Isoindolinone and indazole compounds for degradation of EGFR

Abstract

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

Description

[Technical Field]

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 951,464, filed December 20, 2019, and U.S. Provisional Patent Application No. 62 / 951,467, filed December 20, 2019.

[0002] The present invention provides compounds that degrade epidermal growth factor receptor (EGFR), including mutant forms, by ubiquitination of the EGFR protein and subsequent proteasomal degradation, and are useful in the treatment of various cancers. [Background technology]

[0003] HER family receptor tyrosine kinases are mediators of cell growth, differentiation, and survival. This receptor family includes four distinct members: epidermal growth factor receptor (EGFR, ErbB1 or HER1), HER2 (ErbB2), HER3 (ErbB3), and HER4 (ErbB4). Upon ligand binding, the receptors form homodimers and heterodimers, and the subsequent activation of intrinsic tyrosine kinase activity leads to receptor autophosphorylation and activation of downstream signaling molecules (Non-Patent Document 1). 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 cancer, pancreatic cancer, glioma, head and neck cancer, and lung cancer, particularly non-small cell lung cancer (NSCLC). Several EGFR-targeting agents have been developed over the years (Non-Patent Document 2). Erlotinib (Tarceva™), a reversible inhibitor of EGFR tyrosine kinase, is approved in many countries for the treatment of recurrent NSCLC.

[0004] Although excellent single-agent activity of EGFR tyrosine kinase inhibitors is observed in a subset of NSCLC patients whose tumors harbor somatic kinase domain mutations, clinical benefit is significantly reduced in patients with wild-type EGFR (Non-Patent Document 3). The most common somatic mutations in EGFR are exon 19 deletions, with Δ746-750 being the most common mutation, and exon 21 amino acid substitutions, with L858R being the most frequent mutation (Non-Patent Document 4).

[0005] Treatment resistance frequently occurs and is often due to a secondary T790M mutation in the ATP site of the receptor. Although several mutant-selective irreversible inhibitors have been developed that show high activity against T790M mutants, their efficacy can be compromised by an acquired mutation at C797S, a cysteine ​​residue that forms a critical covalent bond (Non-Patent Document 5). Wang further reported that the C797S mutation is a major mechanism of resistance to EGFR inhibitors that target T790M (Non-Patent Document 6). Additional mutations, such as L718Q, that cause resistance to osimertinib have been described by Yang (Non-Patent Document 7). Strategies targeting additional mutations, including targeting EGFRL858R / T790M and EGFRL858R / T790M / C797S resistance mutations in the treatment of NSCLC, are also known (Non-Patent Document 8).

[0006] Additional examples of EGFR inhibitors, particularly selective inhibitors of EGFR mutants with T790M, have also been described, including those described in Patent Documents 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 2

[0007] Because most available EGFR tyrosine kinase inhibitors target the ATP site of the kinase, new therapeutic agents that work differently are needed, for example, by targeting drug-resistant EGFR mutants.

[0008] Recent studies have suggested that mutant-selective inhibitors may be obtained by intentionally targeting allosteric sites (Non-Patent Document 10).

[0009] The field of small molecule-promoted targeted protein degradation has been intensively researched (Non-Patent Document 11). Protein degradation plays a role in various cellular functions. For example, the body uses proteolysis to regulate the concentration of regulatory proteins through degradation into small peptides and to maintain cellular health and proliferation rates.

[0010] Cereblon is a protein that forms an E3 ubiquitin ligase complex that ubiquitinates various other proteins. Cereblon is known as the primary target of anticancer thalidomide analogs. Increased expression of cereblon has been associated with the efficacy of thalidomide analogs in cancer therapy.

[0011] Compounds have been described as useful modulators of targeted ubiquitination, for example, the compounds described in U.S. Patent Nos. 5,629,999, 5,729,965, 5,730,975, 5,829,985, 5,929,995, and 5,929,995 can be used for targeted ubiquitination. Additional modulators of targeted ubiquitination include those described by Ranok Therapeutics Hangzhou in U.S. Patent No. 5,617,239 and U.S. Patent No. 5,617,239; by Arvinas in U.S. Patent No. 5,617,239; by Dana-Farber Cancer Institute in U.S. Patent No. 5,617,239; by Kymera in U.S. Patent No. 5,617,239; by Kymera in U.S. Patent No. 5,617,239; by C4 Therapeutics Inc. in U.S. Patent No. 5,617,239; by Kymera ...

[0012] Several specific molecules for the degradation of EGFR have also been described, for example, Dana-Farber Cancer Institute describes EGFR degrading agents in U.S. Patent No. 4,629,999. F. Hoffman-La-Roche describes EGFR degrading agents in U.S. Patent No. 4,629,999 and U.S. Patent No. 4,629,999. Arvinas describes EGFR degrading agents in U.S. Patent No. 4,629,999. [Prior art documents] [Patent documents]

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Non-licensed literature

[0014]

Non-licensed literature 1

Non-licensed Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

[0015] Despite these efforts, there remains a need for new EGFR modulators to treat EGFR-mediated disorders in hosts in need thereof, particularly humans. [Means for solving the problem]

[0016]

[0003] Provided are compounds that degrade epidermal growth factor receptor protein (EGFR) via the ubiquitin proteasome pathway (UPP), as well as their uses and production. The present invention provides compounds of Formula I, II, III, or IV, or pharmaceutically acceptable salts thereof, that include a targeting ligand that binds to EGFR, an E3 ligase binding moiety (typically via a cereblon subunit), and a linker that covalently links the targeting ligand to the E3 ligase binding moiety. In certain embodiments, the E3 ligase binding moiety is A or A * and the linker is L 1 or L 2and the remainder of the molecule is the EGFR-targeting ligand portion. In certain embodiments, the compounds of the invention degrade EGFRs having a mutation or combination of mutations, such as a mutation selected from T790M, L858R, and C797S, a combination of two mutations selected from T790M, L858R, and C797S, or a combination of three mutations selected from T790M, L858R, and C797S. In certain embodiments, the compounds of the invention are selective degraders of EGFR mutants having T790M / L858R, T790M / L858R / C797S, L858R, or L858R / C797S.

[0017] The compounds of the invention provided herein, or pharmaceutically acceptable salts thereof and / or pharmaceutically acceptable compositions thereof, can be used to treat disorders mediated by EGFR. In some embodiments, methods are provided for treating a patient having an EGFR-mediated disorder, comprising administering to the patient, typically a human, an effective amount of one or more compounds described herein or pharmaceutically acceptable salts thereof, optionally in a pharmaceutically acceptable composition.

[0018] In one aspect, the present invention provides a compound of formula I: [ka] (In the formula, A is a ring system AF and AG: [ka] is selected from A 1 teeth, i) -NH-, and ii) -O-; A 2 teeth, i)-N-, and ii)-CR 52 - selected from A 3 teeth, i)-N-, and ii)-CR 53 - selected from A 4 teeth, i)-N-, and ii)-CR 54 - selected from A 5 teeth, i)-N-, and ii)-CR 55 - selected from R 1 teeth, i) H, ii) halogens, iii) C 1~6 -alkyl, R 52 teeth, i) H, ii) halogens, iii) cyano, iv) C 1~6 -alkoxy, v) Halo-C 1~6 -alkoxy, vi) C 1~6 -alkyl, vii) Halo-C 1~6 -alkyl, viii) C 3~8 -cycloalkyl, and ix) Halo-C 3~8 -cycloalkyl, R 53 , R 54 and R 55 is independent, i) H, ii) halogens, iii) C 1~6 -alkyl, iv) Halo-C 1~6 -alkyl, v) C 3~8 -cycloalkyl, and vi) Halo-C 3~8 -cycloalkyl, R 2 teeth, i) H, ii) halogens, iii) C 1~6 -alkyl, iv) Halo-C 1~6 -alkyl, v) C 3~8 -cycloalkyl, and vi) Halo-C 3~8 -cycloalkyl, R 3 teeth, i) H, ii) halogens, iii) C 1~6 -alkyl, iv) Halo-C 1~6 -alkyl, v) C 3~8 -cycloalkyl, and vi) Halo-C 3~8 -cycloalkyl, R 4 and R 5 is H or or R 4 and R 5 together -(CH2) q - Forms q is 1 or 2; R 6 teeth, i) H, ii) halogens, iii) cyano, iv) C 1~6 -alkoxy, v) Halo-C 1~6 -alkoxy, vi) C 1~6 -alkyl, vii) Halo-C 1~6 -alkyl, viii) C 3~8 -cycloalkyl, and ix) Halo-C 3~8 -cycloalkyl, R 7 teeth, i) H, ii) halogens, iii) cyano, iv) C 1~6 -alkyl, v) Halo-C 1~6 -alkyl, vi) C 3~8 -cycloalkyl, and vii) Halo-C 3~8 -cycloalkyl, R 70 teeth, i) H, ii) halogens, iii) cyano, iv) C 1~6 -alkyl, v) Halo-C 1~6 -alkyl, vi) C 3~8 -cycloalkyl, and vii) Halo-C 3~8 -cycloalkyl, R 8 is H, R 9 teeth, i) H, and ii) C 1~6 -alkyl, L 1 teeth, [ka] and C is absent or is a ring system F, G and H: [ka] is selected from Y 1 teeth, i)-N-, and ii) -CH-; Y 2 teeth, i)-N-, and ii)-CR 16 - selected from R 12 , R 13 , R 14 and R 15 is independent, i)-H-, ii) halogens, and iii) Hydroxy-C 1~6 -alkyl, R 16 teeth, i)-H-, ii) hydroxy, and iii) selected from fluoro; L 3 does not exist, or i)-(CH2) m -C(O)-, ii) -C(O)-(CH2) p -, iii) -C(O)-C(O)-, iv)-NR 10 -C(O)-, v) -C(O)-NR 10 -, vi) -C(O)O-, vii) -CH2-CF2-CH2-, viii) -CH2-, ix) [ka] x) [ka] and, xi) [ka] is selected from m is 0, 1 or 2; p is 0, 1, 2 or 3; R 10 teeth, i) H, and ii) C 1~6 -alkyl, D is the ring system I, J, K, L, M, N, O, P, Q, R, S, T, U, V, W and X: [ka] and either ring system is selected from R 80 , R81 and R 82 and optionally substituted with 1 to 3 substituents selected from R 80 , R 81 and R 82 is independent, i) halogens, ii) cyano, iii) hydroxy, iv) Hydroxy-C 1~6 -alkyl, v) C 1~6 -alkoxy, vi) Halo-C 1~6 -alkoxy, vii) C 1~6 -alkyl, viii) Halo-C 1~6 -alkyl, ix) C 3~8 -cycloalkyl, and x) Halo-C 3~8 -cycloalkyl, L 4 does not exist, or i)-NR 11 -C(O)-, ii) -CH2-, and iii) -O-; E is the ring system Y, Z, AA, AB and AC: [ka] is selected from L 5 does not exist, or [ka] and B is the ring system AD and AE: [ka] or a pharmaceutically acceptable salt thereof.

[0019] In another aspect of the present invention, a compound of formula II: [ka] (In the formula, A' is the ring system AF, AG and AH: [ka] is selected from R 1 'teeth, i) H, ii) halogens, iii) C 1~6 -alkyl, iv) cyano, v) C 1~6 -alkoxy, vi) Halo-C 1~6 -alkoxy, vii) C 1~6 -alkyl, viii) Halo-C 1~6 -alkyl, ix) C 3~8 -cycloalkyl, and x) Halo-C 3~8 -cycloalkyl, The remaining variables are as defined herein), or a pharmaceutically acceptable salt thereof.

[0020] In certain embodiments, there are provided isotopes, N-oxides, or stereoisomers of Formula I, or pharmaceutically acceptable salts or compositions thereof. In other embodiments, there are provided isotopes, N-oxides, or stereoisomers of Formula II, or pharmaceutically acceptable salts or compositions thereof.

[0021] Another aspect of the present invention is a compound of formula III or formula IV: [ka] (In the formula, A * teeth, [ka] is selected from B * is heteroaryl or aryl, and one, two, or three R 31 optionally substituted with substituents, In certain embodiments, B * teeth, [ka] is selected from y is 0, 1, 2 or 3; R 31 In each case, H, halogen (F, Cl, Br or I), C 1~6 -Alkyl, Cyano, C 1~6 -Alkoxy, Halo-C 1~6 -Alkoxy, Halo-C 1~6 -Alkyl, C 3~8 -cycloalkyl and halo-C 3~8 -cycloalkyl, and when present on a bicyclic ring, may be located on either ring, for example, [ka] teeth, [ka] Including, R 32 is hydrogen, halogen (F, Cl, Br or I), C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 3~8 -cycloalkyl or halo-C 3~8 -cycloalkyl, R 33 is hydrogen, halogen (F, Cl, Br or I), C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 3~8 -cycloalkyl or halo-C 3~8 -cycloalkyl, optionally located on the dihydropyrrole or imidazole ring; R 34 In either case, H, F, C 1~6-Alkyl, Halo-C 1~6 -Alkyl, C 3~8 -cycloalkyl and halo-C 3~8 -cycloalkyl; R 35 In each case, H, halogen (F, Cl, Br or I), C 1~6 -Alkyl, Halo-C 1~6 -alkyl and C 3~8 -cycloalkyl; or R 34 and R 35 and combine to form -(CH2) q - Forms R 36 and R 37 are independently H, halogen (F, Cl, Br or I), cyano, C 1~6 -Alkoxy, Halo-C 1~6 -alkoxy (e.g., F, Cl, or Br), C 1~6 -Alkyl, Halo-C 1~6 -alkyl (e.g., F, Cl, or Br), C 3~8 -cycloalkyl and halo-C 3~8 -cycloalkyl; or R 36 and R 37 and are bonded together to form one, two or three R 31 forming a 5- or 6-membered ring optionally substituted with substituents, R 42 In each case, H, halogen (F, Cl, Br or I), cyano, C 1~6 -Alkoxy, Halo-C 1~6 -alkoxy, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 3~8 -cycloalkyl and halo-C 3~8 -cycloalkyl; R 90 is H, C 1~6 -alkyl or C 3~6 -cycloalkyl, Ring G is one or two R 42heteroaryl optionally substituted with substituents, for example, a 5- or 6-membered heteroaryl ring having 1, 2, or 3 N heteroatoms; A 21 is -NH-, -O-, -CH2- or -NR 100 - and R 100 is alkyl, cycloalkyl, aryl, or heteroaryl, or, to the extent valence allows, R 100 R 37 may be bonded to form a 5- to 8-membered heterocycle or a 5-membered heteroaryl; A 32 , A 33 , A 34 and A 35 are independently -N- and -CR 42 - selected from A 36 -N- or -CR 35 - and L 2 is A * and either an isoindolinone or an indazole, for example, but not limited to, a divalent linking group of formula LI, wherein the remaining variables are as described herein, or a pharmaceutically acceptable salt, isotope, N-oxide, or stereoisomer thereof.

[0022] In certain embodiments, L 2 is the expression: [ka] (In the formula, X 1 and X 2 are independently, in each occurrence, a bond, heterocycle, aryl, heteroaryl, bicycle, alkyl, aliphatic, heteroaliphatic, -NR 27 -, -CR 40 R 41 -, -O-, -C(O)-, -C(NR 27 )—, —C(S)—, —S(O)—, —S(O)—, and —S—, wherein each of the heterocycle, aryl, heteroaryl, and bicycle is selected from R 40optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 20 , R 21 , R 22 , R 23 and R 24 are independently in each occurrence a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, or -C(O)NR 27 -, -NR 27 C(O)-, -O-, -S-, -NR 27 -, oxyalkylene, -C(R 40 R 40 )-, -P(O)(OR 26 )O-, -P(O)(OR 26 )-, bicyclic, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic, glycolic, and carbocyclic, each of which is selected from the group consisting of R 40 optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 26 is independently selected at each occurrence from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic, aliphatic, and heteroaliphatic; R 27 is independently selected at each occurrence from the group consisting of hydrogen, alkyl, aliphatic, heteroaliphatic, heterocyclic, aryl, heteroaryl, —C(O)(aliphatic, aryl, heteroaliphatic, or heteroaryl), —C(O)O(aliphatic, aryl, heteroaliphatic, or heteroaryl), alkene, and alkyne; R 40 are independently hydrogen in each case, R 27, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azido, amino, cyano, -NH(aliphatic including alkyl), -N(aliphatic including alkyl)2, -NHSO2(aliphatic including alkyl), -N(aliphatic including alkyl)SO2alkyl, -NHSO2(aryl, heteroaryl or heterocyclic), -N(alkyl)SO2(aryl, heteroaryl or heterocyclic), -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic, oxo, and cycloalkyl, and further comprising, where valence permits, two R attached to the same carbon. 40 The groups may be joined together to form a 3- to 8-membered spiro ring, R 41 is aliphatic, aryl, heteroaryl or hydrogen).

[0023] Any combination of variables, substituents, embodiments, and compounds resulting from these combinations are considered to be specifically and individually disclosed, as such descriptions are merely for convenience of space and are not intended to describe only a genus or even a subgenus of compounds.

[0024] The compounds of the invention can be used to treat EGFR-mediated disorders such as colon cancer, rectal cancer, lung cancer including non-small cell lung cancer, breast cancer including HER-2 positive breast cancer, ER+ (estrogen positive) 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 renal cancer.

[0025] In certain embodiments, methods of treatment are provided that include administering to a patient, e.g., a human, in need of treatment an effective amount of a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. For example, in certain embodiments, a compound of Formula I, II, III, or IV is administered to a human to treat cancer.

[0026] In certain embodiments, the compounds of the present invention are used to treat lung cancer, hi certain embodiments, the lung cancer is non-small cell lung cancer.

[0027] In certain embodiments, the compounds of the present invention are 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.

[0028] In certain embodiments, the compounds of the present invention are used to treat colon or rectal cancer.

[0029] In certain embodiments, the compounds of the present invention are used to treat head and neck cancer or esophageal cancer.

[0030] In certain embodiments, compounds of the present invention are used to treat glioblastoma, hi certain embodiments, compounds of the present invention are used to treat pancreatic cancer.

[0031] In certain embodiments, the compounds of the present invention are used to treat thyroid cancer.

[0032] In certain embodiments, the compounds of the present invention are used to treat ovarian, uterine, or cervical cancer.

[0033] In certain embodiments, the compounds of the present invention are used to treat kidney cancer, liver cancer, or bladder cancer.

[0034] In certain embodiments, the compounds of the invention may offer one or more advantages over conventional EGFR ligand therapy, and may even offer multiple advantages. For example, the EGFR degrading compounds of the invention may a) overcome resistance in certain cases, b) prolong the kinetics of drug effect by disrupting the protein, thereby requiring protein resynthesis even after the compound is metabolized, c) target all functions of the protein at once rather than specific catalytic activities or binding events, and / or d) have increased potency compared to inhibitors due to the potential for small molecules to act catalytically.

[0035] In one aspect, the compounds of the invention are used to treat EGFR-mediated cancers in which EGFR has mutated from wild-type. There are many possible 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 non-limiting embodiments, the mutation is at L858, E709, G719, C797, L861, T790, or L718, or any combination thereof. In certain embodiments, the mutation is an L858R, T790M, L718Q, L792H, and / or C797S mutation, or any combination thereof.

[0036] In certain embodiments, the cancer develops one or more EGFR mutations after treatment with at least one EGFR inhibitor, which 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 embodiment, the cancer develops one or more EGFR mutations after treatment with an antibody such as cetuximab, panitumumab, or necitumumab. In yet another embodiment, the cancer has one or more EGFR mutations or non-EGFR mutations, such as a somatic exon 20 insertion, a somatic PIK3CA mutation, loss of PTEN expression, a MET amplification, or a KRAS mutation, that render the cancer inherently resistant to EGFR inhibitor treatment.

[0037] In certain embodiments, compounds of the invention are used to treat cancers that are resistant or have acquired resistance to first generation EGFR inhibitors, such as erlotinib, gefitinib, and / or lapatinib. In certain embodiments, compounds of the invention are used to treat cancers that are resistant or have acquired resistance to second generation EGFR inhibitors, such as afatinib and / or dacomitinib. In certain embodiments, compounds of the invention are used to treat cancers that are resistant or have acquired resistance to third generation EGFR inhibitors, such as osimertinib.

[0038] In some embodiments, the mutant EGFR protein in the affected tissue has an L858 mutation, eg, L858R.

[0039] In certain embodiments, the compounds of the invention are used to treat mutant EGFR-mediated disorders in which EGFR has a mutation at at least one or a combination of the amino acid positions listed below, where the mutation may be selected, for example, from one of the exemplary mutations listed, or may be a different mutation.

[0040] TIFF0007757284000020.tif66170

[0041] 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.

[0042] 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 mutations, which may optionally be selected from the table above. In other embodiments, the mutant EGFR-mediated disorder has an L858R mutation and three additional mutations, which may optionally be selected from the table above.

[0043] In certain embodiments, the mutant EGFR-mediated disorder has a T790M mutation and, optionally, one additional mutation selected from the table above. In other embodiments, the mutant EGFR-mediated disorder has a T790M mutation and, optionally, two additional mutations selected from the table above. In other embodiments, the mutant EGFR-mediated disorder has a T790M mutation and, optionally, three additional mutations selected from the table above.

[0044] In certain embodiments, the mutant EGFR-mediated disorder has an L718Q mutation and, optionally, one additional mutation selected from the table above. In other embodiments, the mutant EGFR-mediated disorder has an L718Q mutation and, optionally, two additional mutations selected from the table above. In other embodiments, the mutant EGFR-mediated disorder has an L718Q mutation and, optionally, three additional mutations selected from the table above.

[0045] In certain embodiments, the EGFR-mediated disorder is a mutant EGFR-mediated cancer.

[0046] In certain embodiments, the EGFR-mediated cancer has the following mutations: S768I, L718V, L792H, L792V, G796S, G796C, G724S and / or G719A.

[0047] In certain embodiments, compounds of the invention are used to treat EGFR-mediated cancers with frameshift mutations, e.g., short in-frame deletions. In certain embodiments, compounds of the invention are used to treat EGFR-mediated cancers in which EGFR has an exon 19 deletion. In certain embodiments, the exon 19 deletion is a deletion containing amino acids LREA (L747-A750). In certain embodiments, the exon 19 deletion is a deletion containing amino acids ELREA (E746-A750).

[0048] In certain embodiments, the compounds of the present invention are used to treat EGFR-mediated cancers in which EGFR harbors the L858R mutation in exon 21.

[0049] In certain embodiments, the compounds of the present invention are more active against disorders driven by mutant EGFR than wild-type EGFR.

[0050] In certain embodiments, the compounds of the present invention are used to treat EGFR-mediated cancers in which EGFR has one or more exon 18 deletions.

[0051] In certain embodiments, the compounds of the present invention are used to treat EGFR with an E709 mutation, eg, E709A, E709G, E709K, or E709V.

[0052] In certain embodiments, the compounds of the present invention are used to treat EGFR with an L718 mutation, eg, L718Q.

[0053] In certain embodiments, the compounds of the invention are used to treat EGFR with a G719 mutation, eg, G719S, G719A, G719C, or G719D.

[0054] In certain embodiments, the compounds of the present invention are used to treat EGFR-mediated cancers in which EGFR has one or more exon 19 insertions and / or one or more exon 20 insertions.

[0055] In certain embodiments, compounds of the invention are used to treat S7681 mutant EGFR cancers. In certain embodiments, compounds of the invention are used to treat EGFR L861Q mutant EGFR cancers. In certain embodiments, compounds of the invention are used to treat C797S mutant EGFR cancers.

[0056] In certain embodiments, the compounds of the invention are used to treat T790M, L858R mutant EGFR cancers.

[0057] In certain embodiments, the compounds of the present invention are used to treat L718Q, L858R mutant EGFR cancers.

[0058] In certain embodiments, the compounds of the present invention are used to treat L792H, L858R mutant EGFR cancers.

[0059] In certain embodiments, the compounds of the present invention are used to treat C797S, L858R mutant EGFR cancers.

[0060] In certain embodiments, the compounds of the present invention provide improved efficacy and / or safety profiles compared to at least one known EGFR inhibitor. For example, the degraders of the present invention possess the efficacy of the protein-binding portion of the inhibitor alone combined with the catalytic degradation activity of cereblon-activated proteasomal degradation. This results in rapid activity against the target overexpressed EGFR, with the active portion being able to quickly "return to action" and resume catalytic function. In this way, EGFR is rapidly destroyed, as occurs with covalent suicide inhibitors such as osimertinib, without simultaneously destroying the active drug.

[0061] In certain embodiments, the degrader compounds of the present invention have one or more advantages over the use of enzyme inhibitors alone in the treatment of EGFR-mediated disorders.

[0062] In certain embodiments, less of the compound described herein is required to treat an EGFR-mediated disorder than by mole of the EGFR-targeted ligand moiety alone.

[0063] In certain embodiments, the compounds of the present invention produce at least one less side effect in treating an EGFR-mediated disorder than the EGFR-targeted ligand moiety alone.

[0064] In certain embodiments, the dosing regimen of the selected compounds described herein required to treat an EGFR-mediated disorder is less frequent than the molar administration of the EGFR-targeted ligand moiety alone.

[0065] Another aspect of the present invention provides a compound as described herein, or an enantiomer, diastereomer or stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, for use in the manufacture of a medicament for inhibiting or preventing a disorder mediated by EGFR or modulating or reducing the amount of EGFR.

[0066] Another aspect of the present invention provides a compound as described herein, or an enantiomer, diastereomer or stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or preventing a disease mediated by EGFR.

[0067] In certain embodiments, select compounds described herein are useful for treating disorders involving abnormal cell proliferation, such as tumors or cancers, where EGFR is an oncogenic protein or signaling mediator of an abnormal cell proliferation pathway, and its degradation reduces abnormal cell growth.

[0068] In certain embodiments, select compounds of Formula I, Formula II, Formula III, or Formula IV, or pharmaceutically acceptable salts thereof, have at least one desired isotopic substitution of an atom in an amount above the natural abundance of that isotope, i.e., are enriched.

[0069] In certain embodiments, a compound of Formula I, Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt thereof, comprises a deuterium atom or multiple deuterium atoms.

[0070] In certain embodiments, the compounds of the present invention are useful in the therapeutic and / or prophylactic treatment of cancer.

[0071] In certain embodiments, the compounds of the invention have an E3 ubiquitin ligase binding moiety linked to a moiety that binds to a target protein, EGFR, such that the target protein is brought into proximity with the ubiquitin ligase, thereby achieving degradation of the protein.

[0072] Other features and advantages of the present application will be apparent from the following detailed description.

