1. To a solution of benzyl 6-oxa-3-azabicyclo [3.1.0] hexane-3-carboxylate (11 g, 50 mmol, 1.0 eq) in MeOH (120 mL) and H ₂ O (30 mL) was added NaN ₃ (4.8 g, 75 mmol, 1.4 eq) and NH4Cl (2.6 g, 50 mmol, 1.0 eq). The mixture was stirred at 60 °C for 12 h and quenched with NaOH (0.5 N, 10 mL). The mixture was concentrated to remove MeOH. The residue was extracted with CH2Cl2 (3 x 100 mL) and the combined organic extracts were washed with water, brine, dried over Na2SO4, and then concentrated to give benzyl (3R,4R)-3- azido-4-hydroxy-pyrrolidine-1-carboxylate (11.5 g, 87% yield). [000393] Step 2. To a solution of benzyl (3R,4R)-3-azido-4-hydroxy-pyrrolidine-1-carboxylate (22 g, 84 mmol, 1.0 eq) in DCM (160 mL) was added DAST (27 g, 167 mmol, 2.0 eq) in DCM (80 mL) at -78°C, After addition, the mixture was stirred at -78 °C for 1 h and stirred at 20 °C for 11 h. The mixture was poured into sat. Na2CO3 (200 mL). The separated organic phase was washed with brine (200mL), dried (Na2SO4) and concentrated. The residue was purified by silica column chromatography on silica gel (Petroleum ether: Ethyl acetate from 10/1 to 4/1) to give benzyl (3R,4R)-3-azido-4-fluoro-pyrrolidine-1-carboxylate (18 g, 81% yield). [000394] Step 3. To a stirred solution of benzyl (3R,4R)-3-azido-4-fluoro-pyrrolidine-1- carboxylate (18 g, 68 mmol, 1.0 eq) in THF (180 mL) was added PPh ₃ (22 g, 85 mmol, 1.2 eq) portion wise at 0 °C. The resulting mixture was stirred at 25 °C for 2 h and quenched with H ₂ O (18 mL). The mixture was stirred at 70 °C for 12 h and concentrated. The residue diluted with EtOAc (10 mL) and extracted with HCl (0.5 M, 3 x 10 mL). The combined organic layer was washed with brine (20 mL), dried (Na ₂ SO ₄ ) and concentrated to give a benzyl (3R, 4R)-3-amino-4-fluoro-pyrrolidine-1-carboxylate (18 g, crude). [000395] Step 4. To a solution of benzyl (3R,4R)-3-amino-4-fluoro-pyrrolidine-1-carboxylate (18 g, 75.5 mmol, 1.0 eq) in DCM (300 mL) was added Boc ₂ O (21 g, 98.2 mmol, 1.3 eq) at 0°Cand DIEA (19 g, 151 mmol, 2.0 eq). The mixture was stirred at 25°C for 12 h and concentrated. The residue was purified by silica column chromatography on silica gel (Petroleum ether: Ethyl acetate from 50/1 to 5/1) to give benzyl (3R,4R)-3-(tert- butoxycarbonylamino)-4-fluoro-pyrrolidine-1-carboxylate (16 g, 62% yield). ¹ H NMR (400 MHz, CDCl3): δ 7.35 - 7.23 (m, 5H), 5.08 - 4.87 (m, 3H), 4.45 (s, 1H), 4.27 - 4.06 (m, 1H), 3.76 - 3.50 (m, 3H), 3.45 - 3.31 (m, 1H), 1.37 (s, 9H). [000396] Step 5. Benzyl(3R,4R)-3-(tert-butoxycarbonylamino)-4-fluoro-pyrrolid ine-1- carboxylate (16 g, 47.2 mmol, 1.0 eq) was dissolved in MeOH (200 mL). The mixture was purified by prep-SFC(column: DAICEL CHIRALCEL OJ (250mm x 30mm, 10um); mobile phase: [0.1%NH ₃ H ₂ O MEOH];B%: 30%-30%, 2.6min) to give benzyl (3R,4R)-3-(tert- butoxycarbonylamino)-4-fluoro-pyrrolidine-1-carboxylate (7 g, 43% yield). An amount (7 g) of benzyl (3S,4S)-3-(tert-butoxycarbonylamino)-4-fluoro-pyrrolidine-1- carboxylate was also obtained. [000397] Step 6. To a solution of benzyl (3R,4R)-3-(tert-butoxycarbonylamino)-4-fluoro- pyrrolidine-1-carboxylate (400 mg, 1.18 mmol, 1 eq) in CF ₃ CH ₂ OH (20 mL) was added Pd/C (50 mg, 10% purity) under N2 atmosphere. The mixture was stirred under H2 (15 Psi) at 20 °C for 1 h. The mixture was filtered and concentrated to give tert-butyl N-[(3R,4R)-4- fluoropyrrolidin-3-yl]carbamate (8, 240 mg, crude) as a yellow oil. [000398] Step 7. To a solution of 3-methoxy-1-methyl-pyrazol-4-amine (2.4 g, 19 mmol, 1 eq) and 2,6- dichloro- 9- methyl-purine (3.83 g, 19 mmol, 1 eq) in IPA (40 mL) was added DIEA (2.44 g, 19 mmol, 1 eq). The mixture was stirred at 85 °C for 12 h. The mixture was filtered and concentrated to give 2-chloro-N-(3-methoxy-1-methyl-pyrazol-4-yl)-9-methyl-purin- 6- amine (5.1 g, 92% yield). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.01 (s, 1H), 7.74 (s, 1H), 7.44 (m, 1H), 3.97 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H). [000399] Step 8. To a solution of 2-chloro-N-(3-methoxy-1-methyl-pyrazol-4-yl)-9-methyl- purin-6-amine (1.33 g, 5 mmol, 1 eq) and tert-butyl N-[(3R,4R)-4-fluoropyrrolidin-3- yl]carbamate (8, 1.2 g, 6 mmol, 1.3 eq) in NMP (12 mL) was added DIEA (3 g, 23 mmol, 5 eq). The mixture was stirred at 130 °C for 12 h and purified by prep-HPLC (neutral condition; column: Waters Xbridge C18, 150 x 50mm, 10um;mobile phase: [water( NH4HCO3)- ACN];B%: 28%-58%,10min) to give tert-butyl N-[(3R,4R)-4-fluoro-1-[6- [(3-methoxy-1- methyl-pyrazol-4 -yl)amino]-9-methyl -purin-2-yl] pyrrolidin-3-yl]carbamate (1.51 g, 72% yield). ¹ H NMR (400 MHz, MeOD): δ 8.00 - 7.94 (m, 1H), 7.73 - 7.66 (m, 1H), 5.23 - 5.04 (m, 1H), 4.28 (m, 1H), 3.98 (s, 3H), 3.95 - 3.89 (m, 2H), 3.86 (m, 1H), 3.78 - 3.76 (m, 3H), 3.71 - 3.67 (m, 3H), 3.33 (m, 3H), 1.48 (s, 9H). [000400] Step 9. To a solution of tert-butyl N-[(3R,4R)-4-fluoro-1-[6-[(3-methoxy-1-methyl- pyrazol-4-yl)amino]-9-methyl-purin-2-yl]pyrrolidin-3-yl]carb amate (60 mg, 130 µmol, 1 eq) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at 20 °C for 1 h and concentrated to give the desired compound 2-[(3R,4R)-3-amino-4-fluoro-pyrrolidin-1-yl]-N-(3- methoxy-1-methyl-pyrazol-4-yl)-9-methyl-purin-6-amine (61 mg, crude, TFA) as a yellow oil. Compound J: 5-chloro-4-(((3R,4R)-4-methoxypyrrolidin-3-yl)methoxy)-N-(1- methyl-1H- pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine

[000401] Step 1. To a solution of methyl (E)-3-methoxyprop-2-enoate (12 g, 103 mmol, 11.1 mL, 1.0 eq) in 2-methyltetrahydrofuran (180 mL) and TFA (3.1 g, 27.1 mmol, 2 mL, 0.2 eq) was added N-(methoxymethyl)-1-phenyl-N-(trimethylsilylmethyl)methanami ne (49.1 g, 207 mmol, 2.0 eq) dropwise at 0 °C. After addition, the reaction was allowed to warm to 25 °C and stirred for 2 h. The pH was adjusted to around 7 by progressively adding saturated NaHCO ₃ solution. The mixture was diluted with EtOAc (100 mL) and brine (100 mL). The solution was separated and the organic layer was dried, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (PE/EtOAc = 50/1 to 10/1) to give the product (3S,4R)-methyl 1-benzyl-4-methoxypyrrolidine-3-carboxylate (9.2 g, 36.3 mmol, 35% yield, 99% purity) as a yellow oil. [000402] Step 2. To a solution of methyl (3S,4R)-1-benzyl-4-methoxy-pyrrolidine-3- carboxylate (9.2 g, 37 mmol, 99% purity, 1.0 eq) and Boc2O (15.9 g, 73.1 mmol, 16.8 mL, 2.0 eq) in MeOH (84 mL) was added Pd/C (3.3 g, 10% purity) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (50 psi) at 25 °C for 12 h. The mixture was filtered and the filtrate was concentrated to afford the crude product. The residue was purified by flash silica gel chromatography (PE/EtOAc = 50/1 to 5/1) to yield the product (3S,4R)-1-tert-butyl 3-methyl 4-methoxypyrrolidine-1,3- dicarboxylate (7.6 g, 29.3 mmol, 80% yield) as a colorless oil. ¹ H NMR: (400 MHz, CDCl3) δ 4.15 - 4.12 (m, 1H), 3.73 (s, 3H), 3.66 - 3.61 (m, 3H), 3.45 (m, 1H), 3.36 (s, 3H), 3.08 (m, 1H), 1.46 (s, 9H). [000403] Step 3. To a solution of (3S,4R)-1-tert-butyl 3-methyl 4-methoxypyrrolidine-1,3- dicarboxylate (7.60 g, 29.3 mmol, 1.0 eq) in THF (76 mL) was added LiBH ₄ (2.4 g, 108 mmol, 3.7 eq) at 0 °C. The mixture was stirred at 60 °C for 4 h. The reaction was quenched with saturated NH ₄ Cl (20 mL) at 0 °C and extracted with EtOAc (100 mL x 2). The combined organic layer was washed with saturated aqueous brine (100 mL x 2), dried, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (PE/EtOAc = 10/1 to 1/1) to give the product (3R,4R)-tert-butyl 3-(hydroxymethyl)-4- methoxypyrrolidine-1-carboxylate (3.50 g, 15.1 mmol, 52% yield) as a colorless oil. ¹ H NMR: (400 MHz, CDCl3) δ 3.79 - 3.78 (m, 1H), 3.58 - 3.51 (m, 4H), 3.33 (m, 4H), 3.22 (m, 1H), 2.46 - 2.39 (m, 2H), 1.43 (s, 9H). [000404] Step 4. A mixture of tert-butyl (3R,4R)-tert-butyl 3-(hydroxymethyl)-4- methoxypyrrolidine-1-carboxylate (4.5 g, 19.5 mmol, 1.0 equiv), 2,4,5-trichloro-7H- pyrrolo[2,3-d]pyrimidine (4.3 g, 19.5 mmol, 1.0 equiv) and t-BuOK (8.7 g, 77.8 mmol, 4.0 equiv) in 1,4-dioxane (100 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 0.5 h under N2 atmosphere. The reaction was quenched with saturated NH4Cl (200 mL) at 0 °C and extracted with EtOAc (100 mL x 3). The combined organic layer was washed with saturated aqueous brine (100 mL x 2), dried, filtered and concentrated to give a residue. The residue (3R,4R)-tert-butyl 3-(((2,5-dichloro-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)-4-methoxypyrrolidin e-1-carboxylate (8.0 g, crude) as yellow oil was used in the next step without further purification. [000405] Step 5. A mixture of tert-butyl (3R,4R)-3-[(2,5-dichloro-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)oxymethyl]-4-methoxy-pyrrolidine-1-carboxylate (8.0 g, 16.5 mmol, 86% purity, 1.0 eq), 1-methylpyrazol-4-amine (2.1 g, 21.4 mmol, 1.3 eq), tert-BuXPhos palladacycle (820 mg, 1.2 mmol, 0.1 eq) and t-BuOK (5.5 g, 49.5 mmol, 3.0 eq) in 1,4-dioxane (80 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 90 °C for 1 h under N ₂ atmosphere. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (PE/EtOAc = 50/1 to 1/1) to yield the product. Compound (3R,4R)-tert-butyl 3-(((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)-4-methoxypyrrolidin e-1-carboxylate (5 g, 10.2 mmol, 62% yield, 97% purity) was obtained as a gray solid. ¹ H NMR: (400 MHz, CDCl3) δ 7.75 (s, 1H), 7.53 (s, 1H), 6.62- 6.58 (m, 2H), 4.45 - 4.42 (m, 2H), 3.99 - 3.98 (m, 1H), 3.88 (s, 3H), 3.71 - 3.67 (m, 2H), 3.49 - 3.38 (m, 5H), 2.77 (m, 1H), 1.47 (s, 9H). [000406] Step 6. A mixture of (3R,4R)-tert-butyl 3-(((5-chloro-2-((1-methyl-1H-pyrazol-4- yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)-4-meth oxypyrrolidine-1-carboxylate (260 mg, 544 µmol, 1.0 eq) in TFA (0.5 mL) and DCM (2 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 25 °C for 1 h under N ₂ atmosphere. The mixture was evaporated to afford the crude product 5-chloro-4-(((3R,4R)-4-methoxypyrrolidin- 3-yl)methoxy)-N-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d] pyrimidin-2-amine (180 mg, 457 µmol, 96%purity) as a yellow solid. The residue was used in the next step without further purification. Compound K: 4-(3-aminophenoxy)-N-(4-(4-methylpiperazin-1-yl)phenyl)thien o[3,2- d]pyrimidin-2-amine [000407] Compound K was prepared as described in US 2019/330229. Compound L: N1-(2-(dimethylamino)ethyl)-5-methoxy-N1-methyl-N4-(5-(1-met hyl-1H- indol-3-yl)pyrimidin-2-yl)benzene-1,2,4-triamine [000408] Step 1. To a solution of N-(4-fluoro-2-methoxy-5-nitro-phenyl)-4-(1-methylindol-3- yl)pyrimidin-2-amine (3 g, 7.63 mmol, 1 eq) in DMAC (10 mL) was added DIEA (2.46 g, 19 mmol, 2.5 eq) and N,N',N'-trimethylethane-1,2-diamine (935 mg, 9.16 mmol, 1.2 eq). The mixture was stirred at 80 °C for 2 h and concentrated to give the compound N4-[2- (dimethylamino)ethyl]-2-methoxy-N4-methyl-N1-[4-(1-methylind ol-3-yl)pyrimidin-2-yl]-5- nitro-benzene-1,4-diamine (2.5 g, 69 % yield). [000409] Step 2. To a solution of N4-[2-(dimethylamino)ethyl]-2-methoxy-N4-methyl-N1-[4- (1-methylindol-3-yl)pyrimidin-2-yl]-5-nitro-benzene-1,4-diam ine (2.5 g, 5.26 mmol, 1 eq) in THF (15 mL) was added Pd/C (100 mg, 10% purity) under N2. The mixture was stirred under H ₂ (15psi) at 20°C for 12 h. The mixture was filtered and concentrated to give the compound N1-[2-(dimethylamino)ethyl]-5-methoxy-N1-methyl-N4-[4-(1-met hylindol-3- yl)pyrimidin-2-yl]benzene-1,2,4-triamine (2.3 g, crude). Compound M: 2-(4-(4-((8-(3-aminophenyl)quinazolin-2-yl)amino)-2,3-difluo rophenyl)- piperazin-1-yl)ethan-1-ol [000410] Step 1. To a solution of 1,2,3-trifluoro-4-nitrobenzene (5.00 g, 28.2 mmol, 3.25 mL, 1.0 eq), 2-(piperazin-1-yl)ethan-1-ol (3.68 g, 28.2 mmol, 3.47 mL, 1.0 eq) in DMF (40 mL) was added K ₂ CO ₃ (7.80 g, 56.5 mmol, 2.0 eq) at 0 °C. The mixture was stirred at 20 °C for 12 h. This reaction mixture was poured into 200 mL ice-water. The resulting solid was collected by filtration, washed with cold water three times, and concentrated under reduce pressure to afford 2-(4-(2,3-difluoro-4-nitrophenyl)piperazin-1-yl)ethan-1-ol (6.10 g, 21.2 mmol, 75% yield) as a yellow solid. ¹ H NMR: (400 MHz, CDCl3) δ 7.89 - 7.80 (m, 1H), 6.64 – 6.69 (m, J = 1.9, 7.9, 9.5 Hz, 1H), 3.67 (s, 2H), 3.41 - 3.34 (m, 4H), 2.72 - 2.67 (m, 4H), 2.65 - 2.61 (m, 2H). [000411] Step 2. To a solution 2-(4-(2,3-difluoro-4-nitrophenyl)piperazin-1-yl)ethan-1-ol (6.10 g, 21.2 mmol, 1.0 eq) in MeOH (60 mL) was added Pd/C (610 mg, 21.2 mmol, 10% purity, 1.0 eq) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H ₂ (15 psi) at 20 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to afford 2-(4-(4-amino-2,3-difluorophenyl)piperazin-1- yl)ethan-1-ol (5.4 g, crude) as a brown oil and used for the next step directly. ¹ H NMR: (400 MHz, CDCl3) δ 6.61 - 6.54 (m, 1H), 6.52 - 6.43 (m, 1H), 3.69 - 3.48 (m, 5H), 3.08 - 2.95 (m, 5H), 2.75 - 2.67 (m, 4H), 2.62 (t, J = 5.4 Hz, 2H). [000412] Step 3. To a solution of 8-bromo-2-chloroquinazoline (7.11 g, 29.2 mmol, 1.0 eq) and (3-aminophenyl)boronic acid (4.00 g, 29.2 mmol, 1.0 eq) in H2O (8 mL) and dioxane (80 mL) was added Pd(dppf)Cl2 (3.21 g, 4.38 mmol, 0.15 eq) and Na2CO3 (6.19 g, 58.42 mmol, 2.0 eq). The mixture was stirred at 80 °C for 12 h under N2.The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=5/1 to 1/1) to give 3-(2- chloroquinazolin-8-yl)aniline (4.30 g, 10.9 mmol, 37 % yield) as a yellow solid. [000413] Step 4. To a solution of 3-(2-chloroquinazolin-8-yl)aniline (5.50 g, 21.5 mmol, 1.0 eq) in DCM (50 mL) was added TEA (6.53 g, 64.5 mmol, 8.98 mL, 3.0 eq) and TFAA (6.78 g, 32.3 mmol, 4.49 mL, 1.5 eq). The mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=7/1 to 0/1) to afford N-(3-(2- chloroquinazolin-8-yl)phenyl)-2,2,2-trifluoroacetamide (2.85 g, 8.10 mmol, 38 % yield) as a yellow solid. ¹ H NMR: (400 MHz, CDCl3) δ 9.36 (s, 1H), 8.47 - 8.29 (m, 1H), 8.05 - 7.85 (m, 3H), 7.80 - 7.73 (m, 1H), 7.73 - 7.64 (m, 1H), 7.59 - 7.48 (m, 2H), 5.34 (d, J = 12.4 Hz, 1H), 3.45 - 3.28 (m, 3H). [000414] Step 5. To a solution of N-(3-(2-chloroquinazolin-8-yl)phenyl)-2,2,2- trifluoroacetamide (1.00 g, 2.84 mmol, 1.0 eq), 2-(4-(4-amino-2,3-difluorophenyl)piperazin-1- yl)ethan-1-ol (731 mg, 2.84 mmol, 1.0 eq) in 2-methoxyethanol (10 mL) was added HCl (12 M, 24 uL, 0.1 eq). The mixture was stirred at 100 °C for 1 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 C18, 150 x 40mm, 15um; mobile phase: [water (FA)-ACN]; B%: 20%-50%, 10min) to afford N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxyethyl)piperazin-1- yl)phenyl)amino)quinazolin-8-yl)phenyl)-2,2,2-trifluoroaceta mide (300 mg, 524 µmol, 18% yield) as a yellow solid. ¹ H NMR: (400 MHz, CD3OD): δ 9.17 - 9.13 (m, 1H), 8.57 - 8.46 (m, 1H), 8.22 - 8.15 (m, 1H), 8.00 (s, 1H), 7.78 -7.85 (m, J = 1.3, 7.6, 18.3 Hz, 2H), 7.71 (d, J = 2.2, 6.8 Hz, 1H), 7.59 - 7.53 (m, 2H), 7.49 - 7.39 (m, 2H), 6.50 (t, J = 1.9, 8.8 Hz, 1H), 3.92 - 3.88 (m, 2H), 3.32 - 3.25 (m, 4H), 3.16 - 3.07 (m, 4H), 3.01 - 2.94 (m, 2H). [000415] Step 6. To a solution of N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxyethyl)piperazin-1- yl)phenyl)amino)quinazolin-8-yl)phenyl)-2,2,2-trifluoroaceta mide (200 mg, 349 µmol, 1.0 eq) in THF (1 mL) was added LiOH.H2O (36.6 mg, 873 µmol, 2.5 eq) in H2O (1 mL). The mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with 15mL H ₂ O and extracted with EtOAc (15 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give compound M (145 mg, 304 µmol, 87% yield) as a yellow solid. Compound N: 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methy lpyridin-3- yl)-4-((S)-2-methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1 H)-one

