Nrf2 protein degrading agent

Abstract

The present disclosure provides a compound represented by formula A-I, and a salt or solvate thereof, wherein R 1 , R 2a , R 2b , R 2c , R 3 , R 4a , R 4b , R 4c , R 4d , L, X, Y, and B 1 are as defined herein. The compounds having formula I are nuclear factor erythroid 2-related factor 2 (Nrf2) degraders useful for the treatment of cancer and other diseases. TIFF2025523575000188.tif29128

Description

Technical Field

[0001] Field The present disclosure provides heterobifunctional small molecules as proteolytic agents for nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 proteolytic agents are useful for the treatment of cancer and other diseases.

Background Art

[0002] Background The proteolysis targeting chimera (PROTAC) strategy utilizes proteasome-mediated proteolysis to induce target protein degradation. Raina et al., Proc Natl Acad Sci U S A. 2016, 113, 7124-7129 (Non-Patent Document 1); Zhou et al., J. Med. Chem. 2018, 61, 462-481 (Non-Patent Document 2). A PROTAC molecule is a heterobifunctional small molecule containing one ligand that binds to a target protein of interest, linked together by a chemical linker, and another ligand for the E3 ligase system. Bondeson, D. P.; Crews, C. M. Targeted Protein Degradation by Small Molecules. Annu Rev Pharmacol Toxicol. 2017, 57, 107-123 (Non-Patent Document 3).

[0003] Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates the expression of antioxidant genes. Both Kelch-like ECH-associated protein 1 (Keap1) mutations and Nrf2 mutations contribute to the activation of Nrf2 in cancer cells. Nrf2 activity is associated with, for example, poor prognosis in NSCLC. Zhao et al., Front. Oncol. 10:578315. doi: 10.3389 / fonc.2020.578315 (Non-Patent Document 4).

[0004] The Nrf2 pathway also plays a role in neurodegeneration, diabetes, cardiovascular diseases, kidney diseases, and liver diseases. Nrf2 levels vary widely depending on physiological, temporal, and pathological conditions. Dodson et al., Annu Rev Pharmacol Toxicol 59:555-575 (2019) (Non-Patent Document 5). Nrf2 activation promotes metabolic reprogramming. Inhibition or degradation of Nrf2 can alter metabolic processes and thus suppress tumor growth, prevent metastasis, and / or enhance sensitivity to chemotherapy. There is a need in the art for Nrf2 degraders for treating cancer and other diseases.

Prior Art Documents

Non-Patent Documents

[0005]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Summary of the Invention

[0006] Summary In one aspect, the present disclosure provides heterobifunctional small molecules represented by the following formulas A-I, I, and II, and pharmaceutically acceptable salts and solvates thereof, such as hydrates. These compounds, as well as their salts and solvates, are collectively referred to herein as "Compounds of the Disclosure" or individually as "Compound of the Disclosure". The compounds of the present disclosure are Nrf2 degraders and are thus useful in the treatment of diseases or conditions where degradation of the Nrf2 protein provides a therapeutic benefit to the subject.

[0007] In another aspect, the present disclosure provides a method of treating a condition or disease by administering to a subject, such as a human cancer patient, in need thereof a therapeutically effective amount of a compound of the present disclosure. Diseases or conditions treatable by degradation of Nrf2 include, for example, cancer, neurodegenerative diseases, diabetes, cardiovascular diseases, kidney diseases, or liver diseases.

[0008] In another aspect, the present disclosure provides a method of degrading, e.g., reducing the level of, the Nrf2 protein in a subject in need thereof, comprising the step of administering to the subject an effective amount of a compound of the present disclosure.

[0009] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and an excipient and / or a pharmaceutically acceptable carrier.

[0010] In another aspect, the present disclosure provides a composition comprising a compound of the present disclosure and an excipient and / or a pharmaceutically acceptable carrier for use in the treatment of a disease or condition, such as cancer, where degradation of Nrf2 provides a benefit.

[0011] In another aspect, the present disclosure provides a composition comprising (a) a compound of the present disclosure; (b) a second therapeutic agent; and (c) optionally an excipient and / or a pharmaceutically acceptable carrier.

[0012] In another aspect, the present disclosure provides a compound of the present disclosure for use in the treatment of a disease or condition of interest, such as cancer.

[0013] In another aspect, the present disclosure provides the use of a compound of the present disclosure in the manufacture of a medicament for treating a disease or condition of interest, such as cancer.

[0014] In another aspect, the present disclosure provides a kit comprising a compound of the present disclosure, optionally a second therapeutic agent useful in the treatment of a disease or condition of interest, a packaged composition comprising the compound and the second therapeutic agent, and a package insert containing instructions for use in the treatment of a disease or condition, such as cancer.

[0015] In another aspect, the present disclosure provides a method for preparing a compound of the present disclosure.

[0016] In another aspect, the present disclosure provides a compound represented by the following formula III, and pharmaceutically acceptable salts and solvates thereof, such as hydrates. The compound having formula III can be used, for example, as a synthetic intermediate for preparing a compound of the present disclosure.

[0017] Further aspects and advantages of the present disclosure will be in part set forth in the description which follows, or can be learned by practice of the disclosure. The aspects and advantages of the disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed.

Mode for Carrying Out the Invention

[0018] Detailed Description I. Compounds of the Present Disclosure In one aspect, the compound of the present disclosure is a compound of formula A-1: TIFF2025523575000002.tif, or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 is selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted phenyl, and optionally substituted 5-9 membered heteroaryl; R 2a , R 2b , and R 2c are independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo; R 3 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo; Y is - ^ N(H)C(=O)-, - ^ N(H)C(=O)CH2-, - ^ C(=O)N(H)- and - ^ C(=O)N(H)CH2-; wherein the bond marked with " ^ " is connected to the thiazole; R 4a , R 4b , R 4c , and R 4d are independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo; L is -(CH2) m -, -*(CH2) n (OCH2CH2) o (OCH2CH2) p -Z-(CH2) q -; wherein the carbon marked with "*" is connected to X; m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; n is 2, 3, or 4; o is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; Z is selected from the group consisting of -(CR 6a R 6b )- and -N(R 7 )-; R 6a is selected from the group consisting of halo, hydroxyl, C1-C6 alkyl, C1-C4 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C4-C8 heterocycle, optionally substituted phenyl, and optionally substituted 5-9 membered heteroaryl; R 6b is selected from the group consisting of hydrogen and C1-C6 alkyl; R 7 is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C4 haloalkyl; X is -O-, -NH-, TIFF2025523575000003.tif11128; B 1 is TIFF2025523575000004.tif88134; and R 5a R 5b and R 5c are independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxyl, -S(=O)2CH3, and halo.

[0019] In another aspect, a compound of the disclosure is a compound of formula I: TIFF2025523575000005.tif30128 or a pharmaceutically acceptable salt or solvate thereof.

[0020] In another aspect, a compound of the disclosure is a compound of Formula II: TIFF2025523575000006.tif48128 or a pharmaceutically acceptable salt or solvate thereof.

[0021] In another aspect, a compound of the disclosure is R 1 is optionally substituted C3-C8 cycloalkyl, a compound of any one of Formula A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof. In another aspect, R 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In another aspect, R 1 is cyclopropyl.

[0022] In another aspect, a compound of the disclosure is R 1 is optionally substituted phenyl, a compound of any one of Formula A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof. In another aspect, R 1 is TIFF2025523575000007.tif24128; and R 1a , R 1b , R 1c , R 1d and R 1e are independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo. In another aspect, R 1b , R 1c , R 1d and R 1e are hydrogen. In another aspect, R 1a is C1-C4 alkyl. In another aspect, R 1a is methyl.

[0023] In another aspect, the compound of the present disclosure is a compound of any one of Formula A-1, I, or II, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is an optionally substituted 5- to 9-membered heteroaryl. In another aspect, R 1 is an optionally substituted imidazole. In another aspect, R 1 is TIFF2025523575000008.tif15128.

[0024] In another aspect, the compound of the present disclosure is a compound of any one of Formula A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2a , R 2b , and R 2c are hydrogen.

[0025] In another aspect, the compound of the present disclosure is a compound of any one of Formula A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is C1-C4 alkyl. In another aspect, R 3 is methyl.

[0026] In another aspect, the compound of the present disclosure is a compound of any one of Formula A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4a is selected from the group consisting of hydrogen and fluoro.

[0027] In another aspect, the compound of the present disclosure is a compound of any one of Formula A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4b is selected from the group consisting of hydrogen and fluoro.

[0028] In another aspect, the compound of the present disclosure is a compound of any one of Formula A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4cA compound of any one of Formula A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from the group consisting of hydrogen and fluorine.

[0029] In another aspect, the compounds of the present disclosure are R 4b R 4c and R 4d are hydrogen, a compound of any one of Formula A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof.

[0030] In another aspect, the compounds of the present disclosure are such that L is -(CH2) m - and -*(CH2) n (OCH2CH2) o - selected from the group consisting of, a compound of any one of Formula A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof.

[0031] In another aspect, the compounds of the present disclosure are such that L is -(CH2) m -, a compound of any one of Formula A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof. In another aspect, m is 1. In another aspect, m is 2. In another aspect, m is 3. In another aspect, m is 4. In another aspect, m is 5. In another aspect, m is 6.

[0032] In another aspect, the compounds of the present disclosure are such that L is -*(CH2) n (OCH2CH2) o -, a compound of any one of Formula A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof. In another aspect, n is 2. In another aspect, n is 3. In another aspect, o is 1. In another aspect, o is 2. In another aspect, o is 3. In another aspect, o is 4. In another aspect, o is 5. In another aspect, o is 6.

[0033] In another aspect, the compound of the present disclosure has L being -(CH2) p -Z-CH2) q -, and is a compound of any one of Formulae A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof. In another aspect, p is 0. In another aspect, p is 1. In another aspect, p is 2. In another aspect, p is 3. In another aspect, p is 4. In another aspect, q is 1. In another aspect, q is 2. In another aspect, q is 3. In another aspect, q is 4.

[0034] In another aspect, the compound of the present disclosure has Z being -(CR 6a R 6b )-, and is a compound of any one of Formulae A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof.

[0035] In another aspect, the compound of the present disclosure has Z being TIFF2025523575000009.tif13128, and is a compound of any one of Formulae A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof.

[0036] In another aspect, the compound of the present disclosure has Z being TIFF2025523575000010.tif13128, and is a compound of any one of Formulae A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof.

[0037] In another aspect, the compound of the present disclosure has Z being -N(R 7 ), and is a compound of Formula A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof.

[0038] In another aspect, the compound of the present disclosure has R 6a being halo, and is a compound of any one of Formulae A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof. In another aspect, R 6ais hydroxyl. In another embodiment, R 6a is C1-C6 alkyl. In another embodiment, R 6a is C1-C4 haloalkyl. In another embodiment, R 6a is optionally substituted C3-C8 cycloalkyl. In another embodiment, R 6a is optionally substituted C4-C8 heterocycle. In another embodiment, R 6a is optionally substituted phenyl. In another embodiment, R 6a is optionally substituted 5-9 membered heteroaryl.

[0039] In another embodiment, the compound of the present disclosure is a compound of any one of Formula A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6b is hydrogen. In another embodiment, R 6b is C1-C6 alkyl.

[0040] In another embodiment, the compound of the present disclosure is a compound of any one of Formula A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 is hydrogen. In another embodiment, R 7 is C1-C6 alkyl. In another embodiment, R 7 is C1-C4 haloalkyl.

[0041] In another embodiment, the compound of the present disclosure is a compound of any one of Formula A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -O-.

[0042] In another embodiment, the compound of the present disclosure is a compound of any one of Formula A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -NH-.

[0043] In another embodiment, the compound of the present disclosure is such that X is TIFF2025523575000011.tif is a compound of any one of Formula A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof, where the value is 9128.

[0044] In another aspect, for the compounds of the present disclosure, X is TIFF2025523575000012.tif is a compound of any one of Formula A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof, where the value is 10128.

[0045] In another aspect, for the compounds of the present disclosure, B 1 is B-1, and it is a compound of any one of Formula A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof.

[0046] In another aspect, for the compounds of the present disclosure, B 1 is B-2, and it is a compound of any one of Formula A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof.

[0047] In another aspect, for the compounds of the present disclosure, B 1 is B-3, and it is a compound of any one of Formula A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof.

[0048] In another aspect, for the compounds of the present disclosure, B 1 is B-4, and it is a compound of any one of Formula A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof.

[0049] In another aspect, for the compounds of the present disclosure, B 1 is B-5, and it is a compound of any one of Formula A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof.

[0050] In another aspect, for the compounds of the present disclosure, B 1A compound of any one of formulae A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof, wherein it is B-6.

[0051] In another aspect, the compounds of the present disclosure have R 5a R 5b and R 5c each independently selected from the group consisting of hydrogen and fluoro, a compound of any one of formulae A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof. In another aspect, R 5a R 5b and R 5c are hydrogen.

[0052] In another aspect, the compounds of the present disclosure have B 1 wherein selected from the group consisting of TIFF2025523575000013.tif48146, a compound of any one of formulae A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof.

[0053] In another aspect, the compounds of the present disclosure have B 1 wherein selected from the group consisting of TIFF2025523575000014.tif48146, a compound of any one of formulae A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof.

[0054] In another aspect, the compounds of the present disclosure have B 1 wherein selected from the group consisting of TIFF2025523575000015.tif48146, a compound of any one of formulae A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof.

[0055] In another aspect, the compounds of the present disclosure have B 1 wherein TIFF2025523575000016.tif is a compound of any one of formulae A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof.

[0056] In another aspect, the compounds of the present disclosure are B 1 where TIFF2025523575000017.tif is a compound of any one of formulae A-I, I, or II, or a pharmaceutically acceptable salt or solvate thereof.

[0057] In one aspect, the present disclosure provides a compound of formula III: TIFF2025523575000018.tif 23128 or a pharmaceutically acceptable salt thereof, wherein: R 1' is selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted phenyl, and optionally substituted 5-9 membered heteroaryl; R 2a' , R 2b' , and R 2c' are independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo; R 3' is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo; Z 1 is -O-, and R 8 is hydrogen, C1-C6 alkyl, or aralkyl; or Z 1 is -N(H)-, and R 8 is TIFF2025523575000019.tif 27128; and R​​​​​​​​4a' , R 4b' , R 4c' , and R 4d' are independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo; R 9 is hydrogen and -L 1 -X 1 selected from the group consisting of, X 1 is -OR 10 and -NR 11a R 11b selected from the group consisting of; R 10 is hydrogen; R 11a is selected from the group consisting of hydrogen and -C(=O)OtBu; R 11b is selected from the group consisting of hydrogen and C1-C4 alkyl; L 1 is -(CH2) m' -, -*(CH2) n' (OCH2CH2) o' (OCH2CH2) p' -Z 2 -(CH2) q' - selected from the group consisting of; wherein the carbon marked with "*" is connected to X 1 ; m' is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; n' is 2, 3, or 4; o' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; p' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; q' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; Z 2 is -(CR 6a' R 6b' )- and -N(R 7') selected from the group consisting of; R 6a' is selected from the group consisting of halo, hydroxyl, C1-C6 alkyl, C1-C4 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C4-C8 heterocycle, optionally substituted phenyl, and optionally substituted 5-9 membered heteroaryl; R 6b' is selected from the group consisting of hydrogen and C1-C6 alkyl; and R 7' is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C4 haloalkyl.

[0058] In another aspect, the disclosure provides a compound of formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1' is optionally substituted C3-C8 cycloalkyl. In another aspect, R 1' is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In another aspect, R 1' is cyclopropyl.

[0059] In another aspect, the disclosure provides a compound of formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1’ is optionally substituted phenyl. In another aspect, R 1’ is TIFF2025523575000020.tif24128, and R 1a’ , R 1b’ , R 1c’ , R 1d’ , and R 1e’ are independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxyl, -S(=O)2CH3, and halo. In another aspect, R 1b’ , R 1c’ , R 1d’ , and R 1e’ are hydrogen. In another aspect, R1a’ is C1-C4 alkyl. In another embodiment, R 1a’ is methyl.

[0060] In another embodiment, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1’ is optionally substituted 5- to 9-membered heteroaryl. In another embodiment, R 1’ is optionally substituted imidazole. In another embodiment, R 1’ is TIFF2025523575000021.tif15128.

[0061] In another embodiment, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2a’ , R 2b’ , and R 2c’ are hydrogen.

[0062] In another embodiment, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3’ is C1-C4 alkyl. In another embodiment, R 3' is methyl.

[0063] In another embodiment, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein Z 1 is -O-.

[0064] In another embodiment, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein Z 1 is -N(H)-.

[0065] In another embodiment, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein R 8 is hydrogen. In another embodiment, R 8 is C1-C6 alkyl. In another embodiment, R 8is an aralkyl. In another aspect, R 8 is TIFF2025523575000022.tif27128 and R 4a' R 4b' R 4c' and R 4d' are independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo.

[0066] In another aspect, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 is hydrogen.

[0067] In another aspect, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 is -L 1 -X 1

[0068] In another aspect, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein X 1 is -OR 10 In another aspect, X 1 is -NR 11a R 11b

[0069] In another aspect, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein R 10 is hydrogen.

[0070] In another aspect, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein R 11a is hydrogen. In another aspect, R 11a is -C(=O)OtBu.

[0071] ​​In another aspect, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein R 11b is hydrogen. In another aspect, R 11b is C1-C4 alkyl.

[0072] In another aspect, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 is -(CH2) m' -. In another aspect, L 1 is -*(CH2) n' (OCH2CH2) o' -. In another aspect, L 1 is -(CH2) p' -Z 2 -(CH2) q' -.

[0073] In another aspect, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 is -(CH2) m' -. In another aspect, m' is 2. In another aspect, m' is 3. In another aspect, m' is 4. In another aspect, m' is 5. In another aspect, m' is 6.

[0074] In another aspect, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 is -*(CH2) n' (OCH2CH2) o' -. In another aspect, n' is 2. In another aspect, n' is 3. In another aspect, n' is 4. In another aspect, o' is 1. In another aspect, o' is 2. In another aspect, o' is 3. In another aspect, o' is 4. In another aspect, o' is 5. In another aspect, o' is 6.

[0075] In another aspect, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 is -(CH2) p'-Z 2 -(CH2) q' - provides a compound of formula III, or a pharmaceutically acceptable salt or solvate thereof. In another aspect, p' is 0. In another aspect, p' is 1. In another aspect, p' is 2. In another aspect, p' is 3. In another aspect, p' is 4. In another aspect, q' is 1. In another aspect, q' is 2. In another aspect, q' is 3. In another aspect, q' is 4.

[0076] In another aspect, the present disclosure provides a compound of formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein Z 2 is -(CR 6a' R 6b' )-.

[0077] In another aspect, the present disclosure provides a compound of formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein Z 2 is TIFF2025523575000023.tif13128.

[0078] In another aspect, the present disclosure provides a compound of formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein Z 2 is TIFF2025523575000024.tif13128.

[0079] In another aspect, the present disclosure provides a compound of formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein Z 2 is -N(R 7' ).

[0080] In another aspect, the present disclosure provides a compound of formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a' is halo. In another aspect, R 6a' is hydroxyl. In another aspect, R 6a' is C1-C6 alkyl. In another aspect, R6a' is C1-C4 haloalkyl. In another aspect, R 6a' is optionally substituted C3-C8 cycloalkyl. In another aspect, R 6a' is optionally substituted C4-C8 heterocycle. In another aspect, R 6a' is optionally substituted phenyl. In another aspect, R 6a' is optionally substituted 5- to 9-membered heteroaryl.

[0081] In another aspect, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6b' is hydrogen. In another aspect, R 6b' is C1-C6 alkyl.

[0082] In another aspect, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein R 7' is hydrogen. In another aspect, R 7' is C1-C6 alkyl. In another aspect, R 7' is C1-C4 haloalkyl.

[0083] In another aspect, the compound of the present disclosure is any one or more of the compounds in Table 1, or a pharmaceutically acceptable salt or solvate thereof.

[0084] In another aspect, the present disclosure provides any one or more of the compounds in Table 1-A, or a pharmaceutically acceptable salt or solvate thereof.

[0085]

Table 1

[0086]

Table 1-A

[0087] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier or excipient.

[0088] In another aspect, the present disclosure provides 2-(3-hydroxyphenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide as a synthetic intermediate for preparing a compound of the present disclosure.

[0089] In another aspect, the present disclosure provides 2-(4-fluoro-3-hydroxyphenyl)-N-(5-methyl-4-(1-((2-nitrophenyl)sulfonyl)indolin-5-yl)thiazol-2-yl)acetamide as a synthetic intermediate for preparing a compound of the present disclosure.

[0090] The compounds of the present disclosure may contain asymmetric carbon atoms. In some embodiments, the compounds of the present disclosure are racemic compounds. In other embodiments, the compounds of the present disclosure are enantiomerically enriched, e.g., the enantiomeric excess or “ee” of the compound is about 5% or greater as measured by chiral HPLC. In another embodiment, the ee is about 10%. In another embodiment, the ee is about 20%. In another embodiment, the ee is about 30%. In another embodiment, the ee is about 40%. In another embodiment, the ee is about 50%. In another embodiment, the ee is about 60%. In another embodiment, the ee is about 70%. In another embodiment, the ee is about 80%. In another embodiment, the ee is about 85%. In another embodiment, the ee is about 90%. In another embodiment, the ee is about 91%. In another embodiment, the ee is about 92%. In another embodiment, the ee is about 93%. In another embodiment, the ee is about 94%. In another embodiment, the ee is about 95%. In another embodiment, the ee is about 96%. In another embodiment, the ee is about 97%. In another embodiment, the ee is about 98%. In another embodiment, the ee is about 99%.

[0091] In another embodiment, the cereblon-binding moiety of the compounds of the present disclosure, i.e., B 1 is enantiomerically enriched. In another embodiment, the cereblon-binding moiety of the molecule is racemic. The present disclosure encompasses all possible stereoisomeric forms of the compounds of the present disclosure, e.g., diastereoisomeric forms. If a single enantiomer of the compounds of the present disclosure is desired, it can be obtained by resolution of the final product or by stereospecific synthesis from enantiomerically pure starting materials or by use of chiral auxiliaries. See, e.g., Z. Ma et al., Tetrahedron: Asymmetry, 8(6), pages 883-888 (1997). Resolution of the final product, intermediate, or starting material can be accomplished by any suitable method known in the art. Further, in situations where tautomers of the compounds of the present disclosure are possible, the present disclosure is intended to include all tautomeric forms of the compounds.

[0092] The present disclosure encompasses the preparation and use of salts of the compounds of the present disclosure, including pharmaceutically acceptable salts. As used herein, "pharmaceutically acceptable salts" refers to non-toxic salt forms of the compounds of the present disclosure. See, e.g., Gupta et al., Molecules 23:1719 (2018). The salts of the compounds of the present disclosure may be prepared during the final isolation and purification of the compound or separately by reacting the compound with an acid having a suitable cation. The pharmaceutically acceptable salts of the compounds of the present disclosure can be acid addition salts formed with pharmaceutically acceptable acids. Examples of acids that can be used to form pharmaceutically acceptable salts include inorganic acids such as nitric acid, boric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid. Non-limiting examples of salts of the compounds of the present disclosure include hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethanesulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, naphthalenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, paratoluenesulfonate, undecanoate, lactate, citrate, tartrate, gluconate, methanesulfonate, ethanedisulfonate, benzenesulfonate, and p-toluenesulfonate, but are not limited thereto.Furthermore, the available amino groups present in the compounds of the present disclosure can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. In light of the above, any reference herein to a compound of the present disclosure is intended to include the actual compound, as well as its pharmaceutically acceptable salts, hydrates, or solvates.

[0093] The present disclosure also encompasses the preparation and use of solvates of the compounds of the present disclosure. Solvates generally do not significantly modify the biological activity or toxicity of the compound and can thus function as pharmacologically equivalent substances. As used herein, the term "solvate" refers to a combination, physical association, and / or solvation of a compound of the present disclosure with solvent molecules, e.g., a bis-solvate, a mono-solvate, or a hemisolvate in which the ratio of solvent molecules to the compound of the present disclosure is about 2:1, about 1:1, or about 1:2, respectively. This physical association encompasses various degrees of ionic and covalent bonding, including hydrogen bonding. In certain cases, e.g., when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be isolated. Thus, "solvate" encompasses both solution-phase solvates and isolable solvates. The compounds of the present disclosure can exist in solvated forms with pharmaceutically acceptable solvents such as water, methanol, and ethanol, and the present disclosure is intended to include both solvated and non-solvated forms of the compounds of the present disclosure. One type of solvate is a hydrate. "Hydrate" relates to a specific subgroup of solvates in which the solvent molecule is water. Solvates can generally function as pharmacologically equivalent substances. The preparation of solvates is known in the art. See, for example, M. Caira et al, J. Pharmaceut. Sci., 93(3):601-611 (2004), which describes the preparation of solvates of fluconazole with ethyl acetate and fluconazole with water. Similar preparations of solvates, hemisolvates, hydrates, etc. are described in E.C. van Tonder et al., AAPS Pharm. Sci. Tech., 5(1):Article 12 (2004), and A.L. Bingham et al., Chem. Commun. 603-604 (2001). The usual non-limiting process for preparing a solvate would include dissolving the compound of the present disclosure in a desired solvent (organic solvent, water, or a mixture thereof) at a temperature above 20°C to about 25°C, then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods such as filtration.To confirm the presence of solvent in the crystals of the solvate, analytical techniques such as infrared spectroscopy can be used.

[0094] II. Treatments of the Present Disclosure The compounds of the present disclosure degrade the Nrf2 protein and are thus useful in the treatment of various diseases and conditions. In particular, the compounds of the present disclosure are useful in methods for treating diseases or conditions in which degradation of the Nrf2 protein provides a benefit, such as cancer and proliferative diseases. The compounds of the present disclosure are also useful in methods for treating neurodegenerative diseases, diabetes, cardiovascular diseases, kidney diseases, or liver diseases in a subject.

[0095] The treatment methods of the present disclosure include the step of administering a therapeutically effective amount of the compounds of the present disclosure to a subject in need thereof, such as a cancer patient. The method also includes the step of administering a second therapeutic agent to the subject in combination with the compounds of the present disclosure. The second therapeutic agent is selected from drugs known to be useful in the treatment of diseases or conditions afflicting an individual in need thereof, such as chemotherapeutic agents and / or radiation known to be useful in the treatment of a particular cancer.

[0096] The present disclosure provides the compounds of the present disclosure as Nrf2 protein degrading agents for the treatment of diseases and conditions in which degradation of the Nrf2 protein has an advantageous effect. The compounds of the present disclosure typically have a DC 50 (drug concentration that results in 50% degradation of the Nrf2 protein) value of less than 100 μM, such as less than 50 μM, less than 25 μM, and less than 5 μM, about less than 1 μM, about less than 0.5 μM, or about less than 0.1 μM.

[0097] In one aspect, the present disclosure relates to a method of treating an individual suffering from a disease or condition in which degradation of the Nrf2 protein provides a benefit, the method comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present disclosure. Since the compounds of the present disclosure are Nrf2 protein degraders, a number of diseases and conditions mediated by Nrf2 or genetically related to Nrf2 can be treated by using these compounds. Accordingly, the present disclosure is generally directed to a method of treating a disease or condition in an animal, such as a human, suffering from or at risk of suffering from a disease or condition that responds to degradation of Nrf2, the method comprising administering to the animal an effective amount of one or more compounds of the present disclosure.

[0098] The present disclosure is further directed to a method of degrading the Nrf2 protein in a subject in need thereof, the method comprising administering to the subject an effective amount of at least one compound of the present disclosure.

[0099] In another aspect, the present disclosure provides a method of treating cancer in a subject, the method comprising administering a therapeutically effective amount of a compound of the present disclosure. Without being limited to a particular mechanism, in some aspects, the compounds of the present disclosure treat cancer by degrading Nrf2. Examples of treatable cancers include, but are not limited to, any one or more of the cancers in Table 2.

[0100]

Table 2

[0101] In another aspect, the cancer is a solid tumor. In another aspect, the cancer is a blood cancer. Exemplary blood cancers include, but are not limited to, the cancers listed in Table 3. In another aspect, the blood cancer is acute lymphoblastic leukemia, chronic lymphocytic leukemia (including B-cell chronic lymphocytic leukemia), or acute myeloid leukemia.

[0102]

Table 3

[0103] In another aspect, the cancer is a leukemia, for example, a leukemia selected from acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia (MLL). In another aspect, the cancer is NUT midline cancer. In another aspect, the cancer is multiple myeloma. In another aspect, the cancer is a lung cancer such as small cell lung cancer (SCLC). In another aspect, the cancer is neuroblastoma. In another aspect, the cancer is Burkitt lymphoma. In another aspect, the cancer is cervical cancer. In another aspect, the cancer is esophageal cancer. In another aspect, the cancer is ovarian cancer. In another aspect, the cancer is colorectal cancer. In another aspect, the cancer is prostate cancer. In another aspect, the cancer is breast cancer.

[0104] In another aspect, the cancer is selected from the group consisting of acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mixed lineage leukemia, NUT midline cancer, multiple myeloma, small cell lung cancer, non-small cell lung cancer, neuroblastoma, Burkitt lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colorectal cancer, prostate cancer, breast cancer, bladder cancer, ovarian cancer, glioma, sarcoma, esophageal squamous cell carcinoma, and papillary thyroid carcinoma.

[0105] In another aspect, a compound of the present disclosure is administered to a subject in need thereof to treat lung cancer, breast cancer, ovarian cancer, or prostate cancer. In another aspect, the cancer is breast cancer. In another aspect, the cancer is ovarian cancer. In another aspect, the cancer is prostate cancer. In another aspect, the cancer is metastatic castration-resistant prostate cancer.

[0106] In another aspect, the present disclosure provides a method of treating an autoimmune disease, a respiratory disease, a digestive disease, a cardiovascular disease, a metabolic disease, or a neurodegenerative disease in a subject, the method comprising administering a therapeutically effective amount of a compound of the present disclosure. Without being limited to a particular mechanism, in some aspects, the compounds of the present disclosure treat these diseases by degrading Nrf2.

[0107] In another aspect, the present disclosure provides a method of treating a neurodegenerative disease in a subject, the method comprising administering a therapeutically effective amount of a compound of the present disclosure.

[0108] In another aspect, the present disclosure provides a method of treating diabetes in a subject, the method comprising administering a therapeutically effective amount of a compound of the present disclosure.

