EGFR degraders for treating cancer metastasis to the brain or CNS

Abstract

The present invention provides for the treatment of mutant epidermal growth factor receptor (EGFR)-mediated cancers that have metastasized to the brain or other regions of the central nervous system with compounds that degrade mutant forms of EGFR by ubiquitination and subsequent proteasomal degradation of the EGFR protein. The present invention also provides advantageous drug combinations for the treatment of such cancers that include compounds herein that degrade mutant forms of EGFR in combination with a second anti-cancer agent.

Description

[Technical Field]

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 193,574, filed May 26, 2021, and U.S. Provisional Patent Application No. 63 / 270,488, filed October 21, 2021, which are incorporated herein by reference in their entireties.

[0002] The present invention provides for the treatment of mutant epidermal growth factor receptor (EGFR)-mediated cancers that have metastasized to the brain or other regions of the central nervous system with compounds that degrade mutant forms of EGFR through ubiquitination and subsequent proteasomal degradation of the EGFR protein. The present invention also provides advantageous drug combinations for the treatment of such cancers that include a compound herein that degrades mutant forms of EGFR in combination with a second anti-cancer agent. [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™) and gefitinib (IRESSA™) are first-generation reversible inhibitors of EGFR tyrosine kinase that have been approved for the treatment of recurrent NSCLC in many countries. Osimertinib (TAGRISSO™) is an irreversible inhibitor of EGFR tyrosine kinase and has been approved for the first-line treatment of NSCLC in many countries (Non-Patent Document 3).

[0004] The most common somatic mutations in EGFR are deletions in exon 19 and amino acid substitutions in exon 21. The most common exon 19 deletion is Δ746-750, and the most common exon 21 amino acid substitution is L858R (Non-Patent Document 4).

[0005] After treatment with first-generation EGFR inhibitors, treatment resistance frequently occurs and is often due to a secondary T790M mutation in the ATP-binding site of the receptor. Osimertinib, a mutant-selective irreversible inhibitor, exhibits high activity against T790M mutants, but its efficacy can be impaired by an acquired mutation at C797S, the cysteine ​​residue to which osimertinib forms a critical covalent bond (Non-Patent Document 5). Wang further reported that the C797S mutation is the primary mechanism of resistance to EGFR inhibitors targeting T790M (Non-Patent Document 6). Yang et al. have described additional mutations, such as L718Q, that cause resistance to osimertinib (Non-Patent Document 7). EGFR in NSCLC Treatment L858R-T790M and EGFR L858R-T790M-C797S Strategies for targeting additional mutations, including targeting resistance mutations, 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 in U.S. Patent No. 5,629,292; U.S. Patent No. 5,629,293; U.S. Patent No. 5,629,294; U.S. Patent No. 5,629,295; and Non-Patent Document 9.

[0007] All approved EGFR inhibitors target the ATP-binding site of the kinase. Because secondary mutations that cause resistance to ATP-competitive EGFR inhibitors are located in the ATP-binding site, new therapeutic agents that work differently are needed to overcome resistance to current therapies, for example, by highly selective targeting of 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) Co. Ltd. in U.S. Patent Nos. 5,617,149 and 5,733,522; by Arvinas, Inc. in U.S. Patent Nos. 5,617,159, 5,733,160, 5,745,176, 5,757,180, 5,769,200, and 5,775,522; by Dana-Farber Cancer Institute in U.S. Patent Nos. 5,757,180, 5,769,190, 5,775,200, 5,785,210, 5,795,220, 5,795,230, 5,795,240, 5,795,250, 5,795,260, 5,795,270, 5,795,280, 5,795,290, 6,800, 6,800, 6,810, 6,820, 6,830, 6,840, 6,850, 6,860, 6,870, 6,880, 6,890, 7,910, 7,920, 7,930, 7,940, 7,950, 7,960, 7,970, 7,980, 7,990, 8,910, 8,102, 8,103, 8,104, 8,105, 8,110, 8,111, 8,112, 8,113, 8,114, 8,115,

[0012] Several specific molecules for the degradation of EGFR have also been described, for example, Dana-Farber Cancer Institute describes an EGFR degrader in U.S. Patent No. 4,629,999. F. Hoffman-La-Roche describes an EGFR degrader in U.S. Patent No. 4,629,999 and U.S. Patent No. 4,629,999. Arvinas, Inc. describes an EGFR degrader in U.S. Patent No. 4,629,999. Additional EGFR degraders are described by Jang et al. in Non-Patent Document 12. [Prior art documents] [Patent documents]

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[0014] [Non-Patent Document 1] Yarden, Y., Sliwkowski, MX. Untangling the ErbB signaling network. Nature Review Mol Cell Biol. 2001 Feb;2(2): 127-37

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Non-licensed literature 9

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Non-licensed Document 12

[0015] Despite these efforts, there remains a need for new EGFR modulators to treat disorders mediated by EGFR in hosts in need of treatment, particularly humans, due to life-threatening cancers that exhibit mutations and / or overexpression of EGFR. [Means for solving the problem]

[0016] Methods for treating EGFR-mediated cancer that has metastasized to the brain or central nervous system, e.g., the peripheral nervous system, cerebrospinal fluid, spinal cord, leptomeninges, epidural space, and / or dura mater, are provided, comprising administering to a patient in need of treatment an effective amount of a compound of Formula I, Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt thereof. The compounds of Formula I, Formula II, Formula III, and Formula IV comprise 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 2 and the remainder of the molecule is the EGFR targeting ligand portion.

[0017] The EGFR-targeting ligand may be an allosteric inhibitor. Allosteric binding prior to degradation provides advantages over conventional EGFR inhibitors, covalent modulators, and even non-allosteric degraders. Non-limiting examples of advantages of using the allosteric degradation compounds described herein include increased selectivity for mutant EGFRs, increased catalytic activity, improved efficacy, the ability to overcome resistance to ATP-competitive inhibitors, and / or reduced side effects. In certain embodiments, the allosteric degradation compounds of the present invention effectively bind and degrade EGFRs with mutations that confer resistance to osimertinib and / or erlotinib, such as mutations that replace the active site cysteine ​​with another amino acid. Due to these advantages, the compounds described herein can be used for the treatment of cancers that have metastasized to the brain or CNS and developed resistance to osimertinib (e.g., second-line therapy or treatment of non-small cell lung cancer). In other embodiments, the compounds described herein can be used to treat treatment-naive cancers that have metastasized to the brain or CNS (e.g., first-line therapy or treatment for non-small cell lung cancer). In other embodiments, the compounds described herein can be used to treat cancers that have metastasized to the brain or CNS and have developed resistance to multiple therapies (e.g., third-line therapy or treatment for non-small cell lung cancer).

[0018] In other embodiments, the EGFR targeting ligand may be an active site inhibitor.

[0019] In certain embodiments, provided methods selectively degrade EGFR in tumors that metastasize to the brain or CNS and may have 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 methods use selective degraders of EGFR mutants having L858R-T790M, L858R-T790M-C797S, L858R, or L858R-C797S.

[0020] In certain embodiments, methods are provided for treating EGFR-mediated cancer that has metastasized to the brain or CNS, comprising administering to a patient in need thereof an effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, or Compound 12, or a pharmaceutically acceptable salt thereof. These compounds are allosteric site-binding EGFR degraders (allosteric EGFR degraders). [ka] TIFF2024521791000003.tif195170TIFF2024521791000004.tif197170TIFF2024521791000005.tif197170

[0021] High concentrations of the allosteric EGFR degraders described herein cross the blood-brain barrier. Additionally, compounds described herein, including, for example, Compound 1, are highly selective, degrading mutant EGFR-L858R proteins without appreciably degrading other non-EGFR proteins. In kinome screening (see Example 60 and Figures 13A and 13B), the compounds described herein exhibited negligible binding to hundreds of proteins. Furthermore, similarly high selectivity was observed in global proteomics (see Example 61 and Table 14). Furthermore, the compounds described herein have very low activity in degrading SALL4 and GSPT1, two proteins degraded by IMID compounds such as lenalidomide and CC-885 (see Figures 7 and 8). In the NCI-H1975 (EGFR-L858R-T790M) and NCI-H3255 (EGFR-L858R) human lung cancer lines, 50% degradation of mutant EGFR was achieved in 6 hours using nanomolar concentrations of the allosteric EGFR degrader (see Table 9A). In addition, EGFR phosphorylation was potently inhibited (see Table 10A). In contrast, the allosteric EGFR degrader described herein did not achieve 50% degradation or phospho-EGFR inhibition up to a concentration of 10 μM in the human wild-type EGFR cell line A431. Additionally, the allosteric EGFR degraders described herein inhibit the growth of modified BaF3 cells expressing EGFR mutants, including the L858R, L858R-C797S, L858R-T790M, or L858R-T790M-C797S EGFR mutants, with GI values ​​ranging from 8 nM to 16 nM, compared to a GI of 486 nM in BaF3 cells expressing wild-type EGFR (see Table 10B).

[0022] Oral administration of Compound 1 or Compound 2 was well tolerated in mice. Treatment with Compound 1 in an NCI-H1975 mouse xenograft model resulted in dose-dependent activity and up to 90% tumor regression (see Figure 1). In addition, up to 85% of mutant EGFR was degraded in vivo after a single oral administration of Compound 1, and phospho-EGFR was reduced by more than 95% (see Figures 2A and 2B). In an osimertinib-resistant modified BaF3 EGFR-L858R-T790M-C797S allograft mouse model, oral administration of Compound 1 resulted in 60% tumor regression, in contrast to osimertinib treatment, which showed minimal efficacy (see Figure 3). In a luciferase-expressing NCI-H1975 intracranial model of brain metastasis, oral administration of Compound 1 resulted in tumor regression (see Figure 5A). Oral administration of Compound 1 also resulted in tumor regression in an intracranial model administered intracarotidally (see Figure 14).

[0023] In certain embodiments, the allosteric EGFR degrader is administered as a second-line therapy for the treatment of EGFR-mediated cancer that has metastasized to the brain or CNS; for example, the allosteric EGFR degrader can be administered to patients who have progressed after discontinuing osimertinib. In other embodiments, the allosteric EGFR degrader is administered as a first-line therapy for the treatment of EGFR-mediated cancer that has metastasized to the brain or CNS. In other embodiments, the allosteric EGFR degrader is administered as a third-line therapy for the treatment of EGFR-mediated cancer that has metastasized to the brain or CNS.

[0024] In certain embodiments, the allosteric EGFR degraders bind to an allosteric site created by displacement of the regulatory αC-helix in the "αC-out" conformation. In this embodiment, the allosteric site can be expanded in activation loop mutants, such as exon 21 L858R or L861Q, but is occluded in wild-type EGFR. This mechanism results in selectivity of the mutant over the wild-type. In certain embodiments, the allosteric EGFR degraders described herein resolve mutant EGFR monomers and dimers.

[0025] In certain embodiments, the present invention provides a compound of formula: [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 , 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, isotope, N-oxide, or stereoisomer thereof selected from:

[0026] In certain embodiments, the present invention provides a compound of formula: [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 described herein), or a pharmaceutically acceptable salt, isotope, N-oxide, or stereoisomer thereof.

[0027] Certain embodiments of the present invention are compounds of formula III or 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 are each independently H, halogen (F, Cl, Br or I), C 1~6 -Alkyl, Cyano, C1~6 -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 are in each case independently 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 R37 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 are each 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, 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, 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 -CR42 - 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 bivalent linking group (linker) connecting the compound of formula LI, or a pharmaceutically acceptable salt, isotope, N-oxide, or stereoisomer thereof, wherein the remaining variables are as described herein.

[0028] In certain embodiments, L 2 is the expression: [ka] (In the formula, X 1 and X 2 are, in each occurrence, independently a bond, heterocyclic, aryl, heteroaryl, bicyclic, 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 24 are, in each occurrence, independently 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)(OR26 )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 in each occurrence from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic, aliphatic, and heteroaliphatic; R 27 is independently selected in 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 occurrence, 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).

[0029] All combinations of variables, substituents, embodiments, and methods resulting from these combinations are considered to be specifically and individually disclosed since such description is merely for convenience of space.

[0030] In certain embodiments, a compound of Formula I, Formula II, Formula III, or Formula IV is an allosteric degrader of EGFR, e.g., the compound can induce degradation of the EGFR protein after binding to an allosteric site on EGFR (e.g., a mutant EGFR).

[0031] In certain embodiments, a compound of Formula I, Formula II, Formula III, or Formula IV crosses the blood-brain barrier. By crossing the blood-brain barrier, a compound of Formula I, Formula II, Formula III, or Formula IV can be used to treat EGFR-mediated cancers that have metastasized to the brain or CNS. Non-limiting examples of EGFR-mediated cancers include non-small cell lung cancer, breast cancer, including HER-2 positive breast cancer, ER+ (estrogen positive) breast cancer, PR+ (progesterone positive) breast cancer, or triple-negative breast cancer, head and neck cancer, glioblastoma, pancreatic cancer, thyroid cancer, astrocytoma, esophageal cancer, cervical cancer, synovial sarcoma, ovarian cancer, liver cancer, bladder cancer, and renal cancer.

[0032] In certain embodiments, the compounds described herein are used to treat lung cancer that has metastasized to the brain or CNS. In certain embodiments, the lung cancer is non-small cell lung cancer that has metastasized to the brain or CNS. In certain embodiments, the lung cancer is small cell lung cancer that has metastasized to the brain or CNS. In certain embodiments, the lung cancer is adenocarcinoma that has metastasized to the brain or CNS. In certain embodiments, the lung cancer is squamous cell lung carcinoma that has metastasized to the brain or CNS. In certain embodiments, the lung cancer is large cell undifferentiated carcinoma that has metastasized to the brain or CNS. In certain embodiments, the lung cancer is neuroendocrine carcinoma that has metastasized to the brain or CNS. Additional examples of lung cancer include sarcomatoid carcinoma, adenosquamous carcinoma, oat cell carcinoma, mixed small cell carcinoma, lung carcinoid tumor, central carcinoid, peripheral carcinoid, salivary gland lung carcinoma, mesothelioma, and mediastinal tumor.

[0033] In certain embodiments, the compounds described herein are used to treat breast cancer that has metastasized to the brain or CNS. In certain embodiments, the breast cancer is HER-2 positive breast cancer. In certain embodiments, the breast cancer is ER+ breast cancer. In certain embodiments, the breast cancer is PR+ breast cancer. In certain embodiments, the breast cancer is triple-negative breast cancer.

[0034] In certain embodiments, the compounds described herein are used to treat colon or rectal cancer that has metastasized to the brain or CNS.

[0035] In certain embodiments, the compounds described herein are used to treat head and neck cancer or esophageal cancer that has metastasized to the brain or CNS.

[0036] In certain embodiments, the compounds described herein are used to treat pancreatic cancer that has metastasized to the brain or CNS.

[0037] In certain embodiments, the compounds described herein are used to treat thyroid cancer that has metastasized to the brain or CNS.

[0038] In certain embodiments, the compounds described herein are used to treat ovarian, uterine, or cervical cancer that has metastasized to the brain or CNS.

[0039] In certain embodiments, the compounds described herein are used to treat kidney, liver, or bladder cancer that has metastasized to the brain or CNS.

[0040] In certain embodiments, the compounds described herein are used to treat melanoma that has metastasized to the brain or CNS.

[0041] In certain embodiments, the compounds described herein are used to treat renal cancer, liver cancer, or bladder cancer that has metastasized to the brain or CNS, hi other embodiments, the compounds are used to treat adenocarcinoma, colon cancer, breast cancer, triple-negative breast cancer, renal cell carcinoma, primary brain tumors, astrocytoma, esophageal cancer, or synovial sarcoma.

[0042] In certain embodiments, the compounds described herein cross the blood-brain barrier at concentrations sufficient to treat EGFR-mediated disorders, such as cancer in the brain or CNS, and may have one or more advantages, and may even offer multiple additional advantages over conventional treatment with EGFR inhibitors. For example, the EGFR-degrading compounds described herein 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.

[0043] In one aspect, the compounds described herein are used to treat EGFR-mediated cancers that have metastasized to the brain or CNS and 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.

[0044] 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.

[0045] In certain embodiments, the compounds described herein are used to treat cancers that have spread to the brain or CNS and are resistant to or have acquired resistance to first-generation EGFR inhibitors, such as erlotinib, gefitinib, and / or lapatinib. In certain embodiments, the compounds described herein are used to treat cancers that have spread to the brain or CNS and are resistant to or have acquired resistance to second-generation EGFR inhibitors, such as afatinib and / or dacomitinib. In certain embodiments, the compounds described herein are used to treat cancers that have spread to or have acquired resistance to third-generation EGFR inhibitors, such as osimertinib.

[0046] In some embodiments, the mutant EGFR protein in the affected tissue has an L858 mutation, eg, L858R.

[0047] In certain embodiments, the compounds described herein are used to treat mutant EGFR-mediated cancers in which the EGFR that has metastasized to the brain or CNS has a mutation at at least one or a combination of the amino acid positions listed below, where the mutation may be selected from, for example, one of the exemplary mutations listed, or may be a different mutation.

