NRF2 protein degradation agent

Abstract

The present disclosure provides a compound represented by Formula A-I, and a salt or solvate thereof, wherein R1, R2a, R2b, R2c, R3, R4a, R4b, R4c, R4d, L, X, Y, and B1 are as defined in the specification. Compounds of formula I are nuclear factor E2-related factor 2 (Nrf2) degrading agents useful in the treatment of cancer and other diseases. # imgabs0 #

Description

[0001] background

[0002] field

[0003] The present disclosure provides heterobifunctional small molecules that are degraders of nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 degraders can be used to treat cancer and other diseases.

[0004] background

[0005] The PROTAC strategy utilizes proteasome-mediated proteolysis to induce targeted protein degradation. Raina et al., Proc Natl Acad Sci US A. 2016, 113, 7124-7129; Zhou et al., J. Med. Chem. 2018, 61, 462-481. PROTAC molecules are heterobifunctional small molecules that contain a ligand that binds to the target protein of interest and a second ligand for the E3 ligase system, both of which are connected by a chemical linker. Bondeson, DP; Crews, CM. Targeted Protein Degradation by Small Molecules. Annu Rev Pharmacol Toxicol. 2017, 57, 107-123.

[0006] Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor that regulates the expression of antioxidant genes. Mutations in Kelch-like ECH-associated protein 1 (Keap1) and Nrf2 contribute to Nrf2 activation in cancer cells. For example, Nrf2 activity is associated with poor prognosis in NSCLC. Zhao et al., Front. Oncol. 10:578315. doi:10.3389 / fonc.2020.578315.

[0007] The Nrf2 pathway also plays a role in neurodegeneration, diabetes, cardiovascular disease, kidney disease, and liver disease. Nrf2 levels vary significantly with physiology, time, and pathological context. Dodson et al., Annu Rev Pharmacol Toxicol 59:555-575 (2019). Nrf2 activation promotes metabolic reprogramming. Inhibition or degradation of Nrf2 can alter metabolic processes and thereby inhibit tumor growth, prevent metastasis, and / or increase sensitivity to chemotherapy. There is a need in the art for Nrf2 degraders to treat cancer and other diseases.

[0008] Brief Overview

[0009] In one aspect, the present disclosure provides heterobifunctional small molecules represented by the following formulas AI, I, and II, and pharmaceutically acceptable salts and solvates thereof, e.g., hydrates. These compounds, and their salts and solvates are collectively referred to herein as "Compounds of the Disclosure" or individually as "Compounds of the Disclosure." The compounds of the disclosure are Nrf2 degraders and are therefore useful in treating diseases or conditions in which degradation of Nrf2 protein provides therapeutic benefit to a subject.

[0010] In another aspect, the present disclosure provides a method for treating a condition or disease by administering a therapeutically effective amount of a compound of the present disclosure to a subject in need thereof (e.g., a human cancer patient). Diseases or conditions treatable by degradation of Nrf2 are, for example, cancer, neurodegenerative diseases, diabetes, cardiovascular disease, kidney disease, or liver disease.

[0011] In another aspect, the present disclosure provides methods of degrading (eg, reducing) the level of Nrf2 protein in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the present disclosure.

[0012] 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.

[0013] In another aspect, the present disclosure provides a composition for treating a disease or condition in which degradation of Nrf2 provides a benefit (eg, cancer), comprising a compound of the present disclosure and an excipient and / or a pharmaceutically acceptable carrier.

[0014] In another aspect, the present disclosure provides a composition comprising: (a) a compound of the present disclosure; (b) a second therapeutically active agent; and (c) optionally an excipient and / or a pharmaceutically acceptable carrier.

[0015] In another aspect, the present disclosure provides compounds of the present disclosure for use in treating a disease or condition of interest (eg, cancer).

[0016] In another aspect, the present disclosure provides the use of a compound of the present disclosure for the preparation of a medicament for treating a disease or condition of interest (eg, cancer).

[0017] In another aspect, the disclosure provides a kit comprising a compound of the disclosure and, optionally, a packaged composition comprising a second therapeutic agent useful for treating a disease or condition of interest and a package insert containing instructions for use in treating the disease or condition (e.g., cancer).

[0018] In another aspect, the present disclosure provides methods of preparing the compounds of the present disclosure.

[0019] In another aspect, the present disclosure provides compounds represented by the following Formula III, and pharmaceutically acceptable salts and solvates thereof, for example, hydrates. Compounds having Formula III can be used, for example, as synthetic intermediates to prepare compounds of the present disclosure.

[0020] Other embodiments and advantages of the present disclosure will be partially set forth in the subsequent description and will be derived from the description, or may be learned by practice of the present disclosure. The embodiments and advantages of the present disclosure may be achieved and attained by means of the elements and combinations specifically noted in the appended claims. It should be understood that the foregoing summary and the following detailed description are merely exemplary and explanatory and do not limit the claimed invention.

[0021] Detailed description

[0022] I. Compounds of the Disclosure

[0023] In one embodiment, the compound of the present disclosure is a compound of Formula A-1:

[0024]

[0025] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0026] R 1 is selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted phenyl and optionally substituted 5- to 9-membered heteroaryl;

[0027] R 2a 、R 2b and R 2c independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3 and halogen;

[0028] R 3 is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3 and halogen;

[0029] Y is selected from -^N(H)C(=O)-, -^N(H)C(=O)CH2-, -^C(=O)N(H)- and -^C(=O)N(H)CH2-;

[0030] wherein the bond marked with "^" is connected to the thiazole;

[0031] R 4a 、R 4b 、R 4c and R 4d independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3 and halogen;

[0032] L is selected from -(CH2) m -、-*(CH2) n (OCH2CH2) o - and -(CH2) p -Z-(CH2) q -;

[0033] wherein the carbon marked with "*" is connected to X;

[0034] m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0035] n is 2, 3, or 4;

[0036] o is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0037] p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0038] q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0039] Z is selected from -(CR 6a R 6b )- and -N(R 7 )-;

[0040] R 6a is selected from halogen, hydroxy, C1-C6 alkyl, C1-C4 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C4-C8 heterocycle, optionally substituted phenyl and optionally substituted 5- to 9-membered heteroaryl;

[0041] R 6b Selected from hydrogen and C1-C6 alkyl;

[0042] R 7Selected from hydrogen, C1-C6 alkyl and C1-C4 haloalkyl;

[0043] X is selected from -O-, -NH-,

[0044]

[0045] B 1 Selected from:

[0046]

[0047] and

[0048] R 5a 、R 5b and R 5c Independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3 and halogen.

[0049] In another embodiment, the compound of the present disclosure is a compound of Formula I:

[0050]

[0051] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0052] In another embodiment, the compound of the present disclosure is a compound of Formula II:

[0053]

[0054] or a pharmaceutically acceptable salt or solvate thereof.

[0055] In another embodiment, the compound of the present disclosure is a compound of any one of Formula AI, I or II, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is an optionally substituted C3-C8 cycloalkyl. In another embodiment, R 1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In another embodiment, R 1 It is cyclopropyl.

[0056] In another embodiment, the compound of the present disclosure is a compound of any one of Formula AI, I or II, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is optionally substituted phenyl. In another embodiment, R 1 yes:

[0057] and

[0058] R 1a 、R 1b 、R 1c 、R 1d and R 1e In another embodiment, R 1b 、R 1c 、R 1d and R 1e In another embodiment, R 1a is C1-C4 alkyl. In another embodiment, R 1a It's methyl.

[0059] In another embodiment, 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 embodiment, R 1 is an optionally substituted imidazole. In another embodiment, R 1 yes:

[0060]

[0061] In another embodiment, the compound of the present disclosure is a compound of any one of Formula AI, I or II, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2a 、R 2b and R 2c It's hydrogen.

[0062] In another embodiment, the compound of the present disclosure is a compound of any one of Formula AI, I or II, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is C1-C4 alkyl. In another embodiment, R 3 It's methyl.

[0063] In another embodiment, the compound of the present disclosure is a compound of any one of Formula AI, I or II, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4a Selected from hydrogen and fluorine.

[0064] In another embodiment, the compound of the present disclosure is a compound of any one of Formula AI, I or II, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4b Selected from hydrogen and fluorine.

[0065] In another embodiment, the compound of the present disclosure is a compound of any one of Formula AI, I or II, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4c Selected from hydrogen and fluorine.

[0066] In another embodiment, the compound of the present disclosure is a compound of any one of Formula AI, I or II, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4b 、R 4c and R 4d It's hydrogen.

[0067] In another embodiment, the compound of the present disclosure is a compound of any one of Formula AI, I or II, or a pharmaceutically acceptable salt or solvate thereof, wherein L is selected from -(CH2) m - and -*(CH2) n (OCH2CH2) o -.

[0068] In another embodiment, the compound of the present disclosure is a compound of any one of Formula AI, I or II, or a pharmaceutically acceptable salt or solvate thereof, wherein L is -(CH2) m -. In another embodiment, m is 1. In another embodiment, m is 2. In another embodiment, m is 3. In another embodiment, m is 4. In another embodiment, m is 5. In another embodiment, m is 6.

[0069] In another embodiment, the compound of the present disclosure is a compound of any one of Formula AI, I or II, or a pharmaceutically acceptable salt or solvate thereof, wherein L is -*(CH2) n (OCH2CH2) o -. In another embodiment, n is 2. In another embodiment, n is 3. In another embodiment, o is 1. In another embodiment, o is 2. In another embodiment, o is 3. In another embodiment, o is 4. In another embodiment, o is 5. In another embodiment, o is 6.

[0070] In another embodiment, the compound of the present disclosure is a compound of any one of Formula AI, I or II, or a pharmaceutically acceptable salt or solvate thereof, wherein L is -(CH2) p -Z-CH2) q-. In another embodiment, p is 0. In another embodiment, p is 1. In another embodiment, p is 2. In another embodiment, p is 3. In another embodiment, p is 4. In another embodiment, q is 1. In another embodiment, q is 2. In another embodiment, q is 3. In another embodiment, q is 4.

[0071] In another embodiment, the compound of the present disclosure is a compound of any one of Formula AI, I or II, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -(CR 6a R 6b )-.

[0072] In another embodiment, the compound of the present disclosure is a compound of any one of Formula AI, I or II, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is:

[0073]

[0074] In another embodiment, the compound of the present disclosure is a compound of any one of Formula AI, I or II, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is:

[0075]

[0076] In another embodiment, the compound of the present disclosure is a compound of Formula AI, I or II, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -N(R 7 )-.

[0077] In another embodiment, the compound of the present disclosure is a compound of any one of Formula AI, I or II, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a In another embodiment, R 6a In another embodiment, R 6a is C1-C6 alkyl. In another embodiment, R 6a is C1-C4 haloalkyl. In another embodiment, R 6a is an optionally substituted C3-C8 cycloalkyl. In another embodiment, R 6a is an optionally substituted C4-C8 heterocycle. In another embodiment, R 6a is optionally substituted phenyl. In another embodiment, R 6a is an optionally substituted 5- to 9-membered heteroaryl.

[0078] In another embodiment, the compound of the present disclosure is a compound of any one of Formula AI, I or II, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6b In another embodiment, R 6b It is a C1-C6 alkyl group.

[0079] In another embodiment, the compound of the present disclosure is a compound of any one of Formula AI, I or II, or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 In another embodiment, R 7 is C1-C6 alkyl. In another embodiment, R 7 It is a C1-C4 haloalkyl group.

[0080] In another embodiment, the compound of the present disclosure is a compound of any one of Formula AI, I, or II, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -O-.

[0081] In another embodiment, the compound of the present disclosure is a compound of any one of Formula AI, I, or II, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -NH-.

[0082] In another embodiment, the compound of the present disclosure is a compound of any one of Formula AI, I or II, or a pharmaceutically acceptable salt or solvate thereof, wherein X is:

[0083]

[0084] In another embodiment, the compound of the present disclosure is a compound of any one of Formula AI, I or II, or a pharmaceutically acceptable salt or solvate thereof, wherein X is:

[0085]

[0086] In another embodiment, the compound of the present disclosure is a compound of any one of Formula AI, I or II, or a pharmaceutically acceptable salt or solvate thereof, wherein B 1 It's B-1.

[0087] In another embodiment, the compound of the present disclosure is a compound of any one of Formula AI, I or II, or a pharmaceutically acceptable salt or solvate thereof, wherein B 1 It's B-2.

[0088] In another embodiment, the compound of the present disclosure is a compound of any one of Formula AI, I or II, or a pharmaceutically acceptable salt or solvate thereof, wherein B 1 It's B-3.

[0089] In another embodiment, the compound of the present disclosure is a compound of any one of Formula AI, I or II, or a pharmaceutically acceptable salt or solvate thereof, wherein B 1 It's B-4.

[0090] In another embodiment, the compound of the present disclosure is a compound of any one of Formula AI, I or II, or a pharmaceutically acceptable salt or solvate thereof, wherein B 1 It's B-5.

[0091] In another embodiment, the compound of the present disclosure is a compound of any one of Formula AI, I or II, or a pharmaceutically acceptable salt or solvate thereof, wherein B 1 It's B-6.

[0092] In another embodiment, the compound of the present disclosure is a compound of any one of Formula AI, I or II, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5a 、R 5b and R 5c In another embodiment, R 5a 、R 5b and R 5c It's hydrogen.

[0093] In another embodiment, the compound of the present disclosure is a compound of any one of Formula AI, I or II, or a pharmaceutically acceptable salt or solvate thereof, wherein B 1 Selected from:

[0094]

[0095] In another embodiment, the compound of the present disclosure is a compound of any one of Formula AI, I or II, or a pharmaceutically acceptable salt or solvate thereof, wherein B 1 Selected from:

[0096]

[0097] In another embodiment, the compound of the present disclosure is a compound of any one of Formula AI, I or II, or a pharmaceutically acceptable salt or solvate thereof, wherein B 1 Selected from:

[0098]

[0099] In another embodiment, the compound of the present disclosure is a compound of any one of Formula AI, I or II, or a pharmaceutically acceptable salt or solvate thereof, wherein B 1yes:

[0100]

[0101] In another embodiment, the compound of the present disclosure is a compound of any one of Formula AI, I or II, or a pharmaceutically acceptable salt or solvate thereof, wherein B 1 yes:

[0102]

[0103] In one embodiment, the present disclosure provides a compound of Formula III:

[0104]

[0105] or a pharmaceutically acceptable salt thereof, wherein:

[0106] R 1' is selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted phenyl and optionally substituted 5- to 9-membered heteroaryl;

[0107] R 2a' 、R 2b' and R 2c' independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3 and halogen;

[0108] R 3' is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3 and halogen;

[0109] Z 1 is -O-; and

[0110] R 8 is hydrogen, C1-C6 alkyl or aralkyl; or

[0111] Z 1 is -N(H)-; and

[0112] R 8 yes:

[0113] and

[0114] R 4a' 、R 4b' 、R 4c' and R 4d'independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3 and halogen;

[0115] R 9 Selected from hydrogen and -L 1 -X 1 ;

[0116] X 1 Select from -OR 10 and -NR 11a R 11b ;

[0117] R 10 It is hydrogen;

[0118] R 11a is selected from hydrogen and -C(=O)OtBu;

[0119] R 11b is selected from hydrogen and C1-C4 alkyl;

[0120] L 1 Selected from -(CH2) m' -、-*(CH2) n' (OCH2CH2) o' - and -(CH2) p' -Z 2 -(CH2) q' -;

[0121] The carbon marked with "*" is connected to X 1 ;

[0122] m' is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0123] n' is 2, 3, or 4;

[0124] o' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0125] p' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0126] q' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0127] Z 2 Selected from -(CR 6a' R 6b' )- and -N(R 7' )-;

[0128] R 6a'is selected from halogen, hydroxy, C1-C6 alkyl, C1-C4 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C4-C8 heterocycle, optionally substituted phenyl and optionally substituted 5- to 9-membered heteroaryl;

[0129] R 6b' is selected from hydrogen and C1-C6 alkyl; and

[0130] R 7' is selected from hydrogen, C1-C6 alkyl and C1-C4 haloalkyl.

[0131] In another embodiment, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1' is an optionally substituted C3-C8 cycloalkyl. In another embodiment, R 1' is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In another embodiment, R 1' It is cyclopropyl.

[0132] 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 phenyl. In another embodiment, R 1’ yes:

[0133] and

[0134] R 1a’ 、R 1b’ 、R 1c’ 、R 1d’ and R 1e’ In another embodiment, R 1b’ 、R 1c’ 、R 1d’ and R 1e’ In another embodiment, R 1a’ is C1-C4 alkyl. In another embodiment, R 1a’ It's methyl.

[0135] In another embodiment, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1’ is an optionally substituted 5- to 9-membered heteroaryl. In another embodiment, R 1’ is an optionally substituted imidazole. In another embodiment, R 1’ yes:

[0136]

[0137] 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’ It's hydrogen.

[0138] 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' It's methyl.

[0139] In another embodiment, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein Z 1 Yes -O-.

[0140] In another embodiment, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein Z 1 It is -N(H)-.

[0141] In another embodiment, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein R 8 In another embodiment, R 8 is C1-C6 alkyl. In another embodiment, R 8 In another embodiment, R 8 yes:

[0142] and

[0143] R 4a' 、R 4b' 、R 4c' and R 4d' Independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3 and halogen.

[0144] In another embodiment, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 It's hydrogen.

[0145] In another embodiment, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 Yes-L 1 -X1 .

[0146] In another embodiment, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein X 1 Yes-OR 10 In another embodiment, X 1 Yes-NR 11a R 11b .

[0147] In another embodiment, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein R 10 It's hydrogen.

[0148] In another embodiment, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein R 11a In another embodiment, R 11a It is -C(=O)OtBu.

[0149] In another embodiment, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein R 11b In another embodiment, R 11b It is a C1-C4 alkyl group.

[0150] In another embodiment, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 Yes - (CH2) m' -. In another embodiment, L 1 Yes-*(CH2) n' (OCH2CH2) o' -. In another embodiment, L 1 Yes - (CH2) p' -Z 2 -(CH2) q' -.

[0151] In another embodiment, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 Yes - (CH2) m' In another embodiment, m' is 2. In another embodiment, m' is 3. In another embodiment, m' is 4. In another embodiment, m' is 5. In another embodiment, m' is 6.

[0152] In another embodiment, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 Yes-*(CH2) n' (OCH2CH2) o' -. In another embodiment, n' is 2. In another embodiment, n' is 3. In another embodiment, n' is 4. In another embodiment, o' is 1. In another embodiment, o' is 2. In another embodiment, o' is 3. In another embodiment, o' is 4. In another embodiment, o' is 5. In another embodiment, o' is 6.

[0153] In another embodiment, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 Yes - (CH2) p' -Z 2 -(CH2) q' In another embodiment, p' is 0. In another embodiment, p' is 1. In another embodiment, p' is 2. In another embodiment, p' is 3. In another embodiment, p' is 4. In another embodiment, q' is 1. In another embodiment, q' is 2. In another embodiment, q' is 3. In another embodiment, q' is 4.

[0154] In another embodiment, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein Z 2 Yes-(CR 6a' R 6b' )-.

[0155] In another embodiment, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein Z 2 yes:

[0156]

[0157] In another embodiment, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein Z 2 yes:

[0158]

[0159] In another embodiment, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein Z 2 Yes-N(R 7' )-.

[0160] In another embodiment, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a' In another embodiment, R 6a' In another embodiment, R 6a' is C1-C6 alkyl. In another embodiment, R 6a' is C1-C4 haloalkyl. In another embodiment, R 6a' is an optionally substituted C3-C8 cycloalkyl. In another embodiment, R 6a' is an optionally substituted C4-C8 heterocycle. In another embodiment, R 6a' is optionally substituted phenyl. In another embodiment, R 6a' is an optionally substituted 5- to 9-membered heteroaryl.

[0161] In another embodiment, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6b' In another embodiment, R 6b' It is a C1-C6 alkyl group.

[0162] In another embodiment, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein R 7' In another embodiment, R 7' is C1-C6 alkyl. In another embodiment, R 7' It is a C1-C4 haloalkyl group.

[0163] In another embodiment, the compound of the present disclosure is any one or more of the compounds of Table 1, or a pharmaceutically acceptable salt or solvate thereof.

[0164] In another embodiment, the present disclosure provides any one or more of the compounds of Table 1-A, or a pharmaceutically acceptable salt or solvate thereof.

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186] In another embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier or excipient.

[0187] In another embodiment, 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 to prepare compounds of the present disclosure.

[0188] In another embodiment, 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 to prepare compounds of the present disclosure.

[0189] The compounds of the present disclosure may contain asymmetric carbon atoms. In certain embodiments, the compounds of the present disclosure are racemic compounds. In other embodiments, the compounds of the present disclosure are enantiomerically enriched, for example, the enantiomeric excess or "ee" of the compound is about 5% or more 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%.

[0190] In another embodiment, the cereblon binding portion of the compounds of the present disclosure, i.e., B 1 , is enantiomerically enriched. In another embodiment, the cereblon binding portion of the molecule is racemic. The present disclosure encompasses all possible stereoisomers (e.g., diastereoisomers) of the compounds of the present disclosure. When a compound of the present disclosure is needed as a single enantiomer, it can be obtained by splitting the final product or by performing stereospecific synthesis from an isomerically pure starting material or using a chiral auxiliary reagent, for example, referring to Z.Ma et al., Tetrahedron:Asymmetry, 8 (6), pp. 883-888 (1997). The splitting of the final product, intermediate or starting material can be achieved by any suitable method known in the art. In addition, in the case where a tautomer of a compound of the present disclosure may exist, the present disclosure is intended to include all tautomeric forms of the compound.

[0191] The present disclosure encompasses the preparation and use of salts (including pharmaceutically acceptable salts) of the compounds of the present disclosure. As used herein, "pharmaceutically acceptable salts" represent non-toxic salt forms of the compounds of the present disclosure. See, for example, Gupta et al., Molecules 23:1719 (2018). The salts of the compounds of the present disclosure can be prepared during the final separation and purification of the compounds, or prepared separately by reacting the compounds 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 compounds of the present disclosure include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethanesulfonate, phosphate, hydrogenphosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, hydroxyethyl sulfon ... The compounds of the present invention may be quaternized with the following reagents: methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate; chlorides, bromides, and iodides of decyl, lauryl, myristyl, and steryl groups; and bromides of benzyl and phenethyl groups. In view of the foregoing, any reference to a compound of the present disclosure appearing herein is intended to include the actual compound and a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0192] The present disclosure also encompasses the preparation and use of solvates of the compounds of the present disclosure. Solvates generally do not significantly alter the physiological activity or toxicity of the compound and can therefore function as pharmacological equivalents. As used herein, the term "solvate" refers to a combination, physical association, and / or solvation of a compound of the present disclosure with a solvent molecule, such as, for example, a disolvate, a monosolvate, or a hemisolvate, wherein the ratio of solvent molecules to the compound of the present disclosure is approximately 2:1, approximately 1:1, or approximately 1:2, respectively. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, solvates can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, "solvate" includes both solution phase and separable solvates. The compounds of the present disclosure may exist in solvated form with pharmaceutically acceptable solvents (such as water, methanol, and ethanol), and the present disclosure is intended to include both solvated and unsolvated forms of the compounds of the present disclosure. One type of solvate is a hydrate. "Hydrate" refers to a specific subgroup of solvates in which the solvent molecule is water. Solvates can generally act as pharmacological equivalents. 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 with water. 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) describe similar preparations of solvates, hemisolvates, hydrates, etc. A typical, non-limiting method for preparing a solvate comprises dissolving a 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 (e.g., filtration). Analytical techniques, such as infrared spectroscopy, can be used to confirm the presence of solvent in crystals of the solvate.