[0109] In another aspect, the present disclosure provides a method of treating a cardiovascular disease in a subject, the method comprising administering a therapeutically effective amount of a compound of the present disclosure.

[0110] In another aspect, the present disclosure provides a method of treating a kidney disease in a subject, the method comprising administering a therapeutically effective amount of a compound of the present disclosure.

[0111] In another aspect, the present disclosure provides a method of treating a liver disease in a subject, the method comprising administering a therapeutically effective amount of a compound of the present disclosure.

[0112] The methods of the present disclosure can be achieved by administering the compounds of the present disclosure as a pure compound or as a pharmaceutical composition. Administration of the pharmaceutical composition or pure compound of the present disclosure can be carried out during or after the onset of a disease or condition of interest. Typically, the pharmaceutical composition is sterile and does not contain toxic, carcinogenic, or mutagenic compounds that would cause adverse reactions when administered.

[0113] In one aspect, the compounds of the present disclosure are administered as a single agent to treat a disease or condition in which degradation of the Nrf2 protein provides a benefit. In another aspect, the compounds of the present disclosure are administered in combination with a second therapeutic agent useful in the treatment of a disease or condition in which degradation of the Nrf2 protein provides a benefit. The second therapeutic agent is different from the compounds of the present disclosure. To achieve the desired effect, the compounds of the present disclosure and the second therapeutic agent can be administered simultaneously or sequentially. Further, the compounds of the present disclosure and the second therapeutic agent can be administered as a single pharmaceutical composition or as two separate pharmaceutical compositions.

[0114] The second therapeutic agent is administered in an amount that provides its desired therapeutic effect. The effective dosage ranges for each second therapeutic agent are known in the art, and the second therapeutic agent is administered to an individual in need thereof within such established ranges.

[0115] The compounds of the present disclosure and the second therapeutic agent can be administered together as one unit dose or separately as multiple unit doses, in the latter case, the compounds of the present disclosure being administered before or after the second therapeutic agent. One or more doses of the compounds of the present disclosure and / or one or more doses of the second therapeutic agent can be administered. Thus, the compounds of the present disclosure can be used in combination with one or more second therapeutic agents, such as, but not limited to, anti-cancer agents.

[0116] In the method of the present disclosure, a therapeutically effective amount of a compound of the present disclosure, typically formulated according to pharmaceutical practice, is administered to a subject in need thereof, such as a human cancer patient. Whether such treatment is indicated depends on the individual case and involves a medical assessment (diagnosis) taking into account the signs, symptoms, and / or dysfunctions present, the risk of developing specific signs, symptoms, and / or dysfunctions, and other factors.

[0117] The compounds of the present disclosure can be administered by any suitable route, for example, orally, buccally, by inhalation, sublingually, rectally, vaginally, intravesically, or intrathecally via lumbar puncture, transurethrally, intranasally, percutaneously, i.e., transdermally, or parenterally (including intravenous, intramuscular, subcutaneous, intracoronary, intradermal, intramammary, intraperitoneal, intra-articular, intrathecal, retrobulbar, intralung injection, and / or surgical implantation at a specific site). Parenteral administration can be achieved using needles and syringes or using high-pressure techniques.

[0118] Pharmaceutical compositions include those in which a compound of the present disclosure is administered in an amount effective to achieve its intended purpose. The exact formulation, route of administration, and dosage will be determined by the individual physician in view of the diagnosed condition or disease. Dosage and intervals can be adjusted individually to provide a level of the compound of the present disclosure sufficient to maintain a therapeutic effect.

[0119] The toxicity and therapeutic efficacy of the compounds of the present disclosure can be determined by standard pharmaceutical techniques in cell cultures or experimental animals, for example, to determine the maximum tolerated dose (MTD) of the compound, which is defined as the highest tolerated dose of a chemical substance that can be administered to animals without causing significant toxicity or mortality. The dosage ratio between the maximum tolerated dose and the therapeutic effect (e.g., inhibition of tumor growth) is the therapeutic index. Dosages can vary within this range depending on the dosage form utilized and the route of administration employed. Determination of a therapeutically effective amount is well within the capabilities of those skilled in the art, particularly in view of the detailed disclosure provided herein.

[0120] The therapeutically effective amount of the compounds of the present disclosure required for use in therapy will vary depending on the nature of the condition being treated, the length of time the activity is desired, as well as the age and condition of the patient, and will ultimately be determined by the attending physician. For example, the dosage and interval can be adjusted individually to provide a plasma level of the Nrf2 proteasome inhibitor sufficient to maintain the desired therapeutic effect. The desired dosage may conveniently be administered as a single dose or as multiple divided doses at appropriate intervals, for example, once, twice, three times, four times, or more times per day. Multiple dosing is often desirable or necessary. For example, the compounds of the present disclosure can be delivered once daily for four days (q4d×4) at four-day intervals; four times (q3d×4) at three-day intervals; once daily delivery at five-day intervals (qd×5); once weekly for three weeks (qwk3); a frequency of once daily for five days, a two-day break, once daily again for five days (5 / 2 / 5); or any dosing schedule determined to be appropriate for the situation.

[0121] The compounds of the present disclosure used in the methods of the present disclosure can be administered in amounts of from about 0.005 to about 500 milligrams per dose, from about 0.05 to about 250 milligrams per dose, or from about 0.5 to about 100 milligrams per dose. For example, the compounds of the present disclosure can be administered in amounts of about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 milligrams per dose, which includes all dosages between 0.005 and 500 milligrams.

[0122] The dosage of the composition containing the compound of the present disclosure, or the composition containing the same, can be from about 1 ng / kg to about 200 mg / kg, from about 1 μg / kg to about 100 mg / kg, or from about 1 mg / kg to about 50 mg / kg. The dosage of the composition can be any dosage including but not limited to about 1 μg / kg. The dosage of the composition can be about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg, about 75 μg / kg, about 100 μg / kg, about 125 μg / kg, about 150 μg / kg, about 175 μg / kg, about 200 μg / kg, about 225 μg / kg, about 250 μg / kg, about 275 μg / kg, about 300 μg / kg, about 325 μg / kg, about 350 μg / kg, about 375 μg / kg, about 400 μg / kg, about 425 μg / kg, about 450 μg / kg, about 475 μg / kg, about 500 μg / kg, about 525 μg / kg, about 550 μg / kg, about 575 μg / kg, about 600 μg / kg, about 625 μg / kg, about 650 μg / kg, about 675 μg / kg, about 700 μg / kg, about 725 μg / kg, about 750 μg / kg, about 775 μg / kg, about 800 μg / kg, about 825 μg / kg, about 850 μg / kg, about 875 μg / kg, about 900 μg / kg, about 925 μg / kg, about 950 μg / kg, about 975 μg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg, or any dosage including but not limited to more or less than that. The above dosages are examples of average cases, but in individual cases, a higher or lower dosage may be appropriate, and such cases are within the scope of the present disclosure. In practice, a physician determines the actual dosage regimen most suitable for an individual patient, and the dosage regimen may vary depending on the age, weight, and response of a particular patient.

[0123] As described above, the compounds of the present disclosure can be administered in combination with a second therapeutic agent. In some embodiments, the second therapeutic agent is an epigenetic agent. As used herein, the term "epigenetic agent" refers to a therapeutic agent that targets an epigenetic regulator. Examples of epigenetic regulators include histone lysine methyltransferase, histone arginine methyltransferase, histone demethylase, histone deacetylase, histone acetylase, and DNA methyltransferase. Histone deacetylase inhibitors include, but are not limited to, vorinostat.

[0124] In another embodiment, a chemotherapeutic agent or other anti-proliferative agent can be combined with the compounds of the present disclosure to treat proliferative diseases and cancer. Examples of therapies and anti-cancer agents that can be used in combination with the compounds of the present disclosure include surgery, radiation therapy (e.g., gamma rays, neutron beam radiation therapy, electron beam radiation therapy, proton beam therapy, brachytherapy, and systemic radioisotopes), endocrine therapy, biological response modifiers (e.g., interferons, interleukins, tumor necrosis factor (TNF), hyperthermia, and cryotherapy), agents that reduce adverse effects (e.g., antiemetics), and any other approved chemotherapeutic agents.

[0125] Examples of antiproliferative compounds include, but are not limited to, aromatase inhibitors; antiestrogens; antiandrogens; gonadorelin agonists; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active agents; alkylating agents; retinoids, carotenoids, or tocopherols; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antimetabolites; platinum compounds; methionine aminopeptidase inhibitors; bisphosphonates; antiproliferative antibodies; heparanase inhibitors; Ras oncogene isoform inhibitors; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematological malignancies; Flt-3 inhibitors; Hsp90 inhibitors; kinesin spindle protein inhibitors; MEK inhibitors; antitumor antibiotics; nitrosoureas; compounds that target / decrease the activity of protein kinases or lipid kinases, compounds that target / decrease the activity of protein phosphatases or lipid phosphatases, or any additional antiangiogenic compounds.

[0126] Non-limiting, exemplary aromatase inhibitors include steroids such as atamestane, exemestane, and formestane, and non-steroids such as aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole, and letrozole, but are not limited thereto.

[0127] Non-limiting antiestrogens include tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Antiandrogens include, but are not limited to, bicalutamide. Gonadorelin agonists include, but are not limited to, abarelix, goserelin, and goserelin acetate.

[0128] Exemplary topoisomerase I inhibitors include, but are not limited to, topotecan, gimatecan, irinotecan, camptothecin and its analogs, 9-nitrocamptothecin, and the macromolecular camptothecin conjugate PNU-166148. Topoisomerase II inhibitors include, but are not limited to, anthracyclines such as doxorubicin, daunorubicin, epirubicin, idarubicin, and nemorubicin; anthraquinones such as mitoxantrone and losoxantrone; and podophyllotoxins such as etoposide and teniposide.

[0129] Microtubule active agents include microtubule stabilizing compounds, microtubule destabilizing compounds, and microtubulin polymerization inhibitors, including taxanes such as paclitaxel and docetaxel; vinca alkaloids such as vinblastine, vinblastine sulfate, vincristine, vincristine sulfate, and vinorelbine; discodermolide; colchicine and epothilone and their derivatives, but are not limited thereto.

[0130] Exemplary and non-limiting alkylating agents include cyclophosphamide, ifosfamide, melphalan, and nitrosoureas such as carmustine and lomustine.

[0131] Exemplary and non-limiting cyclooxygenase inhibitors include Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib, rofecoxib, etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acid, such as lumiracoxib.

[0132] Exemplary and non-limiting matrix metalloproteinase inhibitors (“MMP inhibitors”) include peptidomimetic and non-peptidomimetic inhibitors of collagen, tetracycline derivatives, batimastat, marimastat, prinomastat, metastat, BMS-279251, BAY 12-9566, TAA211, MMI270B, and AAJ996.

[0133] Exemplary and non-limiting mTOR inhibitors include compounds such as sirolimus, everolimus, CCI-779, and ABT578 that inhibit mammalian target of rapamycin (mTOR) and possess anti-proliferative activity.

[0134] Exemplary and non-limiting antimetabolites include DNA demethylating compounds such as 5-fluorouracil (5-FU), capecitabine, gemcitabine, 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed.

[0135] Exemplary and non-limiting platinum compounds include carboplatin, cisplatin, cisplatinum, and oxaliplatin.

[0136] Exemplary and non-limiting methionine aminopeptidase inhibitors include benagmid or its derivatives and PPI-2458.

[0137] Exemplary and non-limiting bisphosphonates include etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid.

[0138] Exemplary and non-limiting anti-proliferative antibodies include trastuzumab, trastuzumab-DM1, cetuximab, bevacizumab, rituximab, PR064553, and 2C4. The term "antibody" includes full monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two full antibodies, and antibody fragments as long as they exhibit the desired biological activity.

[0139] Exemplary and non-limiting heparanase inhibitors include compounds such as PI-88 and OGT2115 that target, reduce, or inhibit heparan sulfate degradation.

[0140] As used herein, the term "Ras oncogene isoform inhibitor" such as H-Ras, K-Ras, or N-Ras means a compound that targets, reduces, or inhibits the oncogenic activity of Ras, such as a farnesyltransferase inhibitor such as L-744832, DK8G557, tipifarnib, and lonafarnib.

[0141] Exemplary and non-limiting telomerase inhibitors include compounds such as telomestatin that target, reduce, or inhibit the activity of telomerase, such as compounds that inhibit the telomerase receptor.

[0142] Exemplary and non-limiting proteasome inhibitors include, but are not limited to, bortezomib, and compounds that target, reduce, or inhibit the activity of the proteasome.

[0143] As used herein, the phrase "compound used in the treatment of hematological malignancies" means an FMS-like tyrosine kinase inhibitor (Flt-3R) that is a compound that targets, reduces, or inhibits the activity of the FMS-like tyrosine kinase receptor; interferon, Ι-β-D-arabinofuranosylcytosine (ara-c), and busulfan; and an ALK inhibitor that is a compound that targets, reduces, or inhibits anaplastic lymphoma kinase.

[0144] Exemplary and non-limiting Flt-3 inhibitors include PKC412, midostaurin, staurosporine derivatives, SU11248, and MLN518.

[0145] Exemplary and non-limiting HSP90 inhibitors include compounds that target, decrease, or inhibit the intrinsic ATPase activity of HSP90; or compounds that degrade, target, decrease, or inhibit HSP90 client proteins via the ubiquitin proteasome pathway. Compounds that target, decrease, or inhibit the intrinsic ATPase activity of HSP90 are, in particular, 17-allylamino,17-demethoxygeldanamycin (17AAG), geldanamycin derivatives; other geldamycin-related compounds; radicicol, and compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, such as HDAC inhibitors.

[0146] As used herein, the phrase "compound that targets / reduces protein or lipid kinase activity; or compound that targets / reduces protein or lipid phosphatase activity; or any additional anti-angiogenic compound" refers to protein tyrosine kinase and / or serine and / or threonine kinase inhibitors, or lipid kinase inhibitors, such as: a) compounds that target, reduce, or inhibit the activity of platelet-derived growth factor receptor (PDGFR), such as compounds that target, reduce, or inhibit the activity of PDGFR, such as N-phenyl-2-pyrimidine-amine derivatives like imatinib, SUlOl, SU6668, and GFB-111; b) compounds that target, reduce, or inhibit the activity of fibroblast growth factor receptor (FGFR); c) compounds that target, reduce, or inhibit the activity of insulin-like growth factor receptor I (IGF-IR), such as compounds that target, reduce, or inhibit the activity of IGF-IR; d) compounds that target, reduce, or inhibit the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) compounds that target, reduce, or inhibit the activity of the Axl receptor tyrosine kinase family; f) compounds that target, reduce, or inhibit the activity of the Ret receptor tyrosine kinase; g) compounds that target, reduce, or inhibit the activity of the Kit / SCFR receptor tyrosine kinase, such as imatinib; h) compounds that target, reduce, or inhibit the activity of the c-Kit receptor tyrosine kinase, such as imatinib; i) compounds that target, reduce, or inhibit the activity of members of the c-Abl family, their gene fusion products (such as the Bcr-Abl kinase) and variants, such as N-phenyl-2-pyrimidine-amine derivatives like imatinib or nilotinib; PD180970; AG957; NSC 680410; PD173955; or dasatinib;j) Compounds that target, reduce, or inhibit the activity of protein kinase C (PKC), and members of the Raf serine / threonine kinase family, MEK, SRC, JAK, FAK, PDK1, PKB / Akt, and members of the Ras / MAPK family, and / or members of the cyclin-dependent kinase family (CDK), such as the staurosporine derivatives disclosed in U.S. Patent No. 5,093,330, such as midostaurin; further examples of compounds include UCN-01, safingol, BAY 43-9006, bryostatin 1, perifosine; ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531 / LY379196; isoquinoline compounds; farnesyltransferase inhibitors; PD184352 or QAN697, or AT7519; k) Compounds that target, reduce, or inhibit the activity of protein tyrosine kinases, such as imatinib mesylate, or tyrphostin A23 / RG-50810; AG 99; tyrphostin AG 213; tyrphostin AG 1748; tyrphostin AG 490; tyrphostin B44; tyrphostin B44(+) enantiomer; tyrphostin AG 555; AG 494; tyrphostin AG 556, AG957, and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, adaphostin), etc., tyrphostins; l) Compounds that target, reduce, or inhibit the activity of the epidermal growth factor receptor tyrosine kinase family (EGFR, ErbB2, ErbB3, ErbB4 as homodimers or heterodimers) and their variants, such as CP 358774, ZD 1839, ZM 105180; trastuzumab, cetuximab, gefitinib, erlotinib, OSI-774, Cl-1033, EKB-569, GW-2016, antibodies El.l, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3, and E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; and, m) Compounds that target, reduce, or inhibit the activity of the c-Met receptor are included.;

[0147] Exemplary compounds that target, decrease, or inhibit the activity of protein phosphatase or lipid phosphatase include inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or its derivatives.

[0148] Additional anti-angiogenic compounds include compounds having other mechanisms for activity independent of inhibition of protein kinase or lipid kinase, such as thalidomide and TNP-470.

[0149] Additional non-limiting exemplary chemotherapeutic compounds include daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatinum, PKC412, 6-mercaptopurine (6-MP), fludarabine phosphate, octreotide, SOM230, FTY720, 6-thioguanine, cladribine, 6-mercaptopurine, pentostatin, hydroxyurea, 2-hydroxy-1H-isoindole-1,3-dione derivatives, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate, angiostatin, endostatin, anthranilic acid amide, ZD4190, ZD6474, SU5416, SU6668, bevacizumab, rhuMAb, rhuFab, macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, RPI 4610, bevacizumab, porfimer sodium, anecortave acetate, triamcinolone, hydrocortisone, 11-a-epihydrocortisol, cortisone, 17a-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone, dexamethasone, fluocinolone, plant alkaloids, hormone compounds and / or antagonists, biological response modifiers such as lymphokines or interferons, antisense oligonucleotides or oligonucleotide derivatives, shRNA, and siRNA, and one or more of these can be used in combination with the compounds of the present disclosure.

[0150] Other examples of second therapeutic agents that one or more of which are also combinable with the compounds of the present disclosure include agents for treating Alzheimer's disease such as donepezil and rivastigmine; agents for treating Parkinson's disease such as L-DOPA / carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents for treating multiple sclerosis (MS) such as beta interferon (e.g., AVONEX® and REBIF®), glatiramer acetate, and mitoxantrone; agents for treating asthma such as albuterol and montelukast; agents for treating schizophrenia such as ziprasidone, risperidone, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory agents including immunosuppressive agents such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferon, anticonvulsants, ion channel blockers, riluzole, or anti-Parkinson's disease drugs; agents for treating cardiovascular diseases such as beta blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, or statins; agents for treating liver diseases such as corticosteroids, cholestyramine, interferon, and antiviral agents; agents for treating blood disorders such as corticosteroids, antileukemic agents, or growth factors; or agents for treating immunodeficiency disorders such as gamma globulin, but are not limited thereto.

[0151] In another aspect, the second therapeutic agent is an immune checkpoint inhibitor. Examples of immune checkpoint inhibitors include PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, LAG3 inhibitors, TIM3 inhibitors, cd47 inhibitors, and B7-H1 inhibitors. Thus, in one aspect, the compounds of the present disclosure are administered in combination with an immune checkpoint inhibitor selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, LAG3 inhibitors, TIM3 inhibitors, and cd47 inhibitors.

[0152] In another aspect, the immune checkpoint inhibitor is a programmed cell death (PD-1) inhibitor. PD-1 is a T cell co-inhibitory receptor that plays a central role in the ability of tumor cells to escape the host immune system. Blocking the interaction between PD-1 and its ligand PD-L1 enhances immune function and mediates anti-tumor activity. Examples of PD-1 inhibitors include antibodies that specifically bind to PD-1. Specific anti-PD-1 antibodies include, but are not limited to, nivolumab, pembrolizumab, STI-A1014, and pidilizumab. For the availability, production methods, mechanisms of action, and general considerations of clinical studies of anti-PD-1 antibodies, see U.S. 2013 / 0309250, U.S. 6,808,710, U.S. 7,595,048, U.S. 8,008,449, U.S. 8,728,474, U.S. 8,779,105, U.S. 8,952,136, U.S. 8,900,587, U.S. 9,073,994, U.S. 9,084,776, and Naido et al., British Journal of Cancer 111:2214-19 (2014).

[0153] In another aspect, the immune checkpoint inhibitor is a PD-L1 (also known as B7-H1 or CD274) inhibitor. Examples of PD-L1 inhibitors include antibodies that specifically bind to PD-L1. Specific anti-PD-L1 antibodies include, but are not limited to, avelumab, atezolizumab, durvalumab, and BMS-936559. For availability, production methods, mechanisms of action, and general considerations in clinical studies, see U.S. 8,217,149, U.S. 2014 / 0341917, U.S. 2013 / 0071403, WO 2015036499, and Naido et al., British Journal of Cancer 111:2214-19 (2014).

[0154] In another aspect, the immune checkpoint inhibitor is a CTLA-4 inhibitor. CTLA-4, also known as cytotoxic T lymphocyte antigen 4, is a protein receptor that downregulates the immune system. CTLA-4 has been characterized as a "brake" that binds to co-stimulatory molecules on antigen-presenting cells, prevents interaction with CD28 on T cells, and also generates an overly inhibitory signal that restricts T cell activation. Examples of CTLA-4 inhibitors include antibodies that specifically bind to CTLA-4. Specific anti-CTLA-4 antibodies include, but are not limited to, ipilimumab and tremelimumab. For availability, production methods, mechanisms of action, and general considerations in clinical studies, see U.S. 6,984,720, U.S. 6,207,156, and Naido et al., British Journal of Cancer 111:2214-19 (2014).

[0155] In another aspect, the immune checkpoint inhibitor is a LAG3 inhibitor. LAG3, lymphocyte activation gene 3, is a negative co-stimulatory receptor that modulates T cell homeostasis, proliferation, and activation. Additionally, LAG3 has been reported to be involved in regulatory T cell (Treg) suppression function. Most of the LAG3 molecule is retained near the intracellular microtubule organizing center and is induced only after antigen-specific T cell activation. U.S. 2014 / 0286935. Examples of LAG3 inhibitors include antibodies that specifically bind to LAG3. Specific anti-LAG3 antibodies include, but are not limited to, GSK2831781. For availability, production methods, mechanism of action, and general considerations of research, see U.S. 2011 / 0150892, U.S. 2014 / 0093511, U.S. 20150259420, and Huang et al., Immunity 21:503-13 (2004).

[0156] In another aspect, the immune checkpoint inhibitor is a TIM3 inhibitor. TIM3 (T cell immunoglobulin and mucin domain 3) is a H T C 1 and T +Since it is expressed in T cells and Tregs, it is considered a target for cancer immunotherapy. Anderson, Cancer Immunology Research 2:393-98 (2014). Examples of TIM3 inhibitors include antibodies that specifically bind to TIM3. For the availability, production methods, mechanisms of action, and general considerations of TIM3 inhibitors, see U.S. 20150225457, U.S. 20130022623, U.S. 8,522,156, Ngiow et al., Cancer Res 71: 6567-71 (2011), Ngiow, et al., Cancer Res 71:3540-51 (2011), and Anderson, Cancer Immunology Res 2:393-98 (2014).

[0157] In another aspect, the immune checkpoint inhibitor is a cd47 inhibitor. See Unanue, E.R., PNAS 110:10886-87 (2013).

[0158] The term "antibody" shall include full monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two full antibodies, and antibody fragments, as long as they exhibit the desired biological activity. In another aspect, "antibody" shall include soluble receptors that do not possess the Fc portion of the antibody. In one aspect, the antibody is a humanized monoclonal antibody and its fragments produced by recombinant genetic engineering.

[0159] Another class of immune checkpoint inhibitors includes polypeptides that bind to and block the PD-1 receptor on T cells without inducing inhibitory signaling. Such peptides include B7-DC polypeptides, B7-H1 polypeptides, B7-1 polypeptides, and B7-2 polypeptides, as well as their soluble fragments, as disclosed in U.S. Patent No. 8,114,845.

[0160] Another class of immune checkpoint inhibitors includes compounds having a peptide moiety that inhibits PD-1 signaling. Examples of such compounds are disclosed in U.S. Patent No. 8,907,053.

[0161] Another class of immune checkpoint inhibitors includes inhibitors of certain metabolic enzymes such as indoleamine 2,3-dioxygenase (IDO) expressed by infiltrating myeloid cells and tumor cells. The IDO enzyme inhibits the immune response by depleting the amino acids necessary for assimilation in T cells or through the synthesis of specific natural ligands for cytosolic receptors that can modify lymphocyte function. Pardoll, Nature Reviews. Cancer 12:252-64 (2012); Lob, Cancer Immunol Immunother 58:153-57 (2009). Specific IDO inhibitors include, but are not limited to, levo-1-methyltryptophan (L-1MT) and 1-methyl-tryptophan (1MT). Qian et al., Cancer Res 69:5498-504 (2009); and Lob et al., Cancer Immunol Immunother 58:153-7 (2009).

[0162] In one aspect, the immune checkpoint inhibitor is nivolumab, pembrolizumab, pidilizumab, STI-A1110, avelumab, atezolizumab, durvalumab, STI-A1014, ipilimumab, tremelimumab, GSK2831781, BMS-936559, or MED14736.

[0163] Other examples of a second therapeutic agent, one or more of which are also combinable with the compounds of the present disclosure, include glutamine antagonists. Suitable glutamine antagonists are disclosed, for example, in WO 2017 / 023774 and WO 2019 / 071110. Specific glutamine antagonists include isopropyl (S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)propanamide)-6-diazo-5-oxohexanoate, or a pharmaceutically acceptable salt thereof, isopropyl (S)-2-((S)-6-acetamido-2-((3S,5S,7S)-adamantane-1-carboxamido)hexanamide)-6-diazo-5-oxohexanoate, or a pharmaceutically acceptable salt thereof, (S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)propanamide)-6-diazo-5-oxohexanoic acid, or a pharmaceutically acceptable salt thereof, or 6-diazo-5-oxo-L-norleucine, or a pharmaceutically acceptable salt thereof, but are not limited thereto.

[0164] In one aspect, the second therapeutic agent comprises one of the anti-cancer drugs or combinations of anti-cancer drugs listed in Table 6.

[0165] [Table 6] TIFF2025523575000047.tif238155TIFF2025523575000048.tif238155TIFF2025523575000049.tif228155TIFF2025523575000050.tif232155TIFF2025523575000051.tif232155TIFF2025523575000052.tif233155TIFF2025523575000053.tif104155

[0166] For more detailed descriptions of the anticancer agent and other optional therapeutic agents, those skilled in the art are referred to a number of reference books including, but not limited to, Physician's Desk Reference and Goodman and Gilman's "Pharmaceutical Basis of Therapeutics" tenth edition, Eds. Hardman et al., 2002.

[0167] The second therapeutic active agent, one or more of which can be used in combination with the compounds of the present disclosure, is prepared and administered as described in the art.

[0168] The compounds of the present disclosure are typically administered as a mixture with a pharmaceutical carrier selected with respect to the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions used in accordance with the present disclosure are formulated in the conventional manner using one or more physiologically acceptable carriers including excipients and / or auxiliaries which facilitate the processing of the compounds of the present disclosure.

[0169] These pharmaceutical compositions can be manufactured, for example, by conventional processes of mixing, dissolving, granulating, tablet-making, emulsifying, encapsulating, entrapping, or lyophilizing. Appropriate formulation depends on the selected route of administration. When a therapeutically effective amount of the compound of the present disclosure is administered orally, the composition is typically in the form of tablets, capsules, powders, solutions, or elixirs. The composition may further contain a solid carrier such as gelatin or an adjuvant when administered in tablet form. Tablets, capsules, and powders contain from about 0.01% to about 95%, preferably from about 1% to about 50% of the compound of the present disclosure. When administered in liquid form, a liquid carrier such as water, petroleum, or oils of animal or plant origin may be added. The liquid form of the composition may further contain physiological saline, a solution of glucose or other sugars, or glycols. The composition contains from about 0.1% by weight to about 90% by weight, preferably from about 1% by weight to about 50% by weight of the compound of the present disclosure when administered in liquid form.

[0170] When a therapeutically effective amount of a compound of the present disclosure is administered by intravenous injection, dermal injection, or subcutaneous injection, the composition is in the form of a parenterally acceptable pyrogen-free aqueous solution. Preparation of such parenterally acceptable solutions, taking into account pH, isotonicity, stability, etc., is within the scope of skill in the art. Compositions preferred for intravenous injection, dermal injection, or subcutaneous injection typically contain an isotonic vehicle.

[0171] The compounds of the present disclosure can be readily combined with pharmaceutically acceptable carriers well known in the art. Standard pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed. 1995. Such carriers enable the active agent to be formulated as tablets, pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions, etc. for oral ingestion by the patient to be treated. Oral pharmaceutical formulations can be obtained by adding a compound of the present disclosure to a solid excipient, optionally grinding the resulting mixture, and processing the granule mixture to obtain tablets or dragee cores, after adding suitable auxiliaries if desired.

[0172] Suitable excipients include, for example, bulking agents such as saccharides (e.g., lactose, sucrose, mannitol or sorbitol), cellulose preparations, calcium phosphates (e.g., tricalcium phosphate or calcium hydrogen phosphate), and binding agents such as starch paste (e.g., using corn starch, wheat starch, rice starch, or potato starch), gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone. Optionally, one or more disintegrants such as the aforementioned starch, and further carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or salts thereof such as alginic acid or sodium alginate can be added. Buffering agents and pH regulators can also be added to stabilize the pharmaceutical composition.

[0173] Auxiliaries typically include suitable flow control agents and lubricants such as silica, talc, stearic acid or its salts (e.g., magnesium stearate or calcium stearate), and polyethylene glycol. The sugar-coated tablet core is provided with a suitable coating that is resistant to gastric juice, if desired. For this purpose, a concentrated sugar solution that may optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture can be used. To produce a coating resistant to gastric juice, a solution of a suitable cellulose preparation such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate can be used. For example, dyes or pigments can be added to the tablets or sugar-coated tablet cores for identification or for characterizing combinations of doses of the active compound.

[0174] The compounds of the present disclosure can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Injectable formulations can be presented in unit dosage forms, for example, in ampoules or multi-dose containers, together with added preservatives. The composition can take the form of, for example, a suspension, solution, or emulsion in an oily or aqueous vehicle, and can contain formulating agents such as suspending agents, stabilizers, and / or dispersing agents.