[0073] To this end, the present invention includes at least the following features: (a) a compound of Formula I, Formula II, Formula III or IV as described herein, or a pharmaceutically acceptable salt or isotopic derivative thereof (including deuterated derivatives); (b) a method for treating an EGFR-mediated disorder, such as abnormal cell proliferation, including cancer, comprising administering to a patient in need thereof an effective amount of a compound of Formula I, Formula II, Formula III or Formula IV, as described herein, or a pharmaceutically acceptable salt thereof; (c) a compound of Formula I, Formula II, Formula III or Formula IV, or a pharmaceutically acceptable salt or isotopic derivative thereof (including deuterated derivatives), for use in the treatment of an EGFR-mediated disorder, e.g., abnormal cell growth such as a tumor or cancer; (d) use of an effective amount of a compound of Formula I, Formula II, Formula III or Formula IV, or a pharmaceutically acceptable salt thereof, in the treatment of a patient, typically a human, in need of such treatment, having an EGFR-mediated disorder, e.g., abnormal cell proliferation such as a tumor or cancer; (e) use of a compound of Formula I, Formula II, Formula III or Formula IV, or a pharmaceutically acceptable salt or isotopic derivative thereof (including deuterated derivatives), in the manufacture of a medicament for the treatment of an EGFR-mediated disorder, e.g., abnormal cell growth such as a tumor or cancer; (f) a method for treating mutant EGFR-mediated disorders, such as abnormal cell growth, including cancer, comprising administering to a patient in need thereof an effective amount of a compound of Formula I, Formula II, Formula III or Formula IV, as described herein, or a pharmaceutically acceptable salt thereof; (g) A compound of Formula I, Formula II, Formula III or Formula IV, or a pharmaceutically acceptable salt or isotopic derivative thereof (including deuterated derivatives), for use in the treatment of a disorder mediated by mutant EGFR, e.g., abnormal cell growth such as a tumor or cancer; (h) use of an effective amount of a compound of Formula I, Formula II, Formula III or Formula IV, or a pharmaceutically acceptable salt thereof, in the treatment of a patient, typically a human, in need of such treatment, having a mutant EGFR-mediated disorder, e.g., abnormal cell proliferation such as a tumor or cancer; (i) the use of a compound of Formula I, Formula II, Formula III or Formula IV, or a pharmaceutically acceptable salt or isotopic derivative thereof (including deuterated derivatives), in the manufacture of a medicament for the treatment of a mutant EGFR-mediated disorder, e.g., abnormal cell growth such as a tumor or cancer; (j) a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, Formula II, Formula III or Formula IV, or a pharmaceutically acceptable salt, isotopic derivative thereof, and optionally a pharmaceutically acceptable carrier or diluent; (k) a compound of Formula I, Formula II, Formula III or Formula IV as described herein as a mixture of enantiomers or diastereomers (where appropriate), including a racemate; (l) an enantiomerically or diastereomerically (where appropriate) enriched form of a compound of Formula I, Formula II, Formula III or Formula IV as described herein, including an isolated enantiomer or diastereomer (i.e., greater than about 85%, 90%, 95%, 97% or 99% pure); and (m) A process for making a therapeutic product containing an effective amount of a compound of Formula I, Formula II, Formula III or Formula IV, or a pharmaceutically acceptable salt thereof, as described herein. DETAILED DESCRIPTION OF THE INVENTION

[0074]

[0003] Provided are compounds that degrade epidermal growth factor receptor protein (EGFR) via the ubiquitin proteasome pathway (UPP), as well as their uses and production. The present invention provides compounds of Formula I, II, III, or IV, or pharmaceutically acceptable salts thereof, that include a targeting ligand that binds to EGFR, an E3 ligase binding moiety (typically via a cereblon subunit), and a linker that covalently links the targeting ligand to the E3 ligase binding moiety. In certain embodiments, the E3 ligase binding moiety is A or A * and the linker is L 1 or L 2and the remainder of the molecule is the EGFR-targeting ligand portion. In certain embodiments, the compounds of the invention degrade EGFRs having a mutation or combination of mutations, such as a mutation selected from T790M, L858R, and C797S, a combination of two mutations selected from T790M, L858R, and C797S, or a combination of two mutations selected from T790M, L858R, and C797S. In certain embodiments, the compounds of the invention are selective degraders of EGFR mutants having T790M / L858R, T790M / L858R / C797S, L858R, and / or L858R / C797S.

[0075] In certain embodiments, the compounds of the present invention provide improved efficacy and / or safety profiles compared to at least one known EGFR inhibitor. For example, the degraders of the present invention possess the efficacy of the protein-binding portion of the inhibitor alone combined with the catalytic degradation activity of cereblon-activated proteasomal degradation. This results in rapid activity against the target overexpressed EGFR, with the active portion being able to quickly "return to action" and repeat catalytic function. In this way, EGFR is rapidly destroyed, as occurs with covalent suicide inhibitors such as osimertinib, without simultaneously destroying the active drug.

[0076] I. Definition The following definitions of general terms used herein apply regardless of whether the terms appear alone or in combination with other groups.

[0077] Unless otherwise stated, the following terms used in this application, including the specification and claims, have the definitions set forth below. It must be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0078] "C 1~6The term "-alkoxy" refers to a compound in which R' is C 1~6 -Alkyl groups, in particular C 1~3 represents a group of formula -O-R', which is -alkyl. 1~6 Examples of -alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Particular examples are methoxy, ethoxy and isopropoxy. A more particular example is methoxy.

[0079] "C 1~6 The term "-alkyl", alone or in combination with other groups, refers to a hydrocarbon radical which may be linear or branched, having single or multiple branches, where the alkyl group generally contains from 1 to 6 carbon atoms, e.g., 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, etc. A particular group is methyl.

[0080] The term "cyano" refers to the group -C≡N.

[0081] "C 3~8 The term "cycloalkoxy" refers to a compound in which R' is C 3~8 represents a group of the formula -O-R', which is a cycloalkyl group. Examples of cycloalkoxy groups include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy. A particular example is cyclopropoxy.

[0082] "C 3~8 The term "cycloalkyl" refers to a monovalent saturated monocyclic or bicyclic hydrocarbon group having 3 to 8 ring carbon atoms. Bicyclic refers to a ring system consisting of two saturated carbocyclic rings that share one or two carbon atoms. Monocyclic C 3~8 Examples of -cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl.3~8 An example of a -cycloalkyl is spiro[3.3]heptanyl. 3~8 -cycloalkyl groups are cyclopropyl, cyclobutanyl. More particular monocyclic C 3~8 Cycloalkyl groups include cyclopropyl.

[0083] "Haro-C 1~6 The term "-alkoxy" refers to 1~6 -C in which at least one hydrogen atom of the alkoxy group is replaced by the same or different halogen atom 1~6 -alkoxy group. 1~6 The term "-alkoxy" refers to 1~6 -C in which all hydrogen atoms of the alkoxy group are replaced by the same or different halogen atoms 1~6 -alkoxy group. Halo-C 1~6 Examples of -alkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, trifluoromethylethoxy, trifluorodimethylethoxy, and pentafluoroethoxy. 1~6 -alkoxy groups include fluoromethoxy, fluoroethoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoromethylethoxy and trifluorodimethylethoxy. More particular examples are fluoromethoxy, difluoromethoxy and trifluoromethoxy.

[0084] "Haro-C 1~6 The term "-alkyl" refers to 1~6 -C in which at least one hydrogen atom of the alkyl group is replaced by the same or different halogen atom 1~6 -Alkyl group. "Perhalo-C 1~6 -Alkyl-C 1~6 The term "-alkyl" refers to an alkyl group in which all hydrogen atoms are replaced by the same or different halogen atoms -C 1~6 -Alkyl-C 1~6 - represents an alkyl group.1~6 Examples of -alkyl include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylethyl and pentafluoroethyl. 1~6 -alkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, trifluoroethyl and difluoroethyl. More particular halo-C 1~6 The alkyl group includes fluoromethyl.

[0085] "Haro-C 3~8 The term "cycloalkoxy" refers to the C 3~8 -C in which at least one hydrogen atom of the cycloalkoxy group is replaced by the same or different halogen atom 3~8 - represents a cycloalkoxy group. 3~8 The term "cycloalkoxy" refers to the C 3~8 -C in which all hydrogen atoms of the cycloalkoxy group are replaced by the same or different halogen atoms 3~8 - represents a cycloalkoxy group. 3~8 Examples of -cycloalkoxy include fluorocyclopropoxy, fluorocyclobutoxy, fluorocyclopentyloxy, fluorocyclohexyloxy, fluorocycloheptyloxy, difluorocyclopropoxy, difluorocyclobutoxy, difluorocyclopentyloxy, difluorocyclohexyloxy and difluorocycloheptyloxy.

[0086] "Haro-C 3~8 The term "-cycloalkyl" refers to 3~8 -C in which at least one hydrogen atom of the cycloalkyl group is replaced by the same or different halogen atom 3~8 - represents a cycloalkyl group. 3~8 The term "-cycloalkyl" refers to an alkyl group in which all hydrogen atoms are replaced by the same or different halogen atoms. 3~8 - represents a cycloalkyl group. Halo-C 3~8Examples of -cycloalkyl include fluorocyclopropyl, fluorocyclobutanyl, fluorocyclopentyl, fluorocyclohexyl, fluorocycloheptyl, difluorocyclopropyl, difluorocyclobutanyl, difluorocyclopentyl, difluorocyclohexyl or difluorocycloheptyl.

[0087] The term "halogen", alone or in combination with other groups, refers to chloro (Cl), iodo (I), fluoro (F) and bromo (Br). Particular groups are F and Cl.

[0088] The term "hydroxy" refers to an --OH group.

[0089] "Hydroxy-C 1~6 The term "-alkyl alkyl" refers to 1~6 -C alkylalkyl group in which at least one hydrogen atom is replaced by a hydroxy group 1~6 - represents an alkyl alkyl group. 1~6 Examples of -alkyl include hydroxymethyl, hydroxyethyl and hydroxypropyl. A particular example is hydroxymethyl.

[0090] The term "pharmaceutically acceptable" refers to the attributes of a material useful in making pharmaceutical compositions that are generally safe, non-toxic, not biologically or otherwise undesirable, and acceptable for human as well as veterinary medical use.

[0091] The term "pharmaceutically acceptable salt" refers to a salt suitable for use in contact with human and animal tissues. Examples of suitable salts with inorganic and organic acids include, but are not limited to, acetic acid, citric acid, formic acid, fumaric acid, hydrochloric acid, lactic acid, maleic acid, malic acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, succinic acid, sulfuric acid (sulfuric acid), tartaric acid, trifluoroacetic acid, and the like. Particular acids are formic acid, trifluoroacetic acid, and hydrochloric acid. A specific acid is trifluoroacetic acid.

[0092] The term "pharmaceutically acceptable auxiliary substances" refers to carriers and auxiliary substances, such as diluents or excipients, that are compatible with the other ingredients of the formulation.

[0093] The term "pharmaceutical composition" encompasses not only products containing specified ingredients in predetermined amounts or proportions, but also any product obtained directly or indirectly by combining the specified ingredients in the specified amounts. In particular, the term encompasses not only products containing one or more active ingredients and any carrier, including inactive ingredients, but also any product obtained directly or indirectly by combination, complexation, or aggregation of any two or more ingredients, or dissociation of one or more ingredients, or other type of reaction or interaction of one or more ingredients.

[0094] A "therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a medical condition, is sufficient to effect such treatment for that condition. The therapeutically effective amount will vary depending on the compound, the condition being treated, the severity or disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0095] The terms "as defined herein" and "as described herein" when referring to a variable incorporate by reference the broad definition of the variable, as well as the definitions of "particularly," "more particularly," and "most particularly," if any.

[0096] The terms "treating," "contacting," and "reacting," when referring to a chemical reaction, mean the addition or mixing of two or more reagents under appropriate conditions to produce a specified and / or desired product. It is understood that the reaction that produces a specified and / or desired product does not necessarily result directly from the combination of the two reagents initially added; i.e., there may be one or more intermediates that are produced in the mixture that ultimately result in the formation of the specified and / or desired product.

[0097] The term "pharmaceutically acceptable excipient" refers to any ingredient that has no therapeutic activity and is non-toxic, such as a disintegrant, binder, filler, solvent, buffer, tonicity agent, stabilizer, antioxidant, surfactant, or lubricant, used in the formulation of a pharmaceutical product.

[0098] The term "pharmaceutical composition" encompasses not only products containing specified ingredients in predetermined amounts or proportions, but also any product obtained directly or indirectly by combining the specified ingredients in the specified amounts. In particular, the term encompasses not only products containing one or more active ingredients and any carrier, including inactive ingredients, but also any product obtained directly or indirectly by combination, complexation, or aggregation of any two or more ingredients, or dissociation of one or more ingredients, or other type of reaction or interaction of one or more ingredients.

[0099] The term "inhibitor" refers to a compound that competes with, reduces or prevents the binding of a particular ligand to a particular receptor, or reduces or prevents the function of a particular protein.

[0100] "50% inhibitory concentration (half maximal inhibitory concentration)" (IC 50 The term IC ) refers to the concentration of a particular compound required to obtain 50% inhibition of a biological process in vitro. 50 Values ​​are pIC 50 Value (-log IC 50 ) can be logarithmically transformed into IC, with higher values ​​indicating exponentially greater potency. 50 The IC value is not absolute and depends on the experimental conditions used, e.g., concentration. 50 The value was calculated using the Cheng-Prusoff equation as the absolute inhibition constant (K i ) can be converted to (Biochem. Pharmacol. (1973) 22:3099).

[0101] A "therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a medical condition, is sufficient to effect such treatment for that condition. The therapeutically effective amount will vary depending on the compound, the condition being treated, the severity or disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0102] The term "aromatic" refers to the conventional concept of aromaticity as defined in the literature, in particular in IUPAC - Compendium of Chemical Terminology, 2nd, AD McNaught & A. Wilkinson (Eds). Blackwell Scientific Publications, Oxford (1997).

[0103] Whenever a chiral carbon is present in a chemical structure, all stereoisomers associated with that chiral carbon are intended to be encompassed by that structure, both as pure stereoisomers and mixtures thereof.

[0104] In certain embodiments, isotopes are incorporated into the compounds of the invention. These isotopes include, respectively: 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 17 O. 18 O. 18 F, 35 S and 36 These include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as Cl. In one non-limiting embodiment, isotope-labeled compounds are used in metabolic studies (e.g., 14 C), reaction kinetic studies (e.g. 2 H or 3H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or radiation treatment of patients. Additionally, any hydrogen atoms present in the compounds of the present invention can be replaced by 18 It may be substituted with an F atom, which may be particularly desirable for PET or SPECT studies.

[0105] In one non-limiting embodiment, any compound described herein may have a hydrogen atom substituted with a deuterium atom. For example, an alkyl residue may be deuterated if any of the groups is, or includes, methyl, ethyl, or methoxy, for example, by substitution (such as, in a non-limiting embodiment, CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3). In certain other embodiments, an unsubstituted carbon may be deuterated if two substituents combine to form a cycle. In certain embodiments, at least one deuterium is located on an atom bearing a bond that is broken during metabolism of the compound in vivo, or is 1, 2, or 3 atoms away from the bond that is metabolized (e.g., α, β, or γ, or sometimes referred to as a primary, secondary, or tertiary isotope effect).

[0106] In certain embodiments, the compounds of the invention are isotopically labeled. 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 20 , R 21 , R 22, R 23 , R 24 , R 26 , R 27 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 40 , R 41 , R 42 , R 52 , R 53 , R 54 , R 55 , R 70 , R 80 , R 81 , R 82 , R 90 or R 100 At least one R group independently selected from is isotopically labeled with one, two, or more isotopes, as valence permits. In certain embodiments, the isotopic label is deuterium. In certain embodiments, at least one deuterium is located on an atom bearing a bond that is broken during metabolism of the compound in vivo, or is one, two, or three atoms away from a bond that is metabolized (e.g., α, β, or γ, or sometimes referred to as a primary, secondary, or tertiary isotope effect). In another embodiment, the isotopic label is 13 C. In other embodiments, the isotopic label is 18 It's F.

[0107] In certain embodiments, the compounds of the present invention may form solvates with solvents (including water). Thus, in a non-limiting embodiment, the present invention includes solvated forms of the compounds described herein. The term "solvate" refers to a molecular complex of a compound of the present invention (including its salts) with one or more solvent molecules. Non-limiting examples of solvents include water, ethanol, isopropanol, dimethyl sulfoxide, acetone, and other common organic solvents.

[0108] In certain embodiments, "alkenyl" is a linear or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds that may occur at any stable point along the chain. In one non-limiting embodiment, an alkenyl contains 2 to about 12 carbon atoms, more typically 2 to about 6 carbon atoms or 2 to about 4 carbon atoms. In certain embodiments, an alkenyl is C2, C2-C3, C2-C4, C2-C5, or C2-C6. In certain embodiments, examples of alkenyl radicals include, but are not limited to, ethenyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. In certain embodiments, the term "alkenyl" also embodies "cis" and "trans" alkenyl configurations, or alternatively, "E" and "Z" alkenyl configurations. In certain embodiments, the term "alkenyl" also encompasses cycloalkyl or carbocyclic groups having at least one point of unsaturation.

[0109] In certain embodiments, "alkynyl" is a branched or straight-chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds, which may occur at any stable point along the chain. In one non-limiting embodiment, alkynyl contains 2 to about 12 carbon atoms, more typically 2 to about 6 carbon atoms or 2 to about 4 carbon atoms. In certain embodiments, alkynyl is C2, C2-C3, C2-C4, C2-C5, or C2-C6. In certain embodiments, examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl. In certain embodiments, the term "alkynyl" also encompasses cycloalkyl or carbocyclic groups that have at least one point of triple bond unsaturation.

[0110] II. Compounds of Formula I, Formula II, Formula III and Formula IV The present invention provides compounds of Formula I, Formula II, Formula III and Formula IV, pharmaceutical compositions of these compounds, methods of using and methods of making these compounds.

[0111] Formula I Embodiments All the separate embodiments can be combined.

[0112] E1: One embodiment of the present invention is a compound of formula I: [ka] (In the formula, A is a ring system AF and AG: [ka] is selected from A 1 teeth, i) -NH-, and ii) -O-; A 2 teeth, i) -N-, and ii)-CR 52 - selected from A 3 teeth, i)-N-, and ii)-CR 53 - selected from A 4 teeth, i) -N-, and ii)-CR 54 - selected from A 5 teeth, i) -N-, and ii)-CR 55 - selected from R 1 teeth, i) H, ii) halogens, iii) C 1~6 -alkyl, R 52 teeth, i) H, ii) halogens, iii) cyano, iv) C 1~6 -alkoxy, v) Halo-C 1~6 -alkoxy, vi) C 1~6 - alkyl, vii) Halo-C 1~6 - alkyl, viii) C 3~8 -cycloalkyl, and ix) Halo-C 3~8 -cycloalkyl, R 53 , R 54 and R 55 is independent, i) H, ii) halogens, iii) C 1~6 - alkyl, iv) Halo-C 1~6 -alkyl, v) C 3~8 -cycloalkyl, and vi) Halo-C 3~8 -cycloalkyl, R 2 teeth, i) H, ii) halogens, iii) C 1~6 - alkyl, iv) Halo-C 1~6 - alkyl, v) C 3~8 -cycloalkyl, and vi) Halo-C 3~8 -cycloalkyl, R 3 teeth, i) H, ii) halogens, iii) C 1~6 -alkyl, iv) Halo-C 1~6 - alkyl, v) C 3~8 -cycloalkyl, and vi) Halo-C 3~8 -cycloalkyl, R 4 and R 5 is H or or R 4 and R 5 together -(CH2) q - Forms q is 1 or 2; R 6 teeth, i) H, ii) halogens, iii) cyano, iv) C 1~6 -alkoxy, v) Halo-C 1~6 -alkoxy, vi) C 1~6 - alkyl, vii) Halo-C 1~6 - alkyl, viii) C 3~8 -cycloalkyl, and ix) Halo-C 3~8 -cycloalkyl, R 7 teeth, i) H, ii) halogens, iii) cyano, iv) C 1~6 - alkyl, v) Halo-C 1~6 - alkyl, vi) C 3~8 -cycloalkyl, and vii) Halo-C 3~8 -cycloalkyl, R 70 teeth, i) H, ii) halogens, iii) cyano, iv) C 1~6 - alkyl, v) Halo-C 1~6 - alkyl, vi) C 3~8 -cycloalkyl, and vii) Halo-C 3~8 -cycloalkyl, R8 is H, R 9 teeth, iii) H, and iv) C 1~6 -alkyl, L 1 teeth, [ka] and C is absent or is a ring system F, G and H: [ka] is selected from Y 1 teeth, i)-N-, and ii) -CH-; Y 2 teeth, i)-N-, and ii)-CR 16 - selected from R 12 , R 13 , R 14 and R 15 is independent, i)-H-, ii) halogens, and iii) Hydroxy-C 1~6 -alkyl, R 16 teeth, i)-H-, ii) hydroxy, and iii) selected from fluoro; L 3 does not exist, or i)-(CH2) m -C(O)-, ii) -C(O)-(CH2) p -, iii) -C(O)-C(O)-, iv)-NR 10 -C(O)-, v) -C(O)-NR 10 -, vi) -C(O)O-, vii) -CH2-CF2-CH2-, viii) -CH2-, ix) [ka] x) [ka] and, xi) [ka] is selected from m is 0, 1 or 2; p is 0, 1, 2 or 3; R 10 teeth, i) H, and ii) C 1~6 -alkyl, D is the ring system I, J, K, L, M, N, O, P, Q, R, S, T, U, V, W and X: [ka] and either ring system is selected from R 80 , R 81 and R 82 and optionally substituted with 1 to 3 substituents selected from R 80 , R 81 and R 82 is independent, i) halogens, ii) cyano, iii) hydroxy, iv) Hydroxy-C 1~6 - alkyl, v) C 1~6 -alkoxy, vi) Halo-C 1~6 -alkoxy, vii) C 1~6 - alkyl, viii) Halo-C 1~6 - alkyl, ix) C 3~8 -cycloalkyl, and x) Halo-C 3~8 -cycloalkyl, L 4 does not exist, or i)-NR 11 -C(O)-, ii) -CH2-, and iii) -O-; E is the ring system Y, Z, AA, AB and AC: [ka] is selected from L 5 does not exist, or [ka] and B is the ring system AD and AE: [ka] or a pharmaceutically acceptable salt thereof. E2: A particular embodiment of the present invention is one in which A is a ring system AF and AG: [ka] is selected from A 1 but, i) -NH-, and ii) -O-; A 2 but, i)-N-, and ii) -CH-; R 1 but, i) H, and ii) selected from halogens; R 2 is H, R 3 but, i) H, and ii) selected from halogens; R 4 is H, R 5 is H or or R 4 and R 5 together -(CH2) n - Forms n is 1, R 6 but, i) H, ii) halogens, iii) cyano, and iv) Halo-C 1~6 -alkyl, R 7 is H, R 8 is H, R 9 C 1~6 -alkyl, L 1 but, [ka] and C is absent or the ring system F: [ka] and Y 1 but, i) -N-, and ii) -CH-; Y 2 but, i) -N-, and ii)-CR 16 - selected from R 12 , R 13 , R 14 and R 15 became independent, i) H, and ii) selected from halogens; R 16 but, i) H, and ii) hydroxy; L3 but, i)-(CH2) m -C(O)-, ii) -C(O)-(CH2) p -, iii) —C(O)—C(O)—, and iv)-NR 10 -C(O)-; m is 1, p is 1 or 3, R 10 but, i) H, and ii) C 1~6 -alkyl, D is a ring system I, J, K, L and M: [ka] is selected from L 4 but, i)-NR 11 -C(O)-, ii) -CH2-, and iii) -O-; E is the ring system Y, Z and AA, AB and AC: [ka] is selected from L 5 but, [ka] and B is the ring system AD and AE: [ka] or a pharmaceutically acceptable salt thereof. E3: A particular embodiment of the present invention is one in which A is a ring system AF and AG: [ka] is selected from A1 but, i) -NH-, and ii) -O-; A 2 but, i)-N-, and ii) -CH-; R 1 but, i) H, and ii) selected from fluoro; R 2 is H, R 3 but, i) H, and ii) selected from fluoro; R 4 is H, R 5 is H or or R 4 and R 5 together -(CH2) q - Forms q is 1, R 6 but, i) H, ii) fluoro, iii) cyano, iv) difluoromethyl, and v) trifluoromethyl; R 7 is H, R 8 is H, R 9 is methyl, L 1 but, [ka] and C is the ring system F: [ka] and Y 1 but, i)-N-, and ii) -CH-; Y 2 but, i) -N-, and ii)-CR 16 - selected from R 12 and R 13 is fluoro, R 14 and R 15 is H, R 16 but, i) H, and ii) hydroxy; L 3 but, i)-(CH2) m -C(O)-, ii) -C(O)-(CH2) p -, iii) —C(O)—C(O)—, and iv)-NR 10 -C(O)-; m is 1, p is 1 or 3, R 10 is H, D is a ring system I, J, K, L and M: [ka] is selected from L 4 but, i)-NR 11 -C(O)-, ii) -CH2-, and iii) -O-; E is the ring system Y, Z, AA, AB and AC: [ka] is selected from L 5 but, [ka] and B is the ring system AD and AE: [ka] or a pharmaceutically acceptable salt thereof. E4: A particular embodiment of the present invention is a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein A is the ring system AF. E5: Certain embodiments of the present invention are 1 is -N-; or a pharmaceutically acceptable salt thereof. E6: Certain embodiments of the present invention are 2 is —CH—; or a pharmaceutically acceptable salt thereof. E7: Certain embodiments of the present invention are 1 but, i) H, and ii) halogen. E8: Certain embodiments of the present invention are 1 but, i) H, and ii) fluoro; or a pharmaceutically acceptable salt thereof. E9: Certain embodiments of the present invention are 1 is fluoro; or a pharmaceutically acceptable salt thereof. E10: Certain embodiments of the present invention are 2 is H, or a pharmaceutically acceptable salt thereof. E11: Certain embodiments of the present invention are 3 but, i) H, and ii) halogen. E12: Certain embodiments of the present invention are 3 but, i) H, and ii) fluoro; or a pharmaceutically acceptable salt thereof. E13: Certain embodiments of the present invention are 4 is H, or a pharmaceutically acceptable salt thereof. E14: Certain embodiments of the present invention are 5 is H, or a pharmaceutically acceptable salt thereof. E15: Certain embodiments of the present invention are 6 but, i) H, ii) halogens, iii) cyano, and iv) Halo-C 1~6 -alkyl; or a pharmaceutically acceptable salt thereof. E16: Certain embodiments of the present invention are 7 is H, or a pharmaceutically acceptable salt thereof. E17: Certain embodiments of the present invention are 8 is H, or a pharmaceutically acceptable salt thereof. E18: Certain embodiments of the present invention are 9 C 1~6 -alkyl; or a pharmaceutically acceptable salt thereof. E19: Certain embodiments of the present invention are 9 is methyl; or a pharmaceutically acceptable salt thereof. E20: A particular embodiment of the present invention is a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein n is 1. E21: A particular embodiment of the present invention is a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein C is absent or is the ring system F. E22: A particular embodiment of the present invention is a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein C is the ring system F. E23: Certain embodiments of the present invention are 12 and R 13 is fluoro; or a pharmaceutically acceptable salt thereof. E24: Certain embodiments of the present invention are 14 and R 15 is H, or a pharmaceutically acceptable salt thereof. E25: Certain embodiments of the present invention are 16 but, i) H, and ii) hydroxy; or a pharmaceutically acceptable salt thereof. E26: Certain embodiments of the present invention are 16 is H, or a pharmaceutically acceptable salt thereof. E27: Certain embodiments of the present invention are 3 but, i)-(CH2) m -C(O)-, ii) -C(O)-(CH2) p -, iii) —C(O)—C(O)—, and iv)-NR 10 -C(O)- or a pharmaceutically acceptable salt thereof. E28: A particular embodiment of the present invention is a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein m is 1. E29: A particular embodiment of the present invention is a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein p is 1 or 3. E30: Certain embodiments of the present invention are 10 but, i) H, and ii) C 1~6 -alkyl; or a pharmaceutically acceptable salt thereof. E31: A particular embodiment of the present invention is a 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: Certain embodiments of the present invention are 4 but, i)-NR 11 -C(O)-, ii) -CH2-, and iii) —O— or a pharmaceutically acceptable salt thereof. E33: Certain embodiments of the present invention are 4 but, [ka] or a pharmaceutically acceptable salt thereof. E34: Certain embodiments of the present invention are 5-((2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-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, 5-[2-[2-[1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl]-7-fluoro-3-oxo-isoindolin-5-yl]ethynyl]-N-[1-[2-[4-[(2,6-dioxo-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-oxo-2-(thiazol-2-ylamino)ethyl]-7-fluoro-3-oxo-isoindolin-5-yl]ethynyl]-N-[1-[2-[4-[4-[(2,6-dioxo-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-oxo-2-(thiazol-2-ylamino)ethyl]-7-fluoro-3-oxo-isoindolin-5-yl]ethynyl]-N-[1-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]-2-fluoro-phenyl]-1-piperidyl]acetyl]-4-piperidyl]pyridine-2-carboxamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[4-[2-[4-[4-[(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-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-5H-pyrrolo[1,2-c]imidazol-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-yl)-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-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, 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)-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-c]imidazol-1-yl)-2-[6-[4-[4-[2-[4-[5-[(2,6-dioxo-3-piperidyl)amino]-2-pyridyl]-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-yl)-2-[6-[4-[4-[2-[4-[4-[(2,6-dioxo-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-c]imidazol-1-yl)-2-[6-[4-[4-[2-[4-[4-[(2,6-dioxo-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)amino]phenyl]-1-piperidyl]acetyl]piperazin-1-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, 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-yl]-2-(6,7-dihydro-5H-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-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-(2,4-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-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, 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-yl)-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-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]acetyl]piperazin-1-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-(2-pyridyl)acetamide, 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-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-(((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-c]imidazol-1-yl)-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-yl)-2-(6,7-dihydro-5H-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-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]phenyl]-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-[6-[4-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]-2-fluoro-phenyl]-1-piperidyl]acetyl]piperazin-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-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, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[[1-[2-[4-[4-[(2,6-dioxo-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-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]oxy]phenyl]-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-[[(3R)-2,6-dioxo-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-5H-pyrrolo[1,2-c]imidazol-1-yl)-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-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, 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-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)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, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-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-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-(((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-yl)-2-[6-[4-[[1-[2-[4-[4-[(2,6-dioxo-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, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[(3R)-1-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]phenyl]-1-piperidyl]acetyl]pyrrolidin-3-yl]oxyphenyl]-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-[(3S)-1-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]phenyl]-1-piperidyl]acetyl]pyrrolidin-3-yl]oxyphenyl]-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-yl)-N-(thiazol-2-yl)acetamide, 2-[6-[4-[4-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]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-c]imidazol-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-c]imidazol-1-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-(((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-dioxo-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-c]imidazol-1-yl)-2-[6-[4-[2-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]-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, 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-yl]-N-thiazol-2-yl-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]-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-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, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[2-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]-2-fluoro-phenyl]-1-piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-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-yl]-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]-3,3-difluoro-1-piperidyl]acetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-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-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetyl]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-yl)-2-[6-[4-[[4-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]acetyl]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-yl)-2-[6-[4-[[4-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]-2-fluoro-phenyl]-1-piperidyl]acetyl]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-yl)-2-[6-[4-[[4-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]-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-yl)-2-[6-[4-[[1-[2-[4-[4-[[(3S)-2,6-dioxo-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 or a pharmaceutically acceptable salt thereof. E35: A particular embodiment of the present invention is a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance. E36: A particular embodiment of the present invention is a compound of formula I as described herein or a pharmaceutically acceptable salt thereof for use in the therapeutic and / or prophylactic treatment of cancer, particularly non-small cell lung cancer, more particularly EGFR-mutated non-small cell lung cancer in which the activating mutation is L858R. E37: A particular embodiment of the present invention is a compound of formula I as described herein or a pharmaceutically acceptable salt thereof for use in the therapeutic and / or prophylactic treatment of non-small cell lung cancer, more particularly EGFR-mutated non-small cell lung cancer in which the activating mutation is L858R. E38: A particular embodiment of the present invention is a 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, particularly non-small cell lung cancer, more particularly EGFR-mutated non-small cell lung cancer, wherein the activating mutation is L858R. E39: A particular embodiment of the present invention is a pharmaceutical composition comprising a compound of formula I as described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable auxiliary substance. E40: A particular embodiment of the present invention is a method for the therapeutic and / or prophylactic treatment of cancer, in particular non-small cell lung cancer, more particularly EGFR-mutated non-small cell lung cancer, in which the activating mutation is L858R, by administering to a patient a compound of formula I as described herein or a pharmaceutically acceptable salt thereof. E41: A particular embodiment of the present invention is a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, for use as a medicament in the therapeutic and / or prophylactic treatment of patients suffering from cancer, in particular non-small cell lung cancer, and having an EGFR activating mutation, comprising determining the EGFR activating mutation status in the patient and then administering to said patient a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof. E42: A particular embodiment of the present invention is a compound of formula I as defined herein or a pharmaceutically acceptable salt thereof for use as a medicament in the therapeutic and / or prophylactic treatment of patients suffering from cancer, in particular non-small cell lung cancer, and having the EGFR mutations T790M / L858R, T790M / L858R / C797S, L858R, and / or L858R / C797S, comprising determining the EGFR activating mutation status in the patient and then administering to said patient a compound of formula I as defined herein or a pharmaceutically acceptable salt thereof. E43: A particular embodiment of the present invention is a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, for use as a medicament in the therapeutic and / or prophylactic treatment of patients suffering from cancer, in particular non-small cell lung cancer, and having an EGFR activating mutation as determined using the cobas™ EGFR Mutation Test v2, comprising determining the EGFR activating mutation status in the patient and then administering to said patient a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof. E44: The present invention includes, whenever applicable, all substituents of compounds of formula I in their corresponding deuterated form. E45: The present invention includes, wherever applicable, all optical isomers of the compounds of formula I, i.e. diastereoisomers, diastereomeric mixtures, racemic mixtures, all their corresponding enantiomers and / or tautomers, and solvates thereof.