[0193] II. Therapeutic Methods of the Disclosure

[0194] The compounds of the present disclosure degrade Nrf2 protein and are therefore useful in treating a variety of diseases and conditions. Specifically, the compounds of the present disclosure can be used in methods of treating diseases or conditions in which degradation of Nrf2 protein would provide benefits (e.g., cancer and proliferative diseases). The compounds of the present disclosure can also be used in methods of treating neurodegenerative diseases, diabetes, cardiovascular diseases, kidney diseases, or liver diseases in a subject.

[0195] The treatment methods of the present disclosure comprise administering a therapeutically effective amount of a compound of the present disclosure to a subject in need thereof (e.g., a cancer patient). The methods of the present invention also encompass administering a second therapeutic agent to the subject in combination with the compound of the present disclosure. The second therapeutic agent is selected from drugs known to be useful for treating a disease or condition afflicting an individual in need thereof, for example, chemotherapeutic agents and / or radiation known to be useful for treating a specific cancer.

[0196] The present disclosure provides compounds of the present disclosure as Nrf2 protein degraders for use in treating diseases and conditions in which degradation of Nrf2 protein has a beneficial effect. The compounds of the present disclosure generally have a DC of less than 100 μM. 50 The concentration of the drug that causes 50% degradation of Nrf2 protein may be, for example, less than 50 μM, less than 25 μM, less than 5 μM, less than about 1 μM, less than about 0.5 μM, or less than about 0.1 μM.

[0197] In one embodiment, the present disclosure relates to a method of treating an individual suffering from a disease or condition in which degradation of Nrf2 protein would provide 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 degraders of Nrf2 protein, a variety of diseases and conditions mediated by or genetically associated with Nrf2 can be treated by employing these compounds. Accordingly, the present disclosure generally relates to a method for treating a disease or condition responsive to degradation of Nrf2 in an animal (e.g., a human) suffering from or at risk of suffering from the disease or condition, the method comprising administering to the animal an effective amount of one or more compounds of the present disclosure.

[0198] The present disclosure further relates to a method of degrading 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.

[0199] In another aspect, the present disclosure provides a method of treating cancer in a subject, comprising administering a therapeutically effective amount of a compound of the present disclosure. Although not limited to a specific mechanism, in certain embodiments, 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 listed in Table 2.

[0200] Table 2

[0201]

[0202]

[0203]

[0204] In another embodiment, the cancer is a solid tumor. In another embodiment, the cancer is a hematological cancer. Exemplary hematological cancers include, but are not limited to, those listed in Table 3. In another embodiment, the hematological cancer is acute lymphocytic leukemia, chronic lymphocytic leukemia (including B-cell chronic lymphocytic leukemia), or acute myeloid leukemia.

[0205] Table 3

[0206] Acute lymphoblastic leukemia (ALL) Acute eosinophilic leukemia Acute myeloid leukemia (AML) Acute erythroid leukemia Chronic lymphocytic leukemia (CLL) Acute lymphoblastic leukemia Small lymphocytic lymphoma (SLL) acute megakaryoblastic leukemia Multiple myeloma (MM) Acute monocytic leukemia Hodgkin lymphoma (HL) acute promyelocytic leukemia Non-Hodgkin lymphoma (NHL) Acute myeloid leukemia Mantle cell lymphoma (MCL) B-cell prolymphocytic leukemia Marginal zone B-cell lymphoma B-cell lymphoma Splenic marginal zone lymphoma MALT lymphoma Follicular lymphoma (FL) Precursor T-lymphoblastic lymphoma Waldenstrom's macroglobulinemia (WM) T-cell lymphoma Diffuse large B-cell lymphoma (DLBCL) Mast cell leukemia Marginal zone lymphoma (MZL) Adult T-cell leukemia / lymphoma Hairy cell leukemia (HCL) Aggressive NK-cell leukemia Burkitt's lymphoma (BL) Angioimmunoblastic T-cell lymphoma Richter transformation

[0207] In another embodiment, 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 embodiment, the cancer is NUT-midline carcinoma. In another embodiment, the cancer is multiple myeloma. In another embodiment, the cancer is lung cancer such as small cell lung cancer (SCLC). In another embodiment, the cancer is neuroblastoma. In another embodiment, the cancer is Burkitt's lymphoma. In another embodiment, the cancer is cervical cancer. In another embodiment, the cancer is esophageal cancer. In another embodiment, the cancer is ovarian cancer. In another embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is prostate cancer. In another embodiment, the cancer is breast cancer.

[0208] In another embodiment, the cancer is selected from acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia mixed lineage leukemia, NUT-midline carcinoma, multiple myeloma, small cell lung cancer, non-small cell lung cancer, neuroblastoma, Burkitt's 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 cancer.

[0209] In another embodiment, a Compound of the Disclosure is administered to a subject in need thereof to treat lung cancer, breast cancer, ovarian cancer, or prostate cancer. In another embodiment, the cancer is breast cancer. In another embodiment, the cancer is ovarian cancer. In another embodiment, the cancer is prostate cancer. In another embodiment, the cancer is metastatic castration-resistant prostate cancer.

[0210] In another aspect, the present disclosure provides a method of treating an autoimmune disease, respiratory disease, digestive disease, cardiovascular disease, metabolic disease, or neurodegenerative disease in a subject, the method comprising administering a therapeutically effective amount of a compound of the present disclosure. Although not limited to a particular mechanism, in certain embodiments, the compounds of the present disclosure treat these diseases by degrading Nrf2.

[0211] 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.

[0212] 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.

[0213] In another aspect, the present disclosure provides a method of treating cardiovascular disease in a subject, the method comprising administering a therapeutically effective amount of a compound of the present disclosure.

[0214] In another aspect, the present disclosure provides a method of treating kidney disease in a subject, the method comprising administering a therapeutically effective amount of a compound of the present disclosure.

[0215] In another aspect, the present disclosure provides a method of treating liver disease in a subject, the method comprising administering a therapeutically effective amount of a compound of the present disclosure.

[0216] The methods of the present disclosure can be achieved by administering the compounds of the present disclosure as pure compounds or as pharmaceutical compositions. The pharmaceutical compositions or pure compounds of the present disclosure can be administered during or after the onset of the disease or condition of interest. Typically, the pharmaceutical compositions are sterile and do not contain toxic, carcinogenic, or mutagenic compounds that could cause adverse reactions upon administration.

[0217] In one embodiment, a Compound of the Disclosure is administered as a single agent to treat a disease or condition for which degradation of Nrf2 protein would provide a benefit. In another embodiment, a Compound of the Disclosure is administered in combination with a second therapeutic agent that can be used to treat a disease or condition for which degradation of Nrf2 protein would provide a benefit. The second therapeutic agent is different from the Compound of the Disclosure. The Compound of the Disclosure and the second therapeutic agent can be administered simultaneously or sequentially to achieve the desired effect. Additionally, the Compound of the Disclosure and the second therapeutic agent can be administered as a single pharmaceutical composition or as two separate pharmaceutical compositions.

[0218] The second therapeutic agent is administered in an amount to provide its desired therapeutic effect. The effective dosage range for each second therapeutic agent is known in the art, and the second therapeutic agent is administered to an individual in need thereof within such established ranges.

[0219] The compound of the present disclosure and the second therapeutic agent can be administered together as a single unit dose, or separately as multiple unit doses, wherein the compound of the present disclosure is administered before the second therapeutic agent, or vice versa. One or more doses of the compound of the present disclosure and / or one or more doses of the second therapeutic agent can be administered. Thus, the compound of the present disclosure can be used in combination with one or more second therapeutic agents (for example, but not limited to, anticancer agents).

[0220] In the methods of the present disclosure, a therapeutically effective amount of a compound of the present disclosure (generally formulated in accordance with pharmaceutical practice) is administered to a subject in need thereof, e.g., a human cancer patient. Whether such treatment is warranted depends on the individual case and requires a medical evaluation (diagnosis) that takes into account the presence of signs, symptoms, and / or malfunctions, the risk of developing specific signs, symptoms, and / or malfunctions, and other factors.

[0221] The compounds of the present disclosure may be administered by any suitable route, for example, orally, buccally, by inhalation, sublingually, rectally, vaginally, intracisternal or intrathecal (by lumbar puncture), transurethrally, nasally, transdermally (i.e., transdermally), or parenterally (including intravenous, intramuscular, subcutaneous, intracoronary, intradermal, intramammary, intraperitoneal, intraarticular, intrathecal, retrobulbar, intrapulmonary injection, and / or surgical implantation at a specific site). Parenteral administration may be accomplished using a needle and syringe or using high-pressure techniques.

[0222] Pharmaceutical compositions include those in which the compounds of the present disclosure are administered in an effective amount to achieve their intended purpose. The exact formulation, route of administration, and dosage are determined by the individual physician taking into account the condition or disease being diagnosed. The dosage amount and interval can be adjusted individually to provide a level of the compounds of the present disclosure sufficient to maintain the therapeutic effect.

[0223] The toxicity and therapeutic effect of the compounds of the present disclosure can be determined by standard pharmaceutical procedures in cell culture 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 that can be administered to an animal without causing severe toxicity or death. The dose ratio between the maximum tolerated dose and the therapeutic effect (e.g., inhibition of tumor growth) is the therapeutic index. The dosage can vary within this range, depending on the dosage form employed and the route of administration utilized. The determination of a therapeutically effective amount is entirely within the capabilities of those skilled in the art, particularly in light of the detailed disclosure provided herein.

[0224] The therapeutically effective amount of the compound of the present disclosure required for treatment varies with the nature of the disease being treated, the desired time length of the activity, and the age and condition of the patient, and is ultimately determined by the attending physician. The dosage amount and interval can be adjusted individually to provide a plasma level of the Nrf2 protein degrader sufficient to maintain the desired therapeutic effect. The desired dosage can be conveniently administered in a single dose, or as a multiple dose administered at appropriate intervals, for example, as one, two, three, four or more sub-doses per day. Multiple doses are often needed or required. For example, the compound of the present disclosure can be administered at the following frequency: at four-day intervals, one dose per day, delivering four doses (q4d x 4); at three-day intervals, one dose per day, delivering four doses (q3d x 4); at five-day intervals, one dose per day (qd x 5); one dose per week for three weeks (qwk3); five daily doses, two days of drug withdrawal, and another five daily doses (5 / 2 / 5); or any dosage regimen determined to be suitable for the situation.

[0225] The compounds of the present disclosure used in the methods of the present disclosure can be administered in an amount of about 0.005 to about 500 mg per dose, about 0.05 to about 250 mg per dose, or about 0.5 to about 100 mg per dose. For example, the compounds of the present disclosure can be administered in an amount of about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg per dose, including all doses between 0.005 and 500 mg.

[0226] The dosage of a composition containing a compound of the present disclosure or a composition containing the compound 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 any dosage, including, but not limited to, 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. 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 In some embodiments, the dosage of the present invention is about 100mg / kg, about 20mg / kg, about 25mg / kg, about 30mg / kg, about 35mg / kg, about 40mg / kg, about 45mg / kg, about 50mg / kg, about 60mg / kg, about 70mg / kg, about 80mg / kg, about 90mg / kg, about 100mg / kg, about 125mg / kg, about 150mg / kg, about 175mg / kg, about 200mg / kg or more.Above dosage is the example of general situation, but can have the individual case that needs higher or lower dosage, and these are all within the scope of the present disclosure.In practice, the doctor can determine the actual quantitative administration scheme that is most suitable for individual patient, and this scheme can change with age, weight and response of specific patient.

[0227] As described above, the compounds of the present disclosure can be administered in combination with a second therapeutic agent. In certain embodiments, the second therapeutic agent is an epigenetic drug. As used herein, the term "epigenetic drug" refers to a therapeutic agent that targets an epigenetic regulator. Examples of epigenetic regulators include histone lysine methyltransferases, histone arginine methyltransferases, histone demethylases, histone deacetylases, histone acetylesterases, and DNA methyltransferases. Histone deacetylase inhibitors include, but are not limited to, vorinostat.

[0228] In another embodiment, chemotherapeutic agents or other antiproliferative agents can be combined with the compounds of the present disclosure to treat proliferative diseases and cancer. Examples of therapies and anticancer agents that can be used in combination with the compounds of the present disclosure include surgery, radiotherapy (e.g., gamma-irradiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioisotopes), endocrine therapy, biological response modifiers (e.g., interferons, interleukins, tumor necrosis factor (TNF), hyperthermia and cryotherapy, agents that mitigate any adverse effects (e.g., antiemetics), and any other approved chemotherapeutic drugs.

[0229] Examples of anti-proliferative 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; anti-proliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used to treat hematologic malignancies; Flt-3 inhibitors; Hsp90 inhibitors; kinesin spindle protein inhibitors; MEK inhibitors; antitumor antibiotics; nitrosoureas; compounds that target / reduce the activity of protein or lipid kinases, compounds that target / reduce the activity of protein or lipid phosphatases, or any other anti-angiogenic compound.

[0230] Non-limiting exemplary aromatase inhibitors include, but are not limited to, steroids such as atamestane, exemestane, and formestane, and nonsteroidal such as aminoglutethimide, lotrakide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole, and letrozole.

[0231] Non-limiting examples of antiestrogens include, but are not limited to, 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.

[0232] Exemplary topoisomerase I inhibitors include, but are not limited to, topotecan, gimatine, 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.

[0233] Microtubule active agents include microtubule stabilizing compounds, microtubule destabilizing compounds, and tubulin polymerization inhibitors, including, but not limited to, taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine, vinblastine sulfate, vincristine, and vincristine sulfate, and vinorelbine; dermatolide; colchicine, and epothilones and their derivatives.

[0234] Exemplary, non-limiting alkylating agents include cyclophosphamide, ifosfamide, melphalan, and nitrosoureas, such as carmustine and lomustine.

[0235] Exemplary, non-limiting cyclooxygenase inhibitors include Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acids and derivatives, such as celecoxib, rofecoxib, etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acids, such as lumiracoxib.

[0236] Exemplary, non-limiting matrix metalloproteinase inhibitors ("MMP inhibitors") include collagen peptidomimetics and non-peptide mimetic inhibitors, tetracycline derivatives, batimastat, marimastat, prinomastat, metastat, BMS-279251, BAY 12-9566, TAA211, MMI270B, and AAJ996.

[0237] Exemplary, non-limiting mTOR inhibitors include compounds that inhibit the mammalian target of rapamycin (mTOR) and have anti-proliferative activity, such as sirolimus, everolimus, CCI-779, and ABT578.

[0238] Exemplary, non-limiting antimetabolites include 5-fluorouracil (5-FU), capecitabine, gemcitabine, DNA demethylating compounds such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folate antagonists such as pemetrexed.

[0239] Exemplary, non-limiting platinum compounds include carboplatin, cis-platin, cisplatinum, and oxaliplatin.

[0240] Exemplary, non-limiting methionine aminopeptidase inhibitors include bengamide or its derivatives and PPI-2458.

[0241] Exemplary, non-limiting bisphosphonates include etidronic acid, clodronic acid, tiludronic acid, pamidronate, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid.

[0242] Exemplary, non-limiting, anti-proliferative antibodies include trastuzumab, trastuzumab-DM1, cetuximab, bevacizumab, rituximab, PRO64553, and 2C4. The term "antibody" is intended to include intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity.

[0243] Exemplary, non-limiting heparanase inhibitors include compounds that target, decrease, or inhibit the degradation of heparan sulfate, such as PI-88 and OGT2115.

[0244] As used herein, the term "inhibitor of Ras oncogenic isoforms" such as H-Ras, K-Ras or N-Ras refers to compounds that target, decrease or inhibit the oncogenic activity of Ras, for example, farnesyl transferase inhibitors such as L-744832, DK8G557, tipifarnib and lonafarnib.

[0245] Exemplary, non-limiting telomerase inhibitors include compounds that target, decrease or inhibit the activity of telomerase, such as compounds that inhibit the telomerase receptor, such as telomerstatin.

[0246] Exemplary, non-limiting proteasome inhibitors include compounds that target, decrease or inhibit the activity of the proteasome, including, but not limited to, bortezomib.

[0247] As used herein, the phrase "compounds for treating hematological malignancies" includes FMS-like tyrosine kinase inhibitors, which are compounds that target, decrease or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R); interferon, 1-β-D-arabinofuranosylcytosine (Ara-C), and busulfan; and ALK inhibitors, which are compounds that target, decrease or inhibit anaplastic lymphoma kinase.

[0248] Exemplary, non-limiting Flt-3 inhibitors include PKC412, midostaurin, staurosporine derivatives, SU11248, and MLN518.

[0249] Exemplary, non-limiting HSP90 inhibitors include compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90; or compounds that degrade, target, reduce, or inhibit HSP90 client proteins through the ubiquitin proteasome pathway. Compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90 are particularly compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin (17AAG), geldanamycin derivatives; other geldanamycin-related compounds; radicicol and HDAC inhibitors.

[0250] As used herein, the phrase "a compound that targets / decreases the activity of a protein or lipid kinase, or a compound that targets / decreases the activity of a protein or lipid phosphatase, or any other anti-angiogenic compound" includes protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds that target, decrease or inhibit the activity of platelet-derived growth factor receptor (PDGFR), such as compounds that target, decrease or inhibit the activity of PDGFR, such as N-phenyl-2-pyrimidinyl-amine derivatives, such as imatinib, SU101, SU6668 and GFB-111; b) compounds that target, decrease or inhibit the activity of fibroblast growth factor receptor (FGFR); c) compounds that target, decrease or inhibit the activity of insulin-like growth factor receptor 1 (IGF-IR), such as compounds that target, decrease or inhibit the activity of PDGFR, such as N-phenyl-2-pyrimidinyl-amine derivatives, such as imatinib, SU101, SU6668 and GFB-111; d) compounds that target, decrease or inhibit the activity of the Trk receptor tyrosine kinase family, or pterin B4 inhibitors; e) compounds that target, decrease or inhibit the activity of the Axl receptor tyrosine kinase family; f) compounds that target, decrease or inhibit the activity of the Ret receptor tyrosine kinase; g) compounds that target, decrease or inhibit the activity of the Kit / SCFR receptor tyrosine kinase, such as imatinib; h) compounds that target, decrease or inhibit the activity of the c-Kit receptor tyrosine kinase, such as imatinib; i) compounds that target, decrease or inhibit the activity of members of the c-Abl family, their gene fusion products (e.g., Bcr-Abl kinase) and mutants, such as N-phenyl-2-pyrimidine-amine derivatives, such as imatinib or nilotinib; PD180970; AG957; NSC 680410; PD173955; or dasatinib; j) compounds that target, decrease or inhibit the activity of members of the protein kinase C (PKC) and Raf families of serine / threonine kinases, members of the MEK, SRC, JAK, FAK, PDK1, PKB / Akt and Ras / MAPK families, and / or members of the cyclin-dependent kinase family (CDK), such as staurosporine derivatives disclosed in U.S. Pat. No. 5,093,330, such as midostaurin; examples of other compounds include UCN-01, safinol, BAY 43-9006, bryostatin 1, perifosine; imofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531 / LY379196; isoquinoline compounds; farnesyl transferase inhibitors; PD184352 or QAN697 or AT7519; k) compounds that target, decrease or inhibit the activity of protein-tyrosine kinases, such as imatinib mesylate or tyrosine phosphorylation inhibitors, such as tyrosine phosphorylation inhibitors A23 / RG-50810; AG 99; tyrosine phosphorylation inhibitor AG 213;Tyrosine phosphorylation inhibitor AG1748; tyrosine phosphorylation inhibitor AG 490; tyrosine phosphorylation inhibitor B44; tyrosine phosphorylation inhibitor B44 (+) enantiomer; tyrosine phosphorylation inhibitor AG 555; AG 494; tyrosine phosphorylation inhibitor AG 556, AG957 and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, adaphostin); 1) compounds that target, decrease or inhibit the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such as CP 358774, ZD 1839, ZM 105180; trastuzumab, cetuximab, gefitinib, erlotinib, OSI-774, Cl-1033, EKB-569, GW-2016, antibodies E1.1, 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, decrease or inhibit the activity of c-Met receptors. ;

[0251] Exemplary compounds that target, decrease or inhibit the activity of a protein or lipid phosphatase include inhibitors of phosphatase 1, phosphatase 2A or CDC25, such as okadaic acid or a derivative thereof.

[0252] Other anti-angiogenic compounds include compounds that have another mechanism of their activity unrelated to protein or lipid kinase inhibition, for example, thalidomide and TNP-470.

[0253] Additional, non-limiting, exemplary chemotherapeutic compounds, one or more of which may be used in combination with the compounds of the present disclosure, include: daunorubicin, doxorubicin, cytarabine, VP-16, teniposide, mitoxantrone, idarubicin, carboplatin, 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, dapoxetine ... Biological, l-(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 inhibitor, FLT-3 inhibitor, VEGFR-2 IgGI antibody, RPI 4610, bevacizumab, porfimer sodium, anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocotisol, corticosterone, 17α-hydroxyprogesterone, corticosterone, deoxycorticosterone, 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.

[0254] Other examples of second therapeutic agents (one or more of which may also be combined with a compound of the present disclosure) include, but are not limited to, therapeutic agents for Alzheimer's disease, such as donepezil and rivastigmine; therapeutic agents for Parkinson's disease, such as L-DOPA / carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents used to treat multiple sclerosis (MS), such as beta interferon (e.g., and ), glatiramer acetate, and mitoxantrone; therapeutic agents for asthma, such as albuterol and montelukast; agents used to treat schizophrenia, such as Zyprexa, Risperdal, Seroquel, and haloperidol; anti-inflammatory agents, such as corticosteroids, TNF blockers, IL-1RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulators, including immunosuppressants, such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors, such as acetaminophen, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; agents for treating cardiovascular disease, such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, or statins; agents for treating liver disease, such as corticosteroids, cholestyramine, interferon, and antiviral agents; agents for treating blood disorders, such as corticosteroids, antileukemia agents, or growth factors; or agents for treating immunodeficiency disorders, such as gamma globulin.

[0255] In another embodiment, 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. Therefore, in one embodiment, the compound of the present disclosure is administered in combination with an immune checkpoint inhibitor selected from PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, LAG3 inhibitors, TIM3 inhibitors, and CD47 inhibitors.

