Isoindolinone and indazole compounds for degradation of EGFR

Abstract

To provide compounds that degrade epidermal growth factor receptor (EGFR), including mutant forms, by ubiquitination of the EGFR protein and subsequent proteasomal degradation. The compounds are useful in the treatment of a variety of cancers.SOLUTION: The compound is represented by formula (I) having a specific substituent.SELECTED DRAWING: None

Description

[Technical Field]

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This application is a continuation of U.S. Provisional Patent Application No. 62 / 951,4 filed December 20, 2019. No. 64 and U.S. Provisional Patent Application No. 62 / 951,4 filed December 20, 2019 It asserts the benefit of No. 67.

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

[0003] HER family receptor tyrosine kinases mediate cell growth, differentiation, and survival. This receptor family has four distinct members: epidermal growth factor receptor (EGFR) receptors and epidermal growth factor receptor (EGFR). Receptor (EGFR, ErbB1 or HER1), HER2 (ErbB2), HER3 ( These include ErbB3 and HER4 (ErbB4). Upon ligand binding, the receptor It forms homodimers and heterodimers, and the subsequent activation of its intrinsic tyrosine kinase activity , which causes receptor autophosphorylation and activation of downstream signaling molecules (Non-Patent Document 1) These signaling molecules promote cell growth and proliferation. Deregulation of EGFR due to mutations is a major cause of colorectal cancer, pancreatic cancer, glioma, head and neck cancer, and lung cancer, especially non-small cell lung cancer. It has been implicated in many types of human cancer, including non-small cell lung cancer (NSCLC). EGFR-targeting agents have been developed for many years (Non-Patent Document 2). Erlotinib (Tarceva™), a reversible inhibitor of kinases, is available in many countries. It is approved for the treatment of recurrent NSCLC in

[0004] Superior single-agent activity of EGFR tyrosine kinase inhibitors is due to tumors expressing somatic kinase domains It is observed in a subset of NSCLC patients with mutations, but not in patients with wild-type EGFR The clinical benefit in these patients is significantly reduced (Non-Patent Document 3). The most common cytoplasmic mutation is exon 19 deletion, Δ746-750. and L858R is the most frequent mutation, an amino acid substitution in exon 21 (non-specific Permitted document 4).

[0005] Treatment resistance occurs frequently and is due to a secondary T790M mutation in the ATP site of the receptor. Several mutant-selective irreversible inhibitors have been developed that target the T790M mutation. Although the mutants exhibit high activity, their effectiveness depends on the system that forms the critical covalent bond. This may be impaired by an acquired mutation of the amino acid residue C797S (non-patented Reference 5). The C797S mutation is a factor that contributes to resistance to EGFR inhibitors that target T790M. It was further reported by Wang that this is the main mechanism of action (Non-Patent Document 6). Additional mutations that cause resistance to HIV, such as L718Q, have been described by Yang EGF R858R / T790M in the treatment of NSCLC and additional strategies, including targeting the EGFRL858R / T790M / C797S resistance mutations. Strategies targeting specific mutations are also known (Non-Patent Document 8).

[0006] Patent Document 1, Patent Document 2, Patent Document 3, Patent Document 4, Patent Document 5 and Non-Patent Document 9 EGFR inhibitors, including those described in Additional examples of selective inhibitors of are also described.

[0007] Most of the available EGFR tyrosine kinase inhibitors target the ATP site of the kinase. Therefore, new therapeutics that work differently may be developed, for example by targeting drug-resistant EGFR mutations. Treatment is needed.

[0008] Recent studies have demonstrated that deliberate targeting of allosteric sites results in mutant-selective It has been suggested that inhibitors may be obtained (Non-Patent Document 10).

[0009] The area of ​​small molecule-promoted targeted protein degradation is under intensive investigation (non-specific Protein degradation plays a role in various cellular functions. regulates the concentration of regulatory proteins by breaking them down into small peptides, which contributes to cell health and proliferation Proteolysis is used to maintain the rate.

[0010] Cereblon is an E3 ubiquitin ligase complex that ubiquitinates a variety of other proteins. Cereblon is a protein that forms the body. It is the primary target of anti-cancer thalidomide analogues. Increased expression of cereblon is known to be a factor in the effectiveness of thalidomide analogues in cancer therapy. associated with sex.

[0011] Compounds have been described as useful modulators of targeted ubiquitination, e.g., in patents The following are described in Patent Documents 6, 7, 8, 9, 10, and 11: Compounds that have been shown to be effective in targeting ubiquitination can be used for targeting ubiquitination. Suitable modulators include those disclosed by Ranok Therapeutics Hangzhou in Patent Documents 12 and 13. Those described in Patent Document 13, those by Arvinas in Patent Documents 14 and 15, and those by Patent Document 16. Patent Document 16, Patent Document 17, Patent Document 18, Patent Document 19, Patent Document 20 and Patent Document 2 1, by the Dana-Farber Cancer Institute, U.S. Pat. No. 5,629,999, and U.S. Pat. Patent Document 23, Patent Document 24, Patent Document 25, Patent Document 26, Patent Document 27, Patent Document 28, Patent Documents 29 and 30, and Kymera's patents 31 and 32, Those described in Reference 32 and Patent Document 33, and those by C4 Therapeutics Inc. Patent Document 34, Patent Document 35, Patent Document 36, Patent Document 37, Patent Document 38, Patent Document 3 9, Patent Document 40, Patent Document 41, Patent Document 42, Patent Document 43, Patent Document 44 and Patent Document Examples include those described in Reference 45.

[0012] Several specific molecules for degradation of EGFR have also been described, e.g., Dana-Farber The Cancer Institute describes EGFR degrading agents in U.S. Patent No. 4,629,493. F. Hoffman-La-Roe Che describes EGFR degrading agents in US Pat. No. 5,629,999 and US Pat. No. 5,629,999. Arvinas Reference 49 describes EGFR degrading agents. [Prior art documents] [Patent documents]

[0013] [Patent Document 1] International Publication No. 2014081718 [Patent Document 2] International Publication No. 2014210354 [Patent Document 3] International Publication No. 2018 / 115218 [Patent Document 4] International Publication No. 2018220149 [Patent Document 5] International Publication No. 2020002487 [Patent Document 6] International Publication No. 2013020557 [Patent Document 7] International Publication No. 2013063560 [Patent Document 8] International Publication No. 2013106643 [Patent Document 9] International Publication No. 2013170147 [Patent Document 10] International Publication No. 2016011906 [Patent Document 11] International Publication No. 2019183523 [Patent Document 12] International Publication No. 2020206608 [Patent Document 13] International Publication No. 2020207396 [Patent Document 14] International Publication No. 2015160845 [Patent Document 15] International Publication No. 2016149668 [Patent Document 16] International Publication No. 2016197032 [Patent Document 17] International Publication No. 2017011590 [Patent Document 18] International Publication No. 2017030814 [Patent Document 19] International Publication No. 2018144649 [Patent Document 20] International Publication No. 2018226542 [Patent Document 21] International Publication No. 2019199816 [Patent Document 22] International Publication No. 2016105518 [Patent Document 23] International Publication No. 2017007612 [Patent Document 24] International Publication No. 2017024317 [Patent Document 25] International Publication No. 2017024318 [Patent Document 26] International Publication No. 2017117473 [Patent Document 27] International Publication No. 2017117474 [Patent Document 28] International Publication No. 2018148443 [Patent Document 29] International Publication No. 2018148440 [Patent Document 30] International Publication No. 2019165229 [Patent Document 31] International Publication No. 2019 / 060742 [Patent Document 32] International Publication No. 2019 / 140387 [Patent Document 33] International Publication No. 2020 / 01022 [Patent Document 34] International Publication No. 2017197036 [Patent Document 35] International Publication No. 2017197046 [Patent Document 36] International Publication No. 2017197051 [Patent Document 37] International Publication No. 2017197055 [Patent Document 38] International Publication No. 2018237026 [Patent Document 39] International Publication No. 2019099868 [Patent Document 40] International Publication No. 2019191112 [Patent Document 41] International Publication No. 2019204353

Patent document 42

Patent document 43

Patent document 44

Patent document 45

Patent document 46

Patent document 47

Patent document 48

Patent document 49

Non-licensed literature

[0014] [Non-licensed document 1] Yarden, Y., Sliwkowski, MX. Untangling the ErbB signaling network. Nature Review Mol Cell Biol. 2001 Feb;2(2): 127-37 [Non-licensed document 2] Ciardiello, F., and Tortora, G. (2008). EGFR antagonists in cancer treatment. The New England journal of medicine 358, 1160-1174 [Non-licensed document 3] Paez, J. et al. (2004). EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science (New York, NY 304, 1497-1500

Non-licensed Document 4

[0015] Despite these efforts, there is a lack of evidence that EGFR-mediated disease persists in hosts in need of treatment, particularly in humans. There remains a need for new EGFR modulators to treat disorders mediated by EGFR. There are. [Means for solving the problem]

[0016] Epidermal growth factor receptor protein (EGF) is transduced via the ubiquitin proteasome pathway (UPP). The present invention provides compounds that degrade EGF (Epidermal Growth Factor Receptor Cells), as well as their uses and manufacture. A targeting ligand that binds to R and an E3 ligase binding moiety (typically a cereblon subunit) via a linker that covalently connects the targeting ligand to the E3 ligase binding moiety. or a pharmaceutically acceptable salt thereof. In certain embodiments, the E3 ligase binding moiety is A or A * and the linker is L 1 or L 2 the remainder of the molecule is the EGFR-targeting linker In certain embodiments, the compounds of the present invention are mutated or A combination of mutations, such as a mutation selected from T790M, L858R, and C797S. a combination of two mutations selected from the group consisting of T790M, L858R, and C797S; has a combination of three mutations selected from T790M, L858R, and C797S. In certain embodiments, the compounds of the present invention degrade EGFR, which is involved in T790 M / L858R, T790M / L858R / C797S, L858R, or L858R / It is a selective degrader of EGFR mutants with C797S.

[0017] The compounds of the present invention provided herein, or pharmaceutically acceptable salts thereof and / or The pharmaceutically acceptable compositions are used to treat disorders mediated by EGFR. In some embodiments, the compound may be optionally pharmaceutically acceptable to a patient, typically a human. One or more compounds described herein or pharmaceutically acceptable salts thereof in a suitable composition. and administering to a patient suffering from an EGFR-mediated disorder an effective amount of A method is provided.

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

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

[0020] In certain embodiments, isotopes, N-oxides or stereoisomers of Formula I, or In another embodiment, a pharmaceutically acceptable salt or composition of the compound of formula II is provided. or a pharmaceutically acceptable salt or composition thereof is provided.

[0021] Another aspect of the present invention is a compound of formula III or formula IV: [ka] (In the formula, A * teeth, [ka] is selected from B * is heteroaryl or aryl, and one, two, or three R 31 Any substituent is replaced by In certain embodiments, B * teeth, [ka] is selected from y is 0, 1, 2 or 3; R 31 In each case, H, halogen (F, Cl, Br or I), C 1~6 -Arki Le, Cyano, C 1~6 -Alkoxy, Halo-C 1~6 -Alkoxy, Halo-C 1~6 -a Lukil, C 3~8 -cycloalkyl and halo-C 3~8 -cycloalkyl When present on two rings, they 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, may be located on the dihydropyrrole or imidazole ring, R 34 In either case, H, F, C 1~6 -Alkyl, Halo-C 1~6 - alkyl, C 3~8 -cycloalkyl and halo-C 3~8 -cycloalkyl; R 35 In each case, H, halogen (F, Cl, Br or I), C 1~6 -Arki Le, Halo-C 1~6 -alkyl and C 3~8 -cycloalkyl; or R 34 and R 35 and combine to form -(CH2) q - Forms R 36 and R 37 are independently H, halogen (F, Cl, Br or I), cyano, C 1~ 6-alkoxy, halo-C 1~6 -alkoxy (e.g., F, Cl, or Br), C 1~ 6-Alkyl, Halo-C 1~6 -alkyl (e.g., F, Cl, or Br), C 3~8 - Cycloalkyl and halo-C 3~8 -cycloalkyl; or R 36 and R 37 and are bonded together to form one, two or three R 31 Optionally, the substituent forming a substituted 5- or 6-membered ring, R 42 In each case, H, halogen (F, Cl, Br or I), cyano, C 1~6 -Alkoxy, Halo-C 1~6 -alkoxy, C 1~6 -Alkyl, Halo-C 1~6 -a Lukil, C 3~8 -cycloalkyl and halo-C 3~8 -cycloalkyl Selected, 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 a substituent, e.g., one , a 5- or 6-membered heteroaryl ring having 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 that valence allows, R 100 R 37 and bonded to form a 5- to 8-membered heterocycle or a 5-membered heterocycle. may form a heteroaryl, A 32 , A 33 , A 34 and A 35 are independently -N- and -CR 42 - selected from A 36 -N- or -CR 35 - and L 2 is A * and a divalent linking group ( linker), for example, but not limited to, a double linking group of formula LI, wherein the remaining variables are as defined herein. or a pharmaceutically acceptable salt thereof, an isotope thereof, an N-oxygen atom thereof, and stereoisomers.

[0022] In certain embodiments, L 2 is the expression: [ka] (In the formula, X 1 and X 2 are independently in each occurrence a bond, a heterocycle, an aryl, a heteroaryl, Bicyclic, alkyl, aliphatic, heteroaliphatic, -NR 27 -, -CR 40 R 41 -, -O-, -C(O)-, -C(NR 27 )-, -C(S)-, -S(O)-, -S(O)2- and -S-, wherein each of the heterocycle, aryl, heteroaryl, and bicycle is selected from R 40 optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 20 , R 21 , R 22 , R 23 and R 24 are independently in each case a bond, an alkyl group, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C (S)-, -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 selected from the group consisting of R 40 one, two, three or four independently selected from is optionally substituted with a substituent of R 26 are independently in each case hydrogen, alkyl, arylalkyl, heteroaryl alkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic, aliphatic and heterocyclic (b) selected from the group consisting of aliphatic R 27 are independently in each occurrence hydrogen, alkyl, aliphatic, heteroaliphatic, heterocyclic, Aryl, heteroaryl, -C(O)(aliphatic, aryl, heteroaliphatic or heteroaryl) -aryl), -C(O)O(aliphatic, aryl, heteroaliphatic or heteroaryl), ar selected from the group consisting of kenes and alkynes; R 40 are independently hydrogen in each case, R 27 , alkyl, alkene, alkyne, fluorine Fluoro, bromo, chloro, hydroxyl, alkoxy, azido, amino, cyano, -NH (aliphatic containing alkyl), -N(aliphatic containing alkyl)2, -NHSO2(alkyl aliphatic, -N(aliphatic, including alkyl), -SO2 alkyl, -NHSO2 (aryl -N(alkyl)SO2(aryl, heteroaryl or heterocyclic) or heterocycle), -NHSO2 alkenyl, -N(alkyl)SO2 alkenyl, -NHS O2 alkynyl, -N(alkyl)SO2 alkynyl, haloalkyl, aliphatic, heteroaliphatic Selected from the group consisting of aliphatic, aryl, heteroaryl, heterocyclic, oxo and cycloalkyl Furthermore, if valence permits, two R 40 The foundation is united may form a 3- to 8-membered spiro ring, R 41 is aliphatic, aryl, heteroaryl or hydrogen).

[0023] Any combination of variables, substituents, and embodiments, and compounds resulting from these combinations, are also contemplated. Compounds are not intended to be generic or even sub-genus compounds, as such descriptions are merely for the sake of space. are not intended to be a single statement and are therefore considered to be specifically and individually disclosed. do.

[0024] The compounds of the present invention are useful in treating colon cancer, rectal cancer, lung cancer including non-small cell lung cancer, HER-2 positive breast cancer, ER+ (estrogen positive) breast cancer, PR+ (progesterone positive) breast cancer, or triple Breast cancer, including negative breast cancer, head and neck cancer, glioblastoma, pancreatic cancer, thyroid cancer, astrocytoma, esophageal cancer, For the treatment of EGFR-mediated disorders such as cervical cancer, synovial sarcoma, ovarian cancer, liver cancer, bladder cancer, or renal cancer It can be used.

[0025] In certain embodiments, a patient, e.g., a human, in need of treatment is administered, optionally with a pharmaceutical a compound of Formula I, Formula II, Formula III or Formula IV, or a pharmaceutically acceptable salt thereof, in a physiologically acceptable carrier; The present invention provides a method of treatment comprising administering an effective amount of a physiologically acceptable salt of a compound of formula (I) or (II). In some embodiments, a compound of Formula I, Formula II, Formula III, or Formula IV is used to treat cancer. The substance is administered to a human.

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

[0027] In certain embodiments, the compounds of the present invention are used to treat breast cancer. In certain embodiments, the breast cancer is HER-2 positive breast cancer. In certain embodiments, the breast cancer is ER+ breast cancer. In certain embodiments, the breast cancer is triple-negative breast cancer. do.

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

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

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

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

[0032] In certain embodiments, the present invention is used to treat ovarian, uterine, or cervical cancer. Use a bright compound.

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

[0034] In certain embodiments, the compounds of the present invention are capable of inhibiting conventional EGFR ligand-mediated vasoconstriction. It is possible that one or more benefits to the treatment may be provided, and even multiple benefits may be provided. For example: The EGFR degrading compounds of the present invention a) overcome resistance in certain cases and b) inhibit the activity of proteins. By destroying proteins, the kinetics of drug effect is prolonged, even after the compound has been metabolized. c) protein resynthesis rather than specific catalytic or binding events; d) targeting all functions of a protein at once, and / or e) targeting the catalytic potential of small molecules. Therefore, they may have increased potency compared to inhibitors.

[0035] In one aspect, the compounds of the present invention are EGF receptors in which EGFR is mutated from wild-type. It is used to treat EGFR-mediated cancers. There are many possible EGFR mutations. In a non-limiting embodiment, the mutation is in exon 18, exon 19, exon It is found in exon 20 or exon 21, or any combination thereof. In certain embodiments, the mutations are L858, E709, G719, C797, L8 61, T790 or L718, or any combination thereof. In an embodiment, the mutations are L858R, T790M, L718Q, L792H and / or the C797S mutation, or any combination thereof.

[0036] In certain embodiments, the cancer is treated with non-covalent inhibitors (e.g., gefitinib, erlotinib, lapatinib or vandetanib) or covalent inhibitors (anticoagulants at least one EGF inhibitor, which may be vasopressin, vasorelaxanthin, vasorexin, vasorexin, vasorexin-like protein kinase C (e.g., vasorexin-like protein kinase C), ... In another embodiment, the patient has one or more EGFR mutations after treatment with an EGFR inhibitor. The cancer may progress to one or more recurrences after treatment with antibodies such as cetuximab, panitumumab, or necitumumab. In yet another embodiment, the cancer is characterized in that the cancer expresses an EGFR mutation. One or more EGFR mutations or non-EGFR mutations that confer resistance to GFR inhibitor treatment FR mutations, e.g., somatic exon 20 insertions, somatic PIK3CA mutations, PTEN They have loss of expression, MET amplification, or KRAS mutation.

[0037] In certain embodiments, the compounds of the present invention are effective against erlotinib, gefitinib, and and / or show resistance to or resistance to first-generation EGFR inhibitors such as lapatinib In certain embodiments, the compounds of the present invention are used to treat cancers that have acquired resistance to these compounds. The compound is resistant to second-generation EGFR inhibitors such as afatinib and / or dacomitinib. The present invention is used to treat cancers that exhibit or have acquired resistance to the In this embodiment, the compound of the present invention has an anti-EGFR activity against third-generation EGFR inhibitors such as osimertinib. It is used to treat cancers that have shown or acquired resistance to it.

[0038] In some embodiments, the mutant EGFR protein in the affected tissue is L85 8 mutation, e.g., L858R.

[0039] In certain embodiments, the compounds of the present invention are those in which EGFR is one of the amino acids listed below. Mutant EGFR-mediated disorders with mutations in at least one or a combination of the acid sites The mutation may be selected from one of the exemplary mutations listed. The mutation may be the same or a different mutation.

[0040] TIFF2026010026000020.tif66170

[0041] In certain embodiments, the mutant EGFR-mediated disorder is selected from the table above. In another embodiment, the mutant EGFR-mediated The disorder has three mutations selected from the table above. A naturally-mutated EGFR-mediated disorder has four or more mutations, which may optionally be selected from the table above. do.

[0042] In certain embodiments, the mutant EGFR-mediated disorder is a L858R mutation. and optionally one additional mutation that may be selected from the table above. In some embodiments, the mutant EGFR-mediated disorder is an L858R mutation. and optionally two additional mutations which may be selected from the table above. In this case, the mutant EGFR-mediated disorder is a combination of the L858R mutation and, optionally, a mutation from the table above. and three additional mutations that can be selected.

[0043] In certain embodiments, the mutant EGFR-mediated disorder is a T790M mutant EGFR-mediated disorder. mutation and optionally one additional mutation selected from the table above. In certain embodiments, the mutant EGFR-mediated disorder comprises a T790M mutation and, optionally, one of the mutations listed above. and two additional mutations selected from: A variant EGFR-mediated disorder is characterized by the T790M mutation and any of three mutations selected from the table above. and additional mutations.

[0044] In certain embodiments, the mutant EGFR-mediated disorder is a L718Q mutation. mutation and optionally one additional mutation selected from the table above. In certain embodiments, the mutant EGFR-mediated disorder comprises a L718Q mutation and, optionally, one of the mutations listed above. and two additional mutations selected from: A variant EGFR-mediated disorder is characterized by the L718Q mutation and any of three mutations selected from the table above. and additional mutations.

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

[0046] In certain embodiments, the EGFR-mediated cancer is characterized by the presence of S768I, L718V, L 792H, L792V, G796S, G796C, G724S and / or G719A It has natural mutations.

[0047] In certain embodiments, the compounds of the present invention are capable of inhibiting frameshift mutations, e.g. For example, it may be used to treat EGFR-mediated cancers with short in-frame deletions. In this embodiment, the compound of the present invention is an EGFR medium in which EGFR has an exon 19 deletion. In certain embodiments, the exon 19 deletion is used in the treatment of interstitial cancer. The deletion includes amino acids LREA (L747 to A750). In this case, the exon 19 deletion is a deletion that includes the amino acids ELREA (E746-A750). do.

[0048] In certain embodiments, the compounds of the present invention are useful for treating EGFR exon 21 L8 It is used to treat EGFR-mediated cancers that have the 58R mutation.

[0049] In certain embodiments, the compounds of the present invention inhibit the activity of mutant EGFR over wild-type EGFR. It has activity against EGFR-driven disorders.

[0050] In certain embodiments, the compounds of the present invention are useful for treating EGFR in one or more exons. It is used to treat EGFR-mediated cancers with deletion 18.

[0051] In certain embodiments, the compounds of the present invention contain an E709 mutation, e.g., E7 It is used to treat EGFR with E709A, E709G, E709K or E709V.

[0052] In certain embodiments, the compounds of the present invention contain an L718 mutation, e.g., L7 It is used to treat EGFR with 18Q.

[0053] In certain embodiments, the compounds of the present invention contain a G719 mutation, e.g., G7 It is used to treat EGFR with 19S, G719A, G719C, or G719D.

[0054] In certain embodiments, the compounds of the present invention are useful for treating EGFR in one or more exons. For use in the treatment of EGFR-mediated cancers with exon 19 insertions and / or one or more exon 20 insertions will be done.

[0055] In certain embodiments, the compounds of the present invention inhibit the S7681 mutant EGFR In certain embodiments, the compounds of the present invention are used to treat cancer. It is used to treat L861Q mutant EGFR cancer. The compounds of the present invention are used to treat C797S mutant EGFR cancers.

[0056] In certain embodiments, the compounds of the present invention contain a T790M, L858R mutation. Used to treat variant EGFR cancers.

[0057] In certain embodiments, the compounds of the present invention contain the L718Q, L858R mutation. Used to treat variant EGFR cancers.

[0058] In certain embodiments, the compounds of the present invention comprise the L792H, L858R mutation. Used to treat variant EGFR cancers.

[0059] In certain embodiments, the compounds of the present invention contain the C797S, L858R mutation. Used to treat variant EGFR cancers.

[0060] In certain embodiments, the compounds of the present invention are capable of inhibiting at least one known EGF. These drugs may offer improved efficacy and / or safety profiles compared to R inhibitors. The degraders of the invention exhibit inhibitory activity combined with catalytic degradative activity of cereblon-activated proteasomal degradation. This allows for rapid "return to action" of the inhibitor alone. Rapid targeting of overexpressed EGFR by an active moiety capable of recapitulating catalytic function In this way, EGFR is activated by covalent suicide inhibitors such as osimertinib. The active drug is destroyed quickly, as occurs with toxicants, but the active drug is not destroyed at the same time. do not have.

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

[0062] In certain embodiments, the compounds described herein are indicated for the treatment of EGFR-mediated disorders. The compounds described in are less than the molar equivalents of the EGFR targeting ligand moiety alone.

[0063] In certain embodiments, the compounds of the present invention are useful in the treatment of EGFR-mediated disorders. and at least one side effect is reduced compared to the EGFR-targeting ligand moiety alone. do not have.

[0064] In certain embodiments, the compounds described herein are indicated for the treatment of EGFR-mediated disorders. The administration regimen for the selected compounds described herein is more effective than the molar administration of the EGFR targeting ligand moiety alone. It occurs less frequently.

[0065] Another aspect of the invention is a method for inhibiting or preventing EGFR-mediated disorders or The compounds described herein are used in the manufacture of a medicament for modulating or reducing the amount of EGFR. or an enantiomer, diastereomer or stereoisomer thereof, or a drug thereof and a physiologically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof.

[0066] Another aspect of the present invention is a drug for treating or preventing a disease mediated by EGFR. or an enantiomer or diastereomer thereof, used in the preparation of or a stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or Pharmaceutical compositions thereof are provided.

[0067] In certain embodiments, the selected compounds described herein are compounds that inhibit EGFR expression. Oncoproteins, or signaling mediators of abnormal cell growth pathways, whose degradation Reduces abnormal cell growth, useful for treating disorders involving abnormal cell proliferation, such as tumors or cancer .

[0068] In certain embodiments, select compounds of Formula I, Formula II, Formula III, or Formula IV The compound, or a pharmaceutically acceptable salt thereof, may contain at least one atom in an amount exceeding the natural abundance of the isotope. Both have one desired isotopic substitution, i.e., are enriched.

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

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

[0071] In certain embodiments, the compounds of the present invention bind to the target protein EGFR. the target protein has an E3 ubiquitin ligase binding moiety linked to a moiety that binds to the target protein. The degradation of the protein is achieved by the proximity of the enzyme to the ligase.

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

[0073] To this end, the present invention includes at least the following features: (a) a compound of Formula I, Formula II, Formula III or IV as described herein, or any of its pharmaceutically acceptable salts or isotopic derivatives (including deuterated derivatives); (b) administering to a patient in need thereof a compound according to Formula I, Formula II, Formula III or any of the compounds of Formula I, II, III or any of the compounds according to Formula III or any of the compounds of Formula II or any of the compounds of Formula III ... III or any of the compounds of Formula III or any of The method comprises administering an effective amount of a compound of formula IV, or a pharmaceutically acceptable salt thereof, to a patient suffering from cancer, including methods for treating EGFR-mediated disorders, such as abnormal cell proliferation, (c) for the treatment of disorders mediated by EGFR, such as abnormal cell proliferation, e.g., tumors or cancers. The compound of formula I, formula II, formula III or formula IV used, or a pharmaceutically acceptable salt thereof salts or isotopic derivatives (including deuterated derivatives), (d) a patient in need of treatment for an EGFR-mediated disorder, e.g., abnormal cell proliferation, such as a tumor or cancer; In the treatment of a patient, typically a human, or a pharmaceutically acceptable salt thereof, (e) of a drug for the treatment of an EGFR-mediated disorder, e.g., abnormal cell proliferation, such as a tumor or cancer. The compound of Formula I, Formula II, Formula III or Formula IV, or a pharmaceutically acceptable salt thereof, in the preparation the use of isotopic salts or isotopic derivatives (including deuterated derivatives); (f) administering to a patient in need thereof a compound according to Formula I, Formula II, Formula III or any of the compounds of Formula I, II, III or any of the compounds of Formula III or any of the compounds of Formula II or any of the compounds of Formula ... The method comprises administering an effective amount of a compound of formula IV, or a pharmaceutically acceptable salt thereof, to a patient suffering from cancer, including methods for treating mutant EGFR-mediated disorders, such as abnormal cell proliferation, (g) a disorder mediated by mutant EGFR, e.g., abnormal cell growth, such as a tumor or cancer; A compound of formula I, formula II, formula III or formula IV, or a pharmaceutical formulation thereof, for use in the treatment of acceptable salts or isotopic derivatives (including deuterated derivatives); (h) having a mutant EGFR-mediated disorder, e.g., abnormal cell proliferation such as a tumor or cancer; A therapeutically effective amount of a compound of Formula I, Formula II, Formula III or Formula IV is administered to a patient, typically a human, in need of such treatment. or a compound of formula IV, or a pharmaceutically acceptable salt thereof, (i) for the treatment of mutant EGFR-mediated disorders, such as abnormal cell proliferation, e.g., tumors or cancers; A compound of Formula I, Formula II, Formula III or Formula IV, or a pharmaceutical composition thereof, in the manufacture of a medicament for the use of environmentally acceptable salts or isotopic derivatives (including deuterated derivatives); (j) a compound of Formula I, Formula II, Formula III or Formula IV in an amount effective to treat a patient; its pharmaceutically acceptable salts, isotopic derivatives, and optionally a pharmaceutically acceptable carrier or diluent; a pharmaceutical composition comprising (k) Mixtures of enantiomers or diastereomers (where appropriate), including racemates a compound of formula I, formula II, formula III or formula IV as described herein, (l) isolated enantiomers or diastereomers (i.e., about 85%, 90% , 95%, 97% or over 99% pure) Formula I, Formula II, Formula III or a compound thereof as described herein in enriched form (where appropriate) a compound of formula IV, and (m) a compound of Formula I, Formula II, Formula III or Formula IV described herein, or A process for making a therapeutic product containing an effective amount of a pharmaceutically acceptable salt of DETAILED DESCRIPTION OF THE INVENTION

[0074] Epidermal growth factor receptor protein (EGF) is transduced via the ubiquitin proteasome pathway (UPP). The present invention provides compounds that degrade EGF (Epidermal Growth Factor Receptor Cells), as well as their uses and manufacture. A targeting ligand that binds to R and an E3 ligase binding moiety (typically a cereblon subunit) via a linker that covalently connects the targeting ligand to the E3 ligase binding moiety. or a pharmaceutically acceptable salt thereof. In certain embodiments, the E3 ligase binding moiety is A or A * of and the linker is L 1 or L 2 the rest of the molecule is the EGFR-targeting ligand In certain embodiments, the compounds of the present invention are mutated or abruptly a combination of mutations, for example a mutation selected from T790M, L858R and C797S; a combination of two mutations selected from T790M, L858R and C797S, or T E having a combination of two mutations selected from 790M, L858R and C797S In certain embodiments, the compounds of the present invention reduce GFR by 790M / L. 858R, T790M / L858R / C797S, L858R, and / or L858R / It is a selective degrader of EGFR mutants with C797S.

[0075] In certain embodiments, the compounds of the present invention inhibit at least one known EGFR For example, the present invention provides an improved efficacy and / or safety profile compared to inhibitors. Ming degraders inhibit cereblon-activated proteasomal degradation in combination with catalytic degradation activity The drug has the efficacy of only the protein-binding portion, allowing for a rapid "return to action" Rapid activation of targeting overexpressed EGFR by an active moiety capable of recapitulating catalytic function In this way, EGFR is inhibited by covalent suicide inhibitors such as osimertinib. The active drug is destroyed quickly, as occurs with steroids, but without the simultaneous destruction of the active drug. stomach.

[0076] I. Definition The following definitions of general terms used herein are intended to be limiting when a term appears alone or in combination with other terms. Applies whether or not they appear in combination.

[0077] Unless otherwise stated, the following terms are used in this application, including the specification and claims: The terms have the following definitions: In cases where the singular forms "a," "an," and "the" are used where the context is clear. It should be noted that plural referents are included unless clearly indicated otherwise.

[0078] "C 1~6 The term "-alkoxy" refers to a compound in which R' is C 1~6 - alkyl groups, particularly C1 ~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. Specific examples include methoxy, ethoxy and isopropoxy. A more specific example is methoxy.

[0079] "C 1~6 The term "-alkyl," alone or in combination with other groups, means a linear The alkyl groups may be branched or may have single or multiple branches, and the alkyl groups generally have 1 Hydrocarbon radicals containing 1 to 6 carbon atoms, such as 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 typical group is methyl.