[0048] TIFF2024521791000025.tif97170

[0049] In certain embodiments, the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has two mutations selected from the table above. In other embodiments, the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has three mutations selected from the table above. In other embodiments, the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has four or more mutations, which may optionally be selected from the table above.

[0050] In certain embodiments, the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has an L858R mutation and, optionally, one additional mutation that may be selected from the table above. In some of these embodiments, the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has an L858R mutation and, optionally, two additional mutations that may be selected from the table above. In other embodiments, the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has an L858R mutation and, optionally, three additional mutations that may be selected from the table above.

[0051] In certain embodiments, the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has a T790M mutation and, optionally, one additional mutation selected from the table above. In other embodiments, the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has a T790M mutation and, optionally, two additional mutations selected from the table above. In other embodiments, the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has a T790M mutation and, optionally, three additional mutations selected from the table above.

[0052] In certain embodiments, the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has an L718Q mutation and, optionally, one additional mutation selected from the table above. In other embodiments, the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has an L718Q mutation and, optionally, two additional mutations selected from the table above. In other embodiments, the mutant EGFR-mediated cancer that has metastasized to the brain or CNS has an L718Q mutation and, optionally, three additional mutations selected from the table above.

[0053] In certain embodiments, mutant EGFR-mediated cancers that have metastasized to the brain or CNS have mutations of the following: S768I, L718V, L792H, L792V, G796S, G796C, G724S and / or G719A.

[0054] In certain embodiments, the compounds described herein are used to treat EGFR-mediated cancers that have metastasized to the brain or CNS and have frameshift mutations, e.g., short in-frame deletions. In certain embodiments, the compounds described herein are used to treat EGFR-mediated cancers that have metastasized to the brain or CNS and in which EGFR has an exon 19 deletion. In certain embodiments, the exon 19 deletion is a deletion that includes amino acids LREA (L747-A750). In certain embodiments, the exon 19 deletion is a deletion that includes amino acids ELREA (E746-A750).

[0055] In certain embodiments, the compounds described herein are used to treat EGFR-mediated cancers that have metastasized to the brain or CNS and in which EGFR harbors the L858R mutation in exon 21.

[0056] In certain embodiments, the compounds described herein are more active against disorders driven by mutant EGFR than wild-type EGFR.

[0057] In certain embodiments, the compounds described herein are used to treat EGFR-mediated cancers that have metastasized to the brain or CNS and in which EGFR harbors one or more exon 18 deletions.

[0058] In certain embodiments, the compounds described herein are used to treat EGFR-mediated cancers that have metastasized to the brain or CNS and have an E709 mutation, eg, E709A, E709G, E709K, or E709V.

[0059] In certain embodiments, the compounds described herein are used to treat EGFR-mediated cancers that have metastasized to the brain or CNS and have an L718 mutation, eg, L718Q.

[0060] In certain embodiments, the compounds described herein are used to treat EGFR-mediated cancers that have metastasized to the brain or CNS and have a G719 mutation, eg, G719S, G719A, G719C, or G719D.

[0061] In certain embodiments, the compounds described herein are used to treat EGFR-mediated cancers that have metastasized to the brain or CNS, where EGFR has one or more exon 19 insertions and / or one or more exon 20 insertions.

[0062] In certain embodiments, the compounds described herein are used to treat S7681 mutant EGFR-mediated cancers that have metastasized to the brain or CNS. In certain embodiments, the compounds described herein are used to treat EGFR L861Q mutant EGFR-mediated cancers that have metastasized to the brain or CNS. In certain embodiments, the compounds described herein are used to treat C797S mutant EGFR-mediated cancers that have metastasized to the brain or CNS.

[0063] In certain embodiments, the compounds described herein are used to treat L858R-T790M mutant EGFR-mediated cancers that have metastasized to the brain or CNS.

[0064] In certain embodiments, the compounds described herein are used to treat L858R-L718Q mutant EGFR-mediated cancers that have metastasized to the brain or CNS.

[0065] In certain embodiments, the compounds described herein are used to treat L858R-L792H mutant EGFR-mediated cancers that have metastasized to the brain or CNS.

[0066] In certain embodiments, the compounds described herein are used to treat L858R-C797S mutant EGFR-mediated cancers that have metastasized to the brain or CNS.

[0067] In certain embodiments, the compounds described herein are used to treat L858R-T790M-C797S mutant EGFR-mediated cancers that have metastasized to the brain or CNS.

[0068] Other features and advantages of the present application will be apparent from the following detailed description.

[0069] To this end, the present invention includes at least the following features: (a) a method of treating EGFR-mediated cancer that has metastasized to the brain or CNS, 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; (b) the method of (a), wherein the patient is also administered an ATP site-binding EGFR inhibitor, e.g., osimertinib; (c) the 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 cancer that has metastasized to the brain or CNS; (d) the use of (c), wherein the patient is also administered an ATP site-binding EGFR inhibitor, e.g., osimertinib; (e) a compound of Formula I, Formula II, Formula III or Formula IV, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a patient, typically a human, in need of treatment, having an EGFR-mediated cancer that has metastasized to the brain or CNS; (f) the compound of (e), wherein the patient is also administered an ATP site-binding EGFR inhibitor, e.g., osimertinib; (g) a method of treating mutant EGFR-mediated cancer that has metastasized to the brain, 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; (h) the method of (g), wherein the patient is also administered an ATP site-binding EGFR inhibitor, e.g., osimertinib; (i) the 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 cancer that has metastasized to the brain or CNS; (j) the use of (i), wherein the patient is also administered an ATP site-binding EGFR inhibitor, e.g., osimertinib; (k) a compound of Formula I, Formula II, Formula III or Formula IV, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a patient, typically a human, in need of treatment, having a mutant EGFR-mediated cancer that has metastasized to the brain or CNS; (l) The compound of (k), wherein the patient is also administered an ATP site-binding EGFR inhibitor, e.g., osimertinib. [Brief explanation of the drawings]

[0070] [Figure 1A]1 is a line graph showing the in vivo efficacy of Compound 1 or osimertinib in treating female BALB / c nude mice bearing NCI-H1975 L858R-T790M NSCLC xenograft tumors. Mice were treated with vehicle control, dose response amounts (20 mg / kg / day, 50 mg / kg / day, and 100 mg / kg / day) of Compound 1, or 25 mg / kg / day of osimertinib for 14 days. Compound 1 was administered orally (PO) twice daily (BID), and osimertinib was administered orally (PO) once daily (QD). The x-axis is time measured in days, and the y-axis is NCI-H1975 tumor volume measured in mm3. Experimental procedures are provided in Example 55. [Figure 1B] 1 is a line graph showing the effect of Compound 1 or osimertinib on body weight in female BALB / c nude mice bearing NCI-H1975 NSCLC xenograft tumors. Mice were treated with vehicle control, dose-response amounts (20 mg / kg / day, 50 mg / kg / day, and 100 mg / kg / day) of Compound 1, or 25 mg / kg / day of osimertinib for 14 days. Compound 1 was administered orally (PO) twice daily (BID), and osimertinib was administered orally (PO) once daily (QD). After 14 days of treatment, tumors were monitored for regrowth. The x-axis is time measured in days, and the y-axis is body weight change measured as %. Experimental procedures are provided in Example 55. [Figure 2A-2B] 1 is a graph of the relative protein expression of (A) mutant EGFR-L858R-T790M and (B) phospho-EGFR in NCI-H1975 tumors. BALB / c nude mice were injected with NCI-H1975 tumor cells and Compound 1 was administered as a single oral (PO) dose at 10 mg / kg, 25 mg / kg, or 50 mg / kg, and osimertinib was administered orally (PO) at 25 mg / kg. The x-axis is time measured in hours and represents the time after a single dose, and the y-axis is % protein relative to vehicle control normalized to α-tubulin. The experimental procedure is provided in Example 56. [Figure 3A]1 is a line graph showing the in vivo efficacy of Compound 1 or osimertinib in treating female BALB / c nude mice bearing engineered triple mutant EGFR (L858R-T790M-C797S) BaF3 tumors. Mice were treated with vehicle control, dose-response amounts (20 mg / kg / day, 50 mg / kg / day, and 100 mg / kg / day) of Compound 1, or 25 mg / kg / day of osimertinib for 14 days. All compounds were administered orally (PO) twice daily (BID) for Compound 1 and once daily (QD) for osimertinib. The x-axis is time measured in days, and the y-axis is BaF3 tumor volume measured in mm3. Experimental procedures are provided in Example 57. [Figure 3B] 1 is a line graph showing the effect of Compound 1 or osimertinib on body weight in female BALB / c nude mice bearing engineered triple mutant EGFR (L858R-T790M-C797S) BaF3 tumors. Mice were treated with vehicle control, dose-response amounts (20 mg / kg / day, 50 mg / kg / day, and 100 mg / kg / day) of Compound 1, or 25 mg / kg / day of osimertinib for 14 days. All compounds were administered orally (PO) twice daily (BID) for Compound 1 and once daily (QD) for osimertinib. The x-axis is time measured in days, and the y-axis is body weight change measured in %. Experimental procedures are provided in Example 57. [Figure 4A] 1 is a line graph showing the in vivo efficacy of Compound 2 and osimertinib in treating female BALB / c nude mice bearing engineered triple mutant EGFR (L858R-T790M-C797S) BaF3 tumors. Mice were treated with vehicle control, dose-response amounts (20 mg / kg / day, 50 mg / kg / day, and 100 mg / kg / day) of Compound 2, or 25 mg / kg / day of osimertinib for 14 days. All compounds were administered orally (PO) twice daily (BID) for Compound 2 and once daily (QD) for osimertinib. The x-axis is time measured in days, and the y-axis is BaF3 tumor volume measured in mm3. Experimental procedures are provided in Example 57. [Figure 4B]1 is a line graph showing the change in body weight caused by Compound 2 and osimertinib in the treatment of female BALB / c nude mice bearing engineered triple mutant EGFR (L858R-T790M-C797S) BaF3 tumors. Mice were treated with vehicle control, dose-response amounts (20 mg / kg / day, 50 mg / kg / day, and 100 mg / kg / day) of Compound 2, or 25 mg / kg / day of osimertinib for 14 days. All compounds were administered orally (PO) twice daily (BID) for Compound 2 and once daily (QD) for osimertinib. The x-axis is time measured in days, and the y-axis is body weight change in %. Experimental procedures are provided in Example 57. [Figure 5A] Figure 5 shows the mean in vivo efficacy of Compound 1 in treating female BALB / c nude mice bearing intracranial NCI-H1975-luciferase-expressing NSCLC tumors established by intracranial injection of tumor cells into the forebrain. Mice were treated with vehicle control, 100 mg / kg Compound 1 for 14 days. Compound 1 was administered orally (PO) twice daily (BID). The x-axis is time measured in days, and the y-axis is NCI-H1975-luc BLI (total bioluminescence signal) measured in photons / second x 106. The experimental procedure is presented in Example 58. [Figure 5B] 1 is a line graph showing the average effect of Compound 1 on body weight in the treatment of female BALB / c nude mice bearing intracranial NCI-H1975-luciferase-expressing NSCLC tumors established by intracranial injection of tumor cells into the forebrain. Mice were treated with vehicle control or 100 mg / kg of Compound 1. Compound 1 was administered orally (PO) twice daily (BID). The x-axis is time measured in days, and the y-axis is % change in body weight. The experimental procedure is provided in Example 58. [Figure 6]Figure 1 shows line graphs of the mean plasma and tumor concentration time profiles of Compound 1 after a single oral dose of 50 mg / kg. Female BALB / c nude mice were intracranially injected with NCI-H1975 (EGFR-L858R-T790M) luciferase-expressing cells and received a single oral dose of Compound 1. Plasma and tumor were collected at the indicated time points and injected into an LC / MS / MS system for quantitative analysis. [Figure 7] 1 is a dose-response curve showing the effect of Compound 1 on Sal-like protein 4 (SALL4) degradation compared to lenalidomide. The x-axis is the concentration of Compound 1 or lenalidomide in nM, and the y-axis is the % of SALL4 remaining after 6 hours. Compound 1 had no effect on SALL4 protein levels up to 10 μM. The experimental procedure is provided in Example 62. [Figure 8] 1 is a dose-response curve showing the effect of Compound 1 on G1 to S Phase Transition 1 (GSPT1) degradation compared to CC-885. The x-axis is the concentration of Compound 1 or CC-885 IMiD in nM, and the y-axis is the % of GSPT1 remaining after 6 hours. Compound 1 had no significant effect on GSPT1 up to 10 μM. The experimental procedure is provided in Example 63. [Figure 9] 1 is a density map of tert-butyl 2-[1-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]-2-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetate established by X-ray diffraction. This crystal structure establishes the chirality of Compound 1, which is discussed in the synthesis of Compound 1 below. [Figure 10] 1 is a density map of tert-butyl 2-[1-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]-2-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetate established by X-ray diffraction. This crystal structure establishes the chirality of Compound 1, which is discussed in the synthesis of Compound 1 below. [Figure 11]1 is a density map of tert-butyl (4R)-4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-3,3-difluoro-piperidine-1-carboxylate established by X-ray diffraction. This crystal structure establishes the chirality of Compound 2, which is discussed in the synthesis of Compound 2 below. [Figure 12] 1 shows the crystal structure of tert-butyl (4R)-4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-3,3-difluoro-piperidine-1-carboxylate established by X-ray diffraction, which establishes the chirality of Compound 2 as discussed in the synthesis of Compound 2 below. [Figures 13A-13B] 1 is a human kinome phylogenetic tree binding plot showing the binding selectivity of 100 nM Compound 1 to various proteins from a panel of 486 wild-type and mutant human protein kinases. Each kinase is represented by a circle. Dark and light circles indicate kinases with less than 50% and more than 50% residual binding, respectively. The larger the dark circle, the higher the affinity of binding. The small dark circle is EGFR-L858R, and the large dark circle is EGFR-L861Q. The experimental procedure is provided in Example 60. [Figure 14] 6 is a graph showing the in vivo efficacy of Compound 1 in female BALB / c nude mice bearing intracranial NCI-H1975-luciferase-expressing tumors established by injecting tumor cells into the carotid artery. Mice were treated with vehicle control, 100 mg / kg Compound 1, and Compound 1 was administered orally (PO) twice daily (BID). The x-axis is time measured in days, and the y-axis is NCI-H1975-LUC BLI (photons / second). The experimental procedure is provided in Example 64. [Figure 15]1 is a graph showing in vivo body weight change in female BALB / c nude mice bearing intracranial NCI-H1975-luciferase-expressing tumors established by injecting tumor cells into the carotid artery. Mice were treated with vehicle control, 100 mg / kg of Compound 1. Compound 1 was administered orally (PO) twice daily (BID). The x-axis is time measured in days, and the y-axis is % change in body weight. The experimental procedure is provided in Example 64. [Figure 16] 1 is a graph showing the survival probability of female BALB / c nude mice bearing intracranial NCI-H1975-luciferase-expressing tumors established by injecting tumor cells into the carotid artery. Mice were treated with vehicle control, 100 mg / kg of Compound 1. Compound 1 was administered orally (PO) twice daily (BID). The x-axis is time measured in days, and the y-axis is % survival probability. The experimental procedure is provided in Example 64. [Figure 17] Figure 6 shows a co-crystal structure showing simultaneous binding of the allosteric EGFR-binding portion of Compound 1 with osimertinib in different binding pockets of the L858R mutant EGFR. The allosteric EGFR-binding portion of Compound 1 binds near the L858R mutation. The experimental procedure is provided in Example 66. [Figures 18A-18B] 18A and 18B are SPR sensorgrams of Compound 1 mixed with either 1.5 μM EGFRL858R apo (18A) or 5 μM EGFRL858R osimertinib (18B) injected over immobilized Btn-CRBN-DDB1. The concentration of Compound 1 corresponding to each sensorgram is indicated by the legend. The thin black line represents a fit to a 1:1 Langmuir binding model, and the best fit parameters for each titration experiment are listed on each plot. The experimental procedure is provided in Example 68. [Figure 19] 1 is a Western blot showing the effect of osimertinib on Compound 1-induced EGFR-L858R degradation and downstream signaling in H3255 (EGFR-L858R) cells. The experimental procedure is provided in Example 69. DETAILED DESCRIPTION OF THE INVENTION

[0071]

[0003] Provided are compounds that degrade epidermal growth factor receptor protein (EGFR)-mediated cancers that have metastasized to the brain or CNS via the ubiquitin proteasome pathway (UPP), as well as their uses and manufacture. 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 2 and the remainder of the molecule is an EGFR-targeting ligand portion. In certain embodiments, the compounds described herein 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 described herein are selective degraders of EGFR mutants having L858R-T790M, L858R-T790M-C797S, L858R, and / or L858R-C797S.

[0072] In certain embodiments, the compounds described herein provide improved efficacy and / or safety profiles compared to at least one known EGFR inhibitor. For example, the degraders described herein combine the efficacy of the protein-binding portion of the inhibitor alone with the catalytic degradation activity of cereblon-mediated proteasomal degradation. This results in rapid activity against overexpressed EGFR targets, 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.

[0073] I. Definition The following definitions of general terms used herein apply regardless of whether the terms appear alone or in combination with other groups.