[0256] In another embodiment, the immune checkpoint inhibitor is a programmed cell death (PD-1) inhibitor. PD-1 is a T-cell co-inhibitory receptor that plays a key role in the ability of tumor cells to evade the host immune system. Blocking the interaction between PD-1 and PD-L1 (a ligand for PD-1) 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 a general discussion of the availability, production methods, mechanism of action, and clinical studies of anti-PD-1 antibodies, see US 2013 / 0309250, US 6,808,710, US 7,595,048, US 8,008,449, US 8,728,474, US 8,779,105, US 8,952,136, US 8,900,587, US 9,073,994, US 9,084,776, and Naido et al., British Journal of Cancer 111:2214-19 (2014).

[0257] In another embodiment, 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 a general discussion of availability, production methods, mechanisms of action, and clinical studies, see U.S. Pat. No. 8,217,149, U.S. Pat. No. 2014 / 0341917, U.S. Pat. No. 2013 / 0071403, WO2015036499, and Naido et al., British Journal of Cancer 111: 2214-19 (2014).

[0258] In another embodiment, 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 is characterized as a "brake" that binds to co-stimulatory molecules on antigen-presenting cells, which prevents interaction with CD28 on T cells and also produces significant inhibitory signals to limit 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 a general discussion of availability, production methods, mechanism of action, and 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).

[0259] In another embodiment, the immune checkpoint inhibitor is a LAG3 inhibitor. LAG3 (lymphocyte activation gene 3) is a negative co-mimicking receptor that regulates T cell homeostasis, proliferation, and activation. In addition, LAG3 has been reported to be involved in the inhibitory function of regulatory T cells (Tregs). A large number of LAG3 molecules are retained in cells near the microtubule organizing center and are only induced 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 a general discussion of availability, production methods, mechanism of action, and research, see U.S. 2011 / 0150892, U.S. 2014 / 0093511, U.S. 20150259420, and Huang et al., Immunity 21:503-13 (2004).

[0260] In another embodiment, the immune checkpoint inhibitor is a TIM3 inhibitor. TIM3 (T-cell immunoglobulin and mucin domain 3) is an immune checkpoint receptor that functions to limit T H 1 and T C 1 The duration and intensity of T-cell responses. The TIM3 pathway is considered a target for anticancer immunotherapy because it plays a crucial role in the regulation of dysfunctional CD8 +T cells and Tregs are expressed, and it is reported that these two immune cell populations constitute immunosuppression in tumor tissue. Anderson, Cancer Immunology Research 2: 393-98 (2014). The example of TIM3 inhibitors includes antibodies that specifically bind to TIM3. For a general discussion of the availability, production methods, mechanism of action and research 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).

[0261] In another embodiment, the immune checkpoint inhibitor is a CD47 inhibitor. See Unanue, ER, PNAS 110: 10886-87 (2013).

[0262] The term "antibody" is intended to include intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity. In another embodiment, "antibody" is intended to include soluble receptors that do not have the Fc portion of an antibody. In one embodiment, the antibody is a humanized monoclonal antibody and fragments thereof prepared by recombinant genetic engineering.

[0263] Another class of immune checkpoint inhibitors includes polypeptides that bind to and block the PD-1 receptor on T cells without triggering inhibitor signaling. Such peptides include B7-DC polypeptide, B7-H1 polypeptide, B7-1 polypeptide, and B7-2 polypeptide, and soluble fragments thereof, as disclosed in U.S. Patent 8,114,845.

[0264] Another class of immune checkpoint inhibitors includes compounds with a peptide portion that inhibits PD-1 signaling. Examples of such compounds are disclosed in U.S. Patent 8,907,053.

[0265] Another class of immune checkpoint inhibitors includes inhibitors of certain metabolic enzymes, such as indoleamine 2,3 dioxygenase (IDO), which is expressed by infiltrating myeloid cells and tumor cells. The IDO enzyme suppresses the immune response by depleting amino acids necessary for the anabolic function of T cells or by synthesizing specific natural ligands for cytoplasmic receptors that can alter lymphocyte function. Pardoll, Nature Reviews. Cancer 12:252-64 (2012); Cancer Immunol Immunother 58:153-57 (2009). Specific IDO blockers include, but are not limited to, L-1-methyltryptophan (L-1MT) and 1-methyl-tryptophan (1MT). Qian et al., Cancer Res 69:5498-504 (2009); and et al., Cancer Immunol Immunother 58:153-7 (2009).

[0266] In one embodiment, the immune checkpoint inhibitor is nivolumab, pembrolizumab, pidilizumab, STI-A1110, avelumab, atezolizumab, durvalumab, STI-A1014, ipilimumab, tremelimumab, GSK2831781, BMS-936559, or MED14736.

[0267] Other examples of second therapeutic agents (one or more of which may also be combined with the compounds of the present disclosure) include glutamine antagonists. Suitable glutamine antagonists are disclosed in, for example, WO 2017 / 023774 and WO 2019 / 071110. Specific glutamine antagonists include, but are not limited to, isopropyl (S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)propionamido)-6-diazo-5-oxohexanoate, or a pharmaceutically acceptable salt thereof, isopropyl (S)-2-((S)-6-acetamido-2-((3S, 5S, 7S)-adamantane-1-carboxamido)hexanoamido)-6-diazo-5-oxohexanoate, or a pharmaceutically acceptable salt thereof, (S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)propionamido)-6-diazo-5-oxohexanoic acid, or a pharmaceutically acceptable salt thereof, or 6-diazo-5-oxo-L-norleucine, or a pharmaceutically acceptable salt thereof.

[0268] In one embodiment, the second therapeutic agent comprises one of the anticancer drugs or combinations of anticancer drugs listed in Table 6.

[0269] Table 6

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280] For a more detailed description of anticancer agents and other optional therapeutic agents, one skilled in the art is referred to any number of manuals, including, but not limited to, the Physician's Desk Reference and Goodman and Gilman's "Pharmaceutical Basis of Therapeutics," Tenth Edition, Hardman et al., eds., 2002.

[0281] The preparation and administration of the aforementioned second therapeutically active agents, one or more of which may be used in combination with the compounds of the present disclosure, are described in the art.

[0282] The compounds of the present disclosure are typically administered in admixture with a pharmaceutical carrier selected according to the intended route of administration and standard pharmaceutical practice. Pharmaceutical compositions for use according to the present disclosure are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and / or adjuvants that facilitate the processing of the compounds of the present disclosure.

[0283] These pharmaceutical compositions can be manufactured by, for example, conventional mixing, dissolving, granulating, preparing dragees, emulsifying, encapsulating, embedding or lyophilizing processes. The appropriate formulation depends on the selected route of administration. When a therapeutically effective amount of a compound of the present disclosure is administered orally, the composition is typically in the form of a tablet, capsule, powder, solution or elixir. When administered in tablet form, the composition may additionally contain a solid carrier, such as gelatin or an adjuvant. The tablets, capsules and powders contain about 0.01% to about 95% and preferably about 1% to about 50% of a compound of the present disclosure. When administered in liquid form, a liquid carrier such as water, petroleum or oil of animal or plant origin may be added. The composition in liquid form may further contain physiological saline solution, dextrose or other sugar solution or glycols. When administered in liquid form, the composition contains about 0.1% to about 90% and preferably about 1% to about 50% (by weight) of a compound of the present disclosure.

[0284] When a therapeutically effective amount of a compound of the present disclosure is administered by intravenous, cutaneous, or subcutaneous injection, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable solutions with due consideration of pH, isotonicity, stability, etc. is within the skill of the art. Preferred compositions for intravenous, cutaneous, or subcutaneous injection typically contain an isotonic vehicle.

[0285] The compounds of the present disclosure can be easily 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, 1995, 19th edition. Such carriers enable the active agent to be formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral intake by the patient to be treated. Pharmaceutical products for oral use can be obtained as follows: a compound of the present disclosure is added to a solid excipient, the mixture obtained is optionally ground, and the granular mixture is processed after adding suitable adjuvants (if necessary) to obtain tablets or dragee cores.

[0286] Suitable excipients include fillers such as sugars (e.g., lactose, sucrose, mannitol or sorbitol), cellulose products, calcium phosphates (e.g., tricalcium phosphate or calcium hydrogen phosphate) and adhesives such as starch paste (using, for example, corn starch, wheat starch, rice starch or potato starch), gelatin, tragacanth, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and / or polyvinyl pyrrolidone. If necessary, one or more disintegrants can be added, such as above-mentioned starch and carboxymethyl starch, cross-linked polyvinyl pyrrolidone, agar or alginic acid or its salt, such as sodium alginate. Buffers and pH adjusting agents can also be added to stabilize the pharmaceutical composition.

[0287] The auxiliary agent is normally a flow regulator and a lubricant, such as, for example, silicon dioxide, talc, stearic acid or its salt (for example, magnesium stearate or calcium stearate) and Polyethylene Glycol. The suitable coating of resistance to gastric juice is provided to the dragee core. For this purpose, concentrated sugar solution can be used, which can optionally contain gum arabic, talc, polyvinyl pyrrolidone, Polyethylene Glycol and / or titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture. In order to produce the coating of resistance to gastric juice, the solution of suitable cellulose products such as acetylcellulose phthalate or hydroxypropyl methyl-cellulose phthalate can be used. Dye or pigment can be added to tablet or the dragee coating, for example, for identification or in order to characterize the combination of active compound dosage.

[0288] The compounds of the present disclosure can be formulated for parenteral administration by injection (e.g., by rapid bolus injection or continuous infusion). Injectable formulations can be in unit dosage form, for example, in ampoules or in multi-dose containers, with the addition of preservatives. The compositions can take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain preparatons such as suspending agents, stabilizers, and / or dispersants.

[0289] The pharmaceutical composition for parenteral administration includes an aqueous solution of an active agent in a water-soluble form. In addition, the suspension of the compound of the present disclosure can be prepared into a suitable oily injection suspension. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension. Optionally, the suspension can also contain a suitable stabilizer or an agent that increases the solubility of the compound and allows the preparation of a highly concentrated solution. Alternatively, the composition of the present invention can be in powder form, which is used for preparing with a suitable vehicle (e.g., sterile pyrogen-free water) before use.

[0290] The compound of the present disclosure can also be formulated into rectal compositions, such as suppositories or retention enemas, for example, containing conventional suppository bases. In addition to the preparations previously described, the compound of the present disclosure can also be formulated into depot preparations. Such long-acting preparations can be used by implanting (for example, subcutaneously or intramuscularly) or by intramuscular injection. Therefore, for example, the compound of the present disclosure can be formulated with suitable polymers or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins.

[0291] Specifically, 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 capsules or ovules (alone or mixed with excipients), or in the form of elixirs or suspensions containing flavorings or coloring agents. Such liquid preparations can be prepared with pharmaceutically acceptable additives, such as suspending agents. The compounds of the present disclosure can also be injected parenterally (e.g., intravenously, intramuscularly, subcutaneously, or intracoronarily). For parenteral administration, the compounds of the present disclosure are generally used in the form of sterile aqueous solutions that may contain other substances, for example, salts or monosaccharides such as mannitol or glucose, to render the solution isotonic with the blood.

[0292] The present disclosure provides the following specific embodiments related to using the compounds of the present disclosure to treat a disease in a subject.

[0293] Embodiment 1. A method of treating a subject, comprising administering to the subject a therapeutically effective amount of a compound of the disclosure, wherein the subject has cancer, a neurodegenerative disease, diabetes, cardiovascular disease, kidney disease, or liver disease.

[0294] Embodiment II. The method of Embodiment I, wherein the subject has cancer, eg, any one or more of the cancers of Table 2 or Table 3.

[0295] Embodiment III. The method of Embodiment II, wherein the cancer is prostate cancer or breast cancer.

[0296] Embodiment IV. The method of Embodiment II, wherein the cancer is lung cancer, eg, NSCLC.

[0297] Embodiment V. The method of Embodiment II, wherein the cancer is prostate cancer, eg, metastatic castration-resistant prostate cancer.

[0298] Embodiment VI. The method of any of Embodiments IV, further comprising administering a therapeutically effective amount of a second therapeutic agent useful for treating the disease or condition, eg, an immune checkpoint inhibitor or other anti-cancer agent.

[0299] Embodiment VII. A pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient.

[0300] Embodiment VIII. The pharmaceutical composition of Embodiment VII for use in treating cancer, neurodegenerative disease, diabetes, cardiovascular disease, kidney disease, or liver disease.

[0301] Embodiment IX. The pharmaceutical composition of embodiment VIII, wherein the cancer is prostate cancer or breast cancer.

[0302] Embodiment X. The pharmaceutical composition of Embodiment VIII, wherein the cancer is lung cancer, eg, NSCLC.

[0303] Embodiment XI. The pharmaceutical composition of Embodiment VIII, wherein the cancer is prostate cancer, eg, metastatic castration-resistant prostate cancer.

[0304] Embodiment XII. Compounds of the Disclosure for use in the treatment of cancer, neurodegenerative disease, diabetes, cardiovascular disease, kidney disease, or liver disease.

[0305] Embodiment XIII. A compound of Embodiment XIII for use in the treatment of cancer.

[0306] Embodiment XIV. The compound of Embodiment XIII, wherein the cancer is breast cancer or lung cancer, eg, NSCLC.

[0307] Embodiment XV. The compound of Embodiment XIII, wherein the cancer is prostate cancer, eg, metastatic castration-resistant prostate cancer.

[0308] Embodiment XVI. Use of a compound of the present disclosure for the preparation of a medicament for the treatment of cancer, neurodegenerative disease, diabetes, cardiovascular disease, kidney disease, or liver disease.

[0309] Embodiment XVII. The use of embodiment XVI for treating cancer.

[0310] Embodiment XVIII. The use of embodiment XVII, wherein the cancer is prostate cancer or breast cancer.

[0311] Embodiment XIV. The use of embodiment XVII, wherein the cancer is lung cancer, eg, NSCLC.

[0312] Embodiment XX. The use of embodiment XVII, wherein the cancer is prostate cancer, e.g., metastatic castration-resistant prostate cancer.

[0313] Embodiment XXI. A method of reducing Nrf2 protein in a cell of a subject in need thereof, the method comprising administering a compound of the present disclosure to the subject. In one embodiment, 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 embodiment, 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%.

[0314] Embodiment XXII. The method of Embodiment I or VI, wherein the subject has a neurodegenerative disease.

[0315] Embodiment XXIII. The method of Embodiment I or VI, wherein the subject has diabetes.

[0316] Embodiment XXIV. The method of Embodiment I or VI, wherein the subject suffers from cardiovascular disease.

[0317] Embodiment XXV. The method of Embodiment I or VI, wherein the subject has kidney disease.

[0318] Embodiment XXVI. The method of Embodiment I or VI, wherein the subject has liver disease.

[0319] Embodiment XXVII. The pharmaceutical composition of Embodiment VIII, wherein the subject suffers from a neurodegenerative disease.

[0320] Embodiment XXVIII. The pharmaceutical composition of Embodiment VIII, wherein the subject suffers from diabetes.

[0321] Embodiment XXIX. The pharmaceutical composition of Embodiment VIII, wherein the subject suffers from cardiovascular disease.

[0322] Embodiment XXX. The pharmaceutical composition of Embodiment VIII, wherein the subject suffers from kidney disease.

[0323] Embodiment XXXI. The pharmaceutical composition of Embodiment VIII, wherein the subject suffers from liver disease.

[0324] Embodiment XXXII. The compound of Embodiment XII, wherein the subject has a neurodegenerative disease.

[0325] Embodiment XXXIII. The compound of Embodiment XII, wherein the subject has diabetes.

[0326] Embodiment XXXIV. The compound of Embodiment XII, wherein the subject suffers from cardiovascular disease.

[0327] Embodiment XXXV. The compound of Embodiment XII, wherein the subject has kidney disease.

[0328] Embodiment XXXVI. The compound of Embodiment XII, wherein the subject has liver disease.

[0329] Embodiment XXXVII. The use of embodiment XVI, wherein the subject suffers from a neurodegenerative disease.

[0330] Embodiment XXXVIII. The use of embodiment XVI, wherein the subject has diabetes.

[0331] Embodiment XXXIX. The use of embodiment XVI, wherein the subject suffers from cardiovascular disease.

[0332] Embodiment XL. The use of embodiment XVI, wherein the subject suffers from kidney disease.

[0333] Embodiment XLI. The use of embodiment XVI, wherein the subject suffers from liver disease.

[0334] III. Kits of the Disclosure

[0335] In another embodiment, the disclosure provides a kit comprising a compound of the disclosure (or a composition comprising a compound of the disclosure) packaged in a manner conducive to its use in practicing the method of the disclosure. In one embodiment, the kit comprises a compound of the disclosure (or a composition comprising a compound of the disclosure) packaged in a container (such as a sealed bottle or vessel), and a label attached to the container or contained in the kit describes the compound or composition for use in practicing the method of the disclosure. In one embodiment, the compound or composition is packaged in a unit dosage form. The kit may further include a device suitable for administering the composition according to an intended route of administration.

[0336] IV. Definitions

[0337] The term "disease or condition in which degradation of Nrf2 provides a benefit" and the like relate to a disease or condition in which Nrf2 is important or necessary, for example, for the onset, progression, manifestation of the disease or condition, or a disease or condition known to be treatable by an Nrf2 inhibitor or degrader. Examples of such diseases or conditions include, but are not limited to, cancer, neurodegenerative diseases, diabetes, cardiovascular disease, kidney disease, or liver disease. Dodson et al., Annu Rev Pharmacol Toxicol 59:555-575 (2019). One of ordinary skill in the art can readily determine for any particular cell type whether a compound treats a disease or condition mediated by an Nrf2 degrader, for example, by assays that are readily available for assessing the activity of a particular compound.

[0338] The term "Nrf2 degrader" or the like refers to a heterobifunctional small molecule that degrades the Nrf2 protein. An Nrf2 degrader comprises a first ligand that binds to the Nrf2 protein, a second ligand for use in an E3 ligase system, and a chemical linker connecting the first and second ligands. Table 1 discloses representative compounds of the present disclosure that degrade the Nrf2 protein.

[0339] 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, when cancer is the disease or condition of interest, the second therapeutic agent can be, for example, a known chemotherapeutic drug (such as Taxol) or radiation.

[0340] The term "disease" or "disorder" refers to a disorder and / or abnormality that is generally regarded as a pathological condition or function, and which may manifest itself in the form of specific signs, symptoms and / or dysfunction. The compounds of the present disclosure are degraders of Nrf2 and can be used to treat or prevent diseases and disorders in which degradation of Nrf2 would provide a benefit.

[0341] As used herein, the terms "treat," "treating," "treatment," and the like refer to the elimination, reduction, or amelioration of a disease or condition and / or symptoms associated therewith. Although not excluded, treatment of a disease or condition does not require the complete elimination of the disease, condition, or symptoms associated therewith. The term "treat" and synonyms contemplate the administration of a therapeutically effective amount of a compound of the present disclosure to a subject in need of such treatment. The treatment can be symptomatic, for example, to suppress symptoms. It can be performed over a short period of time, over an intermediate period, or can be long-term treatment, for example, in the context of maintenance therapy.

[0342] As used herein, the terms "prevent," "preventing," and "prevention" refer to methods of preventing the onset of a disease or condition and / or its attendant symptoms, or preventing a subject from developing 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 of a subject developing a disease. The terms "prevent," "preventing," and "prevention" may include "prophylactic treatment," which refers to reducing the likelihood of a disease or condition recurring, or reducing the likelihood of a recurrence of a previously controlled disease or condition, in a subject who does not have the disease or condition or a recurrence of the disease or condition, but is at risk of or susceptible to a disease or condition recurring, or a recurrence of the disease or condition.

[0343] As used herein, the term "therapeutically effective amount" or "effective dose" means an amount of an active ingredient that, when administered by the methods of the present disclosure, is sufficient to effectively deliver the active ingredient to a subject in need thereof to treat the condition or disease of interest. For cancer or other proliferative disorders, a therapeutically effective amount of an agent can reduce (i.e., slow down or stop to some extent) unwanted cell proliferation; reduce the number of cancer cells; reduce tumor size; inhibit (i.e., slow down or stop to some extent) cancer cell infiltration into peripheral organs; inhibit (i.e., slow down or stop to some extent) tumor metastasis; inhibit tumor growth to some extent; and / or alleviate to some extent one or more symptoms associated with cancer. To the extent that the administered compound or composition prevents growth and / or kills existing cancer cells, it may be cytostatic and / or cytotoxic.

[0344] The term "container" refers to any receptacle and closure suitable for storing, transporting, distributing, and / or handling a pharmaceutical product.

[0345] The term "insert" refers to information that accompanies a drug product and provides a description of how to administer the product, as well as safety and efficacy data necessary to allow physicians, pharmacists, and patients to make informed decisions about the product's use. The package insert is often considered the "label" for a drug product.

[0346] "Administered in parallel," "administered in combination," "administered simultaneously," and similar phrases refer to the administration of two or more agents to the subject being treated in parallel. "In parallel" means that each agent is administered simultaneously or sequentially in any order at different time points. However, if not administered simultaneously, it means that they are administered to the subject sequentially and sufficiently close in time to provide the desired therapeutic effect and can act synergistically. For example, a compound of the present disclosure can be administered concurrently as a second therapeutic agent, or sequentially in any order at different time points. The compound of the present disclosure and the second therapeutic agent can be administered separately in any appropriate form and by any suitable route. When the compound of the present disclosure and the second therapeutic agent are not administered in parallel, it should be understood that they can be administered to the subject in need thereof in any order. For example, a Compound of the Disclosure can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapeutic treatment modality (e.g., radiation therapy) to a subject in need thereof. In various embodiments, the Compound of the 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 to 2 hours apart, 2 to 3 hours apart, 3 to 4 hours apart, 4 to 5 hours apart, 5 to 6 hours apart, 6 to 7 hours apart, 7 to 8 hours apart, 8 to 9 hours apart, 9 to 10 hours apart, 10 to 11 hours apart, 11 to 12 hours apart, no more than 24 hours apart, or no more than 48 hours apart. In one embodiment, the components of the combination therapy are administered about 1 minute to about 24 hours apart.

[0347] In the context of describing the present disclosure (especially in the context of the claims), the use of the terms "a", "an", "the" and similar references should be interpreted as covering both the singular and the plural, unless otherwise indicated. Unless otherwise indicated herein, the enumeration of numerical ranges herein is intended only to serve as a shorthand method of individually referring to each individual value falling within the range, and each individual value is incorporated into the specification as if individually set forth herein. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended to better explain the present disclosure and is not a limitation on the scope of the present disclosure, unless otherwise stated. Any language in the specification should not be interpreted as indicating that any undeclared element is essential for the practice of the present disclosure.

[0348] The term "halogen" as used herein alone or as part of another group means -Cl, -F, -Br or -I.

[0349] The term "nitro" as used herein alone or as part of another group refers to -NO2.

[0350] The term "cyano" as used herein alone or as part of another group refers to -CN.

[0351] The term "hydroxy" as used herein alone or as part of another group means -OH.