[0175] Examples of pharmaceutical compositions for parenteral administration include aqueous solutions of the active agent in water-soluble form. Furthermore, suspensions of the compounds of the present disclosure can be prepared as suitable oily injectable suspensions. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. Injectable aqueous suspensions may contain substances that increase the viscosity of the suspension. Optionally, the suspension may also contain suitable stabilizers, or agents that increase the solubility of the compound and enable the preparation of highly concentrated solutions. Alternatively, the composition may be in powder form that is constituted before use with a suitable vehicle, for example, sterile pyrogen-free water.

[0176] The compounds of the present disclosure can also be formulated as rectal compositions, such as suppositories or retention enemas, for example, containing conventional suppository bases. In addition to the formulations already described, the compounds of the present disclosure can also be formulated as depot formulations. Such long-acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the present disclosure can be formulated using suitable polymeric materials or hydrophobic materials (for example, as an emulsion in an acceptable oil) or using ion exchange resins.

[0177] In particular, the compounds of the present disclosure can be administered orally, buccally, or sublingually in the form of tablets containing excipients such as starch or lactose, or in the form of capsules or ovules, either alone or as a mixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. Such liquid formulations can be prepared using pharmaceutically acceptable additives such as suspending agents. The compounds of the present disclosure can also be administered parenterally, for example, by intravenous injection, intramuscular injection, subcutaneous injection, or intracoronary injection. For parenteral administration, the compounds of the present disclosure are usually used in the form of a sterile aqueous solution, which may contain other substances for making the solution isotonic with blood, such as salts, or monosaccharides such as mannitol or glucose.

[0178] The present disclosure provides the following specific aspects regarding treating a disease in a subject with the compounds of the present disclosure.

[0179] Aspect I. A method of treating a subject, the method comprising the step of administering to the subject a therapeutically effective amount of a compound of the present disclosure, wherein the subject has cancer, a neurodegenerative disease, diabetes, a cardiovascular disease, a kidney disease, or a liver disease.

[0180] Aspect II. The method according to Aspect I, wherein the subject has cancer, for example, any one or more of the cancers in Table 2 or Table 3.

[0181] Aspect III. The method according to Aspect II, wherein the cancer is prostate cancer or breast cancer.

[0182] Aspect IV. The method according to Aspect II, wherein the cancer is lung cancer, for example, NSCLC.

[0183] Aspect V. The method according to Aspect II, wherein the cancer is prostate cancer, for example, metastatic castration-resistant prostate cancer.

[0184] Aspect VI. The method according to any one of Aspects I - V, further comprising the step of administering a therapeutically effective amount of a second therapeutic agent useful for treating a disease or condition, such as an immune checkpoint inhibitor or other anti - cancer agent.

[0185] Aspect VII. A pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient.

[0186] Aspect VIII. The pharmaceutical composition according to Aspect VII, for use in the treatment of cancer, neurodegenerative disease, diabetes, cardiovascular disease, kidney disease, or liver disease.

[0187] Aspect IX. The pharmaceutical composition according to Aspect VIII, wherein the cancer is prostate cancer or breast cancer.

[0188] Aspect X. The pharmaceutical composition according to Aspect VIII, wherein the cancer is lung cancer, such as NSCLC.

[0189] Aspect XI. The pharmaceutical composition according to Aspect VIII, wherein the cancer is prostate cancer, such as metastatic castration - resistant prostate cancer.

[0190] Aspect XII. A compound of the present disclosure for use in the treatment of cancer, neurodegenerative disease, diabetes, cardiovascular disease, kidney disease, or liver disease.

[0191] Aspect XIII. A compound according to Aspect XIII for use in the treatment of cancer.

[0192] Aspect XIV. A compound according to Aspect XIII, wherein the cancer is breast cancer or lung cancer, such as NSCLC.

[0193] Aspect XV. A compound according to Aspect XIII, wherein the cancer is prostate cancer, such as metastatic castration - resistant prostate cancer.

[0194] Aspect XVI. Use of a compound of the present disclosure for the manufacture of a medicament for the treatment of cancer, neurodegenerative disease, diabetes, cardiovascular disease, kidney disease, or liver disease.

[0195] Aspect XVII. Use according to Aspect XVI for the treatment of cancer.

[0196] Aspect XVIII. Use according to Aspect XVII, wherein the cancer is prostate cancer or breast cancer.

[0197] Aspect XIV. Use according to Aspect XVII, wherein the cancer is lung cancer, such as NSCLC.

[0198] Aspect XX. Use according to Aspect XVII, wherein the cancer is prostate cancer, such as metastatic castration-resistant prostate cancer.

[0199] Aspect XXI. A method for reducing Nrf2 protein in the cells of a subject in need thereof, the method comprising administering a compound of the present disclosure to the subject. In one aspect, the Nrf2 protein is reduced by about 50% or less, for example, 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or about 45%. In one aspect, the Nrf2 protein is reduced by about 51% or more, for example, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%.

[0200] Aspect XXII. The method according to Aspect I or VI, wherein the subject has a neurodegenerative disease.

[0201] Aspect XXIII. The method according to Aspect I or VI, wherein the subject has diabetes.

[0202] Aspect XXIV. The method according to Aspect I or VI, wherein the subject has a cardiovascular disease.

[0203] Aspect XXV. The method according to Aspect I or VI, wherein the subject has a kidney disease.

[0204] Aspect XXVI. The method according to Aspect I or VI, wherein the subject has a liver disease.

[0205] Aspect XXVII. The pharmaceutical composition according to Aspect VIII, wherein the subject has a neurodegenerative disease.

[0206] Aspect XXVIII. The pharmaceutical composition according to aspect VIII, wherein the subject has diabetes.

[0207] Aspect XXIX. The pharmaceutical composition according to aspect VIII, wherein the subject has a cardiovascular disease.

[0208] Aspect XXX. The pharmaceutical composition according to aspect VIII, wherein the subject has a kidney disease.

[0209] Aspect XXXI. The pharmaceutical composition according to aspect VIII, wherein the subject has a liver disease.

[0210] Aspect XXXII. The compound according to aspect XII, wherein the subject has a neurodegenerative disease.

[0211] Aspect XXXIII. The compound according to aspect XII, wherein the subject has diabetes.

[0212] Aspect XXXIV. The compound according to aspect XII, wherein the subject has a cardiovascular disease.

[0213] Aspect XXXV. The compound according to aspect XII, wherein the subject has a kidney disease.

[0214] Aspect XXXVI. The compound according to aspect XII, wherein the subject has a liver disease.

[0215] Aspect XXXVII. The use according to aspect XVI, wherein the subject has a neurodegenerative disease.

[0216] Aspect XXXVIII. The use according to aspect XVI, wherein the subject has diabetes.

[0217] Aspect XXXIX. The use according to aspect XVI, wherein the subject has a cardiovascular disease.

[0218] Aspect XL. The use according to aspect XVI, wherein the subject has a kidney disease.

[0219] Aspect XLI. The use according to aspect XVI, wherein the subject has a liver disease.

[0220] III. Kits of the Present Disclosure In another aspect, the present disclosure provides a kit comprising a compound of the present disclosure (or a composition comprising a compound of the present disclosure), wherein the compound or composition is packaged to facilitate its use for practicing the methods of the present disclosure. In one aspect, the kit comprises a compound of the present disclosure (or a composition comprising a compound of the present disclosure) packaged in a container such as a sealed bottle or a sealed container, and a label describing the use of the compound or composition for practicing the methods of the present disclosure is affixed to the container or included in the kit. In one aspect, the compound or composition is packaged in a unit dosage form. The kit may further comprise an apparatus suitable for administering the composition according to a desired route of administration.

[0221] IV. Definitions The term “disease or condition in which degradation of Nrf2 provides a benefit” refers to a disease or condition in which Nrf2 is important or required, for example, for the development, progression, or appearance of the disease or condition, or a disease or condition known to be treated by an Nrf2 inhibitor or degrader. Examples of such diseases or conditions include, but are not limited to, cancer, neurodegenerative diseases, diabetes, cardiovascular diseases, kidney diseases, or liver diseases. Dodson et al., Annu Rev Pharmacol Toxicol 59:555-575 (2019). One of ordinary skill in the art can readily determine whether a particular compound treats a disease or condition mediated by an Nrf2 degrader for any particular cell type, for example, by an assay conveniently available for evaluating the activity of the particular compound.

[0222] The term “Nrf2 degrader” refers to a heterobifunctional small molecule that degrades the Nrf2 protein. An Nrf2 degrader contains a first ligand that binds to the Nrf2 protein, a second ligand for an E3 ligase system, and a chemical linker that connects the first ligand and the second ligand. Representative compounds of the present disclosure that degrade the Nrf2 protein are disclosed in Table 1.

[0223] The term "second therapeutic agent" refers to a therapeutic agent that is different from the compounds of the present disclosure and is known to treat the disease or condition of interest. For example, if cancer is the disease or condition of interest, the second therapeutic agent can be, for example, a known chemotherapeutic agent such as taxol, or radiation.

[0224] The term "disease" or "condition" generally refers to a disorder and / or abnormality that is considered to be a pathological condition or function and can manifest in the form of specific signs, symptoms, and / or dysfunctions. The compounds of the present disclosure are Nrf2 degraders and can be used in treating or preventing diseases and conditions in which degradation of Nrf2 provides a benefit.

[0225] As used herein, the terms "treating," "treatment," "treat," etc. refer to removing, reducing, or alleviating a disease or condition and / or symptoms associated therewith. Treating a disease or condition does not necessarily mean completely eliminating the disease, condition, or associated symptoms, but it does not require that either. The term "treating" and synonyms thereof contemplate administering a therapeutically effective amount of the compounds of the present disclosure to a subject in need of such treatment. For example, treatment can be tailored to the symptoms to suppress them. Treatment can be carried out for a short period, adapted for an intermediate period, or, for example, be long-term treatment within the scope of maintenance therapy.

[0226] As used herein, the terms "prevent", "preventing", and "prevention" refer to a method of preventing the onset of a disease or condition and / or its attendant symptoms, or of preventing a subject from contracting a disease. As used herein, the terms "prevent", "preventing", and "prevention" also include delaying the onset of a disease and / or its attendant symptoms, and reducing the risk that a subject will contract a disease. The terms "prevent", "preventing", and "prevention" can include "preventive treatment", which refers to reducing the likelihood of recurrence of a disease or condition, or reducing the likelihood of reappearance of a disease or condition, in a subject who does not have the disease or condition but is at risk of or is likely to experience recurrence of the disease or condition.

[0227] As used herein, the term "therapeutically effective amount" or "effective amount" refers to an amount of an active ingredient that is sufficient to effectively deliver an active ingredient for the treatment of a condition or disease of interest to a subject in need thereof when administered by the methods of the present disclosure. In the case of cancer or other proliferative disorders, a therapeutically effective amount of an agent reduces unwanted cell proliferation (i.e., delays or stops it to some extent); reduces the number of cancer cells; reduces the size of a tumor; inhibits cancer cell infiltration into peripheral organs (i.e., delays or stops it to some extent); inhibits tumor metastasis (i.e., delays or stops it to some extent); inhibits tumor growth to some extent; and / or can alleviate one or more symptoms associated with cancer to some extent. A compound or composition administered can be cytostatic and / or cytotoxic to the extent that it prevents and / or kills the growth of existing cancer cells.

[0228] The term "container" means any receptacle and closure suitable for the storage, transport, dispensing, and / or handling of a drug.

[0229] The term "package insert" means the information attached to a drug, which shows a description of how to administer the drug, along with the safety and efficacy data necessary to enable physicians, pharmacists, and patients to make informed decisions regarding the use of the drug. Generally, the package insert is regarded as the "label" for the drug.

[0230] The terms "co-administered", "administered in combination", "simultaneously administered", and like terms mean that two or more agents are administered to a subject in the same period. "In the same period" means that the agents are administered simultaneously or sequentially in any order at different times. However, if not administered simultaneously, these agents are intended to be administered to the subject sequentially and at sufficiently short time intervals so as to obtain the desired therapeutic effect and act in concert. For example, the compounds of the present disclosure can be administered simultaneously with a second therapeutic agent or sequentially in any order at different times from the second therapeutic agent. The compounds of the present disclosure and the second therapeutic agent can be administered separately in any suitable form and by any suitable route. When the compounds of the present disclosure and the second therapeutic agent are not co-administered, they are understood to be administrable to a subject in need thereof in any order. For example, the administration of the compounds of the present disclosure to a subject in need thereof can be performed before (e.g., 5 minutes before, 15 minutes before, 30 minutes before, 45 minutes before, 1 hour before, 2 hours before, 4 hours before, 6 hours before, 12 hours before, 24 hours before, 48 hours before, 72 hours before, 96 hours before, 1 week before, 2 weeks before, 3 weeks before, 4 weeks before, 5 weeks before, 6 weeks before, 8 weeks before, or 12 weeks before), simultaneously with, or after (e.g., 5 minutes after, 15 minutes after, 30 minutes after, 45 minutes after, 1 hour after, 2 hours after, 4 hours after, 6 hours after, 12 hours after, 24 hours after, 48 hours after, 72 hours after, 96 hours after, 1 week after, 2 weeks after, 3 weeks after, 4 weeks after, 5 weeks after, 6 weeks after, 8 weeks after, or 12 weeks after) the implementation of the treatment modality (e.g., radiation therapy) of the second therapeutic agent. In various embodiments, the compounds of the present disclosure and the second therapeutic agent are administered 1 minute apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 hour apart, 1-2 hours apart, 2-3 hours apart, 3-4 hours apart, 4-5 hours apart, 5-6 hours apart, 6-7 hours apart, 7-8 hours apart, 8-9 hours apart, 9-10 hours apart, 10-11 hours apart, 11-12 hours apart, less than 24 hours apart, or less than 48 hours apart. In one embodiment, the components of the combination therapy are administered about 1 minute to about 24 hours apart.

[0231] The use of the terms "a", "an", "the", and similar indicatives in the description of the present disclosure (especially in the claims) should be construed to cover both the singular and the plural unless otherwise indicated. The recitation of a range of values herein is intended solely as a shorthand way of referring individually to each value within the range, and each value is incorporated herein as if it were individually recited herein, unless otherwise indicated herein. The use of any examples, or exemplary syntax (e.g., "such as") presented herein is intended to better illustrate the present disclosure and should not be construed as limiting the scope of the present disclosure unless otherwise claimed. No syntax herein should be construed to indicate that any non-claimed element is essential to the practice of the present disclosure.

[0232] As used herein, the term "halo", used by itself or as part of another group, refers to -Cl, -F, -Br, or -I.

[0233] As used herein, the term "nitro", used by itself or as part of another group, refers to -NO2.

[0234] As used herein, the term "cyano", used by itself or as part of another group, refers to -CN.

[0235] As used herein, the term "hydroxy", used by itself or as part of another group, refers to -OH.

[0236] As used herein, the term "alkyl", used by itself or as part of another group, refers to a straight or branched chain aliphatic hydrocarbon containing from 1 to 12 carbon atoms, i.e., C1-C 12 alkyl, or a straight or branched chain aliphatic hydrocarbon containing a predetermined number of carbon atoms, e.g., C1 alkyl such as methyl, C2 alkyl such as ethyl, etc. In one aspect, alkyl is C1-C10 is alkyl. In another embodiment, the alkyl is C1-C6 alkyl. In another embodiment, the alkyl is C1-C4 alkyl. In another embodiment, the alkyl is C1-C3 alkyl, i.e., methyl, ethyl, propyl, or isopropyl. Non-limiting and exemplary C1-C 12 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl.

[0237] As used herein, the term "optionally substituted alkyl" used by itself or as part of another group refers to an alkyl group that is unsubstituted or substituted with one, two, or three substituents, where each substituent is independently nitro, haloalkoxy, aryloxy, aralkyloxy, alkylthio, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carbamate, carboxy, alkoxycarbonyl, carboxyalkyl, -N(R 56a )C(=O)R 56b 、-N(R 56c )S(=O)2R 56d 、-C(=O)R 57 、-S(=O)R 56e 、or -S(=O)2R 58 ; where: R 56a is hydrogen or alkyl; R 56b is alkyl, haloalkyl, optionally substituted cycloalkyl, alkoxy, (alkoxy)alkyl, (aryl)alkyl, (heteroaryl)alkyl, (amino)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted C6-C 10 aryl, or optionally substituted heteroaryl; R56c is hydrogen or alkyl; R 56d is alkyl, haloalkyl, optionally substituted cycloalkyl, alkoxy, (alkoxy)alkyl, (aryl)alkyl, (heteroaryl)alkyl, (amino)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted C6-C 10 aryl, or optionally substituted heteroaryl; R 56e is alkyl, haloalkyl, optionally substituted cycloalkyl, alkoxy, (alkoxy)alkyl, (aryl)alkyl, (heteroaryl)alkyl, (amino)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted C6-C 10 aryl, or optionally substituted heteroaryl; R 57 is haloalkyl, optionally substituted cycloalkyl, alkoxy, (alkoxy)alkyl, (aryl)alkyl, (heteroaryl)alkyl, (amino)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, or optionally substituted heteroaryl; and R 58is haloalkyl, optionally substituted cycloalkyl, alkoxy, (alkoxy)alkyl, (aryl)alkyl, (heteroaryl)alkyl, (amino)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, or optionally substituted heteroaryl. Non-limiting exemplary optionally substituted alkyl groups include -CH(CO2Me)CH2CO2Me and -CH(CH3)CH2N(H)C(=O)O(CH3)3.

[0238] As used herein, the term "alkenyl" by itself or as part of another group refers to an alkyl group containing one, two, or three carbon-carbon double bonds. In one embodiment, the alkenyl group is a C2-C6 alkenyl group. In another embodiment, the alkenyl group is a C2-C4 alkenyl group. In another embodiment, the alkenyl group has one carbon-carbon double bond. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0239] As used herein, either by itself or as part of another entity, the term "optionally substituted alkenyl" refers to an alkenyl group that is unsubstituted or substituted with one, two, or three substituents, where each substituent is independently halo, nitro, cyano, hydroxy, amino (e.g., alkylamino, dialkylamino), haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamide, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycle. A non-limiting, exemplary optionally substituted alkenyl group is -CH=CHPh.

[0240] As used herein, either by itself or as part of another group, the term "alkynyl" refers to an alkyl group containing one, two, or three carbon-carbon triple bonds. In one aspect, alkynyl is C2-C6 alkynyl. In another aspect, alkynyl is C2-C4 alkynyl. In another aspect, alkynyl has one carbon-carbon triple bond. Non-limiting, exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.

[0241] As used herein, either by itself or as part of another group, the term "optionally substituted alkynyl" refers to an alkynyl group that is unsubstituted or substituted with one, two, or three substituents, where each substituent is independently halo, nitro, cyano, hydroxy, amino, for example, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamide, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycle. Non-limiting and exemplary optionally substituted alkynyl groups include -C≡CPh and -CH(Ph)C≡CH.

[0242] As used herein, either by itself or as part of another group, the term "haloalkyl" refers to an alkyl group substituted with one or more fluorine, chlorine, bromine, and / or iodine atoms. In one aspect, the alkyl is substituted with one, two, or three fluorine and / or chlorine atoms. In another aspect, the alkyl is substituted with one, two, or three fluorine atoms. In another aspect, the alkyl is C1-C6 alkyl. In another aspect, the alkyl is C1-C4 alkyl. In another aspect, the alkyl group is C1 or C2 alkyl. Non-limiting and exemplary haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and trichloromethyl groups.

[0243] As used herein, the term "hydroxyalkyl" or "(hydroxy)alkyl", either by itself or as part of another group, refers to an alkyl group substituted with one, two, or three hydroxy groups. In one embodiment, the alkyl is C1-C6 alkyl. In another embodiment, the alkyl is C1-C4 alkyl. In another embodiment, the alkyl is C1 or C2 alkyl. In another embodiment, the hydroxyalkyl is a monohydroxyalkyl group, i.e., substituted with one hydroxy group. In another embodiment, the hydroxyalkyl group is a dihydroxyalkyl group, i.e., substituted with two hydroxy groups. Non-limiting and exemplary (hydroxyl)alkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl groups, such as 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-1-methylpropyl, and 1,3-dihydroxyprop-2-yl.

[0244] As used herein, the term "alkoxy", either by itself or as part of another group, refers to an alkyl group bonded to a terminal oxygen atom. In one embodiment, the alkyl is C1-C6 alkyl, and the resulting alkoxy is thus referred to as "C1-C6 alkoxy". In another embodiment, the alkyl is a C1-C4 alkyl group. Non-limiting and exemplary alkoxy groups include methoxy, ethoxy, and tert-butoxy.

[0245] As used herein, the term "haloalkoxy", either by itself or as part of another group, refers to a haloalkyl group bonded to a terminal oxygen atom. In one embodiment, the haloalkyl group is C1-C6 haloalkyl. In another embodiment, the haloalkyl group is C1-C4 haloalkyl group. Non-limiting and exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

[0246] As used herein, either alone or as part of another group, the term "alkylthio" refers to an alkyl group bonded to a terminal sulfur atom. In one embodiment, the alkyl group is a C1-C4 alkyl group. Non-limiting and exemplary alkylthio groups include -SCH3 and -SCH2CH3.

[0247] As used herein, either alone or as part of another group, the term "alkoxyalkyl" or "(alkoxy)alkyl" refers to an alkyl group substituted with one alkoxy group. In one embodiment, the alkoxy is C1-C6 alkoxy. In another embodiment, the alkoxy is C1-C4 alkoxy. In another embodiment, the alkyl is C1-C6 alkyl. In another embodiment, the alkyl is C1-C4 alkyl. Non-limiting and exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, iso-propoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl, tert-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, and pentyloxymethyl.

[0248] The term "heteroalkyl," as used herein by itself or as part of another group, refers to an unsubstituted straight or branched chain aliphatic hydrocarbon containing 3 to 12 chain atoms, i.e., C3-C20 heteroalkyl, or an unsubstituted straight or branched chain aliphatic hydrocarbon containing a predetermined number of chain atoms, wherein at least one -CH2- is replaced by at least one of -O-, -N(H)-, -N(C1-C4 alkyl)-, or -S-. The -O-, -N(H)-, -N(C1-C4 alkyl)-, and -S- groups can be independently located at any position of the aliphatic hydrocarbon chain, provided that each -O-, -N(H)-, -N(C1-C4 alkyl)-, and -S- group is separated from the others by at least two -CH2- groups. In one embodiment, one -CH2- group is replaced by one -O- group. In another embodiment, two -CH2- groups are replaced by two -O- groups. In another embodiment, three -CH2- groups are replaced by three -O- groups. In another embodiment, four -CH2- groups are replaced by four -O- groups. In another embodiment, one -CH2- group is replaced by one -NH- group. Non-limiting and exemplary heteroalkyl groups include CH2OCH3, -CH2OCH2CH2CH3, -CH2CH2CH2OCH3, -NHCH2CH2OCH2CH2OCH2CH3, -CH2CH2OCH2CH2OCH2CH3, -CH2CH2OCH2CH2OCH2CH2OCH2CH3, and -NHCH2CH2CH2CH3.

[0249] The term "cycloalkyl," as used herein by itself or as part of another group, refers to saturated and partially unsaturated (e.g., containing one or two double bonds) monocyclic, bicyclic, or tricyclic aliphatic hydrocarbons containing 3 to 12 carbon atoms, i.e., C 3~12Cycloalkyl, or a saturated and partially unsaturated (e.g., containing 1 or 2 double bonds) monocyclic, bicyclic, or tricyclic aliphatic hydrocarbon containing a predetermined number of carbons, e.g., C3 cycloalkyl such as cyclopropyl, C4 cycloalkyl such as cyclobutyl, etc. In one aspect, the cycloalkyl is bicyclic, i.e., it has 2 rings. In another aspect, the cycloalkyl is monocyclic, i.e., it has 1 ring. In another aspect, the cycloalkyl is C 3~8 cycloalkyl. In another aspect, the cycloalkyl is C 3~6 cycloalkyl, i.e., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In another aspect, the cycloalkyl is C5 cycloalkyl, i.e., cyclopentyl or cyclopentenyl. In another aspect, the cycloalkyl is C6 cycloalkyl, i.e., cyclohexyl or cyclohexenyl. Non-limiting and exemplary C 3~12 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, and spiro[3.3]heptane.

[0250] As used herein, either by itself or as part of another group, the term "optionally substituted cycloalkyl" refers to a cycloalkyl group that is unsubstituted or substituted with one, two, or three substituents, where each substituent is independently halo, nitro, cyano, hydroxy, amino (e.g., -NH2, alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino, or (heterocyclo)alkylamino), heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamide, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, (cyano)alkyl, (carboxamide)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, -N(R 56a )C(=O)R 56b , -N(R 56c )S(=O)2R 56d , -C(=O)R 57 , -S(=O)R 56e , -S(=O)2R 58 , or -OR 59 , where R 56a , R 56b , R 56c , R 56d , R 56e , R 57 , and R 58 are as defined with respect to the term "optionally substituted alkyl", and R 59 is (hydroxy)alkyl or (amino)alkyl. The term "optionally substituted cycloalkyl" also includes a cycloalkyl group having a fused optionally substituted aryl group or optionally substituted heteroaryl group, e.g., It includes TIFF2025523575000054.tif19128.

[0251] As used herein, the term "heterocycle", either by itself or as part of another group, refers to saturated and partially unsaturated (e.g., containing one or two double bonds) monocyclic, bicyclic, or tricyclic groups containing 3 to 18 ring members, including 1, 2, 3, or 4 heteroatoms, i.e., 3- to 18-membered heterocycles. Each heteroatom is independently oxygen, sulfur, or nitrogen. Each sulfur atom is independently oxidized to give a sulfoxide, i.e., S(=O), or a sulfone, i.e., S(=O)2. The term "heterocycle" includes groups in which one or more -CH2- groups are replaced by one or more -C(=O)- groups, including cyclic ureido groups, e.g., imidazolidinyl-2-one, cyclic amide groups, e.g., pyrrolidin-2-one or piperidin-2-one, and cyclic carbamate groups, e.g., oxazolidinyl-2-one. The term "heterocycle" also includes groups having a fused optionally substituted aryl or optionally substituted heteroaryl group, e.g., indoline, indolin-2-one, 2,3-dihydro-1H-pyrrolo[2,3-c]pyridine, 2,3,4,5-tetrahydro-1H-benzo[d]azepine, or 1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one.

[0252] In one aspect, the heterocyclic group is a 4- to 8-membered cyclic group containing one ring and one or two oxygen atoms (e.g., tetrahydrofuran or tetrahydropyran), or one or two nitrogen atoms (e.g., pyrrolidine, piperidine, or piperazine), or one oxygen atom and one nitrogen atom (e.g., morpholine), and optionally, one -CH2- group is replaced by one -C(=O)- group (e.g., pyrrolidin-2-one or piperazin-2-one). In another aspect, the heterocyclic group is a 5- to 8-membered cyclic group containing one ring and one or two nitrogen atoms, and optionally, one -CH2- group is replaced by one -C(=O)- group. In another aspect, the heterocyclic group is a 5- or 6-membered cyclic group containing one ring and one or two nitrogen atoms, and optionally, one -CH2- group is replaced by one -C(=O)- group. In another aspect, the heterocyclic group is an 8- to 12-membered cyclic group containing two rings and one or two nitrogen atoms. The heterocycle may be linked to the remainder of the molecule via any available carbon atom or nitrogen atom. Non-limiting and exemplary heterocyclic groups include TIFF2025523575000055.tif14128.

[0253] As used herein, either by itself or as part of another group, the term "optionally substituted heterocycle" refers to a heterocyclic group that is unsubstituted or substituted with 1 to 4 substituents, where each substituent is independently halo, nitro, cyano, hydroxy, amino (e.g., -NH2, alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino, or (heterocyclo)alkylamino), heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamide, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxyalkyl, (amino)alkyl, (cyano)alkyl, (carboxamide)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, -N(R 56a )C(=O)R 56b 、 -N(R 56c )S(=O)2R 56d 、 -C(=O)R 57 、 -S(=O)R 56e 、 -S(=O)2R 58 、 or -OR 59 , where R 56a , R 56b , R 56c , R 56d , R 56e , R 57 , R 58 , and R 59 are as defined with respect to the term "optionally substituted cycloalkyl". Substitution can occur on any available carbon or nitrogen atom of the heterocyclic group.

[0254] As used herein, either by itself or as part of another group, the term "aryl" refers to an aromatic ring system having from 6 to 14 carbon atoms, i.e., C6-C 14 refers to aryl. Non-limiting and exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups. In one embodiment, the aryl group is phenyl or naphthyl. In another embodiment, the aryl group is phenyl.

[0255] As used herein, either by itself or as part of another group, the term "optionally substituted aryl" refers to aryl that is unsubstituted or substituted with 1 to 5 substituents, where the substituents are each independently halo, nitro, cyano, hydroxy, amino (e.g., -NH2, alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino, or (heterocyclo)alkylamino), heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamide, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, (cyano)alkyl, (carboxamide)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, -N(R 56a )C(=O)R 56b 、-N(R 56c )S(=O)2R 56d 、-C(=O)R 57 、-S(=O)R 56e 、-S(=O)2R 58 、or -OR 59 , where R 56a , R 56b, R 56c , R 56d , R 56e , R 57 , R 58 , and R 59 is as defined with respect to the term "optionally substituted cycloalkyl".

[0256] In one aspect, optionally substituted aryl is optionally substituted phenyl. In another aspect, optionally substituted phenyl has four substituents. In another aspect, optionally substituted phenyl has three substituents. In another aspect, optionally substituted phenyl has two substituents. In another aspect, optionally substituted phenyl has one substituent. Non-limiting and exemplary optionally substituted aryl groups include 2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 2,6-di-fluorophenyl, 2,6-di-chlorophenyl, 2-methyl, 3-methoxyphenyl, 2-ethyl, 3-methoxyphenyl, 3,4-di-methoxyphenyl, 3,5-di-fluorophenyl 3,5-di-methylphenyl, 3,5-dimethoxy, 4-methylphenyl, 2-fluoro-3-chlorophenyl, 3-chloro-4-fluorophenyl, and 2-phenylpropan-2-amine. The term optionally substituted aryl includes aryl groups having fused optionally substituted cycloalkyl groups and fused optionally substituted heterocyclic groups. Non-limiting examples include 2,3-dihydro-1H-inden-1-yl, 1,2,3,4-tetrahydronaphthalen-1-yl, 1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl, 1,2,3,4-tetrahydroisoquinolin-1-yl, and 2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl.

