Isoindolinone and indazole compounds for the degradation of EGFR

Abstract

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

Description

ISOINDOLINONE AND INDAZOLE COMPOUNDS FOR THE DEGRADATION OF EGFR CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application 62 / 951,464 filed December 20, 2019, and U.S. Provisional Application 62 / 951,467 filed December 20, 2019, the entirety of each 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 via the ubiquitination of the EGFR protein and subsequent proteasomal degradation. The compounds are useful for the treatment of various cancers. BACKGROUND OF THE INVENTION The HER family receptor tyrosine kinases are mediators of cell growth, differentiation, and survival. The receptor family includes four distinct members, i.e. epidermal growth factor receptor (EGFR, ErbBl, or HER1), HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4). Upon ligand binding, the receptors form homo and heterodimers and subsequent activation of the intrinsic tyrosine kinase activity leads to receptor auto-phosphorylation and the activation of downstream signaling molecules (Yarden, Y., Sliwkowski, MX. Untangling the ErbB signaling network. Nature Review Mol Cell Biol. 2001 Feb;2(2): 127-37). These signaling molecules promote cell growth and proliferation. Deregulation of EGFR by overexpression or mutation has been implicated in many types of human cancer including colorectal, pancreatic, gliomas, head and neck and lung cancer, in particular non-small cell lung cancer (NSCLC). Several EGFR targeting agents have been developed over the years (Ciardiello, F., and Tortora, G. (2008). EGFR antagonists in cancer treatment. The New England journal of medicine 358, 1160-1174). Erlotinib (Tarceva®), a reversible inhibitor of the EGFR tyrosine kinase is approved in numerous countries for the treatment of recurrent NSCLC. An impressive single agent activity of EGFR tyrosine kinase inhibitors is observed in a subset of NSCLC patients whose tumors harbor somatic kinase domain mutations, whereas clinical benefit in wild-type EGFR patients is greatly diminished (Paez, J. et al. (2004). EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science (New York, NY 304, 1497-1500). The most common somatic mutations of EGFR are exon 19 deletions with delta 746-750 the most prevalent mutation and the exon 21 amino acid substitutions with L858R the most frequent mutation (Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 2007 Mar; 7(3): 169-81). Treatment resistance arises frequently, often due to the secondary T790M mutation within the ATP site of the receptor. Some developed mutant-selective irreversible inhibitors are highly active against the T790M mutant, but their efficacy can be compromised by acquired mutation of C7978, that is the cysteine residue with which they form a key covalent bond (Thress, K. S. et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non- small cell lung cancer harboring EGFR T790M. Nat. Med. 21, 560-562 (2015)). C797S mutation was further reported by Wang to be a major mechanism for resistance to T790M- targeting EGFR inhibitors (Wang ef al. EGFR C7978 mutation mediates resistance to third- generation inhibitors in T790M-positive non-small cell lung cancer, J Hematol Oncol. 2016; 9: 59). Additional mutations that cause resistance to Osimertinib are described by Yang, for example L718Q.(Yang et al, Investigating Novel Resistance Mechanisms to Third-Generation EGFR Tyrosine Kinase Inhibitor Osimertinib in Non-Small Cell Lung Cancer Patients, Clinical Cancer Research, DOI: 10.1158 / 1078-0432.CCR-17-2310). Additional mutations targeting strategies are also known including Targeting EGFRL858R / T790M and EGFRL858R / T790M / C797S resistance mutations in NSCLC treatment (Lu ef al. Targeting EGFRMSSRTM and EGFRMSBRTIOMCTTS resistance mutations in NSCLC: Current developments in medicinal chemistry, Med Res Rev 2018; 1-32). Additional examples of EGFR inhibitors, in particular selective inhibitors of T790M containing EGFR mutants, have also been described including those described in ‘W02014081718, W02014210354, W0O2018 / 115218, W02018220149, W02020002487, and ZHOU et al., "Novel mutant-selective EGFR kinase inhibitors against EGFR T790M", NATURE, (20091224), vol. 462, no. 7276, doi:10.1038 / nature08622, ISSN 0028-0836, pages 1070 - 1074. As most available EGFR tyrosine kinase inhibitors target the ATP-site of the kinase, there is a need for new therapeutic agents that work differently, for example through targeting drug- resistant EGFR mutants. Recent studies suggest that purposefully targeting allosteric sites might lead to mutant- selective inhibitors (Jia ef al. Overcoming EGFR(T790M) and EGFR(C7978) 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 health and productivity of the cells. Cereblon is a protein that forms an E3 ubiquitin ligase complex, which ubiquitinates various other proteins. Cereblon is known as the primary target for the anticancer thalidomide analogs. A higher expression of cereblon has been linked to the efficiency of thalidomide analogs in cancer therapy. Compounds have been described as useful modulators of targeted ubiquitination, for example the compounds described in. W02013020557, W02013063560, W02013106643, WO / 2013170147, WO02016011906, and W( / 2019183523 can be used for targeted ubiquitination. Additional modulators for targeted ubiquitination include those described by Ranok Therapeutics Hangzhou W02020206608 and W(2020207396; those described by Arvinas in WO02015160845, WO02016149668, W02016197032, W02017011590, WO02017030814, W02018144649, W02018226542, and W02019199816; those described by Dana-Farber Cancer Institute in W02016105518, W02017007612, W02017024317, WO02017024318, W02017117473, W0O2017117474, W02018148443, W02018148440, and WO02019165229; those described by Kymera in W02019 / 060742, W02019 / 140387, and WO02020 / 01022; and those described by C4 Therapeutics Inc. in W02017197036, WO02017197046, W02017197051, W02017197055, W02018237026, W02019099868, WO02019191112, W02019204353, W02019236483, W02020132561, W02020181232, and W02020210630. Some specific molecules for the degradation of EGFR have also been described, for example, Dana-Farber Cancer Institute described EGFR degraders in W02017185036. F. Hoffman-La-Roche described EGFR degraders in W02019121562 and W02019149922. Arvinas has described EGFR degraders in W02018119441. Despite these efforts, there remains a need for new EGFR modulators to treat disorders mediated by EGFR in hosts, and in particular humans, in need thereof. SUMMARY OF THE INVENTION Compounds and their uses and manufacture are provided that degrade the epidermal growth factor receptor protein (EGFR) via the ubiquitin proteasome pathway (UPP). The present invention provides compounds of Formula I, II, III, or IV or a pharmaceutically acceptable salt thereof that include a Targeting Ligand that binds to EGFR, an E3 Ligase binding portion (typically via a cereblon subunit), and a Linker that covalently links the Targeting Ligand to the E3 Ligase binding portion. In certain embodiments the E3 Ligase binding portion is a moiety of A or A*, the Linker is a moiety of L! or L?, 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 C7978. 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 which is mediated by EGFR. In some embodiments a method to treat a patient with a disorder mediated by EGFR is provided that includes administering an effective amount of one or more compounds as described herein, or a pharmaceutically acceptable salt thereof, to the patient, typically a human, optionally in a pharmaceutically acceptable composition. In one aspect the present invention provides a compound of Formula I rR? — Re A H J Fh, rR" N O ! \ WY | “rd XX ] R' 0 B I - / or a pharmaceutically acceptable salt thereof’ wherein: A is selected from the ring systems AF and AG; R4 720 RS ~ R70 " RE CN o= xX I 1? % No ATTN =A? 0O= N—& AY | N-N<ge \ ou Al a \ — A R? YN gr hed AF AG Als selected from i) -NH-, and ii) -O- Ais selected from i) -N- and ii) -CR®2- Al is selected from i) -N- and ii) -CR%- A%is selected from i) -N- and ii) -CR%. AS is selected from i) -N- and ii) -CR%- R! is selected from i) H, ii) halogen iii) Cis-alkyl; R*? is selected from i) H, ii) halogen, iii) cyano, iv) Cie-alkoxy, v) halo-Ci¢-alkoxy, vi) Cis-alkyl, vii) halo-Cis-alkyl, viii) Cs.s-cycloalkyl, and ix) halo-Css-cycloalkyl; R%, R%* and R* are independently selected from i) H, ii) halogen, iii) Cis-alkyl, iv) halo-Cis-alkyl, v) Css-cycloalkyl, and vi) halo-Css-cycloalkyl; R2 is selected from i) H, ii) halogen, iii) Cr.s-alkyl, iv) halo-Cis-alkyl, v) Css-cycloalkyl, and vi) halo-Css-cycloalkyl; R3 is selected from i) H, ii) halogen, iii) Crs-alkyl, iv) halo-Cis-alkyl, v) Css-cycloalkyl, and vi) halo-Cs.s-cycloalkyl; Rand R® are H; or R* and R® together form -(CHaz)g-; qislor2; RE is selected from i) H, ii) halogen, iii) cyano, iv) Cie-alkoxy, v) halo-Ci¢-alkoxy, vi) Cis-alkyl, vii) halo-Cis-alkyl, viii) Cs.s-cycloalkyl, and ix) halo-Css-cycloalkyl; R’ is selected from i) H, ii) halogen, iii) cyano, iv) Cis-alkyl, v) halo-Cis-alkyl, vi) Cis-cycloalkyl, and vii) halo-Css-cycloalkyl; Ris selected from i) H, ii) halogen, iii) cyano, iv) Cie-alkyl, v) halo-Ci¢-alkyl, vi) Css-cycloalkyl, and vii) halo-Css-cycloalkyl; Reis H; R® is selected from i) H, and ii) Cie-alkyl; NA AY TONY VN TV Llis ~~ ~~ ~~ C is absent or selected from the ring systems F, G and H; R13 R14 N=N RZ) | —v! " : 5 2] ~“ AN F G H Y!is selected from i) -N-, and ii) -CH-; Y? is selected from i) -N-, and ii) -CR'S-; R'2, RB, R!* and R!* are independently selected from i) -H- ii) halogen, and iii) hydroxy-Cis-alkyl; R!6 is selected from i) -H-, ii) hydroxy, and iii) fluoro; 1.3 is absent or selected from i) -(CH2)m-C(O)-, ii) -C(0)-(CH2)p-, iii) -C(0)-C(0)-, iv) -NRI°-C(0)-, v) -C(O)-NR'"- vi) -C(0)O-, vii) -CH;-CF,-CHa-, viii) -CHa-, = AN ix) © Land bi ad Xx) Sy x1) LL mis0,1or2; pis0,1,2o0r3; RY is selected from i) H, and ii) Cie-alkyl; D is selected from the ring systems I, J, K,L, M,N, O,P,Q,R, S, T, U, V, W and X; all ring systems being optionally substituted by one to three substituents selected from R®, R8! and R82: 4 NH NH A ANNA HOCH HH BH ROX) / \ / = MH FN \ Fk OX CI, OOH WW dO, 0H» Ss u Vv Ww POC xX R®-R¥ and R* are independently selected from i) halogen, ii) cyano, iii) hydroxy, iv) hydroxy- Cis-alkyl, v) Cie-alkoxy, vi) halo-Ci¢-alkoxy, vii) Cis-alkyl, viii) halo-Cis-alkyl, ix) Cjis-cycloalkyl, and x) halo-Css-cycloalkyl; L* is absent or selected from iy -NR'-C(O)-, ii) -CHa-, and iii) -O-; I) E is selected from the ring systems Y, Z, AA, AB and AC, N 7 \ ~ ~ =N N= NN ; Pu ~~ + NAL Chy i) N=N = T= NITY WRN Ne Y Zz AB AC LS is absent or } B is selected from the ring system AD and AE; In another aspect of the invention a compound of Formula II, or a pharmaceutically acceptable salt thereof is provided 2 R NZ N= ~ A R3 Al Va Ll ) OL RS I RY" C B — In wherein A’ is selected from the ring systems AF, AG and AH; R4 70 RE R70 "IY nN 7 \ Ce \ A o RE i O= \ No ATTN = AZ O= N—& N | N-N-ge HN—{ ~ 0 R¢ RO R RS YN = | HN Al 2 A? 0 rR’ AF AG R4 iY Oo= A 7 A* AH A RY is selected from i) H, ii) halogen, iii) Cie-alkyl iv) cyano, v) Cie-alkoxy, vi) halo-Ci¢-alkoxy, vii) Cis-alkyl, viii) halo-Cis-alkyl, ix) Css-cycloalkyl, and x) halo-Css-cycloalkyl; and the remaining variables are as defined herein. In certain aspects an isotope, N-oxide, or sterecisomer of Formula I is provided, or a pharmaceutically acceptable salt or composition thereof. In other aspects an isotope, N-oxide, or stereoisomer of Formula IT is provided, or a pharmaceutically acceptable salt or composition thereof. Other aspects of the present invention provide a compound of Formula III or Formula IV: R32 1 NON “ 2 R33 Va R* 0 N 2 wy 2 A* | N— sig? a / (RE), dé 2 aa? 3 (1) R32 1 TOR I A KANN TRE (RE), C Ren a or a pharmaceutically acceptable salt, isotope, N-oxide, stereoisomer thereof, optionally as part of a pharmaceutical composition; wherein: A¥* is selected from: a 38 R 37 R R* R37 rr AN N\ 8% — \ o= o= xX |! Ay \ R35 i NN \ — R90 NN r N= 0 AY 34 R SKA — \ 235 —( \ 7 Hi \_% N Ngo 0 R34 R34 \ \ wv o=( o= YG \ \ R3 \ G Foe E R o — AB =] Na% \ fT HN 33 A o 1 a2 Xx: r W—\ 0 38 R34 R37 R36 R34 37 R ~~ KF N i 35 wd o= Ao r= = A, A ot fund ad og I rR R Re RY J Vol \ Re Nope Je o= X | I HN—( PEERS HN— AZ a 4 “AR=pA% yy 0 0 B* is heteroaryl or aryl which is optionally substituted with 1, 2, or 3 R*! substituents; — N. v ger <3 N N ~ Jet — J ain embodiments B* is selected from § and = / "R¥, yis0, 1,2, or3; R¥! is independently selected at each occurrence from H, halogen (F, Cl, Br, or I), Ci. s-alkyl, cyano, Cis-alkoxy, halo-Cis-alkoxy, halo-Cis-alkyl, Cs.s-cycloalkyl, and halo-Cs.s- cycloalkyl and can be located on either ring where present on a bicycle, for example 32 R32 ~~ R¥ 4 Ca rT 0 R32 32 R 0 =z le N= R* o = 4 R31 3 { NT - Rr! includes R®' R! and R32 Fa Rr 0 =z [N= ES R31 Ris hydrogen, halogen (F, Cl, Br, or I), Ci.s-alkyl, halo-Ci.¢-alkyl, Cs.s-cycloalkyl, or halo-C3.s-cycloalkyl; R* is hydrogen, halogen (F, CI, Br, or I), C1-alkyl, halo-Ci.s-alkyl, C.s-cycloalkyl, or halo-Cs.s-cycloalkyl and can be located on the dihydropyrrole or imidazole ring; R* is independently selected at each occurrence from H, F, Cig-alkyl, halo-Ci6-alkyl, Cs.s-cycloalkyl, and halo-Cs.s-cycloalkyl; R* is selected at each occurrence from H, halogen (F, Cl, Br, or I), Ci.¢-alkyl, halo-Ci- s-alkyl, and Cs.s-cycloalkyl; or R* and R** combine to form —(CHa)q=; R* and R¥" are independently selected from H, halogen (F, Cl, Br, or I), cyano, C16- alkoxy, halo-Ci.6-alkoxy(for example F, Cl, or Br), C1s-alkyl, halo-Ci.¢-alkyl (for example F, Cl, or Br), Css-cycloalkyl, and halo-C3.s-cycloalkyl; or R3 and RY together are combined to form a 5- or 6- membered cycle optionally substituted with 1, 2. or 3 R3! substituents; R* is independently selected at each occurrence from H, halogen (F, Cl, Br, or I), cyano, Ci.¢-alkoxy, halo-Ci.s-alkoxy, Ci.s-alkyl, halo-Cis-alkyl, Cs.s-cycloalkyl, and halo-Cs. s-cycloalkyl; R% is H, Ci6-alkyl, or C3s-cycloalkyl; Ring G is a heteroaryl optionally substituted with 1 or 2 R*? substituents, for example a 5- or 6-membered heteroaryl ring with 1, 2, or 3 N heteroatoms; A?! is -NH-, -0O-, -CHa-, or -NR0. Ris alkyl, cycloalkyl, aryl, or heteroaryl; or as allowed by valence R'%° may combine with R*” to form a 5-8 membered heterocycle or 5 membered heteroaryl; A A** A* and A are independently selected from -N- and -CR*?-; A36 is 2N- or -CR35-- L? is a bivalent linking group (a linker) that connects A* and either the isoindolinone or indazole, for example but not limited to a bivalent linking group of Formula LI; and wherein the remaining variables are as defined herein. In certain embodiments L2 is of formula: TN TN 3 A xX! Xe “R* RY XxX (LI). wherein, X! and X? are independently at each occurrence selected from bond, heterocycle, aryl, heteroaryl, bicycle, alkyl, aliphatic, heteroaliphatic, -NR?’-, -CR*R*!-, -O-, -C(0)-, -C(NR?")-, -C(S)-, -S(0)-, -S(0)2- and —S-; each of which heterocycle, aryl, heteroaryl, and bicycle is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R*’; R¥, R?, RR? and R* are independently at each occurrence selected from the group consisting of a bond, alkyl, -C(0)-, -C(0)O-, -OC(0)-, -SO2-, -$(0)-, -C(S)-, -C(O)NR?"-, NR¥C(0)-, -O-, -S-, -NRY-, oxyalkylene, -C(R*R*)-, -P(O)(OR¥)O-, -P(0)(ORX)-, 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 R*’; Ris independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocycle, aliphatic and heteroaliphatic; R¥ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, aliphatic, heteroaliphatic, heterocycle, aryl, heteroaryl, -C(O)(aliphatic, aryl, heteroaliphatic or heteroaryl), -C(O)O(aliphatic, aryl, heteroaliphatic, or heteroaryl), alkene, and alkyne; R* is independently at each occurrence selected from the group consisting of hydrogen, RY, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH(aliphatic, including alkyl), -N(aliphatic, including alkyl),, -NHSOx(aliphatic, including alkyl), -N(aliphatic, including alkyl)SOaalkyl, -NHSOa(aryl, heteroaryl or heterocycle), -N(alkyl)SOx(aryl, heteroaryl or heterocycle), -NHSOalkenyl, -N(alkyl)SO.alkenyl, -NHSOzalkynyl, -N(alkyl)SOzalkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocycle, oxo, and cycloalkyl; additionally, where allowed by valence two R* groups bound to the same carbon may be joined together to form a 3-8 membered spirocycle; and R* is aliphatic, aryl, heteroaryl, or hydrogen. Every combination of variables, substituents, embodiments and the compounds that result from these combinations, is deemed specifically and individually disclosed, as such depiction is for convenience of space only and not intended to describe only a genus or even a subgenus of compounds. A compound of the present invention may be used to treat an 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) breast cancer, PR+ (progesterone positive) breast cancer, or triple negative breast cancer; head and neck cancer; glioblastoma; pancreatic cancer; thyroid cancer; astrocytoma; esophageal cancer; cervical cancer; synovial sarcoma; ovarian cancer; liver cancer; bladder cancer; or kidney cancer. In certain embodiments, a method of treatment is provided comprising administering an effective amount of a compound of Formula I, IL, II, or IV, or a pharmaceutically acceptable salt thereof to a patient in need thereof, for example a human, optionally in a pharmaceutically acceptable carrier. For example, in certain embodiments, a compound of Formula I, II, III, or TV 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 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 HER-2 positive breast cancer. In certain embodiments, the breast cancer is ER+ breast cancer. In certain embodiments, the breast cancer is PR+ breast cancer. In certain embodiments, the breast cancer is triple negative breast cancer. In certain embodiments a compound 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 even may provide multiple advantages over traditional treatment with an EGFR ligand. For example, the EGFR degrading compound of the present invention may a) overcome resistance in certain cases; b) prolong the kinetics of drug effect by destroying the protein, thus requiring resynthesis of the protein even after the compound has been metabolized; c) target all functions of a protein at once rather than a specific catalytic activity or binding event; and / or d) have increased potency compared to inhibitors due to the possibility of the small molecule acting catalytically. In one aspect, a compound 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 found in exon 18, exon 19, exon 20, or exon 21, or any combination thereof. In certain nonlimiting embodiments, the mutation is at position L858, E709, G719, C797, L861, T790, or L718 or any combination thereof. In certain embodiments the mutation is a L858R, T790M, L718Q, L792H, and / or a C797S mutation or any combination thereof, In certain aspects, the cancer has developed one or more EGFR mutations following treatment with at least one EGFR inhibitor that can be a non-covalent inhibitor (including but not limited to gefitinib, erlotinib, lapatinib or vandetanib) or a covalent inhibitor (such as afatinib, osimertinib or dacomitinib). In another aspect, the cancer has developed one or more EGFR mutations following treatment with an antibody such as cetuximab, panitumab or necitumab. In yet another aspect, the cancer has one or more EGFR mutations or non-EGFR mutations that renders the cancer intrinsically resistant to EGFR inhibitor treatment, for example, a somatic exon 20 insertion, asomatic PIK3CA mutation, loss of PTEN expression, MET amplification, or a KRAS mutation. In certain embodiments, a compound of the present invention is used to treat a cancer that is resistant to, or has acquired a resistance to, a first generation EGFR inhibitor such as erlotinib, gefitinib, and / or lapatinib. In certain embodiments, a compound of the present invention is used to treat a cancer that is resistant to, or has acquired a resistance to a second generation EGFR inhibitor such as afatinib and / or dacomitinib. In certain embodiments, a compound of the present invention is used to treat a cancer that is resistant to, or acquired a resistance to a third generation EGFR inhibitor such as osimertinib. In some embodiments, the mutated EGFR protein in the diseased tissue has an L858 mutation, for example L858R. In certain embodiments the compound of the present invention is used to treat a mutant EGFR mediated disorder, wherein EGFR has a mutation of at least one of the below listed amino acid sites, or a combination thereof. The mutation may, for example, be selected from one of the listed exemplary mutations, or may be a different mutation. Amino Acid Exemplary Mutations C797 “Jems E709 “E7094, E709G, E709K, E709V G719 GT719A, G719S, G719C, G719D G724 G7248 Amino Acid Exemplary Mutations G119 GI19A G796 G796S, G796C L718 L718V, L718Q L792 L792H; L792V L858 L858R L861 L861Q S768 $7681 eo [Ton ~ 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 one additional mutation which 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 mutation that may optionally be selected from the table above. In other embodiments the mutant EGFR mediated disorder has a L858R mutation and three additional mutation that may optionally be selected from the table above. In certain embodiments the mutant EGFR mediated disorder has a T790M mutation and one additional mutation optionally selected from the table above. In other embodiments the mutant EGFR mediated disorder has a T790M mutation and two additional mutation optionally selected from the table above. In other embodiments the mutant EGFR mediated disorder has a T790M mutation and three additional mutation optionally selected from the table above. In certain embodiments the mutant EGFR mediated disorder has a L718Q mutation and one additional mutation optionally selected from the table above. In other embodiments the mutant EGFR mediated disorder has a L718Q mutation and two additional mutation optionally selected from the table above. In other embodiments the mutant EGFR mediated disorder has a L718Q mutation and three additional mutation 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 an exon 19 deletion. In certain embodiments, the exon 19 deletion is a deletion which includes the amino acids LREA (L747-A750). In certain embodiments, the exon 19 deletion is a deletion which includes the amino acids ELREA (E746-A750). In certain embodiments a compound 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 mutated EGFR than 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 a E709 mutation, for example E709A, E709G, E709K, or E709V. In certain embodiments a compound of the present invention is used to treat EGFR with a 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 exon 19 insertions and / or one or more exon 20 insertions. In certain embodiments, a compound of the present invention is used to treat $7681 mutant EGFR cancer. In certain embodiments a compound of the present invention is used to treat EGFR L861Q mutant EGFR 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 a L718Q, L858R mutant EGFR cancer. In certain embodiments a compound of the present invention is used to treat a L792H, L858R mutant EGFR cancer. In certain embodiments a compound of the present invention is used to treat a C7978, 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 an inhibitor only protein binding moiety combined with the catalytic degradation activity of the cereblon-activiated protesomal degradation. This provides rapid activity against the target overexpressed EGFR by an active moiety that can quickly “return to action” and repeat the catalytic function. In this way, the EGFR is quickly destroyed as done with a covalent suicide inhibitor, like osimertinib, but without at the same time destroying the active drug. In certain embodiments, the degrader compound of the present invention has one or more advantages in the treatment of an EGFR mediated disorders than using an enzyme inhibitor only. In certain embodiments, less of the compounds described herein is needed for the treatment of an EGFR mediated disorder, than by 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 by mole of the EGFR Targeting Ligand portion alone. In certain embodiments, a less frequent dose regimen of a selected compound described herein is needed for the treatment of an EGFR mediated disorder, than the dose by 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 pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition, for use in the manufacture of a medicament for inhibiting or preventing a disorder mediated by EGFR or for modulating or decreasing the amount of EGFR. Another aspect of the present invention provides a compound as described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, or solvate thereof, or its pharmaceutical composition, for use in the manufacture of a medicament for treating or preventing a disease mediated by EGFR. In certain embodiments, a selected compound as described herein is useful to treat a disorder comprising an abnormal cellular proliferation, such as a tumor or cancer, wherein EGFR is an oncogenic protein or a signaling mediator of the abnormal cellular proliferative pathway 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, at an amount above the natural abundance of the isotope, i.e., 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, where the target protein is proximate to the ubiquitin ligase to effect degradation of said protein. Other features and advantages of the present application will be apparent from the following detailed description. The present invention thus includes at least the following features: (a) A 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 for treating an EGFR mediated disorder, such as an abnormal cellular proliferation, including cancer, comprising administering an effective amount of a compound of Formula I, II, ITI, or IV, or pharmaceutically acceptable salt thereof, as described herein, to a patient in need thereof; (c) A compound of Formula IL, IL, 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, for example an abnormal cellular proliferation such as a tumor or cancer; (d) Use of a compound of Formula I, II, ITI, or IV, or a pharmaceutically acceptable salt thereof, in an effective amount in the treatment of a patient in need thereof, typically a human, with an EGFR mediated disorder, for example an abnormal cellular proliferation such as a tumor or cancer, (e) Use of a compound of Formula I, IL 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 cellular proliferation such as a tumor or cancer; ® A method for treating a mutant EGFR mediated disorder, such as an abnormal cellular proliferation, including cancer, comprising administering an effective amount of a compound of Formula I, II, II, or IV, or pharmaceutically acceptable salt thereof, as described herein, to a patient in need thereof’ (g) A compound of Formula I, IL, 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, for example an abnormal cellular proliferation such as a tumor or cancer, (h) Use of a compound of Formula I, IL, III, or IV, or a pharmaceutically acceptable salt thereof, in an effective amount in the treatment of a patient in need thereof, typically a human, with a mutant EGFR mediated disorder, for example an abnormal cellular proliferation such as a tumor or cancer; i) Use of a compound of Formula I, II, ITI, 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 a mutant EGFR mediated disorder, for example an abnormal cellular proliferation such as a tumor or cancer; a) A pharmaceutical composition comprising an effective patient-treating amount of a compound of Formula I, IL, III, or IV, or a pharmaceutically acceptable salt, isotopic derivative thereof’ and optionally a pharmaceutically acceptable carrier or diluent; k) A compound Formula I, II, III, or IV, as described herein as a mixture of enantiomers or diastereomers (as relevant), including as a racemate; 0 A compound of Formula I, II, II, or IV, as described herein in enantiomerically or diastereomerically (as relevant) enriched form, including an isolated enantiomer or diastereomer (i.e., about greater than 85, 90, 95, 97, or 99% pure); and (m) A process for the preparation of therapeutic products that contain 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 Compounds and their uses and manufacture are provided that degrade the epidermal growth factor receptor protein (EGFR) via the ubiquitin proteasome pathway (UPP). The present invention provides compounds of Formula I, II, III, or IV or a pharmaceutically acceptable salt thereof that include a Targeting Ligand that binds to EGFR, an E3 Ligase binding portion (typically via a cereblon subunit), and a Linker that covalently links the Targeting Ligand to the E3 Ligase binding portion. In certain embodiments the E3 Ligase binding portion is a moiety of A or A*, the Linker is a moiety of L! or L?, 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 an inhibitor only protein binding moiety combined with the catalytic degradation activity of the cereblon-activiated proteasomal degradation. This provides rapid activity against the target overexpressed EGFR by an active moiety that can quickly “return to action” and repeat the catalytic function. In this way, the EGFR is quickly destroyed as done with a covalent suicide inhibitor, like osimertinib, but without at the same time destroying the active drug. L DEFINITIONS The following definitions of the general terms used in the present description apply whether the terms appear alone or in combination with other groups. Unless otherwise stated, the following terms used in this application, including the specification and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms “a”, “an,” and “the” include plural referents unless the context clearly dictates otherwise. The term “Ci.s-alkoxy” denotes a group of the formula -O-R’, wherein R’ is an C1.¢-alkyl group, particularly Ci3-alkyl. Examples of Cis-alkoxy groups include methoxy, ethoxy, n- Propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Particular examples are methoxy, ethoxy and isopropoxy. More particular example is methoxy. The term "Cis-alkyl", alone or in combination with other groups, stands for a hydrocarbon radical which may be linear or branched, with single or multiple branching, wherein the alkyl group in general comprises 1 to 6 carbon atoms, for example, methyl (Me), ethyl (Et), propyl, isopropyl (i-propyl), n-butyl, i-butyl (isobutyl), 2-butyl (sec-butyl), t-butyl (tert-butyl), isopentyl, 2-ethyl-propyl (2-methyl-propyl), 1,2-dimethyl-propyl and the like. A specific group is methyl. The term “cyano” denotes a -C=N group. The term “Cs.s-cycloalkoxy” denotes a group of the formula -O-R’, wherein R’ is a Cs.s- cycloalkyl group. Examples of cycloalkoxy group include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy. Particular example is cyclopropoxy. The term “Css-cycloalkyl” denotes a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 8 ring carbon atoms. Bicyclic means a ring system consisting of two saturated carbocycles having one or two carbon atoms in common. Examples of monocyclic Css-cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl. Example of bicyclic Css-cycloalkyl is spiro[3.3]heptanyl. Particular monocyclic Cs.s- cycloalkyl groups are cyclopropyl, cyclobutanyl. More particular monocyclic Cs.s-cycloalkyl groups include cyclopropyl. The term “halo-Ci.s-alkoxy” denotes an Ci.¢-alkoxy group wherein at least one of the hydrogen atoms of the C1s-alkoxy group has been replaced by same or different halogen atoms. The term “perhalo-Ci.s-alkoxy™ denotes an Ci.6-alkoxy group where all hydrogen atoms of the Cis-alkoxy group have been replaced by the same or different halogen atoms. Examples of halo-Ci.s-alkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, triflucromethylethoxy, trifluorodimethylethoxy and pentafluoroethoxy. Particular halo-C.¢-alkoxy groups include fluoromethoxy, rifluoroethoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoromethylethoxy ~~ and trifluorodimethylethoxy. More particular examples are fluoromethoxy, difluoromethoxy and trifluoromethoxy. The term “halo-Ci¢-alkyl” denotes an Cis-alkyl group wherein at least one of the hydrogen atoms of the Cis-alkyl group has been replaced by the same or different halogen atoms. The term “perhalo-Ci.6-alkyl-C1s-alkyl” denotes an-Ci-s-alkyl-Ci.¢-alkyl group where all hydrogen atoms of the alkyl group have been replaced by the same or different halogen atoms. Examples of halo-Cis-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-s-alkyl groups include fluoromethyl. The term “halo-Cs.s-cycloalkoxy™” denotes an Cs.s-cycloalkoxy group wherein at least one of the hydrogen atoms of the Cs.s-cycloalkoxy group has been replaced by same or different halogen atoms. The term “perhalo- Cs.s-cycloalkoxy” denotes an Cs.s-cycloalkoxy group where all hydrogen atoms of the Cs.s-cycloalkoxy group have been replaced by the same or different halogen atoms. Examples of halo-Css-cycloalkoxy include fluorocyclopropoxy, fluorocyclobutoxy, fluorocyclopentyloxy, fluorocyclohexyloxy, fluorocycloheptyloxy, difluorocyclopropoxy, difluorocyclobutoxy, difluorocyclopentyloxy, difluorocyclohexyloxy and difluorocycloheptyloxy. The term “halo-Cs.s-cycloalkyl” denotes an Cs.s-cycloalkyl group wherein at least one of the hydrogen atoms of the Cs.s-cycloalkyl group has been replaced by the same or different halogen atoms. The term “perhalo- Cs.s-cycloalkyl” denotes an- Cs.s-cycloalkyl group where all hydrogen atoms of the alkyl group have been replaced by the same or different halogen atoms. Examples of halo-Css-cycloalkyl include fluorocyclopropyl, fluorocyclobutanyl, fluorocyclopentyl, fluorocyclohexyl, fluorocycloheptyl, difluorocyclopropyl, difluorocyclobutanyl, difluorocyclopentyl, difluorocyclohexyl or difluorocycloheptyl. The term "halogen", alone or in combination with other groups, denotes chloro (Cl), iodo (I), fluoro (F) and bromo (Br). Specific groups are F and Cl. The term “hydroxy” denotes a -OH group. The term “hydroxy-Ci.s-alkyl alkyl” denotes an Ci.s-alkyl alkyl group wherein at least one of the hydrogen atoms of the C.s-alkyl alkyl group has been replaced by a hydroxy group. Examples of hydroxy-Ci.s-alkyl include hydroxymethyl, hydroxyethyl and hydroxypropyl. Particular example is hydroxymentyl. The term “pharmaceutically acceptable” denotes an attribute of a material which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and is acceptable for veterinary as well as human pharmaceutical use. The term "a pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and animals. Examples of suitable salts with inorganic and organic acids are, but are not limited to acetic acid, citric acid, formic acid, fumaric acid, hydrochloric acid, lactic acid, maleic acid, malic acid, methane-sulfonic acid, nitric acid, phosphoric acid, p-toluenesulphonic acid, succinic acid, sulfuric acid (sulphuric acid), tartaric acid, trifluoroacetic acid and the like. Particular acids are formic acid, trifluoroacetic acid and hydrochloric acid. A specific acid is trifluoroacetic acid. The terms “pharmaceutically acceptable auxiliary substance” refer to carriers and auxiliary substances such as diluents or excipients that are compatible with the other ingredients of the formulation. The term "pharmaceutical composition" encompasses a product comprising specified ingredients in pre-determined amounts or proportions, as well as any product that results, directly or indirectly, from combining specified ingredients in specified amounts. Particularly it encompasses a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product that results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. “Therapeutically effective amount” means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state. The “therapeutically effective amount” will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors. The term “as defined herein” and “as described herein” when referring to a variable incorporates by reference the broad definition of the variable as well as particularly, more particularly and most particularly definitions, if any. The terms “treating”, “contacting” and “reacting” when referring to a chemical reaction means adding or mixing two or more reagents under appropriate conditions to produce the indicated and / or the desired product. It should be appreciated that the reaction which produces the indicated and / or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and / or the desired product. The term “pharmaceutically acceptable excipient” denotes any ingredient having no therapeutic activity and being non-toxic such as disintegrators, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants or lubricants used in formulating pharmaceutical products. The term "pharmaceutical composition" encompasses a product comprising specified ingredients in pre-determined amounts or proportions, as well as any product that results, directly or indirectly, from combining specified ingredients in specified amounts. Particularly it encompasses a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product that results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. The term “inhibitor” denotes a compound which competes with, reduces or prevents the binding of a particular ligand to particular receptor or which reduces or prevents the function of a particular protein. The term “half maximal inhibitory concentration” (ICso0) denotes the concentration of a particular compound required for obtaining 50% inhibition of a biological process in vitro. ICs values can be converted logarithmically to pICso values (-log ICso), in which higher values indicate exponentially greater potency. The ICso value is not an absolute value but depends on experimental conditions e.g. concentrations employed. The ICso value can be converted to an absolute inhibition constant (Ki) using the Cheng-Prusoff equation (Biochem. Pharmacol. (1973) 22:3099). “Therapeutically effective amount” means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state. The “therapeutically effective amount” will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors. The term “aromatic” denotes the conventional idea of aromaticity as defined in the literature, in particular in IUPAC - Compendium of Chemical Terminology, 2nd, A. D. McNaught & A. Wilkinson (Eds). Blackwell Scientific Publications, Oxford (1997). Whenever a chiral carbon is present in a chemical structure, it is intended that all stereoisomers associated with that chiral carbon are encompassed by the structure as pure stereoisomers as well as mixtures thereof In certain embodiments, isotopes are incorporated into the compounds of the invention. These isotopes include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine such as 2H, °H, 11C, BC, 1*C, *N, 170, #0, !¥F, 3S, and 3°Cl respectively. In one non-limiting embodiment, isotopically labelled compounds can be used in metabolic studies (with, for example *C), reaction kinetic studies (with, for example *H or *H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. Additionally, any hydrogen atom present in the compound of the invention may be substituted with an '®F atom, a substitution that may be particularly desirable for PET or SPECT studies. In one non-limiting embodiment, the substitution of a hydrogen atom for a deuterium atom can be provided in any compound described herein. For example, when any of the groups are, or contain for example through substitution, methyl, ethyl, or methoxy, the alkyl residue may be deuterated (in non-limiting embodiments, CDH,, CD;H, CD;, CH,CD3, CD2CDs, CHDCH;D, CH,CD;, CHDCHD;, OCDH:, OCD:H, or OCDs etc.). In certain other embodiments, when two substituents are combined to form a cycle the unsubstituted carbons may be deuterated. In certain embodiments, at least one deuterium is placed on an atom that has a bond which is broken during metabolism of the compound in vivo, or is one, two or three atoms remote form the metabolized bond (e.g., which may be referred to as an a, B or vy, or primary, secondary or tertiary isotope effect). In certain embodiments a compound of the present invention is isotopically labeled. In certain embodiments at least one R group independently selected from R!, R%, R3, R, R% R, RE RY, RI, RL R2 R13, RM RIS, RIS, R77, R®, RZ R22, RS, R™ R%, RY, R®L RZ RR, R¥, R¥, RY, R®, RY, R®, R®, R®, R¥, R%, R™, R¥, R¥, R®, R”, or RV is isotopically labeled with 1, 2, or more isotopes as allowed by valence. In certain embodiments the isotopic label is deuterium. In certain embodiments, at least one deuterium is placed on an atom that has a bond which is broken during metabolism of the compound in vivo, or is one, two or three atoms remote form the metabolized bond (e.g., which may be referred to as an ao, f or y, or primary, secondary or tertiary isotope effect). In another embodiment the isotopic label is 1*C. In other embodiments the isotopic label is 5F. In certain embodiments the compounds of the present invention may form a solvate with a solvent (including water). Therefore, in one non-limiting embodiment, the invention includes a solvated form of the compounds described herein. The term "solvate" refers to a molecular complex of a compound 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 linear or branched aliphatic hydrocarbon groups having one or more carbon-carbon double bonds that may occur at a stable point along the chain. In one non-limiting embodiment, the alkenyl contains from 2 to about 12 carbon atoms, more generally from 2 to about 6 carbon atoms or from 2 to about 4 carbon atoms. In certain embodiments the alkenyl is Cz, C2-C3, C2-C4, C2-Cs, or C2-Cs. In certain embodiments, examples of alkenyl radicals include, but are not limited to ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. In certain embodiments the term “alkenyl” also embodies “cis” and “trans” alkenyl geometry, or alternatively, “E” and “Z” alkenyl geometry. In certain embodiments the term “alkenyl” also encompasses cycloalkyl or carbocyclic groups having at least one point of unsaturation. In certain embodiments “alkynyl” is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that may occur at any stable point along the chain. In one non-limiting embodiment, the alkynyl contains from 2 to about 12 carbon atoms, more generally from 2 to about 6 carbon atoms or from 2 to about 4 carbon atoms. In certain embodiments the alkynyl is Ca, C2-C3, C2-Ca, C2-Cs, or C2-Cs. In certain embodiments, examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3- butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4- hexynyl and 5-hexynyl. In certain embodiments, the term “alkynyl” also encompasses cycloalkyl or carbocyclic groups having at least one point of triple bond unsaturation. II. COMPOUNDS OF FORMULA IL, IT, ITI, AND IV The invention provides compounds of Formulas I, II, III, and IV pharmaceutical compositions, methods of using, and methods of preparing these compounds. Embodiments of Formula I All separate embodiments may be combined. El: One embodiment of the invention is a compound of formula I, or a pharmaceutically acceptable salt thereof, rR? A H FS, R™ | N WY TN “or x R' 0 B I or wherein A is selected from the ring systems AF an AG; Rr 4 Ry ™N Ry 7 8 5 R R \ Bs AA O= H W } 5 f ct | — N A Ax 5 Ps Qo NNR? H AF Alis selected from i) -NH-, and i) -0-; A? is selected from i) -N-, and ii) -CR%- Ad is selected from i) -N- and ii) -CR®- A4is selected from i) -N-, and ii) -CR%- AS is selected from i) -N-, and ii) -CR%- R! is selected from i) H, ii) halogen iii) Cie-alkyl; R*2 is selected from i) H, ii) halogen, iii) cyano, iv) Cie-alkoxy, v) halo-Ci¢-alkoxy, vi) Cis-alkyl, vii) halo-Cis-alkyl, viii) Cis-cycloalkyl, and ix) halo-Css-cycloalkyl; R¥, R* and R* are independently selected from i) H, ii) halogen, iii) Cis-alkyl, iv) halo-Cis-alkyl, v) Css-cycloalkyl, and vi) halo-Css-cycloalkyl; R2? is selected from i) H, ii) halogen, iii) Cis-alkyl, iv) halo-Cis-alkyl, v) Css-cycloalkyl, and vi) halo-Css-cycloalkyl; R3 is selected from i) H, ii) halogen, iii) Ci.¢-alkyl, iv) halo-Cis-alkyl, v) Css-cycloalkyl, and vi) halo-Css-cycloalkyl;; Rand R® are H; or R* and R® together form -(CH2)q-; qislor2; RS is selected from i) H, ii) halogen, iii) cyano, iv) Cie-alkoxy, v) halo-Ci¢-alkoxy, vi) Cis-alkyl, vii) halo-Cis-alkyl, viii) Cis-cycloalkyl, and ix) halo-Css-cycloalkyl; R’ is selected from i) H, ii) halogen, iii) cyano, iv) Cie-alkyl, v) halo-Cis-alkyl, vi) Css-cycloalkyl, and vii) halo-Css-cycloalkyl; Ris selected from i) H, ii) halogen, iii) cyano, iv) Cis-alkyl, v) halo-Cis-alkyl, vi) Css-cycloalkyl, and vii) halo-Cs.s-cycloalkyl; Reis H; R® is selected from iii) H, and iv) Cie-alkyl; AY ONIN VY YC )y NYDY NY EY © L'is ~— ~ — C is absent or selected from the ring systems F, G and H; 13 14 RY R15 R Rey | wv Vy « Y! is selected from i) -N- and ii) -CH-; Y2 is selected from i) -N- and ii) -CRI-: R!2, RB R!* and R!® are independently selected from i) -H-, ii) halogen, and iii) hydroxy-Cis-alkyl; R!6 is selected from i) -H-, ii) hydroxy, and iii) fluoro; L? is absent or selected from i) -(CH2)m-C(O)-, i) -C(0)-(CHa2)p-, iii) -C(0)-C(0)-, iv) -NR!-C(0)-, v) -C(O)-NR"- vi) -C(0)O-, vii) -CH-CF;-CHs-, viii) -CHz-, = I~ ply ix) © Land i Nh X) $0 xi) LL misO0,1or2; pis0,1,20r3; Ris selected from i) H, and ii) Cie-alkyl; D is selected from the ring systems I, J, K,L, M,N, O, P, Q,R, S, T, U, V, W and X, all ring system being optionally substituted by one to three substituents selected from R*, R8! and R82: 7 N NN = XY \ N— ™, NN 7 "™ J J K Pas 7 \ IX \ 1 N— ANNA “X NOON +> —~\ h NNS / M N 0 P Spa bd oN XX ON— NL: nN Xe YOn— Ay Xn XO my XO J, Q R Ss I \ N— rl INS TF NN NY On YN ~~ Nt u v w X R¥ R®! and R® are independently selected from i) halogen, ii) cyano, iii) hydroxy, iv) hydroxy- Ci.¢-alkyl, v) Cis-alkoxy, vi) halo-Ci¢-alkoxy, vii) Cis-alkyl, viii) halo-Cis-alkyl, ix) Css-cycloalkyl, and x) halo-Css-cycloalkyl; L*is absent or selected from iy -NR'-C(O)-, ii) -CH;-, and iii) -O-; E is selected from the ring systems Y, Z, AA, AB and AC; ANNA 4) N=N Y Z AA =N x: AN gg AB AC LS is absent or ! B is selected from the ring system AD and AE; AD AE E2: A certain embodiment of the invention is the compound of formula as described herein, or a pharmaceutically acceptable salt thereof, wherein A is selected from the ring systems AF and AG; rE 1 4 Ry 8 Ry O= O= H W H Y5 \ 1 N-Nsge Rr’ ] NN H oO rR H AF AG Als selected from i) -NH-, and ii) -O-; Ais selected from i) -N-, and i) -CH- R!is selected from i) Hand ii) halogen; RZisH; R3 is selected from i) H, and ii) halogen; RYisH RisH; or R* and R® together form -(CH2)u-; nis 1; RS is selected from i) HH, ii) halogen, iii) cyano, and iv) halo-Cis-alkyl; R’isH; Reis H; Ri $ C 16-alk yl; DN AY ANTPN TN TV Llis ~ ~~ ~~ C is absent or the ring system F; 13 14 RY Rts R RS | vA Y!is selected from i) -N-, and ii) ~~ -CH-; Y2 is selected from i) -N- and ii) -CR'- RZ RB R" and RY are independently selected from i) Hand ii) halogen; R!6 is selected from i) H, and ii) hydroxy; 13 is selected from i) -(CH2)m-C(0)-, i) -C(0)-(CHa)p-, iii) -C(0)-C(0)-, and iv) -NRU-C(0)= mis 1; pislor3; R19 is selected from i) H, and ii) Ci6-alkyl; N— / —X M L* is selected from iy NR'-C(0)-, iil) ~~ -CHj-, and iii) -O-; E is selected from the ring systems Y, Z and AA, AB and AC; ~ 4) Y Zz =N \ ANF ng AB AC 15s | B is selected from the ring system AD and AE; E3: A certain embodiment of the invention is the compound of formula as described herein, or a pharmaceutically acceptable salt thereof, wherein A is selected from the ring systems AF and AG; Rr? 1 4 Ry 8 Ry O= O= H H Y% Np N-N<g? R® ] N w N _ a2 H 0 rR H AF AG Al is selected from i) -NH-, and ii) -O-; A? is selected from i) -N-, and ii) -CH-; R! is selected from 1) H, and ii) fluoro; Ris H; R3 is selected from i) H, and ii) fluoro; RYisH Ris H; or R* and R® together form -(CH2)q-; qis 1; RE is selected from i) H, ii) fluoro, iii) cyano, iv) difluoromethyl, and v) trifluoromethyl; R’isH; Reis H; R? is methyl; Ay : DY VY VY "YC yy YDY YE) Lis — ~~ — C is the ring system F; 13 14 RY R15 R RY | vi NAY F Y!is selected from i) -N-, and ii) -CH-; Y2 is selected from i) -N-, and ii) -CRIS.; R!2 and R"3 are fluoro; RM any dR! ar e H; R!6 is selected from i) H, and ii) hydroxy; L3 is selected from i) -(CH2)m-C(0)-, iil) -C(0)-(CH2)p-, iii) ~~ -C(0)-C(0)-, and iv) -NR!-C(0)-; mis; pislor3; Ris H; D is selected from the ring systems I, J, K, L and M; N— / —~X L* is selected from i) -NR!'-C(0)-, iil) ~~ -CHj-, and iii) -O-; E is selected from the ring systems Y, Z, AA, AB and AC; "2 a. N=N Y Zz AA —N NN ging AB AC Lis } B is selected from the ring system AD and AE; AD AE 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. ES; A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein A! 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 A? is -CH-. ET: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R! is selected from i) H, and ii) halogen. E8: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R' is selected from i) H, and ii) fluoro. E9: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R! 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 R? is H. Ell: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R? is selected from i) H, and ii) halogen. E12: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R? is selected from i) H, and ii) fluoro. E13: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R* is H. El4: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R® 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 R° is selected from i) H, ii) halogen, iii) cyano, and iv) halo-Cis-alkyl. El6: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R” is H. Bl: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R® 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 R? is Cis-alkyl. E19: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R® 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 nis 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 ring system F. 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 ring system F. E23: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R'2 and RY 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 R' and R'® 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 R'® is selected from i) H, and ii) hydroxy. E26: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R'6 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 L? is selected from i) -(CH2)m-C(O)-, ii) -C(0)-(CHa2)p-, iii) -C(0)-C(O)-, and iv) -NRI-C(0)-. E28: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein mis 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. E30: A certain embodiment of the invention is the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R'? is selected from i) H, and i) Cis-alkyl. 