[000416] Step 1. To a solution of 2,6-dichloro-5-fluoro-pyridine-3-carboxylic acid (30.0 g, 142 mmol, 1.0 eq) in SOCl ₂ (100 mL) was dropwise DMF (104 mg, 1.4 mmol, 109 uL, 0.01 eq), then it was stirred at 90 °C for 1 h. The reaction mixture was concentrated to afford a crude product.2,6-dichloro-5-fluoro-pyridine-3-carbonyl chloride (32.6 g, crude) was obtained as a red oil. [000417] Step 2. To a solution of 2,6-dichloro-5-fluoro-pyridine-3-carbonyl chloride (32.6 g, 142.8 mmol, 1.0 eq) in THF (200 mL) was added NH ₃ (7.0 M, 102 mL, 5.0 eq) at 0 °C, then it was stirred at 0 °C for 1 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (200 mL x 3). The combined organic phase was dried, filtered and concentrated to give 2,6-dichloro-5-fluoro-pyridine-3-carboxamide (28.0 g, 133 mmol, 93% yield) as a yellow powder. ¹ H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 7.8 Hz, 1H), 8.14 - 7.88 (m, 2H). [000418] Step 3. To a solution of 2,6-dichloro-5-fluoro-pyridine-3-carboxamide (9.0 g, 43 mmol, 1.0 eq) in THF (40 mL) was added oxalyl chloride (7.1 g, 55.9 mmol, 4.9 mL, 1.3 eq) at 0 °C, it was stirred at 60 °C for 0.5 h.2,6-dichloro-5-fluoro-pyridine-3-carbonyl isocyanate (10.12 g, 43.06 mmol, 100% yield) was obtained as a colorless liquid, which was used for next step directly. [000419] Step 4. To a solution of 2,6-dichloro-5-fluoro-pyridine-3-carbonyl isocyanate (10 g, 42 mmol, 1.0 eq) in THF (100 mL) was added 2-isopropyl-4-methyl-pyridin-3-amine (6.4 g, 42.5 mmol, 1.0 eq) in THF (100 mL) at 0 °C, it was stirred at 20 °C for 12 h. The reaction mixture was quenched with saturated NH ₄ Cl (100 mL), then extracted with EtOAc (100 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The crude product was purified by column chromatography (SiO2, PE: EA = 4: 1).2,6-dichloro-5-fluoro-N-[(2-isopropyl-4-methyl-3- pyridyl)carbamoyl]pyridine-3-carboxamide (8.6 g, 22.3 mmol, 52% yield) was obtained as a white solid. ¹ H NMR (400 MHz, CD3OD) δ = 8.32 (s, 1H), 8.20 - 8.11 (m, 1H), 7.21 (s, 1H), 3.48 - 3.39 (m, 1H), 2.34 (s, 3H), 1.27 (d, J = 3.5 Hz, 6H). [000420] Step 5. To a solution of 2,6-dichloro-5-fluoro-N-[(2-isopropyl-4-methyl-3- pyridyl)carbamoyl]pyridine-3-carboxamide (8.6 g, 22 mmol, 1.0 eq) in THF (60 mL) was added KHMDS (1.0 M, 55 mL, 2.5 eq) at 0 °C, then it was stirred at 20 °C for 0.5 h. The reaction mixture was added 50 mL NH4Cl and extracted with EtOAc (50 mL x 2). The combined organic phase was dried, filtered and concentrated to give a residue. The crude product was purified by column chromatography (SiO ₂ , PE: EA = 4:1 to 2:1).7-chloro-6- fluoro-1-(2-isopropyl-4-methyl-3-pyridyl)pyrido[2,3-d]pyrimi dine-2,4-dione (6.8 g, 19 mmol, 87% yield) was obtained as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.50 (d, J = 5.0 Hz, 1H), 8.36 (d, J = 7.2 Hz, 1H), 7.94 (d, J = 7.5 Hz, 1H), 7.31 (d, J = 5.0 Hz, 1H), 2.94 - 2.78 (m, 1H), 2.12 (s, 3H), 1.19 (d, J = 6.8 Hz, 3H), 1.09 (d, J = 6.7 Hz, 3H). [000421] Step 6. To a solution of 7-chloro-6-fluoro-1-(2-isopropyl-4-methyl-3- pyridyl)pyrido[2,3-d]pyrimidine-2,4-dione (6.8 g, 19 mmol, 1.0 eq), DIEA (3.78 g, 29.2 mmol, 5.1 mL, 1.5 eq) in CH ₃ CN (60 mL) was added POCl ₃ (3.9 g, 25.3 mmol, 2.4 mL, 1.3 eq), it was stirred at 80 °C for 1 h. The reaction mixture was concentrated to give a residue.4,7-dichloro- 6-fluoro-1-(2-isopropyl-4-methyl-3-pyridyl)pyrido[2,3-d]pyri midin-2-one (7.2 g, crude) was obtained as a red oil, which was used for next step directly. [000422] Step 7. To a solution of 4,7-dichloro-6-fluoro-1-(2-isopropyl-4-methyl-3- pyridyl)pyrido[2,3-d]pyrimidin-2-one (7.2 g, 19.5 mmol, 1.0 eq) in CH ₃ CN (60 mL) was added DIEA (7.6 g, 58.5 mmol, 10.1 mL, 3.0 eq), tert-butyl (3S)-3-methylpiperazine-1-carboxylate (4.69 g, 23.4 mmol, 1.2 eq) at 0 °C, then it was stirred at 20 °C for 1 h. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (100 mL), extracted with EtOAc (100 mL x 3). The combined organic phase was dried, filtered and concentrated to give a residue. The crude product was purified by column chromatography (SiO2, PE: EA = 3:1 to 1:1) to give tert-butyl (3S)-4-[7-chloro-6-fluoro-1-(2-isopropyl-4-methyl-3-pyridyl) -2-oxo- pyrido[2,3-d]pyrimidin-4-yl]-3-methyl-piperazine-1-carboxyla te (6.1 g, 11 mmol, 58% yield) as a yellow solid. ¹ H NMR (400 MHz, CD3OD) δ = 8.47 (d, J = 5.0 Hz, 1H), 8.27 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 4.8 Hz, 1H), 5.02 - 4.92 (m, 1H), 4.38 - 4.27 (m, 1H), 4.17 - 4.08 (m, 1H), 3.98 (d, J = 13.6 Hz, 1H), 3.77 (t, J = 11.2 Hz, 1H), 3.40 - 3.32 (m, 1H), 3.25 - 3.14 (m, 1H), 2.78 - 2.61 (m, 1H), 2.06 - 2.01 (m, 3H), 1.56 - 1.44 (m, 9H), 1.20 - 1.16 (m, 3H), 1.10 - 1.05 (m, 3H). [000423] Step 8. To a solution of tert-butyl (3S)-4-[7-chloro-6-fluoro-1-(2-isopropyl-4-methyl- 3-pyridyl)-2-oxo-pyrido[2,3-d]pyrimidin-4-yl]-3-methyl-piper azine-1-carboxylate (6.1 g, 11 mmol, 1.0 eq), (2-fluoro-6-hydroxy-phenyl)boronic acid (4.5 g, 28.7 mmol, 2.5 eq) in dioxane (60 mL), H2O (6 mL) was added Pd(dppf)Cl2 (672 mg, 919 µmol, 0.08 eq), K2CO3 (4.8 g, 34.4 mmol, 3.0 eq) at N2 atmosphere, it was stirred at 90 °C for 1 h. The reaction system was cooled to room temperature and diluted with water (50 mL). The solution was extracted with EtOAc (50 mL x 3). The combined organic phase was washed with brine (50 mL), dried, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE: EA = 1:1 to 0:1) to give tert-butyl (3S)-4-[6-fluoro-7-(2-fluoro-6-hydroxy-phenyl)- 1-(2-isopropyl-4-methyl-3-pyridyl)-2-oxo-pyrido[2,3-d]pyrimi din-4-yl]-3-methyl-piperazine-1- carboxylate (6.6 g, 10 mmol, 95% yield) as a yellow solid. ¹ H NMR (400 MHz, CD3OD) δ = 8.39 (d, J = 5.0 Hz, 1H), 8.28 - 8.17 (m, 1H), 7.29 - 7.15 (m, 2H), 6.68 - 6.54 (m, 2H), 4.18 - 4.04 (m, 4H), 3.39 (s, 1H), 3.27 - 3.13 (m, 1H), 2.86 - 2.73 (m, 1H), 2.04 - 2.00 (m, 6H), 1.90 (d, J = 5.0 Hz, 1H), 1.54 - 1.51 (m, 9H), 1.21 - 1.18 (m, 3H), 1.06 - 0.99 (m, 3H). [000424] Step 9. To a solution of tert-butyl (3S)-4-[6-fluoro-7-(2-fluoro-6-hydroxy-phenyl)-1- (2-isopropyl-4-methyl-3-pyridyl)-2-oxo-pyrido[2,3-d]pyrimidi n-4-yl]-3-methyl-piperazine-1- carboxylate (800 mg, 1.3 mmol, 1.0 eq) in DCM (5 mL) was added TFA (5 mL), it was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated to give a TFA salt product.6-fluoro- 7-(2-fluoro-6-hydroxy-phenyl)-1-(2-isopropyl-4-methyl-3-pyri dyl)-4-[(2S)-2-methylpiperazin- 1-yl]pyrido[2,3-d]pyrimidin-2-one N (818 mg, 1.3 mmol, 100% yield, TFA salt) was obtained as a yellow oil. LC-MS: MS (ES ⁺ ): RT = 0.546 min, m/z = 507.[M+H ⁺ ].