[0257] As used herein, either alone or as part of another group, the term "heteroaryl" refers to monocyclic and bicyclic aromatic ring systems having 5 to 14 ring members, i.e., 5- to 14-membered heteroaryl, containing 1, 2, 3, or 4 heteroatoms. Each heteroatom is independently oxygen, sulfur, or nitrogen. In one aspect, heteroaryl has 3 heteroatoms. In another aspect, heteroaryl has 2 heteroatoms. In another aspect, heteroaryl has 1 heteroatom. In another aspect, heteroaryl is 5- to 10-membered heteroaryl. In another aspect, heteroaryl has 5 ring atoms, for example, thienyl, a 5-membered heteroaryl having 4 carbon atoms and 1 sulfur atom. In another aspect, heteroaryl has 6 ring atoms, for example, pyridyl, a 6-membered heteroaryl having 5 carbon atoms and 1 nitrogen atom. Non-limiting and exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzoxazonyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolinyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, and phenoxazinyl.In one aspect, the heteroaryl is selected from thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, and pyrimidin-5-yl), thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl), isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl) and isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl). The term heteroaryl also includes N-oxides. A non-limiting and exemplary N-oxide is pyridyl N-oxide.

[0258] As used herein, either by itself or as part of another group, the term "optionally substituted heteroaryl" refers to heteroaryl that is unsubstituted or substituted with 1 to 4 substituents, where the substituents are, independently, halo, nitro, cyano, hydroxy, amino (e.g., -NH2, alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino, or (heterocyclo)alkylamino), heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamide, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxyalkyl, (amino)alkyl, (cyano)alkyl, (carboxamide)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, -N(R 56a )C(=O)R 56b 、-N(R 56c )S(=O)2R 56d 、-C(=O)R 57 、-S(=O)R 56e 、-S(=O)2R 58 、or -OR 59 , where R 56a , R 56b , R 56c , R 56d , R 56e , R 57 , R 58 , and R 59 are as defined with respect to the term "optionally substituted cycloalkyl".

[0259] In one aspect, the optionally substituted heteroaryl has 2 substituents. In another aspect, the optionally substituted heteroaryl has 1 substituent. Any available carbon or nitrogen atom can be substituted.

[0260] As used herein, the term "aryloxy," either by itself or as part of another group, refers to an optionally substituted aryl bonded to a terminal oxygen atom. A non-limiting, exemplary aryloxy group is PhO-.

[0261] As used herein, the term "heteroaryloxy," either by itself or as part of another group, refers to an optionally substituted heteroaryl bonded to a terminal oxygen atom. A non-limiting, exemplary heteroaryloxy group is pyridyl-O-.

[0262] As used herein, the term "aralkyloxy," either by itself or as part of another group, refers to an aralkyl bonded to a terminal oxygen atom. A non-limiting, exemplary aralkyloxy group is PhCH2O-.

[0263] As used herein, the term "(cyano)alkyl," either by itself or as part of another group, refers to an alkyl substituted with 1, 2, or 3 cyano groups. In one embodiment, the alkyl is substituted with 1 cyano group. In another embodiment, the alkyl is C1-C6 alkyl. In another embodiment, the alkyl is C1-C4 alkyl. Non-limiting, exemplary (cyano)alkyl groups include -CH2CH2CN and -CH2CH2CH2CN.

[0264] As used herein, either by itself or as part of another group, the term "(cycloalkyl)alkyl" refers to an alkyl substituted with one or two optionally substituted cycloalkyl groups. In one embodiment, the cycloalkyl group is an optionally substituted C3-C6 cycloalkyl. In another embodiment, the alkyl is C1-C6 alkyl. In another embodiment, the alkyl is C1-C4 alkyl. In another embodiment, the alkyl is C1 or C2 alkyl. In another embodiment, the alkyl is substituted with one optionally substituted cycloalkyl group. In another embodiment, the alkyl is substituted with two optionally substituted cycloalkyl groups.

[0265] As used herein, either by itself or as part of another group, the term "sulfonamide" refers to the group of formula -SO2NR 50a R 50b wherein R 50a and R 50b are each independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, or optionally substituted heteroaryl; or R 50a and R 50b together with the nitrogen to which they are attached form a 3- to 8-membered optionally substituted heterocyclic group. Non-limiting exemplary sulfonamide groups include -SO2NH2, -SO2N(H)CH3, and -SO2N(H)Ph.

[0266] As used herein, either by itself or as part of another group, the term "alkylcarbonyl" refers to a carbonyl group, i.e., -C(=O)-, substituted with an alkyl group. In one embodiment, the alkyl is C1-C4 alkyl. A non-limiting exemplary alkylcarbonyl group is -COCH3.

[0267] As used herein, either alone or as part of another group, the term "arylcarbonyl" refers to a carbonyl group, i.e., -C(=O)-, substituted by an optionally substituted aryl group. A non-limiting, exemplary arylcarbonyl group is -COPh.

[0268] As used herein, either alone or as part of another group, the term "alkylsulfonyl" refers to a sulfonyl group, i.e., -SO2-, substituted by an alkyl group. A non-limiting, exemplary alkylsulfonyl group is -SO2CH3.

[0269] As used herein, either alone or as part of another group, the term "arylsulfonyl" refers to a sulfonyl group, i.e., -SO2-, substituted by an optionally substituted aryl group. A non-limiting, exemplary arylsulfonyl group is -SO2Ph.

[0270] As used herein, either alone or as part of another group, the term "mercaptoalkyl" refers to an alkyl substituted by a -SH group.

[0271] As used herein, either alone or as part of another group, the term "carboxy" refers to a group of the formula -C(=O)OH.

[0272] As used herein, either alone or as part of another group, the term "ureido" refers to a group of the formula -NR 51a -C(=O)-NR 51b R 51c wherein R 51a is hydrogen or alkyl; and R 51b and R 51c are each independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, or optionally substituted heteroaryl, or R 51b and R 51cTogether with the nitrogen to which they are attached, they form a 4- to 8-membered optionally substituted heterocyclic group. Non-limiting exemplary ureido groups include -NH-C(C=O)-NH2 and -NH-C(C=O)-NHCH3.

[0273] As used herein, the term "guanidino" when used by itself or as part of another group refers to the group of formula -NR 52a -C(=NR 53 )-NR 52b R 52c , where R 52a is hydrogen or alkyl; R 52b and R 53c are each independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, or optionally substituted heteroaryl; or R 52b and R 52c together with the nitrogen to which they are attached form a 4- to 8-membered optionally substituted heterocyclic group; and R 53 is hydrogen, alkyl, cyano, alkylsulfonyl, alkylcarbonyl, carboxamide, or sulfonamide. Non-limiting exemplary guanidino groups include -NH-C(C=NH)-NH2, -NH-C(C=NCN)-NH2, and -NH-C(C=NH)-NHCH3.

[0274] As used herein, the term "(heterocyclo)alkyl" when used by itself or as part of another group refers to alkyl substituted with one, two, or three optionally substituted heterocyclic groups. In one aspect, the alkyl is substituted with one optionally substituted 5- to 8-membered heterocyclic group. In another aspect, the alkyl is C1-C6 alkyl. In another aspect, the alkyl is C1-C4 alkyl. The heterocyclic group can be linked to the alkyl group through a carbon or nitrogen atom.

[0275] As used herein, either alone or as part of another group, the term "carbamate" refers to the group of formula -NR 54a -C(=O)-OR 54b wherein R 54a is hydrogen or alkyl, and R 54b is hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, or optionally substituted heteroaryl. A non-limiting, exemplary carbamate group is -NH-(C=O)-OtBu.

[0276] As used herein, either alone or as part of another group, the term "(heteroaryl)alkyl" refers to an alkyl substituted with one or two optionally substituted heteroaryl groups. In one aspect, the alkyl group is substituted with one optionally substituted 5- to 14-membered heteroaryl group. In another aspect, the alkyl group is substituted with two optionally substituted 5- to 14-membered heteroaryl groups. In another aspect, the alkyl group is substituted with one optionally substituted 5- to 9-membered heteroaryl group. In another aspect, the alkyl group is substituted with two optionally substituted 5- to 9-membered heteroaryl groups. In another aspect, the alkyl group is substituted with one optionally substituted 5- or 6-membered heteroaryl group. In another aspect, the alkyl group is substituted with two optionally substituted 5- or 6-membered heteroaryl groups. In one aspect, the alkyl group is C1-C6 alkyl. In another aspect, the alkyl group is C1-C4 alkyl. In another aspect, the alkyl group is C1 or C2 alkyl.

[0277] As used herein, the term "aralkyl" or "(aryl)alkyl" used by itself or as part of another group refers to alkyl substituted with one, two, or three optionally substituted aryl groups. In one embodiment, the alkyl is substituted with one optionally substituted aryl group. In another embodiment, the alkyl is substituted with two optionally substituted aryl groups. In one embodiment, the aryl is optionally substituted phenyl or optionally substituted naphthyl. In another embodiment, the aryl is optionally substituted phenyl. In one embodiment, the alkyl is C1-C6 alkyl. In another embodiment, the alkyl is C1-C4 alkyl. In another embodiment, the alkyl is C1 or C2 alkyl. Non-limiting exemplary (aryl)alkyl groups include benzyl, phenethyl, -CHPh2, and -CH(4-F-Ph)2.

[0278] As used herein, the term "amide" used by itself or as part of another group refers to the group of formula -C(=O)NR 60a R 60b , wherein R 60a and R 60b are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, haloalkyl, (alkoxy)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, (aryl)alkyl, (cycloalkyl)alkyl, (heterocycle)alkyl, or (heteroaryl)alkyl; or R 60a and R 60b together with the nitrogen to which they are attached form a 4- to 8-membered optionally substituted heterocyclic group. In one embodiment, R 60a and R 60b are each independently hydrogen or C1-C6 alkyl.

[0279] The term "amino", used by itself or as part of another group, refers to a group of the formula -NR 55a R 55b wherein R 55a and R 55b are each independently hydrogen, optionally substituted alkyl, haloalkyl, (hydroxy)alkyl, (alkoxy)alkyl, (amino)alkyl, heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, (aryl)alkyl, (cycloalkyl)alkyl, (heterocycle)alkyl, or (heteroaryl)alkyl.

[0280] In one embodiment, amino is -NH2.

[0281] In another embodiment, amino is "alkylamino", i.e., an amino group in which R 55a is C 1~6 alkyl and R 55b is hydrogen. In one embodiment, R 55a is C1-C4 alkyl. Non-limiting and exemplary alkylamino groups include -N(H)CH3 and -N(H)CH2CH3.

[0282] In another embodiment, amino is "dialkylamino", i.e., an amino group in which R 55a and R 55b are each independently C 1~6 alkyl. In one embodiment, R 55a and R 55b are each independently C1-C4 alkyl. Non-limiting and exemplary dialkylamino groups include -N(CH3)2 and -N(CH3)CH2CH(CH3)2.

[0283] In another embodiment, amino is "hydroxyalkylamino", i.e., an amino group in which R 55a is (hydroxyl)alkyl and R 55b is hydrogen or C1-C4 alkyl.

[0284] In another aspect, amino is "cycloalkylamino", i.e., R 55a is an optionally substituted cycloalkyl and R 55b is hydrogen or C1-C4 alkyl, and is an amino group.

[0285] In another aspect, amino is "aralkylamino", i.e., R 55a is aralkyl and R 55b is hydrogen or C1-C4 alkyl, and is an amino group. Non-limiting and exemplary aralkylamino groups include -N(H)CH2Ph, -N(H)CHPh2, and -N(CH3)CH2Ph.

[0286] As used herein, the term "(amino)alkyl" used by itself or as part of another group refers to an alkyl substituted with one amino group. In one aspect, the amino group is -NH2. In one aspect, the amino group is alkylamino. In another aspect, the amino group is dialkylamino. In another aspect, the alkyl is C1-C6 alkyl. In another aspect, the alkyl is C1-C4 alkyl. Non-limiting and exemplary (amino)alkyl groups include -CH2NH2, CH2CH2N(H)CH3, -CH2CH2N(CH3)2, CH2N(H)cyclopropyl, -CH2N(H)cyclobutyl, and -CH2N(H)cyclohexyl, as well as -CH2CH2CH2N(H)CH2Ph and -CH2CH2CH2N(H)CH2(4-CF3-Ph).

[0287] The present disclosure encompasses any of the compounds of the present disclosure that are isotopically labeled (i.e., radiolabeled) by replacing one or more atoms with atoms having different atomic masses or mass numbers. Examples of isotopes that can be introduced into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, respectively, 2 H (or deuterium (D)), 3 H, 11 C,13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, for example, 3 H, 11 C, and 14 C. In one aspect, provided is a composition in which substantially all of the atoms at a position within a compound of the present disclosure are replaced with atoms having different atomic masses or mass numbers. In another aspect, provided is a composition in which some of the atoms at a position within a compound of the present disclosure are replaced, i.e., the compound of the present disclosure is enriched at positions within atoms having different atomic masses or mass numbers. The isotopically labeled compounds of the present disclosure can be prepared using methods known in the art.

[0288] As described above, the compounds of the present disclosure contain one or more asymmetric carbon atoms and, as a result, can give rise to enantiomers, diastereomers, and other stereoisomeric forms. The present disclosure encompasses the use of all such possible forms, including their racemic and resolved forms and mixtures thereof. Individual enantiomers can be resolved according to methods known in the art in view of the present disclosure. When the compounds described herein contain an olefinic double bond or other geometrically asymmetric center and are not otherwise specified, the compounds described herein are intended to include both E and Z geometric isomers. All tautomers are also encompassed by the present disclosure. All conformational isomers, i.e., stereoisomers generated by rotation around a σ bond, are also encompassed by the present disclosure.

[0289] As used herein, the term "stereoisomer" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. This term includes enantiomers and isomers (diastereomers) of compounds having two or more chiral centers that are not mirror images of each other.

[0290] The term "chiral center" or "asymmetric carbon atom" refers to a carbon atom to which four different groups are attached.

[0291] The terms "enantiomer" and "enantiomeric" refer to molecules that cannot be superimposed on their mirror images and are therefore optically active, where the enantiomer rotates the plane of polarization in one direction and its mirror image compound rotates the plane of polarization in the opposite direction.

[0292] The term "racemic" refers to a mixture of equal amounts of enantiomers, and the mixture is optically inactive. In one aspect, the compounds of the present disclosure are racemic.

[0293] The term "absolute configuration" refers to the spatial arrangement of the atoms of a chiral molecular entity (or group) and its stereochemical description, such as R or S.

[0294] The terms and nomenclature rules related to stereochemistry used herein are intended to be consistent with those described in Pure & Appl. Chem 68:2193 (1996) unless otherwise indicated.

[0295] The term "enantiomeric excess" or "ee" refers to a measure of how much more of one enantiomer is present compared to the other. In a mixture of R and S enantiomers, the percent enantiomeric excess is defined as │R - S│*100, where R and S are the respective molar or weight fractions of the enantiomers in a mixture where R + S = 1. Based on the findings regarding the optical rotation of chiral substances, the percent enantiomeric excess is defined as ([α] obs / [α] max )*100, where [α] obs is the optical rotation of the enantiomer mixture and [α] max is the optical rotation of the pure enantiomer. The determination of enantiomeric excess can be achieved using various analytical techniques including NMR spectroscopy, chiral column chromatography, or polarimetry.

[0296] As used herein, the term "about" includes the recited number ± 10%. Thus, "about 10" means 9 to 11.

[0297] V. Specific Embodiments The present disclosure provides the following specific embodiments. Embodiment 1. A compound of Formula A-I or a pharmaceutically acceptable salt or solvate thereof: TIFF2025523575000056.tif29128 wherein, R 1 is selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted phenyl, and optionally substituted 5-9 membered heteroaryl; R 2a , R 2b , and R 2c are independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo; R 3 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo; Y is - ^ N(H)C(=O)-, - ^ N(H)C(=O)CH2-, - ^ C(=O)N(H)- and - ^ C(=O)N(H)CH2-; herein, the bond with " ^ " attached is connected to thiazole; R 4a , R 4b , R 4c , and R 4dis independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo; L is -(CH2) m -, -*(CH2) n (OCH2CH2) o -, and -(CH2) p -Z-CH2) q selected from the group consisting of -; wherein the carbon marked with "*" is connected to X; m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; n is 2, 3, or 4; p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; o is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; Z is -(CR 6a R 6b )- and -N(R 7 )-selected from the group consisting of; R 6a is selected from the group consisting of halo, hydroxyl, C1-C6 alkyl, C1-C4 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C4-C8 heterocycle, optionally substituted phenyl, and optionally substituted 5-9 membered heteroaryl; R 6b is selected from the group consisting of hydrogen and C1-C6 alkyl; R 7 is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C4 haloalkyl; X is -O-, -NH-, TIFF2025523575000057.tif11128 selected from the group consisting of; B 1 is selected from the group consisting of TIFF2025523575000058.tif91134; and R 5a 、R 5b 、and R 5c are independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo. Embodiment 2. Formula I: a compound of TIFF2025523575000059.tif30128, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 3. Formula II: a compound of TIFF2025523575000060.tif48128, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 4. R 1 is optionally substituted C3-C8 cycloalkyl, a compound of any of Embodiments 1-3, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 5. R 1 is cyclopropyl, the compound of Embodiment 4, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 6. R 1 is optionally substituted phenyl, a compound of any of Embodiments 1-3, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 7. R 1 is TIFF2025523575000061.tif24128; and R 1a 、R 1b 、R 1c 、R 1d 、and R 1e are independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo, The compound of embodiment 6, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 8. R 1b 、R 1c 、R 1d 、and R 1e is hydrogen, the compound of embodiment 7, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 9. R 1a is C1-C4 alkyl, the compound of embodiment 7 or 8, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 10. R 1 is optionally substituted 5- to 9-membered heteroaryl, the compound of any one of embodiments 1 to 3, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 11. R 1 is optionally substituted imidazole, the compound of embodiment 10, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 12. R 2a 、R 2b 、and R 2c is hydrogen, the compound of any one of embodiments 1 to 11, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 13. R 3 is C1-C4 alkyl, the compound of any one of embodiments 1 to 12, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 14. R 3 is methyl, the compound of embodiment 13, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 15. R 4a is selected from the group consisting of hydrogen and fluoro, the compound of any one of embodiments 1 to 14, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 16. R 4b is selected from the group consisting of hydrogen and fluoro, the compound of any one of embodiments 1 to 15, or a pharmaceutically acceptable salt or solvate thereof. Aspect 17. R 4c is a compound of any one of Aspects 1 to 16 selected from the group consisting of hydrogen and fluorine, or a pharmaceutically acceptable salt or solvate thereof. Aspect 18. R 4b R 4c and R 4d are hydrogen, a compound of any one of Aspects 1 to 14, or a pharmaceutically acceptable salt or solvate thereof. Aspect 19. L is selected from the group consisting of -(CH2) m - and -*(CH2) n (OCH2CH2) o -, a compound of any one of Aspects 1 to 18, or a pharmaceutically acceptable salt or solvate thereof. Aspect 20. L is -(CH2) m -, a compound of Aspect 19, or a pharmaceutically acceptable salt or solvate thereof. Aspect 21. L is -*(CH2) n (OCH2CH2) o -, a compound of Aspect 19, or a pharmaceutically acceptable salt or solvate thereof. Aspect 22. L is -(CH2) p -Z-CH2) q -, a compound of any one of Aspects 1 to 18, or a pharmaceutically acceptable salt or solvate thereof. Aspect 23. Z is -(CR 6a R 6b )-, a compound of Aspect 22, or a pharmaceutically acceptable salt or solvate thereof. Aspect 24. Z is -N(R 7 )-, a compound of Aspect 22, or a pharmaceutically acceptable salt or solvate thereof. Aspect 25. X is -O-, a compound of any one of Aspects 1 to 24, or a pharmaceutically acceptable salt or solvate thereof. Aspect 26. A compound of any one of embodiments 1 to 24 wherein X is -NH-, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 27. X is TIFF2025523575000062.tif10128, a compound of any one of embodiments 1 to 24, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 28. X is TIFF2025523575000063.tif10128, a compound of any one of embodiments 1 to 24, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 29. B 1 is B-1, a compound of any one of embodiments 1 to 28, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 30. B 1 is B-2, a compound of any one of embodiments 1 to 28, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 31. B 1 is B-3, a compound of any one of embodiments 1 to 28, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 32. B 1 is B-4, a compound of any one of embodiments 1 to 28, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 33. B 1 is B-5, a compound of any one of embodiments 1 to 28, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 34. B 1 is B-6, a compound of any one of embodiments 1 to 28, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 35. R 5a R 5b and R 5cA compound of any one of embodiments 29 to 34, or a pharmaceutically acceptable salt or solvate thereof, which is independently selected from the group consisting of hydrogen and fluorine. Embodiment 36. R 5a 、R 5b 、and R 5c A compound of embodiment 35, or a pharmaceutically acceptable salt or solvate thereof, wherein R, R, and R are hydrogen. Embodiment 37. A compound of embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, which is any one or more of the compounds in Table 1. Embodiment 38. A pharmaceutical composition comprising a compound of any one of embodiments 1 to 37, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Embodiment 39. A method for treating cancer, neurodegenerative disease, diabetes, cardiovascular disease, kidney disease, or liver disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1 to 37, or a pharmaceutically acceptable salt thereof. Embodiment 40. The method of embodiment 39, further comprising administering a second therapeutic agent to the subject. Embodiment 41. The method of embodiment 39 or 40 for treating cancer in a subject in need thereof. Embodiment 42. The method of embodiment 39 or 40, wherein the cancer is a solid tumor. Embodiment 43. The method of embodiment 39 or 40, wherein the cancer is a blood cancer. Embodiment 44. The method of embodiment 39 or 40, wherein the cancer is one or more of the cancers in Table 2. Embodiment 45. The method of any one of embodiments 40 to 44, wherein the second therapeutic agent is isopropyl (S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)propanamide)-6-diazo-5-oxohexanoate, or a pharmaceutically acceptable salt thereof. Embodiment 46. A method for reducing the nuclear factor erythroid 2-related factor 2 (Nrf2) protein in a target cell, comprising the step of administering to the target a compound according to any one of Aspects 1 to 37, or a pharmaceutically acceptable salt or solvate thereof. Aspect 47. The method according to Aspect 46, wherein the target has cancer. Aspect 48. A compound according to any one of Aspects 1 to 37, or a pharmaceutically acceptable salt thereof, and instructions for administering the compound or a pharmaceutically acceptable salt thereof to a subject having cancer A kit comprising: Aspect 49. A compound of Formula III, or a pharmaceutically acceptable salt thereof: TIFF2025523575000064.tif23128 wherein, R 1' is selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted phenyl, and optionally substituted 5-9 membered heteroaryl; R 2a' , R 2b' , and R 2c' are independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo; R 3' is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo; Z 1 is -O-, and R 8 is hydrogen, C1-C6 alkyl, or aralkyl; or Z 1 is -N(H)-, and R 8 is TIFF2025523575000065.tif27128; and R 4a' 、R 4b' 、R 4c' 、and R 4d' is independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo; R 9 is hydrogen and -L 1 -X 1 selected from the group consisting of, X 1 is -OR 10 and -NR 11a R 11b selected from the group consisting of; R 10 is hydrogen; R 11a is selected from the group consisting of hydrogen and -C(=O)OtBu; R 11b is selected from the group consisting of hydrogen and C1-C4 alkyl; L 1 is -(CH2) m' -, -*(CH2) n (OCH2CH2) o' -, and -(CH2) p' -Z 2 -(CH2) q' -selected from the group consisting of; wherein the carbon marked with "*" is connected to X 1 ; m' is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; n' is 2, 3, or 4; o' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; p' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; q' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; Z 2 is -(CR 6a' R 6b' )-and -N(R7' )- selected from the group consisting of; R 6a' is selected from the group consisting of halo, hydroxyl, C1-C6 alkyl, C1-C4 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C4-C8 heterocycle, optionally substituted phenyl, and optionally substituted 5-9 membered heteroaryl; R 6b' is selected from the group consisting of hydrogen and C1-C6 alkyl: and R 7' is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C4 haloalkyl.

Example

[0298] Example 1 Synthesis of 2-(3-hydroxyphenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (DCP_A017) TIFF2025523575000066.tif101128

[0299] Step 1. Indolin-1-yl(o-tolyl)methanone To a solution of indoline (20.00 g, 167.8 mmol) and triethylamine (67.93 g, 671.3 mmol) in dichloromethane (500 mL) was added 2-methylbenzoyl chloride (25.94 g, 167.8 mmol) at 0 °C. The mixture was stirred at room temperature for 18 hours. The mixture was then quenched with water (200 mL), extracted with dichloromethane (500 mL x 2), the organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was triturated with methyl tert-butyl ether (100 mL) to give indolin-1-yl(o-tolyl)methanone (28.0 g, 70.3% yield) as a yellow solid. MS (ESI) m / z 237.9 [M+H] + .

[0300] Step 2.2-Bromo-1-(1-(2-methylbenzoyl)indolin-5-yl)propan-1-one To a solution of indolin-1-yl(o-tolyl)methanone(28.00 g, 118.0 mmol) and aluminum chloride(47.20 g, 354.0 mmol) in dichloromethane(500 mL) at 0 °C, 2-bromopropanoyl bromide(76.41 g, 354.0 mmol) was added dropwise. After the addition, the mixture was stirred at 50 °C for 5 hours. The mixture was then quenched with water(500 mL), basified to pH 8-10 with 6N aqueous sodium hydroxide solution, extracted with dichloromethane(1.0 L), the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and crude 2-bromo-1-(1-(2-methylbenzoyl)indolin-5-yl)propan-1-one(35.0 g, 79.7% yield) was obtained as a yellow oil. MS (ESI) m / z 372.0 and 374.0 [M+H] + 。

[0301] Step 3.(5-(2-Amino-5-methylthiazol-4-yl)indolin-1-yl)(o-tolyl)methanone A solution of 2-bromo-1-(1-(2-methylbenzoyl)indolin-5-yl)propan-1-one(35.00 g, 94.02 mmol) and thiourea(17.89 g, 235.1 mmol) in ethanol(500 mL) was stirred at 70 °C for 18 hours. The solvent was removed in vacuo, and the residue was purified by flash column chromatography(eluting with 100% dichloromethane) to give (5-(2-amino-5-methylthiazol-4-yl)indolin-1-yl)(o-tolyl)methanone(25.0 g, 76.1% yield) as a white solid. MS (ESI) m / z 349.9 [M+H] + 。

[0302] Step 4.2-(3-Hydroxyphenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of 2-(3-hydroxyphenyl)acetic acid (40 mg, 0.26 mmol), 1,1'-carbonyldiimidazole (64 mg, 0.39 mmol) and N,N-diisopropylethylamine (100 mg, 0.79 mmol) in N,N-dimethylformamide (2.5 mL) was stirred at room temperature for 30 minutes. Then, (5-(2-amino-5-methylthiazol-4-yl)indolin-1-yl)(o-tolyl)methanone (101 mg, 0.29 mmol) was added to the resulting mixture at room temperature. The mixture was stirred at 60 °C for 16 hours, at which time the mixture was cooled to room temperature and purified directly by preparative HPLC (column: Welch Xtimate 21.2 x 250 mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 minutes) to give 2-(3-hydroxyphenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (40 mg, 0.083 mmol, 31.4% yield) as a white solid. TIFF2025523575000067.tif34153 * Multiple signals arising from conformational isomers.

[0303] Example 2 Synthesis of 2-(3-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 1) TIFF2025523575000068.tif103129

[0304] Step 1. 2-((tert-Butoxycarbonyl)amino)ethoxy)ethyl 4-methylbenzenesulfonate A solution of 2-(2-aminoethoxy)ethanol (1.00, 9.51 mmol), di-tert-butyl decarbonate (2.28 g, 10.5 mmol), and triethylamine (2.88 g, 28.5 mmol) in dichloromethane (50 mL) was stirred at room temperature for 6 h. Tosyl chloride (1.99 g, 10.5 mmol) was then added and the mixture was stirred for 16 h. The mixture was diluted with water (50 mL), extracted with dichloromethane (100 mL), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with dichloromethane) to afford 2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl 4-methylbenzenesulfonate (1.5 g, 43.8% yield) as a yellow oil. MS (ESI) m / z 260.1 [M+H-100] + .

[0305] Step 3. tert-Butyl (2-(2-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethyl)carbamate A solution of 2-(3-hydroxyphenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.50 g, 1.03 mmol), 2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl 4-methylbenzenesulfonate (0.37 g, 1.0 mmol), and potassium tert-butoxide (0.35 g, 3.1 mmol) in N,N-dimethylformamide (25 mL) was stirred at 30 °C for 48 h. The mixture was then quenched with water (50 mL) and extracted with dichloromethane (50 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography (eluting with ethyl acetate / petroleum ether = 1 / 10) to give tert-butyl (2-(2-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethyl)carbamate (1.0 g, over weight) as an impure yellow oil. MS (ESI) m / z 671.3 [M+H] + .

[0306] Step 4. 2-(3-(2-(2-Aminoethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of tert-butyl (2-(2-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethyl)carbamate (1.00 g (impure), max. 1.0 mmol) and 4 M HCl / 1,4-dioxane solution (10.0 mL) in 1,4-dioxane (20.0 mL) was stirred at room temperature for 3 h. The solvent was removed in vacuo, and the residue was dissolved in dichloromethane (100 mL), washed with saturated aqueous sodium carbonate, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with dichloromethane / methanol = 5 / 100) to give 2-(3-(2-(2-aminoethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (90 mg, 16% overall yield for two steps) as a white solid. MS (ESI) m / z 571.3 [M+H] + .

[0307] Step 5. 2-(3-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of 2-(3-(2-(2-aminoethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.090 g, 0.16 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (0.046 g, 0.17 mmol) and N,N-diisopropylethylamine (0.061 g, 0.47 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 100 °C for 18 h. The reaction mixture was directly purified by preparative HPLC (column: Welch Xtimate 21.2 x 250 mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 min) to give 2-(3-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (20.5 mg, 15.7% yield) as a yellow solid. TIFF2025523575000069.tif56153 * Multiple signals arising from conformational isomers.

[0308] Example 3 Synthesis of 2-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 20) TIFF2025523575000070.tif65129

[0309] Step 1.2 - (3-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of 2-(3-(2-(2-aminoethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.10 g, 0.18 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (0.048 g, 0.18 mmol) and N,N-diisopropylethylamine (0.068 g, 0.53 mmol) in 1-methylpyrrolidin-2-one (2.0 mL) was stirred at 140 °C for 18 h. The reaction mixture was then purified directly by preparative HPLC (column: Welch Xtimate 21.2 x 250 mm C18, 10 μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 min) to give 2-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (24.0 mg, 16% yield) as a yellow solid. TIFF2025523575000071.tif49153 * Multiple signals arising from conformational isomers.