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 the 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 L* is selected from i) -NR'N-C(0)-, ii) -CHz-, 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 L* is 3 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-(1-(6,7-dihydro-SH-pyrrolo[ 1,2-c]imidazol-1-yl)-2-0x0-2-(thiazol-2- ylamino)ethyl)-7-fluoro-3-oxoisoindolin-5-yl)ethynyl)-N-(1-(2-(4-(4-((2,6- dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)acetyl)piperidin-4-yl)picolinamide; 5-[2-[2-[1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-ox0-2-(thiazol -2- ylamino)ethyl]-7-fluoro-3-oxo-isoindolin-5-yl]ethynyl]-N-[1-[2-[4-[(2,6-diox0-3- piperidyl)amino]phenyl]acetyl]-4-piperidyl]pyridine-2-carboxamide; 5-[2-[2-[1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-0x0-2-(thiazol-2- ylamino)ethyl]-7-fluoro-3-oxo-isoindolin-5-yl]ethynyl]-N-[1-[2-[4-[4-[(2,6-diox0-3- piperidyl)oxy]phenyl]piperazin-1-yl]acetyl]-4-piperidyl]pyridine-2-carboxamide; 5-[2-[2-[1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-0x0-2-(thiazol-2- ylamino)ethyl]-7-fluoro-3-oxo-isoindolin-5-yl]ethynyl]-N-[1-[2-[4-[4-[[(3S)-2,6-diox0- 3-piperidyl]Jamino]-2-fluoro-phenyl]-1-piperidyl]acetyl]-4-piperidylJpyridine-2- carboxamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[4-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]phenyl]-1-piperidyl]acetyl]piperazin-1-yl]phenyl]-4-fluoro-1-oxo- isoindolin-2-y1]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[4-[2-[4-[4-[[(3S)-2,6- dioxo-3-piperidyl]amino]phenyl]-1-piperidyl]acetyl]piperazin-1-yl]phenyl]-4-fluoro-1- oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5SH-pyrrolo[1,2-climidazol-1-yl)-2-[6-[4-[4-[2-[4-[4-[[(3R)-2,6- dioxo-3-piperidyl]amino]phenyl]-1-piperidyl]acetyl]piperazin-1-yl]phenyl]-4-fluoro-1- oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(4-(4-(4-(4-(4-((2,6- dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-4-oxobutyl )piperazin-1-yl)phenyl)-4- fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-(6-(4-(4-(2-(4-(4-((2,6- dioxopiperidin-3-yl)amino)phenyl)cyclohexyl)acetyl)piperazin-1-yl)phenyl)-4-fluoro-1- oxoisoindolin-2-y1)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5SH-pyrrolo[1,2-climidazol-1-y1)-2-(6-(4-(1-(2-(4-(4-((2,6- dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-2-oxoethyl)piperidin-4-yl)phenyl)-4- fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-yl)-2-[6-[4-[4-[2-[4-[5-[(2,6-diox0-3- piperidyl)amino]-2-pyridyl]-1-piperidyl]acetyl]piperazin-1-yl]phenyl]-4-fluoro-1-oxo- isoindolin-2-y1]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-yl)-2-[6-[4-[4-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]acetyl]piperazin-1-yl]phenyl]-4-fluoro- 1-oxo-isoindolin-2-y1]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[4-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]-3-fluoro-phenyl]-1-piperidyl]acetyl]piperazin-1-yl]phenyl]-4-fluoro- 1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide; 2-[6-[4-[4-[2-[4-[2-cyano-4-[(2,6-diox0-3-piperidyl)Jamino]phenyl]-1- piperidyl]acetyl]piperazin-1-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-2-(6,7-dihydro- SH-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide; 2-[6-[4-[4-[2-[4-[2-(difluoromethyl)-4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]acetyl]piperazin-1-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-2-(6,7-dihydro- SH-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(4-(2-(4-(3-((2,6- dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)acetyl)piperazin-1-yl)phenyl)-4- fluoro-1-oxoisoindolin-2-y1)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-(6-(4-(4-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1- yl)acetyl)piperazin-1-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2- yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(4-(4-(2-(1-(4-((2,6- dioxopiperidin-3-yl)amino)-2-(trifluoromethyl)phenyl)-4-hydroxypiperidin-4- yl)acetyl)piperazin-1-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2- yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-yl)-2-(6-(4-(4-(2-(4-(4-((2,6- dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)acetyl)piperazin-1-yl)phenyl)-4- fluoro-1-oxoisoindolin-2-y1)-N-(pyridin-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-yl)-2-[6-[4-[4-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]acetyl]piperazin-1-yl]phenyl]-4-fluoro- 1-oxo-isoindolin-2-y1]-N-(2-pyridyl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-(6-(4-(1-(2-(4-(4-((2,6- dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)acetyl)piperidin-4-yl)phenyl)-4- fluoro-1-oxoisoindolin-2-y1)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(4-(1-(2-(4-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)acetyl)piperidin-4-yl)phenyl)-4- fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(1-(2-(4-(4-((R)-2,6- dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)acetyl)piperidin-4-yl)phenyl)-4- fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-(6-(4-(1-(2-(4-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)piperidin-4- yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol -2-yl)acetamide; 2-(6-(4-(1-(2-(4-(2-cyano-4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1- yl)acetyl)piperidin-4-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-2-(6,7-dihydro-5SH- pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[ 1-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]phenyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl Jphenyl]-4-fluoro-1-oxo- isoindolin-2-y1]-N-thiazol-2-yl-acetamide; 2+(6,7-dihydro-SH-pyrrolo[1,2-cJimidazol-1-yl)-2-[6-[6-[4-[2-[4-[4-[[(3S)-2,6- dioxo-3-piperidyl]amino]-2-fluoro-phenyl]-1-piperidyl]acetylpiperazin-1-yl]-3- pyridyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazol -2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[ 1-[ 1-[2-[4-[4-[[(3S)-2,6- dioxo-3-piperidyl]amino]phenyl]-1-piperidyl]acetyl]-4-piperidyl]pyrazol-4-yl]-4- fluoro-1-oxo-isoindolin-2-yl]-N-thiazol -2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-yl)-2-[6-[4-[1-[2-[4-[4-[[(3S)-2,6- dioxo-3-piperidyl]amino]phenyl]-1-piperidyl]acetyl]-4-piperidyl]pyrazol-1-yl]-4- fluoro-1-oxo-isoindolin-2-yl]-N-thiazol -2-yl-acetamide; 2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-(6-(1-(1-(2-(4-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)acetyl)piperidin-4-yl)-1H-1,2,3- triazol-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide ; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-[6-[4-[[ 1-[2-[4-[4-[(2,6-diox0- 3-piperidyl)amino]phenyl]-1-piperidyl]acetyl]-4-piperidyl oxy ]phenyl]-4-fluoro-1-oxo- isoindolin-2-yl]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5SH-pyrrolo[1,2-climidazol-1-yl)-2-[6-[4-[[ 1-[2-[4-[4-[[(3S)-2,6- dioxo-3-piperidyl]amino]phenyl]-1-piperidyl]acetyl]-4-piperidyl]oxy]phenyl]-4-fluoro- 1-oxo-isoindolin-2-y1]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-[6-[4-[[1-[2-[4-[4-[[(3R)-2,6- dioxo-3-piperidyl]amino]phenyl]-1-piperidyl]acetyl]-4-piperidyl]oxy]phenyl]-4-fluoro- 1-oxo-isoindolin-2-y1]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(4-((1-(2-(4-(4-((2,6- dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperidin-1-yl)acetyl)piperidin-4- yl)oxy)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(4-((1-(2-(4-(4-((2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)piperidin-4- yl)oxy)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(4-((1-(2-(4-(5-((2,6- dioxopiperidin-3-yl)amino)pyridin-2-yl)piperidin-1-yl)acetyl)piperidin-4- yl)oxy)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide; 2-(6-(4-((1-(2-(4-(2-cyano-4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1- yD)acetyl)piperidin-4-yl)oxy)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H- pyrrolo[1,2-c]imidazol-1-yl1)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-(6-(4-((1-(2-(4-(4-((2,4-dioxo- 3-azabicyclo[3.1.1]heptan-1-yl)amino)phenyl)piperidin-1-yl)acetyl)piperidin-4- yl)oxy)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-SH-pyrrolo[1,2-climidazol-1-y1)-2-(6-(4-((1-(2-(4-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)piperidin-4- yl)oxy)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-[6-[4-[[1-[2-[4-[4-[(2,6-diox0- 3-piperidyl)amino]phenyl]-1-piperidyl]-2-oxo-acetyl]-4-piperidylJoxy]phenyl]-4- fluoro-1-oxo-isoindolin-2-yl]-N-thiazol -2-yl-acetamide; 2+(6,7-dihydro-SH-pyrrolo[1,2-cJimidazol-1-yl1)-2-[6-[4-[(3R)-1-[2-[4-[4-[[(3S)- 2,6-dioxo-3-piperidylJamino]phenyl]-1-piperidylJacetyl]pyrrolidin-3-ylJoxyphenyl]-4- fluoro-1-oxo-isoindolin-2-yl]-N-thiazol -2-yl-acetamide; 2+(6,7-dihydro-SH-pyrrolo[1,2-cJimidazol-1-yl)-2-[6-[4-[(3S)-1-[2-[4-[4-[[(3S)- 2,6-dioxo-3-piperidylJamino]phenyl]-1-piperidylJacetyl]pyrrolidin-3-ylJoxyphenyl]-4- fluoro-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide; 2-(6-(4-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1- yl)acetyl)piperazin-1-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-2-((R)-6-fluoro-6,7- dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-N-(thiazol-2-yl)acetamide; 2-[6-[4-[4-[2-[4-[4-[[(3S)-2,6-diox0-3-piperidylJamino]-2-fluoro-phenyl]-1- piperidyl]acetyl]piperazin-1-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-2-[(6R)-6- fluoro-6,7-dihydro-5H-pyrrolo[1,2-cJimidazol-1-yl]-N-thiazol -2-yl-acetamide; 2-[6-[4-[4-[2-[4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-y1]- 1-piperidyl]acetyl]piperazin-1-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-2-[(6R)-6- fluoro-6,7-dihydro-5H-pyrrolo[1,2-cJimidazol-1-yl]-N-thiazol -2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(4-(2-(2-(4-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)-2,7- diazaspiro[3.5]nonan-7-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2- yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[2-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]phenyl]-1-piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]Jphenyl]-4- fluoro-1-oxo-isoindolin-2-yl]-N-thiazol -2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[2-[2-[4-[4-[[(3S)-2,6- dioxo-3-piperidylJamino]-2-fluoro-phenyl]-1-piperidyl]acetyl]-2,6- diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-N-thiazol-2-yl- acetamide; 2+(6,7-dihydro-SH-pyrrolo[1,2-cJimidazol-1-yl)-2-[6-[4-[2-[2-[4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-1-piperidyl]acetyl]-2,6- diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-N-thiazol -2-yl- acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-yl)-2-[6-[4-[2-[2-[4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-3,3-difluoro-1- piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl] phenyl]-4-fluoro-1-oxo-isoindolin-2- yl]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-(6-(4-(6-(2-(4-(4-((2,6- dioxopiperidin-3-yl)amino)phenyl)-3,3-difluoropiperidin-1-yl)acetyl)-2,6- diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2- yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[2-[2-[4-[4-[[(3S)-2,6- dioxo-3-piperidylJamino]-2-fluoro-phenyl]-1-piperidyl]acetyl]-2,6- diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-N-(2- pyridyl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-yl)-2-[6-[4-[2-[2-[4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-1-piperidyl]acetyl]-2,6- diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-N-(2- pyridyl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[2-[2-[4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-y1]-3,3-difluoro-1- piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2- y1]-N-(2-pyridyl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-yl)-2-[6-[4-[[4-[2-[4-[4-[(2,6-diox0- 3-piperidyl)amino]phenyl]-1-piperidyl]acetyl]piperazin-1-ylJmethyl]phenyl]-4-fluoro- 1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-[6-[4-[[4-[2-[4-[4-[(2,6-dioxo0- 3-piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]acetyl]piperazin-1-ylJmethyl]phenyl]- 4-fluoro-1-oxo-isoindolin-2-yl1]-N-thiazol -2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-[6-[4-[[4-[2-[4-[4-[[(3S)-2,6- dioxo-3-piperidylJamino]-2-fluoro-phenyl]-1-piperidylJacetyl]piperazin-1- yl]methyl]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-[6-[4-[[4-[2-[4-[4-[[(3S)-2,6- dioxo-3-piperidylJamino]-2-fluoro-phenyl]-1-piperidyl]-2-oxo-ethyl]piperazin-1- yl]methyl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-[6-[4-[[ 1-[2-[4-[4-[[(3S)-2,6- dioxo-3-piperidylJamino]-2-fluoro-phenyl]-1-piperidyl]acetyl]-4- piperidylJmethyl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazol -2-yl-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 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 the use in the therapeutic and / or prophylactic treatment of cancer, in particular non-small-cell lung cancer, more particularly EGFR-mutant non-small lung cancer wherein 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 the use in the therapeutic and / or prophylactic treatment of non-small-cell lung cancer, more particularly EGFR-mutant non-small 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 non- small-cell lung cancer, more particularly EGFR-mutant non-small lung cancer wherein 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 EGFR-mutant non-small lung cancer 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 the use as a medicament in therapeutic and / or prophylactic treatment of a patient with EGFR activating mutations suffering from cancer, in particular non-small-cell lung cancer, comprising determining the EGFR activating mutations status in said patient and then administering the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, 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 the use as a medicament in therapeutic and / or prophylactic treatment of a patient with EGFR mutations T790M / L858R, T790M / L858R / C797S, L858R and / or L8S8R / C797S suffering from cancer, in particular non- small-cell lung cancer, comprising determining the EGFR activating mutations status in said patient and then administering the compound 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 as a medicament in therapeutic and / or prophylactic treatment of a patient with EGFR activating mutations as determined with a cobas® EGFR Mutation Test v2 suffering from cancer, in particular non- small-cell lung cancer, comprising determining the EGFR activating mutations status in said patient and then administering the compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, to said patient. E44: The invention includes all substituents in its corresponding deuterated form, wherever applicable, of the compounds of formula I. E45: The invention includes all optical isomers, i.e. diastereoisomers, diastereomeric mixtures, racemic mixtures, all their corresponding enantiomers and / or tautomers as well as their solvates, wherever applicable, of the compounds of formula I. Embodiments of Formula II All separate embodiments may be combined. El: One embodiment of the invention is a compound of formula II, or a pharmaceutically acceptable salt thereof, 2 R NZ ON N= ~ 3 R3 Al Va LJ } YE . P'S RY C B [- (In wherein A’ is selected from the ring systems AF, AG and AH; 4 R 70 R® A R70 Xx R8 “i Oo= \ 4 ATTN =A? O= A, va Cx CN * he. [ R® I a AZ o Rr? NN. HN— YD AF AG R4 TN = \ \ AY AH Allis selected from i) -NH-, and ii) -O-; A? is selected from i) -N-, and ii) -CR% Al is selected from i) -N- and ii) -CR%- A%is selected from i) -N- and ii) -CR%- AS is selected from i) -N-, and ii) -CR- RY is selected from i) H, ii) halogen, iii) Cr.s-alkyl iv) cyano, v) Cie-alkoxy, vi) halo-Ci¢-alkoxy, vii) Cis-alkyl, viii) halo-Cis-alkyl, ix) Css-cycloalkyl, and x) halo-Css-cycloalkyl; R* is selected from i) H, ii) halogen, iii) cyano, iv) Cie-alkoxy, v) halo-Ci¢-alkoxy, vi) Cis-alkyl, vii) halo-Cis-alkyl, viii) Cs.s-cycloalkyl, and ix) halo-Css-cycloalkyl; R%, R%* and R* are independently selected from i) H, ii) halogen, iii) Cis-alkyl, iv) halo-Cis-alkyl, v) Css-cycloalkyl, and vi) halo-Css-cycloalkyl; R2 is selected from i) H, ii) halogen, iii) cyano, iv) Crs-alkyl, v) halo-Cis-alkyl, vi) Css-cycloalkyl, and vii) halo-Css-cycloalkyl; R3 is selected from i) H, ii) halogen, iii) Cr.s-alkyl, iv) halo-Cis-alkyl, v) Css-cycloalkyl, and vi) halo-Css-cycloalkyl;; Rand R® are H; or R* and R® together form -(CH2)q-; qislor2; RE is selected from i) H, ii) halogen, iii) cyano, iv) Cie-alkoxy, v) halo-Ci¢-alkoxy, vi) Cis-alkyl, vii) halo-Ci¢-alkyl, viii) Cs.s-cycloalkyl, and ix) halo-Css-cycloalkyl; R’ is selected from i) H, ii) halogen, iii) cyano, iv) Cie-alkyl, v) halo-Cis-alkyl, vi) Cis-cycloalkyl, and vii) halo-Cs.s-cycloalkyl; Ris selected from i) H, ii) halogen, iii) cyano, iv) Cie-alkyl, v) halo-Cis-alkyl, vi) Css-cycloalkyl, and vii) halo-Css-cycloalkyl; Reis H; R? is selected from i) H, and ii) Cre-alkyl; AY 4 5 ONT VY YC )y NYDY XY EY © L'is ~— ~ — C is absent or selected from the ring systems F, G and H; 13 14 RY Ris R RS | vv Vy « F G Y!is selected from i) -N-, and ii) -CH-; Y? is selected from i) -N-, and ii) -CR'S-; R'2, R" R!* and R"* are independently selected from i) -H-, ii) halogen, and iii) hydroxy-Cis-alkyl; R!6 is selected from i) -H-, ii) hydroxy, and iii) fluoro; 1.3 is absent or selected from i) -(CH2)m-C(O)-, ii) -C(0)-(CHa2)p-, iii) -C(0)-C(O)-, iv) -NR-C(0)-, v) -C(O)-NRY- vi) -C(0)O-, vii) -CH;-CF,-CHa-, viii) -CHz-, IN J pli ix) © and VM oN X) No x1) oL mis0,1or2; pis0,1,2o0r3; RY is selected from i) H, and ii) Cie-alkyl; D is selected from the ring systems I, J, K,L, M,N, O, P, Q,R, S, T, U, V, W and X, all ring system being optionally substituted by one to three substituents selected from R¥, R3! and R82: Td I \ INN \ N— ANNA "\ NOON OC ~~ N NN M N Oo P vom yy TX hg AN XO OO \ N— / SE —N NY YX On AUN —N XOn- J, Q R Ss On Ne aN ASN NA Nt uU Vv Ww xX RE R¥ and R* are independently selected from i) halogen, ii) cyano, iii) hydroxy, iv) hydroxy- Cis-alkyl, v) Cie-alkoxy, vi) halo-Ci¢-alkoxy, vii) Cis-alkyl, viii) halo-Ci¢-alkyl, ix) Css-cycloalkyl, and x) halo-Css-cycloalkyl; L* is absent or selected from i) -NR!'-C(0)-, ii) -CHa-, and iii) -O-; =N \ NN — AB AC LS is absent or } B is selected from the ring system AD and AE; AD AE or a pharmaceutically acceptable salt thereof. 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; R4 RE AN 1 TE © R8 “x = \ Oo= DS, N RS [ N a =A? o R7 x. oH HN—( Y AF AG R4 iN O= AH Alis -NH-; A? is selected from i) -N-, and ii) -CH- RY! is selected from i) H, and ii) halogen; R2? is selected from i) H, and ii) halogen; Riis H; Ris H; Ris H; RS is selected from i) H, and ii) halogen; R’isH; Reis H; Ri S C 16-alk yl; ~~ Cc 4 py AN VU TRY Llis ~~ ~~ _ C is the ring system F; 13 14 R | RL15 R RS | IRV EV | F Y'is-CH-; Y2is-N-; R!2Z R¥ RY and R" are H; 1.3 is selected from i) -(CH2)m-C(0)-, and i) -C(O)-(CHa2)p-; mis 1; pis 3; D is selected from the ring systems I and J; —N N— NOX on J L*is absent; E is selected from the ring systems Y and Z; 4) Y Z Lis 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 ring system AF. ES; A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein A! 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 A? is -CH-. ET: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein R!" is selected from i) H, and ii) halogen. E8: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein R!" is selected from i) H, ii) 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 R? is selected from i) H, and ii) halogen. E10: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein R? is selected from i) H, ii) chloro, and iii) fluoro. Ell: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein R? is selected from i) H, and ii) halogen. E12: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein R* 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 R* 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 R® 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 R is selected from i) H, ii) halogen. El6: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein R” 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 R® 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 R® is Cs-alkyl. E19: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein R® 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 ring system F. E21: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein Y! 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 Y? 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 R'2, R'>, R! and R'* 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 L? is selected from i) -(CH2)m-C(O)-, and ii) -C(O)-(CHa)p-. E25: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein mis 1. E26: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein pis 1 or 3. E27: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein D is selected from the 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 the ring system J. E29: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein L* is absent. E30: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein E is selected from the ring systems Y and Z. E31: A certain embodiment of the invention is the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein L® 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-dihydro-SH-pyrrolo[1,2-c]imidazol-1-y1)-2-(6-(6-(4-(4-(4-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)piperidin-1-y1)-4- oxobutyl)piperazin-1-yl)pyridin-3-yl)-7-fluoro-2H-indazol-2-y1)-N-(thiazol-2- yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-cJimidazol-1-y1)-2-(6-(6-(4-(2-(4-(4-((2,6- dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)acetyl)piperazin-1-yl)pyridin-3- yl)-7-fluoro-2H-indazol-2-y1)-N-(thiazol-2-yl)acetamide; 2-[4,7-dichloro-6-[4-[4-[2-[4-[4-[(2,6-diox0-3-piperidy])Jamino]phenyl]-1- piperidyl]acetyl]piperazin-1-yl]phenyl]indazol-2-yl1]-2-(6, 7-dihydro-5SH- pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-SH-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[6-[4-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]acetyl]piperazin-1-y1]-3-pyridyl]-4- fluoro-indazol-2-y1]-N-thiazol -2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]limidazol-1-y1)-2-[6-[6-[4-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]phenyl]-1-piperidyl]acetyl]piperazin-1-yl]-3-pyridyl]-4-fluoro- indazol-2-yl]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[6-[4-[2-[4-[5-[(2,6-diox0-3- piperidyl)amino]-2-pyridyl]-1-piperidyl]acetyl]piperazin-1-yl]-3-pyridyl]-4-fluoro- indazol-2-yl]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]limidazol-1-y1)-2-[6-[6-[4-[2-[4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-y1]-1- piperidyl]acetyl]piperazin-1-yl]-3-pyridyl]-4-fluoro-indazol-2-y1]-N-thiazol -2-yl- acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-(6-(6-(4-(2-(4-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)piperazin-1- yl)pyridin-3-yl)-4-fluoro-2H-indazol -2-y1)-N-(thiazol-2-yl)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 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 the use in the therapeutic and / or prophylactic treatment of cancer, in particular non-small-cell lung cancer, more particularly EGFR-mutant non-small lung cancer wherein 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 the use in the therapeutic and / or prophylactic treatment of non-small-cell lung cancer, more particularly EGFR-mutant non-small 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 non- small-cell lung cancer, more particularly EGFR-mutant non-small lung cancer wherein the activating mutation is L858R. E37: A certain embodiment of the invention is a pharmaceutical composition comprising the compound of formula IT 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 EGFR-mutant non-small lung cancer 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 the use as a medicament in therapeutic and / or prophylactic treatment of a patient with EGFR activating mutations suffering from cancer, in particular non-small-cell lung cancer, comprising determining the EGFR activating mutations status in said patient and then administering the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, 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 the use as a medicament in therapeutic and / or prophylactic treatment of a patient with EGFR mutations T790M / L858R, T790M / L858R / C797S, L858R and / or L858R / C797S suffering from cancer, in particular non- small-cell lung cancer, comprising determining the EGFR activating mutations status in said patient and then administering the compound 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 as a medicament in therapeutic and / or prophylactic treatment of a patient with EGFR activating mutations as determined with a cobas® EGFR Mutation Test v2 suffering from cancer, in particular non- small-cell lung cancer, comprising determining the EGFR activating mutations status in said patient and then administering the compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, to said patient. E42: The invention includes all substituents in its corresponding deuterated form, wherever applicable, of the compounds of formula II. E43: The invention includes all optical isomers, i.e. diastereoisomers, diastereomeric mixtures, racemic mixtures, all their corresponding enantiomers and / or tautomers as well as their solvates, wherever applicable, of the compounds of formula II. Embodiments of Formula III and Formula IV El: In certain embodiments the present invention provides a compound of Formula III or Formula IV: R32 1 NT N 2 R33 Va , R 0 N . L = - Po (RE), dé 2 - (11) R32 1 NO) — -5 5 R33 Va KAN wy CIO (RE), C Ren - av) or a pharmaceutically acceptable salt, isotope, N-oxide, stereoisomer thereof, optionally as part of a pharmaceutical composition; wherein: A¥* is selected from: 36 Re 37 R R RY ir A TN “ — x o= RS ) N Ke yr A ; N—N MN, R90 18 selected from: 38 34 AY RH wr F Y. f hd A3S 4 we A w—( Wi, S o R* R34 A N Sh o=( o= YG \ \ R3 \ G LAL R o — AZ = Nas \ SE HN Rs AS o 1 a21 NN ; a 0 36 RM 37 R R 34 R37 R38 R34 37 7 RY \ / \ R" ; o= A / D o—= xX 1 I vod / N p A - \ a4 Ro 190 ys: tel xX \ EF R RY / RS Nas we XY \ / Nin \ a2! — HN— A2=p3 HN— 'A%2 j— 7 A ro 4 = —y 0 0 B* is heteroaryl or aryl each of which is optionally substituted with 1, 2, or 3 R¥! substituents; yis0, 1,2, or3; R¥! is independently selected at each occurrence ffrom H, halogen (F, Cl, Br, or I), Ci. s-alkyl, cyano, Ci-alkoxy, halo-Cis-alkoxy, halo-Cis-alkyl, Cs.s-cycloalkyl, and halo-Cs.s- cycloalkyl and can be located on either ring where present on a bicycle; R3?is hydrogen, halogen (F, Cl, Br, or I), C16-alkyl, halo-Ci.¢-alkyl, Cs.s-cycloalkyl, or halo-C3.s-cycloalkyl; R¥ is hydrogen, halogen (F, Cl, Br, or I), Cis-alkyl, halo-Ci.¢-alkyl, Cs.s-cycloalkyl, or halo-Cs.s-cycloalkyl and can be located on the dihydropyrrole or imidazole ring; R* is independently selected at each occurrence from H, F, Cig-alkyl, halo-Ci6-alkyl, Cs.s-cycloalkyl, and halo-Cs.s-cycloalkyl; R* is independently selected at each occurrence from H, halogen (F, Cl, Br, or I), C1. s-alkyl, halo-C6-alkyl, and Cs.s-cycloalkyl; or R* and R** combine to form —(CHa)q=; qislor2; R* and R¥ are independently selected from H, halogen (F, Cl, Br, or I), cyano, C16- alkoxy, halo-Ci.¢-alkoxy, Ci¢-alkyl, halo-Ci-alkyl, C3.s-cycloalkyl, and halo-Css-cycloalkyl; or R3 and RY together are combined to form a 5- or 6- membered cycle optionally substituted with 1, 2. or 3 R3! substituents; R% is H, Cis-alkyl, or C3s-cycloalkyl; Ring G is a heteroaryl optionally substituted with 1 or 2 R* substituents; A?! is -NH-, -0O-, -CHa-, or -NR0. Ris alkyl, cycloalkyl, aryl, or heteroaryl; or as allowed by valence R'°° may combine with R¥ to form a 5-8 membered heterocycle or 5 membered heteroaryl; A AB AM and A® are independently selected from -N- and -CR*2-; R* is independently selected at each occurrence from H, halogen (F, Cl, Br, or I), cyano, Ci-alkoxy, halo-Ci.s-alkoxy, Ci.s-alkyl, halo-Ci.¢-alkyl, Cs.s-cycloalkyl, and halo-Cs. s-cycloalkyl; A36 is -N- or -CR33-: L? is a bivalent linking group that connects A* and either the isoindolinone or indazole. E2: The compound of embodiment 1, wherein the compound is selected from: R32 | NN ) 2 ~ < R33 JI , R* oN “rr ¢ I n= / (R¥1), dg 2 — my or a pharmaceutically acceptable salt thereof. E3: The compound of embodiment 1, wherein the compound is selected from: R32 1 ah — = Re JT BAN xy HAST (RS ) C Ren - Iv) or a pharmaceutically acceptable salt thereof. E4: The compound of any one of embodiments 1-3, wherein R* is H. E5: The compound of any one of embodiments 1-3, wherein R¥ is F. E6: The compound of any one of embodiments 1-5, wherein y is 1. E7: The compound of any one of embodiments 1-5, wherein y is 2. E8: The compound of any one of embodiments 1-7, wherein at least one R®! is halo. E9: The compound of any one of embodiments 1-7, wherein at least one R*! is F E10: The compound of any one of embodiments 1-5, wherein y is 0. Ell: The compound of any one of embodiments 1-10, wherein R*? is H. E12: The compound of any one of embodiments 1-10, wherein R¥? is F. E13: The compound of embodiment 1, wherein the compound is selected from: AX Fe xt = ~~ AL = ) RZ go | LI, - 31 2 J ~~ a H a ROY IY R32 = o N’ (») "5 R3! J ie no 7 ¢ o NTN RE RZ oN’ 12 = 12 ¥ Gr O+- v- R31 NH R31 a 2) F J B [AN O 0D IN R33 al o N7 NT oN” NT 2 = © = — — RO JNH SNH i J oD) i J 0) B B A and E14: The compound of embodiment 1, wherein the compound is selected from: R32 H ra) R32 I% EAN) 5 R3! J R32 N’ Ope N— . Re J 0 NH J Mo 33 IN R PNR RL PN CT J SD IL. = Tr oY 2 Nx N wil hil EXOT Ey » = p= RY a a JNH Foe NT N— / \ Nr N= NH au YY TN EI OR R31 NH / ) FO 0 FO rR fd '\ | oN and . E15: The compound of any one of embodiments 1-14, wherein A* is: R¥# y — \ o=' any one of embodiments 1-14, wher AY 34 R re °° — Ne Ngo ° R’ The compound of any one of embodiments 1-14, wherein A* is: > o={( \ R* o — AB = N Sop X | HN R35 _A® o 1 a2 The compound of any one of embodiments 1-16, wherein A** is CH. The compound of any one of embodiments 1-16, wherein A** is N. The compound of any one of embodiments 1-16, wherein A> is CR*2, The compound of any one of embodiments 1-16, wherein A** is CF. The compound of any one of embodiments 1-20, wherein A* is CH. The compound of any one of embodiments 1-20, wherein A* is N. The compound of any one of embodiments 1-20, wherein A* is CR*2. The compound of any one of embodiments 1-20, wherein A** is CF, The compound of any one of embodiments 1-14, wherein A* is: 36 R# =37 R Re RY I Ny Oo \ Rss ) NN N p= a) 0 The compound of any one of embodiments 1-14, wherein A* is: 36 R# 537 R R37 I Ny La \ OO X 1 1 AY R37 ir \ 35 21 < A wy N p- — 0 The compound of embodiment 25 or 26, wherein A2! is NH. The compound of embodiment 25 or 26, wherein A2! is O. The compound of any one of embodiments 1-14, wherein A* is: R34 RY “NN SN R% Oo — Fr \ \ F- A32=, As x a 0 The compound of any one of embodiments 1-29, wherein A> is CH. The compound of any one of embodiments 1-29, wherein A¥ is N. The compound of any one of embodiments 1-29, wherein A¥ is CR*2. The compound of any one of embodiments 1-29, wherein A¥ is CF. The compound of any one of embodiments 1-33, wherein A¥ is CH. The compound of any one of embodiments 1-33, wherein A* is N. The compound of any one of embodiments 1-33, wherein A® is CR*2. The compound of any one of embodiments 1-33, wherein A® is CF. The compound of any one of embodiments 1-14, wherein A* is: R34 “NN NA o— Yo 6G \ R3% ON . See 3, ; 4 vo) The compound of embodiment 38, wherein A?! is NH. The compound of embodiment 38, wherein A is O. The compound of any one of embodiments 1-40, wherein R3* is H. The compound of any one of embodiments 1-40, wherein R3* is F. The compound of any one of embodiments 1-40, wherein R3* is CHs. The compound of any one of embodiments 1-43, wherein R* is H. The compound of any one of embodiments 1-43, wherein R3 is F. The compound of any one of embodiments 1-43, wherein R** is CHs. The compound of any one of embodiments 1-40, wherein R** and R** combine to form a -CH;-. The compound of any one of embodiments 1-47, wherein R3! is independently selected at each occurrence from H, halogen (F, Cl, Br, or I), and Ci.¢-alkyl. The compound of any one of embodiments 1-48, wherein R*? is independently selected at each occurrence from H, halogen (F, Cl, Br, or I), and C1.6-alkyl. E50: The compound of any one of embodiments 1-49, wherein B* is N v got <J E51: The compound of any one of embodiments 1-49, wherein B* is — N N ¢ AS ] E52: The compound of any one of embodiments 1-49, wherein B* is — Ny iN E53: The compound of any one of embodiments 1-49, wherein B* is : = E54: The compound of any one of embodiments 1-53, wherein L? is of formula: RS 5 rz =. Re” =. > (LI). wherein, X! and X? are independently at each occurrence selected from bond, heterocycle, aryl, heteroaryl, bicycle, alkyl, aliphatic, heteroaliphatic, -NR?'-, -CR*R*.-, -O-, -C(0)-, -C(NR?")-, -C(S)-, -S(0)-, -S(0)2- and —S-; each of which heterocycle, aryl, heteroaryl, and bicycle is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R*’; R*, R?', R?, R%, and R* are independently at each occurrence selected from the group consisting of a bond, alkyl, -C(0)-, -C(0)O-, -OC(0)-, -802-, -$(0)-, -C(S)-, -C(O)NR?"-, NR¥C(0)-, -O-, -S-, -NRY-, oxyalkylene, -C(R*R*)-, -P(O)(OR*)O-, -P(0)(OR)-, 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 R*’; Ris independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocycle, aliphatic and heteroaliphatic; R¥ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, aliphatic, heteroaliphatic, heterocycle, aryl, heteroaryl, -C(O)(aliphatic, aryl, heteroaliphatic or heteroaryl), -C(O)O(aliphatic, aryl, heteroaliphatic, or heteroaryl), alkene, and alkyne; R*¥ is independently at each occurrence selected from the group consisting of hydrogen, RY, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH(aliphatic), -N(aliphatic)a, -NHSOx(aliphatic), -N(aliphatic)SOaalkyl, -NHSOx(aryl, heteroaryl or heterocycle), -N(alkyl)SOa(aryl, heteroaryl or heterocycle), -NHSOzalkenyl, -N(alkyl)SO.alkenyl, -NHSOalkynyl, -N(alkyl)SO.alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocycle, oxo, and cycloalkyl; additionally, where allowed by valence two R* groups bound to the same carbon may be joined together to form a 3-8 membered spirocycle; and R* is aliphatic, aryl, heteroaryl, or hydrogen. ESS: The compound of embodiment 54, wherein L? is of formula: 3 ~~ or re” ii XK or Yo RE _RZ R23 Nar E56: The compound of embodiment 54 or 55, wherein X' is bond. E57: The compound of embodiment 54 or 55, wherein X! is heterocycle. E58. The compound of embodiment 54 or 55, wherein X! is NR?, E59: The compound of embodiment 54 or 55, wherein X! is C(O). E60: The compound of any one of embodiments 54-59, wherein X? is bond. E61: The compound of any one of embodiments 54-59, wherein X? is heterocycle. E62: The compound of any one of embodiments 54-59, wherein X* is NR2. E63: The compound of any one of embodiments 54-59, wherein X? is C(O). E64: The compound of any one of embodiments 54-63, wherein R? is bond. E65: The compound of any one of embodiments 54-63, wherein R2° is CHa. E66: The compound of any one of embodiments 54-63, wherein R?° is heterocycle. E67: The compound of any one of embodiments 54-63, wherein R? is aryl. E68: The compound of any one of embodiments 54-63, wherein R?° is phenyl. E69: The compound of any one of embodiments 54-63, wherein R? is bicycle. E70: The compound of any one of embodiments 54-69, wherein R?! is bond. E71: The compound of any one of embodiments 54-69, wherein R*! is CHa. E72: The compound of any one of embodiments 54-69, wherein R?! is heterocycle. E73: The compound of any one of embodiments 54-69, wherein R?! is aryl. E74: The compound of any one of embodiments 54-69, wherein R?! is phenyl. E75: The compound of any one of embodiments 54-69, wherein R2! is bicycle. E76: The compound of embodiment 54, wherein L is a linker of formula: R24 22 - AR 2 “Nga SU E77: The compound of any one of embodiments 54-76, wherein R?? is bond. E78: The compound of any one of embodiments 54-76, wherein R*? is CHa. E79: The compound of any one of embodiments 54-76, wherein R?? is heterocycle. E80: The compound of any one of embodiments 54-76, wherein R?? is aryl. E81: The compound of any one of embodiments 54-69, wherein R?? is phenyl. E82: The compound of any one of embodiments 54-76, wherein R? is bicycle. E83: The compound of embodiment 54, wherein L is a linker of formula; 2 < N 2 rz E84: The compound of any one of embodiments 54-83, wherein R? is bond. E85: The compound of any one of embodiments 54-83, wherein R? is CHa. E86: The compound of any one of embodiments 54-83, wherein R? is heterocycle. E87: The compound of any one of embodiments 54-83, wherein R? is aryl. E88: The compound of any one of embodiments 54-83, wherein R? is phenyl. E89: The compound of any one of embodiments 54-83, wherein R? is bicycle. E90: The compound of any one of embodiments 54-89, wherein R** is bond. E91: The compound of any one of embodiments 54-89, wherein R** is CHa. E92: The compound of any one of embodiments 54-89, wherein R?* is heterocycle. E93: The compound of any one of embodiments 54-89, wherein R* is aryl. E94: The compound of any one of embodiments 54-89, wherein R?* is phenyl. E95: The compound of any one of embodiments 54-89, wherein R** is bicycle. E96: The compound of any one of embodiments 54-89, wherein R** is C(O). E97: In certain embodiments a compound is provided selected from: so) H ~My A = 1 Th Co Or" Of O—r Y's H F 0 se 5-((2-(1-(6,7-dihydro-5H-pyrrolo[ 1,2-cJimidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)- 7-fluoro-3-oxoisoindolin-5-yl)ethynyl)-N-(1-(2-(4-(4-((2,6-dioxopiperidin-3- yl)amino)phenyl)piperidin-1-yl)acetyl)piperidin-4-yl)picolinamide; H NY 7 \ _ / SOOO Ali C a Wa Fyn 0 0 s 2 H H o JR H A. F 5-[2-[2-[1-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-yl)-2-oxo0-2-(thiazol -2- ylamino)ethyl]-7-fluoro-3-oxo-isoindolin-5-yl]ethynyl]-N-[1-[2-[4-[(2,6-diox0-3- piperidyl)amino]phenyl]acetyl]-4-piperidyl]pyridine-2-carboxamide piperidyl)amino]phenyl]acetyl]-4-piperidylpyridine-2-carboxamide 0 o LO OAC bem g N \ 0H NN I~ AT H H NZ == ,~—"N\-A H TX 3 Z ” N N\ N H “rhe (CD EF 5-[2-[2-[1-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-yl)-2-ox0-2-(thiazol -2- ylamino)ethyl]-7-fluoro-3-oxo-isoindolin-5-yl]ethynyl]-N-[1-[2-[4-[4-[(2,6-diox0-3- piperidyl)oxy]phenyl]piperazin-1-ylJacetyl]-4-piperidyl Jpyridine-2-carboxamide - Fp \ AS Sem PY CoS m ry =o AN Nn Ns hn H 0 4 2 E 5-[2-[2-[1-(6,7-dihydro-5H-pyrrolo[1,2-cJimidazol-1-yl)-2-oxo-2-(thiazol -2- ylamino)ethyl]-7-fluoro-3-oxo-isoindolin-5-yl]ethynyl]-N-[ 1-[2-[4-[4-[[(3S)-2,6-diox0-3- piperidyl]amino]-2-fluoro-phenyl]-1-piperidyl]acetyl]-4-piperidyl ]pyridine-2-carboxamide F a 2 os / {) HP H N () NT NO ox" on W NN ~S 0 7 NT = (- H o NY smd AO H 6-[4-T4-[2-[4-[4-[(? 6-diox0-3. NANNY oo ~~ H 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[4-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]phenyl]-1-piperidyl]acetyl]piperazin-1-yl]phenyl]-4-fluoro-1-oxo- isoindolin-2-yl -N-thiazol -2-yl-acetamide NANNY ~ & IU ride F Ct o = A / () H N 9 NT ~~ 0 0 N~ OG H o NY of “AO H FATA? T4-TA-TT(IS)Y.? Adinyr kid BN ~~ H 2-(6,7-dihydro-SH-pyrrolo[1,2-climidazol-1-yl)-2-[6-[4-[4-[2-[4-[4-[[(3S)-2,6-diox0-3- piperidyl]Jamino]phenyl]-1-piperidyl]acetyl]piperazin-1-yl]phenyl]-4-fluoro-1-oxo- isoindolin-2-yl -N-thiazol -2-yl-acetamide + 7s A An oan LN NT) am A ya (Ov o~ I~ © MAO NN H ihydro-SH-pyrrolo[1,2-climidazol-1-y1)-2-[6-[4-[4-[2-[4-[4-[[(3R)-2,6-dioxo- 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-[6-[4-[4-[2-[4-[4-[[(3R)-2,6-diox0-3- piperidyl]Jamino]phenyl]-1-piperidyl]acetyl Jpiperazin-1-yl]phenyl]-4-fluoro-1-oxo- isoindolin-2-yl]-N-thiazol -2-yl-acetamide gi ! =. oO H NNN A A ~T ~~ \ ~ ~~ N- 22 - WA (J ) NT Oo oO OC H Rp Oo” ~~, H 1 “FA FA FA TEP rd var iene od? en 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(4-(4-(4-(4-(4-((2,6-dioxopiperidin-3- | yl)amino)phenyl)piperidin-1-yl)-4-oxobutyl)piperazin-1-yl)phenyl)-4-fluoro-1- oxoisoindolin-2-y1)-N-(thiazol-2-yl)acetamide fl +5 ee yl I ’ — 0 CO) NT LN TY TT WA n Tn LO ~ [ << Ox ~ ~~ PZ N H FRAY TR EA TET Foal mins niin t wo inn ~~ H 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(4-(2-(4-(4-((2,6-dioxopiperidin-3- yl)amino)phenyl)cyclohexyl)acetyl)piperazin-1-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)- N-(thiazol-2-yl)acetamide H Ot o F -— 0 wy Im Oo 0 ONG 7 H o N NY Spey “Oy -(4-(2-(4-(4-((2,6-dioxopiperid > T Ed 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(4-(2-(4-(4-((2,6-dioxopiperidin-3- | yl)amino)phenyl)piperidin-1-yl)-2-oxoethyl)piperazin-1-yl)phenyl)-4-fluoro-1- oxoisoindolin-2-yl)-N-(thiazol -2-yl)acetamide H I LAOLSOINUOLT=2=y 1 )=1v=\ 1d. F oy, N= / NyN N N th Oy A NY (od s WL if -00 N N N a - oO -~ XN er NZ 4 NN-Z 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[4-[2-[4-[ 5-[(2,6-diox0-3- piperidyl)amino]-2-pyridyl]-1-piperidyl]acetyl]piperazin-1-yl]phenyl]-4-fluoro-1-oxo- ~_isoindolin-2-y1]-N-thiazol -2-yl-acetamide H 3] Cro on , AC 230 of AICO ! OC Fn © CA NN F A hvArn AL nvreralall 2enehmidszal 1 vs TANATAT FATA NL? Gl invw ra. 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-yl)-2-[6-[4-[4-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]acetyl]piperazin-1-yl]phenyl]-4-fluoro-1- oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide I ~ H 0 oxo-1soindolin-2-yl -\-thia. F et op AL 3m H \N i Oo =, F 7X N NH Ch in) ~~ OC oF ~N N\N-Z 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-yl)-2-[6-[4-[4-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]-3-fluoro-phenyl]-1-piperidyl]acetyl]piperazin-1-yl]phenyl]-4-fluoro-1- oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide H FE LAE F 1 JOLLA wt RAL NSE A SE Gf oll A Epa ww Ah OS T 6 oxo-isoindolin-2-y1]-N-thiz F SN ~~ N NT HN, © ht wh H off oO H NO an ate Pa IN H oO ri. / {) N—¢ OA ) Nh C o> HN, © 0 Wr A, K4 / 2-[6-[4-[4-[2-[4-[2-cyano-4-[(2,6-diox0-3-piperidyl)Jamino]phenyl]-1- piperidyl]acetyl]piperazin-1-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-2-(6,7-dihydro- SH-pyrrolo[1,2-cJlimidazol-1-y1)-N-thiazol-2-yl-acetamide F SIN H No / {) RP AA {) OC o~ HNN, © — 1 Ay A E H F H o Ay 0: N~¢ " Tot N = F if H TY ~~ S\N “ \ 2» 0 H oO 2-[6-[4-[4-[2-[4-[2-(difluoromethyl)-4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]acetyl]piperazin-1-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-2-(6,7-dihydro- SH-pyrrolo[1,2-c]limidazol-1-y1)-N-thiazol-2-yl-acetamide Rk 3 0 { ) fy AIO OO | od H ~ A. 0 o N a OO n 3 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(4-(4-(2-(4-(3-((2,6-dioxopiperidin-3- yl)amino)phenyl)piperidin-1-yl)acetyl)piperazin-1-yl)phenyl)-4-fluoro-1-oxoisoindolin-2- y1)-N-(thiazol-2-yl)acetamide 7 \ N zy x if \ ok { NY N y ° 0 \=N - (0) p ° DO My - J o \ \ 7 \ . _N F =\ N- “2 NN 1 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-yl)-2-(6-(4-(4-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1- yl)acetyl)piperazin-1-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol-2-yl)acetamide F 3 o “A () i Im = ; H N I NTL RS oN? oO > RP 3 oe N~¢ N F. H FE F: =~ H a | 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(4-(2-(1-(4-((2,6-dioxopiperidin-3- | yl)amino)-2-(trifluoromethyl)phenyl)-4-hydroxypiperidin-4-yl)acetyl)piperazin-1- yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide = RK yx HP H NY ox Nf ~~] A = oy N~Z ON (OG H o NY sap “~~, H (4-(2-(4-(4~((2,6-dioxopiperidi inaa rN. 4 lovers 1 iver arn AT 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(4-(2-(4-(4-((2,6-dioxopiperidin-3- yl)amino)phenyl)piperidin-1-yl)acetyl)piperazin-1-yl)phenyl)-4-fluoro-1-oxoisoindolin-2- y1)-N-(pyridin-2-yl)acetamide E “Ny o N\A , () NS NA () NT oN Cl] rh BR / ~ \ Ppa fo} NT) 7 ALS 7 H o He I~ o ‘N Ob 2 H 6-[4-[4-[2-[4-[4-[(2,6-diox0-3- 2-(6,7-dihydro-SH-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[4-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]acetyl|piperazin-1-yl]phenyl]-4-fluoro-1- oxo-isoindolin-2-y1]-N-(2-pyridyl)acetamide ooo I~ o > LN HN LUM ~ o 1) OAL TE © A N~S Cy Rg? ~ 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(1-(2-(4-(4-((2,6-dioxopiperidin-3- yl)amino)phenyl)piperidin-1-yl)acetyl)piperidin-4-yl)phenyl)-4-fluoro-1-oxoisoindolin-2- 38: NRT Fal lim rmimd 2 wel Rm mimi re snrn od on _y1)-N-(thiazol-2-yl)acetamide H SE n= Fev Ua oO 7 IRN a ~\ 0 G'S Ox ~< \N-2 N “Oe H 2+(6,7-dihydro-5H-pyrrolo[1,2-cJimidazol-1-y1)-2-(6-(4-(1-2-(4-(4-(((S)-2,6- H | dioxopiperidin-3-yl)amino)phenylpiperidin-1-yl)acetyl)piperidin-4-yl)phenyl)-4-fluoro-1- | oxoisoindolin-2-yl)-N-(thiazol -2-yl)acetamide F S 0 Alo ; N N RP H \ Nan oN ~A 8 AN SS CT N-7 OG eT ~~ H 2-(6,7-dihydro-SH-pyrrolo[1,2-c]imidazol-1-y1)-2-(6-(4-(1-(2-(4-(4-(((R)-2,6- H o ~~ ox Nf N 0 (6-(4-(1-2-(A-(4(R)-2.6- H | dioxopiperidin-3-yl)amino)phenyDpiperidin-1-yl)acetyl)piperidin-4-ylphenyl)-4-fluoro-1- | oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide F JS 0 ALO ie N N () I~ oN A NN ~~, AH eo / \ MTN \ oO 7 <M OO H o NY sa “A v H > (6 (A(T AD (A(A-(((S)-D 6 \-N-7 - FH 2-(6,7-dihydro-SH-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(4-(1-(2-(4-(4-(((S)-2,6- | dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yDacety piperidin-4-yl)phenyl)-4- | fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide K I~ rl Ta NP OA () a oN MN 3 HNN ° -% “A wh N F~ “HAN Fm No RP Td \ / ~ os { MN 3 HNN 0 — % N 5A H AN V4 2-(6-(4-(1-(2-(4-(2-cyano-4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1- yl)acetyl)piperidin-4-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-2-(6,7-dihydro-5H- H i pyrrolo[1,2-climidazol-1-yl)-N-(thiazol-2-yl)acetamide F JS 22 0 ~ = Q Nyy () Sa ° N =~ A 0 — I~) 0 dO af Se 2+(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-[6-[4-[ 1-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]phenyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl Jphenyl]-4-fluoro-1-oxo- isoindolin-2-yl]-N-thiazol -2-yl-acetamide 1soindolin-2-yl]-N-thiazol F 3 0 n=X / J AIC, ~A ° LI x Bo: N ~g - ={ { / 7 N° N NA of (OC 7 ~~ 0 py % A \N-7 F H thvdro-SH-nvrrolol 1 2-climidazol-1-v1)-2-T6-[6-[4-[2-[4-T4-[T(3S)-2 6-dioxo H Oy NN-Z Ad 0 H 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-yl)-2-[6-[6-[4-[2-[4-[4-[[(3S)-2,6-diox0-3- piperidyl]amino]-2-fluoro-phenyl]-1-piperidyl]acetylpiperazin-1-yl]-3-pyridyl]-4-fluoro- 1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide 5 F N= 9 | HN oO H N NA N-O = “NA N 0 =N Rott 0 NN NA H N, H © H © 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-yl)-2-[6-[1-[1-[2-[4-[4-[[(3S)-2,6-diox0-3- piperidyl]amino]phenyl]-1-piperidyl]acetyl]-4-piperidyl]pyrazol-4-yl]-4-fluoro-1-oxo- isoindolin-2-y1]-N-thiazol -2-yl-acetamide OA H N H © 150Indolin-2-yl -IN-TNAaZOol-2-Y 1-ac€tamiae Os F Teh, tool N, N N, A or ~ o= NN e LN MN Q oo H © 2-(6,7-dihydro-SH-pyrrolo[1,2-climidazol-1-yl)-2-[6-[4-[ 1-[2-[4-[4-[[(38)-2,6-diox0-3- piperidyl]amino]phenyl]-1-piperidyl]acetyl]-4-piperidyl]pyrazol-1-yl]-4-fluoro-1-oxo- isoindolin-2-y1]-N-thiazol-2-yl-acetamide F Nl ~\ 7! N= COL —N —\ $ 0 Tr N = 0 A, MO / Ee A 1 ON / " N\—N N\ / “NN 0 Ney \ FETS THN 0 2-(6,7-dihydro-SH-pyrrolo[1,2-climidazol-1-yl)-2-(6-(1-(1-(2-(4-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)acetyl)piperidin-4-yl)-1H-1,2,3-triazol-4- yl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol -2-yl)acetamide \, H $ . . R. NA ~ A Lr a? Maso a yipbbialiiioe N KT ANA { H "N. ~~ H I | TYAN AINA N=) [ N NJ : Ce 4 ) Be) 2+(6,7-dihydro-SH-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[[ 1-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]phenyl]-1-piperidyl]acetyl]-4-piperidylJoxy]phenyl]-4-fluoro-1-oxo- isoindolin-2-yl]-N-thiazol -2-yl-acetamide 2\, H CL 5 F or HN—4 ~~ AA a 7 yl-alilal Oe N KT AA H "N. , ~~ H I | THA a N=) 7 N N. a ( J Py 2-(6,7-dihydro-5H-pyrrolo[ 1,2-cJimidazol-1-y1)-2-[6-[4-[[ 1-[2-[4-[4-[[(3S)-2,6-diox0-3- piperidyl]Jamino]phenyl]-1-piperidyl]acetyl]-4-piperidylJoxy]phenyl]-4-fluoro-1-oxo- isoindolin-2-yl]-N-thiazol-2-yl-acetamide 2\, H J # N, fo] 1 HN—4 ~~ A 0 gr ny? ylabiiainnive Rk KT NAD } H "N. . ~ H 1 | THAN es N= 7 ‘ N N.