[0113] Formula II Embodiments All the separate embodiments can be combined.

[0114] E1: One embodiment of the present invention is a compound of formula II: [ka] (In the formula, A' is the ring system AF, AG and AH: [ka] is selected from A 1 teeth, i) -NH-, and ii) -O-; A 2 teeth, i) -N-, and ii)-CR 52 - selected from A 3 teeth, i) -N-, and ii)-CR 53 - selected from A 4 teeth, i)-N-, and ii)-CR 54 - selected from A 5 teeth, i)-N-, and ii)-CR 55 - selected from R 1 'teeth, i) H, ii) halogens, iii) C 1~6 -alkyl, iv) cyano, v) C 1~6 -alkoxy, vi) Halo-C 1~6 -alkoxy, vii) C 1~6 -alkyl, viii) Halo-C 1~6 -alkyl, ix) C 3~8 -cycloalkyl, and x) Halo-C 3~8 -cycloalkyl, R 52 teeth, i) H, ii) halogens, iii) cyano, iv) C 1~6 -alkoxy, v) Halo-C 1~6 -alkoxy, vi) C 1~6 -alkyl, vii) Halo-C 1~6 -alkyl, viii) C 3~8 -cycloalkyl, and ix) Halo-C 3~8 -cycloalkyl, R 53 , R 54 and R 55 is independent, i) H, ii) halogens, iii) C 1~6-alkyl, iv) Halo-C 1~6 -alkyl, v) C 3~8 -cycloalkyl, and vi) Halo-C 3~8 -cycloalkyl, R 2 teeth, i) H, ii) halogens, iii) cyano, iv) C 1~6 -alkyl, v) Halo-C 1~6 -alkyl, vi) C 3~8 -cycloalkyl, and vii) Halo-C 3~8 -cycloalkyl, R 3 teeth, i) H, ii) halogens, iii) C 1~6 -alkyl, iv) Halo-C 1~6 -alkyl, v) C 3~8 -cycloalkyl, and vi) Halo-C 3~8 -cycloalkyl, R 4 and R 5 is H or or R 4 and R 5 together -(CH2) q - Forms q is 1 or 2; R 6 teeth, i) H, ii) halogens, iii) cyano, iv) C 1~6 -alkoxy, v) Halo-C 1~6 -alkoxy, vi) C 1~6 -alkyl, vii) Halo-C 1~6-alkyl, viii) C 3~8 -cycloalkyl, and ix) Halo-C 3~8 -cycloalkyl, R 7 teeth, i) H, ii) halogens, iii) cyano, iv) C 1~6 -alkyl, v) Halo-C 1~6 -alkyl, vi) C 3~8 -cycloalkyl, and vii) Halo-C 3~8 -cycloalkyl, R 70 teeth, i) H, ii) halogens, iii) cyano, iv) C 1~6 -alkyl, v) Halo-C 1~6 -alkyl, vi) C 3~8 -cycloalkyl, and vii) Halo-C 3~8 -cycloalkyl, R 8 is H, R 9 teeth, i) H, and ii) C 1~6 -alkyl, L 1 teeth, [ka] and C is absent or is a ring system F, G and H: [ka] is selected from Y 1 teeth, i)-N-, and ii) -CH-; Y 2 teeth, i)-N-, and ii)-CR 16 - selected from R 12 , R 13 , R 14 and R 15 is independent, i)-H-, ii) halogens, and iii) Hydroxy-C 1~6 -alkyl, R 16 teeth, i)-H-, ii) hydroxy, and iii) selected from fluoro; L 3 does not exist, or i)-(CH2) m -C(O)-, ii) -C(O)-(CH2) p -, iii) -C(O)-C(O)-, iv)-NR 10 -C(O)-, v) -C(O)-NR 10 -, vi) -C(O)O-, vii) -CH2-CF2-CH2-, viii) -CH2-, ix) [ka] x) [ka] and, xi) [ka] is selected from m is 0, 1 or 2; p is 0, 1, 2 or 3; R10 teeth, i) H, and ii) C 1~6 -alkyl, D is the ring system I, J, K, L, M, N, O, P, Q, R, S, T, U, V, W and X: [ka] and either ring system is selected from R 80 , R 81 and R 82 and optionally substituted with 1 to 3 substituents selected from R 80 , R 81 and R 82 is independent, i) halogens, ii) cyano, iii) hydroxy, iv) Hydroxy-C 1~6 -alkyl, v) C 1~6 -alkoxy, vi) Halo-C 1~6 -alkoxy, vii) C 1~6 -alkyl, viii) Halo-C 1~6 -alkyl, ix) C 3~8 -cycloalkyl, and x) Halo-C 3~8 -cycloalkyl, L 4 does not exist, or i)-NR 11 -C(O)-, ii) -CH2-, and iii) -O-; E is the ring system Y, Z, AA, AB and AC: [ka] is selected from L 5 does not exist, or [ka] and B is the ring system AD and AE: [ka] or a pharmaceutically acceptable salt thereof. E2: A particular embodiment of the invention is where A' is a ring system AF, AG and AH: [ka] is selected from A 1 is -NH-, A 2 but, i)-N-, and ii) -CH-; R 1 'but, i) H, and ii) selected from halogens; R 2 but, i) H, and ii) selected from halogens; R 3 is H, R 4 is H, R 5 is H, R 6 but, i) H, and ii) selected from halogens; R 7 is H, R 8 is H, R 9 C 1~6 -alkyl, L 1 but, [ka] and C is the ring system F: [ka] and Y 1 is -CH-, Y 2 is -N-, R 12 , R 13 , R 14 and R 15 is H, L 3 but, i)-(CH2) m -C(O)-, and ii) -C(O)-(CH2) p - selected from m is 1, p is 3, D is ring system I and J: [ka] is selected from L 4 does not exist, E is the ring system Y and Z: [ka] is selected from L 5 is a compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein E3: A particular embodiment of the present invention is a 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 particular embodiment of the present invention is a compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein A is the ring system AF. E5: Certain embodiments of the present invention are 1 is —NH—, or a pharmaceutically acceptable salt thereof. E6: Certain embodiments of the present invention are 2 is —CH—; or a pharmaceutically acceptable salt thereof. E7: Certain embodiments of the present invention are 1 'but, i) H, and ii) halogen; or a pharmaceutically acceptable salt thereof. E8: Certain embodiments of the present invention are 1 'but, i) H, ii) chloro, and iii) fluoro; or a pharmaceutically acceptable salt thereof. E9: Certain embodiments of the present invention are 2 but, i) H, and ii) halogen; or a pharmaceutically acceptable salt thereof. E10: Certain embodiments of the present invention are 2 but, i) H, ii) chloro, and iii) fluoro; or a pharmaceutically acceptable salt thereof. E11: Certain embodiments of the present invention are 3 but, i) H, and ii) halogen; or a pharmaceutically acceptable salt thereof. E12: Certain embodiments of the present invention are 3 is H, or a pharmaceutically acceptable salt thereof. E13: Certain embodiments of the present invention are 4 is H, or a pharmaceutically acceptable salt thereof. E14: Certain embodiments of the present invention are 5 is H, or a pharmaceutically acceptable salt thereof. E15: Certain embodiments of the present invention are 6 but, i) H, and ii) halogen; or a pharmaceutically acceptable salt thereof. E16: Certain embodiments of the present invention are 7 is H, or a pharmaceutically acceptable salt thereof. E17: Certain embodiments of the present invention are 8 is H, or a pharmaceutically acceptable salt thereof. E18: Certain embodiments of the present invention are 9 C 1~6 -alkyl; or a pharmaceutically acceptable salt thereof. E19: Certain embodiments of the present invention are 9 is methyl; or a pharmaceutically acceptable salt thereof. E20: A particular embodiment of the present invention is a compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein C is the ring system F. E21: Certain embodiments of the present invention are 1 is —CH—; or a pharmaceutically acceptable salt thereof. E22: Certain embodiments of the present invention are 2 is —N—; or a pharmaceutically acceptable salt thereof. E23: Certain embodiments of the present invention are 12 , R 13 , R 14 and R 15 is H, or a pharmaceutically acceptable salt thereof. E24: Certain embodiments of the present invention are 3 but, i)-(CH2) m -C(O)-, and ii) -C(O)-(CH2) p or a pharmaceutically acceptable salt thereof. E25: A particular embodiment of the present invention is a compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein m is 1. E26: A particular embodiment of the present invention is a compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein p is 1 or 3. E27: A particular embodiment of the present invention is a compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein D is selected from ring systems I and J. E28: A particular embodiment of the present invention is a compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein D is the ring system J. E29: Certain embodiments of the present invention are 4 is a compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein E30: A particular embodiment of the present invention is a 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: Certain embodiments of the present invention are 5 is a compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein E32: Certain embodiments of the present invention are 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-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, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-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-yl)-N-(thiazol-2-yl)acetamide, 2-[4,7-dichloro-6-[4-[4-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetyl]piperazin-1-yl]phenyl]indazol-2-yl]-2-(6,7-dihydro-5H-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-[6-[4-[2-[4-[4-[(2,6-dioxo-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-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[6-[4-[2-[4-[4-[(2,6-dioxo-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-dioxo-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-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, or a pharmaceutically acceptable salt thereof. 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(6-(4-(2-(4-(4-(((S)-2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)piperazin-1-yl)pyridin-3-yl)-4-fluoro-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide. E33: A particular embodiment of the present invention is a compound of formula II, as described herein, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance. E34: A particular embodiment of the present invention is a compound of formula II as described herein or a pharmaceutically acceptable salt thereof for use in the therapeutic and / or prophylactic treatment of cancer, particularly non-small cell lung cancer, more particularly EGFR-mutated non-small cell lung cancer in which the activating mutation is L858R. E35: A particular embodiment of the present invention is a compound of formula II as described herein or a pharmaceutically acceptable salt thereof for use in the therapeutic and / or prophylactic treatment of non-small cell lung cancer, more particularly EGFR-mutated non-small cell lung cancer in which the activating mutation is L858R. E36: A particular embodiment of the present invention is a 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, particularly non-small cell lung cancer, more particularly EGFR-mutated non-small cell lung cancer, wherein the activating mutation is L858R. E37: A particular embodiment of the present invention is a pharmaceutical composition comprising a compound of formula II as described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable auxiliary substance. E38: A particular embodiment of the present invention is a method for the therapeutic and / or prophylactic treatment of cancer, particularly non-small cell lung cancer, more particularly EGFR-mutated non-small cell lung cancer in which the activating mutation is L858R, by administering to a patient a compound of formula II as described herein or a pharmaceutically acceptable salt thereof. E39: A particular embodiment of the present invention is a compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, for use as a medicament in the therapeutic and / or prophylactic treatment of patients suffering from cancer, particularly non-small cell lung cancer, and having an EGFR activating mutation, comprising determining the EGFR activating mutation status in the patient and then administering to said patient a compound of formula II as described herein, or a pharmaceutically acceptable salt thereof. E40: A particular embodiment of the present invention is a compound of formula II as defined herein or a pharmaceutically acceptable salt thereof for use as a medicament in the therapeutic and / or prophylactic treatment of patients suffering from cancer, in particular non-small cell lung cancer, and having the EGFR mutations T790M / L858R, T790M / L858R / C797S, L858R, and / or L858R / C797S, comprising determining the EGFR activating mutation status in the patient and then administering to said patient a compound of formula II as defined herein or a pharmaceutically acceptable salt thereof. E41: A particular embodiment of the present invention is a compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, for use as a medicament in the therapeutic and / or prophylactic treatment of patients suffering from cancer, in particular non-small cell lung cancer, and having an EGFR activating mutation as determined using the cobas™ EGFR Mutation Test v2, comprising determining the EGFR activating mutation status in the patient and then administering to said patient a compound of formula II as described herein, or a pharmaceutically acceptable salt thereof. E42: The present invention includes, whenever applicable, all substituents of compounds of formula II in their corresponding deuterated form. E43: The present invention includes, whenever applicable, all optical isomers of compounds of formula II, i.e. diastereoisomers, diastereomeric mixtures, racemic mixtures, all their corresponding enantiomers and / or tautomers, and solvates thereof.

[0115] Formula III and Formula IV Embodiments E1: In certain embodiments, the present invention provides a compound of formula III or formula IV: [ka] (In the formula, A * teeth, [ka] is selected from B * is heteroaryl or aryl, each of which is selected from one, two, or three R 31 optionally substituted with substituents, y is 0, 1, 2 or 3; R 31 In each case, H, halogen (F, Cl, Br or I), C 1~6 -Alkyl, Cyano, C 1~6 -Alkoxy, Halo-C 1~6 -Alkoxy, Halo-C 1~6 -Alkyl, C 3~8 -cycloalkyl and halo-C 3~8 -cycloalkyl, which, when present on a bicyclic ring, may be located on either ring; R 32 is hydrogen, halogen (F, Cl, Br or I), C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 3~8 -cycloalkyl or halo-C 3~8 -cycloalkyl, R 33 is hydrogen, halogen (F, Cl, Br or I), C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 3~8 -cycloalkyl or halo-C 3~8 -cycloalkyl, optionally located on the dihydropyrrole or imidazole ring; R 34 In either case, H, F, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 3~8 -cycloalkyl and halo-C 3~8 -cycloalkyl; R 35In each case, H, halogen (F, Cl, Br or I), C 1~6 -Alkyl, Halo-C 1~6 -alkyl and C 3~8 -cycloalkyl; or R 34 and R 35 and combine to form -(CH2) q - Forms q is 1 or 2; R 36 and R 37 are independently H, halogen (F, Cl, Br or I), cyano, C 1~6 -Alkoxy, Halo-C 1~6 -alkoxy, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 3~8 -cycloalkyl and halo-C 3~8 -cycloalkyl; or R 36 and R 37 and are bonded together to form one, two or three R 31 forming a 5- or 6-membered ring optionally substituted with substituents, R 90 is H, C 1~6 -alkyl or C 3~6 -cycloalkyl, Ring G is one or two R 42 heteroaryl optionally substituted with substituents; A 21 is -NH-, -O-, -CH2- or -NR 100 - and R 100 is alkyl, cycloalkyl, aryl, or heteroaryl, or, to the extent valence allows, R 100 R 37 may be bonded to form a 5- to 8-membered heterocycle or a 5-membered heteroaryl; A 32 , A 33 , A 34 and A 35 are independently -N- and -CR 42 - selected from R42 In each case, H, halogen (F, Cl, Br or I), cyano, C 1~6 -Alkoxy, Halo-C 1~6 -alkoxy, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 3~8 -cycloalkyl and halo-C 3~8 -cycloalkyl; A 36 -N- or -CR 35 - and L 2 is A * and either an isoindolinone or an indazole), or a pharmaceutically acceptable salt, isotope, N-oxide, or stereoisomer thereof. E2: The compound is [ka] or a pharmaceutically acceptable salt thereof. E3: The compound is [ka] or a pharmaceutically acceptable salt thereof. E4:R 33 The compound of any one of embodiments 1-3, wherein is H. E5:R 33 The compound of any one of embodiments 1-3, wherein is F. E6: The compound of any one of embodiments 1 to 5, wherein y is 1. E7: The compound of any one of embodiments 1 to 5, wherein y is 2. E8: At least one R 31 The compound of any of embodiments 1-7, wherein is halo. E9: At least one R 31 The compound of any one of embodiments 1-7, wherein is F. E10: The compound of any one of embodiments 1 to 5, wherein y is 0. E11:R 32 The compound of any one of embodiments 1-10, wherein is H. E12:R 32 The compound of any of embodiments 1-10, wherein is F. E13: The compound is [ka] 2. The compound of embodiment 1, selected from: E14: The compound is [ka] 2. The compound of embodiment 1, selected from: E15:A * but, [ka] 15. The compound of any one of embodiments 1-14, wherein E16:A * but, [ka] 15. The compound of any one of embodiments 1-14, wherein E17:A 34 The compound of any of embodiments 1-16, wherein is CH. E18:A 34 The compound of any of embodiments 1-16, wherein is N. E19:A 34 is CR 42 17. The compound of any one of embodiments 1-16, wherein: E20:A 34 The compound of any of embodiments 1-16, wherein is CF. E21:A 35 The compound of any of embodiments 1-20, wherein is CH. E22:A 35 The compound of any of embodiments 1-20, wherein is N. E23:A 35 is CR 4221. The compound of any one of embodiments 1-20, wherein E24:A 35 The compound of any of embodiments 1-20, wherein is CF. E25:A * but, [ka] 15. The compound of any one of embodiments 1-14, wherein E26:A * but, [ka] 15. The compound of any one of embodiments 1-14, wherein E27:A 21 The compound of embodiment 25 or 26, wherein is NH. E28:A 21 The compound of embodiment 25 or 26, wherein is O. E29:A * but, [ka] 15. The compound of any one of embodiments 1-14, wherein E30:A 32 The compound of any of embodiments 1-29, wherein is CH. E31:A 32 The compound of any of embodiments 1-29, wherein is N. E32:A 32 is CR 42 30. The compound of any one of embodiments 1-29, wherein E33:A 32 The compound of any of embodiments 1-29, wherein is CF. E34:A 33 The compound of any of embodiments 1-33, wherein is CH. E35:A 33 The compound of any of embodiments 1-33, wherein is N. E36:A 33 is CR 4234. The compound of any one of embodiments 1-33, wherein: E37:A 33 The compound of any of embodiments 1-33, wherein is CF. E38:A * but, [ka] 15. The compound of any one of embodiments 1-14, wherein E39:A 21 The compound of embodiment 38, wherein is NH. E40:A 21 is O. E41:R 34 The compound of any of embodiments 1-40, wherein is H. E42:R 34 The compound of any of embodiments 1-40, wherein is F. E43:R 34 The compound of any of embodiments 1-40, wherein is CH3. E44:R 35 The compound of any of embodiments 1-43, wherein is H. E45:R 35 The compound of any of embodiments 1-43, wherein is F. E46:R 35 The compound of any of embodiments 1-43, wherein is CH3. E47:R 34 and R 35 and combine to form -CH2-. E48:R 31 In each case, H, halogen (F, Cl, Br or I) and C 1~6 48. The compound of any of embodiments 1-47, wherein: - is independently selected from alkyl. E49:R 42 In each case, H, halogen (F, Cl, Br or I) and C 1~6 -alkyl. E50:B* but, [ka] 50. The compound of any one of embodiments 1-49, wherein: E51:B * but, [ka] 50. The compound of any one of embodiments 1-49, wherein: E52:B * but, [ka] 50. The compound of any one of embodiments 1-49, wherein: E53:B * but, [ka] 50. The compound of any one of embodiments 1-49, wherein: E54:L 2 is the expression: [ka] (In the formula, X 1 and X 2 are independently, in each occurrence, a bond, heterocycle, aryl, heteroaryl, bicycle, alkyl, aliphatic, heteroaliphatic, -NR 27 -, -CR 40 R 41 -, -O-, -C(O)-, -C(NR 27 )—, —C(S)—, —S(O)—, —S(O)—, and —S—, wherein each of the heterocycle, aryl, heteroaryl, and bicycle is selected from R 40 optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 20 , R 21 , R 22 , R 23 and R 24are independently in each occurrence a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, or -C(O)NR 27 -, -NR 27 C(O)-, -O-, -S-, -NR 27 -, oxyalkylene, -C(R 40 R 40 )-, -P(O)(OR 26 )O-, -P(O)(OR 26 )-, bicyclic, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic, glycolic, and carbocyclic, each of which is selected from the group consisting of R 40 optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 26 is independently selected at each occurrence from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic, aliphatic, and heteroaliphatic; R 27 is independently selected at each occurrence from the group consisting of hydrogen, alkyl, aliphatic, heteroaliphatic, heterocyclic, aryl, heteroaryl, —C(O)(aliphatic, aryl, heteroaliphatic, or heteroaryl), —C(O)O(aliphatic, aryl, heteroaliphatic, or heteroaryl), alkene, and alkyne; R 40 are independently hydrogen in each case, R 27, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azido, amino, cyano, -NH(aliphatic), -N(aliphatic)2, -NHSO2(aliphatic), -N(aliphatic)SO2alkyl, -NHSO2(aryl, heteroaryl or heterocyclic), -N(alkyl)SO2(aryl, heteroaryl or heterocyclic), -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic, oxo, and cycloalkyl, and further comprising, where valence permits, two R attached to the same carbon. 40 The groups may be joined together to form a 3- to 8-membered spiro ring, R 41 and n is aliphatic, aryl, heteroaryl, or hydrogen. E55:L 2 is the expression: [ka] 55. The compound of embodiment 54, wherein: E56:X 1 The compound of embodiment 54 or 55, wherein is a bond. E57:X 1 The compound of embodiment 54 or 55, wherein is a heterocycle. E58:X 1 NR 2 56. The compound of embodiment 54 or 55, wherein E59:X 1 The compound of embodiment 54 or 55, wherein is C(O). E60:X 2 The compound of any of embodiments 54-59, wherein is a bond. E61:X 2 The compound of any of embodiments 54-59, wherein is a heterocycle. E62:X 2 NR 2 60. The compound of any of embodiments 54-59, wherein: E63:X2 The compound of any of embodiments 54-59, wherein is C(O). E64:R 20 The compound of any of embodiments 54-63, wherein is a bond. E65:R 20 The compound of any of embodiments 54-63, wherein is CH2. E66:R 20 The compound of any of embodiments 54-63, wherein is a heterocycle. E67:R 20 The compound of any of embodiments 54-63, wherein is aryl. E68:R 20 The compound of any of embodiments 54-63, wherein is phenyl. E69:R 20 The compound of any of embodiments 54-63, wherein is bicyclic. E70:R 21 The compound of any of embodiments 54-69, wherein is a bond. E71:R 21 The compound of any of embodiments 54-69, wherein is CH2. E72:R 21 The compound of any of embodiments 54-69, wherein is a heterocycle. E73:R 21 The compound of any of embodiments 54-69, wherein is aryl. E74:R 21 The compound of any of embodiments 54-69, wherein is phenyl. E75:R 21 The compound of any of embodiments 54-69, wherein is bicyclic. E76:L is the formula: [ka] 55. The compound of embodiment 54, wherein the linker is E77:R 22 The compound of any of embodiments 54-76, wherein is a bond. E78:R 22The compound of any of embodiments 54-76, wherein is CH2. E79:R 22 The compound of any of embodiments 54-76, wherein is a heterocycle. E80:R 22 The compound of any of embodiments 54-76, wherein is aryl. E81:R 22 The compound of any of embodiments 54-69, wherein is phenyl. E82:R 22 The compound of any of embodiments 54-76, wherein is bicyclic. E83:L is the formula: [ka] 55. The compound of embodiment 54, wherein the linker is E84:R 23 The compound of any of embodiments 54-83, wherein is a bond. E85:R 23 The compound of any of embodiments 54-83, wherein is CH2. E86:R 23 The compound of any of embodiments 54-83, wherein is a heterocycle. E87:R 23 The compound of any of embodiments 54-83, wherein is aryl. E88:R 23 The compound of any of embodiments 54-83, wherein is phenyl. E89:R 23 The compound of any of embodiments 54-83, wherein is bicyclic. E90:R 24 The compound of any of embodiments 54-89, wherein is a bond. E91:R 24 The compound of any of embodiments 54-89, wherein is CH2. E92:R 24 The compound of any of embodiments 54-89, wherein is a heterocycle. E93:R 24 The compound of any of embodiments 54-89, wherein is aryl. E94:R 24 The compound of any of embodiments 54-89, wherein is phenyl. E95:R 24 The compound of any of embodiments 54-89, wherein is bicyclic. E96:R 24 The compound of any of embodiments 54-89, wherein is C(O). E97: In certain embodiments, TIFF0007757284000083.tif54170TIFF0007757284000084.tif250170TIFF0007757284000085.tif254170TIFF0007757284000086.tif254170TIFF0007 757284000087.tif254170TIFF0007757284000088.tif254170TIFF00077572 84000089.tif254170TIFF0007757284000090.tif254170TIFF000775728400 0091.tif254170TIFF0007757284000092.tif231170TIFF0007757284000093.tif223170TIFF0007757284000094.tif248170TIFF0007757284000095.tif254170TIFF0007757284000096.tif200170TIFF0007757284000097.tif233170TIFF0007757284000098.tif238170 or a pharmaceutically acceptable salt thereof. E98: In certain embodiments, TIFF0007757284000099.tif248170TIFF0007757284000100.tif241170TIFF0007757284000101.tif249170TIFF0007757284000102.tif235170TIFF0007757284000103.tif254170TIFF0007757284000104.tif212170TIFF0007757284000105.tif249170TIFF0007757284000106.tif254170TIFF0007757284000107.tif254170TIFF0007757284000108.tif254170TIFF0007757284000109.tif236170TIFF0007757284000110.tif238170TIFF0007757284000111.tif251170TIFF0007757284000112.tif253170TIFF0007757284000113.tif246170TIFF0007757284000114.tif230170TIFF0007757284000115.tif246170TIFF0007757284000116.tif245170TIFF0007757284000117.tif254170TIFF0007757284000118.tif254170TIFF0007757284000119.tif254170TIFF0007757284000120.tif254170TIFF0007757284000121.tif254170TIFF0007757284000122.tif243170TIFF0007757284000123.tif223170TIFF0007757284000124.tif248170TIFF0007757284000125.tif251170TIFF0007757284000126.tif251170TIFF0007757284000127.tif221170TIFF0007757284000128.tif224170TIFF0007757284000129.tif254170TIFF0007757284000130.tif254170TIFF0007757284000131.tif229170TIFF0007757284000132.tif81170 or a pharmaceutically acceptable salt thereof. E99: In certain embodiments, the present invention is a compound according to any of embodiments 1 to 98 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, for use as a therapeutically active substance. E100: In certain embodiments, the present invention relates to a compound according to any of embodiments 1 to 98 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, for use in the therapeutic and / or prophylactic treatment of cancer. E101: In certain embodiments, the present invention is a method of treating a patient having an EGFR-mediated disorder, comprising administering a compound according to any 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 cancer, tumor, or abnormal cell proliferation. E104: The method of embodiment 103, wherein the EGFR-mediated disorder is cancer or a tumor. E105: The method of embodiment 103, wherein the EGFR-mediated disorder is abnormal cell 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. E108: The method of any of embodiments 103-107, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with at least one mutation. E109: The method of any of embodiments 103-108, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with an L858R mutation. E110: The method of any of embodiments 103-109, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with a T790M mutation. E111: The method of any of embodiments 103-110, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with a C797S mutation. E112: The method of any of embodiments 103-111, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with the L792H mutation. E113: The method of any of embodiments 103-112, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with an L718Q mutation. E114: The method of any of embodiments 103-108, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with a T790M / L858R mutation. E115: The method of any of embodiments 103-108, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with T790M / L858R / C797S mutations. E116: The method of any of embodiments 103-108, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with the L858R / C797S mutation. E117: The method according to any of embodiments 101-116, wherein an additional EGFR inhibitor is administered. E118: The method of embodiment 117, wherein the additional EGFR inhibitor is a tyrosine kinase inhibitor. E119: The method of embodiment 118, wherein the additional EGFR inhibitor is osimertinib. E120: The method of embodiment 118, wherein the additional EGFR inhibitor is rociletinib. E121: The method of embodiment 118, wherein the additional EGFR inhibitor is avitinib. E122: The method of embodiment 118, wherein the additional EGFR inhibitor is lazertinib. E123: The method of embodiment 118, wherein the additional EGFR inhibitor is nazartinib. E124: The method of embodiment 117, wherein the additional EGFR inhibitor is an antibody against a mutant form of EGFR. E125: The method of embodiment 124, wherein the additional EGFR inhibitor is cetuximab. E126: The method of embodiment 124, wherein the additional EGFR inhibitor is panitumumab. E127: The method of embodiment 124, wherein the additional EGFR inhibitor is necitumumab. E128: The method of any of embodiments 101-127, wherein a MET inhibitor is also administered. E129: The method according to any of embodiments 101-128, wherein the patient is given an additional chemotherapeutic agent. E130: In certain embodiments, the present invention is a compound according to any one of embodiments 1-98 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating an EGFR-mediated disorder in a patient. E131: The use of embodiment 130, wherein the patient is a human. E132: The use according to embodiment 130 or 131, wherein the EGFR-mediated disorder is cancer, a tumor or abnormal cell proliferation. E133: The use according to embodiment 132, wherein the EGFR-mediated disorder is cancer or a tumor. E134: The use according to embodiment 132, wherein the EGFR-mediated disorder is abnormal cell proliferation. E135: The use according to embodiment 132, wherein the cancer is lung cancer. E136: The use according to embodiment 135, wherein the lung cancer is non-small cell lung cancer. E137: The use according to any of embodiments 132 to 136, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with at least one mutation. E138: The use according to any of embodiments 132 to 137, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with the L858R mutation. E139: The use according to any of embodiments 132 to 138, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with a T790M mutation. E140: The use according to any of embodiments 132 to 139, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with a C797S mutation. E141: The use according to any of embodiments 132 to 140, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with the L792H mutation. E142: The use according to any of embodiments 132 to 141, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with the L718Q mutation. E143: The use according to any of embodiments 132 to 136, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with the T790M / L858R mutation. E144: The use according to any of embodiments 132 to 136, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with T790M / L858R / C797S mutations. E145: The use according to any of embodiments 132 to 136, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with the L858R / C797S mutation. E146: The use according to any of embodiments 130 to 145, wherein an additional EGFR inhibitor is administered. E147: The use according to embodiment 146, wherein the additional EGFR inhibitor is a tyrosine kinase inhibitor. E148: The use according to embodiment 147, wherein the additional EGFR inhibitor is osimertinib. E149: The use according to embodiment 147, wherein the additional EGFR inhibitor is rociletinib. E150: The use according to embodiment 147, wherein the additional EGFR inhibitor is avitinib. E151: The use according to embodiment 147, wherein the additional EGFR inhibitor is lazertinib. E152: The use according to embodiment 147, wherein the additional EGFR inhibitor is nazartinib. E153: The use according to embodiment 146, wherein the additional EGFR inhibitor is an antibody against a mutated form of EGFR. E154: The use according to embodiment 153, wherein the additional EGFR inhibitor is cetuximab. E155: The use according to embodiment 153, wherein the additional EGFR inhibitor is panitumumab. E156: The use according to embodiment 153, wherein the additional EGFR inhibitor is necitumumab. E157: The use according to any of embodiments 130 to 156, in which a MET inhibitor is also administered. E158: The use according to any of embodiments 130 to 157, wherein the patient is given an additional chemotherapy agent. E159: In certain embodiments, the invention relates to a compound according to any of embodiments 1-98 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, for use in treating an EGFR-mediated disorder in a patient. E160: The compound of embodiment 159, wherein the patient is a human. E161: The compound of embodiment 159 or 160, wherein the EGFR-mediated disorder is cancer, tumor, or abnormal cell proliferation. E162: The compound of embodiment 161, wherein the EGFR-mediated disorder is cancer or tumor. E163: The compound of embodiment 161, wherein the EGFR-mediated disorder is abnormal cell proliferation. E164: The compound of embodiment 162, wherein the cancer is lung cancer. E165: The compound according to embodiment 164, wherein the lung cancer is non-small cell lung cancer. E166: The compound according to any of embodiments 161-165, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with at least one mutation. E167: The compound according to any of embodiments 161-166, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with the L858R mutation. E168: The compound according to any of embodiments 161-167, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with a T790M mutation. E169: The compound of any of embodiments 161-168, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with a C797S mutation. E170: The compound according to any of embodiments 161-169, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with the L792H mutation. E171: The compound according to any of embodiments 161-170, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with the L718Q mutation. E172: The compound according to any of embodiments 161-166, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with T790M / L858R mutations. E173: The compound according to any of embodiments 161-166, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with T790M / L858R / C797S mutations. E174: The compound according to any of embodiments 161-166, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with the L858R / C797S mutation. E175: The compound of any of embodiments 159-174, wherein an additional EGFR inhibitor is administered. E176: The compound of embodiment 175, wherein the additional EGFR inhibitor is a tyrosine kinase inhibitor. E177: The compound of embodiment 175, wherein the additional EGFR inhibitor is osimertinib. E178: The compound of embodiment 175, wherein the additional EGFR inhibitor is rociletinib. E179: The compound of embodiment 175, wherein the additional EGFR inhibitor is avitinib. E180: The compound of embodiment 175, wherein the additional EGFR inhibitor is lazertinib. E181: The compound of embodiment 175, wherein the additional EGFR inhibitor is nazartinib. E182: The compound of embodiment 174, wherein the additional EGFR inhibitor is an antibody against a mutated form of EGFR. E183: The compound of embodiment 182, wherein the additional EGFR inhibitor is cetuximab. E184: The compound of embodiment 182, wherein the additional EGFR inhibitor is panitumumab. E185: The compound of embodiment 182, wherein the additional EGFR inhibitor is necitumumab. E186: The compound of any of embodiments 159-185, wherein a MET inhibitor is also administered. E187: The compound according to any of embodiments 159-186, wherein the patient is given an additional chemotherapeutic agent. E188: In certain embodiments, the present invention provides a compound according to any of embodiments 1-98 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, for use as a medicament in the therapeutic and / or prophylactic treatment of patients suffering from cancer, in particular non-small cell lung cancer, and having an EGFR activating mutation as determined using the cobas™ EGFR Mutation Test v2, comprising determining the EGFR activating mutation status in the patient and then administering to said patient a compound according to any of embodiments 1-98 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition. E189: In certain embodiments, the invention is a pharmaceutical composition comprising a compound according to any one of embodiments 1-98 and a pharmaceutically acceptable excipient.