[0310] Example 4 Synthesis of 2-(3-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 12) TIFF2025523575000072.tif91128

[0311] Step 1. 2-(2-Hydroxyethoxy)ethyl 4-methylbenzenesulfonate A solution of 2,2'-oxybis(ethane-1-ol) (10.00 g, 94.23 mmol), 4-methylbenzenesulfonyl chloride (10.78 g, 56.54 mmol) and triethylamine (28.61 g, 282.7 mmol) in dichloromethane (300 mL) was stirred at room temperature for 18 h. The solvent was removed and the residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 3 / 7) to give 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate (8.0 g, 54% yield) as a colorless oil. MS (ESI) m / z 161.0 [M+H] + .

[0312] Step 2. 2-(3-(2-(2-Hydroxyethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate (0.30 g, 1.15 mmol), 2-(3-hydroxyphenyl)-N-(4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.66 g, 1.38 mmol), and potassium t-butoxide (0.39 g, 3.46 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 h. The reaction mixture was quenched with water (80 mL), extracted with ethyl acetate (50 mL x 2), washed with brine (20 mL x 1), the organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 2-(3-(2-(2-hydroxyethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.16 g, 24.3% yield) as a yellow solid. MS (ESI) m / z 572.3 [M+H] + .

[0313] Step 3. 2-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of 2-(3-(2-(2-hydroxyethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.16 g, 0.28 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (0.092 g, 0.33 mmol) and triphenylphosphine (0.147 g, 0.56 mmol) in tetrahydrofuran (10 mL) was added with diisopropyl azodicarboxylate (0.068 g, 0.33 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (30 mL), extracted with ethyl acetate (20 mL x 2), the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2 x 250 mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 minutes) to give 2-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (22 mg, 9.5% yield) as a white solid. TIFF2025523575000073.tif49153 * Multiple signals arising from conformational isomers.

[0314] Example 5 Synthesis of 2-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 18) TIFF2025523575000074.tif98128

[0315] Step 1. 2-(3-(2-(2-((5-Methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethyl 4-methylbenzenesulfonate A solution of 2-(3-(2-(2-hydroxyethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (120 mg, 0.21 mmol), tosyl chloride (59.3 mg, 0.31 mmol) and triethylamine (63.6 mg, 0.63 mmol) in dichloromethane (30 mL) was stirred at room temperature for 16 h. The mixture was diluted with water (10 mL), extracted with dichloromethane (30 mL), the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (dichloromethane) to give 2-(2-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethyl 4-methylbenzenesulfonate (80.0 mg, 52.6% yield) as a yellow oil. MS (ESI) m / z 726.3 [M+H] + 。

[0316] Step 2. 2-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of 2-(2-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethyl 4-methylbenzenesulfonate (80.0 mg, 0.11 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (60.2 mg, 0.22 mmol) and potassium carbonate (45.5 mg, 0.33 mmol) in N,N-dimethylformamide (10 mL) was stirred at 50 °C for 16 h. The reaction mixture was then purified directly by preparative HPLC (column: Welch Xtimate 21.2 x 250 mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 min) to give 2-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (7.6 mg, 8.3% yield) as a white solid. TIFF2025523575000075.tif49153 * Multiple signals arising from conformational isomers.

[0317] Example 6 Synthesis of 2-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 2) TIFF2025523575000076.tif115146

[0318] Step 1. 2,2-Dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl 4-methylbenzenesulfonate A solution of 2-(2-(2-aminoethoxy)ethoxy)ethan-1-ol (1.00 g, 6.70 mmol), di-tert-butyl dicarbonate (1.75 g, 8.04 mmol) and triethylamine (2.03 g, 20.1 mmol) in dichloromethane (20 mL) was stirred at room temperature for 6 h. Tosyl chloride (1.53 g, 8.04 mmol) was added and the mixture was stirred for 16 h. The mixture was diluted with water (50 mL), extracted with dichloromethane (100 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane) to give 2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl 4-methylbenzenesulfonate (1.2 g, 44% yield) as a yellow oil. MS (ESI) m / z 304.0 [M+H-100] + .

[0319] Step 2. tert-Butyl (2-(2-(2-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethoxy)ethyl)carbamate A solution of 2-(3-hydroxyphenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.50 g, 1.03 mmol), 2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl 4-methylbenzenesulfonate (0.41 g, 1.03 mmol), and potassium tert-butoxide (0.65 g, 3.09 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 h. The mixture was quenched with water (50 mL), extracted with dichloromethane (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 1 / 10) to afford tert-butyl (2-(2-(2-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethoxy)ethyl)carbamate (0.40 g, 54% yield) as a yellow oil. MS (ESI) m / z 715.5 [M+H]+.

[0320] Step 3. 2-(3-(2-(2-(2-Aminoethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of tert-butyl (2-(2-(2-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethoxy)ethyl)carbamate (0.40 g, 0.56 mmol) and 4 M hydrochloric acid / 1,4-dioxane (4.0 mL) in 1,4-dioxane (4.0 mL) was stirred at room temperature for 6 h. The solvent was removed in vacuo, and the residue was dissolved in dichloromethane (100 mL), washed with saturated aqueous sodium carbonate, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane / methanol = 1 / 20) to give 2-(3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.28 g, 81% yield) as a white solid. MS (ESI) m / z 615.2 [M+H] + .

[0321] Step 4. 2-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of 2-(3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.28 g, 0.45 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (0.15 g, 0.54 mmol) and N,N-diisopropylethylamine (0.17 g, 1.35 mmol) in N,N-dimethylformamide (5.0 mL) was stirred at 100 °C for 16 h. The reaction mixture was purified by preparative HPLC (column: Welch Xtimate 21.2 x 250 mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 min), and 2-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (52.0 mg, 13.1% yield) was obtained as a yellow solid. TIFF2025523575000077.tif56153 * Multiple signals arising from conformational isomers.

[0322] Example 7 Synthesis of 2-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 21) TIFF2025523575000078.tif74128

[0323] Step 1.2 - (3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of 2-(3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.070 g, 0.11 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (0.031 g, 0.11 mmol) and N,N-diisopropylethylamine (0.044 g, 0.34 mmol) in 1-methylpyrrolidin-2-one (3.0 mL) was stirred at 140 °C for 18 h. The reaction mixture was purified by preparative HPLC (column: Welch Xtimate 21.2 x 250 mm C18, 10 μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 min) to give 2-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (20 mg, 21% yield) as a yellow solid. TIFF2025523575000079.tif49153 * Multiple signals arising from conformational isomers.

[0324] Example 8 Synthesis of 2-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 7) TIFF2025523575000080.tif127128

[0325] Step 1. 2-(2-(2-Hydroxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate A solution of 2,2'-(ethane-1,2-diylbis(oxy))diethanol (5.00 g, 33.3 mmol), 4-methylbenzene-1-sulfonyl chloride (3.17 g, 16.7 mmol), and triethylamine (6.74 g, 66.6 mmol) in dichloromethane (100 mL) was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 1:1) to give 2-(2-(2-hydroxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (2.0 g, 39% yield) as a yellow oil. MS (ESI) m / z 305.3 [M+H] + .

[0326] Step 2. 2-(3-(2-(2-(2-Hydroxyethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of 2-(3-hydroxyphenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (1.00 g, 2.07 mmol), 2-(2-(2-hydroxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (0.69 g, 2.27 mmol), and potassium tert-butoxide (0.69 g, 6.2 mmol) in N,N-dimethylformamide (30 mL) was stirred at room temperature for 16 h. The mixture was diluted with water (20 mL), extracted with dichloromethane (50 mL), washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane / methanol = 5 / 100) to give 2-(3-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.70 g, 55.1% yield) as a yellow solid. MS (ESI) m / z 616.4 [M+H]+.

[0327] Step 3. 2-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of 2-(3-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.10 g, 0.16 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (0.049 g, 0.18 mmol) and triphenylphosphine (0.089 g, 0.34 mmol) in tetrahydrofuran (2.0 mL) was added with diisopropyl azodicarboxylate (0.049 g, 0.24 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (10 mL), extracted with dichloromethane (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2 x 250 mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 minutes) to give 2-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yloxy)ethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (52 mg, 37% yield) as a white solid. TIFF2025523575000081.tif56153 * Multiple signals arising from conformational isomers.

[0328] Example 9 Synthesis of 2-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 19) TIFF2025523575000082.tif85136

[0329] 2-(2-(2-(3-(2-((5-Methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate A solution of 2-(3-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (140 mg, 0.22 mmol), tosyl chloride (63.0 mg, 0.33 mmol) and triethylamine (69 mg, 0.66 mmol) in dichloromethane (10 mL) was stirred at room temperature for 16 h. The mixture was diluted with water (10 mL), extracted with dichloromethane (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane) to give 2-(2-(2-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (90 mg, 51.4% yield) as a yellow oil. MS (ESI) m / z 770.1 [M+H] + .

[0330] 2-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of 2-(2-(2-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (90.0 mg, 0.12 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (55.8 mg, 0.20 mmol) and potassium carbonate (70.3 mg, 0.51 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 50 °C for 16 h. The reaction mixture was purified by preparative HPLC (column: Welch Xtimate 21.2 x 250 mm C18, 10 μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 min) to give 2-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (4.5 mg, 4.4% yield) as a white solid. TIFF2025523575000083.tif49153 (Note: Two acidic protons usually around 12.3 ppm and 11.1 ppm are not visible). * Multiple signals arising from conformational isomers.

[0331] Example 10 Synthesis of 2-(3-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 3) TIFF2025523575000084.tif95143

[0332] Step 1. 2,2-Dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azapentadecane-16-yl 4-methylbenzenesulfonate A solution of 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethanol (1.0 g, 5.18 mmol), di-tert-butyl dicarbonate (1.13 g, 5.18 mmol) and triethylamine (1.56 g, 15.5 mmol) in dichloromethane (10 mL) was stirred at room temperature for 6 h. Tosyl chloride (1.00 g, 5.18 mmol) was added and the mixture was stirred at room temperature for 16 h. The mixture was diluted with water (50 mL), extracted with dichloromethane (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane) to give 2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azapentadecane-16-yl 4-methylbenzenesulfonate (0.45 g, 19% yield) as a yellow oil. MS (ESI) m / z 348.2 [M+H-100] + .

[0333] Step 2. tert-Butyl (2-(2-(2-(2-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethoxy)ethoxy)ethyl)carbamate A solution of 2-(3-hydroxyphenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.40 g, 0.83 mmol), 2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azapentadecane-16-yl 4-methylbenzenesulfonate (0.45 g, 1.0 mmol), and potassium tert-butoxide (0.37 g, 3.3 mmol) in N,N-dimethylformamide (5.0 mL) was stirred at room temperature for 48 h. The mixture was quenched with water (50 mL), extracted with dichloromethane (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 3 / 10) to give crude tert-butyl (2-(2-(2-(2-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethoxy)ethoxy)ethyl)carbamate (0.15 g, 23% yield) as a yellow oil. MS (ESI) m / z 759.3 [M+H] + .

[0334] Step 3. 2-(3-(2-(2-(2-(2-Aminoethoxy)ethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of tert-butyl (2-(2-(2-(2-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethoxy)ethoxy)ethyl)carbamate (0.15 g, 0.20 mmol) and hydrochloric acid (4 M in 1,4-dioxane, 5.0 mL) in 1,4-dioxane (10.0 mL) was stirred at room temperature for 3 hours. The solvent was removed, and the residue was dissolved in dichloromethane (100 mL), washed with saturated sodium carbonate solution (20 mL x 2), dried over anhydrous sodium, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane / methanol = 1 / 20) to give 2-(3-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (100 mg, 76% yield) as a white solid. MS (ESI) m / z 659.5 [M+H] + .

[0335] Step 4. 2-(3-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of 2-(3-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.090 g, 0.14 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (0.048 g, 0.17 mmol) and N,N-diisopropylethylamine (0.060 g, 0.45 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 100 °C for 18 h. The reaction mixture was purified by preparative HPLC (column: Welch Xtimate 21.2 x 250 mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 min) to give 2-(3-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (30.1 mg, 24% yield) as a yellow solid. TIFF2025523575000085.tif49153 * Multiple signals arising from conformational isomers.

[0336] Example 11 Synthesis of 2-(3-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 8) TIFF2025523575000086.tif110128

[0337] Step 1. 2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate A solution of 2,2'-((oxybis(ethane-2,1-diyl))bis(oxy))bis(ethan-1-ol) (5.0 g, 25.7 mmol), 4-methylbenzenesulfonyl chloride (2.4 g, 12.6 mmol), and triethylamine (7.8 g, 77.2 mmol) in dichloromethane (100 mL) was stirred at room temperature for 16 h. The mixture was quenched with water (30 mL), extracted with ethyl acetate (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 1:1) to afford 2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (2.0 g, 45% yield) as a yellow oil. MS (ESI) m / z 348.4 [M+H] + 。

[0338] Step 2. 2-(3-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A mixture of 2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (0.81 g, 2.32 mmol), 2-(3-hydroxyphenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (1.00 g, 2.07 mmol), and potassium t-butoxide (0.49 g, 4.34 mmol) in dry N,N-dimethylformamide (20 mL) was stirred at room temperature for 16 h. The reaction mixture was quenched with water (20 mL), extracted with ethyl acetate (30 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give 2-(3-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.66 g, 48.4% yield) as a white solid. MS (ESI) m / z 660.3 [M+H] + .

[0339] Step 3. 2-(3-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of 2-(3-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.13 g, 0.20 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (0.054 g, 0.20 mmol), and triphenylphosphine (0.052 mg, 0.20 mmol) in tetrahydrofuran (3.0 mL) was slowly added with diisopropyl azodicarboxylate (0.048 g, 0.24 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by preparative HPLC (column: Welch Xtimate 21.2 x 250 mm C18, 10 μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 minutes) to obtain 2-(3-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (26.7 mg, 14.8% yield) as a white solid. TIFF2025523575000087.tif56153 * Multiple signals arising from conformational isomers.

[0340] Example 12 Synthesis of 2-(3-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 13) TIFF2025523575000088.tif76135

[0341] Ethyl 4-methylbenzenesulfonate of (2-(2-(2-(2-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethoxy)ethoxy)ethyl A solution of 2-(3-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.25 g, 0.38 mmol), tosyl chloride (0.073 g, 0.38 mmol) and triethylamine (0.091 g, 0.9 mmol) in dichloromethane (10 mL) was stirred at room temperature for 12 h. The mixture was diluted with water (10 mL), extracted with dichloromethane (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane) to give ethyl 4-methylbenzenesulfonate of (2-(2-(2-(2-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethoxy)ethoxy)ethyl (0.12 g, 39% yield) as a yellow oil. MS (ESI) m / z 814.4 [M+H] + .

[0342] 2-(3-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of 2-(2-(2-(2-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (0.10 g, 0.12 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (0.035 g, 0.12 mmol) and potassium carbonate (0.05 g, 0.36 mmol) in N,N-dimethylformamide (8.0 mL) was stirred at 50 °C for 16 h. The reaction mixture was purified by preparative HPLC (column: Welch Xtimate 21.2 x 250 mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 min) to give 2-(3-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (17.1 mg, 15.2% yield) as a white solid. TIFF2025523575000089.tif49152 * Multiple signals arising from conformational isomers.

[0343] Example 13 Synthesis of 2-(3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 6) TIFF2025523575000090.tif93149

[0344] Step 1. 3-((tert-Butoxycarbonyl)amino)propyl 4-methylbenzenesulfonate A solution of tert-butyl (3-hydroxypropyl)carbamate (1.00 g, 5.71 mmol), tosyl chloride (1.31 g, 6.85 mmol) and triethylamine (1.73 g, 17.12 mmol) in dichloromethane (50 mL) was stirred at room temperature for 16 h. The mixture was diluted with water (50 mL), extracted with dichloromethane (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane) to give 3-((tert-butoxycarbonyl)amino)propyl 4-methylbenzenesulfonate (1.0 g, 53% yield) as a yellow oil. MS (ESI) m / z 230.1[M+H-100] + .

[0345] Step 2. tert-Butyl (3-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)propyl)carbamate A solution of 2-(3-hydroxyphenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (150 mg, 0.31 mmol), 3-((tert-butoxycarbonyl)amino)propyl 4-methylbenzenesulfonate (203.9 mg, 0.62 mmol) and potassium tert-butoxide (104.1 mg, 0.93 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 48 h. The mixture was quenched with water (50 mL), extracted with dichloromethane (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 3 / 10) to give crude tert-butyl (3-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)propyl)carbamate (130 mg, 65.4% yield) as a yellow oil. MS (ESI) m / z 641.3 [M+H]+ .

[0346] Step 3.2-(3-(3-Aminopropoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of tert-butyl (3-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)propyl)carbamate (130 mg, 0.20 mmol) and hydrochloric acid (4 M in 1,4-dioxane, 5.0 mL) in 1,4-dioxane (2.0 mL) was stirred at room temperature for 2 hours. The solvent was removed, and the residue was dissolved in dichloromethane (100 mL), washed with saturated sodium carbonate solution (20 mL x 2), dried over anhydrous sodium, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane / methanol = 1 / 20) to give 2-(3-(3-aminopropoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (90 mg, 82.0%) as a yellow solid. MS (ESI) m / z 541.2 [M+H] + .

[0347] Step 4.2-(3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of 2-(3-(2-(2-aminoethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (90 mg, 0.16 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (92 mg, 0.32 mmol) and N,N-diisopropylethylamine (64 mg, 0.48 mmol) in N,N-dimethylformamide (4.0 mL) was stirred at 100 °C for 16 h. The reaction mixture was purified by preparative HPLC (column: Welch Xtimate 21.2 x 250 mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 min) to give 2-(3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (17.4 mg, 13.1% yield) as a yellow solid. TIFF2025523575000091.tif41153 * Hard-to-see broad signals arising from conformational isomers.

[0348] Example 14 Synthesis of 2-(3-((14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 4) TIFF2025523575000092.tif99147

[0349] Step 1. 2,2-Dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecan-19-yl 4-methylbenzenesulfonate A solution of 14-amino-3,6,9,12-tetraoxatetradecan-1-ol (1.0 g, 4.2 mmol), di-tert-butyl dicarbonate (0.9 g, 4.2 mmol) and triethylamine (1.28 g, 12.6 mmol) in dichloromethane (10 mL) was stirred at room temperature for 6 h. Tosyl chloride (0.8 g, 4.2 mmol) was added and the mixture was stirred for 16 h. The mixture was diluted with water (50 mL), extracted with dichloromethane (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane) to give 2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecan-19-yl 4-methylbenzenesulfonate (0.32 g, 15.4% yield) as a yellow oil. MS (ESI) m / z 392.2 [M+H-100] + .

[0350] Step 2. tert-Butyl (14-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)-3,6,9,12-tetraoxatetradecyl)carbamate A solution of 2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecan-19-yl 4-methylbenzenesulfonate (0.30 g, 0.61 mmol), 2-(3-hydroxyphenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.29 g, 0.60 mmol) and potassium tert-butoxide (0.20 g, 1.78 mmol) in N,N-dimethylformamide (15 mL) was stirred at room temperature for 48 h. The mixture was quenched with water (50 mL), extracted with dichloromethane (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 3 / 10) to give tert-butyl (14-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)-3,6,9,12-tetraoxatetradecyl)carbamate (0.30 g, 61% yield) as a yellow oil. MS (ESI) m / z 803.5 [M+H] + .

[0351] Step 3. 2-(3-((14-Amino-3,6,9,12-tetraoxatetradecyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of tert-butyl (14-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)-3,6,9,12-tetraoxatetradecyl)carbamate (0.28 g, 0.35 mmol) and hydrochloric acid (4 M in 1,4-dioxane, 5.0 mL) in 1,4-dioxane (10.0 mL) was stirred at room temperature for 3 h. The solvent was removed, and the residue was dissolved in dichloromethane (100 mL), washed with saturated sodium carbonate solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (dichloromethane / methanol = 1 / 20) to give 2-(3-((14-amino-3,6,9,12-tetraoxatetradecyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (200 mg, 82% yield) as a white solid. MS (ESI) m / z 703.4 [M+H] + .

[0352] Step 4. 2-(3-((14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of 2-(3-((14-amino-3,6,9,12-tetraoxatetradecyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.18 g, 0.26 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (0.07 g, 0.26 mmol) and N,N-diisopropylethylamine (0.066 g, 0.5 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 100 °C for 18 h. The reaction mixture was purified by preparative HPLC (column: Welch Xtimate 21.2 x 250 mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 min), and 2-(3-((14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (29.1 mg, 12% yield) was obtained as a yellow solid. TIFF2025523575000093.tif56152 * Multiple signals arising from conformational isomers.

[0353] Example 15 Synthesis of 2-(3-((17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaheptadecyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 5) TIFF2025523575000094.tif95147

[0354] Step 1. 2,2-Dimethyl-4-oxo-3,8,11,14,17,20-hexaoxa-5-azadocosan-22-yl 4-methylbenzenesulfonate A solution of 17-amino-3,6,9,12,15-pentaoxaheptadecan-1-ol (1.00 g, 3.56 mmol), di-tert-butyl dicarbonate (0.92 g, 4.26 mmol) and triethylamine (0.72 g, 7.10 mmol) in dichloromethane (30 mL) was stirred at room temperature for 6 h. Tosyl chloride (1.01 g, 5.32 mmol) was added and the mixture was stirred for 16 h. The mixture was diluted with water (50 mL), extracted with dichloromethane (100 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane) to give 2,2-dimethyl-4-oxo-3,8,11,14,17,20-hexaoxa-5-azadocosan-22-yl 4-methylbenzenesulfonate (0.55 g, 28.9% yield) as a yellow oil. MS (ESI) m / z 436.0 [M+H-100] + 。

[0355] Step 2. tert-Butyl (17-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)-3,6,9,12,15-pentaoxaheptadecyl)carbamate A solution of 2,2-dimethyl-4-oxo-3,8,11,14,17,20-hexaoxa-5-azadocosan-22-yl 4-methylbenzenesulfonate (550 mg, 1.03 mmol), 2-(3-hydroxyphenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (589 mg, 1.22 mmol), and potassium tert-butoxide (346 mg, 3.08 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 h. The mixture was quenched with water (50 mL), extracted with dichloromethane (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 3 / 10) to afford tert-butyl (17-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)-3,6,9,12,15-pentaoxaheptadecyl)carbamate (360 mg, 41.4% yield) as a yellow solid. MS (ESI) m / z 847.2 [M+H] + .

[0356] Step 3. 2-(3-((17-Amino-3,6,9,12,15-pentaoxaheptadecyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of tert-butyl (17-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)-3,6,9,12,15-pentaoxaheptadecyl)carbamate (0.36 g, 0.42 mmol) and hydrochloric acid (4 M in 1,4-dioxane, 5.0 mL) in 1,4-dioxane (3.0 mL) was stirred at room temperature for 6 h. The solvent was removed, and the residue was dissolved in dichloromethane (100 mL), washed with saturated sodium carbonate solution (20 mL x 2), dried over anhydrous sodium, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane / methanol = 1 / 20) to give 2-(3-((17-amino-3,6,9,12,15-pentaoxaheptadecyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.19 g, 60% yield) as a white solid. MS (ESI) m / z 748.3[M+H] + .

[0357] Step 4. 2-(3-((17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaheptadecyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of 2-(3-((17-amino-3,6,9,12,15-pentaoxaheptadecyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.19 g, 0.25 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (0.15 g, 0.54 mmol) and N,N-diisopropylethylamine (0.04 g, 0.30 mmol) in N,N-dimethylformamide (3.0 mL) was stirred at 100 °C for 16 h. The reaction mixture was purified by preparative HPLC (column: Welch Xtimate 21.2 x 250 mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 min) to give 2-(3-((17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaheptadecyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (25 mg, 10% yield) as a yellow solid. TIFF2025523575000095.tif56153 * Multiple signals arising from conformational isomers.

[0358] Example 16 Synthesis of 2-(3-((14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 9) TIFF2025523575000096.tif114150

[0359] Step 1. 14-Hydroxy-3,6,9,12-tetraoxatetradecyl 4-methylbenzenesulfonate A solution of 3,6,9,12-tetraoxatetradecane-1,14-diol (5.6 g, 23.5 mmol), triethylamine (6.0 g, 59 mmol), and 4-methylbenzenesulfonyl chloride (1.9 g, 10 mmol) in dichloromethane (200 mL) was stirred at room temperature for 16 h. The mixture was quenched with water (50 mL), extracted with ethyl acetate (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 1:1) to give 14-hydroxy-3,6,9,12-tetraoxatetradecyl 4-methylbenzenesulfonate (3.9 g, 98% yield) as a yellow oil. MS (ESI) m / z 393.3 [M+H] + 。

[0360] Step 2. 2-(3-((14-Hydroxy-3,6,9,12-tetraoxatetradecyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A mixture of 14-hydroxy-3,6,9,12-tetraoxatetradecyl 4-methylbenzenesulfonate (0.30 g, 0.76 mmol), 2-(3-hydroxyphenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.33 g, 0.68 mmol), and potassium tert-butoxide (0.22 g, 1.96 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 16 h. The reaction mixture was quenched with water (40 mL), extracted with ethyl acetate (50 mL x 2), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (ethyl acetate / petroleum ether = 1 / 1) to give 2-(3-((14-hydroxy-3,6,9,12-tetraoxatetradecyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.25 g, 52% yield) as a white solid. MS (ESI) m / z 704.4 [M+H] + .

[0361] Step 3. 2-(3-((14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of 2-(3-((14-hydroxy-3,6,9,12-tetraoxatetradecyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (100 mg, 0.14 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (49.0 mg, 0.18 mmol) and triphenylphosphine (89.0 mg, 0.34 mmol) in tetrahydrofuran (5.0 mL) was added with diisopropyl azodicarboxylate (49.0 mg, 0.24 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (10 mL), extracted with dichloromethane (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2 x 250 mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 minutes) to give 2-(3-((14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (52 mg, 39% yield) as a white solid. TIFF2025523575000097.tif63153 * Multiple signals arising from conformational isomers.

[0362] Example 17 Synthesis of 2-(3-((17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-3,6,9,12,15-pentaoxaheptadecyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 10) TIFF2025523575000098.tif95149

[0363] 17-Hydroxy-3,6,9,12,15-pentaoxaheptadecyl 4-methylbenzenesulfonate A solution of 3,6,9,12,15-pentaoxaheptadecane-1,17-diol (5.6 g, 20 mmol), triethylamine (6.0 g, 59 mmol) and 4-methylbenzenesulfonyl chloride (1.9 g, 10 mmol) in dichloromethane (60 mL). The mixture was stirred at room temperature for 16 h. The mixture was quenched with water (50 mL), then extracted with ethyl acetate (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 2:5) to give 17-hydroxy-3,6,9,12,15-pentaoxaheptadecyl 4-methylbenzenesulfonate (4.3 g, 98.5% yield) as a yellow oil. MS (ESI) m / z 437.3 [M+H] + 。

[0364] 2-(3-((17-Hydroxy-3,6,9,12,15-pentaoxaheptadecyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A mixture of 17-hydroxy-3,6,9,12,15-pentaoxaheptadecyl 4-methylbenzenesulfonate (0.30 g, 0.69 mmol), 2-(3-hydroxyphenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.39 g, 0.81 mmol), and potassium t-butoxide (0.15 g, 1.38 mmol) in dry N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 h. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 1:1) to give 2-(3-((17-hydroxy-3,6,9,12,15-pentaoxaheptadecyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.25 g, 48.6% yield) as a white solid. MS (ESI) m / z 748.3 [M+H] + .

[0365] Step 3. 2-(3-((17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-3,6,9,12,15-pentaoxaheptadecyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of 2-(3-((14-hydroxy-3,6,9,12-tetraoxatetradecyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.25 g, 0.33 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (0.11 g, 0.39 mmol) and triphenylphosphine (0.17 g, 0.66 mmol) in tetrahydrofuran (8.0 mL) was added with diisopropyl azodicarboxylate (0.079 g, 0.39 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2 x 250 mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 minutes) to give 2-(3-((17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-3,6,9,12,15-pentaoxaheptadecyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (6.0 mg, 1.8% yield) as a white solid. TIFF2025523575000099.tif49153

[0366] Example 18 Synthesis of 2-(3-((14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 14) TIFF2025523575000100.tif72146

[0367] 14-(3-(2-((5-Methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)-3,6,9,12-tetraoxatetradecyl 4-methylbenzenesulfonate A solution of 2-(3-((14-Hydroxy-3,6,9,12-tetraoxatetradecyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.29 g, 0.41 mmol), tosyl chloride (0.079 g, 0.41 mmol) and triethylamine (0.13 g, 1.23 mmol) in dichloromethane (20 mL) was stirred at room temperature for 12 h. The mixture was diluted with water (10 mL), extracted with dichloromethane (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane) to give 14-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)-3,6,9,12-tetraoxatetradecyl 4-methylbenzenesulfonate (0.15 g, 43% yield) as a white solid. MS (ESI) m / z 858.3 [M+H] + .

[0368] 2-(3-((14-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of 14-((3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)-3,6,9,12-tetraoxatetradecyl 4-methylbenzenesulfonate (0.15 g, 0.17 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (0.05 g, 0.18 mmol) and potassium carbonate (0.07 g, 0.51 mmol) in N,N-dimethylformamide (8.0 mL) was stirred at 50 °C for 16 h. The reaction mixture was purified by preparative HPLC (column: Welch Xtimate 21.2 x 250 mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 min) to give 2-(3-((14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (10.1 mg, 6.2% yield) as a white solid. TIFF2025523575000101.tif56153 * Multiple signals arising from conformational isomers.