| { ri | AN ° = - Cl 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-[6-[4-[[1-[2-[4-[4-[[(3R)-2,6-diox0-3- piperidyl]amino]phenyl]-1-piperidyl]acetyl]-4-piperidylJoxy]phenyl]-4-fluoro-1-oxo- isoindolin-2-y1]-N-thiazol -2-yl-acetamide Hy © F Nt 0 TY AN a J) N N. < MN © TC CC oo J 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-(6-(4-((1-(2-(4-(4-((2,6-dioxopiperidin- 3-yl)amino)-3-fluorophenyl)piperidin-1-yl)acetyl)piperidin-4-yl)oxy)phenyl)-4-fluoro-1- oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide H oA N Ao ; F. N - P F NN We A 0 IT ANA , ~~ H I | TYAN AINA N=) [ N NN / ; Ln a 3 Ay 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-((1-(2-(4-(4-((2,6-dioxopiperidin- 3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)piperidin-4-yl)oxy)phenyl)-4-fluoro-1- oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide oP N Ao Z\, H WAL ~AN 0 YW oP 7H I | THAN a N=) 1 N NN < oN ) oo " 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-((1-(2-(4-(5-((2,6-dioxopiperidin- 3-yl)amino)pyridin-2-yl)piperidin-1-yl)acetyl)piperidin-4-yl)oxy)phenyl)-4-fluoro-1- oxoisoindolin-2-y1)-N-(thiazol-2-yl)acetamide Na H AS N. Ny OF SNA oO Py Ao NS R eps PA Rp H IN 0 ill AN a J ( | —N oy oo 2-(6-(4-((1-(2-(4-(2-cyano-4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1- yl)acetyl)piperidin-4-yl)oxy)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H- pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide ps IT & ~~ H A ~~ N 0 O. ¢ bo oi _N E 4 A 1 —N uN F H 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(4-((1-(2-(4-(4-((2,4-diox0-3- azabicyclo[3.1.1]heptan-1-yl)amino)phenyl)piperidin-1-yl)acetyl)piperidin-4- yl)oxy)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide H oP N Ao ~ pF JX NN 0 PA , ~~ H I | TYAN AINA = [ N NN / < MN © JC Hi 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-(6-(4-((1-(2-(4-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)piperidin-4- yl)oxy)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide 2\, H J F N, oO | HN— ~~ A 0 Lg 7 L aint UCL any Jatelalllidd R ~T PNA "N. H ANN ANA - H a. \ J - h 0 Y AN Py Oo Oo oT 2 Cl i | CLC AN © Ao 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[[1-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]phenyl]-1-piperidyl]-2-oxo-acetyl]-4-piperidyl]oxy]phenyl]-4-fluoro-1- oxo-isoindolin-2-yl]-N-thiazol -2-yl-acetamide 7 CO) \ rs: \ 5 f He Cr H N Ned N RTC Te _o 2-(6,7-dihydro-SH-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[(3R)-1-[2-[4-[4-[[(3S)-2,6-diox0- 3-piperidylJamino]phenyl]-1-piperidyl]acetyl]pyrrolidin-3-yl]oxyphenyl]-4-fluoro-1-oxo- isoindolin-2-yl]-N-thiazol-2-yl-acetamide F / — \ —N, FN EN Il so Qo A a 0 HN NN = s : N= 2 ' ) —I H N N I~ J C oo ~% NN -dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4- 2-(6,7-dihydro-5H-pyrrolo[ 1,2-cJimidazol-1-y1)-2-[6-[4-[(3S)-1-[2-[4-[4-[[(3S)-2,6-diox0- 3-piperidyl]amino]phenyl]-1-piperidyl]acetyl]pyrrolidin-3-yl]oxyphenyl]-4-fluoro-1-oxo- isoindolin-2-y1]-N-thiazol-2-yl-acetamide isoindolin-2-yl]-N-thiazol FE oO a (Ov HN NN 1 o © -) a-\ NT ~~ N N LAN H o NY i ~~, H rt Nt a Venda din] = / " ~~ H 2-(6-(4-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1- yl)acetyl)piperazin-1-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-2-((R)-6-fluoro-6,7- dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide F SN AA Hop F N oe OCS A 0 ~ / N 1 @! C H o N~¢ oO: NY < N = H o Rt Oo N—<¢ 8 No / Nel OY Co St LY ’ "X F =\ N- \ 7 / 1 NN | 2-[6-[4-[4-[2-[4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-y1]-1- piperidyl]acetyl]piperazin-1-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-2-[(6R)-6-fluoro- 6,7-dihydro-5H-pyrrolo[1,2-cJimidazol-1-yl]-N-thiazol-2-yl-acetamide H CoG 7 OO — = H 0 (NY N Co rot ~A\ © ~~" R N ° N NZ F H FE ™ ile den CIT warren] ATT PD Await dace 1 INADA TL IAI ID FA FA (CN MN £ \N-7 = ZH 2-(6,7-dihydro-SH-pyrrolo[1,2-climidazol-1-yl)-2-(6-(4-(2-(2-(4-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)-2,7- diazaspiro[3.5]nonan-7-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2- yl)acetamide = 7 ( H o y J N De OOS ~A o ~ sw)? N N NZ © H A dhvdra SH-nurral af 2cTimidagel 1 uD TET TATA? Erfirval. NAN-7 = ~~ H 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-yl)-2-[6-[4-[2-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]phenyl]-1-piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-ylJphenyl]-4- 0 . fluoro-1-oxo-isoindolin-2-yl -N-thiazol-2-yl-acetamide . F C3 0 n=l / {() Ny @ fi NO) a) 0 3 N N ~_ ~~ N © ~ 3 \-N-Z 0 N' H o i o NY yr “A, F TRA PY pao Cpr Gus FH 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[2-[2-[4-[4-[[(3S)-2,6-diox0-3- piperidyl]Jamino]-2-fluoro-phenyl]-1-piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6- yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide oi” aati yl phenyl [-4-TIuoro-1-0xo-1so1ndolin-2-yl | -IN-th1azc = ll 0 To 0 CN N ST -000- \ F 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-1 Ske A sg 0 A i 3 ee A 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-yl)-2-[6-[4-[2-[2-[4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-1-piperidyl]acetyl]-2,6- diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl- acetamide —\ Ny HN. © Co H N H o ong? C N_ / NO Hag: \ CN 0 ox ~ ~ N 0-00 \ N F ’ F E N AE TodihvdraSHomurralal 1 Jeclimidaralo1 ova TEA [AT (D Ao 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-y1)-2-[6-[4-[2-[2-[4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-3,3-difluoro-1-piperidyl]acetyl]- 2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-N-thiazol -2-y1- acetamide FE H 1! 1 ] T Sees er RD AP F yr I NO) ~F N° or O00 0 N H Sr NO ov ~~ H NN 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(6-(2-(4-(4-((2,6-dioxopiperidin-3- yl)amino)phenyl)-3,3-difluoropiperidin-1-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2- yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide yDphenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-Z = F a () C N I~ A] Se To 1 C- H o NT o <7 “A N F H TY F H 2-(6,7-dihydro-SH-pyrrolo[1,2-climidazol-1-y1)-2-[6-[4-[2-[2-[4-[4-[[(38)-2,6-diox0-3- piperidyl]amino]-2-fluoro-phenyl]-1-piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6- yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-N-(2-pyridyl)acetamide AN F x, { iP WY N o N Ne Cy OE TT ] = = F -N =\ AN ~~ NN 1 2-(6,7-dihydro-SH-pyrrolo[1,2-climidazol-1-y1)-2-[6-[4-[2-[2-[4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-1-piperidyl]acetyl]-2,6- diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-(2- pyridyl)acetamide A LN HN 0 ° H o CN of LI N o N = N. N N— T0002 F + N° E ! 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-yl)-2-[6-[4-[2-[2-[4-[3-(2,4- xohexahydropyrimidin-1-y1)-1-methyl-indazol-6-y1]-3.3-difluoro-1-piperidyl]ace =) 1 pu ¥ A Man HOA aati p." F fr WN F 1 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-yl)-2-[6-[4-[2-[2-[4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-y1]-3,3-difluoro-1-piperidyl]acetyl]- 2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-N-(2- py ridyl )acetamide 2\, H ’ o E N. HN—4 Pr Nn Lr AZ oO mo 4 H — - NPS ANA No H N= 90 OY AN wo) N N_ { i —N @ | =< AN | I N © N_~ my ny 2-(6,7-dihydro-5SH-pyrrolo[1,2-climidazol-1-y1)-2-[6-[4-[[4-[2-[4-[4-[(2,6-diox0-3- | piperidyl)amino]phenyl]-1-piperidyl]Jacetyl]piperazin-1-ylJmethyl]phenyl]-4-fluoro-1-oxo- isoindolin-2-y1]-N-thiazol-2-yl-acetamide H QO oA N Ao ~( oF XC AN A 0 AA a b H 9 MY AN wo) N NN { 2 ~~ | I N © N_~ 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[[4-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]acetyl]piperazin-1-ylJmethyl]phenyl]-4- fluoro-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide H Oo oA N Ao S F. Ng WC A 0 XT PNA J b H 0 Y AAA | | ‘N. » N N. 7 0 -1 roo MN © NO 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[[4-[2-[4-[4-[[(3S)-2,6-diox0-3- piperidyl]amino]-2-fluoro-phenyl]-1-piperidyl]acetylpiperazin-1-ylJmethylJphenyl]-4- fluoro-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide H oA N Ao - S F F No wl XT PNA ) ~~ H N L N ANY Oo 2 0 —N ) CY N © SAN 2+(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-[6-[4-[[4-[2-[4-[4-[[(3S)-2,6-diox0-3- piperidyl]amino]-2-fluoro-phenyl]-1-piperidyl]-2-oxo-ethyl]piperazin-1- yl]methyl]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-N-thiazol-2-yl-acetamide H oA N Ao oO ~{ of XC IN A 0 ANA TNA, A N=) 1 N N. { or NID =< AN MN © J ET ET iy an ¥ oO TY 3 | AN YY oo O ~~ _N. F NT N—\ a { NH NH J Me | NNN [ F N’ No) N— ~ 0) 0 uv he 7 ON 0 J=N s 2 2-[4,7-dichloro-6-[4-[4-[2-[4-[4-[(2,6-diox0-3-piperidyl)amino]phenyl]-1- piperidyl]acetyl]piperazin-1-yl]phenyl]indazol-2-y1]-2-(6,7-dihydro-5H-pyrrolo[1,2- climidazol-1-yl)-N-thiazol -2-yl-acetamide COO i > SN NTS 1 F 1 1 oO F ND N— / \ re N < NH NH J Mo SN UN Na Ud \ No) NT J uv he JON oO )=N s J 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(6-(4-(4-(4-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-4-yl)oxy)piperidin-1-yl)-4-oxobutyl)piperazin-1-yl)pyridin-3-yl)-7- fluoro-2H-indazol-2-y1)-N-(thiazol-2-yl)acetamide 0 ~~ PAN F ND N— / \ N= ~~ NH J No NY Sah rs F N’ : NAN) — N— | J eX pel ANY Por ~~ 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(6-(4-(2-(4-(4-((2,6-dioxopiperidin-3- yl)amino)phenyl)piperidin-1-yl)acetyl)piperazin-1-yl)pyridin-3-yl)-7-fluoro-2H-indazol-2- «TNT Zethl mnrrrml ™ «i: 1 Nv mrad re ten odo y1)-N-(thiazol-2-yl)acetamide AP | HN 0 F pW AN NSIS AN ¢ EF ] —N F < N Z [ 4 OR ik i SONS SA oO 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-yl)-2-[6-[6-[4-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]acetyl]piperazin-1-yl]-3-pyridyl]-4-fluoro- | indazol-2-y1]-N-thiazol-2-yl-acetamide N° NNW oO F Nt AN NINA AN 0 & ¢ ~ | ~N N Z [ N oJ) : VY SONS SN oO 2-(6,7-dihydro-SH-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[6-[4-[2-[4-[4-[(2,6-diox0-3- | piperidyl)amino]phenyl]-1-piperidyl]acetyl ]piperazin-1-yl]-3-pyridyl]-4-fluoro-indazol-2- | NE A aL Co yl -N-thiazol-2-yl-acetamide i AP | HN oO F C3 =( pW AN NNN AN ¢ F A —N, — ; Ly N 7 SN NS \ SONS SN oO 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-yl)-2-[6-[6-[4-[2-[4-[5-[(2,6-diox0-3- | piperidyl)amino]-2-pyridyl]-1-piperidyl]acetyl]piperazin-1-yl]-3-pyridyl]-4-fluoro-indazol- | ya OE ce snl yt ea oy 2-yl]-N-thiazol-2-yl-acetamide NS x F Oy =( pW AN NSN AN 0 E ¢ ~ | —N, _ =< N Z [ N oJ) : a i SNS Fg? Oo 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-yl)-2-[6-[6-[4-[2-[4-[3-(2,4- | dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-1-piperidyl]acetyl]piperazin-1-yl]- | 3-pyridyl]-4-fluoro-indazol -2-yl]-N-thiazol-2-yl-acetamide EP | NH HNN oO F “> N=( py RE a Ee 0 F $ . =N, _ F = N Zz [ A YUE N NY 1 SNS SN oO 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-(6-(6-(4-(2-(4-(4-(((S)-2,6- | dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)piperazin-1-yl)pyridin-3- | yl)-4-fluoro-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide or a pharmaceutically acceptable salt thereof. E98: In certain embodiments a compound is provided selected from: F ND N— / \ NT NAA =U NH J Yo “To Ay Aa ~~ de, ) F N— 2 oY i AN oY oA 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(6-(6-(2-(4-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)-2,6- diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-7-fluoro-2H-indazol-2-y1)-N-(thiazol-2- yl)acetamide ANS F Nt F “AT li et tt tieti———— o Fo f NON NS o ; 4 Na J 7 —N, (F ® N NP N NJ “x 2+(6,7-dihydro-5H-pyrrolo[1,2-cJimidazol-1-yl)-2-(6-(6-(6-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1- yl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-7-fluoro-2H-indazol -2-y1)-N- NY N— / \ SN” NH J Mo thiazol-2-yl)acetamide o NZ ] F nN? SN” Ny _N bs 0 p ~r Ee oO 0 NH o> N ~o 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(6-(6-(2-(1-(4-((2,6-dioxopiperidin-3- yl)amino)-3-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2- yl)pyridin-3-yl)-7-fluoro-2H-indazol-2-y1)-N-(thiazol-2-yl )acetamide 0 AN NG pW F AF NN F NC ° Q@ No ; {NSS : —N_ < oN F "x 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-y1)-2-(6-(6-(4-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1- ylacetyl)piperazin-1-yl)pyridin-3-yl)-4-fluoro-2H-indazol-2-y1)-N-(thiazol-2-yl)acetamide Retin ANS wl wn AAT NSF N NJ 1-1(2H)-yl)-1-methyl-1H-indazol-6-y1)-3,3- yridin-3-yl)-4-fluoro-2H-indazol-2-y1)-N-(t spd N NN NN 0 Fr Ley °C —N__ , QL N Lo A A 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(6-(6-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1- | yl)-2-oxoethyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-7-fluoro-2H-indazol -2-y1)-N- | Loh rvrmrad PY xs rs rvinbirs werd me: thiazol -2-yl acetamide ND N—\ SN” NH J Ye (tmazol-2-yl)acetamide o NZ ] F nN? hg Ns NF © _F NT ™ oO er HN ANT oA | 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-(6-(6-(6-(2-(1-(4-((2,6-dioxopiperidin-3- | yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2- yl)pyridin-3-yl)-7-fluoro-2H-indazol-2-y1)-N-(thiazol -2-yl)acetamide ND N— / \ SN” NH J Yo F o NZ ] N? Sy Ns NY F N— =) 0 F © 1 lo eY i AN oY oA 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(6-(6-(2-(1-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6- diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-4-fluoro-2H-indazol-2-y1)-N-(thiazol-2- yl)acetamide NS F Hel a ST NF NN F To A . e a AS Lo ~~ py F a Q x 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-yl)-2-(6-(4-(6-(2-((R)-4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1- yDacetyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-2H-indazol -2-y1)-N-(thiazol-2- NT N—\ SN N= JN F yl)acetamide o N NY F <7 0 F © 1" 2 a HN T° oA 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(4-(6-(2-(1-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6- diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-2H-indazol-2-y1)-N-(thiazol-2-yl)acetamide ND N— / \ SN” NH J Yo oO Conv y > CE a ~ 0 eY i AN oY oA 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(4-(6-(2-(1-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6- diazaspiro[3.3]heptan-2-yl)phenyl)-7-fluoro-2H-indazol-2-y1)-N-(thiazol-2-yl)acetamide ND N— / \ fz! JPICTIYT = / =] 0 ~ of Uk Cl H JN Cn ~ \ ~ ¥ F 2 N— Y all H HN 7 A 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-(6-(4-(7-(2-(1-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,7- diazaspiro[3.5]nonan-2-yl)phenyl)-4-fluoro-2H-indazol-2-yl)-N-(thiazol -2-yl)acetamide AN > N—\ NH J J F [eo] x a” “0 & YY aA ANT oA 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(4-((1R,4R)-5-(2-(4-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2- yl)acetamide Ny HN 0 Na N—\ Tir ~~ Y NH a VM | = Cord] F J ' Sen s J | 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-yl)-2-(6-(4-((1-(2-(4'-((2,6-dioxopiperidin-3- | yl)amino)-[1,1'-biphenyl]-4-yl)acetyl)piperidin-4-yl)oxy)phenyl)-4-fluoro-1-oxoisoindolin- | PY EX NY Fa ad TY AN pra 2-y1)-N-(thiazol-2-yl)acetamide TM PLN “Nl gD . NN F — 0 J $ 0 ¢ 9) A 4 be & "x 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-yl)-2-(6-(4-((1R,4R)-5-(2-(4-(3-(2,4- | dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)acetyl)-2,5- | diazabicyclo[2.2.1]heptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2- } yl)acetamide Na N—\ SN” NH J Sy. No SN > TARY QO F Ne I F J 2° pel AN 7 oA | 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-(6-(4-(4-(2-(1-(4-((2,6-dioxopiperidin-3- | yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)piperazin-1-yl)phenyl)-4- fluoro-1-oxoisoindolin-2-y1)-N-(thiazol-2-yl)acetamide IN 0, / Nn \ NT N—\ N— / NH a Me —N : AN Cl o N’ - Cord 7 N— =a [o} J wl Niwa 0) 0 28 = NH Sd = 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(4-(4-(2-(4-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)-1,4-diazepan-1- yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide ANP A NG > =( pA ~~ N NJ! £3 0 - Seal al "Xx 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-yl)-2-(6-(4-(1-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2- oxoethyl)piperidin-4-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide yr, NS NY N—\ ~~ NH J V— F g N— ! F J oY pe AN 7 oA 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(4-(4-(2-(4-(4-((2,6-dioxopiperidin-3- yl)amino)-2-fluorophenyl)piperidin-1-yl)-2-oxoethyl)piperidin-1-yl)phenyl)-4-fluoro-1- oxoisoindolin-2-y1)-N-(thiazol-2-yl)acetamide ANS F Wl ST A J E ANN F “To I N oo N a ANS Ce X y! Q 7 F o \ Hn 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-y1)-2-(6-(6-(6-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1- yl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-y1)-4-fluoro-1-oxoisoindolin-2-y1)-N- (thiazol-2-yl)acetamide o un HNN os I N 1 1 \ 0 ANN AANA a) F H pa NN F 0 MN N A | H 0 Q x 4 ZZ —N < oN F 5-((2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-ox0-2-(thiazol-2-ylamino)ethyl)- 7-fluoro-3-oxoisoindolin-5-yl)ethynyl)-N-(1-(2-(4-(3-(2,4-dioxotetrahydropyrimidin- 1(2H)-yl)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1-yl)acetyl)piperidin-4- NT N—\ SN N= J oo F yl)picolinamide o A 7 Na” g 9 nN N > F C+ 0 F 8 no aA HN T or 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(6-(2-(1-(4-((2,6-dioxopiperidin-3- yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2- yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide ND N— / \ SN” NH J Ho 0 F )-4-tluoro-1-oxoisoindolin-z-yl)-IN-(th1azol-2- o N N Of Na” = N > NF g ps lL r 0 Fo © ul: | 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(4-(6-(2-(1-(5-((2,6-dioxopiperidin-3- | yl)amino)-3-fluoropyridin-2-yl)-4-hydroxypiperidin-4-yl)acetyl)-2,6- diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2- yl)acetamide oO EN o ~~ or )0N U0 PLN N_ H | © YY} “AF 1.2.2 HIV dll=2=y 1 JPLCIY 1 }=a=-1LIUOTL= 1 -UR UI yDacetamide F \ = = J 73 o J \ 7 \ 7 "\ NN TN Na YN hE | 1 0 OC N_ i 2-(6,7-dihydro-5H-pyrrolo[ 1,2-cl]imidazol-1-y1)-2-(6-(4-(4-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1- yDacetyl)-1,4-diazepan-1-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2- yl)acetamide 0 JE PLN pw SN Ne ra J 0) < _N BE NN F TA 2+(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(4-(4-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperazin-1- yl)acetyl)piperazin-1-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol-2-yl acetamide PAN F Nl NJ NAF NN F A 5 8 0) OJ AS Li A AN F 0 Ey N 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-yl)-2-(6-(4-(6-(2-((R)-4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1- yl)acetyl)-2,6-diazaspiro[3.3Jheptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N- (thiazol “2-1 )acetamide PAN RY GIN ; F NN F 1 00 g oH @! Le 3 <r Q "x 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-(6-(4-(6-(2-((S)-4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3,3-difluoropiperidin-1- yl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N- (thiazol-2-yl)acetamide NT N—\ J 0 YX F As ~ “ed % F N— JY iAH HN T° ~ 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-(6-(6-(6-(2-(4-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)-2,6- diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2- yl)acetamide H Ad LEN N SAN A I / A Nx 0 N? SN > F J ” F J H | NX on TN HANH J JPN 5-((2-(1-(6,7-dihydro-5H-pyrrolo[ 1,2-cJimidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)- 7-fluoro-3-oxoisoindolin-5-yl)ethynyl)-N-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2- fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)piperidin-4-yl)picolinamide NO N—\ SN” N= J F |)-4-hydroxypiperidin-4-yljacetyl)piperidin-4- o N 7 Sa” J) 2 N N > OC 0 F 8 11 ho TY a ANY hr 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(4-(6-(2-(1-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6- diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2- ND N— / \ SN” NH J Ye F yl)acetamide o N N “ g 0 N? N > : IO 0 F © mn 2X HP AN oA 2+(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-(6-(4-(6-(2-(1-(4-(((R)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6- diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2- yl)acetamide oO NT N— / \ NH J LT “o hd i od? Oo 2 A Ay =N Ww ANY A wf. OC | 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(6-(2-(1-(4-((2,6-dioxopiperidin-3- | yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2- yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(pyridin-2-yl)acetamide PLN ND N— / \ ~~ LAA = Je F J-3-TIUOTO- 1 -0X01S0INAO0I IN -2-Y1 )-IN-{ pyridin-z 0. N. on, ~ C 0 \ gee 0 F © 9 2” a ANY ur 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(4-(6-(2-(4-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)-2-oxoethyl)-2- azaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol-2-yl)acetamide ND N—\ SN” NH J Ye F A SET oY er HN ANT oA | 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-(6-(4-(6-(2-(1-(4-((2,6-dioxopiperidin-3- | yl)amino)-2,6-difluorophenyl)piperidin-4-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2- yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide NS py FS SAF N N 5 oO O oA Lo NAF SH 0 QA, “Ty 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-yl)-2-(6-(4-(6-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3,3-difluoropiperidin-1- yl)-2-oxoethyl)-2-azaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N- (thiazol-2-yl)acetamide NO N— / \ SN” N= Je F “oo “ Ped 9 F. F — Al rd 2% a HN TT oA 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(4-(6-(2-(1-(4-((2,6-dioxopiperidin-3- yl)amino)-2,6-difluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3]heptan- 2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide oO NT N— / \ N= JI oO N Ger Sed? J , 0 F ¢ J NH HN T° A 2-(6-(4-(6-(2-(1-(2-(difluoromethyl)-4-((2,6-dioxopiperidin-3-yl)amino)phenyl)-4- hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1- oxoisoindolin-2-y1)-2-(6,7-dihydro-SH-pyrrolo[ 1,2-c]imidazol-1-yl)-N-(thiazol-2- yl acetamide o ~~ NG H I 1 IF “AF ; . 7S o IN a1 0 ~~ 0 ~ NZ H J ~~ NL A 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-y1)-2-(6-(1-(1-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1- yl)acetyl)piperidin-4-yl)-1H-pyrazol -4-y1)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2- yl)acetamide rr \ A IN Oo AON ATA F “AF “nt No £ Q g Li _N E SN 1 NN F "A 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-yl)-2-(6-(4-(2-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3,3-difluoropiperidin-1- yl)acetyl)-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N- (thiazol-2-yl)acetamide 0 NT N— / \ H JN | | oN 2 oN’ Qo F J HN T° A 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-(6-(4-(2-(2-(1-(4-((2,6-dioxopiperidin-3- yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,7-diazaspiro[3.5]nonan-7- yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol-2-yl)acetamide H SN NN el, Yup Ld EN % SAN z ; / H Nx 0 N? S F J ¥ 2 F J H ( ~~ JNH oA | N-(1-(2-(1-(4-(((R)-2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4- yl)acetyl)piperidin-4-y1)-5-((7-fluoro-2-(1-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[ 1,2- c]imidazol-1-y1)-2-0x0-2-(thiazol-2-ylamino)ethyl)-3-oxoisoindolin-5- yl)ethynyl)picolinamide a PAA ANd POS ~ NN F yl)ethynyl)picolinamide oO N 0 0 b, ao" —N CO N Z F — 7 oO > N x 2+(6,7-dihydro-5H-pyrrolo[1,2-cJimidazol-1-yl)-2-(6-(4-(6-(2-(1-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-4-hydroxypiperidin-4- yl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N- NO N— / \ SN N= JN F thiazol-2-yl)acetamide o N N o 7 SN i. > F N— 0 F 9 11 Ee. i an HN T° oA 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(6-(6-(2-(1-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6- diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2- yl)acetamide ND N— / \ SN” NH J Ho F aq NA o N’ NN | ’ N N ) F N— 0 F © OT oY HN AN oA 2-(6,7-dihydro-5H-pyrrolo[ 1,2-cl]imidazol-1-y1)-2-(6-(6-(6-(2-(1-(4-(((R)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6- diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2- yl)acetamide NO N—\ J 0 F 1 A Ya, 0 g of rd or Yr | 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(4-(6-(2-(4-(5-((2,6-dioxopiperidin-3- | yl)amino)-3-fluoropyridin-2-yl)piperidin-1-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2- yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol-2-yl)acetamide o un HNN os F H Cr K gi ( AA Ar CEH oO M4 ~PN AN 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(6-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3,3-difluoropiperidin-1- | yl)acetyl)-2,6-diazaspiro[3.4]octan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol- | 1am pa emt Ae 2-y] 1)acetamide oO ~~ AN F AF “Nl N= LN 1 NN F / 00 0) N Lio % EF o \ 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-y1)-2-(6-(4-(7-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1- yl)acetyl)-2,7-diazaspiro[3.5]nonan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N- (thiazol-2-yl)acetamide Oo red — or Ano SEWN H l N° ~N 0 SAA OH | 2X ~ NO N—\ JY ogg v b ' d =n SA | 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(7-(2-(1-(4-((2,6-dioxopiperidin-3- | yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,7-diazaspiro[3.5]nonan-2- yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol-2-yl)acetamide F 4 { d J=N 8S | 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(6-(2-(1-(4-((2,6-dioxopiperidin-3- | yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.4]octan-2- yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol-2-yl)acetamide PLN F Wl ST F iy! NN Li a ; i» os 0 , y 2-(6-(4-(6-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)- 3,3-difluoropiperidin-1-yl)acetyl)-2,6-diazaspiro[ 3.3 ]heptan-2-yl)phenyl)-4-fluoro-1- oxoisoindolin-2-yl)-2-((R)-6-fluoro-6,7-dihydro-SH-pyrrolo[ 1,2-c]imidazol-1-yl)-N- ND N—\ SN” NH J Ye 0 YY F (thiazol-2-yl)acetamide o N 7 Na” @ ? N N > . O- 0 F © 11 RI an ANT A 2-(6-(4-(6-(2-(1-(2-chloro-4-((2,6-dioxopiperidin-3-yl)amino)phenyl)-4-hydroxypiperidin- 4-yl)acetyl)-2,6-diazaspiro[3.3 ]heptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7- dihydro-SH-pyrrolo[1,2-c]limidazol-1-yl)-N-(thiazol-2-yl)acetamide N NJ yITOIO| 1,4-C 1m1dazol-1-yl)-IN-1Nn1azol-2-y1 dC aed NN NN P | SNCF « S v —N, N z F N— Qo \_ xX 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-(6-(6-(6-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3,3-difluoropiperidin-1- yl)-2-oxoethyl)-2,6-diazaspiro[3.3 Jheptan-2-yl)pyridin-3-yl)-4-fluoro-1-oxoisoindolin-2- yl)-N-(thiazol-2-yl)acetamide ND N— / \ SN” NH J Ho F 0 N 7 o N” SN J = FF Cw 0 F © vo Yr i AN oY oA 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(4-(6-(2-(1-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6- diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2- NO N—\ SN” N= J 0 F yl)acetamide o N 7 COOL ge ¥ N > ” OX 0 F 8 11 | aH oP 2-(6-(4-(6-(2-(1-(2-chloro-4-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)-4- hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1- oxoisoindolin-2-yl1)-2-(6,7-dihydro-SH-pyrrolo[ 1,2-c]imidazol-1-yl)-N-(thiazol-2- yl )acetamide NT N— / \ 5 0 “A ~~. SN N= TN Cd ¥ 7 ) rT ANT A 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-(6-(4-(7-(2-(1-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,7- diazaspiro[3.5]nonan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol -2- yl)acetamide oO ~~ AN F NY “Nl N= LN 1 NN F 00 0) N : Lio % EF o \ 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-y1)-2-(6-(4-(7-(2-((R)-4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1- yl)acetyl)-2,7-diazaspiro[3.5]nonan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N- (thiazol-2-yl)acetamide NG RY WN Ne HN— A SN gL L NN F Xx HA 4 SN —N F. YQ A A o = Yo N HN \ ( 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-yl)-2-(6-(4-(6-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1- yl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N- (thiazol-2-yl)acetamide ANS Nt NN F — 0 A 00 0) “al ® Lio ¥ ’ <r Q i 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-(6-(4-(6-(2-((3R,4S)-4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-y1)-1-methyl-1H-indazol-6-yl)-3-fluoropiperidin-1- yl)acetyl)-2,6-diazaspiro[3.3 Jheptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N- (thiazol-2-yl)acetamide NS “wl FS ~F NN F 0 A oo 2) J AS Lo 4 oN F 0 = A 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(4-(6-(2-((3S,4R)-4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3-fluoropiperidin-1- yl)acetyl)-2,6-diazaspiro[3.3 Jheptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N- (thiazol-2-yl)acetamide 0 NT N— / \ H JN | | SN 2 0 N Qo F J HN A 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(4-(2-(2-(1-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,7- diazaspiro[3.5]nonan-7-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2- yl)acetamide AYA PUY) HN—4 POS SN SN 1 ANN F yl)acetamide o oe N 0 0 + J SN —N ® Q N Z F — 2 a | N Ug NT N— Q and 3 2 N HN \ \ 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-yl)-2-(6-(4-(6-(2-(1-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-y1)-4- hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1- oxoisoindolin-2-y1)-N-(thiazol-2-yl)acetamide 0 NY N— / \ Sn” H TN SN Df Qo N— F J HN 7 A 2-(6-(4-(2-(2-(1-(2-chloro-4-(((S)-2,6-dioxopiperidin-3-yl)Jamino)phenyl)-4- hydroxypiperidin-4-yl)acetyl)-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)-4-fluoro-1- oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-yl)-N-(thiazol-2- yl)acetamide ANG F gL L ANN F I 00 0) 7 “ Tg FA Se N HN N J 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(4-(6-(2-((S)-4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-y1)-3,3- difluoropiperidin-1-yl)acetyl)-2,6-diazaspiro[3.3 ]heptan-2-yl)phenyl)-4-fluoro-1- oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide ANS F Wel SST NAF SN 1 ANN F 2 #5 2) TH 7 AN Lir™ & AN F o | Ug Fo AL 0 NT =N ON 2-(6,7-dihydro-5H-pyrrolo[ 1,2-cJlimidazol-1-y1)-2-(6-(4-(6-(2-((R)-4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-y1)-3,3- difluoropiperidin-1-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1- oxoisoindolin-2-y1)-N-(thiazol-2-yl)acetamide Te J 0 XX F oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetam o N 7 - QO) o N” N ¢ + 0 F ° no An ANY nL — 2-(6-(4-(6-(2-(1-(4~(((S)-2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4- hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1- oxoisoindolin-2-yl)-2-((R)-6-fluoro-6,7-dihydro-SH-pyrrolo[ 1,2-c]imidazol-1-yl)-N- (thiazol-2-yl)acetamide NOON a NH J Ye F (tmazol-2-yl )acetamide o N N “ J o NZ N > - O- 0 F ° nooo TY HP ANY A 2-(6-(4-(6-(2-(1-(4-(((R)-2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4- hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1- oxoisoindolin-2-y1)-2-((R)-6-fluoro-6,7-dihydro-SH-pyrrolo[ 1,2-c]imidazol-1-yl)-N- (thiazol-2-yl)acetamide ANS “wl YS ~NAE NN F ws TA £ Q 3 ~~ IL Q A 2-(6,7-dihydro-5H-pyrrolo[1,2-c]limidazol-1-y1)-2-(6-(4-(6-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-y1)-1-methyl-1H-indazol-6-yl)-3-fluoropiperidin-1- yl)acetyl)-2,6-diazaspiro[3.3 Jheptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N- (thiazol-2-yl)acetamide 0 NY N— / \ Sn” H TN | | oN OLS I F J HN 7 A 2+(6,7-dihydro-SH-pyrrolo[1,2-cJimidazol-1-y1)-2-(6-(4-(2-(2-(1-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,7- diazaspiro[3.5]nonan-7-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2- NT N—\ SNS H J F yl)acetamide Q N / o N SN J ) haces F F o oA N No 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(6-(2-(1-(4-((2,6-dioxopiperidin-3- yl)amino)-2,5-difluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3]heptan- 2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol-2-yl)acetamide NZ N— / \ SN” N= JL Cl - oo SNS ed \ F — 0 J cl J 2 an HN T° oA 2-(4-chloro-6-(4-(6-(2-(1-(4-(((S)-2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4- hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-1-oxoisoindolin-2- y1)-2-(6,7-dihydro-5SH-pyrrolo[ 1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide NZ N— / \ o af) rl ~~ JN NY Sa gf o N? ; df J J “ 4 F © ANY A 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-y1)-2-(6-(4-(7-(2-(1-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,7- diazaspiro[3.5]nonan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2- yl)acetamide NT N— / \ 5 = 0 “A ~ Sn” H JN CN > ~~ 2) 0 N? eed J F J HN T° A 2-(6-(4-(7-(2-(1-(2-chloro-4-(((S)-2,6-dioxopiperidin-3-yl)amino)phenyl)-4- hydroxypiperidin-4-yl)acetyl)-2,7-diazaspiro[3.5]nonan-2-yl)phenyl)-4-fluoro-1- oxoisoindolin-2-yl1)-2-(6,7-dihydro-SH-pyrrolo[ 1,2-c]imidazol-1-yl)-N-(thiazol-2- ND N—\ SN” NH J Yo 0 YY F yl)acetamide o N “ @ 0 N? N > oy IO | r 0 F o mn ASH ANY oA 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-(6-(4-(6-(2-(1-(5-(((S)-2,6- dioxopiperidin-3-yl)amino)-3-fluoropyridin-2-yl)-4-hydroxypiperidin-4-yl)acetyl)-2,6- diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2- yl)acetamide ON 0 oT F “AF “Nt ON L NN F £3 J . : oV N F oO "y 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-yl)-2-(6-(4-(7-(2-((R)-4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1- yl)-2-oxoethyl)-2,7-diazaspiro[3.5]nonan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N- (thiazol-2-yl )acetamide ON ANY SN L NN F NT £3 J oH : eV N F o "x 2+(6,7-dihydro-5H-pyrrolo[1,2-cJimidazol-1-y1)-2-(6-(4-(7-(2-((S)-4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1- yl)-2-oxoethyl)-2,7-diazaspiro[3.5]nonan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N- thiazol-2-yl)acetamide NT N—\ = Wee tes NH J Ye ee —— Cee ere eerie — N. . § oO N NN = ) — c J F Neo NH J 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-(6-(1-(1-(2-(1-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)piperidin-4- y)-1H-pyrazol-4-yl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol-2-yl)acetamide ~ bo UNG F “AF “Nt CoT 25 2) Nr Sova JN F ON L NN F "y 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-yl)-2-(6-(4-(2-(2-((R)-4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1- yl)-2-oxoethyl)-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N- (thiazol-2-yl )acetamide _O ~T | i) Wl SST TA CoT £3 0) Nort LY JN F SN L NN F "x 2+(6,7-dihydro-5H-pyrrolo[1,2-cJimidazol-1-y1)-2-(6-(4-(2-(2-((S)-4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1- yl)-2-oxoethyl)-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N- NO N— / \ SN N= J F thiazol-2-yl)acetamide o N 7 COOL N > F. Cl 2) aye 0 F o 11 ae oY a HN T° oA 2-(6-(4-(6-(2-(1-(2-chloro-4-(((S)-2,6-dioxopiperidin-3-yl)amino)-6-fluorophenyl)-4- hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1- oxoisoindolin-2-yl1)-2-(6,7-dihydro-SH-pyrrolo[ 1,2-c]imidazol-1-yl)-N-(thiazol-2- yl)acetamide oO H 1 NY N— / \ H i: N° No LAK JY wo Org § ¢ o N? Ped F J FO =n SA | 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-yl)-2-(6-(4-(6-(1-(4-(((S)-2,6-dioxopiperidin- 3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidine-4-carbonyl)-2,6-diazaspiro[3.3 Jheptan- 2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide - M0 XN Q, N N £ \ E F Q, R HO, NH Fone HCH (AIG ° F H 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[2-[2-[ 1-[4-(2,4- dioxohexahydropyrimidin-1-yl)-2-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetyl]-2,6- diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-indazol-2-y1]-N-thiazol-2-yl-acetamide Oo HN— “or o =X >> MN YX nNn—< 7 F " Ho o={ 142, 2S OO, 7 H 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-yl)-2-[6-[4-[2-[2-[(2s,6r)-1-[4-[(2,6-diox0-3- piperidyl)amino]-2-fluoro-phenyl]-4-hydroxy-2,6-dimethyl-4-piperidyl]acetyl]-2,6- diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-indazol-2-y1]-N-thiazol-2-yl-acetamide Oo HN— o= hh Jd x JF SN Hn F N 5 F (AJAY . H H —N —) SN MN nN 2+(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-[6-[4-[4-[2-[4-[4-[[(3S)-2,6-diox0-3- piperidyl]Jamino]-2-fluoro-phenyl]-1-piperidyl]-2-oxo-ethyl]-4-hydroxy-1- piperidyl]phenyl]-7-fluoro-indazol-2-yl]-N-thiazol -2-yl-acetamide Pt =o ~N HH 3 1 \ CLL fd A A A HEALY 1 J HM rd LAY 2 J e™ dyl]phenyl]-7-fluoro-indazol-2-y1]-N-thi R = ~=N , s o = N N N °N H NL _ H { —A yn SN A iy F, J D 0 ( / mL = =aNH o= 2-(6,7-dihydro-5H-pyrrolo[1,2-cJimidazol-1-y1)-2-[6-[6-[4-[2-[4-[4-[[(3S)-2,6-diox0-3- piperidyl]amino]-2-fluoro-phenyl]-1-piperidyl]-2-oxo-ethyl]-4-hydroxy-1-piperidyl]-3- pyridyl]-4-fluoro-indazol-2-yl]-N-thiazol-2-yl-acetamide oO HN o= =N TN Ay I xi CN nn F F BTN N y F OH Ho NA 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-yl)-2-[6-[6-[4-[2-[4-[4-[[(3S)-2,6-diox0-3- piperidyl]amino]-2-fluoro-phenyl]-1-piperidyl]-2-oxo-ethyl ]-4-hydroxy-1-piperidyl]-3- pyridyl]-7-fluoro-indazol-2-yl]-N-thiazol-2-yl-acetamide No CN ridyl]Jamino]-2-fluoro-phenyl]-1-piperidyl]-2-oxo-ethyl]-4-hydroxy-1-pi pyridyl]-7-fluoro-indazol-2-y1]-N-thiazol-2-yl-acetamide R 5 Noo AK) MK \ CO GLIA Dw H 0 0 ha % N__ 1 40 oo Sy he N_~ 0 2-(6,7-dihydro-SH-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[ 1-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]phenyl]-1-piperidyl]acetyl]-4-piperidyl]-2-methyl-phenyl]-4-fluoro-1- oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide \ ~~N Ney 1] : - 3A SHOOT CL 1 N 7 = N SY I I a Ye NONSTN oo / a >< ok & —n son 2+(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-[6-[4-[2-[2-[ 7-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-4-azaspiro[2.5]octan-4-ylJacetyl]- 2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-N-(2- pyridyl)acetamide sy lov rv. a | il H oO Oo HN 0 o os" ~ / SCD-O OOO N° # I 2-(6,7-dihydro-SH-pyrrolo[ 1,2-climidazol-1-yl)-2-[6-[4-[2-[2-[ 7-[3-(2,4- .ohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-4-azaspiro[2.5]octan-4-yl]ace WL ESE TE ORT IE EE acetamide R 7 N— / LI H i 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-[6-[4-[6-[4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-3,3-difluoro-piperidine-1- carbonyl]-2-azaspiro[3.3]heptan-2-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazol-2- yl-acetamide =0 J M0 HA ! F A £ NH J HC FR \ - = rs 9 (3I0m00, 2 N NY H 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-yl)-2-[6-[4-[2-[2-[1-[4-(2,4- dioxohexahydropyrimidin-1-yl)-2-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetyl]-2,6- diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl- acetamide =0 Ho / Q — \ 1 Va - F hE | 1 0 NS Ln =o HO java — a NE MO 0 0 NAOH TH No 0 oO | 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-yl)-2-(6-(4-(6-(2-(1-(4-(2,6-dioxopiperidin-3- yl)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2- yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol-2-yl)acetamide Cl 3 HO Nt ~ “OH ANY 73 5 $2400 JH PN AN 0° dg NTN H | ©o H 2-[6-[4-[2-[2-[1-[2-chloro-4-(2,4-dioxohexahydropyrimidin-1-yl)phenyl]-4-hydroxy-4- | piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-2- (6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-yl)-N-thiazol-2-yl-acetamide N\ AA —~X NK p— Jo og 0 N N Co it 2 TN AN ZF Kv eridyl]acetyl]-2,6-diazaspiro[3.3]heptan: (6,7-dihydro-SH-pyrrolo[1,2-cJim R rs 3 “AN J \ 7 \ AA —A © NZ H 0) on \ \ oN N N SS NY i ATA TT 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-yl)-2-[6-[4-[2-[2-[1-[4-(2,6-diox0-3- piperidyl)-2-fluoro-phenyl]-4-hydroxy-4-piperidylJacetyl]-2,7-diazaspiro[3.5Jnonan-7- yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide R HO —, = OO wl pe of Sma ae A A H | © H 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[ 7-[2-[1-[4-(2,6-diox0-3- piperidyl)-2-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetyl]-2,7-diazaspiro[3.5]nonan-2- yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl1]-N-thiazol-2-yl-acetamide Oo HN—4 o= Va F oa o R CPV OC g OLA STON 9 0 —A H 1 —n oN 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-yl)-2-[6-[4-[2-[2-[(2s,6r)-1-[4-[(2,6-diox0-3- piperidyl)amino]-2-fluoro-phenyl]-4-hydroxy-2,6-dimethyl-4-piperidyl]acetyl]-2,6- diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-N-thiazol -2-y1- acetamide oO nA HN, Rh F F 0 HN. 0 o ~ OC \,. N N N QO NN a, HN F -[6-[4-[2-[2-[4-amino-1-[4-[(2,6-dioxo-3-piperidyl)amino]- ivllacetvl1-2.6-diazaspirol 3.3 Thentan-6-vilphenvl1-4-fluoro-1 2-[6-[4-[2-[2-[4-amino-1-[4-[(2,6-diox0-3-piperidyl)amino]-2-fluoro-phenyl]-4- | piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-2- (6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-yl)-N-thiazol-2-yl-acetamide , aA —~X NK / )N Jo or o ~~ > »>N XN 7 / NH E J Xv eridyl]acetyl]-2,6-diazaspiro[3.3]heptan. (6,7-dihydro-5H-pyrrolo[1,2-c]im F rs 9 =H J \ 7 \ A LA © “N-7 H 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[2-[2-[ 1-[4-(2,4- dioxohexahydropyrimidin-1-yl)-2-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetyl]-2,7- diazaspiro[3.5]nonan-7-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazol -2-yl- acetamide TT CN N = J FE O= + . OH F th HN = b MY 7 \ / "VV oH FF o= WT YS A acetamide E oy 5 $000 LAA > H AS ny gy A 0 NN Ly |somer A1 2-(6,7-dihydro-SH-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[2-[2-[1-[4-[[2,6-diox0-3- piperidyl]amino]-2-fluoro-phenyl]-4-hydroxy-azepan-4-yl]acetyl]-2,6- diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl- acetamide, isomer Al / \ CN N= J EF O= . OH F sh HN = © _acetamide, isomer Al_ : J N Oo \ / N N— QIK 0 (OO, H IN DX NINA Fo Py o |somer A2 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(6-(2-(1-(4-((2,6-dioxopiperidin-3- | yl)amino)-2-fluorophenyl)-4-hydroxyazepan-4-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2- yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol-2-yl)acetamide, isomer A2 7 CN acetamide, isome = = E O= . OH EF sh HN = yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yI)-N-(thiazol R No NO SLI b H AC IN) NITNANTTRy HF 0 ry o |lsomer B1 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(4-(6-(2-(1-(4-((2,6-dioxopiperidin-3- | yl)amino)-2-fluorophenyl)-4-hydroxyazepan-4-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2- yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol-2-yl)acetamide, isomer B1 7 CN Jacetamide, isome \ = EF o0= . OH F Sk HN— 0 L N\_7 \_ / "AUN OH FF o= yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazo E a3 A000 BN NL o STON H AO WW go i 0 NS Yo |lsomer B2 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(6-(2-(1-(4-((2,6-dioxopiperidin-3- | yl)amino)-2-fluorophenyl)-4-hydroxyazepan-4-yl)acetyl)-2,6-diazaspiro[3.3Jheptan-2- yDphenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide, isomer B2 R Cl, C2 SC ~ ny LA NOON ¥ =o H o NH Ao cl o RLY TT eT ge ~P\ 0 d NL 2-(6,7-dihydro-SH-pyrrolo[1,2-climidazol-1-yl)-2-[6-[4-[2-[2-[1-[4-(2,4- dioxohexahydropyrimidin-1-yl)-2-(trifluoromethyl)phenyl]-4-hydroxy-4-piperidyl]acetyl]- 2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl- acetamide R Hi AAI T00 0 Ao ° 2 VN H Nv oN TT = \ / T HY ° ol NH H I —~ NN 2-[6-[4-[2-[2-[1-[2,6-dichloro-4-(2,4-dioxohexahydropyrimidin-1-yl)phenyl]-4-hydroxy-4- piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-2- (6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-yl)-N-thiazol-2-yl-acetamide 7 \ \ Rs =0 h ML / Cl 1zol-2-yl-acetamide ar ! r= or NH Cl 0 (6, / -dihydro->H-pyrrolof 1,2-c imidazol-1 R i) ==" N 038 OX) NZ SN H 0 —N \ =0 °C / iazol-2-yl-acetamide — Pp N N= pad I. / 0 4 2-[6-[4-[7-[2-[1-[2-chloro-4-(2,4-dioxohexahydropyrimidin-1-yl)phenyl]-4-hydroxy-4- | piperidyl]acetyl]-2,7-diazaspiro[3.5]nonan-2-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-2- | (6,7-dihydro-5H-pyrrolo[ 1,2-cJimidazol-1-yl)-N-thiazol-2-yl-acetamide R HO \ / — N N =o OO CI rs 0 \ / % # d PAN N H | o no! H Pn Mn 7 rs =0 / x: oh NH J co’ H 2-[6-[4-[2-[2-[1-[2-cyano-4-(2,4-dioxohexahydropyrimidin-1-yl)phenyl]-4-hydroxy-4- | piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-2- | (6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide E HO Nga rs 0 §) $) N XO / JH A AN 0 Cl 0 N N H , 0 2-[6-[4-[2-[2-[1-[2-chloro-4-(2,4-dioxohexahydropyrimidin-1-yl)phenyl]-4-hydroxy-4- | piperidyl]acetyl]-2,7-diazaspiro[3.5]nonan-7-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-2- | (6,7-dihydro-5SH-pyrrolo[ 1,2-climidazol-1-yl)-N-thiazol-2-yl-acetamide 0 H ad \ ff \X 7 va HC R —_ O NOCH {AIA N™°N H 5 H N |lsomer 1 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-[6-[4-[2-[2-[ 1-[4-[[2,6-diox0-3- piperidyl]amino]-2-fluoro-5-methoxy-phenyl]-4-hydroxy-4-piperidyl]acetyl]-2,6- diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-N-thiazol -2-yl- acetamide, isomer 1 or a pharmaceutically acceptable salt thereof. E99: In certain embodiments the invention is a compound of any one of embodiments 1-98, 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 one of embodiments 1-98, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, for the 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 one of embodiments 1-98, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition. E102: The method of embodiment 101 wherein the patient is a human. E103: The method of embodiment 101 or 102, wherein the EGFR mediated disorder is a cancer, tumor, or abnormal cellular proliferation. E104: The method of embodiment 103, wherein the EGFR mediated disorder is a cancer or a tumor. E105: The method of embodiment 103, wherein the EGFR mediated disorder is an abnormal cellular proliferation. E106: The method of embodiment 104, wherein the cancer is lung cancer. E107: The method of embodiment 106, wherein the lung cancer is non-small cell lung cancer. The method of any one of embodiments 103-107, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with at least one mutation. The method of any one of embodiments 103-108, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the L858R mutation. The method of any one of embodiments 103-109, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the T790M mutation. The method of any one of embodiments 103-110, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the C7978 mutation. The method of any one of embodiments 103-111, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the L792H mutation. The method of any one of embodiments 103-112, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the L718Q mutation. The method of any one of embodiments 103-108, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the T790M / L858R mutation. The method of any one of embodiments 103-108, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the T790M / L858R / C797S mutation. The method of any one of embodiments 103-108, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the L858R / C797S mutation. The method of any one of embodiments 101-116, wherein an additional EGFR inhibitor is administered. The method of embodiment 117, wherein the additional EGFR inhibitor is a tyrosine kinase inhibitor. The method of embodiment 118, wherein the additional EGFR inhibitor is osimertinib. The method of embodiment 118, wherein the additional EGFR inhibitor is rociletinib. The method of embodiment 118, wherein the additional EGFR inhibitor is avitinib. The method of embodiment 118, wherein the additional EGFR inhibitor is lazertinib. The method of embodiment 118, wherein the additional EGFR inhibitor is nazartinib. The method of embodiment 117, wherein the additional EGFR inhibitor is an antibody to a mutated form of EGFR. The method of embodiment 124, wherein the additional EGFR inhibitor is cetuximab. The method of embodiment 124, wherein the additional EGFR inhibitor is panitumab. The method of embodiment 124, wherein the additional EGFR inhibitor is necitumab The method of any one of embodiments 101-127, wherein a MET inhibitor is also administered. The method of any one of embodiments 101-128, wherein the patient receives an additional chemotherapeutic agent. In certain embodiments the invention is a compound of any one of embodiments 1-98, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament to treat an EGFR mediated disorder in a patient. The use of embodiment 130, wherein the patient is a human. The use of embodiment 130 or 131, wherein the EGFR mediated disorder is a cancer, tumor, or abnormal cellular proliferation. The use of embodiment 132, wherein the EGFR mediated disorder is a cancer or a tumor. The use of embodiment 132, wherein the EGFR mediated disorder is an abnormal cellular proliferation. The use of embodiment 132, wherein the cancer is lung cancer. The use of embodiment 135, wherein the lung cancer is non-small cell lung cancer. The use of any one of embodiments 132-136, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with at least one mutation. The use of any one of embodiments 132-137, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the L858R mutation. The use of any one of embodiments 132-138, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the T790M mutation. The use of any one of embodiments 132-139, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the C797S mutation. The use of any one of embodiments 132-140, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the L792H mutation. The use of any one of embodiments 132-141, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the L718Q mutation. The use of any one of embodiments 132-136, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the T790M / L858R mutation. The use of any one of embodiments 132-136, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the T790M / L858R / C797S mutation. The use of any one of embodiments 132-136, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the L858R / C797S mutation. The use of any one of embodiments 130-145, wherein an additional EGFR inhibitor is administered. The use of embodiment 146, wherein the additional EGFR inhibitor is a tyrosine kinase inhibitor. The use of embodiment 147, wherein the additional EGFR inhibitor is osimertinib. The use of embodiment 147, wherein the additional EGFR inhibitor is rociletinib. The use of embodiment 147, wherein the additional EGFR inhibitor is avitinib. The use of embodiment 147, wherein the additional EGFR inhibitor is lazertinib. The use of embodiment 147, wherein the additional EGFR inhibitor is nazartinib. The use of embodiment 146, wherein the additional EGFR inhibitor is an antibody to a mutated form of EGFR. The use of embodiment 153, wherein the additional EGFR inhibitor is cetuximab. The use of embodiment 153, wherein the additional EGFR inhibitor is panitumab. The use of embodiment 153, wherein the additional EGFR inhibitor is necitumab. The use of any one of embodiments 130-156, wherein a MET inhibitor is also administered. The use of any one of embodiments 130-157, wherein the patient receives an additional chemotherapeutic agent. In certain embodiments the invention is a compound of any one of embodiments 1-98, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, for the use in the treatment of an EGFR mediated disorder in a patient. The compound of embodiment 159, wherein the patient is a human. The compound of embodiment 159 or 160, wherein the EGFR mediated disorder is a cancer, tumor, or abnormal cellular proliferation. The compound of embodiment 161, wherein the EGFR mediated disorder is a cancer or a tumor. The compound of embodiment 161, wherein the EGFR mediated disorder is an abnormal cellular proliferation. The compound of embodiment 162, wherein the cancer is lung cancer. The compound of embodiment 164, wherein the lung cancer is non-small cell lung cancer. The compound of any one of embodiments 161-165, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with at least one mutation. The compound of any one of embodiments 161-166, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the L858R mutation. The compound of any one of embodiments 161-167, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the T790M mutation. The compound of any one of embodiments 161-168, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the C797S mutation. The compound of any one of embodiments 161-169, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the L792H mutation. The compound of any one of embodiments 161-170, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the L718Q mutation. The compound of any one of embodiments 161-166, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the T790M / L858R mutation. The compound of any one of embodiments 161-166, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the T790M / L858R / C797S mutation. The compound of any one of embodiments 161-166, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the L858R / C797S mutation. The compound of any one of embodiments 159-174, wherein an additional EGFR inhibitor is administered. The compound of embodiment 175, wherein the additional EGFR inhibitor is a tyrosine kinase inhibitor. The compound of embodiment 175, wherein the additional EGFR inhibitor is osimertinib. The compound of embodiment 175, wherein the additional EGFR inhibitor is rociletinib. The compound of embodiment 175, wherein the additional EGFR inhibitor is avitinib. The compound of embodiment 175, wherein the additional EGFR inhibitor is lazertinib. The compound of embodiment 175, wherein the additional EGFR inhibitor is nazartinib The compound of embodiment 174, wherein the additional EGFR inhibitor is an antibody to a mutated form of EGFR. The compound of embodiment 182, wherein the additional EGFR inhibitor is cetuximab. The compound of embodiment 182, wherein the additional EGFR inhibitor is panitumab. The compound of embodiment 182, wherein the additional EGFR inhibitor is necitumab. The compound of any one of embodiments 159-185, wherein a MET inhibitor is also administered. The compound of any one of embodiments 159-186, wherein the patient receives an additional chemotherapeutic agent. In certain embodiments the invention is a compound of any one of embodiments 1-98, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, for the use as a medicament in therapeutic and / or prophylactic treatment of a patient with EGFR activating mutations as determined with a cobas® EGFR Mutation Test v2, suffering from cancer, in particular non-small- cell lung cancer, comprising determining the EGFR activating mutations status in said patient and then administering the compound of any one of embodiments 1- 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 a compound of any one of embodiments 1-98 and a pharmaceutically acceptable excipient. Additional Embodiments of the Present Invention Chirality Embodiments The 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 moiety R¥* o= X ,\ o0= or (for example 0 or 0 ), one or more stereocenters in the linker, ; R35 oe A 0 ). and / or at least one stereocenter in the EGFR binding ligand moiety of the molecule (e.g. NNT <7 0 > one stereocenter in t N7N eS R38 8 <> 0 > ° or ). 