[0352] The term "alkyl" as used herein alone or as part of another group refers to a group containing 1 to 12 carbon atoms (i.e., C1-C 12 In one embodiment, the alkyl group is C1-C 10 In another embodiment, the alkyl group is a C1-C6 alkyl group. In another embodiment, the alkyl group is a C1-C4 alkyl group. In another embodiment, the alkyl group is a C1-C3 alkyl group, i.e., methyl, ethyl, propyl, or isopropyl. Non-limiting exemplary C1-C 12 Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl.

[0353] The term "optionally substituted alkyl" as used herein alone or as part of another group refers to an alkyl group that is unsubstituted or substituted with 1, 2, or 3 substituents, wherein each substituent is independently nitro, haloalkoxy, aryloxy, aralkyloxy, alkylthio, sulfonylamino, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, urea, guanidino, carbamate, carboxyl, 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 ;in:

[0354] R 56a is hydrogen or an alkyl group;

[0355] 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;

[0356] R 56c is hydrogen or an alkyl group;

[0357] 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;

[0358] 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;

[0359] R 57is 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

[0360] R 58 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. Non-limiting exemplary optionally substituted alkyl groups include-CH(CO2Me)CH2CO2Me and-CH(CH3)CH2N(H)C(=O)O(CH3)3.

[0361] The term "alkenyl" used herein alone or as part of another group represents an alkyl group containing 1, 2 or 3 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 a carbon-carbon double bond. Non-restrictive exemplary alkenyl groups include vinyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl and hexenyl.

[0362] The term "optionally substituted alkenyl" as used herein alone or as part of another group refers to an alkenyl group that is unsubstituted or substituted with 1, 2, or 3 substituents, each of which is independently halogen, nitro, cyano, hydroxy, amino (e.g., alkylamino, dialkylamino), haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, urea, guanidino, carboxyl, carboxylalkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycle. Non-limiting exemplary optionally substituted alkenyl groups include -CH=CHPh.

[0363] The term "alkynyl" as used herein, alone or as part of another group, refers to an alkyl group containing 1, 2, or 3 carbon-carbon triple bonds. In one embodiment, the alkynyl is a C2-C6 alkynyl. In another embodiment, the alkynyl is a C2-C4 alkynyl. In another embodiment, the alkynyl has one carbon-carbon triple bond. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.

[0364] The term "optionally substituted alkynyl" as used herein, alone or as part of another group, refers to an alkynyl group that is unsubstituted or substituted with 1, 2, or 3 substituents, each of which is independently halogen, nitro, cyano, hydroxy, amino, for example, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, urea, guanidino, carboxyl, carboxylalkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycle. Non-limiting exemplary optionally substituted alkynyl groups include -C≡CPh and -CH(Ph)C≡CH.

[0365] The term "haloalkyl" as used herein, alone or as part of another group, refers to an alkyl group substituted with one or more fluorine, chlorine, bromine, and / or iodine atoms. In one embodiment, the alkyl group is substituted with 1, 2, or 3 fluorine and / or chlorine atoms. In another embodiment, the alkyl group is substituted with 1, 2, or 3 fluorine atoms. In another embodiment, the alkyl group is a C1-C6 alkyl group. In another embodiment, the alkyl group is a C1-C4 alkyl group. In another embodiment, the alkyl group is a C1 or C2 alkyl group. Non-limiting 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.

[0366] The term "hydroxyalkyl" or "(hydroxy)alkyl" as used herein, alone or as part of another group, refers to an alkyl group substituted with 1, 2, or 3 hydroxy groups. In one embodiment, the alkyl group is a C1-C6 alkyl group. In another embodiment, the alkyl group is a C1-C4 alkyl group. In another embodiment, the alkyl group is a C1 or C2 alkyl group. In another embodiment, the hydroxyalkyl group 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 exemplary (hydroxy)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.

[0367] The term "alkoxy" as used herein, alone or as part of another group, refers to an alkyl group attached to a terminal oxygen atom. In one embodiment, the alkyl group is a C1-C6 alkyl group and the resulting alkoxy group is thus referred to as a "C1-C6 alkoxy group". In another embodiment, the alkyl group is a C1-C4 alkyl group. Non-limiting exemplary alkoxy groups include methoxy, ethoxy, and tert-butoxy.

[0368] The term "haloalkoxy" used herein alone or as part of another group refers to a haloalkyl group connected to a terminal oxygen atom. In one embodiment, the haloalkyl group is a C1-C6 haloalkyl group. In another embodiment, the haloalkyl group is a C1-C4 haloalkyl group. Non-limiting exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy and 2,2,2-trifluoroethoxy.

[0369] The term "alkylthio" as used herein alone or as part of another group refers to an alkyl group attached to a terminal sulfur atom. In one embodiment, the alkyl group is a C1-C4 alkyl group. Non-limiting exemplary alkylthio groups include -SCH3 and -SCH2CH3.

[0370] The term "alkoxyalkyl" or "(alkoxy)alkyl," as used herein alone or as part of another group, refers to an alkyl group substituted with an alkoxy group. In one embodiment, the alkoxy group is a C1-C6 alkoxy group. In another embodiment, the alkoxy group is a C1-C4 alkoxy group. In another embodiment, the alkyl group is a C1-C6 alkyl group. In another embodiment, the alkyl group is a C1-C4 alkyl group. Non-limiting exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, isopropoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl, tert-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, and pentoxymethyl.

[0371] The term "heteroalkyl" as used herein, alone or as part of another group, refers to an unsubstituted straight or branched aliphatic hydrocarbon containing 3-20 chain atoms (i.e., 3 to 20 membered heteroalkyl) or a specified 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)-, or -S- can be independently located at any position of the aliphatic hydrocarbon chain, as long as each -O-, -N(H)-, -N(C1-C4 alkyl)-, and -S- group is separated 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, a -CH2- group is replaced by a -NH- group. Non-restrictive exemplary heteroalkyl groups include CH2OCH3, -CH2OCH2CH2CH3, -CH2CH2CH2OCH3, -NHCH2CH2OCH2CH2OCH2CH3, -CH2CH2OCH2CH2OCH2CH3, -CH2CH2OCH2CH2OCH2CH3, -CH2CH2OCH2CH2OCH2CH3, -CH2CH2OCH2CH2OCH2CH2OCH2CH3 and -NHCH2CH2CH2CH2CH3.

[0372] The term "cycloalkyl" as used herein alone 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 3-12In one embodiment, the cycloalkyl group is bicyclic, i.e., it has two rings. In another embodiment, the cycloalkyl group is monocyclic, i.e., it has one ring. In another embodiment, the cycloalkyl group is C 3-8 In another embodiment, the cycloalkyl group is C 3-6 In another embodiment, the cycloalkyl group is a C5 cycloalkyl group, i.e., a cyclopentyl group or a cyclopentenyl group. In another embodiment, the cycloalkyl group is a C6 cycloalkyl group, i.e., a cyclohexyl group or a cyclohexenyl group. Non-limiting exemplary C 3-12 Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, and spiro[3.3]heptane.

[0373] The term "optionally substituted cycloalkyl" as used herein alone or as part of another group refers to a cycloalkyl group that is unsubstituted or substituted with 1, 2, or 3 substituents, wherein each substituent is independently halogen, nitro, cyano, hydroxy, amino (e.g., -NH2, alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino, or (heterocyclo)alkylamino), heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, or aralkoxy. alkyl, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, urea, guanidino, carboxyl, carboxylalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxyalkyl, (amino)alkyl, (cyano)alkyl, (formylamino)alkyl, mercaptoalkyl, (heterocycle)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 59 , where R 56a 、R 56b 、R 56c 、R 56d 、R 56e 、R 57 and R 58 As defined for the term "optionally substituted alkyl", and R 59is (hydroxy)alkyl or (amino)alkyl. The term optionally substituted cycloalkyl also includes cycloalkyl groups having fused optionally substituted aryl or optionally substituted heteroaryl groups, such as

[0374]

[0375] The term "heterocycle" as used herein, alone or as part of another group, refers to a saturated and partially unsaturated (e.g., containing one or two double bonds) monocyclic, bicyclic, or tricyclic group containing 3-18 ring members (i.e., 3 to 18-membered heterocycles) comprising 1, 2, 3, or 4 heteroatoms. Each heteroatom is independently oxygen, sulfur, or nitrogen. Each sulfur atom is independently oxidized to produce a sulfoxide, i.e., S(=O), or a sulfone, i.e., S(=O) 2. The term heterocycle includes groups in which one or more -CH 2 -groups are replaced by one or more -C(=O)-groups, including cyclic urea groups such as imidazolidin-2-one, cyclic amide groups such as pyrrolidone or piperidin-2-one, and cyclic carbamate groups such as oxazolidin-2-one. The term heterocycle also includes groups with fused optionally substituted aryl or optionally substituted heteroaryl groups, such as 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]azepine-2-one.

[0376] In one embodiment, the heterocyclic group is a 4 to 8-membered cyclic group containing one ring and one or two oxygen atoms, for example, tetrahydrofuran or tetrahydropyran, or one or two nitrogen atoms, for example, pyrrolidine, piperidine or piperazine, or one oxygen and one nitrogen atom, for example, morpholine, and optionally a -CH2- group is replaced by a -C(=O)- group, for example, pyrrolidone-2-one or piperazine-2-one. In another embodiment, the heterocyclic group is a 5 to 8-membered cyclic group containing one ring and one or two nitrogen atoms, and optionally a -CH2- group is replaced by a -C(=O)- group. In another embodiment, the heterocyclic group is a 5 or 6-membered cyclic group containing one ring and one or two nitrogen atoms, and optionally a -CH2- group is replaced by a -C(=O)- group. In another embodiment, the heterocyclic group is an 8 to 12-membered cyclic group containing two rings and one or two nitrogen atoms. The heterocycle can be connected to the rest of the molecule through any available carbon or nitrogen atom. Non-limiting exemplary heterocyclic groups include:

[0377]

[0378] The term "optionally substituted heterocycle" as used herein alone or as part of another group refers to a heterocycle group that is unsubstituted or substituted with 1 to 4 substituents, wherein each substituent is independently halogen, nitro, cyano, hydroxy, amino (e.g., -NH2, alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino or (heterocyclo)alkylamino), heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, urea, guanidino, carboxyl, carboxylalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxyalkyl, (amino)alkyl, (cyano)alkyl, (formylamino)alkyl, mercaptoalkyl, (heterocycle)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 59 , where R 56a 、R 56b 、R 56c 、R 56d 、R 56e 、R 57 、R 58 and R 59 As defined for the term "optionally substituted cycloalkyl". Substitution may occur on any available carbon or nitrogen atom of the heterocyclic group.

[0379] The term "aryl" as used herein alone or as part of another group refers to an aromatic ring system having 6 to 14 carbon atoms, i.e., C6-C 14 Aryl. Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenylene, and fluorenyl groups. In one embodiment, the aryl group is phenyl or naphthyl. In another embodiment, the aryl group is phenyl.

[0380] The term "optionally substituted aryl" as used herein alone or as part of another group refers to aryl that is unsubstituted or substituted with 1-5 substituents, wherein each of the substituents is independently halo, nitro, cyano, hydroxy, amino (e.g., -NH2, alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino or (heterocyclic)alkylamino), heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, urea, guanidino, carboxyl, carboxylalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxyalkyl, (amino)alkyl, (cyano)alkyl, (formylamino)alkyl, mercaptoalkyl, (heterocycle)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 59 , where R 56a 、R 56b 、R 56c 、R 56d 、R 56e 、R 57 、R 58 and R 59 As defined for the term "optionally substituted cycloalkyl".

[0381] In one embodiment, the optionally substituted aryl is an optionally substituted phenyl. In another embodiment, the optionally substituted phenyl has four substituents. In another embodiment, the optionally substituted phenyl has three substituents. In another embodiment, the optionally substituted phenyl has two substituents. In another embodiment, the optionally substituted phenyl has one substituent. Non-restrictive 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-bis-fluorophenyl, 2,6-bis-chlorophenyl, 2-methyl, 3-methoxyphenyl, 2-ethyl, 3-methoxyphenyl, 3,4-bis-methoxyphenyl, 3,5-bis-fluorophenyl 3,5-bis-methylphenyl, 3,5-dimethoxy, 4-methylphenyl, 2-fluoro-3-chlorophenyl, 3-chloro-4-fluorophenyl, and 2-phenylpropane-2-amine. The term optionally substituted aryl includes an aryl group with a fused optionally substituted cycloalkyl group and a fused optionally substituted heterocyclic group. 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]azepine-2-yl, 1,2,3,4-tetrahydroisoquinolin-1-yl, and 2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepine-1-yl.

[0382] The term "heteroaryl," as used herein alone or as part of another group, 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 embodiment, the heteroaryl has 3 heteroatoms. In another embodiment, the heteroaryl has 2 heteroatoms. In another embodiment, the heteroaryl has 1 heteroatom. In another embodiment, the heteroaryl is a 5- to 10-membered heteroaryl. In another embodiment, the heteroaryl has 5 ring atoms, for example, thienyl, a 5-membered heteroaryl having 4 carbon atoms and 1 sulfur atom. In another embodiment, the heteroaryl has 6 ring atoms, for example, pyridyl, a 6-membered heteroaryl having 5 carbon atoms and 1 nitrogen atom. Non-limiting exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furanyl, benzofuranyl, pyranyl, isobenzofuranyl, benzoxazinonyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, thiazolyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, and phenoxazinyl. In one embodiment, the heteroaryl group 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), pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-5-yl), pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-5-yl, pyridin-6-yl, pyridin-7-yl, pyridin-8-yl, pyridin-9-yl, pyridin-10-yl, pyridin-20-yl, pyridin-3-yl, pyridin-11-yl, pyridin-12-yl, pyridin-13-yl, pyridin-14-yl, pyridin-15-yl, pyridin-16-yl, pyridin-17-yl, pyridin-18-yl, pyridin-19-yl, pyridin-20-yl, pyridin-3-yl, pyridin-1 The term heteroaryl also includes N-oxides. A non-limiting exemplary N-oxide is pyridyl N-oxide.

[0383] The term "optionally substituted heteroaryl" as used herein alone or as part of another group refers to heteroaryl that is unsubstituted or substituted with 1 to 4 substituents, wherein the substituents are independently halogen, nitro, cyano, hydroxy, amino (e.g., -NH2, alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino or (heterocyclo)alkylamino), heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, urea, guanidino, carboxyl, carboxylalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxyalkyl, (amino)alkyl, (cyano)alkyl, (formylamino)alkyl, mercaptoalkyl, (heterocycle)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 59 , where R 56a 、R 56b 、R 56c 、R 56d 、R 56e 、R 57 、R 58 and R 59 As defined for the term "optionally substituted cycloalkyl".

[0384] In one embodiment, the optionally substituted heteroaryl has two substituents. In another embodiment, the optionally substituted heteroaryl has one substituent. Any available carbon or nitrogen atom can be substituted.

[0385] The term "aryloxy" as used herein alone or as part of another group refers to an optionally substituted aryl group attached to a terminal oxygen atom. A non-limiting exemplary aryloxy group is PhO-.

[0386] The term "heteroaryloxy" as used herein alone or as part of another group refers to an optionally substituted heteroaryl group attached to a terminal oxygen atom. A non-limiting exemplary aryloxy group is pyridinyl-O-.

[0387] The term "aralkyloxy" as used herein alone or as part of another group refers to an aralkyl group attached to a terminal oxygen atom. A non-limiting exemplary aralkyloxy group is PhCH2O-.

[0388] The term "(cyano)alkyl" as used herein alone or as part of another group refers to an alkyl group substituted with 1, 2, or 3 cyano groups. In one embodiment, the alkyl group is substituted with one cyano group. In another embodiment, the alkyl group is a C1-C6 alkyl group. In another embodiment, the alkyl group is a C1-C4 alkyl group. Non-limiting exemplary (cyano)alkyl groups include -CH2CH2CN and -CH2CH2CH2CN.

[0389] The term "(cycloalkyl)alkyl" as used herein alone or as part of another group refers to an alkyl group substituted with one or two optionally substituted cycloalkyl groups. In one embodiment, the cycloalkyl group is an optionally substituted C3-C6 cycloalkyl group. In another embodiment, the alkyl group is a C1-C6 alkyl group. In another embodiment, the alkyl group is a C1-C4 alkyl group. In another embodiment, the alkyl group is a C1 or C2 alkyl group. In another embodiment, the alkyl group is substituted with one optionally substituted cycloalkyl group. In another embodiment, the alkyl group is substituted with two optionally substituted cycloalkyl groups.

[0390] The term "sulfonylamino" as used herein alone or as part of another group refers to the formula -SO2NR 50a R 50b residues, where 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, they form a 3- to 8-membered optionally substituted heterocyclic group. Non-limiting exemplary sulfonylamino groups include -SO2NH2, -SO2N(H)CH3, and -SO2N(H)Ph.

[0391] The term "alkylcarbonyl" as used herein alone or as part of another group refers to a carbonyl group substituted with an alkyl group, i.e., -C(=O)-. In one embodiment, the alkyl group is a C1-C4 alkyl group. A non-limiting exemplary alkylcarbonyl group is -COCH3.

[0392] The term "arylcarbonyl," as used herein alone or as part of another group, refers to a carbonyl group substituted with an optionally substituted aryl group, ie, -C(=O)-. A non-limiting exemplary arylcarbonyl group is -COPh.

[0393] The term "alkylsulfonyl" as used herein alone or as part of another group refers to a sulfonyl group substituted with an alkyl group, ie, -SO2-. A non-limiting exemplary alkylsulfonyl group is -SO2CH3.

[0394] The term "arylsulfonyl" as used herein alone or as part of another group refers to a sulfonyl group substituted with an optionally substituted aryl group, ie, -SO2-. A non-limiting exemplary arylsulfonyl group is -SO2Ph.

[0395] The term "mercaptoalkyl" as used herein alone or as part of another group refers to an alkyl group substituted with a -SH group.

[0396] The term "carboxy" as used herein alone or as part of another group refers to a residue of formula -C(=O)OH.

[0397] The term "urea" as used herein alone or as part of another group refers to a group of the formula -NR 51a -C(=O)-NR 51b R 51c residues, where 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 51c Together 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.

[0398] The term "guanidino" as used herein alone or as part of another group refers to a group of the formula -NR 52a -C(=NR 53 )-NR 52b R 52c residues, 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 R52c Together with the nitrogen to which they are attached, they form a 4- to 8-membered optionally substituted heterocyclic group; and R 53 is hydrogen, alkyl, cyano, alkylsulfonyl, alkylcarbonyl, carboxamido or sulfonamido. Non-limiting exemplary guanidino groups include -NH-C(C=NH)-NH2, -NH-C(C=NCN)-NH2 and -NH-C(C=NH)-NHCH3.

[0399] The term "(heterocycle)alkyl" as used herein alone or as part of another group refers to an alkyl group substituted with 1, 2 or 3 optionally substituted heterocyclic groups. In one embodiment, the alkyl group is substituted with an optionally substituted 5 to 8 membered heterocyclic group. In another embodiment, the alkyl group is a C1-C6 alkyl group. In another embodiment, the alkyl group is a C1-C4 alkyl group. The heterocyclic group may be attached to the alkyl group via a carbon or nitrogen atom.

[0400] The term "carbamate" as used herein alone or as part of another group refers to a group of the formula -NR 54a -C(=O)-OR 54b residues, where 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.

[0401] The term "(heteroaryl)alkyl" as used herein alone or as part of another group refers to an alkyl group substituted with 1 or 2 optionally substituted heteroaryl groups. In one embodiment, the alkyl group is substituted with one optionally substituted 5 to 14-membered heteroaryl group. In another embodiment, the alkyl group is substituted with two optionally substituted 5 to 14-membered heteroaryl groups. In another embodiment, the alkyl group is substituted with one optionally substituted 5 to 9-membered heteroaryl group. In another embodiment, the alkyl group is substituted with two optionally substituted 5 to 9-membered heteroaryl groups. In another embodiment, the alkyl group is substituted with one optionally substituted 5 or 6-membered heteroaryl group. In another embodiment, the alkyl group is substituted with two optionally substituted 5 or 6-membered heteroaryl groups. In one embodiment, the alkyl group is C1-C6 alkyl. In another embodiment, the alkyl group is C1-C4 alkyl. In another embodiment, the alkyl group is C1 or C2 alkyl.

[0402] The term "aralkyl" or "(aryl)alkyl" as used herein alone or as part of another group refers to an alkyl group substituted with 1, 2, or 3 optionally substituted aryl groups. In one embodiment, the alkyl group is substituted with one optionally substituted aryl group. In another embodiment, the alkyl group is substituted with two optionally substituted aryl groups. In one embodiment, the aryl group is optionally substituted phenyl or optionally substituted naphthyl. In another embodiment, the aryl group is optionally substituted phenyl. In one embodiment, the alkyl group is C1-C6 alkyl. In another embodiment, the alkyl group is C1-C4 alkyl. In another embodiment, the alkyl group is C1 or C2 alkyl. Non-limiting exemplary (aryl)alkyl groups include benzyl, phenethyl, -CHPh2, and -CH(4-F-Ph)2.

[0403] The term "amido" as used herein alone or as part of another group refers to a group of the formula -C(=O)NR 60a R 60b residues, where R 60a and R 60b 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, they form a 4 to 8 membered optionally substituted heterocyclic group. 60a and R 60b Each is independently hydrogen or C1-C6 alkyl.

[0404] The term "amino" as used herein alone or as part of another group refers to the formula -NR 55a R 55b residues, where R 55a and R 55b and alkyl is 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.

[0405] In one embodiment, the amino group is -NH2.

[0406] In another embodiment, the amino group is an "alkylamino" group, ie, wherein R 55a It is C 1-6 Alkyl and R 55b In one embodiment, R 55a is a C1-C4 alkyl group. Non-limiting exemplary alkylamino groups include -N(H)CH3 and -N(H)CH2CH3.

[0407] In another embodiment, the amino group is a "dialkylamino" group, ie, a group in which R 55a and R 55b Each is independently C 1-6 In one embodiment, R 55a and R 55b Each is independently C1-C4 alkyl. Non-limiting exemplary dialkylamino groups include -N(CH3)2 and -N(CH3)CH2CH(CH3)2.

[0408] In another embodiment, the amino group is a "hydroxyalkylamino" group, ie, a group in which R 55a is (hydroxy)alkyl and R 55b An amino group is hydrogen or a C1-C4 alkyl group.

[0409] In another embodiment, the amino group is a "cycloalkylamino" group, ie, wherein R 55a is an optionally substituted cycloalkyl group and R 55b An amino group is hydrogen or a C1-C4 alkyl group.

[0410] In another embodiment, the amino group is an "aralkylamino" group, ie, wherein R 55a is an aralkyl group and R 55b is hydrogen or a C1-C4 alkyl amino group. Non-limiting exemplary aralkylamino groups include -N(H)CH2Ph, -N(H)CHPh2, and -N(CH3)CH2Ph.