Compound O: 2-((1-(3-chloro-4-methylphenyl)-3-((2-(2,6-dioxopiperidin-3- yl)-1- oxoisoindolin-5-yl)methyl)ureido)methyl)acrylic acid [000425] Step 1. To a solution of tert-butyl 2-(bromomethyl)prop-2-enoate (937 mg, 4.2 mmol, 1.0 eq) and 3-chloro-4-methyl-aniline (600 mg, 4.24 mmol, 1.0 eq) in MeCN (10 mL) was added K ₂ CO ₃ (1.8 g, 12.7 mmol, 3.0 eq). Then the reaction mixture was stirred at 50 °C for 12 h. The resultant mixture was filtered and the filtrate was concentrated under vacuum. The mixture was purified by semi-preparative reverse phase HPLC (0 - 10% acetonitrile + 0.225% formic acid in water, 10 min). to give tert-butyl 2-[(3-chloro-4-methyl-anilino)methyl]prop-2- enoate (0.45 g, 1.6 mmol, 38% yield) as a yellow oil. ¹ H NMR: (400 MHz, CDCl3) δ = 7.00 (d, J = 8.3 Hz, 1H), 6.63 (d, J = 2.4 Hz, 1H), 6.45 (d, J = 2.4, 8.2 Hz, 1H), 6.18 (d, J = 0.9 Hz, 1H), 5.69 (d, J = 1.4 Hz, 1H), 3.96 (s, 2H), 2.25 (s, 3H), 1.52 (s, 9H). [000426] Step 2. To a solution of Triphosgene (580 mg, 1.95 mmol, 1.6 eq) in THF (30 mL) was added drop-wise tert-butyl 2-[(3-chloro-4-methyl-anilino)methyl]prop-2-enoate (350 mg, 1.2 mmol, 1.0 eq) and TEA (1.0 g, 9.9 mmol, 1.4 mL, 8.0 eq) in THF (5 mL) at -40 °C. The mixture was stirred at -40 °C for 0.5 h.3-[5-(aminomethyl)-1-oxo-isoindolin-2-yl]piperidine- 2,6-dione (373 mg, 1.4 mmol, 1.1 eq) was added into the reaction mixture and stirred at 25 °C for 12 h. The mixture was quenched with saturated aqueous solution of NaHCO ₃ (3 mL) and then filtered. The filtrate was concentrated. The mixture was purified by semi-preparative reverse phase HPLC (35 - 55% acetonitrile + 0.225% formic acid in water, 20 min) to give tert- butyl 2-[[3-chloro-N-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin- 5-yl]methylcarbamoyl]-4- methyl-anilino]methyl]prop-2-enoate (240 mg, 413 µmol, 33% yield) as a white solid. ¹ H NMR: (400 MHz, DMSO-d6) δ = 10.98 (s, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.45 (s, 1H), 7.37 (d, J = 4.9, 7.9 Hz, 2H), 7.32 (d, J = 2.1 Hz, 1H), 7.14 (d, J = 2.1, 8.1 Hz, 1H), 6.79 (s, 1H), 6.03 (s, 1H), 5.62 (d, J = 1.0 Hz, 1H), 5.11 (d, J = 5.1, 13.3 Hz, 1H), 4.48 - 4.40 (m, 3H), 4.33 - 4.27 (m, 3H), 2.97 - 2.87 (m, 1H), 2.65 - 2.58 (m, 1H), 2.40 (d, J = 4.5, 13.1 Hz, 1H), 2.31 (s, 3H), 2.03 - 1.95 (m, 1H), 1.39 (s, 9H). [000427] Step 3. To a solution of tert-butyl 2-[[(3-chloro-4-methyl-phenyl)carbamoyl-[[2-(2,6- dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]methyl]amino]methyl ]prop-2-enoate (130 mg, 224 µmol, 1.0 eq) in DCM (2 mL) was added TFA (3.1 g, 27.0 mmol, 2.00 mL, 121 eq) and the reaction mixture was stirred at 25 °C for 12 h. The resultant mixture was concentrated under vacuum. The crude product 2-[[(3-chloro-4-methyl-phenyl)carbamoyl-[[2-(2,6-dioxo-3- piperidyl)-1-oxo-isoindolin-5-yl]methyl]amino]methyl]prop-2- enoic acid O (140 mg, 219 µmol, 98% yield, TFA) was obtained as a brown oil and used into the next step without further purification. [000428] Step 4. A mixture of methyl 4-bromo-2-methyl-benzoate (40.5 g, 177 mmol, 1.0 eq), NBS (31.5 g, 177 mmol, 1.0 eq) and BPO (4.28 g, 17.7 mmol, 0.1 eq) in trifluoromethylbenzene (400 mL) was heated to 85 °C and stirred for 16 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 with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Petroleum ether:Ethyl acetate = 1:0 to 20:1) to afford methyl 4-bromo-2-(bromomethyl)benzoate (50.0 g, crude) as a white solid. ¹ H NMR (400 MHz, CDCl3): δ 7.84 (d, 1H, J = 8.4 Hz), 7.63 (d, 1H, J = 2.0 Hz), 7.50 (dd, 1H, J = 2.0, 8.4 Hz), 4.89 (s, 2H), 3.94 (s, 3H). [000429] Step 5. A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (4.00 g, 13.0 mmol, 1.0 eq), DIPEA (6.71 g, 51.9 mmol, 9.05 mL, 4.0 eq) and 3-aminopiperidine-2,6-dione (4.28 g, 25.9 mmol, 2.0 eq, HCl salt) in DMF (40 mL) was stirred at 50 °C for 2 h. Then the mixture was heated to 80 °C for another 12 h. The reaction mixture was poured into ice-water (100 mL) and the mixture filtered. The filter cake was washed with EtOAc (50 mL) and dried in vacuo to afford 3-(5-bromo-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (4.00 g, 12.4 mmol, 95% yield) as a gray solid. ¹ H NMR (400 MHz, DMSO-d6): δ 7.88 (1H, s), 7.72-7.65 (m, 2H), 5.12-5.07 (m, 1H), 4.55-4.30 (m, 2H), 2.99-2.82 (m, 1H), 2.67-2.54 (m, 1H), 2.45-2.30 (m, 1H), 2.10-1.90 (m, 1H). [000430] Step 6. A mixture of 3-(5-bromo-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (6.30 g, 19.5 mmol, 1.0 eq), Zn(CN) ₂ (1.49 g, 12.7 mmol, 804 uL, 0.65 eq) and Pd(PPh ₃ ) ₄ (2.25 g, 1.95 mmol, 0.1 eq) in DMF (50 mL) was heated to 100 °C and stirred for 12 h under N2. The reaction mixture was diluted with H2O (30 mL). The precipitate solid was collected by filtration and triturated with ethyl acetate (80 mL). The insoluble material was collected by filtration and dried in vacuo to afford 2-(2,6-dioxo-3-piperidyl)-1-oxo- isoindoline-5-carbonitrile (5.00 g, 18.6 mmol, 95% yield) as a white solid. NMR (400 MHz, DMSO-d6): δ 11.03 (s, 1H), 8.17 (s, 1H), 8.03-7.97 (m, 1H), 7.95-7.89 (m, 1H), 5.21-5.11 (m, 1H), 4.60-4.51 (m, 1H), 4.48-4.39 (m, 1H), 2.99-2.90 (m, 1H), 2.66-2.57 (m, 1H), 2.46-2.36 (m, 1H), 2.09-1.98 (m, 1H). [000431] Step 7. To a mixture of 2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindoline-5-carbonitrile (12.0 g, 44.6 mmol, 1.0 eq) in DMF (20 mL) and THF (20 mL) was added Boc2O (15.6 g, 71.3 mmol, 16.4 mL, 1.6 eq) and Raney Ni (4.20 g, 49.0 mmol, 1.1 eq). The mixture was degassed and stirred at 30 °C for 12 h under H ₂ (50 psi). The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was triturated with ethyl acetate (80 mL). The insoluble material was collected by filtration and dried in vacuo. The residue was purified by prep-HPLC (column: Kromasil Eternity XT 250 x 80mm, 10um; mobile phase: [water (0.225%FA)- ACN];B%: 25%-45%,15min) to afford tert-butyl N-[[2-(2,6-dioxo-3-piperidyl)-1-oxo- isoindolin-5-yl]methyl]carbamate (6.00 g, 16.1 mmol, 36% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.98 (s, 1H), 7.72-7.63 (m, 1H), 7.55-7.34 (m, 3H), 5.17-5.04 (m, 1H), 4.50-4.38 (m, 1H), 4.35-4.27 (m, 1H), 4.26-5.14 (m, 2H), 2.99-2.83 (m, 1H), 2.68-2.55 (m, 1H), 2.45-2.29 (m, 1H), 2.06-1.94 (m, 1H), 1.40 (s, 9H). [000432] Step 8. A mixture of tert-butyl N-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5- yl]methyl]carbamate (6.00 g, 16.1 mmol, 1.0 eq) in CH2Cl2 (50 mL) and 4 M HCl/dioxane (50 mL) was stirred at 25 °C for 1 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford 3-[5-(aminomethyl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dion e (4.90 g, 15.8 mmol, 98% yield, HCl salt) as a white solid. NMR (400 MHz, DMSO-d ₆ ): δ 11.00 (s, 1H), 8.62 (s, 3H), 7.83-7.71 (m, 2H), 7.69-7.58 (m, 1H), 5.18-5.09 (m, 1H), 4.53-4.44 (m, 1H), 4.40-4.30 (m, 1H), 4.20-4.09 (m, 2H), 3.01-2.86 (m, 1H), 2.68-2.57 (m, 1H), 2.46-2.35 (m, 1H), 2.08-1.95 (m, 1H), 2.08-1.95 (m, 1H). Compound P: 2-((3R,4R)-3-fluoro-4-(methylamino)pyrrolidin-1-yl)-N-(3-met hoxy-1- methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-amine [000433] Step 1. To a solution of benzyl (3R,4R)-3-(tert-butoxycarbonylamino)-4-fluoro- pyrrolidine-1-carboxylate (0.3 g, 886 µmol, 1 eq) in THF (3 mL) was added NaH (53 mg, 1.33 mmol, 60% purity, 1.5 eq). The mixture was stirred at 0 °C for 0.5 h and MeI (377 mg, 2.66 mmol, 3 eq) was added. The mixture was stirred at 20 °C for 12 h and quenched by addition NH ₄ Cl (100 mL). The mixture was extracted with EA (3 X 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by prep-TLC (SiO2, PE:EA= 3:1) to give benzyl (3R,4R)-3-[tert-butoxycarbonyl(methyl)amino]-4-fluoro-pyrrol idine-1-carboxylate (300 mg, 96 % yield). ¹ H NMR (400 MHz, CDCl3): δ 7.5-7.3 (m, 4 H), 5.16 (s, 2 H), 5.03 (s, 1 H), 4.6-4.4 (m, 1 H), 3.9-3.6 (m, 4 H), 2.80 (s, 3 H), 1.61 (s, 2 H), 1.47 (s, 9 H). [000434] Step 2. To a solution of benzyl (3R,4R)-3-[tert-butoxycarbonyl(methyl)amino]-4- fluoro-pyrrolidine-1-carboxylate (400 mg, 1.14 mmol, 1 eq) in TFE (10 mL) was added Pd/C (50 mg, 10% purity) under N ₂ atmosphere. The mixture was stirred under H2 (15 Psi) at 20 °C for 12 h. The mixture was filtered and concentrated to give tert-butyl N-[(3R,4R)-4-fluoropyrrolidin- 3-yl]-N-methyl-carbamate (240 mg). ¹ H NMR (400 MHz, CDCl3): δ 5.4-5.1 (m, 1 H), 4.3-4.1 (m, 1 H), 3.3-3.1 (m, 2 H), 2.90 (s, 3 H), 2.8-2.6 (m, 2 H), 1.5-1.4 (m, 9 H). [000435] Step 3. To a solution of 2-chloro-N-(3-methoxy-1-methyl-pyrazol-4-yl)-9-methyl- purin-6-amine (300 mg, 1.02 mmol, 1 eq) and tert-butyl N-[(3R,4R)-4-fluoropyrrolidin-3-yl]-N- methyl-carbamate (222 mg, 1.02 mmol, 1 eq) in NMP (5 mL) was added DIEA (660 mg, 5.1 mmol, 5 eq). The mixture was stirred at 130 °C for 12 h and concentrated. The residue was purified by prep-HPLC (column: Phenomenex luna C18, 150 x 40mm, 15um;mobile phase: [water(FA)-ACN]; B%: 32%-62%,10 min) to give tert-butyl N-[(3R,4R)-4-fluoro-1-[6-[(3- methoxy-1-methyl-pyrazol-4-yl)amino]-9-methyl-purin-2-yl]pyr rolidin-3-yl]-N-methyl- carbamate (250 mg, 51 % yield). [000436] Step 4. To a solution of tert-butyl N-[(3R,4R)-4-fluoro-1-[6-[(3-methoxy-1-methyl- pyrazol-4-yl)amino]-9-methyl-purin-2-yl]pyrrolidin-3-yl]-N-m ethyl-carbamate (220 mg, 462 µmol, 1 eq) in DCM (5 mL) was added TFA (2 mL). The mixture was stirred at 20 °C for 0.5 h and concentrated to give 2-[(3R,4R)-3-fluoro-4-(methylamino)pyrrolidin-1-yl]-N-(3-met hoxy- 1-methyl-pyrazol-4-yl)-9-methyl-purin-6-amine P (225 mg, TFA salt). Compound Q: 5-chloro-6-methyl-4-(5-methyl-3-(1-methyl-1H-indazol-5-yl)-1 -(2- azaspiro[3.3]heptan-6-yl)-1H-pyrazol-4-yl)-1H-indazole [000437] Compound Q was prepared as described in WO 2021/124222. Compound R: 2-(6-chloro-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)-3-fl uorophenol [000438] Compound R was prepared as described in WO 2017/100546. Compound S: (S)-2-(((4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahy dro-1H- pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)a crylic acid [000439] To a solution of (S)-4,11-diethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizin o[1,2- b]quinoline-3,14(4H,12H)-dione (1.0 g, 2.5 mmol, 1.0 eq) in DMF (10 mL) was added 2- (bromomethyl) prop-2-enoic acid (630 mg, 3.8 mmol, 1.5 eq) and K2CO3 (528 mg, 3.8 mmol, 1.5 eq) at 25 °C. After addition, the mixture was stirred at 50 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by prep-HPLC (column: Phenomenex Luna C18, 200 x 40mm, 10um;mobile phase: [water (HCl)-ACN];B%: 25%- 55%,10 min) to afford (S)-2-(((4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahy dro-1H- pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)a crylic acid (150 mg, 224 µmol, 9% yield, 71% purity) as a yellow solid. ¹ H NMR: (400 MHz, DMSO-d6) δ 8.13 - 8.00 (m, 1H) 7.61 - 7.36 (m, 2H), 7.28 (s, 1H), 6.33 (s, 1H), 6.08 (s, 1H), 5.47 - 5.37 (m, 2H), 5.36 - 5.26 (m, 2H), 4.97 (s, 2H), 4.13 - 3.96 (m, 2H), 3.20 (q, J = 7.6 Hz, 2H), 1.96 - 1.77 (m, 2H) 1.37 - 1.25 (m, 3H), 0.92 - 0.80 (m, 3H). Compound T: 2-(bromomethyl)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino) -4- methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)p henyl)acrylamide [000440] Step 1. To a solution of N-(4-fluoro-2-methoxy-5-nitro-phenyl)-4-(1-methylindol-3- yl)pyrimidin-2-amine (5.00 g, 12.7 mmol, 1 eq) and N,N',N'-trimethylethane-1,2-diamine (1.43 g, 14.0 mmol, 1.82 mL, 1.1 eq) in DMAC (100 mL) was added DIEA (4.11 g, 31.8 mmol, 5.53 mL, 2.5 eq) at 25 °C. The resulting mixture was stirred at 85 °C for 8 hours. The reaction solution was diluted with 900 ml H2O, then filtered to get the filter cake, which was concentrated under reduced pressure to get crude product N4-[2-(dimethylamino)ethyl]-2-methoxy-N4-methyl-N1- [4-(1-methylindol-3-yl)pyrimidin-2-yl]-5-nitro-benzene-1,4-d iamine (5.70 g, 12.0 mmol, 94 % yield) as a yellow solid. [000441] Step 2. To a solution of N4-[2-(dimethylamino)ethyl]-2-methoxy-N4-methyl-N1-[4-(1- methylindol-3-yl)pyrimidin-2-yl]-5-nitro-benzene-1,4-diamine (5.50 g, 11.6 mmol, 1 eq) in MeOH (200 mL) was added 10% wet Pd/C (2 g, 10% purity, w/w). The suspension was degassed under vacuum and urged with H2 several times. The mixture was stirred under H2 (15 psi) at 25 °C for 8 hours. The reaction mixture was filtered and the filter was concentrated to give crude product N1-[2-(dimethylamino)ethyl]-5-methoxy-N1-methyl-N4-[4-(1-met hylindol-3-yl) pyrim-idin-2-yl]benzene-1,2,4-triamine (4.9 g, 11.0 mmol, 95% yield) as a black-brown solid. [000442] Step 3. To a mixture of N1-[2-(dimethylamino)ethyl]-5-methoxy-N1-methyl-N4-[4-(1- methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine (1.00 g, 2.24 mmol, 1 eq) in THF (5 mL) was added NaHCO3/H2O (5 mL) and then added a solution of prop-2-enoyl prop-2-enoate (368 mg, 2.92 mmol, 1.3 eq) in THF (1.25 mL) at 0 °C. The resulting mixture was then stirred at 25 °C for 8 hours. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with Ethyl acetate 300 mL and washed with H ₂ O 300 mL (100 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, Ethyl acetate/Methanol = 5/1 to 1/2) to give product N-[2-[2-(dimethylamino)ethyl-methyl-amino]-4-methoxy-5-[[4-( 1- methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide (480 mg, 961 µmol, 43% yield) as a brown solid. [000443] Step 4. To a solution of N-[2-[2-(dimethylamino)ethyl-methyl-amino]-4-methoxy-5- [[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]prop-2-e namide (480 mg, 961 µmol, 1 eq), DABCO (140 mg, 1.25 mmol, 137 uL, 1.3 eq) and HCHO (1.56 g, 19.2 mmol, 1.43 mL, 37% purity, 20 eq) in dioxane (7.5 mL) and H2O (2.5 mL) was added Phenol (40.7 mg, 432 µmol, 38.0 µL, 0.45 eq)，the mixture solution was heated to 60 °C and stirred for 72 hours. The reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C18, 75 x 30mm, 3um;mobile phase: [water(FA)-ACN];B%: 8%-38%,7min ) to give product N-[2-[2-(dimethylamino)ethyl-methyl-amino]-4-methoxy-5-[[4-( 1-methylindol-3- yl)-pyrimidin-2-yl]amino]phenyl]-2-(hydroxymethyl)prop-2-ena mide (200 mg, 378 µmol, 39% yield) was obtained as a yellow solid. [000444] Step 5. To a solution of N-[2-[2-(dimethylamino)ethyl-methyl-amino]-4-methoxy-5- [[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]-2-(hydr oxymethyl)prop-2-enamide (200 mg, 378 µmol, 1 eq) in DCM (2 mL) was added DMF (27.6 mg, 378 µmol, 29.1 µL, 1.0 eq) and PBr ₃ (112 mg, 415 µmol, 1.1 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched by addition of 10 mL H2O at 25 °C. The reaction mixture was concentrated by lyophilization to give crude product 2-(bromomethyl)-N-[2-[2- (dimethylamino)ethyl-methyl-amino]-4-methoxy-5-[[4-(1-methyl indol-3-yl)pyrimidin-2- yl]amino]phenyl]prop-2-enamide (120 mg, 203 µmol, 54% yield) as a yellow solid. Compound U: (S)-5-(((3-ethyl-5-(2-(2-hydroxyethyl)piperidin-1-yl)pyrazol o[1,5- a]pyrimidin-7-yl)amino)methyl)pyridin-2-ol [000445] The title compound was prepared based on procedures described above for preparation of Compound F. Compound V: 2-(bromomethyl)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino) -4- methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)p henyl)-N- methylacrylamide