[0074] 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.

[0075] "C 1~6 The 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.

[0076] "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.

[0077] The term "cyano" refers to the group -C≡N.

[0078] "C 3~8 The term "cycloalkoxy" refers to a compound in which R' is C3~8 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.

[0079] "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.

[0080] "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. 1~6Alkoxy groups include fluoromethoxy, fluoroethoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoromethylethoxy and trifluorodimethylethoxy. More particular examples are fluoromethoxy, difluoromethoxy and trifluoromethoxy.

[0081] "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.

[0082] "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. 3~8Examples of -cycloalkoxy include fluorocyclopropoxy, fluorocyclobutoxy, fluorocyclopentyloxy, fluorocyclohexyloxy, fluorocycloheptyloxy, difluorocyclopropoxy, difluorocyclobutoxy, difluorocyclopentyloxy, difluorocyclohexyloxy and difluorocycloheptyloxy.

[0083] "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 3~8 Examples of -cycloalkyl include fluorocyclopropyl, fluorocyclobutanyl, fluorocyclopentyl, fluorocyclohexyl, fluorocycloheptyl, difluorocyclopropyl, difluorocyclobutanyl, difluorocyclopentyl, difluorocyclohexyl or difluorocycloheptyl.

[0084] 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.

[0085] The term "hydroxy" refers to an --OH group.

[0086] "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. 1~6Examples of -alkyl include hydroxymethyl, hydroxyethyl and hydroxypropyl. A particular example is hydroxymethyl.

[0087] 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.

[0088] 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, salts of 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.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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 "in particular," "more particularly," and "most particularly," if any.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] "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).

[0098] 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.

[0099] 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).

[0100] 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.

[0101] 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 3 H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or 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.

[0102] 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).

[0103] In certain embodiments, the compounds described herein 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 , R52 , 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.

[0104] In certain embodiments, the compounds described herein 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 described herein (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.

[0105] 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.

[0106] 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.

[0107] In certain embodiments, the term "CNS" refers to components of the central nervous system, including, for example, the brain, brainstem, peripheral nervous system, cerebrospinal fluid, spinal cord, leptomeninges, epidural space, myelin, thalamus, hypothalamus, pituitary gland, hippocampus, cerebellum, cerebrum, midbrain, pons, frontal lobes, temporal lobes, and / or dura mater.

[0108] II. Methods of Treating EGFR-Mediated Disorders with Compounds of Formula I, Formula II, Formula III, and Formula IV The present invention provides methods of using the compounds of Formula I, Formula II, Formula III and Formula IV.

[0109] E1: In certain embodiments, the present invention provides a method for administering to a patient in need of treatment a compound of the formula: [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 are each independently 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, which may be located on the dihydropyrrole ring or the imidazole ring; R 34 are in each case independently H, F, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 3~8 -cycloalkyl and halo-C 3~8 -cycloalkyl, R 35 are each independently 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 42heteroaryl 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 R 42 are each 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, 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:EGFR degrading compound [ka] or a pharmaceutically acceptable salt thereof. E3:EGFR degrading compound [ka] 2. The method of embodiment 1, wherein the compound is selected from the group consisting of: E4:R 33 The method of any one of embodiments 1 to 3, wherein E5:R 33 The method of any one of embodiments 1 to 3, wherein E6: The method of any one of embodiments 1 to 5, wherein y is 1. E7: The method of any one of embodiments 1 to 5, wherein y is 2. E8: At least one R 31 8. The method of any one of embodiments 1-7, wherein is halo. E9: At least one R 31 The method of any one of embodiments 1 to 7, wherein E10: The method according to any one of embodiments 1 to 3, wherein y is 0. E11:R 32 10. The method of any one of embodiments 1-9, wherein E12:R 32 10. The method of any one of embodiments 1-9, wherein E13: EGFR degrading compound [ka] 2. The method of embodiment 1, wherein the E14: EGFR degrading compound [ka] 2. The method of embodiment 1, wherein the E15:A * but, [ka] 15. The method of any one of embodiments 1 to 14, wherein E16:A * but, [ka] 15. The method of any one of embodiments 1 to 14, wherein E17:A 34 17. The method of any one of embodiments 1-16, wherein is CH. E18:A 34 17. The method of any one of embodiments 1-16, wherein E19:A 34 is CR 42 17. The method of any one of embodiments 1 to 16, wherein E20:A 34 17. The method of any one of embodiments 1-16, wherein is CF. E21:A 35 21. The method of any one of embodiments 1-20, wherein is CH. E22:A 35 21. The method of any one of embodiments 1-20, wherein E23:A 35 is CR 42 21. The method of any one of embodiments 1 to 20, wherein E24:A 35 21. The method of any one of embodiments 1-20, wherein is CF. E25:A * but, [ka] 15. The method of any one of embodiments 1 to 14, wherein E26:A * but, [ka] 15. The method of any one of embodiments 1 to 14, wherein E27:A 21 27. The method of embodiment 25 or 26, wherein is NH. E28:A 21 27. The method of embodiment 25 or 26, wherein E29:A * but, [ka] 15. The method of any one of embodiments 1 to 14, wherein E30:A 32 30. The method of any one of embodiments 1-29, wherein is CH. E31:A 32 30. The method of any one of embodiments 1-29, wherein E32:A 32 is CR 42 30. The method of any one of embodiments 1 to 29, wherein E33:A 32 30. The method of any one of embodiments 1-29, wherein is CF. E34:A 33 34. The method of any one of embodiments 1-33, wherein is CH. E35:A 33 34. The method of any one of embodiments 1-33, wherein E36:A 33 is CR 42 34. The method of any one of embodiments 1 to 33, wherein E37:A 33 34. The method of any one of embodiments 1-33, wherein is CF. E38:A * but, [ka] 15. The method of any one of embodiments 1 to 14, wherein E39:A 21 39. The method of embodiment 38, wherein is NH. E40:A 21 39. The method of embodiment 38, wherein E41:R 34 41. The method of any one of embodiments 1-40, wherein E42:R 34 The method of any one of embodiments 1-40, wherein E43:R 34 41. The method of any one of embodiments 1-40, wherein is CH3. E44:R 3544. The method of any one of embodiments 1-43, wherein E45:R 35 44. The method of any one of embodiments 1-43, wherein E46:R 35 44. The method of any one of embodiments 1-43, wherein is CH3. E47:R 34 and R 35 and combine to form -CH2-. E48:R 31 are in each case independently H, halogen (F, Cl, Br or I) and C 1~6 48. The method of any one of embodiments 1 to 47, wherein the alkyl is selected from -alkyl. E49:R 42 are in each case independently H, halogen (F, Cl, Br or I) and C 1~6 48. The method of any one of embodiments 1 to 47, wherein the alkyl is selected from -alkyl. E50:B * but, [ka] 50. The method of any one of embodiments 1 to 49, wherein E51:B * but, [ka] 50. The method of any one of embodiments 1 to 49, wherein E52:B * but, [ka] 50. The method of any one of embodiments 1 to 49, wherein E53:B * but, [ka] 50. The method of any one of embodiments 1 to 49, wherein E54:L 2is the expression: [ka] (In the formula, X 1 and X 2 are, in each occurrence, independently a bond, heterocyclic, aryl, heteroaryl, bicyclic, 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 24 are, in each occurrence, independently 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 in each occurrence from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic, aliphatic, and heteroaliphatic; R 27is independently selected in 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 occurrence, 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 is aliphatic, aryl, heteroaryl, or hydrogen. E55:L 2 is the expression: [ka] 55. The method of any one of embodiments 1 to 54, wherein E56:X 1 56. The method of embodiment 54 or 55, wherein is a bond. E57:X 1 56. The method of embodiment 54 or 55, wherein is a heterocycle. E58:X 1 NR 2 56. The method of embodiment 54 or 55, wherein E59:X 1 56. The method of embodiment 54 or 55, wherein is C(O). E60:X2 60. The method of any one of embodiments 54-59, wherein is a bond. E61:X 2 The method of any one of embodiments 54-59, wherein is a heterocycle. E62:X 2 NR 2 60. The method of any one of embodiments 54 to 59, wherein E63:X 2 The method of any one of embodiments 54-59, wherein is C(O). E64:R 20 64. The method of any one of embodiments 54-63, wherein is a bond. E65:R 20 The method of any one of embodiments 54-63, wherein is CH2. E66:R 20 The method of any one of embodiments 54-63, wherein is a heterocycle. E67:R 20 The method of any one of embodiments 54-63, wherein is aryl. E68:R 20 The method of any one of embodiments 54-63, wherein is phenyl. E69:R 20 The method of any one of embodiments 54-63, wherein is bicyclic. E70:R 21 70. The method of any one of embodiments 54-69, wherein is a bond. E71:R 21 70. The method of any one of embodiments 54-69, wherein is CH2. E72:R 21 The method of any one of embodiments 54-69, wherein is a heterocycle. E73:R 21 The method of any one of embodiments 54-69, wherein is aryl. E74:R 21 The method of any one of embodiments 54-69, wherein is phenyl. E75:R 21 The method of any one of embodiments 54-69, wherein is bicyclic. E76:L is the formula: [ka] 55. The method of embodiment 54, wherein the linker is E77:R 22 77. The method of any one of embodiments 54-76, wherein is a bond. E78:R 22 The method of any one of embodiments 54-76, wherein is CH2. E79:R 22 The method of any one of embodiments 54-76, wherein is a heterocycle. E80:R 22 The method of any one of embodiments 54-76, wherein is aryl. E81:R 22 The method of any one of embodiments 54-76, wherein is phenyl. E82:R 22 The method of any one of embodiments 54-76, wherein is bicyclic. E83:L is the formula: [ka] 70. The method of any one of embodiments 54 to 69, wherein the linker is E84:R 23 84. The method of any one of embodiments 54-83, wherein is a bond. E85:R 23 The method of any one of embodiments 54-83, wherein is CH2. E86:R 23 The method of any one of embodiments 54-83, wherein is a heterocycle. E87:R 23 The method of any one of embodiments 54-83, wherein is aryl. E88:R 23 The method of any one of embodiments 54-83, wherein is phenyl. E89:R 23 The method of any one of embodiments 54-83, wherein is bicyclic. E90:R 2490. The method of any one of embodiments 54-89, wherein is a bond. E91:R 24 The method of any one of embodiments 54-89, wherein is CH2. E92:R 24 The method of any one of embodiments 54-89, wherein is a heterocycle. E93:R 24 The method of any one of embodiments 54-89, wherein is aryl. E94:R 24 The method of any one of embodiments 54-89, wherein is phenyl. E95:R 24 The method of any one of embodiments 54-89, wherein is bicyclic. E96:R 24 The method of any one of embodiments 54-89, wherein is C(O). E97: The method of any one of embodiments 1 to 96, wherein the patient is a human. E98: The method of any one of embodiments 1 to 97, wherein the cancer is lung cancer. E99: The method of embodiment 98, wherein the lung cancer is non-small cell lung cancer. E100: The method of any one of embodiments 1-99, wherein the cancer has an EGFR protein with at least one mutation. E101: The method of any one of embodiments 1 to 100, wherein the cancer has an EGFR protein with an L858R mutation. E102: The method of any one of embodiments 1 to 101, wherein the cancer has an EGFR protein with a T790M mutation. E103: The method of any one of embodiments 1 to 102, wherein the cancer has an EGFR protein with a C797S mutation. E104: The method of any one of embodiments 1 to 103, wherein the cancer has an EGFR protein with an L792H mutation. E105: The method of any one of embodiments 1 to 104, wherein the cancer has an EGFR protein with an L718Q mutation. E106: The method of any one of embodiments 1 to 105, wherein the cancer has an EGFR protein with a L858R-T790M mutation. E107: The method of any one of embodiments 1 to 106, wherein the cancer has an EGFR protein with a L858R-T790M-C797S mutation. E108: The method of any one of embodiments 1 to 107, wherein the cancer has an EGFR protein with a L858R-C797S mutation. E109: The method of any one of embodiments 1 to 108, wherein an additional EGFR inhibitor is administered. E110: The method of embodiment 109, wherein the additional EGFR inhibitor is a tyrosine kinase inhibitor. E111: The method of embodiment 109, wherein the additional EGFR inhibitor is osimertinib. E112: The method of embodiment 109, wherein the additional EGFR inhibitor is rociletinib. E113: The method of embodiment 109, wherein the additional EGFR inhibitor is avitinib. E114: The method of embodiment 109, wherein the additional EGFR inhibitor is lazertinib. E115: The method of embodiment 109, wherein the additional EGFR inhibitor is nazartinib. E116: The method of embodiment 109, wherein the additional EGFR inhibitor is an antibody against a mutated form of EGFR. E117: The method of embodiment 109, wherein the additional EGFR inhibitor is cetuximab. E118: The method of embodiment 109, wherein the additional EGFR inhibitor is panitumumab. E119: The method of embodiment 109, wherein the additional EGFR inhibitor is necitumumab. E120: The method of any one of embodiments 1-119, wherein a MET inhibitor is also administered. E121: The method according to any one of embodiments 1 to 120, wherein the patient is given an additional chemotherapeutic agent. E122: EGFR degrading compound [ka] or a pharmaceutically acceptable salt thereof. E123: EGFR degrading compound [ka] or a pharmaceutically acceptable salt thereof. E124: EGFR degrading compound [ka] or a pharmaceutically acceptable salt thereof. E125: EGFR degrading compound [ka] or a pharmaceutically acceptable salt thereof. E126: EGFR degrading compound [ka] or a pharmaceutically acceptable salt thereof. E127: EGFR degrading compound [ka] or a pharmaceutically acceptable salt thereof. E128: EGFR degrading compound [ka] or a pharmaceutically acceptable salt thereof. E129: EGFR degrading compound [ka] or a pharmaceutically acceptable salt thereof. E130: EGFR degrading compound [ka] or a pharmaceutically acceptable salt thereof. E131: EGFR degrading compound [ka] or a pharmaceutically acceptable salt thereof. E132: EGFR degrading compound [ka] or a pharmaceutically acceptable salt thereof. E133: EGFR degrading compound [ka] or a pharmaceutically acceptable salt thereof. E134: The method according to any one of embodiments 1 to 121, wherein the EGFR degrading compound is described herein. E135: The method according to any one of embodiments 1 to 121, wherein the EGFR degrading compound is listed in Table 8, Table 9A or Table 9B.

