EGFR degraders to treat cancer metastasis to the brain or CNS

Abstract

The invention provides for the treatment of mutant epidermal growth factor receptor (EGFR) mediated cancer that has metastasized to the brain or other area of the central nervous system with a compound that degrades a mutant form of EGFR via the ubiquitination of the EGFR protein and subsequent proteasomal degradation. The invention also provides advantageous drug combinations for the treatment of such cancer that include a compound herein that degrades a mutant form of EGFR in combination with a second anti-cancer agent.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application 63 / 193,574 filed May 26, 2021, and U.S. Provisional Application 63 / 270,488 filed October 21, 2021, the entirety of each is incorporated by reference for all purposes. FIELD OF THE INVENTION The invention provides for the treatment of mutant epidermal growth factor receptor (EGFR) mediated cancer that has metastasized to the brain or other area of the central nervous system with a compound that degrades a mutant form of EGFR via the ubiquitination of the EGFR protein and subsequent proteasomal degradation. The invention also provides advantageous drug combinations for the treatment of such cancer that include a compound herein that degrades a mutant form of EGFR in combination with a second anti-cancer agent. BACKGROUND OF THE INVENTION The HER family receptor tyrosine kinases are mediators of cell growth, differentiation, and survival. The receptor family includes four distinct members, i.e. epidermal growth factor receptor (EGFR, ErbBl, or HER1), HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4). Upon ligand binding, the receptors form homo and heterodimers and subsequent activation of the intrinsic tyrosine kinase activity leads to receptor auto-phosphorylation and the activation of downstream signaling molecules (Yarden, Y., Sliwkowski, MX. Untangling the ErbB signaling network. Nature Review Mol Cell Biol. 2001 Feb;2(2): 127-37). These signaling molecules promote cell growth and proliferation. Deregulation of EGFR by overexpression or mutation has been implicated in many types of human cancer including colorectal, pancreatic, gliomas, head and neck and lung cancer, in particular non-small cell lung cancer (NSCLC). Several EGFR targeting agents have been developed over the years (Ciardiello, F., and Tortora, G. (2008). EGFR antagonists in cancer treatment. The New England Journal of Medicine 358, 1160-1174). Erlotinib (TARCEVA®) gefitinib (IRESSA®) are first generation reversible inhibitors of the EGFR tyrosine kinase that are approved in numerous countries for the treatment of recurrent NSCLC. Osimertinib (TAGRISSO®) is an irreversible inhibitor of the EGFR tyrosine kinase and is approved in numerous countries for the first line treatment of NSCLC (Soina et al., (2018) The New England Journal of Medicine 378, 113-125). The most common somatic mutations of EGFR are exon 19 deletions and exon 21 amino acid substitutions. The most prevalent exon 19 deletions are delta 746-750 and the prevalent exon 21 amino acid substitution is L858R (Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 2007 Mar;7(3): 169-81). Treatment resistance arises frequently after first generation EGFR inhibitor treatment, often due to the secondary T790M mutation within the ATP binding site of the receptor. Osimertinib, a mutant-selective irreversible inhibitor, is highly active against the T790M mutant, but its efficacy can be compromised by acquired mutation of C797S, which is the cysteine residue with which osimertinib form a key covalent bond (Thress, K. S. et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFRT790M. Nat. Med. 21, 560-562 (2015)). C797S mutation was further reported by Wang et al. to be a major mechanism for resistance to T790M-targeting EGFR inhibitors (Wang et al. EGFR C797S mutation mediates resistance to third-generation inhibitors in T790M-positive non-small cell lung cancer, J Hematol Oncol. 2016; 9: 59). Additional mutations that cause resistance to osimertinib are described by Yang et al., for example L718Q (Yang et al, Investigating Novel Resistance Mechanisms to Third-Generation EGFR Tyrosine Kinase Inhibitor Osimertinib in Non-Small Cell Lung Cancer Patients, Clinical Cancer Research, DOI: 10.1158 / 1078-0432.CCR-17-2310). Additional mutations targeting strategies are also known including targeting egfrL858R-T790M and egfrL85sr-t79om-C797S resistance mutations in NSCLC treatment (Lu et al. Targeting egfrL858R-T790M and egfrL85sr-t79om-C797S resistance mutations in NSCLC: Current developments in medicinal chemistry, Med Res Rev 2018; 1-32). Additional examples of EGFR inhibitors, in particular selective inhibitors of T790M containing EGFR mutants, have also been described including those in WO2014081718, WO2014210354, WO2018 / 115218, WO2018220149, WO2020002487, and ZHOU et al., "Novel mutant-selective EGFR kinase inhibitors against EGFR T790M", NATURE, (20091224), vol. 462, no. 7276, doi:10.1038 / nature08622, ISSN 0028-0836, pages 1070 -1074. All approved EGFR inhibitors target the ATP binding site of the kinase. As secondary mutations that cause resistance to ATP-competitive EGFR inhibitors are located in the ATP binding site, there is a need for new therapeutic agents that work differently to overcome resistance to the current therapies, for example through highly selective targeting of drugresistant EGFR mutants. Recent studies suggest that purposefully targeting allosteric sites might lead to mutant-selective inhibitors (Jia et al. Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors, June 2016, Nature 534, 129-132). The field of targeted protein degradation promoted by small molecules has been intensively studied (Collins et al., Biochem J, 2017, 474(7), 1127-47). Protein degradation plays a role in various cellular functions. For example, the body uses protein degradation to adjust the concentrations of regulatory proteins through degradation into small peptides to maintain the health and productivity of the cells. Cereblon is a protein that forms an E3 ubiquitin ligase complex, which ubiquitinates various other proteins. Cereblon is known as the primary target for the anticancer thalidomide analogs. A higher expression of cereblon has been linked to the efficiency of thalidomide analogs in cancer therapy. Compounds have been described as useful modulators of targeted ubiquitination, for example the compounds described in. WO2013020557, WO2013063560, WO2013106643, WO / 2013170147, WO2016011906, and WO / 2019183523 can be used for targeted ubiquitination. Additional modulators for targeted ubiquitination include those described by Ranok Therapeutics (Hangzhou) Co. Ltd. WO2020206608 and WO2020207396; those described by Arvinas, Inc. in WO2015160845, WO2016149668, WO2016197032, WO2017011590, WO2017030814, WO2018144649, WO2018226542, and WO2019199816; those described by Dana-Farber Cancer Institute in WO2016105518, WO2017007612, WO2017024317, WO2017024318, WO2017117473, WO2017117474, WO2018148443, WO2018148440, and WO2019165229; those described by Kymera Therapeutics in WO2019 / 060742, WO2019 / 140387, and WO2020 / 01022; and those described by C4 Therapeutics, Inc. in WO2017197036, WO2017197046, WO2017197051, WO2017197055, WO2018237026, WO2019099868, WO2019191112, WO2019204353, WO2019236483, WO2020132561, WO2020181232, and WO2020210630. Some specific molecules for the degradation of EGFR have also been described, for example, Dana-Farber Cancer Institute described EGFR degraders in WO2017185036. F. Hoffman-La-Roche described EGFR degraders in WO2019121562 and WO2019149922. Arvinas, Inc. has described EGFR degraders in WO2018119441. Additional EGFR Degraders have been described in the paper by Jang et al. titled “Mutant-Selective Allosteric EGFR Degraders are Effective Against a Broad Range of Drug-Resistant Mutations”, Angewandte Chemie, 59(34), 14481-489. Despite these efforts, because of the life-threatening cancers exhibiting EGFR mutations and / or overexpression, there remains a need for new EGFR modulators to treat disorders mediated by EGFR in hosts, and in particular humans, in need thereof. SUMMARY OF THE INVENTION Methods of treating an EGFR mediated cancer that has metastasized to the brain or central nervous system, for example, the peripheral nervous system, cerebral spinal fluid, spinal cord, leptomeninges, epidural space, and / or dura, are presented that comprise administering an effective amount of a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, to a patient in need thereof. The compounds of Formula I, II, III, and IV include a Targeting Ligand that binds to EGFR, an E3 Ligase binding portion (typically via a cereblon subunit), and a Linker that covalently links the Targeting Ligand to the E3 Ligase binding portion. In certain embodiments the E3 Ligase binding portion is a moiety of A or A*, the Linker is a moiety of L1 or L2, and the remainder of the molecule is the EGFR Targeting Ligand portion. The EGFR Targeting Ligand may be an allosteric inhibitor. Allosteric binding before degradation results in advantages to the use of the compounds of the present invention over traditional EGFR inhibitors, covalent modulators, and even non-allosteric degraders. Nonlimiting examples of the advantages of using the allosteric degrading compounds described herein include increased selectivity for mutant-EGFR, increased catalytic activity, improved efficacy, the ability to overcome resistance to ATP-competitive inhibitors, and / or fewer side effects. In certain embodiments the allosteric degrading compound of the present invention effectively binds and degrades EGFR with a mutation that imparts resistance to osimertinib and / or erlotinib, for example a mutation that replaces an active site cysteine with another amino acid. Because of these advantages the compounds described herein can be used to treat cancer that has metastasized to the brain or CNS and developed resistance to osimertinib (e.g., 2nd line therapy or treatment for non-small cell lung cancer). In other embodiments a compound described herein can be used to treat a cancer that has metastasized to the brain or CNS that is treatment naive (e.g., 1st line therapy or treatment for non-small cell lung cancer). In other embodiments a compound described herein can be used to treat a cancer that has metastasized to the brain or CNS and that developed resistance to multiple lines of therapy (e.g., 3rd line therapy or treatment for non-small cell lung cancer). In other embodiments, the EGFR Targeting Ligand may be an active site inhibitor. In certain embodiments the method provided selectively degrades EGFR in a tumor that has metastasized to the brain or CNS and may have a mutation or combination of mutations, for example a mutation selected from T790M, L858R, and C797S; the combination of two mutations selected from T790M, L858R, and C797S; or the combination of three mutations 5 selected from T790M, L858R, and C797S. In certain embodiments the method utilizes a selective degrader of L858R-T790M, L858R-T790M-C797S, L858R, or L858R-C797S containing EGFR mutants. In certain embodiments a method of treating an EGFR mediated cancer that has metastasized to the brain or CNS comprising administering an effective amount of Compound 10 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, or Compound 12, or a pharmaceutically acceptable salt thereof, to a patient in need thereof is provided. These compounds are allosteric site binding EGFR degraders (allosteric EGFR degraders). 15 Compound 2 Compound 5 Compound 6 Compound 7 Compound 8 Compound 9 Compound 12 Large concentrations of the allosteric EGFR degraders described herein cross the blood brain barrier. Compounds described herein, including for example Compound 1, are also highly selective and degrade mutant EGFR-L858R protein without appreciably degrading other non-10 EGFR proteins. In a kinome screen (see Example 60 and Figure 13A and 13B) a compound described herein had negligible binding against hundreds of proteins. Additionally, in global proteomics similarly high selectivity was observed (see Example 61 and Table 14). Further, the compounds described herein have very low activity for the degradation of SALL4 and GSPT1, two proteins that are degraded by IMID compounds such as lenalidomide and CC-885 (see Figure 7 and Figure 8). In NCI-H1975 (EGFR-L858R-T790M) and NCI-H3255 (EGFR-L858R) human lung cancer lines, degradation of 50% of mutant EGFR was achieved at 6 hours with nanomolar concentrations of allosteric EGFR degraders (see Table 9A). In addition, EGFR phosphorylation is potently inhibited (see Table 10A). In contrast, allosteric EGFR degraders described herein did not reach 50% degradation nor phospho-EGFR inhibition up to a concentration of 10 pM in the human wild-type EGFR cell line A431. An allosteric EGFR degrader described herein also inhibits proliferation of the engineered BaF3 cells expressing EGFR variants including L858R, L858R-C797S, L858R-T790M, or L858R-T790M-C797S EGFR mutants, with GI50 values ranging from 8 to 16 nM, compared to an GI50 of 486 nM in BaF3 cells expressing wild-type EGFR (see Table 10B). Oral dosing of Compound 1 or Compound 2 is well tolerated in mice. Treatment with Compound 1 in an NCI-H1975 mouse xenograft model led to dose-dependent activity and up to 90% tumor regression (see Figure 1). In addition, up to 85% of mutant EGFR was degraded in vivo after a single oral dose of Compound 1, and phospho-EGFR was decreased >95% (see Figures 2A and 2B). In an engineered BaF3 EGFR-L858R-T790M-C797S allograft mouse model of osimertinib resistance, oral dosing of Compound 1 led to 60% tumor regression, in contrast to osimertinib treatment where minimal efficacy was observed (see Figure 3). In a luciferase expressing NCI-H1975 intracranial model of brain metastasis, oral dosing of Compound 1 resulted in tumor regression (see Figure 5A). Oral dosing of Compound 1 also resulted in tumor regression in an intracranial model with intracarotid implementation (see Figure 14). In certain embodiments an allosteric EGFR degrader is administered as second line therapy for the treatment of EGFR-mediated cancer that has metastasized to the brain or CNS, for example, an allosteric EGFR degrader may be administered to a patient that has progressed off osimertinib. In other embodiments an allosteric EGFR degrader is administered as a first line therapy for the treatment of EGFR-mediated cancer that has metastasized to the brain or CNS. In other embodiments an allosteric EGFR degrader is administered as a third line therapy for the treatment of EGFR-mediated cancer that has metastasized to the brain or CNS. In certain embodiments the allosteric EGFR degrader binds to the allosteric site created by the displacement of the regulatory aC-helix in an “aC-out” conformation. In this embodiment the allosteric site may be enlarged in the activation loop mutants such as Exon 21 L858R or L861Q but is occluded in wild type EGFR. This mechanism provides mutant selectivity over wild type. In certain embodiments an allosteric EGFR degrader described herein degrades mutant EGFR monomers and dimers. In certain aspects the present invention provides a method of treating an EGFR-mediated cancer that has metastasized to the brain or CNS comprising administering an effective amount of a compound of Formula: or a pharmaceutically acceptable salt, isotope, N-oxide, or stereoisomer thereof; wherein: A is selected from the ring systems AF and AG; O AG AF A1 is selected from i) -NH-, and ii) -O-; A2 is selected from i) -N-, and ii) -CR52-; A3 is selected from i) -N-, and ii) -CR53-; A4 is selected from i) -N-, and ii) -CR54-; A5 is selected from i) -N-, and ii) -CR55-; R1 is selected from i) H, ii) halogen iii) Ci-6-alkyl; R52 is selected from i) H, ii) halogen, iii) cyano, iv) Ci-6-alkoxy, v) halo-Ci-6-alkoxy, vi) Ci-6-alkyl, vii) halo-Ci-6-alkyl, viii) Cs-s-cycloalkyl, and ix) halo-C3-8-cycloalkyl; R53, R54 and R55 are independently selected from i) H, ii) halogen, iii) Ci-6-alkyl, iv) halo-Ci-6-alkyl, v) C3-8-cycloalkyl, and vi) halo-C3-8-cycloalkyl; R2 is selected from i) H, ii) halogen, iii) Ci-6-alkyl, iv) halo-Ci-6-alkyl, v) C3-8-cycloalkyl, and vi) halo-C3-8-cycloalkyl; R3 is selected from i) H, ii) halogen, iii) Ci-6-alkyl, iv) halo-Ci-6-alkyl, v) Cs-s-cycloalkyl, and vi) halo-Cs-s-cycloalkyl; R4 and R5 are H; or R4 and R5 together form -(CH2)q-; q is 1 or 2; R6 is selected from i) H, ii) halogen, iii) cyano, iv) Ci-6-alkoxy, v) halo-Ci-6-alkoxy, vi) Ci-6-alkyl, vii) halo-Ci-6-alkyl, viii) C3-8-cycloalkyl, and ix) halo-C3-8-cycloalkyl; R7 is selected from i) H, ii) halogen, iii) cyano, iv) Ci-6-alkyl, v) halo-Ci-6-alkyl, vi) C3-8-cycloalkyl, and vii) halo-C3-8-cycloalkyl; R70 is selected from i) H, ii) halogen, iii) cyano, iv) Ci-6-alkyl, v) halo-Ci-6-alkyl, vi) C3-8-cycloalkyl, and vii) halo-C3-8-cycloalkyl; R8 is H; R9 is selected from i) H, and ii) Ci-6-alkyl; C is absent or selected from the ring systems F, G and H; R13 r14 F                G             H Y1 is selected from i) -N-, and ii) -CH-; Y2 is selected from i) -N-, and ii) -CR16-; R12, R13, R14 and R15 are independently selected from i) -H-, ii) halogen, and iii) hydroxy-Ci-6-alkyl; R16 is selected from i) -H-, ii) hydroxy, and iii) fluoro; L3 is absent or selected from i) -(CH2)m-C(O)-, ii) -C(O)-(CH2)P-, iii) -C(O)-C(O)-, iv) -NR10-C(O)-, v) -C(O)-NR10-, vi) -C(O)O-, vii) -CH2-CF2-CH2-, viii) -CH2-, 10 m is 0, 1 or 2; p is 0, 1, 2 or 3; R10 is selected from i) H, and ii) Ci-6-alkyl; D is selected from the ring systems I, J, K, L, M, N, O, P, Q, R, S, T, U, V, W and X, all ring systems being optionally substituted by one to three substituents selected from R80, 15 X R80, R81 and R82 are independently selected from i) halogen, ii) cyano, iii) hydroxy, iv) hydroxy- Ci-6-alkyl, v) Ci-6-alkoxy, vi) halo-Ci-6-alkoxy, vii) Ci-6-alkyl, viii) halo-Ci-6-alkyl, ix) Cs-s-cycloalkyl, and x) halo-C3-8-cycloalkyl; L4 is absent or selected from i) -NRU-C(O)-, ii) -CH2-, and iii) -O-; E is selected from the ring systems Y, Z, AA, AB and AC; AD            AE In certain aspects the present invention provides a method of treating an EGFR-mediated cancer that has metastasized to the brain or CNS comprising administering an effective amount of a compound of Formula: or a pharmaceutically acceptable salt, isotope, N-oxide, or stereoisomer thereof; wherein A’ is selected from the ring systems AF, AG and AH; R1’ is selected from i) H, ii) halogen, iii) Ci-6-alkyl 10                   iv) cyano, v) Ci-6-alkoxy, vi) halo-Ci-6-alkoxy, vii) Ci-6-alkyl, viii) halo-Ci-6-alkyl, 15                    ix) Cs-s-cycloalkyl, and x) halo-C3-8-cycloalkyl; and the remaining variables are as defined herein. In other aspects the present invention provides a method of treating an EGFR-mediated cancer that has metastasized to the brain or CNS comprising administering an effective amount of a compound of Formula: or a pharmaceutically acceptable salt, isotope, N-oxide, or stereoisomer thereof; wherein: A* is selected from: B* is heteroaryl or aryl which is optionally substituted with 1, 2, or 3 R31 substituents; y is 0, 1, 2, or 3; 5           R31 is independently selected at each occurrence from H, halogen (F, Cl, Br, or I), Ci- 6-alkyl, cyano, Ci-6-alkoxy, halo-Ci-6-alkoxy, halo-Ci-6-alkyl, C3-8-cycloalkyl, and halo-C3-8-cycloalkyl and can be located on either ring where present on a bicycle, for example 10           R32 is hydrogen, halogen (F, Cl, Br, or I), Ci-6-alkyl, halo-Ci-6-alkyl, C3-8-cycloalkyl, or halo-Cs-s-cycloalkyl; R33 is hydrogen, halogen (F, Cl, Br, or I), Ci-6-alkyl, halo-Ci-6-alkyl, C3-8-cycloalkyl, or halo-C3-8-cycloalkyl and can be located on the dihydropyrrole or imidazole ring; R34 is independently selected at each occurrence from H, F, Ci-6-alkyl, 15 halo-Ci-6-alkyl, C3-8-cycloalkyl, and halo-C3-8-cycloalkyl; R35 is selected at each occurrence from H, halogen (F, Cl, Br, or I), Ci-6-alkyl, halo-Ci-6-alkyl, and C3-8-cycloalkyl; or R34 and R35 combine to form -(CH2)q-; R36 and R37 are independently selected from H, halogen (F, Cl, Br, or I), cyano, Ci-6-alkoxy, halo-Ci-6-alkoxy(for example F, Cl, or Br), Ci-6-alkyl, halo-Ci-6-alkyl (for example F, Cl, or Br), Cs-s-cycloalkyl, and halo-Cs-s-cycloalkyl; or R36 and R37 together are combined to form a 5- or 6- membered cycle optionally substituted with 1, 2, or 3 R31 substituents; R42 is independently selected at each occurrence from H, halogen (F, Cl, Br, or I), cyano, Ci-6-alkoxy, halo-Ci-6-alkoxy, Ci-6-alkyl, halo-Ci-6-alkyl, Cs-s-cycloalkyl, and halo-Cs-s-cycloalkyl; R90 is H, Ci-6-alkyl, or C3-6-cycloalkyl; Ring G is a heteroaryl optionally substituted with 1 or 2 R42 substituents, for example a 5- or 6-membered heteroaryl ring with 1, 2, or 3 N heteroatoms; A21 is -NH-, -O-, -CH2-, or -NR100-; R100 is alkyl, cycloalkyl, aryl, or heteroaryl; or as allowed by valence R100 may combine with R37 to form a 5-8 membered heterocycle or 5 membered heteroaryl; A32, A33, A34, and A35 are independently selected from -N- and -CR42-; A36 is -N- or -CR35-; L2 is a bivalent linking group (a linker) that connects A* and either the isoindolinone or indazole, for example but not limited to a bivalent linking group of Formula LI; and wherein the remaining variables are as defined herein. In certain embodiments L2 is of formula: wherein, X1 and X2 are independently at each occurrence selected from bond, heterocycle, aryl, heteroaryl, bicycle, alkyl, aliphatic, heteroaliphatic, -NR27-, -CR40R41-, -O-, -C(O)-, -C(NR27)-, -C(S)-, -S(O)-, -S(O)2- and -S-; each of which heterocycle, aryl, heteroaryl, and bicycle is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R40; R20, R21, R22, R23, and R24 are independently at each occurrence selected from the group consisting of a bond, alkyl, -C(O)-, -C(O)O-, -00(0)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR27-, -NR27C(O)-, -0-, -S-, -NR27-, oxyalkylene, -C(R40R40)-, -P(O)(OR26)O-, -P(O)(OR26)-, bicycle, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, and carbocycle; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R40; R26 is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocycle, aliphatic and heteroaliphatic; R27 is independently at each occurrence selected from the group consisting of hydrogen, alkyl, aliphatic, heteroaliphatic, heterocycle, aryl, heteroaryl, -C(O)(aliphatic, aryl, heteroaliphatic or heteroaryl), -C(O)O(aliphatic, aryl, heteroaliphatic, or heteroaryl), alkene, and alkyne; R40 is independently at each occurrence selected from the group consisting of hydrogen, R27, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH(aliphatic, including alkyl), -N(aliphatic, including alkyl)2, -NHSO2(aliphatic, including alkyl), -N(aliphatic, including alkyl)SO2alkyl, -NHSO2(aryl, heteroaryl or heterocycle), -N(alkyl)SO2(aryl, heteroaryl or heterocycle), -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocycle, oxo, and cycloalkyl; additionally, where allowed by valence two R40 groups bound to the same carbon may be joined together to form a 3-8 membered spirocycle; and R41 is aliphatic, aryl, heteroaryl, or hydrogen. Every combination of variables, substituents, embodiments and the methods that result from these combinations, is deemed specifically and individually disclosed, as such depiction is for convenience of space only. In certain embodiments a compound of Formula I, II, III, or IV is an allosteric degrader of EGFR. For example, the compound may bind an allosteric site on EGFR, for example mutated EGFR) and then direct degradation of the EGFR protein. In certain embodiments a compound of Formula I, II, III, or IV crosses the blood brain barrier. By crossing the blood brain barrier the compound of Formula I, II, III, or IV can be used to treat an EGFR-mediated cancer that has metastasized to the brain or CNS. Non-limiting examples of EGFR-mediated cancers include non-small cell lung cancer; breast cancer, including HER-2 positive breast cancer, ER+ (estrogen positive) breast cancer, PR+ (progesterone positive) breast cancer, or triple negative breast cancer; head and neck cancer; glioblastoma; pancreatic cancer; thyroid cancer; astrocytoma; esophageal cancer; cervical cancer; synovial sarcoma; ovarian cancer; liver cancer; bladder cancer; and kidney cancer. In certain embodiments a compound described herein is used to treat lung cancer that has metastasized to the brain or CNS. In certain embodiments, the lung cancer is non-small cell lung cancer that has metastasized to the brain or CNS. In certain embodiments, the lung cancer is small cell lung cancer that has metastasized to the brain or CNS. In certain embodiments, the lung cancer is adenocarcinoma that has metastasized to the brain or CNS. In certain embodiments, the lung cancer is squamous cell lung cancer that has metastasized to the brain or CNS. In certain embodiments, the lung cancer is large-cell undifferentiated carcinoma that has metastasized to the brain or CNS. In certain embodiments, the lung cancer is neuroendocrine carcinoma that has metastasized to the brain or CNS. Additional examples of lung cancers include sarcomatoid carcinoma, adenosquamous carcinoma, oat-cell cancer, combined small cell carcinoma, lung carcinoid tumor, central carcinoid, peripheral carcinoid, salivary gland-type lung carcinoma, mesothelioma, and mediastinal tumors. In certain embodiments a compound described herein is used to treat breast cancer that has metastasized to the brain or CNS. In certain embodiments, the breast cancer is HER-2 positive breast cancer. In certain embodiments, the breast cancer is ER+ breast cancer. In certain embodiments, the breast cancer is PR+ breast cancer. In certain embodiments, the breast cancer is triple negative breast cancer. In certain embodiments a compound described herein is used to treat colorectal or rectal cancer that has metastasized to the brain or CNS. In certain embodiments a compound described herein is used to treat head and neck cancer or esophageal cancer that has metastasized to the brain or CNS. In certain embodiments a compound described herein is used to treat pancreatic cancer that has metastasized to the brain or CNS. In certain embodiments a compound described herein is used to treat thyroid cancer that has metastasized to the brain or CNS. In certain embodiments a compound described herein is used to treat ovarian cancer, uterine cancer, or cervical cancer that has metastasized to the brain or CNS. In certain embodiments a compound described herein is used to treat kidney cancer, liver cancer, or bladder cancer that has metastasized to the brain or CNS. In certain embodiments a compound described herein is used to treat melanoma that has metastasized to the brain or CNS. In certain embodiments a compound described herein is used to treat kidney cancer, liver cancer, or bladder cancer that has metastasized to the brain or CNS. In other embodiments, the compound is used to treat adenocarcinoma, colorectal carcinoma, breast cancer, triple negative breast cancer, renal cell carcinoma, a primary brain tumor, astrocytoma, esophageal cancer or synovial sarcoma In certain embodiments, a compound described herein crosses the blood brain barrier in sufficient concentrations to treat an EGFR-mediated disorder such as cancer in the brain or CNS and has one or more, and even may provide multiple additional advantages over traditional treatment with an EGFR inhibitor. For example, the EGFR degrading compound described herein may a) overcome resistance in certain cases; b) prolong the kinetics of drug effect by destroying the protein, thus requiring resynthesis of the protein even after the compound has been metabolized; c) target all functions of a protein at once rather than a specific catalytic activity or binding event; and / or d) have increased potency compared to inhibitors due to the possibility of the small molecule acting catalytically. In one aspect, a compound described herein is used to treat an EGFR mediated cancer that has metastasized to the brain or CNS, wherein the EGFR has mutated from the wild-type. There are a number of possibilities for EGFR mutations. In certain non-limiting embodiments, the mutation is found in exon 18, exon 19, exon 20, or exon 21, or any combination thereof. In certain nonlimiting embodiments, the mutation is at position L858, E709, G719, C797, L861, T790, or L718 or any combination thereof. In certain embodiments the mutation is a L858R, T790M, L718Q, L792H, and / or a C797S mutation or any combination thereof. In certain aspects, the cancer has developed one or more EGFR mutations following treatment with at least one EGFR inhibitor that can be a non-covalent inhibitor (including but not limited to gefitinib, erlotinib, lapatinib or vandetanib) or a covalent inhibitor (such as afatinib, osimertinib or dacomitinib). In another aspect, the cancer has developed one or more EGFR mutations following treatment with an antibody such as cetuximab, panitumab or necitumab. In yet another aspect, the cancer has one or more EGFR mutations or non-EGFR mutations that renders the cancer intrinsically resistant to EGFR inhibitor treatment, for example, a somatic exon 20 insertion, asomatic PIK3CA mutation, loss of PTEN expression, MET amplification, or a KRAS mutation. In certain embodiments, a compound described herein is used to treat a cancer that has metastasized to the brain or CNS that is resistant to, or has acquired a resistance to, a first generation EGFR inhibitor such as erlotinib, gefitinib, and / or lapatinib. In certain embodiments, a compound described herein is used to treat a cancer that is resistant to, or has acquired a resistance to a second generation EGFR inhibitor such as afatinib and / or dacomitinib. In certain embodiments, a compound described herein is used to treat a cancer that is resistant to, or acquired a resistance to a third generation EGFR inhibitor such as osimertinib. In some embodiments, the mutated EGFR protein in the diseased tissue has an L858 mutation, for example L858R. In certain embodiments a compound described herein is used to treat a mutant EGFR-mediated cancer that has metastasized to the brain or CNS, wherein EGFR has a mutation of at least one of the below listed amino acid sites, or a combination thereof. The mutation may, for example, be selected from one of the listed exemplary mutations, or may be a different 5 mutation. Amino Acid Exemplary Mutations C797 C797S E709 E709A, E709G, E709K, E709V G719 G719A, G719S, G719C, G719D G724 G724S G119 G119A G796 G796S, G796C L718 L718V, L718Q L792 L792H; L792V L858 L858R L861 L861Q S768 S768I T790 T790M In certain embodiments the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has two mutations selected from the table above. In other embodiments the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has three mutations 10 selected from the table above. In other embodiments the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has four or more mutations, which may optionally be selected from the table above. In certain embodiments the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has an L858R mutation and one additional mutation which may optionally be 15 selected from the table above. In some of these embodiments the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has an L858R mutation and two additional mutations that may optionally be selected from the table above. In other embodiments the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has a L858R mutation and three additional mutations that may optionally be selected from the table above. In certain embodiments the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has a T790M mutation and one additional mutation optionally selected from the table above. In other embodiments the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has a T790M mutation and two additional mutations optionally selected from the table above. In other embodiments the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has a T790M mutation and three additional mutations optionally selected from the table above. In certain embodiments the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has a L718Q mutation and one additional mutation optionally selected from the table above. In other embodiments the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has a L718Q mutation and two additional mutations optionally selected from the table above. In other embodiments the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has a L718Q mutation and three additional mutations optionally selected from the table above. In certain embodiments the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has a mutation of S768I, L718V, L792H, L792V, G796S, G796C, G724S, and / or G719A. In certain embodiments, a compound described herein is used to treat an EGFR-mediated cancer that has metastasized to the brain or CNS that has a frameshift mutation, for example a short in-frame deletion. In certain embodiments, a compound described herein is used to treat an EGFR-mediated cancer that has metastasized to the brain or CNS wherein the EGFR has an exon 19 deletion. In certain embodiments, the exon 19 deletion is a deletion which includes the amino acids LREA (L747-A750). In certain embodiments, the exon 19 deletion is a deletion which includes the amino acids ELREA (E746-A750). In certain embodiments a compound described herein is used to treat an EGFR-mediated cancer that has metastasized to the brain or CNS wherein the EGFR has an L858R mutation in exon 21. In certain embodiments a compound described herein is more active against a disorder driven by a mutated EGFR than wild-type EGFR. In certain embodiments, a compound described herein is used to treat EGFR-mediated cancer that has metastasized to the brain or CNS wherein the EGFR has one or more exon 18 deletions. In certain embodiments a compound described herein is used to treat an EGFR-mediated cancer that has metastasized to the brain or CNS with a E709 mutation, for example E709A, E709G, E709K, or E709V. In certain embodiments a compound described herein is used to treat an EGFR-mediated cancer that has metastasized to the brain or CNS with a L718 mutation, for example L718Q. In certain embodiments a compound described herein is used to treat an EGFR-mediated cancer that has metastasized to the brain or CNS with a G719 mutation, for example G719S, G719A, G719C, or G719D. In certain embodiments, a compound described herein is used to treat an EGFR-mediated cancer that has metastasized to the brain or CNS wherein the EGFR has one or more exon 19 insertions and / or one or more exon 20 insertions. In certain embodiments, a compound described herein is used to treat a S7681 mutant EGFR-mediated cancer that has metastasized to the brain or CNS. In certain embodiments a compound described herein is used to treat a EGFR L861Q mutant EGFR-mediated cancer that has metastasized to the brain or CNS. In certain embodiments, a compound described herein is used to treat C797S mutant EGFR-mediated cancer that has metastasized to the brain or CNS. In certain embodiments a compound described herein is used to treat a L858R-T790M mutant EGFR-mediated cancer that has metastasized to the brain or CNS. In certain embodiments a compound described herein is used to treat a L858R-L718Q mutant EGFR-mediated cancer that has metastasized to the brain or CNS. In certain embodiments a compound described herein is used to treat a L858R-L792H, mutant EGFR-mediated cancer that has metastasized to the brain or CNS. In certain embodiments a compound described herein is used to treat a L858R-C797S, mutant EGFR-mediated cancer that has metastasized to the brain or CNS. In certain embodiments a compound described herein is used to treat a L858R-T790M-C797S mutant EGFR-mediated cancer that has metastasized to the brain or CNS. Other features and advantages of the present application will be apparent from the following detailed description. The present invention thus includes at least the following features: (a) A method for treating an EGFR mediated cancer which has metastasized to the brain or CNS comprising administering an effective amount of a compound of Formula I, II, III, or IV, or pharmaceutically acceptable salt thereof, as described herein, to a patient in need thereof; (b) The method of (a) wherein the patient is also administered an ATP site binding EGFR inhibitor, for example osimertinib; (c) Use of a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, in an effective amount in the treatment of a patient in need thereof, typically a human, with an EGFR-mediated cancer, wherein the cancer has metastasized to the brain or CNS; (d) The use of (c) wherein the patient is also administered an ATP site binding EGFR inhibitor, for example osimertinib; (e) A compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a patient in need thereof, typically a human, with an EGFR-mediated cancer, wherein the cancer has metastasized to the brain or CNS; (f) The compound of (e) wherein the patient is also administered an ATP site binding EGFR inhibitor, for example osimertinib; (g) A method for treating a mutant EGFR mediated cancer which has metastasized to the brain comprising administering an effective amount of a compound of Formula I, II, III, or IV, or pharmaceutically acceptable salt thereof, as described herein, to a patient in need thereof; (h) The method of (g) wherein the patient is also administered an ATP site binding EGFR inhibitor, for example osimertinib; (i) Use of a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, in an effective amount in the treatment of a patient in need thereof, typically a human, with a mutant EGFR-mediated cancer, wherein the cancer has metastasized to the brain or CNS; (j) The use of (i) wherein the patient is also administered an ATP site binding EGFR inhibitor, for example osimertinib; (k) A compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a patient in need thereof, typically a human, with a mutant EGFR-mediated cancer, wherein the cancer has metastasized to the brain or CNS; (1) The compound of (k) wherein the patient is also administered an ATP site binding EGFR inhibitor, for example osimertinib. BRIEF DESCRIPTION OF THE FIGURES FIG. 1A is a line graph demonstrating the in vivo efficacy of Compound 1 or osimertinib in