ISOINDOLINONE AND INDAZOLE COMPOUNDS FOR EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) DEGRADATION

Abstract

The invention provides compounds that degrade the epidermal growth factor receptor (EGFR), including mutant forms, through ubiquitination of the EGFR protein and subsequent proteasomal degradation; the compounds are useful for the treatment of various types of cancer.

Description

ISOINDOLINONE AND INDAZOLE COMPOUNDS FOR THE DEGRADATION OF THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of the U.S. Provisional Application. 62 / 951,464 that was filed on December 20, 2019, and the U.S. Provisional Application. 62 / 951,467 which was filed on December 20, 2019, the entirety of which is incorporated by reference, for all purposes. FIELD OF THE INVENTION The invention provides compounds that degrade the epidermal growth factor receptor (EGFR), including mutant forms through ubiquitination of the EGFR protein and subsequent proteasomal degradation. The compounds are useful for the treatment of various types of cancer. BACKGROUND OF THE INVENTION Receptor tyrosine kinases of the HER family are mediators of cell growth, differentiation, and survival. The receptor family includes four different members, i.e., epidermal growth factor receptor (EGFR, ErbBI, or HERI), HER2 (ErbB2), HER3 (ErbB3), and HER4 (ErbB4). Upon ligand binding, the receptors form homo- and heterodimers and subsequent activation of intrinsic tyrosine kinase activity leads to auto-phosphorylation of the receptors and 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, particularly non-small cell lung cancer (NSCLC). Several agents targeting EGFR 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®), a reversible EGFR tyrosine kinase inhibitor, has been approved in numerous countries for the treatment of recurrent NSCLC. Impressive single-agent activity of EGFR tyrosine kinase inhibitors was observed in a subset of NSCLC patients whose tumors harbor mutations in the somatic kinase domain, while clinical benefit in patients with type EGFR Wild ΜΛ / a / ZUZZ / UU / 00» is greatly decreased (Paez, J. et al. (2004). EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science (New York, NY 304, 1497 -1500). Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 2007 Mar;7(3): 169-81). Resistance to treatment arises frequently, often due to secondary mutation of T790M within the ATP site of the receptor. Some selective mulant irreversible inhibitors developed are highly active against the T790M mulant, but their efficacy can be compromised by the acquired mutation of C797S, which is the cysteine ​​residue with which they can form a key covalent bond (Thress, K. S. et al. Acquired EGFR C797S mutation medial resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat. Med. 21, 560-562 (2015). Wang further reported that the C797S mutation is an important mechanism for resistance to EGFR inhibitors targeting T790M (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 causing resistance to Osimertinib are described by Yang, 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). Targeting EGFRL858R / T790Mand EGFRL858R / T790M / C797Sresistance mutations in NSCLC: Current developments in medicinal chemistry, Med Res Rev 2018; 1-32). Additional examples of EGFR inhibitors, in particular selective T790m inhibitors contain Kinase inhibitors against EGFR T790M, NATURE, (20091224), vol. 462, no. 7276, doi:10.1038 / nature08622, ISSN 0028-0836, pages 1070 - 1074. Since most of the available EGFR tyrosine kinase inhibitors target the ATP site of the kinase, there is a need for new therapeutic agents that function differently, for example, through drug-resistant EGFR mulants. Recent studies suggest that deliberately targeting allosteric sites leads to mutant-selective allosteric inhibitors (Jia etal. 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 cell health and productivity. Cereblon is a protein that forms an E3 ubiquitin ligase complex, which ubiquitinates several other proteins. Cereblon is known as the primary target for thalidomide analogues against cancer. Higher cereblon expression has been linked to the efficiency of thalidomide analogues 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 as targeted ubiquitination. Additional modulators for targeted ubiquitination include those described in Ranok Therapeutics Hangzhou WO2020206608 and WO2020207396; those described by Arvinas 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 WO201 9165229; those described by Kymera in WO2019 / 060742, WO2019 / 140387, and WO2020 / 01022; and those described by C4 Therapeutics Inc. in WO2017197036, WO2017197046, WO2017197051, WO2017197055, WO2018237026, WO2019099868, WO2019191112, WO2019204353, WO20 19236483, WO2020132561, WO2020181232, and WO2020210630. Some of the molecules specific for EGFR degradation have also been described, for example, the Dana-Farber Cancer Institute described EGFR degraders in WO2017185036. F. Hoffman-La-Roche described EGFR degraders in WO2019121562 and WO2019149922. Arvinas has described EGFR degraders in WO2018119441. Despite these efforts, there is still a need for new EGFR modulators to treat EGFR-mediated disorders in hosts, and in particular humans, who need them. BRIEF DESCRIPTION OF THE INVENTION Provided are compounds and their uses and manufacture that degrade the epidermal growth factor receptor (EGFR) protein through the ubiquitin proteasome (UPP) pathway. 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 moiety (typically through a subunit cereblon) 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 portion of A or A*, the Linker is a portion of L1 or L2, and the remainder of the molecule is the EGFR Targeting Ligand portion. In certain embodiments, a compound of the present invention 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 three mutations selected from T790M, L858R, and C797S. In certain embodiments, a compound of the present invention is a selective degrader of T790M / L858R, T790M / L858R / C797S, L858R, or L858R / C797S containing EGFR mutants. A compound of the present invention provided herein or its pharmaceutically acceptable salt and / or its pharmaceutically acceptable composition can be used to treat a disorder that is mediated by EGFR. In some embodiments, a method of treating a patient with an EGFR-mediated disorder is provided, which includes administering an effective amount of one or more compounds as described herein, or a pharmaceutically acceptable salt thereof, to the patient, usually a human, optionally in a pharmaceutically acceptable composition. In one aspect, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof; where: A is selected from the AF and AG ring systems; AF AG A1is selected from i) -NH-, and i) -O-; A2is selected from i) -N-, and i) -CR52-; A3is selected from i) -N-, and i) -CR53-; A4 is selected from i) -N-, and i) -CR54-; A5is selected from ¡) -N-, and ¡i) -CR55-; R1is selected from i) H, i) halogen iii) Ci-β alkyl; R52is selected from i) H, i) halogen, iii) cyano, iv) Ci-6 alkoxy, v) halo-Ci-s-alkoxy, vi) Ci-6 alkyl, vii) halo-Ci-6-alkyl, viii ) C3-8 cycloalkyl, and ix) halo-C3-8-cycloalkyl; R53, R54 and R55 are independently selected from i) H, i) halogen, i) C1-6 alkyl, iv) halo-Ci-6-alkyl, v) C3-8 cycloalkyl, and IVIA / S / ZUZZ / UU / 00» vi) halo-Cs-s-cycloalkyl; R2is selected from i) H, i) halogen, iii) Ci-6 alkyl, iv) halo-Ci-e-alkyl, v) C3-8 cycloalkyl, and vi) halo-Cs-s-cycloalkyl; R3is selected from i) H, i) halogen, iii) C1-6 alkyl, iv) halo-Ci-s-alkyl, v) C3-8 cycloalkyl, and vi) halo-Cs 8-cycloalkyl; R4 and R5 are H; or R4 and R5 together form -(CH2)q-; q is 1 or 2; R6is selected from ¡) H, ii) halogen, iii) cyano, iv) C1-6 alkoxy, v) halo-Ci-e-alkoxy, vi) C1-6 alkyl, vii) halo-Ci-e-alkyl, viii) C3-8 cycloalkyl, and ix) halo-Cs-s-cycloalkyl; R7is selected from i) H, i) halogen, iii) cyano, iv) C1-6 alkyl, v) halo-Ci-6-alkyl, vi) C3-8 cycloalkyl, and vii) halo-Cs-s-cycloalkyl; R70is selected from i) H, ii) halogen, iii) cyano, iv) Ci-6 alkyl, v) halo-Ci-6-alkyl, vi) C3-8 cycloalkyl, and vii) halo-Cs-s-cycloalkyl; R8is H; R9is selected from i) H, and i) Ci-e alkyl; F G H Y1is selected from i) -N-, and i) -CH-; Y2is selected from i) -N-, and i) -CR16-; R12, R13, R14 and R15 are selected independently of ¡) -H-, ¡i) halogen, and iii) hydroxy-Ci-6-alkyl; R16is selected from i) -H-, i) hydroxy, and iii) fluoro; L3 is absent or selected IVIA / a / ZUZZ / UU / 00» ¡v) v) vi) vii) viii) -(CH2)m-C(O)-, -C(O)-(CH2)p-, -COCONUT)-, -NR10-C(O)-, -C(O)-NR10-, -C(O)O-, -CH2-CF2-CH2-, -ch2-, ,and x¡) m is 0, 1 or 2; p is 0, 1, 2 or 3; R10 is selected from i) H, and i) Ci-e alkyl; D is selected from the ring sets I, J, K, L, Μ, N, O, P, Q, R, S, T, U, V, W and X, all ring sets are optionally replaced with one to three substituents selected from R80, R81 and R82; IVIA / a / ZUZZ / UU / 00» Reo, R8i and R82 are selected independently from i) halogen, i) cyano, iii) hydroxy, iv) hydroxy-Ci-6-alkyl, v) Ci-6 alkoxy, vi) halo-Ci-6-alkoxy, vii ) Ci-6 alkyl, viii) halo-Ci-e-alkyl, ix) C3-8 cycloalkyl, and x) halo-C3-8-cycloalkyl; L4 is absent or selected from i) -NR^-QO)-, i) -CH2-, and iii) -O-; E is selected from the ring systems Y, Z, AA, AB and AC; A.D. A.E. A.C. In another aspect of the invention, a compound of Formula II, or a pharmaceutically acceptable salt thereof is provided where A' is selected from the ring systems AF, AG and AH; R1' is selected from i) H, i) halogen, iii) Ci-6 alkyl iv) cyano, v) Ci-6 alkoxy, vi) halo-Ci-6-alkoxy, vii) Ci-e alkyl, viii) halo-Ci-e-alkyl, ¡x) C3-8 cycloalkyl, and x) halo-C3-8-cycloalkyl; and the remaining variables are as defined herein. In certain aspects, an isotope, N-oxide or stereoisomer of Formula I or a pharmaceutically acceptable salt thereof or composition thereof is provided. In other aspects, an isotope, N-oxide or stereoisomer of Formula II or a pharmaceutically acceptable salt thereof or composition thereof is provided. Other aspects of the present invention provide a compound of Formula III or Formula or a pharmaceutically acceptable salt, isotope, N-oxide or stereoisomer thereof, optionally as part of a pharmaceutical composition; where: A* is selected from: R31 is independently selected at each occurrence of 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-Cs-scycloalkyl and can be placed on any ring where it is present on a fork, e.g. R32 is hydrogen, halogen (F, Cl, Br, or I), C1-6 alkyl, halo-Ci-6-alkyl, C38 cycloalkyl, or halo-C3-8-cycloalkyl; R33 is hydrogen, halogen (F, Cl, Br, or I), C1-6 alkyl, halo-Ci-6-alkyl, C3 s cycloalkyl, or halo-C3-8-cycloalkyl and can be located on the dihydropyrrole ring or imidazole; R34 is independently selected from each occurrence of H, F, Ci-e alkyl, halo-Ci-6-alkyl, C3-8 cycloalkyl, and halo-C3-8-cycloalkyl; R35 is selected at each occurrence of H, halogen (F, Cl, Br, or I), C1-6 alkyl, halo-Ci-ealkyl, and C3-cycloalkyl; or R34 and R35 combine to form -(CHz)q-; r36 and r37 are independently selected from H, halogen (F, Cl, Br, or I), cyano, C1-6 alkoxy, halo-Ci-6-alkoxy (e.g. F, Cl, or Br), Ci-e alkyl , halo-Ci-6-alkyl (e.g. F, Cl, or Br), C3-8 cycloalkyl, and halo-C3-8-cycloalkyl; or R36 and R37 together combine to form a 5- or 6-membered cycle optionally substituted with 1, 2, or 3 R31 substituents; R42 is independently selected at each occurrence of H, halogen (F, Cl, Br, or I), cyano, C1-6 alkoxy, halo-Ci-e-alkoxy, C1-6 alkyl, halo-Ci-e-alkyl , C3-8 cycloalkyl, and halo-Ca-scycloalkyl; R90 is H, Ci 6 alkyl, or C3 s cycloalkyl; The G ring is an optionally substituted heteroaryl with 1 or 2 R42 substituents, for example, a 5- or 6-membered heteroaryl ring with 1, 2, or 3 N heteroatoms; A21is -NH-, -O-, -CH2-, or -NR100-; riooesaiqUío, cycloalkyl, aryl or heteroaryl; or as valency permits R100 can 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-; A36is -N- or -CR35-; L2 is a bivalent linking group (a linker) connecting A* and any of isoindolinone or indazole, for example, but not limited to a bivalent linking group of Formula LI; and where the remaining variables are as defined herein. In certain L2es modalities of the formula: where, X1 and -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 selected at each occurrence 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 selected at each occurrence from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocycle, aliphatic and heteroaliphatic; R27 is independently selected at each occurrence 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 selected at each occurrence 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)?, -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, -NHSOzalkinyl, -N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocycle, oxo and cycloalkyl; In addition, when valence permits, two R40 groups attached to the same carbon can join to form a 3- to 8-membered spirocycle; and, R41 is aliphatic, aryl, heteroaryl, or hydrogen. Each combination of variables, substituents, modalities, and the compounds that result from these combinations, is considered to be described specifically and individually, as such description is only for convenience of space and is not intended to describe only one genus or even a subgenus of compounds. A compound of the present invention can be used to treat EGFR-mediated disorders such as colon cancer; rectal cancer; lung cancer, including non-small cell lung cancer; breast cancer, including HER-2 positive breast cancer, ER+ (estrogen positive), PR+ (progesterone positive) breast cancer or triple negative breast cancer; Head and neck cancer; glioblastoma; pancreatic cancer; thyroid cancer; astrocytoma; esophagus cancer; cervical cancer; synovial sarcoma; ovarian cancer; Liver cancer; bladder cancer; or kidney cancer. In certain embodiments, a method of treatment is provided comprising 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, e.g. a human, optionally in a pharmaceutically acceptable carrier. For example, in certain embodiments, a compound of Formula I, II, III, or IV is administered to a human, to treat a cancer. In certain embodiments, a compound of the present invention is used to treat lung cancer. In certain embodiments, the lung cancer is a non-small cell lung cancer. In certain embodiments, a compound of the present invention is used to treat breast cancer. In certain embodiments, the breast cancer is a 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 a triple negative breast cancer. In certain embodiments, a compound of the present invention is used to treat colorectal or rectal cancer. In certain embodiments, a compound of the present invention is used to treat head and neck cancer or esophageal cancer. In certain embodiments, a compound of the present invention is used to treat glioblastoma. In certain embodiments, a compound of the present invention is used to treat pancreatic cancer. In certain embodiments, a compound of the present invention is used to treat thyroid cancer. In certain embodiments, a compound of the present invention is used to treat ovarian cancer, uterine cancer, or cervical cancer. In certain embodiments, a compound of the present invention is used to treat kidney cancer, liver cancer or bladder cancer. In certain embodiments, the compound of the present invention provides one or more and may even provide multiple advantages over traditional treatment with an EGFR ligand. For example, the EGFR-degrading compound of the present invention can a) overcome resistance in certain cases; b) prolonging the kinetics of the drug effect by destroying the protein, thereby requiring resynthesis of the protein even after the compound has been metabolized; c) targeting all functions of a protein at once rather than a specific catalytic activity or binding event; and / or d) have greater potency compared to inhibitors due to the possibility of the small molecule acting catalytically. In one aspect, a compound of the present invention 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 located in exon 18, exon 19, exon 20 or exon 21, or any combination thereof. In certain non-limiting embodiments, the mutation is at position L858, E709, G719, C797, L861, T790, or L718 or any combination thereof. In certain embodiments, the mutation is an L858R, T790M, L718Q, L792H, and / or C797S mutation or any combination thereof. In certain aspects, the cancer has developed one or more EGFR mutations after treatment with at least one EGFR inhibitor which may 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 after 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 render the cancer inherently resistant to treatment with EGFR inhibitors, for example, a somatic exon 20 insertion, an asomatic PIK3CA mutation, loss of PTEN expression, MET amplification or a KRAS mutation. In certain embodiments, a compound of the present invention is used to treat a cancer that is resistant to, or has acquired resistance to, a first generation EGFR inhibitor such as erlotinib, gefitinib, and / or lapatinib. In certain embodiments, a compound of the present invention is used to treat a cancer that is resistant to, or has acquired resistance to, a second generation EGFR inhibitor such as afatinib and / or dacomitinib. In certain embodiments, a compound of the present invention is used to treat a cancer that is resistant to, or has acquired 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, the compound of the present invention is used to treat a mutant EGFR-mediated disorder, wherein EGFR has a mutation at one of at least one of the amino acid sites listed below or a combination thereof. The mutation, for example, may be selected from one of the listed exemplary mutations, or may be a different mutation. IVIA / a / ZUZZ / UU / 00» 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 L79 2 L792H; L792V L858 L858R L861 L861Q S768 S768I Amino acid Exemplary mutations T790 T790M IVIA / a / ZUZZ / UU / 00» In certain embodiments, the mutant EGFR-mediated disorder has two mutations selected from the table above. In other embodiments, the mutant EGFR-mediated disorder has three mutations selected from the table above. In other embodiments, the mutant EGFR-mediated disorder has four or more mutations, which may optionally be selected from the table above. In certain embodiments the mutant EGFR-mediated disorder has an L858R mutation and an additional mutation that may optionally be selected from the table above. In some of these embodiments, the mutant EGFR-mediated disorder has an L858R mutation and two additional mutations that may optionally be selected from the table above. In other embodiments the mutant EGFR-mediated disorder has an L858R mutation and three additional mutations that may optionally be selected from the table above. In certain embodiments the mutant EGFR-mediated disorder has a T790M mutation and an additional mutation optionally selected from the table above. In other embodiments, the mutant EGFR-mediated disorder has a T790M mutation and two additional mutations optionally selected from the table above. In other embodiments the mutant EGFR-mediated disorder has a T790M mutation and three additional mutations optionally selected from the table above. In certain embodiments the mutant EGFR-mediated disorder has an L718Q mutation and an additional mutation optionally selected from the table above. In other embodiments, the mutant EGFR-mediated disorder has an L718Q mutation and two additional mutations optionally selected from the table above. In other embodiments the mutant EGFR-mediated disorder has an L718Q mutation and three additional mutations optionally selected from the table above. In certain embodiments, the EGFR-mediated disorder is mutant EGFR-mediated cancer. In certain embodiments, the EGFR-mediated cancer has a mutation of S768I, L718V, L792H, L792V, G796S, G796C, G724S, and / or G719A. In certain embodiments, a compound of the present invention is used to treat an EGFR-mediated cancer that has a frameshift mutation, for example, a short in-frame deletion. In certain embodiments, a compound of the present invention is used to treat an EGFR-mediated cancer, wherein the EGFR has a deletion of exon 19. In certain embodiments, the deletion of exon 19 is a deletion that includes the amino acids LREA (L747 -A750). In certain embodiments, the exon 19 deletion is a deletion that includes the amino acids ELREA (E746-A750). In certain embodiments, a compound of the present invention is used to treat an EGFR-mediated cancer, wherein the EGFR has an L858R mutation in exon 21. In certain embodiments, a compound of the present invention is more active against a disorder driven by a mutant EGFR than a wild-type EGFR. In certain embodiments, a compound of the present invention is used to treat an EGFR-mediated cancer, wherein the EGFR has one or more exon 18 deletions. In certain embodiments, a compound of the present invention is used to treat EGFR with an E709 mutation, for example, E709A, E709G, E709K or E709V. In certain embodiments, a compound of the present invention is used to treat EGFR with an L718 mutation, for example, L718Q. In certain embodiments, a compound of the present invention is used to treat EGFR with a G719 mutation, for example, G719S, G719A, G719C or G719D. In certain embodiments, a compound of the present invention is used to treat an EGFR-mediated cancer, wherein the EGFR has one or more insertions in exon 19 and / or one or more insertions in exon 20. In certain embodiments, a compound of the present invention is used to treat S7681 mutant EGFR cancer. In certain embodiments, a compound of the present invention is used to treat EGFR mutant EGFR L861Q cancer. In certain embodiments, a compound of the present invention is used to treat C797S mutant EGFR cancer. In certain embodiments, a compound of the present invention is used to treat a T790M, L858R mutant EGFR cancer. In certain embodiments, a compound of the present invention is used to treat an L718Q, L858R mutant EGFR cancer. In certain embodiments, a compound of the present invention is used to treat an L792H, L858R mutant EGFR cancer. In certain embodiments, a compound of the present invention is used to treat a C797S, L858R mutant EGFR cancer. In certain embodiments the compound of the present invention provides an improved efficacy and / or safety profile relative to at least one known EGFR inhibitor. For example, the degrader of the present invention has the efficiency of a single inhibitor protein binding moiety combined with the catalytic degradation activity of cereblon-activated protesomal degradation. This provides rapid activity against the target overexpressed EGFR by means of an active moiety that can quickly return to action and repeat the catalytic function. In this way, EGFR is rapidly destroyed as it was with a covalent suicide inhibitor, such as osimertinib, but without at the same time destroying the active drug. In certain embodiments, the degrading compound of the present invention has one or more advantages in the treatment of an EGFR-mediated disorder than using only an EGFR inhibitor. IVIA / a / ZUZZ / UU / 00» enzymes. In certain embodiments, fewer of the compounds described herein are needed for the treatment of an EGFR-mediated disorder than per mole of the EGFR Targeting Ligand portion alone. In certain embodiments, the compound of the present invention has less of at least one side effect in the treatment of an EGFR-mediated disorder than per mole of the EGFR Targeting Ligand portion alone. In certain embodiments, a less frequent dosing regimen of a selected compound described herein is needed for the treatment of an EGFR-mediated disorder than the dose per mole of the EGFR Targeting Ligand portion alone. Another aspect of the present invention provides a compound as described herein, or an enantiomer, diastereomer or stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, for use in the manufacture of a medication to inhibit or prevent an EGFR-mediated disorder or to modulate or decrease the amount of EFGR. Another aspect of the present invention provides a compound as described herein, or an enantiomer, diastereomer or stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or its pharmaceutical composition, for use in the manufacture of a medication for the treatment or prevention of an EGFR-mediated disease. In certain embodiments, a compound selected as described herein is useful for treating a disorder comprising abnormal cell proliferation such as a tumor or cancer, wherein EGFR is an oncogenic protein or a signaling mediator of the proliferation pathway. abnormal cell and its degradation decreases abnormal cell growth. In certain embodiments, the selected compound of Formula I, II, III or IV or its pharmaceutically acceptable salt thereof, has at least one desired isotopic substitution of an atom, in an amount above the natural abundance of the isotope, is say, enriched. In certain embodiments, the compound of Formula I, II, III, or IV, or its pharmaceutically acceptable salt thereof, includes a deuterium atom or multiple deuterium atoms. In certain embodiments, a compound of the present invention is useful for the therapeutic and / or prophylactic treatment of cancer. In certain embodiments, a compound of the present invention has an E3 Ubiquitin Ligase binding moiety that is linked to a moiety that binds to the target protein EGFR, wherein the target protein is proximal to the ubiquitin ligase to effect degradation of said protein. Other features and advantages of the present invention will be apparent from the following detailed description. The present invention thus includes at least the following features: (a) A compound of Formula I, II, III, or IV as described herein, or a pharmaceutically acceptable salt or isotopic derivative (including a deuterated derivative) thereof; (b) A method of treating an EGFR-mediated disorder, such as abnormal cell proliferation, including cancer, comprising administering an effective amount of a compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof , as described herein, to a patient in need; (c) A compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt or isotopic derivative (including a deuterated derivative) thereof for use in the treatment of a disorder that is mediated by EGFR, e.g. an abnormal cell proliferation such as a tumor or cancer; (d) Use of a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, in an amount effective in the treatment of a patient in need thereof, usually a human, with a disorder mediated by EGFR, for example, an abnormal cell proliferation such as a tumor or cancer; (e) Use of a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt or isotopic derivative (including a deuterated derivative) thereof in the manufacture of a medicament for the treatment of an EGFR-mediated disorder , for example, an abnormal cell proliferation such as a tumor or cancer; (f) A method of treating a mutant EGFR-mediated disorder, such as abnormal cell proliferation, including cancer, comprising administering a pharmaceutically effective amount of a compound of Formula I, II, III or IV, or a salt thereof acceptable, as described herein, to a patient in need; (g) A compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt or isotopic derivative (including a deuterated derivative) thereof for use in the treatment of a disorder that is mediated by mutant EGFR, e.g. , an abnormal cell proliferation such as a tumor or cancer; (h) Use of a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, in an amount effective in the treatment of a patient in need thereof, usually a human, with a disorder mediated by Mutant EGFR, for example, an abnormal cell proliferation such as a tumor or cancer; (i) Use of a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt or isotopic derivative (including a deuterated derivative) thereof in the manufacture of a medicament for the treatment of an EGFR-mediated disorder mutant, for example, an abnormal cell proliferation such as a tumor or cancer; Ü) A pharmaceutical composition comprising an effective amount to treat a patient of a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt, isotopic derivative thereof; and optionally, a pharmaceutically acceptable carrier or diluent; (k) A compound of Formula I, II, III, or IV, as described herein as a mixture of enantiomers or diastereomers (as applicable), including a racemate; (I) A compound of Formula I, II, III, or IV, as described herein in enantiomerically or diastereomerically enriched form (as relevant), including an isolated enantiomer or diastereomer (i.e., approximately more than 85 , 90, 95, 97 or 99% purity); and (m) A process for the preparation of therapeutic products containing an effective amount of a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, as described herein. DETAILED DESCRIPTION OF THE INVENTION Provided are compounds and their uses and manufacture that degrade the epidermal growth factor receptor (EGFR) protein through the ubiquitin proteasome (UPP) pathway. 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 moiety (typically through a subunit cereblon) 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 portion of A or A*, the Linker is a portion of L1 or L2, and the remainder of the molecule is the EGFR Targeting Ligand portion. In certain embodiments, a compound of the present invention 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 of the present invention is a selective degrader of T790M / L858R, T790M / L858R / C797S, L858R, and / or L858R / C797S containing EGFR mutants. In certain embodiments, a compound of the present invention provides an improved efficacy and / or safety profile relative to at least one known EGFR inhibitor. For example, the degrader of the present invention has the efficiency of a single inhibitory protein binding moiety combined with the catalytic degradation activity of cereblon-activated protesomal degradation. This provides rapid activity against the target overexpressed EGFR by means of an active moiety that can quickly return to action and repeat the catalytic function. In this way, EGFR is rapidly destroyed as it was with a covalent suicide inhibitor, such as osimertinib, but without at the same time destroying the active drug. I. Definitions The following definitions of general terms used in this description apply whether the terms appear alone or in combination with other groups. Unless otherwise indicated, the following terms used in this application, including the specification and claims, have the definitions as given below. It should be noted that, as used in the specification and the accompanying claims, the singular forms a, an and the / the include plural referents unless the context clearly indicates otherwise. The term Ci-e alkoxy denotes a group of the formula -O-R', where R' is a Ci-6 alkyl group, particularly C1-3 alkyl. Examples of Ci-e alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Particular examples are methoxy, ethoxy and isopropoxy. The most particular example is methoxy. The term Cí e alkyl, alone or in combination with other groups, represents a hydrocarbon radical that may be linear or branched, with single or multiple branching, where the alkyl group generally comprises 1 to 6 carbon atoms, e.g. , methyl (Me), ethyl (Et), propyl, isopropyl (i-propyl), n-butyl, i-butyl (sobutyl), 2-butyl (sec-butyl), t-butyl (tere-butyl), isopentyl, 2-ethyl-propyl (2-methyl-propyl), 1,2-dimethyl-propyl and the like. A specific group is methyl. The term cyano represents a -C=N group. The term C3-8 cycloalkoxy represents a group of the formula -O-R', where R' is a C3-8 cycloalkyl group. Examples of the cycloalkoxy group include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy. The particular example is cyclopropoxy. The term C3-8 cycloalkyl represents a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 8 carbon atoms in the ring. Bicyclic means a ring system consisting of two saturated carbocycles having one or two carbon atoms in common. Examples of monocyclic C3-8 cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl. Example of bicyclic C3-8 cycloalkyl is spiro[3.3]heptanyl. Particular monocyclic C3-8 cycloalkyl groups are cyclopropyl, cyclobutanyl. More particular monocyclic C3-8 cycloalkyl groups include cyclopropyl. The term halo-Ci-6-alkoxy represents a C1-6 alkoxy group where at least one of the hydrogen atoms of the C1-6 alkoxy group has been replaced by the same or different halogen atoms. The term perhalo-Ci-6-alkoxy represents a C1-6 alkoxy group where all of the hydrogen atoms of the Ci-6 alkoxy group have been replaced by the same atoms. IVIA / a / ZUZZ / UU / 00» halogen or different. Examples of halo-Ci-s-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 represents a Ci-6 alkyl group where 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 represents a -Ci-6-alkylCi-6-alkyl group where all hydrogen atoms of the alkyl group have been replaced by the same hydrogen atoms. halogen or different. Examples of halo-Ci-6-alkyl include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylethyl and pentafluoroethyl. Particular halo-Ci-alkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, trifluoroethyl and difluoroethyl. More particular halo-Ci-e-alkyl groups include fluoromethyl. The term halo-Ca-s-cycloalkoxy represents a C3-8 cycloalkoxy group where at least one of the hydrogen atoms of the C3 s cycloalkoxy group has been replaced by the same or different halogen atoms. The term perhalo-Css-cycloalkoxy represents a C3-8 cycloalkoxy group where all hydrogen atoms of the C3-8 cycloalkoxy group have been replaced by the same or different halogen atoms. Examples of halo-Cs 8-cycloalkoxy include fluorocyclopropoxy, fluorocyclobutoxy, fluorocyclopentyloxy, fluorocyclohexyloxy, fluorocycloheptyloxy, difluorocyclopropoxy, difluorocyclobutoxy, difluorocyclopentyloxy, difluorocyclohexyloxy and difluorocycloheptyloxy. The term halo-Cs-s-cycloalkyl represents a C3-8 cycloalkyl group where at least one of the hydrogen atoms of the C3-8 cycloalkyl group has been replaced by the same or different halogen atoms. The term perhalo-C3-8-cycloalkyl represents a C3-8 cycloalkyl group where all hydrogen atoms of the alkyl group have been replaced by the same or different halogen atoms. Examples of halo-C3-8-cycloalkyl include fluorocyclopropyl, fluorocyclobutanyl, fluorocyclopentyl, fluorocyclohexyl, fluorocycloheptyl, difluorocyclopropyl, difluorocyclobutanyl, difluorocyclopentyl, difluorocyclohexyl or difluorocycloheptyl. The term halogen, alone or in combination with other groups, represents chlorine (Cl), iodine (I), fluoro (F) and bromine (Br). The specific groups are F and Cl. The term hydroxy represents an -OH group. The term hydroxy-Ci-6-alkyl alkyl represents a Ci-6-alkyl alkyl group where at least one hydrogen atom 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. The particular example is hydroxymethyl. The term pharmaceutically acceptable represents an attribute of a material that is useful in the preparation of a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and is acceptable for veterinary use as well as for human pharmaceutical use. The term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with human and animal tissues. 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, methanesulfonic acid, nitric acid, phosphoric acid, acid p-toluenesulfonic acid, succinic acid, sulfuric acid (sulfuric 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 other ingredients of the formulation. The term pharmaceutical composition encompasses a product comprising specified ingredients in predetermined amounts or proportions, as well as any product that results, directly or indirectly, from combining the specified ingredients in specified amounts. In particular, 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 the combination, complexation or aggregation of two or more of the ingredients, or from the dissociation of one or more ingredients, or from other types of reactions or interactions of one or more ingredients. Therapeutically effective amount means the amount of a compound that, when administered to a subject to treat a disease state, is sufficient to effect said treatment for the disease state. The therapeutically effective amount will vary depending on the compound, the state of the disease being treated, the severity of the disease treated, the age and relative health of the subject, the route and manner of administration, the judgment of the treating physician or veterinarian, 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 the particular, more particular and more particularly definitions, if any. The terms treat, contact and react when referring to a chemical reaction mean adding or mixing two or more reactants under appropriate conditions to produce the indicated and / or desired product. It should be appreciated that the reaction that produces the indicated and / or desired product may not necessarily result directly from the combination of two reagents that IVIA / a / ZUZZ / UU / 00» were added initially, that is, there may be one or more intermediates that occur in the mixture that ultimately leads to the formation of the indicated and / or desired product. The term pharmaceutically acceptable excipient represents any ingredient that has no therapeutic activity and is non-toxic such as disintegrants, binders, fillers, solvents, pH regulators, toning agents, stabilizers, antioxidants, surfactants or lubricants used in the formulation of pharmaceutical products. The term pharmaceutical composition encompasses a product comprising specified ingredients in predetermined amounts or proportions, as well as any product that results, directly or indirectly, from combining the specified ingredients in specified amounts. In particular, 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 the combination, complexation or aggregation of two or more of the ingredients, or from the dissociation of one or more ingredients, or from other types of reactions or interactions of one or more ingredients. The term inhibitor represents a compound that competes with, reduces or prevents the binding of a particular ligand to a particular receptor or that reduces or prevents the function of a particular protein. The term half maximum inhibitory concentration (CIso) represents the concentration of a particular compound that is required to obtain 50% inhibition of a biological process in vitro. CIso values ​​can be converted logarithmically to pCho (-log CIso) values, with higher values ​​indicating exponentially greater power. The CIso value is not an absolute value but depends on the experimental conditions, for example, concentrations used. The CIso value can be converted to an absolute inhibition constant (K¡) using the Cheng-Prusoff equation (Biochem. Pharmacol. (1973) 22:3099). Therapeutically effective amount means the amount of a compound that, when administered to a subject to treat a disease state, is sufficient to effect said treatment for the disease state. The therapeutically effective amount will vary depending on the compound, the state of the disease being treated, the severity of the disease treated, the age and relative health of the subject, the route and manner of administration, the judgment of the treating physician or veterinarian, and other factors. The term aromatic represents 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, all stereoisomers associated with that chiral carbon are intended to be included in 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, nC, 13C, 14C, 15N, 170, 180, 18F, 35S, and 36CI respectively. In a non-limiting embodiment, isotopically labeled compounds can be used in metabolic studies (with, for example, 14C), reaction kinetics studies (with, for example, 2H or 3H), detection or imaging techniques, such as such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) including substrate or drug tissue distribution assays, or in the radioactive treatment of patients. Additionally, any hydrogen atom present in the compound of the invention may be substituted with a 18F atom, a substitution that may be particularly desirable for PET or SPECT studies. In a non-limiting embodiment, the substitution of a hydrogen atom for a deuterium atom may be provided in any compound described herein. For example, when any of the groups is, or contains, for example, by substitution, methyl, ethyl or methoxy, the alkyl residue may be optionally deuterated (in non-limiting embodiments, CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3etc.). In certain other embodiments, when two substituents combine to form a cycle, the unsubstituted carbons may optionally be deuterated. In certain embodiments, at least one deuterium is placed on an atom that has a bond that is broken during the metabolism of the compound in vivo, or that is one, two or three atoms away from the metabolized bond (for example, to which may be referred to as an α, β, or y isotope effect, or primary, secondary, or tertiary). In certain embodiments, a compound of the present invention is isotopically labeled. In certain embodiments at least one group R independently selected from R1, R2, R3, R4, R6, R7R8R9R10R11R12R13R14R15R16R17R20R21R22R23R24R25R27R31R32R33R34R35R36R37, R40, R41, R42, R52, R53, R54, R55, R70, R80, R81, R82, R90, or R100 is isotopically labeled with 1, 2 or more isotopes as valence allows. In certain embodiments, the isotopic label is deuterium. In certain embodiments, at least one deuterium is placed on an atom that has a bond that is broken during the metabolism of the compound in vivo, or that is one, two or three atoms away from the metabolized bond (for example, which can be referred to as an α, β or y isotope effect, or primary, secondary or tertiary). In another embodiment, the isotopic marker is 13C. In other embodiments, the isotopic marker is 18F. In certain embodiments, the compounds of the present invention can form a solvate with a solvent (including water). Therefore, in a 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 of the present invention (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 branched or linear aliphatic hydrocarbon group that has one or more carbon-carbon double bonds that can occur at a stable point along the chain. In a 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, C2Cs, 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 incorporates the cis and trans alkenyl geometry, or alternatively, the 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 aliphatic hydrocarbon group that has one or more carbon-carbon triple bonds that can occur at any stable point along the chain. In a 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, C2Cs, 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 triple bond unsaturation point. II. COMPOUNDS OF FORMULA I, II, III, AND IV The invention provides compounds of Formulas I, II, III, and IV, pharmaceutical compositions, methods of use, and methods for preparing these compounds. Modalities of Formula I All separate modalities can be combined. The: One embodiment of the invention is a compound of formula I, or a pharmaceutically acceptable salt thereof, A is selected from the AF and AG ring systems; AG A1 is selected from i) -NH-, and i) -O-; A2 is selected from i) -N-, and i) -CR52-; A3 is selected from i) -N-, and ii) -CR53-; A4 is selected from i) -N-, and i) -CR54-; A5 is selected from i) -N-, and ii) -CR55-; R1is selected from ¡) H, ¡i) halogen iii) Ci-e alkyl; R52is selected from i) H, i) 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; R53, R54 and R55 are independently selected from ¡)H, ¡i) halogen, iii) Ci 6 alkyl, iv) halo-Ci 6-alkyl, v) C3 8-cycloalkyl, and vi) halo-Cs 8-cycloalkyl; R2is selected from ¡)H, ii) halogen, iii) C1-6 alkyl, iv) halo-Ci-e-alkyl, v) C3-8 cycloalkyl, and vi) halo-C3-8-cycloalkyl; R3is selected from i)H, i) halogen, i) C1-6 alkyl, iv) halo-Ci-e-alkyl, v) C3-8 cycloalkyl, and vi) halo-C3-8-cycloalkyl;; R4 and R5 are H; or R4 and R5 together form -(CH2)q-; q is 1 or 2; R6is selected from ¡) H, ¡i) halogen, iii) cyano, iv) Ci-6 alkoxy, v) halo-Ci-e-alkoxy, vi) Ci-6 alkyl, vii) halo-Ci-6-alkyl, viii ) C3-8 cycloalkyl, and ix) halo-C3-8-cycloalkyl; R7is selected from ¡) H, ¡i) halogen, iii) cyano, iv) C1-6 alkyl, v) halo-Ci 6-alkyl, vi) C3-8 cycloalkyl, and vii) halo-Cs 8-cycloalkyl; R70is selected from ¡) H, ii) halogen, iii) cyano, iv) C1-6 alkyl, v) halo-Ci-e-alkyl, vi) C3-8 cycloalkyl, and vii) halo-C3-8-cycloalkyl; R8is H; R9 is selected from ii) H, and iv) alkyl from Cí e; C is absent or selected from the F, G, and H ring systems; Y1is selected from i) -N-, and i) -CH-; Y2is selected from i) -N-, and i) -CR16-; R12, R13, R14 and R15 are selected independently of ¡) -H-, ¡i) halogen, and iii) hydroxy-Ci-6-alkyl; R16is selected from ¡) Ή-, ¡i) hydroxy, and iii) fluoro; L3 is absent or selected i) -(CH2)m-C(O)-, i) -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-, x) ,and m is 0, 1 or 2; p is 0, 1, 2 or 3; R10 is selected from i) H, and i) Ci-e alkyl; D is selected from the ring sets I, J, K, L, Μ, N, O, P, Q, R, S, T, U, V, W and X, all ring sets are optionally replaced with one to three substituents selected from R80, R81 and R82; U V W X rso, r8i and r82 are selected independently of i) halogen, i) cyano, iii) hydroxy, iv) hydroxy-Ci-e-alkyl, v) Ci-6 alkoxy, vi) halo-Ci-6-alkoxy, vii) Ci-6 alkyl, viii) halo-Ci-e-alkyl, ix) C3-8 cycloalkyl, and x) halo-Cs-s-cycloalkyl; L4 is absent or selected i) -NR^-CÍO)-, i) -CHz-, and iii) -O-; E is selected from the ring systems Y, Z, AA, AB and AC; AB AC L5is absent or5, B is selected from the ring set AD and AE; AD AE E2: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein A is selected from the AF and AG ring systems; IVIA / a / ZUZZ / UU / 00» AF A1is selected from i) -NH-, and i) -O-; A2is selected from i) -N-, and i) -CH-; R1is selected from i) H, and i) halogen; R2is H; R3is selected from i) H, and i) halogen; R4es H R5is H; or R4 and R5 together form -(CH2)n-; n is 1; R6is selected from i) H, i) halogen, iii) cyano, and iv) halo-Ci-6-alkyl; R7is H; R8is H; R9 is Ci-e alkyl; AG F Y1is selected from i) -N-, and i) -CH-; Y2is selected from i) -N-, and i) -CR16-; R12R13, R14and R15are selected independently of i) H, and i) halogen; R16is selected from i) H,y i i) hydroxy; L3is selected from i) -(CH2)m-C(O)-, ¡i) -C(O)-(CH2)p-, ¡ii) -C(O)-C(O)-, and ¡v) -NR10-C (EITHER)-; m is 1; p is 1 or 3; R10 is selected from i) H, and i) Ci-e alkyl; D is selected from ring systems I, J, K, L and M; IVIA / a / ZUZZ / UU / 00» L Μ L4is selected from i) -NR^-QO)-, i) -CH2-, and iii) -O-; E is selected from the ring systems Y, Z and AA, AB and AC; N=N Y Z AA Ε3: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein A is selected from the AF and AG ring systems; AFAG A1is selected from i) -NH-, and ü) -O-; A2is selected from i) -N-, and i) -CH-; R1is selected from i) H, and i) fluoro; R2is H; R3is selected from ¡) H, and ¡i) fluoro; R4es H R5is H; or R4 and R5 together form -(CH2)q-; q is 1; R6is selected from ¡) H, ¡i) fluoro; i¡) cyano, iv) difluoromethyl, and v) trifluoromethyl; R7is H; R8is H; R9 is methyl; F Y1is selected from i) -N-, and i) -CH-; Y2is selected from i) -N-, and i) -CR16-; R12 and R13 are fluoro; rm and risson R16is selected from ¡) H, and ¡i) hydroxy; L3is selected from i) -(CH2)m-C(O)-, i) -C(O)-(CH2)P-, i) -C(O)-C(O)-, and iv) -NR10-C (EITHER)-; m is 1; p is 1 or 3; R10is H; D is selected from ring systems I, J, K, L and M; IVIA / a / ZUZZ / UU / 00» L4is selected from i) -NR^-QO)-, i) -CH2-, and iii) -O-; E is selected from the ring systems Y, Z, AA, AB and AC; N=N L5es *, B is selected from the ring set AD and AE; A.D. A.E. E4: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein A is the ring system AF. Ε5: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein A1 is -N-. E6: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein A2 is -CH-. E7: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from ¡) H, and ¡i) halogen. E8: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from ¡) H, and ¡i) fluoro. E9: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R1 is fluoro. E10: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R2 is H. Eli: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from ¡) H, and ¡i) halogen. E12: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from ¡) H, and ¡i) fluoro. E13: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R4 is H. E14: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R5 is H. E15: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R6 is selected from i) H, i) halogen, iii) cyano, and iv) halo-Ci-6-alkyl. E16: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R7 is H. E17: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R8 is H. E18: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R9 is Ci-6 alkyl. E19: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R9 is methyl. E20: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein n is 1. E21: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein C is absent or the F ring system. E22: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein C is the F ring system. E23: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R12 and R13 are fluoro. E24: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R14 and R15 are H. E25: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R16 is selected from ¡) H, and ¡i) hydroxy. E26: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R16 is H. E27: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein L3 is selected from i) -(CH2)m-C(O)-, i) -C(O)-(CH2)p-, i) -C(O)-C(O)-, and iv) -NR10-C (EITHER)-. E28: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein m is 1. E29: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein p is 1 or 3. IVIA / a / ZUZZ / UU / 00» Ε3Ο: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R10 is selected from ¡) H, and ¡i) alkyl of Ci-e. E31: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein D is selected from ring systems I, J, K, L and M. E32: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein L4 is selected from i) -NRn-C(O)-, i) -CH2-, and iii) -O-. E33: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein L4 is. E34: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of 5-((2-( l-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-oxo-2-(thiazol-2-ylamino) ethyl)-7fluoro-3-oxoisoindol¡n-5-yl)ethin¡l)-N-(l-(2-(4-(4-((2,6-dioxop¡pend¡n-3-yl)) am¡no)phenyl)pipend¡n-l¡l)acet¡l)piper¡d¡n-4-¡l)p¡col¡namide; 5-[2-[2-[l-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-¡l)-2-oxo-2 -(thiazol-2-¡lano)ethyl]-7fluoro-3-oxo-¡so¡ndolin-5-¡l]ethín¡l]-N-[l-[2-[ 4-[(2,6-dioxo-3-p¡perid¡l)am¡no]phen¡l]acet¡l]-4piper¡d¡l]p¡r¡din-2-carboxamide ; 5-[2-[2-[l-(6,7-d¡hydro-5H-pyrrolo[l,2-c]imidazol-l-¡l)-2-oxo-2- (thiazol-2-lamino)ethyl]-7fluoro-3-oxo-iso¡ndolin-5-l]ethynyl]-N-[l-[2-[4-[4-[ (2,6-dioxo-3-piperidyl)oxy]phenyl]piperaz¡n-l¡l]acet¡l]-4-piper¡d¡l]pyrid¡n-2-carboxam¡de; 5-(2-(2-(1-(6,7-dihydro-5H-pyrrolo[l, 2-c]¡m¡dazol-l-¡l)-2-oxo-2-(t¡ azol-2-¡lam¡no)et¡ l]-7fluoro-3-oxo-¡so¡ndolin-5-yl]et¡n¡l]-N-[l-[2-[4-[ 4-[[(3S)-2,6-dioxo-3-p¡peridyl]amino]-2-fluorophen¡l]-l-p¡per¡d¡l]acet¡l]-4-p¡per ¡d¡l]pyr¡din-2-carboxamide; 2-(6,7-dihydro-5H-pyrrolo[ l,2-c]imidazole-l-[l)-2-[6-[4-[4-[2-[4-[4 -[(2,6-dioxo-3p¡pendyl)amino]phen¡l]-l-p¡peridyl]acetyl]p¡perazin-l-¡l]phenyl]-4-fluoro-l-oxo-¡soindolin-2 -l]-Nthiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[ l,2-c]¡m¡dazol-l-¡l)-2-[6-[4-[4-[2-[4-[4- [[(3S)-2,6-d ioxo-3p¡pend¡l]am¡no]fen¡l]-l-p¡pend¡l]acet¡l]p¡peraz¡n-l-¡l]fen¡l ]-4-fluoro-l-oxo-¡so¡ndolín-2-yl]-Nthiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[l,2-c]midazol-l-yl)-2-[6-[4-[4-[2-[4-[4-[[( 3R)-2,6-dioxo-3piper¡d¡l]amino]phenyl]-l-p¡perid¡l]acetyl]piperaz¡n-l-¡l]phenyl]-4-fluoro-l-oxo-¡so¡ndolin -2-yl]-Nthiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[l,2-c]ímidazol-l-íl)-2-(6-(4-(4-(4-(4-( 4-((2,6-dioxop¡per¡d¡n-3¡l)am¡no)phen¡l)piperidin-l-¡l)-4-oxobut¡l)piperaz¡n-l-¡l )phen¡l)-4-fluoro-l-oxo¡so¡ndolin-2-yl)-N(thiazol-2-¡l)acetamide; 2-(6,7-dihydro-5H-pyrrolo[l,2-c]ímidazol-l-íl)-2-(6-(4-(4-(2-(4-( 4-((2,6-dioxop¡peridin-3yl)amino)phen¡l)cyclohex¡l)acet¡l)p¡peraz¡n-l-yl)phenyl)-4-fluoro-l-oxoisoindole ¡n-2-¡l)-N-(thiazol-2yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[l,2-c]ímidazol-l-íl)-2-(6-(4-(l-(2-(4-( 4-((2,6-dioxop¡per¡d¡n-3¡l)amino)phen¡l)piperid¡n-l-¡l)-2-oxoethyl)piper¡d¡n-4- ¡l)phen¡l)-4-fluoro-l-oxo¡so¡ndolin-2-¡l)-N(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrOlo[l,2-c]m¡dazol-l-¡l)-2-[6-[4-[4-[2-[4 -[5-[(2,6-dioxo-3p¡pend¡l)am¡no]-2-pyridyl]-l-p¡per¡d¡l]acetyl]piperaz¡n-l-¡l]phen¡l]- 4-fluoro-l-oxo-isoandolin-2-yl]-Nthiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-íl)-2-[6-[4-[4-[2-[4-[4 -[(2,6-dioxo-3p¡perídil)amino]-2-fluoro-phen¡l]-l-p¡peridyl]acet¡l]p¡perazin-l-¡l]phen¡ l]-4-fluoro-l-oxo-¡soindolín-2yl]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrOlo[l,2-c]m¡dazol-l-yl)-2-[6-[4-[4-[2-[4- [4-[(2,6-dioxo-3pipend¡l)amino]-3-fluoro-phen¡l]-l-p¡perídyl]acetyl]piperaz¡n-l-¡l]phenyl]-4-fluoro -l-oxo-ísoindolin-2yl]-N-thiazol-2-yl-acetamide; 2-[6-[4-[4-[2-[4-[2-c¡ano-4-[(2,6-dioxo-3-piper¡d¡l)am¡no]fen¡ l]-lp¡pendyl]acet¡l]piperaz¡n-l-¡l]phenyl]-4-fluoro-l-oxo-isoindol¡n-2-yl]-2-(6,7-d¡hydro-5H -pyrrolo[l,2c]imidazol-l-yl)-N-thiazol-2-l-acetamide; 2-[6-[4-[4-[2-[4-[2-(difluoromethyl)-4-[(2,6-dioxo-3-p¡períd¡l) am¡no]phenyl]-lp¡peridyl]acetyl]piperazin-l-yl]phenyl]-4-fluoro-l-oxo-¡soindolin-2-yl]-2-(6,7-dihydro-5H -pyrrolo[l,2c]imidazol-l-l)-N-thiazol-2-yl-acetamide; 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(4-(4-(2- (4-(3-((2,6-dioxop¡per¡d¡n-3¡l)am¡no)phen¡l)piper¡d¡n-l-¡l)acet¡l)p¡peraz ¡n-l-¡l)phen¡l)-4-fluoro-l-oxoiso¡ndolin-2-¡l)-N-(thiazol-2yl)acetamide; 2-(6,7-d¡hydro-5H-pyrrOlo[l,2-c]ímidazol-l-¡l)-2-(6-(4-(4-(2-(4 -(3-(2,4dioxotetrahydropinmidin-l(2H)-yl)-l-methyl-lH-indazol-6-l)pipendin-l-yl)acetyl)piperazin-l¡l)phen l)-4-fluoro-l-oxo¡so¡ndolin-2-¡l)-N-(thiazol-2-¡l)acetam¡de; 2-(6,7-dihydro-5H-pyrrolo[l,2-c]ímidazol-l-yl)-2-(6-(4-(4-(2-(l-(4-( (2,6-dioxop¡pendin-3¡l)am¡no)-2-(tnfluoromet¡l)phen¡l)-4-hydroxypiper¡din-4-¡l)acet¡l)piperaz ¡n-l-¡l)phen¡l)-4-fluoro-144 oxoiso¡ndolin-2-yl)-N-(thiazol-2-¡l)acetamide; 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(4-(4-(2- (4-(4-((2,6-dioxop¡per¡din-3yl)amino)phenyl)piperidin-l-yl)acetyl)piperazin-l-yl)phenyl)-4-fluoro-l -oxoisoindolin-2-yl)-N-(pyridín-2yl)acetamide; 2-(6,7-d¡hydro-5H-pyrrOlo[l,2-c]ímidazol-l-¡l)-2-[6-[4-[4-[2-[4 -[4-[(2,6-dioxo-3piper¡dil)amino]-2-fluoro-phen¡l]-l-piperid¡l]acet¡l]piperazin-l-yl]phenyl]-4 -fluoro-l-oxo-iso¡indol¡n-2yl]-N-(2-pyrid¡l)acetamide; 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(l-(2-(4-(4-(( 2,6-dioxopíperidin-3yl)amino)phenyl)piperidin-l-íl)acetyl)piperidin-4-yl)pheníl)-4-fluoro-l-oxoisoindolin-2-yl)-N -(thiazol-2yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-íl)-2-(6-(4-(l-(2-(4-(4 -(((S)-2,6-dioxopiper¡d¡n3-¡l)amino)phenyl)piperid¡n-l-¡l)acetyl)piperid¡n-4-¡l)phenyl)-4-fluoro -l-oxo¡soindolin-2-yl)-N-(thiazol-2¡l)acetamide; 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(l-(2-(4-(4-(((R .)