[0110] 1. In certain embodiments, a patient in need of treatment is administered: [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 are each independently 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, which may be located on the dihydropyrrole ring or the imidazole ring; R 34 are in each case independently H, F, C 1~6 -Alkyl, Halo-C 1~6 -Alkyl, C 3~8 -cycloalkyl and halo-C 3~8 -cycloalkyl, R 35 are each independently 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 R 42 are each 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, A 36 -N- or -CR 35 - and L 2 is A * and either an isoindolinone or an indazole), or a pharmaceutically acceptable salt thereof. 2. L 2 is the expression: [ka] (In the formula, X 1 and X 2 are, in each occurrence, independently a bond, heterocyclic, aryl, heteroaryl, bicyclic, 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 24 are, in each occurrence, independently 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 in each occurrence from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic, aliphatic, and heteroaliphatic; R 27 is independently selected in 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 occurrence, 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 is aliphatic, aryl, heteroaryl, or hydrogen. 3. The method of embodiment 1, wherein the compound is selected from Table 9A and Table 9B. 4. In certain embodiments, a patient in need of treatment is administered: [ka] A method for treating EGFR-mediated cancer that has metastasized to the brain or CNS is provided, comprising administering an effective amount of a compound selected from TIFF2024521791000062.tif208170TIFF2024521791000063.tif243170TIFF2024521791000064.tif54170, or a pharmaceutically acceptable salt thereof. 5. In certain embodiments, a patient in need of treatment is administered a therapeutically effective amount of a compound having the structure: [ka] or a pharmaceutically acceptable salt thereof. 6. In certain embodiments, a patient in need of treatment is administered a therapeutically effective amount of a compound having the structure: [ka] or a pharmaceutically acceptable salt thereof. 7. In certain embodiments, a patient in need of treatment is administered a therapeutically effective amount of a compound having the structure: [ka] or a pharmaceutically acceptable salt thereof. 8. In certain embodiments, a patient in need of treatment is administered a therapeutically effective amount of a compound having the structure: [ka] or a pharmaceutically acceptable salt thereof. 9. In certain embodiments, a patient in need of treatment is administered a therapeutically effective amount of a compound having the structure: [ka] or a pharmaceutically acceptable salt thereof. 10. In certain embodiments, a patient in need of treatment is administered a therapeutically effective amount of a compound having the structure: [ka] or a pharmaceutically acceptable salt thereof. 11. In certain embodiments, a patient in need of treatment is administered a therapeutically effective amount of a compound having the structure: [ka] or a pharmaceutically acceptable salt thereof. 12. In certain embodiments, a patient in need of treatment is administered a therapeutically effective amount of a compound having the structure: [ka] or a pharmaceutically acceptable salt thereof. 13. In certain embodiments, a patient in need of treatment is administered a therapeutically effective amount of a compound having the structure: [ka] or a pharmaceutically acceptable salt thereof. 14. In certain embodiments, a patient in need of treatment is administered a therapeutically effective amount of a compound having the structure: [ka] or a pharmaceutically acceptable salt thereof. 15. In certain embodiments, a patient in need of treatment is administered a therapeutically effective amount of a compound having the structure: [ka] or a pharmaceutically acceptable salt thereof. 16. In certain embodiments, a patient in need of treatment is administered a therapeutically effective amount of a compound having the structure: [ka] or a pharmaceutically acceptable salt thereof. 17. The method of any one of embodiments 1 to 16, wherein the patient is a human. 18. The method of any one of embodiments 1 to 17, wherein the EGFR-mediated cancer is mediated by mutant EGFR. 19. The method of embodiment 18, wherein the mutant EGFR has an exon 21 mutation. 20. The method of embodiment 19, wherein the mutant EGFR has an L858R mutation. 21. The method of embodiment 19, wherein the mutant EGFR has an L861Q mutation. 22. The method of any one of embodiments 18 to 21, wherein the mutant EGFR has a T790M mutation. 23. The method of any one of embodiments 18 to 22, wherein the mutant EGFR has a C797S mutation. 24. The method of embodiment 18, wherein the mutant EGFR has an L858R mutation and a T790M mutation. 25. The method of embodiment 18, wherein the mutant EGFR has an L858R mutation, a T790M mutation, and a C797S mutation. 26. The method of any one of embodiments 1-25, wherein the compound is administered as part of a pharmaceutical composition. 27. The method of any one of embodiments 1-26, wherein the compound is administered orally. 28. The method of any one of embodiments 1-26, wherein the compound is administered parenterally. 29. The method of any one of embodiments 1-26, wherein the compound is administered intravenously. 30. The method of any one of embodiments 1 to 29, wherein an ATP site-binding EGFR ligand is also administered to a patient in need thereof. 31. The method of embodiment 30, wherein the ATP site-binding EGFR ligand is osimertinib or a pharmaceutically acceptable salt thereof. 32. The method of embodiment 30, wherein the ATP site-binding EGFR ligand is nacotinib or a pharmaceutically acceptable salt thereof. 33. The method of embodiment 30, wherein the ATP site-binding EGFR ligand is mavereltinib or a pharmaceutically acceptable salt thereof. 34. The method of embodiment 30, wherein the ATP site-binding EGFR ligand is spebrutinib or a pharmaceutically acceptable salt thereof. 35. The method of any one of embodiments 1 to 34, wherein the EGFR-mediated cancer is lung cancer that has metastasized to the brain or CNS. 36. The method of any one of embodiments 1 to 34, wherein the EGFR-mediated cancer is non-small cell lung cancer that has metastasized to the brain or CNS. 37. The method of any one of embodiments 1 to 34, wherein the EGFR-mediated cancer is small cell lung cancer that has metastasized to the brain or CNS. 38. The method of any one of embodiments 1 to 34, wherein the EGFR-mediated cancer is an adenocarcinoma that has metastasized to the brain or CNS. 39. The method of any one of embodiments 1 to 34, wherein the EGFR-mediated cancer is squamous cell lung cancer that has metastasized to the brain or CNS. 40. The method of any one of embodiments 1 to 34, wherein the EGFR-mediated cancer is large cell undifferentiated carcinoma that has metastasized to the brain or CNS. 41. The method of any one of embodiments 1 to 34, wherein the EGFR-mediated cancer is a neuroendocrine cancer that has metastasized to the brain or CNS. 42. The method of any one of embodiments 1 to 34, wherein the EGFR-mediated cancer is sarcomatoid carcinoma metastasized to the brain or CNS, adenosquamous carcinoma, oat cell carcinoma, mixed small cell carcinoma, pulmonary carcinoid tumor, central carcinoid, peripheral carcinoid, salivary gland lung carcinoma, mesothelioma, or mediastinal tumor. 43. The method of any one of embodiments 1 to 34, wherein the EGFR-mediated cancer is breast cancer that has metastasized to the brain or CNS. 44. The method of embodiment 43, wherein the EGFR-mediated cancer is HER-2-positive breast cancer. 45. The method of embodiment 43 or 44, wherein the EGFR-mediated cancer is ER+ breast cancer. 46. ​​The method of any one of embodiments 43 to 45, wherein the EGFR-mediated cancer is PR+ breast cancer. 47. The method of any one of embodiments 1 to 34, wherein the EGFR-mediated cancer is triple-negative breast cancer. 48. The method of any one of embodiments 1 to 34, wherein the EGFR-mediated cancer is colon or rectal cancer that has metastasized to the brain or CNS. 49. The method of any one of embodiments 1 to 34, wherein the EGFR-mediated cancer is head and neck cancer or esophageal cancer that has metastasized to the brain or CNS. 50. The method of any one of embodiments 1 to 34, wherein the EGFR-mediated cancer is pancreatic cancer that has metastasized to the brain or CNS. 51. The method of any one of embodiments 1 to 34, wherein the EGFR-mediated cancer is thyroid cancer that has metastasized to the brain or CNS. 52. The method of any one of embodiments 1 to 34, wherein the EGFR-mediated cancer is ovarian cancer, uterine cancer, or cervical cancer that has metastasized to the brain or CNS. 53. The method of any one of embodiments 1 to 34, wherein the EGFR-mediated cancer is renal cancer, liver cancer, or bladder cancer that has metastasized to the brain or CNS. 54. The method of any one of embodiments 1 to 34, wherein the EGFR-mediated cancer is melanoma that has metastasized to the brain or CNS. 55. The method of any one of embodiments 1 to 54, wherein the EGFR-mediated cancer has metastasized to the brain. 56. The method of any one of embodiments 1 to 54, wherein the EGFR-mediated cancer has metastasized to the CNS. 57. The method of any one of embodiments 1-56, wherein the compound is administered to a patient with an untreated EGFR-mediated cancer. 58. The method of any one of embodiments 1 to 56, wherein the EGFR-mediated cancer is recurrent. 59. The method of any one of embodiments 1 to 56, wherein the EGFR-mediated cancer is refractory. 60. The method of any one of embodiments 1 to 56, wherein the EGFR-mediated cancer is recurrent and refractory. 61. In certain embodiments, there is provided the use of a compound described herein (e.g., a compound used in any one of embodiments 1-60) in the manufacture of a medicament for treating a disorder described herein (e.g., a disorder of any one of embodiments 1-60). 62. In certain embodiments, there is provided a use of a compound described herein (e.g., a compound used in any one of embodiments 1-60) in the treatment of a disorder described herein (e.g., a disorder of any one of embodiments 1-60). 63. In certain embodiments, provided is a compound described herein (e.g., a compound used in any one of embodiments 1-60) for use in treating a disorder described herein (e.g., a disorder of any one of embodiments 1-60).

[0111] Additional Embodiments of the Invention Chirality Embodiments The compounds described herein may, for example, be substituted with one or more stereocenters in the E3 ligase binding moiety (e.g., [ka] ), 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 described herein 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.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] In certain embodiments, [ka] teeth, [ka] and R 34 is hydrogen.

[0117] In certain embodiments, [ka] teeth, [ka] and R 34 is hydrogen.

[0118] In certain embodiments, [ka] teeth, [ka] is.

[0119] In certain embodiments, [ka] teeth, [ka] is.

[0120] In certain embodiments, [ka] teeth, [ka] is.

[0121] In certain embodiments, [ka] teeth, [ka] is.

[0122] 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.

[0123] 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.

[0124] 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.

[0125] In certain embodiments, the linker is [ka] Includes.

[0126] In certain embodiments, the linker is [ka] Includes.

[0127] In certain embodiments, the linker is [ka] Includes.

[0128] In certain embodiments, the linker is [ka] Includes.

[0129] In certain embodiments, the linker is [ka] Includes.

[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, 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.

[0139] In certain embodiments, [ka] teeth, [ka] and R 33 is hydrogen.

[0140] In certain embodiments, [ka] teeth, [ka] and R 33is hydrogen.

[0141] In certain embodiments, [ka] teeth, [ka] is.

[0142] In certain embodiments, [ka] teeth, [ka] is.

[0143] In certain embodiments, [ka] teeth, [ka] is.

[0144] In certain embodiments, [ka] teeth, [ka] is.

[0145] In certain embodiments, [ka] teeth, [ka] is.

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

[0147] 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.

[0148] In certain embodiments, the "alkyl" has 1 carbon.

[0149] In certain embodiments, the "alkyl" has two carbons.

[0150] In certain embodiments, the "alkyl" has 3 carbons.

[0151] In certain embodiments, the "alkyl" has 4 carbons.

[0152] In certain embodiments, the "alkyl" has 5 carbons.

[0153] In certain embodiments, the "alkyl" has 6 carbons.

[0154] Non-limiting examples of "alkyl" include methyl, ethyl, propyl, butyl, pentyl and hexyl.

[0155] Additional non-limiting examples of "alkyl" include isopropyl, isobutyl, isopentyl, and isohexyl.

[0156] Additional non-limiting examples of "alkyl" include sec-butyl, sec-pentyl, and sec-hexyl.

[0157] Additional non-limiting examples of "alkyl" include tert-butyl, tert-pentyl, and tert-hexyl.

[0158] Additional non-limiting examples of "alkyl" include neopentyl, 3-pentyl, and active pentyl.

[0159] In alternative embodiments, "alkyl" refers to one, two, three, or four R 31 "Optionally substituted" with substituents.

[0160] 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.

[0161] In certain embodiments, the "cycloalkyl" has 3 carbons.

[0162] In certain embodiments, the "cycloalkyl" has 4 carbons.

[0163] In certain embodiments, the "cycloalkyl" has 5 carbons.

[0164] In certain embodiments, the "cycloalkyl" has 6 carbons.

[0165] In certain embodiments, the "cycloalkyl" has 7 carbons.

[0166] In certain embodiments, the "cycloalkyl" has 8 carbons.

[0167] In certain embodiments, the "cycloalkyl" has 9 carbons.

[0168] In certain embodiments, the "cycloalkyl" has 10 carbons.

[0169] Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl.

[0170] In alternative embodiments, "cycloalkyl" refers to one, two, three, or four R 31 "Optionally substituted" with substituents.

[0171] 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.

[0172] In certain embodiments, the "haloalkyl" has 1 carbon.

[0173] In certain embodiments, a "haloalkyl" has one carbon and one halogen.

[0174] In certain embodiments, a "haloalkyl" has 1 carbon and 2 halogens.

[0175] In certain embodiments, a "haloalkyl" has 1 carbon and 3 halogens.

[0176] In certain embodiments, the "haloalkyl" has two carbons.

[0177] In certain embodiments, the "haloalkyl" has 3 carbons.

[0178] In certain embodiments, the "haloalkyl" has 4 carbons.

[0179] In certain embodiments, the "haloalkyl" has 5 carbons.

[0180] In certain embodiments, the "haloalkyl" has 6 carbons.

[0181] Non-limiting examples of "haloalkyl" include: [ka] Examples include:

[0182] Additional non-limiting examples of "haloalkyl" include: [ka] Examples include:

[0183] Additional non-limiting examples of "haloalkyl" include: [ka] Examples include:

[0184] Additional non-limiting examples of "haloalkyl" include: [ka] Examples include:

[0185] Heterocyclic Embodiments In certain embodiments, "heterocycle" refers to a cyclic ring having one nitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0186] In certain embodiments, "heterocycle" refers to a cyclic ring having one nitrogen, one oxygen, and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0187] In certain embodiments, "heterocycle" refers to a cyclic ring having two nitrogens and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0188] In certain embodiments, "heterocycle" refers to a cyclic ring having one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0189] In certain embodiments, "heterocycle" refers to a cyclic ring having one sulfur and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0190] Non-limiting examples of "heterocycles" include aziridine, oxirane, thiirane, azetidine, 1,3-diazetidine, oxetane, and thietane.

[0191] Additional non-limiting examples of "heterocycle" include pyrrolidine, 3-pyrroline, 2-pyrroline, pyrazolidine, and imidazolidine.

[0192] Additional non-limiting examples of "heterocycle" include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane.

[0193] Additional non-limiting examples of "heterocycle" include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine.

[0194] Additional non-limiting examples of "heterocycle" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, where the point of attachment of each group is on the heterocycle.

[0195] Non-limiting examples of "heterocycle" include: [ka] Other examples include:

[0196] Additional non-limiting examples of "heterocycle" include: [ka] Examples include:

[0197] Additional non-limiting examples of "heterocycle" include: [ka] Examples include:

[0198] Non-limiting examples of "heterocycle" include: [ka] Other examples include:

[0199] Non-limiting examples of "heterocycle" include: [ka] Other examples include:

[0200] Additional non-limiting examples of "heterocycle" include: [ka] Examples include:

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

[0202] In alternative embodiments, the "heterocycle" may contain one, two, three, or four R 31 "Optionally substituted" with substituents.

[0203] Heteroaryl Embodiments In certain embodiments, a "heteroaryl" is a 5-membered aromatic group containing 1, 2, 3, or 4 nitrogen atoms.

[0204] 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.

[0205] Additional non-limiting examples of 5-membered "heteroaryl" groups include: [ka] Examples include:

[0206] In certain embodiments, "heteroaryl" is a 6-membered aromatic group containing 1, 2, or 3 nitrogen atoms (ie, pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl).

[0207] Non-limiting examples of 6-membered "heteroaryl" groups having 1 or 2 nitrogen atoms include: [ka] Examples include:

[0208] In certain embodiments, "heteroaryl" is a 9-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

[0209] Non-limiting examples of bicyclic "heteroaryl" groups include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzisoxazole, benzisothiazole, benzoxazole, and benzothiazole.

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

[0211] Additional non-limiting examples of bicyclic "heteroaryl" groups include: [ka] Examples include:

[0212] Additional non-limiting examples of bicyclic "heteroaryl" groups include: [ka] Examples include:

[0213] In certain embodiments, a "heteroaryl" is a 10-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

[0214] Non-limiting examples of bicyclic "heteroaryl" groups include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine.

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

[0216] In alternative embodiments, a "heteroaryl" can include one, two, three, or four R 31 "Optionally substituted" with substituents.

[0217] Aryl Embodiments In certain embodiments, aryl is phenyl.

[0218] In certain embodiments, aryl is naphthyl.

[0219] In alternative embodiments, "aryl" refers to one, two, three, or four R 31 "Optionally substituted" with substituents.

[0220] 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:

[0221] 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:

[0222] Additional non-limiting examples of divalent bicycles include: [ka] Examples include:

[0223] In alternative embodiments, a "bicycle" may include one, two, three, or four R 31 "Optionally substituted" with substituents.

[0224] Optional Substituent Embodiments While the variable moieties can be optionally substituted, in certain embodiments, the variable moieties are not substituted.

[0225] A variable moiety can be optionally substituted, in certain embodiments, the variable moiety is substituted with one substituent.

[0226] A variable moiety can be optionally substituted. In certain embodiments, the variable moiety is substituted with two substituents.

[0227] The variable moiety can be optionally substituted. In certain embodiments, the variable moiety is substituted with three substituents.

[0228] The variable moiety can be optionally substituted. In certain embodiments, the variable moiety is substituted with four substituents.

[0229] 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, triazinyl, 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.

[0230] 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.

[0231] In certain embodiments, "heteroaliphatic" refers to an aliphatic moiety that contains at least one heteroatom in place of a carbon atom in the chain, such as an amine, carbonyl, carboxy, oxo, thio, phosphate, phosphonate, nitrogen, phosphorus, silicon, or boron 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.

[0232] A and A * Embodiments of the present invention In certain embodiments, A * teeth, [ka] is.

[0233] In certain embodiments, A * teeth, [ka] is.

[0234] In certain embodiments, A * teeth, [ka] is.

[0235] In certain embodiments, A * teeth, [ka] is.

[0236] In certain embodiments, A * teeth, [ka] is.

[0237] In certain embodiments, A * teeth, [ka] is.

[0238] In certain embodiments, R 34 and R 35 and combine to form CH2.

[0239] In certain embodiments, R 34 is H.

[0240] In certain embodiments, R 35 is H.

[0241] In certain embodiments, A 1 is NH.

[0242] In certain embodiments, A 1 is O.

[0243] In certain embodiments, A 21 is NH.

[0244] In certain embodiments, A21 is O.

[0245] In certain embodiments, A 21 is CH2.

[0246] In certain embodiments, A 21 is NR 100 is.

[0247] In certain embodiments, A 32 , A 33 , A 34 and A 35 are each selected from CH, C-halogen and CF.

[0248] In certain embodiments, A 32 is CH.

[0249] In certain embodiments, A 32 is CF.

[0250] In certain embodiments, A 32 is CR 42 is.

[0251] In certain embodiments, A 32 is N.

[0252] In certain embodiments, A 33 is CH.

[0253] In certain embodiments, A 33 is CF.

[0254] In certain embodiments, A 33 is CR 42 is.

[0255] In certain embodiments, A 33 is N.

[0256] In certain embodiments, A34 is CH.

[0257] In certain embodiments, A 34 is CF.

[0258] In certain embodiments, A 34 is CR 42 is.

[0259] In certain embodiments, A 34 is N.

[0260] In certain embodiments, A 35 is CH.