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

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

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

[0083] "Haro-C 1~6 The term "-alkoxy" refers to 1~6 -H atom of alkoxy group C, at least one of which is replaced by the same or different halogen atom 1~6 -Alcoki Represents a silyl group. 1~6 The term "-alkoxy" refers to 1~6 -alkoxy C in which all hydrogen atoms of the group are replaced by the same or different halogen atoms 1~6 -Al represents a halo-C 1~6 Examples of -alkoxy include fluoromethoxy, difluoromethoxy, Fluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy, trifluoro Fluoroethoxy, trifluoromethylethoxy, trifluorodimethylethoxy and pentafluoroethoxy Certain halo-C 1~6 -The alkoxy group is fulve Fluoromethoxy, fluoroethoxy, difluoromethoxy, difluoroethoxy, trifluoro trifluoromethoxy, trifluoromethylethoxy, and trifluorodimethylethoxy. More particular examples are fluoromethoxy, difluoromethoxy and trifluoromethoxy. It is Shi.

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

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

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

[0087] The term "halogen", alone or in combination with other groups, includes chloro (Cl), iodine (Cl), and iodine (I). Specific groups are F and Cl. .

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

[0089] "Hydroxy-C 1~6 The term "-alkyl alkyl" refers to 1~6 -Alkyl C in which at least one hydrogen atom of the alkyl group is replaced by a hydroxy group 1~6 -Al represents an alkyl group. Hydroxy-C 1~6 Examples of -alkyl include hydroxymethyl Specific examples include hydroxymethyl, hydroxyethyl, and hydroxypropyl. It's chill.

[0090] The term "pharmaceutically acceptable" means a substance that is generally safe, non-toxic, and biologically are not undesirable in any other respect and are permitted for medical use in animals as well as in humans. These represent attributes of materials useful in making pharmaceutical compositions that are acceptable.

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

[0092] The term "pharmaceutically acceptable auxiliary substance" means a diluent or a mixture that is compatible with the other ingredients of the formulation. Refers to carriers and auxiliary substances such as additives.

[0093] The term "pharmaceutical composition" does not only refer to a product containing specified ingredients in predetermined amounts or proportions. any compound obtained directly or indirectly by combining the specified ingredients in the specified amounts Specifically, the term encompasses any product containing one or more active ingredients and inactive ingredients. as well as products containing a carrier of any two or more components in combination, complex or agglomeration, or dissociation of one or more components, or other type of reaction or interaction of one or more components. This includes any product obtained directly or indirectly through the use of

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

[0095] The terms "as defined herein" and "as described herein" when referring to a variable moiety are used interchangeably. The term "as shown" refers to the broad definition of the variable parts, as well as "in detail," if any. The definitions of "more particularly" and "most particularly" are incorporated by reference.

[0096] The use of "treating," "contacting," and "reacting" when referring to chemical reactions The term refers to the addition or mixing of two or more reagents under appropriate conditions to produce a specified and / or desired product. It means that a reaction that produces a specified and / or desired product is not necessarily the best. It does not result directly from the combination of the two reagents initially added; and / or there are one or more intermediates that are produced in the mixture that result in the formation of the desired product. Please understand that there is a possibility that

[0097] The term "pharmaceutically acceptable excipient" refers to disintegrants, binders, agents, fillers, solvents, buffers, isotonicity agents, stabilizers, antioxidants, surfactants or lubricants, etc. It refers to any ingredient that has no therapeutic activity and is non-toxic.

[0098] The term "pharmaceutical composition" does not only refer to a product containing specified ingredients in predetermined amounts or proportions. any compound obtained directly or indirectly by combining the specified ingredients in the specified amounts Specifically, the term encompasses any product containing one or more active ingredients and inactive ingredients. as well as products containing a carrier of any two or more components in combination, complex or agglomeration, or dissociation of one or more components, or other type of reaction or interaction of one or more components. This includes any product obtained directly or indirectly through the use of

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

[0100] "50% inhibitory concentration (half maximal inhibitory concentration)" (IC 50 ) The term refers to the specific activity required to obtain 50% inhibition of a biological process in vitro. IC represents the concentration of a specific compound. 50 Values ​​are pIC 50 Value (-log IC 50 ) into logarithmic transformation The IC can be converted into an exponentially greater potency, with higher values ​​indicating greater potency. 50 The value is absolute It is not a fixed value but is determined by the experimental conditions used, e.g., concentration. 50 The value is -The absolute inhibition constant (K i ) can be converted to (Biochem. Pharm acol. (1973) 22:3099).

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

[0102] The term "aromatic" is used in the literature, especially in the IUPAC - Compendium of Chemical Terminology, 2nd, A.D. McNaught & A. Wilkinson (Eds). Blackwell Scientific Publications, Oxf. represents the conventional concept of aromaticity as defined in Ord (1997).

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

[0104] In certain embodiments, isotopes are incorporated into the compounds of the present invention. As coordinates, 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 17 O. 18 O , 18 F, 35 S and 36 Isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as Cl In one non-limiting embodiment, isotopically labeled The compounds were then used for metabolic studies (e.g. 14 C), reaction kinetic studies (e.g. 2 H or 3 H positron emission tomography (PET), including drug or substrate tissue distribution assays ) or single photon emission computed tomography (SPECT), or other detection or imaging techniques; can be used in the radiotherapy of patients. Furthermore, any of the compounds of the present invention may be used in the radiotherapy of patients. The hydrogen atoms of 18 It may be substituted with a F atom, which substitution is particularly useful for PET or SPECT studies. This may be desirable.

[0105] In one non-limiting embodiment, the substitution of a hydrogen atom with a deuterium atom is described herein. For example, if any of the groups is methyl, ethyl, or methoxy, or contains these, for example by substitution, even if the alkyl residue is deuterated. (In non-limiting embodiments, CDH2, CD2H, CD3, CH2CD3, C D2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H or OCD3, etc.). In certain other embodiments, two substituents are combined to form When a cycle is formed, the unsubstituted carbon may be deuterated. In this state, at least one deuterium atom is destroyed during metabolism of the compound in vivo. It is located on an atom bearing a bond to be metabolized or is 1, 2, or 3 atoms away from the bond to be metabolized. (e.g., α, β, or γ, or referred to as primary, secondary, or tertiary isotope effects) (In some cases).

[0106] In certain embodiments, the compounds of the present invention are isotopically labeled. In the embodiment, R 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 , R37 , R 40 , R 41 , R 42 , R 52 , R 53 , R 54 , R 55 , R 70 , R 80 , R 81 , R 82 , R 90 or R 100 At least one R group independently selected from It is isotopically labeled with one, two or more isotopes as permitted by the In certain embodiments, the isotopic label is deuterium. At least one deuterium is on an atom with a bond that is broken during metabolism of the compound in vivo. or is 1, 2, or 3 atoms away from the bond to be metabolized (e.g., α, (sometimes called beta or gamma, or primary, secondary, or tertiary isotope effects). In an embodiment, the isotope label is 13 C. In other embodiments, the isotopic label is 18 It's F.

[0107] In certain embodiments, the compounds of the present invention form solvates with solvents (including water). Thus, in one non-limiting embodiment, the present invention provides a method for producing a medicament for the treatment of a medicament comprising the steps of: The term "solvate" includes solvated forms of the compounds of the present invention (including those It refers to a molecular complex of a solvent (including a salt) with one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, alcohol, isopropanol, dimethyl sulfoxide, acetone and other common organic solvents is.

[0108] In certain embodiments, "alkenyl" refers to one alkyl group that can occur at any stable point along the chain. A linear or branched aliphatic hydrocarbon group having the above carbon-carbon double bond is a non-limiting example. In embodiments, alkenyl has from 2 to about 12 carbon atoms, more typically from 2 to about In certain embodiments, the alkyl group contains 6 carbon atoms or 2 to about 4 carbon atoms. Alkenyl is C2, C2-C3, C2-C4, C2-C5 or C2-C6. In this embodiment, examples of alkenyl radicals include ethenyl, propenyl, allyl, , propenyl, butenyl, and 4-methylbutenyl. In certain embodiments, the term "alkenyl" includes both "cis" and "trans" groups. Also embodied are "Z" alkenyl configurations, or alternatively, "E" and "Z" alkenyl configurations. In certain embodiments, the term "alkenyl" refers to an alkyl group having at least one unsaturated alkyl group. Also included are cycloalkyl or carbocyclic groups having a cyclic ring.

[0109] In certain embodiments, the "alkynyl" can occur at any stable point along the chain. It is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds. In one typical embodiment, alkynyl has 2 to about 12 carbon atoms, more typically 2 In certain embodiments, the alkyl group contains from 1 to about 6 carbon atoms, or from 2 to about 4 carbon atoms. Alternatively, alkynyl is C2, C2-C3, C2-C4, C2-C5 or C2-C6. In certain embodiments, examples of alkynyl include ethynyl, propynyl, 1-butylyl, and 2-butylyl. nyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl , 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl. In the context of alkyl groups, the term "alkynyl" refers to a cycloalkyl group having at least one point of triple bond unsaturation. Alkyl or carbocyclic groups are also included.

[0110] II. Compounds of Formula I, Formula II, Formula III and Formula IV The present invention relates to compounds of formula I, II, III and IV, pharmaceutical compositions of these compounds Also provided are methods of using and making these compounds.

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

[0112] E1: One embodiment of the present invention is a compound of formula I: [ka] (In the formula, A is a ring system AF and AG: [ka] is selected from A 1 teeth, i) -NH-, and ii) -O-; A 2 teeth, i) -N-, and ii)-CR 52 - selected from A 3 teeth, i) -N-, and ii)-CR 53 - selected from A 4 teeth, i) -N-, and ii)-CR 54 - selected from A 5 teeth, i) -N-, and ii)-CR 55 - selected from R 1 teeth, i) H, ii) halogens, iii) C 1~6 -alkyl, R 52 teeth, i) H, ii) halogens, iii) cyano, iv) C 1~6 -alkoxy, v) Halo-C 1~6 -alkoxy, vi) C 1~6 - alkyl, vii) Halo-C 1~6 - alkyl, viii) C 3~8 -cycloalkyl, and ix) Halo-C 3~8 -cycloalkyl, R 53 , R 54 and R 55 is independent, i) H, ii) halogens, iii) C 1~6 - alkyl, iv) Halo-C 1~6 - alkyl, v) C 3~8 -cycloalkyl, and vi) Halo-C 3~8 -cycloalkyl, R 2 teeth, i) H, ii) halogens, iii) C 1~6 - alkyl, iv) Halo-C 1~6 - alkyl, v) C 3~8 -cycloalkyl, and vi) Halo-C 3~8 -cycloalkyl, R 3 teeth, i) H, ii) halogens, iii) C 1~6 - alkyl, iv) Halo-C 1~6 - alkyl, v) C 3~8 -cycloalkyl, and vi) Halo-C 3~8 -cycloalkyl, R 4 and R 5 is H or or R 4 and R 5 together -(CH2) q - Forms q is 1 or 2; R 6 teeth, i) H, ii) halogens, iii) cyano, iv) C 1~6 -alkoxy, v) Halo-C 1~6 -alkoxy, vi) C 1~6 - alkyl, vii) Halo-C 1~6 - alkyl, viii) C 3~8 -cycloalkyl, and ix) Halo-C 3~8 -cycloalkyl, R 7 teeth, i) H, ii) halogens, iii) cyano, iv) C 1~6 - alkyl, v) Halo-C 1~6 - alkyl, vi) C 3~8 -cycloalkyl, and vii) Halo-C 3~8 -cycloalkyl, R 70 teeth, i) H, ii) halogens, iii) cyano, iv) C 1~6 - alkyl, v) Halo-C 1~6 - alkyl, vi) C 3~8 -cycloalkyl, and vii) Halo-C 3~8 -cycloalkyl, R 8 is H, R 9 teeth, iii) H, and iv) C 1~6 -alkyl, L 1 teeth, [ka] and C is absent or is a ring system F, G and H: [ka] is selected from Y 1 teeth, i) -N-, and ii) -CH-; Y 2 teeth, i) -N-, and ii)-CR 16 - selected from R 12 , R 13 , R 14 and R 15 is independent, i)-H-, ii) halogens, and iii) Hydroxy-C 1~6 -alkyl, R 16 teeth, i)-H-, ii) hydroxy, and iii) selected from fluoro; L 3 does not exist, or i)-(CH2) m -C(O)-, ii) -C(O)-(CH2) p -, iii) -C(O)-C(O)-, iv)-NR 10 -C(O)-, v) -C(O)-NR 10 -, vi) -C(O)O-, vii) -CH2-CF2-CH2-, viii) -CH2-, ix) [ka] x) [ka] and, xi) [ka] is selected from m is 0, 1 or 2; p is 0, 1, 2 or 3; R 10 teeth, i) H, and ii) C 1~6 -alkyl, D is the ring system I, J, K, L, M, N, O, P, Q, R, S, T, U, V, W and X: [ka] and either ring system is selected from R 80 , R 81 and R 82 1 to 3 positions to be selected optionally substituted by substituents, R 80 , R 81 and R 82is independent, i) halogens, ii) cyano, iii) hydroxy, iv) Hydroxy-C 1~6 - alkyl, v) C 1~6 -alkoxy, vi) Halo-C 1~6 -alkoxy, vii) C 1~6 - alkyl, viii) Halo-C 1~6 - alkyl, ix) C 3~8 -cycloalkyl, and x) Halo-C 3~8 -cycloalkyl, L 4 does not exist, or i)-NR 11 -C(O)-, ii) -CH2-, and iii) -O-; E is the ring system Y, Z, AA, AB and AC: [ka] is selected from L 5 does not exist, or [ka] and B is the ring system AD and AE: [ka] or a pharmaceutically acceptable salt thereof. E2: A particular embodiment of the present invention is one in which A is a ring system AF and AG: [ka] is selected from A 1 but, i) -NH-, and ii) -O-; A 2 but, i) -N-, and ii) -CH-; R 1 but, i) H, and ii) selected from halogens; R 2 is H, R 3 but, i) H, and ii) selected from halogens; R 4 is H, R 5 is H or or R 4 and R 5 together -(CH2) n - Forms n is 1, R 6 but, i) H, ii) halogens, iii) cyano, and iv) Halo-C 1~6 -alkyl, R 7 is H, R 8 is H, R 9 C 1~6 -alkyl, L 1 but, [ka] and C is absent or the ring system F: [ka] and Y 1 but, i) -N-, and ii) -CH-; Y 2 but, i) -N-, and ii)-CR 16 - selected from R 12 , R 13 , R 14 and R 15 became independent, i) H, and ii) selected from halogens; R 16 but, i) H, and ii) hydroxy; L 3 but, i)-(CH2) m -C(O)-, ii) -C(O)-(CH2) p -, iii) —C(O)—C(O)—, and iv)-NR 10 -C(O)-; m is 1, p is 1 or 3, R 10 but, i) H, and ii) C 1~6 -alkyl, D is a ring system I, J, K, L and M: [ka] is selected from L 4 but, i)-NR 11 -C(O)-, ii) -CH2-, and iii) -O-; E is the ring system Y, Z and AA, AB and AC: [ka] is selected from L 5 but, [ka] and B is the ring system AD and AE: [ka] or a pharmaceutically acceptable salt thereof. E3: A particular embodiment of the present invention is one in which A is a ring system AF and AG: [ka] is selected from A 1 but, i) -NH-, and ii) -O-; A 2 but, i) -N-, and ii) -CH-; R 1 but, i) H, and ii) selected from fluoro; R 2 is H, R 3 but, i) H, and ii) selected from fluoro; R 4 is H, R 5 is H or or R 4 and R 5 together -(CH2) q - Forms q is 1, R 6 but, i) H, ii) fluoro, iii) cyano, iv) difluoromethyl, and v) trifluoromethyl; R 7 is H, R 8 is H, R9 is methyl, L 1 but, [ka] and C is the ring system F: [ka] and Y 1 but, i) -N-, and ii) -CH-; Y 2 but, i) -N-, and ii)-CR 16 - selected from R 12 and R 13 is fluoro, R 14 and R 15 is H, R 16 but, i) H, and ii) hydroxy; L 3 but, i)-(CH2) m -C(O)-, ii) -C(O)-(CH2) p -, iii) —C(O)—C(O)—, and iv)-NR 10 -C(O)-; m is 1, p is 1 or 3, R 10 is H, D is a ring system I, J, K, L and M: [ka] is selected from L 4 but, i)-NR 11 -C(O)-, ii) -CH2-, and iii) -O-; E is the ring system Y, Z, AA, AB and AC: [ka] is selected from L 5 but, [ka] and B is the ring system AD and AE: [ka] or a pharmaceutically acceptable salt thereof. E4: A particular embodiment of the present invention relates to compounds of formula I as described herein, in which A is the ring system AF. or a pharmaceutically acceptable salt thereof. E5: Certain embodiments of the present invention are 1 is -N-, or a pharmaceutically acceptable salt thereof. E6: Certain embodiments of the present invention are 2 is —CH— of formula I as described herein or a pharmaceutically acceptable salt thereof. E7: Certain embodiments of the present invention are 1 but, i) H, and ii) a compound of formula I as described herein or a pharmaceutically acceptable salt thereof, selected from halogen; It is a possible salt. E8: Certain embodiments of the present invention are 1 but, i) H, and ii) a compound of formula I as described herein or a pharmaceutically acceptable salt thereof selected from fluoro It is a possible salt. E9: Certain embodiments of the present invention are 1is fluoro, or a pharmaceutically acceptable salt thereof. E10: Certain embodiments of the present invention are 2 is H. or a pharmaceutically acceptable salt thereof. E11: Certain embodiments of the present invention are 3 but, i) H, and ii) a compound of formula I as described herein or a pharmaceutically acceptable salt thereof, selected from halogen; It is a possible salt. E12: Certain embodiments of the present invention are 3 but, i) H, and ii) a compound of formula I as described herein or a pharmaceutically acceptable salt thereof selected from fluoro It is a possible salt. E13: Certain embodiments of the present invention are 4 is H. or a pharmaceutically acceptable salt thereof. E14: Certain embodiments of the present invention are 5 is H. or a pharmaceutically acceptable salt thereof. E15: Certain embodiments of the present invention are 6 but, i) H, ii) halogens, iii) cyano, and iv) Halo-C 1~6 -alkyl; or and pharmaceutically acceptable salts thereof. E16: Certain embodiments of the present invention are 7 is H. or a pharmaceutically acceptable salt thereof. E17: Certain embodiments of the present invention are 8 is H. or a pharmaceutically acceptable salt thereof. E18: Certain embodiments of the present invention are 9 C 1~6 -alkyl, as defined herein or a pharmaceutically acceptable salt thereof. E19: Certain embodiments of the present invention are 9 is methyl or a pharmaceutically acceptable salt thereof. E20: Certain embodiments of the present invention are compounds of formula I as described herein, wherein n is 1. or a pharmaceutically acceptable salt thereof. E21: A particular embodiment of the present invention is a ring system in which C is absent or is an F ring system, and a compound of formula I as described herein or a pharmaceutically acceptable salt thereof. E22: A particular embodiment of the present invention relates to compounds of formula I as described herein, in which C is the ring system F. or a pharmaceutically acceptable salt thereof. E23: Certain embodiments of the present invention are 12 and R 13 is fluoro, or a pharmaceutically acceptable salt thereof. E24: Certain embodiments of the present invention are 14 and R 15 is H, as described herein or a pharmaceutically acceptable salt thereof. E25: Certain embodiments of the present invention are 16 but, i) H, and ii) a compound of formula I as described herein or a pharmaceutically acceptable salt thereof selected from hydroxy It is an acceptable salt. E26: Certain embodiments of the present invention are 16 is H, or a pharmaceutically acceptable salt thereof. E27: Certain embodiments of the present invention are3 but, i)-(CH2) m -C(O)-, ii) -C(O)-(CH2) p -, iii) —C(O)—C(O)—, and iv)-NR 10 -C(O)- or a compound of formula I as described herein, is a pharmaceutically acceptable salt of E28: A particular embodiment of the present invention is a compound of formula I as described herein, wherein m is 1. or a pharmaceutically acceptable salt thereof. E29: Certain embodiments of the present invention relate to compounds of formula I as described herein, wherein p is 1 or 3. or a pharmaceutically acceptable salt thereof. E30: Certain embodiments of the present invention are 10 but, i) H, and ii) C 1~6 -alkyl, It is a physiologically acceptable salt. E31: A particular embodiment of the present invention is one in which D is selected from the ring systems I, J, K, L and M. , a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof. E32: Certain embodiments of the present invention are 4 but, i)-NR 11 -C(O)-, ii) -CH2-, and iii) a compound of formula I as described herein or a pharmaceutically acceptable salt thereof, selected from -O- It is a possible salt. E33: Certain embodiments of the present invention are 4 but, [ka] or a pharmaceutically acceptable salt thereof. E34: Certain embodiments of the present invention are 5-((2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-1 -yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro- 3-oxoisoindolin-5-yl)ethynyl)-N-(1-(2-(4-(4-(( 2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)a cetyl)piperidin-4-yl)picolinamide, 5-[2-[2-[1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazole -1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl]-7-fluoro 3-oxo-isoindolin-5-yl]ethynyl]-N-[1-[2-[4-[( 2,6-Dioxo-3-piperidyl)amino]phenyl]acetyl]-4-piperidyl] pyridine-2-carboxamide, 5-[2-[2-[1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazole -1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl]-7-fluoro 3-oxo-isoindolin-5-yl]ethynyl]-N-[1-[2-[4-[4 -[(2,6-dioxo-3-piperidyl)oxy]phenyl]piperazin-1-yl] acetyl]-4-piperidyl]pyridine-2-carboxamide, 5-[2-[2-[1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazole -1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl]-7-fluoro 3-oxo-isoindolin-5-yl]ethynyl]-N-[1-[2-[4-[4 -[[(3S)-2,6-dioxo-3-piperidyl]amino]-2-fluoro-phenyl [acetyl]-1-piperidyl]acetyl-4-piperidyl]pyridine-2-carboxamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- [6-[4-[4-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino ]phenyl]-1-piperidyl]acetyl]piperazin-1-yl]phenyl]-4-fu [Fluoro-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetate amides, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- [6-[4-[4-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidinyl [N-(amino)phenyl]-1-piperidyl]acetyl]piperazin-1-yl]phenyl ]-4-Fluoro-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- [6-[4-[4-[2-[4-[4-[[(3R)-2,6-dioxo-3-piperidinyl [N-(amino)phenyl]-1-piperidyl]acetyl]piperazin-1-yl]phenyl ]-4-Fluoro-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- (6-(4-(4-(4-(4-(4-((2,6-dioxopiperidin-3-yl)a (amino)phenyl)piperidin-1-yl)-4-oxobutyl)piperazin-1-yl (phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazole -2-yl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- (6-(4-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)a Amino)phenyl)cyclohexyl)acetyl)piperazin-1-yl)phenyl)-4- Fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetate Toamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- (6-(4-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)a (amino)phenyl)piperidin-1-yl)-2-oxoethyl)piperidin-4-yl) (phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazole -2-yl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- [6-[4-[4-[2-[4-[5-[(2,6-dioxo-3-piperidyl)amino ]-2-pyridyl]-1-piperidyl]acetyl]piperazin-1-yl]phenyl]- 4-Fluoro-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl- acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- [6-[4-[4-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino ]-2-fluoro-phenyl]-1-piperidyl]acetyl]piperazin-1-yl] phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazole- 2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- [6-[4-[4-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino ]-3-fluoro-phenyl]-1-piperidyl]acetyl]piperazin-1-yl] phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazole- 2-yl-acetamide, 2-[6-[4-[4-[2-[4-[2-cyano-4-[(2,6-dioxo-3-pyridyl) 1-piperidyl)amino]phenyl]-1-piperidyl]acetyl]piperazin-1-yl] phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-2-(6,7-diphenyl) Hydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazole-2- yl-acetamide, 2-[6-[4-[4-[2-[4-[2-(difluoromethyl)-4-[(2,6-di Oxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetyl]piperazine -1-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-2 -(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazolinone azol-2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- (6-(4-(4-(2-(4-(3-((2,6-dioxopiperidin-3-yl)a amino)phenyl)piperidin-1-yl)acetyl)piperazin-1-yl)phenyl) -4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2-yl) ) acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- (6-(4-(4-(2-(4-(3-(2,4-dioxotetrahydropyrimidine-1 (2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl )acetyl)piperazin-1-yl)phenyl)-4-fluoro-1-oxoisoindo (thiazol-2-yl)-N-(thiazol-2-yl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- (6-(4-(4-(2-(1-(4-((2,6-dioxopiperidin-3-yl)a (amino)-2-(trifluoromethyl)phenyl)-4-hydroxypiperidin-4-yl )acetyl)piperazin-1-yl)phenyl)-4-fluoro-1-oxoisoindo (thiazol-2-yl)-N-(thiazol-2-yl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- (6-(4-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)a amino)phenyl)piperidin-1-yl)acetyl)piperazin-1-yl)phenyl) -4-fluoro-1-oxoisoindolin-2-yl)-N-(pyridin-2-yl) acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- [6-[4-[4-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino ]-2-fluoro-phenyl]-1-piperidyl]acetyl]piperazin-1-yl] Phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-(2-pyridinyl) acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- (6-(4-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)a amino)phenyl)piperidin-1-yl)acetyl)piperidin-4-yl)phenyl) -4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2-yl) ) acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- (6-(4-(1-(2-(4-(4-(((S)-2,6-dioxopiperidine-3- yl)amino)phenyl)piperidin-1-yl)acetyl)piperidin-4-yl)phenyl (phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazole- 2-yl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- (6-(4-(1-(2-(4-(4-(((R)-2,6-dioxopiperidine-3- yl)amino)phenyl)piperidin-1-yl)acetyl)piperidin-4-yl)phenyl (phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazole- 2-yl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- (6-(4-(1-(2-(4-(4-(((S)-2,6-dioxopiperidine-3- yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)piperidine -4-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N- (thiazol-2-yl)acetamide, 2-(6-(4-(1-(2-(4-(2-cyano-4-((2,6-dioxopiperidinyl phenyl)piperidine-3-yl)amino)phenyl)piperidin-1-yl)acetyl)piperidine-4- yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-2-(6, 7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazolinone) (2-yl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- [6-[4-[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino ]phenyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]phenyl] -4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl -acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- [6-[6-[4-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidinyl [N-(2-fluoro-phenyl)-1-piperidyl]acetyl]piperazine-1 -yl]-3-pyridyl]-4-fluoro-1-oxo-isoindolin-2-yl]- N-thiazol-2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- [6-[1-[1-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidinyl -1-aminophenyl-1-piperidylacetyl-4-piperidylpyrazole 4-yl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazole -2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- [6-[4-[1-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidinyl -1-aminophenyl-1-piperidylacetyl-4-piperidylpyrazole 1-yl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazole -2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- (6-(1-(1-(2-(4-(4-(((S)-2,6-dioxopiperidine-3- yl)amino)phenyl)piperidin-1-yl)acetyl)piperidin-4-yl)- 1H-1,2,3-triazol-4-yl)-4-fluoro-1-oxoisoindole N-(thiazol-2-yl)-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- [6-[4-[[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amine phenyl]-1-piperidyl]acetyl]-4-piperidyl]oxy]phenyl]- 4-Fluoro-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl- acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- [6-[4-[[1-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperi acetyl]-4-piperidyl]oxy]phenyl-1-piperidyl]acetyl phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazole- 2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- [6-[4-[[1-[2-[4-[4-[[(3R)-2,6-dioxo-3-piperidinyl) acetyl]-4-piperidyl]oxy]phenyl-1-piperidyl]acetyl phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazole- 2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- (6-(4-((1-(2-(4-(4-((2,6-dioxopiperidin-3-yl) Amino)-3-fluorophenyl)piperidin-1-yl)acetyl)piperidine-4- yl)oxy)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N -(thiazol-2-yl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- (6-(4-((1-(2-(4-(4-((2,6-dioxopiperidin-3-yl) Amino)-2-fluorophenyl)piperidin-1-yl)acetyl)piperidine-4- yl)oxy)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N -(thiazol-2-yl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- (6-(4-((1-(2-(4-(5-((2,6-dioxopiperidin-3-yl) Amino)pyridin-2-yl)piperidin-1-yl)acetyl)piperidin-4-yl )oxy)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-( thiazol-2-yl)acetamide, 2-(6-(4-((1-(2-(4-(2-cyano-4-((2,6-dioxopiperi phenyl)piperidin-3-yl)amino)phenyl)piperidin-1-yl)acetyl)piperidine-4 -yl)oxy)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)- 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N- (thiazol-2-yl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- (6-(4-((1-(2-(4-(4-((2,4-dioxo-3-azabicyclo[3 .1.1]heptan-1-yl)amino)phenyl)piperidin-1-yl)acetyl) Piperidin-4-yl)oxy)phenyl)-4-fluoro-1-oxoisoindoline -2-yl)-N-(thiazol-2-yl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- (6-(4-((1-(2-(4-(4-(((S)-2,6-dioxopiperidine-3 -yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)piperidin (phenyl-4-yl)oxy)phenyl)-4-fluoro-1-oxoisoindoline-2-yl -N-(thiazol-2-yl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- [6-[4-[[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amine No]phenyl]-1-piperidyl]-2-oxo-acetyl]-4-piperidyl]oxy ]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazo phenyl-2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- [6-[4-[(3R)-1-[2-[4-[4-[[(3S)-2,6-dioxo-3 -piperidyl]amino]phenyl]-1-piperidyl]acetyl]pyrrolidin-3-yl ]oxyphenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thi azol-2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- [6-[4-[(3S)-1-[2-[4-[4-[[(3S)-2,6-dioxo-3 -piperidyl]amino]phenyl]-1-piperidyl]acetyl]pyrrolidin-3-yl ]oxyphenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thi azol-2-yl-acetamide, 2-(6-(4-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl )amino)phenyl)piperidin-1-yl)acetyl)piperazin-1-yl)phenyl (R)-6-fluoro-1-oxoisoindolin-2-yl)-2-((R)-4-fluoro-1-oxoisoindolin-2-yl)-2-((R)-6 ... Oro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N- (thiazol-2-yl)acetamide, 2-[6-[4-[4-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidine Lysyl]amino]-2-fluoro-phenyl]-1-piperidyl]acetyl]piperazine -1-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-2 -[(6R)-6-Fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazo [N-thiazol-1-yl]-N-thiazol-2-yl-acetamide, 2-[6-[4-[4-[2-[4-[3-(2,4-dioxohexahydropyrimidine -1-yl)-1-methyl-indazol-6-yl]-1-piperidyl]acetyl]pi Perazin-1-yl]phenyl]-4-fluoro-1-oxo-isoindoline-2-yl yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c] imidazol-1-yl]-N-thiazol-2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- (6-(4-(2-(2-(4-(4-(((S)-2,6-dioxopiperidine-3- yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)-2,7- Diazaspiro[3.5]nonan-7-yl)phenyl)-4-fluoro-1-oxoiso indolin-2-yl)-N-(thiazol-2-yl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- [6-[4-[2-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino ]phenyl]-1-piperidyl]acetyl]-2,6-diazaspiro[3.3]heptane -6-yl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N -thiazol-2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- [6-[4-[2-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidinyl [N-(2-fluoro-phenyl)-1-piperidyl]acetyl]-2,6-diazo Zaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-iso indolin-2-yl]-N-thiazol-2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- [6-[4-[2-[2-[4-[3-(2,4-dioxohexahydropyrimidine-1 -yl)-1-methyl-indazol-6-yl]-1-piperidyl]acetyl]-2, 6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo so-isoindolin-2-yl]-N-thiazol-2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- [6-[4-[2-[2-[4-[3-(2,4-dioxohexahydropyrimidine-1 -yl)-1-methyl-indazol-6-yl]-3,3-difluoro-1-piperidin [3.3]heptan-6-yl]phenyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4 -Fluoro-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-a cetoamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- (6-(4-(6-(2-(4-(4-((2,6-dioxopiperidin-3-yl)a (amino)phenyl)-3,3-difluoropiperidin-1-yl)acetyl)-2,6-di Azaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1-oxoiso indolin-2-yl)-N-(thiazol-2-yl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- [6-[4-[2-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidinyl [N-(2-fluoro-phenyl)-1-piperidyl]acetyl]-2,6-diazo Zaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo-iso indolin-2-yl]-N-(2-pyridyl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- [6-[4-[2-[2-[4-[3-(2,4-dioxohexahydropyrimidine-1 -yl)-1-methyl-indazol-6-yl]-1-piperidyl]acetyl]-2, 6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo so-isoindolin-2-yl]-N-(2-pyridyl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- [6-[4-[2-[2-[4-[3-(2,4-dioxohexahydropyrimidine-1 -yl)-1-methyl-indazol-6-yl]-3,3-difluoro-1-piperidin [3.3]heptan-6-yl]phenyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4 -Fluoro-1-oxo-isoindolin-2-yl]-N-(2-pyridyl)acetate Mido, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- [6-[4-[[4-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amine phenyl]-1-piperidyl]acetyl]piperazin-1-yl]methyl]phenyl ]-4-Fluoro-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- [6-[4-[[4-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amine 2-fluoro-phenyl-1-piperidylacetylpiperazin-1-yl Methyl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thi azol-2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- [6-[4-[[4-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperi acetyl]piperazine- 1-yl]methyl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl ]-N-thiazol-2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- [6-[4-[[4-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperi 1-piperidyl]amino]-2-fluoro-phenyl]-1-piperidyl]-2-oxo-ethyl] Piperazin-1-yl]methyl]phenyl]-4-fluoro-1-oxo-isoindole N-thiazol-2-yl]-N-thiazol-2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- [6-[4-[[1-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperi [Dil]amino]-2-fluoro-phenyl]-1-piperidyl]acetyl]-4-piperi Dimethyl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]- N-thiazol-2-yl-acetamides, as described herein A compound of Formula I or a pharmaceutically acceptable salt thereof: E35: Certain embodiments of the present invention relate to the use of the compounds described herein as therapeutically active substances. or a pharmaceutically acceptable salt thereof. E36: Certain embodiments of the present invention are directed to the treatment of cancer, particularly non-small cell lung cancer, and more particularly activated leukocyte antigen (LAMP)-associated leukemia (ALA)-associated leukemia (LE ...). It is used for the therapeutic and / or preventive treatment of EGFR-mutated non-small cell lung cancer in which the natural mutation is L858R. The compound of formula I described herein or a pharmaceutically acceptable salt thereof is used in the present invention. E37: Certain embodiments of the present invention are directed to the treatment of non-small cell lung cancer, more particularly those with activating mutations For use in the therapeutic and / or prophylactic treatment of L858R EGFR-mutated non-small cell lung cancer A compound of Formula I as described herein or a pharmaceutically acceptable salt thereof. E38: Certain embodiments of the present invention are directed to the treatment of cancer, particularly non-small cell lung cancer, and more particularly activated leukocyte antigen (LAMP)-associated leukemia (ALA)-associated leukemia (LE ...). for the therapeutic and / or preventive treatment of EGFR-mutated non-small cell lung cancer in which the natural mutation is L858R A compound of formula I or a pharmaceutically acceptable salt thereof as described herein for the manufacture of a medicament for . E39: Certain embodiments of the present invention are directed to compounds of formula I or pharmaceutical compositions thereof as described herein. and pharmaceutically acceptable auxiliary substances. E40: Certain embodiments of the present invention are directed to compounds of formula I or pharmaceutical compositions thereof as described herein. and the like. A method for treating cancer, particularly non-small cell lung cancer, more particularly activated ovarian cancer, by administering to a patient a salt thereof which is acceptable to the patient. Therapeutic and / or preventive treatment of EGFR-mutated non-small cell lung cancer in which the mutation is L858R It is a method. E41: Certain embodiments of the present invention are directed to determining the EGFR activating mutation status of a patient. and then administering a compound of Formula I described herein or a pharmaceutically acceptable salt thereof to the patient. and administering to a patient suffering from cancer, particularly non-small cell lung cancer, a patient with an EGFR activating mutation. for use as a medicament in the therapeutic and / or prophylactic treatment of patients with I or a pharmaceutically acceptable salt thereof. E42: Certain embodiments of the present invention provide a method for determining the EGFR activating mutation status of a patient. and then administering a compound of Formula I described herein or a pharmaceutically acceptable salt thereof to the patient. a patient suffering from cancer, particularly non-small cell lung cancer, with EGFR mutation T790M / L858R, T790M / L858R / C797S, L858R, and / or L858R / Used as a drug in the therapeutic and / or prophylactic treatment of patients with C797S A compound of Formula I as described herein or a pharmaceutically acceptable salt thereof. E43: Certain embodiments of the present invention are directed to determining the EGFR activating mutation status of a patient. and then administering a compound of Formula I described herein or a pharmaceutically acceptable salt thereof to the patient. and administering cobas™ EGFR to a subject suffering from cancer, particularly non-small cell lung cancer. Possess an EGFR activating mutation as determined using Mutation Test v2 for use as a medicament in the therapeutic and / or prophylactic treatment of patients with I or a pharmaceutically acceptable salt thereof. E44: The present invention provides, whenever applicable, replacing all substituents of compounds of formula I with their corresponding Included in deuterated form. E45: The present invention relates, whenever applicable, to all optical isomers of compounds of formula I, i.e. Diastereoisomers, diastereomeric mixtures, racemic mixtures, and all their corresponding This includes enantiomers and / or tautomers, as well as solvates thereof.