-2,6-dioxopiperidin3-yl)amino)phenyl)piperidin-l-yl)acetyl)piperidin-4-yl)phenyl)-4-fluoro-l-oxoisoindolin-2-yl) -N-(thiazol-2yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-íl)-2-(6-(4-(l-(2-(4-(4 -(((S)-2,6-dioxopiper¡d¡n3-yl)amino)-2-fluorophen¡l)piperidin-l-yl)acet¡l)p¡perídin-4- yl)phenyl)-4-fluoro-l-oxoisoindolín-2-íl)-N(thiazol-2-yl)acetamide; 2-(6-(4-(l-(2-(4-(2-cyano-4-((2,6-dioxop¡perídin-3-¡l)amino)phenyl)p perídin-lyl)acetyl)piperidin-4-yl)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[l,2c] ¡m¡dazol-l-yl)-N-(thiazol-2-¡l)acetam¡de; 2-(6,7-dihydro-5H-pyrrolo[l,2-c]ímidazol-l-íl)-2-[6-[4-[l-[2-[4-[4- [(2,6-dioxo-3piper¡dil)amino]phenyl]-l-p¡peridyl]-2-oxo-ethyl]-4-p¡per¡dil]phenyl]-4-fluoro-l-oxo- isoindolin-2-yl]-Nthiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-íl)-2-[6-[6-[4-[2-[4- [4-[[(3S)-2,6-d ioxo-3p¡per¡d¡l]amino]-2-fluoro-phen¡l]-l-p¡per¡d¡l]acetyl]p¡ perazin-l-íl]-3-pyridyl]-4-fluoro-l-oxoísoindolin-2-íl]-N-thiazol-2-íl-acetamíde; 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-¡l)-2-[6-[l-[l-[2- [4-[4-[[(3S)-2,6-d ioxo-3p¡perídyl]amino]phenyl]-l-p¡peridyl]acetyl]-4-piper¡d¡l]p¡razole-4 -]-4-fluoro-l-oxo-isoindolin-2-yl]-Nthiazol-2-yl-acetamide; 2-(6,7-d¡hydro-5H-pyrrOlo[l,2-c]¡m¡dazol-l-¡l)-2-[6-[4-[l-[2-[4 -[4-[[(3S)-2,6-d¡oxo-3p¡peridyl]amino]phenyl]-l-p¡peridyl]acetyl]-4-p¡peridyl]pyrazol-l-yl]-4 -fluoro-l-oxo-isoindolin-2-yl]-Nthiazol-2-yl-acetamide; 2-(6,7-D¡hydro-5H-pyrrolo[l,2-c]ímidazol-l-yl)-2-(6-(l-(l-(2-(4- (4-(((S)-2,6 dioxop¡per¡din-3-yl)amino)phen¡l)p¡per¡d¡n-l-yl)acetyl)p¡per¡d¡ n-4-yl)-lH-l,2,3-tr¡azol-4-¡l)-4-fluorol-oxo¡so¡ndolin-2-¡l)-N-(thiazol-2- ¡l)acetam¡da; 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-[l)-2-[6-[4-[[l-[2-[4 -[4-[(2,6-dioxo-3pipendyl)amino]phenyl]-l-piperidyl]acetyl]-4-piperidyl]oxy]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]- Nthiazol-2-yl-acetamide; 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-¡l)-2-[6-[4-[[l-[2-[ 4-[4-[[(3S)-2,6-d ioxo-3p¡perid¡l]am¡no]phenyl]-l-p¡períd¡l]acet¡l]-4-p¡perid¡ l]ox¡]phen¡l]-4-fluoro-l-oxo-¡so¡ndol¡n-2-yl]-Nthiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-íl)-2-[6-[4-[[l-[2-[4-[ 4-[[(3R)-2,6-dioxo-3piperídyl]amino]phenyl]-l-piperidyl]acetyl]-4-piperidyl]oxy]phenyl]-4-fluoro-l-oxo-isoindolin-2 -yl]-Nthiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazole-l-¡l)-2-(6-(4-((l-(2-(4-(4-(( 2,6-dioxop¡perid¡n-3¡l)amino)-3-fluorophenyl)p¡perídin-l-yl)acetyl)piperid¡n-4-yl)oxy)phenyl)-4- fluoro-l-oxoisoindolin-2-yl)N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-íl)-2-(6-(4-((l-(2-(4-( 4-((2,6-dioxopiperidín-3yl)amino)-2-fluorophenyl)piperídin-l-yl)acetyl)piperidin-4-yl)oxy)phenyl)-4-fluoro-l- oxoisoindolin-2-yl)N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-((l-(2-(4-(5-((2 ,6-dioxop¡perid¡n-3yl)amino)pyridin-2-yl)piperidin-l-yl)acetyl)piperid¡n-4-yl)oxy)phenyl)-4-fluoro-l-oxoisoindoline-2- il)-N(thiazol-2-íl)acetamíde; 2-(6-(4-((l-(2-(4-(2-cyano-4-((2,6-dioxop¡peridin-3-yl)annino)phen¡l)p¡peridin -l¡l)acetyl)piperidin-4-¡l)ox¡)phen¡l)-4-fluoro-l-oxoiso¡ndolin-2-yl)-2-(6,7-dihydro-5H- pyrrolo[l,2c]¡m¡dazol-l-yl)-N-(thiazol-2-¡l)acetamide; 2-(6,7-dihydro-5H-pyrrOlo[l,2-c]imidazol-l-íl)-2-(6-(4-((l-(2-(4-( 4-((2,4-dioxo-3azabicyclo[3.1. l]heptan-l-¡l)amino)phenyl)piperidin-l-yl)acetyl)piperidin-4-¡l)oxy)phen¡l)-4 -fluoro-loxoiso¡ndolin-2-¡l)-N-(thiazol-2-¡l)acetam¡de; 2-(6,7-dihydro-5H-pyrrolo[ l,2-c]imidazole-l-¡l)-2-(6-(4-((l-(2-(4-(4- (((S)-2,6d¡oxopiper¡d¡n-3-yl)amino)-2-fluorophen¡l)piperidín-l-yl)acetyl)p¡peridin-4-¡l)oxy)phen¡ l)-4-fluoro-loxo¡so¡ndolin-2-yl)-N-(thiazol-2-¡l)acetamide; 2-(6,7-dihydro-5H-pyrrOlo[l,2-c]imidazol-l-íl)-2-[6-[4-[[l-[2-[4-[ 4-[(2,6-dioxo-3p¡peridyl)amino]phenyl]-l-p¡peridyl]-2-oxo-acet¡l]-4-p¡peridyl]oxy]phenyl]-4-fluoro- l-oxo-isoindolyn-2yl]-N-thiazol-2-l-acetamide; 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-¡l)-2-[6-[4-[(3R)-l-[ 2-[4-[4-[[(3S)-2,6-dioxo-3piper¡dil]amino]phenyl]-l-piperidyl]acet¡l]pyrrolidin-3-yl]oxyphen l]-4-fluoro-l-oxo-iso¡ndolin-2-yl]-Nthiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[ l,2-c]midazol-l-yl)-2-[6-[4-[(3S)-l-[2-[4- [4-[[(3S)-2,6-dioxo-3p¡per¡d¡l]am¡no]fen¡l]-l-p¡per¡d¡l]acet¡l]pyrrolidin-3- ¡l]oxy¡phen¡l]-4-fluoro-l-oxo-¡so¡ndol¡n-2-¡l]-Nthiazol-2-yl-acetamide; 2-(6-(4-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-l-yl)acetyl)piperazin-lyl)phen! l)-4-fluoro-l-oxo¡so¡ndolin-2-¡l)-2-((R)-6-fluoro-6,7-d¡hydro-5H-pyrrolo[l, 2-c]¡m¡dazol-l-¡l)N-(thiazol-2-yl)acetamide; 2-[6-[4-[4-[2-[4-[4-[[(3S)-2,6-dioxo-3-piper¡d¡l]amino]-2-fluoro-phen ¡l]-lpipend¡l]acet¡l]piperazin-l-¡l]phen¡l]-4-fluoro-l-oxo-¡so¡ndol¡n-2-yl]-2-[(6R) -6-fluoro-6,7-dihydro5H-pyrrolo[l,2-c]imídazol-l-yl]-N-thiazol-2-íl-acetamide; 2-[6-[4-[4-[2-[4-[3-(2,4-d¡oxohexah¡drOp¡r¡m¡din-l-¡l)-l-met¡l-¡ ndazol-6-¡l]-lp¡per¡dil]acetyl]piperaz¡n-l-¡l]phen¡l]-4-fluoro-l-oxo-¡soindol¡n-2-yl]-2-[( 6R)-6-fluoro-6,7-dihydro5H-pyrrolo[l,2-c]imidazol-l-yl]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[l,2-c]ímidazol-l-íl)-2-(6-(4-(2-(2-(4-(4- (((S)-2,6-dioxopiperid¡n3-¡l)amino)-2-fluorophen¡l)p¡pend¡n-l-¡l)acetyl)-2,7-d¡azaspiro[ 3.5]nonan-7-yl)phenyl)-4-fluoro-loxoisoindolin-2-yl)-N-(thiazol-2-yl)acetannide; 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-íl)-2-[6-[4-[2-[2-[4-[4 -[(2,6-dioxo-3p¡pendil)amino]phen¡l]-l-piperidyl]acet¡l]-2,6-d¡azaspiro[3.3]heptan-6-¡ l]pheníl]-4-fluoro-l-oxoisoindolin-2-íl]-N-thiazol-2-yl-acetamíde; 2-(6,7-dihydro-5H-pyrrOlo[l,2-c]imidazol-l-íl)-2-[6-[4-[2-[2-[4-[4 -[[(3S)-2,6-d ioxo-3piperid¡l]am¡no]-2-fluoro-phenyl]-l-p¡per¡d¡l]acet¡l]-2,6-d¡azasp ¡ro[3.3]heptan-6-¡l]phen¡l]-4-fluorol-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-íl)-2-[6-[4-[2-[2-[4-[3 -(2,4dioxohexahydro¡rímidín-l-¡l)-l-methyl-¡ndazol-6-¡l]-l-pipendyl]acetyl]-2,6-d¡azaspiro[3.3]heptan6- yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrOlo[l,2-c]imidazol-l-íl)-2-[6-[4-[2-[2-[4-[3 -(2,4dioxohexahydro¡rim¡din-l-¡l)-l-methyl-indazol-6-¡l]-3,3-difluoro-l-piper¡d¡l]acetyl]-2 ,6d¡azaspiro[3.3]heptan-6-¡l]phen¡l]-4-fluoro-l-oxo-¡soindolin-2-¡l]-N-thiazol-2-¡l-acetam¡de ; 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]ímidazol-l-¡l)-2-(6-(4-(6-(2-(4 -(4-((2,6-dioxop¡peridin-3¡l)amino)phen¡l)-3,3-difluorop¡peridin-l-¡l)acetyl)-2,6 -d¡azaspiro[3.3]heptan-2-yl)phen¡l)-4-fluoro-loxo¡so¡ndolin-2-¡l)-N-(thiazol-2-yl)acetam gives; 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazole-l-[l)-2-[6-[4-[2-[2-[4-[4 -[[(3S)-2,6-d ioxo-3p¡per¡d¡l]amino]-2-fluoro-phen¡l]-l-p¡per¡dyl]acetyl]-2,6-d azaspiro[3.3]heptan-6-l]phenyl]-4-fluorol-oxo-isoindolin-2-l]-N-(2-pyridyl)acetamide; 2-(6,7-dihydrO-5H-pyrrolo[l,2-c]ímidazol-l-yl)-2-[6-[4-[2-[2-[4-[3-( 2,4d¡oxohexah¡drop¡rim¡n-l-¡l)-l-met¡l-¡ndazol-6-¡l]-l-p¡per¡d¡l]acet¡l]-2,6- d¡azasp¡ro[3.3]heptan47 6-¡l]phen¡l]-4-fluoro-l-oxo-¡soindol¡n-2-¡l]-N-(2-pyridyl)acetam¡de; 2-(6,7-dihydro-5H-pyrrolo[ l,2-c]midazol-l-yl)-2-[6-[4-[2-[2-[4-[3-(2, 4dioxohexahydropyrimídin-l-yl)-l-methyl-indazol-6-yl]-3,3-difluoro-l-piperídyl]acetyl]-2,6diazaspiro[3.3]heptan-6-íl] phenyl]-4-fluoro-l-oxo-¡so¡ndolin-2-¡l]-N-(2-pyrid¡l)acetamide; 2-(6,7-d¡hydro-5H-pyrrOlo[l,2-c]ímidazol-l-¡l)-2-[6-[4-[[4-[2-[ 4-[4-[(2,6-dioxo-3piperid¡l)amino]phenyl]-l-p¡per¡d¡l]acet¡l]piperazin-l-yl]methyl]phenyl]-4 -fluoro-l-oxo-¡so¡ndolin-2-yl]N-thiazol-2-yl-acetamide; 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]ímidazol-l-¡l)-2-[6-[4-[[4-[2-[4- [4-[(2,6-dioxo-3piperidyl)amino]-2-fluoro-phenyl]-l-piper¡dil]acet¡l]piperazin-l-¡l]methyl]phenyl]-4 -fluoro-l-oxo¡so¡ndolin-2-¡l]-N-thiazol-2-¡l-acetamide; 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]ímidazol-l-¡l)-2-[6-[4-[[4-[2-[ 4-[4-[[(3S)-2,6-d ¡oxo-3p¡per¡dyl]amino]-2-fluoro-phen¡l]-l-piper¡d¡l]acet¡l]p ¡perazin-l-yl]met¡l]phenyl]-4-fluoro-l-oxo¡so¡ndolin-2-¡l]-N-thiazol-2-¡l-acetam¡de; 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-¡l)-2-[6-[4-[[4-[2-[ 4-[4-[[(3S)-2,6-d ¡oxo-3p¡peridyl]amino]-2-fluoro-phenyl]-l-piperid¡l]-2-oxo-ethyl]piperazin-l- l]methyl]phenyl]-4-fluoro-l-oxoisoandolin-2-yl]-N-thiazol-2-yl-acetamide; 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]ímidazol-l-¡l)-2-[6-[4-[[l-[2-[ 4-[4-[[(3S)-2,6-d ¡oxo-3piper¡dil]amino]-2-fluoro-phen¡l]-l-piperid¡l]acet¡l]-4-piperidyl] methyl]pheníl]-4-fluoro-l-oxoísoíndolin-2-yl]-N-thiazol-2-íl-acetamide. E35: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance. E36: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, for use in the therapeutic and / or prophylactic treatment of cancer, in particular lung cancer. non-small cell, more particularly non-small lung cancer with EGFR mutation where the activating mutation is L858R. E37: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, for use in the therapeutic and / or prophylactic treatment of non-small cell lung cancer, more particularly EGFR mutant non-small cell lung cancer wherein the activating mutation is L858R. E38: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the therapeutic and / or prophylactic treatment of cancer, in particular cancer non-small cell lung cancer, more particularly non-small cell lung cancer with mutation of ΜΛ / a / ZUZZ / UU / 00» EGFR where the activating mutation is L858R. E39: A certain embodiment of the invention is a pharmaceutical composition comprising the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable auxiliary substance. E40: A certain embodiment of the invention is a method for the therapeutic and / or prophylactic treatment of cancer, in particular non-small cell lung cancer, more particularly non-small lung cancer with EGFR mutation wherein the activating mutation is L858R , by administering the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, to a patient. E41: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, for use as a medicament in the therapeutic and / or prophylactic treatment of a patient with activating mutations of EGFR suffering from cancer, in particular non-small cell lung cancer, comprising determining the status of activating mutations of EGFR in said patient and then administering the compound of formula I as described herein, or a pharmaceutically acceptable salt of the himself, to said patient. E42: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, for use as a medicament in the therapeutic and / or prophylactic treatment of a patient with mutations of EGFR T790M / L858R, T790M / L858R / C797S, L858R and / or L858R / C797S suffering from cancer, in particular non-small cell lung cancer, comprising determining the activating mutation status of EGFR in said patient and then administering the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, to said patient. E43: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, for the use of a medicament in therapeutic and / or prophylactic treatment of a patient with activating mutations of EGFR determined with a cobas® EGFR v2 mutation test suffering from cancer, in particular non-small cell lung cancer, which comprises determining the status of activating EGFR mutations in said patient and then administering the compound of formula I as described herein, or one of its pharmaceutically acceptable salts, to said patient. E44: The invention includes all substituents in their corresponding deuterated form, where applicable, of the compounds of formula I. E45: The invention includes all optical isomers, that is, diastereoisomers, diastereomeric mixtures, racemic mixtures, all their corresponding enantiomers and / or tautomers as well as their solvates, when applicable, of the compounds of formula I. Formula II Modalities All separate modalities can be combined. The: One embodiment of the invention is a compound of formula II, or a pharmaceutically acceptable salt thereof, where A' is selected from the ring systems AF, AG and AH; OAFAG R4 AH OR A1 is selected from i) -NH-, and ü) -O-; A2is selected from i) -N-, and i) -CR52-; A3is selected from i) -N-, and i) -CR53-; A4 is selected from i) -N-, and i) -CR54-; A5is selected from i) -N-, and i) -CR55-; R1' is selected from ¡) H, ¡i) halogen, iii) Ci-6 alkyl iv) cyano, v) Ci-6 alkoxy, vi) halo-Ci e-alkoxy, vii) Ci-6 alkyl, viii) halo-Ci-e-alkyl, ix) C3-8 cycloalkyl, and x) halo-C3-8 -cycloalkyl; R52is selected from i) H, i) halogen, iii) cyano, iv) C1-6-alkoxy, v) halo-Ci-6-alkoxy, vi) C1-6-alkyl, vii) halo-Ci-6-alkyl, viii ) C3-8 cycloalkyl, and ix) halo-C3-8-cycloalkyl; R53, R54 and R55 are independently selected from i) H, i) halogen, iii) C1-6 alkyl, iv) halo-Ci-s-alkyl, v) C3-8 cycloalkyl, and vi) halo-C3-8 -cycloalkyl; R2is selected from ¡) H, ¡i) halogen, ¡ii) cyano, iv) C1-6-alkyl, v) halo-Ci-6-alkyl, vi) C3-8-cycloalkyl, and vii) halo-C3-8-cycloalkyl ; R3is selected from ¡) H, ¡i) halogen, iii) Ci 6-alkyl, iv) halo-Ci 6-alkyl, v) C3 8-cycloalkyl, and vi) halo-Cs 8-cycloalkyl;; R4 and R5 are H; or R4 and R5 together form -(CH2)q-; q is 1 or 2; R6is selected from i) H, i) halogen, ii) cyano, iv) C1-6 alkoxy, v) halo-Ci-6-alkoxy, vi) C1-6 alkyl, vii) halo-Ci-6-alkyl, viii) C3-8 cycloalkyl, and ix) halo-C3-8-cycloalkyl; R7is selected from ¡) H, ¡i) halogen, ¡ii) cyano, iv) Ci-6-alkyl, v) halo-Ci-6-alkyl, vi) C3-8-cycloalkyl, and vii) halo-C3-8-cycloalkyl ; R70is selected from ¡) H, ¡i) halogen, iii) cyano, iv) Ci-e alkyl, v) halo-Ci-e-alkyl, vi) C3-8 cycloalkyl, and vii) halo-Cs-s-cycloalkyl; R8is H; R9is selected from ¡) H, and ¡i) alkyl of Cí e; Y1is selected from i) -N-, and i) -CH-; Y2is selected from i) -N-, and i) -CR16-; R12, R13, R14 and R15 are independently selected from i) -H-, i) halogen, and iii) hydroxy-Ci-6-alkyl; R16is selected from i) -H-, i) hydroxy, and iii) fluoro; L3is absent or selected from ¡V) v) v¡) vii) viii) -(CH2)m-C(O)-, -C(O)-(CH2)p-, -C(O)-C(O)-, -NR10-C(O)-, -C(O)-NR10 -, -C(O)O-, -CH2-CF2-CH2-, -ch2-, ix) N=N \ x) EITHER x¡) m is 0, 1 or 2; p is 0, 1, 2 or 3; R10 is selected from or i) H, and i) alkyl of Cí e; D is selected from the ring sets I, J, K, L, Μ, N, O, P, Q, R, S, T, U, V, W and X, all ring sets are optionally replaced with one to three substituents selected from R80, R81 and R82; R80' R81 and R82 are selected independently of i) halogen, i) cyano, iii) hydroxy, iv) hydroxy- Ci e-alkyl, v) Ci-6 alkoxy, vi) halo-Ci-e-alkoxy, vii) Ci-6 alkyl, viii) halo-Ci-e-alkyl, ix) C3-8 cycloalkyl, and x) halo-C3-8-cycloalkyl; L4 is absent or selected i) -NRH-qO)-, ii) -CH2-, and iii) -O-; E is selected from the ring systems Y, Z, AA, AB and AC; N=N Y Z AA AB AC L5 is absent or ; B is selected from the ring set AD and AE; E2: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein A' is selected from the ring systems AF, AG and AH; A1es -NH-; A2 is selected from i) -N-, and i) -CH-; R1' is selected from i) H, and i) halogen; R2 is selected from ¡) H, and ¡i) halogen; R3is H; R4is H; R5is H; R6is selected from i) H, and i) halogen; R7is H; R8is H; R9 is Ci-e alkyl; C is the F ring system; IVIA / a / ZUZZ / UU / 00» F Y1es -CH-; Y2es -N-; R12, R13, R14 and R15 are H; L3is selected from i) -(CH2)m-C(O)-, and i) -C(O)-(CH2)p-; m is 1; p is 3; D is selected from the I and J ring systems; I J L4 is absent; E is selected from the Y and Z ring systems; AND Z L5 is absent; or a pharmaceutically acceptable salt thereof. E3: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein A is selected from the ring systems AG and AF. E4: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein A is the AF ring system. E5: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein A1 is -NH-. E6: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein A2 is -CH-. E7: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein R1' is selected from i) H, and i) halogen. E8: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein R1' is selected from ¡) H, ¡i) chloro, and iii) fluoro. E9: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from i) H, and i) halogen. E10: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from i) H, i) chloro, and iii) fluoro. Eli: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from i) H, and i) halogen. E12: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein R3 is H. E13: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein R4 is H. E14: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein R5 is H. E15: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein R6 is selected from i) H, i) halogen. E16: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein R7 is H. E17: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein R8 is H. E18: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein R9 is Cl-6 alkyl. E19: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein R9 is methyl. E20: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein C is the F ring system. E21: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein Y1 is -CH-. E22: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein Y2 is -N-. E23: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein R12, R13, R14 and R15 are H. E24: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein L3 is selected from i) -(CH2)m-C(O)-, and i) -C(O)-(CH2)p-. E25: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein m is 1. E26: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein p is 1 or 3. E27: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein D is selected from ring systems I and J. E28: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein D is ring system 1 E29: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein L4 is absent. E30: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein E is selected from the Y and Z ring systems. E31: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein L5 is absent. E32: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of 2-(6,7-d¡hydro-5H-p¡nOlo[l,2-c]¡m¡dazol-l-yl)-2-(6-(6-(4-(4-( 4-((2-(2,6-dioxop¡perídin-3-yl)l-oxoisoindolin-4-yl)ox¡)piperidin-l-yl)-4-oxobutyl)piperazin-l -yl)pyridin-3-yl)-7-fluoro-2Hindazol-2-yl)-N-(thiazol-2-íl)acetamide; 2-(6,7-dihydro-5H-pinOlo[l,2-c]ím¡dazol-l-yl)-2-(6-(6-(4-(2-(4-(4 -((2,6-dioxop¡per¡d¡n-3¡l)am¡no)phen¡l)p¡per¡d¡n-l-¡l)acet¡l)p¡peraz¡n-l- il)pyridín-3-íl)-7-fluoro-2H-indazol-2-íl)-N(thiazol-2-yl)acetamide; 2-[4,7-dichloro-6-[4-[4-[2-[4-[4-[(2,6-dixo-3-piperidyl)amino]phen¡l]-lp¡perid ¡l]acet¡l]p¡perazin-l-yl]phen¡l]¡ndazol-2-¡l]-2-(6,7-d¡hydro-5H-pyrrolo[l,2 -c]¡m¡dazol-l¡l)-N-thiazol-2-¡l-acetamide; 2-(6,7-dihydro-5H-p¡nOlo[l,2-c]¡m¡dazol-l-yl)-2-[6-[6-[4-[2-[4- [4-[(2,6-dioxo-3p¡peridyl)amino]-2-fluoro-phenyl]-l-p¡peridyl]acetyl]piperaz¡n-l-¡l]-3-pyrid¡l]-4- fluoro-ndazol-2l]-N-thiazol-2-yl-acetamide; 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]ímidazol-l-¡l)-2-[6-[6-[4-[2-[4 -[4-[(2,6-dioxo-3p¡per¡d¡l)am¡no]fen¡l]-l-p¡per¡d¡l]acet¡l]p¡peraz¡n-l-¡ l]-3-pyr¡d¡l]-4-fluoro-¡ndazol-2-¡l]-Nthiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[6-[4-[2-[4-[5-[(2, 6-dioxo-3p¡peridyl)amino]-2-pyrid¡l]-l-piperidyl]acetyl]p¡perazin-l-yl]-3-p¡r¡d¡l]-4-fluoro-indazol- 2-yl]-Nthiazol-2-yl-acetamide; 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]imidazol-l-¡l)-2-[6-[6-[4-[2-[ 4-[3-(2,4d¡oxohexah¡drop¡r¡m¡din-l-¡l)-l-met¡l-¡ndazol-6-¡l]-l-p¡per¡d¡l]acet ¡l]p¡peraz¡n-l-¡l]-3-p¡r¡d¡l]61 4-fluoro-índazol-2-íl]-N-thiazol-2-íl-acetamíde; 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-íl)-2-(6-(6-(4-(2-(4- (4-(((S)-2,6-dioxop¡peridín-3yl)amino)-2-fluorophenyl)p¡peridin-l-yl)acetyl)piperazin-l-yl)pyridin-3-yl) -4-fluoro-2H-indazol-2íl)-N-(thiazol-2-íl)acetamide; or a pharmaceutically acceptable salt thereof. E33: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance. E34: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, for use in the therapeutic and / or prophylactic treatment of cancer, in particular lung cancer. non-small cell, more particularly non-small lung cancer with EGFR mutation where the activating mutation is L858R. E35: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, for use in the therapeutic and / or prophylactic treatment of non-small cell lung cancer, more particularly EGFR mutant non-small cell lung cancer wherein the activating mutation is L858R. E36: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the therapeutic and / or prophylactic treatment of cancer, in particular cancer non-small cell lung cancer, more particularly non-small lung cancer with EGFR mutation where the activating mutation is L858R. E37: A certain embodiment of the invention is a pharmaceutical composition comprising the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable auxiliary substance. E38: A certain embodiment of the invention is a method for the therapeutic and / or prophylactic treatment of cancer, in particular non-small cell lung cancer, more particularly non-small lung cancer with EGFR mutation wherein the activating mutation is L858R , by administering the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, to a patient. E39: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, for use as a medicament in the therapeutic and / or prophylactic treatment of a patient with activating mutations. EGFR suffering from cancer, in particular non-small cell lung cancer, comprising determining the activating mutation status of EGFR in said patient and then administering the compound of formula II as described herein, or a pharmaceutically acceptable salt of the himself, to said patient. E40: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, for use as a medicament in the therapeutic and / or prophylactic treatment of a patient with mutations of EGFR T790M / L858R, T790M / L858R / C797S, L858R and / or L858R / C797S suffering from cancer, in particular non-small cell lung cancer, comprising determining the activating mutation status of EGFR in said patient and then administering the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, to said patient. E41: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, for the use of a medicament in therapeutic and / or prophylactic treatment of a patient with activating mutations of EGFR determined with a cobas® EGFR v2 mutation test suffering from cancer, in particular non-small cell lung cancer, which comprises determining the status of activating EGFR mutations in said patient and then administering the compound of formula II as described herein, or one of its pharmaceutically acceptable salts, to said patient. E42: The invention includes all substituents in their corresponding deuterated form, where applicable, of the compounds of formula II. E43: The invention includes all optical isomers, that is, diastereoisomers, diastereomeric mixtures, racemic mixtures, all their corresponding enantiomers and / or tautomers as well as their solvates, when applicable, of the compounds of formula II. Modalities of Formula III and Formula IV The: In certain embodiments, the present invention provides a compound of the Formula III or Formula IV: or a pharmaceutically acceptable salt, isotope, N-oxide or stereoisomer thereof, optionally as part of a pharmaceutical composition; where: A* is selected from: R34R37 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 of H, halogen (F, Cl, Br, or I), Ci-6 alkyl, cyano, Ci-e alkoxy, halo-Ci-6-alkoxy, halo-Ci-e-alkyl , C3-8 cycloalkyl, and halo-C3-8cycloalkyl and can be located in any ring where it is present in a bicycle; R32 is hydrogen, halogen (F, Cl, Br, or I), C1-6 alkyl, halo-Ci-6-alkyl, C38 cycloalkyl, or halo-C3-8-cycloalkyl; R33 is hydrogen, halogen (F, Cl, Br, or I), C1-6 alkyl, halo-Ci-6-alkyl, C3s cycloalkyl, or halo-Cs-s-cycloalkyl and can be located on the dihydropyrrole ring or imidazole; R34 is independently selected from each occurrence of H, F, Ci-e alkyl, halo-Ci-6-alkyl, C3-8 cycloalkyl, and halo-Cs-s-cycloalkyl; R35 is independently selected at each occurrence of H, halogen (F, Cl, Br, or I), C1-6 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 selected independently from H, halogen (F, Cl, Br, or I), cyano, C1-6 alkoxy, halo-Ci-6-alkoxy, C1-6 alkyl, halo-Ci-e-alkyl, C3-8 cycloalkyl, and halo-C3-8-cycloalkyl; or R36 and R37 together combine to form a 5- or 6-membered cycle optionally substituted with 1, 2, or 3 R31 substituents; R90 is H, Ci 6 alkyl, or C 3 e cycloalkyl; the G ring is an optionally substituted heteroaryl with 1 or 2 R42 substituents; A21is -NH-, -O-, -CH2-, or -NR100-; rwoesalkyl, cycloalkyl, aryl or heteroaryl; or as valency permits R100 can combine with R37 to form a 5-8 membered heterocycle or a 5-membered heteroaryl; A32, A33, A34, and A35 are independently selected from -N- and -CR42-; R42 is independently selected at each occurrence of H, halogen (F, Cl, Br, or I), cyano, C1-6 alkoxy, halo-Ci-6-alkoxy, C1-6 alkyl, halo-Ci-6- alkyl, C3-8 cycloalkyl, and halo-C3-8cycloalkyl; A36is -N- or -CR35-; L2 is a bivalent linking group connecting A* and isoindolinone or indazole. E2: The compound of modality 1, where the compound is selected from: IVIA / a / ZUZZ / UU / 00» or a pharmaceutically acceptable salt thereof. E3: The compound of modality 1, where the compound is selected from: or a pharmaceutically acceptable salt thereof. E4: The compound of any of the modalities 1 to 3, where R33 is H. E5: The compound of any of the modalities 1 to 3, where R33 is F. E6: The compound of any of the modalities 1 to 5, where y is 1. E7: The compound of any of the modalities 1 to 5, where and 2. E8: The compound of any of the modalities 1 to 7, where at least one of R31s halo. E9: The compound of any of the modalities 1 to 7, where at least one of R31es F. E10: The compound of any of the modalities 1 to 5, where and 0. Eli: The compound of any of the modalities 1 to 10, where R32 is H. E12: The compound of any of the modalities 1 to 10, where R32 is F. E13: The compound of modality 1, where the compound is selected from: Ε14: The compound of embodiment 1, where the compound is selected from: E15: The compound of any of the modalities 1 to 14, where A* is: Ε16: The compound of any of the modalities 1 to 14, where A* is: Ε17: Ε18: Ε19: Ε20: Ε21: Ε22: Ε23: Ε24: Ε25: The compound of any of the modalities 1 to 16, where A34 is CH. The compound of any of the modalities 1 to 16, where A34 is N. The compound of any of the modalities 1 to 16, where A34 is CR42 The compound of any of the modalities 1 to 16, where A34 is CF. The compound of any of the modalities 1 to 20, where A35 is CH. The compound of any of the modalities 1 to 20, where A35 is N. The compound of any of the modalities 1 to 20, where A35 is CR42, The compound of any of the modalities 1 to 20, where A35 is CF. The compound of any of the modalities 1 to 14, where A* is: Ε26: EITHER The compound of any of the modalities 1 to 14, where A* is: Ε27: The compound of modality 25 or 26, where A21 is NH. E28: The compound of modality 25 or 26, where A21 is O. E29: The compound of any of the modalities 1 to 14, where A* is: E30: E31: E32: E33: E34: E35: E36: E37: E38: AND AND AND AND AND AND AND AND E compound of any compound of any compound of any compound of any compound of any compound of any compound of any compound of any compound of any compound of any of the modalities 1 a of the modalities 1 a of the modalities 1 a of the modalities 1 a of the modalities 1 a of the modalities 1 a of the modalities 1 a of the modalities 1 a of the modalities 1 a 29, where A32 is CH. 29, where A32 is N. 29, where A32 is CR42 29, where A32 is CF. 33, where A33 is CH. 33, where A33 is N. 33, where A33 is CR42, 33, where A33 is CF. 14, where A* is: E39: The compound of modality 38, where A21 is NH. E40: The compound of modality 38, where A21 is O. E41: The compound of any of the modalities 1 to 40, where R34 is H. E42: The compound of any of the modalities 1 to 40, where R34 is F. E43: The compound of any of the modalities 1 to 40, where R34 is CH3. Ε44: The compound of any of the modalities 1 to 43, where R35 is H. E45: The compound of any of the modalities 1 to 43, where R35 is F. E46: The compound of any of the modalities 1 to 43, where R35 is CH3. E47: The compound of any of the modalities 1 to 40, where R34 and R35 combine to form -CH2-. E48: The compound of any of embodiments 1 to 47, wherein R31 is independently selected in each case from H, halogen (F, Cl, Br, or I), and C1-6 alkyl. E49: The compound of any of embodiments 1 to 48, wherein R42 is independently selected in each case from H, halogen (F, Cl, Br, or I), and Ci-e alkyl. E50: The compound of any of the modalities 1 to 49, where B* is j--Ír31 E51: The compound of any of the modalities 1 to 49, where B* is \=Ar31 E52: The compound of any of the modalities 1 to 49, where B* is S E53: The compound of any of the modalities 1 to 49, where B* is E54: The compound of any of the modalities 1 to 53, where L2 has the formula: where, X1 and -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 selected at each occurrence 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 selected at each occurrence from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocycle, aliphatic and heteroaliphatic; R27 is independently selected at each occurrence 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 selected at each occurrence 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 valence permits, two R40 groups attached to the same carbon can join to form a 3 to 8 membered spirocycle; and R41 is aliphatic, aryl, heteroaryl, or hydrogen. E55: The compound of modality 54, where L2 has the formula: ^R23^R21^X R24^R ^X1^R23^R E56: The compound of modality 54 or 55, where X1 is a link. E57: The compound of modality 54 or 55, where X1 is a heterocycle. E58: The compound of modality 54 or 55, where X1 is NR2. E59: The compound of modality 54 or 55, where X1 is C(O). E60: The compound of any of the modalities 54 to 59, where X2 is a link. E61: The compound of any of embodiments 54 to 59, where X2 is a heterocycle. E62: The compound of any of the modalities 54 to 59, where X2 is NR2. E63: The compound of any of the modalities 54 to 59, where X2 is C(O). E64: The compound of any of the modalities 54 to 63, where R20 is a link. E65: The compound of any of the modalities 54 to 63, where R20 is CH2. E66: The compound of any of embodiments 54 to 63, where R20 is a heterocycle. E67: The compound of any of the embodiments 54 to 63, where R20 is aryl. E68: The compound of any of embodiments 54 to 63, where R20 is phenyl. Ε69: Ε70: Ε71: Ε72: Ε73: Ε74: Ε75: Ε76: Ε77: Ε78: Ε79: Ε80: Ε81: Ε82: Ε83: The compound of any of the modalities 54 to 63, where R20 is a bicycle. The compound of any of the modalities 54 to 69, where R21 is a bond. The compound of any of embodiments 54 to 69, where R21 is CH2. The compound of any of embodiments 54 to 69, where R21 is a heterocycle. The compound of any of embodiments 54 to 69, where R21 is aryl. The compound of any of embodiments 54 to 69, wherein R21 is phenyl. The compound of any of the modalities 54 to 69, where R21 is a bicycle. The compound of modality 54, where L in a linker of the formula: R24^R2^ A \R23 A. The compound of any of the modalities 54 to 76, where R22 is a bond. The compound of any of embodiments 54 to 76, where R22 is CH2. The compound of any of embodiments 54 to 76, wherein R22 is a heterocycle. The compound of any of embodiments 54 to 76, where R22 is aryl. The compound of any of embodiments 54 to 69, wherein R22 is phenyl. The compound of any of the modalities 54 to 76, where R22 is a bicycle. The compound of modality 54, where L in a linker of the formula: Ε84: Ε85: Ε86: Ε87: Ε88: Ε89: Ε90: Ε91: Ε92: Ε93: Ε94: Ε95: Ε96: Ε97: The compound of anyone The compound of anyone The compound of anyone The compound of anyone The compound of anyone The compound of anyone The compound of anyone The compound of anyone The compound of anyone The compound of anyone The compound of anyone The compound of anyone The compound of any of the modalities 54 to 83, of the modalities 54 to 83, of the modalities 54 to 83, of the modalities 54 to 83, of the modalities 54 to 83, of the modalities 54 to 83, of the modalities 54 to 89 , from modalities 54 to 89, from modalities 54 to 89, from modalities 54 to 89, from modalities 54 to 89, from modalities 54 to 89, from modalities 54 to 89, where R23 is a link. where R23 is CH2. where R23 is heterocycle. where R23 is aryl. where R23 is phenyl. where R23 is a bicycle. where R24 is link. where R24 is CH2. where R24 is heterocycle. where R24 is aryl. where R24 is phenyl. , where R24 is a bicycle. where R24 is C(O). In certain embodiments a compound selected from: 5-((2-( 1-(6,7-d¡hydro-5H-pyrrolo[l,2-c]ímidazol-l-¡l)-2-oxo-2-(t¡ azol-2-¡lam¡no)ethyl)-7-fluoro-3oxoisoindolín-5-yl)ethynyl)-N-(l-(2-(4-(4-((2,6-d oxop ¡per¡d¡n-3-yl)amino)phenyl)p¡per¡d¡n-l¡l)acet¡l)p¡períd¡n-4-¡l)p¡col¡nam¡ gives; 5-[2-[2-[l-(6,7-dihydro-5H-pyrrolo[l,2-c]midazol-l-¡l)-2-oxo-2-(t¡ azol-2-ylamino)ethyl]-7-fluoro-3oxo-isondolin-5-yl]ethynyl]-N-[l-[2-[4-[(2,6-dioxo- 3-p¡peridyl)amino]phenyl]acetyl]-4-piperidyl]pyridine-2carboxamide 5-[2-[2-[l-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazole-l-íl)-2-oxo-2-(thiazol-2-ylamino )et¡l]-7-fluoro-3oxo-isoindolin-5-¡l]ethín¡l]-N-[l-[2-[4-[4-[(2,6-dioxo- 3-piperidyl)oxy]phen¡l]piperaz¡n-l-yl]acetyl]-4p¡períd¡npyridín-2-carboxamide F 5-[2-[2-[l-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-¡l)-2-oxo-2-( thiazol-2-¡lamino)et¡l]-7-fluoro-3oxo-¡so¡ndolin-5-yl]et¡n¡l]-N-[l-[2-[4-[ 4-[[(3S)-2,6-dioxo-3-piperid¡l]amino]-2-fluoro-phenyl]-lpiper¡díl]acet¡l]-4-piper¡d¡l ]p¡r¡din-2-carboxam¡da 2-(6,7-d¡hydro-5H-pyriOlo[l,2-c]imidazol-l-¡l)-2-[6-[4-[4-[2-[4- [4-[(2,6-dioxo-3p¡perid¡l)amino]phenyl]-l-p¡per¡d¡l]acetyl]piperaz¡n-l-¡l]phenyl]-4-fluoro-l- oxo-ísoindolin-2-yl]-N-thiazol-273yl-acetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]imidazol-l-¡l)-2-[6-[4-[4-[2-[ 4-[4-[[(3S)-2,6-dioxo-3p¡per¡d¡l]am¡no]fen¡l]-l-p¡per¡d¡l]acet¡l]p¡ peraz¡n-l-¡l]phen¡l]-4-fluoro-l-oxo-¡so¡ndolin-2-¡l]-N-thiazol-2yl-acetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]imidazol-l-¡l)-2-[6-[4-[4-[2-[ 4-[4-[[(3R)-2,6-dioxo-3piper¡d¡l]amino]phenyl]-l-p¡per¡d¡l]acetyl]piperaz¡n-l-¡l]phen ¡l]-4-fluoro-l-oxo-¡so¡ndolin-2-yl]-N-thiazol-2yl-acetamide 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-íl)-2-(6-(4-(4-(4-(4- (4-((2,6-dioxopiper¡d¡n-3¡l)am¡no)phen¡l)p¡pendin-l-¡l)-4-oxobut¡l)p¡peraz¡n-l-¡ l)phen¡l)-4-fluoro-l-oxo¡so¡ndolin-2-¡l)-N-(thiazol2-¡l)acetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(4-(4-(2- (4-(4-((2,6-dioxop¡períd¡n-3¡l)amino)phen¡l)cyclohex¡l)acet¡l)piperaz¡n-l-¡l )phenyl)-4-fluoro-l-oxo¡soindolín-2-¡l)-N-(thiazol-2yl)acetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-yl)-2-(6-(4-(4-(2-(4- (4-((2,6-d¡oxop¡perídin-3IVIA / a / ZUZZ / UU / 00» il)amino)phen¡l)p¡pendin-l-yl)-2-oxoet¡l)p¡ perazin-l-yl)phenyl)-4-fluoro-l-oxoisoindolín-2-íl)-N-(thiazol-2yl)acetamide 2-(6,7-dihydro-5H-pyrrolo[l,2-c]ímidazol-l-íl)-2-[6-[4-[4-[2-[4-[ 5-[(2,6-dioxo-3-pipendil)am¡no]-2p¡r¡d¡l]-l-p¡per¡d¡l]acet¡l]p¡peraz¡n-l-¡l ]phen¡l]-4-fluoro-l-oxo-¡so¡ndolin-2-¡l]-N-thiazol-2-¡l-acetam¡de 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-íl)-2-[6-[4-[4-[2-[4-[4-[ (2,6-dioxo-3-piperidyl)amino]-2fluoro-phenyl]-l-piperidyl]acetyl]piperazin-l-yl]phenyl]-4-fluoro-l-oxo-isoindolin-2-yl] -N-thiazol-2-ylacetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-¡l)-2-[6-[4-[4-[2- [4-[4-[(2,6-dioxo-3-piper¡d¡l)amino]-3fluoro-phenyl]-l-piper¡d¡l]acetyl]piperazin-l-¡l ]pheníl]-4-fluoro-l-oxo-ísoíndolin-2-yl]-N-thiazol-2-ílacetamide 2-[6-[4-[4-[2-[4-[2-cyano-4-[(2,6-dioxo-3-p¡perídil)amino]phen¡l]-l-p per¡d¡l]acetyl]p¡peraz¡n-l¡l]phen¡l]-4-fluoro-l-oxo-¡so¡ndol¡n-2-¡l]-2-(6,7- d¡hydro-5H-pyrrolo[l,2-c]m¡dazol-l-¡l)-N-thiazol-2-acetamide 2-[6-[4-[4-[2-[4-[2-(difluoromethyl)-4-[(2,6-dioxo-3-peridyl)amino]phenyl]-lp pending dro-5H-pyrrolo[l,2c]imidazol-l-yl)-N-thiazol-2-l-acetamide 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(4-(2-(4-(3- ((2,6-dioxopiper¡din-3¡l)amino)phen¡l)p¡per¡d¡n-l-yl)acet¡l)p¡perazin-l-¡l)phen¡l)- 4-fluoro-l-oxo¡so¡ndolin-2-¡l)-N-(thiazol-2yl)acetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-yl)-2-(6-(4-(4-(2-(4- (3-(2,4-dioxotetrahydropyrimidínl(2H)-yl)-l-methyl-lH-indazol-6-yl)piperidín-l-yl)acetyl)piperazin-l- ¡l)phenyl)-4-fluoro-l-oxo¡soindolin-2yl)-N-(thiazol-2-yl)acetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(4-(4-(2- (l-(4-((2,6-dioxopiperidín-3-l)amino)2-(trifluoromethyl)phenyl)-4-hydroxy¡piperidin-4-¡ l)acetyl)piperazin-l-yl)phen¡l)-4-fluoro-l-oxoisoindolin-2¡l)-N-(thiazol-2-¡l)acetam¡de 2-(6 / 7-dihydro-5H-pyrrolo[l / 2-c]imidazol-l-yl)-2-(6-(4-(4-(2-(4-(4-(( 2,6-dioxopiperidin-3¡l)amino)phen¡l)p¡peridin-l-¡l)acet¡l)p¡peraz¡n-l-yl)phen¡l)-4-fluoro- l- oxoisoindolin-2-yl)-N-(pyridin-2yl)acetamide 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[4-[2-[4-[4-[( 2,6-dioxo-3-piperidyl)am¡no]-2fluoro-phenyl]-l-piperid¡l]acet¡l]p¡perazin-l-yl]phen¡l]-4-fluoro-l-oxo -isoindolin-2-¡l]-N-(2pyridiQacetamide 2-(6,7-dihydro-5H-pyrrolo[l,2-c]ímídazol-l-yl)-2-(6-(4-(l-(2-(4-(4 -((2,6-dioxopiperidin-3yl)amino)phen¡l)p¡peridin-l-¡l)acet¡l)p¡peridin-4-yl)phen¡l)-4-fluoro-l -oxoisoindole¡n-2-¡l)-N-(thiazol-2yl)acetamide 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(l-(2-(4-(4-(((S )-2,6-dioxopiperidin-3yl)amino)phenyl)piperidin-l-íl)acetyl)piperidin-4-yl)phenyl)-4-fluoro-l-oxoisoandolin-2-yl)-N -(thiazol-2yl)acetamide 2-(6,7-dihydro-5H-pyrrolo[l,2-c]ímídazol-l-yl)-2-(6-(4-(l-(2-(4-(4 -(((R)-2,6-dioxop¡pendin-3¡l)am¡no)phen¡l)p¡perid¡n-l-yl)acetyl)p¡perid¡n-4-¡l) phen¡l)-4-fluoro-l-oxo¡so¡ndolin-2-yl)-N-(thiazol-2yl)acetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(4-(l-(2- (4-(4-(((S)-2,6-dioxopiper¡din-377yl)amino)-2-fluorophenyl)p¡peridín-l-¡l)acet¡l)piperidin-4-¡ l)phen¡l)-4-fluoro-l-oxo¡so¡ndolin-2-yl)-N(thiazol-2-yl)acetamide 2-(6-(4-( l-(2-(4-(2-cyano-4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-l-yl) acet¡l)piperidin-4¡l)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[l,2-c]m¡ dazol-l-yl)-N-(thiazol-2yl)acetamide 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[l-[2-[4-[4-[( 2,6-dioxo-3p¡per¡d¡l)am¡no]phenyl]-l-p¡per¡d¡l]-2-oxo-ethyl]-4-p¡per¡d¡l]pheníl ]-4-fluoro-l-oxo-¡so¡ndolín-2-¡l]-Nthiazol-2-yl-acetamide 2-(6,7-d¡hydro-5H-pyrrOlo[lz2-c]imidazol-l-¡l)-2-[6-[6-[4-[2-[4- [4-[[(3S)-2,6-dioxo-3p¡períd¡l]amino]-2-fluoro-phen¡l]-l-p¡perid¡l]acet¡l]p ¡peraz¡n-l-¡l]-3-pyrid¡l]-4-fluoro-l-oxo-¡soindol¡n2-¡l]-N-thiazol-2-yl-acetam¡de 2-(6,7-d¡hydro-5H-pyrrOlo[l,2-c]¡m¡dazol-l-¡l)-2-[6-[l-[l-[2- [4-[4-[[(3S)-2,6-dioxo-3p¡períd¡l]am¡no]phenyl]-l-p¡perid¡l]acet¡l]-4-piper¡ d¡l]p¡razol-4-yl]-4-fluoro-l-oxo-¡so¡ndolin-2-yl]-Nthiazol-2-yl-acetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]imidazol-l-¡l)-2-[6-[4-[l-[2-[ 4-[4-[[(3S)-2,6-dioxo-3p¡per¡d¡l]am¡no]fen¡l]-l-p¡per¡d¡l]acet¡l]-4 -p¡per¡d¡l]p¡razol-l-¡l]-4-fluoro-l-oxo-¡so¡ndol¡n-2-¡l]-Nthiazol-2-yl-acetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(l-(l-(2- (4-(4-(((S)-2,6-d¡oxop¡per¡din-3yl)amino)phenyl)piperidin-l-yl)acetyl)piperidin-4-yl)-lH-l,2 ,3-triazol-4-yl)-4-fluoro-l-oxoisoindolín-2-yl)N-(thiazol-2-yl)acetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]ímidazol-l-¡l)-2-[6-[4-[[l-[2-[ 4-[4-[(2,6-dioxo-3piper¡d¡l)amino]phenyl]-l-p¡perid¡l]acetyl]-4-p¡perid¡l]ox¡]phenyl]-4 -fluoro-l-oxo-¡so¡ndolin-2-yl]-N-thiazol2-yl-acetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]ímidazol-l-¡l)-2-[6-[4-[[l-[2-[ 4-[4-[[(3S)-2,6-dioxo-3piperídyl]amino]phenyl]-l-p¡períd¡l]acetyl]-4-piperid¡l]oxy]phenyl]- 4-fluoiO-l-oxo-ísoindolin-2-yl]-N-thiazol2-yl-acetamide 2-(6,7-dihydro-5H-pyrrolo[l,2-c]m¡dazol-l-¡l)-2-[6-[4-[[l-[2-[ 4-[4-[[(3R)-2,6-dioxo-3p¡períd¡l]amino]phenyl]-l-piper¡dil]acet¡l]-4-piperid¡l]ox ¡]phenyl]-4-fluoro-l-oxo-¡so¡ndolin-2-yl]-N-t¡azol2-yl-acetamide 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(( l-(2-(4-(4-((2 ,6-dioxopiperidin-3-yl)amino)3-fluorophen¡Dp¡pend¡n-l-¡DacetiDp¡pend¡n-4-¡dox¡)phen¡l)-4-fluoro-l-oxo¡so¡ndolin -2-¡l)-N-(thiazol-2¡Dacetamide 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(( 1-(2-(4-(4-((2 ,6-dioxopiper¡din-3-yl)amino)2-fluorophenyl)p¡pend¡n-l-¡l)acet¡l)pipend¡n-4-¡l)ox¡)phen¡l)-4 -fluoro-l-oxo¡so¡ndolin-2-¡l)-N-(thiazol-2yl)acetamide 2-(6,7-dihydro-5H-pyrrolo[l,2-c]mádazol-l-yl)-2-(6-(4-((l-(2-(4-( 5-((2,6-dioxop¡per¡din-3yl)amino)pyridin-2-¡l)pipend¡n-l-yl)acetyl)piper¡d¡n-4-yl)oxy)phenyl)- 4-fluoro-l-oxoisoindolin-2-yl)-N(thiazol-2-yl)acetamide 2-(6-(4-((l-(2-(4-(2-c¡ano-4-((2,6-d¡oxop¡períd¡n-3-¡l)am¡ no)phen¡l)p¡perídin-l-¡l)acetyl)p¡perdin-4¡l)oxy)phen¡l)-4-fluoro-l-oxoiso¡ndole¡n- 2-¡l)-2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]imidazol-l-¡l)-N-(thiazol-2¡ Dacetamide h 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]m¡dazol-l-yl)-2-(6-(4-((l-(2- (4-(4-((2,4-dioxo-380 azabicyclo[3.1.1]heptan-l-yl)amino)phenyl)piperidin-l-yl)acetyl)peridin -4-yl)ox¡)phen¡l)-4-fluoro-loxo¡soindol¡n-2-¡l)-N-(thiazol-2-¡l)acetam¡de 2-(6,7-dihydro-5H-pyrrolo[l,2-c]mádazol-l-yl)-2-(6-(4-((l-(2-(4-( 4-(((S)-2,6-d¡oxop¡per¡din-3yl)amino)-2-fluorophenyl)piper¡din-l-¡l)acet¡l)piperidin-4-¡l)ox ¡)phen¡l)-4-fluoro-l-oxo¡so¡ndolin-2-yl)-N(t¡azol-2-yl)acetam¡de 2-(6,7-dihydro-5H-pyrrolo[l,2-c]midazol-l-l)-2-[6-[4-[[:L-[2-[4 -[4-[(2,6-dioxo-3p¡peridyl)amino]phenyl]-l-p¡peridyl]-2-oxo-acet¡l]-4-p¡peridyl]oxy]phenyl]-4-fluoro- l-oxo-iso¡ndolin-2-¡l]N-thiazol-2-yl-acetamide 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[(3R)-l-[2-[4-[ 4-[[(3S)-2,6-dioxo-3p¡pend¡l]am¡no]fen¡l]-l-p¡per¡d¡l]acet¡l]p¡rrolidin-3-¡l] oxyphenyl]-4-fluoro-l-oxo-soindol-2-l]-Nthiazol-2-yl-acetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[(3S)-l-[ 