[0411] The term "(amino)alkyl" as used herein, alone or as part of another group, refers to an alkyl group substituted with an amino group. In one embodiment, the amino group is -NH2. In one embodiment, the amino group is an alkylamino group. In another embodiment, the amino group is a dialkylamino group. In another embodiment, the alkyl group is a C1-C6 alkyl group. In another embodiment, the alkyl group is a C1-C4 alkyl group. Non-limiting exemplary (amino)alkyl groups include -CH2NH2, CH2CH2N(H)CH3, -CH2CH2N(CH3)2, CH2N(H)cyclopropyl, -CH2N(H)cyclobutyl, and -CH2N(H)cyclohexyl, and -CH2CH2CH2N(H)CH2Ph, and -CH2CH2CH2N(H)CH2(4-CF3-Ph).

[0412] The present disclosure encompasses any of the compounds of the present disclosure that are isotopically labeled (i.e., radioactively labeled) by replacing one or more atoms with atoms having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 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 embodiment, a composition is provided in which substantially all atoms at a position within a compound of the present disclosure are replaced by atoms having a different atomic mass or mass number. In another embodiment, a composition is provided in which a portion 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 with atoms having a different atomic mass or mass number at a position. Isotopically labeled compounds of the present disclosure can be prepared by methods known in the art.

[0413] As noted above, the compounds of the present disclosure contain one or more asymmetric carbon atoms and therefore may produce enantiomers, diastereomers, and other stereoisomeric forms. The present disclosure encompasses the use of all such possible forms, as well as their racemic and resolved forms and mixtures thereof. In view of the present disclosure, each enantiomer can be separated according to methods known in the art. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise indicated, they are intended to include E and Z geometric isomers. The present disclosure also encompasses all tautomers. The present disclosure also encompasses all conformational isomers, i.e., stereoisomers produced by rotation around a σ bond.

[0414] As used herein, the term "stereoisomer" is a general term for all isomers of a single molecule that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).

[0415] The term "chiral center" or "asymmetric carbon atom" means a carbon atom to which four different groups are attached.

[0416] The terms "enantiomer" and "enantiomeric" refer to non-superimposable and therefore optically active molecules that are mirror images, wherein an enantiomer rotates the plane of polarized light in one direction and its mirror image compound rotates the plane of polarized light in the opposite direction.

[0417] The term "racemic" refers to a mixture of equal parts of enantiomers, and the mixture is optically inactive. In one embodiment, the compounds of the present disclosure are racemic.

[0418] The term "absolute configuration" refers to the spatial arrangement of the atoms of a chiral molecular entity (or group) and its stereochemistry description, for example, R or S.

[0419] Stereochemical nomenclature and conventions used in this specification are intended to be consistent with those described in Pure & Appl. Chem 68:2193 (1996), unless otherwise noted.

[0420] The term "enantiomeric excess" or "ee" refers to a measure of how much of one enantiomer is present relative to the other. For a mixture of R and S enantiomers, the percent enantiomeric excess is defined as |RS|*100, where R and S are the respective mole or weight fractions of the enantiomers in the mixture such that R+S=1. Knowing the optical rotation of a chiral substance, the percent enantiomeric excess is defined as ([α] obs / [α] 最大值) *100, where [α] obsis the optical rotation of the mixture of enantiomers, and [α] max is the optical rotation of the pure enantiomer. It is possible to determine enantiomeric excess using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography, or optical polarimetry.

[0421] As used herein, the term "about" includes ±10% of the recited number. Thus, "about 10" means 9-11.

[0422] V. Specific Embodiments

[0423] This disclosure provides the following specific embodiments.

[0424] Embodiment 1. Compounds of Formula AI:

[0425]

[0426] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0427] R 1 is selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted phenyl and optionally substituted 5- to 9-membered heteroaryl;

[0428] R 2a 、R 2b and R 2c independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3 and halogen;

[0429] R 3 is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3 and halogen;

[0430] Y is selected from -^N(H)C(=O)-, -^N(H)C(=O)CH2-, -^C(=O)N(H)- and -^C(=O)N(H)CH2-;

[0431] wherein the bond marked with "^" is connected to the thiazole;

[0432] R 4a 、R 4b 、R 4c and R 4d independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3 and halogen;

[0433] L is selected from -(CH2) m -、-*(CH2) n (OCH2CH2) o - and -(CH2) p -Z-CH2) q -;

[0434] wherein the carbon marked with "*" is connected to X;

[0435] m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0436] n is 2, 3, or 4;

[0437] p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0438] o is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0439] q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0440] Z is selected from -(CR 6a R 6b )- and -N(R 7 )-;

[0441] R 6a is selected from halogen, hydroxy, C1-C6 alkyl, C1-C4 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C4-C8 heterocycle, optionally substituted phenyl and optionally substituted 5- to 9-membered heteroaryl;

[0442] R 6b Selected from hydrogen and C1-C6 alkyl;

[0443] R 7 Selected from hydrogen, C1-C6 alkyl and C1-C4 haloalkyl;

[0444] X is selected from -O-, -NH-,

[0445]

[0446] B 1 Selected from:

[0447]

[0448] and

[0449] R 5a 、R 5b and R 5cIndependently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3 and halogen.

[0450] Embodiment 2. Compounds of Formula I:

[0451]

[0452] or a pharmaceutically acceptable salt or solvate thereof.

[0453] Embodiment 3. Compound of formula II:

[0454]

[0455] or a pharmaceutically acceptable salt or solvate thereof.

[0456] Embodiment 4. The compound of any one of Embodiments 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is an optionally substituted C3-C8 cycloalkyl group.

[0457] Embodiment 5. The compound of embodiment 4 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is cyclopropyl.

[0458] Embodiment 6. The compound of any one of Embodiments 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is optionally substituted phenyl.

[0459] Embodiment 7. The compound of Embodiment 6, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0460] R 1 yes:

[0461] and

[0462] R 1a 、R 1b 、R 1c 、R 1d and R 1e Independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3 and halogen.

[0463] Embodiment 8. The compound of embodiment 7 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1b 、R 1c 、R 1d and R 1e It's hydrogen.

[0464] Embodiment 9. The compound of embodiment 7 or 8, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1a It is a C1-C4 alkyl group.

[0465] Embodiment 10. The compound of any one of Embodiments 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is an optionally substituted 5- to 9-membered heteroaryl.

[0466] Embodiment 11. The compound of embodiment 10 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is an optionally substituted imidazole.

[0467] Embodiment 12. The compound of any one of Embodiments 1-11, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2a 、R 2b and R 2c It's hydrogen.

[0468] Embodiment 13. The compound of any one of Embodiments 1-12, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 It is a C1-C4 alkyl group.

[0469] Embodiment 14. The compound of embodiment 13 or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 It's methyl.

[0470] Embodiment 15. The compound of any one of Embodiments 1-14, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4a Selected from hydrogen and fluorine.

[0471] Embodiment 16. The compound of any one of Embodiments 1-15, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4b Selected from hydrogen and fluorine.

[0472] Embodiment 17. The compound of any one of Embodiments 1-16, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4c Selected from hydrogen and fluorine.

[0473] Embodiment 18. The compound of any one of Embodiments 1-14, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4b 、R 4c and R 4d It's hydrogen.

[0474] Embodiment 19. The compound of any one of Embodiments 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein L is selected from -(CH2)m - and -*(CH2) n (OCH2CH2) o -.

[0475] Embodiment 20. The compound of Embodiment 19, or a pharmaceutically acceptable salt or solvate thereof, wherein L is -(CH2) m -.

[0476] Embodiment 21. The compound of Embodiment 19, or a pharmaceutically acceptable salt or solvate thereof, wherein L is -*(CH2) n (OCH2CH2) o -.

[0477] Embodiment 22. The compound of any one of Embodiments 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein L is -(CH2) p -Z-CH2) q -.

[0478] Embodiment 23. The compound of embodiment 22, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -(CR 6a R 6b )-.

[0479] Embodiment 24. The compound of embodiment 22, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -N(R 7 )-.

[0480] Embodiment 25. The compound of any one of Embodiments 1-24, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -O-.

[0481] Embodiment 26. The compound of any one of Embodiments 1-24, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -NH-.

[0482] Embodiment 27. The compound of any one of Embodiments 1-24, or a pharmaceutically acceptable salt or solvate thereof, wherein X is:

[0483]

[0484] Embodiment 28. The compound of any one of Embodiments 1-24, or a pharmaceutically acceptable salt or solvate thereof, wherein X is:

[0485]

[0486] Embodiment 29. The compound of any one of Embodiments 1-28, or a pharmaceutically acceptable salt or solvate thereof, wherein B 1 It's B-1.

[0487] Embodiment 30. The compound of any one of Embodiments 1-28, or a pharmaceutically acceptable salt or solvate thereof, wherein B 1 It's B-2.

[0488] Embodiment 31. The compound of any one of Embodiments 1-28, or a pharmaceutically acceptable salt or solvate thereof, wherein B 1 It's B-3.

[0489] Embodiment 32. The compound of any one of Embodiments 1-28, or a pharmaceutically acceptable salt or solvate thereof, wherein B 1 It's B-4.

[0490] Embodiment 33. The compound of any one of Embodiments 1-28, or a pharmaceutically acceptable salt or solvate thereof, wherein B 1 It's B-5.

[0491] Embodiment 34. The compound of any one of Embodiments 1-28, or a pharmaceutically acceptable salt or solvate thereof, wherein B 1 It's B-6.

[0492] Embodiment 35. The compound of any one of Embodiments 29-34, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5a 、R 5b and R 5c are independently selected from hydrogen and fluorine.

[0493] Embodiment 36. The compound of embodiment 35, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5a 、R 5b and R 5c It's hydrogen.

[0494] Embodiment 37. The compound of Embodiment 1 or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is any one or more of the compounds in Table 1.

[0495] Embodiment 38. A pharmaceutical composition comprising a compound according to any one of embodiments 1-37 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0496] Embodiment 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 of any one of Embodiments 1-37, or a pharmaceutically acceptable salt thereof.

[0497] Embodiment 40. The method of embodiment 39, further comprising administering a second therapeutic agent to the subject.

[0498] Embodiment 41. The method of embodiment 39 or 40, for treating cancer in a subject in need thereof.

[0499] Embodiment 42. The method of embodiment 39 or 40, wherein the cancer is a solid tumor.

[0500] Embodiment 43. The method of embodiment 39 or 40, wherein the cancer is a hematological cancer.

[0501] Embodiment 44. The method of embodiment 39 or 40, wherein the cancer is one or more of the cancers in Table 2.

[0502] Embodiment 45. The method of any one of Embodiments 40-44, wherein the second therapeutic agent is isopropyl (S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)propionamido)-6-diazo-5-oxohexanoate or a pharmaceutically acceptable salt thereof.

[0503] Embodiment 46. A method of reducing nuclear factor E2-related factor 2 (Nrf2) protein in cells of a subject, the method comprising administering to the subject a compound of any one of embodiments 1-37, or a pharmaceutically acceptable salt or solvate thereof.

[0504] Embodiment 47. The method of embodiment 46, wherein the subject has cancer.

[0505] Embodiment 48. A kit comprising a compound of any one of Embodiments 1-37, or a pharmaceutically acceptable salt thereof, and instructions for administering the compound, or a pharmaceutically acceptable salt thereof, to a subject having cancer.

[0506] Embodiment 49. Compound of Formula III:

[0507]

[0508] or a pharmaceutically acceptable salt thereof, wherein:

[0509] R 1' is selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted phenyl and optionally substituted 5- to 9-membered heteroaryl;

[0510] R 2a' 、R 2b' and R 2c'independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3 and halogen;

[0511] R 3' is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3 and halogen;

[0512] Z 1 is -O-; and

[0513] R 8 is hydrogen, C1-C6 alkyl or aralkyl; or

[0514] Z 1 is -N(H)-; and

[0515] R 8 yes:

[0516] and

[0517] R 4a' 、R 4b' 、R 4c' and R 4d' independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3 and halogen;

[0518] R 9 Selected from hydrogen and -L 1 -X 1 ;

[0519] X 1 Select from -OR 10 and -NR 11a R 11b ;

[0520] R 10 It is hydrogen;

[0521] R 11a is selected from hydrogen and -C(=O)OtBu;

[0522] R 11b is selected from hydrogen and C1-C4 alkyl;

[0523] L 1 Selected from -(CH2) m' -、-*(CH2) n (OCH2CH2) o' - and -(CH2) p' -Z2 -(CH2) q' -;

[0524] The carbon marked with "*" is connected to X 1 ;

[0525] m' is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0526] n' is 2, 3, or 4;

[0527] o' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0528] p' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0529] q' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0530] Z 2 Selected from -(CR 6a' R 6b' )- and -N(R 7' )-;

[0531] R 6a' is selected from halogen, hydroxy, C1-C6 alkyl, C1-C4 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C4-C8 heterocycle, optionally substituted phenyl and optionally substituted 5- to 9-membered heteroaryl;

[0532] R 6b' is selected from hydrogen and C1-C6 alkyl; and

[0533] R 7' is selected from hydrogen, C1-C6 alkyl and C1-C4 haloalkyl. Example

[0534] Example 1

[0535] Synthesis of 2-(3-hydroxyphenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (DCP_A017)

[0536]

[0537] Step 1. Indolin-1-yl(o-tolyl)methanone

[0538] 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), and 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 produce indolin-1-yl(o-tolyl)methanone (28.0 g, 70.3% yield) as a yellow solid. MS (ESI) m / z 237.9 [M+H] + .

[0539] Step 2. 2-Bromo-1-(1-(2-methylbenzoyl)indolin-5-yl)propan-1-one

[0540] 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) was added 2-bromopropionyl bromide (76.41 g, 354.0 mmol) dropwise at 0°C. After the addition, the mixture was stirred at 50°C for 5 hours. The mixture was then quenched with water (500 mL), basified with 6N aqueous sodium hydroxide solution to a pH between 8-10, extracted with dichloromethane (1.0 L), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to yield crude 2-bromo-1-(1-(2-methylbenzoyl)indolin-5-yl)propan-1-one (35.0 g, 79.7% yield) as a yellow oil. MS (ESI) m / z 372.0 and 374.0 [M+H] + .

[0541] Step 3. (5-(2-amino-5-methylthiazol-4-yl)indolin-1-yl)(o-tolyl)methanone

[0542] 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 yield (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] + .

[0543] Step 4. 2-(3-Hydroxyphenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide

[0544] 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 min. (5-(2-amino-5-methylthiazol-4-yl)indolin-1-yl)(o-tolyl)methanone (101 mg, 0.29 mmol) was then added to the resulting mixture at room temperature. The mixture was stirred at 60 °C for 16 hours, at which point the mixture was cooled to room temperature and 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% to 70% in 15.0 min) to yield 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. 1 H NMR (400 MHz, DMSO-d6): δ 12.32 and 12.2* (s, 1H), 9.37 (s, 1H), 8.24 and 5.53* (d, J = 8.4 Hz, 1H), 7.53 (s, 1H), 7.53, 7.49 and 7.04* (m, 1H), 7.37-7.32 (m, 4H), 7.11 (t, J = 13.6 Hz, 1H), 6.75-6.73 (m, 2H), 6.64 (d, J = 7.6 Hz, 1H), 4.22 and 3.74* (m, 2H), 3.64 (s, 2H), 3.13 (m, 2H), 2.46 and 2.35* (s, 3H), 2.29 and 2.18* (s, 3H). MS (ESI) m / z 484.1 [M+H] + . ＊ Multiple signals originating from conformers.

[0545] Example 2

[0546] 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)

[0547]

[0548] Step 1. 2-(2-((tert-Butoxycarbonyl)amino)ethoxy)ethyl 4-methylbenzenesulfonate

[0549] A solution of 2-(2-aminoethoxy)ethanol (1.00, 9.51 mmol), di-tert-butyl dicarbonate (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 hours. Tosyl chloride (1.99 g, 10.5 mmol) was then added and the mixture was stirred for 16 hours. The mixture was diluted with water (50 mL), extracted with dichloromethane (100 mL), and 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 produce 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] + .

[0550] 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

[0551] 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 hours. 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 (eluted 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, overweight) as an impure yellow oil. MS (ESI) m / z 671.3 [M+H] + .

[0552] Step 4. 2-(3-(2-(2-aminoethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide

[0553] 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), 1.0 mmol maximum) and 4M HCl / 1,4-dioxane solution (10.0 mL) in 1,4-dioxane (20.0 mL) was stirred at room temperature for 3 hours. The solvent was removed in vacuo, and the residue was dissolved in dichloromethane (100 mL) and washed with saturated aqueous sodium carbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (eluted 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] + .

[0554] 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

[0555] 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 hours. The reaction mixture was directly 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-(2,6-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. 1 H NMR (400 MHz, DMSO-d6): δ 12.35 and 12.33 (s, 1H) *, 11.10 (s, 1H), 8.25 and 5.56 * (d, J = 8.8 Hz, 1H), 7.57-7.52 (m, 2H), 7.53, 7.46 and 7.04 * (m, 1H), 7.37-7.34 (m, 4H), 7.23 (t, J = 7.75 Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 6.9 Hz, 1H), 6.93-6.89 (m, 2H), 6.84 (dd, J = 8.2 and 0. 95 Hz, 1H), 6.65 (t, J = 6.7 Hz, 1H), 5.06 (dd, J = 12.6 and 5.4 Hz, 1H), 4.22 and 3.70 (m, 2H) *, 4.10 (m, 2H), 3.80 (m, 2H), 3.78-3.65 (m, 4H), 3.51-3.47 (m, 2H), 3.18-3.12 (m, 2H), 2.92-2.84 (m, 1H), 2.60-2.53 (m, 2H), 2.46 and 2.35 (s, 3H) *, 2.30 and 2.18 (s, 3H) *, 2.02-1.99 (m, 1H). MS (ESI) m / z 827.5 [M+H] +＊ Multiple signals originating from conformers.

[0556] Example 3

[0557] 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)

[0558]

[0559] 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

[0560] 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 hours. 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. 1H NMR (400MHz, DMSO-d6): δ12.20 (brs, 1H), 11.09 (brs, 1H), 8.24 and 5.53* (d, J = 8.8Hz, 1H), 7.56-7.53 (m, 3H ),7.37-7.30(m,4H),7.25-7.21(m,2H),7.01(s,1H),6.98-6.89(m,3H),6.83(d,J=7.6,1H),5.03(dd,J= 13.2 and 5.6 Hz, 1H), 4.22 and 3.70 (m, 2H) *, 4.10 (m, 2H), 3.78-3.60 (m, 6H), 3.94-3.80 (m, 2H), 3.13 (t, J = 8.0 Hz, 2H), 2.89-2.83 (m, 1H), 2.59-2.55 (m, 2H), 2.45 and 2.34 (s, 3H) *, 2.30 and 2.18 (s, 3H) *, 2.29-2.03 (m, 1H). MS (ESI) m / z 827.5 [M+H] + . ＊ Multiple signals originating from conformers.

[0561] Example 4

[0562] 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)

[0563]

[0564] Step 1. 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate

[0565] 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 hours. The solvent was removed and the residue was purified by flash column chromatography (ethyl acetate / petroleum ether=3 / 7) to produce 4-methylbenzenesulfonic acid 2-(2-hydroxyethoxy)ethyl ester (8.0 g, 54% yield) as a colorless oil. MS (ESI) m / z 161.0 [M+H] + .

[0566] Step 2. 2-(3-(2-(2-hydroxyethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide

[0567] 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 tert-butoxide (0.39 g, 3.46 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (80 mL), extracted with ethyl acetate (50 mL x 2), washed with brine (20 mL x 1), and 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] + .

[0568] 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

[0569] To 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 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) and 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, 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-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. 1 H NMR (400 MHz, DMSO-d6): δ 12.33 and 12.22 (s, 1H) *, 11.10 (s, 1H), 8.23 ​​and 5.56 * (d, J = 8.4 Hz, 1H), 7.79 (t, J = 7.6 Hz, 1H), 7.54-7.52 (m, 2H), 7.54 & 7.03 * (m, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.37-7.30 (m, 4H), 7.22 (t, J = 8.0 Hz, 1H), 6.92-6.88 (m, 2H), 6.83 (d, J = 8.4 Hz, 1 H), 5.08 (dd, J = 12.8 and 5.6 Hz, 1H), 4.37 (t, J = 4.2 Hz, 2H), 4.21 and 3.74 (m, 2H) *, 4.10 (t, J = 4.2 Hz, 2H), 3.89-3.87 (m, 4H), 3.76-3.67 (m, 2H), 3.13 (t, J = 7.8 Hz, 2H), 2.92-2.83 (m, 1H), 2.60-2.50 (m, 2H), 2.45 and 2.35 (s, 3H) *, 2.29 and 2.18 (s, 3H) *, 2.04-1.99 (m, 1H). MS (ESI) m / z 828.3 [M+H] + . ＊Multiple signals originating from conformers.

[0570] Example 5

[0571] 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)

[0572]

[0573] Step 1. 2-(2-(3-(2-((5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethyl 4-methylbenzenesulfonate

[0574] 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 hours. The mixture was diluted with water (10 mL), extracted with dichloromethane (30 mL), and 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] + .

[0575] 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

[0576] 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 hours. The reaction mixture was then directly 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-(2,6-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. 1 H NMR (400 MHz, DMSO-d6): δ 12.33 (s, 1H), 11.12 (s, 1H), 8.23 ​​and 5.45 * (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.52 (brs, 1H), 7.52 and 7.01 * (brs, 1H), 7.45 (d, J = 4.0 Hz, 1H), 7.35-7.32 (m, 5H), 7.23 (t, J = 15.2 Hz, 1H), 6.92-6.89 (m, 2H), 6.84 (d, J = 8 Hz, 1H), 5.11 (dd, J = 14 and 6.0 Hz, 1H), 4.33 (m, 2H), 4.19 and 3.70 (m, 2H) *, 4.11 (m, 2H), 3.86-3.80 (m, 4H), 3.75-3.67 (m, 2H), 3.12 (t, J = 8.0 Hz, 2H), 2.93-2.84 (m, 1H), 2.68-2.55 (m, 2H), 2.45 and 2.33 (s, 3H) *, 2.29 and 2.18 (s, 3H) *, 2.05-1.96 (m, 1H). MS (ESI) m / z 828.2 [M+H] + . ＊ Multiple signals originating from conformers.

[0577] Example 6

[0578] 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)

[0579]

[0580] Step 1. 2,2-Dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl 4-methylbenzenesulfonate

[0581] A solution of 2-(2-(2-aminoethoxy)ethoxy)ethane-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 hours. Tosyl chloride (1.53 g, 8.04 mmol) was added and the mixture was stirred for 16 hours. 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 produce 4-methylbenzenesulfonic acid 2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecane-13-yl ester (1.2 g, 44% yield) as a yellow oil. MS (ESI) m / z 304.0 [M+H-100] + .

[0582] 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

[0583] 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 hours. 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 give 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]+.

[0584] 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

[0585] 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 4M hydrochloric acid / 1,4-dioxane (4.0 mL) in 1,4-dioxane (4.0 mL) was stirred at room temperature for 6 hours. The solvent was removed in vacuo, and the residue was dissolved in dichloromethane (100 mL), washed with saturated aqueous sodium carbonate solution, 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] + .