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

[0114] E1: One embodiment of the present invention is a compound of formula II: [ka] (In the formula, A' is the ring system AF, AG and AH: [ka] is selected from A 1 teeth, i) -NH-, and ii) -O-; A 2 teeth, i) -N-, and ii)-CR 52 - selected from A 3 teeth, i) -N-, and ii)-CR 53 - selected from A 4 teeth, i) -N-, and ii)-CR 54 - selected from A 5 teeth, i) -N-, and ii)-CR 55 - selected from R 1 'teeth, i) H, ii) halogens, iii) C 1~6 - alkyl, iv) cyano, v) C 1~6 -alkoxy, vi) Halo-C 1~6 -alkoxy, vii) C 1~6 - alkyl, viii) Halo-C 1~6 - alkyl, ix) C 3~8 -cycloalkyl, and x) Halo-C 3~8 -cycloalkyl, R 52 teeth, i) H, ii) halogens, iii) cyano, iv) C 1~6 -alkoxy, v) Halo-C1~6 -alkoxy, vi) C 1~6 - alkyl, vii) Halo-C 1~6 - alkyl, viii) C 3~8 -cycloalkyl, and ix) Halo-C 3~8 -cycloalkyl, R 53 , R 54 and R 55 is independent, i) H, ii) halogens, iii) C 1~6 - alkyl, iv) Halo-C 1~6 - alkyl, v) C 3~8 -cycloalkyl, and vi) Halo-C 3~8 -cycloalkyl, R 2 teeth, i) H, ii) halogens, iii) cyano, iv) C 1~6 - alkyl, v) Halo-C 1~6 - alkyl, vi) C 3~8 -cycloalkyl, and vii) Halo-C 3~8 -cycloalkyl, R 3 teeth, i) H, ii) halogens, iii) C 1~6 - alkyl, iv) Halo-C 1~6 - alkyl, v) C 3~8 -cycloalkyl, and vi) Halo-C 3~8 -cycloalkyl, R 4 and R 5 is H or or R 4 and R 5 together -(CH2) q - Forms q is 1 or 2; R 6 teeth, i) H, ii) halogens, iii) cyano, iv) C 1~6 -alkoxy, v) Halo-C 1~6 -alkoxy, vi) C 1~6 - alkyl, vii) Halo-C 1~6 - alkyl, viii) C 3~8 -cycloalkyl, and ix) Halo-C 3~8 -cycloalkyl, R 7 teeth, i) H, ii) halogens, iii) cyano, iv) C 1~6 - alkyl, v) Halo-C 1~6 - alkyl, vi) C 3~8 -cycloalkyl, and vii) Halo-C 3~8 -cycloalkyl, R 70 teeth, i) H, ii) halogens, iii) cyano, iv) C 1~6 - alkyl, v) Halo-C 1~6 - alkyl, vi) C 3~8 -cycloalkyl, and vii) Halo-C 3~8 -cycloalkyl, R 8 is H, R 9 teeth, i) H, and ii) C 1~6 -alkyl, L 1 teeth, [ka] and C is absent or is a ring system F, G and H: [ka] is selected from Y 1 teeth, i) -N-, and ii) -CH-; Y 2 teeth, i) -N-, and ii)-CR 16 - selected from R 12 , R 13 , R 14 and R 15 is independent, i)-H-, ii) halogens, and iii) Hydroxy-C 1~6 -alkyl, R 16 teeth, i)-H-, ii) hydroxy, and iii) selected from fluoro; L 3 does not exist, or i)-(CH2) m -C(O)-, ii) -C(O)-(CH2) p -, iii) -C(O)-C(O)-, iv)-NR 10 -C(O)-, v) -C(O)-NR 10 -, vi) -C(O)O-, vii) -CH2-CF2-CH2-, viii) -CH2-, ix) [ka] x) [ka] and, xi) [ka] is selected from m is 0, 1 or 2; p is 0, 1, 2 or 3; 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 1 to 3 positions to be selected optionally substituted by substituents, R 80 , R 81 and R 82 is independent, i) halogens, ii) cyano, iii) hydroxy, iv) Hydroxy-C 1~6 - alkyl, v) C 1~6 -alkoxy, vi) Halo-C 1~6 -alkoxy, vii) C 1~6 - alkyl, viii) Halo-C 1~6 - alkyl, ix) C 3~8 -cycloalkyl, and x) Halo-C 3~8 -cycloalkyl, L 4 does not exist, or i)-NR 11 -C(O)-, ii) -CH2-, and iii) -O-; E is the ring system Y, Z, AA, AB and AC: [ka] is selected from L 5 does not exist, or [ka] and B is the ring system AD and AE: [ka] or a pharmaceutically acceptable salt thereof. E2: A particular embodiment of the invention is where A' is a ring system AF, AG and AH: [ka] is selected from A 1 is -NH-, A 2 but, i) -N-, and ii) -CH-; R 1 'but, i) H, and ii) selected from halogens; R 2 but, i) H, and ii) selected from halogens; R 3 is H, R 4 is H, R 5 is H, R 6 but, i) H, and ii) selected from halogens; R 7 is H, R 8 is H, R 9 C 1~6 -alkyl, L 1 but, [ka] and C is the ring system F: [ka] and Y 1 is -CH-, Y 2 is -N-, R 12 , R 13 , R 14 and R 15 is H, L 3 but, i)-(CH2) m -C(O)-, and ii) -C(O)-(CH2) p - selected from m is 1, p is 3, D is ring system I and J: [ka] is selected from L 4 does not exist, E is the ring system Y and Z: [ka] is selected from L 5 A compound of formula II as described herein, or a pharmaceutically acceptable salt thereof, wherein do. E3: Certain embodiments of the present invention are directed to compounds herein in which A is selected from the ring systems AG and AF. or a pharmaceutically acceptable salt thereof. E4: A particular embodiment of the present invention relates to compounds of formula II described herein, in which A is the ring system AF. or a pharmaceutically acceptable salt thereof. E5: Certain embodiments of the present invention are 1 is —NH—, or a pharmaceutically acceptable salt thereof. E6: Certain embodiments of the present invention are 2 is —CH—, or a pharmaceutically acceptable salt thereof. E7: Certain embodiments of the present invention are 1 'but, i) H, and ii) a compound of formula II as described herein or a pharmaceutically acceptable salt thereof selected from halogen; It is an acceptable salt. E8: Certain embodiments of the present invention are 1 'but, i) H, ii) chloro, and iii) a compound of formula II as described herein or a pharmaceutically acceptable salt thereof selected from fluoro, Acceptable salts. E9: Certain embodiments of the present invention are 2 but, i) H, and ii) a compound of formula II as described herein or a pharmaceutically acceptable salt thereof selected from halogen; It is an acceptable salt. E10: Certain embodiments of the present invention are 2 but, i) H, ii) chloro, and iii) a compound of formula II as described herein or a pharmaceutically acceptable salt thereof selected from fluoro, Acceptable salts. E11: Certain embodiments of the present invention are 3 but, i) H, and ii) a compound of formula II as described herein or a pharmaceutically acceptable salt thereof selected from halogen; It is an acceptable salt. E12: Certain embodiments of the present invention are 3 is H, or a pharmaceutically acceptable salt thereof. E13: Certain embodiments of the present invention are 4 is H, or a pharmaceutically acceptable salt thereof. E14: Certain embodiments of the present invention are 5 is H, or a pharmaceutically acceptable salt thereof. E15: Certain embodiments of the present invention are 6 but, i) H, and ii) a compound of formula II as described herein or a pharmaceutically acceptable salt thereof selected from halogen; It is an acceptable salt. E16: Certain embodiments of the present invention are 7 is H, or a pharmaceutically acceptable salt thereof. E17: Certain embodiments of the present invention are 8 is H, or a pharmaceutically acceptable salt thereof. E18: Certain embodiments of the present invention are 9 C 1~6 -alkyl, as defined herein or a pharmaceutically acceptable salt thereof. E19: Certain embodiments of the present invention are 9 is methyl, or a pharmaceutically acceptable salt thereof. E20: A particular embodiment of the present invention relates to compounds of formula II as described herein, in which C is the ring system F. or a pharmaceutically acceptable salt thereof. E21: Certain embodiments of the present invention are 1 is —CH—, I or a pharmaceutically acceptable salt thereof. E22: Certain embodiments of the present invention are 2 is -N-, or a pharmaceutically acceptable salt thereof. E23: Certain embodiments of the present invention are 12 , R 13 , R 14 and R 15 is H , a compound of Formula II as described herein, or a pharmaceutically acceptable salt thereof. E24: Certain embodiments of the present invention are 3 but, i)-(CH2) m -C(O)-, and ii) -C(O)-(CH2) p a compound of formula II as described herein selected from or a pharmaceutically acceptable salt thereof. E25: Certain embodiments of the present invention are compounds of formula II as described herein, wherein m is 1. or a pharmaceutically acceptable salt thereof. E26: Certain embodiments of the present invention are compounds of formula II described herein, wherein p is 1 or 3. or a pharmaceutically acceptable salt thereof. E27: Certain embodiments of the present invention relate to the compounds described herein, in which D is selected from the ring systems I and J. or a pharmaceutically acceptable salt thereof. E28: A particular embodiment of the present invention relates to compounds of formula II as described herein, in which D is the ring system J. or a pharmaceutically acceptable salt thereof. E29: Certain embodiments of the present invention are4 of formula II as described herein, or a pharmaceutically acceptable salt thereof. E30: Certain embodiments of the present invention relate to the compounds described herein, in which E is selected from the ring systems Y and Z. or a pharmaceutically acceptable salt thereof. E31: Certain embodiments of the present invention are 5 of formula II as described herein, or a pharmaceutically acceptable salt thereof. E32: Certain embodiments of the present invention are 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- (6-(6-(4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)- 1-Oxoisoindolin-4-yl)oxy)piperidin-1-yl)-4-oxoisobutanol (Ci)piperazin-1-yl)pyridin-3-yl)-7-fluoro-2H-indazole (thiazol-2-yl)-N-(thiazol-2-yl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- (6-(6-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)a amino)phenyl)piperidin-1-yl)acetyl)piperazin-1-yl)pyridine- 3-yl)-7-fluoro-2H-indazol-2-yl)-N-(thiazol-2-yl) yl)acetamide, 2-[4,7-dichloro-6-[4-[4-[2-[4-[4-[(2,6-dioxo- 3-piperidyl)amino]phenyl]-1-piperidyl]acetyl]piperazine-1-yl 1-[(6,7-dihydro-5H-pyrrolo[1-yl]phenyl]indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1-yl]phenyl]indazol-2-yl) ... ,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- [6-[6-[4-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino ]-2-Fluoro-phenyl]-1-piperidyl]acetyl]piperazin-1-yl]- 3-pyridyl]-4-fluoro-indazol-2-yl]-N-thiazol-2-yl -acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- [6-[6-[4-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino ]phenyl]-1-piperidyl]acetyl]piperazin-1-yl]-3-pyridyl]- 4-fluoro-indazol-2-yl]-N-thiazol-2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- [6-[6-[4-[2-[4-[5-[(2,6-dioxo-3-piperidyl)amino ]-2-pyridyl]-1-piperidyl]acetyl]piperazin-1-yl]-3-pyridyl [4-fluoro-indazol-2-yl]-N-thiazol-2-yl-aceta Mido, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- [6-[6-[4-[2-[4-[3-(2,4-dioxohexahydropyrimidine-1 -yl)-1-methyl-indazol-6-yl]-1-piperidyl]acetyl]pipera [Indazol-1-yl]-3-pyridyl]-4-fluoro-indazol-2-yl]-N-thiazole azol-2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2- (6-(6-(4-(2-(4-(4-(((S)-2,6-dioxopiperidine-3- yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)piperazine -1-yl)pyridin-3-yl)-4-fluoro-2H-indazol-2-yl)- N-(thiazol-2-yl)acetamide, as described herein or a pharmaceutically acceptable salt thereof. E33: Certain embodiments of the present invention relate to the use of the compounds described herein as therapeutically active substances. or a pharmaceutically acceptable salt thereof. E34: Certain embodiments of the present invention are directed to the treatment of cancer, particularly non-small cell lung cancer, and more particularly activated leukocyte antigen (LAMP)-associated leukemia (LEA) and leukemia-associated ... It is used for the therapeutic and / or preventive treatment of EGFR-mutated non-small cell lung cancer in which the natural mutation is L858R. The compound of formula II described herein or a pharmaceutically acceptable salt thereof is used in the present invention. E35: Certain embodiments of the present invention are directed to the treatment of non-small cell lung cancer, more particularly those with activating mutations For use in the therapeutic and / or prophylactic treatment of L858R EGFR-mutated non-small cell lung cancer A compound of Formula II as described herein or a pharmaceutically acceptable salt thereof. E36: Certain embodiments of the present invention are directed to the treatment of cancer, particularly non-small cell lung cancer, and more particularly activated leukocyte antigen (LAMP)-associated leukemia (ALA)-associated leukemia (LE ...). for the therapeutic and / or preventive treatment of EGFR-mutated non-small cell lung cancer in which the natural mutation is L858R The use of a compound of formula II or a pharmaceutically acceptable salt thereof as described herein in the manufacture of a medicament for do. E37: Certain embodiments of the present invention comprise a compound of formula II or a pharmaceutical composition thereof as described herein. and a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable auxiliary substance. E38: Certain embodiments of the present invention comprise a compound of formula II or a pharmaceutical composition thereof as described herein. and the like. The present invention relates to a method for treating cancer, particularly non-small cell lung cancer, more particularly active ingredient in a method for treating cancer, by administering a physiologically acceptable salt thereof to a patient. Therapeutic and / or preventive treatment of EGFR-mutated non-small cell lung cancer in which the mutated mutation is L858R - Patent application This is the method. E39: Certain embodiments of the present invention provide a method for determining the EGFR activating mutation status of a patient. and then combining a compound of formula II described herein or a pharmaceutically acceptable salt thereof with the and administering to a patient suffering from cancer, particularly non-small cell lung cancer, a cancer having an EGFR activating mutation. for use as a medicament in the therapeutic and / or prophylactic treatment of a patient suffering from A compound of Formula II or a pharmaceutically acceptable salt thereof: E40: Certain embodiments of the present invention are directed to determining the EGFR activating mutation status of a patient. and then combining a compound of formula II described herein or a pharmaceutically acceptable salt thereof with the EGFR mutation T790M, comprising administering to a patient suffering from cancer, particularly non-small cell lung cancer. / L858R, T790M / L858R / C797S, L858R, and / or L858 It is used as a drug in the therapeutic and / or prophylactic treatment of patients with R / C797S. or a pharmaceutically acceptable salt thereof. E41: Certain embodiments of the present invention are directed to determining the EGFR activating mutation status of a patient. and then combining a compound of formula II described herein or a pharmaceutically acceptable salt thereof with the cobas™ EGF is administered to a patient suffering from cancer, particularly non-small cell lung cancer. Patients with EGFR activating mutations as determined using the R Mutation Test v2 for use as a medicament in the therapeutic and / or prophylactic treatment of a patient suffering from A compound of Formula II or a pharmaceutically acceptable salt thereof: E42: The present invention provides, whenever applicable, the replacement of all substituents of compounds of formula II with their corresponding substituents. This includes in its deuterated form. E43: The present invention relates, whenever applicable, to all optical isomers of the compounds of formula II, i.e. Diastereoisomers, diastereomeric mixtures, racemic mixtures, and all their corresponding The present invention includes enantiomers and / or tautomers of the formula (I) and solvates thereof.

[0115] Formula III and Formula IV Embodiments E1: In certain embodiments, the present invention provides a compound of formula I, optionally as part of a pharmaceutical composition. II or Formula IV: [ka] (In the formula, A * teeth, [ka] is selected from B * is heteroaryl or aryl, each of which is selected from one, two, or three R 31 substituent optionally replaced by y is 0, 1, 2 or 3; R 31 In each case, H, halogen (F, Cl, Br or I), C 1~6 -Arki Le, Cyano, C 1~6 -Alkoxy, Halo-C 1~6 -Alkoxy, Halo-C 1~6 -a Lukil, C 3~8 -cycloalkyl and halo-C 3~8 -cycloalkyl When present on a bicyclic ring, it may be located on either ring; R 32 is hydrogen, halogen (F, Cl, Br or I), C 1~6 -Alkyl, Halo-C1~ 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, may be located on the dihydropyrrole or imidazole ring, R 34 In either case, H, F, C 1~6 -Alkyl, Halo-C 1~6 - alkyl, C 3~8 -cycloalkyl and halo-C 3~8 -cycloalkyl; R 35 In each case, H, halogen (F, Cl, Br or I), C 1~6 -Arki Le, Halo-C 1~6 -alkyl and C 3~8 - independently selected from 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 Ruka, or R 36 and R 37and are bonded together to form one, two or three R 31 Optionally, the substituent forming a substituted 5- or 6-membered ring, 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 that valence allows, R 100 R 37 and bonded to form a 5- to 8-membered heterocycle or a 5-membered heterocycle. may form a heteroaryl, A 32 , A 33 , A 34 and A 35 are independently -N- and -CR 42 - selected from R 42 In each case, H, halogen (F, Cl, Br or I), cyano, C 1~6 -Alkoxy, Halo-C 1~6 -alkoxy, C 1~6 -Alkyl, Halo-C 1~6 -a Lukil, C 3~8 -cycloalkyl and halo-C 3~8 -cycloalkyl Selected, A 36 -N- or -CR 35 - and L 2 is A * and either isoindolinone or indazole, or a pharmaceutically acceptable salt, isotope, N-oxide, or stereoisomer thereof. Provide. E2: The compound is [ka] or a pharmaceutically acceptable salt thereof. E3: The compound is [ka] or a pharmaceutically acceptable salt thereof. E4:R 33 The compound of any one of embodiments 1-3, wherein is H. E5:R 33 The compound of any one of embodiments 1-3, wherein is F. E6: The compound of any one of embodiments 1 to 5, wherein y is 1. E7: The compound of any one of embodiments 1 to 5, wherein y is 2. E8: At least one R 31 The compound of any one of embodiments 1 to 7, wherein . E9: At least one R 31 The compound of any one of embodiments 1-7, wherein is F. E10: The compound of any one of embodiments 1 to 5, wherein y is 0. E11:R 32 The compound of any one of embodiments 1-10, wherein is H. E12:R 32 The compound of any one of embodiments 1-10, wherein is F. E13: The compound is [ka] 2. The compound of embodiment 1, selected from: E14: The compound is [ka] 2. The compound of embodiment 1, selected from: E15:A * but, [ka] 15. The compound of any one of embodiments 1-14, wherein E16:A * but, [ka] 15. The compound of any one of embodiments 1-14, wherein E17:A 34 The compound of any of embodiments 1-16, wherein is CH. E18:A 34 The compound of any of embodiments 1-16, wherein is N. E19:A 34 is CR 42 17. The compound of any one of embodiments 1-16, wherein: E20:A 34 The compound of any of embodiments 1-16, wherein is CF. E21:A 35 The compound of any one of embodiments 1-20, wherein is CH. E22:A 35 The compound of any of embodiments 1-20, wherein is N. E23:A 35 is CR 42 21. The compound of any one of embodiments 1-20, wherein E24:A 35 The compound of any of embodiments 1-20, wherein is CF. E25:A * but, [ka] 15. The compound of any one of embodiments 1-14, wherein E26:A * but, [ka] 15. The compound of any one of embodiments 1-14, wherein E27:A 21The compound of embodiment 25 or 26, wherein is NH. E28:A 21 The compound of embodiment 25 or 26, wherein is O. E29:A * but, [ka] 15. The compound of any one of embodiments 1-14, wherein E30:A 32 The compound of any of embodiments 1-29, wherein is CH. E31:A 32 The compound of any of embodiments 1-29, wherein is N. E32:A 32 is CR 42 30. The compound of any one of embodiments 1-29, wherein E33:A 32 The compound of any of embodiments 1-29, wherein is CF. E34:A 33 The compound of any of embodiments 1-33, wherein is CH. E35:A 33 The compound of any of embodiments 1-33, wherein is N. E36:A 33 is CR 42 34. The compound of any one of embodiments 1-33, wherein: E37:A 33 The compound of any of embodiments 1-33, wherein is CF. E38:A * but, [ka] 15. The compound of any one of embodiments 1-14, wherein E39:A 21 The compound of embodiment 38, wherein is NH. E40:A 21 is O. E41:R 34 The compound of any of embodiments 1-40, wherein is H. E42:R 34 The compound of any of embodiments 1-40, wherein is F. E43:R 34 The compound of any of embodiments 1-40, wherein is CH3. E44:R 35 The compound of any of embodiments 1-43, wherein is H. E45:R 35 The compound of any of embodiments 1-43, wherein is F. E46:R 35 The compound of any of embodiments 1-43, wherein is CH3. E47:R 34 and R 35 and bond to form -CH2-. The compound described above. E48:R 31 In each case, H, halogen (F, Cl, Br or I) and C 1~ 6-alkyl. E49:R 42 In each case, H, halogen (F, Cl, Br or I) and C 1~ 6-alkyl. E50:B * but, [ka] 50. The compound of any one of embodiments 1-49, wherein: E51:B * but, [ka] 50. The compound of any one of embodiments 1-49, wherein: E52:B * but, [ka] 50. The compound of any one of embodiments 1-49, wherein: E53:B * but, [ka] 50. The compound of any one of embodiments 1-49, wherein: E54:L 2 is the expression: [ka] (In the formula, X 1 and X 2 are independently in each occurrence a bond, a heterocycle, an aryl, a heteroaryl, Bicyclic, alkyl, aliphatic, heteroaliphatic, -NR 27 -, -CR 40 R 41 -, -O-, -C(O)-, -C(NR 27 )-, -C(S)-, -S(O)-, -S(O)2- and -S-, wherein each of the heterocycle, aryl, heteroaryl, and bicycle is selected from R 40 optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 20 , R 21 , R 22 , R 23 and R 24 are independently in each case a bond, an alkyl group, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C (S)-, -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 selected from the group consisting of R 40 one, two, three or four independently selected from is optionally substituted with a substituent of R 26 are independently in each case hydrogen, alkyl, arylalkyl, heteroaryl alkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic, aliphatic and heterocyclic (b) selected from the group consisting of aliphatic R 27 are independently in each occurrence hydrogen, alkyl, aliphatic, heteroaliphatic, heterocyclic, Aryl, heteroaryl, -C(O)(aliphatic, aryl, heteroaliphatic or heteroaryl) -aryl), -C(O)O(aliphatic, aryl, heteroaliphatic or heteroaryl), ar selected from the group consisting of kenes and alkynes; R 40 are independently hydrogen in each case, R 27 , alkyl, alkene, alkyne, fluorine 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 heterocycle), -NHSO2 alkenyl, -N(alkyl)S O2 alkenyl, -NHSO2 alkynyl, -N(alkyl)SO2 alkynyl, haloa alkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic, oxo and cyclo alkyl, and further, when valence permits, two alkyl groups bonded to the same carbon; R 40 The groups may be joined together to form a 3- to 8-membered spiro ring, R 41 is aliphatic, aryl, heteroaryl, or hydrogen. The compound according to any one of claims 1 to 53. E55:L 2 is the expression: [ka] 55. The compound of embodiment 54, wherein: E56:X 1 The compound of embodiment 54 or 55, wherein is a bond. E57:X 1 The compound of embodiment 54 or 55, wherein is a heterocycle. E58:X 1 NR 2 56. The compound of embodiment 54 or 55, wherein E59:X 1 The compound of embodiment 54 or 55, wherein is C(O). E60:X 2 The compound of any of embodiments 54-59, wherein is a bond. E61:X 2 The compound of any of embodiments 54-59, wherein is a heterocycle. E62:X 2 NR 2 60. The compound of any of embodiments 54-59, wherein: E63:X 2 The compound of any of embodiments 54-59, wherein is C(O). E64:R 20 The compound of any of embodiments 54-63, wherein is a bond. E65:R 20 The compound of any of embodiments 54-63, wherein is CH2. E66:R 20 The compound of any of embodiments 54-63, wherein is a heterocycle. E67:R 20 The compound of any of embodiments 54-63, wherein is aryl. E68:R 20The compound of any of embodiments 54-63, wherein is phenyl. E69:R 20 The compound of any of embodiments 54-63, wherein is bicyclic. E70:R 21 The compound of any of embodiments 54-69, wherein is a bond. E71:R 21 The compound of any of embodiments 54-69, wherein is CH2. E72:R 21 The compound of any of embodiments 54-69, wherein is a heterocycle. E73:R 21 The compound of any of embodiments 54-69, wherein is aryl. E74:R 21 The compound of any of embodiments 54-69, wherein is phenyl. E75:R 21 The compound of any of embodiments 54-69, wherein is bicyclic. E76:L is the formula: [ka] 55. The compound of embodiment 54, wherein the linker is E77:R 22 The compound of any of embodiments 54-76, wherein is a bond. E78:R 22 The compound of any of embodiments 54-76, wherein is CH2. E79:R 22 The compound of any of embodiments 54-76, wherein is a heterocycle. E80:R 22 The compound of any of embodiments 54-76, wherein is aryl. E81:R 22 The compound of any of embodiments 54-69, wherein is phenyl. E82:R 22 The compound of any of embodiments 54-76, wherein is bicyclic. E83:L is the formula: [ka] 55. The compound of embodiment 54, wherein the linker is E84:R 23 The compound of any of embodiments 54-83, wherein is a bond. E85:R 23 The compound of any of embodiments 54-83, wherein is CH2. E86:R 23 The compound of any of embodiments 54-83, wherein is a heterocycle. E87:R 23 The compound of any of embodiments 54-83, wherein is aryl. E88:R 23 The compound of any of embodiments 54-83, wherein is phenyl. E89:R 23 The compound of any of embodiments 54-83, wherein is bicyclic. E90:R 24 The compound of any of embodiments 54-89, wherein is a bond. E91:R 24 The compound of any of embodiments 54-89, wherein is CH2. E92:R 24 The compound of any of embodiments 54-89, wherein is a heterocycle. E93:R 24 The compound of any of embodiments 54-89, wherein is aryl. E94:R 24 The compound of any of embodiments 54-89, wherein is phenyl. E95:R 24 The compound of any of embodiments 54-89, wherein is bicyclic. E96:R 24 The compound of any of embodiments 54-89, wherein is C(O). E97: In certain embodiments, TIFF2026010026000083.tif54170TIFF2026010026000084.tif250170TIFF2026010026000085.tif254170TIFF2026010026000086.tif254170TIFF2026 010026000087.tif254170TIFF2026010026000088.tif254170TIFF20260100 26000089.tif254170TIFF2026010026000090.tif254170TIFF202601002600 0091.tif254170TIFF2026010026000092.tif231170TIFF2026010026000093.tif223170TIFF2026010026000094.tif248170TIFF2026010026000095.tif254170TIFF2026010026000096.tif200170TIFF2026010026000097.tif233170TIFF2026010026000098.tif238170 or a pharmaceutically acceptable salt thereof. E98: In certain embodiments, TIFF2026010026000099.tif248170TIFF2026010026000100.tif241170TIFF2026010026000101.tif249170TIFF2026010026000102.tif235170TIFF2026010026000103.tif254170TIFF2026010026000104.tif212170TIFF2026010026000105.tif249170TIFF2026010026000106.tif254170TIFF2026010026000107.tif254170TIFF2026010026000108.tif254170TIFF2026010026000109.tif236170TIFF2026010026000110.tif238170TIFF2026010026000111.tif251170TIFF2026010026000112.tif253170TIFF2026010026000113.tif246170TIFF2026010026000114.tif230170TIFF2026010026000115.tif246170TIFF2026010026000116.tif245170TIFF2026010026000117.tif254170TIFF2026010026000118.tif254170TIFF2026010026000119.tif254170TIFF2026010026000120.tif254170TIFF2026010026000121.tif254170TIFF2026010026000122.tif243170TIFF2026010026000123.tif223170TIFF2026010026000124.tif248170TIFF2026010026000125.tif251170TIFF2026010026000126.tif251170TIFF2026010026000127.tif221170TIFF2026010026000128.tif224170TIFF2026010026000129.tif254170TIFF2026010026000130.tif254170TIFF2026010026000131.tif229170TIFF2026010026000132.tif81170 or a pharmaceutically acceptable salt thereof. E99: In certain embodiments, the present invention provides a method for treating a variety of conditions, including the use of any of the above-mentioned compounds as therapeutically active substances. Optionally, a compound according to any one of embodiments 1 to 98 or a pharmaceutically acceptable salt thereof in a pharmaceutical composition. It is a useful salt. E100: In certain embodiments, the present invention provides a method for the therapeutic and / or prophylactic treatment of cancer. 98. A compound according to any one of embodiments 1 to 98, or a compound thereof, optionally in a pharmaceutical composition, for use in is a pharmaceutically acceptable salt of E101: In certain embodiments, the present invention provides a compound of embodiment 1, optionally in a pharmaceutical composition. 98. A method for treating a rheumatoid arthritis, comprising administering a compound according to any one of claims 1 to 98 or a pharmaceutically acceptable salt thereof. A method of treating a patient with an EGFR-mediated disorder. E102: The method of embodiment 101, wherein the patient is a human. E103: embodiment 101, or 102. The method according to claim 102. E104: The method of embodiment 103, wherein the EGFR-mediated disorder is cancer or a tumor. E105: The method of embodiment 103, wherein the EGFR-mediated disorder is abnormal cell proliferation. E106: The method of embodiment 104, wherein the cancer is lung cancer. E107: The method of embodiment 106, wherein the lung cancer is non-small cell lung cancer. E108: Cancer, tumor or abnormal cell growth is characterized by the presence of EGFR mutations with at least one The method of any one of embodiments 103 to 107, wherein the antibody comprises a protein. E109: Cancer, tumor or abnormal cell growth is caused by EGFR protein with the L858R mutation 109. The method of any one of embodiments 103 to 108, having the following qualities: E110: Cancer, tumor or abnormal cell growth is caused by EGFR protein with T790M mutation 110. The method of any one of embodiments 103 to 109, having the following qualities: E111: Cancer, tumor or abnormal cell growth is caused by EGFR protein with the C797S mutation 111. The method of any one of embodiments 103 to 110, having the following qualities: E112: Cancer, tumor or abnormal cell growth is caused by EGFR protein with the L792H mutation 112. The method of any one of embodiments 103 to 111, having the following qualities: E113: Cancer, tumor or abnormal cell growth is caused by EGFR protein with the L718Q mutation 113. The method of any one of embodiments 103 to 112, having the following qualities: E114: Cancer, tumor, or abnormal cell growth with T790M / L858R mutation The method of any one of embodiments 103 to 108, having a FR protein. E115: Cancer, tumor or abnormal cell growth caused by T790M / L858R / C797S mutation The method according to any one of embodiments 103 to 108, wherein the EGFR protein has the formula: . E116: Cancer, tumor, or abnormal cell growth with L858R / C797S mutation The method of any one of embodiments 103 to 108, having a FR protein. E117: The method according to any one of embodiments 101 to 116, wherein an additional EGFR inhibitor is administered. How to post. E118: The method of embodiment 117, wherein the additional EGFR inhibitor is a tyrosine kinase inhibitor. The method described. E119: The method of embodiment 118, wherein the additional EGFR inhibitor is osimertinib Law. E120: The method of embodiment 118, wherein the additional EGFR inhibitor is rociletinib . E121: The method of embodiment 118, wherein the additional EGFR inhibitor is avitinib. E122: The method of embodiment 118, wherein the additional EGFR inhibitor is lazertinib . E123: The method of embodiment 118, wherein the additional EGFR inhibitor is nazartinib . E124: The additional EGFR inhibitor is an antibody against a mutant form of EGFR, 117. The method according to claim 117. E125: The method of embodiment 124, wherein the additional EGFR inhibitor is cetuximab . E126: The method of embodiment 124, wherein the additional EGFR inhibitor is panitumumab . E127: The method of embodiment 124, wherein the additional EGFR inhibitor is necitumumab . E128: The method of any of embodiments 101-127, wherein a MET inhibitor is also administered. E129: The method according to any one of embodiments 101 to 128, wherein the patient is given an additional chemotherapy agent. How to post. E130: In certain embodiments, the present invention provides a method for treating an EGFR-mediated disorder in a patient. A compound according to any one of embodiments 1 to 98 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of Acceptable salts. E131: The use of embodiment 130, wherein the patient is a human. E132: embodiment 130, wherein the EGFR-mediated disorder is cancer, tumor, or abnormal cell proliferation; or 131. Use according to claim 131. E133: The use according to embodiment 132, wherein the EGFR-mediated disorder is cancer or a tumor. E134: The use according to embodiment 132, wherein the EGFR-mediated disorder is abnormal cell proliferation. E135: The use according to embodiment 132, wherein the cancer is lung cancer. E136: The use according to embodiment 135, wherein the lung cancer is non-small cell lung cancer. E137: Cancer, tumor or abnormal cell growth is characterized by the presence of an EGFR mutation with at least one The use according to any of embodiments 132 to 136, wherein the compound has a protein. E138: Cancer, tumor or abnormal cell growth is caused by EGFR protein with the L858R mutation The use according to any of embodiments 132 to 137, having the following qualities: E139: Cancer, tumor or abnormal cell growth is caused by EGFR protein with the T790M mutation The use according to any of embodiments 132 to 138, having the following qualities: E140: Cancer, tumor or abnormal cell growth is caused by EGFR protein with the C797S mutation Use according to any of embodiments 132 to 139, having the following qualities: E141: Cancer, tumor or abnormal cell growth is caused by EGFR protein with the L792H mutation The use according to any of embodiments 132 to 140, having the following qualities: E142: Cancer, tumor or abnormal cell growth is caused by EGFR protein with the L718Q mutation The use according to any of embodiments 132 to 141, having the following qualities: E143: Cancer, tumor, or abnormal cell growth with T790M / L858R mutation The use according to any of embodiments 132 to 136, comprising a FR protein. E144: Cancer, tumor, or abnormal cell growth is due to the T790M / L858R / C797S mutation Use according to any of embodiments 132 to 136, wherein the EGFR protein has the formula . E145: Cancer, tumor, or abnormal cell growth with L858R / C797S mutation The use according to any of embodiments 132 to 136, comprising a FR protein. E146: The method of any of embodiments 130-145, wherein an additional EGFR inhibitor is administered. Use of the above. E147: The method of embodiment 146, wherein the additional EGFR inhibitor is a tyrosine kinase inhibitor. Use as described. E148: The use of embodiment 147, wherein the additional EGFR inhibitor is osimertinib. For. E149: The use according to embodiment 147, wherein the additional EGFR inhibitor is rociletinib . E150: The use according to embodiment 147, wherein the additional EGFR inhibitor is avitinib. E151: The use according to embodiment 147, wherein the additional EGFR inhibitor is lazertinib . E152: The use according to embodiment 147, wherein the additional EGFR inhibitor is nazartinib . E153: The additional EGFR inhibitor is an antibody against a mutant form of EGFR, 146. Use according to claim 146. E154: The use according to embodiment 153, wherein the additional EGFR inhibitor is cetuximab . E155: The use according to embodiment 153, wherein the additional EGFR inhibitor is panitumumab . E156: The use according to embodiment 153, wherein the additional EGFR inhibitor is necitumumab . E157: The use according to any of embodiments 130 to 156, in which a MET inhibitor is also administered. E158: The method according to any one of embodiments 130 to 157, wherein the patient is given an additional chemotherapy agent. Use of the above. E159: In certain embodiments, the present invention provides a method for treating an EGFR-mediated disorder in a patient. 99. A compound according to any one of embodiments 1-98, optionally in a pharmaceutical composition, for use in the treatment of or a pharmaceutically acceptable salt thereof. E160: The compound of embodiment 159, wherein the patient is a human. E161: embodiment 159, wherein the EGFR-mediated disorder is cancer, tumor, or abnormal cell proliferation; or 160. The compound according to claim 160. E162: The compound of embodiment 161, wherein the EGFR-mediated disorder is cancer or tumor. E163: The compound of embodiment 161, wherein the EGFR-mediated disorder is abnormal cell proliferation. E164: The compound of embodiment 162, wherein the cancer is lung cancer. E165: The compound according to embodiment 164, wherein the lung cancer is non-small cell lung cancer. E166: Cancer, tumor or abnormal cell growth is characterized by the presence of an EGFR mutation with at least one The compound of any one of embodiments 161-165, having a protein. E167: Cancer, tumor or abnormal cell growth is caused by EGFR protein with the L858R mutation 167. The compound of any of embodiments 161-166, having the quality E168: Cancer, tumor or abnormal cell growth is caused by EGFR protein with the T790M mutation The compound of any of embodiments 161-167, having the quality E169: Cancer, tumor or abnormal cell growth is caused by EGFR protein with the C797S mutation The compound of any of embodiments 161-168, having the quality E170: Cancer, tumor or abnormal cell growth is caused by EGFR protein with the L792H mutation 170. The compound of any of embodiments 161-169, having the quality E171: Cancer, tumor or abnormal cell growth is caused by EGFR protein with the L718Q mutation 171. The compound of any of embodiments 161-170, having the following properties: E172: Cancer, tumor, or abnormal cell growth with T790M / L858R mutation The compound according to any of embodiments 161 to 166, having a FR protein. E173: Cancer, tumor, or abnormal cell growth is due to the T790M / L858R / C797S mutation 167. The compound according to any one of embodiments 161 to 166, comprising an EGFR protein having the formula thing. E174: Cancer, tumor, or abnormal cell growth with L858R / C797S mutation The compound according to any of embodiments 161 to 166, having a FR protein. E175: any of embodiments 159-174, in which an additional EGFR inhibitor is administered. The compound described. E176: any of embodiments 175 to 175, wherein the additional EGFR inhibitor is a tyrosine kinase inhibitor. The compound described. E177: The compound of embodiment 175, wherein the additional EGFR inhibitor is osimertinib. Compound. E178: The compound of embodiment 175, wherein the additional EGFR inhibitor is rociletinib thing. E179: The compound of embodiment 175, wherein the additional EGFR inhibitor is avitinib . E180: The compound of embodiment 175, wherein the additional EGFR inhibitor is lazertinib thing. E181: The compound of embodiment 175, wherein the additional EGFR inhibitor is nazartinib thing. E182: The additional EGFR inhibitor is an antibody against a mutant form of EGFR, The compound according to claim 174. E183: The compound of embodiment 182, wherein the additional EGFR inhibitor is cetuximab thing. E184: The compound of embodiment 182, wherein the additional EGFR inhibitor is panitumumab. thing. E185: The compound of embodiment 182, wherein the additional EGFR inhibitor is necitumumab. thing. E186: The compound of any of embodiments 159-185, wherein a MET inhibitor is also administered. thing. E187: Any of embodiments 159-186, wherein the patient is given an additional chemotherapy agent. The compound described in E188: In certain embodiments, the present invention provides a method for treating EGFR activation syndrome in a patient. The mutation status is determined and then optionally administered in a pharmaceutical composition according to any of embodiments 1 to 98. or a pharmaceutically acceptable salt thereof to said patient. cobas™ EGFR Mutation Test v2 for patients with 1-cell lung cancer for the therapeutic and / or prophylactic treatment of patients with EGFR activating mutations determined using 99. The method of claim 1, wherein the compound is a compound selected from the group consisting of benzodiazepines, ... or a pharmaceutically acceptable salt thereof. E189: In certain embodiments, the present invention provides a method for treating a pulmonary arthritis according to any one of embodiments 1 to 98. and a pharmaceutical composition comprising the compound described above and a pharmaceutically acceptable excipient.