2-[4-[4-[[(3S)-2,6-dioxo-3piperid¡l]amino]phenyl]-l-piperidyl]acetyl]pyrrolidin-3-yl]oxyphenyl]-4-fluoro- l-oxo-¡soindolin-2-yl]-Nthiazol-2-yl-acetamide 2-(6-(4-(4-(2-(4-(4-((2,6-dioxopiperidin-3-¡l)amino)phenyl)piperidin-l-¡l)acetyl) p¡perazin-l-yl)phen¡l)-481 fluoro-l-oxo¡so¡ndolin-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-p¡ nOlo[l,2-c]imidazole-l-¡l)-N-(thiazol-2¡Qacetamide 2-[6-[4-[4-[2-[4-[4-[[(3S)-2,6-dioxo-3-peridyl]amino]-2-fluoro-phenyl ]-l-piper¡dil]acet¡l]p¡perazin-l¡l]phen¡l]-4-fluoro-l-oxo-¡soindol¡n-2-yl]-2-[(6R)- 6-fluoro-6,7-dihydro-5H-pyrrolo[l,2-c]imidazole-l-¡l]N-thiazol-2-yl-acetamide 2-[6-[4-[4-[2-[4-[3-(2z4-d¡oxohexah¡drop¡rim¡d¡n-l-¡l)-l-met¡l-¡ndazol-6- ¡l]-lp¡perid¡l]acetyl]p¡perazin-l-¡l]phen¡l]-4-fluoro-l-oxo-¡so¡ndol¡n-2-¡l]-2-[ (6R)-6-fluoro-6,7-dihydro-5Hpírrolo[l,2-c]imidazole-l-íl]-N-thiazol-2-yl-acetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-yl)-2-(6-(4-(2-(2-(4- (4-(((S)-2,6-d¡oxop¡per¡din-3yl)amino)-2-fluorophenyl)piperidin-l-yl)acetyl)-2,7-diazaspiro[3.5]nonan-7 -yl)phenyl)-4-fluoro-loxo¡so¡ndolin-2-¡l)-N-(thiazol-2-yl)acetam¡de 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-¡l)-2-[6-[4-[2-[2- [4-[4-[(2,6-dioxo-3piper¡d¡l)amino]phenyl]-l-p¡per¡d¡l]acet¡l]-2,6-diazaspiro[ 3.3]heptan-6-yl]phen¡l]-4-fluoro-l-oxo¡so¡ndolin-2-¡l]-N-thiazol-2-¡l-acetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]imidazol-l-¡l)-2-[6-[4-[2-[2-[ 4-[4-[[(3S)-2,6-dioxo-3p¡perid¡l]amino]-2-fluoro-phen¡l]-l-p¡períd¡l]acet¡l ]-2,6-diazaspiro[3.3]heptan-6-yl]phen¡l]-4-fluoro-loxo-¡soindol¡n-2-¡l]-N-thiazol-2-¡l-acetam¡de 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[2-[2-[4-[3-(2 ,4-dioxohexahydro¡rim¡din-l¡l)-l-methyl¡l-¡ndazol-6-¡l]-l-p¡per¡d¡l]acet¡l]-2,6-d¡azasp¡ ro[3.3]heptan-6-¡l]phen¡l]-4-fluoro-l-oxo¡so¡ndolin-2-¡l]-N-thiazol-2-yl-acetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-yl)-2-[6-[4-[2-[2-[4- [3-(2,4-dioxohexah¡drop¡r¡midin-lyl)-l-methyl-indazol-6-yl]-3,3-difluoro-l-pipendyl]acetiI]-2,6-diazaspiro[3.3 ] heptan-6-yl]phenyl]-4-fluorol-oxo-isoindolin-2-íl]-N-thiazol-2-yl-acetamíde 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]m¡dazol-l-yl)-2-(6-(4-(6-(2-(4- (4-((2,6-dioxopiper¡din-3yl)amino)phen¡l)-3,3-difluorop¡perídin-l-¡l)acetyl)-2,6-d¡ azaspiro[3.3]heptan-2-yl)phen¡l)-4-fluoro-loxoiso¡ndolin-2-¡l)-N-(thiazol-2-¡l)acetam¡de IVIA / a / ZUZZ / UU / 00» 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-yl)-2-[6-[4-[2-[2-[4-[4 -[[(3S)-2,6-dioxo-3p¡per¡d¡l]amino]-2-fluoro-phen¡l]-l-piperidyl]acet¡l]-2,6-d¡ azaspiro[3.3]heptan-6-¡l]phenyl]-4-fluoro-loxo-¡so¡ndol¡n-2-¡l]-N-(2-pyrád¡l)acetam¡de 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-¡l)-2-[6-[4-[2-[2-[4 -[3-(2,4-dioxohexahydrop¡r¡m¡din-l¡l)-l-met¡l-¡ndazol-6-yl]-l-p¡per¡d¡l]acet¡l]-2 ,6-d¡azasp¡ro[3.3]heptan-6-¡l]phen¡l]-4-fluoro-l-oxo¡so¡ndol¡n-2-¡l]-N-(2-p¡ r¡d¡l)acetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-yl)-2-[6-[4-[2-[2-[4- [3-(2,4-d¡oxohexah¡drop¡rimidín-lyl)-l-methyl-¡ndazol-6-yl]-3,3-difluoro-l-p¡peridyl]acetyl]- 2,6-d¡azaspiro[3.3]heptan-6-yl]phen¡l]-4-fluorol-oxo-¡so¡ndolin-2-yl]-N-(2-pyr¡d¡l)acetamide 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[[4-[2-[4-[4-[ (2,6-dioxo-3p¡peridyl)amino]phen¡l]-l-p¡peridyl]acetyl]p¡peraz¡n-l-l]methyl]phenyl]-4-fluoro-l-oxo-isoindolín- 2-¡l]-Nthiazol-2-yl-acetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-¡l)-2-[6-[4-[[4-[2 -[4-[4-[(2,6-dioxo-3-p¡períd¡l)amino]-2fluoro-phen¡l]-l-p¡peridyl]acet¡l]p¡peraz ¡n-l-¡l]methyl]phen¡l]-4-fluoro-l-oxo-isoindolin-2-¡l]-N-thiazol-2-ylacetamide 2-(6,7-dihydro-5H-pyrrolo[l,2-c]m¡dazol-l-yl)-2-[6-[4-[[4-[2-[4 -[4-[[(3S)-2,6-dioxo-3piper¡dil]am¡no]-2-fluoro-phenyl]-l-p¡per¡dil]acetyl]piperazin-l-¡l]methyl ]phenyl]-4-fluoro-l-oxo-¡soindolin2-¡l]-N-thiazol-2-¡l-acetam¡de 2-(6,7-dihydro-5H-pyrrolo[l,2-c]m¡dazol-l-yl)-2-[6-[4-[[4-[2-[4 -[4-[[(3S)-2,6-dioxo-3p¡perid¡l]amino]-2-fluoro-phenyl]-l-piper¡d¡l]-2-oxo-ethyl ]p¡peraz¡n-l-yl]met¡l]phenyl]-4-fluoro-l-oxo¡so¡ndolin-2-yl]-N-thiazol-2-¡l-acetamide; 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-yl)-2-[6-[4-[[l-[2-[4-[ 4-[[(3S)-2,6-dioxo-3p¡per¡d¡l]amino]-2-fluoro-phen¡l]-l-p¡pend¡l]acet¡l]-4 -p¡perídil]met¡l]phen¡l]-4-fluoro-l-oxo-¡soindol¡n-2ill-N-thiazol-2-yl-acetamide 2-[4,7-dichloro-6-[4-[4-[2-[4-[4-[(2,6-dioxo-3-p¡perídil)amino] phen¡l]-l-p¡per¡dyl]acetyl]p¡peraz¡n-l¡l]phen¡l]¡ndazol-2-¡l]-2-(6,7-d¡hydro-5H-p ¡rrolo[l,2-c]¡m¡dazol-l-¡l)-N-thiazol-2-¡l-acetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-yl)-2-(6-(6-(4-(4-(4- ((2-(2,6-d¡oxop¡per¡din-3-yl)-loxoisoindol¡n-4-¡l)oxy)piperidin-l-¡l)-4-oxobutyl)piperazin-l -¡l)pindin-3-yl)-7-fluoro-2H-¡ndazol-2-yl)N-(thiazol-2-yl)acetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(6-(4-(2- (4-(4-((2,6-dioxop¡per¡din-3yl)amino)phen¡l)p¡peridin-l-¡l)acet¡l)p¡peraz¡n-l -¡l)pyr¡din-3-¡l)-7-fluoro-2H-¡ndazol-2-¡l)-N-(thiazol-2yl)acetarnide EITHER 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]m¡dazol-l-yl)-2-[6-[6-[4-[2-[ 4-[4-[(2,6-dioxo-3-p¡pend¡l)amino]-2fluoro-phenyl]-l-p¡peridyl]acet¡l]piperaz¡n-l-¡l]-3-p ¡r¡d¡l]-4-fluoro-¡ndazol-2-¡l]-N-thiazol-2-¡l-acetam¡de 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imídazol-l-íl)-2-[6-[6-[4-[2-[4-[4-[ (2,6-dioxo-3p¡per¡d¡l)am¡no]phenyl]-l-p¡per¡d¡l]acet¡l]p¡peraz¡n-l-¡l]-3-p¡ r¡d¡l]-4-fluoro-indazol-2-¡l]-N-thiazol-2-¡lacetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-¡l)-2-[6-[6-[4-[2-[4 -[5-[(2,6-dioxo-3-p¡perid¡l)amino]-2p¡r¡d¡l]-l-p¡per¡d¡l]acet¡l]p¡peraz¡n-l- ¡l]-3-pyr¡d¡l]-4-fluoro-¡ndazol-2-¡l]-N-thiazol-2-¡l-acetam¡de ΜΛ / a / ZUZZ / UU 100» 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-yl)-2-[6-[6-[4-[2-[4-[3 -(2,4-dioxohexah¡drop¡r¡midin-lil)-l-methyl¡l-¡ndazol-6-yl]-l-p¡per¡d¡l]acet¡l]p¡perazin-l-¡ l]-3-pyr¡d¡l]-4-fluoro-¡ndazol-2-¡l]-N-thiazol-2-¡lacetamide EITHER 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(6-(4-(2- (4-(4-(((S)-2,6-dioxop¡per¡d¡n-3¡l)amino)-2-fluorophen¡l)p¡períd¡n-l-¡l) acet¡l)piperazin-l-¡l)pyridín-3-yl)-4-fluoro-2H-¡ndazol·2-yl)-N__________________________________________(t¡azol-2-yl)acetam¡ da_______________________________________ or a pharmaceutically acceptable salt thereof. E98: In certain embodiments a compound selected from: yl)amino)-2-fluorophenyl)piper¡din-l-¡l)acet¡l)-2,6-diazaspiro[3.3]heptan-2-yl)pyridín-3-¡l)-7 -fluoro-2H¡ndazol-2-¡l)-N-(thiazol-2-¡l)acetam¡de 2-(6,7-dihydro-5H-pyrrolo[l,2-c]midazol-l-yl)-2-(6-(6-(6-(2-(4-(3 -(2,4-dioxotetrah¡drop¡rimidinl(2H)-yl)-l-methyl¡l-lH-indazol-6-yl)-3,3-difluoropiperidinl-l-¡l)acet¡l) -2,6-diazaspiro[3.3]heptan-2¡l)pyr¡din-3-¡l)-7-fluoro-2H-¡ndazol-2-¡l)-N-(thiazole -2-¡l)acetam¡da 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-yl)-2-(6-(6-(6-(2-(l- (4-((2,6-dioxop¡perídin-3-¡l)amino)3-fluorophenyl)-4-hydroxypiperidín-4-yl)acetyl)-2,6-diazaspiro[ 3.3]heptan-2-yl)pyridin-3-yl)-7-fluoro-2Hndazol-2-l)-N-(thiazol-2-l)acetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-yl)-2-(6-(6-(4-(2-(4- (3-(2,4-dioxotetrah¡drop¡rimidinl(2H)-yl)-l-methyl-lH-¡ndazol-6-yl)-3,3-difluorop¡per¡din-l-yl)acetyl) piperazin-l-íl)pyridin-3-yl)-4-fluoro2H-indazol-2-yl)-N-(thiazol-2-í)acetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-yl)-2-(6-(6-(6-(2-(4- (3-(2,4-dioxotetrahídropírimidinl(2H)-yl)-l-methyl-lH-indazol-6-yl)-3,3-difluoropiperídin-l-yl)-2-oxoethyl) -2,6-diazaspiro[3.3]heptan-2¡l)pyr¡din-3-¡l)-7-fluoro-2H-¡ndazol-2-¡l)-N-(thiazole -2-¡l)acetam¡da 2-(6,7-dihydro-5H-pyrrolo[l,2-c]ímidazol-l-yl)-2-(6-(6-(6-(2-(l-(4-( (2,6-dioxop¡perid¡n-3-¡l)amino)2-fluorophen¡l)-4-hydroxypiperid¡n-4-¡l)acet¡l)-2,6 -diazaspiro[3.3]heptan-2-yl)pyridin-3-l)-7-fluoro-2Hndazol-2-l)-N-(thiazol-2- ¡l)acetam¡da 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(6-(6-(2-(l-(4- (((S)-2,6-dioxop¡per¡din-3¡l)amino)-2-fluorophenyl)-4-hydroxy¡p¡pend¡n-4-yl)acet¡l)-2 ,6-d¡azaspiro[3.3]heptan-2-¡l)pyrídin-3-¡l)-4fluoro-2H-¡ndazol-2-¡l)-N-(thiazol- 2-¡l)acetam¡da EITHER 2-(6,7-dihydro-5H-pyrrolo[l,2-c]ímidazol-l-íl)-2-(6-(4-(6-(2-((R) -4-(3-(2,4-dioxotetrah¡drop¡r¡m¡d¡nl(2H)-¡l)-l-methyl-lH-indazol-6-¡l)-3,3- difluoropiper¡din-l-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2yl)phenyl)-4-fluoro-2H-indazol-2-íl)-N-(thiazol-2-yl acetamide EITHER 2-(6,7-dihydro-5H-pyrrolo[l,2-c]m¡dazol-l-¡l)-2-(6-(4-(6-(2-(l -(4-(((S)-2,6-d¡oxop¡per¡din-3yl)amino)-2-fluorophenyl)-4-hydroxyp¡per¡din-4-yl)acet¡ l)-2,6-d¡azaspiro[3.3]heptan-2-¡l)phen¡l)-4-fluoro2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide EITHER 2-(6,7-dihydro-5H-pyrrolo[l,2-c]ímidazol-l-yl)-2-(6-(4-(6-(2-(l-(4-( ((S)-2,6-dioxopíperidin-3¡l)amino)-2-fluorophen¡l)-4-hydroxypiperidín-4-yl)acet¡l)-2,6- diazaspiro[3.3]heptan-2-yl)phenyl)-7-fluoro2H-índazol-2-íl)-N-(thiazol-2-yl)acetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-yl)-2-(6-(4-(7-(2-(l- (4-(((S)-2,6-dioxop¡períd¡n-3yl)amino)-2-fluorophen¡l)-4-hydroxy¡p¡períd¡n -4-¡l)acet¡l)-2,7-d¡azaspiro[3.5]nonan-2-¡l)phenyl)-4-fluoro2H-indazol-2-yl)-N-(thiazol-2) -yl)acetamide 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-((lR,4R)-5-(2-(4-( 4-(((S)-2,6-dioxop¡perid¡n3-yl)amino)-2-fluorophenyl)piper¡din-l-yl)acetyl)-2,5-diazabicyclo[2.2.1] heptan-2-yl)phenyl)-4-fluoro-loxoiso¡ndolin-2-¡l)-N-(thiazol-2-yl)acetam¡de 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-íl)-2-(6-(4-((l-(2-(4'-(( 2,6-dioxop¡peridin-3-¡l)amino)[l,r-b¡phen¡l]-4-¡l)acetyl)p¡peridín-4-¡l)ox¡)phen¡l) -4-fluoro-l-oxo¡so¡ndolin-2-¡l)-N-(thiazol-2-¡l)acetam¡de EITHER 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-((lR,4R)-5-(2-(4-( 3-(2,4dioxotetrahydropyrim¡din-l(2H)-¡l)-l-methyl-lH-indazol-6-¡l)piperidin-l-yl)acet¡l)-2,5diazabicyclo[2.2. 1]heptan-2-yl)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetannide EITHER 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-yl)-2-(6-(4-(4-(2-(l- (4-((2,6-dioxop¡perídin-3-¡l)amino)2-fluorophen¡l)-4-hydroxy¡piper¡din-4-yl )acet¡l)p¡peraz¡n-l-¡l)phen¡l)-4-fluoro-l-oxo¡so¡ndolin-2-yl)-N(thiazol-2-¡l)acetam gives 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]m¡dazol-l-yl)-2-(6-(4-(4-(2-(4- (4-(((S)-2,6-d¡oxopipendin-3yl)amino)-2-fluorophenyl)piperidin-l-¡l)acet¡l)-l,4-diazepan-l-¡l)phen ¡l)-4-fluoro-l-oxo¡so¡ndolin-2-yl)-N(thiazol-2-¡l)acetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-yl)-2-(6-(4-(l-(2-(4- (3-(2,4-dioxotetrah¡dropírim¡dinl(2H)-¡l)-l-methyl-lH-¡ndazol-6-¡l)p¡peridin-l-¡l)-2 -oxoethyl)p¡peridín-4-¡l)phen¡l)-4-fluoro-loxoiso¡ndolin-2-yl)-N-(thiazol-2-¡l)acetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]ímidazol-l-¡l)-2-(6-(4-(4-(2-(4-( 4-((2,6-dioxopiper¡din-3-¡l)amino)2-fluorophen¡l)p¡perídin-l-yl)-2-oxoethyl)p¡peridin-l- ¡l)phen¡l)-4-fluoro-l-oxoiso¡ndolin-2-yl)-N-(thiazol-2yl)acetamide 2-(6,7-dihydro-5H-pyrrolo[l,2-c]ímídazol-l-yl)-2-(6-(6-(6-(2-(4-(3 -(2,4-dioxotetrah¡drop¡rimidinl(2H)-yl)-l-methyl-lH-indazol-6-¡l)-3,3-difluoropiper¡dinl-l-yl)acetyl)-2,6 -diazaspiro[3.3]heptan-2¡l)p¡r¡d¡n-3-¡l)-4-fluoro-l-oxoiso¡ndol¡n-2-¡l)-N-(t¡ azole-2-yl)acetamide 5-((2-( 1-(6,7-d¡hydro-5H-pyrrolo[l,2-c]ímidazol-l-¡l)-2-oxo-2-(t¡ azol-2-¡lam¡no)et¡l)-7-fluoro-3oxoisoindolín-5-¡l)ethynyl)-N-(l-(2-(4-(3-(2,4-dioxotetrahydrop) ¡r¡m¡d¡n-l(2H)-¡l)-l-methyl¡l-lH-¡ndazol-611)-3,3-difluorop¡períd¡n-l-¡l)acet¡l )p¡per¡d¡n-4-¡l)p¡col¡nam¡da EITHER 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-yl)-2-(6-(4-(6-(2-(l- (4-((2,6-dioxop¡perídin-3-¡l)amino)2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6-d¡azaspiro[ 3.3]heptan-2-yl)phenyl)-4-fluoro-loxo¡soindolin-2-¡l)-N-(thiazol-2-yl)acetam¡de EITHER 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-yl)-2-(6-(4-(6-(2-(l- (5-((2,6-dioxop¡períd¡n-3-¡l)amino)3-fluorop¡rid¡n-2-¡l)-4-hydroxy¡p¡ perídin-4-íl)acetyl)-2,6-diazaspíro[3.3]heptan-2-yl)pheníl)-4-fluoro-195 oxo¡solíndolín-2- l)-N-(thiazol-2-yl)acetamide EITHER 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]m¡dazol-l-yl)-2-(6-(4-(4-(2-(4- (3-(2,4-dioxotetrah¡dropírimidinl(2H)-yl)-l-methyl-lH-indazol-6-yl)-3,3-difluoropiper¡din-l-¡l)acet¡ l)-l,4-diazepan-l-¡l)phen¡l)-4-fluorol-oxo¡so¡ndolin-2-¡l)-N-(thiazol-2-¡l)acetam¡de 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]m¡dazol-l-yl)-2-(6-(4-(4-(2-(4- (3-(2,4-dioxotetrah¡dropírimidinl(2H)-¡l)-l-methyl-lH-indazol-6-yl)p¡peraz¡n-l-yl)acetyl)piperaz¡n-l -¡l)phenyl)-4-fluoro-l-oxo¡soindolin-2yl)-N-(thiazol-2-yl)acetamide EITHER 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-¡l)-2-(6-(4-(6-(2-((R )-4-(3-(2,4-dioxotetrahydropyrim¡din96 l(2H)-¡l)-l-methyl-lH-indazol-6-yl)-3,3-d ¡fluoropiperidin-l-¡l)acet¡l)-2,6-diazaspiro[3.3]heptan-2¡l)phen¡l)-4-fluoro-l-oxo¡so¡ndolin-2- l)-N-(thiazol-2-l)acetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(4-(6-(2-(( S)-4-(3-(2,4-dioxotetrahydropyrimidinl(2H)-yl)-l-methyl-lH-indazol-6-yl)-3,3-difluoropiperidin-l- ¡l)acet¡l)-2,6-diazaspiro[3.3]heptan-2¡l)phen¡l)-4-fluoro-l-oxo¡so¡ndol¡n-2-¡l)-N-( thiazol-2-l)acetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-yl)-2-(6-(6-(6-(2-(4- (4-(((S)-2,6-d¡oxop¡peridin-3yl)amino)-2-fluorophenyl)piperidin-l-¡l)acetyl)-2,6-diazaspiro[3.3]heptan-2- il)pyridin-3-íl)-4-fluoro-loxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide EITHER 5-((2-( l-(6,7-d¡hydro-5H-pyrrolo[l,2-c]ímidazol-l-¡l)-2-oxo-2-(t¡ azole-2-¡lamino)et¡l)-7-fluoro-3oxoiso¡ndol¡n-5-¡l)ethín¡l)-N-(1-(2-(1-(4-(( 2,6-dioxop¡perid¡n-3-¡l)amino)-2-fluorophen¡l)-497 hydroxy¡p¡perídin-4-¡l)acet¡l )p¡per¡d¡n-4-¡l)p¡col¡nam¡da ΜΛ / a / ZUZZ / UU / 00» EITHER 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(6-(2-(l-(4- (((S)-2,6-dioxop¡peridin-3yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acet¡l)-2,6-diazaspiro[3.3]heptan-2 -yl)phenyl)-4-fluorol-oxo¡so¡ndolin-2-yl)-N-(thiazol-2-¡l)acetann¡da EITHER 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(4-(6-(2- (l-(4-(((R)-2,6-dioxop¡per¡din-3yl)amino)-2-fluorophenyl)-4-hydroxyp¡per¡din-4-yl)acet¡ l)-2,6-d¡azaspiro[3.3]heptan-2-¡l)phen¡l)-4-fluorol-oxoiso¡ndolin-2-yl)-N-(thiazol-2-¡ l)acetamide EITHER 2-(6,7-dihydro-5H-pyrrolo[l,2-c]ímidazol-l-yl)-2-(6-(4-(6-(2-(l-(4 -((2,6-dioxopiperidin-3-yl)amino)2-fluorophen¡l)-4-hydroxypyridin-4-¡l)acet¡l)-2,6-d¡ azaspiro[3.3]heptan-2-¡l)phenyl)-4-fluoro-loxo¡soindolín-2-yl)-N-(pyrdín-2-yl)acetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]m¡dazol-l-yl)-2-(6-(4-(6-(2-( 4-(4-(((S)-2,6-dioxop¡per¡din-3¡l)amino)-2-fluorophenyl)p¡perídin-l-¡l)-2- oxoethyl)-2-azasp¡ro[3.3]heptan-2-¡l)phen¡l)-4-fluoro-loxoiso¡ndolin-2-yl)-N-(thiazol-2-¡l) acetamide 2-(6,7-dihydro-5H-pyrrolo[l,2-c]ímídazol-l-yl)-2-(6-(4-(6-(2-(l-(4 -((2,6-dioxopiperidin-3-yl)amino)2,6-difluorophenyl)peridin-4-yl)acetyl)-2,6-diazaspiro[3.3] heptan-2-yl)phenyl)-4-fluoro-l-oxo¡soindolin2-¡l)-N-(thiazol-2-¡l)acetam¡de 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(6-(2-(4-( 3-(2,4-dioxotetrah¡drop¡rimidinl(2H)-¡l)-l-methyl¡l-lH-indazol-6-¡l)-3,3-d¡fluoropiper¡din-l-¡l )-2-oxoethyl)-2-azaspiro[3.3]heptan-2¡l)phen¡l)-4-fluoro-l-oxo¡so¡ndol¡n-2-¡l)-N-(t azol-2-l)acetamide EITHER 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]m¡dazol-l-yl)-2-(6-(4-(6-(2-( l-(4-((2,6-dioxop¡pend¡n-3-¡l)amino)2,6-difluorophenyl)-4-hydroxy¡p¡peridin-4-¡l)acetyl)-2 ,6-d¡azaspiro[3.3]heptan-2-¡l)phen¡l)-4-fluoro-loxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide EITHER 2-(6-(4-(6-(2-(l-(2-(difluoromethyl))-4-((2,6-dioxopiperidin-3-yl)amino)phenyl)-4-hydroxypiperidin -4¡l)acet¡l)-2,6-d¡azasp¡ro[3.3]heptan-2-¡l)phen¡l)-4-fluoro-l-oxo¡so¡ndolin-2- il)-2-(6,7-di¡hydro-5Hpyrrolo[l,2-c]¡m¡dazol-l-¡l)-N-(thiazol-2-¡l)acetam¡de 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(l-(l-(2-(4-(3-(2,4 -dioxotetrahydropinmidinl(2H)-yl)-l-methyl¡l-lH-¡ndazol-6-yl)-3,3-d¡fluoropiper¡n-l-¡l)acet¡l)piper¡d¡ n-4-yl)-lH-pyrazol-4-íl)-4fluoro-l-oxoisoíndolin-2-íl)-N-(thiazol-2-yl)acetamide 100 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(2-(2-(4-(3-(2 ,4-dioxotetrahydropyrimidínl(2H)-íl)-l-methyl-lH-indazol-6-yl)-3,3-difluoropiperídin-l-yl)acetyl)-2,7- diazaspiro[3.5]nonan-7yl)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-yl)-2-(6-(4-(2-(2-(l- (4-((2,6-dioxop¡per¡din-3-¡l)amino)2-fluorophen¡l)-4-hydroxy¡piper¡din-4-¡l) acetyl)-2,7-diazaspiro[3.5]nonan-7-¡l)phen¡l)-4-fluoro-loxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide N-(l-(2-(l-(4-(((R)-2,6-dioxopíperidín-3-yl)amino)-2-fluorophenyl)-4-h¡ droxypiper¡din-4¡l)acet¡l)p¡perídin-4-yl)-5-((7-fluoro-2-(l-((R)-6-fluoro-6,7) -d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-¡l)-2oxo-2-(thiazol-2-¡lamino)ethyl)-3-oxo¡so ndolin-5-yl)ethynyl)picolinamide 101 either 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(6-(2-(l-(3- (2,4-dioxotetrahydropyrimidínl(2H)-íl)-l-methyl-lH-indazol-6-yl)-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 EITHER 2-(6,7-dihídro-5H-pyrrolo[l,2-c]ímídazol-l-íl)-2-(6-(6-(6-(2-(l -(4-(((S)-2,6-dioxop¡perídin-3¡l)amino)-2-fluorophenyl)-4-hydroxy¡p¡pend¡n-4- il)acet¡l)-2,6-d¡azaspíro[3.3]heptan-2-¡l)pyrídin-3-¡l)-4fluoro-l-oxo¡so¡ndolin- 2-l)-N-(thiazol-2-l)acetamide EITHER 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(6-(6-(2-(l-(4-(( (R)-2,6-dioxopiperidin-3¡l)amino)-2-fluorophen¡l)-4-hydroxypiperidín-4-¡l)acet¡l)-2,6-diazasp¡ ro[3.3]heptan-2-yl)pyrdin-3-yl)-4fluoro-l-oxo¡sondolin-2-l)-N-(thiazol-2-l) acetamide 102 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazole-l-¡l)-2-(6-(4-(6-(2-(4-(5-((2 ,6-dioxopíperidin-3-yl)amino)3-fluorop¡r¡d¡n-2-yl)p¡peridín-l-yl)acet¡l)-2,6-d¡ azaspiro[3.3]heptan-2-¡l)phenyl)-4-fluoro-loxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]m¡dazol-l-yl)-2-(6-(4-(6-(2-( 4-(3-(2,4-dioxotetrah¡drop¡rimid¡nl(2H)-¡l)-l-methyl¡l-lH-¡ndazol-6-¡l)-3,3-d¡ fluorop¡per¡n-l-¡l)acet¡l)-2,6-d¡azaspiro[3.4]octan-2yl)phenyl)-4-fluoro-l-oxo¡soindol¡n-2-¡ l)-N-(thiazol-2-yl)acetamide EITHER 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]m¡dazol-l-yl)-2-(6-(4-(7-(2-( 4-(3-(2,4-dioxotetrah¡drop¡rimidinl(2H)-¡l)-l-methyl¡l-lH-¡ndazol-6-¡l)-3,3-d¡fluoropiper¡d¡ n-l-¡l)acet¡l)-2,7-d¡azaspiro[3.5]nonan-2yl)phen¡l)-4-fluoro-l-oxoiso¡ndol¡n-2-¡l)-N -(thiazol-2-l)acetamide 103 2-(6,7-dihydro-5H-pyrrolo[l,2-c]midazol-l-yl)-2-(6-(4-(7-(2-(l-(4 -((2,6-dioxop¡pend¡n-3-¡l)amino)2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,7-d¡azaspiro[3.5]nonan-2- ¡l)phen¡l)-4-fluoro-loxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-l)-2-(6-(4-(6-(2-(l-(4 -((2,6-dioxopiper¡din-3-¡l)amino)2-fluorophen¡l)-4-hydroxypiper¡din-4-¡l)acetyl)-2,6-diazaspiro [3.4]octan-2-yl)phen¡l)-4-fluoro-loxo¡so¡ndolin-2-¡l)-N-(thiazol-2-¡l)acetam¡de 2-(6-(4-(6-(2-(4-(3-(2,4-dioxotetrahydropyrimidín-l(2H)-íl)-l-methyl-lH-índazol-6 -¡l)-3,3d¡fluoropiper¡din-l-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)- 2((R)-6-fluoro-6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-¡l)-N-(thiazol- 2-yl)acetamide 104 2-(6-(4-(6-(2-(l-(2-chloro-4-((2,6-dioxopiperídin-3-¡l)amino)phenyl)-4-h¡ drOxy¡piperidin-4-yl)acet¡l)-2,6diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-l-oxo¡so¡ndolin-2-¡l)-2-(6 ,7-dihydro-5H-pyrrolo[l,2c]imidazol-l-yl)-N-(thiazol-2-yl)acetamide 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(6-(6-(2-(4-(3-(2,4 -dioxotetrahydropyrim¡dinl(2H)-¡l)-l-methyl¡l-lH-indazol-6-yl)-3,3-difluoropiper¡n-l-¡l)-2-oxoethyl)-2, 6-d¡azasp¡ro[3.3]heptan-2¡l)p¡r¡d¡n-3-¡l)-4-fluoro-l-oxo¡ndol¡n-2-¡l)- N-(thiazol-2-yl)acetamide EITHER 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡nn¡dazol-l-yl)-2-(6-(4-(6-(2-(l- (4-(((S)-2,6-d¡oxop¡perídin-3yl)amino)-2,6-difluorophenyl)-4-hydroxyp¡peridin-4-yl)acet¡l )-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-4fluoro-l-oxo¡so¡ndolin-2-¡l)-N-(thiazol-2-¡l)acetam gives 105 EITHER 2-(6-(4-(6-(2-(l-(2-chloro-4-(((R)-2,6-dioxopíperidin-3-yl)amino)pheníl) -4-hydroxyp¡pendin-4-¡l)acetyl)2,6-diazaspiro[3.3]heptan-2-¡l)phenyl)-4-fluoro-l-oxoiso¡ndolin-2- ¡l)-2-(6,7-di¡hydro-5H-pyrrolo[l,2c]imidazol-l-yl)-N-(thiazol-2-yl)acetamide EITHER 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(7-(2-(l-(4-(( (S)-2,6-dioxop¡peridin-3¡l)amino)-2-fluorophen¡l)-4-hydroxy¡p¡pendin-4-¡l)acet¡l)-2,7- d¡azaspiro[3.5]nonan-2-¡l)phen¡l)-4-fluorol-oxo¡so¡ndolin-2-¡l)-N-(thiazol-2-¡l)acetam¡ gives 2-(6,7-dihydro-5H-pyrrolo[l,2-c]m¡dazol-l-¡l)-2-(6-(4-(7-(2-(( R)-4-(3-(2,4-dioxotetrahydropyrimidinl(2H)-íl)-l-methyl-lH-índazol-6-íl)-3,3-difluorop per¡din-l-¡l)acet¡l)-2,7-d¡azasp¡ro[3.5]nonan-2yl)phen¡l)-4-fluoro-l-oxoisoindol¡n-2-¡l )-N-(thiazol-2-yl)acetamide 106 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(6-(2-(4-(3- (2,4-dioxotetrahydropyrimidínl(2H)-yl)-5-fluoro- l-methyl-lH-índazol-6-yl)piperazin-l-íl)acetyl)-2,6- diazaspiro[3.3]heptan-2-yl)phenyl)4-fluoro-l-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazole-l-íl)-2-(6-(4-(6-(2-((3R,4S))- 4-(3-(2,4dioxotetrahydropyrimid¡n-l(2H)-¡l)-l-methyl-lH-¡ndazol-6-¡l)-3-fluorop¡peridín-l-¡l)acet ¡l)-2,6d¡azasp¡ro[3.3]heptan-2-¡l)phen¡l)-4-fluoro-l-oxo¡so¡ndol¡n-2-¡l)-N-(t azol-2-yl)acetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(4-(6-(2- ((3S,4R)-4-(3-(2,4dioxotetrah¡drop¡r¡m¡d¡n-l(2H)-¡l)-l-met¡l-lH-¡ndazol-6-¡ l)-3-fluorop¡perídin-l-¡l)acet¡l)-2,6 107 d¡azaspiro[3.3]heptan-2-¡l)phen¡l)-4-fluoro-l-oxo¡soindol¡n-2-¡l)-N-(thiazol-2-¡l )acetannída 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(4-(2-(2- (l-(4-(((S)-2,6-dioxop¡perídin-3¡l)amino)-2-fluorophenyl)-4-hydroxy¡p¡períd¡ n-4-yl)acet¡l)-2,7-d¡azaspiro[3.5]nonan-7-¡l)phenyl)-4-fluorol-oxoisoindolin-2-yl)-N-(thiazol-2 -yl)acetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-yl)-2-(6-(4-(6-(2-(l- (3-(2,4-dioxotetrah¡drop¡rim¡nl(2H)-¡l)-5-fluoro-l-met¡l-lH-¡ndazol-6-¡l)-4- hydroxy¡p¡peridin-4-¡l)acetyl)-2,6-diazaspiro[3.3]heptan2-yl)phen¡l)-4-fluoro-l-oxo¡soindol¡n-2-yl)- N-(thiazol-2-yl)acetamide 2-(6-(4-(2-(2-( l-(2-chloro-4-(((S)-2,6-dioxopiperidin-3-¡l)amino)phenyl)-4- hydroxy¡piper¡din-4-yl)acetyl)2,7-diazaspiro[3.5]nonan-7-¡l)phen¡l)-4-fluoro-l-oxo¡soindol¡n-2- ¡l)-2-(6,7-dihydro-5H-pyrrolo[l,2c]¡m¡dazol-l-¡l)-N-(thiazol-2-¡l)acetam¡ gives 108 ΜΛ / a / ZUZZ / UU / 00» 2-(6,7-dihydro-5H-pyrrolo[l,2-c]midazol-l-yl)-2-(6-(4-(6-(2-((S)-4-(3 -(2,4-dioxotetrahydropyrimidinl(2H)-yl)-5-fluoro-l-methyl-lH-indazol-6-yl)-3,3-difluoropipehdin-l-íl)acetyl)-2,6diazasp ¡ro[3.3]heptan-2-yl)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(4-(6-(2- ((R)-4-(3-(2,4-dioxotetrahydropyrim¡dinl(2H)-¡l)-5-fluoro-l-methyl-lH-¡ndazol-6-¡ l)-3,3-difluorop¡perid¡n-l-¡l)acet¡l)-2,6d¡azaspiro[3.3]heptan-2-¡l)phen¡l)-4-fluoro-l -oxo¡so¡ndol¡n-2-¡l)-N-(thiazol-2-yl)acetam¡de EITHER 2-(6-(4-(6-(2-( 1-(4-(((5)-2,6-dioxopipendín-3-¡l)amino)-2-fluorophenyl) -4-hydroxy¡piperidín-4-yl)acet¡l)2,6-d¡azaspiro[3.3]heptan-2-¡l)phen¡l)-4-fluoro-l-oxo ¡soindol¡n-2-¡l)-2-((R)-6-fluoro-6,7-d¡hydro-5Hp¡rrolo[l,2-c]¡m¡dazol-l-¡l) -N-(thiazol-2-¡l)acetamide 109 EITHER 2-(6-(4-(6-(2-( l-(4-(((R))-2,6-dioxop¡pendin-3-yl)amino)-2-fluorophen¡l)- 4-hydroxy¡p¡pend¡n-4-¡l)acetyl)2,6-d¡azaspiro[3.3]heptan-2-¡l)phen¡l)-4-fluoro-l-oxo¡so¡ndolin -2-yl)-2-((R)-6-fluoro-6,7-dihydro-5Hpyrrolo[l,2-c]imidazole-l-íl)-N-(thiazol- 2-yl)acetamide EITHER 2-(6,7-dihydro-5H-pyrrolo[l,2-c]m¡dazol-l-¡l)-2-(6-(4-(6-(2-(4 -(3-(2,4-dioxotetrah¡drop¡r¡midinl(2H)-¡l)-l-methyl¡l-lH-¡ndazol-6-¡l)-3-fluorop¡peridin-l-¡ l)acet¡l)-2,6-d¡azas¡ro[3.3]heptan-2-¡l)phenyl)4-fluoro-l-oxo¡so¡ndolin-2-¡l)-N-(t azol-2-yl)acetamide EITHER 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(2-(2-(l-(4-(( (S)-2,6-dioxopiperidin-3yl)amino)-2,6-difluorophen¡l)-4-hydroxy¡p¡peridín-4-yl)acet¡l)-2,7 -d¡azaspiro[3.5]nonan-7-¡l)phenyl)-4fluoro-l-oxoiso¡ndolin-2-¡l)-N-(thiazol-2-yl)acetamide 110 h 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(4-(6-(2- (l-(4-((2,6-dioxop¡per¡n-3-¡l)arn¡no)2,5-difluorophen¡l)-4-hydroxy¡p¡per¡ d¡n-4-¡l)acetyl)-2,6-d¡azaspiro[3.3]heptan-2-yl)phen¡l)-4-fluoro-loxo¡soindolin-2-yl)-N- (thiazol-2-yl)acetamide EITHER 2-(4-chloro-6-(4-(6-(2-(l-(4-(((S))-2,6-dioxopiper¡din-3-¡l)amino )-2-fluorophen¡l)-4-hydroxy¡p¡perídin-4yl)acet¡l)-2,6-diazaspiro[3.3]heptan-2-¡l)phenyl)-l-oxo¡ so¡ndol¡n-2-¡l)-2-(6,7-dihydro-5H-pyrrolo[l,2c]imidazole-l-¡l)-N-(thiazol- 2-yl)acetamide EITHER 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(7-(2-(l-(4-(( (S)-2,6-dioxop¡peridin-3¡l)amino)-2,6-d¡fluorophen¡l)-4-hydroxy¡p¡peridin-4-¡l)acetyl)-2, 7-diazaspiro[3.5]nonan-2-¡l)phenyl)-4fluoro-l-oxo¡so¡ndolin-2-¡l)-N-(thiazol-2-¡l)acetam¡ gives 111 2-(6-(4-(7-(2-( l-(2-chloro-4-(((S)-2 / 6-dioxopipendín-3-¡l)amino)phenyl )-4-hydroxy¡p¡perídin-4-yl)acet¡l)2,7-d¡azaspiro[3.5]nonan-2-yl)phen¡l)-4-fluoro-l -oxo¡so¡ndoline-2-¡l)-2-(6,7-d¡hydro-5H-pyrrolo[l,2c]imidazol-l-¡l)-N-(thiazole -2-yl)acetamide EITHER 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(6-(2-(l-(5-(( (S)-2,6-dioxop¡peridin-3¡l)amino)-3-fluorop¡rid¡n-2-¡l)-4-hydroxy¡p¡peridín-4-¡l) acet¡l)-2,6-d¡azas¡ro[3.3]heptan-2-¡l)phen¡l)-4fluoro-l-oxo¡so¡ndol¡n-2-¡l)-N-( thiazol-2-l)acetamide EITHER 2-(6,7-dihydro-5H-pyrrolo[l,2-c]m¡dazol-l-¡l)-2-(6-(4-(7-(2-(( R)-4-(3-(2,4-dioxotetrahydropyrimidinl(2H)-íl)-l-methyl-lH-indazol-6-íl)-3,3-difluoropiperidin-l- ¡l)-2-oxoethyl)-2,7-d¡azaspiro[3.5]nonan-2yl)phenyl)-4-fluoro-l-oxoisoindolin-2-¡l)-N-(thiazol-2-¡ l)acetamide 112 2-(6,7-dihydro-5H-pyrrolo[l,2<]imidazol-l-yl)-2-(6-(4-(7-(2-((S)-4-(3 -(2,4-d¡oxotetrahydro¡rimidinl(2H)-¡l)-l-methyl¡l-lH-indazol-6-¡l)-3,3-d¡fluorop¡períd¡n-l-yl )-2-oxoethyl)-2,7-diazaspiro[3.5]nonan-2yl)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide EITHER 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-yl)-2-(6-(l-(l-(2-(l- (4-(((S)-2,6-dioxop¡peridin-3yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acet¡l)piperidin-4-yl)-lH- pyrazol-4-yl)-4-fluoro-loxoiso¡ndolin-2-¡l)-N-(thiazol-2-¡l)acetamide 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-íl)-2-(6-(4-(2-(2-((R )-4-(3-(2,4-dioxotetrahydropyrimidinl(2H)-íl)-l-methyl-lH-indazol-6-íl)-3,3-difluoropiperídín-l -l)-2-oxoethyl)-2,7-diazaspiro[3.5]nonan-7yl)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide 113 2-(6,7-dihydro-5H-pyrrolo[l,2<]imidazol-l-yl)-2-(6-(4-(2-(2-((S)-4-(3 -(2,4-d¡oxotetrahydro¡rimidinl(2H)-¡l)-l-methyl¡l-lH-indazol-6-¡l)-3,3-d¡fluorop¡períd¡n-l-yl )-2-oxoethyl)-2,7-diazaspiro[3.5]nonan-7yl)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide EITHER 2-(6-(4-(6-(2-(l-(2-chloro-4-(((S)-2,6-dioxopiper¡din-3-yl)amino))-6 -fluorophen¡l)-4-hydroxy¡p¡perídin-4¡l)acet¡l)-2,6-d¡azaspiro[3.3]heptan-2-¡l)phen¡l)-4 -fluoro-l-oxo¡ndolin-2-¡l)-2-(6,7-dihydro-5Hpyrrolo[l,2-c]m¡dazol-l-¡ l)-N-(thiazol-2-¡l)acetam¡de 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imídazol-l-íl)-2-(6-(4-(6-(l-(4-(((S )-2,6-dioxopiper¡din-3-¡l)amino)2-fluorophenyl)-4-hydroxypiperidin-4-carbonyl)-2,6-d¡azaspiro[3.3]heptan-2-¡l) phenyl)-4-fluoro-loxo¡soindolín-2-¡l)-N-(thiazol-2-yl)acetamide 114 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-yl)-2-[6-[4-[2-[2-[l- [4-(2,4-dioxohexah¡drop¡r¡midín-lil)-2-fluoro-phen¡l]-4-hydroxy-4-p¡pend¡l]acetyl]-2,6-diazasp ¡ro[3.3]heptan-6-yl]phen¡l]-4-fluoro-indazol2-¡l]-N-thiazol-2-yl-acetam¡de 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]imidazole-l-¡l)-2-[6-[4-[2-[2-[(2s ,6r)-l-[4-[(2,6-dioxo-3piper¡d¡l)amino]-2-fluoro-phen¡l]-4-hydroxy¡-2,6- dimethyl-4-piper¡d¡l]acetyl]-2,6-diazaspiro[3.3]heptan-6yl]phenyl]-4-fluoro-ndazol-2-yl]-N- thiazol-2-l-acetamide 2-(6,7-d¡hydro-5H-pyrrOlo[l,2-c]¡m¡dazol-l-¡l)-2-[6-[4-[4-[2- [4-[4-[[(3S)-2,6-dioxo-3p¡períd¡l]amino]-2-fluoro-phen¡l]-l-p¡períd¡l] -2-oxo-ethyl]-4-hydroxy¡-l-p¡per¡dyl]phen¡l]-7-fluoiO-¡ndazol-2¡ll-N-thiazol-2-yl-acetamide 115 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[6-[4-[2-[4-[4-[[ (3S)-2,6-dioxo-3p¡per¡d¡l]am¡no]-2-fluoro-phen¡l]-l-p¡per¡d¡l]-2-oxo-et¡l]- 4-hydroxy¡-l-p¡per¡d¡l]-3-p¡r¡d¡l]-4-fluoroindazol-2-¡l]-N-thiazol-2-yl-acetam¡de 2-(6,7-d¡hydro-5H-pyrc>lo[l,2-c]¡m¡dazol-l-yl)-2-[6-[6-[4-[2-[ 4-[4-[[(3S)-2,6-dioxo-3piperidyl]amino]-2-fluoro-phenyl]-l-piperidyl]-2-oxo-ethyl]-4-hydroxy-l-p per¡clyl]-3-pyridyl]-7-fluoro¡ndazol-2-¡l]-N-thiazol-2-¡l-acetam¡de 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]ímidazol-l-¡l)-2-[6-[4-[l-[2-[4-[ 4-[(2,6-dioxo-3p¡peridyl)amino]phenyl]-l-p¡peridyl]acetyl]-4-piperidyl]-2-methyl-phenyl]-4-fluoro-l-oxo-¡soindolin -2-¡l]-Nthiazol-2-yl-acetamide 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-yl)-2-[6-[4-[2-[2-[7- [3-(2,4-dioxohexah¡drop¡r¡midin-l¡l)-l-methyl-¡ndazol-6-yl]-4-azasp¡ro[2.5]octan-4-¡l] acetyl]-2,6-d¡azasp¡ro[3.3]heptan-6-yl]phenyl]-4116 fluoro-l-oxo-¡so¡ndol¡n-2-yl]-N-(2-p¡ r¡d¡l)acetam¡da 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-yl)-2-[6-[4-[2-[2-[7- [3-(2,4-d¡oxohexahydro¡r¡midín-l¡l)-l-methyl-indazol-6-yl]-4-azaspiro[2.5]octan-4-¡l]acet¡l ]-2,6-d¡azaspiro[3.3]heptan-6-¡l]phen¡l]-4fluoro-l-oxo-isoindolin-2-í]-N-thiazol-2-yl-acetam¡de 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-¡l)-2-[6-[4-[6-[4-[3 -(2,4-dioxohexah¡drop¡r¡m¡din-l-yl)-lmet¡l-¡ndazol-6-¡l]-3,3-difluoro-p¡perid¡n-l-carbon¡ l]-2-azaspiro[3.3]heptan-2-yl]phen¡l]-4-fluoro-loxo-iso¡ndolin-2-¡l]-N-thiazol-2-yl-acetam¡de 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[2-[2-[l-[ 4-(2,4-dioxohexah¡drop¡r¡midín-lil)-2-fluoro-phen¡l]-4-hydroxy-4-p¡períd¡l]acet¡l]- 2,6-d¡azaspiro[3.3]heptan-6-¡l]phen¡l]-4-fluoro-l-oxo¡so¡ndolin-2-¡l]-N-thiazol-2-¡l-acetamide 2-(6,7-d¡hydro-5l-l-pyrrolo[l,2-c]m¡dazol·l-yl)-2-(6-(4-(6-(2-( l-(4-(2,6-dioxop¡perídin-3-yl)-2fluorophen¡l)-4-hydroxyp¡perídin-4-¡l)acetyl)-2, 6-d¡azaspiro[3.3]heptan-2-¡l)phen¡l)-4-fluoro-loxoiso¡ndolin-2-yl)-N-(thiazol-2-¡l)acetamide 117 CL 2-[6-[4-[2-[2-[l-[2-chloro-4-(2,4-dioxohexahydropyrim¡din-l-¡l)phenyl]-4-hydroxy¡-4-piper¡ d¡l]acetyl]-2,6diazaspiro[3.3]heptan-6-¡l]phenyl]-4-fluoro-l-oxo-¡soindol¡n-2-¡l]-2-(6.7 -dihydro-5H-pyrrolo[l,2c]imidazol-l-yl)-N-thiazol-2-l-acetamide 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[2-[2-[l-[4-(2 ,6-dioxo-3-p¡peridyl)-2-fluorophen¡l]-4-hydroxy¡-4-p¡perid¡l]acet¡l]-2,7-d¡azaspiro[3.5 ]nonan-7-¡l]phenyl]-4-fluoro-l-oxo-¡so¡ndolin-2¡l]-N-thiazol-2-yl-acetam¡de 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-yl)-2-[6-[4-[7-[2-[l- [4-(2,6-dioxo-3-p¡períd¡l)-2-fluoropheniI>4-hydroxy-4-p¡períd¡l]acet¡l]-2,7-d¡ azaspiro[3.5]nonan-2-¡l]phen¡l]-4-fluoro-l-oxo-iso¡ndolin-2yl]-N-thiazol-2-yl-acetamide 2-(6,7-d¡hydro-5H-p¡nOlo[l,2-c]im¡dazol-l-¡l)-2-[6-[4-[2-[2-[ (2s,6r)-l-[4-[(2,6-dioxo-3piper¡d¡l)amino]-2-fluoro-phen¡l]-4-hydroxy¡-2, 6-dimethyl-4-piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6¡l]pheníl]-4-fluoro-l-oxo-iso¡ndolin-2-¡l ]-N-thiazol-2-l-acetamide 118 IVIA / a / ZUZZ / UU / 00» 2-[6-[4-[2-[2-[4-am¡no-l-[4-[(2,6-dioxo-3-p¡per¡d¡l)am¡no] -2-fluoro-phen¡l]-4-piper¡d¡l]acet¡l]-2,6d¡azaspiro[3.3]heptan-6-¡l]phen¡l]-4-fluoro-l -oxo-¡so¡ndol¡n-2-¡l]-2-(6,7-dihydro-5H-pyrrolo[l,2c]imidazol-l-yl)-N-thiazol-2- l-acetamada 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol·l-yl)-2-[6-[4-[2-[2-[l-[4-(2 ,4-dioxohexahydrop¡r¡m¡din-lil)-2-fluoro-phen¡l]-4-hydroxy-4-p¡perídyl]acetyl]-2,7-d¡azaspiro[ 3.5]nonan-7-¡l]phen¡l]-4-fluoro-l-oxo¡so¡ndolin-2-¡l]-N-thiazol-2-yl-acetam¡de Isomer A1 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-yl)-2-[6-[4-[2-[2-[l- [4-[[2,6-dioxo-3-p¡períd¡l]amino]-2fluoro-phen¡l]-4-hydroxy-azepan-4-¡l]acet¡l]-2 ,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-l-oxo¡so¡ndolin-2-¡l]-N-thiazol-2-yl-acetam¡de, Al isomer Isomer A2 2-(6,7-dihydro-5H-pyrrolo[l,2-c]ímidazol-l-íl)-2-(6-(4-(6-(2-(l-( 4-((2,6-dioxop¡peridin-3-¡l)amino)2-fluorophen¡l)-4-hydroxyazepan-4-¡l)acet¡l)-2,6- d¡azaspiro[3.3]heptan-2-¡l)phen¡l)-4-fluoro-loxoiso¡ndolin-2-¡l)-N-(thiazol-2-yl)acetam¡de , A2 isomer 119 Isomer Β1 IVIA / a / ZUZZ / UU / 00» 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-íl)-2-(6-(4-(6-(2-(l- (4-((2,6-dioxopiper¡din-3-¡l)amino)2-fluorophenyl)-4-hydroxyzepan-4-¡l)acetyl)-2,6-d ¡azaspiro[3.3]heptan-2-yl)phen¡l)-4-fluoro-loxo¡so¡ndolin-2-yl)-N-(thiazol-2-¡l)acetamide, B1 isomer Isomer B2 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-(6-(4-(6-(2-(l-( 4-((2,6-dioxopiper¡din-3-¡l)amino)2-fluorophenyl)-4-hydroxy¡azepan-4-yl)acet¡l)-2,6 -d¡azaspiro[3.3]heptan-2-¡l)phenyl)-4-fluoro-loxo¡so¡ndolin-2-¡l)-N-(thiazol-2-¡l)acetam¡de, isomer B2 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]¡m¡dazol-l-¡l)-2-[6-[4-[2-[2- [l-[4-(2,4-d¡oxohexahydro¡r¡m¡n-lyl)-2-(trifluoromethyl)phen¡l]-4-hydroxy-4-pipend¡l]acetyl] -2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluorol-oxo-isoandolin-2-l]-N-thiazol-2-yl-acetamide 2-[6-[4-[2-[2-[l-[2,6-dichloro-4-(2,4-dioxohexah¡drop¡r¡midin-l-yl)phenyl]-4-hydroxy¡ -4-piperid¡l]acetyl]2,6-d¡azaspiro[3.3]heptan-6-¡l]phenyl]-4-fluoro-l-oxo-¡so¡ndolin-2-yl]-2-( 6,7-d¡hydro-5H-pyrrolo[l,2c]¡m¡dazol-l-¡l)-N-thiazol-2-l-acetamide 120 IVIA / a / ZUZZ / UU / 00» 2-[6-[4-[7-[2-[l-[2-chloro-4-(2,4-dioxohexahydropyrimidín-l-¡l)pheníl]-4-hydroxy-4-p per¡d¡l]acetyl]-2,7d¡azaspiro[3.5]nonan-2-yl]phen¡l]-4-fluoro-l-oxo-iso¡ndol¡n-2-¡l]-2 -(6,7-dihydro-5H-pyrrolo[l,2c]imidazol-l-íl)-N-thiazol-2-íl-acetamide 2-[6-[4-[2-[2-[l-[2-cyano-4-(2,4-dioxohexahydropyrimidin-l-yl)phenyl]-4-hydroxy-4-piperidyl] acetyl]-2,6diazaspiro[3.3]heptan-6-¡l]phen¡l]-4-fluoro-l-oxo-¡so¡ndol¡n-2-¡l]-2-(6.7 -d¡hydro-5H-pyrrolo[l,2c]¡m¡dazol-l-¡l)-N-thiazol-2-¡l-acetam¡de 2-[6-[4-[2-[2-[l-[2-chloro-4-(2,4-d¡oxohexahydro¡r¡m¡d¡n-l-¡l)phen¡l]-4 -hydroxy¡-4-p¡per¡d¡l]acetyl]-2,7d¡azaspíro[3.5]nonan-7-yl]phen¡l]-4-fluoro-l-oxo-¡sonole ¡n-2-¡l]-2-(6,7-d¡hydro-5H-pyrrolo[l,2c]¡m¡dazol-l-¡l)-N-thiazol-2-¡ l-acetamide Isomer 1 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[2-[2-[l-[4- [[2,6-dioxo-3-piper¡d¡l]amino]-2fluoro-5-methoxy¡-phen¡l]-4-hydroxy¡-4-p¡perid¡l] acet¡l]-2,6-diazasspiro[3.3]heptan-6-¡l]phen¡l]-4-fluoro-loxo-¡so¡ndol¡n-2-¡l]-N-thiazol- 2-l-acetamide, isomer 1 or a pharmaceutically acceptable salt thereof. 121 Ε99: In certain embodiments the invention is a compound of any of the embodiments a 98, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, for use as a therapeutically active substance. E100: In certain embodiments the invention is a compound of any of the embodiments a 98, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, for use in the therapeutic and / or prophylactic treatment of cancer. E101: In certain embodiments the invention is a method of treating a patient with an EGFR-mediated disorder, comprising administering a compound of any of embodiments 1 to 98, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition. E102: The modality 101 method, where the patient is a human. E103: The method of embodiment 101 or 102, wherein the EGFR-mediated disorder is a cancer, tumor or abnormal cell proliferation. E104: The method of embodiment 103, wherein the EGFR-mediated disorder is a cancer or tumor. E105: The method of embodiment 103, wherein the EGFR-mediated disorder is abnormal cell proliferation. E106: The method of modality 104, wherein the cancer is lung cancer. E107: The method of embodiment 106, wherein the lung cancer is a non-small cell lung cancer. E108: The method of any of embodiments 103 to 107, wherein the cancer, tumor or abnormal cell proliferation has an EGFR protein with at least one mutation. E109: The method of any of embodiments 103 to 108, wherein the cancer, tumor or abnormal cell proliferation has an EGFR protein with the L858R mutation. E110: The method of any of embodiments 103 to 109, wherein the cancer, tumor or abnormal cell proliferation has an EGFR protein with the T790M mutation. Elll: The method of any of embodiments 103 to 110, wherein the cancer, tumor or abnormal cell proliferation has an EGFR protein with the C797S mutation. E112: The method of any of embodiments 103 to 111, wherein the cancer, tumor or abnormal cell proliferation has an EGFR protein with the L792H mutation. E113: The method of any of embodiments 103 to 112, wherein the cancer, tumor or abnormal cell proliferation has an EGFR protein with the L718Q mutation. E114: The method of any of embodiments 103 to 108, wherein the cancer, tumor or abnormal cell proliferation has an EGFR protein with the T790M / L858R mutation. 122 Ε115: The method of any of embodiments 103 to 108, wherein the cancer, tumor or abnormal cell proliferation has an EGFR protein with the T790M / L858R / C797S mutation. E116: The method of any of embodiments 103 to 108, wherein the cancer, tumor or abnormal cell proliferation has an EGFR protein with the L858R / C797S mutation. E117: The method of any of embodiments 101 to 116, wherein an additional EGFR inhibitor is administered. E118: The method of embodiment 117, wherein the additional EGFR inhibitor is a tyrosine kinase inhibitor. E119: The method of modality 118, wherein the additional EGFR inhibitor is osimertinib. E120: The method of modality 118, wherein the additional EGFR inhibitor is rocaletinib. E121: The method of modality 118, wherein the additional EGFR inhibitor is avitinib. E122: The method of modality 118, wherein the additional EGFR inhibitor is lazertinib. E123: The method of modality 118, wherein the additional EGFR inhibitor is nazartinib. E124: The method of embodiment 117, wherein the additional EGFR inhibitor is an antibody against a mutated form of EGFR. E125: The method of modality 124, wherein the additional EGFR inhibitor is cetuximab. E126: The method of modality 124, wherein the additional EGFR inhibitor is panitumab. E127: The method of modality 124, wherein the additional EGFR inhibitor is necitumab. E128: The method of any of embodiments 101 to 127, wherein a MET inhibitor is also administered. E129: The method of any of modalities 101 to 128, wherein the patient receives an additional chemotherapeutic agent. E130: In certain embodiments the invention is a compound of any of the embodiments a 98, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating an EGFR-mediated disorder in a patient. E131: The use of modality 130, where the patient is a human. E132: The use of modality 130 or 131, wherein the EGFR-mediated disorder is a cancer, tumor or abnormal cell proliferation. E133: Use of modality 132, wherein the EGFR-mediated disorder is a cancer or tumor. E134: The use of modality 132, wherein the EGFR-mediated disorder is abnormal cell proliferation. E135: The use of modality 132, where the cancer is lung cancer. E136: The use of modality 135, wherein the lung cancer is a lung cancer of 123 non-small cells. E137: The use of any of embodiments 132 to 136, wherein the cancer, tumor or abnormal cell proliferation has an EGFR protein with at least one mutation. E138: The use of any of embodiments 132 to 137, wherein the cancer, tumor or abnormal cell proliferation has an EGFR protein with the L858R mutation. E139: The use of any of embodiments 132 to 138, wherein the cancer, tumor or abnormal cell proliferation has an EGFR protein with the T790M mutation. E140: The use of any of embodiments 132 to 139, wherein the cancer, tumor or abnormal cell proliferation has an EGFR protein with the C797S mutation. E141: The use of any of embodiments 132 to 140, wherein the cancer, tumor or abnormal cell proliferation has an EGFR protein with the L792H mutation. E142: The use of any of embodiments 132 to 141, wherein the cancer, tumor or abnormal cell proliferation has an EGFR protein with the L718Q mutation. E143: The use of any of embodiments 132 to 136, wherein the cancer, tumor or abnormal cell proliferation has an EGFR protein with the T790M / L858R mutation. E144: The use of any of embodiments 132 to 136, wherein the cancer, tumor or abnormal cell proliferation has an EGFR protein with the T790M / L858R / C797S mutation. E145: The use of any of embodiments 132 to 136, wherein the cancer, tumor or abnormal cell proliferation has an EGFR protein with the L858R / C797S mutation. E146: The use of any of modalities 130 to 145, wherein an additional EGFR inhibitor is administered. E147: The use of embodiment 146, wherein the additional EGFR inhibitor is a tyrosine kinase inhibitor. E148: The use of modality 147, where the additional EGFR inhibitor is osimertinib. E149: The use of modality 147, where the additional EGFR inhibitor is rocaletinib. E150: The use of modality 147, where the additional EGFR inhibitor is avitinib. E151: The use of modality 147, where the additional EGFR inhibitor is lazertinib. E152: The use of modality 147, where the additional EGFR inhibitor is nazartinib. E153: Use of embodiment 146, wherein the additional EGFR inhibitor is an antibody against a mutated form of EGFR. E154: The use of modality 153, where the additional EGFR inhibitor is cetuximab. E155: The use of modality 153, where the additional EGFR inhibitor is panitumab. E156: The use of modality 153, where the additional EGFR inhibitor is necitumab. E157: The use of any of the modalities 130 to 156, where a IVIA / a / ZUZZ / UU / 00» 124 MET inhibitor. E158: The use of any of modalities 130 to 157, where the patient receives an additional chemotherapeutic agent. E159: In certain embodiments the invention is a compound of any of embodiments a 98, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, for use in the treatment of an EGFR-mediated disorder in a patient. E160: The compound of modality 159, where the patient is a human. E161: The compound of embodiment 159 or 160, wherein the EGFR-mediated disorder is a cancer, tumor or abnormal cell proliferation. E162: The compound of embodiment 161, wherein the EGFR-mediated disorder is a cancer or tumor. E163: The compound of embodiment 161, wherein the EGFR-mediated disorder is abnormal cell proliferation. E164: The compound of embodiment 162, wherein the cancer is lung cancer. E165: The compound of embodiment 164, wherein the lung cancer is a non-small cell lung cancer. E166: The compound of any of embodiments 161 to 165, wherein the cancer, tumor or abnormal cell proliferation has an EGFR protein with at least one mutation. E167: The compound of any of embodiments 161 to 166, wherein the cancer, tumor or abnormal cell proliferation has an EGFR protein with the L858R mutation. E168: The compound of any of embodiments 161 to 167, wherein the cancer, tumor or abnormal cell proliferation has an EGFR protein with the T790M mutation. E169: The compound of any of embodiments 161 to 168, wherein the cancer, tumor or abnormal cell proliferation has an EGFR protein with the C797S mutation. E170: The compound of any of embodiments 161 to 169, wherein the cancer, tumor or abnormal cell proliferation has an EGFR protein with the L792H mutation. E171: The compound of any of embodiments 161 to 170, wherein the cancer, tumor or abnormal cell proliferation has an EGFR protein with the L718Q mutation. E172: The compound of any of embodiments 161 to 166, wherein the cancer, tumor or abnormal cell proliferation has an EGFR protein with the T790M / L858R mutation. E173: The compound of any of embodiments 161 to 166, wherein the cancer, tumor or abnormal cell proliferation has an EGFR protein with the T790M / L858R / C797S mutation. E174: The compound of any of the modalities 161 to 166, where the cancer, tumor or 125 abnormal cell proliferation has an EGFR protein with the L858R / C797S mutation. E175: The compound of any of embodiments 159 to 174, wherein an additional EGFR inhibitor is administered. E176: The compound of embodiment 175, wherein the additional EGFR inhibitor is a tyrosine kinase inhibitor. E177: The compound of embodiment 175, wherein the additional EGFR inhibitor is osimertinib. E178: The compound of embodiment 175, wherein the additional EGFR inhibitor is rocaletinib. E179: The compound of embodiment 175, wherein the additional EGFR inhibitor is avitinib. E180: The compound of embodiment 175, wherein the additional EGFR inhibitor is lazertinib. E181: The compound of embodiment 175, wherein the additional EGFR inhibitor is nazartinib. E182: The compound of embodiment 174, wherein the additional EGFR inhibitor is an antibody against a mutated form of EGFR. E183: The compound of embodiment 182, wherein the additional EGFR inhibitor is cetuximab. E184: The compound of embodiment 182, wherein the additional EGFR inhibitor is panitumab. E185: The compound of embodiment 182, wherein the additional EGFR inhibitor is necitumab. E186: The compound of any of embodiments 159 to 185, wherein a MET inhibitor is also administered. E187: The compound of any of embodiments 159 to 186, wherein the patient receives an additional chemotherapeutic agent. E188: In certain embodiments the invention is a compound of any of the embodiments a 98, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, for use as a medicament in the therapeutic and / or prophylactic treatment of a patient with activating mutations of EGFR determined with a cobas® EGFR v2 mutation test, suffering from cancer, in particular non-small cell lung cancer, comprising determining the status of activating EGFR mutations in said patient and then administering the compound in accordance with any of embodiments 1 to 98, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition to said patient. E189: In certain embodiments the invention is a pharmaceutical composition comprising ΜΛ / a / ZUZZ / UU z 00» 126 a compound of any of embodiments 1 to 98 and a pharmaceutically acceptable excipient. Μλ / a / zuzz / uu / oo» Additional Embodiments of the Present Invention Modalities of chirality Compounds of the present invention may have multiple stereocenters (e.g., chiral carbon atoms) including, for example, one or more stereocenters in the E3 ligase binding (e.g., ° or °), one or more stereocenters in the linker, and / or at least one stereocenter in the EGFR-binding ligand portion of the ). In certain embodiments, the EGFR-degrading compound of the present invention 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 form (i.e., greater than about 50%, 60%, 70%, 80%, or 90% purity) or even substantially pure (greater than about 95%, 98% or 99% purity) of the R and S stereochemistry. In certain aspects, the EGFR-degrading compound has two enantiomerically enriched and / or substantially pure stereocenters. In a sub-aspect of this, the two enantiomerically enriched and / or substantially pure stereocenters are located in the ligase-binding portion 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 portion 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 portion of the compound and two in the linker. In another aspect, in any of these embodiments, aspects or sub-aspects, additionally, the EGFR binding ligand portion is an enantiomerically enriched or substantially pure form. It has been noted that in some embodiments, the chiral carbon in the portion of the EGFR-binding ligand adjacent to the amide can readily racemize between stereoisomers under the conditions of use and, therefore, in certain embodiments, is not considered for purposes of the designation 127 stereochemistry. In certain embodiments, one stereocenter is in the R configuration and any others present are enantiomerically enriched or substantially pure. In certain embodiments, one stereocenter is in the S configuration and any others present are enantiomerically enriched or substantially pure. In certain embodiments, one stereocenter is in the R configuration and any others present are regardless of stereochemistry, enantiomerically enriched or substantially pure. In certain embodiments, one stereocenter is in the S configuration and any others present are regardless of stereochemistry, enantiomerically enriched or substantially pure. In certain embodiments, there is a stereocenter in the E3 ligase-binding portion (without regard to the stereocenter in the EGFR-binding ligand portion) and is enantiomerically enriched or substantially pure in the R configuration, as indicated below. In another embodiment, there is a stereocenter in the E3 ligase-binding portion (without regard to the stereocenter in the EGFR-binding ligand portion) and is enantiomerically enriched or substantially pure in the S configuration, as indicated below. In certain modalities , where R34 is hydrogen. is O, where R34 is hydrogen. 