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 (i.e., greater than about 50%, 60%, 70%, 80% or 90% pure) or even substantially pure form (greater than about 95%, 98% or 99% pure) of R and S stereochemistry. In certain aspects, the EGFR-degrading compound has two enantiomerically enriched and / or substantially pure stereocenters. In one sub-aspect of this, the two enantiomerically enriched and / or substantially pure stereocenters are located in the ligase-binding moiety of the compound and the linker; or alternatively there are two in the linker. In another sub-aspect, there are three enantiomerically enriched and / or substantially pure stereocenters, with one in the ligase-binding moiety of the compound and two in the linker. In yet another sub-aspect of this, there are three enantiomerically enriched and / or substantially pure stereocenters, with one in the ligase-binding moiety of the compound and two in the linker. In another aspect, in any of these embodiments, aspects or sub-aspects, in addition, the EGFR binding ligand moiety is enantiomerically enriched or in substantially pure form. It has been observed that in some embodiments, the chiral carbon in the EGFR binding ligand moiety adjacent to the amide may easily racemize between stereoisomers under the conditions of use, and therefore in certain embodiments, is not considered for purposes of stereochemistry designation. In certain embodiments one stereocenter is in the R configuration and any others present are either enantiomerically enriched or substantially pure. In certain embodiments one stereocenter is in the S configuration and any others present are either enantiomerically enriched or substantially pure. In certain embodiments one stereocenter is in the R configuration and any others present are without regard to stereochemistry, enantiomerically enriched or substantially pure. In certain embodiments one stereocenter is in the S configuration and any others present are without regard to stereochemistry, enantiomerically enriched or substantially pure. In certain embodiments there is one stereocenter in the E3 ligase binding moiety (disregarding the stereocenter in the EGFR binding ligand moiety) and it is enantiomerically enriched or substantially pure in the R-configuration, as indicated below. In another embodiment there is one stereocenter in the E3 ligase binding moiety (disregarding the stereocenter in the EGFR binding ligand moiety) and it enantiomerically enriched or substantially pure in the S-configuration, as indicated below. R* iL o= X.J\ ox Na Nm In certain embodiments ° is o wherein R* is hydrogen. R34 he o= X.\ ox In certain embodiments 0° is 0° wherein R** is hydrogen. R34 *\ R34 1 o= X ,\ o0= In certain embodiments 0 is R¥* RM NN o= X..,\ o= —\ R¥ Ye Wl we be) In certain embodiments 0 is R \ RM 1 o= X.\ o= In certain embodiments 0 is R¥* R¥ TN o= X ,\ o= —\ R¥® = ed 0 In certain embodiments 0 is In certain embodiments there is one stereocenter in the linker portion and it is a mixture of R- and S-configuration. In another embodiment there is one stereocenter in the linker portion and it is enantiomerically enriched or substantially pure R-configuration. In another embodiment there is one stereocenter in the linker portion and it is enantiomerically enriched or substantially pure S-configuration. In certain embodiments the linker contains one or more moieties with a chiral center. Non-limiting examples include heterocycle with an enantiomerically enriched or substantially pure stereocenter for example piperidine with a substituent meta- or ortho to the nitrogen or linking in the meta- or ortho- configuration; piperazine with a substituent or linking in the meta- or ortho- configuration; pyrrolidinone with or without a substituent; and pyrrolidine with or without a substituent. Additional non-limiting examples of linker moieties with at least one chiral center include an alkyl with an enantiomerically enriched or substantially pure stereocenter; an alkene with an enantiomerically enriched or substantially pure stereocenter; an alkyne with an enantiomerically enriched or substantially pure stereocenter; a haloalkyl with an enantiomerically enriched or substantially pure stereocenter, an alkoxy with an enantiomerically enriched or substantially pure stereocenter; an aliphatic group with an enantiomerically enriched or substantially pure stereocenter; a heteroaliphatic group with an enantiomerically enriched or substantially pure stereocenter; and a cycloalkyl with an enantiomerically enriched or substantially pure stereocenter R40 R40 uy / TN Ay x / OF yo 55 : i NN # N In certain embodiments the linker includes H \ 0 3 / | HX FZ NAy ow fF R40 ry 7 \ 9‘; v & —-N 7 y a Ce EN REN In certain embodiments the linker includes > % RAO R40 R40 J R40 EY TN 7 / tH R40 R40 1 an i MY / y } 7 NE CB certain embodiments the linker includes > 3 - H : : ON Boo In certain embodiments the linker includes NA 3 REO J \N<‘p TO Ny A LY R40 1 40 R 7 ~ -N, \ —~ 40 3 i HX , or / VEY AN 7 N In certain embodiments the linker includes F \ R40 R40 J S\N " { er a / if I FN EN In certain embodiments the linker includes or N / oN R40 1 "t § Fy / / : setae d 15% In certain embodiments the linker includes or 1 7 oH RY R40 oN Ey / 7 ; oo EN EN In certain embodiments the linker includes or .b ( N \ R40 R40 J NN yf RN ff 7 A F \ Co EN HE MH In certain embodiments the linker includes NN or 7 R40 1 "XN uf FE opaed TA SY 7 7 salar? FH FH In certain embodiments the linker includes © > 7 ‘or' \ 7 RY R40 NN ff FE Ty 7 7 co POH EH In certain embodiments the linker includes © 7 or’ NN 7 xr RO pao pao R% / 1 7 7 3 . . hd FN FN In certain embodiments the linker includes or' \ a R40 R40 I Ni: NN 1b fF RY peo / 5 / / N an N an In certain embodiments the linker includes F \ ) or F \ ) l a RO pao pao RO yx 1 7 7 y y ; lhe FN FN In certain embodiments the linker includes ' \ or’ \ In certain embodiments, there is at least one stereocenter in the EGFR ligand portion which is a mixture of R and S. In another embodiment there is at least one stereocenter in the EGFR ligand portion and it is enantiomerically enriched or substantially pure in the R- configuration. In another embodiment there is at least one stereocenter in the EGFR ligand portion and it is enantiomerically enriched or substantially pure in the S-configuration. NT N— / \ R33 NH TN J N- In certain embodiments pa is ° is | / wherein R33 is hydrogen. NT N— / \ R33 NN NH 2 J N- In certain embodiments NS is ° is | / wherein R33 is hydrogen. NT ~ N R33 R33 NH SH J N- In certain embodiments Ag is ° is NT "| N R33 R33 NH Sh J M In certain embodiments Ag is ° is ND N ND N Vl per Nl Dp NH JN J M- In certain embodiments NN is ¢ is NO — N R33 R33 NH JN J M In certain embodiments NN is ¢ is NO ~ N R33 oy R33 NH JN J M- In certain embodiments NS is ° is NTN NTN Al Dr lpn NH JN J Me In certain embodiments Soil is Ce Embodiments of alkyl In certain embodiments “alkyl” is a Ci-Cioalkyl, Ci-Csalkyl, Ci-Csalkyl, Ci-Cralkyl, Ci-Cealkyl, Ci-Csalkyl, C;-Caalkyl, C1-Csalkyl, or C1-Caalkyl. 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. Additional non-limiting examples of “alkyl” include: sec-butyl, sec-pentyl, and sec-hexyl. Additional non-limiting examples of “alkyl” include: tert-butyl, terf-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 R*! substituents. Embodiments of cycloalkyl In certain embodiments “cycloalkyl” is a Cs-Cscycloalkyl, Cs-Crcycloalkyl, Cs- Cscycloalkyl, Cs-Cscycloalkyl, Cs-Cacycloalkyl, Ca-Cscycloalkyl, Cs-Cscycloalkyl, or Cs- Cscycloalkyl. In certain embodiments “cycloalkyl” has three carbons. In certain embodiments “cycloalkyl” has four carbons. In certain embodiments “cycloalkyl” has five carbons. In certain embodiments “cycloalkyl” has six carbons. In certain embodiments “cycloalkyl” has seven carbons. In certain embodiments “cycloalkyl” has eight carbons. In certain embodiments “cycloalkyl” has nine carbons. In certain embodiments “cycloalkyl” has ten carbons. Non-limiting examples of “cycloalkyl” include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl. In an alternative embodiment “cycloalkyl” is “optionally substituted” with 1, 2, 3, or 4 R31 substituents. Embodiments of haloalkyl In certain embodiments “haloalkyl” is a Ci-Ciohaloalkyl, Ci-Cohaloalkyl, Ci- Cshaloalkyl, Ci-Crhaloalkyl, C1-Cshaloalkyl, C1-Cshaloalkyl, Ci-Cshaloalkyl, Ci-Cshaloalkyl, and C;-Czhaloalkyl. In certain embodiments “haloalkyl” has one carbon. In certain embodiments “haloalkyl” has one carbon and one 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. In certain embodiments “haloalkyl” has four carbons. In certain embodiments “haloalkyl” has five carbons. In certain embodiments “haloalkyl” has six carbons. hea Non-limiting examples of “haloalkyl” include: MF and 3 Ng I F F F—. do RF a Additional non-limiting examples of “haloalkyl” include: F J F—. F 7 F—. eX 5 D3 FTE FTE RTE TN FN R F FX OF F F< FF FF FT F~% and oy Sy Additional non-limiting examples of “haloalkyl” include: 5 ,Cl" and F R Wood Additional non-limiting examples of “haloalkyl” include: Cl cr Embodiments of heterocycle In certain embodiments “heterocycle” refers to a cyclic ring with one nitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms. In certain embodiments “heterocycle” refers to a cyclic ring with one nitrogen and one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms. In certain embodiments “heterocycle” refers to a cyclic ring with two nitrogens and 3, 4,5, 6,7, or 8 carbon atoms. In certain embodiments “heterocycle” refers to a cyclic ring with one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms. In certain embodiments “heterocycle” refers to a cyclic ring with one sulfur and 3, 4, 5, 6, 7, or 8 carbon atoms. Non-limiting examples of “heterocycle” include aziridine, oxirane, thiirane, azetidine, 1,3-diazetidine, oxetane, and thietane. Additional non-limiting examples of “heterocycle” include pyrrolidine, 3-pyrroline, 2- pyrroline, pyrazolidine, and imidazolidine. Additional non-limiting examples of “heterocycle” include tetrahydrofuran, 1,3- dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane. Additional non-limiting examples of “heterocycle” include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine. Additional non-limiting examples of “heterocycle” include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran wherein the point of attachment for each group is on the heterocycle ring. Non-limiting examples of “heterocycle” also include: x oN “ ow 04 How i XZ x neo No) WAH HN Lon LU Wo Ny Some eee Try CN ol em J am U0 Kn oS Additional non-limiting examples of “heterocycle” include: + HL Ln XK Cw I x 1 ’ Cand SO Xo > oOo Additional non-limiting examples of “heterocycle” include: a Ng iy Rex we Lomn LU eterocycle” include: ile — Shih Li Siti Sa ab dé LX “NH HN ting examples of “het NH oN mH oa Yo ” ) NH oy NH HN ~o “N woo Udnwe mM Wy 3 Fo NEE bo. XL TEN J oor aT C0 Ng NL) On” NNH HN omm L and NO Non-limiting examples of “heterocycle” also include: A ~ 1 + NN ANS t ANS Sn No” ~~ H and Non-limiting examples of “heterocycle” also include: x Xo Sx x XxX Lod N N / ¢ NH, < O 1 H Yo INH, 7 and “0 Additional non-limiting examples of “heterocycle” include: + x TI A & / —NH > a A , and 4 Additional non-limiting examples of “heterocycle” include: WAN AAA NOX AN 1 On Co yw / “—NH id = In an alternative embodiment “heterocycle” is “optionally substituted” with 1, 2, 3, or 4 R3! substituents. Embodiments of heteroaryl In certain embodiments “heteroaryl” is a 5 membered aromatic group containing 1, 2, 3, or 4 nitrogen atoms. Non-limiting examples of 5 membered “heteroaryl” groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, and thiatriazole. Additional non-limiting examples of 5 membered “heteroaryl” groups include: Mh, IN nN oy a. nN nN 2 . NO RQ mS on RL NO NS oN Or FE Or ORO OO H Of mg nN nN IEE vhs ~N_ N) 0, S, QQ Maa 30 ) NN 4 5 rs [5 nn R "and -S5. . H VE 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: COOL goooOaoTr In certain embodiments “heteroaryl” is a 9 membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur. Non-limiting examples of “heteroaryl” groups that are bicyclic include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole, benzoisothiazole, benzooxazole, and benzothiazole. Additional non-limiting examples of “heteroaryl” groups that are bicyclic include: ; RTD. OCD or N N N N N N N cD CO H ~~ H 7 H 7H ww HTH and a, Additional non-limiting examples of “heteroaryl” groups that are bicyclic include: N\ 0 0 0 0 Ani 0 Additional non-limiting examples of “heteroaryl” groups that are bicyclic include: C0 N JOO CL) C+ H H ~~ HH °° HH = °° 4H TD H , and ) & In certain embodiments “heteroaryl” is a 10 membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur. Non-limiting examples of “heteroaryl” groups that are bicyclic include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine. Additional non-limiting examples of “heteroaryl” groups that are bicyclic include: J CO OO HED Ce OR | NEN N* ANN? 7 ZN ZN 1. aC In an alternative embodiment “heteroaryl” is “optionally substituted” with 1, 2, 3, or 4 R3! substituents. Embodiments of aryl In certain embodiments aryl is phenyl. In certain embodiments aryl is napthyl. In an alternative embodiment “aryl” is “optionally substituted” with 1, 2, 3, or 4 R! substituents. Embodiments of bicycle The term “bicycle” refers to a ring system wherein two rings share at least one atom in common. These rings can be spirocyclic or fused together and each ring is independently selected from carbocycle, heterocycle, aryl, and heteroaryl. Non-limiting examples of bicycle groups include: H H To When the term “bicycle” is used in the context of a bivalent residue such as Linker the attachment points can be on separate rings or on the same ring. In certain embodiments both attachment points are on the same ring. In certain embodiments both attachment points are on different rings. Non-limiting examples of bivalent bicycle groups include: OOH OOH OO NYT HX FN XO JO FX ™ ed ROC, and Additional non-limiting examples of bivalent bicycle include: oR { CL N In an alternative embodiment “bicycle” is “optionally substituted” with 1, 2, 3, or 4 R*! substituents. Embodiments of optional substituents In certain embodiments wherein a variable can be optionally substituted it is not substituted. In certain embodiments wherein a variable can be optionally substituted it is substituted with 1 substituent. In certain embodiments wherein a variable can be optionally substituted it is substituted with 2 substituents. In certain embodiments wherein a variable can be optionally substituted it is substituted with 3 substituents. In certain embodiments wherein a variable can be optionally substituted it is substituted with 4 substituents. In one alternative embodiment any suitable group may be present on a “substituted” or “optionally substituted” position if indicated that forms a stable molecule and meets the desired purpose of the invention and includes, but is not limited to, e.g., halogen (which can independently be F, CI, Br or I); cyano; hydroxyl; nitro; azido; alkanoyl (such as a C»-Cs alkanoyl group); carboxamide; alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy such as phenoxy; thioalkyl including those having one or more thioether linkages; alkylsulfinyl; alkylsulfonyl groups including those having one or more sulfonyl linkages; aminoalkyl groups including groups having more than one N atoms; aryl (e.g., phenyl, biphenyl, naphthyl, or the like, each ring either substituted or unsubstituted); arylalkyl having for example, 1 to 3 separate or fused rings and from 6 to about 14 or 18 ring carbon atoms, with benzyl being an exemplary arylalkyl group; arylalkoxy, for example, having 1 to 3 separate or fused rings with benzyloxy being an exemplary arylalkoxy group; or a saturated or partially unsaturated heterocycle having 1 to 3 separate or fused rings with one or more N, O or S atoms, or a heteroaryl having 1 to 3 separate or fused rings with one or more N, O or S atoms, e.g. coumarinyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, and pyrrolidinyl. Such groups may be further substituted, e.g. with hydroxy, alkyl, alkoxy, halogen and amino. Embodiments of Aliphatic and Heteroaliphatic In certain embodiments “aliphatic” refers to a saturated or unsaturated, straight, branched, or cyclic hydrocarbon. In these embodiments aliphatic is intended to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, and thus incorporates each of these definitions. In certain embodiments, "aliphatic" is used to indicate those aliphatic groups having 1-20 carbon atoms. The aliphatic chain can be, for example, mono-unsaturated, di-unsaturated, tri-unsaturated, or polyunsaturated, or alkynyl. Unsaturated aliphatic groups can be in a cis or trans configuration. In certain embodiments, the aliphatic group contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms. In certain embodiments, the aliphatic group contains from 1 to about 8 carbon atoms. In certain embodiments, the aliphatic group is C1- Ca, C1-C3, C1-Cs4, C1-Cs or C1-Cs. The specified ranges as used herein indicate an aliphatic group having each member of the range described as an independent species. For example, the term C1-Cs aliphatic as used herein indicates a straight or branched alkyl, alkenyl, or alkynyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species. For example, the term C;-Cs aliphatic as used herein indicates a straight or branched alkyl, alkenyl, or alkynyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species. In certain embodiments, the aliphatic group is substituted with one or more functional groups that results in the formation of a stable moiety. In certain embodiments "heteroaliphatic” refers to an aliphatic moiety that contains at least one heteroatom in the chain, for example, an amine, carbonyl, carboxy, oxo, thio, phosphate, phosphonate, nitrogen, phosphorus, silicon, or boron atoms in place of a carbon atom. In certain embodiments, the only heteroatom is nitrogen. In certain embodiments, the only heteroatom is oxygen. In certain embodiments, the only heteroatom is sulfur. In certain embodiments “heteroaliphatic” is intended herein to include, but is not limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl moieties. In certain embodiments, "heteroaliphatic" is used to indicate a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-20 carbon atoms. In certain embodiments, the heteroaliphatic group is optionally substituted in a manner that results in the formation of a stable moiety. Nonlimiting examples of heteroaliphatic moieties are polyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide, polyglycolide, thioether, ether, alkyl-heterocycle-alkyl, -O-alkyl-O-alkyl, alkyl-O-haloalkyl, etc. Embodiments of A and A* 36 R34 ~37 R R* RY I TN oO \ R ) NN Ke yr NN = - Yo) In certain embodiments A* is R# AN Fre \ o=<' oN N I HN TN Ngo In certain embodiments A* is 0 A 34 v0 35 = \ ed Hiv \ + N: Ngo 0 RM R34 "xX TNR o= Y 6G \ x A a2 NN r Hd Yo) In certain embodiments A* is > o= \ 34 RS o = AE —( Nan , HN: R35 AP o 1 a4 In certain embodiments A* is R34 RY TN SN R*® OO vad \_ SE 7 / \ of x 4 Vo) i’ 3 ys hd Msz= AS In certain embodiments A* is Oo 368 R34 37 R RY ra \ Ns \ o= X 1 1 \ R™ 37 Tr \ RC R3 Nas o= X | 21 4 A’ wi, In certain embodiments A* is [eo] In certain embodiments R** and R** combine to form a CHa. In certain embodiments R3* is H. In certain embodiments R3® is H. In certain embodiments A! is NH. In certain embodiments Al is O. In certain embodiments A2! is NH. In certain embodiments A2! is O. In certain embodiments A2! is CH. In certain embodiments A2! is NR 10° In certain embodiments A%2, A%, A, and A3* are each selected from CH, C-halogen, and CF. In certain embodiments A32 is CH. In certain embodiments A32 is CF. In certain embodiments A32 is CR*2 In certain embodiments A32 is N. In certain embodiments A3? is CH. In certain embodiments A>? is CF. In certain embodiments A233 is CR¥2 In certain embodiments A33 is N. In certain embodiments A3* is CH. In certain embodiments A3* is CF. In certain embodiments A3* is CR¥2 In certain embodiments A3* is N. In certain embodiments A3® is CH. In certain embodiments A3° is CF. In certain embodiments A3° is CR¥ In certain embodiments A3° is N. In certain embodiments A36 is N. In certain embodiments R* is hydrogen. In certain embodiments R* is C1-C; alkyl. In certain embodiments R* is Css-cycloalkyl. In certain embodiments R* is methyl. 6 R4 o70 R TN R70 he. [o— \ nN HI N ” Al - 0 — A R7 In certain embodiments A or A* is AF R8 “NN O=— 4 RE A; wr 5 : TA x o=, NA HN— N77 SRe o In certain embodiments A or A* is R% TN o= \ A ‘At AH In certain embodiments A or A* is In certain embodiments, A or A* is selected from: go og 0 oO TL OI ON YN ON NL [of o=<"\ oA, NN oN Jos | o<(") N oC Sy HN NN TC TY wt 0. o=( N py H nT Ny - N° v [o} o H Te IRB ~ F C0 F \ N- o= J OF NN Ll 3200 TOL C0 NN Fr HN ~ oO \ t o= N= > wad MO ox o= — »o=x NH HM Hn = OX N- =f = A= 0 AF md F \ o= oy No gp HN ~ 0 fetes and Embodiments of B and B* In certain embodiments B or B* is In certain embodiments B or B* is N. In certain embodiments B* is heteroaryl. In certain embodiments B* is heteroaryl substituted with one R*! group. In certain embodiments B* is aryl. In certain embodiments B* is aryl substituted with one R*! group. In certain embodiments B* is In certain embodiments B* is [- ) R31 In certain embodiments B* is 5 = In certain embodiments B* is In certain embodiments B* is N I k + . FF In certain embodiments B* is R®' Embodiments of y In certain embodiments y is 0. In certain embodiments y is 1. In certain embodiments y is 2. In certain embodiments y is 3. Embodiments of R*! In certain embodiments at least one R*! is halogen. In certain embodiments at least one R3! is F. In certain embodiments at least one R3! is Cl. In certain embodiments at least one R*! is C1.¢-alkyl. In certain embodiments at least one R3! is halo-Cis-alkyl. In certain embodiments one R3! is halogen. In certain embodiments one R3! is F. In certain embodiments one R3! is Cl. In certain embodiments one R3! is Ci.¢-alkyl. In certain embodiments one R*! is cyano. In certain embodiments one R3! is Cj.¢-alkoxy. In certain embodiments one R3! is halo-Cj.¢-alkoxy. In certain embodiments one R*! is Cs.s-cycloalkyl. In certain embodiments one R*! is halo-Cs.s-cycloalkyl. In certain embodiments R*! is selected from halogen, Ci.s-alkoxy, and Ci.¢-alkyl. In certain embodiments R?! is selected from F, Cl, methoxy, and methyl. Embodiments of R3® and R3’ In certain embodiments R* and R*” together are combined to form a 5-membered cycle optionally substituted with 1, 2, or 3 R3! substituents. In certain embodiments R* and R*” together are combined to form a 6-membered cycle optionally substituted with 1, 2, or 3 R*! substituents. In certain embodiments R* and R¥ together are combined to form a 5-membered cycloalkyl optionally substituted with 1, 2, or 3 R*! substituents. In certain embodiments R* and R¥’ together are combined to form a 6-membered cycloalkyl optionally substituted with 1, 2, or 3 R?! substituents. In certain embodiments R* and RY" together are combined to form a S-membered heteroaryl optionally substituted with 1, 2, or 3 R*! substituents. In certain embodiments R* and R¥’ together are combined to form a 6-membered heteroaryl optionally substituted with 1, 2, or 3 R*! substituents. In certain embodiments R* and RY" together are combined to form a S-membered heterocycle optionally substituted with 1, 2, or 3 R?! substituents. In certain embodiments R* and RY" together are combined to form a 6-membered heterocycle optionally substituted with 1, 2, or 3 R*! substituents. In certain embodiments R* and R¥ together are combined to form a morpholine optionally substituted with 1, 2, or 3 R*! substituents. In certain embodiments R* and R*’ together are combined to form phenyl optionally substituted with 1, 2, or 3 R*! substituents. In certain embodiments the cycle formed by combining R* and R’ is not substituted. In certain embodiments the cycle formed by combining R36 and RY’ is substituted with 1 R3! substituent. In certain embodiments the cycle formed by combining R¥ and R¥ is substituted with 2 R3! substituents. In certain embodiments the cycle formed by combining R¥ and R¥ is substituted with 3 R3! substituents. In certain embodiments R*® is hydrogen. In certain embodiments R® is halogen. In certain embodiments R3¢ is F. In certain embodiments R3® is Cl. In certain embodiments R*® is Cy4-alkyl. In certain embodiments R*® is cyano. In certain embodiments R36 is Cis-alkoxy. In certain embodiments R36 is halo-Ci.s-alkoxy. In certain embodiments R® is Cs.s-cycloalkyl. In certain embodiments R* is halo-Cs.s-cycloalkyl. In certain embodiments R* is selected from hydrogen, halogen, Ci-alkoxy, and Ci.- alkyl. In certain embodiments R*® is selected from hydrogen, F, Cl, methoxy, and methyl. In certain embodiments R?’ is hydrogen. In certain embodiments R*7 is halogen. In certain embodiments R37 is F. In certain embodiments R37 is C1. In certain embodiments R*” is Cy4-alkyl. In certain embodiments R37 is cyano. In certain embodiments R37 is Cj¢-alkoxy. In certain embodiments R?” is halo-C.¢-alkoxy. In certain embodiments R*” is Cs.s-cycloalkyl. In certain embodiments R*’ is halo-Cs.s-cycloalkyl. In certain embodiments R*” is selected from hydrogen, halogen, Cis-alkoxy, and Ci.- alkyl. In certain embodiments R*’ is selected from hydrogen, F, Cl, methoxy, and methyl. Embodiments of R¥ In certain embodiments at least one R* is halogen. In certain embodiments at least one R*2 is F. In certain embodiments at least one R* is Cl. In certain embodiments at least one R* is C1.¢-alkyl. In certain embodiments at least one R*? is halo-C1.¢-alkyl. In certain embodiments R* is hydrogen. In certain embodiments R* is halogen. In certain embodiments R*2is F. In certain embodiments R*? is Cl. In certain embodiments R* is Cis-alkyl. In certain embodiments R* is cyano. In certain embodiments R* is Cjs-alkoxy. In certain embodiments R* is halo-C).¢-alkoxy. In certain embodiments R*? is Cs.s-cycloalkyl. In certain embodiments R* is halo-Cs.s-cycloalkyl. In certain embodiments R* is selected from hydrogen, halogen, Cis-alkoxy, and Ci.6- alkyl. In certain embodiments R* is selected from hydrogen, F, Cl, methoxy, and methyl. Embodiments of Ring G In certain embodiments Ring G is a 5-membered heteroaryl ring optionally substituted with 1 or 2 R*¥ substituents. In certain embodiments Ring G is a 6-membered heteroaryl ring optionally substituted with 1 or 2 R* substituents. In certain embodiments Ring G is selected from: “re mT re , and J n-N J Embodiments of EGFR Targeting Ligand In certain embodiments the compound of the present invention is selected from: ISN—F o NTN oN A» = LE» ) be I N— JN x NH X R31 J Y=N RY J / oN R31 0 )=N RY =n RI HN s J ¢ r B PN F Za F o NNT 0 N7 Ny A = R= GY CN (=) A NH A JH R31 & Nuns R31 0 MN 00 Cn F NTN F NTON— => A~LAACN = 2 NY Of pe = 2 N= (» x (x) ANN oO —N i a ). Jd w = ® d= s A : Dy NNR = 00 =r = 0 0 g NX E ~N a ” NH V=N “Or = 0 wr hg | FN Ya d N H Ne —N FZ NY N— / \ N= _ i. FL Ered oy O&O 0 HN 5% 4 JNH Cy Neti 31 yO) 31 R’ dod HN R3t NT N—\ NT N—\ N= Cad be A=NT / 2 0 N EC A 2 Rr! 5 0) / ] N 3 R31 NN SR J 2B JN a a NZ N / \ 0 NZ NT LPN 4 Bz = (x) Tw (x) TI 5S SNH A SNH 7S NH ~~ & x (R3), 0 =N (R31), F he 7 HF. 4g RM), 0 )=N RY), So )=N S. Ss. A and A In certain embodiments the compound of the present invention is se PSN F o NZ N72 2 Ne o NONE 7 4 5 190 Tan Fed NH a ; Jr o 7 a J=N IN 7 F A SN—F 0 NN O N = L2 - L2 i -Y - & NH & NH cl J cl 0 )=N o » No Es CY Cade = Y Nn ND oO ’ Tt To = = =O hoe + F ne h=N © d 8A 3 NTN F N= a F ISN NZ Ne N —\ EL EE N— — PS SAA NH A PY NH oo oo ~ NN J a ®" ye A = pe ) F AN 2 N7 N—™\ NZ NT LAAN, = LEANN, = TI TI X J—NH x J—NH (CI), F NN (Cn J ba Fo sg 7 N J y r y = / and =r. In certain embodiments the compound of the present invention is selected from: NY N—\ oN o NTTNT ’ EO = 12 Z { % Cn oC 2 I > | )=N o J CY Sg 00) =z [0] 0 20 N— - & NL ; =z 0 J IN ors | —\ Ya d NH Y=N S. © 4 4D ' N7ON =) 7 / o N7 N / T 0 N LE = LE ~ ) oy OM cl cl 0 >N d d 3 ca’ Eee =z pve < {)% “ Lo | a \ Nd ; L2 To Fo ” > " NC -\ Nd \_ as HoT R' (=) J Y=N F J =n 82 and 8S In certain embodiments the compound of the present invention is selected NT N— / \ FEF O )=N F 7 o N” NT ’ 12 SINTON a EO - NH F o =N F J ~ IN | NN N7ON = pp F 0 / ~=N Cl IN o N7'N —\ 12 Sad Soup 12 p NY ed = Ls NH yy Y JY NH O=N cl 0 )=N od 1 3 a 9 by Cl NTN F NTN L2 i “on J 2A 0 N— oS / ~~ Rx H JT JN Cl and TT he 4 "\' )=N Oo )=N s J s J ND N— / \ NH J Me L2 N 3 TR, BE J F In certain embodiments the compound of the present invention is selected from: NY N—\ F TE. Yr IL Cl oN LZ ) EO cl J 2 0 \ oy Jen TE. Tr o N° : L2 ) Er C- cl J o N’ 12 > N— F J I Ay “7 F NT N— / \ NTN =) Cl i” o ND “ Fo \ CO, 0 a oN 0 ND N—\ So NNT Fo NON L2 A = L2 g 4 lr Y—NH Y—NH J. ~~ NY = Fo \ 0 d HO Oo oe ci PTS Y i NI | F Cl 12 oO N Of N— 3 7 Fo \ Opes d J. =~ se HO oO F NT N— / \ og) gw 2 Cl o N > e- N— 0) ~~ Xx NH SL YY J M F 4 " oN’ L2 Eo, N— I 7 oO A ® C0 — — F F J NH @* ’ 5 g F J | Ay (») FC ; ) N— . I : 3 OO") & LI d a cl o © C0 ) o TH N7ON = pup CF; 2 3 0 N \ , Cl — — co NON CFs 0 NZON— 2 =r E V=L_ N= N= JNH J—NH 0 o CFs 0 NZON [PE L2 el Dr be Yl De GC N— MY—NH MY—NH ~~ xX NH TN J N- iN 7 ° ’ FF FF NT 6 NON NT 6 NPN i ay o jy} He o \ O- o- o 3 o and FF N7N = pup Yo N o- N— ) H TN In certain embodiments the compound of the present invention is selected from: ND N—\ No OT NEE 2 N, = Bn PN Gr Tr TR Ste ~l a > Cl Zee ' * J ® Poe NN NON =("F ~NBAAN, ENF R= NH TN XY TN Ce ~ = J Cl N Ken) =, " F d Ye ral OC, ~ = J Cl NT N— / \ cl NTN E NN EAN = BAN, NAF N— N— = NY NH = Y NH 2A EO = N= 3 RR NH TN J M- °O E NTN cl NOON ts Sug ~LE AN A cl N 2 3 i =N, / = N— 3 EN a ED aN nv Ov J—NH o > ad °O EF ND N—\ agM Cl L2 N N ( Y ZN 3 I. ~~ Fy | N’ ER, = Nt F J ® Poe F NN F NTN 12 N, Yel Der L2 =N, = CO GC NH NH FoR) Foo — F Cl UN Cl — cl 2 2 NZ NT nN Es NT 5 N ) . =N, Y r 4%, ~ y cl o NZN = Jp a CF3 N =N, = N= 3 Cl ~~ cl 7 o 2 NO — NN = F sr 2 § NI GY &ee Post LE ~ : NH J B FSF NZON— FF ND N—\ F 2 A Yum] 1 ee 1 7 Y NH wa? ~~ RR H TN a an FF NZN = Jp >" or AN / 3 3 NH J M- Compounds of Formula ITI In certain embodiments the compound of the present invention is selected R36 R# RY NZ NL R3 = o= va) AAR ARES RAIA AAAI RRA AAR RAMA PR anh 2A 34 R36 2 4 RY RY , R o N’ See N— Mor AS A » 0 RA), d NTN RS N= NH J p= R34 o al Ro N A 2 § R* dF ] wi a 4 y N= 31 By NN oR ly d ma nn? R34 NNR =) o=_ NH J M- RM Ro N’ > R3 Gre Zz > } pe 8 “Ty 0 (R7)y d R# NTN RE = NH J = Ly HO RH), J RR RY R36 BR o=_ \ ee R2 SNR? Nao J o N 2 36, 2 me 2, A Ie XL 5 = NX op HN: - JL no no RE oN MWe \ 2 A 0 { {>= ge (re), J no ly RT (re), Jd R# Ra? R%® x H JL RY RY R = xr HN 2 wr Ro nN 2850 (R31), J Zz ooo (Ret), 0 ce: embodiments the compound of the present invention is selected D34 —~17 R36 R2 ”™ SN i ol ON 2 ¥ : JJ ND Le Xo R3 o= NH J \ R* 37 RT Ro N 3 55 12 } =, R | A N— — A33 HN AZ! Yaz=A ) o RM 0 H JL R34 0 Bl Ro N 34 R* AS LL 7 AS XY N— N A o NY r HN—( Ngo RM 0 o SSR R22 \ o== \ NH J h- i = GY “& Oo ND N: HO R31 R3 IN FS ys NA R3 H J R¥ Q oO AB + 7a - _ A o aR 2 o ND wa R3 J R34 RY R3® A \N_ / FN R2 o= R? Noi: gp HN ~ H JN ) no no 2 R X eof Nua 2 N ~~ A%=A® N— Oo R31 J - ~s NA 36 R34 r3? R IN R3 NH J No RH pw B® \ = = 2 2 z HN AZ! wl Ro NT 0 oc > N— R3 J J x o 7s NS Compounds of Formula IV In certain embodiments the compound of the present invention is selected from: R% 34 36 2 R® ry R R i.) NT NDR N= J o= NH J M- RY NX R37 ne RS 1 = NH «el ANN) \, \a2=A% JA AN wh, J NZ NL R® =D H I R34 os Na R2 N? 34 x R% INA) AZ AB Lg J NT o NY 8 > HN—( NN. Rly o 0 gh 2? R# NTN R3 = o= H JL R® ) y= 5 Joel ay en Z s, po ’ he ) ) 7 0 R34 NTN R3® =D JL R# RY R¥ "NN O= NZ NL R® =D Nowe aft HN: —~ NH J p= a 2 weg eT ~ PETC TN =N 0 JA = N=, (r#), d and 34 3 RS ry R “N o= NT NDCRE N=) H JL RX RY R36 HN Le ai , 3 N + ZA > Sail wy, J 2 Joon (Ret), 0 III. ADDITIONAL COMPOUNDS OF THE PRESENT INVENTION In certain embodiments the compound of the present invention is selected from: RE. CNR “NM H R33 ON “NN H 0 3 N | rN 0 Crye-® SX 0 p® { p31) F F (R¥), H RE. NR ly H 1 Ne on LL s _N F ~! SX TOR® aX, 2 (r%), L oo ye ® F H H F ST Gp® STR® 1 =a F { =31\ (r%), F (R3Y), R% R%: s Nw 7 (r%, s Hw { x 0 Crye-® I 0 Ope-® { p31) F F (R¥), REN a H x S STR (R3), In certain embodiments the compound of the present invention is selected from: rR RB, CON CON LN a O pat H 0 H | [J K HL =" o R3 YY o s AN s._N Cc n31 F FF R31 RE CNR “hy H | N= I 1M r3 H [ F H ! FR WY 0 YY" < N F H ? re R3 F H H F ~31 F -~31 R31 F R31 ~~ N O pat he P N N GO-TO of 531 F F R31 RRAN-% bedi H 3 LSA S ot 142,990 R31 In certain embodiments the compound of the present invention is selected from: R® RE NN eS CCN Ie} N= a 0 “N" 0 H + J H I yy" <r oN L2 Pp | F —" Sr R31 NO (») | Rs CON a H ! R33, SON a H ON Ww o¥ s R { r Ss fi LA rl ETT RIT w(x) RT "es g ForCl F R33 On a H RE CON a H hn % CK : ° CN . ~~ — Cr I ” R Lr R31 <N L sory $ I ClorF F R3! oH oR _Y <X ry L iE © w(x) ome | ClorF ha % Sr R31 N o (x) For Cl Ny N= TY “Ne sa 883M Clin 4800 F F N= 0 wo I) Grade @Y Qe-® F ForCl N= a NN Ge <0 NN STO ClorF F ‘ Ny AN 3 N=) uN NN o SNe —N a % LN so Ay Lr 3 wy Lr GT aT e® ClorF ForCl — / N(x) N / In certain embodiments the compound of the present invention is selected from: A, Shy 0 N \ OE LY-OO®) F F Ny ) N / S LL qr { TO co O ForCl oe MC — F ? a I (x) N / N A F — (=) N J On — TY T-O-00L 0 F Ny 0 ) N / S Ll are CO-O O ForCl 00 HO ? N= H [| Forcl I / > N / H 0 2 ForCl 0 ay O00 HO F H I —N NE LA a C-Omoo F E NR “A a Hy UF N N S000 ® F For Cl F F F ForCl F and a) dy 5 H x mn E Ar Cl oo 5 BS { Fora ° SEO 0® F F certain embodiments the compound of the present invention is selected from: F of Oey oo NN 0 F Oe Ye "™ o ND NN F 9 “ 2 — N Ns. wd 3 Tr ~~ \ 7N F "™ o hp) 0 Nz Q Sa N N pt =~ Y 9 ~~ F 7N F F o ] ~ N N S, w= Y 0 ~~ . o RH 3 rel = o N_ / N F and o H F LT F In certain embodiments the compound of the present invention is selected from: H R33 TN 3 og 0 N H at Os og SM WL TR ll a SY. (re), H 1] R33 7 NK H o N 3. AS CO 30 rz © ; N N N—¢ N N ~ 9 rz § Th N (rat), H Q R_ / ™N ” ~ ~ 3 oo HN = 0% Oa, 5 ; vy Lt 1 5 re YO N Op 00-000 (Rat), H o SHO Na ou NON N— \ X NNN N. Nm 1 OF 00-0 (Rat), H Il R33 ~ o H F 0 0 NL SOC oan TAT 3 re YO N OF O00 yh (Rat), H Q R_ / N ” HI ~ ~~ ~ 3 2 N ~ / "N en = 9 NA \_ DON Sm 7 NNR 7 3 re YO N OF O00 (Rat), H R33 " HO R32 o = (1) Nl), eo hn Nm l ) Q 2 OV @%a COT id R32 TNT i N, = 3 MH H ll HN Y = \_ AN F ) Q 2 OV @%a COO on an H oO SAYA Xs oO A: Yo N XN oo \ ne \ H N. IN —— 1 @% COO Gn cel embodiments the compound of the present invention is selected from: N= —N H Lo oo oo -(#) N / No ANN fo &E-000 dy F N= N-(#) N / NA NN fo T0000 F ForCl a — H {| ForcCl 120) N / N i. .N ForCl GRO F N= -(») N I NAN 0 G-O-00L F N= -(») N P "Hn s N -N uy TNO AO F ForCl HO a “oy H | ForcCl Wx) N 3 NA NN ForCl 0 $Y 1 -OR00L 0, r HO F H SS < ETE 000L @ F E F F Ny —N H Sy oo oo H s Na Snes 0 TR OO F ForCl F F A Ny 20 H { + Forcl NOU LN For Cl o G00 L0® F F certain embodiments the compound of the present invention is selected from: Ny —N H i oo = . F \—(*) N / RON Ff 0 GRRL F Pp H + F eo N / No ANF 0 E0000 ForCl N= W() N 7 O00 Loy ForCl N= F NA) \ / H i Nn F 0 YER HO H i oo = Nn H + F NAN Sf 0 SEO -® ForCl hy AN Tals oo J —v 120) N / IY LOO ForCl iN -—] = AYA ) HO For Cl Ny NM H | . FE N. AN F GEL, F Ny Sed H 3 Td = _ H + F Ro NF 0 TTL e ForCl F F and N= NM H N 2 F T3000 ForCl 7 NF . cel embodiments the compound of the present invention is s¢ 3 FOr Crys WN (- o 0 F NN NA HN = ~ 0 oo Nv \ NZ F NN NA F H ~~ N 1 H HOT Oey N c NN of TED od F N Ty Nn fd wt — ~ “y he 2 F N N: 7 “N N. 2 SECC o F SHOy =r 2 F = 0 H RN { Wo ~O- Cr Sot c 0 J F = F and o H F N bem N- ZN N J Che De 1® 7 v ce! embodiments the compound of the present invention is selected Q i A Ny { i ; '® Ot TNS J v QR MAM ~~ J oO NJ OT Fy N Ca F Q Ty Nn i ws mv = Y hY, ~~ " d N F FE " H N.. RN Ce Ye SOT 5 ka 0 H R Ns H = O-7Y R Ty SHC SY 2 and NN N 2 ZN NN HCCI ad In certain embodiments the compound of the present invention is selected from: R¥ TN Q ~~) Q ” P N =, R’ N, N. H a 9 OXON, Je NNN N 2 R32 Nad (Ra), R¥ 7 TN% 3 CS ~ 3 R® NA wo OH XO I~ \_ N >» N 2 R32 Nad (Ra), R¥ JN o H 3} 9 P N—? NS R32 H wo INTO, MA N 2 R32 ‘aad (Rat), 0 H ad au Xe O- "OX A J \ + N of Za wh \ H N Nm O00 For i, N N AN. H v CTE R31 R33 F NK 3 oP Oa N. H N— / ZN N Q EE OOO rg (Ra), R¥ TN o H 3 Q P N—? \ R32 H wo = NOOO, ef N Q I (Ra), [e} H SORA HO o HOG AND 7 W Y N A SAN 7 NNN N Nm Q a oh Ry R32 R33 INK NA 3 H Hi N - \ AN F and 0 EE &, R31), oO SAY i HO 0 (NA N OXON ol H N IN — No H AO = wo Ch 2, N N. H oN NIN Sn I~ NA i 3 J I (Re1), In certain embodiments the compound of the present invention is selected from: oX — O 3 < lly Ye vi { F - F H o=X_, NN \ 5 Nin / es of 0 3 O OOD as 2 F WO 2021 / 127561 o und Ny = Or a C-Or00Lo0s F F SN, P N NX “No . ox G0 -0oLo-0 SN 2 N NX “No . o<_, go F orCl ) F Ny 2 a0 Tt H I 0 o=<X_, —" ° B = Ss Ro P \ 3 STE 0-00 Lo Oo F ForCl ForCl Or ON vi oY 2 For Cl 0 = FOL F Ee F F NA) 0 ee Or ry Ho or Cl O o = NH F H Tr i Hoa Forcl =, bo Co 0 o= — 7 NT) “Oh pl aM Py ForcCl o _ = LR 3 000 pif o=_ "4 g F F and N= 0 uN HN ha o o={ = H vr i Hoa A oo - 0 o=<_, hd \ N N NH F ForCl Co F In certain embodiments the compound of the present invention is selected from: NS o A . 0, " N Nort - SOO ~SOY Fr Q HN— \ JERI YT F F F A I wn 3 Soa Q Tx s ~« \— SN OY 8 1 F v and NN WALLY ; Ti HN N S, 20-0 OOF IY / BE F A In certain embodiments the compound of the present invention is selected from: 1] F SHO Ne 5 I oon Ar °o Jp F H I Q N Q 0 yw oC C=O I0 CR pe Kp oO Cy hy) F Il E ANN Q 7 2 ¢ ad EG OIo0 ny HA Fo colo Fa 0 -O~3- TS F and ; \~ NO) OC ~ Na > F In certain embodiments the compound of the present invention is selected from: ou . NN 7 O00 AA QTD F d F Or Tr F H NN N—Z N Q N 7 ~~ Ya oA Q ~ H ll gq NN Q Rs N BY 0 NA HN ~ / _ N NOON {) CY NANA < / o F e I F Q o \ ] N $Y H SHOOT oO er F ForCl 1] 30 TOO F and ForCl H EF In certain embodiments the compound of the present invention is selected from: 1 8 HOO ry F gf 0 LT5 A oN NN N N hs F l F NL / AG OOO ys F and H ll Q Hg p 0 20 0 ! af N- H F In certain embodiments the compound of the present invention is selected from: x FN SO Om IL — Ned NA Oh OH XX ~O~(3 ry i» F oO N N N N s os Ox 00-O-3y 5 F NN NA ION J he s, * = OH O d o 0 HOO OOO J F So, ¢ HO HN ~= / N VAN Ly o7orE oN Q o NJ Co? Ss i OH 1 S, J o DD F ForCl H Forul oN SO i (Oh OC o Nn Ar > F and ForCl 1 0 H Ih o NP | OY an N ’ y K COO Or F In certain embodiments the compound of the present invention is selected from: H ] Q RN ~~ 8 a 'e - Op O01 A Oh OH OX OC a Yr > F I oo 0 JN 0 o ZF SI f a Op On 7 Ny Oh OH XA OC a I vy > F o F SS, 3 HN = NT) ON ~ MYL 3 ‘ a NA 5 POO F and o H F 3 = (CTY r~ 2 0 ~~ Os COO R s eats stan! F In certain embodiments the compound of the present invention is selected from: H NN Q N 0 N / ND Qo = HN N H " NN OH ! d EAN No N 0 0 N_ NT N yt N {) Ye or a! o 2 = H LBS . F oO " Oey ~ 9 NN 7 \ NNR VS Ugo 0) 1.7 Ocory? Oh OH XX Or ea / IY \p off 0 - F NN 3 Oo K bi of oH COC r= % 0 NP Os COO A 2 oh O Y he F Os OH XX C5 . 0 ForCl A pe 28 an Sg 0 oO F and ForCl n i NN fg 0 oO NO 3 N e ba OOO F In certain embodiments the compound of the present invention is selected from: H o NH ~) Po Q o 0 \) ws Og COO o N. 3 0 “~~ OH () i “y Y 3 F 0 OF " code O00 0 TY o J NT 3 N 1 Ys On “OOo F Le ry Og POO F and o H P o ID aN RAS GU TN 3 . Yr 2 ForCl OH Oy Dy T J. 0 NA OA COO R S OH () I I ¥ F In certain embodiments the compound of the present invention is selected from: LE OO) CA ~~ = TT we O- NOX) OC ~ 3 Ti > F F TN aaa § “P N Hy , AM OO PA OH Op I Y » F TN q H < ~ 9 ° NA H wm PN, AA Ny 3 \ 2? ha OY F 3 al ~ $ 0 wo {Ou Yr p NM NAL Fos, 0 0 id -N NOON . H . {7 Op Ys F Sm 3 1 Lo N SCO 00m Hr EX ~ / SV J \_! ~~ hdl a Lx o N, N N ) tre 00 5 F H SS 5 wt (h~ Oui x 7 NNN AN oo ~ / RE - \ 7 \ fr I~ Rl Qo hav ev CO-OP r o F o H F LL Sel HN CN ON Pv A 33 Ll Sas ate: 5 F o H F ee 0 0 HN NN 1 vr \ OIL Nn 4 iL POY F E JIN H 0 = R77 ~ 2 9 ~~ H ou F o Y= SCO Sony ALR ) CTD F NN r Q 9 a 0 SC OO OY 0 Yo F o . y IS C0 0 F and F Bet 0 H ~~ oo RF >" NS N NA S, HT0H000 fri F In certain embodiments the compound of the present invention is selected from: H SH Con Fen 1 @ 5 POO rs F oN N N N s OHO ry F and C0 Ho ~ Q nw I o H F 0 Q NA 3 FCS N N N y Ss TOOT OO F In certain embodiments the compound of the present invention is selected from: ~~ AN 5 Oo H | N N ; \ N, Ya / —N \ F $00 ) 3 ” N N N f= NH J PN H ] 3 S.C Sor OY F —N =) i J—NH oO Pa i "Yn fo-Coa gy, 110 N N: N i Soy F TS i 5 3 JN Oo, A z ho yO J ) v3 ¥ PT #0 Basi? on oO “\ JO ] | Q NN FOO 00m AY / N Orr Ns i © ID N ~~ 9 TN \ / rr NAN o N_ / —N 7 OO an Nt Mo 2 / “No ~ \) NGA IN 0 ° o H \ A ~~ St 0 Oo J : boy N A ) f 7 NN 1 N\ NO H AN Ory : 0 Ja ; ¢ 0D ~\ and 1 nN ~\ 0 \ | Oho LE he apt J rs F NA, \ AN N A | NHN \ N N \ 7 IN / —N NHN 3 0 Hom, J x N N N pO 3 ag pv In certain embodiments the compound of the present invention is selected from: N-NH ZN" 7 NTT a NA | A F NT 0 . ~~ (0 FAA N = H 0 SLT F bi i E YY i p © “a 0 NTN Day = = 0 N— N—-NH Jy = oO / / S F TR ZF JL - [0 = NH . ag ie 1, R y 7 0 oo ( 4 F ND N—\ TN F NL oA { NN | F N 70g N a_i J N— F J and Ch S NS, IY F EF Nn H 0 N PN N7 NT ox" J { = Uy - N-NH NH 1 d Js Re Y HT 1 0 ys NS In certain embodiments the compound of the present invention is selected from: Ao AN "ON N i H Fl O 3 Da F rr o o AA Date’ a s Ao ul a { @' / z wD re F H i NL AA 3 SE Ao PRO E N—-NH i eo Po a, NTN ~ o NA FN At } ; TE F H N—-NH SQV A No Fert ) o Lda ) 2 Jo 9 H rs t NZ F ON H 3 Nl i 3 a CLOORO-O IY Ayo FT hat g N-NH A No eh N- AA LAT FN MI JAAN o Nl ok 0) 9 NAL ory H N—NH OC Po CIN Od #7 "NTN -~ N N o A Oo drs F NP N-NH i OC N Po Fr NCO : HOA dd Ts F NS N-NH CN A No a JN NY \ ov NI to MAI ND 2 3 AS F Z Hoh J NA H H ANT N\ N-N o NA A Se NH; AA HCE Ayo FT I I > F NTS NP 1! H i , H \ n N-N : ZN " \ F 0, \ ) % PAN )— NF / 02 F - F rN QP N__s, HOCH YD 0-2 PR So oo” ug H H NN N o 0 ha I N OORT Ayo F 1 ( H F 13 and \ H eS _ = F Q N NS . N— N— \ o |W SS Noes 7 N PT [oO In certain embodiments the compound of the present invention is selected from: mS i q TR ANA N~ N Re SHOO(3 J 3 N_ / F F 3 PL Ha (R04 3 bE " OO YD F 7 NWN pS oN > H oo NP 1 H \ mn nN = F oo LY 7 N Poo H H (R®).3 Q il s Soon Y LY, F NN N H ~ "eo Nh o Ry OY R-Fr Ayo Fh B F " n * N-NH i ~m 0 GN 0 = Ayo NO YY Hv F~ MN Nw § NA H ~ 3 N 2 20 F I> Por An s don, L © 9 H NN 0 N 40 N-N 2 f Yo-2 ! ~N AAO Po FT " => H ~POIATNON Wa OS So FT N= o NA H 40: 2 0 io R®R) ) g3 I Hp \ NN A ®%z Q “PH N A N. NNN S, AO 3 OO o WY Ao F F F: “N Tr H F F and (R®)o. o ‘ . / N NN oo N-N. 2 NON ~ \ ] Ao = N bl oo” nN INO NN ~ ON Cs é Dor In certain embodiments the compound of the present invention is selected from: 0 HK 2 NA > OD COO Yr F NN 0 o Qo NA ~~ Os N PAN H polit Sadia’ TO F NN 0 3 aad SOO 0 7 H PC OOTY —~ — N = o > 0 o 2 F \ = EF 0 N ° NN ad O10 0 “ HN - N Noy AH ad 7 Tr oO wo - 30 N: NY | ; R I'D F and 0 ') or Cl 5 NA O00 Mel Wo Tn CY wo FE F In certain embodiments the compound of the present invention is selected from: NN NA N ] ri F % E a Forcl y } TY wo p30 al CST Eokal F \ £ F Xx & F o Cl NN . NA 9 o— \ On MN Wi = N oN ad Foal © F and HN NS Jr Gh F000 E F F oer In certain embodiments the compound of the present invention is selected from: q R ~ 3 el SOOO TY H Q Tr Og OOO ry + O J NN 0 Q NA Q FT NO) N N AN 8 Op XX OCT NS F NN 0 Q HN— \ ov Mon A nN 3 Noy OOOOH F NN 0 . H wo = OH OOO ° F ND NP ForCl L § OO OO-O-CY o F and / “x AN For Cl Q My fy OOO AH N 7 5 / oo - un F HN F In certain embodiments the compound of the present invention is selected from: 9 Ar ~ § bv Wo ~( NO N N Nn i ORO NN F HN OA OY N N, N == Oo N 3 Ls == HN ForcCl FN N= HN d = r ForcCl F F / \_\ 3 CI "Nn ForCl and AS MN ForCl F In certain embodiments the compound of the present invention is selected from: NN H NJ -N 0 R Bh v~! F F oOo. H 3 1 Cry A N “v . . N r SOOO TO F noo B and F oH S$ N § a N LT Pn 3 $$ " he oy pd OH { = 5 0 90 F 1 R90 In certain embodiments the compound of the present invention is selected from: H N. oo Spt Ty oH N Yeo 0 A sol ew NAN IN iC ~ 0 1 Rn 7 9 SNS On > OOF o 17 °N oa H F F FN H NA -N_ A oo SH H Oy N a \ Tr wr J 0 N. § N N x” 0, OH " O-O-CH ) N hy : rg? YY H oo F H \ bs pe a a Sd J H HOO 80 My :. m x 5 oN 5 LR Na o Nn N S, AO OOO Y ph | \ X Ney OH E " ~N N NZ 7, H NN AN EF Oy 0 ~ F \ N— 4 / Fr , H N< N__S CS TO F F o. H Neo FE 5 Aq Q —\ ¢ WNL AN TN J MANY i / NN F F 5 I H N. N S, SOO TI OH F a N. oy K a 0 F QA A A NNN 0 ANNs — OOF TT Fr = “i F F oH NS NTN Ye x od N Nn Ns F H NN » NA~ ~ 7 oo 4 H o_ H MN. re yi FF on \ Se No AH —~ ol N an N__s LSP OO-O~=Y AD oH 7 " F nr F . . “NN Noo 2 YO 0 lr nN Nao ah H 4 SE = 0 FOO TE " NO LF Ia \ Fr % o. H T uy 3 0 0, AN NSS y OOO Y VY, Ney = \ oH . \ Oo H Mo F oo N—N_ A — o oN wy 3 u ve © NA NN 7h Q . . ‘ TSO COO H aN _N 7N 0 F NZ Yer 0 CN Oo H YN a Gall {- £30, ( 0 Tr N N Nn R Ox CO-O-CY oo F H . FZ © H F TY oH R NN Co 0 ANN ys CE ry oo TD T= - NE ot N — \ F HN. _O 0 H IN H 0 ox ¢ N_. / / New O QAM 3 0 N~ \=N 8) NX) —N - 8 F 1 Q, i NN Theo NA SY my Sy or TS OF COOH 0 1 F oH MN 7° oo N oN 9 PY A 500300 ris E F FN J N ~N. FZ \=0 = Bh vv oH YN Lr I F° o ’ I y O00 OC D N FY E F % 3 NN 0 H Oo H JN Ra N, / N\ 3 N Nn | R SOOO F and FN oH Yo > re Q Noy A A NN, N N N ¢ N S, Og 00-O-CFY oH IV. LINKERS A Linker (L' or L?) or a bond is included in the compounds of the present invention. Linker is a chemically stable bivalent group that attaches an E3 Ligase binding portion to an EGFR Targeting Ligand. According to the invention, any desired linker, as described herein, can be 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 itself is pharmaceutically acceptable. Linker as described herein can be used in either direction, i.e., either the left end is linked to the E3 Ligase binding portion and the right end to the EGFR Targeting Ligand, or the left end is linked to the EGFR Targeting Ligand and the right end is linked to the E3 Ligase binding portion. In certain embodiments Linker is a bond. In certain embodiments, the Linker has a chain of 2 to 14, 15, 16, 17, 18 or 20 or more carbon atoms of which one or more carbons can be replaced by a heteroatom such as O, N, S, or P. In certain embodiments the chain has 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous atoms in the chain. For example, the chain may include 1 or more ethylene glycol units that can be contiguous, partially contiguous or non-contiguous (for example, 2,3, 4,5,6,7,8,9, 10, 11 or 12 ethylene glycol units). In certain embodiments the chain has at least 1, 2, 3, 4, 5, 6, 7, or 8 contiguous chains which can have branches which can be independently alkyl, aryl, heteroaryl, alkenyl, or alkynyl, aliphatic, heteroaliphatic, cycloalkyl or heterocycle substituents. In other embodiments, the linker can include or be comprised of one or more of ethylene glycol, propylene glycol, lactic acid and / or glycolic acid. Lactic acid segments tend to have a longer half-life than glycolic acid segments. Block and random lactic acid-co-glycolic acid moieties, as well as ethylene glycol and propylene glycol, are known in the art to be pharmaceutically acceptable and can be modified or arranged to obtain the desired half-life and hydrophilicity. In certain aspects, these units can be flanked or interspersed with other moieties, such as aliphatic, including alkyl, heteroaliphatic, aryl, heteroaryl, heterocycle, cycloalkyl, etc., as desired to achieve the appropriate drug properties. In certain embodiments, L? is a linker selected from: Xo ARE R R X ed A Re ~N w x2 (LI). In one aspect, Linker (L?) is selected from the group consisting of a moiety of Formula LI, Formula LII, Formula LIII, Formula LIV, Formula LV, Formula LVI, Formula LVII Formula LVIIIL, Formula IX and Formula LX: A 2? 2 TN R25” R ~ ar Heteroa nL A XZ (LID), or LA i _-Hetero: aryl ~ R2” RL aN (LIID), Heteroaryl eroaryl R22 R20 p28” Spar” Le (LIV), A x1 R24 22 A J R Aryl x! gas” Net ~~ re (LV), - _ Ary — r2 RY oN (LVI), A » AY R28” 2. re” "2. re (LVID), RE a ” Hetero cyglyl A x2 { (LVIID), A RE w _ Heterocycly] R% of Ret” ~~ A X2© (LIX), and (LX); AL Heterocyclyl 22 X 1 op" A — ” R’ RZ rT gai” ON a ( wherein all variables are as defined herein. In certain embodiments, Linker (L?) is selected from: Re RZ Yo ~~ 2 1 X: SN re ~N Rr? In one aspect, Linker (L?) is selected from the group consisting of a moiety of Formula LDI, Formula LDII, Formula LDII, Formula LDIV, Formula LDV, Formula LDV], and Formula LDVII: eA Rt” RY a (LDI), A R22 Heteroaryl it” A xX (LDII), A _Heteroaryl 20 23 Np R R27 re (LDIII), R22 Aryl At” pet ~~ oe X (LDIV), A — Aryl 2 R23 ~~ re (LDV), A R22 Hetero _ cyclyl a Nee” ey A W { (LDVI), and A Heterocyclyl R ~~ ® ai A 47% A X2 { ~R% TRA XE (LDVID), wherein all variables are described herein. The following are non-limiting examples of Linkers that can be used in this invention. Based on this elaboration, those of skill in the art will understand how to use the full breadth of Linkers that will accomplish the goal of the invention. In certain embodiments L2 is selected from: fo] 0 NA o AN ov NN o AANA o SANNA SANNA Hod Hoy A A oO ANS [N_] oO LAA oN A H / NN o SAN ZF Hof A NN oO oA IT Bl | SN 0 ~~ _N. NTS SANS M0, M0, oO ANS PY FPN oN ONS 1 Li @ SoS rg TC MQ, Oo oh Am oN ONS oO Li SAN oO oN YY ©° NN NPN i NTS NNN o, pal Die ie LL oa et NUN 1 In certain embodiments L2 is selected from: YN oo YN © som oN Ww ™N DE LA, =N on A YY 9 SAAN 0 A } oA A } oA Ae CJ o CJ 0, 0. 