[0116] Additional Embodiments of the Invention Chirality Embodiments The compounds of the invention may, for example, be substituted with one or more stereocenters (e.g., [ka] or ), one or more stereocenters in the linker, and / or at least one stereocenter in the EGFR-binding ligand portion of the molecule. At least one stereocenter (e.g., [ka] ) may have multiple stereocenters (e.g., chiral carbon atoms). In embodiments, the EGFR degrading compounds of the present invention are provided without regard to stereochemistry. In other embodiments, the EGFR degrading compounds are enantiomeric with R and S stereochemistry. enriched in (i.e., greater than about 50%, 60%, 70%, 80%, or 90% pure), or and even one or more compounds presented in substantially pure form (greater than about 95%, 98%, or 99% pure). In certain embodiments, the EGFR degrading compound may have a chiral carbon atom. , having two enantiomerically enriched and / or substantially pure stereocenters. In one sub-aspect of and / or the substantially pure stereocenters are located in the ligase binding portion and linker of the compound. or alternatively, there are two in the linker. In another subembodiment, there are three enantiomers. a merically enriched and / or substantially pure stereocenter is present, and one In this further subembodiment, three enzyme binding moieties are present in the linker. Enantiomerically enriched and / or substantially pure stereocenters are present, one of which is the compound In another embodiment, two of these ligase binding moieties are present in the linker. In any of the embodiments, aspects, or subembodiments, the EGFR binding ligand moiety may further comprise an enantiomer. It may be in thiomerically enriched or substantially pure form.

[0117] In some embodiments, the chiral carbon of the EGFR binding ligand moiety adjacent to the amide It has been observed that the compound can easily racemize between stereoisomers under the conditions used. Therefore, in certain embodiments, it is not considered for purposes of assigning stereochemistry.

[0118] In certain embodiments, one stereocenter is in the R configuration and the other stereocenters present are in the R configuration. The somatic center is enantiomerically enriched or substantially pure. In an embodiment, one stereocenter is in the S configuration and the other stereocenters present are enantiomeric. It may be thiomerically enriched or substantially pure.

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

[0120] In certain embodiments, there is one stereocenter in the E3 ligase binding moiety (E (ignoring the stereocenter of the GFR-binding ligand part), this is the ene in the R configuration as shown below. In another embodiment, the compound is enantiomerically enriched or substantially pure. There is one stereocenter in the E3 ligase binding site (the stereocenter in the EGFR binding ligand site). (ignoring ) whether it is enantiomerically enriched in the S configuration as shown below, or substantially pure.

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

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

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

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

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

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

[0127] In certain embodiments, there is one stereocenter in the linker moiety, which is in the R configuration. In another embodiment, the linker moiety has one stereocenter. There is also a compound that is enantiomerically enriched or substantially pure R-configuration. In embodiments, there is one stereocenter in the linker moiety, which is enantiomerically It is an enriched or substantially pure S configuration.

[0128] In certain embodiments, the linker includes one or more moieties that have a chiral center. Non-limiting examples include enantiomerically enriched or substantially pure stereocenters. Heterocycles having, for example, a substituent meta or ortho to the nitrogen, or Piperidine linked in the meta or ortho configuration, having substituents in the meta or ortho configuration or linked piperazine, pyrrolidinone with or without substituents, and Examples include pyrrolidine with or without a hydroxyl group.

[0129] Additional non-limiting examples of linker moieties having at least one chiral center include: Enantiomerically enriched or substantially pure stereocenter-containing alkyl, enantiomers Enantiomerically enriched or substantially pure stereogenic alkenes, Enantiomerically enriched or substantially pure stereocentered alkynes, enantiomerically enriched alkynes Enantiomerically enriched or substantially pure stereogenic haloalkyls or substantially pure alkoxy with a stereocenter, enantiomerically enriched or Aliphatic groups with qualitatively pure stereocenters, enantiomerically enriched or substantially pure Heteroaliphatic groups with a simple stereocenter and enantiomerically enriched or substantially Cycloalkyls with pure stereocenters are included.

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

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

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

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

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

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

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

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

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

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

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

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

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

[0143] In certain embodiments, the EGFR ligand moiety has at least one stereocenter. is present and is a mixture of R and S. In another embodiment, the EGFR ligand moiety There is at least one stereocenter in the In another embodiment, the EGFR ligand moiety is at least partially or substantially pure. At least one stereocenter is present, which is enantiomerically enriched in the S configuration or is substantially pure.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0164] In alternative embodiments, "alkyl" refers to one, two, three, or four R 31 Place "Arbitrarily substituted" by a substitution group.

[0165] Cycloalkyl Embodiments In certain embodiments, "cycloalkyl" refers to C-C cycloalkyl, C 3~C7 cycloalkyl, C3~C6 cycloalkyl, C3~C5 cycloalkyl, C3 or C4 cycloalkyl, C4-C8 cycloalkyl, C5-C8 cycloalkyl or is a C6-C8 cycloalkyl.

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

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

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

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

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

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

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

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

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

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

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

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

[0178] In certain embodiments, "haloalkyl" refers to a group having one carbon and one halogen. Has.

[0179] In certain embodiments, "haloalkyl" refers to a group having one carbon and two halogens. Has.

[0180] In certain embodiments, a "haloalkyl" refers to a group having one carbon and three halogens. Has.

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

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

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

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

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

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

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

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

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

[0190] Heterocyclic Embodiments In certain embodiments, a "heterocycle" is a ring structure having one nitrogen and three, four, five, six, It refers to a cyclic ring having 7 or 8 carbon atoms.

[0191] In certain embodiments, a "heterocycle" is a ring containing one nitrogen, one oxygen, and three, four, or more alkyl groups. "Cyclic ring" refers to a cyclic ring having 1, 5, 6, 7 or 8 carbon atoms.

[0192] In certain embodiments, a "heterocycle" is a ring containing two nitrogens and three, four, five, six, or , and 7 or 8 carbon atoms.

[0193] In certain embodiments, a "heterocycle" is a ring containing one oxygen and three, four, five, six, or , and 7 or 8 carbon atoms.

[0194] In certain embodiments, a "heterocycle" is a ring containing one sulfur and three, four, five, six, or more alkyl groups. , and 7 or 8 carbon atoms.

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

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

[0197] Additional non-limiting examples of "heterocycle" include tetrahydrofuran, 1,3-dioxo lan, tetrahydrothiophene, 1,2-oxathiolane and 1,3-oxathiolane Examples include:

[0198] Additional non-limiting examples of "heterocycle" include piperidine, piperazine, tetrahydro Pyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholino Examples include phenanthrene and thiomorpholine.

[0199] Additional non-limiting examples of "heterocycles" include indoline, tetrahydroquinoline, tetrahydroquinone, trihydroisoquinoline and dihydrobenzofuran, where the points of attachment of each group are It is on a heterocycle.

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

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

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

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

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

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

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

[0207] In alternative embodiments, the "heterocycle" may contain one, two, three, or four R 31 replacement The group is "optionally substituted."

[0208] Heteroaryl Embodiments In certain embodiments, "heteroaryl" refers to a heteroaryl having 1, 2, 3, or 4 nitrogen atoms. It is a five-membered aromatic group containing a nitrogen atom.

[0209] Non-limiting examples of five-membered "heteroaryl" groups include pyrrole, furan, and thiophene. , pyrazole, imidazole, triazole, tetrazole, isoxazole, oxazole azole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole These include azoles and thiatriazoles.

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

[0211] In certain embodiments, a "heteroaryl" is a heteroaryl having 1, 2, or 3 nitrogen atoms. 6-membered aromatic groups containing (i.e., pyridinyl, pyridazinyl, triazinyl, pyridyl) imidinyl and pyrazinyl).

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

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

[0214] Non-limiting examples of bicyclic "heteroaryl" groups include indole, benzofuran, Isoindole, indazole, benzimidazole, azaindole, azaindazole benzophenone, purine, isobenzofuran, benzothiophene, benzisoxazole, benzoyl Examples include thiazoles, benzoxazoles and benzothiazoles.

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

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

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

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

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

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

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

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

[0223] In certain embodiments, aryl is naphthyl.

[0224] In alternative embodiments, "aryl" refers to one, two, three, or four R 31 Place "Arbitrarily substituted" by a substitution group.

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

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

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

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

[0229] Optional Substituent Embodiments In certain embodiments, the variable moieties can be optionally substituted. do not have.

[0230] In certain embodiments where the variable moieties can be optionally substituted, the variable moieties can be one It is substituted with a substituent.

[0231] In certain embodiments, where the variable moieties may be optionally substituted, the variable moieties may be two It is substituted with a substituent.

[0232] In certain embodiments, where the variable moieties may be optionally substituted, the variable moieties may be selected from three It is substituted with a substituent.

[0233] In certain embodiments, where the variable moieties can be optionally substituted, the variable moieties are It is substituted with a substituent.

[0234] In an alternative embodiment, any suitable group may be used to form a stable molecule and to provide the compounds of the present invention. In the "substituted" or "optionally substituted" positions where indicated, the desired objective of may be present, for example halogen (which may independently be F, Cl, Br, or I); cyano; hydro xyl; nitro; azido; alkanoyl (e.g., C2-C6 alkanoyl group); carboxy Alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryl oxy, e.g., phenoxy; thioalkyl, including those containing one or more thioether linkages; Alkyl sulfonyl; Alkyl sulfonyl, including those with one or more sulfonyl bonds aryl groups; aminoalkyl groups containing groups with two or more N atoms; aryl (e.g., phenyl) phenyl, biphenyl, naphthyl, etc., each ring being either substituted or unsubstituted; for example, 1 to 3 Aryl groups having separated or fused rings and from 6 to about 14 or 18 ring carbon atoms arylalkyl (benzyl is an example of an arylalkyl group); for example, 1 to 3 separate or Arylalkoxy with fused rings (benzyloxy is an example of an arylalkoxy group) or saturated having 1 to 3 separated or fused rings containing N, O, or S atoms or a partially unsaturated heterocycle or a heterocycle containing one or more N, O or S atoms Heteroaryl having one to three separated or fused rings, such as coumarinyl, quinolinyl , isoquinolinyl, quinazolinyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl, pyridyl aryl, thienyl, thiazolyl, thiazinyl, oxazolyl, isoxazolyl, imidazolyl Zolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrazolyl Examples include hydropyranyl, piperidinyl, morpholinyl, piperazinyl, and pyrrolidinyl. Such groups include, but are not limited to, hydroxy, alkyl, alkoxy, and the like. It may be further substituted by oxy, halogen and amino.

[0235] Aliphatic and Heteroaliphatic Embodiments In certain embodiments, "aliphatic" refers to saturated or unsaturated straight chain, branched or cyclic In these embodiments, aliphatic refers to, but is not limited to, Alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkenyl Quinyl moieties are intended to encompass each of these definitions. In the present specification, "aliphatic" is used to refer to an aliphatic group having 1 to 20 carbon atoms. The aliphatic chain may be, for example, monounsaturated, diunsaturated, triunsaturated, or polyunsaturated, or Unsaturated aliphatic groups may be in the cis or trans configuration. In certain embodiments, aliphatic groups have 1 to about 12 carbon atoms, more typically 1 to about 6 carbon atoms. In certain embodiments, the fatty acid may contain from 1 to about 4 carbon atoms. An aliphatic group contains from 1 to about 8 carbon atoms. In certain embodiments, an aliphatic group is C1 to C2, C1 to C3, C1 to C4, C1 to C5, or C1 to C6. The specified ranges used refer to aliphatic groups with each member of the range described as a separate species. For example, the term C1-C6 aliphatic as used herein refers to 1, 2, A straight or branched alkyl, alkenyl or aryl group having 3, 4, 5 or 6 carbon atoms. The groups shown are alkyl, alkynyl, and alkynyl groups, each of which is intended to be described as an independent species. For example, the term C1-C4 aliphatic as used herein includes 1, 2, 3, represents a straight or branched alkyl, alkenyl or alkynyl group having 1 or 4 carbon atoms. and each of these is intended to be described as an independent species. In embodiments, the aliphatic group is substituted with one or more functional groups to form a stable moiety. It will be exchanged.

[0236] In certain embodiments, the term "heteroaliphatic" refers to heteroaliphatic groups having 1 or more carbon atoms in the chain. and at least one heteroatom, such as amine, carbonyl, carboxy, oxo, thi Aliphatic compounds containing phosphate, phosphonate, nitrogen, phosphorus, silicon or boron atoms In certain embodiments, the only heteroatom is nitrogen. In embodiments, the heteroatoms are oxygen only. The alkyl groups are all sulfur. In certain embodiments, "heteroaliphatic" is used herein without limitation. Examples include, but are not limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, hetero heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl moieties In certain embodiments, "heteroaliphatic" refers to a group of 1 to 20 carbon atoms. to denote a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having atoms In certain embodiments, heteroaliphatic groups are used to form stable moieties. Non-limiting examples of heteroaliphatic moieties include polyethylene glycols. Cholesterol, polyalkylene glycol, amide, polyamide, polylactide, polyglycol Ethers, thioethers, ethers, alkyl-heterocycle-alkyls, -O-alkyl-O-alkenyls alkyl, alkyl-O-haloalkyl, etc.

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

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

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

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

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

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

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

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

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

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

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

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

[0249] In certain embodiments, A 21 is O.

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

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

[0252] In certain embodiments, A 32 , A 33 , A 34 and A 35 is CH, C-halo and CF.

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

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

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

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

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

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

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

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

[0261] In certain embodiments, A 34 is CH.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0291] In certain embodiments, y is 1.

[0292] In certain embodiments, y is 2.

[0293] In certain embodiments, y is 3.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0308] In certain embodiments, R 31 is a halogen, C 1~6 -alkoxy and C1 ~6 -alkyl.

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

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

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

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

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

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

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

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

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

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

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

[0320] In certain embodiments, R 36 and R37 The ring formed by bonding is Not replaced.

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

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

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

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

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

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

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

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

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

[0330] In certain embodiments, R36 is C 1~6 -alkoxy.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0359] In certain embodiments, R 42 is C 1~6 -alkoxy.

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

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

[0362] In certain embodiments, R42 Halo-C 3~8 -cycloalkyl.

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

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

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

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

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

[0368] EGFR-Targeting Ligand Embodiments In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026010026000216.tif191170.

[0369] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026010026000218.tif129170.

[0370] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026010026000220.tif96170.

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

[0372] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026010026000223.tif171170.

[0373] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026010026000225.tif234170TIFF2026010026000226.tif103170.

[0374] Compound of Formula III In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026010026000228.tif130170.

[0375] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026010026000230.tif126170.

[0376] Compound of Formula IV In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026010026000232.tif131170.

[0377] III. Additional Compounds of the Invention In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026010026000234.tif166170.

[0378] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026010026000236.tif158170.

[0379] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026010026000238.tif235170TIFF2026010026000239.tif37170.

[0380] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026010026000241.tif154170.

[0381] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026010026000243.tif227170TIFF2026010026000244.tif37170.

[0382] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026010026000246.tif206170.

[0383] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026010026000248.tif114170.

[0384] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026010026000250.tif224170.

[0385] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026010026000252.tif112170.

[0386] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026010026000254.tif223170.

[0387] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026010026000256.tif164170.

[0388] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026010026000258.tif221170TIFF2026010026000259.tif75170.

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

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

[0391] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026010026000263.tif140170.

[0392] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026010026000265.tif69170.

[0393] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026010026000267.tif70170.

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

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

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

[0397] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026010026000272.tif245170TIFF2026010026000273.tif73170.

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

[0399] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026010026000276.tif224170TIFF2026010026000277.tif80170.

[0400] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026010026000279.tif156170.

[0401] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026010026000281.tif242170TIFF2026010026000282.tif205170TIFF2026010026000283.tif46170.

[0402] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026010026000285.tif111170.

[0403] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026010026000287.tif103170.

[0404] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026010026000289.tif41170.

[0405] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026010026000291.tif92170.

[0406] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026010026000293.tif41170.

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

[0408] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026010026000296.tif213170TIFF2026010026000297.tif234170TIFF2026010026000298.tif239170TIFF2026010026000299.tif73170.

[0409] IV. Linkers Linker (L 1 or L 2 ) or bond is included in the compounds of the present invention. A chemically stable divalent group that attaches the gauze-binding moiety to the EGFR-targeting ligand. According to the present invention, any desired linker described herein can be used in combination with a compound having a structure such that the resulting compound is As part of a pharmaceutically acceptable dosage form, for example, at least 1 month, 2 months, 3 months, 6 months As long as it has a stable shelf life of one month or one year and is pharmaceutically acceptable per se. It can be used as such.

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

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

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

[0413] In certain embodiments, the chains may have 2, 3, 4, 5, 6, 7, 8 pieces, 9 pieces, 10 pieces, 11 pieces, 12 pieces, 13 pieces, 14 pieces, 15 pieces, 16 pieces, 17 pieces, 18 pieces For example, the chain may be continuous but partially one or more ethylene glycol units (e.g., For example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ethylene glycol units).

[0414] In certain embodiments, the chains are independently alkyl, aryl, heteroaryl. , alkenyl or alkynyl, aliphatic, heteroaliphatic, cycloalkyl or heterocyclic At least one, two, three, four, five, six, or more branches may be substituted. , having seven or eight consecutive chains.

[0415] In other embodiments, the linker is ethylene glycol, propylene glycol, It may comprise or consist of one or more of lactic acid and / or glycolic acid. Acid segments tend to have longer half-lives than glycolic acid segments. and random lactic-co-glycolic acid moieties, and ethylene glycol and propylene Glycols are known in the art to be pharmaceutically acceptable and are preferred. The hydroxyl group may be modified or configured to obtain a half-life and hydrophilicity. These units may optionally contain aliphatic, e.g., hydroxyl groups, to achieve suitable drug properties. Other groups such as alkyl, heteroaliphatic, aryl, heteroaryl, heterocyclic, cycloalkyl, etc. The portions may be adjacent or interspersed.

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

[0417] In one aspect, the linker (L 2 ) is 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. is selected from.

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

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

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

[0421] In certain embodiments, L 2 teeth, [ka] Selected from TIFF2026010026000305.tif167170.

[0422] In certain embodiments, L 2 teeth, [ka] Selected from TIFF2026010026000307.tif246170.

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

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

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

[0426] In certain embodiments, L 2 teeth, [ka] Selected from TIFF2026010026000312.tif181170.

[0427] In certain embodiments, L 2 teeth, [ka] Selected from TIFF2026010026000314.tif109170.

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

[0429] R 20 , R 21 , R 22 , R 23 and R 24 Additional non-limiting examples of moieties include: [ka] TIFF2026010026000317.tif68170 is an example.

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

[0431] In additional embodiments, the linker (L 2 ) portion has at least one 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 Optionally substituted (poly)ethylene glycol having an optionally substituted O, N, S , P or Si atoms interspersed with optionally substituted alkyl groups.

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

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

[0434] In certain embodiments, the linker (L 2 ) may be a nonlinear chain, It may be or contain an aromatic or heteroaromatic cyclic moiety.

[0435] In any of the embodiments of the compounds described herein, the linker group may be any of the groups described herein. The moiety may be any suitable moiety described in

[0436] In certain embodiments, the linker (L 2 )teeth, [ka] TIFF2026010026000320.tif48170.

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

[0438] In certain embodiments, the linker (L 2 )teeth, [ka] TIFF2026010026000323.tif127170.

[0439] In certain embodiments, the linker (L 2 )teeth, [ka] TIFF2026010026000325.tif105170.

[0440] In certain embodiments, the linker (L 2)teeth, [ka] TIFF2026010026000327.tif42170.

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

[0442] In certain embodiments, the linker (L 2 )teeth, [ka] TIFF2026010026000330.tif37170.

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

[0444] V. Treatment method The compounds of the present invention may be used to treat patients in need of treatment or to treat EGFR-mediated The compounds can be used in effective amounts to treat any disorder that is associated with

[0445] Another aspect of the present invention is a method for treating or preventing cancer in a patient in need thereof. The compounds described herein, or their enantiomers, diastereomers, and / or derivatives, are used in the manufacture of a medicament for A teleomer or stereoisomer, or a pharmaceutically acceptable salt, hydrate, or solvate thereof The present invention provides a method for treating or preventing cancer in which EGFR inhibition is required, and a pharmaceutical composition thereof. will be done.

[0446] In one aspect, the compounds of the present invention are EGF receptors in which EGFR is mutated from wild-type. It is used to treat EGFR-mediated cancers. There are many possible EGFR mutations. In a non-limiting embodiment, the mutation is in exon 18, exon 19, exon 2 0 or exon 21, or any combination thereof. In an embodiment, the mutations are L858, E709, G719, C797, L861 , T790 or L718, or any combination thereof. In the morphology, the mutations are L858R, T790M, L718Q, L792H and / or or a C797S mutation, or any combination thereof.

[0447] In certain embodiments, the cancer is treated with non-covalent inhibitors (e.g., gefitinib, erlotinib, lapatinib or vandetanib) or covalent inhibitors (anticoagulants at least one EGF inhibitor, which may be vasopressin, vasorelaxanthin, vasorexin, vasorexin, vasorexin-like protein kinase C (e.g., vasorexin-like protein kinase C), ... In another embodiment, the patient has one or more EGFR mutations after treatment with an EGFR inhibitor. The cancer may progress to one or more recurrences after treatment with antibodies such as cetuximab, panitumumab, or necitumumab. In yet another embodiment, the cancer is characterized in that the cancer expresses an EGFR mutation. One or more EGFR mutations or non-EGFR mutations that confer resistance to GFR inhibitor treatment FR mutations, e.g., somatic exon 20 insertions, somatic PIK3CA mutations, PTEN They have loss of expression, MET amplification, or KRAS mutation.

[0448] In certain embodiments, the compounds of the present invention are selected from the group consisting of erlotinib, gefitinib, and and / or resistance to first-generation EGFR inhibitors such as lapatinib or In certain embodiments, the compounds of the present invention are used to treat cancers that have acquired resistance. are resistant to second-generation EGFR inhibitors such as afatinib and / or dacomitinib. It is used to treat cancers that have acquired resistance to or against the In this case, the compound of the present invention is effective in treating patients with resistance to third-generation EGFR inhibitors such as osimertinib. These drugs are used to treat cancers that have developed resistance to or show resistance to them.

[0449] In some embodiments, the mutant EGFR protein in the affected tissue is L858 It has a mutation, for example, L858R.

[0450] In certain embodiments, the compounds of the present invention are those in which EGFR is one of the amino acids listed below. It is used to treat mutant EGFR-mediated disorders that have a mutation at one of the sites. The mutation may be selected, for example, from one of the exemplary mutations listed, or may be a different mutation. may be.

[0451] TIFF2026010026000332.tif66170

[0452] In certain embodiments, the mutant EGFR-mediated disorder is selected from the table above. In another embodiment, the mutant EGFR-mediated disorder has three mutations selected from the table above. The EGFR-mediated disorder has four or more mutations, which may optionally be selected from the table above.