128 Μλ / a / zuzz / uu / oo» EITHER In certain modalities EITHER In certain modalities In certain embodiments there is a stereocenter in the linker portion and it is a mixture of the R- and S configuration. In another embodiment there is a stereocenter in the linker portion and it has an enantiomerically enriched or substantially pure R configuration. In another embodiment there is a stereocenter in the linker portion and has an enantiomerically enriched or substantially pure S configuration. In certain embodiments the linker contains one or more portions with a chiral center. Non-limiting examples include heterocycle with an enantiomerically enriched or substantially pure stereocenter, for example, piperidine with a meta or ortho substituent with respect to the nitrogen or a bond in the meta or ortho configuration; piperazine with a substituent or bond in the meta or ortho configuration; pyrrolidinone with or without substituent; and pyrrolidine with or without 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 enantiomerically enriched or substantially pure stereocenter; and a cycloalkyl with an enantiomerically enriched or substantially pure stereocenter. In certain embodiments, the linker includes In certain embodiments, the linker includes 129 In certain embodiments, the linker includes R40 In certain embodiments the linker includes In certain embodiments, the linker includes In certain embodiments, the linker includes In certain embodiments, the linker includes In certain embodiments, the linker includes In certain embodiments, the linker includes R40R40 In certain embodiments, the linker includes R40R40 In certain embodiments, the linker includes 130 In certain embodiments, the linker includes In certain embodiments, the linker includes In certain embodiments, there is at least one stereocenter in the ligand portion of EGFR that is a mixture of R and S. In other embodiments, there is at least one stereocenter in the ligand portion of EGFR and is enantiomerically enriched or substantially pure. in the R configuration. In another embodiment there is at least one stereocenter in the ligand portion of the EGFR and it is enantiomerically enriched or substantially pure in the S configuration. In certain modalities In certain modalities In certain modalities In certain modalities 131 In certain modalities In certain modalities Rental modalities In certain embodiments alkyl is a C1-C10 alkyl, C1-C9 alkyl, Ci-Cs alkyl, C1-C7 alkyl, Ci-Ce alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3, or CiC2 alkyl. 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. 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. 132 Additional non-limiting examples of alkyl include: sec-butyl, sec-pentyl, and 5ec-hexyl. Additional non-limiting examples of alkyl include: tere-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. Cycloalkyl Modalities In certain embodiments cycloalkyl is a C3-C8 cycloalkyl, C3-C7 cycloalkyl, C3-C6 cycloalkyl, C3-C5 cycloalkyl, C3-C4 cycloalkyl, C4-C8 cycloalkyl, C5Cs cycloalkyl, or Ce cycloalkyl. -Cs. 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. Haloalkyl Modalities In certain embodiments haloalkyl is a C1-C10 haloalkyl, C1-C9 haloalkyl, Ci-Cs haloalkyl, C1-C7 haloalkyl, Ci-Cs haloalkyl, C1-C5 haloalkyl, Ci& haloalkyl, C1-haloalkyl. C3, and C1-C2 haloalkyl. In certain embodiments haloalkyl has one carbon. In certain embodiments haloalkyl has a carbon and a halogen. In certain embodiments haloalkyl has one carbon and two halogens. In certain embodiments haloalkyl has one carbon and three halogens. In certain embodiments haloalkyl has two carbons. In certain embodiments haloalkyl has three carbons. IVIA / a / ZUZZ / UU / 00» 133 In certain embodiments haloalkyl has four carbons. In certain embodiments haloalkyl has five carbons. In certain embodiments haloalkyl has six carbons. Non-limiting examples of haloalkyl include: Additional non-limiting examples of heteroalkyl include: Ή θ'Ή Additional non-limiting examples of haloalkyl include:C|,C|, andC| Modalities of the heterocid In certain embodiments, heterocid refers to a cyclic ring with one nitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms. In certain embodiments heterocid refers to a cyclic ring with a nitrogen and an oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms. In certain embodiments, heterocid refers to a cyclic ring with two nitrogens and 3, 4, 5, 6, 7, or 8 carbon atoms. In certain embodiments, heterocid refers to a cyclic ring with one oxygen and 3, 4, 5, 6, 7, or 8 oxygen atoms. In certain embodiments "heterocid" refers to a cyclic ring with a sulfur and 3, 4, 5, 6, 7, or 8 carbon atoms. Non-limiting examples of heterocid include aziridine, oxirane, thiirane, azetidine, 1,3diazetidine, oxetane, and thietane. Additional non-limiting examples of heterocid include pyrrolidine, 3-pyrroline, 2-pyrroline, pyrazolidine, and imidazolidine. Additional non-limiting examples of heterocid include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane. Non-limiting examples of heterocid include piperidine, piperazine, tetrahydropyran, 1,4 134 dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine. Additional non-limiting examples of heterocycle include indoline, tetrahydroquinoline, tetrahydroisoquinoline and dihydrobenzofuran in which the attachment point for each group is on the heterocycle ring. Non-limiting examples of heterocycle also include: Additional non-limiting examples of heterocycle 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: In an alternative embodiment, heterocycle is optionally substituted with 1, 2, 3, or 4 R31 substituents. 135 Heteroaryl Modalities 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. ΜΛ / a / ZUZZ / UU z 00» 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, azaindol, 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: 136 IVIA / a / ZUZZ / UU / 00» 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, cinoline, 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. Modalities of the aril In certain embodiments, aryl is phenyl. In certain embodiments aryl is naphthyl. In an alternative embodiment, aryl is optionally substituted with 1, 2, 3, or 4 R31 substituents. Bicycle modalities The term bicycle refers to a ring system where two rings share at least one atom in common. These rings can be spirocyclic or fused and each ring is independently selected from carbocycle, heterocycle, aryl and heteroaryl. Non-limiting examples of bicycle groups include: NH 137 When the term bicycle is used in the context of a bivalent residue such as Linker, the attachment points may 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 bicyclo groups include: Additional non-limiting examples of bivalent bicycle include: In an alternative embodiment, bicyclo is optionally substituted with 1, 2, 3, or 4 R31 substituents. Modalities of optional substituents In certain embodiments where a variable can be optionally substituted, it is not substituted. In certain embodiments where a variable can be optionally substituted, it is replaced with 1 substituent. In certain embodiments where a variable can be optionally substituted, it is replaced with 2 substituents. In certain embodiments where a variable can be optionally substituted, it is replaced with 3 substituents. In certain embodiments where a variable can be optionally substituted, it is replaced with 4 substituents. In an alternative embodiment, any suitable group may be present in a substituted or optionally substituted position, if indicated, that forms a stable molecule and fulfills the desired purpose of the invention and includes but is not limited to, for example, halogen (which can be, independently, F, Cl, Br or I); cyan; hydroxyl; nitro; azido; alkanoyl (as a Cz-Cs alkanoyl group); carboxamide; alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy such as phenoxy; thioalkyl including those having one or more thioether bonds; alkylsulfinyl; alkylsulfonyl groups including those having one or more sulfonyl bonds; aminoalkyl groups that 138 include groups having more than one N atom; 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 rings separated or fused with benzyloxy being an exemplary arylalkoxy group; or a saturated or partially unsaturated heterocycle having 1 to 3 rings separated or fused with one or more N, O or S atoms, or a heteroaryl having 1 to 3 rings separated or fused with one or more N, O or S, for example, cumarinyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, pipe razinyl , and pyrrolidinyl. Such groups may further be substituted, for example, with hydroxy, alkyl, alkoxy, halogen and amino. Aliphatic and heteroaliphatic modalities 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 therefore incorporates each of these definitions. In certain embodiments, aliphatic is used to indicate aliphatic groups having 1-20 carbon atoms. The aliphatic chain may be, for example, monounsaturated, diunsaturated, triunsaturated, or polyunsaturated or alkynyl. The 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 C1-C2, C1-C3, C1-C4, C1-C5 or Ci-Ce. The ranges specified 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 between 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 1, 2, 3 or 4 carbon atoms and is intended to mean that each of these It is described as an independent species. In certain embodiments, the aliphatic group is replaced with one or more functional groups resulting in the formation of a stable moiety. In certain embodiments heteroaliphatic refers to an aliphatic moiety containing at least one heteroatom in the chain, for example, an amine, carbonite, carboxy, oxo, thio, phosphate, Μλ / a / zuzz / uu / oo» 139 phosphonate, nitrogen, phosphorus, silicon or boron atoms instead 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 herein understood 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 (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) group 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. Non-limiting examples of heteroaliphotic moieties are polyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide, polyglycolide, thioether, ether, alkyl-heterocyclo-alkyl, -O-alkyl-O-alkyl, alkyl-O-haloalkyl, etc. Modalities of A and A* In certain modalities A* is In certain modalities A* is In certain modalities A* is 140 In certain modalities A* is In certain A* modalities In certain embodiments R34 and R35 combine to form CH2. In certain modalities R34es H. In certain modalities R35es H. In certain modalities A1es NH. In certain modalities A1 is O. In certain modalities A21es NH. In certain modalities A21es O. In certain embodiments A21 is CH2. In certain modalities A21 is NR100. In certain embodiments A32, A33, A34, and A35 are each selected from CH, C-halogen, and CF. In certain modalities A32 is CH. In certain modalities A32es CF. In certain modalities A32 is CR42. In certain modalities A32es N. In certain modalities A33es CH. In certain modalities A33es CF. 141 In certain modalities A33 is CR42. In certain modalities A33es N. In certain modalities A34 is CH. In certain modalities A34es CF. In certain modalities A34 is CR42. In certain modalities A34es N. In certain modalities A35 is CH. In certain modalities A35es CF. In certain modalities A35 is CR42. In certain modalities A35es N. In certain modalities A36es 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. In certain modalities A or A* is AF To the R8 TO 5 R9 In certain modalities A or A* is AG 142 R4 AH OR In certain modalities A or A* is In certain embodiments, A or A* is selected from: EITHER F 143 Modalities B and B* In certain B or B* modalities In certain B or B* modalities In certain embodiments B* is heteroaryl. In certain embodiments B* is heteroaryl substituted with an R31 group. In certain embodiments B* is aryl. In certain embodiments B* is aryl substituted with an R31 group. In certain B* modalities In certain B* modalities In certain B* modalities Modalities of and In certain modalities y is 0. In certain modalities and is 1. In certain modalities and it is 2. In certain modalities and it is 3. R31 Modalities 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 an R31 is halogen. In certain embodiments an R31 is F. In certain embodiments an R31 is Cl. In certain embodiments an R31 is Ci-6 alkyl. In certain embodiments an R31 is cyan. In certain embodiments an R31 is Ci-e alkoxy. In certain embodiments an R31 is halo-Ci-6-alkoxy. In certain embodiments an R31 is C3-8 cycloalkyl. In certain embodiments an R31 is halo-C3-8-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. 145 R36 and R37 modalities In certain embodiments, R36 and R37 together combine to form a 5-membered cycle. IVIA / a / ZUZZ / UU / 00» 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 members optionally substituted with 1, 2, or 3 R31 substituents. In certain embodiments, R36 and R37 together are combined to members optionally substituted with 1, 2, or 3 R31 substituents. In certain embodiments, R36 and R37 together are combined to members optionally substituted with 1, 2, or 3 R31 substituents. In certain embodiments, R36 and R37 together are combined to members optionally substituted with 1, 2, or 3 R31 substituents. In certain embodiments, R36 and R37 together are combined to members optionally substituted with 1, 2, or 3 R31 substituents. In certain embodiments, R36 and R37 together combine to form a 5-cycloalkyl to form a 6-cycloalkyl to form a 5-heteroaryl to form a 6-membered heteroaryl 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 morpholino optionally substituted with 1, 2, or 3 R31 substituents. In certain embodiments, R36 and R37 together are combined to form a 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 replaced with 1 R31 substituent. In certain embodiments, the cycle formed by combining R36 and R37 is replaced with 2 R31 substituents. In certain embodiments, the cycle formed by combining R36 and R37 is replaced with 3 substituents R31. In certain embodiments R36 is hydrogen. In certain embodiments R36 is halogen. In certain modalities R36es F. In certain embodiments R36es Cl. In certain embodiments R36 is Ci-6 alkyl. In certain embodiments R36 is cyano. In certain embodiments R36 is Ci-6 alkoxy. 146 In certain embodiments R36 is halo-Ci-6-alkoxy. In certain embodiments R36 is C3-8 cycloalkyl. In certain embodiments R36 is halo-Ca-s-cycloalkyl. In certain embodiments R36 is selected from hydrogen, halogen, C1-6 alkoxy, and Cl-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 modalities R37es F. In certain embodiments R37es Cl. In certain embodiments R37 is C1-6 alkyl. In certain embodiments R37 is cyan. In certain embodiments R37 is C1-6 alkoxy. In certain embodiments R37 is halo-Ci-e-alkoxy. In certain embodiments R37 is C3-8 cycloalkyl. In certain embodiments R37 is halo-C3 s-cycloalkyl. In certain embodiments R37 is selected from hydrogen, halogen, Ci 6 alkoxy, and Cl-6 alkyl. In certain embodiments R37 is selected from hydrogen, F, Cl, methoxy, and methyl. IVIA / a / ZUZZ / UU 100» R42 Modalities 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 C1-6 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 modalities R42es F. In certain embodiments R42es Cl. In certain embodiments R42 is Ci-e alkyl. In certain embodiments R42 is cyano. In certain embodiments R42 is C1-6 alkoxy. In certain embodiments R42 is halo-Ci-6-alkoxy. In certain embodiments R42 is C3-8 cycloalkyl. 147 In certain embodiments R42 is halo-C3-8-cycloalkyl. In certain embodiments R42 is selected from hydrogen, halogen, Ci-6 alkoxy, and Cl-6 alkyl. In certain embodiments R42 is selected from hydrogen, F, Cl, methoxy, and methyl. Modalities of the G Ring 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 the G ring is selected from: EGFR Targeting Ligand Modalities In certain embodiments the compound of the present invention is selected from: 148 (R31)2ο )=Ν (R31)2 ο sxJ sxJ and In certain embodiments the compound of the present invention is selected from: 149 In certain embodiments the compound of the present invention is selected from: 150 In certain embodiments the compound of the present invention is selected from: 151 ΜΛ / a / ZUZZ / UU 100» 153 Cl ν^ν\ F IVIA / a / ZUZZ / UU / 00» 154 Formula III Compounds In certain embodiments the compound of the present invention is selected from: In certain embodiments the compound of the present invention is selected from: 156 157 Formula IV Compounds In certain embodiments the compound of the present invention is selected from: 158 III. Additional compounds of the present invention In certain embodiments the compound of the present invention is selected from: 159 160 161 In certain embodiments the compound of the present invention is selected from: 163 In certain embodiments the compound of the present invention is selected from: 164 ΜΛ / a / ZUZZ / UU / 00» 165 ΜΛ / a / ZUZZ / UU 100» 166R33 R33 R33 R33 R33 167 R33 IVIA / a / ZUZZ / UU / 00» R33 In certain embodiments the compound of the present invention is selected from: F F 168 ΜΛ / a / ZUZZ / UU 100» 172 ΜΛ / a / ZUZZ / UU / 00» IVIA / a / ZUZZ / UU / 00» In certain embodiments the compound of the present invention is selected from: R33 174R33 R33 R33 R33 (r31)yr33 175 176 F F In certain embodiments the compound of the present invention is selected from: 179 F ΜΛ / a / ZUZZ / UU z 00» fy F In certain embodiments the compound of the present invention is selected from: F F 180 F In certain embodiments the compound of the present invention is selected from: F F 181 fy In certain embodiments the compound of the present invention is selected from: F F F In certain embodiments the compound of the present invention is selected from: 182 F F F F F In certain embodiments the compound of the present invention is selected from: 183 F IVIA / a / ZUZZ / UU / 00» F fy F In certain embodiments the compound of the present invention is selected from: F F 185 F In certain embodiments the compound of the present invention is selected from: F 186 In certain embodiments the compound of the present invention is selected from: IVIA / a / ZUZZ / UU / 00» 187 In certain embodiments the compound of the present invention is selected from: F 188 ΜΛ / a / ZUZZ / UU / 00» In certain embodiments the compound of the present invention is selected from: 192 194 F In certain embodiments the compound of the present invention is selected from: N J__ / 195 EITHER In certain embodiments the compound of the present invention is selected from: 196 IVIA / a / ZUZZ / UU / 00» In certain embodiments the compound of the present invention is selected from: F 197 ΜΛ / a / ZUZZ / UU z 00» EITHER In certain embodiments the compound of the present invention is selected from: In certain embodiments the compound of the present invention is selected from: 198 ΜΛ / a / ZUZZ / UU 100» 200 202 IV. LINKERS A Linker (L1 or L2) or a linker is included in the compounds of the present invention. The linker is a chemically stable bivalent group that links an E3 ligase binding moiety to an EGFR targeting ligand. According to the invention, any desired linker, as described herein, can be used as long as the resulting compound has a stable shelf life, for example, at least 1 month, 2 months, 3 months, 6 months or 1 year as part of a pharmaceutically acceptable dosage form and by itself is pharmaceutically acceptable. The linker as described herein can be used in either direction, that is, the left end is linked to the E3 ligase binding portion and the right end to the EGFR targeting ligand, or the left end is linked to the ligand of EGFR targeting and the right end is linked to the E3 ligase-binding portion. In certain embodiments, the Linker is a link. 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 Q. 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 may be contiguous, partially contiguous, or non-contiguous (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 units of ethylene glycol). In certain embodiments, the chain has at least 1, 2, 3, 4, 5, 6, 7, or 8 contiguous chains that may have branches that may independently be alkyl, aryl, heteroaryl, alkenyl or alkynyl, aliphatic, heteroaliphatic substituents. , cycloalkyl or heterocycle. In other embodiments, the linker may include or may 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. It is known in the art that blocky and random lactic acid-co-glycolic acid moieties, as well as ethylene glycol and propylene glycol, are pharmaceutically acceptable and can be modified or arranged to obtain the desired half-life and hydrophilicity. In certain aspects, these units may be flanked or intercalated with other moieties, such as aliphatic, including alkyl, heteroaliphatic, aryl, heteroaryl, heterocycle, cycloalkyl, etc., as desired to achieve appropriate pharmacological properties. In certain embodiments, L2 is a linker selected from: wiA / a / zuzz / uu / oo» 203 In one aspect, the Linker (L2) is selected from the group consisting of a portion of Formula LI, Formula LII, Formula LUI, Formula LIV, Formula LV, Formula LVI, Formula LVII Formula LVIII, Formula IX and Formula LX: ^24r22 Heteroaryl X^ '’R^ ^R21 XX2(LII), ^Heterocyclyl ^R21(LVIII), Heterocyclyl ^R “ ^X2(UX). and Heterocyclyl ^R22^R2°23R21^X2ινΐΛ / a / zuzz / uu í oo» where all variables are as defined herein. In certain embodiments, the Linker (L2) is selected from: ^r23\R21 \X2 In one aspect, the Linker (L2) is selected from the group consisting of a portion of Formula LDI, Formula LDII, Formula LDIII, Formula LDIV, Formula LDV, Formula LDVI, and Formula LDVII: 204 Heteroanlo R23R21X2 HeteroarylR23 R20^X2(LDI), (LDII), (LDIII), -r24 R23 Aril R21(LDIV), Aril R23 / R20 R21(LDV),xr22r23 Heterocyclilox(LDVI),and HeterocyclylXR21Λ2 (LDVII), where all variables are described herein. The following are non-limiting examples of Linkers that may be used in this invention. Based on this elaboration, those skilled in the art will understand how to use the full range of Linkers that will achieve the objective of the invention. In certain L2 modalities, it is selected from: 205 206 ΜΛ / a / ZUZZ / UU / 00» 207 208 210 211 ΜΛ / a / ZUZZ / UU 100» 212 Non-limiting examples of the portions of R20, R21, R22, R23, and R24 include: Additional non-limiting examples of the portions of R20, R21, R22, R23, and R24 include: Additional non-limiting examples of the portions of R20, R21, R22, R23, and R24 include: 213 In further embodiments, the Linker portion (L2) 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 intercalated with O, N, S, P or Si optionally substituted. In certain embodiments, the Linker (L2) is flanked, substituted or intercalated with an aryl, phenyl, benzyl, alkyl, alkylene or heterocycle group. In certain embodiments, the Linker (L2) may be asymmetric or symmetric. In certain embodiments, the Linker (L2) may be a non-linear chain, and may be or include aliphatic or aromatic or heteroaromatic moieties. In any embodiment of the compounds described herein, the Linker group may be any suitable portion 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: 214 In certain embodiments, the linker (L2) is selected from the group consisting of: 215 216 ΜΛ / a / ZUZZ / UU / 00» 217 In certain embodiments, the linker (L2) is selected from the group consisting of: 218 IVIA / a / ZUZZ / UU / 00» In certain embodiments, the linker (L2) is selected from the group consisting of: V. TREATMENT METHODS A compound of the present invention can be used in an effective amount to treat a patient in need thereof or to treat any EGFR-mediated disorder. Another aspect of the present invention provides a compound as described herein, or an enantiomer, diastereomer or stereoisomer thereof, or a salt, hydrate or solvate 219 pharmaceutically acceptable, or a pharmaceutical composition, for use in the manufacture of a medicine for the treatment or prevention of cancer in a patient who needs it; where there is a need for inhibition of EGFR for the treatment or prevention of cancer. In one aspect, a compound of the present invention 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 located in exon 18, exon 19, exon 20 or exon 21, or any combination thereof. In certain non-limiting embodiments, the mutation is at position L858, E709, G719, C797, L861, T790, or L718 or any combination thereof. In certain embodiments, the mutation is an L858R, T790M, L718Q, L792H, and / or C797S mutation or any combination thereof. In certain aspects, the cancer has developed one or more EGFR mutations after treatment with at least one EGFR inhibitor which may 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 after 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 render the cancer inherently resistant to treatment with EGFR inhibitors, for example, a somatic exon 20 insertion, an asomatic PIK3CA mutation, loss of PTEN expression, MET amplification or a KRAS mutation. In certain embodiments, a compound of the present invention is used to treat a cancer that is resistant to, or has acquired resistance to, a first generation EGFR inhibitor such as erlotinib, gefitinib, and / or lapatinib. In certain embodiments, a compound of the present invention is used to treat a cancer that is resistant to, or has acquired resistance to, a second generation EGFR inhibitor such as afatinib and / or dacomitinib. In certain embodiments, a compound of the present invention is used to treat a cancer that is resistant to, or has acquired 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, the compound of the present invention is used to treat a disorder mediated by mutant EGFR, in which EGFR has a mutation at one of the amino acid sites listed below. The mutation, for example, may 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 220 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 has two mutations selected from the table above. In other embodiments, the mutant EGFR-mediated disorder has three mutations selected from the table above. In other embodiments, the mutant EGFR-mediated disorder has four or more mutations, which may optionally be selected from the table above. In certain embodiments the mutant EGFR-mediated disorder has an L858R mutation and an additional mutation that may optionally be selected from the table above. In some of these embodiments, the mutant EGFR-mediated disorder has an L858R mutation and two additional mutations that may optionally be selected from the table above. In other embodiments the mutant EGFR-mediated disorder has an L858R mutation and three additional mutations that may optionally be selected from the table above. In certain embodiments the mutant EGFR-mediated disorder has a T790M mutation and an additional mutation optionally selected from the table above. In other embodiments, the mutant EGFR-mediated disorder has a T790M mutation and two additional mutations optionally selected from the table above. In other embodiments the mutant EGFR-mediated disorder has a T790M mutation and three additional mutations optionally selected from the table above. In certain embodiments the mutant EGFR-mediated disorder has an L718Q mutation and an additional mutation optionally selected from the table above. In other embodiments, the mutant EGFR-mediated disorder has an L718Q mutation and two additional mutations optionally selected from the table above. In other embodiments the mutant EGFR-mediated disorder has an L718Q mutation and three additional mutations optionally selected from the table above. In certain embodiments, the EGFR-mediated disorder is mutant EGFR-mediated cancer. In certain embodiments, the EGFR-mediated cancer has a mutation of S768I, L718V, L792H, L792V, G796S, G796C, G724S, and / or G719A. In certain embodiments, a compound of the present invention is used to treat an EGFR-mediated cancer that has a frameshift mutation, for example, a short in-frame deletion. In certain embodiments, a compound of the present invention is used to treat an EGFR-mediated cancer, wherein the EGFR has a deletion of exon 19. In certain embodiments, 221 exon 19 deletion is a deletion that includes the amino acids LREA (L747-A750). In certain embodiments, the exon 19 deletion is a deletion that includes the amino acids ELREA (E746-A750). In certain embodiments, a compound of the present invention is used to treat an EGFR-mediated cancer, wherein the EGFR has an L858R mutation in exon 21. In certain embodiments, a compound of the present invention is more active against a disorder driven by a mutant EGFR than a wild-type EGFR. In certain embodiments, a compound of the present invention is used to treat an EGFR-mediated cancer, wherein the EGFR has one or more exon 18 deletions. In certain embodiments, a compound of the present invention is used to treat EGFR with an E709 mutation, for example, E709A, E709G, E709K or E709V. In certain embodiments, a compound of the present invention is used to treat EGFR with an L718 mutation, for example, L718Q. In certain embodiments, a compound of the present invention is used to treat EGFR with a G719 mutation, for example, G719S, G719A, G719C or G719D. In certain embodiments, a compound of the present invention is used to treat an EGFR-mediated cancer, wherein the EGFR has one or more insertions in exon 19 and / or one or more insertions in exon 20. In certain embodiments, a compound of the present invention is used to treat S7681 mutant EGFR cancer. In certain embodiments, a compound of the present invention is used to treat EGFR mutant EGFR L861Q cancer. In certain embodiments, a compound of the present invention is used to treat C797S mutant EGFR cancer. In certain embodiments, a compound of the present invention is used to treat a T790M, L858R mutant EGFR cancer. In certain embodiments, a compound of the present invention is used to treat an L718Q, L858R mutant EGFR cancer. In certain embodiments, a compound of the present invention is used to treat an L792H, L858R mutant EGFR cancer. In certain embodiments, a compound of the present invention is used to treat a C797S, L858R mutant EGFR cancer. In certain embodiments, a compound of the present invention is used to treat a cancer that is resistant to at least one EGFR inhibitor, for example, a cancer that is resistant to a first generation EGFR inhibitor such as erlotinib, gefitinib, and / or lapatinib. In certain embodiments, a compound of the present invention is used to treat a cancer that has acquired resistance to a first generation EGFR inhibitor, for example a cancer that has acquired resistance to a first generation EGFR inhibitor such as erlotinib, gefitinib , I 222 lapatinib. In certain embodiments, a compound of the present invention is used to treat a cancer that is resistant to a second generation EGFR inhibitor such as afatinib and / or dacomitinib. In certain embodiments, a compound of the present invention is used to treat a cancer that has acquired resistance to a second generation EGFR inhibitor, for example, a cancer that has acquired resistance to a second generation EGFR inhibitor such as afatinib and / or dacomitinib. In certain embodiments, a compound of the present invention is used to treat a cancer that is resistant to a third generation EGFR inhibitor such as osimertinib. In certain embodiments, a compound of the present invention is used to treat a cancer that has acquired resistance to a third generation EGFR inhibitor, for example a cancer that has acquired resistance to a third generation EGFR inhibitor such as osimertinib. In certain embodiments, the method comprises administering an effective amount of the active compound or its salt as described herein, optionally including a pharmaceutically acceptable excipient, carrier or adjuvant (i.e., a pharmaceutically acceptable composition), or optionally in combination or alternation with another bioactive agent or combination of agents, for a patient who needs it. In certain embodiments, the present invention provides a method of treating any of the disorders described herein, in a patient in need thereof. In other embodiments, an additional therapeutic agent is administered to the patient. In other embodiments, the compound as described herein, and the additional therapeutic agent are administered simultaneously or sequentially. In certain embodiments, the application provides a method of preventing any of the disorders described herein, in a patient in need thereof. In certain embodiments, the patient is a human. As EGFR degraders, the compounds and compositions of this application are particularly useful for treating or lessening the severity of a disease, condition or disorder in which an EGFR is involved in the disease, condition or disorder. In one aspect, the present invention provides a method of treating or lessening the severity of a disease, condition or disorder wherein EGFR is involved in the disease state. Another aspect of the present invention provides a method of treating or preventing a proliferative disease. The method comprises administering an effective amount of a pharmaceutical composition comprising a compound as described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate or solvate thereof and, optionally, a carrier pharmaceutically acceptable for a patient in need. IVIA / a / ZUZZ / UU / 00» 223 In some embodiments, the disease is mediated by EGFR. In other embodiments, EGFR plays a role in the initiation or development of the disease. In certain embodiments, the disease or disorder is cancer or a proliferative disease. In certain embodiments, the EGFR-mediated disorder is an abnormal cellular proliferation, including, but not limited to, a solid or hematological cancer. In certain embodiments, the hematological cancer is acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), T-cell lymphoblastic leukemia, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell, chronic neutrophilic leukemia (CNL), T-cell acute lymphoblastic leukemia, acute monocytic leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, leukemia mixed lineage (MLL), erythroleukemia, malignant lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, T-cell lymphoblastic lymphoma, Burkitt lymphoma, follicular lymphoma, B-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, Myc and leukemia B cell lymphoma (BCL)2 and / or BCL6 rearrangements / overexpression [double and triple hit lymphoma], myelodysplastic / myeloproliferative neoplasia, mantle cell lymphoma, including bortezomib-resistant mantle cell lymphoma. Solid tumors 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 castration-resistant prostate cancer (CRPC), brain cancers, including gliomas, glioblastomas, neuroblastomas and medulloblastoma including MYC-amplified medulloblastoma, colorectal cancers, Wilm's tumor, Ewing 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 bone tumors, thyroid, bladder cancers, urothelial cancers, vulvar cancers, cervical cancers, endometrial cancers, mesotheliomas, esophageal cancers, salivary gland cancers, gastric cancer, nasophalangeal cancers, oral cancers, cancers of the mouth, GIST (tumors of the gastrointestinal stroma), NUT midline carcinomas, testicular cancers, squamous cell carcinomas, hepatocellular carcinomas (HCC), MYCN-driven solid tumors and carcinomas Μλ / a / zuzz / uu / oo» 224 NUT Midline (NMC). In additional embodiments, the disease or disorder is sarcoma of the bones, muscles, tendons, cartilage, nerves, fat or blood vessels. In additional embodiments, the disease or disorder is soft tissue sarcoma, bone sarcoma or osteosarcoma. In additional embodiments, the disease or disorder is angiosarcoma, fibrosarcoma, liposarcoma, leiomyosarcoma, Karposi sarcoma, osteosarcoma, gastrointestinal stromal tumor, synovial sarcoma, pleomorphic sarcoma, chondrosarcoma, Ewing sarcoma, reticular cell sarcoma, meningiosarcoma, botryoid sarcoma, rhabdomyosarcoma or embryonal rhabdomyosarcoma. In certain embodiments, the disorder is a sarcoma of bone, muscle, tendon, cartilage, nerve, fat or blood vessel. In additional embodiments, the disease or disorder is multiple myeloma. In certain embodiments, a compound of the present invention or a pharmaceutical salt thereof is used as a medicament in therapeutic and / or prophylactic treatment of a patient with activating EGFR mutations as determined by next generation sequencing (NGS), suffering from cancer, particularly non-small cell lung cancer, comprising determining the status of activating EGFR mutations in said patient and then administering the compound of the present invention, or a pharmaceutically acceptable salt thereof, to said patient. In other embodiments, the disease or disorder is inflammation, arthritis, rheumatoid arthritis, spondiarthropathies, gouty arthritis, osteoarthritis, juvenile arthritis and other arthritic conditions, neuroinflammation, allergy, pain, neuropathic pain, fever, lung disorders, lung inflammation, respiratory distress in adults, chronic inflammatory pulmonary disease and chronic obstructive pulmonary disease (COPD), liver disease and nephritis, gastrointestinal conditions, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, ulcerative diseases, gastric ulcers, autoimmune disease, graft versus host reaction and allograft rejections, cancer, leukemia, lymphoma, colorectal cancer, brain cancer, bone cancer, neoplasia derived from so-called epithelial carcinoma (epithelial carcinoma), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, cancer of lip, mouth cancer, esophageal cancer, small intestine cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer breast, skin cancer, squamous cell and / or basal cell cancer, prostate cancer, renal cell carcinoma and other known cancers affecting epithelial cells throughout the body, chronic myelogenous leukemia (CML), acute myeloid leukemia (AML) and leukemia 225 acute promyelocytic (APL), angiogenesis including neoplasia, metastasis, central nervous system disorders, central nervous system disorders that have an inflammatory or apoptotic component, peripheral neuropathy or B-cell lymphoma. In other embodiments, the pharmaceutical composition comprising the compound as described herein, and the additional therapeutic agent are administered simultaneously or sequentially. In other embodiments, the disease or disorder is cancer. In further embodiments, the cancer is lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer. , bone cancer, gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, renal papillary carcinoma, head and neck squamous cell carcinoma, leukemias, lymphomas, myelomas, solid tumors, hematological cancers or solid cancers . In some embodiments, said method is used to treat or prevent a condition selected from autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, and immunologically mediated diseases. In certain embodiments, said condition is selected from a proliferative disorder. One aspect of this application provides compounds that are useful for the treatment of diseases, disorders and conditions characterized by excessive or abnormal cell proliferation. Such diseases include, but are not limited to, a proliferative or hyperproliferative disease. Examples of proliferative or hyperproliferative diseases include, without limitation, cancer. The term cancer includes, but is not limited to, the following types of cancer: breast; ovary; cervix; prostate; testes, genitourinary tract; esophagus; larynx, glioblastoma; neuroblastoma; stomach; skin, keratoacanthoma; lung, squamous cell carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma; bone; colon; colorectal; adenoma; pancreas, adenocarcinoma; thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma; seminoma; melanoma; sarcoma; bladder carcinoma; liver and bile duct carcinoma; kidney carcinoma; myeloid disorders; lymphoid disorders, Hodgkin's disease, hair cells; oral cavity and pharynx (oral), lip, tongue, mouth, pharynx; small intestine; colonectum, large intestine, rectum, brain and central nervous system; chronic myeloid leukemia (CML) and leukemia. The term cancer includes, but is not limited to, the following types of cancer: myeloma, lymphoma or a cancer selected from gastric, renal and the following types of cancer: head and neck cancer, oropharyngeal, non-small cell lung cancer (NSCLC), endometrium, hepatocellular carcinoma, non-Hodgkin and pulmonary lymphoma. The term cancer refers to any cancer caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas and 226 similar. For example, types of cancer include, but are not limited to, mesothelioma, leukemias and lymphomas such as cutaneous T-cell lymphomas (CTCL), non-cutaneous peripheral T-cell lymphomas, human T-cell lymphotrophic virus-associated lymphomas ( HTLV) such as adult T-cell leukemia / lymphoma (ATLL), B-cell lymphoma, acute non-lymphocytic leukemias, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, lymphomas and multiple myeloma, non-Hodgkin lymphoma, acute lymphatic leukemia ( ALL), chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, Burkitt lymphoma, adult T-cell leukemia lymphoma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma. Additional examples include myelodysplastic syndrome, childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms tumor, bone tumors and soft tissue sarcomas, common solid tumors in adults such as head and neck cancers, such as oral, laryngeal, nasopharyngeal and esophageal, genitourinary cancers, such as prostate, bladder, renal, uterine, ovarian, testicular cancer, lung cancer, such as small and non-small cell cancer, breast cancer, pancreatic cancer, melanoma and other types of skin cancer, stomach cancer, brain tumors, tumors related to Gorlin syndrome, such as medulloblastoma or meningioma, and liver cancer. Additional exemplary forms of cancer include but are not limited to skeletal or smooth muscle cancer, stomach cancer, small intestine cancer, rectal carcinoma, salivary gland cancer, endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer and pituitary cancer. The types of cancer for which the compounds herein may be useful in prevention, treatment and study are, for example, colon carcinoma, familial adenomatous polyposis carcinoma and hereditary nonpolyposis colorectal cancer, or melanoma. Additionally, types of cancer include, but are not limited to, labial carcinoma, laryngeal carcinoma, hypopharyngeal carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, thyroid cancer (medullary and papillary thyroid carcinoma) , renal carcinoma, renal parenchymal carcinoma, cervical carcinoma, uterine corpus carcinoma, endometrial carcinoma, chorion carcinoma, testicular carcinoma, urinary carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, gallbladder carcinoma, bronchial carcinoma, multiple myeloma, basaloma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma and plasmacytoma. In one aspect of the application, the present application contemplates the use of one or more compounds as described herein, in the manufacture of a medicament for the treatment of cancer, including without limitation, the various types of cancer described herein. . ΜΛ / a / ZUZZ / UU z 00» 227 In some embodiments, the compounds of this application are useful for treating cancer, 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 syndrome, juvenile myelomonocytic leukemia, and systemic mastocytosis. 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 or its corresponding salt, pharmaceutically acceptable isotopic derivative as described herein can be used in an amount effective to treat a host, for example, a human, with a lymphoma or a disorder or abnormality. lymphocytic or myelocytic proliferation. For example, a compound as described herein can be administered to a host suffering from Hodgkin's lymphoma or non-Hodgkin's lymphoma. For example, the host may suffer from non-Hodgkin lymphoma such as, but not limited to: an AIDS-related lymphoma; anaplastic large cell lymphoma; angioimmunoblastic lymphoma; NK cell blastic lymphoma; Burkitt lymphoma; Burkitt-type lymphoma (uncleaved small cell lymphoma); diffuse small 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 gammadelta T-cell lymphoma; lymphoblastic lymphoma; mantle cell lymphoma; marginal zone lymphoma; nasal T-cell lymphoma; pediatric lymphoma; peripheral T cell lymphomas; primary lymphoma of the central nervous system; T cell leukemias; transformed lymphomas; treatment-related T-cell lymphomas; Langerhans cell histiocytosis; or Waldenstrom macroglobulinemia. In another embodiment, a compound or its corresponding pharmaceutically acceptable salt, or isotopic derivative as described herein may be used in an effective amount to treat a patient, for example, a human, with a Hodgkin's lymphoma, such as , but not limited to: nodular sclerosis classical Hodgkin lymphoma (CHL); mixed cellularity CHL; CHL with lymphocyte depletion; lymphocyte-rich CHL; lymphocyte-predominant Hodgkin lymphoma; or HL with predominance of nodular lymphocytes. This application also covers the treatment or prevention of cellular proliferative disorders, such as hyperplasias, dysplasias and precancerous lesions. Dysplasia is the earliest form of precancerous lesion recognizable on a biopsy performed by a pathologist. The compounds can be administered in order to prevent said hyperplasias, dysplasias or precancerous lesions from continuing to expand or becoming cancerous. Examples of precancerous lesions may occur in the skin, esophageal tissue, breast, and cervical intraepithelial tissue. As EGFR protein inhibitors, the compounds and compositions of this application 228 are also useful in biological samples. One aspect of the application is to inhibit 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 ex vivo sample, including, without limitation, cell cultures or extracts thereof; biopsy material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears or other bodily fluids or extracts thereof. Inhibition of protein activity in a biological sample is useful for a variety of purposes known to one skilled in the art. Examples of each purpose include, but are not limited to, blood transfusion, organ transplantation, and storage of biological specimens. Another aspect of this application is the study of the EGFR protein in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by said proteins; and the comparative evaluation of new protein inhibitors. Examples of such uses include, but are not limited to, biological assays such as enzymatic assays and cell-based assays. Accordingly, the present application further provides a method of preventing or treating any of the diseases or disorders described above in a patient in need of said 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 also vary depending on the mode of administration, the particular condition to be treated and the desired effect. SAW. COMBINATION THERAPY The disclosed compounds described herein can be used in an effective amount alone or in combination with another compound of the present invention or another bioactive agent or second therapeutic agent to treat a patient such as a human with an EGFR-mediated disorder. , including but not limited to those described herein. The term bioactive agent is used to describe an agent, other than the compound selected in accordance with the present invention, that can be used in combination or alternation with a compound of the present invention to achieve the desired therapy outcome. In certain embodiments, the compound of the present invention and the bioactive agent are administered such that they are active in vivo for overlapping time periods, for example, have Cmax, Tmax, AUC or other pharmacokinetic parameter overlapping the time period. In another embodiment, the compound of the present invention and the bioactive agent are administered to a patient in need thereof. 229 and which does not have an 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 immunomodulator, 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 block the interaction of PD-1 and PD-L1 by binding to the PD-1 receptor and, in turn, inhibit immunosuppression, include, for example, nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab, AMP-224 (AstraZeneca and Medlmmune), PF-06801591 (Pfizer), MEDI0680 (AstraZeneca), PDR001 (Novartis), REGN2810 (Regeneran), SHR-12-1 (Jiangsu Hengrui Medicine Company and Incyte Corporation), TSR- 042 (Tesara) 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, inhibit immunosuppression, include, for example, atezolizumab (Tecentriq), durvalumab (AstraZeneca and Medlmmune ), KN035 (Alphamab) and BMS-936559 (BristolMyers Squibb). CTLA-4 checkpoint inhibitors that bind CTLA-4 and inhibit immunosuppression 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 (GlaxoSmithKIine), IMP321 (Prima BioMed), LAG525 (Novartis), and PD-1 and LAG inhibitor -3 dual MGD013 (MacroGenics). An example of a TIM-3 inhibitor is TSR-022 (Tesara). 