[0586] 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

[0587] 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 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 min) to give 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) as a yellow solid. 1HNMR (400 MHz, DMSO-d6): δ 12.34 and 12.27 (s, 1H) *, 11.10 (s, 1H), 8.24 and 5.54 * (d, J = 8.8 Hz, 1H), 7.57-7.52 (m, 3H), 7.37-7.34 (m, 4H), 7.22 (t, J = 7.8 Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 7.02 (d, J = 6.8 Hz, 1H), 6.91-6.88 (m, 2H), 6.82 (d, J = 8.0 Hz, 1H), 6.61 (t, J = 5.4 Hz, 1H), 5.05 (dd, J = 12.6 and 5.4 Hz, 1H), 4.21 and 3.70 (m, 2H) *, 4.05 (m, 2H), 3.73-3.70 (m, 4H), 3.60 (m, 6H), 3.47-3.45 (m, 2H), 3.13 (t, J = 7.4 Hz, 2H), 2.91-2.82 (m, 1H), 2.57-2.54 (m, 2H), 2.45 and 2.34 (s, 3H) *, 2.29 and 2.18 (s, 3H) *, 2.02-1.99 (m, 1H). MS (ESI) m / z 871.3 [M+H] + . ＊ Multiple signals originating from conformers.

[0588] Example 7

[0589] 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)

[0590]

[0591] 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

[0592] 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 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 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. 1 H NMR (400 MHz, DMSO-d6): δ 12.34 and 12.27 (s, 1H) *, 11.07 (s, 1H), 8.24 and 5.54 * (d, J = 8.8 Hz, 1H), 7.55-7.52 (m, 3H), 7.37-7.30 (m, 5H), 7.23 (t, J = 6.2 Hz, 1H), 7.0 (s, 1H), 6.92-6.87 (m, 3H), 6.82 (d, J = 6.4 Hz, 1H), 5.03 (dd, J = 10.0 and 4 .4 Hz, 1H), 4.21 and 3.70 (m, 2H) *, 4.06 (m, 2H), 3.73-3.70 (m, 4H), 3.60-3.59 (m, 6H), 3.35 (t, J = 4, 2 Hz, 2H), 3.13 (t, J = 6.6 Hz, 2H), 2.89-2.86 (m, 1H), 2.58-2.54 (m, 2H), 2.45 and 2.34 (s, 3H) *, 2.29 and 2.17 (s, 3H) *, 1.99-1.96 (m, 1H). MS (ESI) m / z 871.4 [M+H] + . ＊ Multiple signals originating from conformers.

[0593] Example 8

[0594] 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)

[0595]

[0596] Step 1. 2-(2-(2-hydroxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate

[0597] 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 hours. The solvent was removed in vacuo, and the residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 1:1) to produce 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] + .

[0598] 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

[0599] 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 hours. 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] +.

[0600] 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

[0601] To 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 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, 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-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. 1HNMR (400 MHz, DMSO-d6): δ 12.33 and 12.22 (s, 1H) *, 11.10 (s, 1H), 8.23 ​​and 5.56 * (d, J = 8.4 Hz, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.52-7.59 (m, 2H), 7.52 & 7.03 * (m, 1H), 7.43 (d, J = 7.2 Hz, 1H), 7.37-7.35 (m, 4H), 7.22 (t, J = 7.8 Hz, 1H), 6.91-6.88 (m, 2H), 6.82 (d, J = 8.0 Hz, 1H), 5.07 (d d, J = 12.8 and 5.6 Hz, 1H), 4.33 (t, J = 4.4 Hz, 2H), 4.21 and 3.74 (m, 2H) *, 4.06 (t, J = 4.2 Hz, 2H), 3.81 (t, J = 4.2 Hz, 2H), 3.82-3.66 (m, 6H), 3.62-3.60 (m, 2H), 3.13 (t, J = 7.8 Hz, 2H), 2.88-2.82 (m, 1H), 2.59-2.55 (m, 2H), 2.48 and 2.33 (s, 3H) *, 2.29 and 2.17 (s, 3H) *, 2.03-1.98 (m, 1H). MS (ESI) m / z 872.3 [M+H] + . ＊ Multiple signals originating from conformers.

[0602] Example 9

[0603] 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)

[0604]

[0605] Step 1. 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

[0606] 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 hours. 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 as a yellow oil (90 mg, 51.4% yield). MS (ESI) m / z 770.1 [M+H] + .

[0607] Step 2. 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

[0608] 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 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 min) to give 2-(3-(2-(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 (4.5 mg, 4.4% yield) as a white solid.

[0609] 1 H NMR (400 MHz, DMSO-d6): δ 8.23 ​​and 5.45* (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.52 (brs, 1H), 7.52 and 7.01* (brs, 1H), 7.44 (d, J = 1.6 Hz, 1H), 7.37-7.30 (m, 5H), 7.23 (t, J = 7.8 Hz, 1H), 6.92-6.89 (m, 2H), 6.83 (d, J = 8.4 Hz, 1H), 5.11 (dd, J = 12.8 and 5.6 Hz, 1H), 4.29 (t, J = 4.4 Hz, 2H), 4.21 and 3.70 (m, 2H)*, 4.07 (m δ (d, 4H), 3.80-3.70 (m, 6H), 3.62 (s, 4H), 3.12 (t, J = 8.0 Hz, 2H), 2.88-2.85 (m, 1H), 2.60-2.55 (m, 2H), 2.45 and 2.33 (s, 3H)*, 2.29 and 2.18 (s, 3H)*, 2.05-2.00 (m, 1H). MS (ESI) m / z 872.3 [M+H]+. (Note: Two acidic protons near 12.3 ppm and 11.1 ppm are not typically visible). ＊ Multiple signals originating from conformers.

[0610] Example 10

[0611] Synthesis of 2-(3-(2-(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)

[0612]

[0613] Step 1. 2,2-Dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azahexadec-16-yl 4-methylbenzenesulfonate

[0614] A solution of 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethane-1-ol (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 hours. Tosyl chloride (1.00 g, 5.18 mmol) was added and the mixture was stirred at room temperature for 16 hours. 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 yield 2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azahexadec-16-yl 4-methylbenzenesulfonate (0.45 g, 19% yield) as a yellow oil. MS (ESI) m / z 348.2 [M+H-100] + .

[0615] 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

[0616] 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-azahexadec-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 hours. 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] + .

[0617] 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

[0618] 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 (4M 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 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)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] + .

[0619] Step 4. 2-(3-(2-(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

[0620] 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 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 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. 1 H NMR (400 MHz, DMSO-d6): δ 12.34 and 12.27 (s, 1H) *, 11.11 (s, 1H), 8.24 and 5.54 * (d, J = 8.8 Hz, 1H), 7.58-7.53 (m, 3H), 7.38-7.36 (m, 4H), 7.23 (t, J = 7.8 Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 6.8 Hz, 1H), 6.92-6.90 (m, 2H), 6.83 (d, J = 7.6, 1H), 6.60 (t, J = 5. 8 Hz, 1H), 5.05 (dd, J = 12.8 and 5.2 Hz, 1H), 4.21 and 3.70 (m, 2H) *, 4.05 (m, 2H), 3.73-3.71 (m, 4H), 3.62-3.55 (m, 10H), 3.47-3.44 (m, 2H), 3.13 (t, J = 8.0 Hz, 2H), 2.91-2.82 (m, 1H), 2.60-2.54 (m, 2H), 2.45 and 2.34 (s, 3H) *, 2.30 and 2.18 (s, 3H) *, 2.03-1.24 (m, 1H). MS (ESI) m / z 915.3 [M+H] + . ＊ Multiple signals originating from conformers.

[0621] Example 11

[0622] Synthesis of 2-(3-(2-(2-(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)

[0623]

[0624] Step 1. 2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate

[0625] A solution of 2,2'-((oxybis(ethane-2,1-diyl))bis(oxy))bis(ethane-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 hours. 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 produce 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] + .

[0626] Step 2. 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

[0627] A mixture of 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 tert-butoxide (0.49 g, 4.34 mmol) in dry N,N-dimethylformamide (20 mL) was stirred at room temperature for 16 hours. 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-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] + .

[0628] Step 3. 2-(3-(2-(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

[0629] To 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) and 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (0.054 g, 0.20 mmol), triphenylphosphine (0.052 mg, 0.20 mmol) in tetrahydrofuran (3.0 mL) was slowly added diisopropyl azodicarboxylate (0.048 g, 0.24 mmol) at 0° C. The reaction 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 min) to give 2-(3-(2-(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 (26.7 mg, 14.8% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.35 and 12.22 (s, 1H) *, 11.12 (s, 1H), 8.24 and 5.56 * (d, J = 8.8 Hz, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.53-7.49 (m, 3H), 7.44 (d, J = 7.2 Hz, 1H), 7.38-7.29 (m, 4H), 7.23 (t, J = 7.6 Hz, 1H), 6.92-6.89 (m, 2H), 6.83 (d, J = 7.2 Hz, 1H), 5.08 (dd, J = 13.4 and 5.4 Hz, 1H ), 4.32 (t, J = 4.4 Hz, 2H), 4.21 and 3.74 (m, 2H) *, 4.06 (t, J = 4.0 Hz, 2H), 3.79 (t, J = 4.2 Hz, 2H), 3.74-3.70 (m, 4H), 3.65-3.63 (m, 2H), 3.57-3.49 (m, 6H), 3.13 (t, J = 8.4 Hz, 2H), 2.89-2.84 (m, 1H), 2.59-2.55 (m, 2H), 2.45 and 2.33 (s, 3H) *, 2.29 and 2.17 (s, 3H) *, 2.03-1.98 (m, 1H). MS (ESI) m / z 916.2 [M+H] + . ＊Multiple signals originating from conformers.

[0630] Example 12

[0631] Synthesis of 2-(3-(2-(2-(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)

[0632]

[0633] Step 1. 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

[0634] 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 hours. 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-(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 as a yellow oil (0.12 g, 39% yield). MS (ESI) m / z 814.4 [M+H] + .

[0635] Step 2. 2-(3-(2-(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

[0636] 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 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 min) to give 2-(3-(2-(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 (17.1 mg, 15.2% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.33 and 12.22 (s, 1H) *, 11.11 (s, 1H), 8.23 ​​and 5.45 * (d, J = 6.8 Hz, 1H), 7.80 (d, J = 6.4 Hz, 1H), 7.52 (brs, 1H), 7.52 and 7.01 * (brs, 1H), 7.43 (d, J = 1.2 Hz, 1H), 7.37 -7.30 (m, 5H), 7.23 (t, J = 6.2 Hz, 1H), 6.92-6.88 (m, 2H), 6.83 (d, J = 5.6 Hz, 1H), 5.11 (dd, J = 10.4 and 4.4 Hz, 1H), 4.28 (t, J = 3.2 Hz, 2H), 4.21 and 3.70 (m, 2H) *, 4.06 (m, 2 H), 3.78-3.70 (m, 6H), 3.56-3.51 (s, 8H), 3.13 (t, J = 6.6 Hz, 2H), 2.91-2.84 (m, 1H), 2.60-2.52 (m, 2H), 2.45 and 2.33 (s, 3H) *, 2.29 and 2.18 (s, 3H) *, 2.04-2.00 (m, 1H). MS (ESI) m / z 916.0 [M+H] + . ＊ Multiple signals originating from conformers.

[0637] Example 13

[0638] 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)

[0639]

[0640] Step 1. 3-((tert-Butoxycarbonyl)amino)propyl 4-methylbenzenesulfonate

[0641] 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 hours. 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 produce 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] + .

[0642] 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

[0643] 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 hours. 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] + .

[0644] Step 3. 2-(3-(3-aminopropyloxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide

[0645] 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 (4M 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 sulfate, 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] + .

[0646] 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

[0647] 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 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 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. 1 H NMR (400MHz, 60℃, DMSO-d6): δ12.07(s,1H),11.91(s,1H),8.24(brs,1H), 7.56-7.51(m,2H),7.39-7.28(m,5H),7.22(t,J=8.0Hz,1H),7.10(d,J=4. 8Hz,1H),7.00(d,J=7.2Hz,1H),6.99(s,1H),6.91-6.85(m,2H),6.65(t,J =5.8Hz,1H),5.04-5.00(m,1H),4.09(t,J=6.2Hz,2H),4.00-4.06(brs,2H) ＊ ,3.70(s,2H),3.49(q,J=3.2Hz,2H),3.14(m,2H),2.91-2.82(m,1H),2.62-2.52(m,2H),2.43(s,3H),2.27(s,3H),2.08-1.99(m,3H). MS(ESI)m / z797.3[M+H] + . ＊ Difficult to see broad signals originating from conformers.

[0648] Example 14

[0649] 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)

[0650]

[0651] Step 1. 2,2-Dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecan-19-yl 4-methylbenzenesulfonate

[0652] A solution of 14-amino-3,6,9,12-tetraoxatetradecane-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 hours. Tosyl chloride (0.8 g, 4.2 mmol) was added and the mixture was stirred for 16 hours. 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 produce 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] + .

[0653] 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

[0654] 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 hours. 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] + .

[0655] 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

[0656] 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 (4M 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×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] + .

[0657] 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

[0658] 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 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 min) to give 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) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 12.34 and 12.27 (s, 1H) *, 11.10 (s, 1H), 8.24 and 5.54 * (d, J = 8.8 Hz, 1H), 7.59-7.53 (m, 3H), 7.38-7.31 (m, 4H), 7.23 (t, J = 7.8 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 6.93-6.89 (m, 2H), 6.84 (d, J = 8.4 Hz, 1H), 6. 60 (t, J = 5, 4 Hz, 1H), 5.05 (dd, J = 13.0 and 5.4 Hz, 1H), 4.21 and 3.70 (m, 2H) *, 4.06 (m, 2H), 3.74-3.71 (m, 4H), 3.62-3.43 (m, 16H), 3.13 (t, J = 7.6 Hz, 2H), 2.88-2.85 (m, 1H), 2.60-2.56 (m, 2H), 2.42 and 2.34 (s, 3H) *, 2.26 and 2.18 (s, 3H) *, 2.03-2.00 (m, 1H). MS (ESI) m / z 959.5 [M+H] + . ＊ Multiple signals originating from conformers.

[0659] Example 15

[0660] Synthesis of 2-(3-((17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaheptadecanyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 5)

[0661]

[0662] Step 1. 2,2-Dimethyl-4-oxo-3,8,11,14,17,20-hexaoxa-5-azadocosan-22-yl 4-methylbenzenesulfonate

[0663] 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 hours. Tosyl chloride (1.01 g, 5.32 mmol) was added and the mixture was stirred for 16 hours. 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 produce 4-methylbenzenesulfonic acid 2,2-dimethyl-4-oxo-3,8,11,14,17,20-hexaoxa-5-azadocosan-22-yl ester (0.55 g, 28.9% yield) as a yellow oil. MS (ESI) m / z 436.0 [M+H-100] + .

[0664] 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-pentaoxaheptadecanyl)carbamate

[0665] 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 hours. 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 give 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-pentaoxaheptadecanyl)carbamate (360 mg, 41.4% yield) as a yellow solid. MS (ESI) m / z 847.2 [M+H] + .

[0666] Step 3. 2-(3-((17-amino-3,6,9,12,15-pentaoxaheptadecanyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide

[0667] 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-pentaoxaheptadecanyl)carbamate (0.36 g, 0.42 mmol) and hydrochloric acid (4M in 1,4-dioxane, 5.0 mL) in 1,4-dioxane (3.0 mL) was stirred at room temperature for 6 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 sulfate, 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-pentaoxaheptadecanyl)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] + .

[0668] Step 4. 2-(3-((17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaheptadecanyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide

[0669] A solution of 2-(3-((17-amino-3,6,9,12,15-pentaoxaheptadecanyl)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 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 min) to give 2-(3-((17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaheptadecanyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide as a yellow solid (25 mg, 10% yield). 1 H NMR (400 MHz, DMSO-d6): δ 12.34 and 12.31 (s, 1H) *, 11.10 (s, 1H), 8.24 and 5.54 * (d, J = 8.8 Hz, 1H), 7.58-7.52 (m, 3H), 7.37-7.34 (m, 4H), 7.23 (t, J = 6.8 Hz, 1H), 7.12 (d, J = 6,8 Hz, 1H), 7.03 (d, J = 6.8 Hz, 1H), 6.93-6.89 (m, 2H), 6.84 (d, J = 7.2 Hz, 1H), 6. 60 (t, J = 5,4 Hz, 1H), 5.05 (dd, J = 12.8 and 5.8 Hz, 1H), 4.21 and 3.70 (m, 2H) *, 4.06 (m, 2H), 3.74-3.70 (m, 4H), 3.61-3.44 (m, 20H), 3.13 (t, J = 4.2 Hz, 2H), 2.92-2.83 (m, 1H), 2.60-2.54 (m, 2H), 2.44 and 2.34 (s, 3H) *, 2.29 and 2.18 (s, 3H) *, 2.05-1.99 (m, 1H). MS (ESI) m / z 1003.5 [M+H] + . ＊ Multiple signals originating from conformers.

[0670] Example 16

[0671] 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)

[0672]

[0673] Step 1. 14-Hydroxy-3,6,9,12-tetraoxatetradecyl 4-methylbenzenesulfonate

[0674] 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 hours. 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 produce 4-methylbenzenesulfonic acid 14-hydroxy-3,6,9,12-tetraoxatetradecyl ester (3.9 g, 98% yield) as a yellow oil. MS (ESI) m / z 393.3 [M+H] + .

[0675] 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

[0676] 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 hours. 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] + .

[0677] 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

[0678] To 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 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 21.2x250mm 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-((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. 1H NMR (400MHz, DMSO-d6): δ12.22 (bs, 1H), 11.11 (s, 1H), 8.23 ​​and 5.56* (d, J = 8.4Hz, 1H), 7.78 (t, J = 7.8Hz, 1H), 7.52-7.49 (m, 2H), 7.52&7.03* (m, 1H),7.44(d,J=7.2Hz,1H),7.37-7.30(m,4H),7.23(t,J=7.8Hz,1H),6.92-6.89(m,2H),6.83(d,J=7.6Hz,1H),5.08(dd,J=12.8 and 5.6Hz,1H),4. 32 (t, J = 4.2 Hz, 2H), 4.21 and 3.72 (m, 2H) *, 4.06 (t, J = 4.0 Hz, 2H), 3.79 (t, J = 4.4 Hz, 2H), 3.73-3.70 (m, 4H), 3.63 (t, J = 4.8 Hz, 2H), 3.57-3.56 (m, 2H), 3.53-3.50 (m, 8H), 3.13 (t, J = 7.8 Hz, 2H), 2.95-2.81 (m, 1H), 2.60-2.53 (m, 2H), 2.45 and 2.33 (s, 3H) *, 2.29 and 2.18 (s, 3H) *, 2.03-2.00 (m, 1H). MS (ESI) m / z 480.9 [M / 2+H] + . ＊ Multiple signals originating from conformers.

[0679] Example 17

[0680] Synthesis of 2-(3-((17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-3,6,9,12,15-pentaoxaheptadecanyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 10)

[0681]

[0682] Step 1. 17-Hydroxy-3,6,9,12,15-pentaoxaheptadecanyl 4-methylbenzenesulfonate

[0683] 3,6,9,12,15-pentaoxaheptadecane-1,17-diol (5.6g, 20mmol), triethylamine (6.0g, 59mmol) and 4-methylbenzenesulfonyl chloride (1.9g, 10mmol) in dichloromethane (60mL). The mixture was stirred at room temperature for 16 hours. The mixture was quenched with water (50mL), then extracted with ethyl acetate (50mL 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 produce 4-methylbenzenesulfonic acid 17-hydroxy-3,6,9,12,15-pentaoxaheptadecane ester (4.3g, 98.5% yield) as a yellow oil. MS (ESI) m / z 437.3[M+H] + .

[0684] Step 2. 2-(3-((17-hydroxy-3,6,9,12,15-pentaoxaheptadecanyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide

[0685] A mixture of 17-hydroxy-3,6,9,12,15-pentaoxaheptadecanyl 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), potassium tert-butoxide (0.15 g, 1.38 mmol) in dry N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (50 mL) and 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-pentaoxaheptadecanyl)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] + .

[0686] Step 3. 2-(3-((17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-3,6,9,12,15-pentaoxaheptadecanyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide

[0687] To 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 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 21.2x250mm 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-4-yl)oxy)-3,6,9,12,15-pentaoxaheptadecanyl)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. 1 H NMR (400MHz, 60℃, DMSO-d6): δ12.11(bs,1H),10.9(s,1H),7.77(t,J=7.8Hz,1H),7.52-7.48(m,2H),7.43(d,J=7.2Hz, 1H),7.37-7.28(m,6H),7.21(t,J=7.8Hz,1H),6.92-6.88(m,2H),6.82(d,J=8.0Hz,1H),5.04(dd,J=12.4 and 5.6Hz,1H),4 .33(t,J=4.6Hz,2H),4.07(t,J=4.8Hz,2H),3.79(t,J=4.6Hz,2H),3.74-3.70(m,5H),3.62(t,J=4.6Hz,2H),3.70(m,2H ),3.53-3.49(m,13H),3.11(m,2H),2.91-2.82(m,1H),2.60-2.51(m,2H),2.42(s,3H),2.26(s,3H),2.06-2.99(m,1H). MS(ESI)m / z 1005.4[M+H] + .

[0688] Example 18

[0689] 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)

[0690]

[0691] Step 1. 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

[0692] 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 hours. 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 as a white solid (0.15 g, 43% yield). MS (ESI) m / z 858.3 [M+H] + .

[0693] Step 2. 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

[0694] 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 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 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. 1 H NMR (400 MHz, DMSO-d6): δ 12.33 and 12.31 (s, 1H) *, 11.11 (s, 1H), 8.24 and 5.45 * (d, J = 9.2 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.53 (brs, 1H), 7.53 and 7.01 * (brs, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.38 -7.30 (m, 5H), 7.23 (t, J = 8.0 Hz, 1H), 6.92-6.89 (m, 2H), 6.84 (d, J = 7.2 Hz, 1H), 5.12 (dd, J = 13.0 and 5.4 Hz, 1H), 4.29 (t, J = 4.2 Hz, 2H), 4.21 and 3.70 (m, 2H) *, 4.07 (t, J = 4.4 Hz, 1H) z, 2H), 3.78-3.70 (m, 6H), 3.59-3.51 (s, 12H), 3.13 (t, J = 7.6 Hz, 2H), 2.90-2.88 (m, 1H), 2.55-2.52 (m, 2H), 2.45 and 2.33 (s, 3H) *, 2.29 and 2.18 (s, 3H) *, 2.05-2.01 (m, 1H). MS (ESI) m / z / 2 480.9 [M+H] + . ＊ Multiple signals originating from conformers.

[0695] Example 19

[0696] Synthesis of 2-(3-((17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3,6,9,12,15-pentaoxaheptadecanyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 15)

[0697]

[0698] 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

[0699] A solution of 2-(3-((17-hydroxy-3,6,9,12,15-pentaoxaheptadecanyl)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 hours. 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] + .