[0453] In certain embodiments, the mutant EGFR-mediated disorder is a L858R mutation. and optionally one additional mutation which may be selected from the table above. In some forms, mutant EGFR-mediated disorders involve the L858R mutation and and two additional mutations, which may optionally be selected from the table above. The mutant EGFR-mediated disorder comprises a L858R mutation and, optionally, a EGFR-mediated disorder selected from the table above. It has three additional mutations that can be added.

[0454] In certain embodiments, the mutant EGFR-mediated disorder is a T790M mutation. and optionally one additional mutation selected from the table above. In this case, the mutant EGFR-mediated disorder is a combination of a T790M mutation and, optionally, a mutation from the table above. and two additional mutations selected. GFR-mediated disorders are characterized by the T790M mutation and three additional mutations, optionally selected from the table above. It has a mutation.

[0455] In certain embodiments, the mutant EGFR-mediated disorder is a L718Q mutation. and optionally one additional mutation selected from the table above. In this case, the mutant EGFR-mediated disorder is a combination of the L718Q mutation and, optionally, a mutation from the table above. and two additional mutations selected. GFR-mediated disorders are characterized by the L718Q mutation and three additional mutations, optionally selected from the table above. It has a mutation.

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

[0457] In certain embodiments, the EGFR-mediated cancer is S768I, L718V, L7 92H, L792V, G796S, G796C, G724S and / or G719A Has a mutation.

[0458] In certain embodiments, the compounds of the present invention are directed to a frameshift mutation, e.g. It is used to treat EGFR-mediated cancers that have short in-frame deletions. In one embodiment, the compounds of the present invention are useful in treating EGFR-mediated EGFR-associated inflammatory diseases, in which EGFR has an exon 19 deletion. In certain embodiments, the exon 19 deletion is In certain embodiments, the deletion includes the LREA (L747-A750). The chthon 19 deletion is a deletion that includes amino acids ELREA (E746 to A750).

[0459] In certain embodiments, the compounds of the present invention are useful for treating EGFR at exon 21 at L85. It is used to treat EGFR-mediated cancers with the 8R mutation.

[0460] In certain embodiments, the compounds of the present invention inhibit the activity of mutant EGFR over wild-type EGFR. It has activity against disorders driven by GFR.

[0461] In certain embodiments, the compounds of the present invention are directed to EGFR in one or more exons 1 and 2. It is used to treat EGFR-mediated cancers with deletion 8.

[0462] In certain embodiments, the compounds of the present invention contain an E709 mutation, e.g., E70 It is used to treat EGFR with E709A, E709G, E709K or E709V.

[0463] In certain embodiments, the compounds of the present invention contain an L718 mutation, e.g., L71 It is used to treat EGFR with 8Q.

[0464] In certain embodiments, the compounds of the invention contain a G719 mutation, e.g., G71 It is used to treat EGFR with 9S, G719A, G719C, or G719D.

[0465] In certain embodiments, the compounds of the present invention are directed to EGFR in one or more exons 1 and 2. It is used to treat EGFR-mediated cancers with exon 9 insertions and / or one or more exon 20 insertions. can be.

[0466] In certain embodiments, the compounds of the present invention are useful in treating S7681 mutant EGFR cancers. In certain embodiments, the compounds of the present invention are used in the treatment of EGFR L In certain embodiments, the present invention is used to treat EGFR 861Q mutant cancers. The compounds of the invention are used to treat C797S mutant EGFR cancers.

[0467] In certain embodiments, the compounds of the present invention contain the T790M, L858R mutation. It is used to treat EGFR cancers.

[0468] In certain embodiments, the compounds of the present invention contain the L718Q, L858R mutation. It is used to treat EGFR cancers.

[0469] In certain embodiments, the compounds of the present invention comprise a compound having the L792H, L858R mutation. It is used to treat EGFR cancers.

[0470] In certain embodiments, the compounds of the present invention contain the C797S, L858R mutation. It is used to treat EGFR cancers.

[0471] In certain embodiments, the compounds of the present invention are administered in combination with at least one EGFR inhibitor. Cancers that are resistant to anticancer drugs, such as erlotinib, gefitinib, and / or lapatinib. It is used to treat cancers that are resistant to first generation EGFR inhibitors. In this regard, the compounds of the present invention are effective in treating cancers that have acquired resistance to first-generation EGFR inhibitors, such as For first-generation EGFR inhibitors such as erlotinib, gefitinib, and / or lapatinib, It is used to treat cancers that have developed resistance to the drug.

[0472] In certain embodiments, the compounds of the present invention are afatinib and / or dacomitrin. It is used to treat cancers that are resistant to second-generation EGFR inhibitors such as nibs. In an embodiment, the compounds of the present invention are directed to treating patients with acquired resistance to second generation EGFR inhibitors. for second-generation EGFR inhibitors such as afatinib and / or dacomitinib It is used to treat cancers that have developed resistance.

[0473] In certain embodiments, the compounds of the present invention are effective against third generation EGFR inhibitors such as osimertinib. In certain embodiments, the compounds are used to treat cancers that are resistant to FR inhibitors. The compounds of the present invention are useful in treating cancers that have acquired resistance to third generation EGFR inhibitors, such as osimertinib. It is used to treat cancers that have acquired resistance to third-generation EGFR inhibitors such as tinib.

[0474] In certain embodiments, the method further comprises the step of optionally adding a pharmaceutically acceptable excipient, carrier or or an adjuvant (i.e., a pharmaceutically acceptable composition), or optionally, another biological agent. In combination or alternation with an effective amount of the active agent or bioactive agent combination described herein. It involves administering the described active compound or salt thereof to a patient in need thereof.

[0475] In certain embodiments, the present invention provides a method for administering the compounds described herein to a patient in need of treatment. Methods for treating any of the disorders described are provided.

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

[0477] In certain embodiments, the present application provides a method for the treatment of a disease described herein in a patient in need of prevention. The present invention provides a method for preventing any of the disorders described above.

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

[0479] The compounds and compositions of the present application act as agents for degrading EGFR, and are useful in treating diseases, conditions, or disorders in which EGFR is involved. These compounds are particularly useful for treating or lessening the severity of a disease, condition, or disorder involving:

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

[0481] Another aspect of the present invention provides a method for treating or preventing a proliferative disorder. The compounds described in the above, or their enantiomers, diastereomers or stereoisomers, or a pharmaceutically acceptable salt, hydrate or solvate thereof, optionally in combination with a pharmaceutically acceptable carrier. and administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising the compound.

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

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

[0484] In certain embodiments, the EGFR-mediated disorder comprises a solid tumor or a hematological cancer, Abnormal cell proliferation is not limited to these.

[0485] In certain embodiments, the hematological cancer is acute myeloid leukemia (AML), acute lymphoblastic leukemia (AML), or leukemia. Blastic leukemia (ALL), lymphoblastic T-cell leukemia, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, chronic neutrophilic leukemia (CNL), acute lymphocytic leukemia (CLL), lymphoblastic T-cell leukemia, acute monocytic leukemia, plasmacytoma, immunoblastic large cell leukemia, Mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic erythroleukemia, 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 Bcl-2 and / or BCL6 rearrangements / overexpression (double hit and triple hit) lymphoma), myelodysplastic / myeloproliferative neoplasms, bortezomib-resistant mantle cell lymphoma It is a mantle cell lymphoma, including thyroid tumors.

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

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

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

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

[0490] In certain embodiments, the injury is to the bone, muscle, tendon, cartilage, nerve, fat, or blood vessels. It is a tumor.

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

[0492] In certain embodiments, the compounds of the present invention, or pharmaceutically acceptable salts thereof, are The EGFR activating mutation status of the subject is then determined, and the subject is then treated with a compound of the present invention or a pharmaceutical agent thereof. The present invention relates to a method for treating cancer, particularly non-small cell lung cancer, comprising administering to said patient a therapeutically acceptable salt of the present invention. Patients with EGFR activating mutations determined by next generation sequencing (NGS) for use as a medicament in the therapeutic and / or prophylactic treatment of patients.

[0493] In other embodiments, the disease or disorder is inflammation, arthritis, rheumatoid arthritis, spondyloarthropathies , gouty arthritis, osteoarthritis, juvenile arthritis and other arthritic conditions, neuroinflammation, allergies -, pain, neuropathic pain, fever, lung damage, lung inflammation, adult respiratory distress, chronic pulmonary inflammatory disease, and Chronic obstructive pulmonary disease (COPD), liver disease and nephritis, gastrointestinal conditions, inflammatory bowel disease, Crohn's disease disease, gastritis, irritable bowel syndrome, ulcerative colitis, ulcer disease, gastric ulcer, autoimmune disease, transplant Host-versus-host reaction and allograft rejection, cancer, leukemia, lymphoma, colon cancer, brain cancer, bone cancer, epithelial cells neoplasm of origin (epithelial carcinoma), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, oral cavity cancer, esophageal cancer, small Intestinal cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, Squamous and / or basal cell carcinoma, prostate cancer, renal cell carcinoma, and other pre-existing cancers affecting epithelial cells throughout the body Common cancers: chronic myeloid leukemia (CML), acute myeloid leukemia (AML), and acute promyelocytic leukemia (APML) Leukemia (APL), angiogenesis including neoplasia, metastasis, central nervous system disorders, inflammatory or It is a central nervous system disorder with an apoptotic component, a peripheral neuropathy, or a B-cell lymphoma.

[0494] In other embodiments, a medicament comprising a compound described herein and an additional therapeutic agent. The compositions may be administered simultaneously or sequentially.

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

[0496] In some embodiments, the method is for treating autoimmune diseases, inflammatory diseases, proliferative diseases, and and hyperproliferative diseases, and immune-mediated diseases. In other embodiments, the condition is selected from a proliferative disorder.

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

[0498] The term "cancer" refers to any cancer caused by the proliferation of malignant neoplastic cells, e.g., tumors. Cancer includes, but is not limited to, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas. However, mesothelioma, leukemia, and lymphoma, such as cutaneous T-cell lymphoma (CTCL), Non-cutaneous peripheral T-cell lymphoma, human T-cell lymphotropic virus (HTLV)-associated lymphoma lymphomas, e.g., adult T-cell leukemia / lymphoma (ATLL), B-cell lymphoma, acute non-lymphoma paralytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia, lymphoma, and multiple myeloma, non-Hodgkin's lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL) Hematologic malignancies (CLL), Hodgkin's lymphoma, Burkitt's lymphoma, adult T-cell leukemia / lymphoma, Acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma. Examples include myelodysplastic syndromes, childhood solid tumors such as brain tumors, neuroblastoma, and retinoblastoma. Carcinoma, Wilms' tumor, bone tumor, and soft tissue sarcoma, common solid tumors in adults, e.g. Head and neck cancers (e.g., oral cavity, laryngeal, nasopharyngeal, and esophageal cancers), 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), small cell lung cancer), breast cancer, pancreatic cancer, melanoma and other skin cancers, stomach cancer, brain tumors, Gorlin's syndrome These include group-related tumors (such as medulloblastoma or meningioma), as well as liver cancer.

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

[0500] Additional cancers for which the compounds described herein may be useful for prevention, treatment, and research include, for example, 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, Cancer, gastric cancer, adenocarcinoma, thyroid cancer (medullary thyroid cancer and papillary thyroid cancer), kidney cancer, renal parenchymal cancer, cervical cancer , uterine cancer, endometrial cancer, choriocarcinoma, testicular cancer, urinary tract cancer, melanoma, brain tumors, e.g. glioblastoma tumors, astrocytomas, meningiomas, medulloblastomas, and peripheral neuroectodermal tumors, gallbladder cancer, bronchial cancer, Multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma sarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and In one aspect of the present application, the present application is directed to, but not limited to, in the manufacture of a medicament for the treatment of cancer, including the various types of cancer disclosed herein, In one embodiment, the present invention provides the use of one or more of the compounds described herein.

[0501] In some embodiments, the compounds of the present application are useful in treating cancers such as colorectal cancer, thyroid cancer, breast cancer, and the like. Cancer, and lung cancer, and myeloproliferative disorders such as polycythemia vera, thrombocytopenia, myeloproliferative disorders such as Myeloid metaplasia with fibrosis, chronic myeloid leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, It is useful for treating chronic myelomonocytic leukemia, and systemic mastocytosis. In embodiments, the compounds described herein are useful in treating hematopoietic disorders, particularly acute myeloid leukemia. (AML), chronic myeloid leukemia (CML), acute promyelocytic leukemia, and acute lymphoblastic leukemia It is useful for treating allergic diseases (ALL).

[0502] In certain embodiments, the compounds described herein, or their corresponding pharmaceutical and the like. The compound is a compound which is capable of treating lymphoma, or lymphocytic or myeloid proliferation. It can be used in an effective amount to treat a host, e.g., a human, having a disorder or abnormality. For example, the compounds described herein may be used to treat Hodgkin's lymphoma or non-Hodgkin's lymphoma. For example, the host may be, but is not limited to, a host suffering from a tumor. IDS-associated lymphoma; anaplastic large cell lymphoma; angioimmunoblastic lymphoma; blastic NK cell Lymphoma; Burkitt lymphoma; Burkitt-like lymphoma (small noncleaved 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 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; Langerhans cell histiocytosis or Waldenstrom macroglobulinemia They may also have non-Hodgkin's lymphoma, such as leukemia.

[0503] In another embodiment, a compound described herein, or its corresponding pharmaceutically acceptable salt thereof, Possible salts or isotopic derivatives include, but are not limited to, nodular sclerosis classical Hodgkin's disease Lymphoma (CHL), mixed cell type CHL, lymphopenic CHL, lymphocyte-rich CHL Hodgkin's lymphoma, such as lymphocyte-predominant Hodgkin's lymphoma or nodular lymphocyte-predominant HL The compounds can be used in effective amounts to treat patients, e.g., humans, suffering from

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

[0505] The compounds and compositions of the present application act as inhibitors of EGFR protein in biological samples. One aspect of the present application is to inhibit protein activity in a biological sample. This method comprises contacting the biological sample with a compound or composition described herein. The term "biological sample" as used herein includes, but is not limited to, However, 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. means an in vitro or ex vivo sample containing a biological sample. Inhibition of protein activity in samples is useful for a variety of purposes known to those of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, and biomedical applications. Examples include body sample storage.

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

[0507] In accordance with the above, the present application provides a method for treating any of the above diseases or disorders in a patient in need of treatment. Further provided is a method for preventing or treating a disease characterized by administering to said patient a compound described herein. or an enantiomer, diastereomer or stereoisomer thereof, or a pharmaceutical The above uses include administering a therapeutically effective amount of an acceptable salt, hydrate or solvate thereof to the subject. In any case, the required dosage will depend on the method of administration, the particular condition to be treated and the desired Varies depending on effect.

[0508] VI. Combination Therapy The disclosed compounds described herein include, but are not limited to, those described herein. The present invention may be used alone or in combination with other agents to treat patients, such as humans, with an unspecified EGFR-mediated disorder. or in combination with another bioactive agent or second therapeutic agent in an effective amount It can be used.

[0509] The term "bioactive agent" refers to a compound that is combined with the compounds of the present invention to achieve a desired therapeutic result. Other actions than the selected compounds according to the present invention that can be used in combination or alternation In certain embodiments, the compounds and biomolecules of the present invention are The bioactive agents are active in vivo during the overlapping period, e.g., Cmax, Tm ax, AUC, or another pharmacokinetic parameter are administered such that there is a period of overlap. In another embodiment, the therapeutic agents do not have overlapping pharmacokinetic parameters, but one is more effective than the other. The compounds and bioactive agents of the present invention have a therapeutic effect on the efficacy of It is administered to the patient.

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

[0511] It blocks the interaction between PD-1 and PD-L1 by binding to the PD-1 receptor, Examples of PD-1 inhibitors that inhibit immunosuppression include nivolumab (Opdivo) and pemafibrate. Brolizumab (Keytruda), pidilizumab, AMP-224 (AstraZeneca and PF-06801591 (Pfizer), MEDI0680 (AstraZeneca) , PDR001 (Novartis), REGN2810 (Regeneron), SHR-12-1 (Jia ngsu Hengrui Medicine Company and Incyte Corporation), TSR-042 (Tesaro) and the PD-L1 / VISTA inhibitor CA-170 (Curis Inc.). 1 receptor, blocking the interaction between PD-1 and PD-L1, resulting in immunosuppression Examples of PD-L1 inhibitors that inhibit this include atezolizumab (Tecentriq), Durvalumab (AstraZeneca and Medimmune), KN035 (Alphamab), and BMS-9 36559 (Bristol-Myers Squibb). CTLA-4 checkpoint inhibitors that inhibit the immune system include ipilimumab and tremelimumab. (AstraZeneca and Medimmune), AGEN1884 and AGEN2041 (Agenus) Examples of LAG-3 checkpoint inhibitors include, but are not limited to, BM S-986016 (Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline ), IMP321 (Prima BioMed), LAG525 (Novartis), and PD-1 and L These include, but are not limited to, the dual inhibitor of AG-3, MGD013 (MacroGenics). An example of a TIM-3 inhibitor is TSR-022 (Tesaro).

[0512] In certain embodiments, the checkpoint inhibitor is nivolumab / OPDIV O™, pembrolizumab / KEYTRUDA™, and pidilizumab / CT -011, MPDL3280A / RG7446, MEDI4736, MSB001071 PDL2 / lg fusion proteins such as 8C, BMS 936559, and AMP 224, B7-H3 (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3 , GAL9, LAG 3, VISTA, KIR, 2B4, CD160, CGEN-150 49, inhibitors of CHK1, CHK2, A2aR, B-7 family ligands, or is selected from the combination of:

[0513] In yet another embodiment, one of the active compounds described herein is administered to treat breast cancer, ovarian cancer, or other cancers. SERMs (selected steroid medications) are used to treat abnormal tissues of the female reproductive system, such as uterine, endometrial, or uterine cancer. Selective estrogen receptor modulators), SERDs (selective estrogen receptor degraders) ), a complete estrogen receptor degrader, or another form of partial or complete estrogen receptor antagonist. an effective amount of an estrogen inhibitor, including but not limited to a agonist or antagonist, Raloxifene and tamoxifene may be administered in combination or alternation in effective amounts. Partial antiestrogens such as xifene inhibit estrogenic stimulation of uterine growth and, in some cases, Therefore, some of the effects of estrogen on the progression of breast cancer may actually stimulate tumor growth. It retains its estrogen-like effects. In contrast, fulvestrant is a full anti-estrogen. has no estrogenic effect on the uterus and is effective in tamoxifen-resistant tumors is.

[0514] Non-limiting examples of anti-estrogenic compounds include those described in International Publication No. 2010 / 002010, assigned to Astra Zeneca. 4 / 19176, WO 2013 / 0909 assigned to Olema Pharmaceuticals 21, International Publication No. 2014 / 203129, International Publication No. 2014 / 203132 and and U.S. Patent Application Publication No. 2013 / 0178445, and U.S. Patent No. 9,078,877. Nos. 1, 8,853,423 and 8,703,810, and U.S. Patent Application Publication Nos. WO 2015 / 0005286, WO 2014 / 205136 and WO 2014 / 205136 Presented in No. 2014 / 205138.

[0515] Additional non-limiting examples of anti-estrogen compounds include anordrin, bazedoxifene, phen, broparestrol chlorotrianisene, clomiphene citrate, cyclophenyl , lasofoxifene, ormeloxifene, raloxifene, tamoxifen, tremifene SERMs such as fen and fulvestrant; aminoglutethimide, testolactone, ana Anti-inflammatory drugs such as strozole, exemestane, fadrozole, formestane, and letrozole Isopropyl myoglobin inhibitors; as well as leuprorelin, cetrorelix, allylestrenol, Chlormadinone acetate, cyproterone acetate, delmadinone acetate, dydrogesterone, methyl acetate Droxyprogesterone, megestrol acetate, nomegestrol acetate, norethinib acetate Antigonadotropins such as steroids, progesterone, and spironolactone are also included.

[0516] Other estrogen ligands that can be used in accordance with the present invention are described in U.S. Pat. No. 18,068; No. 5,478,847; No. 5,393,763; and No. 5, 457,117, WO 2011 / 156518, U.S. Pat. No. 8,455,53 4 and 8,299,112, U.S. Patent Nos. 9,078,871; 8,853 ,423; U.S. Patent Application Publication No. 8,703,810; U.S. Patent Application Publication No. 2015 / 0005286 No. WO 2014 / 205138 and U.S. Patent Application Publication No. 2016 / 0175 289, U.S. Patent Application Publication No. 2015 / 0258080, International Publication No. 2014 / 19 1726, WO 2012 / 084711; WO 2002 / 013802 No.;WO 2002 / 004418;WO 2002 / 003992;International Publication No. 2002 / 003991; International Publication No. 2002 / 003990; International Publication No. 002 / 003989; International Publication No. 2002 / 003988; International Publication No. 2002 / 003986; WO 2002 / 003977; WO 2002 / 0039 76;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. 6777424; U.S. Patent Application Publication No. 2002 / 0016340; U.S. Patent No. 6 326392; U.S. Patent No. 6,756,401; U.S. Patent Application Publication No. 2002 / 0013 327; U.S. Patent No. 6,512,002; U.S. Patent No. 6,632,834; U.S. Patent Application Publication No. Patent Publication No. 2001 / 0056099; U.S. Patent No. 6583170; U.S. Patent No. 64795 35; WO 1999 / 024027; U.S. Pat. No. 6,005,102; European Patent No. 0802184; U.S. Patent No. 5,998,402; U.S. Patent No. 5,780,497, U.S. Patent No. 5880137, International Publication No. 2012 / 048058 and International Publication No. 2007 It is described in issue / 087684.

[0517] In another embodiment, the active compounds described herein are useful in treating male cancers, such as prostate cancer or testicular cancer. For the treatment of abnormal tissues of the reproductive system, selective androgen receptor modulators, selective androgen receptor degraders, complete androgen receptor degraders, or partial or alternative forms of androgen receptor degraders androgen antagonists, including but not limited to full androgen antagonists, in an effective amount. These drugs can be administered in effective amounts in combination with or alternating with other drugs that inhibit hormones (such as testosterone). In certain embodiments, the prostate or testicular cancer is androgen resistant.

[0518] Non-limiting examples of anti-androgen compounds are described in WO 2011 / 156518, and These are presented in U.S. Patent Nos. 8,455,534 and 8,299,112. Additional non-limiting examples of androgenic compounds include enzalutamide, apalutamide, Cyproterone acetate, chlormadinone acetate, spironolactone, canrenone, drospireno Examples of antihistamines include benzodiazepine, ketoconazole, topirutamide, abiraterone acetate, and cimetidine.

[0519] In certain embodiments, the bioactive agent is an ALK inhibitor. Examples of ALK inhibitors include: These include crizotinib, alectinib, ceritinib, and TAE684 (NVP-TAE68 4), GSK1838705A, AZD3463, ASP3026, PF-064639 22, entrectinib (RXDX-101) and AP26113. Not limited to:

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

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

[0522] In certain embodiments, the bioactive agent is a JAK3 inhibitor. An example is tasocitinib.

[0523] In certain embodiments, the bioactive agent is a BCL-2 inhibitor. Examples of agents include venetoclax, ABT-199 (4-[[4-[[2-(4-chlorophenyl) (phenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazine- 1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl) Methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin (4-[4-[[2-(4-chlor-5-yl)oxy]benzamide), ABT-737 (4-[4-[[2-(4-chlor-5-yl)oxy]benzamide), (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-tetrahydrofuran) dro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-( (4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3(( Trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide), GX15- 070 (Ovatoclax mesylate, (2Z)-2-[(5Z)-5-[(3,5-dimethyl methyl-1H-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2-ylidene ]indole; methanesulfonic acid), 2-methoxy-antimycin A3, YC13 7(4-(4,9-dioxo-4,9-dihydronaphtho[2,3-d]thiazole-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-methylphenyl)sulfonyl]phenyl] (ethylethyl)phenyl]methyl]benzamide), Apogossypolone (ApoG2), H A14-1, AT101, sabutoclax, gambogic acid or G3139 (Obli Mersen) is one example.

[0524] In certain embodiments, the bioactive agent is a kinase inhibitor. In some embodiments, the kinase inhibitor is a phosphoinositide 3-kinase (PI3K) inhibitor. , Bruton's tyrosine kinase (BTK) inhibitors or spleen tyrosine kinase (Syk ) inhibitors, or combinations thereof.

[0525] Examples of PI3 kinase inhibitors include wortmannin, demethoxyviridin, and perifosine. , idelalisib, pictilisib, Palomid 529, ZSTK474, PWT33 597, 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-dihydro Imidazo[1,2-d][1,4]benzoxazepin-9-yl]pyrazol-1-yl MLN-1117 ((2R)-1-phenoxy-2-methylpropanamide), -butanyl hydrogen (S)-methylphosphonate; or methyl(oxo){[(2R)-1- phenoxy-2-butanyl]oxy}phosphonium), BYL-719 ((2S)-N 1-[4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl) -4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide), G SK2126458 (2,4-difluoro-N-{2-(methyloxy)-5-[4-( 4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide) ( omipalisib), TGX-221 ((±)-7-methyl-2-(morpholin-4-yl) -9-(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 dihydride chloride), KIN-193 ((R)-2-((1-(7-methyl-2-morpholino- 4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzo aromatic acid), TGR-1202 / RP5264, GS-9820((S)-1-(4-((2 -(2-aminopyrimidin-5-yl)-7-methyl-4-mohydroxypropane hydroxypropan)-1-one), GS-1101 (5-fluoro-3-phenyl-2-([ S)]-1-[9H-purin-6-ylamino]-propyl)-3H-quinazoline-4- On), AMG-319, GSK-2269557, SAR245409(N-(4-( N-(3-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)sulfonyl (amoyl)phenyl)-3-methoxy-4-methylbenzamide), BAY80-6946 (2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydrochloride) Doloimidazo[1,2-c]quinaz), AS 252424 (5-[1-[5 -(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-meta-(Z)- ylidene]-thiazolidine-2,4-dione), CZ 24832 (5-(2-amino- 8-Fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-Nt ert-butylpyridine-3-sulfonamide), buparlisib (5-[2,6-di(4 -morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridine amine), GDC-0941 (2-(1H-indazol-4-yl)-6-[[4-(methylamino)methyl] Thieno[3-(4-morpholinyl)-1-(methylsulfonyl)-1-piperazinyl]methyl]-4-(4-morpholinyl)thieno[3 ,2-d]pyrimidine), GDC-0980 ((S)-1-(4-((2-(2-amino pyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidine -6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (R Also known as G7422), 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)morpholin-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 ) (gedatricisib), LY3023414, BEZ235 (2-methyl-2-{4-[3 -Methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazoline 2,3-Dibenzo[4,5-c]quinolin-1-yl]phenyl}propanenitrile) (Dactolisib( dactolisib), XL-765 (N-(3-(N-(3-(3,5-dimethoxyphenyl Amino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methyl ethylbenzamide) and GSK1059615 (5-[[4-(4-pyridinyl)-6- quinolinyl]methylene]-2,4-thiazolidinedione), PX886([(3aR,6 E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino] Methylidene]-5-hydroxy-9-(methoxymethyl)-9a,11a-dimethyl-1 ,4,7-trioxo-2,3,3a,9,10,11-hexahydroindeno[4,5 h]isochromen-10-yl]acetate (also known as sonolisib) ), LY294002, AZD8186, PF-4989216, piralalisib (pi laralisib), GNE-317, PI-3065, PI-103, NU7441(KU- 57788), HS 173, VS-5584(SB2343), CZC24832, T G100-115, A66, YM201636, CAY10505, PIK-75, PI K-93, AS-605240, BGT226(NVP-BGT226), AZD648 2. Voxtalisib, alpelisib, IC-87114, TGI1007 13, CH5132799, PKI-402, copanlisib (BAY 80-6946) , XL 147, PIK-90, PIK-293, PIK-294, 3-MA(3-Methyl Luadenine), AS-252424, AS-604850, Apitolisib (GDC-09 80; RG7422).

[0526] An example of a BTK inhibitor is ibrutinib (also known as PCI-32765) ( Imbruvica™) (1-[(3R)-3-[4-amino-3-(4-phenoxy)amino] (oxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl ]prop-2-en-1-one), dianilinopyrimidine inhibitors, such as AVL-10 1 and AVL-291 / 292 (N-(3-((5-fluoro-2-((4-(2-methan (ethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acryl amide) (Avila Therapeutics) (U.S. Patent Application Publication No. 2011 / 0117073 (see, for example, the entirety of which is incorporated herein by reference), dasatinib (N -(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)phenyl)phenyl)- Perazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide Voxamide), 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-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-(t ert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholine- 4-Carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazine-2-yl CNX-774 (4-((4-((3-acryl)phenyl)benzamide), Amidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy) -N-methylpicolinamide), CTA056 (7-benzyl-1-(3-piperidine) -1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazoline zo[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-methyl (ethylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide samid), 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-tetrahydropyrazin-2-yl dolobenzo[b]thiophene-2-carboxamide), HM-71224, ACP-19 6, ONO-4059 (Ono Pharmaceuticals), PRT062607 (4-((3-( 2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2 S)-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]naphthyridin-2(1H)-one) and and RN486 (6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3- {1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-yl Amino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H- isoquinolin-1-one), as well as other molecules capable of inhibiting BTK activity, e.g. Akinleye et al., Journal of Hematology & Oncology, 2013, 6:59 (cited in its entirety) and the BTK inhibitors disclosed in US Pat. No. 6,239,999, incorporated herein by reference.

[0527] Syk inhibitors include cerdulatinib (4-(cyclopropylamino)benzoate). (amino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)a (amino)pyrimidine-5-carboxamide), entospletinib (6 -(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1, 2-a]pyrazin-8-amine), fostamatinib ([6-({5-fluoro-2-[ (3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl}amino)-2,2 -Dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]o oxazin-4-yl]methyl dihydrogen phosphate), fostamatinib disodium salt ( Sodium (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amine) (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-[(1 R,2S)-2-amino-cyclohexylamino]-4-(5,6-dimethyl-pyridine -2-ylamino)-pyridazine-3-carboxylic acid amide), imatinib (Gleeva c;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-carbohydrate Voxamide), 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)pyri 4-((3-(2H-1,2, 3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-amino) (3,3-Dimethylcyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), R112(3, 3'-((5-fluoropyrimidine-2,4-diyl)bis(azanediyl))diphenoxy R348 (3-ethyl-4-methylpyridine), R406 (6-((5-fluorophenyl) 2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino 2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazine-3(4H )-one), piceatannol (3-hydroxyresveratrol), YM193306 (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibit ors, J. Med. Chem. 2012, 55, 3614-3643), 7-azaindole, picene Athanol, ER-27319 (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (in its entirety) (see, e.g., the disclosure of which is incorporated herein by reference), Compound D (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. C 2012, 55, 3614-3643, which is incorporated herein by reference in its entirety. (Please refer to PRT060318 (Singh et al. Discovery and Development of Science) en Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (in its entirety) , incorporated herein by reference), luteolin (Singh et al., al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Me d. Chem. 2012, 55, 3614-3643 (incorporated herein by reference in its entirety). ), apigenin (Singh et al. Discovery and Development of Spleen T Cytosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (incorporated in its entirety) (See, e.g., "Citrus nigricans" in "Citrus nigricans"), quercetin (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. C 2012, 55, 3614-3643, which is incorporated herein by reference in its entirety. (Singh et al. Discovery and Development of Spleen Tyros Synechocystine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (cited in its entirety) (See, e.g., "Singh et al. Dis.," 2004, pp. 111-114, which is incorporated herein by reference), myricetin (Singh et al. Dis. 2004, pp. 111-114, which is incorporated herein by reference), covery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is incorporated herein by reference in its entirety. (Singh et al. Discovery and Development of Spleen Tyrosine Kinase) se (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (the entire contents of which are hereby incorporated by reference). These include, but are not limited to, fluoropolymers. See, for example, U.S. Pat. No. 6,229,999, incorporated herein by reference.

[0528] In certain embodiments, the bioactive agent is a MEK inhibitor. MEK inhibitors are known For example, trametinib / GSK1120212 (N-(3-{3-cyclopropyl -5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4, 7-Trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidine-1( 2H)-yl}phenyl)acetamide), selumetinib (6-(4-bromo-2-chloro Ionilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole dazole-5-carboxamide), pimasertib / AS703026 / MSC 1935 369((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 (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-032 5901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro- 2-[(2-fluoro-4-iodophenyl)amino]-benzamide), TAK733 ((R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro -4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7( 3H,8H)-dione), MEK162 / ARRY438162 (5-[(4-bromo- 2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1 -methyl-1H-benzimidazole-6-carboxamide), R05126766(3 -[[3-Fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]- 4-methyl-7-pyrimidin-2-yloxychromen-2-one), WX-554, R 04987655 / CH4987655(3,4-difluoro-2-((2-fluoro- 4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo -1,2-oxazinan-2-yl)methyl)benzamide) or AZD8330 (2-( (2-fluoro-4-iodophenyl)amino)-N-(2hydroxyethoxy)-1, 5-Dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide), U01 26-EtOH, PD184352 (CI-1040), GDC-0623, BI-84 7325, cobimetinib, PD98059, BIX02189, BIX02188, Bini These include metinib, SL-327, TAK-733, and PD318088.