[000446] Step 1. To a solution of N-(4-fluoro-2-methoxy-5-nitro-phenyl)-4-(1-methylindol-3- yl)pyrimidin-2-amine (5.00 g, 12.7 mmol, 1 eq) and N,N',N'-trimethylethane-1,2-diamine (1.43 g, 14.0mmol, 1.82 mL, 1.1 eq) in DMA (100 mL) was added DIEA (4.11 g, 31.8 mmol, 5.53 mL, 2.5 eq) at 25 °C. The resulting mixture was stirred at 85 °C for 8 hours. The solution was diluted with 900 ml H2O, then filtered to get the filter cake, which was concentrated under reduced pressure to get crude product N4-[2-(dimethylamino)ethyl]-2-methoxy-N4-methyl-N1- [4-(1-methylindol-3-yl)pyrimidin-2-yl]-5-nitro-benzene-1,4-d iamine (5.70 g, 12.0 mmol, 94 % yield) as a yellow solid. [000447] Step 2. To a solution of N4-[2-(dimethylamino)ethyl]-2-methoxy-N4-methyl-N1-[4- (1-methylindol-3-yl)pyrimidin-2-yl]-5-nitro-benzene-1,4-diam ine (5.50 g, 11.6 mmol, 1.00 eq) in MeOH (200 mL) was added wet Pd/C (2.00 g, 10% purity, w/w). The suspension was degassed under vacuum and urged with H2 several times. The resulting mixture was stirred under H ₂ (15 psi) at 25 °C for 8 hours. The reaction mixture was filtered and the filter was concentrated to give crude product N1-[2-(dimethylamino)ethyl]-5-methoxy-N1-methyl-N4-[4- (1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine (4.9 g, 11.0 mmol, 95% yield) as a black-brown solid. [000448] Step 3. To a mixture of N1-[2-(dimethylamino)ethyl]-5-methoxy-N1-methyl-N4-[4- (1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine (1.00 g, 2.24 mmol, 1 eq) and HCHO (270 mg, 8.98 mmol, 247 uL, 4 eq) in MeOH (120 mL) were added K2CO3 (620 mg, 4.49 mmol, 2 eq) and NaBH ₃ CN (705 mg, 11.2 mmol, 5 eq) in one portion. The resulting mixture was stirred at 25 °C for 10 hours. The reaction mixture was quenched by addition 15mL saturated aqueous NH ₄ Cl solution at 25 °C, and then diluted with 150 mL ethyl acetate. The combined organic layers were washed with H2O 210 mL (70mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18, 150 x 40mm, 15um;mobile phase: [water(FA)-ACN];B%: 7%-37%,10min ) to give product N1-[2-(dimethylamino)ethyl]-5- methoxy-N1,N2-dimethyl-N4-[4-(1-methylindol-3-yl)pyrimidin-2 -yl]benzene-1,2,4-triamine (458 mg, 987 µmol, 44% yield) as a yellow solid. [000449] Step 4. To a mixture of N1-[2-(dimethylamino)ethyl]-5-methoxy-N1,N2-dimethyl- N4-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triam ine (250 mg, 544 µmol, 1 eq) in THF (3 mL) was added saturated aqueous NaHCO ₃ solution (3 mL) and then added a solution of prop-2-enoyl prop-2-enoate (89.2mg, 707 µmol, 1.3 eq) in THF (1.5 mL) at 0 °C. The resulting mixture was then stirred at 25 °C for 8 hours. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with ethyl acetate 200 mL and washed with H ₂ O 300mL (100 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18, 150 x 25mm, 10um;mobile phase: [water(FA)-ACN];B%: 7%-37%,10min) to give N-[2-[2-(dimethylamino)ethyl-methyl-amino]-4-methoxy-5-[[4-( 1- methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]-N-methyl-prop- 2-enamide (150 mg, 266 µmol, 49% yield) as a yellow solid. [000450] Step 5. To a solution of N-[2-[2-(dimethylamino)ethyl-methyl-amino]-4-methoxy-5- [[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]-N-methy l-prop-2-enamide (30.0 mg, 58.4 µmol, 1 eq), DABCO (29.5 mg, 263 µmol, 28.9 µL, 4.5 eq) and HCHO (180 mg, 2.34 mmol, 174 µL, 37% purity, 40 eq) in dioxane (0.6 mL) and H2O (0.2 mL) was added Phenol (7.42 mg, 78.9 µmol, 6.94 µL, 1.35 eq) at 25 ^o C. The mixture solution was heated to 80 °C and stirred for 72 hours. The reaction mixture was concentrated under reduced pressure to remove solvent. The organic phase was purified by prep-HPLC (column: Phenomenex C18, 75 x 30mm, 3um;mobile phase: [water(FA)-ACN];B%: 8%-38%,7min) to give product N-[2-[2- (dimethylamino)ethyl-methyl-amino]-4-methoxy-5-[[4-(1-methyl indol-3-yl)pyrimidin-2- yl]amino]phenyl]-2-(hydroxymethyl)-N-methyl-prop-2-enamide (19.0 mg, 29.8 µmol, 51% yield) as a white solid. [000451] Step 6. To a solution of N-[2-[2-(dimethylamino)ethyl-methyl-amino]-4-methoxy-5- [[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]-2-(hydr oxymethyl)-N-methyl-prop-2- enamide (85.0 mg, 156 µmol, 1 eq) in DCM (4 mL)was added DMF (11.4 mg, 156 µmol, 12.0 µL, 1 eq)and PBr3 (55.0 mg, 203 µmol, 1.3 eq) at 0 °C. The mixture was stirred at 30 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-TLC (SiO ₂ , MeOH : EtOAc = 40 : 1) to give crude product 2- (bromomethyl)-N-[2-[2-(dimethylamino)ethyl-methyl-amino]-4-m ethoxy-5-[[4-(1-methylindol- 3-yl)pyrimidin-2-yl]amino]phenyl]-N-methyl-prop-2-enamide Compound V (56.7 mg, 93.6 µmol, 60% yield) as a light yellow solid. Compound W: 2-(bromomethyl)-1-((3R,4R)-3-(((5-chloro-2-((1-methyl-1H-pyr azol-4- yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)-4-meth oxypyrrolidin-1-yl)prop- 2-en-1-one [000452] Step 1. To a solution of compound tert-butyl (3R,4R)-3-(((5-chloro-2-((1-methyl-1H- pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)meth yl)-4-methoxypyrrolidine-1- carboxylate (300 mg, 627 µmol, 1.0 eq) in DCM (4 mL) was added TFA (2 mL). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was filtered and concentrated under reduced pressure to give compound 5-chloro-4-(((3R,4R)-4-methoxypyrrolidin-3-yl)methoxy)-N-(1- methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (308 mg, crude, TFA salt) as a white solid and used for the next step directly. [000453] Step 2. To a solution of compound 5-chloro-4-(((3R,4R)-4-methoxypyrrolidin-3- yl)methoxy)-N-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]py rimidin-2-amine (308 mg, 626 µmol, 1.0 eq, TFA salt), compound 2-(((triisopropylsilyl)oxy)methyl)acrylic acid(242 mg, 939 µmol, 1.5 eq) in DMF (5 mL) was added T3P (357 mg, 939 µmol, 372 uL, 1.5 eq) and DIEA (242 mg, 1.88 mmol, 327 uL, 3.0 eq). The mixture was stirred at 25 °C for 0.5 h. compound 1- ((3R,4R)-3-(((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)-7 H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)methyl)-4-methoxypyrrolidin-1-yl)-2-(((triisopropylsi lyl)oxy)methyl)prop-2-en-1-one (387 mg, crude) was obtained as a brown liquid in DMF for next step. [000454] Step 3. To a solution of compound 1-((3R,4R)-3-(((5-chloro-2-((1-methyl-1H- pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)meth yl)-4-methoxypyrrolidin-1-yl)- 2-(((triisopropylsilyl)oxy)methyl)prop-2-en-1-one (387 mg, 625 µmol, 1.0 eq) in DMF (4 mL) was added KF (0.18 g, 3.1 mmol, 73 uL, 5.0 eq). The mixture was stirred at 25 °C for 48 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 C18, 150 x 40mm, 15um; mobile phase: [water (FA)-ACN]; B%: 20 %-50 %, 10min) to afford compound 1-((3R,4R)-3- (((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2 ,3-d]pyrimidin-4- yl)oxy)methyl)-4-methoxypyrrolidin-1-yl)-2-(hydroxymethyl)pr op-2-en-1-one (120 mg, 257 µmol, 41 % yield) as a white solid. ¹ H NMR: (400 MHz, CDCl ₃ ): δ 7.68 - 7.52 (m, 1H), 7.47 (s, 1H), 6.73 (s, 1H), 5.59 - 5.46 (m, 1H), 5.41 - 5.29 (m, 1H), 4.62 - 4.53 (m, 1H), 4.50 - 4.20 (m, 3H), 4.19 - 4.07 (m, 2H), 4.05 - 3.94 (m, 1H), 3.92 - 3.81 (m, 4H), 3.68 - 3.61 (m, 1H), 3.45 - 3.36 (m, 3H), 2.85 - 2.77 (m, 1H). [000455] Step 4. To a solution of compound 1-((3R,4R)-3-(((5-chloro-2-((1-methyl-1H- pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)meth yl)-4-methoxypyrrolidin-1-yl)- 2-(hydroxymethyl)prop-2-en-1-one (900 mg, 194 µmol, 1.0 eq) in DCM (0.5 mL) was added PBr3 (52.7 mg, 194 µmol, 1.0 eq).The mixture was stirred at 0 °C for 0.5 h. The reaction mixture was filtered and concentrated under reduced pressure to give compound W (102 mg, crude) as a white solid. Compound X: 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrol idin-2- yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2 -(cyanomethyl)piperazine-1- carbonyl)allyl methanesulfonate [000456] To a solution of 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolid in-2- yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[2 -(hydroxymethyl)prop-2- enoyl]piperazin-2-yl]acetonitrile (50 mg, 81 µmol, 1.0 eq) in DCM (1 mL) was added DIEA (31 mg, 0.24 mmol, 3.0 eq) and MsCl (0.21 g, 1.82 mmol, 22.5 eq). The mixture was stirred at 25 °C for 0.5 h. LC-MS showed 1 was consumed completely. The residue was added H2O (10 mL) and extracted with EA (10 mL x 3) .The combined organic layers were filtered and concentrated under reduced pressure to afford 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1- methyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d] pyrimidin-4-yl]-2- (cyanomethyl) piperazine-1-carbonyl]allylmethanesulfonate Compound X (54 mg, 95 % yield) as a colorless oil. Compound Y: (4-hydroxy-3,5-dimethoxyphenyl)(6-methoxy-1H-indol-3-yl)meth anone [000457] Compound Y was prepared as described in J. Med. Chem., 2009, 52, 4941. Compound Z: 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrol idin-2- yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2 -(cyanomethyl)piperazine-1- carbonyl)allyl (4-nitrophenyl) carbonate [000458] Step 1.2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrr olidin-2- yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pi perazin-2-yl)acetonitrile ( described in US 2019/144444) and 2-(((triisopropylsilyl)oxy)methyl)acrylic acid (described in Bioorg. Med. Chem. Lett., 2015, 25, 5504) were prepared according to literature accounts. To a solution of 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrol idin-2-yl)methoxy)- 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl )acetonitrile (2.39 g, 3.70 mmol, 1.0 equiv, TFA salt), 2-(((triisopropylsilyl)oxy)methyl)acrylic acid (1.43 g, 5.55 mmol, 1.5 equiv) in DMF (20 mL) was added DIEA (1.43 g, 11.10 mmol, 1.93 mL, 3.0 equiv) and T3P (2.77 g, 5.55 mmol, 3.24 mL, 1.5 equiv). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was diluted with 100 mL H2O and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrol idin-2- yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1 -(2- (((triisopropylsilyl)oxy)methyl)acryloyl)piperazin-2-yl)acet onitrile (5.72 g, crude) as a brown oil and used for the next step directly. [000459] Step 2. To a solution of 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-yl)-1-(2- (((triisopropylsilyl)oxy) methyl)acryloyl)piperazin-2-yl)acetonitrile (5.70 g, 7.38 mmol, 1.0 equiv) in DCM (40 mL) was added TFA (5 mL). The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with 100 mL NaHCO3 and extracted with DCM/MeOH (10:1, 50 mL x 2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate= 0/1 to dichloromethane: methanol =5/1) to afford 2-((S)-4-(7- (8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)me thoxy)-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-(hydroxymethyl)a cryloyl)piperazin-2- yl)acetonitrile (2.17 g, 3.5 mmol, 47 % yield) as a brown solid. ¹ H NMR: (400 MHz, DMSO- d6) δ 7.92 (d, J = 7.7 Hz, 1H), 7.74 (d, J = 3.2, 7.9 Hz, 1H), 7.61 - 7.49 (m, 2H), 7.47 - 7.40 (m, 1H), 7.38 - 7.30 (m, 1H), 5.43 (s, 1H), 5.32 - 4.89 (m, 2H), 4.26-4.37 (m, J = 5.5, 11.0 Hz, 1H), 4.22 - 4.08 (m, 4H), 3.95 (d, J = 13.7 Hz, 1H), 3.88 - 3.64 (m, 2H), 3.62 - 3.36 (m, 2H), 3.26 - 3.01 (m, 6H), 3.00 - 2.58 (m, 4H), 2.52 (s, 1H), 2.38 (s, 3H), 1.96 (s, 1H), 1.80 - 1.58 (m, 3H) [000460] Step 3. To a solution of compound 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-yl)-1-(2- (hydroxymethyl)acryloyl)piperazin-2-yl)acetonitrile (100 mg, 162 umol, 1.0 equiv) in THF (2 mL) was added bis(4-nitrophenyl) carbonate (98 mg, 324 umol, 2.0 equiv) and stirred at 40 °C for 12 h. The crude product 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrol idin- 2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl) -2-(cyanomethyl)piperazine-1- carbonyl)allyl (4-nitrophenyl) carbonate Z (130 mg, crude) was used into the next step without further purification as a yellow solution. Compound AA: 1-Isopropyl-5-(2-(piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4 -yl)pyridin- 2(1H)-one [000461] Compound AA is a known compound per J. Med. Chem., 2021, 64, 15189 – 15213. LC-MS: MS (ES ⁺ ): RT = 0.238 min, m/z = 337.1 [M + H ⁺ ]. Compound AB: 2-((2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin- 1(2H)- yl)methyl)acrylic acid [000462] Step 1. To a solution of NaH (98.87 mg, 2.47 mmol, 60% purity, 0.9 equiv) in DMF (7 mL) was added 6-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1H-quinolin-2-one (as described in WO 2006/113432) (800 mg, 2.75 mmol, 1 equiv) was stirred at 0 °C for 0 .5 h. tert-Butyl 2- (bromomethyl)prop-2-enoate (1.21 g, 5.49 mmol, 2 equiv) in DMF (1.5 mL) was added , and then the mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched by addition solvent H ₂ O 1 mL at 0 °C. The residue was purified by prep-HPLC(column: Waters Xbridge 150*25mm* 5um;mobile phase: [water( NH4HCO3)-ACN];B%: 68%-98%,10min)to give tert- butyl 2-[[2-oxo-6-[4-(trifluoromethyl) phenyl]-3,4-dihydroquinolin-1-yl]methyl]prop-2-enoate (700 mg, 1.62 mmol, 59% yield) as a white solid. ¹ H NMR (400 MHz, CDCl3): δ 7.79 - 7.61 (m, 4H), 7.53 - 7.35 (m, 2H), 7.28 (s, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.22 (s, 1H), 5.33 (s, 1H), 4.81 (s, 2H), 3.12 - 2.99 (m, 2H), 2.81 (d, J = 6.2, 8.6 Hz, 2H), 1.57 (s, 9H). [000463] Step 2. To a solution of tert-butyl 2-[[2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4- dihydroquinolin-1-yl]methyl]prop-2-enoate (700 mg, 1.62 mmol, 1 equiv) in DCM (6 mL) was added TFA (2 mL) .The mixture was stirred at 30 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove solvent to give crude 2-[[2-oxo-6-[4- (trifluoromethyl)phenyl]-3,4-dihydroquinolin-1-yl]methyl]pro p-2-enoic acid (600 mg, 1.60 mmol, 98% yield) as a white solid. Compound AC: 2-((S)-1-(2-(bromomethyl)acryloyl)-4-(7-(8-chloronaphthalen- 1-yl)-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyr ido[3,4-d]pyrimidin-4- yl)piperazin-2-yl)acetonitrile [000464] To a solution of 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolid in-2- yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-[2 -(hydroxymethyl)prop-2- enoyl]piperazin-2-yl]acetonitrile (20 mg, 32.46 umol, 1 equiv) in DCM (0.5 mL) was added PBr3 (8.79 mg, 32.46 umol, 60 uL, 1 equiv) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h. After concentrated, Compound 2-[(2S)-1-[2-(bromomethyl)prop-2-enoyl]-4-[7-(8- chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy] -6,8-dihydro-5H-pyrido[3,4- d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile AC (22 mg, 99 % yield) as a colorless liquid. [000465] Compound AD: (R)-4-((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8- tetrahydropteridin-2-yl)amino)-3-hydroxy-N-(1-methylpiperidi n-4-yl)benzamide hydrogen bromide [000466] Step 1. A solution of DIPEA (0.41 mL, 2.35 mmol) and 4-amino-1-methylpiperidine (101 mg, 0.881 mmol) in DMF (2.0 mL) was added to a solution of (R)-4-((8-cyclopentyl-7- ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)- 3-methoxybenzoic acid (0.31 mL, 0.588 mmol) and TCFH (247 mg, 0.881 mmol) in DMF (3.0 mL) cooled to 0 ºC. The reaction mixture was stirred at rt for 1 h. The volatiles were evaporated under reduced pressure. The crude product was purified by reverse phase chromatography (C18) using a gradient of 0-100% MeCN in water (it contains 0.1% formic acid) to afford (R)-4-((8-cyclopentyl-7-ethyl-5- methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-3-methox y-N-(1-methylpiperidin-4- yl)benzamide (250 mg, 82 %) as a solid. [000467] Step 2. A mixture of (R)-4-((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8- tetrahydropteridin-2-yl)amino)-3-methoxy-N-(1-methylpiperidi n-4-yl)benzamide 3 (50.0 mg, 95.8 µmol) and an aqueous solution of HBr (48%, 1.50 mL) was heated to 100 ºC for 10 h and then cooled to rt. The volatiles were evaporated under reduced pressure. The crude product was purified by reverse phase chromatography (C18) using a gradient of 0-100% MeCN in water (it contains 0.1% HCl) to afford the title compound AD (16.0 mg, 28 %) as a solid. Compound AE: 2-((3-((Z)-((Z)-5-((5-(tert-butyl)-1H-imidazol-4-yl)methylen e)-3,6- dioxopiperazin-2-ylidene)methyl)phenoxy)methyl)acrylic acid [000468] Step 1. To a solution of compound 3-hydroxybenzaldehyde (2.50 g, 20.5 mmol, 1.0 equiv), compound tert-butyl 2-(bromomethyl)acrylate (4.53 g, 20.5 mmol, 1.0 equiv) in CH ₃ CN (25 mL) was added K2CO3 (8.49 g, 61.4 mmol, 3.0 equiv). The mixture was stirred at 80 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=1/0 to 1/1) to afford compound tert-butyl 2-((3-formylphenoxy)methyl)acrylate (5.30 g, 20.2 mmol, 99 % yield) as a yellow oil. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 9.98 (s, 1H), 7.52 - 7.41 (m, 3H), 7.25 - 7.18 (m, 1H), 6.37 - 6.29 (m, 1H), 5.95 - 5.86 (m, 1H), 4.79 (s, 2H), 1.53 (s, 9H). [000469] Step 2. To a solution of compound tert-butyl 2-((3-formylphenoxy)methyl)acrylate (1.81 g, 6.89 mmol, 2.0 equiv), compound (Z)-3-((5-(tert-butyl)-1H-imidazol-4- yl)methylene)piperazine-2,5-dione(1.00 g, 3.44 mmol, 1 equiv) in CH ₃ CN (15 mL) was added K2CO3 (1.43 g, 10.3 mmol, 3.0 equiv). The mixture was stirred at 80 °C for 12 h. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um; mobile phase: [water (FA)-ACN]; B%: 56%-86%, 10min) to afford compound tert-butyl 2-((3-((Z)-((Z)-5- ((5-(tert-butyl)-1H-imidazol-4-yl)methylene)-3,6-dioxopipera zin-2- ylidene)methyl)phenoxy)methyl)acrylate(410 mg, 832 umol, 24 % yield) as a yellow solid. LC-MS: MS (ES ⁺ ): RT = 0.937 min, m/z =493.3 [M+1] ⁺ . ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 12.36 - 12.10 (m, 1H), 9.98 (s, 1H), 7.88 (s, 1H), 7.57 - 7.51 (m, 2H), 7.47 - 7.43 (m, 1H), 7.35 - 7.29 (m, 1H), 7.25 - 7.17 (m, 1H), 7.01 - 6.88 (m, 1H), 6.66 (s, 1H), 6.77 - 6.64 (m, 1H), 6.22 (d, J = 0.9 Hz, 1H), 5.94 (d, J = 1.3 Hz, 1H), 4.79 (s, 2H), 1.50 - 1.39 (m, 18H). [000470] Step 3. To a solution of tert-butyl 2-((3-((Z)-((Z)-5-((5-(tert-butyl)-1H-imidazol-4- yl)methylene)-3,6-dioxopiperazin-2-ylidene)methyl)phenoxy)me thyl)acrylate (400 mg, 812 umol, 1.0 equiv) in DCM (3 mL) was add ed TFA (1.50 mL). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated to afford crude product. The residue was purified by prep-HPLC (column: Waters Xbridge C18150*50mm* 10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 5%-35%, 10min) to afford compound AE (100 mg, 206 umol, 25 % yield) as a yellow solid. Compound AF: (S)-5-(2,5-difluorophenyl)-N-methoxy-N-methyl-2-(3- (methylamino)propyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbox amide hydrochloride AF [000471] Compound AF was synthesized according to procedures in WO 2006/044825. Compound AG:6-methoxy-N1-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-4 -(4- methylpiperazin-1-yl)benzene-1,3-diamine [000472] Compound AG was synthesized according to procedures in Journal of Medicinal Chemistry (2022) vol.65(6), p.4709 – 4726. Compound AH: 2-(((Z)-3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)-6-((Z )-3- nicotinoylbenzylidene)-2,5-dioxopiperazin-1-yl)methyl)acryli c acid [000473] Step 1. A mixture of (Z)-1-acetyl-3-((5-(tert-butyl)-1H-imidazol-4- yl)methylene)piperazine-2,5-dione (J. Med. Chem., 2012, 55, 1056 – 1071) (850 mg, 2.93 mmol, 1 equiv), 3-nicotinoylbenzaldehyde (Bioorg. Med. Chem., 2018, 26, 2061 – 2072) (618 mg, 2.93 mmol, 1.0 equiv), Cs2CO3 (1.91 g, 5.86 mmol, 2.0 equiv) in DMF (20 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 80 °C for 1 h under N ₂ atmosphere. The reaction mixture was poured into H ₂ O (100 mL), and then filtered and to afford the filter cake as crude product. The residue was purified by prep-HPLC (column: Phenomenex C1875*30mm*3um; mobile phase: [water (FA)-ACN]; B%: 28%-58%, 7 min). Compound (Z)-3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)-6-((Z)-3- nicotinoylbenzylidene)piperazine-2,5-dione (620 mg, 1.40 mmol, 47% yield, 100% purity) was obtained as a yellow solid. [000474] Step 2. To a solution of (Z)-3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)-6-((Z)- 3-nicotinoylbenzylidene)piperazine-2,5-dione (440 mg, 996 umol, 1.0 equiv) and tert-butyl 2- (bromomethyl)acrylate (110 mg, 498 umol, 0.5 equiv) in DMF (4 mL) was added Cs ₂ CO ₃ (974 mg, 2.99 mmol, 3.0 equiv). The mixture was stirred at 20 °C for 12 h. The residue was purified by prep-HPLC (column: Waters Xbridge C18150*50mm* 10um; mobile phase: [water (NH4HCO3)-ACN];B%: 45%-75%,10min). Tert-butyl 2-(((Z)-3-((5-(tert-butyl)-1H-imidazol-4- yl)methylene)-6-((Z)-3-nicotinoylbenzylidene)-2,5-dioxopiper azin-1-yl)methyl)acrylate (100 mg, 171 umol, 17% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ):^δ 12.38 (s, 1H), 12.26 (s, 1H), 8.91 (d, J = 1.7 Hz, 1H), 8.85 (dd, J = 1.5, 4.8 Hz, 1H), 8.14 (m, 1H), 7.87 (s, 1H), 7.74 (m, 1H), 7.69 - 7.58 (m, 4H), 7.14 (s, 1H), 6.95 (s, 1H), 5.92 (s, 1H), 5.04 (s, 1H), 4.39 (s, 2H), 1.38 (s, 9H), 1.29 (s, 9H) [000475] Step 3. To a solution of tert-butyl 2-(((Z)-3-((5-(tert-butyl)-1H-imidazol-4- yl)methylene)-6-((Z)-3-nicotinoylbenzylidene)-2,5-dioxopiper azin-1-yl)methyl)acrylate (100 mg, 171 umol, 1.0 equiv) in DCM (1 mL) was added TFA (0.5 mL). The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give 2-(((Z)- 3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)-6-((Z)-3-nico tinoylbenzylidene)-2,5- dioxopiperazin-1-yl)methyl)acrylic acid AH (100 mg, 156 umol, 90% yield, TFA salt) as a yellow gum. Compound AI: 2-(((Z)-3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)-6-((Z )-2,5- difluorobenzylidene)-2,5-dioxopiperazin-1-yl)methyl)acrylic acid [000476] Step 1. To a solution of (Z)-3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)-6-((Z)- 2,5-difluorobenzylidene)piperazine-2,5-dione (WO2012/35436, 2012, A1) (0.64 g, 1.7 mmol, 1.0 equiv), tert-butyl 2-(bromomethyl)acrylate (J. Med. Chem., 2021, 64, 1835) (0.19 g, 0.86 mmol, 0.5 equiv) in DMF (6 mL) was added Cs2CO3 (1.1 g, 3.4 mmol, 2.0 equiv). The mixture was stirred at 25 °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: Waters Xbridge C18150*50mm* 10um;mobile phase: [water( NH4HCO3)-ACN];B%: 51%-81%,10min) tert- butyl 2-(((Z)-3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)-6-((Z )-2,5-difluorobenzylidene)- 2,5-dioxopiperazin-1-yl)methyl)acrylate(0.12 g, 0.23 mmol, 14% yield) was obtained as a white solid. [000477] Step 2. To a solution of tert-butyl 2-(((Z)-3-((5-(tert-butyl)-1H-imidazol-4- yl)methylene)-6-((Z)-2,5-difluorobenzylidene)-2,5-dioxopiper azin-1-yl)methyl)acrylate (120 mg, 234 umol, 1.0 equiv) in DCM (1 mL) was added TFA (0.5 mL). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was filtered and concentrated under reduced pressure to give Compound AI (107 mg, crude, TFA salt) as a white solid. Compound AJ: 2-(((Z)-3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)-6-((Z )-3- hydroxybenzylidene)-2,5-dioxopiperazin-1-yl)methyl)acrylic acid [000478] Step 1. To a solution of (Z)-3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)-6-((Z)- 3-hydroxybenzylidene)piperazine-2,5-dione (J. Med. Chem., 2012, 55, 1056 – 1071) (0.35 g, 0.99 mmol, 1.0 equiv) in DCM (4 mL) was added TBSCl (0.22 g, 1.5 mmol, 0.18 mL, 1.5 equiv) and imidazole (0.21 g, 3.0 mmol, 3.0 equiv). The mixture was stirred at 25 °C for 12 h. To the reaction mixture was added water (20 mL) and the mixture was extracted with EtOAc (20 mL). The combined organic phase was washed with brine (20 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=10/1 to 0/1) to afford (Z)-3-((5-(tert- butyl)-1H-imidazol-4-yl)methylene)-6-((Z)-3-((tert- butyldimethylsilyl)oxy)benzylidene)piperazine-2,5-dione (0.5 g, 1.0 mmol, 99% yield) as a yellow oil. [000479] Step 2. To a solution of (Z)-3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)-6-((Z)- 3-((tert-butyldimethylsilyl)oxy)benzylidene)piperazine-2,5-d ione (0.45 g, 0.96 mmol, 1.0 equiv), tert-butyl 2-(bromomethyl)acrylate (J. Med. Chem., 2021, 64, 1835) (0.11 g, 0.48 umol, 0.5 equiv) in DMF (5 mL) was added Cs2CO3 (0.63 g, 1.9 mmol, 2.0 equiv). The mixture was stirred at 25 °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: Waters Xbridge C18150*50mm* 10um;mobile phase: [water( NH4HCO3)-ACN];B%: 50%-80%,10min) to afford tert-butyl 2-(((Z)-3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)-6-((Z )-3- hydroxybenzylidene)-2,5-dioxopiperazin-1-yl)methyl)acrylate (0.14 mg, 0.28 mmol, 29 % yield) as a white solid. [000480] Step 3. To a solution of tert-butyl 2-(((Z)-3-((5-(tert-butyl)-1H-imidazol-4- yl)methylene)-6-((Z)-3-hydroxybenzylidene)-2,5-dioxopiperazi n-1-yl)methyl)acrylate (0.14 mg, 0.28 mmol, 1.0 equiv) in DCM (1 mL) was added TFA (0.5 mL). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was filtered and concentrated under reduced pressure to give Compound AJ (0.125 g, crude, TFA salt) as a white solid. Compound AK: 2-(((3Z,6Z)-3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)-2 ,5-dioxo-6- (thiophen-2-ylmethylene)piperazin-1-yl)methyl)acrylic acid [000481] Step 1. To a solution of (3Z,6Z)-3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)-6- (thiophen-2-ylmethylene)piperazine-2,5-dione (WO 2012/35436, 2012, A1) (0.38 g, 1.1 mmol, 1.0 equiv), tert-butyl 2-(bromomethyl)acrylate (J. Med. Chem., 2021, 64, 1835) (0.12 g, 0.55 mmol, 0.5 equiv) in DMF (4 mL) was added Cs ₂ CO ₃ (0.72 g, 2.2 mmol, 2.0 equiv). The mixture was stirred at 25 °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: Waters Xbridge C18150*50mm* 10um;mobile phase: [water( NH4HCO3)-ACN];B%: 51%- 81%,10min) Compound 3 (0.08 g, 0.17 mmol, 15% yield) as a white solid. [000482] Step 2. To a solution of tert-butyl 2-(((3Z,6Z)-3-((5-(tert-butyl)-1H-imidazol-4- yl)methylene)-2,5-dioxo-6-(thiophen-2-ylmethylene)piperazin- 1-yl)methyl)acrylate (80 mg, 166 umol, 1.0 equiv) in DCM (1 mL) was added TFA (0.5 mL). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was filtered and concentrated under reduced pressure to give Compound AK (80 mg, crude, TFA salt) as a white solid. Compound AL: 2-(((3Z,6Z)-3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)-6 - (cyclohexylmethylene)-2,5-dioxopiperazin-1-yl)methyl)acrylic acid [000483] Step 1. To a solution of (3Z,6Z)-3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)-6- (cyclohexylmethylene)piperazine-2,5-dione (US2008/221122, 2008, A1) (0.4 g, 1.2 mmol, 1.0 equiv), tert-butyl 2-(bromomethyl)acrylate (J. Med. Chem., 2021, 64, 1835) (0.13 g, 0.58 mmol, 0.5 equiv) in DMF (4 mL) was added Cs ₂ CO ₃ (0.76 g, 2.3 mmol, 2.0 equiv). The mixture was stirred at 50 °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: Waters Xbridge C18150*50mm* 10um;mobile phase: [water( NH4HCO3)-ACN];B%: 55%- 85%,10min). Tert-butyl 2-(((3Z,6Z)-3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)-6 - (cyclohexylmethylene)-2,5-dioxopiperazin-1-yl)methyl)acrylat e (0.1 g, 0.2 mmol, 18% yield) was obtained as a white solid. [000484] Step 2. To a solution of tert-butyl 2-(((3Z,6Z)-3-((5-(tert-butyl)-1H-imidazol-4- yl)methylene)-6-(cyclohexylmethylene)-2,5-dioxopiperazin-1-y l)methyl)acrylate (82 mg, 170 umol, 1.0 equiv) in DCM (1 mL) was added TFA (0.5 mL). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was filtered and concentrated under reduced pressure to give Compound AL (73 mg, crude, TFA salt) as a white solid. Compound AM: 3-((Z)-2-((Z)-benzylidene)-5-((5-(tert-butyl)-1H-imidazol-4- yl)methylene)-3,6-dioxopiperazin-1-yl)-2-methylpropanoic acid [000485] Step 1. To a solution of tert-butyl 2-(((Z)-2-((Z)-benzylidene)-5-((5-(tert-butyl)-1H- imidazol-4-yl)methylene)-3,6-dioxopiperazin-1-yl)methyl)acry late (600 mg, 1.26 mmol, 1.0 equiv) in THF (40 mL) was added Pt/C (200 mg, 5% 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 2 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 C18 150*40mm* 15um; mobile phase: [water (FA)-ACN]; B%: 57%-87%, 9min) to afford tert- butyl 3-((Z)-2-((Z)-benzylidene)-5-((5-(tert-butyl)-1H-imidazol-4- yl)methylene)-3,6- dioxopiperazin-1-yl)-2-methylpropanoate (140 mg, 293 umol, 23 % yield) as a yellow solid. [000486] Step 2. To a solution of tert-butyl 3-((Z)-2-((Z)-benzylidene)-5-((5-(tert-butyl)-1H- imidazol-4-yl)methylene)-3,6-dioxopiperazin-1-yl)-2-methylpr opanoate (70.0 mg, 146 umol, 1.0 equiv) in DCM (0.5 mL) was added TFA (4.49 g, 39.4 mmol, 2.92 mL, 269 equiv). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give Compound AM (61.79 mg, crude) as a yellow oil and used into the next step directly.