0 O. Nr NY FOC QA, KOC, < oO YN oo oN oN CQ, NY oN y 0 “NA oN YON oO ‘NTN } ou Moo A > IT Bl | “oN 0 ~~ _N. NN 0 son A NS | NNN A F fo] FN OO oo A N Na N Ns AN “C, Nw Crs je 0 NY | So NN. | - Z fF NT o NN oo ANN 0 ANS I ~~ Aor | wT ~ om OH L. OH I NTS 0 L “hog CQ, Q, In certain embodiments L2 is selected from: oO “Ne AL BG <Q, Ln UL Q, Yoo ANN 0 YY © “AA nN J ry 7 Ed ’ N—N SANNA oO TA “, oO Oo DE NA + 0 oN I oy 0 I Fr NTS 0 SAN AN H N. ~# A oO oO ANS LL SoA oN ANS ob OH 1 H NTS 0 SAN AN H Nz xX NN Oo 3 "Cu ~~ N TQ, TC, In certain embodiments L2 is selected from: wk So ANA PN Tha d QC, © a RF AX o ANS 0 CF +S 0 ANS 0 “hy “Eo Le Bese NL 0 NN Oo THY ! Ton A JS © ; ANS 0 © Tt 400! Q, Q, ANTS LL NN Oo YN o Soh Ae NA NN SNA “A ~~ 2 ] 2 F oO AN ANN 1 4 NY 0 4 nA Bg, Ody CQ, ANN NN ° sob AN OH I No ok 0 NN Oo ANN o ANAS o a, tg, SANSA SANS 1 OH UN OH wl TY oN o SN Ns Cy, TQ, o YN © oN “So xy QQ, 0 SNTN oo TY Nl Ff 4 and ANS NT A OH Yn, <a In certain embodiments L2 is selected from: es R R R N R25 < ~~ C pe yy x1” 2 RS ~~ 9 wl” yr yy ~ = a ~~ A xt” RC 27% IN x” i" RS rel” 2 . A o 2 R24 ~N re = ~N, rel” 0 XE o AA NS x17 N i 22 ~~ re” rb Oo Aaa x Nr x R 2 R% N ~N. \ Re” J 2A | A RE ’ x” Rt IY Ee ry I A _R% "so re Sga-N or x RZ RZ N A Nga” Spat” ¢ 1 No N x2 NYY N 0 In certain embodiments L2 is selected from: Pa Po Y 2g Tall 2 : 2 Wa ~ Nr oN ~ rz R% ~N re 21 xe 1 1 R22 , At Nee ~ rN «C0, A Ln XE oO Aa 0 Aaa Lo N. - R22 ~N \ Re x a R22 A N. \ R21” ort and | N ARE AY 9 R25 Np 7 ] AEA re Spe R21 | E N 2 N x2 NYY N_~ oO R23 Sy, : RX Non-limiting examples of moieties of R%, R?!, R?2, R? and R?* include: [eo] 0 0 Jor Joa op Farming parang Fasano dy andy rd dn aby SA IX Ay AS Ay A AY vo yy AAA A fo ho Amro Ov XY Xo AA A AA o Ay H Additional non-limiting examples of moieties of R?°, R?!, R?2, R¥, and R?* include: 0 5 1 ox 0 o | | SA XS Ae Ay ha 1 Bh 0 o o ~~ j rh NA Ol AA AN Agen Oy A od NI AA \ JE JO HOO JINR SLE Additional non-limiting examples of moieties of R?°, R?!, R?2, R¥, and R?* include: — ~ A a / Cf Fem 4 NH CN Ay Ay 00, "C0 C0 00 ROO SO In additional embodiments, the Linker (L?) moiety is an optionally substituted (poly)ethylene glycol having at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, ethylene glycol units, or optionally substituted alkyl groups interspersed with optionally substituted, O, N, S, P or Si atoms. In certain embodiments, the Linker (L2) is flanked, substituted, or interspersed with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocycle group. In certain embodiments, the Linker (L?) may be asymmetric or symmetrical. In certain embodiments, Linker (L?) can be a nonlinear chain, and can be, or include, aliphatic or aromatic or heteroaromatic cyclic moieties. In any of the embodiments of the compounds described herein, the Linker group may be any suitable moiety as described herein. In certain embodiments, the Linker (L?) is selected from the group consisting of: A AA 6 NA 9 TN AA H Q A ANA AAAS aA o oY WAN NA AQ TN ANN H Q y SS oA yr? C=O H he \ H \ | I NA XIN 0 ~ rx 3 No ~~ v7 2 H Q H N od A yg =o deo Yo, TOL, H H 0 and “On oO H “Oe, d w IT I du antmrrad Term In certain embodiments, the linker (L2) is selected from the group consisting of: ~~ or TI WTA 0 “2 NY An \ al Bh NN MY Da 2 YX CAAA XY ~ Ss o TD JO XX yi ak A / Ns ff NC et Ax A A “NN 0 ~ 0 NY YY SAA "CO y Ny 0 SI and In certain embodiments, the linker (L?) is selected from the group consisting of: [eo] H O H H H © H Oo H 0 H oO i i Hoo ANS Ap NSA ANY AEA Sou Li Joi ai er A H O H O H O H H O H O H Appr ai € Jou > ai H O H O H O H © H H oO H 0 H fp ApH oo H o H Oo H h Oo B NS A A AISA H O H O H O H H Oo 1 It o ANSASASSA 0! AAS H oO | N J H ASA H H O H H 1 oN © I oo CY hg OA ON a J SoA I I | Argo NY Aoi aol * J) H O H O H AN YY oO AA Woo ANNA 0 ANNA ANA al 1 MH al 1 I 7 gs al a { 0 ANNA PW N_ ANY 1 H Hay AA H H H © 0 oO ov ov AAA Hoo AIASAA OO + .N. HAA ~ oO Pi Shas XN A 3 WY \ 0 NA yor AA he ¥ fi AT AY H O TN 0 0 sedlpgod aN H H o o Asses AA Hb gy H 0 Hoo As pl Oy NN o or nA | H 0 | TN x H id H © Ed In certain embodiments, the linker (L?) is selected from the group consisting of: 0 o ANNA AN AA ANN ON Oo JOE NSA i Joo _ ] N Or S$ YY v ~~ Oo 0 oO wh os © 0 J vo A Ay N_~ H WN © ATA Ns ON MN 0 AA A AA ad Nr oY Na J AS af NS H o ANNA OA AA oO oO A N_ © Ns Ns oY NS Ja oS 9 AAA AIA 0 Nr ~~ i \ MN $i I Or Noha a 0 ~ \ } So CA AN She X ~ SN ve J Mr 7 \ J vw i ih Oo FN FN rN g [EL CONT N Kv FN NH Ho 0 NA 0 0 0 AAA AAA AGA N ANA OA ASA ; JT oy JT JK and ; \ NN xX 4 oe ANA 0 (WN In certain embodiments, the linker (L2) is selected from the group consisting of: CONTR NT NT NA N° A bo a) X ~ NN Fr IN A KX H H xi 1 eS 0 oO NN oo AN - AN o H H ~ ~ N N ox OY Tr JY oO 9 AA i 1b Ny #* an A oo A oo N ae AY H Oo 0 oO 0 TY or vy ory \N NA Nr Nr for X ~ 9 | N WN Nf Nr NN Nr Nr H A AYN YY ony 0 . Ca 0 XC) Cro WT ROH » Wie Oo ~Py H I~ Ay H OY yi NO “2 H O ANA a 3 2 NSN 1 H oO Ns oY XN Q Q / / IN AN PN N and NAN V2 VATE THUR PURE IF . TR RE ST SY N— ~~ B— N— Fo - MN / ln of J rT rT TH ad TH In certain embodiments, the linker (L2) is selected from the group consisting of: N 7 \ a JN N— ~y- 7 yd ~ Ny VARNA ii. Fr IN T= / J [ o N — M— \— yy 4 . of — H— N N N-N Or ry “> my ’ TN ’ a \ V / A N— — HN N— ast JN Ne 7 NN We <_ oO N pat ~~ N po AT "-e IN d \ = / JN o N, ¢g MN , —\ OH N— — HN J >" Ny Wf ~HA ME A I a = — » - fr a of wil > N— 7 J ~3N ~ A { HL a rn so Teg J LS F \ N— oo — H— N— \ FT Jn Ao Noaad / LF { = ~~ ay NH / Jr o pr = / IN o \ N— x / ~ ~~ ~~ ~ MM pra (M4 HN / Ih > 7 N wt / or N | 0) ad / \ N— \ J °c o co and FE IN_ he F ~ / Ty NH Va J In certain embodiments, the linker (L2) is selected from the group consisting of: ! Nn N— HOC LO yl IN oO \ = Co — / Vv VV JN LOO HAH ~—N f JN 7 \ oo LH-OA4 nl _ vv —N b-| 1 habe! \ and \ In certain embodiments linker (L?) or a portion thereof is selected from: 0 0 0, o HN: Q amd — 3 AI CL ~~ — TH Ng x. wd. X No XH De Ne) 2% aly, Ca “Bu ol, HOH oe H a GC A WNC NY ae ne * 0 Q Qty Tp Oy pO ky OOH OOH WO ob V. METHODS OF TREATMENT A compound of the present invention can be used in an effective amount to treat a patient, in need thereof, or to treat any disorder mediated by EGFR. Another aspect of the present invention provides a compound as described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition, for use in the manufacture of a medicament for treating or preventing cancer in a patient in need thereof, wherein there is a need of EGFR inhibition for the treatment or prevention of cancer. In one aspect, a compound 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 found in exon 18, exon 19, exon 20, or exon 21, or any combination thereof. In certain nonlimiting embodiments, the mutation is at position L858, E709, G719, C797, L861, T790, or L718 or any combination thereof. In certain embodiments the mutation is a L858R, T790M, L718Q, L792H, and / or a C797S mutation or any combination thereof, In certain aspects, the cancer has developed one or more EGFR mutations following treatment with at least one EGFR inhibitor that can be a non-covalent inhibitor (including but not limited to gefitinib, erlotinib, lapatinib or vandetanib) or a covalent inhibitor (such as afatinib, osimertinib or dacomitinib). In another aspect, the cancer has developed one or more EGFR mutations following treatment with an antibody such as cetuximab, panitumab or necitumab. In yet another aspect, the cancer has one or more EGFR mutations or non-EGFR mutations that renders the cancer intrinsically resistant to EGFR inhibitor treatment, for example, a somatic exon 20 insertion, asomatic PIK3CA mutation, loss of PTEN expression, MET amplification, or a KRAS mutation. In certain embodiments, a compound of the present invention is used to treat a cancer that is resistant to, or has acquired a resistance to, a first generation EGFR inhibitor such as erlotinib, gefitinib, and / or lapatinib. In certain embodiments, a compound of the present invention is used to treat a cancer that is resistant to, or has acquired a resistance to a second generation EGFR inhibitor such as afatinib and / or dacomitinib. In certain embodiments, a compound of the present invention is used to treat a cancer that is resistant to, or acquired a resistance to a third generation EGFR inhibitor such as osimertinib. In some embodiments, the mutated EGFR protein in the diseased tissue has an L858 mutation, for example L858R. In certain embodiments the compound of the present invention is used to treat a mutant EGFR mediated disorder, wherein EGFR has a mutation at one of the below listed amino acid sites. The mutation may, for example, be selected from one of the listed exemplary mutations, or may be a different mutation. Amino Acid Exemplary Mutations C797 “Jers E709 “E7094, E709G, E709K, ET09V G719 GT719A, G7198, G719C, G719D G724 G724S G119 G119A G796 G7968, G796C L718 L718V,L718Q L792 L792H, L792V 1858 L858R L861 L861Q S768 $7681 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 one additional mutation which 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 mutation that may optionally be selected from the table above. In other embodiments the mutant EGFR mediated disorder has a L858R mutation and three additional mutation that ‘may optionally be selected from the table above. In certain embodiments the mutant EGFR mediated disorder has a T790M mutation and one additional mutation optionally selected from the table above. In other embodiments the mutant EGFR mediated disorder has a T790M mutation and two additional mutation optionally selected from the table above. In other embodiments the mutant EGFR mediated disorder has a T790M mutation and three additional mutation optionally selected from the table above. In certain embodiments the mutant EGFR mediated disorder has a L718Q mutation and one additional mutation optionally selected from the table above. In other embodiments the mutant EGFR mediated disorder has a L718Q mutation and two additional mutation optionally selected from the table above. In other embodiments the mutant EGFR mediated disorder has a L718Q mutation and three additional mutation 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, G7968S, 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 an exon 19 deletion. In certain embodiments, the exon 19 deletion is a deletion which includes the amino acids LREA (L747-A750). In certain embodiments, the exon 19 deletion is a deletion which includes the amino acids ELREA (E746-A750). In certain embodiments a compound 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 mutated EGFR than 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 a E709 mutation, for example E709A, E709G, E709K, or E709V. In certain embodiments a compound of the present invention is used to treat EGFR with a 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 exon 19 insertions and / or one or more exon 20 insertions. In certain embodiments, a compound of the present invention is used to treat $7681 mutant EGFR cancer. In certain embodiments a compound of the present invention is used to treat EGFR L861Q mutant EGFR 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 a L718Q, L858R mutant EGFR cancer. In certain embodiments a compound of the present invention is used to treat a 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, and / or 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, to a patient in need thereof. 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, the patient is administered an additional therapeutic agent. 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 degraders of EGFR, the compounds and compositions of this application are particularly useful for treating or lessening the severity of a disease, condition, or disorder where a EGFR is implicated in the disease, condition, or disorder. In one aspect, the present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where EGFR is implicated 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 pharmaceutically acceptable carrier to a patient in need thereof. 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 proliferation disease. In certain embodiments, the EGFR mediated disorder is an abnormal cell proliferation, including, but not limited to, a solid or hematoligical cancer. In certain embodiments, the hematological cancer is acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), lymphoblastic T-cell leukemia, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), hairy-cell leukemia, chronic neutrophilic leukemia (CNL), acute lymphoblastic T-cell leukemia, acute monocytic leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, mixed lineage leukemia (MLL), erythroleukemia, malignant lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, lymphoblastic T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, B cell acute lymphoblastic leukemia, diffuse large B cell lymphoma, Myc and B-Cell Leukemia (BCL)2 and / or BCL6 rearrangements / overexpression [double- and triple-hit lymphoma], myelodysplastic / myeloproliferative neoplasm, mantle cell lymphoma including bortezomib resistant mantle cell lymphoma. 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 castrate resistant prostate cancer (CRPC), brain cancers including gliomas, glioblastomas, neuroblastoma, and medulloblastoma including MYC-amplified medulloblastoma, colorectal cancers, Wilm's tumor, Ewing's sarcoma, rhabdomyosarcomas, ependymomas, head and neck cancers, melanomas, squamous cell carcinomas, ovarian cancers, pancreatic cancers including pancreatic ductal adenocarcinomas (PDAC) and pancreatic neuroendocrine tumors (PanNET), osteosarcomas, giant cell tumors of bone, thyroid cancers, bladder cancers, urothelial cancers, vulval cancers, cervical cancers, endometrial cancers, mesotheliomas, esophageal cancers, salivary gland cancers, gastric cancest, nasopharangeal cancers, buccal cancers, cancers of the mouth, GIST (gastrointestinal stromal tumors), NUT-midline carcinomas, testicular cancers, squamous cell carcinomas, hepatocellular carcinomas (HCC), MYCN driven solid tumors, and NUT midline carcinomas (NMC). In further embodiments, the disease or disorder is sarcoma of the bones, muscles, tendons, cartilage, nerves, fat, or blood vessels. In further embodiments, the disease or disorder is soft tissue sarcoma, bone sarcoma, or osteosarcoma. In further embodiments, the disease or disorder is angiosarcoma, fibrosarcoma, liposarcoma, leiomyosarcoma, Karposi's sarcoma, osteosarcoma, gastrointestinal stromal tumor, synovial sarcoma, pleomorphic sarcoma, chondrosarcoma, Ewing's sarcoma, reticulum cell sarcoma, meningiosarcoma, botryoid sarcoma, rhabdomyosarcoma, or embryonal rhabdomyosarcoma. In certain embodiments the disorder is a bone, muscle, tendon, cartilage, nerve, fat, or blood vessel sarcoma. In further embodiments, the disease or disorder is multiple myeloma. In certain embodiments a compound of the present invention or a pharmaceutically acceptable salt thereof is used as a medicament in therapeutic and / or prophylactic treatment of a patient with EGFR activating mutations as determined by next-generation sequencing (NGS), suffering from cancer, in particular non-small-cell lung cancer, comprising determining the EGFR activating mutations status in said patient and then administering the compound 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, spondyiarthropathies, gouty arthritis, osteoarthritis, juvenile arthritis, and other arthritic conditions, neurcinflammation, allergy, pain, neuropathic pain, fever, pulmonary disorders, lung inflammation, adult respiratory distress chronic pulmonary inflammatory 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 vs. host reaction and allograft rejections, cancer, leukemia, lymphoma, colorectal cancer, brain cancer, bone cancer, epithelial call-derived neoplasia (epithelial carcinoma), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, squamous cell and / or basal cell cancers, prostate cancer, renal cell carcinoma, and other known cancers that affect epithelial cells throughout the body, chronic myelogenous leukemia (CML), acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL), angiogenesis including neoplasia, metastasis, central nervous system disorders, central nervous system disorders having 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, pancreas cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck squamous cell carcinoma, leukemias, lymphomas, myelomas, solid tumors, hematological cancers or solid cancers. 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 other 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 and hyperproliferative diseases include, without limitation, cancer. The term "cancer" includes, but is not limited to, the following cancers: breast; ovary; cervix; prostate; testis, genitourinary tract; esophagus; larynx, glioblastoma; neuroblastoma; stomach; skin, keratoacanthoma, lung, epidermoid 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 carcinoma and biliary passages; kidney carcinoma, myeloid disorders; lymphoid disorders, Hodgkin's, hairy cells; buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx; small intestine; colonrectum, 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 cancers: myeloma, lymphoma, or a cancer selected from gastric, renal, or and the following cancers: head and neck, oropharangeal, non-small cell lung cancer (NSCLC), endometrial, hepatocarcinoma, Non-Hodgkins lymphoma, and pulmonary. The term "cancer" refers to any cancer caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas and the like. For example, cancers include, but are not limited to, mesothelioma, leukemias and lymphomas such as cutaneous T-cell lymphomas (CTCL), noncutaneous peripheral T-cell lymphomas, lymphomas associated with human T-cell lymphotrophic virus (HTLV) such as adult T-cell leukemia / lymphoma (ATLL), B-cell lymphoma, acute nonlymphocytic leukemias, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, lymphomas, and multiple myeloma, non-Hodgkin lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), Hodgkin's lymphoma, Burkitt lymphoma, adult T- cell leukemia lymphoma, acute-myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma. Further examples include myelodisplastic syndrome, childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, and soft-tissue sarcomas, common solid tumors of adults such as head and neck cancers, such as oral, laryngeal, nasopharyngeal and esophageal, genitourinary cancers, such as prostate, bladder, renal, uterine, ovarian, testicular, lung cancer, such as small-cell and non-small cell, breast cancer, pancreatic cancer, melanoma and other skin cancers, stomach cancer, brain tumors, tumors related to Gorlin's syndrome, such as medulloblastoma or meningioma, and liver cancer. Additional exemplary forms of cancer include, but are not limited to, cancer of skeletal or smooth muscle, stomach cancer, cancer of the small intestine, rectum carcinoma, cancer of the salivary gland, endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer. Additional cancers that the compounds described herein may be useful in preventing, treating and studying are, for example, colon carcinoma, familiary adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer, or melanoma. Further, cancers include, but are not limited to, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, thyroid cancer (medullary and papillary thyroid carcinoma), renal carcinoma, kidney parenchyma carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, testis carcinoma, urinary carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, gall bladder carcinoma, bronchial carcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma, choroidea melanoma, seminoma, rhabdomyosarcoma, craniopharyngeoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma, and plasmocytoma. In one aspect of the application, the present application provides for the use of one or more compound as described herein, in the manufacture of a medicament for the treatment of cancer, including without limitation the various types of cancer disclosed herein. In some embodiments, 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 mast cell disease. In some embodiments, the compound as described herein is useful for treating hematopoietic disorders, in particular, acute-myelogenous leukemia (AML), chronic-myelogenous leukemia (CML), acute- promyelocytic leukemia, and acute lymphocytic leukemia (ALL). In certain embodiments, a compound or its corresponding pharmaceutically acceptable salt, or isotopic derivative, as described herein can be used in an effective amount to treat a host, for example a human, with a lymphoma or lymphocytic or myelocytic proliferation disorder or abnormality. For example, a compound as described herein can be administered to a host suffering from a Hodgkin’s Lymphoma or a Non-Hodgkin’s Lymphoma. For example, the host can be suffering from a Non-Hodgkin’s Lymphoma such as, but not limited to: an AIDS-Related Lymphoma; Anaplastic Large-Cell Lymphoma; Angicimmunoblastic Lymphoma; Blastic NK-Cell Lymphoma; Burkitt’s Lymphoma; Burkitt-like Lymphoma (Small Non-Cleaved Cell Lymphoma); diffuse small-cleaved cell lymphoma (DSCCL); Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma; Cutaneous T-Cell Lymphoma; Diffuse Large B-Cell Lymphoma; Enteropathy-Type T-Cell Lymphoma; Follicular Lymphoma; Hepatosplenic Gamma-Delta T-Cell Lymphoma; Lymphoblastic Lymphoma; Mantle Cell Lymphoma; Marginal Zone Lymphoma; Nasal T-Cell Lymphoma; Pediatric Lymphoma; Peripheral T-Cell Lymphomas; Primary Central Nervous System Lymphoma; T-Cell Leukemias; Transformed Lymphomas; Treatment-Related T-Cell Lymphomas; Langerhans cell histiocytosis; or Waldenstrom's Macroglobulinemia. In another embodiment, a compound or its corresponding pharmaceutically acceptable salt, or isotopic derivative, as described herein can be used in an effective amount to treat a patient, for example a human, with a Hodgkin’s lymphoma, such as, but not limited to: Nodular Sclerosis Classical Hodgkin's Lymphoma (CHL); Mixed Cellularity CHL; Lymphocyte- depletion CHL; Lymphocyte-rich CHL; Lymphocyte Predominant Hodgkin’s Lymphoma; or Nodular Lymphocyte Predominant HL. This application further embraces the treatment or prevention of cell proliferative disorders such as hyperplasias, dysplasias and pre-cancerous lesions. Dysplasia is the earliest form of pre-cancerous lesion recognizable in a biopsy by a pathologist. The compounds may be administered for the purpose of preventing said hyperplasias, dysplasias or pre-cancerous lesions from continuing to expand or from becoming cancerous. Examples of pre-cancerous lesions may occur in skin, esophageal tissue, breast and cervical intra-epithelial tissue. As inhibitors of EGFR protein, the compounds and compositions of this application are also useful in biological samples. One aspect of the application is inhibiting protein activity in a biological sample, which method comprises contacting said biological sample with a compound or composition as described herein. The term "biological sample", as used herein, means an in vitro or an ex vivo sample, including, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. Inhibition of protein activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ- transplantation, and biological specimen storage. Another aspect of this application is the study of EGFR protein in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such proteins; and the comparative evaluation of new protein inhibitors. Examples of such uses include, but are not limited to, biological assays such as enzyme assays and cell-based assays. In accordance with the foregoing, the present application further provides a method for preventing or treating any of the diseases or disorders described above in a patient in need of such treatment, which method comprises administering to said patient a therapeutically effective amount of a compound as described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, or solvate thereof. For any of the above uses, the required dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired. VI. COMBINATION THERAPY The disclosed compounds described herein can be used in an effective amount alone or in combination with another compound 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 selected compound according to the present invention, which can be used in combination or alternation with a compound of the present invention to achieve a desired result of therapy. In certain embodiments, the compound of the present invention and the bioactive agent are administered in a manner that they are active in vivo during overlapping time periods, for example, have time-period overlapping Cmax, Tmax, AUC or another pharmacokinetic parameter. In another embodiment, the compound of the present invention and the bioactive agent are administered to a patient in need thereof that do not have overlapping pharmacokinetic parameter, however, one has a therapeutic impact on the therapeutic efficacy of the other. In one aspect of this embodiment, the bioactive agent is an immune modulator, including but not limited to a checkpoint inhibitor, including as non-limiting examples, a PD- 1 inhibitor, PD-L1 inhibitor, PD-L2 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, TIM-3 inhibitor, V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, small molecule, peptide, nucleotide, or other inhibitor. In certain aspects, the immune modulator is an antibody, such as a monoclonal antibody. PD-1 inhibitors that blocks the interaction of PD-1 and PD-L1 by binding to the PD-1 receptor, and in turn inhibit immune suppression include, for example, nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab, AMP-224 (AstraZeneca and MedImmune), PF- 06801591 (Pfizer), MEDIO680 (AstraZeneca), PDR001 (Novartis), REGN2810 (Regeneron), SHR-12-1 (Jiangsu Hengrui Medicine Company and Incyte Corporation), TSR-042 (Tesaro), and the PD-L1 / VISTA inhibitor CA-170 (Curis Inc.). PD-L1 inhibitors that block the interaction of PD-1 and PD-L1 by binding to the PD-L1 receptor, and in turn inhibits immune suppression, include for example, atezolizumab (Tecentriq), durvalumab (AstraZeneca and MedImmune), KNO35 (Alphamab), and BMS-936559 (Bristol-Myers Squibb). CTLA-4 checkpoint inhibitors that bind to CTLA-4 and inhibits immune suppression include, but are not limited to, ipilimumab, tremelimumab (AstraZeneca and MedImmune), AGEN1884 and AGEN2041 (Agenus). LAG-3 checkpoint inhibitors include, but are not limited to, BMS- 986016 (Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), IMP321 (Prima BioMed), LAGS525 (Novartis), and the dual PD-1 and LAG-3 inhibitor MGDO013 (MacroGenics). An example of a TIM-3 inhibitor is TSR-022 (Tesaro). 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 / Ig fusion protein such as AMP 224 or an inhibitor of B7-H3 (e.g., MGA271 ), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG 3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands, or a combination thereof. In yet another embodiment, one of the active compounds described herein can be administered in an effective amount for the treatment of abnormal tissue of the female reproductive system such as breast, ovarian, endometrial, or uterine cancer, in combination or alternation with an effective amount of an estrogen inhibitor including, but not limited to, a SERM (selective estrogen receptor modulator), a SERD (selective estrogen receptor degrader), a complete estrogen receptor degrader, or another form of partial or complete estrogen antagonist or agonist. Partial anti-estrogens like raloxifene and tamoxifen retain some estrogen- like effects, including an estrogen-like stimulation of uterine growth, and also, in some cases, an estrogen-like action during breast cancer progression which actually stimulates tumor growth. In contrast, fulvestrant, a complete anti-estrogen, is free of estrogen-like action on the uterus and is effective in tamoxifen-resistant tumors. Non-limiting examples of anti-estrogen compounds are provided in WO 2014 / 19176 assigned to Astra Zeneca, W02013 / 090921, WO 2014 / 203129, WO 2014 / 203132, and US2013 / 0178445 assigned to Olema Pharmaceuticals, and U.S. Patent Nos. 9,078,871, 8,853,423, and 8,703, 810, as well as US 2015 / 0005286, WO 2014 / 205136, and WO 2014 / 205138. Additional non-limiting examples of anti-estrogen compounds include: SERMS such as anordrin, bazedoxifene, broparestriol, chlorotrianisene, clomiphene citrate, cyclofenil, lasofoxifene, ormeloxifene, raloxifene, tamoxifen, toremifene, and fulvestratnt; aromatase inhibitors such as aminoglutethimide, testolactone, anastrozole, exemestane, fadrozole, formestane, and letrozole; and antigonadotropins such as leuprorelin, cetrorelix, 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 according to the present invention are described in U.S. Patent Nos. 4,418,068; 5,478,847; 5,393,763; and 5,457,117, WO02011 / 156518, US Patent Nos. 8,455,534 and 8,299,112, U.S. Patent Nos. 9,078,871; 8,853,423; 8,703,810, US 2015 / 0005286; and WO 2014 / 205138, US2016 / 0175289, US2015 / 0258080, WO 2014 / 191726, WO 2012 / 084711; WO 2002 / 013802; WO 2002 / 004418, WO 2002 / 003992; WO 2002 / 003991; WO 2002 / 003990; WO 2002 / 003989; WO 2002 / 003988, WO 2002 / 003986, WO 2002 / 003977, WO 2002 / 003976; WO 2002 / 003975; WO 2006 / 078834; US 6821989; US 2002 / 0128276; US 6777424; US 2002 / 0016340; US 6326392; US 6756401; US 2002 / 0013327; US 6512002; US 6632834; US 2001 / 0056099; US 6583170; US 6479535, WO 1999 / 024027; US 6005102; EP 0802184; US 5998402; US 5780497, US 5880137, WO 2012 / 048058 and WO 2007 / 087684. In another embodiment, active compounds described herein can be administered in an effective amount for the treatment of abnormal tissue of the male reproductive system such as prostate or testicular cancer, in combination or alternation with an effective amount of an androgen (such as testosterone) inhibitor including, but not limited to a selective androgen receptor modulator, a selective androgen receptor degrader, a complete androgen receptor degrader, or another form of partial or complete androgen antagonist. In certain embodiments, the prostate or testicular cancer is androgen-resistant. Non-limiting examples of anti-androgen compounds are provided in WO 2011 / 156518 and US Patent Nos. 8,455,534 and 8,299,112. Additional non-limiting examples of anti- androgen 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- TAEG684), GSK1838705A, AZD3463, ASP3026, PF-06463922, entrectinib (RXDX-101), and AP26113. In certain embodiments, the bioactive agent is an HER-2 inhibitor. Examples of HER- 2 inhibitors include trastuzumab, lapatinib, ado-trastuzumab emtansine, and pertuzumab. In certain embodiments, the bioactive agent is a CD20 inhibitor. Examples of CD20 inhibitors include obinutuzumab, 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-1- en-1-yl]methyl]piperazin-l-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4- yl)methyl]amino]phenyl]sulfonyl]-2-[(IH- pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), ABT- 737 (4-[4-[[2-(4-chlorophenyl)phenylJmethyl]piperazin-1-yl]-N-[4- [[(2R)-4- (dimethylamino)-1-phenylsulfanylbutan-2-yl] ~amino]-3- nitrophenyl]sulfonylbenzamide) (navitoclax), ABT-263 ((R)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[l, 1'-biphenyl]- 2-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)- 3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide), GX15-070 (obatoclax mesylate, (22)-2-[(5Z)-5-[(3,5- dimethyl-IH-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2- ylidene]indole; methanesulfonic acid))), 2-methoxy-antimycin A3, YC137 (4-(4,9-dioxo-4,9- dihydronaphtho[2,3-d]thiazol-2-ylamino)-phenyl ester), pogosin, ethyl 2-amino-6-bromo-4- (1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate, Nilotinib-d3, TW-37 (N-[4-[[2- (1,1-Dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4-trihydroxy-5-[[2-(1- methylethyl)phenyl]methyl]benzamide), Apogossypolone (ApoG2), HA14-1, ATIO01, sabutoclax, gambogic acid, or G3139 (Oblimersen). In certain embodiments, the bioactive agent is a kinase inhibitor. In certain embodiments, the kinase inhibitor is selected from a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton’s tyrosine kinase (BTK) inhibitor, or a spleen tyrosine kinase (Syk) inhibitor, or a combination thereof. Examples of PI3 kinase inhibitors include, but are not limited to, Wortmannin, demethoxyviridin, perifosine, idelalisib, Pictilisib , Palomid 529, ZSTK474, PWT33597, CUDC-907, and AEZS-136, duvelisib, GS-9820, BKM120, GDC-0032 (Taselisib) (2-[4-[2- (2-Isopropyl-5-methyl-1,2,4-triazol-3-yl)-5,6-dihy droimidazo[ 1,2-d][1,4]benzoxazepin-9- yl]pyrazol-1-yl]-2-methylpropanamide), MLN-1117 ((2R)-1-Phenoxy-2-butanyl hydrogen (S)-methylphosphonate; or Methyl(oxo) {[(2R)-I-phenoxy-2-butanyl]oxy }phosphonium)), BYL-719 ((28)-N1-[4-Methyl-5-[2-(2,2,2-trifluoro-1, 1-dimethylethyl)-4-pyridiny1]-2- thiazolyl]-1,2-pyrrolidinedicarboxamide), GSK2126458 (2,4-Difluoro-N-{2-(methyloxy)-5- [4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl }benzenesulfonamide) (omipalisib), TGX-221 ((£)-7-Methyl-2-(morpholin-4-y1)-9-(1-phenylaminoethyl)-pyrido[l,2-a]-pyrimidin-4-one), GSK2636771 (2-Methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H- benzo[d]imidazole-4-carboxylic acid dihydrochloride), KIN-193 ((R)-2-((1-(7-methyl-2- morpholino-4-oxo-4H-pyrido[ 1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid), TGR- 1202 / RP5264, GS-9820 «S)- 1-(4-((2~(2-aminopyrimidin-5-yl)-7-methyl-4- mohydroxypropan- 1 -one), GS-1101 (5-fluoro-3-phenyl-2-([S)]-1-[9H-purin-6-ylamino]- propyl)-3H-quinazolin-4-one), AMG-319, GSK-2269557, SAR245409 (N-(4-(N-(3-((3,5- dimethoxyphenyl)amino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4 methylbenzamide), BAY80-6946 (2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[l,2- c]quinaz), AS 252424 (5-[1-[5-(4-Fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]- thiazolidine-2,4-dione), CZ 24832 (5-(2-amino-8-fluoro-[1,2,4]triazolo[l,5-a]pyridin-6-y1)-N- tert-butylpyridine-3-sulfonamide), Buparlisib (5-[2,6-Di(4-morpholinyl)-4- pyrimidinyl]-4- (trifluoromethyl)-2-pyridinamine), GDC-0941 (2-(1H-Indazol-4-yl)-6-[[4-(methylsulfonyl)-1- piperazinylJmethyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine), GDC-0980 ((S)-1-(4-((2-(2- aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6 yl)methyl)piperazin-1- yl)-2-hydroxypropan-l-one (also known as RG7422)), SF1126 ((8S,14S,17S)-14- (carboxymethyl)-8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15-pentaoxo-1-(4-(4- oxo-8-phenyl-4H-chromen-2-yl)morpholino-4-ium)-2-oxa-7,10,13,16-tetraazaoctadecan-18- oate), PF-05212384 (N-[4-[[4-(Dimethylamino)-1- piperidinyl]carbonyl]phenyl]-N'-[4-(4,6- di-4-morpholinyl-1,3,5-triazin-2-yl)phenylJurea) (gedatolisib), LY3023414, BEZ235 (2- Methyl-2-{4-[3-methyl-2-0x0-8-(quinolin-3-yl)-2,3-dihydro-lH-imidazo[4,5-c]quinolin-1- yl]phenyl}propanenitrile) (dactolisib), XL-765 (N-(3-(N-(3-(3,5- dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide), and GSK1059615 (5-[[4-(4-Pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidenedione), PX886 ([(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylidene]-5-hydroxy-9- (methoxymethyl)-9a,11a-dimethyl-1,4, 7-triox0-2,3,3a,9,10,11- hexahydroindeno[4,5h]isochromen- 10-yl] acetate (also known as sonolisib)), LY294002, AZD8186, PF-4989216, pilaralisib, GNE-317, PI-3065, PI-103, NU7441 (KU-57788), HS 173, VS-5584 (SB2343), CZC24832, TG100-115, A66, YM201636, CAY10505, PIK-75, PIK-93, AS-605240, BGT226 (NVP-BGT226), AZD6482, voxtalisib, alpelisib, IC-87114, TGI100713, CH5132799, PKI-402, copanlisib (BAY 80-6946), XL 147, PIK-90, PIK-293, PIK-294, 3-MA (3-methyladenine), AS-252424, AS-604850, apitolisib (GDC-0980; RG7422). Examples of BTK inhibitors include ibrutinib (also known as PCI- 32765)(Imbruvica™)(1-[(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1- yl]piperidin-1-yl]prop-2-en-1-one), dianilinopyrimidine-based inhibitors such as AVL-101 and AVL-291 / 292 (N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4- yl)amino)phenyl)acrylamide) (Avila Therapeutics) (see US Patent Publication No 2011 / 0117073, incorporated herein in its entirety), Dasatinib ([N-(2-chloro-6-methylphenyl)- 2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5- carboxamide], LFM-A13 (alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-ibromophenyl) propenamide), GDC-0834 ([R-N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)- 4-methyl-5-ox0-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7- tetrahydrobenzo[b]thiophene-2-carboxamide], CGI-560 4-(tert-butyl)-N-(3-(8- (phenylamino)imidazo[1,2-a]pyrazin-6-yl)phenyl)benzamide, CGI-1746 (4-(tert-butyl)-N-(2- methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo0-4,5-dihydropyrazin- 2-yl)phenyl)benzamide), CNX-774 (4-(4-((4-((3-acrylamidophenyl)amino)-5- fluoropyrimidin-2-yl)amino)phenoxy)-N-methylpicolinamide), CTA056 (7-benzyl-1-(3- (piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo[4,5-g]quinoxalin-6(5H)-one), GDC-0834 ((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5- ox0-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2- carboxamide), GDC-0837 ((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2- yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7- tetrahydrobenzo[b]thiophene-2-carboxamide), HM-71224, ACP-196, ONO-4059 (Ono Pharmaceuticals), PRT062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2- aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), QL-47 1-(1- acryloylindolin-6-y1)-9-(1-methyl-1H-pyrazol-4-yl)benzo[h][ 1,6 Jnaphthyridin-2(1H)-one), and RN486 (6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl- piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl } -phenyl)-2H-isoquinolin- 1-one), and other molecules capable of inhibiting BTK activity, for example those BTK inhibitors disclosed in Akinleye et ah, Journal of Hematology & Oncology, 2013, 6:59, the entirety of which is incorporated herein by reference. Syk inhibitors include, but are not limited to, Cerdulatinib (4-(cyclopropylamino)-2- ((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide), entospletinib (6-(1H-indazol-6-y1)-N-(4-morpholinophenyl)imidazo[ 1,2-a]pyrazin-8-amine), fostamatinib ([6-({5-Fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl }amino)-2,2-dimethyl-3- ox0-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl methyl dihydrogen phosphate), fostamatinib disodium salt (sodium (6-((5-fluoro-2-((3,4,5- trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2- b][1,4]oxazin-4(3H)-yl)methyl phosphate), BAY 61-3606 (2-(7-(3,4-Dimethoxyphenyl)- imidazo[1,2-c]pyrimidin-5-ylamino)-nicotinamide HCl), R09021 (6-[(1R,2S)-2-Amino- cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide), imatinib ~~ (Gleevac, 4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3- yl)pyrimidin-2-yl]Jamino}phenyl)benzamide), staurosporine, GSK143 (2-(((3R,4R)-3- aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidine-5-carboxamide), PP2 (1- (tert-butyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), PRT-060318 (2- (((1R,28)-2-aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5-carboxamide), PRT- 062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2- aminocyclohexyl)amino)pyrimidine-5-carboxamide ~~ hydrochloride), R112 (3,3'-((5- fluoropyrimidine-2,4-diyl)bis(azanediyl))diphenol), R348 (3-Ethyl-4-methylpyridine), R406 (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2H- pyrido[3,2-b][1,4]oxazin-3(4H)-one), 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-azaindole, piceatannol, ER-27319 (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), Compound D (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), 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, 3614-3643 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 herein). In certain embodiments, the bioactive agent is a MEK inhibitor. MEK inhibitors are well known, and include, for example, trametinib / GSK1120212 (N-(3-{3-Cyclopropyl-5-[(2- fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6, 7-tetrahydropyrido[4,3- d]pyrimidin-1(2H-yl } phenyl)acetamide), selumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro- N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), ~pimasertib / AS703026 / MSC 1935369 ((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4- iodophenyl)amino)isonicotinamide), XL-518 / GDC-0973 (1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- [(2S)-piperidin-2-yl]azetidin-3-ol), refametinib / BAY869766 / RDEAI 19 (N-(3,4-difluoro-2- (2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1- sulfonamide), PD-0325901 (N-[(2R)-2,3-Dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]- benzamide), TAK733 ((R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2- fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione), MEK162 / ARRY438162 (5-[(4-Bromo-2-fluorophenyl)amino]-4-fluoro-N-(2- hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide), R05126766 (3-[[3-Fluoro-2- (methylsulfamoylamino)-4-pyridylJmethyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one), WX-554, R04987655 / CHA4987655 (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2- hydroxyethoxy)-5-((3-oxo-1,2-oxazinan-2yl)methyl)benzamide), or AZD8330 (2-((2-fluoro-4- iodophenyl)amino)-N-(2 hydroxyethoxy)-1 ,5-dimethyl-6-oxo-1,6-dihydropyridine-3- carboxamide), U0126-EtOH, PD184352 (CI-1040), GDC-0623, BI-847325, cobimetinib, PD98059, BIX 02189, BIX 02188, binimetinib, SL-327, TAK-733, PD318088. In certain embodiments, the bioactive agent is a Raf inhibitor. Raf inhibitors are known and include, for example, Vemurafinib (N-[3-[[5-(4-Chlorophenyl)-1H-pyrrolo[2,3-b]pyridin- 3-yl]carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide), sorafenib tosylate (4-[4-[[4- chloro-3-(triflucromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2- carboxamide;4-methylbenzenesulfonate), AZ628 (3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3- methyl-4-0xo0-3,4-dihydroquinazolin-6-ylamino)phenyl)benzamide), =~ NVP-BHG712 (4- methyl-3-(1-methyl-6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-N-(3- (trifluoromethyl)phenyl)benzamide), ~RAF-265 (1-methyl-5-[2-[5-(trifluoromethyl)-1H- imidazol-2-yl]pyridin-4-yl]Joxy-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine), 2- Bromoaldisine (2-Bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione), Raf Kinase Inhibitor IV (2-chloro-5-(2-phenyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)phenol), Sorafenib N- Oxide (4-[4-[[[[4-Chloro-3(trifluoroMethyl)phenyl]aMino]carbonyl JaMino]phenoxy]-N- Methyl-2pyridinecarboxaMide 1-Oxide), PLX-4720, dabrafenib (GSK2118436), GDC-0879, RAF265, AZ 628, SB590885, ZM336372, GW5074, TAK-632, CEP-32496, LY3009120, and GX818 (Encorafenib). 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), rociletinib (Xegafti), afatinib (Glotriff, Giotriff, Afanix), lazertinib, or nazartib. Additional examples of EGFR inhibitors include rociletinib (CO-1686), olmutinib (Olita), naquotinib (ASP8273), nazartinib (EGF816), PF-06747775, icotinib (BPI-2009), neratinib (HKI-272; PB272), avitinib (AC0010), EAI045, tarloxotinib (TH-4000; PR-610), PF- 06459988 (Pfizer), tesevatinib (XL647; EXEL-7647; KD-019), transtinib, WZ-3146, WZ8040, CNX-2006, 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 rociletinib. 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 in need thereof 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 an 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 ¢-MET inhibitor, for example, crizotinib (Xalkori, Crizonix), tepotinib (XL880, EXEL-2880, GSK1363089, GSKO089), 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, AZDS5363, Honokiol, PF-04691502, and Miltefosine, a FLT-3 inhibitor, including, but not limited to, P406, Dovitinib, Quizartinib (AC220), Amuvatinib (MP-470), Tandutinib (MLNS518), ENMD-2076, and KW-2449, or a combination thereof. In certain embodiments, the bioactive agent is an mTOR inhibitor. Examples of mTOR inhibitors include, but are not limited to, rapamycin and its analogs, everolimus (Afinitor), temsirolimus, ridaforolimus, sirolimus, and deforolimus. In certain embodiments, the bioactive agent is a RAS inhibitor. Examples of RAS inhibitors include but are not limited to Reolysin and siG12D LODER. In certain embodiments, the bioactive agent is a HSP inhibitor. HSP inhibitors include but are not limited to Geldanamycin or 17-N-Allylamino-17-demethoxygeldanamycin (17AAG), and Radicicol. Additional bioactive compounds include, for example, everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, a VEGFR inhibitor, an aurora kinase inhibitor, a PIK-1 modulator, an HDAC inhbitor, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, an IGFR-TK inhibitor, an anti- HGF antibody, a focal adhesion kinase inhibitor, a Map kinase kinase (mek) inhibitor, a VEGF trap antibody, pemetrexed, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, of atumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT- 110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR, KRX-0402, lucanthone, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK- 304709, seliciclib, PD0325901, AZD-6244, capecitabine, L-Glutamic acid, N-[4-[2-(2-amino- 4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl Jbenzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES(diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258); 3-[5-(methylsulfonylpiperadinemethyl)- indolyl-quinolone, vatalanib, AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK- 165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI- 166, GW-572016, Ionafarnib, 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 (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis- retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5- deooxyuridine, cytosine arabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin- 12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortezimib, paclitaxel, cremophor-free paclitaxel, docetaxel, epithilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE- 424, HMR-3339, ZK186619, topotecan, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210,1Y294002, LY292223, 1.Y292696, L.Y293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zolendronate, prednisone, cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2, megestrol, immune globulin, nitrogen mustard, methylprednisolone, ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, an NK-1 receptor antagonist, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa and mixtures thereof. In certain embodiments the compound is administered in combination with ifosfamide. In certain embodiments, the bioactive agent is selected from, but are not limited to, Imatinib mesylate (Gleevac®), Dasatinib (Sprycel®), Nilotinib (Tasigna®), Bosutinib (Bosulif®), Trastuzumab (Herceptin®), trastuzumab-DM1, Pertuzumab (PerjetaTM), Lapatinib (Tykerb®), Gefitinib (Iressa®), Erlotinib (Tarceva®), Cetuximab (Erbitux®), Panitumumab (Vectibix®), Vandetanib (Caprelsa®), Vemurafenib (Zelboraf®), Vorinostat (Zolinza®), Romidepsin (Istodax®), Bexarotene (Tagretin®), Alitretinoin (Panretin®), Tretinoin (Vesanoid®), Carfilizomib (KyprolisTM), Pralatrexate (Folotyn®), Bevacizumab (Avastin®), Ziv-aflibercept (Zaltrap®), Sorafenib (Nexavar®), Sunitinib (Sutent®), Pazopanib (Votrient®), Regorafenib (Stivarga®), and Cabozantinib (CometrigTM). In certain aspects, the bioactive agent is an anti-inflammatory agent, a chemotherapeutic agent, a radiotherapeutic, an additional therapeutic agent, or an immunosuppressive agent. Suitable chemotherapeutic bioactive agents include, but are not limited to, a radioactive molecule, a toxin, also referred to as cytotoxin or cytotoxic agent, which includes any agent that is detrimental to the viability of cells, and liposomes or other vesicles containing chemotherapeutic compounds. General anticancer pharmaceutical agents include: Vincristine (Oncovin®) or liposomal vincristine (Marqibo®), Daunorubicin (daunomycin or Cerubidine®) or doxorubicin (Adriamycin®), Cytarabine (cytosine arabinoside, ara-C, or Cytosar®), L-asparaginase (Elspar®) or PEG-L-asparaginase (pegaspargase or Oncaspar®), Etoposide (VP-16), Teniposide (Vumon®), 6-mercaptopurine (6-MP or Purinethol®), Methotrexate, Cyclophosphamide (Cytoxan®), Prednisone, Dexamethasone (Decadron), imatinib (Gleevec®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosulif®), and ponatinib (Iclusig™). Examples of additional suitable chemotherapeutic agents include, but are not limited to 1-dehydrotestosterone, 5-fluorouracil ~ decarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, adriamycin, aldesleukin, an alkylating agent, allopurinol sodium, altretamine, amifostine, anastrozole, anthramycin (AMC)), an anti-mitotic agent, cis-dichlorodiamine platinum (II) (DDP) cisplatin), diamino dichloro platinum, anthracycline, an antibiotic, an antimetabolite, asparaginase, BCG live (intravesical), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, calcium leucouorin, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU), Chlorambucil, Cisplatin, Cladribine, Colchicin, conjugated estrogens, Cyclophosphamide, Cyclothosphamide, Cytarabine, Cytarabine, cytochalasin B, Cytoxan, Dacarbazine, Dactinomycin, dactinomycin (formerly actinomycin), daunirubicin HCL, daunorucbicin citrate, denileukin diftitox, Dexrazoxane, Dibromomannitol, dihydroxy anthracin dione, Docetaxel, dolasetron mesylate, doxorubicin HCL, dronabinol, E. coli L-asparaginase, emetine, epoetin-o, Erwinia L-asparaginase, esterified estrogens, estradiol, estramustine phosphate sodium, ethidium bromide, ethinyl estradiol, etidronate, etoposide citrororum factor, etoposide phosphate, filgrastim, floxuridine, fluconazole, fludarabine phosphate, fluorouracil, flutamide, folinic acid, gemcitabine HCL, glucocorticoids, goserelin acetate, gramicidin D, granisetron HCL, hydroxyurea, idarubicin HCL, ifosfamide, interferon a-2b, irinotecan HCL, letrozole, leucovorin calcium, leuprolide acetate, levamisole HCL, lidocaine, lomustine, maytansinoid, mechlorethamine HCL, medroxyprogesterone acetate, megestrol acetate, melphalan HCL, mercaptipurine, mesna, methotrexate, methyltestosterone, mithramycin, mitomycin C, mitotane, mitoxantrone, nilutamide, octreotide acetate, ondansetron HCL, paclitaxel, pamidronate disodium, pentostatin, pilocarpine HCL, plimycin, polifeprosan 20 with carmustine implant, porfimer sodium, procaine, procarbazine HCL, propranolol, rituximab, sargramostim, streptozotocin, tamoxifen, taxol, teniposide, tenoposide, testolactone, tetracaine, thioepa chlorambucil, thioguanine, thiotepa, topotecan HCL, toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate. In some embodiments, the compound of the present invention is administered in combination with a chemotherapeutic agent (e.g., a cytotoxic agent or other chemical compound useful in the treatment of cancer). Examples of chemotherapeutic agents include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodopyyllotoxins, antibiotics, L-Asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione substituted urea, methyl hydrazine derivatives, adrenocortical suppressant, adrenocorticosteroides, progestins, estrogens, antiestrogen, androgens, antiandrogen, and gonadotropin-releasing hormone analog. Also included is 5-fluorouracil (5-FU), leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1 ); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine...