[0529] In certain embodiments, the bioactive agent is a Raf inhibitor. Raf inhibitors are known Vemurafenib (N-[3-[[5-(4-chlorophenyl)-1H-pyridinyl]- [2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl] -1-propanesulfonamide), sorafenib tosylate (4-[4-[[4-chloro- 3-(Trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methyl Pyridine-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-pyridin-3-yl)-1H-pyridin-3-yl) Lazolo[3,4-d]pyrimidin-4-ylamino)-N-(3-(trifluoromethyl) )phenyl)benzamide), RAF-265 (1-methyl-5-[2-[5-(trifluoromethyl) (fluoromethyl)-1H-imidazol-2-yl]pyridin-4-yl]oxy-N-[ 4-(trifluoromethyl)phenyl]benzimidazol-2-amine), 2-bromo Aldisine (2-bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepi phen-4,8-dione), Raf kinase inhibitor IV (2-chloro-5-(2-phenyl- 5-(pyridin-4-yl)-1H-imidazol-4-yl)phenol), Sorafen Nib N-oxide (4-[4-[[[[4-chloro-3(trifluoromethyl)phenyl ]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarboxamide 1-oxide), PLX-4720, dabrafenib (GSK2118436), GDC -0879, RAF265, AZ628, SB590885, ZM336372, GW5 074, TAK-632, CEP-32496, LY3009120 and GX818(E entorafenib).

[0530] In certain embodiments, the bioactive agent is, for example, gefitinib (Iressa). , erlotinib (Tarceva), lapatinib (Tykerb), osimertinib (T agrisso), neratinib (Nerlynx), vandetanib (Caprelsa) , dacomitinib (Vizimpro), rociletinib (Xegafri), afatinib (Glotriff, Giotriff, Afanix), lazertinib or nazartinib It is an EGFR inhibitor containing riboflavin.

[0531] Additional examples of EGFR inhibitors include rociletinib (CO-1686), olmutinib, and cefotaxime. (Olita), nacotinib (ASP8273), nazartinib (EGF816), P F-06747775, Icotinib (BPI-2009), Neratinib (HKI-272 ;PB272), avitinib (AC0010), EAI045, taloxotinib (TH- 4000;PR-610), PF-06459988 (Pfizer), tesevatinib (XL6 47;EXEL-7647;KD-019), transtinib, WZ-3 146, WZ8040, CNX-2006, dacomitinib (PF-00299804; Pf izer), brigatinib (Alunbrig), lorlatinib and PF-06747775 (PF7775) is an example.

[0532] In certain embodiments, the bioactive agent is erlotinib, gefitinib, or rapamycin. In certain embodiments, the bioactive agent is a first generation EGFR inhibitor such as rifametinib. are second generation EGFR inhibitors such as afatinib and / or dacomitinib. In this embodiment, the bioactive agent is a third generation EGFR inhibitor, such as osimertinib. do.

[0533] In certain embodiments, the compounds of the present invention are administered as osimer to a patient in need thereof. It is given in combination with tinib.

[0534] In certain embodiments, the compounds of the present invention are administered to patients in need thereof. It is administered in combination with nibs.

[0535] In certain embodiments, the compounds of the present invention are administered to patients in need thereof. It is administered in combination with

[0536] In certain embodiments, the compounds of the present invention are administered to patients in need thereof. It is administered in combination with nibs.

[0537] In certain embodiments, the compounds of the present invention are administered to patients in need thereof. It is administered in combination with nibs.

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

[0539] In certain embodiments, the compounds of the present invention are administered intravenously to patients in need thereof. It is given in combination with mab.

[0540] In certain embodiments, the compounds of the present invention are useful in administering pancreatic cancer therapy to patients in need thereof. It is given in combination with mab.

[0541] In certain embodiments, the compounds of the present invention are administered to patients in need thereof. It is given in combination with mab.

[0542] In certain embodiments, the bioactive agent is a c-MET inhibitor, such as crizotin. (Xalkori, Crizonix), tepotinib (XL880, EXEL-288 0, GSK1363089, GSK089) or tivantinib (ARQ197).

[0543] In certain embodiments, the bioactive agent is MK-2206, GSK690693 , perifosine (KRX-0401), GDC-0068, triciribine, AZD5363 , honokiol, PF-04691502 and miltefosine AKT inhibitors, P406, dovitinib, quizartinib (AC220), amuvatinib (MP-470), tandutinib (MLN518), ENMD-2076 and KW-24 49, or a combination thereof.

[0544] In certain embodiments, the bioactive agent is an mTOR inhibitor. Examples include rapamycin and its analogs, everolimus (Afinitor), thymidine These include rolimus, ridaforolimus, sirolimus, and deforolimus. Not limited.

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

[0546] In certain embodiments, the bioactive agent is an HSP inhibitor. is geldanamycin or 17-N-allylamino-17-demethoxygeldanamycin (17AAG), and radicicol.

[0547] Additional biologically active compounds include, for example, everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244(ARRY-142886) , AMN-107, TKI-258, GSK461364, AZD 1152, Enzas Taurine, vandetanib, ARQ-197, MK-0457, MLN8054, PHA- 739358, R-763, AT-9263, FLT-3 inhibitor, VEGFR inhibitor, - Lorafenib kinase inhibitors, PIK-1 modulators, HDAC inhibitors, c-MET inhibitors , PARP inhibitors, Cdk inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, focal adhesion plaque kinase Enzyme inhibitors, Map kinase (mek) inhibitors, VEGF trap antibodies, pemetrexed Sed, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edoteca Phosphorus, tetrandrine, rubitecan, tesmilifene, oblimersen , ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-60 1, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, I L13-PE38QQR, INO 1001, IPdR1KRX-0402, Lucanto N, LY317615, Neurajiab, Vitespan, Rta 744, Sdx 102, Talampanel, Atrasentan, Xr 311, Romidepsi ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide poside, gemcitabine, doxorubicin, liposomal doxorubicin, 5'-deoxy- 5-Fluorouridine, Vincristine, Temozolomide, ZK-304709, Selicic Rib;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, Campto Tesin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, Anastra zole, exemestane, letrozole, DES (diethylstilbestrol), Tradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258);3-[5-(methylsulfonylpiperazinemethyl)-indolyl- quinolones, vatalanib, AG-013736, AVE-0005, goserelin acetate, acetic acid Leuprolide, Triptorelin Pamoate, Medroxyprogesterone Acetate, Hydroxycaproate Roxyprogesterone, megestrol acetate, raloxifene, bicalutamide, flutamivir , nilutamide, megestrol acetate, CP-724714;TAK-165, HKI- 272, erlotinib, lapatinib, canertinib, ABX-EGF antibody, Erbitac s, EKB-569, PKI-166, GW-572016, lonafarnib, BMS- 214662, tipifarnib; amifostine, NVP-LAQ824, suberoylaniline Suberoyl analide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide Do, amsacrine, anagrelide, L-asparaginase, bacillus Calmette-Guerin (B CG) Vaccines, Adriamycin, Bleomycin, Buserelin, Busulfan, Cal Ivoplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate cete, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, Diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, flu Oxymesterone, flutamide, Gleevec, gemcitabine, hydroxyurea, idaru Bisin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, meconium Loretamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitoxantrone Mycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin methicillin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine , raltitrexed, rituximab, streptozocin, teniposide, testosterone, Thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retin Noinic acid, phenylalanine mustard, uracil mustard, estramustine, alginate Tretamine, Floxuridine, 5-Deoxyuridine, Cytosine Arabinoside, 6-Methionine Lucaptopurine, deoxycoformycin, calcitriol, valrubicin, mitrama Isin, vinblastine, vinorelbine, topotecan, razoxine, marimastat, C OL-3, neovastat, BMS-275291, squalamine, en Dostatin, SU5416, SU6668, EMD121974, interleukin-1 2, IM862, angiostatin, vitaxin, droloxifene, ido Idoxyfene, spironolactone, finasteride, cimitidine e), trastuzumab, denileukin diftitox, gefitinib, bortezomib Paclitaxel, docetaxel, epothilone B, B without taxol, cremophor MS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifene Xifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant , acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3 339, ZK186619, topotecan, PTK787 / ZK 222584, VX-7 45, PD 184352, Rapamycin, 40-O-(2-hydroxyethyl)-rapamycin mycin, temsirolimus, AP-23573, RAD001, ABT-578, BC- 210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG- Ilgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, Zoledr Ionate, prednisone, cetuximab, granulocyte-macrophage colony-stimulating factor, histamine Tolerin, peginterferon alpha-2a, interferon alpha-2a, peginterf Interferon α-2b, interferon α-2b, azacitidine, PEG-L-asparaginase cerebrospinal fluid, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dextromethorphan Surazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-1 -Leukin-2, megestrol, immunoglobulin, nitrogen mustard, methyl Prednisolone, ibritumomab tiuxetan, androgen, decitabine, hexamethasone lumelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, etidronate, Mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase Ze, strontium 89, casopitant, netupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxydi metoclopramide, lorazepam, alprazolam, haloperidol, droperidol , dronabinol, dexamethasone, methylprednisolone, prochlorperazine, gracilis Nisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim erythropoietin, epoetin alfa, darbepoetin alfa, and mixtures thereof. .

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

[0549] In certain embodiments, the bioactive agent is imatinib mesylate (Gleevac( ), dasatinib (Sprycel(TM)), nilotinib (Tasigna(TM) )), bosutinib (Bosulif™), trastuzumab (Herceptin trastuzumab-DM1, pertuzumab (Perjeta™), lapatinib Nib (Tykerb™), gefitinib (Iressa™), erlotinib (Tarceva™), cetuximab (Erbitux™), panitumumab (Vectibix™), vandetanib (Caprelsa™), Vemuraf venib (Zelboraf™), vorinostat (Zolinza™), Midepsin (Istodax™), bexarotene (Tagretin™), Alitretinoin (Panretin®), tretinoin (Vesanoid®) (trademark), carfilzomib (Kyprolis™), pralatrexate (Fol otyn™), bevacizumab (Avastin™), Ziv-Afliverse (Zaltrap™), sorafenib (Nexavar™), sunitinib Sutent™, pazopanib (Votrient™), regorafenib from rivarga (Stivarga™) and cabozantinib (Cometriq™) Selected but not limited to:

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

[0551] Suitable chemotherapeutic bioactive agents include radioactive molecules, also referred to as cytotoxins or cytotoxic drugs. Any action detrimental to cell viability, including but not limited to toxins These include liposomes or other vesicles containing the agent and chemotherapeutic compound. Anti-cancer drugs include vincristine (Oncovin™) or liposomal vincristine. Ristine (Marqibo™), daunorubicin (daunomycin or Cerub idine (trademark) or doxorubicin (adriamycin (trademark), cytarabine ( Cytosine arabinoside, ara-C or Cytosar™, L-asparaginase PEG-L-asparaginase (Elspar™) or PEG-L-asparaginase (PEG-asparaginase or Oncaspar (trademark), etoposide (VP-16), teniposide (Vumon ( 6-mercaptopurine (6-MP or Purinethol™), methotrexate (Metformin, methylparaben ... Trexate, cyclophosphamide (Cytoxan™), prednisone, dexamethasone Methasone (Decadron), imatinib (Gleevec™), dasatinib ( Sprycel™), nilotinib (Tasigna™), bosutinib (Bo sulif™) and ponatinib (Iclusig™).

[0552] Examples of additional suitable chemotherapeutic agents include 1-dehydrotestosterone, 5-fluorouracil, Uracil, dacarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, adriamycin, aldesleukin, alkylating agents, allopurinol sodium, Altretamine, amifostine, anastrozole, anthramycin (AMC), anti- Mitotic agents, cis-dichlorodiamineplatinum(II) (DDP) (cisplatin), diamino Dichloroplatinum, anthracyclines, antibiotics, antimetabolites, asparaginase, BC BCG live (intravesical), betamethasone sodium phosphate and betamethasone acetate, Bicalutamide, bleomycin sulfate, busulfan, leucovorin calcium, calcare Mycobacterium difficile, capecitabine, carboplatin, lomustine (CCNU), carmustine (B SNU), chlorambucil, cisplatin, cladribine, colchicine, conjugated estrogen Gen, cyclophosphamide, cyclothosphamide, cytarabine, Tarabin, cytochalasin B, cytoxan, dacarbazine, dactinomycin, dactino Mycin (formerly actinomycin), daunorubicin HCl, daunorubicin citrate , denileukin diftitox, dexrazoxane, dibromomannitol, dihydroxy Dihydroxy anthracin dione, docetaxel, doracet mesylate Lon, doxorubicin HCl, dronabinol, Escherichia coli (E. coli) L-asparaginase Ze, emetine, epoetin-α, Erwinia L-asparaginase, esterified estradiol Derogen, estradiol, estramustine sodium phosphate, ethidium bromide, Ethinylestradiol, etidronate, etoposide, citrovorum factor, phosphate Toposide, filgrastim, floxuridine, fluconazole, fludarabine phosphate , Fluorouracil, Flutamide, Folinic Acid, Gemcitabine HCl, Glucocorticoids Goserelin acetate, gramicidin D, granisetron HCl, hydroxyurea, ida Rubicin HCl, Ifosfamide, Interferon α-2b, Irinotecan HCl, Trozole, leucovorin calcium, leuprolide acetate, levamisole HCl, lidoca Insulin, lomustine, maytansinoids, mechlorethamine HCl, medroxyprogesterone acetate Telon, megestrol acetate, melphalan HCl, mercaptopurine, mesna, methotrexate Rexate, methyltestosterone, mithramycin, mitomycin C, mitotane, mi Toxantrone, nilutamide, octreotide acetate, ondansetron HCl, paclitaxel Kisel, Pamidronate Disodium, Pentostatin, Pilocarpine HCl, Primicin plimycin, poriflozan 20 carmustine implant, porfimer sodium um, procaine, procarbazine HCl, propranolol, rituximab, sargra Mostim, streptozotocin, tamoxifen, taxol, teniposide, tenoposide (tenoposide), testolactone, tetracaine, thioepa chlorambucil lorambucil), thioguanine, thiotepa, topotecan HCl, toremifene citrate, Rustuzumab, tretinoin, valrubicin, vinblastine sulfate, vincristine sulfate and vinorelbine tartrate.

[0553] In some embodiments, the compounds of the present invention are used in combination with chemotherapeutic agents (e.g., cytotoxic agents, are administered in combination with other chemical compounds useful in the treatment of cancer. Examples of chemotherapeutic agents include These include alkylating agents, antimetabolites, folic acid analogues, pyrimidine analogues, purine analogues and related inhibitors of the vinca alkaloids, epipodophyllotoxins, antibiotics, L-asparagine Enzymes, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracene dimers Substituted ureas, methylhydrazine derivatives, adrenal cortical suppressants, corticosteroids, progestins Chins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropins steroid-releasing hormone analogs, such as 5-fluorouracil (5-FU), leucovorin (leucovorin), and steroid hormone analogs. rinotecan, oxaliplatin, capecitabine, paclitaxel and doxorubicin Also included are cetaxel. Non-limiting examples of chemotherapeutic agents include thiotepa and cyclophosphamide. alkylating agents such as amides; alkylating agents such as busulfan, improsulfan and piposulfan; alkylsulfonates; benzodopa, carboquone, meturedopa aziridines such as opa and uredopa; altretamine, triethylenemelamine Triethylene phosphoramide, triethylene thiophosphoramide and trimethylol mercapto methylamelamines and ethylenimines containing amines; acetogenins (especially camptothecin (including the synthetic analog topotecan); Liostatin; Kallistatin; CC-1065 (including adzelesin, carzelesin and bile including synthetic analogues of zeresin; cryptophycins (especially cryptophycin 1 and cryptophycin Phycin 8); dolastatins; duocarmycins (synthetic analogs KW-2189 and CB 1-TM1); eluterobin; pancratistatin; sarcodictyin; spon Gistatin; chlorambucil, chlornaphazine, cyclophosphamide, estramusti mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, Novenbiquin, fenesterine, prednimastine, trofosfamide, uracilmus Nitrogen mustards such as tard; carmustine, chlorozotocin, fotemustine , lomustine, nimustine, and ranimustine; enediyne antibiotics ( For example, calicheamicin, particularly calicheamicin γ11 and calicheamicin ω11 ( See, e.g., Agnew, Chem. Inti. Ed Engl. 33:183-186 (1994)). Substances; Dynemicins including Dynemicin A; Bisphosphonates such as clodronate; Espera and neocarzinostatin chromophore and related enediyne chromoproteins Biosubstance chromophore), aclacinomycin, actinomycin, anthramycin, Xaserin, bleomycin, cactinomycin, carabicin, kaminomycin Caminomycin, carzinophilin, chromomycin, dactinomycin, daunomycin Rubicin, Detrubicin, 6-Diazo-5-oxo-L-norleucine, ADRIAMY CIN™ (morpholinodoxorubicin, cyanomorpholinodoxorubicin, 2-pyridoxorubicin) Doxorubicin, including lorinodoxorubicin and deoxydoxorubicin), Epirubicin Mitomycins such as esorubicin, idarubicin, marcelomycin, and mitomycin C Syn, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potofycin Potfiromycin, puromycin, quelamycin, rodol Rodorubicin, streptonigrin, streptozocin, tubercidin, ube Nimex, zinostatin, zorubicin; methotrexate and 5-fluorouracil (5 -FU); denopterin, methotrexate, pteropterin, trime Folic acid analogues such as trexatate; fludarabine, 6-mercaptopurine, thiamiprine, thiamin Purine analogues such as guanine; ancitabine, azacitidine, 6-azauridine, carmo Ful, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxacin Pyrimidine analogues such as uridine; calusterone, dromostanolone propionate, epithionyl androgens such as ostanol, mepitiostane, and testolactone; aminoglutethimide anti-adrenals such as mitotane and trilostane; florinic acid ) and other folic acid supplements; aceglatone; aldophosphamide glycoside; aminolevulinic acid; Eniluracil; Amsacrine; Bestravsil; Bisantrene; Edatrexate; De Defofamine; Demecolcine; Diaziquone; Elfomicin thine); elliptinium acetate; epothilone; etoglucide; gallium nitrate; hydroxy Urea; lentinan; lonidamine; maytansinoids such as maytansine and ansamitocin Do;Mitoguazone;Mitoxantrone;Mopidamol;Nitracrine;Pentostatin; Fenamet; Pirarubicin; Losoxantrone; Podophyllic acid; 2-Ethylhydrazine Procarbazine; PSK™ polysaccharide complex (JHS Natural Products, Eugene, OR) ); Razoxane; Rhizoxin; Sizofuran; Spirogermanium; Tenua Triaziquone;2,2',2''-Trichlorotriethylamine;Trichotecene toxins (especially T-2 toxin, verracurin A, roridin A, and anguidine) ;Urethane;Vindesine;Dacarbazine;Mannomustine;Mitobromitol;Mitholactone Thor; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, such as TAXOL™ (paclitaxel) (Bristol-Myers Squibb Oncology, Princeton, NJ), and Cremophor-free Pak ABRAXANE™ (American Pharmaceuticals) is an albumin-modified nanoparticle formulation of ritaxel. Pharmaceutical Partners, Schaumberg, IL) and TAXOTERE™ docetaxel (Rhone-Poulenc Rorer, Antony, France); chlorambucil; GEMZAR® gel Mucitabine; 6-thioguanine; mercaptopurine; methotrexate; cisplatin, Platinum coordination complexes such as oxaliplatin and carboplatin; vinblastine; platinum; etoposide Cid (VP-16); Ifosfamide; Mitoxantrone; Vincristine; NAVEL BINE® Vinorelbine; Novantrone; Teniposide; Edatrexate; Dauno mycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., C PT-11); Topoisomerase inhibitor RFS 2000; Difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; and any of the above drugs The compounds of the present invention may be used in combination with two or more chemotherapeutic agents, such as chemotherapeutic agents, ... or chemotherapeutic agents. It can be used in cocktails administered in combination with other drugs. Dosage regimens are known in the art. For example, combination dosing regimens are described in Saltz et al., Pr oc. Am. Soc. Clin. Oncol. 18:233a (1999) and Douillard et al., Lancet 355(9209): 1041-1047 (2000).

[0554] Additional therapeutic agents that may be administered in combination with the compounds disclosed herein include These include bevacizumab, sutinib, sorafenib, and 2-methoxyestradiol. 2ME2, finasunate, vatalanib, vandetanib, and Flibercept, volociximab, etaracizumab (MEDI-522), cilengitide , erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, dovicib Nibroc.Ibuprofen, figitumumab, atacicept, rituximab, alemtuzumab, aldesleuki aldesleukine, atlizumab, tocilizumab, temsirolimus, everolimus, Lucatumumab, dacetuzumab, HLL1, huN901-DM1, Acip Remod, natalizumab, bortezomib, carfilzomib, marizomib, tanespiimab Shin, saquinavir mesylate, ritonavir, nelfinavir mesylate, indinavir sulfate, Belinostat, panobinostat, mapatumumab, lexatumumab, dulanermin ( dulanermin), ABT-737, oblimersen, plitidepsin, Talmapimod, P276-00, enzastaurin, tipifarnib, periamphetamine fosine, imatinib, dasatinib, lenalidomide, thalidomide, simvastatin, selenium Coxib, bazedoxifene, AZD4547, rilotumumab, oxaliplatin (El oxatin), PD0332991, ribociclib (LEE011), abemaciclib (LY2835219), HDM201, fulvestrant (Faslodex), Semestan (Aromasin), PIM447, ruxolitinib (INC424), B GJ398, necitumumab, pemetrexed (Alimta) and ramucirumab (IMC -1121B).

[0555] In certain embodiments, the additional therapy is a monoclonal antibody (MAb). Some MAbs stimulate an immune response that destroys cancer cells. Similar to antibodies used in cancer therapy, these MAbs "coat" the surface of cancer cells, preventing their destruction by the immune system. For example, bevacizumab may induce tumor cells and other cells in the tumor microenvironment. Vascular endothelial growth factor (VEGF) is a protein secreted by tumor cells that promotes the development of tumor blood vessels. When VEGF binds to bevacizumab, it interacts with its cell receptor. These cells are unable to function, preventing the signaling that leads to new blood vessel growth. MAbs that bind to epidermal growth factor receptors prevent the target receptor from transmitting normal growth-promoting signals. They can induce apoptosis and activate the immune system to destroy tumor cells. There is also a possibility.

[0556] In one aspect of the invention, the bioactive agent is an immunosuppressant. phosphorus inhibitors, such as cyclosporin or ascomycin, e.g., cyclosporin A (NE ORAL™), FK506 (tacrolimus), pimecrolimus, mTOR inhibitors, For example, rapamycin or a derivative thereof, such as sirolimus (RAPAMUNE™), Everolimus (Certican™), temsirolimus, zotarolimus, viola Mus-7, Biolimus-9, rapalogs, e.g., ridaforolimus, azathioprine, c ampath 1H, S1P receptor modulators, such as fingolimod or its analogs an antibody, an anti-IL-8 antibody, mycophenolic acid or a salt thereof, such as a sodium salt or a prodrug thereof; rags, such as mycophenolate mofetil (CELLCEPT™), OKT3 ( ORTHOCLONE OKT3(TM)), Prednisone, ATGAM(TM), TH YMOGLOBULIN™, brequinar sodium, OKT4, T10B9.A- 3A, 33B3.1, 15-deoxyspergualin, tresperimus , leflunomide (ARAVA(TM)), CTLAI-Ig, anti-CD25, anti-IL2R, Basiliximab (SIMULECT™), daclizumab (ZENAPAX™) ), mizoribine, methotrexate, dexamethasone, ISAtx-247, SDZ A SM 981 (pimecrolimus, Elidel™), CTLA4Ig (abatacept belatacept, LFA3Ig, etanercept (Immunex), Enbrel (trade name) (sold under the trademark), adalimumab (Humira®), infliximab ( Remicade™), anti-LFA-1 antibody, natalizumab (Antegren™), (trademark), enlimomab, gavilimomab, antithymocyte immunoglobulin, Prizumab, Alefacept, Efalizumab, Pentasa, Mesalazine, Asacol, Codeine phosphate, benarylate, fenbufen, naprosyn, diclofenac, etodora and indomethacin, aspirin and ibuprofen.

[0557] In some embodiments, the bioactive agent is a cytokine (e.g., a steroid) used in cancer treatment. For example, biological agents such as interferon or interleukin (e.g., IL-2). In some embodiments, the biologic is an anti-VEGF agent, e.g., Angiogenesis inhibitors such as bevacizumab (AVASTIN™). In cancer therapy, biologics agonize targets to stimulate anti-cancer responses or immunoglobulin-based biologics, such as monoclonal antibodies, that target antigens important in cancer (e.g., humanized antibodies, fully human antibodies, Fc fusion proteins, or functional fragments thereof) Such agents include RITUXAN™ (rituximab), ZENA PAX™ (daclizumab), SIMULECT™ (basiliximab), SY NAGIS™ (palivizumab), REMICADE™ (infliximab) , HERCEPTIN™ (trastuzumab), MYLOTARG™ (Gemtu) zumab ozogamicin), CAMPATH™ (alemtuzumab), ZEVALIN (trademark) (ibritumomab tiuxetan), HUMIRA(trademark) (adalimumab), X OLAIR™ (omalizumab), BEXXAR™ (tositumomab-l-13 1), RAPTIVA™ (efalizumab), ERBITUX™ (cetaxel) mab), AVASTIN™ (bevacizumab), TYSABRI™ (natalizumab) Mab), ACTEMRA™ (tocilizumab), VECTIBIX™ (pancreatic (ranibizumab), LUCENTIS™ (ranibizumab), SOURIS™ (eclipse) zumab), CIMZIA™ (certolizumab pegol), SIMPONI™ ( golimumab), ILARIS™ (canakinumab), STELARA™ (us tekinumab), ARZERRA™ (ofatumumab), PROLIA™ (de Nosumab), NUMAX™ (motavizumab), ABTHRAX™ (Raxiba) cumab), BENLYSTA™ (belimumab), YERVOY™ (ipilimumab) vedotin), ADCETRIS™ (brentuximab vedotin), PERJETA™ (pertuzumab), KADCYLA (trademark) (ado-trastuzumab emtansine) and and GAZYVA™ (obinutuzumab). Antibody-drug conjugates are also included. .

[0558] The combination therapy may also include therapeutic agents that are non-drug treatments, such as radiation therapy, cryotherapy, or other non-drug therapies. The compounds can be administered in addition to chemotherapy, hyperthermia and / or surgical removal of tumor tissue.

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

[0560] In certain embodiments, the second therapeutic agent is administered on a different schedule than the compound of the invention. For example, the second therapeutic agent may be administered on days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th or 14th day of treatment In another embodiment, the first therapeutic agent has a therapeutic holiday. For example, The first therapeutic agent is administered on days 1, 2, 3, 4, 5, 6, 7, and 8 of each treatment cycle. , 9, 10, 11, 12, 13 or 14 days off treatment. In embodiments, both the first and second therapeutic agents have treatment holidays.

[0561] VII. Pharmaceutical Compositions The compounds of formula I, II, III or IV or pharmaceutically acceptable salts thereof have therapeutic activity. The substance can be used, for example, in the form of a pharmaceutical preparation. Coated tablets, sugar-coated tablets, hard and soft gelatin capsules, solutions, emulsions In other embodiments, the compound can be administered orally in the form of a solution or suspension. Administration can also be parenteral, for example, by intravenous administration, or rectal, for example, in the form of a suppository. It can also be administered orally or parenterally, for example in the form of injection solutions.

[0562] Compounds of formula I, II, III or IV and pharmaceutically acceptable salts thereof can be used in the preparation of pharmaceutical formulations. For the purpose of preparation, it can be treated with a pharmaceutically inert inorganic or organic carrier. Corn starch or its derivatives, talc, stearic acid or its salts, etc., are added to, for example, tablets. It can be used as such a carrier for coated tablets, dragees and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solids and However, depending on the nature of the active substance, soft gelatin capsules may be used. In the case of cells, a carrier is usually not necessary. Suitable carriers for the preparation of solutions and syrups are, for example, water. Suitable carriers for suppositories are, for example, natural oils or These include hydrogenated oils, waxes, fats, semi-liquid or liquid polyols, etc.

[0563] Pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, humectants, emulsifiers, sweeteners, colorants, flavorings, soaking agents, pharmaceutically acceptable salts, buffers, masking agents or antioxidants to alter osmolality The pharmaceutical preparation may further contain other therapeutically valuable substances. stomach.

[0564] A compound of Formula I, II, III or IV or a pharmaceutically acceptable salt thereof and a therapeutically inactive A pharmaceutical composition containing one or more compounds of formula I, II, III or IV and a suitable carrier can also be used. and / or a pharmaceutically acceptable salt thereof, and optionally one or more other therapeutically beneficial substances. These include formulating the substance into a galenical dosage form together with one or more therapeutically inert carriers. as well as the manufacturing process of the present invention.

[0565] The dosage can vary widely and will, of course, depend on the individual dosage in each particular case. The oral dose for adults is approximately 0.5 mg / day. 0.01 mg to about 1000 mg of a compound of general formula I, II, III or IV, or a corresponding The daily dose can be varied by the amount of a pharmaceutically acceptable salt thereof. The dose may be administered in single or divided doses, and may be increased by up to 100 mg / kg / day if found to be indicated. It may be exceeded.

[0566] The following examples illustrate the invention without limiting it and are merely representative of the invention. The pharmaceutical preparation contains about 1 mg to 500 mg, in particular 1 mg to 100 mg, of the compound of formula I, II, III or Advantageously, the compound of formula IV is contained in the composition. Examples of compositions according to the invention are as follows: be.

[0567] In certain embodiments, the pharmaceutical composition is in a unit dosage form containing from about 0.1 mg to about 2000 mg. mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of the active compound, and optionally from about 0.1 mg to about 2000 mg, from about 10 mg to about 10 00 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of additional activity Examples include dosage forms containing at least 0.1 mg, 1 mg, 5 mg, 10 mg, 25mg, 50mg, 100mg, 200mg, 250mg, 300mg, 400mg, Dosage forms containing 500 mg, 600 mg, 700 mg, or 750 mg of the active compound or its salt is.

[0568] In some embodiments, the compounds disclosed or used as described herein Compounds are administered once daily (QD), twice daily (BID), or three times daily (TID). In some embodiments, the compounds disclosed or used as described herein 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 At least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 1 9 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 for at least 120 days, at least 150 days, at least 180 days or more is also administered once daily.

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

[0570] In certain embodiments, the compounds of the invention are administered orally once daily. In embodiments, the compounds of the invention are administered orally twice daily. In certain embodiments, the compounds of the present invention are administered orally three times daily. The compound is administered orally four times daily.

[0571] In certain embodiments, the compounds of the invention are administered intravenously once daily. In certain embodiments, the compounds of the invention are administered intravenously twice daily. In certain embodiments, the compounds of the present invention are administered intravenously three times daily. The compounds of the present invention are administered intravenously four times daily.

[0572] In some embodiments, the compounds of the present invention may be administered with treatment holidays between treatment cycles. For example, the compound may be administered on days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 3 7, 8, 9, 10, 11, 12, 13 or 14 days off from treatment do.

[0573] In some embodiments, a loading dose is administered to initiate treatment. On the first day of treatment, the dose should be approximately 1.5 times, 2 times, 2.5 times, or 3 times higher than the dose on the remaining days of the treatment cycle. Approximately 3.5 times, approximately 4 times, approximately 4.5 times, approximately 5 times, approximately 5.5 times, approximately 6 times, approximately 6.5 times, approximately 7 times, about 7.5-fold, about 8-fold, about 8.5-fold, about 9-fold, about 9.5-fold, or about 10-fold higher doses of the compound Further exemplary loading doses include those administered over the first 2, 3, or 4 days of treatment. , 4, 5, 6, 7, 8, 9 or 10 days remaining in the treatment cycle Approximately 1.5 times, approximately 2 times, approximately 2.5 times, approximately 3 times, approximately 3.5 times, approximately 4 times, approximately 4 times more than the treatment day. 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. Included are doses that are 5-fold, about 9-fold, about 9.5-fold or about 10-fold higher.

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

[0575] These compositions may contain any amount of active compound that achieves the desired result, for example, 0.1% by weight. It may contain up to 99% by weight (wt%) of the compound, typically at least about 5 wt% of the compound. Some embodiments include about 25 wt% to about 50 wt% or about 5 wt% to about 75 wt% of the compound. Contains substances.

[0576] A pharmaceutically or therapeutically effective amount of the composition is delivered to the patient. The exact effective amount will vary from patient to patient. These vary depending on the species, age, size and health of the subject, the nature and extent of the condition being treated, and the type of treatment being administered. The dosage will depend on the physician's recommendations and the therapeutic agent or combination of therapeutic agents selected for administration. The effective amount for a particular situation can be determined by routine experimentation. The therapeutic dose is, for example, about 0.01 mg / kg to about 250 mg / kg in at least one administration. g of body weight, more typically in the range of about 0.1 mg / kg to about 10 mg / kg The subject is given a therapeutic regimen to reduce and / or alleviate the signs, symptoms, or causes of the disorder in question, or to improve the biological function of the subject. Administration can be as many times as needed to bring about any other desired changes in the system. Optionally, the formulation may have an enteric coating suitable for sustained or controlled release administration of the active ingredient. A formulation can be prepared.