[0116] Additional Embodiments of the Invention Chirality Embodiments The compounds of the invention may, for example, be substituted with one or more stereocenters (e.g., [ka] or ), one or more stereocenters in the linker, and / or at least one stereocenter in the EGFR-binding ligand portion of the molecule (e.g., [ka] ) may have multiple stereocenters (e.g., chiral carbon atoms), including R, S, and S. In certain embodiments, the EGFR-degrading compounds of the present invention are provided without regard to stereochemistry. In other embodiments, the EGFR-degrading compounds may have one or more chiral carbons presented in 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 compounds have 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 portion of the compound and in the linker, or alternatively, there are two in the linker. In another sub-aspect, there are three enantiomerically enriched and / or substantially pure stereocenters, one in the ligase binding portion of the compound and two in the linker. In yet another sub-aspect of this, there are three enantiomerically enriched and / or substantially pure stereocenters, one in the ligase binding portion of the compound and two in the linker. In another aspect, in any of these embodiments, aspects or sub-aspects, further, the EGFR binding ligand portion is in enantiomerically enriched or substantially pure form.

[0117] In some embodiments, it has been observed that the chiral carbon of the EGFR-binding ligand moiety adjacent to the amide may readily racemize between stereoisomers under the conditions used, and therefore, in certain embodiments, is not considered for purposes of assigning stereochemistry.

[0118] In certain embodiments, one stereocenter is in the R configuration and the other stereocenters present are enantiomerically enriched or substantially pure. In certain embodiments, one stereocenter is in the S configuration and the other stereocenters present are enantiomerically enriched or substantially pure.

[0119] In certain embodiments, one stereocenter is in the R configuration and the other stereocenters present are enantiomerically enriched or substantially pure, regardless of stereochemistry. In certain embodiments, one stereocenter is in the S configuration and the other stereocenters present are enantiomerically enriched or substantially pure, regardless of stereochemistry.

[0120] In certain embodiments, there is one stereocenter in the E3 ligase binding moiety (disregarding the stereocenter in the EGFR-binding ligand moiety) that is enantiomerically enriched or substantially pure in the R configuration as shown below. In other embodiments, there is one stereocenter in the E3 ligase binding moiety (disregarding the stereocenter in the EGFR-binding ligand moiety) that is enantiomerically enriched or substantially pure in the S configuration as shown below.

[0121] In certain embodiments, [ka] teeth, [ka] and R 34 is hydrogen.

[0122] In certain embodiments, [ka] teeth, [ka] and R 34 is hydrogen.

[0123] In certain embodiments, [ka] teeth, [ka] is.

[0124] In certain embodiments, [ka] teeth, [ka] is.

[0125] In certain embodiments, [ka] teeth, [ka] is.

[0126] In certain embodiments, [ka] teeth, [ka] is.

[0127] In certain embodiments, there is one stereocenter in the linker moiety that is a mixture of R and S configurations. In other embodiments, there is one stereocenter in the linker moiety that is enantiomerically enriched or substantially pure R configuration. In other embodiments, there is one stereocenter in the linker moiety that is enantiomerically enriched or substantially pure S configuration.

[0128] In certain embodiments, the linker comprises one or more moieties having a chiral center. Non-limiting examples include enantiomerically enriched or substantially pure stereogenic heterocycles, such as piperidine with a meta or ortho substituent or linked in the meta or ortho configuration relative to the nitrogen, piperazine with or linked in the meta or ortho configuration, pyrrolidinone with or without substituent, and pyrrolidine with or without substituent.

[0129] Additional non-limiting examples of linker moieties having at least one chiral center include enantiomerically enriched or substantially pure stereogenic alkyls, enantiomerically enriched or substantially pure stereogenic alkenes, enantiomerically enriched or substantially pure stereogenic alkynes, enantiomerically enriched or substantially pure stereogenic haloalkyls, enantiomerically enriched or substantially pure stereogenic alkoxys, enantiomerically enriched or substantially pure stereogenic aliphatic groups, enantiomerically enriched or substantially pure stereogenic heteroaliphatic groups, and enantiomerically enriched or substantially pure stereogenic cycloalkyls.

[0130] In certain embodiments, the linker is [ka] Includes.

[0131] In certain embodiments, the linker is [ka] Includes.

[0132] In certain embodiments, the linker is [ka] Includes.

[0133] In certain embodiments, the linker is [ka] Includes.

[0134] In certain embodiments, the linker is [ka] Includes.

[0135] In certain embodiments, the linker is [ka] Includes.

[0136] In certain embodiments, the linker is [ka] Includes.

[0137] In certain embodiments, the linker is [ka] Includes.

[0138] In certain embodiments, the linker is [ka] Includes.

[0139] In certain embodiments, the linker is [ka] Includes.

[0140] In certain embodiments, the linker is [ka] Includes.

[0141] In certain embodiments, the linker is [ka] Includes.

[0142] In certain embodiments, the linker is [ka] Includes.

[0143] In certain embodiments, at least one stereocenter is present in the EGFR ligand moiety and is a mixture of R and S. In other embodiments, at least one stereocenter is present in the EGFR ligand moiety and is enantiomerically enriched or substantially pure in the R configuration. In other embodiments, at least one stereocenter is present in the EGFR ligand moiety and is enantiomerically enriched or substantially pure in the S configuration.

[0144] In certain embodiments, [ka] teeth, [ka] and R 33 is hydrogen.

[0145] In certain embodiments, [ka] teeth, [ka] and R 33is hydrogen.

[0146] In certain embodiments, [ka] teeth, [ka] is.

[0147] In certain embodiments, [ka] teeth, [ka] is.

[0148] In certain embodiments, [ka] teeth, [ka] is.

[0149] In certain embodiments, [ka] teeth, [ka] is.

[0150] In certain embodiments, [ka] teeth, [ka] is.

[0151] In certain embodiments, [ka] teeth, [ka] is.

[0152] Alkyl embodiments In certain embodiments, "alkyl" is C1-C 10 alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, or C1 or C2 alkyl.

[0153] In certain embodiments, the "alkyl" has 1 carbon.

[0154] In certain embodiments, the "alkyl" has two carbons.

[0155] In certain embodiments, the "alkyl" has 3 carbons.

[0156] In certain embodiments, the "alkyl" has 4 carbons.

[0157] In certain embodiments, the "alkyl" has 5 carbons.

[0158] In certain embodiments, the "alkyl" has 6 carbons.

[0159] Non-limiting examples of "alkyl" include methyl, ethyl, propyl, butyl, pentyl and hexyl.

[0160] Additional non-limiting examples of "alkyl" include isopropyl, isobutyl, isopentyl, and isohexyl.

[0161] Additional non-limiting examples of "alkyl" include sec-butyl, sec-pentyl, and sec-hexyl.

[0162] Additional non-limiting examples of "alkyl" include tert-butyl, tert-pentyl, and tert-hexyl.

[0163] Additional non-limiting examples of "alkyl" include neopentyl, 3-pentyl, and active pentyl.

[0164] In alternative embodiments, "alkyl" refers to one, two, three, or four R 31 "Optionally substituted" with substituents.

[0165] Cycloalkyl Embodiments In certain embodiments, "cycloalkyl" is C3-C8 cycloalkyl, C3-C7 cycloalkyl, C3-C6 cycloalkyl, C3-C5 cycloalkyl, C3 or C4 cycloalkyl, C4-C8 cycloalkyl, C5-C8 cycloalkyl, or C6-C8 cycloalkyl.

[0166] In certain embodiments, the "cycloalkyl" has 3 carbons.

[0167] In certain embodiments, the "cycloalkyl" has 4 carbons.

[0168] In certain embodiments, the "cycloalkyl" has 5 carbons.

[0169] In certain embodiments, the "cycloalkyl" has 6 carbons.

[0170] In certain embodiments, the "cycloalkyl" has 7 carbons.

[0171] In certain embodiments, the "cycloalkyl" has 8 carbons.

[0172] In certain embodiments, the "cycloalkyl" has 9 carbons.

[0173] In certain embodiments, the "cycloalkyl" has 10 carbons.

[0174] Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl.

[0175] In alternative embodiments, "cycloalkyl" refers to one, two, three, or four R 31 "Optionally substituted" with substituents.

[0176] Haloalkyl Embodiments In certain embodiments, "haloalkyl" is a C-C 10 haloalkyl, C1-C9 haloalkyl, C1-C8 haloalkyl, C1-C7 haloalkyl, C1-C6 haloalkyl, C1-C5 haloalkyl, C1-C4 haloalkyl, C1-C3 haloalkyl, and C1 or C2 haloalkyl.

[0177] In certain embodiments, the "haloalkyl" has 1 carbon.

[0178] In certain embodiments, a "haloalkyl" has one carbon and one halogen.

[0179] In certain embodiments, a "haloalkyl" has 1 carbon and 2 halogens.

[0180] In certain embodiments, a "haloalkyl" has 1 carbon and 3 halogens.

[0181] In certain embodiments, the "haloalkyl" has two carbons.

[0182] In certain embodiments, the "haloalkyl" has 3 carbons.

[0183] In certain embodiments, the "haloalkyl" has 4 carbons.

[0184] In certain embodiments, the "haloalkyl" has 5 carbons.

[0185] In certain embodiments, the "haloalkyl" has 6 carbons.

[0186] Non-limiting examples of "haloalkyl" include: [ka] Examples include:

[0187] Additional non-limiting examples of "haloalkyl" include: [ka] Examples include:

[0188] Additional non-limiting examples of "haloalkyl" include: [ka] Examples include:

[0189] Additional non-limiting examples of "haloalkyl" include: [ka] Examples include:

[0190] Heterocyclic Embodiments In certain embodiments, "heterocycle" refers to a cyclic ring having one nitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0191] In certain embodiments, "heterocycle" refers to a cyclic ring having one nitrogen, one oxygen, and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0192] In certain embodiments, "heterocycle" refers to a cyclic ring having two nitrogens and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0193] In certain embodiments, "heterocycle" refers to a cyclic ring having one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0194] In certain embodiments, "heterocycle" refers to a cyclic ring having one sulfur and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0195] Non-limiting examples of "heterocycles" include aziridine, oxirane, thiirane, azetidine, 1,3-diazetidine, oxetane, and thietane.

[0196] Additional non-limiting examples of "heterocycle" include pyrrolidine, 3-pyrroline, 2-pyrroline, pyrazolidine, and imidazolidine.

[0197] Additional non-limiting examples of "heterocycle" include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane.

[0198] Additional non-limiting examples of "heterocycle" include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine.

[0199] Additional non-limiting examples of "heterocycle" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, where the point of attachment of each group is on the heterocycle.

[0200] Non-limiting examples of "heterocycle" include: [ka] Other examples include:

[0201] Additional non-limiting examples of "heterocycle" include: [ka] Examples include:

[0202] Additional non-limiting examples of "heterocycle" include: [ka] Examples include:

[0203] Non-limiting examples of "heterocycle" include: [ka] Other examples include:

[0204] Non-limiting examples of "heterocycle" include: [ka] Other examples include:

[0205] Additional non-limiting examples of "heterocycle" include: [ka] Examples include:

[0206] Additional non-limiting examples of "heterocycle" include: [ka] Examples include:

[0207] In alternative embodiments, the "heterocycle" may contain one, two, three, or four R 31 "Optionally substituted" with substituents.

[0208] Heteroaryl Embodiments In certain embodiments, a "heteroaryl" is a 5-membered aromatic group containing 1, 2, 3, or 4 nitrogen atoms.

[0209] 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.

[0210] Additional non-limiting examples of 5-membered "heteroaryl" groups include: [ka] Examples include:

[0211] In certain embodiments, "heteroaryl" is a 6-membered aromatic group containing 1, 2, or 3 nitrogen atoms (ie, pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl).

[0212] Non-limiting examples of 6-membered "heteroaryl" groups having 1 or 2 nitrogen atoms include: [ka] Examples include:

[0213] In certain embodiments, "heteroaryl" is a 9-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

[0214] Non-limiting examples of bicyclic "heteroaryl" groups include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzisoxazole, benzisothiazole, benzoxazole, and benzothiazole.

[0215] Additional non-limiting examples of bicyclic "heteroaryl" groups include: [ka] Examples include:

[0216] Additional non-limiting examples of bicyclic "heteroaryl" groups include: [ka] Examples include:

[0217] Additional non-limiting examples of bicyclic "heteroaryl" groups include: [ka] Examples include:

[0218] In certain embodiments, a "heteroaryl" is a 10-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

[0219] Non-limiting examples of bicyclic "heteroaryl" groups include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine.

[0220] Additional non-limiting examples of bicyclic "heteroaryl" groups include: [ka] Examples include:

[0221] In alternative embodiments, a "heteroaryl" can include one, two, three, or four R 31 "Optionally substituted" with substituents.

[0222] Aryl Embodiments In certain embodiments, aryl is phenyl.

[0223] In certain embodiments, aryl is naphthyl.

[0224] In alternative embodiments, "aryl" refers to one, two, three, or four R 31 "Optionally substituted" with substituents.

[0225] Bicyclic Embodiments The term "bicyclic" refers to a ring system in which two rings share at least one atom. The rings may be spirocyclic or fused, and each ring is independently selected from carbocycle, heterocycle, aryl, and heteroaryl. Non-limiting examples of bicyclic groups include: [ka] Examples include:

[0226] When the term "bicyclic" is used in reference to a divalent residue such as a linker, the points of attachment can be on separate rings or on the same ring. In certain embodiments, both points of attachment are on the same ring. In certain embodiments, both points of attachment are on different rings. Non-limiting examples of bivalent bicyclic groups include: [ka] Examples include:

[0227] Additional non-limiting examples of divalent bicycles include: [ka] Examples include:

[0228] In alternative embodiments, a "bicycle" may include one, two, three, or four R 31 "Optionally substituted" with substituents.

[0229] Optional Substituent Embodiments While the variable moieties can be optionally substituted, in certain embodiments, the variable moieties are not substituted.

[0230] A variable moiety can be optionally substituted, in certain embodiments, the variable moiety is substituted with one substituent.

[0231] A variable moiety can be optionally substituted. In certain embodiments, the variable moiety is substituted with two substituents.

[0232] The variable moiety can be optionally substituted. In certain embodiments, the variable moiety is substituted with three substituents.

[0233] The variable moiety can be optionally substituted. In certain embodiments, the variable moiety is substituted with four substituents.

[0234] In an alternative embodiment, any suitable groups may be present at the "substituted" or, where indicated, "optionally substituted" positions that will form a stable molecule and meet the desired objectives of the present invention, such as halogen (which may independently be F, Cl, Br, or I); cyano; hydroxyl; nitro; azido; alkanoyl (e.g., C2-C6 alkanoyl groups); carboxamido; alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, such as phenoxy; thioalkyl, including those with one or more thioether linkages; alkylsulfinyl; alkylsulfonyl groups, including those with one or more sulfonyl linkages; aminoalkyl groups, including groups with two or more N atoms; aryl (e.g., phenyl, biphenyl, naphthyl, etc., where each ring is either substituted or unsubstituted); and groups having, for example, 1 to 3 separated or fused rings and 6 to about 14 or 18 ring carbons. Examples of such groups include, but are not limited to, arylalkyl having 1 to 3 separated or fused rings (benzyl is an example of an arylalkyl group); arylalkoxy having 1 to 3 separated or fused rings (benzyloxy is an example of an arylalkoxy group); or saturated or partially unsaturated heterocycle having 1 to 3 separated or fused rings containing N, O, or S atoms, or heteroaryl having 1 to 3 separated or fused rings containing one or more N, O, or S atoms, such as coumarinyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, thiazinyl, oxazolyl, isoxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, and pyrrolidinyl. Such groups may be further substituted, for example, with hydroxy, alkyl, alkoxy, halogen, and amino.

[0235] Aliphatic and Heteroaliphatic Embodiments In certain embodiments, "aliphatic" refers to a saturated or unsaturated straight-chain, 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 encompasses each of these definitions. In certain embodiments, "aliphatic" is used to refer to an aliphatic group having 1 to 20 carbon atoms. The aliphatic chain can be, for example, mono-, di-, tri-, or polyunsaturated, or alkynyl. Unsaturated aliphatic groups can be in a cis or trans configuration. In certain embodiments, aliphatic groups contain 1 to about 12 carbon atoms, more typically 1 to about 6 carbon atoms or 1 to about 4 carbon atoms. In certain embodiments, aliphatic groups contain 1 to about 8 carbon atoms. In certain embodiments, aliphatic groups are C1-C2, C1-C3, C1-C4, C1-C5, or C1-C6. As used herein, a specified range refers to an aliphatic group with each member of the range described as a separate species. For example, the term C1-C6 aliphatic, as used herein, refers to a linear or branched alkyl, alkenyl, or alkynyl group having 1, 2, 3, 4, 5, or 6 carbon atoms, each of which is intended to be described as a separate species. For example, the term C1-C4 aliphatic, as used herein, refers to a linear or branched alkyl, alkenyl, or alkynyl group having 1, 2, 3, or 4 carbon atoms, each of which is intended to be described as a separate species. In certain embodiments, aliphatic groups are substituted with one or more functional groups to form a stable moiety.

[0236] In certain embodiments, the term "heteroaliphatic" refers to an aliphatic moiety that contains at least one heteroatom in the chain, such as an amine, carbonyl, carboxy, oxo, thio, phosphate, phosphonate, nitrogen, phosphorus, silicon, or boron atom, instead of a carbon atom. In certain embodiments, the heteroatoms are exclusively nitrogen. In certain embodiments, the heteroatoms are exclusively oxygen. In certain embodiments, the heteroatoms are exclusively 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 refer to heteroaliphatic groups (cyclic, acyclic, substituted, unsubstituted, branched, or unbranched) having 1 to 20 carbon atoms. In certain embodiments, heteroaliphatic groups are optionally substituted to form stable moieties. Non-limiting 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, and the like.

[0237] A and A * Embodiments of the present invention In certain embodiments, A * teeth, [ka] is.

[0238] In certain embodiments, A * teeth, [ka] is.

[0239] In certain embodiments, A * teeth, [ka] is.

[0240] In certain embodiments, A * teeth, [ka] is.

[0241] In certain embodiments, A * teeth, [ka] is.

[0242] In certain embodiments, A * teeth, [ka] is.

[0243] In certain embodiments, R 34 and R 35 and combine to form CH2.

[0244] In certain embodiments, R 34 is H.

[0245] In certain embodiments, R 35 is H.

[0246] In certain embodiments, A 1 is NH.

[0247] In certain embodiments, A 1 is O.

[0248] In certain embodiments, A 21 is NH.

[0249] In certain embodiments, A21 is O.

[0250] In certain embodiments, A 21 is CH2.

[0251] In certain embodiments, A 21 is NR 100 is.

[0252] In certain embodiments, A 32 , A 33 , A 34 and A 35 are each selected from CH, C-halogen and CF.

[0253] In certain embodiments, A 32 is CH.

[0254] In certain embodiments, A 32 is CF.

[0255] In certain embodiments, A 32 is CR 42 is.

[0256] In certain embodiments, A 32 is N.

[0257] In certain embodiments, A 33 is CH.

[0258] In certain embodiments, A 33 is CF.

[0259] In certain embodiments, A 33 is CR 42 is.

[0260] In certain embodiments, A 33 is N.

[0261] In certain embodiments, A34 is CH.

[0262] In certain embodiments, A 34 is CF.

[0263] In certain embodiments, A 34 is CR 42 is.

[0264] In certain embodiments, A 34 is N.

[0265] In certain embodiments, A 35 is CH.