Claims

CLAIMS A compound of formula (I), rR? A H N 0 rR" 1 ! N OC fori NN rR! 0 B [¢)) B - / wherein A is selected from the ring systems AF and AG; re 4 Ry TN nr / 8 5 R R \ o= Vv AA O= H H AF AG Alis selected from i) -NH-, and i) -O-; A? is selected from i) -N-, and ii) -CR%- Ad is selected from i) -N-, and ii) -CR%- Ais selected from i) -N-, and ii) -CR%- AS is selected from i) -N-, and ii) -CR%-; R! is selected from i) H, ii) halogen iii) Cis-alkyl; R52 is selected from i) H, ii) halogen, iii) cyano, iv) Cis-alkoxy, v) halo-Cis-alkoxy, vi) Cis-alkyl, vii) halo-Cis-alkyl, viii) Css-cycloalkyl, and ix) halo-Css-cycloalkyl; R*, R* and R* are independently selected from i) H, ii) halogen, iii) Crs-alkyl, iv) halo-Cis-alkyl, v) Css-cycloalkyl, and vi) halo-Css-cycloalkyl; R2 is selected from i) H, ii) halogen, iii) Crs-alkyl, iv) halo-Cis-alkyl, v) Css-cycloalkyl, and vi) halo-Css-cycloalkyl; R3 is selected from i) H, ii) halogen, iii) Ci.s-alkyl, iv) halo-Cis-alkyl, v) Css-cycloalkyl, and vi) halo-Css-cycloalkyl;; R*and R® are H; or R* and R°® together form -(CH2)q-; qislor2; RS is selected from i) H, ii) halogen, iii) cyano, iv) Cis-alkoxy, v) halo-Cis-alkoxy, vi) Cis-alkyl, vii) halo-Cis-alkyl, viii) Css-cycloalkyl, and ix) halo-Cs.e-cycloalkyl; R’ is selected from i) H, ii) halogen, iii) cyano, iv) Cis-alkyl, v) halo-Cis-alkyl, vi) Css-cycloalkyl, and vii) halo-Css-cycloalkyl; Ris selected from i) H, ii) halogen, iii) cyano, iv) Cis-alkyl, v) halo-Cis-alkyl, vi) Css-cycloalkyl, and vii) halo-Css-cycloalkyl; Reis H; RS is selected from i) Hand ii) Cie-alkyl; ~~ C AN VU VY Yc Yb y NEY L'is — ~~ —t C is absent or selected from the ring systems F, G and H; 13 _14 R | R15 R RS | Vy « F G Y! is selected from i) -N- and ii) -CH-; Y2 is selected from i) -N- and ii) CRIS. RZ, R" R!* and RY are independently selected from i) -H- ii) halogen, and iii) hydroxy-Cis-alkyl; R16 is selected from i) -H- ii) hydroxy, and iii) fluoro; L? is absent or selected from i) -(CH2)m-C(O)-, ii) -C(0)-(CHa2)p-, iii) -C(0)-C(0O)-, iv) -NR!°-C(0)-, v) -C(O)-NR!- vi) -C(0)O-, vii) -CH;-CF;-CH:-, viii) -CHa-, Y= AN ix) x) oo A , and $0 xi) OL misO,1or2; pis0,1,2o0r3; R10 ig selected from i) H, and i) Cis-alkyl; D is selected from the ring systems I, J, K,L, M,N, O,P, Q,R, S, T, U, V, Wand X, all ring system being optionally substituted by one to three substituents selected from R®, R®! and R®2; A N— J TN Fo TN \ / \ J K 7 1 ' SYN NOT oN No: —N1\ N— ANA CN ~~ NOONE \ N NN M N oO P ya. YON Xn AN —N Xn 2G, Q s R®-R¥ and R® are independently selected from i) halogen, ii) cyano, iii) hydroxy, iv) hydroxy- Ci¢-alkyl, v) Cis-alkoxy, vi) halo-Ci¢-alkoxy, vii) Cis-alkyl, viii) halo-Cis-alkyl, ix) Css-cycloalkyl, and x) halo-Css-cycloalkyl; 1L* is absent or selected from i) -NR!-C(0)-, ii) -CHa-, and iii) -O-; E is selected from the ring systems Y, Z, AA, AB and 4 )- Y Zz =N ANN ony or a pharmaceutically acceptable salt thereof. The compound of formula I, or a pharmaceutically acceptable salt thereof, according claim 1, wherein A is selected from the ring systems AF and AG; rE 4 4 Ry 8 Ry O= O= H H 5 \ 1 N-Nsge Rr 7 NN H o rR H AF AG Alis selected from i) -NH-, and i) -0- A? is selected from i) -N-, and ii) -CH- Rl! is selected from i) H, and ii) halogen; R?isH; R3 is selected from i) H, and ii) halogen; RYisH R*isH; or R* and R® together form -(CH2)n-; nis 1; RS is selected from i) H, ii) halogen, iii) cyano, and iv) halo-Ci.¢-alkyl; R’isH; Reis H; R?is Ci.¢-alkyl; ~~ Cc VAL AN ALD 2 L Lis — — — C is absent or the ring system F; 13 14 RY Rts R RY | vi NV F Y!is selected from i) -N-, and ii) -CH-; Y? is selected from i) -N-, and ii) CR; RIZR! R" and R' are independently selected from i) H, and ii) halogen; R!6 is selected from i) H, and ii) hydroxy; 1.3 is selected from i) -(CH2)m-C(O)-, iil) -C(O)-(CH2)p-, iii) -C(0)-C(0)-, and iv) -NR-C(0)-; mis 1; pislor3; R19 ig selected from i) H, and ii) Cis-alkyl; D is selected from the ring systems I, J, K, L and M; NN NN > NOX J K N— / —~X M L*is selected from i) -NR'-C(0)-, ii) -CH;-, and ii) -O-; E is selected from the ring systems Y, Z and AA, AB and NN 4 )- N=N Y Z AA =N A NN ny or a pharmaceutically acceptable salt thereof. The compound of formula I, or a pharmaceutically acceptable salt thereof, according claim 1 or 2, wherein A is selected from the ring systems AF and AG; r® 1 4 Ry 8 Ry O= O= H W H 5 Np N-Ng8 rR i NN H 0 rR H AF AG Alis selected from i) -NH-, and ii) -0- A? is selected from i) -N-, and ii) -CH- R! is selected from i) H, and ii) fluoro; R?isH; R3 is selected from i) H, and ii) fluoro; RYisH Ris H; or R* and R® together form -(CH2)q-; qis 1; RE is selected from i) H, ii) fluoro, iii) cyano, iv) difluoromethyl, and v) trifluoromethyl; R’isH; Reis H; R? is methyl; ~~ C VV Ay TN LS L. L NYY YY EY L'is Sor” ~~ — C is the ring system F; 18 14 RY) Rts R RY | vi NAY F Y!is selected from i) -N-, and ii) -CH- Y? is selected from i) -N-, and ii) CR; R!2 and R*? are fluoro: RY and RS are H: R!6 is selected from i) H, and ii) hydroxy; 1.3 is selected from i) -(CH2)m-C(O)-, i) -C(0O)-(CHa2)p-, iii) -C(0)-C(0)-, and iv) -NR-C(0)-; mis 1; pislor3; R%is H; D is selected from the ring systems I, J, K, L and M; NN NN > NOX On J K N— / —X M L* is selected from i) -NR'-C(0)-, ii) -CH;-, and iii) -O-; E is selected from the ring systems Y, Z, AA, AB and AC; NN 4) N=N Y Zz AA =N A NN ny or a pharmaceutically acceptable salt thereof.

4. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3, wherein A is the ring system AF.

5. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4, wherein A! is -N-.

6. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 5, wherein A? is -CH-.

7. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 6, wherein R is selected from i) H, and ii) halogen.

8. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7, wherein R is selected from i) H, and ii) fluoro.

9. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 8, wherein R! is fluoro.

10. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 9, wherein R? is H.

11. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 10, wherein R is selected from i) H, and ii) halogen.

12. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 11, wherein R? is selected from i) H, and ii) fluoro.

13. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 12, wherein R* is H.

14. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 13, wherein R® is H.

15. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 14, wherein R® is selected from i) H, ii) halogen, iii) cyano, and iv) halo-Cis-alkyl.

16. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 15, wherein R’ is H.

17. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 16, wherein R® is H.

18. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 17, wherein R® is Ci.s-alkyl.

19. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 18, wherein R® is methyl.

20. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 19, wherein nis 1, 21. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 20, wherein C is absent or the ring system F.

22. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 21, wherein 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, wherein R'? and R" are fluoro.

24. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 23, wherein R" and R'® are H.

25. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 24, wherein R® is selected from i) H, and ii) hydroxy.

26. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 25, wherein R' is H.

27. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 26, wherein L? is selected from i) -(CH2)m-C(O)-, i) -C(0)~(CHa2)p-, iii) -C(0)-C(0)-, and iv) -NR-C(O)-.

28. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 27, wherein mis 1.

29. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 28, wherein pis 1 or 3.

30. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 29, wherein R'° is selected from i) H, and ii) Cre-alkyl.

31. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 30, wherein 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 any one of claims 1 to 31, wherein L* is selected from i) -NRU-C(O)-, ii) -CHj;-, and iii) -O-.

33. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to 3 any one of claims 1 to 32, wherein L* is 34, The compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 33, that is selected from the group consisting of 5-((2-(1-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-yl)-2-ox0-2-(thiazol -2- ylamino)ethyl)-7-fluoro-3-oxoisoindolin-5-yl)ethynyl)-N-(1-(2-(4-(4-((2,6- dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)acetyl)piperidin-4-yl)picolinamide; 5-[2-[2-[1-(6,7-dihydro-5H-pyrrolo[1,2-c]limidazol-1-yl)-2-ox0-2-(thiazol-2- ylamino)ethyl]-7-fluoro-3-oxo-isoindolin-5-yl]ethynyl]-N-[1-[2-[4-[(2,6-diox0-3- piperidyl)amino]phenyl]acetyl]-4-piperidyl]pyridine-2-carboxamide; 5-[2-[2-[1-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-yl)-2-oxo-2-(thiazol -2- ylamino)ethyl]-7-fluoro-3-oxo-isoindolin-5-y1]ethynyl]-N-[1-[2-[4-[4-[(2,6-diox0-3- piperidyl)oxy]phenyl]piperazin-1-yl]acetyl]-4-piperidyl]pyridine-2-carboxamide; 5-[2-[2-[1-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-yl)-2-ox0-2-(thiazol -2- ylamino)ethyl]-7-fluoro-3-oxo-isoindolin-5-yl]ethynyl]-N-[1-[2-[4-[4-[[(3S)-2,6-diox0- 3-piperidyl]amino]-2-fluoro-phenyl]-1-piperidyl]acetyl]-4-piperidyl pyridine-2- carboxamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-y1)-2-[6-[4-[4-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]phenyl]-1-piperidyl]acetyl]piperazin-1-yl]phenyl]-4-fluoro-1-oxo- isoindolin-2-y1]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-y1)-2-[6-[4-[4-[2-[4-[4-[[(3S)-2,6- dioxo-3-piperidyl]amino]phenyl]-1-piperidyl]acetyl]piperazin-1-ylJphenyl]-4-fluoro-1- oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-SH-pyrrolo[ 1,2-climidazol-1-y1)-2-[6-[4-[4-[2-[4-[4-[[(3S)-2,6- dioxo-3-piperidyl]amino]phenyl]-1-piperidyl]acetyl]piperazin-1-yl]phenyl]-4-fluoro-1- oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-SH-pyrrolo[ 1,2-climidazol-1-y1)-2-(6-(4-(4-(4-(4-(4-((2,6- dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-4-oxobutyl )piperazin-1-yl)phenyl)-4- fluoro-1-oxoisoindolin-2-y1)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-y1)-2-(6-(4-(4-(2-(4-(4-((2,6- dioxopiperidin-3-yl)amino)phenyl)cyclohexyl)acetyl)piperazin-1-yl)phenyl)-4-fluoro-1- oxoisoindolin-2-y1)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-y1)-2-(6-(4-(4-(2-(4-(4-((2,6- dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-2-oxoethyl )piperazin-1-yl)phenyl)-4- fluoro-1-oxoisoindolin-2-y1)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-yl)-2-[6-[4-[4-[2-[4-[ 5-[(2,6-diox0-3- piperidyl)amino]-2-pyridyl]-1-piperidyl]acetyl|piperazin-1-yl]phenyl]-4-fluoro-1-oxo- isoindolin-2-y1]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-[6-[4-[4-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]acetyl]piperazin-1-yl]phenyl]-4-fluoro- 1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-yl)-2-[6-[4-[4-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]-3-fluoro-phenyl]-1-piperidyl]acetyl]piperazin-1-yl]phenyl]-4-fluoro- 1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide; 2-[6-[4-[4-[2-[4-[2-cyano-4-[(2,6-dioxo-3-piperidyl }Jamino]phenyl]-1- piperidyl]acetyl]piperazin-1-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-2-(6,7-dihydro- SH-pyrrolo[1,2-c]imidazol-1-y1)-N-thiazol-2-yl-acetamide; 2-[6-[4-[4-[2-[4-[2~(difluoromethyl)-4-[(2,6-dioxo-3-piperidyl Jamino]phenyl]-1- piperidyl]acetyl]piperazin-1-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-2-(6,7-dihydro- SH-pyrrolo[1,2-c]imidazol-1-y1)-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-SH-pyrrolo[ 1,2-climidazol -1-y1)-2-(6-(4-(4-(2-(4-(3-((2,6- dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)acetyl)piperazin-1-yl)phenyl)-4- fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-y1)-2-(6-(4-(4-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl- 1H-indazol-6-yl)piperidin-1- yl)acetyl)piperazin-1-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol-2- ylacetamide; 2-(6,7-dihydro-SH-pyrrolo[ 1,2-climidazol-1-y1)-2-(6-(4-(4-(2-(1-(4-((2,6- dioxopiperidin-3-yl)amino)-2-(trifluoromethyl)phenyl)-4-hydroxypiperidin-4- yl)acetyl)piperazin-1-yl)phenyl)-4-fluore-1-oxoisoindolin-2-y1)-N-(thiazol-2- ylacetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-(6-(4-(4-(2-(4-(4-((2,6- dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)acetyl)piperazin-1-yl)phenyl)-4- fluoro-1-oxoisoindolin-2-yl)-N-(pyridin-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-[6-[4-[4-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]acetyl]piperazin-1-yl]phenyl]-4-fluoro- 1-oxo-isoindolin-2-yl1]-N-(2-pyridyl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-y1)-2-(6-(4-(1-(2-(4-(4-((2,6- dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)acetyl)piperidin-4-yl)phenyl)-4- fluoro-1-oxoisoindolin-2-y1)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-(6-(4-(1-(2-(4-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)acetyl)piperidin-4-yl)phenyl)-4- fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-(6-(4-(1-(2-(4-(4-((R)-2,6- dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)acetyl)piperidin-4-yl)phenyl)-4- fluoro-1-oxoisoindolin-2-y1)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-(6-(4-(1-(2-(4-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)piperidin-4- yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2-yl)acetamide; 2-(6-(4-(1-(2-(4-(2-cyano-4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1- yl)acetyl)piperidin-4-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H- pyrrolo[1,2-c]limidazol-1-y1)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-SH-pyrrolo[ 1,2-climidazol-1-y1)-2-[6-[4-[ 1-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]phenyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]phenyl]-4-fluoro-1-oxo- isoindolin-2-y1]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-y1)-2-[6-[6-[4-[2-[4-[4-[[(3S)-2,6- dioxo-3-piperidyl]amino]-2-fluoro-phenyl]-1-piperidyl]acetyl]piperazin-1-y1]-3- pyridyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazol -2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-[6-[ 1-[ 1-[2-[4-[4-[[(3S)-2,6- dioxo-3-piperidyl]amino]phenyl]-1-piperidyl]acetyl]-4-piperidyl]pyrazol -4-yl]-4- fluoro-1-oxo-isoindolin-2-yl]-N-thiazol -2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-y1)-2-[6-[4-[ 1-[2-[4-[4-[[(3S)-2,6- dioxo-3-piperidyl]amino]phenyl]-1-piperidyl]acetyl]-4-piperidyl]pyrazol-1-yl]-4- fluoro-1-oxo-isoindolin-2-yl]-N-thiazol -2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-y1)-2-[6-[4-[ 1-[2-[4-[4-[[(3S)-2,6- dioxo-3-piperidyl]amino]phenyl]-1-piperidyl]acetyl]-4-piperidyl]pyrazol-1-yl]-4- fluoro-1-oxo-isoindolin-2-yl]-N-thiazol -2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-[6-[4-[[ 1-[2-[4-[4-[(2,6-diox0- 3-piperidyl)amino]phenyl]-1-piperidyl]acetyl]-4-piperidyl]oxy]phenyl]-4-fluoro-1-oxo- isoindolin-2-y1]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-[6-[4-[[1-[2-[4-[4-[[(3S)-2,6~ dioxo-3-piperidylJamino]phenyl]-1-piperidylJacetyl]-4-piperidylJoxy ]Jphenyl]-4-fluoro- 1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-[6-[4-[[1-[2-[4-[4-[[(3R)-2,6- dioxo-3-piperidyl]Jamino]phenyl]-1-piperidyl]acetyl]-4-piperidyl]oxy]phenyl]-4-fluoro- 1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-(6-(4-((1-(2-(4-(4-((2,6- dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperidin-1-yl)acetyl)piperidin-4- yl)oxy)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol-2-yl acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol -1-y1)-2-(6-(4-((1-(2-(4-(4-((2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)piperidin-4- yl)oxy)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol-2-yl acetamide; 2-(6,7-dihydro-SH-pyrrolo[ 1,2-climidazol-1-y1)-2-(6-(4-((1-(2-(4-(5-((2,6- dioxopiperidin-3-yl)amino)pyridin-2-yl)piperidin-1-yl)acetyl)piperidin-4- yl)oxy)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol-2-yl acetamide; 2-(6-(4-((1-(2-(4-(2-cyano-4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1- yl)acetyl)piperidin-4-yl)oxy)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-2-(6,7-dihydro-5H- pyrrolo[1,2-climidazol-1-y1)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-y1)-2-(6-(4-((1-(2-(4-(4-((2,4-dioxo- 3-azabicyclo[3.1.1]heptan-1-yl)amino)phenyl)piperidin-1-yl)acetyl)piperidin-4- yDoxy)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol-2-yl acetamide; 2-(6,7-dihydro-SH-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(4-((1-(2-(4-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)piperidin-4- yl)oxy)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol-2-yl acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-[6-[4-[[ 1-[2-[4-[4-[(2,6-diox0- 3-piperidyl)amino]phenyl]-1-piperidyl]-2-oxo-acetyl]-4-piperidylJoxy]phenyl]-4- fluoro-1-oxo-isoindolin-2-yl]-N-thiazol -2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-y1)-2-[6-[4-[(3R)-1-[2-[4-[4-[[(3S)- 2,6-dioxo-3-piperidyl]Jamino]phenyl]-1-piperidyl]acetyl]pyrrolidin-3-yl]Joxyphenyl]-4- fluoro-1-oxo-isoindolin-2-yl]-N-thiazol -2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-[6-[4-[(3R)-1-[2-[4-[4-[[(3S)- 2,6-dioxo-3-piperidyl]Jamino]phenyl]-1-piperidyl]acetyl]pyrrolidin-3-yl]Joxyphenyl]-4- fluoro-1-oxo-isoindolin-2-yl]-N-thiazol -2-yl-acetamide; 2-(6-(4-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1- yl)acetyl)piperazin-1-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-2~((R)-6-fluoro-6,7- dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-N-(thiazol-2-yl)acetamide; 2-[6-[4-[4-[2-[4-[4-[[(3S)-2,6-diox0-3 -piperidyl J]amino]-2-fluoro-phenyl]-1- piperidyl]acetyl]piperazin-1-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-2-[(6R)-6- fluoro-6,7-dihydro-5H-pyrrolo[1,2-cJimidazol-1-yl]-N-thiazol -2-yl-acetamide; 2-[6-[4-[4-[2-[4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]- 1-piperidyl]acetyl]piperazin-1-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-2-[(6R)-6- fluoro-6,7-dihydro-5H-pyrrolo[1,2-cJimidazol-1-y1]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-(6-(4-(2-(2-(4-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-flucrophenyl)piperidin-1-yl)acetyl)-2,7- diazaspiro[3.5]nonan-7-yl)phenyl)-4-fluoro-1-oxoisocindolin-2-y1)-N-(thiazol -2- yl)acetamide; 2-(6,7-dihydro-SH-pyrrolo[ 1,2-climidazol-1-y1)-2-[6-[4-[2-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]phenyl]-1-piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4- fluoro-1-oxo-isoindolin-2-yl]-N-thiazol -2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-y1)-2-[6-[4-[2-[2-[4-[4-[[(3S)-2,6- dioxo-3-piperidylJamino]-2-fluoro-phenyl]-1-piperidyl]acetyl]-2,6- diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-N-thiazol-2-yl- acetamide; 2-(6,7-dihydro-SH-pyrrolo[1,2-c]imidazol-1-y1)-2-[6-[4-[2-[2-[4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-1-piperidyl]acetyl]-2,6- diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-N-thiazol -2-y1- acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-y1)-2-[6-[4-[2-[2-[4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-3,3-difluoro-1- piperidyl]acetyl]-2,6-diazaspiro[3.3 ]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2- yl]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-y1)-2-(6-(4-(6-(2-(4-(4-((2,6- dioxopiperidin-3-yl)amino)phenyl)-3,3-difluoropiperidin-1-yl)acetyl)-2,6- diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2- yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-y1)-2-[6-[4-[2-[2-[4-[4-[[(3S)-2,6- dioxo-3-piperidylJamino]-2-fluoro-phenyl]-1-piperidyl]acetyl]-2,6- diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-N-(2- pyridyl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-[6-[4-[2-[2-[4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-1-piperidyl]acetyl]-2,6- diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-N-(2- pyridyl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-[6-[4-[2-[2-[4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-3,3-difluoro-1- piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2- y1]-N-(2-pyridyl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-[6-[4-[[4-[2-[4-[4-[(2,6-diox0- 3-piperidyl)amino]phenyl]-1-piperidylJacetyl]piperazin-1-ylJmethyl]phenyl]-4-fluoro- 1-oxo-isoindolin-2-y1]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-[6-[4-[[4-[2-[4-[4-[(2,6-diox0- 3-piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl acetyl Jpiperazin-1-ylJmethyl]phenyl]- 4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazol -2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-[6-[4-[[4-[2-[4-[4-[[(3S)-2,6- dioxo-3-piperidylJamino]-2-fluoro-phenyl]-1-piperidyl]acetyl]piperazin-1- yl]methyl]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-N-thiazol -2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-[6-[4-[[4-[2-[4-[4-[[(3S)-2,6- dioxo-3-piperidylJamino]-2-fluoro-phenyl]-1-piperidyl]-2-oxo-ethyl]piperazin-1- yl]methyl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-[6-[4-[[1-[2-[4-[4-[[(3S)-2,6- dioxo-3-piperidylJamino]-2-fluoro-phenyl]-1-piperidyl acetyl ]-4- piperidylJmethyl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide; or a pharmaceutically acceptable salt thereof, 35. A compound according to any one of claims 1 to 34 for use as therapeutically active substance.