[0577] In certain embodiments, the dose is from about 0.01 mg / kg to 100 mg / kg ( patient weight), e.g., about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.5mg / kg, about 1mg / kg, about 1.5mg / kg, about 2mg / kg, Approx. 2.5mg / kg, approx. 3mg / kg, approx. 3.5mg / kg, approx. 4mg / kg, approx. 4.5 mg / kg, approx. 5mg / kg, approx. 10mg / kg, approx. 15mg / kg, approx. 20mg / kg , about 25mg / kg, about 30mg / kg, about 35mg / kg, about 40mg / kg, about 45 mg / kg, approx. 50mg / kg, approx. 55mg / kg, approx. 60mg / kg, approx. 65mg / k g, about 70mg / kg, about 75mg / kg, about 80mg / kg, about 85mg / kg, about 9 0 mg / kg, about 95 mg / kg or about 100 mg / kg.

[0578] The pharmaceutical preparation is preferably in unit dosage form. In such dosage form, the preparation contains an appropriate amount of The unit dosage form is a packaged tablet, capsule, and packaged preparations in which the package contains discrete amounts of the preparation, such as powders in vials or ampoules. Alternatively, the unit dosage form may be a capsule, tablet, cachet, or lozenge itself. There may be any suitable number of any of these in packaged form.

[0579] In certain embodiments, the compound is administered as a pharmaceutically acceptable salt. Non-limiting examples of pharmaceutically acceptable salts include acetate, adipate, alginate, Ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, Borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentasiloxane Tanpropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate Salt, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate , hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate , lactobionate, lactate, laurate, lauryl sulfate, malate, maleate Salt, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate Acid salts, oleate, oxalate, palmitate, pamoate, pectinate e), persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, Propionate, stearate, succinate, sulfate, tartrate, thiocyanate, Representative alkali metal salts include benzenesulfonate, undecanoate, and valerate. The salts or alkaline earth metal salts include sodium, lithium, potassium, calcium and Magnesium, as well as ammonium, tetramethylammonium, tetraethylammonium amine, methylamine, dimethylamine, trimethylamine, triethylamine and ethylamine Non-toxic ammonium, quaternary ammonium and amines, including but not limited to Examples include mincations.

[0580] As such, the compositions of the present disclosure may be administered orally (including buccal and sublingually), rectally, nasally, topically, or intravenously. Dermal, pulmonary, intravaginal or parenteral (intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration (including intravenous), injection, inhalation or spray, intra-aortic, intracranial, subdermal l) as pharmaceutical formulations, including those suitable for intraperitoneal, subcutaneous administration, or in conventional pharmaceutically acceptable carriers. The drug may be administered by other means including suitable carriers. Oral, topical or intravenous administration using a convenient daily dosing regimen that can be adjusted depending on the severity of symptoms It is administered internally.

[0581] Depending on the intended method of administration, the pharmaceutical composition may be in a solid, semi-solid or liquid dosage form, e.g., a tablet. tablets, suppositories, pills, capsules, powders, liquids, syrups, suspensions, creams, ointments, lotions Injectable or infusion solutions, transdermal solutions, pastes, gels, sprays, aerosols, foams or oils, patches, subcutaneous patches, inhalation preparations, medical devices, suppositories, buccal or sublingual preparations, parenteral preparations The formulation may be in the form of a liquid medicine, eye drops, or the like, preferably in a unit dosage form suitable for single administration of a precise dose. This can be done.

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

[0583] Carriers include excipients and diluents and are sufficiently high in concentration to be suitable for administration to the patient being treated. The carrier must be of sufficient purity and low toxicity. The amount of carrier used in combination with the compound may be 100 mg / kg or more per unit dose of the compound. Sufficient to provide a useful amount of the substance.

[0584] Carrier classes include adjuvants, binders, buffers, colorants, diluents, disintegrants, additives Additives, emulsifiers, flavorings, gels, glidants, lubricants, preservatives, stabilizers, surfactants, solubilizers These include, but are not limited to, binders, tableting agents, wetting agents or solidifying agents. It will not be done.

[0585] Some carriers may be listed in more than one class, e.g. vegetable oils may be listed in several classes. It can be used as a lubricant in some formulations and as a diluent in others.

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

[0587] Some additives include water, saline, glycerol, polyethylene glycol, Examples of compounds include, but are not limited to, hyaluronic acid, ethanol, and other liquids. For example, solid, liquid, spray-dried, microparticles, nanoparticles as desired depending on the therapeutic purpose. The formulation may be provided in the form of a liquid, a controlled release system, etc. Suitable additives for non-liquid formulations are also known in the art. A thorough discussion of pharmaceutically acceptable excipients and salts is available in Remington's Pharmaceuticals, Inc. Maceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company , 1990).

[0588] Additionally, auxiliary substances, such as wetting or emulsifying agents, physiological buffer substances, surfactants, and the like, may be added to such vehicles. Physiological buffers are those that are pharmacologically acceptable and are present in the formulation as desired. The buffer may be any solution that provides a pH in the physiologically acceptable range. Examples of solutions include saline, phosphate buffered saline, Tris buffered saline, Hank's buffered saline, Examples include saline solution.

[0589] For solid compositions, conventional non-toxic solid carriers can be used, for example, pharmaceutical grade mannitol. Ingredients: tallow, lactose, starch, magnesium stearate, sodium saccharin, Examples of liquid sugars include cellulose, glucose, sucrose, and magnesium carbonate. Pharmaceutically administrable compositions include, for example, an active compound described herein and any pharmaceutical agent. Adjuvants can be added to excipients such as water, saline, aqueous dextrose, glycerol, ethanol, etc. For example, by dissolving and dispersing the compound in an alcohol or the like, thereby forming a solution or suspension. If necessary, the pharmaceutical composition to be administered may contain wetting or emulsifying agents, Non-toxic auxiliary substances such as pH buffers, e.g., sodium acetate, sorbitan monolaurate, Contains small amounts of triethanolamine sodium acetate, triethanolamine oleate, etc. Actual methods for preparing such dosage forms will be known or apparent to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, supra.

[0590] In yet another embodiment, polycations (chitosan and its quaternary ammonium derivatives) are Conductor, poly-L-arginine, aminated gelatin), polyanion (N-carboxymethyl chitosan, polyacrylic acid), and thiolated polymers (carboxymethylcellulose -Cysteine, Polycarbophil-Cysteine, Chitosan-Thiobutylamidine, Chitosan The immersion temperature is 100°C, and the concentration of the immersion temperature is 100°C. The use of permeation enhancing additives is provided.

[0591] In certain embodiments, the additive is butylated hydroxytoluene (BHT), Calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscal Mellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethyl Cellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose Roasted rice, lactose, magnesium stearate, maltitol, mannitol, methionine Ingredients: methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol Polyvinylpyrrolidone, Povidone, Pregelatinized Starch, Propylparaben, Palmitic Acid Retinyl titanate, shellac, silicon dioxide, sodium carboxymethylcellulose, Sodium citrate, sodium starch glycolate, sorbitol, starch (starch) Sorghum), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C and xylitol.

[0592] The pharmaceutical composition / combination may be formulated for oral administration. The compositions generally take the form of tablets, capsules, softgel capsules, or may be aqueous or non-aqueous. It may be an aqueous solution, suspension, or syrup. Tablets and capsules are typical oral Oral tablets and capsules are formulated with lactose and corn starch. The carrier may include one or more of the following commonly used carriers: magnesium stearate, etc. Lubricants are also typically added. Typically, the compositions of the present disclosure contain lactose, starch, sucrose, or the like. , glucose, methylcellulose, magnesium stearate, dicalcium phosphate, sulfate Oral non-toxic pharmaceutically acceptable inorganic salts such as calcium carbonate, mannitol, sorbitol, etc. It can be combined with an active carrier. In addition, if desired or necessary, a suitable binder, Lubricants, disintegrants and coloring agents may also be incorporated into the mixture. Suitable binders include starch. gelatin, natural sugars such as glucose or β-lactose, corn syrup, arabic Natural and synthetic gums such as gum tragacanth, sodium alginate, carboxymethylcellulose, etc. Examples of the formulations include cellulose acetate, polyethylene glycol, and wax. The lubricants used include sodium oleate, sodium stearate, and stearin. Examples of suitable benzoates include magnesium benzoate, sodium acetate, and sodium chloride. Disintegrants include, but are not limited to, starch, methylcellulose, agar, vegetal Examples of suitable cellulose gums include thiamin, ... xanthan gum, etc.

[0593] When a liquid suspension is used, the active agent may be added to any oral suspension such as ethanol, glycerol, water, etc. in combination with a non-toxic, pharmaceutically acceptable inert carrier, and emulsifying and suspending agents. If desired, flavoring agents, coloring agents and / or sweeteners may be added. Other optional ingredients that may be incorporated into oral formulations include preservatives, suspending agents, thickening agents, etc. However, the present invention is not limited to these.

[0594] For intraocular delivery, the compounds may be delivered intravitreally, intrastromally, intracamerally, intratendinously, or intravenously, as desired. Subcapsular, subretinal, retrobulbar, peribulbar, suprachoroidal, conjunctival, subconjunctival, episcleral, periocular, transscleral, bulbar By posterior, posterior juxtascleral, periconeal, or lacrimal injection, or by mucus, mucin, or mucosal barrier The drug can be administered in an immediate or controlled release manner via an intraocular device, or by intraocular device.

[0595] Parenteral formulations are administered as liquid solutions or suspensions, and are often solubilized or suspended in liquid prior to injection. It can be prepared in conventional forms, either as a solid form suitable for suspension or as an emulsion. For example, sterile injectable suspensions may be prepared using suitable carriers, dispersing or wetting agents and suspending agents, as disclosed in the art. The sterile injectable formulation is acceptably non-toxic. It may also be prepared as a sterile injectable solution or suspension in a parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oil, fatty acid ester or polyol is used as a solvent. In addition, parenteral administration requires a certain level of dosage. This may involve the use of a sustained release or sustained release system.

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

[0597] Formulations 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 include propylene glycol, polyethylene glycol, ethylene glycol, vegetable oils such as olive oil and corn oil, gelatin, and olein Such formulations may contain preservatives, wetting agents, emulsifying agents and dispersing agents. These may contain adjuvants such as powders. These may include, for example, bacteria-retaining filters (ba filtration through a sterilizing filter, incorporating a sterilizing agent into the composition, and irradiating the composition. They can be sterilized by heating the composition or by adding sterile water or other suitable solution immediately before use. Any sterile injectable medium may also be used for preparation.

[0598] Sterile injectable solutions may be prepared by adding one or more of the compounds of the present disclosure, as enumerated above, in the required amount, as needed. It is prepared by incorporating it in an appropriate solvent with various other ingredients, followed by sterile filtration. Generally, dispersions consist of a basic dispersion medium and other required components from those listed above. It is prepared by incorporating various sterilized active ingredients into a sterile vehicle containing In the case of sterile powders for the preparation of sterile injectable solutions, the typical preparation method is to pre-sterilize the powder by filtration. Vacuum drying and freeze drying methods produce powders of the active ingredient and any additional desired ingredients from the resulting solution. Thus, for example, a parenteral composition suitable for administration by injection may contain 1.5% by weight of Prepared by stirring the active ingredient into 10% by volume of propylene glycol and water The solution is made isotonic with sodium chloride and sterilized.

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

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

[0601] Formulations for buccal administration include tablets, lozenges, gels, and the like. Buccal administration can be achieved using transmucosal delivery systems known to those skilled in the art. The compounds shown are suitable for use in conventional transdermal drug delivery systems, i.e., where the active substance is typically applied to a body surface. The drug is delivered to the skin using a transdermal "patch" contained within a laminated structure that acts as a drug delivery device. or through mucosal tissue. In such structures, the drug composition typically , contained in a layer or "reservoir" beneath the upper backing layer. The reservoir may include one or more reservoirs. In this embodiment, the reservoir serves to affix the system to the skin during drug delivery. The preferred skin contact adhesive material comprises a polymer matrix of a commercially acceptable contact adhesive material. Examples include polyethylene, polysiloxane, polyisobutylene, polyacrylate, poly Examples include, but are not limited to, polyurethanes and the like.

[0602] Alternatively, the drug-containing reservoir and the skin contact adhesive are present as separate and distinct layers; In this case, the matrix may be a polymer matrix as described above, or a liquid or gel matrix. The adhesive is located under a reservoir which may be a suction cup or take some other form. The underlayer in these stacks, which forms the top surface of the device, is the main structural element of the stack. The backing layer acts as a substrate and gives the device much of its flexibility. It should be substantially impermeable to the active agent and any other materials present.

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

[0604] Alternatively, the active ingredient may be formulated as a dry powder, such as lactose, starch, starch derivatives, Suitable cellulose acetates include hydroxypropyl methylcellulose and polyvinylpyrrolidine (PVP). The compound may be provided in the form of a powder mixture in a suitable powder base. For example, the powder composition may be placed in a capsule or cartridge, e.g., gelatin, to form a gel. The powder may be provided in unit dose form in a blister pack or a blister pack from which the powder is inhaled. It can be administered by injector.

[0605] Formulations suitable for rectal administration are typically presented as unit dose suppositories. with one or more conventional solid carriers, such as cocoa butter, and then the resulting mixture is It can be prepared by molding.

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

[0607] In certain embodiments, the pharmaceutical composition is suitable for transdermal administration and provides long-term It is presented as a discrete patch adapted to remain in intimate contact with the epidermis of the recipient. Formulations suitable for transdermal administration may also be delivered by iontophoresis (e.g., See, for example, Pharmaceutical Research 3 (6):318 (1986)), typically optionally buffered. The active compound is in the form of an aqueous solution.

[0608] In certain embodiments, the microneedle patch or device is applied to biological tissue, particularly Microneedle patches are provided for the delivery of drugs across or into the skin. or the device is capable of crossing or entering the skin or other tissue barrier at a clinically relevant rate. This allows drug delivery in the vascular system with little or no damage, pain or irritation to tissue.

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

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

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

[0612] TIFF2026010026000333.tif52170

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

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

[0615] TIFF2026010026000334.tif55170

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

[0617] A compound of formula I, II, III or IV, lactose and corn starch are first The mixture is mixed in a mixer, followed by a grinder. The mixture is returned to the mixer and talc is added to it. The mixture is then machine-packed into suitable capsules, e.g., hard gelatin capsules. Fill the tank.

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

[0619] TIFF2026010026000335.tif49170

[0620] TIFF2026010026000336.tif49170

[0621] Manufacturing Procedure A compound of Formula I, II, III or IV is dissolved in a warm melt of the other ingredients and the mixture is then mixed appropriately. The filled soft gelatin capsules are then filled according to the usual procedure. Process according to the following.

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

[0623] TIFF2026010026000337.tif28170

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

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

[0626] TIFF2026010026000338.tif33170

[0627] Manufacturing Procedure Compounds of Formula I, II, III, or IV are dissolved in polyethylene glycol 400 and water for injection (100 mL). Dissolve in the mixture of 1 part (2%) of acetic acid and adjust the pH to 5.0. Add the remaining amount of water. Adjust the volume to 1.0 ml using the appropriate overage. Fill into vials and sterilize.

[0628] Example E Sac...

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, A is a ring system AF and AG: 【Chemistry 2】 is selected from A １ teeth, i) —NH—, and ii) —O—; A ２ teeth, i) -N-, and ii) -CR ５２ - is selected from, A ３ teeth, i) -N-, and ii) -CR ５３ - is selected from, A ４ teeth, i) -N-, and ii) -CR ５４ - is selected from, A ５ teeth, i) -N-, and ii) -CR ５５ - is 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 - (CH ２ ) 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, 【Transformation 3】 and C is absent or is a ring system F, G and H: 【Chemistry 4】 is selected from Y １ teeth, i) -N-, and ii) —CH—; Y ２ teeth, i) -N-, and ii) -CR １６ - is selected from, R １２ , R １３ , R １４ and R １５ is independent, i) -H-, ii) a halogen, 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)-(CH ２ ) ｍ -C(O)-、 ii)-C(O)-(CH ２ ) ｐ -、 iii) -C(O)-C(O)-, iv)-NR １０ -C(O)-, v)-C(O)-NR １０ -、 vi) -C(O)O-, vii)-CH ２ -CF ２ -CH ２ -、 vi)i｣ｨ ２ 、 ix) 【Transformation 5】 x) 【Transformation 6】 and, xi) 【Transformation 7】 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: 【Transformation 8】 【change】 and any ring system is selected from R ８０ , R ８１ and R ８２ One to three positions selected from optionally substituted by substituents, 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) -CH ２ - and iii) —O—; E is the ring systems Y, Z, AA, AB and AC: 【Chemistry 9】 is selected from L ５ does not exist, or 【Chemistry 10】 and B is a ring system AD and AE: 【Chemistry 11】 or a pharmaceutically acceptable salt thereof.

2. A is a ring system AF and AG: 【Chemistry 12】 is selected from A １ but, i) —NH—, and ii) —O—; A ２ but, i) -N-, and ii) —CH—; R １ but, i) H, and ii) selected from halogens; R ２ is H, R ３ but, i) H, and ii) selected from halogens; R ４ is H, R ５ is H or or R ４ and R ５ Together - (CH ２ ) ｎ - forms, n is 1, R ６ but, i) H, ii) halogens, iii) cyano, and iv) Halo-C １～６ - alkyl, R ７ is H, R ８ is H, R ９ is C １～６ - alkyl, L １ but, 【Chemistry 13】 and C is absent or the ring system F: 【Chemistry 14】 and Y １ but, i) -N-, and ii) —CH—; Y ２ but, i) -N-, and ii) -CR １６ - is selected from, R １２ , R １３ , R １４ and R １５ became independent, i) H, and ii) selected from halogens; R １６ but, i) H, and ii) selected from hydroxy; L ３ but, i)-(CH ２ ) ｍ -C(O)-、 ii)-C(O)-(CH ２ ) ｐ -、 iii) —C(O)—C(O)—, and iv) -NR １０ -C(O)-; m is 1, p is 1 or 3; R １０ but, i) H, and ii) C １～６ - alkyl, D is a ring system I, J, K, L and M: 【Chemistry 15】 is selected from L ４ but, i)-NR １１ -C(O)-、 ii) -CH ２ - and iii) —O—; E is the ring system Y, Z and AA, AB and AC: 【Chemistry 16】 is selected from L ５ but, 【Chemistry 17】 and B is the ring system AD and AE: [Chemistry 18] 2. The compound of formula I according to claim 1, selected from: or a pharmaceutically acceptable salt thereof.

3. A is a ring system AF and AG: 【Chemistry 19】 is selected from A １ but, i) —NH—, and ii) —O—; A ２ but, i) -N-, and ii) —CH—; R １ but, i) H, and ii) selected from fluoro; R ２ is H, R ３ but, i) H, and ii) selected from fluoro; R ４ is H, R ５ is H or or R ４ and R ５ Together - (CH ２ ) ｑ - forms, q is 1, R ６ but, i) H, ii) fluoro, iii) cyano, iv) difluoromethyl, and v) trifluoromethyl; R ７ is H, R ８ is H, R ９ is methyl, L １ but, 【Chemistry 20】 and C is the ring system F: 【Chemistry 21】 and Y １ but, i) -N-, and ii) —CH—; Y ２ but, i) -N-, and ii) -CR １６ - is selected from, R １２ and R １３ is fluoro, R １４ and R １５ is H, R １６ but, i) H, and ii) selected from hydroxy; L ３ but, i)-(CH ２ ) ｍ -C(O)-、 ii)-C(O)-(CH ２ ) ｐ -、 iii) —C(O)—C(O)—, and iv) -NR １０ -C(O)-; m is 1, p is 1 or 3; R １０ is H, D is a ring system I, J, K, L and M: 【Chemistry 22】 is selected from L ４ but, i)-NR １１ -C(O)-、 ii) -CH ２ - and iii) —O—; E is the ring system Y, Z, AA, AB and AC: 【Chemistry 23】 is selected from L ５ but, 【Chemistry 24】 and B is the ring system AD and AE: 【Chemistry 25】 3. A compound of formula I according to claim 1 or 2, selected from: or a pharmaceutically acceptable salt thereof.

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

5. A １ The compound of formula I or a pharmaceutical composition thereof according to any one of claims 1 to 4, wherein A commercially acceptable salt.

6. A ２ The compound of formula I according to any one of claims 1 to 5, wherein is -CH-. A biologically acceptable salt.

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

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

9. R １ A compound of formula I or a drug thereof according to any one of claims 1 to 8, wherein is fluoro. A biologically acceptable salt.

10. R ２ is H, or a pharmaceutically acceptable salt thereof of the compound of formula I according to any one of claims 1 to 9 Acceptable salts.

11. R ３ but, i) H, and ii) halogen; or a pharmaceutically acceptable salt thereof.

12. R ３ but, i) H, and ii) fluoro, or a pharmaceutically acceptable salt thereof.

13. R ４ is H, or a pharmaceutical composition thereof according to any one of claims 1 to 12 Acceptable salts.

14. R ５ is H, or a pharmaceutical composition thereof according to any one of claims 1 to 13 Acceptable salts.

15. R ６ but, i) H, ii) halogens, iii) cyano, and iv) Halo-C １～６ -alkyl A compound of formula I above or a pharmaceutically acceptable salt thereof.

16. R ７ is H, or a pharmaceutical composition thereof according to any one of claims 1 to 15 Acceptable salts.

17. R ８ is H, or a pharmaceutical composition thereof according to any one of claims 1 to 16 Acceptable salts.

18. R ９ is C １～６ -alkyl. or a pharmaceutically acceptable salt thereof.

19. R ９ The compound of formula I according to any one of claims 1 to 18, wherein is methyl. A biologically acceptable salt.

20. A compound of formula I according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein n is 1. Acceptable salts.

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

22. A compound of formula I according to any one of claims 1 to 21, or a pharmaceutical composition thereof, wherein C is the ring system F. A commercially acceptable salt.

23. R １２ and R １３ is fluoro. or a pharmaceutically acceptable salt thereof.

24. R １４ and R １５ is H, or is a pharmaceutically acceptable salt thereof.

25. R １６ but, i) H, and ii) hydroxy. or a pharmaceutically acceptable salt thereof.

26. R １６ A compound of formula I according to any one of claims 1 to 25, or a pharmaceutical composition thereof, wherein A commercially acceptable salt.

27. L ３ but, i)-(CH ２ ) ｍ -C(O)-、 ii)-C(O)-(CH ２ ) ｐ -、 iii) —C(O)—C(O)—, and iv) -NR １０ 27. The method according to claim 1, wherein the aryl group is selected from the group consisting of —C(O)—, ... or a pharmaceutically acceptable salt thereof.

28. A compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 27, wherein m is 1. Acceptable salts.

29. A compound of formula I according to any one of claims 1 to 28, wherein p is 1 or 3. A biologically acceptable salt.

30. R １０ but, i) H, and ii) C １～６ - alkyl according to any one of claims 1 to 29. I or a pharmaceutically acceptable salt thereof.

31. 31. A compound according to any one of claims 1 to 30, wherein D is selected from the ring systems I, J, K, L and M. or a pharmaceutically acceptable salt thereof.

32. L ４ but, i)-NR １１ -C(O)-、 ii) -CH ２ - and iii) a compound of formula I according to any one of claims 1 to 31 selected from -O- or a pharmaceutically acceptable salt thereof.

33. L ４ but, 【Chemistry 26】 33. A compound of formula I according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, Salt.

34. 5-((2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazole- 1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro -3-oxoisoindolin-5-yl)ethynyl)-N-(1-(2-(4-(4-( (2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl) acetyl)piperidin-4-yl)picolinamide, 5-[2-[2-[1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazo[ -1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl]-7-fluoro 3-oxo-isoindolin-5-yl]ethynyl]-N-[1-[2-[4-[ (2,6-dioxo-3-piperidyl)amino]phenyl]acetyl]-4-piperidyl ]pyridine-2-carboxamide, 5-[2-[2-[1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazo[ -1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl]-7-fluoro 3-oxo-isoindolin-5-yl]ethynyl]-N-[1-[2-[4-[ 4-[(2,6-dioxo-3-piperidyl)oxy]phenyl]piperazin-1-yl ]acetyl]-4-piperidyl]pyridine-2-carboxamide, 5-[2-[2-[1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazo[ -1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl]-7-fluoro 3-oxo-isoindolin-5-yl]ethynyl]-N-[1-[2-[4-[ 4-[[(3S)-2,6-dioxo-3-piperidyl]amino]-2-fluoro-phen [Nyl]-1-piperidyl]acetyl]-4-piperidyl]pyridine-2-carboxamide 、 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -[6-[4-[4-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amine phenyl]-1-piperidyl]acetyl]piperazin-1-yl]phenyl]-4- Fluoro-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetate Toamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -[6-[4-[4-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidinyl [1-piperidyl]acetyl]piperazin-1-yl]phenyl -4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazole-2- yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -[6-[4-[4-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidinyl [1-piperidyl]acetyl]piperazin-1-yl]phenyl -4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazole-2- yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -(6-(4-(4-(4-(4-(4-((2,6-dioxopiperidin-3-yl) Amino)phenyl)piperidin-1-yl)-4-oxobutyl)piperazin-1-yl )phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazo (2-yl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -(6-(4-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl) Amino)phenyl)cyclohexyl)acetyl)piperazin-1-yl)phenyl)-4 -fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)a cetoamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -(6-(4-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl) Amino)phenyl)piperidin-1-yl)-2-oxoethyl)piperazin-1-yl )phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazo (2-yl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -[6-[4-[4-[2-[4-[5-[(2,6-dioxo-3-piperidyl)amine [2-pyridyl]-1-piperidyl]acetyl]piperazin-1-yl]phenyl] -4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl -acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -[6-[4-[4-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amine 2-fluoro-phenyl]-1-piperidyl]acetyl]piperazin-1-yl] [phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazole -2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -[6-[4-[4-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amine 3-fluoro-phenyl]-1-piperidyl]acetyl]piperazin-1-yl] [phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazole -2-yl-acetamide, 2-[6-[4-[4-[2-[4-[2-cyano-4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-1-piperidyl]acetyl]piperazin-1-yl] phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-2-(6,7- Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazole-2 -yl-acetamide, 2-[6-[4-[4-[2-[4-[2-(difluoromethyl)-4-[(2,6- Dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetyl]piperazine phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]- 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N- thiazol-2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -(6-(4-(4-(2-(4-(3-((2,6-dioxopiperidin-3-yl) amino)phenyl)piperidin-1-yl)acetyl)piperazin-1-yl)phenyl )-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2-yl) acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -(6-(4-(4-(2-(4-(3-(2,4-dioxotetrahydropyrimidine- 1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl (I)acetyl)piperazin-1-yl)phenyl)-4-fluoro-1-oxoisoin N-(thiazol-2-yl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -(6-(4-(4-(2-(1-(4-((2,6-dioxopiperidin-3-yl) Amino)-2-(trifluoromethyl)phenyl)-4-hydroxypiperidin-4-yl (I)acetyl)piperazin-1-yl)phenyl)-4-fluoro-1-oxoisoin N-(thiazol-2-yl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -(6-(4-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl) amino)phenyl)piperidin-1-yl)acetyl)piperazin-1-yl)phenyl )-4-fluoro-1-oxoisoindolin-2-yl)-N-(pyridin-2-yl ) acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -[6-[4-[4-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amine 2-fluoro-phenyl]-1-piperidyl]acetyl]piperazin-1-yl] phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-(2-pyridine) diethyl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -(6-(4-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl) amino)phenyl)piperidin-1-yl)acetyl)piperidin-4-yl)phenyl )-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2-yl) acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -(6-(4-(1-(2-(4-(4-(((S)-2,6-dioxopiperidine-3 -yl)amino)phenyl)piperidin-1-yl)acetyl)piperidin-4-yl) (phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazole -2-yl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -(6-(4-(1-(2-(4-(4-(((R)-2,6-dioxopiperidine-3 -yl)amino)phenyl)piperidin-1-yl)acetyl)piperidin-4-yl) (phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazole -2-yl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -(6-(4-(1-(2-(4-(4-(((S)-2,6-dioxopiperidine-3 -yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)piperidin (4-fluoro-1-oxoisoindolin-2-yl)-N-phenyl -(thiazol-2-yl)acetamide, 2-(6-(4-(1-(2-(4-(2-cyano-4-((2,6-dioxopiperi (3-yl)amino)phenyl)piperidin-1-yl)acetyl)piperidine-4 -yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-2-(6 ,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazo (2-yl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -[6-[4-[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amine phenyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]phenyl ]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -[6-[6-[4-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidinyl [2-fluoro-phenyl]-1-piperidyl]acetyl]piperazine- 1-yl]-3-pyridyl]-4-fluoro-1-oxo-isoindolin-2-yl] -N-thiazol-2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -[6-[1-[1-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidin [4-piperidyl]pyrazole -4-yl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazo phenyl-2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -[6-[4-[1-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidinyl [4-piperidyl]pyrazole -1-yl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazo phenyl-2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -[6-[4-[1-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidinyl [4-piperidyl]pyrazole -1-yl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazo phenyl-2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -[6-[4-[[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)a amino]phenyl]-1-piperidyl]acetyl]-4-piperidyl]oxy]phenyl] -4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl -acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -[6-[4-[[1-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidine lysyl]amino]phenyl]-1-piperidyl]acetyl]-4-piperidyl]oxy] [phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazole -2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -[6-[4-[[1-[2-[4-[4-[[(3R)-2,6-dioxo-3-piperidine lysyl]amino]phenyl]-1-piperidyl]acetyl]-4-piperidyl]oxy] [phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazole -2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -(6-(4-((1-(2-(4-(4-((2,6-dioxopiperidin-3-yl )amino)-3-fluorophenyl)piperidin-1-yl)acetyl)piperidine-4 -yl)oxy)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)- N-(thiazol-2-yl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -(6-(4-((1-(2-(4-(4-((2,6-dioxopiperidin-3-yl )amino)-2-fluorophenyl)piperidin-1-yl)acetyl)piperidine-4 -yl)oxy)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)- N-(thiazol-2-yl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -(6-(4-((1-(2-(4-(5-((2,6-dioxopiperidin-3-yl ) amino) pyridin-2-yl) piperidin-1-yl) acetyl) piperidin-4-yl (phenyl)oxy)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N- (thiazol-2-yl)acetamide, 2-(6-(4-((1-(2-(4-(2-cyano-4-((2,6-dioxopipene Lysin-3-yl)amino)phenyl)piperidin-1-yl)acetyl)piperidine- 4-yl)oxy)phenyl)-4-fluoro-1-oxoisoindolin-2-yl) -2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N -(thiazol-2-yl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -(6-(4-((1-(2-(4-(4-((2,4-dioxo-3-azabicyclo[ 3.1.1]heptan-1-yl)amino)phenyl)piperidin-1-yl)acetyl ) piperidin-4-yl)oxy)phenyl)-4-fluoro-1-oxoisoindole N-(thiazol-2-yl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -(6-(4-((1-(2-(4-(4-(((S)-2,6-dioxopiperidine- 3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)piperidin (4-fluoro-1-oxoisoindoline-2-yl)oxy)phenyl)-4-fluoro-1-oxoisoindoline-2- (thiazol-2-yl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -[6-[4-[[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)a amino]phenyl]-1-piperidyl]-2-oxo-acetyl]-4-piperidyl]ox [phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazo aryl-2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -[6-[4-[(3R)-1-[2-[4-[4-[[(3S)-2,6-dioxo- 3-piperidyl]amino]phenyl]-1-piperidyl]acetyl]pyrrolidin-3-yl -1-yl]oxyphenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N- thiazol-2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -[6-[4-[(3R)-1-[2-[4-[4-[[(3S)-2,6-dioxo- 3-piperidyl]amino]phenyl]-1-piperidyl]acetyl]pyrrolidin-3-yl -1-yl]oxyphenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N- thiazol-2-yl-acetamide, 2-(6-(4-(4-(2-(4-(4-((2,6-dioxopiperidine-3-yl (amino)phenyl)piperidin-1-yl)acetyl)piperazin-1-yl)phenyl (R)-6-fluoro-1-oxoisoindolin-2-yl)-2-((R)-6-fluoro-1-oxoisoindolin-2-yl)-4 ... (6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N -(thiazol-2-yl)acetamide, 2-[6-[4-[4-[2-[4-[4-[[(3S)-2,6-dioxo-3-pi ]peridyl]amino]-2-fluoro-phenyl]-1-piperidyl]acetyl]piperazine phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]- 2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazoline [N-thiazol-1-yl]-N-thiazol-2-yl-acetamide, 2-[6-[4-[4-[2-[4-[3-(2,4-dioxohexahydropyrimidin [1-methyl-indazol-6-yl]-1-piperidyl]acetyl] piperazin-1-yl]phenyl]-4-fluoro-1-oxo-isoindoline-2- yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c ]imidazol-1-yl]-N-thiazol-2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -(6-(4-(2-(2-(4-(4-(((S)-2,6-dioxopiperidine-3 -yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)-2,7 -diazaspiro[3.5]nonan-7-yl)phenyl)-4-fluoro-1-oxoyl N-(thiazol-2-yl)-N-(thiazol-2-yl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -[6-[4-[2-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amido [phenyl]-1-piperidyl]acetyl]-2,6-diazaspiro[3.3]hepta phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]- N-thiazol-2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -[6-[4-[2-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidinyl [Dil]amino]-2-fluoro-phenyl]-1-piperidyl]acetyl]-2,6-di azaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo- [isoindolin-2-yl]-N-thiazol-2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -[6-[4-[2-[2-[4-[3-(2,4-dioxohexahydropyrimidine- 1-yl)-1-methyl-indazol-6-yl]-1-piperidyl]acetyl]-2 ,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-ol xo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -[6-[4-[2-[2-[4-[3-(2,4-dioxohexahydropyrimidine- 1-yl)-1-methyl-indazol-6-yl]-3,3-difluoro-1-piperidin diacetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]- 4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl- acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -(6-(4-(6-(2-(4-(4-((2,6-dioxopiperidin-3-yl) amino)phenyl)-3,3-difluoropiperidin-1-yl)acetyl)-2,6- Diazaspiro[3.3]heptan-2-yl)phenyl)-4-fluoro-1-oxoyl N-(thiazol-2-yl)-N-(thiazol-2-yl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -[6-[4-[2-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidinyl [Dil]amino]-2-fluoro-phenyl]-1-piperidyl]acetyl]-2,6-di azaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-oxo- [isoindolin-2-yl]-N-(2-pyridyl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -[6-[4-[2-[2-[4-[3-(2,4-dioxohexahydropyrimidine- 1-yl)-1-methyl-indazol-6-yl]-1-piperidyl]acetyl]-2 ,6-diazaspiro[3.3]heptan-6-yl]phenyl]-4-fluoro-1-ol xo-isoindolin-2-yl]-N-(2-pyridyl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -[6-[4-[2-[2-[4-[3-(2,4-dioxohexahydropyrimidine- 1-yl)-1-methyl-indazol-6-yl]-3,3-difluoro-1-piperidin diacetyl]-2,6-diazaspiro[3.3]heptan-6-yl]phenyl]- 4-Fluoro-1-oxo-isoindolin-2-yl]-N-(2-pyridyl)aceto amides, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -[6-[4-[[4-[2-[4-[4-[(2,6-dioxo-3-piperidyl)a amino]phenyl]-1-piperidyl]acetyl]piperazin-1-yl]methyl]phenyl -4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazole-2- yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -[6-[4-[[4-[2-[4-[4-[(2,6-dioxo-3-piperidyl)a [amino]-2-fluoro-phenyl]-1-piperidyl]acetyl]piperazin-1-yl ]methyl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N- thiazol-2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -[6-[4-[[4-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidine Lysyl]amino]-2-fluoro-phenyl]-1-piperidyl]acetyl]piperazine -1-yl]methyl]phenyl]-4-fluoro-1-oxo-isoindoline-2-yl -N-thiazol-2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -[6-[4-[[4-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidine Lysyl]amino]-2-fluoro-phenyl]-1-piperidyl]-2-oxo-ethyl ]piperazin-1-yl]methyl]phenyl]-4-fluoro-1-oxo-isoindo thiazol-2-yl]-N-thiazol-2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -[6-[4-[[1-[2-[4-[4-[[(3S)-2,6-dioxo-3-piperidine lysyl]amino]-2-fluoro-phenyl]-1-piperidyl]acetyl]-4-piperidine lysyl]methyl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl] -N-thiazol-2-yl-acetamide A compound of formula I according to any one of claims 1 to 33, or A pharmaceutically acceptable salt of

35. A compound according to any one of claims 1 to 34 for use as a therapeutically active substance.

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

37. Cancer, in particular non-small cell lung cancer, more particularly EGFR mutations in which the activating mutation is L858R Use of a compound according to any one of claims 1 to 34 for the treatment or prevention of non-small cell lung cancer.