[0700] Step 2. 2-(3-((17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3,6,9,12,15-pentaoxaheptadecanyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide

[0701] 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-pentaoxaheptadecanyl 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) was stirred at 50° C. for 16 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 min) to give 2-(3-((17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3,6,9,12,15-pentaoxaheptadecanyl)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. 1 H NMR (400MHz, 60℃, DMSO-d6): δ12.15(brs,1H),10.98(s,1H),8.30 and 8.20*(brs,1H),7.81(d,J=8.4Hz,1H),7.53(s,1H),7.43(s,1H),7.38 -7.30(m,6H),7.23(t,J=8.0Hz,1H),6.92-6.89(m,2H),6.84(d,J=7.2Hz, 1H), 5.09 (dd, J = 12.8 and 5.6Hz, 1H), 4.31 (t, J = 4.6Hz, 2H), 4.09 (t, J = 4.8Hz ,2H),3.80-3.72(m,8H),3.60-3.52(s,16H),3.13-3.11(m,2H),2.90-2.8 6(m,1H),2.63-2.52(m,2H),2.44(s,3H),2.28(s,3H),2.08-2.00(m,1H). MS (ESI) m / z / 2: 503.0 [M+H] + . ＊ Multiple signals originating from conformers are very broad and difficult to see.

[0702] Example 20

[0703] 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)

[0704]

[0705] Step 1. Cyclopropyl(indolin-1-yl)methanone

[0706] To 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 hours. The mixture was quenched with water (50 mL), extracted with dichloromethane (50 mL), washed with saturated aqueous ammonium chloride (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to produce cyclopropyl(indolin-1-yl)methanone (6.0 g, 77% yield) as a white solid. MS (ESI) m / z 188.3 [M+H] + .

[0707] Step 2. 2-Bromo-1-(1-(cyclopropanecarbonyl)indolin-5-yl)propan-1-one

[0708] 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), followed by the addition of 2-bromopropionyl bromide (34.58 g, 160.2 mmol). The mixture was stirred at 50 °C for 5 hours. The mixture was quenched with water (200 mL), basified with 6N sodium hydroxide solution to pH = 8-10, extracted with dichloromethane (600 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to yield 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] + .

[0709] Step 3. (5-(2-Amino-5-methylthiazol-4-yl)indolin-1-yl)(cyclopropyl)methanone

[0710] 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 hours. The solvent was removed in vacuo, and the residue was purified by flash column chromatography (ethyl acetate / petroleum ether=1:1) to produce (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] + .

[0711] Step 4. N-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)-2-(3-hydroxyphenyl)acetamide

[0712] 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 minutes. To the resulting mixture was added (5-(2-amino-5-methylthiazol-4-yl)indolin-1-yl)(cyclopropyl)methanone (2.16 g, 7.23 mmol). 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 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] + .

[0713] 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

[0714] 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 hours. 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 / methane = 3 / 97) to give 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] + .

[0715] Step 6. 2-(3-(2-(2-aminoethoxy)ethoxy)phenyl)-N-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)acetamide

[0716] 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 hours. 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 solution, 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, 10 μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30%-70% in 15.0 min) to produce 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] + .

[0717] 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

[0718] 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 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 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 as a yellow solid (4.4 mg, 15% yield). 1 H NMR (400MHz, DMSO-d6): δ11.10(s,1H),8.06(m,1H),7.55(d,J=8.4Hz,1H),7.50(s,1H),7.42(d,J=7.6 Hz,1H),7.25-7.18(m,2H),7.07(s,1H),8.92-6.88(m,3H),6.83(d,J=8.0Hz,1H),5.30(dd,J=13.2 and 5.2 Hz,1H),4.39-4.28(m,2H),4.10-4.09(m,2H),3.78(m,2H),3.70-3.65(m,4H),3.39-3.38(m,2H),3.23 -3.21(m,2H),2.91-2.71(m,1H),2.67-2.57(m,2H),2.43(s,3H),2.00-1.97(m,2H),0.88-0.86(m,4H). MS(ESI)m / z:777.2[M+H] + Note: Acidic protons are usually not visible near 12.3 ppm).

[0719] Example 21

[0720] 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)

[0721]

[0722] Step 1. 1-((2-nitrophenyl)sulfonyl)indoline

[0723] To a solution of indoline (5.00 g, 42.0 mmol) and triethylamine (12.74 g, 125.9 mmol) in dichloromethane (150 mL) was added 2-nitrobenzenesulfonyl chloride (9.29 g, 42.0 mmol) at 0°C. After the addition, the mixture was stirred at room temperature for 16 hours. 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 and concentrated in vacuo to produce 1-((2-nitrophenyl)sulfonyl)indoline (7.0 g, 55% yield) as a yellow solid. MS (ESI) m / z: 305.0 [M+H] + .

[0724] Step 2. 2-Bromo-1-(1-((2-nitrophenyl)sulfonyl)indolin-5-yl)propan-1-one

[0725] 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), followed by the addition of 2-bromopropionyl bromide (14.91 g, 69.07 mmol). The mixture was stirred at 50°C for 5 hours. The mixture was quenched with water (500 mL), basified with 6N NaOH solution to pH = 8-10, extracted with dichloromethane (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to yield crude 2-bromo-1-(1-((2-nitrophenyl)sulfonyl)indolin-5-yl)propan-1-one (9.0 g, 89%) as a yellow oil. MS (ESI) m / z: 439.0 and 441.0 [M+H] + .

[0726] Step 3. 5-Methyl-4-(1-((2-nitrophenyl)sulfonyl)indolin-5-yl)thiazol-2-amine

[0727] 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 hours. 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 produce 5-methyl-4-(1-((2-nitrophenyl)sulfonyl)indolin-5-yl)thiazole-2-amine (6.0 g, 72% yield) as a yellow solid. MS (ESI) m / z: 417.1 [M+H] + .

[0728] Step 4. 2-(3-Hydroxyphenyl)-N-(5-methyl-4-(1-((2-nitrophenyl)sulfonyl)indolin-5-yl)thiazol-2-yl)acetamide

[0729] A solution of 2-(3-hydroxyphenyl)acetic acid (2.00 g, 13.1 mmol), bis(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] + .

[0730] 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

[0731] A solution of 2-(3-hydroxyphenyl)-N-(5-methyl-4-(1-((2-nitrophenyl)sulfonyl)indolin-5-yl)thiazol-2-yl)acetamide (1.50 g, 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 hours. 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] + .

[0732] Step 6. tert-Butyl (2-(2-(3-(2-((4-(indolin-5-yl)-5-methylthiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethyl)carbamate

[0733] 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 hours. 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] + .

[0734] 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

[0735] 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 hours. 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-imidazol-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] + .

[0736] Step 8. 2-(3-(2-(2-aminoethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(1-methyl-1H-imidazol-5-carbonyl)indolin-5-yl)thiazol-2-yl)acetamide

[0737] A solution of tert-butyl (2-(2-(3-(2-((5-methyl-4-(1-(1-methyl-1H-imidazol-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 hours. The solvent was removed in vacuo, and the residue 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 produce 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] + .

[0738] 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

[0739] A solution of 2-(3-(2-(2-aminoethoxy)ethoxy)phenyl)-N-(5-methyl-4-(1-(1-methyl-1H-imidazol-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 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 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. 1 H NMR (400 MHz, DMSO-d6): δ 8.07 and 5.30* (d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 7.59-7.54 (m, 3H), 7.49 (d, J = 4.8 Hz, 1H), 7.25-7.17 (m, 2H), 7.00 (s, 1H), 6.92-6.88 (m, 3H), 6.83 (d, J = 8.0 Hz, 1H), 5.30 (dd, J = 13 and 5.4 Hz,1H),4.36(t,J=8.2Hz,2H),4.10(t,J=4.0Hz,2H),3.80-3.75(m,5H),3.70-3.64(m,4H),3.43-3.3 8(m,2H),3.19(t,J=8.4Hz,2H),2.91-2.80(m,1H),2.79-2.67(m,2H),2.45(s,3H),2.00-1.97(m,1H). MS(ESI)m / z:817.2[M+H] +.(Note: Usually the two acidic protons around 12.3ppm and 11.1ppm are not visible). ＊ Multiple signals originating from conformers.

[0740] Example 22

[0741] Synthesis of 2-(3-((20-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-3,6,9,12,15,18-hexaoxaeicosyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 11)

[0742]

[0743] Step 1. 20-Hydroxy-3,6,9,12,15,18-hexaoxaicosanyl 4-methylbenzenesulfonate

[0744] A solution of 3,6,9,12,15,18-hexaoxaeicosane-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 hours. 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 produce 4-methylbenzenesulfonic acid 20-hydroxy-3,6,9,12,15,18-hexaoxaeicosane ester (1.2 g, 32.6% yield) as a yellow oil. MS (ESI) m / z 481.3 [M+H] + .

[0745] Step 2. 2-(3-((20-hydroxy-3,6,9,12,15,18-hexaoxaeicosyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide

[0746] A mixture of 20-hydroxy-3,6,9,12,15,18-hexaoxaeosyl 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), potassium tert-butoxide (0.21 g, 1.87 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hours. 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-hexaoxaeicosyl)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] + .

[0747] Step 3. 2-(3-((20-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-3,6,9,12,15,18-hexaoxaeicosyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide

[0748] To a solution of 2-(3-((20-hydroxy-3,6,9,12,15,18-hexaoxaeicosyl)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 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 21.2x250mm 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-((20-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-3,6,9,12,15,18-hexaoxaeicosanyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide as a white solid (52 mg, 15%). 1H NMR (400 MHz, DMSO-d6): δ 12.33 and 12.22 (s, 1H) *, 11.11 (s, 1H), 8.23 ​​and 5.45 * (d, J = 8.4 Hz, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.52-7.50 (m, 2H), 7.52 & 7.03 * (m, 1H), 7.45 (d, J = 7.2 Hz, 1H), 7.37-7.30 (m, 4H), 7.23 (t, J = 8.0 Hz, 1H), 6.92-6.89 (m, 2H), 6.84 (d, J = 8.0 Hz, 1H), 5.08 (dd, J = 12.8 and 5.6 Hz, 1H ), 4.33 (t, J = 4.2 Hz, 2H), 4.21 and 3.74 (m, 2H) *, 4.06 (t, J = 4.0 Hz, 2H), 3.79 (t, J = 4.3 Hz, 2H), 3.70-3.63 (m, 4H), 3.64-3.61 (m, 2H), 3.58-3.56 (m, 2H), 3.53-3.47 (m, 16H), 3.13 (t, J = 8.2 Hz, 2H), 2.89-2.83 (m, 1H), 2.60-2.55 (m, 2H), 2.48 and 2.33 (s, 3H) *, 2.29 and 2.17 (s, 3H) *, 2.04-1.00 (m, 1H). MS (ESI) m / z 1048.4 [M+H] + . ＊ Multiple signals originating from conformers.

[0749] Example 23

[0750] Synthesis of 2-(3-((20-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3,6,9,12,15,18-hexaoxaeicosyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 16)

[0751]

[0752] 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-hexaoxaeosyl 4-methylbenzenesulfonate

[0753] A solution of 2-(3-((20-hydroxy-3,6,9,12,15,18-hexaoxaeicosyl)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 hours. 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-hexaoxaeicosanyl 4-methylbenzenesulfonate (0.13 g, 45.4% yield) as a white solid. MS (ESI) m / z 946.4 [M+H] + .

[0754] Step 2. 2-(3-((20-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3,6,9,12,15,18-hexaoxaeicosyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide

[0755] 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-hexaoxaeosyl 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 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 min) to give 2-(3-((20-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3,6,9,12,15,18-hexaoxaeicosanyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (9.0 mg, 7.3%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.33 and 12.22 (s, 1H) *, 11.11 (s, 1H), 8.24 and 5.45 * (d, J = 8.4 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.53 (brs, 1H), 7.53 and 7.01 * (brs, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.37 -7.30 (m, 5H), 7.24 (t, J = 7.8 Hz, 1H), 6.92-6.89 (m, 2H), 6.84 (d, J = 8.4 Hz, 1H), 5.12 (dd, J = 13.0 and 5.4 Hz, 1H), 4.30 (t, J = 4.4 Hz, 2H), 4.21 and 3.69 (m, 2H) *, 4.07 (m, 2H), 3.78-3 .71 (m, 6H), 3.59-3.47 (m, 4H), 3.54-3.46 (m, 16H), 3.13 (t, J = 7.8 Hz, 2H), 2.88-2.85 (m, 1H), 2.62-2.55 (m, 2H), 2.46 and 2.33 (s, 3H) *, 2.30 and 2.18 (s, 3H) *, 2.05-2.00 (m, 1H). MS (ESI) m / z 525 [M / 2+H] + . ＊ Multiple signals originating from conformers.

[0756] Example 24

[0757] Synthesis of 2-(3-((2,3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3,6,9,12,15,18,21-heptaoxatriacosanyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide (Compound No. 17)

[0758]

[0759] Step 1. 23-Hydroxy-3,6,9,12,15,18,21-heptaoxatriacontyl 4-methylbenzenesulfonate

[0760] A solution of 3,6,9,12,15,18,21-heptaoxatriacosan-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 hours. 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 produce 23-hydroxy-3,6,9,12,15,18,21-heptaoxatriacosan-1,23-diol (2.6 g, 99% yield) as a yellow oil. MS (ESI) m / z 525.3 [M+H] + .

[0761] Step 2. 2-(3-((2,3-hydroxy-3,6,9,12,15,18,21-heptaoxatriacosanyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide

[0762] A solution of 23-hydroxy-3,6,9,12,15,18,21-heptaoxatriacontyl 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), potassium tert-butoxide (0.22 g, 2.0 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (20 mL) and 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-heptaoxatriacosanyl)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] +

[0763] 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-heptaoxatriacosanyl methanesulfonate

[0764] To a solution of 2-(3-((23-hydroxy-3,6,9,12,15,18,21-heptaoxatriacosanyl)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 hours. 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-heptaoxatriacosanyl methanesulfonate (0.19 g, 69.5% yield) as a yellow solid. MS (ESI) m / z 914.5 [M+H] + .

[0765] Step 4. 2-(3-((2,3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3,6,9,12,15,18,21-heptaoxatriacosanyl)oxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide

[0766] 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-heptaoxatricinyl methanesulfonate (0.19 g, 0.21 mmol) and 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 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 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-heptaoxatriacosanyl)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. 1H NMR (400MHz, 60℃, DMSO-d6): δ12.10(brs,1H)*,10.9(s,1H),7.82(d,J=8.0Hz,1H),7.53(s,1H),7.43(d,J=2.0Hz,1H),7.40 -7.32(m,7H),7.23(t,J=8.0Hz,1H),6.94-6.86(m,2H),6.85(d,J=8.0Hz,1H),5.09(dd,J= 13.0 and 5.4Hz, 1H), 4.32 (t, J = 4.6Hz, 2H), 4.21 and 3.74 (m, 2H) *, 4.10 (t, J = 4.6Hz, 2H), 3.80 (t ,J=4.6Hz,2H),3.77-3.72(m,4H),3.62-3.60(m,4H),3.56-3.51(m,20H),3.13**(t,J=8.4 Hz,2H),2.88-2.85(m,1H),2.62-2.55(m,2H),2.44(s,3H),2.28(s,3H),2.08-2.01(m,1H). MS(ESI)m / z 1092.4[M+H] + . ＊ Multiple signals originating from conformers. ＊＊ The signal is below the water peak but is clearly visible in NMR performed at room temperature.

[0767] Example 25

[0768] 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)

[0769]

[0770] 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

[0771] 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 hours. 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] + .

[0772] Step 2. N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)-2-(3-(2-(piperazin-1-yl)ethoxy)phenyl)acetamide

[0773] 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 solution, 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] + .

[0774] 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

[0775] 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 hours. 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, 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-(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. 1 H NMR (400 MHz, DMSO-d6): δ 12.35 and 12.27 (s, 1H) *, 11.09 (s, 1H), 8.23 ​​and 5.54 * (d, J = 8.4 Hz, 1H), 7.66 (t, J = 8.4 Hz, 1H), 7.52 (s, 2H), 7.37-7.22 (m, 7H), 6.96 (s, 1H), 6.91-6.86 (m, 2H), 5.07 (dd, J = 12.4 and 5.6 Hz, 1H), 4.21 and 3.70 (m, 2H)*, 4.12 (s, 2H), 3.74-3.71 (m, 2H), 3.44-3.38 (m, 4H), 3.13 (t, J = 8.2 Hz, 2H), 2.89-2.83 (m, 1H), 2.78-2.75 (m, 2H), 2.67-2.63 (m, 4H), 2.56-2.54 (m, 2H), 2.45 and 2.34 (s, 3H)*, 2.29 and 2.18 (s, 3H)*, 2.02-1.99 (m, 1H). MS (ESI) m / z: 853.2 [M+H] + . ＊ Multiple signals originating from conformers.

[0776] Example 26

[0777] 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)

[0778]

[0779] Step 1. 1-((2-nitrophenyl)sulfonyl)indoline

[0780] 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 hours. 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 and concentrated in vacuo to produce 1-((2-nitrophenyl)sulfonyl)indoline (54.0 g, 84.5% yield) as a yellow solid. MS (ESI) m / z: 305.0 [M+H] + .

[0781] Step 2. 2-Bromo-1-(1-((2-nitrophenyl)sulfonyl)indolin-5-yl)propan-1-one

[0782] 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), followed by the addition of 2-bromopropionyl bromide (114.95 g, 532.33 mmol). The mixture was stirred at 50°C for 16 hours. The mixture was cooled to room temperature, quenched with water (500 mL), basified with 6N NaOH solution to a pH of 8-10, extracted with dichloromethane (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to yield crude 2-bromo-1-(1-((2-nitrophenyl)sulfonyl)indolin-5-yl)propan-1-one (76.0 g, 97.5% yield) as a yellow oil. MS (ESI) m / z: 439.0 and 441.0 [M+H] + .

[0783] Step 3. 5-Methyl-4-(1-((2-nitrophenyl)sulfonyl)indolin-5-yl)thiazol-2-amine

[0784] 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 hours. 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) and dried to produce 5-methyl-4-(1-((2-nitrophenyl)sulfonyl)indolin-5-yl)thiazole-2-amine (45.12 g, 62.6% yield) as a yellow solid. MS (ESI) m / z: 417.1 [M+H] + .

[0785] Step 4. 2-(4-Fluoro-3-hydroxyphenyl)acetic acid

[0786] A solution of 2-(4-fluoro-3-methoxyphenyl)acetic acid (19.00 g, 103.2 mmol) in hydrobromic acid (40% aqueous hydrobromic acid, 50 mL) and acetic acid (50 mL) was stirred at 90°C for 18 hours. The solvent was removed in vacuo, and the residue was dissolved in dichloromethane (200 mL), washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to yield 2-(4-fluoro-3-hydroxyphenyl)acetic acid (15.0 g, 85.5%) as a yellow solid. MS (ESI) m / z: 171.0 [M+H] + .

[0787] Step 5. 2-(4-Fluoro-3-hydroxyphenyl)-N-(5-methyl-4-(1-((2-nitrophenyl)sulfonyl)indolin-5-yl)thiazol-2-yl)acetamide

[0788] 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-nitrobenzenesulfonyl)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] + .

[0789] Step 6. tert-Butyl 2-(2-(2-fluoro-5-(2-(5-methyl-4-(1-(2-nitrobenzenesulfonyl)indolin-5-yl)thiazol-2-ylamino)-2-oxoethyl)phenoxy)ethoxy)ethylcarbamate

[0790] A solution of 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) was stirred at room temperature for 18 hours. 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 = 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] + .

[0791] Step 7. tert-Butyl 2-(2-(2-fluoro-5-(2-(4-(indolin-5-yl)-5-methylthiazol-2-ylamino)-2-oxoethyl)phenoxy)ethoxy)ethylcarbamate

[0792] 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 hours. 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] + .

[0793] Step 8. tert-Butyl 2-(2-(5-(2-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-ylamino)-2-oxoethyl)-2-fluorophenoxy)ethoxy)ethylcarbamate

[0794] To 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 hours. 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] + .

[0795] Step 9. 2-(3-(2-(2-aminoethoxy)ethoxy)-4-fluorophenyl)-N-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)acetamide

[0796] 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 hours. The solvent was removed in vacuo, and the residue was dissolved in dichloromethane (40 mL), washed with saturated aqueous sodium carbonate solution, dried over anhydrous sodium sulfate, 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] + .

[0797] 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

[0798] 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 hours. The mixture was diluted with water (10 mL), extracted with ethyl acetate (20 mL×4), dried over anhydrous sodium sulfate, filtered and concentrated. 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 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. 1 H NMR (400 MHz, DMSO-d6): δ 12.29 (s, 1H), 11.06 (s, 1H), 8.07 (d, J = 7.2 Hz, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.49 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.18-7.13 (m, 3H), 6.90-6.87 (m, 2H), 5.03 (dd, J = 13.0 and 5.2, 1H), 4.33 (m ,2H),4.19(t,J=4.4Hz,2H),3.81(t,J=4.4Hz,2H),3.71(s,2H),3.67(t,J=5.4Hz,2H),3.40-3.35(m,2H ),3.24(m,2H),2.91-2.81(m,1H),2.59-2.51(m,2H),2.43(s,3H),1.99-1.96(m,2H),0.88-0.86(m,4H). MS(ESI)m / z:759.2[M+H] + .

[0799] Example 27

[0800] 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)

[0801]

[0802] Step 1. tert-Butyl 4-(3-chloropropyl)piperazine-1-carboxylate

[0803] 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 hours. 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 produce 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] +

[0804] 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

[0805] 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 hours. 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] +

[0806] Step 3. N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)-2-(3-(3-(piperazin-1-yl)propoxy)phenyl)acetamide

[0807] 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 hours. The solvent was removed and the residue was dissolved in dichloromethane (100 mL), washed with saturated aqueous sodium carbonate solution, 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] +

[0808] Step 4. 2-(3-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propyloxy)phenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide

[0809] 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 hours. 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, 10 μm, 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. 1 H NMR (400 MHz, DMSO-d6): δ 12.38 (s, 1H), 11.09 (s, 1H), 8.23 ​​and 5.55 * (d, J = 8.4 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.51 (s, 2H), 7.37-7.21 (m, 7H), 6.93-6.83 (m, 3H), 5.07 (dd, J = 12.8 and 5.2 Hz, 1H), 4.2 and 3.7 * (m, 2H), 4.0 2 (m, 2H), 3.75-3.70 (m, 2H), 3.43 (s, 4H), 3.14-3.10 (m, 2H), 2.89-2.84 (m, 1H), 2.60-2.56 (m, 2H), 2.55-2.52 (m, 4H), 2.49 (s, 2H), 2.44 and 2.3* (s, 3H), 2.29 and 2.18* (s, 3H), 2.02-1.98 (m, 1H), 1.93-1.89 (m, 2H). MS (ESI) m / z: 866.2 [M+H] + . ＊ Multiple signals originating from conformers.