the treatment of female BALB / c nude mice bearing NCI-H1975 L858R-T790M NSCLC xenograft tumors. Mice were treated with the vehicle control, a dose response (20, 50 and 100 mg / kg / day) of Compound 1, or 25 mg / kg / day of osimertinib for 14 days. Compound 1 was administered orally (PO) on a twice a day basis (BID) and osimertinib was administered orally (PO) on a once per day basis (QD). The x-axis is the time measured in days and the y-axis is NCI-H1975 tumor volume measured in mm3. The experimental procedure is provided in Example 55. FIG. IB is a line graph demonstrating the effect on body weight of Compound 1 or osimertinib in the treatment of female BALB / c nude mice bearing NCLH1975 NSCLC xenograft tumors. Mice were treated with the vehicle control, a dose response (20, 50 and 100 mg / kg / day) of Compound 1, or 25 mg / kg / day of osimertinib for 14 days. Compound 1 was administered orally (PO) on a twice a day basis (BID) and osimertinib was administered orally (PO) on a once per day basis (QD). After 14 days of dosing, tumors were monitored for regrowth. The x-axis is the time measured in days and the y-axis is body weight change measured as %. The experimental procedure is provided in Example 55. FIG. 2A and FIG. 2B are graphs of the relative protein expression of (A) mutant EGFR-L858R-T790M and (B) phospho-EGFR in NCLH1975 tumors. BALB / c nude mice were injected with NCI-H1975 tumor cells and Compound 1 was administered as a single oral (PO) dose at 10, 25, or 50 mg / kg and osimertinib was administered orally (PO) at 25 mg / kg. The x-axis is time measured in hours and represents time post-single dose administration and the y-axis is the percent of protein relative to the vehicle control normalized to alpha-tubulin. The experimental procedure is provided in Example 56. FIG. 3 A is a line graph demonstrating the in vivo efficacy of Compound 1 or osimertinib in the treatment of female BALB / c nude mice bearing engineered triple mutant EGFR (L858R-T790M-C797S) BaF3 tumors. Mice were treated with the vehicle control, a dose response (20, 50, and 100 mg / kg / day) of Compound 1, or 25 mg / kg / day of osimertinib for 14 days. All compounds were administered orally (PO) on a twice a day basis (BID) for Compound 1 and once a day basis (QD) for osimertinib. The x-axis is the time measured in days and the y-axis is BaF3 tumor volume measured in mm3. The experimental procedure is provided in Example 57. FIG. 3B is a line graph demonstrating the effect on body weight of Compound 1 or osimertinib in the treatment of female BALB / c nude mice bearing engineered triple mutant EGFR (L858R-T790M-C797S) BaF3 tumors. Mice were treated with the vehicle control, a dose response (20, 50, and 100 mg / kg / day) of Compound 1, or 25 mg / kg / day of osimertinib for 14 days. All compounds were administered orally (PO) on a twice a day basis (BID) for Compound 1 and once a day basis (QD) for osimertinib. The x-axis is the time measured in days and the y-axis is body weight change measured in %. The experimental procedure is provided in Example 57. FIG. 4A is a line graph showing the in vivo efficacy of Compound 2 and osimertinib in the treatment of female BALB / c nude mice bearing engineered triple mutant EGFR (L858R-T790M-C797S) BaF3 tumors. Mice were treated with the vehicle control, a dose response (20, 50, and 100 mg / kg / day) of compound 2, or 25 mg / kg / day of osimertinib for 14 days. All compounds were administered orally (PO) on a twice a day basis (BID) for Compound 2 and once a day basis (QD) for osimertinib. The x-axis is the time measured in days and the y-axis is BaF3 tumor volume measured in mm3. The experimental procedure is provided in Example 57. FIG. 4B is a line graph showing the change in body weight caused by Compound 2 and osimertinib in the treatment of female BALB / c nude mice bearing engineered triple mutant EGFR (L858R-T790M-C797S) BaF3 tumors. Mice were treated with the vehicle control, a dose response (20, 50, and 100 mg / kg / day) of compound 2, or 25 mg / kg / day of osimertinib for 14 days. All compounds were administered orally (PO) on a twice a day basis (BID) for Compound 2 and once a day basis (QD) for osimertinib. The x-axis is the time measured in days and the y-axis is body weight change in percent. The experimental procedure is provided in Example 57. FIG. 5 A is the mean in vivo efficacy of Compound 1 in the treatment of female BALB / c nude mice bearing intracranial NCI-H1975-luciferase expressing NSCLC tumors established by injecting tumor cells intracranially into the forebrain. Mice were treated with the vehicle control, Compound 1 at 100 mg / kg for 14 days. Compound 1 was administered orally (PO) on a twice a day basis (BID). The x-axis is the time measured in days and the y-axis is NCI-H1975-luc BLI (total bioluminescence signal) measured in photons / sxlO6. The experimental procedure is provided in Example 58. FIG. 5B is a line graph demonstrating the mean effect on body weight for Compound 1, in the treatment of female BALB / c nude mice bearing intracranial NCI-H1975-luciferase expressing NSCLC tumors established by injecting tumor cells intracranially into the forebrain. Mice were treated with the vehicle control or Compound 1 at 100 mg / kg. Compound 1 was administered orally (PO) on a twice a day basis (BID). The x-axis is the time measured in days and the y-axis is % change of body weight. The experimental procedure is provided in Example 58. FIG. 6 is a line graph of the mean plasma and tumor concentration time profile of Compound 1 following a single oral dose at 50 mg / kg. Female BALB / c nude mice were injected intracranially with NCI-H1975 (EGFR-L858R-T790M) luciferase-expressing cells and administered a single oral dose of Compound 1. Plasma and tumors were harvested at the indicated time points and injected into the LC / MS / MS system for quantitative analysis. FIG. 7 is a dose-response curve describing the effect of Compound 1 on Sal-like protein 4 (SALL4) degradation compared to lenalidomide. The x-axis is the concentration of Compound 1 or lenalidomide in nM and the y-axis is the % SALL4 remaining after 6 hours. Compound 1 had no effect on SALL4 protein level up to 10 pM. The experimental procedure is provided in Example 62. FIG. 8 is a dose-response curve describing the effect of Compound 1 on G1 to S Phase Transition 1 (GSPT1) degradation compared to CC-885. The x-axis is the concentration of Compound 1 or CC-885 IMiD in nM and the y-axis is the % GSPT1 remaining after 6 hours. Compound 1 had no significant effect on GSPT1 up to 10 pM. The experimental procedure is provided in Example 63. FIG. 9 is a density map of tert-Butyl 2-[l-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]-2-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetate established by X-ray diffraction. This crystal structure establishes the chirality of Compound 1 as discussed in the synthesis of Compound 1 below. FIG. 10 is a density map of tert-Butyl 2-[l-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]-2-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetate established by X-ray diffraction. This crystal structure establishes the chirality of Compound 1 as discussed in the synthesis of Compound 1 below. FIG. 11 is a density map of tert-Butyl (4R)-4-[3-(2,4-dioxohexahydropyrimidin-l-yl)-l-methyl-indazol-6-yl]-3,3-difluoro-piperidine-l-carboxylate established by X-ray diffraction. This crystal structure establishes the chirality of Compound 2 as discussed in the synthesis of Compound 2 below. FIG. 12 is the crystal structure of tert-Butyl (4R)-4-[3-(2,4-dioxohexahydropyrimidin-l-yl)-l-methyl-indazol-6-yl]-3,3-difluoro-piperi dine-1-carboxylate established by X-ray diffraction. This crystal structure establishes the chirality of Compound 2 as discussed in the synthesis of Compound 2 below. FIG. 13 A and FIG. 13B are human kinome phylogenetic tree binding plots showing the binding selectivity of 100 nM of Compound 1 against various proteins from a panel of 486 wild-type and mutant human protein kinases. Each kinase is marked as a circle. Dark colored and light-colored circles indicate kinases with <50% and >50% percent binding remaining, respectively. The size of dark circles indicates higher-affinity binding. The smaller dark circle is EGFR-L858R and the larger dark circle is EGFR-L861Q. The experimental procedure is provided in Example 60. FIG. 14 is a graph illustrating in vivo efficacy of Compound 1 in female BALB / c nude mice bearing intracranial NCI-H1975-luciferase expressing tumors established by injecting tumor cells in the carotid artery. Mice were treated with the vehicle control, Compound 1 at 100 mg / kg. Compound 1 was administered orally (PO) on a twice a day basis (BID). The x-axis is the time measured in days and the y-axis is NCI-H1975-LUC BLI (photons / s). The experimental procedure is provided in Example 64. FIG. 15 is a graph illustrating in vivo body weight change in female BALB / c nude mice bearing intracranial NCI-H1975-luciferase expressing tumors established by injecting tumor cells in carotid artery. Mice were treated with the vehicle control, Compound 1 at 100 mg / kg. Compound 1 was administered orally (PO) on a twice a day basis (BID). The x-axis is the time measured in days and the y-axis is % change of bodyweight. The experimental procedure is provided in Example 64. FIG. 16 is a graph showing the probability of survival of female BALB / c nude mice bearing intracranial NCI-H1975-luciferase expressing tumors established by injecting tumor cells in carotid artery. Mice were treated with the vehicle control, Compound 1 at 100 mg / kg. Compound 1 was administered orally (PO) on a twice a day basis (BID). The x-axis is the time measured in days and the y-axis is the % probability of survival. The experimental procedure is provided in Example 64. FIG. 17 is a cocrystal structure showing the simultaneous binding of of the allosteric EGFR binding portion of Compound 1 and osimertinib in different binding pockets of L858R mutant EGFR. The allosteric EGFR binding portion of Compound 1 binds close to the L858R mutation. The experimental procedure is provided in Example 66. FIG. 18A and FIG. 18B are SPR sensorgrams of Compound 1 mixed with either 1.5 pM EGFRap8058R (18A) or 5 pM EGFR^8sl5^rtinib (18B) injected over immobilized Btn-CRBN-DDB 1. Concentrations of Compound 1 corresponding to each sensorgram are indicated by the key. Thin black lines represent fits to a 1:1 Langmuir binding model, with best-fit parameters for each titration experiment listed in their respective plots. The experimental procedure is provided in Example 68. FIG. 19 is a western blot showing the effect of osimertinib on Compound 1-induced EGFR-L858R degradation and the downstream signaling in H3255 (EGFR-L858R) cells. The experimental procedure is provided in Example 69. DETAILED DESCRIPTION OF THE INVENTION Compounds and their uses and manufacture are provided that degrade via the ubiquitin proteasome pathway (UPP) the epidermal growth factor receptor protein (EGFR) mediated cancer that has metastasized to the brain or CNS. The present invention provides compounds of Formula I, II, III, or IV or a pharmaceutically acceptable salt thereof that include a Targeting Ligand that binds to EGFR, an E3 Ligase binding portion (typically via a cereblon subunit), and a Linker that covalently links the Targeting Ligand to the E3 Ligase binding portion. In certain embodiments the E3 Ligase binding portion is a moiety of A or A*, the Linker is a moiety of L1 or L2, and the remainder of the molecule is the EGFR Targeting Ligand portion. In certain embodiments a compound described herein degrades EGFR with a mutation or combination of mutations, for example a mutation selected from T790M, L858R, and C797S; the combination of two mutations selected from T790M, L858R, and C797S; or the combination of two mutations selected from T790M, L858R, and C797S. In certain embodiments a compound described herein is a selective degrader of L858R-T790M, L858R-T790M-C797S, L858R, and / or L858R-C797S containing EGFR mutants. In certain embodiments, a compound described herein provides an improved efficacy and / or safety profile relative to at least one known EGFR inhibitor. For example, the degrader described herein has the efficiency of an inhibitor only protein binding moiety combined with the catalytic degradation activity of the cereblon-mediated proteasomal degradation. This provides rapid activity against the target overexpressed EGFR by an active moiety that can quickly “return to action” and repeat the catalytic function. In this way, the EGFR is quickly destroyed as done with a covalent suicide inhibitor, like osimertinib, but without at the same time destroying the active drug. I. DEFINITIONS The following definitions of the general terms used in the present description apply whether the terms appear alone or in combination with other groups. Unless otherwise stated, the following terms used in this application, including the specification and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms “a”, “an,” and “the” include plural referents unless the context clearly dictates otherwise. The term “Ci-6-alkoxy” denotes a group of the formula -O-R’, wherein R’ is an Ci-6-alkyl group, particularly Ci-3-alkyl. Examples of Ci-6-alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Particular examples are methoxy, ethoxy and isopropoxy. More particular example is methoxy. The term "Ci-6-alkyl", alone or in combination with other groups, stands for a hydrocarbon radical which may be linear or branched, with single or multiple branching, wherein the alkyl group in general comprises 1 to 6 carbon atoms, for example, methyl (Me), ethyl (Et), propyl, isopropyl (i-propyl), n-butyl, i-butyl (isobutyl), 2-butyl (sec-butyl), t-butyl (tert-butyl), isopentyl, 2-ethyl-propyl (2-methyl-propyl), 1,2-dimethyl-propyl and the like. A specific group is methyl. The term “cyano” denotes a -C=N group. The term “Cs-s-cycloalkoxy” denotes a group of the formula -O-R’, wherein R’ is a C3-8-cycloalkyl group. Examples of cycloalkoxy group include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyl oxy. Particular example is cyclopropoxy. The term “Cs-s-cycloalkyl” denotes a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 8 ring carbon atoms. Bicyclic means a ring system consisting of two saturated carbocycles having one or two carbon atoms in common. Examples of monocyclic Cs-s-cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl. Example of bicyclic Cs-s-cycloalkyl is spiro[3.3]heptanyl. Particular monocyclic Cs-s-cycloalkyl groups are cyclopropyl, cyclobutanyl. More particular monocyclic Cs-s-cycloalkyl groups include cyclopropyl. The term “halo-Ci-6-alkoxy” denotes an Ci-6-alkoxy group wherein at least one of the hydrogen atoms of the Ci-6-alkoxy group has been replaced by same or different halogen atoms. The term “perhalo-Ci-6-alkoxy” denotes an Ci-6-alkoxy group where all hydrogen atoms of the Ci-6-alkoxy group have been replaced by the same or different halogen atoms. Examples of halo-Ci-6-alkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, trifluoromethylethoxy, trifluorodimethylethoxy and pentafluoroethoxy. Particular halo-Ci-6-alkoxy groups include fluoromethoxy, rifluoroethoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoromethylethoxy and trifluorodimethylethoxy. More particular examples are fluoromethoxy, difluoromethoxy and trifluoromethoxy. The term “halo-Ci-6-alkyl” denotes an Ci-6-alkyl group wherein at least one of the hydrogen atoms of the Ci-6-alkyl group has been replaced by the same or different halogen atoms. The term “perhalo-Ci-6-alkyl-Ci-6-alkyl” denotes an-Ci-6-alkyl-Ci-6-alkyl group where all hydrogen atoms of the alkyl group have been replaced by the same or different halogen atoms. Examples of halo-Ci-6-alkyl include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylethyl and pentafluoroethyl. Particular halo-Ci-6-alkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, trifluoroethyl and difluoroethyl. More particular halo-Ci-6-alkyl groups include fluoromethyl. The term “halo-Cs-s-cycloalkoxy” denotes an Cs-s-cycloalkoxy group wherein at least one of the hydrogen atoms of the Cs-s-cycloalkoxy group has been replaced by same or different halogen atoms. The term “perhalo- Cs-s-cycloalkoxy” denotes an Cs-s-cycloalkoxy group where all hydrogen atoms of the Cs-s-cycloalkoxy group have been replaced by the same or different halogen atoms. Examples of halo-Cs-s-cycloalkoxy include fluorocyclopropoxy, fluorocyclobutoxy, fluorocyclopentyloxy, fluorocyclohexyloxy, fluorocycloheptyloxy, difluorocyclopropoxy, difluorocyclobutoxy, difluorocyclopentyloxy, difluorocyclohexyloxy and difluorocycloheptyloxy. The term “halo-Cs-s-cycloalkyl” denotes an Cs-s-cycloalkyl group wherein at least one of the hydrogen atoms of the Cs-s-cycloalkyl group has been replaced by the same or different halogen atoms. The term “perhalo- Cs-s-cycloalkyl” denotes an- Cs-s-cycloalkyl group where all hydrogen atoms of the alkyl group have been replaced by the same or different halogen atoms. Examples of halo-Cs-s-cycloalkyl include fluorocyclopropyl, fluorocyclobutanyl, fluorocyclopentyl, fluorocyclohexyl, fluorocycloheptyl, difluorocyclopropyl, difluorocyclobutanyl, difluorocyclopentyl, difluorocyclohexyl or difluorocycloheptyl. The term "halogen", alone or in combination with other groups, denotes chloro (Cl), iodo (I), fluoro (F) and bromo (Br). Specific groups are F and Cl. The term “hydroxy” denotes a -OH group. The term “hydroxy-Ci-6-alkyl alkyl” denotes an Ci-6-alkyl alkyl group wherein at least one of the hydrogen atoms of the Ci-6-alkyl alkyl group has been replaced by a hydroxy group. Examples of hydroxy-Ci-6-alkyl include hydroxymethyl, hydroxyethyl and hydroxypropyl. Particular example is hydroxymentyl. The term “pharmaceutically acceptable” denotes an attribute of a material which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and is acceptable for veterinary as well as human pharmaceutical use. The term "a pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and animals. Examples of suitable salts with inorganic and organic acids are, but are not limited to acetic acid, citric acid, formic acid, fumaric acid, hydrochloric acid, lactic acid, maleic acid, malic acid, methane-sulfonic acid, nitric acid, phosphoric acid, p-toluenesulphonic acid, succinic acid, sulfuric acid (sulphuric acid), tartaric acid, trifluoroacetic acid and the like. Particular acids are formic acid, trifluoroacetic acid and hydrochloric acid. A specific acid is trifluoroacetic acid. The terms “pharmaceutically acceptable auxiliary substance” refer to carriers and auxiliary substances such as diluents or excipients that are compatible with the other ingredients of the formulation. The term "pharmaceutical composition" encompasses a product comprising specified ingredients in pre-determined amounts or proportions, as well as any product that results, directly or indirectly, from combining specified ingredients in specified amounts. Particularly it encompasses a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product that results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. “Therapeutically effective amount” means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state. The “therapeutically effective amount” will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors. The term “as defined herein” and “as described herein” when referring to a variable incorporates by reference the broad definition of the variable as well as particularly, more particularly and most particularly definitions, if any. The terms “treating”, “contacting” and “reacting” when referring to a chemical reaction means adding or mixing two or more reagents under appropriate conditions to produce the indicated and / or the desired product. It should be appreciated that the reaction which produces the indicated and / or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and / or the desired product. The term “pharmaceutically acceptable excipient” denotes any ingredient having no therapeutic activity and being non-toxic such as disintegrators, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants or lubricants used in formulating pharmaceutical products. The term "pharmaceutical composition" encompasses a product comprising specified ingredients in pre-determined amounts or proportions, as well as any product that results, directly or indirectly, from combining specified ingredients in specified amounts. Particularly it encompasses a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product that results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. The term “inhibitor” denotes a compound which competes with, reduces or prevents the binding of a particular ligand to particular receptor or which reduces or prevents the function of a particular protein. The term “half maximal inhibitory concentration” (IC50) denotes the concentration of a particular compound required for obtaining 50% inhibition of a biological process in vitro. IC50 values can be converted logarithmically to pICso values (-log IC50), in which higher values indicate exponentially greater potency. The IC50 value is not an absolute value but depends on experimental conditions e.g. concentrations employed. The IC50 value can be converted to an absolute inhibition constant (Ki) using the Cheng-Prusoff equation (Biochem. Pharmacol. (1973)22:3099). “Therapeutically effective amount” means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state. The “therapeutically effective amount” will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors. The term “aromatic” denotes the conventional idea of aromaticity as defined in the literature, in particular in IUPAC - Compendium of Chemical Terminology, 2nd, A. D. McNaught & A. Wilkinson (Eds). Blackwell Scientific Publications, Oxford (1997). Whenever a chiral carbon is present in a chemical structure, it is intended that all stereoisomers associated with that chiral carbon are encompassed by the structure as pure stereoisomers as well as mixtures thereof. In certain embodiments, isotopes are incorporated into the compounds of the invention. These isotopes include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine such as 2H, 3H, UC, 13C, 14C, 15N, 170,180,18F, 35S, and 36C1 respectively. In one non-limiting embodiment, isotopically labelled compounds can be used in metabolic studies (with, for example 14C), reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. Additionally, any hydrogen atom present in the compound of the invention may be substituted with an 18F atom, a substitution that may be particularly desirable for PET or SPECT studies. In one non-limiting embodiment, the substitution of a hydrogen atom for a deuterium atom can be provided in any compound described herein. For example, when any of the groups are, or contain for example through substitution, methyl, ethyl, or methoxy, the alkyl residue may be deuterated (in non-limiting embodiments, CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3 etc ). In certain other embodiments, when two substituents are combined to form a cycle the unsubstituted carbons may be deuterated. In certain embodiments, at least one deuterium is placed on an atom that has a bond which is broken during metabolism of the compound in vivo, or is one, two or three atoms remote form the metabolized bond (e.g., which may be referred to as an a, P or y, or primary, secondary or tertiary isotope effect). In certain embodiments a compound described herein is isotopically labeled. In certain embodiments at least one R group independently selected from R1, R2, R3, R4, R6, R7, R8, R9, R10 r11 R12     R14     r!6 r!7 r20 r21 r22 r23 r24 r26 r27 r3 1 R’2 r33 r34 r35 R36, R37, R40, R41, R42, R52, R53, R54, R55, R70, R80, R81, R82, R90, or R100 is isotopically labeled with 1, 2, or more isotopes as allowed by valence. In certain embodiments the isotopic label is deuterium. In certain embodiments, at least one deuterium is placed on an atom that has a bond which is broken during metabolism of the compound in vivo, or is one, two or three atoms remote form the metabolized bond (e.g., which may be referred to as an a, P or y, or primary, secondary or tertiary isotope effect). In another embodiment the isotopic label is 13C. In other embodiments the isotopic label is 18F. In certain embodiments the compounds described herein may form a solvate with a solvent (including water). Therefore, in one non-limiting embodiment, the invention includes a solvated form of the compounds described herein. The term "solvate" refers to a molecular complex of a compound described herein (including a salt thereof) with one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, isopropanol, dimethyl sulfoxide, acetone and other common organic solvents. In certain embodiments “alkenyl” is a linear or branched aliphatic hydrocarbon groups having one or more carbon-carbon double bonds that may occur at a stable point along the chain. In one non-limiting embodiment, the alkenyl contains from 2 to about 12 carbon atoms, more generally from 2 to about 6 carbon atoms or from 2 to about 4 carbon atoms. In certain embodiments the alkenyl is C2, C2-C3, C2-C4, C2-C5, or C2-C6. In certain embodiments, examples of alkenyl radicals include, but are not limited to ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. In certain embodiments the term “alkenyl” also embodies “cis” and “trans” alkenyl geometry, or alternatively, “E” and “Z” alkenyl geometry. In certain embodiments the term “alkenyl” also encompasses cycloalkyl or carbocyclic groups having at least one point of unsaturation. In certain embodiments “alkynyl” is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that may occur at any stable point along the chain. In one non-limiting embodiment, the alkynyl contains from 2 to about 12 carbon atoms, more generally from 2 to about 6 carbon atoms or from 2 to about 4 carbon atoms. In certain embodiments the alkynyl is C2, C2-C3, C2-C4, C2-C5, or C2-C6. In certain embodiments, examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl. In certain embodiments, the term “alkynyl” also encompasses cycloalkyl or carbocyclic groups having at least one point of triple bond unsaturation. In certain embodiments the term “CNS” refers to a component of the central nervous system including, for example, the brain, brain stem, peripheral nervous system, cerebral spinal fluid, spinal cord, leptomeninges, epidural space, myelin, thalamus, hypothalamus, pituitary gland, hippocampus, cerebellum, cerebrum, midbrain, pons, frontal lobe, temporal lobe, and / or dura. II. METHODS OF TREATING EGFR MEDIATED DISORDERS WITH COMPOUNDS OF FORMULA I, II, HI, AND IV The invention provides methods of using compounds of Formulas I, II, III, and IV. El:    In certain embodiments the invention is a method of treating a patient with an 5               EGFR mediated cancer that has metastasized to the brain, central nervous system, peripheral nervous system, cerebral spinal fluid, spinal cord, leptomeninges, epidural space, and / or dura comprising administering an effective amount of an EGFR degrading compound of Formula: or a pharmaceutically acceptable salt, isotope, N-oxide, stereoisomer thereof, optionally as part of a pharmaceutical composition, to a patient in need thereof; wherein A* is selected from: B* is heteroaryl or aryl each of which is optionally substituted with 1, 2, or 3 R31 substituents; y is 0, 1, 2, or 3; R31 is independently selected at each occurrence from H, halogen (F, Cl, Br, or I), Ci-6-alkyl, cyano, Ci-6-alkoxy, halo-Ci-6-alkoxy, halo-Ci-6-alkyl, C3-8-cycloalkyl, and halo-C3-8-cycloalkyl and can be located on either ring where present on a bicycle; R32 is hydrogen, halogen (F, Cl, Br, or I), Ci-6-alkyl, halo-Ci-6-alkyl, C3-8-cycloalkyl, or halo-Cs-s-cycloalkyl; R33 is hydrogen, halogen (F, Cl, Br, or I), Ci-6-alkyl, halo-Ci-6-alkyl, C3-8-cycloalkyl, or halo-C3-8-cycloalkyl and can be located on the dihydropyrrole or imidazole ring; R34 is independently selected at each occurrence from H, F, Ci-6-alkyl, halo-Ci-6-alkyl, C3-8-cycloalkyl, and halo-C3-8-cycloalkyl; R35 is independently selected at each occurrence from H, halogen (F, Cl, Br, or I), Ci-6-alkyl, halo-Ci-6-alkyl, and C3-8-cycloalkyl; or R34 and R35 combine to form -(CH2)q-; q is 1 or 2; R36 and R37 are independently selected from H, halogen (F, Cl, Br, or I), cyano, Ci-6-alkoxy, halo-Ci-6-alkoxy, Ci-6-alkyl, halo-Ci-6-alkyl, C3-8-cycloalkyl, and halo-C3-8-cycloalkyl; or R36 and R37 together are combined to form a 5- or 6- membered cycle optionally substituted with 1, 2, or 3 R31 substituents; R90 is H, Ci-6-alkyl, or C3-6-cycloalkyl; Ring G is a heteroaryl optionally substituted with 1 or 2 R42 substituents; A21 is -NH-, -O-, -CH2-, or -NR100-; R100 is alkyl, cycloalkyl, aryl, or heteroaryl; or as allowed by valence R100 may combine with R37 to form a 5-8 membered heterocycle or 5 membered heteroaryl; A32, A33, A34, and A35 are independently selected from -N- and -CR42-; R42 is independently selected at each occurrence from H, halogen (F, Cl, Br, or I), cyano, Ci-6-alkoxy, halo-Ci-6-alkoxy, Ci-6-alkyl, halo-Ci-6-alkyl, Cs-s-cycloalkyl, and halo-Cs-s-cycloalkyl; A36 is -N- or -CR35-; L2 is a bivalent linking group that connects A* and either the isoindolinone or indazole. E2:    The method of embodiment 1, wherein the EGFR degrading compound is selected from: or a pharmaceutically acceptable salt thereof. E3:    The method of embodiment 1, wherein the EGFR degrading compound is selected from: or a pharmaceutically acceptable salt thereof. E4:    The method of any one of embodiments 1-3, wherein R33 is H. E5:    The method of any one of embodiments 1-3, wherein R33 is F. E6:    The method of any one of embodiments 1-5, wherein y is 1. E7:    The method of any one of embodiments 1-5, wherein y is 2. E8:    The method of any one of embodiments 1-7, wherein at least one R31 is halo. E9:    The method of any one of embodiments 1-7, wherein at least one R31 is F. E10:    The method of any one of embodiments 1-3, wherein y is 0. El 1:    The method of any one of embodiments 1-9, wherein R32 is H. E12:    The method of any one of embodiments 1-9, wherein R32 is F. 5      El 3:    The method of embodiment 1, wherein the EGFR degrading compound is selected from: 10 E14:    The method of embodiment 1, wherein the EGFR degrading compound is selected from: E15:    The method of any one of embodiments 1-14, wherein A* is: E16:    The method of any one of embodiments 1-14, wherein A* is: 10 El 7:    The method of any one of embodiments 1-16, wherein A34 is CH. El 8:    The method of any one of embodiments 1-16, wherein A34 is N. E19:    The method of any one of embodiments 1-16, wherein A34 is CR42. E20:    The method of any one of embodiments 1-16, wherein A34 is CF. E21:    The method of any one of embodiments 1-20, wherein A35 is CH. E22:    The method of any one of embodiments 1-20, wherein A35 is N. E23:    The method of any one of embodiments 1-20, wherein A35 is CR42. E24:    The method of any one of embodiments 1-20, wherein A35 is CF. E25:    The method of any one of embodiments 1-14, wherein A* is: O E26:    The method of any one of embodiments 1-14, wherein A* is: o E27:    The method of any one of embodiments 25 or 26, wherein A21 is NH. E28:    The method of any one of embodiments 25 or 26, wherein A21 is O. E29:    The method of any one of embodiments 1-14, wherein A* is: r34            r37      r36 E30:    The method of any one of embodiments 1-29, wherein A32 is CH. E31:    The method of any one of embodiments 1-29, wherein A32 is N. E32:    The method of any one of embodiments 1-29, wherein A32 is CR42. E33:    The method of any one of embodiments 1-29, wherein A32 is CF. E34:    The method of any one of embodiments 1-33, wherein A33 is CH. E35:    The method of any one of embodiments 1-33, wherein A33 is N. E36:    The method of any one of embodiments 1-33, wherein A33 is CR42. E37:    The method of any one of embodiments 1-33, wherein A33 is CF. E38:    The method of any one of embodiments 1-14, wherein A* is: R34 O E39:    The method of embodiments 38, wherein A21 is NH. E40:    The method of embodiments 38, wherein A21 is O. E41:    The method of any one of embodiments 1-40, wherein R34 is H. E42:    The method of any one of embodiments 1-40, wherein R34 is F. E43:    The method of any one of embodiments 1-40, wherein R34 is CH3. E44:    The method of any one of embodiments 1-43, wherein R35 is H. E45:    The method of any one of embodiments 1-43, wherein R35 is F. E46:    The method of any one of embodiments 1-43, wherein R35 is CH3. E47:    The method of any one of embodiments 1-40, wherein R34 and R35 combine to form a -CH2-. E48:    The method of any one of embodiments 1-47, wherein R31 is independently selected at each instance from H, halogen (F, Cl, Br, or I), and Ci-6-alkyl. E49:    The method of any one of embodiments 1-47, wherein R42 is independently selected at each instance from H, halogen (F, Cl, Br, or I), and Ci-6-alkyl. E50:    The method of any one of embodiments 1-49, wherein B* is E51:    The method of any one of embodiments 1-49, wherein B* is E52:    The method of any one of embodiments 1-49, wherein B* is E53:    The method of any one of embodiments 1-49, wherein B* is E54:    The method of any one of embodiments 1-53, wherein L2 is of formula: wherein, X1 and X2 are independently at each occurrence selected from bond, heterocycle, aryl, heteroaryl, bicycle, alkyl, aliphatic, heteroaliphatic, -NR27-, -CR40R41-, -O-, -C(O)-, -C(NR27)-, -C(S)-, -S(O)-, -S(O)2- and -S-; each of which heterocycle, aryl, heteroaryl, and bicycle is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R40; R20, R21, R22, R23, and R24 are independently at each occurrence selected from the group consisting of a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR27-, -NR27C(O)-, -O-, -S-, -NR27-, oxyalkylene, -C(R40R40)-, -P(O)(OR26)O-, -P(O)(OR26)-, bicycle, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, and carbocycle; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R40; R26 is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocycle, aliphatic and heteroaliphatic; R27 is independently at each occurrence selected from the group consisting of hydrogen, alkyl, aliphatic, heteroaliphatic, heterocycle, aryl, heteroaryl, -C(O)(aliphatic, aryl, heteroaliphatic or heteroaryl), -C(O)O(aliphatic, aryl, heteroaliphatic, or heteroaryl), alkene, and alkyne; R40 is independently at each occurrence selected from the group consisting of hydrogen, R27, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH(aliphatic), -N(aliphatic)2, -NHSO2(aliphatic), -N(aliphatic)SO2alkyl, -NHSO2(aryl, heteroaryl or heterocycle), -N(alkyl)SO2(aryl, heteroaryl or heterocycle), -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocycle, oxo, and cycloalkyl; additionally, where allowed by valence two R40 groups bound to the same carbon may be joined together to form a 3-8 membered spirocycle; and R41 is aliphatic, aryl, heteroaryl, or hydrogen. E55:    The method of any one of embodiments 1-54, wherein L2 is of formula: ^R23  ^R21  ^x2 or E56:    The method of embodiment 54 or 55, wherein X1 is bond. E57:    The method of embodiment 54 or 55, wherein X1 is heterocycle. E58:    The method of embodiment 54 or 55, wherein X1 is NR2. E59:    The method of embodiment 54 or 55, wherein X1 is C(O). E60:    The method of any one of embodiments 54 to 59, wherein X2 is bond. E61:    The method of any one of embodiments 54 to 59, wherein X2 is heterocycle. E62:    The method of any one of embodiments 54 to 59, wherein X2 is NR2. E63:    The method of any one of embodiments 54 to 59, wherein X2 is C(O). E64:    The method of any one of embodiments 54 to 63, wherein R20 is bond. E65:    The method of any one of embodiments 54 to 63, wherein R20 is CH2. E66:    The method of any one of embodiments 54 to 63, wherein R20 is heterocycle. E67: The method of any one of embodiments 54 to 63, wherein R20 is aryl. E68: The method of any one of embodiments 54 to 63, wherein R20 is phenyl. E69: The method of any one of embodiments 54 to 63, wherein R20 is bicycle. E70: The method of any one of embodiments 54 to 69, wherein R21 is bond. E71: The method of any one of embodiments 54 to 69, wherein R21 is CH2. E72: The method of any one of embodiments 54 to 69, wherein R21 is heterocycle. E73: The method of any one of embodiments 54 to 69, wherein R21 is aryl. E74: The method of any one of embodiments 54 to 69, wherein R21 is phenyl. E75: The method of any one of embodiments 54 to 69, wherein R21 is bicycle. E76: The method of embodiment 54, wherein Lisa linker of formula: A \r23  A E77: The method of any one of embodiments 54 to 76, wherein R22 is bond. E78: The method of any one of embodiments 54 to 76, wherein R22 is CH2. E79: The method of any one of embodiments 54 to 76, wherein R22 is heterocycle. E80: The method of any one of embodiments 54 to 76, wherein R22 is aryl. E81: The method of any one of embodiments 54 to 76, wherein R22 is phenyl. E82: The method of any one of embodiments 54 to 76, wherein R22 is bicycle. E83: The method of any one of embodiments 54 to 69, wherein Lisa linker of formula: r2^    Y AT ^R23^ E84: The method of any one of embodiments 54 to 83, wherein R23 is bond. E85: The method of any one of embodiments 54 to 83, wherein R23 is CH2. E86: The method of any one of embodiments 54 to 83, wherein R23 is heterocycle. E87: The method of any one of embodiments 54 to 83, wherein R23 is aryl. E88: The method of any one of embodiments 54 to 83, wherein R23 is phenyl. E89: The method of any one of embodiments 54 to 83, wherein R23 is bicycle. E90: The method of any one of embodiments 54 to 89, wherein R24 is bond. E91: The method of any one of embodiments 54 to 89, wherein R24 is CH2. E92: The method of any one of embodiments 54 to 89, wherein R24 is heterocycle. E93: The method of any one of embodiments 54 to 89, wherein R24 is aryl. E94: The method of any one of embodiments 54 to 89, wherein R24 is phenyl. E95: The method of any one of embodiments 54 to 89, wherein R24 is bicycle. E96: The method of any one of embodiments 54 to 89, wherein R24 is C(O). E97: The method of any one of embodiments 1-96, wherein the patient is a human. E98: The method of any one of embodiments 1-97, wherein the cancer is lung cancer. E99: The method of embodiment 98, wherein the lung cancer is non-small cell lung cancer. E100: The method of any one of embodiments 1-99, wherein the cancer has an EGFR protein with at least one mutation. E101: The method of any one of embodiments 1-100, wherein the cancer has an EGFR protein with the L858R mutation. E102: The method of any one of embodiments 1-101, wherein the cancer has an EGFR protein with the T790M mutation. E103: The method of any one of embodiments 1-102, wherein the cancer has an EGFR protein with the C797S mutation. E104: The method of any one of embodiments 1-103, wherein the cancer has an EGFR protein with the L792H mutation. E105: The method of any one of embodiments 1-104, wherein the cancer has an EGFR protein with the L718Q mutation. E106: The method of any one of embodiments 1-105, wherein the cancer has an EGFR protein with the L858R-T790M mutation. E107: The method of any one of embodiments 1-106, wherein the cancer has an EGFR protein with the L858R-T790M-C797S mutation. E108: The method of any one of embodiments 1-107, wherein the cancer has an EGFR protein with the L858R-C797S mutation. E109: The method of any one of embodiments 1-108, wherein an additional EGFR inhibitor is administered. E110: The method of embodiment 109, wherein the additional EGFR inhibitor is a tyrosine kinase inhibitor. El 11: The method of embodiment 109, wherein the additional EGFR inhibitor is osimertinib. E112: The method of embodiment 109, wherein the additional EGFR inhibitor is rociletinib. E113: The method of embodiment 109, wherein the additional EGFR inhibitor is avitinib. El 14: The method of embodiment 109, wherein the additional EGFR inhibitor is lazertinib. El 15: The method of embodiment 109, wherein the additional EGFR inhibitor is nazartinib. El 16: The method of embodiment 109, wherein the additional EGFR inhibitor is an antibody to a mutated form of EGFR. El 17: The method of embodiment 109, wherein the additional EGFR inhibitor is cetuximab. El 18: The method of embodiment 109, wherein the additional EGFR inhibitor is panitumab. El 19: The method of embodiment 109, wherein the additional EGFR inhibitor is necitumab. E120:    The method of any one of embodiments 1-119, wherein a MET inhibitor is also administered. E121:    The method of any one of embodiments 1-120, wherein the patient receives an additional chemotherapeutic agent. El22:    The method of any one of embodiments 1-121, wherein the EGFR degrading compound is: or a pharmaceutically acceptable salt thereof. E123: The method of any one of embodiments 1-121, wherein the EGFR degrading compound is: or a pharmaceutically acceptable salt thereof. 