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

39. Cancer, in particular non-small cell lung cancer, more particularly EGFR mutations in which the activating mutation is L858R The method according to any one of claims 1 to 34 for preparing a medicament for treating or preventing non-small cell lung cancer. Use of the compounds listed above.

40. A method for treating cancer, in particular cancers, comprising administering an effective amount of a compound according to any one of claims 1 to 34. Non-small cell lung cancer, more particularly EGFR-mutated non-small cell lung cancer in which the activating mutation is L858R A method for treating or preventing cancer.

41. Formula (II): 【Chemistry 27】 (In the formula, A' is the ring systems AF, AG and AH: 【Chemistry 28】 is selected from A １ teeth, i) —NH—, and ii) —O—; A ２ teeth, i) -N-, and ii) -CR ５２ - is selected from, A ３ teeth, i) -N-, and ii) -CR ５３ - is selected from, A ４ teeth, i) -N-, and ii) -CR ５４ - is selected from, A ５ teeth, i) -N-, and ii) -CR ５５ - 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, R ５２ teeth, i) H, ii) halogens, iii) cyano, iv) C １～６ -alkoxy, v) Halo-C １～６ -alkoxy, vi) C １～６ - alkyl, vii) Halo-C １～６ - alkyl, viii) C ３～８ -cycloalkyl, and ix) Halo-C ３～８ -cycloalkyl, R ５３ , R ５４ and R ５５ is independent, i) H, ii) halogens, iii) C １～６ - alkyl, iv) Halo-C １～６ - alkyl, v) C ３～８ -cycloalkyl, and vi) Halo-C ３～８ -cycloalkyl, R ２ teeth, i) H, ii) halogens, iii) cyano, iv) C １～６ - alkyl, v) Halo-C １～６ - alkyl, vi) C ３～８ -cycloalkyl, and vii) Halo-C ３～８ -cycloalkyl, R ３ teeth, i) H, ii) halogens, iii) C １～６ - alkyl, iv) Halo-C １～６ - alkyl, v) C ３～８ -cycloalkyl, and vi) Halo-C ３～８ -cycloalkyl, R ４ and R ５ is H or or R ４ and R ５ Together - (CH ２ ) 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, 【Chemistry 29】 and C is absent or is a ring system F, G and H: 【Transformation 30】 is selected from Y １ teeth, i) -N-, and ii) —CH—; Y ２ teeth, i) -N-, and ii) -CR １６ - is selected from, R １２ , R １３ , R １４ and R １５ is independent, i) -H-, ii) a halogen, 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)-(CH ２ ) ｍ -C(O)-、 ii)-C(O)-(CH ２ ) ｐ -、 iii) -C(O)-C(O)-, iv)-NR １０ -C(O)-, v)-C(O)-NR １０ -、 vi) -C(O)O-, vii)-CH ２ -CF ２ -CH ２ -、 vi)i｣ｨ ２ 、 ix) 【Chemistry 31】 x) 【Chemistry 32】 and, xi) 【Transformation 33】 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: 【Transformation 34】 and any ring system is selected from R ８０ , R ８１ and R ８２ One to three positions selected from optionally substituted by substituents, 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) -CH ２ - and iii) —O—; E is the ring systems Y, Z, AA, AB and AC: 【Chemistry 35】 is selected from L ５ does not exist, or 【Transformation 36】 and B is a ring system AD and AE: 【Chemistry 37】 or a pharmaceutically acceptable salt thereof.

42. A' is a ring system AF, AG and AH: 【Transformation 38】 【change】 is selected from A １ is —NH—, A ２ but, i) -N-, and ii) —CH—; R １ 'but, i) H, and ii) selected from halogens; R ２ but, i) H, and ii) selected from halogens; R ３ is H, R ４ is H, R ５ is H, R ６ but, i) H, and ii) selected from halogens; R ７ is H, R ８ is H, R ９ is C １～６ - alkyl, L １ but, 【Chemistry 39】 and C is the ring system F: 【Chemistry 40】 and Y １ is —CH—, Y ２ is -N-, R １２ , R １３ , R １４ and R １５ is H, L ３ but, i) -(CH ２ ) ｍ -C(O)-, and ii) -C(O)-(CH ２ ) ｐ - is selected from, m is 1, p is 3, D is a ring system I and J: 【Chemistry 41】 is selected from L ４ does not exist, E is a ring system Y and Z: 【Chemistry 42】 is selected from L ５ 42. The compound of formula II of claim 41, or a pharmaceutically acceptable salt thereof, wherein:

43. 43. Compounds of formula II according to claim 41 or 42, wherein A' is selected from the ring systems AG and AF. or a pharmaceutically acceptable salt thereof.

44. Compounds of formula II according to any one of claims 41 to 43, wherein A' is the ring system AF; or and pharmaceutically acceptable salts thereof.

45. A １ is -NH-; or and pharmaceutically acceptable salts thereof.

46. A ２ is —CH—; or a compound of formula II according to any one of claims 41 to 45, and pharmaceutically acceptable salts thereof.

47. R １ 'but, i) H, and ii) a compound of formula II according to any one of claims 41 to 46 selected from halogens or a pharmaceutically acceptable salt thereof.

48. R １ 'but, i) H, ii) chloro, and iii) fluoro The compound or a pharmaceutically acceptable salt thereof.

49. R ２ but, i) H, and ii) a compound of formula II according to any one of claims 41 to 48 selected from halogens or a pharmaceutically acceptable salt thereof.

50. R ２ but, i) H, ii) chloro, and iii) fluoro The compound or a pharmaceutically acceptable salt thereof.

51. R ３ is H. A biologically acceptable salt.

52. R ４ is H. A biologically acceptable salt.

53. R ５ is H. A biologically acceptable salt.

54. R ６ but, i) H, and ii) a compound of formula II according to any one of claims 41 to 53 selected from halogens or a pharmaceutically acceptable salt thereof.

55. R ７ is H. A biologically acceptable salt.

56. R ８ is H. A biologically acceptable salt.

57. R ９ is C １～６ -alkyl of formula II according to any one of claims 41 to 56. The compound or a pharmaceutically acceptable salt thereof.

58. R ９ is methyl, A pharmaceutically acceptable salt of

59. Compounds of formula II or their derivatives according to any one of claims 41 to 58, wherein C is the ring system F. Pharmaceutically acceptable salts.

60. Y １ is —CH—; or a compound of formula II according to any one of claims 41 to 59 and pharmaceutically acceptable salts thereof.

61. Y ２ is -N-, or a compound of formula II or its derivatives according to any one of claims 41 to 60 A pharmaceutically acceptable salt of

62. R １２ , R １３ , R １４ and R １５ is H.

1. A compound of formula II above or a pharmaceutically acceptable salt thereof.

63. L ３ but, i) -(CH ２ ) ｍ -C(O)-, and ii) -C(O)-(CH ２ ) ｐ Any one of claims 41 to 62, selected from or a pharmaceutically acceptable salt thereof.

64. A compound of formula II according to any one of claims 41 to 63, wherein m is 1, or a pharmaceutical composition thereof. A commercially acceptable salt.

65. A compound of formula II according to any one of claims 41 to 64, wherein p is 3, or a pharmaceutical composition thereof. A commercially acceptable salt.

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

67. Compounds of formula II or their derivatives according to any one of claims 41 to 66, wherein D is the ring system J. Pharmaceutically acceptable salts.

68. L ４ A compound of formula II or its derivatives according to any one of claims 41 to 67, wherein Pharmaceutically acceptable salts.

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

70. L ５ 70. A compound of formula II or its derivatives according to any one of claims 41 to 69, wherein Pharmaceutically acceptable salts.

71. 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -(6-(6-(4-(4-(4-((2-(2,6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl)oxy)piperidin-1-yl)-4-oxo (butyl)piperazin-1-yl)pyridin-3-yl)-7-fluoro-2H-indazoline (thiazol-2-yl)-N-(thiazol-2-yl)acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -(6-(6-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl) Amino)phenyl)piperidin-1-yl)acetyl)piperazin-1-yl)pyridine -3-yl)-7-fluoro-2H-indazol-2-yl)-N-(thiazole-2 -yl)acetamide, 2-[4,7-dichloro-6-[4-[4-[2-[4-[4-[(2,6-dioxo -3-piperidyl)amino]phenyl]-1-piperidyl]acetyl]piperazine-1- yl]phenyl]indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -[6-[6-[4-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amido 2-fluoro-phenyl]-1-piperidyl]acetyl]piperazin-1-yl] -3-pyridyl]-4-fluoro-indazol-2-yl]-N-thiazol-2-yl acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -[6-[6-[4-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amido phenyl]-1-piperidyl]acetyl]piperazin-1-yl]-3-pyridyl] -4-fluoro-indazol-2-yl]-N-thiazol-2-yl-acetamide 、 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -[6-[6-[4-[2-[4-[5-[(2,6-dioxo-3-piperidyl)amine [2-pyridyl]-1-piperidyl]acetyl]piperazin-1-yl]-3-pyridyl [4-fluoro-indazol-2-yl]-N-thiazol-2-yl-aceto amides, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -[6-[6-[4-[2-[4-[3-(2,4-dioxohexahydropyrimidine- 1-yl)-1-methyl-indazol-6-yl]-1-piperidyl]acetyl]piperidine Indazol-1-yl]-3-pyridyl]-4-fluoro-indazol-2-yl]-N- thiazol-2-yl-acetamide, 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2 -(6-(6-(4-(2-(4-(4-(((S)-2,6-dioxopiperidine-3 -yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)piperazine (4-fluoro-2H-indazol-2-yl)pyridin-1-yl)pyridin-3-yl) -N-(thiazol-2-yl)acetamide A compound of formula II according to any one of claims 41 to 70, selected from the group consisting of is a pharmaceutically acceptable salt thereof.

72. A compound according to any one of claims 41 to 71 for use as a therapeutically active substance.

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

74. Cancer, in particular non-small cell lung cancer, more particularly EGFR mutations in which the activating mutation is L858R Use of a compound according to any one of claims 41 to 71 for the treatment or prevention of non-small cell lung cancer. 。

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

76. Cancer, in particular non-small cell lung cancer, more particularly EGFR mutations in which the activating mutation is L858R A compound according to any one of claims 41 to 71 for preparing a medicament for treating or preventing non-small cell lung cancer. Use of the compounds described.

77. A method for treating cancer, particularly cancers, comprising administering an effective amount of a compound according to any one of claims 41 to 71. in non-small cell lung cancer, more particularly in EGFR-mutated non-small cell lung cancer in which the activating mutation is L858R A method for treating or preventing lung cancer.

78. The invention described above.

79. Formula III or Formula IV, optionally as part of a pharmaceutical composition: 【Chemistry 43】 (In the formula, A ＊ teeth, 【Chemistry 44】 is selected from B ＊ is heteroaryl or aryl, each of which is selected from one, two, or three R ３１ substituent optionally replaced by y is 0, 1, 2 or 3; R ３１ is in each case H, halogen (F, Cl, Br or I), C １～６ -Arki Le, Cyano, C １～６ -alkoxy, halo-C １～６ -alkoxy, halo-C １～６ -a Lukil, C ３～８ -cycloalkyl and halo-C ３～８ -cycloalkyl When present on a bicyclic ring, it may be located on either ring; R ３２ represents 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 represents 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, may be located on the dihydropyrrole or imidazole ring, R ３４ In either case, H, F, C １～６ -Alkyl, halo-C １～６ - alkyl, C ３～８ -cycloalkyl and halo-C ３～８ -cycloalkyl; R ３５ is in each case H, halogen (F, Cl, Br or I), C １～６ -Arki Le, Halo-C １～６ -Alkyl and C ３～８ -cycloalkyl 、 or R ３４ and R ３５ and bond to form -(CH ２ ) ｑ - forms, q is 1 or 2; R ３６ and R ３７ are independently H, 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 Ruka, or R ３６ and R ３７ and are bonded together to form one, two or three R ３１ Optionally, the substituent forming a substituted 5- or 6-membered ring, 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-, -CH ２ -or-NR １００ - and R １００ is alkyl, cycloalkyl, aryl or heteroaryl, or To the extent that valence allows, R １００ is R ３７ and bonded to form a 5- to 8-membered heterocycle or a 5-membered heterocycle. may form a heteroaryl, A ３２ , A ３３ , A ３４ and A ３５ are independently —N— and —CR ４２ - is selected from, R ４２ is in each case H, halogen (F, Cl, Br or I), cyano, C １～６ -alkoxy, halo-C １～６ -alkoxy, C １～６ -Alkyl, halo-C １～６ -a Lukil, C ３～８ -cycloalkyl and halo-C ３～８ -cycloalkyl Selected, A ３６ is -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.

80. The compound is 【Chemistry 45】 80. The compound of claim 79, or a pharmaceutically acceptable salt thereof, selected from:

81. The compound is 【Chemistry 46】 80. The compound of claim 79, or a pharmaceutically acceptable salt thereof, selected from:

82. R ３３ The compound of any one of claims 79 to 81, wherein is H.

83. R ３３ The compound of any one of claims 79 to 81, wherein is F.

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

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

86. At least one R ３１ is halo. thing.

87. At least one R ３１ The compound of any one of claims 79 to 85, wherein is F. 。

88. 84. The compound of any one of claims 79 to 83, wherein y is 0.

89. R ３２ The compound of any one of claims 79 to 88, wherein is H.

90. R ３２ The compound of any one of claims 79 to 88, wherein is F. 【Request Item 91】 【Chemistry 47】 80. The compound of claim 79, selected from: 【Request Item 92】 【Chemistry 48】 80. The compound of claim 79, selected from:

93. A ＊ but, 【Chemistry 49】 The compound according to any one of claims 79 to 92, wherein

94. A ＊ but, [Transformation 50] The compound according to any one of claims 79 to 92, wherein

95. A ３４ 95. The compound of any one of claims 79 to 94, wherein is CH.

96. A ３４ The compound of any one of claims 79 to 94, wherein is N.

97. A ３４ is CR ４２ The compound according to any one of claims 79 to 94, wherein

98. A ３４ The compound of any one of claims 79 to 94, wherein is CF.

99. A ３５ 99. The compound of any one of claims 79 to 98, wherein is CH.

100. A ３５ The compound of any one of claims 79 to 98, wherein is N.

101. A ３５ is CR ４２ The compound according to any one of claims 79 to 98, wherein

102. A ３５ The compound of any one of claims 79 to 98, wherein is CF.

103. A ＊ but, 【Chemistry 51】 The compound according to any one of claims 79 to 92, wherein

104. A ＊ but, 【Chemistry 52】 The compound according to any one of claims 79 to 92, wherein

105. A ２１ 105. The compound of claim 103 or 104, wherein is NH.

106. A ２１ is O.

107. A ＊ but, 【Chemistry 53】 The compound according to any one of claims 79 to 92, wherein

108. A ３２ The compound of any one of claims 79 to 107, wherein is CH.

109. A ３２ The compound of any one of claims 79 to 107, wherein is N.

110. A ３２ is CR ４２ The compound according to any one of claims 79 to 107,

111. A ３２ The compound of any one of claims 79 to 107, wherein is CF.

112. A ３３ The compound of any one of claims 79 to 112, wherein is CH.

113. A ３３ The compound of any one of claims 79 to 112, wherein is N.

114. A ３３ is CR ４２ The compound according to any one of claims 79 to 112,

115. A ３３ The compound of any one of claims 79 to 112, wherein is CF.

116. A ＊ but, 【Chemistry 54】 The compound according to any one of claims 79 to 92, wherein

117. A ２１ 117. The compound of claim 116, wherein is NH.

118. A ２１ The compound of claim 116, wherein is O.

119. R ３４ The compound of any one of claims 79 to 118, wherein is H.

120. R ３４ The compound of any one of claims 79 to 118, wherein is F.

121. R ３４ is CH ３ The compound according to any one of claims 79 to 118, wherein

122. R ３５ The compound of any one of claims 79 to 121, wherein is H.

123. R ３５ The compound of any one of claims 79 to 121, wherein is F.

124. R ３５ is CH ３ The compound according to any one of claims 79 to 121,

125. R ３４ and R ３５ and bond to form -CH ２ - forming any one of claims 79 to 118 Item 1. The compound according to item 1.

126. R ３１ is in each case H, halogen (F, Cl, Br or I) and C １～６ -a 126. The compound of any one of claims 79 to 125, wherein each of the groups is independently selected from alkyl.

127. R ４２ is in each case H, halogen (F, Cl, Br or I) and C １～６ -a 127. The compound of any one of claims 79 to 126, wherein each of the group is independently selected from alkyl.

128. B ＊ but, 【Transformation 55】 The compound according to any one of claims 79 to 127,

129. B ＊ but, 【Transformation 56】 The compound according to any one of claims 79 to 127,

130. B ＊ but, 【Chemistry 57】 The compound according to any one of claims 79 to 127,

131. B ＊ but, 【Chemistry 58】 The compound according to any one of claims 79 to 127,

132. L ２ is the formula: 【Chemistry 59】 (In the formula, X １ and X ２ are independently in each occurrence a bond, a heterocycle, an aryl, a heteroaryl, Bicyclic, alkyl, aliphatic, heteroaliphatic, -NR ２７ -, -CR ４０ R ４１ -, -O-, -C(O)-, -C(NR ２７ )-, -C(S)-, -S(O)-, -S(O) ２ - and -S-, wherein each of the heterocycle, aryl, heteroaryl and bicycle is selected from R ４０ optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ２０ , R ２１ , R ２２ , R ２３ and R ２４ are independently in each case a bond, an alkyl group, ル、-C(O)-、-C(O)O-、-OC(O)-、-SO ２ -、-S(O)-、-C (S)-、-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 selected from the group consisting of R ４０ one, two, three or four independently selected from is optionally substituted with a substituent of R ２６ are independently in each case hydrogen, alkyl, arylalkyl, heteroaryl alkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic, aliphatic and heterocyclic (b) selected from the group consisting of aliphatic R ２７ are independently in each occurrence hydrogen, alkyl, aliphatic, heteroaliphatic, heterocyclic, Aryl, heteroaryl, —C(O)(aliphatic, aryl, heteroaliphatic or heteroaryl) -aryl), -C(O)O (aliphatic, aryl, heteroaliphatic or heteroaryl), ar selected from the group consisting of kenes and alkynes; R ４０ are independently in each case hydrogen, R ２７ , alkyl, alkene, alkyne, fluorine Fluoro, bromo, chloro, hydroxyl, alkoxy, azido, amino, cyano, -NH (Aliphatic), -N (Aliphatic) ２ ,-NHSO ２ (Aliphatic), -N (Aliphatic)SO ２ アルキ Le, -NHSO ２ (aryl, heteroaryl or heterocyclic ring), —N(alkyl)SO ２ ( aryl, heteroaryl or heterocyclic ring), —NHSO ２ Alkenyl, -N(alkyl)S O ２ Alkenyl, —NHSO ２ Alkynyl, —N(alkyl)SO ２ Alkynyl, haloa alkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic, oxo and cyclo alkyl, and further, when valence permits, two alkyl groups bonded to the same carbon; R ４０ the groups may together form a 3- to 8-membered spiro ring; R ４１ is aliphatic, aryl, heteroaryl or hydrogen.

132. The compound according to any one of claims 1 to 131.

133. L ２ is the formula: 【Transformation 60】 133. The compound of claim 132,

134. X １ 134. The compound of claim 132 or 133, wherein is a bond.

135. X １ is a heterocycle.

136. X １ NR ２ 134. The compound of claim 132 or 133, wherein:

137. X １ 134. The compound of claim 132 or 133, wherein is C(O).

138. X ２ The compound of any one of claims 132 to 137, wherein is a bond.

139. X ２ The compound of any one of claims 132 to 137, wherein is a heterocycle.

140. X ２ NR ２ The compound according to any one of claims 132 to 137,

141. X ２ The compound of any one of claims 132 to 137, wherein is C(O).

142. R ２０ The compound of any one of claims 132 to 141, wherein is a bond.

143. R ２０ is CH ２ The compound according to any one of claims 132 to 141,

144. R ２０ The compound of any one of claims 132 to 141, wherein is a heterocycle.

145. R ２０ The compound of any one of claims 132 to 141, wherein is aryl.

146. R ２０ The compound of any one of claims 132 to 141, wherein is phenyl.

147. R ２０ is a bicyclic ring.

148. R ２１ The compound of any one of claims 132 to 147, wherein is a bond.

149. R ２１ is CH ２ The compound according to any one of claims 132 to 147,

150. R ２１ The compound of any one of claims 132 to 147, wherein is a heterocycle.

151. R ２１ The compound of any one of claims 132 to 147, wherein is aryl.

152. R ２１ is phenyl.

153. R ２１ is a bicyclic ring.

154. L is of the formula: 【Chemistry 61】 The compound of claim 132, wherein the linker is

155. R ２２ The compound of any one of claims 132 to 154, wherein is a bond.

156. R ２２ is CH ２ The compound according to any one of claims 132 to 154,

157. R ２２ is a heterocycle.

158. R ２２ The compound of any one of claims 132 to 154, wherein is aryl.

159. R ２２ is phenyl.

160. R ２２ is a bicyclic ring.

161. L is of the formula: 【Transformation 62】 The compound of claim 132, wherein the linker is

162. R ２３ The compound of any one of claims 132 to 161, wherein is a bond.

163. R ２３ is CH ２ The compound according to any one of claims 132 to 161,

164. R ２３ is a heterocycle.

165. R ２３ The compound of any one of claims 132 to 161, wherein is aryl.

166. R ２３ The compound of any one of claims 132 to 161, wherein is phenyl.

167. R ２３ is a bicyclic ring.

168. R ２４ The compound of any one of claims 132 to 167, wherein is a bond.

169. R ２４ is CH ２ The compound according to any one of claims 132 to 167,

170. R ２４ is a heterocycle.

171. R ２４ The compound of any one of claims 132 to 167, wherein is aryl.

172. R ２４ is phenyl.

173. R ２４ is a bicyclic ring.

174. R ２４ is C(O).

175. A compound selected from the following or a pharmaceutically acceptable salt thereof.

176. A compound selected from the following or a pharmaceutically acceptable salt thereof.

177. Any of claims 79 to 176, optionally in a pharmaceutical composition, for use as a therapeutically active substance.

1. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

178. 79 to 1, optionally in a pharmaceutical composition, for use in the therapeutic and / or prophylactic treatment of cancer 77. The compound according to any one of claims 76 or a pharmaceutically acceptable salt thereof.

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

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

181. Claim 179 or 180, wherein the EGFR-mediated disorder is cancer, tumor, or abnormal cell growth. The method described below.

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

183. 182. The method of claim 181, wherein the EGFR-mediated disorder is abnormal cell proliferation.

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

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

186. the cancer, tumor or abnormal cell growth is a mutated EGFR protein The method of any one of claims 181 to 185, comprising the step of:

187. the cancer, tumor or abnormal cell growth contains an EGFR protein having the L858R mutation.

187. The method of any one of claims 181 to 186, comprising:

188. the cancer, tumor or abnormal cell growth contains an EGFR protein having a T790M mutation.

188. The method of any one of claims 181 to 187, comprising:

189. the cancer, tumor or abnormal cell growth contains an EGFR protein having a C797S mutation.

189. The method of any one of claims 181 to 188, comprising:

190. the cancer, tumor or abnormal cell growth contains an EGFR protein having the L792H mutation.

190. The method of any one of claims 181 to 189, comprising:

191. the cancer, tumor or abnormal cell growth contains an EGFR protein having the L718Q mutation.

190. The method of any one of claims 181 to 189, comprising:

192. the cancer, tumor or abnormal cell growth has an EGFR T790M / L858R mutation 187. The method of any one of claims 181 to 186, comprising a protein.

193. The cancer, tumor or abnormal cell growth has the T790M / L858R / C797S mutation. The method of any one of claims 181 to 186, comprising administering to said subject an EGFR protein.

194. the cancer, tumor or abnormal cell growth is EGFR with L858R / C797S mutation 187. The method of any one of claims 181 to 186, comprising a protein.

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

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

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

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

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

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

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

202. 19. The method of claim 18, wherein the additional EGFR inhibitor is an antibody against a mutant form of EGFR.

5. The method according to claim 5.

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

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

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

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

207. 207. The method of any one of claims 179 to 206, wherein the patient is given an additional chemotherapy agent. How to do it.

208. Any of claims 79 to 176 for the manufacture of a medicament for treating an EGFR-mediated disorder in a patient. Use of the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

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

210. Claim 208 or 209, wherein the EGFR-mediated disorder is cancer, tumor, or abnormal cell growth. Use as described in.

211. 211. The use of claim 210, wherein the EGFR-mediated disorder is cancer or tumor.

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

213. The use of claim 211, wherein the cancer is lung cancer.

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

215. the cancer, tumor or abnormal cell growth is a mutated EGFR protein Use according to any one of claims 210 to 214, comprising a hydroxybenzoate.

216. the cancer, tumor or abnormal cell growth contains an EGFR protein having the L858R mutation.

216. Use according to any one of claims 210 to 215, comprising

217. the cancer, tumor or abnormal cell growth contains an EGFR protein having a T790M mutation.

217. Use according to any one of claims 210 to 216, comprising

218. the cancer, tumor or abnormal cell growth contains an EGFR protein having a C797S mutation.

218. Use according to any one of claims 210 to 217, comprising

219. the cancer, tumor or abnormal cell growth contains an EGFR protein having the L792H mutation.

219. Use according to any one of claims 210 to 218, comprising

220. the cancer, tumor or abnormal cell growth contains an EGFR protein having the L718Q mutation.

220. The use according to any one of claims 210 to 219, comprising

221. the cancer, tumor or abnormal cell growth has an EGFR T790M / L858R mutation 216. The use according to any one of claims 210 to 215, comprising a protein.

222. The cancer, tumor or abnormal cell growth has the T790M / L858R / C797S mutation. The use according to any one of claims 210 to 215, wherein the EGFR protein is

223. the cancer, tumor or abnormal cell growth is EGFR with L858R / C797S mutation 216. The use according to any one of claims 210 to 215, comprising a protein.

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

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

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

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

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

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

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

231. 23. The method of claim 22, wherein the additional EGFR inhibitor is an antibody against a mutant form of EGFR.

4. Use according to claim 4.

232. 232. The use of claim 231, wherein the additional EGFR inhibitor is cetuximab.

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

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

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

236. 236. The method of claim 208, wherein the patient is given an additional chemotherapy agent. Use of.

237. 8. The method of claim 7, optionally in a pharmaceutical composition, for use in treating an EGFR-mediated disorder in a patient. 9 to 176, or a pharmaceutically acceptable salt thereof.

238. The compound of claim 237, wherein the patient is a human.

239. Claim 237 or 238, wherein the EGFR-mediated disorder is cancer, tumor, or abnormal cell growth. The compound described in

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

241. 240. The compound of claim 239, wherein the EGFR-mediated disorder is abnormal cell proliferation.

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

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

244. the cancer, tumor or abnormal cell growth is a mutated EGFR protein The compound according to any one of claims 239 to 243, having a carboxylic acid.

245. the cancer, tumor or abnormal cell growth contains an EGFR protein having the L858R mutation. The compound according to any one of claims 239 to 244, comprising:

246. the cancer, tumor or abnormal cell growth contains an EGFR protein having a T790M mutation. The compound according to any one of claims 239 to 245, comprising:

247. the cancer, tumor or abnormal cell growth contains an EGFR protein having a C797S mutation. The compound according to any one of claims 239 to 246, comprising:

248. the cancer, tumor or abnormal cell growth contains an EGFR protein having the L792H mutation. The compound according to any one of claims 239 to 247, comprising:

249. the cancer, tumor or abnormal cell growth contains an EGFR protein having the L718Q mutation. The compound according to any one of claims 239 to 248, comprising:

250. the cancer, tumor or abnormal cell growth has an EGFR T790M / L858R mutation A compound according to any one of claims 239 to 244, comprising a protein.

251. The cancer, tumor or abnormal cell growth has the T790M / L858R / C797S mutation. A compound according to any one of claims 239 to 244, which has an EGFR protein 。

252. the cancer, tumor or abnormal cell growth is EGFR with L858R / C797S mutation A compound according to any one of claims 239 to 244, comprising a protein.

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

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

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

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

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

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

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

260. 26. The additional EGFR inhibitor is an antibody against a mutant form of EGFR.

3. The compound according to claim 3.

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

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

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

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

265. 265. The method of any one of claims 237 to 264, wherein the patient is given an additional chemotherapeutic agent. The compound described.

266. The EGFR activating mutation status of the patient is determined, and then optionally administered in a pharmaceutical composition. The compound according to any one of claims 79 to 176 or a pharmaceutically acceptable salt thereof cobas™ EGF, comprising administering to a patient suffering from cancer, particularly non-small cell lung cancer. EGFR-activating mutations as determined using the EGFR Mutation Test v2. Optionally, a pharmaceutical composition for use as a medicament in the therapeutic and / or prophylactic treatment of a patient suffering from A compound according to any one of claims 79 to 176 or a pharmaceutically acceptable salt thereof. 。

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

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