[0266] In certain embodiments, A 35 is CF.

[0267] In certain embodiments, A 35 is CR 42 is.

[0268] In certain embodiments, A 35 is N.

[0269] In certain embodiments, A 36 is N.

[0270] In certain embodiments, R 90 is hydrogen.

[0271] In certain embodiments, R 90 is C1-C3 alkyl.

[0272] In certain embodiments, R 90 is C 3~6 -cycloalkyl.

[0273] In certain embodiments, R 90 is methyl.

[0274] In certain embodiments, A or A * teeth, [ka] is.

[0275] In certain embodiments, A or A * teeth, [ka] is.

[0276] In certain embodiments, A or A * teeth, [ka] is.

[0277] In certain embodiments, A or A * teeth, [ka] is selected from.

[0278] B and B * Embodiments of the present invention In certain embodiments, B or B * teeth, [ka] is.

[0279] In certain embodiments, B or B * teeth, [ka] is.

[0280] In certain embodiments, B * is heteroaryl.

[0281] In certain embodiments, B * is one R 31 and heteroaryl substituted with a group.

[0282] In certain embodiments, B * is aryl.

[0283] In certain embodiments, B * is one R 31 It is an aryl substituted with a group.

[0284] In certain embodiments, B * teeth, [ka] is.

[0285] In certain embodiments, B * teeth, [ka] is.

[0286] In certain embodiments, B * teeth, [ka] is.

[0287] In certain embodiments, B * teeth, [ka] is.

[0288] In certain embodiments, B * teeth, [ka] is.

[0289] In certain embodiments, B * teeth, [ka] is.

[0290] y embodiment In certain embodiments, y is 0.

[0291] In certain embodiments, y is 1.

[0292] In certain embodiments, y is 2.

[0293] In certain embodiments, y is 3.

[0294] R 31 Embodiments of the present invention In certain embodiments, at least one R 31 is a halogen.

[0295] In certain embodiments, at least one R 31 is F.

[0296] In certain embodiments, at least one R 31 is Cl.

[0297] In certain embodiments, at least one R 31 C 1~6 - alkyl.

[0298] In certain embodiments, at least one R 31 Halo-C 1~6 - alkyl.

[0299] In certain embodiments, one R 31 is a halogen.

[0300] In certain embodiments, one R 31is F.

[0301] In certain embodiments, one R 31 is Cl.

[0302] In certain embodiments, one R 31 C 1~6 - alkyl.

[0303] In certain embodiments, one R 31 is cyano.

[0304] In certain embodiments, one R 31 C 1~6 -alkoxy.

[0305] In certain embodiments, one R 31 Halo-C 1~6 -alkoxy.

[0306] In certain embodiments, one R 31 C 3~8 -cycloalkyl.

[0307] In certain embodiments, one R 31 Halo-C 3~8 -cycloalkyl.

[0308] In certain embodiments, R 31 is a halogen, C 1~6 -alkoxy and C 1~6 -alkyl.

[0309] In certain embodiments, R 31 is selected from F, Cl, methoxy and methyl.

[0310] R 36 and R 37 Embodiments of the present invention In certain embodiments, R 36 and R 37and are bonded together to form one, two or three R 31 It forms a 5-membered ring optionally substituted with substituents.

[0311] In certain embodiments, R 36 and R 37 and are bonded together to form one, two or three R 31 It forms a 6-membered ring optionally substituted with substituents.

[0312] In certain embodiments, R 36 and R 37 and are bonded together to form one, two or three R 31 The substituents form a 5-membered cycloalkyl optionally substituted.

[0313] In certain embodiments, R 36 and R 37 and are bonded together to form one, two or three R 31 The substituents form a 6-membered cycloalkyl optionally substituted.

[0314] In certain embodiments, R 36 and R 37 and are bonded together to form one, two or three R 31 Forms a 5-membered heteroaryl optionally substituted with substituents.

[0315] In certain embodiments, R 36 and R 37 and are bonded together to form one, two or three R 31 Forms a 6-membered heteroaryl optionally substituted with substituents.

[0316] In certain embodiments, R 36 and R 37 and are bonded together to form one, two or three R 31 It forms a 5-membered heterocyclic ring optionally substituted with substituents.

[0317] In certain embodiments, R 36 and R 37and are bonded together to form one, two or three R 31 It forms a 6-membered heterocyclic ring optionally substituted with substituents.

[0318] In certain embodiments, R 36 and R 37 and are bonded together to form one, two or three R 31 A morpholine optionally substituted with a substituent is formed.

[0319] In certain embodiments, R 36 and R 37 and are bonded together to form one, two or three R 31 The substituents form an optionally substituted phenyl.

[0320] In certain embodiments, R 36 and R 37 The ring formed by bonding of and is not substituted.

[0321] In certain embodiments, R 36 and R 37 The ring formed by bonding is one R 31 It is substituted with a substituent.

[0322] In certain embodiments, R 36 and R 37 The ring formed by bonding two R 31 It is substituted with a substituent.

[0323] In certain embodiments, R 36 and R 37 The ring formed by bonding is made up of three R 31 It is substituted with a substituent.

[0324] In certain embodiments, R 36 is hydrogen.

[0325] In certain embodiments, R 36 is a halogen.

[0326] In certain embodiments, R 36 is F.

[0327] In certain embodiments, R 36 is Cl.

[0328] In certain embodiments, R 36 is C 1~6 - alkyl.

[0329] In certain embodiments, R 36 is cyano.

[0330] In certain embodiments, R 36 is C 1~6 -alkoxy.

[0331] In certain embodiments, R 36 Halo-C 1~6 -alkoxy.

[0332] In certain embodiments, R 36 is C 3~8 -cycloalkyl.

[0333] In certain embodiments, R 36 Halo-C 3~8 -cycloalkyl.

[0334] In certain embodiments, R 36 are hydrogen, halogen, C 1~6 -alkoxy and C 1~6 -alkyl.

[0335] In certain embodiments, R 36 is selected from hydrogen, F, Cl, methoxy and methyl.

[0336] In certain embodiments, R 37 is hydrogen.

[0337] In certain embodiments, R 37 is a halogen.

[0338] In certain embodiments, R 37 is F.

[0339] In certain embodiments, R 37 is Cl.

[0340] In certain embodiments, R 37 is C 1~6 - alkyl.

[0341] In certain embodiments, R 37 is cyano.

[0342] In certain embodiments, R 37 is C 1~6 -alkoxy.

[0343] In certain embodiments, R 37 Halo-C 1~6 -alkoxy.

[0344] In certain embodiments, R 37 is C 3~8 -cycloalkyl.

[0345] In certain embodiments, R 37 Halo-C 3~8 -cycloalkyl.

[0346] In certain embodiments, R 37 are hydrogen, halogen, C 1~6 -alkoxy and C 1~6 -alkyl.

[0347] In certain embodiments, R 37 is selected from hydrogen, F, Cl, methoxy and methyl.

[0348] R 42 Embodiments of the present invention In certain embodiments, at least one R 42 is a halogen.

[0349] In certain embodiments, at least one R 42 is F.

[0350] In certain embodiments, at least one R 42 is Cl.

[0351] In certain embodiments, at least one R 42 C 1~6 - alkyl.

[0352] In certain embodiments, at least one R 42 Halo-C 1~6 - alkyl.

[0353] In certain embodiments, R 42 is hydrogen.

[0354] In certain embodiments, R 42 is a halogen.

[0355] In certain embodiments, R 42 is F.

[0356] In certain embodiments, R 42 is Cl.

[0357] In certain embodiments, R 42 is C 1~6 - alkyl.

[0358] In certain embodiments, R 42 is cyano.

[0359] In certain embodiments, R 42 is C1~6 -alkoxy.

[0360] In certain embodiments, R 42 Halo-C 1~6 -alkoxy.

[0361] In certain embodiments, R 42 is C 3~8 -cycloalkyl.

[0362] In certain embodiments, R 42 Halo-C 3~8 -cycloalkyl.

[0363] In certain embodiments, R 42 are hydrogen, halogen, C 1~6 -alkoxy and C 1~6 -alkyl.

[0364] In certain embodiments, R 42 is selected from hydrogen, F, Cl, methoxy and methyl.

[0365] Embodiments of Ring G In certain embodiments, ring G contains one or two R 42 It is a 5-membered heteroaryl ring optionally substituted with substituents.

[0366] In certain embodiments, ring G contains one or two R 42 It is a 6-membered heteroaryl ring optionally substituted with substituents.

[0367] In certain embodiments, ring G is [ka] is selected from.

[0368] EGFR-Targeting Ligand Embodiments In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF0007757284000216.tif191170.

[0369] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF0007757284000218.tif129170.

[0370] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF0007757284000220.tif96170.

[0371] In certain embodiments, the compounds of the present invention are [ka] is selected from.

[0372] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF0007757284000223.tif171170.

[0373] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF0007757284000225.tif234170TIFF0007757284000226.tif103170.

[0374] Compound of Formula III In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF0007757284000228.tif130170.

[0375] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF0007757284000230.tif126170.

[0376] Compound of Formula IV In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF0007757284000232.tif131170.

[0377] III. Additional Compounds of the Invention In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF0007757284000234.tif166170.

[0378] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF0007757284000236.tif158170.

[0379] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF0007757284000238.tif235170TIFF0007757284000239.tif37170.

[0380] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF0007757284000241.tif154170.

[0381] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF0007757284000243.tif227170TIFF0007757284000244.tif37170.

[0382] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF0007757284000246.tif206170.

[0383] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF0007757284000248.tif114170.

[0384] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF0007757284000250.tif224170.

[0385] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF0007757284000252.tif112170.

[0386] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF0007757284000254.tif223170.

[0387] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF0007757284000256.tif164170.

[0388] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF0007757284000258.tif221170TIFF0007757284000259.tif75170.

[0389] In certain embodiments, the compounds of the present invention are [ka] is selected from.

[0390] In certain embodiments, the compounds of the present invention are [ka] is selected from.

[0391] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF0007757284000263.tif140170.

[0392] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF0007757284000265.tif69170.

[0393] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF0007757284000267.tif70170.

[0394] In certain embodiments, the compounds of the present invention are [ka] is selected from.

[0395] In certain embodiments, the compounds of the present invention are [ka] is selected from.

[0396] In certain embodiments, the compounds of the present invention are [ka] is selected from.

[0397] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF0007757284000272.tif245170TIFF0007757284000273.tif73170.

[0398] In certain embodiments, the compounds of the present invention are [ka] is selected from.

[0399] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF0007757284000276.tif224170TIFF0007757284000277.tif80170.

[0400] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF0007757284000279.tif156170.

[0401] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF0007757284000281.tif242170TIFF0007757284000282.tif205170TIFF0007757284000283.tif46170.

[0402] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF0007757284000285.tif111170.

[0403] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF0007757284000287.tif103170.

[0404] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF0007757284000289.tif41170.

[0405] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF0007757284000291.tif92170.

[0406] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF0007757284000293.tif41170.

[0407] In certain embodiments, the compounds of the present invention are [ka] is selected from.

[0408] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF0007757284000296.tif213170TIFF0007757284000297.tif234170TIFF0007757284000298.tif239170TIFF0007757284000299.tif73170.

[0409] IV. Linkers Linker (L 1 or L 2 ) or bond is included in the compounds of the present invention. A linker is a chemically stable divalent group that attaches the E3 ligase binding moiety to the EGFR-targeting ligand. According to the present invention, any desired linker described herein can be used as part of a pharmaceutically acceptable dosage form, so long as the resulting compound has a stable shelf life, e.g., of at least 1 month, 2 months, 3 months, 6 months, or 1 year, and is itself pharmaceutically acceptable.

[0410] The linkers described herein can be used in either orientation, i.e., the left end is linked to an E3 ligase binding moiety and the right end is linked to an EGFR-targeted ligand, or the left end is linked to an EGFR-targeted ligand and the right end is linked to an E3 ligase binding moiety.

[0411] In certain embodiments, the linker is a bond.

[0412] In certain embodiments, the linker has a chain of 2 to 14, 15, 16, 17, 18, or 20 or more carbon atoms, in which one or more carbons may be replaced by a heteroatom such as O, N, S, or P.

[0413] 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 consecutive atoms in the chain. For example, the chain can include one or more ethylene glycol units (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ethylene glycol units), which can be consecutive, partially consecutive, or discontinuous.

[0414] In certain embodiments, the chain has at least 1, 2, 3, 4, 5, 6, 7, or 8 contiguous chains, which may have branches that may independently be alkyl, aryl, heteroaryl, alkenyl or alkynyl, aliphatic, heteroaliphatic, cycloalkyl, or heterocyclic substituents.

[0415] In other embodiments, the linker may comprise or consist of one or more of ethylene glycol, propylene glycol, lactic acid, and / or glycolic acid. Lactic acid segments tend to have longer half-lives 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 achieve desired half-lives and hydrophilicity. In certain embodiments, these units may be flanked or interspersed with other moieties, such as aliphatic, e.g., alkyl, heteroaliphatic, aryl, heteroaryl, heterocyclic, cycloalkyl, etc., as desired to achieve appropriate drug properties.

[0416] In certain embodiments, L 2 teeth, [ka] is a linker selected from

[0417] In one aspect, the linker (L 2) is a group represented by formula LI, formula LII, formula LIII, formula LIV, formula LV, formula LVI, formula LVII, formula LVIII, formula IX and formula LX: [ka] wherein all variables are as defined herein.

[0418] In certain embodiments, the linker (L 2 )teeth, [ka] is a linker selected from

[0419] In one aspect, the linker (L 2 ) are formula LDI, formula LDII, formula LDIII, formula LDIV, formula LDV, formula LDVI, and formula LDVII: [ka] wherein all variables are as described herein.

[0420] The following are non-limiting examples of linkers that can be used in the present invention: Based on this elaboration, one skilled in the art will understand how to use the full range of linkers to achieve the objectives of the present invention.

[0421] In certain embodiments, L 2 teeth, [ka] Selected from TIFF0007757284000305.tif167170.

[0422] In certain embodiments, L 2 teeth, [ka] Selected from TIFF0007757284000307.tif246170.

[0423] In certain embodiments, L 2 teeth, [ka] is selected from.

[0424] In certain embodiments, L 2 teeth, [ka] is selected from.

[0425] In certain embodiments, L 2 teeth, [ka] is selected from.

[0426] In certain embodiments, L 2 teeth, [ka] Selected from TIFF0007757284000312.tif181170.

[0427] In certain embodiments, L 2 teeth, [ka] Selected from TIFF0007757284000314.tif109170.

[0428] R 20 , R 21 , R 22 , R 23 and R 24 Non-limiting examples of moieties include: [ka] Examples include:

[0429] R 20 , R 21 , R 22 , R 23 and R 24 Additional non-limiting examples of moieties include: [ka] TIFF0007757284000317.tif68170 is an example.

[0430] R 20 , R 21 , R 22 , R 23 and R 24 Additional non-limiting examples of moieties include: [ka] Examples include:

[0431] In additional embodiments, the linker (L 2 ) 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 an optionally substituted alkyl group interspersed with optionally substituted O, N, S, P or Si atoms.

[0432] In certain embodiments, the linker (L 2 ) may be adjacent, substituted or interspersed with aryl, phenyl, benzyl, alkyl, alkylene or heterocyclic groups.

[0433] In certain embodiments, the linker (L 2 ) may be asymmetric or symmetric.

[0434] In certain embodiments, the linker (L2 ) may be a non-linear chain and may be or contain an aliphatic, aromatic or heteroaromatic cyclic moiety.

[0435] In any of the compound embodiments described herein, the linker group can be any suitable moiety described herein.

[0436] In certain embodiments, the linker (L 2 )teeth, [ka] TIFF0007757284000320.tif48170.

[0437] In certain embodiments, the linker (L 2 )teeth, [ka] is selected from the group consisting of:

[0438] In certain embodiments, the linker (L 2 )teeth, [ka] TIFF0007757284000323.tif127170.

[0439] In certain embodiments, the linker (L 2 )teeth, [ka] TIFF0007757284000325.tif105170.

[0440] In certain embodiments, the linker (L 2 )teeth, [ka] TIFF0007757284000327.tif42170.

[0441] In certain embodiments, the linker (L 2 )teeth, [ka] is selected from the group consisting of:

[0442] In certain embodiments, the linker (L 2 )teeth, [ka] TIFF0007757284000330.tif37170.

[0443] In certain embodiments, the linker (L 2 ) or any part thereof, [ka] is selected from.

[0444] V. Treatment method The compounds of the present invention can be used in an effective amount to treat a patient in need of treatment or to treat any disorder mediated by EGFR.

[0445] Another aspect of the present invention provides a compound as described herein, or an enantiomer, diastereomer or stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or preventing cancer in a patient in need thereof, wherein EGFR inhibition is required for the treatment or prevention of cancer.

[0446] In one aspect, the compounds of the present invention are used to treat EGFR-mediated cancers in which EGFR has mutated from wild-type. There are many possible 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 non-limiting embodiments, the mutation is at L858, E709, G719, C797, L861, T790, or L718, or any combination thereof. In certain embodiments, the mutation is L858R, T790M, L718Q, L792H, and / or C797S mutation, or any combination thereof.

[0447] In certain embodiments, the cancer develops one or more EGFR mutations after treatment with at least one EGFR inhibitor, which 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 embodiment, the cancer develops one or more EGFR mutations after treatment with an antibody such as cetuximab, panitumumab, or necitumumab. In yet another embodiment, the cancer has one or more EGFR mutations or non-EGFR mutations, such as a somatic exon 20 insertion, a somatic PIK3CA mutation, loss of PTEN expression, a MET amplification, or a KRAS mutation, that render the cancer inherently resistant to EGFR inhibitor treatment.

[0448] In certain embodiments, compounds of the invention are used to treat cancers that are resistant or have acquired resistance to first-generation EGFR inhibitors, such as erlotinib, gefitinib, and / or lapatinib. In certain embodiments, compounds of the invention are used to treat cancers that are resistant or have acquired resistance to second-generation EGFR inhibitors, such as afatinib and / or dacomitinib. In certain embodiments, compounds of the invention are used to treat cancers that are resistant or have acquired resistance to third-generation EGFR inhibitors, such as osimertinib.

[0449] In some embodiments, the mutant EGFR protein in the affected tissue has an L858 mutation, eg, L858R.

[0450] In certain embodiments, the compounds of the invention are used to treat mutant EGFR-mediated disorders in which EGFR has a mutation at one of the amino acid positions listed below. The mutation may, for example, be selected from one of the exemplary mutations listed, or may be a different mutation.

[0451] TIFF0007757284000332.tif66170

[0452] 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.

[0453] 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 mutations, which may optionally be selected from the table above. In other embodiments, the mutant EGFR-mediated disorder has an L858R mutation and three additional mutations, which may optionally be selected from the table above.

[0454] In certain embodiments, the mutant EGFR-mediated disorder has a T790M mutation and, optionally, one additional mutation selected from the table above. In other embodiments, the mutant EGFR-mediated disorder has a T790M mutation and, optionally, two additional mutations selected from the table above. In other embodiments, the mutant EGFR-mediated disorder has a T790M mutation and, optionally, three additional mutations selected from the table above.

[0455] In certain embodiments, the mutant EGFR-mediated disorder has an L718Q mutation and, optionally, one additional mutation selected from the table above. In other embodiments, the mutant EGFR-mediated disorder has an L718Q mutation and, optionally, two additional mutations selected from the table above. In other embodiments, the mutant EGFR-mediated disorder has an L718Q mutation and, optionally, three additional mutations selected from the table above.

[0456] In certain embodiments, the EGFR-mediated disorder is a mutant EGFR-mediated cancer.

[0457] In certain embodiments, the EGFR-mediated cancer has the following mutations: S768I, L718V, L792H, L792V, G796S, G796C, G724S and / or G719A.

[0458] In certain embodiments, the compounds of the present invention are used to treat EGFR-mediated cancers with frameshift mutations, e.g., short in-frame deletions. In certain embodiments, the compounds of the present invention are used to treat EGFR-mediated cancers in which EGFR has an exon 19 deletion. In certain embodiments, the exon 19 deletion is a deletion containing amino acids LREA (L747-A750). In certain embodiments, the exon 19 deletion is a deletion containing amino acids ELREA (E746-A750).

[0459] In certain embodiments, the compounds of the invention are used to treat EGFR-mediated cancers in which EGFR harbors the L858R mutation in exon 21.

[0460] In certain embodiments, the compounds of the invention are more active against disorders driven by mutant EGFR than wild-type EGFR.

[0461] In certain embodiments, the compounds of the invention are used to treat EGFR-mediated cancers in which EGFR has one or more exon 18 deletions.

[0462] In certain embodiments, the compounds of the invention are used to treat EGFR with an E709 mutation, eg, E709A, E709G, E709K, or E709V.

[0463] In certain embodiments, the compounds of the invention are used to treat EGFR with an L718 mutation, eg, L718Q.

[0464] In certain embodiments, the compounds of the invention are used to treat EGFR with a G719 mutation, eg, G719S, G719A, G719C, or G719D.

[0465] In certain embodiments, the compounds of the invention are used to treat EGFR-mediated cancers in which EGFR has one or more exon 19 insertions and / or one or more exon 20 insertions.

[0466] In certain embodiments, compounds of the invention are used to treat S7681 mutant EGFR cancers. In certain embodiments, compounds of the invention are used to treat EGFR L861Q mutant EGFR cancers. In certain embodiments, compounds of the invention are used to treat C797S mutant EGFR cancers.

[0467] In certain embodiments, the compounds of the invention are used to treat T790M, L858R mutant EGFR cancers.

[0468] In certain embodiments, the compounds of the invention are used to treat L718Q, L858R mutant EGFR cancers.

[0469] In certain embodiments, the compounds of the invention are used to treat L792H, L858R mutant EGFR cancers.

[0470] In certain embodiments, the compounds of the invention are used to treat C797S, L858R mutant EGFR cancers.

[0471] In certain embodiments, the compounds of the invention are used to treat cancers that are resistant to at least one EGFR inhibitor, for example, cancers that are resistant to first generation EGFR inhibitors such as erlotinib, gefitinib, and / or lapatinib. In certain embodiments, the compounds of the invention are used to treat cancers that have acquired resistance to first generation EGFR inhibitors, for example, cancers that have acquired resistance to first generation EGFR inhibitors such as erlotinib, gefitinib, and / or lapatinib.

[0472] In certain embodiments, compounds of the invention are used to treat cancers that exhibit resistance to second-generation EGFR inhibitors, such as afatinib and / or dacomitinib. In certain embodiments, compounds of the invention are used to treat cancers that have acquired resistance to second-generation EGFR inhibitors, such as afatinib and / or dacomitinib.

[0473] In certain embodiments, the compounds of the invention are used to treat cancers that exhibit resistance to third generation EGFR inhibitors, such as osimertinib. In certain embodiments, the compounds of the invention are used to treat cancers that have acquired resistance to third generation EGFR inhibitors, such as osimertinib.

[0474] In certain embodiments, the methods comprise administering to a patient in need thereof an effective amount of an active compound described herein, or a salt thereof, 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 bioactive agents.

[0475] In certain embodiments, the present invention provides methods of treating any of the disorders described herein in a patient in need thereof.

[0476] In other embodiments, the patient is administered an additional therapeutic agent, hi other embodiments, the compound described herein and the additional therapeutic agent are administered simultaneously or sequentially.

[0477] In certain embodiments, the present application provides methods of preventing any of the disorders described herein in a patient in need thereof.

[0478] In certain embodiments, the patient is a human.

[0479] As degraders of EGFR, the compounds and compositions of the present application are particularly useful for treating or lessening the severity of diseases, conditions, or disorders where EGFR is implicated in the disease, condition, or disorder.

[0480] In one aspect, the present invention provides a method for treating or lessening the severity of a disease, condition, or disorder in which EGFR plays a role in the pathology.

[0481] Another aspect of the present invention provides a method for treating or preventing a proliferative disease, the method comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising a compound as described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and optionally a pharmaceutically acceptable carrier.

[0482] In some embodiments, the disease is mediated by EGFR, hi other embodiments, EGFR plays a role in the development or progression of the disease.

[0483] In certain embodiments, the disease or disorder is cancer or a proliferative disease.

[0484] In certain embodiments, the EGFR-mediated disorder is abnormal cell proliferation, including, but not limited to, solid cancer or hematological cancer.

[0485] In certain embodiments, the hematological cancer is selected from acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), lymphoblastic T-cell leukemia, chronic myeloid 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, and the like. Leukemia (MLL), erythroleukemia, malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's 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-hit and triple-hit lymphomas), myelodysplastic / myeloproliferative neoplasms, mantle cell lymphoma including bortezomib-resistant mantle cell lymphoma.

[0486] Solid tumors that can be treated using the compounds described herein include lung cancer, such as small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), breast cancer, such as inflammatory breast cancer, ER-positive breast cancer, including tamoxifen-resistant ER-positive breast cancer, and triple-negative breast cancer, colon cancer, midline carcinoma, liver cancer, kidney cancer, prostate cancer, such as castration-resistant prostate cancer (CRPC), brain cancer, such as glioma, glioblastoma, and glioma. These include, but are not limited to, medulloblastoma and medulloblastoma, including MYC-amplified medulloblastoma, colorectal cancer, Wilms' tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, head and neck cancer, melanoma, squamous cell carcinoma, ovarian cancer, pancreatic cancer, such as pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumor (PanNET), osteosarcoma, giant cell tumor of bone, thyroid cancer, bladder cancer, urothelial carcinoma, vulvar cancer, cervical cancer, endometrial cancer, mesothelioma, esophageal cancer, salivary gland cancer, gastric cancer, nasopharyngeal carcinoma, buccal cancer, oral cancer, GIST (gastrointestinal stromal tumor), NUT midline carcinoma, testicular cancer, squamous cell carcinoma, hepatocellular carcinoma (HCC), MYCN-driven solid tumors, and NUT midline carcinoma (NMC).

[0487] In a further embodiment, the disease or disorder is a sarcoma of bone, muscle, tendon, cartilage, nerve, fat, or blood vessels.

[0488] In further embodiments, the disease or disorder is soft tissue sarcoma, bone sarcoma, or osteosarcoma.

[0489] In further embodiments, the disease or disorder is angiosarcoma, fibrosarcoma, liposarcoma, leiomyosarcoma, Kaposi's sarcoma, osteosarcoma, gastrointestinal stromal tumor, synovial sarcoma, pleomorphic sarcoma, chondrosarcoma, Ewing's sarcoma, reticulum cell sarcoma, meningeal sarcoma, botryoid sarcoma, rhabdomyosarcoma, or embryonal rhabdomyosarcoma.

[0490] In certain embodiments, the disorder is a sarcoma of bone, muscle, tendon, cartilage, nerve, fat, or blood vessels.

[0491] In a further embodiment, the disease or disorder is multiple myeloma.

[0492] In certain embodiments, a compound of the invention or a pharmaceutically acceptable salt thereof is used as a medicament in the therapeutic and / or prophylactic treatment of a patient suffering from cancer, particularly non-small cell lung cancer, who has an EGFR activating mutation as determined by next generation sequencing (NGS), comprising determining the EGFR activating mutation status in the patient and then administering a compound of the invention or a pharmaceutically acceptable salt thereof to said patient.

[0493] In other embodiments, the disease or disorder is inflammation, arthritis, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, juvenile arthritis and other arthritic conditions, neuroinflammation, allergies, pain, neuropathic pain, fever, lung disorders, pulmonary 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, ulcer disease, gastric ulcer, autoimmune diseases, graft versus host reaction and allograft rejection, cancer, leukemia, lymphoma, colon cancer, brain cancer, bone cancer, epithelial cell The cancers include neoplasms of epithelial origin (epithelial cancers), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, oral cancer, esophageal cancer, small intestine cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, squamous cell and / or basal cell carcinoma, prostate cancer, renal cell carcinoma, and other known cancers affecting epithelial cells throughout the body, chronic myeloid leukemia (CML), acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL), angiogenesis including neoplasia, metastasis, central nervous system disorders, central nervous system disorders with inflammatory or apoptotic components, peripheral neuropathy, or B-cell lymphoma.

[0494] In other embodiments, pharmaceutical compositions comprising a compound described herein and an additional therapeutic agent are administered simultaneously or sequentially.

[0495] In other embodiments, the disease or disorder is cancer, hi further embodiments, the cancer is lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, squamous cell carcinoma of the head and neck, leukemia, lymphoma, myeloma, solid tumor, hematological cancer or solid tumor.