5     E124: The method of any one of embodiments 1-121, wherein the EGFR degrading compound is: or a pharmaceutically acceptable salt thereof. E125:    The method of any one of embodiments 1-121, wherein the EGFR degrading 10 compound is: or a pharmaceutically acceptable salt thereof. E126: The method of any one of embodiments 1-121, wherein the EGFR degrading compound is: or a pharmaceutically acceptable salt thereof. 5     E127: The method of any one of embodiments 1-121, wherein the EGFR degrading compound is: or a pharmaceutically acceptable salt thereof. E128:    The method of any one of embodiments 1-121, wherein the EGFR degrading 10 compound is: or a pharmaceutically acceptable salt thereof. E129:    The method of any one of embodiments 1-121, wherein the EGFR degrading compound is: or a pharmaceutically acceptable salt thereof. 5     E130: The method of any one of embodiments 1-121, wherein the EGFR degrading compound is: or a pharmaceutically acceptable salt thereof. E131:    The method of any one of embodiments 1-121, wherein the EGFR degrading 10 or a pharmaceutically acceptable salt thereof. E132:    The method of any one of embodiments 1-121, wherein the EGFR degrading compound is: or a pharmaceutically acceptable salt thereof. 5     E133: The method of any one of embodiments 1-121, wherein the EGFR degrading compound is: or a pharmaceutically acceptable salt thereof. E134:    The method of any one of embodiments 1-121, wherein the EGFR degrading 10               compound is described herein. E135:    The method of any one of embodiments 1-121, wherein the EGFR degrading compound is described in Table 8, Table 9A, or Table 9B. 1. In certain embodiments a method of treating an EGFR mediated cancer that has metastasized to the brain or CNS comprising administering an effective amount of a Compound selected from: or a pharmaceutically acceptable salt thereof to a patient in need thereof is provided; wherein A* is selected from: B* is heteroaryl or aryl each of which is optionally substituted with 1, 2, or 3 R31 substituents; y is 0, 1, 2, or 3; R31 is independently selected at each occurrence from H, halogen (F, Cl, Br, or I), Ci-6-alkyl, cyano, Ci-6-alkoxy, halo-Ci-6-alkoxy, halo-Ci-6-alkyl, C3-8-cycloalkyl, and halo-C3-8-cycloalkyl and can be located on either ring where present on a bicycle; R32 is hydrogen, halogen (F, Cl, Br, or I), Ci-6-alkyl, halo-Ci-6-alkyl, C3-8-cycloalkyl, or halo-Cs-s-cycloalkyl; R33 is hydrogen, halogen (F, Cl, Br, or I), Ci-6-alkyl, halo-Ci-6-alkyl, C3-8-cycloalkyl, or halo-C3-8-cycloalkyl and can be located on the dihydropyrrole or imidazole ring; R34 is independently selected at each occurrence from H, F, Ci-6-alkyl, halo-Ci-6-alkyl, C3-8-cycloalkyl, and halo-C3-8-cycloalkyl; R35 is independently selected at each occurrence from H, halogen (F, Cl, Br, or I), Ci-6-alkyl, halo-Ci-6-alkyl, and C3-8-cycloalkyl; or R34 and R35 combine to form -(CH2)q-; q is 1 or 2; R36 and R37 are independently selected from H, halogen (F, Cl, Br, or I), cyano, Ci-6-alkoxy, halo-Ci-6-alkoxy, Ci-6-alkyl, halo-Ci-6-alkyl, C3-8-cycloalkyl, and halo-C3-8-cycloalkyl; or R36 and R37 together are combined to form a 5- or 6- membered cycle optionally substituted with 1, 2, or 3 R31 substituents; R90 is H, Ci-6-alkyl, or C3-6-cycloalkyl; Ring G is a heteroaryl optionally substituted with 1 or 2 R42 substituents; A21 is -NH-, -O-, -CH2-, or -NR100-; R100 is alkyl, cycloalkyl, aryl, or heteroaryl; or as allowed by valence R100 may combine with R37 to form a 5-8 membered heterocycle or 5 membered heteroaryl; A32, A33, A34, and A35 are independently selected from -N- and -CR42-; R42 is independently selected at each occurrence from H, halogen (F, Cl, Br, or I), cyano, Ci-6-alkoxy, halo-Ci-6-alkoxy, Ci-6-alkyl, halo-Ci-6-alkyl, Cs-s-cycloalkyl, and halo-Cs-s-cycloalkyl; A36 is -N- or -CR35-; L2 is a bivalent linking group that connects A* and either the isoindolinone or indazole. 2. The method of embodiment 1, wherein L2 is of formula: v. / r2< / r2< / r2< yC ^X1   ^R23  ^R21   ^X2  (LI). wherein, X1 and X2 are independently at each occurrence selected from bond, heterocycle, aryl, heteroaryl, bicycle, alkyl, aliphatic, heteroaliphatic, -NR27-, -CR40R41-, -O-, -C(O)-, -C(NR27)-, -C(S)-, -S(O)-, -S(O)2- and -S-; each of which heterocycle, aryl, heteroaryl, and bicycle is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R40; R20, R21, R22, R23, and R24 are independently at each occurrence selected from the group consisting of a bond, alkyl, -C(O)-, -C(O)O-, -00(0)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR27-, -NR27C(O)-, -0-, -S-, -NR27-, oxyalkylene, -C(R40R40)-, -P(O)(OR26)O-, -P(O)(OR26)-, bicycle, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, and carbocycle; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R40; R26 is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocycle, aliphatic and heteroaliphatic; R27 is independently at each occurrence selected from the group consisting of hydrogen, alkyl, aliphatic, heteroaliphatic, heterocycle, aryl, heteroaryl, -C(O)(aliphatic, aryl, heteroaliphatic or heteroaryl), -C(O)O(aliphatic, aryl, heteroaliphatic, or heteroaryl), alkene, and alkyne; R40 is independently at each occurrence selected from the group consisting of hydrogen, R27, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH(aliphatic), -N(aliphatic)2, -NHSO2(aliphatic), -N(aliphatic)SO2alkyl, -NHSO2(aryl, heteroaryl or heterocycle), -N(alkyl)SO2(aryl, heteroaryl or heterocycle), -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocycle, oxo, and cycloalkyl; additionally, where allowed by valence two R40 groups bound to the same carbon may be joined together to form a 3-8 membered spirocycle; and R41 is aliphatic, aryl, heteroaryl, or hydrogen. 5         3. The method of embodiment 1, wherein the Compound is selected from Table 9A and Table 9B. 10 4. In certain embodiments a method of treating an EGFR mediated cancer that has metastasized to the brain or CNS comprising administering an effective amount of a Compound selected from: or a pharmaceutically acceptable salt thereof, to a patient in need thereof is provided. 5. In certain embodiments a method of treating an EGFR mediated cancer that has metastasized to the brain or CNS comprising administering an effective amount of 5             a Compound of structure: or a pharmaceutically acceptable salt thereof, to a patient in need thereof is provided. 6. In certain embodiments a method of treating an EGFR mediated cancer that has metastasized to the brain or CNS comprising administering an effective amount of 10             a Compound of structure: or a pharmaceutically acceptable salt thereof, to a patient in need thereof is provided. 7. In certain embodiments a method of treating an EGFR mediated cancer that has metastasized to the brain or CNS comprising administering an effective amount of a Compound of structure: 5 or a pharmaceutically acceptable salt thereof, to a patient in need thereof is provided. 8. In certain embodiments a method of treating an EGFR mediated cancer that has metastasized to the brain or CNS comprising administering an effective amount of a Compound of structure: 10 or a pharmaceutically acceptable salt thereof, to a patient in need thereof is provided. 9. In certain embodiments a method of treating an EGFR mediated cancer that has metastasized to the brain or CNS comprising administering an effective amount of 5 or a pharmaceutically acceptable salt thereof, to a patient in need thereof is provided. 10. In certain embodiments a method of treating an EGFR mediated cancer that has metastasized to the brain or CNS comprising administering an effective amount of a Compound of structure: 10 or a pharmaceutically acceptable salt thereof, to a patient in need thereof is provided. 11. In certain embodiments a method of treating an EGFR mediated cancer that has metastasized to the brain or CNS comprising administering an effective amount of a Compound of structure: 15 or a pharmaceutically acceptable salt thereof, to a patient in need thereof is provided. 12. In certain embodiments a method of treating an EGFR mediated cancer that has metastasized to the brain or CNS comprising administering an effective amount of a Compound of structure: HN > <r 5 or a pharmaceutically acceptable salt thereof, to a patient in need thereof is provided. 13. In certain embodiments a method of treating an EGFR mediated cancer that has metastasized to the brain or CNS comprising administering an effective amount of a Compound of structure: 10 or a pharmaceutically acceptable salt thereof, to a patient in need thereof is provided. 14. In certain embodiments a method of treating an EGFR mediated cancer that has metastasized to the brain or CNS comprising administering an effective amount of a Compound of structure: 5 or a pharmaceutically acceptable salt thereof, to a patient in need thereof is provided. 15. In certain embodiments a method of treating an EGFR mediated cancer that has metastasized to the brain or CNS comprising administering an effective amount of 10   or a pharmaceutically acceptable salt thereof, to a patient in need thereof is provided. 16. In certain embodiments a method of treating an EGFR mediated cancer that has metastasized to the brain or CNS comprising administering an effective amount of a Compound of structure: or a pharmaceutically acceptable salt thereof, to a patient in need thereof is provided. 17. The method of any one of embodiments 1-16, wherein the patient is a human. 18. The method of any one of embodiments 1-17, wherein the EGFR mediated cancer is mediated by a mutant EGFR. 19. The method of embodiment 18, wherein the mutant EGFR has an Exon 21 mutation. 20. The method of embodiment 19, wherein the mutant EGFR has a L858R mutation. 21. The method of embodiment 19, wherein the mutant EGFR has a L861Q mutation. 22. The method of any one of embodiments 18-21, wherein mutant EGFR has a T790M mutation. 23. The method of any one of embodiments 18-22, wherein mutant EGFR has a C797S mutation. 24. The method of embodiment 18, wherein the mutant EGFR has a L858R and T790M mutation. 25. The method of embodiment 18, wherein the mutant EGFR has a L858R, T790M, and C797S mutation. 26. The method of any one of embodiments 1-25, wherein the Compound is administered as part of a pharmaceutical composition. 27. The method of any one of embodiments 1-26, wherein the Compound is administered orally. 28. The method of any one of embodiments 1-26, wherein the Compound is administered parenterally. 29. The method of any one of embodiments 1-26, wherein the Compound is administered by intravenously. 30. The method of any one of embodiments 1-29, wherein an ATP site binding EGFR ligand is also administered to the patient in need thereof. 31. The method of embodiment 30, wherein the ATP site binding EGFR ligand is osimertinib or a pharmaceutically acceptable salt thereof. 32. The method of embodiment 30, wherein the ATP site binding EGFR ligand is naquotinib or a pharmaceutically acceptable salt thereof. 33. The method of embodiment 30, wherein the ATP site binding EGFR ligand is mavelertinib or a pharmaceutically acceptable salt thereof. 34. The method of embodiment 30, wherein the ATP site binding EGFR ligand is spebrutinib or a pharmaceutically acceptable salt thereof. 35. The method of any one of embodiments 1-34, wherein the EGFR mediated cancer is lung cancer that has metastasized to the brain or CNS. 36. The method of any one of embodiments 1-34, wherein the EGFR mediated cancer is non-small cell lung cancer that has metastasized to the brain or CNS. 37. The method of any one of embodiments 1-34, wherein the EGFR mediated cancer is small cell lung cancer that has metastasized to the brain or CNS. 38. The method of any one of embodiments 1-34, wherein the EGFR mediated cancer is adenocarcinoma that has metastasized to the brain or CNS. 39. The method of any one of embodiments 1-34, wherein the EGFR mediated cancer is squamous cell lung cancer that has metastasized to the brain or CNS. 40. The method of any one of embodiments 1-34, wherein the EGFR mediated cancer is large-cell undifferentiated carcinoma that has metastasized to the brain or CNS. 41. The method of any one of embodiments 1-34, wherein the EGFR mediated cancer is neuroendocrine carcinoma that has metastasized to the brain or CNS. 42. The method of any one of embodiments 1-34, wherein the EGFR mediated cancer is sarcomatoid carcinoma, adenosquamous carcinoma, oat-cell cancer, combined small cell carcinoma, lung carcinoid tumor, central carcinoid, peripheral carcinoid, salivary gland-type lung carcinoma, mesothelioma, or a mediastinal tumor that has metastasized to the brain or CNS. 43. The method of any one of embodiments 1-34, wherein the EGFR mediated cancer is breast cancer that has metastasized to the brain or CNS. 44. The method of embodiment 43, wherein the EGFR mediated cancer is HER-2 positive breast cancer. 45. The method of embodiment 43 or 44, wherein the EGFR mediated cancer is ER+ breast cancer. 46. The method of any one of embodiments 43-45, wherein the EGFR mediated cancer is PR+ breast cancer. 47. The method of any one of embodiments 1-34, wherein the EGFR mediated cancer is triple negative breast cancer. 48. The method of any one of embodiments 1-34, wherein the EGFR mediated cancer is colorectal or rectal cancer that has metastasized to the brain or CNS. 49. The method of any one of embodiments 1-34, wherein the EGFR mediated cancer is head and neck cancer or esophageal cancer that has metastasized to the brain or CNS. 50. The method of any one of embodiments 1-34, wherein the EGFR mediated cancer is pancreatic cancer that has metastasized to the brain or CNS. 51. The method of any one of embodiments 1-34, wherein the EGFR mediated cancer is thyroid cancer that has metastasized to the brain or CNS. 52. The method of any one of embodiments 1-34, wherein the EGFR mediated cancer is ovarian cancer, uterine cancer, or cervical cancer that has metastasized to the brain or CNS. 53. The method of any one of embodiments 1-34, wherein the EGFR mediated cancer is kidney cancer, liver cancer, or bladder cancer that has metastasized to the brain or CNS. 54. The method of any one of embodiments 1-34, wherein the EGFR mediated cancer is melanoma that has metastasized to the brain or CNS. 55. The method of any one of embodiments 1-54, wherein the EGFR mediated cancer has metastasized to the brain. 56. The method of any one of embodiments 1-54, wherein the EGFR mediated cancer has metastasized to the CNS. 57. The method of any one of embodiments 1-56, wherein the Compound is administered to a patient with treatment naive EGFR mediated cancer. 58. The method of any one of embodiments 1-56, wherein the EGFR mediated cancer is relapsed. 59. The method of any one of embodiments 1-56, wherein the EGFR mediated cancer is refractory. 60. The method of any one of embodiments 1-56, wherein the EGFR mediated cancer is relapsed and refractory. 61. In certain embodiments the use of a Compound described herein (for example a Compound used in any one of embodiments 1-60) for the manufacture of a medicament to treat a disorder described herein (for example a disorder of any one of embodiments 1-60) is provided. 62. In certain embodiments the use of a Compound described herein (for example a Compound used in any one of embodiments 1-60) in the treatment of a disorder described herein (for example a disorder of any one of embodiments 1-60) is provided. 63. In certain embodiments the Compound described herein (for example a Compound used in any one of embodiments 1-60) for use in the treatment of a disorder described herein (for example a disorder of any one of embodiments 1-60) is provided. Additional Embodiments of the Present Invention Chirality Embodiments The compounds described herein may have multiple stereocenters (e.g., chiral carbon atoms) including for example one or more stereocenters in the E3 ligase binding moiety (for R34 example          ° or          O ), one or more stereocenters in the linker, and / or at least one stereocenter in the EGFR binding ligand moiety of the molecule (e.g. ). In certain embodiments, the EGFR-degrading compound described herein is provided without regard to stereochemistry. In other embodiments, the EGFR-degrading compound may have one or more chiral carbons presented in an enantiomerically enriched (i.e., greater than about 50%, 60%, 70%, 80% or 90% pure) or even substantially pure form (greater than about 95%, 98% or 99% pure) of R and S stereochemistry. In certain aspects, the EGFR-degrading compound has two enantiomerically enriched and / or substantially pure stereocenters. In one sub-aspect of this, the two enantiomerically enriched and / or substantially pure stereocenters are located in the ligase-binding moiety of the compound and the linker; or alternatively there are two in the linker. In another sub-aspect, there are three enantiomerically enriched and / or substantially pure stereocenters, with one in the ligase-binding moiety of the compound and two in the linker. In yet another sub-aspect of this, there are three enantiomerically enriched and / or substantially pure stereocenters, with one in the ligase-binding moiety of the compound and two in the linker. In another aspect, in any of these embodiments, aspects or sub-aspects, in addition, the EGFR binding ligand moiety is enantiomerically enriched or in substantially pure form. It has been observed that in some embodiments, the chiral carbon in the EGFR binding ligand moiety adjacent to the amide may easily racemize between stereoisomers under the conditions of use, and therefore in certain embodiments, is not considered for purposes of stereochemistry designation. In certain embodiments one stereocenter is in the R configuration and any others present are either enantiomerically enriched or substantially pure. In certain embodiments one stereocenter is in the S configuration and any others present are either enantiomerically enriched or substantially pure. In certain embodiments one stereocenter is in the R configuration and any others present are without regard to stereochemistry, enantiomerically enriched or substantially pure. In certain embodiments one stereocenter is in the S configuration and any others present are without regard to stereochemistry, enantiomerically enriched or substantially pure. In certain embodiments there is one stereocenter in the E3 ligase binding moiety (disregarding the stereocenter in the EGFR binding ligand moiety) and it is enantiomerically enriched or substantially pure in the R-configuration, as indicated below. In another embodiment there is one stereocenter in the E3 ligase binding moiety (disregarding the stereocenter in the EGFR binding ligand moiety) and it is enantiomerically enriched or substantially pure in the S-configuration, as indicated below. In certain embodiments wherein R34 is hydrogen. R34 In certain embodiments          O hydrogen. In certain embodiments In certain embodiments there is one stereocenter in the linker portion and it is a mixture of R- and S-configuration. In another embodiment there is one stereocenter in the linker portion and it is enantiomerically enriched or substantially pure R-configuration. In another embodiment there is one stereocenter in the linker portion and it is enantiomerically enriched or substantially pure S-configuration. In certain embodiments the linker contains one or more moieties with a chiral center. Non-limiting examples include heterocycle with an enantiomerically enriched or substantially pure stereocenter for example piperidine with a substituent meta- or ortho to the nitrogen or linking in the meta- or ortho- configuration; piperazine with a substituent or linking in the meta-or ortho- configuration; pyrrolidinone with or without a substituent; and pyrrolidine with or without a substituent. Additional non-limiting examples of linker moieties with at least one chiral center include an alkyl with an enantiomerically enriched or substantially pure stereocenter; an alkene with an enantiomerically enriched or substantially pure stereocenter; an alkyne with an enantiomerically  enriched  or substantially pure  stereocenter; a haloalkyl  with  an enantiomerically  enriched  or substantially pure  stereocenter; an alkoxy  with  an enantiomerically enriched or substantially pure stereocenter; an aliphatic group with an enantiomerically enriched or substantially pure stereocenter; a heteroaliphatic group with an 5 enantiomerically enriched or substantially pure stereocenter; and a cycloalkyl with an enantiomerically enriched or substantially pure stereocenter In certain embodiments the linker includes R40 In certain embodiments the linker includes In certain embodiments the linker includes or In certain embodiments the linker includes 15 In certain embodiments the linker includes In certain embodiments the linker includes In certain embodiments the linker includes In certain embodiments the linker includes R40       R40 |— / ^N—I  pN N-| In certain embodiments the linker includes     — /   * or    \— / R40       r40 pl / \|-| p / \l—I In certain embodiments the linker includes \’ or    \— / In certain embodiments the linker includes In certain embodiments the linker includes In certain embodiments the linker includes In certain embodiments, there is at least one stereocenter in the EGFR ligand portion which is a mixture of R and S. In another embodiment there is at least one stereocenter in the EGFR ligand portion and it is enantiomerically enriched or substantially pure in the R- configuration. In another embodiment there is at least one stereocenter in the EGFR ligand 10 portion and it is enantiomerically enriched or substantially pure in the S-configuration. In certain embodiments In certain embodiments In certain embodiments is              , wherein R33 is hydrogen. , wherein R33 is hydrogen. Embodiments of alkyl In certain embodiments “alkyl” is a Ci-Cioalkyl, Ci-Cgalkyl, Ci-Csalkyl, Ci-C?alkyl, Ci-C6alkyl, Ci-C5alkyl, Ci-C4alkyl, Ci-C3alkyl, or Ci-C2alkyl. 10          In certain embodiments “alkyl” has one carbon. In certain embodiments “alkyl” has two carbons. In certain embodiments “alkyl” has three carbons. In certain embodiments “alkyl” has four carbons. In certain embodiments “alkyl” has five carbons. 15          In certain embodiments “alkyl” has six carbons. Non-limiting examples of “alkyl” include: methyl, ethyl, propyl, butyl, pentyl, and hexyl. Additional non-limiting examples of “alkyl” include: isopropyl, isobutyl, isopentyl, and isohexyl. Additional non-limiting examples of “alkyl” include: sec-butyl, sec-pentyl, and sec-hexyl. Additional non-limiting examples of “alkyl” include: tert-butyl, tert-pentyl, and tert-hexyl. Additional non-limiting examples of “alkyl” include: neopentyl, 3-pentyl, and active pentyl. In an alternative embodiment “alkyl” is “optionally substituted” with 1, 2, 3, or 4 R31 substituents. Embodiments of cycloalkyl In certain embodiments “cycloalkyl” is a C3-Cscycloalkyl, C3-C?cycloalkyl, C3-Cecycloalkyl, Cs-Cscycloalkyl, C3-C4cycloalkyl, C4-Cscycloalkyl, Cs-Cscycloalkyl, or Ce-Cscycloalkyl. In certain embodiments “cycloalkyl” has three carbons. In certain embodiments “cycloalkyl” has four carbons. In certain embodiments “cycloalkyl” has five carbons. In certain embodiments “cycloalkyl” has six carbons. In certain embodiments “cycloalkyl” has seven carbons. In certain embodiments “cycloalkyl” has eight carbons. In certain embodiments “cycloalkyl” has nine carbons. In certain embodiments “cycloalkyl” has ten carbons. Non-limiting examples of “cycloalkyl” include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl. In an alternative embodiment “cycloalkyl” is “optionally substituted” with 1, 2, 3, or 4 R31 substituents. Embodiments of haloalkyl In certain embodiments “haloalkyl” is a Ci-Ciohaloalkyl, Ci-Cghaloalkyl, Ci-Cshaloalkyl, Ci-C?haloalkyl, Ci-Cehaloalkyl, Ci-Cshaloalkyl, Ci-C4haloalkyl, Ci-Cshaloalkyl, and Ci-C2haloalkyl. In certain embodiments “haloalkyl” In certain embodiments “haloalkyl” In certain embodiments “haloalkyl” In certain embodiments “haloalkyl” In certain embodiments “haloalkyl” In certain embodiments “haloalkyl” In certain embodiments “haloalkyl” In certain embodiments “haloalkyl” In certain embodiments “haloalkyl” has one carbon. has one carbon and one halogen. has one carbon and two halogens. has one carbon and three halogens has two carbons. has three carbons. has four carbons. has five carbons. has six carbons. Non-limiting examples of “haloalkyl” include:        F , and F Additional non-limiting examples of “haloalkyl” include: Cl „ Cl ci^_ >4- ci^4 Additional non-limiting examples of “haloalkyl” include: ^~,CI    , and Cl U eV Additional non-limiting examples of “haloalkyl” include: Cl    , Cl , and Cl Embodiments of heterocycle In certain embodiments “heterocycle” refers to a cyclic ring with one nitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms. In certain embodiments “heterocycle” refers to a cyclic ring with one nitrogen and one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms. In certain embodiments “heterocycle” refers to a cyclic ring with two nitrogens and 3, 4, 5, 6, 7, or 8 carbon atoms. In certain embodiments “heterocycle” refers to a cyclic ring with one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms. In certain embodiments “heterocycle” refers to a cyclic ring with one sulfur and 3, 4, 5, 6, 7, or 8 carbon atoms. Non-limiting examples of “heterocycle” include aziridine, oxirane, thiirane, azetidine, 1,3-diazetidine, oxetane, andthietane. Additional non-limiting examples of “heterocycle” include pyrrolidine, 3-pyrroline, 2-pyrroline, pyrazolidine, and imidazolidine. Additional non-limiting examples of “heterocycle” include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane. Additional non-limiting examples of “heterocycle” include piperidine, piperazine, tetrahydropyran, 1,4-di oxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine. Additional non-limiting examples of “heterocycle” include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran wherein the point of attachment for each group is on the heterocycle ring. Non-limiting examples of “heterocycle” also include: Additional non-limiting examples of “heterocycle” include: Non-limiting examples of “heterocycle” also include: Non-limiting examples of “heterocycle” also include: Additional non-limiting examples of “heterocycle” include: Additional non-limiting examples of “heterocycle” include: ‘°       \ I I , and '“O . In an alternative embodiment “heterocycle” is “optionally substituted” with 1, 2, 3, or 4 R31 substituents. Embodiments of heteroaryl In certain embodiments “heteroaryl” is a 5 membered aromatic group containing 1, 2, 3, or 4 nitrogen atoms. Non-limiting examples of 5 membered “heteroaryl” groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, and thiatriazole. Additional non-limiting examples of 5 membered “heteroaryl” groups include: In certain embodiments “heteroaryl” is a 6 membered aromatic group containing 1, 2, or 3 nitrogen atoms (i.e., pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl). Non-limiting examples of 6 membered “heteroaryl” groups with 1 or 2 nitrogen atoms include: In certain embodiments “heteroaryl” is a 9 membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur. Non-limiting examples of “heteroaryl” groups that are bicyclic include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole, benzoisothiazole, benzooxazole, and benzothiazole. Additional non-limiting examples of “heteroaryl” groups that are bicyclic include: Additional non-limiting examples of “heteroaryl” groups that are bicyclic include: In certain embodiments “heteroaryl” is a 10 membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur. Non-limiting examples of “heteroaryl” groups that are bicyclic include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine. Additional non-limiting examples of “heteroaryl” groups that are bicyclic include: In an alternative embodiment “heteroaryl” is “optionally substituted” with 1, 2, 3, or 4 R31 substituents. Embodiments of aryl In certain embodiments aryl is phenyl. In certain embodiments aryl is napthyl. In an alternative embodiment “aryl” is “optionally substituted” with 1, 2, 3, or 4 R31 substituents. Embodiments of bicycle The term “bicycle” refers to a ring system wherein two rings share at least one atom in common. These rings can be spirocyclic or fused together and each ring is independently selected from carbocycle, heterocycle, aryl, and heteroaryl. Non-limiting examples of bicycle groups include: When the term “bicycle” is used in the context of a bivalent residue such as Linker the attachment points can be on separate rings or on the same ring. In certain embodiments both attachment points are on the same ring. In certain embodiments both attachment points are on different rings. Non-limiting examples of bivalent bicycle groups include: In an alternative embodiment “bicycle” is “optionally substituted” with 1, 2, 3, or 4 R31 substituents. Embodiments of optional substituents In certain embodiments wherein a variable can be optionally substituted it is not substituted. In certain embodiments wherein a variable can be optionally substituted it is substituted with 1 substituent. In certain embodiments wherein a variable can be optionally substituted it is substituted with 2 substituents. In certain embodiments wherein a variable can be optionally substituted it is substituted with 3 substituents. In certain embodiments wherein a variable can be optionally substituted it is substituted with 4 substituents. In one alternative embodiment any suitable group may be present on a “substituted” or “optionally substituted” position if indicated that forms a stable molecule and meets the desired purpose of the invention and includes, but is not limited to, e.g., halogen (which can independently be F, Cl, Br or I); cyano; hydroxyl; nitro; azido; alkanoyl (such as a C2-C6 alkanoyl group); carboxamide; alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy such as phenoxy; thioalkyl including those having one or more thioether linkages; alkyl sulfinyl; alkylsulfonyl groups including those having one or more sulfonyl linkages; aminoalkyl groups including groups having more than one N atoms; aryl (e.g., phenyl, biphenyl, naphthyl, or the like, each ring either substituted or unsubstituted); arylalkyl having for example, 1 to 3 separate or fused rings and from 6 to about 14 or 18 ring carbon atoms, with benzyl being an exemplary arylalkyl group; arylalkoxy, for example, having 1 to 3 separate or fused rings with benzyloxy being an exemplary arylalkoxy group; or a saturated or partially unsaturated heterocycle having 1 to 3 separate or fused rings with one or more N, O or S atoms, or a heteroaryl having 1 to 3 separate or fused rings with one or more N, O or S atoms, e.g. coumarinyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, and pyrrolidinyl. Such groups may be further substituted, e.g. with hydroxy, alkyl, alkoxy, halogen and amino. Embodiments of Aliphatic and Heteroaliphatic In certain embodiments “aliphatic” refers to a saturated or unsaturated, straight, branched, or cyclic hydrocarbon. In these embodiments aliphatic is intended to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, and thus incorporates each of these definitions. In certain embodiments, "aliphatic" is used to indicate those aliphatic groups having 1-20 carbon atoms. The aliphatic chain can be, for example, mono-unsaturated, di-unsaturated, tri-unsaturated, or polyunsaturated, or alkynyl. Unsaturated aliphatic groups can be in a cis or trans configuration. In certain embodiments, the aliphatic group contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms. In certain embodiments, the aliphatic group contains from 1 to about 8 carbon atoms. In certain embodiments, the aliphatic group is Ci-C2, C1-C3, C1-C4, C1-C5 or Ci-Ce. The specified ranges as used herein indicate an aliphatic group having each member of the range described as an independent species. For example, the term Ci-Ce aliphatic as used herein indicates a straight or branched alkyl, alkenyl, or alkynyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species. For example, the term C1-C4 aliphatic as used herein indicates a straight or branched alkyl, alkenyl, or alkynyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species. In certain embodiments, the aliphatic group is substituted with one or more functional groups that results in the formation of a stable moiety. In certain embodiments "heteroaliphatic" refers to an aliphatic moiety that contains at least one heteroatom in the chain, for example, an amine, carbonyl, carboxy, oxo, thio, phosphate, phosphonate, nitrogen, phosphorus, silicon, or boron atoms in place of a carbon atom. In certain embodiments, the only heteroatom is nitrogen. In certain embodiments, the only heteroatom is oxygen. In certain embodiments, the only heteroatom is sulfur. In certain embodiments “heteroaliphatic" is intended herein to include, but is not limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl moieties. In certain embodiments, "heteroaliphatic" is used to indicate a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-20 carbon atoms. In certain embodiments, the heteroaliphatic group is optionally substituted in a manner that results in the formation of a stable moiety. Nonlimiting examples of heteroaliphatic moieties are polyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide, polyglycolide, thioether, ether, alkyl-heterocycle-alkyl, -O-alkyl-O-alkyl, alkyl-O-haloalkyl, etc. Embodiments of A and A* In certain embodiments A* is In certain embodiments A* is In certain embodiments A* is In certain embodiments A* is In certain embodiments A* is In certain embodiments A* is O In certain embodiments R34 and R35 combine to form a CH2. In certain embodiments R34 is H. In certain embodiments R35 is H. In certain embodiments A1 is NH. In certain embodiments A1 is O. In certain embodiments A21 is NH. In certain embodiments A21 is O. In certain embodiments A21 is CH2. In certain embodiments A21 is NR100. In certain embodiments A32, A33, A34, and A35 are each selected from CH, C-halogen, and CF. In certain embodiments A32 is CH. In certain embodiments A32 is CF. In certain embodiments A32 is CR42. In certain embodiments A32 is N. In certain embodiments A33 is CH. In certain embodiments A33 is CF. In certain embodiments A33 is CR42. In certain embodiments A33 is N. In certain embodiments A34 is CH. In certain embodiments A34 is CF. In certain embodiments A34 is CR42. In certain embodiments A34 is N. In certain embodiments A35 is CH. In certain embodiments A35 is CF. In certain embodiments A35 is CR42. In certain embodiments A35 is N. In certain embodiments A36 is N. In certain embodiments R90 is hydrogen. In certain embodiments R90 is C1-C3 alkyl. In certain embodiments R90 is C3-6-cycloalkyl. In certain embodiments R90 is methyl. AF In certain embodiments A or A* is In certain embodiments A or A* is In certain embodiments A or A* is AG In certain embodiments, A or A* is selected from: In certain embodiments B or B* is In certain embodiments B or B* is In certain embodiments B* is heteroaryl. 