[0810] Example 28

[0811] 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)

[0812]

[0813] Step 1. tert-Butyl 4-(4-(3-(2-ethoxy-2-oxoethyl)phenoxy)butyl)piperazine-1-carboxylate

[0814] 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 hours. 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 hours. The mixture was quenched with water (50 mL), extracted with dichloromethane (100 mL x 2), washed with brine (30 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*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 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] +

[0815] Step 2. 2-(3-(4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)butoxy)phenyl)acetic acid

[0816] A solution of tert-butyl 4-(4-(3-(2-ethoxy-2-oxoethyl)phenoxy)butyl)piperazine-1-carboxylate (0.40 g, 0.95 mmol), sodium hydroxide (0.11 g, 2.85 mmol) in water (5 mL) and methanol (20 mL) was stirred at room temperature for 18 hours. The mixture was acidified with 2M aqueous hydrochloric acid to give a pH of 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*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-(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] +

[0817] 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

[0818] 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 hours. 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*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 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] +

[0819] Step 4. N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)-2-(3-(4-(piperazin-1-yl)butoxy)phenyl)acetamide

[0820] 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 (4M 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 solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to yield 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] +

[0821] 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

[0822] 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), N,N-diisopropylethylamine (43.9 mg, 0.34 mmol) in 1-methylpyrrolidin-2-one (2 mL) was stirred at 140° C. for 18 hours. 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. 1 H NMR (400 MHz, DMSO-d6): δ 12.34 and 12.25* (s, 1H), 11.09 (s, 1H), 8.23 ​​and 5.52* (d, J = 8.8 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.52 (s, 1H), 7.52 and 7.04* (m, 1H), 7.37-7.30 (m, 5H), 7.24-7.21 (m, 2H), 6.92-6.83 (m, 3H), 5.07 (dd, J = 12.6 and 5.4 Hz, 1H ), 4.21 and 3.73* (m, 2H), 4.0 (t, J = 5.8 Hz, 2H), 3.70 (s, 2H), 3.41-3.37 (m, 4H), 3.12 (t, J = 8.4 Hz, 2H), 2.91-2.83 (m, 1H), 2.60-2.51 (m, 2H), 2.48 (m, 4H), 2.45 and 2.34* (s, 3H), 2.38 (t, J = 6.8 Hz, 2H), 2.29 and 2.18* (s, 3H), 2.02-2.00 (m, 1H). 1.76-1.75 (m, 2H), 1.65-1.60 (m, 2H). MS (ESI) m / z: 880.3 [M+H] + . *Multiple signals originating from conformers.

[0823] Example 29

[0824] 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).

[0825]

[0826]

[0827] Step 1. 5-(2-(2-hydroxyethoxy)ethylamino)isobenzofuran-1(3H)-one

[0828] 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 hours. 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*250 mm C18, 10 μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30%-70% in 15 min) to produce 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] + .

[0829] Step 2. 2-(2-(1-oxo-1,3-dihydroisobenzofuran-5-ylamino)ethoxy)ethyl methanesulfonate

[0830] To 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 hours. Another portion of methanesulfonyl chloride (3.62 g, 31.61 mmol) was then added at room temperature, and the mixture was stirred at room temperature for another 18 hours. 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 and concentrated in vacuo to give 2-(2-(1-oxo-1,3-dihydroisobenzofuran-5-ylamino)ethoxy)ethyl methanesulfonate (3.80 g, 57.1% yield) as an off-white solid. MS (ESI) m / z: 315.9 [M+H] + .

[0831] Step 3a. Methyl 2-(4-fluoro-3-hydroxyphenyl)acetate

[0832] 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 hours. 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 produce 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] + .

[0833] Step 3. Methyl 2-(4-fluoro-3-(2-(2-(1-oxo-1,3-dihydroisobenzofuran-5-ylamino)ethoxy)ethoxy)phenyl)acetate

[0834] 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 hours. 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 and 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, overweight) as a yellow solid. MS (ESI) m / z: 404.0 [M+H] + .

[0835] Step 4. 4-(2-(2-(5-(carboxymethyl)-2-fluorophenoxy)ethoxy)ethylamino)-2-(hydroxymethyl)benzoic acid

[0836] A solution of methyl 2-(4-fluoro-3-(2-(2-(1-oxo-1,3-dihydroisobenzofuran-5-ylamino)ethoxy)ethoxy)phenyl)acetate (4.20 g, 10.1 mmol maximum) and sodium hydroxide (3.33 g, 83.29 mmol) in methanol (20 mL) and water (20 mL) was stirred at room temperature for 24 hours. 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, 10 μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30%-70% in 15 min) to produce 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] + .

[0837] Step 5. 4-(2-(2-(5-(Carboxymethyl)-2-fluorophenoxy)ethoxy)ethylamino)-2-formylbenzoic acid

[0838] 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 hours. 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, 10 μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30%-70% in 15 min) to produce 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] + .

[0839] Step 6. 4-(2-(2-(5-(Carboxymethyl)-2-fluorophenoxy)ethoxy)ethylamino)-2-((2,6-dioxopiperidin-3-ylamino)methyl)benzoic acid

[0840] To 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 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 hours. 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*250 mm C18, 10 μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30%-70% in 15 min) to produce 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] + .

[0841] 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

[0842] 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 hours. 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*250 mm C18, 10 μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30%-70% in 15 min) to produce N-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)-2-(3-(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. 1H NMR (400MHz, DMSO-d6): δ12.24(s,1H),10.89(s,1H),8.07(d,J=6.8Hz,1H),7.49(s,1H),7.42(d,J=8.4Hz,1H),7.35(d,J=8.0Hz,1H),7 .18-7.13(m,2H),6.90-6.87(m,1H),6.70-6.66(m,2H),6.38(t,J=5.4Hz,1H),5.01(dd,J=12.8Hz,5.2Hz,1H),4.33(t,J=7.6Hz,2H),4.2 5(d,J=16Hz,1H),4.19(t,J=4.4Hz,2H),4.11(d,J=16.8Hz,1H),3.80(t,J=4.6Hz,2H),3.71(s,2H),3.66(t,J=5.6Hz,2H),3.29-3.26(m ,2H),3.23(t,J=8.4Hz,2H),2.93-2.84(m,1H),2.59-2.55(m,1H),2.43(s,3H),2.37-2.25(m,1H),2.00-1.90(m,2H),0.90-0.81(m,4H). MS(ESI)m / z:781.1[M+H] + .

[0843] Example 30

[0844] 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)

[0845]

[0846] Step 1. tert-Butyl (2-(2-(2-fluoro-5-(2-((5-methyl-4-(1-(1-methyl-1H-imidazol-5-carbonyl)indolin-5-yl)thiazol-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethyl)carbamate

[0847] 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 hours. 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 give crude tert-butyl (2-(2-(2-fluoro-5-(2-((5-methyl-4-(1-(1-methyl-1H-imidazol-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] +

[0848] Step 2. 2-(3-(2-(2-aminoethoxy)ethoxy)-4-fluorophenyl)-N-(5-methyl-4-(1-(1-methyl-1H-imidazol-5-carbonyl)indolin-5-yl)thiazol-2-yl)acetamide

[0849] A solution of tert-butyl (2-(2-(2-fluoro-5-(2-((5-methyl-4-(1-(1-methyl-1H-imidazol-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 hours. The solvent was removed in vacuo, and the residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250 mm C18, 10 μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30%-70% in 15.0 min) to produce 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] +

[0850] 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

[0851] A solution of 2-(3-(2-(2-aminoethoxy)ethoxy)-4-fluorophenyl)-N-(5-methyl-4-(1-(1-methyl-1H-imidazol-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 hours. 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, 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)-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. 1H NMR (400MHz, DMSO-d6): δ12.29(brs,1H),11.06(s,1H),8.07(d,J=8.8Hz,1H),7.84(s,1H),7.59(s,1H),7. 57-7.52(m,2H),7.48(d,J=8.4Hz,1H),7.17-7.13(m,3H),6.99(m,1H),6.89-6.87(m,2H),5.04-5.00(m,1H ),4.36(t,J=8.4Hz,2H),4.19(t,J=3.6Hz,2H),3.87-3.76(m,5H),3.71(s,2H),3.66(d,J=5.6Hz,2H),3.44 -3.35(m,2H),3.19(t,J=8.4Hz,2H),2.91-2.82(m,1H),2.61-2.54(m,2H),2.45(s,3H),2.01-1.97(m,1H). MS(ESI)m / z:835.2[M+H] + .

[0852] Example 31

[0853] 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).

[0854]

[0855]

[0856] Step 1. tert-Butyl 5-(2-amino-5-methylthiazol-4-yl)indoline-1-carboxylate

[0857] 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 hours under a nitrogen atmosphere. The mixture was cooled to room temperature, diluted with water (20 mL), extracted with dichloromethane (25 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*250 mm C18, 10 μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30%-70% in 15 min) to produce 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] + .

[0858] Step 2. 4-(2-(2-(5-(Carboxymethyl)-2-fluorophenoxy)ethoxy)ethylamino)-2-formylbenzoic acid

[0859] 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 hours. 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, 10 μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30%-70% in 15 min) to produce 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] + .

[0860] Step 3. 4-(2-(2-(5-(carboxymethyl)-2-fluorophenoxy)ethoxy)ethylamino)-2-((2,6-dioxopiperidin-3-ylamino)methyl)benzoic acid

[0861] To 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 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 hours. 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*250 mm C18, 10 μm, 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] + .

[0862] 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)acetylamino)-5-methylthiazol-4-yl)indoline-1-carboxylate

[0863] 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% (weight %) 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 hours. 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, 10 μm, 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)acetylamino)-5-methylthiazol-4-yl)indoline-1-carboxylate (0.20 g, 37% yield) as a white solid. MS (ESI) m / z: 813.1 [M+H] + .

[0864] 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

[0865] 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 (2M in 1,4-dioxane, 15 mL) and 1,4-dioxane (10 mL) was stirred at room temperature for 18 hours. The mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (100 mL), washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 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) as a white solid. MS (ESI) m / z: 713.3 [M+H] + .

[0866] 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

[0867] A solution of 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% (weight %) in ethyl acetate, 0.67 g, 1.05 mmol), and triethylamine (0.11 g, 1.05 mmol) in ethyl acetate (10 mL) was stirred at 65° C. for 3 hours. The mixture was cooled to room temperature, diluted with water (20 mL), extracted with dichloromethane (30 mL×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, 10 μm, 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. 1H NMR (400MHz, DMSO-d6): δ12.31(brs,1H),10.93(s,1H),8.08(d,J=8.0Hz,1H),7.85(s,1H),7.60(s,1H),7.54(s,1H),7.49(d,J=8.4Hz,1H ),7.37(d,J=8.4Hz,1H),7.19-7.14(m,2H),6.91-6.88(m,1H),6.70-6.66(m,2H),6.40(t,J=5.4Hz,1H),5.01(dd,J=13.2Hz,5.2Hz,1H),4 .37(t,J=8.4Hz,2H),4.24(d,J=16.8Hz,1H),4.19(t,J=4.6Hz,2H),4.11(d,J=16.8Hz,1H)3.82(m,2H)3.80(s,3H),3.72(s,2H),3.66(t,J =5.6Hz,2H),3.29(m,2H),3.19(t,J=8.4Hz,2H),2.93-2.84(m,1H),2.68-2.54(m,1H),2.45(s,3H),2.37-2.26(m,1H),1.95-1.89(m,1H). MS(ESI)m / z:821.0[M+H] + .

[0868] 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:

[0869]

[0870]

[0871] Step 1. tert-Butyl 5-methyl-4-(1-(2-nitrobenzenesulfonyl)indolin-5-yl)thiazol-2-ylcarbamate

[0872] A solution of 5-methyl-4-(1-(2-nitrobenzenesulfonyl)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 hours. The dichloromethane was removed in vacuo. The residue was suspended in diethyl ether (100 mL) and filtered. The filter cake was washed with diethyl ether (30 mL x 2) and dried to produce tert-butyl 5-methyl-4-(1-(2-nitrobenzenesulfonyl)indolin-5-yl)thiazol-2-ylcarbamate (2.50 g, 40.3% yield) as a gray solid. MS (ESI) m / z: 517.1 [M+H] + .

[0873] Step 2. tert-Butyl 4-(indolin-5-yl)-5-methylthiazol-2-ylcarbamate A solution of tert-butyl 5-methyl-4-(1-(2-nitrobenzenesulfonyl)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 hours. 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 give 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] + .

[0874] Step 3. tert-Butyl 5-methyl-4-(1-(1-methyl-1H-imidazole-5-carbonyl)indolin-5-yl)thiazol-2-ylcarbamate

[0875] 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 hours. 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*250 mm C18, 10 μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30%-70% in 15 min) to produce 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] + .

[0876] Step 4. (5-(2-Amino-5-methylthiazol-4-yl)indolin-1-yl)(1-methyl-1H-imidazol-5-yl)methanone

[0877] A solution of tert-butyl 5-methyl-4-(1-(1-methyl-1H-imidazole-5-carbonyl)indolin-5-yl)thiazol-2-ylcarbamate (0.55 g, 1.25 mmol) in hydrochloric acid (2 M in dioxane, 20 mL) was stirred at room temperature for 18 hours. 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) and dried to produce (5-(2-amino-5-methylthiazol-4-yl)indolin-1-yl)(1-methyl-1H-imidazole-5-yl)methanone (0.23 g, 54% yield) as a yellow solid. MS (ESI) m / z: 340.1 [M+H] + .

[0878] Step 5. 5-(2-(2-hydroxyethoxy)ethylamino)isobenzofuran-1(3H)-one

[0879] 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 hours. 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, 10 μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30%-70% in 15 min) to produce 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] + .

[0880] Step 6. 2-(2-(1-oxo-1,3-dihydroisobenzofuran-5-ylamino)ethoxy)ethyl methanesulfonate

[0881] 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) was added methanesulfonyl chloride (6.36 g, 55.53 mmol) at 0°C. After the addition, the mixture was stirred at room temperature for 18 hours. 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 and concentrated in vacuo to yield 2-(2-(1-oxo-1,3-dihydroisobenzofuran-5-ylamino)ethoxy)ethyl methanesulfonate (12.50 g, 85.7% yield) as an off-white solid. MS (ESI) m / z: 316.1 [M+H] + .

[0882] Step 7. Methyl 2-(4-fluoro-3-(2-(2-(1-oxo-1,3-dihydroisobenzofuran-5-ylamino)ethoxy)ethoxy)phenyl)acetate

[0883] 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 hours. 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 and concentrated in vacuo to give 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) as a yellow solid. MS (ESI) m / z: 404.1 [M+H] + .

[0884] Step 8. 4-(2-(2-(5-(Carboxymethyl)-2-fluorophenoxy)ethoxy)ethylamino)-2-(hydroxymethyl)benzoic acid

[0885] 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, 10 μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30%-70% in 15 min) to produce 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] + .

[0886] Step 9. 4-(2-(2-(5-(Carboxymethyl)-2-fluorophenoxy)ethoxy)ethylamino)-2-formylbenzoic acid

[0887] 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 hours. 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*250 mm C18, 10 μm, 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] + .

[0888] Step 10. 4-(2-(2-(5-(Carboxymethyl)-2-fluorophenoxy)ethoxy)ethylamino)-2-((2,6-dioxopiperidin-3-ylamino)methyl)benzoic acid

[0889] To 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 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 hours. The mixture was diluted with water (100 mL), 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*250 mm C18, 10 μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30%-70% in 15 min) to produce 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] + .

[0890] 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

[0891] A solution of 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) was stirred at 65° C. for 5 hours. 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, 10 μm, 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. 1H NMR (400MHz, DMSO-d6): δ12.30(brs,1H),10.93(s,1H),8.08(d,J=8.0Hz,1H),7.85(s,1H),7.59(s,1H),7.54(s,1H),7.49(d, J=8.4Hz,1H),7.37(d,J=8.4Hz,1H),7.19-7.14(m,2H),6.90-6.87(m,1H),6.69-6.65(m,2H),6.40(t,J=5.2Hz,1H),5.00(dd, J=13.2Hz,5.2Hz,1H),4.36(t,J=8.4Hz,1H),4.25-4.09(m,4H),3.89-3.78(m,5H),3.71(s,2H),3.65(t,J=5.6Hz,2H),3.28(q ,J=5.6Hz,2H),3.19(t,J=8.4Hz,2H),2.93-2.84(m,1H),2.67-2.54(m,1H),2.45(s,3H),2.36-2.25(m,1H),1.93-1.89(m,1H). MS(ESI)m / z:821.0[M+H] + .

[0892] Example 32

[0893] 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)

[0894]

[0895]

[0896] Step 1. tert-Butyl 4-(2-(3-(2-ethoxy-2-oxoethyl)phenoxy)ethyl)piperazine-1-carboxylate

[0897] 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 hours. 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 yield 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] + .

[0898] Step 2. 2-(3-(2-(4-(tert-Butoxycarbonyl)piperazin-1-yl)ethoxy)phenyl)acetic acid

[0899] A solution of tert-butyl 4-(2-(3-(2-ethoxy-2-oxoethyl)phenoxy)ethyl)piperazine-1-carboxylate (0.36 g, 0.92 mmol), sodium hydroxide (0.11 g, 2.75 mmol) in methanol (20 mL) and water (20 mL) was stirred at room temperature for 16 hours. 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*250 mm C18, 10 μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30%-70% in 15.0 min) to produce 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] + .

[0900] 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

[0901] 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 hours. 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*250 mm C18, 10 μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30%-70% in 15.0 min) to produce 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] + .

[0902] Step 4. N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)-2-(3-(2-(piperazin-1-yl)ethoxy)phenyl)acetamide

[0903] 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 (2M in 1,4-dioxane, 20 mL) was stirred at room temperature for 16 hours. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (100 mL), washed with saturated aqueous sodium carbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated to yield 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) as an off-white solid. MS (ESI) m / z: 596.2 [M+H] +

[0904] 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

[0905] 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 hours. 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*250 mm C18, 10 μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30%-70% in 15.0 mi...

Claims

1. Compounds of formula AI: or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 is selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted phenyl and optionally substituted 5- to 9-membered heteroaryl; R 2a , R 2b and R 2c independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3 and halogen; R 3 is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3 and halogen; Y is selected from -^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 independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3 and halogen; L is selected from -(CH2) m -、-*(CH2) n (OCH2CH2) o - and -(CH2) p -Z-CH2) q -; wherein the carbon marked with "*" is attached 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 -(CR 6a R 6b )- and -N(R 7 )-; R 6a is selected from halogen, hydroxy, C1-C6 alkyl, C1-C4 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C4-C8 heterocycle, optionally substituted phenyl and optionally substituted 5- to 9-membered heteroaryl; R 6b is selected from hydrogen and C1-C6 alkyl; R 7 is selected from hydrogen, C1-C6 alkyl and C1-C4 haloalkyl; X is selected from -O-, -NH-, B 1 Selected from: and R 5a , R 5b and R 5c Independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3 and halogen.

2. The compound of claim 1, which has formula I: or a pharmaceutically acceptable salt or solvate thereof.

3. The compound of claim 1, which has formula II: or a pharmaceutically acceptable salt or solvate thereof.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is an optionally substituted C3-C8 cycloalkyl group.

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

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

7. The compound according to claim 6 or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 yes: and R 1a , R 1b , R 1c , R 1d and R 1e Independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3 and halogen.

8. The compound according to claim 7 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1b , R 1c , R 1d and R 1e It's hydrogen.

9. The compound according to claim 7 or 8, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1a It is a C1-C4 alkyl group.

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

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

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2a , R 2b and R 2c It's hydrogen.

13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 It is a C1-C4 alkyl group.

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

15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4a Selected from hydrogen and fluorine.

16. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4b Selected from hydrogen and fluorine.

17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4c Selected from hydrogen and fluorine.

18. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4b , R 4c and R 4d It's hydrogen.

19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt or solvate thereof, wherein L is selected from -(CH2) m -and-*(CH2) n (OCH2CH2) o -.

20. The compound of claim 19 or a pharmaceutically acceptable salt or solvate thereof, wherein L is -(CH2) m -.

21. The compound of claim 19 or a pharmaceutically acceptable salt or solvate thereof, wherein L is -*(CH2) n (OCH2CH2) o -.

22. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt or solvate thereof, wherein L is -(CH2) p -Z-CH2) q -.

23. The compound of claim 22 or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -(CR 6a R 6b )-.

24. The compound of claim 22 or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -N(R 7 )-.

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

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

27. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt or solvate thereof, wherein X is:

28. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt or solvate thereof, wherein X is:

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

30. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt or solvate thereof, wherein B 1 It's B-2.

31. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt or solvate thereof, wherein B 1 It's B-3.

32. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt or solvate thereof, wherein B 1 It's B-4.

33. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt or solvate thereof, wherein B 1 It's B-5.

34. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt or solvate thereof, wherein B 1 It's B-6.

35. The compound of any one of claims 29-34, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5a , R 5b and R 5c are independently selected from hydrogen and fluorine.

36. The compound of claim 35 or a pharmaceutically acceptable salt or solvate thereof, wherein R 5a , R 5b and R 5c It's hydrogen.

37. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein the compound 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, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-38, or a pharmaceutically acceptable salt thereof.

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

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

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

43. The method of claim 39 or 40, wherein the cancer is a hematological cancer.

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

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

46. ​​A method of reducing nuclear factor E2-related factor 2 (Nrf2) protein in cells of a subject, the method comprising administering to the subject a compound according to any one of claims 1-37 or a pharmaceutically acceptable salt or solvate thereof.

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

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

49. Compounds having formula III: or a pharmaceutically acceptable salt thereof, wherein: R 1 ' is selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted phenyl and optionally substituted 5 to 9 membered heteroaryl; R 2a '、R 2b ' and R 2c ' is independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3 and halogen; R 3 ' is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3 and halogen; Z 1 is -O-; and R 8 is hydrogen, C1-C6 alkyl or aralkyl; or Z 1 is -N(H)-; and R 8 yes: and R 4a '、R 4b '、R 4c ' and R 4d ' is independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3 and halogen; R 9 Selected from hydrogen and -L 1 -X 1 ; X 1 Select from -OR 10 and-NR 11a R 11b ; R 10 It is hydrogen; R 11a is selected from hydrogen and -C(=O)OtBu; R 11b is selected from hydrogen and C1-C4 alkyl; L 1 Selected from -(CH2) m' -、-*(CH2) n (OCH2CH2) o' -, and -(CH2) p' -Z 2 -(CH2) q' -; 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 Selected from -(CR 6a 'R 6b ')- and -N(R 7 ')-; R 6a ' is selected from halogen, hydroxy, C1-C6 alkyl, C1-C4 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C4-C8 heterocycle, optionally substituted phenyl and optionally substituted 5 to 9 membered heteroaryl; R 6b ' is selected from hydrogen and C1-C6 alkyl; and R 7 ' is selected from hydrogen, C1-C6 alkyl and C1-C4 haloalkyl.

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