[0261] In certain embodiments, A 35 is CF.

[0262] In certain embodiments, A 35 is CR 42 is.

[0263] In certain embodiments, A 35 is N.

[0264] In certain embodiments, A 36 is N.

[0265] In certain embodiments, R 90 is hydrogen.

[0266] In certain embodiments, R 90 is C1-C3 alkyl.

[0267] In certain embodiments, R 90 is C 3~6 -cycloalkyl.

[0268] In certain embodiments, R 90 is methyl.

[0269] In certain embodiments, A or A * teeth, [ka] is.

[0270] In certain embodiments, A or A * teeth, [ka] is.

[0271] In certain embodiments, A or A * teeth, [ka] is.

[0272] In certain embodiments, A or A * teeth, [ka] is selected from.

[0273] B and B * Embodiments of the present invention In certain embodiments, B or B * teeth, [ka] is.

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

[0275] In certain embodiments, B * is heteroaryl.

[0276] In certain embodiments, B * is one R 31 and heteroaryl substituted with a group.

[0277] In certain embodiments, B * is aryl.

[0278] In certain embodiments, B * is one R 31 It is an aryl substituted with a group.

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

[0280] In certain embodiments, B * teeth, [ka] is.

[0281] In certain embodiments, B * teeth, [ka] is.

[0282] In certain embodiments, B * teeth, [ka] is.

[0283] In certain embodiments, B * teeth, [ka] is.

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

[0285] y embodiment In certain embodiments, y is 0.

[0286] In certain embodiments, y is 1.

[0287] In certain embodiments, y is 2.

[0288] In certain embodiments, y is 3.

[0289] R 31 Embodiments of the present invention In certain embodiments, at least one R 31 is a halogen.

[0290] In certain embodiments, at least one R 31 is F.

[0291] In certain embodiments, at least one R 31 is Cl.

[0292] In certain embodiments, at least one R 31 is C 1~6 - alkyl.

[0293] In certain embodiments, at least one R 31 is Halo-C 1~6 - alkyl.

[0294] In certain embodiments, one R 31 is a halogen.

[0295] In certain embodiments, one R31 is F.

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

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

[0298] In certain embodiments, one R 31 is cyano.

[0299] In certain embodiments, one R 31 is C 1~6 -alkoxy.

[0300] In certain embodiments, one R 31 is Halo-C 1~6 -alkoxy.

[0301] In certain embodiments, one R 31 is C 3~8 -cycloalkyl.

[0302] In certain embodiments, one R 31 is Halo-C 3~8 -cycloalkyl.

[0303] In certain embodiments, R 31 is a halogen, C 1~6 -alkoxy and C 1~6 -alkyl.

[0304] In certain embodiments, R 31 is selected from F, Cl, methoxy and methyl.

[0305] R 36 and R 37 Embodiments of the present invention In certain embodiments, R 36and R 37 and are bonded together to form one, two or three R 31 It forms a 5-membered ring optionally substituted with substituents.

[0306] 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.

[0307] 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.

[0308] 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.

[0309] 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.

[0310] 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.

[0311] 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.

[0312] In certain embodiments, R 36 and R37 and are bonded together to form one, two or three R 31 It forms a 6-membered heterocyclic ring optionally substituted with substituents.

[0313] 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.

[0314] 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.

[0315] In certain embodiments, R 36 and R 37 The ring formed by bonding of and is not substituted.

[0316] In certain embodiments, R 36 and R 37 The ring formed by bonding is one R 31 It is substituted with a substituent.

[0317] In certain embodiments, R 36 and R 37 The ring formed by bonding two R 31 It is substituted with a substituent.

[0318] 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.

[0319] In certain embodiments, R 36 is hydrogen.

[0320] In certain embodiments, R 36 is a halogen.

[0321] In certain embodiments, R 36 is F.

[0322] In certain embodiments, R 36 is Cl.

[0323] In certain embodiments, R 36 is C 1~6 - alkyl.

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

[0325] In certain embodiments, R 36 is C 1~6 -alkoxy.

[0326] In certain embodiments, R 36 Halo-C 1~6 -alkoxy.

[0327] In certain embodiments, R 36 is C 3~8 -cycloalkyl.

[0328] In certain embodiments, R 36 Halo-C 3~8 -cycloalkyl.

[0329] In certain embodiments, R 36 are hydrogen, halogen, C 1~6 -alkoxy and C 1~6 -alkyl.

[0330] In certain embodiments, R 36 is selected from hydrogen, F, Cl, methoxy and methyl.

[0331] In certain embodiments, R 37 is hydrogen.

[0332] In certain embodiments, R 37 is a halogen.

[0333] In certain embodiments, R 37 is F.

[0334] In certain embodiments, R 37 is Cl.

[0335] In certain embodiments, R 37 is C 1~6 - alkyl.

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

[0337] In certain embodiments, R 37 is C 1~6 -alkoxy.

[0338] In certain embodiments, R 37 Halo-C 1~6 -alkoxy.

[0339] In certain embodiments, R 37 is C 3~8 -cycloalkyl.

[0340] In certain embodiments, R 37 Halo-C 3~8 -cycloalkyl.

[0341] In certain embodiments, R 37 are hydrogen, halogen, C 1~6 -alkoxy and C 1~6 -alkyl.

[0342] In certain embodiments, R 37 is selected from hydrogen, F, Cl, methoxy and methyl.

[0343] R 42 Embodiments of the present invention In certain embodiments, at least one R 42 is a halogen.

[0344] In certain embodiments, at least one R 42 is F.

[0345] In certain embodiments, at least one R 42 is Cl.

[0346] In certain embodiments, at least one R 42 is C 1~6 - alkyl.

[0347] In certain embodiments, at least one R 42 is Halo-C 1~6 - alkyl.

[0348] In certain embodiments, R 42 is hydrogen.

[0349] In certain embodiments, R 42 is a halogen.

[0350] In certain embodiments, R 42 is F.

[0351] In certain embodiments, R 42 is Cl.

[0352] In certain embodiments, R 42 is C 1~6 - alkyl.

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

[0354] In certain embodiments, R42 is C 1~6 -alkoxy.

[0355] In certain embodiments, R 42 Halo-C 1~6 -alkoxy.

[0356] In certain embodiments, R 42 is C 3~8 -cycloalkyl.

[0357] In certain embodiments, R 42 Halo-C 3~8 -cycloalkyl.

[0358] In certain embodiments, R 42 are hydrogen, halogen, C 1~6 -alkoxy and C 1~6 -alkyl.

[0359] In certain embodiments, R 42 is selected from hydrogen, F, Cl, methoxy and methyl.

[0360] 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.

[0361] In certain embodiments, ring G contains one or two R 42 It is a 6-membered heteroaryl ring optionally substituted with substituents.

[0362] In certain embodiments, ring G is [ka] is selected from.

[0363] EGFR-Targeting Ligand Embodiments In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] is selected from.

[0364] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] is selected from.

[0365] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] is selected from.

[0366] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] is selected from.

[0367] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] Selected from TIFF2024521791000164.tif238170TIFF2024521791000165.tif103170.

[0368] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] Selected from TIFF2024521791000167.tif239170TIFF2024521791000168.tif69170.

[0369] Compound of Formula III In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] is selected from.

[0370] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] is selected from.

[0371] Compound of Formula IV In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] is selected from.

[0372] III. Additional Compounds for Use in the Present Invention In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] is selected from.

[0373] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] is selected from.

[0374] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] Selected from TIFF2024521791000175.tif191170.

[0375] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] Selected from TIFF2024521791000177.tif118170.

[0376] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] Selected from TIFF2024521791000179.tif227170.

[0377] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] Selected from TIFF2024521791000181.tif168170.

[0378] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] Selected from TIFF2024521791000183.tif77170.

[0379] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] Selected from TIFF2024521791000185.tif192170.

[0380] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] Selected from TIFF2024521791000187.tif75170.

[0381] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] Selected from TIFF2024521791000189.tif189170.

[0382] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] Selected from TIFF2024521791000191.tif168170.

[0383] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] Selected from TIFF2024521791000193.tif113170.

[0384] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] is selected from.

[0385] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] is selected from.

[0386] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] is selected from.

[0387] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] is selected from.

[0388] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] is selected from.

[0389] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] is selected from.

[0390] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] is selected from.

[0391] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] is selected from.

[0392] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] Selected from TIFF2024521791000203.tif240170TIFF2024521791000204.tif109170.

[0393] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] is selected from.

[0394] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] Selected from TIFF2024521791000207.tif115170.

[0395] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] Selected from TIFF2024521791000209.tif202170.

[0396] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] Selected from TIFF2024521791000211.tif208170TIFF2024521791000212.tif130170.

[0397] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] Selected from TIFF2024521791000214.tif190170.

[0398] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] is selected from.

[0399] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] is selected from.

[0400] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] is selected from.

[0401] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] is selected from.

[0402] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] is selected from.

[0403] In certain embodiments, the compounds used in the methods of treatment described herein are: [ka] Selected from TIFF2024521791000221.tif238170TIFF2024521791000222.tif244170TIFF2024521791000223.tif152170.

[0404] IV. Linkers Linker (L 1 or L 2 ) or linkage is included in the compounds described herein. 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.

[0405] 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.

[0406] In certain embodiments, the linker is a bond.

[0407] 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.

[0408] 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.

[0409] 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.

[0410] 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-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 aspects, these units may be flanked or interspersed with other moieties, such as aliphatic, including alkyl, heteroaliphatic, aryl, heteroaryl, heterocyclic, cycloalkyl, etc., as desired to achieve appropriate drug properties.

[0411] In certain embodiments, L 2 teeth, [ka] is a linker selected from

[0412] 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.

[0413] In certain embodiments, the linker (L 2 )teeth, [ka] is a linker selected from

[0414] 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.

[0415] 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.

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

[0417] In certain embodiments, L 2 teeth, [ka] Selected from TIFF2024521791000230.tif74170.

[0418] In certain embodiments, L 2 teeth, [ka] is selected from.

[0419] In certain embodiments, L 2 teeth, [ka] is selected from.

[0420] In certain embodiments, L 2 teeth, [ka] is selected from.

[0421] In certain embodiments, L 2 teeth, [ka] is selected from.

[0422] In certain embodiments, L 2 teeth, [ka] is selected from.

[0423] R 20 , R 21 , R 22 , R 23 and R 24 Non-limiting examples of moieties include: [ka] Examples include:

[0424] R 20 , R 21 , R 22 , R 23 and R 24 Additional non-limiting examples of moieties include: [ka] Examples include:

[0425] R 20 , R 21 , R 22 , R 23 and R 24 Additional non-limiting examples of moieties include: [ka] Examples include:

[0426] 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.

[0427] In certain embodiments, the linker (L 2 ) is flanked, substituted or interspersed with aryl, phenyl, benzyl, alkyl, alkylene or heterocyclic groups.

[0428] In certain embodiments, the linker (L 2 ) may be asymmetric or symmetric.

[0429] In certain embodiments, the linker (L 2 ) may be a non-linear chain and may be or contain an aliphatic, aromatic or heteroaromatic cyclic moiety.

[0430] In any of the compound embodiments described herein, the linker group can be any suitable moiety described herein.

[0431] In certain embodiments, the linker (L 2 )teeth, [ka] is selected from the group consisting of:

[0432] In certain embodiments, the linker (L 2 )teeth, [ka] is selected from the group consisting of:

[0433] In certain embodiments, the linker (L 2 )teeth, [ka] is selected from the group consisting of:

[0434] In certain embodiments, the linker (L 2 )teeth, [ka] is selected from the group consisting of:

[0435] In certain embodiments, the linker (L 2 )teeth, [ka] is selected from the group consisting of:

[0436] In certain embodiments, the linker (L 2 )teeth, [ka] is selected from the group consisting of:

[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 ) or any part thereof, [ka] is selected from.

[0439] V. Treatment method The compounds described herein can be used in an effective amount to treat a patient in need of treatment or to treat any disorder mediated by EGFR.

[0440] Another aspect described herein provides a compound 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.

[0441] In one aspect, the compounds described herein 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.

[0442] 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.

[0443] In certain embodiments, the compounds described herein 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, the compounds described herein 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, the compounds described herein are used to treat cancers that are resistant or have acquired resistance to third-generation EGFR inhibitors, such as osimertinib.

[0444] In one aspect, the compounds described herein are used to treat EGFR-mediated cancers that have metastasized to the brain or CNS, 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.

[0445] In certain embodiments, the compounds described herein are used to treat cancers that have metastasized to the brain or CNS and that are resistant to or have acquired resistance to first-generation EGFR inhibitors, such as erlotinib, gefitinib, and / or lapatinib. In certain embodiments, the compounds described herein are used to treat cancers that have metastasized to the brain or CNS and that are resistant to or have acquired resistance to second-generation EGFR inhibitors, such as afatinib and / or dacomitinib. In certain embodiments, the compounds described herein are used to treat cancers that have metastasized to the brain or CNS and that are resistant to or have acquired resistance to third-generation EGFR inhibitors, such as osimertinib.

[0446] In some embodiments, the mutant EGFR protein in the affected tissue has an L858 mutation, eg, L858R.

[0447] In certain embodiments, the compounds described herein are used to treat mutant EGFR-mediated disorders in the brain or CNS, or mutant EGFR-mediated cancers that have metastasized to the brain or CNS, in which the EGFR has at least one mutation at the amino acid sites listed below, or a combination thereof. The mutation may be selected, for example, from one of the exemplary mutations listed, or may be a different mutation.

[0448] TIFF2024521791000247.tif97170

[0449] In certain embodiments, the mutant EGFR-mediated disorder in the brain or CNS or mutant EGFR-mediated cancer that has metastasized to the brain or CNS has two mutations selected from the table above. In other embodiments, the mutant EGFR-mediated disorder in the brain or CNS or mutant EGFR-mediated cancer that has metastasized to the brain or CNS has three mutations selected from the table above. In other embodiments, the mutant EGFR-mediated disorder in the brain or CNS or mutant EGFR-mediated cancer that has metastasized to the brain or CNS has four or more mutations, which may optionally be selected from the table above.

[0450] In certain embodiments, the mutant EGFR-mediated disorder in the brain or CNS, or mutant EGFR-mediated cancer that has metastasized to the brain or CNS, has an L858R mutation and one additional mutation, which may optionally be selected from the table above. In some of these embodiments, the mutant EGFR-mediated disorder in the brain or CNS, or mutant EGFR-mediated cancer that has metastasized to the brain or CNS, 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 in the brain or CNS, or mutant EGFR-mediated cancer that has metastasized to the brain or CNS, has an L858R mutation and three additional mutations, which may optionally be selected from the table above.

[0451] In certain embodiments, the mutant EGFR-mediated disorder in the brain or CNS, or mutant EGFR-mediated cancer that has metastasized to the brain or CNS, has a T790M mutation and, optionally, one additional mutation selected from the table above. In other embodiments, the mutant EGFR-mediated disorder in the brain or CNS, or mutant EGFR-mediated cancer that has metastasized to the brain or CNS, has a T790M mutation and, optionally, two additional mutations selected from the table above. In other embodiments, the mutant EGFR-mediated disorder in the brain or CNS, or mutant EGFR-mediated cancer that has metastasized to the brain or CNS, has a T790M mutation and, optionally, three additional mutations selected from the table above.

[0452] In certain embodiments, the mutant EGFR-mediated disorder in the brain or CNS, or mutant EGFR-mediated cancer that has metastasized to the brain or CNS, has an L718Q mutation and, optionally, one additional mutation selected from the table above. In other embodiments, the mutant EGFR-mediated disorder in the brain or CNS, or mutant EGFR-mediated cancer that has metastasized to the brain or CNS, has an L718Q mutation and, optionally, two additional mutations selected from the table above. In other embodiments, the mutant EGFR-mediated disorder in the brain or CNS, or mutant EGFR-mediated cancer that has metastasized to the brain or CNS, has an L718Q mutation and, optionally, three additional mutations selected from the table above.

[0453] In certain embodiments, the mutant EGFR-mediated disorder in the brain or CNS, or mutant EGFR-mediated cancer that has metastasized to the brain or CNS, has the following mutations: S768I, L718V, L792H, L792V, G796S, G796C, G724S, and / or G719A.

[0454] In certain embodiments, the compounds described herein are used to treat mutant EGFR-mediated disorders in the brain or CNS, or mutant EGFR-mediated cancers that have metastasized to the brain or CNS, in which the EGFR has a frameshift mutation, e.g., a short in-frame deletion. In certain embodiments, the compounds described herein are used to treat mutant EGFR-mediated disorders in the brain or CNS, or mutant EGFR-mediated cancers that have metastasized to the brain or CNS, in which the EGFR has an exon 19 deletion. In certain embodiments, the exon 19 deletion is a deletion that includes amino acids LREA (L747-A750). In certain embodiments, the exon 19 deletion is a deletion that includes amino acids ELREA (E746-A750).

[0455] In certain embodiments, the compounds described herein are used to treat mutant EGFR-mediated disorders in the brain or CNS, or mutant EGFR-mediated cancers that have metastasized to the brain or CNS, in which EGFR has an L858R mutation in exon 21.