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

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

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

39. The use of a compound according to any one 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-mutant non-small 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-mutant non-small lung cancer wherein the activating mutation is L858R, which method comprises administering an effective amount ¢ a compound according to any one of claims 1 to 34. A compound of formula (II), 2 R NT ON N= 2 R3 A’ a L! } OR@e ZS I RY C B Sn?’ am) wherein A’ is selected from the ring systems AF, AG and AH; 4 R 70 RS A R70 CN R8 CN O= Oo= 4 OC wl N\ | re N—N ~ge hd hE ! RS ] N —{ AZ oO R7? Nn. ZF HN—( 0 AF AG R4 "iy = 1 Ad AH Als selected from i) -NH-, and i) -0-; A? is selected from i) -N-, and ii) -CR%-; Al is selected from i) -N-, and ii) -CR%- At is selected from i) -N-, and ii) -CR%- AS is selected from i) -N- and ii) -CR%- RY is selected from i) H, ii) halogen, iii) Cie-alkyl iv) cyano, v) Cis-alkoxy, vi) halo-Ci¢-alkoxy, vii) Cis-alkyl, viii) halo-Cis-alkyl, ix) Css-cycloalkyl, and x) halo-Css-cycloalkyl; R*2 is selected from i) H, ii) halogen, iii) cyano, iv) Cis-alkoxy, v) halo-Ci¢-alkoxy, vi) Cis-alkyl, vii) halo-Ci¢-alkyl, viii) Cs.s-cycloalkyl, and ix) halo-Css-cycloalkyl; R%, R%* and R* are independently selected from i) H, ii) halogen, iii) Cr.s-alkyl, iv) halo-Cis-alkyl, v) Css-cycloalkyl, and vi) halo-Css-cycloalkyl; R2 is selected from i) H, ii) halogen, iii) cyano, iv) Cis-alkyl, v) halo-Cis-alkyl, vi) Css-cycloalkyl, and vii) halo-Css-cycloalkyl; R3 is selected from iy H, ii) halogen, iii) Ci¢-alkyl, iv) halo-Cis-alkyl, v) Css-cycloalkyl, and vi) halo-Css-cycloalkyl;; R*and R® are H; or R* and R® together form -(CH2)q-; qislor2; RS is selected from i) H, ii) halogen, iii) cyano, iv) Cis-alkoxy, v) halo-Ci¢-alkoxy, vi) Cis-alkyl, vii) halo-Ci¢-alkyl, viii) Cs.s-cycloalkyl, and ix) halo-Css-cycloalkyl; R’ is selected from i) H, ii) halogen, iii) cyano, iv) Cis-alkyl, v) halo-Cis-alkyl, vi) Css-cycloalkyl, and vii) halo-Css-cycloalkyl; Ris selected from i) H, ii) halogen, iii) cyano, iv) Cis-alkyl, v) halo-Cis-alkyl, vi) Css-cycloalkyl, and vii) halo-Css-cycloalkyl; Reis H; R® is selected from i) Hand ii) Cre-alkyl; ~~ DY YE C Ay AUT TY Llis bd ~~ ~— C is absent or selected from the ring systems F, G and H; 13 14 R oa] R15 13 14 RY R15 R RS | vA F G H Y!is selected from i) -N-, and ii) -CH-; Y2? is selected from i) -N-, and ii) -CR!S-; R!? RB, R!* and R!* are independently selected from i) -H-, ii) halogen, and iii) hydroxy-Ci.s-alkyl; R16 ig selected from i) -H- ii) hydroxy, and iii) fluoro; 1? is absent or selected from i) -(CH2)m-C(O)-, i) -C(0)-(CHa2)p-, iii) -C(0)-C(0)-, iv) -NR-C(0)-, v) -C(O)-NR!"- vi) -C(0)O-, vii) -CH;-CF2-CHs-, viii) -CHa-, MN AN ix) Ny. WE # Xx) and FO x1) OL mis0,1or2; pis0,1,2o0r3; RY is selected from i) H, and ii) Cie-alkyl; D is selected from the ring systems I, J, K,L, M,N, O,P, Q,R, S, T, U, V, W and X, all ring system being optionally substituted by one to three substituents selected from R®, R8! and R®2; Pa NOT YN No: —N1\ N— NN ANAT TL A) “A ~~ NOONE \ N NN M N oO P i Xn AN —N Xn 2G, Q R s On bth OC u Vv w X R¥R® and R® are independently selected from i) halogen, ii) cyano, iii) hydroxy, iv) hydroxy- Cis-alkyl, v) Cis-alkoxy, vi) halo-Cis-alkoxy, vii) Cis-alkyl, viii) halo-Cis-alkyl, ix) Css-cycloalkyl, and x) halo-Css-cycloalkyl; L*is absent or selected from iy -NR'-C(0)-, ii) -CHa-, and iii) -O-; =N A NN ' +! AB AC L5 is absent or } B is selected from the ring system AD and AE; AD AE or a pharmaceutically acceptable salt thereof. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to claim 41, wherein A’ is selected from the ring systems AF, AG and AH; 8 R* R "NX 1 CL. R8 "NN O= Nd ATTN =A? O= hy \ ) | $ NN N r _ RIN ano A? o R7 Nf HN—( 0 AF AG R4 “NX Oe \ AH Alis -NH-; A? is selected from i) -N- and ii) -CH-; R! is selected from i) H, and ii) halogen; R2 is selected from i) H, and ii) halogen; Ris H; R'is H; R*isH; RS is selected from i) H, and ii) halogen; R’isH; Reis H; R%i s C 1-6-alky! 1: i SN C AN I % 4 Nv BY 8 Y "YC rr NDY YE} Lis — ~ — C is the ring system F; 13 14 R R12 \ R R'® vl NAY F Y!is -CH-; Y? is -N-; R!Z R13 Rand R" are H; L3 is selected from i) -(CH2)n-C(0)-, and ii) -C(O)-(CHa2)p-; mis 1; pis3; D is selected from the ring systems I and J; OXON J L*is absent; E is selected from the ring systems Y and Z; 4H) Y 4 Lis absent; or a pharmaceutically acceptable salt thereof, 43. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 42, wherein A’ is selected from the ring systems AG and AF.

44. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 43, wherein A’ is the ring system AF.

45. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 44, wherein A' is -NH-.

46. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 45, wherein A? is -CH-.

47. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 46, wherein R'is selected from i) H, and ii) halogen.

48. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 47, wherein R'is selected from i) H, ii) chloro, and iii) fluoro.

49. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 48, wherein R? is selected from i) H, and ii) halogen.

50. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 49, wherein R? is selected from i) H, ii) chloro, and iii) fluoro.

51. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 50 wherein R® is H.

52. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 51, wherein R*is H.

53. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 52, wherein R® is H.

54. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 53, wherein R® is selected from i) H, and ii) halogen.

55. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 54, wherein R7 is H.

56. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 55, wherein R®is H.

57. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 56, wherein R’ is C1.¢-alkyl.

58. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 57, wherein Ris methyl.

59. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 58, wherein C is the ring system F.

60. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 59, wherein Y' is -CH-.

61. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 60, wherein Y? is -N-.

62. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 61, wherein RZ, R1®, RM and R!® are H.

63. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 62, wherein L? is selected from 1) -(CH2)n-C(0)-, and ii) -C(O)~(CHa)p-.

64. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 63, wherein mis 1.

65. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 64, wherein pis 3.

66. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 65, wherein 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 one of claims 41 to 66, wherein D is selected the ring system J.

68. The compound of formula II, or a pharmaceutically acceptable salt thereof, according any one of claims 41 to 67, wherein L* is absent.

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

70. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 69, wherein L® is absent.

71. The compound of formula II, or a pharmaceutically acceptable salt thereof, according to any one of claims 41 to 70, that is selected from the group consisting of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol -1-y1)-2-(6-(6-(4-(4-(4-((2-(2,6- dioxopiperidin-3-yl1)-1-oxoisoindolin-4-yl)oxy)piperidin-1-yl)-4-oxobutyl)piperazin-1- yl)pyridin-3-yl)-7-fluoro-2H-indazol-2-y1)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-(6-(6-(4-(2-(4-(4-((2,6- dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)acetyl)piperazin-1-yl)pyridin-3-yl)-7- fluoro-2H-indazol-2-y1)-N-(thiazol-2-yl)acetamide; 2-[4,7-dichloro-6-[4-[4-[2-[4-[4-[(2,6-dioxo-3-piperidylJamino]phenyl]-1- piperidyl]acetyl]piperazin-1-yl]phenyl]indazol-2-y1]-2-(6,7-dihydro-5H-pyrrolo[1,2- climidazol-1-yl)-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]limidazol-1-y1)-2-[6-[6-[4-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]acetyl]piperazin-1-yl]-3-pyridyl]-4- fluoro-indazol-2-yl]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5SH-pyrrolo[1,2-cJimidazol-1-y1)-2-[6-[6-[4-[2-[4-[4-[(2,6-diox0-3~ piperidyl)amino]phenyl]-1-piperidyl]acetyl]piperazin-1-yl]-3-pyridyl]-4-fluoro-indazol- 2-yl]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-SH-pyrrolo[1,2-cJlimidazol-1-y1)-2-[6-[6-[4-[2-[4-[ 5-[(2,6-diox0-3~ piperidyl)amino]-2-pyridyl]-1-piperidyl]acetyl]piperazin-1-yl]-3-pyridyl]-4-fluoro- indazol-2-yl]-N-thiazol-2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-[6-[6-[4-[2-[4-[3-(2,4- dioxohexahydropyrimidin-1-y1)-1-methyl-indazol-6-yl]-1-piperidyl]acetyl]piperazin-1- yl]-3-pyridyl]-4-fluoro-indazol -2-y1]-N-thiazol -2-yl-acetamide; 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-(6-(6-(4-(2-(4-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)piperazin-1- yl)pyridin-3-yl)-4-fluoro-2H-indazol-2-y1)-N-(thiazol -2-yl)acetamide; or a pharmaceutically acceptable salt thereof, 72. A compound according to any one of claims 41 to 71 for use as therapeutically active substance.

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

74. The use of 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- mutant non-small 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 prophylaxis of cancer, in particular non-small-cell lung cancer, more particularly EGFR- mutant non-small lung cancer wherein the activating mutation is L858R.

76. The use of a compound according to any one 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-mutant non-small 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 EGFR-mutant non-small lung cancer wherein the activating mutation is L858R, which method comprises administering an effective amount of a compound according to any one of claims 41 to 71. 78 The invention as hereinbefore described.

79. A compound of Formula III or Formula IV: R32 1 NON J A < R33 Va , R* oN Pi 7 I N= | / (RH), é 2 ~~ (11) R32 1 NN | \ R® Va . d= NT we C 2 A ~ av) or a pharmaceutically acceptable salt, isotope, N-oxide, stereoisomer thereof, optionally as part of a pharmaceutical composition; wherein: A* is selected from: 36 R R# =37 R \ R37 i A TN IN — \ o= R35 ) NN Re or 1 \ N y= geo 1s selected trom: ut AH 38 R* RY R R 4 ~N R35 x / \ A XI = 1 1 21 ~ A%3 HN N HN — A pA —( N— Ngo © o R3* NA o=( o= YG \ \ R35 \ Xa 8 7 WN 34 R34 BR’ oO \ A — AZ. R’ o=—( Na Ker SA HN: 35 A ik A21 “AL —_ R — A o 1 ~ a?1 XN pe N= 0 36 R34 RY R R* ny R = I JO RR” R37 1 B® R EF \ Re 5 o= A _( / NN o= XX 1 1 vod \_ 7 XN 7 Foal 7 A x ld 97 JO RR” iN \ K R \ RE + R35 Ns Yo 7 \ o= X A AN—4 PEERS v—( wo HN: CAT p33 — N A — AR=A a! 0 0 B* is heteroaryl or aryl each of which is optionally substituted with 1, 2, or 3 R! substituents; yis0, 1,2, or3; R*! is independently selected at each occurrence ffrom H, halogen (F, Cl, Br, or I), C1. s-alkyl, cyano, Cis-alkoxy, halo-Cis-alkoxy, halo-Cis-alkyl, Cs.s-cycloalkyl, and halo-Cs.s- cycloalkyl and can be located on either ring where present on a bicycle; R* is hydrogen, halogen (F, Cl, Br, or I), Cis-alkyl, halo-Cy.6-alkyl, Cs.s-cycloalkyl, or halo-Cs.s-cycloalkyl; R* is hydrogen, halogen (F, Cl, Br, or I), C1s-alkyl, halo-Ci.¢-alkyl, Cs.s-cycloalkyl, or halo-Cs.s-cycloalkyl and can be located on the dihydropyrrole or imidazole ring; R* is independently selected at each occurrence from H, F, Cis-alkyl, halo-Ci.s-alkyl, Css-cycloalkyl, and halo-Css-cycloalkyl; R¥ is independently selected at each occurrence from H, halogen (F, Cl, Br, or I), Ci. ¢-alkyl, halo-C1s-alkyl, and Css-cycloalkyl; or R* and R** combine to form —(CHz)g-; qislor2; R* and RY are independently selected from H, halogen (F, Cl, Br, or I), cyano, Ci- alkoxy, halo-Cs-alkoxy, Cis-alkyl, halo-C.¢-alkyl, Cs.s-cycloalkyl, and halo-Cj.s-cycloalkyl; or R* and RY" together are combined to form a 5- or 6- membered cycle optionally substituted with 1, 2, or 3 R*! substituents; R* is H, Cis-alkyl, or Ci-cycloalkyl; Ring G is a heteroaryl optionally substituted with 1 or 2 R*? substituents; A?! ig -NH-, -O-, -CH,-, or -NR!%%_: R'is alkyl, cycloalkyl, aryl, or heteroaryl; or as allowed by valence R'°° may combine with R*7 to form a 5-8 membered heterocycle or 5 membered heteroaryl; A A AM and A* are independently selected from -N- and -CR*2-; R* is independently selected at each occurrence from H, halogen (F, Cl, Br, or I), cyano, Ci.s-alkoxy, halo-Ci.s-alkoxy, Ci.s-alkyl, halo-Cis-alkyl, Cs.s-cycloalkyl, and halo-Cs. s-cycloalkyl; A36 is 2N- or -CR35-: 12 is a bivalent linking group that connects A* and either the isoindolinone or indazole.

80. The compound of claim 79, wherein the compound is selected from: R32 1 NW _] 2 \ R33 J Dl { x v5 y - 4 2 — ay or a pharmaceutically acceptable salt thereof.

81. The compound of claim 79, wherein the compound is selected from: R32 1 NN — wy 5 R33 Va Da J ws ~ 7 y ~ N— C Ren - Iv) or a pharmaceutically acceptable salt thereof.

82. The compound of any one of claims 79-81, wherein R* is H.

83. The compound of any one of claims 79-81, wherein R** is F.

84. The compound of any one of claims 79-83, wherein y is 1.

85. The compound of any one of claims 79-83, wherein y is 2.

86. The compound of any one of claims 79-85, wherein at least one R®! is halo.

87. The compound of any one of claims 79-85, wherein at least one R*! is F 88. The compound of any one of claims 79-83, wherein y is 0.

89. The compound of any one of claims 79-88, wherein R*? is H.

90. The compound of any one of claims 79-88, wherein R*? is F.

91. The compound of claim 79, wherein the compound is selected from: R32 o a 2 N 7 N—\, R* : R32 2 ? \ R31 a : (2 andl o A rR 7 ° o NTN RT RZ oN? L2 = 12 ¥ N= N= R31 NH R31 a ( F J B I AN O CD al R¥ al 0 NNT 0 N7 NT u2 = J 12 = = — ROT SNH SNH i d a i d a B B and 92. The compound of claim 79, wherein the compound is selected from: IN R¥ N— 32 33 oy . R NTN R = ~~ 2_L i N= rR NTN RE RO? NT N- 01 “2 rg pes i» N— N— ~ i SNH RAY J—NH Ret ¢ 5 ° (: 32 ASN— RE NY " dn Nell ~~ R= NH a ~~ ad |. Lid net SE LL, EAN, = LAN, = "a wo RO JNH JH Re Foe NY N—\ N=l SN, TT XY oy R3f SNH pes FO 2 ~d B F J rR ON YON Sl a and .

93. The compound of any one of claims 79-92, wherein A* is: RM A I \ o=x' of claims 79-92, wherein A* 1s: A 34 R CSO — 3s = 7 3 \ t thf NN eo 0 94. The compound of any one of claims 79-92, wherein A* is: > o=( \ R% o — AB = Nas A HN R35 _ZA® Oo | A291 95. The compound of any one of claims 79-94, wherein A** is CH.

96. The compound of any one of claims 79-94, wherein A** is N.

97. The compound of any one of claims 79-94, wherein A3*is CR*2.

98. The compound of any one of claims 79-94, wherein A3* is CF.

99. The compound of any one of claims 79-98, wherein A*® is CH.

100. The compound of any one of claims 79-98, wherein A is N.

101. The compound of any one of claims 79-98, wherein A is CR*.

102. The compound of any one of claims 79-98, wherein A** is CF.

103. The compound of any one of claims 79-92, wherein A* is: 36 RY 37 R rR” RY 1 TN o= \ R } NN N rr 4 0 104. The compound of any one of claims 79-92, wherein A* is: 36 R¥ 237 R R37 i i no \ og XX I 1 AY R37 a \ RS X JF ‘A21 - \ 32 NN yr aa oC 105. The compound of claim 103 or 104, wherein A?! is NH.

106. The compound of claim 103 or 104, wherein A? is O.

107. The compound of any one of claims 79-92, wherein A* is; R¥ RS? TN yg R3 / o= y— 7 AY \ ;, A= " NX yy 0 108. The compound of any one of claims 79-107, wherein A% is CH.

109. The compound of any one of claims 79-107, wherein A% is N.

110. The compound of any one of claims 79-107, wherein A? is CR*2.

111. The compound of any one of claims 79-107, wherein Ais CF.

112. The compound of any one of claims 79-112, wherein A3 is CH.

113. The compound of any one of claims 79-112, wherein A3* is N.

114. The compound of any one of claims 79-112, wherein A* is CR*2, 115. The compound of any one of claims 79-112, wherein A* is CF.

116. The compound of any one of claims 79-92, wherein A* is; R¥# "NN A o= YY GG \ x / ‘a21 AL X- , HN 0 117. The compound of claim 116, wherein A? is NH.

118. The compound of claim 116, wherein A? is O.

119. The compound of any one of claims 79-118, wherein R** is H.

120. The compound of any one of claims 79-118, wherein R** is F.

121. The compound of any one of claims 79-118, wherein R** is CH.

122. The compound of any one of claims 79-121, wherein R*® is H.

123. The compound of any one of claims 79-121, wherein R*® is F.

124. The compound of any one of claims 79-121, wherein R*® is CHs.

125. The compound of any one of claims 79-118, wherein R* and R* combine to form a - CH;-.

126. The compound of any one of claims 79-125, wherein R*! is independently selected at each instance from H, halogen (F, Cl, Br, or I), and Ci.¢-alkyl.

127. The compound of any one of claims 79-126, wherein R* is independently selected at each instance from H, halogen (F, Cl, Br, or I), and Ci.¢-alkyl. N 7 gat —u R 128. The compound of any one of claims 79-127, wherein B* is S — N 3 < AS 129. The compound of any one of claims 79-127, wherein B* is 130. The compound of any one of claims 79-127, wherein B* is — 5 oy 131. The compound of any one of claims 79-127, wherein B* is 132. The compound of any one of claims 79-131, wherein L2 is of formula: + a RE 2 RE XK (LI). wherein, X' and X? are independently at each occurrence selected from bond, heterocycle, aryl, heteroaryl, bicycle, alkyl, aliphatic, heteroaliphatic, -NR?’-, -CR*R*!-, -O-, -C(0)-, -C(NR?")-, -C(S)-, -S(0)-, -S(0O)2- and -S-; each of which heterocycle, aryl, heteroaryl, and bicycle is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R*; RR?! R%, R¥, and R* are independently at each occurrence selected from the group consisting of a bond, alkyl, -C(0)-, -C(0)0-, -OC(0)-, -803-, -8(0)-, -C(S)-, -C(O)NR?’-, -NR?’C(0)-, -O-, -S-, -NR*-, oxyalkylene, -C(R*R*)-, -P(O)OR*)0-, -P(0)(OR%)-, 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 R*’; R* is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocycle, aliphatic and heteroaliphatic; R? is independently at each occurrence selected from the group consisting of hydrogen, alkyl, aliphatic, heteroaliphatic, heterocycle, aryl, heteroaryl, -C(O)(aliphatic, aryl, heteroaliphatic or heteroaryl), -C(O)O(aliphatic, aryl, heteroaliphatic, or heteroaryl), alkene, and alkyne; R* is independently at each occurrence selected from the group consisting of hydrogen, RY", alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH(aliphatic), -N(aliphatic)z, -NHSOx(aliphatic), -N(aliphatic)SOzalkyl, -NHSOx(aryl, heteroaryl or heterocycle), -N(alkyl)SOa(aryl, heteroaryl or heterocycle), -NHSOqalkenyl, -N(alkyl)SOzalkenyl, -NHSO:alkynyl, -N(alkyl)SO.alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocycle, oxo, and cycloalkyl; additionally, where allowed by valence two R* groups bound to the same carbon may be joined together to form a 3-8 membered spirocycle; and R* is aliphatic, aryl, heteroaryl, or hydrogen.

133. The compound of claim 132, wherein L? is of formula: ~ R22 R20 per” Np - FE or wt” R or 5X 134. The compound of claim 132 or 133, wherein X! is bond.

135. The compound of claim 132 or 133, wherein X' is heterocycle.

136. The compound of claim 132 or 133, wherein X' is NR2.

137. The compound of claim 132 or 133, wherein X! is C(O).

138. The compound of any one of claims 132-137, wherein X? is bond.

139. The compound of any one of claims 132-137, wherein X? is heterocycle.

140. The compound of any one of claims 132-137, wherein X? is NR2, 141. The compound of any one of claims 132-137, wherein X? is C(O).

142. The compound of any one of claims 132-141, wherein R? is bond.

143. The compound of any one of claims 132-141, wherein R¥ is CHa.

144. The compound of any one of claims 132-141, wherein R? is heterocycle.

145. The compound of any one of claims 132-141, wherein R? is aryl.

146. The compound of any one of claims 132-141, wherein R% is phenyl.

147. The compound of any one of claims 132-141, wherein R? is bicycle.

148. The compound of any one of claims 132-147, wherein R?! is bond.

149. The compound of any one of claims 132-147, wherein R?! is CH.

150. The compound of any one of claims 132-147, wherein R?! is heterocycle.

151. The compound of any one of claims 132-147, wherein R?! is aryl.

152. The compound of any one of claims 132-147, wherein R?! is phenyl.

153. The compound of any one of claims 132-147, wherein R?! is bicycle.

154. The compound of claim 132, wherein L is a linker of formula: RRR A ES 155. The compound of any one of claims 132-1354, wherein R?? is bond.

156. The compound of any one of claims 132-154, wherein R?? is CH.

157. The compound of any one of claims 132-154, wherein R?? is heterocycle.

158. The compound of any one of claims 132-154, wherein R? is aryl.

159. The compound of any one of claims 132-154, wherein R?? is phenyl.

160. The compound of any one of claims 132-154, wherein R?? is bicycle.

161. The compound of claim 132, wherein L is a linker of formula: R24 7 ZN a 162. The compound of any one of claims 132-161, wherein R? is bond.

163. The compound of any one of claims 132-161, wherein R? is CH.

164. The compound of any one of claims 132-161, wherein R? is heterocycle.

165. The compound of any one of claims 132-161, wherein R? is aryl.

166. The compound of any one of claims 132-161, wherein R?* is phenyl.

167. The compound of any one of claims 132-161, wherein R* is bicycle.

168. The compound of any one of claims 132-167, wherein R** is bond.

169. The compound of any one of claims 132-167, wherein R** is CHa.

170. The compound of any one of claims 132-167, wherein R?* is heterocycle.

171. The compound of any one of claims 132-167, wherein Ris aryl.

172. The compound of any one of claims 132-167, wherein R?* is phenyl.

173. The compound of any one of claims 132-167, wherein R** is bicycle.

174. The compound of any one of claims 132-167, wherein R** is C(O).

175. A compound selected from: oo H N OGIO Om N \ = NTNANCN CO-C Oo O=r v's E H F 0 Fe 5-((2-(1-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-ox0-2-(thiazol-2-ylamino)ethyl)- 7-fluoro-3-oxoisoindolin-5-ylJethynyl)-N-(1-(2-(4-(4-((2,6-dioxopiperidin-3- yl)amino)phenyl)piperidin-1-yl)acetyl)piperidin-4-yl)picolinamide; H N27 7 \ / H o Q 0 N NY) mm H OH LY A= FN 0 fe) 2 H Oo [FR H A F 5-[2-[2-[1-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-yl)-2-ox0-2-(thiazol -2- ylamino)ethyl]-7-fluoro-3-oxo-isoindolin-5-yl]ethynyl]-N-[1-[2-[4-[(2,6-diox0-3- piperidyl)amino]phenyl]acetyl]-4-piperidyl]pyridine-2-carboxamide piperidyl)amino]phenyl]acetyl]-4-piperidylpyridine-2-carboxamide ~~ 0 0 7 NN Ye AH =~ o Nols AN AY X 0° H H No = ~~ | H NW == ~~ H ~~ © NNN N ~ 0 Ar oy Nes = NYA Ie L SJ F 5-[2-[2-[1-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-yl)-2-ox0-2-(thiazol -2- ylamino)ethyl]-7-fluoro-3-oxo-isoindolin-5-yl]ethynyl]-N-[ 1-[2-[4-[4-[(2,6-diox0-3- piperidyl)oxy]phenyl]piperazin-1-yl]acetyl]-4-piperidyl]pyridine-2-carboxamide H tf ~ S 3 9 0 \ (AMT = Ty ~~ @! N Colm AY eo TTT Yn H 0 s) E 5-[2-[2-[1-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-yl)-2-ox0-2-(thiazol -2- ylamino)ethyl]-7-fluoro-3-oxo-isoindolin-5-ylJethynyl]-N-[1-[2-[4-[4-[[(3S)-2,6-diox0-3- piperidyl]amino]-2-fluoro-phenyl]-1-piperidyl]acetyl]-4-piperidyl]pyridine-2-carboxamide FE 78 o oy An () RP H N ) NO NO ox" on VW N~"N a ~S oO J NT = AN H o NY wey “Cy H CTA 4-1 [4T4-1(7 6-dioxa.3 NAN oo ~~ H 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-[6-[4-[4-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]phenyl]-1-piperidyl]acetylJpiperazin-1-yl]phenyl]-4-fluoro-1-oxo- isoindolin-2-y1]-N-thiazol-2-yl-acetamide NANNY ~~ oH Ison Nmzy i -INLIdZY F Ct 0 a As ; {() H N ) NT, ~~ 0 | 7 NT) ~~ LN ly 0 NY of “AO H ALAN? TATAMTEISVW"? Godinye Nr TS oo ~~ H 2-(6,7-dihydro-SH-pyrrolo[1,2-climidazol-1-yl)-2-[6-[4-[4-[2-[4-[4-[[(38)-2,6-diox0-3- piperidyl]lamino]phenyl]-1-piperidyl]acetyl]piperazin-1-yl]phenyl]-4-fluoro-1-oxo- isoindolin-2-y1]-N-thiazol-2-yl-acetamide H 1 1501naolin-z-y! -IN-U1d ZO] F E20 NF / AAO ~ A 5 Lo 2 N N 7 Hy 0 H NN N I © cad Oo NZ H ihydro-SH-pyrrolo[1,2-climidazol-1-y1)-2-[6-[4-[4-[2-[4-[4-[[(3R)-2,6-dioX0- 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol -1-y1)-2-[6-[4-[4-[2-[4-[4-[[(3R)-2,6-diox0-3- piperidyl]amino]phenyl]-1-piperidyl]acetyl Jpiperazin-1-yl]phenyl]-4-fluoro-1-oxo- isoindolin-2-yl1]-N-thiazol-2-yl-acetamide H H 0 re oO 0 eC 7 H Hoo gin ~ “~~, H Vil A A EA TA 2d mins mian anima ol an 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-(6-(4-(4-(4-(4-(4-((2,6-dioxopiperidin-3- | yl)amino)phenyl)piperidin-1 -yl)-4-oxobutyl)piperazin-1 -yl)phenyl)-4-fluoro-1 - oxoisoindolin-2-y1)-N-(thiazol -2-yl)acetamide 2 I NT LN H Ty AA a a CT © CON Rp « Oxy ~ ~~~ I~ N H LAT TA FA TID dl imran sn same od H 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-(6-(4-(4-(2-(4-(4-((2,6-dioxopiperidin-3- yl)amino)phenyl)cyclohexyl)acetyl)piperazin-1-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)- MY FV iil yo an N-(thiazol-2-yl)acetamide H Qe fs | , WA (Dw) 0 0 ON 7 H o a 0. Neg ‘N Uo -(4-(2-(4-(4-((2,6-dioxopiperid nT ~~ H | 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-(6-(4-(4-(2-(4-(4-((2,6-dioxopiperidin-3- | yl)amino)phenyl)piperidin-1-yl)-2-oxoethyl)piperazin-1-yl)phenyl)-4-fluoro-1- oxoisoindolin-2-y1)-N-(thiazol-2-yl)acetamide H 7 MAUI 2 =IN={ LIlld. F Xp N= N / yn NT A oO sr! NT = (CLG LR) ig o yA @ OOS I~ 0 0 av N\N~7 -dihydro-5H-pyrrolo[ 1,2-climidazol -1-y1)-2-[6-[4-[4-[2-[4-[ 5-[(2,6-diox0-3- 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-[6-[4-[4-[2-[4-[ 5-[(2,6-diox0-3- piperidyl)amino]-2-pyridyl]-1-piperidyl]acetylJpiperazin-1-yl]phenyl]-4-fluoro-1-oxo- isoindolin-2-yl]-N-thiazol-2-yl-acetamide H iF _ isoindolin-2-y1]-N-thiazol R E25 = Cam J A “N\ o ~ ay fF N N. NT NY Ty d A of 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]limidazol -1-yl)-2-[6-[4-[4-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]-2-fluoro-phenyl]-1-piperidylJacetyl]piperazin-1-yl]phenyl]-4-fluoro-1- oxo-isoindolin-2-yl -N-thiazol-2-yl-acetamide ) 7 ~~ H 0 oxo-1so1ndolin-2-yl|-IN-1hia: [4 Fel 13 Mr ©» x a RN ZN. 0 ~~ F 7X N NH Chay H 0 Lf (" NA weg ~AN NZ 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-[6-[4-[4-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]-3-fluoro-phenyl]-1-piperidyl Jacetyl]piperazin-1-yl]phenyl]-4-fluoro-1- oxo-isoindolin-2-y1]-N-thiazol -2-yl-acetamide ~~ i iA SSS rn N- = pel AT NL oot N () () wl § O H 0 ~~ a ‘N N A 7’ ~~ A 2-[6-[4-[4-[2-[4-[2-cyano-4-[(2,6-dioxo-3-piperidyl Jamino]phenyl]-1- piperidyl]acetyl]piperazin-1-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl1]-2-(6,7-dihydro- SH-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide F SN oO Hf N OO N_ HN, © ~ % Ay A F- H H o TCO 0n E H F ~ hdl ~~ Wu s, P~ w / F H 0 2-[6-[4-[4-[2-[4-[2-(difluoromethy])-4-[(2,6-dioxo-3-piperidyl Jamino]phenyl]-1- piperidyl]acetyl]piperazin-1-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-2-(6,7-dihydro- SH-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide [4 2) H 2 () NY (do H AM d H —~A. © 0 n I 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-(6-(4-(4-(2-(4-(3-((2,6-dioxopiperidin-3- yl)amino)phenyl)piperidin-1-yl)acetyl)piperazin-1-yl)phenyl)-4-fluoro-1-oxoisoindolin-2- y1)-N-(thiazol-2-yl)acetamide — / \ NyS £ XN Lif Fr Nf N 5 SS N y . O \=N - ( NL ° \ 7 N My = Te g \ \ 4 \ « .N F =\ N- / “2 NN 1 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol -1-y1)-2-(6-(4-(4-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1- yl)acetyl)piperazin-1-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol-2-yl)acetamide N A I~ 0 » LT) De af Va aWs ou Of ho) % > FS 5 RP 2 oN ~~ N F: H FE F ~ H oA 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-(6-(4-(4-(2-(1-(4-((2,6-dioxopiperidin-3- | yl)amino)-2-(trifluoromethyl)phenyl)-4-hydroxypiperidin-4-yl)acetyl)piperazin-1- yDphenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2-yl)acetamide = FE AA H_o H NT an ost N = ~A & I~ = OG: NAL NAA H_o H NT an ost N ~\ © OC NN ° N 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-(6-(4-(4-(2-(4-(4-((2,6-dioxopiperidin-3- yl)amino)phenyl)piperidin-1-yl)acetyl)piperazin-1-yl)phenyl)-4-fluoro-1-oxoisoindolin-2- y1)-N-(pyridin-2-yl)acetamide H If B = N- WA \ N AN Oxy Aelia? Snchiitcbiiloneil d? i F N CX ¢ nA H NT —~— ~ LN oO NT Pats LA Wj H o He an O: ‘N Oy 5 ’ H 5-[4-[4-[2-[4-[4-[(2.6-diox0-3- 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-[6-[4-[4-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]acetyl |piperazin-1-ylJphenyl]-4-fluoro-1- oxo-isoindolin-2-yl]-N-(2-pyridyl)acetamide Fo } oO 0 NZ 0 N H o H N I~ o ~ IPN oo ANN 3 \-N-2 0 N H 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-(6-(4-(1-(2-(4-(4-((2,6-dioxopiperidin-3- yl)amino)phenyl)piperidin-1-yl)acetyl)piperidin-4-yl)phenyl)-4-fluoro-1-oxoisoindolin-2- v1)-N-(thiazol-2-yl)acetamide H Oo) n={ Yo 0 Ws UG H o NT os Mf “ACO H 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(1-(2-(4-(4-(((S)-2,6- H | dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)acetyl)piperidin-d-y phenyl)-4-fluoro-1- | oxoisoindolin-2-y1)-N-(thiazol -2-yl)acetamide F 3 o N= ; {() H N N He H \ NY oN ~A AN SS CT NZ OG TT ~~ H 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-(6-(4-(1-(2(4-(4-((R)-2,6~ Ho N NY ss “Oy (6-4-1 -2-(4-(4-(((R)-2.,6- H | dioxopiperidin-3-yl)aminojphenyl)piperidin-1-yl)acetyl)piperidin-d-y phenyl)-4-fluoro-1- | oxoisoindolin-2-y1)-N-(thiazol -2-yl)acetamide F 7S o 3 , {() HP § N () ~~ oN n NN ~_ a ww / \ I~ \ oO 7 OC H o NY il “A E H Yel B= Af 1 =(2=(A=(A-{((S)-? 6= \-N-7 - gH 2-(6,7-dihydro-SH-pyrrolo[1,2-climidazol-1-y1)-2-(6-(4-(1-(2-(4-(4-(((S)-2,6- | dioxopiperidin-3-yl)amino)-2-fluoropheny!)piperidin-1-yl)acetyl)piperidin-4-yl)phenyl)-4- | © _Tfluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide F x SAL N { ~ 0 i hp HN 0 LI < “0 A N §.- “oR aC— No RP Le \ / ~ oN NT N N_ HN 0 — % N A R LN 7 2-(6-(4-(1-(2-(4-(2-cyano-4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1- yl)acetyl)piperidin-4-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H- H 7 pytrolo[1,2-c imidazol -1-y1)-N-(thiazol-2-yl)acetamide F po = o AR AO ey ° N =~ ~~ AN A — I~) 0 WA 3 24 WIAA Oo ~ 1 S H N N ~\ 0 — “Dy NZ H ihydro-SH-pyrrolo[1,2-¢limidazol -1-y1)-2-[6-[4-[ 1-[2-[4-[4-[(2,6-diox0-3- 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-yl)-2-[6-[4-[ 1-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]phenyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl Jphenyl]-4-fluoro-1-oxo- isoindolin-2-y1]-N-thiazol-2-yl-acetamide 1soindolin-2-yl]-N-thiazol F 1 o =A 7 J dG ~ 0 R oy N ~s = o A \ o ¥ H Oy 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[6-[4-[2-[4-[4-[[(3S)-2,6-diox0-3~ piperidyl]Jamino]-2-fluoro-phenyl]-1-piperidyl]acetyl]piperazin-1-yl]-3-pyridyl]-4-fluoro- 1-oxo0-isoindolin-2-yl]-N-thiazol-2-yl-acetamide 5 F N= 9 | HN Oo H OOO INA MN = N O =n po 0 N / N= H N, H © - H © 2-(6,7-dihydro-SH-pyrrolo[ 1,2-climidazol-1-yl)-2-[6-[ 1-[ 1-[2-[4-[4-[[(3S)-2,6-dioxo-3- piperidyl]Jamino]phenyl]-1-piperidyl]acetyl]-4-piperidyl]pyrazol-4-y1]-4-fluoro-1-oxo- isoindolin-2-yl]-N-thiazol-2-yl-acetamide 3 £ | =o FE a OA H N, H © 1501n4aolin--y1 =IN-U1a ZC -i F \={ iv-L ~~ ~A " hd = Ne NN & \_N N © oo H © 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[ 1-[2-[4-[4-[[(3S)-2,6-diox0-3- piperidyl]Jamino]phenyl]-1-piperidyl]acetyl]-4-piperidyl]pyrazol -1-y1]-4-fluoro-1-oxo- isoindolin-2-y1]-N-thiazol-2-yl-acetamide “Nl ~~ x Le —N ~~ $ oO vr N — 0 \ MOY / a > Nan NN N\_7 4 What Ff el TTS THN 0 2-(6,7-dihydro-SH-pyrrolo[1,2-climidazol-1-y1)-2-(6-(1-(1-(2-(4-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)acetyl)piperidin-4-yl)-1H-1,2,3-triazol -4- y1)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2-yl)acetamide 2\, H ’ 5 N. HN— ~~ A a Lg a H1az01-4-yl)atelalllide f ST NAD ) H “N. , ~~ H I | THAN Ee = 1 N Ns { i : LC 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol -1-y1)-2-[6-[4-[[ 1-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]phenyl]-1-piperidyl]acetyl]-4-piperidyl]Joxy]phenyl]-4-fluoro-1-oxo- isoindolin-2-y1]-N-thiazol-2-yl-acetamide 2\, H Lp ° - HN— ~~ A a gr yl=ateldInide KN SIX , H “N. , ~~ H I | THAN AINA N=) 1 N Ns { 5 hy ® O 2-(6,7-dihydro-SH-pyrrolo[ 1,2-c]imidazol-1-y1)-2-[6-[4-[[ 1-[2-[4-[4-[[(3S)-2,6-diox0-3- piperidyl]Jamino]phenyl]-1-piperidyl]acetyl]-4-piperidylJoxy]phenyl]-4-fluoro-1-oxo- isoindolin-2-y1]-N-thiazol-2-yl-acetamide 2\, H Cl a F N, HN— ~~ A a Lr Pa y -aLtiamiage H N,, AN SIL A | H "N. : ~~ H 1 | ~~ ZZ AN a N Nl a N Py 2-(6,7-dihydro-SH-pyrrolo[ 1,2-climidazol -1-y1)-2-[6-[4-[[ 1-[2-[4-[4-[[(3R)-2,6-diox0-3- piperidylJamino]phenyl]-1-piperidyl]acetyl]-4-piperidylJoxy]phenyl]-4-fluoro-1-oxo- isoindolin-2-y1]-N-thiazol-2-yl-acetamide O ’ A Nt fo] 0 oils AA a J N “N. J a MN o = C 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-(6-(4-((1-(2-(4-(4~((2,6-dioxopiperidin- 3-yl)amino)-3-fluorophenyl)piperidin-1-yl)acetyl)piperidin-4-yl)oxy)phenyl)-4-fluoro-1- oxoisoindolin-2-y1)-N-(thiazol -2-yl)acetamide H oP N Ao 4 F. N - F ~N $l A 0 IT ANA l ~~ H 1 | Pig, = EN AINA N Nl a N “a 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-(6-(4-((1-(2-(4-(4-((2,6-dioxopiperidin- 3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)piperidin-4-yl)oxy)phenyl)-4-fluoro-1- oxoisoindolin-2-y1)-N-(thiazol -2-yl)acetamide oP N Ao 2 H $e CT °° " H 1 | Pu Z EN eo N AN a N “a 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-(6-(4-((1-(2-(4-(5-((2,6-dioxopiperidin- 3-yl)amino)pyridin-2-yl)piperidin-1-yl)acetyl)piperidin-4-yl)oxy)phenyl)-4-fluoro-1- oxoisoindolin-2-y1)-N-(thiazol -2-yl)acetamide Na H A N. ~Ny OF NA A= ~N 0 AN Po Ns N JS oP NL H IN 0 YY AN a J SN F 24 | —N Fe oy ~ $ 1S 2-(6-(4-((1-(2-(4-(2-cyano-4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1- yl)acetyl)piperidin-4-yl)oxy)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-2-(6,7-dihydro-5H- pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide NL T ~~ H To SANS 0 A 0. Lh je _N E NN F H 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-(6-(4-((1-(2-(4-(4-((2,4-diox0-3- azabicyclo[3.1.1]heptan-1-yl)amino)phenyl)piperidin-1-yl)acetyl )piperidin-4- yl)oxy)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol -2-yl acetamide H oP N Ao 8 F. N = 0 F rT We 0 IT PNA y ~~ H n | THAN te N=) 1 N Ns Oo on {i 0 | OLY 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-(6-(4-((1-(2-(4-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)piperidin-4- yl)oxy)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2-yl)acetamide 2\, H Dy 5 7 N. HN— —A a Lr AF LJ=IN Wiles oy allldlllld ¥ ATE "N. l ~~ H 1 | Pig, FZ EN AINA 0 NY AN 0. 8 a N 3 CC 2-(6,7-dihydro-5H-pyrrolo[ 1,2-cJimidazol-1-y1)-2-[6-[4-[[ 1-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]phenyl]-1-piperidyl]-2-oxo-acetyl]-4-piperidyl]oxy]phenyl]-4-fluoro-1- oxo-isoindolin-2-y1]-N-thiazol -2-yl-acetamide 7 —) —N a 3 ? =p nN —) N: ms H N NH \ ~A oo © HN nN 0 Pik TE I ST 2-(6,7-dihydro-SH-pyrrolo[1,2-c]imidazol-1-y1)-2-[6-[4-[(3R)-1-[2-[4-[4-[[(3S)-2,6-diox0- 3-piperidyl]Jamino]phenyl]-1-piperidyl]acetyl]pyrrolidin-3-yl]Joxyphenyl]-4-fluoro-1-oxo- isoindolin-2-yl]-N-thiazol-2-yl-acetamide / — \ —N, zr NX H rr } “oO H N i EN 4 C SO i 1 ) v oo Fy © “0 © HN— Ns ° 2-(6,7-dihydro-SH-pyrrolo[ 1,2-climidazol -1-y1)-2-[6-[4-[(3S)-1-[2-[4-[4-[[(3S)-2,6-diox0- 3-piperidylJamino]phenyl]-1-piperidyl]acetyl]pyrrolidin-3-ylJoxyphenyl]-4-fluoro-1-oxo- isoindolin-2-yl]-N-thiazol-2-yl-acetamide H 0 isoindolin-2-yl]-N-thiazol F gage a (Om HN NON i o © | aA NT) ~~ N N AN NY 0 NP OL / " TH 2-(6-(4-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1- yl)acetyl)piperazin-1-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-2-((R)-6-fluoro-6,7- dihydro-5H-pyrrolo[1,2-climidazol-1-yl)-N-(thiazol-2-yl)acetamide F SN Lx {) H 0 i - O he ~f Wp 0 NT L~) A QN 0 Se N Oh 0 H o Ny o. NY gl iy F H o RN. oN O <4 oN 7 x 7 iy NO TY Ss N EY Co = 7 F = Ns \ 7 / 7 NN i 2-[6-[4-[4-[2-[4-[3-(2,4-dioxohexahydropyrimidin-1-y1)-1-methyl-indazol-6-y1]-1- piperidyl]acetyl]piperazin-1-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-2-[(6R)-6-fluoro- 6,7-dihydro-SH-pyrrolo[ 1,2-cJimidazol -1-y1]-N-thiazol-2-yl-acetamide O00 yr 0 — = H o Ny N~¢ SC, ND °~_ ~ o ~ N N > N NN 7 H FL ™ Ailcrden CLT wcrermmd ATT PD Allen dam~l 1 GIN FE FAD (DY FA FA (FIC MN £ NAN Sg H 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(2-(2-(4-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)-2,7- diazaspiro[3.5]nonan-7-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2- yl)acetamide = 7 C H 0 1 py, N yA DN ro i ~\ © ~ sn? N N \N~Z g H ER aaa NAN-Z = ~~ H 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-[6-[4-[2-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]phenyl]-1-piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4- oO fluoro-1-oxo-isoindolin-2-yl]-N-thiazol -2-yl-acetamide F 3 o a {) ) H 4 OO SC N ~~ 0 nN + NZ o N RP NT ~f “A F H ee =. 7 H F 2-(6,7-dihydro-SH-pyrrolo[1,2-climidazol-1-yl)-2-[6-[4-[2-[2-[4-[4-[[(38)-2,6-diox0-3- piperidylJamino]-2-fluoro-phenyl]-1-piperidylJacetyl]-2,6-diazaspiro[3.3]Theptan-6- yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazol -2-yl-acetamide H ost ON N— N " i yiphenyl |-4-TIUOro- 1 -0X0-1501naolin-2-yi | -IN-thiazc [\ Ny io Con 9 N SC NC F 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol -1-yl)-2-[6- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-1 Br te ih AL a A Ta 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol -1-y1)-2-[6-[4-[2-[2-[4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-1-piperidyl]acetyl]-2,6- diazaspiro[3.3]heptan-6-yl]Jphenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazol -2-y1- acetamide H o anf? ONL 1 HN. © H Yoo o ox" Cos N N / N— / kat ) $<) oC Sas F LF N 2-(6,7-dihydro-SH-pyrrolo[1,2-climidazol -1-y1)-2-[6-[4-[2-[2-[4-[3-(2,4- 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol -1-y1)-2-[6-[4-[2-[2-[4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-3,3-difluoro-1-piperidyl]acetyl]- 2,6-diazaspiro[3.3]heptan-6-y1]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-N-thiazol-2-yl- acetamide F H ai 9 F N° " yA » N N i © oy 0 oO << Coo ry NT © ~~ H NZ 2-(6,7-dihydro-5H-pyrrolo[ 1,2-cJimidazol -1-y1)-2-(6-(4-(6-(2-(4-(4-((2,6-dioxopiperidin-3- yl)amino)pheny!)-3,3-difluoropiperidin-1-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2- yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2-yl)acetamide yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2 = F nw () ) N I~ = o DN N C0 x A H o NY) oN? \ “ ~~ y SY og F H 2-(6,7-dihydro-SH-pyrrolo[1,2-climidazol-1-yl)-2-[6-[4-[2-[2-[4-[4-[[(38)-2,6-diox0-3- piperidylJamino]-2-fluoro-phenyl]-1-piperidylJacetyl]-2,6-diazaspiro[3.3]Theptan-6- yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-N-(2-pyridyl)acetamide —N ’ IAN F | HNO SoS = 0 o Ng? Rey { J OOH, Q pi F 3 | LN Ne \ NN 1 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol -1-y1)-2-[6-[4-[2-[2-[4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-1-piperidyl]acetyl]-2,6- diazaspiro[3.3]heptan-6-ylJphenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-(2- pyridyl)acetamide gllhyllnsnllilve A ~N HN. _©O Yo o NP SN SS N o = S000 v, f F LF N 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol -1-y1)-2-[6-[4-[2-[2-[4-[3-(2,4- xohexahvdropvrimidin-1-v1)-1-methvl-indazol -6-v11-3.3-difluoro-1-piperidv] lace = | \ — ™N x Nn HAO \ \ -N F ' F N 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol -1-y1)-2-[6-[4-[2-[2-[4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-3,3-difluoro-1-piperidyl]acetyl]- 2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-N-(2- pyridyl)acetamide 2\, H CL 5 ¥ N. HN— A a Lr AF A NIN, A 90 OY ANN NJ N Ns ¢ ov —N C | < CN N © No 2-(6,7-dihydro-SH-pyrrolo[ 1,2-climidazol -1-y1)-2-[6-[4-[[4-[2-[4-[4-[(2,6-diox0-3- | piperidyl)amino]phenyl]-1-piperidyl]acetyl |piperazin-1-ylJmethyl]phenyl]-4-fluoro-1-oxo- isoindolin-2-y1]-N-thiazol-2-yl-acetamide 0 oP N Ao Joh Lapa uliadia yl abo alive Ns F R =o F Sy HN— ~N 2 GND —N | TR H : ~~ H 1 | TYAN AINA N=) | f N Nl { No —N Cl | apeve] MN © No 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-[6-[4-[[4-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]acetyl Jpiperazin-1-ylJmethylphenyl]-4- fluoro-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide H Os =( oN N Ao _P F F No Wl 0 SX PA 4 ~~ H I | TYAN Te N=) 1 i 0 OY sp Moo I’ N Nl L N 4 ® i —N roo MN © NS 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-[6-[4-[[4-[2-[4-[4-[[(3S)-2,6-diox0-3- piperidyl]amino]-2-fluoro-phenyl]-1-piperidyl]acetyl Jpiperazin-1-ylJmethylphenyl]-4- fluoro-1-oxo-isoindolin-2-yl]-N-thiazol -2-yl-acetamide oP N Ao im aa de dA amy TN aa may Tree LU Ns F R =( 0 F SP HN— ~N ND —N | 0 H X ~~ H TYAN NNN N= i | 1 {¢ vr ~~ 1) oy | pt Q OQ No g PR SE Af Al 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-[6-[4-[[4-[2-[4-[4-[[(3S)-2,6-diox0-3- piperidyl]amino]-2-fluoro-phenyl]-1-piperidyl]-2-oxo-ethyl Jpiperazin-1- yl]methyl]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-N-thiazol-2-yl-acetamide H oA N Ao [oe] F. N - F NN pS 0 XJ PNA | ~~ H 1 | TYAN AINA = 1 0 YY AAS a) N Nl i _ Feo 2-(6,7-dihydro-SH-pyrrolo[ 1,2-c]imidazol -1-y1)-2-[6-[4-[[ 1-[2-[4-[4-[[(3S)-2,6-diox0-3- piperidyl]amino]-2-fluoro-phenyl]-1-piperidyl]acetyl]-4-piperidyl [methyl ]phenyl]-4- fluoro-1-oxo-isoindolin-2-yl]-N-thiazol -2-yl-acetamide COG AN “UN. NTS | ’ 1 dif Oo 7 1 | | SRL CNY rom NH NH J Ne NN | SN Na ( F N’ oN) N— =~) 0 wv he YN 0 J=N SS 2-[4,7-dichloro-6-[4-[4-[2-[4-[4-[(2,6-diox0-3-piperidyl Jamino]phenyl]-1- piperidyl]acetyl]piperazin-1-yl]phenyl]indazol -2-yl]-2-(6,7-dihydro-5H-pyrrolo[ 1,2- climidazol-1-y1)-N-thiazol-2-yl-acetamide COG AN “UN. NTS | fo] IN pO NUNN I~ dN JY) 5 NO NH H JN NT N ~~ rs F I% Z NO) sw J v he 7 0 )=N SA | 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-(6-(6-(4-(4-(4-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-4-yl)oxy)piperidin-1-yl)-4-oxobutyl)piperazin-1-yl)pyridin-3-yl)-7- fluoro-2H-indazol-2-yl)-N-(thiazol -2-yl)acetamide 0 A ANS F Na N—\ N= ~ NH J Mo NY SAN rs F N° AA) sa | J 2 7 HH ANY A 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-(6-(6-(4-(2-(4-(4-((2,6-dioxopiperidin-3- yl)amino)phenyl)piperidin-1-yl)acetyl)piperazin-1-yl)pyridin-3-yl)-7-fluoro-2H-indazol-2- Tv RT Lt Rh mmr] ™ or Xl mment reves rdm y1)-N-(thiazol-2-yl)acetamide NP | HN oO F Nt AN NESEY AN N N SN ¢ E —N, | o! {ON 7 pt Se N NS | SNS SANA oO 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]limidazol -1-y1)-2-[6-[6-[4-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]-2-fluoro-phenyl]-1-piperidylJacetyl]piperazin-1-y1]-3-pyridyl]-4-fluoro- indazol-2-y1]-N-thiazol-2-yl-acetamide AP | HN oO F Nt AN NSIS AN 0 k { ~ | —N | N 7 ’ N Grin, NN SNS SANA oO 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-[6-[6-[4-[2-[4-[4-[(2,6-diox0-3- | piperidyl)amino]phenyl]-1-piperidyl]acetyl|piperazin-1-y1]-3-pyridyl]-4-fluoro-indazol -2- TY NT ah mim]. My anh yl]-N-thiazol-2-yl-acetamide EP | HN 0 F “Nt AN NSIS AN N N SN 0 F LA " —N, = < N Z [ N ng NY SONS SANA oO 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-[6-[6-[4-[2-[4-[ 5-[(2,6-diox0-3- | piperidyl)amino]-2-pyridyl]-1-piperidyl acetyl ]piperazin-1-yl]-3-pyridyl]-4-fluoro-indazol- PY YY AT tlk am] Pons avid rn enn ol iy 2-yl]-N-thiazol -2-yl-acetamide SN + Nl o 0 F [ {LA —N, _ < Tn I SNNTY | | SNS CNTY ON SN oY 2-(6,7-dihydro-SH-pyrrolo[ 1,2-climidazol -1-y1)-2-[6-[6-[4-[2-[4-[3-(2,4- | dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-1-piperidyl]acetyl]piperazin-1-yl]- 3-pyridyl]-4-fluoro-indazol -2-yl]-N-thiazol -2-yl-acetamide AP ! HN oO F Nt AN NSIS AN £ z —N, | o {ON 7 gH Se N NS | SNS SANA oO 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-(6-(6-(4-(2-(4-(4-(((S)-2,6- | dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)piperazin-1-yl)pyridin-3- | y1)-4-fluoro-2H-indazol-2-y1)-N-(thiazol-2-yl)acetamide or a pharmaceutically acceptable salt thereof.