10          In certain embodiments B* is heteroaryl substituted with one R31 group. In certain embodiments B* is aryl. In certain embodiments B* is aryl substituted with one R31 group. In certain embodiments B* is In certain embodiments B* is 15 In certain embodiments B* is In certain embodiments B* is In certain embodiments B* is In certain embodiments B* is Embodiments of y In certain embodiments y is 0. In certain embodiments y is 1. In certain embodiments y is 2. In certain embodiments y is 3. Embodiments of R31 In certain embodiments at least one R31 is halogen. In certain embodiments at least one R31 is F. In certain embodiments at least one R31 is Cl. In certain embodiments at least one R31 is Ci-6-alkyl. In certain embodiments at least one R31 is halo-Ci-6-alkyl. In certain embodiments one R31 is halogen. In certain embodiments one R31 is F. In certain embodiments one R31 is Cl. In certain embodiments one R31 is Ci-6-alkyl. In certain embodiments one R31 is cyano. In certain embodiments one R31 is Ci-6-alkoxy. In certain embodiments one R31 is halo-Ci-6-alkoxy. In certain embodiments one R31 is Cs-s-cycloalkyl. In certain embodiments one R31 is halo-Cs-s-cycloalkyl. In certain embodiments R31 is selected from halogen, Ci-6-alkoxy, and Ci-6-alkyl. In certain embodiments R31 is selected from F, Cl, methoxy, and methyl. Embodiments of R36 and R37 In certain embodiments R36 and R37 together are combined to form a 5-membered cycle optionally substituted with 1, 2, or 3 R31 substituents. In certain embodiments R36 and R37 together are combined to form a 6-membered cycle optionally substituted with 1, 2, or 3 R31 substituents. In certain embodiments R36 and R37 together are combined to form a 5-membered cycloalkyl optionally substituted with 1, 2, or 3 R31 substituents. In certain embodiments R36 and R37 together are combined to form a 6-membered cycloalkyl optionally substituted with 1, 2, or 3 R31 substituents. In certain embodiments R36 and R37 together are combined to form a 5-membered heteroaryl optionally substituted with 1, 2, or 3 R31 substituents. In certain embodiments R36 and R37 together are combined to form a 6-membered heteroaryl optionally substituted with 1, 2, or 3 R31 substituents. In certain embodiments R36 and R37 together are combined to form a 5-membered heterocycle optionally substituted with 1, 2, or 3 R31 substituents. In certain embodiments R36 and R37 together are combined to form a 6-membered heterocycle optionally substituted with 1, 2, or 3 R31 substituents. In certain embodiments R36 and R37 together are combined to form a morpholine optionally substituted with 1, 2, or 3 R31 substituents. In certain embodiments R36 and R37 together are combined to form phenyl optionally substituted with 1, 2, or 3 R31 substituents. In certain embodiments the cycle formed by combining R36 and R37 is not substituted. In certain embodiments the cycle formed by combining R36 and R37 is substituted with 1 R31 substituent. In certain embodiments the cycle formed by combining R36 and R37 is substituted with 2 R31 substituents. In certain embodiments the cycle formed by combining R36 and R37 is substituted with 3 R31 substituents. In certain embodiments R36 is hydrogen. In certain embodiments R36 is halogen. In certain embodiments R36 is F. In certain embodiments R36 is Cl. In certain embodiments R36 is Ci-6-alkyl. In certain embodiments R36 is cyano. In certain embodiments R36 is Ci-6-alkoxy. In certain embodiments R36 is halo-Ci-6-alkoxy. In certain embodiments R36 is Cs-s-cycloalkyl. In certain embodiments R36 is halo-Cs-s-cycloalkyl. In certain embodiments R36 is selected from hydrogen, halogen, Ci-6-alkoxy, and Ci-6-alkyl. In certain embodiments R36 is selected from hydrogen, F, Cl, methoxy, and methyl. In certain embodiments R37 is hydrogen. In certain embodiments R37 is halogen. In certain embodiments R37 is F. In certain embodiments R37 is Cl. In certain embodiments R37 is Ci-6-alkyl. In certain embodiments R37 is cyano. In certain embodiments R37 is Ci-6-alkoxy. In certain embodiments R37 is halo-Ci-6-alkoxy. In certain embodiments R37 is Cs-s-cycloalkyl. In certain embodiments R37 is halo-Cs-s-cycloalkyl. In certain embodiments R37 is selected from hydrogen, halogen, Ci-6-alkoxy, and Ci-6-alkyl. In certain embodiments R37 is selected from hydrogen, F, Cl, methoxy, and methyl. Embodiments of R42 In certain embodiments at least one R42 is halogen. In certain embodiments at least one R42 is F. In certain embodiments at least one R42 is Cl. In certain embodiments at least one R42 is Ci-6-alkyl. In certain embodiments at least one R42 is halo-Ci-6-alkyl. In certain embodiments R42 is hydrogen. In certain embodiments R42 is halogen. In certain embodiments R42 is F. In certain embodiments R42 is Cl. In certain embodiments R42 is Ci-6-alkyl. In certain embodiments R42 is cyano. In certain embodiments R42 is Ci-6-alkoxy. In certain embodiments R42 is halo-Ci-6-alkoxy. In certain embodiments R42 is Cs-s-cycloalkyl. In certain embodiments R42 is halo-Cs-s-cycloalkyl. In certain embodiments R42 is selected from hydrogen, halogen, Ci-6-alkoxy, and Ci-6- alkyl. In certain embodiments R42 is selected from hydrogen, F, Cl, methoxy, and methyl. Embodiments of Ring G In certain embodiments Ring G is a 5-membered heteroaryl ring optionally substituted with 1 or 2 R42 substituents. In certain embodiments Ring G is a 6-membered heteroaryl ring optionally substituted with 1 or 2 R42 substituents. In certain embodiments Ring G is selected from: Embodiments of EGER Targeting Ligand In certain embodiments the compound for use in the methods of treatment described herein is selected from: 5 In certain embodiments the compound for use in the methods of treatment described herein is selected from: In certain embodiments the compound for use in the methods of treatment described herein is selected from: In certain embodiments the compound for use in the methods of treatment described herein is selected from: In certain embodiments the compound for use in the methods of treatment described 5 herein is selected from: and Compounds of Formula III Compounds of Formula IV In certain embodiments the compound for use in the methods of treatment described 5 herein is selected from: III. ADDITIONAL COMPOUNDS FOR USE IN THE PRESENT INVENTION 5          In certain embodiments the compound for use in the methods of treatment described In certain embodiments the compound for use in the methods of treatment described In certain embodiments the compound for use in the methods of treatment described 5 herein is selected from: In certain embodiments the compound for use in the methods of treatment described herein is selected from: R33 R33 R33 R33 R33 5          In certain embodiments the compound for use in the methods of treatment described herein is selected from: F In certain embodiments the compound for use in the methods of treatment described herein is selected from: For Cl F or Cl In certain embodiments the compound for use in the methods of treatment described herein is selected from: In certain embodiments the compound for use in the methods of treatment described In certain embodiments the compound for use in the methods of treatment described herein is selected from: R33 R33 R33 R33 5          In certain embodiments the compound for use in the methods of treatment described herein is selected from: In certain embodiments the compound for use in the methods of treatment described In certain embodiments the compound for use in the methods of treatment described herein is selected from: In certain embodiments the compound for use in the methods of treatment described In certain embodiments the compound for use in the methods of treatment described herein is selected from: F In certain embodiments the compound for use in the methods of treatment described 5 herein is selected from: In certain embodiments the compound for use in the methods of treatment described 5 herein is selected from: In certain embodiments the compound for use in the methods of treatment described herein is selected from: In certain embodiments the compound for use in the methods of treatment described herein is selected from: In certain embodiments the compound for use in the methods of treatment described herein is selected from: 10 F In certain embodiments the compound for use in the methods of treatment described 5 herein is selected from: F In certain embodiments the compound for use in the methods of treatment described herein is selected from: O 5          In certain embodiments the compound for use in the methods of treatment described herein is selected from: In certain embodiments the compound for use in the methods of treatment described herein is selected from: In certain embodiments the compound for use in the methods of treatment described 5 herein is selected from: 5          In certain embodiments the compound for use in the methods of treatment described herein is selected from: 5          In certain embodiments the compound for use in the methods of treatment described herein is selected from: In certain embodiments the compound for use in the methods of treatment described herein is selected from: 5 IV. LINKERS A Linker (L1 or L2) or a bond is included in the compounds described herein. Linker is a chemically stable bivalent group that attaches an E3 Ligase binding portion to an EGFR Targeting Ligand. According to the invention, any desired linker, as described herein, can be 10 used as long as the resulting compound has a stable shelflife, for example at least 1 month, 2 months, 3 months, 6 months or 1 year as part of a pharmaceutically acceptable dosage form, and itself is pharmaceutically acceptable. Linker as described herein can be used in either direction, i.e., either the left end is linked to the E3 Ligase binding portion and the right end to the EGFR Targeting Ligand, or the 15 left end is linked to the EGFR Targeting Ligand and the right end is linked to the E3 Ligase binding portion. In certain embodiments Linker is a bond. In certain embodiments, the Linker has a chain of 2 to 14, 15, 16, 17, 18 or 20 or more carbon atoms of which one or more carbons can be replaced by a heteroatom such as O, N, S, or P. In certain embodiments the chain has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous atoms in the chain. For example, the chain may include 1 or more ethylene glycol units that can be contiguous, partially contiguous or non-contiguous (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ethylene glycol units). In certain embodiments the chain has at least 1, 2, 3, 4, 5, 6, 7, or 8 contiguous chains which can have branches which can be independently alkyl, aryl, heteroaryl, alkenyl, or alkynyl, aliphatic, heteroaliphatic, cycloalkyl or heterocycle substituents. In other embodiments, the linker can include or be comprised of one or more of ethylene glycol, propylene glycol, lactic acid and / or glycolic acid. Lactic acid segments tend to have a longer half-life than glycolic acid segments. Block and random lactic acid-co-glycolic acid moieties, as well as ethylene glycol and propylene glycol, are known in the art to be pharmaceutically acceptable and can be modified or arranged to obtain the desired half-life and hydrophilicity. In certain aspects, these units can be flanked or interspersed with other moieties, such as aliphatic, including alkyl, heteroaliphatic, aryl, heteroaryl, heterocycle, cycloalkyl, etc., as desired to achieve the appropriate drug properties. In certain embodiments, L2 is a linker selected from: In one aspect, Linker (L2) is selected from the group consisting of a moiety of Formula LI, Formula LII, Formula LIII, Formula LIV, Formula LV, Formula LVI, Formula LVII Formula LVIII, Formula IX and Formula LX: (LVII), Heterocyclyl ^R21 (LVIII), Heterocyclyl Xx2 (LIX), and Heterocyclyl r22      r20 R23^ ^R21^ ^X2   (LX); wherein all variables are as defined herein. In certain embodiments, Linker (L2) is selected from: In one aspect, Linker (L2) is selected from the group consisting of a moiety of Formula LDI, Formula LDII, Formula LDIII, Formula LDIV, Formula LDV, Formula LDVI, and Formula LDVII: Heteroaryl xx2 Heteroaryl ^R21' (LDII), (LDIII), Heterocyclyl Xx2 (LDV), (LDVI), and ^Heterocyclyl ^R^° R23         ^R21   ^X2 (LDVII), wherein all variables are described herein. The following are non-limiting examples of Linkers that can be used in this invention. Based on this elaboration, those of skill in the art will understand how to use the full breadth of Linkers that will accomplish the goal of the invention. In certain embodiments L2 is selected from: Additional non-limiting examples of moi eties of R20, R21, R22, R23, and R24 include: Additional non-limiting examples of moi eties of R20, R21, R22, R23, and R24 include: In additional embodiments, the Linker (L2) moiety is an optionally substituted (poly)ethylene glycol having at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, ethylene glycol units, or optionally substituted alkyl groups interspersed with optionally substituted, O, N, S, P or Si atoms. In certain embodiments, the Linker (L2) is flanked, substituted, or interspersed with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocycle group. In certain embodiments, the Linker (L2) may be asymmetric or symmetrical. In certain embodiments, Linker (L2) can be a nonlinear chain, and can be, or include, aliphatic or aromatic or heteroaromatic cyclic moieties. In any of the embodiments of the compounds described herein, the Linker group may be any suitable moiety as described herein. In certain embodiments, the Linker (L2) is selected from the group consisting of: In certain embodiments, the linker (L2) is selected from the group consisting of: In certain embodiments linker (L2) or a portion thereof is selected from: V. METHODS OF TREATMENT A compound described herein can be used in an effective amount to treat a patient, in need thereof, or to treat any disorder mediated by EGFR. Another aspect described herein provides a compound as described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition, for use in the manufacture of a medicament for treating or preventing cancer in a patient in need thereof; wherein there is a need of EGFR inhibition for the treatment or prevention of cancer. In one aspect, a compound described herein is used to treat an EGFR mediated cancer, wherein the EGFR has mutated from the wild-type. There are a number of possibilities for EGFR mutations. In certain non-limiting embodiments, the mutation is found in exon 18, exon 19, exon 20, or exon 21, or any combination thereof. In certain nonlimiting embodiments, the mutation is at position L858, E709, G719, C797, L861, T790, or L718 or any combination thereof. In certain embodiments the mutation is a L858R, T790M, L718Q, L792H, and / or a C797S mutation or any combination thereof. In certain aspects, the cancer has developed one or more EGFR mutations following treatment with at least one EGFR inhibitor that can be a non-covalent inhibitor (including but not limited to gefitinib, erlotinib, lapatinib or vandetanib) or a covalent inhibitor (such as afatinib, osimertinib or dacomitinib). In another aspect, the cancer has developed one or more EGFR mutations following treatment with an antibody such as cetuximab, panitumab or necitumab. In yet another aspect, the cancer has one or more EGFR mutations or non-EGFR mutations that renders the cancer intrinsically resistant to EGFR inhibitor treatment, for example, a somatic exon 20 insertion, asomatic PIK3CA mutation, loss of PTEN expression, MET amplification, or a KRAS mutation. In certain embodiments, a compound described herein is used to treat a cancer that is resistant to, or has acquired a resistance to, a first generation EGFR inhibitor such as erlotinib, gefitinib, and / or lapatinib. In certain embodiments, a compound described herein is used to treat a cancer that is resistant to, or has acquired a resistance to a second generation EGFR inhibitor such as afatinib and / or dacomitinib. In certain embodiments, a compound described herein is used to treat a cancer that is resistant to, or acquired a resistance to a third generation EGFR inhibitor such as osimertinib. In one aspect, a compound described herein is used to treat an EGFR mediated cancer that has metastasized to the brain or CNS, wherein the EGFR has mutated from the wild-type. There are a number of possibilities for EGFR mutations. In certain non-limiting embodiments, the mutation is found in exon 18, exon 19, exon 20, or exon 21, or any combination thereof. In certain nonlimiting embodiments, the mutation is at position L858, E709, G719, C797, L861, T790, or L718 or any combination thereof. In certain embodiments the mutation is a L858R, T790M, L718Q, L792H, and / or a C797S mutation or any combination thereof. In certain embodiments, a compound described herein is used to treat a cancer that has metastasized to the brain or CNS that is resistant to, or has acquired a resistance to, a first generation EGFR inhibitor such as erlotinib, gefitinib, and / or lapatinib. In certain embodiments, a compound described herein is used to treat a cancer that has metastasized to the brain or CNS that is resistant to, or has acquired a resistance to a second generation EGFR inhibitor such as afatinib and / or dacomitinib. In certain embodiments, a compound described herein is used to treat a cancer that has metastasized to the brain or CNS that is resistant to, or acquired a resistance to a third generation EGFR inhibitor such as osimertinib. In some embodiments, the mutated EGFR protein in the diseased tissue has an L858 mutation, for example L858R. In certain embodiments a compound described herein is used to treat a mutant EGFR mediated disorder in the brain or CNS or a mutant EGFR-mediated cancer that has metastasized to the brain or CNS, wherein EGFR has a mutation of at least one of the below listed amino acid sites, or a combination thereof. The mutation may, for example, be selected from one of the listed exemplary mutations, or may be a different mutation. Amino Acid Exemplary Mutations C797 C797S E709 E709A, E709G, E709K, E709V G719 G719A, G719S, G719C, G719D G724 G724S G119 G119A G796 G796S, G796C L718 L718V, L718Q L792 L792H; L792V L858 L858R L861 L861Q S768 S768I T790 T790M In certain embodiments the mutant EGFR-mediated disorder in the brain or CNS or the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has two mutations selected from the table above. In other embodiments the mutant EGFR-mediated disorder in the brain or CNS or the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has three mutations selected from the table above. In other embodiments the mutant EGFR-mediated disorder in the brain or CNS or the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has four or more mutations, which may optionally be selected from the table above. In certain embodiments the mutant EGFR-mediated disorder in the brain or CNS or the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has an L858R mutation and one additional mutation which may optionally be selected from the table above. In some of these embodiments the mutant EGFR-mediated disorder in the brain or CNS or the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has an L858R mutation and two additional mutation that may optionally be selected from the table above. In other embodiments the mutant EGFR-mediated disorder in the brain or CNS or the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has a L858R mutation and three additional mutation that may optionally be selected from the table above. In certain embodiments the mutant EGFR-mediated disorder in the brain or CNS or the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has a T790M mutation and one additional mutation optionally selected from the table above. In other embodiments the mutant EGFR-mediated disorder in the brain or CNS or the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has a T790M mutation and two additional mutation optionally selected from the table above. In other embodiments the mutant EGFR-mediated disorder in the brain or CNS or the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has a T790M mutation and three additional mutation optionally selected from the table above. In certain embodiments the mutant EGFR-mediated disorder in the brain or CNS or the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has a L718Q mutation and one additional mutation optionally selected from the table above. In other embodiments the mutant EGFR-mediated disorder in the brain or CNS or the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has a L718Q mutation and two additional mutation optionally selected from the table above. In other embodiments the mutant EGFR-mediated disorder in the brain or CNS or the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has a L718Q mutation and three additional mutation optionally selected from the table above. In certain embodiments the mutant EGFR-mediated disorder in the brain or CNS or the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has a mutation of S768I, L718V, L792H, L792V, G796S, G796C, G724S, and / or G719A. In certain embodiments, a compound described herein is used to treat a mutant EGFR-mediated disorder in the brain or CNS or a mutant EGFR-mediated cancer that has metastasized to the brain or CNS that has a frameshift mutation, for example a short in-frame deletion. In certain embodiments, a compound described herein is used to treat a mutant EGFR-mediated disorder in the brain or CNS or a mutant EGFR-mediated cancer that has metastasized to the brain or CNS wherein the EGFR has an exon 19 deletion. In certain embodiments, the exon 19 deletion is a deletion which includes the amino acids LREA (L747-A750). In certain embodiments, the exon 19 deletion is a deletion which includes the amino acids ELREA (E746-A750). In certain embodiments a compound described herein is used to treat a mutant EGFR-mediated disorder in the brain or CNS or a mutant EGFR-mediated cancer that has metastasized to the brain or CNS wherein the EGFR has an L858R mutation in exon 21. In certain embodiments a compound described herein is more active against a disorder driven by a mutated EGFR than wild-type EGFR. In certain embodiments, a compound described herein is used to treat EGFR-mediated cancer that has metastasized to the brain or CNS wherein the EGFR has one or more exon 18 deletions. In certain embodiments a compound described herein is used to treat a mutant EGFR-mediated disorder in the brain or CNS or a mutant EGFR-mediated cancer that has metastasized to the brain or CNS with a E709 mutation, for example E709A, E709G, E709K, or E709V. In certain embodiments a compound described herein is used to treat a mutant EGFR-mediated disorder in the brain or CNS or a mutant EGFR-mediated cancer that has metastasized to the brain or CNS with a L718 mutation, for example L718Q. In certain embodiments a compound described herein is used to treat a mutant EGFR-mediated disorder in the brain or CNS or a mutant EGFR-mediated cancer that has metastasized to the brain or CNS with a G719 mutation, for example G719S, G719A, G719C, or G719D. In certain embodiments, a compound described herein is used to treat a mutant EGFR-mediated disorder in the brain or CNS or a mutant EGFR-mediated cancer that has metastasized to the brain or CNS wherein the EGFR has one or more exon 19 insertions and / or one or more exon 20 insertions. In certain embodiments, a compound described herein is used to treat a S7681 mutant EGFR-mediated disorder in the brain or CNS or a S7681 mutant EGFR-mediated cancer that has metastasized to the brain or CNS. In certain embodiments a compound described herein is used to treat a L861Q mutant EGFR-mediated disorder in the brain or CNS or a EGFR L861Q mutant EGFR-mediated cancer that has metastasized to the brain or CNS. In certain embodiments, a compound described herein is used to treat C797S mutant EGFR-mediated cancer that has metastasized to the brain or CNS. In certain embodiments a compound described herein is used to treat a L858R-T790M mutant EGFR-mediated disorder in the brain or CNS. In certain embodiments a compound described herein is used to treat a L858R- L718Q mutant EGFR-mediated disorder in the brain or CNS. In certain embodiments a compound described herein is used to treat a L858R-L792H mutant EGFR-mediated disorder in the brain or CNS. In certain embodiments a compound described herein is used to treat a L858R-C797S mutant EGFR-mediated disorder in the brain or CNS. In certain embodiments a compound described herein is used to treat a L858R-T790M mutant EGFR-mediated cancer that has metastasized to the brain or CNS. In certain embodiments a compound described herein is used to treat a L858R- L718Q mutant EGFR-mediated cancer that has metastasized to the brain or CNS. In certain embodiments a compound described herein is used to treat a L858R-L792H mutant EGFR-mediated cancer that has metastasized to the brain or CNS. In certain embodiments a compound described herein is used to treat a L858R-C797S mutant EGFR-mediated cancer that has metastasized to the brain or CNS. In certain embodiments, the EGFR mediated cancer that has metastasized to the brain or CNS is a hematological cancer. In certain embodiments, the EGFR mediated cancer that has metastasized to the brain or CNS is acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), lymphoblastic T-cell leukemia, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), hairy-cell leukemia, chronic neutrophilic leukemia (CNL), acute lymphoblastic T-cell leukemia, acute monocytic leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, mixed lineage leukemia (MLL), erythroleukemia, malignant lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, lymphoblastic T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, B cell acute lymphoblastic leukemia, diffuse large B cell lymphoma, Myc and B-Cell Leukemia (BCL)2 and / or BCL6 rearrangements / overexpression [double- and triple-hit lymphoma], myelodysplastic / myeloproliferative neoplasm, mantle cell lymphoma including bortezomib resistant mantle cell lymphoma. Additional EGFR mediated cancer that has metastasized to the brain or CNS that can be treated with the compounds described herein include, but are not limited to lung cancers, including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), breast cancers including inflammatory breast cancer, ER-positive breast cancer including tamoxifen resistant ER-positive breast cancer, and triple negative breast cancer, colon cancers, midline carcinomas, liver cancers, renal cancers, prostate cancers including castrate resistant prostate cancer (CRPC), brain cancers including gliomas, glioblastomas, neuroblastoma, and medulloblastoma including MYC-amplified medulloblastoma, colorectal cancers, Wilm's tumor, Ewing's sarcoma, rhabdomyosarcomas, ependymomas, head and neck cancers, melanomas, squamous cell carcinomas, ovarian cancers, pancreatic cancers including pancreatic ductal adenocarcinomas (PDAC) and pancreatic neuroendocrine tumors (PanNET), osteosarcomas, giant cell tumors of bone, thyroid cancers, bladder cancers, urothelial cancers, vulval cancers, cervical cancers, endometrial cancers, mesotheliomas, esophageal cancers, salivary gland cancers, gastric cancesr, nasopharangeal cancers, buccal cancers, cancers of the mouth, GIST (gastrointestinal stromal tumors), NUT-midline carcinomas, testicular cancers, squamous cell carcinomas, hepatocellular carcinomas (HCC), MYCN driven solid tumors, and NUT midline carcinomas (NMC). In further embodiments, the cancer that has metastasized to the brain or CNS is sarcoma of the bones, muscles, tendons, cartilage, nerves, fat, or blood vessels. In further embodiments, the cancer that has metastasized to the brain or CNS is soft tissue sarcoma, bone sarcoma, or osteosarcoma. In further embodiments, the cancer that has metastasized to the brain or CNS is angiosarcoma, fibrosarcoma, liposarcoma, leiomyosarcoma, Karposi's sarcoma, osteosarcoma, gastrointestinal stromal tumor, synovial sarcoma, pleomorphic sarcoma, chondrosarcoma, Ewing's sarcoma, reticulum cell sarcoma, meningiosarcoma, botryoid sarcoma, rhabdomyosarcoma, or embryonal rhabdomyosarcoma. In certain embodiments the cancer that has metastasized to the brain or CNS is a bone, muscle, tendon, cartilage, nerve, fat, or blood vessel sarcoma. In further embodiments, the cancer that has metastasized to the brain or CNS is multiple myeloma. In certain embodiments a compound described herein or a pharmaceutically acceptable salt thereof is used as a medicament in therapeutic and / or prophylactic treatment of a patient with EGFR activating mutations as determined by next-generation sequencing (NGS), suffering from cancer, in particular non-small-cell lung cancer, comprising determining the EGFR activating mutations status in said patient and then administering the compound described herein, or a pharmaceutically acceptable salt thereof, to said patient. In other embodiments, the cancer that has metastasized to the brain or CNS is selected from lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreas cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck squamous cell carcinoma, leukemias, lymphomas, myelomas, solid tumors, hematological cancers or solid cancers. The term "cancer" refers to any cancer caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas and the like. For example, cancers include, but are not limited to, mesothelioma, leukemias and lymphomas such as cutaneous T-cell lymphomas (CTCL), noncutaneous peripheral T-cell lymphomas, lymphomas associated with human T-cell lymphotrophic virus (HTLV) such as adult T-cell leukemia / lymphoma (ATLL), B-cell lymphoma, acute nonlymphocytic leukemias, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, lymphomas, and multiple myeloma, non-Hodgkin lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), Hodgkin's lymphoma, Burkitt lymphoma, adult T-cell leukemia lymphoma, acute-myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma. Further examples include myelodisplastic syndrome, childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, and soft-tissue sarcomas, common solid tumors of adults such as head and neck cancers, such as oral, laryngeal, nasopharyngeal and esophageal, genitourinary cancers, such as prostate, bladder, renal, uterine, ovarian, testicular, lung cancer, such as small-cell and non-small cell, breast cancer, pancreatic cancer, melanoma and other skin cancers, stomach cancer, brain tumors, tumors related to Gorlin's syndrome, such as medulloblastoma or meningioma, and liver cancer. Additional exemplary forms of cancer include, but are not limited to, cancer of skeletal or smooth muscle, stomach cancer, cancer of the small intestine, rectum carcinoma, cancer of the salivary gland, endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer. Additional cancers that the compounds described herein may be useful in preventing, treating and studying are, for example, colon carcinoma, familiary adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer, or melanoma. Further, cancers include, but are not limited to, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, thyroid cancer (medullary and papillary thyroid carcinoma), renal carcinoma, kidney parenchyma carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, testis carcinoma, urinary carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, gall bladder carcinoma, bronchial carcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma, choroidea melanoma, seminoma, rhabdomyosarcoma, craniopharyngeoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma, and plasmocytoma. In one aspect of the application, the present application provides for the use of one or more compound as described herein, in the manufacture of a medicament for the treatment of cancer, including without limitation the various types of cancer disclosed herein. In some embodiments, a compound described herein is useful for treating cancer which has metastasized to the brain or CNS, such as colorectal, thyroid, breast, and lung cancer; and myeloproliferative disorders, such as polycythemia vera, thrombocythemia, myeloid metaplasia with myelofibrosis, chronic myelogenous leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndromejuvenile myelomonocytic leukemia, and systemic mast cell disease. In some embodiments, the compound as described herein is useful for treating hematopoietic disorders, in particular, acute-myelogenous leukemia (AML), chronic-myelogenous leukemia (CML), acute-promyelocytic leukemia, and acute lymphocytic leukemia (ALL). In certain embodiments, a compound described herein or its corresponding pharmaceutically acceptable salt, or isotopic derivative, as described herein can be used in an effective amount to treat a host with a cancer that has metastasized to the brain or CNS, for example a human, wherein the cancer that has metastasized to the brain or CNS is selected from a lymphoma or lymphocytic or myelocytic proliferation disorder or abnormality. For example, a compound as described herein can be administered to a host suffering from a Hodgkin’s Lymphoma or aNon-Hodgkin’s Lymphoma. For example, the host can be suffering from a Non-Hodgkin’s Lymphoma such as, but not limited to: an AIDS-Related Lymphoma; Anaplastic Large-Cell Lymphoma; Angioimmunoblastic Lymphoma; Blastic NK-Cell Lymphoma; Burkitt’s Lymphoma; Burkitt-like Lymphoma (Small Non-Cleaved Cell Lymphoma); diffuse small-cleaved cell lymphoma (DSCCL); Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma; Cutaneous T-Cell Lymphoma; Diffuse Large B-Cell Lymphoma; Enteropathy-Type T-Cell Lymphoma; Follicular Lymphoma; Hepatosplenic Gamma-Delta T-Cell Lymphoma; Lymphoblastic Lymphoma; Mantle Cell Lymphoma; Marginal Zone Lymphoma; Nasal T-Cell Lymphoma; Pediatric Lymphoma; Peripheral T-Cell Lymphomas; Primary Central Nervous System Lymphoma; T-Cell Leukemias; Transformed Lymphomas; Treatment-Related T-Cell Lymphomas; Langerhans cell histiocytosis; or Waldenstrom's Macroglobulinemia. In another embodiment, a compound described herein or its corresponding pharmaceutically acceptable salt, or isotopic derivative, as described herein can be used in an effective amount to treat a patient, for example a human, with a cancer that has metastazied to the brain or CNS selected from Hodgkin’s lymphoma, such as, but not limited to: Nodular Sclerosis Classical Hodgkin’s Lymphoma (CHL); Mixed Cellularity CHL; Lymphocytedepletion CHL; Lymphocyte-rich CHL; Lymphocyte Predominant Hodgkin’s Lymphoma; or Nodular Lymphocyte Predominant HL. This application further embraces the treatment or prevention of cell proliferative disorders such as hyperplasias, dysplasias and pre-cancerous lesions. Dysplasia is the earliest form of pre-cancerous lesion recognizable in a biopsy by a pathologist. The compounds may be administered for the purpose of preventing said hyperplasias, dysplasias or pre-cancerous lesions from continuing to expand or from becoming cancerous. Examples of pre-cancerous lesions may occur in skin, esophageal tissue, breast and cervical intra-epithelial tissue. As degraders of EGFR protein, the compounds and compositions of this application are also useful in biological samples. One aspect of the application is inhibiting protein activity in a biological sample, which method comprises contacting said biological sample with a compound or composition as described herein. The term "biological sample", as used herein, means an in vitro or an ex vivo sample, including, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. Inhibition of protein activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organtransplantation, and biological specimen storage. Another aspect of this application is the study of EGFR protein in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such proteins; and the comparative evaluation of new protein inhibitors. Examples of such uses include, but are not limited to, biological assays such as enzyme assays and cell-based assays. In accordance with the foregoing, the present application further provides a method for preventing or treating any of the diseases or disorders described above in a patient in need of such treatment, which method comprises administering to said patient a therapeutically effective amount of a compound as described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, or solvate thereof. For any of the above uses, the required dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired. VI. COMBINATION THERAPY The disclosed compounds described herein can be used in an effective amount alone or in combination with another compound described herein or another bioactive agent or second therapeutic agent to treat a patient such as a human with an EGFR-mediated cancer that has metastasized to the brain or CNS, including but not limited to those described herein. The term “bioactive agent” is used to describe an agent, other than the selected compound according to the present invention, which can be used in combination or alternation with a compound described herein to achieve a desired result of therapy. In certain embodiments, the compound described herein and the bioactive agent are administered in a manner that they are active in vivo during overlapping time periods, for example, have timeperiod overlapping Cmax, Tmax, AUC or another pharmacokinetic parameter. In another embodiment, the compound described herein and the bioactive agent are administered to a patient in need thereof that do not have overlapping pharmacokinetic parameter, however, one has a therapeutic impact on the therapeutic efficacy of the other. In one aspect of this embodiment, the bioactive agent is an immune modulator, including but not limited to a checkpoint inhibitor, including as non-limiting examples, a PD-1 inhibitor, PD-L1 inhibitor, PD-L2 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, TIM-3 inhibitor, V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, small molecule, peptide, nucleotide, or other inhibitor. In certain aspects, the immune modulator is an antibody, such as a monoclonal antibody. PD-1 inhibitors that blocks the interaction of PD-1 and PD-L1 by binding to the PD-1 receptor, and in turn inhibit immune suppression include, for example, nivolumab (OPDIVO®), pembrolizumab (KEYTRUDA®), pidilizumab, AMP-224 (AstraZeneca and Medlmmune), PF-06801591 (Pfizer), MED10680 (AstraZeneca), PDR001 (Novartis), REGN2810 (Regeneron), SHR-12-1 (Jiangsu Hengrui Medicine Company and Incyte Corporation), TSR-042 (GlaxoSmithKline plc), and the PD-L1 / VISTA inhibitor CA-170 (Curis Inc.). PD-L1 