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 amount effective for the treatment of abnormal tissue of the female reproductive system such as cancer of the breast, ovary, endometrium or uterus, in combination or alternation with an amount effectiveness 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 antagonist or partial or full estrogen agonist. Partial antiestrogens such as raloxifene and tamoxifen 230 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 that actually stimulates tumor growth. In contrast, fulvestrant, a complete antiestrogen, has no estrogen-like action in the uterus and is effective in tamoxifen-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 US 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, cyclophenyl, 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, allylestrenol, chloromadinone acetate, cyproterone acetate, delmadinone acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethisterone acetate, progesterone and spironolactone. Other estrogenic ligands that can be used in accordance with the present invention are described in U.S. Pat. Nos. 4,418,068; 5,478,847; 5,393,763; and 5,457,117, WO2011 / 156518, U.S. Pat. Nos. 8,455,534 and 8,299,112, U.S. Pat. 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, the active compounds described herein may 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 inhibitor (such such as testosterone) 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, prostate or testicular cancer is androgen resistant. Non-limiting examples of antiandrogen compounds are provided in WO 2011 / 156518 and in US Patent Nos. 8,455,534 and 8,299,112. Examples Additional non-limiting 231 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 a 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, rituximab, 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-lyl]met¡I]piperazin-l-yl ]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(lHpyrrolo[2,3-b]pyridin- 5-¡l)ox¡]benzamide), ABT-737 (4-[4-[[2-(4-chlorophenyl)phen¡l]methyl]piperazin-l-¡l]-N[4-[[( 2R)-4-(dimethylamino)-l-phenylsulfanylbutan-2-l]amino]-3-nitrophenyl]sulfonylbenzamide) (navitodax), ABT-263 ((R)-4-(4- ((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[l,r-biphen¡l]-2¡l)methyl)p¡peraz¡n-l-¡ l)-N-((4-((4-morpholino-l-(phen¡lt¡o)butan-2-¡l)amino)3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide), GX15 -070 (obatoclax mesylate, (2Z)-2-[(5Z)-5[(3,5-dimet¡l-IH-pyrrole-2-¡l)met¡lden]-4 -methoxy¡pyrrole-2-¡liden]idole; methanesulfonic acid))), 2-methoxy¡antimycin A3, YC137 (4-(4,9-dioxo-4,9-dih dronaphtho[2,3-d]thiazol-2-lamino)-phenyl ester), pogosine, 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, demethoxviridine, perifosine, idelalisib, Pictilisib, Palomid 529, ZSTK474, PWT33597, CUDC-907 and AEZS136, duvelisib, GS-9820, BKM120, GDC-0032 (Taselisib) (2-[4-[2-(2-¡sopropyl-5-met¡l-l,2,4-tr¡azol-3¡l)-5,6-d¡hydro¡m¡dazo [l,2-d][l,4]benzoxazepine-9-¡l]p¡razol-l-¡l]-2-methylpropanamide), MLN-1117 ((2R)-l-Phenoxy- 2-butanyl hydrogen (S)-methylphosphonate; or methyl(oxo) {[(2R)-l-phenoxy¡-2 232 butanyl]oxy}phosphonium)), BYL-719 ((2S)-Nl-[4-methyl-5-[2-(2,2,2-trifluoro-l,l-dimethyllethil) -4-pyridinyl]-2thiazolyl]-l,2-pyrrolidinedicarboxamide), GSK2126458 (2,4-difluoro-N-{2-(methyloxy)-5-[4-(4-pyridaz ¡n¡l)-6quinol¡n¡l]-3-pyr¡din¡l}benzenesulfonamide) (omipalisib), TGX-221 ((±)-7-methyl-2-(morphol¡ n-4-¡l)-9- (Iphenylam¡noethyl)-pyr¡do[l,2-a]-pyrimidine -4-one), GSK2636771 acid dihydrochloride (2-methyl-l -(2methyl-3-(trifluoromethyl)benzyl)-6-morpholyno-lH-benzo[d]midazole-4-carboxylic acid), KIN-193 acid ((R) -2((l-(7-methyl-2-morphol¡no-4-oxo-4H-p¡r¡do[l,2-a]p¡r¡m¡d¡n-9-¡l) eth¡l)amino)benzoic), TGR-1202 / RP5264, GS-9820 ((S)-l-(4-((2-(2-am¡nopyrim¡n-5-¡l) -7-methyl-4-mohydroxypropan-l-one), GS-1101 (5-fluoro-3phen¡l-2-([S)]-l-[9H-purín-6 -¡lamino]-prop¡l)-3H-qu¡nazol¡n-4-one), AMG-319, GSK-2269557, SAR245409 (N-(4-(N-(3-((3z5-dimethoxyphenyl)amino)quinoxal¡n-2-¡l)sulfamoyl)phenyl)-3-methoxy¡-4methylbenzamide), BAY80-6946 (2-amino -N-(7-methoxy¡-8-(3-morphol¡nopropoxy¡)-2,3-d¡hydro¡midazo[l,2c]quinaz), AS 252424 (5-[l-[5- (4-fluoro-2-hydroxy¡-phenyl)-furan-2-yl]-meth-(Z)-íliden]-thiazol¡dine-2,4dione), CZ 24832 (5- (2-amino-8-fluoro-[l,2,4]tr¡azolo[l,5-a]pyr¡d¡n-6-yl)-N-tert-but¡lp¡r¡d ¡n-3sulfonamide), Buparlisib (5-[2,6-Di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine), GDC0941 (2-(lH-¡ ndazol-4-yl)-6-[[4-(methylsulfonyl)-l-p¡perazin¡l]methyl]-4-(4-morphol¡n¡l)thiene[3,2d ]pyrimidine), GDC-0980 ((S)-l-(4-((2-(2-aminopyrimidin-5-íl)-7-methyl-4-morpholinothieno[3,2d]pyrimidin- 6¡l)met¡l)p¡perazín-l-¡l)-2-hydroxy¡propan-l-one (also known as RG7422)), SF1126 ((8S,14S,17S)-14-( carbox¡methyl)-8-(3-guan¡dinoprop¡I)-17-(hydroxy¡methyl)-3,6,9,12,15-pentaoxo-l-(4(4-oxo- 8-phenyl)-4H-chromen-2-yl)morphol¡no-4-¡o)-2-oxa-7,10,13,16-tetraazaoctadecan-18-oate), PF05212384 (N-[4-[ [4-(dimethylamino)-l-p¡períd¡n¡l]carbon¡l]phen¡l]-N'-[4-(4,6-di-4-morphol¡n¡l-l ,3,5triazine-2-yl)phenyl]urea) (gedatolisib), LY3023414, BEZ235 (2-methyl-2-{4-[3-methyl-2-oxo-8-(quinolín-3¡ l)-2,3-dihydro-IH-imidazo[4,5-c]quinolin-l-yl]phenyl}propanonitrile) (dactolisib), XL-765 (N-(3-(N-(3(3, 5-dimethoxyphenlamino)qunoxalin-2-l)sulfamo¡lphenyl)-3-methoxyl-4-methlbenzamide) and GSK1059615 (5- [[4-(4-pyridinyl)-6-quinol¡n¡l]methylen]-2,4-thiazol¡denedione), PX886 ([(3aR, 6E, 9S, 9aR, 10R, llaS)6-[[bis(prop-2-enyl)amino]methylidene]-5-hydroxy¡-9-(methoxymethyl)-9a,lla-dimethyl-l,4, 7-trioxo2,3,3a,9,10,ll-hexahydro¡ndene[4,5h]¡socromen-10-¡l]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 (B AY 80-6946), XL 147, PIK-90, PIK-293, PIK-294 , 3-MA (3-methyladenine), AS-252424, AS604850, apitolisib (GDC-0980; RG7422). Examples of BTK inhibitors include ibrutinib (also known as PCI32765)(ImbruvicaT|V|)(l-[(3R)-3-[4-am¡no-3-(4-fenox¡-phen¡l)p ¡razolo[3,4-d] pyrimidin-l-yl]piperidín-lil]prop-2-en-l-one), dianilinopyrimidine-based inhibitors such as AVL-101 and AVL-291 / 292 (N( 3-((5-fluoro-2-((4-(2-methoxyethoxy)phen¡l)amino)pyrimidin-4-l)amino)phenyl)acrylam da)(Avila Therapeutics) (see United States Patent Publication No. 2011 / 0117073, incorporated 233 here in its entirety), Dasatinib ([N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-l-l)-2methyl ¡r¡m¡d¡n-4-¡lam¡no)thiazol-5-carboxamide], LFM-A13 (alpha-cyano-beta-hydroxy-beta-methyl-N-( 2,5¡bromophenyl)propenamide), GDC-0834 ([RN-(3-(6-(4-(1,4-dimethyl-3)-oxop¡perazin-2-yl)phenylamino)-4met¡ l-5-oxo-4,5-di¡hydro¡raz¡n-2-¡l)-2-met¡lfen¡l)-4,5,6,7-tetrah¡drobenzo[b]t ophene-2-carboxamide], CGI-560 4-(tert-but¡l)-N-(3-(8-(phen¡lamino)¡m¡dazo[l,2-a]p¡raz ¡n-6-¡l)phen¡l)benzamide, CGI-1746 (4(tert-but¡l)-N-(2-methyl-3-(4-methyl-6-( (4-(morpholine)-4-carbon¡l)phen¡l)amino)-5-oxo-4,5-d¡hydropyraz¡n-2¡l)phenyl)benzamide), CNX-774 (4 -(4-((4-((3-acrylam¡dophen¡l)amino)-5-fluorop¡r¡m¡din-2yl)amino)phenoxy¡)-N-methylpicol¡namide), CTA056 (7-benz¡l·l-(3-(piper¡d¡n-l-¡l)prop¡l)-2-(4-(p¡r¡d¡n-4-yl) phenyl)-lH -imidazo[4,5-g]quinoxalin-6(5H)-one), GDC-0834 ((R)-N-(3-(6-((4-(l,4-dimethyl-3oxopiperazin-2- il) phen¡l)am¡no)-4-met¡l-5-oxo-4,5-d¡hydro¡raz¡n-2-¡l)-2-met¡lfenyl)-4, 5,6,7tetrahydrobenzo[b]thiophene-2-carboxamide), GDC-0837 ((R)-N-(3-(6-((4-(l,4-dimethyl-3-oxopiperazín- 2¡l)phen¡l)amino)-4-methyl¡l-5-oxo-4,5-dihydro¡raz¡n-2-¡l)-2-met¡lfen¡l)-4, 5,6,7-tetrahydrobenzo[b]thiophene-2carboxamide), HM-71224, ACP-196, ONO-4059 (Ono Pharmaceuticals), PRT062607 (4((3-(2H-l,2) hydrochloride ,3-tr¡azol-2-¡l)phen¡l)amino)-2-(((lR,2S)-2-aminodclohex¡l)amino)p¡r¡m¡din-5-carboxam ¡da), QL-47 (l-(l-acrylo¡indol¡n-6-yl)-9-(l-methyl-lH-pyrazol-4-yl) benzo[h][l, 6]naphthyridine-2(lH)-one), and RN486 (6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{l-methyl-5-[5-(4-methyl-piperazin -l-yl)-pyridin-2¡lam¡no]-6-oxo-l,6-d¡hídro-pyr¡din-3-yl}-phen¡l)-2H-soqu¡ nolin-l-one) and other molecules capable of inhibiting BTK activity, for example, the BTK inhibitors described in Akinleye et al., Journal of Hematology & Oncology, 2013, 6:59, all of which are incorporated here for 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-morpholinophen¡l)¡m¡dazo[l,2-a]pyrazin-8-am¡ne), fostamatinib ([6-dihydrogen phosphate ({5Fluoro-2-[(3,4,5-trimethoxy¡phen¡l)amino]-4-p¡r¡m¡d¡n¡l}amino)-2,2- dimethyl-3-oxo-2,3-dihydro-4Hpyrido[3,2-b][l,4]oxazin-4-yl]methyl), fostamatinib disodium salt (sodium phosphate (6-((5-fluoro-2((3,4,5-trimethoxy¡phen¡l)am¡no)pyrám¡d¡n-4-¡l)am¡no)-2, 2-d¡methyl-3-oxo-2H-pyr¡do[3,2-b][l,4]oxaz¡n4(3H)-yl)methyl), BAY 61-3606 (2-(7 -(3,4-dimethoxy¡phen¡l)-¡m¡dazo[l,2-c]p¡r¡m¡d¡n-5-¡lam¡no)-n¡cot¡namide HCl ), RO9021 (6-[(lR,2S)-2-amino-cyclohexylamine]-4-(5,6-dimethyl-pyridine-2-amide) llamino)pyridazine-3-carboxylic), imatinib (Gleevac; 4-[(4-met¡lp¡perazín-l-¡l)met¡l]-N-(4-rnet¡l-3-{[4-(p¡r¡d¡n-3yl)p¡rim¡d¡n-2-¡l]am¡no}phen¡l)benzamide), staurosporine, GSK143 (2-(((3R , 4R)-3-aminotetrahydro-2Hpyran-4-¡l)amino)-4-(p-tolylamino)pyrámidene-5-carboxamide), PP2 (l-(tert-butyl )-3-(4-chlorophenyl)-lHp¡razolo[3,4-d]pyrám¡din-4-amine), PRT-060318 (2-(((lR, 2S)-2 -aminocyclohex¡l)am¡no)-4-(mtol¡lam¡no)pyrám¡dine-5-carboxamide), PRT-062607 (4-((3-(2H-l) hydrochloride ,2,3-triazol-2¡l)phenyl)amino)-2-(((lR,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide) , R112 (3,3'-((5fluoropinmidin-2,4-d¡l)b¡s(azanediyl))diphenol), R348 (3-ethyl-4-methylp¡r¡dine), R406 ( 6-((5-fluoro-2((3,4,5-tr¡methoxy¡phen¡l)amino)p¡r¡m¡d¡n-4-¡l)amino)-2 ,2-dimet¡l·2H-p¡r¡do[3,2-b][l,4]oxaz¡n-3(4H)-one), IVIA / a / ZUZZ / UU / 00» 234 piceatannol (3-hydroxyresveratol), YM193306 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643), 7-azaindol, piceatannol, ER27319 ( see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated herein in its entirety), Compound D (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 36143643 incorporated in its entirety herein), PRT060318 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 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. Chem. 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. Chem. 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. Chem. 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. Chem. 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. Chem. 2012, 55, 36143643 incorporated in its entirety herein), morin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in its entirety in this document). In certain embodiments, the bioactive agent is a MEK inhibitor. MEK inhibitors are well known and include, for example, trametinib / GSKI 120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro4-iodophenyl)amino]-6,8-d ¡met¡l-2,4,7-tr¡oxo-3,4,6,7-tetrah¡drop¡r¡do[4,3-d]p¡r¡m¡d¡n-l(2Hyl}phenyl )acetamide), selumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxy¡ethoxy¡)-3methylbenzimidazole-5-carboxamide), pimasertib / AS703026 / MSC 1935369 (( S)-N-(2,3-dihydrox¡propyl)3-((2-fluoro-4-iodophenyl)amino)sonicot¡nam¡de), XL-518 / GDC-0973 (l-({3,4-difluoro-2-[(2-fluoro-4iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol), refametinib / BAY869766 / RDEAI 19 ( N-(3,4-difluoro-2-(2-fluoro-4-iodophenylano)-6-methoxyphenyl)-l-(2,3-dihydroxypropyl )cyclopropane1-sulfonamide), PD-0325901 (N-[(2R)-2,3-dihydroxy¡propoxy]-3,4-difluoro-2-[(2-fluoro-4iodophenyl)amino]-benzam ¡da), TAK733 ((R)-3-(2,3-Dihydroxy¡propyl)-6-fluoro-5-(2-fluoro-4iodofen¡lamino)-8-methylpyr¡do[2, 3-d]pyridine-4,7(3H,8H)-dione), MEK162 / ARRY438162 (5-[(4bromo-2-fluorophenyl)amino]-4-fluoro -N-(2-hydroxy¡ethoxy¡)-l-methyl¡l-lH-bendm¡dazole-6-carboxamide), R05126766 (3-[[3-fluoro-2-(methylsulfame¡ lam¡no)-4-p¡r¡d¡l]met¡l]-4-met¡l-7-p¡r¡m¡d¡n-2-¡lox¡chromen-2one), WX- 554, R04987655 / CH4987655 (3, 4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2hydroxy¡ethoxy¡)-5-((3-oxo-l,2- oxazinan-2¡l)methyl)benzamide) or AZD8330 (2-((2-fluoro-4iodophen¡l)amino)-N-(2-hydroxy¡ethoxy¡)-l,5 -d¡met¡l-6-oxo-l,6-di¡hydro¡r¡din-3-carboxam¡da), U0126 235 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]pyridan-3yl ]carbon¡l]-2,4-difluorophen¡l]-l-propanesulfonamide), sorafenib tosylate (4-[4-[[4-chloro-3(trifluoromethyl)phen¡l]carbamine ¡lamino]phenoxy¡]-N-met¡lp¡ridín-2-carboxamide; 4-methylbenzenesulfonate), AZ628 (3-(2-cyanopropan-2-¡l)-N-(4-met¡ l-3-(3-methyl-4-oxo-3,4-dihydroqunazolin-6lamino)phenyl)benzamide), NVP-BHG712 (4-methyl- 3-(l-methyl-6-(pyridin-3-l)-lH-pyrazolo[3,4d]pyrimidin-4-ylamino)-N-(3-(trifluoromethyl)phenyl)benzamide), RAF- 265 (l-methyl-5-[2-[5-(tnfluoromethyl)lH-¡m¡dazol-2-yl]pyridin-4-¡l]ox¡-N-[4-(tnfluoromethyl)phen¡ l]benzimidazol-2-amine), 2-Bromoaldisine (2Bromo-6,7-dihydro-lH,5H-pyrrolo[2,3-c]azepine-4,8-dione), IV inhibitor of Raf kinase (2-chloro-5(2-phenyl-5-(pyridin-4-yl)-lH-imidazol-4-yl)phenol), sorafenib N-oxide (4-[4-[[[[4 -chloro3(trifluoromet¡l)phenyl]am¡no]carbon¡l]am¡no]phenoxy¡]-N-methyl-2pyr¡d¡ncarboxaM¡da 1-oxide), PLX-4720, dabrafenib (GSK2118436), GDC-0879, RAF265, AZ 628, SB590885, ZM336372, GW5074, TAK-632, CEP-32496, LY3009120 and GX818 (Encorafenib). In certain embodiments, the bioactive agent is an EGFR inhibitor, including, for example, gefitinib (Iressa), erlotinib (Tarceva), lapatinib (Tykerb), osimertinib (Tagrisso), neratinib (Nerlynx), vandetanib (Caprelsa), dacomitinib (Vizimpro). ), rocaletinib (Xegafri), afatinib (Glotriff, Giotriff, Afanix), lazertinib, or nazartib. Additional examples of EGFR inhibitors include rocaletinib (CO-1686), olmutinib (Olita), naquotinib (ASP8273), nazartinib (EGF816), PF-06747775, icotinib (BPI-2009), neratinib (HKI-272; PB272); avitinib (ACOGIO), EAI045, tarloxotinib (TH-4000; PR-610), PF-06459988 (Pfizer), tesevatinib (XL647; EXEL-7647; KD-019), transtinib, WZ-3146, WZ8040, CNX-2006, dacomitinib (PF-00299804; Pfizer), brigatinib (Alunbrig), lorlatinib, 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 embodiments, a compound of the present invention is administered to a patient in need thereof in combination with osimertinib. In certain embodiments, a compound of the present invention is administered to a patient in need thereof in combination with rocaletinib. In certain embodiments, a compound of the present invention is administered to a patient in need thereof in combination with avitinib. In certain embodiments, a compound of the present invention is administered to a patient wiA / a / zuzz / uu / oo» 236 who needs it in combination with lazertinib. In certain embodiments, a compound of the present invention is administered to a patient in need thereof in combination with nazartinib. In certain embodiments, a compound of the present invention is administered to a patient in need thereof in combination with EGFR antibody, for example, cetuximab, panitumab or necitumab. In certain embodiments, a compound of the present invention is administered to a patient in need thereof in combination with cetuximab. In certain embodiments, a compound of the present invention is administered to a patient in need thereof in combination with panitumab. In certain embodiments, a compound of the present invention 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, PF04691502 and Miltefosine, an 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 of the themselves. 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, ridaduranteolimus, 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 s¡G12D LODER. In certain embodiments, the bioactive agent is an HSP inhibitor. HSP inhibitors include, but are not limited to, Geldanamycin or 17-N-AI¡lamino-17-demethoxy¡geldanam¡cin (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 (ARRY142886), 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, a kinase inhibitor Aurora, a PIK-1 modulator, HDAC inhibitor, c-MET inhibitor, PARP inhibitor, Cdk inhibitor, IGFR-TK inhibitor, anti-HGF antibody, focal adhesion kinase inhibitor, Map kinase inhibitor (mek), a VEGF trap antibody, pemetrexed, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, atumumab, zanolimumab, IVIA / a / ZUZZ / UU / 00» 237 edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gosypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdRl KRX-0402, Lucantona, Ly317615, Neuradiab, Vitespan, Rta 744, SDX 102, Talampanel, backward, XR 311, RUBIDEPSINA, ADS-100380, SUNITINIB, 5-FLUOROUCIL, VORINOSTITA 5'- deoxy-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4oxo-lH-pyrrolo[2,3-d]pyrimidin-5-yl) ethyl]benzo¡l]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, BMI-1C11, CHIR-258); 3[5-(met¡lsulfon¡lp¡perad¡nemet¡l)-¡ndol¡l-quinolone, vatalanib, AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelin pamoate, acetate for medroxyprogesterone, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, 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, SU11248, Sorafenib, KRN951, Aminoglutethimide, Arnsacrine, Anagrelide, L-Asparaginase, Bacillus Calmette-Guerin (BCGuse), Vaccine, Adriamycin, Bleomycin , buserelin, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, ima tinib, leuprolide , levamisol, lomustine, mecloletamine, melfalan, 6-mercaptopurine, mesna, methotrexate, mythomicin, mythotano, mythoxyntron , teniposide, testosterone, talidomide , thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine , topotecan, razoxine, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxifene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin , gefitinib, bortezimib, paclitaxel, cremophore-free paclitaxel, docetaxel, epitilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolifene, lasofoxifene, idoxifene, TSE-424 , HMR-3339, ZK186619, topotecan, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapacin, temsirolimus, AP-23573, RAD001, ABT -578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoietin, erythropoietin, granulocyte colony-stimulating factor, zolendronate, prednis ona, cetuximab, stimulating factor 238 granulocyte and macrophage colonies, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacytidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane , alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwinaasparaginase, 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 rum , 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 is not limited to, imatinib mesylate (Gleevac®), Dasatinib (Sprycel®), Nilotinib (Tasigna®), Bosutinib (Bosulif®), Trastuzumab (Herceptin®), trastuzumab -DMl, 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®), Zivaflibercept (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 bioactive chemotherapeutic agents include, but are not limited to, a radioactive molecule, a toxin, also called a 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®), Lasparaginase (Elspar®) or PEG-L-asparaginase (pegaspargase or Oncaspar®), Etoposide (VP-16), Teniposide (Vumon®), 6-mercaptopurine (6-MP or Purinetol®), 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, decarbazine 5-fluorouracil, 6-mercaptopurine, 6-thioguanine, actinomycin D, adriamycin, aldesleukin, an alkylating agent, allopurinol sodium, altretamine, 239 amifostine, anastrozole, anthramycin (AMC)), an anti-mitotic agent, cis-dichlorodiamine platinum (II) (DDP) cisplatin), platinum diamine dichloro, anthracycline, an antibiotic, an antimetabolite, asparaginase, live BCG (intravesical), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, calcium leucouorin, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU), chlorambucil, cisplatin, cladribine, colchicine, conjugated estrogens, cyclophosphamide, cyclotosphamide E. coli L- asparaginase, emetine, epoetin-α, Erwinia L-asparaginase, esterified estrogens, estradiol, estramustine sodium phosphate, 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, mercattipurine, mesna, methotrexate, methyltestosterone, mithramycin C, mitomycin C, mitotane, mitoxantrone, nilutamide, octreotide acetate, ondansetron HCL, paclitaxel, disodium pamidronate , pentostatin, pilocarpine HCL, plymicin, polifeprosan 20 with carmustine implant, porfimer sodium, procaine, procarbazine HCL, propranolol, rituximab, sargramostim, streptozotocin, tamoxifen, taxol, teniposide, tenoposide, testolactone, tetracaine, tioepa chlorambucil, thioguanine, thiotepa , topotecan HCL, toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate. In some embodiments, the compound of the present invention is administered in combination with a chemotherapeutic agent (for example, a cytotoxic agent or other chemical compound useful in the treatment of cancer). Examples of chemotherapeutic agents include alkylating agents, antimetabolites, folic acid analogues, pyrimidine analogues, purine analogues and related inhibitors, vinca alkaloids, epipodopilotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes , anthracenedione-substituted urea, methylhydrazine derivatives, adrenocortical suppressor, adrenocorticosteroids, progestins, estrogens, antiestrogens, androgens, antiandrogens and gonadotropin-releasing hormone analogues. Also included are 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 cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, 240 meturedopa, and uredopa; ethyleneimines and methylmelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylololamine; acetogenins (especially bulatacin and bulatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callistatin; CC-1065 (including its synthetic analogues adozelesin, carzelesin and bizelesin); crypto-offices (particularly crypto-office 1 and crypto-office 8); dolastatin; duocarmycin (including synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, colofosfamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembicin, phenesterin, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as enediin antibiotics (for example caliceamicin, especially caliceamicin gammall and caliceamicin omegall (see, for example, Agnew, Chem. Inti. Ed EngL 33:183-186 (1994)); dynemycin, including dynemycin A; bisphosphonates, such as clodronate; anesperamycin; as well as neocarzinostatin chromophore and related chromoprotein enedin antibiotic chromophores), aclacinomycins, actinomycin, autramycin, azaserine, bleomycins, cactinomycin, carabicin, Caminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo5 -oxoL-norleucine, ADRIAMYCIN® (doxorubicin including morpholino-doxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolino-doxorubicin and deoxidoxorubicin), epirubicin, esorubicin, idarubicin, marcelomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, pepl omycin, potfiromycin, Puromycin, Chelamycin, Rhodorubicin, Streptonigrin, Streptozocin, Tubercidin, Ubenimex, Zinostatin, Zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, denopterin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxyfluridine, enocitabine, floxiridine; androgens such as calusterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; supplier of folic acid such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomitin; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinano; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerin; pentostatin; fenamet; pyrarubicin; losoxantrone; podophylinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2-tnchlorotriethilamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethane; vindesine; dacarbazine; manomustine; mitobronitol; 241 mitolactol; pipobroman; gacitosin; arabinoside (Ara-C); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL®, (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE®, cremophore-free, albumin-engineered paclitaxel nanoparticle formulation (American Pharmaceutical Partners, Schaumberg, IL), and TAXOTERE® dexetaxel (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 (eg, 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 may be used in a cocktail to be administered in combination with the compound of the present invention. Suitable dosage regimens of combination chemotherapies are known in the art. For example, combination dosage regimens 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 may be administered in combination with a Compound described herein may include bevacizumab, sutinib, sorafenib, 2-methoxyestradiol or 2ME2, finasunate, vatalanib, vandetanib, aflibercept, volociximab, etaracizumab (MEDI-522), cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, dovitinib, figitumumab, atacicept, ñtuximab, alemtuzumab, aldesleukin, atlizumab, tocilizumab, temsirolimus, everolimus, lucatumumab, dacetuzumab, HLL1, huN901-DMl, atiprimod, natalizumab, bortezomina, carfilzomib, marizomi b, tanespimycin, saquinavir mesylate, ritonavir, nelfinavir mesylate, indinavir sulfate, belinostat, panobinostat, Mapatumumab, Lexatumumab, Dulanermin, ABT-737, Oblimersen, Plitidepsin, Talmapimod, P276-00, Enzastaurin, Tipifarnib, Perifosine, Imitinib, Dasatinib, lenalidomide, thalidomide, simvastatin, celecoxib, bazedoxifene, AZD4547, rilotumumab, oxaliplatin (Eloxatin), PD0332991, ribociclib (LEE011), amebaciclib (LY2835219), HDM201, fulvestrant (Faslodex), exemestane (Aromasin), PIM447, ru xolitinib (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 antibodies produced naturally by B cells, these MAbs can coat the surface of the cancer cell, causing 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 microenvironment that promotes the development of tumor blood vessels. When bound to bevacizumab, VEGF cannot interact with its receptor 242 cellular, which prevents 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 can 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 may be a calcineurin inhibitor, for example, a cyclosporine or an ascomycin, for example, cyclosporine A (NEGRAL®), FK506 (tacrolimus), pimecrolimus, an mTOR inhibitor, for example, rapamycin or a derivative of same, for example, sirolimus (RAPAMUNE®), everolimus (Certican®), temsirolimus, zotarolimus, biolimus-7, biolimus-9, a rapalogue, for example, ridaforolimus, azathioprine, campath 1H, an S1P receptor modulator, for example , fingolimod or an analog 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-deoxyspergualine, tresperimus, leflunomide, ARAVA®, CTLAI-Ig, anti-CD25, anti-IL2R, basiliximab (SIMULECT®), daclizumab (ZENAPAX®), mizorbine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, Elidel®), CTLA4lg (Abatacept), belatacept, LFA3Ig, 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, naprosine, diclofenac, etodolac and indomethacin, aspirin and ibuprofen. In some embodiments, the bioactive agent is a therapeutic agent that is a biologic such as a cytokine (e.g., interferon or an interleukin (e.g., IL-2)) used in the treatment of cancer. In some embodiments, the biologic is an anti-angiogenic agent, such as an anti-VEGF agent, for example, 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 Fe fusion protein, or a functional fragment thereof) that agonizes a target to stimulate an anticancer response, or antagonize an important cancer antigen. 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-l-131); RAPTIVA® (efalizumab); ERBITUX® (cetuximab); AVASTIN® (bevacizumab); TYSABRI® (natalizumab); ACTEMRA® (tocilizumab); VECTIBIX® (panitumumab); LUCENTIS® (ranibizumab); SOURIS® (eculizumab); 243 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 antibody-drug conjugates. Combination therapy may include a therapeutic agent that is a non-drug treatment. For example, the compound could be administered in addition to radiotherapy, cryotherapy, hyperthermia and / or surgical excision of tumor tissue. In certain embodiments, the first and second therapeutic agents are administered simultaneously or sequentially, in any order. The first therapeutic agent can 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, up to 14 hours, up to 16 hours, up to 17 hours, up to 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 to 7, 1 to 14, 1 to 21 or 30 days before or after the second therapeutic agent. In certain embodiments, the second therapeutic agent is administered on a different dosing schedule than the compound of the present invention. For example, the second therapeutic agent may have a treatment break 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 other embodiments the first therapeutic agent has a treatment break. For example, the first therapeutic agent may have a treatment break 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 modalities, both the first and second therapeutics have a treatment break. VII. PHARMACEUTICAL COMPOSITIONS A compound of Formula I, II, III, or IV or a pharmaceutically acceptable salt thereof may be used as a therapeutically active substance, for example, in the form of pharmaceutical preparations. The pharmaceutical preparations may be administered orally, for example, in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. In other embodiments, the compound is administered parenterally, for example, by intravenous administration. However, administration can also be carried out rectally, for example in the form of suppositories, or parenterally, for example in the form of solutions for injection. Compounds of Formula I, II, III, or IV and pharmaceutically acceptable salts thereof can be processed with pharmaceutically inserted, inorganic or organic carriers to IVIA / a / ZUZZ / UU / 00» 244 the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acids or their salts and the like may be used, for example, such as carriers for tablets, coated tablets, dragees and hard gelatin capsules. Suitable carriers for soft gelatin capsules, for example, are semi-solid and liquid vegetable oils, waxes, fats, polyols and the like. However, depending on the nature of the active substance, carriers are generally not 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. In addition, pharmaceutical preparations may contain pharmaceutically acceptable auxiliary substances, such as preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying osmotic pressure, pH regulators, masking agents or antioxidants. They may also contain 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 may also be provided by the present invention, as is a process for its production, comprising carrying one or more compounds of Formula I, II, III or IV and / or their pharmaceutically acceptable salts and, if desired, one or more therapeutically valuable substances in a galenic 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 may range from about 0.01 mg to about 1000 mg per day of a compound of General Formula I, II, III or IV or the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage may be administered as a single dose or in divided doses and, in addition, the upper limit may also be exceeded when considered 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 the compositions according to the invention are: In certain embodiments, the pharmaceutical composition is in a dosage form containing 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. mg of the active compound and optionally of 245 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 the active compound or its salt. In some embodiments, the compounds described herein or used as described, are administered once a day (QD), twice a day (BID), or three times a day (TID). In some embodiments, the compounds described 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 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 at least 150 days, at least 180 days, or more. In certain embodiments, the compound of the present invention is administered once a day, twice a day, three times a day, or four times a day. In certain embodiments the compound of the present invention is administered orally once a day. In certain embodiments the compound of the present invention is administered orally twice a day. In certain embodiments the compound of the present invention is administered orally three times a day. In certain embodiments the compound of the present invention is administered orally four times a day. In certain embodiments the compound of the present invention is administered intravenously once a day. In certain embodiments the compound of the present invention is administered intravenously twice a day. In certain embodiments the compound of the present invention is administered intravenously three times a day. In certain embodiments the compound of the present invention is administered intravenously four times a day. In some embodiments, the compound of the present invention is administered with a treatment break between treatment cycles. For example, the compound may have a treatment break 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 initiate treatment. By Μλ / a / zuzz / uu / oo» 246 example, the compound can be administered approximately 1.5x, approximately 2x, approximately 2.5x, approximately 4.5x, approximately 6.5x, approximately 3x, approximately 5x, approximately 7x, approximately 3.5x, approximately 5.5x, approximately 7.5x, approximately 4x , about 6x, about 8x, ΜΛ / a / ZUZZ / UU z 00» approximately 8.5x, approximately 9x, approximately 9.5x, or approximately 10 times higher doses 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, approximately 8x, approximately 8.5x, approximately 9x, approximately 9.5x or approximately 10x higher doses in the first 2, 3, 4, 5, 6, 7, 8, 9 or 10 days of treatment than in the remaining days of treatment 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 about 1.5:1 to about 4:1 of an anti-inflammatory agent or immunosuppressive agent. These compositions may contain any amount of active compound that achieves the desired result, for example between 0.1 and 99% by weight (wt%) of the compound, and usually at least about 5% by weight of the compound. Some embodiments contain from about 25% by weight to about 50% by weight or from about 5% by weight to about 75% by weight of the compound. A pharmaceutically or therapeutically effective amount of the composition will be administered to the patient. The precise effective amount will vary from patient to patient and will depend on the species, age, size and health of the subject, the nature and extent of the condition being treated, the recommendations of the treating physician, and the therapy or combination. of therapies selected for administration. The effective amount for a given situation can be determined by routine experimentation. For purposes of description, a therapeutic amount, for example, may be in the range of about 0.01 mg / kg to about 250 mg / kg of body weight, more typically about 0.1 mg / kg to about 10 mg / kg, in at least a dose. The subject can be administered as many doses as required to reduce and / or alleviate the signs, symptoms, or causes of the common disorder, or cause 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. 247 In certain embodiments, the dose ranges from about 0.01-100 mg / kg of the patient's body weight, 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, approximately 4.5 mg / kg, approximately 5 mg / kg, approximately 10 mg / kg, approximately 15 mg / kg, approximately 20 mg / kg, approximately 25 mg / kg, approximately 30 mg / kg, approximately 35 mg / kg kg, approximately 40 mg / kg, approximately 45 mg / kg, approximately 50 mg / kg, approximately 55 mg / kg, approximately 60 mg / kg, approximately 65 mg / kg, approximately 70 mg / kg, approximately 75 mg / kg, approximately 80 mg / kg, approximately 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 amounts of the active component. The unit dosage form may be a packaged preparation, the container containing discrete quantities of preparation, such as tablets, capsules and powders packaged in bottles or ampoules. Furthermore, the unit dosage form may be a capsule, a tablet, a tablet, or a lozenge, or may 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, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate , heptonate, hexanoate, hydrobromide, hydrochloride, iodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, 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 metal or alkaline earth metal salts include sodium, lithium, potassium, calcium and magnesium, as well as non-toxic 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 invention can be administered as a pharmaceutical formulation, including one suitable for oral (including buccal and sublingual), rectal, nasal, topical, transdermal, pulmonary, vaginal or parenteral use (including intramuscular, intraarterial, intrathecal , subcutaneous and intravenous), injections, inhalation or spray, intra-aortal, intracranial, 248 subdermal, intraperitoneal, subcutaneous or by other means of administration containing conventional pharmaceutically acceptable carriers. A typical form of administration is oral, topical or intravenous, using a usual daily dosage regimen, which can be adjusted according to the degree of distress. Depending on the intended mode of administration, the pharmaceutical compositions may be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, syrups, suspensions, creams, ointments, lotions, pastes, gels, spray, aerosols, foam, or oil, solution for injection or infusion, a transdermal patch, a subcutaneous patch, a formulation for inhalation, in a medical device, suppository, buccal or sublingual formulation, parenteral formulation or a ophthalmic solution, or the like, preferably in a unit dosage form suitable for single administration of a precise dose. Some dosage forms, such as tablets and capsules, are subdivided into unit doses of suitable size containing appropriate amounts of the active components, for example, an amount effective to achieve the desired purpose. The compositions will include an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier, and may further include other pharmaceutical agents, adjuvants, diluents, pH regulators and the like. Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to make them suitable for administration to the patient being treated. The carrier may be inert or may possess its own pharmaceutical benefits. The amount of carrier used together with the compound is sufficient to provide a practical amount of material for administration per unit dose of the compound. Carrier classes include, but are not limited to, adjuvants, binders, pH regulating agents, coloring agents, diluents, disintegrants, excipients, emulsifiers, flavorings, gels, lubricants, preservatives, stabilizers, surfactants, solubilizers, tableting agents , wetting agents or solidifying material. Some carriers may be included in more than one class, for example, vegetable oil may be used as a lubricant in some formulations and as a diluent in others. Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin; talc, petroleum jelly, lanolin, polyethylene glycols, alcohols, transdermal enhancers and vegetable oils. Optional active agents may be included in a pharmaceutical composition that do not substantially interfere with the activity of the compound of the present invention. Some excipients include, but are not limited to, liquids such as water, saline, 249 glycerol, polyethylene glycol, hyaluronic acid, ethanol and the like. The compound may be provided, for example, in the form of a solid, liquid, atomized material, a microparticle, nanoparticle, controlled release system, etc., as desired according to the objective of the therapy. Suitable excipients for non-liquid formulations are also known to those skilled in the art. A detailed discussion of pharmaceutically acceptable excipients and salts is available in Remington's Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990). Furthermore, auxiliary substances such as wetting agents or emulsifiers, biological pH regulating substances, surfactants and the like may be present in such vehicles. A biological pH regulator can be any solution that is pharmacologically acceptable and that provides formation at the desired pH, that is, a pH is the physiologically acceptable range. Examples of buffer solutions include saline, buffered saline, Tris buffered saline, Hank's buffered saline, and the like. For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate and the like. Pharmaceutically acceptable liquid compositions, for example, can 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 may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH regulating agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine acetate. sodium, triethanolamine oleate and the like. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in the art; for example, see Remington's Pharmaceutical Sciences, mentioned above. In yet another embodiment, the use of permeation-enhancing excipients is provided that includes polymers such as: polycations (chitosan and its quaternary ammonium derivatives, poly-L-arginine, aminated gelatin); polyanions (N-carboxymethylchitosan, polyacrylic acid); and dolated polymers (carboxymethylcellulose-cysteine, polycarbophil-cysteine, chitosan-thiobutylamidine, 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, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropylcellulose , 250 hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, citrate sodium, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C and xylitol. The pharmaceutical compositions / combinations may be formulated for oral administration. For oral administration, the composition will generally take the form of a tablet, capsule or soft gelatin capsule or may be an aqueous or non-aqueous solution, suspension or syrup. Tablets and capsules are typical oral administration forms. Tablets and capsules for oral use may 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 inert, pharmaceutically acceptable, non-toxic, oral carrier such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like. . In addition, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, synthetic and natural gums such as acacia, tragacanth, sodium alginate, carboxymethyl cellulose, 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, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like and with emulsifying and suspending agents. If desired, flavorings, colorings and / or sweeteners can also be added. 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 administration, the compound can be administered, as desired, for example, by the intravitreal, intrastromal, intracameral, sub-spike, sub-retinal, retrobulbar, peribulbar, suprachoroidal, conjunctival, subconjunctival, episcleral, periocular, transscleral, retrobulbar, posterior juxtascleral, circumcorneal or tear duct injections, or through a mucus, mucin or mucosal barrier, in an immediate or controlled release form or by an ocular device. Parenteral formulations can be prepared in conventional ways, either as Μλ / a / zuzz / uu / oo» 251 liquid solutions or suspensions, solid forms suitable for solubilization or suspension in liquid before 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 may also be a sterile injectable solution or suspension in a parenterally acceptable non-toxic diluent or solvent. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. Furthermore, sterile fixed oils, fatty esters or polyols are conventionally used as solvents or suspending media. Additionally, parenteral administration may involve the use of a slow release or sustained release system so that a constant dosage level is maintained. Parenteral administration includes intra-articular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, and includes sterile isotonic aqueous and non-aqueous injection solutions, which may contain antioxidants, pH regulators, bacteriostats, and solutes that make the formulation isotonic. with the blood of the desired subject, and sterile aqueous and non-aqueous suspensions that may include suspending agents, solubilizers, thickening agents, stabilizers and preservatives. Administration through certain parenteral routes may involve the introduction of the formulations of the disclosure into the body of a patient through a needle or catheter, propelled by a sterile syringe or some other mechanical device, such as an infusion system. keep going. A formulation provided by the description can be administered using a syringe, an injector, a pump, or any other device recognized in the art for parenteral administration. Preparations according to the description 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 corn oil, gelatin, and injectable organic asters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preservatives, humectants, emulsifiers and dispensing agents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, 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 description in the required amount in the appropriate solvent with various of the other ingredients listed above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various active and sterilized ingredients into a sterile vehicle containing a basic dispersion medium and the other ingredients required from those. 252 listed above. In the case of sterile powders for the preparation of sterile injectable solutions, typical methods of preparation are vacuum drying or freeze drying techniques that produce a powder of the active ingredient plus any additional desired ingredient from a sterile previously filtered solution thereof. . Thus, for example, a parenteral composition suitable for injection is prepared by stirring 1.5% by weight of the active ingredient in 10% by volume of propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized. Alternatively, the pharmaceutical compositions of the description may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritant excipient which is solid at room temperature, but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. The pharmaceutical compositions of the disclosure may also be administered by nasal spray or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption promoters to improve bioavailability, propellants such as fluorocarbons or nitrogen, and / or other conventional solubilizing or dispersing agents. Formulations for buccal administration include tablets, troches, gels and the like. Alternatively, buccal administration can be carried out using a transmucosal delivery system as is known to those skilled in the art. The compounds of the invention can also be administered through the skin or mucosal tissue using conventional transdermal drug delivery systems, that is, transdermal patches in which the agent is typically contained within a laminated structure that serves as a drug delivery device that is attached to the surface of the body. In such a structure, the drug composition is typically contained in a layer or reservoir, underlying a top backing layer. The laminated device may contain a single reservoir or may contain multiple reservoirs. In certain embodiments, the reservoir comprises a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to secure the system to the skin during drug administration. 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 the skin contact adhesive are present as separate and distinct layers, with the adhesive beneath the reservoir which, in this case, may be a polymeric matrix as described above, or may be a liquid or gel reservoir, or may take some other form. The backing layer in these laminates, which serves ΜΛ / a / ZUZZ / UU z 00» 253 as the top surface of the device, functions as the primary structural element of the laminate structure and provides the device with much of its flexibility. The material selected for the backing layer must be substantially impermeable to the active agent and any other materials that are present. The compositions of the disclosure may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration. The compound, for example, may generally have a small particle size, for example on the order of 5 microns or less. Said particle size can be obtained by means known in the art, for example, by means of micronization. The active ingredient is provided in a pressurized container with a suitable propellant such as chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. The aerosol may also conveniently contain a surfactant such as lecithin. The dose of the drug can be controlled by means of a metered valve. Alternatively, the active ingredients may be provided in a form of a dry powder, for example, a powder mixture of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP). The powdered carrier will form a gel in the nasal cavity. The powder composition may be presented in a unit dosage form for example in capsules or cartridges of, for example, gelatin or blister packs from which the powder may be administered by means of an inhaler. Formulations suitable for rectal administration are typically presented as unit dose suppositories. These can be prepared by mixing the active compound with one or more conventional solid carriers, for example cocoa butter, and then shaping the resulting mixture. In certain embodiments, the...