[0456] In certain embodiments, the compounds described herein are more active against disorders driven by mutant EGFR than wild-type EGFR.

[0457] In certain embodiments, the compounds described herein are used to treat EGFR-mediated cancers that have metastasized to the brain or CNS, where EGFR has one or more exon 18 deletions.

[0458] In certain embodiments, the compounds described herein are used to treat mutant EGFR-mediated disorders in the brain or CNS, or mutant EGFR-mediated cancers that have metastasized to the brain or CNS, that have an E709 mutation, e.g., E709A, E709G, E709K, or E709V.

[0459] In certain embodiments, the compounds described herein are used to treat mutant EGFR-mediated disorders in the brain or CNS, or mutant EGFR-mediated cancers that have metastasized to the brain or CNS, that have an L718 mutation, e.g., L718Q.

[0460] In certain embodiments, the compounds described herein are used to treat mutant EGFR-mediated disorders in the brain or CNS, or mutant EGFR-mediated cancers that have metastasized to the brain or CNS, that have a G719 mutation, e.g., G719S, G719A, G719C, or G719D.

[0461] In certain embodiments, the compounds described herein are used to treat mutant EGFR-mediated disorders in the brain or CNS, or mutant EGFR-mediated cancers that have metastasized to the brain or CNS, in which EGFR has one or more exon 19 insertions and / or one or more exon 20 insertions.

[0462] In certain embodiments, the compounds described herein are used to treat S7681 mutant EGFR-mediated disorders in the brain or CNS or S7681 mutant EGFR-mediated cancers that have metastasized to the brain or CNS. In certain embodiments, the compounds described herein are used to treat L861Q mutant EGFR-mediated disorders in the brain or CNS or EGFR L861Q mutant EGFR-mediated cancers that have metastasized to the brain or CNS. In certain embodiments, the compounds described herein are used to treat C797S mutant EGFR-mediated cancers that have metastasized to the brain or CNS.

[0463] In certain embodiments, the compounds described herein are used to treat L858R-T790M mutant EGFR-mediated disorders in the brain or CNS.

[0464] In certain embodiments, the compounds described herein are used to treat L858R-L718Q mutant EGFR-mediated disorders in the brain or CNS.

[0465] In certain embodiments, the compounds described herein are used to treat L858R-L792H mutant EGFR-mediated disorders in the brain or CNS.

[0466] In certain embodiments, the compounds described herein are used to treat L858R-C797S mutant EGFR-mediated disorders in the brain or CNS.

[0467] In certain embodiments, the compounds described herein are used to treat L858R-T790M mutant EGFR-mediated cancers that have metastasized to the brain or CNS.

[0468] In certain embodiments, the compounds described herein are used to treat L858R-L718Q mutant EGFR-mediated cancers that have metastasized to the brain or CNS.

[0469] In certain embodiments, the compounds described herein are used to treat L858R-L792H mutant EGFR-mediated cancers that have metastasized to the brain or CNS.

[0470] In certain embodiments, the compounds described herein are used to treat L858R-C797S mutant EGFR-mediated cancers that have metastasized to the brain or CNS.

[0471] In certain embodiments, the EGFR-mediated cancer that has metastasized to the brain or CNS is a hematological cancer.

[0472] In certain embodiments, the EGFR-mediated cancer that has metastasized to the brain or CNS is selected from the group consisting of 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, and leukemia. Leukemia, mixed lineage 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.

[0473] Additional EGFR-mediated cancers that have metastasized to the brain or CNS that can be treated using the compounds described herein include lung cancer, including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), inflammatory breast cancer, breast cancer, including 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, including castration-resistant prostate cancer (CRPC), glioma, and glioblastoma. brain cancer, including neuroblastoma, 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, including 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).

[0474] In a further embodiment, the cancer that has metastasized to the brain or CNS is a sarcoma of bone, muscle, tendon, cartilage, nerve, fat, or blood vessels.

[0475] In further embodiments, the cancer that has metastasized to the brain or CNS is a soft tissue sarcoma, a bone sarcoma, or an osteosarcoma.

[0476] In further embodiments, the cancer that has metastasized to the brain or CNS 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.

[0477] In certain embodiments, the cancer that has metastasized to the brain or CNS is a sarcoma of bone, muscle, tendon, cartilage, nerve, fat, or blood vessels.

[0478] In a further embodiment, the cancer that has metastasized to the brain or CNS is multiple myeloma.

[0479] In certain embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are used as medicaments in the therapeutic and / or prophylactic treatment of patients suffering from cancer, particularly non-small cell lung cancer, who have an EGFR activating mutation as determined by next generation sequencing (NGS), comprising determining the EGFR activating mutation status in the patient and then administering to said patient a compound described herein or a pharmaceutically acceptable salt thereof.

[0480] In other embodiments, the cancer that has metastasized to the brain or CNS is selected from lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, 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 tumors, hematologic cancer, or solid tumors.

[0481] 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.

[0482] 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.

[0483] 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.

[0484] In some embodiments, the compounds described herein are useful for treating cancers that have metastasized to the brain or CNS, such as colon 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).

[0485] In certain embodiments, the compounds described herein, or their corresponding pharmaceutically acceptable salts or isotopic derivatives as described herein, can be used in an effective amount to treat a host, e.g., a human, having a cancer that has metastasized to the brain or CNS, and the cancer that has metastasized to the brain or CNS can be selected from lymphoma, or lymphocytic or myeloid proliferative disorders or abnormalities. 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 can be, but is 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.

[0486] In another embodiment, the compounds described herein, or their corresponding pharmaceutically acceptable salts, or isotopic derivatives as described herein, can be used in an effective amount to treat a patient, e.g., a human, having a cancer that has metastasized to the brain or CNS, selected from 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.

[0487] 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.

[0488] The compounds and compositions of the present application are also useful in biological samples as degraders of EGFR protein. One aspect of the present application is inhibiting protein activity in a biological sample. This method involves 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.

[0489] 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.

[0490] 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.

[0491] VI. Combination Therapy The disclosed compounds described herein can be used in effective amounts alone or in combination with another compound described herein or another bioactive agent or second therapeutic agent to treat a patient, such as a human, with an EGFR-mediated cancer that has metastasized to the brain or CNS, including, but not limited to, those described herein.

[0492] 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 described herein to achieve a desired therapeutic outcome. In certain embodiments, a compound described herein 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 described herein 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.

[0493] 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.

[0494] 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 (GlaxoSmithKline plc), 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 Co. Ltd.), 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 plc), IMP321 (Prima BioMed), LAG525 (Novartis), and the dual PD-1 and LAG-3 inhibitor MGD013 (MacroGenics). An example of a TIM-3 inhibitor is TSR-022 (GlaxoSmithKline plc).

[0495] In certain embodiments, the checkpoint inhibitor is selected from nivolumab (OPDIVO™), pembrolizumab (KEYTRUDA™), and PDL2 / lg fusion proteins such as pidilizumab / CT-011, MPDL3280A / RG7446, MEDI4736, MSB0010718C, BMS 936559, 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.

[0496] 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.

[0497] 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.

[0498] 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.

[0499] 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.

[0500] 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 full androgen receptor degrader, or another form of partial or full androgen antagonist, for the treatment of abnormal tissues of the male reproductive system, such as prostate cancer or testicular cancer. In certain embodiments, the prostate or testicular cancer is androgen-resistant.

[0501] 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.

[0502] 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.

[0503] In certain embodiments, the bioactive agent is a HER-2 inhibitor. Examples of HER-2 inhibitors include trastuzumab, lapatinib, ado-trastuzumab emtansine, and pertuzumab.

[0504] In certain embodiments, the bioactive agent is a CD20 inhibitor. Examples of CD20 inhibitors include obinutuzumab (GAZYVA™), rituximab (RITUXAN™), ofatumumab, ibritumomab, tositumomab, and ocrelizumab.

[0505] In certain embodiments, the bioactive agent is a JAK3 inhibitor. Examples of JAK3 inhibitors include tasocitinib.

[0506] 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).

[0507] 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.

[0508] 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).

[0509] 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.

[0510] 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)).

[0511] 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-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol). 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.

[0512] In certain embodiments, the bioactive agent is a Raf inhibitor. Raf inhibitors are known, such as 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)-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 -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 (BRAFTOVI™)).

[0513] In certain embodiments, the bioactive agent is an EGFR inhibitor, including, for example, gefitinib (IRESSA™), lapatinib (TYKERB™), osimertinib (TAGRISSO™), neratinib (NERLYNX™), vandetanib (CAPRELSA™), dacomitinib (VIZIMPRO™), rociletinib (XEGAFRI™), afatinib (GLOTRIFF™, GIOTRIFF™, AFANIX™), lazertinib, or nazartinib.

[0514] 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).

[0515] 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.

[0516] In certain embodiments, Compound 1 is administered in combination with an ATP site binding inhibitor of EGFR or mutant EGFR. Non-limiting examples of EGFR ATP site binding inhibitors include osimertinib, nacotinib, mavereltinib, spebrutinib, and AZ5104.

[0517] In certain embodiments, the compounds described herein are administered in combination with osimertinib to a patient in need thereof.

[0518] In certain embodiments, the compounds described herein are administered in combination with nacotinib to a patient in need thereof.

[0519] In certain embodiments, the compounds described herein are administered in combination with mavereltinib to a patient in need thereof.

[0520] In certain embodiments, the compounds described herein are administered in combination with spebrutinib to a patient in need thereof.

[0521] In certain embodiments, the compounds described herein are administered to a patient in need thereof in combination with AZ5104.

[0522] In certain embodiments, the compounds described herein are administered in combination with rociletinib to a patient in need thereof.

[0523] In certain embodiments, the compounds described herein are administered in combination with avitinib to a patient in need thereof.

[0524] In certain embodiments, the compounds described herein are administered in combination with lazertinib to a patient in need thereof.

[0525] In certain embodiments, the compounds described herein are administered in combination with nazartinib to a patient in need thereof.

[0526] In certain embodiments, the compounds described herein are administered to a patient in need thereof in combination with an EGFR antibody, such as cetuximab, panitumumab, or necitumumab.

[0527] In certain embodiments, the compounds described herein are administered to a patient in need thereof in combination with cetuximab.

[0528] In certain embodiments, the compounds described herein are administered to a patient in need thereof in combination with panitumumab.

[0529] In certain embodiments, the compounds described herein are administered to a patient in need thereof in combination with necitumumab.

[0530] 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).

[0531] 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.

[0532] 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.

[0533] In certain embodiments, the bioactive agent is a RAS inhibitor. Examples of RAS inhibitors include, but are not limited to, Reolysin and siG12D LODER.

[0534] 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.

[0535] 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, megence acetate strolol, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, 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, hydroxyurea Rhea, 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, idoxyfene, squalamine, endostatin ... Pironolactone, 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 , 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, androgen,These include 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.

[0536] In certain embodiments, the compound is administered in combination with ifosfamide.

[0537] 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™).

[0538] In certain embodiments, the bioactive agent is an anti-inflammatory agent, a chemotherapeutic agent, a radiotherapeutic agent, an additional therapeutic agent, or an immunosuppressant.

[0539] 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™).

[0540] 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.

[0541] In some embodiments, the compounds described herein 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 described herein. 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).

[0542] 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, cetuximab, panitumumab, gefitinib, trastuzumab, dovicine, and the like. Nib, figitumumab, atacicept, rituximab, alemtuzumab, aldesleukine, atlizumab, tocilizumab, temsirolimus, everolimus, lucatumumab, dacetuzumab, HLL1, huN901-DM1, atiplimod, natalizumab, bortezomib, carfilzomib, marizomib, tanespimycin, saquinavir mesylate, ritonavir, nelfinavir mesylate ru, 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).

[0543] 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.

[0544] In one aspect of the invention, the bioactive agent is an immunosuppressant. Immunosuppressants include calcineurin inhibitors such as cyclosporine or ascomycin, e.g., cyclosporine A (NEORAL™), FK506 (tacrolimus), pimecrolimus, mTOR inhibitors such as rapamycin or its derivatives, e.g., sirolimus (RAPAMUNE™), everolimus (Certican™), temsirolimus, zotarolimus, biolimus-7, biolimus-9, rapalogs such as ridaforolimus, azathioprine, campath 1H, S1P receptor modulators such as fingolimod or analogs thereof, anti-IL-8 antibodies, mycophenolic acid or a salt thereof, e.g., the sodium salt or a prodrug thereof, e.g., mycophenolate mofetil (CELLCEPT™), OKT3 (ORTHOCLONE™), and the like. 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.

[0545] 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), sumab), NUMAX™ (motavizumab), ABTHRAX™ (raxibacumab), BENLYSTA™ (belimumab), YERVOY™ (ipilimumab), ADCETRIS™ (brentuximab vedotin), PERJETA™ (pertuzumab), KADCYLA™ (adotrastuzumab emtansine), and GAZYVA™ (obinutuzumab). Antibody-drug conjugates are also included.

[0546] 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.

[0547] Compounds administered "in combination," as that term is used herein, can refer to the administration of the two compounds simultaneously or at different times or on different days of a treatment cycle.

[0548] 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.

[0549] In certain embodiments, the second therapeutic agent is administered on a different dosing schedule from the compound described herein. For example, the second therapeutic agent may have a treatment holiday of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle. In another embodiment, the first therapeutic agent has a treatment holiday. For example, the first therapeutic agent may have a treatment holiday of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle. In certain embodiments, both the first and second therapeutic agents have a treatment holiday.

[0550] 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.

[0551] 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.

[0552] 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.

[0553] 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.

[0554] 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.

[0555] 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:

[0556] 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.

[0557] 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.

[0558] In certain embodiments, the compounds described herein are administered once daily, twice daily, three times daily, or four times daily.

[0559] In certain embodiments, the compound described herein is orally administered once a day.In certain embodiments, the compound described herein is orally administered twice a day.In certain embodiments, the compound described herein is orally administered three times a day.In certain embodiments, the compound described herein is orally administered four times a day.

[0560] In certain embodiments, the compound described herein is intravenously administered once a day.In certain embodiments, the compound described herein is intravenously administered twice a day.In certain embodiments, the compound described herein is intravenously administered three times a day.In certain embodiments, the compound described herein is intravenously administered four times a day.

[0561] In some embodiments, the compounds described herein 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.

[0562] 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.

[0563] 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.

[0564] 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.

[0565] 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 may be prepared with enteric coatings suitable for sustained- or controlled-release administration of the active ingredient.

[0566] 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.

[0567] 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.

[0568] 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.

[0569] 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.

[0570] 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.

[0571] 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.

[0572] Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated. Carriers may be inert or may possess medicinal properties in themselves. 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.

[0573] Classes of carriers include, but are not limited to, adjuvants, binders, buffers, colorants, diluents, disintegrants, excipients, emulsifiers, flavorings, gels, glidants, lubricants, preservatives, stabilizers, surfactants, solubilizers, tableting agents, wetting agents or solidifying agents.

[0574] 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.

[0575] 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 compounds described herein may be included in the pharmaceutical composition.

[0576] 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 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).

[0577] 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.

[0578] 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.

[0579] In yet another embodiment, there is provided the use of penetration-enhancing excipients 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).

[0580] 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.

[0581] 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.

[0582] 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.

[0583] 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.

[0584] 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.

[0585] 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.

[0586] 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.

[0587] 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.

[0588] 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.

[0589] 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.

[0590] 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.

[0591] 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.

[0592] 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.

[0593] 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.

[0594] 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.

[0595] In certain embodiments, the pharmaceutical composition is suitable for topical application to the skin using the administration methods defined above.

[0596] 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.

[0597] 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.

[0598] 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.

[0599] In certain embodiments, an oral formulation is provided.

[0600] Example A Tablets of the following composition are prepared in the usual manner:

[0601] TIFF2024521791000248.tif67170

[0602] 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.

[0603] Example B-1 Capsules of the following composition are prepared:

[0604] TIFF2024521791000249.tif67170

[0605] 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.

[0606] 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.

[0607] Example B-2 Soft gelatin capsules of the following composition are prepared:

[0608] TIFF2024521791000250.tif60170

[0609] TIFF2024521791000251.tif60170

[0610] 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.

[0611] Example C Suppositories of the following composition are prepared:

[0612] TIFF2024521791000252.tif36170

[0613] 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.

[0614] Example D An injection solution having the following composition is prepared.

[0615] TIFF2024521791000253.tif44170

[0616] 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.

[0617] Example E Sachets of the following composition are prepared:

[0618] TIFF2024521791000254.tif74170

[0619] 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.

[0620] 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.

[0621] material NCI-H1975 (harboring an EGFR heterozygous L858R-T790M mutation) and NCI-H3255 (harboring an EGFR heterozygous L858R mutation) were purchased from ATCC and NCI, respectively. NCI-H1975+CS (harboring an EGFR heterozygous L858R-T790M-C797S mutation) was generated by Horizon Discovery using CRISPR technology to introduce an additional C797S mutation. A431 (harboring EGFR wild-type) was purchased from ATCC. 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). Phosphorylated (pY1068) EGFR and total EGFR (using L858R-specific detection antibody and pan-EGFR antibody for EGFR mutant and EGFR wild-type cell lines, respectively) HTRF assay kits were purchased from Cisbio (Bedford, MA, USA).