inhibitors that block the interaction of PD-1 and PD-L1 by binding to the PD-L1 receptor, and in turn inhibits immune suppression, include for example, atezolizumab (TECENTRIQ®), durvalumab (AstraZeneca and Medlmmune), KN035 (Alphamab Co. Ltd.), and BMS-936559 (Bristol-Myers Squibb). CTLA-4 checkpoint inhibitors that bind to CTLA-4 and inhibits immune suppression include, but are not limited to, ipilimumab, tremelimumab (AstraZeneca and Medlmmune), AGEN1884 and AGEN2041 (Agenus). LAG-3 checkpoint inhibitors include, but are not limited to, BMS-986016 (Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline plc), IMP321 (Prima BioMed), LAG525 (Novartis), and the dual PD-1 and LAG-3 inhibitor MGD013 (MacroGenics). An example of a TIM-3 inhibitor is TSR-022 (GlaxoSmithKline plc). In certain embodiments the checkpoint inhibitor is selected from nivolumab (OPDIVO®^ pembrolizumab (KEYTRUDA®); and pidilizumab / CT-011, MPDL3280A / RG7446; MEDI4736; MSB0010718C; BMS 936559, a PDL2 / lg fusion protein such as AMP 224 or an inhibitor of B7-H3 (e.g., MGA271 ), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG 3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1 , CHK2, A2aR, B-7 family ligands, or a combination thereof. In yet another embodiment, one of the active compounds described herein can be administered in an effective amount for the treatment of abnormal tissue of the female reproductive system such as breast, ovarian, endometrial, or uterine cancer, in combination or alternation with an effective amount of an estrogen inhibitor including, but not limited to, a SERM (selective estrogen receptor modulator), a SERD (selective estrogen receptor degrader), a complete estrogen receptor degrader, or another form of partial or complete estrogen antagonist or agonist. Partial anti-estrogens like raloxifene and tamoxifen retain some estrogen-like effects, including an estrogen-like stimulation of uterine growth, and also, in some cases, an estrogen-like action during breast cancer progression which actually stimulates tumor growth. In contrast, fulvestrant, a complete anti-estrogen, is free of estrogen-like action on the uterus and is effective in tarn oxifen-resistant tumors. Non-limiting examples of anti-estrogen compounds are provided in WO 2014 / 19176 assigned to Astra Zeneca, WO2013 / 090921, WO 2014 / 203129, WO 2014 / 203132, and US2013 / 0178445 assigned to Olema Pharmaceuticals, and U.S. Patent Nos. 9,078,871, 8,853,423, and 8,703, 810, as well as US 2015 / 0005286, WO 2014 / 205136, and WO 2014 / 205138. Additional non-limiting examples of anti-estrogen compounds include: SERMS such as anordrin, bazedoxifene, broparestriol, chlorotrianisene, clomiphene citrate, cyclofenil, lasofoxifene, ormeloxifene, raloxifene, tamoxifen, toremifene, and fulvestratnt; aromatase inhibitors such as aminoglutethimide, testolactone, anastrozole, exemestane, fadrozole, formestane, and letrozole; and antigonadotropins such as leuprorelin, cetrorelix, allyl estrenol, chloromadinone acetate, cyproterone acetate, delmadinone acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, nor ethisterone acetate, progesterone, and spironolactone. Other estrogenic ligands that can be used according to the present invention are described in U.S. Patent Nos. 4,418,068; 5,478,847; 5,393,763; and 5,457,117, WO2011 / 156518, US Patent Nos. 8,455,534 and 8,299,112, U.S. Patent Nos. 9,078,871; 8,853,423; 8,703,810; US 2015 / 0005286; and WO 2014 / 205138, US2016 / 0175289, US2015 / 0258080, WO 2014 / 191726, WO 2012 / 084711; WO 2002 / 013802; WO 2002 / 004418; WO 2002 / 003992; WO 2002 / 003991; WO 2002 / 003990; WO 2002 / 003989; WO 2002 / 003988; WO 2002 / 003986; WO 2002 / 003977; WO 2002 / 003976; WO 2002 / 003975; WO 2006 / 078834; US 6821989; US 2002 / 0128276; US 6777424; US 2002 / 0016340; US 6326392; US 6756401; US 2002 / 0013327; US 6512002; US 6632834; US 2001 / 0056099; US 6583170; US 6479535; WO 1999 / 024027; US 6005102; EP 0802184; US 5998402; US 5780497, US 5880137, WO 2012 / 048058 and WO 2007 / 087684. In another embodiment, active compounds described herein can be administered in an effective amount for the treatment of abnormal tissue of the male reproductive system such as prostate or testicular cancer, in combination or alternation with an effective amount of an androgen (such as testosterone) inhibitor including, but not limited to a selective androgen receptor modulator, a selective androgen receptor degrader, a complete androgen receptor degrader, or another form of partial or complete androgen antagonist. In certain embodiments, the prostate or testicular cancer is androgen-resistant. Non-limiting examples of anti-androgen compounds are provided in WO 2011 / 156518 and US Patent Nos. 8,455,534 and 8,299,112. Additional non-limiting examples of antiandrogen compounds include: enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topilutamide, abiraterone acetate, and cimetidine. In certain embodiments, the bioactive agent is an ALK inhibitor. Examples of ALK inhibitors include but are not limited to Crizotinib, Alectinib, ceritinib, TAE684 (NVP-TAE684), GSK1838705A, AZD3463, ASP3026, PF-06463922, entrectinib (RXDX-101), and AP26113. In certain embodiments, the bioactive agent is an HER-2 inhibitor. Examples of HER-2 inhibitors include trastuzumab, lapatinib, ado-trastuzumab emtansine, and pertuzumab. In certain embodiments, the bioactive agent is a CD20 inhibitor. Examples of CD20 inhibitors include obinutuzumab (GAZYVA®), rituximab (RITUXAN®), fatumumab, ibritumomab, tositumomab, and ocrelizumab. In certain embodiments, the bioactive agent is a JAK3 inhibitor. Examples of JAK3 inhibitors include tasocitinib. In certain embodiments, the bioactive agent is a BCL-2 inhibitor. Examples of BCL-2 inhibitors include venetoclax, ABT-199 (4-[4-[[2-(4-Chlorophenyl)-4,4-dimethylcyclohex-l- en-l-yl]methyl]piperazin-l-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4- yl)methyl]amino]phenyl]sulfonyl]-2-[(lH- pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-l-yl]-N-[4- [[(2R)-4-(dimethylamino)-l-phenylsulfanylbutan-2-yl] amino]-3- nitrophenyl]sulfonylbenzamide) (navitoclax), ABT-263 ((R)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[l, l'-biphenyl]-2-yl)methyl)piperazin-l-yl)-N-((4-((4-morpholino-l-(phenylthio)butan-2-yl)amino)-3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide), GX15-070 (obatoclax mesylate, (2Z)-2-[(5Z)-5-[(3,5-             dimethyl-lH-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2- ylidene]indole; methanesulfonic acid))), 2-methoxy-antimycin A3, YC137 (4-(4,9-dioxo-4,9-dihydronaphtho[2,3-d]thiazol-2-ylamino)-phenyl ester), pogosin, ethyl 2-amino-6-bromo-4-(l-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate, Nilotinib-d3, TW-37 (N-[4-[[2-(l,l-Dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4-trihydroxy-5-[[2-(l-methylethyl)phenyl]methyl]benzamide), Apogossypolone (ApoG2), HA14-1, AT101, sabutoclax, gambogic acid, or G3139 (oblimersen). In certain embodiments, the bioactive agent is a kinase inhibitor. In certain embodiments, the kinase inhibitor is selected from a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton’s tyrosine kinase (BTK) inhibitor, or a spleen tyrosine kinase (Syk) inhibitor, or a combination thereof. Examples of PI3 kinase inhibitors include, but are not limited to, Wortmannin, demethoxyviridin, perifosine, idelalisib, pictilisib , palomid 529, ZSTK474, PWT33597, CUDC-907, and AEZS-136, duvelisib, GS-9820, BKM120, GDC-0032 (Taselisib) (2-[4-[2-(2-Isopropyl-5 -methyl-1,2,4-tri azol-3 -yl)-5,6-dihydroimidazo[ 1,2-d] [ 1,4]benzoxazepin-9-yl]pyrazol-l-yl]-2-methylpropanamide), MLN-1117 ((2R)-l-Phenoxy-2-butanyl hydrogen (S)-methylphosphonate; or Methyl(oxo) {[(2R)-l-phenoxy-2-butanyl]oxy (phosphonium)), BYL-719 ((2S)-Nl-[4-Methyl-5-[2-(2,2,2-trifluoro-l,l-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-l,2-pyrrolidinedicarboxamide), GSK2126458 (2,4-Difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl(benzenesulfonamide) (omipalisib), TGX-221 ((±)-7-Methyl-2-(morpholin-4-yl)-9-(l-phenylaminoethyl)-pyrido[l,2-a]-pyrimidin-4-one), GSK263 6771           (2-Methyl-1 -(2-methyl-3 -(trifluoromethyl)benzyl)-6-morpholino-lH- benzo[d]imidazole-4-carboxylic acid dihydrochloride), KIN-193 ((R)-2-((l-(7-methyl-2-morpholino-4-oxo-4H-pyrido[l,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid), TGR-1202 / RP5264,      GS-9820      ((S)- l-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4- mohydroxypropan- 1 -one), GS-1101 (5-fluoro-3-phenyl-2-([S)]-l-[9H-purin-6-ylamino]-propyl)-3H-quinazolin-4-one), AMG-319, GSK-2269557, SAR245409 (N-(4-(N-(3-((3,5- dimethoxyphenyl)amino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4 methylbenzamide), BAY80-6946 (2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[l,2-c]quinaz), AS 252424 (5-[l-[5-(4-Fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-2,4-dione), CZ 24832 (5-(2-amino-8-fluoro-[l,2,4]triazolo[l,5-a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide), Buparlisib (5-[2,6-Di(4-morpholinyl)-4- pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine), GDC-0941 (2-(lH-Indazol-4-yl)-6-[[4-(methylsulfonyl)-l-piperazinyl]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine), GDC-0980 ((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6 yl)methyl)piperazin-l-yl)-2-hydroxypropan-l-one (also known as RG7422)), SF1126 ((8S,14S,17S)-14-(carboxymethyl)-8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15-pentaoxo-l-(4-(4-oxo-8-phenyl-4H-chromen-2-yl)morpholino-4-ium)-2-oxa-7,10,13,16-tetraazaoctadecan-18-oate), PF-05212384 (N-[4-[[4-(Dimethylamino)-l- piperidinyl]carbonyl]phenyl]-N'-[4-(4,6-di-4-morpholinyl-l,3,5-triazin-2-yl)phenyl]urea) (gedatolisib), LY3023414, BEZ235 (2-Methyl -2-{4-[3-m ethyl -2-oxo-8-(quinolin-3-yl)-2,3-dihy dro-lH-imidazo[4,5-c]quinolin-l-yl]phenyl}propanenitrile)          (dactolisib),          XL-765          (N-(3-(N-(3-(3,5- dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide), and GSK1059615 (5-[[4-(4-Pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidenedione), PX886 ([(3aR,6E,9S,9aR,10R,l laS)-6-[[bis(prop-2-enyl)amino]methylidene]-5-hydroxy-9-(methoxymethyl)-9a,l la-dimethyl-l,4,7-trioxo-2,3,3a,9,10,ll-hexahydroindeno[4,5h]isochromen- 10-yl] acetate (also known as sonolisib)), LY294002, AZD8186, PF-4989216, pilaralisib, GNE-317, PI-3065, PI-103, NU7441 (KU-57788), HS 173, VS-5584 (SB2343), CZC24832, TG100-115, A66, YM201636, CAY10505, PIK-75, PIK-93, AS-605240, BGT226 (NVP-BGT226), AZD6482, voxtalisib, alpelisib, IC-87114, TGI100713, CH5132799, PKI-402, copanlisib (BAY 80-6946), XL 147, PIK-90, PIK-293, PIK-294, 3-MA (3-methyladenine), AS-252424, AS-604850, apitolisib (GDC-0980; RG7422). Examples of BTK inhibitors include ibrutinib (also known as PCL 32765)(IMBRUVICA®)(l-[(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidin-l-yl]prop-2-en-l-one), dianilinopyrimidine-based inhibitors such as AVL-101 and AVL-291 / 292   (N-(3-((5-fluoro-2-((4-(2-methoxy ethoxy )phenyl)amino)pyrimidin-4- yl)amino)phenyl)acrylamide) (Avila Therapeutics) (see US Patent Publication No 2011 / 0117073, incorporated herein in its entirety), dasatinib ([N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hy droxy ethyl)piperazin-l -yl)-2-methylpyrimidin-4-ylamino)thi azole-5-carboxamide], LFM-A13   (alpha-cyano-beta-hy droxy-beta-methyl-N-(2,5-ibromophenyl) propenamide), GDC-0834 ([R-N-(3-(6-(4-(l,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)- 4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7- tetrahydrobenzo[b]thiophene-2-carboxamide], CGI-560       4-(tert-butyl)-N-(3-(8- (phenylamino)imidazo[ 1,2-a]pyrazin-6-yl)phenyl)benzamide, CGI-1746 (4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)benzamide), CNX-774       (4-(4-((4-((3-acrylamidophenyl)amino)-5 - fluoropyrimidin-2-yl)amino)phenoxy)-N-methylpicolinamide), CTA056 (7-benzyl-1-(3-(piperidin-l-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-lH-imidazo[4,5-g]quinoxalin-6(5H)-one), GDC-0834 ((R)-N-(3-(6-((4-(l,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahy drobenzo[b]thi ophene-2-carboxamide), GDC-0837        ((R)-N-(3-(6-((4-(l,4-dimethyl-3-oxopiperazin-2- yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), HM-71224, ACP-196, ONO-4059 (Ono Pharmaceuticals), PRT062607 (4-((3-(2H-l,2,3-triazol-2-yl)phenyl)amino)-2-(((lR,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), QL-47    (1-(1- acryloylindolin-6-yl)-9-(l-methyl-lH-pyrazol-4-yl)benzo[h][l,6]naphthyridin-2(lH)-one), and RN486 (6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{ l-methyl-5-[5-(4-methyl-piperazin-1 -yl)-pyri din-2 -ylamino]-6-oxo-l,6-dihydro-pyri din-3-yl }-phenyl)-2H-isoquinolin-1-one), and other molecules capable of inhibiting BTK activity, for example those BTK inhibitors disclosed in Akinleye et ah, Journal of Hematology & Oncology, 2013, 6:59, the entirety of which is incorporated herein by reference. Syk inhibitors include, but are not limited to, cerdulatinib (4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-l-yl)phenyl)amino)pyrimidine-5-carboxamide), entospletinib (6-(lH-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[l,2-a]pyrazin-8-amine), fostamatinib ([6-({5-Fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][l,4]oxazin-4-yl]methyl dihydrogen phosphate), fostamatinib disodium salt (sodium (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][l,4]oxazin-4(3H)-yl)methyl phosphate), BAY     61-3 606     (2-(7-(3,4-Dimethoxyphenyl)-imidazo[ 1,2-c]pyrimidin-5-ylamino)- nicotinamide HC1), RO9021 (6-[(lR,2S)-2-Amino-cyclohexylamino]-4-(5,6-dimethyl-pyri din-2-ylamino)-pyridazine-3-carboxylic acid amide), imatinib (Gleevac; 4-[(4-methylpiperazin-l-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide), staurosporine, GSK143 (2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidine-5-carboxamide), PP2 (l-(tert-butyl)-3-(4-chlorophenyl)-lH-pyrazolo[3,4-d]pyrimidin-4-amine), PRT-060318     (2-((( 1R,2 S)-2- aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5-carboxamide), PRT-062607 (4-((3-(2H-l,2,3-triazol-2-yl)phenyl)amino)-2-(((lR,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide         hydrochloride),         RI 12         (3,3'-((5-fluoropyrimidine-2,4- diyl)bis(azanediyl))diphenol), R348 (3-Ethyl-4-methylpyridine), R406 (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one), piceatannol (3-Hydroxyresveratol), YM193306 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chern. 2012, 55, 36143643), 7-azaindole, piceatannol, ER-27319 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chern. 2012, 55, 3614-3643 incorporated in its entirety herein), Compound D (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chern. 2012, 55, 3614-3643 incorporated in its entirety herein), PRT060318 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chern. 2012, 55, 3614-3643 incorporated in its entirety herein), luteolin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chern. 2012, 55, 3614-3643 incorporated in its entirety herein), apigenin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chern. 2012, 55, 3614-3643 incorporated in its entirety herein), quercetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chern. 2012, 55, 3614-3643 incorporated in its entirety herein), fisetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chern. 2012, 55, 3614-3643 incorporated in its entirety herein), myricetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chern. 2012, 55, 3614-3643 incorporated in its entirety herein), morin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chern. 2012, 55, 3614-3643 incorporated in its entirety herein). In certain embodiments, the bioactive agent is a MEK inhibitor. MEK inhibitors are well known, and include, for example, trametinib / GSK1120212 (N-(3-{3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H-yl}phenyl)acetamide), selumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), pimasertib / AS703026 / MSC 1935369 ((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4- iodophenyl)amino)isonicotinamide), XL-518 / GDC-0973 (l-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol), refametinib / BAY869766 / RDEAl 19 (N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-l-(2,3-dihydroxypropyl)cyclopropane-l- sulfonamide), PD-0325901 (N-[(2R)-2,3-Dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]- benzamide), TAK733 ((R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione), MEK162 / ARRY438162              (5-[(4-Bromo-2-fluorophenyl)amino]-4-fluoro-N-(2- hydroxyethoxy)-l-methyl-lH-benzimidazole-6-carboxamide), R05126766 (3-[[3-Fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one), WX-554, R04987655 / CH4987655 (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-l,2-oxazinan-2yl)methyl)benzamide), or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2 hy droxy ethoxy)-1 ,5-dimethyl-6-oxo-l,6-dihydropyridine-3-carboxamide), U0126-EtOH, PD184352 (CI-1040), GDC-0623, BI-847325, cobimetinib, PD98059, BIX 02189, BIX 02188, binimetinib, SL-327, TAK-733, PD318088. In certain embodiments, the bioactive agent is a Raf inhibitor. Raf inhibitors are known and include, for example, Vemurafinib (N-[3-[[5-(4-Chlorophenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl]-l-propanesulfonamide), sorafenib tosylate (4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide;4-methylbenzenesulfonate), AZ628 (3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylamino)phenyl)benzamide), NVP-BHG712 (4-methyl-3-(l-methyl-6-(pyridin-3-yl)-lH-pyrazolo[3,4-d]pyrimidin-4-ylamino)-N-(3-(trifluoromethyl)phenyl)benzamide), RAF-265 (l-methyl-5-[2-[5-(trifluoromethyl)-lH-imidazol-2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine), 2-Bromoaldisine (2-Bromo-6,7-dihydro-lH,5H-pyrrolo[2,3-c]azepine-4,8-dione), Raf Kinase Inhibitor IV (2-chloro-5-(2-phenyl-5-(pyridin-4-yl)-lH-imidazol-4-yl)phenol), Sorafenib N-Oxide (4-[4-[[[[4-Chloro-3(trifluoroMethyl)phenyl]aMino]carbonyl]aMino]phenoxy]-N-Methyl-2pyridinecarboxaMide 1-Oxide), PLX-4720, dabrafenib (GSK2118436), GDC-0879, RAF265, AZ 628, SB590885, ZM336372, GW5074, TAK-632, CEP-32496, LY3009120, and GX818 (encorafenib (BRAFTOVI®)). In certain embodiments, the bioactive agent is an EGFR inhibitor, including, for example gefitinib (IRESSA®), lapatinib (TYKERB®), osimertinib (TAGRISSO®), neratinib (NERLYNX®), vandetanib (CAPRELSA®), dacomitinib (VIZIMPRO®), rociletinib (XEGAFRI™), afatinib (GLOTRIF®, GIOTRIFF™, AFANIX™), lazertinib, or nazartib. Additional examples of EGFR inhibitors include rociletinib (CO-1686), olmutinib (Olita), naquotinib (ASP8273), nazartinib (EGF816), PF-06747775, icotinib (BPI-2009), neratinib (HKI-272; PB272); avitinib (AC0010), EAI045, tarloxotinib (TH-4000; PR-610), PF-06459988 (Pfizer), tesevatinib (XL647; EXEL-7647; KD-019), transtinib, WZ-3146, WZ8040, CNX-2006, dacomitimb (PF-00299804; Pfizer), bngatimb (Alunbng), lorlatimb, and PF-06747775 (PF7775). In certain embodiments, the bioactive agent is a first-generation EGFR inhibitor such as erlotinib, gefitinib, or lapatinib. In certain embodiments, the bioactive agent is a second-generation EGFR inhibitor such as afatinib and / or dacomitinib. In certain embodiments, the bioactive agent is a third-generation EGFR inhibitor such as osimertinib. In certain aspects Compound 1 is administered in combination with a ATP-site binding inhibitor of EGFR or mutant EGFR. Non-limiting examples of ATP-site binding inhibitors of EGFR include osimertinib, naquotinib, mavelertinib, spebrutinib, and AZ5104. In certain embodiments a compound described herein is administered to a patient in need thereof in combination with osimertinib. In certain embodiments a compound described herein is administered to a patient in need thereof in combination with naquotinib. In certain embodiments a compound described herein is administered to a patient in need thereof in combination with mavelertinib. In certain embodiments a compound described herein is administered to a patient in need thereof in combination with spebrutinib. In certain embodiments a compound described herein is administered to a patient in need thereof in combination with AZ5104. In certain embodiments a compound described herein is administered to a patient in need thereof in combination with rociletinib. In certain embodiments a compound described herein is administered to a patient in need thereof in combination with avitinib. In certain embodiments a compound described herein is administered to a patient in need thereof in combination with lazertinib. In certain embodiments a compound described herein is administered to a patient in need thereof in combination with nazartinib. In certain embodiments a compound described herein is administered to a patient in need thereof in combination with an EGFR antibody, for example, cetuximab, panitumab, or necitumab. In certain embodiments a compound described herein is administered to a patient in need thereof in combination with cetuximab. In certain embodiments a compound described herein is administered to a patient in need thereof in combination with panitumab. In certain embodiments a compound described herein is administered to a patient in need thereof in combination with necitumab. In certain embodiments, the bioactive agent is a c-MET inhibitor, for example, crizotinib (Xalkori, Crizonix), tepotinib (XL880, EXEL-2880, GSK1363089, GSK089), or tivantinib (ARQ197). In certain embodiments, the bioactive agent is an AKT inhibitor, including, but not limited to, MK-2206, GSK690693, perifosine, (KRX-0401), GDC-0068, triciribine, AZD5363, honokiol, PF-04691502, and miltefosine, a FLT-3 inhibitor, including, but not limited to, P406, dovitinib, quizartinib (AC220), amuvatinib (MP-470), tandutinib (MLN518), ENMD-2076, and KW-2449, or a combination thereof. In certain embodiments, the bioactive agent is an mTOR inhibitor. Examples of mTOR inhibitors include, but are not limited to, rapamycin and its analogs, everolimus (Afinitor), temsirolimus, ridaforolimus, sirolimus, and deforolimus. In certain embodiments, the bioactive agent is a RAS inhibitor. Examples of RAS inhibitors include but are not limited to Reolysin and siG12D LODER. In certain embodiments, the bioactive agent is a HSP inhibitor. HSP inhibitors include but are not limited to Geldanamycin or 17-N-Allylamino-17-demethoxygeldanamycin (17AAG), and Radicicol. Additional bioactive compounds include, for example, everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON O91O.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, a VEGFR inhibitor, an aurora kinase inhibitor, a PIK-1 modulator, an HD AC inhbitor, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody, a focal adhesion kinase inhibitor, a Map kinase kinase (mek) inhibitor, a VEGF trap antibody, pemetrexed, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, atumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdRi KRX-0402, lucanthone, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-lH-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES(diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258); 3-[5-(methylsulfonylpiperadinemethyl)-indolyl-quinolone, vatalanib, AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, lapatanib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, lonafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid, valproic acid, trichostatin A, FK-228, SUI 1248, sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosine arabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortezimib, paclitaxel, cremophor-free paclitaxel, docetaxel, epithilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zolendronate, prednisone, cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2, megestrol, immune globulin, nitrogen mustard, methylprednisolone, ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, an NK-1 receptor antagonist, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa and mixtures thereof. In certain embodiments the compound is administered in combination with ifosfamide. In certain embodiments, the bioactive agent is selected from, but are not limited to, Imatinib mesylate (Gleevac®), Dasatinib (Sprycel®), Nilotinib (Tasigna®), Bosutinib (Bosulif®), Trastuzumab (Herceptin®), trastuzumab-DM1, Pertuzumab (PerjetaTM), Lapatinib (Tykerb®), Gefitinib (Iressa®), Erlotinib (Tarceva®), Cetuximab (Erbitux®), Panitumumab (Vectibix®), Vandetanib (Caprelsa®), Vemurafenib (Zelboraf®), Vorinostat (Zolinza®), Romidepsin (Istodax®), Bexarotene (Tagretin®), Alitretinoin (Panretin®), Tretinoin (Vesanoid®), Carfilizomib (KyprolisTM), Pralatrexate (Folotyn®), Bevacizumab (Avastin®), Ziv-aflibercept (Zaltrap®), Sorafenib (Nexavar®), Sunitinib (Sutent®), Pazopanib (Votrient®), Regorafenib (Stivarga®), and Cabozantinib (CometriqTM). In certain aspects, the bioactive agent is an anti-inflammatory agent, a chemotherapeutic agent, a radiotherapeutic, an additional therapeutic agent, or an immunosuppressive agent. Suitable chemotherapeutic bioactive agents include, but are not limited to, a radioactive molecule, a toxin, also referred to as cytotoxin or cytotoxic agent, which includes any agent that is detrimental to the viability of cells, and liposomes or other vesicles containing chemotherapeutic compounds. General anticancer pharmaceutical agents include: Vincristine (Oncovin®) or liposomal vincristine (Marqibo®), Daunorubicin (daunomycin or Cerubidine®) or doxorubicin (Adriamycin®), Cytarabine (cytosine arabinoside, ara-C, or Cytosar®), L-asparaginase (El spar®) or PEG-L-asparaginase (pegaspargase or Oncaspar®), Etoposide (VP-16), Teniposide (Vumon®), 6-mercaptopurine (6-MP or Purinethol®), Methotrexate, Cyclophosphamide (Cytoxan®), Prednisone, Dexamethasone (Decadron), imatinib (Gleevec®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosulif®), and ponatinib (Iclusig™). Examples of additional suitable chemotherapeutic agents include, but are not limited to 1-dehydrotestosterone, 5-fluorouracil decarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, adriamycin, aldesleukin, an alkylating agent, allopurinol sodium, altretamine, amifostine, anastrozole, anthramycin (AMC)), an anti-mitotic agent, cis-dichlorodiamine platinum (II) (DDP) cisplatin), diamino dichloro platinum, anthracycline, an antibiotic, an antimetabolite, asparaginase, BCG live (intravesical), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, calcium leucouorin, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU), Chlorambucil, Cisplatin, Cladribine, Colchicin, conjugated estrogens, Cyclophosphamide, Cyclothosphamide, Cytarabine, Cytarabine, cytochalasin B, Cytoxan, Dacarbazine, Dactinomycin, dactinomycin (formerly actinomycin), daunirubicin HCL, daunorucbicin citrate, denileukin diftitox, Dexrazoxane, Dibromomannitol, dihydroxy anthracin dione, Docetaxel, dolasetron mesylate, doxorubicin HCL, dronabinol, E. coll L-asparaginase, emetine, epoetin-a, Erwinia L-asparaginase, esterified estrogens, estradiol, estramustine phosphate sodium, ethidium bromide, ethinyl estradiol, etidronate, etoposide citrororum factor, etoposide phosphate, filgrastim, floxuridine, fluconazole, fludarabine phosphate, fluorouracil, flutamide, folinic acid, gemcitabine HCL, glucocorticoids, goserelin acetate, gramicidin D, granisetron HCL, hydroxyurea, idarubicin HCL, ifosfamide, interferon a-2b, irinotecan HCL, letrozole, leucovorin calcium, leuprolide acetate, levamisole HCL, lidocaine, lomustine, maytansinoid, mechlorethamine HCL, medroxyprogesterone acetate, megestrol acetate, melphalan HCL, mercaptipurine, mesna, methotrexate, methyltestosterone, mithramycin, mitomycin C, mitotane, mitoxantrone, nilutamide, octreotide acetate, ondansetron HCL, paclitaxel, pamidronate disodium, pentostatin, pilocarpine HCL, plimycin, polifeprosan 20 with carmustine implant, porfimer sodium, procaine, procarbazine HCL, propranolol, rituximab, sargramostim, streptozotocin, tamoxifen, taxol, teniposide, tenoposide, testolactone, tetracaine, thioepa chlorambucil, thioguanine, thiotepa, topotecan HCL, toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate. In some embodiments, the compound described herein is administered in combination with a chemotherapeutic agent (e.g., a cytotoxic agent or other chemical compound useful in the treatment of cancer). Examples of chemotherapeutic agents include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodopyyllotoxins, antibiotics, L-Asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione substituted urea, methyl hydrazine derivatives, adrenocortical suppressant, adrenocorticosteroides, progestins, estrogens, antiestrogen, androgens, antiandrogen, and gonadotropin-releasing hormone analog. Also included is 5-fluorouracil (5-FU), leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1 ); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall (see, e.g., Agnew, Chern. Inti. Ed Engl. 33:183-186 (1994)); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo- 5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin, including morpholino-doxorubicin, cyanomorpholino- doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5- FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; antiadrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T- 2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE®, cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, IL), and TAXOTERE® doxetaxel (Rhone-Poulenc Rorer, Antony, France); chloranbucil; GEMZAR® gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE®’ vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-1 1 ); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Two or more chemotherapeutic agents can be used in a cocktail to be administered in combination with the compound described herein. Suitable dosing regimens of combination chemotherapies are known in the ar. For example combination dosing regimes are described in Saltz et al., Proc. Am. Soc. Clin. Oncol. 18:233a (1999) and Douillard et al., Lancet 355(9209): 1041 -1047 (2000). Additional therapeutic agents that can be administered in combination with a Compound disclosed herein can include bevacizumab, sutinib, sorafenib, 2-methoxyestradiol or 2ME2, finasunate, vatalanib, vandetanib, aflibercept, volociximab, etaracizumab (MEDI-522), cilengitide, cetuximab, panitumumab, gefitinib, trastuzumab, dovitinib, figitumumab, atacicept, rituximab, alemtuzumab, aldesleukine, atlizumab, tocilizumab, temsirolimus, everolimus, lucatumumab, dacetuzumab, HLL1, huN901-DMl, atiprimod, natalizumab, bortezomib, carfilzomib, marizomib, tanespimycin, saquinavir mesylate, ritonavir, nelfinavir mesylate, indinavir sulfate, belinostat, panobinostat, mapatumumab, lexatumumab, dulanermin, ABT-737, oblimersen, plitidepsin, talmapimod, P276-00, enzastaurin, tipifarnib, perifosine, imatinib, dasatinib, lenalidomide, thalidomide, simvastatin, celecoxib, bazedoxifene, AZD4547, rilotumumab, oxaliplatin (Eloxatin), PD0332991, ribociclib (LEE011), amebaciclib (LY2835219), HDM201, fulvestrant (Faslodex), exemestane (Aromasin), PIM447, ruxolitinib (INC424), BGJ398, necitumumab, pemetrexed (Alimta), and ramucirumab (IMC-1121B). In certain embodiments, the additional therapy is a monoclonal antibody (MAb). Some MAbs stimulate an immune response that destroys cancer cells. Similar to the antibodies produced naturally by B cells, these MAbs may “coat” the cancer cell surface, triggering its destruction by the immune system. For example, bevacizumab targets vascular endothelial growth factor (VEGF), a protein secreted by tumor cells and other cells in the tumor’s microenvironment that promotes the development of tumor blood vessels. When bound to bevacizumab, VEGF cannot interact with its cellular receptor, preventing the signaling that leads to the growth of new blood vessels. MAbs that bind to cell surface growth factor receptors prevent the targeted receptors from sending their normal growth-promoting signals. They may also trigger apoptosis and activate the immune system to destroy tumor cells. In one aspect of the present invention, the bioactive agent is an immunosuppressive agent. The immunosuppressive agent can be a calcineurin inhibitor, e.g. a cyclosporin or an ascomycin, e.g. Cyclosporin A (NEORAL®), FK506 (tacrolimus), pimecrolimus, a mTOR inhibitor, e.g. rapamycin or a derivative thereof, e.g. Sirolimus (RAPAMUNE®), Everolimus (Certican®), temsirolimus, zotarolimus, biolimus-7, biolimus-9, a rapalog, e.g.ridaforolimus, azathioprine, campath 1H, a SIP receptor modulator, e.g. fmgolimod or an analogue thereof, an anti IL-8 antibody, mycophenolic acid or a salt thereof, e.g. sodium salt, or a prodrug thereof, e.g. Mycophenolate Mofetil (CELLCEPT®), OKT3 (ORTHOCLONE OKT3®), Prednisone, ATGAM®, THYMOGLOBULIN®, Brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxyspergualin, tresperimus, Leflunomide ARAVA®, CTLAI-Ig, anti-CD25, anti-IL2R, Basiliximab (SIMULECT®), Daclizumab (ZENAPAX®), mizorbine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, Elidel®), CTLA41g (Abatacept), belatacept, LFA31g„ etanercept (sold as Enbrel® by Immunex), adalimumab (Humira®), infliximab (Remicade®), an anti-LFA-1 antibody, natalizumab (Antegren®), Enlimomab, gavilimomab, antithymocyte immunoglobulin, siplizumab, Alefacept efalizumab, pentasa, mesalazine, asacol, codeine phosphate, benorylate, fenbufen, naprosyn, diclofenac, etodolac and indomethacin, aspirin and ibuprofen. In some embodiments, the bioactive agent is a therapeutic agent which is a biologic such a cytokine (e.g., interferon or an interleukin (e.g., IL-2)) used in cancer treatment. In some embodiments the biologic is an anti-angiogenic agent, such as an anti-VEGF agent, e.g., bevacizumab (AVASTIN®). In some embodiments the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein or a functional fragment thereof) that agonizes a target to stimulate an anticancer response, or antagonizes an antigen important for cancer. Such agents include RITUXAN® (rituximab); ZENAPAX® (daclizumab); SIMULECT® (basiliximab); SYNAGIS® (palivizumab); REMICADE® (infliximab); HERCEPTIN® (trastuzumab); MYLOTARG® (gemtuzumab ozogamicin); CAMPATH® (alemtuzumab); ZEVALIN® (ibritumomab tiuxetan); HUMIRA® (adalimumab); XOLAIR® (omalizumab); BEXXAR® (tositumomab-1- 131 ); RAPTIVA® (efalizumab); ERBITUX® (cetuximab); AVASTIN® (bevacizumab); TYSABRI® (natalizumab); ACTEMRA® (tocilizumab); VECTIBIX® (panitumumab); LUCENTIS® (ranibizumab); SOURIS® (eculizumab); CIMZIA® (certolizumab pegol); SIMPONI® (golimumab); ILARIS® (canakinumab); STELARA® (ustekinumab); ARZERRA® (ofatumumab); PROLIA® (denosumab); NUMAX® (motavizumab); ABTHRAX® (raxibacumab); BENLYSTA® (belimumab); YERVOY® (ipilimumab); ADCETRIS® (brentuximab vedotin); PERJETA® (pertuzumab); KADCYLA® (ado- trastuzumab emtansine); and GAZYVA® (obinutuzumab). Also included are antibodydrug conjugates. The combination therapy may include a therapeutic agent which is a non-drug treatment. For example, the compound could be administered in addition to radiation therapy, cryotherapy, hyperthermia, and / or surgical excision of tumor tissue. Compounds administered “in combination” as the term is used herein can refer to simultaneous administration or administration of the two compounds at different times or on different days in the treatment cycle. In certain embodiments the first and second therapeutic agents are administered simultaneously or sequentially, in either order. The first therapeutic agent may be administered immediately, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to, 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to hours 16, up to 17 hours, up 18 hours, up to 19 hours up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours up to 24 hours or up to 1-7, 1-14, 121 or 1-30 days before or after the second therapeutic agent. In certain embodiments the second therapeutic agent is administered on a different dosage schedule than the compound described herein. For example the second therapeutic agent may have a treatment holiday of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle. In another embodiment the first therapeutic agent has a treatment holiday. For example the first therapeutic agent may have a treatment holiday of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle. In certain embodiments both the first and second therapeutic have a treatment holiday. VII. PHARMACEUTICAL COMPOSITIONS A compound of Formula I, II, III, or IV or a pharmaceutically acceptable salt thereof can be used as a therapeutically active substance, e.g. in the form of a pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. In other embodiments the compound is administered paternally, for example by intravaneous administration. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions. The compounds of Formula I, II, III, or IV and the pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are however usually required in the case of soft gelatin capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like. The pharmaceutical preparations can, moreover, contain pharmaceutically acceptable auxiliary substances such as preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances. Medicaments containing a compound of Formula I, II, III, or IV or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also provided by the present invention, as is a process for their production, which comprises bringing one or more compounds of Formula I, II, III, or IV and / or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers. The dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. In the case of oral administration the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general Formula I, II, III, or IV or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated. The following examples illustrate the present invention without limiting it, but serve merely as representative thereof. The pharmaceutical preparations conveniently contain about 1-500 mg, particularly 1-100 mg, of a compound of Formula I, II, III, or IV. Examples of compositions according to the invention are: In certain embodiments the pharmaceutical composition is in a dosage form that contains from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of the active compound and optionally from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of an additional active agent in a unit dosage form. Examples are dosage forms with at least 0.1, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of active compound, or its salt. In some embodiments, compounds disclosed herein or used as described are administered once a day (QD), twice a day (BID), or three times a day (TID). In some embodiments, compounds disclosed herein or used as described are administered at least once a day for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, at least 30 days, at least 31 days, at least 35 days, at least 45 days, at least 60 days, at least 75 days, at least 90 days, at least 120 days, at least 150 days, at least 180 days, or longer. In certain embodiments the compound described herein is administered once a day, twice a day, three times a day, or four times a day. In certain embodiments the compound described herein is administered orally once a day. In certain embodiments the compound described herein is administered orally twice a day. In certain embodiments the compound described herein is administered orally three times a day. In certain embodiments the compound described herein is administered orally four times a day. In certain embodiments the compound described herein is administered intravenously once a day. In certain embodiments the compound described herein is administered intravenously twice a day. In certain embodiments the compound described herein is administered intravenously three times a day. In certain embodiments the compound described herein is administered intravenously four times a day. In some embodiments the compound described herein is administered with a treatment holiday in between treatment cycles. For example the compound may have a treatment holiday of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle. In some embodiments a loading dose is administered to begin treatment. For example, the compound may be administered about 1.5x, about 2x, about 2.5x, about 3x, about 3.5x, about 4x, about 4.5x, about 5x, about 5.5x, about 6x, about 6.5x, about 7x, about 7.5x, about 8x, about 8.5x, about 9x, about 9.5x, or about lOx higher dose on the first day of treatment than the remaining days of treatment in the treatment cycle. Additional exemplary loading doses include about 1.5x, about 2x, about 2.5x, about 3x, about 3.5x, about 4x, about 4.5x, about 5x, about 5.5x, about 6x, about 6.5x, about 7x, about 7.5x, about 8x, about 8.5x, about 9x, about 9.5x, or about lOx higher dose on the first 2, 3, 4, 5, 6, 7, 8, 9, or 10 days of treatment than the remaining days of treatment in the treatment cycle. The pharmaceutical composition may also include a molar ratio of the active compound and an additional active agent. For example the pharmaceutical composition may contain a molar ratio of about 0.5:1, about 1:1, about 2:1, about 3:1 or from about 1.5:1 to about 4:1 of an anti-inflammatory or immunosuppressing agent. These compositions can contain any amount of active compound that achieves the desired result, for example between 0.1 and 99 weight % (wt. %) of the compound and usually at least about 5 wt. % of the compound. Some embodiments contain from about 25 wt. % to about 50 wt. % or from about 5 wt. % to about 75 wt. % of the compound. A pharmaceutically or therapeutically effective amount of the composition will be delivered to the patient. The precise effective amount will vary from patient to patient, and will depend upon the species, age, the subject’s size and health, the nature and extent of the condition being treated, recommendations of the treating physician, and the therapeutics or combination of therapeutics selected for administration. The effective amount for a given situation can be determined by routine experimentation. For purposes of the disclosure, a therapeutic amount may for example be in the range of about 0.01 mg / kg to about 250 mg / kg body weight, more typically about 0.1 mg / kg to about 10 mg / kg, in at least one dose. The subject can be administered as many doses as is required to reduce and / or alleviate the signs, symptoms, or causes of the disorder in question, or bring about any other desired alteration of a biological system. When desired, formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient. In certain embodiments the dose ranges from about 0.01-100 mg / kg of patient bodyweight, for example about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, or about 100 mg / kg. The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packed tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. In certain embodiments the compound is administered as a pharmaceutically acceptable salt. Non-limiting examples of pharmaceutically acceptable salts include: acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemi sulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. Thus, the composition of the disclosure can be administered as a pharmaceutical formulation including one suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, transdermal, pulmonary, vaginal or parenteral (including intramuscular, intra-arterial, intrathecal, subcutaneous and intravenous), injections, inhalation or spray, intra-aortal, intracranial, subdermal, intraperitioneal, subcutaneous, or by other means of administration containing conventional pharmaceutically acceptable carriers. A typical manner of administration is oral, topical or intravenous, using a convenient daily dosage regimen which can be adjusted according to the degree of affliction. Depending on the intended mode of administration, the pharmaceutical compositions can be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, syrup, suspensions, creams, ointments, lotions, paste, gel, spray, aerosol, foam, or oil, injection or infusion solution, a transdermal patch, a subcutaneous patch, an inhalation formulation, in a medical device, suppository, buccal, or sublingual formulation, parenteral formulation, or an ophthalmic solution, or the like, preferably in unit dosage form suitable for single administration of a precise dosage. Some dosage forms, such as tablets and capsules, are subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose. The compositions will include an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier and, in addition, can include other pharmaceutical agents, adjuvants, diluents, buffers, and the like. Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated. The carrier can be inert or it can possess pharmaceutical benefits of its own. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound. Classes of carriers include, but are not limited to adjuvants, binders, buffering agents, coloring agents, diluents, disintegrants, excipients, emulsifiers, flavorants, gels, glidents, lubricants, preservatives, stabilizers, surfactants, solubilizer, tableting agents, wetting agents or solidifying material. Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others. Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin; talc, petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers and vegetable oils. Optional active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of the compound described herein. Some excipients include, but are not limited, to liquids such as water, saline, glycerol, polyethylene glycol, hyaluronic acid, ethanol, and the like. The compound can be provided, for example, in the form of a solid, a liquid, spray dried material, a microparticle, nanoparticle, controlled release system, etc., as desired according to the goal of the therapy. Suitable excipients for non-liquid formulations are also known to those of skill in the art. A thorough discussion of pharmaceutically acceptable excipients and salts is available in Remington’s Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990). Additionally, auxiliary substances, such as wetting or emulsifying agents, biological buffering substances, surfactants, and the like, can be present in such vehicles. A biological buffer can be any solution which is pharmacologically acceptable, and which provides the formulation with the desired pH, i.e., a pH in the physiologically acceptable range. Examples of buffer solutions include saline, phosphate buffered saline, Tris buffered saline, Hank’s buffered saline, and the like. For solid compositions, conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, and the like, an active compound as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered can also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and the like. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington’s Pharmaceutical Sciences, referenced above. In yet another embodiment provided is the use of permeation enhancer excipients including polymers such as: polycations (chitosan and its quaternary ammonium derivatives, poly-L-arginine, aminated gelatin); polyanions (A-carboxy methyl chitosan, poly-acrylic acid); and, thiolated polymers (carboxymethyl cellulose-cysteine, polycarbophil-cysteine, chitosanthiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione conjugates). In certain embodiments the excipient is selected from butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (com), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. The pharmaceutical compositions / combinations can be formulated for oral administration. For oral administration, the composition will generally take the form of a tablet, capsule, a softgel capsule or can be an aqueous or nonaqueous solution, suspension or syrup. Tablets and capsules are typical oral administration forms. Tablets and capsules for oral use can include one or more commonly used carriers such as lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. Typically, the compositions of the disclosure can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, com sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. When liquid suspensions are used, the active agent can be combined with any oral, nontoxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like and with emulsifying and suspending agents. If desired, flavoring, coloring and / or sweetening agents can be added as well. Other optional components for incorporation into an oral formulation herein include, but are not limited to, preservatives, suspending agents, thickening agents, and the like. For ocular delivery, the compound can be administered, as desired, for example, via intravitreal, intrastromal, intracameral, sub-tenon, sub-retinal, retro-bulbar, peribulbar, suprachorodial, conjunctival, subconjunctival, episcleral, periocular, transscleral, retrobulbar, posterior juxtascleral, circumcorneal, or tear duct injections, or through a mucus, mucin, or a mucosal barrier, in an immediate or controlled release fashion or via an ocular device. Parenteral formulations can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solubilization or suspension in liquid prior to injection, or as emulsions. Typically, sterile injectable suspensions are formulated according to techniques known in the art using suitable carriers, dispersing or wetting agents and suspending agents. The sterile injectable formulation can also be a sterile injectable solution or a suspension in a acceptably nontoxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils, fatty esters or polyols are conventionally employed as solvents or suspending media. In addition, parenteral administration can involve the use of a slow release or sustained release system such that a constant level of dosage is maintained. Parenteral administration includes intraarticular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, and include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. Administration via certain parenteral routes can involve introducing the formulations of the disclosure into the body of a patient through a needle or a catheter, propelled by a sterile syringe or some other mechanical device such as a continuous infusion system. A formulation provided by the disclosure can be administered using a syringe, injector, pump, or any other device recognized in the art for parenteral administration. Preparations according to the disclosure for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and com oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms can also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They can be sterilized by, for example, filtration through a bacteria retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured using sterile water, or some other sterile injectable medium, immediately before use. Sterile injectable solutions are prepared by incorporating one or more of the compounds of the disclosure in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, typical methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Thus, for example, a parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized. Alternatively, the pharmaceutical compositions of the disclosure can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable nonirritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. The pharmaceutical compositions of the disclosure can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, propellants such as fluorocarbons or nitrogen, and / or other conventional solubilizing or dispersing agents. Formulations for buccal administration include tablets, lozenges, gels and the like. Alternatively, buccal administration can be effected using a transmucosal delivery system as known to those skilled in the art. The compounds of the disclosure can also be delivered through the skin or muscosal tissue using conventional transdermal drug delivery systems, i.e., transdermal “patches” wherein the agent is typically contained within a laminated structure that serves as a drug delivery device to be affixed to the body surface. In such a structure, the drug composition is typically contained in a layer, or “reservoir,” underlying an upper backing layer. The laminated device can contain a single reservoir, or it can contain multiple reservoirs. In certain embodiments, the reservoir comprises a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to affix the system to the skin during drug delivery. Examples of suitable skin contact adhesive materials include, but are not limited to, polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes, and the like. Alternatively, the drug-containing reservoir and skin contact adhesive are present as separate and distinct layers, with the adhesive underlying the reservoir which, in this case, can be either a polymeric matrix as described above, or it can be a liquid or gel reservoir, or can take some other form. The backing layer in these laminates, which serves as the upper surface of the device, functions as the primary structural element of the laminated structure and provides the device with much of its flexibility. The material selected for the backing layer should be substantially impermeable to the active agent and any other materials that are present. The compositions of the disclosure can be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration. The compound may, for example generally have a small particle size for example of the order of 5 microns or less. Such a particle size can be obtained by means known in the art, for example by micronization. The active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. The aerosol can conveniently also contain a surfactant such as lecithin. The dose of drug can be controlled by a metered valve. Alternatively, the active ingredients can be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition can be presented in unit dose form for example in capsules or cartridges of e.g., gelatin or blister packs from which the powder can be administered by means of an inhaler. Formulations suitable for rectal administration are typically presented as unit dose suppositories. These may be prepared by admixing the active compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture. In certain embodiments, the pharmaceutical composition is suitable for topical application to the skin using a mode of administration and defined above. In certain embodiments, the pharmaceutical composition is suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Formulations suitable for transdermal administration may also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6):318 (1986)) and typically take the form of an optionally buffered aqueous solution of the active compound. In certain embodiments, microneedle patches or devices are provided for delivery of drugs across or into biological tissue, particularly the skin. The microneedle patches or devices permit drug delivery at clinically relevant rates across or into skin or other tissue barriers, with minimal or no damage, pain, or irritation to the tissue. Formulations suitable for administration to the lungs can be delivered by a wide range of passive breath driven and active power driven single / -multiple dose dry powder inhalers (DPI). The devices most commonly used for respiratory delivery include nebulizers, metered-dose inhalers, and dry powder inhalers. Several types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. Selection of a suitable lung delivery device depends on parameters, such as nature of the drug and its formulation, the site 5 of action, and pathophysiology of the lung. In certain embodiments an oral formulation is provided. Example A Tablets of the following composition are manufactured in the usual manner: ingredient mg / tablet 5 25 100 500 Compound of Formula I, II, III, or IV 5 25 100 500 Lactose Anhydrous DTG 125 105 30 150 Sta-Rx 1500 6 6 6 60 Microcrystalline Cellulose 30 30 30 450 Magnesium Stearate 1 1 1 1 Total 167 167 167 831 Table 1: possible tablet composition 10 Manufacturing Procedure 1.      Mix ingredients 1, 2, 3 and 4 and granulate with purified water. 2.     Dry the granules at 50°C. 3.     Pass the granules through suitable milling equipment. 4.     Add ingredient 5 and mix for three minutes; compress on a suitable press. Example B-l Capsules of the following composition are manufactured: ingredient mg / capsule 5 25 100 500 Compound of Formula I, II, III, or IV 5 25 100 500 Hydrous Lactose 159 123 148 - Corn Starch 25 35 40 70 Talk 10 15 10 25 Magnesium Stearate 1 2 2 5 Total 200 200 300 600 Table 2: possible capsule ingredient composition Manufacturing Procedure 5   1.      Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes. 2.     Add ingredients 4 and 5 and mix for 3 minutes. 3. Fill into a suitable capsule. The compound of Formula I, II, III, or IV, lactose and corn starch are firstly mixed in a mixer and then in a comminuting machine. The mixture is returned to the mixer; the talc is 10 added thereto and mixed thoroughly. The mixture is filled by machine into suitable capsules, e.g. hard gelatin capsules. Example B-2 Soft Gelatin Capsules of the following composition are manufactured: Table 3: possible soft gelatin capsule ingredient composition ingredient mg / capsule Compound of Formula I, II, III, or IV 5 Yellow wax 8 Hydrogenated Soya bean oil 8 Partially hydrogenated plant oils 34 Soya bean oil 110 Total 165 Table 4: possible soft gelatin capsule composition ingredient mg / capsule Gelatin 75 Glycerol 85 % 32 Kari on 83 8 (dry matter) Titan dioxide 0.4 Iron oxide yellow 1.1 Total 116.5 Manufacturing Procedure The compound of Formula I, II, III, or IV is dissolved in a warm melting of the other 5 ingredients and the mixture is filled into soft gelatin capsules of appropriate size. The filled soft gelatin capsules are treated according to the usual procedures. Example C Suppositories of the following composition are manufactured: Table 5: possible suppository composition ingredient mg / supp. Compound of Formula I, II, III, or IV 15 Suppository mass 1285 Total 1300 Manufacturing Procedure The suppository mass is melted in a glass or steel vessel, mixed thoroughly and cooled to 45°C. Thereupon, the finely powdered compound of Formula I, II, III, or IV is added thereto and stirred until it has dispersed completely. The mixture is poured into suppository moulds of 15 suitable size, left to cool; the suppositories are then removed from the moulds and packed individually in wax paper or metal foil. Example D Injection solutions of the following composition are manufactured: Table 6: possible injection solution composition ingredient mg / inj ection solution. Compound of Formula I, II, III, or IV 3 Polyethylene Glycol 400 150 acetic acid q.s. ad pH 5.0 water for injection solutions ad 1.0 ml Manufacturing Procedure The compound of Formula I, II, III, or IV is dissolved in a mixture of Polyethylene Glycol 400 and water for injection (part). The pH is adjusted to 5.0 by acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized. Example E Sachets of the following composition are manufactured: Table 7: possible sachet composition ingredient mg / sachet Compound of Formula I, II, III, or IV 50 Lactose, fine powder 1015 Microcrystalline cellulose (AVICEL PH 102) 1400 Sodium carboxymethyl cellulose 14 Polyvinylpyrrolidon K 30 10 Magnesium stearate 10 Flavoring additives 1 Total 2500 Manufacturing Procedure The compound of Formula I, II, III, or IV is mixed with lactose, microcrystalline cellulose and sodium carboxymethyl cellulose and granulated with a mixture of polyvinylpyrrolidone in water. The granulate is mixed with magnesium stearate and the flavoring additives and filled into sachets. VIII. PHARMACOLOGICAL TESTS The compounds of Formula I, II, III, or IV and their pharmaceutically acceptable salts possess valuable pharmacological properties. The compounds were investigated in accordance with the test given hereinafter. Materials NCI-H1975 (harboring EGFR heterozygous L858R-T790M mutations) and NCI-H3255 (harboring EGFR heterozygous L858R mutation) were purchased from ATCC and NCI, respectively. NCI-H1975+CS (harboring EGFR heterozygous L858R-T790M-C797S mutations) was generated using CRISPR technology to introduce the additional C797S mutation by Horizon Discovery. A431 (harboring EGFR wildtype) was purchased from ATCC. RPMI 1640 no-phenol red medium and fetal bovine serum (FBS) were purchased from Gibco (Grand Island, NY, USA). Cell culture flasks and 384-well microplates were acquired from VWR (Radnor, PA, USA). Phosphorylated (pY1068) EGFR and Total EGFR (using L858R-specific detection antibody and pan-EGFR antibody for EGFR mutant cell lines and EGFR wild-type cell lines, respectively) HTRF assay kits were purchased from Cisbio (Bedford, MA, USA). EGFR inhibition and degradation analysis Degradation of EGFR protein containing L858R mutation or wild-type was determined based on quantification of FRET signal using a Total EGFR (L858R-specific or pan-EGFR detecting) HTRF assay kit. Phospho-EGFR (pEGFR) inhibition was determined based on quantification of FRET signal using a pY1068 EGFR HTRF assay kit. In separate assay plates, test compounds were added to the 384-well plate from a top concentration of 10 pM with 11 points, half log titration in duplicates. For each assay, 12.5 uL of cells suspended in assay media (RPMI 1640 no-phenol red medium + 10% FBS) at cell densities indicated for each cell line in Table 8 below were dispensed using a multi-channel pipette to 384-well low volume white HTRF microplates containing a duplicate concentration range of test compounds and DMSO controls. The plates were kept at 37 °C with 5% CO2 for 6 hours and then incubated with either phospho EGFR or Total EGFR HTRF detection antibodies according to the cell line and EGFR mutant being assayed. Cells treated in the absence of the test compound were the negative control. Positive control was set by wells containing all reagents but no cells. FRET signal was acquired on EnVision™ Multilabel Reader (PerkinElmer, Santa Clara, CA, USA). Compound concentration that achieves 50% degradation and inhibition was reported as DC50 and IC50, respectively. Table 8. EGFR mutant cancer cell lines: EGFR mutation, source vendor, experimental seeding density. Seeding Density (Cells / Well) Cell Line Mutation Vendor Total EGFR pY1068 EGFR A431 EGFR WT ATCC 2000 10000 NCI-H3255 EGFR L858R NCI 1000 5000 NCI-H1975 EGFR L858R-T790M ATCC 10000 10000 NCI-H1975+CS EGFR L858R-T790M-L797S Horizon (CRISPR-in) 20000 20000 5 Table 9A: Potencies of EGFR mutant protein degradation Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 +CS EGFR DC50 [nM] 1 F n ? rQ-O-NXN- / H I o            Z\0H » CA HN-V tsA-NH 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(6-(2-( l-(4-(((S)-2,6-di oxopiperi din-3 -yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6- diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide *** *** *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 +CS EGFR DC50 [nM] 2 F. / =\   / =\     z\ .0 Z^N 0   / —\ / —(\ / )—N X N-¥ H 1 & N  —v               \ / ^N\Z 0 y / 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(6-(2-((R)-4-(3 -(2,4-dioxotetrahydropyrimidin-1 (2H)-yl)-1 - methyl-lH-indazol-6-yl)-3,3-difluoropiperidin-l-yl)acetyl)- 2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide *** *** *** 3 0 oX N-7 0 V S nx .° o        r ii V-n^>n      F 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[2-[2-[4-[3-(2,4-dioxohexahydropyrimidin-l-yl)-l-methyl-indazol-6-yl]-3,3-difluoro-l-piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-l-oxo- isoindolin-2-yl]-N-thi azol-2-yl-acetamide *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 +CS EGFR DC50 [nM] 4 N=(   0       'r HN— Cqn ^NTrWF h O         °^NX^° H 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(6-(2-(4-(4-((2,6-di oxopiperi din-3-yl)amino)phenyl)-3,3- difluoropiperidin-l-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thiazol-2- yl)acetamide, Isomer 1 *** 5 o hn-A HA \ / ° °\        \ T HN—\ f 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[2-[2-[4-[3-(2,4-dioxohexahydropyrimidin-l-yl)-l-methyl-indazol-6-yl]-3,3-difluoro-l-piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-l-oxo- isoindolin-2-yl]-N-(2-pyridyl)acetamide *** 6 ^ / s N=\ / ° i                      i u T 1 HN \                o         o^n^o VnX* ° XzXX / 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[[4-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-l- piperidyl]acetyl]piperazin-l-yl]methyl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide *** *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 +CS EGFR DC50 [nM] 7 E / =\ AA / \ / \   / ° / "S 0  r—4 / A-N Y W d Zki-J                  n- / o 4     Cl hn—7  y— Isomer 1      0= /      NH 2-(6-(4-(6-(2-(1 -(2-chloro-4-((2,6-di oxopiperi din-3-yl)amino)phenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-N-(thiazol-2-yl)acetamide, isomer 1 *** 8 F / \   / =\   / \ Z\ / ° 0   ।—-T-N\Z\ / N \ h\ &       O0H C # Cl c\ V 2-[6-[4-[2-[2-[l-[2-chloro-4-(2,4-dioxohexahydropyrimidin-l-yl)phenyl]-4-hydroxy-4-piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol- 1 -yl)-N-thiazol-2-yl-acetamide *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 +CS EGFR DC50 [nM] 9 F / "N O                               / / ° < ii II 1 y / y. / /            n-^ VWn / -7   VV / H A 0             / \ 0H N / —\                    \   / __N—' AO HN-V V— / o=( \-NH 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[7-[2-[l-[4-[[(3 S)-2,6-dioxo-3-piperidyl]amino]-2-fluoro-phenyl] -4-hy droxy-4-piperidyl] acetyl] -2,7 -diazaspiro[3.5]nonan-2-yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thi azol-2-yl-acetamide *** 10 F. H X 0             fx / ~N\ / —r N                cX > o hznAX?n^ 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[7-[2-[(4R)-4-[3-(2,4-dioxohexahydropyrimidin-l-yl)-l-methyl-indazol-6-yl]-3,3-difluoro-l-piperidyl]acetyl]-2,7-diazaspiro[3.5]nonan-2-yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thi azol-2-yl-acetamide *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 +CS EGFR DC50 [nM] 11 F H X 0            / ~\ N —.                   \   ) /  \ f o Isomer 1             __4- N 0X^7 N' 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[2-[2-[4-[3-(2,4-dioxohexahydropyrimidin-l-yl)-l-methyl-indazol-6-yl]-3-fluoro-l-piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide, isomer 1 *** 12 F .         O 0 r-A z>—N X-N-A H X °               ( / j? Qjr* HN—\   / 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[2-[2-[l-[4-[[(3 S)-2,6-dioxo-3-piperidyl]amino]-2-fluoro-phenyl] -4-hy droxy-4-piperidyl] acetyl] -2,7 -diazaspiro[3.5]nonan-7-yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thi azol-2-yl-acetamide *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 +CS EGFR DC50 [nM] 13 N=(  0 HN^ N z,N 0          |l 2 ___ VMynh H 0 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[4-[2- [4- [4-[(2,6-di oxo-3 -piperi dyl)amino] -3 -fluoro-phenyl] -1 -piperidyl]acetyl]piperazin-l-yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thi azol-2-yl-acetamide ** 14 I HN^ s- / 0 0        |l J . ^^7 i 0 °^N^° XI1J 2-[6-[4-[4-[2-[4-[2-cyano-4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1 -piperi dyl]acetyl]piperazin-1 -yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1 -yl)-N-thiazol-2-yl-acetamide *** *** *** 15 rO I H, °0 F        H 2-[6-[4-[4-[2-[4-[2-(difluoromethyl)-4-[(2,6-di oxo-3-piperidyl)amino]phenyl]-1 -piperi dyl]acetyl]piperazin-1 -yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolof 1,2-c]imidazol-1 -yl)-N-thiazol-2-yl-acetamide *** *** *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 +CS EGFR DC50 [nM] 16 N=(   0       'i HN^ V^N 0   LA xz                 N » 0 \z^ / "VNV\ O^N^O H 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-(6-(4-(4-(2-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin- 1 -yl)acetyl)piperazin-1 -yl)phenyl)-4-fluoro-1 -oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide ** 17 0 hn-A 0 V S N=(   0 0         [   || HN—\ \-n^n     i 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(4-(2-(4-(3-(2,4-dioxotetrahydropyrimi din-l(2H)-yl)-l-methyl-lH-indazol-6-yl)piperidin-1 -yl)acetyl)piperazin-1 -yl)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide *** *** *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 +CS EGFR DC50 [nM] 18 N=(  0 HN— CQn T I 1             H F F        H 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(4-(2-( 1-(4-((2,6-di oxopiperi din-3 -yl)amino)-2-(trifluoromethyl)phenyl)-4-hydroxypiperidin-4- yl)acetyl)piperazin-l-yl)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide *** 19 Q o £ 0 xz              N > 0 °^N^° Y JL T T H 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-(6-(4-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin- 1 -yl)acetyl)piperazin-1 -yl)phenyl)-4-fluoro-1 -oxoisoindolin-2-yl)-N-(pyridin-2-yl)acetamide ** *** *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 +CS EGFR DC50 [nM] 20 Q O J Cqn h o        °^N^° H 2-(6,7-dihy dro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[4-[2- [4- [4-[(2,6-di oxo-3 -piperi dyl)amino] -2-fluoro-phenyl] -1 -piperidyl]acetyl]piperazin-l-yl]phenyl]-4-fluoro-l-oxo- isoindolin-2-yl]-N-(2-pyridyl)acetamide ** *** *** 21 n      ।                           h 0 °^N^0 T JL1 J H 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-(6-(4-(l-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1 -yl)acetyl)piperidin-4-yl)phenyl)-4-fluoro-1 -oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide *** *** *** 22 55 5¾ H N ' H 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-(6-(4-(l-(2-(4-(4-(((S)-2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1 -yl)acetyl)piperidin-4- yl)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide *** *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 +CS EGFR DC50 [nM] 23 nK / °       i" H o          0^N\^0 H 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(l-(2-(4-(4-(((R)-2,6-dioxopiperidin-3- yl)amino)phenyl)piperidin-1 -yl)acetyl)piperidin-4- yl)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide *** 24 55 N=( o       ’r Hn5 H 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(l-(2-(4-(4-(((S)-2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-l-yl)acetyl)piperidin-4-yl)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thi azol-2-yl)acetamide ** *** *** 25 %% I ■5% H h 2-(6-(4-(1 -(2-(4-(2-cy ano-4-((2,6-di oxopiperi din-3 - yl)amino)phenyl)piperidin-1 -yl)acetyl)piperidin-4-yl)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1 -yl)-N-(thiazol-2-yl)acetamide *** *** *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 +CS EGFR DC50 [nM] 26 0% n=( o       'r 7 ]                H O^N^O H 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-[6-[4-[l- [2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-l- piperidyl]-2-oxo-ethyl]-4-piperidyl]phenyl]-4-fluoro- 1-oxo-isoindolin-2-yl]-N-thi azol-2-yl-acetamide *** 27 N=( o       'i HN^ Co- 0        o^n^o H 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-[6-[6-[4-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]-2-fluoro-phenyl]-l-piperidyl]acetyl]piperazin-l-yl]-3-pyridyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thi azol -2-yl-acetamide *** *** 28 N=( o HN— >— N 1 ]          ,__.    0            .___ co o=\ / hn-A 0 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-[6-[l-[l- [2-[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]phenyl]-l- piperidyl]acetyl]-4-piperidyl]pyrazol-4-yl]-4-fluoro-l-oxo- isoindohn-2-yl]-N-thi azol-2-yl-acetamide *** *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 +CS EGFR DC50 [nM] 29 N=(  0 HN— )—N I 1        ,__\ 0          ,___ Co O=<   / hn-A 0 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-[6-[4-[l-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]phenyl]-l-piperidyl]acetyl]-4-piperidyl]pyrazol-l-yl]-4-fluoro-l-oxo- isoindolin-2-yl]-N-thi azol-2-yl-acetamide *** *** 30 N=( o       'i HN— o=( / hn-A 0 2-(6,7-Dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(l-(1-(2-(4-(4-(((S)-2,6-dioxopiperidin-3- yl)amino)phenyl)piperidin-1 -yl)acetyl)piperidin-4-yl)- 1H-l,2,3-triazol-4-yl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide *** *** 31 OS      F N=( o J                fT I 1 HN \  —fCS         0         o^n^o \ /              Y i i ? 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-[6-[4-[[l -[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-l-piperidyl]acetyl]-4-piperidyl]oxy]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thi azol-2-yl-acetamide *** 32 N ^ / ° i                            1 U J L HN \ J—(1*1          0          o^n^o \ r' "     Y i i 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-[6-[4-[[l -[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]phenyl]-l-piperidyl]acetyl]-4-piperidyl]oxy]phenyl]-4-fluoro-l-oxo-isoindohn-2-yl]-N-thi azol-2-yl-acetamide *** *** *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 +CS EGFR DC50 [nM] 33 N ^ / ° i                              I 1 HN \ J—fl*]           0           O^N^*O H 0   LAoAj 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[[l-[2-[4-[4-[[(3R)-2,6-dioxo-3-piperidyl]amino]phenyl]-l-piperidyl]acetyl]-4-piperidyl]oxy]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thi azol-2-yl-acetamide *** *** *** 34 H 9 f S                               N A n={ ° f                  ify Y^yH / - 0 < 7=\   7        ||  n    f ¥ M Z.N O       U  J  1  J XZ        — / ^Q^— / 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-((l-(2-(4-(4-((2,6-di oxopiperi din-3-yl)amino)-3-fluorophenyl)piperidin-1 -yl)acetyl)piperidin-4-yl)oxy)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide ** *** *** 35 XX                          H ?       TiTi u? o VVU 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-((l-(2-(4-(4-((2,6-di oxopiperi din-3-yl)amino)-2-fluorophenyl)piperidin-1 -yl)acetyl)piperidin-4- yl)oxy)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide *** *** *** 36 OS      F N ^ / °     1                       1 T I 1 HN \ J—li*l          0          O^N^O / v / yUU        h \ Z' Il          II 1 VN^N 0 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-(6-(4-((l -(2-(4-(5-((2,6-dioxopiperidin-3-yl)amino)pyridin-2-yl)piperidin-l-yl)acetyl)piperidin-4-yl)oxy)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 +CS EGFR DC50 [nM] 37 i      nn A ..AAS      o      oW / VA A / -. / - A n J      H sA o o       U A 1 J A / N 2-(6-(4-((l-(2-(4-(2-cyano-4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1 -yl)acetyl)piperidin-4-yl)oxy)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1 -yl)-N-(thiazol-2-yl)acetamide *** *** *** 38 O        / ^- / O^. N \ 00        \ Il T 1 HnA AAV AxX-m-X >—n||   1               n y ।           