Claims

1. A compound of formula (I), characterized in that A is selected from ring systems AF and AG; A1 is selected from i) -NH-, and i) -O-; A2 is selected from i) -N-, and i) -CR52-; A3 is selected from i) -N-, and i) -CR53-; A4 is selected from i) -N-, and i) -CR54-; A5 is selected from i) -N-, and i) -CR55-; R1 is selected from i) H, i) halogen, i) alkyl of C1 and; R52 is selected from i) H, i) halogen, i) cyano, iv) Ci-6 alkoxy, v) halo-Ci-6-alkoxy, vi) Ci-6 alkyl, vii) halo-Ci-6-alkyl, viii) C3-8 cycloalkyl, and viii) halo-C3-8-cycloalkyl; R53, R54 and R55 are independently selected from i) H, i) halogen, i) C1-6 alkyl, iv) halo-Ci-6-alkyl, v) C3-8 cycloalkyl, and viii) halo-C3-8-cycloalkyl; R2 is selected from i) H, ii) halogen, iii) C1-6 alkyl, iv) halo-C1-6-alkyl, v) C3-8 cycloalkyl, and vi) halo-C3-8-cycloalkyl;R3 is selected from i) H, ii) halogen, iii) C1-6 alkyl, iv) halo-C1-6 alkyl, v) C3-8 cycloalkyl, and vi) halo-C3-8 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) C1-6 alkoxy, v) halo-C1-6 alkoxy, vi) C1-6 alkyl, vii) halo-C1-6 alkyl, viii) C3-8 cycloalkyl, and viii) halo-C3-8 cycloalkyl; R7 is selected from i) H, i) halogen, iii) cyano, iv) C1-6 alkyl, v) halo-C1-6-alkyl, vi) C3-8 cycloalkyl, and vii) halo-C3-s-cycloalkyl; R70 is selected from i) H, i) halogen, iii) cyano, iv) C1-6 alkyl, v) halo-C1-6-alkyl, vi) C3-8 cycloalkyl, and vii) halo-C3-8-cycloalkyl; R8 is H; R9 is selected from i) H, and i) C1-6 alkyl; Y1 is selected from i) -N-, and i) -CH-; Y2 is selected from i) -N-, and i) -CR16-; R12, R13, R14 and R15 are 5 independently selected from i) -H-, i) halogen, i) hydroxy-Ci-6-alkyl;R16 is selected from i) -H-, i) hydroxy, i) fluoro; L3 is absent or selected from i) -(CH2)mC(O)-, i) -C(O)-(CH2)P-, i) -C(O)-C(O)-, iv) -NR10-C(O)-, v) -C(O)-NR10-, vi) -C(O)O-, vii) -CH2-CF2-CH2-, viii) -CH2-, N=N m is 0, 1 or 2; p is 0, 1, 2 or 3; R10 is selected from i) H, and i) alkyl of Ci-e; D is selected from 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 with one to three substituents selected from R80, R81, and R82; R80, R81, and R82 are independently selected from i) halogen, i) cyano, ii) hydroxy, iv) hydroxy-Ci-β alkyl, v) Ci-6 alkoxy, vi) halo-Ci-6-alkoxy, vii) Ci-β alkyl, viii) halo-Ci-6-alkyl, ix) C3-8 cycloalkyl, and x) halo-C3-8 cycloalkyl; L4 is absent or selected from i) -NRn-C(O)-, i) -CH2-, and iii) -O-; E is selected from the ring systems Y, Z, AA, AB and AC; AA HA N=N AA AC ; B is selected from the ring system AD and AE;882 AD AE or a pharmaceutically acceptable salt thereof.; 2. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to claim 1, further characterized in that A is selected from ring systems AF and AG; A1 is selected from i) -NH-, and i) -O-; A2 is selected from i) -N-, and i) -CH-; R1 is selected from i) H, and i) halogen; R2 is H; R3 is selected from i) H, and i) halogen; R4 is H, R5 is H; or R4 and R5 together form -(CH2)n-; n is I; R6 is selected from i) H, i) halogen, i) cyano, and iv) halo-Ci-6-alkyl; R7 is H; R8 is H; R9 is Ci alkyl; C is absent or the ring system F; Y1 is selected from i) -N-, and i) -CH-; Y2 is selected from i) -N-, and i) -CR16-; R12, R13, R14, and R15 are selected independently from i) H, and i) halogen; R16 is selected from i) H, and i) hydroxy; L3 is selected from i) -(CH2)mC(O)-, i) -C(O)-(CH2)P-, iii) -C(O)-C(O)-, and iv) -NR10-C(O)-; m is 1; p is 1 or 883 3; R10 is selected from i) H, and ii) alkyl of Ci-&;D is selected from ring systems I, J, K, L and M; IVIA / a / ZUZZ / UU / 00» L4 is selected from i) -NRn-C(O)-, i) -CH2-, and iii) -O-; E is selected from ring systems Y, Z and AA, AB and AC; 10 or a pharmaceutically acceptable salt thereof. 884; 3. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, further characterized in that A is selected from ring systems AF and AG; AF AG 5 A1 is selected from i) -NH-, and i) -O-; A2 is selected from i) -N-, and i) -CH-; R1 is selected from i) H, and i) fluoro; R2 is H; R3 is selected from i) H, and i) fluoro; R4 is H, R5 is H; or R4 and R5 together form (CH2)q-; q is I; R6 is selected from i) H, i) fluoro; iii) cyano, iv) difluoromethyl, and v) trifluoromethyl; R7 is H; R8 is H; R9 is methyl; 10 C is ring system F; F Y1 is selected from i) -N-, and i) -CH-; Y2 is selected from i) -N-, and i) -CR16-; R12 and R13 are fluoro; R14 and R15 are H; R16 is selected from i) H, and i) hydroxy; L3 is selected from i) -(CH2)mC(O)-, i) -C(O)-(CH2)P-, iii) -C(O)-C(O)-, and iv) -NR10-C(O)-; m is 1; p is 1 or 3; R10 is H; D is selected from ring systems I, J, K, L and M;885 L4 is selected from i) -NRn-C(O)-, ii) -CH2-, and iii) -O-; E is selected from the ring systems Y, Z, AA, AB and AC; N=NYZ AA AB AC 5 L5 is ' ; B is selected from the ring system AD and AE; AD AE or a pharmaceutically acceptable salt thereof.; 4. The compound of formula I, or a pharmaceutically acceptable salt thereof, in accordance with any of claims 1 to 3, further characterized in that A 886 is the AF ring system.

5. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4, further characterized in that A1 is -N-.

6. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 5, further characterized in that A2 is -CH-.

7. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 6, further characterized in that R1 is selected from i) H, and i) halogen.

8. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7, further characterized in that R1 is selected from i) H, and i) fluoro.

9. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 8, further characterized in that R1 is fluoro.

10. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 9, further characterized in that R2 is H.

11. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 10, further characterized in that R3 is selected from i) H, and i) halogen.

12. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 11, further characterized in that R3 is selected from i) H, and i) fluoro.

13. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 12, further characterized in that R4 is H.

14. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 13, further characterized in that R5 is H.

15. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any of claims 1 to 14, further characterized in that R6 is selected from i) H, i) halogen, i) cyano, and iv) halo-Ci-e-alkyl.

16. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 15, further characterized in that R7 is H.

17. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 16, further characterized in that R8 is H.

18. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any of claims 1 to 17, further characterized in that R9 is an alkyl of Ci-6.

19. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 18, further characterized in that R9 is methyl.

20. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 19, further characterized in that n is 1.

21. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 20, further characterized in that C is absent or the ring system F is missing.

22. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 21, further characterized in that C is the ring system F.

23. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 22, further characterized in that R12 and R13 are fluoro.

24. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 23, further characterized in that r14 and ris are h 25. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any of claims 1 to 24, further characterized in that R16 is selected from i) H, and i) hydroxy.

26. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 25, further characterized in that R16 is H.

27. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 26, further characterized in that L3 is selected from i) -(CH2)mC(O)-, i) -C(O)-(CH2)P-, ii) -C(O)-C(O)-, and iv) -NR10-C(O)-. 888 28. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 27, further characterized in that m is 1.

29. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 28, further characterized in that p is 1 or 3.

30. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any of claims 1 to 29, further characterized in that R10 is selected from i) H, and ii) Ci-6 alkyl.

31. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 30, further characterized in that D is selected from the ring systems I, J, K, L and M.

32. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 31, further characterized in that L4 is selected from i) -NRn-C(O)-, ii) -CH?-, and iii) -O-.

33. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any of claims 1 to 32, further characterized in that L4 is .

34. The compound of Formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 33, further characterized because it is selected from the group consisting of 5-((2-(1-(6,7-dihydro-5H-p¡rrolo[l,2-c]im¡dazol-l-¡l)-2-oxo-2(thiazol-2-lam¡no)et¡l)-7-fluoro-3-oxo¡so¡ndolin-5 -¡l)et¡n¡l)-N-(l-(2-(4-(4-((2,6-d¡oxop¡per¡d¡n-3yl)am¡no)phen¡l)p¡pend¡nl-yl)acetyl)p¡per¡d¡n-4-yl)nam¡picolda; 5-[2-[2-[l-(6,7-dihydro-5H-p¡rrolo[l,2c]imidazol-l-yl)-2-oxo-2-(thiazol-2-¡lamino)ethyl]-7-fluoro-3-oxo-isoi ndolin-5-¡l]eth¡nyl]-N-[l-[2-[4-[(2,6d¡oxo-3-p¡pend¡l)am¡no]phen¡l]acet¡l]-4-p¡per¡d¡l]p¡r¡d¡n-2-carboxamide; 5-[2-[2-[l-(6,7-dihydro-5Hp¡rrol[l,2-c]¡m¡dazol-l-¡l)-2-oxo-2-(t¡azol-2-ylamino)et¡l]-7-fluoro-3-oxo-¡so¡ndol-5 -yl]ethin¡l]-N-[l-[2[4-[4-[(2,6-d¡oxo-3-p¡per¡dyl)ox¡]phen¡l]piperaz¡nl-¡l]acet¡l]-4-p¡per¡d¡l]pyr¡din-2-carboxam¡da;5-[2-[2[l-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-2-oxo-2-(t¡azol-2-¡lam¡no)et¡l]-7-fluoro-3-oxo-¡so¡ndol¡n5-¡l]et¡n ¡l]-N-[l-[2-[4-[4-[[(3S)-2,6-d¡oxo-3-p¡per¡d¡l]am¡no]-2-fluoro-fenil]-lp¡per¡d¡l]acet¡l]-4p¡per¡dil]p¡r¡d¡n-2-carboxam¡da; 2-(6,7-dihidro-5H-pirrolo[l,2-c]imidazol-l-il)-2-[6-[4-[4-[2-[4-[4[(2,6-d¡oxo-3-p¡pend¡l)am¡no¡l]-lp¡pend¡l]acet¡l]p¡perazin-l-¡l]fen¡l]-4-fluoro-l-oxo-¡so¡ndol¡n-2¡l]-N-tiazol-2-il-acetamida; 2-(6,7-dihydro-5H-pirrolo[l,2-c]imidazol-l-¡l)-2-[6-[4-[4-[2-[4-[4-[[(3S)2,6-dioxo-3-piperidil]am¡no]fen¡l]-l-piperidil]acet¡l]p¡perazin-l-¡l]fenil]-4-fluoro-l-oxo-isoindolin-2-¡l]N-tiazol-2-il-acetamida; 2-(6,7-d¡h¡dro-5H-p¡nOlo[l,2-c]¡m¡dazol-l-¡l)-2-[6-[4-[4-[2-[4-[4-[[(3S)-2,6dioxo-3-p¡per¡d¡l]am¡no]fen¡l]-lp¡perid¡l]acetil]p¡peraz¡nl-¡l]fen¡l]-4-fluoro-l-oxo-¡so¡ndol¡n-2-il]-N 889 tiazol-2-il-acetamida;2-(6,7-dih¡dro-5H-pyrrolo[l,2-c]¡m¡dazol-l-yl)-2-(6-(4-(4-(4-(4-(4-((2,6d¡oxop¡per¡d¡n-3-l)amino)phen¡l )p¡per¡d¡nl-4-oxobut¡l)p¡perazin-l-yl)phen¡l)-4-fluoro-l-oxo¡soindolin2-¡l)-N-(thiazol-2-¡l)acetam¡da; 2-(6z7-d¡h¡drO-5H-pyrrole[lz2-c]¡m¡dazol-l-¡l)-2-(6-(4-(4-(2-(4-(4-((2,6d¡oxop¡pendin-3-¡l)amino)f en¡l)c¡chlohex¡l)acetyl)p¡peraz¡nl-yl)phenyl)-4-fluoro-l-oxoiso¡ndol¡n-2-yl)-N(thiazol-2-yl)acetamide; 2-(6z7-d¡h¡dro-5H-p¡rrol[lz2-c]¡m¡dazol-l-¡l)-2-(6-(4-(4-(2-(4-(4-((2,6d¡oxopiperid¡n-3-¡l)am¡no)phen¡¡ l)p¡per¡d¡nl-¡l)-2-oxoet¡l)piperaz¡nl-¡l)phen¡l)-4-fluoro-l-oxo¡so¡ndol¡n-2yl)-N-(thiazol-2-yl)acetamide; 2-(6z7-d¡h¡dro-5H-pyrrolo[lz2-c]¡m¡dazol-l-yl)-2-[6-[4-[4-[2-[4-[5-[(2z6dioxo-3-piperid¡l)am¡no]-2-pi ridyl]-lp¡per¡d¡l]acetyl]piperazine-l-¡l]phenyl]-4-fluoro-l-oxo-¡so¡ndolin-2-yl]N-thiazol-2-yl-acetamide;2-(6,7-dihydro-5H-p¡nOlo[lz2-c]imidazol-l-¡l)-2-[6-[4-[4-[2-[4-[4-[(2z6-d¡oxo3-p¡per¡d¡l)am¡no]-2-fluoro-fen¡l]-lp¡per¡dil]acet¡l]p¡peraz¡nl-¡l]fen¡l]-4-fluoro-l-oxo-¡so¡ndolin-2-¡l]N-tiazol-2-il-acetamida; 2-(6z7-d¡hidrO-5H-p¡rrOlo[lz2-c]¡midazol-l-¡l)-2-[6-[4-[4-[2-[4-[4-[2,6-d¡oxo3-piperidil)am¡no]-3-fluoro-fenil]-l-piper¡d¡l]acetil]piperazin-l-¡l]fen¡l]-4-fluoro-l-oxo-¡so¡ndolin-2-il]N-tiazol-2-il-acetamida; 2-[6-[4-[4-[2-[4-[2-cyano-4-[(2z6-dioxo-3-piper¡d¡l)am¡no]fenil]-lpiperidil]acet¡l]p¡perazin-l-il]fen¡l ]-4-fluoro-l-oxo-iso¡ndol¡n-2-il]-2-(6z7-dihidro-5H-p¡rrolo[lz2c]im¡dazol-l-il)-N-tiazol-2-il-acetamida; 2-[6-[4-[4-[2-[4-[2-(difluorometil)-4-[(2,6-dioxo-3piperidil)amino]fenil]-l-piperidil]acetil]piperazin-l-il]fenil]-4-fluoro-l-oxo-isoindolin-2-il]-2-(6,7dihydro-5H-pirrolo[lz2-c]imdazol-l-il)-Ntazol-2-il-acetamida;2-(6,7-d¡hidro-5H-pirrolo[l,2c]¡m¡dazol-l-¡l)-2-(6-(4-(4-(2-(4-(3-((2z6-d¡oxop¡per¡d¡n-3-¡l)am¡no)fen ¡l)p¡per¡d¡nl-¡l)acetil)p¡peraz¡nl-il)fenil)-4-fluoro-l-oxoisoindolin-2-¡l)-N-(t¡azol-2-il)acetam¡da; 2-(6,7-dihydro-5H-pirrolo[l,2c]imidazol-l-l)-2-(6-(4-(4-(2-(4-(3-(2,4-doxotetrahidroprmdnl(2H)-il)-l-metl-lH-ndazol-6il)piperidin-l-il)acetil)pperaznl-il)fenil)-4-fluoro-l-oxoisoindolin-2-il)-N-(tiazol-2-il)acetamida; 2(6z7-d¡h¡dro-5H-p¡rrolo[lz2-c]¡m¡dazol-l-¡l)-2-(6-(4-(4-(2-(l-(4-((2z6-d¡oxop¡per¡d¡n-3-¡l)am¡no)-2(trifluorometil)fenil)-4-h¡droxipiperidin-4-il)acetil)piperazin-l-il)fenil)-4-fluoro-l-oxoisoindolin-2-il)-N(tiazol-2-il)acetam¡da; 2-(6z7-dihydro-5H-pirrolo[l,2-c]mdazol-l-il)-2-(6-(4-(4-(2-(4-(4-((2z6dioxopiperid-n-3-l)amino)fenil)pperdnl-l)acetil)piperazin-l-il)fenl)-4-fluoro-l-oxosondolin-2-il)N-(piridin-2-il)acetamide;2-(6z7-dihydro-5H-p¡rrolo[lz2-c]imidazol-l-yl)-2-[6-[4-[4-[2-[4-[4-[(2z6d¡oxo-3-p¡pendil)am¡no]-2-fluorine o-phen¡l]-lp¡per¡d¡l]acet¡l]p¡perazin-l-¡l]phen¡l]-4-fluoro-l-oxo-¡so¡ndol¡n¡n2-¡l]-N-(2-pyr¡d¡d¡l)acetam¡da; 2-(6z7-d¡hydro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-yl)-2-(6-(4-(l-(2-(4-(4-((2z6d¡oxop¡per¡d¡n-3-l)amino)phen l)p¡per¡d¡nl-¡l)acetate¡l)p¡per¡d¡n-4-¡l)phen¡l)-4-fluoro-l-oxo¡so¡ndolin-2-¡l)-N(thiazol-2-yl)acetamide; 2-(6z7-d¡h¡drO-5H-p¡rrolo[lz2-c]¡m¡dazol-l-¡l)-2-(6-(4-(l-(2-(4-(4-(((S)-2z6dioxopiper¡din-3-yl)amino)f en¡I)piperidin-l-yl)acetyl)piperidin-4-yl)phenyl)-4-fluoro-l-oxoisoindolin-2-yl)-N(thiazol-2-yl)acetamide; 2-(6,7-d¡h¡dro-5H-p¡rrOlo[lz2-c]¡m¡dazol-l-¡l)-2-(6-(4-(l-(2-(4-(4-(((R)-2z6dioxop¡pendin-3-yl)amino)fe nil)piperidine-l-yl)acetyl)piperidine-4-yl)phenyl)-4-fluoro-l-oxoindole-2-l)-N(thiazol-2-l)acetaminophen;2-(6z7-d¡h¡dro-5H-p¡rrolo[lz2-c]im¡dazol-l-¡l)-2-(6-(4-(l-(2-(4-(4-(((S)-2z6d¡oxop¡per¡d¡n-3-¡l)amino)-2-fluorofen¡l)p¡peridin-l-¡l)acet¡l)p¡per¡d¡n-4-¡l)fenil)-4-fluoro-l 890 oxoisoindol¡n-2-il)-N-(tiazol-2-il)acetann¡da; 2-(6-(4-(l-(2-(4-(2-cyano-4-((2,6-d¡oxopiperidin-3il)amino)fenil)piper¡d¡nl-il)acetil)piper¡d¡n-4-il)feni l)-4-fluoro-l-oxo¡soindolin-2-¡l)-2-(6,7-d¡hidro-5Hp¡rrolo[l,2-c]¡m¡dazol-l-il)-N-(t¡azol-2-¡l)acetam¡da; 2-(6z7-d¡hidro-5H-p¡rrolo[lz2-c]¡m¡dazol-l-il)-2[6-[4-[l-[2-[4-[4-[(2z6-dioxo-3-piperidil)amino]fenil]-l-piperidil]-2-oxo-etil]-4-piperidil]fenil]-4-fluorol-oxo-¡so¡ndol¡n-2-il]-N-tiazol-2-¡l-acetam¡da; 2-(6z7-d¡h¡dro-5H-p¡rrolo[lz2-c]¡m¡dazol-l-¡l)-2-[6-[6-[4[2-[4-[4-[[(3S)-2z6-d¡oxo-3-p¡peridil]am¡no]-2-fluoro-fenil]-lp¡perid¡l]acet¡l]p¡peraz¡nl-¡l]-3-p¡r¡d¡l]4-fluoro-l-oxo-¡soindolin-2-il]-N-tiazol-2-¡l-acetamida;2-(6z7-d¡h¡dro-5H-pirrolo[lz2-c]¡m¡dazol-l-il)-2[6-[l-[l-[2¿4-[4-[[(3S)-2z6-dioxo-3-p¡per¡d¡l]amino]fen¡l]-lp¡per¡d¡l]acetil]-4-p¡per¡d¡l]p¡razol-4-]-4fluoro-l-oxo-isoindolin-2-¡l]-N-tiazol-2-il-acetam¡da; 2-(6z7-dihidro-5H-pirrolo[lz2-c]imidazol-l-il)-2[6-[4-[l-[2-[4-[4-[[(3S)-2z6-dioxo-3-piperidil]amino]fenil]-l-piperidil]acetil]-4-piperidil]pirazol-l-il]-4fluoro-l-oxo-iso¡ndol¡n-2-¡l]-Nt¡azol-2-¡l-acetamida; 2-(6z7-dihidro-5H-pirrolo[l,2-c]imidazol-l-il)-2[6-[4-[l-[2-[4-[4-[[(3S)-2z6-dioxo-3-p¡pend¡l]am¡no]fen¡l]-lp¡per¡dil]acet¡l]-4-p¡per¡d¡l]p¡razol-l-¡l]-4fluoro-l-oxo-iso¡ndol¡n-2-il]-N-tiazol-2-¡l-acetamida; 2-(6,7-d¡h¡dro-5H-pirrolo[l,2-c]¡nn¡dazol-l-il)-2[6-[4-[[l-[2-[4-[4-[(2z6-dioxo-3-p¡per¡d¡l)am¡no]fenil]-lp¡per¡d¡l]acetil]-4-piper¡d¡l]ox¡]fen¡l]-4-fluorol-oxo-isoindolin-2-il]-Nt¡azol-2-il-acetamida;2-(6,7-dihidro-5H-pirrolo[lz2-c]imidazol·l-il)-2-[6-[4[[l-[2-[4-[4-[[(3S)-2z6-d¡oxo-3-p¡per¡d¡l]am¡no]f en¡l]-lp¡per¡d¡l]acetil]-4-p¡per¡d¡l]ox¡]fen¡l]-4-fluorol-oxo-¡so¡ndolin-2-il]-N-tiazol-2-¡l-acetam¡da; 2-(6z7-d¡hidro-5H-pirrolo[l,2-c]¡midazol-l-il)-2-[6-[4[[l-[2-[4-[4-[[(3R)-2z6-d¡oxo-3-pipend¡l]am¡no]fe n¡l]-l-piper¡d¡l]acet¡l]-4-p¡peridil]oxi]fen¡l]-4-fluorol-oxo-iso¡ndol¡n-2-il]-N-tiazol-2-¡l-acetam¡da; 2-(6z7-dihydro-5H-pirrolo[l,2-c]imdazol-l-il)-2-(6-(4((l-(2-(4-(4-((2z6-dioxopiperid n-3-l)amno)-3-fluorofenl)pperd nl-il)acetil)pperd n-4-l)oxi)fenil)4-fluoro-l-oxoisoindolin-2-il)-N-(tiazol-2-il)acetamida; 2-(6z7-dihidro-5H-pirrolo[lz2-c]imidazol-l-il)-2(6-(4-((l-(2-(4-(4-((2z6-d¡oxop¡pend¡n-3-¡l)amino)-2-fluorofen¡l)p¡perid¡nl-¡l)acetil)p¡per¡d¡n-4¡l)ox¡)fenil)-4-fluoro-l-oxo¡so¡ndol¡n-2-il)-N-(t¡azol-2-¡l)acetamida;2-(6z7-d¡hidro-5H-pirrolo[l,2c]imidazol-l-¡l)-2-(6-(4-((l-(2-(4-(5-((2z6-d¡oxopiperidin-3-¡l)am¡no)pihdin-2-il)pipehdin-lil)acetil)piperid¡n-4-¡l)ox¡)fenil)-4-fluoro-l-oxoisoindol¡n-2-il)-N-(t¡azol-2-il)acetam¡da; 2-(6-(4-((1-(2(4-(2-cyano-4-((2z6-dioxop¡per¡din-3-il)amino)fen¡l)p¡perid¡nl-il)acetil)p¡pendin-4-il)oxi)fe nil)-4fluoro-l-oxo¡soindol¡n-2-il)-2-(6z7-d¡h¡dro-5H-pirrolo[lz2-c]¡midazol-l-¡l)-N-(t¡azol-2-il)acetamida; 2(6z7-d¡h¡dro-5H-p¡rrolo[lz2-c]im¡dazol-l-¡l)-2-(6-(4-((l-(2-(4-(4-((2z4-d¡oxo-3azabiciclo[3.

1. l]heptan-l-¡l)am¡no)fen¡l)p¡perid¡nl-¡l)acet¡l)p¡per¡d¡n-4-¡l)ox¡)fen¡l)-4-fluoro-loxo¡so¡ndol¡n-2-il)-N-(t¡azol-2-¡l)acetam¡da; 2-(6,7-d¡hidro-5H-p¡rrolo[lz2-c]im¡dazol-l-¡l)-2-(6-(4-((l(2-(4-(4-((S)-2z6-dioxopiper¡d¡n-3-¡l)am¡no)-2-fluo rofen¡l)p¡per¡d¡nl-il)acetil)p¡per¡d¡n-4-¡l)oxi)fen¡l)4-fluoro-l-oxoisoindolin-2-il)-N-(t¡azol-2-¡l)acetamida;2-(6,7-d¡h¡dro-5H-pirrolo[lz2-c]¡midazol-l-il)-2[6-[4-[[l-[2-[4-[4-[(2z6-dioxo-3-piperidil)amino]fenil]-l-pipendil]-2-oxo-acetil]-4-pipendil]oxi]fenil]-4fluoro-l-oxo-¡sondol¡n-2-il]-N-tiazol-2-¡l-acetamida; 2-(6z7-d¡h¡dro-5H-p¡rrolo[lz2-c]im¡dazol-l-il)-2[6-[4-[(3R)-l-[2-[4-[4-[[(3S)-2z6-d¡oxo-3-p¡per¡dil]am¡no]fen¡l]-lp¡per¡d¡l]acet¡l]p¡rrol¡d¡n-3 ΜΛ / a / ZUZZ / UU / 00» 891 il]oxifenil]-4-fluoro- l-oxo-isoindol¡n-2-¡l]-Nt¡azol-2-il-acetam¡da; 2-(6,7-dihidro-5H-pirrolo[l,2c]¡m¡dazol-l-¡l)-2-[6-[4-[(3R)-l-[2-[4-[4-[[(3S)-2,6-d¡oxo-3-p¡per¡d¡l]am¡no] fen¡l]-lp¡per¡d¡l]acet¡l]p¡rrol¡d¡n-3-¡l]ox¡fen¡l]-4-fluoro-l-oxo-¡so¡ndol¡n-2-¡l]-Nt¡azol-2-il-acetamida; 2-(6-(4(4-(2-(4-(4-((2,6-d¡oxop¡per¡din-3-¡l)am¡no)fenil)p¡per¡d¡nl-il)acet¡l)piperaz¡nl-il)fen¡l)-4-fluoro -loxo¡soindol¡n-2-¡l)-2-((R)-6-fluoro-6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-il)-N-(t¡azol-2-¡l)acetam¡da;2-[6-[4-[2-[4-[4-[[(3S)-2,6-d¡oxo-3-p¡pendil]amino]-2-fluoro-fen¡l]-l-piperidil]acetil]p¡perazin-lil]fenil]-4-fluoro-l-oxo-isoindolin-2-¡l]-2-[(6R)-6-fluoro-6,7-d¡hidro-5H-pirrolo[l,2-c]¡m¡dazol-l-il]-Ntiazol-2-il-acetamida; 2-[6-[4-[4-[2-[4-[3-(2,4-dioxohexah¡drOp¡r¡midin-l-¡l)-l-met¡l-¡ndazol-6-il]-lpiperidil]acetil]piperazin-l-il]fenil] -4-fluoro-l-oxo-isoindolin-2-il]-2-[(6R)-6-fIuoro-6,7-dihidro-5Hp¡rrolo[l,2-c]¡m¡dazol-l-¡l]-Nt¡azol-2-¡l-acetamida; 2-(6,7-d¡h¡dro-5H-pirrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6(4-(2-(2-(4-(4-(((S)-2,6-d¡oxop¡per¡d¡n-3-¡l)amino)-2-fluorofen¡l)p¡peridin-l-¡l)acetil)-2,7diazaspiro[3.5]nonan-7-il)fenil)-4-fluoro-l-oxoisoindolin-2-il)-N-(t¡azol-2-il)acetam¡da; 2-(6,7-dihidro5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-2-[6-[4-[2-[2-[4-[4-[2,6-d¡oxo-3-piper¡d¡l)am¡no]fen¡l]-lpiperidil]acetil]-2,6-diazaspiro[3.3]heptan-6-¡l]fenil]-4-fluoro-l-oxo-¡soindolin-2-il]-Nt¡azol-2-ilacetamida;2-(6,7-d¡h¡drO-5H-pyrrolo[l,2-c]im¡dazol-l-yl)-2-[6-[4-[2-[2-[4-[4-[[(3S)-2,6-d¡oxo-3p¡per¡d¡l]am¡no]-fluoro-2-phen l]-lp¡per¡d¡l]acetyl]-2,6-d¡azaspiro[3.3]heptane-6-¡l]phen¡l]-4-fluoro-l-oxoiso¡ndol¡n-2-yl]-Nt¡azol-2-¡l-acetamide; 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[4-[2-[2-[4[3-(2,4-dioxohexah¡drop¡r¡m¡din-l-yl)-l-met¡l-¡ndazol- 6-yl]-lp¡per¡dyl]acet¡l]-2,6d¡azasp¡ro[3.3]heptane-6-yl]phenyl]-4-fluoro-l-oxo-¡so¡ndol¡n-2-¡l]-Nt¡azol-2-¡l-acetam¡da; 2-(6,7-dihydro5H-pyrrolo[l,2-c]¡m¡dazol-l-yl)-2-[6-[4-[2-[2-[4-[3-(2,4-d¡oxohexahydropyrimide¡nl-¡l)-l-met¡l-indazol6-yl-3,] 3-difluoro-l-piperidyl]acetyl]-2,6-diazaspiro[3.3]heptane-6-yl]phen¡l]-4-fluoro-l-oxo-isoindoline-2-yl]N-thiazol-2-yl-acetamide; 2-(6,7-d¡h¡dro-5H-pyrrolo[l,2-c]¡m¡dazol-l-yl)-2-(6-(4-(6-(2-(4-(4-((2,6d¡oxop¡per¡din-3-¡l)amino)phenyl)-3,3-difluoro opiper¡d¡nl-¡l)acetyl)-2,6-diazasp¡ro[3.3]heptan-2-yl)phen¡l)4-fluoro-l-oxoisoindolin-2-yl)-N-(thiazol-2-¡l)acetamide;2-(6,7-dihydro-5H-pirrolo[l,2-c]imdazol-l-il)-2[6-[4-[2-[2-[4-[4-[[(3S)-2,6-dioxo-3-p¡pendil]am¡no]-2-fluoro-fen¡l]-lp¡per¡d¡l]acet¡l]-2,6diazasp¡ro[3.3]heptan-6-il]fenil]-4-fluoro-l-oxo-isoindol¡n-2-¡l]-N-(2-piridil)acetam¡da; 2-(6,7-dihydro5H-pirrolo[l,2-c]imidazol-l-il)-2-[6-[4-[2-[2-[4-[3-(2,4-d¡oxohexahidropir¡m¡d¡nl-¡l)-l-metil-¡ndazol6-¡l]-lp¡peridil]acetil]-2,6-d¡azaspiro[3.3]heptan-6-¡l]fen¡l]-4-fluoro-l-oxo-isoindolin-2-¡l]-N-(2pir¡d¡l)acetam¡da; 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-2-[6-[4-[2-[2-[4-[3-(2,4dioxohexah¡drop¡r¡m¡din-l-¡l)-l-met¡l-¡ndazol-6-il]-3,3-d¡fluoro-lp¡peridil]acet¡l]-2,6diazaspiro[3.3]heptan-6-il]fenil]-4-fluoro-l-oxo-¡ndol¡n-2-¡l]-N-(2-pir¡d¡l)acetam¡da; 2-(6,7-dihydro5H-pirrolo[l,2-c]imidazol-l-il)-2-[6-[4-[4-[2-[4-[4-[(2,6-dioxo-3-piperid¡l)amino]fenil]-lpiperid¡l]acet¡l]p¡perazin-l-il]metil]fen¡l]-4-fluoro-l-oxo-¡ndol¡n-2-¡l]-Nt¡azol-2-¡l-acetam¡da;2-(6,7dihidro-5H-pirrolo[l,2-c]¡m¡dazol-l-¡l)-2-[6-[4-[[4-[2-[4-[4-[(2,6-d¡oxo-3-piperid¡l)amino]-2-fl uorofenil]-lp¡per¡d¡l]acet¡l]p¡peraz¡nl-¡l]met¡l]fenil]-4-fluoro-l-oxo-¡so¡ndol¡n-2-il]-Nt¡azol-2-¡l892 acetamida; 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡midazol-l-¡l)-2-[6-[4-[[4-[2-[4-[4-[[(3S)-2,6-d¡oxo-3p¡per¡d¡l]am¡no]-2-fluo ro-fen¡l]-lp¡per¡d¡l]acet¡l]piperaz¡nl-¡l]met¡l]fen¡l]-4-fluoro-l-oxo-¡so¡ndol¡n-2¡l]-Nt¡azol-2-¡l-acetamida; 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-2-[6-[4-[[4-[2-[4-[4-[[(3S)2,6-d¡oxo-3-piper¡d¡l]am¡no]-2-fluoro- fen¡l]-l-piper¡d¡l]-2-oxo-et¡l]p¡peraz¡nl-¡l]metil]fen¡l]-4-fluoro-loxo-¡so¡ndol¡n-2-¡l]-N-tiazol-2-¡l-acetamida; 2-(6,7-dih¡dro-5H-pirrolo[l,2-c]¡m¡dazol-l-¡l)-2-[6-[4-[[l[2-[4-[4-[[(3S)-2,6-d¡oxo-3-p¡peridil]am¡no]-2-fluo ro-fenil]-l-piper¡d¡l]acet¡l]-4-piper¡d¡l]met¡l]fen¡l]-4fluoro-l-oxo-¡so¡ndol¡n-2-il]-N-tiazol-2-¡l-acetamida; o una sal farmacéuticamente acceptable del mismo.; 35. A compound according to any of claims 1 to 34, for use as a therapeutically active substance.

36. A pharmaceutical composition comprising a compound according to any of claims 1 to 34 and a therapeutically inert carrier.

37. The use of a compound as claimed in any of claims 1 to 34 for the treatment or prophylaxis of cancer, in particular non-small cell lung cancer, more particularly EGFR-mutated non-small cell lung cancer wherein the activating mutation is L858R.

38. A compound according to any of claims 1 to 34 for the treatment or prophylaxis of cancer, in particular non-small cell lung cancer, more particularly EGFR-mutated non-small cell lung cancer wherein the activating mutation is L858R.

39. The use of a compound as claimed in any of claims 1 to 34 for the preparation of a medicament for the treatment or prophylaxis of cancer, in particular non-small cell lung cancer, more particularly EGFR-mutated non-small cell lung cancer wherein the activating mutation is L858R.

40. A method for the treatment or prophylaxis of cancer, in particular non-small cell lung cancer, more particularly EGFR-mutated non-small cell lung cancer wherein the activating mutation is L858R, wherein the method comprises administering an effective amount of a compound according to any one of claims 1 to 34.

41. A compound of formula (II), 893 IVIA / a / ZUZZ / UU 100» 5 A1 is selected from i) -NH-, and i) -O-; A2 is selected from i) -N-, and i) -CR52-; A3 is selected from i) -N-, and i) -CR53-; A4 is selected from i) -N-, and i) -CR54-; A5 is selected from i) -N-, and i) -CR55-; R1' is selected from i) H, i) halogen, iii) alkyl of Ci e; iv) cyano, v) alkoxy of Ci-6, vi) halo-Ci-6-alkoxy, vii) alkyl of Ci-6, viii) halo-Ci-6-alkyl, ix) cycloalkyl of C3-8, yx) halo-Cs-s-cycloalkyl; R52 is selected from i) H, i) halogen, iii) cyano, iv) C1-6 alkoxy, v) halo-C1-6-alkoxy, vi) C1-6 alkyl, vii) halo-C1-6 alkyl, viii) C3-8 cycloalkyl, and viii) halo-C3-s-cycloalkyl; R53, R54 and R55 are independently selected from i) H, i) halogen, iiii) C1-6 alkyl, v) halo-C1-6-alkyl, v) C3-8 cycloalkyl, and viii) halo-C3-s-cycloalkyl;R2 is selected from i) H, i) halogen, iii) cyano, iv) C1-6 alkyl, v) haloC1-6 alkyl, vi) C3-8 cycloalkyl, and vii) halo-Cs-s-cycloalkyl; R3 is selected from i) H, i) halogen, iii) C1-6 alkyl, iv) halo-C1-6 alkyl, v) C3-8 cycloalkyl, and vii) halo-Cs-s-cycloalkyl; R4 and R5 are H; either R4 and R5 together form -(CH2)q-; q is either 1 or 2; R6 is selected from i) H, ii) halogen, iii) cyano, iv) Ci-6 alkoxy, v) halo-Ci-6-alkoxy, vi) Ci-β alkyl, vii) halo-Ci-e-alkyl, viii) C3-8 cycloalkyl, and vii) halo-C3-s-cycloalkyl; R7 is selected from i) H, i) halogen, iiii) cyano, iv) C1-6 alkyl, v) halo-Ci-6-alkyl, vi) C3-8 cycloalkyl, and vii) halo-C3-8-cycloalkyl; R70 is selected from i) H, i) halogen, iii) cyano, iv) Ci-e 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 i) Ci-e alkyl; IVIA / a / ZUZZ / UU / 00» FGH Y1 is selected from i) -N-, and i) -CH-;Y2 is selected from i) -N-, and ii) -CR16-; R12, R13, R14 and R15 are independently selected from i) -H-, i) halogen, and iii) hydroxy-Ci-6-alkyl; R16 is selected from i) -H-, i) hydroxy, and iii) fluoro; L3 is either absent or selected from i) -(CH2)mC(O)-, i) -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-, ix) xi) ; m is 0, 1 or 2; p is 0, 1, 2 or 3; R10 is selected from i) H, and i) Ci-6 alkyl; D is selected from 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 with one to three substituents selected from R80, R81 and R82; 895 ML / a / ZUZZ / UU / 00» 5 R80, R81 and R82 are independently selected from i) halogen, i) cyano, i) hydroxy, iv) hydroxy-Ci-6alkyl, v) Ci-6 alkoxy, vi) halo-Ci-6-alkoxy, vii) Ci-β alkyl, viii) halo-Ci-6-alkyl, ix) C3-8 cycloalkyl, yx) halo-C3-8-cycloalkyl;L4 is absent or selected from i) -NR^-QO)-, i) -CH2-, and iii) -O-; E is selected from the Y, Z, AA, AB, and AC ring systems; N=NYZ AA AB AC 896 L5 is absent or ; B is selected from the AD and AE ring system; AD AE or a pharmaceutically acceptable salt thereof.

42. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to claim 41, further characterized in that A' is selected from ring systems AF, AG, and AH; A1 is -NH-; A2 is selected from i) -N- and i) -CH-; Rr is selected from i) H and i) halogen; R2 is selected from i) H and i) halogen; R3 is H; R4 is H; R5 is H; R6 is selected from i) H and i) halogen; R7 is H; R8 is H; R9 is a Ci e alkyl; C is ring system F; Y1 is -CH-; Y2 is -N-; R12, R13, R14, and R15 are H; L3 is selected from i) -(CH2)mC(O)-, and i) -C(O)-(CH2)P-; m is 1; p is 3; D is selected from ring systems I and J; YZ L5 is absent; or a pharmaceutically acceptable salt thereof.

43. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any of claims 41 to 42, further characterized in that A' is selected from the AG and AF ring systems.

44. The compound of formula II, or a pharmaceutically acceptable salt thereof, in accordance with any of claims 41 to 43, further characterized in that A' is the AF ring system.

45. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any of claims 41 to 44, further characterized in that A1 is -NH-.

46. ​​The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any of claims 41 to 45, further characterized in that A2 is -CH-.

47. The compound of formula II, or a pharmaceutically acceptable salt thereof, in accordance with any of claims 41 to 46, further characterized in that R1' is selected from i) H, and i) halogen.

48. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 47, further characterized in that R1' is selected from i) H, ii) chlorine, and iii) fluorine.

49. The compound of formula II, or a pharmaceutically acceptable salt thereof, in accordance with any of claims 41 to 48, further characterized in that R2 is selected from i) H, and i) halogen.

50. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 49, further characterized in that R2 is selected from i) H, ii) chlorine, and iii) fluorine.

51. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 50, further characterized in that R3 is H.

52. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 51, further characterized in that R4 is H.

53. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 52, further characterized in that R5 is H.

54. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any of claims 41 to 53, further characterized in that R6 is selected from i) H, and i) halogen.

55. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any of claims 41 to 54, further characterized in that R7 is H.

56. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 55, further characterized in that R8 is H.

57. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any of claims 41 to 56, further characterized in that R9 is an alkyl of Ci-6.

58. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any of claims 41 to 57, further characterized in that R9 is methyl.

59. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 58, further characterized in that C is the ring system F. 899 60. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any of claims 41 to 59, further characterized in that Y1 is -CH-.

61. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any of claims 41 to 60, further characterized in that Y2 is -N-.

62. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 61, further characterized in that R12, R13, R14 and R15 are H.

63. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any of claims 41 to 62, further characterized in that L3 is selected from i) -(CH2)mC(O)-, and i) -C(O)-(CH2)P-.

64. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any of claims 41 to 63, further characterized in that m is 1.

65. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any of claims 41 to 64, further characterized in that p is 3.

66. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any of claims 41 to 65, further characterized in that D is selected from the ring systems I and J.

67. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any of claims 41 to 66, further characterized in that D is selected from the ring system J.

68. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any of claims 41 to 67, further characterized in that L4 is absent.

69. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any of claims 41 to 68, further characterized in that E is selected from the Y and Z ring systems.

70. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any of claims 41 to 69, further characterized in that L5 is absent.

71. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 70, further characterized because 900 is selected from the group consisting of 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]im¡dazol-l-¡l)-2-(6-(6-(4-(4-(4((2-(2,6-d¡oxopiper¡d¡n-3-¡l)-l-oxopiper¡d¡n-3-¡l)-l-oxoiso-indole-4-l l)ox¡)p¡per¡din-l-yl)-4-oxobutyl)p¡perazine-l-¡l)p¡r¡d¡n-3¡l)-7-fluoro-2H-ndazol-2-l)-N-(t¡azol-2-l)acetaminophen; 2-(6,7-dihydro-5H-p¡rrolo[l,2-c]imidazol-l-yl)-2(6-(6-(4-(2-(4-(4-((2,6-d¡oxop¡per¡din-3-yl)am¡no)phen¡ l)p¡peridin-l-yl)acet¡l)p¡perazine-l-yl)pyrid¡n-3-¡l)-7fluoro-2H-¡ndazol-2-¡l)-N-(t¡azol-2-¡l)acetam¡da; 2-[4,7-dichloro-6-[4-[4-[2-[4-[4-[(2,6-dioxo-3p¡per¡dyl)am¡no]phen¡l]-lp¡per¡dyl]acet¡l]p¡peraz¡ nl-¡l]phen¡l]¡ndazol-2-¡l]-2-(6,7-dihydro-5H-p¡rrolo[l,2c]¡m¡dazol-l-¡l)-Nt¡azol-2-¡l-acetam¡da;2-(6,7-d¡h¡dro-5H-pirrolo[l,2-c]¡m¡dazol-l-¡l)-2-[6-[6-[4-[2-[4[4-[(2,6-d¡oxo-3-p¡per¡dil)am¡no]-2-fluoro-fenil]-l-piperidil]acet¡l]p¡perazin-l-il]-3-piridil]-4-fluoroindazol-2-il]-N-tiazol-2-il-acetamida; 2-(6,7-dihydro-5H-pirrolo[l,2-c]¡m¡dazol-l-il)-2-[6-[6-[4-[2-[4-[4[(2,6-dioxo-3-piperidil)amino]fen¡l]-l-piperidil]acetil]piperazin-l-il]-3-piridil]-4-fluoro-indazol-2-il]-Ntiazol-2-il-acetamida; 2-(6,7-d¡h¡dro-5H-p¡nOlo[l,2-c]¡midazol-l-¡l)-2-[6-[6-[4-[2-[4-[5-[(2,6-d¡oxo-3piperidil)amino]-2-piridil]-l-piperidil]acetil]piperazin-l-íl]-3-piridil]-4-fluoro-indazol-2-il]-N-tiazol-2-iIacetamida; 2-(6,7-dihydro-5H-p¡rrolo[l,2-c]¡nn¡dazol-l-¡l)-2-[6-[6-[4-[2-[4-[3-(2,4dioxohexahidropir¡nn¡din-l-il)-l-metil-indazol-6-il]-lp¡peridil]acet¡l]p¡peraz¡nl-il]-3-pirid¡l]-4-fluoroindazol-2-il]-N-tiazol-2-il-acetamida;2-(6,7-dihydro-5H-pyrrolo[l,2-c]midazol-l-yl)-2-(6-(6-(4-(2-(4-(4(((S))-2,6-dioxopiperidin-3-yl)amino)-2-fluo rophenyl)piperidin-l-yl)acetyl)piperazin-l-yl)pyridin-3-yl)-4fluoro-2H-índazol-2-íl)-N-(thiazol-2-íl)acetamíde; or a pharmaceutically acceptable salt thereof.; 72. A compound according to any one of claims 41 to 71, for use as a therapeutically active substance.

73. A pharmaceutical composition comprising a compound according to any of claims 41 to 71 and a therapeutically inert carrier.

74. The use of a compound as claimed in any of claims 41 to 71 for the treatment or prophylaxis of cancer, in particular non-small cell lung cancer, more particularly EGFR-mutated non-small cell lung cancer wherein the activating mutation is L858R.

75. A compound according to any one of claims 41 to 71 for the treatment or prophylaxis of cancer, in particular non-small cell lung cancer, more particularly EGFR-mutated non-small cell lung cancer wherein the activating mutation is L858R.

76. The use of a compound as claimed in any of claims 41 to 71 for the preparation of a medicament for the treatment or prophylaxis of cancer, in particular non-small cell lung cancer, more particularly EGFR-mutated non-small cell lung cancer wherein the activating mutation is L858R.

77. A method for the treatment or prophylaxis of cancer, in particular non-small cell lung cancer, more particularly non-small cell lung cancer with EGFR 901 mutation wherein the activating mutation is L858R, wherein the method comprises administering an effective amount of a compound according to any one of claims 41 to 71.

78. The invention as described above.

79. A compound of Formula III or Formula IV: or a pharmaceutically acceptable salt, isotope, N-oxide or stereoisomer thereof, optionally as part of a pharmaceutical composition; characterized in that: A* is selected from: B* is heteroaryl or aryl each of which is optionally substituted with 1, 2, or 3 substituents R31; and is 0, 1, 2, or 3; R31 is independently selected at each occurrence of H, halogen (F, Cl, Br, or I), Ci-β alkyl, cyano, Ci-6 alkoxy, halo-Ci-6-alkoxy, halo-Ci-6-alkyl, C3-8 cycloalkyl, and halo-C3-8-cycloalkyl and may be located on any ring where it is present in a bicycle; R32 is hydrogen, halogen (F, Cl, Br, or I), C1-6 alkyl, halo-Ci-6-alkyl, C3-8 cycloalkyl, or halo-C38-cycloalkyl; R33 is hydrogen, halogen (F, Cl, Br, or I), C1-6 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 from each occurrence of H, F, C1-6 alkyl, halo-C1-6 alkyl, C3-8 cycloalkyl, and halo-C3-8 cycloalkyl; R35 is independently selected from each occurrence of H, halogen (F, Cl, Br, or I), C1-6 alkyl, halo-C1-6 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, C1-6 alkoxy, halo-C1-6 alkoxy, C1-6 alkyl, halo-C1-6 alkyl, C3-8 cycloalkyl, and halo-C3-s-cycloalkyl; or R36 and R37 together combine to form a 5- or 6-membered ring optionally substituted with 1, 2, or 3 substituents R31; R90 is H, C1-6 alkyl, or C3-6 cycloalkyl; ring G is a heteroaryl optionally substituted with 1 or 2 substituents R42; A21 is -NH-, -O-, -CH2-, or -NR100-; R100 is alkyl, cycloalkyl, aryl, or heteroaryl;or as permitted by valency R100 can combine with R37 to form a 5-8 member heterocycle or a 5 member heteroaryl; A32, A33, A34, and A35 are independently selected from -N- and -CR42-; R42 is independently selected at each occurrence of H, halogen (F, Cl, Br, or I), cyano, Ci-e alkoxy, halo-Ci-e-alkoxy, C1-6 alkyl, halo-Ci-s-alkyl, C3-8 cycloalkyl, and halo-Cs-s-cycloalkyl; A36 is -N0 -CR35-; L2 is a bivalent linking group connecting A* and either isoindolinone or indazole.

80. The compound according to claim 79, further characterized in that the compound is selected from: 903 or a pharmaceutically acceptable salt thereof.

81. The compound according to claim 79, further characterized in that the compound is selected from: or a pharmaceutically acceptable salt thereof.

82. The compound according to any of claims 79 to 81, further characterized in that R33 is H.

83. The compound according to any of claims 79 to 81, further characterized in that R33 is F.

84. The compound according to any of claims 79 to 83, further characterized in that and is 1.

85. The compound according to any of claims 79 to 83, further characterized in that and is 2.

86. The compound according to any of claims 79 to 85, further characterized in that R31 is halo.

87. The compound according to any of claims 79 to 85, further characterized in that at least one R31 is F.

88. The compound according to any of claims 79 to 83, further characterized in that y is 0.

89. The compound according to any of claims 79 to 88, further characterized in that R32 is H.

90. The compound according to any of claims 79 to 88, 904 further characterized in that R32 is F.

91. The compound according to claim 79, further characterized in that the compound is selected from:

92. The compound according to claim 79, further characterized in that the compound is selected from: 905 The compound according 93. to any of claims 79 92, further characterized in that A* is: any of claims 79 92, 95. The conforming compound is further characterized in that A34 is CH. 10 96. The conformity compound further characterized in that A34 is N.

97. The conformity compound further characterized in that A34 is CR42.

98. The conformity compound 15 further characterized in that A34 is CF.

99. The conformity compound further characterized in that A35 is CH.

100. The compound according to any one of claims 79 to 94, with any one of claims 79 to 94, with any one of claims 79 to 94, with any one of claims 79 to 94, with any one of claims 79 to 98, with any one of claims 79 to 98, further characterized in that A35 is N. 906 101. The compound according to any of claims 79 to 98, further characterized in that A35 is CR42.

102. The compound according to any of claims 79 to 98, further characterized in that A35 is CF.

103. The compound according to any of claims 79 to 92, further characterized in that A* is: IVIA / a / ZUZZ / UU 100» O 104. The compound according to any of claims 79 to 92, further characterized in that A* is:

105. The compound according to claim 103 or 104, further characterized in that A21 is NH.

106. The compound according to claim 103 or 104, further characterized in that A21 is O.

107. The compound according to any of claims 79 to 92, further characterized in that A* is:

108. The compound according to any of claims 79 to 107, further characterized in that A32 is CH.

109. The compound according to any of claims 79 to 107, 907 further characterized in that A32 is N.

110. The compound according to any of claims 79 to 107, further characterized in that A32 is CR42.

111. The compound according to any of claims 79 to 107, further characterized in that A32 is CF.

112. The compound according to any of claims 79 to 112, further characterized in that A33 is CH.

113. The compound according to any of claims 79 to 112, further characterized in that A33 is N.

114. The compound according to any of claims 79 to 112, further characterized in that A33 is CR42.

115. The compound according to any of claims 79 to 112, further characterized in that A33 is CF.

116. The compound according to any of claims 79 to 92, further characterized in that A* is: R34 ML / a / ZUZZ / UU / 00» O 117. The compound according to claim 116, further characterized in that A21 is NH.

118. The compound according to claim 116, further characterized in that A21 is O.

119. The compound according to any of claims 79 to 118, further characterized in that R34 is H.

120. The compound according to any of claims 79 to 118, further characterized in that R34 is F.

121. The compound according to any of claims 79 to 118, further characterized in that R34 is CH3.

122. The compound according to any of claims 79 to 121, further characterized in that R35 is H.

123. The compound according to any of claims 79 to 121, further characterized in that R35 is F.

124. The compound according to any of claims 79 to 121, 908 further characterized in that R35 is CH3.

125. The compound according to any of claims 79 to 118, further characterized in that R34 and R35 combine to form -CH2-.

126. The compound according to any one of claims 79 to 125, further characterized in that R31 is independently selected in each case from H, halogen (F, Cl, Br, or I), and C1-6 alkyl.

127. The compound according to any of claims 79 to 126, further characterized in that R42 is independently selected in each case from H, halogen (F, Cl, Br, or I), and Ci-e alkyl.

128. The compound according to any of claims 79 to 127, further characterized in that B* is θ 129. The compound according to any of claims 79 to 127, further characterized in that B* is 130. The compound according to any of claims 79 to 127, further characterized in that B* is 131. The compound according to any of claims 79 to 127, further characterized in that B* is 132. The compound according to any one of claims 79 to 131, further characterized in that L2 has the formula: wherein, X1 and X2 are independently selected at each occurrence of the linkage, heterocycle, aryl, heteroaryl, bicyclo, 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 bicyclo is optionally substituted with 1, 2, 3 or 4 independently selected substituents from R40; R20, R21, R22, R23, and R24 are independently selected at each occurrence of 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, 909 -C(R40R40)-, -P(O)(OR26)O-, -P(O)(OR26)-, bicyclo, 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 selected independently from R40; R26 is selected independently at each occurrence from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocycle, aliphatic and heteroaliphatic; R27 is selected independently at each occurrence 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 selected independently in each occurrence of 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), -NHSOzalkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocycle, oxo and cycloalkyl; additionally, where valency permits, two R40 groups attached to the same carbon may join together to form a 3- to 8-membered spirocycle; and R41 is aliphatic, aryl, heteroaryl, or hydrogen.; 133. The compound according to claim 132, further characterized in that L2 has the formula: X22 ^R23 ^R21 ^X2 0 ^X1 ^R23 ^R21^ 134. The compound according to claim 132 or 133, further characterized in that X1 is a bond.

135. The compound according to claim 132 or 133, further characterized in that X1 is a heterocycle.

136. The compound according to claim 132 or 133, further characterized in that X1 is NR2.

137. The compound according to claim 132 or 133, further characterized in that X1 is C(O).

138. The compound according to any of claims 132 to 137, further characterized in that X2 is a bond.

139. The compound according to any of claims 132 to 137, further characterized in that X2 is a heterocycle.

140. The compound according to any of claims 132 to 910 137, further characterized in that X2 is NR2.

141. The compound according to any of claims 132 to 137, further characterized in that X2 is C(O).

142. The compound according to any of claims 132 to 141, further characterized in that R20 is a bond.

143. The compound according to 141, further characterized in that R20 is CH2. any of claims 132 to 144. The compound according to 141, further characterized in that R20 is a heterocycle. any of claims 132 to 145. The compound according to 141, further characterized in that R20 is aryl. any of claims 132 to 146. The compound according to 141, further characterized in that R20 is phenyl. any of claims 132 to 147. The compound according to 141, further characterized in that R20 is bicyclo. any of claims 132 to 148. The compound according to 147, further characterized in that R21 is a bond. any of claims 132 to 149. The compound according to 147, further characterized in that R21 is CH2. any of claims 132 to 150. The compound according to 147, further characterized in that R21 is a heterocycle. any of claims 132 to 151. The compound according to 147, further characterized in that R21 is aryl. any of claims 132 to 152. The compound according to 147, further characterized in that R21 is phenyl. any of claims 132 to 153. The compound according to 147, further characterized in that R21 is bicyclo. any of claims 132 to 154. The compound according to claim 132, further characterized in that L is a linker of the formula: R2 / / R\ A \R23 A 155. The compound according to any of claims 132 to 154, further characterized in that R22 is a bond.

156. The compound according to any of claims 132 to 154, further characterized in that R22 is CH?. 911 157. The compound according to any of claims 132 to 154, further characterized in that R22 is a heteroacid.

158. The compound according to any of claims 132 to 154, further characterized in that R22 is aryl.

159. The compound according to any of claims 132 to 154, further characterized in that R22 is phenyl.

160. The compound according to any of claims 132 to 154, further characterized in that R22 is bicyclo.

161. The compound according to claim 132, further characterized in that L is a linker of the formula: VR24 XX ^r23.

162. The compound according to any one of claims 132 to 161, further characterized in that R23 is a linker.

163. The compound according to any one of claims 132 to 161, further characterized in that R23 is CH?.

164. The compound according to any one of claims 132 to 161, further characterized in that R23 is a heteroacid.

165. The compound according to any one of claims 132 to 161, further characterized in that R23 is an aryl group.

166. The compound according to any one of claims 132 to 161, further characterized in that R23 is aphenyl group.

167. The compound according to any one of claims 132 to 161, further characterized in that R23 is bicyclo.

168. The compound according to any one of claims 132 to 167,169. The compound according to any one of claims 132 to 167, further characterized in that R24 is a bond.

170. The compound according to any one of claims 132 to 167, further characterized in that R24 is a heteroacid.

171. The compound according to any one of claims 132 to 167, further characterized in that R24 is an aryl group.

172. The compound according to any one of claims 132 to 167, further characterized in that R24 is a phenyl group.

173. The compound according to any one of claims 132 to 167, further characterized in that R24 is a bicycloalgilic group.

174. The compound according to any one of claims 132 to 167, further characterized in that R24 is a C(O) group.

175. A compound selected from: 5-((2-(1-(6,7-d¡hydro-5H-pyrrolo[l,2-c]m¡dazol-l-¡l)-2-oxo-2-(thiazol-2-lam¡no)et¡l)-7-fluoro-3oxo¡so¡ndolin-5-yl)ethynyl)-N-(l-(2-(4-(4-((2,6-dioxopyridin-3-il)amino)fenil)piperidin-1l)acetyl)pyridin-4-il)picolamine; 5-[2-[2-[l-(6,7-dhydro-5H-pirrolo[l,2-c]mdazol-1l-)-2-oxo-2-(tazol-2-lamno)etl]-7-fluoro-3oxo-isoindolin-5-il]etin-1]-N-[l-[2-[4-[(2,6-dioxo-3-piperidil)amino]fenil]acetyl]-4-piperidil]pyridin-2carboxamide 5-[2-[2-[l-(6,7-dhydro-5H-prrolo[l,2-c]mdazol-l-l)-2-oxo-2-(tazol-2-lamino)etl]-7-fluoro-3oxo-sondol-5-l]etln]-N-[l-[2-[4-[4-[(2,6-doxo-3-pperidl)ox]fenl]pperazl-l]acetl]-4pperdl]pirdln-2-carboxamide 913 5-[2-[2-[l-(6,7-dhydro-5H-prrolo[l,2-c]mdazol-l-)-2-oxo-2-(tazol-2-lamino)etl]-7-fluoro-3-oxo-isoindolin-5-il]etl]-N-[l-[2-[4-[4-[[(3S)-2,6-doxo-3-piperidl]amno]-2-fluoro-fenil]-lpperidl]acetyl]-4-pperidl]prdl-2-carboxamide IVIA / a / ZUZZ / UU / 00» 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡midazol-l-¡l)-2-[6-[4-[4-[2-[4-[4-[(2,6-d¡oxo-3p¡perid¡l)am¡no]fen¡l]-lp¡per¡d¡l]acet¡l]p¡perazin-l-¡l]fen¡l]-4-fluoro-l-oxo-iso¡ndol¡n-2-¡l]-N-tiazol-2il-acetamida 2-(6,7-d¡h¡dro-5H-pirrolo[l,2-c]¡midazol-l-il)-2-[6-[4-[4-[2-[4-[4-[[(3S)-2,6-d¡oxo-3piperid¡l]am¡no] fen¡l]-l-piper¡d¡l]acet¡l]p¡perazin-l-¡l]fenil]-4-fluoro-l-oxo-iso¡ndol¡n-2-¡l]-N-tiazol-2il-acetamida 2-(6,7-dihydro-5H-pirrolo[l,2-c]imidazol-l-il)-2-[6-[4-[4-[2-[4-[4-[[(3R.)-2,6-dioxo-3pperdl]amno]fenil]-lpperdl]acetil]piperaznl-l]fenl]-4-fluoro-l-oxo-iso-ndol-2-il]-Ntazol-2il-acetamida 2-(6,7-dhdrO-5H-prrOlo[l,2-c]mdazol-l-l)-2-(6-(4-(4-(4-(4-(2,6-doxopperdn-3l)amno)fenil)ppendnl-l)-4-oxobutl)pperaznl-l)fenl)-4-fluoro-l-oxosoindoln-2l)-N-(tazol914 2-il)acetamida 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-il)-2-(6-(4-(4-(2-(4-(4-((2,6-d¡oxop¡per¡d¡n-3¡l)am¡no)f enil)ciclohex¡l)acet¡l)piperazin-l-¡l)fen¡l)-4-fluoro-l-oxoiso¡ndol¡n-2-il)-N-(tiazol-2il)acetamida 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(4-(4-(2-(4-(4-((2,6-d¡oxop¡per¡d¡n-3il)amino)fen¡l)p¡per¡din-l-i l)-2-oxoet¡l)p¡perazin-l-¡l)fen¡l)-4-fluoro-l-oxoisoindol¡n-2-¡l)-N-(tiazol-2il)acetamida 2-(6,7-dhydro-5H-prrolo[l,2-c]mdazol-l-l)-2-[6-[4-[4-[2-[4-[5-[(2,6-dioxo-3-pperdl)amino]-2pindil]-l-piperidil]acetl]piperazl-il]fenil]-4-fluoro-l-oxo-isoindolin-2-il]-Ntazol-2-il-acetam 2-(6,7-dihydro-5H-pirrolo[l,2-c]midazol-l-il)-2-[6-[4-[4-[2-[4-[4-[2,6-doxo-3-piperidil)amno]-2fluoro-fenl]-l-piperidil]acetil]piperazin-l-il]fenil]-4-fluoro-l-oxo-isoindol-2-il]-N-tiazol-2-il acetamida 915 ΜΛ / a / ZUZZ / UU / 00» 2-(6,7-dhydro-5H-pirrolo[l,2-c]midazol-l-il)-2-[6-[4-[4-[2-[4-[4-[(2,6-doxo-3-piperidil)amno]-3fluoro-fenl]-l-piperidil]acetil]piperazin-l-il]fenil]-4-fluoro-l-oxo-isoindol-2-il]-N-tiazol-2-ilacetamida 2-[6-[4-[2-[4-[2-c¡ano-4-[(2,6-d¡oxo-3-p¡per¡d¡l)am¡no]fenil]-l-piper¡d¡l]acet¡l]p¡peraz¡nl¡l]fenil]-4-fluoro-l-oxo-¡so¡ndol¡n-2-¡l]-2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-Nt¡azol-2-¡lacetamida 2-[6-[4-[4-[2-[4-[2-(d¡fluoromet¡l)-4-[(2,6-d¡oxo-3-p¡per¡dil)amino]fen¡l]-lp¡per¡dil]acetil]p¡peraz¡nl-¡l]fen¡l]-4-fluoro-l-oxo-¡so¡ndol¡n-2-il]-2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-Nt¡azol-2-¡lacetamida 2-(6,7-dhydro-5H-pirrolo[l,2-c]imidazol-l-il)-2-(6-(4-(4-2-(4-(3-((2,6-dioxopiperidin-3l)amno)fenl)ppendin-l-il)acetil)pperaznl-il)fenl)-4-fluoro-l-oxoisoindolin-2l)-N-(tazol-2il)acetamida 916 ινΐΛ / a / zuzz / uu / oo» 2-(6,7-dih¡dro-5H-p¡rrolo[l,2-c]im¡dazol-l-¡l)-2-(6-(4-(4-(2-(4-(3-(2,4-d¡oxotetrah)¡dropir¡mid¡nl(2H)-¡l)-l-met¡l -lH-indazol-6-¡l)p¡per¡d¡nl-il)acet¡l)p¡peraz¡nl-¡l)fen¡l)-4-fluoro-l-oxo¡so¡ndol¡n-2il)-N-(tiazol-2-il)acetannida 2-(6,7-dihydro-5H-pyrrolo[l,2-c]imdazol-l-l)-2-(6-(4-(4-(2-(l-(4-((2,6-dioxopiper(dn-3-l)amino)2-(tr¡fluorometl)fen¡l)-4-hidrox¡piper¡dn-4-l)acetyl)p¡peraz¡nl-¡l)fenil)-4-fluoro-l-oxo¡soindolin-2l)-N-(tiazol-2-l)acetamida 2-(6,7-d¡h¡dro-5H-pyrrolo[l,2-c]imidazol-l-il)-2-(6-(4-(4-(2-(4-(4-(2,6-dioxopiperidin-3¡l)am¡no)fen¡l)p¡pendin-l-¡l)acetil)p¡peraz¡nl-¡l)fen¡l)-4-fluoro-l-oxo¡ondolin-2-¡l)-N-(p¡r¡din-2il)acetamida 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-2-[6-[4-[4-[2-[4-[4-[(2,6-d¡oxo-3-p¡per¡d¡l)am¡no]-2917 fluoro-fen¡l]-lp¡peridil]acetil]piperaz¡nl-¡l]fenil]-4-fluoro-l-oxo-¡soindolin-2-¡l]-N-(2piridil)acetam¡da 2-(6,7-dihydro-5H-prrolo[l,2-c]imdazol-l-l)-2-(6-(4-(l-(2-(4-(4-((2,6-dioxopiper dn-3l)amno)fenl)pperdin-l-l)acetl)pper dn-4-il)fenl)-4-fluoro-l-oxoisoindol-2l)-N-(tazol-2il)acetamida 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(4-(l-(2-(4-(4-(((S)-2,6-d¡oxopiper¡d¡n-3 il)amino)fenil)piperidin-l-il)acetil)piperidin-4-il)fenil)-4-fluoro-l-oxoisoindolin-2-il)-N-(tiazol-2il)acetamida 2-(6,7-dih¡dro-5H-p¡rrolo[l,2-c]im¡dazol-l-il)-2-(6-(4-(l-(2-(4-(4-(((R)-2),6-dioxop¡per¡d¡n-3¡l)am¡no)fenil)piperidin-l-¡l)acetil)piperidin-4-¡l)fen¡l)-4-fluoro-l-oxoisoindolin-2-il)-N-(tiazol-2il)acetamida 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(4-(l-(2-(4-(4-((S)-2,6-d¡oxop¡perid¡n-3 918 il)amino)-2-fluorofenil)piperidin-l-il)acet¡l)p¡peridin-4-il)fen¡l)-4-fluoro-l-oxoiso¡ndolin-2-¡l)-N(tiazol-2-il)acetamida 2-(6-(4-(l-(2-(4-(2-ciano-4-((2,6-dioxoperidin-3-l)amno)fenl)pperdnl-l)acetil)pperdin-4l)fenil)-4-fluoro-l-oxoiso-ndol-2-il)-2-(6,7-dihydro-5H-pirrolo[l,2-c]imdazol-l-il)-N-(tiazol-2-il)acetamida 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡midazol-l-¡l)-2-[6-[4-[l-[2-[4-[4-[(2,6-d¡oxo-3piperid¡l)amino]feni l]-l-piperidil]-2-oxo-etil]-4-piperidil]fenil]-4-fluoro-l-oxo-¡so¡ndolin-2-il]-Ntiazol-2-il-acetamida 2-(6,7-d¡h¡drc>-5H-pirrolo[l,2-c]¡midazol-l-il)-2-[6-[6-[4-[2-[4-[4-[[(3S)-2,6-d¡oxo-3piper¡d¡l]amino]-2-fluoro-fen¡l]-l-piperidil]acet¡l]piperaz¡nl-¡l]-3-pindil]-4-fluoro-l-oxo-isoindolin2-¡l]-N-tiazol-2-¡l-acetam¡da 2-(6,7-dihydro-5H-p¡nOlo[l,2-c]imidazol-l-il)-2-[6-[l-[l-[2-[4-[4-[[(3S)-2,6-dioxo-3p¡perid¡l]am¡no]fen¡l]-lp¡per¡d¡l]acet¡l]-4-p¡per¡d¡l]pirazol-4-il]-4-fluoro-l-oxo-¡ndol¡n-2-il]-N919 tiazol-2-il-acetamida 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]im¡dazol-l-¡l)-2-[6-[4-[l-[2-[4-[4-[[(3S)-2,6-d¡oxo-3piper¡dil]am¡no]fen ¡l]-l-piperidil]acet¡l]-4-piperidil]p¡razol-l-¡l]-4-fluoro-l-oxo-iso¡ndol¡n-2-il]-Ntiazol-2-il-acetamida 2-(6,7-dhydro-5H-prrolo[l,2-c]mdazol-l-l)-2-(6-(l-(l-(2-(4-(4-(((S)-2,6-doxopiper-dn-3 il)amino)fenil)piperidin-l-il)acetyl)piperidin-4-il)-lH-l,2,3-triazol-4-il)-4-fluoro-l-oxoisoindolin-2-il)N-(tiazol-2-il)acetamida 2-(6,7-d¡h¡dro-5H-p¡nOlo[l,2-c]¡midazol-l-¡l)-2-[6-[4-[[l-[2-[4-[4-[(2,6-d¡oxo-3piper¡dil)am¡no]fen¡ l]-l-piperidil]acet¡l]-4-piperidil]oxi]fen¡l]-4-fluoro-l-oxo-isoindol¡n-2-¡l]-N-tiazol2-¡l-acetamida 2-(6,7-d¡hidro-5H-pirrolo[l,2-c]im¡dazol-l-¡l)-2-[6-[4-[[l-[2-[4-[4-[[(3S)-2,6-dioxo-3p¡per¡d¡l]am¡no]fen¡l]-lp¡per¡d¡l]acet¡l]-4¡perid¡l]ox¡]fen¡l]-4-fluoro-l-oxo-¡ndol¡n-2-¡l]-Nt¡azol2-il-acetamida 920 2-(6,7-d¡hidro-5H-pirrolo[l,2-c]imidazol-l-il)-2-[6-[4-[[l-[2-[4-[4-[[(3R)-2,6-d¡oxo-3p¡perid¡l]amino] fenil]-lp¡per¡d¡l]acetil]-4-piperid¡l]ox¡]fenil]-4-fluoro-l-oxo-¡so¡ndolin-2-il]-Nt¡azol2-il-acetamida 2-(6,7-dihidro-5H-pirrolo[l,2-c]imidazol-l-il)-2-(6-(4-((l-(2-(4-(4-((2,6-dioxopiperidin-3-il)amino) 3-fluorofenil)piperidin-l-il)acetil)piperidin-4-il)oxi)fenil)-4-fluoro-l-oxoisoindolin-2-il)-N-(tiazol-2-il)acetamida 2-(6,7-dhydro-5H-prrolo[l,2-c]mdazol-l-il)-2-(6-(4-(l-(2-(4-(4-((2,6-doxopperdn-3-il)amno) 2-fluorofenil)piperidin-l-il)acetil)piperidin-4-il)oxi)fenil)-4-fluoro-l-oxoisoindolin-2-il)-N-(tiazol-2-il)acetamida 2-(6,7-dihydro-5H-pirrolo[l,2-c]midazol-l-il)-2-(6-(4-((l-(2-(4-(5-((2,6-dioxopperidin-3-yl)amino)prdin-2-yl)piperidin-l-l)acetyl)pridin-4-yl)oxol)fenil)-4-fluoro-l-oxosoindol-2-l)-N(tazol-2-l)acetamida 921 IVIA / a / ZUZZ / UU 100» 2-(6-(4-((l-(2-(4-(2-cyano-4-((2,6-d¡oxop¡peridin-3-il)am¡no)fen¡l)piperidin-l-¡l)acet¡l)piperidin-4il)oxi) fenil)-4-fluoro-l-oxoiso¡ndol¡n-2-¡l)-2-(6,7-dihidro-5H-pirrolo[l,2-c]imidazol-l-il)-N-(tiazol-2il)acetamida 2-(6,7-dhydro-5H-pnOlo[l,2-c]midazol-l-l)-2-(6-(4-(l-(2-(4-(4-((2,4-doxo-3azabiciclo[3.1.l]heptan-l-l)amno)fenl)pperidinl-l)acetyl)pperdin-4-l)ox)fenl)-4-fluoro-loxosoindolin-2-l)-N-(tiazol-2-l)acetam 2-(6,7-dhydro-5H-prrolo[l,2-c]mdazol-l-il)-2-(6-(4-(l-(2-(4-(4-(((S)-2,6-dioxopperdn-3il)amno)-2-fluorofenil)piperdin-l-l)acetyl)piperidin-4-l)ox)fenl)-4-fluoro-l-oxosondoln-2-il)-N(tiazol-2-il)acetamida 2-(6,7-dhydro-5H-pnOlo[l,2-c]imdazol-l-l)-2-[6-[4-[l-[2-[4-[4-[2,6-d¡oxo-3piper¡d¡l)am¡no]fenil]-lp¡per¡d¡l]-2-oxo-acetil]-4-p¡per¡d¡l]ox¡]fen¡l]-4-fluoro-l-oxo-¡so¡ndolin-2-¡l]N-tiazol-2-il-acetamida 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-2-[6-[4-[(3R)-l-[2-[4-[4-[[(3S)-2,6-d¡oxo-3piperid¡l]am¡no] fen¡l]-l-piperidil]acet¡l]pirrolidin-3-il]oxifen¡l]-4-fluoro-l-oxo-isoindol¡n-2-¡l]-Ntiazol-2-il-acetannida 2-(6,7-dihydro-5H-pirrolo[l,2-c]imidazol-l-il)-2-[6-[4-[(3S)-l-[2-[4-[4-[[(3S)-2,6-dioxo-3-pyrrolidin-1]amno]fenil]-lp-pyrrolidin-3-il]oxifen-1]-4-fluoro-l-oxo-soindol-2-il]-Ntiazol-2-il-acetamida 2-(6-(4-(4-(2-(4-(4-((2,6-doxopperdn-3-l)amno)fenl)pperdnl-il)acetl)pperaznl-l)fenl)-4fluoro-l-oxosondoln-2-il)-2-((R)-6-fluoro-6,7-dhdro-5H-prrolo[l,2-c]mdazol-l-l)-N-(tazol-2il)acetamida 2-[6-[4-[2-[4-[4-[[(3S)-2,6-d¡oxo-3-piperidil]amino]-2-fluoro-fenil]-lp¡per¡d¡l]acet¡l]piperaz¡n-lil]fen¡l]-4-fluoro-l-oxo-isoindolin-2-¡l]-2-[(6R)-6-fluoro-6,7-d¡h¡dro-5H-pirrolo[l,2-c]im¡dazol-l-il]N-tiazol-2-il-acetamida 923 2-[6-[4-[4-[2-[4-[3-(2,4-dioxohexahidrop¡rimidin-l-¡l)-l-met¡l-¡ndazol-6-il]-lpiper¡dil]acetil]piperaz¡nl-il]fenil] -4-fluoro-l-oxo-isoindolin-2-il]-2-[(6R)-6-fluoro-6,7-dihidro-5Hp¡rrolo[l,2-c]¡m¡dazol-l-¡l]-Nt¡azol-2-¡l-acetam¡da 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(4-(2-(2-(4-(4-(((S)-2,6-d¡oxopiper¡d¡n-3il)amino)-2-fluorofeni l)piperid¡nl-¡l)acet¡l)-2,7-diazasp¡ro[3.5]nonan-7-il)fenil)-4-fluoro-loxoiso¡ndolin-2-¡l)-N-(tiazol-2-¡l)acetam¡da 2-(6,7-dhydro-5H-prrolo[l,2-c]midazol-l-l)-2-[6-[4-[2-[2-[4-[4-[(2,6-doxo-3piperidl)amno]fenl]-l-piperdl]acetl]-2,6-diazaspiro[3,3]heptan-6-il]fenil]-4-fluoro-l-oxoisoindol[2-l]-Ntazol-2-il-acetam] 2-(6,7-dihydro-5H-prrol[l,2-c]imdazol-l-l)-2-[6-[4-[2-[2-[4-[4-[[(3S)-2,6-dioxo-3prdol]amno]-2-fluoro-fenil]-lprdol]acetol]-2,6-dazasspro[3.3]heptan-6-l]fenol]-4-fluoro-loxo-isoindol-2-il]-N-tiazol-2-il-acetamide 924 2-(6,7-dihydro-5H-prrol[l,2-c]imidazole-l-¡l)-2-[6-[4-[2-[2-[4-[3-(2,4-dioxohexah¡drop¡r¡nnidin-l-l) l-methyl-indazol-6-yl]-lp¡per¡dyl]acetyl]-2,6-diazasp¡ro[3.3]heptane-6-yl]phenyl]-4-fluoro-l-oxoisoindoline-2-yl]-N-thiazol-2-yl-acetamide 2-(6,7-d¡hydro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-2-[6-[4-[2-[2-[4-[3-(2,4-dioxohexah¡drop¡r¡midin-l-l-meth¡l-l-l-l-6] 3,3-difluoro-lp¡per¡d¡l]acetyl]-2,6-diazasp¡ro[3.3]heptane-6-¡l]phen¡l]-4-fluoro-loxo-isoindol¡n-2-¡l]-N-thiazol-2-yl-acetamde 2-(6,7-dih¡dro-5H-p¡rrolo[l,2-c]im¡dazol-l-¡l)-2-(6-(4-(6-(2-(4-(4-((2,6-dioxopipendin-3¡l)am¡no)phenyl)-3,3-difluor opperidin-l-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-loxoiso¡ndol¡n-2-yl)-N-(thiazol-2-¡l)acetam¡da 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡midazol-l-yl)-2-[6-[4-[2-[2-[4-[4-[[(3S)-2,6-d¡oxo-3925 piper¡dyl]amno]-2-fluoro-phen¡l]-lp¡pend¡l]acetyl]-2,6-diazasp¡ro[3.3]heptane-6-yl]phen¡l]-4-fluoro-loxo-iso¡ndol¡n-2-¡l]-N-(2-pyr¡l) 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-2-[6-[4-[2-[2-[4-[3-(2,4-dioxohexah¡drop¡r¡midin-l-¡l)l-met¡l-indazol-6-¡l]-l-piperidil]acetil]-2,6-d¡azaspiro[3.3]heptan-6-il]fenil]-4-fluoro-l-oxoisoindolin-2-¡l]-N-(2-piridil)acetamida 2-(6,7-dhydro-5H-prrolo[l,2-c]imidazol-l-l)-2-[6-[4-[2-[2-[4-[3-(2,4-doxohexahidroprimidin-l-l)l-metl·ndazol-6-l]-3,3-dfluoro-lpperdl]acetl]-2,6-dazasspro[3,3]heptan-6-l]fenl]-4-fluoro-loxo-sondol-2-l]-N-(2-pirdl)acetam 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-2-[6-[4-[[4-[2-[4-[4-[(2,6-d¡oxo-3piperid¡l)am¡no]fen¡l ]-l-piper¡dil]acet¡l]p¡perazin-l-¡l]met¡l]fen¡l]-4-fluoro-l-oxo-¡so¡ndol¡n-2-il]-Ntiazol-2-il-acetamida 926 2-(6,7-dhydro-5H-prrolo[l,2-c]mdazol-l-l)-2-[6-[4-[4-[2-[4-[4-[(2,6-doxo-3-pperdl)amno]-2-fluoro-fenl]-lpperidil]acetyl]pperaznl-l]metil]fenl]-4-fluoro-l-oxo-isoindol-2-l]-Ntazol-2-ilacetamida 2-(6,7-d¡hidro-5H-p¡rrolo[l,2-c]im¡dazol-l-¡l)-2-[6-[4-[4-[2-[4-[4-[[(3S)-2,6-dioxo-3p¡per¡d¡l]am¡no]-2-fluoro-phen¡l]-lp¡per¡d¡l]acet¡l]p¡peraz¡nl-¡l]meth¡l]phen¡l]-4-fluoro-l-oxo-¡soindolin2-yl-nat-acetal-2 2-(6,7-d¡hydro-5H-p¡rrolo[l,2-c]¡midazol-l-¡l)-2-[6-[4-[[4-[2-[4-[4-[[(3S)-2,6-d¡oxo-3piperid¡l]am¡¡no]-2-fluoro-2 phenyl]-lp¡per¡d¡l]-2-oxo-ethyl]p¡peraz¡nl-¡l]methyl]phen¡l]-4-fluoro-1-oxoisoindoline-2-yl]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-p¡rrolo[l,2-c]imidazole-l-¡l)-2-[6-[4-[[l-[2-[4-[4-[[(3S)-2,6-dioxo-3piper¡d¡l]am¡no]-2-flu gold-phen¡l]-lp¡per¡d¡l]acetyl]-4-p¡perdyl]meth¡l]phenyl]-4-fluoro-l-oxo-¡so¡ndolin-2yl]-Nt¡azol-2-¡l-acetamide 927 2-[4,7-dichloro-6-[4-[4-[2-[4-[4-[(2,6-d¡oxo-3-p¡per¡d¡l)amino]phen¡l]-lp¡per¡d¡l]acet¡l]p¡peraz¡ nl¡l]phenyl]¡ndazol-2-¡l]-2-(6,7-d¡hydro-5H-p¡rrolol[l,2-c]¡m¡dazol-l-¡l)-N-thiazol-2-¡l-acetam¡da 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(6-(4-(4-(4-((2-(2,6-dioxopperdn-3-l)-loxosoindolin-4-il)ox)piperidinl-il)-4-oxobutil)pperazin-l-il)piridin-3-il)-7-fluoro-2H-indazol-2-il)N-(tiazol-2-il)acetamida 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(6-(4-(2-(4-(4-((2,6-dioxop¡per¡d¡n-3il)amino)feni) l)piperidin-l-il)acet¡l)piperazin-l-il)pir¡d¡n-3-¡l)-7-fluoro-2H-¡ndazol-2-il)-N-(tiazol-2il)acetamida 928 ινΐΛ / a / zuzz / uu / oo» 2-(6,7-dhydro-5H-prrolo[l,2-c]mdazol-l-l)-2-[6-[6-[4-[2-[4-[4-[(2,6-doxo-3-pperdl)amno]-2fluoro-fenl]-lpperdil]acetl]pperaznl-l]-3-pirdl]-4-fluoro-ndazol-2-l]-Ntazol-2-l-acetam 2-(6,7-dhydro-5H-prrolo[l,2-c]mdazol-l-l)-2-[6-[6-[4-[2-[4-[4-[(2,6-doxo-3pperidl)amno]fenl]-lpperdl]acetl]pperaznl-l]-3-prdl]-4-fluoro-ndazol-2-l]-Ntazol-2-lacetamida 2-(6,7-dihydro-5H-prolo[l,2-c]imidazol-l-l)-2-[6-[6-[4-[2-[4-[5-[(2,6-doxo-3-piperidil)amno]-2piridil]-l-piperidil]acetil]piperazol-l-il]-3-piridil]-4-fluoro-indazol-2-il]-N-tiazol-2-il-acetamida 929 2-(6,7-d¡hydro-5H-pyrrolo[l,2-c]imidazol-l-yl)-2-[6-[6-[4-[2-[4-[3-(2,4-dioxohexahydropyrimidine-l-yl)l-met¡l -indazol-6-¡l]-lp¡per¡dyl]acetate¡l]p¡peraz¡nl-¡l]-3-pyr¡d¡l]-4-fluoro-¡ndazol-2-¡l]-Nt¡azol-2-lacetamide 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(6-(4-(2-(4-(4-(((S)-2,6-d¡oxop¡perid¡n-3yl)amino)-2-flu orophenyl)piperid¡nl-yl)acetyl)p¡perazine-l-¡l)pyridin-3-yl)-4-fluoro-2H-indazol-2-yl)-N(thiazol-2-yl)acetamin or a pharmaceutically acceptable salt thereof.