Compound AN: (S)-2-((5-(((3-ethyl-5-(2-(2-hydroxyethyl)piperidin-1-yl)pyr azolo[1,5- a]pyrimidin-7-yl)amino)methyl)-2-oxopyridin-1(2H)-yl)methyl) acrylic acid [000487] To a solution of 5-(((3-ethyl-5-((S)-2-(2-hydroxyethyl)piperidin-1-yl)pyrazol o[1,5- a]pyrimidin-7-yl)amino)methyl)-1,2-dihydropyridin-2-ol (500 mg, 1.26 mmol, 1.0 equiv), K2CO3 (523 mg, 3.78 mmol, 3.0 equiv) in DMF (5 mL) was added 3-bromo-2- (bromomethyl)propanoic acid (465 mg, 1.89 mmol, 1.5 equiv) in DMF (5 mL) slowly. The mixture was stirred at 45 °C for 12 h. The reaction mixture was acidified to adjust pH=5~6 by CH3COOH. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*40mm* 15um; mobile phase: [water (TFA)-ACN]; B%: 10%-40%, 10min) to afford compound AN (400 mg, 832 umol, 66 % yield) as a white solid. Compound AO: tert-butyl 4-(1-(2-(((3R,4R)-4-fluoro-1-(6-((3-methoxy-1-methyl-1H- pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidin-3-yl)c arbamoyl)allyl)-4-(1- isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrrolo[2,3-b]py ridin-2-yl)piperidine-1- carboxylate

[000488] Step 1. To a solution of tert-butyl 4-(4-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)- 1H-pyrrolo[2,3-b]pyridin-2-yl)piperidine-1-carboxylate (J. Med. Chem., 2021, 64, 20, 15189 – 15213) (1.0 g, 2.3 mmol, 1.0 equiv) in THF (10 mL) was added NaH (0.27 mg, 6.9 mmol, 60% purity, 3.0 equiv) at 0°C over 0.5 h, and then methyl 2-(bromomethyl)acrylate (2.1 g, 11.5 mmol, 5.0 equiv) in THF (15 mL) was added dropwise at 0°C. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by 10 mL NH4Cl at 0 °C. The reaction mixture was diluted with H ₂ O (50 mL) and extracted with EA (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=10/1 to 0/1) to afford tert-butyl 4-(4-(1-isopropyl-6-oxo-1,6- dihydropyridin-3-yl)-1-(2-(methoxycarbonyl)allyl)-1H-pyrrolo [2,3-b]pyridin-2-yl)piperidine-1- carboxylate (0.87 g, 1.6 mmol, 71 % yield) as a yellow oil. [000489] Step 2. To a solution of tert-butyl 4-(4-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)- 1-(2-(methoxycarbonyl)allyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)p iperidine-1-carboxylate (0.87 g, 1.6 mmol, 1.0 equiv) in THF (3 mL) was added LiOH.H2O (205 mg, 4.88 mmol, 3.0 equiv) in H ₂ O (1 mL). The mixture was stirred at 25 °C for 12 h. The reaction mixture was filtered to afford crude product. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*40mm* 15um;mobile phase: [water(FA)-ACN];B%: 35%-65%,10min).2-((2-(1-(tert- butoxycarbonyl)piperidin-4-yl)-4-(1-isopropyl-6-oxo-1,6-dihy dropyridin-3-yl)-1H-pyrrolo[2,3- b]pyridin-1-yl)methyl)acrylic acid (360 mg, 588 umol, 36% yield) was obtained as a white solid. [000490] Step 3. To a solution of 2-((2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-(1- isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrrolo[2,3-b]py ridin-1-yl)methyl)acrylic acid (90 mg, 0.17 mmol, 1.0 equiv) and 2-((3R,4R)-3-amino-4-fluoropyrrolidin-1-yl)-N-(3- methoxy-1-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-amine (82 mg, 0.17 mmol, 1.0 equiv, TFA salt) in DMF (2 mL) was added DIEA (45 mg, 0.35 mmol, 60 uL, 2.0 equiv) and HATU (99 mg, 0.26 mmol, 1.5 equiv). The mixture was stirred at 25 °C for 1 h. The residue was purified by prep-HPLC (column: Phenomenex C1875*30mm*3um; mobile phase: [water(FA)-ACN]; B%: 42%-72%,7min). Compound AO (80 mg, 87 umol, 50% yield) was obtained as a white solid. Compound AP: tert-butyl 4-(1-(2-((3R,4R)-3-(((5-chloro-2-((1-methyl-1H-pyrazol-4- yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)-4-meth oxypyrrolidine-1- carbonyl)allyl)-4-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl )-1H-pyrrolo[2,3-b]pyridin-2- yl)piperidine-1-carboxylate [000491] To a solution of 2-((2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-(1-isopropyl -6-oxo- 1,6-dihydropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)methy l)acrylic acid (Compound AO) (90 mg, 0.17 mmol, 1.0 equiv) and 5-chloro-4-(((3R,4R)-4-methoxypyrrolidin-3-yl)methoxy)- N-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-am ine (J. Med. Chem., 2016, 59, 2005 – 2024) (85 mg, 0.17 mmol, 1.0 equiv, TFA salt) in DMF (2 mL) was added HATU (99 mg, 0.26 mmol, 1.5 equiv) and DIEA (45 mg, 0.35 mmol, 60 uL, 2.0 equiv). The mixture was stirred at 25 °C for 1 h . The reaction mixture was filtered to afford crude product. The residue was purified by prep-HPLC (column: Phenomenex C1875*30mm*3um;mobile phase: [water(FA)-ACN];B%: 50%-80%,7min). Compound AP (65 mg, 69 umol, 40% yield) was obtained as a white solid.