[0496] In some embodiments, the method is used to treat or prevent a condition selected from autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, and immune-mediated diseases, while in other embodiments, the condition is selected from a proliferative disorder.

[0497] One aspect of the present application provides compounds useful for treating diseases, disorders, and conditions characterized by excessive or abnormal cell proliferation. Such diseases include, but are not limited to, proliferative or hyperproliferative diseases. Examples of proliferative and hyperproliferative diseases include, but are not limited to, cancer. The term "cancer" includes, but is not limited to, the following cancers: breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, pharyngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratoacanthoma, lung cancer, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, colorectal cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver and biliary tract cancer, kidney cancer, bone marrow disorders, lymphatic disorders, Hodgkin's disease, hairy cell carcinoma, buccal cavity and pharyngeal cancer (oral cancer), lip cancer, tongue cancer, oral cancer, pharyngeal cancer, small intestine cancer, colorectal cancer, colon cancer, rectal cancer, brain and central nervous system cancer, chronic myeloid leukemia (CML), and leukemia. The term "cancer" includes, but is not limited to, cancers selected from the following: myeloma, lymphoma, or gastric cancer, renal cancer, and / or the following cancers: head and neck cancer, oropharyngeal cancer, non-small cell lung cancer (NSCLC), endometrial cancer, liver cancer, non-Hodgkin's lymphoma, and lung cancer.

[0498] The term "cancer" refers to any cancer caused by the proliferation of malignant new cells, such as a tumor, neoplasm, carcinoma, sarcoma, leukemia, lymphoma, etc. For example, cancer includes, but is not limited to, mesothelioma, leukemia, and lymphoma, such as cutaneous T-cell lymphoma (CTCL), non-cutaneous peripheral T-cell lymphoma, lymphoma associated with human T-cell lymphotropic virus (HTLV), e.g., adult T-cell leukemia / lymphoma (ATLL), B-cell lymphoma, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myeloid leukemia, lymphoma, and multiple myeloma, non-Hodgkin's lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, Burkitt's lymphoma, adult T-cell leukemia-lymphoma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma. Further examples include myelodysplastic syndromes, childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, and soft tissue sarcomas, common adult solid tumors such as head and neck cancers (e.g., oral cancer, laryngeal cancer, nasopharyngeal cancer, and esophageal cancer), genitourinary tract cancers (e.g., prostate cancer, bladder cancer, kidney cancer, uterine cancer, ovarian cancer, testicular cancer), lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), breast cancer, pancreatic cancer, melanoma and other skin cancers, stomach cancer, brain tumors, tumors associated with Gorlin syndrome (such as medulloblastoma or meningioma), and liver cancer.

[0499] Further exemplary forms of cancer include, but are not limited to, skeletal or smooth muscle cancer, gastric cancer, cancer of the small intestine, rectal cancer, cancer of the salivary glands, endometrial cancer, adrenal gland cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer.

[0500] Additional cancers that the compounds described herein may be useful for prevention, treatment, and research are, for example, colon cancer, familial adenomatous polyposis, and hereditary nonpolyposis colorectal cancer, or melanoma. Further, cancers include, but are not limited to, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, thyroid cancer (medullary and papillary thyroid cancer), kidney cancer, renal parenchymal cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, testicular cancer, urinary tract cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroectodermal tumor, gallbladder cancer, bronchial carcinoma, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma. In one aspect, the present application provides the use of one or more compounds described herein in the manufacture of a medicament for the treatment of cancer, including, but not limited to, the various types of cancer disclosed herein.

[0501] In some embodiments, the compounds described herein are useful for treating cancer, such as colorectal cancer, thyroid cancer, breast cancer, and lung cancer, and myeloproliferative disorders, such as polycythemia vera, thrombocytopenia, myeloid metaplasia with myelofibrosis, chronic myeloid leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, juvenile myelomonocytic leukemia, and systemic mastocytosis. In some embodiments, the compounds described herein are useful for treating hematopoietic disorders, particularly acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute promyelocytic leukemia, and acute lymphocytic leukemia (ALL).

[0502] In certain embodiments, the compounds described herein, or their corresponding pharmaceutically acceptable salts, or isotopic derivatives, can be used in an effective amount to treat a host, e.g., a human, having lymphoma, or a lymphocytic or myeloid proliferative disorder or abnormality. For example, the compounds described herein can be administered to a host suffering from Hodgkin's lymphoma or non-Hodgkin's lymphoma. For example, the host may be suffering from, but not limited to, AIDS-related lymphoma; anaplastic large cell lymphoma; angioimmunoblastic lymphoma; blastic NK-cell lymphoma; Burkitt's lymphoma; Burkitt-like lymphoma (small non-cleaved cell lymphoma); small cleaved cell diffuse lymphoma (DSCCL); chronic lymphocytic leukemia / small lymphocytic lymphoma; cutaneous T-cell lymphoma; diffuse large B-cell lymphoma; enteropathic type. The patient may have T-cell lymphoma; follicular lymphoma; hepatosplenic gamma-delta T-cell lymphoma; lymphoblastic lymphoma; mantle cell lymphoma; marginal zone lymphoma; nasal T-cell lymphoma; childhood lymphoma; peripheral T-cell lymphoma; primary central nervous system lymphoma; T-cell leukemia; transformed lymphoma; therapy-related T-cell lymphoma; non-Hodgkin's lymphoma such as Langerhans cell histiocytosis or Waldenstrom's macroglobulinemia.

[0503] In another embodiment, the compounds described herein, or their corresponding pharmaceutically acceptable salts, or isotopic derivatives, can be used in an effective amount to treat patients, e.g., humans, with Hodgkin lymphoma, such as, but not limited to, nodular sclerosing classical Hodgkin lymphoma (CHL), mixed cellularity CHL, lymphopenic CHL, lymphocyte-rich CHL, lymphocyte-predominant Hodgkin lymphoma, or nodular lymphocyte-predominant HL.

[0504] The present application further encompasses the treatment or prevention of cell proliferative disorders, such as hyperplasia, dysplasia, and precancerous lesions. Dysplasia is the earliest form of precancerous lesion that can be recognized by a pathologist in a biopsy. The compounds can be administered to prevent the hyperplasia, dysplasia, or precancerous lesion from continuing to grow or becoming cancerous. Examples of precancerous lesions can occur in the skin, esophageal tissue, breast, and cervical intraepithelial tissue.

[0505] The compounds and compositions of the present application are also useful in biological samples as inhibitors of EGFR protein. One aspect of the present application is inhibiting protein activity in a biological sample. This method includes contacting the biological sample with a compound or composition described herein. As used herein, the term "biological sample" refers to in vitro or ex vivo samples, including, but not limited to, cell cultures or extracts thereof, biopsies or extracts thereof obtained from mammals, and blood, saliva, urine, feces, semen, tears, or other bodily fluids, or extracts thereof. Inhibition of protein activity in biological samples is useful for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusions, organ transplants, and biological sample storage.

[0506] Another aspect of the present application is the study of EGFR proteins in biological and pathological phenomena, the study of intracellular signaling pathways mediated by such proteins, and the comparative evaluation of novel protein inhibitors. Examples of such uses include, but are not limited to, biological assays, such as enzymatic assays and cell-based assays.

[0507] In accordance with the above, the present application further provides a method of preventing or treating any of the above diseases or disorders in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. For any of the above uses, the required dosage will vary depending on the method of administration, the particular condition to be treated, and the desired effect.

[0508] VI. Combination Therapy The disclosed compounds described herein can be used in effective amounts alone or in combination with another compound of the invention or another bioactive agent or second therapeutic agent to treat a patient, such as a human, having an EGFR-mediated disorder, including but not limited to those described herein.

[0509] The term "bioactive agent" is used to describe an agent other than a selected compound according to the present invention that can be used in combination or alternation with a compound of the present invention to achieve a desired therapeutic outcome. In certain embodiments, a compound of the present invention and a bioactive agent are administered such that they are active in vivo during an overlapping period, e.g., their Cmax, Tmax, AUC, or another pharmacokinetic parameter overlaps. In other embodiments, a compound of the present invention and a bioactive agent that do not have overlapping pharmacokinetic parameters, but one has a therapeutic impact on the therapeutic efficacy of the other, are administered to a patient in need thereof.

[0510] In one aspect of this embodiment, the bioactive agent is an immunomodulatory agent, including, but not limited to, checkpoint inhibitors, including, by way of non-limiting example, PD-1 inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, small molecules, peptides, nucleotides, or other inhibitors. In certain embodiments, the immunomodulatory agent is an antibody, such as a monoclonal antibody.

[0511] Examples of PD-1 inhibitors that block the interaction between PD-1 and PD-L1 by binding to the PD-1 receptor and inhibit immunosuppression include nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab, AMP-224 (AstraZeneca and MedImmune), PF-06801591 (Pfizer), MEDI0680 (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.). Examples of PD-L1 inhibitors that block the interaction between PD-1 and PD-L1 by binding to the PD-L1 receptor and inhibit immunosuppression include atezolizumab (Tecentriq), durvalumab (AstraZeneca and MedImmune), KN035 (Alphamab), and BMS-936559 (Bristol-Myers Squibb). Examples of CTLA-4 checkpoint inhibitors that bind to CTLA-4 and inhibit immunosuppression 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), LAG525 (Novartis), and the dual PD-1 and LAG-3 inhibitor MGD013 (MacroGenics). An example of a TIM-3 inhibitor is TSR-022 (Tesaro).

[0512] In certain embodiments, the checkpoint inhibitor is selected from nivolumab / OPDIVO™, pembrolizumab / KEYTRUDA™, and pidilizumab / CT-011, MPDL3280A / RG7446, MEDI4736, MSB0010718C, BMS 936559, PDL2 / lg fusion proteins such as AMP 224, or inhibitors of B7-H3 (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG 3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or combinations thereof.

[0513] In yet another embodiment, one of the active compounds described herein can be administered in an effective amount in combination with or alternating with an effective amount of an estrogen inhibitor, including but not limited to SERM (selective estrogen receptor modulator), SERD (selective estrogen receptor degrader), complete estrogen receptor degrader, or another form of partial or complete estrogen antagonist or agonist, for the treatment of abnormal tissues of the female reproductive system, such as breast cancer, ovarian cancer, endometrial cancer, or uterine cancer.Partial antiestrogen such as raloxifene and tamoxifen retain some estrogenic effects, including estrogenic stimulation of uterine growth, and in some cases, estrogenic effects during the progression of breast cancer, which actually stimulate tumor growth.In contrast, fulvestrant, a complete antiestrogen, does not have estrogenic effects on the uterus, and is effective in tamoxifen-resistant tumors.

[0514] Non-limiting examples of anti-estrogen compounds are provided in WO 2014 / 19176 assigned to Astra Zeneca, WO 2013 / 090921, WO 2014 / 203129, WO 2014 / 203132 assigned to Olema Pharmaceuticals, and U.S. Patent Application Publication No. 2013 / 0178445, as well as U.S. Patent Nos. 9,078,871, 8,853,423, and 8,703,810, and U.S. Patent Application Publication Nos. 2015 / 0005286, WO 2014 / 205136, and WO 2014 / 205138.

[0515] Additional non-limiting examples of anti-estrogen compounds include SERMs such as anordrin, bazedoxifene, broparestrol chlorotrianisene, clomiphene citrate, cyclophenyl, lasofoxifene, ormeloxifene, raloxifene, tamoxifen, toremifene, and fulvestrant; aromatase inhibitors such as aminoglutethimide, testolactone, anastrozole, exemestane, fadrozole, formestane, and letrozole; and antigonadotropins such as leuprorelin, cetrorelix, allylestrenol, chlormadinone acetate, cyproterone acetate, delmadinone acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethisterone acetate, progesterone, and spironolactone.

[0516] Other estrogen ligands that can be used in accordance with the present invention are described in U.S. Pat. Nos. 4,418,068; 5,478,847; 5,393,763; and 5,457,117, WO 2011 / 156518, U.S. Pat. Nos. 8,455,534 and 8,299,112, U.S. Pat. Nos. 9,078,871; 8,853,423; 8,703,810; U.S. Patent Application Publication No. 2015 / 0005286; and WO 2014 / 2020444. 05138, U.S. Patent Application Publication No. 2016 / 0175289, U.S. Patent Application Publication No. 2015 / 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;U.S. Patent No. 6,821,989;U.S. Patent Application Publication No. 2002 / 0128276;U.S. Patent No. 6,777,424;U.S. Patent Application Publication No. 2002 / 0016340;U.S. Patent No. 6,326,392;U.S. Patent No. 6,756,401;U.S. Patent Application Publication No. 2002 / 0013327 No. 6,512,002; U.S. Patent No. 6,632,834; U.S. Patent Application Publication No. 2001 / 0056099; U.S. Patent No. 6,583,170; U.S. Patent No. 6,479,535; WO 1999 / 024027; U.S. Patent No. 6,005,102; EP 0802184; U.S. Patent No. 5,998,402; U.S. Patent No. 5,780,497, U.S. Patent No. 5,880,137, WO 2012 / 048058 and WO 2007 / 087684.

[0517] In another embodiment, the active compounds described herein can be administered in effective amounts 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, for the treatment of abnormal tissue of the male reproductive system, such as prostate cancer or testicular cancer. In certain embodiments, the prostate or testicular cancer is androgen-resistant.

[0518] Non-limiting examples of anti-androgen compounds are provided in WO 2011 / 156518 and U.S. 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, topirutamide, abiraterone acetate, and cimetidine.

[0519] In certain embodiments, the bioactive agent is an ALK inhibitor. Examples of ALK inhibitors include, but are not limited to, crizotinib, alectinib, ceritinib, TAE684 (NVP-TAE684), GSK1838705A, AZD3463, ASP3026, PF-06463922, entrectinib (RXDX-101), and AP26113.

[0520] In certain embodiments, the bioactive agent is a HER-2 inhibitor. Examples of HER-2 inhibitors include trastuzumab, lapatinib, ado-trastuzumab emtansine, and pertuzumab.

[0521] In certain embodiments, the bioactive agent is a CD20 inhibitor. Examples of CD20 inhibitors include obinutuzumab, rituximab, ofatumumab, ibritumomab, tositumomab, and ocrelizumab.

[0522] In certain embodiments, the bioactive agent is a JAK3 inhibitor. Examples of JAK3 inhibitors include tasocitinib.

[0523] 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-1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), and venetoclax (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl). [4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl]-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3((trimethylamino)-4-pyridin-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-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3((trimethylamino)-4-pyridin-1-yl)-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide) (navitoclax), Fluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide), GX15-070 (Ovatoclax mesylate, (2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-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, AT101, sabutoclax, gambogic acid, or G3139 (oblimersen).

[0524] In certain embodiments, the bioactive agent is a kinase inhibitor, hi 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.

[0525] Examples of PI3 kinase inhibitors include 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-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]pyrazol-1-yl]-2-methylpropanamide), MLN-1117 ((2R)-1-phenoxy-2-butanyl hydrogen ( or methyl(oxo){[(2R)-1-phenoxy-2-butanyl]oxy}phosphonium), BYL-719 ((2S)-N1-[4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide), GSK2126458 (2,4-difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide), do) (omipalisib), TGX-221 ((±)-7-methyl-2-(morpholin-4-yl)-9-(1-phenylaminoethyl)-pyrido[1,2-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]pyrimidine-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[1,2-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[1,5-a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide), buparlisib (5-[2,6-di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine), GDC-0941 (2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)-1-piperazinyl ]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine), GDC-0980 ((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-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-tetraazaoctadecane-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)phenyl]urea) (gedatrisib), LY3023414, BEZ235 (2-methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-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), GSK1059615 (5-[[4-(4-pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidinedione), PX886 ([(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylidene]-5-hydroxy-9-(methoxymethyl) (ethyl)-9a,11a-dimethyl-1,4,7-trioxo-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 Examples of such inhibitors include, but are not limited to, 147, PIK-90, PIK-293, PIK-294, 3-MA (3-methyladenine), AS-252424, AS-604850, and apitolisib (GDC-0980; RG7422).

[0526] 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 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 U.S. Patent Application Publication No. 2011 / 0117073, which is incorporated herein by reference 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 (α-cyano-β -hydroxy-β-methyl-N-(2,5-dibromophenyl)propenamide), GDC-0834 (RN-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), CGI-560 4-(tert-butyl)-N-(3-(8-(phenylamino)imidazo[1,2-a]pyrazin-6-yl)phenyl)benzamide, CGI-1746 (4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)benzamide), CNX-774 (4-(4- ((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)-N-methylpicolinamide), CTA056 (7-benzyl-1-(3-(piperidin-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-oxo-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-yl)-9-(1-methyl-1H-pyrazol-4-yl)benzo[h][1,6]naphthyl quinolin-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), as well as other molecules capable of inhibiting BTK activity, such as the BTK inhibitors disclosed in Akinleye et al., Journal of Hematology & Oncology, 2013, 6:59, which is incorporated herein by reference in its entirety.

[0527] Syk inhibitors include cerdulatinib (4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide), entospletinib (6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine), and fostamatinib ([6-({5-fluoro-2-[(3,4,5-trimethoxysilyl)methyl]phenyl]pyrimidine-5-carboxamide). phenyl)amino]-4-pyrimidinyl}amino)-2,2-dimethyl-3-oxo-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), RO9021 (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]amino}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,2S)-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-hydroxyresveratrol), YM193306 (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, which is incorporated herein by reference in its entirety), Compound D (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is incorporated herein by reference in its entirety), PRT060318 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is incorporated herein by reference in its entirety), 3614-3643 (incorporated herein by reference in its entirety)), luteolin (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55,3614-3643 (incorporated herein by reference in its entirety), apigenin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (incorporated herein by reference in its entirety)), quercetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (incorporated herein by reference in its entirety)), fisetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (incorporated herein by reference in its entirety)), 3614-3643 (incorporated herein by reference in its entirety), myricetin (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (incorporated herein by reference in its entirety)), and morin (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (incorporated herein by reference in its entirety)).

[0528] In certain embodiments, the bioactive agent is a MEK inhibitor. MEK inhibitors are known, such as 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 / RDEA119 (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) 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]-benzamide), ]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide), R05126766 (3-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one), WX-554, R04987655 / CH4987655(3,Examples of such compounds include 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-(2hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide), U0126-EtOH, PD184352 (CI-1040), GDC-0623, BI-847325, cobimetinib, PD98059, BIX02189, BIX02188, binimetinib, SL-327, TAK-733, and PD318088.

[0529] In certain embodiments, the bioactive agent is a Raf inhibitor. Raf inhibitors are known and include, for example, vemurafenib (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-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide; 4-methylbenzenesulfonate), AZ628 (3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylamino)phenyl)benzamide), NVP-BHG712 (4-methyl-3-(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)phenyl]benzamide]), methyl)-1H-imidazol-2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine), 2-bromoardisine (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]amino]phenoxy]-N-methyl-2-pyridinecarboxamide 1-oxide), PLX-4720, dabrafenib (GSK2118436), GDC-0879, RAF265, AZ628, SB590885, ZM336372, GW5074, TAK-632, CEP-32496, LY3009120, and GX818 (encorafenib).

[0530] 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 (Xegafri), afatinib (Glotriff, Giotriff, Afanix), lazertinib, or nazartinib.

[0531] Additional examples of EGFR inhibitors include rociletinib (CO-1686), olmutinib (Olita), nacotinib (ASP8273), nazartinib (EGF816), PF-06747775, icotinib (BPI-2009), neratinib (HKI-272; PB272), avitinib (AC0010), EAI045, taloxotinib (TH-4000; PR-610), These include 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).

[0532] 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.

[0533] In certain embodiments, compounds of the invention are administered in combination with osimertinib to a patient in need thereof.

[0534] In certain embodiments, compounds of the invention are administered in combination with rociletinib to a patient in need thereof.

[0535] In certain embodiments, compounds of the invention are administered in combination with avitinib to a patient in need thereof.

[0536] In certain embodiments, compounds of the invention are administered in combination with lazertinib to a patient in need thereof.

[0537] In certain embodiments, compounds of the invention are administered in combination with nazartinib to a patient in need thereof.

[0538] In certain embodiments, the compounds of the invention are administered to a patient in need thereof in combination with an EGFR antibody, such as cetuximab, panitumumab, or necitumumab.

[0539] In certain embodiments, compounds of the invention are administered to a patient in need thereof in combination with cetuximab.

[0540] In certain embodiments, compounds of the invention are administered in combination with panitumumab to a patient in need thereof.

[0541] In certain embodiments, compounds of the invention are administered in combination with necitumumab to a patient in need thereof.

[0542] In certain embodiments, the bioactive agent is a c-MET inhibitor, such as crizotinib (Xalkori, Crizonix), tepotinib (XL880, EXEL-2880, GSK1363089, GSK089), or tivantinib (ARQ197).

[0543] In certain embodiments, the bioactive agent is an AKT inhibitor, including but not limited to, MK-2206, GSK690693, perifosine (KRX-0401), GDC-0068, triciribine, AZD5363, honokiol, PF-04691502, and miltefosine; an FLT-3 inhibitor, including but not limited to, P406, dovitinib, quizartinib (AC220), amuvatinib (MP-470), tanzutinib (MLN518), ENMD-2076, and KW-2449; or a combination thereof.

[0544] 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.

[0545] In certain embodiments, the bioactive agent is a RAS inhibitor. Examples of RAS inhibitors include, but are not limited to, Reolysin and siG12D LODER.

[0546] In certain embodiments, the bioactive agent is an HSP inhibitor, including, but not limited to, geldanamycin or 17-N-allylamino-17-demethoxygeldanamycin (17AAG), and radicicol.

[0547] Additional biologically active 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, FLT-3 inhibitors, VEGFR inhibitors, Aurora kinase inhibitors, PIK-1 modulators, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, Cdk inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, focal adhesion kinase inhibitors, Map kinase (mek) inhibitors, VEGF Trap antibody, pemetrexed, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, 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, IPdR1KRX-0402, lucanton, 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]benzoyl]-, disodium salt heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole,DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogens, bevacizumab, IMC-1C11, CHIR-258; 3-[5-(methylsulfonylpiperazinemethyl)-indolyl-quinolone, vatalanib, AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrogen acetate raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatinib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, lonafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoylanilide hydroxamic acid acid), valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, 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, hydrochloride Roxiurea, 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-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxine, marimastat, COL-3, neovastatin, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxifene e), spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortezomib, paclitaxel, paclitaxel without cremophor, docetaxel, epothilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte-colony stimulating factor, zoledronate, prednisone, cetuximab, granulocyte-macrophage colony stimulating factor Stimulators, histrelin, peginterferon α-2a, interferon α-2a, peginterferon α-2b, interferon α-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan,androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, etidronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium-89, casopitant, netupitant, NK-1 receptor antagonists, 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.

[0548] In certain embodiments, the compound is administered in combination with ifosfamide.

[0549] In certain embodiments, the bioactive agent is imatinib mesylate (Gleevac™), dasatinib (Sprycel™), nilotinib (Tasigna™), bosutinib (Bosulif™), trastuzumab (Herceptin™), trastuzumab-DM1, pertuzumab (Perjeta™), lapatinib (Tykerb™), gefitinib (Iressa™), erlotinib (Tarceva™), cetuximab (Erbitux™), panitumumab (Vectibix™), vandetanib (Caprelsa™), vemurafenib (Zelboraf™), vorinostat (Zol Inza™), romidepsin (Istodax™), bexarotene (Tagretin™), alitretinoin (Panretin™), tretinoin (Vesanoid™), carfilzomib (Kyprolis™), pralatrexate (Folotyn™), bevacizumab (Avastin™), Ziv-aflibercept (Zaltrap™), sorafenib (Nexavar™), sunitinib (Sutent™), pazopanib (Votrient™), regorafenib (Stivarga™), and cabozantinib (Cometriq™).

[0550] In certain embodiments, the bioactive agent is an anti-inflammatory agent, a chemotherapeutic agent, a radiotherapeutic agent, an additional therapeutic agent, or an immunosuppressant.

[0551] Suitable chemotherapeutic bioactive agents include, but are not limited to, radioactive molecules, toxins, also referred to as cytotoxins or cytotoxic drugs, any agent detrimental to cell viability, and liposomes or other vesicles containing chemotherapeutic compounds. Common anti-cancer drugs 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™), elastase (Elspar™) or PEG-L-asparaginase (pegaspargase or Oncaspar™), erythromycin (Erythromycin ... These include toposide (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™).

[0552] Examples of additional suitable chemotherapeutic agents include 1-dehydrotestosterone, 5-fluorouracil, dacarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, adriamycin, aldesleukin, alkylating agents, allopurinol sodium, altretamine, amifostine, anastrozole, anthramycin (AMC), antimitotic agents, cis-dichlorodiamineplatinum(II) (DDP) (cisplatin), diaminodichloroplatinum, anthracyclines, antibiotics, antimetabolites, asparaginase, live BCG bacteria (BCG), live) (intravesical), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, leucovorin calcium, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU), chlorambucil, cisplatin, cladribine, colchicine, conjugated estrogens, cyclophosphamide, cyclothosphamide, cytarabine, cytochalasin B, cytoxan, dacarbazine, dactinomycin, dactinomycin (formerly actinomycin), daunorubicin HCl, daunorubicin citrate, denileukin diftitox, dexrazoxane, dibromomannitol, dihydroxy anthracin dione dione), docetaxel, dolasetron mesylate, doxorubicin HCl, dronabinol, Escherichia coli (E.coli) L-asparaginase, emetine, epoetin-α, Erwinia L-asparaginase, esterified estrogens, estradiol, estramustine sodium phosphate, ethidium bromide, ethinyl estradiol, etidronate, etoposide, citrovorum 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 α-2b, irinotecan HCl, letrozole, leucovorin calcium, leuprolide acetate, levamisole HCl, lidocaine, lomustine, maytansinoids Mechlorethamine HCl, medroxyprogesterone acetate, megestrol acetate, melphalan HCl, mercaptopurine, mesna, methotrexate, methyltestosterone, mithramycin, mitomycin C, mitotane, mitoxantrone, nilutamide, octreotide acetate, ondansetron HCl, paclitaxel, pamidronate disodium, pentostatin, pilocarpine HCl, primycin, porfimer sodium, procaine, procarbazine HCl, propranolol, rituximab, sargramostim, streptozotocin, tamoxifen, taxol, teniposide, tenoposide, testolactone, tetracaine, thioepa chlorambucil chlorambucil), thioguanine, thiotepa, topotecan HCl, toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate.

[0553] In some embodiments, the compounds of the present invention are 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, epipodophyllotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione-substituted ureas, methylhydrazine derivatives, adrenocortical suppressants, corticosteroids, progestins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. Also included are 5-fluorouracil (5-FU), leucovorin (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel, and docetaxel. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; acetogenins (especially bullatacin and bullatacinone); camptothecin (including the synthetic analog topotecan); bryostatin; cins; kallistatins; CC-1065 (including its synthetic analogs adozelesin, carzelesin, and bizelesin); cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatins; duocarmycins (including synthetic analogs KW-2189 and CB1-TM1); eluterobin; pancratistatin; sarcodictyin; spongistatins; chlorambucil, chlornaphazine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobuenbiquine, fenesterine, prednimastine, trofosfamide, nitrogen mustards such as uracil mustard;nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; enediyne antibiotics (e.g., calicheamicin, particularly calicheamicin γ11 and calicheamicin ω11 (see, e.g., Agnew, Chem. Inti. Ed Engl. 33:183-186 (1994)); dynemicins, including dynemicin A; bisphosphonates such as clodronate; esperamicin; and neocarzinostatin chromophore and related enediyne antibiotic chromophores), aclacinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chlamycin ... Romomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN™ (doxorubicin including morpholinodoxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolinodoxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, pepromycin, anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; fludarabine, 6-methamorrhagic acid analogs such as benzodiazepine, benzodiazepine, benzophenone, benzodiazepine, benzodiazepine, benzophenone, benzodiazepine, benzophenone, benzodiazepine, benzophenone, benzodiazepine, benzophenone, benzophenone Purine analogues such as rcaptopurine, thiamiprine, and thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calusterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; anti-adrenals such as aminoglutethimide, mitotane, and trilostane;Folic acid supplements such as furolic acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; eniluracil; amsacrine; bestravcil; bisantrene; edatrexate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; epothilone; etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazide; procarbazine; PSK™ polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A, and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, such as TAXOL™ (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE™ (American Pharmaceuticals, Inc.), an albumin-modified nanoparticle formulation of paclitaxel that is free of cremophor Partners, Schaumberg, IL) and TAXOTERE™ docetaxel (Rhone-Poulenc Rorer, Antony, France); chlorambucil; GEMZAR™ gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE™ vinorelbine; novantrone; teniposide; edatrexate; daunomycin;Examples of suitable chemotherapeutic agents include aminopterin, xeloda, ibandronate, irinotecan (e.g., CPT-11), the topoisomerase inhibitor RFS 2000, difluoromethylornithine (DMFO), retinoids such as retinoic acid, capecitabine, and pharmaceutically acceptable salts, acids, or derivatives of any of the above. Two or more chemotherapeutic agents can be used in cocktails administered in combination with the compounds of the present invention. Suitable dosing regimens for combination chemotherapy are known in the art. For example, combination dosing regimens are described in Saltz et al., Proc. Am. Soc. Clin. Oncol. 18:233a (1999) and Douillard et al., Lancet 355(9209): 1041-1047 (2000).