[0369] Example 19 Synthesis of 2-(3-((17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3,6,9,12,15-pentaoxaheptadecyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 15) TIFF2025523575000102.tif115138

[0370] Step 1.17-(3-(2-((5-Methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)-3,6,9,12,15-pentaoxaheptadecyl 4-methylbenzenesulfonate A solution of 2-(3-((17-Hydroxy-3,6,9,12,15-pentaoxaheptadecyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.25 g, 0.33 mmol), triethylamine (0.10 g, 1.0 mmol) and tosyl chloride (0.064 g, 0.33 mmol) in dichloromethane (15 mL) was stirred at room temperature for 16 h. The mixture was quenched with water (10 mL), extracted with ethyl acetate (50 mL x 2), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 1:1) to give 17-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)-3,6,9,12,15-pentaoxaheptadecyl 4-methylbenzenesulfonate (0.15 g, 49.8%) as a white solid. MS (ESI) m / z 902.3 [M+H] + 。

[0371] Step 2.2-(3-((17-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3,6,9,12,15-pentaoxaheptadecyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of 17-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)-3,6,9,12,15-pentaoxaheptadecyl 4-methylbenzenesulfonate (130 mg, 0.14 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (56 mg, 0.2 mmol), and potassium carbonate (59.0 mg, 0.42 mmol) in N,N-dimethylformamide (8.0 mL). The reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was purified by preparative HPLC (column: Welch Xtimate 21.2 x 250 mm C18, 10 μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 min) to give 2-(3-((17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3,6,9,12,15-pentaoxaheptadecyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (14.2 mg, 10% yield) as a white solid. TIFF2025523575000103.tif41153 * Multiple signals arising from very broad and hard-to-see conformational isomers.

[0372] Example 20 Synthesis of N-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)-2-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)phenyl)acetamide (Compound No. 22) TIFF2025523575000104.tif142152

[0373] Step 1. Cyclopropyl(indolin-1-yl)methanone A solution of indoline (5.00 g, 42.0 mmol) and triethylamine (12.74 g, 125.9 mmol) in dichloromethane (150 mL) was added cyclopropanecarbonyl chloride (4.39 g, 42.0 mmol) at 0 °C. After the addition, the mixture was stirred at room temperature for 18 h. The mixture was quenched with water (50 mL), extracted with dichloromethane (50 mL), washed with saturated aqueous ammonium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo to give cyclopropyl(indolin-1-yl)methanone (6.0 g, 77% yield) as a white solid. MS (ESI) m / z 188.3 [M+H] + .

[0374] Step 2. 2-Bromo-1-(1-(cyclopropanecarbonyl)indolin-5-yl)propan-1-one Cyclopropyl(indolin-1-yl)methanone (6.00 g, 32.0 mmol) and aluminum chloride (21.36 g, 160.2 mmol) were dissolved in dichloromethane (150 mL), then 2-bromopropanoyl bromide (34.58 g, 160.2 mmol) was added. The mixture was stirred at 50 °C for 5 h. The mixture was quenched with water (200 mL), basified to pH = 8 - 10 with 6N sodium hydroxide solution, extracted with dichloromethane (600 mL), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo to give crude 2-bromo-1-(1-(cyclopropanecarbonyl)indolin-5-yl)propan-1-one (10.0 g, 97% yield) as a yellow oil. MS (ESI) m / z 322.0 and 324.0 [M+H] + .

[0375] Step 3. (5-(2-Amino-5-methylthiazol-4-yl)indolin-1-yl)(cyclopropyl)methanone A solution of 2-bromo-1-(1-(cyclopropanecarbonyl)indolin-5-yl)propan-1-one (10.0 g, 31.0 mmol) and thiourea (5.91 g, 77.6 mmol) in ethanol (150 mL) was stirred at 70 °C for 18 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 1:1) to afford (5-(2-amino-5-methylthiazol-4-yl)indolin-1-yl)(cyclopropyl)methanone (7.0 g, 76% yield) as a yellow solid. MS (ESI) m / z 300.1 [M+H] + .

[0376] Step 4. N-(4-(1-(Cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)-2-(3-hydroxyphenyl)acetamide A solution of 2-(3-hydroxyphenyl)acetic acid (1.00 g, 6.57 mmol), di(1H-imidazol-1-yl)methanone (1.60 g, 9.86 mmol) and N,N-diisopropylethylamine (3.40 g, 26.3 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 30 min. (5-(2-Amino-5-methylthiazol-4-yl)indolin-1-yl)(cyclopropyl)methanone (2.16 g, 7.23 mmol) was added to the resulting mixture. The mixture was stirred at 65 °C for 18 h. The mixture was cooled to room temperature, diluted with water (100 mL), extracted with dichloromethane (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane / methanol = 3 / 97) to afford N-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)-2-(3-hydroxyphenyl)acetamide (0.50 g, 17.6% yield) as a white solid. MS (ESI) m / z 434.1 [M+H] + .

[0377] Step 5. tert-Butyl (2-(2-(3-(2-((4-(1-(Cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethyl)carbamate A solution of N-(4-(1-(Cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)-2-(3-hydroxyphenyl)acetamide (0.50 g, 1.15 mmol), 2-(2-((tert-Butoxycarbonyl)amino)ethoxy)ethyl 4-methylbenzenesulfonate (0.46 g, 1.28 mmol), and potassium tert-butoxide (0.39 g, 3.46 mmol) in N,N-dimethylformamide (15 mL) was stirred at room temperature for 24 h. The mixture was quenched with water (50 mL), extracted with dichloromethane (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane / methanol = 3 / 97) to afford crude tert-butyl (2-(2-(3-(2-((4-(1-(Cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethyl)carbamate (0.30 g, 42% yield) as a white solid. MS (ESI) m / z 621.0 [M+H] + 。

[0378] Step 6. 2-(3-(2-(2-Aminoethoxy)ethoxy)phenyl)-N-(4-(1-(Cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)acetamide A solution of tert-butyl (2-(2-(3-(2-((4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethyl)carbamate (0.30 g, 0.48 mmol) in trifluoroacetic acid (30 mL) and dichloromethane (15 mL) was stirred at room temperature for 18 h. The mixture was diluted with water (100 mL) and extracted with 2-methoxy-2-methylpropane (50.0 x 2). The aqueous phase was then basified with saturated aqueous sodium carbonate and extracted with dichloromethane (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2 x 250 mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 min) to give 2-(3-(2-(2-aminoethoxy)ethoxy)phenyl)-N-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)acetamide (20 mg, 8% yield) as a white solid. MS (ESI) m / z 521.0 [M+H] + .

[0379] Step 7. N-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)-2-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)phenyl)acetamide A solution of 2-(3-(2-(2-aminoethoxy)ethoxy)phenyl)-N-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)acetamide (0.020 g, 0.038 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (0.012 g, 0.04 mmol) and N,N-diisopropylethylamine (0.020 g, 0.15 mmol) in 1-methylpyrrolidin-2-one (1.0 mL) was stirred at 140 °C for 18 h. The reaction mixture was purified by preparative HPLC (column: Welch Xtimate 21.2 x 250 mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 min) to give N-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)-2-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)phenyl)acetamide (4.4 mg, 15% yield) as a yellow solid. TIFF2025523575000105.tif41153 Note: The acidic proton usually around 12.3 ppm is not visible).

[0380] Example 21 Synthesis of 2-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(1-methyl-1H-imidazole-5-carbonyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 23) TIFF2025523575000106.tif157149

[0381] Step 1. 1-((2-Nitrophenyl)sulfonyl)indoline A solution of indoline (5.00 g, 42.0 mmol) and triethylamine (12.74 g, 125.9 mmol) in dichloromethane (150 mL) was added with 2-nitrobenzenesulfonyl chloride (9.29 g, 42.0 mmol) at 0 °C. After the addition, the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (50 mL), extracted with dichloromethane (50 mL), washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and 1-((2-nitrophenyl)sulfonyl)indoline (7.0 g, 55% yield) was obtained as a yellow solid. MS (ESI) m / z: 305.0 [M+H] + 。

[0382] Step 2. 2-Bromo-1-(1-((2-nitrophenyl)sulfonyl)indolin-5-yl)propan-1-one 1-((2-Nitrophenyl)sulfonyl)indoline (7.0 g, 23.0 mmol) and aluminum chloride (9.21 g, 69.1 mmol) were dissolved in dichloromethane (150 mL), and then 2-bromopropanoyl bromide (14.91 g, 69.07 mmol) was added. The mixture was stirred at 50 °C for 5 h. The mixture was quenched with water (500 mL), basified to pH = 8 - 10 with 6N NaOH solution, extracted with dichloromethane (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and crude 2-bromo-1-(1-((2-nitrophenyl)sulfonyl)indolin-5-yl)propan-1-one (9.0 g, 89%) was obtained as a yellow oil. MS (ESI) m / z: 439.0 and 441.0 [M+H] + 。

[0383] Step 3. 5-Methyl-4-(1-((2-nitrophenyl)sulfonyl)indolin-5-yl)thiazol-2-amine A solution of 2-bromo-1-(1-((2-nitrophenyl)sulfonyl)indolin-5-yl)propan-1-one (9.0 g, 20.5 mmol) and thiourea (3.89 g, 51.2 mmol) in ethanol (150 mL) was stirred at 75 °C for 18 h. The mixture was cooled to room temperature, diluted with water (100 mL), extracted with dichloromethane (200 mL), washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 1:1) to give 5-methyl-4-(1-((2-nitrophenyl)sulfonyl)indolin-5-yl)thiazol-2-amine (6.0 g, 72% yield) as a yellow solid. MS (ESI) m / z: 417.1 [M+H] + .

[0384] Step 4. 2-(3-Hydroxyphenyl)-N-(5-methyl-4-(1-((2-nitrophenyl)sulfonyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of 2-(3-hydroxyphenyl)acetic acid (2.00 g, 13.1 mmol), di(1H-imidazol-1-yl)methanone (3.19 g, 19.7 mmol) and N,N-diisopropylethylamine (6.79 g, 52.6 mmol) in N,N-dimethylformamide (40 mL) was stirred at room temperature for 30 minutes. 5-Methyl-4-(1-((2-nitrophenyl)sulfonyl)indolin-5-yl)thiazol-2-amine (6.02 g, 14.5 mmol) was added to the resulting mixture. The mixture was stirred at 65 °C for 18 hours. The mixture was cooled to room temperature, diluted with water (100 mL), extracted with dichloromethane (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane / methanol = 3 / 97) to give 2-(3-hydroxyphenyl)-N-(5-methyl-4-(1-((2-nitrophenyl)sulfonyl)indolin-5-yl)thiazol-2-yl)acetamide (1.8 g, 25% yield) as a white solid. MS (ESI) m / z: 551.0 [M+H] + .

[0385] Step 5. tert-Butyl (2-(2-(3-(2-((5-methyl-4-(1-((2-nitrophenyl)sulfonyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethyl)carbamate A solution of 2-(3-hydroxyphenyl)-N-(5-methyl-4-(1-((2-nitrophenyl)sulfonyl)indolin-5-yl)thiazol-2-yl)acetamide (1.50, 2.72 mmol), 2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl 4-methylbenzenesulfonate (1.37 g, 3.81 mmol), and cesium carbonate (1.79 g, 5.45 mmol) in N,N-dimethylformamide (30 mL) was stirred at room temperature for 24 h. The mixture was diluted with water (50 mL), extracted with dichloromethane (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane / methanol = 3 / 97) to give tert-butyl (2-(2-(3-(2-((5-methyl-4-(1-((2-nitrophenyl)sulfonyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethyl)carbamate (1.5 g, 75% yield) as a white solid. MS (ESI) m / z: 738.2 [M+H] + .

[0386] Step 6. tert-Butyl (2-(2-(3-(2-((4-(Indolin-5-yl)-5-methylthiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethyl)carbamate A solution of tert-butyl (2-(2-(3-(2-((5-methyl-4-(1-((2-nitrophenyl)sulfonyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethyl)carbamate (1.40 g, 1.90 mmol), potassium carbonate (0.29 g, 2.09 mmol), and thiophenol (0.42 g, 3.8 mmol) in N,N-dimethylformamide (20.0 mL) was stirred at room temperature for 18 h. The reaction mixture was diluted with water (40 mL), extracted with dichloromethane (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane / methanol = 20 / 1) to give tert-butyl (2-(2-(3-(2-((4-(indolin-5-yl)-5-methylthiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethyl)carbamate (0.8 g, 76% yield) as a white solid. MS (ESI) m / z: 553.2 [M+H] + .

[0387] Step 7. tert-Butyl (2-(2-(3-(2-((5-methyl-4-(1-(1-methyl-1H-imidazole-5-carbonyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethyl)carbamate A solution of 1-methyl-1H-imidazole-5-carboxylic acid (0.05 g, 0.40 mmol), tert-butyl (2-(2-(3-(2-((4-(indolin-5-yl)-5-methylthiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethyl)carbamate (0.26 g, 0.48 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.23 g, 0.59 mmol) and triethylamine (0.14 g, 1.4 mmol) in dichloromethane (20 mL) was stirred at room temperature for 18 h. The mixture was diluted with water (20 mL), extracted with dichloromethane (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane / methanol = 3 / 97) to give tert-butyl (2-(2-(3-(2-((5-methyl-4-(1-(1-methyl-1H-imidazole-5-carbonyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethyl)carbamate (0.12 g, 46%) as a white solid. MS (ESI) m / z: 661.0 [M+H] + .

[0388] Step 8. 2-(3-(2-(2-Aminoethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(1-methyl-1H-imidazole-5-carbonyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of tert-butyl (2-(2-(3-(2-((5-methyl-4-(1-(1-methyl-1H-imidazole-5-carbonyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethyl)carbamate (0.12 g, 0.18 mmol) in trifluoroacetic acid (15 mL) and dichloromethane (15 mL) was stirred at room temperature for 18 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC (column: Welch Xtimate 21.2 x 250 mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 min) to give 2-(3-(2-(2-aminoethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(1-methyl-1H-imidazole-5-carbonyl)indolin-5-yl)thiazol-2-yl)acetamide (65 mg, 65% yield) as a white solid. MS (ESI) m / z: 561.0 [M+H] + .

[0389] Step 9. 2-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(1-methyl-1H-imidazole-5-carbonyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of 2-(3-(2-(2-aminoethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(1-methyl-1H-imidazole-5-carbonyl)indolin-5-yl)thiazol-2-yl)acetamide (0.065 g, 0.12 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (0.036 g, 0.13 mmol) and N,N-diisopropylethylamine (0.061 g, 0.47 mmol) in 1-methylpyrrolidin-2-one (2.0 mL) was stirred at 140 °C for 18 h. The reaction mixture was purified by preparative HPLC (column: Welch Xtimate 21.2 x 250 mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 min) to give 2-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(1-methyl-1H-imidazole-5-carbonyl)indolin-5-yl)thiazol-2-yl)acetamide (6.7 mg, 7% yield) as a yellow solid. TIFF2025523575000107.tif41153 (Note: Two acidic protons usually around 12.3 ppm and 11.1 ppm are not visible). * Multiple signals arising from conformational isomers.

[0390] Example 22 Synthesis of 2-(3-((20-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-3,6,9,12,15,18-hexaoxacyclohexyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 11) TIFF2025523575000108.tif86149

[0391] 20-Hydroxy-3,6,9,12,15,18-hexaoxacyclohexyl 4-methylbenzenesulfonate A solution of 3,6,9,12,15,18-hexaoxacyclohexane-1,20-diol (5.0 g, 15.3 mmol), triethylamine (4.6 g, 45.9 mmol) and 4-methylbenzenesulfonyl chloride (1.4 g, 7.6 mmol) in dichloromethane (50 mL) was stirred at room temperature for 16 h. The mixture was quenched with water (50 mL), extracted with ethyl acetate (80 mL x 2), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 1:1) to give 20-hydroxy-3,6,9,12,15,18-hexaoxacyclohexyl 4-methylbenzenesulfonate (1.2 g, 32.6% yield) as a yellow oil. MS (ESI) m / z 481.3 [M+H] + 。

[0392] Step 2. 2-(3-((20-Hydroxy-3,6,9,12,15,18-hexaoxacyclohexyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A mixture of 20-hydroxy-3,6,9,12,15,18-hexaoxacyclohexyl 4-methylbenzenesulfonate (0.30 g, 0.62 mmol), 2-(3-hydroxyphenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.36 g, 0.75 mmol), and potassium t-butoxide (0.21 g, 1.87 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 h. The reaction mixture was quenched with water (30 mL), extracted with ethyl acetate (30 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 1:1) to give 2-(3-((20-hydroxy-3,6,9,12,15,18-hexaoxacyclohexyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.26 g, 52.6% yield) as a white solid. MS (ESI) m / z 792.4 [M+H] + .

[0393] Step 3. 2-(3-((20-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-3,6,9,12,15,18-hexaoxacyclohexyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of 2-(3-((20-hydroxy-3,6,9,12,15,18-hexaoxacyclohexyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.26 g, 0.33 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (0.10 g, 0.39 mmol) and triphenylphosphine (0.17 g, 0.66 mmol) in tetrahydrofuran (6.0 mL) was added with diethyl azodicarboxylate (0.07 g, 0.39 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (20 mL), extracted with dichloromethane (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2 x 250 mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 minutes) to give 2-(3-((20-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-3,6,9,12,15,18-hexaoxacyclohexyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (52 mg, 15%) as a white solid. TIFF2025523575000109.tif63153 * Multiple signals arising from conformational isomers.

[0394] Example 23 Synthesis of 2-(3-((20-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3,6,9,12,15,18-hexaoxacyclohexyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 16) TIFF2025523575000110.tif71143

[0395] Step 1. 20-(3-(2-((5-Methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)-3,6,9,12,15,18-hexaoxacyclotricosyl 4-methylbenzenesulfonate A solution of 2-(3-((20-Hydroxy-3,6,9,12,15,18-hexaoxacyclotricosyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.24 g, 0.30 mmol), tosyl chloride (0.06 g, 0.30 mmol) and triethylamine (0.091 g, 0.90 mmol) in dichloromethane (10 mL) was stirred at room temperature for 12 h. The mixture was diluted with water (10 mL), extracted with dichloromethane (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane) to give 20-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)-3,6,9,12,15,18-hexaoxacyclotricosyl 4-methylbenzenesulfonate (0.13 g, 45.4% yield) as a white solid. MS (ESI) m / z 946.4 [M+H] + .

[0396] Step 2. 2-(3-((20-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3,6,9,12,15,18-hexaoxacyclotricosyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of 20-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)-3,6,9,12,15,18-hexaoxacyclohexyl 4-methylbenzenesulfonate (0.11 g, 0.12 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (0.03 g, 0.12 mmol) and potassium carbonate (0.07 g, 0.53 mmol) in N,N-dimethylformamide (8.0 mL) was stirred at 50 °C for 16 h. The reaction mixture was purified by preparative HPLC (column: Welch Xtimate 21.2 x 250 mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 min), and 2-(3-((20-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3,6,9,12,15,18-hexaoxacyclohexyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (9.0 mg, 7.3%) was obtained as a white solid. TIFF2025523575000111.tif56153 * Multiple signals arising from conformational isomers.

[0397] Example 24 Synthesis of 2-(3-((23-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3,6,9,12,15,18,21-heptaoxatricosyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 17) TIFF2025523575000112.tif95150

[0398] Step 1. 23-Hydroxy-3,6,9,12,15,18,21-heptaoxatricosyl 4-methylbenzenesulfonate A solution of 3,6,9,12,15,18,21-heptaoxatricosane-1,23-diol (3.7 g, 10.0 mmol), triethylamine (3.0 g, 30 mmol) and 4-methylbenzenesulfonyl chloride (0.95 g, 5.0 mmol) in dichloromethane (30 mL) was stirred at room temperature for 16 h. The mixture was quenched with water (50 mL), extracted with ethyl acetate (50 mL x 2), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 1:1) to afford 23-hydroxy-3,6,9,12,15,18,21-heptaoxatricosyl 4-methylbenzenesulfonate (2.6 g, 99% yield) as a yellow oil. MS (ESI) m / z 525.3 [M+H] + .

[0399] Step 2. 2-(3-((23-Hydroxy-3,6,9,12,15,18,21-heptaoxatricosyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of 23-hydroxy-3,6,9,12,15,18,21-heptaoxatricosyl 4-methylbenzenesulfonate (0.26 g, 0.50 mmol), 2-(3-hydroxyphenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.24 g, 0.50 mmol), and potassium t-butoxide (0.22 g, 2.0 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 h. The reaction mixture was quenched with water (20 mL), extracted with ethyl acetate (30 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 1:1) to give 2-(3-((23-hydroxy-3,6,9,12,15,18,21-heptaoxatricosyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.30 g, 72.4% yield) as a white solid. MS (ESI) m / z 837.5 [M+18] + .

[0400] Step 3. 23-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)-3,6,9,12,15,18,21-heptaoxatricosyl methanesulfonate A solution of 2-(3-((23-hydroxy-3,6,9,12,15,18,21-heptaoxatricosyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.25 g, 0.30 mmol) and triethylamine (0.91 g, 0.90 mmol) in dichloromethane (15 mL) was added methanesulfonyl chloride (0.069 g, 0.60 mmol) at 0 °C. After the addition, the reaction mixture was stirred at room temperature for 16 h. The mixture was quenched with water (10 mL), extracted with ethyl acetate (20 mL x 2), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 2:3) to give 23-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)-3,6,9,12,15,18,21-heptaoxatricosyl methanesulfonate (0.19 g, 69.5% yield) as a yellow solid. MS (ESI) m / z 914.5 [M+H] + .

[0401] Step 4. 2-(3-((23-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3,6,9,12,15,18,21-heptaoxatricosyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of 23-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)-3,6,9,12,15,18,21-heptaoxatricosyl methanesulfonate (0.19 g, 0.21 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (0.057 g, 0.21 mmol), and potassium carbonate (0.072 g, 0.52 mmol) in N,N-dimethylformamide (8.0 mL) was stirred at 50 °C for 16 h. The reaction mixture was purified by preparative HPLC (column: Welch Xtimate 21.2 x 250 mm C18, 10 μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 min) to give 2-(3-((23-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3,6,9,12,15,18,21-heptaoxatricosyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (15.2 mg, 6.7% yield) as a white solid. TIFF2025523575000113.tif49153 * Multiple signals arising from conformational isomers. ** The signal is under the peak of water but is clearly visible in the NMR performed at RT.

[0402] Example 25 Synthesis of 2-(3-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 24) TIFF2025523575000114.tif83148

[0403] Step 1. tert-Butyl 4-(2-(3-(2-((5-Methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethyl)piperazine-1-carboxylate A solution of 2-(3-Hydroxyphenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.50 g, 1.03 mmol), tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate (0.26 g, 1.03 mmol) and cesium carbonate (1.01 g, 3.10 mmol) in N,N-dimethylformamide (15 mL) was stirred at 90 °C for 18 h. The mixture was cooled to room temperature, quenched with water (10 mL), extracted with dichloromethane (50 mL), washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane) to give crude tert-butyl 4-(2-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethyl)piperazine-1-carboxylate (0.10 g, 14% yield) as a yellow solid. MS (ESI) m / z 696.4 [M+H] + 。

[0404] Step 2. N-(5-Methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)-2-(3-(2-(piperazin-1-yl)ethoxy)phenyl)acetamide A solution of tert-butyl 4-(2-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethyl)piperazine-1-carboxylate (0.10 g, 0.14 mmol) in hydrochloric acid (4.0 M in dioxane, 8 mL) was stirred at room temperature for 8 hours. The solvent was removed, and the residue was dissolved in dichloromethane (50 mL), washed with saturated aqueous sodium carbonate, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane / methanol = 1 / 20) to give crude N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)-2-(3-(2-(piperazin-1-yl)ethoxy)phenyl)acetamide (50.0 mg, 58% yield) as a yellow solid. MS (ESI) m / z 596.7 [M+H] + .

[0405] Step 3. 2-(3-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)-2-(3-(2-(piperazin-1-yl)ethoxy)phenyl)acetamide (40.0 mg, 0.067 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (18.5 mg, 0.067 mmol) and N,N-diisopropylethylamine (18.0 mg, 0.14 mmol) in 1-methylpyrrolidin-2-one (2 mL) was stirred at 140 °C for 18 h. The mixture was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (20 mL x 4), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2 x 250 mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 min) to give 2-(3-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (6.5 mg, 11% yield) as a yellow solid. TIFF2025523575000115.tif43154 * Multiple signals arising from conformational isomers.

[0406] Example 26 Synthesis of N-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)-2-(3-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-ylamino)ethoxy)ethoxy)-4-fluorophenyl)acetamide (Compound No. 27) TIFF2025523575000116.tif19128TIFF2025523575000117.tif153138

[0407] Step 1. 1-((2-Nitrophenyl)sulfonyl)indoline To a solution of indoline (25.00 g, 209.8 mmol) and triethylamine (63.68 g, 629.4 mmol) in dichloromethane (300 mL) was added 2-nitrobenzenesulfonyl chloride (46.49 g, 209.8 mmol) at 0 °C. After the addition, the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (100 mL), extracted with dichloromethane (250 mL), washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and 1-((2-nitrophenyl)sulfonyl)indoline (54.0 g, 84.5% yield) was obtained as a yellow solid. MS (ESI) m / z: 305.0 [M+H] + 。

[0408] Step 2. 2-Bromo-1-(1-((2-nitrophenyl)sulfonyl)indolin-5-yl)propan-1-one 1-((2-Nitrophenyl)sulfonyl)indoline (54.0 g, 177.4 mmol) and aluminum chloride (70.98 g, 532.3 mmol) were dissolved in dichloromethane (800 mL), and then 2-bromopropanoyl bromide (114.95 g, 532.33 mmol) was added. The mixture was stirred at 50 °C for 16 h. The mixture was cooled to room temperature, quenched with water (500 mL), basified to pH = 8 - 10 with 6 N NaOH solution, extracted with dichloromethane (300 mL), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and crude 2-bromo-1-(1-((2-nitrophenyl)sulfonyl)indolin-5-yl)propan-1-one (76.0 g, 97.5% yield) was obtained as a yellow oil. MS (ESI) m / z: 439.0 and 441.0 [M+H] + 。

[0409] Step 3. 5-Methyl-4-(1-((2-nitrophenyl)sulfonyl)indolin-5-yl)thiazol-2-amine A solution of 2-bromo-1-(1-((2-nitrophenyl)sulfonyl)indolin-5-yl)propan-1-one (76.0 g, 173 mmol) and thiourea (39.51 g, 519.0 mmol) in ethanol (800 mL) was stirred at 75 °C for 18 h. The mixture was cooled to room temperature, diluted with water (1.5 L), and filtered. The filter cake was washed with water (100 mL x 2), dried, and 5-methyl-4-(1-((2-nitrophenyl)sulfonyl)indolin-5-yl)thiazol-2-amine (45.12 g, 62.6% yield) was obtained as a yellow solid. MS (ESI) m / z: 417.1 [M+H] + .

[0410] Step 4. 2-(4-Fluoro-3-hydroxyphenyl)acetic acid A solution of 2-(4-fluoro-3-methoxyphenyl)acetic acid (19.00 g, 103.2 mmol) in hydrobromic acid (40% hydrobromic acid in water, 50 mL) and acetic acid (50 mL) was stirred at 90 °C for 18 h. The solvent was removed in vacuo, the residue was dissolved in dichloromethane (200 mL), washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and 2-(4-fluoro-3-hydroxyphenyl)acetic acid (15.0 g, 85.5%) was obtained as a yellow solid. MS (ESI) m / z: 171.0 [M+H] + .

[0411] Step 5. 2-(4-Fluoro-3-hydroxyphenyl)-N-(5-methyl-4-(1-((2-nitrophenyl)sulfonyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of 2-(4-fluoro-3-hydroxyphenyl)acetic acid (2.86 g, 16.8 mmol), 1,1'-carbonyldiimidazole (4.09 g, 25.2 mmol) and N,N-diisopropylethylamine (6.51 g, 50.4 mmol) in N,N-dimethylformamide (40 mL) was stirred at room temperature for 30 minutes. 5-Methyl-4-(1-((2-nitrophenyl)sulfonyl)indolin-5-yl)thiazol-2-amine (7.00 g, 16.8 mmol) was added to the resulting mixture. The mixture was stirred at 65 °C for 18 hours. The mixture was cooled to room temperature, diluted with water (100 mL), extracted with dichloromethane (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane / methanol = 1 / 20) to give 2-(4-fluoro-3-hydroxyphenyl)-N-(5-methyl-4-(1-(2-nitrophenylsulfonyl)indolin-5-yl)thiazol-2-yl)acetamide (5.20 g, 54.4% yield) as a yellow solid. MS (ESI) m / z 569.0 [M+H] + .

[0412] Step 6. tert-Butyl 2-(2-(2-fluoro-5-(2-(5-methyl-4-(1-(2-nitrophenylsulfonyl)indolin-5-yl)thiazol-2-ylamino)-2-oxoethyl)phenoxy)ethoxy)ethylcarbamate 2-(4-Fluoro-3-hydroxyphenyl)-N-(5-methyl-4-(1-((2-nitrophenyl)sulfonyl)indolin-5-yl)thiazol-2-yl)acetamide (5.00 g, 8.79 mmol), 2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl 4-methylbenzenesulfonate (3.16 g, 8.79 mmol), and cesium carbonate (5.73 g, 17.59 mmol) in N,N-dimethylformamide (30 mL) were stirred at room temperature for 18 h. The mixture was diluted with water (50 mL) and extracted with dichloromethane (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane / methanol = 1 / 20) to give tert-butyl (2-(2-(2-fluoro-5-(2-((5-methyl-4-(1-((2-nitrophenyl)sulfonyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethyl)carbamate (3.61 g, 54.3% yield) as a yellow solid. MS (ESI) m / z 756.2 [M+H] + .

[0413] Step 7. tert-Butyl 2-(2-(2-Fluoro-5-(2-(4-(indolin-5-yl)-5-methylthiazol-2-ylamino)-2-oxoethyl)phenoxy)ethoxy)ethylcarbamate A solution of tert-butyl (2-(2-(2-fluoro-5-(2-((5-methyl-4-(1-((2-nitrophenyl)sulfonyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethyl)carbamate (3.50 g, 4.63 mmol), potassium carbonate (1.28 g, 9.26 mmol), and thiophenol (0.72 g, 5.56 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 18 h. The reaction mixture was diluted with water (40 mL), extracted with dichloromethane (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane / methanol = 20 / 1) to give tert-butyl 2-(2-(2-fluoro-5-(2-(4-(indolin-5-yl)-5-methylthiazol-2-ylamino)-2-oxoethyl)phenoxy)ethoxy)ethylcarbamate (2.42 g, 91.5% yield) as a yellow solid. MS (ESI) m / z: 571.3 [M+H] + .

[0414] Step 8. tert-Butyl 2-(2-(5-(2-(4-(1-(Cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-ylamino)-2-oxoethyl)-2-fluorophenoxy)ethoxy)ethylcarbamate A solution of tert-butyl 2-(2-(2-fluoro-5-(2-(4-(indolin-5-yl)-5-methylthiazol-2-ylamino)-2-oxoethyl)phenoxy)ethoxy)ethylcarbamate (0.60 g, 1.05 mmol) and triethylamine (0.32 g, 3.15 mmol) in dichloromethane (15 mL) was added cyclopropanecarbonyl chloride (0.12 g, 1.10 mmol) at 0 °C. The mixture was stirred at room temperature for 6 h. The mixture was quenched with water (10 mL), extracted with dichloromethane (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane / methanol = 20 / 1) to give tert-butyl 2-(2-(5-(2-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-ylamino)-2-oxoethyl)-2-fluorophenoxy)ethoxy)ethylcarbamate (0.55 g, 82% yield) as a yellow solid. MS (ESI) m / z 639.3 [M+H] + .