h / \ /                  °vA° An -n f                 A-A - /                           -— / —N—\ / H 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-(6-(4-((l -(2-(4-(4-((2,4-dioxo-3 -azabicyclo[3.1.1 ]heptan-1 -yl)amino)phenyl)piperidin-1 -yl)acetyl)piperidin-4- yl)oxy)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide ** 39 0s      f I      nil " ° VnAn °   U-0 / M 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-(6-(4-((l -(2-(4-(4-(((S)-2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1 -yl)acetyl)piperidin-4- yl)oxy)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide ** 40 0s      f HN AA 'Ai*]          o         o^n'Vq ArAAn nA H o  Ao A S 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-[6-[4-[[l -[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-l-piperidyl]-2-oxo-acetyl]-4-piperidyl]oxy]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide *** *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 +CS EGFR DC50 [nM] 41 N=( O HN^ / Cy NCOC-\         - o'      o               )—K 0=(  \ HN-Z 0 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imi dazol-l-yl)-2-[6-[4-[(3R)-l-[2-[4-[4-[[(3S)-2,6-dioxo-3- piperidyl]amino]phenyl]-l-piperidyl]acetyl]pyrrolidin-3-yl]oxyphenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide *** 42 N=( o hn—Z / -= Co °      O              / —\ 0=(  \ HN—z 0 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imi dazol-l-yl)-2-[6-[4-[(3S)-l-[2-[4-[4-[[(3S)-2,6-dioxo-3- piperidyl]amino]phenyl]-l-piperidyl]acetyl]pyrrolidin-3-yl]oxyphenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide *** 43 i f-00=( / \ Jl JL hno rt °0 h H 2-(6-(4-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-l-yl)acetyl)piperazin-l-yl)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1 -yl)-N-(thiazol-2-yl)acetamide *** *** *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 +CS EGFR DC50 [nM] 44 F f^xx^ / / \ J! JL H, ° 0 h 11 T T F'^-^'N'' \X H 2-[6-[4-[4-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]-2-fluoro-phenyl]-l-piperidyl]acetyl]piperazin-l-yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1 -yl]-N-thiazol-2-yl-acetamide *** *** *** 45 0 HN-X 0=7 J) ° N\ / x                     ___J / ~n^n o      r iT / \ jf J hn—4 °       F ^zN 2-[6-[4-[4-[2-[4-[3-(2,4-dioxohexahydropyrimidin-l-yl)-l-methyl-indazol-6-yl]-l-piperidyl]acetyl]piperazin-l-yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl]-N- thi azol -2-yl-acetami de *** *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 +CS EGFR DC50 [nM] 46 N=(  0 HN— Vn z n o        [1      ___ XZ              N > H 0 °^<N^0 H 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(2-(2-(4-(4-(((S)-2,6-dioxopiperidin-3-yl)amino)-2- fluorophenyl)piperidin-1 -yl)acetyl)-2,7 -diazaspiro[3.5]nonan-7 -yl)phenyl)-4-fluoro-1 -oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide ** ** 47 N=( o      F HN^ / x_Ax Ln z n o       |l A xz            'xz' 0        O^N^O \^Nz^sZ' H 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-[6-[4-[2- [2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-l- piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide *** *** *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 +CS EGFR DC50 [nM] 48 N=( O      F HN^ / NO      |l N^"\ ^^0  H H 2-(6,7-dihy dro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[2-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]-2-fluoro-phenyl]-l-piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide *** *** *** 49 0 hn-A nA 0 n=( o o         r ii HN— Vn^n    i 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[2-[2-[4-[3-(2,4-dioxohexahydropyrimidin-l-yl)-l-methyl-indazol-6-yl]-l-piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide *** *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 +CS EGFR DC50 [nM] 51 O^N^O        0 H H          0 Nu3 "Y^ Ynh F     0 Yn S^ 5-[2-[2-[l-(6Ydihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl]-7-fluoro-3-oxo-isoindolin-5-yl]ethynyl]-N-[l-[2-[4-[4-[(2,6-dioxo-3-piperidyl)oxy]phenyl]piperazin-l-yl]acetyl]-4-piperidyl]pyridine-2-carboxamide *** 52 H f T Y Y CT'N'X)           0 H N      0 H            ° NvXY YNH F      o )=N S\Y 5-[2-[2-[l-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl]-7-fluoro-3-oxo-isoindolin-5-yl]ethynyl]-N-[l-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]-2-fluoro-phenyl]-l -piperi dyl]acetyl]-4-piperidyl]pyridine-2-carboxamide *** *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 +CS EGFR DC50 [nM] 52 N=( O / / / NO / X^\ M o      11 2 xz                   N-^\ h 0          O^Nx^O H 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(6-(2-(4-(4-((2,6-di oxopiperi din-3-yl)amino)phenyl)-3,3-difluoropiperidin-l-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide, Isomer 2 *** 53 Q O F HN—X / / / NC / ^ / ^ Vn ZNO     |l -xZ                       N-^\ 0            O^N-Xf^o ^x^z H 2-(6,7-dihy dro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[2-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]-2-fluoro-phenyl]-l-piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6- yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-(2-py ri dy l)acetami de ** *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 +CS EGFR DC50 [nM] 54 0 - / / ^"N \ / ° °\ r t HN—\ Xr NCXX n^n     f 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[2-[2-[4-[3-(2,4-dioxohexahydropyrimidin-l-yl)-l-methyl- indazol-6-yl]-l-piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-(2- py ri dy l)acetami de *** 55 n=( o       >7 HN^ CQn <5^0^ h X J H 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-[6-[4-[4-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-l-piperidyl]acetyl]piperazin-l-yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thi azol-2-yl-acetamide *** *** *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 +CS EGFR DC50 [nM] 56 A's N=(   0       'i HN— ^lGN 0 XjL h H 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-[6-[4-[4-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]phenyl]-l-piperidyl]acetyl]piperazin-l-yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thi azol-2-yl-acetamide *** *** *** 57 n=( o J                  1 T T 1 OX o 000 2-(6,7-dihy dro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[[4-[2- [4- [4-[(2,6-di oxo-3 -piperi dyl)amino] -2-fluoro-phenyl] -1 -piperidyl]acetyl]piperazin-l-yl]methyl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide *** *** *** 58 N \ / ° i            Till HN \ J—fi^         0         o^n^o zv / vlU,         h 0 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-[6-[4-[[4-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]-2-fluoro-phenyl]-l -piperi dyl]acetyl]piperazin-1 -yl]methyl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide *** *** *** 59 OS      f n \ p                                           lr ] i HN   —[fA]                   o^nA ^yUU,       h \ r' Il         || j |        Y Y-n^n 0                 0 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-[6-[4-[[4-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]-2-fluoro-phenyl]-1 -piperi dyl]-2-oxo-ethyl]piperazin-1 - yl]methyl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thi azol -2-yl-acetami de *** *** *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 +CS EGFR DC50 [nM] n=( o HN V               o N^N 0                  / N. 60 \ II ** *** L Ij 0 hnA^ 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-[6-[4-[[l -[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]-2-fluoro-phenyl]-l-piperidyl]acetyl]-4-piperidyl]methyl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide / ~~n^n      ci Yxi hn—\ Y 0 Cl Ln                 ।   1 61 h Y °^N^° II \ Il ** 1        1 JL 1] H 2-[4,7-di chi oro-6-[4-[4-[2-[4-[4-[(2,6-di oxo-3-piperidyl)amino]phenyl]-1 -piperi dyl]acetyl]piperazin-1 -yl]phenyl]indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-N-thi azol-2-yl-acetamide Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 +CS EGFR DC50 [nM] 62 0                                               i— / NH '           T T । N\ / N"A ( >=o                          / ==^y M LJ    IXH N—, A               ANH oA.    -0                       0 XT        M 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-(6-(6-(4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)oxy)piperidin-l-yl)-4-oxobutyl)piperazin-l-yl)pyridin-3 -yl)-7-fluoro-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide *** 63 0 r      y ।     n^n—\ kA 1             L XLN \ Anh 11 J                     o An o Y                s J hnAnh 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-(6-(6-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1 -yl)acetyl)piperazin-1 -yl)pyri din-3 -yl)-7-fluoro-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide ** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 +CS EGFR DC50 [nM] 64 hn^^nh O   F     A° N \    / °        ^                    H 1 HN— / X / A >—N   ]    ]                  T f>=<          A Vn^n SAx m W 0 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[6-[4-[2- [4- [4-[(2,6-di oxo-3 -piperi dyl)amino] -2-fluoro-phenyl] -1 -piperidyl]acetyl]piperazin-l-yl]-3-pyridyl]-4-fluoro-indazol -2-y 1 ] -N-thi azol -2 -y 1 -acetami de ** 65 hnAnh O    f      A 0 HnA )— N ]    ]                  T a <-n^n         A L J N N A N 0 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-[6-[6-[4-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-l-piperidyl]acetyl]piperazin-l-yl]-3-pyridyl]-4-fluoro-indazol -2-y 1 ] -N-thi azol -2 -yl -acetami de *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 +CS EGFR DC50 [nM] 66 hn^^nh O    F      A 0 n=< pF       r h >—N   ]    ]                  T f>=<          A Vn^n SAx m W 0 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-[6-[6-[4-[2-[4-[5-[(2,6-dioxo-3-piperidyl)amino]-2-pyridyl]-l-piperidyl]acetyl]piperazin-l-yl]-3-pyridyl]-4-fluoro-indazol -2-y 1 ] -N - thi azol -2 -y 1 -acetami de *** *** 67 O HN / 0 aZa" n=( / °          i1                      fl i HnA               X-G >— N I]          T <>=<           X a-n a       k X    L J N N A N Gy 0 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[6-[4-[2-[4-[3-(2,4-dioxohexahydropyrimidin-l-yl)-l-methyl-indazol-6-yl]-1 -piperi dyl]acetyl]piperazin-1 -y 1 ]-3 -pyridyl]-4-fluoro-indazol -2-y 1 ] -N-thi azol -2 -yl -acetami de *** ** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 +CS EGFR DC50 [nM] 68 hn r s       _          x o N \ / °        ^                    H 1 HN— / >—N   ]    ]                  T f>=<          A VfxN   Mx m W 0 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(6-(4-(2-(4-(4-(((S)-2,6-dioxopiperidin-3-yl)amino)-2- fluorophenyl)piperidin-1 -yl)acetyl)piperazin-1 -yl)pyridin-3 -yl)-4-fluoro-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide *** *** Table 9B Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 69 H                F Ax                    F \ i [ \ h"          h 0 A / *n H 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(6-(6-(2-(4-(4-(((S)-2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1 -yl)acetyl)-2,6-diazaspiro[3.3 ]heptan-2-yl)pyri din-3 -yl)-7-fluoro-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide *** *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 70 / =\ / \ / \ / ° Z—S   0   f^\ A \   / —Nx Z\ ZN—\ Gk X / M     ) N N        N    f                  / —N H 1                                 /   \ / --\__ / o \_ / / f 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(6-(6-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)-3,3-difluoropiperidin-l-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-7-fluoro-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide *** *** 71 / "N  O        \ / ? \ II II / \ / \ / N\ / \ b N       N V              _ / 1                      f pOH / \ / / N °^ / > v y HN^N 0 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(6-(6-(2-( 1-(4-((2,6-di oxopiperi din-3 -yl)amino)-3-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3 ]heptan-2-yl)pyri din-3 -yl)-7-fluoro-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 72 F >=\         / —\ / 0 0    f==\   / 7--\    / —N    ,N—\ / A X .X       VA / H 1                                    \     ) / —v'n J ( ) F F HN \ z^T 0= /   N—<\  1 VNx 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(6-(4-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)-3,3-difluoropiperidin-l-yl)acetyl)piperazin-l-yl)pyri din-3-yl)-4-fluoro-2H-indazol-2-yl)-N-(thi azol-2-yl)acetamide *** 73 o     Xa- / \ A I A -\ N H 1                                  1 J kJ F F V / NX / '— 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(6-(6-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)-3,3-difluoropiperidin-l-yl)-2-oxoethyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-7-fluoro-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide *** *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 74 / =\ / =N 0 0   [^\ fl A F / --\"OH rvj \.M—J                  ,==( 0     —F HN— /     " 0=^  \—NH 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(6-(6-(2-( 1-(4-((2,6-di oxopiperi din-3 -yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3 ]heptan-2-yl)pyri din-3 -yl)-7-fluoro-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide *** 75 F / =\   / =N    .  .    0 o / —V0H / n^ \,N—7                / =( °     J)—F HN^ / 0=>f      NH 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-(6-(6-(6-(2-(l-(4-(((S)-2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3 ]heptan-2-yl)pyri din-3 -yl)-4-fluoro-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 76 H   1                            /   \ ! \__ / / "V F ° \_ / HAXL J / N 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(6-(2-((R)-4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)-3,3-difluoropiperidin-l-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide *** 77 F / =\   / =\   / \ Z\ / ° S 0     \ yu—N\ / \ / N—\ / —v0H U-           ( / \,N—J               / =( °     —F HN— \-NH 2-(6,7-dihy dro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(6-(2-(l-(4-(((S)-2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6- diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 78 / =\   / =\           / ° Z^S 0          \ # N^X / N \ \ A. JL J.. —(  x—            / N N Y N    f               >--(- OH _1 < ) J / = / 0     —F HN—V 0=(     NH 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-(6-(4-(6-(2-(l-(4-(((S)-2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6- diazaspiro[3.3]heptan-2-yl)phenyl)-7-fluoro-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide *** 79 F. / A      z\ / —\ P Z^N O        / )—V  V—N ¥  N-< H T              <\OH /       N                         P         / b HN— /  )= / O=^ y-^NH 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-(6-(4-(7-(2-(l-(4-(((S)-2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,7-diazaspiro[3.5]nonan-2-yl)phenyl)-4-fluoro-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 80 E )= / =      0 H 1   0                 <   ) N —i                \__ / / W 0 V / -F HN^ )= / )— NH 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-(6-(4-((lR,4R)-5-(2-(4-(4-(((S)-2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-l-yl)acetyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide ** *** 81 F O n CuN JW OK HN—\  y(     ' "p - - 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-(6-(4-((1 -(2-(4'-((2,6-di oxopiperi din-3 -yl)amino)-[ 1,1'-biphenyl]-4-yl)acetyl)piperidin-4-yl)oxy)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thi azol-2-yl)acetamide ** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 82 F >=\    / =\         0 Z^-N 0    r—4. #--W           / N \ s N                             >—N H 1    0                   (   ) ° \_( hn^m^C / N^ 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-((lR,4R)-5-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)piperidin-l-yl)acetyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide * 83 F. >=\   z^x   / —\  0 Z-N 0           \_ / ~N\__ / N o N   t   u                     / K OH H  1   0               <  > / —\ / / N F\ N-V 0 0=(    NH HN^ 0 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(4-(2-(l-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)piperazin-l-yl)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide *** *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 84 / rO Vn 0 F          L > H o fl \ I            F H 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(4-(2-(4-(4-(((S)-2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1 -yl)acetyl)-1,4-diazepan-1 - yl)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide ** ** 85 F. 0   r"0 / —<X Z>—N—v SANONY^     / 0^° H X 0          \ > N A—v         A / 0=\      Zn HN—N x 0 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(1-(2-(4-(3 -(2,4-dioxotetrahydropyrimidin-1 (2H)-yl)-1 -methyl- lH-indazol-6-yl)piperi din-1 -yl)-2- oxoethyl)piperidin-4-yl)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thi azol-2-yl)acetamide ** *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 86 F b N    X             _ / ^0 H          \\                        /  N Xx 0                \   \ / ---\ N X / N~^       H ,0 \ \\ °X X \__ H 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2- fluorophenyl)piperidin-l-yl)-2-oxoethyl)piperidin-l-yl)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide ** 87 F. H        U N  7—\ H F O=\  N—XI HN—N-N\ 0 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(6-(6-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)-3,3-difluoropiperidin-l-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide *** *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 88 F. 0   r—(\          (' V-?   ,__. HN—Z XN— H X Q                    / "-N n^—r HN-C O' F F 0=(  N-< ] V- / n"N\ 5-((2-(1-(6,7-dihydro-5H-pyrrolo[l, 2-c]imidazol-l-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisoindolin-5-yl)ethynyl)-N-(l-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1 (2H)-yl)-1 -methyl- IH-indazol-6-yl)-3,3-difluoropiperi din-l-yl)acetyl)piperidin-4-yl)picolinamide *** *** 89 F. / =\ / =\         ,0 O r— / 7 N\Z\ / N \ .A HI''          < POH 0 ) H 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(6-(2-( 1-(4-((2,6-di oxopiperi din-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3 ]heptan-2-yl)phenyl)-4-fluoro-1 -oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 90 \             p / -s o f-yrw  x> N N Y                          \    \ H 1    0                 .. af 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-(6-(4-(6-(2-(1-(5-((2,6-di oxopiperi din-3-yl)amino)-3-fluoropyridin-2-yl)-4-hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3 ]heptan-2-yl)phenyl)-4-fluoro-1 -oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide *** 91 p 0=V F             rN^     ' N t   n H 1 o N         i 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(4-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)-3,3-difluoropiperidin-l-yl)acetyl)-1,4-diazepan-1 -yl)phenyl)-4-fluoro-1 -oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide *** ** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 92 E >=\             0 Z^N 0 rA z*-^ V N JCn^ /           ' H 1   0                 (   ) / —\   / / N / —( 0 nA. H ° 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(4-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-m ethyl- lH-indazol-6-yl)piperazin-1 -yl)acetyl)piperazin-1 -yl)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide *** *** 93 H ZXWu . h                    L 1 I H ° NH F      0   ^=N 5 - [2-[2 - [ 1 -(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1 -yl)-2-oxo-2-(thiazol-2-ylamino)ethyl]-7-fluoro-3-oxo-isoindolin-5-yl]ethynyl]-N-[l-[2-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]acetyl]-4-piperidyl]pyridine-2-carb oxamide *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 94 F. / =\ / =\         ,0 0   r—\\ / )—<\ / >—N X N-Y J NV°     q o    # 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(6-(2-((S)-4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)-3,3-difluoropiperidin-l-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thi azol-2-yl)acetamide *** *** *** 95 E XX / =N        n H I o            / -\ N X—v                <  > O HN-X ^= / O=<  5—NH 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(6-(6-(2-(4-(4-(((S)-2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1 -yl)acetyl)-2,6-diazaspiro[3.3 ]heptan-2-yl)pyri din-3 -yl)-4-fluoro-1 -oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 96 F. / =\       / =N O nA—0              / Aoh N-^ <^~^>—F 0=(    NH HN~ / O 5-((2-(1-(6,7-dihydro-5H-pyrrolo[l, 2-c]imidazol-l-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisoindolin-5-yl)ethynyl)-N-(l-(2-(l-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)piperidin-4-yl)picolinamide *** *** 97 H L X Ll O^N"^O          0 H '—         0 H ° NH F      0   )=N 5-((2-(1-(6,7-dihydro-5H-pyrrolo[l, 2-c]imidazol-l-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisoindolin-5-yl)ethynyl)-N-(l-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-l-yl)acetyl)piperidin-4-yl)picolinamide *** *** *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 98 F N o r-A   / —(f=\—        / P / II II 1 V /       / /          N-# SAN\NY           / H I o            Z\0H WJj        \ / - / o HN— / )= / 0= / W"'NH 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-(6-(4-(6-(2-(l-(4-(((R)-2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3 ]heptan-2-yl)phenyl)-4-fluoro-1 -oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide *** *** *** 99 F. / =\   / =\   / \ Z\ / ° p o      N^p / \0H H 1   0                   <  > P \ / F HN—)= / )—NH 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(6-(2-( 1-(4-((2,6-di oxopiperi din-3 -yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3 ]heptan-2-yl)phenyl)-4-fluoro-1 -oxoisoindolin-2-yl)-N-(pyridin-2-yl)acetamide *** *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 100 F 0                          -- / =0 H          \\                           ,—N A o                   / \ / V N                          \    / \ / N~^                  / / 9 C#—F HN—#  Y—y °=C \*NH 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(6-(2-(4-(4-(((S)-2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1 -yl)-2-oxoethyl)-2-azaspiro[3.3 ]heptan-2-yl)phenyl)-4-fluoro-1 -oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide *** 101 F\_            .   0 ci r H 1   0                 \ J F\ / N p \_ / F hn-\ o=(y-NH 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-(6-(4-(6-(2-(1-(4-((2,6-di oxopiperi din-3-yl)amino)-2,6-difluorophenyl)piperidin-4-yl)acetyl)-2,6-diazaspiro[3.3 ]heptan-2-yl)phenyl)-4-fluoro-1 -oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide ** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 102 F. / T~N 0 rV   \ VnW-< H I   V                     / -N X 0             ( \ N     \                    \__ / ^~Nx /              / ~^F 0 y / 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(6-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)-3,3-difluoropiperidin-l-yl)-2-oxoethyl)-2-azaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide *** 103 F Q 5 r{KHX)^ H nV     O' / P \ >-F HN-Y ^= / o=<  y—NH 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-(6-(4-(6-(2-(1-(4-((2,6-di oxopiperi din-3-yl)amino)-2,6-difluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3 ]heptan-2-yl)phenyl)-4-fluoro-1 -oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide *** *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 104 F /  \         Z\      0 o N          rf                                 / H I 0         Hoh / =< F 0 4 )—( HN-Y         F 0=(  VNH 2-(6-(4-(6-(2-(l-(2-(difluoromethyl)-4-((2,6-dioxopiperidin-3-yl)amino)phenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1 -oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1 -yl)-N-(thiazol-2-yl)acetamide *** *** 105 ^ / S             r^N    / —\   O Vn^n   f      y? o CT' 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(l-(1-(2-(4-(3 -(2,4-dioxotetrahydropyrimidin-1 (2H)-yl)-1 -methyl-lH-indazol-6-yl)-3,3-difluoropiperidin-l-yl)acetyl)piperidin-4-yl)-lH-pyrazol-4-yl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 106 F. 7        N 0 nA H 0 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(2-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)-3,3-difluoropiperidin-l-yl)acetyl)-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thi azol-2-yl)acetamide *** 107 F. / =\ / =\   / —\ / x .0 #"N  0 r—V         N V N— / A Vy       / v°h nV?      O / °    Z^F HN-4 O=<  VNH 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(2-(2-( 1-(4-((2,6-di oxopiperi din-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,7-diazaspiro[3.5 ]nonan-7-yl)phenyl)-4-fluoro-1 -oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 108 5=\          HN— / / - N O r-Z / ~= \Z~A '-7 / ° / / °H H 1 0          w ,o H-f HN—?  )= / O=<   / "'NH N-(l-(2-(l-(4-(((R)-2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)piperidin-4-yl)-5-((7-fluoro-2-(l-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-3-oxoisoindolin-5-yl)ethynyl)picolinamide *** 109 F. )=\              0 " 4oh A'n^.n^ ° 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(6-(2-( 1-(3-(2,4-dioxotetrahy dropyrimidin-1 (2H)-yl)-l-methyl-lH-indazol-6-yl)-4-hydroxypiperidin-4-yl)acetyl)-2,6-di azaspiro [3.3 ]heptan-2-yl)phenyl)-4-fluoro-1 -oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 110 F / =\ / =\        o 0 yA / / / — N\X / N \ o          f)°H ___ / 0 ( V- F HN— /  )= / 0= / \-NH 2-(6,7-dihy dro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(6-(6-(2-(l-(4-(((S)-2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3 ]heptan-2-yl)pyri din-3 -yl)-4-fluoro-1 -oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide *** 111 F <0? j?                      N~^° A / n °        o0H N— / P / A-f HN—#  )= / 0=(  )""NH 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-(6-(6-(6-(2-(l-(4-(((R)-2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3 ]heptan-2-yl)pyri din-3 -yl)-4-fluoro-1 -oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 112 F )=\   / =\ Z\ Z\ / ° Z^N 0  I—C / 4 # N\Z^N \ O N T   U                      / —N H  1   °                  (   ) N / ---\                         )--- ^-n. )              n- / O     / -F HN— /  )= / O=<  )—NH 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(6-(2-(4-(5-((2,6-di oxopiperi din-3-yl)amino)-3-fluoropyridin-2-yl)piperidin-l-yl)acetyl)-2,6-diazaspiro[3.3 ]heptan-2-yl)phenyl)-4-fluoro-1 -oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide *** 113 F. N o                  N / \ / 1 HN^Z \\ / n-n o     \ 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(6-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)-3,3-difluoropiperidin-l-yl)acetyl)-2,6-diazaspiro[3.4]octan-2-yl)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thi azol-2-yl)acetamide *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 114 F o   ,—\\ / 9 \ 11 II ' y / X / / N\2\   n-# H X o           Z\0H N T—\                    \   ) F\__,N— # o HN— /  \= / °=^ y—NH 2-(6,7-dihy dro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[7-[2-[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetyl]-2,7- diazaspiro[3.5]nonan-2-yl]phenyl]-4-fluoro- 1-oxo-isoindolin-2-yl]-N-thi azol-2-yl-acetamide *** 115 f.       / =\    / x / —\ / vTy n vv n Ss-XA-ny"7       <~v°h N- / <-A Pj 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-[6-[4-[7-[2-[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetyl]-2,7-diazaspiro[3.4]octan-2-yl]phenyl]-4-fluoro- 1-oxo-isoindolin-2-yl]-N-thi azol-2-yl-acetamide *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 116 F. ax -wxx.; H     U              Z^N A 0                   1 / —\ N          X^zA< f"Ln~^            [ jf f F ©A Yi—ZV \    N—G   1 HNA n-n\ 0 2-[6-[4-[2-[2-[4-[3-(2,4-dioxohexahydropyrimidin-l-yl)-l-methyl-indazol-6-yl]-3,3-difluoro-l-piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H- pyrrolof 1,2-c]imidazol-1 -yl]-N-thiazol-2-yl-acetamide *** 117 F VA o         / \0H /                      Cl\   N— / A HN— /  \= / 0=Ly—NH 2-[6-[4-[2-[2-[l-[2-chloro-4-[(2,6-di oxo-3-piperidyl)amino]phenyl]-4-hydroxy-4-piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-1 -yl)-N-thiazol-2-yl-acetamide *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 118 F \ A A N                 / =° H A 0               < ) / —f N                \_ / A A J      N 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(6-(6-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)-3,3-difluoropiperidin-l-yl)-2-oxoethyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide *** 119 E / \ AA Z\ z\ P 0  r—v  —v / / —N\X N \ o0H 0 AV- F HN—7  )= / Isomer 1      0== / \-NH 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-(6-(4-(6-(2-(1-(4-((2,6-di oxopiperi din-3-yl)amino)-2,6-difluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3 ]heptan-2-yl)phenyl)-4-fluoro-1 -oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide, isomer 1 *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 123 F. / =\ / =\ z\ / \   / ° 0   r—(\ / )—(\ / )—N X N—¥ UN1     V3 x °         c > / \                R   N—' J HJ nV-oXJ 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[2-[2-[4-[3-(2,4-dioxohexahydropyrimidin-l-yl)-5-fluoro-l-methyl-indazol-6-yl]piperazin-l-yl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide *** 125 F. ax-X0""^ H A o            / -< N X—.                \  > / —\ /  \ F ,° V# Isomer 2              JJ / —( N 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[2-[2-[4-[3-(2,4-dioxohexahydropyrimidin-l-yl)-l-methyl-indazol-6-yl]-3 -fluoro-1 -piperi dyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide, isomer 2 *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 127 F / A / =\        / ° 0 r-A / )—<\ / )—N X M « X Y       Hoh N A—\         !Z w \\ / \                      F.     N—' > \__ / jn oAJ 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[2-[2-[l-[3-(2,4-dioxohexahydropyrimidin-l-yl)-5-fluoro-l-methyl-indazol-6-yl]-4-hydroxy-4-piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thi azol-2-yl-acetamide *** 128 F / \ / =\   / —\ / \   / ° 0   ।— / \ / N \ 1       X0H CX / ,N                Cl N-^ Isomer 1           HN—V   — 0= /    NH 2-[6-[4-[2-[2-[l-[2-chloro-4-[[2,6-di oxo-3-piperidyl]amino]phenyl]-4-hydroxy-4-piperidyl]acetyl]-2,7-di azaspiro [3.5 ]nonan-7-yl]phenyl] -4-fluoro-1 -oxo-isoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-N-thiazol-2-yl-acetamide, isomer 1 *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 129 F. / =\ / =\         ,0 0   r—\\ / )—<\ / )—N X N—7 J H 1 o            r \ N                       \__ / \=?~f F 0 Y / Isomer 1             Jl / \ J F N 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[2-[2-[4-[3-(2,4-dioxohexahydropyrimidin-l-yl)-5-fluoro-l-methyl-indazol-6-yl]-3,3-difluoro-l-piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-l-oxo- isoindolin-2-yl]-N-thiazol-2-yl-acetamide, isomer 1 *** 130 F. / =\   / =\ / x     ,0 / T'N 0   r—4 / ) C    N^X N-< V'n\ny         > H 1 o            r \ N 'Y--y                r \__ / Isomer 2                P y_ HNAj-A J      N 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[2-[2-[4-[3-(2,4-dioxohexahydropyrimidin-l-yl)-5-fluoro-l-methyl-indazol-6-yl]-3,3-difluoro-l-piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide, isomer 2 *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 131 F. O u sAA / nA7 ^-7     \ H A o            / \ 0H N 7—\                  \   / AAAf       _^-7 P O-F hn-A o=< Anh 2-[6-[4-[2-[2-[l-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]-2-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H- pyrrolof 1,2-c]imidazol-1 -yl]-N-thiazol-2-yl-acetamide *** 132 F. A~N o  )—(f A—AX—mAA / / ° K II II / A /   A \X,N-A AnAnA ^-7    \ H A o            / \0H __ / N- / zP HN— / O=< \"NH 2-[6-[4-[2-[2-[l-[4-[[(3R)-2,6-dioxo-3-piperidyl]amino]-2-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H- pyrrolol" 1,2-c]imidazol-1 -yl]-N-thiazol-2-yl-acetamide *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 133 F. >=\ zr^x           0 z^n o rA / —f / > S u     1      \\ H  1   0              F—<   ) / —N                   \__ / ° / hnA XV J     N 0^\_J 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[2-[2-[4-[3-(2,4-dioxohexahydropyrimidin-l-yl)-l-methyl-indazol-6-yl]-3 -fluoro-1 -piperi dyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide *** 134 F. .         0 0  r—4 / Xn   / \ / N—\ '                  .—2-oh H X °                   / ) 0 C# F Isomer 1             HN—\    / 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[2-[2-[ l-[4-[[2,6-di oxo-3 -piperi dyl]amino]-2,6-difluoro-phenyl]-4-hydroxy-4-piperidyl]acetyl]-2,7-diazaspiro[3.5]nonan-7-yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide, isomer 1 *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 135 F /  \   / =\ Z\      / ° o rA_ #—\ / / Ny\ / N \ °         r> (>N     %T 0=<   >-NH F 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[2-[2-[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,5-difluoro-phenyl]-4-hydroxy-4-piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide *** 136 Cl h r n                              ) 6)0H F V- / HN-y vy 0==^J^NH 2-[4-chloro-6-[4-[2-[2-[l-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]-2-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-l-oxo-isoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[l,2- c]imidazol-1 -yl)-N-thiazol-2-yl-acetamide *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 137 F. / A / =\   / \ / —\ / ° #"S  0  r—4 / — / / N\ / \ N \ AVY      Z\oh n^7                 >=< o 4     F Isomer 1           HN—7 0= / y—NH 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[7-[2-[ l-[4-[[2,6-di oxo-3-piperi dyl]amino]-2,6-difluoro-phenyl]-4-hydroxy-4-piperidyl]acetyl]-2,7- diazaspiro[3.5]nonan-2-yl]phenyl]-4-fluoro- 1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide, isomer 1 ** 138 F / =\   / =\        \  0 0   r—4  Z>--N       N \ /               / —4-oh H 1   0                  (  \ / —V N \ H                            N—' / =( 0      Z>—Cl isomer 1       HN—7    / — 0= /     NH 2-[6-[4-[7-[2-[l-[2-chloro-4-[[2,6-di oxo-3-piperidyl]amino]phenyl]-4-hydroxy-4-piperidyl]acetyl]-2,7-di azaspiro [3.5 ]nonan-2-yl]phenyl] -4-fluoro-1 -oxo-isoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-N-thiazol-2-yl-acetamide, isomer 1 *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 139 F )=\ / =\        P 0          <> H \ N-y / o 6 N Isomer 1                 y / O=<   )—NH 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-[6-[4-[2-[2-[l-[5-[[2,6-dioxo-3-piperidyl]amino]-3-fluoro-2-pyridyl]-4-hydroxy-4-piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide, isomer 1 *** 140 F. )=0 H X o            AN\ 0 y y d / N 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-[6-[4-[7-[2-[(4R)-4-[3 -(2,4-dioxohexahydropyrimidin-1 -yl)-1 -methyl-indazol-6-yl]-3,3-difluoro-l-piperidyl]-2-oxo-ethyl]-2,7-diazaspiro[3.5]nonan-2-yl]phenyl]-4-fluoro-l- oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 141 F 5? JI 0 y / ASAA 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[7- [2- [(4 S)-4- [3 -(2,4-dioxohexahy dropyrimidin-1 -yl)-1 -methyl-indazol-6-yl]-3,3-difluoro-l-piperidyl]-2-oxo-ethyl]-2,7-diazaspiro[3.5]nonan-2-yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide ** 142 n s-^ 0 HN^ / N XL X / __\ / ° F N-- / HN-X / °K__y NH 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[l-[l-[2-[l-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]-2-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetyl]-4-piperidyl]pyrazol-4-yl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thi azol -2-yl-acetami de *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 143 F o X—      / =0 o N  >< ><                            / h X  °                / ~N\ N X—\                \ / 0 y / hAXX oXZ 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-[6-[4-[2-[2-[(4R)-4-[3 -(2,4-dioxohexahydropyrimidin-1 -yl)-1 -methyl-indazol-6-yl]-3,3-difluoro-l-piperidyl]-2-oxo-ethyl]-2,7-diazaspiro[3.5]nonan-7-yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide ** 144 F ,0 o SAmAZs /   '—  '—    / =0 H I »                        / — N nV?      o / =(Tf 0 y / o^^X-J 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[2- [2- [(4 S)-4- [3 -(2,4-dioxohexahydropyrimidin-1 -yl)-1 -methyl-indazol-6-yl]-3,3-difluoro-l-piperidyl]-2-oxo-ethyl]-2,7-diazaspiro[3.5]nonan-7-yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 145 F. /  \   / =\ Z\ Z\ / ° 0       fl—N\ / \ / N\ .—2-oh H 1   0                  (   ) rn       \ / 0 (      Cl HnY Isomer 1          q= /     NH 2-[6-[4-[2-[2-[l-[2-chloro-4-[[2,6-di oxo-3- piperidyl]amino]-6-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1 -oxo-i soindolin-2-yl] -2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-N-thiazol-2-yl-acetamide, isomer 1 ** 146 F. / =\   / =\   / \ Z\ / ° 0 X YA # N\ / YN \ / 0H O H Y 0                  N F Isomer 1 0, NH „p 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-[6-[4-[2-[l-[4-[[2,6-dioxo-3-piperidyl]amino]-2-fluoro-phenyl]-4-hydroxy-piperidine-4-carbonyl]-2,6- diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide, isomer 1 *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 147 F. )=\ / =\        p p-S 0   r==( ft—4 >7 N\Z\ / N \ N^N^yN'N              ,—Z-OH < > c" c ^NH 0 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[2-[2-[l-[4-(2,4-dioxohexahydropyrimidin-l-yl)-2-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetyl]-2,6- diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-indazol-2-yl]-N-thi azol -2-y 1 -acetami de *** 148 F. / \   / =\ Z\ Z\   / ° ft-S  0                / 7 N\ / X / N  \ x       JL   N                                 / N N               / —\0H F\  N—? °   4 & hny O=<^   / —NH 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[2-[2-[(2s,6r)-l-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-4-hydroxy-2,6-dimethyl-4- piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-indazol -2 -y 1 ] -N-thi azol -2-y 1 -acetami de *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 149 / =\ / =\   / —\ 0H / -S  0  r===\ / 4 # N\ / A_ N            N    F             r~ N H 1                                /    \ / —F.   )—' 0 \ / HN^ )= / 0=(  )—NH 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-[6-[4-[4-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]-2-fluoro-phenyl]-1 -piperidyl]-2-oxo-ethyl]-4-hydroxy-1 -piperidyl]phenyl]-7-fluoro-indazol-2-yl]-N-thi azol-2-yl-acetamide *** 150 a r N          n                  / ^N H 1                              / \ / —\  ,N                F.   )— / HN—)= / 0=<  )—NH 2-(6,7-dihy dro-5H-pyrrolo[l, 2-c]imidazol-l -yl)-2-[6-[6-[4-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]-2-fluoro-phenyl]-l-piperi dyl]-2-oxo-ethyl]-4-hydroxy-l -piperi dyl]-3-pyridyl]-4-fluoro-indazol-2-yl]-N-thiazol-2-yl-acetamide *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 151 / = =N   / —\ OH ns 0 v \ y v       / \- n^x'nx^VN"n / f            / -n H 1                              / \ / —v'N            E  )—' HN—\  )=7 0=^  >—NH 2-(6,7-dihy dro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[6-[4-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]-2-fluoro-phenyl]-l-piperidyl]-2-oxo-ethyl]-4-hydroxy-l -piperi dyl]-3-pyridyl]-7-fluoro-indazol-2-yl]-N-thiazol-2-yl-acetamide *** 152 F. )=\   / =\        0 / "N 0 r-A #—4 #—\  ZN \ X   > s N Y Y      ' H 1   0                 (   ) N 'Y—v                 \__ / P \ / HN^ )= / 0=^ y—NH 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[l-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-l-piperidyl]acetyl]-4-piperidyl]-2-methyl-phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thi azol-2-yl-acetamide ** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR DC50 [nM] 153 F. .           / =\           y\ P r ii 0         —\_ / N\ / \ / N \ ^Ln H A o               / \ / —x n                \_ / 0 )=( hAZI J / N 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[2-[2-[7-[3-(2,4-dioxohexahydropyrimidin-l-yl)-l-methyl-indazol-6-yl]-4-azaspiro[2.5]octan-4-yl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-(2-pyridyl)acetamide ** 154 F.                                0 XX / =n rW          Nz l X! \ / I 0                 )—' HN ° s / ^n              o umA X ZN--HN N^N oAA 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[2-[2-[7-[3-(2,4-dioxohexahydropyrimidin-l-yl)-l-methyl-indazol-6-yl]-4-azaspiro[2.5]octan-4-yl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide *** *** Compound H1975 EGFR DC50 [nM] H3255 EGFR DC50 [nM] H1975 C797S clone EGFR ...