[0554] Additional therapeutic agents that can be administered in combination with the compounds disclosed herein include bevacizumab, sutinib, sorafenib, 2-methoxyestradiol or 2ME2, finasunate, vatalanib, vandetanib, aflibercept, volociximab, etaracizumab (MEDI-522), cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, and the like. Mab, dovitinib, figitumumab, atacicept, rituximab, alemtuzumab, aldesleukine, atlizumab, tocilizumab, temsirolimus, everolimus, lucatumumab, dacetuzumab, HLL1, huN901-DM1, atiplimod, natalizumab, bortezomib, carfilzomib, marizomib, tanespimycin, saquinavir mesylate, ritonavir, nervate mesylate Finavir, indinavir sulfate, belinstat, panobinostat, mapatumumab, lexatumumab, dulanermin, ABT-737, oblimersen, plitidepsin, talmapimod, P276-00, enzastaurin, tipifarnib, perifosine, imatinib, dasatinib, lenalidomide, thalidomide, simvastatin, celecoxib, bazedoxifene These include AZD4547, rilotumumab, oxaliplatin (Eloxatin), PD0332991, ribociclib (LEE011), abemaciclib (LY2835219), HDM201, fulvestrant (Faslodex), exemestane (Aromasin), PIM447, ruxolitinib (INC424), BGJ398, necitumumab, pemetrexed (Alimta), and ramucirumab (IMC-1121B).

[0555] In certain embodiments, the additional therapy is a monoclonal antibody (MAb). Some MAbs stimulate an immune response that destroys cancer cells. Similar to antibodies naturally produced by B cells, these MAbs can "coat" the surface of cancer cells and induce their destruction by the immune system. For example, bevacizumab targets vascular endothelial growth factor (VEGF), a protein secreted by tumor cells and other cells in the tumor microenvironment that promotes the development of tumor blood vessels. When VEGF binds to bevacizumab, it cannot interact with its cell receptor, preventing signaling that leads to the growth of new blood vessels. MAbs that bind to cell surface growth factor receptors prevent the target receptor from sending normal growth-promoting signals. They can also induce apoptosis and activate the immune system to destroy tumor cells.

[0556] In one aspect of the invention, the bioactive agent is an immunosuppressant. The immunosuppressant may be a calcineurin inhibitor, such as cyclosporine or ascomycin, e.g., cyclosporine A (NEORAL™), FK506 (tacrolimus), pimecrolimus, an mTOR inhibitor, such as rapamycin or a derivative thereof, e.g., sirolimus (RAPAMUNE™), everolimus (Certican™), temsirolimus, zotarolimus, biolimus-7, biolimus-9, a rapalog, e.g., ridaforolimus, azathioprine, campath 1H, an S1P receptor modulator, e.g., fingolimod or an analog thereof, an anti-IL-8 antibody, mycophenolic acid or a salt thereof, e.g., the sodium salt or a prodrug thereof, e.g., mycophenolate mofetil (CELLCEPT™), OKT3 (ORTHOCLONE OKT3™), prednisone, ATGAM™, THYMOGLOBULIN™, brequinar sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxyspergualin, tresperimus, leflunomide (ARAVA™), CTLAI-Ig, anti-CD25, anti-IL2R, basiliximab (SIMULECT™), daclizumab (ZENAPAX™), mizoribine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, Elidel™), CTLA4Ig (abatacept), belatacept, LFA3Ig, etanercept (sold as Enbrel™ by Immunex), adalimumab (Humira™), infliximab (Remicade™), anti-LFA-1 antibodies, natalizumab (Antegren™), enlimomab, gavilimomab, anti-thymocyte immunoglobulin, siplizumab, alefacept, efalizumab, Pentasa, mesalazine, Asacol, codeine phosphate, benorylate, fenbufen, naprosyn, diclofenac, etodolac and indomethacin, aspirin and ibuprofen.

[0557] In some embodiments, the bioactive agent is a therapeutic agent that is a biologic, such as a cytokine (e.g., an interferon or an interleukin (e.g., IL-2)) used in cancer treatment. In some embodiments, the biologic is an anti-angiogenesis agent, such as an anti-VEGF agent, e.g., bevacizumab (AVASTIN™). In some embodiments, the biologic is an immunoglobulin-based biologic, such as a monoclonal antibody (e.g., a humanized antibody, fully human antibody, Fc fusion protein, or functional fragment thereof), that agonizes a target, stimulates an anti-cancer response, or antagonizes an antigen important to cancer.Such agents include RITUXAN™ (rituximab), ZENAPAX™ (daclizumab), SIMULECT™ (basiliximab), SYNAGIS™ (palivizumab), REMICADE™ (infliximab), HERCEPTIN™ (trastuzumab), MYLOTARG™ (gemtuzumab ozogamicin), CAMPATH™ (alemtuzumab), and HERCEPTIN™ (trastuzumab). Mab), ZEVALIN™ (ibritumomab tiuxetan), HUMIRA™ (adalimumab), XOLAIR™ (omalizumab), BEXXAR™ (tositumomab-l-131), RAPTIVA™ (efalizumab), ERBITUX™ (cetuximab), AVASTIN™ (bevacizumab), TYSABRI™ (natalizumab), ACTEMRA™ (tocilizumab), VECTIBIX™ (panitumumab), LUCENTIS™ (ranibizumab), SOURIS™ (eculizumab), CIMZIA™ (certolizumab pegol), SIMPONI™ (golimumab), ILARIS™ (canakinumab), STELARA™ (ustekinumab), ARZERRA™ (ofatumumab), PROLIA™ (denosine triphosphate), Antibody-drug conjugates are also included, including NUMAX™ (motavizumab), ABTHRAX™ (raxibacumab), BENLYSTA™ (belimumab), YERVOY™ (ipilimumab), ADCETRIS™ (brentuximab vedotin), PERJETA™ (pertuzumab), KADCYLA™ (adotrastuzumab emtansine), and GAZYVA™ (obinutuzumab).

[0558] The combination therapy may also include therapeutic agents that are non-drug treatments, for example, the compound may be administered in addition to radiation therapy, cryotherapy, hyperthermia, and / or surgical removal of tumor tissue.

[0559] In certain embodiments, the first and second therapeutic agents are administered simultaneously or sequentially in either order. The first therapeutic agent can be administered immediately before or immediately after the second therapeutic agent, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to 16 hours, up to 17 hours, up to 18 hours, up to 19 hours, up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours, up to 24 hours, or up to 1 to 7 days, 1 to 14 days, 1 to 21 days, or 1 to 30 days before or after the second therapeutic agent.

[0560] In certain embodiments, the second therapeutic agent is administered according to a different dosing schedule from the compound of the present invention. For example, the second therapeutic agent may have a treatment holiday of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle. In another embodiment, the first therapeutic agent has a treatment holiday. For example, the first therapeutic agent may have a treatment holiday of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle. In certain embodiments, both the first and second therapeutic agents have a treatment holiday.

[0561] VII. Pharmaceutical Compositions The compound of formula I, II, III or IV or its pharmaceutically acceptable salt can be used as a therapeutically active substance, for example, in the form of a pharmaceutical preparation.The pharmaceutical preparation can be orally administered, for example, in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions.In other embodiments, the compound is administered parenterally, for example, intravenously.Administration can also be carried out rectally, for example, in the form of suppositories, or parenterally, for example, in the form of injection solutions.

[0562] The compounds of formula I, II, III, or IV and their pharmaceutically acceptable salts can be processed with pharmaceutically inert inorganic or organic carriers to prepare pharmaceutical preparations. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used as such carriers for tablets, coated tablets, sugar-coated tablets, and hard gelatin capsules. Suitable carriers for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. However, depending on the nature of the active substance, carriers are usually not required for soft gelatin capsules. Suitable carriers for the preparation of solutions and syrups include, for example, water, polyols, glycerol, vegetable oils, etc. Suitable carriers for suppositories include, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, etc.

[0563] The pharmaceutical preparations may further comprise pharmaceutically acceptable auxiliary substances such as preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying osmotic pressure, buffers, masking agents or antioxidants. The pharmaceutical preparations may further contain other therapeutically valuable substances.

[0564] Medicaments containing compounds of formula I, II, III or IV or pharmaceutically acceptable salts thereof and a therapeutically inert carrier are also provided by the present invention, as is a process for their preparation, which comprises bringing one or more compounds of formula I, II, III or IV and / or pharmaceutically acceptable salts thereof, and optionally one or more other therapeutically valuable substances, together with one or more therapeutically inert carriers, into a galenical dosage form.

[0565] Dosage can vary widely and, of course, must be adjusted according to the individual requirements of each specific case.When administered orally, the dosage for adults can vary from about 0.01 mg to about 1000 mg of the compound of general formula I, II, III or IV or the corresponding amount of its pharmaceutically acceptable salt per day.The daily dosage can be administered as a single dose or in divided doses, and can also exceed the upper limit if it is found to be applicable.

[0566] The following examples illustrate the invention without limiting it and are merely representative of the invention. Pharmaceutical preparations conveniently contain about 1 mg to 500 mg, particularly 1 mg to 100 mg, of a compound of formula I, II, III or IV. Examples of compositions according to the invention are as follows:

[0567] In certain embodiments, the pharmaceutical composition is a dosage form containing about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of active compound per unit dosage form, and optionally about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of an additional active agent. Examples are dosage forms containing at least 0.1 mg, 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 750 mg of active compound or a salt thereof.

[0568] In some embodiments, the compounds disclosed or used as described herein are administered once daily (QD), twice daily (BID), or three times daily (TID). In some embodiments, a compound disclosed or used as described herein is administered at least once daily for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, at least 30 days, at least 31 days, at least 35 days, at least 45 days, at least 60 days, at least 75 days, at least 90 days, at least 120 days, at least 150 days, at least 180 days or more.

[0569] In certain embodiments, the compounds of the invention are administered once daily, twice daily, three times daily, or four times daily.

[0570] In certain embodiments, the compound of the present invention is orally administered once a day. In certain embodiments, the compound of the present invention is orally administered twice a day. In certain embodiments, the compound of the present invention is orally administered three times a day. In certain embodiments, the compound of the present invention is orally administered four times a day.

[0571] In certain embodiments, the compound of the present invention is administered intravenously once a day. In certain embodiments, the compound of the present invention is administered intravenously twice a day. In certain embodiments, the compound of the present invention is administered intravenously three times a day. In certain embodiments, the compound of the present invention is administered intravenously four times a day.

[0572] In some embodiments, the compounds of the invention are administered with a treatment holiday between treatment cycles, for example, the compounds may have a treatment holiday of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle.

[0573] In some embodiments, a loading dose is administered to initiate treatment. For example, on the first day of treatment, the compound can be administered at a dose that is about 1.5 times, about 2 times, about 2.5 times, about 3 times, about 3.5 times, about 4 times, about 4.5 times, about 5 times, about 5.5 times, about 6 times, about 6.5 times, about 7 times, about 7.5 times, about 8 times, about 8.5 times, about 9 times, about 9.5 times, or about 10 times higher than on the remaining treatment days of the treatment cycle. Further exemplary loading doses include a dose that is about 1.5 times, about 2 times, about 2.5 times, about 3 times, about 3.5 times, about 4 times, about 4.5 times, about 5 times, about 5.5 times, about 6 times, about 6.5 times, about 7 times, about 7.5 times, about 8 times, about 8.5 times, about 9 times, about 9.5 times, or about 10 times higher on the first 2, 3, 4, 5, 6, 7, 8, 9, or 10 days of treatment than on the remaining treatment days of the treatment cycle.

[0574] The pharmaceutical composition may contain a molar ratio of the active compound to the additional active agent. For example, the pharmaceutical composition may contain a molar ratio of about 0.5:1, about 1:1, about 2:1, about 3:1, or about 1.5:1 to about 4:1 of the anti-inflammatory or immunosuppressant agent.

[0575] These compositions can contain any amount of the active compound that achieves the desired result, for example, 0.1% to 99% by weight (wt%) of the compound, usually at least about 5% by weight of the compound, with some embodiments containing about 25% to about 50% by weight or about 5% to about 75% by weight of the compound.

[0576] A pharmaceutically or therapeutically effective amount of the composition is delivered to the patient. The precise effective amount will vary from patient to patient and will depend on the species, age, size, and health of the subject, the nature and extent of the condition being treated, the recommendations of the treating physician, and the therapeutic agent or combination of therapeutic agents selected for administration. Effective amounts for a given situation can be determined by routine experimentation. For purposes of this disclosure, a therapeutic amount may be, for example, in the range of about 0.01 mg / kg to about 250 mg / kg of body weight in at least one administration, more typically about 0.1 mg / kg to about 10 mg / kg. A subject may receive as many doses as needed to reduce and / or alleviate the signs, symptoms, or causes of the disorder in question, or to effect any other desired change in a biological system. Where appropriate, formulations can be prepared with enteric coatings suitable for sustained- or controlled-release administration of the active ingredient.

[0577] In certain embodiments, the dose ranges from about 0.01 mg / kg to 100 mg / kg of patient body weight, e.g., about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg or about 100 mg / kg.

[0578] The pharmaceutical preparation is preferably in unit dosage form. In such dosage form, the preparation is subdivided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form may be a packaged preparation in which the package contains discrete quantities of the preparation, such as packaged tablets, capsules, and powders in vials or ampoules. The unit dosage form may also be a capsule, tablet, cachet, or lozenge itself, or the appropriate number of any of these in packaged form.

[0579] In certain embodiments, the compound is administered as a pharmaceutically acceptable salt. Non-limiting examples of pharmaceutically acceptable salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, sodium, lithium, potassium, calcium, and magnesium, as well as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

[0580] As such, the compositions of the present disclosure may be administered as pharmaceutical formulations, including those suitable for oral (including buccal and sublingual), rectal, nasal, topical, transdermal, pulmonary, intravaginal, or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous, and intravenous) administration, injection, inhalation, or spray, intra-aortic, intracranial, subdermal, intraperitoneal, subcutaneous administration, or by other means of administration with conventional pharmaceutically acceptable carriers. Typical methods of administration are oral, topical, or intravenous administration, using a convenient daily dosing regimen that can be adjusted according to the degree of affliction.

[0581] Depending on the intended method of administration, the pharmaceutical composition may be in the form of a solid, semi-solid or liquid dosage form, such as a tablet, suppository, pill, capsule, powder, liquid, syrup, suspension, cream, ointment, lotion, paste, gel, spray, aerosol, foam or oil, injectable or infusible solution, transdermal patch, subcutaneous patch, inhalation formulation, medical device, suppository, buccal or sublingual formulation, parenteral formulation, or eye drops, preferably in a unit dosage form suitable for single administration of a precise dosage amount.

[0582] Some dosage forms, such as tablets and capsules, are subdivided into suitably sized unit doses containing an appropriate amount of the active ingredient, e.g., an amount effective to achieve a desired purpose. The composition contains an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier, and may further include other medicinal agents, adjuvants, diluents, buffers, etc.

[0583] Carriers, including additives and diluents, must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated. Carriers may be inert or may themselves possess medicinal properties. The amount of carrier used in combination with the compound is sufficient to provide a quantity of material useful for administration per unit dose of the compound.

[0584] Classes of carriers include, but are not limited to, adjuvants, binders, buffers, colorants, diluents, disintegrants, additives, emulsifiers, flavorings, gels, glidants, lubricants, preservatives, stabilizers, surfactants, solubilizers, tabletting agents, wetting agents or solidifying agents.

[0585] Some carriers may fall into more than one class; for example, vegetable oils may be used as lubricants in some formulations and as diluents in others.

[0586] Exemplary pharmaceutically acceptable carriers include sugars, starches, cellulose, powdered tragacanth, malt, gelatin, talc, petrolatum, lanolin, polyethylene glycols, alcohols, transdermal enhancers, and vegetable oils. Any active agent that does not substantially interfere with the activity of the compound of the present invention may be included in the pharmaceutical composition.

[0587] Some excipients include, but are not limited to, liquids such as water, saline, glycerol, polyethylene glycol, hyaluronic acid, ethanol, etc. The compound can be provided in the form of a solid, liquid, spray-dried product, microparticles, nanoparticles, controlled release systems, etc., as desired, for example, depending on the purpose of therapy. Suitable excipients for non-liquid formulations are also known to those skilled in the art. A thorough discussion of pharmaceutically acceptable excipients and salts can be found in Remington's Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990).

[0588] Additionally, auxiliary substances, such as wetting or emulsifying agents, physiological buffer substances, surfactants, etc., may be present in such vehicles. The physiological buffer may be any solution that is pharmacologically acceptable and provides the formulation with a desired pH, i.e., a pH within the physiologically acceptable range. Examples of buffer solutions include physiological saline, phosphate-buffered saline, Tris-buffered saline, Hank's buffered saline, etc.

[0589] For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Liquid pharmaceutically administrable compositions can be prepared, for example, by dissolving or dispersing an active compound described herein and any pharmaceutical adjuvants in an excipient, such as water, saline, aqueous dextrose, glycerol, ethanol, or the like, thereby forming a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and the like. Actual methods for preparing such dosage forms are known or will be apparent to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, supra.

[0590] In yet another embodiment, there is provided the use of penetration-enhancing additives including polymers such as polycations (chitosan and its quaternary ammonium derivatives, poly-L-arginine, aminated gelatin), polyanions (N-carboxymethylchitosan, polyacrylic acid), and thiolated polymers (carboxymethylcellulose-cysteine, polycarbophil-cysteine, chitosan-thiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione conjugates).

[0591] In certain embodiments, the excipient is selected from butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0592] The pharmaceutical composition / combination can be formulated for oral administration. For oral administration, the composition generally takes the form of a tablet, capsule, softgel capsule, or may be an aqueous or non-aqueous solution, suspension, or syrup. Tablets and capsules are typical oral dosage forms. Oral tablets and capsules can contain one or more commonly used carriers, such as lactose and corn starch. Lubricants, such as magnesium stearate, are also commonly added. Typically, the compositions of the present disclosure can be combined with non-toxic, pharmaceutically acceptable inert carriers for oral use, such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc. Furthermore, suitable binders, lubricants, disintegrating agents, and coloring agents may be incorporated into the mixture, if desired or necessary. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn syrup, natural and synthetic gums such as gum arabic and gum tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, etc. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc.

[0593] When a liquid suspension is used, the active agent can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier, such as ethanol, glycerol, water, etc., as well as emulsifying and suspending agents. Flavoring agents, coloring agents, and / or sweetening agents may be added as needed. Other optional ingredients incorporated into the oral formulations herein include, but are not limited to, preservatives, suspending agents, thickening agents, etc.

[0594] For intraocular delivery, the compounds can be administered, for example, by intravitreal, intrastromal, intracameral, subtenon, subretinal, retrobulbar, peribulbar, suprachoroidal, conjunctival, subconjunctival, episcleral, periocular, transscleral, retrobulbar, posterior juxtascleral, periconeal, or lacrimal injection, or in an immediate or controlled release manner via a mucus, mucin, or mucosal barrier, or by an intraocular device, as desired.

[0595] Parenteral preparations can be prepared in conventional forms, such as liquid solutions or suspensions, solid forms suitable for solubilization or suspension in liquid prior to injection, or emulsions. Typically, sterile injectable suspensions are formulated according to techniques known in the art using suitable carriers, dispersing or wetting agents, and suspending agents. Sterile injectable preparations can also be sterile injectable solutions or suspensions in parenterally acceptable diluents or solvents that are non-toxic to an acceptable extent. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils, fatty acid esters, or polyols are conventionally used as solvents or suspending media. In addition, parenteral administration can involve the use of sustained-release or sustained-release systems to maintain a constant level of dosage.

[0596] Parenteral administration includes intraarticular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, and includes aqueous and non-aqueous isotonic sterile injection solutions that may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents, solubilizers, thickeners, stabilizers, and preservatives. Administration via certain parenteral routes may involve introducing a formulation of the present disclosure into a patient's body through a needle or catheter propelled by a sterile syringe or some other mechanical device, such as a continuous infusion system. The formulations provided by the present disclosure can be administered using a syringe, infuser, pump, or any other device recognized in the art for parenteral administration.

[0597] Preparations according to the present disclosure for parenteral administration include aqueous or non-aqueous sterile solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. They can be sterilized, for example, by filtration through a bacteria-retaining filter, incorporating a sterilizing agent into the composition, irradiating the composition, or heating the composition. They can also be prepared using sterile water or some other sterile injectable medium immediately before use.

[0598] Sterile injectable solutions are prepared by incorporating the required amount of one or more compounds of the present disclosure into a suitable solvent, optionally containing various other ingredients as listed above, followed by filtration and sterilization. Generally, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and other required ingredients from those listed above. For sterile powders for preparing sterile injectable solutions, typical preparation methods are vacuum drying and freeze-drying, which produce a powder of the active ingredient and any additional desired ingredients from a previously sterile-filtered solution. Thus, for example, a parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of the active ingredient in 10% by volume of propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.

[0599] Alternatively, the pharmaceutical compositions of the present disclosure can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the active ingredient with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0600] The pharmaceutical compositions of the present disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques known in the art of pharmaceutical formulation and may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, propellants such as fluorocarbons or nitrogen, and / or other conventional solubilizing or dispersing agents.

[0601] Formulations for buccal administration include tablets, lozenges, gels, and the like. Alternatively, buccal administration can be achieved using transmucosal delivery systems known to those skilled in the art. The compounds of the present disclosure can also be delivered through the skin or mucosal tissue using conventional transdermal drug delivery systems, i.e., transdermal "patches," in which the active ingredient is typically contained within a laminated structure that serves as a drug delivery device attached to a body surface. In such structures, the drug composition is typically contained in a layer, or "reservoir," beneath an upper backing layer. The laminated device may contain a single reservoir or multiple reservoirs. In certain embodiments, the reservoir comprises a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to attach the system to the skin during drug delivery. Examples of suitable skin contact adhesive materials include, but are not limited to, polyethylene, polysiloxane, polyisobutylene, polyacrylate, polyurethane, and the like.

[0602] Alternatively, the drug-containing reservoir and skin contact adhesive may be present as separate, distinct layers, with the adhesive underneath the reservoir, which may be a polymer matrix as described above, or a liquid or gel reservoir, or some other form. The backing layer in these laminates, which forms the top surface of the device, serves as the primary structural element of the laminate structure and provides the device with much of its flexibility. The material selected for the backing layer should be substantially impermeable to the active agent and any other materials present.

[0603] The compositions of the present disclosure can be formulated for aerosol administration, including intranasal administration, particularly to the respiratory tract. The compound can, for example, generally have a small particle size, for example, about 5 microns or less. Such particle size can be obtained by means known in the art, for example, by micronization. The active ingredient is provided in a pressurized pack with a suitable propellant, such as a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. The aerosol can conveniently also contain a surfactant, such as lecithin. The dose of drug can be controlled by a metered valve.

[0604] Alternatively, the active ingredient can be provided in the form of a dry powder, for example, a powder mixture of the compound in a suitable powder base, such as lactose, starch, starch derivatives, for example, hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form a gel in the nasal cavity. For example, the powder composition can be presented in unit dose form in, for example, gelatin capsules or cartridges, or blister packs from which the powder can be administered by inhaler.

[0605] Formulations suitable for rectal administration are typically presented as unit-dose suppositories, which may be prepared by admixing the active compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.

[0606] In certain embodiments, the pharmaceutical composition is suitable for topical application to the skin using the administration methods defined above.

[0607] In certain embodiments, pharmaceutical compositions are suitable for transdermal administration and can be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Formulations suitable for transdermal administration can also be delivered by iontophoresis (see, e.g., Pharmaceutical Research 3 (6):318 (1986)) and typically take the form of an optionally buffered aqueous solution of the active compound.

[0608] In certain embodiments, microneedle patches or devices are provided for the delivery of drugs across or into biological tissue, particularly the skin, which allow for drug delivery across or into the skin or other tissue barriers at clinically relevant rates with little or no damage, pain, or irritation to the tissue.

[0609] Formulations suitable for pulmonary administration can be delivered by a wide range of passively and actively powered single / multiple dose dry powder inhalers (DPIs). The most commonly used devices for respiratory delivery include nebulizers, metered dose inhalers, and dry powder inhalers. Several types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. The selection of a suitable pulmonary delivery device depends on parameters such as the properties of the drug and its formulation, the site of action, and the pathophysiology of the lungs.

[0610] In certain embodiments, an oral formulation is provided.

[0611] Example A Tablets of the following composition are prepared in the usual manner:

[0612] TIFF0007757284000333.tif52170

[0613] Manufacturing Procedure 1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water. 2. Dry the granules at 50°C. 3. Pass the granules through a suitable milling device. 4. Add ingredient 5, mix for 3 minutes and compress in a suitable press.

[0614] Example B-1 Capsules of the following composition are prepared:

[0615] TIFF0007757284000334.tif55170

[0616] Manufacturing Procedure 1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes. 2. Add ingredients 4 and 5 and mix for 3 minutes. 3. Fill into suitable capsules.

[0617] The compound of Formula I, II, III or IV, lactose and corn starch are mixed first in a mixer, then in a grinder. The mixture is returned to the mixer, talc is added thereto and mixed thoroughly. The mixture is filled into a suitable capsule, such as a hard gelatin capsule, by machine.

[0618] Example B-2 Soft gelatin capsules of the following composition are prepared:

[0619] TIFF0007757284000335.tif49170

[0620] TIFF0007757284000336.tif49170

[0621] Manufacturing Procedure The compound of Formula I, II, III or IV is dissolved in a warm melt of the other ingredients and the mixture is filled into appropriately sized soft gelatin capsules. The filled soft gelatin capsules are treated according to conventional procedures.

[0622] Example C Suppositories of the following composition are prepared:

[0623] TIFF0007757284000337.tif28170

[0624] Manufacturing Procedure The suppository mass is melted in a glass or steel container, thoroughly mixed, and cooled to 45°C. Immediately thereafter, the finely powdered compound of Formula I, II, III, or IV is added thereto and stirred until completely dispersed. The mixture is poured into a suitable suppository mold and allowed to cool. The suppositories are then removed from the molds and individually wrapped in wax paper or metal foil.

[0625] Example D An injection solution having the following composition is prepared.

[0626] TIFF0007757284000338.tif33170

[0627] Manufacturing Procedure A compound of Formula I, II, III, or IV is dissolved in a mixture of polyethylene glycol 400 and water for injection (partially). The pH is adjusted to 5.0 with acetic acid. The remaining amount of water is added to adjust the volume to 1.0 ml. The solution is filtered, filled into vials with appropriate overage, and sterilized.

[0628] Example E Sachets of the following composition are prepared:

[0629] TIFF0007757284000339.tif57170

[0630] Manufacturing Procedure A compound of Formula I, II, III or IV is mixed with lactose, microcrystalline cellulose and sodium carboxymethylcellulose and granulated with a mixture of polyvinylpyrrolidone in water. The granules are mixed with magnesium stearate and flavoring agents and filled into sachets.

[0631] VIII. Pharmacological Testing The compounds of formula I, II, III or IV and their pharmaceutically acceptable salts have valuable pharmacological properties. The compounds were investigated according to the tests set out below.

[0632] material NCI-H1975 (harboring an EGFR heterozygous T790M / L858R mutation) and NCI-H3255 (harboring an EGFR heterozygous L858R mutation) were purchased from ATCC and NCI, respectively. NCI-H1975+CS (harboring an EGFR heterozygous T / 790M / L858R / C797S mutation) was generated by Horizon Discovery using CRISPR technology to introduce the additional C797S mutation. RPMI 1640 phenol red-free medium and fetal bovine serum (FBS) were purchased from Gibco (Grand Island, NY, USA). Cell culture flasks and 384-well microplates were obtained from VWR (Radnor, PA, USA). The Total EGFR (L858R) HTRF assay kit was purchased from Cisbio (Bedford, MA, USA).