[0415] Step 9. 2-(3-(2-(2-Aminoethoxy)ethoxy)-4-fluorophenyl)-N-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)acetamide A solution of tert-butyl 2-(2-(5-(2-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-ylamino)-2-oxoethyl)-2-fluorophenoxy)ethoxy)ethylcarbamate (0.50 g, 0.78 mmol) and trifluoroacetic acid (3 mL) in dichloromethane (5 mL) was stirred at room temperature for 18 h. The solvent was removed in vacuo, and the residue was dissolved in dichloromethane (40 mL), washed with saturated aqueous sodium carbonate, dried over anhydrous sodium, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane / methanol = 1 / 10) to give 2-(3-(2-(2-aminoethoxy)ethoxy)-4-fluorophenyl)-N-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)acetamide (0.35 g, 83% yield) as a yellow solid. MS (ESI) m / z 539.1 [M+H] + .

[0416] Step 10. N-(4-(1-(Cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)-2-(3-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-ylamino)ethoxy)ethoxy)-4-fluorophenyl)acetamide A solution of 2-(3-(2-(2-aminoethoxy)ethoxy)-4-fluorophenyl)-N-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)acetamide (100 mg, 0.19 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (51.1 mg, 0.19 mmol) and N,N-diisopropylethylamine (72.0 mg, 0.56 mmol) in 1-methylpyrrolidin-2-one (2 mL) was stirred at 140 °C for 18 h. The mixture was diluted with water (10 mL), extracted with ethyl acetate (20 mL x 4), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250 mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 min) to give N-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)-2-(3-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-ylamino)ethoxy)ethoxy)-4-fluorophenyl)acetamide (18.1 mg, 12% yield) as a yellow solid. TIFF2025523575000118.tif49153

[0417] Example 27 Synthesis of 2-(3-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 25) TIFF2025523575000119.tif139132

[0418] Step 1. tert-Butyl 4-(3-chloropropyl)piperazine-1-carboxylate A solution of tert-butyl piperazine-1-carboxylate (3.00 g, 16.1 mmol), 1-bromo-3-chloropropane (2.54 g, 16.1 mmol), and potassium carbonate (4.45 g, 32.2 mmol) in N,N-dimethylformamide (40 mL) was stirred at room temperature for 18 h. The mixture was diluted with water (100 mL), extracted with ethyl acetate (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford tert-butyl 4-(3-chloropropyl)piperazine-1-carboxylate (2.0 g, 47% yield) as a colorless oil. MS (ESI) m / z 263.1 [M+H] + .

[0419] Step 2. tert-Butyl 4-(3-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)propyl)piperazine-1-carboxylate A solution of tert-butyl 4-(3-chloropropyl)piperazine-1-carboxylate (0.50 g, 1.9 mmol), 2-(3-hydroxyphenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.92 g, 1.9 mmol) and cesium carbonate (1.86 g, 5.70 mmol) in N,N-dimethylformamide (10 mL) was stirred at 90 °C for 18 h. The mixture was diluted with water (25 mL), extracted with dichloromethane (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane / methanol = 1 / 10) to give tert-butyl 4-(3-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)propyl)piperazine-1-carboxylate (0.14 g, 10.4% yield) as a yellow solid. MS (ESI) m / z 710.3 [M+H] + .

[0420] Step 3. N-(5-Methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)-2-(3-(3-(piperazin-1-yl)propoxy)phenyl)acetamide A solution of tert-butyl 4-(3-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)propyl)piperazine-1-carboxylate (0.14 g, 0.20 mmol) in hydrochloric acid (4 M in 1,4-dioxane, 4 mL) and 1,4-dioxane (2 mL) was stirred at room temperature for 18 h. The solvent was removed, and the residue was dissolved in dichloromethane (100 mL), washed with saturated aqueous sodium carbonate, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane / methanol = 1 / 10) to give N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)-2-(3-(3-(piperazin-1-yl)propoxy)phenyl)acetamide (0.11 g, 91% yield) as a yellow solid. MS (ESI) m / z 610.3 [M+H] + .

[0421] Step 4. 2-(3-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)-2-(3-(3-(piperazin-1-yl)propoxy)phenyl)acetamide (0.11 g, 0.18 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (54.8 mg, 0.20 mmol) and N,N-diisopropylethylamine (69.9 mg, 0.54 mmol) in N-methylpyrrolidone (5 mL) was stirred at 140 °C for 18 h. The mixture was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 min) to give 2-(3-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (16.7 mg, 10.7% yield) as a yellow solid. TIFF2025523575000120.tif41153 * Multiple signals arising from conformational isomers.

[0422] Example 28 Synthesis of 2-(3-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)butoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 26) TIFF2025523575000121.tif124140

[0423] Step 1. tert-Butyl 4-(4-(3-(2-ethoxy-2-oxoethyl)phenoxy)butyl)piperazine-1-carboxylate A solution of ethyl 2-(3-hydroxyphenyl)acetate (1.50 g, 8.32 mmol), 1,4-dibromobutane (1.80 g, 8.32 mmol), and cesium carbonate (8.14 g, 24.97 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 18 h. tert-Butyl piperazine-1-carboxylate (1.55 g, 8.31 mmol) was added to the resulting mixture. The mixture was stirred at room temperature for 18 h. The mixture was quenched with water (50 mL), extracted with dichloromethane (100 mL × 2), washed with brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% at 15.0 min) to give tert-butyl 4-(4-(3-(2-ethoxy-2-oxoethyl)phenoxy)butyl)piperazine-1-carboxylate (0.40 g, 11.5% yield) as a white solid. MS (ESI) m / z 421.3 [M+H] + 。

[0424] Step 2. 2-(3-(4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)butoxy)phenyl)acetic acid A solution of tert-butyl 4-(4-(3-(2-ethoxy-2-oxoethyl)phenoxy)butyl)piperazine-1-carboxylate (0.40 g, 0.95 mmol) and sodium hydroxide (0.11 g, 2.85 mmol) in water (5 mL) and methanol (20 mL) was stirred at room temperature for 18 h. The mixture was acidified with 2 M aqueous hydrochloric acid to give pH = 1 - 3, extracted with dichloromethane (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% at 15.0 min) to give 2-(3-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)butoxy)phenyl)acetic acid (0.26 g, 69.8% yield) as a white solid. MS (ESI) m / z 393.4 [M+H] + .

[0425] Step 3. tert-butyl 4-(4-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)butyl)piperazine-1-carboxylate A solution of 2-(3-(4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)butoxy)phenyl)acetic acid (0.26 g, 0.66 mmol), (5-(2-Amino-5-methylthiazol-4-yl)indolin-1-yl)(o-tolyl)methanone (0.46 g, 1.32 mmol), 2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.50 g, 1.32 mmol) and triethylamine (0.27 g, 2.65 mmol) in N,N-Dimethylformamide (10 mL) was stirred at room temperature for 48 h. The mixture was diluted with water (50 mL), extracted with dichloromethane (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 min) to give tert-Butyl 4-(4-(3-(2-((5-Methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)butyl)piperazine-1-carboxylate (0.11 g, 23.0% yield) as a white solid. MS (ESI) m / z 724.4 [M+H] + .

[0426] Step 4. N-(5-Methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)-2-(3-(4-(piperazin-1-yl)butoxy)phenyl)acetamide A solution of tert-butyl 4-(4-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)butyl)piperazine-1-carboxylate (0.11 g, 0.15 mmol) and hydrochloric acid (4 M in dioxane, 8 mL) in dioxane (8 mL) was stirred at room temperature for 7 hours. The solvent was removed in vacuo, and the residue was dissolved in dichloromethane (80 mL), washed with saturated aqueous sodium carbonate, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo to give N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)-2-(3-(4-(piperazin-1-yl)butoxy)phenyl)acetamide (70.0 mg, 74.8%) as a yellow solid. MS (ESI) m / z 624.3 [M+H] + .

[0427] Step 5. 2-(3-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)butoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)-2-(3-(4-(piperazin-1-yl)butoxy)phenyl)acetamide (0.070 g, 0.11 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (46.1 mg, 0.17 mmol), and N,N-diisopropylethylamine (43.9 mg, 0.34 mmol) in 1-methylpyrrolidin-2-one (2 mL) was stirred at 140 °C for 18 h. The mixture was cooled to room temperature, diluted with water (10 mL), extracted with dichloromethane (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10 μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 min) to give 2-(3-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)butoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (55.0 mg, 55.7% yield) as a yellow solid. TIFF2025523575000122.tif49153*Multiple signals arising from conformational isomers.

[0428] Example 29 Synthesis of N-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)-2-(3-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-ylamino)ethoxy)ethoxy)-4-fluorophenyl)acetamide (Compound No. 28) TIFF2025523575000123.tif223120

[0429] Step 1. 5-(2-(2-Hydroxyethoxy)ethylamino)isobenzofuran-1(3H)-one A solution of 5-fluoroisobenzofuran-1(3H)-one (5.00 g, 32.9 mmol), 2-(2-aminoethoxy)ethanol (4.15 g, 39.4 mmol), and N,N-diisopropylethylamine (12.74 g, 98.61 mmol) in 1-methylpyrrolidin-2-one (50 mL) was stirred at 140 °C for 18 h. The mixture was cooled to room temperature, diluted with water (50 mL), extracted with dichloromethane (25 mL x 8), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15 min) to give 5-(2-(2-hydroxyethoxy)ethylamino)isobenzofuran-1(3H)-one (5.10 g, 65.3% yield) as a white solid. MS (ESI) m / z: 237.9 [M+H] + 。

[0430] Step 2. 2-(2-(1-Oxo-1,3-dihydroisobenzofuran-5-ylamino)ethoxy)ethyl methanesulfonate A solution of 5-(2-(2-hydroxyethoxy)ethylamino)isobenzofuran-1(3H)-one (5.00 g, 21.1 mmol) and potassium carbonate (11.65 g, 84.30 mmol) in dichloromethane (50 mL) was added methanesulfonyl chloride (2.90 g, 25.29 mmol) at 0 °C. After the addition, the mixture was stirred at room temperature for 18 h. Then another methanesulfonyl chloride (3.62 g, 31.61 mmol) was added at room temperature and the mixture was stirred at room temperature for a further 18 h. The mixture was diluted with water (50 mL), extracted with dichloromethane (50 mL x 3), washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and 2-(2-(1-oxo-1,3-dihydroisobenzofuran-5-ylamino)ethoxy)ethyl methanesulfonate (3.80 g, 57.1% yield) was obtained as an off-white solid. MS (ESI) m / z: 315.9 [M+H] + .

[0431] Step 3a. Methyl 2-(4-fluoro-3-hydroxyphenyl)acetate A solution of 2-(4-fluoro-3-hydroxyphenyl)acetic acid (3.00 g, 17.6 mmol), trimethoxymethane (3.74 g, 35.3 mmol) and 4-methylbenzenesulfonic acid (0.30 g, 1.8 mmol) in methanol (30 mL) was stirred at 50 °C for 18 h. The mixture was diluted with water (30 mL), extracted with dichloromethane (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 5 / 1) to give methyl 2-(4-fluoro-3-hydroxyphenyl)acetate (1.90 g, 58.5% yield) as a white solid. MS (ESI) m / z: 185.1 [M+H] + .

[0432] Step 3. Methyl 2-(4-fluoro-3-(2-(2-(1-oxo-1,3-dihydroisobenzofuran-5-ylamino)ethoxy)ethoxy)phenyl)acetate A solution of 2-(2-(1-oxo-1,3-dihydroisobenzofuran-5-ylamino)ethoxy)ethyl methanesulfonate (3.20 g, 10.1 mmol), methyl 2-(4-fluoro-3-hydroxyphenyl)acetate (1.87 g, 10.1 mmol) and cesium carbonate (13.23 g, 40.59 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 18 h. The mixture was diluted with water (40 mL), extracted with dichloromethane (30 mL x 3), washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo to give crude methyl 2-(4-fluoro-3-(2-(2-(1-oxo-1,3-dihydroisobenzofuran-5-ylamino)ethoxy)ethoxy)phenyl)acetate (4.20 g, over weight) as a yellow solid. MS (ESI) m / z: 404.0 [M+H] + .

[0433] Step 4. 4-(2-(2-(5-(Carboxymethyl)-2-fluorophenoxy)ethoxy)ethylamino)-2-(hydroxymethyl)benzoic acid A solution of methyl 2-(4-fluoro-3-(2-(2-(1-oxo-1,3-dihydroisobenzofuran-5-ylamino)ethoxy)ethoxy)phenyl)acetate (4.20 g, maximum 10.1 mmol) and sodium hydroxide (3.33 g, 83.29 mmol) in methanol (20 mL) and water (20 mL) was stirred at room temperature for 24 h. The mixture was diluted with water (20 mL), acidified to pH = 3 with aqueous hydrochloric acid (2 M), extracted with dichloromethane (30 mL x 5), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15 min) to give 4-(2-(2-(5-(carboxymethyl)-2-fluorophenoxy)ethoxy)ethylamino)-2-(hydroxymethyl)benzoic acid (3.10 g, 75.3% yield) as a white solid. MS (ESI) m / z: 408.1 [M+H] + .

[0434] Step 5. 4-(2-(2-(5-(Carboxymethyl)-2-fluorophenoxy)ethoxy)ethylamino)-2-formylbenzoic acid A solution of 4-(2-(2-(5-(carboxymethyl)-2-fluorophenoxy)ethoxy)ethylamino)-2-(hydroxymethyl)benzoic acid (1.50 g, 3.68 mmol) and Dess-Martin reagent (2.34 g, 5.52 mmol) in dichloromethane (20 mL) was stirred at room temperature for 18 h. The mixture was diluted with water (20 mL), extracted with dichloromethane (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15 min) to give 4-(2-(2-(5-(carboxymethyl)-2-fluorophenoxy)ethoxy)ethylamino)-2-formylbenzoic acid (0.90 g, 60% yield) as a white solid. MS (ESI) m / z: 406.2 [M+H] + .

[0435] Step 6. 4-(2-(2-(5-(Carboxymethyl)-2-fluorophenoxy)ethoxy)ethylamino)-2-((2,6-dioxopiperidin-3-ylamino)methyl)benzoic acid A solution of 4-(2-(2-(5-(carboxymethyl)-2-fluorophenoxy)ethoxy)ethylamino)-2-formylbenzoic acid (0.89 g, 2.2 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (0.54 g, 3.3 mmol) in methanol (30 mL) was added with sodium acetate (0.72 g, 8.78 mmol) and sodium borohydride (0.41 g, 6.59 mmol) at room temperature. After the addition, the mixture was stirred at room temperature for 18 h. The mixture was diluted with water (20 mL), extracted with dichloromethane (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15 min) to give 4-(2-(2-(5-(carboxymethyl)-2-fluorophenoxy)ethoxy)ethylamino)-2-((2,6-dioxopiperidin-3-ylamino)methyl)benzoic acid (0.42 g, 37% yield) as a white solid. MS (ESI) m / z: 517.9 [M+H] + .

[0436] Step 7. N-(4-(1-(Cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)-2-(3-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-ylamino)ethoxy)ethoxy)-4-fluorophenyl)acetamide A solution of 4-(2-(2-(5-(carboxymethyl)-2-fluorophenoxy)ethoxy)ethylamino)-2-((2,6-dioxopiperidin-3-ylamino)methyl)benzoic acid (0.20 g, 0.39 mmol), (5-(2-amino-5-methylthiazol-4-yl)indolin-1-yl)(cyclopropyl)methanone (0.15 g, 0.50 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.37 g, 0.97 mmol) and N,N-diisopropylethylamine (0.20 g, 1.55 mmol) in N,N-dimethylformamide (15 mL) was stirred at room temperature for 18 h. The mixture was diluted with water (25 mL), extracted with dichloromethane (30 mL x 3), washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15 min) to give N-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)-2-(3-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-ylamino)ethoxy)ethoxy)-4-fluorophenyl)acetamide (28.0 mg, 9.3% yield) as a white solid. TIFF2025523575000124.tif63153

[0437] Example 30 Synthesis of 2-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)-4-fluorophenyl)-N-(5-methyl-4-(1-(1-methyl-1H-imidazole-5-carbonyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 29) TIFF2025523575000125.tif144128

[0438] Step 1. tert-Butyl (2-(2-(2-fluoro-5-(2-((5-methyl-4-(1-(1-methyl-1H-imidazole-5-carbonyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethyl)carbamate A solution of 1-methyl-1H-imidazole-5-carboxylic acid (0.10 g, 0.79 mmol), tert-butyl (2-(2-(2-fluoro-5-(2-((4-(indolin-5-yl)-5-methylthiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethyl)carbamate (0.45 g, 0.79 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.45 g, 1.19 mmol), and triethylamine (0.28 g, 2.78 mmol) in dichloromethane (20 mL) was stirred at room temperature for 18 h. The mixture was quenched with water (20 mL), extracted with dichloromethane (100 mL), washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane / methanol = 3 / 97) to afford crude tert-butyl (2-(2-(2-fluoro-5-(2-((5-methyl-4-(1-(1-methyl-1H-imidazole-5-carbonyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethyl)carbamate (0.50 g, 93% yield) as an off-white solid. MS (ESI) m / z 679.2 [M+H] + 。

[0439] Step 2. 2-(3-(2-(2-aminoethoxy)ethoxy)-4-fluorophenyl)-N-(5-methyl-4-(1-(1-methyl-1H-imidazole-5-carbonyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of tert-butyl (2-(2-(2-fluoro-5-(2-((5-methyl-4-(1-(1-methyl-1H-imidazole-5-carbonyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethyl)carbamate (0.50 g, 0.74 mmol) and hydrochloric acid (4 M in 1,4-dioxane, 10 mL) in 1,4-dioxane (2 mL) was stirred at room temperature for 18 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 min) to give 2-(3-(2-(2-aminoethoxy)ethoxy)-4-fluorophenyl)-N-(5-methyl-4-(1-(1-methyl-1H-imidazole-5-carbonyl)indolin-5-yl)thiazol-2-yl)acetamide (0.25 g, 58% yield) as a yellow solid. MS (ESI) m / z 579.2 [M+H] + .

[0440] Step 3. 2-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)-4-fluorophenyl)-N-(5-methyl-4-(1-(1-methyl-1H-imidazole-5-carbonyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of 2-(3-(2-(2-aminoethoxy)ethoxy)-4-fluorophenyl)-N-(5-methyl-4-(1-(1-methyl-1H-imidazole-5-carbonyl)indolin-5-yl)thiazol-2-yl)acetamide (0.12 g, 0.21 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (69.0 mg, 0.25 mmol) and N,N-diisopropylethylamine (0.11 g, 0.83 mmol) in 1-methylpyrrolidin-2-one (2 mL) was stirred at 140 °C for 18 h. The mixture was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 min) to give 2-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)-4-fluorophenyl)-N-(5-methyl-4-(1-(1-methyl-1H-imidazole-5-carbonyl)indolin-5-yl)thiazol-2-yl)acetamide (8.5 mg, 4.9% yield) as a yellow solid. TIFF2025523575000126.tif49153

[0441] Example 31 Synthesis of 2-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)amino)ethoxy)ethoxy)-4-fluorophenyl)-N-(5-methyl-4-(1-(1-methyl-1H-imidazole-5-carbonyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 30) TIFF2025523575000127.tif209129

[0442] Step 1. tert-Butyl 5-(2-amino-5-methylthiazol-4-yl)indoline-1-carboxylate A solution of 4-bromo-5-methylthiazol-2-amine (0.28 g, 1.5 mmol), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline-1-carboxylate (0.50 g, 1.5 mmol), tetrakis(triphenylphosphine)palladium (0.17 g, 0.14 mmol) and potassium carbonate (0.60 g, 4.34 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was stirred at 100 °C for 16 h under a nitrogen atmosphere. The mixture was cooled to room temperature, diluted with water (20 mL), extracted with dichloromethane (25 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15 min) to give tert-butyl 5-(2-amino-5-methylthiazol-4-yl)indoline-1-carboxylate (0.20 g, 42% yield) as a white solid. MS (ESI) m / z: 332.0 [M+H] + .

[0443] Step 2. 4-(2-(2-(5-(Carboxymethyl)-2-fluorophenoxy)ethoxy)ethylamino)-2-formylbenzoic acid A solution of 4-(2-(2-(5-(carboxymethyl)-2-fluorophenoxy)ethoxy)ethylamino)-2-(hydroxymethyl)benzoic acid (1.50 g, 3.68 mmol) and Dess-Martin reagent (2.34 g, 5.52 mmol) in dichloromethane (20 mL) was stirred at room temperature for 18 h. The mixture was diluted with water (20 mL), extracted with dichloromethane (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15 min) to give 4-(2-(2-(5-(carboxymethyl)-2-fluorophenoxy)ethoxy)ethylamino)-2-formylbenzoic acid (0.70 g, 47% yield) as a white solid. MS (ESI) m / z: 406.2 [M+H] + .

[0444] Step 3. 4-(2-(2-(5-(Carboxymethyl)-2-fluorophenoxy)ethoxy)ethylamino)-2-((2,6-dioxopiperidin-3-ylamino)methyl)benzoic acid A solution of 4-(2-(2-(5-(carboxymethyl)-2-fluorophenoxy)ethoxy)ethylamino)-2-formylbenzoic acid (0.68 g, 1.68 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (0.41 g, 2.5 mmol) in methanol (30 mL) was added with sodium acetate (0.55 g, 6.71 mmol) and sodium cyanoborohydride (0.32 g, 5.03 mmol) at room temperature. After the addition, the mixture was stirred at room temperature for 18 h. The mixture was diluted with water (20 mL), extracted with dichloromethane (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15 min) to give 4-(2-(2-(5-(carboxymethyl)-2-fluorophenoxy)ethoxy)ethylamino)-2-((2,6-dioxopiperidin-3-ylamino)methyl)benzoic acid (0.41 g, 47.% yield) as a white solid. MS (ESI) m / z: 517.9 [M+H] + .

[0445] Step 4. tert-Butyl 5-(2-(2-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)amino)ethoxy)ethoxy)-4-fluorophenyl)acetamido)-5-methylthiazol-4-yl)indoline-1-carboxylate A solution of 4-(2-(2-(5-(carboxymethyl)-2-fluorophenoxy)ethoxy)ethylamino)-2-((2,6-dioxopiperidin-3-ylamino)methyl)benzoic acid (0.34 g, 0.66 mmol), tert-butyl 5-(2-amino-5-methylthiazol-4-yl)indoline-1-carboxylate (0.26 g, 0.78 mmol), propylphosphonic anhydride solution (50% (wt%) in ethyl acetate, 2.09 g, 3.28 mmol) and triethylamine (0.33 g, 3.28 mmol) in ethyl acetate (12 mL) was stirred at 65 °C for 5 h. The mixture was cooled to room temperature, diluted with water (20 mL), extracted with dichloromethane (30 mL x 3), washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15 min) to give tert-butyl 5-(2-(2-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)amino)ethoxy)ethoxy)-4-fluorophenyl)acetamido)-5-methylthiazol-4-yl)indoline-1-carboxylate (0.20 g, 37% yield) as a white solid. MS (ESI) m / z: 813.1 [M+H] + .

[0446] Step 5. 2-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)amino)ethoxy)ethoxy)-4-fluorophenyl)-N-(4-(indolin-5-yl)-5-methylthiazol-2-yl)acetamide A solution of tert-butyl 5-(2-(2-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)amino)ethoxy)ethoxy)-4-fluorophenyl)acetamido)-5-methylthiazol-4-yl)indoline-1-carboxylate (0.19 g, 0.23 mmol) in hydrochloric acid (2 M in 1,4-dioxane, 15 mL) and 1,4-dioxane (10 mL) was stirred at room temperature for 18 h. The mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (100 mL), washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and 2-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)amino)ethoxy)ethoxy)-4-fluorophenyl)-N-(4-(indolin-5-yl)-5-methylthiazol-2-yl)acetamide (0.16 g, 96% yield) was obtained as a white solid. MS (ESI) m / z: 713.3 [M+H] + .

[0447] Step 6. 2-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)amino)ethoxy)ethoxy)-4-fluorophenyl)-N-(5-methyl-4-(1-(1-methyl-1H-imidazole-5-carbonyl)indolin-5-yl)thiazol-2-yl)acetamide 2-(3-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)amino)ethoxy)ethoxy)-4-fluorophenyl)-N-(4-(indolin-5-yl)-5-methylthiazol-2-yl)acetamide (0.15 g, 0.21 mmol), 1-methyl-1H-imidazole-5-carboxylic acid (29.2 mg, 0.23 mmol), propylphosphonic anhydride solution (50% (wt%) in ethyl acetate, 0.67 g, 1.05 mmol) and triethylamine (0.11 g, 1.05 mmol) in ethyl acetate (10 mL) were stirred at 65 °C for 3 h. The mixture was cooled to room temperature, diluted with water (20 mL), extracted with dichloromethane (30 mL x 3), washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15 min) to give 2-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)amino)ethoxy)ethoxy)-4-fluorophenyl)-N-(5-methyl-4-(1-(1-methyl-1H-imidazole-5-carbonyl)indolin-5-yl)thiazol-2-yl)acetamide (11.4 mg, 6.6% yield) as a white solid. TIFF2025523575000128.tif56153

[0448] 2-(3-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)amino)ethoxy)ethoxy)-4-fluorophenyl)-N-(5-methyl-4-(1-(1-methyl-1H-imidazole-5-carbonyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 30) can also be prepared according to the following alternative route: TIFF2025523575000129.tif159162TIFF2025523575000130.tif126128

[0449] Step 1. tert-Butyl 5-methyl-4-(1-(2-nitrophenylsulfonyl)indolin-5-yl)thiazol-2-ylcarbamate A solution of 5-methyl-4-(1-(2-nitrophenylsulfonyl)indolin-5-yl)thiazol-2-amine (5.00 g, 12.0 mmol), di-tert-butyl dicarbonate (7.86 g, 36.0 mmol), N,N-diisopropylethylamine (7.76 g, 60.0 mmol) and N,N-dimethylpyridin-4-amine (0.01 g, 0.12 mmol) in dichloromethane (100 mL) was stirred at room temperature for 36 h. The dichloromethane was removed in vacuo. The residue was suspended in ether (100 mL) and filtered. The filter cake was washed with ether (30 mL x 2) and dried to give tert-butyl 5-methyl-4-(1-(2-nitrophenylsulfonyl)indolin-5-yl)thiazol-2-ylcarbamate (2.50 g, 40.3% yield) as a grey solid. MS (ESI) m / z: 517.1 [M+H] + .

[0450] Step 2. tert-Butyl 4-(indolin-5-yl)-5-methylthiazol-2-ylcarbamate A solution of tert-butyl 5-methyl-4-(1-(2-nitrophenylsulfonyl)indolin-5-yl)thiazol-2-ylcarbamate (2.40 g, 4.65 mmol), potassium carbonate (0.71 g, 5.1 mmol) and thiophenol (1.02 g, 9.29 mmol) in N,N-dimethylformamide (30 mL) was stirred at room temperature for 18 h. The mixture was diluted with water (50 mL), extracted with dichloromethane (50 mL x 2), washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane / methanol = 10 / 1) to afford tert-butyl 4-(indolin-5-yl)-5-methylthiazol-2-ylcarbamate (0.70 g, 45% yield) as a yellow solid. MS (ESI) m / z: 332.1 [M+H] + .

[0451] Step 3. tert-Butyl 5-methyl-4-(1-(1-methyl-1H-imidazole-5-carbonyl)indolin-5-yl)thiazol-2-ylcarbamate A solution of tert-butyl 4-(indolin-5-yl)-5-methylthiazol-2-ylcarbamate (0.68 g, 2.05 mmol), 1-methyl-1H-imidazole-5-carboxylic acid (0.52 g, 4.1 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.56 g, 4.10 mmol) and triethylamine (0.83 g, 8.2 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 18 h. The mixture was diluted with water (50 mL), extracted with dichloromethane (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15 min) to give tert-butyl 5-methyl-4-(1-(1-methyl-1H-imidazole-5-carbonyl)indolin-5-yl)thiazol-2-ylcarbamate (0.57 g, 63% yield) as a white solid. MS (ESI) m / z: 440.2 [M+H] + .