176. A compound selected from: oO ND N— ~~ Neo An = NH J 3. Q Ay Aa F N— qf J oO aA ANY oA 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-(6-(6-(6-(2-(4-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)-2,6- diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-7-fluoro-2H-indazol-2-yl)-N-(thiazol-2- yl)acetamide oO | ANS F Nl F SAF oO XK N . IY oH NS Ld™ x Lr” & N - N N_ iy 2-(6,7-dihydro-SH-pyrrolo[ 1,2-climidazol -1-y1)-2-(6-(6-(6-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1- ylacetyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-7-fluoro-2H-indazol -2-y1)-N- (thiazol -2-yl)acetamide NZ N— / \ H Ie thiazol-2-yl acetamide o N7 ] F nN? Ng NA) Jo > ~ - Q SN F SH oP N"So | 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-(6-(6-(6-(2-(1-(4-((2,6-dioxopiperidin-3- | yl)amino)-3-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3Jheptan-2- yDpyridin-3-yl)-7-fluoro-2H-indazol -2-yl)-N-(thiazol-2-yl Jacetamide Q ~~ | NS po F ot SF TF N NN ry o N N_~ ’ {LN : —N _ X : JN F ( Oo "yy 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol -1-y1)-2-(6-(6-(4-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1- yl)acetyl)piperazin-1-yl)pyridin-3-y1)-4-fluoro-2H-indazol -2-yl)-N-(thiazol-2-yl)acetamide PLN F Nef ue 5 a NN LY a = @! N IND N N._ y 2-(6,7-dihydro-SH-pyrrolo[ 1,2-climidazol -1-y1)-2-(6-(6-(6-(2-(4-(3~(2,4- dioxotetrahydropyrimidin-1(2H)-y1)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1- yl)-2-oxoethyl)-2,6-diazaspiro[ 3.3 ]heptan-2-yl)pyridin-3-yl)-7-fluoro-2H-indazol-2-yl)-N- thiazol-2-yl)acetamide NT N—\ SN NH J MN © NZ ] F N? woo nA A) F 5 Ty f oO 0 aA ANY PN 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-(6-(6-(6-(2-(1-(4-((2,6-dioxopiperidin-3- yl)amino)-2-flucrophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2- yDpyridin-3-yl)-7-fluoro-2H-indazol-2-yl)-N-(thiazol-2-ylJacetamide NT N— / \ SNE NH J Me 0 i —————————————————————————— ——— eee seen 0 N = N SN Na oN, > F NN 7 0 F © UNH aA ANY PN 2-(6,7-dihydro-SH-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(6-(6-(2-(1-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6- diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-4-fluoro-2H-indazol-2-yl)-N-(thiazol-2- yl)acetamide oO | ANS et F SF N N._ oO A Lea pe YQ o SS iy 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-yl)-2-(6-(4-(6-(2-((R)-4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1- yDacetyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-2H-indazol-2-y1)-N-(thiazol -2- yl)acetamide Nl N— / \ SNE NH J MN 0 rivnitm————————— o N / of SN” 4g AN) F CL , 0 4 F ° UNH aA ANY A 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-(6-(4-(6-(2-( 1-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6- diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-2H-indazol -2-yl)-N-(thiazol -2-yl)acetamide NT N— / \ SN NH J Me © © OLX y NF F CX Ty oO A Oo oO aA ANY PN 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-(6-(4-(6-(2-(1-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6- diazaspiro[3.3]heptan-2-yl)phenyl)-7-fluoro-2H-indazol -2-yl)-N-(thiazol -2-yl)acetamide oO ND N— / \ o oO) Ck Ly H JY oO > ~~ 2) ip ; Or Y rr) H ANY oA 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-(6-(4-(7-(2-(1-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,7- diazaspiro[3.5]nonan-2-yl)phenyl)-4-fluoro-2H-indazol-2-y1)-N-(thiazol-2-yl)acetamide fe) NG NY N— / \ ~ NH J No [eo] An ANT PN 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-(6-(4-((1R,4R)-5-(2-(4-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol-2- ylacetamide Oy ™ | HN Si o ho ND N— / \ NN oO H I YN ; oO )=N SA 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-(6-(4-((1-(2-(4'-((2,6-dioxopiperidin-3- | yl)amino)-[1,1'-biphenyl]-4-yl)acetyl)piperidin-4-yl)oxy)phenyl)-4-fluoro-1-oxoisoindolin- 7 +14 NT 74nd? st Rnb rma) im 2-y1)-N-(thiazol-2-yl)acetamide fo) | ANS “oN 2 ~~ N= N N_! Ty: 2-(6,7-dihydro-5H-pyrrolo[1,2-c]limidazol-1-y1)-2-(6-(4-((1R,4R)-5-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)acetyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol-2- yl)acetamide 0 ND N—\ Sn J Su r on F J 0 aA ANT A 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol -1-y1)-2-(6-(4-(4-(2-(1-(4-((2,6-dioxopiperidin-3- yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)piperazin-1-yl)phenyl)-4- fluoro-1-oxoisoindolin-2-yl -N-(thiazol-2-yl)acetamide Vai 0, Nn \ NT N— / \ N— / N 7h N= J N° 1 ~~" 0 Chef > N— Yq J — x ~~) M0 0° = NH Sod” = 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(4-(2-(4-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)-1,4-diazepan-1- yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2-yl)acetamide 0 hd AS NG po £ ~~ N Nl 8 Q J | LY N i | "A 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol -1-y1)-2-(6-(4-(1-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2- oxoethyl)piperidin-4-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol-2-yl)acetamide O ry ANS ~N NT N—\ ~~ NH J Me F To , SN CL go d " E J 0 AN TT oA 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-(6-(4-(4-(2-(4-(4-((2,6-dioxopiperidin-3- yl)amino)-2-fluorophenyl)piperidin-1-yl)-2-oxoethyl)piperidin-1-yl)phenyl)-4-fluoro-1- oxoisoindolin-2-y1)-N-(thiazol -2-yl)acetamide AN “oN £ F “AF SN Ll ANN F 0 A N N oH NS va oN SA —N p Ql AN F a 3 "A 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol -1-y1)-2-(6-(6-(6-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1- yDacetyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-4-fluoro-1-oxoisoindolin-2-y1)-N- (thiazol -2-yl)acetamide 0 un HNN = i» N | I y 0 AY ANIA H oN £ NN F A ° 7 A No 0 Q > 4 AZ —N < AN F | 5-((2-(1-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-ox0-2-(thiazol -2-ylamino)ethyl)- | 7-fluoro-3-oxoisoindolin-5-yl)ethynyl)-N-(1-(2-(4-(3-(2,4-dioxotetrahydropyrimidin- 1(2H)-y1)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1-yl)acetyl)piperidin-4- ND N—\ SN N= Je 0 F yl)picolinamide 0 a 7 0 N SN ig bs F CI 0 F Go Mm | aA ANT PN | 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-(6-(4-(6-(2-(1-(4-((2,6-dioxopiperidin-3- | yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2- yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2-yl)acetamide ND N—\ SN IY o > F )-4-tluoro-1-oxo1soindolin-z-yl)-N-(thiazol-2- o a 7 Oo N SN ig bs NF CJ N— 9 r 0 F o nm | 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-(6-(4-(6-(2-(1-(5-((2,6-dioxopiperidin-3- | yl)amino)-3-fluoropyridin-2-yl)-4-hydroxypiperidin-4-yl)acetyl)-2,6- diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2- yl)acetamide oO EN AN H | © YN “AF i _ \ — Oy 7S 9 \ 7 \ 7 0 4 0 ! 0 NS Yn x 2-(6,7-dihydro-SH-pyrrolo[ 1,2-climidazol -1-y1)-2-(6-(4-(4-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-y1)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1- yDacetyl)-1,4-diazepan-1-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol -2- yl)acetamide 0 PEN PLN > =( oN £ SN N Nl Ne 30) LD \ F "y 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-y1)-2-(6-(4-(4-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperazin-1- vl)acetyl)piperazin-1-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol-2-yl)acetamide ANS F Wel STN NN F i % 2) a A Lio A oN F o | “x 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-(6-(4-(6-(2-((R)-4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1- yl)acetyl)-2,6-diazaspiro[3.3 Jheptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N- thiazol-2-yl)acetamide NG pW YAS SAF F £. Ll ANN F “To Ms, oq 2) a “ eg AN F ao | A 2-(6,7-dihydro-SH-pyrrolo[ 1,2-climidazol -1-y1)-2-(6-(4-(6-(2-((S)-4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-y1)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1- yl)acetyl)-2,6-diazaspiro[3.3heptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N- thiazol-2-yl)acetamide NY N—\ NH J Ye F Ay 0 N ~ “ord 5 N— J y £ 9 oY HA ANT A 2+(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-yl)-2-(6-(6-(6-(2-(4-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)-2,6- diazaspiro[3.3]heptan-2-y1)pyridin-3-yl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol -2- yl)acetamide H Ns N Sy Z ] Ny o N? ~ - F J i" o , F oN = a» Jk : hy oA 5-((2-(1-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-oxo0-2-(thiazol-2-ylamino)ethyl)- 7-fluoro-3-oxoisoindolin-5-yl)ethynyl)-N-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2- fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)piperidin-4-yl)picolinamide ND N—\ SN NH J Me F 0 N A 7 Ny” J) FN x » ¢ Ow 0 Fo © oY HS ANT A 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(6-(2-(1-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6- diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2- yl)acetamide ND N— / \ SN N= Je 0 xX F ylacetamide o a 7 Sa” J) 2 N_ N > - 0 Fo0 nm HP AN oN 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-(6-(4-(6-(2-(1-(4-(((R)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6- diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2- NT N— / \ SN” NH J Ve yl)acetamide o N 7 Oo N SN g = - 0, 0 F ¢ J NH =N 8 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-(6-(4-(6-(2-(1-(4-((2,6-dioxopiperidin-3- yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2- yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(pyridin-2-yl)acetamide ANS ND N—\ ~ LAA = NH J po F rN OO N ~ i Cd 0 < F J oY HO ANT A 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(6-(2-(4-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)-2-oxoethyl)-2- azaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1-oxoiscindolin-2-yl)-N-(thiazol-2-yl acetamide ND N—\ SN NH J Ye F A SET a YY oY HN ANT A | 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol -1-y1)-2-(6-(4-(6-(2-(1-(4-((2,6-dioxopiperidin-3- | yl)amino)-2,6-difluorophenyl)piperidin-4-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2- vl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2-yl)acetamide wl IANS NAF N “N_, UOro-1-0Xo1801naolin-s-yi IN -| Nazol-2-yi aC HI N NS { 2 J SAF ® ’ fa N Oo \_. A 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol -1-y1)-2-(6-(4-(6-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1- yl)-2-oxoethyl)-2-azaspiro[3.3 ]heptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N- (thiazol -2-yl)acetamide ND N—\ SN NH J Ye F 0 N N 7 So” J) 9 N N > F. F 0) N— 0 Fo © oY HA ANT A 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-(6-(4-(6-(2-(1-(4-((2,6-dioxopiperidin-3- yl)amino)-2,6-difluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3]heptan- 2-yl)phenyl)-4-fluoro-1-oxoisocindolin-2-yl)-N-(thiazol -2-yl Jacetamide oO Ne N— / \ JT 0 N 4 oN SNF J > Qos : y 0 F 9 JN Nu 2-(6-(4-(6-(2-(1-(2-(difluoromethyl)-4-((2,6-dioxopiperidin-3-yl )Jamino)phenyl)-4- hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1- oxoisoindolin-2-yl)-2-(6, 7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-yl)-N-(thiazol-2- yl acetamide oO ON AN H © 1 Ir F rt NF ele ats——— — . ~~ 78 oo SN 3,1 0-0 ~PN ° « NZ H 1 ~N AN "A 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol -1-y1)-2-(6-(1-(1-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-y1)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1- ylacetyl)piperidin-4-y1)-1H-pyrazol-4-yl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2- yl)acetamide 4 \] UNG oO AO | aT em F Ni “Nl N= No £ o 2) Lio _N E LP 1 NN F \ 2-(6,7-dihydro-SH-pyrrolo[ 1,2-climidazol -1-y1)-2-(6-(4-(2-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-y1)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1- yl)acetyl)-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N- thiazol-2-yl)acetamide we N— / \ Sn JT | | SN OLS ul F J | 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol -1-y1)-2-(6-(4-(2-(2-(1-(4-((2,6-dioxopiperidin-3- | yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,7-diazaspiro[3.5]nonan-7- yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2-yl)acetamide H SNE 2 N 5 SAN Z ; , Ns o N? S > F > N— y r o , F 5 7 SN J ’ 2 oA | N-(1-(2-(1-(4-(((R)-2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4- | yl)acetyl)piperidin-4-y1)-5-((7-fluoro-2-(1-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[ 1,2- c]imidazol-1-yl)-2-0x0-2-(thiazol-2-ylamino)ethyl)-3-oxoisoindolin-5- yl)ethynyl)picolinamide a p YJ HN— AA Sn ST | Ll ANN F To ad) oF De Lie SN AN F Q a | NT A 2-(6,7-dihydro-SH-pyrrolo[ 1,2-climidazol -1-y1)-2-(6-(4-(6-(2-(1-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-y1)-1-methyl-1H-indazol-6-y1)-4-hydroxypiperidin-4- yl)acetyl)-2,6-diazaspiro[3.3heptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N- NY N— SN NH J Ye og NN F thiazol-2-yl)acetamide 0 NA o nN? “~~ | 8 N x ) F N— 0 Fo© AnH ANT A 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-(6-(6-(6-(2-( 1-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6- diazaspiro[3.3]heptan-2-y1)pyridin-3-yl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol -2- ND N— / \ SN N= J F yl)acetamide o N._N NI 1] oN N x bs F N— 0 Fo0 sr HP ANT AN 2-(6,7-dihydro-SH-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(6-(6-(2-(1-(4-(((R)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6- diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol-2- yl)acetamide ND N—\ NH J Ye F To A AS “a ® o N? ~ _ NYT Cord? 7 7 oY HA ANT A | 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-(6-(4-(6-(2-(4-(5-((2,6-dioxopiperidin-3- | yl)amino)-3-fluoropyridin-2-yl)piperidin-1-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2- yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2-yl)acetamide oO an HNN od, J N N 1 1 \ 1 1 = \ 1 I F H £ 32 Ono F ~ © "ro ~N NY 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol -1-y1)-2-(6-(4-(6-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1- | yl)acetyl)-2,6-diazaspiro[3.4]octan-2-y1)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol- | IN eR pe oe ihe aa a: 2-ylacetamide 0 EN NY > F “AF pa N= £0) 1 NN F £5 2) N bo ( N F ” "A 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol -1-y1)-2-(6-(4-(7-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1- ylacetyl)-2,7-diazaspiro[3.5]nonan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N- (thiazol -2-yl)acetamide H AN F XC oO H l Ar OH 1 NT N— / \ Fa NTN ~0 0) 0 Dord? F J ; J =n SA | 2-(6,7-dihydro-5H-pyrrolo[ 1,2-cJimidazol -1-y1)-2-(6-(4-(7-(2-(1-(4-((2,6-dioxopiperidin-3- yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,7-diazaspiro[3.5]nonan-2- yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2-yl)acetamide F d 1 d J=N 5A | 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-(6-(4-(6-(2-(1-(4-((2,6-dioxopiperidin-3- | yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.4]Joctan-2- yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2-yl)acetamide ANS Nl F ot ~F F Fon NN win } THA £ J I Q iy 2-(6-(4-(6-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-y1)- | 3,3-difluoropiperidin-1-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1- oxoisoindolin-2-y1)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N- (thiazol -2-yl)acetamide ND N—\ SN NH J Ye F 0 N A 7 Ny” J) FN x » a w= 0 Fo © oY HA ANT A 2-(6-(4-(6-(2-(1-(2-chloro-4-((2,6-dioxopiperidin-3-yl)amino)phenyl)-4-hydroxypiperidin- 4-yl)acetyl)-2,6-diazaspiro[3.3 Jheptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-2-(6,7- dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide ANS wl IS NAF N “N_, yITolo 1,4-C 1miaazoi-1-yi = IN =| Nazol-2-yl aC = NN NN 2 J SAF < x F N N Qo \_.7 A 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol -1-y1)-2-(6-(6-(6-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1- yl)-2-oxoethyl)-2,6-diazaspiro[3.3 ]heptan-2-yl)pyridin-3-yl)-4-fluoro-1-oxoisoindolin-2- ND N— / \ SN N= J 0 xX F yl)-IN-(thiazol-Z-yl)acetamide 0 N 7 0 N C0 F F g N— 0 F ° nm | An ANY IN 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(6-(2-(1-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6- diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2- yl)acetamide ND N—\ SN NH J Ye F 0 N A 7 Ny” J) FN x » a w= 0 Fo © a HA AN A 2-(6-(4-(6-(2-(1-(2-chloro-4-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)-4- hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1- oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol -1-yl)-N-(thiazol-2- yl acetamide NT N— / \ SN” H JN NY > ~0 2) 0 : heyd Tr J I ! 2+(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-(6-(4-(7-(2-(1-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,7- diazaspiro[3.5]nonan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2- yl)acetamide 0 ~~ ANS 5 =( F NA nl NN F ¢ 0 g 5 bo [ N F " "A 2-(6,7-dihydro-SH-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(7-(2-((R)-4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-y1)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1- ylacetyl)-2,7-diazaspiro[3.5]nonan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N- thiazol -2-yl )acetamide PAN a p YJ HN—4 AA on Sn £. In Ll ANN F 0 1 oo N NN PLC bo = AN F 0 ; A NT N— Q and 3 2 N HN \ 2-(6,7-dihydro-SH-pyrrolo[ 1,2-climidazol -1-y1)-2-(6-(4-(6-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-y1)piperazin-1- yl)acetyl)-2,6-diazaspiro[3.3 heptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N- thiazol-2-yl)acetamide AN ~~ “aN £ LR Ll ANN F — 0 A 00 2) a ® Lh 7 STG A 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-(6-(4-(6-(2-((3R,4S)-4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3-fluoropiperidin-1- ylacetyl)-2,6-diazaspiro[3.3 Jheptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N- (thiazol -2-yl)acetamide AN “WN YAS SE SN . ANN F JN GA IAT 0 "A 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol -1-y1)-2-(6-(4-(6-(2-((3S,4R)-4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3-fluoropiperidin-1- yl)acetyl)-2,6-diazaspiro[3.3 heptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N- (thiazol -2-yl)acetamide NZ 17 'N— / \ SN H JN NO J oN Qo, F J 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-(6-(4-(2-(2-(1-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,7- diazaspiro[3.5]nonan-7-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2- yl)acetamide a P YJ HN— Pe " SN top Ll ANN F yl)acetamiae o N N 0 0 ~< J SN CT N F — 7 a | N A A o oy Sf N HN A 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol -1-y1)-2-(6-(4-(6-(2-(1-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-4- hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3heptan-2-yl)phenyl)-4-fluoro-1- oxoisoindolin-2-yl -N-(thiazol -2-yl acetamide NT N— / \ Sn” Net XY = JN SN | Shed F J 2-(6-(4-(2-(2-(1-(2-chloro-4-(((S)-2,6-dioxopiperidin-3-yl)amino)phenyl)-4- hydroxypiperidin-4-yl)acetyl)-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)-4-fluoro-1- oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol -1-y1)-N-(thiazol-2- ylacetamide PAN pW YJ SAF F £. In Ll ANN F To x oq ~~ Lie ie Ie Faw 0 A N iN Did 2-(6,7-dihydro-SH-pyrrolo[ 1,2-cJimidazol-1-y1)-2-(6-(4-(6-(2-((S)-4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-y1)-3,3- difluoropiperidin-1-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1- oxoisoindolin-2-y1)-N-(thiazol -2-yl)acetamide AN F Wel ST NA LR Ll ANN F Fa <$ “A IC Q AN F Oo \ A F. ° o UMN SN HN \ 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-(6-(4-(6-(2-((R)-4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,3- difluoropiperidin-1-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1- oxoisoindolin-2-y1)-N-(thiazol -2-yl)acetamide NOON —[_ pp NH J Me oo YY F oxoisoindolin-2-yl)-IN-(th1azol-2-yl Jacetam o N N SPJ Sn” o N )- ha es’ o F © mo 2-(6-(4-(6-(2-(1-(4-(((S)-2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4- hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3heptan-2-yl)phenyl)-4-fluoro-1- oxoisoindolin-2-y1)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N- thiazol-2-yl)acetamide NN = Jp NH J Me F 0 N N 2 Y xi? 2 N \- ¢ I 0 Fo° 2 NL AN A 2-(6-(4-(6-(2-(1-(4-(((R)-2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4- hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1- oxoisoindolin-2-yl)-2-((R)-6-fluoro-6,7-dihydro-SH-pyrrolo[ 1,2-c]imidazol-1-yl)-N- thiazol-2-yl)acetami de ANS “wl YAS NE NN F X THA £3 ig i! TT Ty 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol -1-y1)-2-(6-(4-(6-(2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-y1)-1-methyl-1H-indazol-6-y1)-3-fluoropiperidin-1- yl)acetyl)-2,6-diazaspiro[3.3 Jheptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N- thiazol-2-yl)acetamide 0 idl N— / \ SN” H JN NL @ oN’ - F J 2+(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-yl)-2-(6-(4-(2-(2-(1-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,7- diazaspiro[3.5]nonan-7-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2- ylacetamide ND N—\ SN H JT F “To x 7 gee OY o™ N No 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-(6-(4-(6-(2-(1-(4-((2,6-dioxopiperidin-3- yl)amino)-2,5-difluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[ 3.3 ]heptan- 2-yl)phenyl)-4-fluoro-1-oxoisocindolin-2-yl)-N-(thiazol -2-yl Jacetamide ND N— / \ SN N= JL 0 yl)-4-tluoro-1-oxoisoinaolin-z-yl)-N-(thiazol -2 o a 7 0 N SN ig bs O- 0 cl o J NH 2-(4-chloro-6-(4-(6-(2-(1-(4-({(S)-2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4- hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-1-oxoisoindolin-2- y1)-2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol -1-y1)-N-(thiazol -2-yl acetamide WZ N— / \ SN” H JN BE > ~0 0) 0 : hepd J J I ! 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-(6-(4-(7-(2-(1-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,7- diazaspiro[3.5]nonan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2- yl)acetamide 0 NY N— / \ o aft) od ~ Sn” No. 2 = H Jo TNE Sa 0 N” Cl > r ed, 1 F © 2-(6-(4-(7-(2-(1-(2-chloro-4-(((S)-2,6-dioxopiperidin-3-yl)amino)phenyl)-4- hydroxypiperidin-4-yl)acetyl)-2,7-diazaspiro[3.5]nonan-2-yl)phenyl)-4-fluoro-1- oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol -1-yl)-N-(thiazol-2- ND N—\ SN NH J Ye 0 xX F ylacetamide 0 N N 7 “ 2) o N7 N > WF I- J r 0 Fo© 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-(6-(4-(6-(2-(1-(5-(((S)-2,6- dioxopiperidin-3-yl)amino)-3-fluoropyridin-2-yl)-4-hydroxypiperidin-4-yl)acetyl)-2,6- diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2- yl)acetamide Ie AN ONT IN ‘ 00 g ; 0 —N < N F oO "x 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-(6-(4-(7-(2-((R)-4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1- yl)-2-oxoethyl)-2, 7-diazaspiro[3.5]nonan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N- (thiazol -2-yl)acetamide SN o or SAF F “Nl oN . NN F ONT nN r ey JI 0 —N ; « N F o "z 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-(6-(4-(7-(2-((S)-4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-y1)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1- yl)-2-oxoethyl)-2, 7-diazaspiro[3.5]nonan-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N- thiazol-2-yl )acetamide NO N— / \ F N= N [o} N 0 J F Sr # COs p NH J Yo F Neo NH rr 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol-1-y1)-2-(6-(1-(1-(2-(1-(4-(((S)-2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)piperidin-4- vyl)-1H-pyrazol-4-y1)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2-yl)acetamide A Tl ToT £9 0) Nat Li AN F "A 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(2-(2-((R)-4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-y1)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1- yl)-2-oxoethyl)-2, 7-diazaspiro[3.5]nonan-7-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N- thiazol-2-y] )acetamide ~ ao TUNG SAF F “Nl ToT rx 7) Pr Lie N F oN . NN F "z 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-(6-(4-(2-(2-((S)-4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-y1)-1-methyl-1H-indazol-6-y1)-3,3-difluoropiperidin-1- yl)-2-oxoethyl)-2, 7-diazaspiro[3.5]nonan-7-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N- ND N— / \ SN N= Je 0 xX F thiazol-2-yl)acetamide o a 7 Sa” J) 2 nN N > air 0 0 Fo0 2-(6-(4-(6-(2-(1-(2-chloro-4-(((S)-2,6-dioxopiperidin-3-yl)amino)-6-fluorophenyl)-4- hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1- oxoisoindolin-2-yl)-2-(6, 7-dihydro-5H-pyrrolo[1,2-¢c]imidazol -1-yl)-N-(thiazol-2- yl acetamide 0 H 1 ND N—\ H [A N° No LCC H NH J Me ° HQ [ ig o N’ F herd? F J Pd =n SA 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-(6-(4-(6-(1-(4-(((S)-2,6-dioxopiperidin- 3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidine-4-carbonyl)-2,6-diazaspiro[3.3]heptan- 2-yl)phenyl)-4-fluoro-1-oxoisocindolin-2-yl)-N-(thiazol -2-yl )acetamide Hy =o nN 0, \ » N N / O \ E F Q, R HO NH - BO AA % F H 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-y1)-2-[6-[4-[2-[2-[1-[4-(2,4- dioxohexahydropyrimidin-1-yl)-2-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetyl]-2,6- diazaspiro[3.3]heptan-6-yl Jphenyl]-4-fluoro-indazol -2-y1]-N-thiazol-2-yl-acetamide Io HN— Hy o ~~ >> MIN XN 7 F R_ wo o= (RIO, od H | wa BN 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-[6-[4-[2-[2-[(2s,61)-1-[4-[(2,6-diox0-3- piperidyl)amino]-2-fluoro-phenyl]-4-hydroxy-2,6-dimethyl-4-piperidyl]acetyl]-2,6- diazaspiro[3.3]heptan-6-ylJphenyl]-4-flucro-indazol-2-y1]-N-thiazol-2-yl-acetamide Oo HN—4 o= MN dg vw FN SN Hn F N 5 F (AIL H H | — An Yoon A NM 2-(6,7-dihydro-SH-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[4-[2-[4-[4-[[(3S)-2,6-diox0-3- piperidyl]amino]-2-fluoro-phenyl]-1-piperidyl]-2-oxo-ethyl]-4-hydroxy-1- piperidyl]phenyl]-7-fluoro-indazol-2-yl]-N-thiazol -2-yl-acetamide \ =o ~N H |! - 1 \ auiiiiV]me MAT PMV AIT LTP YR Te dyl]phenyl]-7-fluoro-indazol-2-yl]-N-thi A = ~=N , rs 0 A) N 2 Noy? N"N N H NL ~ H { “A Voy CN oN nm F, J d 0 é ml = = Sa NH o= 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[6-[4-[2-[4-[4-[[(3S)-2,6-diox0-3~ piperidyl]amino]-2-fluoro-phenyl]-1-piperidyl]-2-oxo-ethyl]-4-hydroxy-1-piperidyl]-3- pyridyl]-4-fluoro-indazol-2-yl]-N-thiazol-2-yl-acetamide O HN—4 o= =N TN AEA F F 0, = = , N N N “N EF H H |, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]limidazol-1-yl)-2-[6-[ 6-[4-[2-[4-[4-[[(3S)-2,6-diox0-3~ piperidyl]amino]-2-fluoro-phenyl]-1-piperidyl]-2-oxo-ethyl]-4-hydroxy-1-piperidyl]-3- pyridyl]-7-fluoro-indazol-2-yl]-N-thiazol-2-yl-acetamide 0 4 — / ed —N CN 1dyl]Jamino]-2-fluoro-phenyl]-1-piperidyl]-2-oxo-ethyl |-4-hydroxy-1-pij pyridyl]-7-fluoro-indazol-2-yl]-N-thiazol-2-yl-acetamide R Ne = 0 Va Vall = / \ \ A O- GLI Ow H o 0 ha % N_~ 1 40 Co he N_ o 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-[6-[4-[1-[2-[4-[4-[(2,6-diox0-3- piperidyl)amino]phenyl]-1-piperidyl]acetyl]-4-piperidyl]-2-methyl-phenyl]-4-fluoro-1- oxo-isoindolin-2-y1]-N-thiazol -2-yl-acetamide 1 —N Ney ; ~~ pa OL 3 -0m00(E A SN Io a Xo = NVR = a PN TTY, — °C ’ on 2-(6,7-dihydro-5H-pyrrolo[1,2-climidazol -1-y1)-2-[6-[4-[2-[2-[7-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol -6-yl]-4-azaspiro[2.5]octan-4-yl Jacetyl]- 2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-N-(2- py ridyl)acetamide H HN. 0 ot oO N N— / So -0- oo \=N N N" F 1 2-(6,7-dihydro-SH-pyrrolo[1,2-climidazol-1-y1)-2-[6-[4-[2-[2-[7-[3-(2,4~ dioxohexahydropyrimidin-1-yl)-1-methyl-indazol -6-yl]-4-azaspiro[2.5]octan-4-ylJacetyl]- 2,6-diazaspiro[3.3]heptan-6-y1]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-N-thiazol-2-yl- acetamide re NH oO R 7 N— H 5 H I 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-y1)-2-[6-[4-[6-[4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-y1]-3,3-difluoro-piperidine-1- | carbonyl]-2-azaspiro[3.3]heptan-2-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazol-2- ] yl-acetamide =0 J —_ / oO ’ F TN I: NH J HC F — X rs 3 \ / \ 7 OC AJA H | ©& H 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol -1-y1)-2-[6-[4-[2-[2-[ 1-[4~(2,4- dioxohexahydropyrimidin-1-yl)-2-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetyl]-2,6- diazaspiro[3.3]heptan-6-yl]Jphenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazol -2-y1- acetamide =0 H~ J A¢ 0 aa F F NE ! 1 0 NS YN =o ili fi aaa a hi cl CO AY r 0 AON TT No 0 oO | 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-(6-(4-(6-(2-(1-(4-(2,6-dioxopiperidin-3- yl)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2- yDphenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol -2-yl)acetamide Cl : 20 = N N 0 8 0-000 Aa A AN ° o N”°N H bo H NAN 2-[6-[4-[2-[2-[1-[2-chloro-4~(2,4-dioxohexahydropyrimidin-1-yl)phenyl]-4-hydroxy-4- | piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-2- (6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-N-thiazol-2-yl-acetamide CN aA —~X NK )— Jo L'8 o N N EA = it 2 M7 XX 2 gh Xv eridyl]acetyl]-2,6-diazaspiro[3.3]heptan- (6,7-dihydro-5H-pyrrolo[1,2-c]im FE Ag SO J \ Ay AA H LA © NY H Cy \ iva N - 4 \ NH / — > J 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-[6-[4-[2-[2-[1-[4-(2,6-diox0-3- piperidyl)-2-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetyl]-2,7-diazaspiro[3.5]nonan-7- yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazol -2-yl-acetamide F HO —, = = — 5 —C 4) No JN © \ 7 \ 7 NOX A J JAN of J STON H | 5 H | depni ble i 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]limidazol -1-y1)-2-[6-[4-[ 7-[2-[ 1-[4-(2,6-diox0-3- piperidyl)-2-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetyl]-2,7-diazaspiro[3.5]nonan-2- vl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazol -2-yl-acetamide Oo HN— o= 0 ~~ > M»>N"XN=< 7 F a 0 LX Cy - Y OC - ~N vg eel \ pu # H I N 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-y1)-2-[6-[4-[2-[2-[(2s,61)-1-[4-[(2,6-diox0-3- piperidyl)amino]-2-fluoro-phenyl]-4-hydroxy-2,6-dimethyl-4-piperidyl]acetyl]-2,6- diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazol -2-yl- acetamide Oo nA HN oY F F <r ZS o \ Obs OOO “N \ \=N 8, HN F -[6-[4-[2-[2-[4-amino-1-[4-[(2,6-dioxo-3-piperidyl)amino]-Z ivllacetvl1-2.6-diazaspirol3 3 Theptan-6-vl phenyl 1-4-fluoro-1 2-[6-[4-[2-[2-[4-amino-1-[4-[(2,6-dioxo-3-piperidyl Jamino]-2-fluoro-phenyl]-4- | piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-2- (6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide , aA 2 —~X N= JN oO fa o ~~ >> »>N YX N= 7 / NH F J Ro HC N N QI SIO 00 H | 4 H | 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol-1-y1)-2-[6-[4-[2-[2-[1-[4-(2,4- dioxohexahydropyrimidin-1-yl)-2-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetyl]-2,7- diazaspiro[3.5]nonan-7-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazol -2-yl- acetamide 7 nN N= J H E O= ~~ . OH F th HN = A - IQ \ / NOC, GLI H 5 N o =O IA DX YT Fo — 0 NX aC |lsomer Al 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-y1)-2-[6-[4-[2-[2-[1-[4-[[2,6-diox0-3- piperidyl]amino]-2-fluoro-phenyl]-4-hydroxy-azepan-4-yl]acetyl]-2,6- diazaspiro[3.3]heptan-6-ylJphenyl]-4-fluore-1-oxo-isoindolin-2-yl]-N-thiazol -2-yl- acetamide, isomer Al SN “NC N= ha Wa. Ff o= + . OH F a HN—( Oo — - 0 On, GLI H 3 Yo ONS NANT oR F = LO AA H A0 iy Ilsomer A2 Cig acetamide, isome ~N — F O= + . OH F & HN—{ 0 & N\ 7 N\_ / "ANN, OH Fooo= WW © HN 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-(6-(4-(6-(2-(1-(4-((2,6-dioxopiperidin-3- yl)amino)-2-fluorophenyl)-4-hydroxyazepan-4-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2- yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide, isomer A2 R NT N \ / NH §) Be TN OC, oH F o= 5 Nn N HN—( H 0 0 gy N 0 NN— RN |lsomer B1 CN )acetamide, isome ~ = a Wa F O= ~~ . OH F 2 HN— 0 o \ 7 \_ / WANN, OH Fooo= Sl © HN 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-(6-(4-(6-(2-(1-(4-((2,6-dioxopiperidin-3- yl)amino)-2-fluorophenyl)-4-hydroxyazepan-4-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2- yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol -2-yl)acetamide, isomer B1 R NZ N \ / NH §) Be vo OO a > ~ OH F o= sN N hy H 3 gy J 0 NN YN |lsomer B2 | 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol -1-y1)-2-(6-(4-(6-(2-(1-(4-((2,6-dioxopiperidin-3- | yl)amino)-2-fluorophenyl)-4-hydroxyazepan-4-yl)acetyl)-2,6-diazaspiro[3.3]heptan-2- yDphenyl)-4-fluoro-1-oxoisoindolin-2-y1)-N-(thiazol-2-yl)acetamide, isomer B2 R Cl, ai o () OO HQ Ny AN NO nh a yo H 0 NH Ao Cl oO N° N'Y TY VN TT = T HY ? cl NH H I PN NN 2-(6,7-dihydro-5H-pyrrolo[ 1,2-climidazol -1-y1)-2-[6-[4-[2-[2-[ 1-[4~(2,4- | dioxohexahydropyrimidin-1-yl)-2-(trifluoromethyl)phenyl]-4-hydroxy-4-piperidyl]acetyl]- 2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-N-thiazol -2-y1- acetamide R HO AAO Ao ° NN N'Y TY VN TT = Ty T HY ® cl SNH Oo H I ~~ NN 2-[6-[4-[2-[2-[1-[2,6-dichloro-4-(2,4-dioxohexahydropyrimidin-1-yl)phenyl]-4-hydroxy-4- piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-2- (6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide NNN 7 \ =a =0 A ME / Cl 1z0l-2-yl-acetamide HO Moy Cl o (6, / -dihydro->h-pyrrolof 1,2-Cjimidazol-1 R THN N 38 SY XC) NZ NN N H 0 — \ oy 2-[6-[4-[7-[2-[1-[2-chloro-4-(2,4-dioxohexahydropyrimidin-1-yl)phenyl]-4-hydroxy-4- | piperidyl]acetyl]-2,7-diazaspiro[3.5]nonan-2-y1]phenyl]-4-fluoro-1-oxo-isoindolin-2-y1]-2- | (6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide 7 =0 RC ! J NANNY N N HE 7° R RC Vr 2-[6-[4-[2-[2-[1-[2-cyano-4~(2,4-dioxohexahydropyrimidin-1-yl)phenyl]-4-hydroxy-4- | piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-2- (6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide \ 7 7 =a =0 co’ N Xv 1z0l-2-yl-acetamide ay cl o H eridyl]acetyl]-2,6-diazaspiro[3.3]heptan- (6,7-dihydro-5H-pyrrolo[1,2-c]im R — =\ Js 9 \ 7 \ 7 / 7 \ (AIA H 0 — _N 2-[6-[4-[2-[2-[1-[2-chloro-4-(2,4-dioxohexahydropyrimidin-1-yl)phenyl]-4-hydroxy-4- | piperidyl]acetyl]-2,7-diazaspiro[3.5]nonan-7-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-2- | (6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide a - 0 HN . FR o= ~ \— NN 38 5 OO = NZ NNN © A H 8 H N Isomer 1 2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]limidazol -1-yl)-2-[6-[4-[2-[2-[ 1-[4-[[2,6-diox0-3- piperidyl]amino]-2-fluoro-5-methoxy-phenyl]-4-hydroxy-4-piperidyl]acetyl]-2,6- diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazol -2-yl- acetamide, isomer 1 or a pharmaceutically acceptable salt thereof.

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

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

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

180. The method of claim 179, wherein the patient is a human.

181. The method of claim 179 or 180, wherein the EGFR mediated disorder is a cancer, tumor, or abnormal cellular proliferation.

182. The method of claim 181, wherein the EGFR mediated disorder is a cancer or a tumor.

183. The method of claim 181, wherein the EGFR mediated disorder is an abnormal cellular proliferation.

184. The method of claim 182, wherein the cancer is lung cancer.

185. The method of claim 184, wherein the lung cancer is non-small cell lung cancer.

186. The method of any one of claims 181-185, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with at least one mutation.

187. The method of any one of claims 181-186, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the L858R mutation.

188. The method of any one of claims 181-187, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the T790M mutation.

189. The method of any one of claims 181-188, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the C797S mutation.

190. The method of any one of claims 181-189, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the L792H mutation, 191. The method of any one of claims 181-189, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the L718Q mutation.

192. The method of any one of claims 181-186, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the T790M / L858R mutation.

193. The method of any one of claims 181-186, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the T790M / L858R / C797S mutation.

194. The method of any one of claims 181-186, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the L858R / C797S mutation.

195. The method of any one of claims 179-194, wherein an additional EGFR inhibitor is administered.

196. The method of claim 195, wherein the additional EGFR inhibitor is a tyrosine kinase inhibitor.

197. The method of claim 196, wherein the additional EGFR inhibitor is osimertinib.

198. The method of claim 196, wherein the additional EGFR inhibitor is rociletinib.

199. The method of claim 196, wherein the additional EGFR inhibitor is avitinib.

200. The method of claim 196, wherein the additional EGFR inhibitor is lazertinib.

201. The method of claim 196, wherein the additional EGFR inhibitor is nazartinib 202. The method of claim 195, wherein the additional EGFR inhibitor is an antibody to a mutated form of EGFR.

203. The method of claim 202, wherein the additional EGFR inhibitor is cetuximab.

204. The method of claim 202, wherein the additional EGFR inhibitor is panitumab.

205. The method of claim 202, wherein the additional EGFR inhibitor is necitumab.

206. The method of any one of claims 179-205, wherein a MET inhibitor is also administered.

207. The method of any one of claims 179-206, wherein the patient receives an additional chemotherapeutic agent.

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

209. The use of claim 208, wherein the patient is a human.

210. The use of claim 208 or 209, wherein the EGFR mediated disorder is a cancer, tumor, or abnormal cellular proliferation.

211. The use of claim 210, wherein the EGFR mediated disorder is a cancer or a tumor, 212. The use of claim 210, wherein the EGFR mediated disorder is an abnormal cellular proliferation, 213. The use of claim 211, wherein the cancer is lung cancer.

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

215. The use of any one of claims 210-214, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with at least one mutation.

216. The use of any one of claims 210-215, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the L858R mutation.

217. The use of any one of claims 210-216, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the T790M mutation, 218. The use of any one of claims 210-217, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the C797S mutation.

219. The use of any one of claims 210-218, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the L792H mutation.

220. The use of any one of claims 210-219, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the L718Q mutation.

221. The use of any one of claims 210-215, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the T790M / L858R mutation.

222. The use of any one of claims 210-215, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the T790M / L858R / C797S mutation.

223. The use of any one of claims 210-215, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the L858R / C797S mutation.

224. The use of any one of claims 208-223, wherein an additional EGFR inhibitor is administered.

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

226. The use of claim 225 wherein the additional EGFR inhibitor is osimertinib.

227. The use of claim 225, wherein the additional EGFR inhibitor is rociletinib.

228. The use of claim 225, wherein the additional EGFR inhibitor is avitinib.

229. The use of claim 225, wherein the additional EGFR inhibitor is lazertinib.

230. The use of claim 225, wherein the additional EGFR inhibitor is nazartinib.

231. The use of claim 224, wherein the additional EGFR inhibitor is an antibody to a mutated form of EGFR. 232, The use of claim 231, wherein the additional EGFR inhibitor is cetuximab.

233. The use of claim 231, wherein the additional EGFR inhibitor is panitumab.

234. The use of claim 231, wherein the additional EGFR inhibitor is necitumab.

235. The use of any one of claims 208-234, wherein a MET inhibitor is also administered.

236. The use of any one of claims 208-235, wherein the patient receives an additional chemotherapeutic agent.

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

238. The compound of claim 237, wherein the patient is a human, 239. The compound of claim 237 or 238, wherein the EGFR mediated disorder is a cancer, tumor, or abnormal cellular proliferation.

240. The compound of claim 239, wherein the EGFR mediated disorder is a cancer or a tumor.

241. The compound of claim 239, wherein the EGFR mediated disorder is an abnormal cellular proliferation.

242. The compound of claim 240, wherein the cancer is lung cancer.

243. The compound of claim 242, wherein the lung cancer is non-small cell lung cancer.

244. The compound of any one of claims 239-243, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with at least one mutation.

245. The compound of any one of claims 239-244, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the L858R mutation.

246. The compound of any one of claims 239-245, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the T790M mutation.

247. The compound of any one of claims 239-246, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the C797S mutation.

248. The compound of any one of claims 239-247, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the L792H mutation.

249. The compound of any one of claims 239-248, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the L718Q mutation.

250. The compound of any one of claims 239-244, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the T790M / L858R mutation.

251. The compound of any one of claims 239-244, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the T790M / L858R / C797S mutation.

252. The compound of any one of claims 239-244, wherein the cancer, tumor, or abnormal cellular proliferation has an EGFR protein with the L858R / C797S mutation.

253. The compound of any one of claims 237-252, wherein an additional EGFR inhibitor is administered.

254. The compound of claim 253, wherein the additional EGFR inhibitor is a tyrosine kinase inhibitor.

255. The compound of claim 254, wherein the additional EGFR inhibitor is osimertinib.

256. The compound of claim 254, wherein the additional EGFR inhibitor is rociletinib.

257. The compound of claim 254, wherein the additional EGFR inhibitor is avitinib.

258. The compound of claim 254, wherein the additional EGFR inhibitor is lazertinib.

259. The compound of claim 254, wherein the additional EGFR inhibitor is nazartinib.

260. The compound of claim 253, wherein the additional EGFR inhibitor is an antibody to a mutated form of EGFR.

261. The compound of claim 260, wherein the additional EGFR inhibitor is cetuximab.

262. The compound of claim 260, wherein the additional EGFR inhibitor is panitumab.

263. The compound of claim 260, wherein the additional EGFR inhibitor is necitumab.

264. The compound of any one of claims 237-263, wherein a MET inhibitor is also administered.

265. The compound of any one of claims 237-264, wherein the patient receives an additional chemotherapeutic agent.

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

267. A pharmaceutical composition comprising a compound of any one of claims 79-176 and a pharmaceutically acceptable excipient,