[0633] EGFR(L858R) decomposition analysis Degradation of EGFR protein carrying the L858R mutation was determined based on FRET signal quantification using a Total EGFR (L858R) HTRF assay kit. Test compounds were added to a 384-well plate in duplicate at an 11-point half-log titration starting from a top concentration of 10 μM. NCI-H1975, NCI-H1975+CS, or NCI-H3255 cells were added to a 384-well plate at a cell density of 10,000, 10,000, or 1,000 cells per well, respectively. The plate was maintained at 37°C and 5% CO2 for 6 hours. Cells treated without test compound served as a negative control. A positive control was set up by wells containing all reagents but no cells. FRET signals were acquired using an EnVision™ Multilabel Reader (PerkinElmer, Santa Clara, CA, USA).

[0634] TIFF0007757284000340.tif191170TIFF0007757284000341.tif191170TIFF0007757284000342.tif247170TIFF0007757284000343.tif246170TIFF0007757284000344.tif182170TIFF0007757284000345.tif245170TIFF0007757284000346.tif200170TIFF0007757284000347.tif189170TIFF0007757284000348.tif182170TIFF0007757284000349.tif190170TIFF0007757284000350.tif245170TIFF0007757284000351.tif224170TIFF0007757284000352.tif243170TIFF0007757284000353.tif195170TIFF0007757284000354.tif203170TIFF0007757284000355.tif220170TIFF0007757284000356.tif177170TIFF0007757284000357.tif208170TIFF0007757284000358.tif188170TIFF0007757284000359.tif220170TIFF0007757284000360.tif193170TIFF0007757284000361.tif206170TIFF0007757284000362.tif224170TIFF0007757284000363.tif231170TIFF0007757284000364.tif188170TIFF0007757284000365.tif202170TIFF0007757284000366.tif201170TIFF0007757284000367.tif206170

[0635] TIFF0007757284000368.tif199170TIFF0007757284000369.tif198170TIFF0007757284000370.tif185170TIFF0007757284000371.tif210170TIFF0007757284000372.tif199170TIFF0007757284000373.tif198170TIFF0007757284000374.tif212170TIFF0007757284000375.tif207170TIFF0007757284000376.tif201170TIFF0007757284000377.tif203170TIFF0007757284000378.tif182170TIFF0007757284000379.tif219170TIFF0007757284000380.tif205170TIFF0007757284000381.tif206170TIFF0007757284000382.tif200170TIFF0007757284000383.tif201170TIFF0007757284000384.tif200170TIFF0007757284000385.tif199170TIFF0007757284000386.tif222170TIFF0007757284000387.tif195170TIFF0007757284000388.tif213170TIFF0007757284000389.tif209170TIFF0007757284000390.tif205170TIFF0007757284000391.tif191170TIFF0007757284000392.tif203170TIFF0007757284000393.tif199170TIFF0007757284000394.tif205170TIFF0007757284000395.tif206170TIFF0007757284000396.tif204170TIFF0007757284000397.tif203170TIFF0007757284000398.tif217170TIFF0007757284000399.tif201170TIFF0007757284000400.tif210170TIFF0007757284000401.tif200170TIFF0007757284000402.tif198170TIFF000 7757284000403.tif203170TIFF0007757284000404.tif217170TIFF0007757284000405.ti f207170TIFF0007757284000406.tif208170TIFF0007757284000407.tif212170TIFF00077 57284000408.tif193170TIFF0007757284000409.tif189170TIFF0007757284000410.tif20 5170TIFF0007757284000411.tif220170TIFF0007757284000412.tif217170TIFF00077572 84000413.tif218170TIFF0007757284000414.tif215170TIFF0007757284000415.tif2121 70TIFF0007757284000416.tif204170TIFF0007757284000417.tif211170TIFF0007757284 000418.tif220170TIFF0007757284000419.tif219170TIFF0007757284000420.tif209170.

[0636] In the table above, *** is less than 50 nM, ** is 50nM to 150nM, * is over 150nM.

[0637] IX. Synthesis method Compounds of Formula I, II, III, or IV may contain one or more asymmetric centers and may occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Additional asymmetric centers may exist depending on the nature of the various substituents on the molecule. Each such asymmetric center independently gives rise to two optical isomers, and all possible optical isomers and diastereomers, in mixtures and as pure or partially purified compounds, are intended to be included in the present invention. The present invention is intended to encompass all such isomeric forms of these compounds. The independent syntheses of these diastereomers or their chromatographic separations can be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry can be determined by x-ray crystallography of crystalline products or crystalline intermediates that are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds can be separated and the individual enantiomers isolated. Resolution can be achieved by methods known in the art, for example, by coupling a racemic mixture of a compound to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods such as fractional crystallization or chromatography.

[0638] In embodiments in which optically pure enantiomers are provided, optically pure enantiomer means that the compound contains greater than 90% by weight of the desired isomer, particularly greater than 95% by weight or more particularly greater than 99% by weight of the desired isomer, where the weight percentage is based on the total weight of the isomer(s) of the compound. Chirally pure or chirally enriched compounds can be prepared by chirally selective synthesis or by separation of enantiomers. Separation of enantiomers can be carried out on the final product or, alternatively, on a suitable intermediate.

[0639] The preparation of compounds of formula I is further illustrated in more detail in the following schemes. [ka]

[0640] Generally, the order of steps used in the synthesis of compounds of formula I may also be varied in certain cases.

[0641] The preparation of compounds of formula II is further illustrated in more detail in the following scheme. [ka] TIFF0007757284000423.tif84170

[0642] In general, the order of steps used in the synthesis of compounds of formula I may also be modified in certain cases, and in certain cases the order of steps shown for formula I or formula II may be applied to or modified for the synthesis of compounds of formula III and formula IV.

[0643] Compound isolation and purification Isolation and purification of the compounds and intermediates described herein can be achieved, if desired, by any suitable separation or purification procedure, such as filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick-layer chromatography, preparative low-pressure or high-performance liquid chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be found in the preparations and examples herein below. However, it should be understood that other equivalent separation or isolation procedures may also be used. Racemic mixtures of chiral compounds of Formula I, II, III, or IV can be separated using chiral HPLC. Racemic mixtures of chiral synthetic intermediates can also be separated using chiral HPLC.

[0644] Salts of compounds of formula I, II, III or IV If the compound of Formula I, II, III, or IV is basic, it can be converted to the corresponding acid addition salt. This conversion is accomplished by treatment with at least a stoichiometric amount of an appropriate acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or an organic acid, such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, or the like. A specific salt is the fumarate salt. Typically, the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol, or methanol, and the acid in a similar solvent is added. The temperature is maintained between 0°C and 50°C. The resulting salt precipitates spontaneously or can be brought out of solution with a less polar solvent.

[0645] Compounds of Formula I, II, III, or IV and all intermediates, unless their preparation is described in the examples, can be prepared by analogous methods or according to the methods described herein. Starting materials are commercially available, known in the art, or can be prepared by or analogous to methods known in the art.

[0646] It will be appreciated that the compounds of general formula I, II, III or IV in this invention may be derivatized at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo.

[0647] X. Experimental Procedure Abbreviation

[0648] TIFF0007757284000424.tif235170TIFF0007757284000425.tif241170TIFF00077572840 00426.tif242170TIFF0007757284000427.tif243170TIFF0007757284000428.tif138170

[0649] Synthesis Example The following examples are presented to illustrate the invention and should not be construed as limiting the scope of the invention, but merely as representative thereof.

[0650] Intermediates Scheme 1: [ka] Basic Procedure A To a mixture of 1-1 (1 mmol) and 1-2 (2 mmol) in dioxane (3 mL) was added N,N-diisopropylethylamine (2 mmol). The resulting solution was heated in a sealed tube at 70°C to 110°C for 24 hours to produce 1-3. The reaction mixture was then cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica, gradient: 0% to 3% methanol in dichloromethane) to give 1-3.

[0651] Intermediate tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-1-carboxylate [ka] tert-Butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-1-carboxylate was synthesized from tert-butyl 4-(4-aminophenyl)-1-piperidinecarboxylate (CAS number 170011-57-1) according to general procedure A (N,N-diisopropylethylamine / dioxane). Yield: 45%. 1H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 6.94 (d, J = 8.16 Hz, 2H), 6.60 (d, J = 7.88 Hz, 2H), 5.64 (d, J = 6.96 Hz, 1H), 4.28-4.24 (m, 1H), 4.07-4.00 (m, 2H), 2.79-2.64 (m, 4H), 2.53-2.48 (m, 2H), 2.11-2.05 (m, 1H), 1.89-1.81 (m, 1H), 1.71-1.64 (m, 2H0, 1.40-1.34 (m, 10H); LC MS: ES+ 386.3.

[0652] Intermediate 3-((3-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride [ka] tert-Butyl 4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-1-carboxylate was synthesized from tert-butyl 4-[3-aminophenyl]-1-piperidinecarboxylate (CAS number 387827-19-2) according to general procedure A. Yield: 25%. LCMS (ESI+): 388.2 (M+H).

[0653] Intermediate 3-((6-(piperidin-4-yl)pyridin-3-yl)amino)piperidine-2,6-dione hydrochloride [ka] tert-Butyl 4-(5-((2,6-dioxopiperidin-3-yl)amino)pyridin-2-yl)piperidine-1-carboxylate was synthesized from tert-butyl 4-(5-aminopyridin-2-yl)piperidine-1-carboxylate (CAS number 885693-48-1) according to the general procedure: yield: 14%, LCMS (ESI+): 389.2 (M+H).

[0654] Scheme 2: [ka] Basic Procedure B: To 2-1 dissolved in methanol (0.1 M) at room temperature was added hydrogen chloride (4 M in 1,4-dioxane, 5 equivalents) and the reaction mixture was heated at 40° C. for 2 hours. The volatiles were evaporated under reduced pressure to give 2-2.

[0655] Intermediate 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride [ka] 3-((4-(Piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride was synthesized from tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-1-carboxylate according to the general procedure (General Procedure-B). Yield -88%; 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.84 (brs, 1H), 8.77 (brs, 1H), 6.95 (d, J = 8.44 Hz, 2H), 6.66 (d, J = 8.48 Hz, 2H), 4.29 (dd, J = 11.4, 4.72 Hz, 1H), 3.35-3.29 (m, 2H), 2.99-2.91 (m, 2H), 2.71-2.53 (m, 3H), 2.10-2.05 (m, 1H), 1.89-1.71 (m, 5H); LC MS: ES+ 288.2.

[0656] Intermediate 3-((3-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride [ka] 3-((3-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride was synthesized from tert-butyl 4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-1-carboxylate according to general procedure B. Yield: 76% 1 H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 9.00 (br.s, 1H), 8.85 (br. S, 1H), 1.02 (t, J = 7.6 Hz, 1H), 6.57-6.55 (m, 2H), 6.47 (d, J = 7.6 Hz, 1H), 4.32 (dd, J = 11.2 Hz, 4.6 Hz, 1H), 3.45-3.39 (m, 2H), 2.80-2.65 (m, 2H), 2.79-2.67 (m, 2H), 2.61-2.53 (M, 1H), 2.11-2.07 (m, 1H), 1.94-1.80 (m, 5H). LCMS (ESI+): 288.2 (M+H).

[0657] Intermediate 3-((6-(piperidin-4-yl)pyridin-3-yl)amino)piperidine-2,6-dione hydrochloride [ka] 3-((6-(piperidin-4-yl)pyridin-3-yl)amino)piperidine-2,6-dione hydrochloride was synthesized from tert-butyl 4-(5-((2,6-dioxopiperidin-3-yl)amino)pyridin-2-yl)piperidine-1-carboxylate according to general procedure B. Yield: 83%, LCMS (ESI+): 289.0 (M+H).

[0658] Synthesis of intermediates tert-butyl 4-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]phenyl]piperidine-1-carboxylate and tert-butyl 4-[4-[[(3R)-2,6-dioxo-3-piperidyl]amino]phenyl]piperidine-1-carboxylate by chiral SFC separation [ka] Separation of tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperidine-1-carboxylate (4 g, 10.32 mmol) by chiral SFC gave two sets of fractions.

[0659] The enantiomers were separated using the following preparative-scale SFC method: Column: Chiralpak ID (250×21mm) 5μm Flow rate: 35g / min Mobile phase: 45% CO2 + 55% isopropyl alcohol ABPR: 100 bar Temperature: 35℃

[0660] The early fraction was lyophilized to give tert-butyl 4-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]phenyl]piperidine-1-carboxylate (1.44 g, 3.70 mmol, 35.88% yield, 99.66% enantiomeric excess, chiral SFC Rt=4.31 min). 1 H NMR (400 MHz,DMSO-D6) δ 10.77 (s, 1H), 6.94 (d, J=8.1 Hz, 2H), 6.60 (d, J=8.2 Hz, 2H), 5.68-5.66 (m, 1H), 4.29-4.23 (m, 1H), 4.05-4.02 (m, 2H), 2.78-2.54 (m, 5H), 2.11-2.07 (m, 1H), 1.89-1.83 (m, 1H), 1.69-1.66 (m, 2H), 1.40-1.36 (m 11H).

[0661] The remaining fractions were lyophilized to give tert-butyl 4-[4-[[(3R)-2,6-dioxo-3-piperidyl]amino]phenyl]piperidine-1-carboxylate (1.56 g, 3.95 mmol, 38.24% yield, 98.06% enantiomeric excess, chiral SFC Rt = 5.96 min). 1H NMR (400 MHz,DMSO-D6) δ 10.77 (s, 1H), 6.94 (d, J=8.2 Hz, 2H), 6.60 (d, J=8.3 Hz, 2H), 5.68-5.66 (m, 1H), 4.29-4.23 (m, 1H), 4.05-4.02 (m, 2H), 2.78-2.58 (m, 5H), 2.11-2.07 (m, 1H), 1.87-1.83 (m, 1H), 1.70-1.67 (m, 2H), 1.40-1.35 (m 11H).

[0662] Synthesis of 2-[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]phenyl]-1-piperidyl]acetic acid trifluoroacetate and 2-[4-[4-[[(3R)-2,6-dioxo-3-piperidyl]amino]phenyl]-1-piperidyl]acetic acid trifluoroacetate tert-Butyl 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetate [ka] To a stirred solution of 3-[4-(4-piperidyl)anilino]piperidine-2,6-dione (2.0 g, 6.96 mmol) in DMF (20 mL) was added triethylamine (3.52 g, 34.80 mmol, 4.85 mL), followed by tert-butyl 2-bromoacetate (1.49 g, 7.66 mmol, 1.12 mL), and the reaction mixture was stirred at rt for 16 h. Water (75 mL) was added, and the product was extracted with ethyl acetate (3 × 150 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 30% ethyl acetate-pet ether as eluent to give tert-butyl 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetate (1.40 g, 3.36 mmol, 48.33% yield) as a green solid.

[0663] SFC separation conditions to obtain tert-butyl (S)-2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetate and tert-butyl (R)-2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl] [ka] The racemic intermediate tert-butyl 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetate (1.40 g, 3.36 mmol) was resolved using chiral SFC on a Chiralcel OD-H column (250 mm × 30 mm; 5 microns) eluted with 40% isopropyl alcohol / CO (flow rate: 3 ml / min; outlet pressure: 100 bar). The first set of eluting fractions was evaporated under reduced pressure to give tert-butyl (S)-2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetate (500 mg, 36% yield, Rt = 3.36 min, 96.22% purity, >99% enantiomeric excess). The second set of fractions was evaporated under reduced pressure to give 500 mg of tert-butyl (R)-2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetate (500 mg, 36% yield, Rt = 4.84 min, 96.22% purity, 99.04% enantiomeric excess). LCMS: first eluting (m / z: 402.4 [M+H]), second eluting (m / z: 402.2 [M+H]).

[0664] 2-[4-[4-[[(3S)-2,6-Dioxo-3-piperidyl]amino]phenyl]-1-piperidyl]acetic acid trifluoroacetate [ka] tert-Butyl 2-[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]phenyl]-1-piperidyl]acetate (500 mg, 1.25 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (12.26 g, 107.51 mmol, 8 mL) was added dropwise at 0 °C, and the reaction was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated. The material was triturated with a 1:4 mixture of methanol and MTBE, the solid was collected, and the volatiles were evaporated under reduced pressure to give 2-[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]phenyl]-1-piperidyl]acetic acid trifluoroacetate (600 mg, 1.24 mmol, 99.6% yield) as an off-white solid. LCMS(ESI+):346.1(M+H)

[0665] 2-[4-[4-[[(3R)-2,6-Dioxo-3-piperidyl]amino]phenyl]-1-piperidyl]acetic acid:trifluoroacetate [ka] tert-Butyl 2-[4-[4-[[(3R)-2,6-dioxo-3-piperidyl]amino]phenyl]-1-piperidyl]acetate (500.00 mg, 1.25 mmol) was treated in a similar manner to 2-[4-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]phenyl]-1-piperidyl]acetic acid trifluoroacetate to give 2-[4-[4-[[(3R)-2,6-dioxo-3-piperidyl]amino]phenyl]-1-piperidyl]acetic acid trifluoroacetate (600 mg, 1.24 mmol, 99.63% yield) as an off-white solid. LCMS (ESI+): 346.1 (M+H).

[0666] Synthesis of intermediate 3-(3-fluoro-4-piperidin-4-yl-phenylamino)-piperidine-2,6-dione hydrochloride [ka] Step-1: Preparation of 4-(4-amino-2-fluoro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester [ka] Sodium carbonate (6.14 g, 57.89 mmol, 2.43 mL) was added to a stirred solution of 4-bromo-3-fluoroaniline (5.00 g, 26.3 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (8.95 g, 29.0 mmol) in water (12 mL), THF (60 mL), and methanol (24 mL), and the flask was thoroughly purged with argon. PdCl(dppf)·dichloromethane (430 mg, 526 μmol) was added, and the reaction mixture was degassed with nitrogen and then heated at 80 °C for 12 h. The reaction mixture was diluted with ethyl acetate, filtered through a short pad of Celite, and washed with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (15% ethyl acetate-hexane) to give tert-butyl 4-(4-amino-2-fluoro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (6.1 g, 20.9 mmol, 79% yield) as a pale yellow solid. LCMS: ESI+ 293 (M+Hs)

[0667] Step-2: Preparation of 4-[4-(2,6-bis-benzyloxy-pyridin-3-ylamino)-2-fluoro-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester: [ka] Cesium carbonate (19.73 g, 60.54 mmol) was added to a stirred solution of tert-butyl 4-(4-amino-2-fluorophenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (5.9 g, 20.2 mmol) and 2,6-dibenzyloxy-3-iodo-pyridine (9.26 g, 22.2 mmol) in t-BuOH (60 mL). The resulting mixture was degassed with argon, and Pd(dba) (924 mg, 1.01 mmol) and Ruphos (942 mg, 2.02 mmol) were added under an inert atmosphere. The resulting mixture was heated at 100 °C for 18 h. The reaction mixture was diluted with ethyl acetate, filtered through a short pad of Celite, and washed with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filter...

Claims

1. Formula III: (In the formula, A ＊ teeth, and B ＊ teeth, and y is 0, 1, 2 or 3; R ３１ In each case, H, F, Cl, C １～６ -Alkyl, cyano, C １～６ -alkoxy, halo-C １～６ -alkoxy, halo-C １～６ -Alkyl, C ３～８ -cycloalkyl and halo-C ３～８ -cycloalkyl, which, when present on a bicyclic ring, may be located on either ring; R ３２ are hydrogen, F, Cl, C １～６ -Alkyl, halo-C １～６ -Alkyl, C ３～８ -cycloalkyl or halo-C ３～８ -cycloalkyl, R ３３ are hydrogen, F, Cl, C １～６ -Alkyl, halo-C １～６ -Alkyl, C ３～８ -cycloalkyl or halo-C ３～８ -cycloalkyl, optionally located on the dihydropyrrole or imidazole ring; R ３４ is H, F, C １～６ -Alkyl, halo-C １～６ -Alkyl, C ３～８ -cycloalkyl and halo-C ３～８ -cycloalkyl; R ３５ are H, F, Cl, C １～６ -Alkyl, halo-C １～６ -Alkyl and C ３～８ -cycloalkyl; or R ３４ and R ３５ and bond to form -(CH ２ ) ｑ - forms, q is 1 or 2; R ３６ and R ３７ are independently H, F, Cl, cyano, C １～６ -alkoxy, halo-C １～６ -alkoxy, C １～６ -Alkyl, halo-C １～６ -Alkyl, C ３～８ -cycloalkyl and halo-C ３～８ -cycloalkyl; or R ３６ and R ３７ and are bonded together to form one, two or three R ３１ forming a 5- or 6-membered ring optionally substituted with substituents, A ２１ is -NH-, -O-, -CH ２ -or-NR １００ - and R １００ is alkyl, cycloalkyl, aryl, or heteroaryl, or, to the extent valence allows, R １００ is R ３７ may be joined to form a 5- to 8-membered heterocycle or a 5-membered heteroaryl; A ３２ and A ３３ are independently —N— and —CR ４２ - is selected from, R ４２ In each case, H, F, Cl, cyano, C １～６ -alkoxy, halo-C １～６ -alkoxy, C １～６ -Alkyl, halo-C １～６ -Alkyl, C ３～８ -cycloalkyl and halo-C ３～８ -cycloalkyl; L ２ is the formula: (In the formula, X １ and X ２ are independently, in each occurrence, a bond, a heterocycle, an aryl, a heteroaryl, a bicycle, an alkylene, -NR ２７ -, -CR ４０ R ４１ -, -O-, -C(O)-, -C(NR ２７ )-, -C(S)-, -S(O)-, -S(O) ２ - and -S-, wherein each of the heterocycle, aryl, heteroaryl and bicycle is selected from R ４０ optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ２０ , R ２１ , R ２２ , R ２３ and R ２４ are independently in each case a bond, alkylene, —C(O)—, —C(O)O—, —OC(O)—, or —SO ２ -, -S(O)-, -C(O)NR ２７ -, -NR ２７ C(O)-, -O-, -S-, -NR ２７ -, oxyalkylene, -C(R ４０ R ４０ )-, bicyclic, alkene, alkyne, aryl, heterocyclic, heteroaryl, and carbocyclic ring, each of which is selected from the group consisting of R ４０ optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ２７ is independently selected at each occurrence from the group consisting of hydrogen, alkyl, heterocycle, aryl, heteroaryl, —C(O)(alkyl, aryl, or heteroaryl), —C(O)O(alkyl, aryl, or heteroaryl), alkene, and alkyne; R ４０ are independently in each case hydrogen, R ２７ , alkyl, alkene, alkyne, fluoro, chloro, hydroxyl, alkoxy, azido, amino, cyano, -NH(alkyl), -N(alkyl) ２ , -NHSO ２ (alkyl), -N(alkyl)SO ２ Alkyl, -NHSO ２ (aryl, heteroaryl or heterocyclic ring), —N(alkyl)SO ２ (aryl, heteroaryl or heterocyclic ring), —NHSO ２ Alkenyl, -N(alkyl)SO ２ Alkenyl, —NHSO ２ Alkynyl, -N(alkyl)SO ２ alkynyl, haloalkyl, aryl, heteroaryl, heterocycle, oxo, and cycloalkyl; or, where valence allows, two R bonded to the same carbon. ４０ the groups may together form a 3- to 8-membered spiro ring; R ４１ is alkyl, aryl, heteroaryl, or hydrogen), or a pharmaceutically acceptable salt thereof.

2. The compound is wherein B is a ring system AD and AE (selected from 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from:

3. The compound is 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

4. The compound has the formula 2. The compound of claim 1, wherein:

5. The compound has the formula 2. The compound of claim 1, wherein:

6. A ２１ The compound of claim 5, wherein is -NH-.

7. The compound has the formula 2. The compound of claim 1, wherein:

8. R ３３ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein is H.

9. R ３３ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein

10. 5. The compound of claim 1, 3, or 4, wherein y is 1, or a pharmaceutically acceptable salt thereof.

11. 5. The compound of claim 1, 3, or a pharmaceutically acceptable salt thereof, wherein y is 2.

12. At least one R ３１ The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein is halo.

13. At least one R ３１ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein

14. 5. The compound according to any one of claims 1, 3 and 4, wherein y is 0, or a pharmaceutically acceptable salt thereof.

15. R ３２ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein is H.

16. R ３２ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein

17. A ２１ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein is NH.

18. A ３２ 6. The compound according to any one of claims 1 to 3 and 5, or a pharmaceutically acceptable salt thereof, wherein is CH.

19. A ３３ 6. The compound according to any one of claims 1 to 3 and 5, or a pharmaceutically acceptable salt thereof, wherein is CH.

20. A ３３ The compound according to any one of claims 1 to 3 and 5, or a pharmaceutically acceptable salt thereof, wherein

21. R ３４ The compound of any one of claims 1 to 3 and 5, or a pharmaceutically acceptable salt thereof, wherein

22. R ３５ The compound of any one of claims 1 to 3 and 5, or a pharmaceutically acceptable salt thereof, wherein

23. R ４２ In each case, H, F, Cl and C １～６ 6. The compound of any one of claims 1 to 3 and 5, or a pharmaceutically acceptable salt thereof, wherein each of the groups is independently selected from: - alkyl.

24. B ＊ but, 5. The compound of claim 1 or 4, wherein:

25. B ＊ but, 5. The compound of claim 1 or 4, wherein:

26. B ＊ but, 5. The compound of claim 1 or 4, wherein:

27. B ＊ but, 5. The compound of claim 1 or 4, wherein:

28. L ２ is the formula:

8. The compound according to any one of claims 1 to 3 and 7, or a pharmaceutically acceptable salt thereof, which is

29. X １ and X ２ 30. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein is independently a bond, a heterocycle, NR27, or C(O).

30. R ２０ , R ２１ , R ２２ , R ２３ and R ２４ are independently bonded, CH ２ 29. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein R is a heterocyclic, aryl, or bicyclic ring.

31. R ２０ , R ２１ , R ２２ , R ２３ and R ２４ 30. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein is independently phenyl.

32. Linker L ２ is the formula:

29. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein the linker is

33. Linker L ２ is the formula:

29. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein the linker is

34. R ２４ 29. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein is C(O).

35. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from:

36. The compound is 36. The compound of claim 35, wherein:

37. The compound is 36. The compound of claim 35, wherein:

38. The compound is 36. The compound of claim 35, wherein:

39. The compound is 36. The compound of claim 35, wherein:

40. The compound is 36. The compound of claim 35, wherein:

41. The compound is 36. The compound of claim 35, wherein:

42. The compound is 36. The compound of claim 35, wherein:

43. 43. A pharmaceutical composition comprising a compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, and an excipient, for the treatment of an EGFR-mediated disorder in a human patient.

44. 44. The pharmaceutical composition of claim 43, wherein the EGFR-mediated disorder is cancer, tumor, or abnormal cell proliferation.

45. 45. The pharmaceutical composition of claim 44, wherein the EGFR-mediated disorder is cancer.

46. 45. The pharmaceutical composition of claim 44, wherein the EGFR-mediated disorder is a tumor.

47. 45. The pharmaceutical composition of claim 44, wherein the EGFR-mediated disorder is abnormal cell proliferation.

48. 46. ​​The pharmaceutical composition of claim 45, wherein the cancer is lung cancer.

49. 49. The pharmaceutical composition of claim 48, wherein the lung cancer is non-small cell lung cancer.

50. 45. The pharmaceutical composition of claim 44, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with at least one mutation.

51. 51. The pharmaceutical composition of claim 50, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with an L858R mutation.

52. 51. The pharmaceutical composition of claim 50, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with a T790M mutation.

53. 51. The pharmaceutical composition of claim 50, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with a C797S mutation.

54. 51. The pharmaceutical composition of claim 50, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with an L792H mutation.

55. 51. The pharmaceutical composition of claim 50, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with an L718Q mutation.

56. 51. The pharmaceutical composition of claim 50, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with a T790M / L858R mutation.

57. 51. The pharmaceutical composition of claim 50, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with a T790M / L858R / C797S mutation.

58. 51. The pharmaceutical composition of claim 50, wherein the cancer, tumor or abnormal cell growth has an EGFR protein with a L858R / C797S mutation.

59. The compound has the structure or a pharmaceutically acceptable salt thereof.

60. The compound has the structure or a pharmaceutically acceptable salt thereof.

61. The compound has the structure or a pharmaceutically acceptable salt thereof.

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