Claims

1. A method of treating an EGFR mediated cancer that has metastasized to the brainor CNS comprising administering an effective amount of a Compound selectedor a pharmaceutically acceptable salt thereof to a patient in need thereof;whereinA* is selected from:B* is heteroaryl or aryl each of which is optionally substituted with 1, 2, or 3 R31 substituents;y is 0, 1, 2, or 3;R31 is independently selected at each occurrence from H, halogen (F, Cl, Br, or I), Ci-6-alkyl, cyano, Ci-6-alkoxy, halo-Ci-6-alkoxy, halo-Ci-6-alkyl, C3-8-cycloalkyl, and halo-C3-8-cycloalkyl and can be located on either ring where present on a bicycle;R32 is hydrogen, halogen (F, Cl, Br, or I), Ci-6-alkyl, halo-Ci-6-alkyl, C3-8-cycloalkyl, or halo-Cs-s-cycloalkyl;R33 is hydrogen, halogen (F, Cl, Br, or I), Ci-6-alkyl, halo-Ci-6-alkyl, C3-8-cycloalkyl, or halo-C3-8-cycloalkyl and can be located on the dihydropyrrole or imidazole ring;R34 is independently selected at each occurrence from H, F, Ci-6-alkyl, halo-Ci-6-alkyl, C3-8-cycloalkyl, and halo-C3-8-cycloalkyl;R35 is independently selected at each occurrence from H, halogen (F, Cl, Br, or I), Ci-6-alkyl, halo-Ci-6-alkyl, and C3-8-cycloalkyl;or R34 and R35 combine to form -(CH2)q-;q is 1 or 2;R36 and R37 are independently selected from H, halogen (F, Cl, Br, or I), cyano, Ci-6-alkoxy, halo-Ci-6-alkoxy, Ci-6-alkyl, halo-Ci-6-alkyl, C3-8-cycloalkyl, and halo-C3-8-cycloalkyl;or R36 and R37 together are combined to form a 5- or 6- membered cycle optionally substituted with 1, 2, or 3 R31 substituents;R90 is H, Ci-6-alkyl, or C3-6-cycloalkyl;Ring G is a heteroaryl optionally substituted with 1 or 2 R42 substituents;A21 is -NH-, -O-, -CH2-, or -NR100-;R100 is alkyl, cycloalkyl, aryl, or heteroaryl; or as allowed by valence R100 may combine with R37 to form a 5-8 membered heterocycle or 5 membered heteroaryl;A32, A33, A34, and A35 are independently selected from -N- and -CR42-;R42 is independently selected at each occurrence from H, halogen (F, Cl, Br, or I), cyano, Ci-6-alkoxy, halo-Ci-6-alkoxy, Ci-6-alkyl, halo-Ci-6-alkyl, Cs-s-cycloalkyl, and halo-Cs-s-cycloalkyl;A36 is -N- or -CR35-;L2 is a bivalent linking group that connects A* and either the isoindolinone or indazole.

2. The method of claim 1, wherein L2 is of formula:V.         / r2< / r2< xT^X1   ^R23  ^R21  ^X2  (LI).wherein,X1 and X2 are independently at each occurrence selected from bond, heterocycle, aryl, heteroaryl, bicycle, alkyl, aliphatic, heteroaliphatic, -NR27-, -CR40R41-, -O-, -C(O)-, -C(NR27)-, -C(S)-, -S(O)-, -S(O)2- and -S-; each of which heterocycle, aryl, heteroaryl, and bicycle is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R40;R20, R21, R22, R23, and R24 are independently at each occurrence selected from the group consisting of a bond, alkyl, -C(O)-, -0(0)0-, -00(0)-, -S02-, -S(0)-, -C(S)-, -C(O)NR27-, -NR27C(O)-, -0-, -S-, -NR27-, oxyalkylene, -C(R40R40)-, -P(O)(OR26)O-, -P(O)(OR26)-, bicycle, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, and carbocycle; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R40;R26 is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocycle, aliphatic and heteroaliphatic;R27 is independently at each occurrence selected from the group consisting of hydrogen, alkyl, aliphatic, heteroaliphatic, heterocycle, aryl, heteroaryl, -C(O)(aliphatic, aryl, heteroaliphatic or heteroaryl), -C(O)O(aliphatic, aryl, heteroaliphatic, or heteroaryl), alkene, and alkyne;R40 is independently at each occurrence selected from the group consisting of hydrogen, R27, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH(aliphatic), -N(aliphatic)2, -NHSO2(aliphatic), -N(aliphatic)SO2alkyl, -NHSO2(aryl, heteroaryl or heterocycle), -N(alkyl)SO2(aryl, heteroaryl or heterocycle), -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocycle, oxo, and cycloalkyl; additionally,where allowed by valence two R40 groups bound to the same carbon may be joined together to form a 3-8 membered spirocycle; andR41 is aliphatic, aryl, heteroaryl, or hydrogen.

3. The method of claim 1, wherein the Compound is selected from Table 9A and Table 9B.

4. A method of treating an EGFR mediated cancer that has metastasized to the brain or CNS comprising administering an effective amount of a Compound selected from:or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

5. A method of treating an EGFR mediated cancer that has metastasized to the brain or CNS comprising administering an effective amount of a Compound of structure:or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

6. A method of treating an EGFR mediated cancer that has metastasized to the brain or CNS comprising administering an effective amount of a Compound of structure:or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

7. A method of treating an EGFR mediated cancer that has metastasized to the brain or CNS comprising administering an effective amount of a Compound of structure:or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

8. A method of treating an EGFR mediated cancer that has metastasized to the brainor CNS comprising administering an effective amount of a Compound of structure:or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

9. A method of treating an EGFR mediated cancer that has metastasized to the brain or CNS comprising administering an effective amount of a Compound of structure:or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

10. A method of treating an EGFR mediated cancer that has metastasized to the brainor CNS comprising administering an effective amount of a Compound of structure:or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

11. A method of treating an EGFR mediated cancer that has metastasized to the brain or CNS comprising administering an effective amount of a Compound of structure:or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

12. A method of treating an EGFR mediated cancer that has metastasized to the brain or CNS comprising administering an effective amount of a Compound of structure:or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

13. A method of treating an EGFR mediated cancer that has metastasized to the brain or CNS comprising administering an effective amount of a Compound of structure:or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

14. A method of treating an EGFR mediated cancer that has metastasized to the brain or CNS comprising administering an effective amount of a Compound of structure:Eor a pharmaceutically acceptable salt thereof, to a patient in need thereof.

15. A method of treating an EGFR mediated cancer that has metastasized to the brain or CNS comprising administering an effective amount of a Compound of structure:or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

16. A method of treating an EGFR mediated cancer that has metastasized to the brain or CNS comprising administering an effective amount of a Compound of structure:or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

17. The method of any one of claims 1-16, wherein the patient is a human.

18. The method of any one of claims 1-17, wherein the EGFR mediated cancer is mediated by a mutant EGFR.

19. The method of claim 18, wherein the mutant EGFR has an Exon 21 mutation.

20. The method of claim 19, wherein the mutant EGFR has a L858R mutation.

21. The method of claim 19, wherein the mutant EGFR has a L861Q mutation.

22. The method of any one of claims 18-21, wherein mutant EGFR has a T790M mutation.

23. The method of any one of claims 18-22, wherein mutant EGFR has a C797S mutation.

24. The method of claim 18, wherein the mutant EGFR has a L858R and T790M mutation.

25. The method of claim 18, wherein the mutant EGFR has a L858R, T790M, and C797S mutation.

26. The method of any one of claims 1-25, wherein the Compound is administered as part of a pharmaceutical composition.

27. The method of any one of claims 1-26, wherein the Compound is administered orally.

28. The method of any one of claims 1-26, wherein the Compound is administered parenterally.

29. The method of any one of claims 1-26, wherein the Compound is administered by intravenously.

30. The method of any one of claims 1-29, wherein an ATP site binding EGFR ligand is also administered to the patient in need thereof.

31. The method of claim 30, wherein the ATP site binding EGFR ligand is osimertinib or a pharmaceutically acceptable salt thereof.

32. The method of claim 30, wherein the ATP site binding EGFR ligand is naquotinib or a pharmaceutically acceptable salt thereof.

33. The method of claim 30, wherein the ATP site binding EGFR ligand is mavelertinib or a pharmaceutically acceptable salt thereof.

34. The method of claim 30, wherein the ATP site binding EGFR ligand is spebrutinib or a pharmaceutically acceptable salt thereof.

35. The method of any one of claims 1-34, wherein the EGFR mediated cancer is lung cancer that has metastasized to the brain or CNS.

36. The method of any one of claims 1-34, wherein the EGFR mediated cancer is nonsmall cell lung cancer that has metastasized to the brain or CNS.

37. The method of any one of claims 1-34, wherein the EGFR mediated cancer is small cell lung cancer that has metastasized to the brain or CNS.

38. The method of any one of claims 1-34, wherein the EGFR mediated cancer is adenocarcinoma that has metastasized to the brain or CNS.

39. The method of any one of claims 1-34, wherein the EGFR mediated cancer is squamous cell lung cancer that has metastasized to the brain or CNS.

40. The method of any one of claims 1-34, wherein the EGFR mediated cancer is largecell undifferentiated carcinoma that has metastasized to the brain or CNS.

41. The method of any one of claims 1-34, wherein the EGFR mediated cancer is neuroendocrine carcinoma that has metastasized to the brain or CNS.

42. The method of any one of claims 1-34, wherein the EGFR mediated cancer is sarcomatoid carcinoma, adenosquamous carcinoma, oat-cell cancer, combined small cell carcinoma, lung carcinoid tumor, central carcinoid, peripheral carcinoid, salivary gland-type lung carcinoma, mesothelioma, or a mediastinal tumor that has metastasized to the brain or CNS.

43. The method of any one of claims 1 -34, wherein the EGFR mediated cancer is breast cancer that has metastasized to the brain or CNS.

44. The method of claim 43, wherein the EGFR mediated cancer is HER-2 positive breast cancer.

45. The method of claim 43 or 44, wherein the EGFR mediated cancer is ER+ breast cancer.

46. The method of any one of claims 43-45, wherein the EGFR mediated cancer is PR+ breast cancer.

47. The method of any one of claims 1-34, wherein the EGFR mediated cancer is triple negative breast cancer.

48. The method of any one of claims 1-34, wherein the EGFR mediated cancer is colorectal or rectal cancer that has metastasized to the brain or CNS.

49. The method of any one of claims 1-34, wherein the EGFR mediated cancer is head and neck cancer or esophageal cancer that has metastasized to the brain or CNS.

50. The method of any one of claims 1-34, wherein the EGFR mediated cancer is pancreatic cancer that has metastasized to the brain or CNS.

51. The method of any one of claims 1-34, wherein the EGFR mediated cancer is thyroid cancer that has metastasized to the brain or CNS.

52. The method of any one of claims 1-34, wherein the EGFR mediated cancer is ovarian cancer, uterine cancer, or cervical cancer that has metastasized to the brain or CNS.

53. The method of any one of claims 1-34, wherein the EGFR mediated cancer is kidney cancer, liver cancer, or bladder cancer that has metastasized to the brain or CNS.

54. The method of any one of claims 1-34, wherein the EGFR mediated cancer is melanoma that has metastasized to the brain or CNS.

55. The method of any one of claims 1-54, wherein the EGFR mediated cancer has metastasized to the brain.

56. The method of any one of claims 1-54, wherein the EGFR mediated cancer has metastasized to the CNS.

57. The method of any one of claims 1-56, wherein the Compound is administered to a patient with treatment naive EGFR mediated cancer.

58. The method of any one of claims 1-56, wherein the EGFR mediated cancer is relapsed.

59. The method of any one of claims 1-56, wherein the EGFR mediated cancer is refractory.

60. The method of any one of claims 1-56, wherein the EGFR mediated cancer is relapsed and refractory.

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