Compound AQ: tert-butyl 4-(1-(2-((2-((2-(dimethylamino)ethyl)(methyl)amino)-4- methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)p henyl)carbamoyl)allyl)-4- (1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrrolo[2,3-b ]pyridin-2-yl)piperidine-1- carboxylate [000492] To a solution of 2-((2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-(1-isopropyl -6-oxo- 1,6-dihydropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)methy l)acrylic acid (Compound AO)(250 mg, 480 umol, 1.0 equiv) and N1-(2-(dimethylamino)ethyl)-5-methoxy-N1-methyl- N4-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)benzene-1,2,4-t riamine (214 mg, 480 umol, 1.0 equiv) in DMF (2 mL) was added HATU (274 mg, 720 umol, 1.5 equiv) and DIEA (124 mg, 960 umol, 167 uL, 2.0 equiv) .The mixture was stirred at 25 °C for 1 h. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 8%-38%,10min). Compound AQ (100 mg, 105 umol, 22% yield) was obtained as a white solid. Compound AR: tert-butyl 4-(1-(2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-yl)-2- (cyanomethyl)piperazine-1-carbonyl)allyl)-4-(1-isopropyl-6-o xo-1,6-dihydropyridin-3-yl)- 1H-pyrrolo[2,3-b]pyridin-2-yl)piperidine-1-carboxylate [000493] To a solution of 2-((2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-(1-isopropyl -6-oxo- 1,6-dihydropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)methy l)acrylic acid (Compound AO)(200 mg, 384 umol, 1.0 equiv) and 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile (Euro. J. Med. Chem., 2022, 230, 114088) (248 mg, 384 umol, 1.0 equiv, TFA salt) in DMF (2 mL) was added HATU (219 mg, 576 umol, 1.5 equiv) and DIEA (99 mg, 768 umol, 134 uL, 2.0 equiv). The mixture was stirred at 25 °C for 1 h. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18150*25mm*5um;mobile phase: [water( NH4HCO3)-ACN];B%: 60%-90%,10min). Compound AR (130 mg, 125 umol, 33% yield) was obtained as a white solid. EXAMPLE 7 – Synthesis of Compound III-10: 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyr ido[3,4-d]pyrimidin-4-yl)-2- (cyanomethyl)piperazine-1-carbonyl)allyl (3-((S)-5-(2,5-difluorophenyl)-3- (methoxy(methyl)carbamoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadi azol-2- yl)propyl)carbamate [000494] A mixture of Compound A (70 mg, 156 µmol, 1.0 eq), Compound B (114 mg, 156 µmol, 1.0 eq, TFA salt) and Et3N (47 mg, 470 µmol, 65 uL, 3.0 eq) in THF (1 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 50 °C for 2 h under N2 atmosphere. The reaction mixture was concentrated to afford a crude product. The residue was purified by prep-HPLC (column: Shim-pack C18, 150 x 25, 10um;mobile phase: [water(FA)-ACN];B%: 30%-60%,10min), prep-HPLC(column: Waters Xbridge 150 x 25mm, 5um;mobile phase: [water ( NH ₄ HCO ₃ )-ACN]; B%: 70%-100%,7min) to afford desired producd 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrol idin-2-yl)methoxy)- 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethy l)piperazine-1-carbonyl)allyl (3- ((S)-5-(2,5-difluorophenyl)-3-(methoxy(methyl)carbamoyl)-2-p henyl-2,3-dihydro-1,3,4- thiadiazol-2-yl)propyl) carbamate (0.8 mg, 0.71 µmol, 0.45 % yield, 94% purity) as a yellow solid. ¹ H NMR (400 MHz, CD3OD): δ 7.87 - 7.78 (m, 2H), 7.68 (m, 1H), 7.55 - 7.43 (m, 4H), 7.37 (t, J = 7.8 Hz, 1H), 7.33 - 7.26 (m, 3H), 7.25 - 7.18 (m, 1H), 7.13 - 7.01 (m, 2H), 5.61 (s, 1H), 5.46 - 5.30 (m, 1H), 4.54 - 4.46 (m, 1H), 4.45 - 4.24 (m, 3H), 4.22 - 3.92 (m, 3H), 3.75 - 3.65 (m, 4H), 3.49 - 3.39 (m, 2H), 3.17 - 2.96 (m, 8H), 2.92 (m, 1H), 2.83 - 2.72 (m, 3H), 2.55 (m, 3H), 2.28 - 2.14 (m, 2H), 2.01 - 1.75 (m, 4H), 1.68 - 1.55 (m, 2H), 1.34 - 1.27 (m, 6H). LC-MS: MS (ES ⁺ ): RT = 2.453 min, m/z = 1062.3 [M+H ⁺ ]; LC-MS Method 25. EXAMPLE 8 – Synthesis of Compound III-11: 2-(((3R,4R)-4-fluoro-1-(6-((3-methoxy-1- methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrroli din-3-yl)carbamoyl)allyl (3-((S)-5-(2,5-difluorophenyl)-3-(methoxy(methyl)carbamoyl)- 2-phenyl-2,3-dihydro-1,3,4- thiadiazol-2-yl)propyl)carbamate [000495] The title compound was synthesized using procedure based on that described in Example 7. LC-MS: MS (ES ⁺ ): RT = 2.681 min, m/z = 446.6, 892.2 [M+H ⁺ ]; LC-MS Method 10. EXAMPLE 9 – Synthesis of Compound II-1: 4-((2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyr ido[3,4-d]pyrimidin-4-yl)-2- (cyanomethyl)piperazine-1-carbonyl)allyl)((R)-8-cyclopentyl- 7-ethyl-5-methyl-6-oxo- 5,6,7,8-tetrahydropteridin-2-yl)amino)-3-methoxy-N-(1-methyl piperidin-4-yl)benzamide [000496] To a solution of 2-[[N-[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin -2-yl]- 2-methoxy-4-[(1-methyl-4-piperidyl)carbamoyl]anilino]methyl] prop-2-enoic acid, Compound D (40 mg, 66 µmol, 1.0 eq), 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolid in-2- yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piper azin-2-yl]acetonitrile, Compound E (35 mg, 66 µmol, 1.0 eq) in DMAC (1 mL) was added Et3N (27 mg, 0.26 mmol, 4.0 eq) and HATU (30 mg, 79 µmol, 1.2 eq). The mixture was stirred at 25 °C for 0.5 h. The residue was purified by prep-HPLC (column: Phenomenex C18, 75 x 30mm, 3um; mobile phase: [water(FA)-ACN]; B%:10%-40%,7min) to give compound 4-[2-[(2S)-4-[7-(8-chloro-1- naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihy dro-5H-pyrido[3,4-d]pyrimidin- 4-yl]-2-(cyanomethyl)piperazine-1-carbonyl]allyl-[(7R)-8-cyc lopentyl-7-ethyl-5-methyl-6-oxo- 7H-pteridin-2-yl]amino]-3-methoxy-N-(1-methyl-4-piperidyl)be nzamide (2.6 mg, 3.38% yield) as a white solid. ¹ H NMR (400 MHz, CD3OD): δ 8.45 (s, 1 H), 8.25 (d, J = 3.18 Hz, 1 H), 7.81 - 7.91 (m, 2 H), 7.64 - 7.79 (m, 3 H), 7.50 - 7.59 (m, 2 H), 7.32 - 7.45 (m, 2 H), 4.59 - 4.65 (m, 2 H), 4.31 - 4.39 (m, 1 H), 4.18 - 4.29 (m, 1 H), 3.95 - 4.02 (m, 2 H), 3.86 - 3.95 (m, 4 H), 3.70 - 3.81 (m, 4 H), 3.57 - 3.69 (m, 4 H), 3.45 - 3.50 (m, 3 H), 3.17 - 3.30 (m, 6 H), 2.97 - 3.12 (m, 6 H), 2.93 (s, 2 H), 2.64 - 2.82 (m, 2 H), 2.17 - 2.34 (m, 4 H) 1.97 - 2.10 (m, 14 H), 1.65 - 1.91 (m, 4 H), 1.31 (d, J = 4.28 Hz, 3 H), 0.83 - 0.86 (m, 3 H). LC-MS: MS (ES ⁺ ): RT = 1.64 min, m/z =1118 [M + H ⁺ ]; LC-MS Method 25. EXAMPLE 10 – Synthesis of Additional Compounds [000497] The compounds in Table 8 were prepared using procedures analogous to those described above. Physical characterization data is provided in Table 9. TABLE 8.

TABLE 9. EXAMPLE 11 – Synthesis of Compound I-34: (S)-N-(2-((2-(dimethylamino)ethyl) (methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrim idin-2-yl)amino)phenyl)- 2-(((5-(((3-ethyl-5-(2-(2-hydroxyethyl)piperidin-1-yl)pyrazo lo[1,5-a]pyrimidin-7- yl)amino)methyl)pyridin-2-yl)oxy)methyl)acrylamide [000498] To a solution of 2-(bromomethyl)-N-[2-[2-(dimethylamino)ethyl-methyl-amino]-4 - methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]pheny l]prop-2-enamide, Compound T (150 mg, 253 µmol, 1 eq) in DMF (3 mL) was added 5-[[[3-ethyl-5-[(2S)-2-(2- hydroxyethyl)-1-piperidyl]pyrazolo[1,5-a]pyrimidin-7-yl]amin o]methyl]pyridin-2-ol, Compound U (130 mg, 329 µmol, 1.3 eq) and K2CO3 (70.0 mg, 506 µmol, 2 eq) at 25 °C for 8 hours. The reaction mixture was filtered. The residue was purified by prep-HPLC (column: Phenomenex C1875 x 30mm, 3um;mobile phase: [water(FA)-ACN];B%: 12%-42%,7min) to give product N-[2-[2-(dimethylamino)ethyl-methyl-amino]-4-methoxy-5-[[4-( 1-methylindol-3- yl)pyrimidin-2-yl]amino]phenyl]-2-[[5-[[[3-ethyl-5-[(2S)-2-( 2-hydroxyethyl)-1- piperidyl]pyrazolo[1,5-a]pyrimidin-7-yl]amino]methyl]-2-pyri dyl]oxymethyl]prop-2-enamide (36.0 mg, 37.8 µmol, 15% yield, 95.3% purity) as a light yellow solid. ¹ H NMR (400 MHz, CD3OD): 8.83 (s, 1H), 8.43 (s, 1H), 8.23 - 8.15 (m, 3H), 7.70 - 7.66 (m, 1H), 7.55 - 7.52 (m, 2H), 7.27 (d, J = 8.0 Hz, 1H), 7.12 - 7.07 (m, 2H), 7.03 - 7.00 (m, 1H), 6.86 (s, 1H), 6.52 (d, J = 9.6 Hz, 1H), 6.10 (s, 1H), 5.59 (s, 1H), 5.35 (s, 1H), 4.92 - 4.86 (m, 2H), 4.50 (s, 2H), 4.23 (s, 2H), 3.89 (s, 3H), 3.78 (s, 3H), 3.39 - 3.34(m, 1H), 2.91 - 2.90 (m, 2H), 2.80 - 2.74 (m, 2H), 2.56 - 2.54 (m, 6H), 2.49 - 2.41 (m, 3H), 1.92 - 1.86 (m, 1H), 1.57 - 1.47 (m, 7H), 1.33 (s, 2H), 1.19 (s, 2H), 1.13 - 1.09 (m, 3H). LC-MS: MS (ES ⁺ ): RT = 1.453 min, m/z = 908.3 [M + H ⁺ ]; LC-MS Method 25. EXAMPLE 12 – Synthesis of Additional Compounds [000499] The compounds in Table 10 were prepared using procedures analogous to those described above. Physical characterization data is provided in Table 11. TABLE 10.

EXAMPLE 13 – Synthesis of Compound V-63: 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyr ido[3,4-d]pyrimidin-4-yl)-1- (2-((2,6-dimethoxy-4-(6-methoxy-1H-indole-3-carbonyl)phenoxy )methyl)acryloyl) piperazin-2-yl)acetonitrile [000500] To a solution of 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolid in-2- yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(c yanomethyl)piperazine-1- carbonyl]allylmethanesulfonate, Compound X (45 mg, 65 µmol, 1.0 eq), (4-hydroxy-3,5- dimethoxy-phenyl)-(6-methoxy-1H-indol-3-yl)methanone, Compound Y (21 mg, 64.82 µmol, 1.0 eq) in DMF (1 mL) was added K ₂ CO ₃ (27 mg, 194 µmol, 3.0 eq). The mixture was stirred at 50 °C for 12 h. The residue was purified by prep-HPLC (column: Phenomenex C18, 75 x 30mm, 3um; mobile phase: [water(FA)-ACN]; B%: 32%-62%,7min) to give compound 2- [(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin -2-yl]methoxy]-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl]-1-[2-[[2,6-dimethoxy-4-(6-metho xy-1H-indole-3-carbonyl) phenoxy]methyl] prop-2-enoyl]piperazin-2-yl]acetonitrile (1.8 mg, 3% yield) as a light yellow solid. LC-MS: MS (ES ⁺ ): RT = 2.453 min, m/z =825.2 [M+H ⁺ ]; LC-MS Method 25. ¹ H NMR (400 MHz, CD3OD): δ 7.82 (d, J = 8.07 Hz, 1 H), 7.67 (d, J = 7.34 Hz, 1 H), 7.45 - 7.62 (m, 3 H), 7.26 - 7.39 (m, 3 H), 7.18 (s, 1 H), 6.96 (d, J = 1.71 Hz, 1 H), 6.77 (dd, J = 8.86, 2.26 Hz, 1 H), 6.58 (d, J = 3.30 Hz, 1 H), 6.16 (d, J = 6.36 Hz, 1 H), 5.27 - 5.44 (m, 2 H), 4.25 - 4.41 (m, 1 H), 3.44 - 3.97 (m, 11 H), 2.27 - 3.30 (m, 6 H), 1.52 - 2.22 (m, 5 H), 1.08 - 1.42 (m, 8 H), 0.81 - 1.01 (m, 1 H). EXAMPLE 14 – Synthesis of Compound I-37: 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyr ido[3,4-d]pyrimidin-4-yl)-2- (cyanomethyl)piperazine-1-carbonyl)allyl-4-(4-(1-isopropyl-6 -oxo-1,6-dihydropyridin-3- yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)piperidine-1-carboxylate [000501] To a solution of 1-isopropyl-5-[2-(4-piperidyl)-1H-pyrrolo[2,3-b]pyridin-4-yl ]pyridin- 2-one (145 mg, 322 umol, 2.0 equiv, TFA salt) in DMF (2 mL) was added dropwise TEA (163 mg, 1.61 mmol, 224 uL, 10.0 equiv) and 2-((S)-1-(2-(bromomethyl)acryloyl)-4-(7-(8- chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)metho xy)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (126 mg, 161 umol, 1.0 equiv) at 0 °C. The resulting mixture was stirred at 20 °C for 1 h. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um; mobile phase: [water( NH ₄ HCO ₃ )-ACN];B%: 48%-78%, 9min) and (column: Phenomenex C1875*30mm*3um;mobile phase: [water(FA)- ACN];B%: 18%-48%,7min) to give desired compound 2-((S)-4-(7-(8-chloronaphthalen-1-yl)- 2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydrop yrido[3,4-d]pyrimidin-4-yl)-2- (cyanomethyl)piperazine-1-carbonyl)allyl-4-(4-(1-isopropyl-6 -oxo-1,6-dihydropyridin-3-yl)- 1H-pyrrolo[2,3-b]pyridin-2-yl)piperidine-1-carboxylate (18 mg, 18 umol, 11% yield, 98% purity) as an off-white solid. ¹ H NMR (400 MHz,CD ₃ OD): δ 8.18 - 8.10 (m, 1H), 8.01 (s, 1H), 7.93 - 7.85 (m, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.54 - 7.42 (m, 2H), 7.41 - 7.30 (m, 1H), 7.29 - 7.16 (m, 1H), 7.13 - 6.97 (m, 1H), 6.67 (d, J = 9.5 Hz, 1H), 6.33 (s, 1H), 5.67 (s, 1H), 5.53 - 5.41 (m, 1H), 5.30 - 5.20 (m, 1H), 5.17 - 5.01 (m, 1H), 4.86 - 4.79 (m, 1H), 4.41 - 4.20 (m, 6H), 4.20 - 3.99 (m, 2H), 3.78 - 3.37 (m, 3H), 3.26 - 2.78 (m, 12H), 2.69 - 2.44 (m, 5H), 2.16 - 2.03 (m, 3H), 1.87 - 1.67 (m, 5H), 1.45 (d, J = 6.7 Hz, 6H). LC-MS: MS (ES ⁺ ): RT = 1.882 min, m/z = 978.3 [M + H ⁺ ]. EXAMPLE 15 – Synthesis of Compound III-12: 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyr ido[3,4-d]pyrimidin-4-yl)-2- (cyanomethyl)piperazine-1-carbonyl)allyl (3-((S)-5-(2,5-difluorophenyl)-3- (methoxy(methyl) carbamoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl )(methyl) carbamate