[0622] EGFR inhibition and degradation assay Degradation of EGFR proteins harboring the L858R mutation or wild-type EGFR was determined based on FRET signal quantification using a Total EGFR (L858R-specific or pan-EGFR detection) HTRF assay kit. Phospho-EGFR (pEGFR) inhibition was determined based on FRET signal quantification using a pY1068 EGFR HTRF assay kit. In separate assay plates, test compounds were added in duplicate to 384-well plates in 11-point, half-log titrations, starting from a top concentration of 10 μM. For each assay, 12.5 μL of cells suspended in assay medium (RPMI 1640 phenol red-free medium + 10% FBS) at the cell densities indicated for each cell line in Table 8 below were dispensed using a multichannel pipette into 384-well low-volume white HTRF microplates containing duplicate concentration ranges of test compounds and DMSO controls. Plates were incubated at 37°C with 5% CO2 for 6 hours and then incubated with either phospho-EGFR or total EGFR HTRF detection antibodies, depending on the cell line and EGFR mutant being assayed. Cells treated in the absence of test compounds served as negative controls. Positive controls were set up in wells containing all reagents but no cells. FRET signals were acquired using an EnVision™ Multilabel Reader (PerkinElmer, Santa Clara, CA, USA). The compound concentrations achieving 50% degradation and inhibition were reported as DC50 and IC50, respectively.

[0623] TIFF2024521791000255.tif50170

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[0626] TIFF2024521791000336.tif235170

[0627] TIFF2024521791000337.tif251170TIFF2024521791000338.tif81170

[0628] 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.

[0629] 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.

[0630] The preparation of compounds of formula I is further illustrated in more detail in the following schemes. [ka]

[0631] Generally, the order of steps used in the synthesis of compounds of formula I may also be varied in certain cases.

[0632] The preparation of compounds of formula II is further illustrated in more detail in the following scheme. [ka] TIFF2024521791000341.tif84170

[0633] 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.

[0634] 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.

[0635] 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.

[0636] 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.

[0637] 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.

[0638] X. Experimental Procedure Abbreviation

[0639] TIFF2024521791000342.tif245170TIFF2024521791000343.tif254170TIFF2024521791000344.tif254170TIFF2024521791000345.tif85170

[0640] 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.

[0641] 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.

[0642] 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.

[0643] 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)

[0644] 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).

[0645] 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.

[0646] 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%. 1 H 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 = LC MS: ES+ 288.2.

[0647] 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).

[0648] 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).

[0649] 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.

[0650] 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℃

[0651] 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).

[0652] 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).

[0653] 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.

[0654] 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]).

[0655] 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)

[0656] 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)

[0657] 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)

[0658] 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, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (15% ethyl acetate-hexane) to give tert-butyl 4-[4-[(2,6-dibenzyloxy-3-pyridyl)amino]-2-fluoro-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (5.9 g, 10.1 mmol, 50% yield) as a pale yellow solid. LCMS: ES+ 582 (M+H + )

[0659] Step-3: Preparation of 4-[4-(2,6-dioxo-piperidin-3-ylamino)-2-fluoro-phenyl]-piperidine-1-carboxylic acid tert-butyl ester: [ka] 10% Pd-C (50% wet, 4.6 g) was added to a stirred, nitrogen-degassed solution of tert-butyl 4-[4-[(2,6-dibenzyloxy-3-pyridyl)amino]-2-fluoro-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (4.6 g, 7.91 mmol) in ethyl acetate (40 mL). The resulting mixture was stirred at ambient temperature under hydrogen balloon pressure for 20 hours. The reaction mixture was filtered through a small pad of Celite and washed with ethyl acetate. The combined filtrates were evaporated under reduced pressure and purified by column chromatography (40% ethyl acetate in hexanes) to give tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]piperidine-1-carboxylate (2.6 g, 6.41 mmol, 81% yield) as a blue solid. LCMS: ES+ 406 (M+H + ).

[0660] Step-4: Preparation of 3-(3-fluoro-4-piperidin-4-yl-phenylamino)-piperidine-2,6-dione hydrochloride [ka] Dioxane-HCl (4 M, 30 mL, 130 mmol) was added to tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]piperidine-1-carboxylate (1.3 g, 3.21 mmol) at 10° C. The resulting mixture was warmed to ambient temperature and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, triturated with ether, and lyophilized to give 3-[3-fluoro-4-(4-piperidyl)anilino]piperidine-2,6-dione (840 mg, 2.73 mmol, 85.25% yield) as a green solid. LC MS: ES+ 306 (M+H + ). 1H NMR (400 MHz, DMSO-d6) δ10.79 (s, 1H), 9.00 (br s, 1H), 8.85-8.83 (m, 1H), 6.96-6.91 (m, 1H), 6.50-6.45 (m, 2H), 4.34-4.30 (m, 1H), 3.32-3.29 (m, 2H), 2.98-2.93 (m, 3H), 2.77-2.69 (m, 1H), 2.60-2.56 (m, 1H), 2.08-2.05 (m, 1H), 1.92-1.81 (m, 5H).

[0661] Intermediate synthesis of 3-(2-fluoro-4-piperidin-4-yl-phenylamino)-piperidine-2,6-dione hydrochloride [ka] Step-1: Preparation of 4-(4-amino-3-fluoro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester: [ka] Sodium carbonate (6.14 g, 57.89 mmol) was added to a stirred solution of 4-bromo-2-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). The resulting mixture was degassed with argon, and PdCl(dppf)·dichloromethane (430 mg, 526 μmol) was added under an inert atmosphere. The resulting mixture was 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, 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-3-fluoro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (6.1 g, 20.9 mmol, 79% yield) as a pale yellow solid. LC MS: ES+ 293 (M+H + ).

[0662] Step-2: Preparation of 4-[4-(2,6-bis-benzyloxy-pyridin-3-ylamino)-3-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-3-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, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (10% ethyl acetate-hexane) to give tert-butyl 4-[4-[(2,6-dibenzyloxy-3-pyridyl)amino]-3-fluoro-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (5.9 g, 10.1 mmol, 50% yield) as a pale yellow solid. LC MS: ES+ 582 (M+H + ).

[0663] Step-3: Preparation of 4-[4-(2,6-dioxo-piperidin-3-ylamino)-3-fluoro-phenyl]-piperidine-1-carboxylic acid tert-butyl ester: [ka] 10% Pd-C (50% wet, 4.6 g) was added to a degassed, stirred solution of tert-butyl 4-[4-[(2,6-dibenzyloxy-3-pyridyl)amino]-3-fluoro-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (4.6 g, 7.91 mmol) in ethyl acetate (40 mL). The resulting mixture was stirred at ambient temperature under hydrogen balloon pressure for 20 hours. The reaction mixture was filtered through a short pad of Celite and washed with ethyl acetate. The combined filtrates were evaporated under reduced pressure and purified by column chromatography (40% ethyl acetate-hexane) to give tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]-3-fluoro-phenyl]piperidine-1-carboxylate (2.6 g, 6.41 mmol, 81% yield) as a blue solid. LC MS: ES+ 406 (M+H + ).

[0664] Step-4: Preparation of 3-(2-fluoro-4-piperidin-4-yl-phenylamino)piperidine-2,6-dione hydrochloride [ka] Dioxane HCl (4 M, 10 mL, 40 mmol) was added to tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]-3-fluoro-phenyl]piperidine-1-carboxylate (1.3 g, 3.21 mmol) at 10° C. The resulting mixture was allowed to warm to ambient temperature and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, triturated with ether, and lyophilized to give 3-[2-fluoro-4-(4-piperidyl)anilino]piperidine-2,6-dione hydrochloride (840 mg, 2.73 mmol, 85% yield) as a green solid. LC MS: ES+ 306 (M+H + ). 1H NMR (400 MHz, DMSO-d6) δ10.82 (s, 1H), 8.85 (br s, 1H), 8.69-8.68 (m, 1H), 6.92-6.89 (m, 1H), 6.83-6.77 (m, 2H), 4.40-4.36 (m, 2H), 3.37-3.31 (m, 2H), 2.98-2.90 (m, 2H), 2.76-2.71 (m, 2H), 2.58-2.56 (m, 1H), 2.05-1.73 (m, 6H).

[0665] Synthesis of (S)-4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine hydrochloride and (R)-4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine hydrochloride Step 1: Chiral separation to obtain tert-butyl 4-(4-(((3S)-2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine-1-carboxylate and tert-butyl 4-(4-(((3R)-2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine-1-carboxylate [ka] Separation of racemic tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine-1-carboxylate (5.96 g) by chiral SFC was carried out using the following method. Column: ChiralCel OJ-H (250 x 21 mm), 5 μm silica Flow rate: 70mL / min Mobile phase: 65% CO2 + 35% isopropyl alcohol ABPR: 100 bar Temperature: 35℃

[0666] SFC separation yielded two sets of fractions: the earlier fraction was lyophilized to give tert-butyl 4-(4-(((3S)-2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine-1-carboxylate (2.51 g, 42% yield, enantiomeric excess >99%, chiral SFC retention time = 0.91 min).

[0667] The subsequent fractions were lyophilized to give tert-butyl 4-(4-(((3R)-2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine-1-carboxylate (2.69 g, 45% yield, 99.6% enantiomeric excess, chiral SFC retention time = 1.26 min).

[0668] The retention times and enantiomeric excess of the two isolated isomers were determined by analytical chiral SFC using the following conditions: Column: ChiralCel OJ-H (100 x 4.6 mm) Flow rate: 4mL / min Pressure: 100 bar Temperature: 40℃

[0669] Step 2: Synthesis of (S)-4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine hydrochloride [ka] Using general procedure B, (S)-4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine hydrochloride was obtained in quantitative yield from tert-butyl 4-(4-(((3S)-2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine-1-carboxylate. LCMS (ESI+): 306.3 [M+H + ]

[0670] Step 3: Synthesis of (R)-4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine hydrochloride [ka] Using general procedure B, (R)-4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine hydrochloride was obtained from tert-butyl 4-(4-(((3S)-2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine-1-carboxylate in quantitative yield. LCMS (ESI+): 306.3 (M+H + )

[0671] Intermediate: 2-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]acetic acid Step-1: Preparation of tert-butyl 2-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]acetate [ka] 3-Bromopiperidine-2,6-dione (13.9 g, 72.4 mmol) followed by sodium bicarbonate (12.2 g, 145 mmol) were added to a stirred solution of tert-butyl 2-(4-aminophenyl)acetate (10.0 g, 48.3 mmol) in DMF (80 mL) in a sealed tube. The resulting mixture was heated at 70° C. for 24 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (35% ethyl acetate-hexane) to give tert-butyl 2-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]acetate (7.5 g, 23.6 mmol, 49% yield). LC MS: ES+ 319 (M+H + )

[0672] Step-2: Preparation of 2-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]acetic acid [ka] TFA (8.47 mL, 110 mmol) was added dropwise to a stirred solution of tert-butyl 2-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]acetate (3.5 g, 10.99 mmol) in dichloromethane (45 mL) at 0° C. The resulting mixture was allowed to warm to ambient temperature and stirred for 5 h. The reaction mixture was concentrated under reduced pressure, triturated with MTBE, and lyophilized to give 2-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]acetic acid (2.9 g, 10.9 mmol, 99% yield) as a gray solid. LC MS: ES+ 263 (M+H + ). 1 H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 6.97 (d, J=8.36 Hz, 2H), 6.63 (d, J=8.36 Hz, 2H), 4.32-4.28 (m, 1H), 3.37 (s, 2H), 2.78-2.71 (m, 1H), 2.61-2.54 (m, 1H), 2.13-2.07 (m, 1H), 1.92-1.81 (m, 1H)

[0673] Intermediate: Synthesis of 1-(6-bromo-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4-dione [ka] Step-1: Preparation of 6-bromo-1-methyl-indazol-3-amine: [ka] Sodium hydride (60% in oil, 2.38 g, 59.4 mmol) was added portionwise to a stirred solution of 6-bromo-1H-indazol-3-amine (7 g, 33.0 mmol, 439 μL) in DMF (150 mL) at 0 °C, and the mixture was stirred for 40 minutes. Iodomethane (5.15 g, 36.3 mmol, 2.26 mL) was added dropwise under cooling, and the resulting mixture was warmed to ambient temperature and stirred for 16 hours. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (50% ethyl acetate-hexane) to give 6-bromo-1-methyl-indazol-3-amine (4.2 g, 18.6 mmol, 56% yield). LC MS: ES+ 227 (M+H + )

[0674] Step-2: Preparation of ethyl 3-[(6-bromo-1-methyl-indazol-3-yl)amino]propanoate: [ka] Ethyl acrylate (14.0 g, 139 mmol) was added to a mixture of 6-bromo-1-methyl-indazol-3-amine (4.2 g, 18.6 mmol) and [DBU][Lac] (prepared by mixing an equimolar mixture of DBU and lactic acid with stirring at ambient temperature for 16 hours, 2.09 g, 14.9 mmol) in five portions (2.8 g each) over a period of 5 days at 80 °C. After completion (LCMS), the reaction mixture was quenched with sodium hypochlorite (30% aq, 5 mL) and diluted with ethyl acetate. The combined organics were washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (50% ethyl acetate-hexane) to give ethyl 3-[(6-bromo-1-methyl-indazol-3-yl)amino]propanoate (2.9 g, 8.89 mmol, 48% yield). LCMS (ESI+): 327 (M+H + ).

[0675] Step-3: Preparation of ethyl 3-[(6-bromo-1-methyl-indazol-3-yl)-cyano-amino]propanoate: [ka] Anhydrous sodium acetate (1.46 g, 17.8 mmol) followed by cyanogen bromide (1.41 g, 13.3 mmol) were added to a stirred solution of ethyl 3-[(6-bromo-1-methyl-indazol-3-yl)amino]propanoate (2.9 g, 8.89 mmol) in ethanol (40 mL) at ambient temperature. The resulting mixture was heated to reflux for 48 hours. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. The combined organics were washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (45% ethyl acetate-hexane) to give ethyl 3-[(6-bromo-1-methyl-indazol-3-yl)-cyano-amino]propanoate (1.65 g, 4.70 mmol, 53% yield). LC MS: ES+ 352 (M+H + ).

[0676] Step-4: Preparation of ethyl 3-[(6-bromo-1-methyl-indazol-3-yl)-carbamoyl-amino]propanoate: [ka] (1E)-Acetaldehyde oxime (1.01 g, 17.1 mmol) followed by indium(III) chloride (126 mg, 569 μmol) were added to a stirred solution of ethyl 3-[(6-bromo-1-methyl-indazol-3-yl)-cyano-amino]propanoate (2 g, 5.69 mmol) in toluene (60 mL) at ambient temperature. The resulting mixture was heated to reflux for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (60% ethyl acetate-hexane) to give ethyl 3-[(6-bromo-1-methyl-indazol-3-yl)-carbamoyl-amino]propanoate (1.4 g, 3.79 mmol, 67% yield). LC MS: ES+ 370 (M+H + ).

[0677] Step-5: Preparation of 1-(6-bromo-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4-dione [ka] Triton-B (40% in methanol, 2.4 mL, 5.69 mmol) was added dropwise to a stirred solution of ethyl 3-[(6-bromo-1-methyl-indazol-3-yl)-carbamoyl-amino]propanoate (1.40 g, 3.79 mmol) in MeCN (70 mL) at ambient temperature. The resulting mixture was stirred at ambient temperature for 45 minutes. The reaction mixture was concentrated in vacuo and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (30% ethyl acetate-hexane) to afford 1-(6-bromo-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4-dione (910 mg, 2.81 mmol, 74% yield) as a white solid. LC MS: ES+ 324 (M+H + ). 1H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 7.97 (s, 1H), 7.61 (d, J=8.6 Hz, 1H), 7.26-7.23 (m, 1H), 3.98 (s, 3H), 3.93 (t, J=6.6 Hz, 2H), 2.76 (t, J=6.6 Hz, 2H).

[0678] Preparation of 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride Step 1: tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate [ka] N was bubbled through a solution of 1-(6-bromo-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4-dione (1.25 g, 3.87 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (2.39 g, 7.74 mmol) for 10 minutes. Cesium fluoride (1.18 g, 7.74 mmol) and Pd(dppf)Cl (566 mg, 774 μmol) were then added, and the mixture was stirred at 85 °C for 2 hours. The mixture was cooled to ambient temperature, diluted with ethyl acetate, and filtered through Celite / silica gel. After washing with ethyl acetate, the filtrate was diluted with water, the layers were separated, and the organic layer was washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by normal phase chromatography (5% to 100% ethyl acetate in hexanes) to give tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (1.04 g, 2.44 mmol, 63% yield). LCMS (ESI+): 426.3 (M+H + )

[0679] Step 2: tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]piperidine-1-carboxylate [ka] Palladium (10% on carbon, Type 487, dried, 1.08 g, 1.02 mmol) was added to a solution of tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (1.44 g, 3.38 mmol) in methanol (30 mL), and the mixture was stirred at ambient temperature under a hydrogen balloon atmosphere. After 24 h, the reaction mixture was filtered through a pad of Celite, washed with a mixture of dichloromethane / methanol (1:1), and concentrated in vacuo to give tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]piperidine-1-carboxylate (1.42 g, 3.32 mmol, 98% yield). LCMS (ESI+): 372.3 (M-tert-butyl + H + ).