176. A selected compound of: 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(6-(6-(2-(4-(4-(((S)-2,6-d¡oxop¡perid¡n-3yl)am¡no-fluorophenyl-2) )piper¡d¡nl-¡l)acet¡l)-2,6-d¡azasp¡ro[3.3]heptan-2-¡l)p¡r¡d¡n-3-yl)-7-fluoro-2Hindazol-2-¡l)-N-(t¡azol-2-acetate) 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(6-(6-(2-(4-(3-(2,4-d¡¡oxotetrah) drop¡r¡midinl(2H)-¡l)-l-methyl-lH-indazol-6-yl)-3,3-difluoropiper¡d¡nl-yl)acetyl)-2,6-diazaspr[3.3]heptan-2il)piridin-3-il)-7-fluoro-2H-indazol-2-il)-N-(tazol-2-il)acetannda 931 2-(6,7-dihydro-5H-prrol[l,2-c]imdazol-l-l)-2-(6-(6-(6-(2-(l-(4-((2,6-dioxopiperidin-3-l)amino)3-fluorofenil)-4-hydroxypiperidin-4-il)acetyl)-2,6-diazaspiro[3,3]heptan-2-il)piridin-3-il)-7-fluoro-2Hndazol-2-l)-N-(tazol-2-l)acetamide 2-(6,7-dih¡dro-5H-p¡rrolo[l,2-c]im¡dazol-l-¡l)-2-(6-(6-(4-(2-(4-(3-(2,4-dioxotetrah)¡drop¡r¡midinl(2H)-il)-l-metil·lH-ind azol·6-il)-3,3-difluoropiper¡d¡nl-il)acetil)piperaz¡nl-il)pir¡din-3-¡l)-4-fluoro2H-¡ndazol-2-il)-N-(t¡azol-2-¡l)acetam¡da 2-(6,7-dhydro-5H-prrolo[l,2-c]mdazol-l-l)-2-(6-(6-(6-(2-(4-(3-(2,4-dioxotetrah-droprmidinl(2H)-il)-l-metil-lH-indazol-6-il)-3,3-difluoropiper-dnl-il)-2-oxoetil)-2,6-diazaspr[3,3]heptan-2l)prrdn-3-l)-7-fluoro-2H-indazol-2-l)-N-(tazol-2-l)acetam 2-(6,7-dhydro-5H-prrolo[l,2-c]mdazol-l-l)-2-(6-(6-(6-(2-(l-(4-((2,6-doxopperdn-3-l)amno)2-fluorofenl)-4-hdroxipiperdn-4-l)acetyl)-2,6-d¡azasp¡ro[3.3]heptan-2-il)p¡r¡d¡n-3-¡l)-7-fluoro-2Hindazol-2-¡l)-N-(t¡azol-2-il)acetam¡da 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(6-(6-(2-(l-(4-(((S)-2,6-d¡oxopiper¡d¡n-3il)amino)-2-fluorofenil)-4-hi drox¡p¡perid¡n-4-il)acet¡l)-2,6-d¡azasp¡ro[3.3]heptan-2-¡l)p¡r¡d¡n-3-il)-4fluoro-2H-indazol-2-il)-N-(tiazol-2-¡l)acetamida 933 2-(6,7-dihydro-5H-prrolo[l,2-c]imdazol-l-l)-2-(6-(4-(6-(2-((R)-4-(3-(2,4-dioxotetrah-dropirimidinl(2H)-l)-l-metl-lH-indazol-6-l)-3,3-dfluoropiper-dnl-l)acetyl)-2,6-diazaspr[3,3]heptan-2l)fenl)-4-fluoro-2H-indazol-2-l)-N-(tazol-2-il)acetam 2-(6,7-dihydro-5H-pirrolo[l,2-c]imidazol-l-il)-2-(6-(4-(6-(2-(l-(4-(((S)-2,6-dioxopiperidin-3l)amno)-2-fluorofenil)-4-hydroxypyridin-4-il)acetyl)-2,6-diazopyridin-4-il)acetyl)-2,6-diazopyridin-2l)fenol)-4-fluoro2H-ndazol-2l)-N-(tazol-2l)acetamide 2-(6,7-dihydro-5H-pirrolo[l,2-c]midazol-l-il)-2-(6-(4-(6-(2-(l-(4-(((S)-2,6-dioxopiper-din-3il)amno)-2-fluorofenil)-4-hydroxopiperidin-4-il)acetyl)-2,6-d¡azasp¡ro[3.3]heptan-2-¡l)fen¡l)-7-fluoro2H-¡ndazol-2-¡l)-N-(t¡azol-2-¡l)acetam¡da 934 2-(6,7-dihidro-5H-p¡rrolo[l,2-c]im¡dazol-l-¡l)-2-(6-(4-(7-(2-(l-(4-((S)-2,6-dioxop¡per¡d¡n-3¡l)amino)-2-fluorofen¡l) -4-hidroxip¡pend¡n-4-¡l)acetil)-2,7-d¡azasp¡ro[3.5]nonan-2-¡l)fen¡l)-4-fluoro2H-indazol-2-¡l)-N-(t¡azol-2-¡l)acetam¡da 2-(6,7-dhydro-5H-prrolo[l,2-c]mdazol-l-l)-2-(6-(4-(lR,4R)-5-(2-(4-(4-(((S)-2,6-doxopiperid n3-l)amno)-2-fluorofenil)pperdnl-l)acetyl)-2,5-dazabcclo[2.2.1]heptan-2-l)fenl)-4-fluoro-loxoisoindolin-2-l)-N-(tiazol-2-l)acetamide 935 ΜΛ / a / ZUZZ / UU 100» 2-(6,7-dhydro-5H-prrolo[l,2-c]mdazol-l-l)-2-(6-(4-((l-(2-(4,-((2,6-dioxopperdn-3-l)amino)[l,l'-bfenl]-4-il)acetyl)piperdn-4-il)oxi)fenil)-4-fluoro-l-oxoisoindolin-2-il)-N-(tiazol-2-il)acetamide 2-(6,7-d¡h¡drO-5H-p¡nOlo[l,2-c]im¡dazol-l-¡l)-2-(6-(4-((lR,4R)-5-(2-(4-(3-(2,4dioxotetrahidropirimidin-l(2H)-¡l)-l-metil-lH-indazol-6-il)piperidin-l-il)acetyl)-2,5d¡azab¡c¡clo[2.2.1]heptan-2-il)fen¡l)-4-fluoro-l-oxo¡so¡ndol¡n-2-¡l)-N-(t¡azol-2-¡l)acetam¡da 936 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(4-(4-(2-(l-(4-((2,6-d¡oxop¡per¡d¡n-3-¡l)am¡no)2-fluorofen ¡l)-4-h¡droxipiper¡d¡n-4-il)acet¡l)piperaz¡nl-¡l)fen¡l)-4-fluoro-l-oxo¡so¡ndol¡n-2-¡l)-N(tiazol-2-il)acetamida 2-(6,7-dhydro-5H-pirrolo[l,2-c]mdazol-l-l)-2-(6-(4-(4-(2-(4-(4-(((S)-2,6-doxopperdn-3l)amno)-2-fluorofenil)pperdin-l-l)acetyl)-l,4-dazepan-l-l)fenl)-4-fluoro-l-oxosondoln-2-il)-N(tiazol-2l)acetam 2-(6,7-dhydro-5H-pirrolo[l,2-c]imidazol-l-il)-2-(6-(4-(l-(2-(4-(3-(2,4-dioxotetrahidropirimdl(2H)-l)-l-metl-lH-indazol-6-l)pperdl-il)-2-oxoetil)pperdn-4-l)fenl)-4-fluoro-loxosoindolin-2-l)-N-(tiazol-2-l)acetamide 937 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(4-(4-(2-(4-(4-((2,6-d¡oxop¡per¡d¡n-3-¡l)am¡no)2-fluoro fen¡l)p¡per¡d¡nl-¡l)-2-oxoet¡l)p¡per¡din-l-¡l)fen¡l)-4-fluoro-l-oxo¡so¡ndol¡n-2-¡l)-N-(t¡azol-2il)acetamida 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(6-(6-(2-(4-(3-(2,4-d¡oxotetrah¡drop¡r¡midinl(2H)-¡l)-l-metil-lH-indazol-6-il)-3,3-difluoropiper¡d¡nl-il)acetil)-2,6-diazasp¡ro[3.3]heptan-2il)pir¡din-3-il)-4-fluoro-l-oxoisoindolin-2-il)-N-(tiazol-2-il)acetamida 938 5-((2-(1-(6,7-dihydro-5H-pirrolo[l,2-c]midazol-l-il)-2-oxo-2-(tazol-2-ilamino)etil)-7-fluoro-3oxoisoindol-5-l)etinil)-N-(l-(2-(4-(3-(2,4-dioxotetrahdroprmdl(2H)-l)-l-metl-lH-ndazol-6l)-3,3-difluoropyrdin-l-l)acetyl)p-peridin-4-l)p-colinamide 2-(6,7-dhydro-5H-prrolo[l,2-c]mdazol-l-l)-2-(6-(4-(6-(2-(l-(4-((2,6-dioxopperdn-3-l)amino)2-fluorofenil)-4-hydroxypiperidn-4-l)acetyl)-2,6-diazaspiro[3,3]heptan-2-il)fenl)-4-fluoro-loxosoindoln-2-l)-N-(tazol-2-l)acetamida 939 2-(6,7-dhydro-5H-prrolo[l,2-c]mdazol-l-l)-2-(6-(4-(6-(2-(l-(5-((2,6-doxopperidin-3-l)amno)3-fluoropiridin-2-il)-4-hidroxipperidin-4-il)acetyl)-2,6-d¡azaspiro[3.3]heptan-2-¡l)fenil)-4-fluoro-loxoiso¡ndolin-2-¡l)-N-(tiazol-2-¡l)acetam¡da 2-(6,7-dhydro-5H-prrolo[l,2-c]mdazol-l-l)-2-(6-(4-(4-(2-(4-(3-(2,4-doxotetrahdroprmidinl(2H)-il)-l-metil-lH-indazol-6-il)-3,3-difluoropiperid¡nl-il)acetyl)-l,4-diazepan-l-il)fenil)-4-fluorol-oxoiso¡ndol¡n-2-¡l)-N-(tiazol-2-¡l)acetamida 940 2-(6,7-dhydro-5H-prolo[l,2-c]mdazol-l-l)-2-(6-(4-(4-(2-(4-(3-(2,4-doxotetrahdroprmdnl(2H)-il)-l-metil-lH-indazol-6-il)piperazin-l-il)acetil)pperazin-l-il)fenil)-4-fluoro-l-oxoisoindolin-2-il)-N-(tiazol-2-il)acetamida 2-(6,7-dhydro-5H-prrolo[l,2-c]mdazol-l-l)-2-(6-(4-(6-(2-((R)-4-(3-(2,4-doxotetrahdropirimidinl(2H)-il)-l-metl-lH-indazol-6-l)-3,3-dfluoropiperidinl-l)acetyl)-2,6-diazaspiro[3,3]heptan-2il)fenl)-4-fluoro-l-oxoisoindolin-2-il)-N-(tazol-2-il)acetamide 941 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(4-(6-(2-((S)-4-(3-(2,4-d¡oxotetrah¡drop¡r¡m¡d¡nl(2H)-il)-l-metil-lH-indazol-6-il)-3,3-difluoropiperidin-l-il)acetyl)-2,6-diazaspiro[3.3]heptan-2-il)fenil)-4-fluoro-l-oxoisoindolin-2-¡l)-N-(t¡azol-2-il)acetamide 2-(6,7-d¡hdro-5H-p¡rrolo[l,2-c]m¡dazol-l-¡l)-2-(6-(6-(6-(2-(4-(4-(((S)-2,6-d¡oxopiper¡d¡n-3il)amino)-2-fluorofenil)piperidin-l-il)acetyl)-2,6-diazaspiro[3.3]heptan-2-il)pir¡din-3-il)-4-fluoro-l oxoisoindol(n-2-l)-N-(tazol-2-l)acetamide 942 5-((2-(1-(6,7-dhydro-5H-pirrolo[l,2-c]mdazol-l-il)-2-oxo-2-(tazol-2-ilamino)etl)-7-fluoro-3oxoisoindol(n-5-l)etl)-N-(l-(2-(l-(4-((2,6-dioxopiper(din-3-il)amino)-2-fluorofen(l)-4-hidroxipiperidin-4-il)acetyl)piperid(n-4-il)picolinamida 2-(6,7-dihydro-5H-pirrolo[l,2-c]imidazol-l-il)-2-(6-(4-(6-(2-(l-(4-(((S)-2,6-dioxopiperidin-3l)amno)-2-fluorofenil)-4-dihydroxopiperidin-4l)acetyl)-2,6-diazopero[3,3]heptan-2l)fenl)-4-fluorol-oxoisoindolin-2l)-N-(tazol-2l)acetamide O 2-(6,7-dihidro-5H-p¡rrolo[l,2-c]im¡dazol-l-¡l)-2-(6-(4-(6-(2-(l-(4-(((R)-2),6-dioxop¡perid¡n-3¡l)am¡no)-2-fluorofenil)-4-hidrox¡p¡per¡d¡n-4-il)acetil)-2,6-d¡az aspiro[3.3]heptan-2-¡l)fen¡l)-4-fluorol-oxoisoindolin-2-il)-N-(tiazol-2-il)acetamida 943 2-(6,7-dhydro-5H-prolo[l,2-c]midazol-l-l)-2-(6-(4-(6-(2-(l-(4-((2,6-doxopperidin-3-l)amno)2-fluorofenil)-4-hidroxipiperdn-4-il)acetyl)-2,6-dazapro[3.3]heptan-2-l)fenil)-4-fluoro-loxoisoindolin-2-l)-N-(piridin-2-l)acetam 2-(6,7-dhydro-5H-prrolo[l,2-c]mdazol-l-l)-2-(6-(4-(6-(2-(4-(4-(((S)-2,6-doxopperidn-3il)amino)-2-fluorofenil)pperdnl-l)-2-oxoetil)-2-azaspro[3,3]heptan-2-l)fenl)-4-fluoro-loxosoindoln-2-il)-N-(tiazol-2-l)acetamide 2-(6,7-dihydro-5H-prolo[l,2-c]midazol-l-l)-2-(6-(4-(6-(2-l-(4-((2,6-dioxyphenylpyridin-3-il)amino)2,6-difluorofenl)proxyphenyl-4-il)acetyl)-2,6-diazoproxyphenyl[3,3]heptan-2-il)fenl)-4-fluoro-l-oxo-soindol-944 ινΐΛ / a / zuzz / uu / oo» 2-il)-N-(tiazol-2-il)acetamida 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡midazol-l-¡l)-2-(6-(4-(6-(2-(4-(3-(2,4-D-oxotetrah-drop-r-midinl(2H)-il)-l-metl-lH-indazol-6-l)-3,3-d-fluoropiperid-nl-il)-2-oxoetil)-2-azaspiro[3,3]heptan-2il)fen-4-fluoro-l-oxoisoindolin-2-l)-N-(tazol-2-il)acetamide 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(4-(6-(2-(l-(4-((2,6-d¡oxop¡per¡d¡n-3-¡l)amino)2,6-difluorofenil)-4-h idroxipiper¡d¡n-4-il)acetil)-2,6-diazaspiro[3.3]heptan-2-il)fenil)-4-fluoro-loxoisoindol¡n-2-¡l)-N-(t¡azol-2-¡l)acetamida 945 2-(6-(4-(6-(2-(l-(2-(difluoromet¡l)-4-((2,6-dioxopiper¡d¡n-3-¡l)am¡no)fenil)-4-h¡drox¡p¡peridin-4il)acetil)-2,6-d¡azaspiro[ 3.3]heptan-2-¡l)fen¡l)-4-fluoro-l-oxo¡so¡ndolin-2-¡l)-2-(6,7-d¡h¡dro-5Hp¡rrolo[l,2-c]¡m¡dazol-l-il)-N-(tiazol-2-¡l)acetamida 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-il)-2-(6-(l-(l-(2-(4-(3-(2,4-dioxotetrah¡drop¡r¡m¡dinl(2H)-¡l)-l-met¡l-lH-indazol-6-¡l)-3z3-d¡fluoropiper¡d¡nl-¡l)ace t¡l)p¡per¡din-4-¡l)-lH-p¡razol·4-¡l)-4fluoro-l-oxoisoindol¡n-2-il)-N-(tiazol-2-¡l)acetamida 2-(6z7-dihydro-5H-prrolo[lz2-c]imdazol-l-l)-2-(6-(4-(2-(2-(4-(3-(2z4-dioxotetrahdroprmidinl(2H)-l)-l-metl-lH-indazol-6-l)-3z3-dfluoropperdnl-l)acetl)-2z7-dazaspiro[3.5]nonan-7il)fenl)-4-fluoro-l-oxoisondoln-2-l)-N-(tiazol-2-l)acetam 946 2-(6,7-dhydro-5H-prrolo[l,2-c]midazol-l-l)-2-(6-(4-(2-(2-l-(4-((2,6-doxopperidin-3-l)amno)2-fluorofenil)-4-hidroxipiperdn-4-il)acetyl)-2,7-dazospero[3.5]nonan-7-l)fenl)-4-fluoro-loxoisoindolin-2-il)-N-(tazol-2-l)acetam N-(l-(2-(l-(4-(((R)-2,6-d¡oxop¡per¡d¡n-3-¡l)am¡no)-2-fluorofen¡l )-4-h¡drOxip¡perid¡n-4il)acet¡l)p¡per¡d¡n-4-¡l)-5-((7-fluoro-2-(l) -((R)-6-fluoro-6,7-d¡h¡dro-5H-pirrolo[l,2-c]¡m¡dazol-l-il)-2oxo-2 -(t¡azol-2-¡lam¡no)et¡l)-3-oxo¡so¡ndol¡n-5-¡l)et¡n¡l)p¡col¡nam¡da 947 2-(6,7-dih¡dro-5H-p¡rrolo[l,2-c]im¡dazol-l-¡l)-2-(6-(4-(6-(2-(l-(3-(2,4-dioxotetrah)¡drop¡r¡midinl(2H)-¡l)-l-met¡l-lH-indazol-6-¡l)-4-h¡drox¡p ¡per¡din-4-¡l)acet¡l)-2,6-diazaspiro[3.3]heptan-2-¡l)fen¡l)4-fluoro-l-oxo¡so¡ndolin-2-il)-N-(t¡azol-2-¡l)acetam¡da CT 2-(6,7-dihydro-5H-pirrolo[l,2-c]imidazol-l-il)-2-(6-(6-(6-(2-(l-(4-(((S)-2,6-dioxopiperidin-3l)amino)-2-fluorofenil)-4-dihydroxopiperidin-4-il)acetyl)-2,6-diazopiro[3,3]heptan-2-l)ppirdin-3-il)-4fluoro-l-oxoisoindolin-2-l)-N-(tazol-2-l)acetamida O 2-(6,7-dihidro-5H-p¡rrolo[l,2-c]im¡dazol-l-¡l)-2-(6-(6-(6-(2-(l-(4-((R)-2,6-dioxop¡per¡d¡n-3¡l)am¡no)-2-fluorofenil)-4-hidr) ox¡p¡per¡d¡n-4-il)acetil)-2,6-d¡azaspiro[3.3]heptan-2-¡l)p¡r¡d¡n-3-il)-4fluoro-l-oxoiso¡ndol¡n-2-¡l)-N-(t¡azol-2-¡l)acetam¡da 948 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(4-(6-(2-(4-(5-((2,6-d¡oxop¡per¡d¡n-3-¡l)am¡no)3-fluoropiridin-2-il)piperidin-l-il)acetyl)-2,6-diazasp¡ro[3.3]heptan-2-il)fen¡l)-4-fluoro-loxoiso¡ndolin-2-¡l)-N-(tiazol-2-¡l)acetam¡da 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(4-(6-(2-(4-(3-(2,4-d¡oxotetrah)¡drop¡r¡midinl(2H)-¡l)-l-met¡l-lH-indazol-6-¡l)-3,3-d¡fluor opiper¡d¡nl-¡l)acet¡l)-2,6-diazaspiro[3.4]octan-2il)fenil)-4-fluoro-l-oxoisoindolin-2-¡l)-N-(t¡azol-2-il)acetam¡da 949 2-(6,7-dhydro-5H-prrolo[l,2-c]mdazol-l-l)-2-(6-(4-(7-(2-(4-(3-(2,4-doxotetrahdroprmdnl(2H)-il)-l-metil-lH-indazol-6-il)-3,3-difluoropiperid(nl-il)acetyl)-2,7-diazaspro[3.5]nonan-2il)fenil)-4-fluoro-l-oxoisoindolin-2-l)-N-(tazol-2-il)acetamide H 2-(6,7-dhydro-5H-prrolo[l,2-c]mdazol-l-l)-2-(6-(4-(7-(2-(l-(4-((2,6-dioxopperdn-3-l)amino)2-fluorofenil)-4-hidroxipiperidin-4-il)acetyl)-2,7-dazapro[3.5]nonan-2-l)fenl)-4-fluoro-1oxoisoindoln-2-l)-N-(tazol-2-il)acetamida 2-(6,7-dihydro-5H-prolo[l,2-c]midazol-l-l)-2-(6-(4-(6-(2-(l-(4-((2,6-doxopperidin-3-l)amno)2-fluorofenil)-4-hydroxypiperdn-4-il)acetyl)-2,6-diazopro[3.4]octan-2-l)fenl)-4-fluoro-l950 oxoisoindoln-2-il)-N-(tazol-2-il)acetamide4-dioxotetradroprimidin-l(2H)-l)-l-metl-lH-indazol-6-l)-3,3difluoropiperidinl-il)acetyl)-2,6-diazospero[3,3]heptan-2-il)fenil)-4-fluoro-l-oxoisoindolin-2-il)-2((R)-6-fluoro-6,7-dihydro-5H-prrolo[l,2-c]midazol-l-l)-N-(tazol-2-il)acetamida 2-(6-(4-(6-(2-(l-(2-doro-4-((2,6-d¡oxop¡per¡din-3-il)am¡no)fen¡l)-4-hidroxip¡per¡d¡n-4-¡l)acetil)-2,6diazaspiro[3.3]he) ptan-2-¡l)fenil)-4-fluoro-l-oxoiso¡ndolin-2-il)-2-(6,7-d¡hidro-5H-pirrolo[l,2c]imidazol-l-il)-N-(t¡azol-2-il)acetam¡da 951 IVIA / a / ZUZZ / UU 100» 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡midazol-l-¡l)-2-(6-(6-(6-(2-(4-(3-(2,4-d¡oxotetrahidrop¡r¡midinl(2H)-¡l)-l-met¡l-lH-indazol-6-¡l)-3,3-d¡fluoropiper¡d¡nl-¡l)-2-oxoetil)-2,6-d¡azasp¡ro[3,3]heptan-2il)piridin-3-il)-4-fluoro-l-oxoisoindol¡n-2-¡l)-N-(tiazol-2-il)acetam¡da 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(4-(6-(2-(l-(4-((S)-2,6-d ¡oxopiper¡d¡n-3il)amino)-2,6-d¡fluorofenil)-4-h¡drox¡p¡per¡d¡n-4-il)acet¡l)-2,6-d¡azaspiro[3.3]heptan-2-¡l)fenil)-4fluoro-l-oxoisoindol¡n-2-il)-N-(t¡azol-2-¡l)acetamida 2-(6-(4-(6-(2-(l-(2-chloro-4-(((R)-2,6-d¡oxopiperid¡n-3-¡l)am¡no)fen¡l)-4-hydroxypiper¡d¡n-4-¡l)acet¡l)952 2,6-diazaspr[3.3]heptan-2-il)fenl)-4-fluoro-l-oxoisoindolin-2-l)-2-(6,7-dihydro-5H-prrolo[l,2c]imdazol-l-l)-N-(tazol-2-l)acetamide 2-(6,7-dihydro-5H-prolo[l,2-c]imdazol-l-l)-2-(6-(4-(7-(2-l-(4-(((S)-2,6-dioxopiper[l,2-il)amino)-2-fluorofenil)-4-hydroxyper[l,4-il)acetyl)-2,7-diazopr[3.5]nonan-2-l)fenl)-4-fluorol-oxoisoindolin-2-il)-N-(tiazol-2-il)acetann 2-(6,7-dihydro-5H-prolo[l,2-c]imdazol-l-l)-2-(6-(4-(7-(2-(R)-4-(3-(2,4-doxotetrahdropinmidinl(2H)-il)-l-metil-lH-indazol-6-il)-3,3-difluoropiperid¡nl-il)acetyl)-2,7-diazaspr[3.5]nonan-2il)fen¡l)-4-fluoro-l-oxoisoindolin-2-l)-N-(tiazol-2-il)acetam¡da MA / a / ZUZZ / UU / 00» 2-(6,7-dhydro-5H-prrolo[l,2-c]mdazol-l-l)-2-(6-(4-(6-(2-(4-(3-(2,4-Doxytetrahydroacetyl(2H)-il)-5-fluoro-l-methyl-lH-ndazol-6-il)piperazin-l-l)acetyl)-2,6-diazasprO[3,3]heptan-2-il)fenl)4-fluoro-l-oxoisondol-2-l)-N-(tazol-2-il)acetamide 2-(6,7-d¡h¡drO-5H-p¡nOlo[l,2-c]im¡dazol-l-¡l)-2-(6-(4-(6-(2-((3R,4S)-4-(3-(2,4dioxotetrahidropirimidin-l(2H)-¡l)-l-metil-lH-indazol-6-il)-3-fluorop¡peridin-l-¡l)acetyl)-2,6d¡azasp¡ro[3.3]heptan-2-¡l)fen¡l)-4-fluoro-l-oxo¡so¡ndol¡n-2-¡l)-N-(t¡azol-2-¡l)acetam¡da 954 ΜΛ / a / ZUZZ / UU / 00» 2-(6,7-dhydro-5H-pirrolo[l,2-c]mdazol-l-l)-2-(6-(4-(6-(2-((3S,4R)-4-(3-(2,4dioxotetrahidropirimidin-l(2H)-il)-l-metyl-lH-indazol-6-il)-3-fluoropiperidin-l-il)acetyl)-2,6dazospero[3,3]heptan-2-l)fenl)-4-fluoro-l-oxosoindol-2-l)-N-(tazol-2-l)acetam 2-(6,7-dhydro-5H-prrolo[l,2-c]mdazol-l-l)-2-(6-(4-(2-(2-l-(4-(((S)-2,6-doxopperdn-3l)amino)-2-fluorofenl)-4-hydroxipperdn-4l)acetyl)-2,7-d¡azasp¡ro[3.5]nonan-7-¡l)fenil)-4-fluorol-oxo¡soindolin-2-¡l)-N-(tiazol-2-il)acetam¡da 955 ΜΛ / a / ZUZZ / UU / 00» 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(4-(6-(2-(l-(3-(2,4-d¡oxotetrah¡drop¡r¡m¡d¡nl(2H)-il)-5-fluoro- l-metil-lH-¡ndazol-6-il)-4-hydrroxipiperidin-4-il)acetil)-2,6-diazaspiro[3.3]heptan2-¡l)fen¡l)-4-fluoro-l-oxo¡so¡ndol¡n-2-¡l)-N-(t¡azol-2-¡l)acetam¡da 2-(6-(4-(2-(2-(l-(2-chloro-4-(((S)-2,6-doxopiperidin-3-l)amno)fenl)-4-hidroxppendin-4-l)acetyl)2,7-dazapiro[3.5]nonan-7-il)fenil)-4-fluoro-l-oxoisoindolin-2-l)-2-(6,7-dihydro-5H-prolo[l,2c]midazol-l-l)-N-(tazol-2-il)acetamide 956 2-(6,7-dhydro-5H-prrolo[l,2-c]mdazol-l-l)-2-(6-(4-(6-(2-(S)-4-(3-(2,4-doxotetrahdroprmdnl(2H)-il)-5-fluoro-l-metil-lH-ndazol-6-il)-3,3-difluoropyridin-l-il)acetyl)-2,6dazol-2-l)fen-4-fluoro-l-oxoso-ndol-2-l)-N-(tazol-2-l)acetam 2-(6,7-dhydro-5H-prrolo[l,2-c]mdazol-l-l)-2-(6-(4-(6-(2-((R)-4-(3-(2,4-D-oxotetrah-dropirimidinl(2H)-il)-5-fluoro-l-methyl-lH-ndazol-6-l)-3,3-d-fluoropyridin-l-il)acetyl)-2,6d-azaspr[3,3]heptan-2-l)fenl)-4-fluoro-l-oxo-so-ndol-2-l)-N-(tazol-2-l)acetamide 957 2-(6-(4-(6-(2-(l-(4-(((S)-2,6-d¡oxop¡per¡d¡n-3-¡l)am¡no)-2-fluorofen¡l)-4-hydroxop¡per¡cl¡n-4-¡l)acet¡l) 2,6-d¡azaspiro[3.3]heptan-2-¡l)fen¡l)-4-fluoro-l-oxo¡so¡ndol¡n-2-¡l)-2-((R)-6-fluoro-6,7-d¡h¡dro-5Hpirrolo[l,2-c]¡m¡dazol-l-il)-N-(tiazol-2-¡l)acetamida O 2-(6-(4-(6-(2-(l-(4-(((R)-2,6-d¡oxopiper¡d¡n-3-¡l)am¡no)-2-fluorofenil)-4-h¡drox¡piperid¡n-4-il)acet¡l)2,6-diazasp¡ro[3.3]hepta) n-2-il)fen¡l)-4-fluoro-l-oxoisoindol¡n-2-¡l)-2-((R)-6-fluoro-6,7-d¡h¡dro-5Hpirrolo[l,2-c]imidazol-l-il)-N-(tiazol-2-¡l)acetam¡da 958 2-(6,7-dih¡dro-5H-p¡rrolo[l,2-c]im¡dazol-l-¡l)-2-(6-(4-(6-(2-(4-(3-(2,4-dioxotetrah)¡drop¡r¡midinl(2H)-¡l)-l-met¡l-lH-indazol-6- ¡l)-3-fluorop¡per¡din-l-¡l)acet¡l)-2,6-diazaspiro[3.3]heptan-2-il)fen¡l)4-fluoro-l-oxo¡so¡ndolin-2-il)-N-(t¡azol-2-¡l)acetam¡da 2-(6,7-dihydro-5H-prrol[l,2-c]mdazol-l-l)-2-(6-(4-(2-(2-l-(4-(((S)-2,6-doxopiperdn-3il)amino)-2,6-difluorofenil)-4-dihydroxopiperdn-4-l)acetyl)-2,7-diazopiro[3.5]nonan-7-l)fenil)-4fluoro-l-oxoisoindolin-2-il)-N-(tiazol-2-il)acetam 2-(6,7-dhydro-5H-prrolo[l,2-c]mdazol-l-il)-2-(6-(4-(6-(2-(l-(4-((2,6-dioxopiperidin-3-l)amino)2,5-dfluorofenl)-4-hidroxipiperidin-4-l)acetyl)-2,6-dazapro[3,3]heptan-2-l)fenl)-4-fluoro-loxosoindolin-2-il)-N-(tiazol-2-l)acetamide 959 2-(4-chloro-6-(4-(6-(2-(l-(4-(((S)-2,6-d¡oxopiper¡d¡n-3-¡l)am¡no)-2-fluorofen¡l)-4-hidrox¡p¡perid¡n-4) il)acetil)-2 / 6-diazaspiro[3.3]heptan-2-il)fenil)-l-oxoisoindolin-2-il)-2-(6,7-dih¡dro-5H-pirrolo[l,2c]im¡dazol-l-¡l)-N-(t¡azol-2-¡l)acetam¡da 2-(6,7-dhydro-5H-prrolo[l,2-c]mdazol-l-l)-2-(6-(4-(7-(2-(l-(4-(((S)-2,6-doxopiper-dn-3il)amno)-2,6-dfluorofenl)-4-hdrox-pper-din-4-il)acetyl)-2,7-d¡azaspiro[3.5]nonan-2-¡l)fenil)-4fluoro-l-oxoisoindol¡n-2-il)-N-(t¡azol-2-¡l)acetamida 2-(6-(4-(7-(2-(l-(2-chloro-4-(((S)-2z6-d¡oxopipend¡n-3-¡l)am¡no)fenil)-4-h¡drox¡p¡per¡d¡n-4-¡l)acet¡l)960 2,7-diazaspr[3.5]nonan-2-il)fenl)-4-fluoro-l-oxoisoindolin-2-l)-2-(6,7-dihydro-5H-prrolo[l,2c]imdazol-l-l)-N-(tazol-2-l)acetamide 2-(6,7-dhydro-5H-prrolo[l,2-c]mdazol-l-l)-2-(6-(4-(6-(2-(l-(5-(((S)-2,6-doxopiperdn-3il)amino)-3-fluoropindn-2-l)-4-hidroxipiperidn-4-il)acetyl)-2,6-diazaspiro[3,3]heptan-2-il)fenil)-4fluoro-l-oxoisoindoln-2-l)-N-(tazol-2-il)acetam 2-(6,7-dihydro-5H-prolo[l,2-c]imidazol-l-l)-2-(6-(4-(7-(2-((R)-4-(3-(2,4-dioxotetrah-dropirimidinl(2H)-il)-l-metil-lH-indazol-6-il)-3,3-dfluoropiperid-nl-il)-2-oxoetil)-2,7-diazaspro[3.5]nonan-2il)fen-4-fluoro-l-oxoisoindol-2-l)-N-(tazol-2-il)acetamide 961 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(4-(7-(2-((S)-4- (3-(2,4-d¡oxotetrah¡drop¡r¡m¡d¡nl(2H)-¡l)-l-met¡l-lH-indazol-6-¡l)-3,3-d¡fluoropiper¡d¡nl-¡l)-2-oxoetil)-2,7-d¡azasp¡ro[3.5]nonan-2il)fenil)-4-fluoro-l-oxoisoindolin-2-¡l)-N-(t¡azol-2-il)acetam¡da 2-(6,7-dihydro-5H-pirrolo[l,2-c]imidazol-l-il)-2-(6-(l-(l-(2-(l-(4-(((S)-2,6-dioxopiperidin-3l)amno)-2-fluorofenil)-4-hidrox-p-peridin-4l)acetyl)p-peridin-4l)-lH-p-razol-4l)-4-fluoro-loxoiso-ndolin-2l)-N-(tiazol-2l)acetamida 2-(6,7-dihydro-5H-prrolo[l,2-c]imdazol-l-l)-2-(6-(4-(2-(2-((R)-4-(3-(2,4-dioxotetrahidropirimidinl(2H)-l)-l-metl-lH-indazol-6-l)-3,3-dfluoropperdnl-l)-2-oxoetil)-2,7-dazasspro[3.5]nonan-7l)fenl)-4-fluoro-l-oxoisoindol-2l)-N-(tiazol-2l)acetamide 962 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-2-(6-(4-(2-(2-((S)-4-(3-(2,4-d¡oxotetrah¡drop¡r¡m¡d¡nl(2H)-¡l)-l-met¡l-lH-indazol-6-¡l)-3,3-d¡fluoropiper¡d¡nl-¡l)-2-oxoetil)-2,7-d¡azasp¡ro[3.5]nonan-7il)fenil)-4-fluoro-l-oxoisoindolin-2-¡l)-N-(t¡azol-2-il)acetam¡da 2-(6-(4-(6-(2-(l-(2-chloro-4-(((S)-2),6-d¡oxopiper¡d¡n-3-¡l)amino)-6-fluorofenil)-4-hidroxip¡perid¡n-4il)acetil)-2,6-d¡azaspiro[3.3]heptan-2-¡l)f en¡l)-4-fluoro-l-oxo¡so¡ndolin-2-il)-2-(6,7-d¡hidro-5Hpirrolo[l,2-c]imidazol-l-il)-N-(tiazol-2-¡l)acetam¡da 2-(6,7-dhydro-5H-pirrolo[l,2-c]imdazol-l-l)-2-(6-(4-(6-l-(4-(((S)-2,6-dioxopiperidin-3-il)amino)2-fluorofenil)-4-hydroxypyridin-4-carbon-l)-2,6-dazapro[3,3]heptan-2-il)fen-4-fluoro-l963 oxoisoindolin-2-il)-N-(tazol-2-il)acetamide 2-(6,7-dih¡dro-5H-p¡rrolo[l,2-c]im¡dazol-l-¡l)-2-[6-[4-[2-[2-[l-[4-(2,4-d¡oxohexah¡dropir¡mid¡nl-¡l)2-fluoro-fen¡l ]-4-h¡droxi-4-p¡per¡d¡l]acet¡l]-2,6-d¡azaspiro[3.3]heptan-6-¡l]fen¡l]-4-fluoro-¡ndazol-2il]-Nt¡azol-2-¡l-acetamida 2-(6,7-dihydro-5H-pirrolo[l,2-c]imidazol-l-il)-2-[6-[4-[2-[2-[(2s,6r)-l-[4-[(2,6-dioxo-3piperidl)amno]-2-fluoro-fenil]-4-hidroxi-2,6-dimetl-4-p-peridil]acetl]-2,6-dazospro[3,3]heptan-6l]fenl]-4-fluoro-ndazol-2-l]-Ntazol-2-l-acetamide2-c]¡m¡dazol-l-il)-2-[6-[4-[4-[2-[4-[4-[[(3S)-2,6-d¡oxo-3piper¡dil]amino]-2-fluoro-fenil]-l-pi peridil]-2-oxo-et¡l]-4-hidroxi-l-piperidil]fenil]-7-fluoro-indazol-2¡l]-Nt¡azol-2-¡l-acetam¡da 964 2-(6,7-dhydro-5H-prrolo[l,2-c]mdazol-l-l)-2-[6-[6-[4-[2-[4-[4-[[(3S)-2,6-dioxo-3pperidl]amno]-2-fluoro-fenl]-lpperdl]-2-oxo-etl]-4-hdrox-lpperdil]-3-prdl]-4-fluorondazol-2-l]-Ntazol-2-l-acetam 2-(6,7-d¡hidro-5H-pirrolo[l,2-c]imidazol-l-il)-2-[6-[6-[4-[2-[4-[4-[[(3S)-2,6-dioxo-3p¡per¡d¡l]am¡no]-2-fluoro -fen¡l]-lp¡per¡d¡l]-2-oxo-et¡l]-4-h¡drox¡-l-piper¡dil]-3-p¡r¡d¡l]-7-fluoro¡ndazol-2-¡l]-Nt¡azol-2-¡l-acetam¡da 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]im¡dazol-l-¡l)-2-[6-[4-[l-[2-[4-[4-[(2,6-d¡oxo-3piperid¡l)amino]fenil] -l-piperidil]acetil]-4-piperidil]-2-metil-fenil]-4-fluoro-l-oxo-isoindolin-2-il]-Ntiazol-2-il-acetamida 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-il)-2-[6-[4-[2-[2-[7-[3-(2,4-dioxohexah¡drop¡r¡midin-l-il)l-metil-indazol-6-¡l]-4-azasp¡ro[2.5]octan-4-il]acet¡l]-2, 6-d¡azasp¡ro[3.3]heptan-6-¡l]fenil]-4-fluorol-oxo-¡so¡ndol¡n-2-¡l]-N-(2-pir¡d¡l)acetam¡da 2-(6,7-dhydro-5H-prrolo[l,2-c]mdazol-l-l)-2-[6-[4-[2-[2-[7-[3-(2,4-doxohexahdroprmidin-l-l)l-metil-indazol-6-il]-4-azaspiro[2.5]octan-4-il]acetyl]-2,6-diazaspiro[3.3]heptan-6-il]fenil]-4-fluorol-oxo-so-ndol-2-l]-Ntazol-2-l-acetamida 2-(6,7-dhydro-5H-prrolo[l,2-c]mdazol-l-l)-2-[6-[4-[6-[4-[3-(2,4-doxohexahdroprmdnl-l)-lmetl-ndazol-6-l]-3,3-difluoro-pperdnl-carbon-l]-2-azaspro[3,3]heptan-2-l]fen-4-fluoro-loxo-sondol-2-l]-N-tiazol-2-l-acetamida 966 2-(6,7-d¡hidro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-2-[6-[4-[2-[2-[l-[4-(2,4-dioxohexahidrop¡r¡midin-l-il)2-fluoro-fenil]-4- h¡droxi-4-piperid¡l]acet¡l]-2,6-diazaspiro[3.3]heptan-6-il]fenil]-4-fluoro-l-oxo¡soindolin-2-il]-N-tiazol-2-¡l-acetamida 2-(6,7-dhydro-5H-prrolo[l,2-c]mdazol-l-l)-2-(6-(4-(6-(2-(l-(4-(2,6-d¡oxop¡per¡d¡n-3-¡l)-2fluorofenil)-4-h¡droxipiper¡d¡n-4-¡l)acetil)-2,6-diazasp ¡ro[3.3]heptan-2-il)fenil)-4-fluoro-loxoiso¡ndolin-2-¡l)-N-(tiazol-2-¡l)acetam¡da 2-[6-[4-[2-[2-[l-[2-chloro-4-(2,4-d¡oxohexahidropirimidin-l-il)fen¡l]-4-hidroxi-4-p¡per¡d¡l]acetil]-2,6diazaspiro[3.3]h eptan-6-il]fenil]-4-fluoro-l-oxo-isoindolin-2-¡l]-2-(6,7-dihidro-5H-pirrolo[l,2c]im¡dazol-l-¡l)-Nt¡azol-2-¡l-acetam¡da 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡midazol-l-¡l)-2-[6-[4-[2-[2-[l-[4-(2,6-d¡oxo-3-p¡perid¡l)-2-fluoro967 fenil]-4-h¡droxi-4-p¡per¡dil]acet¡l]-2,7-d¡azaspiro[3.5]nonan-7-¡l]fenil]-4-fluoro-l-oxo-¡so¡ndolin-2¡l]-Nt¡azol-2-¡l-acetamida 2-(6,7-dihidro-5H-pirrolo[l,2-c]imidazol-l-il)-2-[6-[4-[7-[2-[l-[4-(2,6-d¡oxo-3-piperidil)-2-fluorofen¡l]-4-h¡dro xl·4-p¡perid¡l]acet¡l]-2,7-d¡azaspiro[3.5]nonan-2-¡l]fen¡l]-4-fluoro-l-oxo-¡so¡ndol¡n-2il]-Nt¡azol-2-¡l-acetamida 2-(6,7-dihydro-5H-prrolo[l,2-c]mdazol-l-l)-2-[6-[4-[2-[2-[(2s,6r)-l-[4-[(2,6-dioxo-3piperdl)amno]-2-fluoro-fen]-4-hydrox-2,6-dimethyl-4-piperidil]acetyl]-2,6-diazospero[3,3]heptan-6l]fenl]-4-fluoro-l-oxo-isoindol-2l]-Ntazol-2l-acetam 2-[6-[4-[2-[2-[4-amino-l-[4-[(2z6-doxo-3-piperidil)amino]-2-fluoro-fenil]-4-pperdl]acetl]-2,6diazaspro[3.3]heptan-6-il]fenl]-4-fluoro-l-oxo-isoindol-2-l]-2-(6,7-dihydro-5H-prrolo[lz2c]imdazol-l-l)-N-tiazol-2-l-acetamide 968 2-(6,7-dihydro-5H-pirrolo[l,2-c]imidazol-l-il)-2-[6-[4-[2-[2-[l-[4-(2,4-d¡oxohexahidropirimidin-l-il)2-fluoro-fenil]-4-hydroxy-4-piperid¡l]acet¡l]-2,7-diazaspiro[3.5]nonan-7-il]fenil]-4-fluoro-l-oxo¡soindolin-2-il]-N-tiazol-2-¡l-acetamide Isómero A1 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-2-[6-[4-[2-[2-[l-[4-[[2,6-dioxo-3-p¡per¡d¡l]amino]-2fluoro-fenil]-4-h¡ droxi-azepan-4-¡l]acetil]-2,6-diazasp¡ro[3.3]heptan-6-il]fen¡l]-4-fluoro-1-oxo¡so¡ndol¡n-2-¡l]-Nt¡azol-2-¡l-acetamida, isómero Al Isómero A2 2-(6,7-dhydro-5H-prrolo[l,2-c]mdazol-l-l)-2-(6-(4-(6-(2-(l-(4-((2,6-d¡oxop¡per¡d¡n-3-¡l)am¡no)2-fluorofen¡l)-4-hidrox¡azepan-4-¡l)acet¡l)-2,6-d¡azasp¡ro[3.3]heptan-2-¡l)fen¡l)-4-fluoro-loxo¡so¡ndolin-2-¡l)-N-(tiazol-2-¡l)acetam¡da, isomer A2 969 Isomer ' Β1 2-(6,7-dihidro-5H-pirrolo[l,2-c]imidazol-l-il)-2-(6-(4-(6-(2-(l-(4-((2,6-d¡oxopiperidin-3-¡l)amino) 2-fluorofenil)-4-hidroxazepan-4-l)acetyl)-2,6-dazaspro[3.3]heptan-2-l)fenil)-4-fluoro-loxosoindolin-2-il)-N-(tiazol-2-l)acetamide, isomero B1 Isomero; B2 2-(6,7-dihydro-5H-pirrolo[l,2-c]imidazol-l-il)-2-(6-(4-(6-(2-(l-(4-((2,6-dioxopiperidin-3-il)amino)2-fluorofen¡l)-4-hydroxazepan-4-il)acet¡l)-2,6-diazaspro[3,3]heptan-2-¡l)fen¡l)-4-fluoro-loxoiso¡ndolin-2-¡l)-N-(tiazol-2-¡l)acetam¡da, isomer B2 2-(6,7-d¡h¡dro-5H-p¡rrolo[l,2-c]¡m¡dazol-l-¡l)-2-[6-[4-[2-[2-[l-[4-(2,4-d¡oxohexah¡drop¡r¡m¡d¡nl-¡l)2 -(tr¡fluoromet¡l)fen¡l]-4-h¡drox¡-4-p¡per¡d¡l]acet¡l]-2,6-diazasp¡ro[3.3]heptan-6-¡l]fen¡l]-4-fluoro-l oxo-¡soindol¡n-2-¡l]-Nt¡azol-2-il-acetamida 970 2-[6-[4-[2-[2-[l-[2,6-dichloro-4-(2,4-d¡oxohexahydrop¡r¡m¡d¡nl-l)phenyl]-4-hydroxy¡-4-p¡per¡d¡l]acetyl]2,6-d¡azaspiro[3.3]heptan-6-yl]phenyl l]-4-fluoro-l-oxo-¡so¡dolin-2-yl]-2-(6,7-hydro-5H-pyrrolo[l,2c]im¡dazole-l-¡l)-Nt¡azol-2-l-acetam 2-[6-[4-[7-[2-[l-[2-chloro-4-(2,4-d¡oxohexahydrop¡nm¡din-l-¡l)phen¡l]-4-hydroxy-4-p¡per¡d¡l]acet¡l]-2,7d¡aspr onan-2-yl]phen¡l]-4-fluoro-l-oxo-¡so¡ndol¡n-2-¡l]-2-(6,7-hydro-5H-p¡rrolo[l,2c]im¡dazol-l-¡l)-Nt¡azol-2-yl-acetate 2-[6-[4-[2-[2-[l-[2-cyano-4-(2,4-d¡oxohexahydropyrim¡din-l-¡l)phenyl]-4-hydroxy¡-4-p¡per¡d¡l]acetyl]-2,6diazaspiro[3.3]h heptane-6-yl]phenyl]-4-fluoro-l-oxo-isoindoline-2-¡l]-2-(6,7-dihydro-5H-pyrrolo[l,2c]imidazol-l-yl)-Nt¡azol-2-¡l-acetam¡da 2-[6-[4-[2-[2-[l-[2-chloro-4-(2,4-dioxohexahydropyrrn¡d¡nl-¡l)phen¡l]-4-hydroxy¡-4-piper¡d¡l]acetyl] -2,7diazaspiro[3.5]nonan-7-yl]phen¡l]-4-fluoro-l-oxo-isoindol¡n-2-¡l]-2-(6,7-dihydro-5H-prrolo[l,2- Isomer, r 1 2-(6,7-d¡hydro-5H-p¡rrolo[l,2-c]¡midazole-l-¡l)-2-[6-[4-[2-[2-[l-[4-[[2,6-dioxo-3-piperidylamino-2-fluoro-5-methoxyphenyl-4-hydroxy-4-piperidylacetyl-2,6-diazaspiro[3,3]heptan-6-ylphenyl-4-fluoro-loxo-isoindolin-2-yl-Nthazol-2-yl-acetamide, isomer 1, or a pharmaceutically acceptable salt thereof.

177. A compound according to any one of claims 79 to 176, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition for use as a therapeutically active substance.

178. A compound according to any one of claims 79 to 176, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, for use in the therapeutic and / or prophylactic treatment of cancer.

179. A method for treating a patient with an EGFR-mediated disorder, comprising administering a compound of any one of claims 79 to 176, or a pharmaceutically acceptable salt thereof,optionally in a pharmaceutical composition.

180. The method according to claim 179, further characterized in that the patient is a human.

181. The method according to claim 179 or 180, further characterized in that the EGFR-mediated disorder is a cancer, a tumor, or an abnormal cell proliferation.

182. The method according to claim 181, further characterized in that the EGFR-mediated disorder is a cancer or a tumor.

183. The method according to claim 181, further characterized in that the EGFR-mediated disorder is an abnormal cell proliferation.

184. The method according to claim 182, further characterized in that the cancer is lung cancer.

185. The method according to claim 184, further characterized in that the lung cancer is non-small cell lung cancer.

186. The method according to any one of claims 181 to 185,further characterized in that the cancer, tumor, or abnormal cell proliferation has an EGFR protein with at least one mutation.

187. The method according to any one of claims 181 to 186, further characterized in that the cancer, tumor, or abnormal cell proliferation has an EGFR protein with the L858R mutation.

188. The method according to any one of claims 181 to 187, further characterized in that the cancer, tumor, or abnormal cell proliferation has an EGFR protein with the T790M mutation.

189. The method according to any one of claims 181 to 188, further characterized in that the cancer, tumor, or abnormal cell proliferation has an EGFR protein with the C797S mutation.

190. The method according to any one of claims 181 to 189, further characterized in that the cancer,191. The method according to any one of claims 181 to 189, further characterized in that the cancer, tumor, or abnormal cell proliferation has an EGFR protein with the L792H mutation.

192. The method according to any one of claims 181 to 186, further characterized in that the cancer, tumor, or abnormal cell proliferation has an EGFR protein with the T790M / L858R mutation.

193. The method according to any one of claims 181 to 186, further characterized in that the cancer, tumor, or abnormal cell proliferation has an EGFR protein with the T790M / L858R / C797S mutation.

194. The method according to any one of claims 181 to 186, further characterized in that the cancer,195. The method according to any one of claims 179 to 194, further characterized in that an additional EGFR inhibitor is administered.

196. The method according to claim 195, further characterized in that the additional EGFR inhibitor is a tyrosine kinase inhibitor.

197. The method according to claim 196, further characterized in that the additional EGFR inhibitor is osimertinib.

198. The method according to claim 196, further characterized in that the additional EGFR inhibitor is rociletinib.

199. The method according to claim 196, further characterized in that the additional EGFR inhibitor is avitinib.

200. The method according to claim 196,further characterized in that the additional EGFR inhibitor is lazertinib.

201. The method according to claim 196, further characterized in that the additional EGFR inhibitor is nazartinib.

202. The method according to claim 195, further characterized in that the additional EGFR inhibitor is an antibody against a mutated form of EGFR.

203. The method according to claim 202, further characterized in that the additional EGFR inhibitor is cetuximab.

204. The method according to claim 202, further characterized in that the additional EGFR inhibitor is panitumab.

205. The method according to claim 202, further characterized in that the additional EGFR inhibitor is necitumab.

206. The method according to any one of claims 179 to 205,further characterized in that a MET inhibitor is also administered.

207. The method according to any one of claims 179 to 206, further characterized in that the patient receives an additional chemotherapeutic agent.

208. The use of a compound of any one of claims 79 to 176, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an EGFR-mediated disorder in a patient.

209. The use as claimed in claim 208, wherein the patient is a human.

210. The use as claimed in claim 208 or 209, wherein the EGFR-mediated disorder is a cancer, a tumor, or abnormal cell proliferation.

211. The use as claimed in claim 210, wherein the EGFR-mediated disorder is a cancer or a tumor.

212. The use as claimed in claim 210,212. The use as claimed in claim 211, wherein the EGFR-mediated disorder is abnormal cell proliferation.

213. The use as claimed in claim 211, wherein the cancer is lung cancer.

214. The use as claimed in claim 213, wherein the lung cancer is non-small cell lung cancer.

215. The use as claimed in any of claims 210 to 214, wherein the cancer, tumor, or abnormal cell proliferation has an EGFR protein with at least one mutation.

216. The use as claimed in any of claims 210 to 215, wherein the cancer, tumor, or abnormal cell proliferation has an EGFR protein with the L858R mutation.

217. The use as claimed in any of claims 210 to 216, wherein the cancer, tumor, or abnormal cell proliferation has an EGFR protein with the T790M mutation.

218. The use as claimed in any of claims 210 to 217, wherein cancer,218. The use of a tumor or abnormal cell proliferation has an EGFR protein with the C797S mutation.

219. The use as claimed in any of claims 210 to 218, wherein the cancer, tumor, or abnormal cell proliferation has an EGFR protein with the L792H mutation.

220. The use as claimed in any of claims 210 to 219, wherein the cancer, tumor, or abnormal cell proliferation has an EGFR protein with the L718Q mutation.

221. The use as claimed in any of claims 210 to 215, wherein the cancer, tumor, or abnormal cell proliferation has an EGFR protein with the T790M / L858R mutation.

222. The use as claimed in any of claims 210 to 215, wherein the cancer, tumor, or abnormal cell proliferation has an EGFR protein with the T790M / L858R / C797S mutation.

223. The use as claimed in any of claims 210 to 215, wherein the cancer,224. The use as claimed in any of claims 208 to 223, wherein an additional EGFR inhibitor is administered.

225. The use as claimed in claim 224, wherein the additional EGFR inhibitor is a tyrosine kinase inhibitor.

226. The use as claimed in claim 225, wherein the additional EGFR inhibitor is osimertinib.

227. The use as claimed in claim 225, wherein the additional EGFR inhibitor is rociletinib.

228. The use as claimed in claim 225, wherein the additional EGFR inhibitor is avitinib.

229. The use as claimed in claim 225, wherein the additional EGFR inhibitor is lazertinib.

230. The use as claimed in claim 225, wherein the additional EGFR inhibitor is nazartinib. 975 231. The use as claimed in claim 224,wherein the additional EGFR inhibitor is an antibody against a mutated form of EGFR.

232. The use as claimed in claim 231, wherein the additional EGFR inhibitor is cetuximab.

233. The use as claimed in claim 231, wherein the additional EGFR inhibitor is panitumab.

234. The use as claimed in claim 231, wherein the additional EGFR inhibitor is necitumab.

235. The use as claimed in any one of claims 208 to 234, wherein a MET inhibitor is also administered.

236. The use as claimed in any one of claims 208 to 235, wherein the patient receives an additional chemotherapeutic agent.

237. A compound according to any one of claims 79 to 176 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition,for use in the treatment of an EGFR-mediated disorder in a patient.

238. The compound according to claim 237, further characterized in that the patient is a human.

239. The compound according to claim 237 or 238, further characterized in that the EGFR-mediated disorder is a cancer, a tumor, or an abnormal cell proliferation.

240. The compound according to claim 239, further characterized in that the EGFR-mediated disorder is a cancer or a tumor.

241. The compound according to claim 239, further characterized in that the EGFR-mediated disorder is an abnormal cell proliferation.

242. The compound according to claim 240, further characterized in that the cancer is lung cancer.

243. The compound according to claim 242,further characterized in that the lung cancer is non-small cell lung cancer.

244. The compound according to any one of claims 239 to 243, further characterized in that the cancer, tumor, or abnormal cell proliferation has an EGFR protein with at least one mutation.

245. The compound according to any one of claims 239 to 244, further characterized in that the cancer, tumor, or abnormal cell proliferation has an EGFR protein with the L858R mutation.

246. The compound according to any one of claims 239 to 245, further characterized in that the cancer, tumor, or abnormal cell proliferation has an EGFR protein with the T790M mutation.

247. The compound according to any one of claims 239 to 246, further characterized in that the cancer,248. The compound according to any one of claims 239 to 247, further characterized in that the cancer, tumor, or abnormal cell proliferation has an EGFR protein with the C797S mutation.

249. The compound according to any one of claims 239 to 248, further characterized in that the cancer, tumor, or abnormal cell proliferation has an EGFR protein with the L792H mutation.

250. The compound according to any one of claims 239 to 244, further characterized in that the cancer, tumor, or abnormal cell proliferation has an EGFR protein with the L718Q mutation.

251. The compound according to any one of claims 239 to 244, further characterized in that the cancer, tumor, or abnormal cell proliferation has an EGFR protein with the T790M / L858R mutation.

251. The compound according to any one of claims 239 to 244, further characterized in that the cancer, tumor, or abnormal cell proliferation has an EGFR protein with the T790M / L858R / C797S mutation.

252. The compound according to any one of claims 237 to 252, further characterized in that an additional EGFR inhibitor is administered.

254. The compound according to claim 253, further characterized in that the additional EGFR inhibitor is a tyrosine kinase inhibitor.

255. The compound according to claim 254, further characterized in that the additional EGFR inhibitor is osimertinib.

256. The compound according to claim 254, further characterized in that the additional EGFR inhibitor is rociletinib.

257. The compound according to claim 254,258. The compound according to claim 254, further characterized in that the additional EGFR inhibitor is avitinib.

259. The compound according to claim 254, further characterized in that the additional EGFR inhibitor is lazertinib.

260. The compound according to claim 253, further characterized in that the additional EGFR inhibitor is an antibody against a mutated form of EGFR.

261. The compound according to claim 260, further characterized in that the additional EGFR inhibitor is cetuximab.

262. The compound according to claim 260, further characterized in that the additional EGFR inhibitor is panitumab.

263. The compound according to claim 260, further characterized in that the additional EGFR inhibitor is necitumab.

264. The compound according to any of claims 237 to 263,further characterized in that a MET inhibitor is also administered.

265. The compound according to any one of claims 237 to 264, further characterized in that the patient receives an additional chemotherapeutic agent.

266. A compound according to any one of claims 79 to 176, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, for use as a medicament in the therapeutic and / or prophylactic treatment of a patient with EGFR activating mutations determined by a cobas® EGFR v2 mutation test, suffering from cancer, in particular non-small cell lung cancer, comprising determining the EGFR activating mutation status in said patient and then administering the compound according to any one of claims 79 to 176, or a pharmaceutically acceptable salt thereof,optionally in a pharmaceutical composition for said patient.

267. A pharmaceutical composition comprising the compound according to any of claims 79 to 176 and a pharmaceutically acceptable excipient.