[0452] Step 4. (5-(2-Amino-5-methylthiazol-4-yl)indolin-1-yl)(1-methyl-1H-imidazol-5-yl)methanone A solution of tert-butyl 5-methyl-4-(1-(1-methyl-1H-imidazole-5-carbonyl)indoline-5-yl)thiazole-2-ylcarbamate (0.55 g, 1.25 mmol) in hydrochloric acid (2 M in dioxane, 20 mL) was stirred at room temperature for 18 h. The solvent was removed in vacuo. The residue was treated with saturated aqueous sodium carbonate solution and filtered. The filter cake was washed with water (10 mL x 3), dried, and (5-(2-amino-5-methylthiazol-4-yl)indolin-1-yl)(1-methyl-1H-imidazol-5-yl)methanone (0.23 g, 54% yield) was obtained as a yellow solid. MS (ESI) m / z: 340.1 [M+H] + 。

[0453] Step 5. 5-(2-(2-Hydroxyethoxy)ethylamino)isobenzofuran-1(3H)-one A solution of 5-fluoroisobenzofuran-1(3H)-one (10.00 g, 65.74 mmol), 2-(2-aminoethoxy)ethanol (10.37 g, 98.61 mmol) and N,N-diisopropylethylamine (25.49 g, 197.2 mmol) in 1-methylpyrrolidin-2-one (100 mL) was stirred at 140 °C for 18 h. The mixture was cooled to room temperature, diluted with water (100 mL), extracted with dichloromethane (200 mL x 8), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15 min) to give 5-(2-(2-hydroxyethoxy)ethylamino)isobenzofuran-1(3H)-one (13.00 g, 83.4% yield) as a white solid. MS (ESI) m / z: 238.1 [M+H] + 。

[0454] Step 6. 2-(2-(1-Oxo-1,3-dihydroisobenzofuran-5-ylamino)ethoxy)ethyl methanesulfonate To a solution of 5-(2-(2-hydroxyethoxy)ethylamino)isobenzofuran-1(3H)-one (10.98 g, 46.28 mmol) and potassium carbonate (25.58 g, 185.1 mmol) in dichloromethane (100 mL), methanesulfonyl chloride (6.36 g, 55.53 mmol) was added at 0 °C. After the addition, the mixture was stirred at room temperature for 18 h. The mixture was diluted with water (150 mL), extracted with dichloromethane (100 mL x 3), washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and 2-(2-(1-oxo-1,3-dihydroisobenzofuran-5-ylamino)ethoxy)ethyl methanesulfonate (12.50 g, 85.7% yield) was obtained as an off-white solid. MS (ESI) m / z: 316.1 [M+H] + 。

[0455] Step 7. Methyl 2-(4-fluoro-3-(2-(2-(1-oxo-1,3-dihydroisobenzofuran-5-ylamino)ethoxy)ethoxy)phenyl)acetate A solution of 2-(2-(1-oxo-1,3-dihydroisobenzofuran-5-ylamino)ethoxy)ethyl methanesulfonate (8.00 g, 25.4 mmol), methyl 2-(4-fluoro-3-hydroxyphenyl)acetate (4.67 g, 25.4 mmol) and cesium carbonate (33.06 g, 101.5 mmol) in N,N-dimethylformamide (90 mL) was stirred at room temperature for 18 h. The mixture was diluted with water (120 mL), extracted with dichloromethane (100 mL x 3), washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and crude methyl 2-(4-fluoro-3-(2-(2-(1-oxo-1,3-dihydroisobenzofuran-5-ylamino)ethoxy)ethoxy)phenyl)acetate (9.30 g, 90.9% yield) was obtained as a yellow solid. MS (ESI) m / z: 404.1 [M+H] + 。

[0456] Step 8. 4-(2-(2-(5-(Carboxymethyl)-2-fluorophenoxy)ethoxy)ethylamino)-2-(hydroxymethyl)benzoic acid A solution of methyl 2-(4-fluoro-3-(2-(2-(1-oxo-1,3-dihydroisobenzofuran-5-ylamino)ethoxy)ethoxy)phenyl)acetate (9.20 g, 22.8 mmol) and sodium hydroxide (4.56 g, 114 mmol) in methanol (50 mL) and water (50 mL) was stirred at room temperature for 24 hours. The mixture was diluted with water (50 mL), acidified to pH = 3 with aqueous hydrochloric acid (2 M), extracted with dichloromethane (100 mL x 5), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15 minutes) to give 4-(2-(2-(5-(carboxymethyl)-2-fluorophenoxy)ethoxy)ethylamino)-2-(hydroxymethyl)benzoic acid (6.80 g, 73.2% yield) as a white solid. MS (ESI) m / z: 408.1 [M+H] + .

[0457] Step 9. 4-(2-(2-(5-(Carboxymethyl)-2-fluorophenoxy)ethoxy)ethylamino)-2-formylbenzoic acid A solution of 4-(2-(2-(5-(carboxymethyl)-2-fluorophenoxy)ethoxy)ethylamino)-2-(hydroxymethyl)benzoic acid (6.70 g, 16.5 mmol) and Dess-Martin reagent (10.46 g, 24.67 mmol) in dichloromethane (120 mL) was stirred at room temperature for 18 h. The mixture was diluted with water (60 mL), extracted with dichloromethane (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15 min) to give 4-(2-(2-(5-(carboxymethyl)-2-fluorophenoxy)ethoxy)ethylamino)-2-formylbenzoic acid (4.30 g, 64.4% yield) as a white solid. MS (ESI) m / z: 406.1 [M+H] + .

[0458] Step 10. 4-(2-(2-(5-(Carboxymethyl)-2-fluorophenoxy)ethoxy)ethylamino)-2-((2,6-dioxopiperidin-3-ylamino)methyl)benzoic acid A solution of 4-(2-(2-(5-(carboxymethyl)-2-fluorophenoxy)ethoxy)ethylamino)-2-formylbenzoic acid (4.28 g, 10.6 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (2.61 g, 15.8 mmol) in methanol (100 mL) was added with sodium acetate (3.46 g, 42.2 mmol) and sodium borohydride (1.99 g, 31.7 mmol) at room temperature. After the addition, the mixture was stirred at room temperature for 18 h. The mixture was diluted with water (100 mL), extracted with dichloromethane (100 mL × 5), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15 min) to give 4-(2-(2-(5-(carboxymethyl)-2-fluorophenoxy)ethoxy)ethylamino)-2-((2,6-dioxopiperidin-3-ylamino)methyl)benzoic acid (2.80 g, 51.2% yield) as a white solid. MS (ESI) m / z: 518.2 [M+H] + .

[0459] Step 11. 2-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)amino)ethoxy)ethoxy)-4-fluorophenyl)-N-(5-methyl-4-(1-(1-methyl-1H-imidazole-5-carbonyl)indolin-5-yl)thiazol-2-yl)acetamide 4-(2-(2-(5-(Carboxymethyl)-2-fluorophenoxy)ethoxy)ethylamino)-2-((2,6-dioxopiperidin-3-ylamino)methyl)benzoic acid (0.60 g, 1.16 mmol), (5-(2-amino-5-methylthiazol-4-yl)indolin-1-yl)(1-methyl-1H-imidazol-5-yl)methanone (0.39 g, 1.16 mmol), propylphosphonic anhydride solution (50% (wt%) in ethyl acetate, 3.69 g, 5.80 mmol) and triethylamine (0.59 g, 5.8 mmol) in ethyl acetate (25 mL) were stirred at 65 °C for 5 h. The mixture was cooled to room temperature, diluted with water (30 mL), extracted with dichloromethane (50 mL x 3), washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15 min) to give 2-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)amino)ethoxy)ethoxy)-4-fluorophenyl)-N-(5-methyl-4-(1-(1-methyl-1H-imidazole-5-carbonyl)indolin-5-yl)thiazol-2-yl)acetamide (62.0 mg, 6.5% yield) as a white solid. TIFF2025523575000131.tif49158

[0460] Example 32 Synthesis of 2-(3-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 31) TIFF2025523575000132.tif182141

[0461] Step 1. tert-Butyl 4-(2-(3-(2-ethoxy-2-oxoethyl)phenoxy)ethyl)piperazine-1-carboxylate A solution of ethyl 2-(3-hydroxyphenyl)acetate (0.29 g, 1.61 mmol), tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate (0.40 g, 1.61 mmol) and cesium carbonate (1.57 g, 4.83 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 18 h. The mixture was diluted with water (40 mL), extracted with ethyl acetate (50 mL x 2), washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give tert-butyl 4-(2-(3-(2-ethoxy-2-oxoethyl)phenoxy)ethyl)piperazine-1-carboxylate (0.36 g, 57% yield) as an off-white solid. MS (ESI) m / z 393.2 [M+H] + .

[0462] Step 2. 2-(3-(2-(4-(tert-Butoxycarbonyl)piperazin-1-yl)ethoxy)phenyl)acetic acid A solution of tert-butyl 4-(2-(3-(2-ethoxy-2-oxoethyl)phenoxy)ethyl)piperazine-1-carboxylate (0.36 g, 0.92 mmol) and sodium hydroxide (0.11 g, 2.75 mmol) in methanol (20 mL) and water (20 mL) was stirred at room temperature for 16 h. The mixture was acidified to pH = 3 with aqueous hydrochloric acid (2 M), extracted with dichloromethane (30 mL x 4), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% at 15.0 min) to give 2-(3-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethoxy)phenyl)acetic acid (0.26 g, 78% yield) as a white solid. MS (ESI) m / z: 365.2 [M+H] + .

[0463] Step 3. tert-Butyl 4-(2-(3-(2-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-ylamino)-2-oxoethyl)phenoxy)ethyl)piperazine-1-carboxylate A solution of 2-(3-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethoxy)phenyl)acetic acid (0.24 g, 0.66 mmol), (5-(2-amino-5-methylthiazol-4-yl)indolin-1-yl)(o-tolyl)methanone (0.35 g, 0.99 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.38 g, 0.99 mmol) and N,N-diisopropylethylamine (0.34 g, 2.63 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 18 h. The mixture was diluted with water (30 mL), extracted with dichloromethane (40 mL x 2), washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 min) to give tert-butyl 4-(2-(3-(2-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-ylamino)-2-oxoethyl)phenoxy)ethyl)piperazine-1-carboxylate (0.20 g, 44% yield) as an off-white solid. MS (ESI) m / z: 696.3 [M+H] + .

[0464] Step 4. N-(5-Methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)-2-(3-(2-(piperazin-1-yl)ethoxy)phenyl)acetamide A solution of tert-butyl 4-(2-(3-(2-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-ylamino)-2-oxoethyl)phenoxy)ethyl)piperazine-1-carboxylate (0.20 g, 0.29 mmol) in hydrochloric acid (2 M in 1,4-dioxane, 20 mL) was stirred at room temperature for 16 h. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (100 mL), washed with saturated aqueous sodium carbonate, dried over anhydrous sodium sulfate, filtered, concentrated, and N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)-2-(3-(2-(piperazin-1-yl)ethoxy)phenyl)acetamide (0.14 g, 82% yield) was obtained as an off-white solid. MS (ESI) m / z: 596.2 [M+H] + .

[0465] Step 5. 2-(3-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)-2-(3-(2-(piperazin-1-yl)ethoxy)phenyl)acetamide (0.13 g, 0.22 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (0.18 g, 0.65 mmol) and N,N-diisopropylethylamine (0.11 g, 0.87 mmol) in 1-methylpyrrolidin-2-one (10 mL) was stirred at 120 °C for 18 h. The mixture was cooled to room temperature, diluted with water (15 mL), extracted with dichloromethane (30 mL x 2), washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 min) to give 2-(3-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (51.0 mg, 27%) as a yellow solid. TIFF2025523575000133.tif49153 * Multiple signals arising from conformational isomers.

[0466] Example 33 Synthesis of 2-(3-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 32) TIFF2025523575000134.tif174140

[0467] Step 1. tert-Butyl 4-(3-(3-(2-ethoxy-2-oxoethyl)phenoxy)propyl)piperazine-1-carboxylate A solution of 1-bromo-3-chloropropane (2.50 g, 15.88 mmol), ethyl 2-(3-hydroxyphenyl)acetate (2.86 g, 15.9 mmol) and cesium carbonate (15.52 g, 47.6 mmol) in N,N-dimethylformamide (25 mL) was stirred at room temperature for 24 h. tert-Butyl piperazine-1-carboxylate (2.86 g, 15.4 mmol) was added to the resulting mixture, and then the mixture was stirred at room temperature for 24 h. The mixture was diluted with water (60 mL), extracted with ethyl acetate (50 mL x 2), washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% at 15.0 min) to give tert-butyl 4-(3-(3-(2-ethoxy-2-oxoethyl)phenoxy)propyl)piperazine-1-carboxylate (0.85 g, 13% yield) as a white solid. MS (ESI) m / z 407.3 [M+H] + 。

[0468] Step 2. 2-(3-(3-(4-(tert-Butoxycarbonyl)piperazin-1-yl)propoxy)phenyl)acetic acid A solution of tert-butyl 4-(3-(3-(2-ethoxy-2-oxoethyl)phenoxy)propyl)piperazine-1-carboxylate (0.85 g, 2.09 mmol) and sodium hydroxide (0.25 g, 6.27 mmol) in methanol (15 mL) and water (15 mL) was stirred at room temperature for 18 h. The mixture was acidified to pH = 3 with aqueous hydrochloric acid (2 M), extracted with dichloromethane (40 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 min) to give 2-(3-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propoxy)phenyl)acetic acid (0.60 g, 76% yield) as a white solid. MS (ESI) m / z: 379.2 [M+H] + .

[0469] Step 3. tert-Butyl 4-(3-(3-(2-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-ylamino)-2-oxoethyl)phenoxy)propyl)piperazine-1-carboxylate A solution of 2-(3-(3-(4-(tert-Butoxycarbonyl)piperazin-1-yl)propoxy)phenyl)acetic acid (0.58 g, 1.53 mmol), (5-(2-Amino-5-methylthiazol-4-yl)indolin-1-yl)(o-tolyl)methanone (0.80 g, 2.30 mmol), 2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.87 g, 2.30 mmol) and triethylamine (0.62 g, 6.13 mmol) in N,N-Dimethylformamide (10 mL) was stirred at room temperature for 18 h. The mixture was diluted with water (20 mL), extracted with dichloromethane (35 mL x 2), washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 min) to give tert-Butyl 4-(3-(3-(2-(5-Methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-ylamino)-2-oxoethyl)phenoxy)propyl)piperazine-1-carboxylate (0.32 g, 29% yield) as a white solid. MS (ESI) m / z: 710.2 [M+H] + 。

[0470] Step 4. N-(5-Methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)-2-(3-(3-(piperazin-1-yl)propoxy)phenyl)acetamide A solution of tert-butyl 4-(3-(3-(2-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-ylamino)-2-oxoethyl)phenoxy)propyl)piperazine-1-carboxylate (0.32 g, 0.45 mmol) in hydrochloric acid (2 M in 1,4-dioxane, 25 mL) was stirred at room temperature for 5 hours. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (70 mL), washed with saturated aqueous sodium carbonate, dried over anhydrous sodium sulfate, filtered, concentrated, and N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)-2-(3-(3-(piperazin-1-yl)propoxy)phenyl)acetamide (0.27 g, 98% yield) was obtained as an off-white solid. MS (ESI) m / z: 610.2 [M+H] + .

[0471] Step 5. 2-(3-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)-2-(3-(3-(piperazin-1-yl)propoxy)phenyl)acetamide (0.26 g, 0.43 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (0.35 g, 1.28 mmol) and N,N-diisopropylethylamine (0.22 g, 1.71 mmol) in 1-methylpyrrolidin-2-one (10 mL) was stirred at 120 °C for 18 h. The mixture was cooled to room temperature, diluted with water (20 mL), extracted with dichloromethane (30 mL x 2), washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 min) to give 2-(3-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (0.18 g, 48.8%) as a yellow solid. TIFF2025523575000135.tif49153 * Multiple signals arising from conformational isomers.

[0472] Example 34 Synthesis of 2-(3-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)butoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 33) TIFF2025523575000136.tif161128

[0473] Step 1. tert-Butyl 4-(4-(3-(2-ethoxy-2-oxoethyl)phenoxy)butyl)piperazine-1-carboxylate A solution of 1,4-dibromobutane (1.50 g, 6.95 mmol), ethyl 2-(3-hydroxyphenyl)acetate (1.25 g, 6.94 mmol) and cesium carbonate (6.79 g, 20.84 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 24 h. tert-Butyl piperazine-1-carboxylate (1.29 g, 6.95 mmol) was added to the resulting mixture, and then the mixture was stirred at room temperature for 24 h. The mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 2), washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 min) to give tert-butyl 4-(4-(3-(2-ethoxy-2-oxoethyl)phenoxy)butyl)piperazine-1-carboxylate (0.37 g, 13% yield) as an off-white solid. MS (ESI) m / z 421.3 [M+H] + 。

[0474] Step 2. 2-(3-(4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)butoxy)phenyl)acetic acid A solution of tert-butyl 4-(4-(3-(2-ethoxy-2-oxoethyl)phenoxy)butyl)piperazine-1-carboxylate (0.37 g, 0.88 mmol) and sodium hydroxide (0.11 g, 2.64 mmol) in methanol (10 mL) and water (10 mL) was stirred at room temperature for 18 h. The mixture was acidified to pH = 3 with aqueous hydrochloric acid (2 M), extracted with dichloromethane (30 mL x 4), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% at 15.0 min) to give 2-(3-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)butoxy)phenyl)acetic acid (0.10 g, 29% yield) as a white solid. MS (ESI) m / z: 393.1 [M+H] + .

[0475] Step 3. tert-butyl 4-(4-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)butyl)piperazine-1-carboxylate A solution of 2-(3-(4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)butoxy)phenyl)acetic acid (0.10 g, 0.25 mmol), (5-(2-Amino-5-methylthiazol-4-yl)indolin-1-yl)(o-tolyl)methanone (0.14 g, 0.41 mmol), 2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.16 g, 0.41 mmol) and triethylamine (0.10 g, 1.02 mmol) in N,N-Dimethylformamide (4 mL) was stirred at room temperature for 18 h. The mixture was diluted with water (10 mL), extracted with dichloromethane (20 mL x 2), washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 min) to give tert-Butyl 4-(4-(3-(2-((5-Methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)butyl)piperazine-1-carboxylate (25.0 mg, 14% yield) as an off-white solid. MS (ESI) m / z: 724.3 [M+H] + .

[0476] Step 4. N-(5-Methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)-2-(3-(4-(piperazin-1-yl)butoxy)phenyl)acetamide A solution of tert-butyl 4-(4-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)butyl)piperazine-1-carboxylate (25.0 mg, 0.035 mmol) in hydrochloric acid (2 M in 1,4-dioxane, 5 mL) was stirred at room temperature for 6 hours. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (40 mL), washed with saturated aqueous sodium carbonate, dried over anhydrous sodium sulfate, filtered, concentrated, and N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)-2-(3-(4-(piperazin-1-yl)butoxy)phenyl)acetamide (17.0 mg, 79% yield) was obtained as an off-white solid. MS (ESI) m / z: 624.3 [M+H] + .

[0477] Step 5. 2-(3-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)butoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide A solution of N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)-2-(3-(4-(piperazin-1-yl)butoxy)phenyl)acetamide (17.0 mg, 0.027 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (23.0 mg, 0.08 mmol) and N,N-diisopropylethylamine (14.0 mg, 0.11 mmol) in 1-methylpyrrolidin-2-one (2 mL) was stirred at 120 °C for 18 h. The mixture was cooled to room temperature, diluted with water (10 mL), extracted with dichloromethane (20 mL x 2), washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15.0 min) to give 2-(3-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)butoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (5.0 mg, 21%) as a yellow solid. TIFF2025523575000137.tif49153 * Multiple signals arising from conformational isomers.

[0478] Example 35 Synthesis of N-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)-2-(3-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)ethoxy)ethoxy)phenyl)acetamide (Compound No. 34) TIFF2025523575000138.tif118135

[0479] Step 1. N-(4-(1-(Cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)-2-(3-hydroxyphenyl)acetamide A solution of 2-(3-hydroxyphenyl)acetic acid (0.51 g, 3.4 mmol), di(1H-imidazol-1-yl)methanone (0.82 g, 5.0 mmol) and N,N-diisopropylethylamine (1.73 g, 13.4 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 30 minutes. (5-(2-Amino-5-methylthiazol-4-yl)indolin-1-yl)(cyclopropyl)methanone (1.00 g, 3.34 mmol) was added to the resulting mixture. The mixture was stirred at 50 °C for 18 hours. The mixture was cooled to room temperature, diluted with water (50 mL), extracted with dichloromethane (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane / methanol = 5 / 95) to give N-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)-2-(3-hydroxyphenyl)acetamide (0.62 g, 43% yield) as a yellow solid. MS (ESI) m / z: 434.1 [M+H] + 。

[0480] Step 2. tert-Butyl 2-(2-(3-(2-(4-(1-(Cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-ylamino)-2-oxoethyl)phenoxy)ethoxy)ethylcarbamate A solution of N-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)-2-(3-hydroxyphenyl)acetamide (0.57 g, 1.3 mmol), 2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl 4-methylbenzenesulfonate (0.57 g, 1.6 mmol), and cesium carbonate (0.86 g, 2.63 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 18 h. The mixture was quenched with water (50 mL), extracted with dichloromethane (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane / methanol = 3 / 97) to give tert-butyl 2-(2-(3-(2-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-ylamino)-2-oxoethyl)phenoxy)ethoxy)ethylcarbamate (0.48 g, 59% yield) as a white solid. MS (ESI) m / z: 621.0 [M+H] + .

[0481] Step 3. 2-(3-(2-(2-Aminoethoxy)ethoxy)phenyl)-N-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)acetamide A solution of tert-butyl 2-(2-(3-(2-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-ylamino)-2-oxoethyl)phenoxy)ethoxy)ethylcarbamate (0.48 g, 0.77 mmol) in trifluoroacetic acid (10 mL) and dichloromethane (30 mL) was stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the residue was dissolved in dichloromethane (100 mL), washed with saturated aqueous sodium carbonate, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15 minutes) to give 2-(3-(2-(2-aminoethoxy)ethoxy)phenyl)-N-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)acetamide (0.12 g, 30% yield) as a yellow solid. MS (ESI) m / z 521.0 [M+H] + .

[0482] Step 4. N-(4-(1-(Cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)-2-(3-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)ethoxy)ethoxy)phenyl)acetamide A solution of 2-(3-(2-(2-aminoethoxy)ethoxy)phenyl)-N-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)acetamide (0.10 g, 0.19 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (0.27 g, 0.96 mmol) and N,N-diisopropylethylamine (0.20 g, 1.54 mmol) in 1-methylpyrrolidin-2-one (5 mL) was stirred at 120 °C for 18 h. The mixture was cooled to room temperature, diluted with water (20 mL), extracted with dichloromethane (20 mL x 3), washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30% - 70% in 15 min) to give N-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)-2-(3-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino...

Claims

1. A compound of formula A-I or a pharmaceutically acceptable salt or solvate thereof: Wherein, R 1 is optionally substituted C 1 to C 6 alkyl, optionally substituted C 3 to C 8 cycloalkyl, optionally substituted phenyl, and optionally substituted 5- to 9-membered heteroaryl; R 2a 、 R 2b 、 and R 2c are each independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, cyano, hydroxy, -S(=O) 2 CH 3 , and halo; R 3 is selected from the group consisting of hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, cyano, hydroxy, -S(=O) 2 CH 3 , and halo; Y is - ^ N(H)C(=O)-, - ^ N(H)C(=O)CH 2 -, - ^ C(=O)N(H)- and - ^ C(=O)N(H)CH 2 selected from the group consisting of; Here, the bond with " ^ " attached is connected to the thiazole; R 4a 、R 4b 、R 4c 、and R 4d are each independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, cyano, hydroxy, -S(=O) 2 CH 3 , and halo; L is selected from the group consisting of -(CH 2 ) m -, -*(CH 2 ) n (OCH 2 CH 2 ) o -, and -(CH 2 ) p -Z-CH 2 ) q -; The carbon marked with "*" is connected to X; m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; n is 2, 3, or 4; o is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; Z is selected from the group consisting of -(CR 6a R 6b )- and -N(R 7 )-; R 6a is selected from the group consisting of halo, hydroxyl, C 1 to C 6 alkyl, C 1 to C 4 haloalkyl, optionally substituted C 3 to C 8 cycloalkyl, optionally substituted C 4 to C 8 heterocycle, optionally substituted phenyl, and optionally substituted 5- to 9-membered heteroaryl; R 6b is selected from the group consisting of hydrogen and C 1 to C 6 alkyl; R 7 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 4 haloalkyl; X is -O-, -NH-, Selected from the group consisting of; B 1 is Selected from the group consisting of; and R 5a 、R 5b 、and R 5c are each independently selected from the group consisting of hydrogen, C 1 to C 4 alkyl, C 1 to C 4 haloalkyl, C 1 to C 4 alkoxy, C 1 to C 4 haloalkoxy, cyano, hydroxy, -S(=O) 2 CH 3 and halo.

2. Formula I: The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, having

3. Formula II: The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, having

4. R 1 is optionally substituted C 3 -C 8 ~C cycloalkyl, a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof.

5. R 1 The compound according to claim 4, or a pharmaceutically acceptable salt or solvate thereof, wherein R is cyclopropyl.

6. R 1 The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein R is phenyl which may be substituted.

7. R 1 is And; R 1a 、R 1b 、R 1c 、R 1d 、and R 1e are independently selected from the group consisting of hydrogen, C 1 to C 4 alkyl, C 1 to C 4 haloalkyl, C 1 to C 4 alkoxy, C 1 to C 4 haloalkoxy, cyano, hydroxy, -S(=O) 2 CH 3 and halo, The compound according to claim 6, or a pharmaceutically acceptable salt or solvate thereof.

8. R 1b 、 R 1c 、 R 1d 、 and R 1e is hydrogen, the compound according to claim 7, or a pharmaceutically acceptable salt or solvate thereof.

9. R 1a is C 1 -C 4 The compound according to claim 7 or 8, or a pharmaceutically acceptable salt or solvate thereof, wherein R is C to C alkyl.

10. R 1 The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, which is a 5- to 9-membered heteroaryl which may be substituted.

11. R 1 The compound according to claim 10, or a pharmaceutically acceptable salt or solvate thereof, which is an imidazole which may be substituted.

12. R 2a 、 R 2b 、 and R 2c is hydrogen, a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt or solvate thereof.

13. R 3 is C 1 -C 4 The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt or solvate thereof, wherein R is alkyl.

14. R 3 The compound according to claim 13, or a pharmaceutically acceptable salt or solvate thereof, wherein R is methyl.

15. R 4a The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt or solvate thereof, wherein R is selected from the group consisting of hydrogen and fluoro.

16. R 4b is a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of hydrogen and fluorine.

17. R 4c is a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of hydrogen and fluorine.

18. R 4b 、R 4c 、and R 4d is hydrogen, a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt or solvate thereof.

19. L is selected from the group consisting of -(CH 2 ) m - and -*(CH 2 ) n (OCH 2 CH 2 ) o - and the compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt or solvate thereof.

20. L is -(CH 2 ) m -, the compound according to claim 19, or a pharmaceutically acceptable salt or solvate thereof.

21. L is -*(CH 2 ) n (OCH 2 CH 2 ) o - and is the compound according to claim 19, or a pharmaceutically acceptable salt or solvate thereof.

22. L is -(CH 2 ) p -Z-CH 2 ) q -, a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt or solvate thereof.

23. Z is -(CR 6a R 6b )-, the compound according to claim 22, or a pharmaceutically acceptable salt or solvate thereof.

24. Z is -N(R 7 )-, the compound according to claim 22, or a pharmaceutically acceptable salt or solvate thereof.

25. The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -O-.

26. The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -NH-.

27. X is The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt or solvate thereof, which is

28. X is The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt or solvate thereof, which is

29. B 1 The compound according to any one of claims 1 to 28, wherein it is B-1, or a pharmaceutically acceptable salt or solvate thereof.

30. B 1 The compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt or solvate thereof, wherein it is B-2.

31. B 1 The compound according to any one of claims 1 to 28, which is B-3, or a pharmaceutically acceptable salt or solvate thereof.

32. B 1 The compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt or solvate thereof, wherein it is B-4.

33. B 1 The compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt or solvate thereof, wherein it is B-5.

34. B 1 The compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt or solvate thereof, wherein it is B-6.

35. R 5a 、R 5b 、and R 5c is independently selected from the group consisting of hydrogen and fluoro, the compound according to any one of claims 29 to 34, or a pharmaceutically acceptable salt or solvate thereof.

36. R 5a 、R 5b 、and R 5c is hydrogen, the compound according to claim 35, or a pharmaceutically acceptable salt or solvate thereof.

37. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, which is any one or more of the compounds in Table 1.

38. A pharmaceutical composition comprising the compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

39. A method of treating cancer, neurodegenerative disease, diabetes, cardiovascular disease, kidney disease, or liver disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof.

40. The method according to claim 39, further comprising administering a second therapeutic agent to the subject.

41. The method according to claim 39 or 40 for treating cancer in a subject in need thereof.

42. The method according to claim 39 or 40, wherein the cancer is a solid tumor.

43. The method according to claim 39 or 40, wherein the cancer is a blood cancer.

44. The method according to claim 39 or 40, wherein the cancer is one or more of the cancers in Table 2.

45. The method according to any one of claims 40 to 44, wherein the second therapeutic agent is isopropyl (S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)propanamide)-6-diazo-5-oxohexanoate, or a pharmaceutically acceptable salt thereof.

46. A method of reducing nuclear factor erythroid 2-related factor 2 (Nrf2) protein in the cells of a subject, comprising administering to the subject a compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt or solvate thereof.

47. The method according to claim 46, wherein the subject has cancer.

48. A compound according to any one of claims 1 to 37 or a pharmaceutically acceptable salt thereof, and instructions for administering the compound or a pharmaceutically acceptable salt thereof to a subject having cancer comprising a kit.

49. A compound having formula III, or a pharmaceutically acceptable salt thereof: Wherein R 1' is optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted phenyl, and optionally substituted 5- to 9-membered heteroaryl; R 2a' 、R 2b' 、and R 2c' are independently selected from the group consisting of hydrogen, C 1 to C 4 alkyl, C 1 to C 4 haloalkyl, C 1 to C 4 alkoxy, C 1 to C 4 haloalkoxy, cyano, hydroxy, -S(=O) 2 CH 3 , and halo; R 3' is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, cyano, hydroxy, -S(=O) 2 CH 3 , and halo; Z 1 is -O- and R 8 is hydrogen, C 1 to C 6 alkyl, or aralkyl; or Z 1 is -N(H)- and R 8 is and; R 4a' 、R 4b' 、R 4c' 、and R 4d' are each independently selected from the group consisting of hydrogen, C 1 to C 4 alkyl, C 1 to C 4 haloalkyl, C 1 to C 4 alkoxy, C 1 to C 4 haloalkoxy, cyano, hydroxy, -S(=O) 2 CH 3 , and halo; R 9 is selected from the group consisting of hydrogen and -L 1 -X 1 and is selected from the group consisting of X 1 is -OR 10 and -NR 11a R 11b selected from the group consisting of; R 10 is hydrogen; R 11a is selected from the group consisting of hydrogen and -C(=O)OtBu; R 11b is selected from the group consisting of hydrogen and C 1 -C 4 -alkyl; L 1 is selected from the group consisting of -(CH 2 ) m' -, -*(CH 2 ) n (OCH 2 CH 2 ) o' -, and -(CH 2 ) p' -Z 2 -(CH 2 ) q' -; Here, the carbon marked with "*" is connected to X 1 ; m' is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; n' is 2, 3, or 4; o' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; p' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; q' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; Z 2 is selected from the group consisting of -(CR 6a' R 6b' )- and -N(R 7' )-; R 6a' is selected from the group consisting of halo, hydroxyl, C 1 to C 6 alkyl, C 1 to C 4 haloalkyl, optionally substituted C 3 to C 8 cycloalkyl, optionally substituted C 4 to C 8 heterocycle, optionally substituted phenyl, and optionally substituted 5- to 9-membered heteroaryl; R 6b' is selected from the group consisting of hydrogen and C 1 -C 6 -alkyl; and R 7' is selected from the group consisting of hydrogen, C 1 to C 6 alkyl, and C 1 to C 4 haloalkyl.

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