[000502] Step 1. To a solution of (S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-methoxy- N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide (200 mg, 0.476 mmol) and Boc ₂ O (125 mg, 0.571 mmol) in THF (10 mL) was added DIPEA (0.50 mL, 2.85 mmol) at rt. The reaction mixture was stirred at rt for 1 h. The volatiles were evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using a gradient of 0- 30% EtOAc in hexane to afford tert-butyl (S)-(3-(5-(2,5-difluorophenyl)-3-(methoxy(methyl) carbamoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl )carbamate (162 mg, 65 %) as an oil. LC-MS (method B): MS (ES+): R _t = 1.89 min, m/z = 543.1 [M+Na] ⁺ . [000503] Step 2. To a solution of tert-butyl (S)-(3-(5-(2,5-difluorophenyl)-3-(methoxy (methyl)carbamoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-y l)propyl)carbamate (162 mg, 0.311 mmol) in DMF (6.5 mL) cooled to 0 ºC was added NaH (50.0 mg, 1.24 mmol). After 5 min, MeI (117 uL, 1.87 mmol) was added dropwise. The reaction mixture was stirred at rt for 1.5 h. Few drops of an aqueous solution of NH4Cl was added and the volatiles were evaporated under reduced pressure. Water (10 mL) and DCM (20 mL) were added, and the layers were separated. The aqueous layer was extracted with DCM (3 x 20 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel suing a gradient of 0-50% EtOAc in hexane to afford tert-butyl (S)-(3-(5-(2,5-difluorophenyl)-3-(methoxy(methyl) carbamoyl)-2- phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl)(methyl)carb amate (144 mg, 87 %) as an oil. LC-MS (method B): MS (ES+): R _t = 2.00 min, m/z = 557.2 [M+Na] ⁺ . [000504] Step 3. To a solution of tert-butyl (S)-(3-(5-(2,5-difluorophenyl)-3- (methoxy(methyl) carbamoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2- yl)propyl)(methyl)carbamate (144 mg, 0.269 mmol) in MeOH (5.0 mL) was added a solution of HCl in dioxane (4 M, 5.0 mL, 20 mmol). The reaction mixture was stirred at rt for 1 h. The volatiles were evaporated under reduced pressure to afford (S)-5-(2,5-difluorophenyl)-N- methoxy-N-methyl-2-(3-(methylamino) propyl)-2-phenyl-1,3,4-thiadiazole-3(2H)- carboxamide, hydrochloride (122 mg, 96 %) as HCl salt. LC-MS (method B): MS (ES+): R _t = 1.12 min, m/z = 435.2 [M+H] ⁺ . [000505] Step 4. A solution of (S)-5-(2,5-difluorophenyl)-N-methoxy-N-methyl-2-(3- (methylamino)propyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbox amide, hydrochloride (36.0 mg, 76.4 µmol) and DIPEA (80 µL, 0.46 mmol) in DCM (2.0 mL) was added to a mixture of 4-nitrophenylchloroformate (46 mg, 0.23 mmol) in DCM (1.3 mL) at 0 ºC under nitrogen. The reaction mixture was stirred at rt for 2.5 h. The volatiles were evaporated under reduced pressure. The crude product was purified by reverse phase chromatography (C18) using a gradient of 0-100 MeCN in water (it contains 0.1% formic acid) to afford 4-nitrophenyl (S)-(3- (5-(2,5-difluorophenyl)-3-(methoxy(methyl)carbamoyl)-2-pheny l-2,3-dihydro-1,3,4- thiadiazol-2-yl)propyl)(methyl)carbamate (14.0 mg, 31%) as a solid. LC-MS (method B): MS (ES+): Rt = 1.95 min, m/z = 600.3 [M+H] ^+. [000506] Step 5. To a solution of 4-nitrophenyl (S)-(3-(5-(2,5-difluorophenyl)-3- (methoxy(methyl)carbamoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadi azol-2-yl)propyl)(methyl) carbamate (14.0 mg, 23.3 µmol) in THF (1.0 mL) cooled to 0 ºC was added a solution of LiHMDS (1 M, 60 µL, 60 µmol) in THF. The reaction mixture was heated to 65 ºC for 2 h and then cooled to rt. The volatiles were evaporated under reduced pressure. The crude product was purified by reverse phase chromatography (C18) using a gradient of 0-100 MeCN in water (it contains 0.1% HCl) to afford 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-yl)-2- (cyanomethyl)piperazine-1-carbonyl)allyl (3-((S)-5-(2,5-difluorophenyl)-3-(methoxy(methyl) carbamoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl )(methyl) carbamate (2.00 mg, 7.7 %) as HCl salt. LC-MS (method B): MS (ES+): Rt = 1.68 min, m/z = 1076.8 [M+H] ^+. NMR (DMSO-d ₆ , 400 MHz): δ _H 10.13-9.91 (1H, m), 7.91 (1H, d, J = 8.0 Hz), 7.83-7.71 (1H, m), 7.65-7.50 (4H, m), 7.48-7.25 (8H, m), 5.51 (1H, s), 5.31 (1H, br s), 4.64-4.41 (4H, m), 4.14- 3.62 (11H, m), 3.57-3.43 (4H, m), 3.15-2.81 (15H, m), 2.22-2.17 (1H, m), 2.05-1.87 (5H, m), 1.60-1.40 (1H, m). Note: 3 protons are obscured under DMSO and/or water peaks EXAMPLE 16 – Synthesis of Compound I-38: N-((3R,4R)-4-fluoro-1-(6-((3-methoxy-1- methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrroli din-3-yl)-2-((4-(1- isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(piperidin-4-yl)- 1H-pyrrolo[2,3-b]pyridin-1- yl)methyl)acrylamide trifluoroacetic acid salt [000507] To a solution of tert-butyl 4-(1-(2-(((3R,4R)-4-fluoro-1-(6-((3-methoxy-1-methyl- 1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidin-3-y l)carbamoyl)allyl)-4-(1- isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrrolo[2,3-b]py ridin-2-yl)piperidine-1- carboxylate (Compound AO) (80 mg, 93 umol, 1.0 equiv) in DCM (1 mL) was added TFA (0.5 mL). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was filtered and concentrated under reduced pressure to afford crude product. The residue was purified by prep- HPLC (column: Phenomenex C1875*30mm*3um;mobile phase: [water(FA)-ACN];B%: 10%- 40%,7min) to give the title compound as a trifluoroacetic acid salt (34 mg, 37 umol, 40% yield, TFA salt) as a off-white solid. LC-MS: MS (ES ⁺ ): RT =2.285 min, m/z = 764.3 [M+H] ⁺ ; LCMS Method: 01. ¹ H NMR: (CD ₃ OD, 400 MHz) 8.60 - 8.47 (m, 1H), 8.10 (d, J = 5.1 Hz, 1H), 8.02 - 7.97 (m, 1H), 7.96 - 7.93 (m, 1H), 7.90 - 7.82 (m, 1H), 7.80 - 7.71 (m, 1H), 7.15 - 6.94 (m, 1H), 6.81 - 6.63 (m, 1H), 6.55 - 6.41 (m, 1H), 5.92 - 5.73 (m, 1H), 5.36 - 5.03 (m, 4H), 4.99 - 4.90 (m, 1H), 4.68 - 4.57 (m, 1H), 4.00 - 3.93 (m, 4H), 3.91 - 3.85 (m, 1H), 3.82 - 3.75 (m, 1H), 3.74 - 3.72 (m, 3H), 3.71 - 3.69 (m, 3H), 3.55 - 3.46 (m, 2H), 3.28 - 3.06 (m, 3H), 2.31 - 2.16 (m, 2H), 2.07 - 1.80 (m, 2H), 1.61 - 1.38 (m, 6H). EXAMPLE 17 – Synthesis of Additional Compounds [000508] The compounds in Table 12 were prepared using procedures analogous to those described above. Physical characterization data is provided in Table 13. TABLE 12. TABLE 13. EXAMPLE 18 - Cellular Growth Inhibition Assay for HEK293 cells and HeLa cells [000509] Exemplary compounds were tested for ability to inhibit the proliferation of HEK293 cells or HeLa cells. Experimental procedures and results are provided below. Part I – Experimental Procedure [000510] HEK293 and HeLa cells were cultured in DMEM medium supplemented with 10% fetal bovine serum and 1% Penn/Strep. Cells were seeded in white 384-well plates at 500 cells/well in 25 µL complete medium. Following seeding, plates were spun at 300 × g^for three minutes and cultured at 37°C with 5% CO2^in a humidified tissue culture incubator. [000511] After 24 hours, compounds were titrated in 100% DMSO and diluted in complete cell culture medium. A 25 µL aliquot of compound/media mixture was added to cells to bring total volume in well to 50 µL. DMSO alone was used as a negative control. Plates were then spun at 300×g^for three minutes and stored at 37°C with 5% CO ₂ for three days. [000512] On Day 0 and Day 3 of compound treatment, cell viability was quantified with CellTiter-Glo 2.0 reagent (Promega). After equilibrating microplates at room temperature for 30 minutes, 25 µL CellTiter-Glo 2.0 reagent was dispensed into each well to bring total volume to 75 µL. Plates were mixed on shaker for 2 minutes at 500 rpm, followed by a 10- minute incubation at room temperature. Following a quick spin, luminescence readings were measured with an EnVision Plate Reader. Data was normalized to DMSO treated Day 0 and Day 3 readings. 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 compound. Part II – Results [000513] Results are provided in Table 14 below for exemplary compounds. The symbol “++++” indicates a GI50 less than 0.5 µM. The symbol “+++” indicates an GI50 in the range of 0.5 µM to 1.5 µM. The symbol “++” indicates a GI50 in the range of greater than 1.5 µM to 5 µM. The symbol “+” indicates a GI ₅₀ greater than 5 µM. The symbol “N/A” indicates that no data was available. TABLE 14. EXAMPLE 19 - Cellular Growth Inhibition Assay for HEK293 cells and HeLa cells [000514] Exemplary compounds were tested for ability to inhibit the proliferation of HEK293 cells (ATCC CRL-1573) and HeLa cells (ATCC CCL-2). Experimental procedures and results are provided below. Part I – Experimental Procedure [000515] HEK293 and HeLa cells were cultured in DMEM (Gibco 11995), supplemented with 10% Heat-inactivated FBS (Gibco A38400-01) and 1% Penicillin/Streptomycin (Gibco 15140- 122) at 37°C with 5% CO2^in a humidified tissue culture incubator. Cells were seeded at 500 cells/well in 384-well, Poly-D-lysine-treated black plates (Perkin Elmer 6007710) in 25µL media lacking selection for 18-24 hours. Plates were spun at 300g for 30 seconds and stored in the incubator overnight. After 24 hours, a 25µL aliquot of compound-containing medium was added in each well, at a final top concentration of 10 µM test compound, with 3-fold dilutions, using DMSO alone as a negative control. Plates were then spun at 300×g^for 3 minutes again and cultured at 37°C with 5% CO2. After 72 hours, cell viability was quantified with CellTiter- Glo 2.0 (Promega). After equilibrating cell plates at room temperature for 30 minutes, 25µL CellTiter-Glo 2.0 reagent was dispensed into each well. Plates were mixed on a shaker for 2 minutes at 500 rpm, followed by a 10-minute incubation at room temperature. Luminescence readings were measured with an EnVision Plate Reader (Perkin Elmer). Data was normalized to DMSO treated cell wells. A four-parameter non-linear regression curve fit was applied to dose-response data in Prism to determine the half maximal growth inhibitory concentration (GI50) of each compound. Part II – Results [000516] Results are provided in Table 15 below for exemplary compounds. The symbol “++++” indicates a GI ₅₀ less than 0.5 µM. The symbol “+++” indicates an GI ₅₀ in the range of 0.5 µM to 1.5 µM. The symbol “++” indicates a GI50 in the range of greater than 1.5 µM to 5 µM. The symbol “+” indicates a GI50 greater than 5 µM. The symbol “N/A” indicates that no data was available. TABLE 15.

EXAMPLE 20 – Assay for Inhibition of KRAS G12C [000517] Exemplary compounds were tested for ability to inhibit KRas G12C. Experimental procedures and results are provided below. Part I – Experimental Procedure [000518] KRAS target engagement (IC50 determination) was performed using a KRAS G12C nucleotide exchange assay. Specifically, compounds were tested against KRAS G12C in 10- point concentration IC50 mode with 3-fold serial dilution at a starting concentration of 10 μM. ARS1620 was used as a control. [000519] Briefly, GST-tagged KRAS G12C (amino acids 2-169) was mixed with anti-GST Tb antibody (1.5x solution) and 10 µL was delivered to reaction wells. Compounds were delivered using acoustic dispenser (Echo, Labcyte) and pre-incubated with protein for 1hr at RT. KRAS/anti-GST Tb Ab/compound mixture was incubated for 1 hour at room temperature. A 3x solution of SOS1 (amino acids 564-1049) and GTP-DY-647P1 (GTP*) was prepared in reaction buffer. A 5 µL aliquot of SOS1/GTP* solution was added to reaction well to initiate the exchange reaction. No-SOS1 reaction or max compound concentration was used as blank. The final concentrations of KRAS G12C, SOS1, and GTP* were 30 nM, 20 nM, and 0.15 µM, respectively. SOS1 mediated exchange of GDP to GTP-DY-647P was measured using HTRF (Ex/Em=(320-75/665-7.5; 615-8.5)) using an Envision Plate Reader (Perkin Elmer). IC ₅₀ determination was performed using a Sigmoidal dose response (variable slope) equation. Part II – Results [000520] Results showing inhibition of KRAS G12C are provided in Table 16 below. The symbol “++++” indicates a IC ₅₀ less than 0.1 µM. The symbol “+++” indicates an IC ₅₀ in the range of 0.1 µM to 5 µM. The symbol “++” indicates a IC50 in the range of greater than 5 µM to 10 µM. The symbol “+” indicates a IC ₅₀ greater than 10 µM. The symbol “N/A” indicates that no data was available. TABLE 16. EXAMPLE 21 – Assay for Binding Affinity to EGFR [000521] Exemplary compounds were tested for ability to bind to EGFR T790M L858R (amino acids 669-1011; Accession Number NP_005219.2) expressed from mammalian cells. Compounds were tested using the KdELECT assay at Eurofins DiscoverX Corporation. Experimental procedures and results are provided below. Part I – Experimental Procedure [000522] Kinase-tagged T7 phage strains were prepared in an E. coli host derived from the BL21 strain. E. coli were grown to log-phase and infected with T7 phage and incubated with shaking at 32°C until lysis. The lysates were centrifuged and filtered to remove cell debris. The remaining kinases were produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase 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 non-specific binding. Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). Test compounds were prepared as 111X stocks in 100% DMSO. Kd values were determined using an 11-point 3-fold compound dilution series with three DMSO control points. 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 0.9%. All reactions performed in polypropylene 384-well plate. 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 re-suspended in elution buffer (1x PBS, 0.05% Tween 20, 0.5 μM nonbiotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluates was measured by qPCR. Part II – Results [000523] Results showing ability of an exemplary compound to bind EGFR T790M L858R are provided in Table 17 below. The symbol “++++” indicates a Kd less than 0.05 µM. The symbol “+++” indicates an Kd in the range of 0.05 µM to 0.5 µM. The symbol “++” indicates a Kd in the range of greater than 0.5 µM to 2.5 µM. The symbol “+” indicates a Kd greater than 2.5 µM. The symbol “N/A” indicates that no data was available. TABLE 17. EXAMPLE 22 – Additional Assay for Binding Affinity to EGFR [000524] Exemplary compounds were tested for ability to bind to EGFR WT (amino acids 669-1011, Accession Number NP_005219.2) or EGFR T790M, L858R (amino acids 669-1011 Accession Number NP_005219.2) expressed from bacteria or mammalian cells, respectively. Compounds were tested using the KdELECT assay at Eurofins Discovery. Experimental procedures and results are provided below. Part I – Experimental Procedure [000525] Kinase-tagged T7 phage strains were prepared in an E. coli host derived from the BL21 strain. E. coli were grown to log-phase and infected with T7 phage and incubated with shaking at 32°C until lysis. The lysates were centrifuged and filtered to remove cell debris. The remaining kinases were produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase 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 non-specific binding. Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). Test compounds were prepared as 111X stocks in 100% DMSO. Kd values were determined using an 11-point 3-fold compound dilution series with three DMSO control points. 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 0.9%. All reactions performed in polypropylene 384-well plate. 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 re-suspended in elution buffer (1x PBS, 0.05% Tween 20, 0.5 μM nonbiotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluates was measured by qPCR. Part II – Results [000526] Results showing compound binding to EGFR are provided in Table 18 below. The symbol “++++” indicates a Kd less than 0.05 µM. The symbol “+++” indicates an Kd in the range of 0.05 µM to 0.5 µM. The symbol “++” indicates a Kd in the range of greater than 0.5 µM to 2.5 µM. The symbol “+” indicates a Kd greater than 2.5 µM. The symbol “N/A” indicates that no data was available. TABLE 18.