[0680] Step 3: 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride [ka] Using general method B for deprotection of the tert-butoxycarbonyl protecting group, 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride was obtained in quantitative yield from tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate. LCMS (ESI+): 328.1 (M+H + ).

[0681] Synthesis of 1-((4-(piperidin-4-yl)phenyl)amino)-3-azabicyclo[3.1.1]heptane-2,4-dione hydrochloride [ka] Step-1: Preparation of 3-cyano-3-(4-iodo-phenylamino)-cyclobutanecarboxylic acid methyl ester: [ka] 4-Iodoaniline (13.2 g, 60.1 mmol) followed by trimethylsilyl cyanide (10.8 g, 109 mmol, 13.7 mL) were added to a stirred solution of methyl 3-oxocyclobutanecarboxylate (7 g, 54.6 mmol) in methanol (270 mL). The resulting mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (5% to 10% ethyl acetate-hexanes) to give methyl 3-cyano-3-(4-iodoanilino)cyclobutanecarboxylate (15.2 g, 42.7 mmol, 78% yield) as an off-white solid. LCMS ES+ 357 (M+H + )

[0682] Step-2: Preparation of 3-carbamoyl-3-(4-iodo-phenylamino)-cyclobutanecarboxylic acid methyl ester: [ka] Acetaldehyde oxime (4.98 g, 84.2 mmol) followed by indium chloride (62.1 mg, 281 μmol) were added to a stirred solution of methyl 3-cyano-3-(4-iodoanilino)cyclobutanecarboxylate (10 g, 28.1 mmol) in toluene (120 mL) at ambient temperature. The resulting mixture was heated to reflux for 1 h. Upon completion, the reaction mixture was cooled to ambient temperature and the precipitate formed was filtered, washed with toluene:ether (1:1), and dried to give methyl 3-carbamoyl-3-(4-iodoanilino)cyclobutanecarboxylate (8.4 g, 22.5 mmol, 80% yield), which was used in the next step without further purification. LCMS (ESI+): 375 (M+H + )

[0683] Step-3: Preparation of 1-(4-iodo-phenylamino)-3-aza-bicyclo[3.1.1]heptane-2,4-dione: [ka] Potassium tert-butoxide (4.62 g, 41.2 mmol) was added to a stirred solution of methyl 3-[2-amino-1-(4-iodoanilino)-2-oxo-ethyl]cyclobutanecarboxylate (8 g, 20.6 mmol) in THF (150 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was neutralized with 1 M citric acid solution, adjusted to pH 6, and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residual mass was purified by column chromatography (40% ethyl acetate / hexane) to give 5-(4-iodoanilino)-3-azabicyclo[3.1.1]heptane-2,4-dione (2.9 g, 8.48 mmol, 41% yield). LCMS (ESI+): 343 (M+H + )

[0684] Step-4: Preparation of 4-[4-(2,4-dioxo-3-aza-bicyclo[3.1.1]hept-1-ylamino)-phenyl]-3,6-dihydro-2H-pyridine 1-carboxylic acid tert-butyl ester: [ka] Sodium carbonate (1.98 g, 18.7 mmol) was added to a stirred solution of 5-(4-iodoanilino)-3-azabicyclo[3.1.1]heptane-2,4-dione (2.9 g, 8.48 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (5.24 g, 17.0 mmol) in DMF (32 mL) and water (8 mL), and the reaction was degassed with argon. Pd(dppf)Cl (692 mg, 848 μmol) was added under an inert atmosphere. The resulting mixture was heated at 80 °C for 16 h. The reaction mixture was diluted with ethyl acetate and filtered through a short pad of Celite. The filtrate was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (5% to 10% ethyl acetate-hexanes) to give tert-butyl 4-[4-[(2,4-dioxo-3-azabicyclo[3.1.1]heptan-5-yl)amino]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (1.91 g, 4.81 mmol, 57% yield). LCMS ES+ 398 (M+H + )

[0685] Step-5: Preparation of 4-[4-(2,4-dioxo-3-aza-bicyclo[3.1.1]hept-1...

Claims

A pharmaceutical composition for treating brain or central nervous system metastases of EGFR-mediated cancer in a human patient, comprising: 【Chemical Formula 1】 (wherein, A ＊ is [Chemical Formula 2] selected from B ＊ is heteroaryl or aryl, each optionally substituted with one, two or three R ３１ substituents, y is 0, 1, 2 or 3, R ３１ is, in each case independently, H, F, Cl, Br, 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 any ring, R ３２ is hydrogen, F, Cl, Br, C １～６ -alkyl, halo-C １～６ -alkyl, C ３～８ -cycloalkyl or halo-C ３～８ -cycloalkyl, and R ３３ is hydrogen, F, Cl, Br, C １～６ -alkyl, halo-C １～６ -alkyl, C ３～８ -cycloalkyl or halo-C ３～８ -cycloalkyl, may be located on the dihydropyrrole ring or imidazole ring, R ３４ is, in each case independently, H, F, C １～６ -alkyl, halo-C １～６ -alkyl, C ３～８ -cycloalkyl and halo-C ３～８ -cycloalkyl, and is selected from R ３５ is, in each case independently, H, F, Cl, Br, C １～６ -alkyl, halo-C １～６ -alkyl and C ３～８ -cycloalkyl, or is selected from or R ３４ and R ３５ are combined to form -(CH ２ ) ｑ - q is 1 or 2, R ３６ and R ３７ are independently selected from H, F, Cl, Br, 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 or R ３６ and R ３７ are combined together to form a 5- or 6-membered ring optionally substituted with one, two or three ３１ R substituents, R ９０ is H, C １～６ -alkyl or C ３～６ -cycloalkyl, and Ring G is heteroaryl optionally substituted with one or two Rs ４２ and is optionally substituted with substituents A ２１ is -NH-, -O-, -CH ２ - or -NR １００ - and R １００ is alkyl, cycloalkyl, aryl, or heteroaryl, or, where valences permit, R １００ R ３７ may be combined with to form a 5- to 8-membered heterocycle or a 5-membered heteroaryl; A ３２ , A ３３ , A ３４ and A ３５ are independently selected from -N- and -CR ４２ -, and R ４２ is independently selected, in each case, from H, F, Cl, Br, 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 is -N- or -CR ３５ - and is L ２ is the formula: [Chemical Formula 3] wherein, X1 and X2 are each independently in any case a bond, a heterocycle, an aryl, a heteroaryl, a bicyclic, an alkyl, an aliphatic, a heteroaliphatic, -NR27-, -CR40R41-, -O-, -C(O)-, -C(NR27)-, -C(S)-, -S(O)-, -S(O)2- and -S-, and each of the heterocycle, aryl, heteroaryl and bicyclic is optionally substituted with one, two, three or four substituents independently selected from R40, R20, R21, R22, R23 and R24 are each independently in any case a bond, an alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR27-, -NR27C(O)-, -O-, -S-, -NR27-, an oxyalkylene, -C(R40R40)-, -P(O)(OR26)O-, -P(O)(OR26)-, a bicyclic, an alkene, an alkyne, a haloalkyl, an alkoxy, an aryl, a heterocycle, an aliphatic, a heteroaliphatic, a heteroaryl, lactic acid, glycolic acid and a carbocyclic ring, and each is optionally substituted with one, two, three or four substituents independently selected from R40, R26 is each independently in any case selected from the group consisting of hydrogen, an alkyl, an arylalkyl, a heteroarylalkyl, an alkene, an alkyne, an aryl, a heteroaryl, a heterocycle, an aliphatic and a heteroaliphatic, R27 is each independently in any case selected from the group consisting of hydrogen, an alkyl, an aliphatic, a heteroaliphatic, a heterocycle, an aryl, a heteroaryl, -C(O)(an aliphatic, an aryl, a heteroaliphatic or a heteroaryl), -C(O)O(an aliphatic, an aryl, a heteroaliphatic or a heteroaryl), an alkene and an alkyne, R40, in each case independently, is selected from the group consisting of hydrogen, R27, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH(aliphatic), -N(aliphatic)2, -NHSO2(aliphatic), -N(aliphatic)SO2alkyl, -NHSO2(aryl, heteroaryl or heterocycle), -N(alkyl)SO2(aryl, heteroaryl or heterocycle), -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocycle, oxo and cycloalkyl, and furthermore, where valency permits, two R40 groups bonded to the same carbon may combine to form a 3- to 8-membered spiro ring. R41 is aliphatic, aryl, heteroaryl or hydrogen. A pharmaceutical composition comprising a compound selected from those or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition according to claim 1, wherein the compound is selected from Table 9A and Table 9B.

3. A pharmaceutical composition for treating brain or central nervous system metastases of EGFR-mediated cancer in a human patient, 【Chemical 4】 【Chem.】 【Chem.】 【Chem.】 A pharmaceutical composition comprising a compound selected from those or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition for treating brain or central nervous system metastases of EGFR-mediated cancer in a human patient, having the structure: 【Chemical Formula 5】 A pharmaceutical composition comprising the compound of or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition for treating brain or central nervous system metastases of EGFR-mediated cancer in a human patient, having the structure: 【Chemical Formula 6】 A pharmaceutical composition comprising the compound of or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition for treating brain or central nervous system metastases of EGFR-mediated cancer in a human patient, having the structure: 【Chemical Formula 7】 A pharmaceutical composition comprising the compound of or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition for treating brain or central nervous system metastases of EGFR-mediated cancer in a human patient, having the structure: 【Chemical 8】 A pharmaceutical composition comprising the compound of or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition for treating brain or central nervous system metastases of EGFR-mediated cancer in a human patient, having the structure: 【Chemical Formula 9】 A pharmaceutical composition comprising the compound of or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition for treating brain or central nervous system metastases of EGFR-mediated cancer in a human patient, having the structure: 【Chemical Formula 10】 A pharmaceutical composition comprising a compound of the structure:

10. A pharmaceutical composition for treating brain or central nervous system metastases of EGFR-mediated cancer in a human patient, having the structure: 【Chemical 11】 A pharmaceutical composition comprising a compound of the structure:

11. A pharmaceutical composition for treating brain or central nervous system metastases of EGFR-mediated cancer in a human patient, having the structure: 【Chemical Formula 12】 A pharmaceutical composition comprising a compound of the structure:

12. A pharmaceutical composition for treating brain or central nervous system metastases of EGFR-mediated cancer in a human patient, having the structure: 【Chemical 13】 A pharmaceutical composition comprising a compound of the structure:

13. A pharmaceutical composition for treating brain or central nervous system metastases of EGFR-mediated cancer in a human patient, having the structure: 【Chemical Formula 14】 A pharmaceutical composition comprising a compound of the structure:

14. A pharmaceutical composition for treating brain or central nervous system metastases of EGFR-mediated cancer in a human patient, having the structure: 【Chemical Formula 15】 A pharmaceutical composition comprising a compound of the structure:

15. A pharmaceutical composition for treating brain or central nervous system metastases of EGFR-mediated cancer in a human patient, having the structure: 【Chemical 16】 A pharmaceutical composition comprising a compound of the structure:

16. A pharmaceutical composition for treating brain or central nervous system metastases of EGFR-mediated cancer in a human patient, having the structure: 【Chemical 17】 A pharmaceutical composition comprising a compound of the structure:

17. A pharmaceutical composition for treating brain or central nervous system metastases of EGFR-mediated cancer in a human patient, having the structure: 【Chemical Formula 18】 A pharmaceutical composition comprising a compound of the structure:

18. The pharmaceutical composition according to any one of claims 1 to 17, wherein the EGFR-mediated cancer is mediated by mutant EGFR.

19. The pharmaceutical composition according to claim 18, wherein the mutant EGFR has an exon 21 mutation.

20. The pharmaceutical composition according to claim 18, wherein the mutant EGFR has an L858R mutation.

21. The pharmaceutical composition according to claim 18, wherein the mutant EGFR has an L861Q mutation.

22. The pharmaceutical composition according to claim 18, wherein the mutant EGFR has a T790M mutation.

23. The pharmaceutical composition according to claim 18, wherein the mutant EGFR has a C797S mutation.

24. The pharmaceutical composition according to claim 18, wherein the mutant EGFR has an L858R mutation and a T790M mutation.

25. The pharmaceutical composition according to claim 18, wherein the mutant EGFR has an L858R mutation, a T790M mutation, and a C797S mutation.

26. The pharmaceutical composition according to any one of claims 1 to 17, which is administered orally.

27. The pharmaceutical composition according to any one of claims 1 to 17, which is administered parenterally.

28. The pharmaceutical composition according to any one of claims 1 to 17, which is administered intravenously.

29. The pharmaceutical composition according to any one of claims 1 to 17, wherein an ATP-site binding EGFR ligand is also administered to a patient in need thereof.

30. The pharmaceutical composition according to claim 29, wherein the ATP-site binding EGFR ligand is osimertinib or a pharmaceutically acceptable salt thereof.

31. The pharmaceutical composition according to claim 29, wherein the ATP-site binding EGFR ligand is naquotinib or a pharmaceutically acceptable salt thereof.

32. The pharmaceutical composition according to claim 29, wherein the ATP-site binding EGFR ligand is maviletinib or a pharmaceutically acceptable salt thereof.

33. The pharmaceutical composition according to claim 29, wherein the ATP-site binding EGFR ligand is spebrutinib or a pharmaceutically acceptable salt thereof.

34. The pharmaceutical composition according to any one of claims 1 to 174, wherein the EGFR-mediated cancer is lung cancer.

35. The pharmaceutical composition according to any one of claims 1 to 17, wherein the EGFR-mediated cancer is non-small cell lung cancer.

36. The pharmaceutical composition according to any one of claims 1 to 17, wherein the EGFR-mediated cancer is small cell lung cancer.

37. The pharmaceutical composition according to any one of claims 1 to 17, wherein the EGFR-mediated cancer is adenocarcinoma.

38. The pharmaceutical composition according to any one of claims 1 to 17, wherein the EGFR-mediated cancer is squamous cell lung cancer.

39. The pharmaceutical composition according to any one of claims 1 to 17, wherein the EGFR-mediated cancer is large cell undifferentiated carcinoma.

40. The pharmaceutical composition according to any one of claims 1 to 17, wherein the EGFR-mediated cancer is a neuroendocrine cancer.

41. The pharmaceutical composition according to any one of claims 1 to 17, wherein the EGFR-mediated cancer is a sarcomatoid carcinoma, adenosquamous carcinoma, oat cell carcinoma, mixed small cell carcinoma, pulmonary carcinoid tumor, central carcinoid, peripheral carcinoid, salivary gland type lung cancer, mesothelioma or mediastinal tumor.

42. The pharmaceutical composition according to any one of claims 1 to 17, wherein the EGFR-mediated cancer is breast cancer.

43. The pharmaceutical composition according to claim 42, wherein the EGFR-mediated cancer is HER-2 positive breast cancer.

44. The pharmaceutical composition according to claim 42, wherein the EGFR-mediated cancer is ER+ breast cancer.

45. The pharmaceutical composition according to claim 42, wherein the EGFR-mediated cancer is PR+ breast cancer.

46. The pharmaceutical composition according to any one of claims 1 to 17, wherein the EGFR-mediated cancer is triple negative breast cancer.

47. The pharmaceutical composition according to any one of claims 1 to 17, wherein the EGFR-mediated cancer is colon cancer or rectal cancer.

48. The pharmaceutical composition according to any one of claims 1 to 17, wherein the EGFR-mediated cancer is head and neck cancer or esophageal cancer.

49. The pharmaceutical composition according to any one of claims 1 to 17, wherein the EGFR-mediated cancer is pancreatic cancer.

50. The pharmaceutical composition according to any one of claims 1 to 17, wherein the EGFR-mediated cancer is thyroid cancer.

51. The pharmaceutical composition according to any one of claims 1 to 17, wherein the EGFR-mediated cancer is ovarian cancer, uterine cancer or cervical cancer.

52. The pharmaceutical composition according to any one of claims 1 to 17, wherein the EGFR-mediated cancer is renal cancer, liver cancer or bladder cancer.

53. The pharmaceutical composition according to any one of claims 1 to 17, wherein the EGFR-mediated cancer is melanoma.

54. The pharmaceutical composition according to any one of claims 1 to 17, wherein the EGFR-mediated cancer has metastasized to the brain.

55. The pharmaceutical composition according to any one of claims 1 to 17, wherein the EGFR-mediated cancer has metastasized to the central nervous system.

56. The pharmaceutical composition according to any one of claims 1 to 17, wherein the patient has untreated EGFR-mediated cancer.

57. The pharmaceutical composition according to any one of claims 1 to 17, wherein the EGFR-mediated cancer is recurrent.

58. The pharmaceutical composition according to any one of claims 1 to 17, wherein the EGFR-mediated cancer is refractory.

59. The pharmaceutical composition according to any one of claims 1 to 17, wherein the EGFR-mediated cancer is recurrent and refractory.

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