EXAMPLE 23 – Assay for Binding Affinity to CDK9 [000527] Exemplary compounds were tested for ability to bind to full-length CDK9 (amino acids 1-372; Accession Number NP_001252.1) expressed from bacteria. Compounds were tested using a KdELECT assay. Experimental procedures and results are provided below. Part I – Experimental Procedure [000528] Kinase-tagged T7 phage strains were prepared in an E. coli host derived from the BL21 strain. E. coli were grown to log-phase and infected with T7 phage and incubated with shaking at 32°C until lysis. The lysates were centrifuged and filtered to remove cell debris. The remaining kinases were produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase 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 non-specific binding. Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). Test compounds were prepared as 111X stocks in 100% DMSO. Kd values were determined using an 11-point 3-fold compound dilution series with three DMSO control points. 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 0.9%. All reactions performed in polypropylene 384-well plate. 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 re-suspended in elution buffer (1x PBS, 0.05% Tween 20, 0.5 μM nonbiotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluates was measured by qPCR. Part II – Results [000529] Results showing ability of exemplary compounds to bind CDK9 are provided in Table 19 below. The symbol “++++” indicates a Kd less than 0.05 µM. The symbol “+++” indicates an Kd in the range of 0.05 µM to 0.5 µM. The symbol “++” indicates a Kd in the range of greater than 0.5 µM to 2.5 µM. The symbol “+” indicates a Kd greater than 2.5 µM. The symbol “N/A” indicates that no data was available. TABLE 19. EXAMPLE 24 – Assay for Binding Affinity to PLK1 [000530] Exemplary compounds were tested for ability to bind to PLK1 (amino acids 33-325; Accession Number NP_005021.2) expressed from mammalian cells. Compounds were tested using a KdELECT assay. Experimental procedures and results are provided below. Part I – Experimental Procedure [000531] Kinase-tagged T7 phage strains were prepared in an E. coli host derived from the BL21 strain. E. coli were grown to log-phase and infected with T7 phage and incubated with shaking at 32°C until lysis. The lysates were centrifuged and filtered to remove cell debris. The remaining kinases were produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase 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 non-specific binding. Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). Test compounds were prepared as 111X stocks in 100% DMSO. Kd values were determined using an 11-point 3-fold compound dilution series with three DMSO control points. 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 0.9%. All reactions performed in polypropylene 384-well plate. 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 re-suspended in elution buffer (1x PBS, 0.05% Tween 20, 0.5 μM nonbiotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluates was measured by qPCR. Part II – Results [000532] Results showing ability of an exemplary compound to bind PLK1 are provided in Table 20 below. The symbol “++++” indicates a Kd less than 0.05 µM. The symbol “+++” indicates an Kd in the range of 0.05 µM to 0.5 µM. The symbol “++” indicates a Kd in the range of greater than 0.5 µM to 2.5 µM. The symbol “+” indicates a Kd greater than 2.5 µM. The symbol “N/A” indicates that no data was available. TABLE 20. EXAMPLE 25 - Intact Mass Spec Target Engagement [000533] Exemplary heterobifunctional compounds were for intact mass spectrometry target engagement against KRAS G12C and EGFR T790M L858R, separately. Experimental procedures and results are provided below. Part I – Experimental Procedure [000534] Experimental procedures used when testing exemplary heterobifunctional compounds against KRAS G12C or EGFR T790M L858R are provided below: [000535] KRAS G12C: Samples were prepared using 5 µM of KRAS G12C C51S C80L C118S (amino acids 1-169) and 50 µM of heterobifunctional compound in a buffer containing 20 mM HEPES pH 7.5, 150 mM NaCl, and 1 mM TCEP. Protein was incubated with heterobifunctional compound at RT or 37°C for the given amounts of time then flash-frozen and stored at -80°C until analysis. Samples were transferred to HPLC vials and injected into Dionex UltiMate 3000 FLM HPLC system with a proprietary column (2.1 x 50 mm, 5 um, 1000 Å) at 0.3 mL/minute in a column compartment at 50°C and run on a Q Exactive Hybrid Quadrupole-Orbitrap Mass Spectrometer. Ion Max source with HESI-II probe were used, with a source voltage of 3.5 kV. [000536] EGFR T790M L858R: Samples were prepared using 2 µM of EGFR T790M L858R (amino acids 696-1022) and 20 µM of heterobifunctional compound in a buffer containing 20 mM HEPES pH 7.5, 150 mM NaCl, 1 mM TCEP. Protein was incubated with heterobifunctional compound at RT or 37°C for the given amounts of time then flash-frozen and stored at -80°C until analysis. Samples were transferred to HPLC vials and injected into Dionex UltiMate 3000 FLM HPLC system with a proprietary column (2.1 x 50 mm, 5 um, 1000 Å) at 0.3 mL/minute in a column compartment at 50°C and run on a Q Exactive Hybrid Quadrupole-Orbitrap Mass Spectrometer. Ion Max source with HESI-II probe were used, with a source voltage of 3.5 kV. Part II – Results [000537] Results showing ability of exemplary heterobifunctional compounds to generate a modified target protein via intact mass spectrometry are shown in Table 21 below. The amount of different components identified by mass spectrometry at 24 hours post-reaction are listed in Table 14, wherein the different components include: • Un-modified Protein – this is starting protein material (e.g., KRAS G12C, EGFR T790M L858R) that remained unchanged in the experiment. • Elimination-Conjugate Product – this is a conjugate formed by reaction of protein with the heterobifunctional compound to form a protein conjugate of the following general formula: . Notably, the effector protein ligand component of the heterobifunctional compound has been displaced by the protein. • Addition-Conjugate Product – this is a conjugate formed by reaction of protein with the heterobifunctional compound to form a protein conjugate of the following general formula: Notably, the effector protein ligand component of the heterobifunctional compound has not been displaced by the protein. • Other Material – this is material detected by mass spectroscopy, where the material is other than Un-modified Protein, Elimination-Conjugate Product, or Addition-Conjugate Product. Exemplary Other Material can include, for example, residual impurities in the protein starting material used to conduct the experiment. TABLE 21. EXAMPLE 26 – Release of Effector Protein Ligand from Heterobifunctional Compounds [000538] Exemplary heterobifunctional compounds were evaluated for the ability to release an effector protein ligand in the presence of KRAS G12C or EGFR T790M L858R target proteins. Experimental procedures and results are provided below. Part I – Experimental Procedure [000539] Samples for mass spectrometry for KRAS G12C and EGFR T790M L858R were prepared as described above in connection with the intact mass spectrometry target engagement intact mass spectrometry target engagement experiment, respectively, except rather than flash- freezing, 20 µL of sample was quenched with 50 µL of 100% acetonitrile. As well, a buffer- only control was used to detect latent release of Effector ligand analyte. Internal standard (IS) solution consisted of 200 ng/mL propranolol and 50 ng/mL diclofenac in methanol:water 1:1 (v/v). A 4-point calibration curve (calibration standard (CS)) consisting of each analyte was made at final concentrations of 3 nM, 30 nM, 300 nM, and 3000 nM. Unknown samples were diluted such that the unknown analyte concentration was in the linear range of the calibration curve. [000540] Samples for all proteins were prepared and analyzed from the following:

_t ⁿ _e m ^u _r ^t _s ⁿ _I ^. _C ^L _P H ^e _c ⁿ _e ⁿ _i m ^o _r ^{P u} _z ^d _a m ⁱ _h ^{S h} t _i ^{w d} _e ^l _p u ^o _c ^m _e ^t _s ^y _{s 0} ⁰ _{0 5} ^{0 5} ₃ ^d _a ^u _Q ^e _l ^p i _r ^T x ^e _i ^c _S B ^{A h} t _i ^{w d} _e ^z _y ^l _a ⁿ _ar ^e _h ^t _{: r} w ^u _f ^o _{l e} ^{e r} _{b e h} w ^t _r ^s _e o ^{l f} _{p t} e m _s ^a _{e S} ^r _a ^] _{s 1} n ⁴ ₅ ^o i _t ^{0 i} _{0 d} n ⁰ _[ ^o _c

_: ^a _l u ^m _{r 1} ^o _f ⁰ _{3 g} ⁿ _i w ^o l _l ^o _{f e} ^h _{t s} ^a _{h 1} - ₁ A _d ⁿ _u ^o _p m ^o _C ^] ₂ ⁴ ₅ ⁰ ₀ ⁰ _[ [000543] Compound A1-2 has the following formula: . Part II – Results [000544] Results showing effector protein ligand release from a heterobifunctional compound that binds KRAS G12C are provided below. TABLE 22. [000545] Chemical Structures for compounds denoted in the above table are provided below:

[000546] Results showing effector protein ligand release from a heterobifunctional compound that binds EGFR T790M L858R are provided below. TABLE 23. [000547] Chemical Structures for compounds denoted in the above table are provided below: EXAMPLE 27 - KRAS G12C Cellular Target Engagement Assay [000548] Exemplary compounds were tested for ability to engage cellular KRAS G12C in cells. Experimental procedures and results are provided below. Part I – Experimental Procedure [000549] SW1573 cells (ATCC CRL-2170) were cultured in RPMI 1640 (Gibco A1049101), supplemented with 10% Heat-inactivated FBS (Gibco Cat. # A38400-01) and 1% Penicillin/Streptomycin (Gibco Cat. # 15140-122) in an incubator set at 37⁰ C and 5% CO2. Cells were seeded at 100,000 cells/ml in 1 ml of complete media in a 24-well, tissue culture- treated plate (Falcon 353226) and incubated overnight. Cells were treated with increasing concentrations of compound and let incubate at 37C and 5% CO2 for 17 hours, after which media was aspirated and cells were lysed in 75uL RIPA Lysis and Extraction Buffer (Thermo 89901) supplemented with 5mM MgCl2, Protease and Phosphatase inhibitor cocktail (Thermo 1861281), and Universal Nuclease (Thermo 88700). Plates with RIPA were shaken at 4°C at 600 rpm for 15min. After shaking samples, they were collected and spun down at 21,000g for 15 min at 4°C. Following centrifugation, ~10 ug of lysate was added to Laemmli Sample Buffer (Bio-Rad 1610747) plus 10% beta-mercaptoethanol, boiled for 15 minutes at 65°C and loaded onto 12% Mini-PROTEAN TGX™ Precast Protein Gels (Bio-Rad). Protein was transferred to a nitrocellulose membrane (Thermo LC2000) using the iBlot 2 Dry Blotting System (Thermo). After transfer, membranes were washed in 1x TBST (Bioland Scientific LLC TBST0103) 3x for 5min. Following the wash, blocking buffer (Rockland MB-070) was added for 1 hour at room temperature. Primary antibodies against KRAS (LifeSpan Bio LS‑C175665) and actin (Cell Signaling Technology 8457) were added overnight at 4°C. Membranes were then washed again 3x for 5 min in 1x TBST. Secondary antibodies (LI-COR 926-68072 and 926-68073) were added and shaken for 1hr at room temperature. Membranes were then washed 3x for 5min in 1xTBST and developed. Membranes were placed on an Odyssey imager (LI-COR). Part II – Results [000550] Experimental results showing TE50 observed in the assay are provided in Table 24 below. The symbol “++++” indicates a TE ₅₀ less than 0.25 µM. The symbol “+++” indicates a TE ₅₀ in the range of 0.25 µM to 5 µM. The symbol “++” indicates a TE ₅₀ in the range of greater than 5 µM to 10 µM. The symbol “+” indicates a TE50 of greater than 10 µM. The symbol “N/A” indicates that no data was available. TABLE 24. EXAMPLE 28 - EGFR Cellular Target Engagement Assay [000551] Exemplary compounds were tested for ability to engage the EGFR T790M/L858R kinase domain in cells. Experimental procedures and results are provided below. Part I – Experimental Procedure [000552] HEK293 cells were cultured in DMEM (Gibco 11995), supplemented with 10% Heat-inactivated FBS (Gibco A38400-01) and 1% Penicillin/Streptomycin (Gibco 15140-122) at 37°C with 5% CO2^in a humidified tissue culture incubator. Cells were made stable for EGFR (amino acids 696-1022, T790M, L858R) by lentiviral transduction, followed by selection with 1 µg/ml Puromycin Dihydrochloride (Thermo A1113803). Cells were seeded at 30,000 cells/ml in 0.1 ml of complete media in Poly-D-lysine-treated 96-well plates and incubated overnight. Cells were treated with increasing concentrations of compound and let incubate at 37C and 5% CO2 for 6 hours, after which media was aspirated, washed with 1X PBS and cells were lysed in RIPA Lysis and Extraction Buffer (Thermo 89901) supplemented with 5mM MgCl ₂ , Protease and Phosphatase inhibitor cocktail (Thermo 1861281), and Universal Nuclease (Thermo 88700). Plates with RIPA were shaken at 4°C at 600 rpm for 15min. After shaking samples, they were collected and spun down at 21,000g for 15 min at 4°C. Following centrifugation, ~10 ug of lysate was added to Laemmli Sample Buffer (Bio- Rad 1610747) plus 10% beta-mercaptoethanol, boiled for 15 minutes at 65°C and loaded onto 4-20% Mini-PROTEAN TGX™ Precast Protein Gels (Bio-Rad). Protein was transferred to a nitrocellulose membrane (Thermo LC2000) using the iBlot 2 Dry Blotting System (Thermo). After transfer, membranes were washed in 1x TBST (Bioland Scientific LLC TBST0103) 3x for 5min. Following the wash, blocking buffer (Rockland MB-070) was added for 1 hour at room temperature. Primary antibodies against EGFR (Cell Signaling Technology 3197) and actin (Cell Signaling Technology 3700S) were added overnight at 4°C. Membranes were then washed again 3x for 5min in 1x TBST. Secondary antibodies (LI-COR 926-68072 and 926- 68073) were added and shaken for 1hr at room temperature. Membranes were then washed 3x for 5min in 1xTBST and developed. Membranes were placed on an Odyssey imager (LI-COR). Part II – Results [000553] Experimental results showing TE50 observed in the assay are provided in Table 25 below. The symbol “++++” indicates a TE50 less than 0.25 µM. The symbol “+++” indicates a TE50 in the range of 0.25 µM to 5 µM. The symbol “++” indicates a TE50 in the range of greater than 5 µM to 10 µM. The symbol “+” indicates a TE ₅₀ of greater than 10 µM. The symbol “N/A” indicates that no data was available. TABLE 25. EXAMPLE 29 – Payload Release Assay (GI50 Readout) [000554] Exemplary compounds were tested for ability to inhibit the proliferation of HEK293 cells (ATCC CRL-1573) in the presence of recombinant target protein. Experimental procedures and results are provided below. Part I – Experimental Procedure [000555] HEK293 cells were cultured in DMEM (Gibco 11995), supplemented with 10% Heat-inactivated FBS (Gibco A38400-01) and 1% Penicillin/Streptomycin (Gibco 15140-122) at 37°C with 5% CO ₂ ^in a humidified tissue culture incubator. Cells were seeded at 1500 cells/well in 384-well, tissue culture-treated black plates (Perkin Elmer 6007460) in 10µL media lacking selection for 18-24 hours. Plates were spun at 300g for 30 seconds and stored in the incubator overnight. After 24 hours, a 5µL aliquot of recombinant target protein (final concentration of either 5µM KRAS amino acids 1-169, C51S, C80L, C118S, G12C or 1µM EGFR amino acids 696-1022, T790M, L858R) was added to wells, followed immediately by a 5µL aliquot of 4X compound-containing medium was added in each well, at a final top concentration of 10 µM test compound, with 4-fold dilutions, using DMSO alone as a negative control. Plates were then spun at 300×g^for 3 minutes again and cultured at 37°C with 5% CO ₂ . After 72 hours, cell viability was quantified with CellTiter-Glo 2.0 (Promega). After equilibrating cell plates at room temperature for 30 minutes, 25µL CellTiter-Glo 2.0 reagent was dispensed into each well. Plates were mixed on a shaker for 2 minutes at 500 rpm, followed by a 10-minute incubation at room temperature. Luminescence readings were measured with an EnVision Plate Reader (Perkin Elmer). Data was normalized to DMSO treated cell wells. A four-parameter non-linear regression curve fit was applied to dose- response data in Prism to determine the half maximal growth inhibitory concentration (GI ₅₀ ) of each compound. Part II – Results [000556] Experimental results showing GI50 values observed in the assays are provided in Table 26-28 below. The symbol “++++” indicates a GI ₅₀ less than 0.25 µM. The symbol “+++” indicates a GI50 in the range of 0.25 µM to 5 µM. The symbol “++” indicates a GI50 in the range of greater than 5 µM to 10 µM. The symbol “+” indicates a GI50 of greater than 10 µM. The symbol “N/A” indicates that no data was available. TABLE 26. TABLE 27.

TABLE 28. INCORPORATION BY REFERENCE [000557] The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes. EQUIVALENTS [000558] 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.